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THE ALKALOIDS
Chemistry and Physiology
VOLUME XVI
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THE ALIMLOIDSChemistry and Physiology
E d i t e d by
R . H . F. MANSKE
Department of Chemistry, University of Waterloo
Waterloo, Ontario, Canad a
VOLUME XVI
1977
ACADEMIC PRESS 0 N E W YORK 0 SAN FRANCISCO 0 LONDON
A Subsidiary of Harcourt Brace Jovanovich, Publishers
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COPYRIGHT 977, B Y ACADEMICRESS,NC.ALL RIGHTS RESERVED.
NO PART O F THIS PUBLICATION MAY BE REPRODUCED OR
TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC
OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR A N Y
INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT
PERMISSION IN WRITING FROM THE PUBLISHER.
ACADEMIC PRESS, INC.111 Fifth Avenue. New York, New York 10003
United Kingdo m Edi t ion publ ished byACADEMIC PRESS, INC. (LONDON) LTD.24/28 Oval Road, London NWl
Library of Congress Cataloging in Publication Data
Manske, Richard Helrnuth Fred,
The alkaloids.
Vols. 8-16 edited by R. H. F. Manske.
Includes bibliographical references.
1. Alkaloids. 2. Alkaloids-Physiological effect.
I. Holrnes, Henry Lavergne, joint author. 11. Title:
Thru physiology. [DNLM: 1. Alkaloids. QV628 M288al
ISBN 0-12-469516-7
QD421.M3 547 .I 2 50-5522
PRINTED IN THE UNITED STATES OF AMERICA
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CONTENTS
LISTOF CONTRIBUTORS.. ix
PREFACE xi
CONTENTSF PREVIOUSOLUMES.. xiii
Chapter 1 Plant Systematics and AlkaloidsDAVIDS. SEIGLER
I . Introduction 1
11. Data to Be Utilized 3
UI. Application of the Dat a t iological Problems 8
V.
1V. Alkaloids in Lower Vascular Plant s and Gymnosperms
Alkaloids in the Angiosperms
References 73
Chapter 2 The Tropane Alkaloids
ROBERT . CLARKE
I. Introduction
11. New Tropane A1
107
153
IX. Analytical Methods
References
Chapter 3. Nuphar Alkaloids
JERZY. WR~BEL
I. Introduction
11 C,, Alkaloids 181
111 Sulfur-Containing C,, Alkaloids
IV. Mass Spectrometry.V. Total Synthesis of C,, Nuphar Alkaloids 211
VI. Biosynthesis
213
V
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vi CONTENTS
Chapter 4. Celestraceae Alkaloids
ROGERM. SMITH
I. Introduction11. Occurrence and Isolation
111. Structures of Esters of Nicot AcidIV. Structures of Diesters of Substituted Nicotinic Acids
VI. BiosynthesisVII. Biological Properties
References
V. Structures of Related Sesquiterpene
I.11.
111.
IV.V.
VIVII
VIII.
Chapter 5. The Bisbenzylisoquinoline AlkaloidsOccurrence Structure and Pharmacology
M. P. CAVAK. T. BUCK nd K. L. STUART
IntroductionStructure RevisionsNew AlkaloidsKnown Alkaloids from New SourcesMethods and TechniquesPharmacology
Appendix
Bisbenzylisoquinoline Alkal ated by Molecular Wei gh t..
References
Chapter 6. Syntheses of Bisbenzylisoquinoline Alkaloids
MAURICE HAMMAnd VASSILST. GEORGIEV
I. Introduction
11. Dauricine-Type Alkaloids111. Magnolamine-Type AlkaloidsIV. Berbamine Oxyacanthine Type _ _
V . Thalicberine-Type AlkaloidsVI. Trilobine Isotrilobine TypeA
VII. Menisarine-Type AlkaloidsVIII. Tiliacorine-Type Alkaloids
IX. Liensinine-Type Alkaloids
XI. Miscellaneous SynthesesX K Syntheses Using Phenolic Oxidative Coupling
XIII. Synthesis Using Electrolytic OxidationXIV. Use of Pentafluorophenyl Cop
X. Curine-Chondocurine-Type Alkaloids_
215
216
219
227
241
245
246
246
250
251
257
297
297
300
301
304312
319
320
336
341
348
354
357
359
361
363
381
383
387
387
389
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CONTENTS vii
Chapter 7. The Hasubanan Alkaloids
YASUONUSUSHInd TOSHIROBUKA
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11. Occurrence and Physical Constants of the Hasubanan
III. Structure Elucidations . . . . . . . . . . . . . . . ... . . .. . . . . .IV. Synthesis of the Hasubanan Skeleton . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
VI.
V. Synthesis of Hasubanan Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . .
Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 8. The Monoterpene Alkaloids
GEOFFREY A. CORDEU
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
II. Isolation and Structure Elucidation of the Monoterpene Alkaloids . . . . . .111. Biosynthesis and Biogenesis of the Monoterpene Alkaloids . . . . . . . . . . .IV. Pharmacology of the Monoterpene Alkaloids . . . . . . . . . . . . . . . .. . . . . . .V. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 9. Alkaloids Unclassified and of Unknown Structure
R. H . F. MANSKE
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
II. Plants and Their Contained Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
393
395
395
414
419
427
428
432
432
470
499
502
502
511
511
551
SUBJECT NDE X. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
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LIST O F CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors’ contributions begin.
K. T. BUCK,Depar tmen t of Chemistry, University of Pennsylvania,Phi ladelphia , Pennsylvania (249)
M. P. CAVA,Depar tmen t of Chemistry, University of Pennsylvania,Philadelphia, Pennsylvania (249)
ROBERT . CLARKE, terling-W inthrop R esearch In sti tu te , Rensselaer,New York (83)
GEOFFREY. CORDELL, epar tm ent of Pharmacognosy an d Pharmacol-ogy, College of Pharm acy , Univers i ty of Illinois at the MedicalCe nter, Chicago, Illinois (431)
VASSILST. GEORGIEV, SV Pharm aceutical Corporation, Tuckahoe,New York (319)
TOSHIROBUKA,epa r tmen t of Pharm aceutical Sciences, Kyoto Uni-
versity , Sakyo-ku Kyoto, Ja p a n (393)YASUONUBUSHI,epa r tmen t of Pha rm aceu tical Sciences, Kyoto U ni-
versity , Sakyo-ku Kyoto, Ja p a n (393)
R. H. F. MANSKE, epar tment of Chemistry, University of Waterloo,Water loo, Ontario , C ana da (511)
DAVIDS. SEIGLER: epa r tmen t of Botany, Th e U niversi ty of Illinois,Urbana, I l l inois (1)
MAURICEHAMMA, epar tm ent of Chem istry , The Pennsylvania State
University , Universi ty P ar k, Pennsylvania (319)ROGERM. SMITH,School of N atu ral Resources, Th e Universi ty of the
So uth Pacific, Su va , Fiji (215)
K. L. STUART, epa r tm ent of Chem istry, University of th e W est Indies,Kingston, Jam aica (249)
JERZY T. W R ~ B E L ,epa r tmen t of Chemistry, University of Warsaw,W arsaw, Poland (181)
* Present address: Calle Peria 3166-9”A,Buenos Aires, Argentina.
ix
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PREFACE
The literature dealing with alkaloids shows no obvious signs ofabatement. The classic methods of the organic chemist employed in
structural determinations have evolved into spectral methods, and
chemical reactions are involved largely in confirmatory and peripheral
studies. Inasmuch as the spectral methods have become largelystandardized we incline to limit the details in these volumes.
Many new and already known alkaloids have been isolated from new
and from previously examined sources. Novel syntheses are a promi-
nent feature of recent publications. We attempt to review timely topics
related to alkaloids.
R. H. F. MANSKE
x1
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CONTENTS OF PREVIOUS VOLUMES
Contents of V o l u m e ICHAPTER
1
2 . . . . . . . . . . .3. The Pyrrolidine Alkaloids BY LEOMARION. . . . . . . . .4. Senecio Alkaloids BY NEISONJ .LEONARD . . . . . . . . .5. The Pyridine Alkaloids BY LEOMARION . . . . . . . . .6. The Chemistry of the Tropane Alkaloids BY H.L. HOLMES . . . .7. The Strychnos Alkaloids BY H.L. HOLMES . . . . . . . . .
Sources of Alkaloids and Their Isolation BY R.H.F.MANSKE
Alkaloids i n the Plant BY W . 0 JAMES
. . .
8.1.
8.11.
9.10
11
1 2
13
14
15
16
17
18
1920.2 1.
22.23.24.
Contents of V o l u m e 11
The Morphine Alkaloids I BY H .L.HOLMES . . . . . . . .The Morphine Alkaloids BY H . L. HOLMESND (IN PART) GILBERTTORKSinomenine BY H. L. HOLMES . . . . . . . . . . . .Colchicine BY J .W . COOK ND J . D . LOUDON . . . . . . . .Alkaloids of the Amaryllidaceae BY J W . COOK ND J.D . LOUDON. .Acridine Alkaloids BY J.R .PRICE . . . . . . . . . . .The Indole Alkaloids BY LEOMARION . . . . . . . . . .The Erythrina Alkaloids BY LEOMARION . . . . . . . . .The Strychnos Alkaloids .Part 11BY H. L. HOLMES . . . . . .
Contents of V o l u m e III
The Chemistry of the Cinchona Alkaloids BY RICHARD . TURNERND
. . . . . . . . . . . . . . .Quinoline Alkaloids Other than Those of Cinchona BY H .T.OPENSHAW
The Quinazoline Alkaloids BY H.T OPENSHAW . . . . . . .
Lupine Alkaloids BY NELSON.LEONARD . . . . . . . . .The Imidazole Alkaloids BY A.R. BATCERSBYND H.T. OPENSHAW .The Chemistry of Solanum and Veratrum Alkaloids BY V . PRELOGND
0 EGER . . . . . . . . . . . . . . . . . .P-Phenethylamines B Y L .RETI . . . . . . . . . . . .Ephreda Bases BY L. RETI . . . . . . . . . . . . .TheIpecac Alkaloids BY MAURICE-MARIEANOT . . . . . .
R. B.WOODWARD
Contents of V o l u m e N
25. . . . . .26. Simple Isoquinoline Alkaloids BY L.RETI . . . . . . . . .
27. Cactus Alkaloids BY L.RETI . . . . . . . . . . . . .28. The Benzylisoquinoline Alkaloids BY ALFRED URGER . . . . .
The Biosynthesis of Isoquinolines BY R. H.F. MANSKE
1
15
91
107
165
271
375
1
161
219
261
331
353
369
499
513
1
65
101
119201
247
313
339
363
17
23
29
xiii
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XiV CONTENTS OF PREVIOUS VOLUMES
CHAPTER
29
ASHFORD . . . . . . . . . . . . . . . . . . 7730 . The Aporphine Alkaloids B Y R .H.F.MANSKE . . . . . . . 119
31. The Protopine Alkaloids B Y R. H.F.MANSKE . . . . . . . . 147
32 Phthalideisoquinoline Alkaloids B Y JAROSLAVTANEK AND R. H. FMANSKE . . . . . . . . . . . . . . . . . . 167
34 . The Cularine Alkaloids BY R.H .F .MANSKE . . . . . . . . 249
36. The Erythrophleum Alkaloids BY G DALMA . . . . . . . . 265
The Protoberberine Alkaloids BY R. H. F. MANSKE N D WALTERR.
33. Bisbenzylisoquinoline Alkaloids BY MARSHALLULKA . . . . . 199
35 . a-Naphthaphenanthridine Alkaloids BY R.H.F.MANSKE . . . . 253
37 . The Aconitum and Delphinium Alkaloids BY E . S.STERN . . . . 275
Contents of Volume V
38 .39
40
41.42
43
44
45
46 .47 .48.
1.2.3.4.5.6.7.8.9.
10
11.12
1314
15.16.17.
Narcotics and Analgesics BY HUGOKRUEGER . . . . . . . .Cardioactive Alkaloids BY E.L.MCCAWLEY . . . . . . . .
Respiratory Stimulant s BY MICHAEL.DALLEMAGNE . . . . .
Antimalarials B Y L. H. SCHMIDT . . . . . . . . . . .Uterine Stimulants B Y A. K .REYNOLDS . . . . . . . . .Alkaloids as Local Anesthetics BY THOMAS CARNEY . . . . .Pressor Alkaloids BY K . K. CHEN . . . . . . . . . . .
Mydriatic Alkaloids BY H. R. ING . . . . . . . . . . .Curare-like Effects BY L.E CRAIG . . . . . . . . . . .The Lycopodium Alkaloids BY R .H.F.MANSKE . . . . . . .Minor Alkaloids of Unknown Structure BY R.H. F .MANSKE . . .
Contents of Volume VI
Alkaloids in the Pla nt BY K .MOTHES . . . . . . . . . .
The Pyrrolidine Alkaloids BY LEOMARION. . . . . . . . .
Senecio Alkaloids B Y NELSON LEONARD . . . . . . . . .The Pyridine Alkaloids B Y LEOMARION . . . . . . . . .
The Tropane Alkaloids B Y G.FODOR . . . . . . . . . .
The Strychnos Alkaloids BY J B . HENDRICKSON . . . . . . .The Morphine Alkaloids BY GILBERTTORK . . . . . . . .Colchicine and Related Compounds BY W. C.WILDMAN . . . . .Alkaloids of the Amaryllidaceae B Y W. C.WILDMAN. . . . . .
Contents of Volume V I I
The Indole Alkaloids B Y J .E . SAXTON . . . . . . . . . .
The Erythrina Alkaloids BY V .BOEKELHEIDE
Quinoline Alkaloids Other than Those of Cinchona BY H .T.OPENSHAW
The Quinazoline Alkaloids B Y H. T. OPENSHAW . . . . . . .Lupine Alkaloids B Y NEWON LEONARD . . . . . . . . .Steroid Alkaloids: The Holarrhena Group B Y 0 JEGERND V . PRELOGSteroid Alkaloids: The Solanum Group B Y V .PRELQGND 0 JEGER .
Steroid Alkaloids: Veratrum Group BY 0 JE GE RND V .PRELOG . .
. . . . . . . .
1
79
109
141
163
211
229
243
265
259
301
1
31
35
123
145
179219
247
289
1
201
229
247253
319
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CONTENTS OF P R E V IOU S V OL U ME S xv
CHAFTER18. . . . . . . . .
19. . . . . . . . .20. Phthalideisoquinoline Alkaloids BY JAROSLAVTAN~K . . . . .2 1 Bisbenzylisoquinoline Alkaloids BY MARSHALLULKA . . . . .22 . The Diterpenoid Alkaloids from Aconitum, Delphinium, and Garrya
. . . . . . . . . . . . . .23 . The Lycopodium Alkaloids BY R.H.F. MANSKE . . . . . . .24 . Minor Alkaloids of Unknown Structure BY R. H .F MANSKE . . .
The Ipecac Alkaloids B Y R.H .F MANSKE
Isoquinoline Alkaloids BY R. H.F. MANSKE
Species BY E .S STERN
1
2 .3 .4 .5 .6 .7.8 .9 .
10.11.
12.13.
1 4
15.
16.17 .18.
1 9
20 .21 .2 2 .
Contents of V o l u m e V I I I
The Simple Bases BY J .E . SAXTON
Alkaloids of the Calabar Bean B Y E . COXWORTH
The Carboline Alkaloids B Y R.H.F MANSKE . . . . . . . .The Quinazolinocarbolines B Y R.H .F.MANSKE . . . . . . .Alkaloids of Mitragyna and Ourouparia Species B Y J E.SAXTON .Alkaloids of Gelsemium Species BY J .E . SAXTON . . . . . .Alkaloids ofPicralima nitida BY J.E .SAXTON . . . . . . .
Alkaloids ofAlstonia Species BY J .E . SAXTON . . . . . . .
The Chemistry of the 2,2 -Indolylquinuclidine Alkaloids BY W . I. TAYLOR
The Pentaceras and the Eburnamine (HunteriabVicamine Alkaloids
. . . . . . . . . . . . . . . .The Vinca Alkaloids BY W . I. TAYLOR . . . . . . . . . .RauwolfiaAlkaloids with Special Reference to the Chemistry of Reserpine
B Y ESCHLITTLER . . . . . . . . . . . . . .The Alkaloids ofdspidosperma, Diplorrhyncus,Kopsia, Ochrosia, Pleio-
Alkaloids of Calabash Curare andStrychnos Species BY A.R.BATTERSBY
. . . . . . . . . . . . . . .
. . . . . . . . . . .
. . . . . . .
The Zboga and Voacanga Alkaloids B Y W .I .TAYLOR . . . . . .
BY W . I .TAYLOR
c a r p , and Related Genera BY B.GILBERT . . . . . . . .
AND H. F.HODSON
The Alkaloids of Calycanthaceae B Y R.H .F MANSKE . . . . .Strychnos Alkaloids BY G.F SMITH . . . . . . . . . . .Alkaloids ofHaplophyton cimicidum B Y J .E . SAXTON . . . . .
The Alkaloids of Geissospermum Species BY R. H . F MANSKE ND W .ASHLEY ARRISON . . . . . . . . . . . . . . .
Alkaloids ofPsuedocinchona and Yohimbe B Y R .H.F.MANSKE . .The Ergot Alkaloids BY A.STOLLND A. HOFMA" . . . . . .The Ajmaline-Sarpagine Alkaloids BY W . I . TAYLOR . . . . . .
Contents of V o l u m e I X
1 The Aporphine Alkaloids BY MAURICE HAMMA . . . . . . .2 . . . . . . . . .
3 . Phthalideisoquinoline Alkaloids BY JAROSLAVT A N ~ K . . . . .4 . Bisbenzylisoquinoline and Related Alkaloids BY M. CURCUMELLI-
RODWTAMOND MARSHALLULKA . . . . . . . . . .5 . Lupine Alkaloids B Y FERDINANDOHLMANNND DIETERSCHUMANN6 . Quinoline Alkaloids Other tha n Those of Cinchona BY H.T.OPENSHAW
TheProtoberberine Alkaloids BY P. W .JEFFS
4194 2 3433439
473505509
1
2747555993
119159203238
250272
287
336
515581592673
679694726789
14 1
117
133175223
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xvi CONTENTS OF PREVIOUS VOLUMES
CHAPTER7. The Tropane Alkaloids BY G.FODOR . . . . . . . . . .
8. Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae BY V. ERN+AND F.SORM . . . . . . . . . . . . . . . .9. The Steroid Alkaloids: The Salamandra Group BY GERHARDABERMEHL
10 Nuphar Alkaloids BY J .T.WROBEL . . . . . . . . . . .11 The Mesembrine Alkaloids B Y A.POPELAKND G. LETFENBAUER . .12. The Erythrina Alkaloids B Y RICHARD . HILL . . . . . . . .13. Tylophora Alkaloids BY T.R. GOVINDACHARI . . . . . . .14. The Galbul imima Alkaloids BY E.RITCHIE ND W C.TAYLOR . . .15. The Stemona Alkaloids BY 0 .E .EDWARDS . . . . . . . .
1
2.
3.4.5.
6.
7.8.9.
10
11.12.13.14
1.2.3.4.5.6.7.8.
9.
10.11
12.
Contents of Volum e X
Steroid Alkaloids: The Solanun Group BY KLAUS CHRIEBER . .The Steroid Alkaloids: The Veratrum Group BY S .MORRISKUPCHANN D
ARNOLDW.BY . . . . . . . . . . . . . . . .
Erythrophleum Alkaloids B Y ROBERT . MORIN . . . . . . .The Lycopodium Alkaloids BY D.B .MACLEAN . . . . . . .
Alkaloids of the Calabar Bean BY B.ROBINSON . . . . . . .The Benzylisoquinoline Alkaloids B Y VENANCIODEULOFEU, ORGE
. . . . . . . . . .
The Cularine Alkaloids BY R.H.F.MANSKE . . . . . . . .Papaveraceae Alkaloids B Y R. H.F.MANSKE . . . . . . . .a-Naphthaphenanthridine Alkaloids BY R. H.F. MANSKE . . . .The Simple Indole Bases BY J E.SAXTON . . . . . . . .Alkaloids of Picralima nitida BY J .E . SAXTON . . . . . . .Alkaloids of M i t m g y m and Ourouparia Species BY J . E. SAXTON . .Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE
The Taxus Alkaloids BY B. LYTHGOE . . . . . . . . . .
COMIN. ND MARCELO.VERNENGO
Contents of Vo lum e XIThe Distribution of Indole Alkaloids in Plants BY V.SNIECKUS
The Ajmaline-Sarpagine Alkaloids BY W . I.TAYLORThe 2,2 -Indolylquinuclidine Alkaloids BY W . I TAYLORThe Iboga and Voacanga Alkaloids BY W . I.TAYLORThe Vinca Alkaloids BY W.I.TAYLORThe Eburnamine-Vincamine Alkaloids BY W. I.TAYLORYohimbirw and Related Alkaloids BY H . J . MONTEIROAlkaloids of Calabash Curare and Strychnos Species BY A. R. BATTERSBY
. . . . . . . . . . . . . . .
The Alkaloids of Aspidosperma, Ochrosia, Pleiocarpa, Melodinus, and. . . . . . . . . . .
The Amaryllidaceae Alkaloids BY W . C.WILDMAN . . . . . .Colchicine and Related Compounds BY W .C WILDMANND B.A.PURSEY
The Pyridine Alkaloids BY W . A.AYER ND T. E. HABGOOD . . .
. . .
. . . . . .. . . . .
. . . . . .. . . . . . . . . .
. . . . .
. . . . .
ANDHF.HODSON
Related Genera BY B. GILBERT
269
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529
545
1
193
287
306
383
402
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485
491
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CONTENTS OF PREVIOUS VOLUMES xvii
Contents of Volume XI1
CHAFTER
The Diterpene Alkaloids: General Introduction B Y S. W. PELLETIERND
L. H. KEITH . . . . . . . . . . . . . . . . . .1. Diterpene Alkaloids from Aconitum, Delphinium, and Garrya Species:
The C,,-Diterpene Alkaloids BY S. W. PELLETIERND L. H. KEITH2. Diterpene Alkaloids from Aconitum, Delphinium, and Garrya Species:
The Go-DiterpeneAlkaloids BY S. W. PELLETIERND L. H. KEITH3. Alkaloids ofA l s t on i a Species BY J. E. SAXTON . . . . . . .4. Senecio Alkaloids BY FRANK. WARREN . . . . . . . . .5. Papaveraceae Alkaloids B Y F. SANTAVY . . . . . . . . .6. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE
7. The Forensic Chemistry of Alkaloids B YE.G. C. CLARKE . . . .
Contents of Volume XI I I
1. The Morphine Alkaloids B Y K. W. BENTLEY . . . . . . . .2. The Spirobenzylisoquinoline Alkaloids BY MAURICE HAMMA . . .3. The Ipecac Alkaloids BY A. BROSSI,S. TEITEL, ND G. V. PARRY . .4. Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . . .
5. The Galbulirnima Alkaloids BY E. RITCHIEAND W. C. TAYLOR . . .6. The Carbazole Alkaloids BY R. S. KAPIL . . . . . . . . .7. Bisbenylisoquinoline and Related Alkaloids B Y M. CURCUMELLI-RODC+
8. The Tropane Alkaloids BY G. FODOR . . . . . . . . . .9. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE
STAMO . . . . . . . . . . . . . . . . . . .
2.
3.
4.
5.
6.
7.
8.9.
10.
11.
12.
Contents of Volume X NSteroid Alkaloids: The Veratrum and B w u s Groups BY J. TOMKOND
2. VOTICKP . . . . . . . . . . . . . . . . .Oxindole Alkaloids BY JASJIT. BINDRA . . . . . . . . .Alkaloids of M i t r a g y m and Related Genera BY J. E. SAXTON . . .Alkaloids ofP i c r a l i m a and Alstonia Species BY J . E. SAXTON . . .The Cinchona Alkaloids BY M. R. USKOKOVICND G. GRETHE . . .The Oxoaporphine Alkaloids BY MAURICEHAMMAND R. L. CASTENSONPhenethylisoquinoline Alkaloids B Y TETSUJI KAMETANI ND MASUO
KOIZUMI . . . . . . . . . . . . . . . . . .
Elaeocarpus Alkaloids BY S. R. JOHNSND J. A. LAMBERTON . . .The Lycopodium Alkaloids BY D. B. MACLEAN . . . . . . .TheCancentrine Alkaloids BY RUSSELLRODRIGO . . . . . .The Securinega Alkaloids BY V . SNIECKUS . . . . . . . .Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE
xv
2
136
207
246
333
455
514
1
165
189
213
227273
303
351
397
1
83
123
157
181
225
265
325347
407
425507
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xviii CONTENTS OF PREVIOUS VOLUMES
Contents of V o lu m e X V
CHAPTER
1 . The Ergot Alkaloids BY P. A. STADLERND P . SWTZ . . . . . . 1
2.
MASAHIRATA . . . . . . . . . . . . . . . . 41
3. The Amaryllidaceae A l k a l o i d s ~ ~IAUDIOFUGANTI . . . . . 83
4. The Cyclopeptide Alkaloids BY R. TSCHESCHEND E. U. KAUBMANN 1655. The Pharmacology and Toxicology of the Papaveraceae Alkaloids
B Y V . PREININCER . . . . . . . . . . . . . . . 207
6. Alkaloids Unclassified and of Unknown Structure B Y R. H. F. MANSKE 263
The Daphniphyllum Alkaloids BY SHOSUKE AMAMURAND YOGHI-
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-CHAPTER 1-
PLANT SYSTEMATICS A N D ALKALOIDS
DAVIDS. SEICILER
T h e University of I ~ ~ i n o i s
Urbana, Illinois
I. Introduction ........................................................A. What Is Plan t Systematics ? .......................................B. Major Goals of Plant Systematics ..................................
11. Da ta t o Be Utilized .................................................A. Relationship of Chemical Da ta to Botanical Data ....................B. Rationale for Using Chemical Data.. ...............................C. Botanical and Chemical Literature .................................D. Documentation of Pl an t Materials. . . . . . . . . .
111. Application of the Data to Biological Problems .A. N ature and Sources of Variation in Plants. ..B. Basic Pathways of Alkaloid Biosynthesis ....
IV. Alkaloids in Lower Vascular Plants and Gymnos
V. Alkaloids in the Angiosperms .........................................A. Introduction .....................................................B. The Magnoliopsida (Dicotyledonous Plants) ..........................
ida (Monocotyledonous Plants) .................................................................................
1
22
3
3
3
6
7
8
8
14
20
22
24
65
73
22
I. Introduction
Many scientists, both chemical and biological, have sought t o corre-late chemical characters (i.e., the presence of certain types of compounds)
with various botanical entities. I n the past, several factors have limited
the success of such efforts, and it is only in recent years that such
correlations have been applied to many plant groups. My purpose in
this article is to review several of these earlier attempts as well as to
examine current thinking in this area of endeavor. Several new ideas
concerning the placement of selected plant groups within taxonomic
systems will be discussed, and in addition, certain enigmatic problems
that as yet cannot be clearly resolved will be posed as subjects forfuture investigation. As background to these discussions, I will first
describe the nature and goals of plant systematics to provide the reader
with the necessary perspective to understand the needs of that science.
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1. PLANT SYSTEMATICS 3
plant taxa , (b) provide an inventory of plant taxa via local, regional,
and continental floras, and (c) provide a classification scheme that
at tempts to express natural or phylogenetic relationships and to providean understanding of evolutionary processes and relationships ( 5 ) . n the
subsequent parts of this chapter, I will present and discuss ways in
which chemical data and in particular alkaloid chemical data can be
utilized in meeting these goals.
11. Data to Be Utilized
A. RELATIONSHIPF CHEMICAL ATA O BOTANICALATA
As both morphological and chemical features are determined by
genetics, the structure of a molecule must be as much a character as
any other (7) . Further , all the “characters” of a plant must be related
and self-consistent. Thus, it is scarcely surprising that new cytological,
numerical, and chemical data have provided valuable complementary
information about the placement of groups within the taxonomic
system rather than upsetting the results of extensive morphological
investigations. How did these two types of characters arise and how do
they differ Z
In the course of evolution the fate of any change in the genetic
material of an organism will in large part depend on the function of the
products produced. For example, changes in respiratory proteins, such
as cytochromes, are unlikely t o survive, whereas changes in t he enzymes
that produce alkaloids or other secondary metabolic products are more
likely to persist. The evolution of morphological and chemical features
of an organism must be interrelated, but significantly, the forces of
natural selection do not have the same effect on each type of genetic
expression. These differences in selection are very important from a
systematic standpoint because evolution of chemical constituents
differs from morphological evolution, making the examination of both
morphological and chemical characters an extremely valuable approach
to the study of evolutionary problems (8).Because the structure of any
compound is determined by a series of biosynthetic steps, each of which
is under differing selective forces, not only may the structure of the
compound itself be useful, but the biochemical pathway by which it has
arisen may be of systematic significance.
B. RATIONALEOR USING HEMICALDATA
The two major groups of compounds that have been applied to
t,axonomic problems involve basically different approaches and appear
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4 DAVID S . SEIGLER
to be useful in different manners. To date, these applications involve
niacromolecules (in particular proteins) and micromolecules (mostly
secondary metabolic compounds such as terpenes, flavonoids, alkaloids,cyanogenic and other glycosides, amino acids, and lipids of various
When one utilizes macromolecules, he is examining the primary
products of plant DNA and changes in amino acids within the protein
reflect changes in the base sequence of the DNA. Initial studies of
protein sequencing, especially those studies involving cytochrome C,
indicate that th is dat a provides valuable information about phylogeny
and relationships a t the higher taxonomic categorical levels (families,
orders, classes). Cytochrome c, which occurs in both animals and plants,has been sequenced in several species of animals (9).The fossil record
for animals generally confirms information derived from these phylogen-
etic studies. The number of similarities in amino acids in particular
positions in cytochrome c molecules from different animals makes itstatistically improbable that they could have arisen from more than a
single ancestral type with an ancestral cytochrorne c molecule. By
tracing the differences in amino acid substitutions it is possible to
relate various groups of animals, as successive groups after a modifica-
tion carry the changed cytochrome c molecule.In plants, especially flowering plants, there is no extensive fossil
record and much of the current knowledge of relationships and phy-
logeny in this group is based on extrapolation of studies of morphological
data. To date, relatively few plant cytochromes have been studied, but
in the few that have been investigated, it is apparent from the number
of similarities of amino acid sequences that plant and animal G Y ~ O -
chromes are related. It is also evident that the sequences of amino
acids in genera of the same family me more similar to each other than
to those of other families and that families thought to be closely
related by morphological evidence generally resemble each other more
closely than less related families. The evolutionary history of plant
groups, as well as of animals, appears to be recorded in this and other
proteins.
Much recent work has established that micromolecular chemical
data can also provide valuable insight into evolutionary processes ( 8 ) .
Chemical studies of secondary products have proved useful in resolving
many problems of specification and evolution but in contrast t o protein
sequencing data have generally been applied to the study of lowertaxonomic categories, i.e., problems at the species and genus level
(10,1 1 ) . However, as will be pointed out, they may also be of value a t
higher taxonomic levels.
To understand how secondary compounds can be useful for the study
types).
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6 DAVID S. SEIGLER
lipid compounds for surface coatings as long as the necessary physical
properties are met ; but at tractants for specific pollinators or diterpenes
with hormonal activities must be precisely synthesized (7 ) . Many plantproducts arise by simple processes such as removal of activating groups
(as phosphate or coenzyme A ) or from oxidations, reductions, or
methylations of easily modified groups (7) . In some cases the relative
amounts of products produced may simply reflect the rates of two
enzymes operating on a common precursor. Highly probable reactions,
such as the introduction of an hydroxyl group orthoor para to an existing
one in a phenol, occur frequently in nature. These types of changes
are usually of only minor importance in considering the taxonomic
significance of secondary compounds.
Other reaction sequences are reversible or are controlled by feedback
inhibition controls such that when a given compound disappears it
disappears without a trace or causes accumulation of a compound far
removed in the sequence. For example, polyketide chains, probably as
coenzyme A esters, are rapidly reversible to their initial units unless
some chemically irreversible stage is reached such as reduction or
cyclization (7) . In the fungus Penicillium islandicum which produces
polyketide anthraquinones, mutation simply leads to the complete
absence of these compounds.
We have limited knowledge as to what pathways may be available in
advanced plant groups as we can only see the products of those path-
ways that the plant utilizes a t a particular time. Several lines of work
suggest that many plants are capable of carrying out complex reactions
or reaction series but lack precursors or particular enzymes under
normal situations. For example, when plants of Nicotiana are fed
thebaine and certain other precursors of morphine they are able to
perform several biosynthetic steps and produce morphine (14) hich is
not known to occur naturally in the genus. Interestingly, this conversion
cannot be made by some species of Papaver, although other species of
the genus contain thebaine and morphine.
In assessing the importance of a particular change as an evolutionary
step i t is necessary to decide on the probability of its occurrence.As a
general rule, the more difficult the reactions and the less available the
building blocks or the more reaction steps required in a definite sequence
to give rise to a compound, the rarer will be its convergent formation
C . BOTANICALND CHEMICALLITERATURE
Many earlier publications were based on mass collections of materials,
often gathered from large geographical areas and/or of uncertain origin.
(14).
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1. PLAXT SYSTEMATICS 7
Frequently, only the major constituents-those that were poisonous,
crystallized readily, or had other easily detectable properties-were
examined. These facts must be considered by those who intend to applythe information to a taxonomic problem. Another difficulty in utilizing
chemical data from the literature is a lack of reliability of certain
structure determinations and in particular the identification of plant
products by such physical properties as gas-liquid chromatography
retention time, paper and thin-layer chromatography R, values, color
reactions, and spot tests. Misidentification of compounds by wet
chemical methods is not uncommon in the older literature before
advanced spectral methods became available and must always be
considered.One of the most serious problems in utilizing literature data is that
almost no chemical reports are supported by adequately vouchered
plant materials. Proper vouchering records would make it possible to
examine the original materials and allow comparison with other
collections in order to ascertain whether (a) the material was correctly
identified and (b) certain phenomena, such as hybridization, intro-
gression, or subspecific variations exist. It would also permit subsequent
workers to determine the presence of fungi, lichens, algae, insects, etc.,
that may be involved in the production of certain secondary compounds.
If a small portion of the actual materials utilized for the research is also
preserved, it would permit later analysis for foreign contaminants.
I n other cases, careful perusal of the botanical literature will reveal
that taxonomists have placed taxa of various rank incorrectly. These
incorrect placements may range from questionable or aberrant species
in a genus to the realignment of entire orders of plants. Chemical data
can assist in resolving problems of this type, but they sometimes provide
enigmatic results until sufficient information is available to allow a
reassignment of the taxa involved.
One must look carefully and critically a t all reported data t o be sure
both chemical and botanical portions of the work have been done and
interpreted correctly before applying the data to a problem under
investigation.
D. DOCUMENTATIONF PLANT ATERIALS
As mentioned in the preceding section, many early reports of alka-
loids and other secondary compounds are suspect because accurate
techniques required for assignment of complex structures were notavailable. Nonetheless, the major problem in using these data for
systematic studies is not the reliability of the chemicaldata but the
identity of the plant materials th at were examined ( 1 5 ) .
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1 . PLANT SYSTEMATICS 9
conclusions based on a meager amount of data in comparison to what
was actually needed. Recent combined chemical and morphological
investigations have used this information more fully and proved that,instead of being troublesome, the study of chemical and morphological
variation actually provides a key to the solution of many problems ofbiological speciation, hybridization, and introgression.*
Relationship between plant taxa is established by “ ummarizing”
the similarities between groups of organisms and contrasting their
differences. We consider two plants to be closely related if they have
many common characters and only distantly so (orat higher categorical
levels) if the differences outweigh the similarities. In contrast to this,
the name of the game in evolution is change and the ability to maintainvariability. Few natural populations are without measurable variation;
that is, plants from interbreeding groups that share a gene pool have
phenotypic and genotypic differences that can be seen even by inexperi-
enced observers. How do these variations arise and how are they
maintained
Each individual plant must possess the ability to respond to its
environment, but this variation must remain within the limits set by the
genetic makeup of the taxon ( 1 2 , 1‘7). Thus, phenotypic expression is
determined by both genotypic composition and reaction to a specific
environment. Some characters are little changed by environment--e.g.,
leaf arrangement or floral structure-and these have been considered
“good characters” or to be “genetically fixed.” Other characters are
known to vary radically and are said to be “phenotypically plastic.”
Examples of characters of this type are leaf shape, stem height, and time
of flowering. The effects of environment are superimposed on and may
obscure genotypic variability; further, it is the phenotype produced by
both that is is exposed to the pressures of natural selection. Davis and
Heywood ( 1 7 ) have listed a number of important physical factors in
determining the appearance of a plant in nature. Among these are light,
seasonal variation, elevational differences, terrestrial versus epiphytic
state, photoperiodism, temperature, temperature periodic effects,
water (heterophylly), wind, soil (e.g., halophytes), and biotic factors
such as fungal and bacterial infection, ant habitation, galls, grazing
and browsing, fire, and trampling.
The population is considered by many to be the basic evolutionary
* Introgression is the process by which the genes of one taxon are mixed with thegenes of another by hybridization of the two taxa followed by backcrossing of th e
hybrid plants with either of the two parents. Even when hybrids are not significant in
relative numbers, they can allow gene flow and mixing, producing increased variability
of the two paren tal types.
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1. PLANT SYSTEMATICS 1 1
entiate into a series of populations that may have gradually accrued
differences (clinal variation) or stepwise variations associated with
ecological differences (ecotypic variation) ( 1 7 ) .If the differences between populations increases sufficiently, and
especially if reproductive barriers arise, these differentiating populations
may be recognized as species. Stebbins ( 1 2 ) considers four major
factors in speciation: (a) mutation, (b ) genetic recombination, (c)
natural selection, and (d) isolation. In small, often peripheral popula-
tions, chance may play a greater role in speciation because the proba-
bility of loss of a particular character is greater; recessive genes are
more likely to appear and become homozygous, and the genetic nature
of the population may be determined by the “founders” or “survivors”of a period of catastrophic selection. These phenomena explain many of
the variational patterns observed in the distribution and occurrence
of secondary plant compounds, especially at the lower taxonomic
ranks, and although they have mostly been examined by means of
morphological characters, much evidence suggests that evolution and
speciation may be studied or measured by chemical characters as well.
In the preceding discussion, variation of morphological characters has
been considered. There is no reason to think that variation in chemical
characters has not occurred and is not maintained in a similar manner.
I n contrast to morphological features, however, th e specific structures
an d steps of biosynthetic pathways are easier to quantify and generally
simpler in terms of genetic control (at least in principle).
Secondary compounds are affected by environmental as well as
genetic factors (18 , 19). In a study of alkaloids of the genus Baptisia
(Leguminosae), Cranmer studied the variation of lupine alkaloids
during the development of individual plants in different populations of
Baptisia leucophaea Nutt. ( 2 0 ) . Individual plants in each population
exhibited considerable quantitative variation, while plants from different
populations were similar at similar stages of development. However,
there was striking variation in the specific alkaloids produced, the
relative amounts of each, and in the total quantity of alkaloids present
a t any given time in development. Nowacki encountered similar
variation in lupine alkaloids in the genus Lup inus ( 2 1 ) .
A number of workers have examined the genetics of alkaloid produc-
tion by the study of hybrid plants (1 4 , 21 -25 ) . These results indicate
that the genetic mechanisms that control alkaloid synthesis are complex
and that hybridization and introgression can produce significant
variations in the alkaloid content of plants within a population. Many
past workers have been unaware of natural hybridization and, because
these plants are occasionally indistinguishable f r om the parental species,
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12 DAVID S. SEIGLER
have not been able to interpret th e alkaloid patterns observed ( 1 4 , 15).
Hybridization and introgression in the genus Baptis ia has been ex-
tensively studied by workers a t the University of Texas. Several pop-ulations that contained all possible hybrid combinations, plants
derived from back-crossing these plants with the parental plants, and
the parental plants were examined. The status of these plants was
established by independent methods; subsequently the alkaloid
chemistry was examined. The dat a indicated that the hybrid plants not
only failed to exhibit the alkaloid chemistry of the parent species either
singly or combined, but also showed some striking quantitative
variation among individual hybrid plants. Mabry concludes that this
variation is extremely useful and represents one of the best availabletechniques for detecting and documenting natural hybridization and
introgression ( 2 6 ) .Extensive variation can occur in the different parts of an individual
plant ( 2 7 ) .Changes associated with the reproductive parts of a plant
are often striking; these organs also exhibit the greatest amount of
morphological change during a plant’s growth and development.
Cranmer and co-workers ( 2 0 , 28) observed that in Baptis ia species
alkaloids often showed greater variation between organs of plants from
a single species than between the same organs for different species. Thetotal yield of alkaloids from different organs was also shown to vary
significantly. The most thoroughly investigated plants in this regard
are medicinally important ones such as Papaver somniferum L. and
solanaceous plants of the genera Nicot iana, Atropa , H yoscyamus, and
D a t u m ( 2 7 ) .
At the present time our lack of knowledge of the specific enzymology
of the synthesis of secondary metabolites prevents direct comparison of
many of the pathways involved in various taxa. Examination and
comparisons must frequently be restricted to those systems ascertained
to be related by other reasoning, such as a knowledge of the structures
of other compounds derived from and part of the biosynthetic pathways
in the same and related species of plants.
Secondary compounds have classically been viewed as waste or
excretion products ( l a ) , ut a body of information is accumulating that
suggests that many have important coevolutionary defensive and
attractive roles (29-31) as well as primary metabolic importance
(32-34) . The forces of natural selection seldom operate on a single
organism but on a total biological system. This is undoubtedly onereason convergence in the evolution of both morphological and chemical
characters is observed.
It is well known, for example, that certain habitats are occupied by
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1 . PLANT SYSTEMATICS 13
plants that possess similar morphological features (12 , 27, 35-38). It
has not been definitely established, but i t appears that various chemical
components of plants can be seiected to produce convergence of chemi-cal types. One example that confirms this possibility is that Am m oden-dron conollyi Bge., a legume native to Central Asia, contains the
alkaloids ammodendrine (1) nd sparteine (2),and another plant from
C O C H ,
1
that area, Anabasis aphylla L. , a member of the Chenopodiaceae,
contains similar alkaloids such as lupinine (3),phyllin (a),and anabasin
( 5 ) . n the legume, cadaverine (and hence lysine) serves as a precursor
3
0
4 5
for both types, whereas in Anabas i s , the quinolizidine alkaloids are
formed as in legumes but anabasine is derived from nicotinic acid as in
Nicot iana. Thus, what might appear to be a close similarity is in reality
an analogous route to the same compounds ( 1 4 ) .
In another example, three species of the genus Hymenoxys (Com-
positae), H . scuposa (DC.) K. F. Parker, H . acaulis (Pursh) K. F.Parker, and H . ives ianu (Greene) K. F. Parker, contain more than
thirty flavonoids. The patterns of distribution of these compounds are
correlated more strongly with population positions along an east-west
gradient extending from Arizona to Texas than with the diagnostic
morphological features of the species. The biochemical parallelism
observed for populations of different species in the same region suggests
the action of common selective forces (39).It has been observed that
small, isolated island populations of mainland taxa usually have fewer
and simpler compounds than their mainland ancestors. This may be
because of lowered selection by predation or because island habitats
have different environmental requirements ( 3 5 ) .
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14 DAVID S. SEIQLER
B. BASICPATHWAYSF ALKALOIDIOSYNTHESIS
In the preceding section we have surveyed some of the ways inwhich variation originates and is maintained in plants. A knowledge
of these variations is extremely important in systematic studies at the
lower taxonomic levels (genus-species), but when one wishes to establish
relationships at higher ranks, e.g., at the family, order, and subclass
level, it is necessary to survey as many taxa and individuals as possible
to reduce the effects of these variations. That is, we need to know what
morphological features are produced and what biosynthetic pathways
exist in a particular group of taxa to compare them. This is made more
difficult by our imperfect knowledge of biosynthetic pathways, but, bycareful observation of their products, we can establish certain relation-
ships. In this chapter we will mostly consider the application of
alkaloids to systematic problems. Other secondary compound data can
prove equally usable and should also be considered in a complete study
of the relationship of systematics and secondary compounds. I have
necessarily addressed those problems for which alkaloid data appear to
be most helpful or promising and have not pursued certain relationships
that may be more clearly established by other chemical and mor-
phological data.In this section I will survey some of the fundamental and widespread
pathways of alkaloid biosynthesis. Studies of many of these compounds
have proven useful a t lower taxonomic ranks but, due to the widespread
appearance and presumably simple biosynthetic origin, are not as
valuable for delineating the higher categorical levels, although in a few
cases compounds that appear to be very simple are observed to have
limited distributions.
The simplest alkaloids are several amines derived from common
amino acids such as phenylalanine, tyrosine, histidine, tryptophan,lysine, ornithine, and anthranilic acid. Alkaloids containing simple
aromatic moieties and some of their simply derived relations have been
reviewed (40-46) . These simple amines arise by decarboxylation of the
corresponding amino acids, often with subsequent methylation,
hydroxylation, and addition of other groups. They are widely distrib-
uted, and their presence is usually not of taxonomic significance at the
higher taxonomic ranks. These compounds are important because they
are frequently beginning points for the synthesis of more complex
alkaloids.Phenylalanine gives rise to phenylethylamine (6) and the corre-
sponding methylated compound (7), hile tyrosine produces the corre-
sponding compounds tyramine (8) and N-methyltyrosine (9). In the
Gramineae tyramine is converted to hordenine (lo),which is widespread
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1. PLANT SYSTEMATICS 15
in 1
6 7 8
is family ,ut not restricted to it . Tyrosine is also converteL to two
other important intermediate compounds, dihydroxyphenylalanine
(DOPA) (11) and its cyclic derivative, cycloDOPA (12). These com-pounds are especially common as intermediates in the synthesis of
alkaloids of the benzylisoquinoline and betalaine types as well as
alkaloids widely distributed in the Cactaceae ( 4 7 ,48) (see Section V, B).
In the Rutaceae many of these simple aromatic compounds are con-
verted to the corresponding amides, such as fagaramide (13) from
10 11
12 13
Fagara xanthoxyloides Lam. Although most gymnosperms do not
contain distinctive alkaloids (with the notable exception of the Taxa-
ceae and Cephalotaxaceae), the genus Ephedra (Ephedraceae), a group
only distantly related to more common gymnosperms, contains
methylated phenylethylamines such as 1-ephedrine (14) and d-pseudo-
ephedrine (15),which are also characteristic of this group of plants but
not restricted to it (49-52) .
CH3ICH3I
I IHC-NHCH,CNHCH,
HCOH HO-C-H
8 014 15
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16 DAVID S. SEIGLER
The simple aliphatic compounds putrescine and cadaverine, derived
from ornithine and lysine, respectively, are intermediates in the syn-
thesis of many major groups of alkaloids and presumably occur in manyplant groups but are seldom isolated and studied. Ornithine (or its
successor N-methylputresine) gives rise to N-methylpyrrolidine via the
reactions below (53).
CHa-NH, CHaNHCH3 CHaNHCH3
I I ICHa CHa CHa
ICHa
I
CHNH,I
COaH
__f
-con- H,HS
CH,-NH,HNH,
COaH
CHaNHCH3
A similar reaction series can produce the corresponding piperidinehomolog from lysine. These compounds are easily alkylated by a
number of compounds, for example, p-ketobutyric acid, to produce
simple alkaloids such as hygrine (16) of the pyrrolidine type (43-55) .
In a similar manner attack on an N-methylpiperidium cation yields
16
N-methylisopelletierine, an intermediate in the formation of charac-
teristic alkaloids in the Punicaceae, Lythraceae, and Lycopodiaceae.
Simple pyrrolidine and piperidine alkaloids are widespread among
higher plants. Both groups may serve as substrates for additional
alkylation reactions either internally to yield alkaloids such as tropine
(17) and pseudopelletierine (18) or intermolecularly to yield more
complex alkaloids. Pyrrolidine alkaloids are widespread, no doubt areflection of the relatively small number of biosynthetic steps and
chemical probability of their synthesis, but they are characteristically
proliferated in a few families, such as the Solanaceae and Erythroxy-
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1. PLANT SYSTEMATICS 1 7
laceae and less commonly in others such as the Euphorbiaceae and
Convolvulaceae and doubtfully in the Dioscoreaceae (49-52, 56, 5 7 ) .
Alkaloids of the piperidine type are more widely distributed. Manysimply derived ones are found in the Crassulaceae, Punicaceae, and the
Leguminosae, but they are also found in the Pinaceae, Euphorbiaceae,
Chenopodiaceae, Equisetaceae, Piperaceae, Caricaceae, and Palmae.
17 18
Alkylation by phenylpyruvic acid may occur to produce other
alkaloids characteristic of the Crassulaceae, such as sedamine (19) ( 5 3 )and lobeline (20), found in the genus Lobelia of the Campanulaceae.
Nicotinic acid may also alkylate the pyrrolidinium cation to produce
compounds such as nicotine (21), one of the most widely distributed of
all alkaloids ( 43 , 50, 58). Many related compounds are found in the
Solanaceae, especially in the genus Nicotiana. Anabasine (5) arises inNicotiana by alkylation of the lysine-derived piperidinium cation.
Coniine (22), the principal alkaloid of C o n i u m (Umbelliferae), closely
20
0
22
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18 DAVID S . SEIGLER
resembles intermediates in the synthesis of the isopelletierine alkaloids
but has been demonstrated to be derived via a polyketide pathway
(5 3 ,59) from acetate precursors. This is a clear example of convergencein the types of compounds produced and it demonstrates why a knowl-
edge of biosynthetic pathways is valuable in studies of phylogeny.
Coniine has been reported from several other families ( 5 0 ) . t would be
especially interesting to determine the path of synthesis in each of these.
Simple derivatives of tryptophan are also widely distributed in
nature. Some, such as serotonin (23) and bufotenine (24), involve
subsequent oxygenation. N,N-Dimethyltryptamine (25) and psilocybin
(26) are widely known for their hallucinogenic properties. These com-
pounds are more restricted in distribution than 23 and 24; 25 is
7H3
23 24
0 -
IHO-P=O
25 26
found in several families (50-52) , but 26 appears to be limited to fungi.Tryptamine and its derivatives serve as intermediates for many groups
of alkaloids and by inference must occur in numerous plant taxa .
Another group derived from tryptamine is the /?-carboline alkaloids,
Q - + . L O Z H -Q- ,2--H
' NH
CH30O T J/ N
H H
27
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1 . PLANT SYSTEMATICS 19
which occur in many plant families such as the Passifloraceae, Sym-
plocaceae, Zygophyllaceae, Eleagnaceae, Malphigiaceae, Euphor-
biaceae, and Loganiaceae. Many families which contain alkaloids of the/3-carboline type are otherwise devoid of alkaloids.
Histamine (28)is widespread in higher plants, but only a few alkaloids
derived from the parent amino acid histidine, such as pilocarpine (29))
are known otherwise. Alkaloids of this type are mostly restricted to the
Rutaceae (Casimiroa and Pilocarpus) and certain groups of fungi.
28 29
Dimerization of intermediate compounds from ornithine and sub-
sequent cyclization can
alkaloids ( 5 3 ) . Further
lead to the basic skeleton of the pyrrolizidine
elaboration of basic pyrrolizidine structures
Ornithine + utrescino
HCO'
involves the type of oxidative process noted previously in relation to
the biosynthesis of pyrrolidine and piperidine alkaloids. Pyrrolizidine
alkaloids are usually esterified with mono or dibasic acids, many ofwhich are unique to this series, e.g., heliosupine (30) and senecionine
(31) 49-52, 60-64). Alkaloids of this type are found in several families
CH3
H3C'foHHO--CCHOH--CHB
I
I
H
c=o
30 31
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20 DAVID S. SEIGLER
bu t are characteristic of t he Boraginaceae (several genera), the Com-
positae (tribe Senecioneae), and the Leguminosae (Crotalaria) 49-52,
Similar reactions with cadaverine, derived from lysine, produce lupin
alkaloids such as lupinine (3). In this instance the corresponding
aldehyde may condense with another molecule of piperidine to yield
more complex compounds such as lamprobine (32), parteine (Z), and
matrine (33).Alkaloids of this type are best known from certain genera
of the Leguminosae (28 , 49-52, 65 ).
60-64).
32 33
In this section several fundamental pathways of alkaloids biosyn-
thesis have been examined. We will make frequent reference to thesein the subsequent examination of a number of specific taxonomic
problems because all have been observed to occur in many higher
taxonomic groups.
IV. Alkaloids in Lower Vascular Plants and Gymnosperms
Alkaloids are rarely found in lower plant groups. Algae, bryophytes,
and ferns seldom contain compounds of this type. Among the lowervascular plants there are two notable exceptions; one is the genus
Lycopodium, which contains complex alkaloids such as lycopodine (34)
derived from lysine by means of precursors similar to those involved in
the formation of pelletierine alkaloids in the Punicaceae (49-52, 66-69).
The other exception is the genus Equisetum, which contains several
alkaloids, such as palustrine (35). Nicotine (21) is also reported from
Equisetum species. Although alkaloids are relatively uncommon among
gymnosperms, simple compounds such as pinidine (36)are found in the
Pinaceae and closely related families. The biosynthesis of compoundsof this type has been previously outlined (Section 111, B).
The Taxaceae (Taxales) ( 7 0 ) and Cephalotaxaceae (Cephalotaxales)
( 7 2 , 7 2 , 7 2 a ) contain alkaloids such as taxine (37), hich is possibly
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1. PLANT SYSTEMATICS 21
34
of diterpine origin, and deoxyharringtonine (38),which are restricted to
their respective families (and orders). The homoerythrina alkaloids of
the Cephalotaxaceae are otherwise known only from the families
Aquifoliaceae and Liliaceae ( 7 3 , 7 4 ) . Both groups of alkaloids have
antitumor activity and are extremely toxic.
nu 0 16 H
3 1
OCH,
R = CH CH-CHa-CH2C(OH)4H2COpMe
Ico;
- ~
CH3
38
The presence of complex alkaloids in the Taxaceae and Cephalo-
taxaceae supports the separation of these orders from other gymno-sperms. This separation has been suggested by several workers on both
paleobotanical and morphological grounds (75-77) .
Although the fungi represent a distinct evolutionary line and are
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2 2 DAVID S . SEIGLER
probably as distant from plants as they are from animals in evolutionary
terms I ) , hey do possess several interesting types of alkaloids. Many
ofthese compounds, such as psilocybin 26),which is found mostlyin the genera Psilocybe and Stropharia, are derived from simple amines
which are also widespread in higher plants. Muscarine 40) is a hallu-
cinogenic choline analog found in the fly mushroom, Amanita muscaria.
Others, such as gliotoxin 39) from Trichoderma viride, are more
CH,OH
39 40
complex in structure. Many nitrogen-containing compounds from
Fungi imperfect i , especially the genera Pen icill ium , Streptomyces, and
Aspergillus have pronounced antibiotic activity; these have been
reviewed elsewhere 49, 50, 78-80 . Indole alkaloids of the ergot type
are found in Claviceps and also in t'he angiospermous plant family
Convolvulaceae (Section V, B).
V. Alkaloids in the Angiosperms
A. INTRODUCTION
Among the Angiosperms (flowering plants), Cronquist recognizes six
subclasses of dicotyledonous and four subclasses of monocotyledonous
plants 6) .Alkaloids are scarcely known from some of these, whereas in
others they are common. Among the subclasses of Magnoliopsida
(dicots) he Hamamelidae and Dilleniidae have few alkaloids-primarily
simple bases and 8-carboline types t hat occur in many plant groups.
Benzylisoquinoline alkaloids are characteristic of many orders of the
subclasses Magnoliidae, although some tryptophan-derived bases are
found in a small number of families which do not contain alkaloids of
the benzylisoquinoline type. Diterpene alkaloids are found in several
genera of the Ranunculaceae.
The Caryophyllidae contain alkaloids derived from tyrosine and the
corresponding dihydroxyphenylalanine D O P A ) . Both simple types
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1 . PLANT SYSTEMATICS 23
and betalain pigments occur and their presence is characteristic
of many families of the order.
The situation is more complex in the subclass Rosidae, where families
of some orders synthesize alkaloids and others do not. Those that
produce significant numbers and types of alkaloids are the Rosales
(Leguminosae and Crassulaceae), Myrtales (Lythraceae, Punicaceae),
Proteales (Eleagnaceae), Cornales (Garryaceae, Alangiaceae), Euphor-
biales (Buxaceae, Euphorbiaceae, Daphniphyllaceae, and Pandaceae),
Celastrales (Celastraceae), Rhamnales (Rhamnaceae), Sapindales (Rut-
acae and Peganum of the Zygophyllaceae), Linales (Erythroxylaceae),
and Umbellales (Conium of the Umbelliferae). There is little unity
among the types of alkaloids produced by this group of plants.
The extremely large and diverse family Leguminosae produces many
types of alkaloids, among them are pyrrolizidine (Crotalaria) physo-
stigmine (Physostigma), quinolizidine (several genera), Erythrina
types (Erythrina),and Ormosia types (Ormosia).
The Lythraceae produce an interesting type of quinolizidine alkaloids
not known from other plants; the Punicaceae produce alkaloids similar
to the better known tropane types; and the Garryaceae produce
diterpene alkaloids, otherwise found principally in the Ranunculaceae.
The Buxaceae contain alkaloids derived from triterpene skeletons.
Euphorbiaceae is an extremely diverse family in terms of alkaloid
types; in this regard, it is only rivalled by the Leguminosae and Ruta-
ceae. Benzylisoquinoline, indole(?), emetine( ? ), securinine, nicotine,
polypeptide, Alchornea alkaloids, tropane, p-carboline, and simple
bases are all known to occur within the family. The Daphniphyllaceae
contain diterpene alkaloids of a unique type only known from this
small family. The Pandaceae, Rhamnaceae, and Celastraceae contain
alkaloids with attached polypeptide units.
In the subclass Asteridae, many orders produce alkaloids. Among
these are the Gentianales, Polemoniales (Solanaceae and Convolvula-
ceae) Lamiales (Boraginaceae), Campanulales (Campanulaceae), Rubi-
ales (Rubiaceae) and Asterales (Compositae). The Gentianales and
Rubiales are noted for prolific production of indole alkaloids and less for
others of the tylophorine, monoterpene, and quinine type. The
Solanaceae are known for the production of steroidal, tropane, and
nicotine types, whereas a related family, the Convolvulaceae, produces
both tropane and ergot alkaloids. The Boraginaceae and the tribe Sen-
ecioneae of the Compositae and Crotalaria, a genus of legumes, produce
highly toxic alkaloids of the pyrrolizidine type. The genus Lobelia of
the Campanulaceae synthesizes alkaloids of an unusual type restricted
to that genus.
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24 DAVID S. SEIGLER
B. THEMAGNOLIOPSIDADICOTYLEDONOUSLANTS)
1 . IntroductionThe presence and phylogenetic significance of more advanced
alkaloid groups in the various subclasses and orders of dicotyledonous
plants (Magnoliopsida,sensu Cronquist) will now be examined. As the
simple alkaloids previously discussed (Section 111, B) are of lesser
significance from a systematic view, their presence will only be men-
tioned when appropriate, and numerous records of these compounds,
which may be useful a t the lower categorical levels, will be omitted.
The Caryophyllidae are probably the most primitive group and will
be examined first, followed by the Magnoliidae and Rutaceae. The
Hamamelidae, which do not contain alkaloids of complex structure, are
omitted, as are all families of the Rosidae except for the few that
contain alkaloids, i.e., the Leguminosae, Euphorbiaceae, Daphniphyl-
laceae, and Erythroxylaceae. Following this, a number of alkaloid
types based on terpenoid structures will be examined. Most of these
occur in families of the Asteridae, the most advanced subclass according
to Cronquist, although some orders, such as the Cornales (sensu
Cronquist), and a number of families of the Rosales possess the same
iridoid compounds and certain of their alkaloidal derivatives. Members
of the Nympheaceae (Magnoliidae,Sensu Cronquist) have sesquiterpene
type alkaloids. The Garryaceae (Cornales, subclass Rosidae) and the
genera Delphinum and Aconi tum (Ranunculales, subclass Magnoliidae)
as well as a few other isolated groups contain alkaloids based on a
diterpene structure. The Apocynaceae (Holarrhena), the Buxaceae
(Euphorbiales, subclass Rosidae), the Solanaceae, and many Liliaceous
plants (of the Liliopsida) contain alkaloids based on steroidal and
triterpenoid structures. Alkaloids based on tryptophan and mono-
terpene-iridoid structures and their distribution mostly in the families
Apocynaceae, Loganiaceae, and Rubiaceae (all subclass Asteridae)
will be reviewed.
The relationship of alkaloid chemistry and systematics in several
families of the Asteridae is then examined, e.g., the Solanaceae and the
Convolvulaceae. The distribution of ergot alkaloids in the latter family
and the fungal genus Claviceps is discussed.
2.The CaryophyllidaeThe subclass Caryophyllidae is recognized by Cronquist as having
4 orders, 14 families, and about 11,000 species. Of these orders, the
Polygonales, Plumbaginales, and Batales are largely without alkaloids
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1. PLANT SYSTEMATICS 25
although harman, tetrahydroharman, and harmanine have been
reported from a species of Calligonum of the Polygonaceae (50).
In contrast, alkaloids are widespread in most families of the Caryo-phyllales. They have been reported from the Aizoaceae (2500 species),
Amaranthaceae (900 species), Basellaceae (20 species), Cactaceae
(2000 species), Chenopodiaceae (1500 species), Didieraceae (9 species),
Nyctaginaceae (300 species), Phytolaccaceae (150 species), and Portu-
laceae (500 species), but not from Caryophyllaceae (2000 species) and
Molluginaceae (100 species). Because of the considerable controversy
concerning the relationship of chemistry to the classification of this
order, it has been studied more extensively than many others.
Saponins are widely distributed through the order. They have been
reported from the Aizoaceae, Molluginaceae, Amaranthaceae, Basel-
laceae, Cactaceae, Caryophyllaceae, Nyctaginaceae, and Phytolac-
caceae. Many of these are based on triterpene aglycone skeletons
(78 , 81).
Some species of the Chenopodiaceae contain a number of simple
alkaloids derived from phenylalanine, tyrosine, tryptophane, ornithine,
and lysine. Alkaloids derived from tyrosine are of particular interest
because they are related to both benzylisoquinoline alkaloid precursors
and precursors of the betalain pigments which are widespread in the
order (37, 4 4 , 5 8 ) .Salsolin (41) is an example of an alkaloid of this type.
Several relatively simple piperidine derivatives are found, as well as the
41
alkaloid anabasine (5), which in this instance is structurally but notbiosyntheticalIy related to nicotine. Lupinine (3) and other quinolizidine
alkaloids are found in Anabasis aphylla.
Alkaloids with structures similar to those derived from tyrosine
above are widely distributed in Caetaceae ( 43 , 49-52, 78, 81). One of
these, mescaline (42), is widely known for its hallucinogenic properties.
Others such as anhalidine (43) and anhalonidine (44) show similarity to
OCH, OH
42 43 44
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26 DAVID S. SEIGLER
certain precursors of benzylisoquinoline alkaloids. Other, more complex,
alkaloids involving mevalonate units such as lophocerine (45) and
dimerization of simple alkaloid units occur.
45
The genus Mesembryanthemum and related genera of the Aizoaceae
contain alkaloids such as mesembrine (46), which are also derived from
tyrosine ( 8 2 ) .
CH,46
The most widespread alkaloids of the order, however, are betalain
pigments derived from L-DOPA (83).These red or yellow compounds
have ultraviolet absorptions in the same ranges as anthocyanins and
probably serve much the same function in plants of the Caryophyllales.
The occurrence of the two classes of compounds is mutually exclusive;
no known plant in a betalain-containing family has ever been shown to
contain anthocyanins and vice versa (26 , 83-87) . The families Caryo-
phyllaceae and Molluginaceae contain anthocyanins, a fact that has
been used to suggest that they should be segregated into a closely-related but distinct order ( 8 7 ) . The red-violet pigment of beets is
betanin (47) whereas the related yellow pigment from the cactus
$ C0.HHO
47 48
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1 . PLANT SYSTEMATICS 27
SCHEME
Opuntia f icus- indica Mill. is indicaxanthin (48). The first of these
compounds arises via Scheme 1. Once formed, betanin may be converted
to other compounds via routes similar to those shown in Scheme 2.
Based on both chemical and morphological evidence, Mabry considers
that the Centrospermae families (the Caryophyllales without the
Caryophyllaceae and Molluginaceae) were derived from a common an-
cestral line from some precursor of the angiosperms and that this major
48
SCHEME
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1 . PLANT SYSTEMATICS 29
little can be said of the value of chemical characters for establishing
their taxonomic position. Among these are the Amborellaceae (1
species), Austrobaileyaceae (2 species), Canellaceae ( 16-20 species),Degneriaceae ( 1 species), Schisandraceae (47 species), Trimeniaceae
(7-1 5 species), and Winteraceae (95-120 species). When one compares
the numbers of species in the remaining families, it is evident that at
least several species of the larger families have been examined-
Annonaceae (2100 species), Calycanthaceae (9 species), Eupomatiaceae
(2 species), Hernandiaceae (50-65 species), Himantandraceae (2-3
species), Illiciaceae (42 species), Lauraceae (2000-2500 species),
Magnoliaceae (215-230 species), and Monimiaceae (450 species).
Members of the orders Piperales and Aristolochiales also havespecialized oil cells, but in contrast to the Magnoliales are mostly
herbaceous plants. The families of the small order Piperales, the
Saururaceae (5-7 species), Piperaceae (1490-3000 species) (Cronquist
accepts about 1500), and the Chloranthaceae (65-70 species) are
generally low in alkaloid content but rich in compounds derived from
phenylalanine or tyrosine metabolism via cinnamic acid and its
relatives.
The Aristolochiales, which consist of one family, the Aristolocbiaceae
(600 species), are rich in compounds derived from the metabolism of
cinnamic acid, p-coumaric acid, and their relatives but also contain
many alkaloids.
The Nympheales are aquatic plants that do not possess the oil
glands typical of the three previously described orders. Some workers
have considered the Nelumbonaceae to be sufficiently distinct so as to
comprise a separate order, usually called the Nelumbonales ( 6 ) .
Cronquist separates the Nelumbonaceae ( 2 species) from the Nym-
pheaceae (65-93 species) (but retains both in his order Nympheales),
largely on a basis of morphological characters, and the chemistry of
these two groups has not been investigated with the exception of their
alkaloids. The Ceratophyllaceae (4-1 0 species) has been little studied
chemically.
The Ranunculales also lack ethereal oil glands and most speciesof the
order belong to three large families-the Ranunculaceae, Berberidaceae,
and Menispermaceae. I n morphological features they are generally
more advanced than the Magnoliales and are probably derived from
them (6 ) .
Chemical constituents from the three large families Ranunculaceae
(800-2000 species), Berberidaceae (600-650 species), and Menisperm-
aceae (350-425 species) have been studied extensively, but the remain-
ing families of the order have been little examined. These are the
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1. PLANT SYSTEMATICS 31
intermediate in the biosynthesis of several more highly modified series
of compounds is widely distributed and is known to occur in the
Anonaceae, Hernandiaceae, Lauraceae, Monimiaceae, and Papa-veraceae as well as the non-Magnoliidean family Rhamnaceae (49-52).
Aporphine alkaloids [e.g., glaucine (53) nd bulbocapnine (54)] have
essentially the same distribution as simple benzylisoquinoline types
(49-52) and arise by ortho-para coupling of compounds such as
laudanosoline ( 5 2 ) (5 3 , 9 4 , 99-101) or where ortho-para coupling is not
possible via the intermediacy of proaporphine compounds such as
orientalinone ( 5 5 ) in the biosynthesis of isothebaine (56) in Papaverorientale L. ( 5 3 , 9 3 , 1 0 2 ) .Aporphine alkaloids are known to occur in the
CH,O
CH,O CH3
CH,O HO
OCH, O H
53 5 1 54
cH30O
56
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32 DAVID S. SEIGLER
Berberidaceae, Ranunculaceae, Fumariaceae, Aristolochiaceae, Magno-
liaceae, Lauraceae, Hernandiaceae, Monimiaceae, Menispermaceae,
Nelumbonaceae, Papaveraceae, Symplocaceae, Euphorbiaceae, Ruta -ceae, and the Rhamnaceae.
Morphine alkaloids, such as morphine (57), also arise by ortho-para
coupling of compounds such as 1-reticuline(58) in the family Papaver-
aeeae ( 5 3 , 9 3 , 9 4 , 1 0 3 - 1 0 8 ) .Certain intermediates in this pathway occur
in other families, for example, salutaridine (59) in Croton salutaris
Casar of the Euphorbiaceae.
OH
58
57
In Cryptocarya bowiei (Hook.) Druce, an Australian member of the
family Lauraceae, benzylisoquinoline precursors yield compounds with
closure to the isoquinoline nitrogen such as cryptaustoline (60) ( 5 3 , 1 0 9 ) .In the family Papaveraceae, various species of the genera Argemone
and Eschscholtzia synthesize alkaloids from benzylisoquinoline pre-
HO
60
0
59
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1. PLANT SYSTEMATICS 33
cursors with another type of closure. Representatives of these are
Z-eschscholtzine (61)and Z-munitagine (62) (53 , 93 , 94 , 96 , 110 ) . In the
closely related Fumariaceae, closure occurs to include an oxygen atomring of cularine (63) (48 , 93 , 9 4 , 10 3 ) .
?H
61 62
,OCH,
63
The genus Cocculus of the Menispermaceae synthesizes alkaloids of
the Erythrina type. Alkaloids of this type are known to arise in the
genus Erythrina (Leguminosae) by complex rearrangements of benzyl-
isoquinoline alkaloids such as N-norprotosinomenine (53 , 93 , 94 , 111-
115) .
The N-methyl carbon atom of several benzylisoquinoline alkaloids is
known to participate in formation of a berberine bridge" n compounds
such as berberine (64) 1 1 6 , 1 1 7 ) .Although protoberberine alkaloids are
known to occur in several families (Anonaceae, Ranunculaceae?Aristolochiaceae, Magnoliaceae, and Menispermaceae), they are
characteristic of the genus Berberis (Berberidaceae) and of the genera
Corydalis and Dicentra of the Fumariaceae (49-52) . Stylopine (65) n the
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34 DAVID S. SEIGLER
65 66
latter two genera is converted to protopine (66) 118).The benzophenan-
thridine skeleton encountered in a number of alkaloids of the Papaver-
aceae is also derived from benzylisoquinoline precursors ( 4 8 , 9 3 , 9 4 ) .
Chelidonine (67) s an example of this type of alkaloid.
Phthalideisoquinoline alkaloids, e.g., narcotine (68), are also found
in the Papaveraceae and Fumariaceae with occasional occurrences
in the Berberidaceae and Ranunculaceae (49 , 53 , 93 , 94 , 119) .Coupling of benzylisoquinoline units occurs in a n intermolecular as
well as in an intramolecular fashion ( 5 3 , 9 3 , 9 4 , 1 2 0 , 1 2 1 ) . he individual
components are usually linked by one or two diphenyl ether bridges.
< S O:%’ CH,o
H
0 OCH,
67 68
The distribution of compounds of this type is essentially the same as for
the simple benzylisoquinoline units and aporphine alkaloids; they are
found in the Menispermaceae, Lauraceae, Magnoliaceae, Monimiaceae,
Hernandiaceae, Nelumbonaceae, Aristolochiaceae, and Ranunculaceae,
with a questionable record from the Buxaceae (49-52) .
Aristolochic acid (69) occurs in the Aristolochiaceae and is often
accompanied by aporphine alkaloids. Feeding studies have demon-
strated that this naturally occurring nitro compound is probably
derived from orientalinol (70) ( 9 4 ) . Further, noradrenaline is incor-porated into aristolochic acid with good incorporation rates, suggesting
that 4-hydroxynorlaudanosoline is a precursor and tha t the 4-hydroxyl
group is required for oxidation of the heterocyclic ring.
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1. PLANT SYSTEMATICS 35
70 69
Many botanists agree that the orders of the Magnoliidae according to
Cronquist are related and derived from common ancestors. This con-clusion is largely based on morphological evidence, and chemical
evidence is considered supplemental, although in the subclass only the
order Piperales and the order Nympheales (if one removes the Nelum-
bonaceae) lack either the simple benzylisoquinoline alkaloids or their
more highly evolved derivatives. The Piperales are closely linked to
other orders by the presence of many phenylpropanoid and terpenoid
compounds as well as morphological features. The Nelumbonaceae are
linked by the presence of benzylisoquinoline alkaloids to other orders of
the subclass, but the other families of this order, especially the Nym-pheaceae, do not possess compounds of this type but rather alkaloids
with a sesquiterpene skeleton. Because of the presence of ellagic acid
and the absence of benzylisoquinoline alkaloids, Bate-Smith believes
that the family Nymphaeaceae is completely out of place in this
subclass ( 1 2 2 ) ,a view shared by some other workers (89-91). Pathways
leading to benzylisoquinoline alkaloids are found in many (but not all)
families of the remaining orders. Within these orders the presence of
these types of alkaloids is observed because the plants that contain
them descended from common ancestors and not because the pathwayshave evolved numerous times.
The families Magnoliaceae, Annonaceae, Eupomatiaceae, Monimi-
aceae, Lauraceae, and Hernandiaceae of the Magnoliales contain
benzylisoquinoline alkaloids. The families Himantandraceae, Myristic-
aceae, and Calycanthaceae contain alkaloids of other types, 71,26, and
72, respectively, and do not contain benzylisoquinoline alkaloids. At
least one species of the Winteraceae contains alkaloids of an undeter-
termined type (1 2 3 ) ,whereas species of the Degeneraceae, Austrobailey-
aceae, and Trimeniaceae have been tested and found not to containalkaloids (78, 1234. The Lactoridaceae, Canellaceae, Illiciaceae,
Schisandraceae, Amborrelaceae, and Gomortegaceae have apparently
not been tested. The families Ranunculaceae, Berberidaceae, and
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36 DAVID S. SEIQLER
Menispermaceae contain benzylisoquinoline alkaloids, while members of
the Lardizabalaceae (123u, 123b), Corynocarpaceae (123a), and the
Coriariaceae ( 1 2 3 ~ - 1 2 3 c ) ave been tested and found not to containalkaloids. The Sabiaceae and Circaeasteraceae have apparently not been
tested. The families Aristolochiaceae (Aristolochiales) and the Papaver-
aceae and Fumariaceae (Papaverales) all contain benzylisoquinoline
alkaloids as previously mentioned.
8HC
< N 4 &
71 72
Other lines of reasoning demand that certain families with othertypes of alkaloids [the Myristicaceae, Calycanthaceae (1 2 4 ) , and
Himantandraceae] must be accorded a place in the Magnoliales, but if
so, what is their status Have they lost the ability to synthesize
benzylisoquinoline alkaloids and taken on the ability to synthesize
others ? Or are they derived from non-benzylisoquinoline alkaloid
synthesizing ancestors ? Similar questions may be asked about those
families with no alkaloids, i.e., the Degeneriaceae and Trimeniaceae of
the Magnoliales; the Lardizabalaceae, Coriariaceae, and Coryno-
carpaceae of the Ranunculales; the entire order Piperales; and theNympheales exclu Nelumbonaceae.
The complexity of structures derived from simple benzylisoquinoline
skeleta is generally in accord with the origin of the orders as proposed
by Cronquist. The simpler types of alkaloids are found in families of the
Magnoliales and more highly derived compounds are found in the
Aristolochiales on one hand and in families of the Ranunculales and
Papaverales on the other (125) .Certain genera and species within each of the above groups lack
alkaloids. These should probably be interpreted as cases where muta-tions or metabolic changes have produced blocks to particular lines of
biosynthesis. It is also possible that, for some unknown reason, other
biosynthetic lines have been favored and the machinery needed to make
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1. PLANT SYSTEMATICS 37
benzylisoquinoline alkaloids sits unused. Examples of this are the genus
Aniba of the Lauraceae, which appears to utilize the precursors that
most Lauraceous plants convert into alkaloids to make compounds suchas 6-styryl-2-pyrones, cinnamides, and neolignans; many species of the
Piperaceae; certain species of Asarum of the Aristolochiaceae; and
Podophyllum of the Berberidaceae (125) .The distribution and taxonomic significance of benzylisoquinoline
alkaloids within several families of the subclass have been reviewed.
The distribution of alkaloids in the Lauraceae has been studied by
Gottlieb (126) .The family was subdivided into two subfamilies by
Kostermans (127) . n the subfamily Lauroideae, the tribe Perseae seems
capable of synthesizing only the most primitive types-those withthe benzyltetrahydroisoquinoline skeleton. In contrast, the tribe
Cryptocaryeae can make numerous alkaloids, e.g., aporphines, 1-(w -
aminoethyl)phenanthrenes, benzylisoquinolines, bibenzpyrrocolin, and
pavine types, as well as pleurospermine (73) and compounds similar to
tylophorine (74). The other two tribes, the Cinnamomeae and Litseae,
are in an intermediate position. The other subfamily, the Cossythoideae,
OCH,
73
OCH,
74
consisting mainly of vines, is clearly different as it contains oxyapor-phines and a morphine type alkaloid. The chemistry and distributions
of phenylpropanoid derivatives, which seem to supplant the alkaloids
in certain taxa, is discussed in detail in that work (125, 126) . The
treatment of Kostermans is largely upheld by data of alkaloid, phenyl-
propanoid, terpene, flavonoid, and other chemical origin.
The distribution and systematic significance of alkaloids in the
Menispermaceae has been recently reviewed (128) .The alkaloids of this
family are closely related to those of the Berberidaceae, Papaveraceae,
Annonaceae, Rutaceae, and Ranunculaceae both in the type and range ofalkaloids in agreement with Cronquist’s placement of this family. The
family contains several unique types, such as the hasubanan skeleton
(75) (which have the opposite configuration to t hat found in morphine
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38 DAVID S. SEIGLER
types) and others of the Erythrina type such as dihydroerysodine (76)
that are otherwise known only from the Leguminosae.
In contrast to the findings of Gottlieb in the Lauraceae, there is notsuch clear-cut correlation between the occurrence of specific alkaloid
types and the subfamilies of the Menispermaceae [as proposed by
Engler ( 1 2 9 ) ] , lthough the hasubanan, morphine, Erythrina, and novel
bases are only found in tribes of the subfamily Menispermeae.
CH30 / \CH3 -
0 CH30 ‘OH
75 76
There has been considerable debate in the past about the placement
of the Papaverales in this subclass. This argument has largely been
resolved by means of morphological characters, although the chemistryof this order closely resembles that of the Magnoliidae and especially
the Ranunculales from which Cronquist supposes them to be derived
(5 -7 ) . These alkaloids range from simple bases to some of the most
complex structures derived from the benzylisoquinoline skeleton. Some
of these (e.g., the protopines) are found in both the Papaveraceae and
Fumariaceae, whereas other types are found only in the Fumariaceae
(e.g., cularine, ochotensine, and sendaverine alkaloids) or only in the
Papaveraceae (e.g., the papaverrubrin, pavine, isopavine, and ben-
zophenanthridine types). Cronquist does not feel that the Papaver-aceae and Fumariaceae are clearly distinct on purely morphological
grounds, but the differences in chemistry strongly suggest that they are
distinct a t the familial level ( 6 6 , 8 1 ) .Probably no other genus has been examined for the presence of
alkaloids as extensively as Pupawer (Papaveraceae) (110) comprehen-
sive reviews (108 , 130, 131) have surveyed the results of alkaloid
determinations in many species. Morphologically distinct seetions of the
genus also have distinct alkaloid chemistry (110). In another genus,
Argemone, subgeneric groupings are less distinct and chemistry does notclearly resolve them ( 1 1 0 ) .This evidence does suggest that Argemone is
derived from ancestors that had pavine-type alkaloids.
The variation of alkaloids at the specific and subspecific or infra-
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1. PLANT SYSTEMATICS 39
specific levels in plants of this group has been reviewed extensively
because of their medicinal importance (14 , 37 , 78 , 81 , 107 , 110) . The
effects of many environmental and genetic factors surveyed in SectionI11 are reviewed by TBt6nyi (110 ) .Within individual species quantities
of alkaloids may be modified drastically by environmental factors but
normally not the types produced. Many of these variations must be
accounted for if one wishes to utilize alkaloid chemical data to study
problems a t the specificor subspecific levels in the Papaveraceae.
4 . The Rutaceae
The Rutaceae is one of the more interesting and complex familieswith regard t o alkaloid chemistry as well as the formation of flavonoids;
mono-, sesqui-, and triterpenes; furocoumarins; and other secondary
compounds ( 7 8 , 8 1 ) . The family contains alkaloids based on several
major biosynthetic pathways, such as benzylisoquinoline (tyrosine),
quinoline ( 1 3 2 ) , furoquinoline ( 1 3 3 ) ,quinazoline (134 ) , acridine (135)
(anthranilic acid), imidazole (histidine), ndoloquinazoline (tryptophan),
and both simple aliphatic and aromatic amines (5 3 , 93 , 136-138) .
Quinoline and furoquinoline alkaloids are especially widespread within
the family, being found in four of the five subfamilies from whichalkaloids have been reported ( 1 3 6 ) .Neither the furoquinoline, acridine,
or indoloquinazoline alkaloids, which are derivatives of anthranilic
acid, have been reported from sources other than this family ( 7 8 , 8 1 ) .
Most reports of quinoline alkaloids are also from the Rutaceae. Benzyl-
isoquinoline alkaloids occur widely in the Magnoliidae (Section V , B)
and also in the Rhamnaceae, Euphorbiaceae, and Celastraceae.
Engler (129) divided the Rutaceae into seven subfamilies-the
Rutoidae, Dictyolomatoideae, Spathelioideae, Toddalioideae, Auran-
tioideae, Flindersioideae, and Rhabdodendroidae. Willis ( 1 3 9 )felt thatthe groups that make up the Rutaceae differ to the extent that some
could be regarded as independent families. Airy-Shaw ( 1 4 0 )and Prance
( 1 4 1 ) recognized the Rhabdodendroideae as a close relative of the
Phytolaccaceae; little, if any, chemical work has been done on this
group. The Flindersioideae and Spathelioideae have been elevated to
familial level and the former taxon placed in a position intermediate
between the Rutaceae and the Zygophyllaceae ( 1 4 2 ) , but recent
evidence ( 1 3 7 , 1 43 , l 4 4 ) , largely based on alkaloid structures, sug-
gests that both the Flindersioideae and the Spathelioideae should bemaintained in the Rutaceae. Moore in Hegnauer (145 ) contended that
the Rutoideae is a highly complex subfamily phylogenetically and that
the present classification of the Rutaceae is one which runs directly<
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40 DAVID 5. SEIOLER
0 OCH, OCH,
qH,O JCH,
CH3 \
Acronycine Skimmianine
(an acridine alkaloid) (a furoquinoline alkaloid)
Casimiroine Arborine
(a quinoline alkaloid) (a quinazoline alkaloid)
CH,OQyq6 Or$N / /
OCH3\
(an indoloquinazoline alkaloid)
Hortiacine 5-Methoxyoanthin-6-one
(a canthinone alkaloid)
f
Pilocarpine
(an imidazole alkaloid)
across the lines of specialization in floral anatomy." Waterman, in
agreement with Moore's work, states that Engler's classification of both
major subfamilies Rutoideae and Toddalioideae is untenable and
proposes a new scheme of classification (1 3 7 ) .Support for the view that the Rutaceae isa distinct and homogeneous
group is provided by its essential oils and coumarins. Essential oils and
coumarins are found in at least four subfamilies. This view is also
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1. PLANT SYSTEMATICS 41
confirmed by alkaloid chemical data: (a) furoquinoline alkaloids are
essentially ubiquitous in the family and acridones are also widespread;
(b) magnoflorine (77) and berberine (a),wo of the most commonalkaloids in the Ranunculales and the Magnoliales, occur in species of
Rutaceae along with the chelerythrine (78),which is characteristic of
the Papaveraceae.
CH,O
HO
OCH,CH,O
77 78
O Y O C H ,
OCH,
79 80
Alkaloids of the benzylisoquinoline type are mostly found in the
genera Zanthoxylum (including Fa ga ra ), Phellodendron, and Toddalia.
These three genera, which Engler placed in the Rutoideae-Zanthoxyleae,
Toddalioideae-Phellodendrinae, nd Toddalioideae-Toddaliinae, espec-
tively, are closely related with an apparent phylogenetic link betweenToddalia and Zanthoxylum (1 3 7 ) . In the Boronieae (Rutoideae), only
furoquinolines are produced, whereas in the Diosmeae (Rutoideae) none
are found. In the Ruteae (Rutoideae)no less than five types of alkaloids
are common to the three major genera.
Alkaloids of the 1-benzyltetrahydroisoquinolineype are assumed to
be primitive in the Rutaceae and thus the genera producing them are
the most primitive extant genera of the family ( 7 8 , 8 9 - 9 1 ) .As anthran-
ilate-derived alkaloids are found in the same genera, i t appears that the
evolutionary trend was for direct replacement of one type with another
( 1 3 7 ) . The genera of the Rutaceae that do not have l-benzyltetra-
hydroisoquinoline alkaloids, e.g., the Diosmeae, Boronieae (Rutoideae),
and Aurantioideae, must be relatively advanced.
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1 . PLANT SYSTEMATICS 43
possessed the necessary pathways t o synthesize alkaloids but failed to
express them and later in ancestral Rutaceous stock they became
turned on once more. As previously mentioned, Cronquist (6)and otherphylogenists (6, 6 9 , 142, 147) generally place the family in the Sapin-
dales or in similar groupings, such as the Rutales ( sensuTaktajan). Few
of the plants of these orders possess alkaloids of the appropriate type,
nor do most members of the Rosales, hypothetical ancestors of the
order. At this point we must either accept possibilities (b)or (c) above,
or look for other possible ancestors. Several other workers ( 7 8 , 89-91,
145) have postulated that the origins of the Rutaceae lie in the Mag-
noliidae, near the Ranunculales or Papaverales ( 1 4 5 ) . While this
appears unlikely to many i t should be noted th at this decision has beenreached by several investigators (88, 148) on strictly morphological
grounds.
5. The Leguminosae
The family Leguminosae,as defined by Cronquist, is a member of the
Rosidae and one of the largest plant families with about 13,000 species.
Takhtajan, Stebbins, and Hutchinson considered the group to be
sufficiently distinct to comprise a separate order ( 1 2 , 6 9 , 1 4 2 ) .The threesubfamilies that make up the family, the Mimosoideae, Caesalpinoideae,
and Lotoidae, have all been elevated to familial ranks by various
authors. Most investigators have seen a fairly close relationship between
the Leguminosae and Rosaceae.
The family has many interesting secondary plant compounds, but
none that characterize the family as a whole nor any that establish a
close relationship to the Rosaceae. The alkaloids of this large plant
family have recently been reviewed by Mears and Mabry ( 1 5 ) .These
compounds are widespread throughout the former but are largelymissing from the latter family.
Simple amines derived from phenyalanine, tyrosine, and tryptophan
are widespread throughout the Leguminosae but are most commonly
found in the subfamily Mimosoideae. Derivatives of the preceding
amino acids occur in the genus Acacia and are also found as oxygenated
and methylated derivatives, e.g., candicine (82), phenylethylamine,
tyramine, and tryptamine in the genera Desmodium and Lespedeza.
Physostigmine (83),a representative of an unusual type of alkaloid
with great pharmacognostic value, is isolated from Physostigmavenenosum Baifour, the Calabar Bean (15 , 149, 150) .
Quinolizidine alkaloids are widespread in certain tribes of the
subfamily Lotoideae, among which are the Genistae, Podalyrieae, and
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1. PLANT SYSTEMATICS 45
a7
these alkaloids. The Boraginaceae and the tribe Senecioneae of the
Compositae also contain pyrrolizidine alkaloids.
The biogenesis of Erythrina alkaloids has been reviewed (111-115).These alkaloids are derived from benzylisoquinoline alkaloids by
complex rearrangements (53, 93, 94) and are known only to occur in
the genus Erythrina and in certain genera of the Menispermaceae.
The presence of sphaerocarpine (88) in Ammodendron has led Mears
and Mabry (15) o suggest that this genus should be relocated with the
CH,O O W N H
--CH,Oq
H O
H O
C H 3 09--H 3 0 O H
CH,OqOH
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46 DAVID S . SEIGLER
genera Genista and Adenocarpus, which have long been considered
related and both produce similar alkaloids.
Four of the 15-20 species of Erythrophleum have been reported tocontain alkaloids such as cassamine (89), representing one of the rare
reports of alkaloids from the Caesalpinoidae (151 , 152) .
88 89
The alkaloids of the three subfamilies are derived from distinct
biosynthetic pathways with the exception of certain simple amines
which are widely distributed but primarily found in the subfamily
Mimosoideae. Thus, alkaloid chemical data (and other chemical da ta
such as the distribution of canavanine and certain nonmetabolic amino
acids) support the separation of these three groups. Alkaloid datais less informative with respect to the identification of possible ancestors
of any of the three subfamilies but it is interesting in this regard th at
~ r ~ t h r i n alkaloids occur in the genus ~ r ~ ~ h r i n and also in certain
members of the Menispermaceae and that many of the quinolizidine
alkaloids found in the subfamily Lotoideae also occur in the Berberid-
aceae, Ranunculaceae, Papaveraceae, and Monimiaceae (all of the
Magnoliidae) and only rarely in other sources (145 , 153) . Many of these
records are in need of reexamination, as several of them are based on
unvouchered plant materials and older chemical work. Further, thepresence of numerous alkaloids derived from benzylisoquinoline path-
ways in the same plants suggests problems in identification of smaller
amounts of cooccurring quinolizidine alkaloids. A few previous in-
vestigators (89-91) have considered the possibility that the Legum-
inosae are derived from a ranunculalean-berberidalean line on a
basis of both chemical and morphological lines of evidence.
Recent work by Boulter has shown that the amino acid sequence in
cytochrome c from Phaseolus aureus Roxb. (Leguminosae, Lotoideae)
and Nigella damascena L. (Ranunculaceae) are closely related (88).Alkaloid chemistry has been useful within the Leguminosae for the
investigation of many problems a t the generic, specific, and infraspecific
levels. Several of these have been reviewed by Mears and Mabry ( 1 5 , 2 2 ) .
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1. PLANT SYSTEMATICS 47
6. The Euphorbiales
Cronquist ( 6 ) considers the family Euphorbiaceae (with about 7500
species) to be a member of the Euphorbiales, subclass Rosidae. The
family is extraordinarily diverse in terms of both morphological and
chemical characters and is of considerable economic importance. Qther
workers have a t times placed the family in different orders. The Buxa-
ceae (60 species), Daphniphyllaceae (35 species), and Aextoxicaceae
(1 species), three other families of the order, were not considered closely
allied to the Euphorbiaceae by Webster ( 1 5 4 ) , while the Pandaceae
( 3 5 species) was thought to be related.
Although the Euphorbiaceae contains many types of secondary plant
compounds few of these are so widespread as to characterize the family.
The principal exceptions are esters of phorbol(90) and other diterpenes
which are found in genera belonging to several parts of the Euphorbi-
aceae as well as the Thymeliaceae [which Thorne places in his Euphorbi-
ales, see Thorne (1 4 6 ) l (155-158). These compounds are apparently
responsible for the irritating properties well known for members of this
family.
90
R, = long, R, = short chain fatty acid
The alkaloids of the Euphorbiaceae have been reviewed by Hegnauer
( 1 5 3 ) . Among these are compounds of the securinega type, such as
securinine (91), which are widely distributed in two related genera,
Securinega and Phyllanthus. It has recently been demonstrated that
91
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48 DAVID 9. SEIQLER
these compounds are derived from L-tyrosine in a unique manner (159)in which tyrosine provides carbon atoms 6-13 of the securinine skeleton.
The genera Hymenocaridia and Julocroton contain alkaloids, 92 and 93,respectively, that are based on polypeptide structures (153, 160) . The
genus Croton contains several benzylisoquinoline alkaloids, mostly of
NHC-CH(CH3)aII0
93
HN-H--CH(CH,),
II I0 NH-G-CH-N(CH3)S
II I0 CH(CH3)(Ca&)
92
the proaporphine type such as crotonsine (94). The genera Ric inus and
Trewia contain two unusual alkaloids derived from nicotinic acid,
ricinine (95) and nudiflorine (W),espectively. Alchorneine (97),
alchorneinone (98),and other similar alkaloids have been isolated from
AlchorneaJloribunda (1 6 1 ) .These alkaloids appear to be of an imidazole
OCH,I
HO
CH3F NcrJoI ICH3
95
CH,
96
94
O Me
,OMe
97
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1 . PLANT SYSTEMATICS 49
type. d-(3R, 6R -3a-acetoxy-6/3-hydroxytropane,-2a-benzoyloxy-3/3-
hydroxynortropane, and tropacocaine have been isolated from Peripen-
tadenia mearsii (C. T. White) L. S. Smith (162) .M,-Methyltetrahydro-harman has recently been isolated from Spathiostemon javensis Blume
(=Homoroia riparia Lour.) and represents the first harman alkaloid
from this family ( 1 6 3 ) .A number of other alkaloid records in this family are questionable and
should be reexamined. Among these are the presence of phyllalbine (a
tropane type) in Phyllanthus discoideus Muell. Arg., 4-hydroxyhygrinic
acid in Croton gabouga S. Moore, an ester of vasicine in Croton draco
Schlecht., a bisbenzylisoquinoline alkaloid from Croton turumiquirensis
Steyerm., yohimbine from Alchornea jloribunda Muell. Arg., andphysostigmine from Hippomane mancinella L. [original references given
in Hegnauer ( 1 5 3 ) ] . Vouchering of plant materials is especially
important in this group of plants, many of which are notoriously
difficult to identify. Excluding these reports, the alkaloids of the
Euphorbiaceae coincide reasonably well with the various subfamilial
taxa although a large number of types are represented. Screening
studies suggest that the Euphorbiaceae is still a source of unstudied
alkaloids (123-123c, 1 6 3 ~ ) .
The small family Pandaceae has recently been found to containalkaloids such as 99, which closely resemble that of Hymenocaridia
(Euphorbiaceae) and those of the Rhamnaceae ( 1 6 4 )and Celastraceae
( 1 6 5 ) .
99
The Daphniphyllaceae is a rather small family with 35-40 species,
which most workers have considered to be related to the Euphorbiaceae
(5, 6 ) .Webster ( 5 4 ) , n accord with Hutchinson ( 1 4 2 ) ,would place the
family in the Hamamelidae (sensu Cronquist). The chemistry of the
family has been little studied with the exception of its unusual alkaloids.Some members of the family contain asperuloside, an iridoid monoter-
pene (Section V , B) ( 8 1 , 1 6 6 ) .Compounds of this type are not found in
other families of the Euphorbiales (sensu Cronquist), nor are they
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50 DAVID S. SEIGLER
commonly found in the Hamamelidae. They are, however, found in
the Gentianales, Rubiales, Cornales, etc., which are discussed in
Section V , B. The complex and unique alkaloids of this family, such asdaphniphyllin (loo), have been shown to be of terpenoid origin. Six
mevalonate units are involved in the synthesis of one alkaloid molecule
(2 6 , 167, 168) .
100
Alkaloids which occur in the Buxaceae are derived from triterpenes
and are discussed in Section V , B.
In summary, the Euphorbiaceae are rich in alkaloids of several major
types. Two other families of the order that contain alkaloids, the
Buxaceae and Daphniphyllaceae, do not appear to be closely related,
while the third, the Pandaceae, produce alkaloids similar to a t least onegenus of the Euphorbiaceae. The Aextoxicaceae have apparently not
been investigated.
The ancestry of the Euphorbiaceae has long been in question. The
family has been transferred from place to place although it has generally
been considered close to the Geraniales or other orders of the Rosidae.
Cronquist considers the Euphorbiales to be descended from the Rosales
(6), whereas Stebbins ( 1 2 ) did not consider the Rosales as necessary
intermediates. The genus Croton contains benzylisoquinoline alkaloids.
We should again ask th e questions posed when we considered the originsof the Rutaceae: Did this family come from ancestors that synthesized
benzylisoquinoline alkaloids, i.e., is it linearly descended from the
Magnoliideae; did benzylisoquinoline alkaloids arise independently in
the family or did they come from a long line of intermediates in which
synthesis of benzylisoquinoline alkaloids was “turned off” and in some
proto-Euphorbiaceous ancestors was turned on again 2
7 . The Rhamnaceae and CelastraceaeThe Rhamnaceae (Rhamnales) contain alkaloids of the benzyliso-
quinoline type as well as those with polypeptide skeletons; both of
these types are found in the Euphorbiaceae. Cronquist ( 6 )and other
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52 DAVID S. SEIGLER
that the alkaloids of this family represent a case of independent
evolution of tropane-type alkaloids.
9. Alkaloids with Monoterpene Sesquiterpene and Diterpene Skeletons
A number of monoterpenoid compounds, such as nepetalactone (104)
of the iridoid group ( 4 9 - 5 3 , 9 3 , 9 4 , 1 7 0 ) , ncorporate nitrogen to produce
alkaloids such as actinidine (105).These compounds are found in several
plant families; among them are the Gentianaceae, Apocynaceae,
Actinidiaceae, Bignoniaceae, Loganiaceae, Orobanchaceae, Menyan-
thaceae, Plantaginaceae, Oleaceae, Scrophulariaceae, Valerianaceae,
and Dipsacaceae (49 -52 , l r O a) .One of these compounds, gentianine, hasbeen shown to be an artifact of isolation under certain conditions.
104 105
The parent terpenoids have wide distribution. They occur in ants of
the genus Iridomyrmex and in many plants, primarily as the glycosides.
Several aspects of the biosynthesis, distribution, and chemotaxonomy
of this group of compounds have been reviewed ( 8 1 , 1 6 6 , 1 7 1 ) .Many of
the families in which they occur are in the Asteridae and Rosidae ( sensu
Cronquist) and the presence of iridoid monoterpenes and the monoter-
pene alkaloids (Table I) appears to demonstrate several relationships
within the group. For example, the presence of these compounds
suggests a close relationship between the Actinidiaceae (order Theales)and the Pyrolaceae and Ericaceae (order Ericales), all of the subclass
Dilleniidae. The presence of iridoid compounds in these three families is
anomalous in the subclass. Investigations of plant taxa for the presence
of both iridoids and the corresponding glycosides appears to be a
fertile area to provide additional information for the placement of
several families.
10. Alkaloids Derived from Tryptophan That Contain a Monoterpenoid
A large number of alkaloids that are important medicinally are
derived by union of simple amines derived from tryptophan and an
iridoid monoterpene unit. These are commonly known as the indole
Moiety
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1 . PLANT SYSTEMATICS 53
TABLE I
FAMILIESHAT CONTAIN IRIDOID COMPOUNDS
Rosidae
Escalloniaceae
Daphniphyllaceae ,
Fouquieriaceae
Cornaceae
Garryaceae
Hippuridaceae
Hydrangeaceae (Hydrangea )
Alangiaceae
Hamemelidae
Eucommiaceae
Hamamelidaceae (Liquidambar)
Dilleniidae
Ac tinidaceae
Ericaceae
Proteaceae
As teridae
Rubiaceae
Scrophulariaceae
Orobanchiaceae
Globulariaceae
Plantaginaceae
Buddlejaceae
Lentibulariaceae
Apocynaceae
VerbenaceaeMartyniaceae
Callitrichaceae
Acanthaceae
Dipsacaceae
Pedaliaceae
Labiatae
Myoporaceae
alkaloids. The biosynthesis of simple amines derived from tryptophan
and condensation of these units to produce Calycanthus alkaloids has
previously been mentioned and the distribution of both iridoid monoter-
penes and the corresponding monoterpene alkaloids has been summarized
(Section V, B).
Loganin (106), a precursor of most indole alkaloids, as well as of
emetine alkaloids, is found in several families; among them are the
HO
0-glucosyl
CH30.C CH3O.C
106 107
Apocynaceae, Loganiaceae, Meyanthaceae, and several Lonicera
species (Caprifoliaceae) ( 1 7 1 ) .The corresponding acid, loganic acid isfound in the Gentianaceae, Apocynaceae, Alangiaceae, and Loganiaceae
( 1 1 9 ) . Loganin is converted in certain plants to secologanin (107))
which is a more immediate precursor of indole and emetine alkaloids.
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54 DAVID S. SEIOLER
Relatively unchanged addition products of tryptophan and secologanin
u n i t s such as cordifoline (108)are found in A d i n a cordifolia Hook. of the
Rubiaceae.
108
The corresponding decarboxylated compound strictosidine (109)has
been found in Rhazya and Catharanthus species of the Apocynaceae,
although the compound with opposite configuration a t C = 3 has not
been isolated from the higher plants.
109
The route(s) from intermediates of the above type to the various
types of indole alkaloids has been the subject of much speculation (171).Among the types observed are ajmalacine (110) and its relatives
(Corynanthe type), stemmadinine types ( l l l ) ,spidosperma
types,
such as tabersonine (112),Iboga types such as catharanthine (113),and
Xtrychnos types such as strychnine (114).Several other basic skeletons
are known, and the relation of many of these to the preceding types is
enigmatic.
111
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1. PLANT SYSTEMATICS 55
112 113
114
Indole alkaloids are found in several families-the Nyssaceae,
(Camptotheca acuminata Decne.), Icacinaceae, (Nappia foetidu Miers
and Cassinopsis ilicifolia Kuntze), Alangiaceae, Loganiaceae, Apocy-
naceae, and Rubiaceae (49-52, 172-224). The families Nyssasaceae(8 species) and Alangiaceae(18species) are members of subclass Rosidae
order Cornales, whereas the families Icacinaceae (400 species) is a
member of the order Celastrales. Other workers (225 , 226) consider the
Icacinaceae to be more closely related to the former two families.
There is both chemical and morphological unity among the families
Gentianaceae (1100 species), Menyanthaceae (40 species) (which
Cronquist places in the order Polemoniales, subclass Asteridae),
Loganiaceae (500 species), Apocynaceae (2000 species), Asclepiadaceae
(2000 species), and Rubiaceae (6000-7000 species). All except theAsclepiadaceae contain precursors of the indole alkaloids if not the
alkaloids themselves (e.g., the Gentianaceae and Menyanthaceae). The
complex pathways leading to these compounds preclude independent
evolutionary origin of the indole alkaloids they contain.
The Apocynaceae has been divided into three subfamilies by Pinchon
[see complete series of references in Hegnauer (78j.l Of these, the
Plumerioideae contains indole alkaloids, the Cerberoideae monoterpene
alkaloids, and the Echitoideae steroidal alkaloids ( 7 8 ) .Problems a t the
genus and species level have been extensively investigated in this familybecause of the medicinal importance of the alkaloids; several of these
studies have been reviewed ( 1 8 , 25, 145, 153 , 186, 190-201, 204-212,227 , 228 ) .
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1 . PLANT SYSTEMATICS 57
,A&CH30,C
HN-
116
117
of indole alkaloid precursors. The former (emetine type) are restricted
to the Rubiaceae and occur in several genera, among them Cephaelis and
Psychotria. Quinine and closely related compounds are found in the
genera Cinchona, Rem ija , Contarea, and Ladenbergia of the Rubiaceae.
However, by far the most common alkaloids in the Rubiaceae are those
th at are identical with or derived from those found in the Apocynaceae
and Loganiaceae. There is little question that the Rubiaceae must have
been derived from common ancestors of the Gentianales or from
members of the Gentianales.Did the families of the Asteridae that contain iridoid compounds and
their derivatives come from families of the Rosidae that are iridoid
containing (i.e., the Rosales) as Cronquist suggests? Or have these been
derived from Saxifragalean and Cornalean ' ancestors as other authors
suggest (89-91) The same possibilities of independent origin, dormant
biosynthetic mechanisms, or linear descent rise again.
11 . Alkaloids with Sesquiterpene Structures
Alkaloids with sesquiterpene skeletons are unusual in nature (49-52,2 3 2 , 2 3 3 )but are known to occur in the Nympheaceae (see the discussion
of alkaloids in the Magnoliales). Both Nymphaea and Nuphar contain
compounds such as 118 (26,232 , 233) .
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58 DAVID S. SEIQLER
118
The alkaloids of Nuphar and Xymphaea are not found in the Nelum-
bonaceae, nor are those of Nelumbo found in other families of the order.
A clear dichotomy exists between the groups from both morphological
and chemical grounds suggesting that the two groups are not closelyrelated.
12. Alkaloids with Diterpene Structures
Alkaloids with modified diterpene structures occur in the Garryaceae
(5 species)(order Cornales, subclass Rosidae), th e genera Aconitum and
Delphinum of the Ranunculaceae (order Ranunculales, subclass
Magnoliidae), in Inula royleana DC. (order Asterales, subclass
Asteridae), and Spiraea japonica L. (order Rosales, subclass Rosidae)(49-52, 78, 81) . Many of these compounds are intensely poisonous and
some are among the most toxic materials of plant origin known to man.
Several are used medicinally. These compounds may be divided into
two broad categories. The first of these includes a series of relatively
simple amino alcohols that are modeled on a C-20 skeleton, and the
second group is more highly substituted and frequently based on a C-19
skeleton (234-239). These alkaloids arise from tetra- or pentacyclic
diterpenes in which atoms 19 and 20 are linked with the nitrogen of a
molecule of /3-aminoethanol, methylamine, or ethylamine to form aheterocyclic ring ( 2 3 6 ) .Pour basic skeletons of diterpene alkaloids are
known. The veatchine skeleton, e.g., veatchine (119),which occurs in
the genera Garrya (Garryaceae) and Aconi tum (Ranunculaceae), is
based on a kaurane skeleton (120) and obeys the isoprene rule. The
other three skeletons, the atisine, lycoctonine, and heteratisine types,
€19
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1 . PLANT S Y S T E M A l T C S 59
do not obey the isoprene rule and are found in both Ac o n i t u m and
Delph in ium species. Compounds such as atisine (121), yeoctinine (122),
and heteratisine (123) are respective representatives of these groups.The latter two types are based on a C-19 skeleton. Alkaloids from I n u l a
120 121
O H
122 123
royleana (Compositae) are identical with certain alkaloids of the
lycoctonine type which occur in the genus Ac o n i t u m ('78),whereas those
from Spiraea (Rosaceae) (e.g., 124) represent a unique type.
It is difficult to assess the taxonomic significance of these alkaloids.
The kaurane series of diterpenes also give rise t o gibberellins, which are
OH
124
found in most if not all higher plants. The number of changes necessary
to produce compounds such as veatchine from these intermediates may
be less than would appear on casual observation. No doubt many morechanges are required to produce more complex diterpene alkaloid
types. The Garryaceae are probably not closely related to the Ranun-
culaceae and neither are particularly close to the Compositae.
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60 DAVID S. SEIGLER
13 . Alkaloids Containing Steroidal or Triterpenoid Nuclei
Several plant families produce alkaloids that are biosynthesized fromsteroids (240-249) . The genera Holarrhena, Funtinnia, and Malonetia
of the Apocynaceae and Sarcocca and Pachysandra of the Buxaceae
produce alkaloids based on the 5-a-pregnane skeleton. Cholesterol has
been suggested as an intermediate i n the synthesis of steroidal alkaloids
such as holophyllamine (125) and conessine (126) in species of Holar-
rhena (53).CH,
125 126
The family Solanaceae is widely known for its diverse and plentiful
alkaloid content. The genera So l anum and Lycopersicon (and others)
contain steroidal alkaloids t hat are similar in structure t o the steroidal
saponins they possess. Many of these compounds have complex.di-andtrisaccharide moieties. Alkaloids of this type, such as solanidine (127)
and solanocapsine (128), indicate a close relationship between these
alkaloids and cholesterol.
r
alkaloids and cholesterol.
HO
H
127 128
The structures of several C-nor-D-homosteroids from the genus
Veratrum of the Liliaceae will be discussed in Section V , C.Several members of the Buxaceae (Euphorbiales sensu Cronquist)
contain exceedingly complex mixtures of alkaloids ( 2 5 0 ) .Most of thesealkaloids have substitution patterns that resemble triterpenes but do
not possess the typical C- 17 side chain. Several possess cyclopropane
rings reminiscent of cycloartenol, such as cyclobuxine-D (129), whereas
others, such as buxenine-G (130),have a ring expanded system.
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1. PLANT SYSTEMATICS 61
129 130
B u x u s alkaloids are not known from other plant groups, although
they are widespread in the family. Webster (154)does not feel that theBuxaceae is closely related t o the Euphorbiaceae; the two families have
few chemical characters in common (78). Hutchinson ( 1 4 2 ) suggested
the family was in the Hamamelidales, but there is little chemical
evidence to confirm or deny this placement.
14. The Solanaceae
The Solanaceae is one of the richest families with regard to the
absolute number of species that contain alkaloids. Cronquist places
the Solanaceae in the order Polemoniales of the Asteridae ( 6 ) . t is the
largest family in the order with about 2300 species (about 1700 of these
in the genus So lanum )followed by the Convolvulaceae with about 1400.
While the Solanaceae are extremely rich in alkaloids, few are found in
other families of the order. Pyrrolidine and tropine types have been re-
ported from the genus Convolvulus and ergot alkaloids (Section v, B)
are present in the Convolvulaceae (49 -52 , 5655 ) .A large number of genera of the Solanaceae contain alkaloids derived
from ornithine via pyrrolizidine intermediates (Table 11) (53, 93, 94 ) .The biosynthesis of these alkaloids has been previously discussed
TABLE I1
GENERAOF THE SOLANACEAEHAT CONTAIN ALKALOIDSERIVEDROM
ORNITHINEAND LYSINE
Atropa
Hyoscyamw
Physochlaina
DaturaDuboisia
Latura
Mandragora
Scopolia
Solanum Brugmansia
Solandra Salpiglossis
Physalis Salpichroa
Anisodus StreptosolenNieandra Dunalia
Methysticodendron Cyphomandra
Withania Anthoeereis
Nicotiana
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1 . PLANT SYSTEMATICS 63
132
clavine (132),arise by condensation of tryptophan and mevalonate units
and subsequent cyclization ( 2 7 , 5 3 , 9 3 , 9 4 , 2 1 6 , 2 2 0 , 2 2 1 , 2 5 2 ) .lkaloids
of the clavine series are found in both Claviceps and in the genera Riveaand Ipomoea of the Convolvulaceae. In certain alkaloid-producing
strains of ergot, agroclavine (132) is converted to elymocIavine (133),
which serves as a precursor for lysergic acid (134) and other related
132 133
compounds. Ergine (lysergic acid amide) (135)and erginine (isolysergic
acid amide (136)have been isolated from hydrolyzates of Rivea corym-
bosa (L . )Hall. f. and Ipomoea tricolor Cav., which were used by Mexican
indians as a drug under the name ololiuqui (221 , 253) .
The majority of alkaloids from ergot are peptides of lysergic acid.
The therapeutically most important ergot alkaloids are of this type.There is no question of close relationship between Claviceps (an Ascomy-
cete) and the Convolvulaceae (an angiosperm from an evolutionarily
134 135 136
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1. PLANT SYSTEMATICS 65
isolated from this family, most of which are related to the glucosinolates
which are widespread in the family, although several (e.g.,138),mainly
those from the genus Lunaria appear to be of a unique type ( 7 8 , 8 1 , 2 5 6 ) .
138
C. THELILIOPSIDAMONOCOTYLEDONOUSLANTS)
Alkaloids among the monocotyledonous plants are, with the exception
of simple amines, mostly found in families of the Liliales and the
Orchidales, although a few are known to occur in other families.
Liriodenine, lysicanine (139), and nuciferine have been reported
CH,O
139
from Lysichitum camtschatcense Schott. var. japonicum Makino of theAraceae (order Arales, subclass Arecidae)(2 5 7 ) .Several simple alkaloids,
such a s arecoline (140), are found in the Palmae (order Arecales, sub-
class Arecidae). A number of simple amines, e.g., hordenine (12),
candicine, tyramine, and N-methyltyramine, are widely distributed in
the Gramineae ( 4 9 ) .More complex alkaloids such as festucine (142) and
loline (143), pyrrolizidine alkaloids that occur free in nature, have been
CH,
140 141
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66 DAVID S. SEIGLER
HNCH,
142 143
found in the genera Festuca and Lolium, respectively. Perlolyrine (144)
has also been isolated from the genus Lolium (258).Most alkaloids of the monocotyledonous plants are concentrated in
the Liliidae, especially in the order Liliales, but also in the Orchidales.
CH,OH
144
Alkaloids commonly found in the Liliaceae (including the Amaryllida-
ceae) are derived from phenylalanine and/or tyrosine but differ in
structure from types found in dicotyledonous plants. Alkaloids in the
Orchidaceae are mostly restricted t o several genera of that family and
are of an unusual type.
1 . The Liliales
The Liliales, as defined by Cronquist, comprise 13 families and nearly
7700 species. He combines the Liliaceae and Amaryllidaceae to produce
the largest family of the order, the Liliaceae, which has about 4200
species. Other families in the order are the Iridaceae (1500 species),Dioscoreaceae (650 species), Agavaceae (550 species), Smilacaceae
(300 species), Velloziaceae (200 species), Haemodoraceae (120 species),
Xanthorrhoeaceae (50 species), Pontederiaceae (30 species), Stemona-
ceae (30 species), Taccaceae (30 species), Philydraceae ( 5 species), and
Cyanastraceae (5 species). Of these, alkaloids are known from the
Liliaceae (from members of both the former Liliaceae and Amaryllida-
ceae), Dioscoreaceae, and Stemonaceae (49-52) .
The Liliaceae and Amaryllidaceae were traditionally separated from
one another by the single character of position of the ovary-inferiorin Amaryllidaceae and superior in the Liliaceae ( 6 ) .This difference is
now not considered so significant with separation of the Agavaceae
from this group, and Cronquist says that it appears the traditional
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1. PLANT SYSTEMATICS 67
COMMELINIDAE
FIG.2. Subclasses of Liliopsida according to Cronquist (6).
Amaryllidaceae were really several different groups that had indepen-
dently become epigynous. Steroidal glycosides are widespread among
species of the Liliaceae, Agavaceae, and Dioscoreaceae, but are not
found in the Amaryllidaceae (78 , 8 1 ) .
The Amaryllidaceae alkaloids comprise a unique group of bases that
have so far been found only in that family (49-52,259-261) . Conversely,
with the exception of hordenine, alkaloids of other plant families havenot been found in the Amaryllidaceae. Three major pathways of
alkaloid biosynthesis in this family arise from the compound norbella-
dine (145), which is derived from one molecule of tyrosine and one
molecule of phenylalanine. One of these pathways gives rise to lycorine
HO+&H,NHCH. dO145
(146)and its congeners via Scheme 3. A second gives rise to haemantha-
mine (147), pretazettine (148), and tazettine (149) via Scheme 4. The
third pathway gives rise to compounds such as narwedine (150) and
galanthamine (151) via Scheme 5. All three pathways are present in
many genera of the family (49-52, 7 4 , 7 8 , 81) and in most of the tribes
of the Amaryllidaceae according to Hutchinson ( 78 ) .Other subfamilies,
a number of which were raised to the rank of family by Hutchinson, do
not have these alkaloids ( 1 4 2 ) .In some members of the Liliaceae, one molecule of phenylalanine and
one molecule of tyrosine unite to form series of compounds such as
colchicine (152) and androcymbine (153).
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68 DAVID 5. SEIGLER
Norbelladine --+
CH30 OH
CH.0
++
HO
146
SCHEME
147
HO
148
SCHEME
149
150
CH,O
.*-
151
SCHEME
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1. PLANT SYSTEMATICS 69
\OCH,
‘ 0CH,O
Hutchinson ( 142 )divided the Liliaceae into 28 tribes and a t the same
time elevated a number of groups previously placed in the Liliaceae to
familial level (78) .Of these 28 tribes, the Uvularieae, Anguillarieae, andColchiceae contain colchicine and related alkaloids. These alkaloids are
present in the genera Androcymbium, Colchicum, Gloriosa, Littorica,
Merendera, Camptorrhiza, Kreysigia, Dipidax, and Iphigenia but
absent from many others from which related alkaloids have been
reported (262-265).The Veratreae, a related tribe, contain many alkaloids that are
derived from steroidal precursors such as cholestanol as well as those of
the C-nor-D-homo type (78,247-250). These extremely toxic compounds
are found throughout the genera Ve ratr um , Schoenocaulon, and Zyga-denus and are similar to those found in the Solanaceae, Buxaceae, and
Apocynaceae. An example of the former type is veralkamine (154).
H
154
The genus Fritillaria of the subfamily Lilioideae contains alkaloids
that are similar in structure to those of the Veratreae. The similarity in
alkaloids and in certain lactones leads Hegnauer ( 7 8 ) to suggest a
relationship between the two groups. Others have previously considered
the Lilioideae to be derived from members of the Melanthioideae ( 265 ) .
The Dioscoreaceae is best known for the steroid glycosides its species
contain. These are similar in structure to those found in the Liliaceae,Agavaceae, and certain allied groups. In contrast to the Liliaceae,
however, the Dioscoreaceae contain alkaloids based on a quinuclidine
structure such as 155 (49-52, 78) .It has now been demonstrated that
four acetate units are condensed with a lysine derived piperidine unit to
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70 DAVID S. SEIGLER
yield Dioscorea alkaloids (2 6 6 ) .To date these have only been found in
African and Asian species of the genus, and interestingly, those with
alkaloids were found to be practically free of saponins (78). Earlierreports of tropane alkaloids in this family are probably erroneous.
155
The Stemonaceae, a small family of three genera (4, ave been shownto contain approximately fourteen alkaloids of a unique type such as
tuberostemonine (156).
156
Cronquist views the families of the Liliales as being derived from the
Liliaceae, with the exception of the Philydraceae and Pontederiaceae.
He further views the Amaryllidaceae as several groups of the Liliaceae
that had independently become epigynous. The Dioscoreaceae and
Stemonaceae are broadleaf climbers that are also derived from Lili-
aceous parents. The Iridaceae are much like the Liliaceae in th at theyfrequently exploit the bulbous and cormose habit, but they have not
been reported to contain alkaloids. In summary, alkaloid chemistry
suggests that the Liliaceae and several groups of the Amaryllidaceae are
distinct. The Dioscoreaceae and Stemonaceae contain alkaloids not
found in either and do not contain alkaloids of the type found in the
Liliaceae-Amaryllidaceae.
2. The Orchidaceae
This large family with approximately 20,000 species has been littleinvestigated chemically but is known to contain alkaloids derived from
ornithine. Appropriate alkylation of a pyrrolidine intermediate with an
acetate- and or propionate-derived precursor gives compounds such
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1. PLANT SYSTEMATICS 71
as crepidine (157), which are known principally from the genus Dendro-
bium but also from other genera which have been summarized (78 , 81 ,
267-269). Simpler compounds such as hygrine (16) have also been
I
157
reported from several genera and add credence to the proposed bio-
synthesis of more complex alkaloids by the internal alkylation of a
pyrrolidine moiety. Pyrrolizidine types such as 158 from the genus
Lipuris and Mu&xis are also known.
R' various R and R' substituents
158
The differences between major groups of orchids have few absolute
distinctions and several taxonomic schemes have been proposed, for
example, those by Garay ( 2 7 0 ) , Dressler and Dodson ( 2 7 1 ) , and
Airy-Shaw ( 1 4 0 ) .Most alkaloid-containing species are concentrated in
the group Epidendreae and especially in the genus Dendrobium.
Cronquist views the Orchidaceae as being derived from the Liliales,
probably from Amaryllidaceous ancestors. The alkaloids of this giant
family do not resemble those of the Lilales, nor do the Orchidaceae
contain alkaloids of the types found in either the Amaryllidaceae, the
Liliaceae, or other extant families of the Liliales.
3. Alkaloid Chemical Data and the Origin of the Monocotyledonous
PlantsBessey (272) and several other systematists proposed that the
monocotyledonous plants arose from plants similar to the Ranunculales
and that primitive monocots resembled the Alismatales. Cronquist (6)
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72 DAVID S. SEIGLER
discards this theory and derives them from the Nympheales of his
Magnoliidae, primarily on a basis of resemblance of extant members
of the Nympheales (especially Nymphuea and Nuphur), to a model heproposes for a primitive monocotyledonous plant. Stebbins ( 12 ) re-
jected this hypothesis as well as that of Bessey, as he felt many of the
characters used by both of the previous investigators were secondarily
derived rather than primitive. He further states that no modern orders
of either monocotyledonous or dicotyledonous plants are derived from
extant ancestors and suggests that monocots are derived from ancestors
similar to Drirnys (Winteraceae, subclass Magnoliidae).Chemical data do not clearly resolve problems related to the origin
of monocots. Alkaloids of the monocots are different from those of thedicots. I n only a few cases similar compounds are produced, e.g., some
amaryllidaceous alkaloids resemble those derived from benzylisoquino-
line precursors, certain orchidaceous alkaloids resemble those derived
from ornithine in dicots, and steroidal alkaloids of the Liliaceae resemble
those of the Solanaceae, Apocynaceae, and Buxaceae. Several simple
amines (tyramine, gramine, tryptamine, candicine, etc.) do occur in
monocots and dicots, but as previously discussed these are rarely
significant a t higher taxonomic ranks. If the proposals of either Bessey
or Cronquist are correct it is necessary to derive the monocots from
non-alkaloid-containing lines or to suppose that the ability to synthesize
either benzylisoquinoline alkaloids of advanced types (as occur in the
Ranunculales) or sesquiterpene alkaloids (as occur in the Nympheales)
has been lost. From extant data for the distribution of alkaloids in
monocots it is clear that most primitive monocots (as discerned by
either the system of Bessey or Cronquist) are devoid of alkaloids, and
alkaloid synthesis as seen in monocots, e.g., the Liliales, must be
independently derived. Cronquist suggests that the Winteraceae is one
of the families ancestral to other families of the order Magnoliales. It is
interesting that no benzylisoquinoline alkaloids have been isolated and
characterized from this family. On the other hand, benzylisoquinoline
alkaloids have been reported from at least one monocot, a member of
the Arales (257), although with apparently unvouchered plant mat-
erials. This record should be reexamined since it represents a most
important occurrence for studies of phylogeny and origin of this group.
Studies of the amino acid sequences of cytochrome c by Boulter (88)
indicate that monophyletic origin of the monocots from dicotyledonous
lines is probable. It also appears from this evidence that both the
monocotyledonous and magnolidean lines diverged after those of the
Caryophyllales and thus the flower and chemistry of truly primitive
angiospermous plant may resemble that proposed by Meeuse (89-91)
rather than the Ranalean type, which has become widely accepted.
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1. PLANT SYSTEMATICS 7 3
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~ H A P T E R-
THE TROPANE ALKALOIDS
ROBERT . CLARKE
Sterling Winthrop Research Institute
Remselaer. New York
I. Introduction ...................................................... 84
85
A. Proteaceae ..................................................... 85B. Rhizophoraceae ................................................ 89
C. Solanaceae .................................................... 89
D. Euphorbiaceae ................................................. 92
E . E ~t h r o x y l a c e a e............................................... 92
F. Natural Tropane N-oxides ....................................... 93
G. A Secotropane ................................................. 94
111. Syntheses ......................................................... 95
A. Oxallyl Additions to Pyrroles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
B. Robinson Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
C. Dienone Amine Additions ........................................ 97
D. From Bridged Aziridines ......................................... 98
E. From Pyrrolidines .............................................. 100
F. Nitrone-Induced Cycloadditions .................................. 101
G. 1,3.Dipolar Additions .................... . . . . . . . . . . . . . . . . . . . 102
H. Nitrosation of Phenylalanine Tropanyl Ester . . . . . . . . . . . . . . . . . . . 104
I Phosphorous an d Sulfur Analogs .................................. 105
J . Radiolabeled Tropanes .......................................... 106
IV. Reactions ......................................................... 107
A. Quaternization ................................................. 107
B. N-Oxides . . . . . . . . .................................. 112
C
.Nitroxide Radicals
....................................... .114
D.Cocaine Analogs . . ....................... 116
E. Demethylation ................................................. 120
F. Reduction of Tropinone ............................... 123
G. Tropanyl Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
H . Miscellaneous Reactions ......................................... 125
V. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
A . Tropane Moiety ................................................ 136
B. Carboxylic Acid Moiety ......................................... 138
C. Transformations ................................................ 141
D. Tissue Culture Studies........................................... 144
E . Miscellaneous Biosyntheses ....................................... 146VI. Biological Activit ........................................ 147
V I I I Stereochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
162
References .......................... ........................... 167
I1. New Tropane Alkaloids .............................................
VII. Plant Content . . . ........................................ 153
I X Analytical Methods ................................................
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2. TROPANE ALKALOIDS 85
II. New Tropane Alkaloids
A . PROTEACEAE
In 1971 , the first report of isolation of a tropane alkaloid from the
family Proteaceae marked the beginning of a flurry of activity in this
area. Some drastically different types of substituents on the tropane
skeleton have been encountered and the first apparent racemic mixtures
of naturally occurring, unsymmetrical tropane skeletons have been
isolated.
1. Bellendena m ontana R . Br.
Bellendine, the first alkaloid to be isolated from the Proteaceae,
has been shown to be 2,3-(2,3-tropeno)-5-methyl-y-pyrone3) (7 ) .Racemic bellendine has now been synthesized (8 )starting with tropi-
none: Reflux of this ketone with sodium hydride in benzene for 20
(1) NaH
3
hours followed by treatment with 3-methoxymethacryloy1 chloride
gave diketone 2. Acid catalyzed cyclization of the ketone afforded
bellendine (3) n low overall yield ( 8 ) . The acylation process alsoproduced some O-acylated material 4.
Also isolated from this species were isobellendine ( 5 ) and cis-endo-dihydroisobellendine (6) (9 ) .The same group has indicated privately
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86 ROBERT L. CLARKE
( 1 0 ) that this source also provided three esters of tropane-3a,6/3-diol,
namely the 3-acetate (7, R = H , R ’ = CH,CO-), the 3-acetate-6-
isobutyrate (7, R = (CH,),CHCO--, R’ = CH,CO-), and the 3-
isobutyrate-6-acetate (7,R = CH,CO-, R‘ = (CH,),CHCO-). Theabsolute configurations of these B . montana compounds have not been
established.
6Rf7
2 . Darlingia ferruginea J. F. Bailey
The major alkaloid of this species, darlingine, is a methylated form
of bellendine with the structure 8 ( 1 1 ) .Analyses and spectroscopic data
established its identity. It has also been isolated from D . darlingiana
(F.Muell) L. A . S . Johnson ( 1 1 ) .A minor constituent, called ferrugine,
c C P h
8 9
proved to be 2a-benzoyltropane (9) (11). t appears to have a close
biosynthetic relationship with the 2-benzyltropanes described below,
but ferrugine shows [a]1f9+55O,whereas the 2-benzyltropanes appearto be racemates. If there is indeed a relationship between the two series,
it will be interesting to find out whether ferrugine has the 1R or 1sconfiguration.
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2. TROPANE ALKALOIDS 87
Another surprise lay in the isolation of ferruginine (2-acetyltrop-2-
ene, 10) from this same species (10).
0
c&kcH3 10
3 . Knightia deplanchei Vieill. ex Brogn. e t Gris
A total of six new tropanes have been isolated from K . deplanchei thatare unique in having a benzyl group on C-2. Four of these will be
considered first (11, 12, 13, and 14) because the benzyl group is unsub-
stituted ( 1 2 ) .
CHiPh
0II
O q P h
11
CHaPh
0
0-CCH,II
12
CH3
CH,N
PhCOI \ ) T C H 2 € ’ h r J ) TOH OX\; ; /H
C==C/ \
H Ph
13
14
The nature and location of the substituents in these four compounds
were established primarily by mass spectrometry with supportive
evidence from IR, MR, and hydrolytic data. All of these alkaloids
showed zero optical rotations and are apparently racemates. The
configurations of the various substituents were established later by 13C
NMR spectral studies ( 1 2 ~ ) .he latter studies also distinguished the
points of attachment of the hydroxyl groups on the ethylene bridges of
13 and 14.
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2. TROPANE ALKALOIDS 89
B. RHIZOPHORACEAE
Bruguiera sexangular (Lour ) Poir ; Bruguiera exaristata Ding Hou
Several esters of tropine have been found in these two related species
( 1 5 , 1 6 ) . Esters identified were the acetate, propionate (a new natural
ester), isobutyrate, butyrate (new), a-methylbutyrate or isovalerate
(not differentiated), benzoate, and the 1,2-dithiolane-3-carboxylate
(the major component, a new alkaloid called brugine).
Studies on brugine showed that the skew sense of the C-S-S-Csystem is right handed in the 1,2-dithiolane-3-carboxyliccid portion
of the ester ( 1 5 ) .Optically active brugine has since been synthesizedfrom 1,2-dithiolane-3-carboxyliccid of known absolute configuration
( 1 7 )so that the natural d-alkaloid can be represented by 17.
I
0-
17
C. SOLANACEAE
1. Datura suaveolens H. and B. ex Willd.
Some new esters have been isolated from D. suaveolens, a species
indigenous to South America. From the aerial parts were isolated
3a,6/3-ditigloyloxytropane-7/3-ol18, R1 = R2 = tigloyl), hyoscine,
norhyoscine, meteloidine, atropine, noratropine, 1- and dl-3a-tigloyloxy-tropane-6/3-01 (not previously shown conclusively to be a normal
constituent of plant material), and a new alkaloid, 6p-tigloyloxy-
tropane-3a,7P-diol (18, R' = H, R2= tigloyl) ( 1 8 ) .
O R '
1s
0- C\ ,H
CH3\
c=cCH3
19
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2. TROPANE ALKALOIDS 91
Biosynthesis of the acid moiety of this ester will be discussed in Section
V . No information has appeared yet on the other two bases.
4. Datura sanguinea R. and P
a-Hydroxyscopolamine (21A) has been isolated ( 1975) from the
leaves of Datura sanguinea from Ecuador (22) .The scopolamine from
this plant is quaternized with n-butyl bromide to form a commercial
antispasmodic drug. The reportedly new tropane alkaloid 21A was
OH
21A
first isolated in quaternized form as an impurity in the crude commercial
product. Hydrolysis of this quaternary salt afforded known 2-phenyl-
glyceric acid.
Pure 21A, isolated from scopolamine mother liquors by preferential
extraction a t pH 9 followed by chromatography, proved to be 400-fold
less soluble in chloroform containing 2% ethanol than is scopolamine.
No literature reference was recorded for this base (optically active).
The dl-form of a-hydroxyscopolamine was reported six years earlier,
its being prepared by hydroxylation of aposcopolamine (22a) . Here
again there was no reference to earlier preparations. On the other hand
there is a Chinese report (1973) (copy not available) (22b) hat describes
the distribution of a-hydroxyscopolamine (called anisodine) in 19
genera and 54 species of Chinese solanaceous plants. A rapid scan of
Chemical Abstracts formula and subject indexes revealed no further
references to this compound. Anisodamine is a name given to tropane-
3a,6fl-diol 3-tropate (22c),the synthesis of which is described in this
reference.
5.Physochlaina alaica
E.Korot.
Physochhina alaicu has been found to contain 3a-(pmethoxyphenyl-
acetoxy)-tropane-6fl-o1(22), called physochlaine, together with some
apoatropine (23) .
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92 R OB E R T L. CLARKE
D. EUPRORBIACEAE
Peripentadenia mearsii (C. T. White) L . S. Smith
Two new alkaloids were isolated from this Queensland tree along with
tropacocaine (3~-benzoyloxytropane)2 4 ) .Although the identity of the
specimen was confirmed, further collections of P. mearsii in the same
area failed to yield any tropane alkaloids.
One of the new alkaloids was d-tropane-3ct,6/3-diol 3-acetate (23)[1R-(3-endo-6-exo)J, dentified by analysis, I R, NMR, and mass spectra
and by comparison of i ts diacetate with the enantiomeric 1-tropane-3a76/3-
diol diacetate prepared from valeroidine by hydrolysis and acetylation.
OCOCH,23 24
The absolute configuration of valeroidine was established earlier (25).This same ester was found in Bellendena montana (see above) ( 1 0 ) .
The other new alkaloid proved to be d-2~-benzoyloxynortropan-3fl-ol
(24) of unknown absolute configuration. Initial structural studies were
done on the natural alkaloid. It was then N-methylated (benzoate
cleaved) and acetylated to give tropane-2a,3fl-diol diacetate which was
used for the final structural studies ( 2 4 ) .
E. ERYTHROXYLACEAE
Erythroxylum monogynum Roxb.
An ether extract of the alkaline root bark of E. monogynum was
chromatographed to give five crystalline components of different
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2. TROPANE ALKALOIDS 93
molecular weights ( 2 6 ) .One of these proved t o be 3a-( ,4,5-trimethoxy-
benzoy1oxy)-tropane (25),dentified by spectral and hydrolytic studies.
Also present was 3a-( ,4,5-trimethoxycinnamoyloxy)tropane(26),
C H s N
0A O A G O C H 3CH, 2% O - - C C H = C Hi
OCH, OCHa
a5 26
previously reported as a constituent of E . el l ipt icum leaves (27). The
most recently reported compounds from E. mo n o g y n u m are tropane-
3a,6p-diol 3-(3',4',5'-trimethoxycinnamate)-benzoate (26A),he first
heterodiester to be found in Ery throxy lum (27a )and tropane-3a,6p,7/3-
trio1 3-(3',4',5'-trimethoxybenzoate) 27b) .
26A wOCH,
F. NATURALROPANE-OXIDES
Until very recently there were no reports of isolation of tropane
N-oxides from natural sources although several other types of alkaloids
have been isolated in this form. In one search for such tropane oxides
authentic samples of the N-oxides of both hyoscyamine and hyoscine
were prepared. Each formed a mixture of axial and equatorial oxides,
the components of which were separated and characterized. With this
reference background, both isomers of hyoscyamine N-oxide wereisolated from the roots, stems, leaves, flowers, pericarps, and seeds of
dt ro pa belladonna L., Hyo scyam us niger L., and Datura s t ramonium L.The equatorial AT-oxideof hyoscine was isolated from all parts of the
latter two species and from the leaves of A . belladonna. The roots, stems,
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94 ROBERT L. C W K E
and leaves of Scopolia lurida Dun. and S . carniolicaJacq. contained the
two N-oxides of hyoscyamine and the equatorial oxide of hyoscine.
Mandragora oficinarum L. roots, stems with leaves, and fruits containedboth oxides of hyoscyamine. These oxides were probably missed
heretofore because they are not soluble in the solvents customarily
used for alkaloid extraction. The proportions of N-oxide to tertiary base
varied among the organs examined and with different stages of plant
development ( 2 8 ) .
Another oxide, 3a-tigloyloxytropane N-oxide (27), was isolated from
the roots of Physalis alkekengi L. var. francheti Hort., formerly P.
I
04\ / H/C=c
\
-J)-yJ J>x/ H CH3 CH,
I0 4
> C d ,CH3 CH3
2’1 28
bunyardii Makino. Also isolated were tigloidine (28), tropine, pseudo-
tropine, an unidentified alkaloid, and the previously reported 3a-
tigloyloxytropane (29). An investigation of Physochlaina alaica has
revealed the presence of the N-oxide of 6-hydroxyhyoscyamine ( 3 0 ) .
G. A SECOTROPANE
Physoperuvine (28A), new alkaloid isolated from the roots of
Physalis peruviana Linn., appears to be a biogenetic variant of the
tropane alkaloids. The genus Physalis (Fam. Solanaceae) is well known
for its elaboration of a novel group of C,,-secosteroids called physalins
but its alkaloid content has not been determined. The structure of
physoperuvine was established by NMR and mass spectral studies of
QNHCH3 QNTZ
0 OH
Z8A Z8B
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2 . TROPANE ALKALOIDS 95
the parent base, its N-benzoyl derivative, and of a methylated a,nd
reduced form 28B. Present knowledge of biogenetic pathways to
tropanes indicates that this alkaloid is a shunt product and not anintermediate in tropane biosynthesis ( 3 0 ~ ) .
III. Syntheses
A. OXALLYLADDITIONSO PYRROLES
A new route to tropanes involved oxyallyl intermediates of the type
29 (L = Br, CO, solvent, etc. and R = alkyl) generated from a,a'-
dibromoketones and iron carbonyls. Trapping these intermediates with
N-carbomethoxypyrrole or N-acetylpyrrole led to substituted tropanes
(30) 3 1 ) . The method suffered in that dibromoacetone could not be
used to give tropanes without substituents a t C-2 or C-4.
29 30
A modified synthesis by the same investigators (32) allowed more
generality. Thus, a,a,a',a'-tetrabromoacetone could be used to give a
2,4-dibromotropen-3-one(31). ebromination was accomplished essen-
tially quantitatively to give 32 n SOY0 yield based on N-carbomethoxy-
pyrrole.
31 32
A simultaneous investigation accomplished the synthesis usingN-methylpyrroles and dibromoketones in the presence of sodium iodide
and copper (33).The yields ranged from 50 to 89Yo. These reactions
have the advantage of being run under neutral conditions.
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96 ROBERT L. CLARKE
Another oxallyl equivalent is produced by treatment of silylated
epoxide 32A with fluoride ion whereupon an allene oxide-cyclopropa-
none system 32B s presumed to form. Trapping of this intermediate
- h b ]
-H H
32B
f F A C H z
P h ? iPh, F-
H CH,CI
32A
with N-carbomethoxypyrrole afforded N-carbomethoxy-2-phenylnor-
trop-6-ene-3-one 32c)n 49y0 yield ( 3 3 a ) .An earlier example of this
type of reaction involved dimethylcyclopropanone (3%) .
12c
B. ROBINSONYNTHESIS
whereas earlier expansions of the classic Robinson synthesis ( 3 4 )involved variation of the nitrogen substituent, a recent study (35 , 35a)successfully (25y0yield) substituted acetonylacetone for succindialde-
hyde. The optimum pH for production of 33was 9.Use of heptane-2,B-
dione and diacetonylsulfide gave 1$-dimethylated granatanes and
thiagranatanes , respectively.
31
The same investigators ( 3 5 ) determined the effect of space require-
ments of the alkylamine on yield in the Robinson reaction:
Methylamine 100 180-butylamine 22%
Ethylamine 90% Go-propylamine 50j,
n-Propylamine 74y0 tert-butylamine 0%
n-Butylamine 35y0
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2. TROPANE ALKALOIDS 97
A polarographic study of the synthesis of tropinone by the Robinson-
Schoepf method was used to obtain optimum reaction conditions.
Using a 15% excess of acetonedicarboxylic acid and 3% excess ofmethylamine a t 40°C for 30 minutes gave an 82y0 yield of tropinone
(35b) .The synthesis of the optical isomers of tropan-2a-01 and tropan-2/3-01
on a large scale was studied from an economic standpoint (36).The most
efficient route started with acetonedicarboxylic acid and 2,5-diethoxy-
tetrahydrofuran in a Robinson-type synthesis and ultimately produced
dl-anhydroecgonine amide (34). Rearrangement of this amide to
34 35
dl-tropan-2-one and reduction to dl-tropan-2a-ol by known procedures
( 3 7 )gave the material chosen for resolution. Tartaric acid served as the
resolving agent. The enantiomeric 2a-01s could then be epimerized to
2/I-ols (35) by strong alkali (37). One further slight modification of the
Robinson-type synthesis has been reported (37a).
C. DIENONE MINE ADDITIONS
The reaction of 2,6-cycloheptadienone (36) with amines has been
studied further ( 3 8 ) .See Fodor ( I ) or earlier work. Dienone 36 reacted
36 37 38
with p-RC,H,NH, (R = MeO, Me, H, C1, NO,) to give corresponding
N-arylnortropinones (37) n 45--93Yn yields. The lowest yield was
obtained with p-nitroaniline. However, when even one equivalent ofmorpholine was added to 36, a 2:1 adduct (38)was formed. With two
equivalents of morpholine, 38 was formed in 74y0yield.
Another study on addition of amines t o 36 was directed principally
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98 ROBERT L. CLARKE
to the preparation of optically active compounds (39) 3 9 )suitable for
study of their circular dichroism (CD). Development of this mode of
tropane synthesis was particularly useful for the large number ofN-substituted derivatives desired (alkyl, aralkyl, cycloalkyl, carboal-
koxyalkyl, and aryl). NMR data were fully discussed. CD information
was published later ( 4 0 )and is discussed in Sections IV-A and VIII.
A further extension of this reaction involved addition of hydrazines and
hydroxylamines to dienone 36 ( 4 1 ) .Acetylhydrazine and 1) -dimethyl
hydrazine gave 40 (R = CH,CONH-) and 40 (R = (CH,),N-),respectively; hydroxylamine gave 40 ( R = OH). 1,2-Dimethyl-
89 40 41
hydrazine, however, produced a diazabicydo[3.2.2]nonane ( 4 1 ) andN-methylhydroxylamine formed both possible N-oxides, 42 and 43.The picrate of the axial oxide shows no carbonyl absorption in its IR
spectrum and presumably exists in the cyclic form 44 ( 4 1 ) .
0
t
picric
X -
4L 43 44
D. FROM RIDGEDZIRIDINES
5-Aminocycloheptene (45) was the starting material for another
tropane synthesis ( 4 2 ) . Lead tetraacetate converted this olefin to abridged aziridine (46) which corresponds to the hypothetical aziridin-
ium salt (47) proposed by Archer et al. ( 4 3 ) to interpret the ready
racemization of d-2-tropanol acetate (48).
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2. TROPANE ALKALOIDS 99
46 46
( d ) - 4 8 47 (Z)-48
Reaction of the bridged aziridine 46 with diethyl pyrocarbonate
followed by reduction (LAH) produced dl-tropan-2a-01 49. Quaterniza-
tion of 46 produced 50 which reacted with sodium dimethyl malonate
to form the tropanylmalonic ester 51.
EtOCON CH,N
49
CH , N
CH(COOCH3),
&sC H ( C O 0 CH&
51
6 iFCH3-
50
In another transformation of aziridines into tropanes, ethyl 8
azabicyclo[5.1.O]oct-3-ene-8-carboxylate(51A) rearranged into N -
carbethoxynortropidine (51E)n the presence of dichlorobis-(benzoni-
tri1e)palladium as catalyst. On the basis of NMR and product isolation
studies the reaction appears to involve four steps. A palladium-7r olefin
complex (51B) robably first forms which then undergoes attack by
chlorine on the aziridine ring with cleavage of one C-N bond (giving
51C). Regioselective intramolecular attack on the olefinic bond by-NCOOEt furnishes tropane 51D, nd loss of PdC1, gives the observed
product. This postulated reaction course is supported by diversion of
some of the intermediates with added reagents (43a).
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100 ROBERT L. CLARKE
51E51D
E. FROMYRROLIDINES
An earlier study (1961) (44) of the reaction of cis-N-tosyl-2,5-bis-
(chloromethy1)pyrrolidine (52 , R = tosyl) with phenylacetonitrile
(NaNH,, PhCH,) reported isolation of only one (53) f the two possibleisomeric products (28y0). Condensation of the corresponding N-benzyl-
Ph
CH&l
N-R + PhCH,CN +
r:H&I
CN
52 53 64
pyrrolidine (52,R = PhCH,) with phenylacetonitrile in the presence of
NaH and DMF allowed isolation of both isomers (53and 54, R =
PhCH,) (4107, combined yield) ( 4 5 ) .The endo-nitrile 54 predominated
threefold. Separation of the mixture of isomers could be accomplishedby selective hydrolysis, the endo-nitrile being considerably shielded and
difficult to cleave (1 hour at 150°C in 80% H,SO, for the p-nitrile; 48
hours under these conditions for the a-nitrile).
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2. TROPANE ALKALOIDS 101
The degree of shielding of the 3a-position is such th at the 3a-acid
chloride can be recovered essentially unchanged following a 3-hour
reflux period in EtOH ( 4 5 ) .Esterification of the pair of acids formed from hydrolysis of 53 and 54
afforded two rigid analogs of meperidine ( 4 5 )which are discussed in the
section on Biological Activity (VI).The 13Cand proton magnetic spectra
of these esters are discussed in Section VI I I .
F. NITRONE-INDUCEDYCLOADDITIONS
In the process of a Cope rearrangement on 5-allyl-3,3,5-trimethyl-l-
pyrroline-1 oxide (55) n boiling toluene the expected product (56)cyclized partially during the reaction to form isoxazolidine 57. The
isolated nitrone 56 was slowly converted to cycloadduct 57 in boiling
0 -
55
__f
CH,
CH;
56 57
xylene. Reduction of 57 with LAH or Pt/H, afforded 1,6,6-trimethyl-
nortropan-3/3-01(58, = H). Catalytic reduction of the methiodide of
57 gave 58 R= CH,) ( 4 6 ) .
RN
58
A similar cyclization was reported shortly thereafter. 4-Nitrobutene,
upon reaction with acrolein in methanol containing sodium methoxide
followed by acidification with dry HC1, afforded nitroacetal 59.Thisnitroacetal was converted to nitrone 60 by zinc (NH,Cl) and the latter
was cyclized by heat to form isoxazolidine 61. Quaternization with
CHJ and reduction with LAH then afforded tropan-3/3-01(62) 47 ) .
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102 ROBERT L. CLARKE
62
G. DIPOLAR ADDITIONS
A communication and a follow-up paper (48) describe the synthesis
of some tropanes (64, 65) that are considerably different from those
found in nature. However, structural modification of natural tropane
alkaloids is leading to compounds of such interesting biological activity
(see Section VI) that it appears desirable to record all routes to this
system.
Anhydro-3-hydroxy-1-methylpyridinium ydroxide (63) reacts with
N-phenylmaleimide, acrylonitrile, and methyl acrylate in the first
examples of the C-6-N-C-2 unit of a simple pyridine ring acting as the
1,3-dipole in a dipolar addition.
Compound 63 reacted with phenylmaleimide in refluxing THF to
form 64 n 60% yield, the ex0 configuration being demonstrated by
NMR. In a similar manner (but with hydroquinone present) acrylo-
nitrile added to form 65 with R = CN in an ex0 configuration. Withmethyl acrylate a 1 : 1 isomer mixture (R = COOMe) was reported.
Dimethyl acetylenedicarboxylate gave only resinous products. Maleic
anhydride formed a salt.
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2. TROPANE ALKALOIDS 103
Further studies on this reaction (49 ) involved the N-phenyl analog
66 which failed to react with maleic anhydride (see above) and merely
formed a saIt. However, with N-phenylmaleimide, acrylonitrile, andmethyl acrylate this betaine (66) gave the expected cycloadducts as
mixtures of endo and exo isomers in good yields. Unlike the methyl
Ph
66
series, the isomers were easily separable and the structures could be
confirmed by IR, mass, and NMR spectra. Attempted quaternization
with CH,I failed, probably because of the large steric requirements of
the N-phenyl group. In some related work on the N-phenyl analog 66,
it was found that diethyl maleate and diethyl fumarate would react
with 66 to form the expected 3-tropen-2-ones as mixtures of isomers
In a similar reaction N-carbomethoxy-2,3-homopyrrole7 (R = H)
reacted with N-phenylmaleimide (100°C) to form a mixture of exo and
(49u).
COOCH,
I
COOCH:,
I
0 68
p67
endo isomers 68. This same pyrrole reacted with dimethyl acetylene-
dicarboxylate to form 69 (R = H ) . If the pyrrole 67 has R = COOCH,,
this group assumes an ezo configuration in the product 69 (R =
COOCH,). An intermediate dipole (70) is postulated for the reaction
( 5 0 ) .FOOCH,I
COOCH,I
OOCH,I
CH30C H 3 0 aI /
H - H
R -R
69 70
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104 ROBERT L. CLARKE
The work on 1,3-dipolar additions to form tropenones has been done
principally by A . R. Katritzky's group, quite a few other papers by
them having appeared. A review on the subject is now available (50u)which contains references to all pertinent publications so only one
other will be described. Treatment of tropenone 70A with a very strong
acid (CF,SO,H) caused cyclization with formation of 70B. Several
analogs were prepared (50b) .
( -N
NCF.SOaH
70A 70B
H. NITROSATIONF PHENYLALANINEROPANYLSTER
A synthesis of atropine (73), ittorine (76), apoatropine (74), and
related alkaloids has been accomplished ( 5 1 )by a one-step deamination
reaction of dl-phenylalanine 3a-tropanyl ester (72). This amino acid
ester was obtained by coupling tropine with N-phthalyl-dl-phenylalanyl
chloride 71 followed by hydrazinolysis with an equimolar amount of
hydrazine hydrate.
PhCHa-CH-COCI PhCHa-CH-COORI I
71
O \
U0PhCH CH-COOR
INHa
N2H4A
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2. TROPANE ALKALOIDS 105
Nitrosation of amino ester 72 using NaNO, and 2N H,S04 a t room
temperature gave a mixture of six tropine esters, 7%78, two of which
(73 nd 74) involved phenyl migration.
Ph4H-COOR Ph---CHz-CH-COOR
IO H
ICHzOH
73 76
E O N 072 ___f
P h - G - C O O R P h 4 H d H - C O O R
c i s 77
74 tram8 78
IICHZ
Ph-CH-CH&OOR
IOH
75
A related synthesis of natural littorine and hyoscyamine also started
with phenylalanine, in this case with the D-isomer. I n this sequence the
amino acid was deaminated and the resulting phenyllactic acid was
esterified with tropine, giving littorine. The tosylate derivative (78A) of
this ester was solvolyzed with trifluoroacetic acid in the presence ofsodium trifluoroacetate, phenyl group migration occurring in the process
and producing the trifluoroacetate ester (78B)of hyoscyamine. Hydroly-
sis with aqueous HC1 then give hyoscyamine (51a).
ooc 0
II00s
H +-O T~ H++CH,OCCF,- -
phazCH,Ph
78A 78B
I. PHOSPHOROUSND SULFURNALOGS
Although the phosphorous analogs of natural tropanes are quite
different f rom the natural alkaloids, it appears worthwhile to acknowl-
edge their existence. Structures of types 79-82 have been prepared (52).
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106 ROBERT L. CLARKE
0
IIR-P
79 80
81 82
Formulas 82A and 82B llustrate two of eight sulfuranalogs of tropanes
which have been synthesized (5%).
82A 82B
J. RADIOLABELEDROPANES
Acid catalyzed exchange tritium labeling of cocaine gave randomlylabeled [3H]cocaine of 98y0 sotopic purity and specific activity of 630
pCi/mg. Similar tritiation of ecgonine followed by esterification,
benzoylation, and exhaustive purification provided ring-labeled [3H]-cocaine of 99% isotopic purity and specific activity of 48 pCi/mg (53 ) .
Z-(p-Butoxybenzyl-a-t hyoscyaminium bromide (83)was prepared by
condensation of p-butoxybenzyl-a-t bromide with I-hyoscyamine in
40 yield. The tritiated benzyl bromide was prepared by reducing
p-n-butoxybenzaldehyde with tritium-enriched hydrogen and treating
the resulting benzyl alcohol with 48y0 HBr ( 5 4 ) . Esterification ofbenzoylecgonine and benzoylnorecgonine with tritiated methanol
afforded cocaine and norcocaine bearing a label on the methyl ester
group ( 5 3 4 .
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2. TROPANE ALKALOIDS 107
The reaction of neonorpsicaine (84,R = H, R’ = C3H7)with CTH,I
yielded [N-3H,-methyl] neopsicaine (84, R = CTH,, R’ = C3H7).In
order to obtain a randomly labeled sample of psicaine (84, R = R’ =CH,) this compound was adsorbed on silica gel and exposed to tritium
8 ,CHT-CeH,OBu
COOR‘~3I Br- J>xOCOPhCHpOH
0--CCH-Ph
83 84
gas at room temperature for 11 weeks (modified Wilzbach method).
Chromatography of the material eluted from the silica gel gave a 32y0
yield of single tlc spot psicaine with a specific activity of 90.7 mCi/gm
corresponding to 30.8 mCi/mmole. The distribution of tritium in this
[3H]psicaine in the benzoic acid, in the pseudoecgonine, and in the
CH30 group was 84.5:11.5:4 (55).
IV. Reactions
A. QUARTERNIZATION
The stereochemistry of quaternization of tropanes has been the
subject of controversy for quite a few years. Fodor’s 1971 review of
tropanes in this treatise concluded that equatorial attack (with respect
to the piperidine moiety) predominated, although in many cases asubstantial product was formed from simultaneous axial attack. The
observed facts seem to indicate that diaxial interaction of the 28- and
4p-hydrogens with the approaching reagent is greater than that caused
by the 68- and 78-hydrogens. Angular deformation of the five-mem-
bered ring helps to diminish this latter compression. Furthermore, the
group already bound to nitrogen can accommodate more easily to
2,4-diaxial compression than the incoming group, which, in the tran-
sition state, is a charge-separated and solvated species ( 1 ) .
In a review on quaternization of piperidines in which tropanequaternization was discussed at about this same stage of development
(1970) (56 ) , McKenna still had some reservations about the steric
course of these reactions. He concluded that, with a nitrogen atom
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108 ROBERT L. CLARKE
positioned commonly to two different rings, qualitative predictions of
stereospecificity are difficult.
Another review appeared in 1970 by Bottini (5 7 )who reported thatthe discrepancies in the controversy had been pretty well resolved and
that equatorial attack seemed to be the predominant mode in tropane
quaternization. He published a summary table showing reported
quaternizations, reaction conditions, and product ratios.
The possibility tha t it is the pyrrolidine ring of the tropane system
that is the directing influence was considered by Otzenberger et al. (58).With tropane viewed as a piperidine, N-alkylation has t o be considered
as primarily equatorial, in contrast to the wealth of data demonstrating
that piperidines undergo preferential axial alkylation. This anomalycan be eliminated, however, by considering tropane as a substituted
pyrrolidine. Therefore, in this series we can expect axial alkylation.
Bottini et al. (5 9 ) substantiated the configurational assignment of
N-ethylpseudotropinium bromide by means of X-ray analysis. They
also made the interesting observation that in the process of quaternizing
tropinone there was an 88:12 equatorial: axial attack ratio a t 70y0
reaction ( 3 0 minutes) and a 7 7 : 2 3 ratio at the end of 2 4 hours. With
added tropinone or pyridine, this ratio fell to 50:50. In this instance, an
equilibration may be occurring through reverse Michael addition withtransient formation of cycloheptadienone followed by readdition. Such
addition of secondary amine salts to cycloheptadienone has been
observed (38 , 39, 4 1 ) .
Another example of this equilibration &furnished by Kashman and
Cherkez who found that aqueous solutiens of N-[(AS)-a-phenethyll-
nortropinone methiodide underwent equilibration a t room temperature
in 48 hours to give a 40:60 mixture of 85 and 86, respectively. The
equilibrium could be attained from either-ure isomer ( 4 0 ) . This same
work possibly provides a means for establishing the structures of certainisomeric quaternary salt pairs, namely through measurement of circular
dichroism induced by a chiral center awched t o the nitrogen. A
85 86
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2. TROPANE ALKALOIDS 109
carbonyl group at C-3 enhances this effect for that isomer with the
chiral group in an axial configuration (85). Some further discussion of
this work is given in Section VIII.Supple and Eklum (60)quaternized some tropidines (87) where the
pathway for axial approach of the alkylating agent would be less
CHaPhe/
H3iR, phcHhR e l Br- c
I -
87 88 89
hindered by axial hydrogens, whereas equatorial approach would
suffer essentially the same interactions as in the tropanes. Larger
proportions of products from axial attack might be expected. Treatment
of tropidine (87, R = CH,, R‘ = H) and 3-phenyltropidine (87, R =
CH,, R’ = Ph) with benzyl bromide gave 92 and 91% yields, respec-
tively, of the products resulting from equatorial attack (88,R = H and
88, R = Ph). The same predominance of equatorial attack was observed
upon inverse addition of the substituents on the nitrogen. Thus,N-benzylnortropidine (87, R = PhCH,, R’ = H) reacted with methyl
iodide to give 8 4 7 , of 89.
It should be kept in mind that the configurational assignments in the
Supple-Eklum work are based primarily on the generally assumed
principle that a reference compound, “3-phenyltropine, should quater-
nize principally by equatorial attack.” In this series, the axial methyls
were upfield of the equatorial methyls, a finding in accord with earlier
reports from established series ( I ) .There were some NMR data on non-
equivalence of ,certain benzylic methylene protons that stronglysupported the assigned structures.
Thut (61)studied the stereochemistry of quaternization of tropane,
tropine, pseudotropine, and tropinone with ethyl haloacetates, benzyl
halides, and benzyl benzenesulfonates but the results were incon-
clusive.
A sophisticated I3C NMR study has just appeared that shows the
practicality of determining configurations about the nitrogen of
tropane quaternaries using this tool. The systems studied bore only
alkyl groups on the nitrogen (61a).For further details see Section VII I .At this time, there seemed to be a rather consistent picture of
predominantly equatorial attack with respect to the piperidine moiety
in tropanes. But in 1974, a report by Szendey and Mutschler (62)
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110 ROBERT L. CLARKE
appeared that stated that benzylic bromides reacted with tropine
principally by axial attack.
The “direct” reaction (Eq. 2) gave the isomers shown with a selec-tivity of 98,96, and SOY o , respectively forR1,2,nd R3.The previously
reported patterns of quaternization ( I )and observed downfield locations
R(1.2.3)
e /
d H d H
R’ = PhCHi-
R2 = PhCeH4CHz-
R3 = -CH~CBH,CBH*CH~
(NMR) of methyl groups (1) versus the reverse isomers) would lead
ordinarily to assignment of configurations opposite t o those shown here.
However, the authors made their structural assignments on the basis
of mass spectral fragmentation patterns. Their basic assumption was
that equatorially bound ligands would have a higher energetic stability
than the axial ligands, and thus a greater amount of RBr (or fragments
thereof) than CH,Br would appear from the above isomers. In like
manner, the isomeric forms (90) would produce a preponderance of
CH,Br.
CH3e/
R(1.2.W-N
IOH
90
The mass spectral data (reported for R2 nd R3)showed consistent
patterns that were considered valid enough to use as a basis for assign-
ment of the structures shown. Unfortunately, there are no data available
on mass spectral fragmentation patterns of quaternary salts of provenconfiguration. Even so, i t would be hazardous to extrapolate those data
to these benzylic systems. Hopefully it will be possible to settle this
question eventually by X-ray analysis.
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2. "ROPANE ALKALOIDS 111
Referring again to the work described above by Supple and Eklum
( 6 0 ) , those authors found that direct benzylation of tropidine with
benzyl bromide gave a 92:8 isomer mixture and that methylation(CH,I) of N-benzylnortropidine gave a 16:84 mixture, i.e., a consider-
able predominance of specific attack in each case. Szendey and Mutschler
( 6 2 )found that benzylation of tropine gave a 98:2 ratio of products but
that methylation (CH,Br) of N-benzylnortropine gave a 5 5 :45 ratio
(rather nonstereospecific).
Reaction rate measurements were used by Weisz et al. ( 6 3 ) o deter-
mine the effect of various substituents in the tropane skeleton upon the
reactivity of the tropane tertiary nitrogen. Cocaine (91) and ecgoninol
(92), with axial substituents on C-2, react slowly with CH,I a t room
CH,N J
2)OHCPh OH
91 92
temperature and not a t all with ethyl iodoacetate. [This reaction
selectivity was used elsewhere to separate a mixture of tropanes that
were epimeric at C-2 ( 6 4 ) . ]Likewise, the two p-hydroxyl groups of
teloidine (93, R = a-OH) and teloidinone (93, R = 0) greatly hinder
quaternization. But surprisingly, the single 6j3-hydroxyl function of
HOHR HoJ?T
R93 94
3a,6p-dihydroxytropane (94, R = a-OH) and 6p-hydroxytropinone
(94, R = 0) does not affect the rate of methylation as compared with
the corresponding derivatives containing no 6p-hydroxyl group.
Under more vigorous conditions ( S O T ) , ecgoninol diacetate reacts
with ethyl iodoacetate (65), but in boiling toluene this addition is
reversed (66).
The preparation of quaternary salts is often complicated by accom-panying dehydrohalogenation of the alkyl halide used. A hydrohalidesalt of the tertiary amine then precipitates together with the quaternary.
It has been found that addition of ethylene oxide to such reaction
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112 ROBERT L. CLARKE
mixtures acts as a scavenger of the acid, regenerating the amine which
is again free to quaternize. 1-Scopolamine was quaternized with 3,3-
dimethylallyl bromide, (2-methylcyclopropyl)methyl bromide, cyclo-butylmethyl bromide, and 2-cyclopropylethyl bromide to give the
corresponding quaternary salts in 66,48,51, and 61% yields, respectively
(67)..
Tropine, atropine, and hyoscyamine were treated with propane-
sultone(1,3) and butanesultone-(1,4) to give inner salts of type 95 where
n = 3 or 4. These crystalline salts were quite soluble in most common
organic solvents and had high melting points ( 6 8 ) .
CH3(-)O&I--(CH~)~-N, Ll
OR
95
B. N-OXIDES
A reaction related to quaternization and one that raises the same
questions about stereochemical course is the formation of tropane
N-oxides. The major product from the N-oxidation of scopolamine has
been fully characterized by X-ray crystallographic analysis in the form
of 1-scopolamine N-oxide hydrobromide monohydrate. I t s N-methyl
group is axial and the oxide function is equatorial (96).
0
t
o ~ o ~
0 CHaOHOR
97OR II I
96 R = -G-CH-Ph
Huber et al. went on to examine by 100 MHz NMR spectroscopy the
crude reaction mixtures from oxidation of scopolamine, atropine, and
tropine (H 20 2 n EtOH at 30°C). Both atropine and tropine gave
product ratios of 3:l of the N-oxides, the major N-methyl resonances
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2. TROPANE ALKALOIDS 113
being a t lower field in each ( A S = 0.1 and 0.03 ppm, respectively). In
contrast, the methyl resonance of the major oxide from scopolamine
appears at higher field (AS = 0.21 ppm). Assuming that the majorproduct from atropine and tropine has an equatorial oxide configuration,
it must be concluded that the epoxide oxygen of the scopolamine
deshields the equatorial methyl of (97)and causes the observed reversal
of methyl signals in th at substance relative to tropine and atropine (69).
Isomeric pairs were not isolated in pure form.
About the same time Werner and Schickfluss ( 7 0 ) described the
oxidation of tropine with H 202 n EtOH (reflux) with actual isolation
of the two possible N-oxides. On the basis of their NMR spectra (100
MHz but not very well defined), the major product (65y0)was tenta-tively assigned the configuration with oxygen axial; the minor product
(2.8y0)was drawn with the oxygen equatorial. No interpretation was
given to the N-methyl peak positions. The configurational assignments
[the reverse of the assignments for tropine in the study just described
(69)l were made on the basis of the positions of what were assumed to
be the C-2 and C-4 axial hydrogen peaks.
A 220 MHz study by Bachmann and Philipsborn ( 7 1 ) of this same
pair of isomeric N-oxides (one pure; one a 2 : l mixture) gave very clear
spectra that allowed assignment of each hydrogen resonance. Thefallacy in assignment of the C-2 and C-4 axial hydrogen peaks in the
100 MHz work just described was demonstrated and the major product
was shown to have the oxygen actually in the equatorial configuration.
This equatorial oxygen deshields the 6/3 and 7 8 hydrogens quite
significantly. The N-methyl peaks are reported with a difference of only
0.01 ppm, the major product (axial methyl) being a t lower field.
The final chapter of this particular story was written by Werner’s
group recently (71a) when dipole moments were determined on both
pure isomers, X-ray structure analysis was performed on one of these
and 200 MHz NMR spectral studies were made of both isomeric
[2,2,4,4-D4]tropine-N-oxides.he assignments of the Huber, the
Bachmann and the Werner groups are now in agreement. Yet another
study of tropine N-oxides was not very satisfactory since the isomers
were not separated ( 7 2 ) .An analytical procedure for the determination
of N-oxides such as t,hose from atropine and scopolamine involves
controlled potential coulometry ( 7 3 ) .
The isolation of some N-oxides from plant sources was described
in Section 11, F (28-30) .Although an earlier report expressed preference for H,02 over
m-chloroperbenzoic acid for N-oxide formation (69), the most recent
paper on the subject recommended the peracid ( 2 8 ) .
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114 ROBERT L. CLARKE
C. NITROXIDE ADICALS
Stable dialkyl nitroxide radicals other than sterically hindereddi-tert-alkyl nitroxides were unknown until 1966. Those nitroxide
radicals that were unstable (98) appeared to decompose by dismutation
to a nitrone (99) and a hydroxylamine (100) or, a t least, to involve a
nitrone as an important intermediate. A clever solution to the stability
98 99 100
problem was achieved through the synthesis of norpseudopelletierine-
N-oxyl (101),a ring system that does not allow formation of a double
bond between the nitrogen and an adjacent carbon (Bredt's rule). This
radical, although stable in the solid state and in benzene or water
solution, is very reactive (much more so than the related 2,2,6,6-
tetramethylpiperidine-N-oxyl), and the ESR absorption disappears
rapidly in acidic or in basic solution ( 7 4 ) .
The same group went on to study 1,5-dimethylnortropinone-N-oxyl(102) and determined all proton hyperfine splitting constants with
0 .I
0 .
IN N
101 102
magnitude and sign and with complete specific assignments ( 7 5 ) .X-ray
analysis of this N-oxyl ( 7 6 ) has shown that the N-0 bond (103) is
inclined a t an angle of 24.9" to the plane of C-1-N-C-5. This angle
is comparable with those shown by other nitroxyls and is less large than
th at of 30.5"shown by granatane-N-oxyl. As in the granatane case and
contrary to the finding with pseudotropine, the N-0 bond is inclined
toward the ring containing the carbonyl group. This inclination has
been predicted by calculation of conformational effects ( 7 5 ) .Nortropine-N-oxyl was reported in 1970 from oxidation of nortropine
with 307' H202 in the presence of NaWO,. I ts EPR spectrum was
shown ( 7 7 ) .
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2. TROPANE ALKALOIDS 115
101 104
The first of a series of papers by a Canadian group (78) reported that
nortropane-N-oxyl (104) is stable a t room temperature in neutral
solution. Since the electron paramagnetic resonance signal due to this
radical in solution could be reversibIy decreased and increased by cooling
and warming, it was assumed th at 104 could form a diamagnetic dimer
at low temperatures. The free nitroxide radical is relatively more
abundant below room temperature in CF,Cl, than in isopentane.
During the course of studies on this reversible dimerization of
nortropane-N-oxyl(79), it was discovered t hat an irreversible dimeriza-
tion was occurring. This change was accelerated by heat but transpired
fairly readily at room temperature in CC1, ( 8 0 y 0 in 12 days). The
principal dimeric product was 105.However, when dimerization took
place in the presence of silver oxide, a second dimeric product (106)was
isolated (dark red crystals, 2%). It was also noted in this report that
0
?--@ fjqh05 106
nortropane-N-oxyl oxidized aqueous hydrogen peroxide rapidly a t room
temperature with copious gas evolution, whereas 2,2,6,6-tetramethyl-
piperidine-N-oxyl was inert to these conditions.
The material in the communication just discussed (79) is reported in
more detail in two follow-up papers ( 8 0 ) .Here, the N-oxyls of nortro-
pine and norpseudotropine were also described. Labeling studies showedthat the bridgehead hydrogens were not involved in the irreversible
dimerization to form 105. The most recent paper in this Canadian
series (81) overs some calorimetric and equilibrium studies on nitroxide
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116 ROBERT L. CLARKE
and iminoxy radicals. Equilibrium constants are given for some radical-
oxime reactions in benzene where nortropane-N-oxyl is one of the
radicals utilized.Excellent yields of nitroxides in nonaqueous medium have been
obtained with m-chlorobenzoic acid and with CH,CN-CH,OH-WO,
(very little water) (81~).
Electrochemical oxidation of seven different nitroxyl radicals (two
tropanes) has been investigated in CH,CN with a platinum electrode.
The oxidation is a reversible, one-electron process leading to an
oxammonium ion (Eq. 3) 8 2 ) .
D. COCAINEANALOGS
Some cocaine analogs have been prepared for biological purposes;
the testing results are described in Section VI. However, the chemical
reactions are appropriately detailed here.
Benzoylation of tropane-ZP,3p-diol with one equivalent of benzoic
anhydride with a routine work-up gave the 3-benzoate (107) as the
major product together with a small amount of 2-benzoate (108)and a
very small amount of dibenzoate. It was shown that the %benzoate is
107 108
intermediate in the formation of the 3-benzoate. Acetylation of these
benzoates then gave some reverse-ester analogs of cocaine ( 8 3 ) .
8-Ethoxycarbonylnortropane-2/3,3/3-diol,n intermediate used in thesynthesis just described, reacted with variously substituted benzalde-
hydes to form isomeric acetals 109 and 110 (R = EtOCO-). Configura-
tions were assigned to these isomers on the basis of NMR data. Lithium
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2. TROPANE ALKALOIDS 1 1 7
109 110
aluminum hydride converted them to the corresponding N-methyl
acetals 109 and 110 (R = CH,).Acetals 109 and 110 (R = EtOCO-) were converted by N-bromo-
succinimide (BaCO,) into a single bromoester, 111, which was trans-
formed by aqueous alcoholic potassium carbonate into the 2/3,3,%epoxide
Br
111 112
112. Hydrolysis of this epoxide produced a diaxial diol, 113, which
failed to form acetal 114 (Eq. 4). Such acetal formation would have
required a boat conformation for the piperidine moiety ( 8 4 ) .
nIE t O C N E t O C N
I \ OH I
O H113 114
A series of central nervous system stimulants was prepared in which
the elements of COz were (formally) removed from cocaine, i.e., the
aromatic ring was attached directly to carbon-3. Phenylmagnesium
bromide reacted with anhydroecgonine methyl ester (115) in ether at
- 0°C in the absence of copper salts to form a 1:3 mixture of 28-carboxylate 116 and 2a-carboxyIate 1I?. Structural assignment was
based upon NMR data and reduction to the corresponding alcohols
(118 and 119), one of which showed intramolecular hydrogen bonding.
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118 ROBERT L. CLARKE
CH,N
\\ ,COOCH3
115
CH,N
115 COOCHj
Ph
PhMgBr4 16
CH,N
I\
117
The axial ester 116 quaternizes more slowly than the equatorial ester
117, fact that can be used to separate isomer mixtures when it is
desired to recover only the axial (stimulative) isomer. Attempts to
influence the ratio of isomers formed in the Grignard reaction failed
( 6 4 ) .
-**‘H-o\
z)<phX Y H
118 119
Treatment of either the axial ester 116 or the equatorial ester 117
with polyphosphoric acid at 150°C produced a single product, a 1,3-
ethanoindeno[2,1-c]pyridine, 120. A series of such compounds was
studied for analgesic activity (85).
120
In 1896 tropan-3-one was found to react with HCN to form a single
crystalline cyanohydrin (86).Only one crystalline isomer was obtainedby addition of HCN to nortropan-3-one many years later (1957) (87),and both compounds were shown to belong to the same series, i.e.,
a-cyano-p-ols (121). These cyanohydrins were then converted by
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2. TROPANE ALKALOIDS 119
CN
1 2 1
COOCHB
122
conventional means to a position isomer of cocaine called a-cocaine
(122). Recently, N-benzylnortropan-3-one was treated with HCN and,
when the adduct could not be induced to crystallize, the crude oil was
hydrolyzed with concentrated hydrochloric acid and the resulting
carboxylic acid was esterified (see Eq. 5 ) . Both of the possible epimers
were isolated (123 and 124). Presumably both cyanohydrins ordinarily
CN
COOCH,123
I
OH
P h C H a N
O H124
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120 R O B E R T L. C L A R K E
form, but if one crystallizes (as was the case with tropan-3-one and
nortropan-3-one), the equilibrium is shifted and little of the other
epimer remains. Hydrolysis of the oily N-benzyl cyanohydrin was thusable to provide both forms. The new ester (124) afforded an opportunity
to make the unknown /?-cocaine. Benzoylation of the axial hydroxyl
group proved difficult, but treatment with potassium hydride followed
by benzoyl chloride was effective (see Eq. 6 ) . Debenzylation and
methylation then afforded /3-cocaine (125) (88).
PhCH&,
(1) K H ( 1 ) HdPd
( 2 ) PhCOCl (2) H C H O
-H C O O HCOOCH,
IOCOPh
OCOPh
125
E. DEMETHYLATION
For many years the primary route to nortropanes lay in demethyla-
tion of tropanes by KMnO,, K,Fe(CN),, or cyanogen bromide. Another
method, which has found little use (89), as first reported in 1927 (90).
The N-oxides of several tropanes were treated with acetic anhydride
and the resulting N-acetylnortropanes were hydrolyzed (see Eq. 7)
(89).Trifluoroacetic anhydride has also been used in this transformation
(29).The usefulness of these early methods should not be discounted.
Proper control of pH in the oxidation of cocaine by permanganate has
furnished a yield of norcocaine based on recovered starting
material ( 9 0 ~ ) .
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2. TROPANE ALKALOIDS 121
Recently, the use of chloroformic esters has become the method of
choice (83,91-93).Although ethyl chIoroformate reacts with tropan-3a-
01 acetate t o give urethane 126 in high yield, the same reagent reactswith tropan-3a-01 (the free alcohol) to produce a large amount of
0 0
EOJ) I t ~ EJ) II ~ 3)OAc OH OH
126 127 128
resinous material and only a little of the desired urethane 127. Both
products, however, are easily hydrolyzed with strong hydrochloric acid
to nortropan-3a-01 (128). With tropinone, the ethyl chloroformate
reaction goes well, but the hydrolytic step fails to produce any of the
desired nortropinone (93).
This problem in demethylation of tropan-3-one has been solved by
formation of an ethylene ketal (129),which reacted cleanly with ethyl
0II
129 130 131
chloroformate. The resulting urethane (130)was then hydrolyzed with
potassium hydroxide to generate the nor product (131).Acid hydrolysis
removed the protecting group (94).
Another variation of the N-demethylation procedure utilizing alkyl
chloroformates involved phosgene. Thus, treatment of tropan-3-one in
toluene at 10°C with phosgene in toluene and heating the product inwater until CO, evolution ceased gave nortropan-3-one. The hydroxyl
group of scopolamine was protected by acetylation prior to phosgenetreatment (95).
It should be noted that benzyl chloroformate gave very poor yields
of urethanes in the demethylation procedure under discussion (96).
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122 ROBERT L. CLARKE
Phenyl chloroformate gave good yields a t room temperature ( 9 2 ) ,and
vinyl chloroformate was quite effective, reacting exothermically a t
room temperature ( 9 6 ) .2-Chloroethyl chloroformate was used to demethylate a 3-phenyl-
tropane-2-carboxylic ester with the expectation that the resulting
urethane (132) ould be cleaved with zinc and alcohol, thus avoiding
hydrolysis with strong acid which would attack the ester. When zinc
0
132‘0
133
and alcohol (or acetic acid) failed to effect reaction the function on the
nitrogen was cleaved with chromous perchlorate ( 6 4 ) .
It turns out tha t 2,2,2-trichloroethyl chloroformate is the reagent of
choice for tropane demethylation. It produced from tropinone a good
yield (95y0) f trichloroethyl carbamate (133) hich was easily cleaved
by zinc in methanol or acetic acid ( 6 2 % ) ( 9 7 ) .
In addition to their usefulness as intermediates in the preparation of
nortropanes, the urethanes under discussion can be reduced with
lithium aluminum deuteride to form labeled tropanes. Thus, N-
ethoxycarbonyltropine is converted (6 6 y 0 ) to 133A (97a ) .
OH
133A
In the von Braun demethylation procedure, an intermediate N-
cyanoammonium salt structure has been considered probable. Such
intermediates have been isolated as crystalline solids by combining
tropine, pseudotropine, and tropinone with cyanogen bromide a t - 0°Cto - 0°C. These salts ordinarily decompose near 0°C to give N-cyano-
amines and CH,Br. However, conversion to fluoroborates (AgBF,)
effected considerably greater stability ( 9 8 ) .
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2. TROPANE ALKALOIDS 123
Photooxidation of tropinone (98a) , tropan-3a-01, tropan-3/3-01, and
deoxyscopoline (98b) has caused N-demethylation. The presence of a
benzoate chromophore as found in cocaine, benzoyltropine, andbenzoylpseudotropine aids in the removal of the N-methyl group.
Cocaine yielded 20y0norcocaine together with 70y0 recovered cocaine.
It is not necessary that the benzoyl group be in close proximity to the
N-methyl reaction center but the specificity of the reaction for bicyclic
compounds with N-methyl bridges compared to monocyclic ones isapparently due to the operation of Bredt’s rule on a proposed imine
intermediate (98c).
F. REDUCTIONF TROPINONE
Until recently, reduction of tropinone to tropine with high stereo-
selectivity has been achieved only by catalytic reduction (see 99).Thisselectivity depends upon the presence of the basic nitrogen as evidenced
by the fact that 8-ethoxycarbonylnortropan-3-one s reduced by
Pt/EtOH (or HOAc) to give a 3:l mixture of the 3a- and 3p-01~espec-
tively ( 8 3 ) .A stereoselective chemical reduction has now been described.
Diisobutylaluminum hydride in tetrahydrofuran at - 78°C reducestropinone to form of the 3a-01 accompanied by only 3y0 of the
3p-01 ( 100) .Another example of this is described by Noyori et al. ( 3 2 ) .In a comparison of various methods of reduction of tropinone the
results tabulated below were obtained ( 2 9 ) .~~
3a/58-01Reagent Ratio
Na/EtOH 1/24Na/i-BuOH 1/27
Hz, PtOa, EtOH 99.410.6
NaBH, 54/46
Hz, PtOa, EtONa 1211
A somewhat surprising catalytic hydrogenolysis of ketone to methyl-
ene has been reported (101). ropinone, tropan-6-one, and 6p-hydroxy-
tropinone are reduced to ropane, tropane, and tropan-6p-01,respectively,
by hydrogen in the presence of PtO, in weight equal to that of the
ketone and a molar excess of acid. The obvious alcohol intermediatesin the reaction are untouched by the reaction conditions. Earlier
examples of this type of reduction are to be found in some work on
cyclitols ( 102) .
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124 ROBERT L. CLARKE
In a reaction conducted on a thin-layer chromatographic plate,
tropinone was reduced with a NaBH, spray reagent a t 50°C. The
products were then separated by normal plate development ( 1 0 3 ) .Photochemical studies indicate that /?-aminoketones (especially
tropinone) are subject to photochemical reduction, probably yielding a
highly fluorescent p-amino alcohol among the reaction products (1 0 3 a ) .
G. TROPANYLTHERS
Until fairly recently there was no good general method for preparing
tropanyl ethers. In 1968 a report appeared (1 0 4 ) of the conversion of3a-chloro-, 3a-bromo-, and 3a-mesyloxytropanes in to 3a- and 3/?-phenyl,
n-butyl, methyl, and thiophenyl ethers in moderate (21-48y0) yields
with concomitant elimination and fragmentation. More recently, this
same group published four papers (105-105c) that described many more
ethers and showed that (a ) for strong nucleophiles (PhO-, PhS-), S,2
reactions predominated over SN1and gave /?-substituted tropanes; (b)weaker nucleophiles (CN- , N3-) involved both mechanisms; (c) with
compounds containing basic nitrogen (PhCH,NH,, PhCH,CHMeNH,)
the SN1 mechanism predominated, giving a-derivatives; (d) the
character of the displaced group played a role, i.e., PhO- reacted with
the 3a-mesylate with inversion but with the 3a-chloride with retention
of configuration. I n configurational studies it was shown by dipole
moments that a C-3 phenoxyl group in the a-orientation causes con-
siderable distortion of the tropane skeleton.
The mechanism for formation of benzhydryl ethers from /?-di-
alkylaminoalcohols has been postulated ( 1 0 5 4 as involving initial
formation of a quaternary ammonium salt followed by a nucleophillic
attack by oxygen on the tertiary carbon atom and extrusion of the
nitrogen (see I33B). Since such a mechanism would be impossible in the
formation of 3a-tropinyl o-methyl-0’-methoxybenzhydrylther (133C),only a direct attack on oxygen can be considered (105e) .
l33B 133C
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2. TROPANE ALKALOIDS 125
Another approach to ether formation at C-3 featured treating the
anion from 8-benzylnortropane-3a-01 or ,9-01) (134) with m- or p -
fluorobenzotrifluoride (135) in dimethylformamide a t 60-70°C (seeEq. 8). The ethers produced (136) have the same C-3 configuration as
that of the tropanol used. The benzyl group was then cleaved and other
substituents placed on the nitrogen for biological studies ( 106) .
(8)hCH,NApq q c F 3 - p h ~ k i o d
0 - / \-134 135 136
H. MISCELLANEOUS EACTIONS
A study of asymmetric induction involving an optically active
Wittig reagent [(R)-benzylidenemethylphenylpropylphosphorane137)]
included its reaction with tropan-3-one to produce optically active
3-benzylidine-8-methyl-8-azabicyclo[3.2.loctane (138)of unknown con-figuration and optical yield (107) .
CH3N,
HPh\+ - /
C3H,-P-C
CH,/ ‘Ph
137“H
138
Willstgtter et al. (108) obtained an unknown crystalline product by
benzoylation of methyl 3-oxotropane-2-carboxylate139). PMR and IR
spectrometry have shown (109) his product to be methyl 3-benzoyloxy-
trop-2-ene-2-carboxylate140). Attempted hydrogenation of 140 to a
cocaine epimer failed.
CH3N
COOCH,
0
4>---qXOCH3
‘&C-Ph
139 140
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126 ROBERT L. CLARKE
The preparation and characterization of the tropic acid esters of
tropan-3j3-01 and granatan-3a and 3p-01 are described (110).
Earlier efforts to prepare tropane-3j3-aceticacid (141) had given verypoor yields (111). urther studies have developed a satisfactory route
to the corresponding 3a-acetic acid 142 (llZ),ut none of the 3j3 epimer.
141
CH,COOH
142
N-Acetylnortropanone (143) reacted with malononitrile in the presence
of piperidine and acetic acid to form a dicyanomethylene derivative
(144). Catalytic hydrogenation followed by acid hydrolysis led exclu-
sively to the 3a-acid 142 (Eq. 9).
CH,CON
- 42 (9)
*oH* 143 144 ‘\CNCN
Addition of HCN to the dicyanomethylene intermediate 144 gave
trinitrile 145,which hydrolyzed and decarboxylated to form dicarboxylic
acid 146 (Eq. 10). Attempts to esterify this dicarboxylic acid failed.
CHaCON
144- H< +H CH,COOH (10)
CN COOH
145 146
Approaches to the 3j3-acetic acid 141through halomethyl or tosyloxy-
methyl intermediates (147, R = C1 or OTs) failed owing to ready
quaternization forming 148 (Eq. 11).
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2. TROPANE ALKALOIDS 127
R - ( 1 1 )
148147
This problem of intramolecular alliylation in the synthesis of 3/3-
substituted tropanes was avoided by protecting the nitrogen with atosyl group. Tosylated nortropane carboxylic ester 148A was reduced
to tropanemethanol148B which was then sequenced through R’ = OTs,
TsN R N
1 4 8 A 148B , R = Ts, R’ = O H148C, R = H, ’ = C O O H
R’ = CN and R’ = COOEt to 148C, the acid desired earlier. The
tosylate group was removed in the process of nitrile hydrolysis.The /?-configurationof the acetic acid group was demonstrated by
converting the 3/3-acetic ester substituent above to hydroxyethyl, to
chloroethyl (148D), and finally (cyclizing) to tropaquinuclidine 148E
(112a) .
HN
148D 148E
Several dl-tropic acid esters of tropan-3-01s were prepared by a
transesterification procedure. Thus, tropine reacted with the aldehydo-
ester 148F to form tropine ester 1486 (R = CH,). Reduction of the
aldehyde function then gave atropine. The method was applied to
ICHO
IPh-CH-COOCH,
1 4 8 F
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128 ROBERT L. CLARKE
nortropan-3a-01s carrying a broad variety of groups on the nitrogen.
N-isopropylnortropan-3~-01 nderwent the same transformations
(112b) .Tropane-3,6-diol esters were used to demonstrate the selective
hydrolysis of dihydrocinnamate esters (DHC)by a-chymotrypsin. The
mixed ester 149 was hydrolyzed only a t position 3 by a-chymotrypsin,
ODHC
149
Y--chymotrypsin
J
O H
150
ODHC
151
forming 150. Carefully controlled basic hydrolysis gave selective
cleavage a t position 6 with formation of 151 (113) .
Solvolysis of unsaturated tosylate 151A in 70ojb aqueous dioxane
occurred 2.1 x lo5 faster than did solvolysis of its saturated analog
151B. The reaction involving the saturated tosylate 151B produced only
O T s
l 5 l A
C H z \ O T a
151B
a trace of the parent alcohol together with 37% of 3-methylenetropane,
20y0 of 3-methyltrop-2-ene, 9% of 3,8-methyltropan-3a-01,and 10% of3a-rnethyltropan-3/3-01.Synthesis of the required tosylates was accom-
plished via hydroboration of appropriate 3-methylene intermediates
(113~).
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2. TROPANE ALKALOIDS 129
Grignard reactions on tropinone have not been very satisfactory,
presumably owing to formation of insoluble complexes with the amine
moiety prior t o reaction. Conversion of tropinone to urethane 152 bymeans of ethyl chloroformate gave a neutral ketone th at reacted with
aliphatic Grignard reagents to form 153 n moderate yields (R = benzyl,
0 0
II IIE t O C N
h52 E t o a R53 OH
5 0 % ; R = methyl, 32%; R = ethyl, 33%; R = propyl, 23%). Although
the urethane moiety was claimed not t o be attacked, some 4070of the
reactants were not accounted for in the highest yield reported. The
single isomers isolated were presumed to have axially oriented hydroxyl
groups; with 153 (R = benzyl), the orientation was proved ( 1 1 4 ) .
A spiro tropane (154) was prepared by the following sequence of
reactions (Eq. 12) ( 115) .The authors were not aware of the Heusner
CH,NH2 CH2-NH
I54
work on HCN addition to tropinone ( 8 7 )and agree (private correspon-
dence) th at the configurations shown here a t C-3 are correct. In a
second phase of this work, butyronitrile was condensed with tropinone.
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130 ROBERT L. CLARKE
CHsN CH3N CH3N
& h + , A l H A + , H O HH,CH&HCONHp ~ ~ / o \ c N opHs-CH H
CH&H&HCN
155 156 157
The resulting cyanoalcohol (155) was hydrolyzed (156) and converted
to oxazolidone 157. On the basis of present information, the con-
figuration at C-3 in this series remains unproved.
e PH3CH3N
~ 1 1 ~~ H . - Q - ; ~ N H ~__tNso3-
0
158
Tropinone reacts with O-(mesitylenesu1fonyl)hydroxylamine inCH,CI, to form (80y0)a hydrazinium mesitylenesulfonate (158).
N-Amination appears to proceed faster than oxime formation. The
configuration about the nitrogen was not determined (116) .Pyrolysis of the hydrochloride of ethyl 3a-phenyltropane-3j3-
carboxylate (159) caused ring cleavage and chlorine insertion with
formation of pyrrolidone 160 (117).
.HC1
COOCaH,
4159 160
The racemization of hyoscyamine has been studied in refluxing
methanol, isobutyl alcohol, toluene, and dioxane ( 1 1 8 ) .Racemizationin water was studied earlier (119).
In some microchemical investigations of medicinal plants (1 2 0 ) ,scopolamine was hydrolyzed in microgram amounts with Ba(OH), at
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2 . TROPANE ALKALOIDS 131
25°C n I hour to give scopine. At 100°C the main product was scopo-
line. Atropine and homatropine were similarly hydrolyzed at 25°C
while apoatropine remained unchanged.Some enamines (161and 162) of tropinone were prepared by treating
this ketone with cyclic secondary amines such as piperidine and
morpholine in the presence of an organic solvent, p-toluenesulfonic acid,
and a water-absorbing agent such as zeolite (121) .
CH,N CH3N
161 162
A tropanyl Grignard reagent was prepared (122) by heating 3a-
chlorotropane with magnesium turnings in refluxing THF for 24 hours
(the p-isomer failed to react with magnesium under similar conditions).
This reagent reacted with 2-(trifluoromethyl)thioxanthen-9-oneo form
2-trifluoromethyl-9-(3-tropanyl)thioxanthen-9-01163). This alcohol
was dehydrated and then reduced to form the 9-tropanyl derivative 164.
HO R CFS qR CF,
164163 R =
In accord with earlier work on tropinone (98a) ,photooxidation oftropan-3a-01, tropan-38-01, and deoxyscopoline (165) produced N -
demethylated and N-formylated products. Scopoline (166), however,
formed tetrahydrooxazine (167)along with the N-formylated derivative.
165 166 167
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2. TROPANE ALKALOIDS 133
0 0
I1 II
NH3 \IH NKO’29 0
I70C 170D,R = CH,
170E,R = COCH,170F,R = C H O
Hydroboration of tropidine (171) ith oxidative work-up gave a 68%
yield of tropanols with a ratio of 43: 3:50:3 2a: 2/3: 3a: 3p. Principal
attack of the double bond from the a-face presumably resulted from
blockage of the p-face by an amine-borane complex. With a phenyl group
on carbon-3, only a-01s were isolated, 3/3-phenyltropan-2a-01(172)eing
171
L Z d
172
produced in threefold greater amount than the 3a-01. Substituents on the
aromatic ring modified this ratio ( 125) .
Oxidation of the 2a-01 (172) o 3p-phenyltropan-%one could not be
accomplished with the usual oxidizing agents, so it was treated with
ethyl chloroformate, and the resulting urethane was oxidized with Jones’
reagent to produce 173.Reduction of 173 with LAH then gave 3/3-
E t O C O N
4Jkb73 2qQ74
phenyltropan-2p-o1(174), hich was wanted for biological testing ( 126) .Some 2a-01 was also formed in this reduction.
Variation of the substituent on the nitrogen of norscopolamine and
noraposcopolamine has been accomplished through reaction of these
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2. TROPANE ALKALOIDS 135
transferred to form deuterated benzaldehyde, two molecules of which
then attack a single tropinone. The structure of the deuterated product
was confkmed by NMR and mass spectroscopy.Tropinone reacted with the lithium salt of o-lithium-benzoic acid
(178A) t -78°C o form a spiro tropane (178B)n 58 yield. Reduction
II0
178A 178B
of this lactone (178B) ith LAH-BF, afforded spiro ether 178C n 81%
yield. Reaction of tropinone with o-lithium-phenol gave the phenolic
alcohol 178D n 20% yield ( 1 3 1 ~ ) .
178C 178D
The radiation yield from the 6oCo irradiation of dilute aqueous
atropine sulfate and scopolamine hydrobromide was independent of
alkaloid concentration but decreased with increasing radiation dose.
The biological activity of irradiated solutions correlated with radiolytic
decomposition. Atropine yielded tropine and tropic acid, indicating
radiation-induced ester cleavage (1 2).
Cocaines labeled with deuterium on the aromatic ring a t position 4
and (separately) a t positions 3 and 5 (179) ere prepared by reductivedehalogenation (NaBD,-PdC1,) of the corresponding chlorobenzoates.
Hydrolysis of the methyl ester functions then provided the correspond-
ingly labeled benzoylecgonines (180) 1 3 3 ) .
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136 ROBERT L. CLARKE
D
D
V. Biosynthesis
A. TROPANEOIETY
Substantial evidence has accumulated to support Scheme 2 as the
route for bioconversion of ornithine to hyoscyamine. A detailed review
of this evidence appeared in “The Alkaloids” (London) in 1971 ( 134) .Only a few key experiments will be reported here. Incorporation of
[Z-14C, 6-15N]ornithine 181),[1,4-14C,]putrescine, and [4-3H]N-methyl-
putrescine (182) nto hyoscyamine has been observed. Evidence indicated
that these precursors were confined almost entirely to the pyrrolidine
ring ( 1 3 5 ) .
N-Methylputrescine ( 1 8 2 ) was a much better precursor for hyoscya-mine in Scopolia lurida Dun. than either putrescine or ornithine ( 135) .Whereas 6-N[3H]-methylornithine served as a good precursor for
hyoscyamine with a major portion of the radioactivity confined to the
N-methyl group, ~t-N-[~H]-methylornithinehowed only minute non-
specific incorporation ( 1 3 6 ) . When this experiment was done with
6-N-[14C]-methyl-[2-14C]-ornithine,egradation experiments indicated
that all of the activity was located in the tropine base a t the bridgehead
carbon C-1 [having the (R)-configuration]and on the N-methyl group
(137‘).dZ-N-[14C]Methyl[2’-14C]hygrine as incorporated into hyoscyamine
by D . stramonium L. ( 1 3 8 ) .
A slightly different sequence has been proposed wherein ornithine is
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2. TROPANE ALKALOIDS 137
181 Ornithine 182
ICHB
ICH,
0 183 Hygrine
Tropinone
SCHEME
said to be converted to aminobutyraldehyde, which then gives y -(N-methylamino)-butyraldehyde (139).A further different sequence
postulates that hygrine-a-carboxylic acid is the key intermediate in
tropane synthesis. Radioactive hygrine showed a lower incorporation into
tropane alkaloids than did [2-14C]-ornithine.The same study showed
that [1-l4C]-acetate gave rise to labeling of the carboxyl group of
ecgonine (140 ) .
Another proposal for tropine biosynthesis is an outgrowth of studies
with tissue cultures. A cell suspension culture of Datura ferrox L.,when
supplied with dl-[2-l4C]ornithine, yielded radioactive a-keto-Bamino-valeric acid (184), among other products. However, none of the tropane
alkaloids produced was radioactive. It was proposed that this in vitro
cell culture lacks the enzyme that catalyzed the reaction between
A1-pyrroline-2-carboxyliccid (185) and acetoacetylcoenzyme A. This
condensation product can ultimately yield hygrine and then tropine, as
illustrated in Scheme 3 (141 ) .
Finally, there is the observation that [1,4-14C,]succinic acid is incor-
porated in Datura species, the molecule becoming carbons 1, 5 , 6, and 7
of the tropane structure. [1 3-14C,]acetone and [14C]methylaminewerealso utilized ( 1 4 2 ) .
An enzyme (atropinase) is believed to play an important role in the
biosynthesis of tropane alkaloids (142a).
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138 ROBERT L. CLARKE
0
ItCOOH C S - C O AOOH
0
COOH CS-COAI I
184 185
tropinone
- L O -ck-oHygrine
SCHEME
B. CARBOXYLICCIDMOIETY
A critical review of the biosynthesis of tropic acid appeared in Biosyn-thesis ( 1 4 3 ) in 1973. Feeding experiments using variously labeled
phenylalanine have shown that all of its carbon atoms are incorporated
into tropic acid but that the carboxyl group migrates fiom C-2 to C-3 in
the process (Eq. 13) (143 ) .The intramolecular character of thisrearrange-
ment was demonstrated by feeding phenylalanine containing 13C a t
Phenylalanine Tropic acid
positions 1 and 3 to Dutura innoxiu. Movement of the two labeled
carbons to contiguous locations resulted in the appearance of satellite
peaks (NMR) due to spin-spin coupling, symmetrically located about
the corresponding singlet peaks. If the rearrangement had been inter-
molecular, endogenous unlabeled phenylalanine would have diluted this
effect beyond visibility ( 1 4 4 ) .
Although it had been shown earlier that cinnamic acid, a metabolite ofphenylalanine, failed to serve as a precursor of tropic acid ( l 4 5 ) , here was
the possibility that rearrangement might occur after esterification of
tropine with an acid derived from phenylalanine. Therefore, [2-14C]-
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2. TROPANE ALKALOIDS 139
cinnamoyl N[14C]methyltropine was fed to D . stramonium. Although
activity was found in both hyoscyamine and scopolamine, all of i t was
located in the N-methyl groups, indicating that hydrolysis of the esterhad occurred with no use of the cinnamic acid in biosynthesis of tropic
acid (1 4 6 ) .Similarly, [2-14C]cinnamicacid was not incorporated into the
alkaloids of D . innoxia plants when fed via the roots. I n this same study,
(dZ)-[2-14C]phenyllactic cid served as a better precursor than [2-14C]-
phenylalanine for tropic acid in hyoscine and hyoscyamine and for
atropic acid in apohyoscine. Phenylalanine served as an effective
precursor for the phenyllactic acid moiety of littorine ( 1 4 6 ~ ) .I n contrast with the above observations, a feeding of [2-14C]cinnamic
acid to D. innoxia through the stem via the wick method has recentlyshown specific incorporation into the tropic acid moiety of atropine. The
tropic acid was labeled at C-3. This 0.0S70 incorporation of [2-14C]-
cinnamic acid into atropine compares favorably with that reported by
others for the incorporation of radioactive phenylalanine into this
alkaloid (147 ) .
Biosynthetic studies of hyoscyamine in callus tissue and intact plants
of A . belladonna showed that addition of phenylpyruvate produced a
significant increase in alkaloid production. Phenylalanine had little
effect and cinnamic acid inhibited both growth and alkaloid production.
I n a tagged precursor study using leaf discs, tyrosine showed less
incorporation than did phenylalanine ( 1 4 7 ~ ) .Whereas considerable attention has been given to the formation of
tropic acid from phenylalanine, little attention has been devoted to its
biosynthesis from phenylacetic acid (148) and from tryptophan (149)
following these early studies. A criticism leveled at the proposed route
from tryptophan (149) (see Scheme 4) was that the [3-14C]tryptophan
I I1R--CH,-CH-COOH ---- - E H ~ - - C - C O O H + - ~ H ~ C O O H-+ REHO
NHz 0
R = (J--3-"C] Tryptophan
H
COOH - COOH
Tropic acid
SCHEME
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140 ROBERT L. CLARKE
used for the study did not show that tryptophan was able to furnish the
entire carbon skeleton of tropic acid. Recently (154 , [benzene ring
U-14C]tryptophan and [2-ind01yl-~~C]tryptophanere converted totropic acid by D . innoxia roots. The bulk (My0)of the benzene labeling
appeared in the phenyl ring of the tropic acid and 61% of the 2-indolyl-
14C label appeared at C-3 in the tropic acid, thus substantiating the
earlier hypothesis (149). 1-14C]Phenylalanine, -14C]phenylaceticacid,
[3J4C]serine, and [14C]formicacid were also utilized.
Dually labeled littorine, 3a-([l-14C]-2-hydroxy-3-phenylpropionyl-
0xy)[3-~H]tropane,was fed to D . stramonium which then yielded
radioactive hyoscyamine. Both the tropine and the phenyllactic acid
halves of the molecule were incorporated into the hyoscyamine moiety,but the ratio of labeled atoms was so drastically changed that there
was indication that the ester was hydrolyzed to tropine and phenyl-
lactic acid, the latter undergoing rearrangement to tropic acid before
being reesterified by tropine (146).
The origin of the phenyllactic acid moiety of littorine in D . sanguinea
is phenylalanine. A specific incorporation of [1J4C]- and [3-14C]phenyl-
alanine was observed into carbons 1and 3, respectively, of the side chain
of the phenyllactic acid portion of littorine. The fact th at phenylalanine
appears to be a better precursor for littorine than for hyoscyamine andscopolamine suggests that phenylalanine is more readily converted to
phenyllactic acid than to tropic acid (151).
Whereas tropic acid and 3-phenyllactic acid are formed from phenyl-
alanine, the tiglic acid of tigloidine and related esters and the 2-methyl-
butanoic acid of 6/3-(2-methylbutanoyloxy)tropan-3cr-olhave their
origin in (8)-isoleucine. (8)-Isoleucine was first shown to be a precursor
for the tigloyl moiety of tropine tiglate (186), tropane-3a,6/3-diol
ditiglate (187), meteloidine (188), and tropane-3a,6/3,7/3-triol 3,6-
ditiglate (189) in D . innoxia and in D . meteloides D. C. ex Dunal in 1966
(152). The next year these findings were substantiated when the
0
-0-c HII
\ /
Tig = ,c=c \
CH3 CHa
Tig
186
187
188
189
R' = H, Ra = H
R' = Tig, R1 = H
R' = OH, Ra = OH
R1 = Tig, Ra = OH
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2 . TROPANE ALKALOIDS 141
radioactivity of [2-14C](S -isoleucine was specifically incorporated into
the ester carbonyl of meteloidine (188)in D. meteloides ( 1 5 3 ) .The tiglic
acid moiety of tigloidine (pseudotropine tiglate) and tropine tiglatefrom Physalis peruviana L. is also derived from (S -isoleucine (154) .
The intermediacy of 2-methylbutanoic acid in this conversion was
indicated when d l - [ -14C]-2-methylbutanoicacid was fed t o D . innoxiaand the root alkaloids tropane-3a,6/3-diol ditiglate (187) and tropane
3a76/3,7/3-triol ,6-ditiglate (189) were isolated. In each case, the radio-
activity was located in the ester carbonyl group (155) .The same sort of
incorporation was observed when dl-[l-14C]2-methylbutanoic cid was
fed to D . meteloides, radioactive meteloidine being isolated. It was
predicted that i t is the (S)-2-methylbutanoic acid which is the actualprecursor of the tiglic acid since it is the ( S ) orm of isoleucine that
starts the sequence (1 5 6 ) .The tiglic acid observed in these alkaloids apparently is formed by a
direct dehydrogenation of 2-methylbutanoic acid, although nothing is
known of the stereochemistry of elimination. In order to discount the
possibility that the dehydrogenation first gave angelic acid which then
isomerized, [l-14C]angelicacid was fed to D. innolcia plants. There was
no incorporation, thus clearly indicating that angelic acid is not a
precursor to tiglic acid. Tiglic acid was incorporated under these same
conditions (1 5 7 ) .2-Methylbutanoic acid, which was an intermediate in the conversions
j u s t described, appears as an end product in tropane-3a76/3-&o1 -(2-
methylbutanoate) from D. ceratocaula. The origin of this acid was
demonstrated by feeding [U-l*C](S -isoleucine(22).
Leucine and valine appear able to act as precursors of the isovaleryl
and senecioyl moieties of the tropane alkaloids, although such a
conversion may not occur in a normal plant. Radioactivity from
[U-14C](S)-leucine nd [U-l*C](S)-valinewas incorporated into the acid
portions of tropine senecioate and isovalerate, tropane-3,6-diol diseneci-
oate, and diisovalerate, and into tropane-3,6,7-triol 3-senecioate,
3-isovalerate, 3,6-disenecioate, and 3,6-diisovalerate. The species fed
were D. sanguinea and D . stramonium (158) .
C. TRANSFORMATIONS
The principal pathways for the biotransformation of cocaine in menand in animals are N-demethylation and deesterification. Monkeys
injected intraperitoneally with cocaine were shown to develop identifi-
able levels of norcocaine in brain tissue (extraction, gas chromatography
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142 ROBERT L.CLARKE
and mass spectrum). This metabolite is about as active as cocaine in
inhibiting 3H-norepinephrine uptake by synaptosomes prepared from
rat brain (159) .It has been observed that ditiglate esters of tropane-3a,6f15-diolnd
tropane-3a,6fl,7/3-triol xist in the roots of Datura species, bu t th at only
monotiglate esters are found in the leaves. The isolation of some
ditiglate esters in transpiration streams led t o the hypothesis that such
diesters are metabolized to monoesters in the leaves. The idea was
substantiated when tropane-3a,6/3-diol ditiglate was fed to D . innoxiaand D. cornigera Hook. leaves where it underwent hydrolysis to yield
the 3-tiglate, the 6-tiglate, and tropane-3a,6/3-diol (160) .
A subsequent substantiation of the process was effected usingsolanaceous species that normally do not contain tiglate esters. Experi-
ments with tropane-%a,6/3-diol itiglate in Atropa belladonna L. and
Lywpersicum esculentum (L.) Mill. and with tropane-3a,6/3-dioldisene-
cioate in L. esculentum and Datura ferox indicated their conversion to
monoesters (161) .[3/3-3H,N-14C-methyl]tropinewas fed to D . meteloides, giving rise to
radioactive meteloidine, scopolamine, hyoscyamine, and tropane-
30,6/3,7/3-triol 3,6-ditiglate. These products had essentially the same
3Hj'4C ratio as in the administered tropine. Degradation of the metel-
oidine established that all of its 3H was located at C-3 and all of the 14Cwas on the N-methyl group, indicating that tropine is a direct precursor
of teloidine (162) . Feeding of [N-14C-methyl-6,8,7/3-3H,ltropineo D .
inmoxia and D. meteloides produced hyoscyamine with a 3H/14Cratio
essentially t h e same as that of the administered tropine. However, the
meteloidine and scopolamine formed retained only small amounts of
tritium. Thus, the dihydroxylation of the tropine moiety proceeds with
retention of configuration. If previous work on the biosynthesis of
scopolamine is accepted, the present results indicate that a cis-dehydra-
t i on is involved in the formation of 6,7-dehydrohyoscyamine from
6bhydroxyhyoscyamine(16%).A mutual interconversion between scopolamine and hyoscyamine has
been ascertained during incubation of shoots and roots of D . innoxia.
When [N-14C-methyl]scopolamine as added, radioactive hyoscyamine
could be isolated. When [N-14C-methyl]hyoscyamine as added,
labeled scopolamine was formed. 6-Hydroxyhyoscyamine was an
iutermediary (163).
In studies concerning the biosynthesis of tropane-$a,6/3-diol, ropane-
3a,6/3,7jS-triol, and their tigIate esters it has been shown by feeding
experiments with [14CO][N-14Me]3a-tigloyloxytropane nd [ l4C0][P4Me]valtropine that neither precursor is incorporated intact togipe diesters. Extensive reversible hydrolysis occurs ( 1 6 3 ~ ) .
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2. TROPANE ALKALOIDS 143
A different approach to this problem involved the determination of
whether the entering tigloyl groups labeled equally the 3a and 6p
positions in ditigloyl esters. Two different mechanisms appeared to beinvolved when [1-14C]tiglicacid was fed toD. eteloides. 3a,6p-Ditigloyl-
oxytropane contained roughly equal radioactivity a t positions 3 and 6.
This suggested hydroxylation of tropine followed by simultaneous
esterification. In contrast, 3a,6/3-ditigloyloxytropan-7~-01ad only 9%
of the label a t position 3.It may well have been formed by hydroxylation
of 3a-tigloyloxytropane (163b) .A third study by the same group resorted to feeding [N-14Me]tropine,
a known precursor that does not lose its label, alongside postulated
intermediates in each of the biosynthetic schemes to act as competitiveinhibitors. The results favored two separate routes for the biosynthesis
of the tigloyl esters of tropane-3a,6/3-diol and tropane-3a,6p,7/3-triol
(1 3c):
a) ither
or more probably,tropine+ ropane-3a,6fi-diol 3a,6fi-ditigloyloxytropane
tropine+ a-tigloyloxytropane+ fi-hydroxy-3a-tigloxytropane.+
3a,6fi-ditigloyloxytropane
(b)tropine+ 3a-tigloyloxytropane -f 7fi-hydroxy-3a-tigloyloxytropane
6fi,7fi-dihydroxy3a-ditigloyloxytropane-f 3a,6fi-ditigloyloxytropane-7~-ol
An independent study of this same question involved feeding a 1 :1
mixture of 3a[l-14C]tigloyloxytropane nd 3a-tigloylo~y[3/3-~H]tropane
to D . innoxia. The 7/3-hydroxy-3a,6/3-ditigloyloxytropaneo formed
contained the same 3H/14C atio as that fed. From this result it seems
probable that hydroxylation at C-6 and C-7 occurs on the preformed
%a-tigloyl ster ( 1 6 3 d ) .
In another study of hyoscyamine and scopolamine, the latter was
infiltrated into shoots of intact Solandra gra nd if lra Sw. In addition to
the normal alkaloidsto be found there, dl-scopolamine, aposcopolamine,
dl-norscopolamine, and oscine were isolated. It was inferred that the
new metabolites arose from scopolamine and that racemization of the
optically active bases is in keeping with the normal occurrence of
atropine and noratropine in the plant. In another experiment [GJ4C]-
hyoscyamine and unlabeled hyoscyamine were infiltered into alkaloid-
free scions of s. grandi f l ra grafted onto tomato stocks. Atropine,
noratropine, and tropine were isolated ( 164) .[2-14C]Acetate, [3H]atropine, and [N-14C-methyl]tigloidine were
applied to seedlings and cut off young stem ends of D. innoxia and the
disposition points were determined by autoradiograms. The tigloidine
was not transformed into scopolamine in 3 days. However, within 1 day
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144 ROBERT L. CLARKE
radioactivity appeared in 6-hydroxyhyoscyamine and tropane-3a,6/lB,7/l-
trio1 3,6-ditiglate. On the second day i t was detected in meteloidine (165).
Two other metabolic studies in animals have been reported. Themetabolism in rats of methylscopolammonium methylsulfate, a
quaternary developed as an anticholinergic agent, was investigated.
The major pathway apparently involved introduction of a hydroxy or
methoxy group in the para position of the benzene ring. There was also
indication of glucuronide formation (166). njection of [N-14C-methyl]-
scopolammonium methylsulfate and two related salts into rats (intra-
venously) resulted in localization of the radioactivity in the lysosomes
of the light mitochondria1 fraction of the liver (167).
D. TISSUECULTURESTUDIES
It was hoped tha t tissue cultures of alkaloid-producing plants would
be an ideal system for studying biosynthetic routes since these systems
could be so well controlled. Unfortunately, these systems produce
much poorer yields of alkaloids than the intact plants and work of this
type has proved disappointing.
Cell cultures of Datura innoxia have developed shoots that in a
different medium have developed into complete plants. During root
differentiation and plant development, scopolamine synthesis begins
and there is progressive increase in alkaloid content. The majority of
plants develop a normal pattern of alkaloid content (168).
The alkaloid spectrum of tissue cultures of D. metel, D. stra-
monium var. stramonium, and D. stramonium var. tatula was
found to differ considerably from that of intact plants. Neither
hyoscyamine nor scopolamine was detected in these tissue cultures.
Hyoscyamine, added to the cultures, was steadily consumed over a
14-day period but no scopolamine developed, a transformation that
occurs in intact plants (169). n contrast to the results of that study,
calius tissue cultures of D . myoporoides leaves contained at least five
alkaloids which corresponded by tlc to those found in leaves and roots
of intact plants. The main alkaloids identified were scopolamine,
valtropine and atropine ( 1 6 9 ~ ) .allus cultures from leaves of anther
regenerates of D. f e r ox , D. inermis, D . meteloides and D. tatula were
analyzed for their ability to produce tropane alkaloids and t o excrete
these into the culture fluid (169b).Optimum release of alkaloids into the
broth of cultures of D. innoxia and S. stramonijolia occurred a t 25 and
15 atmospheres of sucrose osmotic pressure (169~) . yoscyamine
production by anther cell suspensions of D. metel was highest when the
Murashige-Skoog medium was used (169d).
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2. TROPANE ALKALOIDS 145
In excised root cultures of D. innoxia, the addition of tritium-
labeled atropine did not affect the normal synthesis of atropine and
scopolamine. Part of the exogenous atropine was converted to scopola-mine. The relation between unchanged and converted substrate
indicated a regulation of the enzyme required for this conversion (170) .Formation of tropoyl esters in cultures of D . innoxia stem callus was
stimulated by dl-tropic acid, phenylpyruvate, or tropine but was little
affected by (S -phenylalanine or (8-ornithine. Acetyltropine was
formed in large quantity by cultured cells when tropine was supplied to
cultures of D . innoxia and D . tatula L. (171) .Another study also observed
evidence for the presence of enzymes for tropine acetylation in Datura
cultures (172) .A . belladonna, S. lurida,and H . niger cultures did notesterify tropine ( 1 7 3 ~ ) .
A three- to sixfold increase in atropine production resulted from
addition of (,Y)-phenylalanine or (S -tyrosine to tissue cultures of
D. metel (173) . Addition of dl-[l-14C]tyrosine to this same kind of
culture yielded radioactive atropine (174) .The shapes of cells in tissue cultures of D. i nnoz ia depended on
growth conditions, while their size depended upon origin. Biomass
formation was faster in calluses from leaves and petioles than in those
from stem, root, or seed. Amino acids, such as ornithine, phenylalanine,serine, aspartic acid, methionine, and glycine, caused an increase in
alkaloid synthesis by the medium (175) . In contrast, another report
states that addition of (S -ornithine, (#)-proline, or (S)-hydroxyproline
caused no appreciable synthesis of tropane derivatives in D . metel stem
and root cultures and in D . stramonium var. tatula root cultures. These
cultures do not produce tropane alkaloids without addition of some sort
of precursor, however. Addition of tropine caused production of a large
quantity of hyoscyamine ( 1 6 ) .In order to maximize the alkaloid formation in tissue cultures of
D . innoxia seeds and Scopolia stramonifolia roots, a two-factor dispersion
analysis was applied. Studied were the method of sterilization of the
medium, the number of transplantations, the revolution speed of the
cultures, and the volume of the nutrient medium (177) . In tissue
cultures of callus cells of S. stramonifolia, the total alkaloid content was
highest after 3-month cultivation (0.1157J. Additives such as trypto-
phan and ATP caused higher proportions of scopolamine and hyo-
scyamine to form ( 1 7 7 ~ ) .Suspension and static cultures of tissues of D . innoxia and S. stramoni-
fo l ia exhibited similar annual rhythms, manifested in uneven growth
and production of alkaloids. Greatest productivity of alkaloids occurred
in spring; least occurred in winter. There appeared to be a reciprocal
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146 ROBERT L. CLARKE
relationship between growth and alkaloid formation. Diurnal rhythms
were expressed in the mitotic activity and annual rhythms in the
metabolism of nitrogen, principally in proteins and amino acids (1?7b).A relationship has been demonstrated between protein synthesis and
alkaloid synthesis in root cultures of D . stramonium var. tatula (178).Studies in several nutrient media were conducted on root explants of
D . stramoniurn var. tatula, D . stramonium var. stramonium, D . stra-monium var. chalybea, D. nnoxia and D . ferox. D . stramonium var.
stramonium grew best in Torrey’s medium without vitamins. Production
of atropine and scopolamine was confirmed by chromatography (178a).The possibility of replacing the production of hyoscyamine and
scopolamine from Scopolia himalaiensis root callus tissues on agaror from whole plants by production from liquid suspension cultures
was explored. The process has the advantage of ease of nutrient
addition and simplified product isolation. The results were promising
(179) .Aeration of a suspension culture of D . innoxia stimulated tissue
growth and alkaloid productivity. While the content of alkaloids in
callus tissue increased under these conditions of intensified oxygen
supply, excretion into the medium decreased (179a).In tissue cultures
of Scopolia species leaves the presence of tropane alkaloid precur-
sors is said to lower the total yield of alkaloids (180) . The effect ofsome aminoacid precursors on the growth and alkaloid-production of
callus tissue cultures of severalScopolia species was studied. Tryptophan,
phenylalanine, glutamic acid, proline, ATP, and various combinations
of these were added. Tryptophan, followed by glutamic acid and ATP,
showed strong induction of hyoscyamine and scopolamine formation
(181). Addition of atropine sulfate to D. innoxia cultures stimulated
growth and biosynthesis of hyoscyamine and scopolamine (181a).
E. MISCELLANEOUSIOSYNTHESES
Exposure of D . stramonium plants to l4CO; resulted in incorporation
of radioactivity into all the alkaloids present. The ratio of radioactivity
of hyoscyamine to that of scopolamine was much higher in the roots
than in the foliage. This activity was present in both the acidic and
basic moieties of these alkaloids (182) .Atropa belladonna that had been grown to maturity in aqueous
nutrient solution died within a week when transplanted into 1 0 0 ~ oD,O. Plants lived only about three weeks in 7 5 7 , D,O but survived in
50 and 60% D,O. Alkaloid production was drastically reduced in these
survivors (183) .
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2. TROPANE ALKALOIDS 147
Autoradiographic studies of histological structures of various
freeze-dried animal organs permitted the location of atropine and its
metabolites in the animal. Atropine and atropine 9’-glucuronide were
found in largest amounts followed by 4’-hydroxyatropine and itsglucuronide. Tropine and tropic acid were found in small amount. There
was a direct relationship between these concentrations and the pharma-
cological activity (1 4).
M. Biologid Activity
Only a selected few biological activities will be reported here, those
being of unusual degree or involving tropanes with other than stereo-
typical structures. The vast literature on biological properties of cocaine
and the various tropan-3-01 esters will be omitted.
One of the first properties observed about cocaine was its ability t o
produce numbness of the tongue. When Willstltter prepared a position
isomer of cocaine in 1896 called a-cocaine (190), he observed bhat it
produced no local anesthetic action on the tongue ( 8 6 ) .I n 1955 it was
demonstrated that a-cocaine was actually one-third to one-eighth as
strong a local anesthetic as cocaine in an intradermal infusion test (185) .
J q 0 l P hOOCHB Jk$COPhOOCH,
190 191
Two years later it was proved that the isomer prepared by Willstltter
had the carbomethoxy group in the endo configuration as drawn (190)
Recently (1975) , ?-cocaine(191) was prepared (see Section IV, D).
It proved also to have no local anesthetic action on the tongue but was
one-third as active as cocaine in the intradermal wheal test (88).Thus,
the two isomers have similar local anesthetic activities. , ?-Cocainedoes
not have the stimulative action shown by cocaine ( 186) .a-Cocaine has
not been studied in this respect.Several further modifications of cocaine have been studied pharma-
cologically. The preparation of these compounds is described in Section
IV, D. A L‘reverse ster” of cocaine (192) was found to be devoid of
(87).
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148 ROBERT L. CLARKE
stimulative action (83).However, some benzaldehyde acetal derivatives
(193) of the intermediate diol used in the preparation of this “reverse
ester” proved to be stimulants ( 8 4 ) .Those isomers in the group which
0
CH,N
i\ O---CCHBCH,N
I\ H
192 193
had the aromatic ring in the a configuration showed activity in thereserpine-induced eyelid ptosis test. Included in this same study were
the benzaldehyde acetals of ecgoninol and pseudoecgoninol (194), only
the former of which was active. The latter was the most lethal of all the
compounds tested.
dl-3/?-Phenyltropan-2/?-01195) has about the same activity as does
cocaine in the reserpine-induced ptosis test but is more active as a
locomotor stimulant. The activity appears to reside in only the 1-
enantiomer. Curiously, the racemate appears to be more active than the
active enantiomer alone. The ethylene bridge of the tropane system isrequired for activity. Acetylation of 195 produces a decreasein activity
(1 2 6 ) .
In contrast to the above observations, i t is the acetate of the 2a-01
(196) that is a strong stimulant. The alcohol produces questionable
depression (1 2 6 ) .
195 196
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2. TROPANE ALKALOIDS 149
The most dramatic change in the cocaine activity profile resulted
from elimination of the elements of CO, from cocaine, i.e., attachment
of the benzene ring directly to carbon-3. The compound of structure197 (R = p-F) is about 65 times as active as cocaine as a locomotor
197
CH3?,
198
COOCH,&199
stimulant, about 20 times more active in inhibition of tritiated nor-
epinephrine (NE-3H)uptake in mouse heart, 25 times more active ininhibition of NE-3Huptake in r at brain, 5 times as active in preventing
reserpine-induced eyelid ptosis and 20 times more active in reversing
this ptosis, one-tenth as strong a local anesthetic, and about one-fourth
as toxic as cocaine intravenously. The oral therapeutic ratio as a
locomotor stimulant is about 300 ( 8 5 ) .
This compound (subcutaneously) was able to cause a 5970 inhibition
of NE-3H uptake in rat brain at a 5.3 mg/kg dose as compared to a
6-87, inhibition (subcutaneously)by desmethylimipramine a t 20 and 40
mg/kg. The latter compound, one of the most active NE-3H uptakeinhibitors known, apparently is not very effective in penetrating the
blood-brain barrier ( 187) .
The sensitivity of 197 (R = p - F ) o structural change is demonstrated
by the fact that removal of the ethylene bridge (198) or epimerization
a t carbon-2 (199) destroys the central nervous system stimulation. It is
the levorotatory enantiomer (with the cocaine absolute configuration)
that is active. The dextro enantiomer actually produces a slight
depression ( 8 5 ) .
One of the metabolites of cocaine is norcocaine. It has been found tobe about as active as cocaine in inhibiting uptake of NE-3Hby synap-
tosomes prepared from rat brain. Other metabolites were found to be
relatively inactive (159).
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150 ROBERT L. CLARKE
Central nervous system stimulant activity has been reported for
another type of tropane ester, namely ethyl A3*a-tropeneacetate200),
prepared by a Wittig reaction on tropinone (188).A somewhat similarstimulant (201)was prepared from tropinone via treatment with a
reagent prepared from P$P, t-BuOK, and trichloromethane ( 1 8 9 ) .
200 201
The fact that a synthetic homolog of batrachotoxin containing a
2,4,5-trimethylpyrrole-3-carboxylate as twice as active as batra-
chotoxin prompted the esterification of some hydroxylated alkaloids
with this acid. Scopoline 2,4,5-trimethylpyrrole-3-carboxylate202)
was 20y0more active than codeine as an analgesic in the hot plate assay.
202
It had no effect on release of tritiated norepinephrine from heart tissue
Earlier, the troprtneanalog(203)f meperidine (204)was found to haveabout the same activity as meperidine as a narcotic analgesic (1 9 1 ) .Recently, the epimeric form (205) of this tropane analog was prepared
(190).
kO O E t cH3N% C O O E t
C H 3 N
A k hO O E t
203 204 205
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2. TROPANE ALKALOIDS 151
(45) and found to be about one-third to one-fourth as active as the
earlier epimer. The difference in activity is not great and could be due
to differences in rate of passage into the brain. It suggests that theanalgesic activity in meperidine-like compounds is not very sensitive
to the conformation of the phenyl group. These results tend to support
the findings of other workers with regard to phenyl group configuration
(192, 193). Since 203, 204, and 205 all have equal local anesthetic
activity, the study also shows that there is little conformational
requirement for local anesthetic activity.
Of nine tropane esters studied only tigloidine (206) and 3/?-senecioyl-
oxytropane (207) significantly reduced the hypothermia induced by
tremorine. None of the esters reduced the tremors caused by this agent.Only dZ-3,6-bis(2-methylbutyryloxy)tropane educed the salivation.
Tigloidine has been shown to be beneficial in the treatment of parkin-
sonism like atropine, but without many of the undesirable side effects
of the latter drug. The antihypothermic effects of ester 207 suggest
No-C / H
\206 R = \C-c
C H / C H 3
No-c\ /CH3
H/ CH,\
207 R = c=c
a possible use of this agent in the symptomatic treatment of parkin-
sonism (194) .A patent claims that some N-(ethoxycarbony1)nortropi-
none derivatives are also useful in the treatment of Parkinson's disease
(195) .Some 3-phenoxynortropanes of structure 208 where R = NH,,
CH,NH, (CH,),N, or C,H,NH and R' = m-CF, or p-CF, have shown
anticonvulsant activity. While none of these compounds is quite as
active as diphenylhydantoin in suppressing electroshock-induced
convulsions, several had protective ED,, values against pentylene-tetrazole lower than that of ethosuximide. Both 3a- and 3fi-isomers
were included in the study (106) .The preparation of these compounds is
described in Section IV, G .
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152 ROBERT L. CLARKE
208 209
3-Phenoxytropane (209) and six derivatives carrying substituents in
the aromatic ring are reported to induce hypermotility, potentiate
the action of norepinephrine and inhibit that of tyramine on bloodpressure, and to antagonize some effects of tranquilizers. The unsub-
stituted phenyl derivative was the most active (196) . Another broad
study of tropanyl ethers showed indications of antidepressant and
anticholinergic activities. fl-Phenoxytropane and /?-(p-chlorophenoxy)-
tropane seemed to be active enough antidepressants and antiparkinson
agents to warrant clinical trials (105).3a-Hydroxy-8-isopropyltropaniumbromide (dZ)-tropate (Ipratro-
piumbromide) (209A) as pronounced anticholinergic properties. As
O-C-CH-CH~OH
209A
an inhibitor of the secretion of free hydrochloric acid in the stomach, it
is five times more effective than atropine. A whole issue of ArzneimittelForschung is devoted to the synthesis, pharmacology, toxicology, and
clinical trials of this compound ( 1 9 6 ~ ) .
S
210
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2. TROPANE ALKALOIDS 153
Duboisia myoporoides is used by New Caledonian natives as an
N-(Allylthiothiocarbony1)tropane 210) is reported to have herbicidal
antidote against ciguatera poisoning (196b).
activity (192').
W. lant Content
Since the thrust of this review is primarily chemical and biochemical
and not botanical, a detailed discussion of new or repeat isolations of
known tropane alkaloids from new or old sources will not be given.
However, the literature search for this review has provided what ishoped are essentially all references to work of this nature in the period
reviewed. It appeared useful a t least to catalog these references here as
resource material. They are organized alphabetically according to
family, genus, and species.
Family Erythroxylaceae
Erythroxylum momgynum Roxb. ( 2 6 ) .
E. Ellipticum R. Br. ex Benth. ( 2 7 ) .
E. coca vm. nOv0granaterwi.q ( 1 9 8 ) .
Peripentadenia m r 8 i i ( C . T. White) L.S. Smith (24) .
Agastachys dw a ta R. Br. ( 9 ) .
Belkndena mntana R. Br. (7 -9) .
Darlingkaferruginea J. F. Bailey ( 1 1 ) .
Darling&&rlingiana (F. Muell) L.A. S. Johnson ( 1 1 ) .
Knight& de-phnchei Vieill. ex Brogn. et Gria (12-14) .
Brugukra 8exanghr (Lour.) oir ( 1 5 , 1 6 ) .
B. ezarktata Ding Hou ( 1 5 , 1 6 ) .
Family Euphorbiaceae
Family Proteaceae
Family Rhizophoraceae
Family Solanaceae (1 9 8 a ) -A broad study of some 19 genera and 54 species of Chinese
solanaceous plants focused on the distribution of four tropane alkaloids, hyoscyamine,
scopolamine, anisodamine (6-hydroxyatropine), and anisodine (a-hydroxyscopolamine)
(211), and a nontropane alkaloid, cuscohygrine. These alkaloids were distributed in
Ph
311
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154 ROBERT L. CLARKE
Solmeae, Hyoscyaminae, Mandragorinae, and Datureae but not in Nicandreae, Lyeiinae,
Solaninae, and Cestreae. Przewalskk ahebbearei and P. tangutica were the best sources
of these alkaloids (22b).
AnthocerA litto7ea. Labill (199).
A. tasmanica Hook. F . (200).
A. ViacosaR.Br. (199).
Atropa belladonnu L. 28, 147a, 201-205, 205a, 205b).
Cyphnzandra betacea Sendtn. (206).
Datura dba Nees (206a).
D. arborea L. (207).
D. bernhardii Lundstrom (208).
D. candida (Persoon) Safford (209).
D. ceratocaula Jacq. (20 , 21).
D. Cornigera Hook. (209).D. discolor B e d . (210, 211).
D. fastuosa L. (212).
D. ferox L. (169b, 209, 209a).
D. godronii (212a).
D. inno& Miller (16, 19, 20, 169c, 207, 209, 212a, 213-218, 218-218e).
D. leichardtii Muell ex Benth. (206a, 208, 209).
D. Metel L. (207, 218-220, 218f, 218g).
D. Metel var. fastuosa ( B e d . ) Dannert (209, 221, 221a).
D. meteloides DC. ex Dun. (169b, 207, 209, 222).
D. pruimsa Greenm. (223).
D. sanguima R. and P. (22, 209, 224).D. stramni um L. (28, 201, 207-209, 213, 225-230, 230a).
D. s tramnium var. inermis (207).
D. stramnium var. tatula (230b).
D. stramni um x D. discolor (231).
D . suaveolens H. and B. ex Willd. (18, 232).
D. tatula L. (169b, 207).
D. tatula var. immzis (169b, 207).
Duboisia hopwodii F . (233).
D. myoporoides R.Br. (169a, 196b, 234, 235, 235a).
Hyoscyamw d b w L. (236).
H. aurew L. (233).
H. n@er L. (28, 201, 233).
H. orientdis Bieb (236a).
H. pu8illw L. (233).
Mandragora autumnalis Bertol. (237).
M . oficinarum L. ( v e d i s ) 28, 237).
Nicotiana tabacum L. (238).
Physali.9 alkekengi L. var. Franchetti Hort. (formerly bunyardii Makino) (29, 239).
P. peruViana Mill. (30a, 154).
Physochlaina a l a k E. Korot. (23, 30, 240, 241).
P r m a k k i u shebbeurei (22b).
P . tangutica Maxim. (22b).
Salpichroa or-iginifolia (Lam.)Baillon [S. rhomboidea (Hook) Miers] (242).
ScopolBa carnblica Jacq. (28, 206a, 225, 243-246).
S. himalaiensis (179).
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2. TROPANE ALKALOIDS 155
S. a p o n ic a Maxim. (2 4 7 , 2 4 7 a ) .
S. Zurida Dun. (2 8 , 2 2 5 ) .
S. a&&ra (Dun.)Nakai (2 2 2 , 2 4 7 , 2 4 7 a , 2 4 8 ) .S . 8inesisHemsl. (2 4 9 , 2 5 0 ) .
S. tranzonifolia (1 69c , 251-254).
S. tangut& Maxim. (2 2 5 , 250, 251 , 255-261 , 261a) .
S o la n d r a g r a n d i f i r a Sw. ( 2 6 2 ) .
S . guttata D. Don ex Lindley ( 2 6 2 ) .
S. hartwegii N. Br. ( 2 6 2 ) .
S. hirauta Dun. (262).
S. muwantha Dun. ( 2 6 2 ) .
VIII. Stereochemistry
The determination of molecular configuration using NMR, IR, and
mass spectra has become so routine and such an incidental part of so
many publications on tropane alkaloids that no attempt will be made
to give overall references. In a few cases where spectral studies are the
principal thrust of the paper, a description will be given in this section.
A novel approach to establishing configurations of molecules has
involved attaching a chiral group to the nitrogen of some piperidones,
tropan-3-ones, and pseudopelletierine systems ( 4 0 ) .Where the chiral
Ph CH3‘3 @ /
212 cH 213 0
group was in closer proximity to the carbonyl (as in 212) the amplitude
of the circular dichroism was enhanced over that of the isomer with the
more distant chiral center (213).Both quaternary and tertiary chiral
bases were studied. The conformer populations and their Cotton effect
signs and amplitudes as predicted by the octant rule and theoretical
considerations were confirmed by circular dichroic measurements.
I3C NMR data are beginning to accumulate on tropanes. Shiftassignments have been made for the carbons of tropane ( 2 6 3 ) ;nortro-
pane ( 2 6 3 ) tropinone ( 2 6 3 ) tropinone ethylene ketal ( 2 6 3 ) tropine
(263 , 264) and its benzoate ( 2 6 3 ) ; tropine (61a ,263), t? methobromide
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156 ROBERT L. CLARKE
(61a ,263, 264 ) ,and other alkyl quaternaries ( 6 1 a ) ;pseudotropine (263 )
and its benzoate ( 2 6 3 ) ; tropidine ( 2 6 3 ) ; scopolamine (263 , 264 ) ;
scopolamine N-oxide (263 ) ; ropic acid (264 ) ethyl 3-phenyltropane-3-carboxylate (both isomers) ( 4 5 ) ;and 3-benzoyl-3-phenyltropaneboth
isomers) (45).It is worthy of note that Wenkert’s group (263 ) has assigned the
6 2 5 .7 peak to carbons 6 and 7 of tropine and the 39 .1 peak to carbons
2 and 4, whereas Maciel’s group ( 2 6 4 )has made the reverse assignment.
The latter group observed that atropine methobromide (214) showed
methyl peaks at 6 4 4 . 8 5 and 51.54. The N-methyl of atropine (known to
/
OTr
214
be equatorial) appeared at 39.57, in fair accord with the lower of thetwo values seen for the quaternary. X-ray work (265 )has indicated an
axial configuration for the N-methyl of scopolamine. The observed
NMR shift for this carbon in scopolamine was S 53 .42 , in agreement
with the other methyl peak location ( 6 5 1 .5 4 ) found in atropine
methobromide. With proper control studies, it might be possible to
use 13C NMR effectively for structural assignments of tropane quater-
naries. (The work following disagrees with these quaternary peak
assignments.)
This possibility of using 13C NMR has now been carefully exploredfor quaternaries carrying methyl, ethyl, n-propyl, isopropyl, n-butyl,
and n-octyl groups on the nitrogen. The shift differences between peaks
for the two nonring carbons attached to the nitrogen and the peaks for
the ring carbons at C-6/C-7, C -l /C-5, and C-2/C-4 have been correlated
to show definite and distinct trends relatable to the orientation of the
R groups on the nitrogen. This study allows configurational assignments
for alkyl groups where one group is methyl but has not yet been exten-
ded to pairs of higher alkyl groups or to aralkyl substituents ( 6 1 ~ ) .
The normal 13C population in molecules is so low that a specificallylabeled 13C position stands out prominently in proton noise decoupled
13C NMR spectra. Likewise, adjacent 13C atoms give rise to satellite
peaks (due to 13C-13C spin-spin coupling) that are symmetrically
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2. TROPANE ALKALOIDS 157
located about the singlet peaks. This phenomenon was utilized in
establishing that phenylalanine (215) is a precursor of tropic acid (216)
biosynthetically by intramolecular migration of the carboxyl group. No
215 Phenylelenine 216 Tropic acid
satellite peaks were visible in the dl-[l ,3-13C,]-phenylalanine fed t o
Datura innoxia, but they were plainly visible in the hyoscyamine and
scopolamine isolated from the plant tissues (Eq. 14) (144).
While on the subject of tropic acid, NMR studies (100 and 220 MHz)
of it, its methyl ester, and the methyl ester acetate indicated a prefer-
ence for the conformation where the phenyl and hydroxyl (or acetoxyl)
groups were in anti positions to each other. Solvent and concentration
effects upon the coupling were weak (266) .Dipole moment, NMR and temperature-dependent NMR studies and
qualitative considerations of van der Waals interactions provided data
on the conformation of atropine (267) .Since the primary focus was on
the conformation of the ester function, acetyltropine, trimethyl-
acetyltropine, benzoyltropine, hexahydrobenzoyltropine, and diphenyl-
acetyltropine served as models. The structure wherein the C=O is
cis to the tropane skeleton (218)appears to be the preferred conformation
rather than the trans form (217). This brings the N to C=O distance to
4.5-5.0 A, which is close to that found for acetylcholine.An earlier study
II
0,,CHPhCH,OH O\,@
II0
217
ICHPhCHaOH
218
(268) on tropine benzoate and pseudotropine benzoate had concluded
that the former prefers the conformation 219 while the latter is anequilibrium mixture of 220 and 221. All of this work was directed
toward gaining information on the characteristics of cholinergic
receptors.
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158 ROBERT L. CLARKE
I
O\,//O
IPh
219 220 121
The question of whether the lone electron pair or hydrogen assumes
the equatorial position on nitrogen in piperidines and nortropanes hasbeen the focal point of much controversy. A low temperature 13C-NMR
study, directed toward a solution in the latter case, has revealed an
almost equal population of axial and equatorial hydrogens (268,).The conformations of both phenyl tropan-3a-yl ether and p-chloro-
phenyl tropan-3a-yl ether as well as their 3b-epimers were determined by
analysis of IR , NMR, dipole moment, and Ken constant data. The
piperidine ring of the tropane was found to be in a chair form and the
N-methyl occupied an equatorial position. Where the 3-substituent was
oriented a , steric repulsion with the ethylene bridge caused flatteningof the piperidine chair at the C-3 end (105b) .
In order to determine the effect of esterification on the conformational
preference of tropine and pseudotropine, PMR studies were made on
their acetates and benzilates as well as on atropine. On the basis of half
bandwidths of the C-3 hydrogen, it was concluded that the conformation
of the piperidine moiety was unaffected by esterification of the alcohol
function (2 6 9 ) .A tropane analog222 (191)of meperidine (223) was at one time (270 ,
271) considered to have a large skew-boat population (as shown) on thebasis of analogy with a distorting interaction between the a-phenyl group
and the ethylene bridge of the 3b-benzoyl-3a-phenyl analog 224 (2 7 2 ) .With the advent of NMR spectroscopy a detailed analysis of these com-
pounds led to the conclusion that the meperidine analog actually exists
COOEt
PPh
C O O E t
dH.-N
223 224222
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160 ROBERT L. CLARKE
interactions of the kind that would be expected to occur in a boat form
such as 224 are known to introduce large up-field shifts in the 13C-
carbonyl signal (274) .There is a negligible difference in the 13C-carbonylsignals of epimers 228 ( =224) and 230. The proximity of a carbonyl to
the nitrogen of such a boat form (224) should cause a difference in N -methyl shift. There is no difference in N-methyl resonance position
between ester 227 (flattened chair) and the ketone in question (224
versus 228).
It should be noted t hat there are reversals in the assignments of the
proton resonances for the equatorial hydrogens a t C-2(4) and a pair of
those at C-6(7) n these two NMR tructural studies. In the latter work,
the models for assignment of the C-6(7) protons were two 2,4-tetra-deuterated tropanes.
N-Oxides were discussed in Section IV, B, but attention is called
here to the very clear 220 MHz NMR pectra of the two isomeric oxides
of tropine in CD30D. These data were used in assigning configurations
to the two N-oxide isomers ( 7 1 ) .The mass spectra of these two oxides
have been recorded ( 7 0 ) .Correlations between NMR shifts and struc-
ture have also been investigated for the isomeric N-oxides of hyoscya-
mine and hyoscine. In addition, the mass spectral fragmentation
patterns of these oxides were given ( 2 8 ) .The advantage of chemical ionization (CI) mass spectrometry over
conventional electron impact (EI)mass spectrometry was demonstrated
with homatropine among other alkaloids ( 2 7 5 ) .In C I mass spectrom-
etry, the quasimolecular ion M + 1 is invariably more abundant than is
the molecular ion in EI spectrometry. In the case of homatropine (231)
the C I method gave a moderately strong M + 1 peak and showed an
ion at m/e 258 (M + 1 - H,O). In the EI spectrum this substance gave
bCO-CH-Ph
231
only a weak molecular ion and no ion at m/e 258. The same research
group has reported the mass spectra of cocaine and scopolamine ( 2 7 6 ) .
Application of isobutane chemical ionization mass spectroscopy to
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2. TROPANE ALKALOIDS 161
the forensic identification of drugs has been reported in considerable
detail. Data on 303 drugs and common diluents have been tabulated.
Most of these compounds show an MH+ peak with four or fewerfragmentation ions in abundances greater than 10%. Described are
atropine, cocaine, homatropine (molecular weight should be 275),
hyoscyamine [shows a 237 peak (20y0) ot listed for atropine], scopola-
mine, and tropine ( 2 7 7 ) .An earlier report by this group reported the
spectra of 62 commonly abused drugs (278) .Fragmentation patterns produced by eleven tropane derivatives
under the conditions of electron impact mass spectrometry were related
to the nature of the substituents. Unsaturation in the six-membered
ring caused preferential fragmentation of the two-carbon bridge. Asaturated six-membered ring containing poor leaving groups (OH and
CN) underwent preferential fragmentation of that ring (279) .Data on defocused metastable ions were obtained for a series of
structurally significant fragment ions in the mass spectrum of tropine.
These data, in conjunction with parallel information on 6,7-d2-tropine,
provide important insights into the details of fragmentation processes
(280) .A paramagnetic shift reagent, tris(dipivalomethanato)europium(III),
has been used to obtain simplified NMR spectra of tropine, pseudo-
tropine, nortropine, tropinone, and nortropinone. Evidence was
presented for a distorted chair conformation in the a- and /3-tropines
and tropinones. This work demonstrates the applicability of shift
reagents where two centers for coordination are present. The order of
coordination was secondary amine > secondary alcohol > tertiary
amine 2 ketone (281) .Further evidence for this flattening (semiplanar
form) in tropanes was gathered using Ni(I1) acetylacetonate and
Co(I1)acetylacetonate as shift reagents. Tropine benzoate, homatropine,
and tropinone were studied (282) .An attempt was made by X-ray diffraction analysis to show the
conformation of the N-methyl group in 3a-chlorotropane. The crystal
proved to be a monohydrate with the water apparently bonded to the
nitrogen, so the primary purpose of the investigation was not realized.
It was determined, however, that interaction between the chlorine and
the ethylene bridge causes a flattening of the C-2, C-3, C-4 portion of
the molecule toward the plane established by C-1, C-2, C-4, and C-5
(283) .Another approach to this conformational problem also involved
3a-chlorotropane along with 3a-bromotropane. NMR spectroscopy and
dipole moment measurement indicated that perhaps up t o lOyoof the
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162 ROBERT L. CLARKE
N-methyl groups occupied an axial position and that a flattening of the
piperidine chair occurred as described in the X-ray work immediately
above (284).
M.AnalyticalMethods
Microchemical identification of methylatropine, methyl homa-
tropine, hyoscine, and hyoscyamine has been accomplished through
formation of salts, including reineckates, chloroplatinates, hexacyano-
ferrates, and chloromercurates (285) . Salts of atropine, homatropine,
scopolamine, cocaine, and tropacocaine with arenesulfonic acids aresparingly soluble and have sharp melting points (286) . Complexes of
alkaloids, including tropanes, with potassium tetraiodomercurate (287),
radiolabeled (l3II) otassium tetraiodomercurate (288),and antimony-
containing acids (289) have also been studied. Microcrystalloscopic
reactions have been used to identify apoatropine and tropic acid in the
presence of atropine ( 290) .A rapid and sensitive gas-liquid chromatographic method (GLC) is
described for detecting small amounts of ecgonine and benzoylecgonine
in cocaine. It is necessary to silylate these polar substances in order t o
achieve adequate volatility (291) .A similar procedure was used for the
detection of cocaine and its principal metabolite, benzoylecgonine (BE),
in urine. Separate simultaneous determinations of cocaine and BE were
accomplished by analyzing both a methylated (combined cocaine and
BE) and an unmethylated (cocaine only) aliquot of the specimen
extract. Detection limits were < 0.1 and 0.2 pg/ml for cocaine and BE
respectively (291a) . A broad study of GLC of tropane alkaloids in-
vestigated column materials and packings. Extracts from Datura ferox,
D . innoxia, D . stramonium, and Atropa belladonna were used in the
study ( 292) .Hyoscyamine and scopolamine (293)and these plus tropine,
pseudotropine, nortropine, scopoline, pseudoecgonine, cochlearine, and
meteloidine (294)have been separated and identified by GLC. Cocaine
has been detected at 20-30 ng/ml by the same technique (295) .GLC has
also been used for identification of unknown drugs in forensic chemistry
(295a) .See refs. 277 and 278 for other forensic studies. Simultaneous
determination of the major alkaloids of D . innoxia and any fungicide
Vitavax present in the sample was also accomplished by this technique
(295b) .GLC was effective for assay of belladonna but marked differences
in results were related to different isolation schemes in sample prepara-
tion (295c) .Approximately 1000 tons of Duboisia plants are grown yearly to
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2. TROPANE ALKALOIDS 163
obtain the mydriatic alkloid scopolamine. Control analyses by GLC are
most satisfactory when phenylacetyltropine is used as an internal
standard. Silanization of the samples prevents dehydration to apoforms. The alkaloid content from a commercial bale of Duboisiamyoporoides varied with sample position in the bale (2 3 5 ) .
A GLC-mass spectrometric method for scopolamine sensitive to
50 pg/ml for a 4-ml plasma or urine sample has been reported (296) .The
method used a deuterated internal standard and involved hydrolysis
to scopoline followed by heptafluorobutyrate formation.
High-speed, high pressure liquid chromatography has been used (297)for separation of similar tropane alkaloids. It offers the advantages that
it is not necessary to liberate free bases prior to analysis as with gaschromatography, the analysis can be performed a t room temperature,
and the procedure can be scaled up easily if preparative samples are
required. A separate study applied this technique to tropine, scopola-
mine, and cocaine, among other alkaloids, using six solvent systems and
UV monitoring (298).Flow rates and retention times were recorded. Asecond study by this latter group dealt with atropine, scopolamine and
apoatropine ( 2 9 8 ~ ) .
Paper and thin-layer chromatography have been used extensively
for separation and identification of tropane alkaloids. The followingnotations are from papers dealing primariIy with these problems. Paper
and thin-layer plates (299)and paper alone (3 0 0 )were used to separate
atropine and scopolamine. Gel chromatography has been used for the
study of scopolamine in forensic chemical analysis (300a). odine is a
good reagent for developing spots sinde i t is nondestructive (300, 301) .
Dipping paper chromatographs in 1,-KI produces a blue color for
atropine and a red-orange color for hyoscyamine (3 0 2 ) .Alkaloid spots
have also been located with potassium iodoplatinate and cerium
sulfate-H,SO, (303) and with Dragendorff’s reagent followed by
NaNO, (3 0 4 ) . Experiments designed for transferring alkaloids from
drug samples directly to chromatoplates a t elevated temperatures
using water-charged molecular sieve as a propellant showed that
alkaloid decomposition limited the applicability of the process ( 3 0 4 ~ ) .
A combination of extractive prOcedures and chromatographic
separation allowed the determination of hyoscyamine and scopolamine
in Solanaceae within 2% error (3 0 5 ) . For the determination of hyo-
scyamine and scopolamine in the total alkaloids of belladonna, MeOH-
benzene was used for plate development, and UV absorption was used
for quantitation (3 0 6 ) . A similar study was done on atropine and
scopolamine (3 0 7 ) . For alkaloids in Caucasian scopolia roots and
belladonna leaves, 95:5 acetone-lO~oNH,OH was used to separate
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164 ROBERT L. CLARKE
hyoscyamine, apoatropine, and scopolamine ( 308) . A 97: 3 acetone
NH,OH solvent system separated atropine, apoatropine, Cropine, tropic
acid, tropinone, scopolamine, scopoline, scopine, and aposcopolamine(309). In this case, the colors obtained using fourteen chromogenic
reagents were reported. A 6:3:1 CH3COC2H5-CH30H-7.5yo NH,OH
system effectively separated essentially this same group of bases ( 310) .A partial paper chromatographic separation of hyoscyamine and
atropine (dZ-hyoscyamine) is reported that allows estimation of the
compositions of mixtures of these substances. A periodate of the
alkaloid hydriodide is formed which subsequently liberates iodine ( 311) .
No asymmetric reagent was used to impregnate the paper or to develop
the system.Five solvent systems were studied in the separation of metabolites
of atropine by thin-layer chromatography ( 2 9 0 ) .
Partition chromatography on chromatoplates using cellulose coatings
allowed the detection of microgram quantities of tropane alkaloids;
0.7 M H,S04 + 0.7 M NaCl was used as the stationary phase and
BuOH served as the mobile phase ( 3 1 2 ) .A related study used cellulose-
coated plates, a borate/phosphate buffer at pH 6.6, and n-butanol
saturated with water. Assay involved a colorimetric method ( 313) .
Thin-layer electrophoresis of atropine, homatropine, and cocaine has
been accomplished on glass plates coated with cellulose powder using
both acidic and alkaline electrolytes ( 314) .Electrophoretic identification
of these same substances plus scopolamine and tropacine (3a-tropanyl
diphenylacetate) was studied at a variety of pH values from 1.8 to 8.0
with spot detection by iodine ( 3 1 5 ) .A group of local anesthetics studied
by this same technique included cocaine ( 3 1 6 ) .Paper electrophoresis
followed by ultraviolet spectrophotometry for assay of atropine,
dicaine, cocaine, novacaine and scopolamine was found suitable for
forensic purposes (316a) .Electrophoretic separation of some Datura and Atropa samples
afforded atropine, hyoscyamine, apoatropine, 6-hydroxyhyoscyarnine7
scopolamine,3,6-ditigloyloxy-7-hydroxytropane,nd meteloidine. Their
relative migratory rates were recorded a t pH 8 ( 3 1 7 ) .The same method
with pH 9.5 borate buffer showed that hyoscyamine is the pharmaco-
logically active principal of the hybrid Atropa martiana (belladonna)
( 3 1 8 ) . Electrophoretic separation has also been used with Duturu
bernhardii (319)and D. stramonium ( 2 2 9 ) .
The polarographic properties of several amine oxides have been
determined including those of 3-tropanol N-oxide ( 3 2 0 ) .Thermal analysis of d and Z-hyoscyamine mixtures containing from
0 o 50y0 d-hyoscyamine indicated an unbroken series of isomorphic
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2. TROPANE ALKALOIDS 165
mixed crystals. Two polymorphs of 1-hyoscyamine were observed, a
stable one melting at 107-109°C and a metastable one melting at
104"C, but no polymorphism of atropine was observed (321) .Tropic acid ester hydrolase and tropic acid dehydrogenase, enzymes
obtained from P s e u d o m o m putidu, were used for enzymatic assay
of atropine sulfate, hyoscyamine sulfate, and tropic acid in the
10-7-10-4 M range (322) . Atropinesterases from nine Pseudomonasstrains were compared with respect to activity and composition (323) .
Photometry was used to assay atropine, homatropine, cocaine,
scopolamine, and tropazine. Reaction with barbituric acid or thio-
barbituric acid in dimethyl or diethyl oxalate was used to develop the
chromophore (324) .The highest sensitivity was obtained with diethyloxalate and thiobarbituric acid. Another colorimetric method was used
to determine the alkaloids in Solanaceae extracts (325) .The alkaloids
were nitrated by a mixture of HNO, and H,SO,, extracted by CH,Cl,,
and assayed by the Vitali reaction in dimethyl sulfoxide (326) .A third colorimetric method, used on atropine, homatropine,
scopolamine, and the methobromides of the last two named, has been
based on the hydroxylaminolysis of the ester function to produce
hydroxamic acids followed by addition of ferric ion to produce the
colored complex (327) .Quantitative methods for determination of microamounts of solan-
aceous alkaloids are few, none involving direct UV measurement. It has
been found that about a 50-fold increase in the UV molar absorptivities
of the tropane alkaloids can be achieved via charge-transfer complex
formation with iodine in chlorinated hydrocarbon solvents. This
allows adequate assay of single drug tablets ( 3 2 7 ~ ) .ltraviolet measure-
ment can also be used for determination of scopolamine in the 0.16-1 .OO
mg/cm3 range when this alkaloid is complexed as Scopolamine H[Cr-
(NCS),-(p-toluidine),] (327b).Immunoassay offers the most sensitive measurement available for
specific alkaIoidal substances. Benzoylnorecgonine and norcocaine have
been derivatized on nitrogen with groups susceptible to diazotization.
Coupling of these derivatives to antigenic substances has allowed the
preparation of antibodies to cocaine and benzoylecgonine. Other
derivatives are also described ( 3 2 7 ~ ) .n a similar approach, atropine
was coupled via its hemisuccinate ester to bovine and serum albumin to
produce antibodies (327d) .Several variations on and evaluations of pharmacopeia methods of
various countries for tropane alkaloid assay have appeared. Four
studies related specifically to belladonna (328-331), variations being
made in extractive techniques and ultimate titration methods. Drying
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2. TROPANE ALKALOIDS 167
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1 7 0 ROBERT L. CLARKE
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174 ROBERT L. CLARKE
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203. J. F. E. Van Kessel and J. A. C. Van Pinxteren, Pharm. Actu Helv. 45, 164-168
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205a. G. Seifert, Herba Hung. 14, 23-28 (1975); CA 83, 175454s (1975).
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211. A. H. Saber, S. I. Balbaa, G. A. El Hossary, an d M. S. Karawya, Lloydia 33,
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218c. J. Jankulov and K. Alipur, Dokl. S-kh. Akad.. Sofa 8, 47-50 (1975); CA 84,
218d. H. D. Shell, M. Carsteanu, A. Nasta, I. Cornoiu, 0. Gozia, and T. Bentia, Stud.
218e. R. P. Nandi and S. K. Chatterjee, Indian Biol. 7, 31-35 (1976); CA 85, 74989f
218f. A. I. Gabr, E. N. Abou-Zied, M. R. Shedeed, and S. E. E l Sherbeeny, Herba Pol.
(1970); CA 72, 10378 2~1970).
CA 76, 23166s (1972).
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May 2, 1975;C A 83, 65453h (1975).
73, 77448s (1970).
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29, 357-360 (1976).
401-402 (1970); CA 74, 505360 (1971).
BangladeshJ.Sci. Ind.Rea. 9, 79-81 (1974); CA 82, 28529w (1975).
55194f (1976).
64-68 (1973);C A 83, 126883~1975).
(1972);C A 77, 85746k (1972).
(1973); C A 80, 130509k (1974).
5, 1-15 (1973);C A 81, 101848% 1974).
(1972).
55756v (1975).
Acta Pharm. Hung. 45, 167-174 (1975); CA 83, 142865~1975).
132796h (1976).
Cercet. Biochirn. 19, 101-107 (1976);CA 85, 107891~1976).
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21, 192-200 (1975);C A 84, 2674711 (1976).
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176 ROBERT L. CLARKE
218g. E. N. Abou-Zied, Egypt. J . Bot. 16, 137-144 (1973); C A 84, 26764m (1976).
218h. S. Gupta a nd C. L. Madan, Indian J . Pharm. 38, 44-47 (1976).
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220. L. Cosson. Phytochemistry 8, 2227-2233 (1969).
221. K. Anwar and A. Ghani, Bangladeah Pharm. J . 2, 25-27 (1973); CA 80, 57429~
221a. S. Gupte and C. L. Madan, PZanta Med. 28, 193-200 (1975).
222. M. Konoshima, M. Tabata, Y. Kano, an d S. Tanaka, Shoyakugaku Zasshi 24,
223. W. C. Evan s and P. G. Treagust, Phytochemistry 12, 2077-2078 (1973).
224. J. D. Leary, Lloydia 33, 264-266 (1970).
225. L. V. Selenine, V. I. Gladkov, an d G. L. Glinskaya, Tr. Leningr. Khim.-Farm. Inat.
226. I. Tammaru, Tartu Riikliku Ulik. Toim. No. 270, 19-27 (1971); CA 76, 33171d
227. I. Tammaru, Tartu Riikliku Ulik. Toim. No. 270,3-18 (1971);CA 76,33212t (1972).
228. I. Tammaru, Tartu Riikliku Ulik. Toim. No. 270, 28-40 (1971); C A 76, 33177k
229. V. Koppel, Tartu Riikliku Ulik. Td m . No. 270, 63-70 (1971);C A 76,23078q (1972).
230. N. G. Bozhko, Khim.-Farm. Zh. 4, 42-44 (1970); C A 74, 34568j (1971).
230a. M. Dorer and R. Malnersic, Farm. Veatn. (Ljubljana) 25, 169-195 (1974); C A 83,
230b. L. Stecka, A. Mruk-Luczkiewicz, and S. Wilk, Herba Pol. 21, 17-23 (1975); C A
231. M. Al-Yakya an d W. C. Evans, J . Pharm. Ph am co l. 27 Suppl., 87P (1975).232. S. I. Balbaa, A. H. Saber, M. S. Karawya, an d G. A. E l Hossary, J . Pharm. Sci.
233. G. S. Kennedy, Phytochemistry 10, 1335-1337 (1971).
234. K. J. Sipply, PZanta Med. Suppl. 186-188 (1975).
235. W. J. Griffin, H. P. Brand, and J. G. Dare, J . Pharm. Sci. 64, 1821-1825 (1975).
235e. L. Cosson, J. C. Vaillant, and E. Dequeent, Phytochemwtry 15, 818-820 (1976).
236. A. Ghani, W. C. Evans, and V. A. Woolley, Bangladwh Pharm. J . 1, 12-14 (1972);
236a. N. I. Telezhko, Aktual. Vopr . Farm. 2 , 45-48 (1974); CA 84, 102349~1976).
237. B. P. Jackson and M. I. Berry, Phytochemistry 12, 1165-1166 (1973).
238. D. E. Koeppe, L. M. Rohrbaugh, E. L. Rice, and S. H. Wender, Phyeiol. Plant. 23,
239. K. Basey and J. G. Woolley, Phytochemistry 12, 2557-2559 (1973).
240. R. T. Mirzamatov, V. M. Malikov, K. L. Lutfullin, 0. Khakimov, and S. Y .Yunusov, Khim. Pr ir. Soedin. 9, 566 (1973); C A 80 45709f (1974).
241. R. T. Minamatov, K. L. Lutfullin, V. M. Malikov, and S. Y. Yunusov, Khim. P&.
Soedin. No. 3, 416-417 (1974); C A 81, 16 63 59 ~1974).
242. W. C. Evans, A. Ghani, en d V. A. Woolley, Phytochemistry 11, 469 (1972).
243. L. N. Bereznegovskaya and G. M. Fedoseeva, Rastit. Resur. 5, 512-519 (1969);CA
244. I. L. Krylova, L. N. Shakhnovskii, S. V. Rusakova, end E. F. Mikhailova, Rastit.
245. B. Srepel, Acta Pharm. Jugosl. 21, 8 6 9 0 (1971); CA 75, 1439 44~1971).
246. I. L. Krylova, L. N. Shakhnovskii, and S. V. Rusakova, Rastit. Resur. 8, 54-59
(1974).
105-110 (1970); C A 75, 67420d (1971).
26, 40-55 (1968); CA 73, 63233f (1970).
(1972).
(1972).
142837r (1975).
83, 1305252 (1975)..
U.A.R. 10, 125-134 (1969); C A 73,127727e (1970).
GA 79, 758712 (1973).
258-266 (1970).
72, 75609v (1970).
Rwur. 7, 9-18 (1971); C A 74, 108128q (1971).
(1972);CA 76, 124146r (1972).
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2. TROPANE ALKALOIDS 177
247. M. Tabata, H. Yamamoto, N. Hiraoka, A. Oka, K. Kawashima, an d M. Konoshha ,
247s. Y. Watanabe, I. Yasuda, T. Seto, K. Nakajima, and Y. Nishikawa, Tokyo ToritsU
248. M. Tab ata , H. Yamamoto, N. Hiraoka, an d M. Konoshima, Phytochemistry 11,
249. M. Szymanska, Pol. J . Pharmacol. Pharm. 25, 201-206 (1973); CA 79, 102854e
250. S. A. Minina and E. A. Marchenko, Rmtit. Reaur. 9, 203-205 (1973); CA 79,
251. S. A. Minina, L. P. Mashkova, an dL. A. Kulikova, Rmtit. Reaur. 5 , 385-390 (1969);
252. M. Gorunovic, N. Prum , and J. Raynaud, Plant. Med. Phytother. 4, 286-291 (1970);
253. M. Yankulova and I. Yankulova, Dokl. Akad. Nauk Bolg. 4, 299-307 (1971); C A
254. M. Gorunovic and P. Lukic, Acta P h r m . Jugosl. 22, 69-71 (1972); C A 77,79580k
255. G. M. Ulicheva, Rmtit Resur. 6, 528-534 (1970); C A 74, 95405a (1971).
256. I. Barene and S. A. Minina, Rasti t. Resur. 7 , 124-128 (1971);CA 74,108131k (1971).
257. B. A. Samoryadov and S. A. Minina, Khim. Pri r. Soedin. No. 7, 209 (1971); CA 75,
258. I. Barene and S. A. Minina, Khim. Prir. Soedin. No. 7 , 379-380 (1971); CA 75,
259. G. M. Ulicheva, Rastit. Resur. 7 , 18-24 (1971); CA 74, 108126n (1971).260. S. A. Minina and I. Barene, Bwl. Akt. Veshcheatva F l q Fauny Dal'n. Vost.
261. N. I. Ryabova, Rastit. R w r . 9, 548-550 (1973); CA 80, 105856~1974).
261a. S. A. Minina, T. V. Astakhova, and N. V. Nazarova, Rastit. Resur. 11, 493-496
262. W. C. Evans, A. Ghani, and V. A. Woolley, Phytochemistry 11, 470-472 (1972).
263. E. Wenkert, J. S. Bindra, C.-J. Chang, D. W. Cochran, and F. M. Shell, Ace. Chem.
264. L. Simeral and G. E. Maciel, Org. Magn. Reson. 6, 226-232 (1974).
265. P. Pauling and T. J. Petcher, Chem. Commun. 1001-1002 (1969).
266. V. S. Dimitrov, S. L. Spasov, and T. Radeva, J. Mol. Struct. 27, 167-176 (1975).
267. P. Scheiber and K. NBdor, Arzneim.-Forsch. 25, 375-378 (1975).
268. K. NBdor and P. Scheiber, Arzneirn.-Forsch. 22, 459-462 (1972).
268a. H.-J. Schneider an d L. Sturm, Angew. Chem. Int. Ed. Eng. 15, 545-546 (1976).
269. A. F. Casy and W. K. Jeffery, Can. J . Chem. 50, 803-809 (1972).
270. A. F. Casy, Prog. Med. Chem. 7 , 265-276 (1971).
271. P. S. Portoghese, A. A. Mikhail, and H. J. Kupferberg, J . Med. Chem. 11, 219-225
272. M. R. Bell an d S. Archer, J . Am. Chem. SOC. 2, 151-155 (1960).
273. A. F. Casy and J. E. Coates, Org. Magn. Reson. 6, 441-444 (1974).
274. T. T. Nakashima and G. E. Maciel, Org. M q n . Reson. 4, 321-326 (1972).275. H. M. Fales, H. A. Lloyd, and G. W. A. Milne, J . Am. Chem. SOC. 2, 1590-1597
276. H. M. Fales, G. W. A. Milne, and N. C. Law, Arch. Mass Spectral Data 2, 654-657
Shoyakugaku Zasshi 23, 83-88 (1969); CA 73, 73844v (1970).
Ebei Kenkyuaho Kenkyu Nempo 26, 90-92 (1975); CA 85, 10345k (1976).
949-955 (1972).
(1973).
15907f (1973).
C A 72, 3978% (1970).
C A 74, 108125rn (1971).
77, 45657a (1972).
(1972).
31332n (1971).
115920r (1971).
Tikhogo Okeana 22-23 (1971); C A 77, 111461k (1972).
(1975); C A 84, 56481j (1976).
Res. 7 , 46-51 (1974).
(1968).
(1970).
(1971).
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180 ROBERT L. CLARKE
328. M. Dorer and M. Lubej, Arch. Pharm. Ber. B@ch. €’harm. Urn. 305,273-276 (1972);
329. A. Puech, M. Jacob, J. Dupy, and J. Grevoul, J . Pharm. BeZg. 24, 389-396 (1969);
330. A. Puech, M. Jacob,J. Dupy, and J. Grevoul, J . Pharm.BeZg. 26, 520-524 (1971);
331. W. Wisniewski and H. Piasecka, Acta: Pol. Pharm. 28,55-58 (1971);C A 75,25456q
332. W. Wisniewski and S. Gwiazdzinska,Acta Pol. Pharm. 29, 347-348 (1972);CA 77,
333. I. S. Simon, T. A. Pletneva, T. N. Gubina, and Y. V. Shostenko,Khim.-Farm.Zh. 4,
333a. S . A. H. W alil and S. El-Masry, J . Pharm. Sci. 65, 614-615 (1976).
334. M. J. Solomon and F. A. Crane, J. Pharm. Sci. 59, 1680-1682 (1970).335. Y. V. Shostenko,I. S. Simon, and T. N. Gubina. Otkqtinya, Izobret., Prom. Obraztsy,
336. S . Bukowski and A. Bartosiak, Farm. Pol. 28,125-127 (1972);C A 77,9559m (1972).
336a. A. L. H. DeDujovne and J. Helman, Rev. Farm. (BW?%08ires) 117,66-72 (1975);
337. L. P. Khudyakova, Aktual. V o w . Farm. 1, 127-129 (1970);C A 76,63129~1972).
338. V. Kamedulski, B. Bozhanov, I. Tonev, and M. Dzherova, B’armatsiya (So$a) 25,
CA 77, 39316x (1972).
CA 72, 82995b (1970).
CA 77, 393268. (1972).
(1971).
137031~1972).
58-60 (1970);C A 74, 34639h (1971).
Tovarnye Z m k i 51, 68 (1974);CA 80, 146395f (1974).
CA 85, 2154g (1976).
11-15 (1975);C A 85, 831526 (1976).
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-CHAPTER 3-
NUPHAR ALKALOIDS*
JERZY. W R ~ B E L
University of Warsaw
Warsaw, P o l a d
I. Introduction
........................................................181
11. C,, Alkaloids ....................................................... 181
A. Chemistry....................................................... 181
B. Absolute Configuration............................................ 185
C. New Compounds ................................................. 186
111. Sulphur-ContainingC,, Alkaloids ..................................... 195
197
B. C,, Alkaloids of Carbinolamine Structure.. .......................... 198
IV. Mass Speotromet y .................................................. 204
V. Total Synthesis of CI5 Nuphar Alkaloids ............................... 211
VI. Biosynthesis ........................................................ 213
References ......................................................... 213
A. C,, Alkaloids of Sulfoxide Structure ................................
I. Introduction
Nuphar alkaloids were extensively studied in the last decade mainly
in Poland and Canada, as well as in Japan, the United States, and the
Soviet Union. Several new C15 and thio-C,, alkaloids were isolated.
Special attention was paid to conformational and configurational
problems studied by various chemical and spectral methods. The
fragmentation of both C,, and thio-C,, systems was studied by massspectrometry, and general conclusions were formulated concerning the
mechanism of fragmentation and its structural implications. Preliminary
biosynthetic studies were carried out using I4C-labeledmevalonic acid.
II. C,, Alkaloids
A. CHEMISTRY
Nupharidine and deoxynupharidine were the most extensively
studied C,, alkaloids. Arata et al. ( 1 ) oxidized nupharidine (1) ntodehydrodeoxynupharidine (2) using ferric nitrate. The reaction was
* For the first review on Nuphar alkaloidsby J. T. Wrbbel, see Vol. IX of “The Alka-
loids.” Chapter 10, p. 441.
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182 JERZY T.W R ~ B E L
1 2
shown to have a more general preparative value, as exemplified by
oxidation of 4-phenyl-quinolizidine N-oxide. Several derivatives of
deoxynupharidine (3), substituted in the furan ring, were prepared
b///,,/ e3
3a R = NO13b R = COCH,
3e R = -c> O2
using certain electrophilic reagents (2).5-Acetyl-deoxynupharidinewas
transformed to the 3-hydroxy-2-methylpyidyl erivative (4) on
heating with aqueous ammonia and ammonium chloride (2).
M eI
M e
4
Polonovski transformation of ( + )-nupharidine carried out in a large
excess of acetic anhydride resulted in A6-enamine 5 )(3).Hydrogenation
of 5 resulted in (- deoxynupharidine and ( - -7-epideoxynupharidine
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184 JERZY T. W R ~ B E L
demonstrated that the hydrogen atom eliminated in the Polonovski
transformation was the 6a-hydrogen.
The oxidation of deoxynupharidine to nupharidine was found to bealmost three times faster than the oxidation of 7-epideoxynupharidine.
This was explained in terms of oxidation of deoxynupharidine with
inversion on nitrogen to give a cis-fused quinolizidine N-oxide (10)
(Eq. 3). The cis-fused conformation of nupharidine was confirmed by
H? I
X-ray studies. In view of the cis ring fusion in 1, the Polonovski
transformation was considered to be a t rans8 elimination; the mecha-
nism would then involve the steps shown in Eq. 4.
Me Me
Me Me
(+ )-Nupharidine was transformed to A3-dehydrodeoxynupharidine
11)using a modified Meisenheimer rearrangement ( 4 ) (Eq. 5 ) .
M e
l -
( 5 )
11
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186 JERZY T. W R ~ B E L
h
e
14 15
M eI Me
16
18
C. NEWCOMPOUNDS
1 . 7-Epideoxynupharidine (19)
This alkaloid was isolated by LaLonde et al. ( 9 , 10) from Nupharluteum Sibth. et Sm. subsp. variegatum. The structure was confirmed
by IR and NMR spectra and hydrogenation of As-dehydrodeoxynu-
pharidine ( 5 ) ,which produced deoxynupharidine (3) nd the 7-epiisomer
(19).
Me
19
The NMR spectrum of 19 displayed methyl resonance doublets a t
9.08 and 9.26 T (J = 3 and 5.4 Hz, respectively). In comparison withNMR data for deoxynupharidine (3), he axial methyl groups with
lower field signals and larger splittings and the equatorial methyl groups
with higher field signals and smaller splittings can be correlated-a
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3. N U P HAR ALKALOIDS 187
phenomenon well-known in quinolizidine chemistry ( IO U ) .The absolute
configuration of 7-epideoxynupharidine represented by structure 19
follows correlation through 5 with deoxynupharidine (3).
2. Nuphenine (20) and Anhydronupharamine (24)
20
Nuphenine (20) was isolated first by Forrest et al. (11, l l a ) . Itsmolecular formula was determined as C,,H,,NO (mw = 233). The I R
spectrum shows N-H (3310 cm-l), Bohlmann bands (2800 and 2730
cm-l), furan (1505, 880 cm-l) ; the NMR spectrum indicates the
presence of a substituted double bond (multiplet at 4.88 7 -
Nuphenine can be hydrogenated either to a dihydro compound (21)or
to hexahydro derivative (22) (Eq. 7 ) . The 4.88 signal is absent in the
20
22 21
NMR spectrum of 21, and the peak at 8.3 r (6H,S) in nuphenine is
shifted to 8.75 T (6H,d); his, together with the peaks at mle 164 (M-69)
in the mass spectrum of 20 and at mle 168 in the spectrum of 22,
confirms the presence of the (CH3)2C=CH-CHz- (m/e 69) group in
20. Easy loss of this group suggests that it is located in the position
alpha to nitrogen in the piperidine ring. SinceH, is split by only one ring
proton, the methyl group is assumed to be located on the adjacent
carbon; the protons H, and H, with a coupling constant of 2.5 Hz must
be in an axial-equatorial or equatorial-equatorial relation to one another( 1 2 ) .The presence of bands at 2800 and 2730 cm-l in the IR spec-
trum of nuphenine was taken as evidence for t.wo hydrogens axial to the
nitrogen atom. The proposed configuration ofnuphenine is shown in 23.
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188 JERZY T.W R ~ B E L
~ b - k - ~ e\ /Me
He /C=C\Me
23
Isomeric with nuphenine is anhydronupharamine (24) isolated by
Arata et al. ( 13 , 1 4 ) from Nuphar japonicum DC. It proved to beidentical with the dehydratation product of (- -nupharamine (15) and
therefore it s configuration should be as in 24.
24
3. Nuphamine (17)
17
The chemistry of this alkaloid was further studied and its configura-
tion was related to deoxynupharidine (3) and nupharamine (15). The
transformations in Eq. 8 have been effected. On the basis of Eq. 8,
nuphamine is thought to have configuration 17. A study of the con-
figuration around the double bond in nuphamine led to the conclusion
th at in the side chain the methyl group and hydrogen were in the transposition ( 1 5 ) .This deduction is based on a general observation that inthe X-CH,-C(CH,)=CH,-Y system a trans relationship between
the methyl group and the vinyl proton results in a higher r value
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3. N U PHAR ALKALOIDS 189
Na2C03, C H d17 24
( A T = 0.06-0.07) for the methyl protons than that observed for the
cis isomer. Thus, the absolute configuration 27 of nuphamine (17) was
established:
4. 3-Epinuphamine (28) (C,,H2,N02)
The alkaloid was isolated by LaLonde et al. ( 1 6 ) from Nupharluteum subsp. variegatum and was shown to have configuration 28. I ts
molecular formula was confirmed by mass spectroscopy. The IR and
NMR spectra indicate the presence of a %fury1 group. Attachment of
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190 JERZY T.W R ~ B E L
this group to the carbon a to nitrogen (C-6) was concluded from the
presence of the proton (3 . 58 6) deshielded by the fury1 group and the
nitrogen. The presence of OH and NH groups was established inthe conversion of 28 to an N,O-dibenzoyl derivative. The presence of a
28
trisubstituted double bond was indicated by the I R and NMR spectra;
the latter showed a hydroxymethyl group (3 . 93 6, 2H, broad singlet), a
vinyl methyl group (1.65 6, 3 H , broad singlet), and a methylene group.
The trans stereochemistry of the double bond was based on the charac-
ter of the vinyl proton signal in the NMR, as it was shown in nuphamine
( 1 5 ) .Oxidation of 28 with MnOz resulted in an aldehyde (29), giving
additional support to the proposed double bond stereochemistry. The
F YM eM e
29
UV spectrum of this aldehyde was in accord with known trans-2-methyl-
2-pentanal. a-Attachment of the side chain to nitrogen was consistent
with the appearance of an ion at m/e 164 ( l O O ~ o ) n the mass spectrum.
The NMR spectrum showed the C-2 proton as a triplet of doublets,
which could be explained as a coupling to the side chain methylene
group and to a single proton. This implied substitution a t C-3 of a
methyl group whose presence is indicated by a doublet at 0 . 99 6.The substitution pattern in piperidine was determined by converting
both the N,O-dibenzoyl derivative (30) and nuphenine benzamide to
the aldehyde (32):
0
30
31
R = CH,OCOCeH,, R’ = C e H 5 C 0
R = Me, R’= CeH,CO
32
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3. N U PHAR ALKALOIDS 191
The presence of an axial methyl group at C-3 is implied by a doublet
a t 0.99 6, which is at a lower field than the resonance (0.91 6) displayed
by the equatorial methyl of nuphamine. Other characteristics of NMRspectra are consistent with this assignment.
5 . Nupharolidine (33) C,,H2,N02)
33
This alkaloid isolated from the rhizome of Nuphar luteum by Wr6bel
and Iwanow ( I Y ) ,was the first among the C,, alkaloids to be shown to
have its hydroxyl group situated in the quinolizidine ring.
The suggested structure of this alkaloid was based on spectroscopic
correlation (IR , NMR, and mass spectra) with three other C,, bases-deoxynupharidine (3),castoramine (34), and nuphamine (17). The
M e
34 R1 CHaOH, Ra = H
crucial observations pertaining to the structure beside the trans-
quinolizidine and a B-substituted furan ring indicated the presence of
two CH-CH, groups ( T = 9.12 and 8.80; doublets), CH,-O&
( 7 = 6.35, and 4.75,; IR, 3342 cm-l).
The presence of two methyl groups, which appear as two doublets,ruled out the presence of a hydroxymethyl group and eliminated the
possibility of C-1 and C-7 being the points of O H substitution. Since a
strong signal at mle 178 (fragment 35) was observed in the mass
spectrum the presence of an OH group at C-6 position was also ruled out.
\ \
/ /
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192 JERZY T. W R ~ B E L
M e
35
The presence of the fragment 35 and of two others at mle 7 1 and 206
to which structure 36 and 37were ascribed, respectively, point to C-9 as
the location of the hydroxyl group. Thus, nupharolidine is thought to
have structure 33.
36
m/e 7 1
37m/e 206
6. Nupharolutine (38) (C,,H,,NO,)
Nupharolutine is another C,, alkaloid with a hydroxyl group. It was
isolated and its structure was established by the Polish-Canadian
group of workers (18).It is isomeric with nupharidine (1) and castor-
amine. Structure 38 for nupharolutine was based on spectroscopic and
chemical data.
M e
38
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3. NUPHAR ALKALOIDS 193
The IR spectrum shows the presence of an intermolecularly bonded
hydroxyl group and a trans-quinolizidine system. Unsuccessful at-
tempts at acetylation indicate the tertiary character of the hydroxyl.The NMR spectrum of the new alkaloid shows a doublet centered a t
0.92 and a singlet (3H) at 1.21 6. The singlet peak and its chemical shift
are compatible with a -C --C(CH3)OH-C-- grouping in the molecule.
Other signals in the NMR spectrum were in accord with those observed
for deoxynupharidine and indicated the presence of a p-substituted
furan ring in the equatorial position (C-4-Haxial uartet 3.03 8 , J = 8.3
and 6.0 Hz). The final data for structure 38 were obtained from themass spectrum. High resolution studies gave the composition of the ions
observed, thereby giving further insight into the fragmentation process.
The fragmentation is discussed later with that of other Nupharalkaloids.
Nupharolutine was correlated wiih deoxynupharidine (3)as in Eq. 9.
I I I
I I I
This sequence offers the final proof for the proposed structure and for
the absolute configuration of nupharolutine. A dimeric compound
related to nupharolutine was isolated by LaLonde et al. (19).Spectro-
scopic data indicate structure 39. This structure was confirmed by a
synthesis beginning with dehydrodeoxynupharidine (14) (Eq. 10).
Osmium tetroxide oxidation of 14 yielded diol 40, which wa,s trans-
formed upon dehydration into 39, borohydride reduction of which
generated a mixture of 41 and 42.
Me
M e
39
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194 JERZY T. W R ~ B E L
14
40
b R 2i
Q4 1 Rl = O H , R, H
42 Rl = H RZ = OH
NaBH 9
7. Epinupharamine (Epi-15) (C,,H,,NO,)
3-Epinupharamine (epi-15) was isolated by Forrest and Ray who
established its structure. Its structure was proved on the basis of its
spectra and by its synthesis from nuphenine (20). Mass spectrometry
confirmed the molecular formula and the presence of the 3-methyl-3-
hydroxybutyl side chain (peak at mle 164). The IR and NMR spectra
Epi - 15
showed the presence of the hydroxyl group (3575, 3150 em-, and
T = 7.35) and the furan ring (IR, 1500, 1170, and 875 cm-l; NMR,
2.63 (2H), 3.57 (1H) T ; CH-CH, (ring) 9 .03~d nd a gem-CH, 8.83 T,
8.75 T). This assignment of the structure and stereochemistry was
verified by the conversion of nuphenine (20) into a compound identical
with the naturally occurring epi-15.
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3. N U PHAR ALKALOIDS 195
111. Sulfur-ContainingC,, Alkaloids
Thiobinupharidine (43) (C3,H,,N,02S)
" A s
43
It was shown earlier (20 , 21) that 43 is isomeric with neothiobi-
nupharidine (44) and both 43 and 44have almost the same characteristic
structural pattern (quinolizidine, furan, -S-CH,-, two methyl
groups, and similar pK, values). Extensive spectroscopic studies led todeduction of the structure and of the relative configuration of 43. The
structure has been firmly established and the absolute configuration
has been determined by a study of the crystal structure of thiobinu-
pharidine dihydrobromide dihydrate ( 2 2 ) .
The structure of thiobinupharidine was established by Wr6bel and
MacLean ( 2 2 )by comparing the IR , NMR, and mass spectra with those
previously obtained for neothiobinupharidine (44) ( 2 0 ,2 1 ) . The I R and
NMR studies ( 2 3 )of the alkaloid in question, of some model compounds,
and of reduction products of biscarbinolamines led LaLonde to thesame conclusion. Equimolecular solutions of 43 and 44 examined under
the same conditions showed Bohlmann bands of nearly equal intensities.
This indicates the presence of two trans-quinolizidine rings in 43.
High-resolution mass measurements showed identical compositions of
the major ions in the spectra of 43 and 44. The NMR spectra of the two
alkaloids have been examined at 220 MHz, and the anomalies of the
earlier studies (20 , 21 ) have been clarified. There is a signal of area 6
centered at 6 0.91 ( J = 5 Hz) assignable to two CH-m groups
(compare 6 0.85, J = 5.5 Hz for 44 and 6 0.92, J = 5.6 Hz, for 3 assignals for the equatorial methyl groups). Observations concerning the
furan proton are in accord with those made earlier ( 2 0 , 2 1 ) . In the
region 6 2.7-3.08, complex signals of area 4 appear that are attributed
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196 JERZY T. WROBEL
to two protons in the furan ring (a t C-4 and C-4') and to the two equa-
torial protons at C-6 and C-6'. These assignments are made by analogy
with the chemical shifts of the corresponding protons in 3.The spectrum of 43 also contains a well-defined AB pair of doublets
centered at 6 2 . 3 2 (J = 1 1 . 5 Hz) and attributed to the CH2-S group
(compare with a singlet at 6 2 . 6 7 , W + = 3 Hz, in the spectrum of 44).
By analogy to the studies on model compounds ( 2 4 ) the absorption of
the thiomethylene group suggests an equatorial conformation of the
CH2-S with respect to the quinolizidine ring.
0-
44
The equatorial linkage of the sulfur atom to the second ring was basedon evidence presented by LaLonde (25) for the equatorial character of
the C-7-S linkage in thionuphlutine A , which in turn was shown to be
identical with thiobinupharidine.
All the evidence indicates structure 43 or thiobinupharidine. It has
been confirmed by an X-ray crystal structure determination of thiobinu-
pharidine dihydrobromide dihydrate. The observed bond lengths are in
good agreement with the accepted values. The only bond that exceeds
the average value is that between C-17' and C-7'. The alkaloid has a
pseudo-twofold axis. The nonpolar character of the S-containing ringand the inequivalence of S and C-17' destroy this element of symmetry.
LaLonde et al. (23)provided further evidence consistent with structure
43.
The 1 0 0 MHz NMR spectrum of thiobinupharidine determined in
benzene shows the two C-4 protons as two overlapping quartets both
with splittings of 1 . 5 and 1 0 Hz. Such a splitting pattern may be
ascribed to an axial (3-4 proton rather than to an equatorial one.
Evidence for the stereochemistry of the C-1 and C-1' methyl group
comes from the direction of the solvent-induced shift of the C-1 methylgroup observed in the NMR spectrum. The C-7 axial methyl group in
deoxynupharidine is shifted downfield by 4 . 2 Hz and the C-1 equatorial
methyl is shifted upfield by 5.0 Hz when deuterochloroform is replaced
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198 JERZY T. WROBEL
B. C,, ALKALOIDSP CARBINOLAMINE TRUCTURE
A number of C,, sulfur-containing alkaloids have hydroxyl or alkoxylgroups in the 6 position to the nitrogen atom (27-30) . Compounds of
that type of structure are listed in Table I1 (23 , 26-34) (Compounds
2-1 0). Spectroscopic chemical and mass spectrometric studies (see
Table I) led to the structures of a number of carbinolamines.
Nuphleine (46) (C,,H,,N,O,S) was shown to have two hydroxyl
groups. Sodium borohydride as well as catalytic reduction yielded
thiobinupharidine (43). Thus, nuphleine was shown to be a dihydroxy
derivative of 43.
Thionupharoline (47) (C,,H,,N203S) recognized first as a mono-hydroxy derivative of the C,,H,,N202S alkaloids ( 2 8 ) was recently
proved by MacLean, Wrbbel, et al. ( 3 1 ) o be 6-hydroxythiobinuphari-
dine, a compound identical with 6-hydroxythionuphlutine A isolated by
LaLonde ( 2 3 ) ,who independently elucidated its structure.
The alkaloid was isolated as its immonium ammonium diperchlorate,
which revealed in the I R spectrum the presence of the C = N band
a t 6 . 0 2 ~nd R,N+H absorption at 4 . 3 5 ~ . he immonium monoper-chlorate showed Bohlmann bands a t 3 . 6 0 ~ . hese observations sugges-
ted the dual amine-hemiaminal character of the free base. The latter
recovered from the perchlorate showed in its mass spectrum the highest
mass fragment at m/e 492 (M+-H,O). The I R spectrum revealed
Bohlmann bands and absorption characteristics of the 3-fury1 group,
whereas the NMR spectrum showed the presence of one proton ex-
changeable with D20.Reduction of 51 with sodium borohydride results
in thiobinupharidine (43), and reduction with sodium borodeuteride
gives thiobinupharidine-6-d,. Since the NMR spectrum displays a
singlet a t 6 3.98 attributed t o the proton HO-C€J-N , a o nitrogen
and t o the hydroxyl group, the lat ter can only be located a t C-6or C-6'.
The location of the hydroxyl group a t the C-6 position was supported
by NMR and MS studies of the thiobinupharidine-d, obtained by
reduction of 51 with sodium borodeuteride. NMR spin decoupling
experiments on the deuterated sample showed C-6' axial and C-6'
equatorial protons at 6 1.41 and 3.16, resp and a C-6 axial proton at6 1.91. These findings demonstrate that the C-6 position was reduced
stereospecifically with the introduction of an equatorial deuterium.
Incorporation of the equatorial deuterium indicated that the hydroxyl
\ + /
/ \
/
\
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TABLE IC1, Nuphar ALKALOIDSND THEIR ROPERTIES
Compound
Melting point
oormula ("C)
7-Epideoxynupharidine (19) C15H23NO - - 9
Nuphenine (20) (anhydronupharamine) CI5Hz3NO - -23 (Hg)
-Epinuphamine (28) Ci,Hzi"zNupharolidine (34) C15H2,N02 110 -
Nupharolutine (38) C15H23N02 9&98 - 105
7 -Epinupharamine (epi-15) c1a sNO2 -
- -41.5
6,7-Oxidodeoxynupharidine 39) C3,H*2N20, 165-170 - 9 3-
a Cf. Table I in Wr6bel (5).
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TABLE I1
NATURALLYOCURRINQc30SULFUR-CONTAININQALKALOIDSND THEI
Compound
Melting point
Formula ("C) an Melting p
Neothiobinupharidine sulfoxide (45)
Thionupharoline (47)
(6-hydroxythiobinupharidine)
6-Hydroxythionuphlutine B (54)
6'-Hydroxythiobinupharidine (55)
6,W-Dih ydroxythiobinupharidine
6,6'-DihydroxythionuphlutineB (53)
Nuphleine (46)
Thionupharodioline (48)
Ethoxythiobinupharidine (49)Diethoxythiobinupharidine (50)
(6,6'-dihydroxythionuphlutineA) (52)
240-242
Amorphous
Amorphous
156-158
Amorphous-
-
- 2HC104,
C104
+34 2HC104,
+44.5 2HC104,
- 2HC104,
- ~ H C ~- 2HC104,
- 9
-
a Cf. Table I1 in Wr6bel ( 5 ) .
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3. N U P H A R ALKALOIDS 201
group is located a t C-6, since th e reduction a t C-6' results in incorpora-
tion of an axial deuterium atom. The stereochemistry of the reduction
was established through studies on 6,6'-dihydroxythiobinupharidineand on model compounds (23).In addition, it was pointed out ( 2 3 , 30)th at the fragments of m/e 228 (37-3970) and 176 (37-10070) observed
in the spectra of 6,6'-dihydroxy Nuphar C, , alkaloids, although present
in the spectra of thio- and neothiobinupharidine, are of very low
intensity. The appearance in th e mass spectrum of 6-hydroxythiobinu-
pharidine of these fragments with intermediate intensities (62 and goy0)seems to confirm the presence of one hydroxyl group a t the 6- or 6'-
position in 51.
MeIp'-'\
mle 228 m/e 178
MacLean, Wr6be1, et al. (31) presented further experimental data,
which led to structure 51 for thionupharoline (47). Of special value
were extensive NMR studies a t 220 MHz, which very clearly recognized
the following protons (in CDC1,); 6 2.26 ( O H exchangeable with D,O),
2.89 ( lH , C-4'), 2.92 ( l H , C-6 H eq), 3.70 ( l H , C-4), and 3.97 ( lH, C-6
sharpens on addition of D,O).
The 220 MHz NMR spectrum of thiobinupharidine-6d (obtained
from the reduction of 47 with sodium borodeuteride) allowed the
protons a t C-4 (4') and C-6) (6') to be more precisely recognized.The following data were obtained in CDC1,: 6 1.45 (C-6' H,,), 1.70
(broad singlet superimposed on envelope C-6 H,,), 2.79 (0.55, C-6 H,,),
M e
51
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202 JERZY T. W R ~ B E L
2.93 (C-4 H, C-4’ H), 2.93 (C-6’ Heq); nd in CsD,: 1.40 (C-6’ H,,),1.93 (0.32 H, C-6 H,,), 2.80 (2H, C-4’ Ha, and C-4 H,,), 3.10 (0.62 H,
6,6’-Dihydroxythiobinupharidine 6,6’-dihydroxythionuphlutine )
(52) (C3,H4,N2O4S)was first isolated by LaLonde et al. (89) from
C-6 Heq),3.18 (1.04 H, C-6’ Heq).
1 7 ’7 s
52
Nuphar luteum subsp. macrophyllum ( 2 3 , 31, 33). The NMR spectrum
a t 220 M Hz ( 3 1 ) showed signals at 6 3 . 9 8 ( l H , C-6 Heq)and at 4.24
( l H , C-6’ Heq) in CDCl,. I n C6D6+ D,O solution, these protons
appeared at 6 4.23 (1H, C-6 Heq)and 4.35 ( lH , C-6’ Heq).An axialconfiguration was assigned to the hydroxyl groups a t C-6 and C-6‘.
Thionupharodioline (48) C,,H,,N,O,S is isomeric with 52. Wr6bel
et al. ( 3 0 )suggested that the two alkaloids differ in the configuration a t
C-6 and C-6’. It was isolated from Nuphar luteum (Polish origin) and is a
crystalline solid of mp 156-158°C. Both potassium borohydride and
catalytic reductions resulted in thiobinupharidine. The strong hydrogen
bonding observed in the IR spectrum and the very low intensities of the
Bohlmann bands indicate equatorial configurations for O H groups at
C-6 and C-6’. The proposed structure (48) is shown below.
M e
48
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3. N U P H A R ALKALOIDS 203
Ethoxythiobinupharidine (49) and diethoxythiobinupharidine (50)
were isolated from Nuphar luteum ( 3 0 ) .Their structures were based on
on IR , NMR, and mass spectrometry studies as well as on the productof reduction with potassium borohydride, which in both cases gave
thiobinupharidine (43).The configuration of the ethoxyl groups has not
yet been established. Since no ethylating agents were used during the
49 R1 = O E t , R, = H or R, = H , R, = OEt
50 R, = R, = OEt
isolation procedure of 49 and 50, the ethoxy group could not have been
introduced during the process ( 3 0 ) .The structure of 6,6'-dihydroxythionuphlutine (53) (C,,H,,N,O,S)
isolated by LaLonde (29)was recognized as isomeric with those of both
thio- and neothiobinupharidine ( 2 3 , 3 2 )dihydroxy- derivatives. On the
53
54
R,,R, = H,OH; R,,R4 = H, OH
R1, R, = H, H; R, = R, = H
basis of extensive NMR studies of 53 and of its deuterated reductionproducts, it was possible to show that this alkaloid contains an axial
sulfur atom attached to t he A B quinolizidine system and an equatorial
-CH2-S- group attached to the A'B' quinolizidine system.
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204 JERZY T. W R ~ B E L
6-Hydroxythionuphlutine B (54) is another monohemiaminal
isolated and investigated by LaLonde ( 3 4 ) .The evidence for the position
of O H group was based on NMR, mass, and CD data. The significantdifference in the chemical shifts of the carbinyl hemiaminal protons
were observed (for C-6 and C-S’, 4.08 and 3.94 6, respectively).
The mass spectrometry of thiaspiran singly labeled by deuterium
showed a mle 1 7 8 to m/e 179 shift. It was found th at the singly deuter-
ated thiaspirans th at were labeled at C-6 resulted in m/e 178 shifting to
1 7 9 by g o y o , and those labeled a t C-6’ resulted in a 10% shift only. The
CD of C-6’ hemiaminals in acid solution showed positive bands but
those with C-6 hydroxy substitution showed both positive and negative
bands. These results allowed LaLonde ( 3 4 ) to establish the structureof 6’-hydroxythiobinupharidine 55) (C,,H,,N,03S).
IV. Mass Spectrometry
Considerable progress has been made in the mass spectrometry of
Nuphar alkaloids C,, and C3,,. MacLean and Wr6bel gave the basic
mechanism of the fragmentation of several types of Nuphar alkaloids
using high-resolution mass spectrometry. The mass spectra of followingC,, alkaloids were recorded: deoxynupharidine (3), upharidine ( l ) ,
castoramine (34), nd nupharolutine (38) see Scheme 1 ) . The mass
Me M e
C
SCHEME
D
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3. N U P H A R ALKALOIDS 205
spectrum of deoxynupharidine was first reported in 1964 ( 3 5 ) . High
resolution studies confirmed the composition assigned to the intense
ions in the previous work ( 3 5 ) and allowed the composition of lessintense ions to be determined.
The fragmentation involves the four bonds in position /3 to nitrogen,
to yield molecular ions A, B, C, D. The ion C either splits further into
homologous ions a, b, c or undergoes the retro Diels-Alder reaction to
yield ions d and e. Ions D and C can also result in ions f and g. Another
pa th of decomposition of 3 consists in a loss of the furan ring and forma-
tion of the h ion (Scheme 2).
The formation of the major ions in the spectrum of 3 is shown in
Scheme 3. All the major ions at m/e = 136 ( j ) , 98 (k), 97 (l),94 (m), and55 (n ) originate in the ion C.
When fragmentation proceeds with hydrogen transfer, as shown in
route 3d (there is no evidence that the hydrogen actually originates
from site C-2, as schematically shown), the resulting ion is k a t m/e 98.
The recent labeling studies (29) are in accord with the structure
proposed for these ions. Further fragmentation of the ion j , a t m/e 136,
has also been observed (cf. Scheme 3 routes 3e and 3f).
Fragmentation of castoramine (34)is similar to th at of deoxynuphari-
dine, as shown by parallel Schemes 1-3. The spectrum of 34 shows ionsabsent in the spectrum of 3, owing to the presence of the hydroxyl
group, as also shown in Schemes 1-3.
Recent work ( 2 6 ) on the spectra of neothiobinupharidine (44) nd
related systems showed that the dimeric compounds have many ions
in their spectra whose formation may be interpreted in terms of the
schemes suggested above. The fact that the fragmentation of 3 and 34
and many of the fragmentations of 44 may be interpreted through
Schemes 2 and 3 lends credibility to them.
The hydroxyl group present in 34 leads to new ions in its spectrum,
which are absent in the spectrum of 3.Thus, a strong ion a t m/e 96
can be ascribed to 34K-H20;an ion a t m/e 164 to 34K-H20and the ions
a t m/e 218 and 219 to the loss of C H 2 0 and C H 2 0 H from the molecule
as shown in Scheme 4. The spectrum of nupharolutine (38) has many
features in common with that of castoramine, but it is distinctly
different from that of nupharidine.
The differences between the spectra of 38 and 34 are compatible with
the structural differences. Thus, the loss of Me and OH is favored more
in 38 than in 34 as would the formation of ion f. The spectra bear this
out. It should be noted that the loss of H20 from m/e 114 to form m/e
96 is more pronounced in 38, the tertiary alcohol, than i t is in 34, he
primary alcohol.
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206 JERZY T.W R ~ B E L
a b C
3 m/e 204 (Cl3H1,NO) m/e 190 (ClzH16NO) m/e 178 (CllHl,NO)
38 and 34 m/e 220 (Cl,Hl,NOa) m/e 204 (C12H16NOz) mle 192 (C1iHiiN"a)
y cJ? P M e
d e h
3, 38, nd 34 3, 38,and 34 3 mje 166 (C11HaoN)
m/e 162 (Cl,H12NO) m/e 148 (C,H,,,NO) 38 and 34 m/e 182 (ClIHa0NO)
C'I D f
M e
( J Q R z H transfer I ';z3, 38, and 34 n / e 178 (C,,H,,NO)
g C
SCHEME
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3. N U P HAR ALKALOIDS
Route 3b
d’2‘NQR, K . 1
0 0
j
3. 38. and 34 m/e 136 (CsH,,O)
V
207
3 m/e 97 (C,H,,N)
38 and 34 m/e 113 (C&,,NO)
3, 38, and 34
mle 55 C,H,N)
0
m/e 136 (C,H,,O)
k
3 m/e 98 (C,H,,N)
38.34 m/e 114 (C.H,,NO)
\ * 3,38,and 1 4
3, 38, and 34
m /e 94 (C,H,O)
rn
SCEEME
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208 JERZY T. W R ~ B E L
mle 219 mle 218
SCHEME
The spectrum of nupharidine ( l ) ,ike those of other N-oxides, showsthe loss of oxygen and OH [peaks a t r n /e 232 and 231 ( 3 6 ) ] .The peak
at m/e 220 does not result from loss of an ethyl fragment but from loss of
CHO, a fragmentation characteristic of furans.
In Scheme 5 , suggestions are made for the derivation of the major
ion at m/e 114 and related fragments based upon a determination of
their compositions by high resolution studies (18).MacLean and Wr6bel
( 2 6 )have also suggested a mechanism of fragmentation of C,, alkaloids,
such as neothiobinupharidine (44),hiobinupharidine (43), and neo-
thiobinupharidine sulfoxide (45). pectra of these compounds show anumber of ions identical with those shown in Schemes 1-3.
Fragmentation of neothiobinupharidine (44) and of related systems
M e M e Me
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3 . N U P HAR ALKALOIDS 209
( 2 6 ) ,as well as of 54, can also be interpreted in terms of Schemes 2-3.This lends credibility to the suggested reaction paths.
Ions at m/e 461 and 4 4 7 have no counterpart in the spectrum of 3,and they owe their origin to the loss of SH and CH,SH, respectively,
from the molecular ion. An ion at mfe 359 formed by loss of C,H,,O
Me
44
from the molecular ion may be represented as in Scheme 6. The anal-
ogous ion in 3 appears at m/e 9 8 . If hydrogen transfer does not occur
and the charge remains with the furan moiety an ion at mle 136 results
with the same mass and composition as in the spectrum of 3.
The spectrum shows ions at mle 230, 178, 107, and 9 4 besides that at
mle 1 3 6 . The ions at mfe 94 and 107 , which also appear in 3 can be
M e
H transfer/J
Me
m/e 359, C,,H,,N,OS
+
SCHEME
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2 1 0 JERZY T. W R ~ B E L
formed from 44 in a similar way. The structure of the ion a t m/e 230(C,,H,,NO) is formulated and derived as shown in Scheme 7 . If a
hydrogen is transferred to the sulfur-containing fragment and chargeis retained on this fragment, the ion at m/e 264 is observed (C15H22-
NOS). The most intense ion of the spectrum a t m/e 178 corresponds in
Me
44 M + = 494
mle 231
Me M e
m/e 264, C1,H,,NOS m/e 230, C,,H,,NO
SCHEME
composition t o C,,H,,NO. Its derivation is shown in Scheme 8. Charge
is also carried by the residual fragment, for a peak of low intensity isalso present a t m/e 316 (CISH,,NOS). An ion of m/e 178 is present in 3,
but i ts intensity is relatively weak.
I n their study of the reduction products of the thionuphlutines,
LaLonde et al. (29)came to t he same conclusion regarding the derivation
of the ions a t m/e 178 and 230 . New fragments due to the oxygen
function on sulfur appear in th e spectrum of 45, which has a sulfoxide
structure bu t the general pathway of fragmentation remains unchanged.
The mass spectrum of 45 shows losses of SOH and CH,SO from the
molecular ion at m/e 461 and 447 paralleling the losses of SH andCH,SH from neothiobinupharidine. An intense peak a t m/e 4 9 3
corresponds to the loss of OH. The rest of t he spectrum of 45 is similar
to tha t of neothiobinupharidine. Thus, the peaks a t m/e 230, 178, 136,
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3. N U P H A R ALKALOIDS 211
44 M + = 494
* I+Me
Me1
+\CH,
107, and 94 are all present and have composition identical with those
found in the spectrum of 44. ons of low intensity are also present at
m/e 280 (C,,H,,NO,S), 262 (280-HZO), 375 (C,,H,,N,O,S), and
(357-H20). The mle 280 ion is cognate to mle 230, while m/e 375 is
cognate to mle 136-H.
V. Total Synthesis of C,, Nuphar Alkaloids
Racemic forms of nupharamine (15) and 3-epinupharamine (epi-15)
were synthesized by Szychowski et al. (37) from @-acetylfuran(56)
(Eq. 12). The Claisen type condensation of 56 with ethyl formate
resulted in ketoenolate 57, which with /I-aminocrotonate yielded the
furylpyridine derivative (58 ) (Eq. 13).
C-CHSHONe
(12)W E t l 0
56 57
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212 JERZY T.W R ~ B E L
NH2I CO,Et
Me-C-CH-COzEt
benzene/AcOH57
M e
58
The O H group in compound 59, obtained by LAH reduction of 58,
was replaced with hydrogen resulting in 60. This compound in the
presence of NaNH,/liquid NH, reacted with ,t?-methallyI chloride.
Compound 61 had the required carbon skeleton; the NMR proton
characteristics are given in 61. Nupharamine and 3-epinupharamine
7.3803)
HI 2.31
1.84M e
(2M.92H~ r ~ N ^ . H 2 - c H 2 - c ~ ~ 2
2.92 2.5 4.78
(2)7.5H 10; ) (10: 5)
8.05
61
were prepared from 61 in two steps. The first consisted in the selective
and stereospecific hydrogenation of 61 with sodium/ethanol in xylene
resulting in a mixture of epimers 62 on carbon C-3 with both equatorial:fury1 group and the side chain. Compound 62 was hydrated with formic
acid (catalytic amount of HCIO,) ; subsequent chromatography on
alumina resulted in two racemates of ( )-nupharamine and ( & )-3-
epinupharamine.M eb:.*
NH /
-
6
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3. N U P H A R ALKALOIDS 213
VI. Biosynthesis
The sesquiterpenoid structure of Nuphar alkaloids suggests thattheir carbon skeleton may be derived from mevalonic acid, but the
biosynthesis of the furan and spirotetrahydrothiophene rings can not
be clearly predicted. Preliminary evidence indicates that label from
[3,4-14C]mevalonateenters thiobinupharidine (38).Partial degradation
was carried out, but the results remain inconclusive, since their inter-
pretation was based on a structure of thiobinupharidine that was
incorrect. Incorporation of [1 ,5-14C]cadaverine ( 3 8 ) was presumably
indirect.
REFERENCES
1. Y. Arata, S. Yasuda, and K. Yamanouchi, Chem. Pharm. Bull. 16,2074 (1968).
2. Y. Arata and K. Yamanouchi, Yakugaku Zasshi 91, 76 (1971) .
3. R. T. LaLonde, E. Auer, C. F. Wong, and V. P. Muralidharan, J. Am . Chem. SOC.
4. R. T. LaLonde, J. T. Wooleveler, E. Auer, and C . F. Wong, Tet . Lett. 1503 (1972) .
5. J. T. Wr6be1, i n “The Alkaloids” (R. H. F. Manske, ed.), Vol. IX, p. 450, 1967.
6. D. C. Aldridge, J. J. Armstrong, R. N. Speake, and W. B. Turner, J . Chem. SOC.
7. C. F. Wong, E. Auer, and R. T. LaLonde, J . Org. Chem. 35, 17 (1970) .
8. K. Oda and H. Koyama, J . Chem. SOC. 450 (1970) .
9 . C. F. Wong and R. T. LaLonde, Phytochemistry 9, 417 (1970) .
93, 2501 (1971) .
Academic Press, New York.
1667 (1967).
10. C. F. Wong and R. T. LaLonde, Phytochemistry 9, 59 (1970) .
10a. T. M. Moynehan, K. Schofield, R. A. Y. Jones, and A. R. Katritzky,J. ChemSoc.
11. R. Barchet and T. P. Forrest, Tet . Lett. 4229 (1965).
l l a . T. P. Forrest and S. Ray, Can. J . Chem. 49, 1774 (1971) .
12. C. Y. Chen and R. J. W. LeFevre, J . Chem.SOC. 467 (1965) .13. Y. Arata, T. Ohashi, M. Yonemitsu, and S. Yasuda, Yakugaku Zmshi 87, 1094
14. Y. Arata end T. Ohashi, Chem. Pharm.Bull. 13, 1247 (1965).
15. Y. Arata and T. Ohashi, Chem. Pharm. Bull. 13, 1365 (1965) .
16. C. F. Wong and R. T.LaLonde, Phytochemktry 9, 851 (1970) .
17. J. T. Wr6bel and A. Iwanow, Rocz. Chem. 43, 997 (1969) .
18. J. T. Wrbbel, A. Iwanow, C. Braeckman-Danheux, T. I. Martin, and D. B. MacLean,
19. R. T. LaLonde, C. F. Wong, and K. C . Das, J.Am . Chem. SOC.4, 522 (1972).
20. 0. Achmatowicz and J. T. Wr6be1, Tet. Lett. 129 (1964).
21. G. I. Birnbaum, Acta Crystabgr. 23,526 (1967) .22. J. T. Wrbbel, B. Bobeszko, T. I. Martin, D. B. MacLeen, N. Krishnamachari, and
23. R. T. LaLonde, C. F. Wong, and K. C . Das, J . Am . Chem.SOC.5, 342 (1973) .
24. R. T. LaLonde, C. F. Wong, and H. G . Howell, J . Org. Chem. 36, 3703 (1971) .
2637 (1962).
(1967) .
Can. J . Chem. 50, 1831 (1972).
C. Calvo, Can. J . Chem. 51,2810 (1973).
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-CHAPTER4
THE CELASTRACEAE ALKALOIDS
ROGERM. S ~ H
School of Natural Resources
The University of the South Pacijk
Suva, Fiji
I. Introduction ....................................................... 215
11. Occurrence and Isolation ............................................ 216
111. Structures of Esters of Nicotinic Acid ................................. 219
219
B. Esters of C 1 5 Hz 6 0 6Polyols ....................................... 224
C. Esters of Cl5HZ6O7Polyols ....................................... 224
D. Esters of Cl5HZ6Os Polyols ....................................... 226
IV. Structures of Diesters of Subs tituted Nicotinic Aci ds .. .................. 227
A. Structures of the Diacids ......................................... 227
229
231239
241
VI. Biosynthesis ....................................................... 245
VII. Biological Properties ................................................ 246
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
A. Esters of Cl5HZ6O5Polyols .......................................
B. Esters of Cl5HZ4O9Ketopolyol ....................................
C. Esters of Cl5HZ4Ol0 Ketopolyol.. ..................................D. Esters of C15H260, , Polyols.. .....................................V. Structures of Related Sesquiterpene Esters an d Polyols.. . . . . . . . . . . . . . . . .
I. Introduction
In 1970 the structures of the nicotinoyl alkaloids maytoline (I)*andmaytine (2) from Maytenus ovatus Loes. (Celastraceae) were reported as
prototypes of a new family of alkaloids ( I ) . Subsequently, the closely
related structures or partial structure for twenty-two further alkaloids
from a number of different species in the family Celastraceae have been
elucidated. They all contain either a nicotinate or substituted n k o -
tinate group and are polyesters of hydroxy derivatives of dihydro-
agarofuran (3).7The other ester groups can include benzoate, acetate,
and 3-furoate. Many of these alkaloids had been isolated previously,
* All the sesquiterpene polyols have been aasumed to have the same absolute stereo-
chemistry as bromoacetylneoevonine (SO), the only member of the series to have been
fully elucidated.
t The sesquiterpene nucleus is numbered in accordance with Chemical Abetracts.
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216 ROGER M. SMITH
but their structures had not been fully elucidated, although in most
cases the presence of a C,, nucleus and a nicotinic acid group had been
recognized.A number of closelyrelatednonbasic sesquiterpene polyestersand free polyols have also been reported.
This review covers the isolation and chemistry of the nicotinoyl
polyester alkaloids reported up to late-1975. Previous reviews of the
pyridine alkaloids ( 2 , 3 ) have included the substituted nicotinic acids,
but the full structures of the alkaloids were not then known. More general
reviews of members of this family have considered the constituents
including alkaloids of Khat (Catha edulis Forskal) ( 4 , 5 ) and the
pharmacology of alkaloids and terpenes from the Celastraceae and
Hippocrateaceae ( 6 ) .
CH3
1 Maytoline R = OH
2 Meytine R = H
11. Occurrence and Isolation
The first report of the presence of highly oxygenated C,, ompoundsin the Celastraceae was during a study in 1938 of the seed oil ofCelastrus
paniculatus Willd. (7) . Hydrolysis of a methanol-soluble fraction
yielded formic, acetic, and benzoic acids, and a tetraol (c15&,@5).
Nicotinic acid would, however, not have been detected.
The first Celastraceae alkaloids, base A (C,,H,,NO,,), base B
(C27H35N012),nd base C (C,,H,,NO,,), were isolated in 1947 from
the spindle tree E u o n y m u s (or Ev ony mu s) europaeus L . , which is used in
folk medicine. They were thought to be tetra-, tri- , and pentaacetates,
respectively, and on acetylation both A and B were converted to base C(8). Because of a n interest in their pharmaceutical activity, the ripe
seeds were later reexamined by Pailer and Libiseller in 1961 ( 9 ) ,who
isolated evonine (base C), the principal alkaloid. They showed that the
basic function of evonine was evoninic acid (4), a substituted nicotinic
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4. CELASTRACEAE ALKALOIDS 217
acid, present as its diester of an unidentified polyhydroxy nucleus
(C15Hz6010)1 0 ) .TLC examination showed the presence of other basic
components, but these were not isolated.Similarities were recognized between the partial structure of evonine
and five partially characterized alkaloids that had been isolated between
1950 and 1 9 5 3 from the thunder god vine (Trip teryg ium wilfordii Hook.)
by Acree and Haller ( 1 1 )and by Beroza (12-15) using a combination of
partition chromatography and countercurrent distribution (16, 7 ) .
These alkaloids contained a common polyol nucleus (C15H26010),
which was esterified with a substituted nicotinic acid, either wilfordic
(6) or hydroxywilfordic acid (7 ) 1 8 ) ,acetic acid, and either 3-furoic or
benzoic acid ( 1 4 , 1 5 ) .
N CHz-CHZ4(CH3)-CO2HIR
m;&&RH 3 cICozHA A
H3C H
4 Evoninic acid R = CO,H 6 Wilfordic acid R = H
5 R = OH 7 Hydroxywilfordic acid R = OH
The stimulating effect of Khat, Catha edulis another member of theCelastraceae, had been widely studied, and the major alkaloidal
constituents have been found to be norpseudoephedrine and related
compounds ( 4 , 5 ) . During a search in 1 9 6 4 for further alkaloids, a
weakly basic compound, cathidine D (C,,H,,NO,,) was isolated ( 1 9 ) .Analysis showed it to be a polyester of acetic, benzoic, and nicotinic
acids and an undefined polyol (C,,H,,06), and it was suggested that i t
could be related to the other Celastraceae nicotinoyl alkaloids.
For some years, no further work in this area was reported, until, in
1970, Kupchan, Smith, and Bryan, investigating Maytenus ovatus fortumor inhibitory compounds, isolated the weakly basic but inactive
alkaloids maytoline (1) and maytine (2) and determined their full
structure and relative stereochemistry by NMR spectroscopy and X-ray
crystallography (1 ,ZO) .These compounds were based on a hydroxylated
tricyclic dihydroagarofuran nucleus, and i t was suggested that this was
structurally related to the C,, polyols of the Euonymus and Tripterygiuma1kaloids.
Following this report, a series of papers appeared on the alkaloids of
Eu on ym us Sieboldianus Blume by Yamada and his co-workers, whoreported the isolation and structures of a series of related alkaloids
including evonine (21-24) and by X-ray crystallography determined
their absolute stereochemistry ( 2 5 )and confirmed their relationship to
maytoline.
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218 ROGER M. SMITH
TABLE IOCCURRENCEND ISOLATIONF CELASTRACEAELKALOIDS
Alkaloid (synonyms) Plant Part Reference
Alatamine
Cathidine D
Celapagine
Celapanigine
Celapanine
2-Deacetylevonine
2,6-Dideacetylevonine
Euonine
Euonymine
Evonine (alkaloid C)
Evonoline (4-deoxyevonine)
Evozine (alkaloid B)
Isoevonine (evonimine)
Isoevorine (alkaloid D)
Maytine
Maytolidine
Maytoline
Neoeuonymine
Neoevonine (evorine, alkaloid A)
Wilfordine
Wilforgine
Wilforine
Wilforgine
Wilforzine
Euonymua alatusa -
Leavesatha edulis
Celastrus paniculatus Seeds
paniculatus Leaves
paniculatus Seeds
Euonymus europaeus Seeds
europaeus Seeds
Sieboldianus Seeds
alatus Seeds
Sieboldianus Seeds
alatus Seeds
europaeus Seeds
Sieboldianus Seeds
europaeus Seeds
europaeus Seeds
europaeus Seeds
SieboldianusSeeds
europaeus Seeds
Maytenus ovatus Seeds
ovatus Seeds
w a t m Seeds
Euonyrnua Sieboldianus Seeds
europaeus Seeds
Sieboldianus Seeds
alatus Seeds
Tripterygium wilfordii Roots
wil ford i i Roots
Maytenus senegalensis' Stems and
Tripterygium wil fordi i Roots
wilfordii Roots
wilfordii Roots
roots
26
19, 27
28
28, 29
28, 29
30
30
31
26
23
26
8 , 9 , 3 2 - 3 5
21
32, 34 , 36
8 , 33
36, 37
3133
1, 38
38
1 , 38
23
8 , 3 3 , 34
23
26
1 1 , 1 2
13
39
12
1 3
15
E. alatus forma striatus (Thunb.) Makino.
Known subsequently as M . arbutifolfolia(Hochst. ex A. Rich.) R. Wilczek ( 4 1 )andnow
as M . sewata (Hochst. ex A. Rich.) R. Wilczek (persona1 communication from Professor
S. M. Kupchan).
M . senegalem's (Lam.) Exell.
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4. CELASTRACEAE ALKALOIDS 219
Subsequent investigations of these and other members of the family
Celastraceae have yielded further alkaloids (see Table I) ( 1 , 8 , 9 , 11-13,
15 , 19 , 21 , 23 , 26-41) . The nature of the sesquiterpene nucleus andester functions is known in each case, but for some of the alkaloids, the
position of the acyl groups have not yet been determined. The alkaloids
can be grouped into those containing an unsubstituted nicotinate group
and into the generally larger and more complex compounds in which the
basic function is a substituted nicotinate group.
Many studies have reported the presence of alkaloids in these and
other members of the Celastraceae by TLC spot tests or as crude basic
extracts. However, as well as the nicotinoyl alkaloids, a wide range of
other alkaloids have been isolated, more than one type frequentlyoccurring in the same plant. M ayten us ovatus, in addition to maytine
and maytoline, has yielded the antitumor ansa macrolide maytansine
( 4 0 ) from the seeds and the spermidine alkaloid celacinnine from the
twigs ( 4 1 ) . Maytenus Chuchuhuashu Raymond-Hamet and Colas has
given an open chain spermidine alkaloid maytenine ( 4 2 )and Maytenus
buchanii has yielded a further ansa macrolide ( 4 3 ) .A series of peptide
alkaloids was found in Eu ony mu s europaeus following TLC analysis ( 4 4 )
and Catha edulis has been reported to contain a number of alkaloids
related to norpseudoephedrine ( 4 5 ) .In addition, a number of nonbasic polyesters and polyalcohols have
been isolated with sesquiterpene nucleii similar or identical with those
found in the alkaloids (see Section V).
III. Structures of Esters of Nicotinic Acid
Seven alkaloids have been isolated in which the basic function is a
nicotinate group (Table 11). Similarities in the NMR spectra havesuggested that in each case the nicotinate group is at C-9.
A . ESTERSF C,,H,,O, Polyols
1. Celapanine
Celapanine (8) was isolated together with a neutral diester malkan-
gunin (see Section V), and much of its structure was derived by their
interrelation ( 2 8 , 2 9 , 4 6 ) .The mass spectrum of celapanine (C,oH,,NO,o)
(mle 569) confirmed the molecular formula and suggested the presenceof nicotinate (m/e 106 and 78) and 3-furoate (m/e 95) groups. These
conclusions were in agreement with bands in the NMR and UV spectra.
The NMR spectrum (Table 111) also contained signals for two acetyl
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4. CELASTRACEAE ALKALOIDS 221
groups (6 1.68,2.12), four tertiary and one secondary methyl groups, and
coupled signals at 6 2.60, 5.73, and 5.4, which were assigned to the
grouping -CH,-CHOAcyl-CHOAcyl-. The alkaloid is therefore, atetraester of a C,,H,,O, nucleus, celapanol. As the infrared spectrum,
vmaX1740,1730,1590,1560cm-l , contained no bands for a free hydroxyl
or ketonic carbonyl groups, the remaining oxygen must be an ether
8
9
10
11
Celapanine Ac Fur Ac Nic Bz = benzoyl
Celapanigine Ac Bz Ac Nic
Celapagine Ac Bz H Nic
Celapano1 H H Nic = nicotinoyl
Fur = 3-furoyl
group. Dehydrogenation of 8 yielded eudalene (12),which was also
obtained from the diester malkangunin (13) 28, 4 6 ) . Comparisonof theNMR spectrum of 8 with that of malkagunin suggested that the sesqui-
terpene nucleus in both cases contained similar tricyclic dihydroagaro-
furan skeletons, 9 and 14, respectively.
One acetate group was positioned a t C-1 in 8 as the high-field position
(6 1.68) was considered to be due to interaction with a nicotinate group
at C-9. A similar relationship had been previously reported in maytoline
(1) (I).The 3-furoyl group was placed a t C-6 as in the related alkaloid,
celapanigine (lo), it is the position of a benzoyl group. The second
acetate group was assigned to C-8 from the NMR spectrum.The stereochemistry of the ring system and substituents was based
by Wagner and his co-workers on the structural assignments in mal-
kangunin (13) 4 6 ) .A spin-spin coupling between the protons at C-8
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4. CELASTRACEAE ALKALOIDS 223
I11
C O N T ~ ~ I N GNICOTINATEROUP"
C-8 c - 9 c-12 C-13 C-14 (3-15 OAc Reference
5.73 ddc 5.4 d o 1.59 s 1.42 s 1.01 d
5.70 ddc 5.36 d o 1.61 s 1.45 8 1.04 d
4.66 ddc 5.30 dc 1.60 s 1.44 s 1.01 d
(397) (7 ) (7 )
(3, 7 ) (7) (7)
(39 7 ) (7 ) (7)C-Methyl
1.42 s 1.68 46
1.49 s 1.67 46
1.38 s 1.64 46
2.12
1.92
- 5.75 m 1.40(3H), 1.54(6H), 1.66(3H)
- 5.47 m 1.51 6H), 1.56(3H)
- 5.49 bd 1.54(6H) 1.61 3H)
(7.5)
- 5.52 bd 1.55(3H), 1.59(3H), 1.61(3H)
(7.5)
5.01 s 1.66 27
4.39, 4.93d 1.60 1, 38
2.12
(13) 2.09
2.10
2.26
(13) 2.15
2.18
2.30
(13) 2.142.30
2.34
4.40, 4.96d 1.66 1, 38
4.43, 4.90d 1.64 38
Unresolved multiplet 1.4-2.2 ppm.
Position determined by spin-spin decoupling.
AB quartet.
coupling of 7 Hz seems more appropriate. Examples elsewhere in this
series of alkaloids have found J 8 , gax,eq = 6 Hz; ax,ax = 10 Hz (50) .This group also isolated polyalcohol B to which they assigned
structure 67 identical with celapanol (9). However, in this compound
J 8 , g= 10 Hz and J , , 8 = 3 Hz, in contrast with the values for the
alkaloids.
2. Celapanigine and Celapagine
The spectra of celapanigine (10) (C32H3,N09)and celapagine (11)
(C30H,,N08) were very similar to those of celapanine, except thatinstead of the bands assigned to the 3-furoyl group, there were signals
characteristic of benzoate ( m le 105 and 77) (28, 29, 4 6 ) ; 10 contained
two acetyl groups ( 6 1.92, 1.67, NMR spectroscopy) but 11 only one,
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224 ROGER M. SMI TH
? H : 9R' O H OR'
W O R 2R2
13 R' = Bz, 2 = AC 15 R' = Bz,R2 AC
14 R'= R2 = H 16 R' = R2 H
H3C CH3 HSC 0 CH3
CH3 CH3
which from it s chemical shift (8 1.64) was assigned to C-1 due to the
influence of a C-9 nicotinate group. The free hydroxyl group in 11 was
secondary (-CHOH 6 4.66 dd, J = 7, 3 Hz) and from decoupling
studies was assigned to C-8 ( J 8 , 9= 7 Hz, J , , 8 = 3 Hz). The remaining
ester function, the benzoate group, must be a t C-6. Compound 10 was
thus based on the same polyol (9) as celapanine but contained a 6-
benzoate group instead of a furoate group, 11 being the corresponding
8-deacetyl compound. The stereochemical assignments were based on
the same arguments as those for celapanine.
B. ESTERSF C,,H,,06 POLYOLS
Although a number of pentaols have been isolated from hydrolyzates
of Celmtrus paniculatus (Section V), so far no corresponding alkaloids
have been reported.
C. ESTERSF Cl5HZ6O7 OLYOLS
1. Cathidine D
Analysis and mass spectroscopy of cathidine D (17) confirmed the
molecular weight of this weakly basic alkaloid from Catha edulis.
Hydrolysis yielded nicotinic acid, benzoic acid, and 2 mole equivalents
of acetic acid. Two of the remaining oxygen functions were assigned to a
vicinal diol from the IR spectrum (v,,, 3565, 3480 cm-l unchanged ondilution). The formation of a monoacetate and NMR spectra suggested
that one hydroxyl was secondary and the other tertiary. This assign-
ment was confirmed on treatment with lead tetraacetate, which cleaved
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4. CELASTRACEAE ALKALOIDS 225
the diol quantitatively to give a ketoaldehyde. Cathidine was thus a
tetraester of the C,,H,,O, hexaol, cathol ( 1 9 ) .
Subsequent reexamination of the structural studies and comparisonof the NMR spectrum with that of maytoline and maytine (Table111)suggested that cathidine D contained the same C-1 to C-3 system as
maytoline but lacked an ester function at C-6. As in maytine, the C-1
acetate group (6 . 66 ) apparently interacted with a C-9 nicotinate group.
However, it was not possible to distinguish between the possible posi-
tions for the benzoate and the second acetate groups. Cathidine was
thus assigned the partial structure 17 (27), the stereochemistry of the
nucleus cathol (18) being based on the similarities of the coupling con-
stants t o those of maytoline (1).
CH3
17 Cathidine D R' = Ac, Ra = Nic, R3 = Bz, R* = AC
or R3 = Ac, R4 = Bz
18 R' = RS = R3 = R4 = H
OAc
I
VH*
A C O , ~ : ,c? ; VAc OAc
AcO
H3C' O H OAc
, CH3
CHa-OAc
19
A recent note reported that cathidine (as a crude alkaloid fraction) on
hydrolysis and then acetylation yielded octaacetyl euonyminol (19)
(51 ) . This result conflicts with the formula and structure of purifiedcathidine D, and this derivative is presumably derived from further
alkaloids in C. edulis th at have yet to be isolated.
2. Maytine
Maytine (2) (CZ9H,,NO,,) and maytoline (1) were isolated togetherfrom Maytenus ovatus, and a comparison of their NMR and IR spectra
suggested th at they were very similar ( 1 ) .Both contained a nicotinate
and four acetate groups. However, the NMR spectrum of maytine
lacked the signal at 6 3.60 (d, J = 3.5 Hz) assigned to the C-3 protonin maytoline, and the signal for the adjacent C-2 proton (6 5.47) was a
multiplet instead of a triplet. Maytine contained a free hydroxyl group
(v,,, 3550 cm-l ), which was unreactive on attempted acetylation and
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4. CELASTRACEAE ALKALOIDS 227
on acidification. The formula was determined by high resolution mass
spectroscopy (HRMS) and elemental analysis, and IR spectroscopy
showed the presence of hydroxyl, vmax 3500 cm-l, and ester groups,vmax 1735 cm-l. The nicotinate group gave characteristic mass ( m / e
124 and 106),UV, and NMR spectra. The NMR spectrum also contained
signals for the partial structure -CHOAcyl-CHOAcyl-CHOH-
6 5.91 (d, J = 3.5 Hz), 5.60 (t, = 3.5 Hz), and 3.60 (d,J = 3.5 Hz) ,a
primary C&OAcyl 6 4.96 and 4.40 (ABq J = 13 Hz), and two secon-
dary esters (CHOAcyl) 6 6.16 s, 5.49 (d, J = 7 . 5 Hz), and a D,Oexchangeable proton. Acetylation converted the partial structure to
-(CHOAcyl)3- and the signal a t 6 3.60 shifted t o 6 4.87 (d, J = 3.5
Hz). On hydrolysis, maytoline gave maytol(22), C15H2608, hose NMRspectrum contained signals for three quaternary methyl groups and no
olefinic protons. Maytoline was readily converted to a methiodide,
which was examined by X-ray crystallographic analysis ( 2 0 ) . The
structure and relative configuration were determined but the absolute
configuration could not be defined. The results agreed well with the
NMR spin-spin couplings.
2. Maytolidine
Maytolidine (23) (C36H41N014) ave UV, NMR, and mass spectros-
copy signals assignable to a benzoyl, four acetyl, and a nicotinoyl
groups ( 3 8 ) . Hydrolysis yielded maytol (22) and acetic and benzoic
acids. Benzoylation of 1 gave 3-benzoylmaytoline, which was isomeric
with maytolidine but showed a different NMR spectrum, principally in
the chemical shifts of the acetyl methyl groups. Detailed examination
of the spectrum suggested that the benzoyl group in 23 was at C-6;
C-6H 6 6.23 compared with 6 6.08 in 3-benzoylmaytoline.
IV. Structures of Diesters of Substituted Nicotinic Acids
On hydrolysis, seventeen of the Celastraceae alkaloids (Table IV)yield a pyridine dicarboxylic acid, which in the intact alkaloid is present
as a diester at C-3 and (2-12 on the sesquiterpene nucleus. This nucleus
is more highly oxygenated than in the alkaloids containing an unsub-
stituted nicotinate group, and in some cases a (2-8 keto group is present.
A . STRUCTURESF THE DIACIDS
Three pyridine diacids have been found, each containing a five-carbon
side chain at the 2 position of nicotinic acid.
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TABLE I VPROPERTIESF CELASTRACEAELKALOIDSONTAININQ DIESTER
Alkaloid Formula Mol, wt. (m/e) mp ("C) [alOa Sesquiterpene nucleus Formula
~~ ~~ ~~
Evonoline (24) C3eH43NOie 745 150-158 + 6.0' Evonolinol C,,H,,Og
(4-deoxyevoninol)
Evonine (25) C3eH&Oi, 761 184-190 +8.4 Evoninol C,,H,4010
Isoevorine C34H4iNOie 719 185-188 +2 2. l0 Evoninol Cl~H 2401
Evoninol C,,H,,O,, ,B-Didmetylevonine (29) C,,H,,NO,, 677 141 -Evozine (27) C32H39N016 677 288-290 + 13' Evoninol C,,H,,O,,
2-Deacetylevonine (28) C.34H41N018 7l9 135 - Evoninol C,,H,40,,
Neoevonine (28) C34H41N018 719 264-265 +24.9' Evoninol C,,H,40,,
Isoevonine (47) C38H43NOl, 761 Amorphous + 30.50b Evoninol C,,H,40,,
210
Alatemine (48) C41H46N018 839 185-193 +44' Evoninol C,,H,40,,
Euonymine (50) C,eH4,NOi, 805 - - 0' Euonyminol C,,H,eOl,
Neoeuonymine ( 5 1 ) C3eH4sNOi7 763 259-262 - 1' Euonyminol C,,H,,O,o
Euonine (52) C 3dbNOie 805 149-153 - .5" Euonyminol C,,H,,Olo
Wilforzine C41H47N017 - 177-178 + 6 O C Euonyminol C,,H,,O,,
Wilforgine (55) C41H47N019 857 21 1 + 25OC Euonyminol C,,H,,O,,
Wilfordine (53) C43H49N019 883 175-176 + 1ZoC Euonyminol Cl,H,,O,,
Wilfortrine (58) C4,H4,N0,, 873 237.6-238 + ooc Euonyminol C,,H,,O,,
Wilforine (54) C43H48N018 867 169-170 + 3OoC Euonyminol C,,H,,O,,
Solvent CHCl, unless noted.
ECOH.
Acetone.
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230 ROGER M . SMITH
and analysis of evonoline showed that it contains one less oxygen than
evonine, and the IR spectrum lacked a band for a hydroxyl group. In
the NMR spectrum, the C-4 methyl signal was a doublet 6 1.29 ppm(J = 8 Hz) and thus secondary, unlike the tertiary C-4 (Me)OH group
in evonine; the rest of the spectra were very similar (see Table V ) .From the long range coupling of C-2H and C-4H (J = 1.1 Hz) these
protons were assigned to a W diequatorial configuration, and thus the
C-4 methyl group was axial, in the same orientation as in evonine. The
C-1H and C-9H must both be axial as a strong nuclear Overhauser
effect (NOE) (20y0)was demonstrated between them. Evonoline was
therefore assigned the structure 24 (32).
OAc
IFHZ
AcQ 9R4
24 Evonoline Ac H Ac Ac
25 Evonine Ac OH Ac Ac
26 Neovonine Ac OH H AC
27 Evozine Ac OH K H
28 2-Deacetylevonine H OH Ac Ac
29 2,6-Dideacetylevonine H OH H AC
80 Bromoacetylneoevonine Ac OH BrAc Ac
A n independent report by Budzikiewicz and co-workers ( 3 4 ) eached
the same conclusion for the structure of a compound they named
4-deoxyevonine. Their paper illustrated the hWR and mass spectra of
24. Analysis of the mass spectrum suggested that a Maclafferty re-arrangement of the C-3 ester group involving a coplanar and hence
equatorial C-4H led to a ready loss of COz not found in the mass
spectrum of evonine.
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4. CELASTRACEAE ALKALOIDS 231
C. ESTERSF C,5H,,010 KETOPOLYOL
1. EvonineEvonine (25) (C3,H4,NO13)was initially isolated as “base C ” by
Doebel and Reichstein and reported to be a pentaacetate with the
tentative formula C31H39N0148). It was reisolated by Pailer and
Libiseller as the major component from E. europaeus and named
evonine (C36H43-45Nol,)9). Hydrolysis of evonine yielded formalde-
hyde, 5 moles of acetic acid, and a diacid Cl1H,,NO4, subsequently
elucidated as evoninic acid (4) ( 1 0 ) .X-ray analysis of evonine suggested
the mol. wt. 7 6 4 .6 and thus the formula C36H45N017mol. w t . 763 .73)
( 5 4 ) .The formula of polyol nucleus would therefore be C,,H2,010.Studies in Budapest found that if the crude alkaloid mixture from
E. europaeus was acetylated, the yield of evonine (semisynthetic) was
70y0 compared to a usual 2 3 y 0 ( 3 5 ) . On hydrolysis of 25, 7 moles of
alkali were consumed to give a polyol that reacted with periodate. The
polyol could be converted into a perbenzoate whose IR spectrum still
contained a band at 3500 cm-I from an unacylated tertiary hydroxyl
group. A NMR spectrum suggested two C-methyl groups were present
in the polyol nucleus, which was thus probably a terpene rather than a
sugar ( 5 5 ) .Following the report of the structure of maytoline, two groups,
Yamada and his co-workers in Japan (21 , 22 , 24) and Pailer and his
co-workers in Austria ( 3 2 ) ,almost simultaneously but independently
published reports of the structure determination of evonine (C36H43-
NO,,; mass spectrum, m / e 761) based on a polyol nucleus evoninol (31)
(C15H24010).
HoqcH3 VHaOH
HO..
H d O H
~ H ~ O H
51 Evoninol R = =O
H
OH32 Euonyminol R = <.
OH33 IsoeuonyminoI R = <
‘H
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232 ROGER M . SMITH
TABLE
lH NMR SPECTRAF CELESTRACEAE
Alkaloid c-1 c-2 c- 3 c-4 C-6
Evonoline (24)
Evonine (25)
2-Deacetylevonine (28)
Neoevonine (26)
2,6-Dideacetylevonine (29)
Evozine (27)
Isoevonine (47)
Alatamine (48)
Euonymine (50)
Euonine (52)c
Wilfordine (53)
5.79 d
(3.4)5.71 d
(3.2)5.73 d
(3)5.72 d
(3.2)
5.67 d
(3)5.87 d
(3.4)5.70 d
(3.5)5.90 d
(3.5)5.55 d
(4.0)5.64 d
(3.2)5.77 d
(3.0)
5.33 ddd
(3.4, 2.6, 1.1)
5.29 t
4.00 t
(3)5.34 t
(3.2)
3.95 t
(3)5.22 dd
(3.4, 3.0)
5.15 t
5.46 dd
(3.5, 3.0)
5.23 dd
(4.0, 2.5)
5.15 dd
(3.2, 3.0)
(3.2)
(3.5)
-
4.84 dd
(2.6, 1.2)
4.78 d
5.14 d
4.82 d
5.24 t
4.80 d
4.97 d
5.18 d
4.72 d
4.93 d
5.08 d
(3.2)
(3)
(3.2)
(3)
(3.0)
(3.0)
(3.0)
(2.5)
(3.0)
(2.8)
7.13 qdd 6.45 d
(8.0, 1.2, 1.1) (0.9)- 6.72 d
- 6.78 bs(1.0)
- 5.41 d
(1.5)
- 5.36 d(1)
- 5.20 s
- 6.72 d
(1.0)- 6.82 d
(1.0)- 7.02 d
(1.0)6.90 s
~ ~~ ~ ~ ~ ~~~~
a Spectra run on solutions in CDCl, unless noted. Chemical shifts are in parts per million
relative to TMS. Figures in parentheses are couplings in Hertz. Bands were present as appro-
priate for ester groups.
Subsequent full papers by Yamada and his co-workers have discussed
the details of the structure determination (50) and the chemicalreactivity (56)of evonine. They found that the NMR spectrum showed
the presence of five acetate methyls, two tertiary methyl groups, an
aceotoxymethylene (-CH,-OAc), and a hydroxyl group adjacent
to a tertiary methyl group (Table V). Decoupling experiments showed
the presence of a 1,2,3-triester (-CHOAcyl-),. Reduction of 25 with
LAH gave two isomeric C,,H,,O,, polyols, euonyminol (32)and
isoeuonyminol (33), implying a keto group was originally present.
Analysis of the NMR spectra of their peracetates confirmed this view
and led to the partial structure -CHOH-CO-CH- in evonine.Chemical degradation of 25 with NaOMe-NaON gave a pentadeacetyl
evonine (mp 257'C), which reacted with 2,2-dimethoxypropane to give
an acetonide. Comparison of the spectra of this compound and 25
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4. CELASTRACEAE ALKALOIDS 233
V
ALEALOIDS ONTAINING DIESTER~
c-7 C-8 c-9 c-126 C-13 C-14 C-15 Reference
3.09 d
3.04 d(0.9)
(1.0)-
3.02 d
(1.5)
-
3.22 d
3.02 d
3.10 d
2.33 dd
(3.8, 1.0)
2.62 d
2.40 dd
(1.2)
(1.0)
(1.0)
(3.0)
(1.0, 4.5)
-
-
-
-
--
-
-
5.51 dd
(3.8, 6.2)
5.48 dd
(3.0,6.7)-
5.50 s
5.57 8
5.63 s
5.59 8
5.69 s
4.49 8
5.53 s
5.65 s
5.34 d
(6.2)5.20 d
(6.7)-
4.90, 5.34
(11.3)
3.76, 6.04
(11.7)
3.87, 5.82
3.78, 6.10
3.76, 6.04
3.74, 6.09
(11.5)
3.79, 5.81
3.80, 5.94
5.94 d(1H)
4.10, 5.77
3.77, 5.82
(13.0)
(12)
(12.0)
(13)
(12.0)
(12.0)
(12)
(12.0)
1.47 s
1.61 s
1.54 s
1.64 s
1.61 s
1.51 s
1.55 s
-
-
-
-
1.29 d
1.61 s
1.24 s
1.90 s
1.28 s
1.84 s
1.61 s
(8.0)
-
-
-
-
4.46, 4.80
(12.8)
4.58, 4.82
(13.0)
5.03, 4.60
(11.0)
4.47, 4.92
(13.0)
4.50, 5.18
(13)4.62 s
4.47, 4.85
4.85 s
4.50, 5.13
(13.5)
4.43, 5.42
(13.0)
4.21, 4.50
(13.0)
(13)
32
50
30
50
30
57
36
26
23
31
26
b AB quartet.
C Solvent (CD&CO.
showed that evonine contained one primary and four secondary acetate
groups and that the triester could be assigned the partial structure-CHOAcyl(CHOAc),-. Acetylation of the acetonide afforded an
acetonide triacetate 34, which with aqueous acetic acid was converted
to a triacetate. The NMR spectra showed that the primary hydroxyl
and the hydroxyl of the a-ketol had been involved in the acetonide
formation and must thus be in a 1,3 relationship.
Cleavage of the triacetate with Pb(OAc), gave an aldehyde ester
triacetate (35). he changes in the coupling constants enabled a second
of the secondary alcohols to be related to the ketone in evonine as
-CHOH. CO .CH .CHOH-. Potassium tert-butoxide reacted with thealdehyde ester to yield an a$-unsaturated aldehyde ester (36) nd
formaldehyde. This retroaldol reaction enabled the correlation of most
of the partial structures in evonine as 37.The remaining alcohol group,
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234 ROGER M . SMITH
YH,OH
Ac? j
C02CH3
H3C OH OAc
34 35
C(OH)Me, was related to the triester by the conversion of evonine to a
pentamethyl ether by the replacement of acetate by methyl, reduction
of the remaining ester functions with LAH to give 38, cleavage of the
3,4-diol o an aldehyde methyl ketone (39), and thus the partial
structure 40 could be derived.
A n important degradation led to the l,%napthoquinone 41, as this
related the side chain to the carbon skeleton. Only one oxygen was
uncharacterized at this point, and it was deduced to be ethereal and
must be attached to the ring junction and give the tertiary hydroxyl
in 41.
The structure was then complete except for the orientation of the
diacid. Partial methanolysis of evonine gave 42 and complete hydrolysis
CHzOAcI
AcO&o
AcylO 'HH
OAc
37
36
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4. CELASTRACEAE ALKALOIDS 235
~ H , O H
38
~ H ~ O H
39
CHaOAc
A c O h H
Hcyl-0
OH OAcH3C
40
then yielded monomethyl evoninate with the free carboxyl group onthe side chain, which therefore must have been attached to C-3.
The stereochemistry of the substituents was derived from NMRspectra and by NOE enhancement studies ( 2 4 ) . These confirmed that
the ring junction was trans and that the C-4 methyl and C-6 protons
were diaxial. These conclusions were disputed by KlBsek et al. (57),
OHI9 2
0 OH ?H
CH,OOH
AcO
41
42
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236 ROGER M. SMITH
although they agreed with the structure from their own unpublished
studies, but were reemphasized in the full paper ( 5 0 )by Yamada. The
stereochemistry was conclusively established by the relationship ofevonine to neoevonine (6-deacetylevonine) (26) ( 2 3 ) and the X-ray
crystallographic analysis of bromoacetylneoevonine (30) ( 2 5 ) .During
the structural determination, a number of unusual reactions involving
the oxygen functions of evonine and neoevonine were noted (56 ) .The independent study by Pailer and his co-workers followed a
similar argument t o th at of the Japanese workers and reached the same
conclusion ( 3 2 ) .The key compound in their analysis was the unexpected
acetal (43) formed by the action of periodic acid on evoninol, which on
acetylation gave 44 (c23 13).This compound contained a ketaland hemiketal (NMR spectra) and led to the elucidation of the tetraol
ring system. Further analysis gave the complete structure, the orienta-
tion of the diester being derived from the anisotropic effect of the
pyridine ring on the C-12 methylene group.
Reichstein’s group, who were first to work in this area, have sub-
sequently reported the full details of their studies on the isolation and
properties of evonine and a number of related alkaloids (33).In a recent study, a selective recombination of evoninic acid as the
43 R = H44 R = AC
CH,? : OCH,
CO,CO,Et
CH3
45
J.
25
46
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4. CELASTRACEAE ALKALOIDS 237
trityl ether 45 and the acetonide 46 yielded a monoester, which after
conversion of the trityl group to a methyl ester and then removal of the
acetonide, yielded evonine on treatment with sodium hydride ( 5 8 ) .
2. Neoevonine, Evozine, Isoevorine, 2-Deacetylevonine, and 2,6-Dide-
acet ylevonine
These five deacetylevonine alkaloids have all been found as con-
stituents of Euonymus species. The positions of substitution were
principally derived by analysis of the NMR spectra (Table V).Originally “alkaloid A ” (8),neoevonine (26) (C,,H,,NO,,) was
isolated and the structure reported by the Japanese group ( 2 3 ) , andalmost simultaneously the full details of its isolation as “evorine” were
reported by Reichstein ( 3 3 ) .Acetylation of neoevonine yielded evonine,
and the NMR spectrum showed th at 26 was 6-deacetylevonine. It was
used during the structural and chemical studies on evonine ( 5 0 , 5 6 ) nd
could be prepared from evonine by controlled mild hydrolysis (2 3 , 5 0 ) .It also could be obtained in high yield by the treatment of evonine with
an enzyme preparation from the fruit of E. europaeus ( 3 3 ) .On bromo-
acetylation, 26 yielded a crystalline derivative (30))which was exam-
ined by X-ray crystallography ( 2 5 ) to give its relative and absoluteconfiguration. “Alkaloid B ) ) ( 8 )was reisolated a s evozine (27) (C32H3s-
NO,,) ( 3 3 ) ,and its structure was determined by NMR spectroscopy as
6,9-dideacetylevonine ( 5 7 ) .Hydrolysis of evonine, followed by the acetylation of the pentade-
acetyl product, as well as yielding evonine and neoevonine, also gave a
second monodeacetylevonine, isoevorine (C,,H,,NO,,), identical with
a previously isolated but unpublished “alkaloid D” ( 3 3 ) .However, its
NMR spectrum was not reported nor a structure proposed, except that
it differed from both 2- and 6-deacetylevonines.
2-Deacetyl (28) (C,,H,,NO,,) and 2,6-dideacetylevonine (29)
(C,,H,,NO,,) were isolated from E. europaeus as minor alkaloids and
their structures elucidated by NMR spectroscopic comparison with
evonine ( 3 0 ) .
3. Isoevonine
Isoevonine (47) (C,,H,,NO,,) was reported almost simultaneously by
groups in Czechoslovakia (3 6 , 3 7 ) and in Japan (3 1 ,named evonimine).It is isomeric with evonine, but on methanolysis yielded the dimethyl
ester of wilfordic acid (6).Similarities between the NMR spectra of the
two alkaloids suggested that the rest of the molecules were probably
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238 ROGER M . SMITH
identical (Table V ) . Both contained five acetoxyl groups and could be
converted into the hexaacetate of evoninol (31) or by reduction and
acetylation into euonyminol octaacetate (19) ( 3 1 ) .Selective hydrolysisof the aromatic ester group enabled the orientation of the wilfordic
diester to be established ( 3 1 ) .
4. Alatamine
Alatamine (48) (C,1H,5N0,,) on mild reduction and acetylation was
readily converted to a mixture of the previously isolated alkaloid
wilfordine (53) and its C-7 epimer (26). Thus, alatamine was derived
from a C,,H,,O,, keto-polyhydroxy compound, which from itsrelationship t o wilfordine, was linked to benzoic acid, hydroxywilfordic
acid, and 4 moles of acetic acid. Acetylation of alatamine and methanol-
ysis yielded a methyl ester, which on comparison with the spectra of
the acetate, showed th at one of the diacid ester linkages was to C-12.
Further acetylation to a hexaacetate, reduction, and cleavage gave 49.
This compound could also be prepared from the evonine derivative 42
on acetylation and benzoylation followed by reduction. Thus, both the
position of the benzoate and acetate groups, of the second diester
linkage, and the presence of evoninol (31) as the nucleus of alatamine
were confirmed. The benzoate position also agreed with an NMR study
of model C-1, C-2, and C-3 benzoates prepared from evonine.
R ' O . . M
47 Isoevonine R' = Ac, RZ= H
48 Alatamine R1 Bz, Ra = OH
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4. CELASTRACEAE ALKALOIDS 239
' D. ESTERSF C15H,,010 POLYOLS
I . Euonymine and Neoeuonymine
Reduction of euonymine (50) (C38H47N018) ith LAH yielded the
diol5 (from evoninic acid) and euonyminol (32) ( 2 3 ) , dentical with one
of the reduction products of evonine ( 2 1 ) .A comparison of the spin
couplings of C-9H in euonyminol (32) ( J 8 , g= 6 Hz) and isoeuonyminol
(33)( J E S g 10 Hz) showed th at in 50 the C-8 hydroxyl was axial. This
assignment was confirmed by an NOE interaction between the diaxial
C-6H and C-8H in the octaacetate of isoeuonyminol(33)( 2 4 ) .Methanol-
ysis confirmed the number and position of the acetyl groups in euony-mine and that the evoninic acid aromatic carboxyl was attached to
Neoeuonymine (51) (C,,H4,NO1,), isolated with 50, was converted
to euonymine on acetylation and, from its NMR spectrum, which lacked
the C-6H signal in the 6-7 region (euonymine 6 7 .02) , was deduced to be
6-deacetyleuonymine (23).
The stereochemistry of both compounds was derived from the
relationship of euonyminol to evonine ( 2 4 ) .
C-12 (23).
OAcIFHz
AcO i OAc
AcO- &, OAc
50 Euonymine R = Ac
51 Neoeuonyrnine R = H
2. Euonine
Euonine (52) (C38H47N018)s isomeric with euonymine and on
exhaustive methanolysis and acetylation afforded also euonyminol
octaacetate, but dimethyl wilfordate rather than dimethyl evoninate
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240 ROGER M . SMITH
( 3 1 ) . Partial methanolysis gave hexadeacetyleuonine methyl ester.Comparison of the NMR spectra enabled the position of the acetyl
groups and the orient*ationof the wilfordic acid group to be determined.
AcO OAc
R’ Ra
52 Euonine Ac H53 Wilfordine Bz O H54 Wilforine Bz H (postulated)
55 Wilforgine Fur H (postulated)
56 Wilfortrine Fur OH (postulated)
3. Wilfordine
Initial studies on Tripterygium wilfwdii yielded the crude alkaloid
triptergine (C,,H,,NO1 (59),reisolation by Acree and Haller yielded
“wilfordine,” but it was still a mixture ( 1 1 ) .Wilfordine (C43H4gN0,g)was finally obtained pure by Beroza ( 1 2 ) ,who assigned the formula.
He showed that i t contained 1 mole of benzoic acid, 5 moles of acetic
acid, and 2 moles of a non-steam-volatile acid. Further studies ( 1 4 )
identified the nucleus as “C15K16(OH)10” nd the acid as hydroxywil-
fordic (7) 1 4 , 1 8 ) , but no structure was proposed.
Subsequently, Yamada et al. isolated wilfordine from E uonym us
alatus and related it to the product of the reduction and acetylation of
alatamine (48) ( 2 6 ) .The stereochemistry of the introduced acetate was
determined by LAH reduction of wilfordine to euonyminol (32), hosestereochemistry had already been established ( 2 4 ) .Thus, wilfordine (53)
must have the same ester substitution pattern as alatamine and an
additional axial C-8 acetate instead of a keto group.
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4. CELASTRACEAE ALKALOIDS 241
4. Wilforine and Wilforzine
Wilforine (C,3H,gNOl,) was first isolated by Beroza ( 2 2 )who showedit to contain one fewer oxygen than wilfordine. Degradation yielded 5
moles of acetic acid, 1mole of benzoic acid, 1 mole of wilfordic acid, and
a "Cl5H1,(OH),, " nucleus ( 1 4 ) . Further isolation studies yielded
wilforzine (C,,H,,NO,,), whose formula and hydrolysis suggested it was
deacetylwilforine ( 1 5 ) .It could be converted to wilforine on acetylation
(25) and was shown not t o be artifact. The C15 nucleus in both wilforzine
and wilforine was found to be identical with that from wilfordine by
X-ray analysis (14).
Despite the recent isolations of wilforine from Maytenus senegalensis( 3 9 )and T . wilfordii ( 5 3 ) , he full structure has not yet been reported.
The biogenetic relationship to wilfordine and the presence of the same
nucleus (32) uggest that wilforine differs only in the diacid group and
is probably 54. Wilforzine is probably the 6- or 2-deacetyl derivative of
54, by analogy with the derivatives of evonine and euonymine.
The name wilforine is noted to be also in use to describe a pregnane
from Cynadum wilfordii ( 3 9 ) .
5 . Wilforgine and Wilfortrine
Wilforgine (C,,H,,NOlg) and wilfortrine (C,,H,,NO,,) were also
isolated from T . wilfordii by Beroza ( 1 3 ) and were found to yield
3-furoic acid, 5 moles of acetic acid, and wilfordic or hydroxywilfordic
acid, respectively, on hydrolysis. They both contained the same C15
nucleus as wilfordine ( 1 4 ) .Although these alkaloids have recently been
reisolated ( 5 3 ) , their structures have not yet been reported. They
probably correspond to those of wilfordine and wilforine in which the
benzoate group is replaced by a 3-furoate group (i.e., 55 and 56).
V. Structures of Related Sesquiterpene Esters and Polyols
As well as the sesquiterpene alkaloids that have been found in the
Celastraceae, a number of neutral polyester sesquiterpenes have been
isolated (Table VI). These compounds are clearly related to the alka-
loids and are also based on hydroxylated dihydroagarofurans, in some
cases identical with those found in the alkaloids.
The ester malkangunin (13) (C24H3207)rom Celastrus pan iculatuswas shown by Wagner and his co-workers to be the acetate benzoate of
malkanguniol (14) (CI5H,,O5) ( 4 6 ) .Doubt has been cast on the stereo-
chemical assignments by the work of den Hertog and his co-workers,
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TABLE VI
NATURALLYCCURRINGPOLYESTERESQUITERPENES ROM CELAS
Ester
Ahtolin (61)
Euolalin (65)
Mctlkangunin (13)
Ester A-1 (57)
A-2 (58)
Ester B-1 (62)
B-4 (63)
A-3 (59)
Source a Formula. Mol. wt. (m/e)
EA
EA
C P
EE
E E
EE
EE
EE
756
694
432
756
694
652
674
684
Amorphous
240-245
219-221
95-100
188-192
85-90
112-120
106-110
CP = Celaatrms paniculatwr, EA = Euonymua alatua, E E = E . europaeua.Alternative structure 15 based on polyol 16 (47 ) .
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4. CELASTRACEAE ALKALOIDS 243
who established the different stereochemical structure 16 for malkan-
guniol obtained by the hydrolysis of C. paniculatus seed oil ( 47 ) (see
Section 111, Al) . The position of the benzoate group in 13was based onthe chemical shift of the C-9 proton, 6 6.22, compared with the value
of 6 5.3-5.4 in the related Celastrus alkaloids (Table 111).
A series of five polyesters has been reported from E m y m u s europaeusbut their full structures have not yet been determined ( 6 0 ) .Three-
A-1 (57), A-2 ( 5 8 ) , and A-3 (59)-are based on the hexaol (60), the
remainder-B-1 (62) and B-4 (63)-are based on the isomeric hexaol
(64).The substituents and the structures of the hexaols were determined
by mass, IH, and 13C NMR spectroscopy, but it was not possible to
assign the positions of the ester functions.
OR
CH3
57 Ester A-1 R = 3 x Ac, 3 x Bz58 Ester A-2 R = 4 x Ac, 2 x Bz
59 Ester A-3 R = 3 x Ac, 2 x Bz
60 R = H
61 Alatolin R = 3 x Ac, 3 x Bz
CH,
62 Ester B-1
63 Ester B-2
64 R = H
R = 2 x Fur, 2 x Ac, 2-methylbutanoyl
R = 2 x Ac, 3 x Fur
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244 ROGER M . SMITH
A closely related compound, alatolin (61), also based on the hexaol
60 has been isolated from Euonymus alatus ( 61 ) . Hydrolysis of 61
yielded 60 (named alatol), whose structure was determined by NMRstudies, including the NOE and by its synthesis from evoninol (32).The
NMR spectra of 61 and 57 were measured in different solvents, and
insufficient data have been reported to enable a comparison to be made
to determine if these two compounds are identical or positional isomers.
Euon ymu s alatus has also yielded euolalin (65) (C,,H4,Ol2), which
on hydrolysis gave deoxymaytol (21), 2 moles of benzoic acid, and 2
moles of acetic acid ( 6 2 ) .From the mass and NMR spectra, a fifth ester
group, a-methylbutyrate, was identified. The substitution pattern was
determined by partial hydrolysis and synthetic studies.
Studies on further components in Celastrus oils have continued in
three laboratories. Work on the hydrolysis products of nonglyceride
OAcI
CH3
65 Euolelin
-CHaCH,
CH3
R' R2 R3 R4 R5 RE66 PolyalcoholA OH H OH ---OH -OH OH
67 Polyalcohol B OH H OH -OH ---OH H
68 Polyalcohol C OH H OH -OH -OH OH
69 Polyelcohol D OH OH H ---OH -OH H
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4 . CELASTRACEAE ALKALOIDS 245
esters in C . paniculatus oils, as well as yielding malkanguniol 16),ave
four related polyols, polyalcohol A 66) C15H2,0,; mp 185-186.5"c),
polyalcohol B 67) C15H2605; mp 236-239"C), polyalcohol C 68)(C,,H,,O,; mp 205-207"C), and polyalcohol D 69) C15Hzs05; mp
243-245°C) ( 4 7 ) .Their structures have been determined and related to
malkanguniol by IH and 13C NMR spectroscopy. The hydrolysis also
yielded acetic, benzoic, 3-furoic, and nicotinic acids, and thus, these
nuclei may represent further Celastrus alkaloids. Polyalcohol B 67)
has the same structure and stereochemistry as that reported by Wagner
for celapanol 9) 4 6 ) ;however, the coupling in 67 (J8,9 10Hz) ( 4 7 )
differs markedly from the value in the alkaloids 8,10, nd 11 (Js ,9=
7 Hz). Clearly, further studies in this area are needed to clear up theconfused stereochemistry.
A further group is studying the seed oil of C . orbiculatus and has
isolated three esters based on a trio1 (C15H2,04)containing acetic,
benzoic, and/or trans-cinnamic acids ( 6 3 ) .Detailed structures are under
study ( 6 4 ) .
VI. Biosynthesis
A systematic 14C-labeling study of t4he Tripterygium wilfordiialkaloids ( 5 3 ) has shown that the pyridine rings of wilfordic acid and
hydroxywilfordic acid are derived from nicotinic acid or nicotinamide
adenosine dinucleotide (NAD). However, no work has been reported
on the origin of the C, side chains of the substituted nicotinic acids.
A similar C5 unit is present in the polyesters 62 6 0 )and 65 (62) s
a-methylbutyrate, as the carbon skeleton of 3-furoate in the esters 62
and 63 go), and in the alkaloids celapanine S), ilforgine (55),and
wilfortrine 56). -Furoic acid has been found naturally with a limited
distribution, principally in the Celastraceae ( 6 5 ) .It was isolated as thefree acid from Euonymus autropurpureus ( 6 6 )and E . europaeus ( 6 7 )and
as an ester in t,he cinnamoyl spermidine alkaloid celafurine from
T. wilfordii ( 4 1 ) .
The high degree of hydroxylation of the dihydroagarofuran nucleus
is unusual in a sesquiterpene and is a characteristic feature of this
family. The stereochemistries of the poiyols have some common
features. The C-4 methyl group is axial irrespective of a C-4 hydroxyl
group. With the exception of polyalcoholD 69) 4 7 ) , he C-1, C-2, C-3,
and C-6 hydroxyl groups are, respectively, equatorial, axial, axial, andequatorial. Substitution at C-S and C-9 is highly variable in the nico-
tinoyl alkaloids (including the polyalcohols) but constant equatorial-
equatorial in the 0, and Ol0 alcohols.
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246 ROGER M . SMITH
W. iological Properties
Much of the work on this group of alkaloids was prompted by theirinsecticidal properties. The thunder god vines, Tripterygium wilfordii
and l‘ Forrestii, were both widely used as contact insecticides in rural
Chins (68,69).Plants were introduced for testing into the United States
(70, 71) nd England (72). The American studies led t o the isolation of
the alkaloids from T. ilfordii, which were all active against selected
larvae (11, 3) but nontoxic to mammals (73).During these studies, insecticidal activity was also found to be
present in an unidentified Celastrus species (71), elastrus angu latus (69),
and Euonymus europaeus (72), but so far, the isolated Celastrusalkaloids have not been tested. The isolated alkaloids of Euonymusshowed no activity in rats ( 7 4 )but possessed insecticidal properties (33).
The alkaloids of M ayten us owatus were found to be inactive as antitumor
agents (38),the activity of the seeds being due to maytansine (40). I n
the recent isolation of wilforine from M . senegalesis, it was found to be
inactive in antitumor assays (39).E . europaeus (75) and C . paniculatus (2 8 ) are both used in folk
medicine as cardiototic agents, emetics, and purgatives or as sedatives,
but these activities have been related to the presence of cardenolide
glycosides rather than to the alkaloids.
Note added in proof. Wagner et al. ( 7 6 ) have recently reported the
isolation and structural elucidation of cassinine from Cassine matabelicaLoes. (Celastraceae.) The alkaloid is based on a new sesquiterpene
nucleus, 4-deoxyeuonyminol, and contains a unique pyridine diacid
cassinic acid (3-carboxy -ethyl-2-pyridinebutanoic cid).
Further alkaloids have been reported from Catha edulis (77) and the
full details of the structural determination of the polyesters from
Eumymus europaeus (78) and Celastrus orbiculatus (79) have been
reported.
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4. CELASTRACEAE ALKALOIDS 247
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THE BISBENZYLISOQUINOLINE ALKALODS-OCCURRENCE. STRUCTURE. AND PHARMACOLOGY
M. P. CAVA. K. T BUCK.
University of Penmylvania
Philadelphia. Penmylvania
and K . L STUARTUniversity of the West Indies
Kingston. Jamaica
I. Introduction ...................................................... 250
I1. Structure Revisions ................................................ 251
A. Chondrocurine ................................................. 251
B.Chondrofoline.................................................. 252
C. Fetidine ....................................................... 252
D. Micranthine.................................................... 253
E. Thalfoetidine .................................................. 255
F. Tubocurarine Chloride .......................................... 255
. New Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
A. Belarine ....................................................... 257
B. Bisjatrorrhizine Chloride ........................................ 258
C. N,N-Bisnoraromoline ........................................... 258
D. Cancentrine.................................................... 260
F. Chelidimerine .................................................. 261
G
.Cocsuline ( = Effirine, Trigilletine) ................................ 262
H. Cycle~ur ine.................................................. 263
I. Cycleadrine.................................................... 264
J . Cycleahomine Chloride .......................................... 265
K. Cycleanorine................................................... 266
L. Cycleapeltine .................................................. 267
M . Dauricinoline .................................................. 267
N. Dauricoline .................................................... 268
0 . 0-Desmethyladiantifoline ....................................... 269
P. N'-Desmethyldauricine.......................................... 270
Q. 12'.O.Desmethyltrilobine ........................................ 270
R. 0, .Dimethy1micranthine ....................................... 271S. (-))-Epistephanine .............................................. 272
T. Espinidine..................................................... 272
U. Espinine ...................................................... 273
V. Funiferine ..................................................... 274
E. Cepharanoline.................................................. 261
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250 M . P. CAVA. K. T. BUCK. AND K . L. STUART
W.Isotenuipine ...................................................X . 0-Methyldauricine ..............................................
Y. 0-Methylmicranthine ...........................................Z . Nemuarine ....................................................A A. 2.N.Norberbamine ............................................BB 2-N-Norobamegine ............................................CC. Nortiliacorine.A, Nortiliacorinine.A, and Nortiliacorinine-B ........DD. Oxoepistephanine .............................................EE. Pakistanamine ...............................................FF. Pakistanine ..................................................GG. Penduline ....................................................HH. Stepinonine ..................................................I1 Telobine .....................................................
JJ. Thalfhe .....................................................K K. Thalfinine ....................................................LL. Thalictrogamine ..............................................MM. Thalictropine .................................................NN. Thalidoxine ..................................................00. Thalisopidine .................................................PP. Thalmelatidine ...............................................QQ. Thalmineline .................................................RR . Thalrugosamine ..............................................
TT. Thalrugosine (E haligine) ....................................UU. Toxicoferine ..................................................W . Tricordatine..................................................
IV. Known Alkaloids from New Sources..................................V. Methodsand Techniques ...........................................
A. Spectrometry ..................................................B. Chemical Methods ..............................................
VI Pharmacology .....................................................VII. Bisbenzylisoquinoline Alkaloids Tabulated by Molecular Weight .........
VIII. Appendix .........................................................References ........................................................
SS. Thalrugosidine ...............................................
275
275
276276
277
278
278
279
280
281
282
283
285
286287
287
288
289
289
290
291
292
293
294
295
296
297
297
297
298
300
301
304
312
I. ntroduction
It is the purpose of this chapter to review the recent chemistry of the
bisbenzylisoquinoline alkaloids. The previous review in this treatise
covered the literature up to the beginning of 1970. With the exception
of a few 1969 references. which were inadvertently omitted from
the previous review (Volume XI11 of this treatise). we have covered the
period 1970-1973. the 1973 coverage being defined as inclusive of thelast issue of Chemical Abstracts for th at year. and an appendix similarly
covers the 1 9 7 4 period. All aspects of bisbenzylisoquinoline research
have been included. with the exception of synthesis. which is the subject
of Chapter 6 in this volume.
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5. BISBENZYLISOQUINOLINE ALKALOIDS 251
We have defined a bisbenzylisoquinoline alkaloid in the broadest
sense, so as to cover compounds in which one (e.g., fetidine) or even both
(e.g., cancentrine) of the monomeric benzylisoquinoline units may bebiogenetically modified. We have included a table (seeSection VII)of all
bisbenzylisoquinoline alkaloids arranged in increasing order of molecu-
lar weight. We feel that this table should be of considerable practical
utility to workers in this area who wish to determine rapidly if a com-
pound they have isolated and examined only mass spectrometrically
may be identical with one of these alkaloids.
The authors have also introduced a brief section describing new and
useful techniques, both chemical and spectroscopic, dealing with
methods of structure elucidation of bisbenzylisoquinoline alkaloids.The section on pharmacology is not intended to be an exhaustive
coverage but should serve as a guide to current general aspects of this
area for these alkaloids during the period under review.
II. Structure Revisions
A. CHONDROCIJRINE
The sodium thiophenoxide N-demethylation of ( R , R ) - ( )-tubo-
curarine chloride (new structure 1) has been reported as giving the
presumably new base (+)-tubocurine ( 1 ) .Direct comparison of the
latter with ( + )-chondrocurine has now shown these t o be identical (2).
The former structure 2 for chondrocurine must therefore be discarded
in favor of structure 3. The bismethochloride of 3 is (+)-chondro-
curarine chloride, ( 4 ) ; he latter structure has recently been confirmed
by an X-ray crystallographic analysis (3).
1 R = H
4 R = M e
2
3
R1 = H , R , = Me
R, = Me,R, = H
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252 M . P. CAVA, K. T. BUCK, AND K. L. STUART
B. CHONDROFOLINE
Chondrofoline was originally shown by King to have the sameskeleton as curine, and the alternative structures 5 and 6 were proposed
for it ( 4 ) .The new structure 7 has recently been assigned to chondro-
foline on the basis of a comparative NMR and mass spectral study of
chondrofoline, its 0-trideuteriomethyl derivative, and related known
alkaloid derivatives of established stereochemistry ( 5 ) .
M e o w
5
6
R, = Me,R, = H
R, = H , R , = Me
M e 0
OH
7
C. FETIDINE
On the basis of earlier reported chemical degradation, fetidine was
assigned structure 8 ( 6 ) . Subsequently, mass spectral data in general
support of this structure have been reported (7) . More recently, a220 MHz NMR study of fetidine revealed the presence of an AB quartet
(J = 8 . 5 Hz) centered at 6 6 . 7 5 (1H) and 6 6 . 8 1 (lH), indicating the
M e N K3'.=
\/ OMe M e 0
O Me0
8
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5 . BISBENZYLISOQUINOLTNE ALKALOIDS 253
M e N P I
0
M e 0
presence of an adjacent pair of aromatic hydrogens. This fact, inconjunction with earlier evidence, requires a revision of the structure
of fetidine from 8 to 9 (8).
D. MICRANTHINE
In 1953, structure 10 was proposed for micranthine (9).Reinvestiga-
tion of this alkaloid [mp 193-195°C; C34H32N205M+ 548)] by NMR
IOH
10
R, = H, Ra = Me or vice verm
R, = H, R, = M e or vice versa
OH10
R, = H, Ra = Me or vice verm
R, = H, R, = M e or vice versa
indicated the presence of one methoxyl and one AT-methylgroup, and
of key significance, ten aromatic protons, thus invalidating structure
10. The trilobine-type structure (11) has now been proposed for micran-thine (10, 1).
The mass and IR spectra of 0,N-dimethylmicranthine (12) (mp
210-214°C) and isotrilobine were very similar, and the NMR spectra
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254 M . P. CAVA, K. T. BUCK, AND K. L. STUART
0
11 R1 = R, = H
12 R1 Ra = M e
13 R1 = CD,, R, = M e
were superimposable, but the specific rotations of these compounds
were opposite in sign. Both 12 and isotrilobine yielded the same
Hofmann degradation product. Since the structure of isotrilobine has
been confirmed by synthesis ( 1 2 )and its stereochemistry is known from
degradation to be S,S ( 1 3 ) , t follows that micranthine must be R,R, s
shown in structure 11. The position of the phenolic hydroxyl, previously
established by ethylation and degradation, was confirmed by mass
spectrometry.
The location of the secondary and tertiary amine functions was
determined by the following experiments. Oxidative photolysis of 12yielded the dialdehyde 14 and a lactam carbinolamine, which was
reduced with NBH to the aminolactam 15. When O-methyl-N-tri-
C HO OMe
I I
14
M e
15 R = M e16 R = CD,
deuteriomethylmicranthine (13,50%deuterium incorporation, preparedby alkylating 0-methylmicranthine with formaldehyde-d, and NBD)
was similarly degraded, the product was shown by NMR to be 16, thus
establishing the secondary nitrogen at position 2' of 11.
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5 . BISBENZYLISOQUINOLINE ALKALOIDS 255
E. THALFOETIDINE
Thalfoetidine was previously assigned structure 17 (14).Its earlierchemistry supports the structural features of 17apart from the location
of the ether termini of the isoquinoline units. Direct comparison has
now shown that 0-methylthalfoetidine is identical with thalidasine (18).
Thalfoetidine must therefore be assigned structure 19 (15, 1 6 ) . In
further support of structure 19, the racemic form of the thalfoetidine
degradahion product 20 has been synthesized and the spectral identity
of its diethyl ether with naturally derived material has been established
( 1 7 ) .
?HMe
I
"H "H
OH
17 20
18 R = M e19 R = H
F. TUBOCURARINEHLORIDE
The long-accepted bisquaternary structure 4 for ( + )-tubocurarine
chloride has been shown to be incorrect; the alkaloid is actually the
related monoquaternary salt 1 (2).The NMR of 1 shows only threeN-methyls, one of which shifts upfield on basification, showing it to be
a tertiary N-methyl. Benzylation of tubocurarine did not give an 0-
dibenzyl derivative as required by the old structure 4, but rather an
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5. BISBENZYLISOQUINOLINE ALKALOIDS 257
A variable temperature NMR study of 1 has revealed interesting
aspects of its solution conformation ( 2 0 ) . The very highly shielded C,.
proton at 6 4.80 moves slightly downfield to 6 5.08 a t 125OC as thedisubstituted central benzene ring begins to rotate. Indeed, the protons
of the latter ring (at Cl0,, Cllr, C1,,, and C,,,) are nonequivalent a t room
temperature but begin to coalesce to an AA'BB' pattern as rotation
increases at elevated temperatures. The trisubstituted central ring is
frozen even a t 125OC, and the protons a t Cl0, C13, and C,, are unaffected
by temperature changes.
III. New Alkaloids
A. BELAXIXE
Belarine (25) [C,,H,,N,O,; mp 158-160°C; [aID- 22" (CHCI,)] has
been isolated from the root bark of Berberis laurina Billb. ( 2 1 ) .Methyla-
tion of belarine yielded the previously isolated alkaloid O-methyl-
H'
25 R = H26 R = M e
isothalicberine (26). Structural proof of belarine therefore also firmlyestablishes the structure of isothalicberine. 0-Ethylation of belarine
followed by sodium-ammonia cleavage yielded the tetrahydroiso-
quinolines27 and 28, the latter being identified as the diethyl derivative
29.
When belarine was treated with D,O under basic conditions no proton
exchange was noted; this fact provides evidence in support of an ether
bridge at C, rather than a t C,, since a hydrogen ortho to a phenolic
group (C,) should have exchanged. Further support for the absence of a
C,-linked ether bridge was obtained by an acid-catalyzed exchangeexperiment on 25 in D,O; when the product was ethylated and subjected
to sodium-ammonia cleavage, compound 27 was obtained in which
deuterium was shown to be located at C, by NMR and mass spectrometry.
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5. BISBENZYLISOQUINOLINE ALKALOIDS 259
HO
MeO% ' M0M0
32
I 2c1-
OMe
31
33
34
Rl = R, = H
R, = H, R, = M e
Rl = Ra = M e
MeO'N '
36
37
38
Rl = Ra = H
Rl = Me, Ra = H
Rl = Ra = Me
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260 M . P. CAVA, K . T. BUCK, AND K. L. STUART
gave obaberine (38). Since the absolute configuration of aromoline is
known from sodium-ammonia cleavage studies (25, 26), N,N-bis-
noraromoline is therefore unambiguously established as 36. It isapparently the first reported bisbenzylisoquinoline alkaloid containing
two secondary nitrogens, perhaps because of the low solubility in
common organic solvents observed for 36 and expected for similar
alkaloids.
D. CANCENTRINE
Cancentrine (39) (C,,H,,N,O,, mp 238°C) occurs in Dicentracanadensis Walp (27). It was, in fact, first isolated and characterized
over forty years ago as FZ2,n alkaloid of unknown structure (28, 9).
The IR spectrum of cancentrine reveals the presence of both hydroxyl
and carbonyl bands. Its NMR shows t,he presence of three aromatic
methoxyls and one N-methyl group. The second nitrogen of 39 is
essentially nonbasic. The phenolic group of 39 can be methylated, af-
fording 0-methylcancentrine (40), and acetylated to give O-acetyl-
cancentrine (41). Conversion of 39 to its methiodide, followed by a
Hofmann degradation, gave the methine base 42. Hydrogenation of 42followed by treatment with diazomethane afforded the 0-methyl
dihydromethine base 43. The structure of 43 was revealed by an X-ray
crystallographic determination of its hydrobromide. Spectral studies
(UV and NMR) showed that only the expected single chemical changes
\ I-42
OM0 OM0
439 R = H
40 R = M e
41 R = Ac
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262 M. . CAVA, K . T. BUCK, AND K. L. STUART
'i\ / o
OH -
4 1
46 RlR2 OCH,O
48 R1 = R, = OMe
G. COCSULINE33)[=EFFIRINE3 4 ) ,TRIGILLETINE3 5 ) ]
Cocsuline (49) (C35H34N205;mp 272-2'74°C; [aID+ 280 ) was first
isolated from the leaves and stems of Cocculus pendulus Diels ( 3 3 ) .Cocsuline yielded a picrate (mp 194-196"C), O-methylcocsuline (mp 212-
214"C, [D + 289"), and O-ethylcocsuline. Recently, cocsuline has also
been reported from Triclisia gillettii (DeWild) Staner ( 3 4 ,35) and
T . ubcordata Oliv. ( 3 5 )under the names effirine ( 3 4 )and trigilletine ( 3 5 )[mp 272-274°C; [a]g2+348.2' (pyridine); acet,ate, mp 166-168"C] ( 3 5 ) .
O-MethyIcocsuIine was shown to be identical with the known alkaloid
isotrilobine (50). The location of the free hydroxyl group of 49 a t
position 12' rather than at 6 was established by mass spectral comparison
OMe
0 12'
OR
49 R = H50 R = M e
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5. BISBENZYLISOQUINOLINE ALKALIODS 263
of the alkaloid, its ethyl ether and acetate. In all cases, intense peaks
were observed at mle 350 and m/2e 175 (loss of the top portion of the
molecule at a).
H. CYCLEACTJRINE
Cycleacurine (51) [C35H3,N20S.H,O; - 02’ (MeOH)] was
isolated from Cyclea pe2tatu Hook. f. et Thorns. ( 3 6 ) ;purification was
effected by way of the bishydrobromide (mp 293-296°C). Its batho-
chromic UV shift in base revealed its phenolic nature. Diazomethane
+
OR
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264 M . P. CAVA, K. T. BUCK, AND X. L. STUART
alkylation of cycleacurine afforded the 0-trimethyl derivative (52),
which was identical with 0-dimethyl-(S)-curine 53) (37),except for the
opposite sign of i ts rotation; 52 is consequently the optical antipode of53. The positions of the phenolic functions of cycleacurine were de-
ducible from a study of the sodium-ammonia cleavage of O-triethyl-
cycleacurine (54). The structure of the diphenolic cleavage product ( 5 5 )was apparent, since it contained an ethoxyl group. The nonphenolic
product was assigned structure 56 from spectral considerations. Its
mass spectrum gave an isoquinoline fragment at m /e 220 showing that
one of the two ethoxyls must be an isoquinoline substituent. The meth-
oxyl of 56 appears in its NMR a t 6 3.84, indicative of a C, methoxyl
rather than a more shielded C, methoxyl.
I. CYCLEADRINE
Cycleadrine (57) (C,,H,,N,OG; mp 160-162"C) is an optically inactive
base found in the roots of Cyclea peltata (3 6 ).Alkali caused a batho-
chromic shift in its UV spectrum, indicating its phenolic nature.
Reaction of cycleadrine with diazomethane afforded an 0-methyl
derivative 58 , which was identical with isotetrandrine (59), except for
it s lack of optical activity. The mass spectrum of cycleadrine showed a
strong peak at m/e 381 for the linked isoquinoline units revealing that
fM e O m
57 R = H
58 R = Me ( R S + 5R acemate)
MeN O q N M O
H' - * H
5.9
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5. BISBENZYLISOQUINOLINE ALKALOIDS 265
one of these must contain the phenolic hydroxyl group. It is known that
only the right hand isoquinoline unit of a C,-C,, head-to-head base is
lost singly ( 3 8 ) ; he peak at mle 417 (M-191) indicates th at this unit incycleadrine must bear a methoxyl at C6, nd tha t the hydroxyl must be
born on the left-hand head unit. Finally, the hydroxyl must be at C,rather than a t C,, since a C, methoxyl in related compounds is highly
shielded ( 8 3.20), whereas the highest field methoxyl of cycleadrine
appears a t 6 3.73.
J. CYCLEAHOMME HLORIDE
Cycleahornine chloride (60) [C,,H,,N,O,C1; mp 190-194"C, [ID+ 103" (CHCl,)] was isolated from Cyclea peltata roots ( 3 6 ) . I t s NMRshowed one tertiary N-methyl a t 6 2.37 and two quaternary N-methyls
at 6 3.54 and 6 3.30. Cycleahomine was shown to be a monoquaternized
tetrandrine, since reaction of 60 with methyl iodide gave tetrandrine
bismethiodide (61). On the other hand, reaction of tetrandrine with one
equivalent of methyl iodide affords not cycleahomine iodide, but the
C1- Me,N+
H
\,-Me
60
61
isomer 62. Since the demethylative carbamylation of tetrandrine isknown to occur selectively at the right-hand isoquinoline unit (see
cycleanorine), the selective N-methylation giving 62 must occur a t the
same site. Cycleahomine is therefore the isomer of 62, namely 60.
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266 M. P . CAVA, K . T.BUCK, AND K. L. STUART
62
K. CYCLEANORINE
Cycleanorine (63) [C,,H,,N,O,; mp 171-172°C; [aID+ 308" (CHCl,)]was isolated from CycZeapeZtataroots ( 3 6 ) . ts NMR showed the presence
of only one N-methyl (at 6 2.33). N-Methylation of cycleanorine by
formaldehyde and sodium borohydride (39)gave tetrandrine (64).The
position of the secondary nitrogen of cycleanorine was revealed by its
mass spectrum, which showed a peak at m/e 431 (M-177),characteristic
of the loss of the right-hand isoquinoline unit of a C,-C7, dimeric alka-
loid. Finally, cycleanorine was prepared from tetrandrine (64) by
selective N-demethylation using the carbamate method ( 4 0 ) . Thus,reaction of 64with methylchloroformate gave the monocarbamate 65,
alkaline hydrolysis of which afforded 63.
63
64 R = M e
65 R = COOMe
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5. BISB ENZY LISOQUINOLINE ALKALOIDS 267
L.CYCLEAPELTINE
Cycleapeltine (66) [C3&40X206; mp 232-234OC;[aID- 106 CHCI,)]was isolated from the roots of Cyclea peltata ( 3 6 ) .The NMR and mass
spectral data for cycleapeltine were in accord with those reported for
limacusine (67),except that the optical rotation w-as of opposite sign.
Cycleapeltine should therefore be the optical antipode (66)of limacusine.
In accord wit,h this proposal, reaction of (66) with diazomethane gave
an O-methyl derivative that was identical with the known O-methyl-
repandine (68).
M e N
wo: q N M e
H "H
66 R = H68 R = M e
M. DAURICINOLINE
Dauricinoline (69) [C,,H4,N206;pale yellow powder; [a] 1-94.6(MeOH)] was isolated from Menispermum dauricum DC. (41). MR
evidence was given to support the presence of two N-methyl, three
methoxyl, and two hydroxyl groups. Treatment with diazomethane
yielded O-methyldauricine, thus establishing dauricinoline as the
O-methyl derivative (70) of the alkaloid dauricoline (71), also isolated
from Menispermum dauricum ( 4 2 ) . n further confirmation of structure69, sodium-ammonia cleavage of the 0,O-diethyl derivative 72 afforded
(R)-() - 1 -(p-ethoxybenzyl)-6-ethoxy-7-methoxy-2-methyl-1,2,3,4-
tetrahydroisoquinoline (29) and (R)-( -armepavine (73).
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268 M. P. CAVA, K. T. BUCK, AND K. L. STUART
O M 0 M e 0
69
7 0
71
7 2
R, = H, Ra = M e
R, = R, = M e
R, = R, = H
R, = Et, R, = M e
MeO'q N & f eH
73
29
R, = Me, R, = H
R, = R, = Et
N. DAURICOLINE
Menispermum dauricum yielded dauricoline (71) [C,,H,,N,O,;yellow powder; - 150" MeOH)] 42).The NMR showed the presence
of three hydroxyl groups at 6 5.53 (exchangeable with D,O). Treatment
with diazomethane gave t,he 0-methyl derivative (70) of dauricine (74).
Final proof was provided by sodium-ammonia cleavage of O,O,O-
triethyldauricoline, which yielded the two tetrahydroisoquinolines 29
and 75.
71
74
70 R, = R, = M e
R, = R, = H
R1 = M e , R, = H
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5. BISBENZYLISOQ UINOLINE ALKALOIDS 269
29 R = Et
75 R = OH
0. -DESMETHYLADIANTIFOLINE
0-Desmethyladiantifoline (76) (C41H,,N20,; mp 125-126°C; [a],,
+ 18") was isolated from the roots of Thalietrum minus f. datum (43) .
I t s 0-methyl derivative, formed by reaction with diazomethane, was
identical with adiantifoline (77).The position of the phenolic hydroxyl
of 76 was revealed by permanganate oxidation of its 0-ethyl ether (from
76 and diazoethane), which afforded the known isoquinoline 78 and
aldehyde 79, a known adiantifoline degradation product.
76 R = H77 R = Me
OMe
MeNp:0
79 78
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5. BISBENZYLISOQUINOLINE ALKALOIDS 2 7 1
H,‘
R1 / /
12 ’\
0\
82 R, = R, = H
83 R, = H, R, = Me
49 R, = Me, R, = H
R . O,N-DIMETHYLMICRANTHINE
0,N-Dimethylmicranthine (12) (C,,H,,N,O,; mp 210-214°C; [.ID- 241°),was isolated from the bark of a Daphnandra sp. and Daphnandramicrantha Benth. ( l 0 , I I ) .
This alkaloid gave IR and mass spectra matching those of isotrilobine
(50)but of opposite specific rot,ation, and 12was identical with material
prepared by N-methylating 0-methylmicranthine (84).
Me0
I
OMe
12
50
84
R = Me, chiral centers 1 and 1’ = R (as shown)
R = Me, chiral centers 1 and 1’ = S
R = H. chiral centers 1 and 1’ = R
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272 M. P. CAVA, K . T. BUCK, AND X.L. STUART
S. ( - )-EPISTEPHANINE
(- -Epistephanine (85) [C,,H,,N,O,; mp 198-206°C (MeOH); [.ID- 216" (CHCl,)] was isolated from the stems of Anisocycla grandidieri
(45). It was identical by NMR, UV, and I R with authentic (R)-() -
epistephanine (86), but its optical rotation was the opposite. It was
therefore assigned structure 85.
M e 0
85
86 Chirel center = S
C h i r d center = R (as shown)
T . ESPINIDINE
Espinidine 87) C,,H42N206; amorphous; [ID +31" (CHCI,)] was
isolated from Berberis laurina ( 4 6 ) .Espinidine is a diphenolic base and is
converted by diazoethane to an 0-ciiethyl derivative (88) and by diazo-
methane to an 0-dimethyl derivative; the latter was found to be
identical with 0-trimethylespinine (89). Espinidine must therefore be
an 0-methylespinine. Except for a very weak molecular ion a t m/e 610,
the mass spectrum of 87 was practically identical with that of espinine,
showing that the additional methyl group must be in the lower diphenyl
ether portion of the molecule. Confirmation of structure 87for espinidine
was obtained by sodium-ammonia cleavage of its diethyl ether 88,
which gave the two known benzylisoquinoline fragments 90 and 27.
MeNFoMeRM e 0 " q N M e.H
H"
87 R = H88 R = Et
89 R = M e
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5. BISBENZYLISOQUINOLINE ALKALOIDS 273
H*' I I"'H
27 90
U. ESPININE
Espinine (91) [C,,H,,N,O,; mp 123-125°C; [a]=+ 25 (CHCl,)] was
isolated from Berberis laurina ( 4 6 ) .It is a triphenolic base, giving an
0-trimethyl derivative (89) with diazomethane and an 0-triethyl
derivative (92) with diazoethane. Espinine gives a very weak (< 1%)
molecular ion, characteristic of a dimeric benzylisoquinoline joined only
in a tail-to-tail manner; the base peak a t m/e 192 reveals an N-methyl-
isoquinoline unit bearing m e hydroxyl and one methoxyl. The structure
91 for espinine was assigned on the basis of the identification of the
known monomeric benzylisoquinolines 90 and 56 as the sodium-ammonia cleavage products of 0-triethylespinine (92).
91 R = H
92 R = Et
89 R = Me
56 90
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274 M . P. CAVA, K. T. BUCK, AND K . L. STUART
V. FUNIFERINE
Funiferine (93) [C,,H,,N,06; mp 232-234°C (EtOH) or 168-169°C(MeOH); [elD + 171.4’ (MeOH) or + 184.3” (CHCl,)] was isolated in
1965 from Tiliacora funif era Oliver ( T .warneckei ), although its struc-
ture could not be assigned a t that time ( 4 7 ) .I ts NMR spectrum shows
the presence of two N-methyls and four methoxyls. As a monophenolic
base, funiferine is converted by diazomethane to 0-methylfuniferine
(94)) which was shown by direct comparison to be identical with the
known 0-methylrodiasine. Conversion of funiferine to 0-ethylfuniferine
dimethochloride, followed by permanganate oxidation, afforded 2-
ethoxy-2’-methoxy-5,5’-dicarboxybiphenyl95); the correspondingdimethoxydiacid (96)was obtained by oxidation of 0-methylfuniferine
(94).Funiferine is therefore the positional isomer of rodiasine (97))fromwhich it differs only in the placement of the phenolic hydroxyl group
in the biphenyl system. The structure was confirmed by a comparative
mass spectral study of funiferine (93), rodiasine (97))and their common
methyl ether (94). In all cases, weak but significant ions were apparent
that correspond t o the loss of the lower left-hand benzyl unit (cleavage
a-b); ions corresponding to the loss of the other half of the biphenyl
unit (cleavage b-c) are not observed. The stereo-chemistry of funiferine
cannot be assigned a t this time, although it must be the same as th at of
rodiasine ( 48 ) .
93
94
97
R, = H, R, = Me
R, = R, = M e
R, = Me, Rz H
OR O M e
95 R = Et96 R = M e
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5. BISBENZYLISOQUINOLINE ALKALIODS 275
W. ISOTENWINE
Bark material from a Daphnandra sp. collected over thirty years agoin Australia yielded isotenuipine (98) [C,,H&&; mp 240°C; [a];,
+ 129" (CHCI,); dimethiodide mp 278°C (decornp.);[ - 50" (as)].
0 - J
98
Placement of substituents was based on the fact that the mass
spectrum shows an ion a t m/e 485 (M-151) , indicating that the methylene-
dioxy is attached to ring E and also on NMR comparison with the
structurally similar known bases (R)- r (8 -tenuipine, tetrandrine,
isotetrandrine, and phaeanthine. Evidence for the stereochemistryassigned was also based on a comparison of the specific rotation ofisotenuipine with those of the above-mentioned bases.
X. 0-METHYLDAURICIXE
0-Methyldauricine (70) (C39H46N206;morphous; [aID - 28") was
isolated from Popowia cf. cyanocarpa Laut. and K. Schum. It s crystal-
line dimethiodide (mp 179-181°C) was identical with material preparedfrom dauricine (74) by methylation ( 5 0 ) .The bark of Colubrina asiatica
Brongn. has also been found to contain 70 as the major alkaloid ( 51 ) .
M e 0
74 R = H70 R = M e
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276 M . P. CAVA, K. T. BUCK, AND K . L. STUART
Y. O-METHYLMICRANTHINE
O-Methylmicranthine (84) [C,,H,,N,O,; mp 163-165°C (dec.); [cz]i0
-208"] from a Daphnandra sp. and D . micranthu was assigned its
structure by direct correlation with micranthine, for which the correct
structure 11was reported a t the same time ( 1 1 ) .The N-acetyl derivative
has mp 1 7 P 1 7 9 C (dec.); - 03" (CHCI,).
M e 0
OR
84 R = M e11 R = H
Z. NEMUARINE
Nemuarine (99) [C37H40N206; p 222-223°C; [.ID - 42.7" (CHCl,)]
was isolated from the leaves of Nemuaron wieillardii Baill. (52,53). ts
mass spectrum shows intense ions a t M-213 and (M-212)/2, ndicative
of the loss of a diphenyl ether fragment from a head-to-head dimer
molecule. Nemuarine is monophenolic and reacts with diazomethane togive O-methylnemuarine (loo), the mass spectrum of which indicates
clearly that the phenolic function of 99 must reside in the diphenyl
ether moiety. Sodium-ammonia cleavage of ether 100 gave (R)-N-
methylisococlaurine (28) and (R)-O-methylarmepavine(30). Prolonged
heating of ether 100 with 3% DC1 in DzO a t 120°C resulted in the
introduction of one deuterium ; sodium-ammonia cleavage of the
deuterated 100 gave undeuterated 28 along with the deuterated
armepavine derivative 101, in which the shielded C, proton signal at
8 5.98 had virtually vanished. Nemuarine was therefore established asstructure 99 and represents the first example of a C,-C6. linked bis-
benzylisoquinoline alkaloid. It appears to be derived biogenetically
from two isococlaurine units.
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5. BISBENZYLISOQ UINOLINE ALKALOIDS 277
O M e M e 0
99 R = H100 R = M e
M e 0
HOLy30 R = H
101 R = D
28
Pyenarrhena australiana F. Muell. afforded 2-N-norberbamine (102)
[C36H38N206;p 166-188°C; [a]=+ 117" (CHCl,)] (54 ) .Formaldehyde-
NBH methylation of it gave berbamine (103).Comparison of the NMRresonance of the N-methyl of 102 (6 2.62) with those of 103 "'-Me
6 2.65, N-Me 6 2.25 (55)] enabled the unambiguous assignment of
102 R = H103 R = Me
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278 M. P. CAVA, K. T. BUCK, AND K. L. STUART
structure 102 o 2-N-norberbamine. Further support for this structure
was provided by the mass spectrum which shows ions a t mle 192
(cleavage a-c) and 174 (cleavage b-c).
BB. 2-N-NOROBAMEGINE
The two Australian menispermaceous vines Pycnarrhena australiana( 5 4 )and Pycnarrhena ozantha ( 2 4 )have been independently reported as
sources of 2-N-norobamegine (104) [C35H3&&6; mp 188-190°C (dec.)
(CHC1, or acetone); [aID +290" (CHCI,) ( 5 4 ) and [a]i5 - 146" (0.1 N
HCl)] ( 2 4 ) .N-Methylation of 104 gave obamegine (105)and subsequenttreatment of this product with diazomethane afforded isotetrandrine
(59). The structure and absolute stereochemistry of obamegine are
known from cleavage experiments (56).The relative location of the
secondary and tertiary nitrogens of 104 was revealed by the NMRspectrum, which showsa signal at 6 2.52, as expected for a 2'-N-methyl
not subject to the shielding effect normally observed for the 2-N-methyl
group in similar alkaloids ( 55 ) [S 2.27 for 2-N-methyl in 105 (54)].
104 R , = R2 H
105 R, = Me, R, = H
59 R, = R2 M e
CC. NORTZIACORINE-A,ORTILIACORININE-A,
AND NORTILLWORTNINE-B
Tiliacora racemosa Colebr. [synonymous with T. cuminata (Lam.)
Miers] yielded the alkaloids nortiliacorinine-A [originally called pseudo-
tiliarine (57) l [mp 262-268°C (dec.) (acetone); [a]D +268.8" (pyridine)]
and nortiliacorinine-B [mp 218-220°C (dec.) (acetone-MeOH); [ID
+ 356.2" (pyridine)] ( 5 8 ) . Tiliacora funifera (T. arneckei Engl. exDiels) also afforded nortiliacorinine-A and, in addition, nortiliacorine-A
[originally isotiliarine (57)l [mp 258-260°C; [ID + 194.5"(CHCI,)] ( 59 ) .All three alkaloids were shown to possess the same molecular formula
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5. BISBENZYLISOQUINOLINE ALKALOIDS 279
(C,SH3,N,0,). On N-methylation, nortiliacorine-A gave tiliacorine,while nortiliacorinine-A and nortiliacorinine-B afforded tiliacorinine.
Tiliacorine and tiliacorinine are isomeric bases (C,,H,,N,O,) to whichthe partial structure 106has been assigned from degradative and spectral
studies (58 ) . Thus, although more work is required to establish the
substitution pattern and stereochemistry of nortiliacorinine-A, norti-
liacorinine-B, and nortiliacorine-A, they may be assigned the pre-
liminary structures 107 or 108.
OMe
OR3 0
106
107
108
R, = Rz Me, R, and R 4 e , H or v i c e versaR , = H, R , = Me, R, and R, = Me, H or v ice versa
R, = Me, R, = H, R1 and R, = Me, H or v i c e v e r s a
DD. OXOEPISTEPHANINE
Stephnia hernandifolia Walp. afforded oxoepistephanine
[C3,H,,N,0,; mp 22P226"C (dec.) (MeOH-ether);[a]:' +272" (CHCl,)]
( 6 0 ) .The NMR spectrum was very similar to that of epistephanine (86),isolated from the same plant, except for a downfield shift of one of the
aromatic resonances. The IR band at 5.97 p indicated a conjugated
carbonyl and the mass spectral peak at mle 380 suggested that this was
380
109
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280 M . P. CAVA, K. T. BUCK, AND K. L. STUART
86
located in the lower portion of the molecule. Structure 109 was proposed
as most reasonable for oxoepistephanine; however, several attempts to
interrelate chemically his alkaloid with epistephanine were unsuccessful.
EE.P A K I S T A N ~ N E
The first proaporphine-benzylisoquinoline dimer, pakistanamine
(110) (C,,H,,N,O,), has been isolated from Berberis baluchistanicu as
its picrate [mp 158-162°C (dec.)]. The free base darkens readily to a
deep purple color, but the hydrochloride [mp 215OC; [.II, + 20 (MeOH)]
is fairly stable (6 1 ,62).
H
a
1 O
UV, IR, and NMR da ta are in accord with structure 110, and mass
spectrometry shows the major cleavagesa, , and c .When pakistanamine
was reduced with NBH, a mixture of diastereomeric dienols was
produced. Acid treatment of this product with 3 N H2S04 afforded
1-0-methyl-10-deoxypakistanine111)via a dienol-benzene rearrange-
ment, while direct treatment of pakistanamine with 3 N H z S 0 4 esulted
in a dienone-phenol rearrangement to 1 0-methylpakistanine (112) .
Acetylation of the latter gave the corresponding acetate, and methyl-ation yielded 1,lO-di-0-methylpakistanine113).Catalytic reduction of
pakistanamine hydrochloride with Pd/C afforded 11 ,lZ-dihydro-
pakistanamine. ORD data are reported for most of these products.
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5 . BISBENZYLISOQUINOLINE ALKALOIDS 281
OMe
111 R = H
112 R = OH
113 R = OMe
The occurrence of the alkaloids pakistanine and pakistanamine in t,hesame plant lends substantial support t o the earlier suggested biogenetic
sequence (63) benzylisoquinoline--f bisbenzylisoquinoline --f proapor-
phine-benzylisoquinoline dimer+ porphine-benzylisoquinoline.
FF. PAEISTANINE
Pakistanine (114) [C3,H4,,N206;mp 15P-156OC; [a]g5 + 106' (MeOH)]
was also isolated from Berberis baluchistanica (6 1 , 6 2 ) .The UV spectrumis similar to that of 9-phenylboldine, and the other spectral data are in
accord with a linked aporphine-benzylisoquinoline structure. Sodium-
b
114
113
C
R = H
R = Me
ammonia cleavage of the 0,O-dimethyl derivative 113 yielded (8)-()-
armepavine (115) and (R)-()-2,lO-dimethoxyaporphine116).
The presence of two phenolic hydroxyl groups in 114 was confirmed
by the formation of an amorphous diacetate and by a bathochromicshift in the UV spectrum on the addition of base. The fact that paki-
stanine gave a negative test with phloroglucinol, a reagent that has been
used to detect o-diphenols, was cited as evidence in partial support of
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5. BISBENZYLISOQUINOLINE ALKALOIDS 283
penduline shows a characteristic head-to-head fragment at rnle 198(doubly charged ion), showing that the free hydroxyl must reside in the
diphenyl ether portion of the molecule. Sodium-ammonia cleavage ofethyl ether 118 gave (8)-0-ethylarmepavine (119) nd (8)-N-methyl-
coclaurine (24). The structure 117 was therefore established for
penduline.
119 24
Penduline is apparently the enantiomer of the known alkaloid
pycnamine (65 ) .Also, 0-methylpenduline (mp 150-152°C; [.ID + 218";
hydrochloride, mp 272-275"C) picrate, mp 251-253OC) should be
identical with tetrandrine (Sa). However, direct comparisons of these
compounds were not reported.
HH. STEPINONINE
Stepinonine (120) [C36H34N20,; p 24&245"C, 2 8OOC (dimorphism);
[a];'' - 8 (pyridine)] was recently isolated from Stephania japonica
Miers ( 6 6 ) .The IR YE^ 3500 (OH), 166 3 (C=O) cm-l] and NMR [ 6 5.60-7.37
(10 H-aromatic), 3 .37 , 3 .85 , 3 .96 (3 OMe), 2.54 (N-Me)] revealed thefunctional groups present. Acetylation yielded a monoacetate and
OH
n o
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5. BISBENZYLISOQUINOLINE ALKALOIDS 285
OEt
124
lowed by reductive fission to armepavine (115) nd 125, euterated at
C, and C6,, respectively. The identity of 125 was established by com-
parison with racemic synthetic material ( 67 ) .This new dimeric benzyl-
isoquinoline-Z-phenyl-sec-homotetrahydroisoquinolineype could be
biogenetically closely related to the rhoeadine-type alkaloids.
11. TELOBINE
Another new alkaloid which was reported from a Daphnandra sp. was
named telobine (126) C,,H,,N,O,; mp 185-195°C (dec.); [a];' + 188"
(CHCl,)] ( 1 1 ) . Telobine yielded the derivatives N-acetyltelobine
[mp 180-185°C (dec.);[a];, + 111" (CHCl,)] and N-methyltelobine (127)
H
M e
OMe
126 R = H
127 R = M e
[C,,H,,N,O,, (M + 576.2624); mp 175-180°C (dec.); [a]h8 +248"
(CHCI,)]. NMR evidence indicated a diastereomeric relationship
between N-methyltelobine (127) nd 0,N-dimethylmicranthine (12);also, the properties of N-methyltelobine (mp and specific rotation) were
in good agreement with those of a base structure 127prepared by partial
synthesis from oxyacanthine (68).
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286 M . P. CAVA, K. T. BUCK, AND K. L. STUART
JJ. THALFINE
The novel structure 128 has been proposed for thalfine, [C38H,SN,08;mp 141-142°C (dec.); [a]b5 +69" (EtOH)] isolated from Thalictrum
foetidurn L . (69) .
OMeI 4 '
128
Two Hofmann degradations on thalfine dimethiodide produced
trimethylamine, but in addition, a product that still contained nitrogen,
suggesting the presence of an isoquinoline moiety in the structure.
Reduction of thalfine dimethiodide with zinc in 20y0 H,SO, yielded
N-methyltetrahydrothalfbe methiodide, which on treatment withethanolamine gave N-methyltetrahydrothalfine. This product has an
IR spectrum identical with that of another new alkaloid from the same
plant, thalfinine (132), which is discussed in the next section.
The substitution pattern of the lower portion of 128 was established
by oxidation with KMnO, in acetone. The acid product afforded with
diazomethane the dimethyl ester 129. Cleavage of thalfine with sodium-
CO,Me
OMe
129
ammonia afforded the main products laudanidine (130) and 0-methylarmepavine (131) of unspecified stereochemistry. The formation
of 130 seems to be the result of an unexpected cleavage, perhaps
resulting from the influence of the isoquinoline system.The placement of the other methoxyl and of the methylenedioxy
group seems to be based mainly on NMR data. It is of interest to note
that no mention was made of a quartet in the NMR spectrum expected
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5. BISBENZYLISOQUINOLINE ALKALOIDS 287
130 R = OH
131 R = H
for the protons at C3, and C4, in ring D. Since no evidence is presented
for the chirality of 130and 131, o definitive assignment of configuration
can be made for 128.
KK. THALFINDTE
Thalfinine (132) [C39H42N208; amorphous, mp 117-1 18°C; [a]h6
+ 115 (EtOH); perchlorate, mp 23P235"C (dec.); hydrochloride,
mp 223-226°C (dec.)] wits isolated from Thulictrum foetidurn (69) . I ts
NMR showed two N-methyl groups (6 2.54, 2.30), four methoxyls
(6 3.36, 3.43, 3.66 and 3.80), a methylenedioxy ( 6 5.80) , and a C8H a t
6 5.92. As mentioned in the previous section, thalfinine was obtained
from thalfine by N-methylation and reduction. The structure 132 has
been proposed for thalfinine; however, no stereochemistry was assigned
to either chiral center.
OMe8
132
LL. THALICTROQAMINE
The alkaloid thalictrogamine (133), tructurally related to thali-
carpine (134),was isolated from Thulictrum polygamum Muhl. ( 7 0 ) .Thalictrogamine (C3,H44N20,) an amorphous base [ [a ]g5 + 3 5 O
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288 M . P. CAVA, K. T.BUCK, AND K. L. STUART
133 R, = Rz = H
134
135
R, = R, = M e
R1 Me, R2 H
(MeOH)] on treatment with diazomethane gave a mixture of thalictro-
pine (135) nd thalicarpine (134). he mass spectrum [M+ 668 , m/e 4 7 6(M-a), 326 (M-b), 309 (M-c-1) , 192 (a, base)] provides evidence for the
placement of one hydroxyl group on the tetrahydroisoquinoline ring Band the other on the aporphine moiety. From a study of space-filling
models it was suggested that a C8. aromatic proton near 6 6 .4 , rather
than near 6 6 .2 in the NMR spectrum is diagnostic of the presence of a
C7, phenolic substituent.
MM. THALICTROPINE
Thalictropine (135) C40H4,N,08; mp 167°C (MeOH); + 120'
(MeOH)] was recently isolated from Thalictrumpolygumum (7'0).The
presence of the phenolic group was evidenced by a bathochromic shift
of the UV spectrum on the addition of base and by the preparation ofthalictropine acetate (mp 182-183°C).
The NMR spectrum of thalictropine was superimposable upon that
of 1-0-demethylthalicarpine synthesized in advance of its isolation
c
135
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5. BISBENZYLISOQUINOLINE ALKALOIDS 289
from nature ( 8 ) .The mass spectrum [M+ 682, m/e 476 (M-a), 326 (M-b),
310 (M-c), and 206 (a, base peak)] clearly indicated that the phenolic
hydroxyl was located on the aporphine residue.
Thalidoxine (136) [C,,H,,N,O,; amorphous; + 113" (MeOH)]
from Thalictrum dioicum L. (7 1 ) s a substitutional isomer of thalictro-
pine (135); accordingly, treatment with diazomethane yielded
thalicarpine (134).
C
136
134
137
R, = H, R, = M e
R, = R, = M e
R, = Ac, R, = Me
135 R, = Me, R, = H
Thalidoxine acetate (137) produced NMR evidence for the location
of the hydroxyl at Clz,. Although the Cll, proton was only slightly
shifted (0.10 ppm) to lower field in 137 than in 136, there was observed
a relative upfield shift of either 0.10 or 0.17 ppm in one of the aromatic
resonances of 137, stated from inspection of molecular models to bepossible for a C12, but not a Cll, acetoxylated system.
NMR values are tabulated ( 7 1 ) or 136 and several other thalicarpine-
type alkaloids. The mass spectrum of 136 shows the major fragmenta-
tions a, b, and c.
00. THALISOPIDINE
Thalisopidine (138) [C,,H,,NzO,; mp 215-216°C; - 9" (EtOH)]was isolated from Thulictrum isopyroides C. A . Mey. (72). The NMR
spectrum showed two N-methyl groups (6 2.44, 2.49), three methoxyls
(6 2.96, 3.30, 3.70), and a C8, proton a t 6 6.30.
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290 M . P. CAVA, K. T. BUCK, AND K . L. STUART
OH
M e N
\ /
\0 RO
138 R = H139 R = M e
The structural assignment for thalisopidine is based solely on acomparison of its NMR with that of thalisopine (139); egradative,
mass spectral, and NMR evidence exists in support of the structure
suggested for this lat ter alkaloid ( 7 3 ) .It is noteworthy, however, that
no direct comparison was reported for 0,O-dimethylthalisopidine
(mp 238-239°C) and 0-methylthalisopine (amorphous; mp 163-166"C),
which should be identical if the assigned structures 138 and 139 are
correct.
PP. THALMELATIDINE
Thalmelatidine (140) [C42H48N2010;p 120-122OC; [a]= +47
(CHCl,)] was isolated from the roots of Th l i c t ru mminus f. elatum ( 7 4 ) .
Structure 140was assigned t o thalmelatidine on the basis of its NMRspectrum, as well as the formation of isoquinolone 141 and aldehyde 79
by permanganate oxidation. Aldehyde 79was identical with the known
aldehyde formed from adiantifoline 77) y a similar oxidation ( 4 3 ) .
Isoquinolone141was synthesized from the known base142 y an unusualreaction sequence involving (a) bromination, (b) treatment with meth-
v140
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5 . BISBENZYLISOQUINOLINE ALKALOIDS 291
MeN@)0
Me
0
1 4 1 142
OM eIMee 0
1
7-NMe
U-
79
anolic sodium methoxide, (c) treatment with diazomethane, and (d)
permanganate oxidation. The S,S configuration for 140 (shown below)was suggested as likely from its positive rotation and analogy with
related alkaloids.
QQ. THALMINELINE
Thalmineline (143) [C,,H,,N,O,, ; mp 96-98°C (ether-hexane) or
mp 108-110°C (EtOH);[aID +22" (MeOH)]was isolated from the roots
of Thalictrurn minus var. elaturn (75).Thalmineline is a phenol that hasan unsubstituted position ortho or para to the hydroxyl function, since
it not only gives a positive ferric chloride test but also couples with
diazotized p-nitroaniline. Structure 143 has been assigned to thalminel-
ine on the basis of NMR and mass spectral analogy with the related
known bases thalicarpine (234) and adiantifoline (77).A salient feature
of the NMR spectrum of 143 is the high field aromatic singlet at 6 5.71 ,
attributed to the C, aromatic proton. Also, the mass spectrum of 143
shows a base peak at r n / e 222, characteristic of an N-methyltetrahydro-
isoquinoline unit bearing two methoxyls and a hydroxyl. The possibilityth at the hydroxyl may be at C7, ather than a t C5, cannot be discounted,
and the stereochemistry of 143 is apparently assigned by analogy withrelated bases.
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292 M . P. CAVA, K. T. BUCK, AND K . L. STUART
143
R
134 R = H77 R = OMe
RR. TRALRUUOSAMINE
Thalrugosamine (144) [C,7H,,N20,; mp 122-125°C; + 280"
(MeOH)]was isolated from Thalictrum rugosum Ait. (T.laucum Desf.)
(2'6).It was converted by diazomethane into O-methyloxyacanthine
(145). The mass spectrum of thalrugosamine reveals a head-to-head
fragment ion, mle 382, showing that the phenolic hydroxyl must be
attached to an isoquinoline unit. Methyl ether 145, but not the parent
alkaloid 144, shows a high field methoxyl signal at 6 3.20 characteristic
of a C,-methoxyl; the hydroxyl of 144 must therefore be a t C,. Chemical
confirmation of structure 144 was obtained by diazoethane alkylationof thalrugosamine to give ethyl ether 146. Sodium-ammonia cleavage
of 146 afforded the known monomeric bases 147 and 148, which were
identical with reference samples (after methylation of 147).
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5. BISBENZYLISOQUINOLINE ALKALOIDS 293
144 R = H
145 R = M E
146 R = Et
M ~ N ;mlI o m N M e
mle 382
M e N
H*' "H
H M e 0
147 148
SS. THALRUBOSIDINE
Thalrugosidine (149) [C,,H,,N,O,, ( M+ 638); mp 172-174°C;
- 185" (MeOH)] was isolated from Thalictrumrugosum (77). Treatment
with CH,N, yielded the known alkaloid thalidasine (18) previouslyisolated from this plant. The location of the phenolic group was
established by sodium-ammonia cleavage of thalrugosidine ethyl ether,
OR M e 0
149 R = H
18 R = M e
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294 M. P.CAVA, K. T. BUCK, AND K.L. STUART
which gave compounds 150 and 20. Compound 150 was shown to be the
optical antipode of a cleavage product derived from thalrugosine (151),
while 20 was identical with the phenolic cleavage product of 18. Thal-rugosidine is the substitutional isomer of thalfoetidine (19).
OH
150 20
TT. TRALRUGOSINE77) [=THALIGINE78)l
Thalrugosine (151)[C3,H40N20S,M+ 608-2848); mp 212-214°C; [a] 0
+128" (MeOH)] was isolated from Thalictrum rugosum
(77).Treatment
of thalrugosine with CH2N, gave the monomethyl ether (mp 180-
182"C), which proved to be identical with isotetrandrine (59).
151 R = H
5 9 R = M e
The mass spectrum showed linked isoquinoline units a t m/e 382- 1877
and m/2e 191.0938 (cleavage at a), requiring the free OH to be in the
top portion of the molecule. NMR data supported a C, located hydroxyl
in that the spectrum of thalrugosine shows no methoxyl signal higherthan 6 3.77, while compound 59 shows one at 6 3.15.
Sodium-ammonia cleavage of thalrugosine ethyl ether yielded 27,
identified as its methiodide, and 24, identified by conversion to 0-
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5. BISBENZYLISOQUINOLINE ALKALOIDS 295
Me
27 24 R = H
15 R = Me
methylarmepavine (152) (IR, UV, thin-layer chromatography, and CDevidence).
Thalrugosine has also been reported independently from T h l i c t r u m
polygamum under the name thaligine [mp 153OC; + 87" (MeOH)]
(78). Structural assignment was based on NMR, UV, ORD, and mass
spectral data and conversion with CH2N2 o 59. The identity of thal-
rugosine and thaligine has recently been established by direct com-
parison (79). The racemic form of 151 is the alkaloid cycleadrine (57).
UU. TOXICOFERINE
Toxicoferine (153) [C3,H3,N206;mp 286OC; [.ID - 63" ( 1 N HCI in
EtOH)] was isolated from the stems of Chondodendron toxicoferum
(Wedd.) Kruk. et Mold. (80).O-Ethylation of 153 with phenyltriethyl-
156 157\ J
Y
153
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296 M . P. CAVA, K. T. BUCK, AND K. L. STUART
ammonium ethoxide gave the amorphous 0-diethyl derivative, which
was cleaved by sodium-ammonia to give (R)-N-methylcoclaurine(154)
and racemic0-diethyl-N-methylcoclaurine (155). The cleavage products
H
MeN /
'E t
OH
154 155
indicate that toxicoferine (153) must be a molecular complex of
(- -curine [= chondodendrine (156)] and (- -tubocurine [= ( - -
chondrocurine (1571,he enantiomer of 31.
VV. TRICORDATINE
Tricordatine (158) [C,,H,,N,O,; mp 280°C (dec.); + 247.9'
(pyridine)]was found in TricZisia subcordata Oliv. (35).The 0,O-dimethyl
PH
IOH
158
dimethiohde derivative was shown to be identical with isotrilobinedimethiodide. Further support for the assigned structure 158 was
provided by mass spectral data for 0,O-diethyltricordatine ( M + 604)
and the 0,O-diacetate ( M + 632).
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5 . BISBENZYLISOQUINOLINE ALKALOIDS 297
IV. Known Alkaloids from New Sources
Reference Plant
45 Anisocycla grandidieri
81 Berberis lycium Royle
82 Berberis petwlaris Nall.
84 Ephwtrum willosum (Exell) Troupin
83 cyczea sp 9 )
85
44
8654
60
87
88
8 9 , 9 0
Mahonia aquifolium Nutt.
Menispermum mnadense
Pachygone pubeacens Benth.Pycharrhna australiana F. Muell.
Stephania hernandifoliaWalp.
Stephania sasakii Hayata
Thalictrum lawum L.
Thalictrum minus L.
4 3 Thalictrum minus f. elatum
91 Thalictrum minus, race B
7 1 Thalictrum polygamum
90 Thalictrum rugosum
Alkaloids
Stebisimine, trilobine
Berbamine (= berbenine)
Berbamine
Tetrandrine
Cycleanine, isochondoden-
Berbamine
Daurinoline
IsotrilobineBerbamine, isotetrandriine
Epistephanine
Berbamine
Thalicarpine
0-Methylthalicberine,
drine, norcycleanine
thalicberine, O-methyl-
thalicberine, thalidazine
Adiantifoline
Adiantifoline, thalline
Thalicarpine
Thalidazine, thalsimine
V. Methods and Techniques
A. SPECTROMETRY
1. Mass Spectrometry
Mass spectrometry has now been established as one of the most
important tools in the structure determination of bisbenzylisoquinoline
alkaloids. The general aspects of its use have already been reviewed in
Volume XI11 of this treatise. Three important papers have now ap-
peared that extend and elaborate previous studies. In the first of these
papers, detailed mass spectral data are presented for some simple
alkaloid dimers derived from two coclaurine units joined tail to tail.
Examples include molecules containing one, two, and three ether links;
the head units (isoquinolines), when linked, all contain a C,-C,, etherbridge. Deuterated derivatives were used in a number of cases to support
the proposed cleavage patterns ( 3 8 ) . In the second paper, a similar
analysis is made of alkaloids containing two ether bridges (head-to-head
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298 M. P. CAVA, K. T. BUCK, AND K. L. STUART
and tail-to-tail linked) and containing head units linked by the more
unusual C5-C,,, C,-c,#, and C,-C5, ether bridges (92).Finally, the last
paper discusses the mass spectra of those alkaloids containing two etherbridges in which the monomer units are joined in a head-to-tail manner
(93).
2. Optical Rotatory Dispersion (ORD)
ORD curves have been recorded for a number of bisbenzylisoquinoline
alkaloids. These include thalsimidine, thalsimine, hernandezine, thal-
isopine, thalmine, O-methylthalicberine, thalfoetidine, and fetidine ( 9 4 ) )
as well as berbamunine and magnoline (95 ) .
B. CHEMICALMETHODS
1. New Deuteration Procedures
A simple method for the preparation of O-trideuteriomethyl deriva-
tives of phenolic alkaloids has been reported. The procedure involves use
of a solution of diazomethane in dimethyl sulfoxide containingD,O ( 1 1 ) .
The selective introduction of deuterium into bisbenzylisoquinolineshas been accomplished by heating with 3 7 , DC1 in D,O a t 120°C for
144 hours. Under these conditions, O-methyloxyacanthine (145) ex-
changed all protons ortho to methoxyl groups (bu t none ortho to the
diphenyl ether bridges), as shown by subsequent cleavage of the deu-
terated derivative (159) o 160 and 161; the location of deuterium in the
cleavage products was readily established by NMR spectroscopy (96).
However, extension of this deuteration procedure to the newly isolated
alkaloid nemuarine (99) resulted in the introduction of only one
deuterium, a t position C, (52 ,5 3 ) . It thus appears that ' the location ofthe ether bridging, the stereochemistry, and the substitution pattern
of the system govern the extent to which deuterium is incorporated.
Further work is clearly needed to evaluate these factors, as well as to
extend the utility of this method of deuteration in structural elucidation.
The utility of the sodium-ammonia cleavage of bisbenzylisoquinoline
alkaloids as a tool for structure proof has been extended by utilization
of ND, rather than NH,. Since deuterium is introduced at the points of
cleavage of the diphenyl ether linkages, this variation provides addi-
tional information of particular advantage for alkaloids containing twoether bridges, as in the case of belarine (25) ( 2 1 ) . ND, may be con-
veniently prepared from D,O and Mg,N, (28).
In the case of alkaloids containing one secondary and one tertiary
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5. BISBENZYLISOQUINOLINE ALKALOIDS 299
MeN
R
145 R = H
159 R = D
MeN
H
’ H
160
D
161
amine function, treatment with formaldehyde-d, and NBD introduces
a trideuteriomethyl group on the secondary nitrogen. Oxidative photol-
ysis (see nex t section) and NMR studies of the products may then be
used to establish the nitrogen alkylation pat tern of the original alkaloid
( I 0 , I I ) . Use of this procedure made possible the assignment of the
correct structure to micranthine(11).
2 . Photooxidative Degradation
Sodium-ammonia cleavage has long been the dominant method for
the chemical degradation of bisbenzylisoquinoline alkaloids. Oxidation
procedures have been of limited utility in the past and have seldom
resulted in the isolation of fragments derived from all parts of the origi-
nal alkaloid. A mild photooxidative degradation has been reported
recently that promises to complement sodium-ammonia cleavage as ageneral degradative method for bisbenzylisoquinoline alkaloids (97) . In
a model case, isotetrandrine (59) was irradiated with a Hanovia lamp
in dilute methanol solution at room temperature in the presence of
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300 M . P. CAVA, K. T. BUCK, AND K . L. STUART
oxygen. The diphenyl ether portion of the molecule was isolated directly
as the dialdehyde 14 in 50y0 yield. After borohydride reduction, the
crystalline head-to-head isoquinoline fragment 162 could also be iso-lated. Phenolic alkaloids also seem amenable to photooxidative degra-
dation. For example, berbamine (103) gave the phenolic aldehyde 163
(35%)as well as the lactam base 162 (15%).
59 R = Me103 R = H
162
14 R = M e163 R = H
VI. Pharmacology
Thalidasine and obamegine were found to be active in vitro against
Mycobacterium smegma tis; thalrugosine, thalrugosamine, and thalrugo-
sidine were all very weakly active against the same organism(7'6, 77, 98).
Tetrandrine showed strong tuberculostatic activity againsta number of
strains of Mycobacterium tuberculosis in vitro; it also found to signifi-
cantly prolong the life expectancy of mice infected with various tuber-
culosis strains (99).Thalsimine, dihydrothalsimine, and hernandezine were found to
inhibit the conditioned avoidance reactions and the motor conditioned
reflexes associated with movement and eating in rats. In addition,
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5. BISBENZYLISOQUINOLINE ALKALOIDS 301
thalsimine and dihydrothalsimine were found to temporarily reduce the
time for dogs to run through a labyrinth ( 100) .
The tertiary bases tetrandrine, cycleanine, and dauricine exhibitedantiinflammatory and anesthetic properties; the related quaternary
salt cycleanine dimethiodide was a curare-like agent ( 1 0 1 ) .Thalmine
and 0-methylthalicberine were active against experimental idamma-
tion in mouse paw ( 1 0 2 ) .The cardiovascular and hypotensive activity of thalicarpine has been
studied in the isolated dog heart and in the rhesus monkey. Thali-
carpine hypotension appears to be due to a nonspecific vasodilation and
myocardial depression ( 1 0 3 ) .Fetidine is claimed to have hypotensive
activity ( 104) . Both thalisopine and fetidine depress high nervous
activity in mice ( 1 0 5 ) .The toxicity of thalicarpine has been examined in monkeys and in
dogs. Lethal doses in monkeys and maximum nonlethal doses in both
species were determined ( 106) .The alkaloids thalicmine, dihydrothalicmine, hernandezine, thalmine,
thalictrinine, and fetidine were more active against experimental
inflammation than either aminopyrine or sodium salicylate ( 107) .
VII. Bisbenzylisoquinoline Alkaloids Tabulated by Molecular W eight
This table includes all reported bisbenzylisoquinoline alkaloids;
references are to the most recent compilation in which each alkaloid is
discussed. Molecular weights cited for alkaloids that have not been
examined by mass spectrometry must be regarded as provisional unless
corroborated by synthetic studies. Also, assignments based on corre-
lation with alkaloids of subsequently revised structure (e.g., micranthine)
should be considered questionable.
MW Formula Alkaloid Ref. ( M W Formula Alkaloid Ref.
548 C34H3zNz05 12’-O-Desmethyltrilo-
bine
Micranthine
Tricordatine
562 C,SH,,NzO, Cocsuline 2 rigille-
tine, effirine)
0-Methylmioranthine
Nortiliacorine-A
Nortiliacorinine-A
Nortilimorinine-B
a
a
a
a
a
a
a
a
Telobine
Trilobine
566 C34H34Nz06N,N-Bisnoramoline
576 C35H3zNz06 Normenisarine
576 C36H3SNz0s 0,N-Dimethylmicran-
thine
Isotrilobine
Tiliacorine
Tiliacorinine
578 C35H,4Nz0s No name
C
b
a
e
(conrinued )
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302 M. P. CAVA, K. T. BUCK, AND K. L. STUART
MW Formula Alkaloid Ref.~580 C35H36N206Cycleacurine a
Daphnoline ( = triloba- c
mine)
2-N-Norobamegine
582 C35H38NzO6 Ocotine
590 C36H34Nz06 Menisarine
592 C36H36N206Cepharanoline
Stebisimine
Hypoepis ephanine
Thalmethine
Tiliarine
Atherospermoline
Base A
Chondrocurine
Curine (F bebeerine,
chondrodendrine)
Daphnandrine
Demerarine
Dinklageine
Dryadodaphnine
Hayatine (= ( & ) -
Isochondrodendrine
Neoprotocuridine
2-N-Norberbamine
Obamegine
Ocoteamine
Protocuridine
Sepeerine
Thalicrine
Tomentocurine
Toxicoferine
Dauricoline
Espinine
Magnoline
606 C36H34N207Stepinonine
Cancentrine
606 C3.,H3,NZ06 Cepharanthine
Cissampareine
Coclobine
Epistephanine
(- -Epistephanine
594 C36H38N206Aromoline
~ur ine]
596 C36H40Nz06Berbamunine
a
C
C
b
a
C
b
C
C
b
d
&
C
C
b
e
b
b
b
d
a
C
d
e
d
a
b
a
a
b
a
a
b
b
b
b
C
a
MW Formula Alkaloid Ref.
Insulanoline C
0-Methylthalmethine b
608 C37H40N206Belarine a
Berbamine b
Chondrofoline a
Cycleadrine a
Cycleanorine a
Cycleapeltine a
Dryadine b
Fangchinoline bHayatidine b
Hayatinine b
Himanthine e
Homoaromoline C
Homothalicrine e
Lauberine b
Limacine b
Limacusine b
Menisidine d
4"-O-Methylbebeerine b
Nemuarine aNorcycleanine C
Ocodemerine b
0 ocamine b
Oxyacanthine b
. Pakistanine a
Penduline a
Pycnamine b
Repandine b
Thalicberine b
Thalmine b
Thalrugosamine a
Thalrugosine ( = hali- a
609 C37H41N20tProtochondrocurarine e
Tubocurarine a
610 C37H42N206 uspidaline b
Dauricinoline a
Daurinoline b
N'-Desmethyl- &
Dirosine b
( = thalmidine)
gine)
dauricine
Espinidine a
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5 . BISBENZYLISOQUINOLINE ALKALOIDS 303
MW Formula Alkaloid Ref.
612
612
616
620
620
622
622
624
624
624
632
Isoliensinine
Liensinine
Norrodiasine
C35H36Nz08 Base B
C36H40Nz07Aztequine
C38H36N20~Phaeantharine
C37H36Nz0, Oxoepistephanine
C38H40N206Insularine
C3,H38N207 De-N-methyltenuipine
Magnolamine
Repanduline
Nortenuipine
Thalsimidine
C38H42Nz08 Cycleanine ( = O-me-
thylisochondroden-
drine
Funiferine
Isotetrandrine
Melanthioidine
Menisine
0 Methylisothalic
berine0-Methylrepandine
0-Methylthalicberine
Obaberine
Pakistanamine
Phaeanthine
Rodiasine
Tetrandrine
C3,H4,Nz0, Thalidopidine
C38H44N206Dauricine
C38H44Nz0zChondrocurarine
Isochondrocurarine
Neochondrocurarine
C3,H4,NzOS Pycnarrhenamine
b
b
b
d
b
b
d
a
b
d
b
b
C
C
a
b
b
d
b
d
b
b
a
b
b
b
a
b
a
e
e
b
MW Formula Alkaloid Ref.
636 C38H40N20, Isotenuipine
tenuipine)
Repandinine (= (k ) .
Tenuipine
Thalsimine
637 C39H45NzOs+ ycleahomine
638 C38H42N207Thalfoetidine
Thalidezine
Thalisopine
Thalrugosidine
Neferine638 C39H4BN206 -Methyldauricine
642 C38H46N207Thalictrinine
646 C36H42N209 ycnarrhenine
648 C38H36N208Thalfine
652 C39H44N207Hernandezine
666 C39H42N208Thalfinine
668 C39H44N208bhalibrunine
674 C40H38N20iBisjatrorrhizine
680 C40H44N208Dehydrothalmelatine682 C40H46N208 halictropine
Thalixodine
Thalmelatine
Thalidasine
Thalictrogamine
694 C41H46N208 Dehydrothalicarpine
696 C41H48N208Fetidine
Thalicarpine
698 C40H46N20s Thaldimerine
712 C41H48N209O-Desmethyl-
720 C43H32N209Chelidimerine
726 C42H50N209Adiantifoline
740 C42H48NZ010halmelatidine
742 C42H50Na0~0halmineline
adiantifoline
a
d
C
b
a
a
b
b
a
ab
e
b
a
b
b
a
b
a
a
ba
a
b
a
b
b
a
a
b
a
a
C
References; (a) This work. (b) M. Curcumelli-Rodostamo, in “The Alkaloids” (R. H. F.
Manske, ed.), Vol. XI II, Chapter 7. Academic Press, New York, 1971. (c) M. Curcumelli-Rodo-
stamo and M. Kulka, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. I X , Chapter 4. Academic
Press, New York, 1967. (d ) M. Kulka in “The Alkaloids” (R. H . F . Manske, ed.), Vol. VII ,
Chapter 21. Academic Press, New York, 1960. (e) T. K ametani, “The Chemistry of the Isoquino-
line Alkaloids,” Chapter 6 . Elsevier, Amsterdam, 1969.
Corrected molecular formula; th e formula cited in reference b is in error due to a n internal
inconsistency in the original paper.
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304 M . P. CAVA, K. T. BUCK, AND K. L. STUART
VIII. Appendix
It is the function of this appendix to abstract papers on bisbenzyliso-quinoline alkaloids that appeared in 1974 and the first half of 1975, as
defined by the Chemical Abstracts coverage stated in Section I, and also
amend the text. The structural formulas, basic physical constants, and
plant sources of new alkaloids are noted, but the reader is referred tothe original papers for details of structural elucidation. It is intended
that material included here will be incorporated in expanded form in
an appropriate later volume of this treatise. This appendix has been
organized in conformity with the plan of the foregoing main discussion,
and a miscellaneous section has been included to draw attention to someinteresting transformations of particular alkaloids that were recently
reported.
1. NEWALKALOIDS
a. Sanguidimerine (164)
+21.2O (pyridine)] was isolated fromrhizomes of Sanguinam'a canadensis L. and is diastereomeric with the
meso alkaloid chelidimerine (46) (108) . These natural products along
with 48 are the first representatives of the class of bisbenzophenanthri-
dine alkaloids and are included in our review because of their dimeric
nature and their formal 4-phenethylisoquinoline structure unit.
This alkaloid [mp 174°C;
164
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5. BISBENZYLISOQUINOLINE ALKALOIDS 305
b. Cocsulinine (165)
Cocsulinine [mp 260-263OC; [.ID +312" (CHCl,)] was isolated fromCocculus pend ulus ( 108)and possesses anticancer activity. The structure
was assigned from spectral data, deuterium exchange experiments,
Hofmann degradation, and sodium-ammonia cleavage.
165
c. Cocsoline (166)
Isolated also from Cocculus pendulus (110) was cocsoline [mp 197-199°C; [.ID + 204" (CHCl,)]; it was assigned st,ructure 166 on the basis
of MS and NMR data and conversion to isotrilobine (50).
AH
166
d. Tiliageine (167)
+ 132.6" (pyridine)] (111).The structural assignment was based on IR
and NMR data and conversion to O-methylfuniferine (94). The stereo-
chemistry is still undetermined.
Tiliacora dinklagei Engl. has yielded this alkaloid [mp 270°C;
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3 0 6 M . P. CAVA, K. T. BUCK, AND K . L. STUART
167
e. Pennsylpavine (168) and Pennsylpavoline (169)
Thalictrum polygamum afforded the first two aporphine-pavinedimers; pennsylpavine (168) [mp 122-123°C; [a]g5 - 74" (MeOH)] and
pennsylpavoline (169)[mp 145-146°C; [a]g5 - 45" (MeOH)].Structural
assignments were based entirely on spectral data (UV, NMR, mass,
C D ) . The related alkaloids pennsylvanine (170) and pennsylvanamine
(171) were also reported from T . polygamum (112).
f . Pennsylvanine (170) and Pennsylvanamine (171)
The chemical and spectral data leading to the structures of these twonew alkaloids have now appeared ( 1 1 3 ) :pennsylvanine (170) [mp 112-
113°C (ether); [a]g4 + 131" (MeOH)] and pennsylvanamine (171)
[mp 128-129°C (acetone-ether), 107-108°C (ether); + 119"
(MeOH)].
170 R = M e
171 R = H
168 R = M e169 R = H
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5 . BISBENZYLISOQUINOLINE ALKALOIDS 307
g. Monomethyltetrandrinium Chloride (172)
The Thai Menispermaceae drug krung kha mao yielded this alkaloid[mp 208°C; [a]gO+ 51.5 (MeOH)] (114).This new berbamine alkaloid
was assigned structure (172) ased on spectral data and partial syn-
thesis from tetrandrine (64); he nitrogen methylation pattern was not
established.
OMe
172 R = H, R, = Me, or vim versa
h. Baluchistanamine (173)
Baluchistanamine (173) mp 122-124°C (cyclohexane-benzene)] has
been reported from Berberis ba~ u~ hi ~t an ic a.D data are given for thisfirst example of an isoquinoline-benzylisoquinoline type of alkaloid
(115).
173 R = H
174 R = Me
MeNp LMe q N M e
3 8 R = M e176 R = H
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308 M . P. CAVA, K. T.BUCK, AND K. L. STUART
Oxidation of obaberine (38) with KMnO, in acetone afforded 0-methylbaluchistanamine (174), while corresponding treatment of
oxyacanthine (175) gave 173 in low yield. Apparently, 173 arisesbiogenetically from the cooccurring oxyacanthine (175).
i. Phlebicine
Cremastosperma polyphlebum (Diels) Fries yielded phlebicine (176)
(mp 195°C; sint, 180"C), for which ORD and CD data are given.
Partial methylation of 176 afforded rodiasine (97) and NMR and M Scomparisons of 176 and its dideuterio, deuteriomethyl, 0-acetyl, and
0-ethyl derivatives permitted unambiguous assignment of it s skeleton( 116) .The stereochemistry of the asymmetric centers, however, is not
yet determined.
176 R = H97 R = Me
j . Thalibrunine (177)
Thalibrunine (177) from Th ali cfr um ochebruniannum Franch. e t Sav.
has been assigned the structure shown on the basis of chemical andspectral data ( 117) .
MeN O M eM e o q N & f e
H - * H
177
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5 . BISBENZYLISOQUINOLINE ALKALOIDS 309
2. KNOWN LKALOIDSROM NEWSOURCES
Reference Plant Alkaloids
~
118 Triclisia gillettii
118 27. patens Oliver
118 T . subcordata
119 Anisocycla grandidieri
120 Cyclea barbata Miers
(C.peltata Hk. f. et.
Thorns).
121 C. barbata
~ -Stebisimine, isotetrandrine, cocsuline (49)
Pycnamine, cocsuline (49)
Fangchinoline, tricordatine
( -)-Epistephanine ( 8 5 ) , stebisimine
( + )-Tetrandrine, sotetrandrine, limacine,
berbamine, homoaromoline
( & )-Fangchinoline, ( + )-isofangchinoline
[thalrugosine (151)]
3. PHARMACOLOGY
Kupchan and Altland (122 ) have made a study of the structural
requirements for tumor-inhibitory activity among bisbenzylisoquinoline
alkaloids and related compounds. Pharmacological evaluations of a
number of bisbenzylisoquinolinealkaloids and synthetic analogs againstWalker carcinosarcoma 256 in rats were used to study structural
requirements for therapeutic activity. Only one linkage of the iso-
quinoline unit appears necessary, and activity is seemingly unaffected
by the configurationof the asymmetric centers or whether the nitrogens
are secondary or tertiary. However, the presence of two methylimino
groups destroys activity.
Thalmine has been shown to be significantly active against ascites
lymphoma NK/Ly in mice and rats. Thalsimine, thalmidine, thalic-
trinine, and hernandezine were weakly active against lymphoma NK/Ly,alveolar hepatoma PC-1, or Pliss lymphosarcoma (123 ) .
Two new reports of antimicrobial studies have appeared. Thali-
carpine isolated from Thalictrum polygamum was shown to be active
against Mycobacterium smegmatis but not against five other bacterial
species (124 ) . Extracts of Berberis vulgaris have been examined for
antibiotic activity; oxyacanthine chloride at 1 :10,000 dilution killed
Bacillus subtilis and Colpidium colpoda (125 ) .
The effects of thalicarpine on the heart and carotid artery flow in
anesthetized monkeys and on isolated dog hearts has been studied. The
principal activity seemed to reside in the aporphine portion of the
molecule (126 ) .
The action of hayatine methochloride and ( + )-tubocurarine chloride
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310 M. P. CAVA, K . T. BUCK, AND K . L. STUART
on autonomic ganglia in cats has been examined. Hayatine metho-
chloride was 2.5-4 times less active than tubocurarine chloride on
sympathetic ganglia of cats. Details are given in the Chemical Abstract(1 2 7 ) ..
Toxicity studies by Menez et al. (1 2 8 ) on (+)-tubocurarine labeled
with iodine or tritium showed that tritium in the 13’ position had no
effect on its acute toxicity. Tubocurarine chloride, when given intra-
venously to rabbits or subcutaneously to rats, induced hypercalcemia
and hypophosphatemia but did not affect blood pH ( 1 2 9 ) .The lymphotoxic effect of d-tetrandrine in dogs and monkeys has
been demonstrated, as was related toxicity levels on these test animals
(1 3 0 ) . Phaeanthine, isolated from Phaeanthus ebracteolatus, has beenshown to have anticancer activity, and in a review of the chemistry and
biochemistry of alkaloids from this plant, this property was discussed
in relation to structurally similar bisbenzylisoquinolines ( 1 3 1 ) .
The neuromuscular blocking potencies of (+ )-tubocurarine chloride,
N,N’-dimethyl-(+ )-chondrocurine and N,N’-dimethyl-(- -curine have
been evaluated on rat diaphram, cat tibiales, and superior cervical
ganglion ( 1 3 2 ) . In another related study, the same authors (1 3 3 )examined five bisbenzylisoquinolines that have head-to-head and tail-
to-tail linkage and were shown to have negligible blocking action on cat
tibiales and superior cervical ganglion in relation to ( + )-tubocurarine.
N,N ‘-Dimethylberbamine, however, showed substantial activity.
4 . MISCELLANEOUS
a. Hofmann Elimination Effected by Diazomethane
When the quaternary curare bases ( + )-tubocurarine chloride l),
( + )-isotubocurarine chloride 178),nd chodrocurarine chloride (4) were
treated with excess diazomethane, in addition to the expected O-methyl
derivatives, the respective Hofmann elimination products 179),
180),nd 181) ere also produced (1 3 4 ) .The nature of the products
(styrene versus stilbene) is apparently governed by steric factors.
b. Conversion of Stepinonine 120)nto a ConventionalBisbenzylisoquinoline Skeleton
As a sequel to their full account of the structural elucidation of
the novel benzylisoquinoline-2-phenyl-sec-homotetrahydroisoquinoline
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5 . BISBENZYLISOQUINOLINEALKALOIDS 311
1 R1 Me, R, = H ( Cl - )
178 R1 = H, R, = M e ( C l - )
4 R, = R, = M e ( C l - )
M e o p N M ee 0 .H
Me,N
180
179
181
alkaloid, stepinonine ( 135) , Inubushi and co-workers have succeeded
in a chemical conversion of stepinonine to identifiable bisbenzyliso-
quinoline alkaloids ( 1 3 6 ) .Stepinonine (120) was first converted to its
reduced derivative (121) and then oxidation by Jones' reagent fol-
lowed by reduction (zinc-acetic acid, then sodium borohydride) gave
a mixture of the enantiomer (68)of 0-methylrepandine and O-methyl-
oxyacanthine (145).
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312 M . P. CAVA, K. T. BUCK, AND K . L. STUART
H
68
MeN OMee o G N M e
H 'H
145
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89. Kh. B. Duchevska, A. V. Georgieva, N. M. Mollov, P. P. Panov, and N. K. Kotsev,
90. N. M. Mollov, P. Panov, Lemat Thuan, and L. Panova, Dokl. Bolg. Akad. Nauk
91. C. W. Geiselman, S. A. Gharbo, J. L. Beal, and R. W. Doskotch, Lloydia 35, 296
92. J. Baldas, I. R. C. Bick, M. R. Falco, J. X. DeVries, and Q. N. Porter, J . Chem.
93. J. Baldas, I. R. C. Bick, T. Ibuka, R. S. Kapil, and Q. N. Porter, J . Chem. SOC.,
94. G. P. Moiseeva, 2. F. Ismailov, and S. Yu. Yunusov, Khim. Pri r. Soedin. 6 , 705
95. T. Kametani, H. Iida, K. Sakurai, S. Keno, and M. Ihara, Chem. Phurm. Bull.
96. Y. Inubushi, T. Kikuchi, T. Ibuk a, and I. Saji, Tet. Lett. 423 (1972).
97. I. R. C. Bick, J. B. Bremner, and P. Wiriyachitra, Tet. Lett. 4795 (1971).
98. L. A. Mitscher, W.-N. Wu, R. W. Doskotch, and J. L. Beat, J.Chem. SOC.D 589
99. S . A. Vichkanova, L. V. Makarova, and L. F. Solov'eva, Farmakol. ToksikoZ.
100. N. Tulyaganov and F. Sadritdanov, Farmakol. Alkaloidov. Serdechnykh Glikozidwv
Soedin. 4, 394 (1968); C A 70 , 88033 (1969).
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72, 97303 (1970).
72, 55716 (1970).
(1970).
Med. 22, 402 (1972); C A 78, 69230 (1973).
(1971);C A 75 , 148465 (1971).
(1972).
(1969);C A 73,4072 (1970).
(1970); CA 74, 1042 (1971).
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23, 181 (1970); CA 73, 2285 (1970).
(1972); C A 7 8 , 13766 (1973).
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(1970);C A 74, 112278 (1971).
17, 2120 (1969); C A 72, 2092 (1970).
(1971).
( M o s c o w ) 36,74 (1973);CA 78,106079 (1973).
132 (1971); CA 78, 79631 (1973).
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316 M. P. CAVA, K. T. BUCK, AND K . L. STUART
101. V. V. Berezhinskaya, Postep Dziedzinie Leku Rosl ., Pr . Ref. Dosw. Wygloszone
102.F.
Sadritdinov andM.
B. Sultanov,Farmakol. Alkaloidow Serdechnykh Glikozidov
103. E. H. Herman and D. P. Chadwick, Toxicol. Appl. Pharmacol. 26, 137 (1973).
104. Zh. S. Nuralieva and P. K. Alimbaeva, Fizwl. Akt. Soedin. Rust. Kirg. 99 (1970);
105. I. Khadamov, F. Sadritdinov, and M. B. Sultanov, Farmakol. Alkaloidov Serdech-
106. P. E. Palm, M. S. Nick, E. P. Arnold, D. W. Yesair, and M. M. Callahan, U.S.
107. F. Sadritdinov, Farmakol. Alkaloidov Serdechnykh Olikozidov 122 (1971); C A 78 ,
108. M. Tin-Wa, H. H. S. Fong, D. J. Abraham, J. Trojanek, and N. R. Farnsworth,
109. P. P. Joshi, D. S. Bhakuni, and M. M. Dhar, Indian J.Chem. 12, 517 (1974); CA
110. P. P. Joshi, D. S. Bhakuni, and M. M. Dhar, Indian J. Chem. 12, 649 (1974); C A
111. A. N. Tackie, D. Dwuma-Badu, T. T. Dabra, J. E. Knapp, D. J. Slatkin, and P. L.
112. M. Shamma and J. L. Moniot, J.Am . Chem. SOC. 6, 3338 (1974).
113. M. Shamma and J. L. Moniot, Tet . Lett. 2291 (1974).
114. B. Hoffstandt, D. Moecke, P. Pachaly, and F. Zymalkowski, Tetrahedron 30, 307
115. M. Shamma, J. E. Foy, and G. A. Miana, J. Am . Chem. SOC. 6, 7809 (1974).
116. M. P. Cava, K. Wakisaka, I. Noguchi, D. L. Ed ie, and A. I. daRocha, J. Org. Chem.
39, 3588 (1974).
117. M. P. Cava, J. M. Saa, M. V. Lakshmikantham, M. J. Mitchell, J. L. Beal, R. W.
Doskotch, A. Ray, D. C. DeJongh, and S. R. Shrader, Tet. Lett. 4259 (1974).
118. A. N. Tackie, D. Dwuma-Badu, T. Okarter, J. E. Knapp, D. J. Slatkin, and P. L.
Schiff, Jr., Lloydia 37, 1 (1974).
119. A. Groebe1,H. Kruse, and N. Weber, German Pate nt 2,243,253 CA 81, 6264 (1974).
120. T. Yupraphat, P. Pachaly, and F. Zymalkowski, Planta Med. 2 5 , 315 (1974); C A
121. C. Goepel, T. Yupraphat, P. Pachaly, and F. Zymalkowski, Planta Med. 26, 94
122. S . M. Kupchan and H. W. Altland, J. Med. Chem. 16, 913 (1973).
123. Sh. U. Ismailov and D. A, Asadov, Parmakol. Alkaloidow Ikh. Proizvodnykh 171
124. S. A. Gharbo, J. L. Beal, R. W. Doskotch, and L. A. Mitscher, Lloydia 36, 349
125. E. Andronescu, P. Petcu, T. Goina, and A. Radu, Clujul Med. 46, 627 (1973);C A
126. E. H. Herman and D. P. Chadwick, Pharmacology 10, 178 (1973).
127. G. K. Patnaik, S. N. Pradhan, and M. M. Vohra, Indian J.Ezp. Biol. 11, 89 (1973);
128. A. Menez, F. Bouet, J. P. Changeux, A. M. Rousseray, P. Boquet, and P. From-
129. P. Szabo an dT. Ferenczy, Acta Biol.Debrecina9, 101 (1973);CA 81, 114747 (1974).
Symp., 1970 164 (1972);C A 7 8 , 119087 (1972).
120 (1971); C A 7 8 , 66916 (1973).
C A 76, 17765 (1972).
nykh Glilcozidov 135 (1971); C A 77 , 122095 (1972).
N.T.I .S . P B Rep . PB-201 914 (1971); C A 76 , 68093 (1972).
79555 (1973).
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81, 136346 (1974).
81, 152477 (1974).
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(1974).
81, 82289 (1974).
(1974);CA 81, 87983 (1974).
(1972); C A 80, 103857 (1974).
(1973);CA 80, 12512 (1974).
81, 100062 (1974).
CA 80, 103855 (1974).
ageot, Biochimie 55, 919 (1973);CA 80, 116086 (1974).
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5. BISBENZYLISOQ UINOLINE ALKALOIDS 317
130. E. J. Gralla, G. L. Coleman, and A. M. Jonas, Cancer Chenwther. Rep,, Part 3 5
131. A. C. Santos, Acta Man ila m, Ser. A 12, 48 (1974); C A 82, 95236 (1975).132. I. R. C. Bick and L. J. McLeod, J . Phurm. Pharmacol. 26, 985 (1974).
133. I. R. C. Bick and L. J. McLeod, J . Phurm. Pharamcol. 26, 988 (1974).
134. J. Neghaway, N. A. Shaath, and T. 0. Soine, J . Org. Chem. 40, 539 (1975).
135. T. Ibuka, T. Konoshima, and Y. Inubushi, Chem. Pharm. Bull. 2 3 , 114 (1975).
136. T. Ibuka, T. Konoshima, and Y. Inubushi, Chem. Pharm. Bull. 23, 133 (1975).
79 (1974); C A 82, 51463 (1975).
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-CHAPTER 6---
SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS
MAURICESHAMMA
ThePennsylvania State University
University Par k, Pennsylvania
AND
VASSILST. GEORGIEVU S V Pharmaceutical Corporation
Tuekahoe, N e w York
I. Introduction. . . . . .............................................. 319
11. Dauricine-Type A1 oids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
IV. Berbamine-Oxyacanthine-TypeAlkaloids. . . ...................... 341
V. Thalicberine-Type Alkaloids . . . . . . . . . . . . . . ...................... 348
VII. Menisarine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
VI II . Tiliacorine-Type Alkaloids ....................... . . . . . . . . . . . . . . . . 359
X. Curine-Chondocurine-TypeAlkaloids. ................................ 363
383
XI II . Synthesis Using Electrolytic Oxidation. ....................... . . 387
XIV. Use of Pentafluorophenyl Copper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
References . . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . 389
111. Magnolamine-Type Alkaloids. ....................................... 336
VI. Trilobine-Isotrilobine-Type Alkaloids . . . . . . ...................... 354
IX. Liensinine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
XI. Miscellaneous Syntheses ............................................ 381
XI I. Syntheses Using Phenolic Oxidative Coupling .........................
I. Introduction
Well over a hundred bisbenzylisoquinoline alkaloids are presently
known. The two benzylisoquinoline units may be bonded together by
one, two, or three diaryl ether linkages. When only one diaryl linkage
is present, this bond is involved in tail-to-tail or head-to-tail coupling
and never in head-to-head coupling. When linked by two or three diarylether linkages, the two benzylisoquinoline units can be bonded either
head-to-head or head-to-tail. The resultant diversity in the structures of
the bisbenzylisoquinoline alkaloids, coupled with their known or
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320 MAURICE SHAMMA AND VASSIL ST.GEORGIEV
potential pharmacological activity, has stimulated substantial interest
in their synthesis. This chapter will deal with the preparation of bis-
benzylisoquinolines in the order of their structural complexity.Although several interesting and reliable syntheses of bisbenzyliso-
quinolines have been worked out, e.g., those of ( )-cepharanthine,
( +)-isotetrandrine and related bases, ( + )-0-methylthalicberine, ( k -
N-methyldihydromenisarine, ( k -0-methyltiliacorine, and ( k -cycle-
anine, no reliable synthesis of the pharmacologically important
( + )-tubocurarine as yet exists. Furthermore, the complexity of the
synthetic problem is such that the successful syntheses referred to above
are invariably long and must involve the judicious use of several
functional protective groups.
Biogenetic-type syntheses using phenolic oxidative coupling of
monomeric benzylisoquinolines have unfortunately proven of limited
value due sometimes to low yields, bu t more importantly because it is
head-to-head coupling that occurs most readily in vitro, a mode of
coupling not encountered in nature.
A novel approach to bisbenzylisoquinoline synthesis concerns the
electrolytic oxidation of the salts of monomeric phenolic benzyliso-
quinolines, but so far only one such example has been reported. The
most promising new route t o the bisbenzylisoquinolines involves the use
ofpentafluorophenyl copper in the formation of the diary1 linkage and
this method will be discussed toward the end of this chapter.
11. Dauricine-Type Alkaloids
The first att empt a t the synthesis of a dauricine degradation product
was carried out a number of years ago when dauricine methyl methine
(2) was prepared and was found to be identical with material derivedfrom naturally occurring ( - -dauricine (3),Scheme 1 ( 1 ) .
The sequence in Scheme 1 represents one of the early pioneering
efforts in the bisbenzylisoquinoline series. The use of the Erlenmeyer
azlactone synthesis in the preparation of th e dicarboxylic acid 1 should
be noted. Several syntheses of enantiomeric and diastereomeric mixtures
of dauricines ( 5 ) are available. The first synthesis was accomplished
through the Ullmann -+ Arndt-Eistert +Bischler-Napieralski sequence
(Scheme 2) . It was not possible to separate the components of the final
mixture (2-5).The second synthesis is a variation of the one described above (4-6) .
Condensation of the diacid chloride of 6 with homoveratrylamine gave
the required diamide 4.
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0 X
-
0 /\ \5
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U
N m
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 323
6
In the third instance, Ullmann condensation of the racemic bromo-
tetrahydrobenzylisoquinoline 7 with racemic armepavine (8) yielded,
following hydrolysis, a mixture of dauricines (4-6) .
7
R = benzyl or scetyl
8
The first synthesis of a clean optically active derivative of dauricineinvolves the preparation of (- -O-methyldauricine ( l l ) ,dentical with
material derived from the natural product (7 ) . Controlled bromination
of ( - -armepavine yielded ( - -3'-bromoarmepavine (9).O-Methylation
then furnished 10, which was condensed under Ullmann conditions with
( - -armepavine to supply 11, Scheme 3.
Several other syntheses of O-methyldauricine are also available. The
first of these follows the now well established route involving initial
synthesis of the diacid chloride of 1 and its further condensation with
homoveratrylamine. The ultimate product was again a product withmixed stereochemical landscape-an enantiomeric-diastereomerk
mixture (8). A more arresting approach to O-methyldauricine was
carried out primarily to prove the usefulness of Reissert intermediates
(9). _+ )-Armepavine was first prepared in high yield through a Reissert
sequence as indicated in Scheme 4 . The other required moiety, ( f -lo,was generated by either of the two routes described in Scheme 5.
A related approach to O-methyldauricine involves a rare instance of
bis-Reissert reaction. The dialdehyde 13 was first prepared and then
condensed with 2 moles of 12 to yield th e dibenzoate 14. The corre-sponding diol (15)was hydrogenolyzed with hydrogen bromide and zinc
in acetic acid to the bisbenzylisoquinoline 16. N-Methylation and
reduction then furnished a mixture of O-methyldauricines (9). The
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m
c E- - 0X
fp
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326 MAURICE SHAMMA AND VASSIL ST.GEORGIEV
CH30
1. K O H ,ethanol,water
CH,OH30Q N , c , P h -ldehyde,0°C CH30$r 2. zn. nnr
3-Rromoanis-
phenyi lithium,
0--CPh -0
CH30CN II
012
CH30
CH30r
3.. C H JaBH,
cH3Or CH3
\CH3OCH30
( k1-10
or
CH30%aH, Br@ NaBH4
CH30
0 CH,O
1 . Zn,H B r2. CH.13. NaBH+
-+ ) - l oBr
CH30
SCHEME 5
yields were unusually high throughout this sequence and represent a
distinct improvement over the previous syntheses.
Yet another synthesis of an 0-methyldauricine mixture utilizing
Reissert intermediates proceeded via the condensation of 2 moles of theanion of 12with the diphenyl ether 17. Basic hydrolysis then yielded
the bisbenzylisoquinoline 16 (9 ) .The use of Reissert compounds in the
synthesis of bisbenzylisoquinolines has been recently further extended
(94.
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 327
oHcOCH,
13
R*o<R \ OCH,
14 R = P h - C O O
15 R = O H
16 R = H
17
A synthesis of (- -0-methyldauricine (11)was achieved as a result of
preparative work in the berbamunine series. Ullmann condensation of
(-)-18 with (-)-armepavine yielded the dimer 19 which upon acid
hydrolysis, and diazomethane 0-methylation supplied (- -0-methyl-
dauricine 11) ( 1 0 ) .
Br
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\
W
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330 MAURICE SHAMMA AND VASSIL ST.GEORGIEV
Sodium in liquid ammonia reduction of the synthetic dimer 20, a
diastereomeric racemate prepared as indicated, afforded diamines
21 and 22. Compound 21 corresponds to a mixture of dauricines, while22 is a mixture of deoxydauricines, Scheme 6 ( 1 1 ) .An alternate syn-
thesis of 22 is also available through Ullmann condensation of ( k -23
with (k -24 ( 1 2 ) . The latest and most efficient synthesis of ( f -0-
OH
23 24
methyldauricine follows the classical lines outlined in Scheme 7 above.
The final product was a mixture of diastereomers from which
( & )-0-methyldauricine could be separated ( 1 3 ) .The diary1 ether 25, obtained through an Ullmann sequence, was
condensed with two moles of 3-methoxy-4-benzyloxyphenethylamine.
The product was the diamide 26, which was converted stepwise into a
mixture of 0-methyl-0,O-dibenzylmagnolamine27), Scheme 8 ( 1 4 ) .
The dimeric immonium hydrochloride 28 had previously been obtained
by a similar sequence ( 1 5 ) .
H C1010 H OCHaPh PhCHaO
28
A first attempt to synthesize magnoline followed the course outlined
A modified route was then adopted which eventually provided a
in Scheme 9 but aborted when dimer 29 failed to debenzylate ( 1 6 ) .
mixture of magnolines (30), Scheme 10 (16).
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OCH,
0
/pc1‘ G C H S> C H a - C \ ’-‘ CH, \
25 2
SCHEME
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332 MAURICE SHAMMA AND VASSIL ST. GEORGIEV
H o o G c H 2 D o a C H & O O H 2.. 9061.thylhloroformate
\H
O\\ No 3-Methoxy-4-,C-CH,benzyloxy.
c1 \C1 phenethylamine
OCH, CH,O
1 . POCI.pN\.. CH.1a R H,
Fo H 4. E O H , ethanol
SCHEME
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 333
0 0
C1
//CHz--6, 3-Methoxy-4-hydroxy-
c1 phenethylaminef
OCOOC,H,
1. Ethyl chloroformatem1r3 H3.. CHDIOCla
H / t b o & H 5.. N a OH,aBH, ethanol +
\\ OCOOCzH5
H3C’
30
SCHEME0
3 1 31
33
SCHEME1
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334 MAURICE SHAMMA AN D VASSIL ST.GEORGIEV
The alternate pathway to a bisbenzylisoquinoline, namely, condensa-
tion of two tetrahydrobenzylisoquinoline units by means of an Ullmann
reaction, was also tried and provided a mixture of magnolines (30)( 1 7 ) .The same sequence was then applied using optically active inter-
mediates. Thus, ( + )-31was condensed with (-)-32.- -Magnoline(33)was generated following hydrolysis of the benzyloxy protective groups,
Scheme 1 1 (18).It should be noted here that (-)-magnoline 33) s
enantiomeric with ( + )-berbamunine. In related work, ( 5 )-34 was
condensed with ( _+ )-35 o give rise to a mixture of daurinolines 36,
Scheme I 2 ( 1 9 ) .Daurinoline itself has the (- - or (R, ) configuration.
34 35
36
SCHEME2
The alkaloid (- -cuspidaline is representedby expression 37, nd a
synthesis of ( f -cuspidaline was carried out through a bis-Bischler-
Napieralski reaction. Following reduction, h7-methylation, and
catalytic debenzylation, it was possible to separate the diastereo-
meric mixture of ( 5 )-cuspidaline by fractional crystallization, Scheme
13 ( 2 0 ) . ( & )-4’-O-Methylberbamunine (38) has also been obtained byessentially the same route ( 2 0 ) .An alternate but closely related prepara-
tion of a mixture of cuspidalines is also available using the intermediate
39 (21).
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 335
COOH
3-Methox y-4-benzyloxy-
decalin, ACHaCOOH phcnethylamine.
I
P
1
Fractionalcrystallization
_____j
/H3C
SCHEME 13
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 337
0 C H 3
40
OCH,
4 1
and
OH
42
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PhCH2CI,COOCH, NaOH,
CHBOH
-H300C
I
OH
c H 3 o o c ~C O O C H 3 2.. BasicOCl,,hydrolysisyridine
3. CAaN2t
OCH,Ph
OCH,Ph
3-Methoxy-4-benzyloxy-phenethylamine,
silver benzoate,N(C2Hda
(Arndt-Eistert)
OCH,Ph
1. POC13
3. NaRH,4. Conc. HCI,
ethanol
-
2. C H ~ I
OCHaPh
H3C CH3
OH
Mixture of enantiomeric and diastereomeric magnolamines
SCHEME4
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OCH,
c ’ - c H z ~ o ~ ~ ~ &CN,cetonethanol,
OCH,
OCH,
CHa-CN
Hydrolysis
-OCH,
HOOCCH,poa\
\ OCH,I
OCH,
44or alternatively,
Br
OCH,
C H 3 0 0 C - H ~ C ~ o ~ C H 2 C O O C H 3-ydrolysis 44
\ OCH,
OCH,then,
1. 3-Methoxy-4-benzyloxyphenethylamine
S 0 C l 2 2. PC15, CHCI. (Bischler-Napieralski)44 Diacid chloride 9
OCH,
45
SCHEME6
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340 MAURICE SHAMMA AND VASSIL ST.GEORGIEV
also been prepared through Ullmann condensation of two tetrahydro-
benzylisoquinoline units. This sequence, which uses both benzyloxy and
ethoxycarbonyloxy protective groups, is shown in Scheme 16 ( 2 7 ) .Thesimple analog 46 of magnolamine has also been prepared through the
Ullmann condensation of two tetrahydrobenzylisoquinoline units and
was obtained a s an isomeric mixture (28).
PhCH,O’
3H30
P hCH,O
1. POCI., toluene2. CH313. N a R H ,
t
H O,H,OOCOwthen,
ylC H z P h
C H 3 0
C H 3hCH,O
+H O
OCH,Ph
1. Ullmann2. Hydrolysis
Mixture of enantiomeric and
diastereomeric magnolamiries
SCHEME6
P o d\
46
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 341
IV. Berbamine-Oxyacanthe-Type Alkaloids
Initial efforts in this series provided preparations of such inter-mediates as 47 to 50 (29-34) . The first synthesis of ( + )-tetrandrine (54)
was achieved in low yield by Ullmann condensation of ( + )-N-methyl-
coclaurine (53)with (- )-3’,8-dibromo-N,O,O-trimethylcoclaurine51)
48
H O O C C O O H
49
50
obtained by bromination of 53 followed by 0-methylation. 0 , O -
Dimethylbebeerine (55) should have been a by-product of this con-
densation but was not actually isolated and characterized, Scheme 17
An interesting total synthesis of optically active natural ( + )-
isotetrandrine (65) (- -phaeanthine ( 6 6 ) ,and ( + )-tetrandrine (54) has
been achieved ( 3 6 ,3 7 ) .The first required intermediate, ( - -0-benzyl-8-
bromolaudanidine (56),was prepared through exploitation of a Will-
gerodt reaction as shown in Scheme 18.
(35).
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342 MAURICE SHAMMA A N D VASSIL ST. GEORGIEV
rtl. K I . K ~ ( : o ~ .pyridinr. A
SCHEME7
Another intermediate was N-tert-butoxycarbonyl-4-hydroxy-3-
methoxyphenethylamine (57) and the preparation of this urethan is
given in Scheme 19. The tert-butoxycarbonyl group is removable by acid
but is resistant to hydrogenolysis and base hydrolysis under relatively
mild conditions. Ullmann condensation of 56 with 57 furnished the
diary1 ether 58 in good yield. Catalytic debenzylation was followed by
55
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6. SYNTHESES O F BISBENZYLISOQUINOLINE ALKALOIDS 343
S
ll ACF,--CN 0
CHa
c=o
9, morpholine, A NaOH
OCHIPh OCH,Ph
OCH3 OCH,
OCH,Ph
OCH,
1. P O C l 32. NaBR,3. Resolution via
I-(+ )-tartaricacid salts
4. HCOH.NaBH,
Br
/
H3C H-
a:-56
SCHEME8
another Ullmann condensa-ion with the -bird required intermediate,
namely, methyl p-bromophenylacetate, to supply the bisdiaryl ether
59, again in good yield, Scheme 20.
When the bisdiaryl ether 60 was heated, the amide 61 was produced,
which generated the key imine 62 upon Bischler-Napieralski cyclization.
tcrt-Rutyl aaidoformate, Hz.N(CzH,)3, cthyl acetate
PhCH,OH 3 0 p N H z PhCH,O
0- tert-butyl
HO
0-&t-butyl
57
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1 . H z
Cu
/
2. MCUO. KzCOa,pyridine, A
56 + 57
58
1 . OH(hyd
2. p-N(est
fo 3. CF,O--t&-butyl (rem
/N
/ tcrt
59
SCHEME0
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 345
D M F ,pyridine, A
60- POCI3,CHC13A
61
The reduction of imine 62 was studied under a variety of experimental
conditions. With sodium borohydride in methanol, a 3 : 2 ratio of
bisbenzylisoquinolines 63 and 64 was obtained, which wereN-methylated to ( + )-isotetrandrine (65) and ( - -phaeanthine (66),
respectively. But when zinc in sulfuric acid was utilized on the racemate
of 62, only 64, as the racemate, could be isolated. No stereospecificity
in the reduction of 62 was observed with Adains catalyst containing a
trace of concentrated hydrochloric acid. AT-Methylationof racemic 64
gave a racemic compound composed of ( - )-phaeanthine (66) and its
enantiomer (+)-tetrandrine(54), Scheme 21 ( 3 7 ) .Since ( )-66has been
isolated from a natural source and resolved into its optical antipodes
( 3 7 a ) , the present synthesis amounts also to a total synthesis of( + )-tetrandrine.
The first successful syntbssis of (i -cepharanthine (73),belonging to
the oxyacanthine series, w5Fachieved through the Bischler-Napieralski
cyclization of the key bislGtam 72. One precursor of this important
intermediate was the substituted aminourethan 69, which was prepared
from species 67 and 68 as shown in Schemes 22 and 23 ( 3 8 , 3 9 ) .
The lower half of cepharanthine was prepared as in Scheme 24,
taking advantage of the fact that a benzyloxy group can be hydrogen-
olyzed while a tert-butyl ester is immune.Condensation of 69 with90 furnished the urethan 71, which was
converted to the bislactam 32. Bischler-Napieralski cyclization gave a
bisimine, which could be rexuced to a bis secondary amine either with
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 347
I
Br Br
67
SCHEME2
Adams catalyst or with sodium borohydride. Since the ratios of the two
diastereomers obtained from each of these reductions were different,
the available mixtures of secondary amines were combined, N -methylated, and then separated by chromatography. One of the prod-
ucts isolated proved to be ( & )-cepharanthine (73), cheme 25 (38'39).
It was found possible to convert the unusual bisbenzylisoquinoline
alkaloid stepinonine (74) to N,O-dimethyltetrahydrostepinonine 75),
which in turn could be selectively oxidized with Jones' reagent to the
H0. Ethyl
2. Zn /Hn , HCI CI
Ph-CH, -0- CH 3 0 r o1 chloroformate,yridine
C,H,OCOI t
O
0
C H 3 0
H O
0 O C H p P h O C H I P h
68
then,
1 . CuO, K1C03. pyridine, A2. Dil. HCI (formyl hydrolysis)
67 + 68
OCH,Ph
69
SCHEME3
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348 MAURICE SHAMMA AND VASSIL ST.GEORGIEV
COOH CO O - t e r t - Bu
ter2-Butyl alcohol,
H a , PdtC
bOCH2€?h AOC13, pyridine ~
O C H S P h
COO- tert-Bu ~ O O C H .
p-Toluen esulfonic
acid (removal of+
CU,A ( ~ l ~ r n a n n ) tcrl-Bu group)
7 0
SCHEXE 4
ketone 76. R e d u c h n of this ketone first with zinc in acetic acid andthen with sodium borohydride yielded a mixture of O-methylrepandine
(77) and O-methyloxyacanthine (78) (39a).
A mixture of enantiomeric and diastereomeric berbamines (82)
and oxyacanthines (83) was obtained through the following sequence.
Schotten-Baumann reaction of the diamine 47 with the diacid chloride
79 gave amides 80 and 81,which could be separated. Bischler-Napieralski
cyclization using phosphorus oxychloride produced the corresponding
3,4-dihydroisoquinolines. -Alkylation with methyliodide, borohydride
reduction, and subsequent acid hydrolysis generated isomeric mixturesof berbamine 82 and oxyacanthine 83, respectively (39b).
V. Thalicberine-Type Alkaloids
( + )-Thalicberine (84) and ( +)-O-methylthalicberine (85) are repre-
sentative of a group of bisbenzylisoquinoline alkaloids found in
Thalictrum species (Ranunculaceae), and a synthesis of ( + )-O-methyl-
thalicberine has been reported ( 4 0 ,4 1 ) . Ullmann condensation of( + )-O-benzyl-8-bromolaudanidine (86) with the phenolic tert-butyl-
urethan 87 afforded the diary1 ether 88, which was then hydrogenolyzed
to the phenol 89, Scheme 26.
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CH,O'
1. POClD2. H., Pt or NaRHI3 . HCOH.NaBH, H3C
4. ChromatographyH
HN
79.
SCHEME5
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352 MAURICE SHAMMA AN D VASSIL ST. GEORGIEV
84 R = H
85 R = CH,
CuO, K,CO.,
+0-tert-Bu
OCHaPh
86 87
0- tert-Bu
OCH,Ph88
0- ert-Bu
OH
89
SCHEME 26
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m
\
a
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354 MAURICE SHAMMA AN D VASSIL ST. GEORGIEV
Phenol 89 was condensed in a second Ullmann condensation with
methyl-p-bromophenylacetate to yield the ether 90, which was con-
verted to the amide 91 by the p-nitrophenyl ester method. Bischler-Napieralski cyclization then gave the imine 92. Reduction of this
imine with sodium borohydride gave only a single compound, namely,
the desired amine 93. N-Methylation furnished the final product,
(+ )-O-methylthalicberine ( 8 5 ) ) identical with the natural material,
Scheme 27.
VI. Trilobine-Isotrilobine-TypeAlkaloids
The alkaloids ( + )-trilobine (94) and ( + )-isotrilobine (95) possess a
diphenylenedioxy bridge connecting the two top aromatic rings. It has
been possible to interrelate chemically bases of the berbamine-
oxyacanthine group, which contain two diary1 ether linkages, to those
belonging to the trilobine-isotrilobine series, and these interrelationships
will be discussed briefly here. When naturally occurring ( + )-iso-
tetrandrine (65) was heated with hydrobromic acid at lOO"C, the
demethyl derivative 96 was obtained. This derivative cyclized to the
trilobine-type compound 97 upon more drastic treatment with hydro-bromic acid, and diazomethane O-methylation yielded the methyl ether
98, Scheme 28 ( 4 2 ) .
94 R = H95 R = CH,
In a similar vein, ( + )-tetrandrine (54)) which is diastereoisomeric
with ( + )-isotetrandrine (65),was converted to the diphenylenedioxy
derivative 99 ( 4 3 ) .
The starting alkaloids in the two examples above belong to theberbamine series, but diphenylenedioxy formation can also be brought
about in the oxyacanthine series. Thus, oxyecanthine (100)itself was
converted into the derivative 101 ( 4 4 ) while N-methyldihydro-
epistephanine 102) ed to the levorotatory antipode 103 of natural
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 355
CH3 HBr, 100°C,3 hoursH
3C
65
H3C /NH / HBr. 130-135°C, 3 hours
/
\\ OH 0
96
97 R = H98 R = CH3
SCHEME8
54
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 357
104
1. HBr, HOAc, 100°C
2. HBr, 140-145°C
3. CHaNat (+-1-95
SCHEME9
( + )-isotrilobine ( 4 5 ) .Finally, taking advantage of the known fact that
in dilute acid (+ )-oxyacanthine (100) undergoes isomerization to
( - -repandine (104), t was found possible to convert ( + )-oxyacanthine
into natural ( + )-isotrilobine, Scheme 29 ( 4 6 ) .
Inubushi and co-workers have recently adapted their synthesis of
( + )-isotetrandrine and (- -phaeanthine to preparations of ( + )-
obaberine and ( -t -trilobine (46a).
VII. Menisarine-Type Alkaloids
The alkaloid (+ )-menisarine possesses the structure 105, which
incorporates a diphenylenedioxy bridge, and an interesting synthesis of
( )-N-methyldihydromenisarine (107) has been achieved. The firststage of the synthesis concerned the preparation of the diamine 106,
which was carried out via a double Ullmann, as shown in Scheme 30
(4 7 , 4 8 ) . The lower half (1) of the molecule was prepared using a
Willgerodt reaction as per Scheme 31.
105
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358 MAURICE SRAMMA AND VASSIL ST. OEORGIEV
cu, pyridine.
A t
Br OCH,
OH OH
OCH, OCH,
106
SCHEME0
Condensation of the diacid chloride of 1 with the diamide 106 a t high
dilution, followed by Bischler-Napieralski ring closure, reduction, and
Eschweiler-Clarke N-methylation furnished the desired racemic
product 107, Scheme 32 ( 4 7 , as) , which was spectrally identical with
the product derived from the reduction and N-methylation of natural
( + )-menisarine (105).
1. CH&OCI, AICI.,
d o n. DlmethylS. sulfate
0
II
' ~ 0 0 c ~ c H 3illgerodt
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6. SYNTHESES O F BISBENZYLISOQUINOLINE ALKALOIDS 359
108 + Diacid chloride of 1
2. NaBH,
107
SCHEME2
VIII. Tiliacorine-TypeAlkaloids
( + )-Tiliacorine and it s diastereomer ( + )-tiliacorinine have been
assigned structure 108 on the basis of extensive degradative studies
( 4 t h ) .These two alkaloids are unusual in having a biphenyl system inlieu of the usual diary1 linkage. A total synthesis of ( k -O-methyl-
tiliacorine (109) has been described in detail ( 4 9 ) . Unsymmetrical
Ullmann condensation of the bromophenols 110 and 111 yielded a
mixture of three products from which the desired diester 112 was
isolated by chromatography. Homologation and conversion to the
diamine 113 was followed by condensation with the diacid chloride 114.
The resulting bisamide 115 was converted to a mixture of ( f)-0-methyltiliacorine and O-methyltiliacorinine by well established trans-
formations. Careful chromatography of this mixture yielded ( f -0-methyltiliacorine, spectroscopically and chromatographically identical
with material derived from the alkaloid. The diastereoisomeric ( f)-0-
methyltiliacorinine was obtained only in trace amounts, Scheme33 ( 4 9 ) .
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360 MAIJRICE S H A M M A AND VASSIL ST.GEORGIEV
1. K salts formation
C H 3 O O C ~ O C H a BrDc c.. Cu-bran=,hromatographyiphenyl ether, A
t
\H HO
Br
110 111
1 . LiAlH,
C H 3 0 0 C v C O O C H , 2.. S 0 C l zC N
4. H., NYR)
-o\
112
113
then,
113 + COCl
__f
114
115
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 361
1. CHJ2. Na B H ,3. POC1.
4. H2, Pt5. HCOH, HCOOH
t
108 R = H109 R = CH,
SCHEME3
IX.Liensinine-Type Alkaloids
The alkaloid ( + )-liensinine (118) incorporates head-to-tail coupling
through a diary1 ether linkage. A total synthesis of this alkaloid was
achieved on the heels of the initial isolation and characterization reports.
Ullmann condensation of ( - -116with ( - -117followed by hydrolysis
gave the optically active alkaloid (50 ,5 1 ) . A synthesis of a diastereo-
meric mixture of liensinines, by a somewhat similar pathway, is alsoavailable ( 5 2 ) .
The related alkaloid ( - -isoliensinine (122)yields ( - -O,O-dimethyl-
isoliensinine (121)on treatment with diazomethane. Derivative 121 was
synthesized by Ullmann condensation of (- -119 with ( - -120 (53).Finally, optically active (- -isoliensinine (122) was obtained by the
sequence in Eq. 1 ( 5 4 ) .Worthy of attention are the new conditions for
the Ullmann condensation ( 5 2 , 5 4 ) nvolving the use of copper powder,
potassium carbonate, a small amount of potassium iodide, and dry
pyridine heated to 155-160'c in a current of nitrogen. These conditionsgive better yields (about 15y0) han the usual Ullmann condensation.
The newer base (- -neferine (123), related to liensinine and isolien-
shine, was synthesized by a similar approach (Eq. 2 ) (55).
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CH,O
1. Ullmann
2. H,OBHO \
Y~ c H ,I I I I Y \ C H 3r /
-\ PhCH,O \PhCH,O
116 117
cH30CH,
O b F O O HHac,5:>
OCH,
119 120
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 363
CH,O PhCH,O
CuO, K.COa.
-CH, pyridine, A
HOH30LYCH30
0 \ C H ,
1CH, OCH,
OCH,
123
X. Curine-Chondocurine-Type Alkaloids
It was conclusively demonstrated in 1970 that the hitherto accepted
structure for the alkaloid ( + )-tubocurarine,which had been represented
as 124, was in error and that the correct structure is 125 ( 56 ,57) . This
finding was of particular interest not only because of the importance of( + )-tubocurarine as a neuromuscular blocking agent, but also because
of the fact that supposed total syntheses of the racemic di-0-methyl
ether of tubocurarine iodide as well as of racemic tubocurarine iodide
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364 MAURICE SHAMMA AND VASSIL ST. GEORGIEV
X 0
c H 3 0 m m ,H
\0
4
124 125
had been claimed previously. A description of the synthetic work on
tubocurarine follows. This description is complicated not only because
of the above mentioned change in structural assignment, but also by
the failure of the workers involved in the synthetic work in clearly
differentiating between enantiomers, racemates, and diastereomers
while comparing samples (58-62) .As a preliminary attempt at th e synthesis of the dimethyl ether of
tubocurarine, the simple dimer 126 was constructed as described in
Scheme 34. The product 126 was obtained as a mixture of two diastereo-
mers from which the predominant racemate (mp 96-99°C) could be
isolated (58).
Essentially the same approach was utilized in the preparation of the
so-called “di-0-methyl ether of tubocurarine iodide ’) (127), Scheme 35
( 5 8 ,59). The UV spectrum of one salt so obtained was apparently close
to or identical with the spectrum of an authentic sample of the di-0-
methyl ether of ( + )-tubocurarine iodide, and this finding was taken as
proof of structure.* It must be pointed out, however, that most
tetrahydrobenzylisoquinolines, as well as bisbenzylisoquinolines such
as tubocurarine or its dimethyl ether, exhibit a maximum absorption
near 280 nm, so that UV spectroscopy is not a reliable basis for com-
parison. Another criterion used was a mixture melting point between the
* There seems to be some confusion in the assignments of melting points of the final
products. I n reference ( 5 8 ) , two supposed diastereomeric tubocurarine iodides wereobtained (m p 131-135°C and 223-228°C). But in reference ( 5 9 ) ,only one melting point
was quoted [mp 257-268°C (ethanol)]. This la tt er material apparent ly gave no melting
point depression with a sample of the natural sa lt (mp 262-264”C), even though no fo rmal
resolution was carried out on the synthetic material.
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 365
CH,O CH,O3C H , O P " r ~
N,C H3 C H 3 0
h C H, O HO
___, +
CH,O CH,O
I . H,, P t
N\CH3 2 . HC'OH,HCOOH,..jCx; -
2. PO('I3 5'C H 3 0 \ /
1. Homoveratrylaminr
(636N \ C H ,
\ /
CH, OCH, CH, OCH3
I
OCH,
COOCH,
SCHEME4
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FOOH
cH30)3?JyHO ' N H a PhCH,O
PhCH,OLy
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. 209. HCI, A , 2 hours
OCH,Ph
OCH,
OCH,
1. Zn, dil. HOAc,A , 1.5 hours
2. CHJ.CH30H
OCH,
S CH E M E5
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em a0m
w
U
m
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t
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 371
naturally derived dextrarotatory di-0-methyl ether of tubocurarine
iodide and the synthetic isomer, in which apparently no depression was
observed. Such a comparison is, of course, invalid since (a)a racemateusually has a different melting point from th at of a pure enantiomer, (b)
melting points of bisbenzylisoquinoline salts are often unreliable and
difficult to reproduce, and (c) the structure assigned to ( + )-tubocurarine
and its di-0-methyl ether was in error in the first place. A synthesis of
the unsubstituted tubocurarine analog 129 is also known, Scheme 36
(63).The product proved to be a mixture of two racemates, mp 225-
227°C and 121-124°C.
As an extension of the synthetic work on the so-called “di-0-methyl
ether of tubocurarine,” a preparation of the di-0-methyl ether of racemicchondodendrine (130)was carried out, Scheme 37 ( 6 4 ) .
A slightly different approach t o the so-called “di-0-methyl ether of
tubocurarine” has also been recorded, Scheme 38 (60).The starting
material was the diimine 131, which was known from previous work.
Each of the two diastereomeric racemates of 132 gave two bis-
methiodides upon treatment with methyl iodide, a result that is some-
what difficult to rationalize; and one of these four isomeric salts,
namely, tha t melting 257.5-259”c, was claimed to be identical with the
dextrorotatory di-0-methyl ether iodide of natural ( + )-tubocurarineiodide. The criteria for comparison were simply closeness of UV spectra
and melting points.
A claim of a synthesis of a material assumed to be identical with
natural ( + )-tubocurarine iodide was put forward, even though an actual
CH, % ismethiodide
1. Cu, K,COa,
2. Z n , H O A c
salts
131 133
SCHEME8
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372 M A U R I C E S H AM M A A N D V A S S I L ST. G E O R G I E V
CH30
K@ ‘0 ,Cu, A
+
OCHaPh
CH,O
Ac.0,pyridine----.-+
0
A
OCHaPhOCHaPh
CHa
COOCH,Ha
H OCH,
133
C H d , NaOH,C H 3 0 H , A
OCH,
OCH,PhH,CH,Ph3”’ Br
OCH, H CH,
135HNd
184
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374 MAURICE SHAMMA AND VASSIL ST.GEORGIEV
Finally, a synthesis of racemic so-called ( ( N , N ’-demethylchondo-
dendrine ” (137))erroneously assumed by the authors to be identical
with chondrofoline, has also been advanced and is described in Scheme40( 6 2 ) .T w o products were obtained a t the conclusion of the sequence, and
one of them was assumed to correspond t o chondrofoline on the basis of
UV spectral comparisons and a negative Millon test. It was later shown
by other workers th at the correct structure for chondrofoline is 138 (65))so that the claim of a synthesis of chondrofoline is unfounded ( 6 2 ) .
H 3 c , : ~ 3
OCH,
138
In other attempts at the synthesis of tubocurarine-type bases,
Ullmann condensation of the dibromotetrahydrobenzylisoquinoline 139
with the N-methylcoclaurine salt 140 was investigated but did not lead
to characterizable product (66).Studies of the efficient Ullmann con-
densation of phenols with aromatic halides substituted a t the ortho
position(s)with nitro group(s)have been carried out and have culminatedin the preparation of the imide 141 (67-69).
0,O-Dimethylcurine (143)was presumably obtained in the course of
the previously described syntheses. But a more reliable preparation of
this compound involves the Ullmann condensation between the levo-
rotatory dibromotetrahydrobenzylisoquinoline 139 and the levorotatory
diphenolic tetrahydrobenzylisoquinoline 142 (70). When the catalyst
for the condensation consisted of cuprous chloride in the presence of
potassium carbonate and pyridine and the conditions were heating a t
155-165’C for 24 hours, a small yield of optically active 0,O-dimethyl-curine (143)together with a larger amount of 144 was obtained. When,
however, the two starting tetrahydrobenzylisoquinolines were racemic
rather than levorotatory and the catalyst was cupric oxide in pyridine
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 375
141
heated at 160-170°C for 50 hours, the products consisted of a small
yield of a mixture of 0,O-dimethylcurines together with a mixture of
tetrandrines and isotetrandrines (54), as well as a mixture of 144.
Ullmann condensation of 2 moles of the racemic phenolic tetrahydro-benzylisoquinoline 145 followed by N-methylation yielded the hayatine
analog 146 (2'1).
Turning now to the structurally simpler alkaloid (- -cycleanbe (147),a promising route to i ts preparation appeared to be Ullmann condensa-
tion of 2 moles of 8-bromoarmepavine, since the alkaloid is symmetrical.
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376 MAURICE SHAMMA AND VASSIL ST. G EO R G I EV
1. Cu, aq. Na O H , A2. C H J
c1145 OCH, 'o
O CH 3
146
One such attempt using ( k -8-bromoarmepavine (148)and the superior
cupric oxide-potassium carbonate-pyridine catalyst gave some of the
dimer 149 but none of the expected mixture of cycleanines (72).
A fully authenticated first total synthesis of ( k -cycleanine (147)
involved as a first hurdle the synthesis of the amino acid 151as well as
that of its corresponding methyl ester 155 (73, 7 4 ) . The aldehyde 150was condensed with nitromethane to give a yellow nitrostyrene.
Catalytic hydrogenation over Adams catalyst in acetic acid then gave
the required amino acid 151, Scheme 41.
Furthermore, the methyl ester 155 of the acid 151was synthesized by
the following alternate route. 3,4-Dimethoxy-5-bromophenethylamine,
prepared by the reduction of the nitrostyrene 152 under Clemmensen
CH,O
C H 3 0 :\CH3 ::::r CH, cH3H,O CH3
+ I 6H 44H 3 c \ : M 0 C H 3 CH,
OCH, OCH,
147 I4948
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 377
C H 3 0 1. CH3NOa T N H ,H 3 0
cH30vc. Ha, Pt, HOAc
4H,COOH *(IH,COOH
150 151
SCHEME1
conditions, was converted to the N-carbobenzoxy derivative 153.
Ullmann condensation between 153 and methyl p-hydroxyphenyl-
acetate afforded the product 154, and catalytic removal of the blocking
group gave rise to the desired methyl ester 155, Scheme 42.
The amino acid 151 was next protected as its N-carbobenzoxy
derivative 156. Condensation between 155 and 156 furnished the amide
1. Zn/Hg, HCl
c H 3 0 T v " 0 2 2. Ph-CHP-O-C '01
C H 3 0
Br
152
CH,OH o ~ c H 2 - - C O O C H I .
c H 3 0 q T uO, K.CO3, pyridine t
Br OCH,Ph
153
C H 3 0
CH&OOCH, CH2COOCHS
154 155
SCHEME2
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0
=I IG
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380 MAURICE SHAMMA AND VASSIL ST. GEORGIEV
157, which was converted to the carboxylic acid 158. Esterification of
158with p-nitrophenol and DCC was followed by treatment with hydro-
gen bromide to remove the carbobenzoxy group. The resulting aminehydrobromide 159 readily suffered cyclization to the bisamide 160, and
Fischler-Napieralski cyclization followed by reduction led to a mixture
of tetrahydroisoquinolines. N-Methylation finally furnished a mixture
CH,O
cH30 P o C H 3 0cH3\ C H 3
44 66
HN z”̂
H C N )
OCH,Ph OCH,Ph
OCH,163 164
O C H a P hI
I
H,CLN& CH ,
OCH,
165
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 381
of products which generated ( -cycleanhe (147)after chromatography.
T w o other products obtained from the chromatographic separation
were the dimers 161 and 162, Scheme 43.A later study in the cycleanine series demonstrated that Bischler-
Napieralski cyclization of the amide 163 proceeds in two directions to
supply ultimately amines 164 and 165 (75).
XI. Miscellaneous Syntheses
The alkaloid aztequine was supposedly isolated from the leaves of
yoloxochitl, Tabma mexicana Don. (Magnoliaceae) and was assigned
structure 166 with no delineation of stereochemistry. This assignment
is certainly in error, since in the same paper the unlikely claim was made
that hydroiodic acid ruptured the diaryl ether linkage of the alkaloid
without touching the methoxyl groups (?‘G).
I IO H O H
166
Attempted syntheses of 166 either involve initial preparation of the
diaryl ether corresponding to the two bottom rings, followed by further
elaboration to construct the two tetrahydroisoquinoline units, or
include an Ullmann condensation to bond together the two tetrahydro-
benzylisoquinoline units (77-79).The bisbenzylisoquinolines167, 168, and 169, which have no analogs
in nature, have been synthesized through Ullmann condensation between
170 and 171 in the case of 167; 172 and 173 in the case of 168;and 174
and 175 in the case of 169 ( 8 0 , S l ) .
167
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382 MAURICE SHAMMA AND VASSIL ST. GEORGIEV
168
169
170 R, = OH, R, = H
171
173
175
R1 = Br, R, = H
R, = H, R, = Br
R, = Br, R, = H
172 R, = H, Ra = OH
174 R1 = H, RP = OH
The dimer 176 has also been prepared in the course of a study ofstructural requirements for tumor-inhibitory activity among bis-
benzylisoquinolines ( 1 3 ) .
Lastly, an important related synthesis that should be a t leastmentioned here in passing is that of the alkaloid ( + )-thalicarpine(177),which is an aporphine-benzylisoquinoline rather than a bisbenzyliso-
quinoline (82-84).
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 383
XU. Syntheses Using Phenolic Oxidative Coupling
Historically, significant attempts a t the phenolic oxidative coupling
of tetrahydrobenzylisoquinoline free bases were reported as early as
1932, but they generated only dibenzopyrrocolines (85, 8 6 ) . The first
phenolic oxidative coupling leading to a bisbenzylisoquinoline was not
reported until 1962, when i t was shown that ferricyanide oxidation of
the quaternary salt ( +_ )-magnocurarine iodide (178)at pH 10 yieldedthe dimer 180 n 1Sy0yield (87, 88).
RO
-0‘178 R = H
179 R = CH3
OR
XQ
0180 R
181 R
RO
#@
= H
= CH,
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 385
Similarly, ( f -4’-O-methylmagnocurarine iodide (179) furnished the
corresponding dimer 181, while ( )-armepavine methiodide, which has
a methoxy group at C-7 and a hydroxy at C-4‘ , could not be dimerized(87-89) .
In a variation on this theme, and using the free base instead of the
quaternary salt, it was demonstrated that ferricyanide oxidation of
( f -4’-O-methyl-N-methylcoclaurine182) in a two-phase system of
chloroform-0.1 N sodium carbonate (pH 11.4) a t or below room tem-
perature resulted in formation of the racemic diastereomers 183 and
184 in about 15% yield and separable by chromatography, Scheme 44
It will be recalled that in an initial attempt i t had been found th at( k -armepavine methiodide did not dimerize at room temperature.
Reexamination of this oxidation under more severe conditions, namely,
0.1 N sodium carbonate solution and potassium ferricyanide on a steam
bath or 1 N sodium hydroxide and silver nitrate a t room temperature,
produced the carbon-carbon dimer 185 in about 15y0 yield ( 9 1 , 9 2 ) .
(901.
185
In an atte.mpt to prepare the aporphine base ( f -N-methylcaaverine
(186) by phenolic oxidative coupling, the ferric chloride oxidation of
racemic tetrahydrobenzylisoquinoline 187 was investigated. The
products were the dienone 188 in 2.4y0yield and the dimeric benzyliso-
quinoline 189 in 1.1% yield, Scheme 45 (93).
A few studies have also been concerned with the enzymatic oxidation
of tetrahydrobenzylisoquinolines. Oxidation of ( 5 )-N-norarmepavine
(190) a t pH 6.5 with crude horseradish peroxidase and hydrogen
peroxide yielded a complex mixture that included small yields of theisoquinolines 191, 192, and 193, Scheme 46 (94). Other investigations
have dealt with the enzymatic oxidation of phenethyltetrahydroiso-
quinolines ( 9 5 ,96).
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c H 3 0 p N \ C H 3O aq. FeCl,, 30:40'C CH3
188187
+ H3C' N&KJHO \
186
SCHEME5
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 387
H OJ9190
191
H O
O H
192
SCHEME6
cH30H,O
O H
198
XIII. SynthesisUsing Electrolytic Oxidation
The first preparation of a naturally occurring bisbenzylisoquinoline
alkaloid, namely, dauricine, using an oxidative method occurred when
the sodium salt of ( )-N-carbethoxy-N-norarmepavine (194) was
subjected to electrolysis using tetramethylammonium perchlorate as
the electrolyte, a graphite anode, and a platinum cathode (97). Amixture of the dimers 195 and 196 was obtained and separated. The
dimer 196 then furnished a racemic and diastereomeric mixture of
dauricines 3 following 0-benzylyation, reduction, and catalytic de-
benzylation. Such an electrolytic oxidative dimerization was unsuccess-
ful when the nitrogen function was not protected, Scheme 47 .
XIV. Use of Pentafluorophenyl Copper
The most promising avenue to the bisbenzylisoquinolines presently
appears t o be via a n improved Ullmann diary1 ether synthesis utilizing
pentafluorophenyl copper in dry pyridine. Thus condensation of
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388 MAURICE SHAMMA AND VASSIL ST.GEORGIEV
CaH5OOC /N
mzElectrolysisn wet
acetonitrile-b O e ee
194
C 2 H , 0 0 C / N O C H , CH,O
195
+
196
then,
1.. PhCH.CI,miAIH4 base H3C’ N O C H 3CH3 cHH3O
3. H., PdIC196 t
SCEEME7
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6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 389
( + - 6'-bromolaudanosine (197)with ( + )-armepavine and pentafluoro-
phenyl copper in dry pyridine gave an impressive53y0yield of the dimer
198, the S,S isomer of tetra-0-methylmagnolamine (98). Analogous
condensations have also led to the preparation of aporphine-benzyliso-
quinoline dimers (98).
IOCH,
198
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6. SYNTHESES O F BISBENZY LISOQUINOL INE ALKALOIDS 391
48a. M. Shamma, J. E. Foy, T. R. Govindachari, and N. Viswanathan, J . Org. Chem.
49. B. Anjaneyulu, T. R. Govindachari, and N. Viswanathan, Tetrahedron27,439 (1971).50. Y.-Y. Hsieh, P.-C. Pan, W.-C. Chen, and Y.-S. Kao, Sci.Sin. 12, 2018 (1964); CA 62,
51. Y.-Y. Hsieh, P.-C. Pan , W.-C. Chen, and Y .3. Kao, Yao Hsueh Hw eh Pao 13, 166
52. T. Kametani, S. Takano, K. Masuko, and F. Sasaki, Chem. Pharm. Bull. 14,67 (1966).
53. M. Tomita, H. Furukawa, T. H. Yang, and T. J. Lin, Tet . Lett. 2637 (1964).
54. T. Kametani, S. Takano, H. Iida, and M. Shinbo, J. Chem. SOC. 298 (1969).
55. H. Furukawa, Yakugaku Zasshi 85, 335 (1965).
56. A. J. Everett, L. A. Lowe, and S. Wilkinson, Chem. Commun. 1020 (1970).
57. H. M. Sobell, T. D. Sakore, S. S. Tavale, F. G. Canepa, P. Pauling, an d T. J. Petcher,
Proc. Natl. Acad. Sci. U. S. A. 69, 2212 (1972).58. L. V. Volkova, 0. N. Tolkachev, and N. A. Preobrazhenskii, Dokl. Akad. NaukSSSR
102, 521 (1955); CA 50, 4990i (1956).
59. 0. N. Tolkachev, V. G. Voronin, and N. A. Preobrazhenskii, Zh. Obshch. Kh im. 29,
1192 (1958).
60. V. G. Voronin, 0. N. Tolkachev, and N. A. Preobrazhenskii, Izv. Vyssh. Uchebn.
Zaved. Khim. Khim. Tekhnol. 5, 449 (1962); C A 59, 2877e (1963); and V.Voronk,
0.Tolkachev, A. Prokhorov, V. Chernova, and N. Preobrazhenskii, Khim . Geterotsikl.
Soedin. 4, 606 (1969); CA 31, 79277p (1970).
61. V. G. Voronin, 0. N. Tolkachev, and N. A. Preobrazhenskii, Dokl. Akad. Nauk
SSSR 122, 77 (1958);C A 53, 1345f (1959).
62. 0. N. Tolkachev, L. P. Kvashnina, and N. A. Preobrazhenskii, Zh. Obshch. Khim.
36, 1764 (1966).
63. E. N. Tzvetkov, I. N. Gorbacheva, and N. A. Preobrazhenskii, Zh. Obsch. Khim. 27,
3370 (1957).
64. V. I. Shvets, L. V. Volkova, and 0. N. Tolkachev, Izv. Vyssh. Uchebn. Zaved. Khim.
Khim. Tekhnol. 5, 445 (1962); CA 59, 2876h (1963).
65. J. Baldas, I. R. C. Biek, Q. N. Porter, and M. J. Vernengo, Chem. Commun. 132
(1971).
66. H. Hellmann an d W. Elser, Ann. 639, 77 (1961).
67. M. F. Grundon and H. J. H. Perry, J.Chem. SOC. 531 (1954).
68. J. R. Crowder, M. F. Grundon, and J. R. Lewis, J. Chem. SOC. 142 (1958).
69. M. F. Grundon, J. Chem. Soc. 3010 (1959).
70. T. Kametani, H. Iida, and K. Sakurai,J.Chem. SO C. 1024 (1971).
71. K. P. Agarwal, S. Rakhit, S. Bhattarcharji, and M. M. Dhar, J.Sci. Ind . Res., Sect. B
72. M. Tomita, Y. Aoyagi, Y. Sakatani, and K. Fujitani, Chem. Pharm. Bull. 15, 1996
73. M. Tomita, K. Fujitani, and Y. Aoyagi, Tet. Lett. 4243 (1966).
74. M. Tomita, K. Fujitani, and Y. Aoyagi, Chem. Pharm. Bull. 16, 62 (1968).
75. M. Tomita, Y. Aoyagi, Y. Sakatani, and K. Fujitani, Chem. Pharm. Bull. 16, 56
76. E. S. Pallares and E. M. Garza, Arch. Biochem. 16, 275 (1948).77. T. Kametani, K. Fukumoto, and M. Ro, Yakugaku Zusshi 84, 532 (1964).
78. T. Kametani, M . Ro, and Y. Iwabuchi, Yakugaku Zasshi 85, 355 (1965).
79. T. Kametani, H. Iida, M. Shinbo, and T. Endo, Chem. Pharm. Bull. 16, 949 (1968).
80. J. Niimi, Yakugaku Zusshi 80, 451 (1960).
41, 1293 (1976).
9184b (1965).
(1966); CA 65, 8979d (1966).
19, 479 (1960); CA 55, 16585a (1961).
(1967).
(1968).
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392 MAURICE SHAMMA AND VASSIL ST.GEORGIEV
81. J. Niimi, Yakugaku Zasshi 80, 791 (1960).
82. S. M. Kupchan and A. J. Liepa, Chem. Commun. 599 (1971).
83. S. M. Kupchan, A. J. Liepa, V . Kameswaran, and K. Sempuku, J . Am . Chem. SOC.
95, 2995 (1973).
84. For other syntheses of aporphine-benzylisoquinoline lkaloids, see M. Tomita, H.
Furukawa, S.-T. Lu, and S. M. Kupchan, Tet . Lett. 4309 (1965);Chem. Pharm. Bull.
15, 959 (1967);R. W. Doskotch, J. D. Phillipson, A. B. Ray, and J. L. Beal, Chem.
Commum. 1083 (1969);J . Org. Chem. 36, 2409 (1971).
85. C. Schopf and K. Thierfelder, Ann. 497, 22 (1932).
86. R. Robinson and S. Sugasawa, J. Chem. SOC. 89 (1932).
87. B. Franck, G. Blaschke, and G . Schlingloff, Tet. Lett. 439 (1962).
88. B. Franck and G. Blaschke, Ann. 668, 145 (1963).
89. B. Franck, G. Blaschke, and G. Schlingloff, Angew. Chem., Int. Ed. Engl. 3, 192
90. M. Tomita, Y . Masaki, K . Fujitani, and Y. Sakatani, Chem. Pharm. BuZZ. 16, 688
91. A. M. Choudhury, I. G. C. Coutts, A. K. Durbin, K . Schofield, and D. J. Humphreys,
92. See also M. Tomita, Y. Masaki, and K. Fujitani, Chem. Pharm. BuZZ. 16, 257 (1968) ;
93. T. Kametani and I. Noguchi, J . Chem. SOC. 502 (1969).
94. Y. Inubushi, Y. Aoyagi, an d M. Matsuo, Yet. Lett. 2363 (1969).
95. T. Kametani, S. Takano, and T. Kobari, J . Chem. SOC. 9 (1969).
96. T. Kametani, H. Nemoto, T. Kobari, and S. Takano, J . HeterocycZ. Chem. 7, 181
97. J. M. Bobbitt and R. C. Hallcher, Chem. Commun. 543 (1971).
98. M. P. Cava and A. Afzali, J.Org. Chem. 40, 1553 (1975).
(1964).
(1968).
J.Chem.SOC. 2070 (1969).
M. Tomita, I(.Fujitani, Y. Masaku, and K.-H. Lee, ibid. 251.
(1970).
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-CHAPTER 7-
THE HASUBANAN ALKALOIDS
YASUONUBUSHIND TOSHIROBUKA
K y o t o U n i v e r s i t y
S a k y o .k u . K y o t o . J a p a n
I. Introduction ........................................................ 393
395
395
395
398
414
415
416
418419
419
A. Cepharamine .................................................... 420
B. Hasubanonine a nd Aknadilactem .................................. 422
C. Metaphanine .................................................... 424
V I. Biosynthesis ....................................................... 427
References ......................................................... 428
I1. Occurrence and Physical Constants of Hasubanen Alkaloids ..............I11. Structure Elucidations ...............................................
A. Mass Spectroscopy ...............................................B. Structures of Hasubenan Alkaloids .................................
IT. Synthesis of the Hasubanan Skeleton ................................. 414
A. Synthesis via Ketolactones ........................................B. Synthesis via'Ketonitriles .........................................
Synthesis v ia Cyclic Enrtmines .....................................
D. Synthesis via Spiroketone..........................................E. Synthesis by Phenol Oxidation .....................................V. Synthesis of Hasubanan Alkaloids .....................................
C.
I. ntroduction
Work on alkaloids of the hasubanan group up to 1970 have been
reviewed in Volume XI11 of this treatise ( 1 ) In the succeeding four
years that are covered in the present review. significant advances in this
field have been made in discovering thirteen new congeners and also in
synthetic studies of the hasubanan skeleton and of this type of
alkaloids.So far as we know. the occurrence of the hasubanan alkaloids has
been noted in Stephania species only. and no alkaloid has been found in
other species of Menispermaceae of special interest from the chemo-
taxonomical viewpoint.
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TABLE IPLANTOURCEND PHYSICALROPERTIES
Plant species Alkaloid
Meltin
Formula point ("
Stephania abyssinica Walp. Metaphanine
StephabyssineStephaboline
Prostephabyssine
Stephavanine
Stephania cephalantha Hayata Cepharamine
Stephania delavayi Diels Delavaine
16-Oxodelavaine
Stephania hernandifolia Walp. Aknadicine
Aknadinine
Hernandine
Methylhernandine
Hernandolinol
Hernandifoline
Hernandoline
3-0-Demethylhernandifoline
Protostephabyssine
S ephisoferuline
Prome taphanine
16-Oxoprometaphanine
Homostephanoline
Hasubanonine16-Oxohasubanonine
Miersine
Stephasunoline
S epham iersine
Epistephamiersine
Oxostephamiersine
Alrnadinine
Stephania japonica Miers Metaphanine
Stephania sasakii Hayata Aknadilactam
233
178-18186-18
196-198
229-23
186-1 8
140-15
221-22
156
7 0
197-19
152-15
114-11
227-22
19G19
148-14
196-19
133-13
232
207
115
233
116-11
161
222
233
165
98
290
2 0-21
-
" Constants for methiodide. Constants for hydrobromide.
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7. HASUBANAN ALKALOIDS 395
The numbering system of the hasubanan skeleton (1) (2,3,4,5-
tetrahydro-3a,9b-butano-l-benz[e]indole), which is used throughout
this review, is that proposed by Tomita et al. in their earlier paper ( 2 , 3 2 ) .
3
IH1
11. Occurrence and Physical Constants of the
Hasubanan Alkaloids
Table I gives a survey of the occurrence and physical constants of
hasubanan alkaloids.
III. Structure Elucidations
A . MASS SPECTROSCOPY
From the measurements of IR, UV, and NMR spectra, i t is difficult
to determine the hasubanan skeleton of unknown alkaloids. The mass
spectral feature, however, exhibits a very characteristic fragmentation
pattern and therefore provides a rapid and convenient method for
structure elucidation of hasubanan alkaloids, especially that of alka-
loids obtained in small amounts ( 3 ,5 , 1 3 , 1 6 , 4 0 ) .
1 . Hasubanan Derivatives Possessing No Oxygen Function at C Ring
In the mass spectra of 3,4-dimethoxy-N-methylhasubanan 2),
3-methoxy-4-hydroxy-N-methylhasubanan3), nd lO-oxo-3,4-dimeth-
oxy-N-methylhasubanan (4), the most abundant and diagnostic
peak appears at m/e M-56. The first rupture occurs in ring C to
furnish an ion, a or e . The additional loss of methyl or hydrogen from
the fragment ion a must give rise to ion b or c and the loss of a methoxylradical from the ion c produces ions d and/or d' . The fragmentation
pattern of these compounds is a primary breakdown path for all
hasubanan alkaloids ( 4 4 , 4 5 ) .
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396 YASUO INU BUSH I AND TOSHIRO IBUKA
O M e O M e
r J *
& 3
f NM e
;.19+ /
I I
M e
M e
2 R = M e a m/e 245 ( R = M e ) d m/e 2133 R = H M - 5 6
(?Me
+ /
O M e
M e M eb m/e 230 c m/e 244
& &_f + /
0
Iu:
t N
M e
Me
4 e m/E 259
SCHEME
O M e
IM e
d' rn/e 213
O M e
Me
e' m/e 259
2. Alkaloids Possessing a Hemiketal or .a Ketal Ether Linkage
between C-8-C-10: Metaphanine ( 5 ) and Stephamiersine (6)
The mass spectrum of metaphanine ( 5 ) (3, 20, 21, 4 4 ) exhibits themost abundant ion peak (aor a') a t m/e 245, which may arise from the
intermediatef by homolysis of the C-5-C-13 bond and the associatedhydrogen transfer from C - 5 or C-6 to C-10 or (2-13. The hydro,aen source
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398 YASUO INUBUSHI AND TOSHIRO IBUKA
derived from the intermediate f by the loss of hydrogen and the
associated C-5-C-13 bond fission (5 , 40, 44, 45 ). The cleavage mode
mentioned above is quite common for all metaphanine type alkaloidspossessing an ether linkage between c-8and C-10, and a ketone function
at (2-7. By contrast, the fragmentation of stephamiersine (6)and episte-
phamiersine (7)) which possess an ether linkage between C-8 and C-10
and a ketone function at C-6, produces the most abundant ion, i at
mle 243 rather than an ion a' a t m/e 245. This difference may be of
diagnostic significance, as it demonstrates the presence of a ketone
function a t C-6 in metaphanine type alkaloids (4U).
3. Alkaloids Possessing an +Unsaturated Ketone Group a t C Ring:
Iso-6-dehydrostephine (8) and Hasubanonine (129)
Alkaloids such as hasubanonine (129), possessing an a,/?-unsaturated
carbonyl group a t C ring, show a similar breakdown pathway as that of
metaphanine and others. An important feature of the spectra of these
alkaloids is that two intensive ion peaks are observed-one is an ion aor a' and the other is an io nj, which occurs by the loss of the ethanamine
chain from the molecule. In the case of isodehydrostephine (8)) the
most abundant ion peak, j , was found at mle 301 ( 6 ) .
0 1 +
IH
8
SCHEME
j mle 301
B. STRUCTURESF HASUBANANLKALOIDS
1. Stephisoferuline (9)
Stephisoferuline was isolated from Stephania hernandifolia, and thepresence of four methoxyl groups, one secondary amino group, an
a$-unsaturated ester moiety, and two phenolic hydroxyl groups was
shown (19).A new hasubanan ester-ketal structure (9) was assigned to
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7. HASUBANAN ALKALOIDS 399
stephisoferuline on the following evidence. Hydrolysis of stephiso-
feruline afforded stephuline (10) and isoferulic acid. The former gave
N-methylstephuline (11) on methylation, confirming the presence of asecondary amino group. Treatment of 10 with dilute hydrochloric acid
led to facile demethylation of acetalmethyl t o give 8-demethylstephuline
(12) and oxidation of 10 with Jones’ reagent provided 6-dehydro-
stephuline (13).On the other hand, acetylation of 10, followed by acid
treatment, resulted in the triacetyl derivative 14, and the downfield
shift of the signal for the C-7 H (6 4.20) of 14 in its NMR spectrum
compared with that of stephisoferuline (6 3 .75) supported the assignment
of the ketone function a t C-8. ydrogenation of the triacetyl derivative
14 furnished the dihydrotriacetyl derivative 15, which on treatmentwith acetone dimethylacetal in the presence of p-toluenesulfonic acid
afforded the rearrangement product 16.The compound 16 was identified
with the base derived from aknadicine (= 4-demethylnorhasubanonine)
(17) ( 1 0 , 1 1 ) as follows. Reduction of 17 with N R H gave the C-6
epimeric alcohols 18. Acetylation of 18 gave the products that were
converted to the triacetyl derivative 16 by letting their chloroform
solution stand. This chemical correlation established the planar structure
of stephisoferuline, the stereochemistry a t C-8, C-10, -13, nd C-14,
and the absolute configuration of the molecule. Since reduction of6-dehydrostephuline (13)with NBH gave stephuline (10)solely, and the
hydride attack from the a side of 13 was predictable from inspection of
the molecular model, th e /3 configuration of the C-6 hydroxyl group was
suggested. On the other hand, chemical, spectral, and crystallographic
examinations suggested the same configuration of five of the six asym-
metric centers of stephisoferuline (9) with those of stephavanine (19)
( 6 ) .From the biogenetic analogy, the /3 equatorial configuration of the
C-7methoxyl group of 9 was presumed ( 1 9 ) .
OMe
H
9
R210
11 R, = R, = M e
12
R, = Me, R, = H
R1 R, = H
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400 YASUO INUBUSHI AND TOSHIRO IBUKA
M e 0 k
HI
18
AC
14
Ac
15
AcO
\M e 0
M e 0 N M e 0 N
HI
HI
Ac
16 17 1s
2 . Stephavanine (19)
Stephavanine was isolated from Stephania abyssinica grown in
Eastern and Southern Africa, and the presence of one methylenedioxy,
two hydroxyl, one secondary amino, and two methoxyl groups in its
molecule was shown (6) .The mass spectrum of stephavanine revealed a
diagnostic fragment ion k for hasubanan alkaloids at m/e 2 1 4 (44 ,45 ) .Alkaline hydrolysis of stephavanine gave vanillic acid and stephine (20),
and the 6,7-bistrirnethylsilyl ether 21 was derived from the latter. The
NMR spectrum of 21 showed two unsplit aromatic proton signals,
indicating the methylenedioxy group attached to C-2 and C-3 of an
aromatic ring. Oxidation of 20 with Jones’ reagent provided 6-dehydro-
stephine (22), which on treatment with sodium hydroxide solution gave
isodehydrostephine (8). Of six chiral centers of 19, the relative con-
figurations of C-8, (2-10, C-13, and C-14 were inevitably established
because of the cage ring system of the stephavanine moIecuIe. The/%axial configuration of the C-6 hydroxyl, which forms an ester linkage
with vanillic acid, was deduced from the NMR spectral examination and
the /I-equatorial configuration of the C-7 hydroxyl group was suggested
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7. HASUBANAN ALKALOIDS 401
by the fact that oxidation of the diol20 provided selectively the mono-
ketone 22. Thus, the structure 19 was assigned to stephavanine ( 6 ) .
This conclusion was supported by X-ray crystallographic study ofstephavanine hydrobromide ( 6 ) .
M e 0
H O G
IH
19
?"\
"H
M e 0 N
IH
22
"H
RO
M e 0 N
IH
20 R = H
21 R = &(Me),
c/
H
k mle 214
3 . Stephabyssine (23), Stephaboline (24), and Prostephabyssine (25)
Examination of basic constituents of Stephania abyssinica. collected
in Ethiopia resulted in the isolation of three new phenolic hasubanan
alkaloids-stephabyssine, stephaboline, and prostephabyssine ( 5 ) .
Stephabyssine (23) had one N-methyl, one methoxyl, one saturated
ketone, and two hydroxyl groups. The presence of a phenolic hydroxyl
group with an unsubstituted para position was presumed by a positive
color reaction with Gibbs' reagent. Methylation of 23 with methyl
iodide in the presence of potassium carbonate provided O-methyl-stephabyssine, which was identified with metaphanine (5)
(4 ,20 -25 , 46 , 47 ) . Thus, the structure of stephabyssine was established
as 4-demethylmetaphanine (23).
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402 YASUO INUBUSHI AND TOSHIRO IBUKA
OM e OMe
"H HO "H. .HO N HO N
I I
0J 3 3 $ . H..HO
I
HO
I
M e
23 R = H
5 R = M e
Me
24
Stephaboline (24) was shown to possess one N-methyl, one methoxyl,and three hydroxyl groups ( 5 ) .The close relationship of stephaboline
with stephabyssine (23)was indicated by similarities in their NMR
spectra as well as positive reactions of each compound with ferric
chloride and the Gibbs reagent. Since NBH eduction of stephabyssine
gave stephaboline in a high yield, the structure of stephaboline was
established except for the configuration of the C-7 hydroxyl group. The
NMR pectrum of 24 exhibited a diffused multiplet a t S 4.4 assignable
to the C-7 H. This signal changed to a pair of doublets (JAx= 5 Hz,
J B X = 1 1 Hz)by treatment with D,O, and the magnitude of the couplingconstant of J B X suggested the axial configuration of the C-7 H, hus
confirming the equatorial configuration of the C-7 hydroxyl group (5).When treated with aqueous hydrochloric acid solution under mild con-
ditions, prostephabyssine (25) gave stephabyssine (23)with loss of the
elements of methanol in high yield. This facile hydrolysis demonstrated
the presence of an enol methyl ether located at C-6-(2-7. Consequently,
the structure 25 was assigned to prostephabyssine. Determination of the
NMR pectra of prostephabyssine in a variety of solvents gave complex
patterns indicative of the presence of the hemiketal25a and ketone 25bforms in equilibria similar to the solvent-dependent equilibria observed
in prometaphanine (26,27).
?Me ?Me
OH
HO N
I IMe Me
258 25 25bSCHEME
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7. HASUBANAN ALKALOIDS 403
4. Stephamiersine (6), Epistephamiersine (7), Oxostephamiersine (26),
and Stephasunoline (28)
Reinvestigations of basic constituents of Stephania japonica grown
in Kagoshima Prefecture (the sourthern part of Japan) resulted in
isolations of four new hasubanan alkaloids: stephamiersine, epistepha-
miersine, oxostephamiersine, and stephasunoline (4 0 ,41). That the
structures of these alkaloids were closely related to each other was
presumed on the basis of their spectral data which are summarized in
Table I1 and Table 111.
TABLE I1
PHYSICALONSTANTS ND SPECTRALATA F SOMEALKALOIDSFROM Stephania japonica Miers
mp [aID IR Y : W EtoHsx MS m l e ) M+,
A1kaloid ("C) (CHCl,) (cm-') (nm) ( 6 ) base peak
Stephamiersine (6) 165 +33 1725 286 2200 389,243
Epistephamiersine (7 ) 98 +64.1 1735 286 2300 389,243
Oxostephamiersine 26) 290 +88.3 1730, 1680 286 2000 403,257
Stephasunoline (28) 233 $121.4 3550 286 2000 377,245
TABLE I11
NMR SIGNALSF SOME LKALOIDSROM Stephania japonica Miers4
Aromatic
protons N-Methyl
Alkaloid (2H) C-7-H C-10-H Methoxyl groups group
6 6.67 3.52 4.72 3.92, 3.82, 3.34, 3.31 2.64
7 6.66 4.27 4.82 3.89, 3.76, 3.52, 3.45 2.63
26 6.77 3.63 4.79 3.92, 3.83, 3.33, 3.29 3.1228 6.67 3.62 4.88 3.90, 3.82, 3.46 2.57
O Chemical shifts are quoted in 6 values.
Equilibrium experiments of either stephamiersine (6)or epistephamier-
sine (7) with 1yosodium hydroxide solution gave an equilibrium mixture
consisting of 6 and 7 in a 1:3 ratio. Consequently, 6 and 7 were epimers
attributable to an asymmetric center adjacent to a carbonyl group, and
7 was thermodynamically more stable. Furthermore, permanganate
oxidation of stephamiersine (6) gave the lactam, which was identifiedwith oxostephamiersine (26). Reduction of epistephamiersine (7) with
NBH provided dihydroepistephamiersine (27),* which on treatment
J. von Wyk.* Later. this compound waa obtained in nature from Stephuniu abyssinica by Dr. A.
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404 YASUO INUBUSHI AND TOSHIRO IBUKA
with methanolic hydrochloric acid solution under mild conditions gave
stephasunoline (28).This facile hydrolysis of dihydroepistephamiersine
suggested the presence of the labile acetal methyl ether in its molecule.Thus, the chemical correlations among6,7,26,and 28 were established.
Acetolysis of stephamiersine (6) and epistephamiersine (7) provided
1,3-diacetoxy-2,5,6-trimethoxyphenanthrene29) and 1,2,3-triacetoxy-
5,6-dimethoxyphenanthrene 30), respectively. On the other hand,
acetolysis of dihydroepistephamiersine (27)gave the known 1 acetoxy-
2,5,6-trimethoxyphenanthrene (31) (26,27). On the occasion of
acetolysis of morphinan and hasubanan series alkaloids,it is well known
that a ketone function in the original molecule remains an acetoxyl
group on the phenanthrene nucleus, and an alcoholic hydroxyl group isremoved by dehydration in the course of the aromatization process
( 2 0 , 2 1 , 2 6 , 2 7 , 1 , 4 8 , 4 9 ) .From the structures of these phenanthrene
derivatives derived from 6 ,7 ,and 27, the positions of five of six oxygen
functions were confirmed, and particularly, the C-3, C-4, and C-7
positions of three of four methoxyl groups and the C-6 position for an
oxygen function in the original alkaloid molecule were established.
In the NMR spectra of 6 , 7 , and 28, a signal due to C-10 H appeared
around 6 4.8 (doublet, J = 6.5 Hz). In the spectrum of 7, the NOE
[I3y0enchancement of the signal of this doublet ( 6 4.82)] was observedwhen irradiated a t the aromatic proton signal. The signals a t 6 1.47
(doublet,J = 10.5 Hz) and 6 2.46 (double doublet,J = 10.5 and 6.5 Hz)
were assigned to the C-9 methylene protons by the double resonance
technique. From these assignments, it is obvious that an acetal ether
linkage attaches to C-10.
NBH reduction of oxostephamiersine (26) provided compound 33,
which on treatment with perchloric acid-acetic anhydride gave com-
pound 34. Oxoepistephamiersine (32) derived from epistephamiersine
(7) by permanganate oxidation was reduced with NBH to give com-
pound 35, which on treatment with perchloric acid-acetic anhydride
also afforded compound 34. Catalytic hydrogenation of 34 provided the
conjugated ketone 36. On the other hand, NBH reduction of 16-
oxohasubanonine (37) (28,38) gave epimeric alcohols (38), which on
treatment with dilute mineral acid gave the same conjugated ketone
36. From these results, the skeletal structure and the attached positions
of oxygen functions, C-6, C-7, C-8, and C-10 of oxostephamiersine (26)
were established.
The configurations of the C-7 OCH, group of these alkaloids were
deduced from the NMR spectral experiments. In the spectrum of
stephamiersine (6), signals due to the C-5 methylene protons were
observed at 6 2.86 ( l H , double doublet, J = 11.5, 1.5 Hz) and 6 3.67
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7 . HASUBANAN ALKALOIDS 405
( l H , doublet, J = 11.5 Hz). The long-range coupling between the C-7
H and one of two C-5 methylene protons ( 6 2.86) was observed by the
homonuclear INDOR technique. On the other hand, the spectrum ofepistephamiersine (7)evealed signals assignable to the C-5 methylene
protons a t 6 2.99 (IH, doublet, J = 11.5 Hz) and 6 3.18 ( IH, doublet,
J = 11.5 Hz) and the NOE (6.5y0 nhancement) of the C-7 H signal
was observed when irradiated the signal a t 6 3.18 but no signal enhance-
ment was observed between the C-7 H and the signal at 6 2.99. From
these findings, together with the equilibrium experiments previously
discussed, the configuration of the C-7 OCH, was established to be a-
axial in 6 and p-equatorial in 7.The configurations of C-6 O H and
C-7 OCH, of stephasunoline (28) were also deduced from the NMRspectral examinations. The spectrum of stephasunoline exhibited signals
assignable to the C-5 methylene protons a t 6 2.46 ( IH, double doublet,
J = 14.3, 2.4 Hz) and 6 2.82 ( lH , double doublet, J = 14.3, 3.8 Hz).
When irradiated at the signal appearing at 6 2.46, the NOE (120J,
enhancement) of the C-7 H signal (6 3.62, doublet, J = 3.9 Hz) was
observed. This result, together with analysis of coupling constant values
of the signals for four protons attached t o C-5, c-6, and C-7, led to the
conclusion that the C-7 OCH, group should be p-equatorial and the
C-6 OH p-axial. Thus, the structure 28 was assigned to stephasunoline
( 4 0 , 4 1 ) .The planar structure of stephasunoline (28) is the same as that
proposed for miersine (39) ut the stereochemistry of C-6 OH and
C-7 OCH, of the lat ter has not been established (1,39).
5 . 16-Oxohasubanonine(37)
This alkaloid was isolated from Stephania japonica and identified
with 16-0xohasubanonine, which had been derived from hasubanonine
by permanganate oxidation (28, 38) .
6. 16-Oxoprometaphanine (40)
This alkaloid was isolated from Stephaniajaponica (28) .On hydrolysis
with dilute mineral acid 16-oxoprometaphanine gave known oxo-
metaphanine (41) (50, 51) and compound 34, which had been derived
from stephamiersine (6)and epistephamiersine (7 ) 4 0 , 4 1 ) . Acetylation
of 16-oxoprometaphanine gave acetyl-16-oxoprometaphanine (42),
which on treatment with dilute hydrochloric acid afforded compound
34. These chemical correlations and the NMR spectral examinations of
16-oxoprometaphacine and its transformation products supported the
structure 40 for 16-oxoprometaphanine (28).
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On-
4 i
0
+ ;b Ot? O
?
2
30a
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408 YASUO I NUB USHI AND TOSHIRO IBUKA
?Me ?Me
M e 0
IMe
40s 40
SCHEME
IMe
40b
@ &* .H M e 0 OAc
. .HO Fi ‘ 0 O N ‘0
I
M e
I
Me41 42
7. Delavaine (43)
Delavaine was isolated from Stephania delavayi (8) and its IR
spectrum exhibited bands at 1670 cm- (cr,p-unsaturated ketone) and
1608 cm-l (C=C double bond) (8).Hydrolysis of the methylenedioxy
group of delavaine with sulfuric acid and phloroglucinol gave the corre-
sponding dihydroxy derivative 46, which on acetylation afforded thediacetyl derivative 47. The IR absorption of the ester carbonyl (1775-
1780 cm-l) in 47 showed the phenolic nature of the hydroxyls, from
which it follows that the methylenedioxy group is attached to an
aromatic ring. On the other hand, the NMR spectrum of delavaine
exhibited two unsplit aromatic proton signals a t 6 6.41 and 6 6.64.
Consequently, it is obvious that the methylenedioxy group is at the
C-2 and C-3 position of the aromatic ring. The Hofmann degradation of
delavaine methiodide formed the methine base 44,which on acetolysis
furnished the acetoxy-methoxy-phenanthrene derivative 45 (8),suggesting that delavaine belongs to the hasubanan alkaloids. In the
NMR spectrum of delavaine, signals were present for N-methyl (6 2.49)
and methoxyl(6 4.06 and 6 3.60) groups, and the C-5 methylene proton
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7 . HASUBANAN ALKALOIDS 409
0 1
IMe
43
M e 0
M e 0& M e 0/ \
Me Me
4 4
45M e
46 R = H47 R = Ac
signals appeared a t 6 2.46 (doublet, J = 16 Hz) and 6 3.00 (doublet,
J = 16Hz). However, no C-9 H signal of the morphinan skeleton
between 6 3.00 and 6 4.00 (52-55) was observed, thus demonstrating
the hasubanan skeleton for delavaine. Consequently, structure 43 was
proposed for delavaine ( 8 ) , but no positive evidence regarding the
stereochemistry of the ethanamine bridge is presented.
8. 16-Oxodelavaine(48)
16-Oxodelavaine was isolated from Stephunia delavayi grown in
Transcaucasia ( 9 ) .The UV spectrum of this alkaloid was similar to that
of delavaine (8), and the IR spectrum showed bands for an a,/?-
unsaturated ketone (1686 cm-') and a lactam carbonyl (1670 cm-l)
function. In the NMR spectrum, signals were present for two isolatedaromatic protons ( S 6.64, 1H, singlet and S 6.46, 1H, singlet), methylene-
dioxy ( 6 5.88, 2H, singlet), two methoxyl ( 6 4.10 and 3.66 each 3H and
singlet), and an N-methyl (6 2.96, 3H, singlet) groups, and the c-5
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410 YASUO INUBUSHI AND TOSHIRO IBUKA
methylene protons (6 2.90, lH, doublet, J = 16 Hz and 6 2.66, lH,
doublet, J = 16 Hz). After various chemical, physicochemical, and
spectral investigations, the structure 48 was proposed for16-oxodelavaine (9).
M e
48
9. Hernandifoline (49)
Hernandifoline was isolated from Stephania hernandifolia grown in t h e
Black Sea littoral of Caucasia ( 1 6 ) .The presence of four methoxyl, onesecondary amino, two hydroxyl, and one a,p-unsaturated ester groups
was shown. Methylation of hernandifoline (49) with methyl iodide
afforded A'-methylhernandifoline (50), and alkaline hydrolysis of 49
gave a base (51) and hesperetic acid. The NMR spectrum of 51 revealed
signals for two aromatic protons (6 6.49, 2H, singlet), C-10 H (6 4.76,
doublet, J = 5.8 Hz) , C-6 H (6 4.07, multiplet), C-7 H ( 6 3.62, doublet,
J = 4.0 Hz), C-3 OCH, (6 3.67, singlet), C-8 OCH, ( 6 3.50, singlet),
C-7 OCH, (6 3.38, singlet), C-5 methylene protons (6 3.04, 1H, quartet ,
J = 14.9, 3.5 Hz and 6 1.85, 1H, quartet , J = 14.9, 2.8 Hz), C-6 OH(6 2.13, l H , double t,J = 10.0 Hz), C-9 methylene protons (6 2.34, 1H,
quartet, J = 10.8, 5.8 Hz and 6 1.80, lH, doublet, J = 10.8 Hz). The
mass spectrum of 51 showed the pattern characteristic for the hasuba-
nan alkaloids (44 ) ,m/e 363 ( M + ) ,217, and 216. Methylation of 51 with
methyl iodide in methanol gave substance52and the further methylation
of 52 with diazomethane gave compound 53. Following spectral investi-
gations of the alkaloid and its degradative compounds, the structure of
hernandifoline except the configuration at the C-7 OCH, group was
proposed as 49 (16).This structure is the same as that proposed forstephisoferuline (9) ( 1 9 ) ,except for the configuration of the C-7 OCH,
group. The reported melting points of hernandifoline (49) (227-227.5"C),
the compound (51) (225-226"C), and the compound (52) (154-155°C)
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7. HASUBANAN ALKALOIDS 411
HO
M00Q7=~Lo@\ Ho&
* .H.H
. . M e 0 . :
IR2
M e 0
* .M e 0 N
R
M e 0 kI
49 R = H
50 R = M e51
52
53
R, = R, = H
R, = H, R, = M e
R, = R, = M e
differ from those of stephisoferuline (9) (133-135OC), stephuline (10)
(223-225°C)) and N-methylstephuline (11) (126-128%), but there has
been no report of direct comparisons of these alkaloids.
10. 3-0-Demethylhernandifoline (54)
3-0-Demethylhernandifoline was isolated from Stephania hernandi-folia,and the presence of three hydroxyls, one secondary amino, and
three methoxyl groups was shown ( 1 8 ) . The IR spectrum exhibitedbands for OH and NH a t 3560, 3440, and 3200-2700 cm-l, a carbonyl
group at 1695 crn-l, and a conjugated double bond a t 1640 cm-l. In
the NMR spectrum signals were present for three methoxyls (6 3.89,
3.41, and 3.40), ortho-coupled aromatic protons (6 6.50, lH, doublet,
J = 8.0 Hz and 6 6.60, 1H, doublet, J = 8.0 Hz), the C-5 methylene
protons (6 2.02, lH, double doublet, J = 15.0, 2.3 Hz and 6 3.17,1H,
double doublet, J = 15.0, 4.1 Hz), C-6 H (6 5.40, lH, multiplet), C-7 H(6 3.74), and C-10 H (6 4.88, l H , doublet, J = 5.8 Hz) .
On alkaline hydrolysis, 3-0-demethylhernandifoline gave hesperetic
acid and an amine (55))which gave an intense color reaction with ferric
IH
54
IH
55
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412 YASUO INUBUSHI AND TOSHIRO IBUKA
chloride characteristic for o-phenols. Methylation of 55 with methyl
iodide, followed by treatment with diazomethane, furnished the
N,O,O-trimethyl derivative, which was identical with compound 53 ( 1 6 )derived from hernandifoline. From these chemical correlations, structure
54 was proposed for 3-0-demethylhernandifoline.
11 . Hernandine ( 5 6 )
Hernandine was isolated from Xtephania hernandifolia, and the pres-
ence of one N-methyl, two methoxyl, and three hydroxyl groups was
suggested ( 1 3 ) .The mass spectrum of this alkaloid revealed a character-
istic fragment ion peak for hasubanan alkaloids a t m/e 231 (13 , 44 , 45).The NMR spectrum of hernandine showed signals for C-10 H (8 4232,
OMeI
. :/J
R20 N
M e
56
I
R, = H, R, = M e
R, = Me, Ra = Hr
1H, doublet, J = 6.2 Hz), C-9 methylene protons (8 1.51, lH, doublet,
J = 10.8 Hz and S 2 . 8 5 , 1H, double doublet, J = 10.8, 6.2 Hz), C-6 H
( 6 4.15, lH, multiplet), C-7 H (8 3.58, lH, doublet, J = 3.8 Hz) , and
C-5 methylene protons (6 3.09, lH, double doublet, J = 14.6, 3.5 Hz
and 6 1.95, l H , double doublet, J = 14.6, 2.4 Hz) . The axial con-
figuration of C-6 OH was determined from the values of th e spin-spin
coupling between the C-5 methylene protons and c-6 H . From these
results, st ructure 56 was proposed for hernandine ( 1 3 ) ,but the absolute
configuration of the ethanamine bridge, the configuration of the C-7
oxygen function, and the position of one of two methoxyl groups have
not been definitely established.
12. Methylhernandine (57 )
Methylhernandine was isolated from Steph ania hernandifolia, and the
presence of one N-methyl, two hydroxyl, and three methoxyl groups
was suggested ( 1 4 ) . On acetylation, methylhernandine gave diacetyl-
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7 . HASUBANAN ALKALOIDS 413
methylhernandine, the IR spectrum of which showed carbonyl bands
a t 1775 and 1730 cm-l, indicating that one of two hydroxyl groups is
phenolic and the other alcoholic. In the NMR spectrum of methylhern-andine, signals were present for C-5methylene protons (S 1.93,lH, double
doublet, J = 14.8, 2.9 H z and 6 3.00, lH, double doublet, J = 14.8,
: : /M e 0 N
M e
57
3.4 H z ) , C-6 H ( 6 4.05, H, multiplet), C-6 O H (6 2.24, doublet, J =
9.8 H z ) , C-7 H (6 3.62, lH, doublet, J = 4.1 Hz), C-10 H (6 4.81, lH ,
doublet, J = 6.2 H z ) , and C-9 methylene protons ( 6 1.45,1H, doublet,
J = 10.8 Hz and 6 2.63, l H , double doublet, J = 10.8, 6.2 Hz). Since
methylhernandine was identified with compound 52 ( 1 6 )derived fromhernandifoline (49) ( 1 6 ) , structure 57 was proposed for methyl-
hernandine ( 1 4 ) .
13. Hernandolinol (58)
Hernandolinol was isolated from Stephunia hernandifolia grown in
Caucasia, and the presence of one N-methyl, three methoxyl, and two
hydroxyl groups was suggested. On Hofmann degradation, hernandol-
in01 gave the methine base (mp l14-115°C), which on acetolysisafforded the diacetoxydimethoxyphenanthrene derivative (mp 163-
164OC) ( 1 5 ) . This methine base and phenanthrene derivative were
OMe
Me
58
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414 YASUO INUBUSHI AND TOSHIRO IBUKA
identified with the methine base and phenanthrene derivative derived
from hernandoline, respectively (I? ),and hernandolinol was proved to
be identical with the reduction product of hernandoline with sodiumborohydride. Thus, structure 58, without stereochemical implications,
was proposed for hernandolinol (15 ) .
IV. Synthesisof the Hasubanan Skeleton
The synthesis of the hasubanan skeleton has been undertaken in
several laboratories with a remarkable degree of variability in thesynthetic schemes.
A. STNTHESISIA KETOLACTONES
Annelation reaction of the ketoester 59 with methyl vinyl ketone
provided the ketolactone 60. Three methods available for introduction
of the nitrogen atom into this ketolactone have been reported. The first
method was reported by Inubushi et al. Treatment of the ketal lactone61 from the ketolactone 60 with methylamine in the presence of methyl-
amine hydrochloride gave the ketolactam 63 and the ketal amide 68
(56-58). Similarly, the ketoester 64 rovided the ketal lactone 66 and the
ketolactam 67 via the ketolactone 65. The second method was developed
by Evans et al. Reaction of the ketolactone 60 with methyl iodide in the
presence of potassium carbonate gave the unsaturated ketoester 62,
which on treatment with LAH-methylamine furnished the ketolactam
63 ( 5 9 , 6 0 ) .The last method was reported by Tahk et al. Reaction of the
ketal lactone 61 with a large excess of methylamine gave the ketal amide68, which was reduced with LAH to give the amino alcohol 69, acid
R R R
59 R = H 60 R = H64 R = OMe 65 R = OMe
61 R = H66 R = OMe
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7. HASUBANAN ALKALOIDS 415
62
M e
63 R = H
67 R = OM e
IMe
68 R = O69 R = Hz
IMe
70
treatment of which afforded 7-0x0-N-methylhasubanan (70) ( 6 1 ,6 2 ) .The main disadvantage of these three methods was the low yield in the
nitrogen introduction step.
B. SYNTHESISIA KETONITRILES
This procedure consists in the Robinson annelation reaction of the
ketonitrile (71 or 72) with methyl vinyl ketone. Treatment of the
ketonitrile 71 with methyl vinyl ketone provided the separable stereo-
isomeric mixture 73.Treatment of the mixture with sodium alkoxide
NC
4Nc8H
&%
Mo OH IH
71 R = H 73 R = H
72 R = O M e 74 R = O M e
75 R = H
76 R = OMe
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416 YASUO INUBUSHI AND TOSHIRO IBUKA
gave the ketolactam 75. Similarly, the ketonitrile 72gave the ketolactam
76 (57, 5 8 ) . This procedure is of practical value because of acceptable
yields and simpler operations compared with the former methods.
C. SYNTHESISIA CYCLICENAMINES
1. Stork-Robinson Annelation Reaction
Synthesis of the key intermediate, the cyclic enamine 79, is analogous
to that of 3-arylpyrroline in the mesembrine synthesis (63-65) . Three
methods available for synthesis of this intermediate have been developed.
Reaction of /3-tertralone (77)with 1,2-dibrornoethane gave the
spiroketone 78, which on treatment with methylamine furnished the
cyclic enamine 79 ( 6 1 ) .On the other hand, ketalization of the ketoester
77 R = H 78
59 R = CH,CO,Et
80
M e
79
Me
81
59, followed by treatment with LAH-methylamine, afforded the ketal
amide 80. Successive treatments of 80 with LAH and aqueous acid
solution provided the cyclic enamine 79 (59, 60). Further, reaction of
p-tetralone (77) with excess methylamine, followed by treatment with
titanium tetrachloride, yielded the enamine 81. When reacted with iso-
propylmagnesium chloride, this enamine gave the "bidentate" nucleo-
phile which on treatment with bromochloroethane gave the cyclicenamine 79 (60). The cyclic enamine 79 thus synthesized was reacted
with methyl vinyl ketone to yield 7-oxo-N-methylhasubanan (70) in a
moderate yield (60-62).
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7. HASUBANAN ALKALOIDS 417
2 . [4 + 21 Cycloaddition and [2,3] Sigmatropic Rearrangement
A unique and elegant synthesis of hasubanan derivatives was re-
ported by Evans e t al. (66).Upon heating equimolar quantities of the
sulfoxide 82 with the cyclic enamine 79, diastereoisomer mixture of
the sulfoxide 83 as well as some rearrangement amino alcohol 84 was
obtained, indicating that [4 + 21 cycloaddition and [2,3] sigmatropic
rearrangement were occurring consecutively. When heated with sodium
sulfite, the unpurified reaction product from 79 and 82 afforded the
<82 R = S-CSH,
J.0
85 R = C 0 ,Me
. .C,H,-S N
10 Me
83
M e84
M e86
desired amino alcohol 84. The evidence th at 84 is a single isomer rather
than an epimeric mixture was derived from its behavior on tlc, its
cleanly resolved NMR spectrum, and the sharp melting range of the
amine salt. The syn relationship between hydroxyl and nitrogen func-
tion was deduced from the observance of intramolecular hydrogen
bonding in the IR spectrum. Similarly, addition of methyl pentadienoate
to the cyclic enamine 79was also found to afford the nicely crystallinetetracyclic ester 86 in 50% yield. Qualitatively, it appeared that the
sulfoxide-substituted diene 82 was slightly less reactive than the ester-
substituted diene 85 (66) .
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418 YASUO INUBUSHI AND TOSHIRO IBUKA
D. SYNTHESISIA SPIROKETONE
Another synthetic route for hasubanan derivatives was devised re-cently by the Bristol-Myers group. Alkylation of 7-methoxytetralone
(87)with 1,4-dibromobutane n the presence of sodium hydride gave the
87
OMeI
91
88 89 R = CN90 R = CH2NH,
OMe
(-yg. Br
IH
92
spiroketone 88, which was transformed into the hydroxynitrile 89 by
treatment with acetonitrile in the presence of n-butyllithium. LAH
reduction of 89 furnished the amine 90, which on treatment with con-
centrated hydrochloric acid gave the amine 91. Treatment of 91 with
one equivalent of bromine yielded 3-methoxy-9-bromohasubanan92)
in good yield (67, 74 ) .
A new synthetic method of dl-3-methoxy-N-methylhasubananas
been explored recently (75). Treatment of 91 with formalin in formicacid afforded dl-9,10-dehydro-3-methoxy-N-methylhasubanan,hich
was derived into dl-3-methoxy-N-methylhasubanan y catalytic
hydrogenation (75).
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7 . HASUBANAN ALKALOIDS 419
E. SYNTHESISY PHENOLXIDATION
Treatment of reticuline (93) with trifluoroacetic anhydride, followedby catalytic hydrogenation yielded the amide 94. Treatment of 94 with
vanadium oxytrichloride gave rise, by phenol oxidation, to the dienone
95, which was transformed into the enone96 by treatment with aqueous
potassium carbonate solution. When reacted with methanolic hydro-
chloric acid, the enone 96 provided the cepharamine analog 97 (68).
O M e
HO
M e 0 )y93
M e 0 ,M e 'COCF3
Md3(3Ho / , /
M e 0u
94 95
O M e O M e
I
M e96
IM e
97
V. SynthesisofHasubanan Alkaloids
The syntheses of hasubanan alkaloids are of interest in connection
with their pharmacological activities, since these alkaloids involve the
structural unit of prafadol (98) (69) ,which is used as a potent analgesic.
Hasubanan alkaloids are classified into three groups-the cepharamine,
hasubanonine, and metaphanine types-on the basis of the oxidationstage at the B and C rings. The representative of each group has been
synthesized from the common intermediate, the ketolactam 67, with an
exception of one of two cepharamine syntheses.
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7. HASUBANAN ALKALOIDS 421
OMe OMe OMe
Me
106
Me
107
IMe
108
Another synthetic route to cepharamine utilizing photocyclizationwas designed. Heating of 2’-bromoreticuline (109) with trifluoroacetic
anhydride, followed by catalytic hydrogenation, provided the dihydro-
methine 110. Irradiation of 110 with a mercury lamp in the presence of
sodium hydroxide and sodium iodide gave the dienone 111. Hydrolysis
of the amide function of 111 caused the Michael addition to yield an
isomer of cepharamine. Transesterification of 112with hydrochloric acid
in methanol provided a mixture of cepharamine (108)and the starting
material 112, from which cepharamine was isolated in a pure state (7 1 ) .
M e 0
HO
H o d
M e 0109
?Me
M e 0
ICOCF,
111
HO
yJJM e 0
110
M e 0&I
M e
112
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422 YASUO INU BUSH I AND TOSHIRO IBUKA
B. HASUBANONINEND AKNADILACTAM
In the synthesis of hasubanonine (129) from the ketolactam 67,introduction of two more oxygen functions at the C-6 and C-8 positions
are required. Oxidation of the ketolactam 67 with lead tetraacetate in
the presence of boron trifluoride etherate gave three acetates-l13,114,
and 115. In order to avoid the production of the undesired acetates 114
and 115, a lowering of the electron density of an aromatic ring was
preferable. Thus, similar oxidation of the ketolactam 104 possessing an
acetoxy group a t C-4 with lead tetraacetate was tried, and the acetoxy-
ketone 116was solely obtained in 65% yield. Treatment of 116with two
equimoIar quantities of bromine, followed by heating with sodiumacetate, provided the enol acetate 117 and the bromoacetate 118 in a
1 O : l ratio, but the yield of 117 was rather poor. However, the acetoxy-
ketone 116 was brominated with pyridinium hydrobromide perbromide,
and the reaction product 119 was heated with sodium acetate to give
solely the enol acetate 117. Partial hydrolysis of the enol acetate func-
tion of 117 provided the a-diketone 120, which was brominated to give
@\ o& o&A(
N/-0. .H . f
\O- .
R N \O AcO N
I I I
Me
67 R = H
113 R = OAc
Me
114
Me
115
R O RO. .R N
I IMeMe
104 R = H 117 R = AC 118 R = AC
116 R = OAc 120 R = H 121 R = H
122 R = Me
M e
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7 . HASUBANAN ALKALOIDS 423
O MeM eM e
Br\
&0 . :
0
M e 0
Br
M e 0. :fro
AcO NI I
M eI
M ee
1 1 9 1 2 3 1 2 4
OMe OM0 ?Me
0
M e 0
M e 0
M e 0
IM eMe
IM e
1 2 925 R = M e
127 R = H
126 R = M e1 2 8 R = H
the bromoketone 121 in high yield. Methylation of 121 with diazo-
methane furnished compound 122, which was heated in an aqueous
sulfuric acid according to the Hesse’s procedure to produce pre-dominantly the p-diketone 123 together with the compound 124. The
p-diketone 123 was methylated with diazomethane, and silica gel
chromatographic separation gave 16-oxohasubanonine (125) and its
isomer (126) from the earlier eluate in a 1:1 ratio, and continued elution
provided aknadilactam (127) and its isomer (128) in a 1 1 ratio. On the
other hand, permanganate oxidation of hasubanonine produced optically
active 16-oxohasubanonine (28,38),a sample of which was proved to be
identical with th at of the synthetic one (125)except in optical rotation.
Since LAH reduction of 16-oxohasubanonine followed by oxidationwith activated manganese dioxide regenerated hasubanonine, the syn-
thesis of 16-oxohasubanonine is equivalent to the complete synthesis of
hasubanonine (129) (38, 72).
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424 YASUO INUBUSHI AND TOSHIRO IBUKA
C. METAPHANINE
The ketolactam 67 was also chosen as the starting material for themetaphanine synthesis. Since the introduction of an oxygen function
at the C-S position of 67 had been established during the synthesis of
hasubanonine, the major problems are the stereoselective introduction
of the C-10 hydroxyl group trans to the ethanamine bridge and the
selective reduction of the lactam carbonyl group when both the lactam
carbonyl and the hemiketal ring are present. Oxidation of 100 and 130with chromic anhydride-acetic acid gave lo-0x0 compounds 131 and
132, espectively, but the yields were rather poor and irregular. The
synthetic intermediate that had been utilized for the hasubanoninesynthesis was converted to its ketal derivative 133.Chromic anhydride
oxidation of 133 provided the 10-0x0 ketal lactam 134 in high yield.
Hydrolysis of the acetoxyl groups of 134, ollowed by methylation with
diazomethane, produced 10-0x0 compound 135.For the purpose of the
hemiketal formation between C-8 and C-10, the relative configuration of
the hydroxyl group derived from C-10 0x0 group must be trans to the
ethanamine bridge. (The terms “cis” and “trans” in this section are
H
Me Me Me
100 R = H, 130 R = H, 133 R = H,131 R = 0 132 R = 0 134 R = 0
“OR
M e Me Me
135 136 R = H 137
143 R = Ac
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7 . HASUBANAN ALKALOIDS
O M e O M e
425
OMo
M e
138 R = H
139 R = AC
140 R = THP
M e
141 R = Ao
142 R = THP
IM e
144
used to express the relative configuration of the C-10 hydroxyl group to
the ethanamine bridge.) Reduction of 135 with various metal hydrides
was tried, but the major product was the undesired cis C-10 hydroxyl
compound 136, although the cis-trans ratio varied depending on sol-
vents and metal hydrides used. Catalytic hydrogenation of the C-10
0x0 compounds 135 and 137was unfruitful. Next, reduction of 135 with
sodium in various alcohols was examined, and in this case, the yield of
the trans isomer was superior to that of the cis isomer. However, thetotal yield was rather poor. Finally, reduction of 135 was successfully
carred out by the Meerwein-Varley procedure to give the trans C-10
hydroxyl compound 138 in an excellent yield. After the hydroxyl
group at C-10 of 138 was protected as an acetoxyl group or a pyranyl
ether group, the acetate 139 or the pyranyl ether 140 was oxidized to
produce the C-8 0x0 compound 141 or 142, Removal of the protected
group afforded 16-oxometaphanine.
Jones’ oxidation of the cis C-10 acetoxyl compound 143 gave the
ketoacetate 144, which on treatment with aqueous sodium carbonatesolution produced the C-10 0x0 compound 135.This rearrangement was
assumed to be caused by an intramolecular 1,4 hydride shift from C-10
to C-S of compound 144. In order to demonstrate this mechanism, 135
was converted to the deuterated c is C-10 hydroxyl compound 145,
which gave the deuterated cis C-10 acetate 146 by acetylation. Jones’
oxidation of 146 gave the C-S 0x0 compound 147, which on treatment
with aqueous sodium carbonate solution produced quantitatively the
C-10 0x0 compound possessing deuterium a t C-S with the ,l3 configura-
tion, as indicated by the mechanism shown in 148.Thus, validity of the1,4-hydride shift was verified, and the stereochemistry of the C-10
oxygen functions, which was based on the NMR spectral analyses, was
chemically established.
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426 YASUO INUBUSHI AND TOSHIRO IBUKA
OR
M eI
Me Me
147 14845 R = H
146 R = Ac
"H OTHP
M e Me Me
149 150 R = 0 151155 R = S
. H
HO N
Me Me
156 157
IMe
152 Rl = <:I, R, = 0
153 Rl = 0, R, = S
154 1, 0, R, = H,
The last step of this synthesis was reduction of the lactam carbonyl
group of 150. Since this compound possesses a masked carbonyl group,
the protection of the C-8 hemiketal hydroxyl group was examined, bu tall trials were unfruitful. Reduction of the pyranyl ether 142 with LAHand then oxidation of the resulting amine 151did not lead to the desired
(2-8 0x0 compound. Furthermore, Raney nickel reduction of the thio-
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7. HASUBANAN ALKALOIDS 427
lactam 153 derived from the ketal lactam 152 gave the amino ketone
154, whereas a similar reduction of the thiolactam 155 derived from the
compound 150 did not give the corresponding amino ketal. Finally, thelactam carbonyl group of 150 was converted to the imino ether by
treatment with th e Meerwein reagent, and reduction of this imino ether
with NBH resulted in the amino ketal 156. Finally, hydrolysis of the
ketal function provided metaphanine (157) (50, 5 1 ) .
VI. Biosynthesis
Although the biosynthesis of the hasubanan alkaloids has not beenfully established, hasubanonine (158) and protostephanine (159) have
been shown by tracer experiments to be biosynthesized from two
different C-6-C-2 units (73).The nature of the building block of 158 and 159 was examined by
feeding (2RS)-[2-14C]tyrosine (160), (2RS)-[2-14C]dopa (161), [2-14C]-
tyramine (162),and [2-14C]dopamine 163) to Stephaniajaponica plants.
The results from these experiments showed that (a) both alkaloids are
built from two different C,-C, units derivable from tyrosine; (b) one
unit is a phenethylamine formed from both tyramine (162)and dopamine(163), and it generates ring C with i ts attached ethanamine residue for
both natural products; and (c) dopa (161) affords only this same
phenethylamine unit.
OMe
IMe
158
OMe
@ e
MeO" OMe
159 160 R = H161 R = OH
162 R = H
163 R = O H
H O R2
166 R, = OH, Rz = OMe64 R = OH
165 R = O M e 167 R1= OMe, F22 = OH
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428 YASUO INGRUSHI AND TOSHIRO IBUKA
168
R = H or OMe HoDc‘
169
R = OH or OBIe
Four I*C-labeled amines (164-167) and the putative isoquinoline
intermediates were synt,hesized and tested in Stephania japonica plants.
None of the isoquinolines was incorporated, but the amines 164 and
165 acted as precursors of 158 and 159. Degradation of hasubanonine
proved th at the trioxygenated C,-C, unit had been built specifically
to form ring C and its ethanamine side chain. These findings show thatthe biosynthesis of hasubanonine (158) and protostephanine (159) in
Xtephania japonica involves the first of the two alternatives above, and
rejection by the plants of bases 166 and 167 indicates t ha t further 0-methylation is not the next step. By combining building block 165
with residue 168 or 169, a set of isoquinolines and bisphenethylamines
can be designed to allow selection of the natural advanced inter-
mediatefs)for the biosynthesis of 158 and 159 from the large number of
structures that are possible (73) .
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430 YASUO INU BUSH I AND TOSHIRO IBUKA
48. K. W. Bentley, i n “The Chemistry of the Morphine Alkaloids,” p. 358. Oxford
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-CHAPTER 8-
THE MONOTERPENE ALKALOIDS
GEOFFREY. CORDELL
University of Illilzois
Chicago. Illinois
I. Introduction ........................................................ 432
432
A. Skytanthine ..................................................... 432
B. Tecomine and Tecostanine ........................................ 435
C. Tecostidine ...................................................... 437
D. Hydroxy- a nd Dehydroskytanthines ................................ 438
E. Actinidine ....................................................... 440
F. The Quaternary Alkaloids of Valeriana oflcinalis .................... 442
G. Boschniakine (Indicaine) an d Boschniakinic Acid (Plantagonine) . . . . . . . 443
H. N.Normethy1skytanthine .......................................... 445
I. 4-Noractinidine .................................................. 446
J. Cantleytine ...................................................... 446
K. Venoterpine (Gent ialutine) an d Isogentialutine ....................... 448
L. Leptorhabine .................................................... 450
M.Bakankoside ..................................................... 450
N. Gentianine ...................................................... 452
0 . Fontaphilline .................................................... 454
P. Gentianadine .................................................... 455
Q. Gentianidine ..................................................... 456
R
.Gentianamine ................................................... 457
S. Gentioflavine .................................................... 457
T. Gentiocrucine, Enicoflavine, and Gentianaine ........................ 458
U. Jasminine ....................................... ............. 462
V. Gentiatibetine and Oliveridine ..................... . . . . . . . . . . . . . 463
w .Unnamed Alkaloids from Gentiana tibetica .......................
I1. Isolation an d Structure Elucidation of the Monoterpene Alkaloids .........
..............................................d Pediculinine ...................................... 466
111- Biosynthesis and Biogenesis of the Monoterpene Alkaloids ................ 470
A. Skytanthines .................................................... 470
B. Alkaloids of Tecoma st am ......................................... 487c. Actinidine and the V a l e k n a Alkaloids ............................. 487
D. Gentianine ...................................................... 488
E. Gentioflavine .................................................... 489
. Pedicularine, Pedicularidine, and Pediculine ......................... 467
F. Biogenesis. . . . . . . . . . . . ................................... 492
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432 GEOFFREY A. CORDELL
IV. Pharmacology of the Monoterpene Alkaloids. ...........................A. Actinidine .......................................................
B. Tecomine and Tecostanine ........................................C. Gentianadine ....................................................D. Gentianine ......................................................E. Skytanthine .....................................................F. Summary .......................................................References .........................................................
499
500
500500
500
502
502
502
I. Introduction
Original thoughts on the biogenesis of the monoterpene alkaloids, inparticular gentianine (l), entered on the prephenic acid hypothesis.
When Thomas ( 2 )and Wenkert ( 3 ) ntroduced their theories on indole
alkaloid biosynthesis from an iridoid precursor, i t became clear that the
other alkaloids could also be derived from the iridoids. The alkaloids,
rather than condensing with tryptamine/tryptophan with subsequent
reaction, would condense with ammonia and give a series of alkaloids
containing a C,, unit. Since these early days, a substantial number of
alkaloids formed in this manner have been isolated. As further com-
pounds of this type were isolated, two distinct types became apparent,the iridoids and those with a cleaved cyclopentane ring, the secoiridoids.
The organization of this chapter is based on this distinction as applied
to the monoterpene alkaloids. Thus, the alkaloids derived from a
secoiridoid are treated later. This approach is continued in the section
dealing with the biosynthesis and biogenesis.
Original interest in many of the plants from which these alkaloids
have been isolated was in most cases based on experimental or folkloric
experience with the crude drug. This data and subsequent work on the
pharmacology of the alkaloids isolated from these drugs concludes thischapter. A number of reviews of this general area are available (4-18) .
11. IsoIation and Structure Elucidationof theMonoterpene Alkaloids
A, SKYTANTHINE
Coincidentally, in 1961, two groups (19-22) isolated “skytanthine”
from the Chilean shrub Skytanthus acutus (Apocynaceae)and a year later
a third isolation was reported (23).Degradation of skytanthine demon-
strated the bicyclic nature and the location of one of the methyl groups
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8. MONOTERPENE ALKALOIDS 433
and permitted formulation 1 in which the methyl group on the five-
membered ring could not be placed ( 2 0 , 2 2 ) .
One of the first applications of NMR spectroscopy in the area ofnatural product structure elucidation was used successfully for sky-
tanthine ( 2 0 , 2 2 ) .The NMR spectrum of the dehydrogenation product
established the presence of thirteen protons, and together with the
analytical data for the picrate, supported a molecular formula of
C1,H,,N. Five lines of a sextet were visible in the NMR spectrum at
6 3.2 ppm. Thus, the dehydrogenation product could be represented as
either 2 or 3,and the latter was favored on biogenetic grounds. Com-
pound 3 was very similar to the actinidine isolated by Sakan ( 2 4 ) .
Direct comparison of the natural actinidine and the dehydrogenationproduct of skytanthine confirmed their identity. Skytanthine, therefore,
has structure 4, for which no stereochemistry could be assigned.
CH3
1 2 3
A different approach was used by the Italian workers ( 1 9 , 2 1 ) .
Analytical data indicated two C-methyl and one N-methyl groups and
a molecular formula C,,H,,N. Dehydrogenation afforded a substituted
pyridine, which must also be joined to a five-membered ring. On this
basis, it was suggested that skytanthine was a monoterpene alkaloid,
and three structures were proposed in accordance with the isoprene rule.
Once again, the dehydrogenation product was established as actinidine.Differences in the physical constants of the materials isolated by the
Italian group (19 , 21 ) and by Appel and Miiller (23)led to a more careful
examination of the problem.
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434 GEOFFREY A. CORDELL
Gas chromatography of skytanthine indicated the presence of four
peaks ( 2 5 ) .A number of stereochemical possibilities are available for
skytanthine, and four of these were synthesized ( 2 5 ) from the a-, ?-,y-, and 6-nepetalinic acids ( 2 6 ) by LAH reduction, ditosylation, and
cyclization with excess methylamine. I n this way the pure skytanthines
5 ,6 , 7 ,and 8 were obtained having [.ID and picrate properties as shown
( 2 5 ) . Similarly, the Italian group also synthesized a-, ?-, -, and
S-skytanthine (2 7 , 2 8 ) . Preparative gas chromatography demon-
strated that a-, ?-,nd &skytanthine were present in the original
skytanthine, the /? isomer 6 predominating (25). Later, gas chromatog-
raphy (2 9 , 3 0 ) and thin-layer chromatography (31 , 32) were used to
demonstrate that the percentages of /3-, a-, nd &isomers were 70, 20,and 3oJ, respectively.
CH,
5
a
r a 1 D + 79"
Picrate mp 120°C
CH,
B
6
+ 16'
135°C
ICH3
7
Y
+59
162°C
I
CH38
6
+ 9"
139°C
A study of the Hofmann elimination of a-,?-,- , and 6-skytanthines
( 3 0 ) unearthed pronounced differences in product composition. These
subtle differences were correlated with the stereochemistry of the
starting materials, resulting in differences in the elimination versus
regeneration of tertiary amine reactions.Careful isolation work demonstrated that both the a- and /?-Sky-
tanthines were absent from freshly collected roots of Skytanthus acutus( 3 3 , 3 4 )but were present in the dried branches.
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8. MONOTERPENE ALKALOIDS 435
Aspects of the early work on Skytanthus alkaloids have been
summarized ( 4 ,6) .
Oxidation of /3-skytanthine (6)with 30y0 ydrogen peroxide affordedthe N-oxide (9) and this process was reversed with Zn/dilute HC1
( 3 3 , 3 5 ) . 3-Skytanthine N-oxide was also obtained from the leaves ( 3 3 )and roots ( 3 5 )of S. acutus. The precursors of a- and /3-skytanthine in
S. acutus are still unknown, but it has been suggested that the N-oxide
(9) is the natural product, which is reduced during steam distillation by
the sugars present.
Further investigation of S. acutus by Gross and co-workers ( 3 6 )afforded a base, which by its mass spectrum was shown to be a fully
saturated skytanthine derivative. The characteristic ions a t m/e 84 dueto 10 as well as smaller fragments at m/e 58, 11, the base peak, and
mle 44, 12, were observed in the mass spectrum.
The base formed a picrate (mp 144-146°C) and a methiodide (mp 300-
302°C). This information together with the low optical rotation
+ loo) ndicated that the free base was &skytanthine (8) ( 3 6 ) .
‘‘(@,cH3 7 CHZN ,CH3
CH3 N @
N@ CH3Y\o@ CH,’ \CH,CH3
9 10 11
12
B. TECOMINE13) AND TECOSTANINE16)
Tecoma stuns (Bignoniaceae) and a number of other Tecoma species
are used in Mexico by the natives for the control of diabetes (3 7 ,3 8 ) .The two alkaloids tecomine (tecomaine) and tecostanine have been
isolated and characterized and are apparently responsible for hypo-
glycemic activity of the plant (see Section IV) .
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436 GEOFFREY A. CORDELL
Tecomine was isolated by Hammouda and Motawi in 1959 (39) by
chromatography of the alkaloid fraction. Little structure work was
attempted except for the demonstration of the presence of a carbonylgroup and the formation of several derivatives. Subsequently, Jones
and co-workers ( 4 0 , 4 1 ) obtained an unstable liquid alkaloid from
T. stuns. The alkaloid formed both a picrate and a methiodide, and the
UV and I R spectra indicated the presence of an cc$-unsaturated cyclo-
pentenone. Only one aromatic proton was present in the NMR spectrum
together with two three-proton doublets and an N-methyl group.
Reduction in acetic acid and subsequent Huang-Minlon reduction gave
a mixture of three bases which upon Pd-C dehydrogenation gave actini-
dine (3).The gross structure of tecomanine was therefore establishedas 13 ( 4 0 , 4 1 ) .Catalytic reduction in ethanol added one molar equivalent
of hydrogen, and the major dihydro derivative was obtained by re-
crystallization of the picrate. Huang-Minlon reduction gave a single
base, which again was characterized as the picrate. Comparison with the
four known synthetic ( 2 5 ) skytanthine picrates indicated that the
derivative was new.
Tecomanine and tecomine were subsequently shown to be identical
by direct comparison of their I R spectra and mixed melting point
determination of their picrates ( 4 2 ) . t remains to determine the stereo-chemistry of tecomine. A study of the stability of tecomine indicated
that degradation is pH dependent, being most rapid at high pH, and
that antioxidants are beneficial in preventing decomposition ( 4 3 ) .
Tecostanine, a crystalline base, was also obtained by Hammouda
( 4 2 ) , and its structure was subsequently established in collaboration
with Le Men and Plat ( 4 4 ) .The I R spectrum indicated the presence of
an alcohol function, and this was confirmed by the facile acetylation to
give a monoacetate derivative ( 4 2 ) .The oxygen atom was removed by
tosylation and LAH reduction. The resulting deoxy base was dehydro-
genated (Pd-C), and the product was shown to be identical with actini-
dine (3).The deoxy base therefore has structure 4, but again, the deoxy
compound was not identical with any of the synthetic skytanthine
isomers ( 2 5 )or the deoxy derivative of tecomine ( 4 0 , 4 1 ) .
Tecostanine is therefore a hydroxyskytanthine derivative, and the
nature of the hydroxyl function was readily determined to be a primary
alcohol from the NMR spectrum (broad two-proton doublet a t 3.56 ppm).
A decision on the position of the hydroxyl function was made after
careful examination of the mass spectrum ( 4 4 ) . Fragment ions were
observed at m/e 100, 58 (11),and 44 (12).The ion a t m/e 100 was shifted
to m/e 84 in deoxytecostanine and to m/e 85 when LAD was used in
place of LAH in the formation of deoxytecostanine. These data are in
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8. MONOTERPENE ALKALOIDS 437
H0cHa??cH3 CH3
16
accord with a fragmentation such as 14 to give the ion 15 as shown in
Scheme 1. The primary hydroxyl function is therefore located as shownin 16 ( 4 4 ) , nd i t remains to determine the stereochemistry of tecostanine.
C. TECOSTIDINE
A further alkaloid of the actinidine type has also been isolated from
T . tuns ( 4 5 ) .From the mother liquor after crystallization of tecostanine,
an unstable base was obtained that gave a crystalline picrate and
showed a small negative rotation. The UV spectrum indicated thepresence of a 3,4,5-substituted pyridine, and the IR spectrum showed
the presence of an alcohol function. The base could not be reduced
catalytically, and the presence of an actinidine-type structure was
suggested. Thirteen protons could be observed in the NMR spectrum
and this, together with an observed molecular ion of m/e 163, suggested
a molecular formula of C,,H,,NO. The NMR spectrum proved defini-
tive in determining the structure, €or two singlets were observed at
6 8 . 2 2 and 8.27 ppm corresponding to the 2- and 6-protons of the
pyridine ring and a three-proton doublet at 6 1.27 ppm. The methyl
group is therefore in the cyclopentane ring and the hydroxyl group
(singlet for two protons at 6 4.65 ppm) on the carbon attached to the
pyridine nucleus. Tecostidine therefore has structure 17 (45 ) .
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438 GEOFFREY A. CORDELL
From Pedicularis rhinantoides, Abdusamatov and Yunusov ( 4 6 )
isolated a base having a molecular formula Cl,,Hl,NO and showing
hydroxyl absorption in the IR spectrum. Oxidation of the base withalkaline permanganate afforded a carboxylic acid that was shown to be
identical with boschniakinic acid (18) ( 4 7 ) .The base from P. hinan-
toides therefore has the gross structure 17, but since the [ of this base
was +59”, i t is the optical antipode (19) of the material from T. tuns.
17 18
C H 1 O . i p 3 goCH, CH3
IS 20
Confirmation of the structure of tecostidine was obtained by syn-
thesis of the d isomer (19) from d-pulegone (20) ( 4 8 , 4 9 )using a route
similar to that used for actinidine ( 50 ,5 1 ) (see below, Section E,Scheme 2).
D. HYDROXY-ND DEHYDROSKYTANTHINES
In 1961 Appel and Muller isolated from S. acutus a crystalline
nonvolatile alkaloid (23)and suggested that i t was a hydroxy derivative
of skytanthine. Subsequently, this compound, alkaloid D, was subjected
to more careful analysis (52). The IR spectrum confirmed the presence
of a hydroxyl group, and the NMR spectrum indicated th at this group
was probably tertiary and attached at the site of one of the methyl
groups (three-proton singlet at 6 1.24 ppm). Also observed were a
secondary methyl group (three-proton doublet at 6 0.85 ppm) and an
N-methyl group (three-proton singlet at 6 2 . 3 ppm). On this basis,structures 21 and 22 were proposed for alkaloid D ( 5 2 ) .
In 1967, alkaloid D was reisolated from S. acutus together with a
second isomeric alkaloid (53).The NMR spectrum of this alkaloid was
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8. MONOTERPENE ALKALOIDS 439
similar to that of alkaloid D, showing methyl singlets a t 6 2.18 ppm for
the N-methyl group and at 6 1 . 1 2 ppm for the methyl group of the
tertiary alcohol. Thus, alkaloid D, renamed hydroxyskytanthine I, andthe isomer hydroxyskytanthine 11, had structures 21 and 22 or the
reverse ( 5 3 ) .A decision on these structure assignments was made on
the basis of NMR and mass spectral analysis.
In the NMR spectrum of hydroxyskytanthine I, the 3a- and 3p-
protons were readily discerned to be doublets, whereas in hydroxy-
skytanthine I1 both doublets are further coupled. Hydroxyskytanthine
I, therefore, has the structure 22 (53). The mass spectrum of hydroxy-
skytanthine I1 (21) showed ions at mle 84 and mle 110 ascribed to the
species 15 (R = H ) and 23.These ions were not observed in the massspectrum of hydroxyskytanthine I.
A s well as the hydroxyskytanthines I and I1 isolated from Skytanthus
acutus, two additional hydroxyskytanthines have been isolated from
Tecoma stuns (41). Both bases showed no UV absorption and had
ICH,
21
ICH,
22
ICH,
23
m/e 110
molecular formulas of C,,H,,NO. The oxygen function was traced to a
hydroxyl group from the IR spectrum. Two C-methyl doublets and a n
N-methyl group were observed in the NMR spectrum, and in the
absence of low-field methine or methylene protons, the hydroxyl
function must be tertiary. This data and consideration of the massspectrum led to structures 24 and 25 for the two hydroxyskytanthines.
A distinction between these two possible structures was made on the
basis of an examination of the IR spectrum. In the spectrum of the
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440 GEOFFREY A. CORDELL
base mp 82-94'C, intramolecular hydrogen bonding was observed,
suggesting structure 25 for this compound and structure 24 for the base
mp 91-99"C (41).Two other skytanthine-type alkaloids have been isolated and shown
to be dehydroskytanthines. Casinovi and co-workers ( 2 9 , 5 2 )obtained
a base by preparative gas chromatography and showed th at i t had the
molecular formula C,,H,,N. The NMR spectrum indicated the presence
of an olefinic methyl group (singlet at 6 1.50 ppm integrating for three
protons), and reduction with PtO, in acetic acid afforded 6 skytanthine
having the configuration 8. On this basis, the structures 26 and 27 were
suggested for this dehydroskytanthine (2 9 , 5 2 ) .
Treatment of hydroxyskytanthine I (alkaloid D) with thionyl
chloride gave dehydroskytanthine identical with that obtained pre-
viously ( 5 2 ) .The elucidation of the structure of hydroxyskytanthine I as
22 permitted deduction of the structure of dehydroskytanthine to be
27 (53).
cH3fl+' C H 3 f l HOH CH3 czQfl:ICH3
I ICH3 CH,
26 27 28
In 1973, Gross and co-workers ( 3 6 )obtained another alkaloid, which
by the molecular ion a t mle 165 suggested th at i t was a dehydroskytan-
thine. The base formed a picrate and a methiodide. Catalytic hydrogena-
tion (5y0Pd-C) gave a dihydro derivative identical with a-skytanthine
(8).The NMR spectrum indicated the presence of two secondary methyl
groups and only one oIefinic proton ( 6 5 .5 ppm). Since the mass spectrumshowed the presence of ions a t mle 58 and 44, the double bond must be
at the A5 position, and this dehydroskyanthine therefore has the
structure 18 ( 3 6 ) .
E. ACTINIDINE37)
Actinidine, one of the simplest monoterpenoid alkaloids, was fistisolated from Actinidia polygama ( 2 4 , 54 , 55 ) and subsequently from
A . arguta ( 5 6 ) ,Valeriana oflcinalis (5 7, 5 8 ), Tecoma radicans (56),and
T . u lva (59 ) .Co-occurring with actinidine in A . polygama was a non-
nitrogenous neutral substance, metatabilactone ( 2 4 , 55) (from the
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8. MONOTERPENE ALKALOIDS 44
Japanese colloquial name for A . polygama, matatabi). Hydrolysis ofmatatabilactone gave a hydroxy acid, which upon permanganate
oxidation afforded two isomeric dicarboxylic acids identical with thenepetalinic acids (26) obtained from nepetalactone. On this basis,
structure 29 was suggested for matatabilactone ( 2 4 , 5 5 ) .
CH3 0 COaH CH3 0i’G ‘ +
CH3 CH3
29 30 31
Permanganate oxidation of actinidine gave, among other products,
5-methylpyridine-3,4-dicarboxyliccid, and on the basis of biogenetic
considerations, the probable structure 3 was suggested for actinidine
( 2 4 ) .Confirmation of this gross structural assignment was obtained by
synthesis. Nepetalinic acid imide (31) on treatment with PCl, a t 100°C
afforded a 2,6-dichloropyridine, which was dehalogenated with Pd-C
to give actinidine ( 2 4 , 6 0 ) .
I n 1960, Sakan and co-workers published a series of papers describingfully their work on actinidine (51,55, 60-62). Synthetic dl-actinidinewas prepared in five steps from 32 and resolved with dibenzoyl-1-tartaric
acid ( 6 2 ) (Scheme 2). The absolute configuration of natural actinidine
7H3 7H3 0”1 . NaCN/H,SOI
3. HCI, A 2. PdCI,/KOAc
q C O z C 2 H 6 OH
2. SnC1,lpyridine 1 . POCID, 200°C+ 3
CH3
32
CH3
35
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442 GEOFFREY A . CORDELL
was also determined by synthesis ( 5 0 , 5 1 ) (Scheme 2 ) . (+)-Pulegone
(20) was converted to methyl pulegenate (33), hich was ozonized, and
the ketone was treated with the potassium salt of ethyl cyanoacetate togive 34, he sodium salt of which on treatment with methyl iodide
followed by hydrolysis gave optically active 35, which was transformed
into d-actinidine (36) s before. Natural actinidine, therefore, has the
I-configuration and the structure 37. A number of monoterpenoid
alkaloids have been correlated with actinidine. These include bosch-
niakine ( 6 3 ) , ecomine ( 4 0 ) ,skytanthine ZO ) , tecostidine (as), nd an
unnamed Valerianu alkaloid ( 64 , 65 ) . The chemistry of Actinidia
polygama has been reviewed (9 , 6 6 ) .
36 37
F. THEQUATERNARY LKALOIDSF Valerianu oficinalis (38 and 39)
I n addition to actinidine ( 5 7 , 5 8 ) , two other alkaloids in this series
have been isolated from the roots of Valeriana oficiana lis (57 , 6 4 , 6 5 ) .
Both alkaloids are quaternary, and because of their close similarity,
they will be discussed together. One of these alkaloids showeda molecular
formula of C18H2,NOCI and the other C18H2,N02C1, indicating the
presence of a hydroxyl group in the second isolate.
The first alkaloid isolated ( 6 4 , 6 5 ) showed strong hydrogen bonding
in the IR spectrum in addition to characteristic aromatic bonds indi-
cating the presence of a para-substituted aromatic ring. Nn carbonylbands were observed. The UV spectrum also indicated the presence of
cH3flH,R
I
38 R = H
39 R = O H
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8. MONOTERPENE ALKALOIDS 443
both pyridine and phenolic chromophores, the latte r shifting from 222
and 267 nm to 242 and 292 nm on addition of alkali. Essentially
identical data were observed for the second alkaloid (65),but in the IRspectrum, further absorptions at 3200 and 1047 cm-l confirmed the
presence of an additional nonphenolic hydroxyl group.
The NMR spectra of the alkaloids and their derivatives was par-
ticularly revealing. Two singlets at 6 8.90 and 8.83 ppm were ascribed
to the 2,6 protons on a pyridine nucleus and two doublets ( J = 8.8 Hz)
a t 6 7.04 and 6.73 pprn to a para-substituted aromatic nucleus. Both
compounds showed a complex four-proton multiplet in the region
6 4.70 ppm, which could be ascribed to two low-field methylene groups,
and each compound showed a three-proton doublet a t about 6 1.23 ppm,indicative ofa secondary methyl. However, whereas the first (and major)
alkaloid showed a three-proton singlet at 6 2.34 pprn for an aromatic
methyl group, the second compound showed the presence of a two-
proton singlet at 6 4.68 ppm, indicating th at the second hydroxyl group
was on the aromatic methyl ( 6 5 ) .Strong peaks in the mass spectrum of the trifluoroacetate of the
major alkaloid were observed at m/e 268 (parent pyridinium species)
147, 132 (base peak), and 120. It was clear that cleavageof the molecule
tQgive m/e 147 and 120 had occurred, the latter being the phenolic partand the former the pyridine nucleus ( 6 4 ) . n the mass spectrum of the
minor alkaloid, the pyridine fragment was shifted to m/e 163 and the
base peak to m/e 148 ( 6 5 ) .Pyrolysis ( 6 4 , 65) of the major alkaloid and isolation of the base as
the picrate indicated an identity with (8 ) - () actinidine (37). On this
basis, structure 38 was proposed for the major alkaloid and structure
39 for the minor alkaloid. Treatment of (IS)-() actinidine (37) with
p-hydroxyphenylethyl bromide and formation of the picrate confirmed
structure 38 for the major alkaloid ( 6 5 ) .The enantiomer of 38 has alsobeen synthesized ( 57 ) .
G . BOSCHNIAKINEINDICAINE)44) ND BOSCHNIAKINICCID
(PLANTAGONINE)IS)
Indicaine was first isolated in 1952 from Plantago indica ( 67 ) . The
Russian workers suggested a molecular formula of C,,H,,NO. Sub-sequently, indicaine was isolated from Plantago ramosa (68)and Pedicu-
laris olgae (69-71). Preliminary structure work demonstrated that
indicaine was an amino aldehyde. The compound gave a picrate
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444 GEOFFREY A. CORDELL
(mp 151-153OC) (6 7 , 68) and could be oxidized with silver oxide or
nitric acid to an acid (68). This acid, called plantagonine, was also
obtained as a natural product, initially from P. ramosa (68) and subse-quently from P. olqae (69, 7 0 ) .
On the basis of degradative and spectral evidence, structure 40 was
proposed for plantagonine ( 7 0 )and by inference 44 or indicaine. The
UV spectrum was characteristic of a pyridine and supported the
presence of a methyl group at a secondary carbon atom. Exhaustive
KMnO, oxidation gave an amino acid, which was decarboxylated to
nicotinic acid on heating. The amino acid was identified as pyridine-3,
5-dicarboxylic acid (42) by comparison with an authentic sample ( 7 0 ) .
In 1968, the structures for plantagonine and indicaine were revisedwhen it was demonstrated that alkali permanganate oxidation ofplantagonine gave pyridine-3,4,5-tricarboxyliccid (43), and therefore
to have structures 18 and 44, respectively ( 4 7 ) . ndependently, Torssell
arrived at the same structural conclusions for plantagonine and indi-
caine based on examination of their spectral properties ( 7 1 ) and by
comparison with the ethyl ester of plantagonine (45), which had been
prepared independently ( 4 8 ) .Also isolated at this time was an alkaloid, boschniakaine, from
Boschniakia rossica ( 7 2 ) .This base formed a picrate and a carbazone,
thereby indicating that it was an amino aldehyde, and this was con-
firmed by the I R spectrum. Also isolated was an acid that could be
derived from the aldehyde by silver oxide oxidation. The structures 18
and 44 were assigned to these compounds ( 7 2 ) . n order t o confirm the
40 R = CO,H 42 R = H I8 R = CO,H
41 R = C H O 43 R = C O p H 44 R = C H O45 R = CO,C.H,
structure assignments and determine the absolute stereochemistry,
boschniakine (dl and d ) was synthesized by a route analogous to that
used for the synthesis of actinidine ( 5 0 , 5 1 ) Scheme3 ) . The product was
identical with the natural boschniakine(44) nd therefore belongs to the
opposite antipodal series than the other actinidine-type alkaloids.
Boschniakine has also been isolated from Tecoma stuns ( 4 4 , where it
co-occurs with a d-actinidine derivative, and from T. radieans ( 5 6 ) .
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8. MONOTERPENE ALKALOIDS 445
1. Oa/CCI*
2. K CH,CO.C.HS
~
QOH . POCla8 2. PdC12IKOAc
40
I ,NH.CN
CN
CH,
SnCl./HClQ- 4
CN
SCHEME
In 1973, Gross and co-workers (73) demonstrated that in spite of
apparent differences in the physical properties of boschniakine and
indicaine, they were in fact identical. I n particular, recrystallization of
the picrate from ethanol gave a product of mp 126OC. Plantagonine and
boschniakinic acid are also probably identical, bu t no direct comparison
has been made.
Isolated from P . olgae as a picrate (mp 125-127°C) was a quaternary
alkaloid analyzing for Cl2H1,NO+ ( 7 4 ) .The I R spectrum indicated th e
presence of an aldehyde, and this was confirmed by the NMR spectrum
(singlet at 6 3.49 ppm and a six-proton multiplet at 6 1.25 ppm,
suggesting the presence of a N-ethyl and a methyl group). Oxidation of
I
CZHS
46
indicainine, as the compound was named, gave boschniakinic acid (18).
Indicsinine was therefore assigned the structure 46. The correctness of
this structure has been questioned (73).
H. N-NORMETHYSKYTANTHINE (47)
A further alkaloid from Tecoma stuns analyzed for C,,HI9N (41).The
IR spectrum indicated the presence of NH, and no N-methyl group was
observed in the NMR. Dehydrogenation afforded actinidine (3),
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446 GEOFFREY A. CORDELL
identified as its picrate. The base was therefore identified as N-
normethylskytanthine (47). N-Methylation afforded a skytanthine
derivative, which was similar to the skytanthine derived from tecost-anine ( 4 4 ) .The stereochemistry of N-normethylskytanthine remains to
be determined.
CH3
47
I. 4-NORACTINIDINE (48)
From Tecoma stuns, Dickinson and Jones ( 4 1 ) isolated an alkaloid
C9H,,N as the picrate. The UV spectrum at 259.5 and 267 nm indicated
a 3,4-disubstituted pyridine, and this assignment was confirmed by the
NMR spectrum, which showed three aromatic protons. A three-proton
doublet was observed 6 1.6 ppm, and five other protons were observed
as multiplets, including three “benzylic” protons in the 6 3.2-3.8 ppmregion. The structure 4-noractinidine (48), with the d configuration, was
assigned to this compound ( 4 1 ) . Its picrate showed no melting point
depression with a synthetic sample of 8-epi-4-noractinidine picrate
derived from asperuloside (75) .
c p 3
48
J . CANTLEYINE 50)
From an unidentified Jasminum species (designated N G F 29929)
Johns and co-workers ( 7 6 ) solated a new pyridine derivative. The new
alkaloid had an elemental composition of C,,H,,NO, by analysis, and
this was supported by a molecular ion at mle 207. The IR spectrumindicated the presence of hydroxyl and ester functions. The UV spec-
trum was identical with that of 49, a synthetic compound.A study of the
NMR spectrum confirmed the 3,4,5-trisubstitution, the methyl ester,
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8. MONOTERPENE ALKALOIDS 447
and a secondary methyl group. The magnitude of the coupling con-
stants as determined by double resonance studies revealed the cis nature
of the methyl and hydroxyl functions and confirmed that the methylenegroup is on the carbon adjacent to the ester function. The alkaloid
therefore has structure 50, with absolute stereochemistry as shown ( 76 ) .The possibility of its artifactual nature was noted.
co2c*cH3 co2c*3 co2c*3
N N 0 OGlu49 50 51
The same alkaloid was also isolated by Potier and co-workers (77)from Cantleya corniculata (Icacinaceae) and given the name cantleyine.
Three principal fragmentation ions were observed in the mass spectrum
of cantleyine (50),and these are thought to arise as shown in Scheme
4 (77). The location of the C-methyl group was deduced from an absence
r.
na/e 207I r n l e 179
mle 207
l+. r
mle 175 mje 147
SCHEME
t .
of nuclear Overhauser effect ( N O E ) when the methyl protons of the
ester group were irradiated. Cantleyine(50),dentical with the “natural ”
material, was obtained by treatment of loganin (51) with ammonia for
2 hours (77) . The compound was not isolated from C . cornicuEata in the
absence of ammonia.
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448 GEOFFREY A. CORDELL
Two further isolations of cantleyine have been reported from
Dipsacus azureus ( 7 8 )and Strychnos n u x vomica ( 7 9 ) . n both instances,
ammonia was used in the work-up.
K. VENOTERPINEGENTIALUTINE)52) AND ISOGENTIALUTINE55)
Another alkaloid of this same general type but lacking the carbo-
methoxyl side chain present in cantleyine 50)s venoterpine (gentia-
lutine) (RW-47) (52). Venoterpine was first isolated from RauwolJia
verticillata (Apocynaceae) by Arthur and Loo in 1966 ( 8 0 ) under the
designation RW-47. Although some physical data were obtained, nostructure work was carried out. Collaborative work on RW-47 with
Johns and Lamberton ( 8 1 )deduced two plausible structures for RW-47,
of which one was favored on biogenetic grounds.
The molecular ion a t m/e 149 in the mass spectrum and elemental
analysis gave a molecular formula for RW-47 of C,H,,NO. Hydroxyl
but no carbonyl absorption was observed in the IR spectrum. The UVspectrum indicated t he presence of a pyridine and the 3,4 disubstitution
was confirmed by the NMR spectrum. A secondary methyl group
(doublet a t S 1.32 ppm) as well as a hydroxyl were observed (singlet6 .96 ppm, removed with D,O). This hydroxyl group was shown to be
secondary, with the methine proton as a multiplet a t S 4.50 ppm.
Double irradiation of this methine proton simplified the remaining
benzylic region to an AB system and a quartet, the la tter coupling with
the methyl group. On this basis, the relative stereochemistry of the
methyl and hydroxyl groups, which must be on adjacent carbons, was
deduced to be cis. Biogenetic reasoning suggested structure 52 for
One feature remained to be explained, namely, the base peak in themass spectrum at m/e 120, a loss of 29 mu from the molecular ion.
Deuteration shifted the base peak to mle 121, indicating that the
hydroxyl proton was transferred in this process and -CHO lost.
In 1968 Ray and Chatterjee ( 8 2 ) isolated venoterpine (52) from
Alston ia venenata (Apocynaceae). Once again, the NMR spectrum gave
important information for the purposes of structure elucidation, but the
upfield shift of the hydroxyl group deceived the Indian workers into
believing that they had a different stereoisomer than the Australian
group. The coupling constants for the methylene and methine protonsmitigated against this, however.
Finally, RW-47 and venoterpine were compared directly ( 8 3 ) and
found to be identical. In addition, the ORD-CD spectrum of veno-
RW-47 ( 81 ) .
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449. MONOTERPENE ALKALOIDS
terpine demonstrated that it was of the opposite absolute configuration
to (A')-( - actinidine (38) ( 2 4 ,50). Structure 52 therefore also represents
the correct absolute configuration of venoterpine (83).Gentialutine was first isolated from Gentiana Zutea (84) and has
subsequently been isolated from G. tibetica, G. asclepiadea (as), nd
Henyanthes trifoliata (86). The molecular weight was determined to
be 149 ( 8 4 ,87), which by elemental analysis could be ascribed to
C,H,,NO. The compound lacked carbonyl absorption, but showed
substantial hydroxyl absorption ( 8 4 ,87). The UV spectrum was th at of
a vinyl pyridine, and on this basis, structure 53 was proposed ( 8 4 ) .
This structure was not supported by the NMR spectrum, which showed
two a-pyridine protons at 6 8 .22 and 5.25 ppm and the /3-pyridineproton at 6 7.15 ppm. The vinyl protons were not found. Instead, a
methyl doublet was observed at 6 1.35 pprn and the alcohol methine
proton at 6 4.60 ppm. Although these data negate structure 53 for
gentialutine, no new structure was proposed at this time.
These data are, however, in agreement with the gross structure 52
for gentialutine, rather than that previously assigned (84). No stereo-
chemical work has been carried out, but the close melting point of
gentialutine with that of venoterpine indicated the probable identity of
the two compounds. Recently, the structure of gentialutine was revised(88)and determined to be the same as venoterpine (52),although no
direct comparison was made.
oH
52 53 54 55
Also obtained a t this time from Gentiana tibetica was a new alkaloid,
isomeric with gentialutine, which was named isogentialutine (88).The
IR spectrum indicated the presence of a hydroxyl function but absence
of other functional groups. The UV spectrum demonstrated the
presence of a pyridine derivative and from the NMR spectrum the
substitution pattern was determined to be 3,4. In addition, a three-
proton doublet at 6 1.33pprn (secondary methyl) coupled to a protonat 6 3.18 ppm (benzylic methine) indicated a close similarity to gen-
tialutine (52). Indeed, CrO,/pyridine oxidation of isogentialutine and
gentialutine afforded an identical product, the five-membered ketone
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450 GEOFFREY A. CORDELL
54, albeit a t differing rates. Gentialutine and isogentialutine, therefore,
differ in the configuration of t he hydroxyl group. Further evidence for
this was obtained from the NMR spectrum, where the pyridylic methineproton appeared as doublet of doublets ( J = 7 Hz and 5H z) . The
hydroxymethine proton gave coupling constants of 5 Hz and 3 Hz,
indicating two trans- and one cis-oriented protons on adjacent carbon
atoms. Isogentialutine therefore has structure 55 (88) .
L . LEPTORHABINE57)
From the epigeal part of Leptorhabdos parvijlora (Scrophulariaceae),the Tashkent group recently isolated another new monoterpene pyridine
alkaloid, to which the name leptorhabine was given (89) .Permanganate
oxidation under alkaline conditions pyridine 3,4-dicarboxylic acid (56),
56 57
thereby defining the substitution on the pyridine ring. The NMRspectrum confirmed this substitution pattern and also indicated a sec-
ondary methyl group and a benzylic hydroxyl group showing a methine
proton at 5.06 ppm. Two methylene protons were observed as a
multiplet at 1.98 ppm. On the basis of this and substantiating spectral
evidence leptorhabine was assigned the structure 57, without stereo-
chemistry.
M. BAKANKOSIDE60)
Bakankoside was one of the first monoterpene alkaloids isolated,
being obtained from seeds of the Madagascan Strychnos vacacoua (90) .The name arises from the local name for seeds, bakanko. The highly
stable crystalline compound was hydrolyzed by dilute acid to afford
d-glucose (90) .Hydrolysis with emulsin was not complete after 7 weeks(90) . The high negative rotation [.ID - 195") clearly aroused the
attention of these workers. A further sample was obtained from the
fruits of S. vacacoua (91) ,and subsequent work indicated a molecular
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8. MONOTERPENE ALKALOIDS 451
weight of 359. Analytic data suggested (correctly)a molecular formula
C,,H,,NOB + H,O for the parent compound and C,,H,,N03 for
bakankoside itself ( 9 1 ) .It was forty-four years before the work on bakankoside was resumed,
this time by Prelog’s group ( 9 2 ) . t was demonstrated t hat bakankoside
had no alkoxy, AT-methyl, r C-methyl groups; that i t was neither acidic
nor basic; and that i t did not give derivatives for a carbonyl group or a
color reaction with ferric chloride. Catalytic hydrogenation gave a
dihydroderivative, and both bakankoside and the dihydroderivative
formed tetraacetates. Osmium tetroxide oxidation of bakankoside and
acetylation afforded hexaacetate, indicating the presence of a vinyl
group.Dihydrobakankoside was hydrolyzed by emuslin to dihydrobakanko-
genin. In 0.1 N sodium hydroxide, the UV maximum was shifted from
238 nm to 276 nm. No shift was observed for bakankosin. The shift is
characteristic of the addition of a double bond in conjugation. Prelog
and co-workers interpreted this as conversion of 58 to 59 ( 9 2 ) .The IR
spectrum confirmed the presence of an a$-unsaturated amide, showing
two carbonyl bonds at 1670 and 1625 cm-l. Zinc dust distillation of
bakankoside gave crotonaldehyde, pyridine, and ,3-picoline.
Several structures were proposed a t this time for bakankoside, butneither the carbon skeleton nor the relationship of the glucose to the
rest of the structure could be deduced. Biichi ( 9 3 , 9 4 ) subsequently
suggested structure 60 for bakankoside, which accounts for the physical
and degradative work, and this structure has remained unchallenged.
The probable stereochemistry of bakankoside will be discussed later
when biosynthetic aspects of the monoterpene alkaloids are discussed.
/ /
CC-C=C-C-N\ + = C C = C C - N \
0II0
II0
I
58 59
OGlu
H
60
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452 GEOFFREY A. CORDELL
N. GENTIANINE62)
Gentianine is the best known of the monoterpene pyridine alkaloidsand is possibly the most widely distributed. Much of the early structure
work on gentianinine was done by Proskurnina ( 9 5 ) . Hydrogenation
gave a dihydro derivative having a molecular formula CloH,,N02. Oxi-
dation with permanganate gave an acid C,H,NO,. Distillation of this
acid with zinc gave pyridine ( 9 5 ) ,and decarboxylation gave 4-vinyl-
pyridine ( 9 6 ) . Proskurnina and co-workers ( 9 6 ) originally assigned
structure 61 to gentianine, but later (92') amended this to 62, since
gentianine was optically inactive. In addition, the IR spectrum also
supported the presence of a 6 rather than a y-lactone (absorption at1715 cm-l).
61 62 63
At this time, Govindachari and co-workers (9 8 ,9 9 ) synthesized
dihydrogentianine (63) from 5-ethyl-4-methylnicotinic acid (64) bytreatment with formaldehyde, thereby establishing the structure of
gentianine (62). Subsequently, Govindachari and co-workers ( 100)synthesized gentianine by the route shown in Scheme 5 .
In 1963, the first NMR study of gentianine was published ( 101) .The
vinylic protons were observed a t 6 5.77,5.95, and 7.08 ppm, the pyridine
protons at 6 4.67 and 3.24 ppm. Prior to a study of the biosynthesis of
gentianine, Marekov and Popov investigated the products of its oxida-
tion (102) .
Gentianine, as can be seen from Table I, has been isolated from anumber of plants, but often the question is raised as to its natural
occurrence. Much of the early isolation work on the crude alkaloid
fraction was done with the aid of ammonia, and there is no doubt th at
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8. MONOTERPENE ALKALOIDS 453
+ 1. POCI.
2. PdCL, K O A cHO
\CONH,
SCHEME
in many instances gentianine was isolated as an artifact. Evidence for
this comes from a number of sources.
Swertiamarin, a secoiridoid isolated from Swertia japonica (103-109)and other species (110-115), was treated with ammonia for 3 days a t
room temperature to give gentianine ( 1 1 6 , 1 1 7 ) .Subsequent work with
Anthocleista procera and Enicostemma littorale (1 1 8 ) indicated thatswertiamarin was probably responsible for the gentianine isolated in
these cases, since no gentianine was isolated in the absence of ammonia.
The relationship to gentianine helped to establish the structure of
swertiamarin as 65 (1 1 2 ) .Similarly, another secoiridoid glycoside, gentiopicroside, has been
shown to be transformed into gentianine by treatment with ammonia
(119-121).Gentiopicroside has been isolated from a number of genera in
the Gentianaceae (1 2 2 ) and has structure 66 (109 , 123 , 1 24) . As far as
possible, the isolation of gentianine from plants that contain swertia-marin or gentiopicroside and that have involved ammonia in the isola-
tion procedure are designated by an asterisk in Table 1 .
A further problem has also been uncovered in the isolation of genti-
anine ( 8 1 ) .The chloroform residue, after thorough extraction with acid
buffer and treatment with methanol, deposited crystals having the
elemental composition C,,H,,NO,Cl,. The UV spectrum indicated a
great similarity to dihydrogentianine (63),and the IR spectrum indi-
cated the presence of an unsaturated lactone and the pyridine nucleus.
Oxidation with permanganate in acetone gave an acid (67) identicalwith that obtained from gentianine. The NMR spectrum confirmed the
substitution showing two singlets a t 6 9.06and 8.84 ppm. One methylene
group was observed at 6 4.54 ppm and three methylene groups centered
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454 GEOFFREY A. CORDELL
65
OGlu
66 67
68
at 6 3.00 ppm. On this basis, structure 68 was proposed for this chloro-
form adduct of gentianine ( 8 6 ) .Treatment of a chloroform solution of
gentianine with benzoyl peroxide also gave 68 (86) .
0. FONTAPHILLINE69)
Another plant in the Oleaceae giving rise to monoterpenoid alkaloids
is Pontanesia phillyreoides, and this species has been investigated by
Budzikiewicz (1 2 5 ) . n addition to gentianine, a new crystalline alkaloid,
fontaphilfine, was isolated. Elemental analysis indicated a molecular
formula C18H,,N0,, and this was confirmed by the mass spectrum
which showed an M + a t mle 327. Acid hydrolysis of fontaphillineafforded two components, identified as 4-hydroxybenzoic acid and
gentianine (62).Fontaphilline was therefore suggested to be 69, and this
structure was substantiated by spectroscopic data (1 2 5 ) .
The I R spectrum indicated a para-substituted benzene (850 cm- l) ,
an aromatic carboxylic ester (1723 cm-I ), and a hydroxylic group. The
NMR spectrum indicated two pyridine a-protons as singlets at 6 8.75
and 9.0 ppm, two pairs of ortho-aromatic protons a t 6 6.80 and
7.85 ppm, and a carbomethoxyl group as a singlet a t 6 3.95 ppm. A
two-proton multiplet a t 6 5.60 pprn and ;t highly deshielded multipleta t 6 7.30 pprn confirmed the presence of a vinyl group. The remaining
two groups of methylene protons were observed as multiplets a t 6 3.60
and 4.55 ppm.
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8. MONOTERPENE ALKALOIDS 455
The mass spectrum showed a molecular ion a t m/e 327 and a base peak
a t m/e 121 having sructure 70. The electronegative mass spectrum how-
ever was more informative. The base peak appeared at mle 137 corre-sponding to the p-hydroxybenzoyl anion. Three other fragment ions were
observed at m/e 206 (ion 71), m/e 189 (fragment 72), and m/e 174 (ion
73), in agreement with the assigned structure of fontaphilline ( 125) .
P. GENTIANADINE74)
Gentianadine was first isolated from the aerial parts of Gentiana
turkestanorum by Yunusov and co-workers (1 2 6 ) .The crystalline base
showeda carbonyl absorption at 1730 cm -l characteristic of a &lactone.
The UV spectrum was similar to that of dihydrogentianine (63),but theelemental composition of C,H,NO, indicated a loss of two-carbon units
(1 2 6 ) .The base was apparently very similar to 74, a compound pre-
synthesized by Govindachari and co-workers (99). Slight differences in
physical properties were noted, however, and thus gentianadine was
degraded to confirm this structure assignment. Alkali potassium per-
manganate gave pyridine-3,4-dicarboxylic cid and decarboxylation
gave an oily product identified as 4-vinylpyridine. Gentianadine there-
fore has structure 74 ( 1 2 6 ) .
This structure was further confirmed by the NMR spectrum ( 1 2 7 ) ,which showed two-proton triplets at 6 4.52 nd 3.04 ppm for the lactone
methylene groups and three pyridine protons at 6 9.12, 8.64, and
7.19 pm with coupling as expected. I ts mass spectrum (128 )gave the
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456 GEOFFREY A. CORDELL
molecular ion m / e 149 as the base peak and important fragment ions by
ring expansion and loss of CO a t m/e 120 and further losses of CO to
m/e 92 and H C N to m / e 6 5 .Gentianadine also occurs in G. olgae (129 , 130) and G . olivieri ( 1 3 1 ) .
A novel route to its synthesis was recently described by Dolby and
co-workers ( 1 3 2 , 1 3 3 ) . The quaternary 2-dehydroquinuclidine-3-
carboxylic acid ester 75, when heated, rearranges via two consecutive
1,3 sigmatropic shifts to a mixture of 76 and 77, the former pre-
dominating. Palladium-carbon dehydrogenation afforded gentianadine
(74) in 9% overall yield (132 , 133) .
74 75 76 77
Q. GENTIANIDINE 79)
From Gentiana macrophylla, Chinese workers isolated another mono-
terpene alkaloid type (134 ) . Gentianidine was obtained in crystalline
form and was optically inactive. The IR spectrum indicated the presence
of a &lactone and alkali permanganate oxidation gave berberonic acid
(78). N M R spectral evidence indicated probable structure 79 for
gentianidine, and support for this came from condensation of 4,6-
dimethylnicotinic acid (80) and formaldehyde at 100°C ( 1 3 4 , 1 3 5 ) .The
78 79 80
mass spectrum of 79 has been described (136 ) . Gentianidine (79) hasalso been isolated from Erythraea centaurium (137 ) ,Menyanthes trifoliata(138 ) , G . asclepiadea (112 ) , and Xwertia japonica, but not from X.
japonica in the absence of ammonia (139 ) .
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8. MONOTERPENE ALKALOIDS 457
R.GENTIANAMINE81)
A further novel type of Gentiana alkaloid has been obtained fromG. oliuieri (86,126, 131) and G . turkestanorum (126).Gentianamhe is a
crystalline alkaloid having a molecular formula C,,H,,NO,. The IR
spectrum indicated the presence of hydroxy and %lactone functions
and a double bond. The UV spectrum was very similar to gentianine.
Monoacetylation confirmed the presence of a hydroxyl group ( 126) ,and
catalytic reduction afforded a dihydro derivative, which contained a
C-methyl group, thereby confirming the presence of a vinyl group.
Alkali oxidation afforded pyridine 3,4,5-tricarboxylic acid (43).
On this basis, gentianamine was assigned structure 82, and this wassupported by the mass spectrum. The molecular ion, m/e 205, succes-
sively lost CH,O and CO, to give m/e 131 (126). n addition, dihydro-
gentianamine (12) was syntheszed from dihydrogentianine (63);
treatment with formaldehyde at 100°C gave a 50% yield of dihydro-
gentianamine identical with th at prepared from the natural material.
The NMR spectrum of acetylgentianamine (83) (127) indicated the
presence of a vinyl group (absorption at 6 5.8 and 6.94 pprn), two a-
pyridine protons (8 9.06 and 8.85 pprn), and the acetate ( 6 2.04 pprn).
Further assignments were not made.
+ q&Lo CH, r f i o
C H O f i oH3
N N
81 R = H 82 84
83 R = Ac
H H
85
S. GENTIOFLAVINE8 5 )
Gentioflavine was first isolated as Alkaloid IV from a number of
Gentiana species ( 1 4 0 ) .A molecular ion of C,,H,,NO, was derived from
elemental analysis and mass spectrometry ( 1 4 0 , 1 4 1 ) . The IR spectrum
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458 GEOFFREY A. CORDELL
shows the presence of an NH group (3235 m-l), conjugated lactone
(1700 m-l) , and a conjugated carbonyl group (1640 m-l).
The NMR spectrum showed two methylene groups (4.35 nd 3 ppm),a methyl doublet (1.3 pm) with the corresponding methine proton a t
5 . 2 ppm. A singlet 10.1ppm was ascribed to an aldehyde group. The
other two singlets a t 8.45 and 8.8 ppm were assigned to an NH and
another highly deshielded proton (1 4 1 ) .The aldehyde group was con-
firmed by the formation of semicarbazone and oxime derivatives.
Oxidation of gentioflavine with nitric acid gave pyridine 3,4,5-
tricarboxylic acid (43),and treatment with bromine water gave a basic
compound, bromogentioflavine (C,H,BrNO,). The I R spectrum of this
derivative indicated a S-lactone (1740 m-l) and a pyridine ring. The
NMR spectrum showed an aromatic methyl 6 2.76ppm), the two
methylene groups (6 4.57 and 3.16 pprn), and an a-pyridine proton
(6 9.03ppm). On this evidence, structure 84 was assigned to bromo-
gentioflavine ( 1 4 1 , 1 4 2 ) .Treatment of bromogentioflavine with Raney
nickel afforded gentianidine (79), identical with the natural product.
Gentioflavine was therefore assigned the novel structure 85 ( l a l ) ,
bromine water affecting an oxidative decarboxylation of the aldehyde
group (1 4 3 ) .The mass spectrum of gentioflavine (1 3 6 ) showed an initial loss of
15 m u to m/e 178 with subsequent losses of formaldehyde, CO, CO, and
finally HCN t o give the cyclopentadienyl ion, m / e 65.
T. GENTIOCRUCINE87),ENICOFLAVINEgo),AND GENTIANAINE92)
Gentiocrucine was originally isolated by Marekov and Popov from
Gentiana cruciata ( 1 4 2 , 1 4 4 ) , and on the basis of spectral evidence
structure 86 was assigned. Ghosal and co-workers have recently re-investigated the structure of gentiocrucine isolated from Enicostemma
hyssopifolium (1 4 5 ) and have concluded that in fact 87 is the correct
structure for th is compound.
Gentiocrucine gave two 2,4-dinitrophenyIhydrazones 1 4 5 ) , ndicating
th at the formulation as an amide was erroneous. In the mass spectrum,
a substantial loss of 27 mu was observed, and this could not be accounted
for on structure 86 bu t could be accounted for by the loss of HCN from
87 (1 4 5 ) .
The PMR spectrum indicated the presence of adjacent methylenegroups at 6 2.4 and 4.3 ppm, two exchangeable proton a t 6 9.2 and
10.0 ppm, and a complex multiplet a t S 8.1 ppm. The lat ter was simpli-
fied to two doublets ( J = 9 and 17 HE)on addition of D,O, indicating
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8. MONOTERPENE ALKALOIDS 459
the presence of cis and trans isomers of the methine proton on the
vinylogous amide. The CMR spectrum of gentiocrucine conclusively
demonstrated the existance of two isomers, fourteen carbon resonancesbeing observed (88 and 89) ( 145) .
CONH,no86
cis and trans
87
H. 97.42\
35.70-
\
35.70-
63.59 ‘168.69 63.48 ‘168.49
88 89
It should be noted t hat hydrogen bonding of the nonlactonic carbonyl
in the cis isomer shifts this resonance downfield by 3 ppm to 194 ppm.
As we shall see, gentiocrucine, although not apparently a monoterpene
alkaloid turns out to be intimately involved with this group of
compounds.
Recently, Ghosal and co-workers have examined some of the more
reactive monoterpene alkaloids, the concept being tha t there must be a
number of intermediates between the secoiridoids and the normally
isolated monoterpene alkaloids. From Enicostemma hyssopifolium, a newalkaloid, enicoflavine, was isolated, and the structures 90 and 91 were
proposed for the isomeric mixture ( 146) .Elemental and mass analysis established the molecular formula as
C,oH,lNO,. Selective tlc sprays indicated the presence of an aldehyde
(2,4-DNP and Tollens test) and the absence of a conventional nitrogen
function (negative Dragendorf). The UV spectrum indicated the
presence of a vinylogous amide cross-conjugated to a lactone group, a
system found in gentiocrucine ( 1 4 5 ) .In the IR spectrum, bands were
observed for NH/OH, an aldehyde, an unsaturated lactone function,and a vinyl group.
The NMR spectrum ( 146) supported these functionalities, showing
an aldehyde a t 6 9.3 ppm and vinylic and allylic methine proton in the
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8. MONOTERPENE ALKALOIDS 46 1
methylene adjacent to nitrogen. A further signal at 6 8.50 ppm was
ascribed to the aldehyde proton, which was confirmed by reaction with
Tollens reagent.The spectrum of gentianaine in deuteropyridine showed two addi-
tional one-proton signals at 6 4.88 ppm for the hydroxy proton and
8.26 ppm for the amide proton. The enolic nature of the 1,3-dicarbonyl
function could not be deduced from the spectrum (1 2 7 ) .The mass spectrum of gentianaine (129)showed losses of CHO and
CO to give ions m/e 1 2 and m/e 1 13 from the molecular ion at m/e 1 4 1 .
The base peak was at m/e 69, and the structure 93 was suggested for
H
92 93
this ion. This seems highly unlikely, since two protons would need to be
lost from adjacent methylenes. More probable appears to be a syn-
chronous loss of ethylene and HNCO from the M + - peak as shown(Scheme 7 ) to give th e ion 94. Gentianaine is therefore another simple
H m/e 69
94
SCHEME
derivative of a monoteqene unit, probably arising by loss of croton-
aldehyde by retroaldol reaction from a compound such as 95, i.e., a
hydroxybakankoside derivative.
H o A C H O
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462 GEOFFREY A. CORDELL
U. JASMININE96)
In 1968, Lamberton and co-workers ( 1 4 8 ) isolated another alkaloidderived from the secoiridoid skeleton. Jasminine, as the alkaloid was
named, was obtained from a number of J a s m i n u m species and from
Ligustrum novoguineense. Subsequently, the same compound was iso-
lated from a third member of the Oleaceae, Olea paniculata ( 1 4 9 ) .
Unique among the monoterpenoid alkaloids, jasminine was found to
contain two nitrogen atoms and has the molecular formula C,,H,,N,O,
( M + , m/e 220) . Two intense carbonyl bands were observed-at
1725 cm-l attributed to an ester and at 1680 cm-l attributed to an
amide ( 1 4 8 ) .In the NMR spectrum ( 1 4 8 ) two a-pyridine protons were found at
S 9 .0 1 and 8.57 ppm together with a broad signal at S 8 .17 ppm, ex-
changeable with D,O and assigned to the amide NH. A three-proton
doublet at S 1 .5 8 ppm was assigned to a secondary methyl group, and
a three-proton singlet at 8 3.93 ppm was assigned to the methyl ester
function. The methylene protons were deshielded, appearing as quartets
at 8 5 . 1 2 and 4.87 ppm, and the methine proton was also deshielded
appearing as a broad multiplet at 8 4.75 ppm. Double irradiation
studies confirmed the proton assignments. On this basis two struc-tures, 96 and 97, were proposed ( 1 4 8 ) for jasminine, the former being
considered more likely on biosynthetic grounds.
96 97 98
The mass spectrum ( 1 4 8 )of jasminine shows a base peak of m/e 205
(loss of methyl radical) and subsequent important fragments a t
m/e 173, 145, 118, 117, and 9 0 . For structure 96, these fragments can be
rationalized as in Scheme 8. Confirmatory evidence for the structure
came from an examination of the concentrated acid hydrolysis product
of jasminine, which, on the basis of spectroscopic evidence, was assigned
the structure 98 ( 1 4 8 ) .Chemical considerations indicate t hat hydrolysiswould not be expected to result in decarboxylation of the acetic acid
residue. Jasminine was not considered to be an artifact of isolation
( 1 4 8 , 1 4 9 ) .
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8. MONOTERPENE ALKALOIDS 463
mle 205 m/e 173
m/e 90
SCHEME
m/e 145
pc,
wle 118
v. GENTIATIBETINE100) ND OLTVERIDINE (103)
In 1967, Rulko and co-workers ( 150) described the isolation and
characterization of a further type of monoterpene alkaloid. From theroots of Gentiana tibetica, a crystalline alkaloid was isolated (150)showing a molecular ion at mle 165, which by elemental analysis corre-
spond to C,H,,N02. The I R spectrum indicated the presence of a
pyridine derivative and a hydroxyl group. The NMR spectrum sub-
stantiated the presence of a pyridine ring, but in this case substitution
was 2,3,4, since two doublets ( J = 5 Hz) were observed at 6 6.85 and
8.21 ppm. A methyl singlet was observed at 6 2.53 pprn and was
assigned to a methyl group at the 2-position on a pyridine ring sub-
jected to additional deshielding. A sharp singlet was observed at6 5.94 ppm, suggesting a methine proton attached to two oxygen atoms.
That one of these oxygens was a hydroxyl function was demonstrated
by deuterium exchange. The four remaining protons were observed as
separate, complex multiplets indicative of two adjacent methylene
groups with differing chemical shifts. One pair of protons ( 6 2.56 and
2.98 ppm) was apparently benzylic, whereas the other pair (6 4.29 and
3.88 ppm) was adjacent to oxygen. In the absence of carbonyl and vinyl
groups, the structures 99 and 100 were proposed (1 5 0 ) , he latter being
favored on the basis of an enhanced deshielding of the methyl group bythe proximate hemiacetal. Oxidation with chromium trioxide afforded
a lactone 101.
An interesting observation was made in the mass spectrum of this
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464 GEOFFREY A. CORDELL
compound. The parent ion mle 165 loses 31 mu initially and subse-
quently 28 mu, but in the monodeutero compound (sample crystallized
from C,H,OD) both these ions were shifted by one mass unit. Thissomewhat surprising result was rationalized in terms of a loss of form-
aldehyde from an M + - 1 species giving a species 102, which may lose
CO, retaining the label (150) .
HO
D
102 103
This alkaloid (100)has been named gentiatibetine (1 5 0 ) ,and has beenisolated from a number of other species in the Gentianaceae (see
Table I).Also isolated from G . oliwieri (1 3 1 )was an alkaloid oliveridine,
which gave spectral data similar to those of 100, but which from the
mass spectrum was 14 mu larger. Loss of methoxyl from the molecular
ion gave the base peak mle 148, which subsequently lost C2H, and CO.Structure 103 was proposed on this evidence and Scheme 9 was sug-
gested to account for the mass spectral breakdown ( 131) .This scheme
should be compared with that proposed for the de-0-methyl derivative
m/e 179 mle 148 m/e 120
mle 91SCHEME
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8. MONOTERPENE ALKALOIDS 465
W . UNNAMEDLKALOIDROM Gentiana tibeticu
Chinese workers have isolated a n alkaloid having the st ructure 104from Gentiana tibetica (151) . Evidence for the s tructure came mainly
from the spectral properties after elemental analysis indicated a
molecular formula C,,H, 1N03.The I R spectrum indicated th e presence
of a pyridine nucleus and a conjugated carbonyl. The latter functionality
104
was traced to an aldehyde (6 9 .7 ppm) from the NMR spectrum. Also
observed were a deshielded N-methyl group (6 3.26 ppm) and a slightly
deshielded C-methyl doublet at 6 1.20 ppm, with the methine proton
appearing at 6 4.66 ppm, indicating proximity to both an oxygenfunction and an aromatic system. The remaining protons were observed
as two methylene groups a t 6 3.02 and 4.33 ppm. These da ta are in
agreement with structure 104.
X. OLIVERAMINE105)
Isolated from the chloroform-soluble alkaloids of G. olivieri ( 1 5 2 )was
a crystalline base that analyzed for C,,H,,NO, bu t that by massspectrometry had a molecular weight of 352. The molecular formula
was therefore C2,H2,N204,so th at the compound is dimeric.
Oliveramine, as the compound was named, gave a typical pyridine
UV spectrum and showed the presence of a 6-lactone in the IR spec-
trum, and from the E value, two of these functions were demonstrated.
Four aromatic 2,6-pyridine protons were observed, bu t no olefinic
protons. A three-proton doublet at 6 1.44 ppm indicated a secondary
methyl, and four-proton multiplets a t 6 2 .97 and 1 .98 ppm accounted
for the methylene groups of the 6-lactone. Two two-proton multipletswere also observed, corresponding to two adjacent methylenes, and the
remaining methine proton was masked by other absorptions a t about
6 3.00 ppm. These data suggested structure 105 for oliveramine (152),
which is therefore a reduced dimer of gentianine (62).
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466 GEOFFREY A. CORDELL
105
296 mle
106
Mass spectral analysis of oliveramine indicated that a cleavage
predominates to givemle 1 7 6 as the base peak. A predominant alternate
mode of fragmentation gives rise to m/e 296 (106) by successive losses
of two carbon monoxide molecules (1 5 1 ) .
Y. PEDICULIDINE108)AND PEDICULININE109)
Two further alkaloids of novel structure were isolated from Pedicularis
olqae (153 , 154 ) . As we shall see, although both are C,, alkaloids, their
terpenoid derivation is questionable in view of their structural nature.
Pediculidine (1 5 3 ) , having the molecular formula C,,H,NO, showed
three maxima in the UV for an extended pyridine chromophore, and
this was supported by the IR spectrum which indicated an unsaturated
carbonyl function.
The NMR spectrum of pediculidine confirmed the presence of anolefinic band, and from the observed coupling constant ( J = 12.2 Hz),it was cis-disubstituted. Three aromatic protons were observed, and
from their chemical shift the pyridine ring was 3,4-disubstituted. The
four remaining protons were in the 6 2.45-3.15 ppm region, correspond-
ing to two deshielded methylene functions. On this basis, structures 107
and 108 were proposed (153)for pediculidine, the latte r being favored
on biogenetic reasons. No degradations were performed.
Pediculinine (1 5 4 ) ,also isolated from Verbascum nobile (1 5 5 ) ,on the
other hand, showed a characteristic pyridine UV spectrum and nobands in the carbonyl region of the IR spectrum. The molecular formula
(C,,H,,NO) indicated the presence of a single oxygen atom and this was
traced to a hydroxyl group from the IR and NMR spectra. Acetylation
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8. MONOTERPENE ALKALOIDS 467
gave a monoacetyl derivative in which the methine proton had shifted
from 6 4.01 ppm to 6 5.08 ppm. Substitution of the pyridine ring was
found to be 3,4 from the NMR spectrum, and alkali permanganateoxidation t o pyridine 3,4-dicarboxylic acid (56). The remaining protons
were observed as a four-proton multiplet in the region 6 3.05-2.40 ppm
and as two two-proton triplets at 6 1.98 and 1.57 ppm.
107 10s 109
Structure 109 was assigned (154) to pediculinine on the basis of this
evidence. Pediculidine was not interrelated with pediculinine. Although
structure 108 was chosen on the basis of biogenetic reasoning, it is not
immediately obvious what the biosynthesis of these compounds
involves. They are included here because of their Cl0 skeleton, and their
co-occurrence with monoterpene alkaloids.
Z. PEDICULARINE110),PEDICULARIDINE113),
AND PEDICULINE
Pedicularine was first isolated from Pedicularis olgae in 1963 by the
Tashkent group (69)after separation of plantagonine (18)and boschni-
akine (44). The base was optically inactive and contained a carboxylic
acid group. Subsequent work (156)indicated th at the original materialwas a mixture. Separation by repeated recrystallization afforded pure
pedicularine (mp 207"-209"C). The molecular formula was established
to be C,,H,,N02, supported by a molecular ion a t m/e 177. The UVspectrum indicated a simple pyridine derivative, and the IR spectrum
the presence of a carbonyl function (1710 cm-l).
Alkali oxidation afforded pyridine 3,4-dicarboxylic acid (56) thereby
establishing the substitution. The NMR spectrum confirmed this sub-
stitution, showing three pyridine protons a t 6 8.92, 8.47, and 8.07 ppm,
the latter being coupled doublets. At 6 1.07 ppm, a three-protondoublet was observed corresponding to a secondary methyl group. TWO
One-proton multiplets a t S 1.67 and 2.18 ppm were assigned to two
nonequivalent methylene protons, and the methine group for the
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468 GEOFFREY A. CORDELL
methyl was observed a t 6 3.08 ppm. Also at 6 3.08 ppm, a second methine
signal was observed, and on the basis of the two proposed structures 110
and 111, this would have to be assigned to the methine adjacent to thecarboxylic acid (156) .
110 111 113
The mass spectrum (156 ,157) ndicated losses of methyl radical, Hradical, and carbon dioxide by one fragmentation pathway and carbon
dioxide followed by methyl radical in a second pathway, as shown in
Scheme 10. Biogenetic consideration suggested th at structure 110 was
the more likely. The methyl ester of pedicularine (112)showed losses of
methyl and carbomethoxyl as expected (157)(Scheme 10).
Pedicularis olgae also afforded (158) an alkaloid, pedicularidine,
closely related to pedicularine (110).The base was optically active and
had a molecular formula C,,H,,NO. The UV spectrum confirmed thepresence of a pyridine ring, and the oxygen function was traced to a
saturated aldehyde or ketone from the IR spectrum. The mass spectrum
showed losses of 1mu and 29 mu, indicating the presence of an aldehyde,
and this was confirmed when silver oxide oxidation afforded an amino
acid identical, except for optical rotation, with pedicularine (110).The
gross structure 113 was suggested (158)for pedicularidine. No stereo-
chemistry was derived for this compound.
In 1968 the Tashkent group isolated from Pedicularis olgae a com-
pound th at they named pediculine (159) .Elemental analysis and massspectrometry indicated a molecular formula C,,H,,NO. The UVspectrum demonstrated the presence of a pyridine nucleus, and the IRspectrum indicated the presence of a hydroxyl group and no carbonyl
group, thereby assigning the oxygen function. Hydrogenation gave an
uptake of one molecule of hydrogen.
The mass spectrum showed the molecular ion as a base peak and
important fragment ions at m/e 146 and mle 117. These ions were
thought to be due to losses of methyl and formyl radicals. No NMR data
were reported for pediculine. On the basis of this evidence, the impossiblestructure 114 was proposed (159) or pediculine.
A number of possible alternative structures could be proposed for
pediculine, and of these 115 seems reasonable as a working structure.
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T xu
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470 GEOFFREY A. CORDELL
CH,OH
114 115
The isolation and physical data for the monoterpenoid alkaloids are
summarized in Tables I (160-198) and 11, respectively. Table I11
(199 ,200) summarizes the isolation of a number of alkaloids of unknown
structure from plants shown to contain monoterpene alkaloids.
111. Biosynthesis and Biogenesis of the Monoterpene Alkaloids
The biosynthesis of the monoterpene alkaloids has been the subject
of only limited study, and yet a considerable number of reviews of
varying degrees of completeness have appeared ( 5 - 8 , 1 0 , 1 1 , 1 3 - 1 8 , 5 7 ,
12 2, 201-204). This biosynthetic work is reviewed here and is followed
by a brief discussion of related areas of iridoid biosynthesis and an
outline of the biogenesis of the monoterpene alkaloids.The problem that possibly some or even all of the monoterpenoid
alkaloids may be the result of addition of ammonia to a preformed
iridoid or secoiridoid during work-up has been the subject of some
discussion. Whereas yields of alkaloid isolated are sometimes unaffected
by the use of sodium carbonate in place of ammonia ( 7 6 , 1 1 9 ) , n other
cases, no alkaloids are isolated in the absence of ammonia ( 7 7 , 1 1 8 , 1 1 9 ) ,and in some instances the yield of alkaloid is merely increased by the use
of ammonia (1 9 7 ) .
The leading work in this area is that of Floss and co-workers (1 1 9 ) ,who found that 91% D [15N]gentianine(62) from G. lutea was from
added labeled ammonia. Only G. fet isowii afforded similar quantities
of gentianine by procedures involving ammonia and sodium carbonate.
A . SKYTANTHINES
In 1961, the skytanthines were suggested as belonging to the mono-
terpene group of alkaloids ( 2 1 ) , nd subsequent work has confirmed thisconcept. Feeding [2-14C] mevalonate (116) to Skytanthus acutus (2 0 5 )afforded, as predicted (2 0 6 ) , radioactively labeled skytanthine (a),whereas labeled phenylalanine and acetate gave an inactive product
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TABLE I
ISOLATIONF MONOTERPENELKALOIDS
lkaloid Plan t name
I. Iridoid-derived
Actinidine (37)
(+)-Boschniakine (44) (indicaine)
Actin ida arguta Franchiet Sav.
A . polygama Miq.
Tecoma fu lva G . Don
T . radicans Juss.
Valeriana oficinalis L.
Boschniakia rossica G . Beck
Pedicularis ludwigi Regel
P. olgae Regel
Plantago albicans L.
P . indica L.P. major L.
P. notata Lag.
P . psyllium Dene.
P. ramosa Aschers.
(- )-Boschniakine
( + )-Boschniakinic acid (18) (plantagonine)
Tecoma rndicans J u s s .
T . stuns J u s s .
Incarvillea olgae Regel
Boschniakia rossica
Pedicularis dolichorrhiza Schrenk.
P. ludwigi Regel
P. olgae Regel
Plantago albicans
P . coronopus L.
P. crassifolia Roth
P. crypsoides Boiss.
P. cylindrica Forsk.
P. indica
P. major
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TABLE I (continued)
Alkaloid Plant Name
P. notataP. ovata Forsk.
P. psyllium
P. ramoea
(-)-Boschniakinic acid
Cantleyine (50)
A5-Dehydroskytanthine 28)
A'-Dehydroskytanthine (27)Hydroxyskytanthine I (22)
Hydroxyskytanthine I1 (21)
Indioainine (46)
Isogentialutine (55)
Leptorhabine (57)
4-Noractinidine (48)
N-Normethylskytanthine (47)
Skytanthine (4)
S-Skytanthine(8)
8-Skytanthine-N-oxide(9)
Tecomine (13)
Tecostanine (16)
(- -Tecostidine(17)
(+)-Tecostidine (19)
Venoterpine (52) (gentialutine)
Verbascum songaricum Schrenk.
Incarvillea olgae
Cantleya corniculata
Dipsacus azureus Schrenk.
Jasminum species NGF 29929
Strychnos nu x v o m i c a L.
Tecoma stam
Skytanthus acutue MeyenSkytanthus acutus
Skytanthus acutus
Pedicularis olgae
Gentiana tibetica King
Leptorhabdos parwifolia
Tecoma stans
Tecoma stans
Skytanthus acutus
Skytanthus acutus
Skytanthus acutus
Tecoma fu lva G . Don
Tecoma etans
Tecoma stuns
Tecoma stuns
Pedicularw rhinantoides Hook. f
Alstonia venenata R. Br.
Gentiana asclepiadea L.
G. utea L.
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Unnamed I (24)
Unnamed I1 (25)
Unnamed I (38)Unnamed I1 39)
11. Secoiridoid-derived
Bakankoside (40)
Enicoflavine (90)
Fontaphilline
Gentianadine (74)
Gentianaine (92)
Gentianamine (81)
Gentianidine (79)
Gentianine (62)
G. ibetica
Menyanthes trifoliata L.
Rauwolfia verticillata (Lovr.) Baill.
Tecoma stans
Tecoma stam
Valeriana oflcinalisValeriana oflcinalis
Strychnos vacacoua Baill.
Enicostemma hyssopifolium (Willd.) Ve
Fontanesia phillyraeoides Labill.
Gentiana olgae Regel
G. livieri Griseb.
a. turkestanorum Gandoger
Gentiana caucasa Bieb.
G. aufmanniana Regel e t Schmalh.
G. lgae
Q. olivieri
G. urkestanorum
Gentiana olivieri
G. urkestanorum
Erythraea centaurium Pers.
Gentiana asclepiadea
G.macrophylla Pall.
Menyanthes trifoliata
Swertia japonica MakinoAnthocleista procera Lepr.
A . rhizophoroides Baker
Centaurium pulchella Hayek
Dipsacus azureus
Enicostemma littorale 331.
Erythraea centaurium
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TABLE I (continued)
Alkaloid Plant Name
Fagrea fragrans Roxb.
Fontanesia phillyreoides Labill.
aentiana angu.stifoZiaMichx.
C . asclepiadea
G . axillariJora Lev. et Van.
B. xillaris Reichb.
0. barbata Froel.
a. biebersteinii Bunge
a. bulgarica Velon
0. clusii Perr. et Song.
a. cruciata L.a. decumbens L. f.
8. inaerica G. Beck
G . fetisowii Regel e t Winkler
G .freyniana Bornm.
0. gracilipes Turrill
Q. kauffmanniana
U. Zutea
a. macrophylla Pall.
Q . olivieri
B. neumonanthe L.
a. punctata L.
Q. purdomrii Marquand
a.purpurea L.
a. scabra Bunge
B. chistocalyx C. Koch
0. septem$dea Pall.
a. sino-ornata Balf.
a. straminea Maxim.
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Gentiatibetine (100)
Gentiocrucine (86)
Gentioflavine (85).
B. ianschanica Rupr.
B. ibetica
Q. turlcestanorum
G . vvendenakyi Grossheim
B.wutaiensis Merquand
Ixanthus wiscosus Griseb.
Lomatogonium rotatum Fries.
Menyanthes trifoliata
Ophelia diluta Ledeb.
Swertia connata Schrenk
S. raci$ora Gontsch.
S. berica Fisch.
8.aponica Makino
S.marginata Schrenk
Bentiana mclepiadea
0.uteaB.olivieri
B.punctata
B. purprea
B. ibetica
Menyanthes trgoliata
Enicostemma hyssopifolium
Qentiana cruciata
Erythrea centaurium
Bentiana mclepiadea
B.bulgarica
B. cruciata
B. utea
Q. olgae
a. olivieri
B. unctata
Q . tianshanica
a. viriiowi
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TABLE I (continued)
lkaloid Plant Name
Jasminine (96)
Oheramine (105)
Olivericline (103)Pedicularidine (113)
Pedicularine (110)
Pediculidine (108)
Pediculinine (109)
Unnamed I (104)
111. Unknown structures
Alkaloid I
Alkaloid I1
Alkaloid IVb
Alkaloid V
Swertia connata
S. racilifolia Gentsch.
8. arginata
Ja sm in u m d o ma t iigerum Lingelsh.
J. gracile Andr.
J. lineare R . Br.
J . schumanni i Lingelsh.
Lingustrum novoguineense Lingelsh.
Olea panicula ta R. Br.
Gentiana olivieri
Gentiana oliveriPedicularis olgae
Pedicularis olgae
Pedicularis olgae
Pedicularis olgae
Ver basc um nobile Vel.
Gentiana tibetica
Gentiana asclepiadea
G. puncta ta
Gentiana asclepiadea
0 . bulgarica
G. cruciata
G. lutea .G. puncta ta
Gentiana cruciata
Gentiana asclepiadea
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Alkaloid VI
Alkaloid B
Alkaloid B
Alkaloid C
Alkaloid E
Gentianamine (81)
Indicanine
cf. bulgarica
B. cmciata
B. luteaB. punctata
B. bulqarica
Q. cruciataQentiana macrophylla
Skytanthus acutus
Bentiana macrophyllaSkytanthus acutus
Bentiana caucasia
B . kauffmnniana
B . olqae
Q. olivieri
a. tianthanica a. turkestanorum
0. vvedenskyi
Swertia conmta
S . qraciJEora
S. marginata
Pedicularh dolichorrhiza
Plantaqo albicans
P . indica
P . notata
P . ovata
P . psyllium
Oliverine (105) Bentiana olivieri
Pediculine (115) Pedicularis olqae
Spicatine Centaurium spicaturn Fritsch.
Bentiana aaclepiadea
a Asterisk indicates that ammonia was involved in the isolation procedure.
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TABLE I1PHYSICALROPERTIESF THE MONOTERFENEALKALOI
uv NMR MassMolecular IR spectrum spectrum spectrum
lkaloid Formula mp/hp (mm) spectrum A,,, (log c) ( 6 ppm) W e )
I. Iridoid-DerivedActinidine (37) 100-103°C 191 ( 6 4 )
( 2 4 , 5 4 , 5 5 ,6 1 , 6 2 )
1.27(d, 3)
2.18 (s,3)8.01 (s, 1)
8.11 (9, 1)
( 2 0 )
147, 120 ( 6 4 ) -
-
Boschniakine(44)(indicaine)
SO-90°C [3]
214-216°C
( 2 4 )
( $ 9 )
( z j r , 4 1 )
( 2 4 , 6 9 , 1 6 2 )
239, 268, 282
( 2 4 )
(70, 1, 62)
1.38 (d, 3)8.77 (9, 1)
8.99 (9, 1)10.45 (s,1)
( 4 1 )
(70)
1.15 (d, 3)
1.32 (d, 3)
161, 146, 132,118, 117, 91,
77 (70, 3,196)
oschniakinic acid (18)
(plantagonine)
177, 162, 146,
133. 118. 91.( + ) 218-220°C
( - ) 218-22ooc
( 2 4 , 62, 7,
69, 60)
(162)
( + ) 226-227°C
( 1 6 2 )
77 (70,Y1,196)9.15 (s, 1)
8.64 (8,l)
(71)
Methyl ester
( 4 7 )
1.31 (d, 3)3.78 (s, 3)
8.29 s , 1 )
8.77 s , 1)
(76, 7)
207, 179, 176,
147, 132, 117,
91, 77 (76,
77)
antleyine (50) 132-133OC
130°C (77)( 7 6 )
( 7 6 , 77) 271 (3.39)
(76 , 77)
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(36)s-Dehydroskyt anthine CllHlsN (36) _-(28)
A7-Dehvdrosk~tanthine C,,H,.N (29. - -. .. _ _ . ,
(29) 52, 53)
(22) (alkaloid D)
Hydroxyskytnnthlne I CllHPINO (52) 93°C (23, 52) (52)
94-95OC (53)
Hydroxyskytanthine I1 Cl1HlaNO (53) 119-120°C (53) -(21)
( 7 4 )ndicainine (46) CiaHieN + 0 -( 7 4 )
Isogentialutine ( 5 5 ) CsIIllNO ( 8 s ) 131°C (88) ( 8 8 )
5CD
Leptorhabine (57) CsIIiiNO (89) - ( 8 9 )
261 (3.52)
268 (3.48)
( 7 4 )
254,260,267
( 8 8 )
263,269 (89)
( 4 1 )-Noractinidine (48) CBHIIN 4 1 ) - -
1.0 (d, 3)
1.3 (d , 3)
2.9 (9, 3)5.5 (m, 1 )
(36)
1.50 (s, 3)
0.82 (d, 3)
1.24 (s, 3)
2.3 (s, 3)
1.00 (d, 3)1.12 (5, 3)2.18 (s, 3)
(53)
3.498.55 (s , 1)8.75 (9 , 1)10.13 (s, 1)
( 7 4 )
1.33 (d, 3)3.05-2.98
(m, 2)3.18 (m, 1)
3.69 (b, 1)4.53 (td, 1 )
7.15 (d, 1)
8.28 ( 8 , 1)8.28 (d, 1 )
( 8 8 )1.20 (d, 3)1.97 (m, 1)
3.30 (m, 2)
5.06 (m, 1 )6.94 (bs,1)
7.15 (d , 1)8.07 (d, 1 )
8.11 (4, 1)
( 8 9 )8.03 (d, 1)8.8 ( 5 , 2)8.85 (d, 1)
1.6 (d, 3)
( 52)
(52)
( 4 1 )
165, 150,12 2, -89"
107, 79, 58,44 (36)
-+35.8
(23+ 38.
(53)
110, 84, 58, 44 -38.5
(53)
190,162,161, +14.146, 133,132, ( 7 4
118, 117 , 91,77 ( 7 4 )
149, 120, 105, -98, 79 ( 8 8 )
149, 132,131,
118,117,106,
79 (89)
- +3"
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TABLE II ( con t inued )
uv NMR Mass
Molecular I R spectrum spectrum spectrumAlkaloid Formula mp/ bp (mm) spectrum A,,, (logs) (8 ppm) (mid
N-Normethylskytan- CloHlsN (41 ) 125130' (3) ( 4 1 ) - 0.9 (d, 3) 153 (41 ) +3
Skytanthine (4) ClIHZ1N 54" (1.5 ) (21 , (19 , 165 ) - 1.27 (d, 3) - +4
1.02 (d, 3)hine (47) ( 4 1 )( 4 1 )
(19,-21, 165) 22) 2.18 (s, 3) 262" (1) (23) (19 , 20, 1 6 5 ) + 3
62 (1.5) (19, +2
21, 165)
a-Skytanthine(5)
@-Skytanthine6)
y-Skytanthine (7)
+7
- ( 3 0 ) +1
+5( 3 0 )
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&Skytanthine (8) -
&Skytanthine "oxide C l lH2 , N O- 218-222% ( 3 5 )
Tecomine (13) CI1Hl7NO 125°C (0.1) (39-41)(9) 2H20 ( 3 3 , 3 5 ) ( 3 3 , 3 5 )
(tecomanine) ( 3 9 - 4 1 ) ( 4 0 , 4 1 )
Tecostanine (16) CllHllNO 82OC ( 4 2 , 4 4 ) ( 4 2 , 4 4 )
( 4 ~ ~ 4 4 )
Tecostidine (17) and (19) CIOIIllNO
ifr ( 4 5 , 4 6 )
co
Venoterpene (52) C & l l N O 13&132OC (81-85 , 88)( 8 0 , 8 1 , 8 4 ) ( 8 0 . 8 1 )
128-130°C
(82 , 84 ,86-
88, 1 3 8 )
Unnamed I from CloHziNO 91-92OC ( 4 1 )( 4 1 ) ( 4 1 )ecoma slam (24)
Unnamed I1 from Cl oIIz l NO 82-94' ( 4 1 )T e c m slam (25) ( 4 1 ) ( 4 1 )
-226 (4.1)
(39-41)
-
( 4 5 , 4 6 )
259 (3.50)( 8 1 - 8 5 , 8 8 )
( 4 1 )
( 4 1 )
-
-1.07 (d , 3)
1.12 (d, 3 )
2.75 (5, 3)5.95 ( 8 , 1)
( 4 0 , 4 1 )
0.98 (d, 3 )2.25 ( 9 , 3)3.56 (d, 2)
( 4 4 )
1.27 (d, 3)
4.65 ( 8 , 2)
8.22 ( s , 1)8.27 ( s , 1)
( 4 5 )1.32 (d, 3)2.9-3.3
(m, 3)4.50 (m, 1)5.60 (6,l)
7.09 (d. 1)
167,186,152, +10
110, 84, 58, (244 (30 , 36)
4
- 0' (
-17
- 1
00. 58.44 ( 4 4 ) 0 (
163 (45 , 46) -4"
+5.
+ 2149, 134,132,120,106.77
(80-82)
8.18 id, 1)
8.21 ( 8 , 1)
(81-83. 85.88)
(Benzoate) (41)0.9 (d, 3)
1.0 (d, 3)
2.3 ( 8 , 3)
( 4 1 )
0.95 (d, 3)1.24 (d, 3) 74,55 ( 4 1 )2.27 (9, 3)
183, 166, 150,
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TABLE I1 (confinued)
uv N M R Mass
Molecular IR spectrum spectrum spectrumAlkaloid Formula mp/bp (mm ) spectrum Amax (log e) ( 8 ppm) (mle)
222, 267 ( 6 4 ) 1.23 (d, 3) 288, 147, 132, 4.120 ( 6 4 . 6 5 ).34 (s. 3)
Unnamed I fromVnleriana ofleinalii,(88)
Unnamed I1 fromValeriana offkinalin(39)
11. Secoiridoid-derived
Bakankoside (60)
,+ Enicoflavine(90)
00N
Fontaphilline (69)
Gentianadine (74)
ClsHazNOCl 201-203°C ( 6 4 )
157" and 200°C -( 9 0 )
162" and 211OC( 9 3 )
80" and 121°C ( 1 2 5 )
(125)
C8H7NOz (126) 77-78°C ( 1 2 6 , (126)129)
76-77°C ( 1 3 2 ,1 3 3 )
8748°C ( 9 9 )
. .
4.73 im, 4)6.73 (d , 1)
7.04 (d, 1)
8.83 (8 . 1)
8.90 (s, 1)( 6 4 , 6 5 )
(65 ) ( 6 5 ) +
40, 270 ( 1 4 6 ) 1.6 (m, 2) ( 1 4 6 )
2.45 (b, 1 )
212 (4.49)
257 (4.25)
( 1 2 5 )
( 9 9 )
4.4 (m, 2)5.8-5.96 (dd, 2)6.9-6.98 (m, 2)
8.2 (m, 1)
8.9 (b, 1)
9.3 s , 1)10.1 (b, )
(116)3.60 (t, 2)3.95 (s, 3)4.55 ( t , 2) ( 1 2 5 )
5.60 (m, 2)6.80 (d, 1)7.30 (m, 1)
7.85 (d, 1)
8.75 (9, 1)9.00 (5, 1)
3.04 ( t , 2)
4.52 ( t ,2) ( 1 2 8 )7.19 (9. )
8.64 (d, 1)9.12 (d, 1)
( 1 2 5 )149, 120, 92, 65
(127)
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Gentianaine (92) CeH,NO, ( 1 2 7 , 149-150°C ( 1 2 9 )1 2 9 ) ( 1 2 7 , 1 2 9 )
Gentianamine (81) CIIH~INOB 149-150°C ( 1 2 6 )
( 1 2 6 ) ( 1 2 6 )
231 (4.16) 2.88 (4.16) 141.113. 112. 9268 (4.1)' 4.70m, 2) ( i z . 9 )
( 1 2 9 ) 8.50m, 2)( 1 3 7 )
( 1 2 6 ) 5.80 q, 2) 205, 75, 31,
117, 1 1,OG).94 (rl, 1)8.85 a , 1)
9.06 a , 1)( 1 2 7 )
Gentianidine(79) CgHsN02 129-13OoC ( 1 3 4 , 1 3 7 ) ( 1 3 4 ) ( 1 3 4 ) ( 1 3 6 )
Gentianine (62) CIOH.O, ( 9 5 , 8042°C 8 4 , ( 8 4 , 8 5 , 9 7 , ( 8 4 . 8 5 , 99, ( 1 0 1 , 1 1 3 ) 175,147,117,( 1 3 4 , 1 3 9 ) ( 1 3 7 -1 3 9 )
1 2 5 , 1 7 6 ) 8 5 , 85 , 9 9 , 9 9 , 1 0 1 , 1 7 5 , 1 0 1 , 1 4 7 , 91 ( 1 2 5 )1 0 1 , 113, 1 9 1 ) 1 6 9 )
1 3 8 , 1 4 7 ,1 6 8 , 1 7 1 ,1 7 6 , 1 8 1 ,1 8 3 , 1 X 6 )
83°C 1 3 8 , 1 9 3 )
Gentlatibetine (100) CsHllNOa 159-160°C ( 1 5 0 )
( 1 5 0 ) ( 1 3 1 )161.5"C
( 8 6 , 1 3 8 , 1 5 0 )
( 1 5 0 ) 2.53 a, 3) 165
2.56 m, 1) 134
2.98 m, 1) 1063.88 (m, 1) ( 1 5 0 )4.29 m, 1)5.94 a , 1)6.85 d, 1)8.21 d, 1)
( 1 5 0 )
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TABLE I1 cont inued)
uv N M R MassMolecular I R spectrum spectrum spect,rum
(midlkaloid Formula mp/bp (mm) spectrum Amax (log 6) ( 8 ppm)
Gentiocrucine (86) CeR7N03 1 4 4 ) - ( 1 4 4 ) 232, 283 ( 1 4 4 ) 2.58 (m, 2)
4.40 (m. 2)
Gentioflavine 85) CioHllNOB 207-208°C ( 1 4 0 , 1 4 1 ) 235,298, 410( 1 4 0 , 1 4 1 ) ( 1 7 1 ) ( 1 4 0 , 1 4 1 )
218-220°C
(140-I42)
Jasrninine (96) CiiHmNzOQ 175-176OC ( 1 4 8 )( 1 4 8 ) ( 2 4 8 , 1 4 9 )
Ollveridine(103) C ~ O H ~ O N O ~60°C ( 1 3 2 ) ( 1 3 1 )
( 1 3 1 )Pedicularidiue (113) CloH1,NO 211-212OC ( 2 5 8 )
( 1 5 8 ) ( 1 5 8 )
Pedicularine (110) C I O H ~ ~ N O Z203-204°C ( 1 5 6 , 1 5 8 )( 1 5 6 , 1 5 7 ) ( 1 5 8 )
207-209°C(dec.) ( 6 9 ,1 5 6 )
Pediculidine (108) CioHgNO ( 1 5 3 ) 74-75°C ( 2 5 3 ) ( 2 5 3 )
( 1 3 1 )
236 (3.36)270 (3.32)
( 1 5 8 )272 ( 1 5 6 ,
1 5 8 )
268 (3.97)273 (3.96)
293 (3.36)
( 1 5 3 )
8.10 (bd, 1)
( 1 4 4 )
1.3 (d, 3)
3.0 ( t , 2)4.35 ( t ,2)
5.2 (9, 1)8.45 9,1)8.80 (a, 1)10.10 (8, 1)
( 1 4 1 )1.58 (d, 3)
4.75 rn, 1)
4.87 ( % I )
5.12 ( I)8.57 (8 , 1)
9.01 (8 , 1)
( 1 4 8 )1.44 (d, 3)
1.98 (m, 2)2.67 (m, 2)2.96 (m, 5 )4.46 (m, 4)
8.43 (8 , 1)
8.76 (8 , 1)8.94 (8, 1)9.00 (s, 1)
( 1 5 2 )-
-
8.07
8.478.92
( 1 5 6 )
2.45-3.15 ( m )6.34 (d)
141,113
111,97 ( 1 4 4 )
-
20,205, 173, -33"
145, 118,117,91 ( 2 4 8 ) - 3 7 .
352, 296,176
( 1 5 2 )
179, 151, 148,
120, 91 ( 1 3 1 ) 67.1 5 8 )
(156-158) 0 (
- 5
( 2f 52
( 1159, 158, 131, Picr
30. 118. 117.7.12 id j 104,' 103,' 102,'7.15 (d) 77 ( 1 5 3 )
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Pediculinine (109) CIOHI~NO 133-134°C ( 1 5 4 )
( 1 5 4 ) ( 1 5 4 , 1 5 5 )
Unnamed from G'entiana CloH,,NO3 208-210°C ( 1 5 1 )
tibetica ( 1 0 4 ) ( 1 5 1 ) ( 151 )
111. Unknown Structures
Alkaloid I C13HteNaO3
Alkaloid I1 -1 4 0 )
183-187°C
( 1 4 0 )
138-140°C
( 1 9 7 )240°C ( 1 9 7 )
248-252OC
128-130°C
( 1 4 7 )190°C (15)
(23)206-208°C
( 1 4 7 )120-140°C
(28)375-380°C
-
( 1 4 0 )
( 1 2 6 , 1 2 9 )-
206-207°C
( 1 3 1 )188-189T
( 1 8 9 )182-183°C
( 1 9 8 )
262 (3.33)
269 (3.23)
( 1 5 4 )
234 (4.21)
296 (4.32)
402 (3.95)
( 1 5 1 )
269,316 ( 1 4 0 )
-
234, 266 ( 1 4 7 )
8.41 (d )8.51 (9)
( 1 5 3 )1.57( t , 2)
1.98 (t , 2)
3.05-2.10
( m , 4)
4.01 (m, 2)6.93 (d , 1)8.19 (rn, 2)
( 1 5 4 )1.20 (d , 3)3.02 (m, 2)
3.26 (s, 3)
4.33 ( m , 2)
4.66 (u . 1)7.74(s, 1 )
9.70 (s, 1)
( 1 5 1 )
-
-
-
-
-
-
-
-
--
-
---
161, 146, 145,131, 130, 118,
117, 91, 77
( 1 5 4 )
- 0.80
-
-
61, 146, 117, + 6
91 ( 1 5 8 )
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486 GEOFFREY A. CORDELL
TABLE I11
POSSIBLE ISOLATIONS O F MONOTERPENELKALOIDSUNIDENTIFIED)
Compound Pla nt name mp/bp ("C) Reference
Alkaloid I11
Alkaloid I11
Alkaloid I11 (aerial
Alkaloid I11 (roots)
Alkaloid 111-1
Alkaloid 111-2
Alkaloid IVa
Alkaloid VIIAlkaloid E-2
Base A
Base B
E-1
E-2
J-5-2
Substance V
Substance V I
Substance VII
VP-2
VP-3
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
UnknownUnknown
TJnknown
parts)
Centiana bulgarica
G . cruciata
G. punctatu
Q. punctata
G. asclepiadea
C. asclepiadea
G . punctata
C . punctataErythraea celztaurium
Plantago notata
P. albicana
Erythrae centaurium
E . centaurium
Jasmi num fruticans
J . fruticans
Menyanthes trifoliata
M . trifoliata
M . trifoliata
Va le ri am stolonifera
V . stolonifera
Anthocleista rhizophoroides
Qentiana asclepiadea
G . asclepiadea
Qentiana sp.
Qentiana sp.
Gentiana sp.
Skytanthus acutus
S. acutus
Swertia japonicaTecoma stana
Verbascum songaricum
---
-
157-160---
72
106-
-
260
143-144
oil
---
-
-
249-252
240
189-191
Picrate, mp 125-127-
--
-
197
197
197
197
197
197
194
140137
61
61
178
178
199
199
138
138
138
200
200
169
86
86
142
142
142
166
33
19339
164
(205,207).Work with S. acutus in vitro gave a labeled product from
[2-14C]rnevalonate(2 0 8 ) . Skytanthine is therefore derived from a
terpenoid precursor.
Similar results were subsequently reported by Waller and co-workers
(209);[2-14C]mevalonatewas incorporated, but [2-14C]lysinewas not.
Different specific activities of the skytanthines from different plantparts were observed both from feeding labeled mevalonate and labeled
methionine. The latter was shown to be a specific precursor of the
N-methyl group (209).
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8. MONOTERPENE ALKALOIDS 487
A further complication was also uncovered, for considerable random-
ization of the label in the monoterpene terminal carbon atoms was
observed in 3-year-old plants, yet essentially no randomization wasfound in experiments with 1.3-year-old plants (209). In the biosynthesis
of iridoids (12 4, 210-214) and indole alkaloids (201 ) , andomization of
label is consistently observed. Some of these problems have been
discussed by Appel (215 ) ,who considers that multiple labeling must
have occurred in order to have labeled the methyl group, C-9. Much of
this work on skytanthines has been summarized by Marini-Bettolo ( 6 ) .
B. ALKALOIDSF T. stuns
A more extensive study of the biosynthesis of the alkaloids of Tecomastuns, has been carried out by Gross and co-workers (216) . [2-I4C]-
Acetate and [2-14C]mevaIonate ach labeled the alkaloids %skytanthine
(8), tecostanine (16),ecomine (13), and boschniakine (44). 2-14C]-
Acetate was also incorporated into A5-dehydroskytanthine (28). The
monoterpenoid nature of these alkaloids is therefore established. The
N-methyl groups in 8, 28, 13, nd 44 were derived from methionine.
Neither loganin ( 5 7 ) , uniformly labeled, nor actinidine (3) wereincorporated into these alkaloids. Thus, the branching point for the
formation of the skytanthine-type alkaloids occurs at a stage prior to
formation of loganin, and the oxidation of the piperidine ring to a
pyridine ring is not reversible. Uniformly-labeled &skytanthine (8),
however, gave rise t o moderate incorporation into tecostanine (16)and
tecomine (13),bu t almost no incorporation into 44 or 28. N-Normethyl-
skytanthine (47), on the other hand, gave excellent incorporation into
tecostanine, moderate incorporation into 13 and 8, but very low
incorporation into 44 (216) .
C. ACTINIDINE3) ND THE Vuleriuna ALKALOID8
The biosynthesis of actinidine was first studied by Waller and CO-
workers (217 ) ,who demonstrated that i t was not derived from lysine,
aspartic acid, or quinolinic acid, but rather by a monoterpene route.
Thus, [2-14C]acetate, 2-14C]mevaIonate 116),and [ 1-14C]geranylpyro-
phosphate (117) were each incorporated into actindine in Actinidiupolygumu. [2-14C]Mevalonate abeled actinidine (3) o the extent of
0.12% after only 24 hours, indicating the quite rapid alkaloid formation
in this plant.
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488 GEOF FREY A. CORDELL
Experiments by Gross and co-workers ( 5 7 )with Valeriana o#cinalis
demonstrated that [2-14C]mevalonatewas an effective precursor of both
actinidine and the quaternary alkaloid 38 to the extent of 0.1 and0.47%, respectively. Phenylalanine was not a precursor of the phenyl
ring in 38, but tyrosine was found to be incorporated. Uniformly-
labeled actinidine (3) was also incorporated into 38.
C H 3
H O C H x WIII Hs Gy./ \ 0Hs Hr Hr CO,H
C H , C H 3 N
116 117 118
0 = degraded, active
A = degraded, inactive
0 '4 'OH H0''''''B7\\ 0 G l u HY%H, CO&H3
3G l u 0 0OGlu CO,R \ o
66 R = O H120 R = H
51 R = C H 3119 R = H
1 2 1
D. GEENTIANINE62)
The incorporation of glycine into a number of terpenoid-derived
alkaloids has been observed ( 2 0 1 ) .When [2-14C]glycinewas administered
to young Gentiana asclepiadea plants ( 1 8 2 ) labeled gentianine was
produced ( 1 8 2 ) . Degradation and isolation indicated the labeling ofgentianine as shown in 118. This labeling corresponds to a biosynthesis
from [2J4C]acetate, but in the formation of acetate, current theories
suggest that labeling should be at the 1 position of acetate ( 2 1 8 ) .
Clearly there is much to learn about the utilization of glycine in terpine
biosynthesis. Further work by the Bulgarian group ( 2 1 9 )was aimed at
evaluating the role of pyruvate in gentianine biosynthesis. Neither
[l-14C]pyruvatenor [1-l4C]formatewas incorporated.
It was mentioned previouly that both gentiopicroside (66) and
swertiamarin (65)are in vitro precursors of gentianaine (220 , 221 ) .It istherefore pertinent to comment on some aspects of the biosynthesis of
gentiopicroside. A number of labeled mevalonates have been shown to
be precursors ( 1 2 4 , 2 1 2 - 2 1 4 , 2 2 1 - 2 2 3 ) . Experiments with [4-3H,2-14C]-
(4R)-nd (4s)-mevalonates (116) indicated that as expected the 48-
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8. MONOTERPENE ALKALOIDS 489
protons were lost and only one 4R-proton was retained. This tritium
was located a t the ring junction hydrogen as indicated by conversion to
a tritiumless gentianine (221 ) . Similar experiments with [2-2H,2-14C]-(2R)- and (2s)-mevalonates indicated th at the tritium was lost from
the 2S-labeled species and approximately half of the tritium from the
2R-labeled species. There was no tritium loss between loganic acid (119)
and gentiopicroside, and subsequent work deduced that most of the
tritium was at C-7 (224 ) .
Loganin (51) ( 2 2 0 , 2 2 1 )and loganic acid ( 2 2 1 , 2 2 3 )are also excellent
precursors of 66. [5,9-3H, 3,7,1 -14C]Loganic acid was incorporated into
66 with loss of half the tritium label (221 , 223 ) ) so that oxidation is
regiospecific. Sweroside (120) is also a precursor of gentiopicroside(225 ,226 ) .
More recently an iridoid gentioside (121) was isolated from three
Gentiana species ( 2 2 7 )and shown to be a precursor of gentiopicroside
and, by implication, of gentianine.
E. GENTIOFLAVINE85)
The novel monoterpene alkaloid gentioflavine was investigated by the
Bulgarian group (142 , 194 , 228 ) . [l-14C]Geraniol (122) and [1-14C]-linalool (123) were each incorporated. Degradation of the labeled
gentioflavine indicated that the activity was specifically a t the aldehyde
group, thereby demonstrating the monoterpene derivation of gentio-
flavine (194 ) . It was also demonstrated that a t least some of the
biosynthetic reactions of the alkaloids may be reversible. Feeding uni-
formly labeled gentiopicroside to G. asclepiadea gave a 23% incorpora-
CH, A H,
123
tion into gentioflavine ( 2 2 8 ) .Previously, however, it had been demon-
strated that gentioflavine was also a precursor of gentianine, gentian-
idine (79), and possibly gentianadine (74) (229 ) .Labeled gentioflavine
was not incorporated into gentiopicroside (228 ) hence, another routenot involving gentiopicroside must exist for the conversion of 85 to 62.
Experiments using 14C0, indicated that labeling of the alkaloids ap-
peared in gentioflavine before gentianine (229).The biosynthetic data
for the monoterpene alkaloids are summarized in Table I V .
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TABLE IV
INCORPORATIONATA OR MONOTERPENE LKALOIDS
Incorporationa
Alkaloid precursor Pl an t % Reference
Actinidine
[2-14C]acetate
[2-14C]aspartate
[2- 14C]lysine
[2-'4C]mevalonate
[ l-14C]geranyl pyrophosphate
[2,3,5,7-'4C4]quinolinic cid
[' 4C methionine
[2 - 4C]acetate
[2-14C]mevalonate
[U-3H]loganin
[U-3H]N-normethylskytanthine
[U-3H16-skytanthine
[U-3H]actinidine
A'-Dehydroskytanthine
[14C]methionine
[2-14C]lysine
[2-14C]mevalonate
A5-Dehydroskytanthine
['4C]rnethionine
[2-14C]aceate
[2- 4C]mevalonate
[W3H loganin
[U-3H N-normethylskytanthine
[U-3H1G-sl~ytanthine
[U-3H]actinidine
[U-'4C]gentioflavine
[U-'4C]gentioflavine
Boschniakine
Gentianadine
Gentianine1 4 ~ 0 ,
[14C]formate
[ -14C]acetate
[2-14C]acetate
[2-14C]glycine
[I-"%Tpyruvate
[2-'*C]mevalonate
[U 4C]gent oflavine
Gentioflavine
1 4 ~ 0 ,
[1-14C]geraniol
[1 14C]nerol
[U-'4C]gentiopicroside
Actinid ia polygama
A . polygama
A . polygama
A . polyrJamu
Valeriana osci nal is
A . polygama
A . polygama
Tecoma stans
T . stans
T . stans
T . stans
T . stans
T . stans
T . stans
Skytanthus acuttu
S. acutw
S. acutus
Tecoma stans
T . stans
T . stans
T . stans
T . stans
T . stans
T . stans
Gentiana asclepiadea
G. asclepiadea
G . asclepiadea
G. asclepiadea
G . asclepiadea
G. asclepiadea
G. asclepiadea
G. asclepiadea
G . asclepiadea.
G. aactepiadea
Gentiana asclepiadea
G. asclepiadea
G. asclepiadea
0 . aaclepiadea
0.04
0
0
0.17
0.47
0.06
0
L
L
L0
0
0
0
4.0
0
0.2
LL
L
0
0.03
0.04
0
NG
NG
NG
0
L
NG
NG
0
NG
NC
NG
3.0
3.0
2.3
2 1 7
2 1 7
21 7
57
21 7
21 7
216
2 1 6
216
21 6
2 1 6
216
2 1 6
209
209
209
2 1 6
21 6
2 16
216
21 6
2 1 6
2 1 6
229
2 2 9
2 2 0
220
1 9 9
1 1 9
1 8 2
2 1 9
1 8 2
1 9 4 ,
2 2 8 ,
229
2 2 9
1 9 4
194
2 2 8
21 7
490
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TABLE I V (conrinued)
Incorporationa
Referencelkaloid precursor Pl an t %
Skytanthine
[2-'4C]acet.ate
[2-'*C]mevalonate
a-Skytanthine
[14C]methionine
[2-'4C]lysine[2-'4C]mevalonate
['4C]methionine
[2-l4C]1ysine
[2-14C]mevalonate
[14C]methionine
[2-14C]acetate
[2-14C]mevalonate
[U-3H]loganin
[U-3H]N-normethylskytanthine
[U-3H]G-skytanthine
[U-3H]actinidine
[14C]methionine
[2-'4C]acetate
[2-'4C]mevalonate
[U-3H]loganin
[U-3H]N-normethylskytanthine
[U-3H]G-skytanthine
[U-3H]actinidine
8-Skytanthine
6-Skytanthine
Tecomine
Tecostanine
[ 4C]methionine
[2-14C]acetate
[2-'4C]mevalonate
[U-3H]loganin
[U-3H]N-normethylskytanthine
[U-3H]6-skytanthine
[U-3H]actinidine
Valeliana alkaloid (38)
[Z-4C]mevaIonate[U-'4C]phenylalanine
[2-'4C]tyrosine
[U-3H]actinidine
Skgtanthw aeulus
S. acutw
S. acutus
S . acutus
Skytanthus acutils
S . acutusS. acutus
Skytanthus acutus
S. acutus
S . a e u t u s
Tecoma stuns
T . stam
T . stans
T . stuns
T . stans
T . stuns
T . stans
Tecoma stuns
T . stuns
T . stuns
T . stuns
T . stuns
T . slam
T . stuns
Tecoma stuns
T , stuns
T . stans
T . stuns
T . s tam
T . stuns
T . stam
Valeriana of lc ina l isv.oflcinali.9
v. o f i c i n a l i s
V. oficicinalis
0
L
L ( ~ T Z itro)
0
4.0
00.17
10.0
0
0.2
1 .1
L
L
00.1
0.9
0
0.2
L
L
0
0.1
0.1
0
0.6
L
L
0
1.4
0.6
0
0.10
0.02
0.04
6, 206,
208
6 , 205 ,
207
208
6 , 205 ,
20 7
209
209209
209
209
209
216
216
216
21 6216
21 6
216
216
216
216
216
216
216
21 6
216
216
216
216
216
216
216
5757
57
57
a L = low incorporation; NG = not given.
491
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492 GEOFFREY A . CORDELL
F. BIOGENESIS
It was mentioned in the introduction to this chapter that much ofthe stimulation of interest in these alkaloids came as a result of the
general interest in the iridoids and indole alkaloids following the pro-
posals of Thomas ( 2 ) and Wenkert ( 3 ) . The biogenesis of the mono-
terpene alkaloids, a frequently discussed topic ( 1 , 1 0 , 11, 14, 15 , 44 , 48 ,
5 7 , 8 1 , 8 4 , 8 6 , 1 1 2 , 1 2 5 , 1 3 7 , 1 4 1 , 1 4 8 ) , is intimately entwined with the
biosynthesis of the iridoids and secoiridoids. It is therefore pertinent a t
this point to summarize briefly some of the results and biosynthetic
schemes developed in this area that are applicable to the monoterpene
alkaloids.A scheme for the formation of the iridoids and secoiridoids from
geraniol is shown in Scheme 1 1 . The scheme highlights some of the
potential precursors of the monoterpene alkaloids, and each of these is
discussed sequentially. (R)-()-Mevalonic acid 116) s sequentially
phosphorylated to 5-phosphomevalonic acid and 5-phosphomevalonic
124 125
OPPCHa '1$ . "'Hs
, Hr
4 2 5 126
CH,OPP CH,OPP
117 R = PP
122 R = H
127
SCHEME1
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8. MONOTERPENE ALKALOIDS 493
$f
&LH,OH rc--
6H,OH
CHO CH20H CHaOPP
CH, Hr CH, Hr CH3
132 131
COaRISkytanthines
CH3 OGlu
154 128 R = CH3
137 R = H
Hr y2R iH O X o +-- HO-@ C 51
OGlu H°CH2 OGlu
129 R = CH,
130 R = H
I139
120- 5 ---+ Monoterpem alkaloids
SCHEME1 ( conr inued)
acid (124). rans elimination ( 2 3 0 , 2 3 1 ) ffords isopentyl pyrophosphate,
which undergoes enzyme-mediated stereoselective loss of the pro-4S
hydrogen (2 3 2 )and stereoselective addition of hydrogen t o the re side
of the double bond (2 3 3 ) o produce dimethylallyl pyrophosphate ( 2 3 4 ) .
Stereoselective loss of the pro-48 (in mevalonate) proton ( 2 2 1 , 2 2 3 , 2 3 0 ,2 3 5 , 2 3 6 ) from isopentyl pyrophosphate (125) in the coupling-
elimination reaction with dimethylallyl pyrophosphate (126) roduces
geranyl pyrophosphate (117) n which both pro-4S hydrogens of
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494 GEOFFREY A. CORDELL
mevalonate have been lost, and this has been confirmed using doubly-
labeled mevalonates into loganin (51)and loganic acid (119) (221 , 223).
After trans-cis isomerization of the 2,3 double bond in geranylpyrophosphate (97) to give neryl pyrophosphate (127),cyclization and
formation of the cyclopentanol ring occurs. I n the case of the iridoids
and indole alkaloids thus far studied, this cyclization is stereospecifically
cis and proceeds with retention of both hydrogen atoms as indicated.
Steps after the cyclization and prior to the formation of deoxyloganin
(128)are still in some doubt.
Deoxyloganin is a precursor of loganin (237 ) and a number of
secoiridoids (224,238-240) ,and it has been demonstrated tha t hydroxyl-
ation of deoxyloganin is stereospecific (225 ) .The derivation of loganin(124, 222, 241) and secologanin (129) (242) from [2-14C]mevalonate is
well established, as is their formation from variously labeled geraniols
( 2 2 2 , 2 3 5 , 2 4 2 - 2 4 4 ) . Loganin is a precursor of secologanin, ( 2 4 5 )
secologanic acid (130) ( 2 4 2 , 2 4 6 ) ,and a number of other secoiridoids
( 2 2 0 , 2 2 1 , 2 2 3 , 2 2 4 , 2 3 9 , 2 4 7 - 2 4 9 ) . ecologanin has been demonstrated
to be a precursor of a number of secoiridoids ( 2 4 9 )and this route from
loganin to the secoiridoids as well as another route have been investi-
gated by Inouye and co-workers (249 ) .
Returning to a point in the biosynthesis scheme where the cyclo-pentane ring has just formed, we observe that a number of possible
routes exist, depending upon the various stages of oxidation of the two
alcohol functions and the methyl group in 131. In the formation of the
Skytanthus alkaloids, oxidation of the two alcohol functions occurs to
the dialdehyde 132, with subsequent condensation with ammonia.
The labeling a t C-9 of skytanthine (4) from [2-14C]mevalonate(209)
would imply a randomization a t some point and would involve an
unlikely oxidation, subsequent reduction of the methyl group, and
N-methylation with methionine. Oxidation after condensation with
ammonia, rather than reduction, affords actinidine (3).Several oxidized
actinidine/skytanthine-type lkaloids are known; for example, teco-
stanine (16)and tecostidine (17), n which one of the ring methyl groups
has been hydroxylated. This oxidation may occur after formation of the
nucleus, but it seems more probable that a hydroxydialdehyde such as
133 is involved.
It has been implied that the series of compounds, actinidine, teco-
stidine, boschniakine (44), boschniakinic acid (18),and 4-noractinidine
(48) forms a neat biosynthetic oxidative series. No experiments to
prove or disprove this concept have been reported. However, it seems
more likely that oxidation of the C-8 methyl group of nerol occurs after
formation of the cyclopentane ring and before alkaloid formation; thus,
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8. MONOTERPENE ALKALOIDS 495
species of the type 133 and 134 and other highly oxidized species should
be involved.
A number of hydroxyskytanthines are known (see earlier), and againthe problem arises as to their derivation from an alkaloid (skytanthine)
precursor or an oxidized monoterpene. No experiments in this area have
been reported. I n the case of hydroxyskytanthines I and I1 (22 and 21),
i t may be tha t hydroxylation is part of the initial cyclization reaction
giving 135 and 136, which subsequently condense with ammonia and
are reduced.
133 135 136
In the hydroxyskytanthines, where the ring junction is hydroxylated,
it seems more probable that a preformed alkaloid is a precursor.
Cantleyine (50) was shown to be an artifact in Cantleya corniculata
formed by ammonia addition to loganin (51) (77) . In a similar manner,
boschniakinic acid (18)may be derived by ammonia condensation with
deoxyloganic acid (137) ( 224) .Decarboxylation of 18 leads to 4-noractinidine (48) as noted pre-
viously. A number of 4-noriridoids are also known, so that again this
presents an alternative biosynthetic route. The same comments apply
to the formation of venoterpine (52), which may or may not be derived
from the carboxylic acid corresponding to cantleyine (138).
50 R = CH,
138 R = H140
Cleavage of the cyclopentane ring of loganin probably proceeds via
10-hydroxyloganin(139)(250)to give secologanin (129).The subsequentelaborations of secologanin by condensation and rearrangement are
numerous and are evidenced by the wide array of known secoiridoids.
This structure diversification is almost matched in the monoterpene
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496 GEOFFREY A. CORDELL
alkaloids. There are six basic structure types of monoterpene alkaloids
derived from the secoiridoid skeleton thus far isolated. In simple terms,
we can envisage the formation of these skeleta as occurring from theester trialdehyde 140 by selective condensation reactions. This highly
functionalized compound is merely the hydrolysed version of seco-
loganin, and it serves a useful purpose in analyzing the probable bio-
synthetic origin of the monoterpene alkaloids.
For the purpose of deriving the alkaloid skeleta, we will consider five
different orientations of this unit in condensation with ammonia. These
orientations are depicted in Scheme 1 2 and the primary alkaloid from
this orientation is shown. This, of course, is only a schematic representa-
tion, and we must look more carefully if we are to discern the probableiridoid precursors of each alkaloid. Unlike the indole alkaloids where
structure diversification takes place a t the alkaloid level, it appears that
structure modification in the monoterpene alkaloids occurs a t the
iridoid level.
0
Fontaphilline (69)
/*
Gentianine (62)
Jasminine (96)
SCHEME2. Biogenesis of the monoterpene alkaloids.
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8. MONOTERPENE ALKALOIDS 497
Gentiatibetine (100)
CHO COaCH3
NH3 H
Bakankoside (60)
'02CH3 CH$
&A o 2 P C H 3
CHO CHO
NH3N
Pedicularine (110)
rH0\
CH3
104
SCHEME2 (continued)
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498 GEOFFREY A. CORDELL
A s was mentioned previously, both gentiopicroside (66) and swertia-
marin (65) condense readily with ammonia to give gentianine, thereby
delineating a possible biosynthetic precursor. Swertoside (119) is at alower oxidation state than 66, and condensation of the lactone ring with
ammonia would give bakankoside (60) having the absolute stereo-
chemistry indicated. Similar condensation with ammonia in the lactone
ring of kingiside (142) would give jasminine (96).
A study of the iridoids of Gentiana punctata (195) afforded a new
secoiridoid, gentioflavoside (142). Treatment with aqueous ethanolic
ammonia afforded gentioflavine (95)) but no details are available on
the formation of 141. Condensation with ammonia in the lactol ring of
$CH3 o
HCH, OGlu
141 a-CH3
146 /I-CH,
142
secologanin (129), reduction of the aldehyde, and condensation with
p-hydroxybenzoic acid would lead t o fontaphilline (69).
The biogenesis of gentiatibetine (100) presents an interesting prob-
lem. One possibility is shown in Scheme 12, but a second possibility
also exists involving a compound such as tetrahydroantirride (143) as a
precursor as shown in Scheme 13. The probable biogenesis of enico-
flavine (90) and gentiocrucine (87) was mentioned previously. It is
pertinent to note here the isolation of erythrocentaurin (144) from
E . hyssopifolium and Swertia lawii ( 251) , ince this is another compound
derived from swertiamarin (65) via the lactonic dialdehyde 145.
OGlu CH, OGlu
143
SCHEME 13
100
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8. MONOTERPENE ALKALOIDS 499
The existence of optical antipodes of some of the alkaloids also pre-
sents a slight problem. In most instances, this is due to the opposite
configuration at C-8. There are several examples of iridoids in whichboth C-8 epimers occur naturally, and the situation with kingiside (141)
(252) and epikingiside (146) has been studied by Inouye’s group ( 2 5 3 ) ,
who demonstrated the operation of two separate routes for the forma-
tion of these substances.
144 145 147
For the situation in the series of a monoterpene alkaloids that are
formed from a monoterpene prior to iridoid formation, we must
envisage a different biogenesis in which 8-epiiridoidal (147) is an inter-
mediate. It was suggested by Inouye (253) that d- and Z-citronellals are
the intermediates which give rise to the opposite C-8 configurations.
Citronella1 (148) was not a precursor of the indole alkaloids ( 2 5 4 ) .Ex-tensive further work is required before the subtle details of the bio-
synthesis of both the monoterpene alkaloids and the iridoids are clarified.
IV. Pharmacology of the Monoterpene Alkaloids
The original interest in the plants of the Gentianaceae arose because
of the widespread use of gentian in Europe ( 2 5 5 ) .At the turn of the
century, Gentiana spp. were current in no less than twenty pharmaco-paeias, the important species being Gentiana lutea, G. purpurea , G .
punctata , and G. panon ica (256).A discussion of the pharmacological
action of these alkaloids concludes this review.
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500 GEOFFREY A. CORDELL
A. ACTINIDINE3)
Actinidia polygama is a potent feline attractant ( 2 5 7 ) , and theprincipal alkaloid, actinidine, has been shown to exhibit strong at tr act-
ant activity for several species of Felidae, including the cat, lion, tiger,
and leopard ( 5 4 ) .Actinidine also has a marked effect on the EEG of the
cat (258 , 259) , since during EEG flattening positive spikes were
distinctly observed similar to those obtained with acetylcholine. A
number of side effects have been observed (260 ) . The pharmacology
of actinidine has been reviewed ( 2 6 1 ) .
B. TECOMINE13) AND TECOSTANINE16)
The leaves of various Tecoma species have enjoyed a wide and
prolonged use by the natives of Mexico in the control of diabetes ( 3 7 , 3 8 ) .
Tecomine citrate and tecostanine hydrochloride were examined for
hypoglycemic activity in rabbits ( 2 6 2 , 2 6 3 ) . Both alkaloids showed
activity at 20 mg/kg intravenously and 50 mg/kg orally in fasting ani-
mals. In depancreatized rabbits, the compounds were ineffective.
Alloxan-induced hyperglycemia was effectively reduced at a dose of20 mg/kg. Problems associated with the stability of tecomine have also
been examined ( 4 3 ) .
C. GENTIANADINE74)
Gentianadine, isolated from several Gentiana sp., exhibits hypo-
thermic ( 2 6 4 , 2 6 5 ) ,hypotensive (264) ,antiinflammatory ( 2 6 4 , 2 6 6 ) , nd
muscular relaxant actions ( 2 6 4 ) . t is only very mildly toxic and shows
no effect on behavior or growth on prolonged administration (267).
D. GENTIANINE42)
Gentianine is the most widely studied of the Gentiana alkaloids.
Preliminary examination indicated no antifungalor antibacterial effects.
LOW oxicity was observed, and gentianine exhibits a central nervous
system stimulant action, but in higher doses has a paralyzing a d o n . A t
a dose of 90 mk/kg, gentianine reduces formalin-induced rat hind legswelling ( 1 8 7 , 2 6 8 ) ,and i t was suggested to act via the nervous and
hypophyseal system ( 2 6 8 ) .Simihr to gentianadine (74), i t exerts hypo-
tensive, antiinflammatory, and muscular relaxant actions but is more
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8. MONOTERPENE ALKALOIDS 501
effective than 74. Prolonged administration of gentianine had no
effect on behavior or growth (267).
A comparative study (266)of the antiinflammatory activity of severalpyridine alkaloids indicated that the most active alkaloids (25 mg/kg,
oral) were oliverine and gentianine, followed by gentianadine and
gentianamine (81 .
TABLE V
PRARMALOGICALROPERTIESF MONOTERPENEALKALOIDS
Alkaloid Pharmaoological action Reference
Gentianadine (74)
Gentianamine (81)
Gentianaine (92)
Gentianine (62)
Oliverine
Skytanthine (4 )
Actinidine (37) Feline attractant
Affects cholinergic neurons of t he brain
Sialogogue
No feline attraction
Vomiting (on parenteral administration)
Olfactory reflex stimulation
Anesthetic potentiator
Decreased motility
Hypothermic
Hypotensive action
Antiinflammatory effectMuscular relaxant
No effect on behavior or growth
Antiinflammatory
Low antiinflammatory effect
Central nervous system
Hypothermic
Hypotensive
Antiinflammatory
Antihistamine
Decreases motility
Muscular relaxantNo effect on growth or behavior
No antibacterial action
No antimalarial activity
No antifungal activity
No antiamoebic effect
Antiinflammatory
Nicotine-like conditioned discriminated
Sedative action
Toxicity
No psychotropic effects
avoidance behavior
Tecomine (13) Hypoglycemic
Tecostanine (16) Hypoglycemic
Valerianu alkaloid (38) Cholinesterase inhibitor
54, 55, 6 2
258, 259
260
260
260
27 3
264
264, 265
264, 265
264
264, 266265
267
266, 274
266, 274
271
264, 265
264, 271
268
1 1 3
264, 265
264, 265264 , 267
2 71
175
271
179
266
272
272
272
272262, 263
262, 263
65
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502 G E O F F R E Y A. CORDELL
The principal folkloric reputation of Gentiana sp. is as a tonic, which
may be related to the hypotensive and muscle-relaxant activity of
gentianine ( 2 6 4 ) . Enicostema littorale is used in Indian traditionalmedicine as an antimalarial ( 2 6 9 ) ,and this activity was traced to the
chloroform-soluble alkaloid fraction ( 2 7 0 ) . Gentianine, the principal
alkaloid, had no affect on Ptasmodium gallinaceum (271) or P . berghei( 1 7 9 ) , o th at the activity must be attributed to some other constituent.
Further work ( 2 6 5 )on gentianine and gentianadine has indicated that
both compounds exhibit central muscle-weakening action, inhibition of
provoked aggression, and analgesic potentiating effects.
E. SKYTANTHINE4)
The pharmacology of the skytanthine alkaloids has been investigated
by Gatti and Marotta (272 ) .It exhibits no curare-like action but does
induce tremors. It has a facilitating effect on the rate of acquisition of
avoidance behavior (like nicotine). Low toxicity was observed. Its
pharmacology has been reviewed ( 6 ) . Valerian preparations are widely
used as a mild sedative. The major alkaloid (38) is a highly active
inhibitor of cholinesterase activity but shows less acetylcholinesteraseactivity ( 6 5 ) .The available data on the pharmacology of the isolated
alkaloids are summarized in Table V .
V. Summary
The monoterpene alkaloids are a comparatively undeveloped group
of alkaloids. Although some forty alkaloids have been isolated andcharacterized mostly from pharmacologically active plants, more data
are required to evaluate their potential usefulness.
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8. MONOTERPENE ALKALOIDS 507
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78, 15995 6~1973).
304 (1971).
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457 (1969).
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8, 132 (1973).
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SSR 23, 36 (1966); CA 67, 8680a (1967).
CA 78, 13729e (1973).
195 (1968).
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75, 148463~1971).
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508 GEOFFREY A. CORDELL
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200. Yu. I. Kornievskii, A. G. Nikolaeva, an d K. E. Koreshchuk, Farm. Zh. (Kiev)27,
81 (1972); CA 77, 2804d (1972).
201. G. A. Cordell, Lloydia 37, 219 (1974).
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203. A. R. Battersby, Bwchem. J. 111, 26P (1969).
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205. C. G. Casinovi, G. Giovannozzi-Sermanni, and G. B. Marini-Bettolo, Gazz. Chim.
206. G. B. Marini-Bettolo, in “Biologenesi delle Sostanze Naturali,” Corso Estivo di
207. C. G. Casinovi, G. Giovannozzi-Sermanni, and G. B. Marini-Bettolo, Rend. Acead.
208. M. A. Luchetti, Ann. Ist . Super. Sanita 1, 563 (1965); CA 65, 9349a (1966).
209. H. Auda, H. R. Juneja, E. J. Eisenbraun, G. R. Waller, W. R. Kays, and H. H.
210. D. A. Yeowell an d H. Schmid, Ezperientiu 20, 250 (1964).
211. J. E. S. Hiini, H. Hilterband, H. Schmid, D. Groger, S. Johne, and K. Mothes,
212. C. J. Coscia an d R. Guarnaccia, J. Am . Chem. SOC. 9, 1280 (1967).213. H. Inouye, S. Ueda, and Y. Nakamura, Tet. Lett. 3221 (1967).
214. H. Inouye, S. Ueda, and Y. Nakamura, Chem. Pharm. Bull. 18, 2043 (1970).
215. H. H. Appel, Scientia 35, 128 (1968); CA 71, 124733b (1969).
216. D. Gross, W. Berg, and H. R. Schutte, Biochem. Physiol. Pflanz. 163, 576 (1972).
CA 73, 11391m (1970).
(1962).
(1968).
134156 (1959).
(1960);CA 5 5 , 202i (1961).
CA 54, 12490e (1960).
(1964).
(1970);C A 74, 20401n (1971).
(1968).
Ital. 94, 1356 (1964).
Chimica, Academia Nazionale Dei Lincei ’(1962).
Naz. Yo (Quaranta)16-17, 89 (1965-6); C A 68, I0289u (1968).
Appel, J. Am . Chem. Soc. 89, 2476 (1967).
Ezperientia 22, 656 (1966).
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8. MONOTERPENE ALKALOIDS 509
217. H. Auda, G. R. Waller, and E. J. Eisenbraum, J. Biol. Chem. 242, 4157 (1967).
218. S. P. J. Shah and L. J. Rogers, Biochem. J. 114, 395 (1969), and references therein.
219. N. Marekov, S. Popov, a nd G. Georgiev, C. R. Acad. Bulq. Sci. 19, 827 (1966);CA
220. D. Groger and P. Simchen, 2. Naturforsch., Teil B 24, 356 (1969).
221. C. J. Coscia, L. Bot ta, and G. Rocco, Arch. Biochem. Bwphys. 136, 498 (1970).
222. C. J. Cosia an d R . Guarnaccia, Chem. Commun. 138 (1968).
223. R. Guarnaccia, L. Botta, and C. J. Coscia J . Am . Chem. SOC . 1, 204 (1969).
224. H. Inouye, S. Ueda, Y. Aoki, and Y. Takeda, Tet. Lett. 2351 (1969).
225. H. Inouye, S. Ueda, and Y. Takeda, Tet. Lett. 3453 (1968).
226. H. Inouye, S. Ueda and Y. Takeda, Chem. Pharm. Bull. 19, 587 (1971).
227. S. Popov and N. Marekov, Phytochemistry 10, 3077 (1971).
228. N. Marekov, S. Popov, an d M. Arnaudov, Dokl. Bolg. Akad. Nauk 23, 955 (1970).
229. N. Marekov, N. Arnaudov, an d S. Popov, Dokl. Bolq. Akad. Nauk 23, 81 (1970).230- G. Popjak an d J. W. Cornforth, Biochem. J. 101, 553 (1966).
231. J. W. Cornforth, R. H. Cornforth, G. Popjak, and L. Vengoyan, J.BioL Chepn. 241,
232. J.W. Cornforth, R. H. Cornforth, C. Donninger. and G. Popjak, Proc. R. Yoc., Ser.
233. K. Clifford, J. W. Cornforth,R.Mallaby. and G. T.Phillips, Chens. Concmun. 1599
234. B. W. Agranoff, H. Eggerer, V. Henning, and F. Lynen, J. Biol. Chem. 235, 326
235. A. R. Battersby, T. C. Byrne, R. S. Kapil, J.A. Martin, T. G. Payne,D. Arigoni, and
236. M. J. 0. Francis, D. V. Banthorpe, an d G. N. J. LePatourel, Nature (London)228,
237. A. R. Battersby, A. R. Burne tt, and P. G. Parsons, Chem.Commun. 26 (1970).
238. H. Inouye, S. Ueda, and Y. Takeda, Tet. Lett. 3351 (1970).
239. H. Inouye, S. Ueda, and Y. Takeda, Tet . Lett. 4073 (1971).
240. H. Inouye, S. Ueda, Y. Aoki, and Y. Takeda, Chem. Pharm. BUCI. 20, 1287 (1972).
241. R. Guarnaccia, L. Botta, and C. J. Coscia, J. Am . Chem. SOC. 4, 6098 (1970).
242. R. Guarnaccia and C. J. Coscia, J. Am. Chem. SOC. 3, 5320 (1971).
243. A. R. Battersby, R. T. Brown, R. S. Kapil, J. A. Martin, and A. 0 . Plunkett,
244. A. R. Battersby, E. 8. Hall, and R. Southgate,J.Chem. SOC. 721 (1969).
245. A. R. Battersby, A. R. Burnett, and P. G. Parsons, J. Chem.SOC. 1187 (1969).
246. R. Guarnaccia, L. Botta, and C. J. Coscia, J . Am. Chem. SOC. 6, 7079 (1974).
247. H. Inouye, S. Ueda, and Y. Takeda, 2. Naturforsch., Teil B 24, 1666 (1969).
248. H. Inouye, S. Ueda, and Y. Takeda, Tet. Lett. 4069 (1971).
249. H. Inouye, S. Ueda, K. Inoue, and Y. Takeda, Chem. Pharm. Bull. 22, 676 (1974).
250. L.-F. Tietze, J. Am. Chem. SOC . 6, 946 (1974).
251. S. Ghosal, A. K. Singh, P. V. Sharma, and R. K. Chaudhuri, J. Pharm. Sci. 63,
252. H. Inouye, T. Yoshida, S. Tobita, K. Tanaka, and T. Nishioka, Tetrahedron 30,
253. H. Inouye, in “Pharmacognosy and Phytoehemistry” (H. Wagner and L. Hor-
254. A. R. Battersby, S. H. Brown, and T. G. Payne, Chem. Commun. 827 (1970).
255. M . Luckner, 0. essler, and P. Schroeder, Pharmazie 20, 16 (1965).
66, 8845j (1967). .
3970 (1966).
B 163,492 (1966).
(1971).
(1960).
P. Loew, Chem.Commun. 951 (1968).
1005 (1970).
Chem. Commun. 812 (1966).
944 (1974).
201 (1974).
hammer, eds.), p. 290ff. Springer-Verlag, Berlin and New York, 1971.
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510 GEOFFREY A. CORDELL
256. R. Osterwalder, Schweiz. Apoth.-Ztp. 58, 201 (1920).
257. T. Sakan, Tampakushitsu Kakusa n Koso 12, 2 (1967); C A 73, 42351~1970).
258. N. Yoshii, K. Hano, and Y. Suzuki, Folia Psychiatr. Neurol. Ja pa n 17, 335 (1964);
259. N. Yoshii, K. Hano, and Y. Suzuki, Med. J. Osaka Univ. 15, 155 (1964); CA 65,
260. T. Khayashi, Rejleksy Golovn. Mozga, Dokl. Mezhdunur. Konf., 1963 431 (1965);CA
261. K . Hano, Tampakushitsu Kakusan Koso 12, 10 (1967); C A 73, 43432s (1970).
262. Y. Ham mouda , A. K. Rashid, and M. S. Amer, J.Pharm. Pharmacol. 16,833 (1964).
263. Y. Hammouda and M. S. Amer, J . Pharm. Sci.55, 1452 (1966).
264. F. S. Sadritdinov an d N. Tulyaganov, Farmakol. Alkaloidov Glikozidov 128 (1967);
265. N. Tulaganov, B. L. Danilevskll, and F. S. Sadritdinov, Farmakol. Alkaloidov
266. F . Sadritdinov, Farmakol. Alkaloidov Serdechnykh Glikozidov 146 (1971); C A 78,
267. N. Tulyaganov, S. A. Gamiyants, and F. Sadritdinov, Farmakol. Alkaloidov
268. H.-C. Chi, K.-T. Liu, an d C.-Y. Sung, Sheng Li Hsueh Pa0 23, 151 (1959); C A 57.
269. C. J. Bamber, “ Plant s of the Punjab,” p. 157, 1916.
270. P. N. Natarajan and S. Prasad, Planta Med. 22, 42 (1972).
271. E. Steinegger and T. Weibel, Pharm. Acta Helw. 26, 333 (1951).
272. G. L. Gatti and M. Marotta, Ann. Ist. Super. Sanita 2, 29 (1965); C A 65, 14293e
273. T. Hayashi, Abh. Dsch. Akad. W w s . Berlin, KZ. Med. 101 (1966); C A 67, 202 47 ~
274. F. Sadritdinov, Farmakol. Alkaloidov Serdechnykh Glikozidov 151 (1971); C A 78,
CA 61, 13376g (1964).
6138g (1966).
67, 10216x (1967).
C A 70, 2217v (1969).
Serdechnykh Glikozidov 148 (1971); C A 78, 66918~1973).
Serdechnykh 79634b (1973).
Serdechnykh Glikozidov 153 (1971); C A 78, 924 81 ~1973).
11821g (1962).
(1966).
(1967).
92480t (1973).
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---CHAPTER9-
ALKALOIDS UNCLASSIFIED AND OF UNKNOWNSTRUCTURE
R . H. F. MANSKE
University of Waterloo
Waterloo, Ontario, Canada
I. Introduction ........................................................ 511
11. Plants a nd their Contained Alkaloids ................................... 511
References .......................................................... 551
I. Introduction
Much of the data collected in this chapter was gleaned from ChemicalAbstracts and is so indicated by listing a Chemical Abstracts reference,
although such a reference is often included for the convenience ofreaders even where the original was available. Many of the alkaloids
are of structural types not treated in recent chapters of earlier volumes.
This chapter is supplementary to Volume XV, Chapter 6.
11. Plants and Their Contained Alkaloids
1 . Adaline (XV,264)*
The ketone Me(CH,), .CO -CH=CH,, prepared from the correspond-ing carbinol by Jones oxidation, was cyclized with methoxyethylene to
the dehydropyran 1, which upon acid hydrolysis generated the keto-
aldehyde Me(CH,),CO(CH,),CHO, which underwent a Mannich reaction
with p-ketoglutaric acid and ammonium chloride to give ( f -adaline
(2) (1).
2
* The roman numeral followed by a n arabic number refers to volume number and page
where the subject of t he heading has been treated in previous volumes.
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512 R. H.F. MANSKE
2. Alphonsea ventricosa Hook. f. et Thorns. (Anonaceae)
Norglaucine and glaucine (2).
3. Ancistrocladus hamatus Gilg. (A . ahlii Am.)
(Ancistrocladaceae; Dipterocarpaceae) (XIV,509; XV,265)
Hamatine (3) CZ5Hz9O4N; p 250-252'C). It is phenolic and its 0-
methyl derivative is enantiomeric with 0-methylancistrocladine (3).
OMe GMe
OMe Me
a
4. Ancistrocladus heyneanus Wall.
- 149.7') has structure 4 s determined on spectral evidence (4).
(XIV,509; XV,265)
The new alkaloid ancistrocladidine (Cz5Nz,0,N; mp 245-247OC;
O Me OH
M e
4
5. An iba duckei Kostermans (Lauraceae) (XI,496)
The new 3-pyridyl ketone, duckeine (5; I3Hl1O4N;mp 243-245'C),
was isolated from this plant. 2,6,4'-Trihydroxy-4-methoxybenzophenone
was also isolated (5) .
OH
OH
5
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 513
6. Ankorine (X,546; XIII,191)
The structure of this alkaloid has been revised to 6 on th e evidence
that none of the four possible synthetic racemic forms represented by the
earlier structure are identical with the natural alkaloid (6).
HO
CH2I
CH,OH6
7. Ant irrh inum spp. (Scrophulariaceae) (XIV,511)
Some tertiary bases or mixtures of bases were present in A . molle L.,
A . moll iss imum (Pau)Rothm., and A . hispanicum Chav. One of these
bases was identified as 4-methyl-2,6-naphthyridinend another was
given the impossible formula C,,H,,O,N, (7).
8 . Ariocarpus agavioides (Castaii.) E. F. Anders
(Neogomesia agavioides Castaii.) (XIV,512; XV,293)
This plant yielded N,N-dimethyl-4-hydroxy-3-methoxyphenethyl-
amine and the related Pelecyphora aselliformis Ehrenb. yielded N , N -
dimethyl-3-hydroxy-4,5-dimethoxyphenethylamine.n addition, seven
previously known alkaloids were isolated from these plants ( 8 ) .
9. Aristolochia argentina Griseb. (Aristolochiaceae)A reexamination of this plant has yielded four closely related lactones
(7, mp 271°C; 8, mp 275°C; 9, mp 247-25OOC; 10, mp 225°C) which
(XII,460)
7 R = R ’ = H
8 R = H , R ’ = OMe
9 R = M e , R ’ = H
10 R = Me, R’ = O Me
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514 R. H. F. MANSKE
presumably arise from catabolism of preformed aporphines or analogous
bases. They were separated on a column of silicic acid (9).
10. Ata lantia monophylla Correa (Rutaceae)
(XII,500; XIV,513; xV,267)
Atalaphyllinine (C,,H,,O,N; mp 205-207°C). I ts structure 11)was
indicated by an examination of its spectra and was confirmed by con-
version to bicycloatalaphylline (10) .
11
11. Azureocereus ayacuchensis Johns. (Cactaceae)
tyramine (0.135y0) n this cactus (11).
Though mescaline was absent there was a comparative abundance of
12. Bathiorhamnus cryptophorw (H.Perrier) R. Capuron (Rhamnaceae)
Two new piperidine-type alkaloids were isolated and their structures
indicated by spectral examination and confirmed in part by chemical
reactions; cryptophorine (C,,H,,ON; mp l l&l lS°C; [a]578 61'; 0-
acetyl-, mp 103-104'c) (12); cryptophorinine (C,,H,,O,N; [ a ] 5 7 8- 8")(13). The former yielded an octahydro derivative (14) upon catalytic
reduction which upon catalytic dehydrogenation generated a pyridine
derivative ( 1 2 ) .
M e 0 RI
M e
12 R = W
OH
14 R = n-C,,H,,
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 515
13. BauereZZa baueri (Schott) Engler (Rutaceae)
Melicopidine (mp 121-122"C) and acronycine (mp 172-175°C) ( 1 3 ) .
14. Bruguiera cylindrica L. (Rhizophoraceae) (XIII,353)
Brugine, a n unusual tropeine, was isolated from the stems and bark
( 1 4 ) -
15. Bur kea africana Hook. (Leguminosae)
Tetrahydroharman, harman, and harmalan (15 ) .
16. Gadia eZZisiana Baker (Leguminosae)
This very toxic plant yielded some fifteen bases, three of which were
identified as multiflorine, 13-hydroxylupanine, and its pyrrole carboxylic
ester calpurnine ( 1 6 ) .The last is highly toxic to mice and fish ( 1 7 ) .
(IX,206)
17. Camptothecine (XII,464; XIV,515; XV,269)
Yet another synthesis of this alkaloid has been reported in which
2,5-pyridine dicarboxylic acid was the starting material, being convertedinto 15 in 8 5 yield in three steps. Subsequent steps involved several
convergent routes which gave, as a late intermediate, compound 16.
The ingenuity shown in the choice of reactions was equaled only in the
experimental skill necessary to bring them about, even though only
300 mg of dl-camptothecine was obtained ( 1 8 ) .
0
5B o
C Oa H
0
15 16
18. Cannabis satiwa L. (Urticaceae)
This much investigated plant has now yielded an alkaloid. Cannabis-ativine (C,,H,,O,N,; m p 167-168°C; + 55.1") (17) was obtained
from the roots and its structure was determined by an X-ray study of
the base crystallized from acetone, Other spectral data are consistent
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516 R. H. F. MANSKE
with this structure. Its presence in the leaves was indicated by thin-
layer chromatography. It is the first example of a palustrine-type base
from flowering plants (19).
19. Cathu edzdis Forskal (Celastraceae)
(111,343; XI,489; XII,539; XV,280)
The alkaloid previously named cathidine has been shown to be a
mixture comprised of a polyalcohol esterified with different amounts
of acetic, benzoic, trimethoxybenzoic, evoninic, and nicotine acids.
Reductive hydrolysis generates a polyalcohol which on acetylation
provides an octaacetate identical with that similarly obtainable fromevonine ( 2 0 ) .
20. Cephalotaxus harringtoniana (Forbes) K. Koch (Cephalotaxaceae)
(X,552; XIII,400; XIV,319; Xv,272)
The new alkaloid, desmethylcephalotaxinone (C,,H,,O,N; mp 102-
+213"),was given structure 18 on the basis of its spectra0 7 O C ;
and on its partial synthesis from cephalotaxine ( 2 1 ) .
9O 0
18
21. Cephalotaxus harringtonia Sieb. e t Zucc.
The variety drupacea of this plant was found to yield the new
alkaloids 1 1-hydroxycephalotaxine (C,,H,,O,N; [a]i6- 139') (19) and
drupacine (C,,H2,0,N; [ c z ] ; ~ - 137') (20) whose given structures were
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 517
determined largely by spectral methods and partly confirmed by
hydrolysis of 19 to 20 (22).
““ if O
Ho
OMe bMl3
19 20
22. Clausena heptaphylla Wt. and Am. (Rutaceae)
(XII,467 ; XII17274;XV,273)
Heptazolidine from the above plant was given structure 21, largely
on the basis of spectral methods (23).
23. Clausena indica O h . (XII,467; XIII,274; xV,2 73)
Indizoline (22), a new alkaloid, was isolated along with 3-methyl-
carbazole ( 2 4 ) .
22
24. Clitocybe fasciculata Bigelow
(L ep ista caespitosa (Brosadola) Singer) (Agaricaceae)
This fungus proved to be rich in alkaloids yielding 2.4Yo7 he major
component being lepistine (C,,H,,O,N,, liquid, bp 140-150°C/0.01 mm;
B . HCl, mp 242°C; B .HI, mp 250-253°C; B.MeI, mp 198-199°C). A n
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518 R.H. F. MANSKE
X-ray examination of the hydrobromide defined its structure (23) nd
other spectral properties are consonant therewith (25).
mco.M 23
25. Cocculus laurifolius DC. (Menispermaceae)
Three new dibenz(d,f )azonine alkaloids were reported-laurifonine
(C,oH,,03N; perchlorate, mp 182-185OC, [elD 10”) (24); laurifine
(C,,H,,O,N, amorphous, [elD f ) (25); and laurifinine (C1,HZ3O3N,perchlorate, mp 243-245OC) (26). The structures were arrived at by
spectral studies and confirmed in part by interconversions ( 2 6 ) .
(X,406)
OR‘
24 R = R‘ = M e
25
26
R = H , R = M e
R = Me, R’ = H
26. Cocculus carolinus DC. (XII,468; XIII,325)
The new alkaloid carococculine (27) (C,,H,,O,N; mp 219-220°C).
The spectral properties of the alkaloid and of its 0-methyl and 0-acetyl
derivatives indicated its structure. Its relation to other morphinane
alkaloids is apparent (27).
MOoO
OH
27
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 519
27. Codonocarpus australis A. Cunn. (Phytolaccaceae) (xIV,579)
The structure of codonocarpine, previously reported, ha5 been con-firmed and the N-methyl base (C,,H,,O,N,; mp 167-171°C) (28) has
been isolated from the plant and prepared from codonocarpine by
N-methylation with formic acid followed by NBH reduction. Acetyl
and other methyl derivatives have been described and extensive chemical
degradations are reported (28).
b04H O M e
28
28. Coryphantha calipensis H. Bravo (Cactaceae) (XII,468; XV,274)
Normacromerine, N-methyl-3,4-dimethoxyphenethylamine,nd two
new alkaloids, namely, (- -N-methyl-3,4-dimethoxy-~-methoxyphen-
ethylamine and (- - N,N-dimethyl-3,4-dimethoxy-~-methoxyphen-
ethylamine. It is noted that the new alkaloids are /I-methoxy derivatives
of macromerine (29).
29. Couroupita guianensis Aubl. (Myrtaceae)
Couroupitine A (C,,H,0,N2; mp 265-266°C; [a],, f ). Spectral
examination was consistent with structure 29. A second base (mp >340°C; [.ID f ; N-acetyl, mp 186°C) of molecular weight 304 ( M + ) of
unknown structure was also obtained ( 3 0 ) .
29
30. Crotalaria assarnica Benth. (Leguminosae) (XII,247; XV,274)
Monocrotaline (31).
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520 R. H. F. MANSKE
31. Crotalaria burhia Buch.-Ham. (XII,247; XIV,522)
Crotalarine (30). ts structure was based on its alkaline hydrolysis andother chemical transformations ( 3 2 ) .Another examination of the same
plant yielded monocrotaline and an alkaloid, croburine (mp 167-1 68°C).
Hydrolysis of i t generated retronecine and 2,3-dihydroxy-4-ethy1-2,3,4-
trimethylglutaric acid, also new. Structure 30 was also proposed (33).
30
32. Crotalaria m adu ronsis Wight
Isocromadurine (C,,H,,O,N; mp 135-1 36°C; [elk5+43.5 ), solated
from the seeds of this plant, on alkaline hydrolysis generated retronecine
and the symmetrical HO,C .CH(Me)C(OH)Me-CHMe .CO,H (mp 129-
130OC). Therefore its structure is 31 ( 3 4 ) .
(XII,247; XIV,522)
31
33. Crotalaria spp.
Seeds of C . leioloba Bartl. (C. ferruginea R. Grah.) yielded mono-
crotaline while those of C. tetragona Roxb. gave integerrimine and
trichodesmine, two alkaloids previously isolated only from Senecio spp.
( 3 5 ) .
34. Cryptocarya alba Auth? (Lauraceae) (X,577; XIII,403; XIV,522)
( + )-Reticdine was the only base isolated from the leaves and bark
(36).
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522 R. H. F. MANSKE
37. Dendrobates histrionicus (XIII,405 XV,277)
The frogs of the genus Dendrobates elaborate a series of toxins of
importance in the study of neuromuscular transmission. The venom of
D . histrionicus has yielded histrionicotoxin (38), its octahydro derivative
(39), and its perhydro derivative (40). A synthesis of the last, the
optically inactive form, had been achieved starting from the known
compound 41. By a series of ingenious steps this was converted t o 42,
and after another four steps the perhydro compound was isolated by
chromatography on silica (39). A more extensive examination of the
alkaloids from the frog has yielded four analogs of histrionicotoxin
whose structure (43) was determined by an X-ray analysis of its
hydrochloride. A fifth compound, HTX-D [mp 231-232°C (dec.)],
corresponds in empirical formula to tetrahydrohistrionicotoxin but its
mass spectrum indicates a different structural pattern ( 4 0 ) .
CH2.R
0
41
42 43
38. Dendrobates pumilio (XIII,405;XV,277)
Pumiliotoxin C, the toxic base isolated from the above-named frog,has been synthesized as its dl form. The starting material was a mixture
of the known cis and trans forms of tetrahydro-1-indanone ( M ) , he
oxime of which generated a hydroquinolone. Further transformations,
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9. ALKALOIDS UNCLA SSIFIED AND OF UNKNOWN STRUCTURE 523
over ten in number and utilizing some novel reactions and skilful
techniques, finally generated the dl base (45) with the correct stereo
structure (41 ) .
& &H H M e
44 45
46
39. Dendrobine (XII,475; XIII,406; XIV,525; Xv,277)
The total synthesis of this ( ) base has been reported. The starting
material t o achieve this in twenty steps was the ketol 41, which by aseries of standard reactions was converted to the ketolactam 47. Another
series of reactions converted 47 into the enone 48 and subsequently into
the hydroxyester 49 which on hydrolysis and lactonization generated
( k -oxodendrobine (50, X = 0) and which was converted to (4 -dendrobine (50, X = H,) on Birch reduction (42 ) .
The biosynthesis of this alkaloid is consistent with its derivation from
: :;1*' fi0M e0
H Me H
47 48
0
49 50
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524 R. H. F. MANSKE
mevalonate involving successive transformations to farnesol, germa-
crane, and cadalane skeletons. Degradation of the labeled dendrobine
confirmed that the labeled carbon of [4-14C]mevalonate ppeared in theanticipated positions ( 4 3 ) .
40. Dendrobium chrysanthum Wall. (Orchidaceae)
Exhaustive spectral studies and a synthesis of ( ~fr -trans-dendro-
chrysine obtained from this plant proved the structures of the cis and
trans alkaloids (51). They were obtained only as viscous oils with
[a]:, - 19" and with [ a ] i 2- 1l0 , respectively ( 4 4 ) .
(XV,279)
IpJJ-jN N
M eoI
ICH=CH. Ph
51
41. Dendrobium crepidatum Lindl.
Crepidine (C18H2502N,mp 107-109"C, [a] 500-600) , crepidamine(C,,H,,O,N, mp 221°C) [a ]g4 - 2(MoH)), and dendrocrepine
(C33H4403N, p 158-163"C, [4]~~0-600) were isolated from this plant.
An X-ray study of its methiodide showed th at crepidine has structure
52. Crepidamine was shown to have structure 53 on the basis of a mass
spectrum. Dendrocrepine, on the basis of a more elaborate spectral
study, was given structure 54 ( 4 5 , 4 6 ) .
(XIV,525; Lv,297)
Me
;:f i-3HO' ::a
HO
Ic=o
Me*-H
M e
Me
52 53 54
42. Dendrobium nobile Lindl. (XII,475; XIII,406; XIV,525; XV,279)
4-Hydroxydendroxine (55) and nobilomethylene (56) were isolated.
Spectral methods were used in determining these structures and 56 was
prepared from nobilinone (57) ( 4 7 ) .
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9. ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE 525
55 56 57
43. Desmodium cephalotes Wall. (Leguminosae)
(XI,] ;XIII,406; XV,279)
/3-Phenethylamine, salsolidine, hordenine, tyramine, candicine,
choline, and several unidentified quaternary bases, many only in trace
amounts ( 4 8 ) .
44. Dolichothele sphaerica Britton et Rose (Cactaceae)
When selected precursors are presented to this plant it generates
“unnatural ” alkaloids. When simultaneously given the lower homolog
of histamine and isocaproic acid it produced 58, an analog of dolicothe-line. Similarly, the aberrant alkaloid 59 was formed when 3-amino-
ethylpyrazole was fed ( 4 9 ) .
(XIV,526)
H NllCH, .NH .CO .CH2 .CH, .CHMe,
58
45. Dolichotele surculosa (Boed.) Buxb.
The four major alkaloids from the above-named plant were N-
methylphenethylamine, hordenine, N-methyltyramine, and synephrine.
Four other plants of the genus, namely, D . longimamma (DC.)Br. e t R.,
D . uberiformis (Zucc.) Br. et R., D . melaleuca (Kar.) Craig, and D .haumii (Boed.) Werd. et F. Buxb. were also examined. They were rich
in alkaloids but the constituent bases differed essentially from those of
Mammillaria and these differences appear tohave taxonomic significance
(XIV,526)
(50) .
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526 R. H. F. MANSKE
46. Doryphora sassafras Endl. (Monimiaceae) (XIV,228)
A total of eleven crystalline alkaloids was isolated from the bark ofthis plant. The four alkaloids from the nonphenolic fraction were
liriodenine, doryanine, ( + )-isocorydine,and (- -anonaine. The phenolic
fraction yielded ( + )-reticuline, corypalline, doryphornine (60)(mp 215-
217OC), and two bases, A (mp 169-171°C) and B ( m p 201-203"C, [a]z5
- 15.6'), not further examined. Extensive use was made of
chromatography ( 5 1 ) .
60
47. Erythrophleum chlorostachys Baill. (Leguminosae)
(X,561; XII,533; XIV,528)
The structure of norerythrostachaldine (61) was established by LAHreduction to a tetrol (62) identical with one prepared from norerythro-
stachamine (63)52).
R'
61
63
R = CHO. R' = CO, .CHa.CH, .NHMe
R = C02Me, R' = C O , . CH,. CH, .NHMe
62 R = CHSOH, R' = CH,.OH
48. Erythrophleum ivorense A . Chevalier (X,561; XII,533; XIV,528)
Two new variants of the cassaine-type alkaloids have been isolated
from this plant. They are 3-(3-methylcrotonyl)cassaine 64) and 19-
hydroxycasesine (65) (53).
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 527
64
65
66
R = CO.CH=CH,, R = M e
R = H , R' = CHzOHR = H, R' = CO,Me, C O is -OH
49. Erythrophleum chlorostachys Baill.
Norerythrostachamine, a new alkaloid (C,,H390,N, amorph.), was
shown to have structure 66. The nonnitrogen fragment was identical
with the N B H reduction product of erythrophlamic acid. In addition
there were isolated cassaidine, cassamidine, norcassamidine, and a
number of amides ( 5 4 ) .
(x,561; XII,533; XIV,528)
50. Ery throxy lum monogynum Rox b. (Erythroxylaceae)
(XII,476; XIII,355)
The 3,4,5-trimethoxybenzoyl and 3,4,5-trimethoxycinnamoy1de-
rivatives of laH,5aH-tropen-3~~-01(67)ere isolated from the roots ( 5 5 ) .
67
51. Eschscholtzidine (x,478; XII,371)
A synthesis of'this alkaloid by standard methods has been announced.
The optically inactive base was characterized as its methiodide
(mp 305OC) ( 5 6 ) .
5 2 . Euxylophora paraensis Hub. (Rutaceae)1 -Hydroxyrutaecarpine (68)(Cl8Hl3O2N3,mp 3 1 8-32OoC; O-methyl,
mp 2 5 3 °C) was isolated. Its structure was derived from a spectral
exa.mination and confirmed by a synthesis (57').
(XII,477)
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528 R . H. F. MANSKE
68
53. Fagara xanthoxyloides Lam. (Rutaceae)
Another examination of this plant yielded the alkaloid fagaronine, aquaternary base (chloride, mp 200°C, followed by solidification and
remelting at 26OoC) which proved to be an extremely active anti-
leukemic (58 ) . t s proposed structure (69)was confirmed by a synthesis.
The known compound 70 (R = H) was prepared by a new route and the
hydroxyl was protected by the isopropyl group. Condensation of 70
(R = Pr') with o-bromveratraldehyde and subsequent cyclization with
sodamide in liquid ammonia followed in turn by reaction with dimethyl
sulfate generated the 0-isopropyl ether of fagaronine methosdfate as
well as the methosulfate of fagaronine (59) .
(XIV,530; XV,300)
M e 0
69
P O RMe
NO270
54. Fagopyrum esculentum Moench. (Polygonaceae)
The basic fraction obtained from buckwheat seed provided a crystal-
line base, fagomine (C,H,,03N; B .HCl, rno 176-177OC). Its structure
(71) was arrived a t by an exhaustive spectral study and confirmed in
part by chemical reactions ( 6 0 ) .
71
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 529
55. Gentiana sp. (Gentianaceae)
A new alkaloid (CloHllO,N, mp 208-210°C, [a],, .8") has been iso-lated from a Chinese gentian. I ts structure (72) as revealed by spectral
methods. Like at least some other gentian alkaloids, i t may be an
artifact ( 6 1 ) .
(XI,487; xV,282)
H
72
56. Gymnocactus (Cactaceae)
known 8-arylethylamines along with traces of unidentified bases ( 6 2 ) .Seven species of this genus were shown to contain predominantly
57. Haloxylon persicum Bunge ( H . ammodendron Bunge)
(Chenopodiaceae) (XI1,480; XIV,534)
Anabasine was the major component of a total of 5.4y0 alkaloids in
this plant. Traces of nicotine were also detected ( 6 3 ) .
58. Haplamine
4-Hydroxy-6-methoxy-2-quinolinewas alkylated with Me,C=
CH .CH,Br and the resulting mono-0-alkyl ether cyclized by
reaction with dichlorodicyanobenzoquinone to yield haplamine
(mp 199°C)(72a) 6 4 ) . t had been isolated from Ha plophyllum perfora-
t u m Kar. et Kir. and the correct struction had been proposed ( 6 5 ) .
(IX,229; X,565; XII,480; XII1,408; XIV,534)
59. Haplophyl lum fol iosum Vved. (Rutaceae)
Folirninine, isolated from the aerial parts of the above plant, was given
structure 72b on the basis of a spectral examination. Hydrogenation
(IX,225; XV,284)
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530 R. H. F. MANSKE
generated a tetrahydro derivative (73) nd reaction with methyl iodide
gave 74 (66).
p -p:H pMe
72b 73 74
60. Hap lophyl lum perforatum Kar. e t Kir.
The 7-isopentyloxy derivative of y-fagarine was isolated and pre-
pared by the 0-alkylation of haplopine with Me,C=CH .CH,Cl. Its
structure (75)was determined on the basis of spectral data. Hydrogena-
tion generated the quinolinone 76 ( 6 7 ) .Methylevoxine, a new alkaloid
from this plant, is 77 as determined by spectral methods ( 6 8 ) .Glycoperine 78) nd haplophydine (79) were later isolated from this
plant. Their structures are based on spectral data and upon the hydrol-
ysis of 78 to haplopine and L-rhamnose (69, 7 0 ) .
(IX,229; XV,283)
?Me O M e
Me,CH. C O z .CH,O@:J IJ OMeM e
Me$: CH.C H I O
7 5 76
?Me
\ IC .C H CH,O
Me’ I OMeO M e
77
RhO*JO M e OCH,. CH:CMez
78 79
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 531
61. Haplophyllum latifolium Kar. et Kir.
haploperine, and dubamine were identified from this plant ( 7 1 ) .
(x ,565;XIV,535)
In addition to six unknown compounds the known skimmianine,
62. Hedera helix L. (Araliaceae)
been reported (72).
The unusual occurrence and isolation of emetine from this plant has
63. Heimia salicifoliaLink e t Otto (Lythraceae)
Abresoline (C,,H,,O,N, amorphous) was isolated in very low yield.
Hydrolysis in the presence of alkali generated transferulic acid and the
quinolizidol 80 so that its structure is 81. This was confirmed by a
synthesis of its dihydro derivative (73).
(X,566; XIV,525)
9,.OMe
80 R = O H
81 R = M e 0
HO
64. Heimia salicifolia Link et Otto
In addition to the known sinicuichine, cryogenine, and nesodine, there
were isolated two new alkaloids, ALC-I (C,,H,,O,N, mp 335-345"c,
+ 115.6", [a]436 235") and ALC-2 (C2,H2g0,N, mp 309-310"C7
[a]589 72.3", [a]436 154.6")which were shown to be stereoisomers
of lythrine. The former yielded a monomethyl ether melting at 230-
233°C and that of the latter melted at 235-237°C ( 7 4 ) .
(X,566; XIV,525)
65. Hippodamine (XIV,518; XV,284)
An X-ray diffraction analysis of crystals of convergine hydrochloride,
the N-oxide derivative of hippodamine, showed that it is 82 and
consequently the structure of hippodamine is also known (75).
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5 3 2 R. H. F. MANSKE
AM e
82
66. Hydrastis canadensis L. (Ranunculaceae)
Canadaline (C2,H230,N, mp 117-1 lS°C, [.ID + 43O), a new alkaloidfrom this much investigated plant, was shown to have structure 83.
Spectral examination and chemical manipulation served this purpose
( I V , 8 7 ; IX,49; X,423)
( 7 6 ) -
O M e
83
6 7 . Indicaine ( X I I I , 4 1 7 )
The alkaloid described as boschniakine was shown to be identical
with the previously known indicaine (84) ( 76a ) .
84
68. Isoharringtonine (XIV,SI9)
This alkaloid ( 8 5 ) s an ester of cephalotoxine, the acid component of
which is dibasic, contains two asymmetric carbons, and is also a methyl
ester. Methanolysis of the alkaloid generated a dimethyl ester that was
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 533
shown, by a synthesis, to have the erythro configuration 86. This was
achieved by hydroxylating the corresponding maleic acid with osmium
tetroxide and hydrogen peroxide. Hydroxylation of the corresponding
fumaric acid generated an acid of t,hreo configuration (77) .
0053)--
85 86
69. K nig htin deplanchei Vieill. (Proteaceae) (XV,287)
Two tropane alkaloids (87 and 88) were isolated. Their structureswere determined by spectral methods ( 7 8 ) .
Ph. COz
O R
'CH(0H)Ph
87 R = CO.CH:CH.Ph
88 R = H
70. Kreysigia rnulti ora Reichb. (Liliaceae)
(X,569; XII,483; XIII,146; XIV,268; XV,298)
In addition to the alkaloids previously isolated from this plan t there
have been isolat,ed hree new ones: ( - -multifloramine (89)(C21H,505N,mp 209-2 12°C) [a]g - 1og ) , kreisiginone (90) (mp 193-1 94°C)) and
deacetylcolchicine. Methylation of 89 and of Aoramultine with diazo-
methane gave a mixture of kreisigine (91)an d 0-niethylkreysigine (92).
Spectral examination, culminated by a synthesis, confirmed the struc-
t,ures and ascertained that of the previously known floramultine (93)( 7 9 ) .Extensive biosynthetic studies showed th at these homoaporphines
arise from 1 -phenethylisoquinolines, specifically from automnaline (94)
labeled as shown (SO).
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 535
72. Leptorhabdos parvijlora Benth. ( L . benthumiana W a l p . )(Scrophulariaceae)
The structure of t,he new alkaloid, leptorhabine (98), was determined
by spectral methods and confirmed in part by permanganate oxidation
to pyridine-3,4-dicarboxylic cid (82).
98
73. Lindera benzoin Meissn. (Benzoin aestivale Nees.) (Lauracea,e)
(XIII,412; XV,287)
Laurotetanine was isolated (83).
74. Liriodendron tulipifera L. (Magnoliaceae)
The leaves of this plant yielded lirinine N-oxide (99) and lirinine
0-methyl ether which was also obtained by reducing the AT-oxide to
lirinine (100).Spectral methods were employed in the structural deter-
mination ( 8 4 ) . In addition to the known nonphenolic alkaloids (iso-
remerine, liriodenine, lysicamine) the new isolaureline (101) was also
isolated. It s structure is based on spectral data ( 8 5 ) .
(XIV,227)
M e O pO H-- H O
c : g r : e/
\ \ \
OMe OMe O M e
99 100 101
7 5 . Lophophora diffusa (Croizat)H. Bravo (Cactaceae)
(XII,488; xv,288)
naturally, was isolated (86).
O-Methylpellotine (102), an alkaloid not previously known to occur
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5 3 6 R. H. F. MANSKE
O M e M e
102
76 . Magnolia obovata Thunb. (Magnoliaceae)
(X,407; XII,489; XIV,228)
In addition to the known bases, liriodenine, anonaine, glaucine,
asimilobine, reticuline, and magnocurine, this plant yielded a new
alkaloid, obovanine, whose st,ructure (103) was determined from itsspectral data (87).
103
7 7 . Mappia foetida Miers (Oliacinaceae)
In addition to the previously reported camptothecine (88,89) this
plant has yielded mappicine (C,,H,,O,N,, mp 251-252°C). It forms an
acetyl derivative (mp 191-1 92°C) and on exhaustive spectral examina-
tion proved to be a relative of comptothecine with structure 104. Apartial synthesis from camptothecine was achieved (90).
Et .CHOH
104
78. M ay ten us arbutifolia (A. Rich.) R. Wilczek (Celastraceae)
(XI,460; XIV,541; XV,Z89)
Celacinnine (C,,H,O,N,, mp 203-204"C, - 19") (105) was iso-
lated from this plant and also from Tr ip terygium wilfordii Hook.
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9. ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE 537
Spectral studies of i t indicated structural features that were consonant
with chemical degradations. It yielded a dihydro derivative (mp 172°C)
and vigorous acid hydrolysis generated spermidine. The isomericcelallocinnine (mp 172-173"c, [a]g5 -24) (106), also present in M .
arbutifolia, differed from 105 in that the cinnamoyl group is cis oriented.
Its dihydro derivative is identical with that of 105. Two analogous
alkaloids isolated from T . wilfordii are celabenzine (C23H,902N3,
mp 156-158"C, [a] i5 0 ) (107) and celafurine (C,,H,,O,N,, mp 154-
155OC, [a]g5- 11 ) (108), whose structures were assigned on the evi-
dence of spectral and chemical properties ( 9 1 ) .
R
105 R = t m m - P h . C H : C H . C O , R' = H
106 R = c - P h . C H : C H . C O , R' = H
107
108 R = 0 : R ' = H
R = P h . C O , R' = H
79. Melicope perspiczsinerva Merr. et Perry (Rutaceae) (XIV,542)
In addition to a new flavone (melinervin) and other neutral compounds
this plant yielded skimmianine, kokusaginine, ( )-platydesmine, and
halfordinine (mp 150-152°C) the last of which was shown to be 6,7,8-
trimethoxydictamnine ( 9 2 ) .
8 0 . Murraya koenigii Spreng (Rutaceae)
(XI I,49 1; XIII ,54 4; XIV,274,414; XV,290)
The new murrayacinine is given structure 109 on the basis of its
spectra and on a synthesis from 2-hydroxy-3-methylcarbazole93).
M e
109
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538 R . H. F. MANSKE
81. J l y r rh a octodecimguttata (XIV,518)
The report of the chemical study of the above Coccinellidae containsthe isolation of a new alkaloid, myrrhine (C13H2,N, iquid) (110),and a
review of the relationship that exists among the alkaloids that have
been isoated from a number of arthropods, namely, coccinelline,
convergine, hippodamine, and propyleine. The structure of 110 was
confirmed by correlation with propyleine (precoccinelline) as well as by
varied spectral studies. Coccinelline was shown to be biosynthesized via
the polyacetate pathways. These alkaloids have been shown to be
involved in the defensive behavior of the insects (94) .
H
110
82. Oncinotis nitida Benth. (Apocynaceae)
Three new spermidine alkaloids have been isolated. The structural
assignments are based on spectral studies and upon chemical degrada-
tion to known fragments. Oncinotine (111) (C,3H,50N,, oil, [.ID - 3");
neooncinotine (112),obtained only in admixture with 111; isooncinotine
(112a) (C2,H,,0N3, mp 66-71°C, [a],, - 37"). Acetyl and reduced
derivatives as well as hydrolytic products were prepared (95). Asynthesis of ( )-oncinotine was also achieved. Some fifteen steps were
involved in which one of the starting substances was HO(CH,),CO,H.
An isomer of oncinotine was shown to be present in the natural base ( 9 6 ) .
(XIII,415; XIV,546)
G - y y JR O
111 R = (CH,),NH,
112 R = (CH,),NH,
H H
l l 2 a
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 539
83. Op untia clavata Eng. (Cactaceae)
M-Methyltyramine was isolated (97) .
84. Pandaca calcarea (Pichon) Mgf. and P. debrayi Mgf.
(Apocynaceae) (VIII,203; XI,14 7)
(- -Apparicine and ( - -dregamine, known alkaloids, and the new
pandoline (C21H2s03N2, amorphous, [ID +417') and pandine
(C21H,,03N,, mp 108-1 13°C; [ID + 273") (98).
85. PassiJlora sp.
Traces of harman were detected in P. caerulea I,., P. decaisneana
Hyb., P. edulis Sims, P . oetida L., P. incarnata I,., P. subpeltata? ( P .
subulata Masf.), and P. warmingi i Masf., but neither harmine, harma-
h e , harmol, nor harmalol could be detected (99).
86. Pau ridiantha lyall i i (Baker) Bremek. (Rubiaceae)
lated ( 1 0 0 , 1 0 1 ) .
(XIV,547)
Two new indole alkaloids lyaline (113) and lyadine (114) were iso-
C0,Me
113 R = CH=CHg
114 R = C H ( 0 H ) M e
87. Pelea barbigera Hillebr. (M elicope barbigera A. Gray) (Rutaceae)
(IX,229; XIV,542)
Kokusaginine, isoplatydesmine (115), and eduline, which was re-
garded as an artifact ( 1 0 2 ) .
M e
115
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540 R . H. F. MANSKE
8 8 . Penicil l ium oxalicum
The alkaloid oxaline (C,,H,,O,N,, mp 2 2 0 °C, [a];, - 45') is unique ina number of respects, as is evident upon an inspection of its structure
(116) which was determined by X-ray methods. Spectral methods and
particularly mass spectra are consonant with this structure (103,104).
116
89. Pergularia pallida Wight et Am. (Asclepiadaceae)
(IX,518; XIII,425; XIV,562)
Three major alkaloids proved to be tylophorine, tylophorinidine, and
O-methyltylophorinidine. Minor constituents proved to be 3,6,7-
trimethoxyphenanthroindolizine and one of uncertain structure with
four methoxyls in the phenanthrene portion and an alcoholic hydroxyl
a t C-14 (105) .
90. Peripterygia marginata Loes. ( Pterocelastrus m argina tus Baill.)
(Celastraceae)
The alkaloid periphylline isolated from this plant has structure 117
as determined by spectral methods. Alkaline hydrolysis gave trans-
cinnamic acid and alkali fusion of its tetrahydro derivative generatedspermidine ( 1 0 6 ) .
H
H
1 7
91. Petteria ramentacea Presl. (Leguminosae)
stages of this plant. Anagyrine and lupanine appeared later ( 1 0 7 ) .
Cystine and its N-methyl derivative appeared in the early growth
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542 R. H. F. MANSKE
96. Poranthera corymbosa Brogn. (Euphorbiaceae)
(XIV,551; XV,294)
The plant yielded porantherine, porantheridine, porant,hericine (121)
(C,,H,,ON, amorphous [.ID - 20"; B.HBr, mp 308"C), O-acetyl-
poranthericine (amorphous, [a],,+ 2 ) , porantheriline (C,,H,,O,N, mp
76-77°C; [.ID + 87 ) ,and porantherilidine (CzzH,302N, morphous, [.ID
-47 ; B.HBr, mp 251-252°C) (122). The structure of 122 was arrived
a t on the basis of an X-ray study of its hydrobromide. Porantherline on
hydrolysis generates acetic acid and an alcohol (mp 124-126°C) which
was shown to be enantiomeric with 121 a t the hydroxyl position (116).
H
Et
HO-
121 12%
97 . Porantherine (XIV,551; XV,294)
This tetracyclic base (123), whose structure was determined largely
by X-ray analyses, has been synthesized. Not only was there involved
a multitude of intermediates, new to chemistry, but the experimental
skill was evidently of a high order. The sequence of reactions was based
upon a retrosynthetic analysis involving five key intermediates which
were obt,ained from the first reaction product 124 of the Grignard
reagent derived f rom 5-chloro-Z-pentanone ethylene ketal with ethyl
formate (1.27).
Me
123 124
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 543
98. Prosopis nigra (Gris.) Hieron. (Leguminosae)
/3-Phenethylamine, harman, tryptamine, N-acetyltryptamine, andtyramine all separated in the order given from a column of alumina (118).
(XI,12,492)
99. Prosopis spicigera L. (XI,492)
The new amino acid spicigerine was given structure 125 (219).
125
100. Ptelea trifoliata L. (Rutaceae)
This much-investigated plant has yielded a new quaternary base,
O-methylptelefolium (126) (220).Another examination of P . trifoliatasubsp. pallida disclosed the presence of hydroxylunine and balfouridine
(XIII,417; XIV,553)
(121).
OM0
126
101. Retama monosperma Boiss. (Genista monosperma Lam.)
(Leguminosae) (IX, 99; XV,276)
The subspecies rhodorrhizoides yielded d-sparteine, retamine, ana-
gyrine, sophocarpine, a,nd traces of sophoridine, N-methylcytisine,
cytisine, and sophoramine (122).
102.Retan illa ephedra Brogn. (Rhamnaceae)
The following were isolated and identified: boldine, norboldine,
armepavine, norarmepavine, coclaurine, and N-methylcoclaurine, as
well as two cyclopeptides-integerresine and crenatine A (223).
(XV,295)
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544 R. H. F. MANSKE
103. R u ta bracteosa DC. (R . halepensis L. (Rutaceae)
(IX,224; XII,462; XIV, 5 5 3 ; XV,283)
In addition to three furocoumarins this plant yielded rutamine (127)( 1 2 4 ) .
Me
127
104. Rutaceae (XII,503; XIII,423; XV,292)
A number of plants of this family when examined for alkaloids and
triterpenes yielded results of possible taxonomic significance.Araliopsis
tabouensis AubrBv. e t Pellegr. yielded ( - - )-A'-methylplatydesminium
ions, a second furoquinoline, and flindissol. Diphasia lclaineana Pierre
yielded lupeol, evoxanthine, arborinine, and skimmianine. Teclea
verdoorniuna Excell. et Mendonga yielded lupeol and exoxanthine (125) .
105. Sceletium Alkaloids (IX,468; XIV,554; XV,296)
Three new alkaloids were isolated from S . namaguense (L . ) Bolus in
addition t o other known bases and sceletium A,, whose structure (128)was revealed largely by spectral methods; A7-mesembrenone (129)(C,,H,,03N, oil) previously prepared from mesembrine;N-formyltor-
tuosamine (130) C21H,,0,N,, oil); and sceletenone (131)C,,H,,O,N,oil). S. tricturn (L.) Bolus also yielded a number of known alkaloids
and the new 41-O-demethylmesembrenone (132) (C,,H,,O,N, oil)methylation of which generated mesembrenone (126) .
128 129
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9. ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE 545
130 131 R = H
132 R = OMe
106. S e d u m m a x i m u m Suter (Crassulaceae)
The alkaloids, sedamine, sedinine, and sedridine were identified in the
alkaloid mixture which was present to the extent of 0.008 to 0.01% in the
dry plant ( 1 2 7 ) .
(XI,462)
107. Senecio cineraria DC (Compositae) (XII,256)
Jacobine, senecionine, seneciphylline, and retrorsine ( 2 2 8 ) .
108. Senecio erraticus Bertol. (XII,245,251; XV,297)
Three alkaloids of mp 229-231°C, 221-222"C, ([a],,+ 1 l 0 ) , and 192-
193°C were isolated. Apart from limited IR data no identities were
suggested (2 2 9 ) .
109. Senecio petasitis DC. (XII,245; XV,297)
The alkaloid from this plant on hydrolysis generated retronecine and
isolinecic acid and in consequence its structure is 133, n full conformity
with spectral data (2 3 0 ) .
OH Me ?H
I nEt ---fl--CH,--CH-$-Me
IcoI
I 0
Ico
133
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546 R. H. F. MANSKE
110. Senecio swaziensis Compton
(XII,245; XlII,400; XIV,537; XV,297)
Swazine (C,,H,,O,N, mp 165"C, [a],, - 103.5"), which had been
isolated from the above-named species and also fromS. barbellatus DC.
(1 3 1 ) ,has been subjected to chemical degradation and to spectral study.
Acid hydrolysis generated retrorsine and a spirodilactone (134). Of the
possible structures that could be derived from the above fragments
th at represented by 135 is favored (1 3 2 ) .
O J ' i CQ CHz
co II 0
134 135
111. Sida cardifolia L. (Malvaceae)
/3-Phenethylamine, ephedrine, #-ephedrine, methyl ester of N,-
methyltryptophan, hypaphorine, vasicinone, vasicine, vasicinol, and
liberal amounts of choline and betaine (1 3 3 ) .
(X,581)
112. Skimmianine and y-Fagarine
These alkaloids were found in the following species of Haplophyllum :
H . schelkovnikovii Grossheim, H . villosum G . Don( ?), H . kowalenskyi
(Auth?), nd H . t enue (Auth?) 1 3 4 ) .
(X,565; XlI,480; XV,284)
113. Sophora a l o ~ o c u r ~ d e s. (Leguminosae)
(VII,258; IX,208; XIV,557; XV,298)
In addition to the known sophoridine, sophoramine, sophocarpine,
and aloperine there was isolated neosophoramine (C,,H,,ON,) whichwas regarded as the 5-epimer of sophoramine ( 1 3 5 ) . Tricrotonyl-
tetramine (136) (C,,H,,N,; mp 101-103°C) was later reported as a
constituent of this legume ( 1 3 6 ) .
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9. ALKALOIDS UNCLASSXFIED AND O F UNKNOWN STRUCTURE 547
M eI
jJ.-J.-.M e M e
H H
136
114. Sophora proda nii E. Anders
Sparteine and cytisine (1 3 7 ) .
(IX,208; XIV,257)
115. Streptomyces Species N 337 (XIII,421)
The structure of the base from this Streptomyces, M. ich had been
regarded previously as a pyrrolidine derivative, has been revised to
( E , )-2-pentadienyl-3,4,5,6- etrahydrop yridine (137) ( 1 3 8 ) .
137
116. Sw ain son a galegifolia R. r. (S.coronillaefolia Salisb.)
(Leguminosae) (X,581; XIV,558)
Spherophysine was identified as a constituent (139).
1 17 . Syneilesis palma ta Maxim. (Compositae) (XII,245)
Syneilesine (C,,H,,O,N; mp 195"C),a highly cytotoxic alkaloid, was
shown to have structure 138.Aside from spectral studies, hydrolysis and
?H H ?H
E t - C H - C - C - C - M e
H M e C O
II I I
A A I
I0
coI
138
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548 R. H. F. MANSKE
hydrogenolysis gave critical information. Hydrolysis gave three new
closely related lactones which confirmed the nature of the acid moiety.
Hydrogenolysis generated dihydrodeoxysyneilesine-11,14-olide (139)(mp 109°C) which on hydrolysis also yielded three lactones and the
necine, dihydrodesoxyotonecine (140) (140 ) .
I
co
Me
139
I
M e
140
118. Talaum a mex icana G. Don (Magnoliaceae) (VII,445; XIV,227)
Liriodenine ( 1 4 1 ) .
119. Teclea boiviniana (Baill.) H. Perrier (Evodia boiviniana Baill.)
(XII,503 XIII,423;XV,292)Rutaceae)
Malicopine, tecleanthine, and evoxanthine, all known acridones, were
isolated. In addition, this plant yielded 6-methoxytecleanthine (141)
and 1,3,5-trimethoxy-lO-methylacridene142) (142 ) .
0 OMe
M e 0
1 4 1 142
120. Teclea grand ifolia Engl.
Tecleanone (C,,H,SO,N; mp 190OC) was obtained in 0.00670 yield in
the form of yellow crystals. Its structure (143) was determined largelyfrom its mass spectrum and other spectral data. It bears a formal
resemblance to tecleanthine in that it is the open form of a possible
acridone ( 1 3 ) .
(XIII,423; XV,292)
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 549
121. Teclea un ifoliata Auth 1
alkaloid mixture which was obtained in 0.5y0 1 4 4 ) .
(XXI,503; XIII,423; XV,292)
Maculine, skimmianine, and kokusaginine were separated from the
122. Tem pletonia retusa (Vent.) R. Br. (Leguminosae)
A new alkaloid, (- -templetine (C20H35N3;mp 120-3 22OC; [.ID- 2 O ) , was isolated in 0.02y0 yield as well as the known ( - -cytisine,
(- -anagyrine, ( + )-lupanine, and ( & )-piptanthine. Vigorous dehydra-
tion of it afforded ( - -dehydropiptanthine (CZ6Hz3N3). pectral
methods including an X-ray analysis indicated the complete stereo
structure (144) f this alkaloid. Since this alkaloid has now been related
to ( - )-ormosanine and to (-)-panamine, i t is possible to assign thecorrect stereo structure to those as well ( 1 4 5 ) .
(IX,213)
144
123. Trichocereus pachano i Britten et Rose (Cactaceae)
(XII,506;XV,298)
The presence of mescaline and 3-methoxytyramine was proved (1 4 6 ) .
124. Tylophora cordifolia Thw. and T. Eava Trirnen (Asclepiadaceae)
(IX,518; XIII,425; XIV,562; XV,298)The former yielded tylophorinine and three unidentified alkaloids on
a chromatogram. Similar examination of T . ava gave tylophorine and
four unidentified alkaloids ( 1 4 7 ) .
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550 R. H . F. MANSKE
125. Tylophora indica Merrill (T.sthmatica)(IX,518; XIII,425; XIV,562)
A reexamination of the structure of tylophorinidine by an X-ray study
of its methiodide diacetyl derivative confirmed it to be 145 ( 1 4 8 ) .Other
spectral methods are consonant with that structure (1 4 9 ) .
IOMe
145
126. Ulugbekia tschimganica (B. Fedtsch.) Zakirov (Boraginaceae)
determined by spectral methods ( 150) .Uluganine from this plant has structure 146 (R = trachelanthoyl) as
CH(0H)Me/
90.
WaoR46
127. Vaccinium (Cranberry) (Ericaceae)
A new alkaloid (mp 168-170°C) was obtained from the leaves of a
cranberry native to New Brunswick. It s structure (147)was determined
almost exclusively by spectral methods and confirmed by a synthesis.
Tryptamine was condensed under physiological conditions with glu-
tardialdehyde and the condensation product reduced with NBH. The
147
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9. ALKALOIDS UNCLASSIFIED AN D OF UNKN OWN STRUCTURE 551
resulting base was methylated with methyl iodide in the presence of
sodium amide and the 1-methyl base (147)was identical wit'h the natural
product (1 5 1 ) .
128. Zanthoxylum americanum Mill. (Rutaceae)
Nitidine and laurifoline were isolated from the root and stem bark as
well as the coumarins xanthyletin and xanthoxyletin. The presence of
chelerythrine, tembetarine, magnoflorine, and candicine was demon-
strated. The root bark of Z . clava-herculis was shown to contain lauri-
foline, magnoflorine, tembetarine, and candicine (152) .
(XII,478; XIV,530)
129. Zanthoxylzcm arnottianum Maxim.
In addition to a host of neutral compounds and a quaternary iso-quinoline derivative isolated as picrate (C,,H,GO,N+ C,H,O,N; ;
mp 256-26O0C), this plant yielded dictamnine, robustine, and haplopine
(1 5 3 ) .
(X,423; XII,478; XIV,530)
130. Zanthoxylum tsihanimposa H . Perr.
(XII,506; XIII,427; XIV,530)
The bark of this plant yielded y-fagarine, skimmianine, and 1 1 -
dihydrochelerythrinylacetone, as well as two further derivatives of
chelerythrine which appear t o be artifacts (1 5 4 ) .
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57. B. Danieli, G. Palmisano, and G. Rainoldi, Phytochemistry 13, 1603 (1974); CA
58. W. M. Messmer, M. Tin-Wa, H. H. S. Fong, C. Bevelle, N. R. Farnsworth, D. J.
59. J. P. Gillespie, L. G. Amoros, and F. R. Stermitz, J . O r g . Chem. 38, 3239 (1974).
60. M. Koyama and S. Sakamura, Agric. Biol.Chem. 38, 1111 (1974); C A 81, 148445s
61. Z. Xu e and X.-T. Liang, K’o Hsueh T’ung Pao 19, 378 (1974);CA 82,13964k (1975).
62. L. G. West, R. L. Vanderveen, and J. L. McLaughlin, Phytochemistry 13,66 5 (1974);
63. A. A. M. Habib, M. M. A. Hassan, and F. J. Muhtadi, J. Pharm. Pharmacol. 26,
64. P. Venturella, A. Bellino, and F. Piozzi, Heterocycles 3, 367 (1975);C A 83, 435548
65. V. I. Akhamedzhanova, J. A. Bessanova, and S. Yu. Yunusov, Khim. Prir. Soedin.
66. I. A. Bessanovaand S. Yu. Yunusov, Khim. Prir.Soedin. 52 (1974);CA 80,121152m.
67. I. A. Bessanova, V. I. Akhamedzhanova, and S. Yu. Yunusov, Khim. Pri r. Soedin.
68. V. I . Akhamedzhanova, I. A. Bessanova, and S. Yu. Yunusov, Khim. Pr ir. Soedin.
69. K. A. Abdullaeva, I. A. Bessanova, and S. Yu. Yunusov, Khim. Pri r. Soedin. 680
70. K. A. Abdullaeva, I. A. Bessanova, and S. Yu. Yunusov, Khim. Pr ir . Soedin. 684
71. E. F. Nesrnelova and G. P. Sidyakin, Khim. Prir. Soedin. 9, 548 (1973); C A 80,
72. G. H. Mahran and S. H. Hilal, Egypt. J . Pharm.Sci.13,32 1 (1972);CA 81, 169679m
27, 1982 (1973), CA 8 0 , 27416d (1974).
C A 75, 26524x (1971).
(1973); CA 8 0 , 27413a (1974).
Bull. 20, 418 (1972) ; CA 77, 5645p (1972).
(1974).
Lloydia 37, 493 (1974); CA 82, 82983C (1975).
Aust. J. Chem. 27, 179 (1974); CA 80, 68397s (1974).
ll lP -1 12 P (1974); CA 82, 167464j (1975).
82, 28576j (1975).
Abraham, and J. Trojanek, J . Pharm. Sci.61, 1858 (1972).
(1974).
C A 81, 1309s (1974).
837 (1974); CA 82, 108817d (1975).
(1975).
10, 109 (1974); C A 80, 121153n (1974).
677 (1974); CA 82, 86462e (1975).
272 (1975); CA 83, 97662s (1975).
(1974);C A 82, 73261n (1975).
(1974); C A 82, 73260n (1975).
105845J (1974).
(1974).
8/12/2019 35980975 the Alkaloids Chemistry and Physiology Volume 16 1977 IsBN 0124695167
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554 R. H. I?. MANSKE
73. R. B. Harhammer, A. E. Schwarting, and J. M. Edwards, J . Org. Chem. 40, 156
74. X. A. Dominguez, J. Marroquin, B. S. Quintero, and B. S. Vargas, Phytochemistry
75. B. Tursch, D. Daloze, J. C. Bralkman, C. Hootele, A. Cravador, D. Losman, and
76. J. Gleye, A. Ahond, and E. Stanislas, Phytochemistry 13, 675 (1974); C A 81,
76a. D. Gross, W. Berg, and H. R. Schuette, Z . Chem. 13, 296 (1973); C A 80, 3679r
77. T. Ipaktchi and S. M. Weinreb, Tet. Lett. 3895 (1973); CA 80, 71001p (1974).
78. M. Launasmaa, Planta Med. 27, 83 (1975); C A 83, 4938y (1975).
79. A. R. Battersby, R. B. Bradbury, R. B. Herbert, M. H. G. Muro, and R. Ramage,
80. A. R. Battersby, P. Bohler, M. H. G. Munro, and R. Ramage, J. Chem. Soc.,
81. M. Hanaoka, H. Sassa, N. Ogawa, Y. Arata, and J. P. Ferris, Tet . Lett. 2533 (1974);
82. K. A. Kadyrov, V. I. Vinogradova, A. Abdusamatov, and S. Yu. Yunusov, Khim.
83. A. Philip and A. B. Segelman, J. Pharm. Sci. 63, 1495 (1974);CA 82, 13999a (1975).
84. R. Ziyaev, A. Abdusamatov, and S. Yu. Yunusov, Khim. Prir. Soedin. 505 (1973);
85. R. Ziyaev, A. Abdusamatov, and S. Yu. Yunusov, Khim. Prir. Soedin. 685 (1974);
86. J. G. Brun and S. Agurell, Phytochemistry14, 1442 (1975); CA 83, 1607608 (1975).
87. K. It o and S. Asai, Yakugaku Zamhi 94, 729 (1974); C A 81, 166344n (1974).
88. T. R. Govindachari and N. Viswanathan, Indian J. Chem. 10, 453 (1972).
89. T. R. Govindachari and N. Viswanathan, Phytochemistry11, 3529 (1972).
90. T. R. Govindachari, K. R. Ravindranath, and N. Viswanathan, J. Chem. Soc.,
91. S. M. Kupchan, H. P. J. Hintz, R. M. Smith, A. Karim, M. W. Cass, W. A. Court,
92. S. T. Murphy, E. Ritchie, and W. C. Taylor, A w t .J.Chem. 27, 187 (1974); C A 80,
93. D. P. Chekraborty, P. Battacharya, A. Islam, and S. Roy, Chern. Ind. ( L o n d o n )
94. B. Tursch, D. Daloze, J. C. Braekman, C. Hootele, and J. M. Pasteels, Tetrahedron
95. A. Guggisberg, M. M. Badawi, M. Hesse, and H. Schnid, Helw. Chim. Acla 59, 414
96. F. Schneider, K. Bernauer, A. Guggisberg, P. van den Brock, M . Hesse, and H.
97. R. L. Vanderveen, L. G. West, and J. L. McLaughlin, Phytochemistry 13, 866
98. M. J. Hoizey, M. M. Debray, L. LeMen-Olivier, and J. LeMen, Phytochemistry13,
99. J. Loehdefink and H. Kating, Planta Med. 25, 101 (1974); CA 81, 355313' (1974).
100. J. Levesque, J. L. Pousset, A. Cave, and A. Cave, C. R. Acad. Sci. (Ser. C ) 278, 959
(1975); C A 82, 112187r (1975).
14, 1833 (1975); CA 84, 2212d (1976).
R. Karrlson, Tet . Lett. 409 (1974).
1327643 (1974).
(1974).
J . Chem. SOC ., erkin Trans. 1394 (1974).
Perkin Trans. 1 1399 (1974).
CA 82, 4445q (1975).
Prir. Soedin. 683 (1974); C A 82, 73262q (1975).
CA 80, 60055h (1974).
CA 82, 8640c (1975).
Perkin Trans. 1 1215 (1974).
and M. Yatagai, J. Chem. Soc., Chem. Commun. 329 (1974).
80074s (1974).
165 (1974); C A 81, 4103f (1974).
31, 1541 (1975).
( 1974).
Schmid, Helw. Chim., Aeta 57, 434 (1974).
(1974);CA 81, 35584t (1974).
1995 (1974);C A 82, 829723. (1975).
(1974); CA 81, 74819u (1974).
8/12/2019 35980975 the Alkaloids Chemistry and Physiology Volume 16 1977 IsBN 0124695167
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9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 555
101. J. L. Pousset, J. Levesque, A. Cave, F. Picot, P. Potier, and R. R. paris, plants
102. T.Higa and P. J. Scheuer, Phytochemistry 13, 1269 (1974); A 81, 166385b (1974).
103. P. S. Steyn, Tetrahedron 26, 51 (1970).
104. D. W . Nagel, K. G. R. Pachler, P. S. Steyn, P. L. Wessels, G. Gafner, and G . J .
Kruger, Chem. Commun. 1021 (1974).
105. N.B.Mulchandani an d S. R. Venkatachalam, India, A.E.C., Bhabha &.R ~ .ent.
[Rep.]B.A.R.C.-764, 8 (1974); A 82, 108862q (1975).
106. R. Hocquemiller, M. Leboeuf, B. C. Das, H. P. Husson, P. Potier, and A. Cave,
C . R. Hebd. Seances Acud. Sci., Ser. C 278, 525 (1974); A 80, 133673~ 1974).
107. E. teinegger, Pharm. Acta Helv. 48, 517 (1973); A 80,575052 (1974).
108. R. T.Mirzamatov, K. L. Lutfullin, V. M. Malikov, and S. Yu. Yunusov, Khim.
109. R. T.Mirzamatov, K. L. Lutfullin, V. M. Malikov, and S. Yu. Yunusov, Khim.
110. R. T.Mirzamatov, K. L. Lutfullin , V. M. Malikov, an d S. Yu. Yunusov, Khim.
111. W. Loewe and K. H. Pook, Ann. 1476 (1973).
112. J. Singh, M. A. Potdar, C. K. Atal, and K. L. Dhar, Phytorhemistry 13,677 (1974);
113. S. McLean, P.L. Lau, S. K. Cheng, and D. G. Murray, Can. J. Chem. 49, 1976
114. S.McLean, M. L. Roy, H. J. Lin, and D. T. Chu, Can. J . Chem. 50, 1639 (1972).
115. M. F.Mackay, L. Satske, and A. M. Mathieson, Tetrahedron 31, 1295 (1975).
116. S. R. ohns, J. A. Lamberton, A. A. Sioumis, and H. Suares, Aust. J. Chem. 27,2025 (1974); A 81, 120833t (1974).
117. E.J. Corey and R . D. Balanson, J . Am. Chem. SOC. 6, 6516 (1974).
118. G. A,Moro, M. N. Graziano, and J. D. Coussio, Phytochemistry 14,827 (1975); A
119. K. Jewers, M. J. Nagler, K. A. Zirvi, F. Amir, and F. H. Cottee, Pahlavi Med. .J . 5 ,
120. J.Reisch, G. W. Mirhom, J. Korosi, K. Szendrei, and I. Novak, Phytochemistry 12,
121. K. zendrei, I.Novak, M. Petz, J. Reisch, H. E. Bailey, and V. L. Bailey, LZoydia
122. A. Morales Mendez, A. Gonzalez Gonzalez, and F. Diaz Rodriquex, Rev. Fac.
123. D. . Bhakuni, C. Gonzalez, P. G. Sammes, and M. Silva, Rev. Latinoam. Quim. 5 ,
124. A.Gonzalez Gonzalez, R. Estevez Reyes, and E. DiazChico,An.Quim.70,281(1974);
125. G. Wsterman, Biochem. Syst. 2, 153 (1973); A 80, 5650e (1974).
126. P. W. effs, T. Caps, D. B. Johnson, J. M. Karle, N. H. Martin, and B. Rauckman,
127. S. Logar, N. Mesicek, M. Pcrpar, and E. Seles, Farm. Vestn. (Ljubljana) 25, 21
128. A. Klasek, V. A, Mnatsakanyan, and F. Santavy, Collect. Czech. Chem. Commun.
129. R. I.Gaiduk, M. V. Telezhenetskaya, and S. Yu. Yunusov, Khim. Prir. Soedin 414
Med. Phytother. 8,51 (1974); A 81, 117054J (1974).
Pr ir. Soedin. 415 (1974); A 81, 152460k (1974).
Pr ir. Soedin. 416 (1974); A 81, 166359~ 1974).
Pr ir. Soedin. 540 (1974); A 82, 82957x (1975).
C A 81, 35577t (1974).
(1971).
83, 93851e (1975).
1 (1974); A 81, 230973. (1974).
2552 (1973); A 80,12480w (1974).
36, 333 (1973); A 80,12510f (1974).
Farm., Uniu. Los Andes 8,77 (1971); A 82, 121629~ 1975).
158 (1974); A 82,108803~ 1975).
C A 81,117048k (1974).
J . Org. Chem. 39, 2703 (1974).
(1974); A 82, 82916h (1975).
40, 2524 (1975): A 83, 175453r (1975).
(1974); A 82, 54167w (1975).
8/12/2019 35980975 the Alkaloids Chemistry and Physiology Volume 16 1977 IsBN 0124695167
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556 R. H. F. MANSKE
130. A. Gonzalez Gonzalez, G. De la Fuente , and M. Reina, An . Quim. 69, 1343 (1973);
131. C. G. Gordon-Gray, R. B. Wells, M. B. Hursthouse, S. Neidle, and T. P. Toube,
132. C. G. Gordon-Gray and R. B. Wells, J . Chem.. Soc., Perkin Trans. 1 1556 (1974).
133. S. Ghosal, Phytochemistry 14, 830 (1975); CA 83, 93854h (1975).
134. L. Y. Isaev and I. A. Bessanova, Khim. Pri r. Soedin. 815 (1974); C A 82, 1216 77~
135. T. E. Monakhova, 0. N. Tolkachev, V. 8. Kabanov, M. E. Perel’son, and N. F.
136. T. E. Monakhova, 0. N. Tolkachev, M. E. Perel’son, V. S. Kabanov, and N. F.
137. N. Paslarasu and A. Badauta-Tocan, Farmacia (Bucharest)21, 693 (1973); CA 81,
138. M. Onda, Y . Konda, G. Narimatsu, H. Tanaka, J. Awaya, and S. Omura, Chem.
139. J. Steineger and G. Reuter, Pharmazie 28, 682 (1973); CA 80, 1181 96~1974).
140. M. Hikichi and T. Furuya, Tet. Lett. 3657 (1974).
141. T. Kametani, H. Terasawa, M. Iha ra, and J. Iriarte, Phytochemistry 14, 1884 (1975);
142. J. Vaquette, M. 0. Cleriot, M. R. Paris, J. L. Pousset, A. Cave, and R. R. Paris,
143. A. C. Casey and A. Malhotra, Tet. Lett. 401 (1975).
144. J. Vaquette, J. L. Pousset, and A. Cave, Plant. Med. Phytother. 8, 72 (1974);CA 81,
145. J. R. Cannon, J. R. Williams, J. F. Blount, and A. Brossi, Tet. Lett. 1683 (1974).
146. D. M. Crosby and J. L. McLaughlin, Lloydia 36, 416 (1974); C A 80, 68385m
147. J. D. Phillipson, L. Tezcan, and P. J. Hylands, Planta Med. 25, 301 (1974);CA 81,
148. V. K. Wadhawan, S. K. Sikka, and L. B. Mulchandani, India,A.E.C., Bhabha
149. N. B. Mulchandani, S. S. Iyer, and L. P. Badheka, India, A.E.C. Bhabba At.
150. M. A. Wasanova, U. A. Abdulaev, M . V. Telezhenskaya, and S. Yu. Yunusov,
151. K. Jankowski, S. Godin, and N. E. Cundasawmy, Can. J. Chem. 52, 2064 (1974);
152. F. Fish, A. I. Gray, P. G. Waterman, and F. Donachie, Lloydia 38, 268 (1975);CA
153. H. Ishii, K. Hosoya, T. Ishikawa, E. Ueda, and J. Haginiwa, Yakugaku Zasshi 94,
154. N. Decaudain, N. Kunesch, and J. Poisson, Phytochembtry 13, 505 (1974); C A 81,
CA 80, 96194s (1974).
Tet. Lett. 707 (1972).
(1975).
Proskurnina, Khim. Pri r. Soedin. 472 (1974); CA 82, 541764. (1975).
Proskurnina, Khim. Prir . Soedin. 752 (1974); CA 82, 121666~1975).
87965n (1974).
Phurm. Bull. 23, 2463 (1975); CA 84, 5213r (1976).
C A 84, 2213e (1976).
Plant. Med. Phytother. 8, 57 (1974); CA 81, 60857s (1974).
6085911 (1974).
(1974).
117038g (1974).
At . Res. Cent. [Rep.]B.A.R.C.-764, 6 (1974); CA 82, 171258n (1975).
Res. Cent. [Rep. ]B.A.R.C.-764, 3 (1974); C A 82, 171257m (1975).
Khim. Prir . Soedin. 809 (1974);C A 82, 140349~1975).
CA 81, 63831q (1974).
83, 128689n (1975).
322 (1974); CA 81, 132753e (1974).
74879n (1974).
8/12/2019 35980975 the Alkaloids Chemistry and Physiology Volume 16 1977 IsBN 0124695167
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SUBJECT INDEX
A
Abresoline, 531
Acacia, 43
2-Acetyltrop-2-ene, 87
N-Acetyltryptamine, 543Acnistus, 62
Aconitum, 24, 58
Acronycine, 515
Actinidia argista, 440
Actinidia polygama, 440
Actin idine, 52, 433, 436, 441
Adaline, 5 11
Adiantifoline, 269, 297
Adenocarpus, 46Adina cordifolia, 54
Agastachys odorata, 153Agroclavine, 63Ailanthus giraldii, 42
Ajrnalicine, 54
Aknad icine, 394
Aknadilactam, 394, 422
Aknad inine, 394
Alatamine, 218, 238
Alatolin, 242
Alchornea fioribunda, 48Alchorneine, 48
Alchorneinone, 48
Alphonsea venfricosa, 512
Alstonia venenata, 448Amanita Muscaria, 22
Ambrosia, 5
Ammodendron conollyi, 13, 45
Anabasine, 17, 25, 51
Anabasis aphylla, 13, 25Anabasine, 529Anagerine, 549
Anagy rine, 540, 543
Ancistrodadine, 512Ancistrocladus hamatus, 5 12
Ancistrocladus heyneanus, 5 12
Ancistrocladus vahlii, 5 12Androcymbine, 67, 69
9-Angelylretronecine, 5 1
Anhalidine, 25
Anhalon idine, 25
Anhydronupharamine, 185, 187Aniba duckei, 512Anisocycla grandidieri, 270, 291, 309
Anisodarnine, 91
Anisodas, 61
Anisodine, 91
Ankorine, 513
Anon aine, 526, 536
Anthocercis, 61
Anthocercis littorea, 154
Anthocercis tasmanica, 154
Anthocercis viscosa, 154
Anthocleisra procera, 453
Anthocleista rhizophoroides, 473
Anthranilic Acid, 14
Antirrhinum, 10
Antirrhinum hispanicum, 5 13Anfirrhinum molie, 513
Antirrhinum mollissimum, 5 13
Apoatropine, 91, I04
Apparicine, 539
Aquilegia, 10Araliopsis tabouensis, 544
Arborinine, 544
Arecoline, 65
Argemone, 32, 38
Ariocarpus agavioides, 5 13
Aristolochia argenrina, 513
Arrnepavine, 51, 267, 323
Armepavine, 543Arornoline, 258Asimilobine, 536
Aspergillus, 22Aspidosperma, 54
Atalantia monophylla, 5 14Atalaphylline, 514
557
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558 SUBJECT INDEX
Atisine, 58 C
Atropa, 10, 12, 61
Atropa belladona, 93, 139, 146, 154, 162
Cadalene, 524
Cad aver ine , 16Atropa martiana, 164Atrophine, 104Atropine, 89, 127, 162
Azureocercus ayacuchensis, 5 14
B
Bacillus subtilis, 309
Bakanko side, 450
Baluchistanamine, 307
Baptisia leucophia, 11Bathiorhamnus cryptophorus, 5 14Belarine, 257
Bellendena montana, 85, 153
Bellendine, 85
2a-Benzoyloxynortropan-3~-01,92
2a-Benzoyltropane, 86
2-Benzyltropanes, 86
Benzoin aestivale, 535
Berbamine, 41, 297, 309, 348Berbamu nine, 334
Berbenine, 297Berberis , 33
Berberis baluchistanica, 280, 307
Berberis laurina, 257, 272Berberis lycium, 297Berberis petiolaris, 297
Berberis vulgaris, 309
Bhesa archboldiana, 5 1Bisjatrorrhizine, 258
N,N -Bisnoraro mo line , 258
Boemeria cylindrica, 64
Boehmeria platyphylla, 64Boldine, 543Boschniakine, 443, 532
Boschniaka rossica, 444Boschniakinic Acid, 438
Brugmansia, 61
Bruguiera exaristata, 89, 153
Bruguiera sexangular, 89, 153
Bruguiera cylindrica, 5 15Brugine, 515, 89
Bufotenine, 18
Bulbocapnine, 31Burkea africana, 515
Buxenine-G, 60Buxus, 61
Cadia ellisiana, 515Calligonum, 25
Calpurnine, 5 15
Calycanthine, 51
Calycanthus, 53
Camptorrhiza, 69
Camprotheca acuminata, 55Candicine, 65 , 525
Camptothecine, 515, 536
Canadaline, 532
Cantlega corniculata, 447Cantleyine, 446Canc entr ine , 260
Cannabis sativa, 515Cannabisatar ine, 515
Capsicum, 62
Caro coccu line, 5 18
Casimiroa, 19
Cassam ine, 46
Cassine matabelica, 246
Cassinic Acid, 246
Cassinine, 246Cass nopsis ilic ifolia, 55
Castoram ine, 191
Catharan thine , 54
Catharanthus, 54
Catha edulis, 216, 218, 516Cathidine D, 217, 218, 220, 224, 516
Ca thol , 225Celabenzine, 537
Celacinnine, 219, 536
Celafurine, 537
Celullocinnine, 537
Celapagine, 218, 220
Celap anigin e, 218, 220
Celapanine, 218, 220
Celapanol, 22 1
Celastrus angulatus. 246
Celastrus orbiculaius, 246
Celastrus panicufatus, 216, 218
Centaurium pulchella, 473
Centaurium spicatum, 477
Cephaelis, 57Cephalotaxus harringtonia, 5 16
Cephalofoxine, 532
Cephaeamine, 394, 420Cepharanoline, 261
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SUBJECT INDEX 559
Cepharanthine, 261, 345
Cestrum, 62
Chelerythrine, 41
Chelidimerine, 261
Chelidonium majus, 261
Chondodent, 296, 371
Chondodendron toxicoferum, 295
Chondrucurine, 25 I , 296
Chondrofoline, 252, 374
Cinchona, 57
Cis-endodihydroisobellendine, 5
Clausena heptaphylla, 5 17
Clausena indica, 517
Claviceps, 22, 62Clitogbe fascicutata, 5 17
Cocaine, 51, 162
a-Cocaine, 119, 147
p-Cocaine, 120, 147
Coccineline, 538
Cocculus, 33
Cocculus carolinus, 58
Cocculus laurifolius, 518
Coclaurine, 543
Cocsoline, 305
Cocsuline, 262, 270, 309Cocsulinine, 305
Cocculus leaeba, 282
Cocculus pendulus, 262, 282, 305
Codonocarpine, 519
Colchicine, 67
Colchicurn, 69
Colpidium colpoda, 309
Colubrina asiatica, 275
Conessine, 60
Coniine, 17
Conium, 17, 23Contarea, 57Convergine, 538
Convolvulus, 61
Cordifoline, 54
Corydalis, 33
Corypalline, 526
Couroupita guianensis, 519
Couroupitine A , 519
Coryphantha calipensis, 5 19
Cremastosperma polyphlebum, 308
Crenatine 17, 543Crepidamine, 524
Crepidine, 7 1 524
Cratalaria, 207, 237, 44
Crotalaria assamiea, 519
Crotalaria burhia, 520
Crotalaria ferruginea, 520Crotalaria leioloba, 520
Crotalaria rnadurensis, 520
Crotalaria tetragona, 520
Crotalarine, 520
Croton, 48
Croton diaco, 49
Croton gabouga, 49
Croton salutaris, 32
Croton turumiquirensis, 49
Crotonosine, 48
Cryptocarya bowiei, 32, 64Cryptospermine, 64
Cryogenine, 531
Cryptophorine, 514
Cryptophorinine, 5 14
Cularine, 33
Curine, 296
Cuscohygrine, 90, 153
Cuspidaline, 334
Cyclea barbata, 309
Cyclea peltata, 263, 209
Cycleacurine, 263Cycleadrine, 264
Cycleahomine, 265
Cycleanine, 297, 375
Cycleanorine, 266
C ycleapeltine, 267
Cyclea sp. (?), 297
Cyclobuxine-D, 60
Cynadum wilfordii, 241
Cynanchum, 56, 64
Cyphomandea betacea, 154
Cystine, 540, 549Cyphomandra, 61
Cytisine, 44, 547
D
Daphnandra micrantha, 271
Daphneteijasmanine, 5 21
Daphmigraciline, 521Daphniphylline, 50
Daphniphyllum gracile, 521
Daphniphyllum teijsmanii, 521Daphrigracine, 521
Darlingia darlingiana, 86, 153
Darlingia ferruginea, 86, 153
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560 SUBJECT INDEX
Darlingine, 86Datura, 12, 61
Datura alba, 154Datura arborea, 154Datura bernhardii, 154, 164
Datura candida, 154
Datura ceratocaula, 90, 141, 154Datura cornigera, 142, 154
Datura discolor, 154Datura fastuos a, 154
Datura fer ox , 137, 154, 162
Da fura godronii, 154Datura inermis, 144
Datura innoxia, 90, 138, 154, 162Datura leichardtii, 154
Datura metel, 154
Datura meteloides, 140, 154
Datura myoporoides, 144Datura pruinosa, 154
Datura sanguinea, 91, 140, 154
Datura sframon ium, 93, 136, 140, 154, 162Dafura suaveolens, 89, 154
Da tura tatula, 144, 154
Dauricine, 320, 387
Dauricinoline, 267Dauricoline, 268
Daurinoline, 297, 3342-Deacetylevonine, 218, 237
Delavaine, 394, 408
Dehydrodeoxynupharidine, I85
Dehydroskytanthine, 440
Delphinium, 24, 58N,N-Demethyl-3,4-dimethoxy
3-O-Demethylhernandifoline, 94, 41 1
4'-O-Demethylmesembrenone, 544Dendrobates histrionieus, 522Dendrobates pumilio, 522
Dendrobium, 7 1
Dendrobium chrysanthum, 524
Dendrobium erepidatum, 524
Dendrobium nobile, 524
Dendrobine, 523
(* -trans-Dendrochrysine, 524Dendrocrepine, 524
4-Deoxyeu onym inol, 246
CD eoxye vonin e, 218, 230
Deoxyharr ingtonine, 203-Deox ymayto1 , 226
Deoxynupharidine, 181
Deoxyscopoline, 132
&m ethoxyphenethy lamine, 5 19
Dercetylcolchicinu, 5320-Desmethyladiantifoline, 269
N ' -Desmethyldauricine, 27012'-O-Desmethyltrilobine, 270Desmodium, 43
Desmodium cephalotes, 525
Diethoxythiobinupharidine, 200
Dicaine, 164Dicentra, 33
Dicentra canaden sis, 260
2,6-Dideacetylevonine, 218, 237Dihydroerysodine, 38
6,6*-Dihydroxythio-binupharidine,00
6,6'-Dihydroxythionuphlutine,200Diphasia klainiana, 544
0,O-Dimethylcur ine , 374
0,N-D imethy lmicran thine , 271
N,N-Dimethyltryptamine, 18
Dipidax, 69Dipsacus aureus, 448
3a,6P-DitigIoyloxytropan-7B-O 89
Dolichotele baumii, 525
Dolichotele longim amm a, 525
Dolichotele melaleuca, 525
Dolichotele sphaerica, 525Dolichotele surculosa, 525
Dolichotele uberiformis, 525
Doryanine, 526
Doryophora sassajias, 526
Dorypho rnine, 526
Dregamine, 539
Drimys, 72
Drupacine, 516
Dubam ine, 531
Duboisia, 61
Duboisia hopwoodii, 154
Duboisia myoporoides, 153, 163
Du ckeine , 5 12
Dunalia, 61
E
Ecgonine, 162
Eduline, 539Effirine, 262
Elymoclavine, 63
Em etin e, 56, 531Enicoflavine, 458
Enicostemma hyssopitfolia, 458Enicostemma littorale, 453Enonymine, 218. 239
Ephedra, IS
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SUBJECT INDEX 561
Ephe dr ine , 15, 546
-Ephedrine, 546
7-Epideoxynu pharidine, 182, 199
Epinetrum villosum, 297
3-Epinuphamine, 185, 189, 1%
Epin upha rarnine, 194, 199, 21 1
Epioxodap hnigraciline, 521
Epipilosine, 541Epistephamiersine, 394, 403Epistephanine, 272, 297, 309
Equisetum, 20Ergine, 63
Erginine, 63
Erythraea centaurium, 456Erythrina, 23, 33, 48, 44Erythrophleum, 46
Erythrophleum chlorosthehys, 526, 527
Erythrophleum ivorense, 526Erythrophleum monogynum, 527
Erythroxylum coca, 153
Erythroxylum ellipticum, 93, 153
Erythroxylum monogynum, 92, 153
Eschscholtzia, 32
Eschscholtzidine, 527
Eschsch ol tz ine , 33Espinidine, 272Espinine, 273
Ethoxythiobinupharidine, 200
Euda lene, 221Euolalin, 241
Eu onin e, 218, 239
Euonymus Europaeits, 51Euonyminol, 225, 231
Euonymus aiatus, 218
Euonymus europaeus, 216, 218
Euonymus sieboldianus, 217, 218Euxylophora paraensis. 527
Evodia boiviniana, 548
Evonimine, 218
Evo nine, 216, 218, 231, 516
Evonine Acid, 216, 229, 231
Evonoline, 218, 229
Evo r ine , 218
Evo xanthin e , 544, 548Ev ozin e, 218, 237
FFagara xanthoxyloides, 15. 528SF ag arin e, 530, 546, 551
Fagaronine, 528Fagomine, 528
Fagopyrum esculentum, 528
Fagrea fragrans, 474
Fangchinoline, 309Farnesol, 524Ferrugine, 86
Ferruginine, 86Festuca, 66
Festucine , 65
Fetidine, 252
Ficus, 64Fontanesia phillyroides, 454
Fontaphill ine, 454
N-Forrnyltortuosamine, 544
Fritillaria, 6 9Funiferine, 274Funtumia, 6 0
G
Galanthamine, 67
Garrya, 58
Genista, 46Genista monosperma, 543
Gentiabetine, 463
Gentialutine, 448
Gentiana angustifolia, 474Gentiana asclepiadea, 449, 456
Gentiana axillaris, 474
Gentiana axillijlora, 474
Gentiana barbata, 474
Gentiana biebersteinii, 474
Gentiana bulgarica, 474Gentiana caucasia, 473
Gentiana clusii, 474
Gentiana cruciata, 458
Gentiana decumbens, 474
Gentiana dinaerica, 474Gentiana fetisowii, 474Gentiana freyniana, 474
Gentiana greacilipes, 474
Gentiana kaufmanniana, 473Gentiana lutea, 449
Gentiana macrophylla, 456Gentiana olgue, 456
Genriana olivieri, 456, 457, 464Genfiana pneumonanthe, 474
Gentiana punctata, 474
Gentiana purdomrii, 474Gentiana purpurea, 474
Gentiana scabra. 474Gentiana schistocaktx, 474Gentiana septenfidea. 474
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562 SUBJECT INDEX
Gentiana sino-ornata, 474
Gentiana spp,, 529
Gentiana straminea, 474Gentiana tibetica, 463
Gentiana turkestanorum, 455, 457Ge ntiana wirilowi, 475
Gentiana vvendenskyi, 475
Gentiana wutaiensis, 475
Gentianadine, 455
Gentianamine, 457
Gentianidine, 456
Gentianaine, 459
Gentianine, 52, 432, 452
Gentiocrucine, 458Gentioflavine, 457
Germacrane, 524
Glaucine, 31, 512, 534
Gliotoxin, 22
Gloriosa, 69
Glycoperine, 530
Glymnocactus , 529
H
Haemanthamine, 67Halfordinine, 537
Haloxylon amm odendron, 529
Hamatine, 5 12
Haplamine, 529
Haploperine, 531Haplophydine, 530
Haplophyllum latifolium, 53
Haplophyllum kowalenskyi, 546
Haplophyl lum perforatum, 529, 530
Haplophyllum schelkovnikovii, 546
Haplophyl lum tenue, 546Haplophyllum villosun, 546
Haplopine, 530, 551
Harmalan. 515
Harman, 25, 515, 539
Hasubanonine, 394, 398, 422, 427
Hedera helix, 531
Heimia salicifolia, 531
Heliosupine, 19
Heptazolidine, 517Hernandifoline, 394, 410
Hernandine, 394, 412Hernandoline, 394
Hernandolinol, 394, 413Heteratisine, 58
Hippodamine, 531, 538
Hippomane mancinelia, 49
Histamine, 19
Histidine, 14Histrionicotoxin, 522
Holarrhena, 24, 60
Holophyllamine, 60
Homatropine, 162
Hornoaromoline, 309
Homoroia riparia. 49
Homostephanoline, 394
Hordenine, 14, 65, 525
Hydrastis canadensis, 532
19-Hydroxycassaine, 526
1I-Hydroxycephalotaxine, 5 164-Hydroxydendroxine, 524
4-Hydroxyhygrinic Acid, 49
Hydroxylunine, 543
13-Hydroxylupanine, 5 15
1-Hydroxyrutaecarpine, 527
a-Hydroxyscopolamine, 91
Hydroxyskytanthine I, 439
6 -H ydrox ythiobinupharidine, 200
6-Hydroxythionuphlutine B, 200
Hydroxywilfordic Acid, 217, 229
Hygrine, 16, 51, 71Hymenocaridia, 48
Hymenoxys , 5
Hym enoxys acaulis , 13
Hymenoxys ives iana, 13
Hymenoxys scaposa , 13
Hyoscyamine, 90, 136, 162
Hyoscine, 89, 162
Hyoscyamus , 12. 61
Hyoscyamus a lbus , 154
Hyoscyamus aureus , 154
Hyoscyamus n iger , 93, 145, 154
Hyo scyam us orientalis , 154
hyoscyamus p ius i l lus , 154
Hypaphorine, 546
I
Idotetrandrine, 264, 294, 297, 309, 341
Incarvillea olgae, 471
Indicaine, 532
Indicaxanthine, 27
Indizoline, 517
Integerrimine, 520
Integerrisine, 543Inula rogleana, 58
Zphigenia, 69
Ipomoca, 63
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SUBJECT I N D E X 563
Iridomyrmex, 52Isobellendine, 85
Isochondodendrine, 297Isocorydine, 526
Isocromadurine, 520
Isoeuonyminol, 23 1
Isoevo nine, 218, 237Isoevo rine, 218, 237
Isofangchinoline, 309Isogentialutine, 448Isoharningtonine, 532
Isolaureline , 535Isoliensinine, 361
Isooncinotine, 538Isoplatydesmine, 539
Isotheb aine, 31
Isoremerine, 535Isotenuipine, 275Isothalicbe rine, 257Isotril obin e, 253, 262, 271
Zxanthus niscosus, 475
J
Jabob ine, 545
Jasm inine, 462Jasminum domatiigerum, 476
Jasminum frutican s, 486
Jasminum gracile, 476
Jasmium lineare, 476
Jasminum SPP, 446, 463Jaborosa, 62
Jatrorrhiza paim ata, 258
Julocroron, 48
K
Knightia deplanchei, 87, 153, 532Kokusagine, 537, 549
Kokusaginine, 539Kreisiginone, 532Kreys igia , 69
Kreysigia multiflora, 532
L
Ladenbergia , 57Lagerine, 534
Lagerstroemia indiea, 534
Lamprobine, 20, 44Lapanine, 540, 549Laurifine, 5 18
Laurifinine, 518Laurifoline, 55 1
Laurifonine, 518
Laurotetanine, 535
Latura, 61Lepis ta caespi tosa, 5 17
Lepistine, 517
Leptorhabdos parvijlora, 450, 535Leptorhabine, 450, 535Lespedeza, 43Liensinine, 361Limacine, 309Limacu sine, 267
Lindera bemzoiin, 535
Liparis, 71
Lirine, 535Liriodenine, 65, 526, 535, 536, 548Liriodendron tulipifera, 535Littorica, 69
Littorine, 104, 139
Lobelia, 17Lomatogonium rotatum, 475
Loline, 65Lolium, 66Lonicera, 53
Lophocerine, 26
Lophophora diffusa, 535Lunaria, 65Lupinine, 25, 44
Lupinus, 71
Lyadine, 539
Lyaline, 539
Lycopersicum esculentum, 142
Lysicamine, 535Lysine, 14
Lycocfonine, 58
Lycopers icon, 60
Lycopodine, 20Lycopodium, 20
Lyco nne , 67Lysicanine, 65
Lysichitum camtschatcense, 65Lythrine, 531
M
Maculine, 549
Magnocurine, 536
Magnoflorine, 41, 551
Magnolamine, 336Magnoline, 334Magnolia obovata, 536Mahonia aquifolia, 297Malaxis, 71
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564 SUBJECT INDEX
Malkangunin, 221, 241
Malkanguniol, 222, 245
Malonetia. 60Mandragora, 61
Mandragora autumnalis, 154
Mandragora oficinarum, 94, 154
Mappiene, 536
Mappia foctida, 55, 536
Matrine, 20
Maytansine, 2 19
Maytenus arbutifolia, 218, 536
Maytenus buchanii, 2 19
Maytenus chuchuhuasha, 219
Maytenus ovaius, 215, 218Maytenus senegalense, 218
Maytenus serrata, 218
Maytine, 215, 218, 220, 225
Maytol, 227
Maytolidine, 218, 220, 227
Maytoline, 215, 218, 220, 225
Melicope barbigera, 539
Melicope perspicuinerva, 537
Melicopidine, 515
Melicopine, 518
A'-Membrenone, 544
Menisarine, 357
Menispermum canadense, 297
Menispermum dauricum, 267
Menyanthes trifoliata, 449, 458
Meperidine, 101, I50
Merendera, 69
Mescaline, 25, 549
Mesembrine, 26
Mesembryanthemum, 26
N-Methylisopelletierine, 16
N-Methylpyrrolidine, 16
N-Methyltyramine, 65
Methysticodendron, 6
Mesodine, 531
Meteloidine, 89, 141
Metaphanine, 394, 396, 424
6-Methoxyteeleanthine, 548
3a-(p-Methoxyphenylacetoxy)-Tropan-6po,
3-Methoxytyramine, 549
0-Methylancistrocladine, 5 12
6P(2-Methylbutanoyloxy) tropan-3a-o I ,
3(3-Methylcrotonyl)-cassaine, 526
0-Methyldauricine, 275N-Methyl-3,4-dimethoxy-fi-methoxy-
91
90
phenethylamine, 5 19
N-Methyl-3,4-dimethoxyphene-
thylamine, 519Methylhernandine, 394, 412
0-Methyllagerine, 534
0-Methylmieranthine, 276
4-Methyl-2,6-naphthyridine,5 13
0-Methyloxyacanthine, 292
0-Methylpellotine, 535
N-Methylplatydesminium, 544
0-Methylptelefolium, 543
0-Methylthalicberine, 297, 348
N-Methyltyramine, 539
0-Methyltyrophorinidine, 540Miersine, 394
Micranthine, 253
Monocrotaline, 519, 520
Monomethyltetrandinium, 307
Morphine, 32
Munitagine, 33
Multiflorine, 5 15
Multifloramine, 532
Murrayacinine, 537
Murray a Koenigii, 537
Muscarine, 22Mycobacterium smetmatis, 300, 309
Mycobacterium tuberculosis, 300
Myrrhina, 538
N
Namedi ne, 67
Neferine, 361
Nelumbo, 57
Nemuarine, 276
Nemuaron vieillardii, 276
Neoeuonymine, 218, 239
Neoevonine, 218, 237
Neogomesia agavioides, 5 13
Neooneinotine, 538
Neothiobinupharidine sulfoxide, 197, 200
Neosophoramine, 546
Nicandra, 61
Nicojiana, 6, 12, 17, 61
Nicotiana tabacum, I54
Nicotine, 20, 25Nigella damascena, 46
Nitidine, 551
Nohilomethylene, 524
4 Noractinidine, 446
Noradrenaline, 34
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SUBJECT INDEX 565
Noratropine, 89
Norbelladine, 67
2-N-Norberbamine, 277Norboldine, 543
Norcocaine, 123
Norcycleanine, 297
Norerythrostachaldine, 526
Norglaucine, 512
Norhyoscine, 89
Norlaudanosine, 30
Normacromerine, 519
N-Normethylskytanthine, 445
2-N-Norobamegine, 278
Norpseudoephedrine, 217Norpsicaine, 134
Nortilliacorine-A, 278
Nortiliacorinine-A, 278 ,
Nortiliacorinine-B, 278
Novacaine, 164
Nuciferine, 65
Nudiflorine, 48
Nuphamine, 185, 188
Nuphar, 57, 72
Nupharamine, 183, 185, 211
Nupharidine, 181Nuphar japonicum, 188
Nuphar luteum, 186, 197
Nupharolidine, 191, 199
Nupharolutine, 192, 199
Nuphenine, 187, 199
Nuphleine, 198, 200
Nymphaea, 57, 72
0
Obaderine, 260, 357
Obovanine, 536Olea paniculaia, 462
Oliveridine, 463
Oliveramine, 465
Oncinotine, 538
Oncinoris nijida, 538
Ophelia diluta, 475
Opuntia clavata, 539
Opuntia jicus-indica, 27
Orientalinol, 34
Orientalinone, 31
Ormocastrine, 541Ormosanine, 549
Ormosia, 23, 44
Ormosia semicastrata, 541
Ornithine, 14
Oscine, 143
Oxaline, 540
6,7-Oxidodeoxynupharidine, 99Oxodaphnigraciline, 521
Oxodaphnigracine, 521
16-Oxodelavaine, 394, 409
Oxoepistephanine, 279
16-Oxohasubanonine, 394, 405
16-Oxoprometaphanine, 394, 405
Oxostephamiersine, 394, 403
Oxyacanthine, 348
P
Pachygone pubescens, 297Pachysandra, 60
Pakistanamine, 280
Pakistanine, 281
Palustrine, 20
Panamine, 549
Pandaca calcarea, 539
Pandaca debragi, 539
Pandine, 539
Pandoline, 539
Papaver, 6, 12, 38
Papaver orientale, 31Papaver somniferum, 30
Papaverine, 30
Parthenium, 5
Passijlora coerulea, 539
. Passiyora decaisneana, 539
Passijora edulis, 539
Passij7ora foetida, 539
Passijora incarnara, 539
Passijlora, subpeltata, 539
Passijlora subulata, 539
Passijlora warmingii, 539Pauridianiha hyaflii, 539Pauwoljia verticillata, 448
Pedicularidine, 467
Pedicularine, 467'Pedicularis dolichorrhiza, 47
Pedicularis ludwigi Regel, 471
Pedicularis olgae, 443, 466
Pedicularis rhinanthoides, 472
Pedicularis rhinanthoides, 438
Pediculidine, 461
Pediculine, 467Pediculinine, 466
Peganum, 23, 42
Pelea barbigera, 539
Pelecyphora aselliformis, 5 13
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566 SUBJECT INDEX
Penduline, 282
Penicillium, 22
Penicillium islandicum, 6Penicillium oxalicum, 540
Pennsylpavine, 306
Pennsylpavoline, 306
Pennsylvanamine, 306
Pennsylvanine, 306
Pergularia pal l ida, 540
Peripentadenia m earsii , 49, 92, 153
Periphylline, 540
Peripterygia marginata, 540
Petter ia ramentac ca , 540
Phaeanthine, 341Phaeanthus ebracteolatus, 3I0
Phaseolus aureus, 46
PPhenethylamine, 525, 543, 546
Phelline, 51
Phellodendron, 41
Phenethylamine, 14
Phenylalanine, 14, 43
2-Phenylglyceric Acid, 91
Phlebicine, 308
Phyllanthus, 47, 49
Physalis. 61Physalis a lkak engi , 94, 154
Physalis bunyardii, 94
Physalis peruviana, 94, 141, 154
Physochlaina, 61
Physochlaina alaica, 91, 154, 541
Physochlaine, 91, 541
Physos t igma , 23, 49
Physosrigma vertenosum, 43
Physostigmine, 23
Physoperuvine, 94
Picrasma ailrnthoides, 42Pilocarpine, 19
Pilocarpus, 19
Pilocarpus microphyllus, 541
Pilosine, 541
Pinidine, 20
Piper trichostachyon, 541
Piptanthine, 549
Pipranrhus, 44Plantago albicans, 471
Plantago coronop us, 471
Plantago crassifolia, 47
Plantago crypsoides, 471
Plantago cylindrica, 471, 443
Plantago m ajor , 471
P antago nota ta , 471
Plantago ovata, 472
Plantago psyl l ium, 47
Plantago ram osa, 443Plantagonine, 443Platydesmine, 537
Pleurospermine, 37
Podopetaline, 541
Podopetu lum ormondii , 541
Popowia cyanocaupa, 275
Poranthera corymbo sa , 542
Poranthericine, 542
Porantheridine, 542
Porantherilidine, 542
Parantheriline, 542Porantherine, 542
Pretazettine, 67
Prometaphanine, 394
6PF’ropanoyloxy-3a-tigloyloxytropane, 0
Propyleine, 538
Prosopis nigra, 543
Prosopis spicigera, 543
Protostephabyssine, 394, 401
Protostephanine, 427
Przewalskia shebbearei, 154
Przewalskia tangiotica, 154Pseudoephedrine, 15
Pseudotropine, 51, 109
Pseudornonas putid a, 165
Psicaine, 107
Psilocybe, 22
Psilocybin, 18, 22
Psychotria, 57
Pielen trifoliata, 543
Pterocelastrus marginatus, 540
Pumiliotoxin C , 522
Putrescine, 16
Pycnamine, 283, 209
Pycnarrhena australiana, 277, 297
Pycnarrhena ozantha , 258, 278
R
Remij ia , 57
Repandine, 357
Retama monosperma , 543
Retamine, 543
Reianilla ephedra , 543
(+)-Reticuline, 30, 520, 526, 536, 419
Retronecine, 545
Retrorsine, 545
R h a z y a , 54
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SUBJECT INDEX 567
Ricinine, 48
Ricinus, 48
Rivea, 63
Robustine, 551
Rodiasine, 274
Ruta bracteosa, 544
Ruta chalepensis, 544
Rutamine, 544
S
Salpichroa, 61
Salpichroa originifolia, 154
Salpiglossis, 61
Salsolidine, 525Salsoline, 25
Salutaridine, 32
Sanguidimerine, 304
Sanguinaria canadensis, 304
Sarcocca, 60
Sceletenone, 544
Sceletium namaquense, 544
Sceletium strictum, 544
Schoenocaulon, 69
Scopolia, 61
Scopolamine, 162Scopolia carniolica, 94, 154
Scopolia himalaiensis, 140, 154
Scopolia japanica, 155
Scopolia lurida, 94, 136, 145, 155
Scopolia parviyora, 155
Scopolia sinesis, 155
Scopalia stramonifolia, 145, 155Scopolia tangutica, 155
Scopoline, 131
Securinega, 47
Securinine, 47Sedamine, 17
Sedumo maximum, 545
Senecio barbellatus, 546
Senecio cineraria, 545
Senecio eraticus, 545
Senecio petasites, 545
Senecio swaziensis, 546
Senecionine, 19, 545
Seneciphylline, 545
Serotonin, 18
Sida cordifolia, 546Silene, 10
Sinicuichine, 531
Skimmiancine, 531, 537, 544, 546, 549, 551
Skytanthine, 433
Skythanthines, 434, 470
GSkythanthine, 435
Skytanthus acutus, 432Solandra, 61
Solandra grandijlora, 143, 155
Solandra guttata, 155
Solandra harrwegii, 155
Solandra hirsuta, 155
Solandra macrantha, I55
Solanidine, 60
Solanocapsine, 60
Solanurn, 60, 61
Sophocarpine, 543, 546
Sophora alopeouroides, 546Sophora prodanii, 547
Sophoramine, 546
Sophoridine, 546
Sphaerocarpine, 45
Sparteine, 44, 20, 543. 547
Spathiostemon javensis, 49
Spherophysine, 547
Spicigerine, 543
Spiraea japonica, 58
Stehisimine, 297, 309
Stemmadinine, 54Stephaboline, 394, 401
Stephamiersine, 394, 403 .Stephania abyssinica, 394
Stephania cepharantha, 261, 394
Stephania delavayi, 394
Stephania hernandifolia, 279, 297, 394
Stephania japonica, 283, 394
Stephania sasakii, 297, 394
Stepinonine, 283, 310, 347
Stephasunoline, 394, 403
Stephavanine, 394, 400Stephisoferuline, 394, 398
Stephuline, 399
Streptomyces, 22
Streptomyces N337, 547
Streptosolen, 61
Stropharia, 22
Strychnine, 54
Strychnos, 54
Strychnos vacacoua, 450
Swainsonia coronillaefolia, 547
Swainsonia galegifolia, 547Swazine, 546
Swentia connata, 475
Swentia gracipora, 475
Swertia gracij?ifolia, 476
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568 SUBJECT INDEX
Swertia japon ica, 453, 456
Swertia marginata, 475
Swertia sibirica, 475
Syneilesis palrnata, 547
Syneilsine, 547
T
Tabersonine, 54
Talauma mexicana, 381, 548
Taxine, 20
Tazettine, 67
Teclea boiviniana, 548
Teclea grandifolia, 548
Teclea unifoliata, 549Teclea verdoerniana, 544
Tecleanone, 548
Tecleanthine, 548
Tecoma fu lv a , 440
Tecom a radicans, 440
Tecoma stuns, 435
Tecomaine, 435
Tecomine, 435
Tecostanine, 30, 435
Tecostidine, 437, 438
Telobine, 285Teloidine, 111
Teloidinone, 111
Ternbetarine, 551
Templetonia retusa, 549
Templetine, 548
Tetrahydroharman, 25, 515
Tetrandrine, 266, 297, 309, 341
Thalfine, 286
Thalfinine, 287
Thalfoefidine, 255
Thalibruinine, 308Thalicarpine, 289, 297, 382
Thalicberine, 297, 348
Thalictrogarnine, 287
Thalictropine, 288
Thalictrum dioicum , 289
Thalictrum f oetidum , 286
ThalictrumJlavum, 297
Thalictrum glaucum , 292
Thalictrum isopyroid es, 289
Thalictrum minus, 269, 290, 297
Thalictrum polygam um , 287, 297, 306
Thalictrum rochebrunianum, 308
Thalictrum rugosum , 292, 297
Thalidasine, 255, 293
Thalidazine, 297
Thalidoxine, 289
Thaligine, 294
Thalisopidine, 289Thalmelatidine, 290
Thalmineline, 291
Thalrugosarnine, 292
Thalrugosidine, 293
Thalrugosine, 294, 309
Thalsrninine, 297
Thiobinupharidine, 195
Thionupharodioline, 200
Thionupharoline, 198, 200
Thionuphlutine, 196
Tigloyidine, 1403a-Tigloyloxytropan-6p01, 89
6~-Tigloyjoxytropan-3a-7pdiol,89
Tiliacora dinklagei, 305
Tiliacora fun ifera , 274
Tiliacora race mo sa, 278
Tiliacora w arneckei, 274
Tiliacorine, 279, 359
Tiliacorinine, 279, 359
Tiliageine, 305
Toddalia, 41
Toxicoferine, 295Trewia, 48
Trichocereus pa chan oi, 549
Trichoderma viride, 22
Trichodesmine, 520
Triclisia gillettii, 262, 309
Triclisia pa ten s, 309
Triclis ia su bcord ata, 262, 296, 309
Tricordatine, 296
Tricrotonylteteamine, 546
Trigilletine, 262
Trilobine, 270, 297, 3543a-(3,4,5-Trimethoxybenzogloxy)-tropane,
Triptergine, 240
Tripterygium forrestii , 246
Tripterygium wilfordii, 217, 218, 536
Tropacine, 164
Tropcocaine, 92, 162
Tropan-3a, 6P-dio1, 86, 91, 93
Tropan-2& 3P-dio1, 116
Tropane, 109, 123
Tropan-3a-01, 121
Tropan-3P-01, 101
Tropan-6po1, 123
Tropan-3-one, 12 1
Tropan-3a, 6P, 7ptrio1, 93
93
8/12/2019 35980975 the Alkaloids Chemistry and Physiology Volume 16 1977 IsBN 0124695167
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SUBJECT INDEX 569
Tropanyl Ethers, 124Tropidine, 109, 133Tropine, 61, 109
Vasicinone, 546
Vavicinol, 546