Molecules 2008, 13, 1875-1896; DOI: 10.3390/molecules13081875

molecules ISSN 1420-3049

www.mdpi.org/molecules

Review

Rigorous Biogenetic Network for a Group of Indole Alkaloids Derived from Strictosidine†

László F. Szabó

Department of Organic Chemistry, Semmelweis University, Hőgyes utca 7, H-1092 Budapest, Hungary; E-mail: szalasz@szerves.sote.hu

† Chemotaxonomy of Indole Alkaloids, Part 5 (for Part 4, see [15]). This paper is dedicated to Prof. Heinz G. O. Becker on the occasion of his 85th birthday.

Received: 5 August 2008; in revised form: 24 August 2008 / Accepted: 26 August 2008 / Published: 27 August 2008

Abstract: Strictosidine, the precursor of more than 2,500 indole alkaloids, was isolated from four species of three plant families. By searching the Dictionary of Natural Products on DVD it was found that about 150 indole alkaloids were obtained from the same species (coalkaloids), which is a direct proof of their common origin. On the base of their three-dimensional structure, taxonomic properties and standard reaction mechanisms an extended network was established which involved the four fundamental skeletons, the three types of carbon framework in the secologanin subunit and all major groups of indole alkaloids derived from secologanin and tryptamine (except a few minor groups, in which only less then 10 alkaloids were known). The system was extended to the heterodimer indole alkaloids and the quinoindole alkaloids as well.

Keywords: Secologanin, coalkaloid, dimer alkaloid, reaction mechanism, computer searching, chemotaxonomy.

Introduction The monoterpenoid indole alkaloids form a uniform group of natural products. Several generations

of researchers have worked on their isolation, structure determination, chemical transformations and synthesis. Much effort has also gone into elucidating their biogenesis, and as a consequence, the main

OPEN ACCESS

Molecules 2008, 13

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pathways of their formation are already known [1-4]. However, the applied methods consume much time, material and human energy. In addition, it is often dubious if the postulated in vitro or biomimetic reactions really take place in vivo [5]. There is a certain gap between the level of the biological micromolecules (alkaloids) and macromolecules (enzymes and genes), and it is difficult to follow the processes on the micromolecular level. Although a large amount of knowledge has been accumulated concerning the starting steps and the formation of some key compounds [6-8], many questions are still unanswered at the more remote points and in special groups.

Recently, specialized data bases and their electronic searching features have offered an alternative tool for chemotaxonomic studies. The fact that more than 2,500 indole alkaloids were isolated mainly from three plant families (Rubiaceae/Naucleaceae RUB, Loganiaceae/Strychnaceae LOG and Apocynaceae APO) and formed from two building blocks [secologanin (1) and tryptamine (2) or tryptophane] through a single precursor [strictosidine (3)] suggested a strong coherence in this collection of alkaloids. Compounds isolated from the same cells, species, genera and/or families in parallel and/or consecutive reactions may be guideposts in their genesis, and in cases where highly reactive or sensitive intermediates cannot be isolated in intact form from biological sources, they can be postulated according to standard organic reaction mechanisms. The rich collections of structural, physical, chemical and taxonomic data effectively contribute to such an approach. It seems, therefore, that the isolated compounds themselves could give a more realistic basis and complementary method for these studies.

Our previous work in the chemistry of secologanine and especially of strictosidine provided good starting points [9-10]. The internal consistance was further supported by the mechanism of chirality transfer at C-15 and C-3 in the type I class of indole alkaloids, and some stereoselectivity could be demonstrated even in the type II and III classes as well [11, 12]. Extended biogenetic networks could be established by studies in the large group of type I alkaloids [13] and in the small but highly specific group of Melodinus alkaloids [14]. In addition, a long evolutionary line was constructed for the formation of ellipticine from ajmalicine (corynanthean skeleton) and an analogous line postulated for olivacine from isodihydrocadambine (malindan skeleton) [15].

In this paper we look for those indole alkaloids which have a direct chemotaxonomic contact with strictosidine, the primary precursor of indole alkaloids. In this relation two main questions were to be answered:

1. Compounds isolated from the same species reveal their common origin. Which alkaloids could be isolated from those plant species which produce also strictosidine (3)? In other terms: which are the “coalkaloids” of this universal precursor of indole alkaloids?

2. The monomer components necessarily coexist in the same species, from which the dimer alkaloids were isolated. This fact likewise reveals chemotaxonomic connections among the individual alkaloids and species. Which types of monomer components are connected in the dimers?

As the reaction mechnisms were already discussed previously or will be so in the future, they are mentioned in this paper only briefly and schematically, however, the chemotaxonomic connections are analyzed in detail.

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Scheme 1. The Coupling Reaction.

1

2

34

56

7 8

9

10

11 OH3CO

O

H

O

O

H O

OHOH

OHHO

1

2

5 6

“trioxo aglikon”

16

NHN

H3CO

O

OH H HH

OH

17

2021

1 4

22

18

19

“primer aglikon”

NHN

OH3CO

O

OHH H HH

tryptamine

glc = β-D-glucopyranosylsecologanin ISS38

Strychnos nux vomica LOGLonicera xylosteum APO

1

910

11

12 1332

45

678

14

15

1617

1819

2021

22

NHN

OH3CO

O

OglcH H HH

3 3α-H, strictosidine CCF30

4 3β-H, vincoside CCK08 Vinca rosea APO

Anthocephalus cadamba RUB

Rhazya stricta APOCatharanthus roseus APOStrychnos mellodora LOG

αβ

NH2N

H

H

II. III.

3 2114

15

16 1718

1920

22

type I skeleton

3 2114

1819

22

151716 20

type II skeleton

21 314

1520

1819

171622

type III skeleton

Compounds Tested in the Coupling Reaction in the Presence of Strictosidine Synthase

only reactions involving secologanin, 8,10-dihydro secologanin and tryptamine w ere catalyzed by strictosidine synthaseand the product w ith 3S conf iguration w as formed exclusively

2-oxo-2,3-dihydro-tryptamine

secologanin~ tetraacetyl~ 8,10-dihydro~ tetraacetyl,

8,10-dihydro

1

7-hydoxy-N-methyl-bakankozin~ 8,10-dihydro

N(a)-methyl tryptamineN(b)-methyl tryptamineN(b)-benzyl tryptamine

tryptamine

2 23

N NH2

HO

7

810

ON

O

Ogkc

HH

Me

HO

The necessary structural, chemical and taxonomic data were taken from the database Dictionary of

Natural Products on DVD Version 16.2 (in the following DNP) [16], and completed occasionally with data from the Beilstein Crossfire and the Chemical Abstracts online data bases. In the structural formulas and throughout the text, the biogenetic numbering system shown in formula of strictosidine (3) was used [17]. The only exceptions are the building blocks 1 and 2, which are numbered as indicated in their own formulas. All isolated compounds in the schemes and in Table 1 were provided with Chapman and Hall (C&H) code numbers, which give access to the rich primary literature sources. The figures giving the numbers of alkaloids in the different taxons are approximative and in several cases only estimations, as they are changed by the continuous renewal of the database and depend on the selection principles used as well. The Biogenetic-type System of Indole Alkaloids

In this work the indole alkaloids natural products are considered, which are formed from

secologanine (1) and tryptamine (2) (or tryptophan). However, even within this field certain limitations had to be applied.

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Scheme 2. System of Indole Alkaloids Derived from Secologanin.

N

N2

721

1716

22

19

20

18

3

14

15

21

3

1819

20

14

15

N

N

H16

1722

N

N

H

N

N

22

1716

314

15

21

7

2019

18

β2

N Nα2

321

22 1617 14

15

7

20

19

18

17

N

Nβ72

22 16

21

20

19 18

3

14

15

N

N

21

16 17

22

31415

18

19

2072

β

N Nα2

321

22 1617

14

15

7

20

1918

N N

N

N

H

2

321

1516

22 17

14

2019

18β 714

20

19

18

72

321

22 17

1615

β

N

N

H

910

1 4

N N

H

3

22

15

16 17

2

7

2019

18

21α

5

68

13

11

12

14

N N

H

vincosan

>1000 alkaloidsRUB, LOG, APO

including cyclovincosans

ibogan

84 alkaloidsAPO

isoibogan

5 alkaloidsLOG

plumeran

340 alkaloiidsAPO

eburnan

56 alkaloidsAPO

stemmadenine derivativeAPO

4 alkaloids

14 alkaloids

isoplumeranAPO

8 alkaloidsAPO

isoeburnan

aspidospermatan

28 alkaloidsAPO

I αI β S I β A

II α

II β

II III

III α

III β- HX

(RUB), LOG, APOstrychnan

530 alkaloids

type II skeleton

3 21

14

18

1922 151716 20

21 3

1415

20

181917

16

22

type III skeleton

II. III.

3 2114

15

16 1718

1920

22

type I skeleton

1517

N

N21

22 1614

2 2019 18

β7 3

APO7 alkaloids

secodine derivative

In the “quinoindole” alkaloids group (about 100 isolated natural products), the original indole

subunit is extended into a quinoline subunit during the biosynthesis. They are dispersed among all three plant families mentioned above, as well as in some additional ones. Their special groups are the camptothecan (in the Icacinaceae and Nyssaceae families), as well as the cinchonan and melodan alkaloids. In another group of alkaloids derived from secologanin, the heterocyclic base in the coupling reaction is a substituted phenylethyl amine and provides the isoquinoline ring system which was found in some 90 isolated natural products (“Ipecacuanha” alkaloids) mainly in the Rubiaceae and Alangiaceae families. The problem of the quinoindole alkaloids will be discussed briefly, and the group of the Ipecacuanha alkaloids temporarily disregarded.

Previously, the system of indole alkaloids was based mainly on formal, structural properties of the individual compounds [18, 19]. For our purposes, a chemically and biologically oriented system was constructed [11] which is shown in Scheme 2 with slight modifications. It is based on the following principles:

level 0: formation of strictosidine (3) from secologanin and tryptamine and removal of the glucosyl subunit (Scheme 1);

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level 1: cyclization of the secologanin subunit to N-1 or/and N-4 of the tryptamine subunit (Scheme 2 shows only cyclizations to N-4); level 2: in the secologanin subunit, transformation of the type I skeleton into the type II and type III ones (Scheme 1); level 3: attachment of C-3 or C-21 or neither of them to C-2 (α) or C-7 (β) position of the the indole ring; level 4: further cyclizations between the secologanin and the tryptamine subunits; level 5: further cyclizations inside the secologanin subunit; level 6: further transformations (e.g. rearrangements, ring extensions and ring contractions; fragmentation of the tryptamine side chain, formation of sesqui- and dimers, which are temporarily omitted).

The system is shown in Scheme 2 up to level 4. It has an internal consistancy and predictive power, hard in principles, but soft for accomodating any existing or new alkaloid. The Main Precursor Strictosidine

The precursor of most indole alkaloids is strictosidine (3), having S configuration at C-3 (Scheme

1). Its formation from secologanin and tryptamine is catalyzed by the enzyme strictosidine synthase. Both the chemo- and stereoselectivities of the enzyme are high in vitro (i.e. under cell-free conditions). It was demonstrated [20], that of the components shown in Scheme 1 only the 8,10-dihydro derivative of 1 (of course over 1 and 2) can participate in the coupling reaction, and no trace of vincoside (4) (with 3R configuration) was formed. In the absence of the enzyme the reaction is much slower, and neither chemically, nor stereochemically selective [9a]. The complete stereoselectivity is remarkable, because strictosidine synthase was isolated both from Catharanthus roseus [21] and Rauwolfia serpentina [22]. From the first species strictosidine (3) with 3S and vincoside (4) with 3R configuration were isolated, and from the second species ajmaline (GQZ67) with 3S and reserpine (CFD56) with 3R configuration. This raises the obvious question, what is the source of the 3R chirality in the species mentioned above? The answer is not known yet.

The S chirality of C-15 in both compounds comes from the C-5 center of secologanin. Most of the type I alkaloids having a bridged skeleton with participation of C-15 (e.g. the akuammidan, akuammilan, pleiocarpaman, strychnan and aspidospermatan alkaloids) have S configuration at C-3, which suggests that their precursor is strictosidine, and the formation of the bridge is possible only with the cis orientation of the hydrogens attached to C-3 and C-15 [11a]. However, in a limited number of alkaloids with fused skeleta, the configuration at C-3 is R. The cause of it is likewise unknown.

Strictosidine (like vincoside) belongs to the type I α alkaloids, i.e. it contains the secologanin subunit in its unrearranged form, and its C-3 is attached to the α-position of the indole ring (vincosan skeleton 7 in Scheme 3). The biosynthetic power of strictosidine is mainly revealed after deglucosylation. The primarily formed aglucone 5 cannot be isolated, as it undergoes many types of isomerizations (which are represented in the trioxo form 6 in Scheme 1) [23]. Subsequent cyclizations and further transformations provide a high number of type I α alkaloids, whose formation was discussed previously [13].

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Scheme 3. Primary Cyclizations of Vincosan.

N N

H

α

1821 19

16

4 17

20

22

1αN N

H22 17

20

18419

21

16

1N N

H

α

16

21 1918

N N

H

4 22

17

20

N N

H

10

7 5

N N

H

H H

18

19

20

21

161722

α

15

NN

H

αβ

20

12

3

45

678

910

11

1213

1415

1617

1819

21

22

NN

O

OglcH HH

H3CO2C

OH

H

1819

2021

2216

17

N N

CO2Me

OHC

H

H H

18

1920

21

16

17

2222

1617

20

1918

NN

OO

MeO

H

H

H

H21

22

16

17

N N

OH

H H

Oglc

O

212019

18

RUB, LOG, APO

vallesiachotaman24 alkaloids

RUB, LOG, APO

malindan38 alkaloids

RUB, LOG, APO

corynanthean~1000 alkaloids

The Primary Skeletons (Cyclovincosans)

Representatives of the Primary Skeletons

RUB, LOG, APO44 alkaloidsvincosaman

7

8 9 11

12 13 14 15

vallesiachotamine CCH53Rhazya stricta APO

Vallesia dichotoma APO

isodihydrocadambine GPX51Anthocephalus cadamba RUB

geissoschizine CDP34Rhazya stricta APO

Tabernamontana tetrastachya APO

strictosamide GPX64Rhazya stricta APO

Nauclea latifolia APO

RUB, LOG, APO53 alkaloids

vincosan, I α alkaloid

Strictosidine was isolated from four plant species (in this paper they are called “strictogenic

species”) ranked into three plant families (Anthocephalus cadamba, Rubiaceae, Strychnos mellodora, Loganiaceae, Catharanthus roseus (=Vinca rosea; the two names are considered as synonyms, and in this paper mainly the first name is used) and Rhazya stricta, Apocynaceae). The next step in the further molecular evolution of strictosidine is the primary cyclization between the nucleophilic N-4 center and one of the four electrophilic centers (C-17, C-19, C-21 and C-22) of the secologanin subunit, which gives the vallesiachotaman, malindan, corynanthean and vincosaman skeletons 8-11, respectively (primary “azacyclizations”). These “cyclovincosan” skeletons and their probable first representatives (12, 13, 14, and 15) are shown in Scheme 3. During the biosynthesis, some structural elements (mainly C-17 or C-22) may be lost (“truncated” alkaloids). Analogous cyclizations also take place with participation of N-1, and gives nearly 100 alkaloids, however, they will not be discussed in this paper.

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Coalkaloids of Strictosidine in Type I α Class Fortunately, coalkaloids resulting from all four types of azacyclizations were found in the

strictogenic species, as is shown in Schemes 3 and 4, as well as in Table 1. Azacyclization to C-22 corresponds to a simple (often spontaneous) lactamization. The group of the vincosaman alkaloids, 11, is rather homogenous, and contains nearly 50 alkaloids, among others strictosamide (15) from the strictogenic Strychnos mellodora (Loganiaceae), and its C-3 epimer vincosamide from Adina rubescens (Rubiaceae), found as glucosides.

Scheme 4. Further Representatives of the Malindan and Vallesiachotaman Skeletons.

N N

H

HH

HO18

21 19

16

17

20

NN

N

HH 20 21

1819

N N

O

H H

H

MeO2C Oglc

O

2021

19

18N N

O

H H

H

MeO2C Oglc

OHH

2021

19

18

vallesiachotaman

anthirine natural form CGV97 Rhazya stricta APO

malindan

normalindine LCQ52Strychnos johnsonii LOG

16 17 18 19

isomalindan

dihydrocadambine GPX71Anthocephalus cadamba RUB

Nauclea latifolia RUBNauclea diderrichii RUB

isomalindan

cadambine CFJ83Anthocephalus cadamba RUB

Nauclea latifolia RUB

Azacyclization to C-19 (Scheme 4) results in the formation of the malindan skeleton 9. It can take place likewise on the glycosidic level, after activation of C-19 of the vinyl group, e.g. by epoxidation. This activation is known in secologanin chemistry [24], and is suggested in the present case by the hydroxy group at C-18 of isodihydrocadambine (13). The corresponding glycoside was isolated from the strictogenic Anthocephalus cadamba, Rubiaceae. The six-membered ring D of the fused cyclic system might be extended into a seven-membered azepin ring (20(19→18)-abeo-) (isomalindan skeleton), which was supported by isolation of dihydrocadambine (16) and cadambine (17) from the same species (Scheme 4). The (iso)malindan skeleton appears in more than 40 alkaloids (e.g. normalindine, 18), partially also on higher levels and even at the end of the molecular evolution, in the derivatives of olivacine (66) (Scheme 12).

Table 1. Coalkaloids of Strictosidine (parent name, number of derivatives, C&H number, type of skeleton).

Anthocephalus cadamba (RUB) (8 alkaloids) Rhazya stricta (APO) (50 alkaloids) Cadambine, CFJ 83, isomalindan Akuammicine deriv. GNP98, strychnan Cadamine, 2 derivs. HFP34, GZM28, malindan Akuammidine CGS53, akuammidan Dihydrocadambine, 2 derivs. GPX71, GPX73, isomalindan Akuammiline deriv. CGS78, akuammilan Isodihydrocadambine, 2 derivs. GPX51, GPX53, malindan Anthirine deriv. CGV97, anthiran Strictosidine, CCF30, vincosan Aspidospermidine 2 derivs. NSG56, NGX40, plumeran Bharhingine GRD15, strychnan Catharanthus roseus (= Vinca Rosea) (APO) (49 alkaloids) Burnamine deriv. CGP15, akuammilan

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Table 1. Cont. Ajmalicine deriv. BFV84 (VR), GNX93, corynanthean Decarboxymethoxytetrahydrosecodine deriv NQD29

secodan Ajmalicine hydroxyindolenine deriv. GNX49, corynanthean Dihydrocorynantheol deriv. GNZ33, corynanthean Akuammicine deriv. CGS34, strychnan Dihydroeburnamenine LCR84, eburnan Akuammiline deriv. LTT85, akuammilan Eburenine 2 derivs. GZP25, LNJ42, plumeran Alioline, OSQ04, ibogan Geissoschizine CDP34, corynanthean Alstonine 2 derivs. GNX52 (VR), CCC44, corynanthean Isorhazicine BQR50, secoajmalan Apparicine (S)-form, CGW23, vallesaman Isositsirikine 4 derivs. LCS06, CCW87, NBV19, NBV18,

corynanthean Bannucine CQG04, plumeran Lanceomigine deriv. CHL97, akuammilan Catharanthine CFM58 ibogan (VR) Leuconolam NNZ31, plumeran Fluorocarpamine indoxyl deriv. GRG17 pleiocarpaman Nor-C-fluorocurarine deriv. HHZ45, strychnan Isositsirikine 3 derivs. CCW78 (VR), CCW86, CCW87, corynanthean

Quebrachamine deriv. CFB72, plumeran

Lochneridine BQS00 (VR) strychnan Rhazidigenine hydroxyindolenine 2 derivs. CFF52, CFF54, plumeran

Perivine 2 derivs. CGN81 (VR), CGN86 (VR), vobasan Rhazimine 2 (quinoline) derivs. CFK02, CFK05, FYL18, akuammilan

Preakuammicine CGQ70 (VR), strychnan Rhazinaline 2 derivs. CDR88, NXF68, akuammilan Rosicine CFK07, plumeran/isoplumeran Rhazinilam 2 derivs. GPF00, FNO12, plumeran Sarpagin deriv BCC19 (VR) akuammidan Rhazizine LDC76, strychnan Sitsirikine 2 derivs. HJQ31 (VR), BCF50 (VR), corynanthean

Secodine 2 derivs. CHM24, BFV95, secodan

Strictamine deriv. CFF61, akuammilan Stemmadenine CCD41, strychnan/aspidospermatan Strictosidine CCF30 (+VR), vincosan Strictamine 3 derivs. HHT53, CDR79, BFY65, akuammilanStrictosidine 2 derivs. CCK08 (VR), CCK10 (VR) Strictanine BQS42, plumeran Tabersonine 2 derivs. GQZ42, HJQ42 (VR), plumeran Stricticine GRD24, GRG17, plumeran Talpinine deriv. GQW95, akuammidan Strictine GRD25, pleiocarpaman Tombozine deriv. GRC35 (+VR), akuammidan Strictosamide GPX64, vincosaman Venalstonine deriv. CCH72, plumeran Strictosidine CCF30, vincosan Vincadifformine deriv. CCJ46 (VR), plumeran Vallesiachotamine 3 derivs. CCH54, CCH55, LXQ87,

anthiran Vincarodine GNK80, eburnan Vincadifformine 3 derivs. HBN54, LHX61, CCJ49,

plumeran Vincoline CCK01 (VR), plumeran Vincamajine deriv. LJB72, akuammidan Vindolidine 5 derivs. KLJ88 (+VR), JHQ68, JRJ50 GQZ38 GQZ39, plumeran

Vindolinine 4 derivs. BQX53 (+VR), MVY20, BQX56, BQX57, plumeran

Strychnos mellodora (LOG) (5 alkaloids)

Voalutein indoxyl deriv. CFK06, ibogan Lyaloside 2 derivs. GVY09, GVY10, vincosan (VR) indicates alkaloids isolated (also) from Vinca rosea Strictosidine CCF30, vincosan Strictosidine 2 derivs. LHX56, MTN39, vincosan

After deglucosylation, the other two previously masked electrophilic centers will be free, and the

azacyclizations involving C-17 and C-21, respectively, can take place. Azacyclization to C-17

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provides the vallesiachotaman skeleton 8, with nearly 25 compounds, in the majority of which C-22 is lost during the biosynthesis (i.e. .in the anthirine derivatives). Both vallesiachotamine (12) and anthirine (19), the characteristic alkaloids of this group, were isolated from the strictogenic Catharanthus roseus (Apocynaceae). If C-17 (in vallesiachotaman) or C-22 (in vincosaman) was removed during the biogenetic process, the two “truncated” skeletons 8 and 11 became formally (but not biogenetically) indentical.

Scheme 5. Further Cyclic Systems Derived from the Corynanthean Skeleton.

2.

2.

5

3

7

1819

2021

N N

MeO2CO

H

H15

1617

22

αβ

N

NH

HMeO2C OH

2 16

3

7

1722

N N

Me02CH O

H

OH

H

H3

217

2015

1617

NN

MeO2C

H

H

4

2114

2019

O

18

3

15

1

16

NN

MeO2C

HH

OH22

16 4

6

2

17

15

5

NN

MeO2C CHO

H

72

3

15

16

22 17

4

N N

MeO2CO

H

HH H

3

7

1819

2021

N N

MeO2CO

H

HH H

3

7

1819

2021

N

OMeO2C

H

H

H7

N

O

H

3

N

OMeO2C

H

H

H2

7N

O

H

3

20

21 2223

24b

24d

25

2624c

akuammidine CGS53Rhazya stricta APO

Vinca rosea APOakuammidan

strychnan deriv. I β

preakuammicine CGQ70Vinca rosea APO

N N

HO

HO

MeO2C

3

14

1516

17

22

20

akuammilanRhazya stricta APORhazinaline CRD88

GNX49

corynanthean

ajmalicine hydroxyindolenine

Catharanthus roseus APO

abeoN1(16→17) pleiocarpaman

apogeissoschizine2,7-dihydro, 2α,7α-dihydroxy MTM06

Strychnos gossweileri APO

25a

24

GNX79

corynanthean

ajmalicine, 19,20-diepimer

Rauwolfia nitida APOUncaria elliptica RUB

rauniticine oxindole AGQX05

Uncaria elliptica RUBoxindole deriv. I βpseudoindoxyl deriv.

Uncaria elliptica RUB

rauniticine pseudoindoxylGRG13

pleiocarpamanRhazya stricta APO

strictine GRD25

corynanthean

ajmalicine BFV84 Vinca rosea APO

alstonine GNX52Vinca rosea APO

Strychnos gossweileri LOGRauwolfia nitida APO

corynanthean

1.

2.

2.

3.

3.

1. primary coalkaloid2. secondary coalkaloid

3. tertiary coalkaloid

N N

H

H H

OH

910

1 43

15

1617

2

7

2019

18

21

5

68

13

11

12

14

N

NH

HO

O

Me4

1

5

6

78

910

11

1213

2 3

14 1518

1920

21

16

17

N

N

H H17

12

3

45

71415

16

18

19

20

21

8

910

11

12 13

11

N N

O

HO

1 23 4

56

78

910

12 13

1415

1617

22

1819

20

21

27 28 29 30

dihydrocorynantheol (-)-formGNZ33

Rhazya stricta APOAspidosperma marcgravianum APO

corynanthean I α

dihydroquinidine

Aspidosperma marcgravianum APORemijia pedunculata APO

cinchonan I α

CFC07Catharanthus roseus APOErvatamia heyneana APO

apparicine (S)-form

vallesaman I β

CGW23

Camptotheca acuminata APOErvatamia heyneana APO

camptothecin (S)-form

camptothecan I α

CFK59

Molecules 2008, 13

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N-4 azacyclization to C-21 gives the corynanthean skeleton 10, which was found in nearly a thousand compounds, and provides the largest subclass of indole alkaloids. One of its first representatives is geissoschizine (14). Some additional characteristic structures are shown in Scheme 5. There are two main sources of the great variability of the corynanthean alkaloids: “secondary” cyclizations and oxidations.

The central element of the additional cyclizations is C-16 and mainly directed to C-5, C-7 or N-1. In the first case the akuammidan (including also the ajmalan skeleton), in the second the akuammilan, and in the third the pleicarpaman skeletons are formed. They are represented in Scheme 5 by akuammidine (21), rhazinaline (22) and strictine (23), respectively; all were isolated from the strictogenic Rhazya stricta and are primary coalkaloids of strictosidine. A typical compound in this evolutionary line is ajmalicine (20), isolated from the likewise strictogenic Vinca rosea. From this species several other ajmalicine derivatives were obtained. One of them is alstonine (24), a stereoisomer of ajmalicine (20), in which, however, ring C is aromatized. Fortunately, 24 was also isolated from Rauwolfia nitida and Strychnos gossweileri, and according to this fact, it may be a biogenetic link in the pathway towards the oxidized derivatives of the corynanthean skeleton.

From Strychnos gossweileri a dihydroxy derivative 24a of the unnatural apogeissoschizine could be obtained, which is a secondary coalkaloid of strictosidine. Its skeleton may be considered a 1(16→17)-abeo-derivative of the pleiocarpaman skeleton in 23. In Rauwolfia nitida a further ajmalicine stereoisomer 24b, likewise a secondary coalkaloid, was found, which was isolated from Uncaria elliptica as well. This last species, which belongs already to the Rubiaceae family, also provided the two main representatives of the pseudoindoxyl and the oxindole alkaloids, rauniticine pseudoindoxyl (24c) and rauniticine oxindole A (24d), respectively, both of which are tertiary coalkaloids. As it is shown, there are grades in the coalkaloid relation depending on the number of species concerning the parent and the derived compounds in each case. when the name “coalkaloid” is used without qualification (secondary, etc.), they are considered as primary coalkaloids, i. e. isolated from one common species.

Finally, ajmalicine hydroxyindolenine (25), a fourth variant of the oxidized I α alkaloids was isolated from the tissue culture of strictogenic Catharanthus roseus. Its main importance is shown in its formula: according to the electron stream indicated by curved arrows in the formula of 25, C-3 can be shifted from C-2 (indole α-position) to C-7 (indole β-position) and simultaneously (or subsequently) C-16 attached to C-2, i.e. a type I α alkaloid could be transformed into a type I β alkaloid. After a potential reduction of the formyl group, the first representative of the strychnan alkaloids, preakuammicine (26) would be formed similarly in Catharanthus roseus. It is clear that already the type I oxindole alkaloids should be considered as type I β compounds because C-3 is attached to C-7 (β-position of the indole ring) in them. It is also known that the oxindole, pseudoindoxyl and hydroxyindolenine derivatives were found in the type II and type III alkaloids as well. The oxidative processes shown above were carried out also under in vitro conditions [25-27]. The chemical mechanisms of the cyclizations and the formation of the oxidative derivatives were discussed previously [13a]. In addition, the last line of Scheme 5 shows that this analysis could even be extended to the two important subgroups of the “quinoindole alkaloids”. Both dihydrocorynantheol (-)-form 27 and apparicine (S)-form 29 were isolated from strictogenic species (primary coalkaloids from Rhazya stricta and Catharanthus roseus, respectively). The first, 27, was obtained also from

Molecules 2008, 13

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Aspidosperma marcgravianum which provided also dihydroquinidine (28, cinchonan skeleton), the other, 29, was found also in Ervatamia heyneana, together with camptothecine (S)-form (30, camptothecan skeleton), consequently both 28 and 30 are secondary coalkaloids of strictosidine.

Of course, the coexistance of these alkaloids (in Scheme 5 and elsewhere) in the given species does not mean that they are formed immediately one from other, but more probably from some common precursors which, however, were not found in natural sources, perhaps because of their high reactivity. As a final conclusion, it should be remarked, that of the four primary azacyclizations only the malindan and the corynanthean skeletons may be transformed into the type I β structure. Coalkaloids of Strictosidine in Type I β Class

The three main subclasses of the type I β alkaloids are the type I oxindoles (e. g. 24d, Scheme 5),

the strychnan (I β S) (34) and the aspidospermatan (I β A) (35) alkaloids (Scheme 6). The strychnan group 34 is rather uniform and its alkaloids (together with the type I oxindole alkaloids) number nearly 400. Several coalkaloids of strictosidine were found among them. The small group (less than 30 compounds) of the aspidospermatan alkaloids 35 is likewise uniform, but has no coalkaloid of strictosidine 3 and only indirect chemotaxonomic connections to it. Therefore it is of high importance that the formation of the aspidospermatan alkaloids (I β A) is biogenetically strongly related to that of the strychnan alkaloids (I β S), as is shown in the formulas and family tree of Scheme 6.

Scheme 6. Chemotaxonomic Interrelations between Strychnan and Aspidospermatan Alkaloids.

Family tree of the main representatives of the strychnan and aspidospermatan alkaloids

preakuammicine precondylocarpine

akuammicine condylocarpine

Catharanthus roseus Rhazya stricta

Strychnos angolensis

Vallesia dichotoma

Diplorhynchus condylocarpon

stemmadenine

vallesiachotamine

strictosidine

26 31 32 33

34 3536 37

18

56

16

14

321

15

19 20

N

N

HH

MeO2C OH

H

H

stemmedenine-A+stemmedenine-S+

+ H+

- H+-H+,+H+

-H+,+H+ + H+- H+

14

1

456

8

910

11

12 13 20

19

18

N

N

H

H72

3

21

17

16

15β

(22)

N

N

H

H2

3

21

1516

17

14

201918

β 7

(22)

21

7

OH

N

NH

HMeO2C

+ H2O

16

56

213

18

19

20

14

15

N

N

HH

MeO2C

H

OH

H

3

7

OH

N

NH

HMeO2C

N

NH

HH

CO2Me

N

NH

HH

CO2Mecondylocarpine CFR40

Diplorhynchus condylocarpon Strychnos angolensis

preakuammicine CGQ70Vinca rosea

precondylocarpine CHJ55Vallesia dichotoma

4 alkaloidshypothetic monoseco derivatives

akuammicine CGS34Catharanthus roseusStrychnos angolensis

530 alkaloids LOG, APOstrychnan (I β S)

28 alkaloids APOaspidospermatan (I β A)

Molecules 2008, 13

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In the formula of preakuammicine (26) curved arrows show the electron stream in the N-4→N-1 direction, which is increased by protonation. The result may be the cleavage of the C-3–C-7 bond and the formation of the charged monoseco structure stemmadenine-S+ (31), which can be tautomerized by deprotonation–reprotonation to give stemmadenine-A+ (32). In these intermediates the tryptamine and secologanin subunits can be turned around one another along the C-5–C-6 bond and around C-16, consequently in a further proton-catalyzed step, the C-7 center can be reclosed either to the original C-3 in 31 or to the alternative C-21 center in 32, as the centers are in analogous positions. In this latter case, after deprotonation, precondylocarpine 33 (aspidospermatan skeleton) can be formed. Preakuammicine (26) and precondylocarpine (33) are structural isomers formed by simple rotation and without any change of chirality at C-15. Although the charged stemmadenine-S+ (31) and stemmadenine-A+ (32) are hypothetic monoseco intermediates, some of their reduced derivatives (e. g. stemmadenine, 38) were found in the strictogenic Rhazya stricta (and other species as well).

There is a tight chemotaxonomic connection between these structural and stereoisomers. Preakuammicine (26) from Catharanthus roseus is a primary coalkaloid of strictosidine, unlike precondylocarpin (33), which could be isolated only from the non-strictogenic Vallesia dichotoma. However, from this species vallesiachotamine was likewise isolated which could be obtained from Rhazya stricta as well. The chemotaxonomic relation is further supported in the case of the analogous pair akuammicine (36, strychnan) and condylocarpine (37, aspidospermatan), which are in the same structural and stereoisomeric relation as their precursors 26 and 33, and both were isolated from Strychnos angolensis. Akuammicine (36) was directly obtained also from the strictogenic Catharanthus roseus. On the other line the contact is indirect: condylocarpine (37) was isolated from Diplorhynchus condylocarpon producing also stemmadenine (38), which was isolated from Rhazya stricta (and from several other species as well). In the family tree it can easily be recognized that preakuammicine and akuammicine are primary, and precondylocarpine and condylocarpin secondary coalkaloids of strictosidine; in addition, preakuammicine and akuammicine, as well as akuammicine and condylocarpine, are primary, while precondylocarpine and condylocarpine are tertiary coalkaloids of each other.

Tautomeric stemmadenine-S+ (31) and stemmadenine-A+ (32) may be starting points in the formation of those indole alkaloids in which the ethylene side chain of the tryptamine subunit is partially or completely absent (vallesaman, ulean, ellipticen and olivacen skeletons). In these groups until now only a single coalkaloid, apparicine (29, Scheme 5) was found, however, by detailed analysis some indirect chemotaxonomic relations could be demonstrated. Moreover, of the azacyclized skeletons 8–11 only the malindan and the corynanthean skeletons 9 and 11 can undergo this degradation, as is proved by isolation of both olivacine (66) and ellipticine (65), respectively (Scheme 12). But details of this work are already beyond the limits of the present paper [13b].

The Central Role of Stemmadenine and Secodine Derivatives

Now, the molecular evolution of the indole alkaloids is arrived at an important phase which is

shown in Schemes 7 and 8. In the charged tautomeric structures 31 and 32 shown in Scheme 7, ocurrence of a further fragmentation (shown again by curved arrows) is possible, which probably requires activation at C-17 either by enzyme or by acetylation. The possible fragmentation would

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involve the cleavage of bond C-15–C-16 (“strategic bond”) by which the bisseco tautomeric and charged structures secodine-S+ (39) and secodine-A+ (40) could be formed. This bond can really be cleaved under mild abiotic conditions by proton or base catalysis in simple vincoside derivatives [9b] or even in secologanin derivatives as well [28]. In the charged structures 39 and 40 extended conjugated systems are present, from which neutral tautomeric secodine-S (41) and secodine-A (42) can be formed. Though all these structures are again hypothetic intermediates, some alkaloids stabilized by hydrogenation were isolated from natural sources [e.g. 16,17-dihydrosecodine (43) from Rhazya stricta].

Scheme 7. Central Role of Stemmadenine and Secodine Derivatives.

17

18

56

16

14

321

15

19 20

N

N

H MeO2C OHH22

17

16

56

213

18

19

20

14

15

N

N

HH

MeO2C OH

H

stemmedenine-A+stemmedenine-S+

-H+,+H+

-H+,+H+

4 alkaloidshypothetic monoseco derivatives

31 32

22

2021

1716

22

1918

3

1415

N

N

OHMeO

-H+,+H+

-H+,+H+ 42 41

2021

1716

22

19

18

31415

N

N

MeO OH

-H+,+H+

-H+,+H+39

2021

1716

22

19

18

3

1415

N

N

MeO OH

H

40

2021

1716

22

1918

3

1415

N

N

OHMeO

HN

N

HH

MeO2C OH

16

56

213

18

19

20

14

15

1722

N

N

MeO2CH

20

21

171622 19

18

3

14

15

456

7

21

- H- H

secodine-A+secodine-S+

- H2O - H2O

stemmadenine CCD41Rhazya stricta APO

Diplorhynchus condylocarpon APOsecodine, 16,17-dihydro CHM 24

Rhazya stricta

-H+,+H+

-H+,+H+

7 alkaloidshypothetic bisseco derivatives

secodine-S secodine-A

38 43

Scheme 8. Formation of Type II and Type III Alkaloids.

2021

1514

3

1617

N

N

OH

OMe

1

4

N

N

MeO2CH22

16

1415

220

β7

17

314

1520

21

1617

N

N

OH

OMe

22

16

20

21

3

14

157

17N

N

OH

OMe

H

22

16

2021

3

14

157

17N

N

OH

OMe

H

2222

C-14→C-17C-16→C-21

C-20→C-17C-16→C-3

1

4

17

N

N

MeO2C

H

β7

222

1620

3

14

15

+ H+, - H+ + H+, - H+ + H+, - H+ + H+, - H+

ibogan (II)84 alkaloids APO

isoibogan (III)5 alkaloids LOG

secodine-A secodine-S'

C-20→C-17C-7→C-21

C-14→C-17C-7→C-3

1

4

N

N

CO2MeH

21

1617

22

14

152072

β1

4

N

N

CO2MeH 22

17

16

314

15

7

20

β2

secodine-S secodine-A'plumeran (III β)

340 alkaloids APO

21

41

42

42'

41'

44 45

4647

14 alkaloids APOisoplumeran (II β)

isoeburnan (II α)8 alkaloids APO

eburnan (III α)56 alkaloids APO

-H+,+H+

-H+,+H+

-H+,+H+

-H+,+H+

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In the structures of neutral conformer pairs secodine-S 41=41’ and secodine-A 42=42’ (Scheme 8) strongly polarized conjugated double bond systems are preformed, which may formally undergo four types of Diels–Alder reactions, as indicated by curved arrows in Scheme 8. In these cyclizations the isoplumeran (type II β), plumeran (type III β), isoibogan (type III) and ibogan (type II) skeletons 44-47can be formed. The details of these possible transformations were previously analyzed [11b]. Here it should be noted only that in some alkaloids of the new, rearranged type II and type III skeletons the double bonds (indicated by black lines) are conserved or formed just in the positions which are required by the hypothetical Diels–Alder reactions. It should also be mentioned that in the synthetic work by G. Kalaus, C. Szántay et al. for preparation of pandoline-like molecules, detailed quantum chemical calculations supported the two-step character of an analogous transformation [29].

In alkaloids having the isoplumeran (II β) or plumeran (III β) skeletons 44 and 45, C-7 (β position in the indole ring) has a covalent bond to C-3 or C-21, respectively. This bond can be shifted to the α- position of the indole ring (arrows in the formulas) and give in several steps the eburnan (III α) and isoeburnan (II α) alkaloids (see in Scheme 2), respectively. This would be the last phase in the molecular evolution of the indole alkaloids. Finally, it should be emphasized that the transition from the type I to the type II/III class of indole alkaloids is possible only in the evolution line of the corynanthean skeleton. Coalkaloids of Strictosidine in Type II and Type III Classes

In alkaloids which are formed after rearrangement of the original (type I) carbon skeleton of

secologanin subunit into the type II and type III ones, the number of coalkaloids is strongly reduced, however several of them were found. The isolation of natural products from their biological sources rarely means a fully systematic work; many different and accidental motivations influence which species of which families were investigated and which compounds obtained from them. Therefore the number of isolated compounds is very different.

The plumeran group with its nearly 400 individual compounds represents the third largest group of indole alkaloids, the isoibogan and isoeburnan groups are the smallest ones with 5 and 8 natural products, respectively. In these latter two groups, as well as in the isoplumeran group no coalkaloids of strictosidine were found. Some representatives of really existing coalkaloids having a rearranged secologanin subunit are shown in Scheme 9.

The ibogan group shows an interesting phenomenon: in the secologanin subunit of catharanthine (48) all chirality centers have configurations opposite to those found in rosamine (49) (and other ibogan alkaloids), however, both were isolated from strictogenic species. The aspidospermidan subgroup of the plumeran alkaloids has several monomer alkaloids isolated from strictogenic species (e.g. 50, 52 and 53), and in addition dimeric alkaloids of vinblastine (57, Scheme 11) as well.

Interestingly, both enantiomers of vincadifformine (50) were isolated from plants: the (+)-form from the strictogenic Rhazya stricta, the (-) form from the closely related Vinca minor. From the same species the eburnan alkaloid vincamine (51) was also obtained.

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Scheme 9. Some Coalkaloids with Rearranged Secologanin Subunits.

N

N

H

HO

O

5

20

21

191817

16

22β

3

N

N

H

CO2MeH

3

2021

1918

22

16

17

β

N

N

H

7

21

2019

1817

16

3

N

N

CO2MeH

H

O1415

N N

HO

MeO2C

H

162120

1918

17

N

N

H

CO2MeH

21

4

721

16

20

17

N

N

CO2MeH

HO

73 21

16

N

N

CO2MeH H

216

21

37

48 4950

51

52 53 54 55

β

β α

ibogan

catharanthine CFM28Vinca rosea APO

HJQ42

aspidospermidan

tabersonine; 14,15α-epoxide

Vinca rosea APOAmsonia tabernaemontana APO

ibogan

rosamine CFK06Catharanthus roseus APO

aspidospermidan

quebrachamine CFB72Rhazya stricta APO

Aspidospermaquebracho-blanco APO

vincadif formine, (-)-form HHM43

aspidospermidan

Vinca minor APOvincadif formine, (+)-form HBN54

Rhazya stricta APO

aspidofractinan

venalstonine CCH72Catharanthus roseus APO

Alstonia venenata APOMelodinus australis APO

eburnanVinca minor APO

vincamine (+)-form BCL77

kopsan

5,22-dioxokopsane GRG22Alstonia venenata APO

The transformation of vincadifformine into vincamine is indicated by curved arrows in formula 50

and was carried out in several steps even under abiotic conditions [30]. In the tabersonine derivative 52 the position of the epoxide oxygen shows the place of the previous double bond, which remained after the hypothetic Diels–Alder cyclization. In the aspidofractinan subgroup the sole alkaloid is venalstonine (54), which was obtained from the strictogenic Catharanthus roseus. However, it is a key structure isolated also from Alstonia venenata and Melodinus australis. The first species produces also 5,22-dioxokopsan (55), the second one condylocarpine (37), both of which are secondary coalkaloids of strictosidine, and show further chemotaxonomic connections to two other special groups of alkaloids, i.e. 55 to the kopsan subgroup of the plumeran group, 37 to the aspidospermatan group. The seco alkaloid quebrachamine (53) isolated from Rhazya stricta is likewise an important key compound in the biogenesis of the type III alkaloids. In the eburnan group only two alkaloids were isolated from strictogenic species, one of them is dihydroeburnamenine (62, Scheme 12) (from Rhazya stricta) which is probably the last coalkaloid in this molecular evolution.

From these data it may be concluded that most of the characteristic groups of indole alkaloids have primary (direct) and/or secondary/tertiary (indirect) coalkaloids of strictosidine, and they form an extended biogenetic network. However, at certain points there are holes on this net. In the isoibogan and isoeburnan groups no coalkaloids of strictosidine were found, a fact whch can easily be interpreted by the low number of known isolated compounds in them. In the isoplumeran and aspidospermatan groups the absence of coalkaloids can hardly be attributed to any low statistical probability. However, this lack of coalkaloids is compensated by the high number of dimeric alkaloids having an intact or seco isoplumeran subunit (see below) and by a strong chemotaxonomic relation between the aspidospermatan and the strychnan groups.

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At this point the importance of the two strictogenic species of the Apocynaceae family should be emphasized. As seen in Table 1, only a small number of coalkaloids were isolated from Anthocephalus cadamba of Rubiaceae and Strychnos mellodora of Loganiaceae having the malindan and vincosaman skeletons, respectively. However, in the Apocynaceae family from Catharanthus roseus (=Vinca rosea) 30 monomers and 20 homo- or heterodimers, from Rhazya stricta 50 monomers, 8 homodimers, as well as some stemmadenine and secodine derivatives of key importance were isolated. Most of them have the corynanthean, and only a few the vallesiachotaman skeleton. These two species together provide about 130 primary coalkaloids, of which only two are common in the two species!

Scheme 10. Types of Heterodimer Indole Alkaloids.

type IIItype α

eburnan

13 heterodimers1 homodimer56 monomers

α2

3N N21

22 1617

1415

7

20

19 18

N

N

21

16 17

22

31415

18

19

2072

β

type IIItype β

plumeran 340 monomers43 homodimers60 heterodimers

N

N21

22 1614

15

2 2019 18

β7 3

17

type II

ibogan84 monomers3 homodimers

73 heterodimers

14

1

456

8

910

11

12 13 20

19

18

N

N

H

72

321

22 17

1615

β

type Itype β S

530 monomers15 homodimers24 heterodimers

strychnan

N

N

H

2

321

1516

22 17

14

2019

18β 7

type Itype β A

aspidospermatan28 monomers

no dimers

N

N

22

1716

314

15

21

7

2019

18

β2

type IItype β

isoplumeran14 monomers

no homodimers41 heterodimers

α2

3N N21

22 1617 14

15

7

20

19

18

type IItype α

isoeburnan8 monomers

no dimers

17

N

Nβ72

22 16

21

20

19

18

3

14

15

type III

isoibogan5 monomers

no dimers

N

N

HH3CO O

H2

721

1716

22

19

20

18

3

14

15

seco intermediates7 monomers

9 homodimers

24

69

8

4

36

11

910

1

43

22

15

16 17

2

7

2019

18

21α

5

68

13

11

12

14

N N

H

type Itype α

>1000 alkaloids73 homodimers

100 heterodimers

vincosan

The Significance of Dimer Alkaloids in the Biogenesis of Indole Alkaloids In the class of the indole alkaloids nearly 300 dimer compounds are known, which are formed from

two monomer units (each monomer unit contains a tryptamine and a secologanin subunit). In the

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minority of these dimers the two monomers or at least their basic skeletons are identical (“homodimers”). From chemotaxonomic point of view the dimers having two different basic skeletons (“heterodimers”) are much more important because they indicate that in the species from which they were isolated the different monomers coexist, i. e. their origin is common: they were formed directly one from the other or indirectly from common precursors. Therefore their biogenetic relatedness is evident.

It is not the aim of this paper to analyze the mechanism of the formation of these dimers and investigate the types of the molecular connection between the monomer units (this study is in progress). The types of the heterodimers and the numbers of the subunit monomers are shown in Scheme 10. The connection may concern either the tryptamine or the secologanin subunit, or both of them. In the group of the seco intermediates (stemmadenine, secodine and secamine derivatives in the center of Scheme 10) no heterodimers were found. The phenomen, perhaps, depends on the chemical character of their ring systems. Likewise no dimers having either an isoibogan or an isoeburnan monomer are known, as even the number of the known free monomers is low.

Some examples of existing heterodimers are shown in Scheme 11. In geissospermine (60) and tenuicausine (59) the monomer components belong to the same type of skeleton (both type I or type III, respectively), but their attachment to the indole ring is different (α and β). 60 suggests an α→β bond shift, 59 a backward β→α shift between the two monomers.

Scheme 11. Selected Examples of Heterodimer Indole Alkaloids.

57 58

59 60 61

N

N

MeO2CH

HO

ibogan IIplumeran III β

N

N

H

CO2Me

O

H

β

eburnan III αplumeran III β

αN NH

H

β

N

NHMeO

H CO2Me

akuammidan I αisoplumeran III β

N

N

HH

β

akuammidan I α

NN

Me2OCH

Me

H

α

Tabernaemontana elegans APOHOP56

capuvosidine

strychnan I βcorynanthean I α

NN

MeO2C

H

H

H

H

α

N

N

H

O

β

vinblastineBCL63

Catharanthus roseus APO

β

β

isoplumeran II βplumeran III β

N

NOH

MeO2CH

H

N

NMeO

Me

H

HOAc

HO CO2Me

geissospermine

Geissospermum vellosii APOCDP43LDH28

Melodinus tenuicaudatus APO

tenuicausine tetrastachyneGRB68

Tabernaemontana tetrastachya APO

56

demethyltabernamine

Tabernaemontana dichotoma APOGPM42

N

N

HH

NN

HH

MeO2C H

H

α

akuammidan I α

ibogan II(perivine CGN81)

(ibogamine CCR72)

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In tetrastachyne (61) and vinblastine (57) (with several derivatives) the monomers have two differently rearranged skeletons. It proves that type II and type III skeletons coexist in the cells, and should be formed at least in the same species. Several derivatives of vinblastine (57) emphasize the importance of this connection. Moreover, it was mentioned that no isoplumeran monomer is known as coalkaloid of strictosidine, however, in the 57 and its derivatives some isoplumeran subunits (in seco form) became important coalkaloids because most of the dimers of type 57 were isolated from the strictogenic Catharanthus roseus (=Vinca rosea). In 56 and 58 one of the monomers has a (differently) rearranged skeleton (type II or type III), and the other monomer has the original secologanin skeleton. These facts suggest that the monomers having an intact skeleton and any of the rearranged ones are produced of the same species. In 58 one of the components is again an isoplumeran monomer (now in its intact form) and by this fact its significance is further increased. Finally, in demethyltabernamine (56) the two monomers are perivine (akuammidan- and mainly vobasan-type) and ibogamine (ibogan-type). The dimer and both monomers were isolated from several Tabernaemontana species and in addition perivine from the strictogenic Vinca rosea as well. This latter fact is very important because it represents the chemotaxonomic link between strictosidine and the tabernamine-type dimers (about 70 alkaloids!). Outlook

The first line of Scheme 12 shows once more the precursor strictosidine 1, the central intermediate stemmadenine (38) and dihydroeburnamenine (62) as one of the final products of this long molecular evolution.

Scheme 12. Some Special Structures.

NHN

OH3CO

O

OglcH H HH

1

910

11

12 1332

45

678

14

15

1617

1819

2021

22

3 38 62

63 64

N

N

HMeO2C

HO

H

N

N

H O

O

OH21

31415

2019

18

17

16

N NO

O16 17

2120

1918

3

1415

20N

N

R'

H

R

12 3

4

1415

7

1617

N NH

3

141516

17 2021

1819

N

N

R'

H

R

20

12 3

4

1415

7

1617

vincosan, type I skeleton

strictosidine CCF30

Anthocephalus cadamba RUB

Rhazya stricta APOCatharanthus roseus APOStrychnos mellodora LOG

65 ellipticen (R = H, R' = Me = C-18)

66 olivacen (R = Me = C-18, R'=H)Aspidosperma subincanum APO

ellipticine HGP59

type I skeleton

olivacine CDW84Aspidosperma olivaceum APO

eburnan, type III skeleton

eburnamenine16,17-dihydro LCR84Rhazya stricta APO

stemmadenine CCD41

type I skeleton

Rhazya stricta APOstrychnan/aspidospermatan

plumeran / type III sleletonLeuconotis eugenifolia APO

Rhazya stricta APOleuconolam GDP93

plumeran / type III skeletonLeuconotis eugenifolia APO

leuconoxine MTM42

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In the second line the unusual leuconolam (63) and leuconoxine (64) as well as the ellipticine–olivacine pair 65 and 66 are placed which look to be, at least in appearence, very different to strictosidine or even stemmadenine, nevertheless they could find their appropriate position in the system. Compound 63 was isolated from the strictogenic Rhazya stricta and in addition from Leuconotis eugenifolia, in which 64 was also found as a secondary coalkaloid of strictosidine.

In Scheme 13 the case of the ellipticine–olivacine pair illustrates well the potential of the electronic searching in the special data bases [14]. Both compounds 65 and 66 are type I class alkaloids and structural isomers as the position of C-18 is different in the common ringsystem. They were isolated from closely related Aspidosperma species (Apocynaceae). It could be demonstrated, that their evolutionary lines branched at the very beginning, on the primary azacyclization level.

The evolution of ellipticine (65) started from ajmalicine (20) (coryanthean skeleton with nearly thousand alkaloids) isolated from the strictogenic Catharanthus roseus (Apocynaceae) and the main steps of its evolutionary line could be followed stepwise [14]. In the other case only the first and last compounds were found as natural products. The evolution of olivacine (66) started from isodihydrocadambine (13) (malindan skeleton with 40 alkaloids) isolated from the likewise strictogenic Anthocephalus cadamba (Rubiaceae) but its formation could not be followed stepwise because of the low number of isolated alkaloids having the malindan skeleton. However, it may be stated with high probability that the molecular evolution of olivacine passed steps analogous to those of ellipticine.

Scheme 13. A Special Case.

NN

OH3CO

O

OglcH H HH

OH3

4

15

1617

1819

2021

NN

OH3CO

O

H HH

H E18

4

19

17

15

3 21

16

Anthocephalus cadamba RUBCatharanthus roseus APO

3S strictosidine CCF30

malindan

isodihydrocadambine GPX51Anthocephalus cadamba RUB

corynanthean

ajmalicine BFV84Vinca rosea APO Aspidosperma subincanum APO

ellipticine HGP59

olivacine CDW84Aspidosperma olivaceum APO

NN

OH3CO

O

H HH

H E18

4

19

17

15

321

16

66

65

13

20

3

NHN

OH3CO

O

OglcH HH

H

1

910

11

12 1332

45

678

14 15

1617

1819

2021

22

12

3

4

1514

2120

1918

1617

78

910

11

12 13N

N

H

12

3

4

1514

2120

1918

1617

78

910

11

12 13N

N

H

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Summary In this paper chemotaxonomic investigations were carried out on 133 monomer and 25 dimer

coalkaloids, as well as on 152 dimers of strictosidine. The results are summerized in Table 2. It can be seen, that the isolated compounds form a biogenetic network. Coalkaloids and/or heterodimers were found in all three basic types I, II and III, and nearly all important taxonomic units of indole and quinoindole alkaloids (except such groups in which only a few alkaloids are known). Of course, the search for further indirect (secondary/tertiary) coalkaloids could and should be continued, in order to make the molecular network more dense. The results underline also the importance of the computer searching in the specialized large databases.

Table 2. Summary of Chemotaxonomic Relationships between Indole Alkaloids.

isoibogan IIIplumeran III βeburnan III α

not foundnot found

foundfound

type III

36 4

11

8

vincosan I αstrychnan I β S

aspidospermatan I β Aibogan II

isoplumeran II βisoeburnan II α

coalkaloid

foundfound

foundnot found

indirect

heterodimer skeleton

type I

type II

69

24

Acknowledgements

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