Amaryllidaceae Alkaloids

J. R. Lewis Chemistry Department, Aberdeen University, Aberdeen AB9 2UE

Reviewing the literature published between July 1987 and December 1989 (Continuing the coverage of literature in Natural Product Reports, 1989, Vol. 6, 79)

1 Occurrence and Structural Studies 2 Synthesis 3 Biological Activity 4 References

The Amaryllidaceae alkaloids have been reviewed by Martin1 the coverage being for the period to early 1987. A review has also appeared (in Chinese) which includes biological data.2

1 Occurrence and Structural Studies During the period covered by this review sixteen new alkaloids have been isolated and are included in Table 1. Known alkaloids that have been obtained from new sources are also appended in this

The leaves of Allium tuberosum3 contain L-tyrosine and (-)- (3s)- 1,2,3,4-tetrahydro-,8-carboline-3-carboxylic acid (1). The aerial parts of a number of Allium L. species found in the Buryat

Table 1 The isolation of amaryllidaceae alkaloids Species Allium tuberosum (leaves)

Allium L. (aerial parts) Clivia nobilis

Crinum americanum (rhizomes) Crinum americanum (rhizomes)

(leaves)

Crinum asiaticum (fruit) Crinum zeylanicum (rhizome) Crinum zeylanicum (rhizomes) Haeman thus kalbreyeri (rhizomes)

Haemanthus multiflorus

* = New alkaloids.

Alkaloid (structure) (-)-(3S)- 1,2,3,4-Tetrahydro-P- carboline-3-carboxylic acid (1) L-tyrosine Alliin (2)

*Nobilisine (3) Clivatine (4) Lycorine (5) *Crinan type (6)

Augustine (7) Dihydrocrinidine (8) Hamayne (9) Lycorine ( 5 ) Tazettine (10) Hemanthamine (1 1) Crinamine (1 2) Buphamisine (1 3) Crinidine (14) *Isocraugsodine (1 5 )

*Zeylamine (1 7) Crinidine (14) Flexinine (1 8) 6-Hydroxypowelline (1 9) *7-Deoxypancratistatine (20) 7-Deoxynarciclasine (2 1) *Pancratiside (22) Haemanthamine (1 1) Haemanthidine (23) Kalbretorine (24) Lycorine (5) Narciclasine (25) Lycorine (5) Galanthamine (26) Sanguinine (27)

Ref. 3

4

5

6

7

8

9

11 12

13

14

Republic of the USSR showed only minor alkaloid ~a r i a t ion .~ In this TLC comparative study seven of the ten species examined contained alliin (2). Details of the new alkaloid, nobilisine, briefly reported previously' and obtained from species of Clivia nobilis cultivated in Egypt have now appeared. It has been characterized by mass spectroscopy and lH NMR

(1 ) Tetrahydro-~carboline-3-carboxylic acid

V

(2) Alliin

Species Hymenocallus rotata (rhizomes)

Lapiedra martinezii

Lycoris guangxiensis (rhizomes)

Narcissus assoanus

Narcissus confusus (rhizome and aerial) Narcissus dubius Narcissus jacetanus

Narcissus pallidulus (aerial) Narcissus radinganorum

Narcissus species ' Fortune' (leaves) Pancratium maritimum

Alkaloid (structure) *8-0-Demethylmaritidine (28) *( -)-N-Demethyllycoramine (29) Vittatine (30) Alkaloid 13 (3 1) 3-Epimacronine (32) Isimine (33) Pretazettine (34) Lycoramine (35) *Homolycorine N-oxide (36) *O-Methyllycorenine N-oxide (37) Homolycorine (38) * N-Allylnorgalanthamine (39) Lycorine ( 5 ) Narwedine (40) Galanthamine (25) Lycoramine (35) Crinine (41) Norgalanthamine (42) Pseudolycorine (43) 1 -0-Acet ylpseudolycorine (44) 2-0-Acetylpseudolycorine (45) Pseudolycorine (43) Homolycorine (38) *9-O-Demethylhomolycorine (47) *Dubiusine (48) Assoanine (49) Oxoassoamine (50) Pseudolycorine (43) Lycorine (5) Mesembrenone (5 1)

*9-0-Demethylmaritidine (52) Homolycorine (38) 8-0-Demethylhomolycorine (53) *Fortwine (54)

* Ungiminorine N-oxide (5 5 )

Ref. 15

16

17

18

19

20 21

22

23

24

16

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NATURAL PRODUCT REPORTS, 1990

(3) Nobilisine R’ ,R2 = CH2; R3 = OH (38) Homolycorine R’ = R2 = Me; R3 = H

OMe

(6) Alkaloid

0

(4) Clivatine (5) Lycorine R’ = R 2 = H

R 2

R 4

(7) Augustine R’ + R 2 =,O; R3 = OMe; R4 = H (8) Dihydrocrinidine R’ = R 2 = R 4 = H; R 3 = OH

(14) Crinidine R’ + R 2 = double bond; R3 = OH; R4 = H (13) Buphanisine R’ + R 2 = double bond; R 3 = OMe; R4 = H (41) Crinine R’ + R 2 = double bond; R 3 = R 4 = H (18) Flexunine R’ + R 2 = 0; R3 = R 4 = H (19) 6-Hydroxypowelline R’ + R 2 = double bond; R 3 = H; R 4 = OMe

OMe I

(9) Harnayne R’ = R 2 = H (12) Crinamine R’ = Me; R 2 = H

( 10) Tazettine

Me0

(15) lsocraugsodine

as 5a-hydroxy-3a,5a-epimasan-7-one (3). The chemical shift associated with the N-methyl group assisted in the stereo- chemical assignment for this alkaloid and the use of 2D, solvent shift, and COSY NMR measurements enabled the full stereochemistry to be determined.5

A tentative structure (6) has been given to the alkaloid isolated from the rhizomes of Crinum umericunum.6 Also

(1 1 ) Haernantharnine R’ = Me; R 2 = H; R3 = OH

obtained were minor alkaloids augustine (7), dihydrocrinidine (8), and hamayne (9)’ while the leaves contained lycorine (5 ) tazettine (1 0) , haemanthamine (1 l), crinamine (1 2), bupha- misine (13), and crinidine (14).8

The isolation of isocraugsodine (15) from the fruits of Crinum usiuticum9 (its isomer craugsodine was reported in the previous report)1° further lends support to the involvement of such compounds in the biogenesis of the Amaryllidaceae alkaloids. This natural product was shown to be in equilibration with two other isomeric structures (Scheme 1) and on treatment with diazomethane followed by borohydride reduction bel- ladine (16) was produced. The synthesis of (15) was also reported in this publication.

Zeylamine (17), which is a new member of the crinine group of Amaryllidaceae alkaloids was obtained in 0.18 70 yield from the air dried rhizomes of Crinum zeylunicum. l1

Huemanthus species are well known sources of isocarbostyril alkaloids and two new members of this group have been isolated from the resting bulbs of Huemanthus kalbreyeri.l3 7-

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NATURAL PRODUCT REPORTS, 1990-J. R. LEWIS 551

Me0

(1 5a)

'H

(1 5b)

OH 1

6 0 g$: ' 0

(17) "Zeylamine

V

i, CHINz

ii, NaBH,

.) Me0

M e o w : -

OMe (16) Belladine

Scheme 1

R O

<& 0

HO 0 (24) Kalbretorine

(20) 7-Deoxypancratistatine R' = R 2 = H (22) Pancratiside R' = fl-D-glUCOSyl; R 2 = OH

(21) 7-Deoxynarciclasine R = H (25) Narciclasine R = OH

HoH

(28) 8-0-Demethylmaritidine R' = Me; R 2 = H

Deoxypancratistatine was assigned structure (20) on the basis of its acetylation to a tetraacetate and a triacetate.13 This latter compound is identical with the triacetate of 7-deoxynarciclasine (21) and is accounted for by elimination of acetic acid from the tetraacetate. The other new alkaloid pancratiside is the p-D- glucoside (22) of pancratistatine.

R'O

(26) Galanthamine R' = R 2 = Me (27) Sanquinine R' = H; R 2 = Me (39) N-Allylnorgalanthamine R' = Me; R 2 = CH2-CH=CH2 (42) Norgalanthamine R' = Me; R 2 = H

:p Me0

(29) (-)-N-Demethyllycoramine R = H Lycbr=Me'\ . .- ,/

The bulbs of Hymenocallis rotata have produced thirteen alkaloids (see Table 1) : two are new and were identified as 8-0- demethylaritidine (28) and ( - )-N-demethyllycoramine (29).16 The former structure was determined by spectroscopic means and confirmed by its methylation giving maritidine while the latter structure followed from the conversion of the alkaloid

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552 NATURAL PRODUCT REPORTS, 1990

OMe

(30) Vittatine R' = R 2 = R3 = H (31) Alkaloid 13 R' = R3 = H; R2 = OH

Me0

Me0

(36) Homolycorine N-oxide R' + R 2 = 0 (37) U-Methyllycorenine N-oxide R' = 0-OMe; R 2 = H

(32) 3-Epimacronine R' = 0-H; R 2 + R3 = 0 (34) Pretazettine R' = 0-H; R 2 = H; R3 = OH

Me0

NMe

(40) Narwedine

F N H M e

(33) lsimine

(43) Pseudo I yco r i ne

HO&

Ho /

- Phenylalanine

HO H Me0 (43) Pseudolycorine / JE

HO

T yrosi ne HO& Ho,&$, M&&

Me0 \

Me0 \ Me0

(49) Assoanine (44) 1 -U-acetylpseudolycorine (45 1 2-O-acet y 1 pseudo 1 ycor i ne

Scheme 2

R ' 0 , *-R3

R 2 0 & \ 0

(46) 0-Demethylhomolycorine R' = H or Me; R 2 = MeOH; R3 = H (47) 0-Demethylhomolycorine R' = R3 = H; R 2 = Me (48) Dubiusine R' = COCH&H(OH)CH3; R 2 = Me; R3 = OAc

I Me0& MeO

0 (50) Oxoassoanine

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NATURAL PRODUCT REPORTS, 1990-J. R. LEWIS 553

OMe I

eoH N-'

/ H Me

(51 1 Mesernbrenone

M€!o&

HO

(54) Fortucine

(52) 9-0-Dernethylrnaritidine R' = H; R 2 = Me

0- (55) Ungiminorine N-oxide

(58)

Reagents : i, BunLi, THF, - 50 "C; ii, Urushibara's Ni, Pr'OH, 50 psi, 45-55 "C, 48 h

Scheme 3

(59)

into lycorine (5) by treatment with boric acid, formalin, and borohydride.

The first examples of N-oxides in the Amaryllidaceae have been found in Lapiedra martinezii and Pancratium maritimum. l6 The whole plant extract of the former produced homolycorine N-oxide (36) and 0-methyllycorenine N-oxide (37). Following identification of the lycorine type skeleton (NMR, IR spec- troscopy) and its similarity to homolycorine (38) the structure of (36) was confirmed by the conversion of homolycorine into its N-oxide quantitatively with hydrogen peroxide in ethanol. The P-configuration in (36) was deduced through a 2D- NOESY experiment. The ketal functionality in (37) was obtained by NMR analysis and confirmed by the failure to N- oxidize O-methyllycorenine with hydrogen peroxide, only (38) being produced through ring opening of the ketal grouping. MCPBA did introduce oxygen without modification however. Of the eight alkaloids obtained from Lycoris guangxiensis bulbs1? N-allylnorgalanthamine (39) has been reported in detail for the first time (see page 309 in reference 1).

Through an ontogenic studyl8 of the alkaloids of Narcissus assoanas, namely pseudolycorine (43), 1 -0-acetylpseudo- lycorine (44), 2-0-acetylpseudolycorine (49, assosoanine (49), and oxoassoanine (50), it has been proposed that they are biosynthesized in the aerial parts of the plant. Phenylalanine and tyrosine are also present and the interrelationships are shown in Scheme 2.

By the application of 2D NOE techniques on the NMR spectrum of one of the alkaloids isolated from the bulbs of Narcissus confu~us~~ it was possible to determine the position of the hydroxy group in 0-demethylhomolycorine (46). Being at

39

C-9 this makes the alkaloid (47) a new one. The aerial parts of the rare species Narcissus dubius has now been examined phytochemically by the Bastida group at Barcelona20 and they have found, surprisingly, only one alkaloid dubiusine to be present. It is a new member of the homolycorine group with a 3-hydroxybutryl substituent at C-9 (48). The same group have studied Narcissus jacetanus21 and found assoanine (49), oxoassoanine (50), pseudolycorine (43), and lycorine (5).

The unexpected presence of mesembrenone (51) in the aerial parts of Narcissus pallidulus has been reported22 and a new haemanthamine derivative 9-0-demethylmaritidine (52) has been obtained from Narcissus radingan~rum.~, The position of the free hydroxy group was also determined by the results of NOE experiments, where irradiation at H-10 did not effect the OCH, signal whereas irradiation at H-7 did to the extent of

A new alkaloid called fortucine (54) has been isolated from the leaves of a Narcissus variety called 'Fortune'. It has a unique stereochemistry with a cis coupling of the B and c rings in the lycorine ring

A third N-oxide derivative has been isolated which is based on the ungiminorine ring system (55). This and the previous two (36) and (37) reported in this review are not artefacts as the extractive techniques employed for Pancratiurn maritimum and Lapiedra mastinezii did not convert the free bases into their N- oxide counterpart. l6

A possible route to the montanine alkaloid system has been suggested by the Sanchez group.25 Conjugate addition of the benzylcyanide (56) to nitrocyclo-hexene (57) gives a mixture of 'cis' and 'trans' adducts (58; R = CN). Reduction

27 yo.

N P R 7

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554 NATURAL PRODUCT REPORTS, 1990

OH OH

Br

(62)

OH I

liii HO 6

iv

MeO

* " M e O ~ c H o

6 r

(63) (64) (65)

Reagents: i, NaHCO,, MeOH, 50 "C; ii, NaBH,, MeOH, rt; iii, conc. HC1, EtOH, reflux; iv, HCO,Et, EtOH, K,CO,, mol. sieve, reflux; v, LiAlH,, 1 ,Zdimethoxyethane, reflux Scheme 4

OMe I OMe

I Q Q MgBr I C02Me

M e 0 m 2 M e Me0 - M e o r C H 2 C O z H

Me0

l i i i

OMe

Me0

OMe

OMe

M e O ~ H MeO 0

I iv V f---

vii -

c------- CH2NCO

MeO M e o w C H 2CON

Me0 (67) (66)

OH g ...

V l l l ____)

M e o G N M e HO 0 M e o ~ N M e HO \ M e O q N M e MeO

0 (71) (70) (69)

Reagents: i, CuI,, ether; ii, K,CO,, H,O, EtOH, reflux; iii, COCl,, NaN,; iv, POCl,, 90 "C; v, SnCl,, CH,Cl,; vi, NaH, benzene, MeI; vii, Me$,

Scheme 5 CH,SO,H, 60 "C; viii, LiAlH,, THF, reflux

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NATURAL PRODUCT REPORTS, 1990-J. R. LEWIS 555

(73)

ii-iv I (72)

V M e o f l o - vi-ix

1 ) r \ Me0 Me0

R (75) (76) (77) Dihydromaritidine R = 0-OH

(78) lsodihydromaritidine R = a-OH

Reagents: i, 50% NaOH, H,O, benzene, 18-crown-6; ii, NaBH,, MeOH, rt; iii, Ai,O; iv, OsO,; NaIO,, dioxan, H,O; v, NaBH,CN, MeNH,HCl,

Scheme 6

MeOH, r.t., 3 days; vi, LiAIH,, ether; vii, H, IPdCI,I C, MeOH; viii, 30% HCHO, MeOH; ix, 10% HCI, r.t.

CH3 I 0

(79)

(Me,CHCH,j,AlH of the 'cis' isomer gave the aldehyde (58; R = CHO) which could be reductively cyclized to the indole (59) (Scheme 3).

2 Synthesis The alkaloid latifine (65) obtained from Crinium latifolium has been synthesized in its racemic form2s by condensation of 6- bromovanillin (60) with ( + )-octopamine hydrochloride (61) to give the bromo derivative of ( k )-hydroxy-0-methylnorbell- adine (62). Intramolecular dehydration was easily achieved under acidic conditions to give the ortho cyclized product (63) (relative to the hydroxy group). The bromine substituent prevented para ring closure as was observed2' in the synthesis of cherylline (70). Subsequent N-formylation, debromination, and reduction gave the natural amine (65) (Scheme 4).

A variant, utilizing the isocyanate cyclization procedure as developed by Tsueda enabled the tetrahydroisoquinol- 1 -one (69) to be prepared in four steps from the propionic acid (65) via the acid azide (66) through Curtis rearrangement to the isocyanate (67) and cyclization prior to a selective demethyl- ation procedure. The use of methyl sulphide in methane sulphonic acid resolved in the selective removal of two of the 0- methyl groups (in 69) to give (70). Reduction with LiAlH, then yielded (+)-cherylline (71) (Scheme 5). (+)-Latifine (65) was also synthesized by this procedure.28

The synthesis of mesembrine (76; R = Me) (Sceletium alkaloids) has been accomplished through a novel procedure for alkylating the cyclohexanone (72) (Scheme 6). Alkyl halides or acrylonitrile condense with (72) in a two phase system with the aid of 18-cr0wn-6.~~ Subsequently the ally1 derivative (73) was reduced, acetylated, and oxidized to the acetoxy-aldehyde (75) which on reductive amination (MeNH,) followed by acid

treatment gave (+)-mesembrine (76; R = Me). Alternatively the use of benzylamine gave (76; R = CH2Ph) which on LiAlH, reduction gave an epimeric mixture of alcohols whose acetylation, debenzylation, formylation, and acid treatment produced (+)-dihydromaritidine (77). Its isomer (78) was also synthesized by this procedure.

The nonplanarity of haemanthamine (1 l), the alkaloid from Narcissus confusus, has been confirmed through crystal struc- ture meas~rements.~~ The C-1 1-hydroxy group is anti with respect to the aromatic ring and this together with the half chair conformation of ring c leads to a nonplanar molecule (79).

3 Biological Activity The biological activity associated with Amaryllidaceae alka- loids covers analgesic, central nervous system, antitumour, and antiviral effects.' In this latter effect the suppression of cell division, cell elongation and DNA replication may be the causative process.

Of the ten alkaloids isolated from the bulbs of Lycoris chinensis only lycorine (5) showed any activity towards t ~ m o u r s . ~ ~ This alkaloid also displayed antiviral properties and was shown to inhibit ascorbic acid biosynthesis.21 A study of the effect of Amaryllidaceae alkaloids on the herpes simplex virus demonstrated that alkaloids with a hexahydroindole structure with two hydroxy groups showed most promise.32 This antiviral activity was due to the inhibition of mul- tiplica tion.

4 References 1 S. F. Martin, in 'The Alkaloids', ed. E. Brossi, Academic Press,

1987, Vol. 30, p. 251. 2 L. Ruan, Yaoxue Tongbae, 1988,23,453 (Chem. Abstr., 1988,110,

9 1 979). 3 J. S. Choi, J. Y. Kim, W. S. Woo, and H. S. Young, Arch.

Pharmacol. Res., 1988, 11,270 (Chem. Abstr., 1989,110,228627). 4 T. P. Antsupova and A. V. Polozhii, Rastit. Resur., 1987, 23, 436

(Chem. Abstr., 1987, 107, 214830). 5 P. W. Jeffs, L. Mueller, A. H. Abou-Donia, A. D. S. El-Din, and

D. Campau, J. Nat. Prod., 1988, 51, 549. 6 Z . Trimino, C. Iglesias, and I. Spengler, Rev. Cubana Quim., 1987,

3, 67 (Chem. Abstr., 1988, 109, 1872510). 7 Z . Trimino, C. Iglesias, and I. Spengler, Rev. Cubana Quim., 1987,

3, 62 (Chem. Abstr., 1988, 109, 3881). 8 Z. Trimino, C. Iglesias, L. M. Shanchez, and I. Spengler, Rev.

Cubana Quim., 1987, 3, 57 (Chem. Abstr., 1988, 109, 3880). 39-2

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9 S. Ghosal, A. Shanthy, and S. K. Singh, Phytochemistry, 1988,27, 1849.

10 M. F. Grundon, Nut. Prod. Rep., 1989, 6, 79. 11 W. Doepke, E. Reich, E. Sewerin, R. Donau, D. Ferras, C. Igle-

sias, I. Spengler, and Z. Trimino, 2. Chem., 1986,26,438 (Chem. Abstr., 1987, 107, 172408).

12 Z. Trimino, C. Iglesias, and I. Spengler, Rev. Cubana Quim., 1988, 4, 13 (Chem. Abstr., 1988, 111, 150588).

13 S. Ghosal, S. Singh, Y. Kumar, and R. S. Srivastava. Phyto- chemistry, 1989, 28, 61 1.

14 A. A. Ali, H. M. Sayed, 0. M. Abdalla, W. Steglich, and E. Dague, Bull. Pharm. Sci. Assiut. Univ., 1987, 10, 157 (Chem. Abstr., 1989, 110, 4737).

15 M. Kihara, T. Koike, Y. Imakura, K. Kida, T. Shingu, and S. Kobayashi, Chem. Pharm. Bull., 1987, 35, 1070.

16 R. Suau, A. I. Gomez, R. Rico, M. P. V. Tato, L. Castedo, and R. Riguera, Phytochemistry, 1988, 27, 3285.

17 Hui-Yin Li, Guang-En Ma, Y. Xu, and Shan-Hai Hong, Planta Med., 1987, 53, 259 (Chem. Abstr., 1988, 108, 52751).

18 F. Viladomat, J. M. Llabres, J. Bastida, R. M. Cusido, and C. Codina, Physiol. Plant, 1986, 68, 657 (Chem. Abstr., 1987, 106, 116 556).

19 J. Bastida, J. M. Llabris, F. Viladomat, C. Codina, M. Rubiralta, and M. Feliz, J . Nut. Prod., 1987, 50, 199.

20 J. Bastida, J. M. Llabris, F. Viladomat, C. Codina, M. Rubiralta, and M. Feliz, Phytochemistry, 1988, 27, 3657.

21 J. Bastida, F. Viladomat, J. M. LlabrCs, C. Codinaz, and M. Rubiralta, Planta Med., 1988, 54, 362.

22 J. Bastida, F. Viladomat, J. M. Llabres, G. Ramirez, C. Codina, and M. Rubiralta, J. Nut. Prod., 1989, 52, 478.

23 J. Bastida, J. M. Llabres, F. Viladomat, C. Cordina, M. Rubi- ralta, and M. Felix, Planta Med., 1988, 54, 524.

24 G. M. Tokhtabaeva, V. I. Sheichenko, I. V. Yartseva, and 0. N. Tolkachev, Khim. Prir. Soedin, 1987, 872 (Chem. Abstr., 1988, 109, 89687).

25 I. H. Sanchez, M. 1. Larraza, I. Rojas, K. Brena, H. J. Flores, and K. Jankowski, Heterocycles, 1985, 23, 3033 (Chem. Abstr., 1987, 106, 18906).

26 S. Kobayashi, T. Tokumoto, S. Iguchi, M. Kihara, Y. Imakura, and Z. Taira, J . Chem. Res. (S ) , 1986, 281.

27 M. A. Schwartz and S. W. Scott, J. Org. Chem., 1971, 36, 1827. 28 J. Katakawa, H. Yoshimatsu, M. Yoshida, Y. Zhang, H. Irie,

and H. Yajima, Chem. Pharm. Bull., 1988, 36, 3928. 29 0. Hoshino, S. Sawaki, N. Shimamura, A. Onodera, and B.

Umezawa, Chem. Pharm. Bull., 1987, 35, 2734. 30 J. M. Amigo, J. Bastida-Guairan, M. M. Reventos, A. Cantarero,

and T. Debaerdemaeker, Acta Crystallog. Sect. C , 1988,44, 1497. 31 G. Ma, H. Li, H. Huang, L. Yan, and S. Hong, Zhongeaoyao,

1987, 18, 342 (Chem. Abstr., 1987, 107, 242490). 32 J. Renazrd-Nozaki, T. Kim, Y. Imakura, M. Kihara, and S.

Kobayashi, Res. Virol., 1989, 149, 115 (Chem. Abstr., 1989, 111, 49925).

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