The Alkaloids: Chemistry and Pharmacology: 41 0124695418, 9780124695412

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THE ALKALOIDS Chemistry and Pharmacology VOLUME 41

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THE ALKALOIDS Chemistry and Pharmacology Edited by Arnold Brossi National Institutes of Health Bethesda, Maryland

Geoffrey A . Cordell College of Pharmacy University of Illinois ut Chicago Chicago, Illinois

VOLUME 41

Academic Press, Inc.

Hurcourt Bruce Jouanouich, Publishers

San Diego New York Boston London Sydney Tokyo Toronto

This book is printed on acid-free paper. @

Copyright 0 1992 by ACADEMIC PRESS, INC. All Rights Reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher.

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United Kingdom Edition published by

Academic Press Limited

24-28 Oval Road, London NWl 7DX Library of Congress Catalog Number: 50-5522 International Standard Book Number: 0-12-469541-8 PRINTED IN THE UNITED STATES OF AMERICA 9 2 9 3 9 4 9 5 9 6 9 1

QW

9 8 1 6 5 4 3 2 1

CONTENTS

CONTRIBUTORS .................................................................................. PREFACE .........................................................................................

vii ix

Chapter I . Alkaloids from the Plants of Thailand BAMRUNG TANTISEWIE A N D SOMSAK RUCHIRAWAT I. 11. 111. IV.

Introduction ........................ ..... ..... .... .............. ............ ...... ........ Isoquinoline and Isoquinoline-Derived Alkaloids ................................ Indole Alkaloids ..... ..... ............. .... ........ .... ................... ........ ...... Miscellaneous Alkaloids .............................................................. References .....................................................

i 2 19

33 36

Chapter 2. Marine Alkaloids I 1 JUN'ICHIKOBAYASHI A N D MASAMI ISHIBASHI

I. Introduction

..... ........................ ..... .......... ................ .... .... ... .... ..

11. Guanidine Alkaloids ................................................................... 111. Indole Alkaloids ... ...........

IV. V. VI. VII. VIII. IX.

Pyrrole Alkaloids ..... P-Carboline Alkaloids Polycyclic Alkaloids Polyketides .... .... .... ..... .................. ..... ...... .... Peptides ........................... Miscellaneous Alkaloids

................. .....................

.....................................................

42 42 50 58 63 68 76 87 98 112

Chapter 3. Tropolonic Colchicitrn Alkaloids and Allo Congeners OLIVIER Boy6 A N D ARNOLDBROSSI 1. Introduction 11. New Alkaloid

......................................... .......................

.................................... ............... VI1. Clinical Data ..... ..... ..... .... ..... ......... .......... ....... .... ....-............ ..... VIII. Conclusions .............................................................................. IX. Addendum ........ .................................................... References ............................................................................... V

125

126 132 141 161 163 169 170 170 172

vi

CONTENTS

Chapter 4. The Cevane Group of Vrrutrrrrn Alkaloids JOHN

I . Introduction .

V . GREENHILL A N D PAULGRAYSHAN

..............................................................

I77 I79

111. Tabulations of Vrrutrum Alkaloids ........................................ References ................................. ................................

23 I

CUMULATIVE INDEX OF TITLES............................................................. INDEX .............................................................................................

239 245

186

CONTRIBUTORS

Numbers in parentheses indicate the pages on which the author's contributions begin.

OLIVIER Boy15 (129, Natural Products Section, Laboratory of Structural Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 ARNOLD BROSSI(1 2 3 , Natural Products Section, Laboratory of Structural Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 PAULGRAYSHAN (177), Process Research and Development, Merck Ltd., Poole, Dorset BH12 4NN, England JOHNV. GREENHILL (177), Department of Chemistry, University of Florida, Gainesville, Florida 3261 1 MASAMIISHIBASHI (41), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 606, Japan JUN'ICHI KOBAYASHI (41), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 606, Japan SOMSAK RUCHIRAWAT (l), Department of Chemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand BAMRUNG TANTISEWIE ( l ) , Department of Pharmacognosy , Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand

vii

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PREFACE

Thailand is one of the richest botanical regions of the world and many of its plants are used by its people in their traditional medicine. The review on “Alkaloids from the Plants of Thailand” lists the alkaloids which have been isolated from plants growing in Thailand. The structures of many alkaloids isolated from marine organisms are intriguing and show pronounced biological effects. The review on “Marine Alkaloids 11,” listing nitrogen-containing compounds from marine sources, is a continuation of an earlier chapter (The Alkaloids, Volume 24) and will be useful to chemists and biochemists working in this field. Progress in the chemistry of colchicine made since the last review on this subject (The Alkaloids, Volume 23) is summarized in a chapter entitled, “Tropolonic Colchicum Alkaloids and A110 Congeners.” It includes the preparation of many analogs of colchicine which were assayed for their antitubulin effect, permitting a much better understanding of how colchicine may interact with tubulin at the molecular level. Allo congeners with a benzenoid ring C have for the first time been included in this chapter. Data on the Veratrum alkaloids, last reviewed in this series in 1973 (Volume 14), are updated and presented in 31 tables in “The Cevane Group of Veratrum Alkaloids.” This should be a useful reference. The authors of these reviews represent many different countries and backgrounds, proving once again that the chemistry and pharmacology of alkaloids is a multidisciplinary and multinational effort. Arnold Brossi The National Institutes of Health Bethesda, Maryland Geoffrey A. Cordell College of Pharmacy University of Illinois at Chicago Chicago, Illinois

ix

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-CHAPTER

1-

ALKALOIDS FROM THE PLANTS OF THAILAND BAMRUNG TANTISEWIE Department of Pharmacognosy Faculty of Pharmaceutical Sciences Chulalongkorn University Bangkok 10330, Thailand

SOMSAK RUCHIRAWAT Department of Chemistry Faculty of Science Mahidol University Bangkok 10400, Thailand 1. Introduction .................... 11. Isoquinoline and Isoquinoline-Deriv

...................

loids ..............

A. Distribution and Occurrence.. ..................................... 2 B. Bisbenzylisoquinoline Alkaloids C . Protoberberine Alkaloids.. ........................................ 13 D. Aporphine Alkaloids. ........... E. Miscellaneous Isoquinoline and Isoquinoline-Derived Alkaloids.. . . . . . . 18 111. lndole Alkaloids .................... A. Distribution and Occurrence ...... B. Non-Tryptarnine-Derived Alkaloids C . Corynantheine-Heteroyohirnbine-Yohirnbine Group and Related Oxindoles ............ .............. .................. 25 D. Sarpagine-Ajrnaline-Pic E. Miscellaneous Indole Alkaloids ....... IV. Miscellaneous Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

I. Introduction Thailand is uniquely located to represent the fauna and flora which characterize the biogeographic province of Indo-Burma (1). A number of the eastern Himalayan temperate taxa penetrate south into the northern mountains of Thailand whereas the southern part is evergreen forest, thus 1

THE ALKALOIDS, VOL. 41 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.

2

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

making this area one of the richest floristic regions of the world. It has been estimated that the vascular plants in Thailand number not less than 10,000 species of about 1763 genera from 245 families (2). The numbers of alkaloid-containingplants are estimated to be only about 266 species of 176 genera in 67 families, based on the Thai plant names (3) and parts of the uncompleted flora of Thailand. Many of the plants are used by the natives as folk medicine.

11. Isoquinoline and Isoquinoline-Derived Alkaloids

A. DISTRIBUTION AND OCCURRENCE Isoquinoline alkaloids occur mainly in the families of Papaveraceae, Magnoliaceae, Annonaceae, Lauraceae, Alangiaceae, Berberidaceae, Ancistrocladaceae, and Menispermaceae. Studies have been carried out mostly on plants in the family Menispermaceae, some of which are used as folk medicines such as plants in the genera Tinospora, Stephania, Cyclea, Archangelisia, Fibrauria, and Tiliacora. Isoquinoline alkaloids from the genus Ancistrocladus (Ancistrocladaceae) have also been reported. Tiliucora triandru is used not only as folk medicine, but also as a local food ingredient. A summary of the isoquinoline and the isoquinoline-derived alkaloids is given in Table I.

ISOQUINOLINES

AND

TABLE I ISOQUINOLINE-DERIVED ALKALOIDS FROM THE PLANTS OF T H A I L A N D

Plant name

Family

Ancisrrocladus rectorius (Lour.) Merr. (entire plant, leaves) Annona squamosu Linn. (leaves) ArchangelisiaJava Merr. (roots) Cissampelos pareiru Linn." (roots)

Ancistrocladaceae Annonaceae Menispermaceae Menispermaceae

Crinum asiaricirm Linn. (bulbs)

Amaryllidaceae

Alkaloids (Ref.) Ancistrocladidine ( 4 3 ) Ancistrotectorine (38.441 Lanuginosine ( 4 5 ) Berberine ( 4 6 ) Monomethyltetrandrinium (7) (+)-Tetrandrine (4,47) Crinamine (41 ) Crinine ( 4 / ) Flexinine ( 4 1 ) Haemanthamine ( 4 1 ) Lycorine (41) (conhued)

3

1. ALKALOlDS FROM THE PLANTS OF THAILAND TABLE I (Conrinued) Plant name

Family

Alkaloids (Ref.)

Cyclea urjehensis Forman (leaves)

Menispermaceae

Cyclea barbara Miers (roots)

Menispermaceae

Eryfhrina uariegata Linn. (seeds)

Leguminosae

Gloriosa superba Linn. (corms) Kmeria duperreana (Pierre) Dandy (stem

Liliaceae Magnoliaceae

(-)-Argemonine (34) (+)-Cycleatjehenine ( 2 3 ) (+)-Cycleatjehine (23) ( - )-Curicycleatjenine (22) ( - )-Curicycleatjine (22) (+)-N-Formylnornantenine(34) ( - )-lsocuricycleatjenine (22) (-)-Isocuricycleatjine (22) ( + )-Laurotetanine (34) (-)-Norargemonine (34) (+)-Nornantenine ( 3 4 ) Berbamine (5) Chondocurine ( 8 ) a-Cyclanoline (9) P-Cyclanoline (9) dl-Fangchinoline ( 6 ) Homoaromoline (5) Isochondocurine ( 8 ) lsotetrandrine (5) Limacine (5) (2)-Tetrandrine (5) Tetrandrine N-2’-oxide (8) (+)-Tetrandrine ( 4 . 5 ) Thalrugosine (isofangchinoline) ( 6 ) Erysodine (40) Erysotine ( 4 0 ) Erysovine ( 4 0 ) Colchicine (48) Liriodenine ( 3 6 )

Mahonia siamensis Takeda (stem bark)

Berberidaceae

Michelia longifolia BI. (syn.

Magnoliaceae

bark)

(stem bark)

M. a

h DC.)

Michelia rajaniana Craib. (stem bark) Neolitsea aureo-sericea Kosterm. (stem

Magnoliaceae Lauraceae

Papauer somniferum Linn. (flower heads,

Papaveraceae

bark)

latex)

Berberine ( 2 5 ) Isotetrandrine ( 2 5 ) Liriodenine (49) Liriodenine (37) Bisnorargemonine (50) lsoboldine (50) Norcinnamolaurine (50) (+)-Reticdine (50) Codeine (5/) Morphine ( 5 l ) Narcotine (51) Papaverine ( 5 1 ) Thebaine (51) (continued)

4

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

TABLE I (Continued) Plant name

Family

Alkaloids (Ref.)

Paruba~nasagitrata Miers (leaves)

Menispermaceae

Paramichelia baillonii (Pierre) Hu (stem bark) Stephania glabra (Roxb.) Miers (tuberous roots)

Magnoliaceae

Berberine (26) 0-Meth ylthaicanine (26) (-)-Tetrahydropalmatine (26) (-)-Thaicanine (26) Liriodenine (35)

Menispermaceae

( - )-Capaurine

Stephania pierrei Diels (syn. S . erecta Craib) (tuberous roots)

Menispermaceae

Stephania suberosa Forman (tuberous roots)

Menispermaceae

(52) )-Tetrahydropalmatine ( 5 2 ) (-)-Xylopine (53) ( + )-Aromoline (21) ( + )-Berbamunine (21) ( + Kepharanthine (20,21) Coclaurine (21) ( - )-Cycleanine (21) (+)-Daphnandrine (21) Dehydroapetaline (21) ( - )-N-Desmethylcycleanine (+)-Hornoarornoline (20,21) (+)-Isocorydine (21) ( + )-Isotetrandrine (21) (+)-N-Methylcoclaurine (21) (+)-2-Norberbamine (21) (+ )-2-Norcepharanoline (21 ) ( + )-2‘-Norcepharanthine (21 ) (-)-2-Norisocepharanthine (21) ( + )-2-Norisotetrandrine (21) (+)-2’-Norisotetrandrine (21) ( + )-2-Norobaberine (21) (+)-2’-Norobaberine ( 2 / ) (+)-Obaberine (21) ( + )-Reticuline (21) (+)-Stephibaberine (21) ( + )-Stepierrine (21) ( + )-Capaurine (24) (+)-Cepharanthine (18) (+)-Cepharanthine 2’-/3-N oxide (18) (-)-Coreximine (24) (-)-Corytenchine (24) Delavaine (39) (-)-Discretine (24) (-)-Kikemanine (24) (+)-2-Norcepharanthine (18) Nordelavaine (39) (-

(continued)

1. ALKALOIDS FROM T H E PLANTS OF THAILAND

5

TABLE I (Continued) Plant name

Stephania uenosa (BI.) Spreng. (leaves,

tuberous roots)

Family

Menispermaceae

Alkaloids (Ref.) (+)-Norstephasubine (18) 8-Oxypseudopalmatine (24) Pseudopalmatine (24) (-Gtephabinamine (24) Stephabine (24) Stephanubine (39) Stephaphylline (39) Stephasubimine (18) (+)-Stephasubhe (18) (-)-Stepholidine (24) ( - )-Tetrahydropalmatine (24) (-)-Tetrahydropalmatrubine (24) ( - )-Tetrahydrostephabine (24) ( - )-Xylopinine (24) (-)-cis-Xylopinine N-oxide (24) ( -)-trans-Xylopinine N-oxide (24) (-)-0-Acetylsukhodianine (29) (-)-Anonaim (30) (-)-Apoglaziovine (30) (-)-Asimilobine (30) Ayuthianine (28) ( - )-N-Carboxamidostepharine (30) ( - )-Crebanine (29.3032) Dehydrocrebanine (29,301 (-)-4a-Hydroxycrebanine (30) (-)-Kikemanine (29. 30) Liriodenine (29) (-)-Mecambroline (30) ( - )-0-Methylstepharinosine (30) (-)-Nuciferoline (30) Oxocrebanine (2Y) Oxostephanine (29) Oxostephanosine (29) (+)-Reticdine (30) (- )-Stephadiotamine P-Noxide (30) (+)-Stepharine (30) (-)-Stepharhosine (30) ( - ) -Stmakine (30) (-)-Sukhodianine (28-30) ( - )-Sukhodianine P-N-oxide (30) (-,)-Tetrahydropalmatine (2930) Thailandine (33)

6

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

TABLE I (Continued) Plant name

Family

Alkaloids (Ref.) ~

Diels (roots, leaves, stems, aerial parts)

Tiliucoru triundru

Tinosporu buenzigeri

Forman (stems)

Tinosporu cordifoliu’j Miers

(stems)

Menispermaceae

Menispermaceae

Menispermaceae

Tinosporu c r i s p (L.) Hook. f. et

Thorns.

Menispermaceae

Tinosporu sinensis (Lour.) Merr.

(stems)

Menispermaceae

(stems. aerial roots)

~~~~~

(+ )-Thalrugosamine (30) (-)-Tuduranine (30) (-)-Ushinsunine (28-30) Ushinsunine p-N-oxide (30) Uthongine (33) Dinklacorine (13.14) Magnoflorine (15) Norisoyanangine (15) Nortiliacorine A (15) Nortiliacorinine A (10,12,14) Noryanangine ( 1 5 ) Tiliacorine (10,12.14) Tiliacorinine (10,/2,14) Tiliacorinine 2-N-oxide ( 1 1 ) Tiliacorinine 2‘A”oxide (10,15) Tiliageine (lS,l’f?)( 1 6 ) Tilianangine (14) Tiliatriandrine (16) Yanangcorinine (12) Yanangine (13) Berberine (27) Jatrorrhizine (27) Magnoflorine (42) Tembetarine (27) Magnoflorine (42) Tembetarine (42) Berberine (27) N-cis-Feruloyltyramine (53) N-trans-Feruloyltyramine(53) Jatrorrhizine (27) Palmatine (27) Tembetarine (27) Palmatine (27)

“ The plant was later identified as Cvcleu burhuru Miers.

* The plant was later identified as Tinosporu baenzigeri Forman.

B. BISBENZYLISOQUINOLINE ALKALOIDS Investigation of the Thai folk medicine, krung kha mau, the roots of Cycfea barbata Miers (formerly identified as Cissampelus pareira L . ) , has yielded many bisbenzylisoquinolines. d-Tetrandrine, the main alkaloid in this plant, occurs together with other alkaloids: df-tetrandrine, isotetrandrine, lirnacine, berbarnine, and homoaromoline ( 4 3 . From the same plant, dl-fangchinoline, thalrugosine (d-isofangchinoline) (6),and the

1.

ALKALOIDS FROM THE PLANTS OF THAILAND

7

1

01

R=H. R=ML

R'=Mc

R~=H

new berbamine-type alkaloid monomethyltetrandrinium chloride (1)have also been isolated and identified by spectroscopic methods and chemical reactions (7). The structure (1)was confirmed by comparison with the product derived from the partial methylation of tetrandrine. Tetrandrine N-2'-monoxide has also been isolated from this plant, and the alkaloid appears to be the first of the small group of N-oxides of the bisbenzylisoquinoline alkaloids (8). From the aerial parts of Tifiacora triandra Diels at least 10 alkaloids have been isolated. These alkaloids are identified as nortiliacorine A (2), tiliacorinine 2'-N-oxide (3),tiliacorinine 2-N-oxide (4),tiliacorinine (S), tiliacorine (6),dinklacorine (7),yanangine (8), yanangcorinine (9),tilianangine (lo),tiliageine (ll),nortiliacorinine A (l2),tilitriandrine (13), noryanangine (14),and norisoyanangine (15)(10-16). The bisbenzylisoquinoline alkaloids have recently been fully discussed in this treatise (17). Among the species of Stephania, the presence of bisbenzylisoquinoline alkaloids in Stephania suberosa Forman has been confirmed. Five new bisbenzylisoquinoline alkaloids have been isolated from the tuberous roots of Stephania suberosa. In addition to the known (+)-cepharanthine (16, R = Me), which was isolated as the major alkaloid in this plant, the new alkaloids are characterized as (+)-2-norcepharanthine (16, R = H), (+)-cepharanthine 2'-P-N-oxide (17), (+)-stephasubhe (18), (+)norstephasubine (19),and stephasubimine (20)(18). The last three compounds are relatively rare examples of bisbenzylisoquinolines incorporating an aromatic isoquinoline moiety. (+)-2-Norcepharanthine (16,R = H, C36H36N206) shows a mass spectral molecular weight 14 a.m.u. less than for cepharanthine. A strong molecular peak at m/z 592 (78%) is flanked by a base peak at mlz 591, a salient feature often encountered with bisbenzylisoquinolines bearing a secondary amine function. The 'H-NMR spectrum of (+)-2norcepharanthine is very close to that of (+)-Zcepharanthine, except for

8

BAMRUNG TANTISEWIE A N D SOMSAK RUCHIRAWAT

2 R R'

a'

0113 0

~

4

R'

R1

R'

R'

H

H

Mc MC Mc M

H It H

3 M c w 4 1 % 5 M c 6 % 7 Me

€1 H

It H €I

H

ai I1

8 M c 9 M c 10 12 14 15

1 %

hlc

H H

ai

lLIC

H

11

H

Mc H Mc

(1R.I'S) (lS,l*S)

(N-(-24)

(IS,l'S) (lR,l'S) (1R.l.S) (ISJS) (lS,l'S)

It

11

OMe

R' 11

13

MC It

K2

R3

H

% ,

% ,

It

(1S.l.R) (lS,l'R)

the absence of an upfield N-methyl singlet near 6 2.56 and the displacement of the broad H-1 singlet from 6 3.60 in cepharanthine to 6 4.32 in the nor analog. The structure was finally confirmed by its N-methylation to (+Icepharanthine employing formaldehydelformic acid. (+)-Cepharanthine 2I-P-N-oxide (17,C37H38N207) shows an 'H-NMR spectrum very close to that of cepharanthine. A significant difference is observed for the absorptions of the right-hand 2'-N-methyl group and the adjoining H-1', which are both shifted downfield. The 2'-N-methyl singlet at 6 3.31 and the H-I' broad singlet at 6 4.63 are characteristic of a trans relationship between the N-oxide oxygen and H-1'. A nuclear Overhauser effect (NOE) study has been used to confirm this trans relationship. (+)-Stephasubhe (18, C36H34N206) shows a strong molecular ion in the mass spectrum at mlz 590 (76%), whereas mlz 589 is the base peak. The NMR spectrum shows the presence of the aromatic isoquinoline protons at 6 7.48 and 8.45 (J = 5.6 Hz) together with two doublets at 6 4.52 and 5.37 ( J = 13.8 Hz) which represent the geminal coupling of the two benzylic methylene protons adjacent to the isoquinoline ring. The presence of the H-1 broad singlet upfield at 6 3.56 accompanied by an N-methyl signal at 6

1. ALKALOIDS FROM T H E PLANTS OF T H A I L A N D

R N K q ‘4/

H\8**

/

‘

Me

9

e M p‘. N e K q “tH fo “Me

\

C

M

~

O

OMe

’

16

0 17

HO

HO

18

19

20

2.51 argues convincingly in favor of placing the N-methyl group at the left-hand side of the dimer (19). (+)-Norstephasubine (19, C35H32N2o6)shows a fragmentation pattern in the mass spectrum similar to that of (+)-stephasubine, except that the molecular ion is 14 a.m.u. less than that for 18. The absence of N-methyl signal coupled with the downfield displacement of H-1 from 6 3.56 to 4.02 are indicative of the nor character of this dimer. As expected, Nmethylation of 19 gave (+)-stephasubine (18). Stephasubimine (20, C35H3&O6) is the imine counterpart of 19. The NMR spectrum shows an extra geminal coupling of the two benzylic methyl-ene protons of a dihydroisoquinoline as two doublets at 6 3.33 and 3.63 (J,,, = 12 Hz). Finally, NaBH4 reduction of this compound provides norstephasubine (19). Another Thai plant, Stephania pierrei Diels (syn. Stephania erecta Craib), has also been extensively investigated. The tubers of this plant are used locally as an analgesic and tonic as well as a skeletal muscle relaxant. The isolation of the known alkaloids (+)-cepharanthine and (+)-

10

BAMRUNG TANTISEWIE A N D SOMSAK RUCHIRAWAT

homoaromoline from Stephuniu pierrei was reported in 1982 (20). This plant has been reinvestigated recently by Shamma’s group (21). A number of known bisbenzylisoquinoline alkaloids have been isolated and characterized as head-to-tail dimers [ (-)-cycleanhe and (-)-A/desmethylcycleanine] and tail-to-tail dimers [ (+)-berbamunine and (+)-dehydroapateline]. Dimers commonly found in the Menispermaceae, namely, the isotetrandrine subgroup (8-7’, 11-12’), have also been isolated and identified as (+)-isotetrandrine, (+)-thalrugosamine, (+)-2norberbamine, (+)-2’-norisotetrandrine, and the new alkaloids (+ )-2norisotetrandrine (21) and (+)-stepierrine (22). (+)-2-Norisotetrandrine (21, C37H40N206), with a positive specific rotation [ a ] D of + 100” (0.16, CHCI3), possesses the same absolute configuration as (+)-isotetrandrine, namely, lR, 1’s.(+)-Stepierrine (22, C35H32N206) is also dextrorota0.1, CHC13)and incorporates the 1 ‘ S absolute configuratory ( [ a ] D +So, tion. The other isolated bisbenzylisoquinoline alkaloids, which belong to the oxyacanthine subgroup (7-8’, 11-12’), include (+)-obaberine, (+)homoaromoline, (+)-aromoline, (+)-cepharanthine, (+)-2-norobaberine, (+)-daphnandrine, (+)-2-norcepharanthine, (+)-2’-norobaberine (U), (+)-stephibaberine (24), (+)-2’-norcepharanthine (25), (+)-2-norcepharanoline (261, and (-)-2-norisocepharanthine (27). The last five dimers are new (21). (+I-2’-Norobaberine (23, C37H40N206) presents the same mass spectrum and a similar NMR spectrum to those of (+)-2-norobaberine, but with only one N-methyl singlet at 6 2.60 and the H-1 signal at 6 3.65. The H-I’ multiplet is situated downfield at 6 4.70 owing to the presence of secondary amine function at ring B’. (+)-Stephibaberine (24, C37H40NZ06) is a phenolic alkaloid and exhibits a mass spectrum close to that for 2’norobaberine. The two N-methyl singlets in the NMR spectrum appear at 6 2.59 and 2.67 and the three methoxy singlets at 6 3.26, 3.61, and 3.90, suggesting that the phenolic function should be on the upper part of the molecule. The most upfield of the methoxy singlets is due to the substi-

21

22

1.

ALKALOIDS FROM THE PLANTS OF THAILAND

11

tution at C-7' ; this fact coupled with the absence of a methoxy signal around 6 3.80 argues conclusively for the placement of the phenolic function at C-6'. (+)-2'-Norcepharanthine (25, C36H36N206) exhibits the same molecular ion as well as the same base peak in the mass spectrum as does (+)-2norcepharanthine. The NMR spectrum shows the typical set of two close doublets at 6 5.56 and 5.61 (J = 1.3 Hz) for the methylenedioxygroup. The N-methyl singlet appears at 6 2.58, and the H-1 multiplet is at 6 3.61; on the other hand, the H-1' signal resonates at 6 4.56, indicating that the secondary amine function involves N-2' rather than N-2 (21).The phenolic (+)-2norcepharanoline (26, C3#3&.06), with a mass 14 daltons less than that of (+)-2-norcepharanthine, shows the mass fragment of the top half of the molecule at mlz 365, the same as in (+)-Znorcepharanthine, allowing placement of the phenolic function in the lower half of the molecule at c-12. (-)-2-Norisocepharanthine (27, C36H36NZ06) displays a mass spectrum very close to that of (+)-2-norcepharanthine, but the NMR spectrum is significantly different. Of particular interest is the appearance of H-10 at 6 6.39 instead of 6 5.58. Moreover, H-I, which is adjacent to the secondary amine function, is at 6 4.57 instead of 6 4.32. The specific rotation [ a ]of~ -84" (0.25, CHCl3) is suggestive of a IS, I 'S configuration (21). Recently the leaves of another species, Cycfea atjehensis Forman, have been investigated by Shamma's group (22). It was found that the alkaloids of C. atjehensis are head-to-tail bisbenzylisoquinoline alkaloids of the curine type. Four new and novel amidic bisbenzylisoquinolines

12

BAMRUNG TANTISEWIE A N D SOMSAK RUCHIRAWAT

27

26

were identified as (-)-curicycleatjenine (28), (-)-curicycleatjine (29), (-)-isocuricycleatjenine (30), and (-)-isocuricycleatjine (31). Significantly, all four alkaloids contain the methylenedioxy group, an unusual feature among this particular subgroup of bisbenzylisoquinoline alkaloids (22). Alkaloids 28 and 29 possess lS,1 ‘R configuration, whereas alkaloids 30 and 31 incorporate the IR,I’R configuration. The N-acetyl function, another unusual substituent among the bisbenzylisoquinolines, is found in these alkaloids. The proton-NMR spectrum reveals the presence of two isomeric species in each compound owing to the geometric isomerism of the N-acetyl group. The absolute configurations are established by using sodium in liquid ammonia cleavage followed by identification of the cleavage products, namely, the derived benzylisoquinoline derivatives (22). The main alkaloids from the leaves of C. atjehensis have been identified as (+)-cycleatjehenine (32) and (+)-cycleatjehine (33), which constitute a new bisbenzylisoquinoline subgroup. This novel subgroup, like cissampareine-type alkaloids, is characterized by the presence of a methylenedioxy bridge. In the cissampareine-type bisbenzylisoquinoline alkaloids, the methylenedioxy bridge connects C-7 to C- 12’ in the head-to-tail fashion, and there is a link of C-12 to C-8’. In the new subgroup, however, the methyleneoxy bridge connects C-7 to C-12’ in a head-to-tail fashion with an ether linkage occurring between C-1 1 and C-7’. Sodium in liquid ammonia reduction of the 0-methylated derivative was again used as a means to confirm the structure of the alkaloid. The configuration at po-

28 29

R=Me R=H

30 31

R=Mc R=II

1. ALKALOIDS FROM THE

32

PLANTS OF T H A I L A N D

13

33

sition 1 is still undetermined (23). A mechanism for the formation of the methylenedioxy bridge in the biosynthesis of this new subgroup of the bisbenzylisoquinolines has been proposed (23).

C. PROTOBERBERINE ALKALOIDS The protoberberine alkaloids are widely distributed in the families Berberidaceae, Menispermaceae, and Papaveraceae as well as in other families. Stephania suberosa (Menispermaceae), locally known as borupet pungchang, is commonly used in Thailand for the treatment of a variety of ailments. From this plant the following 16 protoberberine alkaloids have been isolated and identified: (-)-tetrahydropalmatine, (-)-tetrahydropalmatrubine, (-)-stepholidine, (-)-kikemanine, (-)-capaurimine, (-)-coreximine, (-)-corytenchine, (-)-discretine. pseudopalmatine, (-)-xylopinine, (-)-tetrahydrostephabine (34), (-)stephabinamine ( 3 3 , stephabine (36), 8-oxypseudopalmatine (37), (-)trans-xylopinine N-oxide (38),and (-)-cis-xylopinine N-oxide (39). The latter six alkaloids are new, naturally occurring protoberberines. It is interesting to note that this plant produces both normal-type protoberberines (C-2, 3,.9, 10 substitution) and pseudo-type protoberberines (C-2, 3, 10, 11 substitution) (24). (-)-Tetrahydrostephabine (34, C2,H2sNOS) with its mass molecular peak at mlz 371 is 16 mass units greater than xylopinine. The difference extends to the important peak at mlz 208, as compared to that at mlz 192 for xylopinine, indicating the presence of an extra hydroxyl group in ring A or B. The NMR spectra of these two alkaloids are somewhat similar. The lack of one of the aromatic protons in the NMR spectrum of 34 indicates that the hydroxyl function resides on ring A. The upfield shift (0.71 ppm) of the H-4 proton in the NMR spectrum recorded in deuterated dimethyl sulfoxide (DMSO-&) plus NaOD as compared with that recorded in DMSO-d6 is used as a criterion for placing the hydroxyl group at the C-1 position. (-)-Stephabinamine (35, C20H23N05)is structurally related to (-)-tetrahydrostephabine. One methoxy group of (-)-tetrahydrostepha-

14

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

OH

OMe

34

35

36

37

38

39

bine at C-11 is replaced with hydroxyl group in (-)-stephabinamine. Stephabine (36, C ~ , H ~ ~ N O S + C was I - )isolated as the chloride salt. Sodium borohydride reduction of this alkaloid leads to racemic tetrahydrostephabine, and conversely iodine oxidation of tetrahydrostephabine furnishes stephabine. 8-Oxypseudopalmatine(37,C Z I H ~ I N O gives ~ ) a blue spot with the Dragendorff reagent which is characteristic of 8-oxyprotoberberines. This alkaloid has been previously known synthetically, and in this instance it could be an artifact of isolation. The structures of the (-)-trans-xylopinine N-oxide (38), and the (-)-cis analog (39) have been elucidated by direct comparison with the known ( 2 )-trans- and ( 2 )-cis-xylopinine N-oxides obtained by in vitro oxidation of ( t )-xylopinine (24). Muhonia siamensis Takeda (Berberidaceae) yields the common alkaloid berberine as well as the known bisbenzylisoquinoline alkaloid isotetrandrine from the stem bark (25). Two new tetrahydroprotoberberine alkaloids have been isolated from the leaves of Parabaena sagittata Miers (Menispermaceae) along with the known alkaloids (-)-tetrahydropalmatine and berberine. The two new alkaloids are named (-)-0-methylthaicanine (40) and (-)-thaicanine (41). The structures of (-)-0-methylthaicanine (40, C22H27N05) and (-)-thaicanine (41, C21H25N05) are similar to that of (-)-tetrahydropalmatine except that the proton at C-4 is replaced with methoxy and hydroxy groups, respectively (26). The occurrence of berberine in stems of Tinospora baenzigeri Forman and in the leaves of T. crispa (L.) Hook f. et Thoms. and ofjatrorrhizine in

1. ALKALOIDS FROM T H E PLANTS OF T H A I L A N D

15

the stems of T. crispa has been reported as well as the isolation of palmatine from the stems of T. crispa (27). In Stephania uenma (BI.) Spreng., the common (-)-tetrahydropalmatine is present along with (-1kikemanine (29,30).

D. APORPHINE ALKALOIDS Stephania uenosa (Menispermaceae), locally known in Thailand as sabu leuad or blood-soap because of its red juice, is a very rich source of isoquinoline-derived alkaloids. The plants are sometimes used as a bitter tonic. Detailed investigation of this plant has resulted in the isolation of 23 alkaloids, some of which were previously unknown and are somewhat unusual. From the dried tuberous root powder of S. uenosa, two new 7-hydroxylated aporphines have been isolated and characterized as ayuthianine (42, C19H19N04) and sukhodianine (43, C ~ O H ~ ~ N(28). O S )Ayuthianine (42) has an NMR spectrum showing H-7 as a doublet at 6 5.52 (J = 2.4 Hz), suggesting a cis relationship between H-6a and H-7. The same cis relationship between H-6a and H-7 is also indicated by the NMR spectrum of sukhodianine (43), which shows the H-7 as a doublet at 6 5.47 (J = 2.7 Hz) (28). From the leaves of this plant, the new (-)0-acetylsukhodianine (44) has also been isolated as well as (-)sukhodianine, indicating the biogenetic relationship of the two alkaloids (29). The new oxoaporphine oxostephanosine (45) has also been isolated from the leaves of this plant. The structure was proved by 0-methylation

‘OH OMe

42

43

16

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

OMe 44

of oxostephanosine (45) with diazomethane to give the known oxostephanine (1,2-methylenedioxy-8-methoxyoxoaporphine) which significantly is the most abundant alkaloid in the leaves (29). Three other new 7-hydroxylated aporphines have also been isolated from the tuberous roots of S. venom; they are all identified to be the N-oxides of identical configuration, namely, (-)-sukhodianine P-N-oxide (46),(-)-ushinsunine P-N-oxide (47), and (-)-stephadiolamine P-N-oxide (48). The cis relationship between H-6a and H-7 is indicated from the NMR spectrum, and a partial NMR NOE study clarified the configuration of the N-oxide function (30). It is interesting to note that the occurrence of C-7 oxygenated aporphine alkaloids with the C-6a R configuration is limited to the families Annonaceae, Lauraceae, Magnoliaceae, and Menispermaceae. Aporphine alkaloids oxygenated at both C-4 and C-7 have been found in the Annonaceae, but (-)-stephadiolamine P-N-oxide (48) is the first known alkaloid hydroxylated at both C-4 and C-7 and having a cis relationship between H-6a and H-7. (-)-0-Acetylsukhodianine is the first known example of a naturally occurring 7-acetoxylated aporphine (30). Stephania uenosa also yielded the first two 4,5,6,6a-tetradehydro-Nmethyl-7-oxoaporphinium salts, named uthongine (49) and thailandine (50). Compounds 49 and 50 are rather unstable and partially decompose on chromatography (silica gel) to give 7-oxocrebanine and 7-oxostephanine, respectively (33).

46

47

48

1.

ALKALOIDS FROM THE PLANTS OF THAILAND

17

R 49 50

R=OMc

R=H

Three new proaporphines were also isolated from the rhizomes of S. uenosa, and they are identified as (+)-N-carboxamidostepharine (Sl), (-)-0-methylstepherinosine (52), and (-)-stepharinosine (53). (+)A” Carboxamidostapharine (51) is the first proaporphine incorporating an urea functionality, whereas (-)-0-methylstepharinosine (52) and (-)stepharinosine (53) are the only proaporphine alkaloids oxygenated at C-12. The positive specific rotation for N-carboxamidostepharine and the negative specific rotations for the two anti-dihydroproaporphines are all indicative of the C-6a R configuration (30).The controlled catalytic hydrogenation of the proaporphine (+ )-stepharine has been recently reported to proceed by preferential approach of the catalyst from the side opposite H-6a to give (+)-8,9-dihydrostepharine, accompanied by a small amount of (-)-I 1, 12-dihydrostepharineand (+)-tetrahydrostepharine (31). The other known alkaloids that have been isolated from S. uenma include (-)-crebanine, dehydrocrebanine, oxocrebanine, oxostephanine, liriodenine, (-)-anonaine, (-)-asimilobine, (-)-nuciferoline, (-)apoglaziovine, (-)-tuduranine, (-)-mecambroline, (-)-stesakine, (-)-ushinsunine, and (-)-4a-hydroxycrebanine. The two major alkaloids found are the known norproaporphine, (+)-stepharine,and the aporphine (-)-crebanine (28-32). (+)-N-Formylnornantenine (54), a new amidic aporphine alkaloid, has been isolated from Cyclea atjehensis. Analysis of the NMR spectrum at

18

BAMRUNG TANTISEWIE A N D SOMSAK RUCHIRAWAT

54

500 MHz reveals that two species are actually present in solution owing to isomerism about the amidic bond. Even though the spectra of the two isomers can be clearly differentiated, the compounds cannot be separated. Cyclea arjehensis also produces two known aporphine alkaloids, (+)laurotetanine and (+)-nomantenhe (34). Liriodenine, known to be widely distributed in many plants, is also found in Paramichelia baillonii (Pierre) Hu (35),Kmeria duperreana (Pierre) Dandy (36),and Michelia rajaniana Craib (37).The stems of Tinospora baenzigeri (27,42)and the aerial parts of Tiliacora triandra (16) have been reported to contain the alkaloid magnoflorine. (+)-Isocorydine has also been isolated from Stepphania pierrei (21). E. MISCELLANEOUS ISOQUINOLINE AND ISOQUINOLINE-DERIVED ALKALOIDS Ancistrocladus, the only genus in the plant family Ancistrocladaceae, is known as a source of the naphthalene-isoquinoline group of alkaloids. Investigation of the leaves of the plant Ancistrocladus tectorius (Lour.) Merr., locally used to treat dysentery and malaria, yielded the new alkaloid, ancistrotectorine (55, C26H31NO4). Ancistrocladeine, ancistrocladine, hamatine, and ancistrocline, all known alkaloids, have been previously isolated from this plant. Ancistrotectorine (55) is the second known alkaloid of the 7,3’-linked naphthalene-isoquinoline group to be isolated and identified. Its structure was deduced through single-crystal X-ray crystallography and spectroscopic methods (38).

55

1.

ALKALOIDS FROM T H E PLANTS OF TH A I LA N D

19

Two new hasubanan alkaloids, nordelavaine (56, CIYHZINOS) and stephanubine (57, C20H2sNOS)rhave been isolated from the tuberous roots of Stephania suberosa along with the known hasubanan delavaine (39). Erysovine, erysodine, and erysotine, the known Erythrina alkaloids, have been identified in seeds of Erythrina uariegata L. (Leguminosae). Variation in the alkaloid content is observed for different samples of seeds of the same species collected at different times and places (40). From the bulbs and leaves of Crinum asiaticum L. (Amaryllidaceae), five alkaloids have been isolated and identified as lycorine, haemanthamine, crinamine, crinine, and flexinine (41).Tembetarine, a quaternary benzylisoquinoline, is found in the stems of Tinospora baenzigeri (27). (-)-Argemonine, (-)norargemonine, which are pavinan alkaloids have been isolated from Cyclea atjehensis; this is the first recorded occurrence of pavines within a member of the Menispermaceae (34). (+)-Retidine has been isolated from Stephania uenosa (30);(+)-reticdine as well as (+)-coclaurine and (+)-N-methylcoclaurine have been isolated from Stephania pierrei (21). OM0

OM0

57

56

111. Indole Alkaloids

A. DISTRIBUTION AND OCCURRENCE

Many families of higher plants in Thailand, such as the Alangiaceae, Apocynaceae, Convolvulaceae, Leguminosae, Loganiaceae, Rubiaceae, Rutaceae and Strychnaceae, are rich sources of indole alkaloids. Some of these plants are used locally as folk medicines, like RauwolJia serpentina Benth. ex Kurz, Strychnos nux vomica Linn., S . lucida R.Br., and Mitragyna speciosa Korth. The leaves of Mitragyna speciosa, or kratom in the local language, are chewed by natives seeking the protective effect against strong sunlight. The effects of the leaves are similar to those of coca leaves

20

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

(Erythroxylum coca) of South America. Krutom is classified as a narcotic drug, and it is illegal to grow M. speciosa in Thailand. During the period 1963-1969, the Chelsea group of scientists led by Beckett and Shellard conducted extensive investigations on Mitragyna spp. and related genera. They reported the isolation and identification of many indole and oxindole alkaloids from M. speciosa, but none of the alkaloids could be proved to be an addictive substance. Most of the studies of indole alkaloids have been carried out on plants of the families Apocynaceae, Loganiaceae, and Rubiaceae. The plant names and their isolated alkaloids are given in Table 11. TABLE I1 INDOLEALKALOIDS FROM PLANTS OF THAILAND Plant name Adino cordgolia Hook. f. (valid name: Haldina cordifolia Ridsd.) (bark) Alsronia scholaris R.Br. (root bark, stem bark)

Family

Alkaloid (Ref.)

Rubiaceae

Cadambine ( 9 4 )

Apocynaceae

Akuammicine (81.82) Akuarnrnicine N,-methiodide (81.82) Akuammicine Nh-oxide (81.82) N,,-Demethylechitamine (81.82) Echitamine (81.82) Hydroxy- 19.20-dihydroakuammicine (81.82) Picrinine (81.82) Pseudoakuammigine (81.82) Tubotaiwine (81.82) 3a-Dihydrocadambine (95)

Anfhocepholus chinensis (Lamk.) A. Rich ex Walp. (leaves) Cinchona succirubru Pav. (leaves)

Rubiaceae

Clausena hurmandionu Pierre (root bark)

Rutaceae

Eruarumia coronuria (Jacq.) Stapf. var. plena (entire plant)

Apocynaceae

Ru biaceae

3-Epiquinarnine (98) 10-Methoxycinchonamine (98) Quinamine (98) Heptaphylline (54) 2-Hydroxy-3-formyl-7methoxycarbazole (55) 7-Methoxyheptaphylline (55) Coronaridine ( 9 1 ) Coronaridine hydroxyindolenine ( 91 ) Heyneanine (91 ) ( 19S)-Heyneanine hydroxyindolenine (91)

3-Oxocoronaridine (91) 3-Oxovoacangine ( 9 1 ) Voacangine ( 9 1 ) Voacangine hydroxyindolenine (91) Voacri5tine ( Y I ) Voacristine hydroxyindolenine ( 9 1 )

1. ALKALOIDS FROM THE PLANTS OF THAILAND

21

TABLE I1 (Continued) Plant name

Family

Alkaloid (Ref.)

Celsemium elegans Benth. (leaves, roots, seeds)

Loganiaceae

Kopsia jasminifora Pitard (leaves)

Apocynaceae

Mitragyna brunonis Craib (leaves)

Ru biaceae

Mitragyna hirsuta Havil (leaves, and stem bark)

Rubiaceae

Mitragyna javanica Koord. el Val. var. microphylla Craib (leaves)

Rubiaceae

19-(Z)-Akuammidine(86) 16-Epivoacarpine (85,86) Gelsemine (85.86) Gelsemine N-oxide (86) Gelsenicine (85,86) Gelsevirine (85,86) Humantenine (85,86) 19-H ydroxydihydrogelsevirine (85,86) 14-Hydroxygelsedine (85 14-Hydroxygelsenicine (85,86) Koumidine (86) Koumine (85,86) Koumine N-oxide (86) 19-Oxogelsenicine (86) 19-cis-Taberpsychine (86) 14,15-Dehydrokopsijasminilam(92) 10-Demethoxykopsidasinine(93) 20-Deoxykopsijasminilam (92) Fruticosamine (92) Fruticosine (92) Jasrniniflorine (92) Kopsijasmine (92) Kopsijasminilam (92) Ciliaphylline (69) Isorhynchophylline (69) Rhynchophylline (69) Specionoxeine (69) Angustoline (64) Harman (64) Hirsuteine (63) Hirsutine (63) lsomitraphylline (63) lsorhynchophylline (63) Mitraphylline (63) Mitrdjavine (63) Rhynchophylline (63) Uncarine C (pteropodine) (64) Uncarine D (speciophylline) (64) Uncarine E (isopteropodine) (64) Uncarine F (64) Ajmalicine (65) Augustine (=Pa-6) (65.68) lsomitraphylline (65) (continued)

22

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

TABLE 11 (Confinicedl Plant name

Family

Mirrugynu speciosu Korth. [leaves, stem bark, root bark; mature, young plants]

Rubiaceae

Mirrruvu puniculafu Jack (roots) Mitrruyu siamensis Craib (roots)

Rutaceae Rutaceae

Alkaloid (Ref.) Javaphylline (=Pa-7) (65) Mitrajavine (65) Mitraphylline (65) Ajmalicine (66.67) Akuammigine (67) Ciliaphylline (66,673 Corynantheidine (66) Corynoxeine (66) Corynoxine (66) Corynoxine B (66) 3-lsoajmalicine (67) lsocorynantheidine (67) Isomitrafoline (66) lsomitraphylline (66.67) Isopaynantheine (67) Isospeciofoline (66) Isorhynchophylline (66,67) lsospecionoxeine (67) Javaphylline (67) Mitraciliatine (67) Mitrafoline (66) Mitragynine (66.67) Mitragynine oxindole A (66.67) Mitragynine oxindole B (66,671 Mitrajavine (67) Mitraphylline (66,67) Pdynantheine (66) Rhynchociline (66.67) Rhynchophylline (66.67) Speciociliatine (66.67) Speciofoline (66) Speciogynine (66.67) Specionoxeine (67) (Speciophylline)(66 Uncarine D Yuehchukene (57) 3-Formyl-2.7-dimethoxy carbazole ( 5 9 ) 3-Formyl-2-methoxy carbazole ( 5 9 ) Girinimbine (57.58) Heptaphylline ( 5 9 ) 2-Hydroxy-3-formyl-7methoxycarbazole (59) 7-Methoxyheptaphylline ( 5 9 ) (continued)

1. ALKALOIDS FROM

23

THE PLANTS OF THAILAND

TABLE I1 (Continued) Plant name

Musa paradisiaca Linn. (fruits) Nauclea coadunatu Roxb. ex S. E. Smith (valid name: N . orientalis Linn.) RuuwolJu cambodiana Pierre ex Pitard

RauwolJin serprntitiu (Benth. ex Kurz (roots)

Strychnos ignatti

Berg. (stem bark)

Strychnos lucida R.Br. (leaves)

Branches (without leaves)

Stem bark

Family

Musaceae Rubiaceae

Alkaloid (Ref.) 7-Methoxymurrayacine (59) Mukonal(59) Murrayanine (56) 5-Hydroxytryptamine (62) Angustine (68)

Ajmaline (73) Aricine (73) Isoreserpiline (73) Pelirine (73) Reserpiline (73) Reserpine (73) Apocynaceae Ajmalicidine (72) Ajmalimine (83) Ajmalinimine (84) lndobine (60) lndobinine (61) Rescinnamidine (71) Rescinnaminol (70) Strychnaceae Brucine ( 9 0 ) Di h ydrolongicaudat ine (90) Geissoschizol (90) Longicaudatine (90) Polyneuridine (90) Strychnine (90) Strychnaceae Brucine (89) Brucine N-oxide ( 8 9 ) P-Colubrine (89) Normacusine B (89) Pseudobrucine ( 8 9 ) Pseudostrychnine (89) Strychnine (89) Brucine (89) Brucine N-oxide ( 8 9 ) Diaboline (89) Normacusine B (89) Pseudobrucine ( 8 9 ) Strychnine (89) Akuammidine ( 8 9 ) Brucine (89) Brucine N-oxide (89) a-Colubrine ( 8 9 ) P-Colubrine ( 8 9 ) Diaboline (89) Pseudobrucine (89) Apoc ynaceae

(continued)

24

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

TABLE 11 (Continued) Plant name

Family

Alkaloid (Ref.) ~

Root bark

Uncuriu uttenuuta Korth. (leaves)

Rubiaceae

Uncuriu canescens Korth. subsp. canescens (leaves) Uncuriu ellipfica R.Br. ex G. Don. (leaves)

Rubiaceae

Uncariu homomalla Miq. (syn. U. quadrangularis Geddes) (leaves, stem

Rubiceae

Uncuria mucrophyllu Wall. (leaves)

Rubiaceae

Rubiaceae

bark)

Strychnine (89) Brucine (89) P-Colubrine (89) Longicaudatine (88.89) Normacusine B (89) Pseudobrucine (89) Strychnine (89) 19-Epi-3-isoajmalicine(76) 14a-Hydroxy-3-isorauniticine(74.75) 3-lsoajmalicine (76) Mitraphylline (76) Rauniticine (74) Tetrahydroaistonine (74) Uncarine B (76) Harman (96) Ajmalicine (77) Akuammigine pseudoindoxyl(77) 19-Epiajmalicine (77) 19-Epi-3-isoajmalicine(77) 14P-Hydroxy-3-isorauniticine(7) 3-lsoajmalicine (77) Isomitraphylline (77) 3-lsorauniticine (77) 3-Isorauniticine pseudoindoxyl (77) Mitraphylline (77) Rauniticine (77) Rauniticine oxindole A (77) Rauniticine pseudoindoxyl(77) Tetrahydroalstonine (77) Tetrahydroalstonine N-oxide (77) Uncarine A (77) Uncarine B (77) lsomitraphylline (78) Mitraphylline (78) Uncarine C (pteropodine)(78,79) Uncarine D (speciophylline) (79) Uncarine E (isopteropodine) (78,79) Uncarine F (79) Corynoxine (80) Corynoxine B (80) Dihydrocorynantheine (80) Isorhynchophylline (80) Rhynchophylline (80)

1.

ALKALOIDS FROM T H E PLANTS OF T H A I L A N D

25

B. NON-TRYPTAMINE-DERIVED ALKALOIDS The known alkaloid heptaphylline has been isolated from the roots of Clausena harmandiana Pierre (Rutaceae) along with two new carbazole alkaloids identified as 2-hydroxy-3-formyl-7-methoxycarbazole(58) and 7-methoxyheptaphylline (59). The 'H- and 13C-NMR spectra have been analyzed and used to position the various functional groups (54,55).Other carbazole alkaloids isolated from the roots of Murraya siamensis Craib are identified as murrayanine, girinimbine, and mukonal, which occur together with heptaphylline and compounds 58 and 59 (56-58). Three new alkaloids have also been isolated from M. siamensis and named 3formyl-2,7-dimethoxycarbazole (60), 3-formyl-2-methoxylcarbazole(0methylmukonal)(61),and 7-methoxymurrayacine(62) (59). From the roots of Rauwolfia serpentina, the new alkaloid indobine (63)(60), the benzyl ester, and indobinine (64) (61), the cyclohexyl ester of indolepropionic acid, have been isolated and identified. GROUPA N D C. CORYNANTHEINE-HETEROYOHIMBINE-YOHIMBINE RELATED OXINDOLES The indole alkaloids of Mitragyna hirsuta Havil, M . jauanica Koord. et Val. var. microphyllu Craib, M. speciosa, and Nauclea coadunata are mostly in the corynantheine-heteroyohimbine-yohimbine group. The alkaloids isolated from the leaves of Mitragyna hirsuta have been identified as hirsutine, rhynchophylline, isorhynchophylline, mitraphylline, isomi-

58

R~=oM~.R~=H

60

R'=OM~.R~=MC R'=H.R~=MC

61

62

59

64

R=

A

a

26

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

traphylline, hirsuteine, mitrajavine, uncarine C (pteropodine), uncarine E (isopteropodine), uncarine D (speciophylline), uncarine F, and angustoline. From stem bark of the same plant only mitraphylline and isomitraphylline have been isolated (63,64).Leaves of the related species Mitragyna javanica var. microphylla Craib yielded the known alkaloids mitraphylline, isomitraphylline, and ajmalicine and new alkaloids named mitrajavine, javaphylline (Pa-7), and Pa-6 (65). The alkaloid Pa-6 has been characterized as angustine, which is also found in the leaves of Nauclea orientalis L. (syn. N . coadunata Roxb. ex. S. E. Smith) (68). Mitragyna speciosa has been found to be a good source of alkaloids. Its alkaloid content differs slightly with locality. Leaves of the plants from Thailand yield mitraphylline, isomitraphylline, speciophylline, ajmalicine, corynantheidine, speciogynine, paynantheine, speciociliatine, speciofoline, isospeciofoline, isomitrafoline, mitrafoline, mitragynine, and corynoxine (66). Leaves of the same plant have been examined monthly throughout the year, and in addition to the above alkaloids, other alkaloids such as corynoxine, rhynchophylline, isorhynchophylline, corynoxeine, mitragynine oxindole B, and traces of mitragynine oxindole A have been identified. All the above alkaloids are also found in young twigs, and stem bark together with ciliaphylline and rhynchociline (67). Young, 2-year-old plants of Mitragyna speciosa have also been investigated. The major alkaloids, as distinct from those found in the mature plants, are compounds of the C-3HP configuration with isocorynantheidine, isopaynantheine (two new alkaloids), and mitraciliatine being the dominant ones, although speciogynine, a C-3Ha indole alkaloid, also occurs as one of the main alkaloids (67). Specionoxeine and isospecionoxeine, formerly found in the species from New Guinea, were isolated for the first time from the species in Thailand (66). From the leaves of Mitragyna brunonis Craib, the following alkaloids have been isolated: ciliaphylline, rhynchophylline, isorhynchophylline, and specionoxeine (69). Recently, the isolation of new alkaloids has been reported, including rescinnaminol(65) (70),rescinnamidine (66) (71), and ajmalicidine (67) (72) from the roots of RauwolJiu serpentine. The claimed isolation of hemiacetal 65 is considered very unlikely because of the known instability of the normal hemicetal. Further work is clearly needed to scrutinize the proposed structure of 65. From the roots of RauwolJia cumbodianu Pierre ex Pitard, the alkaloids aricine, reserpiline, isoreserpiline, and reserpine have been characterized, together with pelirine and ajmaline which belong to the sarpagine-ajmaline-picraline group. The pattern of alkaloids in Ruuwo&a cambodiana is similar to that in RauwolJiu perukensis, suggesting that the plants may be the same species (73).

1. ALKALOIDS

(?)

27

FROM THE PLANTS OF T H A I L A N D

I

65

OMe

6H 67

MeO

0 II

6Me

OM0

66

Investigations of the leaves of Uncaria attenuata Korth. have resulted in the identification of the alkaloids tetrahydroalstonine, ruaniticine, and an alkaloid initially proposed to be 14p-hydroxy-3-isorauniticine,with the structure later being revised to 14a-hydroxy-3-isorauniticine(68) (74,75). Other alkaloids of U . attenuata leaves (initially identified as U . safaccensis Bakh. f. nom prouis) are identified to be 3-isoajmalicine, 19-epi-3isoajmalicine, mitraphylline, and uncarine B (76). Investigations on six samples of leaves of Uncaria efliptica R.Br. ex G . Don lead to the identification of tetrahydroalstonine and its N-oxide, ajmalicine, 3-isorauniticine, 19-epiajmalicine, 19-epi-3-isoajmalicine,rauniticine, isorauniticine, 14phydroxy-3-isorauniticine(14a-hydroxy-3-isorauniticine?),mitraphylline, isomitraphylline, uncarine A, uncarine B, rauniticine pseudoindoxyl(69), isorauniticine pseudoindoxyl (70), akuammigine pseudoindoxyl (71), rauniticine oxindole A (72). The last four alkaloids were isolated for the first

Me H

68

28

BAMRUNG TANTISEWIE A N D SOMSAK RUCHIRAWAT

69

(allo. H-3a. l l - z a , Me-180) (C-7A configuration)

70

(cpiallo. 11-30, 11-2Oa.Me-180) (3.19-di-epimer)

0

time as natural products (77). Mitraphylline and isomitraphylline are found in leaves of Uncaria quadrangularis Geddes (valid name: U.homomalla Miq.), whereas the stem bark contains uncarine C (pteropodine) and uncarine E (isopteropodine) (78). Leaves of Uncaria homomalla yield the known alkaloids uncarine E, uncarine C, uncarine F , and uncarine D (speciophylline) (79). The alkaloids dihydrocorynantheine, corynoxine, corynoxine B, rhynchophylline, and isorhynchophylline are obtained from the leaves of Uncaria macrophylla Wall. (80). D. SARPAGINE-AJMALINE-PICRALINE GROUP From the roots of Rauwolfia cambodiana, the alkaloids pelirine and ajmaline have been isolated (73). The alkaloids akuammicine, akuammicine Nb-oxide, akuammicine Nb-methiodide, pseudoakuammigine, and tubotaiwine have been newly recorded from the root bark of Alsronia scholaris R.Br. (Apocynaceae); echitamine is isolated as the major alkaloid, along with Nb-demethylechitamine, as well as three unidentified echitamidine isomers, and other known alkaloids. The stems of the same plant yielded echitamine, Nb-demethylechitamine, tubotaiwine, pricrinine, and other unidentified echitamidine isomers (81,82).Apart from the alkaloids in the heteroyohimbine group from roots of Rauwolfia serpentina, a new base, named ajmalimine (73) (83), and ajmalinimine (74)

1.

ALKALOIDS FROM THE PLANTS OF THAILAND

29

(84) have also been isolated. On hydrolysis, ajmalimine yielded 3,4,5trimethoxybenzoic acid and a base which was identical with ajmaline. The presence of the hydroxyl group at C-17 is supported by the formation of a monoacetyl derivative (83). The structure of ajmalinimine (74, C24H30N2 0 4 ) has been proposed on the basis of chemical and spectroscopic data; the presence of the C-acetyl group is a novel feature of this compound (84). Recently a number of new alkaloids have been isolated from the roots of Gelsemium elegans Benth. (Loganiaceae) (85,86), whose known alkaloids are identified as gelsemine, gelsevirine, koumine, gelsenicine, 14hydroxygelsenicine, humantenine, koumidine (79, and akuammidine (76). The new alkaloids have been identified to be 16-epivoacarpine (77), 19hydroxydihydrogelsevirine (78), 19-(Z)-taberpsychine (79). The structures of koumidine and akuammidine, previously isolated by Chinese investigators, were revised to the 19-(Z)-ethylidene configuration. 14Hydroxygelsedine is found in the seeds. The highly oxidized new alkaloids from the leaves are identified to be koumine N-oxide (go), gelsemine N-oxide (81),and 19-oxogelsenicine (82). From the same plant, elegan-

CHzOH COOMe

77

30

BAMRUNG TANTISEWIE A N D SOMSAK RUCHIRAWAT

samine (C29H36N206),representing a new class of indole alkaloids, has been isolated; its structure is identified as 83 on the basis of spectral data and X-ray structural analysis (87). Biosynthetic routes to the Gelsemium alkaloids have been proposed (86).

E. MISCELLANEOUS INDOLE ALKALOIDS Investigation of Kopsiu jusminijloru Pitard (Apocynaceae) has yielded two known compounds, fruticosine and fruticosamine, as well as six new is the first example of a compounds. Kopsijasminilam (84, C23H26NZ06) 20,21-secokopsinine skeleton, and structure 84 has been identified by spectral data and X-ray crystallography. Two related alkaloids, deoxykopsijasminilam (85, C2#2&05) and 86 (A'4-kopsijasminilam),have also been isolated and identified by comparison of the spectroscopic data.

80

19

78

I

ti

OM 81

82

I.

ALKALOIDS FROM THE PLANTS OF THAILAND

31

Kopsijasmine (87, C23H26N204),jasminiflonne (88, C21H24N203), and 10demethoxykopsidasinine (8% C23H26N205) are the three additional new alkaloids that have been isolated and characterized from detailed analysis of spectral data (92,93). The alkaloids from Eruatamia coronaria (Jacq.) Stapf. var. plena are good representatives of the ibogamine group. The whole plant has afforded a new Zboga alkaloid, ( - )-( 19S)-heyneanine hydroxyindolenine (W), along with nine other known alkaloids: coronaridine, coronaridine hydroxyindolenine, voacangine, voacangine hydroxyindolenine, ( - )(19S)-heyneanine, voacristine, 3-oxocoronaridine, 3-oxovoacangine, and voacristine hydroxyindolenine. Alkaloid 90 ( C Z I H ~ ~ Nexhibits ~ O ~ ) the characteristic property of the indolenine chromophore in the UV spectrum 223, 260, 282 (sh), and 290 nm and displays C-2 markedly shifted at,,,A downfield to about 188 ppm with C-7 shifted to about 87 ppm in the I3C-NMR spectrum. These signals are highly diagnostic for the proposed skeleton (91). Strychnos lucida and Strychnos ignatii Berg. have been investigated for their alkaloid contents. Alkaloids isolated from the leaves of S . lucida include strychnine, brucine, pseudobrucine, normacusine B, P-colubrine, pseudostrychnine, and brucine N-oxide. The alkaloids in the branches (without leaves) are the same as in the leaves except for the absence of pseudostrychnine and the addition of diaboline. In the root bark of this

rJQ

R

N

84

as 86

R=011

a7

R=H

R=OiI, A"

89

32

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

90

plant the alkaloids are found to be strychnine, brucine, p-colubrine, pseudobrucine, normacusine B, and the dimer longicaudatine; in the stem bark all the above alkaloids except longicaudatine were isolated together with the following alkaloids: a-colubrine, diaboline, akuammidine, brucine N-oxide, and ethyldiaboline (88,89).In the stem bark of S . ignatii, the dimer dihydrolongicaudatine was isolated along with the known alkaloids strychnine, brucine, geissoschizol, and polyneuridine (90). Longicaudatine (91), a bisindole alkaloid, has been isolated from the root bark of Strychnos lucida and several other Strychnos species (88). The alkaloid is a dimer of strychnine and geissoschizine alkaloids, and in some species it co-occurs with bisnor-C-alkaloid H, an isomeric base which has similar chromatographic and chromogenic properties. Bisnor-C-alkaloid H is a dimer of Wieland-Gumlich aldehyde and 18-deoxy-Wieland-Gumlich aldehyde (88).The stem bark of S . ignatii also yields longicaudatine and dihydrolongicaudatine(90). Glycosidic indole alkaloids have also been isolated: cadambine from the bark of Adina cordifolia Hook. f. (94) and 3a-dihydrocadambine from leaves of Anthocephalus chinensis (Lamk.) A. Rich ex Walp. (95). The p-carboline alkaloid harman is found in the leaves of both Mitragyna hirsuta (64)and Uncaria canescens Korth. (96).

91

1.

ALKALOIDS FROM THE PLANTS OF THAILAND

33

92

Leaves of Cinchona succirubra Pav. from a trial plantation in the north of Thailand have been reported to contain the typical bases of quinoline alkaloids (cinchonine, cinchonidine, quinidine, quinine, dihydroquinidine, and dihydroquinine) together with the indole bases quinamine and 3-epiquinamine (97,98). 10-Methoxycinchonamine (92) has also been isolated from this plant for the first time. Except for the inclusion of alkaloid 92, the alkaloid pattern in C. succirubra is the same as that in the cross-species C. succirubra x C . ledgeriana from Guatemala.

IV. Miscellaneous Alkaloids

The two sulfur-containing amides entadamides A (93) and B (94) have been isolated from the seeds and entadimides A and C (95) from the leaves of Entada phaseoloides M e n . (valid name: Entada rheedii Spreng.) (Leguminosae) (99-101). The known isobutylamide alkaloid pellitorine ( N isobutyl-2E,4E-decadienamide)is found in the aerial parts of Piper ribesoides Wall. (102). Pellitorine has also been isolated from the fruits of P .

MeS,

C'

MeS,

H

i,SMe H

II

0

0

94

93

0

95

34

BAMRUNG TANTISEWIE A N D SOMSAK RUCHIRAWAT

sarmentosum Roxb. (Piperaceae) together with a new pyrrole alkaloid, N-(3-phenylpropanoyl) pyrrole (96), and two new pyrrolidine alkaloids, sarmentine (97)and sarmentosine (98) (103). The structure of the pyrrole alkaloid (96)has been confirmed by synthesis (103). Pyrrolidine alkaloids named odorine (99) and odorinol (100) have been isolated from the leaves ofAglaia odorata Lour. (Meliaceae)(104), and the alkaloid piriferine (101) has been found in the leaves of A . pirifera Hance (105). The structures of odorine and odorinol have been conclusively assigned by spectral data analysis and X-ray crystallography (106). Roxburghilin and hydroxyroxburghilin have been isolated from Agfaiu roxburghiana Miq. (107);these two pyrrolidine bases are found to be identical with odorine and odorinol, respectively. The stem bark of Holarrhena antidysenterica Wall. (Apocynaceae) yielded the known steroidal alkaloids holarrhimine, isoconessimine, and conimine (108).Leaves of Holarrhena curtisii King et Gamble yielded the known as well as new aminoglycosteroidalalkaloids holacurtine (102)and N-demethylholacurtine (103), respectively (109). The known diterpenoid norerythrophlamide has been isolated from the stem bark of Erythrophleum teysmannii Craib var. puberulum Craib 0

0

dN3

\

91

96

wo HN"

R

99 100

R=H R=OH

101

1. ALKALOIDS FROM THE PLANTS OF THAILAND

102 103

35

R'=II. R2=Me R'=R2=fl

(Leguminosae) ( 1 10). The macrocyclic spermidine alkaloid palustrine, formerly known from the genus Equisetum (Equisetaceae), is reported to be present in the bark of AIbizia myriophylla Benth. (Leguminosae) (111). Flindersine, a known quinoline alkaloid, has been isolated from the leaves of Micromelum minutum (Forst. f.) Seem. (syn. Micromehm pubescens Blume) (Rutaceae) ( 1 12). The alkaloids ammodendrine, anagyrine, lupanine, 5,6-dehydrolupanine, a-isolupanine, ormosanine, panamine, and a-isosparteine, all known quinolizidine alkaloids, have been reported to be present in the seeds of the leguminous plant Ormosia sumatrana (Miq.) Prain (113). The new alkaloid kayawongine (104) has been isolated from Cissus rheifolia Planch. (Vitaceae) as the major component along with known alkaloid cryptopleurine (114). Analysis of the mass spectral data allowed the placement of the 4-methoxyphenyl substituent at C-3 rather than C-2 of the quinolizidine ring. From the family Euphorbiaceae, Phyllanthus niruri L. yielded the new alkaloid nirurine (105) in addition to the former reported occurrence of 4-methoxynorsecurinine and norsecurinine in the same plant (115,116). The structure of (105) was elucidated by analysis of spectral data and X-ray crystallography (1 17). The pyrrolizidine alkaloid phalaenopsine La (106)

104

105

36

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

106

(IS, 8R)-form

has been isolated from Doritis pulcherimu Lindl. (Orchidaceae) (118). Fruits of Zunthoxyfum budrungu Wall. ex Hook. f. (valid name: Z . limonellu Alston) (Rutaceae) have yielded two alkaloids: arborine, a quinazoline alkaloid, and dictamnine, a furoquinoline alkaloid (119).

Acknowledgments We wish to express our thanks to Professors N. R. Farnsworth and G. A. Cordell for information from the NAPRALERT database and to Dr. Poolsak Sahakitpichan. Miss Hunsa Prawat, Mrs. Kalaya Pharadai. and Mr. Somchai Pisutjaroenpong for preparation of the manuscript. REFERENCES I . P. S. Ashton. in “Biodiversity in Thailand” (S. Wongsiri and S. Lorlohakarn. eds.), p. 51. Prachachon. Bangkok. 1989. 2. T. Santisuk, in “Biodiversity in Thailand” (S. Wongsiri and S . Lorlohakarn, eds.), p. 81. Prachachon, Bangkok, 1989. 3. T. Smitinand, “Thai Plant Names.” Funny Publ., Bangkok, 1980. 4. C. Goepel, S. V. Kiirten, T. Yupraphat, P. Pachaly, and F. Zymalkowski, Planra Med. 22,402 (1972). 5 . T. Yupraphat, P. Pachaly, and F. Zymalkowski, Planta Med. 25,315 (1974). 6. C. Goepel, T . Yupraphat, P. Pachaly, and F. Zymalkowski, Planta Med. 26,94 (1974). 7. B. Hoffstadt, D. Moecke, P. Pachaly, and F. Zymalkowski, Tetrahedron 30,307 (1974). 8. K. Dahmen, P. Pachaly, and F. Zymalkowski, Arch. Pharm. (Weinheirn, Ger.) 310,95 ( 1977). 9. J. M. Heinz, P. Peter, and Z. Felix, Arch. Pharm. (Weinheirn. Ger.) 310, 314 (1977). 10. P. Wiriyachitra and B. Phuriyakorn, Aust. J . Chem. 34,2001 (1981). 11. D. Pornsiriprasert, W. Rittitid. C. Janaakul, and P. Wiriyachitra. Abstracts of the 10th Conference of Science and Technology. Thailand, p. 371. Chiangmai University. Chiengmai, Thailand, 1984. 12. P. Pachaly, T . J. Tan, H. Khosravian, and M. Klein. Arch. Phurrn. (Weinheirn Ger.) 319, 126 (1986). 13. P. Pachaly and T. J. Tan, Arch. Pharm. (Weinheirn. Gar.)319, 841 (1986). 14. P. Pachaly and T. J. Tan, Arch. Pharm. (Weinheim, Ger.) 319, 872 (1986). 15. P. Pachaly and H. Khosravian, Planta Med. 54,433 (1988).

1.

ALKALOIDS FROM THE PLANTS OF THAILAND

37

16. P. Pachaly and H. Khosravian, PIanra Med. 54,516 (1988). 17. K. T. Buck, in “The Alkaloids” (A. Brossi, ed.), Vol. 30, p. I . Academic Press, New York, 1987. 18. A. Patra, A. J. Freyer, H. Guinaudeau, M. Shamma, B. Tantisewie, and K. Pharadai, J. Nut. Prod. 49,424 (1986). 19. H. Guinaudeau, A. J. Freyer, and M. Shamma, Nar. Prod. Rep., 477 (1986). 20. U. Prawat, P. Wiriyachitra, V. Lojanapiwatna, and S. Nimgirawath, J . Sci. Soc. Thailand 8,65 (1982). 21. B. Tantisewie, S. Amurrio, H. Guinaudeau, and M. Shamma, J. Nar. Prod. 52, 846 ( 1989). 22. B. Tantisewie, T. Pharadai, A. J. Freyer, H . Guinaudeau, and M. Shamma, J. Nor. Prod. 53, 553 (1990). 23. B. Tantisewie, K. Pharadai, S. Amnauypol, A. J. Freyer, H. Guinaudeau, and M. Shamma, Tetrahedron 46, 325 (1990). 24. A. Patra, C. T. Montgomery, A. J. Freyer, H. Guinaudeau, M. Shamma, B. Tantisewie, and K . Pharadai, Phyfochernistry 26,547 (1987). 25. N. Ruangrungsi, W. De-Eknamkul, and G. L . Lange, Planta Med. 50,432 (1984). 26. N. Ruangrungsi, G. L. Lange, and M.Lee, J. Nut. Prod. 49,253 (1986). 27. N. G. Bisset and J. Nwaiwu, PIanra Med. 48, 275 (1983). 28. H. Guinaudeau, M. Shamma, B. Tantisewie, and K. Pharadai, J. Nut. Prod. 45, 355 ( 1982). 29. K. Pharadai, T. Pharadai, B. Tantisewie, H. Guinaudeau. A. J. Freyer, and M. Shamma, J . Nar. Prod. 48,658 (1985). 30. B. Charles, J. Bruneton, K. Pharadai, B. Tantisewie, H. Guinaudeau, and M. Shamma, J . Nut. Prod. 50, I 1 13 (1987). 31. H . Guinaudeau, A. J. Freyer, and M. Shamma, Tetrahedron 43, 1759 (1987). 32. K. Pharadai, B. Tantisewie, S. Ruchirawat, S. F. Hussain, and M.Shamma, Hererocycles 15, 1067 (1981). 33. H. Guinaudeau, M. Shamma, B. Tantisewie, and K. Pharadai, J. Chem. Soc.. Chem. Commun., 1118 (1981). 34. B. Tantisewie, T . Pharadai, M. Pandhuganont, H. Guinaudeau, A. J. Freyer, and M. Shamma, J. N a f . Prod. 52,652 (1989). 35. N. Ruangrungsi, A. Rivepiboon, G. L. Lange, M.Lee, C. P. Decicco, P. Picha. and K. Preechanukool, J. Nut. Prod. 50, 891 (1987). 36. X. Dong, I . - 0 . Mondranondra, C.-T. Che, H. H. S. Fong, and N. R. Farnsworth, Pharm. Res. 6,637 (1989). 37. N. Ruangrungsi, K . Likhitwitayawuid, S. Kasiwong, G. L. Lange, and C. P. Decicco, J. Nut. Prod. 51, 1220 (1988). 38. N. Ruangrungsi, V. Wongpanich, P. Tantivatana, H. J. Cowe, P. J . Cox, S. Funayama, and G. A. Cordell, J. Nar. Prod. 48,529 (1985). 39. A. Patra, Phytochemistry 26,2391 (1987). 40. I. Barakat, A. H . Jackson, and M. I. Abdulla, Lloydia 40,471 (1977). 41. D. Beutner and A. W. Frahm, PIanra Med. 52,523 (1986). 42. P. Pachaly and C. Schneider, Arch. Pharm. (Weinheim, Ger.) 314,251 (1981). 43. D. Meksuriyen, G. A. Cordell, N. Ruangrungsi, V. Wongpanich, and P. Tantivatana, Abstracts of the 27th Annual Meeting American Society of Pharmacognosy, July 27-30, Ann Arbor, Michigan, Abstract 39, 1986. 44. P. Dhumma-upakorn, N. Ruangrungsi. S. Pasupat. and C. Kekosol, Asiun J . Pharm. Suppl. 6,88 (1986). 45. N. Petasai, M.S.Thesis, Fac. Pharm. Sci., Chulalongkorn Univ.. Bangkok (1986).

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BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

46. T . Tojirakorn and P. Chumsri, Asian J. Pliarm. Suppl. 6, 122 (1986). 47. G.Rojanasoonthorn, M.S. Thesis, Fac. Sci., Mahidol Univ., Bangkok (1970). 48. P. Chumsri, Asian J. Pharm. Sicppl. 6 , 123 (1986). 49. K.Likhitwitayawuid, N. Ruangrungsi, M. Boriboon, G. L. Lange, and C. P. Decicco. J . Sci. Soc. Thailand 14,73 (1988). 50. P. Siripong, M.S. Thesis, Fac. Pharm. Sci., Chulalongkorn Univ.. Bangkok (1986). 51. J. Bernath, B. Danos, T. Veres, J. Szanto, and P. Tetenyl, Biochem. Sysr. Ecol. 16, 171 (1988);S. Kengtong, M.S. Thesis, Fac. Pharm. Sci.. Chulalongkorn Univ., Bangkok (1983). 52. M. Sitinavavit, M.S. Thesis, Fac. Pharm. Sci.. Chulalongkorn Univ.. Bangkok (1985). 53. N . Fukuda, M. Yonemitsu, and T. Kimura, Abstracts of the 8th International Research Conference on Natural Products, Abstract 34. Univ. of North Carolina. Chapel Hill, July 7-12, 1985. 54. J. D.Wangboonskul, S . Pummangura. and C. Chaichantipyuth, J. Nar. Prod. 47, 1058 (1984). 55. C. Chaichantipyuth, S. Pummangura. K. Naowsaran, D. Thanyavuthi, J. E. Anderson, and J. L . McLaughlin, J. Nar. Prod. 51, 1285 (1988). 56. M. Fiebig. J. M. Pezzuto. D. D. Soejarto, and A. D. Kinghorn. Phyrochemistry24,3041 (1985). 57. Y. C. Kong, K. H. Ng, P. P. H. But, 0. Li, S. X. Yu, H. T. Zhang, K. F. Cheng, D. D. Soejarto, W. S. Kan, and P. G. Waterman, J . Efhnopharmacol. 15, 195 (1980). 58. Y. C. Kong, K. F. Cheng, K. H. Ng, P. P. H . But, 0. Li, S. X. Yu, H. T. Chang, R. C. Cambie, T. Kinoshita, W. S. Kanf, and P. G. Waterman. Biochem. Sysr. Ecol. 14,491 (1986). 59. N. Ruangrungsi, J. Ariyaprayoon. G. L. Lange, and M. G. Organ, J. Nar. Prod. 53,946 (1990). 60. S. Siddiqui, S. I. Haider, and S. S. Ahmad, Z. Nafurforsch.,B: Anorg. Clzem., Org. Chem. 42,783 (1987). 61. S.Siddiqui, S. S. Ahmad, and S. 1. Haider, Indian J. Chem. 268,279 (1987). 62. S. Poonpatana, P. Visondilok, and F. Lelapityamit. Mahidol Uniu. J. Pharm. Sci.4, 14 (1977). 63. J. D. Phillipson, P. Tantivatana. E. Tarpo, and E. J. Shellard, Phytocliemisrry 12, 1507 (1973). 64. J. D. Phillipson, S. R. Hemingway, and C. E. Ridsdale, J . Nar. Prod. 45, 145 (1982). 65. E. J. Shellard, A. H. Beckett, P. Tantivatana, J. D. Phillipson, and C. M. Lee, Planra Med. 15, 245 (1967). 66. E. J. Shellard, P. J. Houghton, and M. Resha, Planta Med. 34,26 (1978). 67. E. J. Shellard, P. J. Houghton. and M. Resha, PIanra Med. 34,253 (1978). 68. J. D. Phillipson, S. R. Hemingway. N. G. Bisset, P. J. Houghton. and E. J. Shellard. Phytochemisrry 13,973 (1974). 69. T. Soontranont. M.S. Thesis, Fac. Pharm. Sci., Chulalongkorn Univ., Bangkok (1979). 70. S. Siddiqui, S. S. Ahmad, and S. 1. Haider, Pak. J. Sci. f n d . Res. 29,401 (1986). 71. S.Siddiqui, S. 1. Haider, and S. S. Ahmad, J . Nut. Prod. 50,238 (1987). 72. S. Siddiqui, S. S. Ahmad, S. I. Haider, and B. S. Siddiqui, Phptochemisrry 26, 875 ( 1987). 73. W. Boonchuay and W. E. Court, Planra Med. 29,201 (1976). 74. D.Ponglux, T. Supavita, R. Verpoorte, and J. D. Phillipson. Pliytochemistry 19,2013 (1 980). 75. E. Yamanaka, E. Maruta, S. Kasamatsu, N. Aimi, S.-i. Sakai, D. Ponglux, S. Wongseripipatana, T . Supavita, and J. D. Phillipson, Chem Pharm. Bull. 34,3713 (1986).

1. ALKALOIDS FROM THE PLANTS OF THAILAND

39

76. P. Tantivatana, D. Ponglux. S. Wongseripipatana. and J. D. Phillipson, Planta Med. 40, 299 (1980). 77. J. D. Phillipson and N . Supavita, Phytochemistry 22, 1809 (1983). 78. P. Tantivatana, D. Ponglux. V. Jirawongse. and Y. Silpvisavanont, Planto Med. 35,92 (1979). 79. D. Ponglux, P. Tantivatana, and S. Pummangura. Plunta Med. 31, 26 (1977). 80. S. Seridhoranakul, M. S. Thesis, Fac. Pharm. Sci., Chulalongkorn Univ.. Bangkok ( I98 1 ). 81. W. Boonchuay and W. Court, Phytochemistry 15,821 (1976). 82. W. Boonchuay and W. Court, Planta Med. 29,380 (1976). 83. S. Siddiqui, S. S. Ahmad. and S. I. Haider, Planta Med. 53,288 (1987). 84. S. Siddiqui, S. I. Haider, and S. S. Ahmad, Heterocycles 26,463 (1987). 85. S.4. Sakai, S. Wongseripipatana, D. Ponglux. M. Yokota, K. Ogata, H. Takayama, and N. Aimi, Chern. Pharm. Bull. 35,4668 (1987). 86. D. Ponglux, S. Wongseripipatana, S. Subhadhirasakul. H. Takayama, M. Yokota. K. Ogata, C. Phisalaphong, N. Aimi, and S.-i. Sakai. Tetrahedron 44,5075 (1988). 87. D. Ponglux. S . Wongseripipatana, H. Takayama. K. Okata. N. Aimi, and S.4. Sakai. Tetrahedron Lett., 5395 (1988). 88. G. Massiot, M. Zeches. C. Mirand. L. Le Men-Olivier. C. Delaude. K. H. C. Baser. R. Bavovada, N . G. Bisset, P. J. Hylands. J. Strombom. and R. Verp0orte.J. Org. C/irm. 48, 1869 (1983). 89. R. Bavovada. Ph.D. Thesis, Chelsea College. Univ. of London (1983). 90. C. Pingsuthiwong, M.S. Thesis. Fac. Pharm. Sci.. Chulalongkorn Univ., Bangkok (1986). 91. P. Sharma and G. A. Cordell. J. Nut. Prod. 51, 528 (1988). 92. N . Ruangrungsi, K. Likhitwitayawuid, V. Jongbunprasert, D. Ponglux. N . Aimi, K. Ogata. M. Yasuoka. J. Hajiniwa. and S.-i. Sakai. Tetrahedron Lett., 3679 (1987). 93. M. 0. Hamburger, G. A. Cordell, K. Likhitwitayawuid, and N . Ruangrungsi, Phytochemistry 27, 2719 (1988). 94. J. R. Cannon, E. I. Ghisalberti. and V. Lojanapiwatna, J. Sci. Soc. Tliuiland 6 , 54 (1980). 95. N . Ruangrungsi, M.S. Thesis, Fac. Pharm. Sci.. Chulalongkorn Univ., Bangkok (1977); S. S. Handa, R. P. Borris, G. A. Cordell, and J. D. Phillipson. J. Nut. Prod. 46,325 (1983). 96. J. D. Phillipson and S. R. Hemingway. Phytocliemistry 14, 1855 (1975). 97. A. T. Keene, L. A. Anderson. and J. D. Phillipson. J . Pharni. Pliarmacol. 33 (Suppl.), 15P (1981). 98. A. T. Keene, L. A. Anderson, and J. D. Phillipson. J . Chrornatogr. 260, 123 (1983). 99. F. lkegami. I. Shibasaki, S. Ohmiya, N. Ruangrungsi. and I. Murakoshi, Chern. Pliarm. Bull. 33,5153 (1985). 100. F. Ikegami, S. Ohmiya, N. Ruangrungsi. S.-i. Sakai. and I. Murakoshi. Phyrocliemistry 26, 1525 (1987). 101. F. Ikegami, T. Sekine, S. Duangteraprecha, N. Matsushita, N. Matsuda, N . Ruangrungsi, and I. Murakoshi, Phytochemistry 28, 881 (1989). 102. A. Kijjao, M. M. M. Pinto, B. Tantisewie, and W. Herz, Planta Med. 55, 193 (1989). 103. K . Likhitwitayawuid, N. Ruangrungsi, G. L. Lange, and C. P. Deccico, Tetrahedron 43, 3689 (1987). 104. D. Shiengthong, A. Ungphakorn, D. E. Lewis, and R. A. Massey-Westropp, Tetrahedron Lett. 24,2247 (1979). 105. E. Saifah, V. Jongbunprasert, and C. J. Kelley, J . Nar. Prod. 51,80 (1988).

40

BAMRUNG TANTISEWIE AND SOMSAK RUCHIRAWAT

106. P. J. Babidge, R. A. Massy-Westrop, S. G. Pyne, D. Shiengthong, A. Ungphakorn, and G. Veerachat, Aust. J. Chem. 33, 1841 (1980). 107. K. K. Purushothaman, A. Sarada, J. D. Connolly, and J. A. Akinniyi, J. Chem. SOC., Perkin Trans. I , 3171 (1979). 108. S . Praraggamo, M.S. Thesis, Chulalongkorn Univ., Bangkok (1970). 109. J. R. Cannon, E. L. Ghisalberti, and V. Lojanapiwatna, J. Sci. SOC. Thailand 6 , 81 (1 980). 110. K. Suwanborirux, M.S. Thesis, Fac. Pharm. Sci., Chulalongkorn Univ., Bangkok (1982). 11 I . S. Homchantara, M.S. Thesis, Fac. Pharm. Sci., Chulalongkorn Univ., Bangkok ( 1985). 112. P. Tantivatana, N. Ruangrungsi, V. Vaisiriroj, D. C. Lankin, N . S. Bhacca, R. P. Boms, G. A. Cordell, and L. F. Johnson, J. Org. Chem. 48,268 (1983). 113. D. Kinghorn, R. A. Hussain, E. F. Robbins, M. F. Balandrin, C. H. Stirton, and S. V. Evans, Phytochemistry 27,439 (1988). 114. E. Saifah, C. J. Kelley, and J. D. Leary, J. Nut. Prod. 46,353 (1983). I 15. N . B. Mulchandani and S. A. Hassarajani, Planra Med. 50, 104 (1984). 116. R. Rouffiac and J. Parello, Plant Med. Phyrother. 3,220 (1969). 117. P. Petchnaree, N . Bunyapraphatsara, G. A . Cordell, H. J. Cowe, P. J. Cox, R. A. Howie, and S. L. Patt, J. Chem. Soc., Perkin Trans. I , 1551 (1986). 118. S. Brandange, B. Luning, C. Moberg, and E. Sjostrand, Acta Chem. Scand. 26,2558 ( 1972). 119. N . Ruangrungsi, P. Tantivatana, R. P. Borris, and G. A. Cordell, J. Sci. Soc. Thailand 7, 123 (1981).

-CHAPTER

2-

MARINE ALKALOIDS I1 JUN’ICHIKOBAYASHI A N D MASAMIISHIBASHI Faculty of Pharmaceutical Sciences Hokkaido University Sapporo 060. Japan

1. Introduction ........................................................ I1. Guanidine Alkaloids ................................................. A . Tetrodotoxin and Saxitoxin . ................. B . Oroidin-Related Compounds ....................................... C . Other Guanidines ................................................. I11. Indole Alkaloids ......................... ...... A . Simplelndoles ................................................... B . Other Indoles ..... ................................ 1V . Pyrrole Alkaloids ............................................ A . Simple Pyrroles .................................................. B . Tetrapyrroles ....................... ................ C. Pyrrolidine- or Proline-Related Alkaloids ............................ V . P-Carboline Alkaloids ................................................ A . Eudistomins ..................... ... B . Manzamines ..................................................... ........................................ VI . Polycyclic Alkaloids . . A . Aromatic Compounds .....................

............................. ............................. VII . Polyketides . . A . Kabiramide Group .................................. B . Other Polyketides ................................................ VIII . Peptides ..................................... A . Di-, Tri-, and Tetrapeptides ........................................ B . Didemnins and Patellamides ....................................... C . Dolastatins and Majusculamides.............. D . Other Peptides ................................................... IX . Miscellaneous Alkaloids . . . . . .... ................... A . Tyrosine-Derived Alkaloids ........................................ B . Pyridine and Piperidine Alkaloids................................... C. Pyrimidine, Purine, and Related Alkaloids . D. Imidazole, Thiazole, and Related Alkaloids .......................... E . Other Alkaloids ...................................... References ............................. 41

..

42 42 42 45 46 50 50 52 58 58 58 60 63 63 67

68

68 74 76 76 80 87 87 89 93 95 98 98 102

104 106

I09 112

.

THE ALKALOIDS VOL . 41 Copyright 8 1992 by Academic Press Inc . All righls of reproduction in any form reserved.

.

42

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

I. Introduction Since the previous review by C. Christophersen in Volume 24 of this treatise (Z), a great number of new marine alkaloids have been discovered. Most of these marine alkaloids exhibit a variety of the biological activities and have therefore been of great importance in many fields of biological sciences. This chapter covers the reports on marine alkaloids that have been published between 1985 and 1989 (partially 1990) and provides an update of the previous review by Christophersen in 1985 ( 1 ) . According to Christophersen’s definition, all nitrogen-containing secondary metabolites are considered as “alkaloids” in this review. As the recognition of primary metabolites separate from secondary ones is, in many cases, still obscure in marine organisms, the selection of compounds may be arbitrary and depends on the interest of the reviewers to some extent. Classification of the compounds also basically follows that of the previous review ( I ) , but four sections on p-carbolines, polycyclic alkaloids, peptides, and nitrogen-containing polyketides have been added, since a substantial number of new compounds belonging to these four groups have been reported since 1985. Although many nitrogen-containing terpenoids and steroids, particularly those possessing isocyanide, isothiocyanate, and formamide functionalities, have been discovered in marine organisms, this chapter deliberately excludes these compounds. A continuous series of very excellent reviews on marine natural products by D. J. Faulkner has appeared in Natural Products Reports (2-6), covering all aspects of the literature on marine natural products, organized phylogenetically. Excellent reviews on “Marine Alkaloids and Related Compounds” (7)and “Recent Developments in the Field of Marine Natural Products with Emphasis on Biologically Active Compounds” (8)were written by W. Fenical and H. C. Krebs, respectively. Besides these reviews, numerous books dealing with general or specialized topics in marine natural products research have appeared in recent years (9-13). Biosynthetic studies on marine natural products were recently reviewed by M. J. Garson (14). 11. Guanidine Alkaloids A. TETRODOTOXIN AND SAXITOXIN Tetrodotoxin (TTX, 1) is one of the best known marine toxins and exhibits potent neurotoxicity by specifically blocking the sodium channels of excitable cell membranes. The etiology of TTX has been an interesting topic because of the wide distribution of the toxin among genetically

2.

43

MARINE ALKALOIDS

unrelated animals and the remarkable regional as well as individual variations in toxin contents. The source of TTX has been demonstrated to be marine bacteria, since TTX and its analogs were detected in the culture broth of bacteria identified as species of Alteromonas ( 1 3 , Vibrio (16), and Psuedomonas (17) that had been isolated from a red alga of the genus Janiu, a xanthid crab (Atergatisfloridus),and the skin of a pufferfish (Fugu poecilontus), respectively. Although the biosynthetic pathway for TTX is still unknown, many natural TTX derivatives have been isolated owing to the development of a fluorometric HPLC method designed for microdetection of TTX analogs (18). Five derivatives were isolated from pufferfish tissue extracts: tetrodonic acid (2), 4-epi-TTX (3), and 4,Panhydro-TTX (4) from Japanese Takifugu pardulis and T . poecilonotus (19), 1 l-nor-TTX-6(R)-ol (5) from Fugu niphobles (20), and 1 1-0x0-TTX (6) from Micronesian Arothron nigropunctutus (21). From the Okinawan newt Cynops ensicanda 6-epiTTX (7) and 1 1-deoxy-TTX (8) were isolated (22). Structural determination of these TTX analogs was achieved mainly through NMR measure-ooc&

H OH

c

OH

R’

1 3 5 6 7 8 9

H OH H H H H H

R2 OH H OH OH OH OH OH

R3 OH OH H OH CH2OH OH CH3 OH CH(OH)CH(NH,) COOH R

S

?-

11 R=H 12 R=OH

44

JUN'ICHI KOBAYASHI AND MASAMI ISHIBASHI

ments. The poor resolution of 'H- and 13C-NMRspectra of TTX caused by hemiacetal-lactone tautomerism was markedly improved by the addition of CF3COOD to the solvent to allow the 'H and I3C signals to be firmly assigned. Biosynthesis of TTX (1) supposedly involves arginine and a C5 unit derived from either amino acids, isoprenoids, shikimates, or branched sugars. Isolation of 6-epi-TTX (7)and 11-deoxy-TTX(8)suggested that an isopreniod unit is favored because it possesses both an sp2 carbon oxidizable to either 1or 7 and a methyl that remains in 8 (23). The structure of chiriquitoxin (9), isolated from the Costa Rican frog Atelopus chiriquiensis, was determined to be a TTX analog with a glycine molecule attached to C-11 (24). A hypnotic barbitone (10) was isolated from the pufferfish Sphaeroides oblongus collected at the Bay of Bengal(25). The structural patterns of 10 show some similarity to TTX (1).Synthetic studies to form optically active TTX (1)in a stereocontrolled manner have been reported (26-28). Saxitoxin (STX, 11)and its analogs are well-known paralytic shellfish poisons (PSP) (29) produced by a variety of organisms, including dinoflagellates of the genus Gonyaulax, the blue-green alga Aphanizomenon 30s-aquae (freshwater), and the red alga Jania. The presence of STX was found in the common Atlantic mackerel, Scomber scombrus (30). The occurrence of this toxin in taxonomically varied species as well as productivity differences within the same species suggests the presence of common vectors. While the bacterial production of STX was hotly discussed, it was reported that the toxin in the culture broth of a bacterium isolated from the dinoflagellate Protogonyaulax tamarensis was identified as STX (31). Further studies are expected to substantiate PSP-producing bacteria (32). Biosynthesis of STX analogs was investigated by feeding experiments with I3C-labeled precursors in Aphanizomenon 30s-aquae ( 3 3 , and the following pathway was proposed. The tricyclic skeleton is formed by a Claisen-type condensation of an acetate unit or its equivalent onto the amino-bearing a carbon of arginine followed by decarboxylation, introduction of a guanidine moiety, and cyclization (34). The side-chain carbon (C-13) of neo-STX (12)is derived from a methionine methyl group by the electrophilic attack of S-adenosylmethionine (SAM) on a dehydro intermediate followed by hydride migration and proton loss; further elaboration of the side chain probably involves an intermediary aldehyde (Scheme 1) (35). Detailed discussions have been presented for some physico-chemical properties (pK,, charge distribution, and molecular conformation) of the toxins that may serve in the interpretation of neurophysiological experimental data (36).

2.

45

MARINE ALKALOIDS

Neosaxitoxin

SCHEME 1

B. OROIDIN-RELATED COMPOUNDS Oroidin was first isolated from the Mediterranean sponge Agelas oroides (37)and was later assigned structure 13 (38).Hymenidin (14), a 2-debromo derivative of oroidin (13), was isolated from an Okinawan sponge (Hyrneniacidon sp.) as a novel antagonist of serotonergic receptors (39). Hymenidin (14) appears to be a biogenetic precursor of the dimeric metabolite sceptrin (W), an antimicrobial agent previously obtained from the sponge Agelas sceptrurn (40).The sponge Hyrneniacidon also contained hymenin (16), a cyclized oroidin derivative which exhibits a potent a-adrenoceptor blocking activity (41). In the rabbit isolated aorta, hymenin (16, lop6 M) caused a parallel rightward shift of the dose-response curve for contraction of the aorta induced by norepinephrine, whereas concentration-response curves for histamine and KCI were not affected by hymenin (16). Thus, hymenin (16) was suggested to be a competitive antagonist of aadrenoceptors in vascular smooth muscle (42). The presence of the sevenmembered lactam ring may play an important role in the development of a-adrenoceptor blocking activity, as ring-opened analogs such as oroidin (13), hymenidin (14), and sceptrin (15) show no a-adrenoceptor activity, though 13-15 exhibit marked antiserotonergic activity. Stevensine (17), which is related to oroidin (13) by oxidative cyclization, was isolated from an unidentified Micronesian sponge (43). The identical compound (17), named odiline, was obtained from agueous extracts of a New Caledonian sponge, Pseudaxinyssa cantharella (44). This sponge also contained many other oroidin analogs: dibromocantharelline [(+) -181, compounds 19, 20, 21, and (+)-dibromophakeline (22). The

46

JUN'ICHI KOBAYASHI A N D MASAMI ISHIBASHI

H;&g 19 20

R=H R=Br

Br

16

23 B

r

0 q

H

tiHz

15 17 21

structure of (+)-22 was confirmed by X-ray diffraction and turned out to be the enantiomer of a known compound (45). The structure of dibromocantharelline [ (+) -181 was also determined by X-ray analysis. The enantiomer of dibromocantharelline, named dibromoisophakeline [(-)-MI, was later isolated from an Madagascan sponge Acanthella carteri (46). The structure was also based on X-ray studies to give the ( 6 S , 1OR) configuration for (-)-18. Two pyrrololactams (19 and 20) that appear to be cleavage products of cyclized oroidin derivatives were also contained in Hymeniacidon aldis, a sponge from Guam, and named aldisin and 2-bromoaldisin, respectively (47). Aldisin (19) had been prepared previously (48) but this was the first isolation from a natural source. From a Tanzanian sponge (Agelas sp.) dibromoagelaspongin (23) was isolated, with the structure being confirmed by X-ray analysis (49). C. OTHERGUANIDINES

Nine 2-amino imidazole alkaloids were isolated from a Red Sea calcareous sponge, Leucetta chagosensis (50,5Z). They belong to four differ-

2.

MARINE ALKALOIDS

47

ent groups and were named naamidines A-D (24-27),isonaamidines A (a),B (29),naamines A (30),B (31),and isonaamine A (32).The structures of these compounds were elucidated from extensive spectroscopic analyses. Hydrolysis of naamidine A (24) and isonaamidine A (28) with 5% HBr-MeOH afforded naamine A (30)and isonaamine A (32),respectively. A nudibranch (Notodoris citrina) feeding on the L . chagosensis sponge was found to concentrate these imidazole alkaloids (51). Clathridine (33), which is structurally related to naamidines, was isolated from a Neapolitan sponge (Cfathrina cfathrus) and exhibits antimycotic activity (52). The sponge also contained a Zn complex of clathridine (34)which showed a molecular ion cluster at mlz 744.1430 in the electron-impact (EI) mass spectrum, establishing the molecular formula C32H28N100sZn. The structure of 34 was confirmed by X-ray analysis (53).Two naamidine-related alkaloids, pyronaamidine (35)and kealiiquinone (36),were isolated from a Guam sponge tentatively identified as a Leucetta sp. Compound 36 appears to be biogenetically derived from compound 35 (54). The structure of 36 was based on X-ray analysis. Compound 35 showed cytotoxicity against KB cells, whereas 36 was not cytotoxic.

48

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

J

34

Me0

Me’

Me0

0

36 35

OMe

OMe

Grossularins I(37)and I1 (38),the first examples of naturally occurring a-carbolines, were obtained from a French solitary tunicate (Dendrodoa grossularia) and were found to be cytotoxic toward L1210 leukemia cells (55). Previously the structure of grossularin I was proposed as 39 (56), which was revised to 37 on the basis of comparison with the structure of grossularin I1 (38).Structural proof for 38 was unambiguously provided by X-ray analysis. The same tunicate contained 3-indolyl-4H-imidazol-4-one (40),the structure of which was confirmed by synthesis (57). The imidazolone compound (40)was devoid of cytotoxicity. 6-Bromoaplysinopsin (41) and 6-bromo-4’-N-demethylaplysinopsin (42),isolated from a Caribbean sponge (Smenospongean aurea), had no significant antimicrobial activity (58).6-Bromoaplysinopsin (41)was also obtained from a Mediterranean anthozoan (Astroides calycularis) (59), which also contained smaller amounts of n-propionyl derivatives (43and 44) in addition to aplysinopsin (49,a cytotoxic metabolite previously known from marine sponges (60-62). Aplysinopsin (45)was also found in a Japanese scleractinian coral (Tubastrea aurea) and shown to inhibit development of fertilized sea urchin eggs (63). The same coral collected at Okinawa contained tubastrine (a), a guanidinostyrene possessing antiviral activity (64).Recently a novel alkaloid, named ptilomycalin A (47), was isolated from the Caribbean sponge Ptilocaulis spiculifer and a red sponge Hemimycale sp. from the Red Sea. This compound belongs to a new class of polycyclic guanidine alkaloids, which are linked through an

2.

"'b

MARINE ALKALOIDS

\

OH NMe,

39

40 41 R1 = Br. R2 = H

43 44 45

42

R' R'

H. R2 = COCH2CH, Br. R2 = COCH,CH, R1= R2=H =

=

49

50

JUN'ICHI KOBAYASHI AND MASAMI ISHIBASHI

o-hydroxy acid to spermidine, and exhibits antitumor, antiviral, and antifungal activity (65). Spermidine amide (48) was also contained in both sponges. H

OH

46

111. Indole Alkaloids

A. SIMPLE INDOLES Simple indole compounds have been isolated from a variety of marine sources, including sponges, tunicates, acorn worms, red algae, and symbiotic bacteria. The Caribbean sponge Srnenospongia aurea (58), from which bromoaplysinopsin derivatives (41 and 42) were obtained, contained the previously known (66) 5-bromo- and 5.6-dibromo-NJVdimethyltryptamines (49 and 50) as the basic antimicrobial components. 4-Hydroxy-5-(indol-3-yl)-5-oxopentan-2-one (51) was isolated from the Bermudian sponge Dysidea etheria (67) together with known indole-3acetamide (52) (68) and indole-3-carboxyaldehyde(53) (69). Compound 51 was also found in extracts of the sponge Ufosa ruetzferi and might be

2.

51

MARINE ALKALOIDS

formed by condensation of acetone with the ketoaldehyde (54). Compounds 51 and 52 exhibited promoting activity in the root growth assays of lettuce seedlings (67). 3-Formylindole (53) was also isolated from a Pakistani red alga (Borryocladia lepropoda) (70). A deep-water (-215) sponge (Dercirus sp.) collected at Bahama contained l,l-dimethyl-5,6dihydroxyindolinium chloride (55) (71). A sample of Dercirus sp. from shallow water had been reported to contain aplysinopsin (45) and aplysinopsin analogs (62). From a Fijian tunicate (Polycirrorella rnariae) citrorellamine, possessing cytotoxic and antimicrobialactivity, was isolated, and the structure was assigned to be 56 (72). This structure was later revised to the disulfide (57) on the basis of total synthesis (73). 4,6-Dibromoindole (58)and 4,6-dibromo-2-methylindole (591, belonging to a new substitution class of halogenated indoles, were isolated from an Okinawan acorn worm (Glossobalanus sp., phylum Hemichordata) (74). Previously, bromine substitution at the 4 and 6 positions without any substituents at the 3 position had never been reported from natural sources. In the biosynthesis of 58 and 59 it was proposed that halogenation of an aromatic amino acid may occur at an earlier stage than the formation of the indole ring. The 2- and 3-methylsulfinylindoles, named itomanindoles A and B (60 and 61), were isolated from the Okinawan red alga Laurencia brongniarrii, and both compounds exhibited optical activity (75). The structure of 60,and hence 61 by comparison, was determined by X-ray crystallography

49

R = H

51 R

50

R =Br

52 R

= COCH(OH)CHzCOCH, = CH,CONH,

55

53 R = C H O 54 R

57

=

COCHO

56

52

JUN’ICHI KOBAYASHI A N D MASAMI ISHIBASHI

50

R’=R2=H

59

R ’ = M e , R2

65

H

= SMe

60

R’

S(=O)Me, R2

61

R’

SMe, R2 = S(=O)Me

62

R’

= Br, R2

63

R’

R2 = Br

64

R’

SMe, R2

H

H

and revealed a pair of hydrogen-bonded molecules possessing a center of inversion. Although all optical activity was clearly lost on recrystallization, optical purity was established and the configuration of natural 60 was determined by means of asymmetric synthesis, supporting the conclusion that in the alga both enantiomeric forms of 60 are present, but with at least a 2% excess of the form having the (R) configuration. Three other indoles with 4,6-dibromo substituents (62-64) as well as a bisindole (65) were also contained in the Okinawan L. brongniartii. The structure of 65 was established by X-ray analysis (76). 2,3-Indolinedione (M),known as isatin, was isolated from the culture medium of Alteromonas sp., a bacterial strain consistently isolated from the surface of the embryos of the shrimp Plaemon macrodactylus (77). By producing and liberating this antifungal metabolite (M),the commensal Alteromonas bacteria protect the shrimp embryos from infection by the pathogenic fungus Lagenidium callinectes.

B. OTHERINDOLES Dramacidin (67), a cytotoxic bisindole alkaloid, was isolated from a deep-water (- 148 m) Caribbean sponge (Dramacidon sp.) and was found to inhibit the growth of several cancer cell lines (78). Dramacidin (67) contains two tryptamine units and an unoxidized piperazine ring, which had never been found in marine natural products. Dramacidons A (68)and B (69)were isolated from the Pacific Ocean sponge Hexadella sp. collected off the coast of British Columbia. Dramacidon A (68) shows in vitro

2.

53

MARINE ALKALOIDS

cytotoxicity, whereas dramacidon B (69) is inactive (79). Fascaplysin (70), a blood red pigment, was obtained from a Fijian sponge (Fascaplysinopsis sp.) and exhibits antimicrobial and cytotoxic properties (80).The structure of 70 was based on X-ray analysis and represents the first naturally occurring compound with the pentacyclic ring system 12-H-pyrido[ 1,2-a:3, 4-b‘ldiindole. Caulerpin (71), a previously known pigment found in some green algae (81),was shown to act as a plant growth regulator (82),and the distribution of 71 in the algal genus Caulerpa was investigated (83).From these studies it was proposed that caulerpin (71) may be a valid chemotaxonomic marker in Caulerpa species and may function as a growth hormone or auxin precursor in the algae. Topsentins A (72), B l (73), and B2 (74) were isolated from the Mediterranean sponge Topsentia genitrix (84)and were weakly toxic for the fish Lebistes reticulatus and for dissociated cells of the freshwater sponge Ephydatia fluuiatilis. Compound 73 (named topsentin) and 74 (named bromotopsentin) were also obtained from a Caribbean deep-sea sponge of the genus Spongosorites (85), which contained 4,5-dihydro-6deoxybromotopsentin (75) as well. Compounds 73-75 were shown to have antitumor and antiviral activities. Topsentin C (76), differing from 75 only by the additional bromosubstituent at C - 6 and the methyl group attached

70

54

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

R H

72

R=R’=H

73

R=OH, R ’ = H

74

R

75

OH, R ’ = Br 7

N

76

to N-1, was isolated together with dramacidons A (68)and B (69) from the sponge Hexadella sp (79). Topsentin C (76) is inactive in cytotoxicity assays in uitro. Synthesis of topsentin A (72) (86) and topsentin Bl(73) and several analogs (85) was achieved to investigate further structure-activity relationships. Unique p-lactam indole alkaloids, namely, chartellines A (77) ( 8 3 , B (78), and C (79), methoxydechlorochartelline A (80) (88),and chartellamides A (81) and B (82) (891, were isolated from a marine bryozoan (Chartella papyruceu) collected in North Britanny waters. The structure of chartelline A (77) was confirmed by X-ray analysis, and the absolute

CI, R2 = R3 = Br

77

R’

78

R3 = H, R’

79

R2

R3 = H, R’ =CI

80

R‘

OMe, R2 = R3 = Br

= CI, R2 =

Br

81

R = H

82

R=Br

2. MARINE ALKALOIDS

55

configuration around C-20 was determined to be S. Methoxydechlorochartelline A (80) was an isolation artifact and was prepared from chartelline A (77) by addition of methoxide in methanol. Chartelline A (77) as well as the crude mixture of these alkaloids is devoid of any significant antimicrobial activity, but chartelline A (77) exhibits cytotoxicity in uitro against KB and PS cell lines (88). The biosynthesis of this new class of alkaloids appears quite interesting, as is the question whether they are true bryozoan metabolites or originate via some microorganisms. A series of tricyclic indole alkaloids (physostigmine alkaloids) has been obtained from the cheilostome bryozoan Flustru foliuceu (90). In addition, flustramide B (83) and flustrarine B (84) were isolated from this bryozoan (91). Flustrarine B (84) was prepared from previously known flustramine B (85)(92) via oxidation with hydrogen peroxide. Five flustramine derivatives, dihydroflustramine C (86) and its N-oxide (87), flustramine D (88) and its N-oxide (89), and isoflustramine D (901, were isolated from the methylene chloride fraction of the aqueous methanol extract of a Canadian F. foliuceu, and these alkaloids were found to be responsible for the antimicrobial activity of the extract (93). Oxidation of dihydroflustramine C (86) and flustramine D (88) with rn-chloroperbenzoic acid afforded the corresponding N-oxides (87 and 88, respectively).

86

R‘=R2=H

80

R1=)=r

90

R ’ = H , R2

,

R2=H

=)=r

56

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

The marine mollusc Nerita albicilla was found to contain an oxindole alkaloid that was identified as isoteropodine (91),a previously known plant metabolite (94), by extensive NMR spectroscopic techniques (95). Four indole derivatives, named polyandrocarpamides A-D (92-95), were isolated from the colonial ascidian Polyandrocarpa sp. collected in the Philippines (96). The aqueous acetone extracts of the Australian sponge Trikentrion flabelliforme show antimicrobial activity, which was ascribed to five tricyclic indole alkaloids, cis-trikentrin A (96), trans-trikentrin A (97), transtrikentrin B (98), cis-trikentrin B (99),and iso-trans-trikentrin B (100)(97). Synthesis of racemic cis-trikentrin A (96) was achieved through an aryl radical cyclization (98), and (-)-cis-trikentrin A (96) and (-)-transtrikentrin A (97), enantiomers of the natural compounds, were synthesized from (R)-(+)-pulegone, establishing the absolute configuration to be (l”R,J”S)and (l”S,3”S)for natural 96 and 97, respectively (99). The total synthesis of racemic cis-trikentrin B (99) was recently attained through a new indole synthesis comprising an intramolecular Diels-Alder reaction (100). Herbindoles A-C (101-103) were isolated from a Western Australian sponge (Axinella sp.), and the three compounds 101-103 were demonstrated to be cytotoxic against KB cells and to act as fish antifeedants (101). A clue to a possible a-phenylindole origin of these compounds was recently provided by the isolation of trikentramine (104) from the Senegalese sponge Trikentrion loeve (102).

0

91 H

H

H

95

0

//

92

X=Br

93

X = l

94

X = H

57

2. MARINE ALKALOIDS

98

99

100

The absolute configuration of lyngbyatoxin A (105 = teleocidin A-I) and teleocidin A-2 (106), potent tumor promoters isolated from the bluegreen alga Lyngbya majuscula or terrestrial Streptomyces mediocidicus, was determined to be (14R) and (149, respectively, by chemical degradation including ozonolysis (103). Another surugatoxin derivative, named prosurugatoxin (107), was isolated from the toxic Japanese ivory shell Babylonia japonica and deduced to be des-xylopyranosylneosurugatoxin on the basis of physical and chemical data (104). It had been reported that neosurugatoxin (108)was responsible for half the total toxicity of the mollusc ( 1 0 3 , and prosurugatoxin (107) was found to be responsible for the remaining toxicity. Prosurugatoxin (107) possesses mydriasis-evoking and antinicotinic activities. These activities are about one-fifth as potent as those of neosurugatoxin (lOS), but the content of prosurugatoxin (107) in the mollusc is 5 to 6 times that of neosurugatoxin (108). These toxins may be useful in studies on nicotinic cholinergic receptors. A microbial origin for these toxins is strongly indicated because toxicity was found only in shellfish from a limited area of Suruga Bay and the toxicity disappeared and reappeared on displacing the shellfish to other areas and vice versa. Hundreds of strains of bacteria were isolated from the seabed sliqe of the toxic area and from the toxic shellfish, and it was found that neosurugatoxin (108) and prosurugatoxin (107) were produced by a coryneform bacterium isolated from the digestive gland of the shellfish B . japonica (106).

58

JUN'lCHl KOBAYASHI AND MASAMI 1SHlBASHl

101

R=CH3

102

R

103

R

=

104

CHZCHj

=

W R

6 105

14R

106

14s

107

R

= 6-myoinositol

108

R

= 6'-(myoinositol

- xylopyranose 3

P

1

IV. Pyrrole Alkaloids A. SIMPLE PYRROLES

Two extremely unstable bromopyrrole metabolites, characterized as 2,3-dibromopyrrole(109)and 2,3-dibromo-5-methoxymet h y lpy rrole (110), were isolated from a sponge (Agelus sp.) together with five previously known dibromopyrroles (111-115)(107). Methanol extracts of a sponge of the genus Lissodendroryx from Sri Lanka contained the previously known (108) pyrrole carboxylic acid methyl esters (113 and 116)(47). The known (37) compound 4,5-dibromo-2-pyrrolic acid (111)was isolated from a Caribbean deep-water (- 155 m) sponge (Agelus Jlabelliformis) and was shown to possess potent in uitro immunosuppressive activity (109).

B. TETRAPYRROLES A highly unusual porphynoid (117),named tunichlorin, was isolated from the Caribbean tunicate Trididemnum sofidumfrom which didemnins (Section VIII), anticancer cyclopeptides, had previously been obtained

2. MARINE ALKALOIDS

59

OH

I

R’

R2

R3

109

H

Br

H

110

H

Br

CH,OMe

111

H

Br

COOH

112

Me

Br

COOH

113

H

Br

COOMe

114

Me

Br

COOMe

115

ti

Br

CONH,

116

H

H

COOMe

I

coon 117

(110).Tunichlorin (117)is apparently the first nickel-containing chlorin and only the second nickel-containing porphyrin-related compound identified from living organisms. Many other chlorophyll-like pigments were obtained from T. solidum such as pheophytin a (118),pheophorbide a (119), and chlorophyll a (120). It is not yet known whether tunichlorin (117)is produced by the tunicate or the cyanobacterium growing commensally with it. From the Japanese bryozoan Bugula dentata, an antimicrobial blue pigment (121)was isolated (111) and found to be identical with a tetrapyrrole previously isolated from a mutant strain of Serratia marcescens ( 1 12). The color of the bryozoan B. dentata is unusually dark blue, suggesting that the pigment 121 is ubiquitously present in the animal. Whether compound 121 is biosynthesized by the bryozoan itself or by an associated microorganism or derived from food sources such as prodigiosinproducing bacteria is still unknown. 132,173-Cyclopheophorbide enol (122) a nonmetalated chlorophyll a derivative was isolated from a New Zealand sponge (Darwinella oxeata) and its structure determined by X-ray measurements (113). Although 132,173-cyclopheophorbide enol (122) was first isolated from natural sources, it had previously been synthesized during a study of ring E enolization of chlorophyll derivatives (114). A new pheophorbide a-related compound named chlorophyllone a (123)was isolated from extracts of the short-necked clam Ruditapes philippinarum (115).Compound 123 exhibits antioxidative activity.

60

JUN'ICHI KOBAYASHI A N D MASAMI ISHIBASHI

121

COOR'

118

R, = phytyl, R,

119

R,=H, R,=H,H

120

R , = phytyl, R, = Mg

H, H

OH

122

Substance F (124),the light emitter in krill bioluminescence, was isolated fom the krill Euphansia pacifca by using alumina and ion-exchange chromatography at low temperature under an inert atmosphere. The structure of 124 was elucidated on the basis of chemical degradation as well as spectroscopic data of F (124)and oxy-F (125) (116). Dinoflagellate luciferin (126)was isolated from cultured Pyrocystis lunula (117), and its structure was elucidated by comparing the spectroscopic data with those of krill fluorescent substance F (124).From crude extracts of luciferin, an air oxidation product (127) with a characteristic blue color was isolated. The bioluminescence of dinoflagellates involves oxidation of luciferin (enzyme substrate) by luciferase (enzyme). The nonenzymatic oxidation of luciferin (126) afforded 128 without emission of light, whereas the enzymatic oxidation of 126 yielded 129 with the emission of light at 474 nm. Dinoflagellate luciferin (126) and krill fluorescent substance F (124)are apparently members of the family of bile pigments, and they are the first naturally occurring bile pigments that are structurally related to chlorophylls rather than to hemes.

C. PYRROLIDINEOR PROLINE-RELATED ALKALOIDS A new Dragendorff-positive compound, 4-hydroxy-N,N-dimethylpyrrolidino-3-carboxylate (130), was isolated from the neutral amino acid

2. MARINE ALKALOIDS

uo

61

124

R=OH

126

R = H

125

R = OH

128

R=H

COONa

fraction of the Mediterranean red alga Grateloupia proteus (118). A novel (131),was isolated betaine, N,N-dimethyl-A*-pyrrolidino-3-carboxylate from another Mediterranean red alga (Pterocladia capillacea) (119). Although these compounds seem to be biogenetically derived from P-proline, this amino acid has not been found in nature so far. N-Carbamoylpyrrolidine (132)was isolated as a major component of the Mediterranean sponge Aplysina (= Verongia) cauernicola (120). Compound 132 had previously been prepared (121) but never reported as a natural product. A hexachloro metabolite, named dysidamide (133),was isolated from a Red Sea sponge (Dysidea sp.) (122). The bryozoan Amanthia wilsoni from coastal waters of southern Australia contained a series of brominated proline-derived alkaloids named amanthamides (123,124).The geographical variation of the content of amanthamides A-F (134-139)was investigated by GC-MS analysis. No significant variation was found in the alkaloid content of different colonies of the bryozoan at the same location, but differences occur between samples obtained from different collection sites. Isodomoic acids A-C (140-142)were isolated from aqueous extracts of a Japanese red alga (Chondria armata);they exhibit significant insecticidal

62

JUN'ICHI KOBAYASHI A N D MASAMI ISHIBASHI

COONa

activity against the American cockroach (125). Further examination of extracts of this alga led to the isolation of two other amino acids containing a y-lactone ring in the side chain, namely, domoilactones A (143) and B (la), which, however, showed no activity against the American cockroach (126).

NHz

132

131

130

133 O

M

H Br

R,

Rz

134

H

H

136

Br

CH,

138

Br

H

Me0

I Br

OM

% ;Br B *r

Br

137

135

R=H

139

R=Br

2.

MARINE ALKALOIDS

"Np;;u

63

COzH

HN

HOzC COZH

140

COzH

141

V. P-Carboline Alkaloids A. EUDISTOMINS Eudistomins A-Q (145-161)were extracted from the Caribbean colonial tunicate Eudistoma olivaceum (127-129). Four groups of eudistomins were isolated, including simple P-carbolines (eudistomins D (la), J (154),N (158),and 0 (159)),pyrrolyl-P-carbolines(A (143,B (146),and M (157)),pyrrolinyl-P-carbolines(G (151),H (152),I (153),P (la),and Q (161)),and tetrahydro-P-carbolines with an oxathiazepine ring (C (147),E (149),F (l50),K (155),and L (156)).Syntheses have been described for eudistomins D, H, I, M, N , 0, and Q , confirming their structures (129). The isolated eudistomins were assayed against herpes simplex virus I (HSV-1) and show antiviral activity. The most active by far are those compounds containing the oxathiazepine ring (C, E, K, and L). The isolated eudistomins also exhibit antimicrobial activity to widely differing degrees, with the oxathiazepines being generally the most active. Interestingly, a mixture of eudistomins N and 0 display a remarkable degree of synergism. Either synthetic eudistomin N or 0 alone is inactive, but a mixture displays antimicrobial activity. Several of the eudistomins have been proved to induce calcium release from the sarcoplasmic reticulum (SR). The application of specific drugs which affect the Ca2+-releasingaction from the SR is an effective approach to the resolution of an important problem in muscle biology concerning the

64

145

157

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

R’

R2

OH

Br

OH

H

cNH

R’

R‘

148

H

Br

152

Br

H

153

H

H

R’

R2

R3

151

Br

OH

H

154

H

OH

Br

158

H

Br

H

160

OH

Br

Br

161

OH

H

159

Br

H

R3

R4

OH

Br

H

1 4 9 Br

OH

H

H

150 H

OH

Br

C2H302

155 H

H

Br

H

156 H

Br

H

H

)xf

R* H

R2

147 H

R’

N

mechanism in the excitation-contraction coupling between nerve and muscle. The Ca2+-releasing effect is especially pronounced with 7bromoeudistomin D (BED, 162)(130),which is prepared from 6-methoxyp-carboline and 9-methyl-7-bromoeudistomin D (MBED, 163)(131); MBED was synthesized based on structure-activity relationships between BED and caffeine, a well-known inducer of Ca2+ release from the SR, using computer graphics. The Ca2+-releasingeffect of compounds 162 and 163 is approximately 400 and 1000 times more potent than caffeine, respectively. Thus, MBED (163)is used as a valuable tool for elucidating the molecular mechanism of Ca2+release from the SR. Eudistomins D (la),N (158),and 0 (159)and several synthetic p-carbolines with halogeno (Br, CI, or I) and alkyloxy (RO--, with R = H, CH3, or Ac) groups on the benzenoid ring (162,164-166)proved to be novel inhibitors of CAMPphosphodiesterase (132). Eudistomidin A (167)was isolated from an Okinawan tunicate (Eudistornu gluucus) and exhibited strong calmodulin-antagonistic activity (133). Compound 167 was the first calmodulin antagonist of marine origin and is about 15 times more potent than W-7, a well-known calmodulin antagonist. Eudistomidins B, C, and D (168-170)were obtained from the same

2.

65

MARINE ALKALOIDS

tunicate (134). The absolute stereostructure of 168 was elucidated from NMR and circular dichroism (CD) data, whereas that of 169 was determined by synthesis of 6-0-methyl- lO(R)-eudistomidin C. These new P-carbolines (168-170)show antileukemic activity. Eudistomidin B (168) inhibits Na+, K+-ATPase but activates actomyosin ATPase, whereas eudistomidin C (169)shows calmodulin-antagonisticactivity. Eudistomidin D (170)induces Ca2+release from the SR. Eudistomin K (155)(135) and its sulfoxide (171)(136) were isolated from the New Zealand ascidian Ritterelfa sigiffinoides. The sulfoxide (171)also shows antiviral activity. The structure of 155 was determined by X-ray analysis (137) and that of 171 by semisynthesis from 155. Three other P-carbolines, named eudistomins R, S, and T (172-174)were obtained from a Bermudian tunicate (E. ofiuaceurn) by using an amino-bonded HPLC column (138). A 2-methyl-],2,3,4-tetrahydro-P-carbolinewith an N-methylpyrrolidine at C-1, named woodinine (175),was isolated from a New Caledonian ascidian (Eudistornu frugurn) (139), extracts of which exhibit antimicrobial activity. Marine bryozoans and hydroids also contain P-carboline alkaloids. (S)-l-(1 '-hydroxyethy1)-P-carboline (176) was obtained from the Tas-

iT fR R' *2

\

BrpTf

/N

W

OH

R'

N

R'

R2

R3

R4

R5

162

Br

OH

Br

H

H

163

Br

OH

Br

H

Me

164

I

165

CI

OH

166

Br

OMe H

OMe H CI

167

OAc H H

H

OAc H Br

BI I

I

A/s\w

Me

MeHN

169

170

171

66

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

0

172 173

Br

H Br

174

H

H

175

R’

R2

177

Et

H

178

Me

H

179

Et

Br

HO

176

u

manian bryozoan Costaticella hastata (140) together with some known P-carbolines previously reported from terrestrial plants. Three new brominated P-carbolines (177-179)were isolated from the Mediterranean hydroid Aglaophenia pluma (141), and their structures were firmly established by synthesis. The synthesis of eudistomin alkaloids has been extensively investigated by many organic chemists because of their remarkable biological activities. The total synthesis of eudistomin L (156)in an optically pure form was accomplished by using a Pictet-Spengler reaction of Nbhydroxytryptamines and cysteinals (242-144), providing direct evidence for the absolute configuration of eudistomins. (-)-Eudistomin F (150)was also synthesized in optically pure form (145). N’O-Acetyleudistomin L was prepared in a convergent synthesis from 5-bromoindoleand L-cysteine by applying a modification of the Pictet-Spengler reaction (146). The synthesis of eudistomins S (173)and T (174)was achieved from tryptamine precursors (147). Simple and concise syntheses of eudistomins I(153)and T (174)were reported which utilized silver ion-mediated cyclization of a-ketoimidoyl chlorides (148). The total synthesis of eudistomidin A (167)

2.

MARINE ALKALOIDS

67

was achieved by applying Fischer indolization of O-sulfonyloxyphenylhydrazones (149). B. MANZAMINES Manzamines comprise a new group of p-carboline alkaloids having polycyclic ring systems, the provenance of which is problematical as there appears to be no obvious biogenetic path. Manzamine A (180)was isolated from an Okinawan sponge (Haliclona sp.) and shown to exhibit antitumor activity. Its structure and absolute configuration were determined by X-ray analysis (150). From an Okinawan sponge (Peflinasp.) keramamines A (180)and B (181)were isolated as antimicrobial substances (151), and keramamine A was found to be identical with manzamine A. Further investigation of the Okinawan sponge Haficfona sp. resulted in the isolation of manzamines B-F (182-186),which show cytotoxic activity (252-154). The structures of manzamines B (182)and C (183)were based on X-ray analysis. Manzamine F (186)was found to be identical with keramamine B, the structure of which with a 1,2,3-triazacyclohexane moiety (181)was revised to structure 186 containing a hexahydro-5(2H)azocinone ring. Total synthesis of manzamine C (183)was achieved by the

182

68

JUN’ICHI KOBAYASHI A N D MASAMI ISHIBASHI

conjunction of 6-(Z)-azacycloundecene and 1-substituted P-carboline derivatives (155). Synthetic approaches to manzamine A (180)are also being hotly investigated (156,157).

VI. Polycyclic Alkaloids A. AROMATIC COMPOUNDS

Fused tetra- and pentacyclic aromatic alkaloids are a new, emerging group of compounds from marine organisms. Amphimedine (187)was isolated from a Pacific sponge (Amphimedonsp.) as a cytotoxic compound in 1983 and was the first example of a polycyclic alkaloid (158). A pigment from the sea anemone Calfiactisparasitica, named calliactine, has been known for many years, but the structure elucidation of calliactine was a difficult problem (159). In 1987 the structure of calliactine was proposed to be 188 on the basis of modem spectroscopic methods as well as chemical

2.

69

MARINE ALKALOIDS

investigation, although other possibilities for the structure of calliactine were not definitely ruled out (160). Tunicates have proved to be a rich source for polycyclic aromatic alkaloids possessing a common tetracyclic ring system (189), (a pyrido [4,3,2-mn]acridine skeleton or benzo-3,6-diazaphenanthroline ring), which is also contained in amphimedine (187) and calliactine (188). 2Bromoleptoclinidinone(190) was isolated from an ascidian that was tentatively identified as a species of Leptoclinides collected at Truk Lagoon (161). This alkaloid was shown to be toxic to cell cultures of lymphocytic leukemia cells, and the structure was determined by making extensive use of long-range proton-carbon couplings. The initial structure 191 was revised to 190 (162) after the structure of ascididemin (192)was published. Ascididemin (192) is an antileukemic alkaloid obtained from an Okinawan tunicate (Didemnum sp.) (163). Unambiguous proof of the structure of ascididemin (192) was provided by total synthesis (164,165). Cystodytins A-C (193-195) were isolated from the Okinawan tunicate Cystodytes dellechiajei and show potent antineoplastic activity and powerful Ca*+-releasingactivity in the sarcoplasmic reticulum (166). Alkaloids closely related to cystodytins were obtained from a Fijian tunicate (Lissoclinum vareau) and named varamines A (196) and B (197); they exhibit cytotoxic activity but no antifungal activity (167). Diplamine (198), isolated from another Fijian tunicate (Diplosoma sp.), is also structurally related to cystodytins and varamines and shows cytotoxic and antimicrobial activity (168). From the Guam tunicate Trididemnum sp. were isolated

0 187

189

188

0

191

192

70

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

RNH

194 R=

195 R=

0

\ MeS

/

OMe 196 R=Me 197 R=Et

OH

R

\

N’

N’

MeS 0 198

199 R=Br 200 R=H

the thiazinone-containing pentacyclic alkaloids shermilamines A (199) (169) and B (200) (170). The structure of shermilamine A (199) was solved by X-ray analysis, and that of shermilamine B (200), lacking bromination at C-6, was based on spectral comparisons. No biological activity was reported for shermilamine A or B. Six alkaloids possessing the common tetracyclic ring system (189) were isolated from a purple Red Sea tunicate identified as an Eudistoma sp. (171-173). They are segoline A (201), segoline B (202), isosegoline A (2031, norsegoline A (204), debromoshermilamine A (205 = shermilamine B, 200), and eilatin (206). The structure of segoline A (201) was established by X-ray methods (171). Those of compounds 202-205 were elucidated on the basis of spectroscopic data and chemical transformations. The relative configurations of chiral compounds 201-203 were suggested by CD measurements (173). The sixth compound, eilatin (206), was unusual in having a symmetrical heptacyclic structure, which was determined by X-ray analysis (172). Sponges also contain alkaloids of this family other than the first example, amphidemine (187). Petrosamine (207), a pigment possessing antimicrobial activity, was isolated from a sponge (Petrosia sp.) collected at Belize, and its structure was determined by X-ray analysis (174). The color of petrosamine solutions varied significantly with the solvent. Extracts of two sponges belonging to the family Pachastrellidae, a deep violet Dercitus sp. and a red Stelletta sp., collected in the Bahamas, inhibit the growth of murine leukemia cells. Fractionation of the Dercitus extract by centrifugal

2. MARINE ALKALOIDS

n 201

202

71

203

204

countercurrent chromatography yielded dercitin (208)as the major antitumor alkaloid (175) together with cyclodercitin (209)and two N-oxides of dercitin (N-1 and N-15), whereas the extract from Stelletfa sp. gave nordercitin (210),dercitamine (211),and dercitamide (212)(176). Dercitin (208) is a violet pigment that exhibits antitumor, antiviral, and immunomodulatory properties in uitro and antitumor activity in uiuo. Kuanoniamines A-D (213-216)were isolated from an unidentified Micronesian purple colonial tunicate and its predator, Chelynotus semperi, and exhibits cytotoxicity (177).Judging from the more than 20 examples mentioned above, it seems likely that these metabolites embracing the common tetracyclic unit (189)should be classed together biosynthetically. The diversity of source organisms would suggest that the metabolites are produced by symbionts. The highly fused structures of alkaloids of this family have proved to be challenging targets for synthesis. Synthetic approaches to amphimedine (187)were investigated (178), and three groups completed total syntheses using the hetero-Diels-Alder reaction (1 79,180) or ring expansion of an azafluorenone precursor (181). Ascididemin (192) was prepared by a coupling reaction of quinoline-5 ,&quinone and o-aminoacetophenone (164). The ring system of cystodytins (193-195)was assembled in a sequence involving a modified Knoevenagel-Stobbe pyridine synthesis (182).

Two pentacyclic aromatic alkaloids, plakinidines A (217)and B (218) were recently isolated from a Vanuatuan red sponge of the genus Plakortis

72

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

207

75%)

~(ClO%)

29 (84%)

3Q (91%)

FIG. 10. Photodecomposition of azidocolchicinoids

ylation of 29 with diazomethane afforded the methyl ether 30, found to be a potent inhibitor of binding of tritiated colchicine to tubulin (45). Reaction of colchicine with amines affords colchiceinamides with the methoxy group at C-10 replaced by an amino group (50). This line of products was recently extended by coupling amino acids (51) and peptides

3. TROPOLONIC COLCHICUM ALKALOIDS

147

(52) with a demethoxycolchinyl moiety. Colchicine also reacts at the methoxy group at C-I0 with diamines, and the diamide 31, shown in Fig. 11, was prepared as follows (53).

Biscolchiceine-1,3-propanediamide(31). To colchicine ( 100 mg) in methanol (2 ml) was added 1,3-diaminopropane (0.02 ml), and the reaction mixture was stirred at room temperature for 48 hr. After further addition of colchicine (10 mg), the reaction mixture was left for another 24 hr. Following addition of CH2C12(20ml), the organic extracts were washed with 5% HCl, 5% NaOH, and brine, to afford, after drying (MgS04),evaporation of solvent, and crystallization from CH2C12/Et20,the diamide 31 (78mg) as yellow crystals: m/p 197-199°C; [aID-285”(0.2,CHC13);CIMS 809 (M+). Another dimer of thiocolchicine was obtained by reacting 7-isothiocyanato-7-deacetamidothiocolchicinewith 1,3-diaminopropane in CH2C12 to give thiourea 32 (53).Compound 32 surprisingly displayed a positive optical rotation. Preparation of Thiourea 32. 7-Isothiocyanato-7-deacetamidothiocolchicine (30 mg, 0.072 mmol) was dissolved in CH2C12 (10 ml), 1,3diaminopropane (2.7mg, 0.031 mmol) was added, and the reaction mixture was stirred at room temperature for 24 hr. The organic solution was washed with 5% HCl and brine and dried (Na2S04). Filtration and evapo-

CH,O

FIG. 11. “Colchicine dimers.”

148

OLlVlER BOYC A N D ARNOLD BROSSI

ration of solvent gave a residue which was chromatographed (SiO2, CHCIJMeOH, 9 : 1) to give dimer 32 as yellow crystals, recrystallized from methanol (29 mg, 89%): mp 205-207°C; [ a ] +~160"(0.33, CHCl,); MS [fast atom bombardment (FAB)] 905 (M + l ) + . Catalytic reduction of colchicine over Pd/C catalyst in ethanol, after absorption of 2 mol of hydrogen, gave two isomeric tetrahydrocolchicines, whereas exhaustive hydrogenation led to four isomeric hexahydrocolchicines (54). Isocolchicine (33)(only ring C is shown in Fig. 12), when reacted with sodium methane thiolate in aqueous methanol, was reported to give two reaction products, with the isothiocolchicine structure 34 assigned to the minor one (55). It has been shown on the basis of a detailed 'H-NMR analysis that the major reaction product is the pseudothiocolchicine (35) (56).Addition of the methyl sulfide occurred on either side of the carbonyl group. Both compounds, 34 and 35 shown in Fig. 12, afforded on reduction with Raney nickel the same isocolchicide (36).

34

3.3

FIG. 12. Isothiocolchicine (34) and pseudothiocolchicine (35) prepared from isocolchicine (33).

D. TOTALSYNTHESIS 1. Colchicinoids ( ? )-Deacetamidocolchicine (18) has served as a key intermediate in several formal total syntheses of colchicine (1)(I). It has to be realized, however, that several additional steps are required for completing the synthesis of 1from 18 the introduction of an amino group at C-7, the

3. TROPOLONIC COLCHICUM ALKALOIDS

149

methylation of deacetylcolchiceine and separation of the natural enol ether from the is0 isomer, the optical resolution of (2)-deacetylcolchiceine or ( ? )-deacetylcolchicine, and acetylation of (-)-deacetylcolchicine. The Boger synthesis of 18 is another approach added to the already many existing syntheses of colchicine, pioneered by van Tamelen (39) and Eschenmoser (38). The Boger synthesis of tropone 37 from Eschenmoser’s pyrone 38 by thermal [3 - 41 cycloaddition of cyclopentenone ketals is worth noting since it afforded tropone 37 in 70% overall yield (57). Details of the Boger synthesis of (+)-18are outlined in Fig. 13.

n

7

0

0

+ ‘NH,

FIG. 13. Boger synthesis of (+)-deacetamidocolchicine(18).

150

OLIVIER BOY6 A N D ARNOLD BROSSI

Eschenmoser’s pyrone 38 on treatment with cyclopropenone ketal39 in refluxing benzene afforded lactone 40 (73%). Lactone 40 on hydrolysis with acetic acid at 100°C afforded, after deprotection and decarboxylation, tropone 37 (70%). Introduction of the tropolonic hydroxyl group was achieved with hydrazine hydrate in ethanol, to give a mixture of deacetylcolchiceinamides41 (53%)and 42 (37%),followed by reaction with ethanolic potassium hydroxide, which afforded tropolones 43 and 44, respectively. Tropolone 43 was converted to 44 which, therefore, became the major reaction product. Methylation of 44 gave a mixture of enol ether 18 and 45 which were separated by chromatography. Another synthesis of deacetamidocolchicine (18) was developed by Banwell according to a methodology used to synthesize 5-aryltropones (Fig. 22) (58,59). The Banwell synthesis shown in Fig. 14 starts with the tricyclic ketone 46, obtained by Robinson annelation of 2,3,4-trimethoxybenzocyclohepten-5-onewith methylvinylketone. Conversion of 46 to 47 was achieved via a-acetoxylation with manganese(II1) acetate and reaction with dichlorocarbene in a similar fashion as illustrated in Fig. 22 for the synthesis of the Banwell’s chlorophenyltropolone. The dichloride precursor of 47 failed to undergo ring opening with strong base. However, monochloride 47, obtained from the dichloride with zinc and KOH in refluxing ethanol, afforded directly, on treatment with 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) in benzene, deacetamidoisocolchicine (48) in 84% yield. Compound 48 was converted to 18, a key intermediate in the synthesis of colchicine (38). L H 3 CH,O 0 @

CHZ@ CH,O

CH,O

cH323 0

0

bCH,

46

42

0

OCH,

48

FIG. 14. Banwell synthesis of (2)-deacetamidoisocolchicine(48).

2. Monosecocolchicine

Attempts to prepare methoxy-substituted 1,3-diarylpropanes with an acetamido group in the side chain, anticipating that these secoallocolchicinoids would mimic the biological actions of colchicine, had already been

3. TROPOLONIC

151

COLCHICUM ALKALOIDS

explored by Lettr6 with negative results (60). A synthesis of seco compound 49 with disconnected rings A/C compared to colchicine was elaborated by Banwell and is shown in Fig. 15 (61). It was also hoped that compound 49 could be cyclized, but this step did not materialize. Dibromocyclopropene 50 was transformed to its lithiated derivative 51

P

49

FIG. 15. Banwell synthesis of monosecocolchicine (49).

152

OLIVIER BOY6 A N D ARNOLD BROSSI

which, on reaction with 3,4,5-trimethoxycinnamaldehyde (52) at low temperature, gave 53 as a mixture of diastereoisomers. Catalytic reduction followed by benzoylation of the alcohol and deprotection of the acetonide produced a mixture of diols 54. Regioselective elaboration of both isomers, including Swern oxidation, 0-methylation with dimethyl sulfate in the presence of potassium carbonate, and treatment with DBU in benzene, gave methyl ether 55. Replacement of the benzoate group in 55 with an acetamido group ultimately afforded secocolchicine (49). Compound 49 was devoid of activity in tubulin-binding assays, which is consistent with the notion that the ring A/C axis in colchicinoids and all0 congeners is essential for binding to tubulin. 3. Allocolchicinoids Treatment of (-)-colchicine (1)and (-)-isocolchicine with sodium methylate in refluxing methanol affords, by contraction of the tropolonic ring, (-)-allocolchicine (12) (Fig. 16) (15,62,63). (-)-Allocolchicine is a natural alkaloid with a benzenoid ring C instead of a tropolonic ring C as in colchicine (14). Allocolchicine (12)and the chemically related compounds allocolchiceine (56) (27), N-acetylcolchinol (57) (64), and its methyl ether 58 (65) have played an important role in the structure determination of colchicine, and 12 and 58 have served as standards to measure antitubulin activity in vitro (2a-4. Recently, alcohol 59 (mp 219-220 "C) was prepared in our laboratory by reduction of allocolchicine (12) with diisobutylaluminum hydride (DIBAL), and aldehyde 60 (mp 164-165°C) was obtained after oxidation of the alcohol with pyridinium chlorochromate. The preparation of compounds 59 and 60 is reported below.

(-)-(aS,7S)-mlchicine1

FIG. 16. Allocolchicinoids derived from natural colchicine (1).

3. TROPOLONIC COLCHICUM ALKALOIDS

153

Preparation of Allocolchinol 59. A solution of allocolchicine (3.0 g, 7.5 mmol) in tetrahydrofuran (THF) (40 ml) was cooled to 4°C and added dropwise with DIBAL (40 ml, 1.0 M solution in THF). The reaction mixture was stirred at 0-4°C for 2 hr and was quenched by adding methanol (20 ml). The resulting emulsion was added slowly to 1 N HCI (150 ml). The compound was extracted with CH2C12/MeOH(9 : 1). The organic layer was dried (Na2S04) and evaporated to give 59 as a powder which was recrystallized from methanol as white crystals (1.8 g, 67%): mp (dec.) >260"C; [a]D -68.4" [ O H , CHCI3/MeOH (9 : l)]; '€4-NMR (CDC13)6 1.86 (s, 3H, COCH3), 3.45 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.82 (s, 3H, OCH3),4.52 (m, 3H, 7-H, CH2),5.20(brs,IH, OH), 6.77 (s, lH, 4-H), 7.21 (d, J = 7.8 Hz, lH, Ph), 7.26 (d, J = 7.8 Hz, Ph), 8.41 (brd, lH, NH); CIMS m / z 372 (MH+). Preparation of Aldehyde 60. A solution of alcohol 59 (2.5 g, 2.6 rnrnol) and pyridinium chlorochromate (PCC) (927 rng) in CH2C12was stirred at room temperature for 1.5 hr. PCC was precipitated with ether. The brown precipitate was washed with CH2CI2/MeOH(9 : 1) and filtered on a short pad of Florisil. After evaporation of the filtrate, the crude residue was purified by chromatography on silica gel (CH2CI2/MeOH 98 : 2) to give 60 (1.8 g, 72%): mp 164-165°C; [a]D -199" (0.2, CHCI,); UV 308 nm; IR 1680 (C=O, aldehyde), 1650 (C=O, amide) cm-'; CIMS mlz 370 (MH+). Compounds of the allo series are much easier to access by total synthesis than their tropolonic counterparts, and this has recently attracted considerable attention. a. Macdonald Synthesis of ( 4 )-N-Acetylcolchinol. Phenylpropionaldehyde (61),prepared by conventional chemistry from the corresponding dihydrocinnamic acid, afforded, on reaction with tert-butyldimethylsilyloxyphenylmagnesium bromide, the alcohol 62.Alcohol 62 was reacted in a one-pot reaction with butyllithium, tosyl chloride, and sodium azide in THF to afford the azide 63. Reduction of 63 was difficult to accomplish but was finally achieved with PdlC catalyst in the presence of Florisil, affording the desired amine and, on acetylation, the amide 64. Nonphenolic oxidative coupling of 64 in the presence of freshly distilled boron trifluoride etherate gave (4)-N-acetylcolchinol (65)in 71% yield (66) (Fig. 17). Compound 65,except for being racemic, was found to be identical with the optically active material prepared from colchicine (65,67).Compound 65 showed the presence of a 3 : 1 mixture of rotamers. Although the synthesis of optically active material by this route seems feasible, this was not accomplished.

154

OLIVIER B O Y 6 A N D ARNOLD BROSSI

CH,O cH30*

O “C*H,O

/

OHC

OTBS

61

B

f3

a

R-OH R=N3 R-NHCOCH3

OH

§!i

FIG. 17. Macdonald synthesis of (?)-N-acetylcolchinol(65).

b. Boye-Brossi Synthesis of Dibenzo [a,c]cycloheptanes. Biphenyl-2carbaldehyde 66, with a methoxy substitution pattern analogous to that one found in N-acetylcolchinyl methyl ether (58), has proved to be a convenient intermediate in preparing tricyclic compounds through chain lengthening and acid-catalyzed ring closure (68). Propionic acid 67 was prepared from 66 by Wittig reaction with ethyl(diethoxyphosphory1)acetate, followed by reduction of the double bond and saponification of the intermediate ester (Fig. 18). Cyclization of 67, effected at room temperature with a 1 : 1 mixture of trifluoroacetic acid and trifluoroacetic anhydride, afforded a mixture of tricyclic ketone 68 (70%) and indanone 69 (30%). Both ketones were readily separated by chromatography. The yield of ketone 68 was significantly improved (>90%), by lowering the temperature of the reaction to 0°C. The carbonyl group in 68 could be removed by a Wolff-Kishner reduction, but this could be much better accomplished by first reducing the ketone to an alcohol with sodium borohydride in methanol, followed by thermal dehydration at 200°C and reduction of the olefin. These latter reactions are sketched in Fig. 19 for a series of analogs lacking one of the methoxy groups in the A ring. 1’,2’,3-Trimethoxybiphenylaldehyde 70 was obtained from pyruvic acid 71 in a classic series of reactions, including notably a Robinson annelation with methylvinylketone and an aromatization of the resulting cyclohexenone ring with Pd black at 210°C. The 2’,3’,3-trimethoxy isomer of 70 was obtained in a masked form as the oxazoline 72 following chemistry developed by Meyers (69). Deprotection of the aldehyde was made by quaternization with methylsulfonate and hydrolysis with oxalic acid. Chain lengthening and cyclization gave the corresponding ketones 73a (RI=R2=OCH3,R3=H) and 73b (Rz=R3=OCH3, RI=H). Reduction of ketones 73 to alcohols, dehydration of the latter at

3. TROPOLONIC COLCHICUM ALKALOIDS

155

cH30b -cH306

CH,O

CH,O

I

Vc"" OCH,

OCH,

66

CH,O

cH3@

&H,

€a 68% IR: 1675cm.' MS. 329 (MH') rrp: 107'C

QJ OCH,

I 30% IR: 1700cm.' MS: 329 (MH') mp: 145-146%

FIG.18. Boyk-Brossi synthesis of dibenzo[a.c]cycloheptan-5-one.

220°C in high vacuum, and catalytic reduction of the 5,6-olefins led to dibenzocycloheptanes 74 and 75, respectively. Dibenzocycloheptane 76 was obtained from ketone 68 by removal of the most hindered methoxy group at C-2 with sodium in refluxing 2-propano1, directly affording alcohol 77, which gave 76 after dehydration and reduction. Tricyclic compound 78 is the only compound which was prepared from an optically active natural precursor. For this (-)-N-acetylcolchinol (79) was converted to its phenyltetrazolyl ether and the latter reduced over Pd/C catalyst in acetic acid. Removal of the acetamido group was achieved after hydrolysis, N-methylation, Hofmann elimination, and reduction (69). The availability of ketone 68 made possible for the first time the introduction of an amide group at C-5 instead of C-7, as found in natural colchicine (1)and N-acetylcolchinyl methyl ether (58), and to study the effects of this modification on biological activity. The synthesis of the

156

cH303$

OLlVlER B O Y 6 A N D ARNOLD BROSSI

cH30y

CH,O

-

/

CH,O I'

,

coon

n

cH3 @ :

CHO

o

OCH,

\

/

/

OCH,

OCH,

\N

22

CH,O

'NHCOCH,

Rp=

I

fa

& =OCH3, R 1 = H

R.

RQ36

R

0

FIG. 19. Convergent approaches to dibenzocycloheptanes.

5-substituted derivatives is shown in Fig. 20. Ketone 68 was converted to the oxime and the latter reduced with hydrazine in ethanol in the presence of Raney nickel to afford the racemic amines (80A plus 80B). The racemic mixture was resolved into enantiomers with 0,O'-dibenzoyltartaric acids to give 80A and 80B, and acetamides 81A and 81B after acetylation. The absolute configurations shown in Fig. 20 were deduced by CD and 'HNMR analysis (69). The CD spectrum of 80A showed a strong negative

(&,5S)

(aR.59 (-)-5-iso-N-acetulcolchinyl methyl ether CH, c H0 'O %NH2

cCH,O H , o ~ H c o c H 3

t

OCH3 Raney Ni NzH4.H2O EtOH. 95OC

-

(-) Dibenzoykartariacki

,NHCOCH,

CH,O

CH,O

MeOH

6 -

0

OCH,

HPB

CHCb

\

OCH, (aS,5R) (+)-5-iso-N-acetylcolchinyl methyl ether

OCH,

FIG. 20. 5-Substituted analogs of N-acetylcolchinyl methyl ether

158

OLIVIER BOY6 A N D ARNOLD BROSSI

Cotton effect at 269 nm, suggesting that the biphenyl helicity was the same as for natural (-)-allocolchicine (12). However, with the displacement of the amino group in position C-5 instead of C-7, the priority order of the cY,cY'-substituentsof the central bond is changed, and an (aR)configuration has to be attributed to 80A according to IUPAC rules. The absolute configuration of the asymmetric carbon at C-5 was established using 'HNMR spectral data (69). Amine 80A has, therefore, the (aR,5S) absolute configuration, and so does the major conformer of 81A in methanol. Whereas amines 80A and 80B are stable in solution, acetamides 81A and 81B show a solvent-dependent equilibration between atropoisomers. These equilibrations can be measured by CD since the conversion of (aR)to (as)-configurated isomers in this series of compounds is accompanied by a reversal of the sign of the Cotton effects at 260 nm. Also, protons 5-H of the (aR)and (as) conformers could easily be distinguished in the 'HNMR spectra. 4. 2-Methoxy-5-aryltropones Although 2-methoxy-5-aryltropones lacking the B ring of colchicine are not true colchicinoids, they are discussed since some were found to be potent inhibitors of tubulin polymerization in uitro. (70). This has stimulated much interest in this type of compound as well as research to achieve their practical synthesis. A four-step synthesis, accomplished from 5-hydroxytropolone (82) (71,72)at the Smith Kline & French Laboratories, is shown in Fig. 21 (73). Reaction of 82 with triflic anhydride in the presence of 2,6-lutidine in dichloromethane at -30°C afforded the highly sensitive bistriflate 83. Monotriflate 84 was obtained by reaction of 83 with methanol in the presence of triethylamine at room temperature and was purified by flash chromatography on silica gel. Reaction of 84 with 2,3,4-trimethoxyphenylzinc chloride in the presence of tetrakis(tripheny1phospine)palladium cata-

P

FIG. 21. Smith Kline & French synthesis of 2-methoxy-5-aryltropones.

3. TROPOLONIC

159

COLCHICUM ALKALOIDS

lyst gave Fitzgerald’s aryltropone 85 in 43% yield. Similar reaction of other arylzinc chlorides with monotriflate 84 resulted in analogs of 85. Quite a different approach toward the synthesis of phenyltropones was developed by Banwell (74)(Fig. 22). a-Acetoxylation of the readily available trimethoxyphenylcyclohexenone 86 provided compound 87, which was converted by conventional chemistry to a mixture of diacetates 88. Dichlorocarbene addition to 88 followed by a base-promoted hydrolysis gave a mixture of diols 89. Swern-type oxidation of 89 with 3.1 mole equivalents of trifluoroacetic anhydride-activated dimethyl sulfoxide produced the free tropolone 90, and enol ether isomers 91 after methylation. The latter were separated by chromatography, and the structure of the enol ether with the natural tropolone arrangement was secured by X-ray analysis. Swern oxidation of 89 with 2.1 equivalents of oxidant afforded the hydroxyenone 92, which was 0-methylated to give 93. Treatment of 93 with DBU resulted in a rapid ring enlargement to the chloro-substituted

92 93

R-H R=Me

90

-

8-H

3 R

FIG. 22. Banwell synthesis of chlorophenyltropones.

Me + iso-isaner

160

OLIVIER BOY6 A N D ARNOLD BROSSI

phenyltropone 91, with an arrangement of the aromatic substituents corresponding to colchicine (59). 5 . Biphenyls Mimicking Rings A/C of Allocolchicinoids

The high in vitro potency of Fitzgerald’s phenyltropolone 85 and Banwell’s chloro analog 91 (for the naturallike isomer) in assays measuring antitubulin effects suggested that biphenyls, by mimicking rings A/C of allocolchicinoids, might similarly display such activities. It was shown that biphenyl 94 (Fig. 23), prepared together with isomers having the methoxy group in ring B in different positions, was the only compound which had substantial activity (75). This clearly pointed to the importance of the location of this methoxy group. The introduction of an alkyl group at C-2‘, hindering the rotation around the biphenyl axis, led to compounds 95 and 96. Compounds 95 and 96 were found to be similarly potent as 94, but the benzylamine 97, which was tested as its hydrochloride, was found to be completely inactive (76). Replacing the methoxy group at C-4’ in 94 by a carbomethoxy group led to ester 98, which was obtained in an Ullman in reaction of methyl 4-iodobenzoate and 1,2,3-trimethoxy-4-iodobenzene the presence of a copper catalyst (77a). Ester 98, which was found to be a potent inhibitor of microtubule assembly, and one of its isomers were studied by X-ray analysis (77b).A series of biphenyls similar to 94 and 98 were prepared by Australian investigators (78). The ethyl-substituted biphenyl 96 and its inactive benzylamine analog 97 were both analyzed by X-ray crystallography, and their conformations are shown in Fig. 24. It is seen that in biphenyl 96 the two aromatic rings are perpendicular, whereas 97 adopts a gauche orientation which is not suitable for binding to tubulin.

94 R = H

95

R=C&

92

R = CHflHCb . HCI

98

I R=CH&&

FIG. 23. Biphenyls active in antitubulin assays.

3.

TROPOLONIC COLCHICUM ALKALOIDS

a C(6,

161

P

FIG. 24. X-Ray structures and conformations of biphenyls % and 97.

V. Marking the Colchicine Binding Site on Tubulin Much research has been devoted to analyzing the process of binding of colchicine (79-84), allocochicine (85),and thiocolchicine (86,87)to tubulin by applying various physical methods. However, the data so far reported show that relatively little has changed since Dustin’s fundamental treatise, Microtubules, was published in 1978 (88). Colchicine binds to tubulin dimers of 100,000 daltons in a 1 : 1 stoichiometry at the same site as podophyllotoxin. Colchicine does not interact with intact microtubules, but rather binds with high specificity to free tubulin, possibly on the p subunit (89). The formation of the colchicine-tubulin complex prevents the formation of microtubules. A change in the torsion angle of the A/C rings of colchicine from approximately 53” to an essentially coplanar arrangement during the binding process has been calculated. An associated modi-

162

OLIVIER B O Y 6 A N D ARNOLD BROSSI

fication in the conformation of the protein is believed to be involved which would explain the blockage of microtubule elaboration. The exact location of the colchicine binding site on tubulin and the mechanism by which these spindle toxins interact with the protein on the molecular level are still not known. Focus is given here to investigations which were carried out with marker molecules designed to covalently interact with the protein by forming a marker-protein complex. Characterization of the complex by spectral methods, X-ray diffraction analysis, or amino acid sequencing were methods thought to solve the problem. Synthesis of spin-labeled colchicinoids (90) and allo congeners (91,92) gave relatively little useful information, except the finding that the sulfhydryl groups on tubulin reacted differently in the presence of colchicine (91). Synthesis of colchicinoids marked with the UV- and fluorescent-sensitive dihydrofiuorescein diacetate (DADF) label (33) and photolysis of 10-azido-10-demethoxycolchicine, which resulted in the photodecomposition of the molecule ( 4 3 , also did not give the expected information. Introduction of a chemically reactive group into the colchicine molecule has now been extended to isothiocyanato-labeled compounds, with the label expected to react covalently at the binding site. The introduction of the NCS group into the thiocolchicine molecule at C-4 and at C-7 afforded highly potent inhibitors of tubulin polymerization in v i m , but the compounds failed to react specifically with the colchicine binding site on tubulin (93).The synthesis of the more promising isothiocyanate 99, which was prepared with a I4C label in the methoxy group at C-2, is shown in Fig. 25 (94). Amine 100,available by Curtius rearrangement of allocolchiceine (56) with sodium azide (16), afforded on reaction with thiophosgene in

s

cH30G?, OCH.

CH30

C

t

% *,

;H

\

?

-

"*

NI-ICOCH,

"NHC :OCH,

NHCOCI'3

A

1p1 R-NHz R-NHCHO

A U 3Q4

99

R-NH-CHO R-NH2 R=NCS

FIG. 25. Synthesis of 14C-labeled9-isothiocyanato-9-deoxycolchinol.

3. TROPOLONIC

COLCHICUM ALKALOIDS

163

chloroform and aqueous sodium hydrogenocarbonate the crystalline isothiocyanate 99. To prepare the radioactive material, amine 100 was treated with concentrated sulfuric acid at 50°C to afford after work-up the aminophenol 101, and formamide 102 after reaction with ethyl formate. Selective hydrolysis of labeled formamide 103, obtained on methylation with [14C]methyliodide, was accomplished with 0.5 N hydrochloric acid. The resulting amine (104)was then reacted with thiophosgene to give radioactive isothiocyanate 99 (94). Cold isocyanate 99 was found to be a potent inhibitor of tubulin polymerization, which demonstrates its ability to bind to tubulin, but its potential as a specific marker of the colchicine binding site awaits the testing of the labeled material.

VI. Biological Activities of Colchicinoids and Allo Congeners Colchicine (1)and allocolchicine (12)are capable of binding to tubulin, preventing its assembly into microtubules. There are, however, pharmacological effects of these drugs which are unrelated to microtubule poisoning. To collect additional information regarding this point, several colchicinoids were tested for antimalarial activity in Plasmodium berghei clones and found inactive (95). There are reports that colchicine has an effect in anti-inflammatory disorders, such as phlebitis, which is unrelated to inhibition of microtubule assembly (96). Testing of several colchicinoids in assays measuring anti-inflammatory properties was undertaken. None of the colchicinoids, which included colchicine, cornigerine, speciosine, and 5,6-dehydrodeacetamidocolchicine,affected 5-lipoxygenase in vitro, an enzyme important in the metabolic conversion of arachidonic acid to leukotrienes (97). Inhibition of platelet aggregation, a crucial factor in ischemic disorders (98),was studied. The most active compounds in inhibiting platelet aggregation induced by adenosine 5’-phosphate, arachidonic acid, and collagen were those which were most active in inhibiting tubulin polymerization (99). However, assays measuring inhibition of carrageenin-induced footpad edema in rats after intramuscular (i.m.) injection of the drug into the site of inflammation, revealed, as shown in Table IV, considerable differences between compounds active as anti-inflammatories and as inhibitors of binding of radiolabeled colchicine (100). The unnatural 1demethylcolchicine, which is a relatively poor inhibitor of binding of radiolabeled colchicine (41), has a high anti-inflammatory activity in the assay, whereas thiocolchicine, which is one of the most potent spindle toxins (101), is not very active.

I64

OLIVIER BOY6 AND ARNOLD BROSSI TABLE IV ANTI-INFLAMMATORY ACTIVITY A N D ANTlTUBULlN EFFECTS OF SELECTED COLCHICINOIDS" Carrageenin edemah Compound

3 hr

5 hr

Antitubulin effect' (96)

Colchicine I-Demethylcolchicine N-Carbethox ydeacet ylcolchicine Thiocolchicine N-Pyruvyldeacetylcolchicine

44 30 13 26 2

53 46 20 23

90 26 86 96 78

19

" Six rats used per assay. Percent inhibition of swelling after i.m. application of drug suspended in Tyrode solution. ' Data on inhibition of binding of radiolabeled colchicine were taken from the literature (2u. 2 h )

There are several reports which extend the interaction of colchicine to proteins other than tubulin (102). Antibodies to colchicine, prepared by coupling deacetylcolchicine to serum albumin, showed that the antibody binding site tolerated numerous changes in the tropolonic moiety of colchicine and did not promote fluorescence, in contrast to tubulin (103). It appears that the antibody binding site for colchicine is a large domain which is less stringent toward chemical changes in the tropolonic C ring. Most therapeutic indications for colchicine, including gout, familial Mediterranean fever (FMF), and disorders of the liver, are, together with its activity against tumors, directly related to its inhibition of microtubule assembly (89,96).It is for this reason that in uitro assays measuring inhibition of binding of radiolabeled colchicine to tubulin (104,and inhibition of tubulin polymerization (10.51,were developed as primary screenings. Measuring in uiuo activity of compounds found active in the primary screenings was made using, notably, lymphocytic leukemia P388 infection in mice (41,101).The primary screening has now been amended with a new screening measuring activity against human tumor cell lines, which is hoped to be additionally helpful in selecting candidate compounds for clinical trials (106).The systematic effort to recognize the positions in the three rings of colchicine which could be altered without impairing binding of tubulin has continued in our NIH laboratories and now gives a more complete picture than that presented earlier (1,2b). Phenolic colchicines found as plant consituents and as metabolites ( 1 ) are less potent antitubulin compounds than their fully methylated analogs (Fig. 26). It can be seen that 10-SCH3 analogs of colchicines (thiocolchicines) were always more potent inhibitors of tubulin polymerization

3.

R = OCH3 R = SCH3

R = OCH3

R = SCH3

165

TROPOLONIC COLCHICUM ALKALOIDS

2.4 1.3

2.1 1.5

2.4') 1.3

2.9

2.0

3.5 2.0

FIG. 26. Comparison of tubulin binding afhities of naturual colchicinoids with thio congeners. ICso values ( p M )of inhibition of tubulin polymerization are given.

than their oxygenated analogs (Fig. 26). Thiocolchicine (105) is a better inhibitor than colchicine of cell growth and of tubulin polymerization, and it is bound more rapidly (107). Also shown in Fig. 27 is cornigerine (106), which is a natural alkaloid (1) and more potent than colchicine in L1210 murine leukemia cells assays and in assays of other drug-tubulin interactions (108). 3-Demethylthiocolchicine (1@7), indicated earlier to be a potent inhibitor of microtubule assembly, and possibly less toxic than colchicine (2a,b),continues to be a potential clinical candidate for a variety of disorders now treated with colchicine. Compound 107 was found as effective as colchicine in blocking amyloidogenesis, and doses 3 times higher than those of colchicine were tolerated (109). Esterification of phenolic colchicinoids and their thio congeners restored the original activity of the fully methylated analogs (46),as already observed by Santav? (110). The importance of the three methoxy groups in ring A of colchicine and that in the tropolonic ring C was recently explored in the allo series. Tetramethoxydibenzo[a,clcycloheptane (108) (Fig. 28), the basic tricyclic structure of allocolchicine (12), has potent antitubulin activity (68). A comparison of 108 with analogs 74,75,76, and 78 lacking one methoxy group (Fig. 19), showed only 76 to have modest activity in an assay measuring inhibition of tubulin polymerization (69). This result, together with the finding that (aR,7R)-(+)-colchicine (2a) and (aR)-(+)-

166

OLIVIER BOYE A N D ARNOLD BROSSI

105 ThDcoWliine

R = OCH, 3-DWllBlhykhWlchicine R = OH

1p6 Comigerine

FIG. 27. Highly potent inhibitors of tubulin polymerization.

deacetamidocolchicine (32) with a clockwise helical arrangement of ring A/C were inactive in assays measuring binding to tubulin, permits a summary of the molecular requirements of compounds related to colchicine as inhibitors of microtubule assembly as follows: I . Only colchicinoids with a counterclockwise configuration of the phenyltropolone backbone bind to tubulin. The clockwise enantiomers are inactive. 2. Thio congeners with a SCH3 group at C-10 of colchicinoids are always more potent than colchiceinamides with a N(R)2 group at this position, and the latter are more potent than the natural alkaloids with an OCH3 group. 3. Phenolic congeners of colchicine are less potent than the fully methylated alkaloids, and the activity decreases in the following order: colchicine > 3-demethylcolchicine > 2-demethylcolchicine > l-demethylcolchicine > 2,3-demethylcolchicine > 1,2-demethyIcolchicine > colchiceine. 4. Isocolchicine, having a reversed oxygen pattern in the tropolonic moiety, and colchicide, lacking the methoxy group in the C-ring, are both inactive. 5 . The acetamido group in colchicine is not necessary for binding (32), and it can be replaced without loss in potency with the following groups: NHCHO, NHCOCF3 (111), NHCOCH2F (112), NHCOCH2COCH3 (113), and NHCOCH20H (114). 6. Introduction of a carbaldehyde group at C-4 in thiocolchicine affords a highly potent compound (93). 7. Switching the acetamido group from C-7 to C-5 in the all0 series affords inactive compounds (69). 8. All oxygen atoms of the four methoxy groups are highly important as points of interaction with the binding site on tubulin (69).

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167

9. Zwitterionic compounds, with a phenolic group in ring A and a basic amino group at C-7, are always inactive (46).

FIG. 28. Hypothetical model of deacetamidocolchinyl methyl ether (108)interacting with two sites on tubulin.

In looking at these conclusions, one could speculate that rings A and C in these spindle toxins are most important, and they may bind to different loci on the colchicine binding site. It is suspected that two sites of tubulin which respectively bind to rings A and C of colchicine and its bioactive analogs are part of a polypeptide segment which is arranged in a helix, as shown in Fig. 28. Although the allocolchicinoidsallocolchicine (12)and N-acetylcolchinyl methyl ether (58) were found to be highly potent in uitro, their in uiuo activity in the P388 lymphocytic leukemia mouse screen, with TIC values of 114 for 12, and 108 for 58, at the highest doses, was much less than expected (115). It may well be that the isomerization of these compounds to inactive isomers which occurs much easier in the all0 series is the reason for the relatively weak in uiuo activity of the all0 compounds so far tested. N-Deacetylcolchicine (109)and N-deacetylcolchiceine(110)are analogs of colchicine which appear to be less toxic than the parsnt alkaloid, and for this reason they were investigated in some detail. It was shown that 110 decreased collagen production (1 16) and significantly inhibited formation of noncollagen proteins (117). The drug was also found to be a useful

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substitute for colchicine in gout (118)and in treating scleroderma (119) and cirrhosis of the liver (120). N-Deacetylcolchicine (109), on the other hand, was shown to be effective in melanoma (121) and in Hodgkin's disease (122). Some biochemical parameters measuring the effects of 109 and 110 in the blood and serum of rats after intraperitoneal (i.p.) injection and in liver homogenates were recently reported (123). It was found that 109 increased the activity of serum aspartate and serum alanine transferase, whereas 110 inhibited cytochrome P-450 activity in uitro and in uiuo. The structures of these analogs of colchicine, including that of demecolchine (lll),which was earlier clinically evaluated as antitumor agent, are shown in Fig. 29. Only one report on the metabolism of drugs related to colchicine has appeared (124).Demecolcine (lll),which has a biological activity similar to colchicine, is biotransformed by rat liver microsomal enzymes, and it is expected that this mimics its in uiuo transformation in humans. About 9% of the drug was metabolized in v i m , and 20% of the drug remained unchanged. In the absence of microsomal enzymes all of the drug remained unchanged. In using preparative TLC and HPLC it was demonstrated that the major metabolites were the 0-demethylated compounds 2-demethyldemecolcine, 3-demethyldemecolcine, and demecolceine. The 3-demethylated product was the major metabolite. This pattern of metabolic breakdown is similar to that observed earlier for colchicine (1,96). Formation of phenolic metabolites which are, as shown in Table V, less toxic than the parent drugs is obviously a mechanism of detoxification and excretion as conjugates.

1p9 R=CH3 Ilp R = H

FIG. 29. Clinically effective colchicinoids.

3.

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TROPOLONIC COLCHICUM ALKALOIDS

TABLE V ACUTETOXICITY OF A N D THlo CONGENERS"

A N T l T U B U L l N ACTIVITY A N D

Compound Colchicine 1-Demethylcolchicine 2-Demethylcolchicine 3-Demethylcolchicine Thiocolchicine

1-Demethylthiocolchicine

2-Demethylthiocolchicine 3-Demethylthiocolchicine

PHENOLIC COLCHICINOIDS

% Tubulin bindingh

LDroin mice (ma/knY

90 26 50 68 96 0

1.6 50 24 14.6

73 84

1 .o NTd 68 11.3

From Refs. 28,41, and 98. Percentage by which the binding of 13H]colchicine (2.5 p M )to tubulin from rat brain is reduced in the presence of the drug given at 25 pM. After i.p. administration. Not tested.

VII. Clinical Data There are several reports which suggest that colchicine might be useful in the treatment of liver disorders, particularly cirrhosis (125).Hyperprolinemia and hyperlactacidemia seen in cirrohotics were normalized in patients when orally treated with colchicine. Beneficial effects in treating cirrhotic animals and patients with colchicine (126) suggest that the drug lowers cholesterol, normalizes the fluidity of the plasma membrane, and decreases the cholesterol-phospholipid ratio (127). It was shown that colchicine is an excellent drug for an efficient liposome-hepatocyte interaction (128). After parenteral administration of colchicine incorporated into liposomes, the initial toxic peak was reduced and adequate levels of drug were maintained in the liver for several days. The encapsulated drug was more than 10 times as active as colchicine injected subcutaneously (s.c.) in inducing alkaline phosphatase in rats. Colchicine was recently found useful in the treatment of patients with amyloidosis, a disorder characterized by the deposition of protein in various organs and tissues (129).It was suggested that colchicine, acting on macrophages, may retard amyloid deposition by suppressing the production of angmyloid enhancing factor. Deacetylcolchicine (109), now in phase I1 clinical trials, has shown

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activity against Hodgkin’s lymphoma, chronic granulocytic leukemia, and melanoma. An assay to investigate the pharmacokinetics in patients using the drug permitted detection at less than 5 ng/ml in plasma, serum, or urine when administered at therapeutic doses (130). The method uses HPLC on a reversed-phase column, measuring UV absorbances at 254 and 350 nm. Therapeutically effective doses of colchicine in gout are 2-3 mg per patient on day 1 with smaller doses later, and 0.5-1 mg/day for 1-3 years given orally in familial Mediterranean fever (131). Side effects such as ileal dysfunction, decreased vitamin B12 absorption, and an increased absorption of steroids occur after intake of 7-10 mg/day, which if continued for 4-5 days result in dehydration and renal shutdown (96). The three congeners of allocolchicine,jerusalemine, salimine, and suhailamine, which all had (-)-rotations were isolated from Colchicum decaisnei Boiss. (141). VIII. Conclusions Practical synthesis of natural (aS,7S)-colchicineand its 3-demethyl analog remain a challenge for organic chemists. Variation of the structure of colchicine has led to several possibly less toxic analogs, such as deacetylcolchicine and 3-demethylthiocolchicine. Whereas the former can readily be applied in the form of water-soluble salts, the latter, which is not very soluble in water or commonly used solvents, requires study about its formulation. Information on the metabolism of colchicine and its analogs in humans is still inadequate. The same conclusion holds for the biosynthesis of colchicine, which lacks details in the construction of the tropolonic unit and in the formation of the acetamido group. The beneficial effects of colchicine reported in amyloidosis, familial Mediterranean fever, and cirrhosis, for which presently no good therapeutic agents are available, may stimulate interest in the development of one of its less toxic analogs, including phenyltropolones and biphenyls with proper substitution and proper axial chirality.

IX. Addendum The sugar alkaloid colchicoside and its synthetic sulfur analog thiocolchicoside were acylated with esters of trifluoroethanol and with isopropenylacetate in pyridine in the presence of the enzyme subtilisin from Bacillus subfilis (132). The 13C-NMR spectra of the ester alkaloids, which

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were isolated on silica gel with ethyl acetate-methanol-water solvent systems, allowed the characterization of the compounds as 6’-mono- and 3‘,6’-diesters. Particularly good yields of the 6’-mono ester were obtained with trifluoroethyl butyrate at 90°C. Reports that colchicine showed promising activity as an inhibitor of human immunodeficiency virus (HIV) replication (133,134) initiated the synthesis of derivatives of colchicine and thiocolchicine as potential inhibitors of HIV replication in H9 lymphocytic cells (135). Colchicine was found to be slightly active at nontoxic doses. All the other compounds, which were found inactive in this assay, were derivatives of colchiceine and/or N-deacetylcolchicine. It is well established that both of these structural changes reduce dramatically binding to tubulin, and the reported results are, therefore, not completely surprising. Treatment of colchicine and deacetycolchicine with a large excess of boron tribromide, followed by hydrolysis, afforded 1,2,3-tridemethylated compounds which were fully characterized (135). A series of phenyltropolones representing rings A/C of colchicine were prepared by crosscoupling of bromotropolones with various aryltrimethylstannates and arylboronic acids. They were tested for inhibition of tubulin polymerization in comparison with active standards (136). It was found that the methoxy group in the phenyl ring which corresponds to that at C-2 in colchicine was the least important and that the methoxy groups corresponding to those at C-1 and C-3 in colchicine were critical. This finding is in perfect agreement with recent data reported for tricyclic analogs of colchicine (69). Ultraviolet irradiation of the tritiated colchicine-tubulin complex led to direct photolabeling with low but, still, practical efficiency. The bulk of the labeling occurred on the p subunit of tubulin. Glycerol increased the p/a distribution. The possibility that the drugs bind at the interface between a and p subunits, and span this interface, and that both subunits may contribute to the binding site was suggested (137). Radiolabeled 3-demethyl-3-chloroacetylthiocolchicinewith a I4C label in the chloroacetyl moiety (DCTC) was found to be a potent inhibitor of tubulin polymerization and of colchicine binding to tubulin. The reaction was 80-90% inhibited in the presence of saturating-amounts of known antitubulin compounds such as podophyllotoxin, combretastatin A-4, and colchicine itself. The tubulin /3 subunit was labeled 5-6 times faster than the a subunit. Cyanogen bromide digestion of the p subunit which had reacted covalently with DCTC indicated that at least three positions in p-tubulin had reacted with DCTC. Purification and amino acid sequencing of these peptides are in progress (138). Phase I toxicity and pharmacology studies of deacetylcolchicine

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(TMCA) given orally daily for 5 days every 3 weeks were performed in 19 patients with advanced malignancies (139). Myelosuppression and mucositis were the major toxicities observed. Serum TMCA levels were monitored and appear to be useful in predicting toxicity. A partial response was seen in one lymphoma patient, and stabilization of disease was noted in two patients with prostatic or ovarian cancers. From a variety of 10-substituted analogs of colchicine it was found that 10-demethoxy-10-ethylcolchicinewas a good inhibitor of tubulin polymerization, suggesting that steric, rather than electronic, effects of the 10substituent are of importance for binding to tubulin (140).

Acknowledgments The authors would like to thank Drs. Anjum Muzzafar, Herman H. J. C. Yeh, and Ernest Hamel from the National Institutes of Health in Bethesda, Maryland, for their profound interest in the topic discussed and for splendid collaboration. We also would like to thank Drs. Hans-Ekart Radunz from the Pharmaceutical Division of E. Merck & Co., Inc., in Darmstadt, Germany, and Dr. Bernhard Witkop, Institute Scholar, for their help in finalizing this review.

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112. H. Lettrk, K. H. Donges, K. Bathold, andT. J. Fitzgerald, Liebigs Ann. Chem. 758,185 (172). 113. A. Muzaffar, A. Brossi, and E. Hamel, J . Nut. Prod. 53, 1021 (1990). 114. A. Brossi, P. N. Sharma, L. Atwell, A. E. Jacobson, M. A. Iorio, M. Molinari, and C. F. Chignell, J . Med. Chem. 26, 1365 (1983). 115. F. R. Quinn, National Cancer Institute, National Institutes of Health, personal communication. Allocolchicine was tested under the code number NSC 406042, and N acetylcolchinyl methyl ether was tested under the code number NSC 51046. 116. K. Tmovsky and S. Kopecky, Med. Exp. 15,322 (1966). 117. Z. Tmovska, D. Mikulova, and K. Tmovsky, Agents Actions 7,563 (1977). 118. S. Wallace, Semin. Arthritis Rheum. 3,369 (1974). 119. F. Gazarek, F. Santavy, M. Vykydal, V. Jorda, and E. Pegrimova, Acla Univ. Palacki. Olomouc. Fac. Med. 6 0 , 5 (1971). 120. D. Kershenobich, M. Uribe, G. I. Suarez, J. M. Mata, R. P. Tamayo, and M. Rojkind, Gastroenterology 77,532 (1979). 121. D. Stolinsky, E. Jacobs, J. Bateman, J. Hazen, J. Kuzma, D. Wood, and J. Steinfeld, Cancer Chemother. Rep. 51,25 (1967). 122. D. Stolinsky, E. Jacobs, L. Irwin, T. Pajak, and J. Bateman, Oncology 3, 151 (1976). 123. V. LukiC, 0.Gasic, M. R. Popovic, D. Walterova, and V. Simhnek, Proc. 5th I n t . Con$ Chem. Biotech. Biol. Active Nat. Prod., Varna, Bulgaria, Sept. 13-23, 1,392 (1989). 124. V. LukiC, D. Walterova, A. Husek, 0. Gasic, and V. S i m h e k , Acta Univ. Palacki. Olomouc. Fac. Med. 1u),429 (1988). 125. D. Kershenobich, G. Garcia-Tsao, S. Alvarez Saldana, and M. Rojkind, Gastroenterology 80, 1012 (1981). 126. M. Rojkind, M. Mourelle, and D. Kershenobich, “Myelofibrosis and the Biology of Connective Tissues,” p. 475. Alan R. Liss, New York, 1984. 127. P. Yahuaca, A. Amaya, M. Rojkind, and M. Mourelle, Lab. Invest. 53,541 (1985). 128. J. Cerbon, M. Noriega, and M. Rojkind, Biochem. Pharmcol. 35,3799 (1986). 129. J. P. Swyers, Res. Resour. Rep. 14, 5 (1990) [Publication by the US. Dept. of Health and Human Services, Washington, D.C.]. 130. R. J. KO, W. Y. Li, and R. T. Koda, J. Chromatogr. 525,411 (1990). 131. P. Bellet, Essaydali Sci. (Tunisia) 17, 5 (1985). 132. B. Danieli, P. De Bellis, G. Carrea, and S. Riva, Gazz. Chim. ltal. U1, 1 ( 1 9 9 1 ) . 133. R. Baum and R. Dagani, Chem. Eng. News No. 7 (June 26, 1989). 134. S. Read, M. Lions, H. Lee, and J. Zabriskie, 5th I n t . Conf. AIDS, Montreal, Canada, 1989, Abstr. p. 528. 135. H. Tatematsu, R. E. Kilikuskie, A. J. Corrigan, A. J. Bodner, and K. H. Lee, J. Nut. Prod. 54,632 (1991). 136. M. G. Banwell, J. M. Cameron, M. P. Collis, G. T. Crisp, R. W. Gable, E. Hamel, J. N. Lambert, M. F. Mackay, M. E. Reum, and J. A. Scoble, Aust. J. Chem. 44, (1991). 137. J. WOW, L. Knipling, H. J. Cahnmann, and G. Palumbo, Proc. Natl. Acad. Sci. U . S . A . 88,2820 (1991). 138. S . Grover, Z. Getahun, A. Muzzafar, A. Brossi, and E. Hamel, Abstracts of the 1991 meeting of ASCB. 139. E. Hu, R. KO, R. Koda, P. Rosen, S. Jeffers, M. Scholtz, and F. Muggia, Cancer Chemother, Pharmacol. 26,359 (1990). 140. M. E. Staretz and Susan B. Hastie, 4th Chem. Congr. North America, Med. Chem. Div., New York, August, 1991, Abstr. 16. 141. Musa H. Abu Zargo, S. S. Sabri, T. H. AI-Tel. A. U . Rahman, Z. Shah, and M. Feroz, J . Nut. Prod. 54,936 (1991).

-CHAPTER 4-

THE CEVANE GROUP OF VERATRUM ALKALOIDS JOHN V. GREENHILL Department of Chemistry University of Florida Gainesville. Florida 32611

PAULGRAYSHAN Process Research and Development Merck Ltd Poole, Dorset BH12 4 N N , England 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Synthetic Methods.. ............................................... 111. Tabulations of Verarrum Alkaloids. .................................. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

177 179

I86 23 I

I. Introduction Many of the alkaloids from Veratrum,Zygadenus and related genera are based on the cevane structure 1. The chemistry of the Veratrum alkaloids has been reviewed from time to time both in this treatise (1-3) and elsewhere (4-6). The most recent of these articles was published in 1973, and many new compounds have been discovered since then. Recent years have seen the announcement of many X-ray crystal structure determinations on these stereochemically complex alkaloids. A total synthesis has been reported for only one of the natural products, namely, verticine (7). The work that lead to this notable achievement has been reviewed (8).The pharmacology of both the alkaloids (9-12) and their synthetic derivatives (13) has been reviewed, although not since 1977. This chapter takes a different approach from previous reviews. The chemical reactions used for structure determination and modification are first summarized, but the main part of the chapter is a series of tables which include all the known cevane derivatives, both old and new. This is intended as a reference source for future workers in the field. The literature has been covered to the end of Volume 113 of Chemical Abstracts (1990). 177

THE ALKALOIDS, VOL. 41 Copyright 0 1992 by Academic Press. Inc. All rights of reproduction in any form reserved.

178

JOHN V . GREENHILL A N D PAUL GRAYSHAN 21

4

6 1

Two distinct groups of Veratrurn alkaloids were recognized as long ago as 1959, and with a few minor exceptions the division still holds (14). The jeveratrum alkamines have one to three oxygen atoms and occur free or as glucosides. Most members of this group are based on other parent structures, but those based on cevane are in Tables I through VIII. The ceveratrum alkylamines are all based on cevane, have seven to nine oxygen atoms, and usually occur as esters but have not been found as glycosides. A number of the compounds have attracted attention for their pharmacological activity, and some have been used clinically for the treatment of hypertension (9). Esters of the ceveratrum alkaloids zygadenilic acid (Table IX), zygadenine (Table x ) , sabine (Table XI), germine (Table XIII), veracevine (Table XV), and protoverine (Table XIX) have been shown to be hypotensive agents. Plant extracts containing them and partially purified alkaloids have been used on and off in the clinic since the midninteenth century (10). Most interest centered on protoveratrine (an isomer mixture) and later on protoveratrine A (Table XIX), which was used clincally for a number of years (15,16). However, the emergence of undesirable side effects-the drugs had to be withdrawn from many patients because of the powerful emetic properties-and the availability of alternative treatments have led to a reduction in interest during recent years (10). Veratrine, a mixture containing cevine (Table XIV), cevadine (Table XV), veratridine (Table XV), and sabadine (Table XI) are stated to be cardio-

4. CEVANE GROUP OF

VERATRUM ALKALOIDS

179

toxic (17). Veratridine is widely used in experimental pharmacology, as it binds to the sodium channel and keeps it permanently open and active (18). It has been suggested that three of the oxygen atoms of veratridine hydrogen bond to the &-aminogroup of lysine (19). Among other applications, some of these alkaloids have found important use as insecticides (11). A hexacyclic molecule with up to 17 chiral centers presents a considerable challenge to the structure chemist. Details of the methods used to assign structures appear in the reviews already cited, the most comprehensive of which are by Jeger and Prelog ( I ) and by Kupchan and By (2). Many of the structural assignments are now supported by X-ray crystallographic analyses of key compounds, including 3-acetylveramarine(20,21) (Table VIII), cevine (22) (Table XIV), chuanbeinone (23) (Table XXI), delavinone (24)(Table XXI), ebeiedine diacetate (25)(Table XXI), ebeienine (25) (Table XXI), imperialine (26) (Table V), isobaimonidine (27,28) (Table V), protoveratrine C (29)(Table XIX), shinonomenine (30) (Table XXI), tortifoline (31)(Table XXI), ussurienine (32) (Table XXI), veratrenone (33)(Table XXI), veratridine perchlorate (34)(Table XIV), verticine N-oxide (35) (Table V), verticinone hydrochloride (36)(Table V), verticinone methobromide (37)(Table V), and zygacine acetonide hydrochloride (38)(Table X). For imperaline it was shown that the D/E ring fusion is cis (26),although a review published subsequently still showed it as trans (39).

11. Synthetic Methods

The application of traditional chemical methods to structure determination in Veratrum alkaloids is next illustrated by reference to selected examples. Some recent structural work, not previously reviewed, is included at the end of this section. In Schemes 1 and 2 the preparations of various esters of germine (2) are shown. Reaction with acetic anhydride in pyridine at steam bath temperature results in esterification of secondary alcohol groups (3), but not the hemiketal or tertiary alcohol (40). With a more powerful catalyst, usually perchloric acid, the hemiketal is also esterified; in this example, the pentaacetate 4 results (41,42).A hemiacetal has been esterified in pyridine in only a few cases (43-46). Where an alkaloid has an a-hydroxyl group at both C-14 and C-15, treatment with acetone and a stroqg acid catalyst gives an acetonide, for example, 5. Acetic anhydride/pyridine then gives the 3,16-diacetate acetonide 6; the secondary alcohol group at C-7 is presumably hindered by the protective group. The acetone is removed by brief

180

JOHN V . GREENHILL A N D PAUL GRAYSHAN

L OH

AcO

OAc

f

/Lo.

SCHEME 1

4. CEVANE GROUP OF

181

VERATRUM ALKALOIDS

on 6

I

on

h

8

on

10

9

SCHEME 2

treatment with dilute acid to give germine-3,16-diacetate (7) (41). In another method, methanolysis at room temperature selectively deesterifies C-16 to give the monoacetate acetonide 8 which with dilute acid goes to germine-3-acetate 9. The ease of methanolysis shown by Verutrum alkaloid esters is a consequence of the tertiary amine group which basifies the medium (47). Neighboring group assistance may also be a factor in selective deesterifications (48,49).

182

JOHN V. GREENHILL A N D PAUL GRAYSHAN

The identity of various derivatives is established by periodate titrations

(41). Hydrolysis of the acetonide diacetate 6 by sulfuric acid in the

presence of 2,4-dinitrophenylhydrazine(DNP) gives a small yield of the 16-acetate10 (1). Also typical of the series, but not shown in the schemes, the C-7 alcohol group of compound 6 is oxidized to a ketone by chromium trioxide in pyridine (48,49). Attempts to prepare angelates by several routes all resulted in isomerization to give tiglates. An alternative route which allows unequivocal preparation of angelates identical with natural products is illustrated in Scheme 3. Veracevine (11)treated with 3-bromoangelolylchloride in pyridine gives the 3-monoester 12 which on hydrogenolysis over palladium gives the pure 3-angelate, cevadine (13) (50). Treatment of veracevine with alkali, or alkaline hydrolysis of its esters, can lead to one of two products. Brief boiling with dilute sodium hydroxide in methanol results in opening of the hemiketal bridge and preferential isomerization at C-5 to give the ketone cevagenine (14) where the trans A/B ring fusion prevents the formation of a hemiketal. Concentrated potassium hydroxide in ethanol produces a second inversion at C-5 and epimerization at C-3. The hemiketal reforms and the product, cevine (W), is the thermodynamically stable C-3 epimer of veracevine (11)(43). Compounds carrying three a-hydroxyl groups on ring D form orthoacetates with acetic anhydride under perchloric acid catalysis. For example, in Scheme 4, cevadine (W) gives the D-orthoacetate diacetate derivative 16. Mild alkaline hydrolysis selectively removes the simple ester groups but leaves the D-orthoacetate intact (17); more vigorous basic treatment completes the isomerization of ring A to give cevine Dorthoacetate (18). However, the A/B trans D-orthoacetate 17 can be induced to isomerize to the more stable C-orthoacetate in one of two ways. Dilute mineral acid at room temperature catalyzes this change to give 19. More surprisingly, simple esterfication with acetic anhydride in pyridine is accompanied by isomerization to the C-orthoacetate (20) (44). A similar series of reactions for cevine (W) has been studied (49). However, the derived D-orthoacetate triacetate was shown to come into equilibrium with “cevine tetraacetate” in aqueous acetic acid. Although the tetraacetate was isolated and characterized, it is not known which of the three tertiary alcohol groups of ring D carried the fourth acetate residue. More recently a third type of orthoester was produced (51) (Scheme 5). Germine (2) was treated with triethyl orthoacetate and p-toluenesulfonic acid in dimethyl sulfoxide (DMSO) to give neogermine B/C-orthoacetate (21) which could be isomerized with sodium methoxide at room temperature to the isogermine derivative (22). Similarly,germine-3,16-diacetate(7)

4. CEVANE GROUP OF

183

VERATRUM ALKALOIDS

12

13

OH

HO

on 11

on

KOH

no

no on

0 14

15

SCHEME 3

SCHEME 4

4. CEVANE GROUP OF

VERATRUM ALKALOIDS

2

22

23

SCHEME S

186

JOHN V . GREENHILL A N D PAUL GRAYSHAN

gave the B/C-orthoacetate diacetate 23, hydrolysis (AcOH,H20) of the orthoacetate group of which gave gerrnine-3,15,16-triacetate(24). The migration of the 7,9,14-orthoacetate group to give a 15-ester with concomitant restoration of the 4,9-hemiketal link proved to be characteristic of this series, and a possible mechanism for the rearrangement has been proposed (51). Triester 24 could be further esterified with acetic anhydride in pyridine to the tetraacetate 3. Treatment of 23 with phosgene followed by 2-propanol gave the 15-isopropylcarbonate25. Methanolysis removed the 16-acetate group, and dilute acid hydrolysis then gave germine-3,7diacetate-15-isopropylcarbonate(26) (Scheme 6) (51). Substitution of dimethylamine for the alcohol in this routine gave the analogous 15dimethylcarbamate. Veracevine (ll),cevine (W),or cevagenine (14)may be oxidized with bismuth oxide to the same 6-lactone (27)(45,52). This undergoes the simple reactions shown in Scheme 7 to give the other five-membered ring A derivatives 28-31. Two natural products (32,33)having five-membered A rings and &lactone structures have been isolated and are recorded along with their synthetic derivatives in Table IX. N-Bromosuccinimide(NBS) reacted with the free tertiary alcohol group of veracevine D-orthoacetate triacetate 34 to cause a (presumably) free radical insertion into ring F, giving the carbinolamine 35. Cevine Dorthoacetate triacetate similarly gave 36, which on alkaline hydrolysis gave 37 (see Table XVIII) (4733).Treatment of triacetylcevine with NBS gave 38 (47). Ketones in the germine series can be stereospecifically reduced to alcohols by sodium triacetoxyborohydride. The reagent, which is not powerful enough to reduce simple ketones, complexes with hydroxyl groups in the alkaloid molecule and delivers its hydride ion from one side of the carbonyl group. Solvolysis of germine-3-tosylate-14,Sacetonide (39)gives the rearranged ring A product 40. The new C-4 ketone group was reduced with sodium borohydride to the endo-alcohol but with sodium triacetoxyborohydride to the exo-alcohol(54). 111. Tabulations of Veruhurn Alkaloids

The tables are arranged in the order of lower to higher oxidation levels. Thus, the relevant jeveratrum alkaloids appear in the first eight tables and the ceveratrum derivatives in the following tables. Within each table the same rule applies: the least oxidized compound comes first and the most oxidized last.

4. CEVANE GROUP OF VERATRUM ALKALOIDS

23 1) c o c 1 2

2) 'PrOH

OH

AcO

25

2) aq. AcOH

OH

26

SCHEME 6

187

188

JOHN V. GREENHILL A N D PAUL GRAYSHAN

11 M 14 or IS

29

CH20H

m.p. 235.231'

l a l +Do ~ (EiOH) M

31

SCHEME 7

4. CEVANE GROUP OF

189

VERATRUM ALKALOIDS

OH

OAc

AcO

NBS

OAc

H

OAc

OAc

34

39

35

40

TABLE I KORSELIMINE GROUP

z

R'

No.

Compound

X

Y

R'

R2

41 42 43 44

Korselimine Diacetylkorselimine Sewerzine Korseveridinine Compound Korseveridine

a-OH a-OAc H2 H2 H2 H2

p-OH P-OAc p-OH a-OH WOAC P-OH

H H OH H H H

H H H OH OAC OH

Korseveridinone Korseliminedione

H2 H2 0

P-OAC 0 0

H H H

OAC OH H

45 46

47

48 49 a

Cf, Chloroform; Me,methanol. Py, PF'yridine.

Preparation

44,AczO.P~~

46,AczO,Py 44;46,CrOz,AcOH

mp PC)

[all3 (")

Refs.

282-284

-39.5, CfMel1:l"

55 55 56 57,58

290-292 HCI 325-326 HBr 314-315 HI 304-306 Me1 310-312 200-201 122-124

-49.3, 10% AcOH

5759.60

58

60

58,60 55

TABLE I1 KORSEVERILINE GROUP

No.

50

Y

X

Compound

Me-27

Preparation

H2

H2

a

66, NaOH, EG“

a-OH

a-OH

u-OAC

a-OAC

a a

51, A c ~ Of, i b 55, KOH, MeOH

51 52

Korseveramine

53

Korseveriline

a-OH

P-OH

a

54 55

KorseverilineN-oxide Severine

a-OAc

P-OH

a

56, KOH, MeOH

mp (“C)

[alo (“1

166- i67 HCI 180-182 HBr 308-309 Me1 290-291

Refs.

61

62 62 240-242 Me1 300-301 259-260 144-146

-15, Et

57,61

-20.9, CP‘

63 57,64 (continued)

TABLE I1 (Continrred) No. 56 57 58 59

Y

X

Me-27

P-OAC a-OH P-OH

a

P-OAC P-OAC P-OH

a a

Severtzidine

@-OH P-OAC P-OH

64 65 66

Korseverilinone Korseverilinedione

P-OAC a-OH 0

P-OAC 0

P

0

a

67

Severtzidinedione

0

0

P

61 62 63

Sewedarnine Sevedine Sevedine N-oxide Acetylsevedine

EG, Ethanediol. Py, Pyridine. ' Cf. Chloroform. Solvent not given.

Preparation 55, H202

CI-OAC P-OH P-OH

60

N

Compound Severine N-oxide

mp ("C)

[all3("1

255-257 172- 173

O.Od

60,Zn. AcOH

21 2-214

- 17.2, Cf

63 61 65

a a

Refs.

66,67 66

P

59, A c ~ OPy ,

63, A c ~ OPY ,

a

63, CrO,

202-204 244-245 HCI 224-226 222-223 217-218 HCI 335-336 HBr 322-323 HCI04 274-275 137- 139

-46.4, Cf

68 67 69,70

-18.8, Cf

69 70 61

69

TABLE I11 PETILININE GROUP

X Y No.

Compound

Y

X

Z

CID C-27

68

H2

Hz

Hz

Cis

a

69 petilinine

wOH. P-H

a-OH. P-H

Hz

Cis

a

70 Hupehenine 71 Hupeheninoside 72 73 Stenanzidine

a-OH. P-H a-OGlu, P-H a-OH. P-H a-H, P-OH

a-OH. P-H a-OH, P-H a-H. P-OH a-OH. P-H

Hz Hz H2 Hz

Cis Cis Cis NDh

p p

a a

Preparation 82,Huang Minlon

mp ("C)

[ a l ~ ( O ) Refs. 71

150-151

277-278 HCI 296-297 HBr 281-283 241-244 254-256 275-277

-9.6, MeICf" 71-73 74 - 17".

Et'

75 76 77

(continued)

TABLE I1 (Continued) No.

Compound

X

Y

Z

a-H, P-OAC a-H, P-OH a-H, P-OAC a-H, P-OGlu 0 a-0H.P-H a-H,P-OH a-H.P-OAc 0 0 0 a-H. P-OH a-H, P-OH a-OH, P-H a-OAc, P-H 0

CX-OAC.P-H a-H, P-OH a-H, P-OAC a-H, P-OH a-0H.P-H 0 0 0 0 0 0 a-H. p-OH a-OH, P-H a-H, P-OH a-H, P-OAc 0

H2 H2 H? Hz Hz H2 H2 H2 H2 H2 H2 a - H , P-OH a-H, p-OH a-OH. P-H a-OAc, P-H a-OH,P-H

CID C-27

Preparation

mp ("C)

[Q]D(")

Refs.

~

74 Diacetylstenanzidine 75 Harepermine 76

5

77 Hareperminside 78 Hupehenizine 79 Hupehenirine 80 Eduardine

81 82 83 Stenanzidinedione

84 Hypehenine 85 Edpetitidine 86 Edwardinine 87 Edpetisinine 88 89

I'

Cf. Chloroform; Me, methanol. C / D and DIE ring fusions not determined. El, Ethanol. Py, Pyridine.

ND" Cis Cis Cis Cis Cis Trans

a a

Cis ND" Cis

a

Cis Cis Cis Cis

193- 194

a a

P P P P

a

P

P P P P

80, A c ~ OPyd , 146-147 69, CrO, 226-228 174-176

87, C r 0 3

247-248 199-201 200-202

-45.6, Me

77 78 71 78 79 79 80,81 80 71,76 77 79 80 82 83 83 83

TABLE IV KORSELIDINE GROUP

Y

No. Compound

X

Y

R'

R

H-22

C-27

Ref.

90 Wanpeinine

a-H, P-OH a-H, P-OH a-H, p-OH a-H, P-OAC a-H, P-OH

wOH, P-H a-H, 0-OH a-H, p-OH a-H, P-OAC

H OH H H OH H

OH H OH OH H OH

P

P P

84,85 86

91 92 93 94 95

Ddafrine Korselidine Diacetylkorselidine Delafrinone Korselidinedione

0

0 0

a a a a a

a a

a a

87 87 86 87

TABLE V IMPERIALINEGROUP

W rn

Y No.

Name

X

H2 a-H,P-OH a-H,P-OH a-H,P-OAc 100 H2 101 0 102 NNHCONHZ 103 0 104 0 105 Isobaimonidine a-OH, P-H 106 Baimonidine a-OH, P-H 107 a-OAc, j3-H 108 Verticine a-H, P-OH %

97 98 99

Y H2 H2 H2 H2 0 H2 H2 H2 H2 a-OH. P-H a-H, P-OH a-H, P-OAc a-OH, P-H

D/E Unsaturation Trans Cis Trans Trans Trans Cis Cis Trans Trans Trans Trans Trans Trans

Preparation

123, NzH4, KOH 114, N2H4, KOH 117,N2H4, KOH A4,5

As.9

98, CrO,

123, Na, EtOH; Li, MeOH

mp ("C) 121-122 228-230 157-159 183 122-123 195- 196 240-242 170- 171 238-241 179- 182 139- 141 244-245

Refs.

[alo(")

88 89 88,90 88 88 89 89 7,88,90 91 -59.2, Cf" 92 -36.4, Cf 93,94 93 94 + 17.0, Cf 7,8,74,93, 95-99 ~

109 Verticine Noxide

-

3

110

a-OH, P-OAC a-OAc, P-H Trans

111 Isoverticine

a-H, P-OH

a-H, P-OH

112 1l3 112 N-oxide

a - ~p O , Ac

a-H, p-OAc Trans

114 Imperialine

a-H,P-OH

0

Trans

Cis

108,H202

HCI 310-312 HI04 279 HCNS 263-265 283-288(d)

123, NaBH4; H2, R

117-120 HCI 212 135-137'

206-214' 124 112,PhCO3H, AcOH, 229-230 H2S04 262-265

115 Imperialine Noxide 116 Verticinone

a-H,P-OH

0

Trans

117 Verticinone N-

116,H2OZ

oxide

118 119 Imperialone

a-H,P-OAc

0

0 0

120 Imperialone

NOH

0

dioxime 121 Verticindione

108, CrO3

"Cf, Chloroform. Me, Methanol. Inconsistent literature melting points. dSalt claimed but no mp given.

266-268 MeBr 268-270 212-213' 172- 175' HCld HI04 199 Me1 287 283-285(d)

+8.4, Meb 34,100 88.90 -45.0, Cf

84-86, 94 24,88,97,101 88 90

-40.4, Cf -48.2, Me

-54.5, Me

26,72,73,81, 95,102-1 08 72,73,109 25 24,84,85,88 93,94,96,110 36,40 90 37.100 100

114,CrO3, AcOH

NOH

Trans Cis Cis

173-174 237-238 HC104 246-249

37,88,93 89 89

0

Trans

108,111,Cr03

167- 168

88,93

TABLE VI KORSEVERINE GROUP

X Y No.

Name

X

Y

R'

R2

123 Korsidine

a-OH, 0-H a-OH,P-H

a-OH,P-H a-H,P-OH

H H

H H

l24 Korseverine 125 l26 127

a-H, 8-OH a-H,P-OAc 0 0

0 0 0 0

H H H H

H H H H

122 Korseverinine

Me-27

Preparation

mp CC)

[a],,(")

111

a

3 16-3 18

a

P P a

P

Refs.

0.0, 10% AcOH

76 39,112

W,ACZO,PY 123,CroS l24,C a 3 , AcOH

185- 187 215-217 223-224

112 76

I12

128 Edpetisidine 129 Korsine

a-OH,@-H a-H, P-OH OH H a - ~ , p - a~ - ~ , @ - O H H OH

a a

a-H,@-OH a-H,P-OH H a-H,@-OAc a-H,@-OAc H

a

131,KOH,MeOH

257-259 259-260 HCI 301-303 HBr 324-326 HI 292-294 Me1 273-275

-33.63, Me” 112,113 . +87.9, Etb 39,114

155-158 HC104 290-292

-68.2, Cf‘

l30 Korsine N-oxide W1 Korsinamine 132 “Me, Methanol. bEt, Ethanol. ‘Cf. Chloroform.

OAc OAC

Wl,ACzO,Py

115 116,117 114

TABLE VII VERALODINE GROUP

H

No.

Name

Unsaturation

133

w

135

A4.5

l36

137 138 139 140

Veralodine

A4.5

Veralodinone

Data from Ref. 118. bCf, Chloroform.

a

A4.5 A4.5

(“1

X

Y

2

Preparation

mp C‘C)

wH, P-OH 0 wH,p-OH a-H, P-OH a-H, P-OAC 0 0 0

a-H, P-OH 0 a-H, P-OH 0-H, P-OH a-H, P-OAC a-H, P-OH a-H,P-OAc 0

H2 H2 0 0 0 0 0 0

137, LiA1H4 133,Cr03 l38,LiAIH4 135, H2r Pt 136, A c ~ O Py ,

251-253 166-168 234-236

+14.5, Cfb

254-251 249-250

+%.4, Cf

138, A c ~ O Py , 138, Cr03

[alD

+16.4, Cf + 156, Cf

TABLE VIII

VERAMARINE GROUP

6 ~~

~~

2

No.

Name

141 142 143 144 145

Fritillarizine

146 147

X

Unsaturation

R

Preparation

mp ("(2)

85.6

a-0H.P-H a-0Ac.P-H a-OPh,P-H a-H,P-OH a-H,P-OAc

H H H H H

Dihydroveramarine

-

a-H, p-OH

OH

Veramarine

A5.6

a-H,P-OH

OH

A5.6

a-H, P-OAC

OH

147, AczO, Py

254-255

a-H, P-OAC a-H, P-OAC

OAC OAC

147, ACzO, Py 146, AczO, Py 146, Cr03, AcOH

208-2 1 1 192 Amorphous

A5.6 ~ 5 . 6 A5.6

Veraflorizine

148 149 150 151

A5.6

~ 5 . 6

-c -

~

"Cf, Chloroform. 'Et, Ethanol. Stereochemistry not specified.

0

0

147, HI, Pt,AcOH

[alo (")

142-143

-18.6, Cf"

175- 176 201-204

-91, Cf -88, Cf - 120, Etb -32, Cf -28, Et -85, Cf -71, Et -91, Cf -14, Et -58.3, Cf - 16, Cf - 129, Cf

Amorphous 119-122

Refs. 119,120 119,120 119,120 37,119-121 119,120 122,123 93.121-126 26,93,122,323 93,122,123 93 122,123

TABLE IX ZYGADENYLIC ACID&LACTONE GROUP

~~

No.

Name

32 152 153 33

Zygadenylic acid S-lactone

w

155 156 Solvent not given. bDi,Dioxane.

R2

R3

H H Acetonide Acetonide H H Acetonide H Ac H Ac

H H Ac An An Ac An

R‘

Preparation 32, acetone, HI 152, A c ~ O 33, acetone, HI 32, AczO, Py 33, AczO, PY

mp CC) 236-238 28 1 235-238 235 206 250-253 182

[fflD

(“)

-49” -43, Dib - 10.9, Di -43, Di

-32, Di

_____

Refs. 127,128 127,129 127 129 129 129 129

TABLE X ZYGADENINE GROUP

OH

No.

Name

157 Zygadenine

R1 H

RZ H

R' H

R4

Preparation"

H

158 Zygadenine acetonide H

Acetonide H

157,acetone, HI

159 Pseudozygadenine 160 Zygacine 161 Zygacine acetonide

H H H H Acetonide H H H H

157, EtONa

162 163

H' Ac Ac iB MB

H H H H H

160,acetone, HI 158,iBCI. Py;H,O+

mp P-3 218-220, HCI 231-234, HzS04 237-242 220-230, HCI 232-233, HI 292-295 169- 171 Amorphous 253-255 250 175

X ID 0

Refs.

-48.5, Cfb

130-136

- 17.0, CF

137,138

-33, Cf -22, Cf +2, Cf -4 -7.8

131 139.140 38,137,141 138 138 (continued)

TABLE X (Continued) No.

Name

R'

R2

R3

R4

Preparation"

mp C'C)

[aID

164 165 Angeloylzygadenine 166 167 168 169 Vanilloylzygadenine 170 Veratorylzygadenine

RMB An An Tig Bz Va Ve

H H H H H H Acetonide H H H H H H H H H H H H H

192-194 222-224 165, acetone, 6 N HCI HI 267-269 158,TigCI, Py;H30+ 229-232 157, BzCI, Py 220-225 258-259 169, CH2Nr;172, H 3 0 + 270-271

- 37

171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186

Ve TMG Ac Ac An An An Ve Ve Ve AC Ac' An An Ve Ve

Acetonide H H H H Acetonide H H H H Acetonide Acetonide H H Acetonide H AC H AC H Ac H Pr H Ac H Pr

158, VeCI, Py 158,TMGCI,Py;H30+ 174,H30+ 158, Ac20 166,Ac20;H30+ 177,H30+ 166, Pr20 171, Ac20 180,H30+ 171, Pr20 160,Ac20 159,A~2O,Py 165or175, Ac20 176, Pr20 170, Ac20 170, Pr20

- 17 - 17

H H Ac H Ac

Pr

Pr Ac

Pr Pr

AC AC Ac Pr Ac

Pr

240-245 181 255-257 271-272 187-190 224-226 228-230 102-104 220-223 195- 197 271-273 235-236 168- 170 2 10-2 I 3 175- 178 250-255

("1

-15, Cf -27.5, Cf -27.6, Cf; i-34, Py

-29, Py - 10 -34

Refs. 138 133,134,142,143 142,38 138 138 131 95,124,13/,133,139, 141,144-149 138 138 59 59 138 138 138 138

138 - 12

-28, Cf -33, Cf

138 137 131 138.142 138 138 138

IB, Isobutyryl; An, angeloyl; Bz, benzoyl; MB, (-)-2-methylbutyryl; RMB, (+)-2-methylbutyryl; Tig, tiglyl; TMG, trimethylgalloyl; Va, vanilloyl; Ve,

0 '

veratroyl. Cf, Chloroform. Attached carbon epimerized.

TABLE XI SABINEGROUP

R1O

R1O

R’

R2

R3

A

H

H

H

B

H

H

H

No.

Name

Formula

187

Sabine (neosabadine)

188 189

Sabine N-oxide Sabine orthoacetate

Preparation”

187, H202 194,20mMKOH, MeOH

mp CC) 173-176, HCI 230, HN03 298 2 10-215 305-310

[6lD (“1

Refs.

-33, Et”

150-152

+25, Cf“; +42, Et

I50 I52 (continued)

.

TABLE XI (Continued) No.

Name

Formula

R'

R2

R3

Preparation"

Sabadine (sabatine)

A A B

Ac Ac AC Ac AC

H Ac H Ac AC

H H AC Ac AC

194,MeOH, H20,20"C 189, Ac~O,20°C 1870r190,Ac20,Py 190,Ac2O,HCI04

195

B

Ac

Tig

Ac

1% 197

B B

AC AC

AC K

K AC

190 191 192 193 194

a

K,Ketone; Py. Pyridine; Tig, tiglyl. Et, Ethanol. Cf, Chloroform.

B B

190, TigCI, Py;Ac20, HC104 191,CrO3,AcOH 192,Cr03,A~OH

mp ("'2)

[61D (")

Refs.

256-258 274-275 248-25 I 221-222 255-257, HC104 244-245 252-259

-11, Et +72, Cf +105, Cf +9, Cf +94, Cf

151,152 152 152 152 150,152

+97, Cf

152

+57, Cf

152 152

255-258 212-2 14

TABLE XI1 ISOGERMINEGROUP

~~

No.

Name

198 199

Isogermine

200 201 202

Isoprotoverine

203 204 a

Et, Ethanol.

Py. Pyridine.

R'

R2

R3

H H

H H

H H

Ac H H Ac AC

H H OH OH Acetonide Acetonide OAC OAC

R4

R5

R6

H H Acetonide

H H

Acetonide H H Acetonide Acetonide H AC

Ac H H Ac AC

Preparation 2,NaOH 198, acetone, Hi or 5, MeOH, NaOH 199, Ac20, Py 293, NaOH 201, acetone, HI 202, Ac20, Py 201,A~2O,Py

mp(OC)

b]D(O)

Refs.

259-262 293-295

-46.5, Eta -34, Pyb

41,81,153.154 41

225-230 264 246-247 300-301 191

-56, Py

41 153,155,156 155 155 155

-42, -20, -31, -67,

Py Py Py Py

TABLE XI11 GERMINE GROUP

No.

p'

Name

R2

R3

R4

2 Germine 5 Germine acetonide 205 Pseudogermine 206 Pseudogermine acetonide 9 8 10 207

R5

R6

Preparation"

H H

H H

H H

H

H Acetonide

H H

H* H*

H H

H H

H

H Acetonide

H H

Ac Ac H MB

H H H H

H H H H

H

H Acetonide H H H H

mp("C)

[(YID

("1

H H Ac H

2, acetone, HCI 2, 20% KOH 205, acetone, HCI 8, H3Of 6, MeOH 6, DNP, HzS04 2, MBCl, Py

Refs. ~~

~

~~

~

220-225 235-239. HCI 275 205-208 237-239. HCI 283-284 219-22 1 259-262 225-227 236-238

+4, Etb; -15, Py'

+ 12, Et; + 11.4, Py +27, Et

+ 10, Py -19, Py -25.6, Py

38,41,140,153 157 40,153 40 41,158 41 41 155

m

H

H

H

209

210 211 39 7 6 212

An H H Ts Ac Ac Ac

H H H H H H H

H H H H H Tig H H V e H Acetonide H H H H Acetonide H H i B

H H H H Ac Ac H

213 Germidine

Ac

H

H

B

H

214 Neogerrnidine (isogermidine) 215 216 217 218 Germanidine

H

H

MB

H

Ac MB An An

H H H H

H H V e H H Tig H H A n H H M B

H H H H

219 220 Germerine 221 Neogermbudine 222 Germbudine 223 24 224

BAn HMB eDMB tDMB AMB Ac Ac

H H H H H H H

H H M B H H M B H H M B H H M B H H M B H H A c Ac H iB

H H H H H Ac H

Ac

H

M

H

M H

B

H

220 or 234, NaBH4

224-226

-21.5, Py

2, TigCI, Py

224-225 Amorphous

-7, PY -2.2. Cfd

6, H30+ 5, Ac20, PY 377, AcOH, H20

205-210 198 245-248

-4, PY +31.6,Py -9.6,Py

230-231

+13, Cf; -11, Py

221-223

-25, Cf; -60, Py

Amorphous 180- 181

+6.6,Cf +3,PY

210, MBCI, Py 219, H2/Pd or 232 MeOH 208, BAnCI, Py 234, MeOH 235, MeOH

221-222

30.3,Et

Amorphous 200-203 149- 152 160-164

+16, Et + 16,Cf; -1,Py -12, Py -7, PY

23, AcOH, H20 278, HCI

228-233

-21.2, Py -80.0, Py

14.159-161 162 163 124,164 52 41,165 166 50 42,125,155,166168 12.169 124,164 I63 162 144,163 I63 42,160,170-1 72 173-175 12,I 73,I 74 I 72 50 50 (continued)

TABLE XI11 (Continid)

No. 2 !0

Name

R'

R2

R3 R4

R'

R6

26

Ac

H

Ac

H

COOPr'

225

Ac

H

Ac

H

CONMe2 H

226 Neogermitrine 227 228 229

234 Germitrine

Ac Ac iB iB iB CYR An Tig HMB

H H H H H H H H H

Ac H H H H* H* Ac Ac Ac

H H H H H H H H H

MB Ve iB iB iB iB MB Tig MB

H Ac Me iB iB Me H H H

235

DMB

H

Ac

H

MB

H

230

231 232 Germanitrine 233 Maackinine

H

Reparation" 23, COC12, Py;

mp("C)

[ a h("1

Refs.

223-226

-57.1, Py

50

262-264

-65.5, Py

50

211, Ac20, Py

234-235 Amorphous

-77.3, Py -4.5, Et

218, A c ~ O

228-229

0, Cf; -61, Py

2 16-2 19

-4, Cf; -69, Py

12,144,176 164 52 52 52 52 144,162 134 42, 152, 160, 166, 177 175

Pr'OH; MeOH 23, COCl2, Py; Me2NH; MeOH

236, MeOH

236 Germitetrine 237 3

238 239 4

240

241 242 243

Germitetrone

244 t . l =

= 2 4 6

AMB MB Ac Ac* MB Ac

H

Ac H H Ac H Ac H Ac Ac Ac

H H H H H H

Ac Ac Ac

H H H

K K Ac

H

AMB

H

Ac

H

iB iB CyFY

H H H

H

MB HMB Ac Ac Ac Ac

H Acetonide H MB MB

K H i B K H i B H iB K

H

Ac AC 29Ac20,Py AC 2 0 5 , A ~ 2 O , P y AC 24?7,Ac2O,Py AC 2,AcZO. NaOAc, HC104 Ac 241,H30’ AC 69Cr03, Py K 224Cr03, AcOH K u6,Cfi3, AcOH Me iB Me

229-230

- 12,

Cf; -74, Py

260-261 190-210 257-259 285-287

-98, PY -59, PY -92, PY -65, Py

172,175.178 179 40,50 40 155 41,42,180

235-237 267-269 215-216

-68, Py -42, Py - 192, Py

41 41 12,180

222-223

- 167,4,

181 52 52 52

a AMB, eryfhro-3-Acetoxy-2-hydroxy-2-methylbutyryl: An, angeloyl: BAn, 3-bromoangeloyl: C y h . cyclopropyl; DNP, 2.4-dinitrophenylhydrazine; eDMB. i-)-ery~hro-2.3-dihydroxy-2-methylbutyryl:HMB. 2-hydroxy-2-methylbutyryl: iB, isobutyryl; K, ketone; MB, (-)-2-methylbutyryl; IDMB, (+)-rhreo-2,3dihydroxy-2methylbutyryl; Tig. tigloyl: Ts, tosyl; Ve. veratroyl.

’EL Ethanol. ‘Py, Pyridine. “Cf. Chloroform.

TABLE XIV CEVINEGROUP

k

N-4

OH

~

No.

Name

15 Cevine

R' H

R'

R3

H

H

Preparation" 1 1 , l 3 , 1 4 , o r 2 6 6 , K O H , EtOH

247 Cevine N-oxide 248

Ac

H

H

249

H

H

Ac 262, MeOH; HC104, AcOEt

250 251 252

RMB H Bz H H H

15,AcCI. KOH

H 15,KOH,RMBCl H 15,KOH,BzCl Bz 263,MeOH

[aID("1

mp ("C) 190

Me1 250-253 272-274 168-170 HCI 248-250 182-184, HC104 306-307 198-200 159- 161 194- 196

-29, Ath; -27.5, Cf'; - 18.9, Etd - 5 , Me'

Refs. 22,34,41,44,45,47, 137.182

-3.35, Et

44 183

+9.5, Et +10.5, Cf; +11, Et + 10.4, Et -22, Cf

45 45,184 45 183 45

253 254 255 256 257

258 259 260

261 262 263 264 265

W N

MOB Ve BVe TVe AVa TMG DBS ABS Ac Ac Bz AC AC

H H H H H H H H Ac H H AC AC

H H H H H H H H H Ac Bz AC K

lS,KOH,MOBCI 15,KOH,VeCl 11,BVeCl 255,T2, Pd 15,KOH,AVaCl lS,KOH,TMGCl 15,KOH,DBSCl lS,KOH,ABSCl 264,MeOHor,H2,Pt lS,KOH,AcCl lS,KOH,BzCl lS,AcZO,Py 261,CrO3

139- 140 147- I49 157

+11.6, Et + 12.5, Et

175- I76 152- 153 202-204 ]%-I97 275-278 214 202 307-308 279-280

+13.4, Et +8, Et +4.5, Et +9.6, Et + 14, At; +28, Et -5.7, Et +19, At; +23.7, Cf; +30, Et

183 183 185 i85 183 183

183 183

45.47,I84

183 183 45,46 184

a ABS, 4-Acetoxy-3-rnethoxybenzenesulfonyl; AVa, 4-acetoxy-3-methoxybenzoyl; BVe, 3-bromo-4,5-dimethoxybenzoyl; Bz, benzoyl; DBS, 3,4-dirnethoxybenzenesulfonyl; K, ketone; MOB,4-rnethoxybenzoyl; RMB (+)-2-methylbutyryl; TMG,trimethylgalloyl; Ve, Veratroyl; TVe, 3-tritioveratoryl. bAt, Acetone. Cf, Chloroform. dEt, Ethanol. ‘Me, Methanol.

TABLE XV VERACEVINE GROUP

~

No.

11 266

267

268 269

R’

Name Veracevine (protocevine) Cevacine

R2

R3

H

H

H

Ac MB (+)-MB RMB

H H H H

H H H H

Preparation“

267, MeOH or 12, NaOH, MeOH 11, AcCI, Py a,H2, Pd a,H2, Pd 11, RMBCI, Py,

c6H6

_______________

mp (“C) 220-225, HCIO., 228-230 205-201 222-223 190-192 198-200

[alo (“1

Refs.

-33, Cfb; -26, Et‘ -9.6, Et -27, Cf -0.69, Et +7.1, Et -23.8, Et

29,43,90,140,153 153 43,45 44 44 45

BAn An Va Ve

H H H H

H H H H

272 273 274 275 276

H Ac An RMB Ve

H Ac H H H

Ve H Ac RMB Ve

277 278

Ac An

AC AC

AC AC

12 l3

270 271

Cevadine Vanilloylveracevine Veratridine

11, BAnCI, Py

12, H2, Pd

11, VeCI, Py or 270, CH2N2

11,VeCI, Py

277, MeOH

l3, A c ~ O

11, (RMB)2O 11or 271 or 272,

Ve20, Py 11,A~2O,Py W,Ac2O,Py

Amorphous 209-21 1 257-258 170-178, HC104 259-260 173-174 286-287 225-228 273-274 224-225 239-241 258-260

-4, Et + 1 1 , Et

186

153,186,187

I88

-9.5, Cf -24.5, Cf +11.3, Et -27, Cf; +8, Et -5.5, Cf; +4.5, Et

]9,34,43,153,185, 187,44,45 45 45 189 45 45

-22, Cf -13, Et

43,44 43,48,189

+8.2, Et

TABLE XVI CEVAGENINE GROUP

No.

Name

14

Cevagenine (isoveracevine)

279

280 281

R’ H

R2

Preparation

mp (“C)

[ a h(“1

Refs.

H

13 or 271, NaOH, MeOH

241-242, HClOd 199-201 217-220 248-249 243 263-264

-47.8, Eta

43,44,190 44 44 44 45 45

Cevagenine N-oxide Cevagenine oxime RMBb Ac

282

Et, Ethanol.

’RMB, (*)-2-methylbutyryl. Cf, Chloroform.

H AC

14,RMBCI, Py 14, A c ~ O Py ,

-48.6, Et -42, Cf‘ -46, Et

TABLE XVII ORTHOACETATES CEVAGENINE, CEVINE,A N D VERACEVINE

ORz No.

Formula

R’

R2

A B B B B

a-OH P-OAnb WOAC 0-OAn

H H AC Ac

H H H H

P-OAn P-OAn

Ac H

Hd Ac

R3

0

B

Preparation

mp (“0

C [alD

(“1

Refs.

~

17

18 283 20 284

285 286

B B

16, KOH, MeOH 287, KOH, EtOH

284, NaOH, MeOH 287, MeOH 13, Ac20. HCIOI or 16, MeOH or 284, NaBH4 289,NaBH4 283,Ac20,Py

175-185 245-250 220-222 283-285 283-285, HCI 161-163 314-316 165- 170

+20, Eta +62, Et +91.4, Et + 104, Cf‘ t 7 3 , Cf; +79. Et +65, Cf +83, Cf

191 46 184,189 184 47,48,184, 189,192 47,192 184 (continued)

TABLE XVIl (Confinitedl ~

No.

R'

Formula

R2

R'

Preparation

mp ("C) 282-284 HC104 268-269

h)

34

B

p-OAc

Ac

Ac

11,319, or 323, Ac20, HC104

16

B

p-OAn

Ac

Ac

13,329, or 371, Ac20, HC104

288 289 19

B B C

a-OAC P-OAn H

AC Ac

K"

290

C

Ac

20,CrO',AcOH 284,Cr03,AcOH 20, KOH, EtOH or 285, KOH; HzS04 19,AczO, Py

L

m

Et, Ethanol. An, Angeloyl. Cf, Chloroform. Attached carbon epimerized. ' AcOH, Acetic acid. Me, Methanol. K, Ketone.

a

K H

AC

254-255. HCIO, 253-255 271-272. HC104 24 1-245 275-276 269-270 276-279 285-287

[UID (")

+ 127, AcOH';

+ I l l , Cf; + 118, AcOH; +I@, Me/ +77, Et

Refs. 45,46

43,45

+90, Cf

43,48,184

+98, Cf +59, Cf -10, Cf

184 184 47,191 , I 92

-4, Et

43,143

TABLE XVIII CARBINOLAMINES

R'O

No.

Formu1a

37

A B B

36 35

291 292

R2

R'

Preparation

mp C'C)

H

B

H* AcC Ac

Ac Ac

H Ac Ac

264, NBSa 35, KOH, EtOH 287, NBS 34, NBS

B

An

Ac

Ac

16, NBS

294-295 283-284 256-257 280-282, HC104 222-224, CH3I 244 259-260

NBS,N-Bromosuccinimide.

'FV,Pyridine.

Attached carbon epirnerized. Di, Dioxane. Cf, Chloroform.

R'

[alD

(")

Ref.

+33, Did

41 47 47 47

+42, Cf'

48

+5, P y b +3, PY +58,

PY

TABLE XIX PROTOVERINE GROUP

No.

Name

293

Protoverine

294 295 2% 297 298 299

Pseudoprotoverine

R2

R3

R4

R5

H

H

H

H

H

H

H

H

H

Acetonide

Hb

H

H

H

H

H H H H

H H H H

Ac iB iB H

H H H H

H H H H Acetonide H MB

R'

R6 H

H

R7 H H

H H H H H

Reparation"

345or346, NaOH, MeOH 293, acetone, HCI 201or293, 20% KOH, EtOH 293,AcCI,Py 298,H30+ 294, IBCI, Py 345,MeOH

mp ("c) 195-200

- 12, Py

243, HC1213 163- 17 1 180-190 219-222 270-27 1 218-220

Refs.

[ a l D (")

38,156,159 155,193 194

-15, Py -37, Py -2, PY -18, Py

195 I55 155 15

H Ac H H

H H H H

Ts Ac Ac Ac

H H H H

Acetonide Acetonide H Ac H H

309 310 311 312 313 314 315 316 317 318 319 31 321 322

H H iB iB iB H HMB Ac Ac H Ac Ac iB H H iB iB iB HMB

H H H H H H H H H H H H H

H H H H H H

Ac Ac iB iB H iB H Ac Ac Ac iB iB Ac Ac Ac iB Ac iB Ac

H H H H H H H H H H H H H Ac H H H H H

Acetonide H MB H H Acetonide H iB H iB H MB H H Acetonide H Ac H H Acetonide H Ac H MB H MB H Ac H iB H iB H MB

323

DMB

H

Ac

H

H

300 301 302

303

304 305 306 3@7

308

~

c!

MB

H H H Ac

294,TsCI, Py 312, MeOH 293,AcCl, Py 304 or 312, H30+ Ac 3l2,NaBH4 H 318, MeOH 307,H30+ H 294,iBC1, Py H 320, MeOH H H 293, iBCI, Py 345, MeOH H Ac 312, H30+ Ac 294, A c ~ O Py , Ac 303,AcCI, Py Ac 315, H,O+ , Ac 298, A c ~ O Py 302,iBCI, Py H H 246, HI04 Ac 303, MBCl, Py H 306,AcCI, Py H 296, iBC1, Py H 293,iBC1, Py H 345, MeOH; H,O+ H 346, MeOH; H30+

230-23 1 257-259 235-236 246-248 236-238 248-249 160-170 231-233 185-190 190-191 203-205 236-238 261-262 242-243 232-233 252-253 Amorphous 231-233 2 17-2 I9 165-168 Amorphous Amorphous 200-201, Me1 231-233 20 I -202

+ 10, Py

+26,4, -27, Py - 1 1 , Py -23, PY - 10, Py +24, Py -10, Py -34, Py -19, Py -4, PY +21, Py -18, Py -7, PY +21, PY -10, Py -46, Py -26, Py -7, PY -12, Py -11, Py -11, Py -8, PY

155 155 195

I55 155,196 I96 195

I55

195 195

15,125 155

I55 195 195 195 195 I5 196 I95 195 195

171,I 7 5 1 96 173,196,I97

(continued)

TABLE XIX (Continued) No.

Name

R2

R3 R4

R'

R6

R7

Preparation"

mp YC)

343 344 Escholerine

Ac Ac Ac Ac Ac Ac iB Ac Ac Ac iB iB iB iB Ac iB iB iB Ac BAn An

H H H H H H H H H H H H H H H H H H H H H

Ac Ac Ac Ac iB iB Ac Ac iB iB Ac Ac Ac iB iB Ac iB iB Ac Ac Ac

H iB Ac H Ac H Ac iB Ac iB Ac iB H Ac iB iB Ac iB H Ac Ac

H H H H H H H H H H H H H H H H H H H H H

Ac Ac iB iB Ac Ac Ac iB iB Ac iB Ac iB Ac iB iB iB Ac MB MB MB

Ac H H Ac H Ac H H H H H H Ac H H H H H Ac H H

311, AcCI, Py 353, MeOH 352,MeOH 311, IBCI, Py 354,MeOH 314, AcCI, Py 316,AczO, Py 355, MeOH 356,MeOH 357,MeOH 358,MeOH 359, MeOH 303,iBCI, Py 360,MeOH 362,MeOH 363,MeOH 364,MeOH 319,iBCl.P~ 3ll,MBCI,Py 317, BAnCl, Py 343, Hz, Pd

345

HMB

H

Ac

Ac

H

MB

H

235-236 243-244 248-249 228-229 265-266 111-179 249-250 252-253 231-238 221-228 222-223 214-216 Amorphous 262-263 Amorphous Amorphous 234-235 239-241 234-235 Amorphous 235, Picrate 260 210-21 1,

324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339

340

341 342

Protoveratrine A

346 Protoveratrine B

R'

tDMB

H

Ac

Ac

H

MB

H

HCI 238-239 268-270 HCI 242-244, Picrate 233

[~IDP) -1, PY -48, PY -40, PY -3, PY -41, Py -4, PY -39, PY -46, PY -46, Py -42, PY -42, Py -37, PY -16, PY -40, PY -38, PY -30, PY -46, PY

-4, PY

-4, PY -16, PY +7, Cf'; -30, Py - 10.5, Cf; -36, Py -3.5, Cf; -37, Py

Refs.

196 i95 I 95 195 I 95 195 195 195 195 I 95 I 95 195 195 195 195 195 195 195 15 198 198,199

14,15,125 * I 75, 200,201,202

14,15,18,173, I75 I93 ~

N

3

347 Protoveratrine C 348 349 350 351 352 353 354 355 356 357 358 359 360 361

eDMB TDMB HMB Ac Ac Ac Ac Ac Ac Ac Ac iB iB iB Ac

H H H Ac H H H H H H H H H H H

Ac Ac Ac Ac Ac Ac Ac iB Ac iB iB Ac Ac iB Ac

Ac Ac H Ac Ac Ac iB Ac iB Ac iB Ac iB Ac Ac

H H H H H H H H H H H H H H H

MB MB MB Ac Ac iB Ac Ac iB iB Ac iB Ac Ac MB

H H iB H Ac Ac Ac Ac Ac Ac Ac Ac Ac Ac Ac

346, TsCI, Py 366, H3O+ 368,MeOH 293,A c ~ O Py , 327, A c ~ O Py , 324,iBCI, Py w7, AczO, Py 311, iBCI, Py 309, Ac20, PY 329,iBCI, Py 336, A c ~ O Py , 3l3, iBCI, Py 306,Ac20, PY 299 or 327, Ac20,

258-260 214-217 235-236 259-260 257-258 258-259 257-259 219-220 224-225 254-255 Amorphous 259-260 Amorphous 2 10-2 12 262-263

-6.6 -22, Py -15, Py -65, Py -53, PY -46, Py -46, Py -51, Py -45, Py -49, Py -50, Py -48, Py -40, Py

-44,PY -46,PY

29 15 i96 155 155 195 195 195 I 95 I 95 195 I 95 I 95 I 95 I 95

362 363 364 365 366 367

Ac iB iB HMB HMB Ac

H H H H H H

iB Ac iB Ac Ac Ts

iB iB Ac Ac Ac Ac

H H H H H H

iB iB iB MB MB Ac

Ac Ac Ac Ac iB Ac

314,iBCI, Py 303, iBCI, Py 321, A c ~ O Py , 345, Ac20, Py 345,iB20, Py 300, H30+;

233-234 232-233 234-236 249-250 245-246 225-230

-39, Py -37, Py -44, PY -52, Py -41, Py -57, Py

195 195 195 15 15 155

368

Ac

Ac

Ac

Ac

H

Ac

Ac

293,Ac20,

28 1-282

-72, Py

155

369 370

HMB Ac

iB H

Ac Ac

Ac K

H H

MB H

iB Ac

2 10-2 15 217

-39, Py -46, Py

15 155

PY

Ac20, PY

HC104 345,iB20, HCIO4 371, H3O+

(continued)

TABLE XIX (Continued) No.

h)

!g

Name

R1

R2

R3

R4

R'

R6

371 372

Ac Ac

H H

Ac Ts

K K

Acetonide Acetonide

373 374 375 376 377

Ac HMB HMB TDMB Ac

H H H H Ac

AC AC Ac Ac Ac

K AC K Ac Ac

H H H H H

AC MB MB MB Ac

R7 Ac Ac

Preparation"

3U,CrO3,AcOH 300,Ac20,Py; Cr03, AcOH AC 324,Cr03,AcOH K 345,CrO3, Py iB 349,Cr03, AcOH K 348,Cr03,AcOH K 350,CrOl.AcOH

mprc)

Refs.

[alDr)

261-262 215-216

-32,Py -69, Py

155 155

228-229 221-223 239-241 194-197 194-195

-39,Py -97,Py -47,Py -66, Py -128, Py

196 15

196

I5

155

An, Angeloyl; BAn, 3-bromoangeloyl; DMB, 2.3-dihydroxy-2-methylbutyryl; eDMB, (+)-eryrhro-2,3-dihydroxy-2-methylbutyryl;HMB, 2-hydroxy-2methylbutyryl; iB, isobutyryl; K, ketone; MB (-)-2-methylbutyryl; F'y, pyridine; tDMB, (+)-fhreo-2,3dihydroxy-2-methylbutyryl;TDMB, 2-hydroxy-2-methyl-3-ptoluenesulfonylbutyryl; Ts, p-toluenesulfonyl. * Attached carbon epimerized. Cf, Chloroform.

TABLE XX

RINGB/C ORTHOESTERSO

R'O

N N bl

No.

R'

R2

R3

R4

AIB

Preparation

mp CC)

H H Ac Ac Ac Ac COPr' Ac Ac Ac Ac

Me Me Pr ' Me Me Pr ' Me Me Me Me Me

H H H COPr' H H COPr' COPr' COOPr' CONMez CONMe2

H H H H Ac Ac H Ac Ac Ac H

Cis Trans Cis Cis Cis Cis Trans Cis Cis Cis Cis

2, MeCH(OEt),, TsOH, DMSO 21 or 23, MeONa, MeOH 380, MeOH 382, MeOH 7, MeCH(OE03, TsOH, DMSO 7, Pr'CH(OEt),, TsOH, DMSO 22, Pr'COCI, 23, (PriCO)ZO,Py 23, COCIz;Pr'OH 23, COCl2;Me1NH 383,second fraction from above

168- 175 266-267

[alD

c), py

~

21 22 378 379 23

380 381 382 25

383 384

Data from Ref. 51.

2 19-220 180- 18 1

-62.9 -54.8 -62.4 -66.3 -83 -72.9 -58.8 -76.9 -50.6

0

z

R' = OH, R2 = H Delavine (24) mp 182-183°C [a]D-20.0" (Cf) R',R* = 0 Sinpeinine (203) [Delavinone (24)] mp 182-184°C HCI 217-219°C [a]D-54" (Cf)

X = a-H, /3-OH; R = a-Me Ebeiedine (25) mp 118-120"C; [a]D-37.9" (Cf) diacetate mp 143.5-146°C X = 0 Ebeiedinone (25) mp 102-105°C [a]D-62.2" (Cf) acetate mp 88-91.5"C

N N 4

HO Cordiline (204)

RO

H

OR R

R

= =

H Ebeienine (25) Ac (25) (conriniied)

TABLE XXI (Continued)

Edpetisidinine (205) mp 263-265°C [Q]~ 15.3" (Me/Cf, 9 : 1 )

Ziebeimine (206)

N N m

OR

R = H Stenanzamine (207) R = Ac (partial structures published)

R = H Heilonine (208) mp 284-286°C R = Ac mp 243-246°C [Q]D +34" (Cf

Pingbeinone (208) mp 200-202" [a]D -22" (Cf) H

Seveline (209) mp 267-269°C [aid -48.8" (EtCf,1 : I)

h X = a-H, &OH; R = H Ussuriedine (32,210) mp 190-193"C;[a]D + 19"(Cf) X = 0;R = H Ussuriedinone rnp 268-272°C;[ a ] +12" ~ (Cf) X = a-H, p-OH; R = Me Ussurienine mp > 300°C;[a]D +20° (Cf) X = 0;R = Me Ussunenone rnp 110-116"C;[a]D +8" (Cf)

Veratrenone (33)

(continued)

4. CEVANE GROUP OF VERATRUM ALKALOIDS

23 1

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234

JOHN V. GREENHILL AND PAUL GRAYSHAN

92. K. Kaneko, N. Naruse, K. Haruki, and H. Mitsuhashi, Chem. Pharm. Bull. 28, 1345 ( 1980). 93. S. Ito, T. Ogino, and J. Tomko, Collect. Czech. Chem. Commun. 33,4429 (1968). 94. K. Kaneko, M. Tanaka, H. Haruki, N. Naruse, and H. Mitsuhashi, Tetrahedron Lett. 39,3737 (1979). 95. A. Stoll and E. Seebeck, Helv. Chim. Acta 36, 1570 (1953). 96. J. Kitajima, T. Komori, T. Kawasaki, and H. R. Schulton, Phytochemistry 21, 187 (1982). 97. R. N. Nuriddinov and S. Yu Yusunov, Khim. Prir. Soedin., 458 (1971); Chem. Nat. Compd. (Engl. Transl.) 7,435 (1971). 98. A. Nabiev, I. Nakhatov, R. Shakirov, and S. Yu Yunusov, Khim. Prir. Soedin., 528 (1982); Chem. Nat. Compd. (Engl. Transl.) 18, 502 (1982); Chem. Abstr. 98, 198586 ( 1983). 99. I. MasterovaandJ. Tomko, Chem. Zvesti32,116(1978); Chem. Abstr. 89,20324(1978). 100. J. Kitajima, N. Noda, Y. Ida, K. Miyahara, and T. Kawasaki, Heterocycles 15, 791 (1981). 101. R. N. Nuriddinov and S. Yu Yunusov, Khim. Prir. Soedin., 458 (1971); Chem. Nat. Compd. (Engl. Transl.) 7,435 (1971). 102. H. G. Boit, Chem. Ber. 87,472 (1954). 103. A. Chattajee, K. P. Dhara, C. Pascard, and T. Prange, TetrahedronLett., 2903 (1976). 104. D. Xu, B. Zhang, W. Huang, Y. Qi, and J. Ma, Zhongcaoyao 13, 337 (1982); Chem. Abstr. 98, 14329 (1983). 105. D. Xu, B. Zhang, Y. Qi. and Ma, Zhongcaoyao 14,55 (1983); Chem. Abstr. 98,212853 ( 1983). 106. D. Xu, B. Zhang, H. Li, and M. Xu, Yaoxue Xuebao 17,355 (1982); Chem. Abstr. 97, 107068 (1982). 107. K. Samikov, R. Shakirov, and S. Yu Yunusov, Khim. Prir. Soedin., 350 (1979);Chem. Nat. Compd. (Engl. Transl.) 15, 303 (1979); Chem. Abstr. 91,207406 (1979). 108. G. P. Moiseeva, R. Shakirov, and D. Yu Yunusov, Khim. Prir. Soedin., 630 (1976). 109. A. Nabiev, R. Shakirov, and S. Yu Yunusov, Khim. Prir. Soedin., 676 (1976); Chem. Abstr. 86, 136313 (1977). 110. M. Xu, D. Xu, E. Huang, and W. Zheng, Zhongyao Tongbao 13,480 (1988); Chem. Abstr. 110, 101564 (1989). 1 11. R. N. Nuriddinov and S. Yu Yunusov, Khim. Prir. Soedin. 7,767 (1971); Chem. Abstr. 76, 141110 (1972). 112. R. N. Nuriddinov and S. Yu Yunusov, Khim. Prir. Soedin., 390 (1968); Chem. Nat. Compd. (Engl. Transl.) 4,332 (1968). 113. R. Shakirov, A. Nabiev, and S. Yu Yunusov, Khim. Prir. Soedin., 416 (1978); Chem. Nat. Compd. (Engl. Transl.) 14, 357 (1978); Chem. Abstr. 90,23341 (1979). 114. R. N. Nuriddinov, A. I. Saidkhodzhaev, and S. Yu Yunusov, Khim. Prir. Soedin., 161 (1968); Chem. Nat. Compd. (Engl. Transl.) 4, 139 (1968). 115. K. Samikov, R. Shakirov, and S. Yu Yunusov, Khim. Prir. Soedin., 251 (1986); Chem. Abstr. 105,206273 (1986). 116. K. Samikov, R.Shakirov, and S. Yu Yunusov, Khim. Prir. Soedin., 233 (1978); Chem. Nat. Compd. (Engl. Transl.) 14, 192 (1978); Chem. Abstr. 89, 197795 (1978). 117. K. Samikov, R. Shakirov, V. V. Kul’kova, and S. Yu Yunusov, F.E.C.S. Int. Conf. Chem. Biotechnol. Biol. Act. Nat. Prod. (Proc.)4,397 (1985);Chem. Abstr. 109,208291 (1988). 118. K. Samikov, R. Shakirov, and S. Yu Yunusov, Khim. Prir. Soedin. 8,770 (1972). 119. K . Kaneko, N. Kawamura, T. Kuribayashi, M. Tanaka, H. Mitsuhashi, and H. Koyama, Tetrahedron Lett., 4801 (1978).

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120. K. Kaneko, N . Naruse, M. Tanaka, N. Yoshida, and H. Mitsuhashi, Chem. Pharm. Bull. 28, 3711 (1980). 121. K . Kaneko, M. Tanaka, K. Haruki, N. Naruse, and H. Mitsuhashi, Tetrahedron Lett., 3737 (1979). 122. J. Tomko, Z. Voticky, H. Budzikiewicz, and L. J. Durham, Collect. Czech. Chem. Commun. 30,3320 (1%5). 123. J. Tomko and A. Vassova, Pharmazie 20,385 (1965). 124. K. Kaneko, M. Tanaka, T. Kuribayashi, H . Mitsuhashi, and J. Tomko, Collect. Czech. Chem. Commun. 48,2840 (1983). 125. J. Tomko and A. Vassova, Farm Obz. 50, 115 (1981); Chem. Absrr. 94,205391 (1981). 126. N . V. Bondarenko, Khim.Prir. Soedin., 415 (1979); Chem. Nut. Compd. (Engl. Transl.) 15, 366 (1979); Chem. Abstr. 91,207412 (1979). 127. B. Shimizu, Yakugaku Zasshi79,993 (1959); Chem. Abstr. 54,5724 (1960). 128. B. Shimizu, Yakugaku Zasshi78,444 (1958); Chem. Abstr. 52, 17314 (1958). 129. A. Yagi and T. Kawasaki, Chem. Pharm. Bull. 10,519 (1962). 130. F. W. Hey1 and M. E. Herr, J. A m . Chem. Soc. 71, 1751 (1949). 131. S. M. Kupchan and C. V. Deliwala, J. A m . Chem. SOC.75, 1025 (1953). 132. A. Yagi and T. Kawasaki, Yakugaku Zasshi 82, 210 (1962); Chem. Abstr. 58, 5748 ( 1963). 133. G. Liang and N. Sun, Yaoxue Xuebao 19, 131 (1984);Chem. Abstr. 101,97524 (1984). 134. W. Zhao, Y. Tezuka, T. Kikuchi, J. Chen, and Y. Guo, Chem. Pharm. Bull. 37,2920 (1989). 135. I. K. To, Y. Dezuka, and T. Kikuchi, Wakan Iyaku Gakkaishi 5, 382 (1988); Chem. Abstr. 111, 102595 (1989). 136. G. Liang and N. Sun, Youji Huaxue, 37 (1984); Chem. Abstr. 101,55412 (1984). 137. S. M. Kupchan, D. Lavie, and R. D. Zonis. J. Am. Chem. Sor. 77,689 (1955). 138. B. Shimizu, Yakugaku Zasshi80,32 (1960); Chem. Abstr. 54, 12178 (1960). 139. S. M. Kupchan, C. V. Deliwala, and R. D. Zonis, J. Am. Chem. SOC.77,755 (1955). 140. F. A. Carey, W. C. Hutton, and J. C. Schmidt, Org. Magn. Reson. 14, 141 (1980). 141. B. Shimizu, Yukugaku Zasshi 79,609 (1959): Chem. Abstr. 53,22050 (1959). 142. M. Suzuki, Y. Murase, R. Hayashi, and N. Sanpei, Yakugaku Zasshi 79, 619 (1959); Chem. Abstr. 53,22050 (1959). 143. W. Zhao, J. Chen, Y. Guo, and L. Xu, Zhongyuo Tongbao 11,294(1986); Chem. Abstr. 105, 39404 (1986). 144. M. W . Klohs, M. D. Draper, F. Keller, S. Koster, W. Malesh, and F. J. Petracek, J. A m . Chem. SOC.75,4925 (1953). 145. Z. Jia, W. Li, Y. Li, L . Yang, and Z. Zhu, Lanzhou. Daxue Xuebao, Ziran Kexueban 19,203 (1983); Chem. Abstr. 100,99912 (1984). 146. K. Kaneko, H. Mitsuhashi, K. Hirayama, and N. Yoshida. Phytochemistry 9, 2489 ( 1970). 147. N . V. Bondarenko, Khim. Prir. Soedin., 527 (1981);Chem. Abstr. 96,65653 (1982). 148. D. Graneai, J. Meckova, V. Suchy, and J. Tomko, Chem. Zuesti33,547 (1979);Chem. Abstr. 92, 72733 (1980). 149. E. M. Taskhanova and R. Shakirov, Khim. Prir. Soedin., 404 (1981); Chem. Abstr. 95, 147138 (1981). 150. H. Auterhoff and H. Mohrle, Arch. Pharm. (Weinheim. Ger.) 291, 288 (1958); Chem. Absrr. 54,6785 (1960). 151. H. Mitchner and L. M. Parks,, J. Am. Pharm. Assoc. Sci. Ed. 48, 303 (1959). 152. S. M. Kupchan, N. Gruenfeld, and N. Katsui, J. Med. Pharm. Chem. 5,690 (1%2). 153. S. W. Pelletier and W. A. Jacobs, J. Am. Chem. SOC.75,3248 (1953). 154. L. C. Craig and W. A. Jacobs, J . Biol. Chem. 149,451 (1943).

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155. S. M. Kupchan, C. I. Ayres, M. Neeman, R. H. Hensler, T. Masamune, and S. Rajagopalan, J. Am. Chem. SOC.82,2242 (1960). 156. W. A. Jacobs and L. C. Craig, J. Biol. Chem. 149, 271 (1943). 157. L. C. Craig and W. A. Jacobs, J. Biol. Chem. 148,57 (1943). 158. F. L. Weisenborn and J. W. Bolger, J . Am. Chem. SOC.76, 5543 (1954). 159. S. M. Kupchan and N. Gruenfeld, J. Am. Pharm. Assoc. Sci. Ed. 48,737 (1959). 160. N. V. Bondarenko, Khim. Prir. Soedin. 9,54 (1973). 161. I. Nakhatov, R. Shakirov, and S. Yu Yunusov, Khim. Prir. Soedin., I18 (1983);Chem. Nat. Compd. (Engl. Transl.) 19, 120 (1983); Chem. Abstr. 99,71047 (1983). 162. C. Yang, R. Liu, J. Zhou, Z. Cui, F. Ni. and Y. Yang, Yunnan Zhiwu Yanjiu 9, 359 (1987); Chem. Abstr. 108, 147145 (1988). 163. S. M. Kupchan and A. Afonso, J. Am. Pharm. Assoc. Sci. Ed. 48,731 (1959). 164. J. Tomko and A. Vassova, Chem. Zvesti 25,69 (1971). 165. E. M. Cohen, R. Aczel, M. L. Torchiana, R. Tull, and E. J. J. Grabowskii, J. Med. Chem. 17,769 (1974). 166. F. L. Weisenborn, J. W. Bolger, D. B. Rosen, L. T. Mann, L . Johnson, and H. L . Holmes, J. Am. Chem. SOC.76, 1792 (1954). 167. A. L. Shirkarenko and N. V. Bondarenko, Khim. Prir. Soedin. 2, 293 (1966); Chem. Absrr. 65, 20509 (1966). 168. A. L. Shirkarenko and N. V. Bondarenko, Rasrit. Resur. 2,45 (1966);Chem. Abstr. 65, 9343 (1966). 169. S . M. Kupchan and C. V. Deliwala, J. Am. Chem. SOC.74,3202 (1952). 170. S. M. Kupchan,J. Am. Chem. SOC.81, 1921 (1959). 171. N. V. Bondarenko, Khim. Prir. Soedin., 105(1979);Chem. Nat. Compd. (Engl. Transl.) 15,92 (1979); Chem. Abstr. 91, 16719 (1979). 172. R. Shakirov and S. Yu Yunusov, Khim. Prir. Soedin., 116 (1983);Chem. Nat. Compd. (Engl. Transl.) 19, 118 (1983); Chem. Abstr. 99,71046 (1983). 173. S . M. Kupchan and C. V. Deliwala, J. Am Chem. Soc. 76,5545 (1954). 174. G. S. Myers, P. Morozovitch, W. L. Glen, R. Barber, G. Papineau-Couture, and G. A. Grant, J. Am. Chem. SOC.77,3348 (1955). 175. G. S. Myers, W. I. Glen, P. Morozovitch, R. Barber, G. Papineau-Couture, and G. A. Grant, J. Am. Chem. Soc. 78, 1621 (1956). 176. S. M. Kupchan C. V. Deliwala, J. Am. Chem. SOC.75,4671 (1953). 177. R. Shakirov and S. Yu Yunusov, Khim. Prir. Soedin. 11,532 (1975); Chem. Abstr. 84, 59816 (1976). 178. W. L. Glen, G. S. Myers, R. Barber, P. Morozovitch, and G. A. Grant, Nature (London)170,932 (1952). 179. K. Samikov, R.Shakirov, and S. Yu Yunusov, Khim. Prir. Soedin. 7,790 (1971);Chem. Absrr. 76, 141099 (172). 180. S. M. Kupchan and C. R. Narayanan, Chem. Ind. (London,) 1092 (1956). 181. S. M. Kupchan and C. 1. Ayres, J. Am. Pharm. Assoc. Sci. Ed. 48,440 (1959). 182. D. H. R. Barton and J. F. Eastham, J. Chem. SOC.,424 (1953). 183. Z. J. Vejdelek and V. Trcka, Chem. Lisry 49,529 (1955);Chem. Abstr. 50,2621 (1956); Collect. Czech. Chem. Commun. 21,743 (1956). 184. D. H. R. Barton, C. J. W. Brooks, and P. De Mayo, J. Chem. Soc., 3950 (1954). 185. H. L. Tripathi and G. A. Yost, J. Labelled Compd. Radiopharm. 15,619 (1978);Chem. Absrr. 91,20902 (1979). 186. S. M. Kupchan and A. Afonso, J. Am. Pharm. Assoc. Sci. Ed. 49,242 (1960). 187. D. DeMarcano, B. Mendez, H. Parada, and A. Rojas, Org. Magn. Reson. 16, 314 (1981).

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237

188. D. M. Stuart and L. M. Parks, J . Am. Pharm. Assoc. Sci. Ed. 45,252 (1956). 189. A. Stoll and E. Seebeck, Helv. Chim. Acta 35, 1942 (1952). 190. Z. J. Vejdelek, K. Macek, and B. Kakac, Collect. Czech. Chem. Commun. 21, 995 (1956). 191. S. M. Kupchan, J. Am. Chem. SOC. 77,686 (1955). 192. S. M. Kupchan and W. S. Johnson, J. Am. Chem. Soc. 78,3864 (1956). 193. M. W. Klohs, R. Arons, M. D. Draper, F. Keller, S. Koster, W. Malesh, and F. J. Petracek, J. Am. Chem. Soc. 74,5107 (1952). 194. H. Auterhoff and F. Gunther, Arch. Pharm. (Weinheim, Ger.) 288,455 (1955). 195. S. M. Kupchan, R. H. Hensler,and L. C. Weaver, J . Med. Pharm. Chem. 3,129(1%1). 196. S . M. Kupchan, C. I. Ayres, and R. H. Hensler, J . Am. Chem. Soc. 82,2616 (1960). 197. M. W. Klohs, M. D. Draper, F. Keller, W. Malesh, and F. J. Petracek, J . Am. Chem. SOC. 75,3595 (1953). 198. S. M. Kupchan and C. I. Ayres, J . Am. Pharm. Assoc. Sci. Ed. 48,735 (1959). 199. M. W. Klohs, M. Draper, F. Keller, S. Koster, W. Malesh, and F. J. Petracek, J. Am. Chem. SOC. 76, 1152 (1954). 200. N . V. Bondarenko, Khim. Prir. Soedin., 529(1982);Chem. Nar. Compd. (Engl. Transl.) 18,504 (1982); Chem. Abstr. 98, 50344 (1982). 201. W. A. Jacobs and L. C. Craig, J . Biol. Chem. 149,271 (1943). 202. A. Stoll and E. Seebeck, Helv. Chim. Acta 36,718 (1953). 203. Q. Liu, X. Jia, Y. Ren, Muhatal, and X. Liang. Yaoxue Xuebao 19,894 (1984); Chem. Abstr. 103, 19851 (1984). 204. V. V. Kul’kova, K. Samikov, and S . Yu Yunusov, Khim. Prir. Soedin., 253 (1985); Chem. Abstr. 103, 85048 (1985). 205. P. Shakirov, A. Navier, and S. Yu Yunusov, Khim. Prir. Soedin., 584 (1979); Chem. Nat. Compd. (Engl. Transl.) 15,512 (1979); Chem. Abstr. 92, 147002 (1980). 206. J. Z. Wu, X. P. Pan, M. A. Lou, X. S. Wang, and D. K. Ling, Yaoxue Xuebao 24,600 (1989); Chem. Abstr. 112,95497 (1990). 207. K. Sarnikov, B. Shakirov, and S. Yu Yunusov, Khim. Prir. Soedin., 399 (1984); Chem. Nat. Compd. (Engl. Transl..) 379 (1984);Chem. Abstr. 102, 146097 (1985). 208. Y. Kitamura, M. Nishizawa, K . Kaneko, M. Shiro, Y. P. Chen, and Y. H. Hsu, Tetrahedron 45,7281 (1989). 209. K. Sarnikov, D. U. Abdullaeva, R. Shakirov, and S. Yu Yunusov, Khim. Prir. Soedin.. 529 (1979);Chem. Nat. Compd. (Engl. Transl.) 15,459 (1979);Chem. Abstr. 92,215589 (1 980). 210. Y. Kitarnura, M. Nishizawa, K. Kaneko, M. Ikura, K. Hikichi, M. Shiro. Y.-P. Chen, and H.-Y. Hsu, Tetrahedron Lett. 29, 1959 (1988). 21 1. D. M. Xu, S. Q. Wang, E. X. Huang, M. L. Xu, Y. X. Zhang, and X. G. Wen, Yaoxue Xuebao 23,902 (1988); Chem. Abstr. 111,74773 (1989). 212. E. S. Waight, Org. Mass Spectrom. 24,565 (1989).

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CUMULATIVE INDEX OF TITLES Aconiturn alkaloids, 4, 275 (1954). 7, 473 (1960). 34,95 (1988) C I 9diterpenes, 12, 2 (1970) Czoditerpenes, 12, 136 (1970) Acridine alkaloids. 2, 353 (1952) Acridone alkaloids, experimental antitumor activity of acronycine 21, I (1983) Actinomycetes, isoquinolinequinones. 21, 55 (1983) N-Acyliminium ions as intermediates in alkaloid synthesis, 32, 271 (1988) Ajmaline-Sarpagine alkaloids, 8, 789 (19651, 11, 41 (1968) Alkaloid production, plant biotechnology of 40, 1 (1991) Alkaloid structures spectral methods, study, 24, 287 (1985) unknown structure, 5, 301 (1955). 7, 509 (1960). 10, 545 (1967). 12, 455 (1970). 13, 397 (1971), 14, 507 (1973). 15, 263 (1975). 16, 511 (1977) X-ray diffraction, 22, 51 (1983) Alkaloids forensic chemistry of, 32, I (1988) histochemistry of. 39 165 (1990) in the plant, 1, 15 (1950), 6, I (1960) Alkaloids from Amphibians, 21, 139 (1983) Ants and insects, 31, 193 (1987) Chinese Traditional Medicinal Plants, 32, 241 (1988) Mammals, 21, 329 (1983) Marine organisms, 24, 25 (1985). 41, 4 (1992) Mushrooms, 40, 189 (1991) Plants of Thailand, 41, I (1992) Allo congeners, and tropolonic Colcliicrtm alkaloids, 41, 125 (1992) Alstoniu alkaloids, 8, 159 (1965). 12, 207 (1970). 14, 157 (1973) Amaryllidaceae alkaloids, 2, 331 (19521, 6, 289 (1960). 11, 307 (1968). 15, 83 (1975). 30, 251 (1987) Analgesic alkaloids, 5, 1 (1955) Anesthetics, local, 5, 211 (1955) Anthranilic acid derived alkaloids, 17, 105 (1979). 32, 341 (1988). 39, 63 (1990) Antimalarial alkaloids, 5, 141 (1955) Antitumor alkaloids, 25, 1 (1985) Apocynaceae alkaloids, steroids, 9, 305 (1967) Aporphine alkaloids, 4, 119 (19541, 9, 1 (1967). 24, 153 (1985) Aristolochiu alkaloids, 31, 29 (1987) Aristofeliu alkaloids, 24, I13 (1985) Aspergillus alkaloids, 29, 185 (1986) Aspidospermu alkaloids, 8, 336 (1965), 11, 205 (1968). 17, 199 (1979) Azafluoranthene alkaloids, 23, 301 (1984) 239

240

CUMULATIVE INDEX OF TITLES

Bases simple. 3, 313 (1953), 8, I (1965) simple indole. 10, 491 (1967) simple isoquinoline. 4, 7 (1954). 21, 255 (1983) Benzodiazepine alkaloids, 39, 63 (1990) Benzophenanthridine alkaloids, 26, 185 (1985) Benzylisoquinoline alkaloids, 4, 29 (1954). 10, 402 (1967) Betalains, 39, 1 (1990) Biosynthesis, isoquinoline alkaloids, 4, 1 (1954) Bisbenzylisoquinoline alkaloids, 4, 199 (1954). 7, 439 (1960). 9, 133 (1967), 13, 303 (1971). 16, 249 (1977). 30, I (1987) synthesis, 16, 319 (1977) Bisindole alkaloids, 20, 1 (1981) Bisindole alkaloids of Curharuntiiris. C-20' Position as a Functional Hot Spot in, 37, 133 (1990) Isolation, Structure Elucidation and Biosynthesis. 37, 1 (1990) Medicinal Chemistry of, 37, 145 (1990) Pharmacology of, 37, 205 ( 1990) Synthesis of, 37, 77 (1990) Therapeutic Use of, 37, 229 (1990) Birxirs alkaloids. steroids, 9, 305 (1967). 14, I (1973), 32, 79 (1988) Cactus alkaloids, 4, 23 (1954) Calabar bean alkaloids. 8, 27 (1965). 10, 383 (1967). 13, 213 (1971). 36, 225 (1989) Calabash curare alkaloids. 8, 515 (1965). 11, 189 (1968) Calycanthaceae alkaloids, 8, 581 (1965) Camptothecine, 21, 101 (1983) Cancentrine alkaloids, 14, 407 (1973) Catinahi.~srrtiuu alkaloids. 34, 77 (1989) Canthin-6-one alkaloids. 36, 135 (1989) Capsicum alkaloids. 23, 227 (1984) Carbazole alkaloids. 13, 273 (1971). 26, I (1985) Carboline alkaloids, 8, 47 (1965), 26, I (1985) 6-Carboline congeners and Ipecac alkaloids. 22, 1 (1983) Cardioactive alkaloids. 5, 79 (1955) Celastraceae alkaloids. 16, 215 (1977) Crphulotaxus alkaloids, 23, 157 (1984) Cevane group of Vrratrirni alkaloids. 41, 177 (1992) Chemotaxonomy of Papaveraceae and Fumaridaceae, 29, I (1986) Chinese medicinal plants, alkaloids from, 32, 241 (1988) Chromone alkaloids. 31, 67 (1987) Cinchonrr alkaloids, 3, I (1953). 14, 181 (1973). 34, 332 (1989) Colchicine, 2, 261 (1952). 6, 247 (1960). 11, 407 (1968). 23, I (1984) Colchicrrm alkaloids and allo congeners. 41, 125 (1992) Configuration and conformation. elucidation by X-ray diffraction, 22, 5 I ( 1983) Corynantheine, yohimbine. and related alkaloids, 27, 131 (1986) Cularine alkaloids. 4, 249 (1954). 10, 463 (1967). 29, 287 (1986) Curare-like effects, 5, 259 (1955) Cyclic Tautomers of Tryptamine and Tryptophan, 34, 1 (1989) Cyclopeptide alkaloids, 15, 165 (1975)

CUMULATIVE INDEX O F TITLES Daphniplivlluni alkaloids. 15, 41 (1975). 29, 265 (1986) Delphinium alkaloids, 4, 275 (1954). 7, 473 (1960) Clo-diterpenes, 12, 2 (1970) C?,-diterpenes. 12, 136 (1970) Dibenzazonine alkaloids, 35, 177 (1989) Dibenzopyrrocoline alkaloids, 31, 101 (1987) Diplorrhvncus alkaloids, 8, 336 ( 196.0 Diterpenoid alkaloids Aconitrtm, 7. 473 (1960). 12, 2 (1970). 12, 136 (1970). 34, 95 (1989) Delphinirrm. 7, 473 (1960). 12, 2 (1970). 12, 136 (1970) Garryn. 7, 473 (1960). 12, 2 (1960). 12, 136 (1970) chemistry, 18, 99 (1981) general introduction. 12, xv (1970) structure, 17, I (1970) synthesis, 17, I (1979)

Eburnamine-Vincamine alkaloids. 8, 250 (1965). 11, 125 (1968). 20, 297 (1981) Elueocurpus alkaloids. 6, 325 (1960) Ellipticine and related alkaloids. 39, 239 (1990) Enamide cyclizations in alkaloid synthesis. 22. 189 (1983) Enzymatic transformation of alkaloids, microbial and in uito. 18, 323 (1981) Ephedra alkaloids, 3, 339 (1953) Ergot alkaloids. 8, 726 (1965). 15, I ( 1975).39, 239 (1990) Erytlirinu alkaloids, 2, 499 (1952). 7, 201 (1960). 9, 483 (1967). 18, I (1981) Ervtlirophlerim alkaloids. 4, 265 (1954). 10, 287 (1967) Eirpomatiu alkaloids. 24, I (1985) Forensic chemistry, alkaloids. 12, 514 (1970) by chromatographic methods, 32, I (1988) Gulhrrlirnimu alkaloids. 9, 529 (1967). 13, 227 (1971) Gardneriu alkaloids. 36, 1 (1989) G a r p a alkaloids, 7, 473 (1960). 12, 2 (1970). 12, 136 (1970) Geissospermrtrn alkaloids. 8, 679 ( 1965) Gelsemirim alkaloids. 8, 93 (1965). 33, 84 (1988) Glycosides. monoterpene alkaloids. 17, 545 ( 1979)

Guutteriu alkaloids. 35, I (1989)

Haplophvton cirnic.idrrm alkaloids. 8, 673 (1965) Hasubanan alkaloids, 16, 393 (1977). 33, 307 (1988) Histochemistry of alkaloids, 39, 165 (1990) Holurrhenu group, steroid alkaloids. 7, 319 (1960) Hiinreria alkaloids. 8, 250 (1965) lhoga alkaloids, 8, 203 (196% 11, 79 (1968)

Imidazole alkaloids. 3, 201 (1953). 22, 281 (1983) lndole alkaloids, 2, 369 (1952). 7, 1 (1960). 26, I (1985) distribution in plants, 11, I (1968) simple, 10, 491 (1967). 26, 1 (1985) Reissert synthesis of, 31, I (1987)

24 1

242

CUMULATIVE INDEX OF TITLES

Indolizidine, simple and quinolizidine alkaloids, 28, 183 (1986) 2.2'-Indolylquinuclidine alkaloids, chemistry, 8, 238 (1965).11, 73 (1968) Ipecac alkaloids, 3, 363 (1953).7, 419 (1960).13, 189 (1971).22, 1 (1983) Isolation of alkaloids, 1, I (1950) lsoquinoline alkaloids, 7, 423 (1960) biosynthesis. 4, 1 (1954) "C-NMR spectra, 18, 217 (1981) simple isoquinoline alkaloids, 4, 7 (1954).21, 255 (1983) Reissert synthesis of, 31, I (1987) lsoquinolinequinones. from Actinomycetes and sponges. 21, 55 (1983) Khat (Ccrthu edidis) alkaloids. 39, 139 (1990) Kopsia alkaloids, 8, 336 (1965) Lead tetraacetate oxidation in alkaloid synthesis, 36, 70 (1989) Local anesthetics, 5, 211 (1955) Localization in the plant, 1, I5 (1950).6, I (1960) Lupine alkaloids, 3, 119 (1953).7, 253 (1960).9, 175 (1967).31, 16 (1987) Lvcopodiitm alkaloids. 5,265 (1955).7,505 (1960). 10,306 (1%7). 14,347 (1973).26,241 (1985) Lythraceae alkaloids, 18, 263 (1981).35, 155 (1989) Mammalian alkaloids. 21, 329 (1983) Marine alkaloids. 24, 25 (1985).41, 41 (1992) Maytansinoids, 23, 71 (1984) Melanins. 36, 254 (1989) Melodinirs alkaloids, 11, 205 (1968) Mesembrine alkaloids, 9, 467 (1967) Metabolic transformation of alkaloids, 27, 323 (1986) Microbial and in uitro enzymatic transformation of alkaloids, 18, 323 (1981) Mirrugynu alkaloids. 8, 59 (1965).10, 521 (1967).14, 123 (1973) Monoterpene alkaloids. 16, 431 (1977) glycosides, 17, 545 (1979) Morphine alkaloids, 2, 1 (part I, 1952).2, 161 (part 2. 1952).6, 219 (1960).13, I (1971) Muscarine alkaloids, 23, 327 (1984) Mushrooms, alkaloids from, 40, 190 (1991) Mydriatic alkaloids, 5, 243 (1955) a-Naphthophenanthridine alkaloids. 4, 253 (1954).10,485 (1967) Naphthylisoquinoline alkaloids, 29, 141 ( 1986) Narcotics. 5, 1 (1955) Nuphar alkaloids, 9, 441 (1967).16, 181 (1977).35, 215 (1989) Ochrosia alkaloids, 8, 336 (1965).11, 205 (1968) Oiiroiiparia alkaloids, 8, 59 (1965).10, 521 (1967)

Oxazole alkaloids, 35, 259 (1989) Oxoaporphine alkaloids, 14, 225 (1973) Oxindole alkaloids, 14, 83 (1973)

Papaveraceae alkaloids. 10, 467 (1967).12, 333 (1970).17, 385 (1979) pharmacology, 15, 207 (1975) toxicology, 15, 207 (1975)

CUMULATIVE INDEX OF TITLES

243

Pauridiantha alkaloids, 30, 223 (1987) Pavine and isopavine alkaloids, 31, 317 (1987) Pentaceras alkaloids, 8, 250 (1965) Peptide alkaloids, 26, 299 (1985) Phenanthrene alkaloids, 39, 99 (1990) Phenanthroindolizidine alkaloids, 19, 193 (1981) Phenanthroquinolizidine alkaloids. 19, 193 (1981) P-Phenethylamines. 3, 313 (1953). 35, 77 (1989) Phenethylisoquinoline alkaloids, 14, 265 (1973). 36, 172 (1989) Phthalideisoquinoline alkaloids, 4, 167 (1954). 7, 433 (1960). 9, 117 (1967). 24, 253 (1985) Picralima alkaloids, 8, I19 (1965). 10, 501 (1967). 14, 157 (1973) Piperidine alkaloids, 26, 89 (1985) Plant Biotechnology. for alkaloid production. 40, 1 (1991) Plant systematics. 16, I (1977) Pleiocarpa alkaloids, 8, 336 (1965). 11, 205 (1968) Polyamine alkaloids, 22, 85 (1983) Pressor alkaloids, 5, 229 (1955) Protoberberine alkaloids, 4, 77 (1954). 9, 41 (1967). 28, 95 (1986) transformation reactions of, 33, 141 (1988) Protopine alkaloids, 4, 147 (1954). 34, 181 (1989) Pseudocinchona alkaloids, 8, 694 (1965) Purine alkaloids, 38, 226 (1990) Pyridine alkaloids, 1, 165 (1950). 6, 123 (1960). 11, 459 (1968). 26, 89 (1985) Pyrrolidine alkaloids, 1, 91 (1950). 6, 31 (1960). 27, 270 (1986) Pyrrolizidine alkaloids. 1, 107 (1950). 6, 35 (1960). 12, 246 (1970). 26, 327 (1985)

Quinazolidine alkaloids, see Indolizidine Alkaloids Quinazoline alkaloids, 3, 101 (1953). 7, 247 (1960). 29, 99 (1986) Quinazolinocarbolines. 8, 55 (1965), 21, 29 (1983) Quinoline alkaloids related to anthranilic acid, 3, 65 (1953). 7, 229 (1960). 17, 105 (1979). 32, 341 (1988) Quinolizidine alkaloids, and indolizidine. 28, 183 (1985) Rauwo&a alkaloids, 8, 287 (1965) Reissert synthesis of isoquinoline and indole alkaloids. 31, I (1987) Reserpine, chemistry, 8, 287 (1965) Respiratory stimulants. 5, 109 (1955) Rhoeadine alkaloids, 28, 1 (1986) Salamandra group, steroids, 9, 427 (1967) Sceletium alkaloids, 19, I (1981) Secoisoquinoline alkaloids, 33, 23 I (1988) Securinegu alkaloids, 14, 425 (1973) Senecio alkaloids, see Pyrrolizidine alkaloids Simple indole alkaloids, 10, 491 (1967) Simple indolizidine alkaloids, 28, 183 ( 1986) Sinomenine, 2, 219 (1952) Solanum alkaloids chemistry, 3, 247 (1953) steroids, 7, 343 (1960). 10, 1 (1967). 19, 81 (1981)

244

CUMULATIVE INDEX OF TITLES

Sources of alkaloids, 1, I (1950) Spectral methods, alkaloid structures. 24, 287 (1985) Spermidine and related polyamine alkaloids. 22, 85 (1983) Spermine and related polyamine alkaloids. 22, 85 (1983) Spirobenzylisoquinoline alkaloids, 13, 165 (1971). 38, 157 (1990) Sponges. isoquinolinequinone alkaloids from, 21, 55 (1983) Stefnoncr alkaloids, 9, 545 (1967) Steroid alkaloids Apocynaceae, 9, 305 (1967). 32, 79 (1988) Btrxrts group, 9, 305 (1967). 14, 1 (1973). 32, 79 (1988) Holorrhencr group, 7 , 319 (1960) Salarncrndru group. 9, 427 ( 1967) Solanrrni group, 7, 343 (19601, 10, I (I967), 19, 81 (1981) Verrrtrrrm group. 7, 363 (1960). 10, 193 (1967). 14, I (1973). 41, 177 (1992) Stimulants respiratory. 5, 109 (1955) uterine. 5, 163 (1955) Structure elucidation. by X-ray diffraction, 22, 51 (1983) Strvchnos alkaloids. 1, 375 (part I . 1950).2, 513 (part 2. 1952). 6, 179 (1960). 8, 515, 592 (1965). 11, 189 (1968). 34, 211 (1989). 36, I , (1989) Sulfur-containing alkaloids, 26, 53 ( 1985) Synthesis of alkaloids, Enamide cyclizations for. 22, 189 (1983) Lead tetraacetate oxidation in, 36, 70 (1989) T~rhevnueniunrrrnrralkaloids. 27, I (1983)

Taxrrs alkaloids. 10, 597 (1967). 39, 195 (1990)

Thailand. alkaloids from the plants of, 41, I (1992) Toxicology, Papaveraceae alkaloids, 15, 207 ( 1975) Transformation of alkaloids, enzymatic, microbial and iri uifro, 18, 323 (1981) Tropane alkaloids, chemistry, 1, 271 (1950). 6, 145 (1960). 9, 269 (1967). 13, 351 (1971). 16, 83 (1977), 33, 2 (1988) Tropoloisoquinoline alkaloids. 23, 301 (1984) Tropolonic Colchicrun alkaloids. 23, I ( I 984). 41, I25 ( 1992) Tvlophora alkaloids. 9, 517 (1967) Uterine stimulants. 5 , 163 (1955) Vercrtrrtm alkaloids

cevane group of, 41, 177 (1992) chemistry, 3, 247 (1952) steroids. 7, 363 (1960). 10, 193 (1967). 14, I (1973) Vincu alkaloids. 8, 272 (1965). 11, 99 (1968). 20, 297 (1981) Vocrcungrr alkaloids. 8, 203 (1965). 11, 79 (1968) X-ray diffraction of alkaloids. 22, 51 (1983) Yohimbe alkaloids, 8, 694 (1965). 11, 145 (1968). 27, 131 (1986)

A

Aaptamine, 72

Antitubulin effect, of colchicinoids. 166

Acanthella curteri,

alkaloids of, 46

Apcinisotnenon Jos-aqrtrre,

alkaloids of, 44

Acetoacetyldeacetylcolchicine. 127 2-Aceyt-2-demethylthiocolchcine,

Aplidirrtn ,fii.seirm.

alkaloids of, 104 Aporphine alkaloids, from plants of Thailand, 15 Aragupetrosine A. 75 Araguspongines B-H. 75

X-ray structure of, 136 N-Acetylcolchinol. 153 Acetylcolchinyl methyl ether, 167 0-Acetylsukhodianine, 15 Adinu cordijolia.

alkaloids of, 32 Adociaquinones A-B. 11 I

Agrlus Jlabelliformis

Arothron nigroprtnctutrrs,

alkaloids of, 43 Arsenic in marine chemicals, 109

~

alkaloids of, 34

Ascitlici nigru,

Agluia odorutu,

alkaloids of, 100 Ascididemin. 69. 71

alkaloids of, 34

Agluopheniu plirmu,

alkaloids of, 66 Ajmalicidine, 26 Ajmalimine, 28 Ajmalinimine. 28 Akuammidine. 29 Akuammigine pseudoindoxyl, 27 Aldisin. 46 alkaloids of, 57 Allocolchiceine, 162 Allocolchicine, 130, 152 Allocolchinal, 153 Allocolchinol, 153 Amanthamides A-F, 61 3-Amino-3-deoxyglucose, 109 Amphikuemin, 110 Amphimedine. 68

As troides c~alvcirloris.

alkaloids of. 48

A.rinc4la sp.,

alkaloids of, 57 Ayuthianine. 15

B Baimondine. 196 Batzellines A-C. 74 Bengamides A-F, 84 Biphenyls, methoxy substituted analogs, 160 Bisbenzylisquinoline alkaloids, from plants of Thailand, 6 Biscolchiceine- I .3-propanediamide. I47 Bistramide A. 84 6-Bromo-4’-N-demethylaplysinopsin, 48 5-Bromo-N.N-dimethyltryptamine, 50 6-Bromoaplysinopsin, 48 7-Bromocavernicolenone, 1 10 7-Brornoeudistomin D, 64 Brornoleptoclinidinone. 68 Bromotopsentin, 53

Amphiprion perideruion.

alkaloids of. I10

Ancistrocladus tectoriirs Lour.

alkaloids of, 18 Ancistrotectorine, 18 Androbiphenyline, 131 Angeloylzygadenine, 204

4,9-Anhydrotetrodotoxin,43 Anomian A. 100

Birgrrici dentura.

245

246

INDEX

alkaloids of, 59 Bursatellin, 109 C

Caffeine, 105 Caissarone, 105 Calliactine, 68 Calyculines A-D, 82 N-Carboxamidostepharine, 17 Caulerpin, 53 Cephalodiscus gilchristi, alkaloids of, 112 Cephalostatins, 112 Cepharanthine, 7 Cepharanthine-2'4"oxide Cevacine, 214 Cevadine, 182, 215 Cevagenine N-oxide, 216 Cevagenine, 182, 216 Cevane. 178 Cevine N-oxide. 213 Cevine orthoacetate, 182 Cevine, 182 Chartella papyracea, alkaloids of, 54 Chartellamides A.B. 54 Chartellines A,B,C, 54 Chelynotus semperi, alkaloids of, 71 Chiriquitoxin, 44 7-Chlorocavernicolenone, 1 10 Chlorophyllone, 59 Chondria armata, alkaloids of, 6 Chuanbeinone, 226 Cinchona sicccirubra. alkaloids of, 33 Cissus rheifolia, alkaloids of, 35 Clathridine, 47 Colchibiphenyline, 131 Colchicine, 125 biological activities of, 163 chromatography of, 140 clinical data of, 169 configuration of, 126 optical properties of, 139 spectroscopy of, 131 synthesis of, 148 X-ray structures of, 135

Colchiceinamide, 127, 146 Colchiceinazide, I45 Colchiceine benzoate, X-ray structure of. 135 Colchiceine. 142 Colchicide. 145 Colchicone. 127 Colchicoside, 170 Colchicum airtumnalr alkaloids of, 127 Colchicum cilium, alkaloids of, 127 Colchicrcm cornigericni. alkaloids of, 130 Cornigerine. 162, 165 Cornigerone, 127 Curicycleatjenine, 12 Curucycleatjine, 12 C v d e a atjehensis, alkaloids from, 1 I Cycleatjehenine. 12 alkaloids from, 6 Cycleatjehine, 12 Cyclodercitin. 71 Cyclopheophorbide enol. 59 Cynops cnsicnndu. alkaloids of, 43 Cystod.vtes dellechiajei, alkaloids of, 69 Cystodytins A-C, 69

.

D Durwinella oxeuta, alkaloids of, 59 Deacetamidocolchicine, optical resolution of, 140 synthesis of, 142

Deacetamidoisocolchicine, 148 Deacetylcolchiceine, biological activity of, 167 3-Deacetylcolchiceine. 127 Deacetylcolchicine, Deacetylisocolchicine, 141 Debromoshermilarnine. 70 Dehydrodeacetamidocolchicine. I43 Delafrine, 195 Delafrinone, 195 Delavine, 227 Demecolceine, 168

INDEX Demecolcine, biological activity of, 167 10-Demethoxy-10-ethylcolchicine,172 Demethyloxyaaptamine. 72 3-Demethyl-3-chloroacetylthiocolchicine, binding of labeled, 171 Demethylaaptamine, 72 3-Demethylcolchicine X-ray structure of, 135 2-Demethylcolchicine, 144 I-Demethylcolchicine, 163 3-Demethylcolchicone, I27 2-Demethyldemecolcine, 168 Demethyldysidenin, 109 N-Demethylholacurtine, 34 Demethylspeciosines, I26 3-Demethylthiocolchicine. 144, 165 Dendrodoa prossularia, alkaloids of. 48 9-Deox y-methylthio-x ylofuranosyladenine. 105 Deoxykopsijasminilam, 30 Deoxymalyngamide C, 84 1 I-Deoxytetrodotoxin, 44 2-Deoxyuridine-5’-carboxylicacid, 104 Deoxyzoanthenamine. 112 Dercitin, 71 Dermasrerias imbricata, alkaloids of, 107 Desmethylphidolopin, 105 Dibenzo[a,c]cycloheptanes, 154 Dibromoisophakeline. 46 Dibromocantharelline, 45 4,6-Dibromo-2-methylindole, 51 2.3-Dibromo-5-methoxymethylpyrrole, 58 5.6-Dibromo-N,N-dimethyltryptamine, 50 Dibromoagelaspongin, 46 4,6-Dibromoindole, 5 I Dibromophakeline, 45 2.3-Dibromopyrrole. 58 Dibromopyrrolic acid, 58 2,3-Didemethylcolchicine,142 Didemnin B, 89 Didemnitm chartaceum, alkaloids of, 102 Dideoxyfistularin 3, 100 Dideoxymalyngamide C, 84 4,5-Dihydro-6-deoxybromotopsentin. 53 Dihydrofluorescein diacetate, as an analytical reagent, 140. 162

247

Dihydroflustramine C, 55 Dihydrohalichondramide, 78 Dihydroveramarine. 201 Dihydroxyaerothionine. 100 Diketopiperazines. from marine organisms, 88 I , I-Dimethyl-5,6-dihydroxyindolinium chloride, 51 Dimethyl-6-imino-8-oxopurine. 105 Dimet hyl-dehydropiperidino-3carboxylate. 103 Dinklacorine. 7 Diplamine, 69 Discodermicr calyx, alkaloids of, 82 Discodermins, 97 Discorhabdin A-D, 73 Dolabellu uuricrilaria. alkaloids of, 93 Dolastatin. 10. 93 Domoilactones A-B, 62 Dramacidin. 52 Dramacidons A.B. 52 Dyidazirine. 86 Dysideo etheria, alkaloids of, 50

E

Ebeiedine. 227 Ebeiedinone, 227 Edpetidine. 194 Ed pe t isid ine , 199 Edpetisidinine, 228 Edpetisinine, 194 Eduardine. 194 Edwardinine. 194 Eilatin. 70 Elegansamine, 30 Entadamides A-C, 33 6-Epitetrodotoxin, 43 16-Epivoacarpine. 29 Eruatumia coronuriu. alkaloids of. 31 Erytlirina uariepatu. alkaloids of. 19. 26 Escholerine, 222 3-Ethoxycarbonyl-3-demethylcolchicine. I42 N-Ethoxycarbonyldemecolcine, 127 Etzionin. 88

248

INDEX

Eudistoma oliuuceum, alkaloids of. 63 Eudistoma Rlaucus, alkaloids of, 64 Eudistomines A-Q, 63 Euphonasia paciJca. alkaloids of. 60

F

Fascaplysin. 53 alkaloids of, 53 Fascaplysinopsis sp., Fenestins A-B. 89 Flitstra foliacea. alkaloids of, 55 Flustramines B-D. 55 Flustramine-N-oxides. 55 Flustrarine B, 55 3-Formyl-2,7-dimet hox ycarbazole., 25 3-Formyl-2-methoxycarbazole,25 3-Formylindole. 5 I from marine organisms, 88 N-Formylnornantenine. 17 Fritillarizine, 201 from marine organisms. 88 Ficgic poecilontus, alkaloids of, 43

G Gelsemiutn eleguns, alkaloids of, 29 Geodiamolides A-B, 96 Germanidine, 209 Germanitrine, 210 Germbudine, 209 Germerine. 209 Germidine, 209 Germine, chemical reactions of, 180. 182, 208 Germitetrine, 21 I Germitetrone, 21 1 Germitrine, 210 Grossularins I and 11, 48 Guanidine alkaloids, 42

H

Halichondramide, 78 Haliclamines A-B, 76 Haliclona sp., alkaloids of, 67

Haliclonadiamine, 74 Harepermine, 194 Hareperminside. 194 Heilonine, 229 Herbindoles A-C, 56 Hexabrunchus sanguineus, alkaloids of, 77 Hexadellins, 100 Heyneanine hydroxyindolenine. 3 I Holacurine, 34 Holarrhena antidysentericw alkaloids of, 35 Homoaromline, 10 Homopahutoxin, 87 Hormothamnion enteromorphoides. alkaloids of, 98 Hupehenine, 193 Hupeheninoside, 193 Hupehenizine, 194 2-Hydroxy-3-formyl-7-methoxycarbazole. 25 14-Hydroxy-3-isorauniticine.27 4-Hydroxy-5-( indol-3-yl)-5-oxopentan-2one, 50 4-Hydroxy-N,N-dimethylpyrrolidino-3carboxylate, 60 Hydroxyaerothionine, 100 I-Hydroxyethyl P-carboline, 65 Hydroxytropolone, 158 Hymeniacidon aldis, alkaloids of, 46 Hvmeniacidon, sp.. alkaloids of, 45 Hymenidin, 45 Hymenin. 45 Hypehenine, 194

.

I Ianthelline, 98 Iejimalides A-B, 81 Imbricatine, 107 2-Iminomethyl-3-methyl-6-aminomethyl9H-purine, 104 Indobinine, 25 Indole alkaloids, from plants of Thailand, 20 2.3-Indolinedione. 52 Indolyl-4H-imidazole-4-one. 48 Isocolchicide, 148 Isocolchicine, 130

249

INDEX lsocuricycleatjenine, 12 Isocuricycleatjine, 12 lsodomoic acids A-C, 61 Isoflustramine D.55 Isohalichondramide, 78 Isonaamidines A,B, 47 lsonaamine A, 47 Isoquinoline alkaloids. from plants of Thailand, 2 Isorauniticine pseudoindoxyl, 27 lsosarain I. 76 lsosegoline A, 70 Isoteropodine, 56 Isothiocolchicine. 144. 148 lsothiocyanates of colchicine. 162 7-Isothiocyanato-7-deacetamidocolchicine. 147 Isotrikentrin B, 56 Itomanindoles A,B. 5 I Janolusimide. 88 Jasminiflorine, 3 I Jaspamide. 95 Jasplakinolide. 95 Jerusalemine, 172

J

L Lamellarins A-D. 101 Latrirnciilia hreuis,

alkaloids of. 73 Latrunculines A-B. 80 Larrwnc~iahrongniarti,

alkaloids of. 51, 52 Leptosphaerin. 110 Leitr,ettu cliagosensis, alkaloids of. 51. 52 Leucettidine. 105 Lipopurealin A-C. 98 Liriodenine. occurrence of. 18 Lissocliamides. 91 Lis.soclinirm pcr tc4la, alkaloids of. 91 Longicaudatine. 32 Luciferin. 60 Lumazines. 106 Lyngh,vu tnajrtscitla.

K

Kabiramides, 77 Kayawongine. 35 Keliiquinone. 47 Kermamines A-B, 67 Ketoadociaquinone A. 1 I1 Kopsia jasminiforu,

Korsinamine. 199 Korsine. 199 Koumidine. 29 Koumine N-oxide. 29 Kuanoniamines A-D. 71

alkaloids of. 30 Kopsijasmine, 31 Kopsijasminilam, 30 Korselidinedione, 195 Korselimine. 190 Korseliminedione. 190 Korseveramine. 191 Korseveridine, 190 Korseveridinone. 190 Korseveriline. 191 Korseverilinedione. 192 Korseverilinone. 192 Korseverine, 198 Korseverinine. 198 Korsidine. 198

alkaloids of. 84 Lyngbyatoxin, 57

M Muhonia s i a t n e n i s , alkaloids of, 14 7-Methoxyheptaphylline. 25 7-Methoxymurrayacine. 25 U-Methylmukonal. 25 0-Methylstepharinosine, 17 occurrence of, 18 Mitrag.vnct speciosa. alkaloids from, 19. 26 Monomethyltetrandrinium chloride. 7 Manackinine. 210 2-Methoxy-5-aryltropones. 158 Malyngamide C-D, 84 Manzamines. 67 Methoxycarbonyltubercidin. 106 3-Methoxydechlorochartelline A. 54 MethyL2’-deoxycytidine. 104 3-Methyl-2’-deoxyuridine. 104

9-Methyl-7-bromoeudistominD. 64

INDEX 3-Methyladenine, 105 Mycalamides A-B.82 Mycalisin A-B,106 Mycot hiazole, I08

N

Naamidines A-D. 47 Naamines A-B,47 Neogermbudine, 209 Neogermidine, 209 Neoqermitrine, 210 Neosegoline A. 70 Neosurugatoxin, 57 Nerito alhicilla, alkaloids of, 56 Niphatynes A-B. 102 Nirurine, 35 2-Norcepharanoline, 10 2-Norcepharanthine, 10, I 1 Norcepharathin, 7 Nordelavaine, 19 Nordidemnine B, 90 Norisocepharanthine, 10. 1 1 2-Norisotetetrandrine, I0 Norisoyanangine, 7 Normajusculamide C-D. 94 2-Norobaberine, 10 I I-Nortetrodotoxin-6-01. 43 Norvanagine, 7 Norstephasubine, 7. 9

0

Odiline, 45 Odontosyllis rtndecimdontu, alkaloids of, 106 Odorine, 34 Odorinol, 34 Onnaide A, 82 Oroidin. 45 Ovothiols A-C,107 8-Oxopseudopalmatine. 13, 14 Oxostephanosine. 15 I I-Oxotetrodotoxin, 43 Papuamine, 74 Paradaxins, 97 Patellamide D, 91 Patellazoles A-C,81 Perebaenu sagituta,

P

alkaloids from, 14 Petilinine. 193 Petrosamine. 70 Phalaenopsine La, 35 Pheophorbide. 59 Pheophytin, 59 Pingbeinone, 229 Piper surmentosrrm. alkaloids of. 34 Piriferine, 34 Pluemon rnacroductylrrs. alkaloids of. 52 Plakinidines A-B,71 Polyandrocarpamides A-D.56 Polycarpamines A-E.1 I I Polycitrorella rnuriui~. alkaloids of, 51 Prelissoclinamide. 2, 91 Prepatellamide B formate, 91 Preulicyclamide, 91 Priunos tnelanos, alkaloids of, 73 Prianosine A, 73 Prorocentrolide, 81 Prosurutoxin, 57 Protoberberine alkaloids. from plants of Thailand, 13 Protogotivurrlax tutnciretisis. alkaloids of, 44 Protoveratrines A-B.222 Protoveratrine C, 223 Protoverine. 220 Psammaplin A, 99 Psammaplysins, 98 Pseudiuinyssu i~unthuri4lu. alkaloids of, 45 Psi~rrdodistotnakonoko, alkaloids of, 103 Pseudodistomins A-B,103 Pseudogermune. 208 Pseudoindoxyl, 27 Pseudoprotoverine. 220 Pseudothiocolchicine. 148 Pseudozygadenine. 203 Pterocladia cupillucea, alkaloids of, 61 Ptilocuulis spiculijer, alkaloids of, 48 Ptilomycalin A, 48 Purealin. 98

INDEX Pyronamidine. 47 Pyrrole carboxylic acid methylester, 58

R

Rauniticine oxindole A, 27 RauwolJa cambodiana, alkaloids of. 26, 28 Reniera sarai, alkaloids of, 76 Renieramycins A-D,103. 104 Renierol, 103 Rescinnamidine, 26 Rescinnaminol, 26 Rhizochalin, 86 Rigidin, 106 Ritterella sigillinoides, alkaloids of, 64 Rttditupes philippinurum. alkaloids of, 59

S Sabadine. 206 Sabine. 205 Sagartia troglodytes, alkaloids of, I10 Salimine, 172 Sarmentine. 34 Sarmentosine, 34 Saxitoxin. 42, 44 Sceptrin, 45 Schotteru nicaeensis. alkaloids of, I10 Secocolchicine, 150 Segoline A-B.70 Sevedamine, 192 Sevedine N-oxide, 192 Sevedine, 192 Seveline, 229 Severine. 191 Severtzidine. 192 Severtzidinedione, 192 Sewerzine. 190 Shermilamines A-B,70 Shinonomenine. 226 Sinpeinine, 227 Smenospongia uiireu. alkaloids of, 50 Solunderia secunda. alkaloids of, 87

Speciosine. 163 Spermidine amide. 50 Spliueroides oblongits. alkaloids of, 44 Stelettamide A. I12 Stenanzamine. 229 Stenanzidine. 193 Stenanzidinedione, 194 Stephabinamine. 13 Stephabine, 13. 14 Stephadoilsomine N-oxide. 16 Stepphrtniu pierreis alkaloids of, 9. 19 Stepliania srtberosa, alkaloids of, 13 Stepliunict srtberosu. alkaloids of, 7 Stepliunia uerosa. alkaloids of, 15. 19 Stepharinosine. 17 Stephasubimine, 7 Stephasubine. 7. 8. 19 Stephinbaberine. 10 Stepierrine. 10 Stevensine. 45 Strychnos Itrt~ida, alkaloids of, 3 I Stylocheilamide. 84 Substance F. 60 Suhailamine. 172 Sukhodianine N-oxide, 16 Sukhodianine, 15 Symbioramide, 86

T Taberpsychine. 29 Telocidin. 57 Tetrahydrochalichondramide, 80 Tetrahydrocolchicine. 148 Tetrahydrostephabine. 13 Tetrandrine N-2'-oxide. 7 Tetrodonic acid. 43 Tetrodotoxin, 42. 44 Thailandine. 16 Theonelladins, 102 Theonellamide. 97 Theonellapeptolides, 97 Thiocolchicine. 138, 165 Thiocolchicinethione. 144 Thymidine-5'-carboxylic acid, 104

25 1

252

INDEX

Tiliacorine, 7 Tiliacorine-2’-N-oxide, 7 Tiliacorinine A, 7 Tiliacorinine, 7 Tiliageine, 7 Tilianangine. 7 Tiliandrine, 7 Tinosporu buenzigereri. alkaloids from, 14, 19 Topsantiu genitrix, alkaloids of. 53 Topsentins A.B. 53 Toyocamycin, 106 Tridemethylcolchiceine. 171 Trididemnirm solidrim. alkaloids of, 58 Trihydroxyquinoline-2-carboxylic acid. I03 Trikentramine, 56 Trikentrins A,B, 56 Trikentrion Juhrllififorma alkaloids of, 56 Trimethylguanine, 104 Tubastraine, 103 Tubastrine. 48 Tubulin, colchicine binding site on. 161 Tunichlorin, 58 Tunichrome B-I. 101

.

U Ulapualides A-B, 76 Ulithiacyclamide B, 91 Ulosu riretzlrri, alkaloids of, 50 Uncuriu utteniiutu, alkaloids of. 27 Uncuriu homomullii alkaloids of, 28 Uncuriu qiiudrirngiilaris. alkaloids of, 28 Ushinsunine N-oxide. 16 Ussuriedine, 230 Ussuriedinone. 230 Ussurienine, 230

Ussurienone. 230 Uthongine. 16 V Vanilloylimidazole, 107 Vanilloylzygadenine. 204 Veracevine, 182. 214 Veraflorizine, 201. 226 Veralodine. 200 Veralodinone. 200 Veramarine, 201 Veramines A-B. 69 Veratrenone, 230 Veratridine, 215 Veratroylzygadenine, 204 Vrrutrirm alkaloids, 177 Verticindione. 197 Verticine N-oxide. 197 Verticine. 181. 212 Verticinone. 197 Vibrio iingirilluriini, alkaloids of, 107 Wanpeinine, 195 Woodinine. 65

W

X

Xestoquinone. I 1 I Xl~stospongir~ sp.. alkaloids of, 75 Xylopinine N-oxide. 13 Yanangcorinine. 7 Yanangine. 7

Y

2

Zgacine, 203 Ziebeimine. 228 Zoanthamide, I12 Zoanthamine, I12 Zoanthaminone, 112 Zoanthenamune, 112 Zygadenine, 203 Zygadenylic acid lactone. 202