The Alkaloids: Chemistry and Pharmacology, Volume 41

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

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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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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 )

bark) Mahonia siamensis Takeda (stem bark) Michelia longifolia BI. (syn.

M. a

h DC.)

Berberidaceae Magnoliaceae

Berberine ( 2 5 ) Isotetrandrine ( 2 5 ) Liriodenine (49)

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

Magnoliaceae Lauraceae

bark)

Papauer somniferum Linn. (flower heads,

latex)

Papaveraceae

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)

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

Menispermaceae

Menispermaceae

Menispermaceae

Thorns.

Menispermaceae

(stems)

Menispermaceae

(stems. aerial roots)

Tinosporu sinensis (Lour.) Merr.

~~~~~

(+ )-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'

Mc MC Mc M

H It H

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

11

1 %

H

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

H

H

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

€1 H

It H €I

8 M c 9 M c

ai I1

10 12 14 15

H hlc

H H

ai

lLIC

H

Mc H Mc

(N-(-24)

It 11

OMe

R'

K2

R3

11

MC

H

% ,

13

It

% ,

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

0

OMe

’

16

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

Rubiaceae

bark)

Uncuria mucrophyllu Wall. (leaves)

Rubiaceae

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

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

(?)

I

65

OMe

27

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

R=011

as

R=H

86

R=OiI, A"

a7

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

H

i,SMe

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).

38

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

19 20

R=H R=Br

H;&g 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

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

=

=

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

3

P

1

- xylopyranose

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.

63

MARINE ALKALOIDS

"Np;;u COzH

HN

HOzC

COzH

COZH

140

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

cNH

H

R’

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

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

171 170

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

189

188

187 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

71

n 203 201

202

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

<+

208

S

H

214 HNRR= 210 211 212

215

R=N(Me), R=NHMe R=NHCOEt

A=

AA L A 0

216

A=

and shown to exhibit anthelmintic activity (183). The structures were determined from extensive two-dimensional NMR experiments, and 217 and 218 turned out to be the first examples of alkaloids having a pyrrolo[2,3,4-kC]acridineskeleton. Plakinidines A (217)and B (218)might be biogenetically related to the amphimedine alkaloids described above since the plakinidines have only the A/B/Ctricyclic nucleus in common with parent array of 189 as the D ring is contracted. Plakinidines A (217)and B (218)together with the 9,IO-dehydro derivative of 217, named plakinidine C (219),were isolated from a Fijian sponge (Pfukortissp.), and the structure of 217 was established by X-ray analysis (184). The Okinawan yellow sponge Auptos uupfos contained a new type of alkaloid, aaptamine (220),having a 1H-benzo[de][I ,6] naphthyridine skeleton (18.5). Demethylaaptamine (221)and demethyl(oxy)aaptamine (222)

0

$3

9

217 A’=H,

R’=CH,

218 R’SH,, RLCH, 219 R’=H, R*=CH,, 9.10-dehydo

R=Me 221 R=n 220

222

2.

73

MARINE ALKALOIDS

were also isolated from the same sponge (186). Aaptamine (220) shows the most powerful a-adrenoceptor blocking activity on vascular smooth muscle (187), whereas demethylaaptamine (221) and demethyl(oxy)aaptamine (222) are cytotoxic and antimicrobial substances. Because of their unusual structures as well as useful biological activities, syntheses of aaptamine alkaloids were well investigated, and the total synthesis of aaptamine (220) (188-192) and demethyloxyaaptamine (222) (193) were achieved by different methods. The highly cytotoxic pigment discorhabdin C (223) was isolated from a New Zealand red-brown sponge of the genus Latrunculia. An X-ray diffraction study showed that discorhabdin C (223) contains a new tetracyclic iminoquinone chromophore with a spiro-2,6-dibromocyclonexadienone unit (194). From the Okinawan green sponge Prianos melanos prianosin A (224) was isolated, and its absolute stereostructure was established by X-ray analysis (195). Prianosin A (224) is active in assays for antileukemic activity and for release of Ca2+ from the sarcoplasmic reticulum. This compound (224) was also obtained from the New Zealand sponge Latrunculia brevis and designated as discorhabdin A (196). This sponge yielded discorhabdins B (225) (196) and D (226) as well (197); the latter was also

Br

Br 0

0

223

0

224

225

227

228

R=OH

229

R=H

0

226

74

JUN’ICHI KOBAYASHI A N D MASAMI ISHIBASHI

6 dNH2 0

Br

0

Br

0 ’

A

230

R’

R2

231

Me

SMe

232

H

SMe

233

Me

H

contained in an Okinawan sponge of the genus Priunos (197). Discorhabdins A-C (224,225,and 223)are strongly cytotoxic and antimicrobial but do not show in uiuo antitumor activity, whereas discorhabdin D (226) exhibits significant in uiuo antitumor activity. The Okinawan sponge Priunos melunos also contained prianosins B-D (227-229), which are cytotoxic against murine lymphoma cells and human epidermoid carcinoma cells in uitro. Prianosin D (229)induces Ca2+release from the sarcoplasmic reticulum, whereas such activity is not observed for prianosin B (227) or C (228)(198). Prianosins and discorhabdins comprise a new type of nitrogenous pigment with a novel molecular skeleton, the biogenesis of which may involve tyrosine and tryptophan. In this connection a tyrosine metabolite (230) has been known previously from another sponge (199), and more recently batzellines A-C (231-233) were isolated from a deep-water Bahamian sponge (Batzellines sp.), with the structure of 231 based on X-ray analysis (200). Batzellines and compound 230 may well be the biosynthetic precursors of prianosins or discorhabdins. Because of the unusual structures as well as significant biological activities the prianosin alkaloids have been the subject of total syntheses (201-203). B. NONAROMATIC COMPOUNDS Papuamine (u4)is a pentacyclic nonaromatic alkaloid with antifungal activity that was isolated from a sponge of the genus Haliclona collected at Papua New Guinea (204). Haliclonadiamine (235), an unsymmetrical diastereomer of 234, was isolated together with 234 from a sponge of the same genus collected at Palau (205), and the structure of 235 was established by X-ray analysis. Both papuamine (234)and haliclonadiamine (235) exhibit antimicrobial activity.

2.

75

MARINE ALKALOIDS

235

Macrocyclic quinolizidine or 1-oxaquinolizidine alkaloids, araguspongines B-H (236-242) and J (243) (206) and aragupetrosine A (244) (207)were isolated from an Okinawan sponge (Xestospongiu sp.) together with the previously known petrosin (245) (208)and petrosin A (246) (209). These alkaloids show vasodilating activity.

245

246

76

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

247

249

248

250

The Mediterranean sponge Reniera sarai is a rich source of new macrocyclic alkaloids, named sarains, which may be biogenetically related to petrosin (246) or araguspongins (236-243). The structures of sarains 1-3 (247-249) (210) and isosarain 1 (250) (211) were clarified on the basis of extensive spectroscopic analyses. The position of the double bond in 249 remains to be determined. The more polar fraction of this sponge contained three UV-absorbingalkaloids, named sarains A-C. The structure of the diacetylated derivative of sarain A (251) was established by X-ray analyis (212). From a Japanese sponge of the genus Huliclonu two cytotoxic alkaloids, haliclamines A and B (252 and 253), were isolated (213). They are proposed to be biogenetic precursors of the petrosins or sarains.

MI. Polyketides A. KABIFUMIDEGROUP Several nitrogen-containing macrolides were reported to be obtained from marine sources. Ulapualides A (254) and B (255), possessing unique structures with three contiguous oxazoles, were isolated from the egg

2. MARINE ALKALOIDS

77

AcO

251

252 253

A14

masses of the Hawaiian nudibranch Hexabranchus sanguineus. They were shown to exhibit cytotoxic and antifungal activity (214). Kabiramide C (256), an antifungal macrolide with a structure closely related to ulapualides, was isolated from the egg masses of an Okinawan nudibranch (215).These substances may play some role in chemical defense, as the egg masses are avoided by predators in spite of their quite distinct shape and color. From Hexabranchus egg masses six other macrolides, kabiramides A (257), B (258), D (259), and E (260), dihydrohalichondramide (261), and

Me

254 R

=0

255 R

OMe

OMe

78

JUN'ICHI KOBAYASHI A N D MASAMI ISHIBASHI

I

Me

256 R'=CONH2 R2=H R3=CH3 257 R'=CONH2 H'=OH 258 R'=CONH, 259 R'=H

R3=CH3

R2=H R3=H

OH

OMe

R2=H R3=CH,

260 R'=CONH2 R2=H R3=CH

33-methyldihydrohalichondramide (262) were isolated, and they were determined to be cytotoxic against murine leukemia cells and fertilized sea urchin eggs (216). Kabiramides B (258) and C (256) were also isolated from a sponge (Hulichondriu sp.) collected in Palau. The same sponge contained halichondramide (263) (227), a related antifungal macrolide, as the major constituent and dihydrohalichondramide (261)and isohalichondra, (263,imide (266), and ester (267) as minor metabolites. mide ( W ) acid

263

2. MARINE ALKALOIDS

79

OMe

HOOC OMe

OMe

0

265 OMe

0

266

OMe

267

80

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

The compounds isolated from the nudibranch Hexabranchus sanguineus varied with collecting location but usually included dihydrohalichondramide (261) and tetrahydrohalichondramide (268). Compounds 261, 263, 265, and 268 show antifungal activity and inhibit cell division in the fertilized sea urchin egg assay (218). Three cytotoxic macrolides, mycalolides A-C (269-271), were isolated from a Japanese sponge of the genus Mycale, and their structures were elucidated to be hybrids of ulapualides and halichondramide (219).

B. OTHERPOLYKETIDES Latrunculins A (272) and B (273) are two fish toxins first isolated from the Red Sea sponge Latrunculia magnifica (220,221). Two minor toxins named latrunculins C (274) and D (275) were isolated from the same sponge (222). Latrunculin A (272) was isolated from the Pacific nudibranch Chromodoris elisabethina (223), and latrunculin B (273) was obtained from a nudibranch Glossodoris quadricolor (224);these nudibranchs are known

w

268

on

oMe

0

OMe

0 OAc

269 R = 0 270 R =

< OMe

271 R =

< OMe

2.

81

MARINE ALKALOIDS

\\<\.."'

HN3 b

HN

0

0

273

272

OH

HN3 b 0

274

275

to feed on sponges. Latrunculin A (272) was also found in the Fijian sponge Spongia mycojijiensis and the associated nudibranch Chromodoris lochi and exhibits cytotoxicity (225). The toxins (272 and 273) were suggested to serve as defense allomones. Rearrangement and ring-opening reactions of latrunculin B (273) were investigated to obtain several new biologically active derivatives (226). The Okinawan tunicate Eudistoma cf. rigida contained novel nitrogencontaining macrolides, namely, iejimalides A (276) and B (277) which show potent cytotoxicity against murine leukemia cells (227). Iejimalides possess a unique structure with N-formyl-L-serine in the side chain and are the first macrolides isolated from a tunicate. A new family of novel thiazole-containing polyketide metabolites, patellazoles A-C (278-280), were isolated from the didemnid tunicate Lissochinum patella collected at Fiji (228) and Guam (229). Patellazoles are potent cytotoxins with antifungal activity. From the benthic dinoflagellate Prorocentrum lima, prorocentrolide (281) was isolated as a toxic macrocycle with a lethality in mice of 0.4 mg/kg (i.p.1 (230). Prorocentrolide (281)

82

JUN’ICHI KOBAYASHI A N D MASAMI ISHIBASHI

appears to be formed from a C49fatty acid and incorporates a C27 macrolide and a hexahydroisoquinoline in its unique structure. The Japanese sponge Discodermia calyx was shown to contain calyculins A-D (282285) (231,232),novel spiroketals with an unprecedented skeleton bearing phosphate, oxazole, nitrile, and amide functionalities. Calyculins A-D (282-285) showed significant activity in starfish and sea urchin egg assays and were also highly cytotoxic against murine leukemia cells. Calyculin A exhibited in uiuo antitumor activity in mice. Mycalamides A (286) (233) and B (287) (234) were isolated from a New Zealand sponge of the genus Mycale and exhibit significant in uiuo antiviral and antitumor activity. From an Okinawan sponge (Theonella sp.) onnamide A (288) with a structure closely related to mycalamides was isolated,

OH

on

278 R’=H

R2=H

279 R’=H

R2=OH

280 R’=OH

R2=OH

281

2. MARINE ALKALOIDS

83

203 R’=H R2=CN R3=H 204 R‘=CN R2=H R3=CH3 205 R’=H R2=CN H3=CH3

GOOH

QH

H

KNH2 NH

200

84

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

and onnamide A shows in uitro antiviral activity (235). The structures of the mycalamides and onnamide A closely resemble pederin isolated from a terrestrial beetle as an insect toxin (236).Total synthesis of mycalamides A (286) and B (287) in an optically pure form was accomplished to establish their absolute configurations (237). Bistramide A (C40H68N208) was isolated from the tunicate Lissoclinum bistratum collected at New Caledonia and shown to possess neuro- and cytotoxic activity. Although extensive two-dimensional NMR studies were used, its complete structure remains to be established (238). Bengamides A-F (289-294) (239,240),isobengamide E (299, and bengazoles A (2%) and B (297) (241)are suggested to be of mixed ketide-amino acid biosynthetic origin; the compounds were isolated from an undescribed sponge of the family Jaspidae collected at the Fiji Islands, guided by an anthelminthic bioassay. The entire absolute stereochemistry of the bengamides were assigned via chemical degradation and spectroscopic analyses (242). Malyngamide C (298) is a chlorine-containing amide of 7(S)methoxytetrade~-4(E)-enoicacid, which was found as a major constituent of the marine blue-green alga Lyngbya mujuscufa from Fanning Island. This alga also contained malyngamide C acetate (299), deoxymalyngamide C (300), and dideoxymalyngamide C (301) (243). Previously, stylocheilamide was isolated from the sea hare Stylocheifus longicauda, and its structure was closely similar to malyngamide C (244).Stylocheilamide is

289

-O,C( CH2),,CH3

H

290

-02C( CH2)12CH3

CH3

291

OH

292 293

OH

H CH3

H

H

2.

MARINE ALKALOIDS

85

295

presumably a dietary constituent of this gastropod and may arise from ingestion of the blue-green alga. Two malyngamides (302 and 303) were isolated from L . majuscula from the Caribbean and named malyngamide D and malyngamide D acetate (245). The name malyngamide D, however, had previously been used for another compound (246).

86

JUN'ICHI KOBAYASHI AND MASAMI ISHIBASHI

The sponge Dysidea fragifis collected at Fiji contained a new azacyclopropene carboxylic acid ester, dysidazirine (304)(247),which was the first example of the ring-strained class of heterocycles from a marine source. The absolute configuration of 304 was determined via the CD spectrum of a 4-bromobenzamide derivative, and a biogenetic relation to sphingosine was suggested. Dysidazirine (304)is cytotoxic against murine leukemia cells and inhibits the growth of gram-negative bacteria and yeast. Two epimeric amino alcohols, 2(S)-aminotetradeca-5,7-dien-3(S)-and -3(R)-ol(305and 306) were isolated from a sponge from Papua New Guinea (Xestospongia sp.) (248).The absolute stereochemistry was disclosed by degradation to L-alanine, and these amino alcohols (305 and 306) were suggested to be biosynthesized from fatty acids and alanine. Compounds 305 and 306 show antimicrobial activity. Rhizochalin (307) was isolated from the Madagascan sponge Rhizochafina incrustata as an antimicrobial constituent (349). The biosynthetic pathway for 307 is unknown but is conventionally believed to be derived from alanine and a polyketide precursor(s). A sphingosine derivative, symbioramide (308),was obtained from the laboratory-cultured dinofagellate Symbiodinium sp. as a Ca*+-ATPase activator in the sarcoplasmic reticulum (250). The complete stereostructure of 308 was established by total synthesis (251). The occurrence of erythro-docosasphinga-4,8-dienine,as an ester (W), was found in Anemonia sufcata(252).This is the first example of a sphinga-4,8-dienineester. A

OH

305 304

OH

306

OH 307

CH,QH

2. MARINE

ALKALOIDS

87

OH

no

0

308 OH

'on 309

31 0

hemolytic choline chloride ester homopahutoxin (310)was found in mucous secretions of the Japanese boxfish Ostracion immaculatus together with previously isolated pahutoxin (253). Three hemolytic constituents were isolated from the Japanese hydroid Solanderia secunda and identified as 1 -hexadecyl-sn-glycerol-3phosphorylcholine (311), 1-tetradecyl-sn-glycerol-3-phosphorylcholine (3l2),and 1-( l-hexadecenyl)-sn-glycerol-3-phosphorylethanolamine(313) (254) Eighteen long-chain aliphatic a,o-bisisothiocyanates (314-331)and three a-isothiocyano-o-formyl compounds (332-334)were isolated from a Fijian sponge (Pseudaxinyssa sp.) (255).

VIII. Peptides A. DI-, TRI-,AND TETRAPEPTIDES

The Fijian undescribed Jaspidae sponge which yielded the bengamides and bengazoles contained a diketopiperazine cyclo-(4-hydroxyprolinyl)~phenylalanine (335) along with N-acetyl-L-phenylalanine methyl ester (336).The configuration of all of the constituent amino acids was shown to

88

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI CHPOCH~(CH~)I&H,

I

HO-C-H

0

I

II

CH~O-P-OCH~CH~~~~CH,),

I

0 311 CH,OCH=CH(CH2),3CH,

I

HO-C-H

0

I

II I

CH20-P-OCH2CH2NH3

0 313

S

C

N

V

N

C

S

S C N F N S C

314

n=14

318

n=ll

322

n=16

327

n=13

315

n=8

319

n=12

323

n=9

328

n=14

316

n=9

320

n=13

324

n=10

329

11.15

317

n=10

321

n=15

325

n=ll

330

n=17

326

n=12

331

n=18

S C N q C H o 332

n.15

333

n=9

334

n=16

be L by total chiral synthesis (240). Etzionin (337),a diketopiperazine hydroxamate derivative, was isolated from an unidentified Red Sea tunicate and exhibited antifungal activity (256).(-)-Gliovictin (338), a diketopiperazine previously isolated from terrestrial fungi of the genera Helminthosporium and Penicillium, was obtained from culture broths of the marine deuteromycete Astermyces cruciutus (257). Three diketopiperazines (339-341) formerly isolated from the sponge Teduniu ignis (258)were found in the laboratory culture media of a marine bacterium (Micrococcus sp.) which was isolated as a symbiont from the sponge T . ignis (259).This was the first demonstration that a bacterium associated with a sponge produces secondary metabolites ascribed to the sponge host. A lipophilic tripeptide, janolusimide (342),was isolated from the Mediterranean nudibranch Junolus cristutus and was found to be toxic to mice (260). From the Swedish sponge Geodiu buretti barettin, a cyclic polypeptide, was isolated and found to show inhibiting activity on electrically induced contractions of isolated guinea pig ileum (261). Barettin is composed of dehydro-6-bromotryptophan and proline. The initial proposed

2.

MARINE ALKALOIDS

89

structure (343) proved to be incorrect, and the cyclic tetrameric structure (344)was suggested based on the viewpoint of peptide synthesis (262).The cyclic tetrapeptides fenestins A (345) and B (346) were isolated from the Fijian sponge Leucophloeus fenestrata (263) together with a known diketopiperazine (340) (258). No activity is shown by either fenestin against murine lymphoma or human colon tumor cells.

338

B. DIDEMNINS A N D PATELLAMIDES Didemnin B (347) is a cyclic depsipeptide isolated from the Caribbean tunicate Trididemnum solidum and is currently in phase I1 clinical trials as an anticancer agent. Didemnin B also shows antiviral and immunosuppressive activity. The structure of didemnin B was revised to 347 containing

9o

JUN'ICHI KOBAYASHI AND MASAMI ISHIBASHI 0

343

344

(3S,4R,5S) the configuration of isostatine based on total synthesis (264) and X-ray crystal analysis (265).Two other total syntheses of didemnin B were achieved (266,267).The conformation in solution of didemnin B (347) was examined using two-dimensional NMR, and it was suggested that the NH groups of leucine and isostatine are oriented inward (268).Nordidemnin B (348)was isolated from the Caribbean Trididemnum solidum and proved to be a lower methylene homolog of didemnin B (347) (269).The structures of patellamides A-C were revised to be 349-351 on the basis of total synthesis (270-273). The absolute configuration of ascidiacyclamide (352) was determined by total synthesis (274).X-Ray analysis of synthetic 352 was carried out (275),and the solution and solid state conformations of 352 were disclosed by 'H-NMR spectroscopy (276).Two total syntheses of ulithiacyclamide (353) were achieved (277,278),and the conformational

2.

91

MARINE ALKALOIDS

properties of 353 were investigated by extensive NMR spectroscopic studies and molecular mechanics energy minimizations (279). Three other cyclic peptides, prelissoclinamide 2 (354),prepatellamide B formate (353, and preulicyclamide (356)were isolated from the tunicate Lissoclinum patella (280). A cytotoxic cyclic peptide, ulithiacyclamide B (357),was isolated from the tunicate L. patella from Pohnpei (281).The same tunicate collected in Australia contained four cytotoxic cyclic peptides, patellamide D (358)and lissoclinamides4,5, and 6 (359-361)(282). The structure and absolute configuration of patellamide D (358)were determined by X-ray crystallography. Computer modeling indicated that the energyminimized conformation of 358 closely resembled that found in the crystalline form.

349

350 351

RnCH2CH(CH,)2 R:CH(CH,),

92

JUN'ICHI KOBAYASHI A N D MASAMI ISHIBASHI

358

2. MARINE

93

ALKALOIDS

C. DOLASTATINS AND MAJUSCULAMIDES The sea hare Dolabella auricularia was recorded to exhibit exceptionally potent biological properties, which were known to certain ancient Greeks and Romans. The most important antineoplastic constituent of D. auricularia was dolastatin 10 (362)(283), a linear pentapeptide that was reported to be the most potent antineoplastic substance known to date. The absolute configuration of 362 was ascertained by total synthesis (284). Synthetic studies revealed that the initial structure (285) proposed for dolastatin 3 was incorrect (286-291). The structure of dolastatin 3 was reassigned as 363, and its absolute chirality was established by synthesis (292). The minimum energy conformation of 363 in solution was estab-

362

A

94

JUN'ICHI KOBAYASHI AND MASAMI ISHIBASHI

364

R'=CH,CH(CH,),

369 R'.CH(CH,)CH,CH,,

R2=Me R'=H

lished by NMR spectroscopy and force field calculations, being characterized by three intramolecular hydrogen bonds (29.3). Further examination of cytostatic depsipeptide constituents of the Indian Ocean shell-less mollusc D . auricularia resulted in the isolation of dolastatins 1 1 (364)(294), 13 (365) together with its dehydro derivative (366)(295), 14 (367)(296), and 15 (368)(297). Each dolastatin exhibits strong cytotoxic activity against the P388 lymphocytic leukemia cell line, whereas dehydrodolastatin 13 (366)proved to be marginally active. Normajusculamide C (369),which is closely related to dolastatin 1 1 (364),was isolated from a deep-water variety of the blue-green alga Lyngbya majuscula collected at Enewetak Atoll in the Marshall Islands (298).Compound 369 exhibits antimycotic activity. From the same alga L. rnajuscula were isolated the lipopentapeptides majusculamide D (370)and deoxymajusculamide D (371),with both compounds showing moderate cytotoxicity (299).

2. MARINE ALKALOIDS

367

95

n 0

368

370 371

REOH R=H

D. OTHERPEPTIDES From sponges of the genus Juspis collected at Fiji (300,300,Palau (300), and Papua New Guinea (302),jaspamide (jasplakinolide, 372) was isolated; the compound shows potent insecticidal, antifungal, anthelminthic, and ichthyotoxic activity. The structure was determined by X-ray analysis (300). The solution conformation of 372 was reported using NMR, molecular mechanics, and dynamics calculations (30.3).A complexation study was carried out with 372 and the univalent metal ions Li?, N a + , and K + . Li+ binding was observed, and the complex was characterized by NMR and molecular mechanics calculations (304). Jaspamide (372) has potent in

96

JUN'ICHI KOBAYASHI AND MASAMI ISHIBASHI OH

373 374 375 376 377 378

372

R'=l R2=Me R'=Br R2=Me R'=CI R2=Me R'=I R2=H R'=Br R2=H R ' X I R2=H

vitro cytotoxicity against tumor cells and in vitro and in uiuo antifungal activity. Jaspamide (372) was the first macrocyclic mixed polyketide depsipeptide reported from a marine organism, and it has been the subject of total synthesis (305,306). Geodiamolides A (373) and B (374) were isolated from a sponge (Geodiu sp.) and their stereostructures determined by X-ray crystallography; they exhibit antifungal activity (307).Geodiamolides C-F (375-378) were isolated from a sponge (Pseuduxinyssu sp.) collected in Papua New Guinea

379 R=pAla 380 R=MeDAla

2. MARINE

97

ALKALOIDS

and exhibit in vitro cytotoxicity, in vivo antineoplastic activity, and in vitro antimicrobial activity (308). Geodiamolides contain a tripeptide unit joined to a polypropionate unit common to jaspamide (372), and total syntheses of the geodiamolides were also studied (309,310). Theonellapeptolides Id (311) [=theonellamine B (312),3791 and l e (380) (313) were isolated from an Okinawan sponge (Theonella sp.). These pep.Xe \x\~ntsxe.n.t tm.ny\ts cony
382

98

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

383 Rzo-r-Leu- L-r-Le u 384 Rzo-Val-L-I-Leu 385 R=D-I-Le u L- V a I 386 R=o-Val-L-Val ~

the defense secretion of the sole (Pardachirus pauoninus), and they are probably responsible for the predator (shark)-repellingproperty of the sole (329). A Caribbean cyanobacterium Hormothamnion enteromorphoides was found to produce a complex mixture of cytotoxic and ichthyotoxic peptides, hormothamnins, which may explain the apparent absence of predation on these potentially palatable life forms. Initial chemical characterization suggested that the major peptide, hormothamnin A, is a cyclic undecapeptide containing six common and five uncommon amino acid residues (320).

IX. Miscellaneous Alkaloids

A. TYROSINE-DERIVED ALKALOIDS Sponges of the order Verongida possess interesting chemical and biological features and frequently contain secondary metabolites derived from bromotyrosine. Purealin (390)(321)and lipopurealinsA-C (391-393) (322) were isolated from an Okinawan sponge (Psammaplysilla purea) and found to be unique modulators of enzymatic reactions of ATPases (323326). Purealin (390) and lipopurealins A-C (391-393) show inhibitory activity on Na+, K+-ATPase. Purealin (390)is the first natural product that activates myosin K+,EDTA-ATPase, whereas this enzyme was inhibited by lipopurealin B (392). Psammaplysin A (394)and B (393, which had been isolated from a Red Sea sponge (Psammaplysilla purpurea) (327), were found as antimicrobial constituents in the same sponge collected in Palau, and their structures were revised to have a spiro[4,6]dioxazundecane skeleton on the basis of l3C-I3C connectivity and X-ray diffraction studies

2 . MARINE ALKALOIDS

Bl

390

n

(328). Psammaplysins appear to be biogenetically derived from dibromotyrosine through an intermediate containing an arene oxide and oxime (329). Ianthelline (3%) was isolated from the sponge Zanthella ardis collected in the Bahamas and possessed antimicrobial activity (330). A dimeric bromotyrosine derivative containing a disulfide linkage, named psammaplin A (397), was obtained from an unidentified Guam sponge of the family Verongidae ( H I ) , a sponge of the genus Psammaplysiffa from the Kingdom of Tonga (332), and a Guam sponge Thorectopsamma xana (333).The E,E and E,Z isomers of the oxime groups were found, and the E,Z (or the Z,Z) isomer was suggested to be natural and isomerized to the E,Eform during isolation (331).The sponge T. xana also contained the tetramer (398) (333).Psammaplin A (397) is cytotoxic (332), and both 397 and 398 show antimicrobial activity (333).

394 R=H 395 R=OH

100

JUN'ICHI KOBAYASHI AND MASAMI ISHIBASHI

I

HO

397 398

Dihydroxyaerothionine (399) was isolated from the deep-water sponge Verongula rigida collected in the Bahamas, but 399 was reported to be devoid of biological activity (334).The sponge Hexadella sp. collected in British Columbia contained antimicrobial bromotyrosine derivatives, hexadeltins A (400)and B (401) (335). 11,19-Dideoxyfistularin 3 (402)and 1 1-hydroxyaerothionine (403) were isolated from an Australian verongid sponge (Pseudoceratine durissima) and shows in vitro antimicrobial activity (336). Anomoian A (404) was obtained from another Australian verongid sponge (Anomoianthella popeae) and also shows antimicrobial activity (337). OMe

OMe

HO

0

HO

OMe

2.

MARINE ALKALOIDS

101

Tunicates selectively accumulate vanadium (or iron) in their specialized blood cells. The reducing blood pigment tunichrome B-1 (405) (338,339) and two other related tripeptides (406 and 407) were isolated from Ascidia nigra, and two additional tunichromes (408 and 409) were obtained from the iron-sequestering tunicate Molgula manharrensis (340).Purification of tunichromes entailed unusual chromatographic techniques, all performed anaerobically. Tunichromes were reported as the compounds responsible for metal accumulation. However, cells strongly fluorescent owing to the presence of tunichromes proved to contain no vanadium (341). From a Palau prosobranch mollusc (Lamellaria sp.) were isolated lamellarins A-D (410-413) (342). The skeleton of the lamellarins resembles those of tunichromes and is possibly biosynthesized via sequential hydroxylations of a tripeptide precursor containing tyrosine or dopa. Interestingly, colonial tunicates are a staple of molluscs closely related to Lamellaria sp. The structure of lamellarin A (410) was established by an X-ray crystallographic study. Lamellarins C (412) and D (413) inhibit cell division in sea urchin embryos, whereas lamellarins A (410) and B (411) are inactive. Lamellarins E-H (414-417) were isolated from the ascidian Didemnum

102

JUN'ICHI KOBAYASHI AND MASAMI ISHIBASHI

..408 409

Meb Meo

R=H R=i-Bu

c

411 R'=Me, R2=OMe 413 R'=H, R 2 = H

414 R'=H, R2=Me, R 3 4 , R'zMe, 415 R'=H, R2=Me, R3=Me, R'zMe, 416 R'=Me, R2=H, R 3 4 , R'4,

R5=OH R5=OH R5=H

41 7

chartaceurn from the Indian Ocean, and the structure of 414 was based on X-ray analysis (343).This finding suggests that lammelarins A-D isolated from the mollusc Lamellaria sp. were most likely sequestered from an ascidian in the diet of the mollusc.

B. PYRIDINE A N D PIPERIDINE ALKALOIDS Niphatynes A (418) and B (419) are pyridine derivatives with alkyne and methoxylamine functionalities isolated from the Fijian sponge Niphates sp. (344). Niphatyne A (418) exhibits cytotoxic activity. Theonelladins A-D (420-423) are other pyridine alkaloids obtained from the Okinawan sponge Theonella swinhoei and exhibit antineoplastic activity (345).These

103

2. MARINE ALKALOIDS

pyridine metabolites may be biogenetically related to halitoxins (346), haliclamines (213),petrosin (208),or sarains (210).An uncommon pyridine derivative substituted at C-2 by a bicyclic polyketide-derived C 16 alkadienone (424) was isolated from the Hawaiian caphalaspidean mollusc Philinopsis speciosa (347). Extracts of the Okinawan tunicate Pseudodistoma kanoko contained the antineoplastic piperidine alkaloids pseudodistomins A (425), and B (426) which also showed calmodulin-antagonistic activity (348). Pseudodistomins were the first piperidine alkaloids found from marine sources. Tubastraine (427), the first example of a chromonecontaining metabolite of a marine invertebrate, was isolated from the Pacific stony coral Tubastraea micrantha and was speculated to be responsible for the avoidance response of the crown-of-thorns seastar, Acanthaster planci, the major predator of stony corals (349). N,N-Dimethyl-l,2,3,6-tetrahydropyridinio-2-carboxylate (428) was obtained from the Mediterranean red alga Pterocladia capillacea; no biological activity was reported (350).An antibacterial yellow pigment of the Antarctic sponge Dendrilla membranosa was identified as 4,5 ,&trihydroxyquinoline-2-carboxylic acid (429), and its structure was confirmed by synthesis (351). Renierol(430), an isoquinoline quinone with antimicrobial and cytotoxic activity, was isolated from the Fijian sponge Xestospongia caycedoi (352).Two very unstable isoquinoline derivatives, renieramycins

4 -

\

N

425

NHR

420

R=H

421

R=Me

AfvvvW,..,.n 426

NHR 422 423

R-H R=Me

Br Me 424

427 Br

JUN’ICHI KOBAYASHI

104

A N D MASAMI ISHIBASHI

428

Me0

P

I 437 438

COOH OH 429

431 432 433 434 435 436

R’=OH R2=R3=H R’=OH R2=H R3=OMe R‘=R*=H RLOH R’=R2=H R3=OEt R’,R~=o R ~ = O H R’,R2=0 R3=OEt

R ’ = + N H ~ ,R ~ = H R’=o, R ~ = H

Rf?&o

qIH ‘V R20

Me0

H OH

430

439 440

R’=Me. R 2 = H R’=Rz=Me

E (431) and F (432), were isolated from the Palau sponge Reniera sp. (353). The structures of renieramycins A-D previously found in a sponge of the same genus (354) were reassigned to 433-436, in which the stereochemistry is identical with that of saframycins, metabolites of Streptomyces sp. whose structures were based on X-ray analysis (355). C. PYRIMIDINE, PURINE, A N D RELATED ALKALOIDS 3-Methyl-2’-deoxycytidine (437) and 3-methyl-2’-deoxyuridine(438) were isolated from the Swedish sponge Geodia baretti. Compound 437 exhibits strong contractile activity in the isolated guinea pig ileum assay, whereas 438 had no effect on contractions (356).Thymidine-5’-carboxylic acid ( W ) ,which were preacid (439) and 2’-deoxyuridine-5’-carboxylic viously known only as synthetic products, were found in extracts of the ascidian Aplidium fuscum of the East Pyrenean coast (357). 2-Iminomethyl-3-methyl-6-aminomethyl-9H-purine (441) was isolated from the sea anemone Sagartia troglodytes collected in the Bay of Naples. The structure of 441 was determined by X-ray analysis. The synthetic 2,6-diaminopurine (DAP) shows a wide variety of biological activities such as inhibition of the growth of tumors, viruses, plants, or bacteria, whereas the trimethyl derivative (441)shows considerably less inhibitory capacity than DAP (358).A new purine, 1,3,7-trimethyI-guanine(442), was isolated

2.

105

MARINE ALKALOIDS

from the New Zealand sponge Latrunculia breuis but has no detectable cytotoxic, antiviral, or antimicrobial activity (359). Caffeine (443)was separated from the extract of the gorgonian Paramuricea chamaeleon collected at Istanbul (360) and 3-methyladenine (444) was contained in the French sponge Topsentia genitrix (361). 9-[5’-Deoxy-5’-(methylthio)-~-~-xylofuranosyl]-aden~ne (44% the first naturally occumng analog of methylthioadenosine, was isolated from the nudibranch mollusc Doris uerrucosa. Compound 445 was also the first naturally occurring purine carrying a xylose derivative substituent (362). 1,9-Dimethyl-6-imin0-8-oxopurine (446)was obtained from the English Channel sponge Hymeniacidon sanguinea, and the structure was determined by X-ray analysis of its acetyl derivative (363). 3,9-Dimethyl-6methylimino-8-oxo-3,6,8,9-tetrahydropurine,named caissarone (447), was isolated from the Brazilian sea anemone Bunodosama caissarum, and the structure was elucidated by X-ray diffraction analysis (364). The northeast Pacific bryozoans Phidolopora pacifica contained two nitrophenols, desmethylphidolopin (448)and 3-nitro-4-hydroxybenzyl alcohol (449) (365).Desmethylphidolopin (448)showed antimicrobial activity. 2-Amino-6-[ (1 ’R,2’S)-1‘,2’-dihydroxypropyl]-3-methylpterin-Cone (450) was isolated from the anthozoan Astroides calycularis collected in the Bay of Naples and exhibited cell growth-inhibiting activity (366).The structure of leucettidine, a pteridine derivative found in Leucetta microra-

MeN

I Me

H

441

0

OH

M e N k N r

N R’

Me 442 443

445

OH

MeNj$N>o R=NH R.0

4,

N Me

446

450

Me 444

447

451

106

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI 0

452 453 454

0

R’=H, R2:Me R’=R2=Me R’=Rz=H

457 458 459 460

R’=CO,Me, R’zribose R’=CN, R2=ribose R‘=CO,Me, R2=H R’=CN, R2=H

=$$a Me0

on

455

MeQ

OH

456

461

phis (367), was revised to 6-( 1-hydroxypropy1)-1-methyllumazine(451) on the basis of unambiguous synthesis (368). Three 6-propionyl lumazine derivatives (452-454) were isolated from the Japanese polychaete Odontosyffis undecimdonta. Whether the lumazines (452-454) are related to the luminescent system in Odontosyffis bioluminescence is not yet known (369).

Two pyrrolo[2,3-d]pyrimidine nucleosides, mycalisins A (455) and B (456) were obtained from a Japanese sponge Mycafe sp., and both compounds inhibit cell division of fertilized starfish eggs (370). Two cytotoxic

pyrrolo[2,3-6]pyrimidine nucleosides, 5-(methoxycarbony1)tubercidin (457) and toyocamycin (458), were isolated from the Fijian sponge Jaspis johnstoni and showed anticandidal and cytotoxic activities (371). Compound 457 was previously known as a synthetic intermediate, and this is the first time it was isolated as a natural product. Toyocamycin (458) was previously obtained from Streptomyces sp., and this is the first isolation from a marine source. Small amounts of the corresponding aglycones (459 and 460)were also isolated. A nonnucleoside pyrrolopyrimidine alkaloid, named rigidin (461), was isolated from the Okinawan tunicate Eudistoma cf. rigida and exhibits calmodulin-antagonisticactivity (372).

D. IMIDAZOLE,THIAZOLE, AND RELATEDALKALOIDS One imidazole- and two thiazole-containingmetabolites (462-464) were isolated fom the Australian ascidian Aplydium pficferum (373). The structures of 462 and 463 were confirmed by synthesis. cis-S-Hydroxy-4-(4’-

2.

107

MARINE ALKALOIDS

hydroxy-3‘-methoxyphenyl)-4-(2”-imidazolyl)1,2,3-trithiane (465) was isolated from the New Zealand ascidian Aplidium sp. D and show cytotoxic and antimicrobial activities. Compound (465) was shown to be a which was generated from 465 by precursor for 2-vanilloyl imidazole (a), standing in neutral solution at room temperature for 1 month; identification of 464 was made by X-ray diffraction (374). An imidazole-containing benzyltetrahydroisoquinolinealkaloid, named imbricatine (466),was separated from the starfish Dermasterias imbricata and shown to be capable of inducing a swimming response in the northeastern Pacific anemone Stomphia coccinea at very low concentrations (375). Imbricatine (466)also exhibits significant antineoplastic activity. Ovothiols A-C (467-469) were isolated from the starfish Euasterias troschellii, the scallop Chlamys hastata (376),and the sea urchin Strongylocentrotus purpuratus (377). Ovothiols readily oxidize in air to disulfide dimers, and the reduced forms confer NAD(P)H-O* oxidoreductase activity on ovoperoxidase, an enzyme exocytosed at fertilization. Ovothiols possess the N-methyl-5-thiohistidine fragment that is common to imbricatine (466). Anguibactin (470) is a unique siderophore (microbial iron-transport compound) isolated from iron-deficient cultures of a fish pathogenic bacterium, Vibrio anguillarum (378).The structure of 470 was determined by X-ray diffraction studies of its anhydro derivative. Another related compound copurified with 470 was identified as 2-(2’,3’-dihydroxypheny1)thiazoline-4-carboxylicacid methyl ester (471) (379).

HO

OMe

462

OMe

464 466

P” no OMe

463

Me0

SH 465 467 468 469

R’,R~=H R’=H,R2=Me R’,Rz=Me

I08

JUN'ICHI KOBAYASHI AND MASAMI ISHIBASHI

0 H NKOMe

473 472 R=l-P-o-glucopyranosyluronic acid

A bioluminescent substance, watasenia preluciferyl /3-D-glucopyranosiduronic acid (472), was isolated from the liver of the myctophina fish Diaphus elucens or D . coeruleus, representative luminous fish in Japan (380). An unusual thiazole-containing compound, mycothiazole (473), was isolated from the sponge Spongia rnycofijiensis collected at Vanuatu; it exhibits anthelminthic activity and high toxicity in mice (381). It was

bOH

o Y - o L

on

Br

HN

480

on

d Me

O=As AI

e

w

no 481

c

n

402

Nccn,cn,o

b""'

z ncn2so,n

OH R

483

NHCHO

2.

MARINE ALKALOIDS

109

suggested that mycothiazole (473) is biogenetically related to latrunculin B (271). Total synthesis of (+)-demethyldysidenin (474) was achieved (382) and led to a revision of the absolute stereochemistry of six compounds (474-479) in the dysideninhodysidenin series (383-385). An oxazolidinone-containing metabolite (480)was isolated from a sponge (Aplysina aerophoba) ofthe Canary Islands, and the structure was established by X-ray analysis (386). E. OTHERALKALOIDS Marine algae were shown to accumulate arsenic, and the Japanese edible seawead Hizikia fusiforme contained arsenic-including ribofuranosides, one of which proved to be 2-amino-3-[5-deoxy-5(dimethylarsinoyl)-~-~-ribofuranosyloxy]propene-1-sulfonic acid (481) (387). 3-Amino-3-deoxy-~-glucose(482) was found as a compound having considerable antibacterial activity in the culture broth of a gram-positive bacterium, a strain of Bacillus, isolated from sediments at a depth of 4310 m in the Pacific basin (388). The structure of bursatellin, a metabolite from the Puerto Rican sea hare Bursatella leachii pleii (389), was revised to be 483, possessing an N formyl amide functionality, by detailed spectroscopic analysis using the compound (483) isolated from the Mediterranean B. leachii leachii and B. leachii savignyana (390). The optical rotation of bursatellin (483) from the Mediterranean sample, however, was of opposite sign to that reported

on 488

Me

110

JUN’ICHI KOBAYASHI AND MASAMI ISHIBASHI

earlier from the Puerto Rican sample, indicating that the isolates are most likely antipodal. 7-Bromocavernicolenone (484)(391)and 7-chlorocavernicolenone (485) (120)were isolated from the Mediterranean sponge Aplysina (= Verongia) cavernicola. Compound 484 is mildly antibacterial, and its structure was determined by X-ray analysis. Involvement of halogenated tyrosine or dopa was envisaged in the biogenesis of 484 and 485. Two epimeric dibromo nitriles (486 and 487) were isolated from the Australian sponge Aplysina laevis. Both compounds are antimicrobial, and biogenetically they are likely to be derived from dibromotyrosine (392). The structure and relative configuration of leptosphaerin, a metabolite of the marine ascomycete Leptosphaeria oraemaris, were established to be 488 by X-ray analysis ( 3 9 3 , and the absolute configuration was confirmed by its total synthesis (394,395). A pyridinium compound, amphikuemin (489), was isolated from a sea anemone (Radianthus kuekenthali) as a compound secreted by the sea anemone to elicit the symbiotic behavior of the anemone fish Amphiprion perideraion (396). 6-Amino-6-carboxy-2-trimethylammoniohexanoate (490) was found in a Mediterranean red alga (Schottera nicaeensis). The distribution of 490 in about 50 species of red algae was investigated to reveal that 490 was present in only three species, S. nicaeensis, Gastroclonium clavatum, and Liagora distenta (397). 5-Dimethylsulfono-4-hydroxy-2-aminovalerate (491) was isolated from the basic amino acid fraction of the Mediterranean red alga Lophocladia lallemandi (118).

l.+/J

Meo*s

M O es* Me0

Me0

s Me$ 495

owe

s

o

s Me$

Me$ 496

Me0 499 498

500

0

s 497

2. MARINE

111

ALKALOIDS

% o

H

Me""...,,, 0'

N

0

506

Adociaquinones A (492) and B (493) and 3-ketoadociaquinone A (494) were obtained from a sponge Adocia sp. collected in Truk Lagoon (398). Compounds 492 and 493 were synthesized from xestoquinone (399) by heating with hypotaurine. Adociaquinone B (493) was mildly cytotoxic. Polycarpamines A-E (495-499) with a rare, sulfur-containing benzenoid

112

JUN'ICHI KOBAYASHI AND MASAMI ISHIBASHI

"'.'qH 0

0

I

structure were isolated from a Philippine solitary ascidian (Polycarpa auzata) (400). Polycarpamine B (4%) exhibited significantantifungal activ-

ity. An indolizidine alkaloid, stellettamide A (500), was isolated from a Japanese sponge of the genus Stelletta. Compound 500 showed antifungal and cytotoxic activity (401). A new species of a colonial zoanthid of the genus Zoanthus collected in the Bay of Bengal contained a new class of alkaloids: zoanthamine [Sol, the structure of which was based on X-ray analysis (402)],zoanthenamine (502), zoanthamide (503) (403), 28-deoxyzoanthenamine (504), 22-epi28-doxyzoanthenamine(505) (404), and zoanthaminone (506) (405). Compounds 501-504 possess inhibitory activity in the phorbol myristate acetate (PMA)-inducedmouse ear inflammation assay as well as analgesic activity. These zoanthamine alkaloids are of unknown biosynthetic origin. Although some elements may suggest a triterpenoid origin, the carbon skeleton is far from a normal polyisoprenoid system. Cephalostains 1-6 (507-512), powerful cell growth inhibitory substances against the PS cell line, were isolated from the marine worm Cephalodiscus gilchristi collected in the Indian Ocean (406408). The structure of cephalostatin 1 (507) was determined by X-ray analysis. Cephalostatins apparently result from a biosynthetic condensation of 2amino-3-oxosteroid units to yield dimeric steroidal molecules connected by a pyrazine ring. REFERENCES I . C. Christophersen, in "The Alkaloids" (A. Brossi, ed.), Vol. 24, p. 25. Academic Press, New York, 1985. 2. D. J. Faulkner, Nar. Prod. Rep. 1,251 (1984). 3. D. J. Faulkner, Nar. Prod. Rep. 1,551 (1984). 4. D. J. Faulkner, Nut. Prod. R e p . 3, 1 (1986).

2. MARINE ALKALOIDS

I13

5 . D. J. Faulkner, Nat. Prod. Rep. 4,539 (1987). 6. D. J. Faulkner, Nat. Prod. Rep. 5,613 (1988). 7. W. Fenical, in “Alkaloids: Chemical and Biological Perspectives” (S. W. Pelletier, ed.), Vol. 4, p. 275 Wiley, New York, 1986. 8. H. C. Krebs, in “Progress in the Chemistry of Organic Natural Products” (W. Herz, H. Grisebach, G. W. Kirby, and C. Tamm, eds.), Vol. 49, p. 151. Springer-Verlag, Wein and New York, 1986. 9. P. J. Scheuer, ed., “Bioorganic Marine Chemistry,” Vol. 1. Springer-Verlag, Berlin, 1987. 10. P. J. Scheuer, ed., “Bioorganic Marine Chemistry,” Vol. 2. Springer-Verlag, Berlin, 1988. 11. D. G. Fautin, ed., “Biomedical Importance of Marine Organisms,” California Academy of Science, San Francisco, California, 1988. 12. C. W. Jefford, K. L. Rinehart, and L. S. Shield, eds., “Pharmaceuticals and the Sea,” Technomic Publ., Lancaster, Pennsylvania, 1988. 13. D. M. Anderson, A. W. White, and D. G. Baden. eds., “Toxic Dinoflagellates.” Elsevier, New York, 1985. 14. M. J. Carson, N a t . Prod. Rep. 6, 143 (1989). 15. T. Yasumoto, D. Yasumra, M. Yotsu, T. Michishita, A. Endo, and Y. Kotaki, Agric. B i d . Chem. 50,793 (1986). 16. T. Noguchi, J.-K. Jeon, 0. Arakawa, H. Sugita, Y. Deguchi, Y. Shida, and K. Hashimoto, J. Biochem. (Tokyo) 99, 31 I (1986). 17. M. Yotsu, T. Yamazaki, Y. Meguro, A. Endo, M. Murata, H. Naoki, and T. Yasumoto, Toxicon 25,225 (1987). 18. T. Yasurnoto and T. Michishita, Agric. Biol. Chem. 49, 3077 (1985). 19. M. Nakamura and T. Yasumoto, Toxicon 23,271 (1985). 20. A. Endo, S. S. Khora, M. Murata, H. Naoki, and T. Yasumoto, Tetrahedron Lett. 29, 4127 (1988). 21. S. S. Khora and T. Yasumoto, Tetrahedron Lett. 30,4393 (1989). 22. T . Yasumoto, M. Yotsu, M. Murata, and H. Naoki, J. Am. Chem. Soc. 110,2344 (1988). 23. T . Yasumoto, M. Yotsu, A. Endo, M. Murata, and H. Naoki, Pure Appl. Chem. 61,505 ( 1989). 24. M. Yotsu, T. Yasumoto, Y. H. Kim, H. Naoki, and C. Y. Kao, Tetrahedron Lett. 31, 3187 (1990). 25. S . K. Mitra, B. Sanyal, S. N. Ganguly, and B. Mukhejee, J. Chem. Soc., Chem. Commun., 16 (1989). 26. M. Isobe, T. Nishikawa, N. Fukami, and T. Goto, Pure Appl. Chem. 59, 399 (1987). 27. M. Isobe, T. Nishikawa, S. Pikul, and T. Goto, Tetrahedron Lett. 28,6485 (1987). 28. M. Isobe, Y. Fukuda, T. Nishikawa, P. Chabert. T. Kawai, and T . Goto, Tetrahedron Lett. 31, 3327 (1990). 29. Y. Shimizu, in “Progress in the Chemistry of Organic Natural Products” (W. Herz, H. Grisebach, G. W. Kirby, and C. Tamm, eds.), Vol. 45, p. 235. Springer-Verlag. Wien and New York, 1984. 30. Y. Shimizu, S. Gupta, K. Masuda, L. Maranda, C. K. Walker, and R. Wang, Pure Appl. Chem. 61,513 (1989). 31. M. Kodama, T. Ogata, and S. Sato, Agric. Biol. Chem. 52, 1075 (1988). 32. K. Hashimoto and T. Noguchi, Pure Appl. Chem. 61,7 (1989): 33. Y. Shimizu, Pure Appl. Chem. 58, 257 (1986). 34. Y. Shimizu, M. Norte, A. Hori, A. Generah, and M. Kobayashi, J . Am. Chem. Soc. 106,6433 (1984).

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JUN’ICHI KOBAYASHI A N D MASAMI ISHIBASHI

35. S. Gupta, M. Norte, and Y. Shimizu, J. Chem. Soc., Chem. Cornmun., 1421 (1989). 36. Y. Shimizu, Ann. N . Y. Acad. Sci. 479,24 (1986). 37. S. Forenza, L . Minale, R. Riccio, and E. Fattoruso, J . Chem. Soc., Chem. Commun.. 1129 (1971). 38. E. E. Garcia, L . E. Benjamin, and R. I. Fryer, J. Chem. SOC.,Chem. Commun.,78 ( 1973). 39. J. Kobayashi, Y. Ohizumi, H. Nakamura, and Y. Hirata, Experientia 42, I176 (1986). 40. R. P. Walker, D. J. Faulkner, D. Van Engen, and J. Clardy, J. A m . Chem. SOC. 103, 6772 (1981). 41. J. Kobayashi, Y. Ohizumi, H . Nakamura, Y. Hirata, K. Wakamatsu, andT. Miyazawa, Experientia 42, 1064 (1986). 42. J. Kobayashi, H. Nakamura, and Y. Ohizumi, Experientia 44,86 (1988). 43. K. F. Albizati and D. J. Faulkner, J . Org. Chem. 50,4163 (1985). 44. G. De Nanteuil, A. Ahond, J. Guilhem, C. Poupat, E. Tran Huu Dan, P. Potier, M. Pusset, J. Pusset, and P. Laboute, Tetrahedron 41,6019 (1985). 45. G. Sharma and B. Magdoff-Fairchild, J . Org. Chem. 42,4118 (1977). 46. S. A. Fedoreyev, N. K. Utkina, S. G. Ilyin, M. V. Reshetnyak, and 0. B. Maximov, Tetrahedron Lett. 27,3177 (1986). 47. F. J. Schmitz, S. P. Gunasekera, V. Lakshmi, and L. M. V. Tillekeratne, J. Nat. Prod. 48,47 (1985). 48. G. M. Sharma, J. S. Buyer, and M. W. Pomerantz, J. Chem. Soc., Chem. Commun., 435 (1980). 49. S. A. Fedoreyev, S. G. Ilyin, N. K. Utkina, 0. B. Maximov, M. V. Reshetnyak, M. Yu Antipin, and Y. T . Struchkov, Tetrahedron 45, 3487 (1989). 50. S. Carmely and Y. Kashman, Tetrahedron Lett. 28,3003 (1987). 51. S. Carmely, M. Ilan, and Y. Kashman, Tetrahedron 45,2193 (1989). 52. P. Ciminiello, E. Fattorusso, S. Magno, and A. Mangoni, Tetrahedron 45,3873 (1989). 53. P. Ciminiello, E. Fattorusso, A. Mangoni, B. DiBlasio, and V. Pavone, Tetrahedron 46, 4387 (1990). 54. R. K. Akee, T. R. Carroll, W. Y. Yoshida, P. J. Scheuer, T. J. Stout, and J. Clardy, J. Org. Chem. 55, 1944 (1990). 55. C. Moquin-Pattey and M. Guyot, Tetrahedron 45, 3445 (1989). 56. C. Moquin and M. Guyot, Tetrahedron Lett. 25,5047 (1984). 57. M. Guyot and M. Meyer, Tetrahedron Lett. 27,2621 (1986). 58. A. A. Tymiak, K. L. Rinehart, Jr., and G. J. Bakus, Tetrahedron 41, 1039 (1985). 59. E. Fattorusso, V. Lanzotti, S. Magno, and E. Novellino, J. Nat. Prod. 48,924 (1985). 60. R. Kazlauskas, P. T. Murphy, R. J. Quinn, and R. J. Wells, Tetrahedron Lett., 61 (1977). 61. K. H. Hollenbeak and F. J. Schmitz, J. Nat. Prod. 40,479 (1977). 62. P. Djura and D. J. Faulkner, J. Org. Chem. 45,735 (1980). 63. N. Fusetani, M. Asano, S. Matsunaga, and K. Hashimoto, Comp. Eiochem. Physiol. E 85,845 (1986). 64. R. Sakai and T. Higa, Chem. Lett., 127 (1988). 65. Y. Kashman, S. Hirsh, 0. J. McConnell, 1. Ohtani, T. Kusumi, and H. Kakisawa, J. A m . Chem. Soc. 111,8925 (1989). 66. P. Djura, D. B. Stierle, B. Sullivan, D. J. Faulkner, E. Arnold, and J. Clardy, J. Org. Chem. 45, 1435 (1980). 67. J. H. Cardellina 11, D. Nigh, and B. C. Van Wagenen, J. Nat. Prod. 49, 1065 (1986). 68. E. Maeda and T. A. Thorpe, Phytomorphology 29, 146 (1980). 69. B. K. Chowdhury and D. P. Chakraborty, Phytochemistry 10,481 (1971). 70. S. Bano, N . Bano, V. U. Ahmad, M. Shameel, and S. Amjad, J. Nat. Prod. 49, 549 (1986).

2. MARINE

ALKALOIDS

1 I5

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380. 381. 382. 383. 384.

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TROPOLONIC COLCHICUM ALKALOIDS AND ALL0 CONGENERS* OLIVIER BovB A N D ARNOLD BROW Natural Products Section Laboratory of Structural Biology National Institute of Diabetes, Digestive. and Kidney Diseases National Institutes of Health Bethesda, Maryland 20892

I. Introduction ..................... ............ II. New Alkaloids from Colchicrtm Spec 111. Physical Properties ..................................... A. NMR Spectroscopy.. . . . . . . . . . . .................. B. X-Ray Structure Determinations ......................... C. Optical Properties D. Chromatography .......................

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B. Deacetamidocolchicine.. ...........................

VII. Clinical D a t a . . .....................

...........

148

..........

169

1X. Addendum . . . . . . .

1. Introduction

The chemistry and pharmacology of colchicine, the major alkaloid from Colchicum autumnale, have been repeatedly reviewed ( I ) , and findings made since 1984 have been reported ( 2 a - 4 . Recent developments in the * This paper is dedicated to the memory of Dr. Shigehiko Sugasawa. Professor Emeritus of the Faculty of Pharmaceutical Sciences. Tokyo University, Japan, who died on March I . 1991. I25

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

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chemistry and pharmacolology of colchicinoids have now been summarized and are presented in this chapter. This review includes allo congeners with a six-membered benzenoid ring C not discussed in the earlier review ( 1 ) . The most important recent development concerns the absolute configuration of the phenyltropolone backbone in colchicine. Natural (7S)-( -)-colchicine (l),as suspected earlier (I), displays molecular asymmetry derived from a noncoplanar arrangement of the tropolonic ring C and the benzenoid ring A. These rings are twisted out of the plane, with a torsion ange of about 53”,and this was found to be critical for the binding of colchicine to tubulin. Natural (7S-( -)-colchicine (1)has the two aromatic moieties arranged in a counterclockwise helicity, which implies an (as) absolute configuration according to the “steering-wheel rule” (3). The counterclockwise helicity of rings A/C present in the biologically active (-)-rotating colchicinoids and allo congeners will be shown throughout this chapter.

Natural (-)-(aS,7S)akhicineW

11. New Alkaloids from Colchicum Species

Extraction of dried plant materials from Cofchicumspecies with methanol afforded, after separation into neutral and basic fractions and chromatography on silica, several tropolonic and allo congener alkaloids (listed in Table I and 11). 1. Demethylspeciosines

Two demethyl congeners of speciosine (1) were found in Cofchicum ritchii from southern Jordan (4). The structures of these alkaloids, 2demethylspeciosine (2), named speciocolchine, and 3-demethylspeciosine (3), named specioritchine, were elucidated by mass and ‘H-NMR spectro-

3. TROPOLONIC COLCHICUM ALKALOIDS

I27

scopy. Their negative specific rotation implies that they have the same absolute configuration as colchicine (1).The synthesis of 2 was accomplished from 2-demethyldemecolcine (5) and 2-bromophenyl acetate (6), by a procedure previously used for the synthesis of speciosine (7).

2. N-Ethoxycarbonyldemecolcine Although carbamates of deacetylcolchicine were prepared earlier and found to be potent inhibitors of tubulin polymerization, and of binding of radiolabeled colchicine to tubulin (8),a natural representative of this class of compounds only recently was found in extracts of Colchicum cicilium (9). The structure of carbamate 4 was established on the basis of spectral data and was proved to be correct by synthesis from demecolcine and ethylchloroformate. 3. Acetoacetamide Analogs of Colchicine Acetoacetamide 5 was found by Santavjj et a/. to be a novel member of the cochicinoid family present in the seeds of Colchicum autumnule (10). Its structure was proposed on the basis of spectral data. The presence of a tropolonic ring C was signaled by the loss of CO and a C4H7N02 fragment on mass spectral analysis and is supported by the UV maximum at 353 nm which is typical for colchicinoids. The IR spectrum showed the presence of three different carbonyl frequencies, originating from the tropolonic carbonyl and the two carbonyl groups in the acetoacetamide side chain. A compound of this structure was recently obtained from deacetylcolchicine and 2,4,6-trichlorophenylacetoacetate(6). The synthetic material gave spectra identical to those reported for the natural alkaloid, had the same optical rotation, but differed considerably in its melting point (222-223°C for the natural and 183-184°C for the synthetic alkaloid). The synthetic material afforded deacetylcolchiceine on hydrolysis with 20% sulfuric acid. There was no natural material left to make a comparison of the two samples by TLC or by HPLC. The possibility exists that the two compounds are dimorphous. Extraction of leaves and seeds of Colchicum autumnale has afforded 2-demethyl-Nacetoacetyldeacetylcolchicine (6), yet another representative of the Nacetoacetyldeacetyl series ( 1 I). 4. Nonnitrogenous Tropolones Related to Colchicinoids

Colchicum ritchii from southern Jordan afforded, on extraction of the bulbs and removal of the alkaloids, three nonnitrogenous compounds named colchicone (7), 3-demethylcolchicone(8), and cornigerone (9) (12). Because of their close chemical relationship with colchicinoids they are discussed here and are listed in Table I. The structures of these ketones were elucidated mainly on the basis of 'H-NMR and MS analysis, as well

TABLE 1 NEWTROFQLONICALKALOIDS A N D RELATED COMFQUNDS FROM Colchicum SPECIES

Structure

00 N

Formula (MW)

(2) 2-Demethylspeciosine

C27%9N06

(speciocolchine)

dP ("C)

[a],,, room temperaturea

Amorphous

-37' (CHCI,) ( 4 ) -33" (CHCI,) ( 6 )

MS (4,6), UV ( 6 ) , 'H NMR (4.6)

Amorphous

-57" (MeOH) ( 4 )

MS ( 4 ) , 'H NMR ( 4 )

Amorphous

-190" (CHCI,) (9)

MS, IR, UV, 'H NMR (9)

(463.28)

R, = H, R, = CH,, R, = -N

/CH, \

C

H

2

Other data

0

-

HO

No 6

(3)3-Demethylspeciosine (specioritchine)

27 29

(463.28)

R, = CH,, R, = H, R, = -N

/CH, \CH2Q

HO

(4) N-Ethoxycarbonyldemecolcine

R, = R, = CH,, R7 =-N

/CH, \COOEt

C24H29N07

(443.19)

-

( 5 ) N-Acetoacetyldeacetylcolchicine R2 = R, = CH,, = NHCOCH,COCH,

C24H27N07

(6) 2-Demethylacetoacetyldeacetylcolchicine R, = H, R, = CH,, R7 = NHCOCH,COCH,

(7) Colchicone (7-oxodeacetamidocolchicine) R2=R,=CH, (8) 3-Demethylcolchicone

K, = CH,, R, = H (9) Cornigerone - 3 =-CH,R,-R

221-223 (10) 183-184 (6)

-194" (CHCI,) (10) -199" (CHCI,) (6)

UV, MS, IR (6.10)

C2,H,sNO, (427.50)

(111

(11)

1/11

C20H,"NO6 (356.36)

232 ( 1 2 ) 229-230 (13)

-

IP I P O 6 (342.1 I )

2 6 6 2 6 2 (12)

-

MS, UV, IR ( 1 2 )

Amorphous

-

MS, UV, IR (12)

(441.52)

C I9H I 6 0 6 (340.1 1 )

MS, UV. IR (12.13)

" For concentrations see original literature. The stnrctures of 1-9 are shown in a conformation suitable for binding to tubulin but which cannot be isolated at rmm temperature. where these compounds exist as a mixture of atropoisomers.

130

OLIVIER B O Y 6 A N D ARNOLD BROSSI

as the UV maxima between 320 and 398 nm which are typical for compounds containing a tropolone ring. These ketones are in a conformational equilibrium at room temperature and were for this reason optically inactive. Bromination of colchicone (7)with N-bromosuccinimide (NBS) gave the 4-bromo analog, and acetylation of 8 afforded an 0-acetate. Ketone 7 was found earlier as a microbial metabolite of 1 and it was obtained by bromination of 1with sodium hypobromite and hydrolysis of the imide ( 1 ) . Ketone 7 was also obtained from deacetylcolchiceine via the Schiff base prepared with benzaldehyde, aldimine-ketimine equilibration, hydrolysis, methylation of the enol with diazomethane, and separation of the enol isomers (13). The enol of 7, named 7-oxodeacetamidocolchiceine,was analyzed by X-ray crystallography and found to be a 3 : 2 mixture of isomers with colchicine and isocolchicine structures, respectively (13). Reductive amination of 7 with methylamine, which is reported to give ( 5 ) demecolcine (12), parallels chemical reactions used earlier in a synthesis of (+)-deacetylcolchicine (13). It is somewhat unfortunate that this information was not appropriately given in the paper describing the isolation of 7 from plant materials. Alcohol 10, obtained from 7 on reduction with sodium borohydride, and acetate 11,prepared from 10 by acetylation (12),are obviously mixtures of isomers, and as such they are of little value for evaluating their antitubulin effects. Testing of an optically pure isomer of 11,as shown below, which is isosteric to colchicine, would be of interest. CH,O CH30 CH30$

7

.',*

R

CH,O

5. Naturally Occurring Allocolchicinoids Allocolchicine (12)is found in small amounts in Cofchicum cornigerum (14) and is identical with material prepared from colchicine and isocolchicine with sodium methoxide in refluxing methanol (15-16). It is also identical with so-called substance 0 obtained by Santavg from the flowers

TABLE I1 NEWALLOCONGENER ALKALOIDS FROM Colchicum SPECIES

COOMe

l2

Structure

(It)Allowlchicine (13) Androbiphenyline R, = CH3, Rz = H (14) Colchibiphenyline R, = Rz = H “

For concentrations see original literature

Formula (MW) CzzHZ5NO6 (399.42) C~IH?~N (387.47) O~ CzoHZ3N06(373.46)

mp (“0 261-262 ( 1 5 ) 140-146 (12) Amorphous

[ab,room temperature” - 141.7” (MeOH) (14,15)

-27” (MeOH) (12) -25.5” (meOH) (1.2)

Other data IR, MS, ‘H NMR (12) MS, ‘H NMR (12)

132

OLIVIER BOY6 A N D ARNOLD BROSSI

Colchicum autumnale (17). With the isolation of monophenol androbiphenyline (13)and the diphenol colchibiphenyline(14) from Colchicum ritchii from southern Jordan (12), two more representatives of this group of alkaloids became available. The structures of 13and 14 were elaborated on the basis of spectral data and the positions of the hydroxyl groups established by nuclear Overhauser effect (NOE) experiments (Table 11). Both compounds gave acetates on acetylation and identical fully methylated 0-methylandrobiphenylines on treatment with diazomethane. Both phenols exist in CDC13 solution as a mixture of atropisomers, but the acetates and the fully methylated alkaloids are present in solution as one conformer only. The bulky substituent at C-8 present in these derivatives forces the acetamido group at C-7 into an axial position, with concomitant flipping of the (as) configuration of the biphenyl system to an (aR) configuration.

111. Physical Properties

A. NMR SPECTROSCOPY The 'H-NMR signals of the aromatic protons in colchicine and the I3C-NMR signals of the carbon atoms have been assigned ( 1 ) . The threebond spin-spin coupling constants of the five-spin system in the B ring of the natural (7S)-colchicine were measured on a 360-MHz instrument, and the observed and calculated values listed in Table 111 were reported (2a). The measured vicinal coupling constants J(6a,7) and J(6b,7) of 11 and 5.5 Hz, respectively, indicate the methine proton at C-7 to be axially oriented. with the acetamido group in a pseudoequatorial orientation. This is consistent with the structure of conformer I, having the aromatic rings A/C in a counterclockwise arrangement corresponding to an (as) configuration (Fig. 1) (3).The coupling constants for the minor conformer [J(6a,7) = 6.4 Hz, J(6b,7) = 1.0 Hz] suggest the presence of an equatorially oriented methine proton at C-7 with the acetamido group in a pseudoaxial orientation. This requires the biaryl system to be present in an (aR) configuration (conformer I1 in Fig. 1). The rates of (as-(aR) interconversion measured in CDC13 and ChDhfor analogs of colchicine differently substituted at C-1 were found to be of the order of to sec-' at 22"C, corresponding to a free energy of activation of 22-24 kcal/mol. Equilibration studies by 'H NMR revealed that an equatorial orientation of the acetamido group in colchicine and

3. TROPOLONIC COLCHICUM ALKALOIDS

133

TABLE 111 VICINAL COUPLING CONSTANTS OF RINGB PROTONS OF NATURAL (7S)-COLCHICINE Conformer I (as) Coupling Constant

Calculated (Hz)“

J( 5a ,6a) J(5a,6b) J(5b,6a) J(Sb.6b) J(6b,7) J(6a.7)

6.5 12.0 1.1 6.5 6.3

Found ( H Z ) ~

12.0

Conformer I1 (a), calculated (Hz)”

6.7

6.7

11.8

11.8

1.3 6.2

1.3 6.2

5.5 11.0

6.2

1.o

These calculated values were obtained using the empirical Karplus equation and torsional angles derived from X-ray data. Spectrum obtained in [*H]acetone at 300 MHz. Couplings were determined by inspection. Chemical shifts of pertinent protons, verified by decouplingexperiments, are 4.504 (H-7). 2.590 (H-5b). 2.338 (H-Sa). 2.140 (H-6b). and 1.904 (H-6a).

cH30zg,;@,+: : ConformerI

Conlormer II

-

CH30

NHCOCH, CH,O l o

0

NHCOCH, CH,O

(-)-(aS,7S)-cokhicine

lo

(+)-(aR,7S)cobhcine

NATURAL (-)- (7S)-COLCHICINE

-

c

(-)-(aS,7R)colchicine

(+)-(aR,7R)-colchcine

UNNATURAL (+)- (7R)-COLCHICINE

FIG. 1. Configurationsof natural (7S)-colchicine and unnatural (7R)-colchicine.

134

OLIVIER BOY6 A N D ARNOLD BROSSI

analogs is energetically favored by 1-3 kcal/mol over an axial orientation. This in turn determines the (as)-biaryl configuration for natural (7s)colchicine and the (aR)-biaryl configuration for unnatural (7R)-colchicine. The rate of isomerization of the biaryl system in colchicinoids is largely controlled by steric interactions between the substituent at C-1 in ring A and the hydrogen atom at C-12 in ring C, since a decrease in the rate of interconversion was found when the size of the substituent was increased from OAc to OBz. The position of the (as)-(aR) equilibrium in colchicinoids is decisive for binding of these molecules to tubulin, and it also hinges largely on the nature of the B ring. The power of modern spectroscopy in determining the structure of complex molecules is exquisitely illustrated in the case of colchicone (7), isolated from Colchicum ritchii (12). The I3C-NMR spectrum confirmed the presence of the tropolonic carbonyl group in ring C as a singlet at 6 179.4 ppm and a carbonyl group at C-7 in ring B as a singlet at 6 205.7 ppm. Of the four methoxy singlets, the most upfield at 6 3.55 ppm was assigned to the highly hindered C-1 OMe and the signals at 6 3.86 and 3.87 ppm to the C-2 OMe and C-3 OMe groups, respectively, whereas the most downfield signal at 6 4.00 ppm represents the tropolonic C-10 OMe. The two aromatic protons, C-4 H and C-8 H, appeared as singlets, whereas the two protons at C-1 1 and C-12 appeared as doublets, with a coupling constant of 10.7 Hz. The aliphatic protons in ring B analyzed on a 500-MHz instrument appeared as doublets of doublets of doublets, with chemical shifts and coupling constants as follows. The pseudoequatorial protons C-5p H at 6 2.67 ppm and C-6a H at 6 2.95 ppm showed NOES with the aromatic protons at C-4 and C-8, respectively. The coupling constant between the pseudoaxial C-5a H at 6 3.11 ppm and C-6p H at 6 2.82 ppm was large (J = J5pm 13.7

3. TROPOLONIC

COLCHICUM ALKALOIDS

135

13.6 Hz), indicating a dihedral angle of about 170". The coupling constant between C-5p H and C-6p H, on the other hand, was smaller ( J = 5.0 Hz), reflecting a dihedral angle of about 38". The analysis suggested that ring B in 7 was present in a boatlike conformation. Similar analysis of spectral data was used to secure the structure of the novel alkaloids androbiphenyline (13) and colchibiphenyline (14), which exist in CDC13 solution as an almost equal mixture of atropoisomers. Esterification and 0-methylation of 13 and 14 afforded derivatives which were almost exclusively present in conformation b, with the acetyl protons appearing at 6 1.58 ppm (Fig. 2).

B. X-RAYSTRUCTURE DETERMINATIONS There were several more colchicinoid structures analyzed by singlecrystal X-ray diffraction since the last review. (I). Colchiceine benzoate, prepared from colchiceine and benzoyl chloride in pyridine and obtained as yellow crystals, was found to have ring C in an isocolchicine arrangement (18). Rings A and B had similar conformations as in other colchicinoids. The molecular packing showed the presence of a water molecule, which formed a relatively strong hydrogen bond with the amide carbonyl and a short contact with the oxygen atom at C-I. 3-Demethylcolchicine, which crystallized from acetone solvated with one molecule of solvent, was also analyzed (19). It was shown that the molecular conformation bore considerable resemblance to that of the

Ro\

6.62

496m

b b

FIG.2. Conformations of colchibiphenyline (14) and androbiphenyline (13) in CDC13 SJlution.

136

OLIVIER BOYE A N D ARNOLD BROSSI

previously reported and biologically active colchicinoids ( 1 ) . There were two hydrogen bonds, connecting the amide proton with the tropolonic carbonyl and the phenolic proton with the acetyl carbonyl of another molecule, producing a network of molecules with holes filled with acetone. The most important X-ray structure is that of (aS,7S)-2-acetyl-2demethylthiocolchicine [mp 186-188°C; [aID- 185" (CHC13)],which crystallized from acetone with one molecule of acetone (20). The analysis was used to prove the absolute configuration at C-7, although already established by chemical degradation to be (7s) (21).This absolute configuration was determined by several methods, which all concurred (22). The conformation of this compound resembled that of the previously reported and biologically active colchicinoids. A major influence in the packing of the molecule (Fig. 3) is a hydrogen bond connecting the amide proton with the tropolonic carbonyl group. Another X-ray analysis reported is that of the urea 15 obtained from (-)-colchinyl methyl ether derived from natural colchicine and (R)-(+)-1phenylethyl isocyanate (23) (Fig. 4). The asymmetric carbon in the urea side chain is of known absolute configuration, and it served as a marker to indirectly assign the absolute configurations of C-7 and of the biphenyl unit. The results of the analysis confirmed that urea 15 has the (aS,7S, 15R) absolute configuration. The negative Cotton effect at 260 nm in the CD spectrum of urea 15 indicated the two aromatic rings to be arranged in a

FIG. 3. ORTEP drawing of (aS7S)-2-acetyl-2-demethylthiocolchicine.

3. TROPOLONIC COLCHICUM ALKALOIDS

137

FIG. 4. X-Ray analysis of urea 15 showing a thermal ellipsoid plot from experimentally determined coordinates.

counterclockwise fashion, supporting the X-ray derived (as) absolute configuration of the biphenyl unit. Another X-ray structure reported is that of (+)-colchicine which shows unusual physical properties: a melting point of 280-282°C and a much lower solubility than that of the natural colchicine (1) in commonly used solvents (5). The X-ray data showed an extensive three-dimensional pattern of hydrogen bonding, linking chains of alternate D and L molecules related by a glide plan and hydrogen bonded by the interaction N-H .......0-9. Each colchicine molecule is hydrogen bonded by two donor bonds O(water l)-H-------0-3and O(water2)-H.......O(acetyl), and each water molecule is hydrogen bonded to another two water molecules. This gives numerous links between the chains. An interesting X-ray structure is that of the dibromo compound 16 of the unnatural allo series shown in Fig. 5 (24). Compound 16 was obtained by bromination of the amine obtained from allo colchiceine by Curtius rearrangement (16,25). Compound 16, in contrast to allocolchicine (12) analyzed earlier (26a), is a representative of the unnatural (aR) series with the biphenyl system adopting a clockwise arrangement instead of the counterclockwise arrangement [(as) configuration] found in the natural series. This inversion is the result of a steric interaction between the C-8 bromo substituent and the acetamido group, causing this one to switch from a pseudoequatorial orientation, as found in natural colchicine, to a

I38

OLIVIER BOY6 A N D ARNOLD BROSSI

FIG. 5. X-Ray structure of (aS,7S)-dibromo compound 16.

pseudoaxial orientation. This leads to a change in the conformation of the B ring and a flipping of the aromatic moieties around the central bond to a clockwise arrangement. As in other solid-state conformations of colchicinoids and allo congeners containingthree neighboring methoxy groups in ring A, the methoxy groups C-1 and C-2 are nearly orthogonal to the ring, whereas, the one at C-3 lies close to the ring plane. But the methoxy groups at C-1 and C-2 point in opposite directions, contrary to the same orientation found in colchicine. These groups, however, are flexible owing to the free rotation around the O - C H 3 bond and adopt some conformations which could be influenced by packing forces (266). Compound 16, as expected because of its opposite axial configuration as compared to colchicine, did not inhibit tubulin polymerization.

PROPERTIES C. OPTICAL Naturally occurring colchicinoidsand allo congeners have negative specific optical rotations in CHCb and MeOH, and the is0 isomers show greater negative rotational values than the natural isomers (27). Thiocolchicines (28) and colchiceinamides (29) also have strong negative rotational values. Unusually high negative specific rotations were found in thioketones, prepared from thiocolchicine by reaction with Lawesson’s reagent, and they are strongly mutarotating (28). Exchanging the acetamido group in colchicine (1)with other amide groups does not change the rotational behavior of the compounds, suggesting that the specific rotational values measured are primarily associated with the skewed biaryl system.

3.

TROPOLONIC COLCHICUM ALKALOIDS

139

CD spectra of (-)- and (+)-colchicine and (-)-all0 congeners show Cotton effects at 260 nm, and additionally at 340-350 nm in colchicinoids, as shown in Fig. 6 (23,30).In the presence of stoichiometric amounts of tubulin, (-)- and (+)-colchicinoids showed a notable difference in the Cotton effect at 3 4 0 nm: a reduction of the ellipticity above 3 1 0 nm for natural (-)-colchicine (1)and a positive Cotton effect at 3 4 0 nm for unnatural (+)-colchicine (31). These observations indicate that tubulin interacted only with (-)-(aS,7S)-colchicine having a properly configurated biaryl system. This was further demonstrated in another CD study with tubulin and a racemic mixture of (-+)-colchicine,as well as with deacetamidocolchicine which lacks the chirality at C-7 and exists in solution as an optically inactive equilibrium of atropoisomers. In both instances a positive Cotton effect at 3 4 0 nm was observed, resulting from the selective binding to tubulin of the (-) isomer while the (+) isomer was left in solution. In the case of deacetamidocolchicine this positive Cotton effect disappeared after 24 hr, suggesting an (aR)-(as) equilibration of the (+) isomer left in solution.

I

t

200

. . .

l

250

.

.

.

.

l

.

300

.

.

.

I

.

350

,

nm

FIG. 6. CD spectra of colchicine and analogs in ethanol.

140

OLIVIER

BOY6 A N D ARNOLD BROSSI

It is assumed that all the biologically active colchicinoids with negative specific optical rotations have a phenyltropolone backbone of (as) configuration. Changes seen in the rotational values of sterically hindered colchicinoids on heating are explained by the isomerization of negative rotating (as) isomers into positive rotating (aR) isomers (20).The CD spectra show even more clearly such isomerizations on analysis of the changes occurring in the strongly negative Cotton band at 260 nm (23). Optical resolution of (+)-deacetamidocolchicine was accomplished on a cellulose triacetate column at low temperature (32). Only (-)-(as)deacetamidocolchicine (18) was found to bind to tubulin; the (+)-(aR) enantiomer was inactive. This firmly established, as already shown earlier (2a), that the aromatic rings A/C in colchicinoids and related allo congeners must be arranged in a counterclockwise fashion to allow a binding to tubulin. This corresponds to a P helicity of the biaryl system (32). D. CHROMATOGRAPHY It is well known that colchicine exhibits UV maxima at 243 and 350 nm in CHCl3 and ethanol. The latter is associated with the tropolonic moiety since it disappears on ring contraction to allocolchicine (12) which has a six-membered benzenoid ring C (25).TLC analysis of very small amounts of deacetylcolchicine and deacetylisocolchicine was made possible by making their DADF (dihydrofluorescein diacetate) derivatives (Fig. 7). Hydrolysis of the DADF derivatives with aqueous ammonia converted the

1 b

TLC. Silica pl

b

TLC: S i b gel

Solvent: CH2C12/MOOH4 9 1 1

S0)vent: CH2Cl2/M.DH 19.11

D w d o m n t : I ~ I N H I O H .Iblii

Dwslopmnr: i)

DADF:

DF:

I IrO

&w

1; OII

no

0"

FIG. 7. Chromatographic separation of DADF- and DF-amides of deacetylcolchicine and its is0 isomer.

3. TROPOLONIC COLCHICUM ALKALOIDS

141

acetates to phenols, which also separated well on TLC plates (SiOz, CHZClz/MeOH, 9: 1). Coloration was made by exposing the plates to ammonia and then to iodine vapors ( 3 3 ~ )By . this procedure the dihydrofluorescein derivatives are converted to red-colored erythrosine derivatives which have UV maxima at 540-550 nm. The method of preparation of such derivatives is given below. Deacetylisocolchicine-DADF-amide. A mixture of deacetylisocolchicine (170 mg, 0.47 mmol), DADF (170 mg, 0.40 mmol), dicyclohexylcarbodiimide (198 mg, 0.96 mmol), and 4-dimethylaminopyridine (14 mg) in dry CHZCIZ(4ml) was stirred at room temperature for 1 hr. The reaction mixture was washed with 5% HCI, 10% NaHC03, and brine, then dried (NaZSO4)to afford, after evaporation of solvent, a yellow residue (160 mg). This material was dissolved in CHzClz (5 ml) and passed through a silica gel column (2 g), to give, after evaporation of solvent and crystallization from methanol, the DADF derivative of isocolchicine (140 mg, 40%): mp 230232°C; [(Y]D-2or(0.14, CHCI,); chemical ionization (CI)MS 757 (M+); UV (EtOH) 210 and 344 nm. Deacetylisocolchicine-DF-amide. A solution of the DADF derivative (40mg, 0.05 mmol) in methanol (2ml) was added with 4 drops of concentrated ammonium hydroxide, and the solution was stirred at room temperature for 0.5 hr. The solvent was evaporated and the residue crystallized from CHZC12 to afford orange crystals (30 mg, 90%): mp 220°C; [a]~-198"(0.1, MeOH); CIMS 674 (M+); UV (EtOH) 210 and 344 nm, (EtOH + NaOH) 237 and 346 nm. The solvent systems benzene/ethyl acetate/diethylamine/methanol/ water (15:22:3:6: 1, v/v) and benzene/ethyl acetate/diethylamine ( 5 5 : I , v/v) containing 8% methanol were used to separate a number of analogs of colchicine, deacetylcolchicine, and their N-formyl derivatives (3%).

IV. Chemistry A. UNNATURAL ( +)-COLCHICINOIDS Only a few unnatural (+)-colchicinoids with a clockwise arrangement of the phenyltropolone backbone have so far been reported. This includes unnatural (+)-(aR,7R)-colchicine (Fig. 1) and (+)-deacetamidocolchicine [which lacks the acetamido group of (+)-colchicined. Both compounds were crucial in determining the absolute (as) configuration of natural (7S)-colchicine. The dibromo compound 16 of the all0 series, which was discussed in Section III,B, also belongs to this group of compounds.

142

OLIVIER BOYk A N D ARNOLD BROSSI

Racemic colchiceine was obtained by Corrodi and Hardegger by abasecatalyzed equilibration of the Schiff base obtained by reacting deacetylcolchiceine with benzaldehyde (34). Aldimine-ketimine isomerization was found to be the mechanism by which the racemization had occurred (35). The optical resolution of deacetylcolchiceinewas accomplished with camphorsulfonic acids, affording, after O-methylation with diazomethane, separation of the enolate isomers and after N-acetylation, unnatural (+)and natural (-)- colchicine (Fig. 1). Racemization of colchicine in refluxing acetic anhydride followed by mild hydrolysis of the intermediate triacetate represents a much improved method of preparing (*)-colchicine (36). The BladC-Font procedure was later extended to the preparation of (?)-3demethylcolchicine and other racemic analogs (5). Hydrolysis of (+)-colchicine with 0.1 N HCI affords (+)-colchiceine, and (+)-deacetylcolchiceine is obtained on hydrolysis of (2)-colchicine with 20% H2S04 and AcOH. Treatment of (+)-deacetylcolchiceine with trifluoroacetic anhydride afforded a trifluoroacetamide which, on methylation with diazomethane, gave a mixture of (+)-trifluoroacetyldeacetylcolchicine and (2)-trifluoroacetyldeacetylisocolchicine. The latter compounds were separated by chromatography and hydrolyzed with potassium carbonate in acetone/water to give (+)-deacetylcolchicine and (+)-deacetylisocolchicine(37). An easy chemical resolution of (+)-deacetylcolchicine with 10-camphorsulfonic acid in methanol afforded the optically pure amines, and (+)- and (-)-colchicine after N-acetylation. The chemical resolution of (+)-deacetylisocolchicine was achieved by using ditoluoyl-L-tartaric acid as the resolving agent (5) and gave (+)- and (-)-isocolchicine after N-acetylation. It is interesting to note that the (+)-colchicine-chloroform complex and the (-)-colchicine-ethyl acetate complex, obtained after recrystallization, showed unexpected differences in their CD spectra (37).However, these spectra became fully symmetrical after thorough drying of the crystals in high vacuum at 50-60°C. In addition, racemic (+)-colchicine was obtained by mixing stoichiometric amounts of the two complexes (5). B. DEACETAMIDOCOLCHICINE

(+)-Deacetamidocolchicine(18)was prepared by the classic syntheses of Eschenmoser (38)and van Tamelen (39). The racemate was resolved by medium-pressure liquid chromatography on swollen, microcrystalline cellulose triacetate prepared at 5"C, and the enantiomers were collected at -70°C (32). The (-)-enantiomer with the same biaryl configuration as natural (aS,7S)-colchicine(1)was eluted first and found to be essentially optically pure. Thermal racemization of the optical isomers gave the ther-

3. TROPOLONIC

COLCHICUM ALKALOIDS

143

ma1 barriers of rotation around the biaryl central bond of 22.1 kcal/mol for the (as) enantiomer and 23.4 kcal/mol for the (aR) enantiomer. Kinetic binding measurements showed that the (as) isomer binds approximatively 62 times faster than colchicine to tubulin, whereas the (aR) isomer, and both enantiomers of deacetamidoisocolchicine,which were also prepared, did not bind at all. The most stable conformation of 18 has the methoxy groups at C-1 and C-2 perpendicular to the aromatic ring and antiparallel to each other, so that the methyl group of the substituent at C-1 points away from H-C-1 2 of the tropolone ring. The methoxy group at C-3 is more flexible and is essentially coplanar with the aromatic ring A. A variation of the Eschenmoser synthesis of (-+)-deacetamidocolchicine was accomplished from 5,6-dehydro compound 17 (40,41)as shown in Fig. 8 and, since it has not been previously been reported, is summarized below. (+)-Deacetamidocolchicine from 5.6-Dehydro analog 17. Dehydrodeacetamidocolchicine (17,214 mg,mp 172-174°C) was dissolved in ethyl acetate (10 ml) and hydrogenated over Pd/C catalyst (lo%, 50 mg) at room temperature for 1 hr. After filtration of the catalyst and evaporation of solvent, the residue was chromatographed (SiOz, CHzCl2/MeOH,200: 1 and 100:1). The first fractions contained material which was overreduced. Fractions eluted with CHzCl2/MeOHat 100:1 were combined and crystallized from EtOH to give 18 (55 mg), mp 182-183°C [lit. (38) m.p. 182184°C). The 1R and 'H-NMR spectra of 18 were identical with those reported.

c. CHEMICAL REACTIONS I N RINGS A A N D c OF COLCHICINOIDS Phenolic colchicinoids avd colchiceines are well-known compounds, and some of them were found to be metabolites of colchicine (1). Improved procedures to make the phenolic congeners have now been developed

CH,O

CH,O

FIG. 8. Preparation of (*)-deacetamidocolchicine (18) from semisynthetic 5,6-dehydro analog 17.

144

OLlVlER BOY6 A N D ARNOLD BROSSI

by substituting the Lewis acid acetyl chloride-aluminum chloride (42)with concentrated sulfuric acid (41,43). Regioselective cleavage of the sterically most hindered methoxy group at C-2 in colchicine is readily accomplished with concentrated sulfuric acid at 45-50°C, affording 2-demethylcolchicine in 42% yield (43). Heating of colchicine or 2demethylcolchicine with sulfuric acid at 85-90°C afforded 1,2-didemethylcolchicine and 2,3-didemethylcolchicine as the major and minor products, respectively. Similar treatment of 3-ethoxycarbonyl-3-demethylcolchicine, prepared from 3-demethylcolchicine with ethyl chloroformate, afforded 2,3-didemethylcolchicine in 32% yield (43). Ether cleavage of thiocolchicine proceeds similarly (43,44). Refluxing colchicinoids with 0.1-0.2 N hydrochloric acid results in a cleavage of the methoxy group at C-10 in the tropolonic ring and gives colchiceines. These compounds exist in solution as mixtures of natural and is0 isomers (43).Etherification of colchiceines with diazomethane affords two ether isomers which are separated by chromatography. Tosylation gives two tosylates which also were separated and used later for chemical reactions. Conversion of colchicinoids to thio congeners with the OMe group at C-10 replaced by a SCH3 group can be accomplished with sodium methanethiolate in water or in aqueous systems. It is described here for the preparation of the antitumor agent 3-demethylthiocolchicine (43).

3-Demethylthiocolchicine from 3-Demethylcolchicine. Sodium methanethiolate (800 mg) was added to a solution of 3-demethylcolchicine (600 mg) in water (6 ml). The reaction mixture was stirred at room temperature for 24 hr, diluted with 2% acetic acid (15 ml), and extracted with chloroform (3 times 100 ml). Drying (Na2S04) and evaporation of the combined chloroform extracts afforded 3-demethylthiocolchicine as a pale yellow powder (530 mg), which was recrystallized from acetone (400 mg, 67%): mp 310°C; [aID-259" (0.1, CHCI,). This material was identical in every respect with the one prepared from colchicoside (I). Thioketones of colchicine, with the tropolonic carbonyl oxygen replaced by a sulfur atom, were prepared from thiocolchicine (19) with Lawesson's reagent. When carried out at room temperature in toluene solution, this led to a mixture of the thioketone and thioketone-thioacetamide, the latter having the amide carbonyl oxygen replaced by a sulfur atom (46). The thioketone of isocolchicine was similarly prepared from isothiocolchicine and Lawesson's reagent (47). Both thioketones show muvarotation, and their hydrolysis with 20% sulfuric acid afforded a similar mixture of deacetylthiocolchicine and deacetylthioisocolchicine,sug-

3. TROPOLONIC

145

COLCHICUM ALKALOIDS

gesting that an intramolecular, acid-catalized transmethylation had occurred. Reaction of colchiceinamide with phosgene and with thiophosgene in the presence of triethylamine resulted in the formation of a new ring (48). These tetracyclic compounds, already described by Eschenmoser (38), exhibit unusually high optical rotations, suggesting that addition of the new hetero D ring changes the original aromaticity of the C ring dramatically. Colchicide ( 10-demethoxycolchicine,21), reported earlier to have good antitumor activity and, since it is less toxic than colchicine, considered as a potential candidate for clinical trials ( I ) , was recently prepared as shown in Fig. 9. Thiocolchicine (19),when reduced with hydrogen in the presence of Raney nickel catalyst, afforded 8,10,11,12-tetrahydro-l0demethoxycolchicine (20),which was purified by chromatography. Oxidation of 20,accomplished over Pd/C catalyst in refluxing toluene, afforded 21. The yellow, crystalline hydrochloride of 21 used for antitumor testing was found to be completely inactive (49). Analysis of the previously used material, and believed to be active, showed it to be contaminated with 1.3% of thiocolchicine (19). The azido derivatives 22 and 23 of colchicine and isocolchicine, respectively, prepared from the corresponding tosylates with sodium azide, underwent an interesting photolytic decomposition (4.9, and the results are summarized in Fig. 10. Colchiceinazide(22),when photolyzed in either methanol or dioxane at a short wavelength of 254 nm, afforded nitrile 24 and the trans-nitrile 25 as the major and minor reaction products, respectively. They apparently were formed by trapping of the intermediate ketene 26 by the amide nitrogen. The products obtained in a similar photolysis of the azide 23 in the is0 series were found to be dependent on the nature of the solvent used. In methanol the conjugated ester 27 and the conjugated nitrile 28 were the major products. In dioxane the aromatic nitrile 29, present in a 2 : 1 atropoisomer ratio, was the only reaction product. MethCH,O

CH,O

CH,O

I

cH300 CH,O

0

2p

FIG. 9. Synthesis of colchicide 21.

21

cH30q

146

OLIVIER BOY6 A N D ARNOLD BROSSI

CH,O

OCH,

0

2

2

%

CN

N,

CN CN

26

24 (>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

OLlVlER B O Y 6 A N D ARNOLD BROSSI

cH303$

cH30y

CH,O

-

/

CH,O I'

,

coon

n

cH3 @ :

CHO

o

OCH,

\

/

/

OCH,

OCH,

\N

22

CH,O

'NHCOCH,

Rp=

I

& =OCH3, R 1 = H

R.

fa

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 OCH3 Raney Ni NzH4.H2O EtOH. 95OC

t

(-) 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-

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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.

C

CH30

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).

3. TROPOLONIC

COLCHICUM ALKALOIDS

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

168

OLIVIER BOY6 A N D ARNOLD BROSSI

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.

169

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

PHENOLIC COLCHICINOIDS

% Tubulin bindingh

LDroin mice (ma/knY 1.6 50 24 14.6

1-Demethylthiocolchicine

90 26 50 68 96 0

2-Demethylthiocolchicine 3-Demethylthiocolchicine

73 84

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

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

170

OLIVIER BOY6 A N D ARNOLD BROSSI

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

3. TROPOLONIC COLCHICUM ALKALOIDS

171

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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OLIVIER BOY6 A N D ARNOLD BROSSI

(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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A. Muzaffar, M. Chrzanowska, and A. Brossi, Heterocycles 28,365 (1989). P. N. Sharma and A. Brossi, Heterocycles 20, 1587 (1983). M. E. Staretz and S. Bane Hastie, J. Org. Chem. 56,428 (1991). A. Muzaffar, A. Brossi, C. M. Lin, and E. Hamel, J. Med. Chem. 33,567 (1990). A. Muzaffar and A. Brossi, Synth. Commun. 20,713 (1990). A. Muzaffar, E. Hamel, and A. Brossi, Heterocycles 31,2037 (1990). R. Dumond, A. Brossi, C. F. Chignell, F. R. Quinn, and M. Suffness,J. Med. Chem. 30, 732 (1987). 50. J. L. Hartwell, M. V. Nadekarni, and J. Leitner, J. Am. Chem. SOC.74,3180 (1952). 51. V. V. Kiselev, Zh. Obsh. Khim, 31,334 (1961). 52. E. 0. Esbolajev, K. A. Tojbajeva, and N. A. Ajkhohina, Proc. 5th I n t . Con$ Chem. Biotechnol. Biol. Active Nat. Prod. Varna, Bulgaria, Sept. 2, 184 (1989). 53. Diamide 31 was prepared at the NIH laboratory by Dr. A. Muzaffar, and compound 32 was made by Dr. 0. Boyt. 54. M. A. Iorio, A. Laurenzi, A. Mazzeo-Farina, and G. Cavina, Gazz. Chim. Ital. 116,631 (1986). 5 5 . L. Velluz and G. Muller, Bull. SOC.Chim. Fr., 198 (1955). 56. B. Danieli, G. Lesma, G. Palisano, and R. Riva, Helv. Chim. Acta 68,2173 (1985). 57. D. L. Boger and C. E. Brotherton, J. Am. Chem. SOC.108,6713 (1986). 58. M. G. Banwell, J. N. Lambert, J. M. Gulbis, and M. F. Mackay, J . Chem. Soc.. Chem. Commun., 1450 (1990). 59. M. G. Banwell, Aust. J. Chem. 44,34 (1991). 60. H. Lettrk and H. Fernholtz, Hoppe-Seyler’s Z. Physiol-Chem. 278, 175 (1943). 61. M. G. Banwell, G. L. Gravatt, J. S. Buckleton, C. R. Clark, and C. E. F. Rickard, J . Chem. Soc., Chem. Commun., 865 (1989). 62. W. C. Wildman, in “The Alkaloids” (R. H. F. Manske. ed.), Vol. 6, p. 247. Academic Press, New York, 1960. 63. M. Sorkin, Helv. Chim. Acta 29,246 (1946). 64. N. Barton, J. W. Cook, and J. D. Loudon, J . Chem. Soc., 176 (1945). 65. M. A. Iorio, Heterocycles 22,2207 (1984). 66. J. S. Sawyer and T. L. Macdonald, Tetrahedron Lett. 29,4839 (1988). 67. J. Cech and F. Santavq, Collect. Czech. Chem. Commun. 14,532 (1949). 68. 0. Boyt, Y. Itoh, and A. Brossi, Helv. Chim. Acta 72, 1690 (1989). 69. 0. Boyt, E. Hamel, H. J. C. Yeh, V. Toome, B. Wegrzynski, and A. Brossi, Can J. Chem. (in press). 70. T. J. Fitzgerald, Biochem. Pharmacol. 25, 1383 (1976). 71. W. Oda and Y.Kutahara, Tetrahedron Lett., 3295 (1969). 72. G. A. Russell, C. M. Tanger, and Y.Kosugi, J. Org. Chem. 43,3278 (1978). 73. R. M. Keenan and L. I. Kruse, Synth. Commun. 19,793 (1989). 74. M. G. Banwell, K. A. Herbert, J. S. Buckleton, J. S. Clark, C. E. F. Rickard, C. M. Lin, and E. Hamel, J. 0rg.Chem. 53,4945 (1988). 75. Y. Itoh, A. Brossi, E. Hamel, and C. M. Lin, Helv. Chim. Acta 71, 1 1 9 9 (1988). 76. Y. Itoh, A. Brossi, E. Hamel, J. L. Flippen-Anderson, and C. George, Helv. Chim. Acta 72, 1% (1989). 77a. F. J . Madrano, J. M. Andreu, M. J. Gorbunoff, and S. N. Timasheff, Biochemistry 28, 5589 (1989). 77b. M. F. Mackay, H. L . Sands, E. Lacey, and P. Burden, Acta Crystullogr. C45, 1783 (1989). 78. T. R. Watson, P. Burden, and E. Lacy, personal communication on data presented at meetings of the Australian Chemical Society in 1987. 79. R. P. Rava, S. Bane Hastie, and J. C. Myslik, J. A m . Chem. SOC.109, 2202 (1387). 43. 44. 45. 46. 47. 48. 49.

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80. S . Bane Hastie and R. P. Riva, J. Am Chem. SOC.111,6993 (1989). 81. R. M. Chabin, F. Feliciano, and S. Bane Hastie, Biochemistry 20, 1869 (1990). 82. G. Herman, S. Busson, M. J. Gorbunoff, P. Maudit, S . N. Timasheff, and B. Rossignol, Proc. Natl. Acad. Sci. U.S.A. 86,4515 (1989). 83. F. Feliciano, R. M. Chabin, R. P. Riva, and S. Bane Hastie, Biochem. Biophys. Res. Commun. in press (1991). 84. S . Bane Hastie, R. C. Williams, D. Puett, and T. L. Macdonald, J. Biol. Chem. 264, 6682 (1989). 85. S . Bane Hastie, Biochemistry 28,7753 (1989). 86. P. Lincoln, J. Nordh, J. Deinum, J. Angstrom, and B. Norden, Biochemistry 30, 1179 (1991). 87. R. M. Chabin and S. Bane Hastie, Biochem. Biophys. Res. Cornmun. 161,544 (1989). 88. P. Dustin, “Microtubules,” 2nd Ed. Springer-Verlag, New York, 1978. 89. E. Hamel, National Cancer Institute, Bethesda, Maryland, personal communication. 90. P. N. Sharma, A. Brossi, J. V. Silverton, and C. F. Chignell, J. Med. Chem. 27, 1729 (1984). 91. J. Deinum, P. Lincoln, T. Larson, C. Lagercrantz, and L. J. Erkell, Acta Chim. Scand. 835,677 (1981). 92. J. Deinum and P. Lincoln, Biochim. Biophys. Acta 870,226 (1986). 93. A. Muzaf€ar, E. Hamel, R. Bai, and A. Brossi, Collect. Czech. Chem. Commun. 1,142 (1991). 94. 0. Boyt, E. Hamel, and A. Brossi, Med. Chem. Res. in press ( 1 9 9 1 ) . 95. C. Canfield, Biol. Systems, Inc., Gaithersburg, Maryland 20879, personal communication on compounds tested at the Walter Reed Army Institute of Research in Washington, D.C. %. S. L. Wallace, I n “Textbook on Rheumatology”(W. N. Kelly, E. D. Hams, Jr., S. Ruddy, and C. B. Sledge, eds.), p. 871. Saunders, Philadelphia, Pennsylvania, 1985. 97. D. W. Brook, Abbott Laboratories, Abbott Park, Illinois 60064, personal communication. 98. M. Verstraets, E. Dejana, V. Fuster, E. Moncada, J. F. Mustard, G. Tans, and B. B. Vargaftig, Haemostasis 15,89 (1985). 99. A. Brossi, R. Dumont, H. S. Yun-Coi, and J. R. Lee, Arch. Pharm. Res. 10, lOO(1987). 100. K. Sugio, M. Maruyama, S. Tsurufuji, P. N. Sharma, and A. Brossi, Life Sci. 40, 35 (1987). 101. P. Kerekes, P. N. Sharma, A. Brossi, C. F. Chignell, and R. F. Quinn, J . Med. Chem. 28, 1204 (1985). 102. J. Wolffand J. Williams, Rec. Prog. Horm. Res. 29,229 (1973) 103. J. Wolf€, H. G. Capraro, A. Brossi, and G. H. Cook, J. Biol. Chem. 255,7144 (1980). 104. M. H. Zweig and C. F. Chignell, Biochem. Pharmacol. 22,2141 (1973). 105. J. K. Batra, G. J. Kang, L. Lurd, and E. Hamel, Biochem. Pharmacol. 37,2595 (1988). 106. M. Boyd, Pinc. Pract. Oncol. 3, I(1989). 107. G. J. Kang, Z. Gethunt, A. Muzaffar, A. Brossi, and E. Hamel, J. Biol. Chem. 265, 10255 (1990). 108. E. Hamel, H. H. Ho, G. J. Kang, and C. M. Lin, Biochem. Pharmacol. 37,2445 (1988). 109. M. Ravid, M. Gotfried, J. Berheim, B. Chen, and A. Brossi, in “Amyloids and Amyloidosis” (G. C. Glenner, ed.), p. 833. Plenum, New York, 1988. 110. M. Cernoch, J. Malinsky, 0. Telupilova, and F. SantavL, Arch. fnt. Pharmacodyn. Ther. 99, 141 (1954). I 1 I. I. Ringel, D. Jaffe, S. Alerhand, A. Muzaffar, 0. Boyt, and A. Brossi, J. Med. Chem. (in press).

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OLlVlER BOY6 A N D ARNOLD BROSSI

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

23

22

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

NBS OAc

AcO

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

mp PC)

[all3 (")

282-284

-39.5, CfMel1:l"

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

-49.3, 10% AcOH

44,AczO.P~~

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

Refs. 55 55 56 57,58

58 5759.60

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

Refs.

61

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

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

-15, Et

57,61

144-146

-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

P-OAC a-OH 0

P-OAC 0

P

Korseverilinone Korseverilinedione

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

59, A c ~ OPy ,

P

202-204 244-245 HCI 224-226

-46.4, Cf

68 67 69,70

-18.8, Cf

69 70

63, A c ~ OPY ,

a

63, CrO,

222-223 217-218 HCI 335-336 HBr 322-323 HCI04 274-275 137- 139

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

-9.6, MeICf" 71-73

74

241-244 254-256 275-277

- 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

P P P

193- 194

a a

P P P P

a

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

P

P

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

a

87 87 86 87

91 92 93 94 95

Ddafrine Korselidine Diacetylkorselidine Delafrinone Korselidinedione

0

0 0

a a a a a

a

a a

TABLE V IMPERIALINEGROUP

-

Y

W rn

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

98, CrO,

mp ("C) 121-122 228-230 157-159 183 122-123 195- 196 240-242 170- 171

As.9

123, Na, EtOH; Li, MeOH

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 N-

108,H202

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

123, NaBH4; H2, R

117-120 HCI 212 135-137'

+8.4, Meb 34,100

oxide

-

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

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-

108, CrO3

116,H2OZ

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

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

oxide

118 119 Imperialone

a-H,P-OAc

0

0 0

120 Imperialone

NOH

dioxime 121 Verticindione

0

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

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],,(")

a

111

a

P P a

P

Refs.

3 16-3 18

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

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

(“1

+16.4, Cf + 156, Cf

TABLE VIII

VERAMARINE GROUP

6 ~~

~~

2

mp ("(2)

Unsaturation

X

A5.6

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

148

A5.6

a-H, P-OAC

OH

147, AczO, Py

254-255

149 150 151

~ 5 . 6

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

OAC OAC

0

0

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

208-2 1 1 192 Amorphous

No.

Name

141 142 143 144 145

Fritillarizine

146 147

~ 5 . 6 A5.6

Veraflorizine

A5.6

-c ~

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

R

Preparation

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* H*

H H

H H

H

Ac Ac H MB

H H H H

H H H H

H

H Acetonide

H H

H Acetonide

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'

38,41,140,153 157

+ 12, Et; + 11.4, Py

40,153 40

+27, Et

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

41,158 41 41 155

m

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

H

230-231

+13, Cf; -11, Py

MB

H

221-223

-25, Cf; -60, Py

H H H H

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

H H H H

Amorphous 180- 181

+6.6,Cf +3,PY

221-222

30.3,Et

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

Amorphous 200-203 149- 152 160-164

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

228-233

-21.2, Py -80.0, Py

H

H

H

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

214 Neogerrnidine (isogermidine) 215 216 217 218 Germanidine

H

H

Ac MB An An

219 220 Germerine 221 Neogermbudine 222 Germbudine 223 24 224

BAn HMB eDMB tDMB AMB Ac Ac

209

Ac

H

M

H

M H

B

H

210, MBCI, Py 219, H2/Pd or 232 MeOH 208, BAnCI, Py 234, MeOH 235, MeOH 23, AcOH, H20 278, HCI

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

26

R' Ac

R2 H

R'

R3 R4 Ac

H

COOPr'

R6

[ a h("1

Refs.

23, COC12, Py;

223-226

-57.1, Py

50

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

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

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

231 232 Germanitrine 233 Maackinine

mp("C)

H

225

230

Reparation"

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

Cf; -74, Py

229-230

- 12,

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

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

190

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

Refs.

[aID("1

mp ("C)

Preparation"

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

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

12 l3

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

270 271

Cevadine Vanilloylveracevine Veratridine

11, BAnCI, Py

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

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

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

239-241 258-260

12, H2, Pd 11, VeCI, Py or 270, CH2N2

11,VeCI, Py 277, MeOH

l3, A c ~ O

-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 (")

Refs.

+ 127, AcOH';

45,46

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

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

(")

+5, P y b +3, PY

Ref.

+33, Did

41 47 47 47

+42, Cf'

48

+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

38,156,159 155,193

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

Refs.

[ a l D (")

194

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

195 I55 155 15

300

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

301 302

303

304 305 306 3@7

308

~

c!

MB

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+ H H H Ac

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) 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,

No.

Name

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,

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+;

368

Ac

Ac

Ac

Ac

H

Ac

Ac

iB Ac

369 370

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

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

293,Ac20,

28 1-282

-72, Py

155

HC104 345,iB20, HCIO4 371, H3O+

2 10-2 15 217

-39, Py -46, Py

15 155

PY

Ac20, PY

HMB Ac

iB H

Ac Ac

Ac K

H H

MB H

(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

REFERENCES 1. 0. Jeger and V. Prelog, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 7, p. 363. Academic Press, New York, 1960. 2. S. M. Kupchan and A. N . By, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 10, p. 193. Academic Press, New York, 1968. 3. J. Tomko and Z. Voticky, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 14, p. 1. Academic Press, New York, 1973. 4. C. R. Narayanan, in “Progress in the Chemistry of Organic Natural Products” (L. Zechmeister, ed.), Vol. 20, p. 298. Springer-Verlag, Vienna, 1%2. 5 . S. M. Kupchan, J. H. Zimmerman, and A. Afonso, Lloydia 24, I (1961). 6. D. H. R. Barton, 0. Jeger, V. Prelog, and R. B. Woodward, Experientia 10,81 (1954). 7. J. P. Kutney, C. C. Fortes, T. Honda, Y. Murakami, A. Preston, and Y. Ueda, J . Am. Chem. SOC.99,964 (1977). 8. J. P. Kutney, Bioorg. Chem. 6,371 (1977). 9. 0. Krayer and G. H. Acheson, Physiol. Reu. 26,383 (1946). 10. S. M. Kupchan and W. E. Flacke, In “Anti-Hypertensive Agents” (E. Schlittler, ed.), p. 429. Academic Press, New York, 1967. 1I. D. G. Crosby, In “Naturally Occurring Insecticides” (M. Jacobson and D. G. Crosby, eds.), p. 177. Dekker, New York, 1971. 12. J. M. Benforado, W.Flacke, C. R. Swaine, and W. Masimann, J . Pharmacol. Exp. Ther. WO, 311 (1960). 13. S. M. Kupchan, J . Pharm. Sci. 50,273 (l%l). 14. L. F. Fieser and M. Fieser, in “Steroids,” p. 867. Reinhold, New York, 1959. 15. H. A. Nash and R. M. Brooker, J. A m . Chem. SOC.75, 1942 (1953). 16. S. M. Kupchan and C. I. Ayres, J. A m . Chem. SOC. 82,2252 (1960). 17. W. Sneader, in “Comprehensive Medicinal Chemistry” (C. Hansch, P. G. Sammes, and J. B. Taylor, series eds. P. D. Kennewell, ed.), Vol. 1, p.14. Pergamon, Oxford, 1990.

18. A. G. Lee, in, “Comprehensive Medicinal Chemistry” (C. Hansch, P. G. Sammes, and J. B. Taylor, series eds. J. C. Emmett, ed.), Vol. 3, p. 35. Pergamon, Oxford, 1990; see also D. J. Triggle, p. 1058 of the same volume. 19. E. X. Albuquerque and J. W.’ Daly, Recept. Recognir. Ser. A 1,299 (1976). 20. F. Pavelcik and J. Tomko, Acra Crystallogr. B35, 1790 (1979). 21. F. Pavelcik and 3. Tomko, Tetrahedron Letr., 887 (1979). 22. W. T. Eeles, Tetrahedron Lerr. 7,24 (1960). 23. K. Kaneko, T. Katsuhara, H. Mitsuhashi, Y.-P. Chen, H.-Y. Hsu, and M. Shiro, Tetrahedron Leu. 27,2387 (1986). 24. K. Kaneko,T. Katsuhara, H. Mitsuhashi, Y.-P. Chen, H.-Y. Hsu,andM. Shiro, Chem. Pharm. Bull. 33,2614 (1985). 25. P. Lee, Y. Kitamura, K. Kaneko, M. Shiro, G.-J. Xu, Y.-P. Chen, and H.-Y. Hsu, Chem. Pharm. Bull. 36,4316 (1988). 26. S. Ito, Y. Fukazawa, and M. Miyashita, Tetrahedron Lerr., 3161 (1976). 27. I. Masterova, V. Kettmann, J. Majer, and J. Tomko, Arch. Pharm. (Weinheim Ger.) 315, 157 (1982); Chem. Absrr. %, 196495 (1982). 28. V. Kettermann, F. Pavelcik, I. Masterova, and J. Tomko, Acra Crysrallogr., Secr. C: Crysr. Srrucr. Commun. C41,392 (1985). 29. A. K. Saksena and A. T. McPhail, Terrahedron Leu. 23,811 (1982). 30. K. Kaneko, N. Kawamura, M. Tanaka, and H. Mitsuhashi, Koen Yoshishu-Tennen Yuki Kagobursu Toronkai 22nd, 55 (1979); Chem. Absrr. 93,8387 (1980).

232

JOHN V. GREENHILL AND PAUL GRAYSHAN

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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 Antitubulin effect, of colchicinoids. 166

Aaptamine, 72 Acanthella curteri,

Apcinisotnenon Jos-aqrtrre,

alkaloids of, 46

Acetoacetyldeacetylcolchicine. 127 2-Aceyt-2-demethylthiocolchcine,

alkaloids of, 44 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.

Arothron nigroprtnctutrrs,

alkaloids of, 32 Adociaquinones A-B. 11 I Agrlus Jlabelliformis

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,

As troides c~alvcirloris.

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

alkaloids of. 48 A.rinc4la sp.,

alkaloids of, 57 Ayuthianine. 15

4,9-Anhydrotetrodotoxin,43

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

Anomian A. 100

Birgrrici dentura.

Amphiprion perideruion.

alkaloids of. I10 Ancistrocladus tectoriirs Lour.

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

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

247

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

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 J Janolusimide. 88 Jasminiflorine, 3 I Jaspamide. 95 Jasplakinolide. 95 Jerusalemine, 172

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

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,

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

P Papuamine, 74 Paradaxins, 97 Patellamide D, 91 Patellazoles A-C,81 Perebaenu sagituta,

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 W

Wanpeinine, 195 Woodinine. 65

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

Y Yanangcorinine. 7 Yanangine. 7 2

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