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THE ALKALOIDS Chemistry and Pharmacology VOLUME 35

This Page Intentionally Left Blank

THE ALKALOIDS Chemistry and Pharmacology Edited by Arnold Brossi Natk~mlInstitutes of H d t h &the&. Maryland

VOLUME 35

Academic Press, Inc

Harcourt Brace Jovanovich, Publishms

San Diego New York Berkeley Boston London Sydney Tokyo Toronto

COPYRIGHT 0 1989 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, 01 any information storage and retrieval system, without permission in writing from the publisher.

ACADEMIC PRESS, INC. San Diego, California 92101 United Kingdom Edition published by ACADEMIC PRESS LIMITED 24-28 Oval Road, London NW 1 7DX

LIBRARY OF CONGRESS CATALOG CARD NUMBER: 50-5522

ISBN 0-12-469535-3 (alk. paper)

PRINTED IN THE UNITED STATES OF AMERICA 8 9 9 0 9 1 9 2

9 8 7 6 5 4 3 2 1

IN MEMORY OF TETSUJI KAMETANI Dr. Tetsuji Kametani, who died on October 11, 1988, in Tokyo, Japan, was a giant in the field of chemistry of natural products. He had mastered total synthesis of most biologically active natural products, and his work has stimulated many working in the field. After his departure from the Pharmaceutical Institute at Tohoku University in Sendai in 1980, his contributions to science did not diminish. On the contrary, they continued to flow and to be important despite his election to deanship and presidency at Hoshi College in Tokyo in 1981. The Japanese journal Hemvcycles, which is written in English and which he founded in 1973, became a prestigious journal for many working with heterocyclic compounds. Only time will tell how much the scientific communities in Japan and in the world have lost with his passing away. It is with admiration and thanks to my colleague and friend Dr. Rtsuji Kametani that I dedicate this volume of “The Alkaloids” to his lasting memory. Arnold Brossi


CONTENTS

CONTRIBUT~RS ............................... ;. ........................... PREFACE ................................................................

ix xi

Chapter 1. Alkaloids from Guuneria ANDIG+ CAV~ MICH~L , LEBOEUF, AND BRUCE K. CASSELS I. 11. 111. IV. V. VI. VII. VIII.

Introduction ....................................................... Botanical Considerations ............................................ Alkaloids from Chemically Investigated Guut&ria Species. ............... Structure Elucidation and Chemistry.. ................................ Biogenetic Hypotheses .............................................. Chemosystematics .................................................. Pharmacology. ..................................................... Appendix .......................................................... References .........................................................

1 2 3 3 57 65 69 71 73

Chapter 2. 8-Phenethylamines and Ephedrines of Plant Origin JANLLJNDSTR~M I. Introduction ....................................................... 11. Occurrence ........................................................ 111. Isolation, Identification, and Determination Procedures ................. IV. Synthesis .......................................................... V. Biosynthesis ....................................................... VI. Biological Effects.. ................................................. References .........................................................

77 77 131 132 137 142 144

Chapter 3. Lythraceous Alkaloids I. 11. 111. IV.

KAORU FUJI Introduction ....................................................... Synthesis .......................................................... Occurrence and Biosynthesis ........-. ............................... Spectroscopic Studies ............................................... References .........................................................

vii

155 155 172 173 175

viii

CONTENTS Chapter 4. Dibenzazonine Alkaloids AND DOMINGO DOMINGUEZ LUISCASTEDO

I. Introduction

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

11. Occurrence and Classification ........................................

111. Structure Determination .............................................

IV. Synthesis .......................................................... V. Biosynthesis ....................................................... VI. Pharmacological Properties ..........................................

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

VII. Related Alkaloids: Dibenzazecines References .........................................................

177 179 180 183 205 209 209 212

Chapter 5. Nuphar Alkaloids JACEK CYLIULSKI AND JERZY T. WROLIEL I. Introduction ....................................................... 11. Significance of Nuphar Species in the Aquatic Habitat .................. 111. New Nuphar Alkaloids.. ............................................ IV. Stereochemical'Itansformations of Nuphar Alkaloids ................... V. Chemistry of Nuphar Alkaloids and Manifestation of Sulfur.. VI. Synthesis of Nuphar Alkaloids ....................................... VII. Spectroscopy of Nuphar Alkaloids.. .................................. VIII. Pharmacology. ..................................................... References .........................................................

...........

215 216 220 227 232 239

244 253 256

Chapter 6. Oxazole Alkaloids HELENM. JACOBS AND BASIL A. BURKE

I. Introduction ....................................................... 11. Oxazoles of the Gramineae .......................................... 111. Oxazoles of the Rutaceae ............................................ IV. Marine Oxazoles ................................................... V. Bacterial Oxazoles .................................................. VI. Biological Activity .................................................. VII. Isolation and Spectral Characteristics ................................. References .........................................................

259 260 262 269 27 1 295 304 307

CUMULATIVE INDEX OF TITLES .......................................... IND U( ..............................................................

311 317

CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

BASILA. BURKE(259), The Plant Cell Research Institute, Inc., Dublin, California 94568 BRUCEK. CASSELS (l), Laboratoire de Pharmacognosie, UA 496 Centre National de la Recherche Scientifique (CNRS), Facultt de Pharmacie, Universitt de Paris-Sud, F-92296 Chiitenay-Malabry Cedex, France LUISCASTEDO(177), Departamento de Quimica Orghica, Facultad de Quimica, Universidad de Santiago, 15706 Santiago de Compostela, Spain AND^ C A (l),~ Laboratoire de Pharmacognosie, UA 4% Centre National de la Recherche Scientifique (CNRS), Facultt de Pharmacie, Universitt de Paris-Sud, F-92296 Chatenay-Malabry Cedex, France (215), Department of Chemistry, University of Warsaw, JACEKCYBULSKI Warsaw, Poland DOMINGO DOMINGUEZ (177), Departamento de Quimica Orghica, Facultad de Quimica, Universidad de Santiago, 15706 Santiago de Compostela, Spain KAoRU FUJI (155), Institute for Chemical Research, Kyoto University, Uji, Kyoto 611, Japan HELENM. JACOBS (259), Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica MICHELLEBOEUF(l), Laboratoire de Pharmacognosie, UA 4% Centre National de la Recherche Scientifique (CNRS), Facultt de Pharmacie, Universitt de Paris-Sud, F-92296 Chiitenay-Malabry Cedex, France JANLUNDSTR~M (77), Department of Drug Metabolism, Astra Research Centre, S-151 85 Sodertalje, Sweden JERZYT. WR6BEL (215), Department of Chemistry, University of Warsaw, Warsaw, Poland

ix


PREFACE

The chapter on “0-Phenethylamines and Ephedrines of Plant Origin,” which includes the well-known alkaloids mescaline, ephedrine, and khat alkaloids, was last discussed in Vol. 3 of this treatise some 35 years ago with details on the analytical detection of these alkaloids given in Vol. 32 (1988). These groups of alkaloids and their occurrence in plants have now been summarized. The chapter on “Lythraceous Alkaloids,” last discussed in Vol. 18 (1981), is updated here with focus on chemistry. This also applies to “NuphurAlkaloids,” presented first in Vol. 9 (1%7) and then in Vol. 16 (1977). This chapter lists 21 new alkaloids and includes a discussion on pharmacological properties of this group of alkaloids. “Alkaloids from Guatteria” is a chapter that illustrates the immense variety of alkaloids a plant can produce. More than 130 different alkaloids have been isolated so far, and some of them have unique structures. “Dibenzazonine Alkaloids,” represented by eight naturally occurring alkaloids and several synthetic congeners prepared from thebaine, is a chapter presented here for the first time. A first show also with a discussion of pharmacological properties is “Oxazole Alkaloids,” which occur in plants, bacteria, and marine organisms. Again, a unique blend of contributors from seven different countries is responsible for the successful completion of this volume. Arnold Brossi


-CHAPTER

1-

ALKALOIDS FROM GUAlTEMA ANDRBCAVB,MICHELLEBOEUF, AND BRUCE K. CASSELS Laboratoire de Pharmacognosie UA 496 Centre National de la Recherche ScientiJique(CNRS) Faculte' de Pharmacie UniversitC de Paris-Sud F-92296 Chritenay-Malabry Cedex, France

I. Introduction .......................................................... 11. Botanical Considerations ................................................ 111. Alkaloids from Chemically Investigated Gu

1v.

Structure Elucidation and Chemistry ...................................... A. Benzylisoquinolines and Saxoguattine B. Bisbenzylisoquinolines ............................

............................................ ......................... E. Miscellaneous Aporphinoid-Related Alkaloids ...........................

............................. V. Biogenetic Hypotheses . VI . Chemosystematics ................................................ VII. Pharmacology ........................................................ ....... VIII. Appendix . . . . . . . . . . . . . References ...........................................................

1 2

3 3 3 20 28 29 46 57 65 69 71 73

I. Introduction Although the very large genus Guatreria Ruiz et Pav. (Annonaceae) has only recently begun to be studied from a phytochemical viewpoint, it has already yielded over 130 different alkaloids, many of them new. Some of these compounds are the first known representatives of novel structural types. Others confirm the rich diversity of biosynthetic, and probably degradative, capabilities found elsewhere in the Annonaceae. The vast majority of these substances clearly belong to the broad class of isoquinoline (or, more specifically, benzylisoquinoline) alkaloids, and the biogenetic derivation of a small number of unusual structures, although not so obvious, is also quite probably related to the same extensive category. Previous volumes of this treatise have addressed the occurrence, chemistry, and pharmacology of the major structural types of alkaloids found in Guatreria. Nevertheless, of the 20 bisbenzylisoquinolines described to date as Guarreria constituents, only 2 are discussed in the chapter by Cava et al. ( I ) , and only 1

THE ALKALOIDS, VOL. 35 Copyright 0 1989 by Academic Ress. Inc. All rights of repduction in any form reserved.

2

ANDRE CAVE ET AL.

7 others may be considered as classical compounds which have been reisolated from new sources.* The most recent contributions concerning specific alkaloid types found in this genus are those by Bhakuni and Jain on protoberberines ( 2 ) and by Kametani and Honda on aporphines (3).The former covers all 10 Guatteria alkaloids known to possess the protoberberine skeleton. The latter, on the other hand, though published in 1985, already appears seriously outdated. Recent reviews on the aporphinoids in general and on the Annonaceae in particular are those by Shamma and Moniot ( 4 , 5 ) ,Shamma and Guinaudeau ( 6 ) ,Guinaudeau et al. (7),and Cave et al. (8). The emergence of the azafluorenone alkaloids as a sizable group and the discovery of the azaanthracenes and azahomoaporphines, all represented in Guatteria, are very new developments. This chapter reviews these novel substances as completely as possible, discusses a small number of structurally unusual though not unprecedented compounds, and also updates the older contributions on the mainline isoquinoline alkaloids insofar as the genus Guatteria is concerned.

11. Botanical Considerations

The Annonaceae is a medium-sized family of tropical and subtropical trees, shrubs, and climbers (about 2100 species) which are generally grouped with other so-called primitive angiosperm families in the order Magnoliales (Magnoliaceae, Degeneriaceae, Himantandraceae, Eupomatiaceae, Canellaceae, Myristicaceae, and Winteraceae) (9, ZO). Of the somewhat more than 100 genela constituting the Annonaceae, Guatreria is the largest, comprising about 250 species. This genus is exclusively neotropical, reaching from southern Mexico to southern Brazil. The Amazon basin and the Guianas are its main center of distribution, with secondary centers in the coastal states of Brazil and in Central America. The most thorough revisions of this family and genus to date are those of R. E. Fries (11, 12). Within the framework of Fries’ classification, largely based on floral morphology, Guatteria forms a group with the tiny tropical American genera Guatteriella, Guatteriopsis, and Heteropetalum and belongs to the most primitive annonaceous tribe, the Uvarieae. The Guatteria group is placed after the Uvaria, Duguetia (including Malmea), Asimina, and Hexalobus groups, suggesting that it is the most advanced within the Uvarieae. The four genera Guatteria, Guatteriella, Guatteriopsis, and Heteropetalum are also grouped in the informal Guatteria tribe on palynological grounds (13, 14). Walker’s Guatteria tribe

* A new review of the bisbenzylisoquinoline alkaloids, entitled “The bisbenzylisoquinoline alkaloids,” which covers some of the Guutreriu constituents described here, appeared in print after this chapter had been submitted for publication: K.T. Buck, in “The Alkaloids” (A. Brossi, ed.), Vol. 30, pp. 1-222. Academic Press, San Diego, California, 1987.

1. ALKALOIDS FROM GUAlTERlA

3

seems more satisfactory from a phytogeographic viewpoint than Fries’ large, pantropical Uvarieae, considering that American and African Annonaceae must have been virtually isolated from each other after the Paleocene, about 54 million years ago (15). In Walker’s scheme, the Guatteria tribe appears after the Malmea and Uvaria tribes, constituting the Malmea subfamily, which is considered primitive, and in this sense agrees broadly with Fries’ system. The haploid chromosome number of Guutteriu is 14, presumably derived from the postulated original base chromosome number of angiosperms, n = 7 (16). Thus, floral and pollen morphology and chromosome counts suggest that Guatteriu conserves a number of archaic characteristics. A plant analyzed in 1972 as G. subsessiiis ( 1 7 ) has since been reclassified as Heteropetulum brusiliense ( 18). The medicinal box-ek-lemuy of YucatBn, better known in Europe as yumef, appears persistently in the phytochemical and pharmacological literature as Guutteriu guumeri Greenm. in spite of the fact that Fries removed it to Mulmeu as far back as 1939 (12);its currently accepted binomial is Mulmeu guumeri (Greenm.) Lundell (19, 20). For the sake of completeness, we have included the alkaloids found in these two species, indicating their proper botanical classification.

111. Alkaloids from Chemically Investigated Gmtteriu Species

The 17 Guutteriu species studied for their alkaloid content are listed in Table I, together with the alkaloids found therein, in alphabetical order. Alkaloids 1 to 138, known to occur to date in the genus Guutteriu [including guattegaumerine (7) from the generally misclassified Mulrneu guumeri], are listed by structural classes in Table I1 and alphabetically, together with synonyms, in Table IV (see Appendix). Guutteriu alkaloids can be classified into eight main types depending on the structural characteristics of their skeleton; these types and subtypes are presented in Fig. 1. These eight skeletal types are biosynthetically related, or at least conceivable proposals for their formation in vivo have been reported.

IV. Structure Elucidation and Chemistry A. BENZYLISOQUINOLINES AND SAXOGUATTINE 1. Unelaborated Benzylisoquinolines (1-5) Only five unelaborated benzylisoquinolines have been found in Guutteriu. All have been isolated previously from botanical sources belonging to different plant families. Four of them (1-4) are biogenetically commonplace, whereas the fifth, juziphine (5), is one of the relatively rare 7,8-dioxygenated analogs of this gen-

4

ANDRE CAVE EFAL.

TABLE I CHEMICALLY INVESTIGATED Guatteria SPECIESAND THEIRCONTAINED ALKALOIDS Species G. chrysopetalu (Steud.) Miq.

Alkaloid Codamine

O.N-Dirnethylliriodendronine

G. cubensis Bisse G. diekana R.E. Fr.

G. discolor R.E. Fr.

G. elata R.E. Fr.

Isoboldine Lanuginosine Liriodenine Lysicamine Nornuciferine Reticuline Corydine Liriodenine Dielsine Dielsinol Dielsiquinone Isomoschatoline Liriodenine 6-Methoxyonychine 0-Methylmoschatoline Onychine Argentinine Atherosperminine Atherosperminine N-oxide Corypa1mine 10-0-Dernethyldiscretine Discoguattine Discretamine Discretine Guacolidine Guacoline Guadiscidine Guadiscine Guadiscoline Isocalycinine 10- 0-Methylhernovine 0-Methylpukateine Noratherosperminine Oxoisocalycinine Oxoputerine Puterine Reticuline Saxoguattine Xylopine Norlaureline Oxolaureline

Structure Reference(s) 4 95 65 100 94 93 41 3 78 94 137 138 134 96 94 136 97 135 128 130 131 28 31 75 27 33 121 122 109 110 114 74 79

60 129 106 102 58 3 6 54 55 101

21 21 21 21 21 21 21 21 18 18 22, 23 22, 23 22 22 22 22, 23 22 22 24 24. 25 24. 25 24, 25 24 24, 26 24 24 24 24 24 24, 26 24. 26 24 25 24, 25 25 24 25 24. 25 25 24 25 27 27

5

1. ALKALOIDS FROM GUAlTERIA

TABLE I (Continued) Species

G . gaumeri Greenm. = Malmea gaumeri

Alkaloid

Structure Reference(s)

Oxoputerine Puterine Guattegaumerine

102 58 7

27 27 28

Dehydroneolitsine Goudotianine

85 126 48 65 70 5 76 94 69 73 67 66 37 3 13 8 22 11 10 9 I5 16 12 20 23 19 21 17 14 18 26 24 25 115 48 65 119

29 29 29 29 29 29 29 29 29 29 29 29 29 29 30 30 31 30 30 30 30 30 30 31 31 31 31 31 30 31 32 32 32 35 33 34 35 33 33

(Greenm.) Lundell G . goudotiana Tr. et PI.

3-H ydroxynomuciferine

G . guianensis (Aubl.) R.E. Fr.

G . megalophylla Diels

G . melosma Diels

Isoboldine Isodomesticine Juziphine Lindcarpine Liriodenine N-Methyllaurotetanine Neolitsine Norisodomesticine Norpredicentrine Pallidine Reticuline Apateline Aromoline 2,2’-Bisnorguattaguianine Coclobine Daphnandrine Daphnoline 1,2-Dehydroapateline 1,2-Dehydrotelobine 12-0-Demethylcoclobine Guattamine Guattaminone 2’-Norfuniferine 2’-Norguattaguianine 2’-Nortiliageine Telobine Tiliageine 0.0-Dimethylcurine Isochondodendrine 12-0-Methylcurine Guattescidine 3-Hydroxynomuciferine Isoboldine Isoguattouregidine Isomoschatoline Liriodenine

%

94

(continued)

6

ANDRk CAVE ETAL.

TABLE 1 (Continued) Species

G. modesru Diels G. morulesii (Maza) Urb. G. ouregou Dun.

G.psilopus Mart. G. sufordiunu Pittier G. sagorinnu R.E. Fr.

Alkaloid Melosmidine Melosmine Oxoanolobine Pallidine Liriodenine Roemerine Corydine Coreximine Dehydroformouregine Dehydronornuciferine 10-0-Demethylxylopinine Dihydromelosmine Formouregine N-Formylnornuciferine Gouregine Guattouregidine Guattouregine 3-Hydroxynornuciferine 3-Hydroxynuciferine Isopiline Lirinidine Lysicamine Melosmine 3-Methox ynuciferine 0-Methyldehydroisopiline N-Methylisopiline 0-Methy lisopiline 0-Methylmoschatoline Norcepharadione B Nornuciferine Nuciferine Ouregidione Oureguattidine Oureguattine Pentouregine Subsessiline Atherospemnidine Guatterine Lysicamine 0-Methylmoschatoline Anolobine Armepavine Dehydroroemerine Dehydrostephalagine Dragabine

Structure Reference(s) 113 111 99 37 94 45 78 32 83

80 34 112 51 42 132 118 120 48 49

46 39 93 111 52 82 47 50 97 107 41 43 108 61 62 127 103 98 91 93 97 53 2 81 84 133

34 34 36 33 37 37 18 38, 39 39 39 38, 39 38, 40 39 39 38, 41 38, 40 38. 40 39 39 38, 39 39 38, 39 38. 41 39 39 39 38, 39 38, 39 39 38, 39 39 39 38 39 39. 42 38, 39 47 47 44 44 45 45 45 45 45, 46

7

1. ALKALOIDS FROM GUATTERIA

TABLE I (Continued) Species

G. scundens Ducke

Alkaloid Duguespixine Elmerrillicine Glaziovine Guatterine Guatterine N-oxide 3-H ydroxynomuci ferine Lirinidine Liriodenine N-Methylcoclaurine N-Methylelmemllicine 0-Methylpukateine Norlaureline Nomuciferine Noroliveroline Nuciferidine Obovanine Oliveroline Oliveroline N-oxide Oxoanolobine Oxolaureline Oxoputerine Pachyconfine F'ukateine Puterine Roemerine Trichoguattine Xylopine Actinodaphnine Anolobine Asimilobine Atheroline Dicentrinone Discretine Guattescidine Guattescine Lanuginosine Laurotetanine Liriodenine 0-Methylisopiline N-Methyllaurotetanine Nordicentrine Norpredicentrine Saxoguattine Xylopine Xylopinine

Structure Reference(s) 123 63 38

91 92 48 39 94 1 64

60 55 41 88 87 56 89 90 99 101 102

86 57 58 45 124 54 71 53

40 104 105 33 115 116 100 68 94 50 69 72 66 6 54 36

45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 45 47 47 47 47 47 47 47-49 47-49 47 47 47 47 47 47 47 24 47 47

(continued)

8

ANDUB CAW? ETAL.

TABLE 1 (Continued) Species

Alkaloid

G . schomburgkiana Mart.

G. subsessilis

Structure Reference(s)

Anolobine Anonaine Belemine Coreximine Corydine Corytenchine Dehydroguattescine N-Formy lputerine Guadiscine Guattescine lsoboldine Kikemanine Lanuginosine Liriodenine 0-Methylpukateine Norcorydine Oxoputerine hterine Reticuline Tetrahydropalmatine X y1opine X ylopinine Not studied"

53 44 125 32 78 35 117 59 110 116 65 29 100 94

50, 51 51 50. 51 51 52 51 50. 51 51 50. 51 50, 51 52 52 51 51, 52 51 52 51, 52 51, 52 52 51 51 51

60 77 102 58 3

30 54 36

0-Methylmoschatoline and subsessiline were isolated from Hereroperalum brasiliense, misidentified as G . subsessilis (17. 18, 53).

TABLE I1 ALKALOIDS ISOLATED FROM Guarreria SPECIES

Alkaloid type and name Benzylisoquinoline ( -)-N-Methylcoclaurine (+)-Annepavine (+)-Reticdine

(+)-Codamine Juziphine

Structure

Molecular formula (MW)

1 3

C,,H2,N03 (299) (313) C,,H,,NO, CI9H2,NO, (329)

4 5

C2,,H2,N0, (343) C,,H2,N03 (299)

2

Species

Reference(s)

G . sagotiana G . sagotiana G. chrysoperala G . discolor G . goudoriana G . schomburgkiana G . chrysoperala G . goudotiana

45 45 21 25 29 52 21 29

9

1. ALKALOIDS FROM GUA7TERlA

TABLE I1 (Continued)

Alkaloid type and name Aminoethylbenzil Saxoguattine Bisbenzylisoquinoline ( -)-Guattegaumerine (+)-Ammoline ( +)-Daphnoline ( +)-Daphnandrine (+)-Coclobine (+)-12-0-Dernethylcoclobine (+)-Apateline (+)-Telobine (+)-1,2-Dehydroapateline (+)-1,2-Dehydrotelobine (+)-2'-Nortiliageine ( )-Tiliageine (+)-2'-Norfuniferine (+)-Guattarnine (+)-2'-Norguattaguianine (+)-2,2'-Bisnorguattaguianine ( +)-Guattaminone ( +)-Isochondodendrine (-)- 12-0-Methylcurine 0.0-Dirnethylcurine Berbine ( -)-Discretarnine ( -)-Corypalmine ( - )-Kikemanine (-)-Tetrahydropalmatine (-)- 10-0-Dernethyldiscretine ( -)-Coreximine

+

StNCture

6

7 8 9 10 11

12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

30 31 32

( -)-Discretine

33

(-)- 10-0-Dernethylxylopinine ( -)-Corytenchine ( -)-Xylopinine

34 35 36


Species

Reference(s)

G . discolor G . scandens

25 25

Malmea gaumeri" G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . guianensis G . megalophylla G . megalophylla G . megalophylla

28 30 30 30 30 30 30 30 30 30 31 31 31 31 31 31 31 32 32 32

G . discolor G . discolor G . schomburgkiana G . schomburgkiana G . discolor G . ouregou G . schomburgkiana G . discolor G . scandens G . ouregou G . schomburgkiana G . scandens G . schomburgkiana

24 24, 25 52 51 24 38, 39 51 24 47 38. 39 51 47 51

Morphinandienone ( -)-Pallidineb

37

G . goudotiana G . melosma

29 33. 35

F'roaporphine ( -)-Glaziovine

38

G . sagotiana

45 (continued)

10

ANDRE CAVE ETAL

TABLE I1 (Continued) ~~

Alkaloid type and name Aporphine sensu strict0 (- )-Lirinidine

StNCtufe

39

( - )-Asimilobine ( - )-Nornuciferine

40

(- )-N-Formlynornuciferine (-)-Nuciferine ( -)-Anonaine (-)-Roemerine

42 43 44 45

(- )-Isopiline ( -)-N-Methylisopiline ( -)-3-Hydroxynornuciferine

46

( - )-3-Hydroxynuciferine ( - )-0-Methylisopiline

49 50

(- )-Formouregine ( - )-3-Methoxynuciferine

( -)- Anolobine

51 52 53

(-)-Xylopine

54

(-

)-Norlaureline

(- bobovanine ( - )-Pukateine

( - )-F'uterine

( -)-N-Formylputerine ( -)-0-Methylpukateine

41

47 48

55 56 57 58

59

60


Species

Reference(s)

G . ouregou G . sagotiana G . scandens G . chrysopetala G . ouregou G . sagotiana G . ouregou G . ouregou G . schomburgkiana G . modesta G . sagotiana G . ouregou G . ouregou G . goudoriana G . melosma G . ouregou

G . sagoriana G . ouregou G . ouregou G . scandens G . ouregou G . ouregou G . sagotiana G . scandens G . schomburgkiana G . discolor G . sagotiana G . scandens G . schomburgkiana G . elata G . sagotiana G . sagotiam G . sagorianu G . discolor G . elara G . sagotiana G . schomburgkiana G . schomburgkiana G . discolor G . sagotiana G . schomburgkiana

39 45 47 21 38. 39 45 39 39 51 37 45 38, 39 39 29 33, 35 39 45 39 38, 39 47 39 39 . 45 47 50, 51 25 45 47 51 27 45 45 45 24, 25 27 45 51, 52 51 24. 25 45 51

11



Alkaloid type and name (-)-Oureguattidine ( -)-Oureguattine ( -)-Elmerrillicine ( -)-N-Methylelmerrillicine

(+)-Isoboldine

StNCture 61 62 63 64 65

(

+)-Norpredicentrine

66

(

+)-Norisodomesticine

67 68 69

+

( )-Laurotetanine (

+)-N-Methyllaurotetanine

( (

+)-Isodomesticine +)-Actinodaphnine

(+)-Nordicentrine (+)-Neolitsine ( -)-Isocalycinine ( -)-Discoguattine (+)-Lindcqine ( +)-Norcorydine (+)-Corydine

70 71 72 73 74 75 76 77 78


Species

G . ouregou G . ouregou G . sagotiana G . sagotiana G . chrysopetala G . goudotiana G . melosma G. schomburgkiana G . goudotiana G . scandens

G . ouregou G . sagotiana G . ouregou G . ouregou G . sagotiana G . goudotiana

39 45 39 39 45 29 45 45 45 45 45 43 45 45

87 88 89 90 91

G . sagotiana G . sagotiuna G . sagotiana G. sagotiana G . sagotiana G . psilopus

(-)-Guatterine N-oxide

92

G . sagotiana G . sagorianu

86

52

G . goudotiana G. scandens G . goudotiana G . scandens G . goudotiana G . scandens G . scandens G . goudotiana G . discolor G . discolor G. goudotiana G . schomburgkiana G . cubensis G . moralesii G . schomburgkiana G . discolor

79

81 82 83 84 85

38 39 45 45 21 29 34 29 47 29 47 29 47 29 47 47 29 24 24. 26 29 52 18 18 52 25

(+)-10-0-Methylhernovine Dehydroaporphine Dehydronornuciferine Dehydroroemerine 0-Methyldehydroisopiline Dehydroformouregine Dehydrostephalagine Dehydroneolitsine 7-Hydroxyaporphine ( -)-Pachyconfine (- )-Nuciferidine (-)-Noroliveroline ( -)-Oliveroline (-)-Oliveroline N-oxide ( -)-Guatterine

80

Reference(s)

(continued)

12

ANDRE

CAVE ET AL.


Alkaloid type and name

Structure

Oxoaporphine Lysicamine

93

Liriodenine

94

N,O-Dimethylliriodendronine Isomoschatoline

95 96

0-Methylmoschatoline

97

Atherospermidine Oxoanolobine

98 99

Species

Reference(s)

21 38, 39 44 21 18 22 29 33, 35 37 45 47 51 21 22 33 22 38, 39 44 43 34 45 21 47 . 51 27 45 25 27 45 51 38, 39

104 105 106

G . chrysopetala G . ouregou G . saffordiana G . chrysopetala G . cubensis G. dielsiana G . goudotiana G . melosma G . modesta G . sagotiana G . scandens G . schomburgkiana G . chrysopetala G. dielsiana G . melosma G . dielsiana G . ouregou G. saffordiana G . psilopus G . melosma G . sagotiana G. chrysopetala G . scandens G . schomburgkiana G . elata G . sagotiona G . discolor G . elata G . sagotiana G . schomburgkiana G . ouregou Heteropetalum brasiliense' G . scandens G . scandens G . discolor

107 108

G . ouregou G . ouregou

39 39

109

G . discolor

24

Lanuginosine

100

Oxolaureline

101

Oxoputerine

102

Subsessiline

103

Atheroline Dicentrinone Oxoisocalycinine 4,s-Dioxoaporphine Norcepharadione B Ouregidione 7-Alky laporphine Guadiscidine


47 47 24

13



Alkaloid type and name

StNCture

Guadiscine

110

Melosmine

111

Dihydromelosmine Melosmidine Guadiscoline ( -)-Guattescidine

112 113 114 115

( +)-Guattescine

116

Dehydroguattescine ( -)-Guattouregidine

Isoguattouregidine ( - )-Guattouregine (- )-Guacolidine ( -)-Guacoline Duguespixine Trichoguattine Belemine Goudotianine 1, I 1-Oxymethyleneaporphine ( -)-Pentouregine Aminoethylphenanthrene Argentinine Noratherosperminine Atherosperminine Atherosperminine N-oxide Cularinoid Gouregine Azahomoaporphine Dragabine Azaanthracene Dielsiquinone Azafluorene Onychine 6-Methoxyonychine Dielsine Dielsinol


Species

Reference(s)

117 118 119 120 121 122 123 124 125 126

G . discolor G . schomburgkiana G . melosma G . ouregou G . ouregou G. melosma G . discolor G . melosma G . scandens G . scandens G. schomburgkiana G . schomburgkiana G . ouregou G . melosma G . ouregou G. discolor G. discolor G . sagotiana G. sagotiana G . schomburgkiana G. goudotiana

24. 26 50, 51 34 38. 41 38. 40 34 24, 26 35 47-49 47-49 50, 5I 50, 51 38. 40 35 38. 40 24 25 45 45 50. 51 29

127

G . ouregou

39, 42

128 129 130 131

G . discolor G . discolor G . discolor G. discolor

24 25 24, 25 24. 25

132

G. ouregou

38. 41

133

G. sagotiana

45, 46

134

G. dielsiana

22

135 136 137 138

G. dielsiana

22 22. 23 22, 23 22. 23

Guatteria gaumeri in Ref. 28. [ale measured in MeOH, therefore S configuration. Guarreria subsessilis in Refs. I7 and 53.

G . dielsiana G. dielsiana

G . dielsiana

BENZYLISCQUINOLINE TYPE

AMINOETHYLBENZIL TYPE

BISBENZYLISCQUINOLINE TYPE

Dauricine subtype

oxyacanthinc subtype

FIG. 1. Structural types of alkaloids isolated from Guurreriu species. 14

Apateline subtype

Tiliageine subtype

FIG. 1.

See legend on p. 14. 15

Isochondodendrinesubtype

BERBINE TYPE

MORPHINANDIENONE TYPE

PROAPORPHINE TYPE

FIG. I . See legend on p. 14. 16

APORPHINOID TYPE

Aporphine sensu strict0 subtype

Dehydroaporphine subtype

7-Hydroxyaporphine subtype

Oxoaporphine subtype

4,5-Dioxoaporphine subtype

7-Alkylaporphine subtype

0

FIG. I . See legend on p. 14. 17

1.1 1-0xymethyleneaporphine subtype

Aminoethylphenanthrene subtype

MISCELLANEOUS APOWHINOID-RELATED TYPES

Cularinoid subtype

kehomoapocphine subtype

Azaanthracene subtype

Azafluorene subtype

FIG. 1 . See legend on p. 14.

19

I. ALKALOIDS FROM GUATTERlA

era1 type that occur quite frequently in the Fumariaceae but only sporadically in other plant families.

HO 1

3:RnH

2

I

4:RrC.

2. Saxoguattine (6) An aminoethylbenzil, saxoguattine (6),isolated from G. discolor (24) and G. scandens ( 2 4 ) , is the second known example of this structural class and is rather obviously derived from the benzylisoquinoline skeleton (544).The mass spectrum of saxoguattine is characterized by a base peak at mlz 58, characteristic of the aminoethylbenzyl side chain, and two medium intensity peaks at rnlz 236 and 151 corresponding to cleavage of the molecule between the two carbonyl groups. The ‘H-NMR spectra in CDCI, and in CD,OD with NaOD added led to the positioning of the substituents as shown in 6. This structure was further confirmed by periodate oxidation of the borohydride reduction product of saxoguattine (6) to 4,5-dimethoxy-2-dimethy~aminoethyl-benzaldehyde (139) and isovanillin (140) (24).

20

ANDRE CAVE ET AL.

6

139

U O C H ,

140

B. BISBENZYLISOQUINOLINES The bisbenzylisoquinolines found in Guatteria are either of the head-to-tail type ( G . megalophylla) or the tail-to-tail type ( G . guianensis), the latter sometimes incorporating a biphenyl linkage. Several bisbenzylisoquinolineshave only been isolated from these plants, and their distribution in the genus appears to be rather limited as, out of 17 species studied so far, they have only been found in 2. It should be stressed here that the only known source of the tail-to-tail alkaloid guattegaumerine (7) is not a Guatteria species but in fact Malmea gaumeri, which figures in the chemical and pharmacological literature as G . gaumeri. 1. Dauricine-Type Dimers (1 1 - 12’ aryl ether linkage)

By far the most abundant alkaloid in the stem bark of the medicinally important Malmea gaumeri, and until now the only one isolated from this source, was named guattegaumerine on the basis of a misclassification of the plant material. Its structure, 7, was elucidated by the usual spectroscopic methods and supported by chromatographic comparison with the N,N’-dimethyl derivative of the previously known lindoldhamine, and its absolute configuration (C-1 R , C-1’ R ) was deduced from its CD curve (28). Guattegaumerine (7) is thus a diastereoisomer of (R ,S)-berbamunineand (S,R)-magnoline.

7

1. ALKALOIDS FROM GUA7TERIA

21

2. Oxyacanthine-Type Dimers (7-8’, 11-12‘ aryl ether linkages) (8-12) Aromoline (S),daphnoline (9), and daphnandrine (lo), are well-known members of the bisbenzylisoquinoline group, differing in their degree of methylation at N-2 and 0-12 and sharing the C-1 R , C-1’ S configuration, that have been found recently in G. guianensis (30). These substances cooccur with two 1,2didehydro analogs, coclobine (11)and 12-0-demethylcoclobine (12), in which the only chiral center, C-l’, also has the S configuration.

H

The presence of an imine function in coclobine and 12-0-demethylcoclobine was deduced from the very low mass spectral relative abundance of the bisisoquinoline fragment that normally results from double benzylic cleavage of bisbenzylisoquinolines (55), as well as from the acid-induced bathochromic shift in

22

ANDRE CAVE ETAL.

the UV spectra of these alkaloids. In the mass spectrum, the loss of ring C‘ afforded a peak at m / z 485 [(M - 107)+, 8%]. This fragmentation is in favor of an imine group placed at 1,2 in this type of dimer (55). Thus, the tertiary amine function (6 2.60 ppm on the ‘H-NMR spectrum) should be located at position 2’. The positive optical rotation of these two dimers shows that their absolute configuration is C-I’ S (56). Coclobine (11)was identified on the basis of its spectral characteristics. It had been isolated only once before, from a Cocculus species (Menispermaceae) (57). The structure of 12-0-demethylcoclobine (12)was deduced from its mass and NMR spectra, which show that the upper half of this new imino bisbenzylisoquinoline dimer bears three methoxyl groups and that one of the “lower” benzyl rings carries a phenol function. 0-Methylation of 12 gave coclobine (ll), showing that the hydroxyl group is located at C-12. Reduction of the imine function of 12 with sodium borohydride afforded two diastereoisomers in a 1 :2 ratio, with R , S and S,S configurations, respectively (30).The former is the previously undescribed 2-noroxyacanthine (141),and the latter is already known as demerarine (142).

141

142

1 . ALKALOIDS FROM GUATTERIA

23

3. Apateline-Type Dimers (6-7’, 7-8’, 11- 12’ aryl ether linkages) (13-16)

Apateline (13), telobine (14), and their 1 ,2-dehydro counterparts (15 and 16, respectively) are well-known bisbenzylisoquinoline alkaloids. They were iso-

15:RrH 16 : R

=

CHI

lated for the first time from the Monimiaceae, specifically, Daphnandra apatela (58, 59), and reported again in several menispermaceous plants (60). Their isolation from C. guianensis (30) is the first Occurrence of this type of dimer in an annonaceous species. 4. Tiliageine-Type Dimers ( 1 1- 1 1’ biphenyl and 8-7’ aryl ether linkages) (17-23)

Compounds 17-23, which are new natural dimers of the tiliageine type, have been isolated from G. guianensis ( 3 1 ) . The mass spectrum of 2’-nortiliageine

24

ANDRE CAVE ET AL.

(17) gave the molecular formula C,,H,,N,O, ( m l z 594,58%). The base peak corresponded to the singly charged bisisoquinoline ion ( m l z 367), and another intense signal arose by loss of a hydrogen atom from the molecular ion ( m l z 593, 88%). These features are characteristic of bisbenzylisoquinolines with a secondary amine function (55). The single N-methyl resonance at 2.41 ppm in the 'HNMR spectrum suggested that N-2' was the unmethylated one, on the basis of the complete assignment of the spectrum of antioquine (143) (61).Similarly,

143

the absence of a three-proton singlet near 3.45 ppm, assignable to a methoxyl group at C-7, suggested that this position is occupied by a phenol function. N-Methylation of 17 afforded tiliageine (M), which was also isolated from G. guiunensis (31) and had been reported for the first time as a constituent of Tiliucoru dinklugei (Menispermaceae) (62). Its structure was discussed in Volume 16 of this treatise ( I ) . The structure of 2'-norfuniferine (19) was established similarly, aided by selective decoupling of the aryl proton resonances and a complete NOE analysis that allowed a phenol function to be placed at C-12 and a methoxyl at C- 12', as in

I . ALKALOIDS FROM GUATTERIA

25

17 and 18. The specific rotations of 17, 19, and their N-methylation products 18 and funiferine (144) were all positive and in the 180-200” range, and their CD

144

curves were superimposable. These properties closely resemble those described for antioquine (143), for which the S,R configuration had already been determined by anomalous X-ray dispersion (61).The two new dimers 17 and 19 and the previously reported tiliageine (18) and funiferine (144) must therefore have the same stereochemistry. The absolute configuration suggested for tiliageine (18) on the basis of a biosynthetic study (63) is confirmed by this work ( 3 1 ) . Guattamine (20) gave a very abundant molecular ion at mlz 606 (94%) on electron impact, a moderately abundant doubly charged molecular ion at mlz 303 (13%), and a mass spectral base peak arising from loss of a hydrogen atom from the molecular ion, all features suggestive of an imine bisbenzylisoquinoline structure. The presumed presence of the imine function was supported by an acid-induced bathochromic shift in the UV spectrum. The IH-NMR spectrum of guattamine exhibited a high field N-methyl singlet at 2.32 ppm indicative of methylation at N-2, and a complete selective decoupling and NOE study led to the proposal of structure 20 (31).In CDC1, solution, between 30 and 60°C, the ‘H-NMR spectrum showed the presence of two conformers in a 7 :3 ratio. The positive optical rotation of this alkaloid was taken as an indication that its absolute configuration at C-1 should be S. Borohydride reduction of guattamine (20) led to the formation of two diastereoisomers, 2’-norfuniferine (19) and 2’-norguattaguianine (21), which were also present in the plant (31). A complete IH-NMR spectral study of 2’-norguattaguianine supported structure 21 which differs from that of 2’-norfuniferine (19) only in the configuration at the newly formed chiral center. N-Methylation of 2’-norguattaguianine afforded the corresponding diastereoisomer of funiferine (144), named guattaguianine (145), which has not yet been found in nature. The structure of 2,2’-bisnorguattaguianine(22) was deduced from spectral data and comparison with those of 2’-norguattaguianine (21), as well as N,N’dimethylation to give guattaguianine (145).

26

AND& CAVE ET AL.

21 : R r CHI

22:R=H

145

The ‘H-NMR spectrum of guattaminone (23) resembled that of guattamine (20), although some resonances, notably those due to H-10’ and H-14’, were shifted considerably downfield (to 7.66 and 8.36 ppm, respectively, in the cases


27

mentioned). The IR spectrum indicated the presence of a conjugated ketone function (1660 cm-I), and additional 'H-NMR studies led to the assignment of structure 23 (31). The positive optical rotation of guattaminone (23) suggested that its absolute configuration is S , like guattamine (20). The 'H-NMR spectra of the S,S and S , R 1 1 - 1 1 ' biphenyl and 8-7' aryl etherlinked dimers show subtle differences that allow both stereoisomeric series to be differentiated. Most obvious is the higher, broader range of chemical shifts of the aryl protons (6.4-7.6 ppm) observed in the spectra of the S,S bases as compared with the corresponding range (6.3-7.3 ppm) found for the S , R substances. The CD spectra of these alkaloids are complex, but a positive extremum can always be observed near 220 nm for the S,S dimers and a negative one for their S,R counterparts. A more readily accessible criterion is provided by the magnitude of the specific rotation of these compounds in chloroform, which is around 40"for the S,S and about 190" for the S,R alkaloids. Application of these rules to a number of other bases of this type allowed their absolute configurations to be established (31).

5. Chondodendrine- and Isochondodendrine-Type Dimers (8- 12', 1 1-7' and 8- 12', 12-8' aryl ether linkages) (24-26) Isochondodendrine ( a ) , 12-0-methylcurine (25), and 0,O-dimethylcurine (26) were isolated in 1975 from G. megulophyllu ( 3 2 ) ,but the interpretation of the IH- and I3C-NMR spectra of the last two compounds was reported later (64). These dimers, which are members of a structural subclass characteristic of the Menispermaceae, are the only compounds of this type isolated thus far from a Guatteria species.

24

28

ANDRE CAVE ETAL.

25:RrH 26 : R

I

CH3

C. BERBINES A total of 10 berbines (27-36)have been reported as constituents of four different species of Guatteria. (-)- 10-0-Demethyldiscretine (31) is the only sub-

stance of this group which has been found in a Guatteria species and nowhere else (24). (-)- 10-0-Demethylxylopinine(34)also appears to be relatively rare, as it is known to occur only in one member of this genus (38, 39) and in one


29

belonging to the rather closely related, chemically similar genus Duguetia. As all these substances have been reviewed in Volume 28 of this treatise (2), we do not discuss them further. Pallidine (37)and glaziovine (38),the only representatives

37

0-

38

of the morphinandienone and proaporphine types, respectively, isolated from Guatteria (three species), are common alkaloids; therefore, these structures are not discussed here.

D. APORPHINOIDS Aporphinoids are by far the most abundant alkaloids in this genus and also, generally speaking, in the family Annonaceae. Guatteria has proved to be a rich source of unusual structures of this general type. Aporphines have been reviewed in Volume 24 of this treatise (3)and elsewhere ( 4 - 7 ) , and a review on aporphinoids of the Annonaceae has just been published (8). For this reason we address the structures and chemistry of only a few alkaloids of this type that have not been included in the Kametani and Honda review (3).

30

ANDRE CAVE ET M.

1 . Aporphines Sensu Strict0 (39-79) A total of 41 aporphines sensu strict0 have been isolated from 12 Guatteria species. These include aporphines, noraporphines, and N-formylnoraporphines, differing by their substitution pattern on the two aromatic rings, but no quaternary aporphinium alkaloids have been reported.

44:R=H 45 : R

=

CHa

31


(TH \

/ 9

53 : R = H

55

54:RrCy

OH 61:R=H 62 : R

CHI

67:R=H 70 : R

OR

71:RrH CHI

72 : R

(F Hs-

0

OR

74:R=H 75 : R

CHI

73

=

CH3


33

The “new” N-methylelmerrillicine (64) was isolated from G. sagoripnu, where it cooccurs with elmerrillicine (63) (45). The latter alkaloid had been described previously only as its N-acetyl derivative (65). Elmerillicine was isolated as its N-trifluoroacetamide, from which the original secondary amine could be recovered through mild alkaline hydrolysis (45). The structures of both natural products, 63 and 64, were determined by the usual spectroscopic methods, and correlated by N-methylation of 63 to 64. Like elmerillicine, norlaureline (55) and puterine (58), also isolated from G. sagorianu (45), had been described first as their N-acetyl derivatives (66). Two previously undescribed N-formyl noraporphines have been discovered in G. ouregou (39). N-Formylnornuciferine(42) and formouregine (51) are the formylation products of the widespread nornuciferine (41) and O-methylisopiline (SO), respectively, both of which are found in the same plant. Their structure elucidation was based on the usual spectroscopic techniques. As is usually the case with this type of compound, two rotamers are distinguishable in their ’H-NMR spectra. Oureguattidine (61) and oureguattine (62) were also isolated from G. ouregou (38, 39). The mass spectrum of 61 showed the usual signal pattern corresponding to a noraporphine, and the ‘H-NMR spectra in CDCl, and in C,D,N led to the placement of all its substituents, confirmed by the completely assigned I3C-NMR spectrum (38). Oureguattine (62) was prepared semisynthetically from 61 and shown to have the same substitution pattern as the oxoaporphine subsessiline (103), from which it was also obtained by zinc-hydrochloric acid reduction ( 3 9 ) . Isocalycinine (74) and discoguattine (75) are the only two aporphines of Guatreria known to possess a 9,ll-dioxygenated ring D, which had seemed to be a characteristic feature of Dugueria (Annonaceae) (67). Both alkaloids were isolated from G. discolor ( 2 4 ) , and their structures were easily determined by the usual spectroscopic methods. In both, a meta-coupled AB system was the only outstanding feature recognizable in the ‘H-NMR spectra which, however, had to be recorded in C,D,N to achieve adequate resolution and, in the case of isocalycinine (74), to confirm the location of the phenol function at C-9.

2. Dehy droaporphines (80-85) Dehydrostephalagine (84), a “new” dehydroaporphinewhich was found in G. sagorianu ( 4 3 , does not require particular comment. Dehydronornuciferine(80) and O-methyldehydroisopiline (82) have been isolated from G. ouregou ( 3 9 ) , where they cooccur with the corresponding noraporphines (41 and 50) and the N formyl derivatives dehydroformouregine(83) and formouregine (51). The structure elucidation of dehydronornuciferine (80) and O-methyldehydroisopiline

34

ANDRE CAVE ETAL.

R

R

80:RzH 82 : R

z

OCH,

83

81 : R z H

84 : R

I

OCH,

85

(82) was quite straightforward on the basis of their UV and ‘H-NMR spectra. Such dehydronoraporphineshave been rarely reported as natural compounds because of their relative instability. Dehydronornuciferine(80) had previously been prepared by synthesis (68). The only known N-formyl-6,6a-didehydronoraporphine without a methyl group at C-7 is dehydroformouregine (83), from G. ouregou (39). Its structure was established spectroscopicallyand by formylation of U-methyldehydroisopiline (82).

3. 7-Hydroxyaporphines (86-92) Nuciferidine (87) is a “new” 6a,7-truns-7-hydroxyaporphine isolated from the species G. sagorianu ( 4 5 ) , in which several other alkaloids of this type occur. Its IH-NMR spectrum pointed to a structure derivable by methylation of the phenol function of the cooccurring pachyconfine (M), and treatment of 86 with diazomethane confirmed this hypothesis.


86:RzH 87 : R

CHI

90

91

a2

35

36

ANDRE CAVE ET AL

4. Oxoaporphines (93-106)

N.0-Dimethylliriodendronine(95), isolated in fairly large amounts from G . chrysopetala ( 2 1 ) , stands out among the oxoaporphine alkaloids found in Guatteria in that it is a zwitterion related to the highly colored compounds of Glaucium (Papaveraceae). Neutral and basic solutions of the rather insoluble N,O-

83

84

91

OR 99:RrH 100 : R

I

CHa

37


102

101

Hac

0

0

Ham 0

Haco

OH

0 OH

105

104

(F HaC

0

OCHa 101

OH

106

dimethylliriodendronine (95) are green, whereas in acid the alkaloid turns red. The IR spectrum shows the usual conjugated carbonyl band at 1628 cm-', and the 'H-NMR spectrum indicates the presence of strongly deshielded N-methyl (4.89 ppm) and methoxyl(4.35 ppm) groups. Natural N,O-dimethyllirodendronine(95) is identical to the semisynthetic product (69)

38

ANDRECAVE ETAL

Oxoisocalycinine (106), which cooccurs with the ring D-9,ll-dioxygenated isocalycinine (74) and discoguattine (75) in G. discolor (24), is the only example to date of an oxoaporphine with this unusual substitution pattern. The alternative oxocalycinine and oxoisocalycinine structures were suggested by mass and ‘H-NMR spectra, which are quite unexceptional, and the actual positions of the substituents were established by zinc-hydrochloric acid reduction to isocalycinine (74) (24). 5 . 4,5-Dioxoaporphines (107 and 108)

Ouregidione (108) is a “new” 4,5-dioxoaporphine isolated from G. ouregou, where it is found together with the previously described norcepharadione B (107)

107 : R

= H

(39). Ouregidione was obtained as a red, microcrystalline powder which was ‘ only sparingly soluble in the usual solvents. Its structure was established by the usual spectroscopic methods, which indicated that it is the 3-methoxy derivative of norcepharadione B. 6. 7-Alkylaporphinoids (109- 126)

The only two 7,7-dimethyl-4,5,6,6a-tetradehydroaporphines known so far, melosmine (111) and its 0-1-methyl ether melosmidine (113), metabolites of G. melosma, were the first 7-alkylaporphinoidsto be discovered, and their unusual structures were supported by mass and ‘H-NMR spectra and a single-crystal X-ray diffraction analysis (34). Simultaneously,the I3C-NMR spectrum of melosmine was assigned (41). Melosmine has also been found in G. ouregou along with its 4,5-dihydro derivative (112) (38, 40).

39


1 0 9 : R = H 1 1 0 : R = CHI

111 : R 113 :R

I P

H C&

bcmN HO

OH 112

114

The mass spectrum of dihydromelosmine (112) indicated the molecular formula C,,,HH,,NO,, with a rather stable molecular ion (mlz 339, 64%) and no highly characteristic fragment ions aside from one arising from loss of a methyl group ( m l z 324, 100%). Its IH-NMR spectrum was characterized by the presence of a six-proton singlet at 1.41 ppm arising from the gem-dimethyl portion and by two triplets at 2.55 and 3.56 ppm that could be assigned to H-4 and H-5. The positions of the hydroxyl and methoxyl groups were deduced from comparison of the IH-NMR spectra in CDCl, and C,D,N and confirmed by borohydride reduction of both melosmine (111) and dihydromelosmine (112) to the same tetrahydro derivative (38.40). Dihydromelosmine (112), guadiscine (110), guadiscidine (109), and guadiscoline (114) are the only 7,7-dimethyl-6,6adidehydroaporphines known to date. A total synthesis of N,O,O-trimethyltetrahydromelosmine (146) has been reported, and the final compound was judged

40

ANDRE CAVE ETAL

146

identical with that obtained when natural melosmine (111) was 0-methylated, reduced, and then N-methylated (70). Guadiscine (110) and guadiscoline (114) were first described as constituents of G. discolor in 1982 (26).Guadiscine was shown to have the molecular composition C,H,,NO, by high-resolution electron-impact mass spectrometry. An acidinduced bathochromic shift in the UV spectrum suggested the presence of an imine function, whereas the IH-NMR spectrum pointed to a 1,2,9-trioxygenated aporphinoid skeleton with a methylenedioxy group at C-1/C-2 and a methoxyl at C-9. The 1,2-methylenedioxy group gave a singlet, however, indicating that the biphenyl ring system is flat, a situation which can be ascribed to the presence of the imine double bond. A striking six-proton singlet was observed at 1.5 ppm, suggestive of 7,7-dimethylation of a flat ring system as in the case of the 4,5,6,6atetradehydroaporphinemelosmine (11l),which had been described shortly before (34). Comparison of the I3C-NMR spectra of guadiscine (110) and melosmine (111) evidenced the great similarity of the C-6a to C-1 la regions of both molecules, supporting the proposed structure. Confirmation was obtained by borohydride reduction of guadiscine to afford the racemic dihydro derivative which, aside from the strong singlet of the gem-dimethyl moiety, gave a,IH-NMR spectrum barely distinguishable from that of xylopine (54), also present in G. discolor ( 2 5 ) . Guadiscoline (114) differs from guadiscine (110) only in the presence of an additional methoxyl group at C- 11, which causes the expected changes in the mass, IH, and I3C-NMR spectra. Guadiscine and guadiscoline were the first 6,6a-didehydro-7,7-dimethylaporphines to be characterized. Guadiscidine (109), the phenolic counterpart of guadiscine (110), was described later (24). The spectral differences between these two substances leave no doubt as to the structure of guadiscidine, which was confirmed by 0-methylation to guadiscine. Guattescidine (115) and guattescine (lla), the first 7-hydroxy-7-methylaporphinoids to be described, were obtained initially from G. scandens (48), al-

41


OR 115 : R 116 : R

= =

H

117

CHI

though the structures proposed originally (as 6a-methyl-7-oxoaporphines) had to be revised subsequently (47, 49). Guattescine has also been isolated from G. schumburgkiana ( 5 0 , 5 1 ) ,and guattescidine has been mentioned as an additional constituent of G. melusrna (35).The correct molecular formulas (CIBH,,NO,and C,,H,,NO,, respectively) were indicated by the mass spectra, an IR absorption of guattescine at 1648 cm-' was interpreted as arising from conjugated ketone, and the 'H-NMR spectra showed three-proton singlets near 1.45 ppm and H-8 signals shifted downfield to 7.43 ppm as the only important differences with regard to the xylopine (54) spectrum. The facile acetylation of guattescine also seemed consistent with a secondary amine functionality rather than a tertiary alcohol. The presence of an imine function was suggested, however, by the weakness of the IR peak at 1648 cm-' and by an acid-induced bathochromic shift in the UV spectrum. Nevertheless, the nonequivalence of the methylenedioxy protons in the NMR spectra, an important difference with regard to the spectra of the 7,7-dimethyl-6,6a-didehydroaporphinesfound more or less simultaneously in G. discolor and G . ouregou, was thought to argue against a presumably planar imine structure in spite of the fact that even if the ring system were flat the methylenedioxy hydrogens would still be diastereotopic owing to the two different substituents at C-7. Dihydroguattescine, obtained by borohydride reduction of the alkaloid, gave a monoacetyl derivative with acetic anhydride in pyridine. The failure of attempts to methylate the presumed amine group, and the fact that guattescine crystallized reasonably well, led to an X-ray diffraction study which removed all ambiguity and proved the presently accepted structure 116 ( 4 7 , 4 9 ) .In the crystal form, molecules of guattescine (116) occur in pairs linked by hydrogen bonds between N-6-HO-7' and N-6'-HO-7, the two constituents of the pair being of different chirality. Therefore, the guattescine ring system is not planar: the biphenyl moiety is twisted by about 20°, with the C-7 hydroxyl group pseudoequatorial and the C-methyl pseudoaxial, thus contributing to the NMR nonequivalence of the methylenedioxy protons. Also, although crude guat-

42

ANDRE CAVE FT AL.

tescine was appreciably dextrorotatory, the purified crystals were racemic. The unexpectedly facile acetylation of the tertiary alcohol function can be explained by very efficient intramolecular base catalysis by the appropriately located imine group ( 4 9 ) .The spectra of guattescidine (115) are very similar to those of guattescine (116) and suggest that the only difference is the presence of a phenol function in place of the methoxyl group, as could be confirmed by O-methylation with diazomethane (47, 4 8 ) . Dehydroguattescine (117) was found in G. schomburgkiuna (50,51). Its spectral properties showed that it resembled guattescine (116) quite closely. Its mass spectrum, however, indicated a molecular weight lower than that of guattescine by 2, and the 'H-NMR spectrum exhibited a typical pyridine AB system at 7.44 and 8.38 ppm ( J = 6 Hz). These data led to the proposal of structure 117, which received support from its semisynthetic preparation by m-chloroperbenzoic acid oxidation of O-methylbelemine (147) (see below). Dehydroguattescine is the only 7-hydroxy-7-methyl-4,5,6,6a-tetradehydroaporphine known so far. Guattouregine (120) and guattouregidine (118) were isolated from G. ouregou (38, 40). Their relationship to guattescine and guattescidine, readily apparent

OR 121 : R

= H

122 : R

=

CHa

from their spectral properties, led initially to their description as 6a-methyl-7oxoaporphines (40). The distribution of phenolic hydroxyl and methoxyl groups around the ring system was correctly assigned by means of the usual UV and 'H-NMR analyses (40), and the structures were revised to 118 and 120 (38), once the correct structure of guattescine became known ( 4 9 ) .The closely related isoguattouregidine has been reported to be a constituent of G. melosma, and the structure 119 was deduced from its spectral data (35). Guacolidine (121) and guacoline (122) were isolated from G. discolor (24). The mass spectrum of guacoline indicated the molecular formula C,,H,,NO,. Its

43

1. ALKALOIDS FROM GUAlTERlA

mass and IH-NMR spectra were similar to that of guattescine (116), with differences which could be ascribed to the presence of an extra methoxyl group at C-1 1. The spectral data of guacolidine (121) clearly show that it is an 0demethyl analog of guacoline (122). The position of the hydroxyl group was established as C-9 by the comparison of the IH-NMR spectra in different solvents and by the addition of NaOD in CD,OD. Guacolidine (121), like guattescine (116), has been shown to be an enantiomeric mixture, in this case with an excess of the (-)-isomer. Belemine (125), from G. schornburgkiana (50, 5 1 ) , is the oldest example of a 6a,7-didehydro-7-methylaporphine.Its mass spectrum suggested the molecular formula C,,H,,NO,, and its UV spectrum was typical of a 6a,7-didehydroaporphine. Its 'H-NMR spectrum was characterized by two methyl singlets at 2.57 and 2.78 ppm which were assigned to the C-7 methyl and N-methyl

123

124

OH

OR

125 : R

x

H

126

147 : R 4 CHS

groups, respectively. The methylenedioxy singlet at 6.17 ppm and the aryl proton resonance pattern led to the assignment of structure 125. The acetate ester and the methyl ether were prepared and provided additional spectral evidence of

44

ANDUB CAVE ET AL.

OH 53

OCH3 140

OH 125

0CH3 147

ow3 117

SCHEME1 . Reagents andconditions: i , CH2N2/Et20.room temperature, 24 hr, ii, HCHO, NaBH4, CH2NzIEt20; iii, HCHO/CH,OH, 105"C, 72 hr; iv, m-CIC6H4CO3H/CH2CI2,5"C, 1 hr.

the structure of belemine, which was also supported by partial synthesis of 0methylbelemine (147) from anolobine (53), via isolaureline (148) ( 5 1 ) , following a previously described sequence (71) (Scheme 1). Goudotianine was obtained from the Colombian species G. goudofiana (29). The structure 126, proposed as a poster in London in 1984, rests primarily on the IH-NMR spectrum associated with NOE results. The placement of the A-ring hydroxyl group at C-2 rather than C-3 is based on the anticipated instability of an aporphinoid with both C-3 and C-9 phenolic groups. This structure has not been confirmed until now. Duguespixine (123), found originally in Duguetia spixiana (72), was later reisolated together with trichoguattine (124) from G. sagotiana (45). Duguespixine exhibits an IR band around 1635 cm-' attributed to an N-formyl group that also manifests itself as a singlet in the IH-NMR spectrum at 8.13 ppm. The remaining spectral properties resemble those attributable to 6a,7-didehydroaporphines, whereas a three-proton singlet at 3.28 ppm suggested the presence of a 7-methyl group deshielded by the proximity of the formamide function. 7Formydehydronuciferine (149) was synthesized from nuciferine (43), and com-

45


parison with 150, the 0-methyl derivative of duguespixine, showed them to be different; thus, structure 123 for duguespixine was supported (73). Trichoguat-

43

149

123 : R 150 : R

= =

H CH3

tine, found in trace amounts in G . sagorianu ( 4 3 , exhibited spectral data closely related to those of the duguespixine, and structure 124 was attributed on this evidence. Nevertheless, the structures assigned to trichoguattine (124) and duguespixine (123) have been disputed on the basis of the synthesis of a substance believed to possess structure 124, which was found to differ from natural trichoguattine (74). Additional studies are in progress to clarify this point.

7. 1,ll-Methyleneoxynoraporphine(127) Pentouregine (127) was isolated from G: ouregou (39, 42). Its mass spectrum was characteristic of a noraporphine but indicative of the presence of an addi-

127

tional ring. The IH-NMR spectrum exhibited a gem-AB system at 4.94and 5.15 ppm, indicating the presence of a methyleneoxy bridge, and correspondingly lacked any downfield aryl proton resonance attributable to the nonexistent H-11 . The absence of a singlet near 6.6 ppm indicated that H-3 was substituted with

46

ANDRE CAVE ET AL

either the hydroxyl or the methoxyl group whose presence could be deduced from the mass, UV, and NMR spectral data. As the UV spectrum in basic solution showed a negligible hyperchromic effect, structure 127 was preferred, in which the phenol should not be strongly conjugated with ring D. This hypothesis was confirmed by closer analysis of the mass spectrum of the N,O-diacetyl derivative, which gave no indication of any fragments at [M - 591 and [M - 1011 (75).

8. Aminoethylphenanthrenes (128-131) The aminoethylphenanthrenes are a small group of alkaloids in the Annonaceae. Four of them (128-131), already described from other Annonaceae species (8),were isolated from G. discolor (24, 2 5 ) .

131

E. MISCELLANEOUS APORPHINOID-RELATED ALKALOIDS A number of structural types that have been found in Guatteria species and occasionally in other genera of the Annonaceae appear to be related biogenetically to the aporphinoids. The lack of experimental proof of this derivation, which is discussed in a later section (see Section V), makes it advisable to consider these compounds separately. 1. Gouregine (132) A unique compound with a 7,7-dimethylated cularine skeleton bearing oxygen substituents at positions 1, 2, 3, and 9 was isolated from G. ouregou and named gouregine (132) (38, 41). Its molecular formula was determined as C,H,,NO,

I . ALKALOIDS FROM GUATERIA

47

OH 132

by elementary analysis and high-resolution mass spectrometry. The mass spectrum showed an abundant molecular ion and a base peak arising from loss of 30 molecular mass units (mmu). The UV spectrum exhibited bathochromic shifts on the addition of both base and acid. The IH-and I3C-NMR spectra completed the range of data relating gouregine to the 7,7-dimethyl-4,5,6,6a-tetradehydroaporphine melosmine (111): a trioxygenated A ring, an aromatic B ring, a gemdimethyl grouping at C-7, and a monosubstituted ring D, with some shifts in the positions of certain signals that are due to the presence of a supplementary oxygen atom in the molecule of gouregine which could only be included in ring C. The positions of the substituentson rings A and D, established by the usual spectroscopic methods, led to the assignment of structure 132 on the assumption of a cularine skeleton for gouregine, which was supported by comparison of the spectra of gouregine, its 0,O-diacetyl, 0,O-dimethyl, and tetrahydro derivatives. This totally unprecedented substitution pattern for a cularinoid is the same as found in melosmine ( I l l ) , and, in fact, melosmine could be converted to gouregine (132) in 90% yield by oxidation with Fenton’s reagent (hydroxyl radicals generated from hydrogen peroxide with ferrous sulfate). As diacetylgouregine gave good crystals, an X-ray diffraction analysis was carried out to confirm the structure assigned on the basis of spectral data (41). 2. Azahomoaporphines The recent isolation and structure elucidation of dragabine (133) from G . sagofiana and nordragabine (151) from Meiogyne virgafa (Annonaceae) ( 4 6 )opened up the new field of the azahomoaporphines, two more of which have been isolated since from Duguetia spixiana (Annonaceae) (76). The structure of dragabine (133) was determined on the basis of its high-resolution mass spectrum (which gave the correct molecular formula C,,H,,N,O,), UV, IH- and 13C-NMR spectral studies, and investigation of its borohydride reduction product (46). The

48

ANDRECAVE ET AL.

mass spectrum showed that the molecular ion was fairly stable and lost a hydrogen atom to give the base peak, or alternatively underwent a retro-Diels-Alder cleavage with loss of CH,NCH,, pointing to an aporphinelike structure. The extrusion of HCN was the main fragmentation process of the M - H and retroDiels- Alder products, suggesting that this moiety was preformed in the dragabine molecule. The hypothesis of an imine structure was supported by the IR spectrum, in which a weak band was apparent at 1665 cm-I, and by an acidinduced bathochromic shift in the UV spectrum. The IT-NMR spectrum again indicated the close relationship between dragabine and the aporphines, but an extra tertiary carbon signal could be seen at 161.7 ppm that could be ascribed to the imine carbon. The IH-NMR spectrum was very similar to that of roemerine (45), although an AB system with a coupling constant of 2.5 Hz was observed at 4.37 and 8.42 ppm; the latter resonance was found to be weakly coupled to two of the aromatic ring protons in a two-dimensional experiment, and this evidence was considered sufficient to propose structure 133. Borohydride reduction of dragabine gave a tetrahydro derivative which, on the basis of its spectra and those of its acetylation product, was shown to result from the cleavage of ring C, possibly via the aminal.

OR 133 : R

= CH3

151 : R = H

152 : R

= CHI

153 : R

H

Once the structure of dragabine was established, its relationship to the relatively unstable nordragabine (151), isolated in trace amounts from Meiogyne virgum, became obvious (46). Shortly thereafter two minor constituents of Duguetia spiriana, named spiguetine (152) and spiguetidine (153), were isolated and shown to belong to the same structural class (76). The mass spectrum of spiguetine was very similar to that of dragabine, but the major peaks were shifted by 30 mmu to higher mlz values. The main difference in the 'H-NMR spectra was that spiguetine (152) showed the presence of a methoxyl group which, on the basis of the aromatic ring proton resonance pattern, had to be placed at C-9 or C-10. On the assumption that the aryl hydrogen ortho doublet resonating at lowest field is located at C-1 1, as in the case of the aporphines, the methoxyl

49


group was situated at C-9. This assignment was supported by a NOE observed between the 8.24 ppm doublet corresponding to H-7 and the meta doublet of the AMX system. The spectral data of spiguetidine (153) were very similar to those of spiguetine, suggesting that the only difference lay in the presence of a phenol function in place of the methoxyl group. This hypothesis was proved by methylation of spiguetidine to give spiguetine. Dragabine (133) and nordragabine (151) seem to be optically inactive ( 4 6 ) . Spiguetine (152) appeared to give a very small negative optical rotation ( 7 6 ) , which may not be significant. Molecular models show that the biphenyl moiety of the azahomoaporphinering system must be strongly twisted, implying that the enantiomers of these alkaloids should have large specific rotations, and it must therefore be concluded that the bases isolated from Guatteria, Meiogyne, and Duguetia are racemic ( 4 6 ) .

3. Azaanthracene Alkaloids Dielsiquinone (134) is the only Guatteria alkaloid known to possess the 1-azaanthracene ring system (22). This skeleton was found for the first time in the parent compound cleistopholine (154), isolated successively from the Annonaceae Cleistopholis patens ( 7 7 ) and Meiogyne virgatu (78), and later also from Annonu cherimolia ( 7 9 ) and A . huyesii (80). The latter species also contains the related annopholine (155). Annona ambotay (81) is the only known

134

154

155

source of geovanine (156 or 157). As this type of alkaloid has never been reviewed before, we feel that all four compounds should be treated together here. The structure of cleistopholine (154), was suggested by its high-resolution mass spectrum and its IR and NMR spectra ( 7 7 ) .The 'H-NMR spectrum indicated the presence of a nearly symmetrically ortho-disubstituted benzene ring and a 2,3-disubstituted 4-methylpyridine ring that could best be accommodated by the 4-methyl- 1-azaanthra-9,1O-quinonestructure. Complete assignment of its

50

ANDRE CAVE ET AL

IH- and 13C-NMRspectra was possible on the basis of a two-dimensional heteronuclear chemical shift-correlated spectrum ( 78). Cleistopholine has been synthesized by a hetero-Diels- Alder cycloaddition of naphthoquinone and 1-N,Ndimethylamino-l-azapenta-l,3-diene(82 ). A similar spectroscopic study led to the conclusion that annopholine is the 0,O-dimethylated hydroquinone analog (155) of cleistopholine (80). The Cmethyl, one of the methoxyl singlets, and two of the aromatic proton multiplets appeared at deceptively low fields (3.03,4.26,8.29, and 8.44 ppm, respectively) in the IH-NMR spectrum of annopholine. Nuclear Overhauser effects between the C-methyl group and the methoxyl resonating at 3.99 ppm, and between the methoxyl groups and the benzene ring protons peri to each of them, supported structure 155 and made complete assignment of the spectrum possible. Thus, the more strongly deshielded methoxyl group must be located peri to the pyridine nitrogen lone pair (at C-9), and the protons resonating as multiplets at 8.29 and 8.44 ppm are bonded to C-5 and C-8, respectively. The structure of dielsiquinone (134) was derived largely from its mass, IH-NMR, and UV spectra (22). The C-methyl and benzene ring proton resonances were rather similar to those of cleistopholine, but the pyridine ring protons were lacking. A strongly deshielded methoxyl signal (4.17 ppm) was observed in the IH-NMR spectrum, suggesting the presence of a neighboring carbonyl group. Evidence for the a-pyridone structure of dielsiquinone (or its 2pyridinol tautomer) was provided by the base-induced bathochromic shifts in its UV spectrum, which could be seen even after adding sodium acetate. Such behavior would not be expected if the structure were that of a 2-methoxy-4methyl-3-pyridino1,and in such a case, as there would be no lactam carbonyl to deshield it, the methoxyl IH-NMR signal would presumably appear around or below 4 ppm. Geovanine combines structural features of dielsiquinone (134) and annopholine (155). Its structure, again, was derived spectroscopically but is not totally unambiguous (81). The presence of an a-pyridone system was apparent from its IR spectrum and from the bathochromic shift observed in its UV-VIS spectrum on adding base. Its IH-NMR spectrum showed that, unlike dielsiquinone, C-3 was unsubstituted. The signature of three vicinal aromatic ring protons and the presence of three methoxyl resonances led to the conclusion that geovanine is l-aza-5(or 8),9,10-trirnethoxy-4-methyl-2-oxo1,2-dihydroanthracene (156 or 157). This alkaloid is the first known example of a natural I-azaanthracene derivative oxygenated on ring C. It should be possible in principle to distinguish between the alternative 5- and 8-methoxylated annopholine lactam structures on the basis of long-range heteronuclear couplings or NOES measured at high resolution, for instance. Nevertheless, owing to the proximity of the methoxyl resonances on one hand and the chemical shifts of the ring C protons on the other, it may be necessary to resolve the structure synthetically.

51

I . ALKALOIDS FROM GUA7TERlA

156

157

4. Azafluorene Alkaloids (135- 138)

Azafluorene alkaloids have been found in a number of Annonaceae and have not yet been reviewed. Three of these compounds (136-138) were first isolated from a Guarteria species (22, 23) while the parent substance of this group, onychine (135), and the other congeners known until now have been found in different genera of the family Annonaceae.

135 : R 136 : R

= H = OCHj

137 : R

= H

138 : R

=

158

OH

Onychine (135) was first described as a natural product in 1976, when its isolation from Onychoperalum amazonicum (Annonaceae) was reported ( 8 3 ) ,and (158) on the basis of its structure was given as 4-methyl-1-azafluoren-9-one elemental analysis and high-resolution MS, as well as UV, IR, and 'H-NMR spectra. As in all the azafluorenone alkaloids discovered to date, the complex U V spectrum is reminiscent of that of fluoren-9-one, and the 'H-NMR spectrum clearly indicates the presence of a 2,3-disubstituted 4-methylpyridine moiety. The immediate conclusion, therefore, is that onychine is either 1-methyl4 azafluoren-Pone (135) or 4-methyl- 1-azafluoren-9-one (158), which is supported by the spectral properties of the secondary alcohol obtained by reduction of the ketone group and of the acetylation and hydrogenolysis products of this

52

ANDRECAVE ET AL

carbinol. The key argument against the placement of the carbonyl function and the C-methyl group peri to each other (as in the actual structure 135) was the fact that the proton chemical shift of the latter substituent decreased by 0.12 ppm and not more on reduction of the ketone with sodium borohydride (83). Nevertheless, unambiguous syntheses of both 4-methyl- 1-aza- and 1-methyl-4-azafluoren-9-ones and comparison of their IH-NMR spectra and those of their borohydride reduction products with spectra reported for natural onychine and dihydroonychine showed that the alkaloid is correctly represented by formula 135 (84). It was pointed out that onychine had been synthesized on two occasions, slightly before and shortly after its isolation from 0. amazonicum (85, 86). This compound has since been found in Cleistopholis patens (77), Guatteria dielsiana (22), and Unonopsis spectabilis (87), all members of the Annonaceae. 13C-NMR chemical shifts of onychine were first assigned on the basis of the erroneous 4-methyl- 1-azafluoren-9-one structure (77). These assignments have now been rectified, and some ambiguities in the ‘H-NMR shifts have been removed using the short- and long-range correlations observed in heteronuclear two-dimensional NMR spectra of this alkaloid and confirmed by low-power decoupling techniques (88, 89). 6-Methoxyonychine (136) has been found so far only in G . dielsiana (22). Its relationship to onychine was obvious from its spectra, which also allowed the single methoxyl group to be placed para with regard to the ketone function. The formula published initially, however, was based on the 1-aza-4-methylfluorenone skeleton (22). The revised structure (136), confirmed by synthesis using an extension of Koyama’s preparation of onychine ( 8 4 ) ,was published subsequently (23). 6-Hydroxyonychine (159) has been described as a constituent of a Peruvian sample of Oxandra xylopioides (Annonaceae), unfortunately without UV and NMR spectral data (90). A partial description of its dihydro derivative, obtained by reduction of the ketone function, was published in support of the structure.

159

1. ALKALOIDS

FROM GUAlTERIA

53

The natural product was synthesized together with its 8-hydroxy isomer (160) via the cyclization of 4-methyl-2-(3-hydroxyphenyl) nicotinic acid (90). All four ring C monohydroxylated onychines have been prepared by a different, unambiguous route and their mass, UV, and 'H-NMR spectra discussed in detail, showing that the base- and aluminum chloride-induced bathochromic shifts are useful criteria for the location of phenol functions on the benzene ring of azafluorenones (91). Macondine (161) is known only as a constituent of Oxandra xylopioides bark from Colombia, described at first as Oxandra cf. major (92). Its structure was proposed on the basis of mass, UV, IH-, and 13C-NMRspectra and comparison with its 0-acetyl and 0-methyl derivatives. An orrho-coupled AB system was compatible with either C-5,6, C-7,8, or C-5,8 disubstitution. As acetylation of the phenol function led to shielding of the methoxyl group and deshielding by 0.17 and 0.11 ppm of the ring C protons, it was concluded that the hydroxyl lies between one of these hydrogen atoms and the methoxyl, ruling out the C-5,8 substitution pattern. The unusually large chemical shift of the methoxyl group in macondine (4.22ppm) could be taken as a further indication that this function lies next to the carbonyl or to the pyridine nitrogen lone pair. The UV-VIS spectrum of a basified solution of macondine showed no intense absorption beyond 400 nm, suggesting that the phenol function is either at C-5 or C-7 ( 9 1 ) , and macondine was therefore formulated as 7-hydroxy-8-methoxyonychine(92). This alkaloid was subsequently isolated from Unonopsis specrabilis (87). Ursuline (162) appears to have been discovered simultaneously in two different laboratories as a constituent of the stem bark of two Oxandra xyfopioides accessions. The same plant material from Colombia that gave macondine (161) yielded a small amount of ursuline, which was separated from the former alkaloid as its 0-acetyl derivative (92). The two acetyl esters were found to be isomeric, but 0-methylursuline was shown to differ from 0-methylmacondine. Beside the usual methylated pyridine ring signature and the acetyl resonance, a methoxyl signal at 4.09ppm (cf. 4.14ppm in 0-acetylmacondine) and an orrho-

54

ANDRE CAVE ETM

coupled AB system at 7.10 and 7.50 ppm (cf. 7.25 and 7.58 ppm) were apparent in the IH-NMR spectrum of 0-acetylursuline. Therefore, ursuline had to be one of the four possible monophenolic monomethoxylated onychines bearing oxygen substituents at C-5,6 or C-7,8; however, a more precise structure was not assigned (92 ). Oxundru major bark from Peru afforded an alkaloid for which the structure 5hydroxy-6-methoxyonychine (163) was postulated (90). The 5,6-dioxygenation pattern was confirmed by comparison of the alkaloid’s methyl ether with synthetic 5,6-dimethoxyonychine,and the location of the methoxyl group at C-6 was preferred because of the NOE observed between this substituent and H-7 (90). It must be noted, however, that if the methoxyl group were located at C-5, its preferred orientation should be almost perpendicular to the plane of the azafluorenone skeleton owing to its compression between the hydroxyl group at C-6 and the nitrogen lone pair, and in these circumstances an easily observable NOE with H-7 should not be surprising. It is suggestive that the methoxyl protons in this natural product resonate at 4.21 ppm (cf. 4.22 ppm for macondine), a value which decreases to 4.08 ppm on acetylation of the neighboring hydroxyl group (cf. 4.14 for 0-acetylmacondine). Furthermore, acetylation of this alkaloid leads to a very appreciable downfield shift of the H-7 resonance (by 0.1 I ppm) and a considerably smaller effect on H-8 (0.03 ppm) which would seem to be explained satisfactorily by derivatization of a phenol function at C-6 and not at C-5. Another argument in favor of the placement of the hydroxyl group at C-6 (and therefore the methoxyl at C-5) is the strong bathochromic shift experienced by the long-wavelength absorption band of “5-hydroxy-6-methoxyonychine’~ to 450 nm (log E 3.28) on adding base to the solution (90), which would seem to be explained better by the presence of a phenol function at C-6 or C-8 than at C-5 or C-7 (91). The published spectral data of 0-acetylursuline (92) and the 0-acetyl derivative of “5-hydroxy-6-methoxyonychine”(90) agree very well, suggesting strongly that both products are identical. Ursuline, consequently, should be formulated as 6-hydroxy-5-methoxyonychine(162). More recently, ursuline was reisolated from Unonopsis spectubilis (Annonaceae). Its structure was confirmed by a more complete spectral study that included the borohydride reduction product, in the ‘H-NMR spectrum of which an NOE could be observed between the methine hydrogen at C-9 and H-8, ruling out the possibility of C-5,8 dioxygenation (87). 0-Methylursuline, with methoxyl resonances at 3.97 and 4.09 ppm gave an NOE only between the former and the ring C hydrogen resonating further upfield (87). Isoursuline (5-hydroxy-6-methoxyonychine)(163)cooccurs with ursuline in I/. spectubilis (87). Its 0-methyl derivative was identical to 0-methylursuline, which established the 5,6-dioxygenationpattern and left the assigned structure as the sole possibility. Moreover, an NOE was observed between the methoxyl group, resonating at 3.98 ppm, and the upfield proton resonating at 6.80 ppm,

55

1 . ALKALOIDS FROM GUATTERIA

which must therefore be assigned to H-7 (87). Comparison of the UV spectra of basified solutions of ursuline and isoursuline (87) showed an intense peak of 460 nm (log E 3.61) in the former, as expected for an azafluorenone bearing a phenol function at C-6 ( 9 1 ) . Nevertheless, isoursuline exhibited a shoulder at 420 nm (log E 3.38) and a peak at 484 nm (3.42) suggesting that this criterion must be used with caution in the structure elucidation of plyoxygenated azafluorenones. The Oxundru xylopioides material from the Darien region of Colombia, referred to above as a source of the isomers macondine (161) and ursuline (162), also yielded a related alkaloid with an additional methoxyl group for which the name darienine was chosen ( 9 2 ) . This substance was shown to be 5,6dimethoxy-7-hydroxyonychine(164) by spectroscopic studies of the alkaloid itself, of its 0-acetyl and 0-methyl derivatives, and of the secondary alcohol obtained by borohydride reduction of the ketone group. In the latter case, a clear NOE could be observed between the methine hydrogen nucleus and the single proton bonded to the benzene ring, leaving no doubt that the oxygen substituents are located at C-5, -6, and -7. It was concluded that the phenolic function must be at C-7, as acetylation led to appreciable deshielding (0.09 ppm) of H-8 and shielding (0.08ppm) of one of the methoxyl groups ( 9 2 ) .A posteriori, this conclusion is supported by the lack of any readily observable absorption maximum in the visible region of the spectrum of a basified solution of darienine; such a band would be expected if the hydroxyl group were located at C-6 or -8 ( 9 1 ) .

& 164

OCH3

OH 165

Concurrently, a minor constituent of Meiogyne virgutu (Annonaceae) collected on Mount Kinabalu in Borneo, which was given the trivial name kinabaline, was formulated as 5,8-dimethoxy-6-hydroxyonychine(165). Its structure was suggested by mass, UV-VIS, and 'H-NMR spectra and the corresponding data of its borohydride reduction product (78). A singlet at 6.47 pprn (in DMSO) was assigned to an aromatic ring proton flanked by the phenol function and the methoxyl group resonating at the somewhat greater 6 value of 3.84 ppm (versus 3.79 ppm for the other), which was correlated with the one-proton singlet by an

56

ANDRE CAVE ET AL.

NOE. After reduction of the ketone function, the downfield methoxyl resonance appeared to be more shielded, suggesting that it should be placed at C-8 and that the benzene ring hydrogen atom should consequently be at C-7 and the phenol function at C-6 (78). At the time when kinabaline was isolated, nothing was known about the spectral properties of phenolic azafluorenones. Later work showing that 6- and 8-hydroxyonychines in basic solution exhibit a strong absorption maximum near 450 nm ( 9 1 ) supports the proposed structure, as a basified solution of kinabaline presented a band at precisely this wavelength (log E 3.62) (78). 6-Hydroxy- and 6-methoxyonychine, macondine, ursuline, isoursuline, darienine, and kinabaline are all l-methyl-4-azafluoren-9-one (onychine) derivatives with oxygen substituents on the benzene ring. A rather different situation is presented by dielsine (137) and dielsinol(138), two substances which cooccur with onychine and 6-methoxyonychine in G. dielsiana ( 2 2 ) . Although the mass spectra of dielsine and dielsinol suggested that they were onychine derivatives with one and two additional oxygen atoms, their UV-VIS spectra did not show the acid-induced bathochromic shifts characteristic of fluorenone and its aza analogs. In basic solution, however, dielsine exhibited strong absorption at 489 nm (log E 3.77), and both compounds showed lactam bands in their IR spectra, consistent with pyridone structures. This conclusion was supported by the ‘H-NMR spectra of dielsine and dielsinol in which H-2 appeared as a singlet at 7.18 or 7.32 ppm, respectively. The usual C-methyl resonance, present in the spectrum of dielsine, is replaced by a hydroxymethyl signal in the case of dielsinol. On the basis of these data and the erroneous l-aza-4-methylfluoren-9-’one structure of onychine ( 8 3 ) , dielsine was described as 1-aza-4-methyl-2-0~0-1,2dihydrofluorenone and dielsinol as its 4-hydroxymethyl analog ( 2 2 ) . These structures were later rectified to 137 and 138, in line with the revised formulation of onychine as 4-aza- 1-methylfluoren-9-one (135) ( 2 3 ) . The Peruvian Oxandra xylopioides sample that contained 6-hydroxyonychine and ursuline also afforded an onychine derivative isomeric with darienine (164) and kinabaline (165) ( 9 0 ) .In the ‘H-NMR spectrum of this compound, the three aromatic ring protons appeared as singlets, compatible only with oxygenation at C-2, -6, and -7 or C-3, -6, and -7. The singlet at 7.83 ppm was assigned to H-3 and shown to bear an ortho relationship to one of the methoxyl groups, which was therefore placed at C-2. The UV-VIS spectrum of this alkaloid “revealed a remarkable color change and absorption around 485 nm” on the addition of base, a behavior which was considered suggestive of the presence of the phenol function at C-7 and which led to the proposal of its structure as 2,6-dimethoxy-7hydroxyonychine (166) ( 9 0 ) .Although the intensity of the absorption band at 485 nm was not reported, we feel that the “remarkable color change” observed on adding base may be better explained by the presence of the phenol function at C-6; that is, the alkaloid is more probably 2,7-dimethoxy-6-hydroxyonychine (167).


57

V. Biogenetic Hypotheses The biogenetic relationship between aromoline (8), daphnoline (9),and daphnandrine (lo),on one hand, and coclobine (11) and 12-0-demethylcoclobine (12),on the other, seems fairly obvious, although not all of the putative intermediates have been found in G. guianensis. Aromoline (8) could be formed by N-methylation of daphnoline (9),although the converse may well be the case. In this regard, it should be pointed out that demethylation of N-2 in berbamunine (168),which is the immediate precursor of aromoline in cell cultures of Berberis stolonifera, appears to be the major biosynthetic fate of the former alkaloid (93).

168

In this system, at least, berbamunine is the first bisbenzylisoquinoline formed [together with its diastereoisomer guattegaumerine (7)] from the monomeric precursors. The 2-norbisbenzylisoquinolines daphnoline (9) and its 12-0methylation product daphnandrine (10)would have to be methylated at 0-7', giving 2-noroxyacanthine (141)and 2-norobaberine (169),respectively, before

58

ANDRE CAVE ETAL..

= H : R = CH3

141 : R

169

these could afford 12-0-demethylcoclobine (12) and coclobine (11) by 1,2dehydrogenation of the half of the molecule with R chirality. Neither of these 2-norbisbenzylisoquinolines has been found in G . guianensis, a possible indication that they are dehydrogenated very efficiently. The order in which the 0-methylation and dehydrogenation occur could obviously be reversed, though, in which case one would expect to find the 7’-demethyl counterparts of 11 and 12 in this plant. It is perhaps unfortunate that the convention generally used to depict and number the formulas of bisbenzylisoquinoline alkaloids should be arbitrarily based on the degree of oxidation of each monomer moiety, as its application to 1 1- 11’ biphenyl linked dimers obscures the structural relationship of these bases to the 1 1- 12’ diary1 ethers which are found in the same plants. A simple example of this is provided by the obaberine- antioquine pair of Pseudoxandra sclerocarpa (61). In the case of G. guianensis, reversal of the formulas of the 2‘-nortiliageine (17)-tiliageine (18) and 2’-nortiliageine (17)-2’-norfuniferine (19)-guattamine (20)-guattaminone (23) sequences highlights the parallelism between this biogenetic scheme and the daphnandrine (10)-coclobine (11) and daphnoline (9)- 12-0-demethylcoclobine (12) sequences. It is probably not a coincidence that when one secondary amine function is present in one of these compounds, it belongs to the R half of an R , S dimer which should lose its chirality on dehydrogenation. Regarding the only two S,S dimers of G. guianensis, 2’norguattaguianine (21) and 2,2’-bisnorguattaguianine(22), they may arise by hydrogenation of guattamine (20) and subsequent demethylation (or perhaps by hydrogenation of the unknown norguattamine). An attractive alternative hypothesis is their formation by an independent route from two units of ( S ) coclaurine or (S)-N-methylcoclaurine, with an enzyme capable of dehydrogenation of secondary amines with the S configuration being either inefficient or absent. The biogenetic origin of the Guatteria bisbenzylisoquinolines with three linkages between the monomeric units can be traced to the cooccurring oxyacanthine-

1. ALKALOIDS

FROM GUATTERIA

59

type dimers, although the formal elimination of methanol to create the 6,7' aryl ether linkage is not related to the usual oxidative phenol coupling process. Here, again, a pair of 2-norbisbenzylisoquinolineswith the R,S configuration, apateline (13)and telobine (14), can be related to a pair of dimers incorporating an imine function presumably formed by 1,Zdehydrogenation. The biogenesis and biosynthesis of aporphines in general can by now be considered classic and hardly open to dispute (94). Nevertheless, the unusual aporphinoids incorporating a C-9/C- I I -dioxygenated ring D, represented in Guatteria by isocalycinine (74), discoguattine (75), oxoisocalycinine (106), guadiscoline (114), guacolidine (121), and guacoline (122), deserve some comment. According to biogenetic theory, this oxygenation pattern should arise by a dienolbenzene rearrangement. The immediate precursors should either be reduced proaporphines with two neighboring oxygen atoms on ring D, in which case the substituent at C-9 or C-l 1 of the final aporphine would have to be introduced after the rearrangement, or with three vicinal oxygen atoms (95). No proaporphines are known to possess the latter oxygenation pattern, and the corresponding benzylisoquinolines are extremely rare and unknown in the Annonaceae. Therefore, the possiblity that one of the oxygen substituents on ring D is introduced meta with regard to the other at the aporphine stage seems to be more reasonable. It is interesting that G. discolor should be the only Guutteria species known to accumulate these metabolites (see Section VI). In this plant, circumstantial evidence seems to point to C-9 hydroxylation of the C-1 I-oxygenated puterine (58) and C- I 1 hydroxylation of the C-9-oxygenated guadiscine (IlO), so that if meta hydroxylation indeed occurs the process may not be very regiospecific. It has been postulated that the key step in the formation of 7-methylaporphinoids is the alkylation of dehydroaporphines at the relatively nucleophilic C-7, possibly by S-adenosylmethionine, to give 7-methyl-6a,7-didehydroaporphinesas the initial products (50). These intermediates, at least in the nor series, could then evolve further by subsequent methylation or hydroxylation at C-7 to afford either 7,7-dimethyl-6,6a-didehydro-and 4,5,6,6a-tetradehydroaporphines or 7-hydroxy-7-methyl-6,6a-didehydroaporphines,respectively. The fact that aporphinoids with and without methyl groups at C-7 but with the same oxygenation patterns around the aporphine skeleton are found in each Guatteriu species examined may be taken as circumstantial evidence that C-methylation indeed occurs at the aporphine (or dehydroaporphine) stage. No C-7-methyl proaporphines or C-a-methyl benzyl-isoquinolines are known. Pentouregine (127) (39, 42) is the only 1,ll-oxymethylene-bridged aporphinoid known to occur in Guatteria. The biogenesis of this type of compound, found previously in Thalictrum (Ranunculaceae)and Phellodendron (Rutaceae), has been discussed before (96). Most of the aminoethylphenanthrenes are formally no more than Hofmann

60

ANDRE CAVE ETAL.

elimination products of quaternary aporphinium salts, and as such may be artifacts formed from the latter under basic extraction conditions. The structures of a number of these substances, however, require some elaboration of the dimethylaminoethyl side chain or a Hofmann-like ring opening of a nonquaternary aporphine, both of which hypotheses would seem to implicate enzymes and thus suggest that these compounds are actual plant metabolites. The one such product found in a Guatteria species is noratherosperminine (129), which could be derived biogenetically either from atherosperminine(130) (which is also present in the plant) by demethylation or, less probably, from nuciferine (43) by an elimination reaction. It is noteworthy that the only other known sources of noratherosperminine are Duguetia calycina (97) and Fissistigrna glaucescens (98), both plants belonging to the Annonaceae. Moreover, with the exception of secophoebine (170) isolated from Phoebe valeriana (Lauraceae) (99), the only other known methylaminoethylphenanthrene,noruvariopsamine (171), is a constituent

170

171

of Uvariopsis guineensis (Annonaceae)(100). It therefore seems reasonably certain that some members of this family are able to carry out Hofmann ring openings on quaternary aporphinium salts and then remove a methyl group from the nitrogen atom of the dimethylaminoethylphenanthrene formed initially, or perhaps open ring B or protonated tertiary aporphines. Gouregine (132) is the only C-7-methylated cularinoid known to date (38, 41). It has been suggested that, unlike the usual cularines of the Fumariaceae which are derived from 8-hydroxylated benzylisoquinolines, gouregine may be formed by an oxidative rearrangement of melosmine (111) which is present in the same plant (41, 94). Epoxidation of the C- 1 1,1 I a bond could lead to an intermediate capable of rearranging to give an oxepine ring (Scheme 2). In support of this hypothesis, melosmine was converted efficiently to gouregine by oxidation with hydroxyl radicals (Fenton's reagent) (41).

61


OH

on 132

111

SCHEME 2.

When the first two members of the azahomoapoorphine group of alkaloids, dragabine (133) and nordragabine (151), were described (46), it was noted that their structures could be related biogenetically to the widespread anonaine (44) and roemerine (45). It was then suggested that these putative precursors could be hydroxylated at C-7 to give norushinsunine (172) or ushinsunine (173) and that such 7-hydroxyaporphines could be oxidized, perhaps by a metalloenzyme, to give the corresponding iminoaldehydes or seco-C-aporphines (174, 175). The

172 : R 173 : R

=

H

174 : R

=

H

CH3

175 : R

=

CHS

(?? \

133 : R

151 : R

= =

CH3 H

SCHEME 3.

62

A N D R ~CAVE ETAL.

hypothetical iminoaldehydes could finally capture ammonia with formation of the azepine ring of the azahomoaporphine skeleton, as shown in Scheme 3. It appears that if ammonia is utilized in this sequence it must be present in the plant, in view of the fact that azahomoaporphines can be isolated even when exogenous ammonia is excluded (46, 76). This, however, does not necessarily point to an enzyme-catalyzed ammonia capture, as these alkaloids are most probably racemic. If this biogenetic scheme approaches reality, the key enzymatic step would seem to be the cleavage of the C-6a/C-7 bond. It should be noted here that analogous bond cleavages have been invoked to explain the formation of seco-bisbenzylisoquinolines(101 ). In connection with this biogenetic hypothesis it may be significant that norushinsunine (172) is one of the major alkaloids of Meiogyne virgara (78), the sole known source of nordragabine (151) (46). Spiguetine (152) and spiguetidine (153), the ring-D-oxygenated azahomoaporphines of Dugueriu spixiuna (Annonaceae) (76), can be related, according to this hypothesis, to the aporphines isolaureline (176) and roemeroline (177), which were not found in the plant although the corresponding 7-hydroxy derivatives oliveridine (178) and roemerolidine (179) are the main alkaloids.

176 : R

=

CHI

177 : R x H

178 : R

P

C%

i r n : R = ~

Azafluoranthene, diazafluoranthene, “tropoloisoquinoline,” 1-azaanthracene, and azafluorenone alkaloids are generally found in plants or plant families in which liriodenine or other oxoaporphines abound. A biogenetic hypothesis formulated several years ago (102) and its more recent extensions (8, 78) are attractive because they rationalize the cooccurrenceof oxoaporphineswith a fairly large variety of diverse alkaloid types which seem to be characteristic of the closely related Annonaceae, Eupomatiaceae, and Menispermaceae. The aporphinoid biogenesis of the diazafluoranthenes, 1-azaanthracenes, and azafluorenones (Scheme 4)involves an extradiol cleavage of liriodendronine (180) between C-1 and C-la, giving (l-aza[5.10]anthraquinon-4-yl)pyruvic acid (181). This acid

63


180

H

154

/

135

XN 0" 181

L

NPNP 0

182

0

183

SCHEME4.

may then undergo a ..ydrolytic loss of oxalic acid to give cleistopholine (1 1) in a single step, by analogy with the known base-catalyzed reversion of (Cazafluoren9-on- 1-yl)pyruvic acid to onychine (135) (85). Moreover, the azaanthraquinone acid (181) may be converted in several steps to the 1-aza-7-oxoaporphine (182), a hypothetical precursor of the diazafluoranthene eupolauridine (183) (8). Owing to the complete lack of experimental evidence, the 1-azaanthracene alkaloids can just as reasonably be derived from nonaporphinoid precursors. It has been suggested that 1-azaanthraquinones might arise in nature by condensation of shikimic and glutamic acids ( 2 2 ) , or by cyclization of a polyketide ( 9 2 ) . All three hypotheses have been examined in the light of the distributions of oxygen substituents known to occur in aporphinoids, 1-azaanthracene, and azafluorenone alkaloids, and none of them was considered adequate to provide a general explanation of the variety of oxygenation patterns; nevertheless, the concept that biosynthetically late hydroxylations might hold the key to the structural diversity of these alkaloids was retained as a likely possibility ( 9 2 ) . The biogenetic relationship between cleistopholine (154) and annopholine (155) is trivial. Dielsiquinone (134), on the other hand, raises the question of

64

ANDRE CAVE ETM.

whether it ought to be derived from cleistopholine by two successive oxygenations and an 0-methylation on ring A or whether one of these oxygen atoms, at least, is a leftover from a biogenetic precursor. The first hypothesis seems to be preferable if the aporphinoid or shikimate-glutamate routes are considered. Still, considering the aporphinoid biogenetic hypothesis, the methoxyl group of dielsiquinone can be regarded as a feature already present in a 4-methoxyaporphinoid precursor. A polyketide origin of the 1-azaanthracenes could lead to the initial formation of lactams, which could then be reduced initially to cleistopholine (154) or cleistopholineanalogs or oxidized further to give products more closely related to dielsiquinone (134). If 1-azaanthraquinones are thought of as precursors of the corresponding lactams, a likely route would involve covalent hydration of the 1,2 bond and subsequent oxidation of the intermediate aminol. Considering the very electron-deficient character of the pyridine ring in 1-azaanthraquinones, it seems possible that such a covalent hydration might occur nonenzymatically while treating the plant material or its extracts with aqueous base. The hypothetical azaanthraquinone covalent hydrates, by analogy with berberine pseudobase, for example, might well undergo air oxidation or intermolecular oxidation-reduction. It therefore seems of interest to determine whether lactams like dielsiquinone (134) are authentic natural products or artifacts. When onychine (135) was discovered in 1976 it was stated that this alkaloid might be a biosynthetic derivative of phenylalanine and mevalonate on the basis of the proposed 4-methyl- 1-azafluoren-Pone structure (83).Once this structure was proved to be wrong (84), the aforementioned biogenetic hypothesis became untenable. The discovery of cleistopholine (154) and its cmccurrence with onychine in Cleisropholis patens (77) made it appear very likely that the latter is formed by decarbonylation of the former, an idea which was first mentioned in a review on the aporphinoids of the Annonaceae (8).This proposal is an extension of a general reaction postulated to explain the formation of azafluoranthene, diazafluoranthene, and “tropoloisoquinoline” alkaloids (102). A photochemical mechanism had been suggested to explain the hypothetical decarbonylation of oxoaporphines to azafluoranthenes (94). This mechanism suffers from the drawback that, when applied to the case of cleistopholine (154), it does not explain the specific loss of the carbonyl group next to the pyridine nitrogen atom. To overcome this limitation, a metalloenzyme-catalyzed decarbonylation has been invoked (78),in which the metal atom could initially bind the pyridine nitrogen, and perhaps the neighboring carbonyl oxygen, to facilitate the elimination of (possibly metal-bound) carbon monoxide. The possible origins of highly conjugated lactam groups has been discussed above in connection with the biogenesis of dielsiquinone (134). Similar considerations may be applicable to dielsine (137), dielsinol (138), and 2,7(or 6)dimethoxy-6(or 7)hydroxyonychine (166, 167). In the case of the latter compound, as with dielsiquinone, the methoxyl group at C-2 can be traced back to a hypothetical 4-methoxylated aporphinoid precursor.

65


VI. Chemosystematics Our present knowledge of the chemistry of Guurreriu is too incomplete to say much about any possible relationships between alkaloid content and systematics within this taxon. It should be clear from Table IJJ that the 17 Guurreriu species studied so far can hardly be considered representative of the genus as a whole. In addition, many phytochemical publications do not record Occurrences of known

TABLE 111 BOTANICAL CLASSIFICATION OF THE CHEMICALLY STUDIED OF Guurreriu (SUBGENUS Guurreriu)" SPECIES Section

Fraction studiedb

Austroguatteria Dimorphopetalum Cordylocarpus Trichoclonia

0125

Leptophyllum Guatteria (=Eu-Guatteria) Sclerophyllum Macmguatteria Oligocarpus Stenocarpus F'teropus

012

Tylodiscus

2/20

Brachystemon Cephalocarpus Trichostemon Dolichocarpus Leiophyllum Megalophyllum

018 118 015 116 1I2 212

Mecocarpus

2/18

Dichrophyllum Stigmatophyllum Chasmantha Undetermined Reclassified

111 01 1 012

a

01 1 01 1 2/36

Species

G . ouregou Dun. G . psilopus Mart.

0118 1I6 1/10 015 016 2/16

G . goudorium Tr. et P1. G . sa.ordiuna Pittier

G . eluru R.E. Fr. G . modestu Diels G . chrysoperulu (Steud.) Miq. G . sagorianu R.E. Fr. G . schomburgkiunu Mart. G . morulesii (Maza) Urb. G . scandens Ducke G . megUlOphyh Diels G . melosma Diels G . dielsiunu R.E. Fr. G . guiunensis (Aubl.) R.E. Fr. G . discolor R.E. Fr.

G . cubensis Bisse G . guumeri Greenm.C G . subsessilis Mart.d

Following Ref. I I . Only one species (unstudied) is classified in subgenus Anomulunrhu. Number of species studiedlnumber of species in section. Mulmeu guumeri (Greenm.) Lundell. Hereropetulum brusiliense Benth.

66

ANDRE CAVB ET AL

compounds which may have been isolated together with new ones and which, in fact, may be the major secondary metabolites. Although the misplacement of Malmea gaumeri in Guatteria is almost certainly an extreme case, the difficulties involved in the classification of many Annonaceae and the all-too-frequent lack of adequate documentation of botanical specimens raise the possibility that some of the plant materials listed in Table I may have to be renamed. With the foregoing caveat in mind, and considering the alkaloids found in higher concentrations, Guatteria seems to be on the whole a rather typical annonaceous genus characterized by the almost universal presence of aporphinoids. These compounds are often accompanied by unexceptional berbines and/or protoberberines as well as occasional monomeric benzylisoquinolines. Many of the structural variations of the aporphines of Guatteria are found quite often in other annonaceous genera and are by no means family specific. Still, oxygenation at C-7 and aromatization of ring B to give 7-hydroxy- and 7-oxoaporphines,generally present in Guatteria species, seem to occur more frequently in the Annonaceae than in some other isoquinoline alkaloid-containing families. The hypothetical role of these compounds as precursors of azahomoaporphines (seco-C-aporphinoids), 1-azaanthracenes, and azafluorenones (seco-Aaporphinoids) (see Section V), which have only been found to date in the Annonaceae, suggests the possibility that this otherwise primitive botanical family has specialized by evolving a unique set of catabolic routes leading to at least one alkaloid, cleistopholine (154), which may be of considerable adaptive advantage (see Section VII). Guatteria, Duguetia, and Fissistigma are the only genera known to contain aporphinoids with ring D dioxygenated at C-9 and C- 11. The two former, which are neotropical genera, although belonging to the tribe Uvarieae, are not viewed by botanists as close relatives. As regards the large genus Guatteria, however, these alkaloids seem to be restricted to the single species ( G . discolor) constituting the section Dichrophyllum. It would be interesting to know if this plant is in any way an atypical Guatteria or if it appears to be closer to Duguetia in some nonchemical sense. However, G . discolor, like many other Guatteria species, contains 7-alkylaporphinoids, a character specific of this genus. Also, it seems likely that the same or similar compounds may be found in other genera of the Uvarieae, close to Guatteria and Duguetia. The same can be said, afortiori, of the possibly more ancient azahomoaporphines. In any case, the impression remains that the oxygenation pattern of isocalycinine (74), discoguattine (75), and oxoisocalycinine (106), quite rare, although evolved before these genera radiated from common ancestors, does not constitute a particularly useful adaptation. It is also noteworthy that where the meta-disubstituted aporphines are phenolic, the phenol function is located at C-9 in the G . discolor alkaloids, whereas it is always at C-l l in the alkaloids isolated from Duguetia. Guatteria and Duguetia seem to be exceptional among American Annonaceae


67

These alkaloids, which in that they accumulate 6a,7-trans-7-hydroxyaporphines. appear so far to be restricted to the Annonaceae ( 7 )and which occur in G . psilopus and G . sagotiam, are mainly known as constituents of the African genera Polyalthia and Pachypodanthium (103). The 7-methylated aporphinoids (including the biogenetically related cularinoid gouregine) occur in G . discolor, G . schomburgkianu, G . melosma, G . ouregou, G . scandens, G . sagotiana, and G . goudotiana. Rather surprisingly, all these species are placed by Fries ( 1 1 ) in different sections: Dichrophyllum, Cephalocarpus, Megalophyllum, Trichoclonia, Leiophyllum, Tylodiscus, and Sclerophyllum, respectively. A similar situation persists even when the subgroups (7methyl-6a,7-didehydro-, 7-hydroxy-7-methyl-6,6a-didehydro-, and 7,7-dimethyl -6,6a-didehydro-, and 4,5,6,6a-tetradehydroaporphines) are considered, so it seems that the ability to methylate aporphinoids at C-7, although restricted until now to Guatteria, has no systematic value whatsoever within this genus. Guatteria melosma, which produces 7-hydroxy-7-methyl and 7,7-dimethyl aporphinoids, belongs to the section Megalophyllum. The only other species of this section is G . megalophylla, and from the chemosystematic viewpoint it is noteworthy that head-to-tail bonded bisbenzylisoquinolines are the sole reported constituents of this plant (32). Guatteria ouregou belongs to the large section Trichoclonia which includes G . psilopus as the only other species which has been investigated for alkaloids (43). Although the latter plant does not seem to contain any unusual compounds in appreciable quantities, it almost certainly needs to be studied more exhaustively. Guutteria sugoriuna belongs to the large section Tylodiscus. Here again, the only other species of the section which has been studied chemically, G . chrysopetala, appears to contain only the most commonplace isoquinoline alkaloids (2 1 ) . 1-Azaanthracenes and azafluorenones have already been isolated from a number of somewhat distantly related Old and New World representatives of the Annonaceae, a situation suggestive of a rather ancient origin for these compounds. Both l-azaanthracenes and azafluorenones are usually found in very low concentrations, and it seems quite possible that careful analyses of plants belonging to closely allied families may reveal the presence of such substances. Considering the biogenetic relationships (see Section V) between these alkaloids and the diazafluoranthene eupolauridine (183) of Cananga and Cleistopholis (Annonaceae) and Eupomatia (Eupomatiaceae), it would be interesting to know if the putative parallel routes to 1-azaanthracenes on one hand and diazafluoranthenes on the other are mutually exclusive or perhaps cooccur. Azahomoaporphines have been found in the east Asian species Meiogyne virgata ( 4 6 ) ,in Guatreriu sugotiana ( 4 6 ) ,and in Duguetia spixiana (76).the latter two being representatives of exclusively American genera. Here again, it seems reasonable to think that, barring parallel evolution, the route leading to these alkaloids must have originated before the breakup of Gondwanaland and that this

68

ANDRE CAVE ET AL

archaic character is conserved here and there by some descendants of the early Annonaceae. The occurrence of azahomoaporphines in both Guatteria and Duguetia, however, is striking considering that these genera are the only ones known to contain ring D-9,1 I-dioxygenated aporphinoids, as discussed above. Considering the number of species studied, the presence of bisbenzylisoquinoline alkaloids in Guatteria megalophylla (32) and G . guianensis (30, 31) appears to be exceptional. Furthermore, these dimers are of the head-to-tail type in the former species and tail-to-tail in the latter, and therefore they are not very closely related from a biogenetic viewpoint. It has already been noted that the two species constituting section Megalophyllum seem to differ profoundly in the types of alkaloids they contain. A similar situation is found regarding the much larger section Mecocarpus, in which G . dielsiana has only been mentioned in the chemical literature as a source of 1-azaanthracenes and azafluorenones (22) whereas G . guianensis contains mainly tail-to-tail bisbenzylisoquinolines (30, 31).

It is possible that misclassifications are responsible for the radical differences recorded for the chemistry of the Megalophyllum and Mecocarpus species and the smaller but still apparently significant variations noted in the few other Guatteria sections in which more than one species has been studied. If all these species have been correctly classified, however, the necessary conclusion is that the alkaloid chemistry of Guatteria is not correlated with the morphologically based taxonomy of the genus. At a suprageneric level, on the other hand, a few questions have been raised that require careful, comparable analyses of many species of Annonaceae. In particular, it will be interesting to investigate whether Guatteria and Duguetia are part of a cluster of genera, presumably belonging to the tribe Uvarieae, in which isocalycinine analogs and/or azahomoaporphines have been conserved. Similarly, it should be determined if diazafluoranthenes (and perhaps their putative precursors, the hypothetica 1-aza-7-oxoaporphines) are really restricted to Cananga and Cleistopholis in e Annonaceae, analyzing the meaning of their distribution in relation to Eup, mafia. At a higher taxonomic level, the question should be addressed whethqr the latter genus (constituting the monogeneric Eupomatiaceae) and other fa “lies closely related to the Annonaceae contain any 1-azaanthracenes or azafluo enes. From a chemosystematic viewpoint, much remai to be done with the genus Guatteria and its relatives. Aside from the probable di covery of additional new structural types of alkaloids and other secondary metabolites, and in spite of the limited success obtained to date in attempts to correlate the occurrence of particular groups of compounds with the systematic position of their sources, this line of research can still be expected to shed some light on the systematics and evolution of so-called primitive angiosperms.

i $.,


69

VII. Pharmacology Of the approximately 250 species which make up the genus Guatteria, very few seem to have any recorded use in traditional medicine. Schultes (104) reports that an unidentified Guatteria species known to the Warani Indians of Ecuador as menedowe (jaguar tree) is used by this ethnic group to reduce fevers: the bark is crushed and mixed with water and then rubbed on the head and shoulders, a procedure which presumably bears little relationship to the pharmacologic activities of the constituents of the plant. The bark of another species, G. modesta, a climber which is known in the Peruvian Amazon as carahuasca, is the source of a preparation thought to be contraceptive (104). Finally, an aqueous-alcoholic extract of the bark of Malmea gaumeri (G. gaumeri), a native tree of Yucatan (ek-le-muy in Mayan language, or yumel), has been used extensively in southeastern Mexico to eliminate gallstones; yumel leaves are also used as poultices to treat pellagra (105). Aside from guattegaumerjne (7), extracted from M. gammri, none of the alkaloids known exclusively as Guatteria metabolites seem to have been subjected to specific pharmacological studies. Nevertheless, most of the Guatteria bases belong to groups whose pharmacological activities are known, and the specific properties of some of these alkaloids have been studied after their isolation in large quantities from other plant sources. Among the benzylisoquinolines, coclaurine, N-methylcoclaurine (l),and reticuline (3) have been shown to interfere wiU central dopaminergic transmission, judging from their effects on behavioral. parameters following intracerebroventricular administration in mice (106). Coclaurine inhibited locomotor activity and produced ptosis, catalepsy, and stereotyped behavior such as sniffing and gnawing. Reticuline also produced catalepsy and decreased locomotor activity. Both coclaurine and reticuline blocked locomotor activation and rotational behavior induced by the dopamine agonist apomorphine, but those induced by the neurotransmitter releaser methamphetamine were suppressed only by coclaurine. N-Methylcoclaurine (1) produced muscular twitches and tremor, and clonic convulsions were observed at higher doses. Coclaurine (20 mg/kg, i.v.) suppressed dopamine uptake in mouse iris after pretreatment with a-methyltyrosine. It was concluded that coclaurine has neurolepticlike properties in blocking some effects of dopaminergic stimulants but that the mode of action of reticuline (3) may be different (106). The bisbenzylisoquinolines have been the subject of many pharmacological studies, motivated originally by the knowledge that quaternary alkaloids of this type are the active constituents of tube curare. Certain nonquaternary bisbenzylisoquinolines, notably belonging to the curine group, are also smooth muscle relaxants; many bisbenzylisoquinolines are hypotensive, and a few possess anti-

70

ANDRB CAV6 ETAL.

tumor properties (60). In particular, guattegaumerine (7) is strongly cytotoxic at 10 pg/ml toward cultured murine L1210 lymphocytic leukemia and B 16 melanoma cells. Although B 16 melanoma is a relatively resistant tumor, guattegaumerine still exhibits some activity at concentrations below 5 pg/ml and is more than two times less toxic toward normal human cells 107). Many berbine alkaloids exhibit pharmacologic activities affecting the cardiovascular system (hypotensive action) and the entral nervous system (neuroleptic, tranquilizing, and analgesic actions) (2). The proaporphine alkaloid

d

/

8

glaziovine (38) showed some activity in the b99%)

133

2. @-PHENETHYLAMINESAND EPHEDRINES

A.

ArCHO + CH3N02 +ArCH=CHN02 LAH

B.

ArCH20H

-

ArCH2C1

\u

ArCH2NR1R2

C.

D.

ArCOCl

ArCOCHN 2\ ArCH2C02H 9

ArCOCH3

__t

ArC02H

d ArCOCl

* ArCH2CH2NH2

ArCH2CN

f

ArCH2CH2NH2

ArCHZCONH2

ArCOCN

i'

ArCH2CH2NH2

ArCH2CH2NH2 ArCHCH2NH2 I OH

E.

ArCOCHzNR1R2

F.

ArCH-CN I OH

G.

ArCHO

-

ArCHCH2NR1Rz I OH

ArCHCH2NH2 I OH

ArCHCN I

BH3'THF

OSiMe3

H.

PhCHO + CH3CH2N02 -2 K Co-3

+Ph-CH - CH-NH2 I

OH

1

Me

ArCHCH2NH2 I OH Ph-CH - CH-N02 I 1 OH Me

-

Ph-CH - CH-NHMe I I OH Me

SCHEME1. Methods for synthesis of P-phenethylamines and congeners.

134

JAN LUNDSTROM

erythro selectivity (319). Reduction of 6 with lithium aluminum hydride gave L-ephedrine in 80% yield. Another method employed a highly enantiospecific

& -

+ HSiPh,Me -TFA ,

&NHcooEt

NHCOOEt

6

L-Ephedrine

Me,CHCH 4 , &

Me2CHCH,

I

'

KMnO, 1-BuOH

n-BuLi

THF,-85"C

____*

%o (Z)-R- 7

-

1. NaOI

H

o

b

&

(E)-IS,ZR- 8

Me0,C

h-

HO

2S,3R- 9

\

MeHN

HO

e ephedrine ( 1 R , 2 S )

135

2. P-PHENETHYLAMINES AND EPHEDRINES

and erythro-selective [2, 31-Wittig rearrangement of the chiral (Z)-(R)-allylic benzylether 7 (320).Investigation of products 8 and 9 showed that the rearrangement proceeded with a high erythro selectivity (96%)and a high degree of asymmetric transfer (94%). A stereospecific synthesis of (S)-( -)-cathinone that utilizes the Friedel-Crafts reaction has been described (317).Reaction of the acid chloride obtained from N-(methoxycarbony1)-L-alanine (10) in benzene by AlCI, catalysis provided the N-protected a-amino ketone 11 with retention of chiralty; 11 was deprotected by hydrolysis with potassium hydroxide. A more recently published method (408) - Me

HOOC-

NHC0,Me

1. PC1,

KOH

+Me

2. *IC13 PhH,CH2C12

__*

kHCOzMe

\

s- 11

s- 10

eM NH,

\

S-Cathinone

utilized Boc-L-alanine [(S)-12], which was reacted with 3 equiv phenyllithium to afford the ester (S)-13. The tert-butoxycarbonyl protecting group was removed with trifluoroacetic acid in dichloromethane. A similar synthesis was described

HOOC

-

0

vMe PhLi HiC02-r-Bu

s- 12

HNCOZ-t-Bu

CF,COOH HC1,EtzO

S- 13

NHL S-Cathinone

for merucathinone (408). In this case Boc-L-alanine [( 9-12] was deprotonated with 2 equiv butyllithium followed by reaction with 1 equiv styryllithium to afford the ester (S)-14. The latter was deprotected to merucathinone in high yield. HOOC

-

Me -HNCO,-r-Bu

s- 12

_____, CF,COOH

1) 2Eq.BuLi

4

Me HNC0,- r- Bu

1 Eq.

0"ii \

NH2

S-Merucathinone

S- 14

-

I36

JAN LUNDSTROM

The synthesis of merucathinone described above followed a procedure that was also utilized for the synthesis of two other khat constituents, merucathine and pseudomerucathine (408). The ethyl carbamate of L-alanine [(S)-15] was deprotonated with 2 equiv butyllithium and subsequently reacted with 1 equiv styryllithium to yield the ester (S)-16. Reduction of (S)-16 with diisobutylaluminum hydride gave a 1 : 1 diastereomeric mixture of (IS,2S)-17 and (lS,2R)-17. Treatment of this diasteromeric mixture with 1 M potassium hydroxide in methanol at room temperature for 4 hr resulted in the formation of the epimeric oxazolidines (4S,5R)-18 and (4S,5S)-18 in high yield. These epimers could easily be separated quantitatively by flash chromatography. Ring opening of epimers 18 was accomplished by treatment with potassium hydroxide in methanol-water under reflux. 0 1) 2Eq. BuLi

HooCyMe HNC0,Et -1

HNC0,Et

. P -

5- 15

5- 16

KOH

3R.45-Merucathine

4S,5R- 18

02

HNC0,Et

tS,ZRS- 17

0-v

OH i

KOH ___*

Me

35,4S-Pseudo-Merucathine

4s,5s- 18

The preferential cleavage of the middle of three vicinal methoxy groups with mineral or Lewis acids has been demonstrated for various aromatic alkaloidal systems (410, 41 1 ) . Selective ether cleavage of mescaline and trichocereine thus

Meo HO

Me0 I

OMe

OMe

Mescaline

19

2. P-PHENETHYLAMINES A N D EPHEDRINES

137

afforded the corresponding 4-demethylated analogs (e.g., 19)in high yield (412, 4 13). Finally, synthesis of specifically )H-and I4C-labeledphenethylamines and phenethanolamines has been described (321-325).

V. Biosynthesis The earliest studies on the biosynthesis of phenethylamines using labeled precursors reported on the biosynthesis of hordenine in barley seedlings (326).The biogenesis of plant-derived phenethylamines was, however, studied mainly in cactus species. Most studies have concerned the biosynthesis of mescaline and related compounds in the peyote cactus Lophophora williamsii and in Trichocereuspachanoi (for reviews, see Refs. 10, 1 1 , and 327). Phenethylamine and N-methylphenethylamine were studied in Dolichorhele sphaericu (328) and 3,4-dimethoxyphenethylamine (homoveratrylamine) in Echinocereus merkerii (329). The biosynthesis of the 0-hydroxylated alkaloids normacromerine and macromerine were studied in Coryphanrha macromeris (330-334) and synephrine in Citrus species (375).The biosynthesis of ephedrine was studied in Ephedra distachya (336-342) and that of d-norpseudoephedrine in Catha edulis (343). The methods used mainly involved feeding the various plants suitably labeled postulated precursors of the alkaloids. The identification of trace intermediates has also been most informative (10, 11). The biosynthetic work on mescaline in the peyote cactus L . williarnsii and in the Peruvian cactus T. pachanoi has led to the formulation of biosynthetic pathways according to Scheme 2. A major pathway probably involves decarboxylation of tyrosine followed by hydroxylation to yield dopamine. Dopamine is methylated on the meta hydroxy group to 4-hydroxy-3methoxyphenethylamine (3-methoxytyramine) which then undergoes hydroxylation to the key intermediate 4,5-dihydroxy-3-methoxyphenethylamine(20). Para-0-methylation of 20 yields 3,4-dimethoxy-5-hydroxyphenethylamine(21), which is the immediate precursor of the main phenolic tetrahydroisoquinolines of peyote. Alternatively, meta-0-methylation yields 3,5-dimethoxy-4-hydroxyphenethylamine (19), which is further efficiently methylated to mescaline. Parallel pathways involving N-methylated compounds probably exist in these cacti (10). Dopamine may alternatively be formed from tyrosine via hydroxylation of L-dopa which is decarboxylated. However, inverse isotope dilution experiments to study the formation of dopamine and dopa have shown that this is probably a minor pathway in peyote ( I 76). It has been shown that L-tyrosine is incorporated into alkaloids in peyote three times more efficiently than into protein (344). 4-Hydroxy-3-methoxyphenethylamine can be methylated to 3,4-dimethoxyphenethylamine (homoveratrylamine),which may be viewed as a dead-end product in Scheme 2 (10, 203). Phenylalanine is probably not a precursor of the

138

JAN LUNDSTROM

L -Tyrosine

Tyramine

Dopamine

3-Methoxyt yramine

Homoveratry lamine

/ HO Ho 20

\ Hz

I

Meo

Me0

1

HO

19

I 21

4

MR2O e o w N R , Me6

R@

R,

Tetrahydroisoquinoline Cactus Alkaloids (R=HorMe)

Mescaline

SCHEME 2.

peyote alkaloids (10);however, this amino acid may be decarboxylated to phenethylamine, which is further N-methylated to N-methylphenethylamine in Dolichothele sphaerica (328). It was early known that hordenine is formed in barley from tyrosine by decarboxylation and N,N-dimethylation (326). More recently it has been shown that N-demethylation of hordenine also can occur in barley (345). Similar N-methylations and N-demethylations are known to occur with simple tetrahydroisoquinolines in peyote (10. 346). The biosynthesis the P-hydroxylated compound synephrine has been studied in Citrus species (325). An elegant experiment carried out in Cleopatra mandarin seedlings showed that tyramine is rapidly methylated to N-methyltyramine

6E 1

S3NIBa3Hd3 CINV S3NIVWIAHEIN3Hd-d ‘2

D m FIG. 1. Distribution of radioactivity among phenolic amines during 3 months after feeding [ I-14C]tyramine to a Cleopatra mandarin seedling. (0---0) Hordenine, (0-0) synephrine, (O---O) N-methyltyramine, and (0-0) tyramine. (Reprinted with permission from Phyrochemisrty, Vol. 8, T. A. Wheaton and 1. Stewart, Biosynthesis of synephrine in citrus, Copyright 1969, Pergamon Journals Ltd.)

H003

I Ho

Ho@NHNJ

t

;“Do Ho

i

‘HN

140

JAN LUNDSTROM

which in turn is either P-oxidized to synephrine or further N-methylated to hordenine (Fig. 1). Other Citrus species are able to hydroxylate tyramine to octopamine, and biosynthetic pathways according to Scheme 3 were postulated (335). The most abundant alkaloid in Coryphanrha macromeris, normacromerine, has been shown to originate from tyrosine (330).Tyramine and N-methyltyramine are efficiently incorporated into normacromerine while octopamine and dopamine are poor precursors. Norepinephrine, epinephrine, normetanephrine, and metanephrine have all been shown to be biosynthetically incorporated into normacromerine, and they have also been shown to be naturally occurring trace intermediates in this cactus species (331, 334). Normacromerine is only slowly converted to macromerine in C. macromeris (332).The results indicate that alternative pathways to normacromerine exist; precise conclusions regarding the biosynthesis of normacromerine must await further studies. OH

R2

HO

\

Tyramine

" HO * ' m I

OH Meo@NMeR Me0

(R' = RZ = H)

Norepinephrine (R' = R3 = H)

(R = H)

Normacromerine

N-Methyltyramine (R' = Me, R2 = H)

Epinephrine (RI = Me, R3 = H)

Macromerine (R = Me)

Octopamine (R1 = H, Rz = OH)

(R1= H,R3 = Me)

Normetanephrine

Metanephrine (R1 = R3 = Me)

The first studies on the biosynthesis of ephedrine in Ephedra distachya suggested that phenylalanine was incorporated via a C,-C2-N unit (339). When this was reinvestigated more recently, it was found that while C-3 and the aromatic ring of phenylalanine are incorporated, C-2 is not (341, 342). Specific incorporation of C-3 of phenylalanine into norpseudoephedrine in Catha edulis had also been reported (343). Further incorporation experiments showed that [ ~arboxyl-~~CIbenzoate, [7-I4-C]benzaldehyde,and [3-'4C]cinnamicacid are all efficiently incorporated into the a carbon of ephedrine, and the participation of a c6-cl intermediate rather than a c6-c2 unit appears to be well supported (341,342)(Scheme 4). Studies favor a biosynthetic scheme for ephedrine where C6-C, compounds such as benzoic acid or benzaldehyde react with C,-N compounds or equivalents to give ephedrine. The origin of the C,-N unit is still obscure. Methyl groups for N-methylation were previously shown to be donated from methionine or formate (338).

141

2.0-PHENETHYLAMINES AND EPHEDRINES

WHY0" o"cooH L -Phenylalanine

1 II

Shikimate

- -- -

Aspartare

----;+

Forrnate

7

I

0

0

COOH

CHO

C,N

0

- - - - -p

Methionine

t-Ephedrine SCHEME 4.

Several enzymes involved in the biosynthesis of phenethylamines in plants have been studied. A tyrosine carboxy-lyase (decarboxylase) isolated from barley seedlings and barley roots has been studied in considerable detail (347-349). The enzyme is rather specific for L-tyrosine and meta-tyrosine; ortho-tyrosine and L-dopa are decarboxylated slowly. Tyrosine carboxylase activity was also demonstrated in wheat and maize (348). Cytisus scoparius contains dopa carboxy-lyase which decarboxylates D- and L-dopa at about the same rate (350). Tyrosine is decarboxylated 15 times slower. A similar enzyme has been found in the alga Monostroma juscum ( 174). An enzyme preparation isolated from the pulp of the banana fruit was shown to contain tyramine hydroxylase activity (351). Dopamine is the main product when tyramine serves as substrate. A similar enzyme oxidizing tyrosine to dopa has also been found in banana (352). The peyote cactus contains an 0-methyltransferase that has been isolated and characterized (353).By using variously substituted phenolic phenethylamines as substrates for this enzyme, the previously postulated biosynthetic pathways to mescaline in this cactus could be verified (354, 327).

142

JAN LUNDSTROM

VI. Biological Effects The most well known of the naturally occurring phenethylamine derivatives (Table I) are the transmitters of the sympathetic nervous system, epinephrine, norepinephrine, and dopamine. All these compounds are 3,4-dioxygenated in the aromatic nucleus and are collectively known as the catecholamines. Norepinephrine is the transmitter of most sympathetic postganglionic fibers, dopamine is the predominant transmitter of the mammalian extrapyramidal system and of several mesocortical and mesolimbic neuronal pathways, and epinephrine is the major hormone of the adrenal medulla (363).The literature that has accumulated on the action of these compounds in higher animals is enormous. Metanephrine and normetanephrine are known from animals as deactivated metabolites of epinephrine and norepinephrine that result from the action of the enzyme catechol 0-methyltransferase (364). P-Phenethylamineitself is produced endogenously from phenylalanine in mammalian tissue (365,366)and has been suggested to exert a neuromodulatoryaction in brain (367, 368). It decreases norepinephrine and dopamine levels in brain probably via an amphetamine-like catecholamine-releasing action (369-371). Phenethylamine was first detected in mouse brain (365)and later also in rat brain and human urine (372).The levels in human urine were found to be elevated in manic and reduced in depressed patients. Judging mainly from such clinical findings, phenethylamine has been hypothesized to be involved in the etiology of depression (372, 373), schizophrenia (374),migraine (375),and stress (376). In contrast to phenolic and in particular catecholic biogenic amines, P-phenethylamine is well absorbed in the gastrointestinal tract, and it also easily penetrates the blood-brain barrier (377). It has been shown that dietary phenethylamine may trigger migraine attacks (375), probably by a cerebrovascular vasoconstrictor reaction (378).Many of the phenethylamine-containingplants of Table I are food plants, and ingestion of these may induce physiologically significant effects such as migraines. However, by far the most common dietary migraine trigger is chocolate, which contains large amounts of phenethylamine, at least 3 mg per 2-ounce bar (375). Tyramine is another dietary biogenic amine that has been suspected to be involved in the etiology of migraine (362, 379,380). A seemingly greater problem with dietary tyramine, however, has been its pressor activity in patients treated with monoamine oxidase (MAO) inhibitors as antidepressants (362).Normally, ingestion of tyramine in the food does not constitute a problem, as the compound is efficiently metabolized and deactivated by MA0 present in the gut wall and in the liver. However, inhibition of MA0 will significantly reduce this first pass metabolism and greatly increase the amount of tyramine reaching the systemic circulation (381).Fatal cases of hypertensive response have thus occurred in patients treated with certain M A 0 inhibitors after ingestion of food containing tyramine (382, 383). Cheese, pickled herring, and red wine are commonly

2. B-PHENETHYLAMINESAND EPHEDRlNES

143

thought of as food products containing high amounts of tyramine, but vegetables such as avocado pear, cabbage, cucumber, potato, and spinach may also be rich in tyramine (Table 11). The action of tyramine on nerve receptors is mainly indirect by release of norepinephrine and dopamine from neuronal storage sites (363,384).Tyramine and its P-oxidized counterpart octopamine have been referred to as false neurotransmitters because these compounds can be taken up, stored, and released from nerve endings in a way similar to those of the principal neurotransmitters norepinephrine and dopamine (385). Octopamine was first discovered in salivary glands of octopods (386). The compound is widely distributed in the animal kingdom and is present in high amounts in the nervous system of several species of invertebrates such as molluscs and arthropods, where it acts as a specific transmitter substance (387). Octopamine may also play a role in the regulation of adrenergic neurotransmission in mammals (387).Administration of octopamine to intact animals produces a transient rise in blood pressure (388). Synephrine is a sympathomimetic agent with mainly direct effects on a-adrenergic receptors. It has been used to treat hypotension and also as an ocular decongestant (389).It occurs in tangerines (Table 11) in concentrations high enough to be physiologically active (119). Mescaline is one of the earliest known hallucinogenic substances (390).The most well-known natural source of mescaline is the small peyote cactus Lophophora williamsii. Dried upper slices of this cactus (mescal buttons) have been employed by Indian tribes in the southern parts of the United States and in northern Mexico as a medicine, an amulet, and.a hallucinogenic religious sacrament (390, 391). Another important natural source of mescaline is the huge column cactus Trichocereuspachanoi, which has been used by Indians in Peru for preparation of the hallucinogenic drink cimora (392). Many reviews covering the ethnobotanical aspects of peyote (306, 390, 391, 393, 394) and the pharmacological action of mescaline and similar phenethylamines (395, 396) may be found in the literature. It is doubtful if any of the other cactus phenethylamines are psychoactive, although the P-oxidized macromerine has been claimed to be hallucinogenic (227). The crude drug Ma Huang or Mao prepared from certain Ephedra species has been employed for centuries as a sudorfic, antipyretic, and antitussive in oriental medicine (2). Its principal alkaloid ephedrine is a sympathomimetic agent which is used mainly in the treatment of bronchospasm, as a decongestant, and in certain allergic disorders. The alkaloid has also been employed as a pressor agent, particularly during spinal anesthesia. Ephedrine owes part of its peripheral action to release of norepinephrine but has also direct effect on receptors (363). Pseudoephedrine and phenylpropanolamine [(?)-norephedrine1 are sympathomimetic agents with actions similar to those of ephedrine and are most commonly used for the relief of nasal congestion (363). Pseudoephedrine has been stated to have less pressor activity and central nervous system effects than ephedrine.

144

JAN LUNDSTROM

Phenylpropanolamine also has been used as an anoretic, and the mechanism of the anoretic effect has been shown to be similar to that of amphetamine (397). Ma Huang has an anti-inflammatory activity (398). A survey for the active principle in the crude drug demonstrated that the most active one is pseudoephedrine. Ephedroxane was also isolated as a minor anti-inflammatory principle. The mechanism of the anti-inflammatory action of these compounds does not involve the central nervous system. Of several mechanisms considered, inhibition of prostaglandin E, biosynthesis may be of great importance (398). The fresh leaves of the khat shrub (Carha edulis) are chewed by several millions of people in East Africa and the Arabian peninsula for their euphoric and stimulating properties (284). The rather newly discovered alkaloid cathinone [(S)-a-aminopropiophenone]is responsible for the stimulating properties of khat (284). It has been shown that cathinone induces release at physiological catecholamine storage sites in a manner similar to that of amphetamine. Further results suggest that cathinone and amphetamine produce their stimulant effects via the same dopaminergic mechanism (399). The more recently discovered khat constituents merucathinone, merucathine, and pseudomerucathinewere found to have only weak dopamine-releasing effects and were therefore considered unlikely to play an important role in the stimulatory actions of khat leaves (414). The function of secondary metabolites such as phenethylamine and ephedrine derivatives in the plants that produce them remains obscure. A widespread belief is that they act as poisons or repellants to predators, parasites, and competitors (400, 401). There is very little evidence for such hypotheses; however, a few examples from the phenethylamine group of alkaloids may possibly point in this direction. For instance, hordenine shows antimicrobial activity (402)and is also a feeding repellant for grasshoppers (403). Furthermore, the resistance of the sugar beet (Beta vulgaris) to attack by fungi may be related to the presence of dopamine (179). High levels of dopamine are also found in the cacti Curnegia gigantea and Lophocereus schottii, and the latter cactus species is known to be toxic to most Drosophila species (404). Phenethylamine derivatives may also have growth-regulating properties (405). 3-Demethylmescaline, dopamine, and the methiodides of candicine and trichocereine showed strong growth-inhibitory activity in a bean second internode bioassay and the latter three compounds also in a sorghum bioassay (405). REFERENCES I . L. Reti, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 3, p. 313. Academic Press, New York, 1953. 2. L. Reti, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 3, p. 339. Academic Press, New York, 1953. 3. H. G . Boit, “Ergebnisse der Alkaloid Chemie bis 1960.” Akademie-Verlag. Berlin, 1961. 4. T. A. Smith, Phyrochemisrry 16, 9 (1977). 5. R. Mata and J. L. MacLaughlin, Rev. Larinoam. Quim. 12,95 (1982).

2.pPHENETHYLAMINE.S AND EPHEDRINES

145

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-CHAPTER

3-

LYTHRACEOUS ALKALOIDS KAORUFUJI Institute for Chemical Research Kyoto University Uji. Kyoto 611. Japan 1. Introduction

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

155

C. Cyclophane Alkaloids ..............

References

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

I75

I. Introduction Over 40 alkaloids have been isolated from Lythraceous plants since Ferris isolated 7 alkaloids from Decodon verticillutus in 1962 ( I ) . Before the last review in this treatise (2), the structures and stereochemistries of all Lythraceous alkaloids had been established. No reports on the isolation of new alkaloids from this family have been published since 1981. On the other hand, development of new synthetic technologies has opened new avenues to the total synthesis of Lythraceous alkaloids. The earlier classification (types A-E) of Lythraceous alkaloids introduced by Fuji et ul. (3)and adopted in the last review (2) is not used in this chapter because it does not indicate the structural features. This chapter covers the literature from 1979 to 1987, except for two papers (4, 5) already included in the last review (2) in Volume 18 of this treatise. 11. Synthesis

A. ARYLQUINOLIZIDINE ALKALOIDS Naturally occurring arylquinolizidine alkaloids synthesized within the period 1979- 1987 include demethyllasubine (l),lasubine I (2), 10-epidemethoxyabresoline (3), subcosine 1(4), demethyllasubine I1 (S), lasubine I1 (6),and abresoline

(7). Arylquinolizidine alkaloids are divided into two general classes. One class possesses a cis-quinolizidine skeleton, and the other has a rruns-quinolizidine 155

THE ALKALOIDS, VOL. 35 Copyright 0 IYXY by Academic Press. Inc. A / / rights ofrepmducfionin any farm rrservcd.

156

KAORU FUJI

structure. Four alkaloids (1-4) belong to the cis-quinolizidine series, while the others are trans-quinolizidines. OMe

OMe OR @OH

7 8

OH

1 ,R H ( demethyllasublneI ) 2 , R = Me ( lasublnel)

OH 3 ( 10-epidemethoxyabresollne)

OMe

OMe

H

oL@" OMe

4 ( subcosine I )

6 , R = M e lasublne II )

OMe

7 ( abresollne )

1. Mechanism of the Pelletierine Condensation Earlier syntheses of arylquinolizidine alkaloids mainly utilized the pelletierine condensation to construct the basic skeleton, 4-aryl-2-quinolizidinone(11) (Scheme 1). Two mechanistic pathways, involving (a) initial aldol condensation of pelletierine (8)with an aromatic aldehyde followed by intramolecular Michaeltype addition of the resulting enone 9 (6, 7) and (b) a Mannich-type reaction through 10 (8, 9), were proposed without any experimental evidence. Preparation and cyclization studies of the intermediate 9, however, gave conclusive evidence to show that the pelletierine condensation proceeded through pathway a (10).

157

3. LYTHRACEOUS ALKALOIDS

c

Wo+ ACHO

8

cN&

0 9

a

J

Ar

11

b

0 10

SCHEMEI .

Condensation of N-tert-butoxycarbonylpelletierine (12)with benzaldehyde proceeded smoothly in aqueous methanolic sodium hydroxide to afford the enone 14 in 90% yield. Deprotection with either hydrogen chloride in nitromethane or trifluoroacetic acid in methylene chloride furnished 9 (Ar = C,H,), which had been considered as an intermediate in pathway a (Scheme 1). The cyclization of 9 (Ar = C,H,) in CDCl, without base, monitored by 'H-NMR, revealed that the reaction was completed after 3 days to give the cis isomer 15 as a sole product. None of the trans isomer 16 was formed under these conditionseven after 2 weeks.

12 R = BoC

13 R = CH(0H)Ph

H 14

15

0

H

0

16

Intramolecular cyclization of 9 (R = C,H,) takes place easily under the normal conditions for pelletierine condensation (entries 1-4 in Table I). The yields and ratios of 15 to 16 are compatible with those of the intermolecular cyclizations under similar conditions (entries 5 - 8 in Table I). Attempts to synthesize the other intermediate (10,R = C,H,) or its equivalent (13) in pathway b were unsuccessful. Thus, the experimental evidence suggests pathway a to be more plausible.

2. Demethyllasubine I (l),Demethyllasubine I1 (S), 10-Epidemethoxyabresoline(3), and Abresoline (7) Recent strategy for the synthesis of phenylquinolizidine alkaloids involves inter- or intramolecular [3 + 21 dipolar cycloadditions of nitrones. The intermo-

158

KAORU FUJI

TABLE I FORMATION OF

Cis- A N D Wan~-4-PHENYL-2-QUlNOLlZlDINONES (15 A N D

Entry"

Solvent

NaOH (equiv)

I

Water Water Aq MeOH Aq MeOH Water Water Aq MeOH Aq MeOH

9 9 9 9 6 6 6 6

2 3 4 5 6 1

8

Reaction timeb (hr)

Yield

1

10

14

69 62 79

1

16 1

=

Ratio 15: 16

(%)

3.8 0.67 3.4 0.20 3.6

62

16 I 17

Entries 1-4, Intramolecular cyclization of 9 (R pelletierine condensation of 8 with benzaldehyde. At 55°C.

16)

66 61

1.1

2.9 0.14

62

C,H,) (see Scheme I); entries 5 - 8 , normal

lecular 1,3-dipolar cycloaddition approach was applied by Takano and Shishido to the synthesis of two naturally occurring arylquinolizidine alkaloids, demethyllasubines I (1) and I1 (9, for the first time (Scheme 2) (11, 12). Aldehyde 17 was converted to the homoallylic alcohol 18 with Grignard reagent. 1,3-Dipolar cycloaddition of 3,4,5,6-tetrahydropyridine 1-oxide (19) with the homoallylic alcohol 18 in refluxing toluene afforded adduct 20 in quantitative yield. On mesylation adduct 20 gave quaternary salt 21, which was directly reduced with zinc OCHzPh OH P h C H Z O n CHO a PYHzO

?

Me0

Me0 17

r

18

I

1

OM^

19

OMe

OMe OCHZPh

OCHzPh

C

H 21

OAC 22

H

23

SCHEME 2. Reagents: a, CH2=CHCH2MgBr;b, toluene/reRux; c, MsCVpyridine; d, Zn/AcOH;

e, AeO/pyridine.

159


in 50% aqueous acetic acid to provide rrans-quinolizidine 22 (38%) and cisquinolizidine 23 (25%) after acetylation. Hydrolysis of 23 followed by debenzylation afforded demethyllasubine I (1) in 16% overall yield from 17. The configuration of the substituent at C-2 in 22 was inverted through two steps. Thus, hydrolysis of 22 followed by treatment with diethyl azodicarboxylate and triphenylphosphine in the presence of benzoic acid furnished the benzoate 24. Compound 24 was converted to demethyllasubine 11 (5) by sequential removal of the benzoyl and benzyl protecting groups; the overall yield from 17 was 19%. OMe

3 O C H z P h

H 24

OCOPh

OMEM

H 25,R-Ac 26,R=H

H 27,R=Ac 28,R-H

OR

0 0 CHo

“‘ODMe0

OMEM

MEMO 30

29

OMe

OMe OMEM

OMEM

OMe

31

32

OMEM

P-Methoxyethoxymethyl (MEM)-protected arylquinolizidines 25 and 27 were prepared from MEM-protected isovanillin (29) through the same sequence as shown in Scheme 2. Treatment of the alcohol 28, obtained by basic hydrolysis of 27, with the anhydride 30 gave 31 in 73% yield. Removal of the MEM groups with trifluoroacetic acid in methylene chloride afforded 10-epidemethoxyabresoline (3) in 12% overall yield from 29. The alcohol 26 was prepared from the acetate 25 on hydrolysis. Simultaneous inversion of the configuration at C-2 and formation of cinnamate necessary for

160

KAORU FUJI

formation of abresoline (7) were accomplished under Mitsunobu conditions, utilizing 3-methoxy-4-(~-methoxyethoxymethoxy)cinnamic acid to give 32. Abresoline (7) was obtained by deprotection of 32 with trifluoroacetic acid in methylene chloride in 16% overall yield from 29 ( 1 2 , 13). 3. Lasubine I (2) and Subcosine I (4) Lasubine I(2) and subcosine I(4) were synthesized by an intermolecular [3 + 21 dipolar cycloaddition strategy (Scheme 3) (14, 15). The dipolarophile 34 was prepared from 3,4-dimethoxybenzaldehyde (33) by the Wittig reaction as a mixture of E and Z isomers in a ratio of 9:5.The intermolecular [3 + 21 dipolar cycloaddition of mixture 34 with 3,4,5,6-tetrahydropyridine1-oxide (19) in refluxing toluene gave the corresponding Z and E cycloadducts 35 and 36 in 22 and 49% yield, respectively. Diastereomeric ratios of 35 and 36 were 5 : I and 10:3, respectively, with preference for the trans isomers 35a and 36a in each case. Addition of hydrogen chloride to the double bond of 36 was followed by intramolecular cyclization via reductive cleavage of the N - 0 bond by hydrogenation over palladium on carbon in ethanol to give lasubine I (2) in 44% yield along with its C-2 epimer 37 (14%). Esterification of the lithium salt of lasubine I (2) with 3,4-dimethoxycinnamicanhydride provided subcosine I (4) in 48% yield. The disadvantage of the intermolecular dipolar cycloaddition strategy is nonstereoselectivity. A recent stereoselective synthesis of lasubine I (2) utilizes the intramolecular T cyclization of an N-acyliminium ion as a key step (Scheme 4) (16). The reaction of carbinol 38, prepared from 3,4-dimethoxybenzaldehyde (33) and allylmagnesium bromide, with glutarimide under Mitsunobu conditions

Me0

?-

CHO

+

_ E M B Me0 OD-

Me0

33

3 5 a . R ~ p-H 35b,R= a-H

34

36a,R= 36b,R=

0b

19

B-H a-H

37

SCHEME3. Reagents: a, Ph~P=cHCH=CH2/ether;b, toluene/reRux; c, HCUCHCI,; d, H2/Pd-C.

161


OMe

+ C : H

Me0

0

38

&OMe

c d

lasublnel(2)

&OH 40

'

-

NH

OH

H 41

SCHEME4. Reagents: a, PPh3/MeOOCN=NCOOMelTHF; b, NaB&/EtOH/-35 HCOOH; d, KOHlaq EtOH; e, LiAlH+/THF.

to -30°C; c,

afforded 39 in 47% yield. Partial reduction of 39 with sodium borohydride was performed under carefully controlled conditions at -35 to -30°C to give the hydroxy lactam 40 in 55% yield. The cyclized lactam 41 was obtained in 81% yield from 40 by treatment with formic acid followed by the hydrolysis with potassium hydroxide. Reduction of 41 with lithium aluminum hydride afforded lasubine 1(2) in 78% yield. Lasubine I(2) was also synthesized with the pelletierine condensation as a key step ( 15). Condensation of pelletierine (8) with 3,4-dimethoxybenzaldehyde (33) under standard conditions gave the cis- and trans-quinolizidines 42 and 43 in 46 and 22% yield, respectively. Reduction of cis-quinolizidine 42 with sodium borohydride afforded lasubine I (2) in 83% yield. OMe

OMe

0 42

H

0

43

4. Lasubine I1 (6) Lasubine I1 (6) was synthesized by three different routes. The first involves the traditional pelletierine condensation ( 1 5 ) , in which trans-quinolizidine 43 was

162

KAORU FUJI

converted to lasubine I1 (6) in 19% yield by reduction with sodium borohydride. The major product of this reduction was the unnatural derivative 2-epilasubine I1 (44). OMe

OMe

44

The second synthesis of lasubine I1 (6) by Narasaka et al. utilizes stereoselective reduction of a P-hydroxy ketone 0-benzyl oxime with lithium aluminum hydride, yielding the corresponding syn-P-amino alcohol (Scheme 5) (17, 18). The 1,3-dithiane derivative 45 of 3,4-dimethoxybenzaldehydewas converted to 46 in 64% yield via alkylation with 2-bromo- 1,l-dimethoxyethane followed by acid hydrolysis. Treatment of the aldol, obtained from condensation of 46 with the kinetic lithium enolate of 5-hexen-2-one, with 0-benzylhydroxylamine hy-

n

n

-MeoflcHo c ,d

a,b

Me0

Me0 45

sn

e

46

Me0

S ,

47

0

O H NH2

OH NHBoc

f,g

___)

M

e

40 O

F

49

i'k

H 50

lasublnefl(6)

OH

H 51

SCHEME5. Reagents: a, ~-BUL~IBICH,CH(OM~)~; b, conc HCIITHF; c, CH2=C(OLi)CH2CH2CH=CH2; d, PhCH2ONH2 . HClIpyridine; e, LiAIhfKOMe; f, Boc-S; g, NCS/AgN03; h, CF, COOH; i, LiAIhINaOMe; j, disiamylborane, then H202INaOH; k, TsClIpyridine.

163


drochloride in pyridine afforded the 0-benzyl oxime 47 as a I : 1 mixture of syn and anti isomers in 80% yield from 46. Stereoselective reduction of 47 with lithium aluminum hydride in the presence of potassium methoxide furnished a syn-&amino alcohol (48) with the relative configuration between the hydroxyl and amino groups necessary for lasumine I1 (6). Protection of the amino group of 48 with ferf-butoxycarbonyl (Boc) followed by dethioacetalization gave 49 in 56% yield. Removal of the Boc group with trifluoroacetic acid provoked spontaneous cyclization to provide a labile imine (SO), which was directly reduced with lithium aluminum hydride in the presence of sodium methoxide to give cis-2,6-disubstituted piperidine 51 in 60% yield from 49. Lasubine 11 (6) was obtained from 51 on hydroboration-oxidation followed by treatment of the resulting alcohol with p-toluenesulfonyl chloride in pyridine in 61% yield. The third synthesis of lasubine I1 (6) involves stereoselective intramolecular nitrone cycloaddition as a key step (Scheme 6 (19). The hydroxylamine 54 was obtained from 3,4-dimethoxybenzaldoxime(52) by reflux in carbon tetrachloride with ethylene glycol boronate 53 in 68% yield. Condensation of 54 with methyl 5-oxopentanoate (55) afforded the nitrone 56, which was directly subjected to cycloaddition in refluxing toluene to give a 1-ma-7-oxanorbornane (57) in 50% OH

NHOH

?l MeoDCH:N Me0

8-0

Me0

a_

53

52

+

OHC(CH&COOMe

Me0

54

55

b

_cc

OMe

i , lasublne I1(6) MeOOC

OH 58

59

60

SCHEME6. Reagents: a, CC14/reflux;b, molecular sieves (3A)/CH2C12/2 kbar; c , tohenelreflux; d, Zn; e , trimethylsilylimidazole; f , 2-pyridinoll160"C; g, B y N F h, PPh,/Et00CN=NCOOEt/ PhCO; i, KOH/MeOH; j, LiAIH4.

164

KAORU FUJI

yield from 54 along with other stereoisomers. All-cis substituted piperidine 58 was obtained by reduction of 57 with zinc in acetic acid in 95% yield. Protection of the hydroxyl group of 58 as a trimethylsilyl (TMS) ether was followed by lactam formation with 2-pyridinol to afford 59 after deprotection with tetrabutylammonium fluoride. Inversion of the configuration at C-2 of lactam 59 was accomplished by the Mitsunobu procedure and subsequent alkaline hydrolysis in 74% overall yield. Exposure of the resulting alcohol 60 to lithium aluminum hydride gave lasubine I1 (6) in 76% yield.

B. LACTONIC ALKALOIDS Two lactonic arylquinolizidine alkaloids, vertaline (61) and decaline (62), which possess a diphenyl ether moiety have been synthesized (20-22). The former alkaloid has a cis-quinolizidine ring, while the latter possesses a trunsquinolizidine structure. Unnatural 17-0-methyllythridine (63), a derivative of lythridine (a), was synthesized utilizing a new strategy for macrolide cyclization (23).

61 (vertaline)

63, R = Me 64,R=H

62 (decallne)

1

1. Vertaline (61)

Vertaline (61) was synthesized through two routes that involve an N-acyliminium ion cyclization (20) and an intermolecular [3 21 cycloaddition (21, 22) as the key steps, respectively. Model studies (20, 24) for assembling the quinolizidine moiety by the N-acyliminium ion cyclization are shown in Scheme 7. The benzyl alcohol 65 was converted to glutarimide 66 by the Mitsunobu procedure in 55% yield. Reduction of imide 66 with diisobutylaluminum hydride afforded 67, which was subjected to N-acyliminium cyclization to give the lactam 68 in 40% overall yield from 66. Lactam 68 possesses the correct stereochemistry at all chiral centers required for vertaline (61). With this background, the total synthesis of vertaline (61) was completed starting from the aromatic aldehydes 69a and 69b (Scheme 8). Successive treatment

+

165

3. LYTHRACEOUS ALKALODS

H 65

OH 67

66

OCHO 68

SCHEME 7. Reagents: a, EtOOCN = NCOOEt/PPh3/glutarimide; b, i-Bu2A1H; c, HCOOH.

-

X

CHO,

+

MeOOC(CH,),CH(OMe),-

b

Me0

Me0

OMe 6913,X = Br 69b, X = I

71

OMe 70

OMe

OMe

C

Me0

73

OMe

74

OMe

Me0

Me0

+

OCHO

"

76

OMe

Me0

+ OAc 78a,X=Bt 78b,X=I

HO~CH,CH,COOMe 79 OR'

COoR2

80, R' = AC, R ~ w = ~I,R~=R~=H

SCHEME 8. Reagents: a, LiN(TMS)z/CH,-CHCHMgBr/THFb, AIMe3; c, HCOOH/CH2C12;d, BH,.THF e, AqO/pyridine; f, pyridinelreflux; g , NaOH/aq MeOH.

166

KAORU FUJI

of bromoaldehyde 69a with lithium bis(trimethylsily1)amide and allylmagnesium bromide afforded amine 70 in 97% yield. Amide 72 was obtained by condensation of 70 with methyl 5,5-dimethoxy-pentanoate(71) in 88% yield, using the method involving activation of the amine with trimethylaluminum. Treatment of 72 with formic acid in dichloromethane afforded the desired quinolizidine 75, the C-2 epimer 76, and olefin 77 as a mixture in 60, 9, and 21% yield, respectively, via a hydroxylamine (73) and an N-acyliminium ion (74). On reduction with borane in tetrahydrofuran followed by acetylation, amide 75 furnished amine 78a in 90% yield, which was converted to diphenyl ether 80 in 32% yield by reaction with the copper salt of methyl 3-(4-hydroxyphenyl)propionate (79). Hydrolysis of diphenyl ether 80 followed by a lactonization procedure developed by Corey et al. (25)afforded a 53% yield of vertaline (61). The same sequence of reactions starting from the iodide 69b provided precursor 78b for the diphenyl ether 80. However, use of iodide 78b found no advantage in the Ullmann ether synthesis. Another synthesis of vertaline (61) involves an intermolkcular [3 21 cycloaddition of nitrone 19 as a key step (Scheme 9) (21, 22). Ullmann reaction of bromide 82 with 79 in the presence of a phase-transfer catalyst such as tetrabutylammonium bromide gave the diphenyl ether 83 in about 50% yield. The cycloadduct 84 was prepared in 99% yield by heating 83 with the nitrone 19 in refluxing toluene. Treatment of 84 with methanesulfonyl chloride afforded an in-

+

OMe

+ 79

Meo& Me0 82

1

COOMe

(x?i
C-6',,, > C-6,, with 70% of incorporation of deuterium. LaLonde's final conclusions are as follows: 1. The strength of the internal S/C=N+ complex is the principal influencing factor. 2. Axial introduction of deuterium to a-thioiminium ions occurs faster than to P-thioiminium ions (Scheme 3) because at a given pH the a ions exist mostly as the active intermediates whereas the f3 ions, owing to solvation, are present mostly in the nonactive P-thiohemiaminal form.

SCHEME 3. Relationship between a-and P-thiohemiarninals and corresponding iminium salts.

3. Steric hindrance and the direction of nucleophilic attack are the other factors determining the rate of the reduction of a-thioiminium ions. Attack at the p face of the molecule by the reducing nucleophile is faster than at the a face which is more hindered (Scheme 4). The NaBH, and NaBD, reductions of thiohemiaminals carried out in ethanol by MacLean et al. (56)correspond only in part to the results obtained in methanol. Using 6,6'-dihydroxythiobinupharidine (54) and 6-hydroxythiobinupharidine (53) for the reduction, they concluded that at C-6' the reduction follows only one steric mode, introducing deuterium in an axial configuration (95% incorporation). This observation corresponds to results described earlier by LaLonde. However, the reduction at C-6 in ethanol as opposed to methanol follows two steric modes, introducing 60% of the deuterium in an axial fashion and 40% equatorially (95% incorporation of deuterium). Furthermore, the differences in the course of the reduction were also shown as a more rapid reduction at C-6' as compared with C-6 and 95% incorporation of deuterium in comparison with 70%

236

JACEK CYBULSKI AND JERZY T. WROBEL

S equatorial

face

S axial

D

D

SCHEME4. Deuteration of iminium salts of Nuphar alkaloids.

obtained in methanol (the opposite was observed in methanol). A rationale for this phenomenon is still needed. The NaBD, reduction of sulfoxides of thiohemiaminals performed on 6hydroxythiobinupharidine syn-sulfoxide (24), 6’-hydroxythiobinupharidinesynsulfoxide (25), and 6,6’-dihydroxythiobinupharidinesyn-sulfoxide (26) follows a single steric mode (90% of deuterium incorporation) and introduces axial deuterium at both C-6and C-6’.This reduction may not follow a mechanism with intermediate iminium salt formation (36). The presence of strong hydrogen bonding and the absence of a-iminium salts in the reacting mixture support this conclusion. The quaternization of nitrogen and/or sulfur seems to be more dependent on steric hindrance and stereochemistry around the sulfur atom; different products are obtained in the series of alkaloids with equatorial sulfur as compared with those in which sulfur is axial. Thiobinupharidine (16) (sulfur equatorial) can be easily quaternized on nitrogen, resulting in only isomeric mono- or dimethiodides (57). In this reaction, partial trans-cis transformation of the quinolizidine ring was observed. This isomerization seems to be influenced by the presence of sulfur and does not follow the pattern observed for the C,,Nuphar alkaloids (41) where direct dependence on the configuration of C-7is controlling. No methyla-

5. NUPHAR ALKALOIDS

237

tion on sulfur was observed in the thiobinupharidine series (57). Stepwise Hofmann degradation of mono- and dimethiodides of thiobinupharidine results in products in usual manner. The final product of the degradation of dimethiodide is shown by structure 55 (58, 59). In alkaloids with an axial sulfur atom (neothiobinupharidine (17) and thionuphlutine B (18), in addition to quaternization on nitrogen, methylation on sulfur also takes place (60, 61). The rate of sulfonium salt 56 formation as compared with quaternization must be greater since they are formed in the first step. It was observed that monomethiodides of sulfonium salts can be transformed to

238


OH

I

one steric mode C-6'dauterium 100% axial

C-6 deuterium 90% axial I

I

I

-

in mono and di thiohemiaminals

-

D

55

compounds 57 and 58 in which the C-7-S bond is cleaved, a double bond formed, and the ring junction of the AB quinolizidine system inverted to the cis orientation. The C-7-S bond cleavage is explained in terms of syn-elimination, whereas inversion on nitrogen results from unfavorable 8-syn-diaxial interaction of the N+-CH, group with the sulfur atom (Scheme 5). This degradation sequence

5 . NUPHAR ALKALOIDS

239

seems to be a selective method of degradation and C-S bond cleavage, exclusive to alkaloids with axially oriented sulfur in the quinolizidine ring. The degradation products (type c in Scheme 5 ) , under basic conditions, result in compounds of type d. The formation of compounds with conjugated double bonds cannot follow a straightforward 1 ,Zelimination pathway but are considered to arise from vinylogous Hofmann-type elimination. The set of reactions described above represents a very selective degradation, which affects only the tetrahydrothiophene ring and the AB quinolizidine system (61).

VI. Synthesis of Nuphar Alkaloids 7-Demethyldeoxynuphaidine (5) was synthesized from (-)-castoramine (59) in six steps (Scheme 6) (26). Syntheses of (-+)-nupharolutine(50) and of (*)7-epinupharolutine (60) were completed from cyclopentanone derivative 61 (Scheme 7) (62).A stereocontrolled synthesis of (+)-anhydronupharamine (62) was achieved in six steps from cyclopentanone derivative 63 (Scheme 8) (63). Tufariello (64)pointed out the possibility of synthesizing of 7-demethylodeoxynupharidine ( 5 ) from nonfunctionalized nitrones such as 64 (Scheme 9). Compound 65, after cyclization and removal of the ketone group, would furnish a synthesis of alkaloid 5.

240

JACEK CYBULSKI AND JERZY T.WROBEL

SCHEME 5 . Degradation of neothiobinupharidine S.N-methiodides.

1. CICO2CH3 2. A 500. *'CH2OH 59

1.OsOklNaIO4 * 2. LiAIHb 3. resolv.

b: & 2 .rnci3/py 1. H~lPd-c~

KOH

5

SCHEME 6. Transformation of (-)-castommine (59) to 7-demethyldeoxynupharidine(5).

24 1


A

1. NH2OH 2. PClgIether

*-R1

%O

II

61

0

m- CI-C6H&03H t

OH

II

yield 45-68%

corresponding epoxides

NoHl benzene refl. under N2

BuLiIhexone

H

H

0

e~ (t)-nuphorolutine 50

+

(~)7-epinuphorolutine

60

SCHEME 7. Synthesis of (+)-nupharolutine (SO) and (+)-7-epinupharolutine (60) from cyclopentanone derivative 61.

The synthesis of quinolizidine (3-spiro-2’)-tetrahydrothiophene(67a, 67b), a model compound for the synthesis of dimeric sulfur alkaloids, was reported (65, 66). The compound was prepared from 2-cyanotetrahydrothiophene (66)by two independent routes, both utilizing phase-transfer catalysis (Scheme 10). Two new approaches to the synthesis of deoxynupharidine (14) and its C-1 and C-7 epimers were reported. Arata et al. (67) made use of the Mannich reaction of a suitable derivative of isopelletierine and 3-furylaldehyde; (+)-7-epideoxynupharidine (15) and ( 2 ) I--epideoxynupharidine(8)were proved to be the main products of the reaction. The synthetic route is shown in Scheme 11. Intramolecular Diels-Alder condensation of l-Azadienes was shown (68) to be a stereoselective route to the total synthesis of (-)-deoxynupharidine (14). The key steps are shown in Scheme 12; from synthon A in four steps alkaloid 14 was obtained.

242

J A C K CYBULSKI AND JERZY T. WROBEL

0

-

1. NHzOH, 2. PC15

CH3 63

O

X

N

L CH30CO

C

H

3

l.H+ 2. A,CoO)

1. NoBHq k)-anhydronuphoromine 85% 2. chrornotogrophy~ nuphenine 15 %

62

SCHEME 8. Synthesis of (5)-anhydronupharamine(62) from cyclopentanone derivative 63.

64

1. reduction

2. corbomate 3. oxid. X = protecting group 65

SCHEME 9. Routes for the synthesis of Nuphar alkaloids from nitrones.

243


muta b

SCHEME 10. Routes for the synthesis of spirotetrahydmthiophene-quinolizidine derivatives.

1.

-

2. Wolff Kishner

(i)- 7 - epideoxynupharidine (151 +

-

kl -1 epideoxynupharidine (81

SCHEME 1 1 . Synthesis of (*)-7-epi- and (2)-I-epideoxynuphaidine(15 and 8).

1.

A

2. H 2 I Pd-C 3. 3-lithiofuranC 4.BU3. sMe2

&ACH3 U 0

(-1-deoxynupharidine

A

SCHEME 12. Synthesis of (-)-deoxynupharidine (14).

(14 I

244

JACEK CYBULSKI AND JERZY T.WROBEL

VII. Spectroscopy of Nuphar Alkaloids A. NMR SPECTROSCOPY 1.

l 3 C-NMR

Spectroscopy

l 3 C-NMR spectrometry has assumed a very efficient role in the determination of the structure and stereochemistry of Nuphar alkaloids and their derivatives. Accurate assignments of chemical shift values to particular carbon atoms in the molecules and clear changes in chemical shift values of particular carbon atoms, owing to conformational transformations, are well within the rules generally accepted for I3C-NMR spectroscopy, which facilitates identification of the signals in the I3C-NMR spectra. For the C Nuphar alkaloids containing quinolizidinerings, deoxynupharidine (14), 7-epideoxynupharidine (lS), nupharolutine (50), and 7-epinupharolutine (60), and also for the synthetic model compounds 3(e)-methyL3(a)-rnethylthiomethylquinolizidine (68) and 3(a)-methyl-3(e)-methylthiomethylquinolizidine (69), the diagnostic carbon atoms that determine the conformation of the methyl and methylthiomethyl substituents are the carbon atoms of those groups as well as the carbon atoms of the quinolizidine ring at which the substituents are situated (67). For substituents in an axial conformation, the above-mentioned carbon

atoms exhibit a diamagnetic shift, as compared with similar carbon atoms with the equatorial substituents [cf. C-7 and C-7’ in deoxynupharidine (14) and 7epideoxynupharidine (lS), or the C-7 and C-7’ carbon atoms in nupharolutine (SO) and 7-epinupharolutine (60)]. It has been found that quaternization of the nitrogen affects the chemical shift value of quinolizidine carbons. If quaternization of the nitrogen atom does not cause any conformational transformations in the quinolizidine ring, as is the case for 7-epinupharidine(31) and 7-epideoxynupharidine methiodide (70), all carbon atoms in a position p with respect to the new N+-0- or N+-C bond exhibit a paramagnetic shift (- 10 ppm) (41, 69).


245

Different changes are observed when quaternization causes inversion of the quinolizidine ring from trans to cis, as is observed in the case of nupharidine (which is an N-oxide) (32)and deoxynupharidine methiodide (71) (41, 69). In such cases the tertiary carbon atoms in the p position ((2-4, C-10) with respect to the new N+-0- or N+-C bonds exhibit a paramagnetic shift, and the secondary carbon atom (C-6) exhibits a diamagnetic shift in comparison with similar carbon atoms in the free base. As well as those mentioned above, the following carbon atoms are also diagnostic for quaternary quinolizidine salts: the quaternary carbon atom of the substituted p-furan ring, which as a result of y-gauche interactions between the carbon atom and the oxygen of the N-oxide group or the carbon of the N+-methyl group exhibits a diamagnetic effect of about 10 ppm, and also, in the case of the methiodide, the carbon atom of the N+-methylgroup, which in methiodides with a trans conformation of the quinolizidine ring is situated upfield compared to the same carbon atom in a methiodide with a cis conformation (- 10 ppm) (43, 69). Analysis of the I3C-NMR spectra of Cu quinolizidine alkaloids and model compounds can be used to formulate spectroscopic criteria for determining the stereochemistry of dimeric Nuphar alkaloids, their quaternary salts, and products of chemical degradation. For determination of stereochemistry of the main C,, Nuphur alkaloids, thiobinupharidine (16), thionuphlutine B (18), and neothiobinupharidine (17), the diagnostic carbon atoms are C-17 and C-17’ of the spirotetrahydrothiophene (69). The C- 17 carbon atom, situated diaxially with respect to the quinolizidine ring in thiobinupharidine (16), exhibits a diamagnetic shift in comparison with the same carbon in thionuphlutine B (18) (axial and equatorial conformation with respect to the quinolizidine rings). On the other hand, C-17 in thionuphlutine B (18) exhibits a diamagnetic shift in comparison with the same carbon atom in neothiobinupharidine (17) (C-17 diequatorial with respect to both quinolizidine rings). A comparable change in chemical shift values observed for C-17’ is due to the different stereochemistry of C-7 and C-7’ in dimeric Nuphar alkaloids (69). The C-17 shift is also diagnostic for determining the stereochemistry of mono- and dimethiodides of thiobinupharidine containing a cis N-substituted AB and/or A‘B‘ quinolizidine ring (43). The change of conformation of the N-substituted quinolizidine ring from trans to cis (as a result of quaternization of nitrogen) causes a change of stereochemistry of C-7 or C-7’. In consequence, C-17 changes from a diaxial relationship in thiobinupharidine (16) to an axial-equatorial one or, in the case of cis-AB, cis-A‘B’ thiobinupharidine dimethiodide (41), to an equatorial-equatorial relationship. This causes a signal shift for C-17 downfield by 5 and 10 ppm, respectively (43). Similarly, as in the case of quaternary salts of C,5 Nuphar quinolizidinium alkaloids, the diagnostic carbon atoms apart from C-17 for the quaternary salts of dimeric Nuphar alkaloids are those situated a with respect to the quaternary nitrogen atom and the N+-methyl group. In the case of thiobinupharidine methio-

246


dides containing trans-quinolizidine rings, all carbon atoms ci to the nitrogen exhibit a paramagnetic shift in comparison with the same atoms in free bases. In cis-quinolizidinium rings the tertiary carbon atoms exhibit a paramagnetic shift while a secondary carbon atom exhibits a diamagnetic shift relative to the corresponding carbons in the free base. The carbon atom of the N+-methyl group in a cis-quinolizidiniumring is situated downfield (- 10 ppm) in comparison with the corresponding carbon in a trans-quinolizidinium ring. In some cases quaternization in dimeric Nuphar alkaloids results in deformation of the spirotetrahydrothiophene ring ( 4 1 , 4 3 ) (Schemes 13, 14, and 15). The diagnostic carbons which permit detection of deformation of the spirotetrahydrothiophene are C-6 and C-8 or C-6' and C-8' in the nonsubstituted quinolizidine rings. Carbon 6 or 6', as a result of the disappearance of the H-H 1,3-diaxial interaction between the proton at those atoms and that at C-17, and also because of introduction of a new 8-syn-diaxial interaction between C-6 and C-8' or C-6' and C-8, exhibits a diamagnetic shift of about 1.5 ppm. Deformation of the spirotetrahydrothiophenering causes a new H-H 1,3-diaxial interaction between the hydrogen on C-8 or C-8' and that on C-17, which in turn results in a paramagnetic shift of the signal of this carbon. The diagnostic carbon for determination of the stereochemistry of methiodides containing a double bond in the N-substituted quinolizidine ring is C-6, which is situated a to the quaternary nitrogen and ct to the double bond. This

w., -

AB

A'B

SCHEME 13. I-Syn-diaxial interactions in ?runs-thiobinupharidinemethiodides.

CH3

$ 0

0

68

0

6. OXAZOLE ALKALOIDS

27 1

V. Bacterial Oxazoles A. PIMPRININE, PIMPRINETHINE,

AND PIMPRINAPHINE

The bacterial oxazoles span a wide range in structural complexity. The most simple are the indolyl compounds pimprinine (70), pimprinethine (71), and pimprinaphine (72). All three compounds, which are colorless and crystalline, cooccur in Streproverticillium olivoreticuli (28), with pimprinine (70) having

H

70 Pimprinine R = CH3 71 Pimprinethine R = CH2CH3 72 Pimprinaphine R = CHzC6H5

been previously isolated from Strepromyces pimprina by Bhate et al. (29). The structure of compound 70 was elucidated by Joshi et al. (30)by a combination of degradation and synthesis. Pimprinethine (71), discovered by chemical screening of Streptomyces cinnamomeus, was subjected to X-ray crystallography which indicated that the S-cis conformation as illustrated in 70-72 is preferred (31). The indolyl oxazoles are regarded as masked tryptamines, and the published syntheses inevitably employ tryptamine derivatives as starting materials. For the first preparation of pimprinine (70) (Scheme 6), 3-aminoacetylindole hydrobromide 73 was acetylated, and the diacetyl derivative 74 thus formed quantitatively was cyclodehydrated with phosphorus oxychloride to N-acetylpimprinine (75), acid hydrolysis of which yielded 70 (30). The syntheses of Oikawa et al. (32, 33) are biomimetic in that DDQ was used to simulate the action of the then recently isolated crystalline hemoprotein from Pseudomonas known as tryptophan side chain a,p-oxidase (34). The natural products 70-72 as well as a number of related compounds were prepared by this method. N-Acetyltryptamine 76, on treatment with 2 equiv DDQ under anhydrous conditions, gave pimprinine (70) in only 10% yield (32). Reaction of the

SCHEME6. Preparation of pimprinine (70).

272

HELEN M . JACOBS AND BASIL A. BURKE

a-pTcH3 \

ZDDQ, 50 min,THF argon reflux

N

"

~

70

76

N-acyltryptamines 76-78 with DDQ in aqueous THF gave good yields of the 3acylamido indoles 79-81 which were then cyclodehydrated to the natural products 70-72 (32).

a-firR \

H N

76 R = CH3 77 R = CH2CH3 78 R = CH2CgH-j

ZDDQ, THF - HzO

RT

*O-J!'~ -

poci3 70 71

\N

H

72

79 R = CH3 80 R = CH2CH3 81 R = CHzCgHs

The mechanism of the DDQ oxidation under anhydrous conditions [shown for the formation of pimprinine (70)] is thought to involve dehydrogenation to 82 followed by intramolecular nucleophilic addition to form the dihydrooxazole 83; a second dehydrogenation yields intermediate 84 which isomerizes to the alkaloid 70. The low yield of 70 obtained from this reaction was rationalized on the

basis that the second step, 82 to 83, requires a strongly electron-releasing substituent on the carbonyl carbon for the reaction to proceed smoothly. Under aqueous conditions the dehydro compound 82 is probably hydrated to the Phydroxytryptamine derivative 85, dehydrogenation-isomerization of which yields the P-keto compound 79 (32, 33).

213


For the preparation of 70-72 Koyama er af. (28)employed the 5-3'-(indolyl)oxazole 88 obtained from ethylindole-3-carboxylate (87) and isocyanomethyl lithium. The oxazole 88 was refluxed in acetic anhydride-acetic acid or propionic anhydride-propionic acid to afford pimprinine (70) and pimprinethine (71) in 13 and 19%yield, respectively. Hydrolysis of these reaction mixtures and that produced with phenylacetic acid anhydride-phenylacetic acid gave high yields (84-92%) of the 3-acylamidoindoles 79-81, which could be smoothly cyclized with phosphorus oxychloride to the natural products 70-72 (28). OCH2CH3

LiCH>N =

g

-60" to -30" llh

H 87

/

H

(RC0)20, RCOzH

H

70 R = CH3 71 R = CH2CH3 72 R = CHzCgHg

H

79 R = CH3 80 R = CH2CH3 81 R = CHzCgH5

B. GROUPA PEPTIDE ANTIBIOTICS OF THE

MIKAMYCIN/STREPT~CRAMIN/VIRGINIAMYCIN FAMILY The structural complexity and plurality of sources of this relatively small group of group A peptide antibiotics (six members) are such that tremendous nomenclatural problems have arisen, with one compound having as many as four synonyms (35).The distinct structures recognized thus far are griseoviridin (89), virginiamycin M1 (ostreogrycin A, 90), virginiamycin M2 (ostreogrycin G, 91), madumycin I1 (A2315A, 92), madumycin I (93), and A170002C (94). These

274

HELEN M. JACOBS AND BASIL A. BURKE

34

29

0

28

89

OH

Me

0

OH

Me

33

32

31

H

30

90

NAo H

91

+; 0

\

0

OH

Me

93

OH

O N ' H

OH

Me

H

94

OH

95

compounds are regarded as modified cyclic depsipeptides. They occur as complexes with the B series of these antibiotic families (which do not contain the oxazole moiety), with which they are synergistic in regard to their activity against gram-positive bacteria. This activity is significant enough to have merited considerable effort in structure elucidation, conformational and configurational studies, structure-activity relationships, biosynthetic studies, and approaches to total synthesis of the members of the A series.

275


Griseoviridin (89), isolated from Srrepromyces griseus (36),was the first compound of the group to have been assigned a structure, 95, the result of largely chemical evidence (37-42). Structure 95 which does not contain the oxazole moiety was subsequently revised to the present structure 89 largely on the basis of NMR and mass spectroscopic data as well as X-ray crystallography (43, 44). Griseoviridin (89) is one of only two members of the series whose absolute configuration is known. The early degradative studies had, by the isolation of D-cysteine from a hydrolysate of griseoviridin, established the absolute configuration at C-24 (38) so that the configuration at C-2, C-13, and C-15 could be deduced from subsequent X-ray analysis as R , S, and R, respectively (43, 44). The carbon-carbon double bonds are both trans, as are the amide linkages (44). The bond lengths within the oxazole portion indicated that the charged canonical forms 97 and 98 each contribute approximately 10% to the overall structure, with the unchanged species 96 making the major contribution of 80% (43).

-

NY

96

-

NY

97

-

08

0 N
G O

0

126

O ' Et

127

correspondence between the spectral data of 127 and that expected for 125 necessitated the application of chemical methods to establish the identity of 127 (75). In preliminary studies the methyl group of 2-methyl-4-carboxyoxazole113 was entirely resistant to all attempts at deprotonation (70). Treatment with various bases (under conditions favoring both kinetic and thermodynamic products) followed by deuteration or alkylation yielded products substituted at position 5 only (70). As an alternative to the alkylation of 113 for the preparation of compounds of type 103-105, 110, and 111, Meyers et af. developed a variant of the Cornforth oxazole synthesis. This had been used previously to prepare 113-115 (67, 70). In this scheme, the imino ether 128, the adduct of methanol, HCI, and acetonitrile, is condensed with methyl glycinate (129) to yield 130, which is formylated to 131. Deprotonation of the formyl anion 131 at the incipient 2-methyl position of the oxazole followed by alkylation with the electrophile of choice [in this case the acetonide 132 derived from (S)-malic acid] and Lewis acid-

NH.HCI

129

128

1.

0 131

130

OCH?

LDA.THF

3. ZnCl2

0

I

* O

N

28 1


mediated ring closure affords the 2-substituted-4-carbalkoxyoxazole111 as a mixture (67). Initial attempts by Fujita et al. to effect alkylation at the methyl group of 2methyl-4-carbo-tert-butoxylcarbonyloxazole(116) entailed blockage of the 5 position with a trimethylsilyl group by preparation of 133 (76). Treatment of 133 with n-butyllithium, tert-butyllithium, and sodium hydride, followed by methyl iodide in each case, yielded the ketone 134, the 5-tert-butyl derivative 135, and the starting ester 116, respectively, with no evidence of deprotonation-alkylation of the methyl group (76). Resort was therefore made to haloOBut

116

I

0-7

tBuLi, THF TMSCI -98" - -78"

n-BuLi, THF Me,,/

f o

Y OButY

TMS

C

0

133

H

3

TMS

.

qe" L , T H-98" F

0

NaH, 18-crown-6 THF Mel,RT \A

CH3

134

OBut

0

o*yCH3 tBu

0

q

135 7

C

H

3

116

genation-sulfonation of 116 to form compound 136,2-benzenesulfonylmethyl-4tert-butoxycarbonyl-I ,3-oxazole (BSMBO), the synthetic equivalent of anion 118. Side chain alkylation of 136 was easily effected by deprotonation with sodium hydride and addition of any one of a number of electrophiles. The initial alkylation products were then reductively desulfonated with AI-Hg, overall yields from BSMBO (136) ranging between 55 and 86% (76). A synthetic equivalent of cation 117 was identified in 2-bromomethyl-4-tert-butoxycarbonyl1,3-oxazole (BMBO, 141) prepared by NBS treatment of 116 (68). BMBO could be made to react with a variety of nucleophiles in fairly good yield (68). Ganem's solution to the problem of side chain alkylation of 2-methyl-4-carbalkoxyoxazoles entailed formation of the dianion 143 of the 5-silyl acid 142, addition of electrophile, and quantitative desilylation to afford products 145a14% in yields of 77-90% (77).

OBut

OBut NBS, CC14, hu $SOzNa.2H20 MeCN, 18-crown-6

0 - 7 ~ ~ 3

0

2.5 tBuLi,THF -40" STMSCI

116

2 tBuLi THF, -78"

L

0

i

TMS

o

2

143

c

-

CH2 ~ Li~

E' TMS

144

a) E = CH3

b) E =

X? OH

145

a) E = CH3

b) E =

X? OH

283


There have been two reports of elaboration of the oxazole moiety. Meyers et al. (67) resolved the racemic alcohols 111 via the cyclic acetal of the syn secondary hydroxy groups of 146, formed by reaction with the dimethyl acetal of mesityl aldehyde. The free anti alcohol 111 could be recovered from this process.

CH2C12, 0".48h

O

OH G O\(

OH

0

O Y O Ar

111 ( 1 : l mixt.) S

O

O

Y

C

H

3

/=&oc"3 O

N

111

Y

146

N

k,

147

Careful 'H-NMR analysis of the aldehyde 147derived from 146 by Swern oxidation established the syn relationshipof the oxygens of the cyclic acetal and hence the R configuration at C-15 (griseoviridin numbering) as the configuration of C-13 was S, consistent with its derivation from (S)-malic acid (67). This 13S,15R configuration has been designated for griseoviridin (44) although the formulation 89 (43, 44) for the natural product suggests that the stereochemistry is in fact 13S,15s. Combination of 147 with the imine phosphonate 148 afforded the pure trans aldehyde 149, while replacement of 148 with the trimethylsilylimine 150 gave the methyl analogs 151 as a 3: 1 mixture of E and Z isomers. This ratio was converted to a 14: 1 E:Z mixture by heating with pyridine hydrochloride (67). Elongation of aldehydes 149 and 151 to the ally1 amines 103 and 105 was accomplished by application of the Schweizer reaction-essentially a Wittig reaction of the adduct of sodiophthalidimide and tri-n-butylphosphonium bromide with an aldehyde. The geometry of the double bond of the alkyl phthalidimide derivatives 152 and 153 formed in this reaction was exclusively E. Liberation of the amine and 1,3-diol functionalities of 152 and 153 was accomplished by hydrazine reduction followed by acid and then base treatment (78).

284


YY O Y O

147

Ar

I

Pyr-HCI

E ( 1 5 : 1)

z

A O C H 3

O

9

N

+l-/H R o II

O Y O

0

Ar

149 151

R = H R = CH3

I 52 153

II

/H2NNH2 2. HCI 103 105

3 . Base

R = H R = CH3

285


Model experimentsgeared toward elongation of the 2-methyl-4-carbalkoxyoxazole for the synthesis of the virginiamycins have been completed by Fujita (71). One of these consists of base-mediated condensation of 2-benzenesulfonylmethyl4-tert-butoxycarbonyl-1,3-oxazole (BSMBO, 136) with the asymmetrically synthesized derivative 154 of acetyl-4(R)-methyl-5(S)-phenyloxalolidine-2-thione (AMPOT, 155) to afford 156, an analog of the virginiamycin fragment 104 (71). Product 156 has the correct stereochemistry at the position corresponding to

136

155

0

154

156

C-13 in the natural product. This chirality is-derived from 154 which itself was prepared by enantioselective alkylation of 155 with 3-methylbuten-2-a1, the heterocycle of 155 functioning as a chiral auxiliary (71). C. OXALOMYCIN, NEOOXALOMYCIN, CURROMYCIN A, AND CURROMYCIN B

The four related compounds oxalomycin (157), neooxalomycin (158), curromycin A (159), and curromycin B (160) were reported in 1985; 157 and 158 were isolated from a yet to be identified Streptomyces species (79, 80) and 159 and 160 from an ethidium bromide-treated strain of S. hygroscopicus (81, 82). The absolute configuration of oxalomycin (157) and neooxalomycin (158) has been determined by application of a combination of X-ray crystallography and chemical correlation to degradation products, the important derivatives being the p-bromobenzoate 161, obtained from 157 by ozonolysis-reduction, acetylation, partial hydrolysis, and reacylation with p-bromobenzoyl chloride, and the erythro acetate 162 which was obtained along with the threo compound 163 after acetylation of the ozonolysis products of 157 (79, 80). No stereochemical infor-

286


N H

158

neooxalomycin

0

" i " " V H

159 160

A d

R = CH20CH3 R = CH3

curromycinA curromycin B

0

OAc

161

162

1 63

mation is incorporated into the structures given for curromycin A and curromycin B , nor has there been any speculation concerning the origin of the oxazole ring.

287


D. BERNINIAMYCIN

Berniniamycin, a complex peptide antibiotic substance produced by Streptomyces bernensis (83),was on careful purification found to consist of two similar compounds, berniniamycin A and berniniamycin B . Berniniamycin A, the major component, was after extensive spectroscopic and degradative studies shown to possess structure 164 (84-85). One of the key degradation products

/

NH

N q p 4 2 C

co

I

I

c,

HN

I

c?

CH2

H2C

CH

=i /

oxazole A

NH

I

co /

{

NH

H3C-

C-NH H2C4

HN-CO

I co \

NH / \ CH CO-C

I

H /N\

\ CHr

H3C-C-OH

I

CH3

164

OH

165

I

C'CH2

/

co

288

HELEN M.JACOBS AND BASIL A . BURKE

166 167

R = CH3 R = C2H5

was the novel compound berniniamycinic acid (165), the structure of which was established by X-ray crystallography (84). The presence of the oxazole moieties was inferred from the occurrence of 166 and 167 and derivatives thereof in products of reduction and methanolysis of berniniamycin A (85). The remainder of molecule 164 is composed of five units of dehydroalanine, one of hydroxyvaline, and one of threonine (86). Feeding experiments utilizing I4C-1abeled precursors, notably DL-[ 1-I4C]serine, ~-[U-I~C]serine, DL-[1-l4C]alanine, and ~-[U-~~C]cysteine, led to high incorporation of L-serine in the dehydroalanine residues, with the incorporation of alanine being only 1% that of serine (87). This suggests that the dehydroalanyl fragments in 164 arise by dehydration of serine and not by dehydrogenation of alanine, the latter being thought to be one of the operative steps in the conversion of L-alanine to D-alanine in the biosynthesis of madumycin I1 (60). Significant incorporation of labeled serine, cysteine, and L-alanine into berniniamycinic acid (165) was also observed. Appreciable incorporation of threonine is attributed to its utilization in the threonine unit, all of oxazole B, and part of oxazole A, the remainder of which consists of a dehydroalanyl fragment (88). E. CALCIMYCIN (A23 187) AND NOCOBACTIN

The compounds calcimycin (A23187, 168) and nocobactin (187) contain the common feature of an oxazole ring but otherwise differ widely in functionality; they are grouped together on the basis of their being cation ionophores. Calcimycin (A23187, 168) occurs in Streptomyces chartreusensis, from which it may be isolated as the mixed magnesium-calcium salt (89, 90). The structure of the free acid, a crystalline solid, was determined spectroscopically to be 168

NHMe

168 169

R = H R = CH3

CO2R

289


(91). This was confirmed, and the relative configuration was determined by Xray crystallography, which also indicated the presence of three intramolecular quasi-ionic attractions in the solid state between one carboxylate oxygen and the nitrogens of the pyrrole and benzoxazole and between the other carboxylate oxygen and the amine nitrogen (91). On the basis of precedent in polyether compounds containing spiro six-membered rings, calcimycin was tentatively assigned the absolute configuration shown (91). The free acid 168 and its calcium complex have been subjected to rigorous conformational analysis utilizing I H- and l 3 C-NMR spectroscopy and molecular modeling studies (92).Measured spin-lattice relaxation and rotational correlation times confirm that the calcium complex is comprised of two molecules of 168 and one calcium ion. Absence of line doubling in the spectra of the complex indicates C, symmetry. The planarity of the pyrrole and benzoxazole portions and the rigidity of the spiroketal allow for the identification of two “hinge” regions in the molecule where rotation is relatively unhindered, i.e., the C-9-C-10 and the C-18-C-19 single bonds. Changes in dihedral angle (derived from H-H coupling constants) in going from free acid to calcium complex suggest that the major conformational adjustment consists of a 20-40” change in dihedral angle about the C-9-C-I0 single bond, an observation which was germane to the generation of a model for the complex. The model is comprised of two pseudocyclically folded calcimycin molecules disposed around the central cation which binds to one carboxyl oxygen and to the pyrrole and the oxazole nitrogens of each calcimycin molecule (92). A number of halogenated derivatives of 168 have been prepared and assessed for efficiency and specificity of divalent ion transport (93). Two formal total syntheses of calcimycin have been achieved (94-96). They are similar in concept in that the retrosynthetic analyses entail disconnection of the 1,7-dioxaspir0[5.5]undecane moiety of 168 to the ketodiol precursor 170 which would readily yield calcimycin on acid-catalyzed cyclization (spiroketalization). Further retrosynthetic fragmentation of ketodiol 170 into the pyr-

tOzR

OR2

171

0

1 72

173

COOH

290


role derivative 171, ketodiol 172, and benzoxazole 173 affords the initial target compounds. The most challenging of these is the ketodiol 172, and the major thrust of both syntheses (and the main difference between them) is the enantioselective preparation of the aldehyde 175 which is the synthon of 172.

175

In both syntheses the benzoxazole synthon 176 was prepared from methyl 5hydroxyanthranilate (177), the amino group of which was trifluoroacetylated to give 178. Nitration of 178 gave the 6-nitro derivative 179 as the major product (in a 2: 1 mixture with the 4-nitro compound); catalytic reduction to the 6amino-5-hydroxy compound 180 was followed by refluxing with acetyl chloride in xylene to afford the benzoxazole 181, N-methylation of which yielded 176, the overall yield from 177 being 60% (94).

C02CH-j

176

COJCH3

177

NHCOCF3 C02CH3

178

C02CH3

179

Condensation of the aldehyde 175 with the lithiated derivative of benzoxazole 176 gave an 88 : 12 mixture of chromatographically separable diastereomeric al-

29 1


cohols in which the desired compound 182 was predominant. Treatment of 182 with oxalic acid yielded the dihydropyran 183 from which the silyl and trifluoroacetyl groups were removed with tetra-n-butylammonium fluoride. Collins oxidation of the alcohol and condensation of the resultant aldehyde 184 with the zinc enolate of the pyrrole derivative 185 yielded a mixture of erythro and threo aldol adducts 186. Treatment of 186 with an acidic ion-exchange resin gave the methyl ester of calcimycin 169. The resin effected equilibration to the more stable configuration at the epimerizable center as well as spiroketalization and deprotection of the pyrrole nitrogen (94). The free acid obtained by hydrolysis of the synthetic methyl ester was identical in all respects including optical properties with natural calcimycin (168), thus establishing that the absolute configuration of 168 is as illustrated (94).

LiHzC 0

OH

H

HONH CO2H CH3

190 asteroidic acid

I

(CH2)4 -I-

I

H2NCHCOzH

+

CH3C02H

19 1 E-hydroxyl ysine

UV characteristics of the natural product, while further hydrolysis (under acid conditions) yielded asteroidic acid (190)-the chromophoric fragment-together with E-hydroxylysine (191) and acetic acid (97). For the synthesis of asteroidic acid (IN),N-salicyloylglycine (192) was condensed with triethyl orthoacetate to afford 2-(o-hydroxy)phenyl-4-(1 '-ethoxy)ethylidene-5-oxazolone (193). This product on treatment with base underwent Cornforth rearrangement,

293


192

193

via loss of ethanol, ring opening, and recyclization (98),to yield 190, identical to the naturally derived compound ( 9 7 ) . The neutral products from the initial base hydrolysis of the natural compounds were shown to be cobactin acid NA (189) ( 9 7 ) . Mycobactin M (194), isolated from certain Mycobucterium species, differs from nocobactin NA by one oxidation level in the five-membered heterocycle and the length of the side chain, possessing an oxazoline instead of an oxazole ring. These heterocycles are thought to originate from L-threonine (97 ).

H

194

OH

n = mainly 15and 17

F. CONGLOBATIN Conglobatin (193, a C, symmetrical 16-membered macrodiolide, is produced by Streptomyces conglobutus (99).Its structure and relative configuration were determined by X-ray crystallography, and the absolute configuration illustrated was assigned by analogy with other C , symmetrical macrolides (99).To date no biological activity has been reported for this compound.

294


The total synthesis of conglobatin has been completed by Seebach and Schregenberger (100, 101), the main challenges being the enantioselective preparation of the monomeric hydroxy acid 1% and its dimerization-cyclization. The

Rl =

196 R = H 196a R = H 196b R = CH2CC13

H

= AC Rl = H Rl

alcohol 201 could be produced as a 1 :1 mixture of epimers either by addition of the lithium enolate of N,N-dimethylacetamide (198)to the half-ester 197 followed by borohydride reduction of 199 or by addition of 198 to the aldehyde 200. The chirality of the C-methyl groups in both 197 and 200 derives from that of ( -)-(2.9,4R)-2,4-dimethylglutaric acid. I I

OCH3

II

HO,C*

OLi 198

-C O 2 H

I

197

0 II

0 I1

N,

199

NaBH4, EtOH

Formation of the racemate of the oxazole 196 was effected by Schollkopf's method: addition of lithiated methyl isonitrile to the amide function of 201 (102, 103).The most efficient dimerization of seco acid derivatives 1%-196b entailed 20 1

LiCH2-N = C

*

196

reaction of the mixed anhydride of 1%a and 2,4,6-trichlorobenzoic acid, formed in siru, with the trichloroethyl ester 1%b. Cyclization of the hydroxy acid 202a obtained by hydrolysis of the diester 202 was effected by high-dilution mixed anhydride-acylation methodology and yielded a mixture of four conglobatins which were separated chromatographically. The optical rotation of the synthetic compound of the absolute configuration designated in 195 was opposite in sign to that of the natural product, necessitating a reversal of the assigned chirality of the asymmetric centers of natural conglobatin (100, 101).

295

6 . OXAZQLE ALKALOIDS

+

CI C 3CH O JzC z-

1966 OH

0

VI. Biological Activity No biological testing or activity has been reported for annuloline (1) or the Rutaceae oxazoles, although a number of rutaceous plants from which oxazole alkaloids have been isolated are used in indigenous systems of medicine. The leaves and fruits of Aegle murmelos, which produces 0-isopentenylhalfordinol (19) (11, 104), are prescribed as a cure for intestinal ailments; Amyris plumieri, a source of 0-isopentenylhalfordinol(19) (13), 0-geranylhalfordinol (21), and 2-pyridyl-5-(3-methoxy-4,5-methylenedioxy)phenyloxazole (25) (13) is purported to be useful against cancer (105). The marine oxazoles ulapualide A (62) and ulapualide B (63)appear to function as defense substances for the nudibranch egg masses that produce them as these eggs evidently have no natural predators (25). Ulapualide A and B are reported to inhibit L1210 leukemia cell proliferation and the growth of Candida albicans (25). The related compound kabiramide C (64) has been identified as the active antifungal principle in lipophilic extracts of egg masses of an unknown nudibranch ( 2 6 ) . Organisms against which the extracts were found to be active include Candida albicans, Aspergillus niger, Penicillium citrium, and Trichophyton interdigirae ( 2 6 ) . Among the indolyl bacterial oxazoles 70-72, pimprinine (70) has been reported to be antiepileptic (106). It has also been shown to possess monoamine oxidase inhibitory activity (107).

296


Griseoviridin (89), virginiamycin M1 (90), and virginiamycin M2 (91) have long been known to be individually bacteriostatic and, with the cooccurring B components of the mikamycin/streptogramin/virginiamycinseries, to display synergistic bacterial activity against gram-positive bacteria. Most of the B compounds are cyclic heteroderic peptides of general structure 203. These com-

aoH co I

NH

R’

CH, -CH2\

I I I C ,H2 M e - CH - CONH - CH - CON - CH I

0

I

I

CO

I NR2

I

CH2

I

CH2

pounds are topographically quite similar to the members of the A series (52, 108) . although differing widely in functionality. Madumycin I1 (A2315A, 92) is unique among the group A compounds in that it occurs alone, without a corresponding member of the B series (56, 60). A number of these antibacterial complexes have found clinical application in human and veterinary medicine and are widely used as feed additives for growth promotion in domestic animals. The literature to 1979 regarding the range of activity, mode of action, and applications of antibiotics of the virginiamycin family has been comprehensively reviewed by Cocito (108). Although subject to challenge (109) the prevailing view is that these complexes inhibit bacterial protein synthesis by the transient binding of a member of the A series to the 5 0 4 ribosomal subunit. This produces a stable conformationalchange in the ribosome, increasing its affinity for members of the B series. The virtually irreversible binding of the B compound, thus facilitated, blocks the elongation of the peptide chains (108, 110, 111). Aspects of this process which have been studied include the kinetics (112) and the action of ions and pH (113). The effect of the antibiotics on polypeptide formation in cell-free systems has also been explored


297

( 1 14) as has the action of virginiamycin M on the peptidyltransferase ( 1 15). Results from the latter study indicate that both the acceptor and donor substrate binding sites of the peptidyltransferase, which interact with the aminoacyl portion of tRNA, change irreversibly after exposure to virginiamycin M ( I 15). Structure-activity studies (116,117) on virginiamycin M1 (90) have established the importance of the macrocyclic ring and the 13-OH group. Oxidation of the latter resulted in loss of activity, whereas the products of nonstereoselective reduction of the C- 15 carbonyl group retained biological activity ( I16,I I7 ). Virginiamycins have been demonstrated to enhance lactation in ruminants (118)and to protect HeLa cell monolayers infected with Herpes simplex type I virus ( I19). Oxalomycin (157) and neooxalomycin (158) were obtained in an Ehrlich ascites tumor assay-directed isolation and therefore display inhibitory activity against these cells (79,80).Oxalomycin (157) is also active against P388 leukemia and gram-positive bacteria (79).Investigations probing the structureactivity relationship, with respect to L12 10 cells, around the 5-substituted oxazole of 157 are in progress as compounds containing this moiety exhibit in vitro cytoxicity (80).Curromycin A (159) and curromycin B (160) are very similar in activity, having antibacterial action against Bacillus subtilis and Pseudomonas cepacia and being cytotoxic to B 16 melanoma and mouse P388 leukemia cells

(81,82). Berniniamycin (164) has been reported to adversely affect the growth of grampositive bacteria, notably Bacillus subtilis in packed yeast, in vitro. The compound has evidently not found chemotherapeutic application, however, as it is reported to be relatively inactive against the same types of organisms in vivo (120). Berniniamycin is an inhibitor of protein biosynthesis, the site of action being the ribosomes, where it is thought to interfere with various functions, e.g., tRNA release, movement of peptide chains, and/or movement of mRNA (120). The mechanism whereby the producing organism Streptomyces bernensis tolerates its own product has also been elucidated (121). Streptomyces bernensis has been found to possess ribosomal RNA methylases which effect specific pentosemethylation of 23 S ribosomal RNA, thus conferring resistance to berniniamycin (164) on its ribosomes (121). Calcimycin (A23187, 168), although described as an antibiotic, has found its most useful application as a specific divalent cation ionophore, transporting cations through lipophilic biological membranes (89,90). This compound is widely used as a tool to probe and elucidate the role of divalent cations in various physiological processes, at both the cellular and subcellular levels. A sizable body of literature now exists which details the results of studies on the calcium-magnesium sequestering effect of 168 on oxidative phosphorylation, ATP hydrolysis (89,90),and other processes (92,122). The ferric complex of nocobactin NA (187) is produced by Nocardia as-

TABLE 111 PHYSICAL A N D SPECTROSCOPIC DATAOF OXAZOLE ALKALOIDS

Alkaloid name Annuloline (1)

Molecular formula C,,H,,NO,

Melting point (solvent) (reference) 105-106°C (benzenepetroleum ether) ( I ) HCI 174- 177°C (EtOH)

UV, nm (solvent) (reference)

Max. 354 (log E 4.48). min. 285 (3.85) (cyclohexane) ( I )

(1)

Halfordinol (16)

C,,H ,,,N,O,

Picrate 216-218°C (EtOH) ( 1 ) 255-256°C (MeOH) (6)

N-Methylhalfordinium chloride

C,H,,N20,CI

235°C (dec.) (6)

Halfordine (17)

C,,H,,N,O,

163-164°C (MeOH) (6)

Halfordinone (18)

C ,,H ,8N203

0-Isopentenylhalfordinol (19)

C,,H,,N,O,

132- 133°C (Me,CO-petroleum ether) (6) 115-118"C(MeOH)(12)

17H ISN0,

99- 100°C (hexane) (18)

255 (log E 4.02). 323 (4.39) (EtOH) (16)

98-99°C (EtOH) (14)

266 (log E 3.92). 306 (sh, 3.90), 326 (4.14), 348 (3.61) (EtOH)

(23

Balsoxin (25)

O-Methylhalfordinol (22)

C15H12N202

265 (log E 4 . 1 3 , 305 sh (3.8), 362 (4.15) (6) 253 (log E 3.93), 330 (4.21) (EtOH) (6) -

250 (log E 4.06), 261 (4.03). 328 (4.40) (EtOH); 261 346 (4.24) (EtOH- HCl) (12)

(14)

0-Geranylhalfordinol (21)

C24H26NZO2

Oil

298

IR, cm-' (medium) (reference)

IH-NMR, 6 (solvent) (reference)

I3C-NMR (solvent) ( 6)

Mass spectrum (reference)

966 ( 2 )

3400, 1620, 1610, 1510, 1460, 1260 (nujol) (6) -

340 (M'), 238 (100%) (6) -

-

-

1616, 1605, 1582, 1175, 822 (CHCI,) ( 1 2 )

1.80(6H. bs), 4.70(2H, d, J 6.5 Hz), 5.62 (IH. t, J6.5), 6.44 (2H. d, J 9), 7.43 (IH. m), 7.47 (IH, s), 8.44 (2H. d, J 9). 8.47 (IH, dt, 5 7 , 1.8 Hz), 8.52 (IH, d, J 5), 9.47 (IH. bs) (CDCI,) ( 1 2 ) 1603, 1508 (CHCI,) ( 1 6 ) 3.89,3.94 (ea. 3H. s), 6.87 (IH, d, J 8 Hz), 7.28 (IH, s), 7.33 (4H. m), 8.04 (3H, m) ( C w I , ) (16) 1618, 1600, 1500, 1460, 3.83 (3H, s), 6.95 (2H. d, J 8.5 Hz), 7.32 1412, 1300, 1260, (IH. s), 7.33 (IH, dd, 1180 (CHCI,) ( 1 4 ) J 8.5, 5). 7.63 (2H. d, J 8.5), 8.30 (1H. d, J 8), 8.64 ( I H, d, J 5). 9.28 (IH, s) (CDCI,) (14)

1615, 1607 (CHCI,) (13) 1.62, 1.68, 1.95 (ea. 3H. s), 1.95-2.45 (4H. m), 4.57 (2H, d), 4.95-5.62 (2H. m), 7.30(1H, s), 7.60 (2H, d), 7.43-9.25 (4H) (CDCI,) (13) 299

306(12.7%), 238 (loo), 210, (4.4). 209 (2.3). 183 (31.9) (12)

252 (M', 100%) 273 (86). 224 (20). 209 (68). 197 (82). 182 (82), 167 (52), 154 (62). 146 (32). 135 (78). 126 (SO), I17 (32). I12 (49). 92 (6% 78 (65). 63 (65). 51 (62) ( 1 4 ) -

(continued)

TABLE 111 (Continued)

Alkaloid name

Molecular formula

Melting point (solvent) (reference)

Compound 24

CI6Hl2N2O4

188-189T (13)

Texamine (26)

Cl6HlINO,

134- 137°C (EtOAc-hexane) ( 1 7 )

Texaline (27)

C15H10N203

UV, nm (solvent) (reference) 205 (log E 4.37). 247 (4.00). 331 (4.18) (EtOH); 213 (4.37). 267 (4.01), 347 (4.03) (EtOH-HCI) (13) 215 (log E 4.53). 253 (4.39), 324 (4.63) (MeOH) ( 1 7 )

171-174°C (EtOAc-hexane) ( 1 7 )

202 (log E 4.64), 221 (sh), 257 (4.24). 331 (4.50) (MeOH), 264, 348 (MeOH-acid) (17)

Oil Oil

246 ( E 33,000) (25)

C4XH71N50i4

Colorless, noncrystalline solid

245 ( E 2600) (26)

Pimprinine (70)

C12Hl,N20

205°C (30)

Pimprinethine (71)

C,,H12N20

161°C (CHCI,) ( 3 1 )

224 (log E 4.36), 266 (4.17), 284 (sh, 4.07). 300 (sh, 4.02) (EtOH) (30) 295 (sh), 278 (sh), 266 ( E 14.100). 244 (22,200) (MeOH);304(19,900), 283 (sh), 270 (sh), 219 (23,800) (MeOHHCI) (31)

Pimprinaphine (72)

C,,H 1 4 N 2 0

200-201°C (28)

Ulapualide A (62) Ulapualide B (63). Ialo -21.7' (0.138, MeOH) (25) Kabiramide C (64).[a], +20° (0.1, CHCI,) (26)

C5,H,N,OI, 5' 1

H74N40

I6

300

225 (log E 4.44), 272 (4.19), 286 (sh, 4.15), 302 (sh, 4.10) (EtOH) (28)


'H-NMR, 6 (solvent) (reference)

13C-NMR (solvent) ( 6)

1608, 1588 (CHCI,) (13) 4.02 (3H, s), 6.08 (2H, s), 6.95 (2H, s), 7.40 (IH, s), 7.46-9.35 (4W (CDCI,) (13) 1600, 1585, 1543, 1495,

1480, 1445, 1240,948 (KBr) ( 1 7 )

5.96(2H, s), 6.84(IH, d, J 8), 7.13 (IH, d, J 1.6). 7.19 (IH, dd, J 8, 1.6). 7.27 (1H. s), 7.44 (3H, m), 8.05 (2H. m) (CDCI,) ( 1 7 )

Mass Spectrum (reference) 296 (100%). 268, 241, 240, 106.78 (13)

101.5, 105.0 (2C).

108.9, 118.4, 122.4, 122.5, 126.3 (2C). 127.7, 128.9 (2C). 130.3, 148.4 (2C). 148.4, 151.3, 160.8 (CDCI,) ( 1 7 ) 101.7, 105.1, 109.1, 118.4, 121.9, 122.7, 123.8, 124.0, 133.5, 147.6, 148.4, 148.5, 150.9, 152.2, 158.4 (CDCI,) ( 1 7 )

265 (100%). 251 (12). 237 (19), 236 (6). 210 (9). 209 (10). 180 (36). 152 (82). 121 (1 I), 105 (21). 77 (33) (17)

1608, 1580, 1568, 1485, 6.00 (2H, s), 6.87 (IH, d, J 8 Hz), 7.14 (IH, 1445, 1427, 1230,928 d, J l.6), 7.21 (IH. (KBr) ( 1 7 ) dd, J 8, 1.6). 7.32 (IH. s), 7.39 (IH, dd, J 7.9.4.9). 8.3 (1H. dt, J 8.1, 1.9), 8.67 (1H. d, J 4.8). 9.30 ( I H , s) ( C D q (17) 212.05 ( 2 5 ) 7.41 (IH, d, J 1.5 Hz) 131-170 (9C) ( 2 5 ) ;OX8.09(1H. s), 8.10 azole signals only (IH, s) (25);oxazole signals only 129.9, 131.1, 135.5, 3450, 3350, 3150, 1720, 7.55 (IH, d, J I Hz), 1650 ( 2 6 ) 8.01 (lH, s), 8.07 136.8, 137. I , 141.6, 155.5, 156.4, 163.2 (IH. s) (CDCI,) (26); oxazole signals only (CDCI,) (26);oxazole signals only 3150, 1640, 1630, 1590 2.54 (3H, s), 7.1-7.98 (6H, m), 8.40 (1H. s) (nujol) (30) (CDCl,) ( 2 8 ) 3200, 1633, 1617, 1582, 1572 (KBr) ( 3 l )

-

1.43 (3H, t, 57.5 Hz), 11.5 (q), 22.2 (t), 105.0 (s), 112.5 (d), 118.1 2.90 (2H. q, J 7.5). (d), 120.1 (d), 121.0 7.18 (IH. s), 7.25 (IH, m), 7.29 (IH, (d), 123.1 (d), 123.4 (d), 125.0 (s), 137.8 m), 7.44 (IH. m), 7.52 (IH, d, J 2.6). (s), 149.5 ( s ) , 164.5 7.85 (1H.m), 8.83 (s) CDCl,) ( 3 1 ) ( I H . bs) (CDCI,) (31) 4.18 (2H, s), 7.1-7.96 (IlH. m), 8.55 (IH, s) (CDCl,) ( 2 8 )

212 (M', 100%). 197 (36). 183 (10). 170 (6). 169 (13). 157 (22), 156 (24), 142 (38). 130 (18). 89 (13) (31)

(continued)

30 1

302



Alkaloid name

Molecular formula


UV,nm (solvent) (reference)

Griseoviridin (89). [ffb -232" (0.2, MeOH) (44)

161-163°C (dec.) (MeOH) (44); 228-230°C (37)

220.5 ( E 44,000).277.5 infl. (1500) (EtOH) (37)

Virginiamycin MI (90, ostreogrycin A), [a],-218" (0.34, EtOH)

203-205°C (EtOAc) (48)

228 (log E 4.51), 272 (4.00) (EtOH); 303 (4.20) (EtOH -HCI ) (48)

(48)

Virginiamycin M2 (91, ostreogrycin G), [a],+78" (1.36, EtOH) (54) Madumycin I1 (92, A2315A). -132" (0.375, MeOH)

122-127°C (dec.) ( 5 4 )

215 (log E 4.53) (EtOH) (54)

Noncrystalline (58)

214 (log E 4.55) (EtOH) (58)

(58)

158°C (dec.) ( 5 9 )

Madumycin l(93) A17002C (94). [aID-21" (0.95, MeOH) (59) Oxalomycin (157)

Amorphous (79)

Neooxalomycin (158)

214 (log E 4.12) (EtOH) (59)

265 ( E 28,000). 275 (34,000), 285 (27,000) ( 79) 230, 265, 275, 285 (80)

Cummycin A (159) Cummycin B (160) [QID +35" (0.I , MeOH) (82) Berniniamycin (164)

C51H50N 141' 6'

>290"C (dec.) (85)

288 ( E 19,000), 267 (sh, 15,600). 275 (19,000), 285 (sh, 14,400) (MeOH) (82) 210-280, intense broad absorption (~>15,000) (EtOH) ( 8 5 )

303



'H-NMR, 6 (solvent) (reference)

',C-NMR (solvent) ( 6 )

131.8, 145.3, and one of 477 (M'), 459,441, three signals between 366, 339, 322, 246, 153.8 and 163.9 168, 141, 138, 136, 127, 110, 108 (100%). (DMF-d,) (44); OXazole signals only 99 ( 4 4 ) 136. I or 137.2 (s), 145.4 525, 507 (49) (d), 156.2 (s) (CDCI,) (45, 64);oxazole signals only

3300, 1748, 1684, 1645, 1515 (CHCI,) (37)

7.84 ( I H , s) (DMF-d6) (44);oxazole signal only

3360, 1725, 1670, 1636 (infl.), 1619, 1584, 1537 (48. 52) (CHCI,)

7.84 ( I H , s) (CDCI,) (48); oxazole signal onty

3290, 1736, 1669, 1624, 1582, 1537 (54)

8.01 ( I H , s) (CDCI,) (54);oxazole signal only

-

3623, 3413, 1730, 1672, 1639 (infl.), 1626, 1600 (CHCI,) (58)

8.08 ( I H . s) (CDCI,) (58);oxazole signal only

135.6, 140.7, 162.2 (CDCI,) (64); oxazole signals only

8.38 ( 1 H . S) (DMSO-d, -D,O) (59); oxazole signal only 1825 (79)

1765 (SO)

3350, 1825, 1690, 1640 (KBr) ( 8 2 )

3370, 2980, 1665 (br), 1510, 1200, 885 (KBr) (85)

135.4 (s), 141.1 (d), 159.5 (s) (DMSO-d6) (59)

7.80 ( I H , s) (CDCI,); oxazole signal of diacetate (79) 7.81 ( I H , s) (CDCI,); oxazole signal of triacetate (80)

-


527 (2%). 509 (54)

503 (M', 7%), 485 (20). 467 (14) (59)

-

487 (M', loo%), 469 (25) (59)

122.4, 150.2, 160.7 (CDCI,) (82); oxazole signals only 122.3, 149.8, 160.3 (CDCI,) (82); oxazole signals only

-

134.9, 135.5, 155.0, 155.5, 157.1, 158.2 (C,D,N) (85); oxazole signals only

-

-

(continued)

304


TABLE 111 (Conrinued)

Alkaloid name Calcimycin (A23187, 168). [a],-56" (0.01. CHCl,) (94) Nocobactin NA (187) Conglobatin (19%

Molecular formula


UV, nm (solvent) (reference)

I8 1- I 82°C (acetone) (91)

C29H37N306

C3E-mH57-6,N509 124- 126°C (97) 124- 126°C (ether-hexane) (99)

C28H3EN206

[aID

-

256, 261, 267, 213, 279, 309,318 (EtOH) ( 9 7 ) 214 ( E 43,800) (EtOH) (99)

-44" (1 .00, CHCI,) (99)

reroides grown under iron-deficient conditions. The lipophilic deferri compound functions as an ionophore, sequestering and transporting iron across the lipidrich cell boundary of the bacterium (97). No biological activity has been reported for conglobatin (195).

VII. Isolation and Spectral Characteristics The physicochemical properties of oxazoles to 1972 have been comprehensively reviewed by Lakhan and Ternai (3)whose work constitutes a point of departure for this section. Mention is made here only of those properties relevant to the detection, isolation, structure elucidation, and behavior of the natural compounds. The oxazole moiety in nature is usually embedded in a variety of functionality, and the rather innocuous properties of the parent molecule do not dominate or influence the behavior of the oxazole alkaloids to the extent that these compounds can be collectively regarded as displaying any characteristic set of physicochemical properties. Table I11 lists the physical and spectral properties of the compounds covered in this chapter.

A. pK,

AND

ISOLATION

Oxazoles are extremely weak bases, oxazole itself being approximately 10,OOO times weaker in basicity than pyridine (3, 123). Virtually all of the natural compounds have been isolated under neutral conditions using standard or reversedphase chromatography, depending on the complexity of the mixture. The weak


305


IH-NMR, 6 (solvent) (reference)

I3C-NMR (solvent) ( 6)

1640, 1696 (CHCI,) (91)

-

-

523 (M'), 318, 206, 123, 94 ( 9 1 )

-

-

-

795, 767,430 (A1 complex) (97) 498 (M') (99)

1705, 1650, 1610, 1505, 1275 (KBr) (99)

6.78 (2H, s) 7.75 (2H. s) Fourteen peak spectrum oxazole signals only consistent with CZsdi(99) meric structure (99)


basicity of annuloline (1) and the attendant lack of efficiency of extraction with hydrochloric acid were notable ( I ) .

B . ULTRAVIOLETSPECTROSCOPY The UV and fluorescence characteristics of simple substituted oxazoles have been discussed in the early review, which also made mention of the utility of 2,5diary1 derivatives as scintillators ( 3 ) . Among the natural products, the 2,5-diaryl compounds halfordinol (16), halfordine (17), 0-isopentenylhalfordinol (19), balsoxin (25), O-methylhalfordinol(22), compound 24, texamine (26), and texaline (27) reportedly display a high intensity (log E 3.61-4.63) band in the range 323-354 nm (Table 111). In the 2-pyridyl-5-phenyl derivatives this band undergoes a bathochromic shift of 17-23 nm on acidification (Table III), which may be rationalized by the formation of the pyridinium salt (e.g., 204) for 0isopentenylhalfordinol (19). In 204 the 2-pyridinium substituent is obviously

H

cle

204

more electron withdrawing than the pyridyl residue of 19, causing a red shift of the long wavelength (internal charge-transfer) band (12, 123). The long wavelength maximum of pimprinethine (71) also shifts bathochromically in acid (31).

306

HELEN M.JACOBS AND BASIL A. BURKE

C. INFRARED SPECTROSCOPY The extensive functionalization of natural oxazoles is such that infrared spectroscopy is not a useful method for initial detection of the moiety. Infrared values reported in the literature for oxazole alkaloids are listed in Table 111.

D. 'H-

AND

I3C-NMR SPECTROSCOPY

The oxazole proton (H-4 oxazole numbering) of the 2,5-diaryloxazole alkaloids 19,21,22, and 24-27 appears as a sharp singlet, resonating in the range 67.27-7.47 (Table III), somewhat shielded relative to the corresponding proton in 2,5-diphenyloxazole, in which it appears at 67.82 (124). In the marine compounds ulapualide B (63) and kabiramide C (64) the protons of the trisoxazole moiety (formally all H-5, oxazole numbering) range in chemical shift from 7.41 to 8.10 (Table III), deshielded with respect to the protons in simple model systems (3) as a result of the highly unusual ensemble. For the indolyl compounds pimprinine (70), primprinethine (71), and pimprinaphine (72), H-4 (oxazole numbering) appears in the range of 68.40-8.83 (Table III), again highly deshielded relative to H-4 in simple oxazoles. The chemical shifts of the oxazole protons (H-5oxazole numbering) of the group A antibiotics of the virginiamycin family (89-94), 67.80-8.38 (Table III), are centered around 68.17, the shift observed for H-5 of 2-methyl-4-carbethoxyoxazole (3). I3C-NMRdata for some of the more complex and/or recently discovered alkaloids have been reported (Table 111). The structure of the trisoxazole portion of ulapualide B (63) was elucidated largely by analysis of fully coupled and partially decoupled I3C-NMR spectra. A series of simple oxazoles has been subjected to systematic analysis by I 3 C-NMR spectroscopy and provides useful models (125).

E. MASSSPECTROSCOPY Comparison of the mass spectral fragmentation patterns of 2,4-, 2 5 , and 4 5 diphenyloxazole with those of halfordinol (16) and halfordine (17) and elucidation of the fragmentation mechanisms (dominated by the oxazole function) of the model compounds were crucial to the confirmation of the structure of this group of alkaloids (126). In the more complex and highly functionalized natural oxazoles, however, this moiety is a less important determinant of the mass spectral fragmentation pathway. Indeed, as the complexity and functionalization of the molecule containing the oxazole moiety increase, the plethora of other functionalities tends to dwarf the characteristic spectral features of the oxazole moiety reviewed above. In these complex molecules, therefore, spectral characteristics outlined herein become decreasingly significant as indicators of the


307

oxazole moiety. Nevertheless, they remain of significant value in structural elucidation.

Acknowledgments The authors acknowledge the support of the Department of Chemistry, University of the West Indies, and the Plant Cell Research Institute (PCRI) during the preparation of this manuscript. Special thanks go to Ms. Karen Long of PCRI for presenting the manuscript in its final form.

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CUMULATIVE INDEX OF TITLES Aconitum alkaloids, 4. 275 (1954). 34. 95 (1988) diterpenoid. 7, 473 (1960) CI9diterpenes, 12, 2 (1970) C, diterpenes, 12, 136 (1970) Acridine alkaloids, 2, 353 (1952) Acridone alkaloids, experimental antitumor activity of acronycine, 21, 1 (1983) Actinomycetes, isoquinolinequinones. 21, 55 (1983) N-Acyliminium ions as intermediates in alkaloid synthesis, 32, 271 (1988) Ajmaline-Sarpagine alkaloids, 8, 789 (1%5), 11, 41 (1968) Alkaloid structures spectral methods, study, 24, 287 (1985) unknown structure minor alkaloids, 5. 301 (1955), 7, 509 (1960) unclassified alkaloids, 10, 545 (1%7), 12. 455 (1970). 13, 397 (1971), 14, 507 (1973). 15. 263 (1975). 16, 511 (1977)

Alkaloids in Cannabis sativa L.. 34, 77 (1988) the plant, 1, 15 (1950). 6, 1 (1960) Alkaloids from Ants and insects, 31, 193 (1987)

Aspergillm, 29, 185 (1986) Rzuridiantha species, 30, 223 (1987) Tabemaemontma.27, 1 (1986) Alstonia alkaloids, 8. 159 (1%5). 12, 207 (1970). 14. 157 (1973)

Amaryllidaceae alkaloids, 2, 331 (1952), 6, 289 (1960), 11, 307 (1%8), 15, 83 (1975). 30. 251 (1987)

Amphibian alkaloids, 21, 139 (1983) Analgesics, 5, 1 (1955) Anesthetics, local, 5, 211 (1955) Anthranilic acid, related to quinoline alkaloids, 17, 105 (1979), 32, 341 (1988) Antimalarials, 5, 141 (1955) Antitumor alkaloids, 25, 1 (1985) Apocynaceae alkaloids, steroids, 9. 305 (1967) Aporphine alkaloids, 4, 119 (1954), 9, 1 (1%7), 24, 153 (1985) Aristolochia alkaloids, 31, 29 (1987) Aristofelia alkaloids, 24. 113 (1985) Aspidospefma alkaloids, 8, 336 (1%5), 11, 205 (1%8). 17, 199 (1979) Azafluoranthene alkaloids, 23, 301 (1984) Bases simple, 8. 1 (1%5) simple indole, 10, 491 (1967) 311

312

CUMULATIVE INDEX OF TITLES

Benzophenanthridine alkaloids, 26, 185 (1985) Benzylisoquinolinealkaloids, 4, 29 (1954), 10, 402 (1967) Bisbenzylisoquinolinealkaloids, 4, 199 (1954), 7, 439 (1960), 9, 133 (1967). 13, 303 (1971),

30, l(1987) occurrence, 16, 249 (1977) structure, 16, 249 (1977) pharmacology, 16, 249 (1977) synthesis. 16, 319 (1977) Bisindole alkaloids, 20, 1 (1981) &xus alkaloids, steroids, 9,305 (1967), 14, 1 (1973)

Cactus alkaloids, 4, 23 (1954) Calabar bean alkaloids, 8, 27 (1965), 10. 383 (1%7), 13, 213 (1971) Calabash curare alkaloids, 8. 515 (1965), 11, 189 (1968) Calycanthaceae alkaloids, 8, 581 (1965) Camptothecin, 21, 101 (1983) Cancentrine alkaloids, 14, 407 (1973) Chpsicum species, pungent principle of, 23, 227 (1984) Carbazole alkaloids, 13, 273 (1971), 26, 1 (1985) Carboline alkaloids, 8, 47 (1%5), 26, 1 (1985) 8-Carboline congeners and ipecac alkaloids, 22, 1 (1983) Cardioactive alkaloids, 5, 79 (1955) Celestraceae alkaloids, 16, 215 (1977) Cephulotuxus alkaloids, 23, 157 (1984) Chemotaxonomy of papaveraceae and fumariaceae, 29, 1 (1986) Chinese medicinal plants. alkaloids, 32, 241 (1988) Chromone alkaloids, 31, 67 (1987) Cinchona alkaloids, 14, 181 (1973), 34, 331 (1988) chemistry, 3, 1 (1953) Colchicine, 2, 261 (1952), 6, 247 (1960), 11, 407 (1%8), 23, 1 (1984) Configuration and conformation, elucidation by X-ray diffraction, 22, 51 (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 tryptamines and tryptophans, chemistry and reactions, 34, 1 (1988) Cyclopeptide alkaloids. 15, 165 (1975) Daphniphyllum alkaloids, 15, 41 (1975), 29, 265 (1986) Delphinium alkaloids, 4, 275 (1954) diterpenoid, 7, 473 (1960) Clo-diterpenes,12, 2 (1970) C,,-diterpenes, 12. 136 (1970) Dibenzopyrrocolinealkaloids, 31, 101 (1987) Diplomhynw alkaloids, 8, 336 (1%5) Clp-Diterpenealkaloids Aconitum, 12, 2 (1970) Delphinium, 12, 2 (1970) Gunyu,12, 2 (1970) structure, 17, 1 (1970) synthesis, 17, 1 (1979)


C,-Diterpene alkaloids Aconitum, 12, 136 (1970) chemistry, 18, 99 (1981) Delphinium, 12, 136 (1970) Gurryu, 12, 136 (1970) Distribution of alkaloids in traditional Chinese medicinal plants, 32, 241 (1988) Diterpenoid alkaloids Aconitum, 7, 473 (1%0), 12, 2 (1970) Delphinium. 7, 473 (1960), 12, 2 (1970) Gurryu, 7, 473 (1960). 12, 2 (1960) general introduction, 12, xv (1970) C,,-diterpenes. 12, 2 (1970) C,-diterpenes, 12. 136 (1970) Eburnamine-Vincamine alkaloids, 8, 250 (1965). 11, 125 (1968). 20, 297 (1981) Elaeocarpus alkaloids, 6, 325 (1960) Elucidation, by X-ray diffraction structural formula, 22, 51 (1983) configuration, 22. 51 (1983) conformation, 22, 51 (1983) Enamide cyclizations. application in alkaloid synthesis, 22. 189 (1983) Enzymatic transformation of alkaloids, microbial and in vim, 18, 323 (1981) Ephedra bases, 3. 339 (1953) Ergot alkaloids, 8. 726 (1965), 15, 1 (1975) Eryfhrinu alkaloids, 2, 499 (1952). 7, 201 (1960). 9. 483 (1967), 18, 1 (1981) Erythmphleum alkaloids, 4, 265 (1954), 10, 287 (1967) Eupomufiu alkaloids, 24, 1 (1985) Forensic chemistry, alkaloids, 12, 514 (1970) by chromatographic methods, 32. 1 (1988)

Gulbulimimu alkaloids, 9, 529 (1%7), 13, 227 (1971) Gurryu alkaloids diterpenoid, 7, 473 (1960) C,,V-diterpenes, 12. 2 (1970) Cl0-diterpenes, 12, 136 (1970) Gehspermum alkaloids, 8, 679 (1%5), 33, 84 (1988) Gekemium alkaloids, 8, 93 (1965). 33, 83 (1988) Glycosides, monoterpene alkaloids, 17, 545 (1979)

Huplophyton cimicidum alkaloids, 8, 673 (1965) Hasubanan alkaloids, 16, 393 (1977), 33, 307 (1988)

Holurrhenu group, steroid alkaloids, 7, 319 (1960) Hunteriu alkaloids, 8, 250 (1965) h g u alkaloids, 8. 203 (1%5), 11, 79 (1968) Imidazole alkaloids, 3, 201 (1953). 22, 281 (1983) Indole alkaloids, 2, 369 (1952), 7, 1 (1960). 26, 1 (1985) distribution in plants, 11, 1 (1968) simple, including 0-carbolines and 0-carbazoles. 26, 1 (1985)

313

314


Indole bases, simple, 10, 491 (1967) Indolizidine, simple and quinolizidine alkaloids, 28, 183 (1986) 2,2'-Indolylquinuclidinealkaloids, chemistry, 8, 238 (1965). 11, 73 (1%8) In vim and microbial enzymatic transformation of alkaloids, 18, 323 (1981) Ipecac alkaloids, 3, 363 (1953), 7, 419 (1960), 13, 189 (1971). 22, 1 (1983) fl-CarboIinealkaloids, 22, 1 (1983) Isolation of alkaloids, 1, 1 (1950) Isoquinoline alkaloids, 7, 423 (1960) biosynthesis 4, 1 (1954) 'T-NMR spectra, 18. 217 (1981) simple isoquinoline alkaloids, 4, 7 (1954), 21, 255 (1983) Isoquinolinequinones. from actinomycetes and sponges, 21, 55 (1983)

Kopsicl alkaloids, 8, 336 (1%5) Local anesthetics, alkaloids, 5, 211 (1955) Localization of alkaloids in the plant, 1, 15 (1950), 6, 1 (1960) Lupine alkaloids, 3, 119 (1953), 7, 253 (1960), 9, 175 (1%7), 31, 116 (1987) Lycopodium alkaloids, 5, 265 (1955). 7, 505 (1960), 10, 306 (1%7), 14, 347 (1973). 26, 241 (1985)

Lythracae alkaloids, 18, 263 (1981) Mammalian alkaloids, 21, 329 (1983) Marine alkaloids, 24, 25 (1985) Maytansinoids, 23, 71 (1984) Melodinus alkaloids, 11, 205 (1968) Mesembrine alkaloids, 9, 467 (1967) Metabolic transformation of alkaloids, 27, 323 (1986) Microbial and in vim enzymatic transformation of alkaloids, 18, 323 (1981) Mifragynualkaloids, 8. 59 (1%5), 10, 521 (1967). 14, 123 (1973) Monoterpene alkaloids, 16, 431 (1977) glycosides, 17, 545 (1979) Morphine alkaloids, 2, 1 (part 1, 1952), 2, 161 (part 2, 1952). 6,219 (1960), 13, 1 (1971) Muscarine alkaloids, 23, 327 (1984) Mydriatic alkaloids, 5, 243 (1955) a-Naphthaphenanthridine alkaloids, 4, 253 (1954), 10, 485 (1%7) Naphthyl isoquinoline alkaloids. 29, 141 (1986) Narcotics, 5, 1 (1955) "C-NMR spectra of isoquinoline alkaloids, 18, 217 (1981) Nuphar alkaloids, 9, 441 (1%7), 16, 181 (1977)

Ochrosia alkaloids, 8, 336 (1%5), 11, 205 (1968) Ournuparia alkaloids, 8, 59 (1%5). 10, 521 (1967) Oxaporphine 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) Pavine and isopavine alkaloids, 31, 317 (1987)


315

Antucerm alkaloids, 8, 250 (1965) Peptide alkaloids, 26, 299 (1985) Phenanthroindolizidine alkaloids, 19, 193 (1981) Phenanthroquinolizidine alkaloids. 19, 193 (1981) fl-Phenethylamines, 3, 313 (1953) Phenethylisoquinoline alkaloids, 14, 265 (1973) Phthalideisoquinoline alkaloids, 4, 167 (1954), 7, 433 (1960), 9, 117 (1967). 24, 253 (1985) Rcdim alkaloids, 14, 157 (1973) Picraim niridu alkaloids, 8, 119 (1%5), 10, 501 (1967) Piperidine alkaloids, 26, 89 (1985) Plant systematics, 16, 1 (1977) Pleiocnrpa alkaloids, 8, 336 (1%5), 11, 205 (1968) Polyamine alkaloids, putrescine, spermidine, spermine, 22, 85 (1983) Pressor alkaloids, 5, 229 (1955) protoberbeine alkaloids, 4, 77 (1954), 9, 41 (1967), 28, 95 (1986), 33, 141 (1988) Protopine alkaloids, 4, 147 (1954), 34, 181 (1988) pseudocinchom alkaloids, 8, 694 (1965) Putrescine and related polyamine alkaloids, 22, 85 (1983) Pyridine alkaloids, 1, 165 (1950). 6, 123 (1960). 11, 459 (1%8), 26, 89 (1985) Pyrrolidine alkaloids, 1, 91 (1950), 6, 31 (1960), 27, 270 (1986) Pyrrolidine 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) Quinazolinowbolines, 8. 55 (1%5), 21, 29 (1983) Quinoline alkaloids other than Cinchom, 3, 65 (1953), 7, 229 (1960) related to anthranilic acid, 17, 105 (1979), 32, 341. (1988)

Ruuwo~ualkaloids, 8, 287 (1965) Reissert synthesis of isoquinoline and indole alkaloids, 31, 1 (1987) Reserpine, chemistry, 8, 287 (1965) Respiratory stimulants, 5, 109 (1955) Rhoeadine alkaloids, 28, 1 (1986) solamcurdm group, steroids, 9, 427 (1%7) Sceleriurn alkaloids, 19, 1 (1981) Senecio alkaloids, see Pyrrolizidine alkaloids Secoisoquinoline alkaloids, 33, 231 (1988) Senrrinegu alkaloids, 14, 425 (1973) Sinomenhe, 2, 219 (1952) Solunum alkaloids chemistry, 3, 247 (1953) steroids, 7, 343 (1960), 10, 1 (1%7), 19, 81 (1981) Sources of alkaloids, 1, 1 (1950) Spectral methods, alkaloid structures, 24, 287 (1985) Spermidine and related polyamine alkaloids. 22, 85 (1983) Spermine and related polyamine alkaloids, 22, 85 (1983) Spirobenzylisoquinolinealkaloids, 13, 165 (1971) Sponges, isoquinolinequinones, 21, 55 (1983) Stemom alkaloids, 9, 545 (1%7)

316


Steroid alkaloids Apocynaceae, 9, 305 (1%7). 32, 79 (1988) &wus group, 9, 305 (1967), 14, 1 (1973). 32, 79 (1988) Holarrhena group, 7, 319 (1960) Stahmandm group, 9, 427 (1967) S o h u m group, 7. 343 (1960), 10, 1 (1%7), 19, 81 (1981) K?mtrum group, 7, 363 (1%0), 10, 193 (1%7), 14, 1 (1973) Stimulants respiratory, 5, 109 (1955) uterine, 5, 163 (1955) Structural formula, elucidation by X-ray diffraction, 22, 51 (1983) Sfrychnos alkaloids, 1, 375 (part 1-1950), 2, 513 (part 2-1952), 6, 179 (1960), 8, 515. 592 (1%5). 11, 189 (1%8), 34, 211 (1988) Sulfur-containing alkaloids, 26, 53 (1985)

2kxu.s alkaloids, 10, 597 (1967) Toxicology, Papaveraceae alkaloids, 15, 207 (1975) ’Ifansformation of alkaloids, enzymatic, microbial and in vim, 18, 323 (1981) nopane alkaloids, 1, 271 (1950). 6, 145 (1960). 9, 269 (1967). 13, 351 (1971), 16, 83 (1977). 33, 1 (1988) Tropoloisoquinoline alkaloids, 23, 301 (1984) ’Ifopolonic Colchicum alkaloids, 23, 1 (1984) lJ4ophom alkaloids, 9, 517 (1967) Uterine stimulants, 5, 163 (1955) K?mtrum alkaloids chemistry, 3, 247 (1952) steroids, 7, 363 (1%0), 10, 193 (1967), 14. 1 (1973) “Vinca” alkaloids. 8, 272 (1965), 11. 99 (1968) Vwcanga alkaloids, 8, 203 (1965). 11, 79 (1%8)

X-Ray diffraction. elucidation of structural formula, configuration, and conformation, 22, 51 (1983) Yohimbe alkaloids, 8, 694 (1%5) Yohimbine alkaloids, 11, 145 (1%8), 27, 131 (1986), see also Coryantheine

INDEX A A170002C. 273 Abresoline, 156. 157 N-Acetyl-3,4-dimethoxy-5hydroxyphenethylamine, 110 N-Acetylmescaline, 111 N-Acetyltyramine, 109 0-Acetylursuline, 54 Aegeline, 112, 265 Alatamide, 110 7-Alkylaporphine, subtype, 17, 38 Aminoethylbenzil, 14 Aminoethylphenanthrene, subtype, 18, 46 Annonaceae, 2 Annopholine, 49, 63 Annuloline, 112. 260, 298 biosynthesis of, 261, 264 synthesis of, 260 Anolobine, 10, 44 Antioquine, 24 Apateline, 5, 9. 15, 23 Aporphinoids, in Guatteria species, 29 Aromoline, 5, 9. 21 Atherosperminine, 60 Azaanthracene, subtype, 18, 49 Azafluorene, subtype, 18, 51

B Balsamide, 265 Balsoxin, 263, 298 Belemine, 8, 13, 43 Beniniamycin, 287, 297, 302

N-Benzoyl-0-methyltyramine,110 0-Benzoylpseudoephedrine, 116 N-Benzoyltyramine, 109 Benzylisoquinolinealkaloids, 14 Bernines, from Guaneria species, 28 Berniniamycinic acid, 288

Bisbenzylisoquinolines,occurrence in Guatteria species, 20 2,2'-Bisnorguattaguianine,5, 9, 25 Bractazonine, 178, 179, 183

C

Calcimycin. 288,297, 304 Calipamine, 105 Candicine, Occurrence of, 91 Castoramine, 239 Cathinone, 116, 135 Chondodendrine, subtype, 15 Cinnamic acid phenethylamides, 265 N-Cinnamoyltyramine, 109 Cleistopholine, 49, 63 Cocculine, 201 Coclobine, 5, 9, 21 Conglobatin, 293, 304 Coryneine, 94 Coryphanthine, 101 Crassifolazonine, 178-180 Curromycin, 302

D

Daphnandrine, 5, 9, 21 Daphnoline, 5. 9, 21 Darienine, 55 Dauricine, subtype, 14 Decaline, 164 Dehydroapateline, 5,9,23 Dehydroaporphine, subtype, 17. 33 6-Dchydrodeoxynupharidine,232 Dehydroformoureghe, 6, 11, 33 Dehydmguattescine, 8, 13, 42 Dehydronornuciferine, 6, 11. 33 Dehydronupharolutin,233 Dehydrostephalagine, 6, 11 317

318

INDEX

Dehydrotelobine, 5, 9, 23 Demerarine, 22 12-O-Demethylcoclobine, 5, 9, 21 7-Demethyldeoxynupharidine,221. 222, 240 10-O-Demethyldiscretine,4, 9, 28 DemethyllasubineI, 156. 157 Demethyllasubine 11, 156 3-Demethylmescaline, 98 10-O-Dernethylxylopinine, 6, 9, 28 Deoxynupharidine, 222 Dibenzazecineq 209 Dibenzazonine alkaloids, 177 biosynthesis of, 205 from Eryrhrhrihn alkaloids, 200 Occurrence of, 179 pharmacological properties of, 209 structures of, 178 synthesis of, 183 unnatural dibenzazonines, 187 Dictamnine, 267 Dielsine, 51, 56 Dielsinol, 51, 56, 64 Dielsiquinone, 50, 64 Dihydroerysotdne, 200 conversion into dibenzazozines, 201 Dihydromelsomine, 13, 39 Dihydroonychine, 52 3,4-Dihydroxy-5-methoxyphenethylamine,98 6,6'-Dihydroxyneothiobinupharidine, 222, 227 6,6'-Dihydroxythiobinupharidine, biological activity of, 254 6,6'-Dihydroxythiobinupharidinesulfoxide, 221, 227 3.5-Dimethoxy-5-hydroxyphenethylamine,99 O,ODimethylcurine, 5. 9, 27 Nfl-Dimethyl- 3,4-dimethoxy-5hydroxyphenethylamine, 99 Nfl-Dimethylhomoveratrylamine, 98 N,ODmethylliriodendronine, 4, 12, 36 N,ODimethyllythranidine. 174 Nfl-Dimethyl4methoxyphenethylamine,93 Nfl-Dimethyl-3-methoxyt~~ne, 95 Nfl-Dimethylphenethylamine, Occurrence of, 81 4,5-Dioxoaporphineq subtype, 7, 38 Dioxymethylenecinnamic acid phenethylamide, 109 Discoguattine, 4, 11, 33, 38 Dopamine, Occurrence of, 93 Dragabine, 47

Duguespixine, 13, 44 Dysazecine, 209 from 1-phenethylisoquinolines, 211

E Elmerrillicine, 7, 11, 33 Ephedralone, 116 Ephedrines, 106 Occurrence of, 113 Ephedroxane, 116 l&Epidemethoxyabresoline, 156, 157 1-Epideoxynupharidine,221-223, 243 7-Epideoxynupharidine, 223. 243 l-Epi-7-epideoxynupharidine, 221 1-Epi-1'-epithiobinupharidine, 221. 226 6'-Epihydroxythiobinupharidine, 221, 226 2-Epilasubine 11, 162 Epinephrine, 104, 134 Epinine, 93 7-Epinupharolutin, synthesis of, 241 1-Epithiobinupharidine, 221, 226 1'-Epithiobinupharidine, 221, 226 Erybidine, 178-180 Erysodienone, 187, 202 Erythroculinol acetate, 201 Eupolauridine, 63

F Formouregine, 6, 10, 33 Formyldehydronuciferine, 44

N-Formyl-3,4-dimethoxy-5hydroxyphenethylamine, 110 N-F~rmylme~caline,111 N-Formylnormacromerine, 112 N-Formylnornuciferine, 6, 10, 33 Funiferine, 5, 9, 25 5-(3-Furyl)-8-methylocathydroindolizine,220

G Geovanine, 49 O-Geranylhalfordinol. 262, 298 Glaziovine, 7, 9. 29. 70 Gouregine, 6, 13.46, 60 Griseoviridine, 273, 2%. 302 Guacolidine, 4, t3. 43

319

INDEX Guacoline, 4, 13, 43 Guadiscidine, 4, 12, 39 Guadiscine, 4, 13, 39, 40 Guadiscoline, 4, 13, 39, 40 Guattaguianine, 25 Guattaminone, 5, 9, 26 Guattegaumerine, 20, 70 Gutterfa alkaloids, 1 alphabetic listing, 71 biosynthesis, 57 chemosystematics,65 pharmacology, 69 Guattescidine, 5, 13, 40 Guattescine, 8, 13, 40 Guattouregidine, 6, 13, 42 Guattouregine, 6, 13, 42

H Halfordamine, 267 Halfordine, 262, 298 Halfordinine, 267 Halfordinol, 262, 298 Halfordinone, 262, 298 Halostachine, 101 Haplopine, 268 Herclavine, 110 N-Homoveratroylhornoveratrylamide,110 Hornomtrylamine, occurrence of, % Hordenine, occurrence of, 88 Hydromelsomine, 39 7-Hydroxyaporphine, subtype, 17, 34 dHydroxyinychine, 52 5-Hydroxy-6-methoxyonychhe,54 6-Hydmxyneothiobinupharidine,221, 227,253 6-Hydroxythiobinupharidine, 253 6-Hydroxythionuphlutine Ei, 253 I

Isocalycinine, 4, 11, 33, 38 Isocastoramine, 221, 223 Isochondodendrine, 5 , 9, 16, 27 Isoguattouregidine, 13, 42 Isolaureliine, 44, 62 0-Isopentenylhalfordinol,262 photodegradation of, 267 Isoursuline, 54

J

Juziphine, 19

K K a b w i d e C, 269. 300 Kinabaiine, 55 Koenigine, 268 1

Lasubine I, 156, 160 Lasubhe 11, 156, 161 Laurifime, 178. 179, 182 L a u r i f i i , 178, 179. 182 Laurifonine, 178, 179, 182 Liriodendronine, 62 Liriodenine, 70 Longimammamine, 103 Lythraceous alkaloids, 155 biosynthesis of, 172 occurrence of, 172 spectroscopy of, 173 Lythrancepines I1 and 111, 169 Lythrancine V, 172 Lyfhranidine, 168

M Macondine, 53 Macromerine, 105 Madumycin I and 11, 273, 302 Melosmidine, 6, 13, 38 Melosmine, 6, 13, 38, 47 Merucathine, 116, 136 Merucathinone, 116, 135 Mescaline biosynthesis of, 138 occurrence of, 99 Mescaline citrimide, 111 Mescaline isocitrimide lactone, 111 Mescaline maleimide, 111 Mescaline succinimide, 111 Metanephrine, 104 4Methoxy-&hydroxyphenethylamine, 103 6-Methoxyonychine, 52 4Methoxyphenethylamine,occurrence of, 92

320

INDEX

2-Methoxytyramine, 95 3-Methoxytyramine, 94 O-Methylbelemine, 42 N-Methylcalipamine, 105 0-Methylcandicine, 93 N-Methylcoclaurine, 69 12-O-Methylcurine, 5, 9, 27 0-Methyldehydroisopiline, 6, 11, 33 Methyl-3,4-dimethoxy-5-hydroxyphenethylamine, 98 N-Methylelmerrillicine, 7, 11, 33 N-Methylephedrine, 115 N-Methylepinephrine, 104 Methylflavinantine, 197 Methylflavinantinol, 194 N-Methylhalfordinium chloride, 262, 298 0-Methylhalfordinol, 262, 298 N-Methylhomoveratrylamine,occurrence of, 97 17-O-Methyllythridine, 167 17-O-Methyllphrine, 167 N-Methylmescaline, 100 N-Methylmetanephrine, 104, 134 N-Methyl-3-methoxytyramine,95 N-Methylphenethylamine, occurrence of, 80 N-Methylpseudoephedrine, 115 0-Methylsynephrine, 102 N-Methyltyramine, occurrence of, 86 Morphinanedienone, 16 Mycobactin M, 293

N Neodihydrothebaine, 178, 179, 183 Neooxalomycin, 285, 297, 302 Neothiobinupharidine, 224 derivatives of. 227, 247 syn-Neothiobinupharidinesulfoxide reduction of, 236 thermal transformation of, 230 3-Nitro4hydroxyphenethylamine, 106 Nocobactin, 288, 304 Nocobactin NA, 292, 297 Noratherosperminine, 60 2-Norbababerine, 57 Norcepharadione B, 6, 12, 38 Nordragabine, 47. 62 Norephedrine, occurrence of, 113 Norepinephrine, occurrence of, 103 2‘-Norfuniferine, 5, 9, 24

2’-Norguattaguianine, 5, 9, 25 Norlaureline, 7, 10, 33 Normacromerine, 105 Nornuciferine, 6, 10, 33 2-Noroxyacanthine, 22, 57 Norpseudoephedrine, occurrence of, 113 Z’-Nortiliageine, 5, 9, 23 Norushinsunine, 61 Noruvariopsamine, 60 Nuciferidine, 7, 11, 34 Nuphacristine, 221, 224, 250 Nuphur alkaloids, 215 new alkaloids, 220 nonalkaloidal constituents, 218 pharmacology of, 253 spectroscopy of, 244 stereochemical transformations, 227 Nupharidine, 245 Nupharolidine, 221, 223 Nupharolutin, 233 spectral data, 244 synthesis of, 241 Nupharopumiline, 221, 222 Nuphar sulfoxides, 233

0

Octopamine biosynthesis, 139 occurrence of, 101 Oliveridine, 62 Oliveroline, 70 Onychine, 51 Ostreogrycin A, 275 Ouregidione, 6, 12, 38 Oureguattidine, 6, 11, 33 Oureguattine, 6, 11, 33 Oxalomycin. 285, 297, 302 Oxazole alkaloids, 259 from bacteriae, 271 from Gramineae, 260 from marine sources, 269 pharmacology of, 295 from Rutaceae, 262 spectral data, 298, 304 N-Oxides of Deoxynupharidine, transformations of 228 Oxoaporphine, subtypes, 17, 36 Oxoputerine, 70 Oxyacanthine, subtype, 14

32 1

INDEX

Oxyisocalycinine, 4, 12, 38 1,ll-Oxymethyleneaporphine, subtype, 18,45

P Pachyconfine, 7, 11, 34 Pallidine, 5, 9, 29 Pelletierine, 157 Pentouregine, 6, 13, 45 Peyoglunal, 112 Peyonine, 112 Phenethylamines biological effects, 141 biosynthesis of, 137 occurrence in food plants, 107 occurrence of, 79 synthesis of, 132 N-Phenethylcinnamamide, 109 Pimprinaphine, 271, 300 Pimprinethine, 271, 300 Pimprinine, 271, 300 Predicentrine, 198 Proaporphine, 16 Protostephanine, 178, 179, 182 Pseudoephedrine, occurrence of, 114 Pseudomerucathine, 116, 136

Reticuline, 69 Roemerine, 30, 48 Roemerolidine, 62 Roemeroline, 62 Rubescamide, 110

Salicifoline, 95 Salutaridinol, 206 Saxoguattine, 4, 6 Secodihydrocastoramine,221, 223 Secophoebine, 60

Skimmianine, 268 Spiguetidine, 48 Spiguetine, 48 Styrylamides in Amyris plumieri, 266 Subcosine I, 156. 160 Subsessiline, 6, 12, 33 Synephriie biosynthesis of, 139 occurrence of, 102

T Telobine, 5, 9, 23 Tembamide, 112 Texaline, 263, 300 Texamine, 263, 300 Thebaine, rearrangement of, 189 Thiobinupharidine, 224 derivatives of, 225 spectra of, 245 Thiobinupharidine sulfoxide, 221, 226 Thionuphlutine B, 222, 227 derivatives of, 225 spectra of, 245 Tiliageine, subtype, 5, 9, 15, 24 Trichocereine, 101 Trichoguattine, 7, 13, 44 bramides in Amyris plumieri, 266 5ramine, occurrence of, 81

U Ubine, 101 Ulapualide A and B, 269, 295, 300 Ursuline, 53 Ushinsunine, 61

V Vertaline, 164 Virginiamycin M1,270 Virginiamycin M2, 273. 2%


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