The Alkaloids: Chemistry and Pharmacology, Volume 35

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THE ALKALOIDS Chemistry and Pharmacology VOLUME 35

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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

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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

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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

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-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

Molecular formula (MW)

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

Molecular formula (MW)

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

1. ALKALOIDS FROM GUATTERIA

TABLE I1 (Continued)

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

Molecular formula (MW)

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.

TABLE I1 (Continued)

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

Molecular formula (MW)

47 47 24

13

1. ALKALOIDS FROM GUATTERIA

TABLE I1 (Continued)

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

Molecular formula (MW)

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

I . ALKALOIDS FROM GUATTERIA

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

1. ALKALOIDS FROM GUATTERIA

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

I . ALKALOIDS FROM GUATTERIA

(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

I . ALKALOIDS FROM GUATTERIA

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.

1. ALKALOIDS FROM GUA7TERIA

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

1. ALKALOIDS FROM GUA7TERIA

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. ALKALOIDS FROM GUATTERIA

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

I . ALKALOIDS FROM GUATTERIA

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

1. ALKALOIDS FROM GUATTERIA

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

1. ALKALOIDS FROM GUATTERIA

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).

1. ALKALOIDS FROM GUATTERIA

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

1. ALKALOIDS FROM GUATTERIA

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

1. ALKALOIDS FROM GUATTERIA

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

I . ALKALOIDS FROM GUATTERIA

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

I . ALKALOIDS FROM GUATTERIA

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 $.,

1. ALKALOIDS FROM GUATTERIA

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 b
1. ALKALOIDS FROM GUATTERIA

71

now placed in the genus Malmea. Furthermore, its interesting abilities to lower blood cholesterol (116) and dissolve gallstones (117), associated with its traditional use in Mexico, are not due to its major alkaloid guattegaumerine (7), but to neutral propenylbenzene derivatives, especially a-asarone ( I18- 120).

VIII. Appendix The 138 alkaloids isolated through 1988 from the genus Guarreria are listed alphabetically, together with synonyms, in Table IV. TABLE IV ALPHABETICAL LISTOF ALKALOIDS OF THE GENUS Guurreriu (INCLUDING SYNONYMS) Name Actinodaphnine Anolobine Anonaine Apateline Argentinine Ahepavine Aromoline Asimilobine Atheroline Atherospermidine Atherosperminine Atherosperminine N-oxide Belemine 2.2'-Bisnorguattaguianine Coclobine Codamine Coreximine Corydine Corypalmine Corytenchine Daphnandrine Daphnoline I ,2-Dehydroapateline Dehydroformouregine Dehydroguattescine Dehydroneolitsine Dehydronornuciferine Dehydroroemerine Dehydrostephalagine 1,2-Dehydrotelobine

Structure 71 53 44 13 128 2 8

40 104 98 130 131 125 22 11 4 32 78 28 35 10 9 15 83 117 85

80 81 84 16

Name 12-0-Demethylcoclobine 10-0-Demethyldiscretine 10-0-Demethylxylopinine Dicentrinone Dielsine Dielsinol Dielsiquinone Dihydromelosmine 0.0-Dimethylcurine

N,N-Dimethyllindoldhamine 0.N-Dimethylliriodendronine Discoguattine Discretamine Discretine Dragabine Duguespixine Elmerrillicine Formouregine N-Formylnornuciferine N-Formylputerine Glaziovine Goudotianine Gouregine Guacolidine Guacoline Guadiscidine Guadiscine Guadiscoline Guattamine Guattaminone

StNCture 12 31 34 105 137 138 134 112 26 7 95 75 27 33 133 123 63 51 42 59

38 126 132 121 122 109 110 114 20 23 (continued)

72

ANDRE CAVE ET AL.

TABLE IV (Continued) Name Guattegaumerine Guatterine Guatterine N-oxide Guattescidine Guattescine Guattouregidine Guattouregine Homomoschatoline 3-Hydroxynornuciferine 3-H ydroxynuciferine Isoboldine Isocalycinine Isochondodendrine Isodomesticine lsoguattouregidine Isomoschatoline lsopiline Juziphine Kikemanine Lanuginosine Laurotetanine Lauterine Lindcarpine Liridine Lirinidine Lirinine Liriodenine Lysicamine Melosmidine Melosmine 3-Methoxpuciferine 6-Methoxyonychine 0-Methylcalycinine N-Methylcoclaurine 12-0-Methylcurine 0-Methyldehydroisopiline N-Methylelmenillicine 10-0-Methy lhernovine N-Methylisopiline 0-Methy lisopiline N-Methyllaurotetanine 0-Methyllirinine 0-Methylmoschatoline 0-Methylnorlirinine 0-Methy lpachyconfine 0-Methylpukateine

Structure 7 91 92 115 116 118 120

97 48 49 65 74 24 70 119 96

46 5 29 100 68 101 76 97 39 49 94 93 113 111 52 136 75 1 25 82 64 79 47 50 69 52 97 50 87

60

Name N-Methylputerine Neolitsine Noratherosperminine Norcepharadione B Norcorydine Nordicentrine 2’-Norfuniferine 2’-Norguattaguianine Norisodomesticine Norlaureline Norlirinine Nornuciferine Noroliveroline Norpredicentrine 2’-Nortiliageine Nuciferidine Nuciferine Obovanine Oliveroline Oliveroline N-oxide Onychine Ouregidione Oureguattidine Oureguattine Oxoanolobine Oxoisocalycinine Oxolaureline Oxonuciferine Oxoputerine Oxoushinsunine Oxoxylopine Pachyconfine Pallidine Pen touregine Pukateine Puterine Reticuline Roemerine Saxoguattine Subsessiline Telobine Tetrahydropalmatine Tiliageine Trichoguattine Xylopine Xylopinine

Structure

60 73 129 107 77 72 19 21 67 55 48 41 88 66 17 87 43 56 89

96 135 108 61 62

99 106 101 93 102 94 100

86 37 127 57 58 3 45 6 103 14

30 18 124 54 36

I . ALKALOIDS FROM GUA7TERIA

73

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-CHAPTER

2-

P-PHENETHYLAMPNES AND EPMEDRINES OF PLANT ORIGIN JAN LUNDSTR~M Department of Drug Metabolism Astra Research Centre S-151 85 Sodertalje, Sweden 1. Introduction 11. Occurrence

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

77 77

A. P-Phenethylamines

Ill. IV. V. VI.

B . P-PhenethylamineC ................... C. Ephedrines ...... Isolation, Identification, Synthesis ............................................................ Biosynthesis ......................... Biological Effects ..................................................... References .................

78

I32 137 142 144

I. Introduction P-Phenethylamine and ephedrine as well. as several of their derivatives are physiologically active compounds and have therefore been of great importance in many fields of biological sciences. Although several phenethylamines occur in both animals and plants, this chapter deals only with compounds present in plants. Since the previous reviews by Reti in Volume 3 of this treatise ( I , 2), rather few new compounds of this class have been discovered; however, numerous new sources of substituted phenethylamines were reported. This chapter attempts to include all reports through 1987 on the occurrence of phenethylamines and ephedrines in plants, updating similar reviews which were published (3, 4 ) . Historical aspects on isolation and identification of the first discovered phenethylamines and ephedrines are covered in Reti’s early reviews ( 1 , 2). 11. Occurrence A. ~PHENETHYLAMINES

Naturally occurring phenethylamines, including those carrying hydroxy or methoxy substituents at carbon atoms or N-methyl substituents, are listed to77

THE ALKALOIDS. VOL. 35 Coyprighc 0 1989 by Academic F’ress. Inc. A,,

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78

J A N LUNDSTROM

gether with the species of origin in Table I. Species containing various phenethylamines are also listed separately in Table V. Phenethylamines are found in many plant families throughout the plant kingdom. Particularly rich in variously substituted phenethylamines are the families Cactaceae and Leguminosae. A comprehensive tabular summary by Mata and McLaughlin ( 5 ) included not less than 141 cactus species that contain phenethylamines. Phenethylamine itself occurs mainly in fungi and legumes. Most common among the natural phenethylamines are para-hydroxylated derivatives, tyramine, N-methyltyramine, and hordenine, and these compounds occur in most of the plant families listed in Table V. Tyramine is generally recognized as a plant constituent and is perhaps ubiquitous in trace amounts as a decarboxylation product of L-tyrosine. Compounds that are dioxygenated in the aromatic nucleus are found mainly in the Cactaceae and in the Leguminosae while compounds carrying three oxygens in the aromatic nucleus are found almost exclusively in the Cactaceae. Side chain oxygenated (p)compounds are mainly found in Coryphantha species of the Cactaceae, in Citrus species of the Rutaceae, and in a few species of the family Leguminosae. The coexistence of primary amines with the corresponding secondary or tertiary amines in the same or related plant species is frequently observed in the phenethylamine group of alkaloids. Several reports on the amounts of phenethylamine alkaloids in plants have appeared. Rather high levels have been determined in a few species. For instance, dopamine is found in Carnegia gigantea at 0.3-0.4% fresh weight (6, 7), and noradrenaline is found in Portulaca oleracea at about 0.2% fresh weight (8). A species that is very rich in substituted phenethylamine and tetrahydroisoquinoline derivatives is the peyote cactus Lophophora williamsii (9-12). The total alkaloidal content of peyote has been estimated at 0.4% fresh weight (9, 10). The most abundant alkaloid in peyote is the hallucinogen mescaline, which constitutes about 30% of the total alkaloid fraction (10). Hordenine amounts to about 8% and 3-demethylmescaline to 1-5% of the alkaloid fraction (10). Other phenethylamines found in peyote (Table V) may be regarded as trace constituents (10). Special interest has been focused on the presence of biogenic amines in food plants (45, 90,360-362), since digestion of food products rich in, e.g., tyramine can induce physiological effects, especially in patients using monoamine oxidase inhibitors as antidepressants (see below). Concentrations of alkaloids reported in food plants are summarized in Table 11. B. ~ P H E N E T H Y L A MCONJUGATES INE A N D RELATED COMPOUNDS

Several phenethylamine conjugates with aromatic amino acids are known and are primarily found in species of the family Rutaceae (Table 111). Formyl and acetyl amides have been isolated in particular from the peyote cactus (Lophophora

79

2. R-PHENETHYLAMINES AND EPHEDRINES

TABLE I OCCURRENCE OF ~ P H E N E T H Y L A M II N E PLANTS S ~~

Compound

Family

Species

~~~

~~

Molecular formula

Reference(s)

Phenethylamine

(Algae)

(Fungi)

Amaryllidaceae Araceae Asclepiadaceae Cactaceae

Caprifoliaceae Cornaceae

Lauraceae Leguminosae

Ceranium rubrum Cystodonium purpureum Desmarestia aculeata Dumontia incrassata Polyides rotundus Polysiphonia urceolata Armillaria matsutake Boletus edulis Boletus luteus Claviceps purpurea Coprinus atramentarius Coprinus micaceus Inocybe patouillardi Marasmius peronam Nematoloma fasciculare Phallus impudicus Philadelphus delavayi Phlegmacium mellioleus Pholiota mutabilis Polyporus sulphureus Pancratium biojorum Arum maculatum Vincetoxum oficinale Islaya minor Opuntia ficus-indica Pereskia autumnalis Pereskia pititache Pereskia tampicana Pereskiopsis chupisrle Viburnum lanata Cornus alba ssp. tartarica Cornus sanguinea Ocotea pretiosa Acacia accola Acacia acinacea Acacia buxgolia Acacia cardiophylla

13 13 13 13 13 13

14 15 16 17 18 19 20 21 21 22 21 21 21 23 25 26 21 27 24 27 27 27 27 26 21 21 101 28 29 29 28 (continued)

80

JAN LUNDSTROM

TABLE I (Continued)

Compound

Family

Loranthaceae Malvaceae Musaceae Rosaceae

Saxifragaceae Solanaceae

Theaceae N-Methylphenethylamine

Species Acacia cultriformis Acacia jloribunda Acacia harpophylla Acacia kettlewelliae Acacia Iongifolia Acacia lunata Acacia podalyriaefolia Acacia praetervisa Acacia pravissima Acacia prominensis Acacia spectabilis Acacia suaveolens Acacia verticillata Albizzia adianthifolia Alhagi pseudalhagi Desmodium cephalotes Desmodium gangeticum Desmodium gyrans Desmodium trifrorum Prosopis alba Prosopis nigra Phoradendron jlavescens Viscum album Sida cordifolia Musa paradisica Crataegus ( 3 spp.) Crataegus (8 spp.) Malus sp. Prunus amygdalus Prunus padus Prunus communis Sorbaria sorbifolia Sorbus aucuparia Spiraea bracteata Philadelphus delavayi Atropa belladonna Nicotiana tabacum Thea sinensis

Molecular formula

Reference(s) 30 30 31 28, 31 30 30 28, 30 28 30 30, 32 28 30 29 33 34, 35 36 161, 162 37 38 39 350 40, 41 41 -43 44' 45 26 21 26 46 26 21 21 21 26 21 26 47-49 416 50

81

2. f3-PHENETHYLAMINES AND EPHEDRINES

TABLE I (Continued)

Compound

Family

Species

Cactaceae

Molecular formula

Reference(s)

Dolichothele sphaerica Dolichothele surculosa Gymnocactus aquirreanus Gymnocactus beguinii Gymnocactus horripilis Gymnocactus knuthianus Gymnocactus mandragora Gymnocactus roseanus var. el Chipon Gymnocactus viereckii Chenopodiaceae Arthrophytum leptocladum Acacia accola Leguminosae Acacia adunca Acacia augustissima Acacia berlandieri Acacia constricta Acacia greggi Acacia kettleweilliae Acacia praetervisa Acacia prominens Acacia rigidula Acacia roemeriana Acacia texensis Alhagi pseudalhagi Cassia marilandica Desmodium gangeticum Gleditsia triacanthos

57. 58 56 56 28, 31 28 30, 32 56 56 56 34, 35 56 161. 162 56

Cactaceae Orchidaceae

59

5i

52 53 53 53 53. 54 53 53 53 55

28 31 56

NN-Dimethy lphenethylamine

Backebergia militaris Eria jarensis

359

Tyramine

(continued)

82

JAN LUNDSTROM

TABLE I (Continued)

Compound

Family (Fungi)

Agavaceae Amaryllidaceae

Anacardiaceae Araceae Berberidaceae Bignoniaceae Cactaceae

Species Armillaria matsutake Boletus edulis Boletus zelleri Claviceps purpurea Coprinus atramentarius Coprinus comatus Phallus impudicus Polyporus spp. Cordulinae terminalis Amaryllis vittata Crinum comantus Crinum spp. Crinum yuccaforurn Haemanthus katharinae Hymenocallis americana Liriope spicata Pancratium bioforum Pancratium maritimum Schinus terebinthifolius Colocasia antiquorum Nandina domestica Jacaranda acutifolia Pyrostegia ignea Azureocereus ayacuchensis Cereus aethiops Cereus forbesii Cereus glaucus Cereus jamacaru Cereus peruvianus Cereus peruvianus monstruosus Coryphantha macromeris var. runyonii Coryphantha missouriensis Echinopsis rhodotricha Espostoa huanucensis Gymnocalycium leeanum Isalya minor Lobivia alegriana Lobivia aurea Lobivia backebergii Lobivia binghamiana Lobivia huashua

Molecular formula

Reference(s) i4 15 60 61 18 62 22 60 45 45 45 45 63 45 45 45 25 64. 65 45 45 45 45 45 66

67 68 68 69 68, 70 68 68, 70 72 73 74 75 27 76 76 76 76 76

83

2. p-PHENETHYLAMINES AND EPHEDRINES

TABLE I (Continued)

Compound

Family

Species Lobivia pentlandii Lophophora williamsii Mamillaria elongata Melocactus delessertianus Melocactus maxonii Obregonia denegrii Opuntia clavata Opuntia imbricata Opuntia invicta Opunria kleiniae Opunria schorrii Opuntia spinosior Opuntia stanlyi var. kunzei Opuntia stanlyi var. stanlyi Opuntia versicolor Pereskia aculeata Pereskia aurumnalis Pereskia corrugara Pereskia cubensis Pereskia grandqolia Pereskia grandipora Pereskia pititache Pereskia tampicana Pereskiopsis chapistle Pereskiopsis scandens Pilosocereus maxionii Pseudolobivia kermesim Stetsonia coryne Trichocereus bridegesii Trichocereus camarguensis Trichocereus candicans Trichocereus couranrii Trichocereus cuzcoensis Trichocereusfulvianus Trichocereus knurhianus Trichocereus macrogonus Trichocereus manguinii Trichocereus pachanoi

Molecular formula

Reference( s) 76 10. 77

78 27 27 54.80, 81 82 83 83 83 83 84, 85 83 83 83 27 27 27 27 27 27 27 27 27 27 86 76 73 68 68

74 73 73 73 73

68 73 68. 87 (continued)

84

IAN LUNDSTROM

TABLE I (Continued)

Compound

Family

Species

Trichocereus pasacana Trichocereus peruvianus Trichocereus purpureopilosus Trichocereus santiaguensis Trichocereus spachianus Trichocereus tunariensis Trichocereus werdermannianus Caprifoliaceae Sambucus canadensis Viburnum odoratissimum Chenopodiaceae Beta vulgaris var. cruenta Haloxylon salicornicum Spinacia oleracae Compositae Aster linariifolius Silyburn marianum Cruciferae Brassica oleracea Capsella bursapastoris Raphantus sativus Cucurbitaceae Citrullus vulgaris Cucumis sativus Cyperaceae Cyperus papyrus Mariscus jamaicensis Geraniaceae Erodium cicutarium Graminae Hordeum vulgare Panicum miliaceum Zea mays Juglandaceae Juglans nigra Labiatae Lamium album Lauraceae Persea americana Leguminosae Acacia berlandieri Acacia greggi Acacia roemeriana Acacia texensis Calliandra haematocephala Cassia alata Cytisus scoparius Desmodium cephalotes Desmodium tiliaefolium Erythrina cristagalli

Molecular formula

Reference(s) 88 68 73 73 68, 74 73 87 45 45 360 89 90 45 91, 92 360 93 360 360 360 45 45 94 95, 96 97, 98 99 45 100

90 57, 58 56 56 56 45 45 102, 158 36 103 45

85

2. /3-PHENETHYLAMINES AND EPHEDRINES

TABLE I (Continued)

Compound

Family

Species

Gleditsia triacanthos Phaseolus radiatus Pisum sativum Prosopis alba Prosopis glandulosa Prosopis nigra Trifolium alexandrinum Liliaceae Chlorophytum capense Cordyline terminalis Liriope spicata Loranthaceae Phoradendron sp. Phoradendron argentinurn Phoradendron fivescens Phoradendron hieronymi Phoradendron wattii Phoradendron liga Phoradendron villosum Phyrgilanthus Jagellaris Psittacanthus cuneifolius Viscum album Magnoliceae Magnolia spp. Musaceae Musa paradisica Cattleya spp. Orchidaceae Papaveraceae Chelidonium majus Plumbaginaceae Limonium vulgare Ranunculaceae Aconitum napellus Prunus domestica Rosaceae Rubus idaeus Rutaceae Citrus limon Citrus medica X sinensis Citrus reshni Citrus reticulata Citrus reticulata X sinensis Citrus sinensis Solanaceae Lycopersicon esculentum Nicotiana tabacum Solanum melongena Solanum tuberosum

Umbelliferae Vitaceae

Daucus carota Vitis vinifera

Molecular formula

Reference(s) 56 104 105, 106 39 56 350 107 45 45 45 45 108 40, 41 108 109 109 42 109 109 41-43 110- 113 45. 90

114 115 116 117

90 118 119, 120 119 120 45 119

45 45, 90 47-49 45, 90 90,121. 360 360 361

(continued)

86

JAN LUNDSTROM

TABLE I (Continued)

Compound

Family

Species

Molecular formula

Reference(s)

N-Methyltyramine

(Fungi) Amaryllidaceae

Cactaceae

Boletus zelleri Polyporus spp. Amaryllis vittata Haemanthus katharinae Pancratium maritimum Ariocarpus fissuratus var. fissuratus and var. lloydii Ariocarpus kotschoubeyanus Ariocarpus retusus A riocarpus schapharostrus Ariocarpus trigonus Coryphantha calipensis Coryphantha cornifera Coryphantha cornifera var. echinus Coryphantha duranguensis Coryphantha elephanatidens Coryphantha macromeris var. runyonii Coryphantha missouriensis Coryphantha ottonis Coryphantha pectinata Coryphantha radians Coryphantha ramillosa Dolichothele sphaerica Dolichothele surculosa Dolichothele uberiformis Echinocereus merkerii Espostoa huanucensis Gymnocactus aquirreanus Gymnocactus beguinii Gymnocactus mandragora

60

60 45 45 64, 65 122,204

123 124 125 126 127, 128 129 129 129 129 130 72 129 54. 129 128 133 51 52 136 137 138 53 53 53

87

2. P-PHENETHYLAMINES AND EPHEDRINES

TABLE I (Continued)

Compound

Family

Species Gymnocactus roseanus var. el Chijlon Gymnocalycium leeanum Islaya minor Lobivia alegriana Lobivia aurea Lobivia backebergii Lobivia binghamiana Lobivia huashua Lobivia pentlandii Lophophora williamsii Mamillaria elongata Mamillaria microcarpa Obregonia denegrii

Opuntia clavata Opuntia invicta Opuntia kleiniae Opuntia schottii Opuntia stanlyi var. kunzei Opuntia stanlyi var. stanlyi Opuntia versicolor Pilosocereus m o n i i Solisia pectinata Stetsonia coryne Trichocereus camarguensis Trichocereus candicans Trichocereus courantii Trichocereusfulvianus Trichocereus manguinii Trichocereus pasacana Trichocereus purpureopilosus Trichocereus schickendantzii Trichocereus spachianus Trichocereus thelegonus Chenopodiaceae Anabasis jarartica Haloxylon salicornicum Euphorbiaceae Croton humilis Gramineae Hordeum vulgare

Molecular formula Reference(s)

53 70 27 76 76 76 76 76 76 77 78 131

54,80, 81 82 83 83 83 83 83 83 86 80 73 68 74 73 73 73 88 73 68 68,74 73 132 89 134 95. % ( conrinued)

88

JAN LUNDSTROM

TABLE I (Continued)

Compound

Family

Leguminosae

Rutaceae

Species

Molecular formula

Panicum miliaceum Triticum vulgare Acacia berlandieri Acacia rigidula Acacia roemeriana Alhagi pseudalhagi Desmodium gangeticum Prosopis glandulosa Citrus limon Citrus reshni Citrus reticulata Citrus sinensis

Hordenine

Reference(s) 138 96. 139 57, 58 56 56 34, 35 161, 162 56 119. 120 120 45 45

p L *

C10H15N0

HO

(Algae) (Fungi)

Amaryllidaceae

Beberidaceae Cactaceae

Phyllophora nervosa Boletus zelleri Fomes pini Polyporus berkeleyi Poiyporus spp. Pancratium bioflorum Pancratium maritimum Ungernia ferganica Ungernia trisphaera Ungernia victoris Nandina domestica Ariocarpus agavoides Ariocarpus jissuratus var. jissuratus Ariocarpus jissuratus var. lloydii Ariocarpus kotschoubeyanus Ariocarpus retusus Ariocarpus schapharostrus Ariocarpus trigonus Cereus aethiops Cereus alacriportanus Cereus glaucus Cereus peruvianus

140 60 60 141 60 25 64, 65 142 143 144 45 80 122 122 123 124 125 126 67 68 68 68, 70

89

2. P-PHENETHYLAMINES AND EPHEDRINES

TABLE I (Continued)

Compound

Family

Species

Coryphantha bumamma Coryphantha cornifera var. echinus Coryphantha duranguensis Coryphantha elephanatidens Coryphantha greenwoodii Coyphanrha macro-

meris var. runyonii Coryphantha missouriensis Coryphantha ottonis Coryphantha pectinata Coryphantha poselgeriana Coryphantha radians Coryphantha ramillosa Coryphantha vivipara Coryphantha vivipara var. arizonica Dolichothele surculosa Dolichothele Uberiformis Echinocereus merkerii Echinopsis eyriesii Echinopsis rhodotricha Gymnocactus aquirreanus Gymnocactus beguinii Gymnocactus horripilis Gymnocactus roseanus var. el Chifon Gymnocalycium leeanum Gymnocalycium schickendantzii Helianthocereushuascha Helianthocereus pasacana lslaya minor Lobivia alegriana Lobivia aurea Lobivia backebergii

Molecular formula

Reference(s) 128, I45 i29 129

129 68, 130 68. 71. 130 131 129 54. 129 129 128 133 128, 148 149 52 68, 84. 136 137 68 73 53 53 53 53 70. 75 67 68 68 27 76 76 76

(continued)

90

JAN LUNDSTROM

TABLE I (Continued) ~

Compound

Family

~~

Species Lobivia binghamiana Lobivia huashua Lobivia pentlandii Lophophora williamsii Mamillaria elongara Mamillaria microcarpa Notocactus otronis Obregonia denegrii

Cannabinaceae Euphorbiaceae

Opuntia aurantiaca Opunria clavata Opuntia invicta Opuntia maldonensis Opuntia schottii Opuntia versicolor Opuntia vulgaris Pelecyphora aselliformis Pelecyphora pseudopectinata Solisia pectinata Trichocereus candicans Trichocereus lamprochlorus Trichocereus pachanoi Trichocereus santiaguensis Trichocereus schickendantzii Trichocereus skottsbergii Trichocereus spachianus Trichocereus striogosus Trichocereus taquimbalensis Trichocereus thelegonus Trichocereus thelegonoides Trichocereus tunariensis Turbinicarpus pseudomacrochele Wigginsia erinacea Wigginsia macrocantha Wigginsia tephracantha Cannabis saliva Securinega virosa

Molecular formula

Reference(s)

76 76 76 77. 150 151 131. 415 70 54.80. 81 70 82 83 70 83 83 70 73. I35 80 80 68 68 68,87. 73 68 73 68 73 73 73 73 73 80 70 70 70 147 152

91

2.8-PHENETHYLAMINES AND EPHEDRINES

TABLE I (Continued)

Compound

Family Graminae

Leguminosae

Liliaceae Loranthaceae Nandinaceae Polygonaceae

Ranunculaceae Rutaceae

Species

Molecular formula

Reference(s)

Andropogon sorghum Hordeum murinum Hordeum vulgare Panicum miliaceum Phalaris arundinacea Sorghum vulgare Triticum vulgare Acacia berlandieri Acacia harpophylla Acacia holocerica Acacia spriorbis Alhagi pseudalhagi Desmodium cephalotes Desmodium Jloribundum Desmodium gangeticum Desmodium rriforum Eremurus regelii Phoradendron J7avescens Nandina domestica Eriogonum alarum Eriogonum annuum Eriogonum campanulatum Eriogonum influrum Aconitum tanguticum Citrus reshni Citrus reticulata Teclea simplicifolia

153 I54 95, 96 97, 98 I55 139, 153 96, 139 57, 58 31 31 30, 160 34, 35 36 424 161, 162 38 163 40, 41 45 423 423 423

Cereus aerhiops Gymnocalycium schickendantzii Lophophora williamsii Trichocereus candicans Trichocereus chilensis Trichocereus lamprochlorus Trichocereus pasacana Trichocereus spachianus

67 67

423 157 45 45 164

Candicine

Cactaceae

165 74. 167 168 169 88 74

(continued)

92

JAN LUNDSTROM

TABLE I (Continued)

Compound

Family Leguminosae Magnoliaceae Rutaceae

4-Methoxyphenethylamine

Species

Molecular formula

Reference(s) 36 I61 I62 110-113 187, I88 159 170. 171

Desmodium cephalotes Desmodium gangeticum Magnolia spp. Fagara spp. Phellodendron amurense Zanthoxylum clavaherculis

~

9H I 3 No Me0

Cactaceae

Ericaceae

Coryphantha cornifera Coryphantha ottonis Coryphantha poselgeriana Erica lusitania

129 129 I29

Ariocarpus retusus (Anhalonium prismaticum) Coryphantha bumamma Coryphantha cornifera Coryphantha cornifera var. echinus Coryphantha elephanatidens Coryphantha macromeris var. runyonii Coryphantha ramillosa Dolichothele uberiformis Eriogonum alatum Eriogonum annuum Eriogonum campanulatum Eriogonum inflatum

124. I73

172

N-Methyl-4-methoxyphenethylamine

Cactaceae

Polygonaceae

128. 145 I29 129 I29 147 I33 136 423 423 423 423

93

2. P-PHENETHYLMNES AND EPHEDRINES

TABLE I (Continued)

Compound

Family

N,N-Dimethyl-4-methoxyphenethylamine

Molecular formula

Species

MP

N

M

.

Reference(s)

,

Rutaceae

Teclea simplicifolia

164

Cactaceae

Coryphantha greenwoodii

166

0-Methylcandicine

Dopamine HO " O V N H 2

Monosioma fuscwn Annona reticulata Carnegiea gigantea Lophoeereus schoitii Lophophora williamsii Chenopodiaceae Beta vulgaris Spinacia oleracea Persea americana Lauraceae Cyiisus scoparius Leguminosae E n i d pursaetha (glucoside) Spartiwn scopariwn Musa paradisica Musaceae Hermidiurn alipes Nyctaginaceae Piper amalago Piperaceae Portulaca oleracea Portulaceae Ranunculaceae Aconiium napellus Solanum iuberosurn Solanaceae Stachytarpheta Verbenaceae jamaicensis

(Algae) Annonaceae Cactaceae

174 175 6, 7 177 176 178, 179 90. 180

90 102 181 182 45, 90

183 109 8 117

90, 121 109

Epinine

(coniinued)

94

JAN LUNDSTROM

TABLE I (Continued)

Compound

Family Cactaceae Leguminosae

Species Lophophora williamsii Cytisus scoparius Spartiurn scoparium Vicia faba

Molecular formula

Referenceb) i76

i02 182 184

Coryneine " W HO

Cactaceae Leguminosae Rutaceae

Y M . ,

Sfetsonia coryne Alhagi pseudalhagi Desmodium friflorum Fagara hyemalis Fagara spp.

185, I86 34, 35 38 187 187, I88

Backebergia rnilitaris Carnegiea giganfea Echinocereus merkerii Islaya minor Lophophora williamsii Opunfia imbricafa Opunfia spinosior Opuntia subulafa Pachycereus pectenaboriginum Pereskia corrugara Pereskia grandifolia Pereskiopsis chapistle Sfetsonia coryne Trichocereus bridgesii Trichocereus camarguensis Trichocereus courantii Trichocereus cuzcoensis Trichocereus knufhianus Trichocereus macrogonus Trichocereus pachanoi

189, I 9 0 191 137 27 . 192 83 84. 85 83 69, I93

3-Methoxytyramine

Cactaceae

27 27 27 73. I85 68 68 73 73 73 68 68, 87, I94

95

2.8-PHENETHYLAMINES AND EPHEDRINES

TABLE I (Conrinued)

Compound

Family

Molecular formula

Species Trichocereus peruvianus Trichocereus raquirnbalensis Trichocereus werdermannianus

Reference(s) 68, I95 73

87

N-Methyl-3methoxytyramine

Cactaceae

Pilosocereus maxonii Trichocereus courantii

86 73

Cactaceae Magnoliaceae

Ariocarpus agavoides Magnolia sprengeri

80 I56

N,N-Dimethyl-3methoxytyramine

Salicifoline MeO H o p y M e ,

Magnoliaceae

Magnolia denudara Magnolia grandijora Magnolia kobus Magnolia liliimra Magnolia salicifolia Magnolia spp. Magnolia srelellara Michelia alba

2-Methox ytyramine

I% 111 I97 200 I98 110-113 I99 113

OMe

HO P

Cactaceae

N

H

.

Trichocereus courantii

73 (continued)

96

JAN LUNDSTROM

TABLE I (Continued)

Compound

Family

Species

Molecular formula

Reference(s)

Homoveratrylamine (3,4-dimethoxy-Pphenethylamine)

Cactaceae

Backebergia militaris Carnegiea gigantea Echinocereus merkerii lslaya minor Lophophora williamsii Melocactus maxonii Neoraimondia arequipensis var. rosiflora Opuntia acanthocarpa Opuntia echinocarpa Opuntia imbricata Opuntia spinosior Opuntia whipplei Pachycereus pectenaboriginum Pelecyphora aselliformis Pereskia corrugata Pereskia tampicana Pereskiopsis scandens Pilosocereus maxonii Polaskia chende Pseudolobivia kermesiana Pterocereus ,foeridus Pterocereus gaumeri Stenocereus beneckei Stenocereus eruca Stenocereus stellatus Stenocereus treleasei Stetsonia coryne Trichocereus bridgesii Trichocereus camarguensis Trichocereus courantii Trichocereus macrogonus Trichocereus pachanoi

201 191 137 27 202 420 420

420 420 83 84, 85 83 69, 193 73, I35 27 27 27 86 420 76 420 420 420 420 420 420 73, I85 68 68 73 68 68, 203, 209

97

2. P-PHENETHYLAMINES AND EPHEDRINES

TABLE I (Continued)

Compound

Family

Leguminosae N-Methylhomoveratrylamine

Molecular formula

Species

Trichocereus peruvianus Trichocereus taquimbalensis Trichocereus werdertnannianus Desmodium tiliaefolium MeO MeOV

Cactaceae

68, 195 73 87 103 II

N

H

M

Reference(s)

17N02

e

Ariocarpus agavoides A riocarpus jissuratus var. jissuratus Ariocarpus retusus A riocarpus schapharostrus Ariocarpus trigonus Backebergia militaris Coryphantha bumamma Coryphantha calipensis Coryphqntha cornifera Coryphantha cornifera var. echinus Coryphantha duranguensis Coryphantha elephanatidens Coryphantha macromeris var. runyonii Coryphantha missouriensis Coryphantha pectinata Dolichothele uberiformis Echinocereus cinerascens Echinocereus merkerii Lophophora williamsii Mamillaria heyderii Pelecyphora aselliformis Pilosocereus chrysocanthus Pilosocereus guerreronis

80 204

I 73 125 126 359 128, 145 127, 128 129 129 129

129 71 72 54, 129 84, 136 205 137 176 80 73. 135 205

206

(continued)

98

JAN LUNDSTROM

TABLE I (Continued)

Compound

Family

Species

N,N-Dimethylhomoveratrylamine

Molecular formula

Reference(s)

12H19N02

Cactaceae

A riocarpus

Leguminosae

schapharostrus Backebergia rnilitaris Coryphantha calipensis Coryphantha greenwoodii Echinocereus merkerii Pilosocereus guerreronis Desmodium tiliaefoliurn

3.4-Dihydroxy-5-methoxyphenethylamine

125 359 127, 128 128, 146 137 206 103

C9H 13 NO3

Cactaceae 3,4-Dimethoxy-5hydroxyphenethy lamine (3demethylmescaline)

I 76

Lophophora williamsii , O H I5

OH

Cactaceae

Lophophora williamsii Trichocereus cuzcoensis Trichocereus pachanoi

176. 214 73 87, 213

Cactaceae

Lophophora williarnsii

176

N-Methyl-3,4-dimeth-

ox y-5-hydrox yphenethylamine

99

2.8-PHENETHYLAMINESA N D EPHEDRINES

TABLE I (Continued) Compound

Family

N,N-Dimethyl-3,4-dimethoxy-5-h ydrox y phenethylamine

Species M e o p N M e 2

MfO

Cactaceae

Molecular formula Reference(s) C12H,9N03

on

Lophophora williamsii Pelecyphora aselliformis

176 73, 135

"&VNH*

3,5-Dimethoxy-4-hydroxyphenethylamine

C10H,5N03

HO OMe

Cactaceae

Escontria chiotilla Melocactus maronii Neoraimondia arequipensis var. rosrflora Lophophora williamsii Opuntia acanthocarpa Opuntia basilaria Opuntia echinocarpa Opuntia exaltata Polaskia chende Pterocereus foetidus Pterocereus gaumeri Stenocereus beneckei Stenocereus eruca Stenocereus stellatus Stenocereus treleasei Trichocereus pachanoi Trichocereus peruvianus Trichocereus werdermannianus

Mescaline

420 420 420 213 420 420 420 420 420 420 420 420 420 420 420 87 87 87

II

17

OMe

Cactaceae

Gymnocactus gibbosum Gymnocalycium leeanum Lophophora diffusa

75 70, 75 357

(continued)

100

JAN LUNDSTROM

TABLE I (Continued)

Compound

Family

Species Lophophora echinata Lophophora williamsii

Opuntia acanthocarpa Opuntia basilaria Opuntia echinocarpa Opuntia spinosior Pelecyphora aselliformis Pereskia corrugata Pereskia tampicana Pereskiopsis scandens Polaskia chende Pterocereus gaumeri Stenocereus beneckei Stenocereus eruca Stenocereus stellatus Stenocereus treleasei Stetsonia coryne Trichocereus bridgesii Trichocereus cuzcoensis Trichocereus fulvianus Trichocereus macrogonus Trichocereus pachanoi Trichocereus peruvianus Trichocereus taquimbalensis Trichocereus terscheckii Trichocereus validus Trichocereus werdermannianus

Molecular formula

Reference(s) 421 10-12, 25, 207, 208 420 420 420 85 73, 135, 42 1 27 27 27 420 420 420 420 420 420 73, 185 68 73 73 68 68, 94, 209 68, 195 73 68 73 87

N-Methylmescaline M e 0e o v H M e OMe

CaCtaceae Leguminosae

Lophophora williamsii Pelecyphora aselliformis Alhagi pseudalhagi

210 73, 135 34. 35

.

101

2. p-PHENETHYLAMINES AND EPHEDRINES

TABLE I (Continued)

Compound

Family

Trichocereine

Species M e o T N M e 2

Molecular formula

Reference(s)

C13H21N03

MeO OMe

Cactaceae

Trichocereus terscheckii

211, 212

(R)-( - )-Halostachine

Chenopodiaceae Halostachys caspica

215

Cactaceae

Dolichothele uberiformis

I36

Cactaceae

Coryphanrha greenwoodii

166

Amaryllidaceae Cyperaceae

Amaryllis vittata Cyperus papyrus Cyperus rotundus Lolium multijlorum Lolium spp. Liriope spicata Citrus Iimon Citrus medica X sinensis Citrus reshni Citrus reticulata Citrus reticulata X sinensis Capsicumfrutescens

45 45 45 216 216 45 119, I20 119 120 45 119

Ubine

(S)-( +)-Coryphanthine

(R)-(-)-Octopamine

Graminae Liliaceae Rutaceae

Solanaceae

45

(continued)

102

JAN LUNDSTROM

TABLE I (Continued) Compound

Family

Species

Synephrine

?H

Molecular formula C9H13N02

Amaryllis vittata Eucharis grandifora Haemanthus katharinae Coryphantha cornifera Cactaceae Coryphantha cornifera var. echinus Coryphantha duranguensis Coryphantha elephanatidens Coryphantha greenwoodii Coryphantha macromeris var. runyonii Coryphantha ottonis Coryphantha pectinata Coryphantha poselgeriana Coryphantha ramillosa Dolichothele longimamma Dolichothele sphaerica Dolichothele surculosa Dolichothele uberiformis Mamillaria elongata Chenopodiaceae Haloxylon salicornicum Ficus bengalensis Moraceae Citrus limon Rutaceae Citrus medica X sinensis Citrus reshni Citrus reticulata Citrus reticulata X sinensis Citrus sinensis Amaryllidaceae

P- 0-Methylsynephrine

45 45 45 129 I29 129 I29 128, 146 147 I29 129 129 133 217 51 52 136 I51 89 45 119, 120 119 45, 120 45 119 45. 90 10H1SN02

HO

Reference@)

103

2.0-PHENETHYLAMINES AND EPHEDRINES

TABLE 1 (Continued)

Compound

Family Cactaceae

Rutaceae

Species

Molecular formula Reference(s) 129 I29

Coryphantha cornifera Coryphantha cornifera var. echinus Coryphantha greenwoodii Coryphantha pectinata Coryphantha ramillosa Dolichothele sphaerica Mamillaria elongata

128. 146 54. I29 133 51 151 218

“Dancy” mandarin

4-Methoxy-P-hydrox yphenethylarnine

C9H13N02

Cactaceae

Coryphantha cornifera Coryphantha cornifera var. echinus Coryphantha elephanatidem Coryphantha pectinata Pereskia godsefiana Pereskia tampicana

129 129

Cactaceae

Dolichothele longimamma

217

Cactaceae

Coryphantha macromeris var. runyonii Hydrastis canadensis Albizzia julibrissin Mimosa pudica

331

129 54, 129 27 27

Longimammamine

(R)-(-)-Norepinephrine (noradrenaline)

Hydrastinaceae Legurninosae

220 105 I05 (continued)

104

JAN LUNDSTROM

TABLE I (Continued)

Compound

Family

Musaceae

Passifloraceae Portulaceae Ranunculaceae Rosaceae Rutaceae Solanaceae

Species

Molecular formula

I05 105, 106 105 90, 221. 222 219 I05

Phaseolus multiporus Pisum sativum Samanea samam Musa paradisica Musa sapientum Passipora quadrang ularis Portulaca oleracea Aconitum napellus Aconitum paniculatum Prunus domestica Citrus sinensis Solanum tuberosum

( R ) - (-)-Epinephrine (adrenaline)

Reference(s)

8 117. 223 223

90 45, 90 90, 121 C'3H13N03

Cactaceae

(R)-(- )-N-Methylepinephrine (N-methyladrenaline)

33 I

Coryphantha macromeris var. runyonii C10H15N03

'HO OflNMe,

Ranunculaceae

224

Aconitum nasutum

(R)-(-)-Metanephrine

C10H15N03

NHMe

Cactaceae

147

Coryphantha macromeris var. runyonii

(R)-(-)-N-Methylmetanephrine

1I

M HO aflNMe2

17N03

105

2.6-PHENETHYLAMINES AND EPHEDRINES

TABLE I (Continued)

Compound

Family

Species

Molecular formula

Reference(s)

Cactaceae

Coryphanrha macromeris var. runyonii

147

Cactaceae

Coryphanrha calipensis Coryphantha greenwoodii Coryphantha macromeris var. runyonii Dolichothele longimamma Dolichorhele uberiformis

127, 128 128. 146

(R)-(-)-Normacromerine

(R)-(-)-Macromerine

225 52, 217 68, 136 C12H19N03

MeO

Cactaceae

Coryphonrha cornifera var. echinus Coryphanrha elephanaridens coryphantha macromeris Coryphanrha macromeris var. runyonii Coryphantha pectinata

(R)-(- )-Calipamine

129 129 226, 227 225 54, 129 lZH

MeO

Cactaceae

Coryphantha calipensis

127. 128, 228 128. 147

Coryphanrha greenwoodii (R)-(-)-N-Methyl-

calipamine

13HZlN03

M MeOe O d i M e .

(continued)

106

JAN LUNDSTROM

TABLE 1 (Conzinued)

Compound

Family Cactaceae

3-Nitro-4-hydroxyphenethylamine

Species

Reference(s) 128. 146

Coryphantha calipensis

HO

Cactaceae

Molecular formula

Cereus validus

C*H,ON*O,

300

williamsii). This cactus also contains several Krebs cycle acid conjugates of mescaline and two pyrrole derivatives (Table 111).

C. EPHEDRINES

The oriental crude drug Ma Huang or Mao, prepared from certain species of the genus Ephedra, contains ephedrine, pseudoephedrine, and homologous compounds ( 2 ) .Although alkaloids of the ephedrine type occur in several Ephedru species, only a few other plant sources are known (Table IV and V). The six optically active alkaloids ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, and the N-methylated N-methylephedrine and Nmethylpseudoephedrine are described in detail in Reti’s review ( 2 ) . Two new alkaloids of related structure have since been identified in Ephedra species, namely, O-benzoylpseudoephedrine (271) and the oxazolidine derivative ephedroxane (272).The 4-quinolone derivative ephedralone, recently isolated from Ephedra a h a (273), may be of similar biogenetic origin as the ephedrines. Ephedra species also contain macrocyclic alkaloids of more complex structure (275).The two major Ephedra alkaloids (-)-ephedrine and (+)-pseudoephedrine are diastereomers. (-)-Ephedrine has the erythro and (+)-pseudoephedrine has the threo configuration. The genus Ephedra is found in the temperate and subtropical regions of Asia, Europe and America. The production of ephedrine alkaloids has also been investigated in callus tissue cultures (280-283). Different species of Ephedra may be used in the preparation of the crude drug Ma Huang; however, the most common ones appear to be E . distachya, E. sinica, and E. equisetina ( 2 ) . Since Ma Huang has been of great medical interest, numerous studies have been carried out to determine the content of ephedrine alkaloids in different species ( 2 , 257,

TABLE I1 CONCENTRATIONS (mg/kg) OF ~HENETHYLAMINEALKALOIDS IN FOODPLANTS

Family and species Araceae Colocasia antiquorum Chenopodiaceae Beta vulgaris var. cruenta Spinacia oleracea Cruciferae Brassica oleracea

Raphantus sativus

Cucurbitaceae Citrullus vulgaris Cucumis sativus Lauraceae Persea americana Musaceae Musa paradisica

Common name

Elephant ear Red beet Spinach Cabbage Cauliflower Radish (root)

Tyramine

N-Methyl- Hordetyramine nine

Octopamine

Synephrine

Dopamine

Norepinephrine

84

45

160

0-680

360 90

0

0 440-800 400 0 200

45

360 360 45

360

Watermelon Cucumber

460 250

Avocado pear

23

4-5

Banana (peel) Banana (pulp)

65

700 8

I

Reference(s)

360 360 0

90

122 2

90 90 (continued)

TABLE I1 (Continued)

Family and species

Common name

Tyramine

N-Methyl- Hordetyramine nine

Octopamine

Synephrine

Dopamine

Norepinephrine

45 45 45 45

Reference(s)

Rutaceae Citrus reticulata

Citrus sinensis

Tangerine (leaf) Tangerine (fruit) Cleopatra mandarin (leaf) Cleopatra mandarin (hit) Orange (leaf)

11

19

-

24

I

15 31

-

I

8

12

203 1 125 2215

58

7

2

280

28

6

45 45

Orange (fruit) Solanaceae Lycopersicon esculentum Solanum melongera Solanum tuberosum

Tomato (fruit) Eggplant Potato Potato (tuber)

51 0.5-3 1 560-1300

0

0

0

0

0

0.1-2

45, 90 45, 90 45 90,360

Umbelliferae Daucus carota

Carrot

0-230

45.360

Vitaceae Vitis vinifera

Grape

0 240-1400

0

361 90

109

2. @-PHENETHYLAMINESAND EPHEDRINES

TABLE I11 OCCURRENCE OF P-PHENETHYLAMINE CONJUGATES AND RELATED COM~UND INSPLANTS

Compound

Family

Species

mNp

N-P-Phenethylcinnamamide

Molecular formula Reference(s) 17N0

0

Compositae

Spilunrhes ocymifoliu

(E)-3,4-Dioxymethylenecinnamic acid P-phenethylamide

229 ISH 17N03

0

Compositae

Crironiellu ucuminura

422

Compositae

Critoniellu ucuminuru

422

(Fungi)

Srrepromyces griseus

230

(2)-3 ,CDioxymethylenecinnamic acid P-phenethylamide

N-Acetyltyramine

N-Benzoyltyramine

UN02

HO 0

23 I

Rutaceae Cusimiroa edulis (Santhalaceae) N-Cinnamoyltyramine

C17H17N02

HO

0

Rutaceae

Evodiu beluhe

232 (continued)

TABLE 111 (Continued)

Compound

Family

Species

Molecular formula

Reference(s)

DNfl

N-Benzoyl-0methyltyramine

MeO

0

Rutaceae

Pleiospermium alatum

Alatamide MeO

243

DN> 0

Rutaceae

Pleiospermium alarum

243

mNp

Herclavine

0

MeO

Rutaceae

Zanthoxylum clavaherculis

170

N-Homoveratroylhomoveratrylamine Me0 OMe

Rutaceae

Pleiospermium alatum

238

Rutaceae

Fagura rubescens

239

Cactaceae

Lophophoru williamsii

240

Rubescamide

N-Formyl-3,Cdimethoxy-5-hydroxyphenethylamine

N-Acetyl-3 ,Cdimethoxy-5-hydroxyphenethylamine

MeO MeO w

N

y

OH

M

e

0

I10

TABLE Ill (Continued)

Compound

Family

Species

Cactaceae N-Formylmescaline

Molecular formula

Lophophora williamsii :

p

N

y

"

Reference(s) 240

1 Z H 17N04

0

OMe

Cactaceae

Lophophora williamsii

240

Cactaceae

Lophophora williamsii

241, 240

N-Acetylmescaline

Mescaline succinimide

ISH

OMe

Cactaceae

240

Lophophora williamsii

Mescaline malimide

ISH

OH

Cactaceae

240

Lophophora williamsii

Mescaline citrimide

17'21

CH,COOH

Cactaceae

Lophophora williamsii

Mescaline maleimide

242 I S H 17N05

Me0 OMe

Cactaceae

-

Lophophora williamsii

Mescaline isocitrimide lactone

240 C17H

0

Cactaceae

Lophophora williamsii

242 (continued)

111

112

IAN LUNDSTROM

TABLE 111 (Continued)

Compound

Family

Molecular formula

Species

Reference(s)

MeOyp 0""

Peyonine

MeO 'Me

Cactaceae

254

Lophophora williarnsii

Peyoglunal

C17H21N05

MeO

Cactaceae

242

Lophophora williarnsii

mN& OH

Tembamide MeO

16H 17N03

0

Rutaceae

233 234 235 187 236

Aegle rnarmelos Clausena brevistyla Fagara hyemalis Fagara spp. Znnthoxylum conspersipunctaturn

Aegelin

dHp

C18H19N03

MeO

0

Rutaceae

233, 237

Aegle rnarmelos

Annuloline

.OMe Meo w \

/s

C

Graminae

H

2OH2ONo4

=C H a O M e

244

Loliurn rnultiporurn

N-Formylnormacromerine

C12H17N04

MeO Meo&yH

0

Cactaceae

Coryphantha macromeris var. runyonii

147

113

2. fl-PHENETHYLAMINES AND EPHEDRINES

TABLE IV OCCURRENCE OF EPHEDRINES IN PLANTS

Compound

Family

Species

( 1R , 2 9 4 -)-Norephedrine

Molecular formula

Reference(s)

C9H

Celastraceae Ephedraceae

Carha edulis Ephedra distachya Ephedra equisetina Ephedra gerardiana Ephedra intermedia Ephedra procera Ephedra regeliana Ephedra sinica Ephedra tweediana Ephedra vulgaris

250 253 253 253 253 253 253 253, 355 253 258

Celastraceae Ephedraceae

Catha edulis Ephedra distachya Ephedra equisetina Ephedra gerardiana Ephedra intermedia Ephedra procera Ephedra regeliana Ephedra sinica Ephedra tweediana

248-250 253 253 253 253 253 253 253, 355 253

Araceae Celastraceae Ephedraceae

Pinellia ternara Catha edulis Ephedra alata Ephedra altissima Ephedra americana Ephedra andina Ephedra californica Ephedra distachya

256 248 3 , 257, 258 3, 258 3 , 258 3 , 259 258 3 , 253, 258, 26I

(1S,2S)-( +)-Norpseudo-

ephedrine (cathine)

( 1R,2S)-( -)-Ephedrine

~~

(continued)

TABLE IV (Continued)

Compound

Family

Species Ephedra equisetina Ephedra fragilis Ephedra gerardiana Ephedra gerardiana var. sikkimensis Ephedra gracilis Ephedra helvetica Ephedra intermedia Ephedra monosperma Ephedra monostachya Ephedra nebrodensis Ephedra nevadensis Ephedra pachyclada Ephedra procera Ephedra regeliana Ephedra sinica

Ephedra triandra Ephedra trifurca Ephedra tweediana Ephedra vulgaris Malvaceae Sida acuta Sida cordifolia Sida sp. Papaveraceae Roemeria refracta Ranunculaceae Aconitum napellus Taxaceae T a u s baccata

Molecular formula

Reference(s) 3 , 253, 258, 260 3 , 258 3. 251. 253,265 251 3. 258 3 , 258 3 , 251, 253. 258. 259, 262 258 258 3 , 251. 258,263 3 , 258. 264 3 , 259 3 , 253, 258, 259 253 3 , 253. 257. 258, 259. 355 3 , 258 258 3, 253, 258 258 . 295 44. 298 266 267 268 269

( 1S,2S)-( +)-Pseudo-

ephedrine

Ephedraceae

Ephedra alata Ephedra alenda Ephedra altissima Ephedra californica Ephedra distachya Ephedm equisetina Ephedra fragilis Ephedra gerardiana Ephedra gracilis

1 I4

3. 257. 258 258 3 , 258 258 3 , 253. 258, 261 3 , 253. 258, 260 3. 258 3 , 251, 253, 265 3 , 258

TABLE IV (Continued) Compound

Family

Species Ephedra helverica Ephedra intermedia Ephedra major Ephedra monosperma Ephedra monostachya Ephedra nebrodensis Ephedra nebrodensis var. procera Ephedra pachyclada Ephedra procera Ephedra regeliana Ephedra sinica

Mafvaceae Papaveraceae

Ephedra trifurca Ephedra lweediana Ephedra viridis Ephedra vulgaris Sida cordifoIia Roemeria rejiacta

Molecular formula

Reference(s) 3. 258 3. 251, 258. 259, 253, 262 270 258 258 3 , 251, 258.263 251 3 , 259 3 , 253, 258, 259 253 3, 253, 257, 258, 259, 355 258 3. 253, 258 258 258 44

267

(1R,2S)-(-)-N-Methylephedrine

Ephedraceae

Ephedra gerardiana var. sikkimemis Ephedra intermedia Ephedra major Ephedra nebrodensis var. procera Ephedra sinica Ephedra vulgaris

25 1

258, 259, 355 258

Ephedra sinica

258, 259

251 270 251

(1 S,?S)-(+)-N-Methyl-

pseudoephedrine

Ephedraceae

(continued) 115

TABLE IV (Continued) ~~~

Compound

Family

Species

(lS,2S)-( +)-0-Benzoylpseudoephedrine

Molecular formula

~

Reference(s)

C17H19N0

Ephedraceae

Ephedra sp.

271

Ephedraceae

Ephedra intermedia

2 72

Ephedraceae

Ephedra alata

2 73

Celastraceae

Catha edulis

245-247

Celastraceae

Carha edulis

274, 407, 409

Celastraceae

Carha edulis

407, 409

Celastraceae

Catha edulis

274, 407, 408

Ephedroxane (4S,SR)

Ephedralone

( 9 4 - )-Cathinone

(E)-(3S,4S)-Pseudomerucathine

(E)-(S)-Merucathinone

116

TABLE V A N D EPHEDRINES PLANTS CONTAINING PHENETHYLAMINES Family and species (Algae) Ceranium ruburum Cystodonium purpureum Desmarestia aculeata Dumontia incrassata Monostoma fuscum Phyllophora nervosa (DC.) Grev. Polyides rotundus Polysiphonia urceolata (Fungi) Armillaria matsutake Boletus edulis Bull. Boletus luteus L. Boletus zelleri Murr. Claviceps purpurea (Fr.) Tulasne Coprinus atramentarius Bull. Coprinus comatus Gray Coprinus micaceus Bull. Fomes pini (Thore ex Fr.) Overh. Inocybe patouillardi Bres. Marasmius peronatus Nematoloma fasciculare Phallus impudicus L. Philadelphus delavyi L. Phlegmacium mellioleus Pholiota mutabilis Polyporus berkeleyi Fr. Polyporus sulphureus Bull. ex Fr. Po1.yporus spp. Streptomyces griseus Agavaceae Cordulinae terminalis Amaryllidaceae Amaryllis vittata Ait. Crinurn comantus Crinum spp. L. Crinum yuccaforum Salisb. Eucharis grandifora Planch. Haemanthus katharinae Baker Hymenocallis americana Roem. Liriope spicata Pancratium bioforum Pancratium maritimum L. Ungerniaferganica Vved. Ungernia trisphaera Bnge. Ungernia victoris Vved.

Reference(s)

Alkaloid"

Phe Phe Phe Phe DOP Hord Phe Phe Phe, Tyr Phe, Tyr Phe Tyr, Me-Tyr, Hord Phe, Tyr Phe, Tyr TYr Phe Hord Phe Phe Phe Phe, Tyr Phe Phe Phe Hord Phe Tyr, Me-Tyr, Hord N-Acetyl-Tyr

i3 i3 13 13 I 74 140 13

13 14 15 10 60

17. 61 \

I

'

18 62 19

60 20 21 21 22 21 21 21 141 23 60 230

TY

45

Tyr, Me-Tyr, Oct, Synephr TYr TY TYr Synephr Tyr, Me-Tyr, Synephr TYr TYr Phe, Tyr, Hord Phe, Tyr, Me-Tyr, Hord Hord Hord Hord

45 45 45 63 45 45 45 45 25 64. 65 142 143 144 (continued)

117

118

JAN LUNDSTROM

TABLE V (Continued) Family and species Anacardiaceae Schinus terebinthifolius Raddi. Annonaceae Annona reticulata L. Araceae Arum maculatum L. Colocasia anriquorum Schott Pinellia ternata Breit. Asclepiadaceae Vinceroxum oficinale Berberidaceae Nandina domesrica Thunb. Bignoniaceae Jacaranda acutifolia Humb. et Bonpl. Pyrostegia ignea Presl. Cactaceae Ariocarpus agavoides (Castefiada) E. F. Anderson Ariocarpus jssuratus var. jssuratus (Engelm.) Schum. Ariocarpus jssuratus var. lloydii (Rose) Marsh. Ariocarpus kotschoubeyanus (Lem.) Schum. Ariocarpus retusus Scheid. (Anhalonium prismaricum Lem.) Ariocarpus schapharosrrus Boed. Ariocarpus trigonus (Web.) Schum. Azureocereus ayacuchensis Johns. Eackebergia militaris (Andot) Bravo ex Sanches Mejorada Carnegiea gigantea (Engelm.) Br. et R. Cereus aethiops Haw. Cereus alacriportanus Pfeiff. Cereus forbesii 0. Cereus glaucus SD. Cereus jamcaru DC . Cereus peruvianus (L.) Mill. Cereus peruvianus monstruosus DC. Cereus validus Haw. Coryphantha bumamma (Ehren.) Br. et R.

Alkaloid"

Reference(s)

45 175

Phe TYr EPh

26 45 256

Phe

21

Tyr, Hord

45 45 45

Hord, N-Me-Homova, N,N-diMe-3-MeO-Tyr Hord, N-Me-Tyr N-Me-Homova Hord, N-Me-Tyr

122 204 122

Hord, N-Me-Tyr

123

Hord, N-Me-Tyr N-Me-4-MeO-Phe, N-Me-Homova Hord, N-Me-Tyr, N-Me-Homova, N,N-diMe-Homova H o d , N-Me-Tyr, N-Me-Homova TYr Homova, N-Me-Homova, N,N-diMeHomova, 3-MeO-Tyr 3-MeO-Tyr, Homova, Dop

124

Tyr, H o d , candicine Hord TYr Tyr, Hord TYr Tyr, Hord S r 3-N02-Tyr Hord, N-Me4-MeO-Phe, N-MeHomova

80

173

125 126 66 189, 190, 201. 359 6, 7, 191 67 68 68 68 69 68. 70 68 300

128, 145

119

2. P-PHENETHYLAMINES AND EPHEDRINES

TABLE V (Continued) Family and species Coryphantha calipensis H. Bravo

Coryphantha cornifera (DC.) Lem.

Coryphantha cornifera (DC.) Br. et R. var. echinus (Engelm.) L. Benson Coryphantha duranguensis (Riinge) Br. et R. Coryphantha elephanaridens Lem.

Coryphanrha greenwoodii H. Bravo

Coryphantha macromeris (Engelm.)

Lem. Coryphantha macromeris var. runyonii L. Benson

Coryphantha missouriensis (Sweet) Br. et R. Coryphantha ottonis (Pfeiff.) Lem. Coryphanrha pectlnara (Engelm.) Br. et R. Coryphanrha poselgeriana (Dietr.) Br. et R. Coryphantha radians (DC.) Br. et R. Coryphantha ramillosa Cutak. Coryphantha vivipara (Nutt.) Engelm. Coryphanrha vivipara (Nutt.) Br. et R . var. arizonica (Engelm.) W. T. Marshall Dolichothele longimamma (DC.) Br. et R.

Alkaloid' N-Me-Tyr, Hord, N-Me-Homova, N,N-diMe-Homova, nor-Macr, calipamine, N-methylsalipamine 4-MeO-Phe, Hord, N-Me-Homova, 4-MeO-P-OH-Phe, Synephr, p-0Me-Synephr N-Me-Tyr, H o d , N-Me-4-MeO-Phe, N-Me-Homova, 4-MeO-p-OH-Phe, Synephr, p-0-Me-Synephr, Macr Hord, N-Me-Homova, Synephr N-Me-Tyr, Hord, N-Me-Homova, NMe-4-MeO-Phe, 4-MeO-p-OHPhe, Synephr, Macr Hord, N-Me-Homova, N,N-diMeHomova, 0-Mecandicine, p-0Me-Synephr, Synephr, nor-Macr, calipamine, N-Me-calipamine Macr

Reference( s) 127. 128, 146. 228 129

129

129 129

128, 146, 166

226, 227

Tyr, N-Me-Tyr, Hord, N-Me-4-MeOPhe, N-Me-Homova, Synephr, metanephrine, N-methylmetanephrine, nor-Macr, Macr, N-formylnor-Macr Tyr, N-Me-Tyr, Hord, N-Me-Homova

68. 70. 130, 147. 225

N-Me-Tyr, Hord, 4-MeO-Phe, Synephr N-Me-Tyr, Hord, N-Me-Homova, 4-MeO-p-OH-Phe, Synephr, p-0Me-Synephr N-Me-Tyr, Hord, 4-MeO-Phe, Synephr N-Me-Tyr, Hord N-Me-Tyr, Hord, N-Me-4-MeO-Phe, Synephr, P-0-Me-Synephr Hord

129

128. 148

Hord

149

Synephr, nor-Macr, longimammamine

52, 21 7

72

54. 129

129 128 133

(continued)

120

JAN LUNDSTROM

TABLE V (Continued) Family and species Dolichothele sphaerica (Dietr.) Br. et R. Dolichothele surculosa (Boed.) F. Buxb. Dolichothele uberiformis (Zucc.) Br. et R. Echinocereus cinerascens (DC.) Riimpler Echinocereus merkerii Hildm. Echinopsis eyriesii (Turpin) Zucc. Echinopsis rhodotricha K. Schum. Escontria chiotilla (Web.) Rose Esposroa huanucensis Ritt. Gymnocactus aquirreanus Glass et Foster Gymnocactus beguinii (Web.) Backbg . Gymnocactus horripilus (Lem. ) Backbg . Gvmnocactus knurhianus (Boed.) Backbg . Gymnocactus mandragora (Fric.) Backbg. Gymnocactus roseanus var. el Chifon Gymnocactus viereckii (Werd. ) Backbg. Gymnocactus gibbosum (Haw.) Pfeiff. Gymnocalycium leeanum (Hook.) Br. et R. Gymnocalycium schickendantzii (Web.) Br. et R. Helianthocereus huascha (Web.) Backbg. Helianrhocereus pasacana (Web. ) Backbg. Islaya minor Backbg. Lobivia alegriana Backbg. Lobivia aurea (Br. et R.) Backbg. Lobivia backebergii (Werd.) Backbg. Lobivia binghamiana Backbg. Lobivia huashua (Web.) W. T. Marshall Lobivia penrlandii (Hook.) Br. et R.

Alkaloid

Reference(s)

(1

N-Me-Phe, N-Me-Tyr, Synephr, p-0Me-Synephr N-Me-Phe, N-Me-Tyr, Hord, Synephr N-Me-Tyr, Hord, N-Me-4-MeO-Phe. N-Me-Homova, Synephr, nor-Macr, ubine N-Me-Homova, N,N-diMe-Homova

51 52 68, 84, 136

205

3-MeO-Tyr, Hord, Homova, N-MeHomova, N,N-diMe-Homova Hord Tyr, Hord 3.5-DiMe0-4-OH-Phe Tyr, N-Me-Tyr, Hord N-Me-Phe, N-Me-Tyr, Hord

68 73 420 74, I38 53

N-Me-Phe, N-Me-Tyr, Hord

53

N-Me-Phe, Hord

53

N-Me-Phe

53, 54

N-Me-Phe, N-Me-Tyr

53

N-Me-Phe, N-Me-Tyr, Hord N-Me-Phe

53 53

Mesc Tyr, N-Me-Tyr, Hord, Mesc

'

137

75 70, 75

Hord, candicine

67

Hord

68

Hord

68

Phe, Tyr, N-Me-Tyr, Hord, 3-Me0Tyr, Homova, Mesc Tyr, N-Me-Tyr, Hord Tyr, N-Me-Tyr, Hord Tyr, N-Me-Tyr, Hord Tyr, N-Me-Tyr, Hord Tyr. N-Me-Tyr, Hord

27 76 76 76 76 76

Tyr, N-Me-Tyr, Hord

76

121

2.8-PHENETHYLAMINES AND EPHEDRINES

TABLE V (Continued) Family and species Lophocereus schorrii (Engelm.) Br. et R. Lophophoru drfusu (Croizat) H. Bravo Lophophoru echinutu Lophophoru wifliumsii (Lem.) Coult.

Alkaloid"

DOP

i77

Mesc

357

Mesc Tyr, N-Me-Tyr, Hord, N.N-diMe-3MeO-Phe, 3-MeO-Tyr. Homova. epinine, Dop, candicine, 3, 4-diOH-5-MeO-Phe. 3-OH-4, 5-diMeO-Phe, N-Me-3-OH-4, 5-diMeO-Phe, N.N-diMe-3OH-4.5-diMeO-Phe

421 1, 10-12, 25, 77, 150. 165, 176. 192, 202, 207. 208. 210. 213

N-formyl-3-OH-4,5-diMeO-Phe, N-acetyI-3-OH-4,5diMeO-Phe, Mumillaria elongura DC. Mumilluriu heyderii Muhl. Mumilluriu microcurpa Engelm. Melocactus delesserriunus Lem. Melocactus muxonii (Rose) Giirke Neoruimondiu orequipensis var. ros$oru (Werd. et Backbg.) Rauh Norocactus otronis (Lem.) Berg. ex Backbg. et Knuth. Obregoniu denegrii Fric. Opunriu ucunrhocurpu Engelm. et Bigel. Opuntiu aurantiucu Lindley Opunriu busiluriu Engelm. et Bigel. Opunriu cluvutu Engelm. Opunriu echinocurpa Engelm. et Bigel. Opuntiu exulruta (Berg.) Backbg. Opunriu Jicus-indicu Opunriu imbricuru Haw. Opunriu invicru Brandeqee Opunriu kleiniue DC. Opunriu muldonensis Arech. Opuntiu rumosissimu Engelm. Opunriu schorrii Engelm. Opunfiu spinosior (Engelm.) Tourney Opunfiu sfunfyi Engelm. var. var. kunzei (Rose) L. Benson

Reference( s)

Mesc, N-Me-Mew, N-formylMesc, N-acetyl-Mew Tyr, ff-Me-Tyr, Hord, Synephr, 8-0Me-Synephr N-Me-3.4-diMeO-Phe Tyr, N-Me-Tyr, Hod, Homova TYr Tyr, Homova, 3,5-diMeO-4-OH-Phe Homova. 3-5-diMeO-Q-OH-Phe

420

Hord

70

Tyr, N-Me-Tyr, Hord Homova, Mesc, 3.5diMe0-4-OHPhe Hord 3,5-DiMe0-4-OH-Phe, Mesc Tyr, N-Me-Tyr, Hord Homova, Mesc, 3.5-diMe0-4-OHPhe Homova, 3,5-diMe04OH-Phe Phe Tyr, 3-MeO-Tyr, Homova, Mesc Tyr, N-Me-Tyr, Hord Tyr, N-Me-Tyr Hord Homova Tyr, N-Me-Tyr, Hord Tyr, 3-MeO-Tyr, Homova, Mesc Tyr, N-Me-Tyr

54, 80. 81 420

78. IS1 80 131, 415 27 27, 420 \

70 420 82 420 420 24 83 83 83 70 420 83 84. 85 83

(continued)

122

JAN LUNDSTROM

TABLE V (Continued) Family and species Opuntia sranlyi var. sranlyi Engelm. Opunria subulara (Muhlenpf.) Engelm. Opuntia versicolor Engelm. Opuntia vulgaris Mill. Opuntia whipplei Engelm. et Bigel. Pachycereus pecten-aboriginum (Engelm.) Br. et R. Pelecyphora aselliformis Ehren. Pelecyphora pseudopectinara Backbg . Pereskia aculeata Mill. Pereskia autumnalis (Eichlam) Rose Pereskia corrugara Cutak. Pereskia cubensis Br. et R. Pereskia godseflana (Sand.) Knuth. Pereskia grandifolia Haw. Pereskia grandifora Hort. Pereskia piritache (Karwinsky) Br. et R. Pereskia rampicana Web. Pereskiopsis chapisrle (Web.) Br. et R. Abbey Pereskiopsis scandens Br. et R. Pilosocereus chrysacanthus (Web.) Byl. et Rowl. Pilosocereus guerreronis (Backbg.) Byl. et Rowl. Pilosocereus maxonii (Rose) Byl. et Rowl. Polaskia chende (Gossel.) Gibs. et Horak Pseudolobivia kermesina Kainz. Pterocereus foetidus M a c h u g . et Mir. Pterocereus gaumeri (Br. et R.) M a c h u g . et Mir. Solisia pectimta (B. Stein) Br. et R. Stenocereus beneckei (Ehren.) Buxb. Stenocereus eruca (Brandeg.) Gibs. et Horak Stenocereus stellatus (Pfeiff.) Rice.

Alkaloid'

Reference(s)

Tyr, N-Me-Tyr 3-MeO-Tyr

83 83

Tyr, N-Me-Tyr, Hord Hord Homova 3-MeO-Tyr, Homova, 3-OH-4-Me0Phe Hord, Mesc, N-Me-Mesc, Homova, N-Me-Homova, N.N-diMe-3OH-4.5-diMeO-Phe Hord TYr Phe, Tyr Tyr, 3-MeO-Tyr, Homova, Mesc TYr 3-MeO-P-OH-Phe Tyr, 3-MeO-Tyr Tyr, P-OH-Mesc Phe, Tyr

83 70 83 69. 193 73. 135, 421

80 27 27 27 27 27 27 27 27

Phe, Homova, Mesc Phe, Tyr, 3-MeO-Tyr, 4-MeO-P-OHPhe Tyr, Mesc, 3,4-diMeO-P-OH-Phe N-Me-Homova

27 27

N-Me-Homova, N,N-diMe-Homova

206

Tyr, N-Me-Tyr, N-Me-3-MeO-Tyr, N,N-diMe-3-MeO-Tyr, Homova, N-Me-Homova Homova, 3.5-diMe0-4-OH-Phe. Mesc Tyr, Homova Homova, 3,5-diMeO-4-OH-Phe

86

Homova, Mesc, 3.5-diMe0-4-OHPhe N-Me-Tyr, Hord Homova, Mesc, 3,5-diMe0-4-OHPhe Homova, Mesc, 3,5-diMe0-4-OHPhe Homova, Mesc, 3,5-diMe0-4-OHPhe

27 205

420 76 420 420 80 420 420 420

2. P-PHENETHYLAMINES A N D EPHEDRlNES

123

TABLE V (Continued) Family and species Stenocereus treleasei (Br. et R . ) Backbg. Srersonia coryne (SD.) Br. et R .

Trichocereus bridgesii (SD.) Br. et R. Trichocereus carnarguensis Card. Trichocereus candicans (Gill.) Br. et R. Trichocereus chilensis (Colla.) Br. et. R. Trichocereus courantii (K. Schum.) Backbg. Trichocereus cuzcoensis Br. et R. Trichocereus fulvianus Ritt. Trichocereus larnprochlorus (Lem.) Backbg. Trichocereus knuthianus Backbg. Trichocereus rnacrogonus (SD.) Ricc. Trichocereus rnanguinii Backbg. Trichocereus pachanoi Br. et R .

Trichocereus pasacana (Web.) Br. et R. Trichocereus peruvianus Br. et R . Trichocereus purpureopilosus Wgt. Trichocereus santiaguensis (Speg.) Backbg. Trichocereus schickendanrzii (Web.) Br. et R. Trichocereus skotrsbergii Backbg . Trichocereus spachianus (Lem.) Ricc. Trichocereus strigosus (SD.) Br. et R. Trichocereus tuquirnbalensis Card. Trichocereus terscheckii (Parm. ) Br. et R. Trichocereus thelegonus (Web.) Br. et R. Trichocereus thelegonoides (Speg. ) Br. et R. Trichocereus tunariensis Card. Trichocereus vulidus (Monv.) Backbg.

Alkaloid"

Reference( s)

Homova, Mesc, 3,5-diMe0-4-OHPhe Tyr, N-Me-Tyr, Homova, 3-Me0Tyr, Mesc, coryneine, oxycandicine Tyr, 3-MeO-Tyr, Homova, Mesc Tyr, N-Me-Tyr, 3-MeO-Tyr, Homova Tyr, N-Me-Tyr, Hord, candicine

68 68 68, 74, 167

Candicine

168

Tyr, N-Me-Tyr, 2-MeO-Tyr, Homova, N-Me-3-MeO-Tyr Tyr, 3-MeO-Tyr, 3-OH-4, 5-diMeOPhe, Mesc Tyr, N-Me-Tyr, Mesc Hord, Candicine

73

Tyr, 3-MeO-Tyr Tyr, 3-MeO-Tyr, Homova, Mesc Tyr, N-Me-Tyr, Hord, 3-MeO-Tyr Tyr, Hord, 3-MeO-Tyr, Homova, Mesc, 3,5-diMeO-4-OH-Phe, 3.4-diMeO-5-OH-Phe Tyr, N-Me-Tyr, Hord, candicine

420 73, 185. 186

73 73 68, 169

73 68 73 68. 87, 197, 209, 213 88

Tyr, 3-MeO-Tyr, Mesc, Homova, 3,5-diMeO-4-OH-Phe Tyr, N-Me-Tyr Tyr, Hord

73 73

N-Me-Tyr, Hord

68

N-Me-Tyr, Hord Tyr, N-Me-Tyr, Hord, candicine Hord Hord, 3-MeO-Tyr, Homova, Mesc Mesc. trichocereine

73 68. 74 73 73 68. 211, 212

N-Me-Tyr, Hord

73

Hord

73

Tyr, Hord Mesc

73 73

195

(continued)

JAN LUNDSTROM

TABLE V (Continued) Family and species Trichocereus werdermannianus Backbg. Turbinicarpuspseudomarrochele (Backbg.) F. Buxb. et. Backbg. Wigginsia erinacea (Haw.) D.M. Porter Wigginsia macrocantha (Arech.) D. M. Porter Wigginsia tephracantha (L. et 0.) D. M. Porter Cannabinaceae Cannabis sativa L. Caprifoliaceae Lonicera maackii Maxim Sambucus canadensis L. Viburnum lanata L. Viburnum odoratissimum Ker. Celastraceae Catha edulis Forsk.

Chenopodiaceae Anabasis jarartica (Bge.) Benth. Arthrophytum leptocladum M. Pop. Beta vulgaris L. Beta vulgaris var. cruenta L. Halostachys caspica Haloxylon salicornicum (Moq.-Tand.) Boiss. Spinacia oleracea L. Compositae Aster linariifolius L. Critoniella acuminata Silybum marianum (L.)Gaertn. Spilantes ocymifolia Cornaceae Cornus alba L. ssp. tartarica Cornus sanguinea L. Cruciferae Erassica oleracea L. Capsella bursapastoris (L.) Medic. Raphantus sativus L. Cucurbitaceae Citrullus vulgaris Schrad. Cucumis sativus L.

Alkaloid

Reference( s)

Tyr, 3-MeO-Tyr, Homova, Mesc, 3.5-diMe0-4-OH-Phe Hod

80

Hord

70

Hord

70

Hord

70

Hod

147

Phe TYr Phe TYr

26 45 26 45

Eph, nor-Eph, nor-eEph, cathinone, merucathine, pseudomerucathme, merucathinone

245 -248, 250, 407409

N-Me-Tyr N-Me-Phe DOP TYr Halostachine Tyr, N-Me-Tyr, Synephr

I32 55 178, 179. 360 215 89

Tyr, Dop

90. 180

TYr

(0and (3-Dioxymethylenecinnamic

45 422

acid phenethylamide TYr N-Phenethylcinnarnamide

91, 92 229

Phe Phe

21 21

73, 87

360 93 360 360 360

125

2.8-PHENETHYLAMINES AND EPHEDRINES

TABLE V (Continued) Family and species Cyperaceae Cyperus papyrus L. Cyperus rotundus L. Mariscus jamaicensis Crantz Ephedraceae Ephedra alata Decne.

Alkaloid a

Tyr, Oct Oct TYr

45

Eph, JIEph, ephedralone

3 , 257, 258, 2 73 258 3. 258 3 , 258 3. 259 258 3 , 253, 258. 261 3 , 253. 258. 260 3 , 258 3 , 251. 253, 265 251

Ephedra alenda (Stapf.) Andreanszky Ephedra alrissima Desf. Ephedra americana Humb. et Bonpl. Ephedra andina Poepp. Ephedra californica Wats. Ephedra distachya L.

Wph Eph, W p h EPh EPh Eph, JlEph Eph, JIEph, nor-Eph, nor-JIEph

Ephedra equiserina Bnge

Eph, JIEph, nor-Eph, nor-JIEph

Ephedra fragilis Desf. Ephedra gerardiana Wall.

Eph, JIEpf Eph, JIEph, N-Me-Eph, nor-Eph, nor-JIEph Eph, N-Me-Eph

Ephedra gerardiana Wall. var. sikkimensis Ephedra gracilis R. Phil. Ephedra helvetica C. A. Mey Ephedra intermedia Schrenk et C. A. Mey

Eph, JIEph Eph, W p h Eph, JIEph, nor-Eph, nor-JIEph, ephedroxane

Ephedra major Ephedra monosperma S . G . Gmel. Ephedra monostachya L. Ephedra nebrodensis Tineo

JIEph, N-Me-Eph Eph, JIEph Eph, JIEph Eph, JIEph, N-Me-Eph

Ephedra nebrodensis var. procera Ephedra nevadensis Wats. Ephedra pachyclada Boiss. Ephedra procera C. A. Mey

JIEph, N-Me-Eph EPh Eph, W p h Eph, JIEph, nor-Eph, nor-JIEph

Ephedra regeliana Florin Ephedra sinica Stapf.

Eph, nor-Eph, JIEph, nor-JIEph Eph, JIEph, N-Me-Eph, N-Me-$Eph, nor-Eph, nor-JIEph 0-Benzoyl-JIEph EPh Eph, JIEph Eph, nor-Eph, JIEph, nor-JIEph Eph, JIEph Eph, JIEph, nor-Eph, N-Me-Eph

Ephedra sp. Ephedra niandra Tulasne Ephedra rrifurca Tom. Ephedra hveediana C. A. Mey Ephedra viridis Coville Ephedra vulgaris L. C. Rich

Reference( s)

45

45

3. 258 3 , 258 3. 251. 253. 258, 259. 262, 272 2 70 258 258 3 , 251, 258, 263 251 3 , 258, 264 3, 259 3. 253. 258, 259 253 3, 253, 257-259 271 3. 258 258 253. 258 258 252, 258

(continued)

126

IAN LUNDSTROM

TABLE V (Continued) Family and species Ericaceae Erica lusitanica Rud. Euphorbiaceae Croton humilis L. Securinega virosa Baill. Geraniaceae Erodium cicutarium L. Graminae Andropogon sorghum Hordeum murinum L. Hordeum vulgare L. Lolium multiforum Lam. Lolium spp. Panicum miliaceum L. Phalaris arundinacea L. Sorghum vulgare Pers. Triricum vulgare Vill. Zea mays L. Hydrastinaceae Hydrastis canadensis Juglandaceae Juglans nigra L. Labiatae Lumium album L. Lauraceae Ocorea pretiosa Persea americana Mill. Leguminosae Acacia accola Maiden et Betche Acacia acinacea Lindley Acacia adunca Acacia augustissirna Acacia berlandieri Acacia buxifolia Cunn. Acacia cardiophylla Acacia constricta Acacia culrriformis Cunn. Acacia floribunda Sieb. Acacia greggi Acacia harpophylla Acacia holocerica Acacia kettleweilliae Maiden Acacia longifolia Willd. Acacia lunata Sieb.

Alkaloid"

Reference( s)

4-MeO-Phe

I72

N-Me-Tyr, Me-homotyr Hord

I34 I52

TYr

94

Hord Hord Tyr, N-Me-Tyr, Hord, candicine Oct, annuloline Oct Tyr, N-Me-Tyr, Hord Hord Hord N-Me-Tyr, Hord TY~

153 I54 95, 96 216, 244 216 97, 98. I38 155 139, I53 96. 139 99

Nor-Epi

220 45 100

Phe Tyr, Dop

101 90

Phe, N-Me-Phe Phe N-Me-Phe N-Me-Phe N-Me-Phe, Tyr, Phe Phe N-Me-Phe Phe Phe N-Me-Phe, Tyr Phe, Hord Hord Phe, N-Me-Phe Phe Phe

28 29 31 56 ile-Tyr, Hord

57, 9

29 28 56 30 30 56

31 31 28, 31 30 30

127

2. P-PHENETHYLAMINES AND EPHEDRINES

TABLE V (Continued) Family and species Acacia podalyriaefolia Cunn. Acacia praetervisa Domin. Acacia pravissima F.v.M. Acacia prominens Cunn. Acacia pruinosa Cunn. Acacia rigidula Acacia roemeriana Acacia schottii Acacia spectabilis Cunn. Acacia spriorbis Labill. Acacia suaveolens Willd. Acacia texenis Acacia verticillata Willd. Albizzia adianthifolia (Schum.) W. F. Wight Albizzia julibrissin Durazz. Alhagi pseudalhagi (Bieb.) Desv.

Calliandra haematocephala Hassk. Cassia alta L. Cassia marilandica L. Cytisus scoparius (L.) Link Dalea frutescens Desmodium cephalotes Wall. Desmodium jloribundum Desmodium gangeticum DC. Desmodium gyrans DC. Desmodium tiliaefolium (G.) Don. Desmodium triforum DC. Entada pursaetha DC. Erythrina cristagalli L. Gleditsia triacanthos L. Mimosa pudica L. Phaseolus multiforus Lam Phaseolus radiatus L. Pisum sativum L. Prosopis alba Gris. Prosopis glandulosa Prosopis nigra Samanea saman Merr. Spartium scoparium Trifolium alexandrinum L. Vicia faba L.

Alkaloid" Phe Phe, N-Me-Phe Phe Phe, N-Me-Phe Phe N-Me-Phe, N-Me-Tyr N-Me-Phd, Tyr, N-Me-Tyr N-Me-Phe Phe Hord Phe N-Me-Phe, Tyr Phe Phe Nor-Epi Phe, N-Me-Phe, N-Me-Tyr, Hord, N-Me-Mesc, coryneine, N.N. N-triMe-3-MeO-4-OH-Phe TY TYr N-Me-Phe Tyr, Dop, N-Me-Dop, epinine N-Me-Phe Phe, Tyr, Hord, candicine Hord Phe, N-Me-Tyr, Hord, candicine Phe Tyr, Homova, N,N-diMe-Homova, N-Me-3,CdiMeO-P-OH-Phe Phe, Tyr, Hord, coryneine Dop-3-0-glucoside TYr N-Me-Phe, Tyr Nor-Epi Nor-Epi TYr Tyr, nor-Epi Phe, Tyr Tyr, N-Me-Tyr Phe, Tyr Nor-Epi Dop, Epinine TYr Epinine

Reference(s) 28, 31 28 31 30, 32 30 56 56 56 28 30, 160 30 56 29 33 105 34. 35

45 45 56

102, I58 56 36 424 161, I62 37 103 38 181 45 56 105 105 104

I05,I 0 6 39 56 350 105 182 107 184 (continued)

128

JAN LUNDSTROM

TABLE V (Coniinued) Family and species Liliaceae Chlorophyium capense Kuntze Cordyline terminalis Knuth. Eremurus regelii Vved. Liriope spicaia Lour. Loranthaceae Phoradendron sp. Phoradendron argentinum Urb. Phoradendron jlavescens Nun. Phoradendron hieronymi Trel. Phoradendron wattii Kr. et Urb. Phoadendron liga (Gill.) Eichlam Phoradendron villosum Phyrgilanihusjlagellaris (Chapm . et Schlecht) Eichlam Psitiacanrhus cuneifolius (Ruiz et Pav.) Blume Viscum album L. Magnoliaceae Magnolia denudata Magnolia grandipora Magnolia kobus Magnolia liliijora Magnolia salicipora Magnolia spp. Magnolia sprengeri Magnolia stellaia Michelia alba Malvaceae Sida acuia Sida cordifolio L. Sida sp. Moraceae Ficus bengalensis L Musaceae Musa paradisica L. Musa sapienium Nandinaceae Nandina domesiica N yctaginaceae Hermidium alipes Wats. Orchidaceae Caiileya spp. Erin jarensis

Alkaloid"

TYr TYr Hord Tyr, Oct

Reference(s)

45 45 163 45 45 I08 40.41 I08 109 109 42 I09 109

Phe, Tyr

41-43

Salicifoline Salicifoline Salicifoline Salicifoline Salicifoline Tyr, salicifoline, candicine N.N-DiMe-3-MeO-Tyr Salicifoline Salicifoline

1% 111 197

EPh Phe, Eph, #Eph EPh

200

I98 110-113 156

.

199

113 295 44. 298 266 45

Nor-Epi

45, 90.221, 222 219

Hord

45

Phe, Tyr, nor-Epi, Dop

183

TYr N.N-DiMe-Phi

114 59

129

2. P-PHENETHYLAMINES AND EPHEDRINES

TABLE V (Continued). Family and species Papaveraceae Chelidonium majus L. Roemeria refracra DC. Passifloraceae PassiJlora quadrangularis L. Piperaceae Piper amalago L. Plumbaginaceae Limonium vulgare Mill. Polygonaceae Eriogonum alarum Eriogonum annuum Eriogonum campanularum Eriogonum infatum Portulaceae Portulaca oleracea L. Ranunculaceae Aconirum napellus L. Aconitum nasutum Aconitum paniculatum Lam. Aconitum tanguticum Rosaceae Craraegus ( 3 spp.) Crataegus (8 spp.) Malus sp. Prunus amygdalus Batsch. Prunus domesrica L. Prunus padus L. Prunus communis L. Rubus idaeus L. Sorbaria sorbifolia A. Br. Sorbus aucuparia L. Spiraea bracreata Zabel Rutaceae Aegle marmelos Corn. Casimiroa edulis Llave et Lex. Citrus limon Burm. Citrus medica L. X sinensis Osbeck Citrus reshni Hort. ex Tan. Cirrus reticulata Blanco Citrus reticulata Blanco X sinensis Osbeck Citrus sinensis Osbeck Clausena brevistyla Evodia belahe

Alkaloid"

Reference( s)

115

267

Nor-Epi

I05 109 116

Hord, N-Me-4-MeO-Phe Hord, N-Me-4-MeO-Phe Hord, N-Me-4-MeO-Phe Hord. N-Me-4-MeO-Phe

423 423 423 423

Dop, nor-Epi

8

Tyr, Dop, nor-Epi, Eph N-Me-Epi Nor-Epi Hord

117, 223 224 223 157

Phe Phe Phe Phe Tyr, Nor-Epi Phe Phe Tyr Phe Phe Phe

26 21 26 46 90 26 21 118 21 21 26

Aegelin, tembamide N-Benzoyl-Tyr Tyr, N-Me-Tyr, Oct, Synephr Tyr, Oct, Synephr Tyr, N-Me-Tyr, Oct, Synephr Tyr, N-Me-Tyr, Hord, Oct, Synephr Tyr, Oct, Synephr

233. 237 23 I 119. I20 119 45, 120 45

Tyr, N-Me-Tyr. Synephr, nor-Epi Tembamide N-Cinnamoy I-Tyr

45, 90 234 232

119

(continued)

130

JAN LUNDSTROM

TABLE V (Continued) Family and species Fagara hyemalis Fagara rubescens Fagara spp. Phellodendron amurense Rupr. Pleiospermium alatum (Wight et Am.) Swingle Teclea simplicifolia Zanthoxylum clava-herculis L. Zanthoxylum conspersipunctatum Saxifragaceae Philadelphus delavayi Solanaceae Atropa belladonna L. Capsicum frutescens L. Lycopersicon esculentum Mill. Nicotiana tabacum L. Solanum melongena L. Solanum tuberosum L. Taxaceae Taxus baccata L. Theaceae Thea sinensis L. Umbelliferae Daucus carota L. Verbenaceae Stachytarpheta jamaicensis Vahl. Vitaceae Vitis vinifera L.

Alkaloid' Coryneine, tembamide Rubescamide Candicine, coryneine, tembamide

Reference(s) 187, 235 239 187, 188. 235 159 243, 238

Candicine Alatamide, N-benzyl-CMeO-Tyr, Nhomoveratroyl-Homova N.N-DiMe-4-MeO-Phe, Hord Herclavin, candicine Tembamide

170, 171 236

Phe

21

Phe Oct TYr Phe, Tyr TYr Tyr, Dop, nor-Epi

26 45 45, 90 47-49. 416 90 90, 121, 360

EPh

269

Phe

50

164

360 109 361

Key to alkaloids: Dop, dopamine; Epi, epinephrine; Eph, ephedrine; $Eph, pseudoephedrine; Homova, homoveratrylamine; Hord, hordenine; Macr, macromerine; Mesc, mescaline; Oct, octopamine; Phe, phenethylamine; Synephr, synephrine; Tyr, tyramine.

260, 26.3, 265, 276, 277) as well as the variation of alkaloidal content with place of growth and time of harvest (2,262-264,278,279).The most abundant alkaloids in Ephedru species are ephedrine and pseudoephedrine, and the other alkaloids appear to be minor constituents. A good grade of Mu Huung should yield 1-2% of total alkaloids ( 2 ) . Another important source of alkaloids of the ephedrine type is the khat shrub Cutha edufis (284), cultivated in certain parts of eastern Africa and southern Arabia. Two major alkaloids in khat are norpseudoephedrine and norephedrine, which occur in a proportion of approximately 4: 1 (250). A new alkaloid, (S)-2-aminopropiophenone,has been discovered in fresh leaves of khat and

2. B-PHENETHYLAMINESAND EPHEDRINES

131

given the name cathinone (245-247, 255). This alkaloid is present mainly in young leaves of the khat shrub and may account for more than two-thirds of the total phenylalkylamine alkaloids (285, 286). When cut leaves wilt, cathinone is converted to norpseudoephedrine (286). Findings indicate that cathinone is responsible for the stimulating properties of the khat drug (284). The total content of phenylalkylamine alkaloids in commercial samples of khat varies between 0.1 and 0.5% of dry weight (287). In khat of Kenyan origin, the novel phenylalkylamines merucathinone, merucathine, and pseudomerucathine have been found (274, 407-409).

111. Isolation, Identification, and Determination Procedures The methods employed for isolation of the alkaloids depend on the nature of the compounds, and specific conditions have frequently been devised for the selective isolation of particular types of compounds. Usually, fresh or dried plant material is extracted with dilute acid solution or with alcohol, and the extract obtained is further fractionated by extraction into organic solvents with variation of pH. Extraction columns (288), membrane processes (425), and ion-exchange materials (288-290) may be particularly useful for subfractionation or isolation procedures. For further identification and isolation of separate compounds, preparative thin-layer chromatography, (288, 291, 292, 426), liquid chromatography (293,294), or gas chromatography may be used (202,296,297). Because some of the products reviewed in this chapter occur naturally in very small amounts, they have not been isolated in crystalline form. Gas chromatographymass spectrometry (87,213,299), mass fragmentography (192), and mass spectrometry-mass spectrometry (301, 359) have proved to be particularly useful techniques for identification of trace alkaloids in complex mixtures. The oriental crude drug Mu0 (Epedrae Herba) is contained in various oriental pharmaceutical preparations (255). Since the content of ephedrine alkaloids in this drug may vary with the Ephedru species used for its preparation and with, e.g., harvest conditions, it has been important to develop quantitative analytical methods in order to evaluate the quality. In recent years several sensitive and specific methods for the simultaneous determination of ephedrine alkaloids in plant material have been published. These include thin-layer chromatography (292,426), gas chromatography (251), straight-phase and reversed-phase high-performance liquid chromatography (253, 255, 302, 355, 427), isotachophoresis (303, 356), and I3C-NMR (304). Resolution of enantiomeric alkaloids by HPLC has been achieved on chiral stationary phases (417, 418) or after derivatization with a chiral agent on an achiral stationary phase (419). Chromatographic separation and analytical detection of

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khat alkaloids and cactus alkaloids were reviewed in Volume 32 of this treatise (406).

IV. Synthesis A wide variety of methods have been described for the synthesis of variously substituted phenethylamines. Some frequently used procedures are presented in Scheme 1. Most of these have been discussed in previous reviews (305. 306). Condensation of an appropriately substituted benzaldehyde with nitromethane followed by reduction of the nitrostyrene (Method A) has proved to be a versatile method which has been employed by numerous workers (cf. 306, 358). Another common method (Method B) affords the amines by reduction of substituted phenylacetonitriles obtained via benzylchlorides (cf.. 306) or benzylamines (307). Reduction of phenylacetamides with lithium aluminum hydride (Method C) has also been applied successfully (308, 309). The substituted phenylacetamides were obtained either via diazoketones by an Arndt-Eistert synthesis (308) or by transformation of the corresponding acetophenones (310). Reduction of oxonitriles (Method D) may afford either phenethylamines or phenylethanolamines, depending on the reaction conditions (311, 312). Alternative methods for the synthesis of phenylethanolamines are exemplified by reduction of 2-aminoacetophenones (Method E) (313) or by reduction of cyanohydrines (Method F) (314). Octopamine has been recently synthesized in high yield via a BH,.THF-catalyzed reduction of a trimethylsilyl cyanide adduct (Method G) (315). Two other amino alcohols were synthesized in similar yields, suggesting that this method is of general value for the preparation of this class of compounds. The synthesis of ephedrine shown in Method H is of commercial interest (316). Condensation of benzaldehyde with nitroethane gives a diastereomeric mixture of nitro alcohols. Reduction yields a separable mixture of (*)-norephedrine and (+)-norpseudoephedrine. Methylation of (+.)-norephedrineyields (*)-ephedrine, which can be resolved into optical antipodes by chemical methods. A stereoselective synthesis of (*)-ephedrine and (*)-methylephedrine has been described (318). The method utilizes a carbanion, in which the negative charge is located a! to the nitrogen, formed by deprotonation of 1. Subsequent reaction with benzaldehyde yields the 2-oxazolidone 2, and thermal removal of the diphenylphosphinyl group gives the 2-oxazolone 3. Hydrogenation of 3 proceeds with perfect stereoselectivity to yield the erythro isomer 4, which is easily converted to (+.)-ephedrine or (+.)-N-methylephedrine. Two new stereospecific syntheses of L-ephedrine were reported in 1984. Reduction of the N-protected amino ketone 5 with dimethylphenylsilanein trifluoroacetic acid (TFA) gave the N-protected amino alcohol 6 with high (>99%)

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).

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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).

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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

3. LYTHRACEOUS ALKALOIDS

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

3. LYTHRACEOUS ALKALOIDS

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

3. LYTHRACEOUS ALKALOIDS

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<

COOMe OMe

Me0

-

COOL

H 85

86

SCHEME9. Reagents: a, CuO/K2C03/Bu4NBr/pyridine;b, 19/toluene/reRux; c, MsCUpyridine; d, Zn/AcOH.

167

3. LYTHRACEOUS ALKALOlDS

termediate quaternary salt (85), which was directly reduced with zinc in aqueous acetic acid to provide 80 (51%) and 86 (44%). Vertaline (61) was obtained from 81, prepared by basic hydrolysis of 80, in 59 or 54% yield on treatment with 2,2'-dipyridyl disulfide and triphenylphosphine or with diphenyl phosphochloridate followed by 4-(dimethylamino)pyridine, respectively.

2. Decaline (62) The minor product 86, obtained in the synthesis of vertaline (61) from 84 (Scheme 9), was treated with diethyl azodicarboxylateand triphenylphosphine in the presence of benzoic acid to give the benzoate 87, with inversion of the configuration at C-2, in 77% yield. Hydrolysis of 87 followed by lactonization under Mukaiyama-Corey or Masamune conditions afforded decaline (62) in 57 or 45% yield, respectively. OMe

87

3. 17-0-Methyllythridine (63) It was reported that mercuric acetate-assisted hydroxylation of 17-0-methylIythrine (88) did not afford 17-0-methyllythridine (63)but the compound 89, OMe

OMe

80

89

which has incorrect stereochemistry at C-13;as a sole product (26). In the total synthesis of 17-0-methyliythridine (63), intramolecular enolate anion addition

168

KAORU FUJI

c CN

H

91

L 63

H 92

OCOCH,SiMe, 93

SCHEME 10. Reagents: a, NaOH/aq THFIMeOH; b, MeOH/reRux: c, L-Selectride; d, Me,SiCH=C=O/THF e, n-Bu,NF/THF.

to the aromatic aldehyde triggered by fluorodesilylation was utilized to create the correct stereochemistry at C-13 (Scheme 10) (23). Thus, the pelletierine condensation of 90, prepared by the Ullmann reaction of 6-bromo-3,Cdimethoxybenzaldehyde (69a) with 4-cyano-2-iodoanisole, afforded trans-quinolizidinone 91 in 70% yield after equilibration in refluxing methanol. Simultaneous reduction of the carbonyl and cyano groups was accomplished with L-Selectride to give 92 in 93% yield. Trimethylsilylacetylation of 92 was followed by treatment with fluoride ion in tetrahydrofuran to afford the desired 17-0-methyllythridine (63) in 21% overall yield from 92. Attempts to construct the framework of lactonic alkaloids by an intramolecular phenol coupling with vanadium(V) oxidizing agents were unsuccessful (27). C. CYCLOPHANE ALKALOIDS Although a number of alkaloids belonging to the simple arylquinolizidine class and the lactonic type had been synthesized, no successful synthesis of cyclophane alkaloids was accomplished until that of lythranidine (94), a unique alkaloid with a 2,6-trans disubstituted piperidine structure, was reported (28, 29). Quinolizidine metacyclophane alkaloids lythrancepines I1 (95) and 111 (W) have also been synthesized recently (30, 31). A review on the synthesis of lythranidine (94) is available in Japanese (32).

169

3. LYTHRACEOUS ALKALOIDS

H ooMe 13

*.OH HO

12

7

94 (lythranldlne)

95, R 3: H (lythranceplne a) 96, R IAc(lythnnc6plne Ill)

1. Lythranidine (94)

The Wittig reaction of dialdehyde 97 with bisphosphonium salt 98 afforded a 76% yield of the macrocycle 99 (Scheme 11). Confirmation of the 17-membered skeleton was obtained by conversion to a tetrahydro derivative which was identical with an authentic specimen derived from lythranidine (94) (33).Epoxidation of 99 followed by hydrogenolysis over palladium on charcoal and subsequent acetylation gave 100 in 70% overall yield from 99. 2,6-Cis disubstituted piperidine 101 was obtained quantitatively by hydrogenation of 100 over Raney nickel under high pressure. Conversion of cis-piperidine 101 to the trans derivative was accomplished via the N-nitroso derivative,.becauseit was known that N-nitroso2,6-trans disubstituted piperidines are thermodynamically more stable than the corresponding cis isomers (34). Thus, the N-nitroso derivative of 101 on equilibration with potassium rert-butoxide in dimethyl sulfoxide at 90°C followed by the removal of nitroso moiety by hydrogenolysis over Raney nickel and hydrolysis afforded a mixture of stereoisomeric diols 102. Treatment of diol mixtures 102 with p-toluenesulfonic acid and ethyl orthoformate allowed extraction of the compound with the correct stereochemistry required for lythranidine (94) in the form of amidoacetal 103. The overall yield of 103 from 101 was 14%. Partial demethylation of the amidoacetal 103 by a combination system with a hard acid (AlCl,) and a soft nucleophile (EtSH) (35)and subsequent acid hydrolysis gave lythranidine (94), which was characterized as its acetic acid salt, in 45% yield.

2. Lythrancepine I1 (95) and Lythrancepine 111 (96) A mixture of epimeric phenylquinolizidines 104 and 105 was prepared in 54% overall yield from 3-iodoanisaldehyde through a sequence similar to that shown in Scheme 8. Benzylation of the mixture afforded 106 and 107 in 66 and 10%

170

9

KAORU FUJI

M e o oMe

Meo oMe P h+ 3 P = C H O/C H = P P a_ h3

CHO OHC

98

97 \

Meo oMe

&X!+A d~

o

Meo oMe

A

c

~

100

99

c

~

f , g~ ,h,i

o

A

101

Meo oMe

HH Q

102

"*

H

lythranldlne (94)

103

SCHEME 11. Reagents: a, reflux in CHzC12; b, MCPBA; c , H2/Pd-C/MeOH; d, AqO/Et,N; e, H2/Pt02-Raney Ni/20 tom; f, isopentyl nitrite/CH2CI,; g, r-BuOK/DMS0/9O0C; h, H2/Raney Ni/30 tom; i , KOHlaq MeOH; j, TsOHIHC(0Eth; k, AICh/EtSH/CH*C12;1, 20% HCl/reflux.

104, R = OH, R' z H 105, R H, R'= OH 106, R = OCH,Ph, R' = H 107, R = H, R' = OCH,Ph

yield, respectively. Treatment of the lactam 106 with 2,4-bis(4-methoxyphenyl)1,3-dithia-2,4-diphosphetane2,4-disulfide (Lawesson's reagent) gave the thiolactam 108 in 98%yield. The reaction of thiolactam 108 with ethyl bromoacetate was

c

171

3. LYTHRACEOUS ALKALOIDS

108

109

-

I IyulranCepiMtII

h

PhCH20'"

110

(95)

114

SCHEME 12. Reagents: a, BrCHzCOOEtlDABCOIPh3P; b, NaBH3CN; c, (Me0)2P(0)CH2Li; d, 3-iodoanisaldehydelNaH; e, LiEt3BH; f, TsNHNH2/NaOAc; g, Ac201Et3N/DAMP h, Ni(PPh3)4/DME; i, BBr3.

followed by treatment with 1,4-diazabicyclo[2.2.2]0ctane and triphenylphosphine to afford 109 in 92% yield (Scheme 12). Reduction of 109 with sodium cyanoborohydride provided 110 (88%) along with its epimer (10%). p-Keto phosphonate 111 was prepared from 110 with dimethyl (1ithiomethyl)phosphonate in quantitative yield. The Homer-Wadsworth-Emmons reaction with 3iodoanisaldehyde followed by successive reduction with lithium triethylborohydride and diimide converted 111 to 112 in 53% overall yield. Biphenyl coupling was performed on corresponding acetate 113 (85% from 112) with an excess of tetrakis(triphenylphosphine)nickel(O) in dimethylformamide to give 114, having the desired skeleton, in 20% yield. Debenzylation of 114 with boron trifluoride in dichloromethane afforded lythrancepine I1 (95) in 54% yield. Lythrancepine 111 (96)was obtained in 64% yield by acetylation of lythrancepine I1 (95).

172

KAORU FUJI

3. Model Studies for Lythrancine V (115) Some quinolizidine metacyclophane alkaloids have vicinal dioxygen substitution in the quinolizidine ring. Lythrancine V (115)is an example of this type. In model studies, the vicinal diacetate 116 was prepared from 117 through four steps (36).

H AcO

AcO

116

115

117

111. Occurrence and Biosynthesis

Production of alkaloids by shoots of Heimia salicifolia grown in vitro was investigated (37). Four known arylquinolizidine alkaloids, demethyllasubine I (l), 10-epidemethoxyabresoline(3),demethyllasubine I1 (3,and demethoxyabresoline (118),and three diphenyl lactonic alkaloids, vertine (cryogenine) . (119), lyfoline (120),and lythrine (121),were shown to occur in media containing kinetin. Though suspension cultures were readily developed without kinetin, no detectable amounts of alkaloids were produced. via a symmetrical intermediate, caIncorporation of dl-[4,5-13C,,6-14C]1ysine daverine (122),into ring A of vertine (119)and lythrine (121)was reported (38). More importantly, it was shown that tritium-labeled dl-cis- and dl-trans-quinolizidinones 123 and 124 were incorporated into vertine (119)(trans-quinolizidine ring) and lythrine (121)(cis-quinolizidine ring), respectively and specifically.

al,, OMe

OMe

OMe

H

118 (demthoxyabresollne)

120, R = H (lylolh) 121, R = Me (lythrlne)

3. LYTHRACEOUS ALKALOIDS

173

On the other hand, neither 123 nor 124 was utilized for alkaloid biosynthesis when one of phenolic hydroxyl groups was methylated. Thus, the two phenolic hydroxyl groups should remain unmethylated until after phenol oxidative coupling. Compound 125 is proposed to be the intermediate in which coupling takes place.

IV. Spectroscopic Studies The biphenyl group in both lactonic and metacyclophane alkaloids poses an interesting question about chirality. Ferris et al. (39) reported that the biphenyl moiety in lactonic alkaloids was inherently dissymmetric. Its chirality was determined by comparison of the circular dichroism (CD) curves with those of dihydrothebaines with known chiralities. The biphenyl group of metacyclophane alkaloids with a piperidine ring, however, should exist as an equilibrium between two rotamers with (R) chirality (126a)and (S)chirality (126b)in solution as

126a

exemplified for N, 0-dimethyllythranidine, because the two orrho-methoxyl groups of a biphenyl are not bulky enough to distinguish each rotamer. Thus, biphenyls in piperidine alkaloids are not inherently dissymmetric but chiral owing to a biased population rotamers. The conformational chirality of the biphenyl group in piperidine alkaloids and their derivatives was determined by the

174

KAORU FUJI

CD spectra (40). The hydrobromide ethanol solvate of bromolythramine (127) served as a reference compound since the absolute structure including the chirality of the biphenyl group had previously been determined by an X-ray analysis (41). The biphenyl with a conformational chirality of (R) showed a positive Cotton effect at long wavelengths coupled with a negative Cotton effect at short wavelengths in the 200-240 nm region, and vice versa for (S)-biphenyls. The biphenyl chiralities of 128, 129, and 130 obtained from CD data were confirmed by X-ray determinations of these compounds (42).

127, R = H 128, R = Ac

129, R = CHO

130

The free energy difference between the two rotamers 126a and 126b was estimated to be 0.8 kcal/mol in favor of 126a by temperature-dependent CD curves (40). Free energy differences of derivatives 103,131, and 132 were estimated to be 1.O, 0.7, and 0.2 kcal/mol, respectively. This shows that the important factor in determining the conformational chirality of the biphenyl moiety is the presence of the 2,6-trans disubstituted piperidine ring in the molecule.

131

132

N,O-Dimethyllythranidine(126) exists in mobile equilibrium in solution involving mainly two dynamic processes, namely, rotation about the carbon-carbon bond between the two phenyl rings and reversal of the piperidine ring. Tempera-

3. LYTHRACEOUS ALKALOIDS

175

ture-dependent I3C-NMRstudies disclosed that a rather higher free energy of activation (- 15.6kcal/mol) was required for piperidine ring reversal (43). Carbon-13 chemical shifts of the biphenyl ring were averaged at ambient temperature, whereas chemical shift differences due to piperidine ring flip were not. This provided another example of the concept of so-called selective kinetic equalization of chemical shifts introduced by Lambert et al. ( 4 4 ) .

REFERENCES 1. J. P. Ferris, J. Org. Chem. 27, 2985 (1962). 2. W. M. Golebiewski and J. T. Wr6be1, in “The Alkaloids” (R. H. F. Manske and R. G. A. Rodrigo. eds.), Vol. 18, p. 263. Academic Press, New York, 1981. 3. K. Fuji, T. Yamada, E. Fujita, and H. Murata, Chem. Phurm. Bull. 26, 2515 (1978). 4. R. N. Gupta, P. Horsewood, S. H. Koo, and 1. D. Spenser, Can. J. Chem. 57, 1606 (1979). 5 . P. Horsewood, W. M. Golebiewski, J. T. Wrbbel, I. D. Spenser, I. F. Cohen, and F. Comer, Can. J . Chem. 57, 1615 (1979). 6. J. T. Wr6bel and Golebiewski, Bull. Acad. Pol. Sci., Ser. Sci. Chim. 23, 593 (1975). 7. J. Quick and R. Oterson, Tetrahedron Lerr.. 603 (1977). 8. M. Hanaoka, N. Ogawa, K. Shimizu, and Y. Arata, Chem. Phurm. Bull. 23, 1573 (1975). 9. 1. Lantos, C . Razgaitis, H. van Hoeven, and B. Loev, J. Org. Chem. 42, 228 (1977). 10. J. Quick and C. Meltz, J. Org. Chem. 44,573 (1979). 11. S. Takano and K. Shishido, J . Chem. Soc., Chem. Cornmun.. 940 (1981). 12. S. Takano and K. Shishido, Chem. Phurm. Bull. 32,3892 (1984). 13. S. Takano and K. Shishido, Heterocycles 19, 1439 (1982). 14. H. lida, M. Tanaka, and C. Kibayashi, J . Chem. SOC..Chem. Commun., I143 (1983). 15. H. lida, M. Tanaka, and C. Kibayashi, J. Org. Chem. 49, 1909 (1984). 16. H. Ent, H. de Koning, and W. N. Speckamp, Heterocycles 27, 237 (1988). 17. K. Narasaka, S . Yamazaki, and Y. Ukaji, Chem. Lert.. 1177 (1985). 18. K. Narasaka, Y. Ukaji, and S. Yamazaki, Bull. Chem. Soc. Jpn. 59,525 (1986). 19. R. W. Hoffmann and A. Endesfelder, Liebigs Ann. Chem.. 1823 (1986). 20. D. J. Hart and K. Kanai, J. Org. Chem. 47, 1555 (1982). 21. K. Shishido, K. Tanaka, K. Fukumoto, and T. Kametani, Tetrahedron Lett. 24, 2783 (1983). 22. K. Shishido, K. Tanaka, K. Fukumoto, and T. Kametani, Chem. Pharm. Bull. 33,532 (1985). 23. D. E. Seitz, R. A. Milius, and J. Quick, Tetrahedron Lett. 23, 1439 (1982). 24. D. J. Hart, J. Am. Chem. Soc. 102, 397 (1980). 25. E. J. Corey, K. C. Nidolaou, and L. S. Melvin, J. Am. Chem. Sor. 97,654 (1975). 26. 1. Lantos, C. Razgaitis, B. Loev, and B. Douglas, Can. J. Chem. 58, 1851 (1980). 27. J. Quick and R. Ramachandra, Tetrahedron 36, 1301 (1980). 28. K. Fuji, K. Ichikawa, and E. Fujita, TetrahedronLerr., 361 (1979). 29. K. Fuji, K. Ichikawa, and E. Fujita, J. Chem. Soc.. Perkin Trans. 1. 1066 (1980). 30. D. J. Hart and W.-P. Hong, J . Org. Chem. 50, 3670 (1985). 3 1. D. J. Hart, W.-P. Hong, and L.-Y. Hsu, J. Org. Chem. 52.4665 (1987). 32. K. Fuji, Yakugaku Znsshi 101, 203 (1981). 33. E. Fujita, K. Fuji, and K. Tanaka, J. Chem. Sac. C, 205 (1971). 34. R. T. Fraser, T. B. Grindley, and S. Passannanti, Can. J. Chem. 53, 2473 (1975). 35. K. Fuji, in “Nucleophilicity” (J. M. Harris and S. P. McManus, eds.), Advances in Chemistry Series 215, p. 219. American Chemical Society, Washington, D.C., 1987. 36. J. Quick, Y. Khandelwal, P. C. Meltzer, and J. S. Weinberg, J . Org. Chem. 48,5199 (1983). 37. A. Rother, J. Nut. Prod. 48,33 (1985).

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38. S. H. Hedges, R . B. Herbert, and P. C. Wordmald, J. Chem. Soc., Chem. Commun., 145 (1983). 39. J. P. Ferris, C. B. Boyce, R . C. Briner, U. Weiss, 1. H. Qureshi, and N. E. Sharpless, J . Am. Chem. Soc. 93, 2963 (1971). 40. K. Fuji, T. Yamada, E. Fujita, K. Kuriyama, T. Iwata, M. Shiro, and H. Nakai, Chem. Pharm. Bull. 32, 55 (1984). 41. R. J. McClure and G . A. Sim, J . Chem. Soc., Perkin Truns. 2, 2073 (1972). 42. K. Fuji, T. Yamada, E. Fujita, H. Nakai, and M. Shiro, Chem. Pharm. Bull. 32, 63 (1984). 43. K. Fuji, T. Yamada, and E. Fujita, Chem. Pharm. Bull. 32,70 (1984). 44. J. B. Lambert, M. W. Majchrzak, and D. Stec 111, J . Org. Chem. 44,4689 (1979).

-CHAPTER

4-

DIBENZAZONINE ALKALOIDS LUISCASTEDO AND DOMINGO DOMINGUEZ Departamento de Quimica Orgcinica Facultad de Quimica Universidad de Santiago 15706 Santiago de Compostela, Spain

I. Introduction

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

I77

11. Occurrence and Classification ............................................ 111. Structure Determination . . . . . . .......... ..........

179

A. TypeA Dibenzazonines ............................................. B. Type B Dibenzazonines . . . ................. Synthesis ............................................................ A. From Biphenyl Derivatives .......................................... B. Formation of the Biphenyl Bond .................... C. By Rearrangement ... .......................................... Biosynthesis .................... ........ A. From Bisphenethylamines ........................................... B. Via Morphinandienols ............................ C. Via Proerythrinadienones . .......... Pharmacological Properties . . . . . . . . . . . . . . ; ............................... Related Alkaloids: Dibenzazecines ...................... References .............................................

180

IV.

V.

VI. VII.

I80 182 I83 183 184

I89 205 205 205 206 209 209 212

I. Introduction The first dibenzazonine alkaloid reported was protostephanine (3), which was isolated as early as 1927 from Stephaniu juponicu; its chemistry was reviewed by Shamma in 1972 ( 1 ) . A chapter on dibenzazonines was later included in Shamma’s book on isoquinoline research between 1972 and 1977 (2). These alkaloids have also been regularly covered in the Specialist Periodical Reports of the Royal Chemical Society (The Alkaloids) under the heading “Erythrina and Related Alkaloids” (3). This chapter represents the first comprehensive coverage of the dibenzazonine alkaloids in this treatise; previously, they had only been dealt with piecemeal in chapters dedicated to Erythrina alkaloids ( 4 ) . Dibenzazonines are characterized by a tricyclic structure featuring a nine-membered ring including a nitrogen atom. The Chemical Abstracts name for the basic structure 177

THE ALKALOIDS, VOL. 35 CopyriRh! 8 1989 by Academic Ress. lnc. All rights of reproduction in any form reserved.

178

LUIS CASTEDO EXPOSITO AND DOMING0 DOMINGUEZ FRANCISCO

is 6,7,8,9-tetrahydro-SH-dibenz[d,fIazonine. In Section VII, brief mention is made to the higher homologs known as the dibenzazecines. 3

TABLE I NATURALLY OCCURRING DIBENZAZONINES Alkaloid

Specics

Melting point, "C

Erythrina xbidwilli (5-7). E. crysta-gulli (8. 9 ) , E . arborescens ( l o ) , E. orientalis (11). E . poeppigiana (12, 13), E . gluucu (12), E . variegara (12), E. herbuceu (14) Corydulis claviculatu (15)

178- 180 (5)

Protostephanine (3)

Stephania japoniru (16-21)

Laurifonine (4)

Cocculus laurifolius

90-95 (16) 73-74 (19) 207 - 209 (picrate) (18) 182- 185 (perchlorate)

Erybidine (1)

Crassifolazonine (2)

(22, 23) Laurifine (5) Laurifinine (6)

Cocculus laurifolius (22, 23) Cocrulus laurifolius (22. 23)

160-162 (15)

Pupaver bracteatum (24)"

UV (15). IH NMR (IS), I3C NMR (15). MS (13, (15) UV (16, 21). IR (16, 21), 'H NMR (16, 18, 21, 24), MS (21, 24)

107 ( 2 4 )

UV (23). IR (23).IH NMR (23, 24). MS (23, 24) UV (23), IR (23).'H NMR (23), MS(23) UV (23), IR (23).'H NMR (23, 24), MS (23. 24) IH NMR (24),MS (24)

101 (24)

'H NMR (24),MS (24)

(23) Amorphous 243-245 (perchlorate)

(23) Neodihydrothebaine (7) and bractazonine (8)

Additional data

Alkaloids 7 and 8 were obtained as an inseparable mixture. Data are for synthetic samples.

179

4. DIBENZAZONINE ALKALOIDS

11. Occurrence and Classification

Dibenzazonines have been found in plants of the families Menispermaceae, Leguminosae, Fumariaceae, and Papaveraceae. To date only eight naturally occurring dibenzazonines are known: botanical sources and key references to physical data are listed in Table I. On the basis of their biogenetic origin, Shamma and Moniot (2) classified dibenzazonines into two groups: type A, which comprises the fully oxygenated bases, and type B, which includes alkaloids that have undergone a net deoxygenation with respect to their biogenetic precursors. The first group is represented by erybidine (1) and crassifolazonine (2), which both have substituents at C-2 and C-3 but differ in the oxygenation pattern of ring C. Alkaloids of type B are more numerous and include the unusually tetrasubstituted protostephanine (3) and the trisubstituted laurifonine (4), laurifine (9,laurifinine (6), neodihydrothebaine (7), and bractazonine (8) (Scheme 1).

OH

N-Me

Me0

N-Me

Me0

Me0 OMe

5 Rl=H,R2=Me

OMe

OR2 6 Rl=Me,R2=H

Me0

OH

SCHEME 1.

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LUIS CASTEDO EXP()SITO AND DOMING0 DOMINGUEZ FRANCISCO

111. Structure Determination

The structures of dibenzazonines have been determined on the basis of degradation studies and/or spectroscopic properties. Structural determinations are further confirmed by comparison with synthetic samples. A. TYPEA DIBENZAZONINES

1. Erybidine Erybidine (1)crystallizes as colorless needles and has the characteristic UV absorption at 284 nm. Its I H-NMR spectrum shows the presence of an N-methyl (2.82) and three methoxyl groups 13.92 (3H) and 3.87 ( 6 H ) ] . Treatment with diazomethane gives a tetramethoxy derivative identified as 0-methylerybidine (9) on the basis of degradation studies and comparison with a synthetic sample, thus establishing the monophenolic nature of the alkaloid. The hydroxyl group of

1 Rl=H,R2=Me

N-Me

9 R,=R2=Me

erybidine was located at C-3 by comparison of the methoxyl resonances in the H-NMR spectra of compounds 1 , 9 , and 10 ( 5 ) . The above assignment was later corroborated by synthesis of 1 from erysodienol(95) ( 7). 2. Crassifolazonine Crassifolazonine (2) was obtained as optically active colorless crystals. Its UV spectrum shows the two bands at 232 and 286 nm characteristic of the twisted biphenyl system present in the dibenzazonine alkaloids; a bathochromic shift is observed on addition of base, indicating the phenolic nature of the alkaloid. Its I H-NMR spectrum in the aromatic region exhibits a pair of doublets arising from two ortho-coupled protons and two singlets for two para protons. In addition, the following are observed: a broad signal at 5.88 and a broad singlet at 5.36(W,,* = 11.4 Hz), which both disappear with D,O; two singlets arising from methoxyl

4. DIBENZAZONINE ALKALOIDS

181

groups; a complex aliphatic region between 2.63 and 2.36 (8H); and a singlet at 2.29 for an N-methyl group. The I3C-NMR spectrum of 2 shows characteristic signals for the saturated carbons of the azonine ring, which appear as triplets at 33.83, 34.21, 57.97, and 58.14. In addition, two quartets at 47.32 (N-Me) and 55.94 (2 0-Me) are observed. The aromatic region exhibits four doublets ( 1 10.15, 112.21, 115.69, and 120.04), four singlets resulting from nonoxygenated quaternary carbons (126.90, 127.70, 134.22, and 134.91), and four singlets arising from quaternary carbons bound to oxygen (142.59, 144.91, 145.04, and 145.55). The above data clearly suggest a dibenzazonine structure with two methoxyl and two hydroxyl groups as substituents, their locations being determined by nuclear Overhauser effect difference spectroscopy experiments (Fig. 1). Several derivatives of crassifolazonine (2) were prepared and characterized (2a-2c). Final proof for the proposed structure of crassifolazonine (2) was obtained by its total synthesis (15).

OH

FIG. 1. Nuclear Overhauser effect difference spectroscopy of crassifolazonine (2).

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LUIS CASTEW E X F ~ S I T O AND DOMINGO WMINGUEZ FRANCISCO

B. TYPEB DIBENZAZONINES 1. Protostephanine Although protostephanine (3) was first isolated over 60 years ago, its dibenzazonine structure was not deduced until 20 years later, following extensive degradation studies by Kondo and Takeda (16) (reviewed by Shamma in Ref. I). Its I H-NMR spectrum shows a characteristic aromatic region with two singlets at 6.82 and 6.74 for the two para protons of ring C and two doublets (6.54 and 6.41, J = 3 Hz) for the meta hydrogens of ring A; this establishes its substitution pattern. The UV absorption spectrum of 3 indicates a twisted biphenyl system (25). 2. Laurifonine Laurifonine (4) was isolated as an amorphous powder whose dibenzazonine structure was suggested by UV absorption bands at 221 and 283 nm. The 'HNMR spectrum has signals for an N-methyl(2.32) and three aromatic methoxyl groups (3.90,3.80, and 3.76) that were located at C-2, C-11, and C-12 by identification of degradation products. The aromatic part of the I H-NMR spectrum confirms this type of substitution, exhibiting two singlets at 6.72 and 6.68 for two para protons while H-1 resonates as a doublet (7.05, J = 2.5 Hz), H-3 as a double doublet (6.80, J = 8.5 and 2.5 Hz), and H-4 as a doublet (7.18, J = 8.5 Hz) (23). 3. Laurifine Laurifine (5) has an 1R absorption band at 3450 cm-I, indicating the presence of an -NH or hydroxyl group. Its UV spectrum exhibits bands at 221 and 284 nm that remain unchanged on addition of alkali, thus ruling out the presence of a phenolic hydroxyl group. 'HNMR reveals no N-methyl signal, but the spectrum is otherwise similar to that of laurifonine (4). N-Methylation of laurifine (5) with formaldehyde-sodium borohydride afforded laurifonine (4) (23). 4. Laurifinine The IH-NMR spectrum of laurifinine (6) exhibits signals for an N-methyl (2.32) and only two aromatic methoxyl groups (3.82 and 3.80). Its UV spectrum undergoes a bathochromic shift on addition of alkali, suggesting the presence of a phenolic hydroxyl group (IR 3400 cm-I ). 0-Methylation with diazomethane furnished laurifonine (4), thus establishing the same type of substitution. The

4. DIBENZAZONINE ALKALOIDS

183

location of the hydroxyl group in laurifinine at C-1 1 was established by double resonance and alkali-catalyzed deuterium exchange experiments (23). This assignment contradicts a previous one which on biogenetic grounds placed the phenolic function at C-12 (22); the issue was finally resolved by Ito et al., whose photochemical synthesis of laurifinine definitely established structure 6 for this alkaloid (26).

5 . Neodihydrothebaine and Bractazonine

Neodihydrothebaine (7), which was known as a synthetic derivative of thebaine ( 4 3 , has been found in Papaver bracteaturn, from which it was extracted as an inseparable mixture with bractazonine (8).The composition of the mixture was determined by GC-MS analysis and I H-NMR studies and was further confirmed by comparison with an artificial mixture of synthetic neodihydrothebaine (7) and bractazonine (8) (24). Both alkaloids are considered to be biogenetically derived from thebaine (45) or its immediate precursor salutaridinol(lO3).

IV. Synthesis Dibenzazonines have been synthesized by three general approaches: (A) construction of the azonine ring from an appropriately substituted biphenyl derivative, (B) formation of the aryl-aryl bond, and (C) by rearrangement of various types of alkaloids.

DERIVATIVES A. FROM BIPHENYL Synthesis of dibenzazonines from biphenyl derivatives was first developed by Takeda (27), who carried out the synthesis of protostephanine (3) from polysubstituted diphenic acid 11. Application of this methodology to the synthesis of natural dibenzazonines is nevertheless hampered by the difficulty of preparing appropriately substituted biphenyl derivatives. Thus, although a convenient procedure for constructing 3 from 12 has been reported (28), the synthesis of 12 requires 16 steps from veratralacetone (29). The unsubstituted dibenzazonines 14a-14e have been prepared by treatment of 13 with different amines (29-31), and, more recently, laurifonine (4) was synthesized from biphenyl-dialdehyde 15 following the homologation procedure developed by Pecherer and Brossi (32) (Scheme 2).

184

LUIS CASTEDO E X P ~ S I T O AND DOMINGO DOMINGUEZ FRANCISCO

MeoQoMe Br

CCILH

11

Me0 OMe

0

-Me0 OMe

W

-

R

cd R=Me R=Et

Meop e R=CHz-CHZH*

Me0

M

m

z

M

e

O

p

-------*

0

/

Me0

‘ OMe

15

Me0

‘

0

Me0

OMe

‘

4

OMe

SCHEME 2.

B. FORMATION OF THE BIPHENYL BOND Diary1 bond formation from properly functionalized precursors has been achieved ( 1 ) photochemically, (2) by oxidative coupling, and (3) by intramolecular coupling of diiodides.

185

4. DIBENZAZONINE ALKALOIDS

1. Photochemical Pathway The photochemical strategy, first applied by It0 and Tanaka in their synthesis of erybidine (1) (33), was later extended to the preparation of laurifine (5), laurifonine (4), and laurifinine (6). These three 2 , l l ,lZtrisubstituted dibenzazonines were prepared employing the photochemical cyclization of amide 16 as the key step (Scheme 3): irradiation of 16 in methanolic sodium hydroxide solution gave a mixture of 17,18, and 19 from which the major compound was separated and transformed into the above-mentioned derivatives (26). The cyclized product 18 was later used as a precursor in the synthesis of neodihydrothebaine (7) (34). Me0

Me0

hv NaOW MeOH

* HO

p:

Me0

Me0

OH

........

I

16 R=Br

17 R=H(16%)

i I

Po

5

*\

6

I

4

SCHEME 3.

Bractazonine (8) was synthesized following the same approach from the protected derivative 20, which on irradiation produced a mixture of 22 and 23, the cyclized products resulting from attack at the positions respectively ortho and para to the phenol, along with minor amounts of the reduced derivative 21 (Scheme 4). Further processing of 23 gave bractazonine (8) (24). A variation of the above procedure using compound 24, in which the monooxygenated ring bears a bromine atom, afforded a mixture of 25, 26, and 27 (Scheme 5) from which compound 26 was isolated to be reduced and N-methylated as before to give bractazonine (8) (34). The photochemically induced aryl-aryl coupling reaction of the diphenolic amide 28 was used as the key step in the synthesis of crassifolazonine (2). In this case, in addition to small amounts of the reduced derivative 29, indoline 30 was obtained as the result of N-attack (Scheme 6). Cyclization took place exclusively at the position para to the hydroxyl group to give a low yield of 31, which was transformed by the usual two-step procedure to crassifolazonine (2) ( 1 5 ) .

186

LUIS CASTEDO E X P ~ S I T O AND WMINGO WMINGUEZ FRANCISCO

OH

HO

22 (2%)

23 (58%)

20 R=Br 21 R=H (6%)

Me1

N-Me

HO

-

HO

Me0

Me0

Me0

8 (90%)

(93%)

(7 1%)

6 6N-H &N-H+&N-H

NaOH hv I McOH

~

Ho

Me0

Me0

OH

24 R=Br

25 R=H(9%)

\

\

0

26 (19%)

i

bractazonine

ScnmE 5 .

(8)

Me0

0 OH 27 (38%)

187

4. DIBENZAZONINE ALKALOIDS

OH

P

""b N -H

hv

O

OH

M OHe

+

w

NaOH I MeOH

-H

Me0 HO&

HO 30 (7%)

MeO 28 R=Br

3 1 (10%)

i

29 R=H

crassifolazonine ( 2 )

SCHEME6.

The photochemical procedure has also been applied to the synthesis of several dibenzazonines which have not yet been found in nature, such as 32 ( 2 4 ) , 33a-33d ( 3 3 , and 33e (36).

g

a Rl=OMe, R2=R3=R4=R6=H, R5=Me

b R2=OMe, R,=R3=R4=R6=H, R5=Me c R3=OMe, R,=R2=R4=R6=H, R5=Me

N-Me

Ho Me0

/

'

32

/

d R4=OMe, Rl=R2=R3=R6=H, R5=Me e R3=OH, R,=R2=R4=R5=H, R,=Me

\ R6°

OMe

33

2. Oxidative Coupling Aryl-aryl bond formation by phenolic oxidative coupling of the bisarylethylamine Ma with potassium ferricyanide leads to the Erythrina derivative 36 (37, 38) (Scheme 7). Barton et a f . (39) have suggested that this process takes place via the dibenzazonine 35a, which under oxidative conditions would give diphenoquinone as the ultimate precursor of 36; this hypothesis is supported by the high yield of erysodienone (36) afforded by ferricyanide oxidation of 35a. The proposed mechanism was confirmed by further work with compounds 34b-34, which on oxidation gave the corresponding nine-membered ring derivatives 35 (40).

188

LUIS CASTEDO EXF6SITO AND DOMING0 DOMINGUEZ FRANCISCO

-

X

for 35a

Me0

Me0

Me0

a X=CH,, Y=NH b X=CO, Y=NH c x=co,Y=NH d X=Y=CHZ

35a

SCHEME I.

A comprehensive study of the oxidative coupling process in which variously functionalized precursors and oxidants were used to stop the process at the dibenzazonine stage has been reported by McDonald and Wylie ( 4 1 ) . The cyclized product 39 was obtained from the N-trifluoroacetamide 37 by VOF, oxidation. By starting from the tetramethoxy derivative 38 and using thallium tristrifluoroacetate, the yield of the cyclized product 40 was raised to 36% ( 4 1 ) (Scheme 8).

D%

Me0

N-COCF3

N-COCF3

Me0

Me0

OR

OR

39 R=H(11%)

37 R=H 38 R=Me

40 R=Me(36%)

SCHEME 8.

I89

4. DIBENZAZONINE ALKALOIDS

3. Intramolecular Coupling of Iodides Biphenyl bond formation has been achieved in the diiodobiaryl derivative 41

by an intramolecular aryl halide coupling reaction promoted by tetrakis (triphenylphosphine)nickel. This short and efficient route gave the dibenzazonine 42 in good yield (42) (Scheme 9). In a similar way, tetrasubstituted derivative 43 was successfully coupled with the more easily prepared tris (triphenylphosphine)nickel, giving 44 in 62% yield. Subsequent debenzylation led to the most efficient synthesis of dibenzazonine 35a reported to date (43).

$rKN-Me OMC

OMe

@

Ni(Pph3), DMF

0

\

41

OMe 4 2 (60%)

OMe

OMe Ni(PPh3)3M

*

Me0 Me0

OBz 43

0 \

g N-BZ

b

PdK

OBz 44

0 Me0 OH 35a (85%)

SCHEME 9.

C. BY REARRANGEMENT Rearrangements of several types of alkaloids that led to a variety of dibenzazonines have been described.

1. From Thebaine and Related Alkaloids Extensive work with the opium alkaloid thebaine (45) has shown that treatment with Grignard reagents produces dibenzazonines substituted at C-8 via a

I90

LUIS CASTEDO EXMSITO AND DOMING0 DOMINGUEZ FRANCISCO

1) HCl

Me0

R=Ph R=Me(Ref. (Ref.444) 4) R=(CH,),-Ar (Ref. 4 5 ) R=H (Ref. 46.47, and 24)

HO

Me0

& \

-Me

'

R

41

SCHEME10.

process in which the magnesium halide induces the rearrangement (Scheme 10). Thus, when thebaine (45) is treated with magnesium bromide or iodide the iminium salt 46 is produced, which on reduction with LiAlH, or NaBH, gives a good yield of neodihydrothebaine (47, R = H). Other Lewis acids (AIC1,) (48) and protic acids (trifluoroacetic acid) ( 2 4 , 4 9 )are also effective in promoting the rearrangement. Recent work by Theuns et al. showed that when thebaine hydrochloride was subjected to brief treatment with trifluoroacetic acid (TFA) at room temperature, followed by reduction with a large excess of NaBH,, a complex mixture was formed from which the diphenolic dibenzazonine 48 was isolated in 25% yield (24) (Scheme 10). Dibenzazonines such as 47 and 48, owing to restricted rotation, have molecular asymmetry and can exist in form of optical isomers. They isomerize on heating (44-47). Grignard reaction of thebaine (45) with phenylmagnesium bromide affords four distinct optical isomers of 47 (R = Ph), which were investigated in detail by Small et al. (43a).Their results were correctly interpreted by Robinson and Bentley (44-48). These data are summarized in Scheme 11 with expression of the biphenyl configuration. These findings were recently substantiated by additional studies by Brossi et al. (48a), including X-ray analysis of individual phenyldihydrothebaines as perchlorate salts and X-ray analysis of biphenyl (-)-35" obtained by catalytic reduction over Pd/C catalyst (Fig. 2). It is interesting that in the latter molecule the methoxy-substituted phenyl ring has turned and now lies almost perpendicular to the trisubstituted phenyl ring, allowing the

191

4. DIBENZAZONINE ALKALOIDS

a R , 8R (+) -10'

.

aS 8R (+)-131°

\

J

aS ,8S

6 )-10"

SCHEME 1 1 . Phenyldihydrothebaines of Small er al. ( 4 3 ~ ) .

methylaminoethyl group to interact with the phenolic group in forming a betaine structure. A biomimetic synthesis of neodihydrothebaine (7) and bractazonine (8) from thebaine (45) has been reported (50). Irradiation of 45 in MeOH containing NaOH and NaBH, promotes the opening of the ether bridge to give the phenolate 49, which in the usual way can rearrange by alkyl migration to give neodihydrothebaine (7) via the neospirine 50 (Scheme 12). Alternatively, participation of the nitrogen lone pair would favor aryl migration, giving bractazonine (8) by way of the proerythrinadienone 51. In fact, a mixture of both compounds was obtained in 19% joint yield.

192

LUIS CASTEDO EXP~SITOAND DOMINGO DOMINCUEZ FRANCISCO a

FIG. 2. Structures determined by X-ray analysis of Small and co-worker's (43a) phenyldihydrothebaines shown in Scheme I I . (a) Perchlorate of aR.8R-phenyldihydrothebaine base of (+)-lo", (b) perchlorate of aS,8R-phenyldihydrothebainebase of (+)-I3 I"; and (c) antipode of biphenyl (-)-35".

193

4. DIBENZAZONINE ALKALOIDS

FIG. 2c.

45

-t

49

hv

OMe

SCHEME 12.

194

LUIS CASTEDO E X P ~ S I T O AND DOMINGO DOMINGUEZ FRANCISCO

MeMgI

-Me

HO

MeMgI

Me

Me0 53

52

54 R,=H, Rz=Me 55 R,=Me, Rz=H

SCHEME 13.

The thebaine analog 52 reacts with methylmagnesium iodide to give a product for which the dibenzazonine structure 53 was proposed (Scheme 13). A more recent investigation of this reaction, however, showed the formation of two epimers, 54 and 55, which retain the morphinan skeleton ( 5 1 ) .

2. From Morphinandienols The dienol-benzene rearrangement of morphinandienol56 was considered by Barton as a key step in the late stages of the biogenesis of protostephanine (3) (52) (Scheme 14). A few years later this transformation was accomplished by Battersby et al. by sulfuric acid treatment of the dienol57, which led to an 80% yield of the neospirinedienone 58. Magnesium iodide-promoted fragmentation of 58, followed by reduction of the iminium salt intermediate, afforded a 46% yield of a mixture of phenols, which was 0-methylated with diazomethane to give protostephanine (3) (53).Full experimental details of this work published in 1981 included an improved, TFA-based procedure to promote the dienol-benzene rearrangement of 57, after which reduction with borohydride gave protostephanine (3) in 60% yield (54) (Scheme 14). In a similar way, 0-methylflavinantinol (59) rearranges under the action of boron trifluoride etherate to give, via the neospirinedienone60, the iminium salt 61, whose catalytic reduction produces laurifonine (4) in excellent overall yield ( 5 5 ) (Scheme 15). Laurifonine (4) has also been obtained by TFA-promoted dienol-benzene rearrangement of 59 followed by reduction with sodium borohydride (24).

200

LUIS C A S T E W EXPOSITO AND W M I N G O DOMINGUEZ FRANCISCO

hand, when 75 was heated with BF,-OEt, in refluxing benzene and then hydrogenated over Pt in methanol, the aporphine 67 (8%), the erybidine isomer 76 (35%), and the unnatural aporphine 77 (25%) were obtained ( 5 8 ) (Scheme 20). OMe

76 (35%)

Treatment of the N-formylneospirine derivative 78 in methanol with dry HCl gas produced the ketal79 (7 I%), which on reduction with excess LiAlH, gave an 8 1% yield of 0-methylerybidine (9). The rearrangement involved in this process probably takes place as shown in Scheme 21 (62).

6. From Erythrina Alkaloids

Several Erythrina bases have been transformed into dibenzazonines. The first report, by Prelog et al. ( 6 3 ) ,described the transformation of dihydroerysotrine (80) to the simple dibenzazonine 81 by degradation with cyanogen bromide followed by reduction with lithium aluminum hydride. In a similar way, treatment

196

LUIS CASTEDO E X P ~ S I T OAND WMINGO WMINGUEZ FRANCISCO

3. From Morphinandienones The dienone-phenol rearrangement of morphinandienones gives, as before, neospirinedienone intermediates that further evolve to dibenzazoninium salts, whose redwction yields the corresponding dibenzazonines. Examples of this transformation were reported by Frank and Teetz (56) and Kupchan and Kim (57) in their syntheses of 62 and erybidine (l),respectively (Scheme 16). Interestingly, when 0-methylflavinantine (63) was heated in a steam bath with concentrated hydrochloric acid, a high yield of the aporphine 66 was obtained. This result has been tentatively explained by Kupchan and Kim (57) as being due to the participation of the nitrogen lone pair to give the aziridinium 64, in which 0

OH

OH

OH

SCHEME 16.

OH "-

I97

4. DIBENZAZONINE ALKALOIDS

stereoelectronic factors favor migration of the aryl group to give the proerythrinadienone intermediate 65, the likely precursor of 66. By contrast, those acid-catalyzed rearrangements of morphinandienones which involve minimal nitrogen participation (e.g., with boron trifluoride etherate or amide derivatives) result in migration of the alkyl group to yield neospirine derivatives from which dibenzazonines are derived (Scheme 16). Further work by Kupchan and Kim (58) demonstrated the temperature dependence of the rearrangement of 0-methylflavinantine (63).Heating with BFyOEt, in refluxing benzene gave rise to a complicated situation involving competitive migration of alkyl and aryl groups to give proerythrinadienone and neo-

HO

67 (28%)

Me0 OMe

Me0

--

Me0

Me0

\

OMe

N-Me

Me0 0

Me0

Me0

OMe

OMe

SCHEME17.

\

OMe

70 (8%)

198

LUIS CASTEW E X P ~ S I T O AND WMINGO WMINGUEZ FRANCISCO

spirinedienone derivatives, whose further evolution led to various substituted aporphines and (after reduction) to erybidine (Scheme 17).

4. From Proerythrinadienones The spirodienones postulated earlier as intermediates in the acid-catalyzed rearrangement of morphinandienones to aporphines and dibenzazonines (Scheme 17) were prepared and isolated as borane complexes and their behavior studied in detail by Kupchan and Kim (58).Heating the borane complex of 68 with boiling hydrochloric acid gave predicentrine (70) in 75% yield, whereas treatment with BF,-OEt, at room temperature, followed by hydrogenation over Pt in methanol, afforded 70 and erybidine (1)in 44 and 35% yield, respectively. When this latter reaction was initiated in refluxing benzene, 70 (47%), erybidine (1)(44%),and 69 (8%) were obtained. Finally, treatment of the borane complex of 68 with 1 N NaOH in MeOH, followed by NaBH, reduction, gave erybidine (1) in 76% yield. In a similar way, sodium hydroxide hydrolysis of the proerythrinadienone 71 (obtained by VOF, oxidation of norprotosinomenine trifluoroacetamide) brings about its rearrangement to an intermediate which on reduction gives the diphenolic dibenzazonine 35a in excellent yield ( 5 9 ) (Scheme 18). In contrast, OH

Me0

VOF,

(40%)

*

1) NaOH

2) NaBH4

7 1 (40%)

35a (80%)

OH

OH

OH

H+

Me0

M

a

p

-

* (8.5%)

Me0

Me0 OH

\

Me0

OH

SCHEME18.

’

OH

*

199

4. DIBENZAZONINE ALKALOIDS

when proerythrinadienols are subjected to acid-catalyzed rearrangement aporphines are produced instead of dibenzazonines (55). In the reaction of the benzylisoquinoline 72 with dimsyl sodium, it has been suggested that a proerythrinadienone intermediate results from nucleophilic attack on a benzyne formed in the lower ring. This postulated intermediate was thought then to rearrange to an iminium salt which is trapped by the dimsyl sodium to give 73a, which on reduction and desulfuration would finally lead to dibenzazonine 74 (60) (Scheme 19). Later work, however, proved that the product of the dimsyl sodium treatment is instead the dibenz[b,f]azonine (73b). which is formed by N-attack on the intermediate benzyne followed by cleavage of the C-N+ bond ( 6 1 ) . HO Me0 I\

\ / Me0

c

I

I L

\

NaCH2SOCH,

~

Me0 OMe

' OMe

I

~ e o OMe

OH

HO

OMe

73b

'

OMe

OMe

74

SCHEME 19.

5. From Neospirinedienones The borane complex 75 when treated either with BF,-OEt, at room temperature followed by hydrogenation over Pt in methanol or with 1 N NaOH in methanol followed by reduction with sodium borohydride gave the tetrasubstituted dibenzazonine 76 in 75% yield (Scheme 20). This result supports the hypothesized intermediacy of N-methylneospirinedienones in the acid-catalyzed rearrangement of morphinandienones to dibenzazonines, as in Scheme 16. On the other

200

LUIS C A S T E W EXPOSITO AND W M I N G O DOMINGUEZ FRANCISCO

hand, when 75 was heated with BF,-OEt, in refluxing benzene and then hydrogenated over Pt in methanol, the aporphine 67 (8%), the erybidine isomer 76 (35%), and the unnatural aporphine 77 (25%) were obtained ( 5 8 ) (Scheme 20). OMe

76 (35%)

Treatment of the N-formylneospirine derivative 78 in methanol with dry HCl gas produced the ketal79 (7 I%), which on reduction with excess LiAlH, gave an 8 1% yield of 0-methylerybidine (9). The rearrangement involved in this process probably takes place as shown in Scheme 21 (62).

6. From Erythrina Alkaloids

Several Erythrina bases have been transformed into dibenzazonines. The first report, by Prelog et al. ( 6 3 ) ,described the transformation of dihydroerysotrine (80) to the simple dibenzazonine 81 by degradation with cyanogen bromide followed by reduction with lithium aluminum hydride. In a similar way, treatment

4.

OMe

Me0 Me0

0

$7

OMe I

-COH

Me0

20 I

DIBENZAZONINE ALKALOIDS

-COH HCI

LiAlH,

McOH

Me0

Me0 OMe

OMe

OMe

Q-methylerybidine (9)

SCHEME 21

OMe

1) BrCN 2) LAH

Me0

81

80

of erythroculinol acetate (82) under von Braun degradation conditions gave the cyano compound 83, whose reduction and N-methylation lead to the dibenzazonine 84 (64). OMe

-

OMe

N-CN

Me0 82

Mondon et al. (6 5 )reported a multistep transformation of the erythrinandione 85 to the dibenzazonine 81 (Scheme 22). Other routes to ring expansion in the policyclic system of Erythrina derivatives have been reported. Thus cocculine (86) rearranges by treatment with acetic anhydride to give the N.0-diacetyl derivative 87 (66).

202

LUIS CASTEW E X F ~ S I T OAND WMINGO WMINGUEZ FRANCISCO

OMe

OMe

OMe

OMe

SCHEME 22.

Erysodienone (36) has been transformed reductively to the dibenzazonine 35a: treatment of 36 with chromous chloride (67) or titanium(ll1) chloride (68) in aqueous hydrochloric acid gave 35a in good yield (Scheme 23). Other reductive conditions such as sodium in liquid ammonia or zinc in acetic acid also produce ring fission (39). Methylation of erysodienone (36) with methyl iodide in methanol at 50" C led to the methiodide 88, which on alkaline treatment in methanol or ethanol produced the 9-alkoxydibenzazonines 89 and 90, respectively (69) (Scheme 23). This latter transformation contrasts with that reported earlier by Barton et al. ( 3 9 ) , who found that the reaction of 36 with benzyl chloride and potassium carbonate in ethanol led to incorporation of an ethoxyl group in an aromatic ring, giving 91. Erythrinadienols have also been transformed to dibenzazonines. Thus, when 93 was heated with HCI in MeOH, a 50% yield of the pentasubstituted dibenzazonine 94 was obtained (Scheme 24). This compound could also be p ~ pared directly from 92 by chromous chloride reduction (70). Erysodienol (9s)

203

4. DIBENZAZONINE ALKALOIDS

OH

Me0

Me0 35a

Me0

N-Bz

Me0 ‘OH

Me0

Me0

Me0

OH 89 R=Me 90 R=Et

OBz 91 R, or R,=OEt SCHEME 23.

MflsoMT “9 OH

Ho

0

Me0

MeOH HCI

I I

Me0

0

92

0

OMe

Me0

Me0

OH 93

‘

OMe

OH 94

SCHEME 24.

rearranges under the action of Rodinov’s reagent to give 9 and erybidine (1) (7), whereas treatment with methyl iodide in warm methanol led to 97 in a process thought to occur by fission of the spirodienol ring of intermediate salt 96 (69) (Scheme 25). In 1985, a synthesis of laurifonine (4) and laurifine (5) was described that employs a methyl chloroformate-induced ring expansion of the erythrinanone 98 (71) (Scheme 26). Compound 98 reacts with methyl chloroformate in refiuxing

204

LUIS CASTEW E X P ~ S I T OAND WMINGO WMINGUEZ FRANCISCO

HO Me1 I MeOH

Me0 OH 95

OH

I -Me

M Me0 *%N

&e

'

OH

97

9 R=Me SCHEME 25

OMe

OMe

Me0 MeOCOCl

/

0

99

Me0

$" SCHEME 26.

benzene in the presence of potassium carbonate to give the enone 99 in good yield. Aromatization and concomitant methylation of 99 using copper(I1) bromide in methanol then gave the dibenzazonine derivative 100, which could easily be transformed to laurifonine (4). Laurifine (5) was obtained in low yield by direct hydrolysis of carbamate 100 or, more conveniently, by N-demethylation of 4 by the von Braun procedure and reduction of the intermediate cyanamide. Interestingly, attempts to carry out the ring expansion of 98 using cyanogen bromide under various conditions failed (71).

205

4. DIBENZAZONINE ALKALOIDS

V. Biosynthesis The dibenzazonines are intermediates in the biosynthesis of Erythrina alkaloids ( 7 2 ) . Several biogenetic routes have been proposed to explain the formation of dibenzazonines in plants. A. FROMBISPHENETHYLAMINES The nine-membered nitrogenous ring might be formed directly by oxidative phenolic coupling of the bisphenethylamine Ma to give 35a. The dibenzazonine thus formed can be further oxidized to give Erythrina alkaloids (Scheme 27). a process which has been achieved chemically (see Scheme 7). Feeding experi-

Me0

N-H

Me0

35a

34 a

OH

Me0

OH

0 ,

i

Erythrina alkaloids

SCHEME 21

ments, however, showed very little incorporation of bisphenethylamine 34a into alkaloids of Erythina crysta-galli,providing in vivo evidence against 34a being a biogenetic precursor (73). More recently, Battersby found no incorporation of several bisphenethylamines into protostephanine (3) in feeding experiments with Stephania japonica plants, thus putting an end to biogenetic speculations that involve bisphenethylamine-type precursors ( 74). B. VIA MORPHINANDIENOLS Oxidative phenolic coupling of benzylisoquinolines gives morphinandienones, in which reduction to a morphinandienol followed by dienol-benzene rearrangement leads to a neospirine that further rearranges to a dibenzazonine. This hypothesis was suggested by Barton to explain formation of protostephanine (3) in S. japonica (52) (Scheme 28). Feeding experiments carried out by Battersby et

206

LUIS CASTEDO E X P ~ S I T OAND WMINGO DOMINGUEZ FRANCISCO

OH

' ' 4 -

0

~~0 \ OH

OH

0

,ol

.,IN-Me

1

%-

"para-para'' 101R=OMe 102 R=OH

Me0

.,IN

1

0

' OH

OH

OH

SCHEME 28.

al. with radiolabeled I -benzyltetrahydroisoquinolines, however, showed no incorporation of the most obvious precursor, 101, into protostephanine (3), thus ruling out its involvement (75). Extensive investigation with a wide range of different substituted 1-benzylisoquinolines finally led to the discovery that only benzylisoquinolines with phenolic groups at C-7 and C-8 (such as 102) can act as precursors of protostephanine (3) (74). The biosynthesis of protostephanine is thus unique in the sense of requiring two phenolic hydroxyl groups in one of the rings undergoing coupling. A parallel biogenetic scheme has been suggested by Theuns er al. (24) for the formation of neodihydrothebaine (7 ) in Papaver bractearurn. In this case the route proceeds through the isomeric salutaridinol (103), which is derived by para-ortho coupling of reticuline (Scheme 29). It has been suggested that salutaridinol (103) (or thebaine) is the precursor of bractazonine (8), but in this case via a proerythrinadienone formed by aryl migration in the dienol-benzene rearrangement (24) (Scheme 30).

C. VIA PROERYTHRINADIENONES Oxidative phenolic coupling of protosinomenine can lead to proeythrinadienones, which by dienone-phenol rearrangement can act as precursors of type A (fully oxygenated) dibenzazonines in a process which has been suggested to explain the biogenetic origin of erybidine (1) (2) and crassifolazonine (2) (15)

4. DIBENZAZONNE ALKALOIDS

207

0

Me0

Me0

HO MeO

8

-

HO

"para-ortho"

Me0

Reticuline

Me0

N-Me HO

\

Me0

0

7

% & :M e

-

\

Me0

I

SCHEME29.

(Scheme 31). The biogenetic pathway shown in Scheme 31 has been proved to be operative for the biosynthesis of Erythrinu alkaloids, at least when starting from norprotosinomenine, which was efficiently incorporated into erythraline (76) (Scheme 32). A proerythrinadienone(such as 103a) has also been suggested as a possible intermediate in the biogenetic route to erybidine (1). Furthermore, feeding experiments with Cocculus luurifolius have shown incorporation of (+)-norprotosinomenine into laurifinine (6) in a process which is thought to occur by reduction of 103a to the dienol 104, which by rearrangement to 105 and further evolution produces laurifinine (6) (77) (Scheme 32).

OH

-

Me0

[HI

MeO

N-Me \

Me0 M" e0q

-

M

OH

e

Me0

-

"para-ortho"

OH

Me0

protosinomenine

OMe

HO

HO

Me0

Me0

'

SCHEME 31.

OH

OH

norprotosinomenine

I [OI

MeO N-Me

Me0

104

Me0

MeO OMe

------105

Me0 OH

erythraline

Me0 OH

SCHEME 32.

4. DIBENZAZONINE ALKALOIDS

209

VI. Pharmacological Properties Hydrochlorides of dibenzazonines 14b, 106,107, and 108 have been tested by Pecherer and Brossi (29) for analgesic and anti-inflammatory activity, antiappetite and blood pressure effects, and activity against a series of infections. The alkaloid protostephanine (3) exerts a moderately strong and persistent hypotensive effect. Most of the other compounds show some central nervous activity. Independent studies have also found CNS activity for compounds 107, 109, and 110, all of which behave as hypotensive agents (30).

RzF Rl

\

RZ

/ R2

-R3

14b Rl=R2=R3=H 106 Rl=R3=H, R2=OMe 107 Rl=Rz=H, R3=Me 3 Rl=H, R2=OMe, R3=Me 108 R1=Br, R2=OMe, R3=Me 109 RI=R,=H, R,=Et 110 Rl=Rz=H, R,=CH*=CH-CH,-

A series of dibenzazonines with the general structure 111 (R, R , = H, alkyl, alkoxy, halo; R, = H, alkyl; R, = H, alkyl, alkanoyl; n = 1, 2) were prepared from thebaine (45) and found to have antiarrhythmic activity similar to that of procainamide and local anaesthetic activity lasting longer than that of tetracaine (45). One compound of this series, named asocainol (111, R = R, = H, R, = Me, R, = H, n = 2), is a useful drug whose mechanism of action in isolated guinea pig papillary muscles has been studied in detail (78, 79).

VII. Related Alkaloids: Dibenzazecines To date only one natural dibenzazecine is known, which was isolated from Dysoxylurn lenricellare Gillespie (Meliaceae) (80). Dysazecine (114) is an optically active base, [a],+ 83", with UV absorptions at 230 and 291 nm; the melting point of its crystalline picrate is 217-219" C. The IH-NMR spectrum of dysazecine shows three singlets arising from aromatic protons r6.76 (2H), 6.53 (lH), and 6.52 ( l H) ] and signals for a methylenedioxy group [5.98 (d, J = 1.5, 1H) and 5.96 (d, J = 1.5, lH)], two methoxyls (3.92 and 3.82), and one Nmethyl which appears at a uniquely shielded position (2.10). The remaining aliphatic hydrogens are found in three complex multiplets (2.6-2.5,2.4-2.15, and 1.8-1.4). The I3C-NMR spectrum shows the presence of four oxygenated quaternary carbons ( 144.7- 148.3), four quaternary aromatic carbons ( 1 33135.4), four protonated aromatic carbons (107.5- 112.8), and five aliphatic

210

LUIS CASTEW E X P ~ S I T O AND DOMINGO WMINGUEZ FRANCISCO

methylene groups (two deshielded by attachment to nitrogen at 49.6. and 59.0 and three others resonating between 27.8 and 30.5) (80). Dibenzazecines are probably biogenetically derived from a phenethylisoquinoline such as 112 via the homoproerythrinadienone 113 (Scheme 33). The resulting dibenzazecine can either give dysazecine 114 or be further oxidized to a homoerythrina derivative such as 115. This biogenetic pathway parallels that of the Eryrhrina alkaloids (see Scheme 32). Dysazecine has been synthesized by a photochemical route. Irradiation of 116 gave the reduced derivative 117 (17%) and the cyclized products 118 (13%) and OH

SCHEME 33. OH

OH

NaOH

0 L

\ O

118

116 R=Br 117 R=H

0

\

L o

119

: i

Dysazecine (114) SCHEME 34.

21 1

4. DIBENZAZONINE ALKALOIDS

119 (26%).The latter was transformed to dysazecine (114) by the usual threestep procedure (81) (Scheme 34). Other synthetic routes to dibenz[dflazecines have been reported. Oxidative coupling of tetramethoxy derivative 120 promoted by thallium tristrifluoroacetate (TTFA) gives an excellent yield of 121 ( 4 1 ) (Scheme 35). A biogenetic type approach to dibenz[d,f]azecines has been deOMe

OMe

N-COCF3

Me0

TIFA 60%

~

$M *

-COCF,

Me0

120

OMe

'

121

OMe

SCHEME 35.

OH

Me0

1) NaOH D

2) NaBH4

Me0

Me0

::v OH

OH

,ol

I

'

124

OH

Me0

Me0 OH

125

C

I

OH

C/ I

\

126

0

I

-

I I

___)

A

: ~

127

Me0

OH SCHEME 36.

scribed that starts from the phenethylisoquinoline 122, which by phenolic oxidative coupling leads to the homoproerythrinadienoneintermediate 123. Subsequent hydrolytic fragmentation followed by reduction of the intermediate imine leads to dibenz[df]azecine 124 (82) (Scheme 36). Dibenzazecine 124 has also been synthesized from the N-acyltetrahydroquinoline125 by oxidation to the di-

~

~

P

212

LUIS CASTEDO EXP6SITO AND WMINGO DOMINGUEZ FRANCISCO

enone lactam 126 and reductive cleavage to the dibenzazecinone 127, which is finally reduced to 124 (83)(Scheme 36).

REFERENCES I . M. Shamma, in “The Isoquinoline Alkaloids,” Chap. 22. Academic Press, New York, 1972. 2. M. Shamma and J. L. Moniot, in “Isoquinoline Alkaloids Research 1972-1977,” Chap. 18. Plenum, New York, 1978. 3. Specialist Periodical Reports, “The Alkaloids,: Vols. I - 13. Royal Chemical Society, London, 1971- 1983. Coverage continues in the review journal Natural Product Reports of the Royal Chemical Society. 4. S. F. Dyke and S. N. Quessy, in “The Alkaloids” (R. G. A. Rodrigo, ed.), Vol. 18, p. I . Academic Press, New York, 1981; R. K. Hill, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 9, p. 483. Academic Press, New York, 1967. 5. K. Ito, H. Furukawa, and H. Tanaka, Chem. Phurm. Bull. 19, 1509 (1971). 6. K. Ito, H. Furukawa, and H. Tanaka, Yukuguku Zusshi 93, 1211 (1973). 7. K. Ito, H.Furukawa, H. Tanaka, and T. Rai, Yukuguku Zusshi 93, 1218 (1973). 8. K. Ito, M. Haruna, Y. Jinno, and H. Furukawa, Chem. Phurm. Bull. 24, 52 (1976). 9. K. Ito, H.Furukawa, M. H m n a , and M. Ito, Yukuguku Zusshi 93, 1674 (1973). 10. K. Ito, H. Furukawa, and M. Haruna, Yukuguku Zusshi 93, 161I (1973). 11. K. Ito, H. Furukawa, M. Haruna, and S.-T. Lu, YukugukuZusshi93, 1671 (1973). 12. K. Ito, M. Haruna, and H. Furukawa, Yukuguku Zusshi 95,358 (1975). 13. A. H.Jackson and A. S. Chawla, Allertoniu 3,39 (1982). 14. V. U. Ahmad, Q. Najmus-Sagib, K. Usmanghani, and G. A. Miana, Sci. Phurm. 48, 169 ( 1980). 15. J. M. Boente, D. Dominguez, and L. C. Castedo, Heterocycles 23, 1069 (1985). 16. T. Kametani, “The Chemistry of lsoquinoline Alkaloids,” Vol. 1, Chap. 19. Hirokawa Publ., Tokyo, 1968. [Contains a list of references concerning protostephanine prior to 1966.1 17. M. Tomita and T. Ibuka, Yukuguku Zasshi 83,996 (1963). 18. D. H. R. Barton, G. W. Kirby, and A. Wiechers, J. Chem. Soc. C, 2313 (1966). 19. M. Tomita, Y. Innubushi, and T. Ibuka, Yukuguku Zusshi 87, 381 (1967). 20. M. Matsui, M. Uchida, I. Usuki, Y. Saionji, H. Murata, and Y. Watanabe, Phytochemistry 18, 1087 (1979). 21. H. Ripperger, A. Preiss, and M. Diaz, Phytochemistry 22, 2603 (1983). 22. H.Uprety and D. S. Bhakuni, Tetrahedron Lett.. 1201 (1975). 23. H. Pande and D. S. Bhakuni, J. Chem. Soc.. Perkin Trans 1 . 2197 (1976). 24. H. G. Theuns, H. B. M. Lenting, C. A. Salemink, H. Tanaka, M. Shibata, K. Ito, and R. J. I. C. Lousberg, Phytochemisrry 23, I157 (1984). 25. A. W. Sangster and K. L. Stuart, Chem. Rev. 65,69 (1965). 26. K. Ito, H. Tanaka, and M. Shibata, Heterocycles 9,485 (1978). 27. K. Takeda, ltsuu Kenkiusho Nempo 13,45 (1963). 28. B. Pecherer, R. C. Sunbury, and A. Brossi, J . Med. Chem. 12, 149 (1969). 29. B. Pecherer and A. Brossi. Helv. Chim. Acru 49, 2261 (1966); B. Pecherer and A. Brossi, J . Org. Chem. 32, 1053 (1967). 30. K. Katsumi and K. Ryonosuke, Jpn. Patent 5384 (1966); Chem. Abstr. 65,2236h (1966). 31. K. Katsumi, M. Michiko, M. Sadao, 0. Tetsuo, H. Yoshinori, K. Ryonosuke, H. Katsumi, E. Masami, J. Hirokuni, and S. Hatsuo, Shionogi Kenkyusho Nempo 17,88 (1967). 32. D. S . Bhakuni and V. K. Mangla, Indian J. Chem. Sect. B 20B, 531 (1981). 33. K. Ito and H.Tanaka, Chem. Phorm. BUN. 22, 2108 (1974).

4. DIBENZAZONINE ALKALOIDS

213

34. H. G. Theuns, H. B. M. Lenting, C. A. Salemink, H. Tanaka, M. Shibata. K. Ito, and R. J. J. C. Lousberg, Heterocycles 22, 2007 (1984). 35. H. G. Theuns, H. B. M. Lenting, C. A. Salemink, H. Tanaka, M. Shibata. K. Ito, and R. J. J. C. Lousberg, Heterocycles 22, 1995 (1984). 36. H. Tanaka, M. Shibata, and K. Ito, Chem. Pharm. Bull. 32, 1578 (1984). 37. A. Mondon and M. Ehrhardt, TefruhedronLeff.. 2557 (1966). 38. J. E. Gervay, F. McCapra, T. Money, G. M. Sharma, and A. 1. Scot, J. Chem. Soc.. Chem. Commun., 142 (1966). 39. D. H. R. Barton, R. B. Boar, andD. A. Widdowson, J. Chem. Soc. C. 1208(1970). 40. A. G. M. Barret, D. H. R. Barton, G. Franckoviak, D. Papaioannu, and D. A. Widdowson. J . Chem. Soc., Perkin Trans. I , 662 (1979). 41. E. McDonald and R. D. Wylie, J. Chem. Soc.. Perkin Trans 1. 1104 (1980). 42. S. Brandt, A. Marfat, and P. Helquist, Tetrahedron Leff., 2193 (1979). 43. F. R. Hewgill and M. C. Pass, Ausr. J. Chem. 38,537 (1985). 43a. L. Small, L. J. Sargent, and J. A. Bralley, J . Org. Chem. 12, 839 (1947). 44. K. W. Bentley and R. Robinson, J. Chem. Soc.. 947 (1952);see also J. A. Berson and M. A. Greenbaum, J. Am. Chem. SOC. 80,445 (1958). 45. G. Satzinger, M. Herrmann, E. Fritschi, H. Bahrmann, V. Ganser, B. Wagner, and W. Steinbrecher, Ger. Offen. DE 3007710;Chem. Absfr. 96, 35125d (1982). 46. K. W. Bentley, J. Am. Chem. Soc. 89,2464 (1967). 47. M. Hall and W. W. T. Manser, J. Chem. Soc.. Chem. Commun.. 112 (1967). 48. K. W. Bentley, J. W. Lewis, and J. B. Taylor, J. Chem. Soc. C , 1945 (1969). 48a. Personal communication by Dr. A. Brossi, NIH. Recrystallization of two perchlorate samples of phenyldihydrothebaines from Dr.Small's sample collection and resynthesis of the biphenyl isomer of Small] for X-ray diffraction of (-)-35"from (aR,8R)-phenyIdihydrothebaine[(+)-a analysis were performed by Dr. Yoshikuni Itoh, who was on sabbatical leave from the Fujisawa Pharmaceutical Co., Ltd., in Japan. The X-ray data shown in Fig. 2 were collected and elaborated by Judith L. Hippen-Anderson and colleagues at the Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, D.C. 20375.Tables of hydrogen coordinates, bond length, and angles will be deposited with the Crystallographic Data Center, Cambridge University Chemical Laboratory, Cambridge CB2 IEW, England. The CD spectra listed below were measured by Dr. Voldemar Toome and Bogda Wegnynski, Research Division, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110. I . (aS,8R)-Phenyldihydrothebaine [HCI O4 (+) - 131°]: CD (C 0.004 M , MeOH) [ ~ I ~ I s0;, [61277. -4,125; [e]263.0; [012s4,+1,250; [01247, 0; [elmr -18,250;[ O h . 0; [ e h . +88.OW [elzw, 0; [e1203,~ [ ~ I I w .,0;lel19s. ~ +71,200 (last). 2. (aR,8R)-Phenyldihydrothebaine [HCI 0,(+)- IO"]: CD (c 0.0044 M , MeOH) [ ~ I ~ I s0;. [eho,+12,750; [ e h .0;[e1241, -18.950; [81234. -17,370; [ehl6, - 158,845;[eh,,,,, 0;[ehl,+342,960;[el,,, 0 (last). 3. (as)-Phenyltetrahydrothebaine [( -)-35']: CD ( c 0.005 M , MeOH) 0; -2,450; [eiZl5.- 1.200;[ei,,. 0; ieiZN. +2,100; - 19,800;[e1220,-7,600; [eizI3. - 12,000;[el,, 0; iei,,. + 14.000; [ell98,0;1 ~ l l c 2 , - 34.500;[0lrs8.0 (last). 48b. The absolute configurations shown in Scheme 1 I and supported by solid state X-ray diffraction analysis were deduced on the basis of rules established by R. S.Cahn, C. Ingold, and V. Prelog [Angew. Chem. Inf. Ed. 5,385 (1966)land by K. Mislow [Angew. Chem. 70,683 (1958)l.aR and aS refer to axial ( R ) and (S), respectively. 49. R. T. Channon, G. W. Kirby, and S. R. Massey, J . Chem. Soc. D , 92 (1969). 50. H. G. Theuns, G. F. L a Vos, M. C. ten Noever de Brauw, and C. A. Salemink, Terruhedron Lefi.. 4161 (1984).

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LUIS CASTEW EXP~SITOAND WMINGO WMINGUEZ FRANCISCO

51. H. G. Theuns, R. H. A. M. Janssen, A. V. E. George, and H. W. A. Biessels, J. Chem. Res. ( m ) . 1458 (1985). 52. D. H. R. Barton, Pure Appl. Chem. 9, 35 (1964). 53. A. R. Battersby, A. K. Bhatnagar, P. Hackett, C. W. Thornber, and J. Staunton, J . Chem. Soc., Chem. Commun., 1214 (1968). 54. A. R. Battersby, A. K. Bhatnagar, P. Hackett, C. W. Thornber, and J. Staunton, J. Chem. SOC.,ferkin Trans. 1. 2002 (1981). 55. S. M. Kupchan. C.-K. Kim, and K. Miyano, Heterocycles 4, 235 (1976). 56. B. Frank and V. Teetz, Angew. Chem. fnt. Ed. 10,411 (1971). 57. S. M. Kupchan and C.-K. Kim, J. Am. Chem. Soc. 97,5623 (1975). 58. S. M. KupchanandC.-K. Kim, J. Org. Chem. 41,3210 (1976). 59. S. M. Kupchan, C.-K. Kim, and J. T. Lynn, J. Chem. SOC.,Chem. Commun.. 86 (1976). 60. S. Kano, T. Ogawa, T. Yokomatsu, E. Komiyama, and S. Shibuya, Tetrahedron Lett., 1063 (1974). 61. S. Kano, T. Yokomatsu, and S. Shibuya, Heterocycles 6 , 1735 (1977). 62. S. M. Kupchan, A. J. Liepa, V. Kameswaran, and R. F. Bryan, J. Am. Chem. Soc. 95, 6861 (1973). 63. V. Prelog, B. C. McKusick, J. R. Merchant, S. Julia, and M. Wilhelm, Helv. Chim. Acta 39, 498 (1956). 64. Y. Innubushi, H. Furukawa, and M. Ju-ichi, Tetrahedron Lett., 153 (1969). 65. A. Mondon, H. J. Nestler, H. G . Vilhuber, and M. Ehrhardt, Chem. Ber. 98,46 (1965).

66. R. Razakov, S. Yu Yunusov, S.-M. Nasyrov, A. N. Chekhlov, V. G. Andrianov, and Y. T. Struchkov, J. Chem. Soc.. Chem. Commun.. 150 (1974). 67. D. H. R. Barton, R. James, G. W. Kirby, D. W. Turner, and D. A. Widdowson, J. Chem. SOC. C. 1529 (1968). 68. D. H. R. Barton, R. D. Bracho, C. J. Potter, and D. A. Widdowson, J. Chem. SOC.. ferkin Trans. 1. 2278 (1974). 69. K. Ito and H. Tanaka, Chem. fharm. Bull. 25, 3301 (1977). 70. T. Kametani, T. Kohno, and K. Fukumotu, Chem. fharm. Bull. 20, 1678 (1972). 71. J. B. Bremner and C. Dragar, Heterocycles 23, 1451 (1985). 72. D. H. R. Barton, R. B. Boar, and D. A. Widdowson, J. Chem. SOC. C. 1213 (1970). 73. D. H. R. Barton, R. James, G. W. Kirby, and D. A. Widdowson, J. Chem. SOC., Chem. Commun.. 266 (1967). 74. A. R. Battersby, R. C. F. Jones, A. Minta, A. P. Ottridge, and J. Staunton, J. Chem. SOC., f e r k i n Trans. I . 2030 (1981). 75. A. R. Battersby, R. C. F. Jones, R. Kazlankas, C. W. Thornber, S. Ruchirawat, and J. Staunton, J . Chem. SOC.. f e r k i n Trans. I , 2016 (1981). 76. D. H. R. Barton, C. J. Potter, and D. A. Widdowson, J. Chem. SOC.. ferkin Trans. 1. 346 (1974). 77. D. S. Bhakuni and S. Jain, Tetrahedron. 3171 (1981). 78. F. Spach, J. Cardiovasc. fharmacol. 6 , 1027 (1984); Chem. Abstr. 102, 3059318 (1985). 79. W. Herrmann, G. Satzinger, Ger. Offen. DE 3.419.099; Chem. Abstr. 105,43135b (1986). 80. A. J. Aladesanmi, C. J. Kelley, and J. D. Leary, J. Nut. Prod. 46, 127 (1983). 81. H. Tanaka, Y. Takamura, K. Ito, K. Ohira, and M. Shibata, Chem. fharm. Bull. 32, 2063 (1984). 82. J. P. Marino and J. M. Samanen, J. Org. Chem. 41, 179 (1976). 83. E. MacDonald and A. Suksamrarn, J. Chem. SOC..ferkin Trans. 1. 434 (1978).

-CHAPTER 5-

NUPHAR ALKALOIDS JACEK

CYBULSKI A N D

JERZY T. W R 6 B E L

Department of Chemistry University of Warsaw Warsaw. Poland 1. Introduction

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

11. Significance of Nuphar Species in the Aquatic Habitat . . . . . . . . . . . . . . . . . . . . . . . . Ill. New Nuphar Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

A. 5-(3-Furyl)-8-methyloctahydroindolizine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. 7-Demethyldeoxynupharidine . . . . . . C. Nupharopumiline . . . . . D. I-Epideoxynupharidine G. Isocastoramine .................................................... H. Secodihydrocastoramine ............................................

........... V. Chemistry of Nuphar Alkaloids and Manifestation of Sulfur . . . . . . . . . . . . . . . . . . . VI. Synthesis of Nuphar Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . V11. Spectroscopy of Nuphar Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. NMR Spectroscopy ... B. Mass Spectrometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. CircularDichroism ................................................ VIII. Pharmacology . . ............ References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

215 216 220 220 222 222 222 223 223 223 223 224 226 226 226 227 227 227 232 239 244 244 249 252 253 256

I. Introduction The two previous reviews of Nuphar alkaloids published in this treatise covered the literature up to 1974 (I). Since then, 21 new alkaloids have been isolated and characterized. Most of these are simple variants of already known structures, and only in one case has a different ring system been discovered. For the first time, the chemistry of Nuphar alkaloids has been characterized in greater detail. The ring systems present in this group of alkaloids continue to 215

THE ALKALOIDS. VOL. 35 Copyright 0 1989 by Academic Press. Inc. All rights of rcproduclion in any form reserved.

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JACEK CYBULSKI AND JERZY T. W R ~ B E L

challenge chemists interested in alkaloid synthesis. Although major progress toward synthesis has been made, total synthesis of a sulfur-containing Nuphar alkaloid is still awaited. I H-NMR and I3C-NMRspectroscopy have been successfully applied to solve many structural and stereochemical problems. Interesting observations were made in both mass spectrometry and circular dichroism with respect to determination of structure and stereochemistry. Biosynthetic studies, unlike the other studies, have not been pursued, possibly because of the technical difficulties of working with an aquatic plant that does not grow well in unnatural conditions. The chemotaxonomy of the genus Nuphar has been reviewed (2, 3). Biological and environmental aspects of Nuphar species have been discussed in a number of publications.

11. Significance of Nuphar Species in the Aquatic Habitat

The water lily (Nuphar lutea, N . variegatum, or N . japonicum) was found to be a convenient medium for investigations into the accumulation of various chemical elements, mainly because its common occurrence in the waters of Finland, Japan, Poland, the Soviet Union, and the United States; this species is one of the most important representatives of aquatic plants. In addition, 82% of its biomass is rhizomes and roots and only 18% leaves and petioles. The water lily can thus play the role of a biological indicator of metal contamination, as it fulfills most of the requirements proposed by Ray and White (4) for using a plant as a biological indicator. These are the following: (1) the plant should be representative of a given area, (2) it should be ubiquitous and easy to collect, (3) it should be easily identified, and (4) the plant should exhibit a high metal tolerance and a high concentration factor. The yellow water lily has been used for investigations into the content of various elements in water samples. Sometimes these investigations gave inconsistent results, but this may be explained by the fact that the plants were collected from different areas and also at different times. The copper content was examined in different parts of Nuphar lutea (L.) Sm. and also in samples obtained below waste discharge points ( 5 ) . The highest amounts were found in the petioles and leaves and unexpectedly low amounts in belowground organs. It has been found that N . lutea is able to survive and grow, without any visible damage to its structure, in the presence of high copper concentrations. This points to a high tolerance against contamination with heavy metals, and thus it was suggested that N. lutea can be a biological indicator for water pollution. On the other hand, it was found that N . variegatum (growing at Flin Flon, Manitoba, Canada) does not accumulate elements such as Zn, Cu, and Cd in amounts comparable to the water milfoil (Myriophyllum exalbescens) and so cannot be used as a biological indicator of contamination (6). The possibilities

5 . NUPHAR ALKALOIDS

217

of scandium, yttrium, and rare earth element accumulation by Nuphar lutea (Willd.) Pers. were also examined. In N . lutea collected from Dow Loch, Scotland, it was found that Sc. Y, and rare earth elements did not accumulate in the buds and leaves (7). This is contrary to the results obtained earlier by Cowgill (8),who found concentration of these elements in Nuphar udvena Ait. Investigations were also carried out on the content of potassium, sodium, calcium, magnesium, and iron in Nuphar lurea (L.) Sm. ( 9 ) .Potassium concentrations were found to be higher in belowground organs than in aboveground leaves (laminae). Also, sodium concentrations were three times higher in the petioles than in the laminae. Calcium had the highest concentrations in petioles and the lowest in rhizomes. Magnesium concentrationswere higher in leaves and petioles than in roots and rhizomes. Regarding iron, its highest concentrations were in roots (about 2.5 times more than in laminae and petioles). Samples of Nuphar lurea (L.) Sm., collected from the same locations as before, were also tested for the presence of nitrogen, carbon, and phosphorus (10). It was found that the aboveground laminae have much higher nitrogen concentrations in comparison with the belowground parts of the plant. Also, the carbon content was somewhat higher in the aboveground parts than in belowground ones. Phosphorus concentrations, however, were approximately the same in all parts. Comparison of numerical values of concentrations of particular elements in certain organs of N . lutea showed that, apart from carbon and oxygen, potassium content was the highest, followed by nitrogen, calcium, sodium, magnesium, and iron. Nuphar lutea, a plant very sensitive to perturbations such as those which may accompany the mining of metal ores, was also examined in order to measure the content of radionuclides in a series of uranium group elements ( I I). In experiments carried out in the Okanagan region of south-central British Columbia, N . lutea was found to accumulate natural uranium and 226Ra,and the amounts of these elements were found to depend on the season and also on the pH of the mud. Nuphar lurea was also used in investigations into the concentration of 137Cs and potassium in Lake Ulkesjon in the southern part of Sweden ( 1 2 ) . Nuphar lutea was employed for testing phosphorus absorption, translocation, and secretion (13). Laboratory studies have shown that the level of absorption depends on the type of organ of N . lutea examined, being highest in the roots. In natural habitats (Chowan River, North Carolina) it was found that the translocation of phosphorus proceeds in two directions, favoring the acropetal way (i.e., from roots to laminae). The level of phosphorus translocation depends on the season; it is highest in summer and less in spring and winter. The phosphorus is stored by the roots and then secreted by underwater laminae in the summer. Nuphar lutea was found to be an excellent medium not only for determining the concentration of particular elements but also for examining the flow of gas in the plant. It was found that N . lutea operates a flow-through venilation system ( 1 4 ) . Oxygen from the air flows to the young, emerging leaves and then through

218

JACEK CYBULSKI AND JERZY T. WROBEL

petioles to the rhizomes; this was confirmed by Ieo0,tracer experiments. The experiments also showed that most of 0, contained in the rhizomes had its origin in the atmosphere. In other investigations concerned with methane secretion from N . lutea, it was found that CH, is secreted to the atmosphere while flowing from the roots and rhizomes to petioles and surface leaves ( 1 5 ) . Nuphar variegatum Engelm. was used, among others, to examine microbial decomposition processes (16, 1 7 ) . These investigations were carried out in the hope of finding a natural transformation of plant biosynthetic products into such a form that they could be used again in a synthetic process. Microbial decompositions were performed for dissolved organic matter obtained from N . variegatum. The presence of oxygen was found to accelerate the decomposition process considerably, and the rate of decomposition was found to be affected by temperature as well. The process of decomposition was also investigated for particulate organic matter from N . variegatum. It was found that under various conditions (with varying temperature and performing the experiment in the presence/absence of 0,)out of a group of five aquatic plants, Scirpus acutus Bigel., Myriophyllum heterophyllum Michx, Najas Jlexilis Willd., Scirpus subterminalis Torr., and Nuphar variegatum Engelm., the last undergoes decomposition most rapidly. In addition, the process of carbohydrate reduction (total nonstructural) is greatest for N . variegatum (17 ) . As the water plants exhibit different decomposition rates, it was deemed worthwhile to find the relationship between decomposition rate and chemical composition of the plants. To address this problem, Nuphar variegatum Engelm. was subjected to pyrolysis and mass spectrometry techniques (18). It was found that N . variegatum is characterized by pyrolysis products of carbohydrates, proteins, and several phenolic components. On the other hand, pyrolysis of particular residues of decomposition products revealed a decrease in carbohydrate content and increases in protein, N-acetyl amino sugars, and lignins in comparison with natural N . variegatum. On the basis of these results Boon and Haverkamp (18) suggest that the proteins and N-acetyl amino sugars are of microbial origin. The presence of sesquiterpene alkaloids is characteristic of the water lily ( N . lutea, N . variegatum, N . japonicum). Most water plants do not contain alkaloids; this is confirmed by an investigation by Su et al. (19), who tested 22 water plants occurring in different lakes of Minnesota for the presence of alkaloids. Only in two cases, Nymphaea tuberosa and Nuphar variegatum, was the presence of basic nitrogen compounds found. Apart from the occurrence of nitrogen compounds in Nuphar variegatum, the presence of flavonols, p-sitosterol, and saponins was established (19). Forrest and Ray (20) isolated from N . variegatum caffeic acid, ferulic acid, and 3,4-dimethoxy-trans-cinnamicacid, the structures of which were confirmed by spectroscopic methods. Similar nonalkaloidal classes of compounds were isolated from Nuphar lutea; thus, the presence of trans-cinnamic, arachidic, behenic, and palmitic acids was confirmed in rhizomes (21) and that of ellagic, caffeic, p-coumaric, sinapic, and

219

5 . NUPHAR ALKALOIDS

ferulic acids in the leaves (22). From Nupharjaponicum DC. two gallotannins (1 and 2) were isolated, as well as ellagitannin (3) (23). On the basis of spectroscopic analysis and chemical transformations, compound 1 was assigned the structure 1,2,6-tri-O-galloyl-a-~-glucose, compound 2 the structure 1,2,3,4,6penta-0-galloyl-a-D-glucose, and 3 the structure 1,2,6-tri-O-galloy1-3,4-(S)hexah ydroxydiphenyl-a-D-glucose.

2

1

bH

OH

3

The interest of researchers was not merely confined to isolating and determining the structures of as many compounds occurring in the water lily as possible; it was also focused on explaining the biochemistry which takes place in this very specific plant. Thus, from Nuphar lutea (L.) Sibth. the iron-containing superoxide dismutase (Fe SOD) was isolated (24). The molecular weight of the enzyme was established as 46,000,and it was found that this enzyme is a dimer. The Fe SOD was found to be sensitive to H,O, and azides and insensitive to cyanide. It was also found that antibodies to the Nuphar enzyme, which were made up from rabbit serum, do not cross-react with purified Fe SOD or with raw extracts from prokaryotic or eukaryotic organisms which are known to contain Fe SOD. This indicates immunological uniqueness of the iron-containing enzyme from N. lutea. Owing to the fact that no cooccurring Cu-Zn-containing superoxide dismutase was found, N . lutea thus emerges as a unique plant. A question remains to be

220

JACEK CYBULSKI AND JERZY T.WROBEL

solved: Why does Nuphar lutea not contain a Cu-Zn-containing superoxide dismutase even though the analysis, performed for the detection of metals, showed it to contain Cu in amounts only slightly different from that found in ground plants which do contain Cu-Zn SOD? Finally, it was also found that the tissue of Nuphar advena Ait. contains cyclic adenosine 3'-5'-monophosphate (CAMP) in amounts similar to those published for algae (25). 111. New Nuphar Alkaloids

New Nuphar alkaloids isolated since 1974 are listed in Table I. Table I includes monomeric C,, alkaloids and dimeric C30sulfur-containing alkaloids. A. 5-(3-FURYL)-8-METHYLOCTAHYDROINDOLIZINE

5-(3-Furyl)-8-methyloctahydroindolizine(4) was isolated from Castorjber L. and is the first example of a Nuphar alkaloid with an indolizine chromophore (26). Structure 4 was proposed by the examination of mass spectra.

0

4

5

22 1

5. NUPHAR ALKALOIDS

TABLE I NEW Nuphar ALKALOIDS

bl: Name 5-(3-Furyl)-8-methyloctahydroindolizine (4) 7-Demethy ldeox ynupharidine (5) Nupharopumiline (6) I-Epideoxynupharidine (7) I-Epi-7-epideoxynupharidine (8) Nupharolidine ( 9 )

lsocastoramine (10)

Source

Melting point

(solvent)

Molecular formula, M

Reference(s)

Castor fiber L. Castor fiber L. Nuphar pumila (Timm.) DC Castor,fiber L.

Amorphous

C14H21N0*

26

195- 197°C

219 C,SH2INO7 23 1

27

Amorphous

C1SH23N0,

26

233 Castor fiber L.

Amorphous

26

ISH23N0,

233 Nuphar lutea

Casror fiber L.

Secodihydrocastoramine (11) Nuphacristine (12)

Nuphar japonicum Nuphar lutea

I-Epithiobinupharidine (1% 1'-Epithiobinupharidine (20) 1-Epi-1'-epithiobinupharidine (21) 6'-Epihydroxythiobinupharidine (22)

Nuphar lutea

Thiobinupharidine sulfoxide (syn) (23) 6-Hydroxythiobinupharidine sulfoxide (syn) (24) 6'-Hydroxythiobinupharidine sulfoxide (syn) (25) 6.6'-Dihydroxythiobinupharidine sulfoxide (syn) (26) 6-Hydroxyneothiobinupharidine (27)

110°C (hydrochloride) 240245°C (dec.) 109°C Amorphous

ISH23N02

9

28

249

- 124"

C15H23N027

(-)

249

-

Amorphous

26

C15HZSN02*

29. 30

25 1 c ISHdJO, * 265

31 32

Isolated as an inseparable mixture

32

Nuphar lutea

30.9"

Nuphar lutea

-

Nuphar lurea

Nuphar lutea

Presence shown by spectral data and reduction to 6'thiobinupharidine-d, Amorphous -7.7"

Nuphar lutea

-

+3.4" (CHCl,)

160- 165°C

+39"

Nuphar lutea

Nuphar lutea

(CHCI,) Nuphar lutea

Presence shown by spectral data and reduction to 6 4 , derivative of neothiobinupharidine

C ~ O H ~ ~ O S N 36 ~S. 542 C,oH,20,N2S, 510

37, 38

(continued)

222

JACEK CYBULSKI AND JERZY T. WROBEL

TABLE I (Continued)

14; Name

Source

Melting point

6'-Hydroxyneothiobinupharidine (28)

Nuphar /urea

6.6'-Dihydroxyneothiobinupharidine (29)

Nuphar /urea

Thionuphlutine B sulfoxide (syn) (30)

Nuphar /urea

(solvent)

Presence shown by spectral data and reduction to 6'-d, derivative of neothiobinupharidine Presence shown by spectral data and reduction to neo-

Molecular formula, M

Reference(s)

C3,H,,0,N,S, 5 10

37. 38

C3,H,,0,N2S,

33

526

thiobinupharidine-6.6'-d2

B.

Presence shown by spectral data and reduction to thionuphlutine B

C,,H,,O,N,S,

34, 39

510

7-DEMETHYLDEOXYNUPHARIDINE

IR, NMR, and mass spectroscopy furnished the structure of 7-demethyldeoxynupharidine ( 5 ) ( 2 6 ) . Independently, 5 was obtained in six steps from (-)-castoramine, as shown below in Scheme 6. C. NUPHAROPUMILINE Nupharopumiline (6) was isolated from Nuphar pumila (Timm.) DC. ( 2 7 ) .Its structure was determined by catalytic hydrogenation, which resulted quantitatively in (-)-deoxynupharidine (14). IR, 'H-NMR, and mass spectra of 6 were typical of known alkaloids of this group.

D. I-EPIDEOXYNUPHARIDINE 1-Epideoxynupharidine (7) was isolated from Castorjber L. and is epimeric with deoxynupharidine on carbon C-l . The structure was determined by NMR spectroscopy ( 2 6 ) .

223

5 . NUPHAR ALKALOIDS

E.

1-EPl-7-EPIDEOXYNUPHARlDlNE

1-Epi-7-epideoxynupharidine(8) is diastereoisomeric with deoxynupharidine on C-1 and C-7. Configurations at these carbon atoms were proposed on the basis of NMR spectroscopy (26).

F. NUPH AROLIDINE Nupharolidine (9) was isolated from Nuphar lutea (28). Its structure was determined by IR, ‘H-NMR, and mass spectroscopy. Compound 9 was the first example of a Nuphar alkaloid with a hydroxyl group in the quinolizidine system. This alkaloid is isomeric with castoramine (59), nuphamine, and isocastoramine (10).

G . ISOCASTORAMINE Isocastoramine (10) was isolated from Castor jiber L. ( 2 6 ) and represents an alkaloid with a hydroxyl group in the B ring (C-8) of the quinolizidine system. The structure of 10 was determined by spectroscopic methods and by transformation of 10 into a mixture of (-)-deoxynupharidine (14) and (-)-7epideoxynupharidine (15).

*OH

0

“CH3

I

10

Ag2C03-

& z:

Wolff -KishnerR1

mixture of H-deoxynupharidine 14 and M7-epidcoxynupharidine 15

H. SECODIHYDROCASTORAMINE Secodihydrocastoramine (11) was isolated from Nuphar japonicum (29, 30). The structure was determined by IR and ‘H-NMR measurements. The hydrochloride of 11 on treatment with phosphorus tribromide produced an epimer of deoxycastoramine.

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JACEK CYBULSKI AND JERZY T. WROBEL

I. NUPHACRISTINE Nuphacristine (12) was isolated from Nuphar lutea (31), and its structure and stereochemistry were determined chemically and spectroscopically. Reduction of 12 with NaBH, resulted in diol 13, which in a one-pot reaction yielded a 1.5 : 1 mixture of deoxynupharidine (14) and 7-epideoxynupharidine (15). I H-NMR, I3C-NMR, and mass spectra pointed out the presence of an a, P-unsaturated aldehyde and together with chemical results confirmed structure 12 for nuphacristine.

HMPA 2. NoBH3CN HMPA

t

16 R1 =CH3 ; R2.H 15 R1= H ; R2:CH3

As shown in Table I, 12 new sulfur-containing alkaloids were isolated from Nuphar species. They are derivatives of known Nuphar alkaloids: eight are derived from thiobinupharidine (16), three from neothiobinupharidine (17), and one from thionuphlutine B (18). The new alkaloids are represented by structures 19-30. These new compounds were shown to be epimers of thiobinupharidine (16) at C- 1 and C- 1' (19-21), sulfoxides of thiobinupharidine (23) or thionuphlutine B (30), thiohemiaminals of neothiobinupharidine (27-29), or thiohemiaminals of thiobinupharidine sulfoxides (24-26).

pH

H3C

16

18

17

T l& *'.

27 R2=R3=CH3 ; Z=OH 28 Rz=R3=CH3 Z'=OH 29 R2=R3=CH3 Z = Z'=OH

I 0\

X

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JACEK CYBULSKI AND JERZY T.WROBEL

22 : R ~ = R F R ~ = HR4=OH ; X=: 2.4 : R1 =OH ,R2=R3=R&=W x =0 25 : R1= R21R.4; R3=OH

x=o 26 : R1=R3=OH; RqrR4.H

x=o

J. THIOBINUPHARIDINE DERIVATIVES ~-EPI-~'-EPI ISOMERS)

( I-EPI, I '-EPI, A N D

The three new alkaloids 1-epi- (19), 1'-epi- (20), and 1-epi- 1'-epithiobinupharidine (21) were isolated from Nuphar lutea (32).These compounds are epimeric to thiobinupharidine with respect to the configuration of carbon atoms C-1 andlor C-1'. The methyl groups, which in most of these alkaloids are in an equatorial conformation, are axial in these three cases. The structures of these alkaloids were determined by I 3 C NMR.

K. 6'-EPIHYDROXYTHIOBINUPHARlDlNE A new thiohemiaminal type of alkaloid was also isolated from Nuphar lutea (33),and its structure was determined by NMR spectroscopy and by NaBD, reduction to thiobinupharidine-6'-dI.The new compound is thus 6'-epihydroxythiobinupharidine (22).

L. THIOBINUPHARIDINE SULFOXIDES AND DERIVATIVES

syn-Thiobinupharidine sulfoxide (23) was identified as a new component of extracts from Nuphar lutea (34-36). Its structure was determined by PCI, reduction to thiobinupharidine and by NMR spectroscopy. 6-Hydroxy-thiobinupharidinesulfoxide (syn) (24) was isolated from Nuphar lutea, and its structure was determined by NaBH, reduction followed by PCI, reduction, which resulted in thiobinupharidine. The syn configuration of compound 24 was demonstrated by the anisotropic effect of the sulfonyl group on the C-6 protons. The known absolute configuration of thiobinupharidine therefore allowed the (S)configuration to be assigned to the sulfoxide (36). The axial conformation of the hydroxyl group was shown by 'H- and 13C-NMRspectroscopy. 6'-Hydroxythiobinupharidine sulfoxide (syn) (25), isomeric with compound 24,was also isolated from Nuphar lutea (36).Its structure was determined by a similar chemical procedure and spectroscopic measurements. The total skeleton

5 . NUPHAR ALKALOIDS

227

was shown by the transformation into thiobinupharidine and the position of hydroxyl group by the mass spectrometric fragmentation of the NaBD, reduction products and their IH-NMR spectra (ASIS, LIS, and S-0 anisotropy techniques) (36). 6,6’-Dihydroxythiobinupharidine sulfoxide (syn) (26) was isolated from Nuphar lutea as the most polar compound in comparison with alkaloids 24 and 25. Its structure was determined by the same methods applied to compounds 34 and 35. M. NEOTHIOBINUPHARIDINE THIOHEMIAMINALS

6-Hydroxyneothiobinupharidine(27) was isolated from Nuphar luteu (37, 38). Its structure was elucidated by NaBH, and NaBD, reductions to neothiobinupharidine and neothiobinupharidine-6-dI,respectively, by the mass spectra, ‘H-NMR spectra, and finally by CD, which suggested the (7R) configuration for alkaloid 27. 6-Hydroxyneothiobinupharidine (28) was also isolated from Nuphar lutea (37,38). Reduction of 28 with NaBH, and NaBD, resulted in neothiobinupharidine (17) and neothiobinupharidine-6’-dIthus proving the skeleton of the alkaloid. Mass spectra, ‘H NMR, and CD measurements finally furnished the position of the hydroxyl group and the (S) configuration for C-7’. 6,6’-Dihydroxyneothiobinupharidine(29), isolated from Nuphur lutea (33, 37),on reduction with NaBH, and NaBD, resulted in neothiobinupharidine and neothiobinupharidine-6,6’-d2, respectively. I 1H-NMR spectra of the later compound confirmed the structure of 29.

N. DERIVATIVES OF THIONUPHLUTINE B syn-Thionuphlutine B sulfoxide (30) (34, 39)was isolated from Nuphar lutea together with sulfoxide 23 and was separated chromatographically. The structure was determined by 1R and H-NMR spectroscopy and by reduction with PCl, which resulted in thionuphlutine B (18).

’

IV. Stereochemical Transformationsof Nuphur Alkaloids The quinolizidine system in monomeric C,, alkaloids in some cases is susceptible to inversion of the ring junction, which is accompanied by inversion of the relative configuration of C-7. Protonation of the nitrogen atom, quaternization, or N-oxide formation are the conditions which cause such transformations.

228

JACEK CYBULSKI A N D JERZY T. WROBEL H

The protonation of deoxynupharidine (14) (methyl group axial on C-7) results partially in the stereochemical transformation of the ring junction from trans to cis; inversion of the relative configuration of C-7 accompanies this change (40). The stereochemistry of 7-epideoxynupharidine (15) (methyl group equatorial on C-7) is not affected by protonation. The same was observed for quaternization of 7-epideoxynupharidine (15) which also was not transformed stereochemically. On the contrary, the axial methyl group at C-7 of deoxynupharidine(14) behaves differently, for on reaction with iodomethane a methiodide with a cis ring junction and an equatorial methyl group at C-7 is produced (41). This rule also holds true for N-oxide formation from deoxynupharidine (32) and its 7-epi isomer (31) ( 4 2 ) .

31

32

70

71

These changes of stereochemistry in C ,5 Nuphur methiodides are detectable in their l 3 C-NMR spectra: when the trans-quinolizidine system is retained, para-

5 . NUPHAR ALKALOIDS

229

magnetic chemical shifts of all carbon atoms cx to nitrogen are observed. The presence of a cis junction causes a paramagnetic shift of the C-10 and C-4 signals, a diamagnetic shift of the C-6 signal (as compared to the free base), and a downfield shift of the N+-CH, signal as compared with the trans isomer. Unfavorable 1,3-diaxial interaction between N+-H, N+-CH,, or "-0-and 7-CH3 (axial) has been suggested as an explanation for these trans-cis interconversions. The stereochemistry of the skeleton of Nuphar thiaspiranes can undergo some inversion processes on particular atoms or molecular fragments. Thermal interconversion of sulfoxides and quaternization of the quinolizidine system are the circumstances when this phenomenon was observed. Most of these transformations have a certain feature in common, e.g., inversion of the configuration of C-7; however, inversion on C-7' can also take place, and a trans-cis change of the quinolizidine ring junction may accompany this. Specific interconversion of the configuration was described by LaLonde and Wang (35).Thermolysis of isomeric Nuphar syn-sulfoxides results exclusively in inversion of the configuration at C-7, thus converting thiobinupharidine (16) (sulfur equatorial) to thionuphlutine B (18) (sulfur axial) or converting neothiobinupharidine (17) (sulfur axial) to thionuphlutine C (33)(sulfur equatorial); compound 33 has not yet been isolated from natural sources.

In analogy to the transformations observed for other compounds, a similar process was proposed for the interconversion of thiaspirane sulfoxides and to explain the dependence of the thermolytic process on sulfoxide stereochemistry. Scheme 1 shows the probable mechanism of the transformation. Stereochemical transformations of the C,, Nuphur thiaspiranes have been observed on quarternization of thiobinupharidine (16) (equatorial sulfur atom). The quaternized quinolizidine system is transformed from the trans to the cis form with inversion of the relative configuration of the corresponding C-7 or C-7'. Inversion of quinolizidine system from trans to cis in monomethiodides can occur in the AB or A'B' ring, corresponding to the nitrogen atom, which becomes quaternary. Structures of this type are represented by thiobinupharidine monomethiodides 36 and 37 (43). In the dimethiodides the inversion was ob-

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JACEK CYBULSKI AND JERZY T. WROBEL

syn , naothiobinuphoridine sulfoxide ( S oxiol

S oxiol or equatorial

SCHEME1. Thermal transformation of syn-neothiobinupharidinesulfoxide.

3k

35

37

23 1

5 . NUPHAR ALKAMIDS

38

39

211-1 40

41

served in one quinolizidine ring or in both (44). The structures 38 (A'B' trans, AB trans), 39 (A'B' trans, AB cis), 40 (A'B' cis, AB trans), and 41 (A'B' cis, AB cis) represent the stereoisomeric dimethiodides and their stereochemistry. It has been suggested that the trans-cis transformation and the inversion of the C-7 or (2-7' relative configuration are caused by unfavorable 3-syn-diaxial interaction between the N+-CH, group and C-17. The stereochemistry of eight isomeric thiobinupharidine methiodides was determined by I H-NMR spectroscopy ( 4 5 ) (in a cis-quinolizidinium salt the signal of the N+-CH, group occurs at lower field relative to a trans-quinolizidinium), but more effective was "C-NMR spectroscopy. The shifts of carbon atoms a to the nitrogen as well as the signals of N+-CH, group are diagnostic of trans or cis isomers (see Section VII, A, 1) (44). Another stereochemical phenomenon in the series of thiaspiranes is deformation of the spiro-tetrahydrothiophenering. The N+-CH3group present in A'B'trans and A'B'-cis in the monomethiodides of thiobinupharidine may be responsible for the deformation of the spiro ring (41). This was interpreted in terms of an unfavorable 3-syn-diaxial interaction between the carbon atom of the N+-CH, group and C-17 (in the case of A'B'-trans and AB-trans monomethiodides) or between the N+-CH, group and C-17' (A'B'-cis monomethiodides) ( 4 1 , 43). Deformation of the tetrahydrothiophene ring causes, on the one hand, disappearance of the H-H 1,3-diaxial interaction between one of the protons on C-6 or

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JACEK CYBULSKI AND JERZY T. WROBEL

C-6’ and one of the protons on C-17 and, on the other, creation of an H-H 1,3diaxial interaction between protons on C-8 or C-8‘ and one of the protons on C-17. A new 6-syn-diaxial interaction between C-6 and C-8’ (A’B’ trans and A’B’ cis) or between C-6’ and C-8 (AB trans) was observed. As a stereochemical consequence of this interaction, the distance between the two quinolizidine rings decreases. The tetrahydrothiophene ring adopts a conformation between an envelope and a half-chair. Such stereochemistry in thiobinupharidine methiodide (34) was confirmed by X-ray single-crystal measurements (46). Protonation of compounds 16, 17, and 18 does not bring about any changes in the stereochemistry of their quinolizidine rings (40). V. Chemistry of Nuphar Alkaloids and Manifestation of Sulfur

6-Dehydrodeoxynupharidine (42) reacts with electrophilic thiating agents, such as ArSX, resulting in a separable mixture ( 1 : 1) of two diastereomeric adducts 43 and 44 (47). The reaction of 42 with p-toluenesulfonyl chloride was studied in detail (48) and products 45-49 identified. The configuration at C-7 was determined by circular dichroism (48).

43

44

233

5. NUPHAR ALKALOIDS

Nupharolutine (50) was selectively transformed to A'-dehydronupharolutine (51), a compound prepared for the first time. Treatment of 51 with methyl iodide produced the corresponding methiodide 52,which retained a trans ring junction (49).

"

51

52

In the last decade more chemical attention has been focused on those Nuphar alkaloids which contain sulfur. The chemical behavior of this group is very much dependent on the presence of sulfur. Sulfur introduces additional steric hindrance to the molecule, creates a new nucleophilic center, and increases the stability of carbanions in sulfoxides; the C-S bond in sulfonium salts is strongly polarized. Isomeric C,, alkaloids (sulfur atom axial or equatorial) can be oxidized with standard oxidizing agents to produce sulfoxides (35,50, 51) and/or sulfones (52). Nuphar sulfides are resistant to catalytic hydrogenation of both furan rings. This is explained in terms of preferential complexing of sulfur to the catalyst, thus preventing the furan ring from reaching the catalyst surface (53).Such behavior also prevents the S-C,, molecules from being successfully subjected to the Alder-Riecker degradation, for the crucial step (catalytic hydrogenation) cannot be effected. The chemical reactivity of sulfoxides as compared with sulfides is much greater. The effect of the sulfinyl group on adjacent methylene protons allows chlorination and the Pummerer rearrangement to take place. The chlorination is stereospecific, resulting in cis products. The Pummerer rearrangement results in two possible isomers (Scheme 2) (53). The Nuphar sulfoxides can be epimerized on carbon C 7 by thermal rearrangement (see Section IV, Scheme 1). The presence of sulfur is manifested strongly in the stereochemical course of the sodium borohydride reduction of Nuphar thiaspirane hemiaminals. This

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JACEK CYBULSKI AND JERZY T. WROBEL

neothiobinupharidine Raney nickel #

1

Pummerer rearrangement

H

cis CP, a) reduction

a'

B'

a' hydrolysis

a' Raney nickel neothiobinupharidine

SCHEME 2. Chlorination and Pummerer rearrangementof neothiobinupharidine sulfoxides.

reaction was studied by LaLonde et al. (54, 55) and McLxan et al. (56). LaLonde's work led to the conclusion that the reduction of a-thiohemiaminals by NaBD, carried out in methanol is stereospecific and depends on the configuration of the spiro carbon atom C-7 which carries the sulfur. LaLonde showed that there is intramolecular three-membered cyclic interaction between sulfur and the iminium carbon, which forces hydride attack to take place on the face of the piperidine opposite to sulfur. This conclusion has been confirmed in the reduction of many natural thiohemiaminals and model synthetic compounds. The stereochemistry of the reduction of P-thiohemiaminals follows different route; it is not dependent on the configuration of C-7', and the incorporation of deuterium is exclusively axial.

5. NUPHAR ALKALOIDS

235

The sulfur in a-thioiminium ions interacts more strongly than the sulfur in f3 ions, and experiments show that the introduction of deuterium follows the order C-6,, > 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%

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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

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JACEK CYBULSKI AND JERZY T. WROBEL

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.

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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

5 . NUPHAR ALKALOIDS

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.

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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

5 . NUPHAR ALKALOIDS

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

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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).

5 . NUPHAR ALKALOIDS

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

JACEK CYBULSKI AND JERZY T. WROBEL

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

<@H

C-17'

S

CH3

N-J

+

c-17

H A' 0'

c-8'

c-17 H AB

SCHEME 14. I-Syn-diaxial interactions in cis-thiobinupharidine methiodides.

CH3

247

5 . NUPHAR ALKALOlDS

c-7w c-17' HH -

H/'-l7@'

c-a

c-17 c-7

H

c-9

C-6

a8

H-----H

c-17' c-7

$sJ,;

H

C-6

SCHEME 15. H-H, 1.3-diaxial interactions in thiobinupharidine methiodides.

carbon atom in compounds 57 and 58 exhibits a diamagnetic shift in comparison with A'-dehydronupharolutine methiodide (52) (61), which contains a transquinolizidinium system. In these compounds also, the carbon atom of the Smethyl group, which occurs in the upfield region (-17 ppm), is a diagnostic one. On the other hand, for thionuphlutine B S-methiodide (56) the following carbon atoms are diagnostic: the S+-methyl group (-20 ppm) and the carbons in positions a to the sulfur atom, which exhibit a clear paramagnetic shift in comparison with the sulfide (60). The stereochemistry of neothiobinupharidine S-oxides 72 and 73 and of thiobinupharidine S-oxides 23 and 74 was determined on the basis of the chemical shift values of C-6 and C-8 in the AB quinolizidine ring (35,50). It was found that for one of the S-oxides of neothiobinupharidine and thiobinupharidine the difference in chemical shift values for C-6 is much larger relative to the sulfide than for the other S-oxide of neothiobinupharidine and thiobinupharidine. The

72 X = 0 ; Y = Electron pair 73 X = Electron pair ; Y.0

248

JACEK CYBULSKI AND JERZY T. WROBEL

74 X = O ; Y=Electron pair 23 X= Electron pair ; Y= 0

compound which exhibits a higher negative value for AS,,, occurs in the syn configuration of neothiobinupharidine sulfoxide (72) and thiobinupharidine sulfoxide (23). The neothiobinupharidine S-oxide (73) and thiobinupharidine Soxide (74), with a lower negative values for ASc4 were assumed to have the anti configuration. It was also found that the higher negative value of is accompanied by a lower negative value of and vice versa. l3 C-NMR spectroscopy was very helpful in determining the stereochemistry of 1-epi- 1 ’-epithiobinupharidine (21), 1-epithiobinupharidine (19), and 1’epithiobinupharidine (20) (32). In agreement with the general rules, the carbon atoms of axial methyl groups were shifted diamagnetically (by 5 ppm) relative to analogous equatorial methyl groups in thiobinupharidine (16). Also, the carbons a to the axial methyl groups (C-l and C-]’), p (C-2, C-2‘, C-10, and C-lo’), and 6 (C-3, C-3’, C-9, and C-9’) exhibit diamagnetic shifts in comparison with the analogous carbons in thiobinupharidine. This is in agreement with the chemical shift values in 1(e)-methylquinolizidine and 1(a)-methylquinolizidine ( 70).

-

2. I H-NMR Spectroscopy As for l3 C-NMR spectroscopy where the diagnostic carbon atoms were most frequently those a to the nitrogen atom, so too in H-NMR spectroscopy the diagnostic protons are most frequently those at carbons a to the nitrogen, principally H-6e and H-6’e. Also often helpful were the signals from protons attached to carbons of the spirotetrahydrothiophene ring, i.e., H-l7A, H-l7B, H-l7’A, and H-17’B. In the course of determining the configuration of the sulfur atom in thionuphlutine B S-oxides (30 and 75) (39) it was found that the diagnostic protons were the equatorial ones at C-6 and C-6’. The observation of a benzene-induced shift permitted the conclusion that for compound 30 the diagnostic protons H-6e and H-6’e have a rather low value in this experiment, whereas the protons of the

5 . NUPHAR ALKALOIDS

249

30 X=Electron pair ; Y - 0

75 Y=Electron poir; X = O

thiomethyl group exhibit a value of A6 +0.33. In compound 75 H-6e, H-6’e, and the p proton of the furan ring show higher values than for compound 30. Application of the shift reagent Eu(fod), resulted, for compound 75, in a paramagnetic effect on H-6e, H-6’e, H-4a, and H-4’a. For compound 30 no such paramagnetic effect was observed. Thus compound 75 was ascribed the a configuration (anti) and compound 30 the p configuration (syn) of the S-oxide bond. Analysis of the I H-NMR spectra of neothiobinupharidineS-oxides (72 and 73) was based on the same principles (52). The complexation of anti-neothiobinupharidine S-oxide (73)with benzene results in a downfield shift of H-6e, H-17B, H-l7’B, and H-83 owing to orientation of the aromatic ring on the /3 side of the sulfoxide. Conversely, in the case of syn-sulfoxide72 complexation with the aromatic ring is from the a side of the molecule, and the signals of H-6‘e, H-8’e, H- 17’A, and H-17A are therefore shifted downfield. I H-NMR spectroscopy turned out to be an insufficient method for determining the structure and stereochemistry of thiobinupharidine methiodides. It is possible, however, to determine the stereochemistry of quinolizidine rings on the basis of chemical shift values of the protons of the N+-methyl group. In cisquinolizidinium rings, the signal arising from N+-CH3 protons occurs more downfield than for trans-quinolizidinium rings. Quarternization of the nitrogen in AB or A’B’ quinolizidine rings results in a downfield shift of the protons of one of the furan rings, namely, H-4a, H-6e, H-lOe or H-4’a, H-6‘e, and H-lO’a. On the basis of chemical shift analysis, however, it is not possible to determine which of the quinolizidine rings actually underwent the quaternization reaction (45). B. MASSSPECTROMETRY Mass spectrometry was used to determine the structure of dimeric hemiaminals of C3,, Nuphar alkaloids, including the position of the hydroxyl group (71). Ions formed as a result of loss of OH, H 20 , SH, CH,S, and CH3S are

250

JACEK CYBULSKI AND JERZY T. WROBEL

characteristic of hemiaminals. In many cases the molecular ion as well as mlz 178 and 230 ions, characteristic of C,, alkaloids, are not observed. On the other hand, the mass spectra of hemiaminals are characterized by the presence of mlz 176 and 228 ions. The m / z 176 ion is a diagnostic one, because its relative intensity is higher in mass spectra of 6-substituted hemiaminals than in 6'-substituted ones. The observed dependence was also useful to determine the structure of the sulfoxides of thiobinupharidine hemiaminals, which had been isolated from the rhizomes of Nuphar lutea (36). The mass spectra of deuterated C, alkaloids, obtained as a result of reduction of hemiaminals with NaBD4, confirmed the fragmentation pathway leading to the mlz 178 ion (72). As shown in Scheme 16, deuteration at C-6 results in an increase of the mlz 178 ion by one mass unit. On the other hand, deuteration at C-6' does not increase the mass of the ion. In spectra of dideuterated compounds an mlz 179 ion appears, i.e., increased by one mass unit. On the basis of the above data it was concluded that the characteristic fragment ( m l z 178 ion) of the C, alkaloids derives from the AB quinolizidine ring. Mass spectrometry confirmed the structure of a new C,, alkaloid (31),nuphacristine (12), containing a hydroxymethyl group at C-1, an aldehyde at C-7, and a double bond between C-6 and C-7, features not previously encountered in this

I-

R=OH , R1 =H

176

\ R=D ; R1.H 1

7

1

7

!\ R=H ; Rt=D +H

9 178

SCHEME 16. Mass spectral fragmentation of thiohemiaminals of C N Nuphar alkaloids.

25 1

5 . NUPHAR ALKALOIDS

//

1

1

group of compounds. The mass spectrum of 12 (Scheme 17) is characterized by the presence of m/z 107 and 94 ions, which are also present in the mass spectrum of deoxynupharidine (14) and castoramine (59), thus indicating that this part of the quinolizidine is the same in all three compounds. The mlz 190 and 110 ions in 12 have their counterparts in the mass spectrum of deoxynupharidine (14) (mlz 178 and 98) as well as in that of castoramine (59) (mlz 194 and 114). The presence of the OH, CH,OH, and CH=O groups in 12 is confirmed by the occurrence of the M + - 17, M+ - 31, and M + - 29 ions. Such a fragmentation course indicates that the CH,OH group is situated in ring A and the CH=O in ring B of the quinolizidine, in agreement with the proposed structure. The intensity of the main fragment ions in the mass spectra is the main criterion for establishing the configuration of the sulfur atom in neothiobinupharidine sulfoxides (52). The relative intensity of diagnostic ions mlz 178 and 230 is higher by 30-70% for the syn isomer in comparison with the anti one (Scheme 18). This is explained by the formation, via a McLafferty rearrangement, of a six-membered intermediate ring in the case of the anti isomer, and a fivemembered intermediate ring in the case of the syn isomer. Thus the m / z 230 and 178 ions are formed from the same molecular fragment via the six-membered ring route, which diminishes their relative intensity. In the case of the fragmentation of the syn isomer, the mlz 230 and 178 ions are formed from two different portions of the molecule, which increases their relative intensity (Scheme 19).

252

w$4c& JACEK CYBULSKI AND JERZY T. WROBEL

I

1

H

3F

1

'q@\ lCH2SOl

3F

I

@ mlz 3F 231

3F

rnlz 178

rnlz 230

neither

NCH2 mh

230 nor m h 170

1

rnlz 230

I rnlz 170 SCHEME 18. Fragmentation of syn- and anti-sulfoxides of neothiobinupharidine.

mlz 178 and230 high intensity

mlz 170 and 230 low intensity

cis (C-7 to C-8)(a) anti

SCHEME 19. Possible intermediates in the McLafferty rearrangement of Nuphar sulfoxides.

C. CIRCULAR DICHROISM Circular dichroism was used to determine the absolute configuration of thiobinupharidine, thionuphlutine B, and neothiobinupharidine hemiaminals (73). As the absolute configuration of the fundamental C, alkaloids thionuphlutine B (18) and thiobinupharidine (16) was not known, use was made of a pseudoenantiomeric pair of (-)-deoxynupharidine hemiaminal derivatives 76 and 77. Their

5 . NUPHAR ALKALOIDS

253

structure and stereochemistry were established as a result of spectroscopic studies of their reduction products (55). The pseudoenantiomeric pair 76 and 77, as iminium perchlorates 78 and 79 in 95% ethanol, gave positive and negative

CD bands, respectively (73). Since the relative configuration of C-7 was known and 76 and 77 were prepared from (R,S,S,S)-(-)- 1,4,7,10-deoxynupharidine, the correlation of the C-7 configuration with the sign of the CD band for athioiminium ions was secured. On the basis of the above data it was found, by comparing the CD surves with standard curves of perchlorates 78 and 79, that 6-hydroxythiobinupharidine (53), with a C-7 equatorial sulfur atom, possesses the (S)-7 configuration; 6hydroxythionuphlutine B (81) and 6-hydroxyneothiobinupharidine(27) (Section V), with C-7 axial sulfur atoms, possess the (R)-7 configuration. It was also found that 6’-hydroxythiobinupharidine (80)- and 6’-hydroxythionuphlutine B (82) have the (S)-7’ configuration, and 6’-hydroxyneothiobinupharidine(28) has the (R)-7’ configuration. For bishemiaminals 6,6‘-dihydroxythiobinupharidine (54) and 6,6’-dihydroxythiobinuphlutineB (83) it was found that the relative configuration of the sulfur atom at C-7 is the same in the model compound 76 as in 54, and in the model compound 77, the same as in compound 83 (54, 72, 74).

.

VIII Pharmacology Studies of the biological activity of Nuphar alkaloids have been carried out in two ways, either by concentrating on biological activity of plant extracts or, as in the case of research carried out by LaLonde, by focusing attention on a particular chemical compound of determined structure and stereochemistry. Investigations were carried out on the antibiotic activity of a mixture of alkaloids, isolated from Nuphar futea,.but of unknown structure (75-77). Studies were also performed on hot water extracts from N. juponicum for their inhibitory effect on beef heart phosphodiesterase (78). A positive result for the extract from N . juponicum

254

JACEK CYBULSKI AND JERZY T. WROBEL

points to the biological activity of organic compounds present in this plant. An alcohol extract (80%) from N . variegatum was found to exhibit an inhibitory effect against Staphylococcus aureus and Mycobacterium smegmatis. In addition, Skellysolve F stem extracts from N. variegarum were active against Candida albicans (79). Among known Nuphar alkaloids, 6,6’-dihydroxythiobinupharidine(54) was found to exhibit biological activity (80). This compound was tested on eight human pathogenic fungi: Histoplasma capsulatum Darling (No. 1098), Blastomyces dermatitidis Gilchrist and Stokes (No. 1099), Trichophyton mentagrophytes (Robin) Blanchard (No. 1 100), T. tonsurans Malmsten (No. 1101), Microsporum gypseum (Bodin) Guiart and Grogorakis (No. 1102), M . canis Bodin (No. 1103), Cryptococcus neoformans (Sanfelice) Vuillemin (No. 1104), and Candida albicans (Robin) Berkhout (No. 1105). The effect of 6,6’-dihydroxythiobinupharidine (54) on the growth of Histoplasma and Blastomyces was measurable. At 100 pg/ml, the compound inhibited the growth of H . capsulatum up to 3 weeks, whereas it completely suppressed the growth of B. dermatitidis. At the same concentration the alkaloid suppressed the growth rate of M . gypseum and M . canis up to 3 weeks; the growth of T. mentagrophytes and T. tonsurans was suppressed up to 5 weeks. However, the alkaloid exerted no inhibitory effect against yeastlike Candida or Cryptococcus. The results indicate that 6,6’dihydroxythiobinupharidine has antifungal activity in vitro. As biological activity was exhibited by a C,, alkaloid containing a hydroxyl group a to the nitrogen atom, it was decided to examine synthetic derivatives of hemiaminals containing the quinolizidine system. The following compounds were examined: a-thiohemiaminal84, a mixture of two diastereoisomers 76 and 77, a-hydroxyhemiaminal85, a mixture of compounds 86 and 87, and a mixture of diastereoisomers 88 and 89 (81). In the first series of tests, the activity of the compounds was tested against two isolates each of Histoplasma capsulatum and Blastomyces dermatitidis and against one isolate each of Sporotrichum schenckii, Trichophyton rubrum, and Microsporum gypseum. The tests showed that only a-thiohemiaminal84 and a mixture of compounds 76 and 77 are active in vitro against H . capsulatum and B . dermatitidis, and the activity of the mixture of compounds 76 and 77 is slightly lower than that of 84. A mixture of 76 and 77 as well as a-thiohemiaminal 84 at a concentration 40-80 pglml exhibited a similar degree of activity against S . schenckii and T. rubrum. However, both organisms were sensitive to compound 85, a mixture of 86 and 87, and a mixture of compounds 88 and 89, with the exception of T. rubrum whose growth rate was suppressed by a mixture of compounds 86 and 87 at a concentration of 80 pg/ml. In view of the fact that both a-thiohemiaminal 84 and the mixture 76 and 77 exhibited biological activity, their activity was compared with that of the wellknown active compound amphotericin B and derivative 90 (not containing the

5 . NUPHAR ALKALOIDS

255

methyl group on C-1 and the furane ring on C-4). When these compounds were tested on Histoplasma capsulatum and Blastomyces dermatitidis, it was found that 84 as well as the mixture 76 and 77 are more effective than amphotericin B in suppressing the growth rate of four cultures ( H . capsulatum Nos. 1098 and 1 106 and B. dermutitidis Nos. 1099 and 1107). In addition it was observed that athiohemiaminal90 is much less active than compound 84, a mixture of 76 and 77, or amphotericin B. On the basis of the results obtained it seems that the following factors are indispensable for biological activity: the presence of a-thioherniarninal grouping (a-hydroxyaminals exhibit no activity against H. capsulatum and B . dermutitidis), the presence of an equatorial methyl group in position C- I , and also the presence of an equatorial 3-fury1 group in position C-4. As the antifungal tests were carried out in media with pH values in the range 5.5-6.5, it seems that a significant role in the antifungal activity of a-thiohemiaminals is played by the formation of an iminiurn ion according to Scheme 20.

dR

I-OR SCHEME 20. Formation of iminium ions.

256

JACEK CYBULSKI AND JERZY T. WROBEL

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43. J. Cybulski, K. Wojtasiewicz, and J. T. Wrobel, J. Mol. Srrucr. 101, 127 (1983). 44. J. Cybulski and K. Wojtasiewicz, J. Mol. Srrucr. 117, 193 (1984). 45. J. Cybulski, Bull. Acad. Pol. Sci., Ser. Sci. Chim. 32, 269 (1984). 46. A. Kozid, J. Mol. Srrucf. 130, 327 (1985). 47. R. T. LaLonde and T. S. Eckert, Can. J. Chem. 59, 2298 (1981). 48. R. T. LaLonde, A. I.-M. Tsai, and C. F. Wong, J . Org. Chem. 41, 2514 (1976). 49. J. Cybulski, K. Wojtasiewicz, and J. T. Wrobel, Bull. Acad. Pol. Sci.. Ser. Sci. Chim. 35, 17 (1987). 50. R. T. LaLonde, C. F. Wong, A. I.-M. Tsai, J. T. Wrobel, J. Ruszkowska, K. Kabzinska, T. I. Martin, and D. B. MacLean, Can. J. Chem. 54, 3860 (1976). 5 I . J. T. Wrobel, A. Iwanow, J. Szychowski, J. Poptawski, C. K. Yu, T. 1. Martin, and D. B. MacLean, Can. J. Chem. 50, 1968 (1972). 52. J. T. Wrobel, J. Ruszkowska, and H. Bielawska, Pol. J. Chem. 53, 39 (1979). 53. J. T. Wrobel, H. Bielawska, A. Iwanow, and J. Ruszkowska, in “Natural Sulphur Compounds” (D. Cavallini, ed.), p. 353. Plenum, New York, 1980. 54. R. T. LaLonde, Ace. Chem. Res. 13, 39 (1980). 55. R. T. LaLonde, C. F. Wong, and K. C. Das, J. Am. Chem. Soc. 95,6342 (1973). 56. T. 1. Martin, D. B. MacLean, J. T. Wrobel, A. Iwanow, and W. Starzec, Can. J. Chem. 52, 2705 ( 1974). 57. J. Cybulski, J. Jurczak, K. Wojtasiewicz, and J. T. Wrobel, Bull. Acad. Pol. Sri.. Ser. Sci. Chim. 30, 31 (1982). 58. J. Cybulski, K. Wojtasiewicz, and J. T. Wrobel, Hererocycles 20, 1773 (1983). 59. J. Cybulski, K. Wojtasiewicz, and J. T. Wrobel, Heterocycles 22, 2541 (1984). 60. J. Cybulski, A. Scholl-Aleksandrowicz, K. Wojtasiewicz, and J. T. Wrobel, Coll. Czech. Chem. Commun. 52, 2083 (1986). 61. J. T. Wrobel, A. Scholl-Aleksandrowicz, J. Cybulski. and K. Wojtasiewicz, unpublished results. 62. R. T. LaLonde, N. Muhammad, C. F. Wong, and E. R. Sturiale, J . Org. C h m . 45, 3664 ( 1980). 63. R. T. LaLonde, N. Muhammad, and C. F. Wong, J. Org. Chem. 42, 21 13 (1977). 64. J. J. Tufariello, Acc. Chem. Res. 12, 396 (1979). 65. J. T. Wrobel and E. Hejchmann. Synthesis 5 , 452 (1987). 66. J. T. Wrobel and E. Hejchmann, Bull. Acad. Pol. Sci.. Ser. Sci. Chim. 35,21 (1987). 67. S. Yasuda, M. Hanaoka, and Y. Arata, Chem. Pharm. Bull. 28, 831 (1980). 68. Y. C. Hwang and F. W. Fowler, J. Org. Chem. 50,2719 (1985). 69. R. T. LaLonde, T. N. Donvito, and A. I.-M. Tsai, Can. J. Chem. 53, 1714 (1975). 70. R. T. LaLonde and T. N. Donvito. Can. J . Chem. 52, 3778 (1974). 71. R. T. LaLonde, C. F. Wong, and A. I.-M. Tsai, Org. Mass. Specrr. 11, 183 (1976). 72. R. T. LaLonde, C. F. Wong, and K. G. Das, J . Org. Chem. 39,2892 (1974). 73. R. T. LaLonde and C. F. Wong, J . Org. Chem. 38,3225 (1974). 74. R. T. LaLonde and C. F. Wong, Pure Appl. Chem. 49, 169 (1977). 75. A. P. Tatarov, Farmarsiya 8, 29 (1945). 76. S. I. Novikova, Mikrobiol. Zh., Acad. Nauk Ukr. R.S.R. 23,51 (1961). 77. K. G. Bel’tyukova and L. T. Pastushenko, Mikrobiol. Zh., Acad. Nauk Ukr. R.S.R. 25, 36 (1963). 78. T. Nikaido, T. Ohmoto, H. Noguchi, T. Kinoshita, H. Saitoh, and U. Sankawa, Planra Med. 43, 18 (1981). 79. K. L. Su, Y.Abul-Hajj, and E. J. Staba, Lloydia 36, 80 (1973). 80. W. P. Cullen, R. T. LaLonde, C. J. Wang, and C. F. Wong, J . Pharm. Sci. 62, 826 (1973). 81. R. T. LaLonde, A. I.-M. Tsai, C. J. Wang, C. F. Wong, and G. Lee. J. Med. Chem. 19, 214 (1976).

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-CHAPTER

6-

OXAZOLE ALKALOIDS HELENM. JACOBS Department of Chemistry University of the West lndies Mona, Kingston 7 . Jamaica AND

BASILA. BURKE The Plant Cell Research Institute, Inc. Dublin. California 94568 1. Introduction .......................................................... 11. Oxazoles of the Gramineae .............................................. 111. Oxazoles of the Rutaceae ..... .............................. IV. MarineOxazoles ...................................................... V. Bacterial Oxazoles . ................

B. Group A Peptide Antibiotics of the MikamycinlStreptograminlVirginiamycinFamily ........................ C. Oxalomycin, Neooxalomycin, Curromycin A, and Curromycin B ........... D. Berniniamycin ......... ..... ..... E. Calcimycin (A23187) and actin .................................. F. Conglobatin ............................................ VI. Biological Activity ..................................................... VII. Isolation and Spectral Characteristics ......................................

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

259 260 262 269 27 I 27 I 273 285 287 288 293 295 304 304 305 306 306 306 307

I. Introduction Thirty-four naturally occurring compounds that incorporate the oxazole moiety have been isolated thus far. The sources are diverse-plants of the families Gramineae and Rutaceae, nudibranch egg masses, and microorganisms, the latter having furnished the majority of the compounds. With three exceptions, the marine and bacterial oxazoles appear to have been formed from peptides of aliphatic amino acids, while the oxazoles of the Gramineae and Rutaceae arise from the chorismic acid-phenylalanine pathway. The oxazoles have not been 259

THE ALKALOIDS. VOL. 35 Copyright 8 1989 by Academic Ress. Inc. All rights of reproduction in any form reserved

260

HELEN M . JACOBS AND BASIL A. BURKE

previously reviewed in this treatise. This chapter treats the oxazole alkaloids in the context of their sources and possible biosynthetic origins. Approaches to the total synthesis of natural oxazoles are also covered.

11. Oxazoles of the Gramineae Annuloline (l),the first natural oxazole isolated, occurs in seedlings of the annual rye grass Lolium multijorum (I). The structure was confirmed by syn-

thesis (2) (Scheme 1) involving condensation of the aminoketone 2 with 3,4dimethoxycinnamoylchloride (3)to yield the amide 4 from which annuloline (1) was obtained by cyclodehydration with phosphorus oxychloride. The isomeric possibility 5 was also prepared via the amide 8 derived from aminoketone 6 and 3,4-dimethoxybenzoyl chloride (7) (Scheme 2). On the basis of the fluorescence of annuloline (1) under long wavelength UV light, the seedlings of L . multiflorum could be distinguished from those of the perennial rye grass, L. perenne (I). This fluorescence is characteristic of 2,5-diaryloxazoles and their vinylogs ( 3 ) , related synthetic compounds having found application as scintillators ( 4 ) . This feature may serve as a useful preliminary method of detection in natural systems. OCH3 C

H

3

O

w

N

2

H

2

e

+

o

C

H

3

0

J.

OCH3

wNp4-0cH3

CHO3

-

l4

0 0

POCl3

1

SCHEME1. Synthesis of annuloline (1).

6. OXAZOLE ALKALOIDS

26 1

5 SCHEME 2. Synthesis of an isomer of annuloline.

The biosynthesis of annuloline (1) in L. mulfiforum seedlings has been studied using radiolabeledprecursors (5).The p-methoxy-P-phenylethyl portion (Scheme 3) was demonstrated by high percentage incorporation of labeled tyramine (11) to originate from phenylalanine (9) via tyrosine (10). Increasingly efficient incorporation of radiolabel in the portion bearing the 3,4-dimethoxycinnamoyl residue

15

1 1

SCHEME 3. Proposed biosynthesis of annuloline (1).

262

HELEN M. JACOBS AND BASIL A. BURKE

along the sequence tyrosine (10) to p-coumaric acid (13) to caffeic acid (14) suggests one possibility for the genesis of this moiety. This does not, however, preclude operation of the pathway phenylalanine (9) to cinnamic acid (12) to pcoumaric acid (13) to caffeic acid (14), as the observed incorporation of labeled cinnamic acid (12) could be construed as proof of this. Although neither administered nor isolated in this study, the P-phenylethylamide 15 resulting from condensation of tyramine (11) with caffeic acid (14) is implicated as the key intermediate in the formation of the oxazole nucleus. Low incorporation of 0methylated precursors suggests that methylation is the final step in the biosynthetic sequence. This is an interesting observation, as the involvement of Crow and Hodgkin’s putative quinone-methene intermediates 31 and 32 (6) in the essential dehydrogenation stage, after annelation of the P-phenylethylamide 28 (videinfra),requires that the tyramine residue be unsubstituted at the oxygen for oxazole formation to take place.

111. Oxazoles of the Rutaceae

Oxazoles of the Rutaceae number some dozen alkaloids: halfordinol (16) (6, 7), halfordine (17) (6, 8, 9), halfordinone (18) (6, 8), 0-isopentenylhalfordinol

w N N o m 0 R

16 17 18 19 20 21 22

Halfordinol Halfordine Halfordinone 0-isopentenylhalfordinol 0-geranylhalfordinol 0-methylhalfordinol

R=H R = CH2CH(OH)C(OH)(CH3)2 R = CH2COCH(CH3)2 R = CHzCH = C(CH3)2 R = CH2CH2-C( = CH2)CH3 R = transgeranyl R = CH3

vNo-

CI

@ YCH3

A

23 N-methylhalfordinium chloride

263

6. OXAZOLE ALKALOIDS

(19)and its double bond isomer 20 (10-12, 17), 0-geranylhalfordinol(21) (13), 0-methylhalfordinol (22)( 1 4 ) , N-methylhalfordinium chloride (23)(IS),24 OCH3 oO (*-CH3

25 balsoxin

26 texamine

WN0&2 N

27 texaline

(13), balsoxin (25)( 1 6 ) , texamine (26)(17), and texaline (27)(17). With the exceptions of balsoxin (25)and texamine (26),these compounds are derivatives of halfordinol, 2-pyridyl-5-(4-hydroxy)phenyloxazole ( 16). The compounds and their sources are listed in chronological order of isolation in Table I. The majority of the Rutaceae oxazoles have been isolated from the Old World genera Halfordia, Aegle, Aeglopsis, and Micromelum; Amyris is the TABLE I OXAZOLES OF RUTACEAE: REP~RTED ISOLATIONAND STRUCTURE ELUCIDATION IN CHRONOLOGICAL ORDER Year

Compound and source

Reference

1958 1963 1964 I964 I964 1968 1968 1968 1968 1973 1978 I978 1979 1982 1984 1984 1988 1988 1988

Halfordinol (16) (Aegle marmelos) N-Methylhalfordinium chloride (23) (Halfordia scleroxvlu) Halfordine (17) (Halfordia scleroxylu) Halfordinone (18) (Halfordia scleroxylu) Halfordinol (16) (Halfordia scleroxyla) Halfordine (17) (Halfordia kendack) Halfordinone (18) (Halfordia kendack) 0-Isopentenylhalfordinol(19) (Aeglopsis chevalieri) Compound (20) (Aeglopsis chevalieri) Halfordine (17) (Halfordia pupuana) 0-lsopentenylhalfordinol(19) (Aegle marmelos) 0-Isopentenylhalfordinol(19) (Amyris plumieri) Balsoxin (25) (Amyris balsamifera) 0-Methylhalfordinol (22) (Micromelum zeylanicum) 0-Geranylhalfordinol (21) (Amyris plumieri) Compound (24) (Amyris plumieri) Texamine (26) (Amyris texana) Texaline (27) (Amyris texana) 0-Isopentenylhalfordinol (19) ( k y r i s texana)

7 15 6 6

6 8 8 10 10 9 11 12 16

14 13 13 17 17 17

264

HELEN M . JACOBS AND BASIL A . BURKE

only New World oxazole-producing genus recognized thus far. The first oxazoles reported in the Rutaceae were halfordinol (16) (6, 7), halfordine (17) (6, 8), halfordinone (18) (6, 8), and N-methylhalfordinium chloride (23)( 1 3 , all isolated from the Australian plants Halfordia scleroxyla and H . kendack by Crow and Hodgkin. The New Guinea species H . pupuana was subsequently demonstrated to contain halfordine (17) (9). While the isolation of halfordinol(l6) from Aegle marmelos (7) predates the structure elucidation of the compounds from Halfordia, the Aegle alkaloid was not originally recognized as an oxazole structure. Crow and Hodgkin quickly recognized the possible biosynthetic link between the 2-pyridyl-5-(4-hydroxy)phenyloxazolesand the (3-phenylethylamides, none of which accumulate in Hulfordia. To account for oxazole formation these authors proposed two similar biogenetic pathways commencing with the ahydroxy-P-phenylethylamide28. Both pathways (Scheme 4) entail, in different order, cyclization, dehydration, dehydrogenation, and alkylation. The point was made that the intermediacy of the quinone-methene intermediates 31 and 32 would be crucial to the cyclization-alkylation (32to 33)and dehydrogenationalkylation (31 to 34).The obvious precondition for the formation of intermediates 31 and 32 would be the presence of an unsubstituted phenolic oxygen on the tyramine residue. Alkylation or lack of it at this position would therefore determine the nature of the final product, open chain amide or oxazole.

CeH

HO

.1

OH

30

31

R = e.g., C,H,CH = CH;

H

33

34

X = e.g., H e or MezC = C H C H ~ O P O ~ H Z

SCHEME4. Proposed biosynthetic pathway of oxazoles from P-phenylethylamides.

265

6. OXAZOLE ALKALOIDS

Although the biosynthesis of 2-pyridyl-5-phenyloxazoleshas not been studied, the likely veracity of this sequence has been borne out by the biosynthetic study of annuloline (1) ( 5 ) and the cowcurrence in the rutaceous genera Aegle and Amyris of oxazoles and open chain P-phenylethylamides( I1-13, 16, 18). In the biosynthesis of annuloline (I), the low incorporation of 0-methylated precursors was a notable point ( 5 ) lending support to the possible intermediacy of quinonemethene type compounds such as 31 and 32 and the operation of either a cyclization-alkylation (e.g., 32 to 33) process or a dehydrogenation-alkylation (e.g., 31 to 34) process. Aegfe marmelos, which produces halfordinol (16) (7) and O-isopentenylhalfordinol (19) ( 1 I), also accumulates the P-phenylethylamides aegeline (39, N-2-methoxy-2-(4-methoxyphenyl)ethylcinna~ide (36), N-2-ethoxy-2-(4-methoxypheny1)ethylcinnamide (37), and N-2-methoxy-2-[(4-(3’,3’-dimethylallyloxy)phenyl]ethylcinnamide (38) ( 1I). The coincidence in compounds 36, 37,

35 36 37 38 39

R R R R R

= = = =

CH3 CH3 CH3 CH2CH:C(CH3)2; = CH2CH:C(CH3)2;

rnOJ-q--J

R‘ R’ R’ R’ R‘

= = = =

H CH3 CH2CH3 CH3 = H OH

1MHCI

N

19

-

RT, 5 rnin OCH3 N

16

40

and 38 of the alkoxy groups (methoxy and ethoxy) on the a carbon of the tyramine residue with those of the extracting solvent (methanol and ethanol) suggests that these compounds may be artifacts, the true natural products being aegeline (35) and the hitherto unknown structure 39 ( 1 1 ) . The possibility was raised that halfordinol (16), the only known natural oxazole unsubstituted at the tyramine oxygen, may also be an artifact. Treatment of 0-isopentenylhalfordinol (19) with 1 M hydrochloric acid at room temperature for 5 min afforded, after workup, a quantitative yield of halfordinol (16) (12). Balsoxin (25), isolated from Amyris bafsamifera (16)cooccurs with the closely related amide balsamide (40), N-2-hydroxy-2-(3,4-dimethoxyphenyl)ethylbenzamide. Balsamide (40),on oxidation followed by treatment with phosphorus oxychloride yielded balsoxin (25) (16).

266

HELEN M. JACOBS AND BASIL A. BURKE

In addition to the oxazoles O-isopentenylhalfordinol(19) (12), O-geranylhalfordinol (21) (13), and 2-pyridyl-5-(3-methoxy-4,5-methylenedioxy)phenyloxazole (24) (13), Amyris plumieri produces a number of novel chromenylated tyramides 41-43 and the P-styrylamide 44 (12-14, 18). The only other isolable metabolites from this plant were nicotinamide (45) and 4-(3,3-dimethyl) allyloxybenzoic acid (46)(12, 18). These two latter compounds are thought to R

41

0

QJCONH2 45

HO

arise from degradation of O-isopentenylhalfordinol(19) involving 1,4-addition of singlet oxygen to the oxazole to yield the bicyclic peroxide 47 as the initial product (Scheme 5 ) . Addition of singlet oxygen to the oxazole nucleus is a wellknown and documented process (19). The mechanism of 02*addition and decomposition of peroxides of type 47 has been rigorously eluciated by Wasserman largely by IeOzisotope studies (20). This reaction has also found extensive synthetic application (21). Breakdown of the transannular peroxide 47 via a route involving a BaeyerVilliger-type rearrangement would furnish the imino anhydride 48 which could then easily rearrange to the triamide 49, hydrolysis of which would yield formic acid (SO), nicotinamide (45), and the acid 46 (Scheme 5 ) . The suggestion that the acid 46 was an artifact arising from oxidation, photolytic or otherwise, of 0isopentenylhalfordinol (19) was reinforced by the cooccurrence of these compounds in fractions of a relatively fresh extract of A. plumieri and the absence of the oxazole 19 and the presence of the acid 46 in fractions from an extract which had been set aside for several months (18).This evident photolability of oxazoles may be one factor contributing to the scattered and relatively infrequent reports

261

6. OXAZOLE ALKALOIDS

0

0-+ CONHL

N

o/c/

45

’

0

H i

I ‘OH 50

‘-2

0

+

HO

46

51 SCHEME 5. Photodegradation of 0-isopentenylhalfordinol(19).

of their isolation from natural sources. Consideration of this should inform future investigations of related taxa. The Rutaceae oxazoles are evidently derived from N-nicotinoyl-P-(p-hydroxy)phenylethylamide (Sl), with the exception of balsoxin (25) and texamine (26) in which the nicotinoyl moiety is replaced by benzoyl. The condensation of these tyramine and nicotinic acid residues does not represent any major departure from the standard routes of alkaloid biosynthesis in the Rutaceae, for it has long been recognized that the alkaloids of this family are all derived from either phenylalanine (52), tyrosine, (53), or anthranilic acid (54) (22), the latter being the acknowledged precursor to nicotinic acid in most organisms (23). The formation of the putative oxazole precursor 51 or its equivalent therefore constitutes a convergence of the two predominant modes of alkaloid biosynthesis in the family. In the oxazole-containingspecies recognized thus far, anthranilate is evidently not always shunted into nicotinate formation as some of these taxa accumulate products attributable to a more direct utilization of anthranilate. Hulfordiu kenduck contains the quinoline alkaloid halfordamine (55) and the furanoquinoline halfordinine (56) (8, 22), while small quantities of dictamnine (57) occur in H.

268

HELEN M. JACOBS AND BASIL A. BURKE

qTC0’”

HO

54

NH2

OCH 3

OCH3

56

57

CH3O

I

CH~O

OCH,

55

OCH3

I

RO

qJ2Q c H ; p T J OCH3

58a 58b

H

R = H haplopine R = CH3 skimmianine

\

59

scleroxyla ( 8 ) . The Occurrence of the furanoquinolines 58a and 58b has been reported in Aegle marmelos ( 1 1 ) while Micromelum zeylanicum, in addition to 0-methylhalfordinol (22), produces the carbazole alkaloid koenigine (59) ( 1 4 ) . Virtually no taxonomic utility has been ascribed to the Rutaceae oxazoles by Waterman (22), and certainly their incidence (although confined to two of the three major subfamilies, Table 11) seems too infrequent-perhaps as a consequence of their photolability-for any valid taxonomic conclusions to be drawn.. Formation of the oxazole nucleus in the Rutaceae therefore seems to be an elaboration (oxidation, cyclodehydration) of the basic P-phenylethylamide skeleton, which at present has no far-reaching implications for the phylogeny of this wellstudied family. TABLE I1 OXAZOLE-CONTAINING RUTACEOLJS TAXA Species

Subfamily

Tribe

Reference(s)

Aegle marmelos Aeglopsis chevalieri Micromelum reylanicum Halfordia scleroxyla Halfordia kendack Halfordia papuana Amyris plumieri Amyris balsamifera Amyris texana

Aurantioideae Aurantioideae Aurantioideae Toddalioideae Toddalioideae Toddalioideae Toddalioideae Toddalioideae Toddalioideae

Citrinae Citrinae Hesperathusineae Toddaliniiae Toddaliniiae Toddaliniiae Amyridinae Amyridinae Amyridinae

7. I1 10

I4 6 . 15 8 9 12, 13 I6 I7

269

6. OXAZOLE ALKALOIDS

Brossi and Wenis have prepared halfordinol(l6) by cyclodehydration of the aamido ketone 60 followed by hydrolysis of the intermediate 0-benzyl derivative 61 ( 2 4 ) .

IV. Marine Oxazoles The eggs of the nudibranch Hexabranchus sanguineus collected off the coast of Hawaii have yielded the macrolides ulapualide A (62) and ulapaulide B (63) (25) both of which incorporate the unprecedented trisoxazole moiety. These compounds were obtained as colorless oils whose structure determination was

M

0

e

+

e-

M&e

Me

“0IIh

-

0 *

Me0

62 R =

63 R = H,\o

=0

R

OAc

N

II

~

Me

Ulapualide A Ulapualide B

+Me OMe

the result of extensive application of high-resolution and two-dimensional NMR spectroscopy. A third marine oxazole isolated from the egg masses of an unidentified Pacific nudibranch is the closely related compound kabiramide C (64)( 2 6 ) . Isolation of these compounds is the result of the first forays into the chemistry of nudibranch egg masses. Both the ulapualides and kabiramide C exhibit significant antitumor and/or antifungal activity (25, 26), which would seem to impli-

H

270

HELEN M . JACOBS AND BASIL A. BURKE

64

MeO’

cate them as important chemical defense substances for the producing organisms, which evidently have no natural predators. It has been hypothesized that the trisoxazole moiety in kabiramide C (64) arises by cyclization of the dehydrotriserine residue 65. This conjecture is consistent with the established mode of formation of the bacterial oxazole virginiamycin M 1 90 from an acylserine (vida infra). A more recent suggestion is that the trisoxazole 69 may arise by cyclization of the Beckmann rearrangement product 68 of the trioxime 67 derived from the polyketide 66 (27).

NH

66

67

- -?XW>$ 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

6. OXAZOLE ALKALOIDS

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

6. OXAZOLE ALKALOIDS

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<

98

Virginiamycin M 1 (ostreogrycin A, 90) occurs in Streptomyces virginiue (45) and S . ostreogriseus, from which it has been isolated as part of the so-called ostreogrycin complex (46). It also occurs in S.'alborectus ( 4 7 ) . This compound was the first of the series whose structure was correctly solved. For the structure elucidation of 90 Todd et ul. utilized a combination of chemical and spectroscopic techniques, the latter entailing relatively early applications of nuclear magnetic double-resonance and high-resolution mass spectrometry (48-50). This compound was one of the first natural products in which the oxazole ring was recognized-the others which were known at the time were pimprinine (70), annuloline (l),and halfordine (17). The gross structure and relative configuration of 90 were confirmed by X-ray crystallography (51). The X-ray data coupled with comparison of griseoviridin (89) facilitated a tentative assignment of the absolute configuration at C-2, C-3, and C-13 as R , R , and S, respectively (52). These assignments were confirmed by correlation with lactone 99 synthesized enantioselectively as part of an approach to the total synthesis of virginiamycin M1 (90) (53). This lactone (99) had been obtained from degradation of 90 (48),

99

276

HELEN M. JACOBS AND BASIL A. BURKE

and the optical properties of the synthetic compound were, within experimental error, in good agreement with those of the virginiamycin-derived lactone (53). Virginiamycin M2 (91) is a minor component of the ostreogrycin complex (45-47). Its structure, also elucidated by Todd et ul. (54), differs from virginiamycin M 1 (90)in that it incorporates a proline as opposed to a dehydroproline unit. Isolation of D-prOline from degradation products of 91 established the chirality of this residue as D; by derivation, 91 is assumed to have the same stereochemistry as 90 at C-2, C-3, and C-13 (51, 54). Madumycin I1 (A2315A, 92) and the closely related madumycin I (93) almost always cooccur. Relatively recent additions to the series, these compounds were first isolated from Actinomuduru flavu (55, 56) and subsequently from various Actinopfunes species (57-60). The latest addition to the series A170002C (94) is very closely related to the madumycins, with which it cooccurs in at least one organism (59). Comparison of the I3C-NMR data of madumycin I1 (92) with those of grisoviridin (89) and virginiamycin MI (90)(whose absolute configurationsare known) led to the conclusion that the geometry of 92 and its relative configuration at C-2, C-3, C- 13, and C- 15 are identical to the corresponding centers in 89 and 90 (52). The I3C-NMR data in conjunction with comparison of observed and calculated interproton coupling constants between NH-7 and CH,-8 and NH-23 and CH/ CH,-24, where relevant, indicated that the torsion angles between H-7 and H-8 of all three compounds are similar in solution and that the solution conformations of griseoviridin (89) and virginiamycin M1 (90) are very close to those adopted in the crystal lattice. It was also concluded that the C-1 to C-16 section of madumycin I1 (92) is, in solution, conformationally very similar to griseoviridin (89) and virginiamycin MI (W), with the C-16 to C-25 portion more closely resembling that of griseoviridin (89). This spectral evidence coupled with the detection of D-alanine in the hydrolysate of 92 strongly suggests that the absolute configuration of madumycin I1 is as shown in 92 (52). The linkage in madumycin I1 (92) of the D-alanine and oxazole residues (the latter thought to arise by cyclization of an acyldehydroserine) is considered significant insofar as the cowcurrence of D- and dehydro amino acids in microbial compounds had been previously noted (61), and a possible relationship between these systems suggested. Several microbial metabolites which display antibiotic properties incorporate a,P-dehydro amino acids and their derivatives (62). The biosynthesis of virginiamycin MI in Streptomyces virginiue has been studied using both radiolabeled precursors (63) and stable isotope techniques (45, 63-65). Incorporation of [2-I4C]acetate, L - [ m e t h ~Hlmethionine, f-~ DL-~I4C]serine, ~ - [ 3 , 4H,]proline, -~ and [2J4C]glycine established these compounds as the main precursors (63).The assumption that carbons 2,26, 27, and 28 arose from valine was supported by the observation that no incorporation of appropriately labeled mevalonolactone was observed (65). On the basis of the radio-

6. OXAZOLE ALKALOIDS

277

isotope experiments it was inferred that the N-7 to C-8 fragment originated from glycine, the N-23, C-24, C-37, C-36, C-35, C-25, and 0-38 residue from proline, and the N-18, C-19, C-20, 0-21 fragment of the oxazole ring with the attached N-23 and 0-34 from serine. The latter inference was corroborated by the observed enhancement of the C-13 NMR signal arising from C-20 in the spectrum of the antibiotic harvested from the microorganism incubated with ~ ~ 4 3Clserine. - l ~ This confirmed previous hypotheses concerning the origin of the oxazole ring in these compounds (52). The C-13 NMR spectrum obtained in this experiment also displayed an approximately twofold enhancement of the signals arising from carbons 3,5, 10, 12, 14, 16, and 31, consistent with their genesis from acetyl-coenzyme A derived from serine via pyruvate. Predictably, these seven peaks were also enhanced in the spectrum of 90 obtained from incubation of the organism with [2J3Clacetate. This, coupled with observed incorporation of [l-13C]acetateat positions 4, 6, 11, 13, 15, and 17, established that carbons 3 through 6 and 10 to 17 arose from tri- and tetraketide precursors and led to the suggestion that acetate was functioning as a methylating agent on the carbon chain (65). Stable isotope methodology has been applied to the study of the biosynthesis of madumycin I1 (A2315A, 92) in Actinoplunes philippensis (60, 64).As with virginiamycin MI (90), carbons 2,26, 27, and 28 were found to be derived from valine, C-29 from methionine, C-3 to C-6 from acetate, N-7, C-8, and C-9 from glycine, carbons 10 to 17 and C-31 from acetate, and N-18, C-19, C-20, 0-21, C-32, and 0-34 from serine. The origin of the D-alanine residue, N-23, C-24, C-25, C-35, and 0-36, was of particular interest in this study. No incorporation of DL-[U-'~Clserine was observed in the alanine portion of the molecule, eliminating the intermediacy of the a$-dehydro alanine unit 101 derivable from the acylserine precursor 100. This was corroborated by the observed incorporation into the molecule of intact doubly labeled ~-[3-'~C,3,3,3-*H]alanine. DL-[ 1I4C]Alaninewas also efficiently incorporated. These results and those from de-

tailed precursor product studies utilizing mixtures of DL-[~-' Hlalanine with L-[ 1I4C]-, D-[1-14C]-, and D L - [ ~Hlalanine -~ demonstrated conclusively that both epimers of alanine were incorporated into madumycin I1 (92) with equal efficiency, suggesting the operation of an alanine racemase in the enzyme system under consideration (60).

278

HELEN M . JACOBS AND BASIL A. BURKE

Griseoviridin (89), the virginiamycins (90 and 91), and madumycin I1 (92) are the targets of total synthesis. One common feature of the retrosynthetic analyses is the disconnection of the amide linkages C-6-N-7 and C-22-N-23 giving rise to the 2-alkyl-4-carboxyloxazoles103-105 (67-70). The remaining fragment

OH

O

Y

N 7

NH2

R

OH

R’

for griseoviridin (89) is the thiolactone 106; for madumycin I1 it is the ester of Dalanine 107, and for virginiamycin M1 and M2 the dehydroproline and D-proline esters 108 and 109. Thiolactone 106 has been prepared in enantiomerically pure form (66, 67, 72, 73)as has the alkyl portion of the esters 107-109 (5 3 ,6 9 ),the first preparation of which established the absolute configuration of the carbons bearing the isopropyl and methyl groups (53).

More pertinent to this chapter is the synthesis of the oxazole fragments 103105. Meyers’ retrosynthesis postulates a disconnection of C-1 1 -C-12 of 103 (numbering derived from 89) giving rise to the synthons 110 and 111, and a further disconnection through what was originally the C- 15-C-16 bond, leading to fragments 112 and 113 (67, 72). Fujita’s analysis omits the C-11-C-12 disconnection and proposes the combination of synthons 117 and 120 or 118 and 119 for the preparation of compound 104 (68, 71). All of the proposed synthetic schemes require alkylation of the methyl group of the 2-methyl-4-

279

6. OXAZOLE ALKALOIDS

\’ OH

OH

\

NH2

OH

H

103

OH

110

CH3

OH

113 114 115 116

O V -

111

R R R R

= H = Et =Me =~Bu

112

carbalkoxyoxazoles 113-116, a process for which there seemed to be fair precedent. Thus, the methyl groups at position 2 in 2,4,5-trimethyloxazole (121), 2,5dimethyl-4-phenyloxaole (122), and 2,4-dimethyl-5-phenyloxazole (123) were alkylated by treatment with base and various electrophiles, exclusively and in high yield (74).

117 118

119 120

A = @ A = 8

121

122

B = 0 B = e

123

The reaction of 2-methyl-4-carbethoxyoxazole (114) with ethyl acetate under basic conditions had been reported to result in the product of alkylation on the methyl group of 124 which was thought to exist in the enol form 125 (49). On reinvestigation of the reaction it was revealed that the product was actually that of Claisen condensation (126) which existed in the enol form 127 (75). The close

280

HELEN M. JACOBS AND BASIL A . BURKE

125

124

H

3

C

q

xOEt

H $ f > 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

6. OXAZOLE ALKALOIDS

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

6. OXAZOLE ALKALOIDS

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

HELEN M. JACOBS AND BASIL A. BURKE

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

6. OXAZOLE ALKALOIDS

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

HELEN M. JACOBS AND BASIL A. BURKE

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

6. OXAZOLE ALKALOIDS

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

6. OXAZOLE ALKALOIDS

(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

HELEN M . JACOBS AND BASIL A. BURKE

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

6. OXAZOLE ALKALOIDS

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<3? NMeCOCF3 C02CH3

175

w

-100"

NMeCOCF3

(COOH),, MeOH. 25"

COzCHj

*

R35iw 4 I

CF3COMeN

*

1.

B u ~ N FTHF. ,

2.

2 5" Collins

*

N

C02CH3

C02CH3

183

184

(Zinc enolate) CH2CH3

Bu'OrC

*

6UtO2C

186

185

1

2.

H ion exch. resin HOHs +

* 168

COrCH3

292

HELEN M. JACOBS AND BASIL A. BURKE

Nocobactin NA is the generic name given to a series of compounds obtained after dissociation of a ferric complex isolated from the bacterium Nocardia asteroides grown under iron-deficient conditions (97 ). Spectroscopic, degradative, and partial synthetic studies led to the formulation 187 for the compounds. The nocobactins are lipid-soluble ionophores whose function appears to be the transport of iron across the lipid-rich cell boundary of the producing organism. Base-mediated hydrolysis of nocobactin NA (187) afforded an acidic and a neutral fraction. The acidic compound, nocobactic acid NA (188) retained the

&>

HO- N -COCH3

I

(CH2)4

CONH

I - CH -C02

0

-

-CH CH -CO-N KIH d n CH3 I

CH3 n = mainly9and 1 1

0 0"

I

H

I

N

OH

187 NaoH

HO-N-COCH3

I

OH

I - . .

I

I

188 nocobactic acid NA

189 cobactin NA n = mainly9and 1 1

HCI

&> 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

6. OXAZOLE ALKALOIDS

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

HELEN M. JACOBS AND BASIL A. BURKE

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

HELEN M . JACOBS AND BASIL A. BURKE

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

6. OXAZOLE ALKALOIDS

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)

IR, cm-' (medium) (reference)

'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

HELEN M. JACOBS AND BASIL A. BURKE

TABLE I11 (Continued)

Alkaloid name

Molecular formula

Melting point (solvent) (reference)

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

6. OXAZOLE ALKALOIDS

IR, cm-' (medium) (reference)

'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)

-

Mass spectrum (reference)

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

HELEN M. JACOBS AND BASIL A. BURKE

TABLE 111 (Conrinued)

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

Molecular formula

Melting point (solvent) (reference)

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

6. OXAZOLE ALKALOIDS

305

IR, cm-' (medium) (reference)

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)

Mass spectrum (reference)

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

6. OXAZOLE ALKALOIDS

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.

REFERENCES 1. B. Axelrod and J. R. Belzile, J . Org. Chem. 23, 919 (1958). 2. R. S. Karimoto, B. Axelrod, J. Wolinsky, and E. D. Schall, Tetrahedron Lett.. 83 (1%2). 3. R. Lakhan and B. Ternai, in “Advances in Heterocyclic Chemistry,” (A. R. Katritzky and A. J. Boulton, eds.), Vol. 17, pp. 99-21 1. Academic Press, New York, 1974. 4. 1. J. Tiirchi and M. J. S. Dewar, Chem. Rev. 75, 389 (1975). 5 . D. G.O’Donovan and H. Horn. J. Chem. SOC. C . 331 (1971). 6. W. D. Crow and J. H. Hodgkin, Aust. J . Chem. 17, I19 (1964); W. D. Crow, J. H. Hodgkin, and J. S. Shannon, Aust. J. Chem. 18, 1433 (1965). 7. A. Chatterjee, S. Bose, and S. K. Srimany, J. Org. Chem. 24,687 (1959). 8. W. D. Crow and J. H. Hodgkin, Aust. J. Chem. 21, 3075 (1968); R. D. Storer and D. W. Young, Tetrahedron 29, 1215 (1973). 9. T. G.Hartley, E. A. Dunstone, J. S. Fitzgerald, S . R. Johns, and J. R. Lamberton, Lloydia 36, 217 (1973). 10. D. L. Dreyer, J. Org. Chem. 33, 3658 (1968). 11. M. A. Manandhar, A. Shoeb, R. S. Kapil, and S . P. Popli, Phytochemistry 17, 1814 (1978); D. Basu and R. Sen, Phytochemistry 13,2339 (1974); A. Shoeb, S. P. Popli, and R. S. Kapil, Phytochemistry 12, 2071 (1973). 12. B. A. Burke and H. Parkins, Tetrahedron Lett.. 2723 (1978). 13. S. Philip, B. A. Burke, and H. Jacobs, Heterocycles 22,9 (1984). 14. I. H. Bowen and K. P. W. C. Perera, Phytochemistry 21,433 (1982). 15. W. D. Crow and J. H. Hodgkin, Tetrahedron Lett., 85 (1963). 16. B. Burke, H. Parkins, and A. M. Talbot, Heterocycles 12, 349 (1979). 17. A. Dominguez, G.de la Fuente, A. G.Gonzalez, M. Reina, and I. Timon, Heterocycles 27, 35 (1988). 18. H. M. Parkins, Ph.D. thesis. University of the West Indies 1978. 19. H. H. Wasserman, F. J. Vinick, and Y. C. Chang, J. Am. Chem. SOC.94,7180 (1972). 20. H. H. Wasserman and G.R. Lenz, Heterocycles 5 (special issue), 409 (1976). 21. H. H. Wasserman, K. E. McCarthy, and K. S. Prowse, Chem. Rev. 86,845 (1986). 22. P. G.Waterman, Biochem. Syst. Ecol. 3, 149 (1975). 23. F. Lingens, Angew. Chem. Int. Ed. Engl. 7, 350 (1968). 24. A. Brossi and E. Wenis, J. Heterocycl. Chem. 2, 310 (1965). 25. J. A. Roesener and P. J. Scheuer, J. Am. Chem. SOC. 108, 846 (1986). 26. S. Matsunaga, N. Fusetani, K. Hashimoto, K. Koseki, and M. Noma, J. Am. Chem. SOC. 108, 847 ( 1986).

308

HELEN M. JACOBS AND BASIL A. BURKE

27. M. Ishibashi, R. E. Moore, G. M. L. Patterson, C. Xu,and J. Clardy, J. Org. Chem. 51,5300 ( 1986). 28. Y. Koyama, K. Yokose, and L. J. Dolby, Agric. Eiol. Chem. 45, 1285 (1981). 29. D. S. Bhate, R. K. Hulyalkar, and S. K. Menon, Experenria 16, 56 (1960). 30. B. S. Joshi, W. I. Taylor, D. S. Bhate, and S. S. Karmarkar, Tetrahedron 19, 1437 (1963). 31. M. Noltemeyer, G. M. Sheldrick, H. Hoppe, and A. Zeeck, J . Anribior. 35, 549 (1982). 32. Y. Oikawa, T. Yoshioka, K. Mohri, and 0. Yonemitsu, Heterocycles 12, 1457 (1979). 33. T. Yoshioka, K. Mohri, Y. Oikawa, and 0. Yonemitsu, J . Chem. Res. (S), 194 (1981). 34. Y. Noda, K. Taki, T. Tokuyama, S. Narumiya, H. Ushiro, and 0. Hayashi, J. Biol. Chem. 252, 4413 (1977). 35. P. Crooy and R. de Neys, J. Anribior. 25, 37 (1972). 36. Q. R. Bartz, J. Standiford, J. D. Mold, D. W. Johannessen, A. Ryder, A. Maretzki, and T. H. Haskell, Antibiot. Annu.. 777 (1954- 1955). 37. D. E. Ames, R. E. Bowman, J. F. Cavalla, and D. D. Evans, J. Chem. Soc., 4260 (1955). 38. D. E. Ames and R. E. Bowman, J. Chem. Soc., 4264 (1955). 39. D. E. Ames and R. E. Bowman, J. Chem. Soc.. 2925 (1956). 40. P. de Mayo and A. Stoessl, Can. J . Chem. 38,950 (1960). 41. M. C. Fallona, T. C. McMorris, P. de Mayo, T. Money, and A. Stoessl, J. Am. Chem. SOC.84, 4162 (1%2). 42. M. C. Fallona, T. C. McMorris, P. de Mayo, T. Money, and A. Stoessl, Can. J. Chem. 42, 371 (1964). 43. G. 1. Birnbaum and S. R. Hall, J. Am. Chem. SOC.98, ,1926 (1976). 44. B. W. Bycroft and T. J. King, J. Chem. SOC.. Perkin Trans. 1. 1996 (1976). 45. D. G. 1. Kingston and M. X . Kolpak, J. Am. Chem. SOC. 102,5964 (1980). 46. S. Ball, B. Boothroyd, K. A. Lees, A. H. Raper, and E. Lester Smith, Eiochern. J. 68, 24P (1958). 47. K. Ogata, M. Matsuura, H. Irie, T. Uneo, Y. Tani, and H. Yamada, J. Anribiot. 31, 1313 ( 1978). 48. G. Delpierre, F. W. Eastwood, G. E. Gream, D. G. I. Kingston, P. S. Sarin, Lord Todd, and D. H. Williams, J. Chem. SOC. C . 1653 (1966). 49. D. G. 1. Kingston, Lord Todd, and D. H. Williams, J. Chem. SOC. C , 1669 (1966). 50. G. R. Delpierre, F. W. Eastwood, G. E. Gream, D. G. 1. Kingston, Lord Todd, and D. H. Williams, Tetrahedron Lerr.. 369 (1966). 51. F. Durant, G. Evrard, J. P. Delclerq, and G. Germain, Cryst. Srrucr. Commun. 3,503 (1973). 52. B. W. Bycroft, J. Chem. SOC. Perkin Trans. 1, 2464 (1977). 53. R. D. Wood and B. Ganem, Tetrahedron Lerr. 23,707 (1982). 54. D. G. 1. Kingston, P. S. Sarin, LordTodd, and D. H. Williams, J. Chem. SOC.C . 1856(1966). 55. T. S. Maksimova, Zenrralbl. Bakreriol., Parasirenkd., Infekrionskr.. Hyg. Abr 1 Suppl. 1976 (publ. 1978),6 (Norcardia Streptomyces) 377-379 (Engl.); Chem. Absrr. 88, 168436n (1978). 56. M. G. Brazhnikova, M. K. Kudinova, N. P. Potapova, T. M. Filippova, E. Borowski, Y. Zelinskii, and Y. Golik, Bioorg. Khim. 1, 1383 (1975); Chem. Absrr. 84, 140654a (1976). 57. R. L. Hamill and W. M. Stark, U.S. Patent 3,923,980 (1975); Chem. Absrr. 81,2390~(1974). 58. J. W. Chamberlin and S. Chen, J. Anribior. 30, 197 (1977). 59. E. Martinelli, L. F. Zerilli, G. Volpe, H. Pagani, and B. Cavalleri, J. Anribior. 32, 108 (1979). 60. J. W. LeFevre and D. G. I. Kingston, J. Org. Chem. 49,2588 (1984). 61. B. W. Bycroft, Nature (London) 224,595 (1969). 62. U. Schmidt, J. Hausler, E. Ohler, and H. Posel, Prog. Chem. Org. Nor. Prod. 37,251 (1979). 63. M. Roberfroid and P. Dumont, Ind. Chim. Belge 32, 307 (1967). 64. J. W. LeFevre, T. E. Glass, M. X. Kolpak, D. G. 1. Kingston, and P: N. Chen, J. Nut. Prod. 46,475 (1983).

6 . OXAZOLE ALKALOIDS

309

65. D. G. I. Kingston, M. X. Kolpak, J. W. LeFevre, and 1. Borup-Grotchtmann, J. Am. Chem. Sor. 105, 5106 (1983). 66. L. Liu, R. S. Tanke, and M. J. Miller, J. Org. Chem. 51, 5332 (1986). 67. A. I. Meyers, J. Lawson, R. A. Amos, D. G. Walker, and R. F. Spohn, Pure Appl. Chem. 54, 2537 (1982). 68. Y. Nagao, S. Yamada, and E. Fujita, Tetrahedron Lett. 24, 2287 (1983). 69. R. H. Schlessinger, E. H. Iwanowicz, and J. P. Springer, J. Org. Chem. 51,3073 (1986). 70. A. I. Meyers and J. P. Lawson, Tetrahedron Len. 22, 3163 (1981). 71. E. Fujita, Heterocycles 21,41 (1984). 72. A. 1. Meyers and R. A. Amos, J. Am. Chem. SOC. 102, 870 (1980). 73. I. Butera, J. Rini, and P. Helquist, J. Org. Chem. 50, 3676 (1985). 74. B. H. Lipshutz and R. W. Hungate, J. Org. Chem. 46, 1410 (1981). 75. A. 1. Meyers and D. G. Walker, J. Org. Chem. 47,2999 (1982). 76. Y. Nagao, S. Yamada, and E. Fujita, Tetrahedron Lett. 24,2291 (1983). 77. R. D. Wood and B. Ganem, Tetrahedron Lett. 24,4391 (1983). 78. A. I. Meyers, J. P. Lawson, and D. R. Carver, J. Org. Chem. 46, 31 19 (1981). 79. T. Mori, K. Takahashi, M. Kashiwabara, D. Uemura, C. Katayama, S. Iwadare, Y. Shizuri, R. Mitomo, F. Nakano, and A. Matsuzaki, Tetrahedron Lett. 26, 1073 (1985). 80. K. Takahashi, M. Kawabata, D. Uemura, S. Iwadare, R. Mitomo, F. Nakano, and A. Matsuzaki, Tetrahedron Lett. 26, 1077 (1985). 81. M. Ogura, H. Nakayama, K. Furihata, H. Seto, and N. Otake, J. Antibiot. 38, 669 (1985). 82. M. Ogura, H. Nakayama, K. Furihata, A. Shimazu, H. Seto, and N. Otake, Agric. B i d . Chem. 49, 1909 (1985). 83. M. Bergy, J. H. Coats, and F. Reusser, U.S. Patent 3,689,639 (1969); Chem. Abstr. 77, P150582v (1 972). 84. J. M. Liesch, 1. A. McMillan, R. C. Pandey, I. C. Paul, K. L. Rinehart, Jr., and F. Reusser, J. Am. Chem. SOC. 98, 299 (1976). 85. J. M. Liesch, D. S. Millington, R. C. Pandey, and K. L. Rinehart, Jr., J. Am. Chem. Sor. 98, 8237 (1976). 86. J. M. Liesch and K. L. Rinehart, Jr., J. Am. Chem. SOC.99, 1645 (1977). 87. C. J. Pearce and K. L. Rinehart, Jr., J. Am. Chem. Sor. 101,5069 (1979). 88. K. L. Rinehart, Jr., D. D. Weller, and C. J. Pearce, J. Nut. Prod. 43, I (1980). 89. P. W. Reed and H. A. Lardy, J . Biol. Chem. 247,6970 (1972). 90. D. T. Wong, J. R. Wilkinson, R. L. Hamill, and J. S. Horng, Arch. Biochem. Biophvs. 156, 578 (1973). 91. M. 0. Chaney, P. V. Demarco, N. D. Jones, and J. L. Occolowitz, J. Am. Chem. Sor. 96, 1932 (1974). 92. C. M. Deber and D. R. Pfeiffer, Biochemistry 15, 132 (1976). 93. M. Debono, R. M. Molloy, D. E. Dorman, J. W. Paschal, D. F. Babcock, D. M. Deber, and D. R. Pfeiffer, Biochemistry 20,6865 (1981). 94. D. A. Evans, C. E. Sacks, W. A. Kleschick, and T. R. Taber, J. Am. Chem. Soc. 101, 6789 (1979). 95. P. A. Grieco, K. Kanai, and E. Williams, Heterocycles 12, 1623 (1979). 96. P. A. Grieco, E. Williams, H. Tanaka, and S. Gilman, J. Org. Chem. 45,3537 (1980). 97. C. Ratledge and G. A. Snow, Biochem. J. 139,407 (1974) and references therein. 98. G. Stuckwisch and D. D. Powers, J. Org. Chem. 25, 1819 (1960). 99. J. W. Westley, C. M. Liu, R. H. Evans, and J. F. Blount, J. Antibiot. 32, 874 (1979). 100. C. Schregenberger and D. Seebach, Tetrahedron Lett. 25,5881 (1984). 101. C. Schregenberger and D. Seebach, Jusrus Liebigs Ann. Chem. 2081 (1986). 102. U. Schollkopf, Agnew. Chem. 82,795 (1970).

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U. Schollkopf and R. Schriider, Angew. Chem. Inr. Ed. Engl. 10,333 (1971). B. R. Sharma and P. Sharma, Planra Med. 43, 102 (1981). J. L. Hartwell, Lloydia 31,71 (1968). N. J. Narasimhan, Jr., and V. G.Ganla, Hindusrun Anribior. Bull. 9, 138 (1967); Chem. Absrr.

67, 20358j (1967). 107. T. Takeuchi, K. Ogawa, I. Iinuma, H. Suda, K. Ukita, T. Nagatsu, M. Kato, H. Umezawa, and 0. Tanabe, J. Anribior. 26, 162 (1973). 108. C. Cocito, Microbiol. Rev. 43, 145 (1979). 109. M. Aumercier, S. Bouhallab, M. L. Capmau, and F. Le Goffic, J. Antibior. 39, 1322 (1986); Chem Absrr. 105, 167068g (1986). 110. C. Cocito, F. Vanlinden, and C. Branlant, Biochem. Biophys. Acra 739, 158 (1983). 111. P. Moureau, M. diciambattista, and C. Cocito, Biochem. Biophys. ACIU 739, 164 (1983). 112. P. Moureau, Y. Engelborghs, M. diGiambattista, and C. Cocito, J. Biol. Chem. 258, 14233 ( 1983). 113. M. diGiambattista and C. Cocito, Biochem. Biophys. Acra 757,92 (1983). 114. C. Cocito and F. Vanliden, Arch. Microbiol. 135, 8 (1983). 115. G.Chinali, P. Moureau, and C. Cocito, J. B i d . Chem. 259, 9563 (1984). 116. F. Le Goffic, M. L. Capmau, J. Abbe, L. Charles, and J. Montstier, Eur. J. Med. Chem. Chim. Ther. 16.69 (1981). 117. F. Le Goffic, J. Anrimicrob. Chemrher. 16 (Suppl. A), 13 (1985). 118. C. C. Scheifinge, U.S. Patent 4,336,250 (1981); Chem. Absrr. 97, PI089342 (1982). 119. B. Alarcon, J. C . Lacal, J. M. Fernandez-Sousa, and L. Carrasco, Antiviral Res. 4, 231 ( 1984). 120. F. Reusser, Biochemistry 8, 3303 (1969). 121. J. Thompson, E. Cundliffe, and M. J. R. Stark, J . Gen. Microbid. 128,875 (1982). 122. D. R. Pfeiffer, R. W.Taylor, and H. A. Lardy, Ann. N.Y. Acad. Sci. 307, 402 (1978) and references therein. 123. D. J. Brown and P. B. Ghosh, J. Chem. Soc.B, 270 (1969). 124. D. L. Deavenport, C. H. Harrison, and D. W. Rathburn, Org. Magn. Reson. 5, 285 (1973). 125. H. Hiemstra, H. A. Houwing, 0. Possel, and A. M. van Leusen, Can. J . Chem. 57, 3168 (1979). 126. W. D. Crow, J. H. Hodgkin, and I. S. Shannon, Aust. J. Chem. 18, 1433 (1965).

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)

CUMULATIVE INDEX OF TITLES

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

CUMULATIVE INDEX OF TITLES

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)

CUMULATIVE INDEX OF TITLES

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

CUMULATIVE INDEX OF TITLES

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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