alkaloids chemistry & pharmacology

THE ALKALOIDS

Chemistry and Pharmacology

VOLUME 35

This Page Intentionally Left Blank

THE ALKALOIDS Chemistry and Pharmacology

Edited by Arnold Brossi

Natk~ml Institutes of H d t h &the&. Maryland

VOLUME 35

Academic Press, Inc Harcourt Brace Jovanovich, Publishms

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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

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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 Pharma- ceutical Institute at Tohoku University in Sendai in 1980, his contributions to science did not diminish. On the contrary, they continued to flow and to be important despite his election to deanship and presidency at Hoshi College in Tokyo in 1981. The Japanese journal Hemvcycles, which is written in English and which he founded in 1973, became a prestigious journal for many working with heterocyclic compounds. Only time will tell how much the scientific communities in Japan and in the world have lost with his passing away. It is with admiration and thanks to my colleague and friend Dr. Rtsuji Kametani that I dedicate this volume of “The Alkaloids” to his lasting memory.

Arnold Brossi

CONTENTS

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

Chapter 1. Alkaloids from Guuneria

ANDIG+ C A V ~ , MICH~L LEBOEUF, AND BRUCE K. CASSELS I. Introduction .......................................................

11. Botanical Considerations ............................................ 111. Alkaloids from Chemically Investigated Guut&ria Species. ............... IV. Structure Elucidation and Chemistry.. ................................ V. Biogenetic Hypotheses ..............................................

VI. Chemosystematics .................................................. VII. Pharmacology. .....................................................

VIII. Appendix .......................................................... References .........................................................

ix xi

1 2 3 3

57 65 69 71 73

Chapter 2. 8-Phenethylamines and Ephedrines of Plant Origin

JAN LLJNDSTR~M I. Introduction ....................................................... 77

11. Occurrence ........................................................ 77 111. Isolation, Identification, and Determination Procedures ................. 131 IV. Synthesis .......................................................... 132 V. Biosynthesis ....................................................... 137

VI. Biological Effects.. ................................................. 142 References ......................................................... 144

Chapter 3. Lythraceous Alkaloids KAORU FUJI

I. Introduction ....................................................... 155 11. Synthesis .......................................................... 155

111. Occurrence and Biosynthesis ........ -. ............................... 172 IV. Spectroscopic Studies ............................................... 173

References ......................................................... 175

vii

viii CONTENTS

Chapter 4. Dibenzazonine Alkaloids LUIS CASTEDO AND DOMINGO DOMINGUEZ

I. Introduction ....................................................... 177 11. Occurrence and Classification ........................................ 179

111. Structure Determination ............................................. 180 IV. Synthesis .......................................................... 183 V. Biosynthesis ....................................................... 205 VI. Pharmacological Properties .......................................... 209

VII. Related Alkaloids: Dibenzazecines .................................... 209 References ......................................................... 212

Chapter 5. Nuphar Alkaloids JACEK CYLIULSKI AND JERZY T. WROLIEL

I. Introduction ....................................................... 215 216 220 227 232 239 244

VIII. Pharmacology. ..................................................... 253 References ......................................................... 256

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

Chapter 6. Oxazole Alkaloids HELEN M. 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 .........................................................

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

259 260 262 269 27 1 295 304 307

311 317

CONTRIBUTORS

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

BASIL A. BURKE (259), The Plant Cell Research Institute, Inc., Dublin, Cali- fornia 94568

BRUCE K. 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

LUIS CASTEDO (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

JACEK CYBULSKI (215), Department of Chemistry, University of Warsaw, 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 61 1 , Japan

HELEN M. JACOBS (259), Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica

MICHEL LEBOEUF (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

JAN LUNDSTR~M (77), Department of Drug Metabolism, Astra Research Centre, S-151 85 Sodertalje, Sweden

JERZY T. WR6BEL (215), Department of Chemistry, University of Warsaw, Warsaw, Poland

ix

PREFACE

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

Arnold Brossi

-CHAPTER 1-

ALKALOIDS FROM GUAlTEMA

I. 11.

111. 1v.

V. VI .

VII. VIII.

ANDRB CAVB, MICHEL LEBOEUF, 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

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Botanical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alkaloids from Chemically Investigated Gu

A. Benzylisoquinolines and Saxoguattine B. Bisbenzylisoquinolines ............................

Structure Elucidation and Chemistry ......................................

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

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

Biogenetic Hypotheses . ............................. Chemosystematics ................................................ Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 Guat- teria alkaloids known to possess the protoberberine skeleton. The latter, on the other hand, though published in 1985, already appears seriously outdated. Re- cent reviews on the aporphinoids in general and on the Annonaceae in particular are those by Shamma and Moniot ( 4 , 5 ) , Shamma and Guinaudeau (6) , Guinau- deau 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 Guat- teria, 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 (Magno- liaceae, Degeneriaceae, Himantandraceae, Eupomatiaceae, Canellaceae, My- risticaceae, 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 Guat- teriella, 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, Guat- teriella, 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 (17) 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 bino- mial is Mulmeu guumeri (Greenm.) Lundell (19, 20). For the sake of com- pleteness, 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 SPECIES AND THEIR CONTAINED ALKALOIDS

Species Alkaloid Structure Reference(s)

G. cubensis Bisse

G. diekana R.E. Fr.

G. discolor R.E. Fr.

G. chrysopetalu (Steud.) Miq. Codamine O.N-Dirnethylliriodendronine Isoboldine Lanuginosine Liriodenine Lysicamine Nornuciferine Reticuline Corydine Liriodenine Dielsine Dielsinol Dielsiquinone Isomoschatoline Liriodenine 6-Methoxyonychine 0-Methylmoschatoline Onychine Argentinine Atherosperminine Atherosperminine N-oxide Cory p a 1 mine 10-0-Dernethyldiscretine Discoguattine Discretamine Discretine Guacolidine Guacoline Guadiscidine Guadiscine Guadiscoline Isocal ycinine 10- 0-Methylhernovine 0-Methylpukateine Noratherosperminine Oxoisocalycinine Oxoputerine Puterine Reticuline Saxoguattine Xylopine

G. elata R.E. Fr. Norlaureline Oxolaureline

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

1. ALKALOIDS FROM GUAlTERIA 5

TABLE I (Continued)


Oxoputerine Puterine

G . gaumeri Greenm. Guattegaumerine = Malmea gaumeri (Greenm.) Lundell

G . goudotiana Tr. et PI. Deh ydroneolitsine Goudotianine 3-H ydroxynomuciferine 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

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

G . megalophylla Diels

G. melosma Diels

102 58 7

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 % 94

27 27 28

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

(continued)

6 ANDRk CAVE ETAL.

TABLE 1 (Continued)


G. modesru Diels

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

G. psilopus Mart.

G. sufordiunu Pittier

G. sagorinnu R.E. Fr.

Melosmidine Melosmine Oxoanolobine Pallidine Liriodenine Roemerine Corydine Coreximine Deh ydro formouregine Dehydronornuci ferine 10-0-Demethylxylopinine Dihydromelosmine Formouregine N-Formylnornuci ferine Gouregine Guattouregidine Guattouregine 3-Hydroxynornuciferine 3-Hydroxynuciferine Isopiline Lirinidine Lysicamine Melosmine 3-Methox ynuciferine 0-Methyldehydroisopiline N-Meth ylisopiline 0-Methy lisopiline 0-Methylmoschatoline Norcepharadione B Nornuciferine Nuciferine Ouregidione Oureguattidine Oureguattine Pentouregine Subsessiline Atherospemnidine Guatterine Lysicamine 0-Methylmoschatoline Anolobine Armepavine Dehydroroemerine Dehydrostephalagine Dragabine

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

1. ALKALOIDS FROM GUATTERIA 7

TABLE I (Continued)


G. scundens Ducke

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 X ylopine Xylopinine

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)


G. schomburgkiana Mart. Anolobine Anonaine Belemine Coreximine Cory dine

G. subsessilis

Corytenchine Dehydroguattescine N-Formy lputerine Guadiscine Guattescine lsoboldine Kikemanine Lanuginosine Liriodenine 0-Methylpukateine Norcor ydine Oxoputerine hter ine Reticuline Tetrahydropalmatine X y 1 opine X ylopinine Not studied"

53 50, 51 44 51

125 50. 51 32 51 78 52 35 51

59 51 117 50. 51

110 50. 51 116 50, 51 65 52 29 52

100 51 94 51, 52 60 51 77 52

102 51, 52 58 51, 52 3 52 30 51 54 51 36 51

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

TABLE I1 ALKALOIDS ISOLATED FROM Guarreria SPECIES

Struc- Molecular Alkaloid type and name ture formula (MW) Species Reference(s)

Benzylisoquinoline ( - )-N-Methylcoclaurine 1 C,,H2,N03 (299) G. sagotiana (+)-Annepavine 2 C,,H,,NO, (313) G. sagotiana (+)-Reticdine 3 CI9H2,NO, (329) G. chrysoperala

G. discolor G . goudoriana G . schomburgkiana

(+)-Codamine 4 C2,,H2,N0, (343) G. chrysoperala Juziphine 5 C,,H2,N03 (299) G. goudotiana

45 45 21 25 29 52 21 29

1. ALKALOIDS FROM GUA7TERlA 9

TABLE I1 (Continued)

StNC- Molecular Alkaloid type and name ture formula (MW) Species Reference(s)

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

( - )-Discretarnine ( - )-Corypalmine ( - )-Kikemanine (-)-Tetrahydropalmatine (-)- 10-0-Dernethyldiscretine ( -)-Coreximine

Berbine

( - ) -Discretine

(-)- 1 0-0-Dernethylxylopinine ( -)-Corytenchine ( - )-Xylopinine

Morphinandienone ( -)-Pallidineb

F'roaporphine ( - )-Glaziovine

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

33

34 35 36

37

38

G. discolor G . scandens

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

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

G . goudotiana G . melosma

G. sagotiana

25 25

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

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

29 33. 35

45

(continued)

10 ANDRE CAVE ETAL

TABLE I1 (Continued) ~~

StNC- Molecular Alkaloid type and name tufe formula (MW) Species Reference(s)

Aporphine sensu strict0 (- )-Lirinidine

( - )-Asimilobine ( - )-Nornuciferine

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

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

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

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

(-)-Xylopine

(- )-Norlaureline

(- bobovanine ( - )-Pukateine ( - )-F'uterine

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

39

40 41

42 43 44 45

46 47 48

49 50

51 52 53

54

55

56 57 58

59 60

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




(-)-Oureguattidine ( -)-Oureguattine ( -)-Elmerrillicine ( - )-N-Methylelmerrillicine (+)-Isoboldine

( + )-Norpredicentrine

( + )-Norisodomesticine ( + )-Laurotetanine ( + )-N-Methyllaurotetanine

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

(+)- 10- 0-Methylhernovine

Dehydronornuciferine Dehydroroemerine 0-Methyldehydroisopiline Deh ydro formouregine Dehydrostephalagine Dehydroneolitsine

7-Hydroxyaporphine ( - )-Pachyconfine (- )-Nuciferidine (-)-Noroliveroline ( - )-Oliveroline (-)-Oliveroline N-oxide ( - )-Guatterine

Dehydroaporphine

(-)-Guatterine N-oxide

61 62 63 64 65

66

67 68 69

70 71 72 73 74 75 76 77 78

79

80 81 82 83 84 85

86 87 88 89 90 91

92

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

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

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

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

39 45 39 39 45 29

45 45 45 45 45 43 45 45

(continued)

12 ANDRE CAVE ET AL.


Struc- Molecular Alkaloid type and name ture formula (MW) Species Reference(s)

Oxoaporphine Ly sicamine

Liriodenine

N,O-Dimethylliriodendronine Isomoschatoline

0-Methylmoschatoline

Atherospermidine Oxoanolobine

Lanuginosine

Oxolaureline

Oxoputerine

Subsessiline

Atheroline Dicentrinone Oxoisocalycinine

4,s-Dioxoaporphine Norcepharadione B Ouregidione

7-Alky laporphine Guadiscidine

93

94

95 96

97

98 99

100

101

102

103

104 105 106

107 108

109

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

G . ouregou G . ouregou

G . discolor

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

47 47 24

39 39

24




Guadiscine

Melosmine

Dihydromelosmine Melosmidine Guadiscoline ( - )-Guattescidine

( +)-Guattescine

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

110

111

112 113 114 115

116

117 118 119 120 121 122 123 124 125 126

127

128 129 130 131

132

133

134

135 136 137 138

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

G . ouregou

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

G. ouregou

G. sagotiana

G. dielsiana

G. dielsiana G . dielsiana G. dielsiana G . dielsiana

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

39, 42

24 25 24, 25 24. 25

38. 41

45, 46

22

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.

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

Isochondodendrine subtype

BERBINE TYPE

PROAPORPHINE TYPE

MORPHINANDIENONE TYPE

FIG. I . See legend on p. 14.

16

APORPHINOID TYPE

Aporphine sensu strict0 subtype Dehydroaporphine subtype

7-Hydroxyaporphine subtype

4,5-Dioxoaporphine subtype

0

Oxoaporphine subtype

7-Alkylaporphine subtype

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.

I . ALKALOIDS FROM GUATTERlA 19

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

HO

2 1

3 : R n H

4 : R r C .

I

2. Saxoguattine (6)

An aminoethylbenzil, saxoguattine (6), isolated from G. discolor (24) and G. scandens (24 ) , 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 rn lz 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 posi- tioning 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).


6 U O C H , 139 1 4 0

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 bisbenzylisoquinolines have 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)-berbamunine and (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 1,2- didehydro 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).

1 4 1 1 4 2

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-

1 5 : R r H

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 (31 ) . The mass spectrum of 2’-nortiliageine


(17) gave the molecular formula C,,H,,N,O, (mlz 594,58%). The base peak cor- responded to the singly charged bisisoquinoline ion (m lz 367), and another intense signal arose by loss of a hydrogen atom from the molecular ion (m lz 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 'H- NMR spectrum suggested that N-2' was the unmethylated one, on the basis of the complete assignment of the spectrum of antioquine (143) (61). Similarly,

1 4 3

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 Vol- ume 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

1 4 4

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 (31) .

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

2 2 : R = H

1 4 5

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


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 ether- linked 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 (32) , 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.

2 5 : R r H

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


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.

4 4 : R = H

45 : R = CHa


\

/ (TH 9

53 : R = H

5 4 : R r C y

OH

6 1 : R = H

62 : R CHI

5 5

OR

7 1 : R r H

72 : R CHI

Hs- (F 0

OR

7 4 : R = H

75 : R CHI

6 7 : R = H

70 : R = CH3

73


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 (39) .

Isocalycinine (74) and discoguattine (75) are the only two aporphines of Guat- reria 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. Deh y droaporphines (80 - 85)

Dehydrostephalagine (84), a “new” dehydroaporphine which was found in G. sagorianu ( 4 3 , does not require particular comment. Dehydronornuciferine (80) and O-methyldehydroisopiline (82) have been isolated from G. ouregou (39) , 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

R

ANDRE CAVE ETAL.

R

8 0 : R z H

82 : R z OCH, 81 : R z H

84 : R I OCH,

83 85

(82) was quite straightforward on the basis of their UV and ‘H-NMR spectra. Such dehydronoraporphines have 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-didehydronorapor- phine without a methyl group at C-7 is dehydroformouregine (83), from G. ouregou (39). Its structure was established spectroscopically and 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 (45) , 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.


8 6 : R z H

87 : R CHI

90

91 a 2

36 ANDRE CAVE ET AL

4. Oxoaporphines (93-106)

N.0-Dimethylliriodendronine (95), isolated in fairly large amounts from G . chrysopetala (21) , stands out among the oxoaporphine alkaloids found in Guat- teria in that it is a zwitterion related to the highly colored compounds of Glau- cium (Papaveraceae). Neutral and basic solutions of the rather insoluble N,O-

8 3

9 1

84

OR

9 9 : R r H

100 : R I CHa


1 0 1 1 0 2

Hac 0

0

OH

Ham 0

Haco 0 OH

105 104

OCHa

HaC (F 0

OH

1 0 1 1 0 6

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 ANDRE CAVE 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-alkylaporphinoids to 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).


1 0 9 : R = H

1 1 0 : R = CHI

bcmN H O

OH

1 1 1 : R I H

1 1 3 : R P C&

1 1 2 1 1 4

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 (mlz 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-6,6a- didehydroaporphines known to date. A total synthesis of N,O,O-trimethyltetra- hydromelosmine (146) has been reported, and the final compound was judged

40 ANDRE CAVE ETAL

1 4 6

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 acid- induced 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 4,5,6,6a- tetradehydroaporphine melosmine (1 1 l), 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 (25 ) .

Guadiscoline (114) differs from guadiscine (110) only in the presence of an additional methoxyl group at C- 1 1, 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 (l la), the first 7-hydroxy-7-methylaporphinoids to be described, were obtained initially from G. scandens (48), al-


OR

115 : R = H

116 : R = CHI

1 1 7

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 (50,51) , 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 weak- ness 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-didehydroaporphines found 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 (47 ,49) . 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 (49) . 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, 48) .

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-7- oxoaporphines (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 (49) . 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

1. ALKALOIDS FROM GUAlTERlA 43

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 0- demethyl 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, 51) , 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-didehydro- aporphine. 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

OR

125 : R x H

147 : R 4 CHS

1 2 4

OH

1 2 6

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

5 3

OH

1 2 5

OCH3 0 C H 3 ow3

1 4 0 1 4 7 1 1 7

SCHEME 1 . 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 0- methylbelemine (147) from anolobine (53), via isolaureline (148) (51) , 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). Dugues- pixine 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. 7- Formydehydronuciferine (149) was synthesized from nuciferine (43), and com-


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

4 3 1 4 9 123 : R = H 150 : R = 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 4.94 and 5.15 ppm, indicating the presence of a methyleneoxy bridge, and correspondingly lacked any downfield aryl proton resonance attributable to the nonexistent H-1 1 . 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 Annona- ceae. Four of them (128-131), already described from other Annonaceae species (8), were isolated from G. discolor (24, 25) .

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

1 3 2

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 gem- dimethyl 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 substituents on 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 . sago- fiana 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


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 ex- trusion of HCN was the main fragmentation process of the M - H and retro- Diels- 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 acid- induced 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 152 : R = CHI

151 : R = H 153 : R H

Once the structure of dragabine was established, its relationship to the relatively unstable nordragabine (151), isolated in trace amounts from Meiogyne vir- gum, became obvious (46). Shortly thereafter two minor constituents of Du- guetia 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


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 (46) . Spiguetine (152) appeared to give a very small negative optical rotation (76) , which may not be significant. Molecular models show that the biphenyl moiety of the azahomoaporphine ring 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 (46) .

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 An- nonaceae Cleistopholis patens (77) and Meiogyne virgatu (78), and later also from Annonu cherimolia (79) and A. huyesii (80). The latter species also contains the related annopholine (155). Annona ambotay (81) is the only known

1 3 4 1 5 4 1 5 5

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 (77) . 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-quinone structure. Complete assignment of its

50 ANDRE CAVE ET AL

IH- and 13C-NMR spectra 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,N- dimethylamino-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 C- methyl, 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 2- pyridinol 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-4- methyl-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-oxo- 1,2-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.

I . ALKALOIDS FROM GUA7TERlA 51

1 5 6 1 5 7

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 = H 137 : R = H 1 5 8

136 : R = OCHj 138 : R = OH

Onychine (135) was first described as a natural product in 1976, when its isolation from Onychoperalum amazonicum (Annonaceae) was reported (83) , and its structure was given as 4-methyl-1-azafluoren-9-one (158) on the basis of 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 UV 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 ANDRE CAVE 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). Neverthe- less, 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 (84) , 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-NMR spectra 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 0.1 1 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 (4.22 ppm) 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 (91) , 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 4.09 ppm (cf. 4.14 ppm 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 5- hydroxy-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. An- other 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 (Annona- ceae). 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-dioxygenation pattern 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,

1 . ALKALOIDS FROM GUATTERIA 55

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 (91 ) . 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, re-

ferred 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 (92 ) . This substance was shown to be 5,6- dimethoxy-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 (0.08 ppm) of one of the methoxyl groups (92 ) . 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 (91 ) .

& OCH3 OH

1 6 4 1 6 5

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


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 (91) 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 (83) , dielsine was described as 1-aza-4-methyl-2-0~0- 1,2- dihydrofluorenone 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) (90) . 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-7- hydroxyonychine (166) (90) . 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).


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).

1 6 8

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 12-0- methylation 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..

141 : R = H

169 : R = CH3

these could afford 12-0-demethylcoclobine (12) and coclobine (11) by 1,2- dehydrogenation 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 - 1 1 ’ 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-


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-norbisbenzylisoquinolines with 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. Accord- ing to biogenetic theory, this oxygenation pattern should arise by a dienol- benzene 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-didehydroaporphines as 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 di- methylaminoethyl 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

1 7 0 171

of Uvariopsis guineensis (Annonaceae) (100). It therefore seems reasonably certain that some members of this family are able to carry out Hofmann ring open- ings 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).


OH

1 1 1

on

1 3 2

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 H

173 : R = CH3

174 : R = H

175 : R = CHS

(?? \

133 : R = CH3

151 : R = 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 ex- ogenous 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 (An- nonaceae) (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 cooccurrence of oxoaporphines with 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


1 8 0

H XN 0"

1 8 1

/ L

1 5 4

NP 0

1 8 2

SCHEME 4.

1 3 5

NP 0

1 8 3

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 (Cazafluoren- 9-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 (22 ) , or by cyclization of a polyketide (92 ) . 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 (92 ) .

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 oxygena- tions 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 cleistopholine analogs 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 pseudo- base, 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 draw- back 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.


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

SPECIES OF Guurreriu (SUBGENUS Guurreriu)"

Section Fraction studiedb Species

Austroguatteria Dimorphopetalum Cordylocarpus Trichoclonia

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

Tylodiscus

Brachystemon Cephalocarpus Trichostemon Dolichocarpus Leiophyllum Megalophyllum

Mecocarpus

Dichrophyllum Stigmatoph yllum Chasmantha Undetermined Reclassified

0125 01 1 01 1 2/36

012 0118 1 I6 1/10 015 016 2/16

2/20

018 118 015 116 1 I2 212

2/18

111 01 1 012

G . ouregou Dun. G . psilopus Mart.

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

a 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-A- aporphinoids) (see Section V), which have only been found to date in the An- nonaceae, 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- 1 1. 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


in that they accumulate 6a,7-trans-7-hydroxyaporphines. These alkaloids, which 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 Poly- althia 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, Cepha- locarpus, Megalophyllum, Trichoclonia, Leiophyllum, Tylodiscus, and Sclero- phyllum, respectively. A similar situation persists even when the subgroups (7- methyl-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 An- nonaceae, 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. Consider- ing the biogenetic relationships (see Section V) between these alkaloids and the diazafluoranthene eupolauridine (183) of Cananga and Cleistopholis (Annona- ceae) 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 vir- gata (46) , in Guatreriu sugotiana (46) , 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 Du- guetia, 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 Guat- teria 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 ques- tions have been raised that require careful, comparable analyses of many species of Annonaceae. In particular, it will be interesting to investigate whether Guat- teria 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, i 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 An- nonaceae contain any 1-azaanthracenes or azafluo enes.

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.

From a chemosystematic viewpoint, much remai


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 Ec- uador 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 south- eastern 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 intracerebro- ventricular 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 con- vulsions 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 re- laxants; 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 d activities affecting the cardio- vascular system (hypotensive action) and the entral nervous system (neuro-

glaziovine (38) showed some activity in the b<B cell culture cytotoxicity assay (108). Moreover, glaziovine is a nondepresdant anxiolytic; it has neither anti- convulsant nor muscle-relaxing activities, is aqo devoid of analgesic, anesthetic, antimorphine, and antitryptamine activities, and at daily doses of 30-60 mg can be considered a useful antianxiety agent (109). In connection with this tranquilizing activity, glaziovine showed a clear antiulcer effect when given under various experimental conditions to laboratory animals with gastric ulcers (If 0) .

The pharmacology of aporphines has been reviewed (3). Their main activities affect dopaminergic neurotransmission, as was shown initially for apomorphine and later for a large number of natural and synthetic analogs. Neumeyer er al. have carried out a number of structure-activity analyses in this field, pointing out the importance of certain structural features (phenol function at C-1 I , configuration at C-6a) for the appearance of dopamine agonist or antagonist activities in aporphine derivatives ( I 11 ).

Among the 7-hydroxyaporphines, oliveroline (89) has been shown to display antiparkinsonian activity (112), presumably acting as a dopamine agonist. Re- garding the oxoaporphines, almost all the pharmacological studies published to date concern liriodenine (94), which is by far the most widespread alkaloid belonging to this class. Liriodenine has shown antitumor, antibacterial, and antifungal activities (113, 114). According to a 1986 report (115), oxoputerine (102) is also a potent bactericidal agent and exhibits remarkable activity against Candida albicans.

To the best of our knowledge, no pharmacological studies have been published regarding Guatreria alkaloids belonging to other structural types, namely 7-alkylaporphines, aminoethylphenanthrenes, azahomoaporphines, azaanthracenes, and azafluorenes. It was reported, however, that the azafluorene alkaloid onychine (135) exhibited significant activity against Candida albicans B3 1 1 in yeast nitrogen broth, and it was therefore considered potentially worthy of further development (88). Cleistopholine (154) has recently been shown to be a potent antibacterial agent (79). This activity presumably protects the plants which contain this alkaloid from attack by bacteria, adding to and perhaps potentiating the weaker actions of oxoaporphines such as the widespread liriodenine (94).

In conclusion, we must note the paradox that the only “Guatteria” which has been the object of reasonably thorough pharmacological studies, G. gaumeri, is

leptic, tranquilizing, and analgesic actions) 8 / (2). The proaporphine alkaloid


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 (I 18- 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 LIST OF 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 StNCture

12-0-Demethylcoclobine 12 10-0-Demethyldiscretine 31 10-0-Demethylxylopinine 34 Dicentrinone 105 Dielsine 137 Dielsinol 138 Dielsiquinone 134 Dihydromelosmine 112 0.0-Dimethylcurine 26 N,N-Dimethyllindoldhamine 7 0.N-Dimethylliriodendronine 95 Discoguattine 75 Discretamine 27 Discretine 33 Dragabine 133 Duguespixine 123 Elmerrillicine 63

N-Formy lnornuciferine 42

Glaziovine 38 Goudotianine 126 Gouregine 132 Guacolidine 121 Guacoline 122 Guadiscidine 109 Guadiscine 110 Guadiscoline 114 Guattamine 20 Guattaminone 23

Formouregine 51

N-Formylputerine 59

(continued)


TABLE IV (Continued)

Name Structure

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

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 Structure

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

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 .......................................................... 77 11. Occurrence ........................................................... 77

A. P-Phenethylamines

C. Ephedrines . . . . . . Ill. Isolation, Identification, IV. Synthesis ............................................................ I32

VI. Biological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 References ................. 144

B . P-Phenethylamine C . . . . . . . . . . . . . . . . . . . 78

V. Biosynthesis ......................... 137

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 to-

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

A, , _:-I.._ .̂- I__^ _I ...............

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 M I N E CONJUGATES AND 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

2. R-PHENETHYLAMINES AND EPHEDRINES 79

TABLE I OCCURRENCE OF ~PHENETHYLAMINES IN PLANTS

~~ ~~~ ~~

Molecular Compound Family Species 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.

Cornus sanguinea Ocotea pretiosa Acacia accola Acacia acinacea Acacia buxgolia Acacia cardiophylla

tartarica

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)


Loranthaceae

Malvaceae Musaceae Rosaceae

Saxifragaceae Solanaceae

Theaceae

N-Methylphenethylamine

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

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

2. f3-PHENETHYLAMINES AND EPHEDRINES 81

TABLE I (Continued)


NN-Dimethy lphen- ethylamine

Tyramine

Cactaceae

Chenopodiaceae

Leguminosae

Dolichothele sphaerica Dolichothele surculosa Gymnocactus

Gymnocactus beguinii Gymnocactus horripilis Gymnocactus knuthianus Gymnocactus

Gymnocactus roseanus

Gymnocactus viereckii Arthrophytum

leptocladum Acacia accola 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

aquirreanus

mandragora

var. el Chipon

5i 52 53

53 53 53. 54 53

53

53 55

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

Cactaceae Backebergia militaris Orchidaceae Eria jarensis

359 59

(continued)

82 JAN LUNDSTROM

TABLE I (Continued)


(Fungi)

Agavaceae Amaryllidaceae

Anacardiaceae Araceae Berberidaceae Bignoniaceae

Cactaceae

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 macro-

meris var. runyonii Coryphantha

missouriensis Echinopsis rhodotricha Espostoa huanucensis Gymnocalycium leeanum Isalya minor Lobivia alegriana Lobivia aurea Lobivia backebergii Lobivia binghamiana Lobivia huashua

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

2. p-PHENETHYLAMINES AND EPHEDRINES 83

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.

Opuntia stanlyi var.

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

Trichocereus candicans Trichocereus couranrii Trichocereus cuzcoensis Trichocereus fulvianus Trichocereus

knurhianus Trichocereus

macrogonus Trichocereus manguinii Trichocereus pachanoi

kunzei

stanlyi

camarguensis

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)


Caprifoliaceae

Chenopodiaceae

Compositae

Cruciferae

Cucurbitaceae

Cyperaceae

Geraniaceae Graminae

Juglandaceae Labiatae Lauraceae Leguminosae

Trichocereus pasacana Trichocereus peruvianus Trichocereus

Trichocereus

Trichocereus spachianus Trichocereus tunariensis Trichocereus

werdermannianus Sambucus canadensis Viburnum odoratissimum Beta vulgaris var.

Haloxylon salicornicum Spinacia oleracae Aster linariifolius Silyburn marianum Brassica oleracea Capsella bursapastoris Raphantus sativus Citrullus vulgaris Cucumis sativus Cyperus papyrus Mariscus jamaicensis Erodium cicutarium Hordeum vulgare Panicum miliaceum Zea mays Juglans nigra Lamium album Persea americana Acacia berlandieri Acacia greggi Acacia roemeriana Acacia texensis Calliandra

Cassia alata Cytisus scoparius Desmodium cephalotes Desmodium tiliaefolium Erythrina cristagalli

purpureopilosus

santiaguensis

cruenta

haematocephala

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

2. /3-PHENETHYLAMINES AND EPHEDRINES 85

TABLE I (Continued)


Liliaceae

Loranthaceae

Magnoliceae Musaceae Orchidaceae Papaveraceae Plumbaginaceae Ranunculaceae Rosaceae

Rutaceae

Solanaceae

Umbelliferae Vitaceae

Gleditsia triacanthos Phaseolus radiatus Pisum sativum Prosopis alba Prosopis glandulosa Prosopis nigra Trifolium alexandrinum Chlorophytum capense Cordyline terminalis Liriope spicata Phoradendron sp. Phoradendron

argentinurn Phoradendron fivescens Phoradendron hieronymi Phoradendron wattii Phoradendron liga Phoradendron villosum Phyrgilanthus Jagellaris Psittacanthus cuneifolius Viscum album Magnolia spp. Musa paradisica Cattleya spp. Chelidonium majus Limonium vulgare Aconitum napellus Prunus domestica Rubus idaeus Citrus limon Citrus medica X sinensis Citrus reshni Citrus reticulata Citrus reticulata X

Citrus sinensis Lycopersicon esculentum Nicotiana tabacum Solanum melongena Solanum tuberosum

sinensis

Daucus carota Vitis vinifera

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)


N-Methyltyramine

(Fungi) Boletus zelleri Polyporus spp.

Amaryllidaceae Amaryllis vittata Haemanthus katharinae Pancratium maritimum

Cactaceae 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 macro-


missouriensis Coryphantha ottonis Coryphantha pectinata Coryphantha radians Coryphantha ramillosa Dolichothele sphaerica Dolichothele surculosa Dolichothele uberiformis Echinocereus merkerii Espostoa huanucensis Gymnocactus

Gymnocactus beguinii Gymnocactus

aquirreanus

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

2. P-PHENETHYLAMINES AND EPHEDRINES 87

TABLE I (Continued)


Gymnocactus roseanus

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.

Opuntia stanlyi var.

Opuntia versicolor Pilosocereus m o n i i Solisia pectinata Stetsonia coryne Trichocereus

camarguensis Trichocereus candicans Trichocereus courantii Trichocereus fulvianus Trichocereus manguinii Trichocereus pasacana Trichocereus

Trichocereus

Trichocereus spachianus Trichocereus thelegonus

Haloxylon salicornicum

var. el Chijlon

kunzei

stanlyi

purpureopilosus

schickendantzii

Chenopodiaceae Anabasis jarartica

Euphorbiaceae Croton humilis Gramineae Hordeum vulgare

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)


Leguminosae

Rutaceae

Hordenine

(Algae) (Fungi)

Amaryllidaceae

Beberidaceae Cactaceae

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

HO pL* 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

138 96. 139 57, 58 56 56 34, 35 161, 162 56 119. 120 120 45 45

C10H15N0

140 60 60 141 60 25 64, 65 142 143 144 45 80 122

122

123

124 125

126 67 68 68 68, 70


TABLE I (Continued)


Coryphantha bumamma Coryphantha cornifera



elephanatidens Coryphantha

greenwoodii Coyphanrha macro-


missouriensis Coryphantha ottonis Coryphantha pectinata Coryphantha

Coryphantha radians Coryphantha ramillosa Coryphantha vivipara Coryphantha vivipara

Dolichothele surculosa Dolichothele Uberiformis

Echinocereus merkerii Echinopsis eyriesii Echinopsis rhodotricha Gymnocactus

Gymnocactus beguinii Gymnocactus horripilis Gymnocactus roseanus

Gymnocalycium leeanum Gymnocalycium

Helianthocereus huascha Helianthocereus

pasacana lslaya minor Lobivia alegriana Lobivia aurea Lobivia backebergii

poselgeriana

var. arizonica

aquirreanus

var. el Chifon

schickendantzii

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) ~ ~~


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

Opuntia aurantiaca Opunria clavata Opuntia invicta Opuntia maldonensis Opuntia schottii Opuntia versicolor Opuntia vulgaris Pelecyphora aselliformis Pelecyphora

Solisia pectinata Trichocereus candicans Trichocereus

Trichocereus pachanoi Trichocereus

Trichocereus

Trichocereus skottsbergii Trichocereus spachianus Trichocereus striogosus Trichocereus

Trichocereus thelegonus Trichocereus

Trichocereus tunariensis Turbinicarpus pseudo-

Wigginsia erinacea Wigginsia macrocantha Wigginsia tephracantha

pseudopectinata

lamprochlorus

santiaguensis

schickendantzii

taquimbalensis

thelegonoides

macrochele

Cannabinaceae Cannabis saliva Euphorbiaceae Securinega virosa

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

2.8-PHENETHYLAMINES AND EPHEDRINES 91

TABLE I (Continued)


Graminae Andropogon sorghum Hordeum murinum Hordeum vulgare Panicum miliaceum Phalaris arundinacea Sorghum vulgare Triticum vulgare

Leguminosae Acacia berlandieri Acacia harpophylla Acacia holocerica Acacia spriorbis Alhagi pseudalhagi Desmodium cephalotes Desmodium Jloribundum Desmodium gangeticum Desmodium rriforum

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

Liliaceae Eremurus regelii 163 Loranthaceae Phoradendron J7avescens 40, 41 Nandinaceae Nandina domestica 45 Polygonaceae Eriogonum alarum 423

Candicine

Eriogonum annuum Eriogonum

campanulatum Eriogonum influrum

Ranunculaceae Aconitum tanguticum Rutaceae Citrus reshni

Citrus reticulata Teclea simplicifolia

Cactaceae Cereus aerhiops Gymnocalycium

Lophophora williamsii Trichocereus candicans Trichocereus chilensis Trichocereus

Trichocereus pasacana Trichocereus spachianus

schickendantzii

lamprochlorus

423 423

423 157 45 45 164

67 67

165 74. 167 168 169

88 74

(continued)

92 JAN LUNDSTROM

TABLE I (Continued)


4-Methoxyphen- ethylamine

Leguminosae Desmodium cephalotes 36 Desmodium gangeticum I61 ~ I62

Rutaceae Fagara spp. 187, I88 Phellodendron amurense 159 Zanthoxylum clava- 170. 171

Magnoliaceae Magnolia spp. 110-113

herculis

Cactaceae

Ericaceae

N-Methyl-4-methoxyphenethylamine

9H I 3 No

M e 0

Coryphantha cornifera Coryphantha ottonis Coryphantha

poselgeriana Erica lusitania

Cactaceae Ariocarpus retusus (Anhalonium prismaticum)

Coryphantha bumamma Coryphantha cornifera Coryphantha cornifera



meris var. runyonii Coryphantha ramillosa Dolichothele uberiformis

Eriogonum annuum Eriogonum

campanulatum Eriogonum inflatum

Polygonaceae Eriogonum alatum

129 129 I29

172

124. I73

128. 145 I29 129

I29

147

I33 136 423 423 423

423

2. P-PHENETHYLMNES AND EPHEDRINES 93

TABLE I (Continued)


N,N-Dimethyl-4-methoxyphenethylamine

0-Methylcandicine

Dopamine

Epinine

M P N M . ,

Rutaceae Teclea simplicifolia

Cactaceae Coryphantha greenwoodii

(Algae) Annonaceae Cactaceae

Chenopodiaceae

Lauraceae Leguminosae

Musaceae Nyctaginaceae Piperaceae Portulaceae Ranunculaceae Solanaceae Verbenaceae

HO " O V N H 2

Monosioma fuscwn Annona reticulata Carnegiea gigantea Lophoeereus schoitii Lophophora williamsii Beta vulgaris Spinacia oleracea Persea americana Cyiisus scoparius E n i d pursaetha

(glucoside) Spartiwn scopariwn Musa paradisica Hermidiurn alipes Piper amalago Portulaca oleracea Aconiium napellus Solanum iuberosurn Stachytarpheta

jamaicensis

164

166

174 175 6 , 7 177 176 178, 179 90. 180 90 102 181

182 45, 90 183 109 8 117 90, 121 109

(coniinued)

94 JAN LUNDSTROM

TABLE I (Continued)

Molecular Compound Family Species formula Referenceb)

Coryneine

3-Methoxytyramine

Cactaceae Lophophora williamsii Leguminosae Cytisus scoparius

Spartiurn scoparium Vicia faba

" W Y M . , HO

Cactaceae Sfetsonia coryne Leguminosae Alhagi pseudalhagi

Rutaceae Fagara hyemalis Desmodium friflorum

Fagara spp.

Cactaceae Backebergia rnilitaris Carnegiea giganfea Echinocereus merkerii Islaya minor Lophophora williamsii Opunfia imbricafa Opunfia spinosior Opuntia subulafa Pachycereus pecten-

aboriginum Pereskia corrugara Pereskia grandifolia Pereskiopsis chapistle Sfetsonia coryne Trichocereus bridgesii Trichocereus

Trichocereus courantii Trichocereus cuzcoensis Trichocereus knufhianus Trichocereus

Trichocereus pachanoi

camarguensis

macrogonus

i76 i02 182 184

185, I86 34, 35 38 187 187, I88

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

27 27 27 73. I85 68 68

73 73 73 68

68, 87, I94


TABLE I (Conrinued)


N-Methyl-3- methoxytyramine

N,N-Dimethyl-3- methoxytyramine

Salicifoline

Cactaceae

Cactaceae Magnoliaceae

Magnoliaceae

2-Methox ytyramine

Cactaceae

Trichocereus peruvianus Trichocereus

Trichocereus raquirnbalensis

werdermannianus

Pilosocereus maxonii Trichocereus courantii

Ariocarpus agavoides Magnolia sprengeri

MeO H o p y M e ,

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

OMe

HO P N H .

Trichocereus courantii

68, I95 73

87

86 73

80 I56

I% 111 I97 200 I98 110-113 I99 113

73

(continued)

96 JAN LUNDSTROM

TABLE I (Continued)


Homoveratrylamine (3,4-dimethoxy-P- phenethylamine)

Cactaceae Backebergia militaris Carnegiea gigantea Echinocereus merkerii lslaya minor Lophophora williamsii Melocactus maxonii Neoraimondia are-

quipensis var. rosiflora

Opuntia acanthocarpa Opuntia echinocarpa Opuntia imbricata Opuntia spinosior Opuntia whipplei Pachycereus pecten-

aboriginum 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

Trichocereus courantii Trichocereus

Trichocereus pachanoi

camarguensis

macrogonus

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


TABLE I (Continued)


N-Methylhomo- veratrylamine


Trichocereus taquimbalensis

werdertnannianus Leguminosae Desmodium tiliaefolium

MeO

MeO V N H M e

Cac taceae Ariocarpus agavoides A riocarpus jissuratus

var. jissuratus Ariocarpus retusus A riocarpus

schapharostrus Ariocarpus trigonus Backebergia militaris Coryphantha bumamma Coryphantha calipensis Coryphqntha cornifera Coryphantha cornifera





missouriensis Coryphantha pectinata Dolichothele uberiformis Echinocereus

cinerascens Echinocereus merkerii Lophophora williamsii Mamillaria heyderii Pelecyphora aselliformis Pilosocereus

chrysocanthus

68, 195 73

87

103

I I 17N02

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

Pilosocereus guerreronis 206

(continued)

98 JAN LUNDSTROM

TABLE I (Continued)


N,N-Dimethylhomo- veratrylamine

3.4-Dihydroxy-5-methoxyphenethylamine

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

Cactaceae

Leguminosae

Cactaceae

Cactaceae

N-Methyl-3,4-dimeth- ox y-5-hydrox yphen- ethylamine

A riocarpus schapharostrus

Backebergia rnilitaris Coryphantha calipensis Coryphantha

Echinocereus merkerii Pilosocereus guerreronis Desmodium tiliaefoliurn

greenwoodii

Lophophora williamsii

OH

Lophophora williamsii Trichocereus cuzcoensis Trichocereus pachanoi

12H19N02

125

359 127, 128 128, 146

137 206 103

C9H 13 NO3

I 76

, O H I5

176. 214 73 87, 213

Cactaceae Lophophora williarnsii 176


TABLE I (Continued)


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

3,5-Dimethoxy-4-hydroxyphenethylamine

Mescaline

M e o p N M e 2 C12H,9N03

M f O on

Cactaceae Lophophora williamsii 176 Pelecyphora aselliformis 73, 135

"&VNH* C10H,5N03

HO OMe

Cactaceae Escontria chiotilla Melocactus maronii Neoraimondia arequi-

pensis 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

I I 17

OMe

420 420 420

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

Cactaceae Gymnocactus gibbosum 75 Gymnocalycium leeanum 70, 75 Lophophora diffusa 357

(continued)

100 JAN LUNDSTROM

TABLE I (Continued)


N-Methylmescaline

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

Trichocereus pachanoi macrogonus


taquimbalensis Trichocereus terscheckii Trichocereus validus Trichocereus

werdermannianus

M e o v H M e M e 0

OMe

CaCtaceae Lophophora williamsii

Leguminosae Alhagi pseudalhagi Pelecyphora aselliformis

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

210 73, 135 34. 35

2. p-PHENETHYLAMINES AND EPHEDRINES 101

TABLE I (Continued)


Trichocereine

Cactaceae

(R)-( - )-Halostachine

Ubine

M e o T N M e 2 C13H21N03

MeO OMe

Trichocereus terscheckii 211, 212

Chenopodiaceae Halostachys caspica 215

Cactaceae

(S)-( +)-Coryphanthine

Cactaceae

(R)-( - )-Octopamine

Dolichothele uberiformis

Coryphanrha greenwoodii

Amaryllidaceae Amaryllis vittata Cyperaceae Cyperus papyrus

Cyperus rotundus Graminae Lolium multijlorum

Lolium spp. Liliaceae Liriope spicata Rutaceae Citrus Iimon

Citrus medica X sinensis Citrus reshni Citrus reticulata Citrus reticulata X

sinensis Solanaceae Capsicum frutescens

I36

166

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

45

(continued)

102 JAN LUNDSTROM

TABLE I (Continued)

Molecular Compound Family Species formula Reference@)

S ynephrine

Amaryllidaceae

Cactaceae

Chenopodiaceae Moraceae Rutaceae

P- 0-Methylsynephrine

?H

Amaryllis vittata Eucharis grandifora Haemanthus katharinae Coryphantha cornifera Coryphantha cornifera



elephanatidens Coryphantha

greenwoodii Coryphantha macro-

meris var. runyonii Coryphantha ottonis Coryphantha pectinata Coryphantha

Coryphantha ramillosa Dolichothele

Dolichothele sphaerica Dolichothele surculosa Dolichothele uberiformis Mamillaria elongata Haloxylon salicornicum Ficus bengalensis Citrus limon Citrus medica X sinensis Citrus reshni Citrus reticulata Citrus reticulata X

Citrus sinensis

poselgeriana

longimamma

sinensis

C9H13N02

10H1SN02

HO

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


TABLE 1 (Continued)


4-Methoxy-P-hydrox y- phenethylarnine

Longimammamine

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

Cactaceae Coryphantha cornifera Coryphantha cornifera

Coryphantha

Coryphantha pectinata Coryphantha ramillosa Dolichothele sphaerica Mamillaria elongata

var. echinus

greenwoodii

Rutaceae “Dancy” mandarin

129 I29

128. 146

54. I29 133 51 151 218

C9H13N02

Cactaceae Coryphantha cornifera 129 Coryphantha cornifera


elephanatidem Coryphantha pectinata Pereskia godsefiana Pereskia tampicana

Cactaceae Dolichothele longimamma

Cactaceae Coryphantha macromeris var. runyonii

Hydrastinaceae Hydrastis canadensis Legurninosae Albizzia julibrissin

Mimosa pudica

129

129

54, 129 27 27

217

331

220 105 I05

(continued)

1 04 JAN LUNDSTROM

TABLE I (Continued)

Compound Family Molecular

Species formula Reference(s)

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

(R)-( - )-N-Methyl- epinephrine (N-methyl- adrenaline)

(R)-( -)-Metanephrine

(R)- ( -)-N-Methyl- metanephrine

Musaceae

Passi floraceae

Portulaceae Ranunculaceae

Rosaceae Rutaceae Solanaceae

Phaseolus multiporus Pisum sativum Samanea samam Musa paradisica

Musa sapientum Passip ora

quadrang ularis Portulaca oleracea Aconitum napellus Aconitum paniculatum Prunus domestica Citrus sinensis Solanum tuberosum


' O f l N M e , HO

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

8 117. 223 223 90 45, 90 90, 121

C'3H13N03

33 I

C10H15N03

Ranunculaceae Aconitum nasutum 224

C10H15N03

NHMe


1 I 17N03

M a f l N M e 2 HO

147


TABLE I (Continued)


(R)-( - )-Normacromerine

(R)-( - )-Macromerine

(R)-( - )-Calipamine

Cactaceae Coryphanrha macromeris var. runyonii

Cactaceae Coryphanrha calipensis Coryphantha

Coryphantha macro-

Dolichothele

Dolichorhele uberiformis

greenwoodii

meris var. runyonii

longimamma

C12H19N03

MeO

Cactaceae Coryphonrha cornifera var. echinus

Coryphanrha elephanaridens

coryphantha macromeris

Coryphanrha macromeris var. runyonii

Coryphantha pectinata

l Z H

MeO

Cactaceae Coryphantha calipensis

Coryphanrha greenwoodii

147

127, 128 128. 146

225

52, 217

68, 136

129

129

226, 227

225

54, 129

127. 128, 228 128. 147

(R)-( -)-N-Methyl- 1 3 H Z l N 0 3

calipamine M e O d i M e . MeO

(continued)

106 JAN LUNDSTROM

TABLE 1 (Conzinued)


3-Nitro-4-hydroxyphenethylamine

Cactaceae Coryphantha calipensis 128. 146

HO C*H,ON*O,

Cactaceae Cereus validus 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 N- methylpseudoephedrine 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 ~HENETHYLAMINE ALKALOIDS IN FOOD PLANTS

N-Methyl- Horde- Octop- Syneph- Dopa- Norepi- Family and species Common name Tyramine tyramine nine amine rine mine nephrine Reference(s)

Araceae

Chenopodiaceae Colocasia antiquorum Elephant ear

Beta vulgaris var. cruenta Spinacia oleracea Spinach

Red beet

Cruciferae Brassica oleracea

Raphantus sativus

Cucurbitaceae Citrullus vulgaris Cucumis sativus

Persea americana Lauraceae

84

160 0-680

Cabbage 0

Cauliflower 400 Radish (root) 0

200

440-800

Watermelon 460 Cucumber 250

Avocado pear 23 Musaceae

Musa paradisica Banana (peel) 65 Banana (pulp) I

0

45

360 90

45 360 360 45 360

360 360

4-5 0 90

700 122 90 8 2 90

(continued)


N-Methyl- Horde- Octop- Syneph- Dopa- Norepi- Family and species Common name Tyramine tyramine nine amine rine mine nephrine Reference(s)

Rutaceae Citrus reticulata Tangerine (leaf) 11

Tangerine (fruit) I

Cleopatra mandarin < I

Cleopatra mandarin 28 (leaf)

( h i t ) Citrus sinensis Orange (leaf) 6

Orange (fruit) Solanaceae

Lycopersicon esculentum Tomato (fruit) 51 Solanum melongera Eggplant 0.5-3 Solanum tuberosum Potato 1

Potato (tuber) 560-1300 Umbelliferae

Vitaceae Daucus carota Carrot 0-230

Vitis vinifera Grape 0 240-1400

19 - 24 203 1 15 - I 125 31 8 12 2215

58 7 2 280

0 0

45 45 45

45

45 45

0 45, 90 0 45, 90

45 0 0.1-2 90,360

45.360

361 0 90

2. @-PHENETHYLAMINES AND EPHEDRINES 109

TABLE I11 OCCURRENCE OF P-PHENETHYLAMINE CONJUGATES AND RELATED C O M ~ U N D S IN PLANTS


N-P-Phenethyl- 17N0 m N p cinnamamide

0

Compositae Spilunrhes ocymifoliu 229

(E)-3,4-Dioxymethylene- ISH 17N03 cinnamic acid P-phenethylamide

0

(2)-3 ,CDioxymethylene- cinnamic acid P-phenethylamide

N- Acetyltyramine

Compositae Crironiellu ucuminura

Compositae Critoniellu ucuminuru

422

422

(Fungi) Srrepromyces griseus 230

UN02 N-Benzoy ltyramine

HO 0

Rutaceae Cusimiroa edulis (Santhalaceae)

23 I

N-Cinnamoyltyramine C17H17N02

HO 0

Rutaceae Evodiu beluhe 232

(continued)

TABLE 111 (Continued)


N-Benzoyl-0- methyltyramine

Alatamide

Herclavine

N-Homoveratroyl- homoveratrylamine

Rubescamide

N-Formyl-3,Cdimeth- oxy-5-hydroxyphenethylamine

N-Acetyl-3 ,Cdimeth- oxy-5-hydroxyphenethy lamine

MeO DNfl 0

Rutaceae Pleiospermium alatum

MeO DN> 0

Rutaceae Pleiospermium alarum

MeO mNp 0

Rutaceae Zanthoxylum clava- herculis

M e 0

OMe

Rutaceae Pleiospermium alatum

Rutaceae Fagura rubescens

Cactaceae Lophophoru williamsii

MeO

MeO w N y M e

OH 0

243

243

170

238

239

240

I10

TABLE Ill (Continued)


N-Formylmescaline

N- Acetylmescaline

Mescaline succinimide

Mescaline malimide

Mescaline citrimide

Mescaline maleimide

Mescaline isocitrimide lactone

Cactaceae Lophophora williamsii 240

: p N y " 1 Z H 17N04

OMe 0

Cactaceae Lophophora williamsii


ISH

OMe


ISH

OH


17'21

CH,COOH

240

241, 240

240

240


I S H 17N05

Me0 OMe -


C 1 7 H

0


(continued)

1 1 1

112 IAN LUNDSTROM



Peyonine MeO MeOyp 'Me 0""

Peyoglunal

Tembamide

Aegelin

Annuloline

Cactaceae Lophophora williarnsii

MeO

Cactaceae Lophophora williarnsii

OH

MeO mN& 0

Rutaceae Aegle rnarmelos Clausena brevistyla Fagara hyemalis Fagara spp. Znnthoxylum

conspersipunctaturn

MeO dHp 0

Rutaceae Aegle rnarmelos

.OMe

Meo w s C H = \ / C H a O M e

Graminae Loliurn rnultiporurn

N-Formylnormacromerine

MeO Meo&yH

0


254

C17H21N05

242

16H 17N03

233 234 235 187 236

C18H19N03

233, 237

2OH2ONo4

244

C12H17N04

147

2. fl-PHENETHYLAMINES AND EPHEDRINES 113

TABLE IV OCCURRENCE OF EPHEDRINES IN PLANTS


( 1 R , 2 9 4 -)-Norephedrine C9H

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

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

Celastraceae Carha edulis Ephedraceae Ephedra distachya

Ephedra equisetina Ephedra gerardiana Ephedra intermedia Ephedra procera Ephedra regeliana Ephedra sinica Ephedra tweediana Ephedra vulgaris

Celastraceae Catha edulis Ephedraceae Ephedra distachya

Ephedra equisetina Ephedra gerardiana Ephedra intermedia Ephedra procera Ephedra regeliana Ephedra sinica Ephedra tweediana

Araceae Pinellia ternara Celastraceae Catha edulis Ephedraceae Ephedra alata

Ephedra altissima Ephedra americana Ephedra andina Ephedra californica Ephedra distachya

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

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

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

~~

(continued)



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

Ephedra equisetina Ephedra fragilis Ephedra gerardiana Ephedra gerardiana

var. sikkimensis Ephedra gracilis Ephedra helvetica Ephedra intermedia

Ephedra

Ephedra

Ephedra

Ephedra nevadensis Ephedra

pachyclada Ephedra procera Ephedra regeliana Ephedra sinica

monosperma

monostachya

nebrodensis

Ephedra triandra Ephedra trifurca Ephedra tweediana Ephedra vulgaris

Sida cordifolia Sida sp.

Malvaceae Sida acuta

Papaveraceae Roemeria refracta Ranunculaceae Aconitum napellus Taxaceae Taus baccata

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

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

3. 258 3, 258 3, 251, 253.

258 258. 259, 262

258

3, 251. 258,263

3, 258. 264 3, 259

3, 253, 258, 259 253 3, 253. 257.

3 , 258 258 3, 253, 258 258 295 . 44. 298 266 267 268 269

258, 259. 355

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

1 I4



(1R,2S)-( -)-N-Methyl- ephedrine

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

Ephedra helverica Ephedra intermedia

Ephedra major Ephedra

monosperma Ephedra

monostachya Ephedra

nebrodensis Ephedra nebroden-

sis var. procera Ephedra

pachyclada Ephedra procera Ephedra regeliana Ephedra sinica

Ephedra trifurca Ephedra lweediana Ephedra viridis Ephedra vulgaris

Mafvaceae Sida cordifoIia Papaveraceae Roemeria rejiacta

3. 258 3. 251, 258.

270 258

259, 253, 262

258

3, 251, 258.263

251

3, 259

3, 253, 258, 259 253 3, 253, 257,

258 3. 253, 258 258 258 44 267

258, 259, 355

Ephedraceae Ephedra gerardiana 25 1

Ephedra intermedia 251 Ephedra major 270 Ephedra nebroden- 251

Ephedra sinica 258, 259, 355 Ephedra vulgaris 258

var. sikkimemis

sis var. procera

Ephedraceae Ephedra sinica 258, 259

(continued)

115

TABLE IV (Continued) ~~~ ~


(lS,2S)-( +)-0-Benzoyl- pseudoephedrine

C17H19N0

Ephedraceae Ephedra sp. 271

Ephedroxane (4S,SR)

Ephedraceae Ephedra intermedia 2 72

Ephedralone

Ephedraceae Ephedra alata 2 73

(94- )-Cathinone

(E)-(3S,4S)-Pseudo- merucathine

(E)-( S)-Merucathinone

Celastraceae Catha edulis 245-247

Celastraceae Carha edulis 274, 407, 409

Celastraceae Carha edulis 407, 409

Celastraceae Catha edulis 274, 407, 408

116

TABLE V PLANTS CONTAINING PHENETHYLAMINES AND EPHEDRINES

Family and species Alkaloid" Reference( s)

(Algae) Ceranium ruburum Cystodonium purpureum Desmarestia aculeata Dumontia incrassata Monostoma fuscum Phyllophora nervosa (DC.) Grev. Polyides rotundus Polysiphonia urceolata

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

Cordulinae terminalis

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. Ungernia ferganica Vved. Ungernia trisphaera Bnge. Ungernia victoris Vved.

(Fungi)

Agavaceae

Amary llidaceae

Phe Phe Phe Phe

Hord Phe Phe

DOP

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

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

TYr

TY

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

i3 i3 13 13 I 74 140 13 13

14 15 10 60 17. 61 18

' 62 19 60 20 21 21 22 21 21 21 141 23 60 230

45

45 45 45 63 45 45 45 45 25 64. 65 142 143 144

\ I

(continued)

117

118 JAN LUNDSTROM

TABLE V (Continued)

Family and species Alkaloid" Reference(s)

Anacardiaceae

Annonaceae

Araceae

Schinus terebinthifolius Raddi.

Annona reticulata L.

Arum maculatum L. Colocasia anriquorum Schott Pinellia ternata Breit.

Vinceroxum oficinale

Nandina domesrica Thunb.

Jacaranda acutifolia Humb. et Bonpl. Pyrostegia ignea Presl.

Ariocarpus agavoides (Castefiada)

Ariocarpus jssuratus var. jssuratus

Ariocarpus jssuratus var. lloydii

Ariocarpus kotschoubeyanus (Lem.)

Ariocarpus retusus Scheid.

Ariocarpus schapharosrrus Boed.

Asclepiadaceae

Berberidaceae

Bignoniaceae

Cactaceae

E. F. Anderson

(Engelm.) Schum.

(Rose) Marsh.

Schum.

(Anhalonium prismaricum Lem.)

Ariocarpus trigonus (Web.) Schum. Azureocereus ayacuchensis Johns. Eackebergia militaris (Andot) Bravo

Carnegiea gigantea (Engelm.)

Cereus aethiops Haw. Cereus alacriportanus Pfeiff. Cereus forbesii 0. Cereus glaucus SD. Cereus jamcaru DC . Cereus peruvianus (L.) Mil l . Cereus peruvianus monstruosus DC. Cereus validus Haw. Coryphantha bumamma (Ehren.)

ex Sanches Mejorada

Br. et R.

Br. et R.

Phe TYr EPh

Phe

Tyr, Hord

Hord, N-Me-Homova,

Hord, N-Me-Tyr N-Me-Homova Hord, N-Me-Tyr

N,N-diMe-3-MeO-Tyr

Hord, N-Me-Tyr

Hord, N-Me-Tyr N-Me-4-MeO-Phe, N-Me-Homova Hord, N-Me-Tyr, N-Me-Homova,

H o d , N-Me-Tyr, N-Me-Homova

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

3-MeO-Tyr, Homova, Dop

Tyr, Hod, candicine Hord

Tyr, Hord

Tyr, Hord

3-N02-Tyr Hord, N-Me4-MeO-Phe, N-Me-

Homova

N,N-diMe-Homova

TYr

TYr

TYr

S r

45

175

26 45 256

21

45

45 45

80

122 204 122

123

124 173 125

126 66 189, 190,

6, 7, 191

67 68 68 68 69 68. 70 68 300 128, 145

201. 359


TABLE V (Continued)

Family and species Alkaloid' Reference( s)

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.)

Coryphantha macromeris var. Lem.

runyonii L. Benson

Coryphantha missouriensis (Sweet)

Coryphantha ottonis (Pfeiff.) Lem.

Coryphanrha pectlnara (Engelm.)

Br. et R.

Br. et R.

Coryphanrha poselgeriana (Dietr.)

Coryphantha radians (DC.) Br. et R. Coryphantha ramillosa Cutak.

Br. et R.

Coryphantha vivipara (Nutt.)

Coryphanrha vivipara (Nutt.) Engelm.

Br. et R . var. arizonica (Engelm.) W. T. Marshall

Br. et R. Dolichothele longimamma (DC.)

N-Me-Tyr, Hord, N-Me-Homova, 127. 128, N,N-diMe-Homova, nor-Macr, 146. 228 calipamine, N-methylsalipamine

4-MeO-P-OH-Phe, Synephr, p-0- Me-Synephr

N-Me-Homova, 4-MeO-p-OH-Phe, Synephr, p-0-Me-Synephr, Macr

4-MeO-Phe, Hord, N-Me-Homova, 129

N-Me-Tyr, H o d , N-Me-4-MeO-Phe, 129

Hord, N-Me-Homova, Synephr 129

N-Me-Tyr, Hord, N-Me-Homova, N- 129 Me-4-MeO-Phe, 4-MeO-p-OH- Phe, Synephr, Macr

Hord, N-Me-Homova, N,N-diMe- 128, 146, Homova, 0-Mecandicine, p-0- 166 Me-Synephr, Synephr, nor-Macr, calipamine, N-Me-calipamine

Macr 226, 227

Tyr, N-Me-Tyr, Hord, N-Me-4-MeO- Phe, N-Me-Homova, Synephr, 147. 225 metanephrine, N-methylmetanephrine, nor-Macr, Macr, N-formyl- nor-Macr -

68. 70. 130,

Tyr, N-Me-Tyr, Hord, N-Me-Homova 72

N-Me-Tyr, Hord, 4-MeO-Phe, 129

N-Me-Tyr, Hord, N-Me-Homova, 54. 129 Synephr

4-MeO-p-OH-Phe, Synephr, p-0- Me-Synephr

Synephr N-Me-Tyr, Hord, 4-MeO-Phe, 129

N-Me-Tyr, Hord 128 N-Me-Tyr, Hord, N-Me-4-MeO-Phe, 133

Hord 128. 148 Synephr, P-0-Me-Synephr

Hord 149

Synephr, nor-Macr, longimammamine 52, 21 7

(continued)

120 JAN LUNDSTROM

TABLE V (Continued)

Family and species Alkaloid (1 Reference(s)

Dolichothele sphaerica (Dietr.)

Dolichothele surculosa (Boed.)

Dolichothele uberiformis (Zucc.)

Br. et R.

F. Buxb.

Br. et R.

Echinocereus cinerascens (DC. )

Echinocereus merkerii Hildm. Riimpler

Echinopsis eyriesii (Turpin) Zucc. Echinopsis rhodotricha K. Schum. Escontria chiotilla (Web.) Rose Esposroa huanucensis Ritt. Gymnocactus aquirreanus Glass et

Gymnocactus beguinii (Web.)

Gymnocactus horripilus (Lem. )

Gvmnocactus knurhianus (Boed. )

Gymnocactus mandragora (Fric.)

Gymnocactus roseanus var. el Chifon Gymnocactus viereckii (Werd. )

Gymnocactus gibbosum (Haw.) Pfeiff. Gymnocalycium leeanum (Hook.)

Gymnocalycium schickendantzii

Helianthocereus huascha (Web.)

Helianrhocereus pasacana (Web. )

Islaya minor Backbg.

Foster

Backbg .

Backbg .

Backbg .

Backbg.

Backbg.

Br. et R.

(Web.) Br. et R.

Backbg.

Backbg.

Lobivia alegriana Backbg. Lobivia aurea (Br. et R.) Backbg. Lobivia backebergii (Werd.) Backbg. Lobivia binghamiana Backbg. Lobivia huashua (Web.)

Lobivia penrlandii (Hook.) Br. et R. W. T. Marshall

N-Me-Phe, N-Me-Tyr, Synephr, p-0-

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

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

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

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

Hord Tyr, Hord 3.5-DiMe0-4-OH-Phe Tyr, N-Me-Tyr, Hord N-Me-Phe, N-Me-Tyr, Hord

Homova, N,N-diMe-Homova

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

N-Me-Phe, Hord

N-Me-Phe

N-Me-Phe, N-Me-Tyr

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

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

Hord, candicine

Hord

Hord

Phe, Tyr, N-Me-Tyr, Hord, 3-Me0-

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

Tyr, N-Me-Tyr, Hord

Tyr, Homova, Mesc

51

52

68, 84, 136

205

137

68 73 420 74, I38 53

53

53

53, 54

53

53 53

75 70, 75

67

68

68

27

76 76 76 76 76

76


TABLE V (Continued)


Lophocereus schorrii (Engelm.)

Lophophoru drfusu (Croizat)

Lophophoru echinutu Lophophoru wifliumsii (Lem.) Coult.

Br. et R.

H. Bravo

Mumillaria elongura DC.

Mumilluriu heyderii Muhl. Mumilluriu microcurpa Engelm. Melocactus delesserriunus Lem. Melocactus muxonii (Rose) Giirke

Neoruimondiu orequipensis var.

Norocactus otronis (Lem.) Berg. ex

Obregoniu denegrii Fric. Opunriu ucunrhocurpu Engelm. et

Opuntiu aurantiucu Lindley Opunriu busiluriu Engelm. et Bigel. Opunriu cluvutu Engelm. Opunriu echinocurpa Engelm. et

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.

ros$oru (Werd. et Backbg.) Rauh

Backbg. et Knuth.

Bigel.

Bigel.

var. kunzei (Rose) L. Benson

DOP

Mesc

Mesc Tyr, N-Me-Tyr, Hord, N.N-diMe-3-

MeO-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-3- OH-4.5-diMeO-Phe N-formyl-3-OH-4,5-diMeO-Phe, N-acetyI-3-OH-4,5diMeO-Phe, Mesc, N-Me-Mew, N-formyl- Mesc, N-acetyl-Mew

Me-Synephr Tyr, ff-Me-Tyr, Hord, Synephr, 8-0-

N-Me-3.4-diMeO-Phe Tyr, N-Me-Tyr, Hod, Homova TYr Tyr, Homova,

Homova. 3-5-diMeO-Q-OH-Phe 3,5-diMeO-4-OH-Phe

Hord

Tyr, N-Me-Tyr, Hord Homova, Mesc, 3.5diMe0-4-OH-

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

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

Phe

Phe

i77

357

421 1, 10-12,

25, 77, 150. 165, 176. 192, 202, 207. 208. 210. 213

78. IS1

80 131, 415 27 27, 420 \

420

70

54, 80. 81 420

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 Alkaloid' Reference(s)

Opuntia sranlyi var. sranlyi Engelm. Opunria subulara (Muhlenpf.)

Opuntia versicolor Engelm. Opuntia vulgaris Mill. Opuntia whipplei Engelm. et Bigel. Pachycereus pecten-aboriginum

Pelecyphora aselliformis Ehren.

Engelm.

(Engelm.) Br. et R.

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)

Pereskia rampicana Web. Pereskiopsis chapisrle (Web.) Br. et

Pereskiopsis scandens Br. et R. Pilosocereus chrysacanthus (Web.)

Pilosocereus guerreronis (Backbg.)

Pilosocereus maxonii (Rose) Byl. et

Br. et R.

R. Abbey

Byl. et Rowl.

Byl. et Rowl.

Rowl.

Polaskia chende (Gossel.) Gibs. et

Pseudolobivia kermesina Kainz. Pterocereus foetidus M a c h u g .

Pterocereus gaumeri (Br. et R.)

Solisia pectimta (B. Stein) Br. et R. Stenocereus beneckei (Ehren.) Buxb.

Horak

et Mir.

M a c h u g . et Mir.

Stenocereus eruca (Brandeg.) Gibs. et

Stenocereus stellatus (Pfeiff.) Rice. Horak

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

Tyr, N-Me-Tyr, Hord Hord Homova 3-MeO-Tyr, Homova, 3-OH-4-Me0-

Phe Hord, Mesc, N-Me-Mesc, Homova,

N-Me-Homova, N.N-diMe-3- OH-4.5-diMeO-Phe

Hord

Phe, Tyr Tyr, 3-MeO-Tyr, Homova, Mesc

3-MeO-P-OH-Phe Tyr, 3-MeO-Tyr Tyr, P-OH-Mesc Phe, Tyr

TYr

TYr

Phe, Homova, Mesc Phe, Tyr, 3-MeO-Tyr, 4-MeO-P-OH-

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

Phe

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

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

Mesc Homova, 3.5-diMe0-4-OH-Phe.

Tyr, Homova Homova, 3,5-diMeO-4-OH-Phe

Homova, Mesc, 3.5-diMe0-4-OH-

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

Homova, Mesc, 3,5-diMe0-4-OH-


Phe

Phe

Phe

Phe

83 83

83 70 83 69. 193

73. 135, 421

80 27 27 27 27 27 27 27 27

27 27

27 205

206

86

420

76 420

420

80 420

420

420

2. P-PHENETHYLAMINES AND EPHEDRlNES

TABLE V (Continued)

123


Stenocereus treleasei (Br. et R.)

Srersonia coryne (SD.) Br. et R . Backbg.

Trichocereus bridgesii (SD.) Br. et R. Trichocereus carnarguensis Card. Trichocereus candicans (Gill.)

Trichocereus chilensis (Colla. )

Trichocereus courantii (K. Schum.)

Trichocereus cuzcoensis Br. et R.

Br. et R.

Br. et. R.

Backbg.

Trichocereus fulvianus Ritt. Trichocereus larnprochlorus (Lem.)

Trichocereus knuthianus Backbg. Trichocereus rnacrogonus (SD.) Ricc. Trichocereus rnanguinii Backbg. Trichocereus pachanoi Br. et R .

Backbg.

Trichocereus pasacana (Web.)

Trichocereus peruvianus Br. et R . Br. et R.

Trichocereus purpureopilosus Wgt. Trichocereus santiaguensis (Speg.)

Trichocereus schickendanrzii (Web.)

Trichocereus skotrsbergii Backbg . Trichocereus spachianus (Lem.) Ricc. Trichocereus strigosus (SD.) Br. et R. Trichocereus tuquirnbalensis Card. Trichocereus terscheckii (Parm. )

Trichocereus thelegonus (Web.)

Trichocereus thelegonoides (Speg. )

Trichocereus tunariensis Card. Trichocereus vulidus (Monv.)

Backbg.

Br. et R.

Br. et R.

Br. et R.

Br. et R.

Backbg.


Tyr, N-Me-Tyr, Homova, 3-Me0- Phe

Tyr, Mesc, coryneine, oxy- candicine

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

Candicine

Tyr, N-Me-Tyr, 2-MeO-Tyr, Homova, N-Me-3-MeO-Tyr

Tyr, 3-MeO-Tyr, 3-OH-4, 5-diMeO- Phe, Mesc

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

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

Tyr, 3-MeO-Tyr, Mesc, Homova,

Tyr, N-Me-Tyr Tyr, Hord

3,5-diMeO-4-OH-Phe

N-Me-Tyr, Hord

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

N-Me-Tyr, Hord

Hord

Tyr, Hord Mesc

420

73, 185. 186

68 68 68, 74, 167

168

73

73

73 68, 169

73 68 73 68. 87, 197,

209, 213

88

195

73 73

68

73 68. 74 73 73 68. 211, 212

73

73

73 73

(continued)

JAN LUNDSTROM

TABLE V (Continued)

Family and species Alkaloid Reference( s)

Trichocereus werdermannianus Backbg.

Turbinicarpus pseudomarrochele (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

Cannabis sativa L.

Lonicera maackii Maxim Sambucus canadensis L. Viburnum lanata L. Viburnum odoratissimum Ker.

Catha edulis Forsk.

Cannabinaceae

Caprifoliaceae

Celastraceae

Tyr, 3-MeO-Tyr, Homova, Mesc,

H o d 3.5-diMe0-4-OH-Phe

Hord

Hord

Hord

H o d

Phe

Phe TYr

TYr

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

Chenopodiaceae Anabasis jarartica (Bge.) Benth. Arthrophytum leptocladum M. Pop. Beta vulgaris L. Beta vulgaris var. cruenta L. Halostachys caspica Haloxylon salicornicum (Moq.-Tand.)

Spinacia oleracea L.

Aster linariifolius L. Critoniella acuminata

Boiss.

Compositae

Silybum marianum (L.) Gaertn. Spilantes ocymifolia

Cornus alba L. ssp. tartarica Cornus sanguinea L.

Erassica oleracea L. Capsella bursapastoris (L.) Medic. Raphantus sativus L.

Citrullus vulgaris Schrad. Cucumis sativus L.

Cornaceae

Cruciferae

Cucurbitaceae

N-Me-Tyr N-Me-Phe DOP TY r Halostachine Tyr, N-Me-Tyr, Synephr

Tyr, Dop

TYr (0- and (3-Dioxymethylenecinnamic

acid phenethylamide

N-Phenethylcinnarnamide TYr

Phe Phe

73, 87

80

70

70

70

147

26 45 26 45

245 -248, 250, 407- 409

I32 55 178, 179. 360 215 89

90. 180

45 422

91, 92 229

21 21

360 93 360

360 360


TABLE V (Continued)

Family and species Alkaloid a Reference( s)

Cyperaceae Cyperus papyrus L. Cyperus rotundus L. Mariscus jamaicensis Crantz

Ephedra alata Decne. Ephedraceae

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

Ephedra equiserina Bnge

Ephedra fragilis Desf. Ephedra gerardiana Wall.

Ephedra gerardiana Wall. var.

Ephedra gracilis R. Phil. Ephedra helvetica C. A. Mey Ephedra intermedia Schrenk et

sikkimensis

C. A. Mey

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

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

Ephedra regeliana Florin Ephedra sinica Stapf.

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

Tyr, Oct Oct TYr

Eph, JIEph, ephedralone

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

Eph, JIEph, nor-Eph, nor-JIEph

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

nor-JIEph Eph, N-Me-Eph

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

ephedroxane

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

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

Eph, nor-Eph, JIEph, nor-JIEph Eph, JIEph, N-Me-Eph, N-Me-$Eph,

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

nor-Eph, nor-JIEph

45 45 45

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

3. 258 3, 258 3. 251. 253.

258, 259. 262, 272

2 70 258 258 3, 251, 258,

251 3, 258, 264 3, 259 3. 253. 258,

259 253 3, 253,

271 3. 258 258 253. 258 258 252, 258

263

257-259

(continued)

126 IAN LUNDSTROM

TABLE V (Continued)


Ericaceae

Euphorbiaceae Erica lusitanica Rud.

Croton humilis L. Securinega virosa Baill.

Erodium cicutarium L.

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.

H ydrastinaceae Hydrastis canadensis

Juglandaceae Juglans nigra L.

Labiatae Lumium album L.

Lauraceae Ocorea pretiosa Persea americana Mill.

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.

Geraniaceae

Graminae

Leguminosae

4-MeO-Phe

N-Me-Tyr, Me-homotyr Hord

TYr

Hord Hord Tyr, N-Me-Tyr, Hord, candicine Oct, annuloline Oct Tyr, N-Me-Tyr, Hord Hord Hord N-Me-Tyr, Hord T Y ~

Nor-Epi

Phe Tyr, Dop

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

ile-Tyr, Hord

I72

I34 I52

94

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

220

45

100

101 90

28 29 31 56 57, 9 29 28 56 30 30 56 31 31 28, 31 30 30


TABLE V (Continued)


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.)

Albizzia julibrissin Durazz. Alhagi pseudalhagi (Bieb.) Desv.

W. F. Wight

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.

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

N-Me-Phe, Tyr Nor-Epi Nor-Epi TYr Tyr, nor-Epi Phe, Tyr Tyr, N-Me-Tyr Phe, Tyr Nor-Epi Dop, Epinine

Epinine

TYr

TYr

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 Alkaloid" Reference(s)

Liliaceae Chlorophyium capense Kuntze Cordyline terminalis Knuth. Eremurus regelii Vved. Liriope spicaia Lour.

Phoradendron sp. Phoradendron argentinum Urb. Phoradendron jlavescens Nun. Phoradendron hieronymi Trel. Phoradendron wattii Kr. et Urb. Phoadendron liga (Gill.) Eichlam Phoradendron villosum Phyrgilanihus jlagellaris (Chapm . et

Schlecht) Eichlam Psitiacanrhus cuneifolius (Ruiz et

Pav.) Blume Viscum album L.

Magnolia denudata Magnolia grandipora Magnolia kobus Magnolia liliijora Magnolia salicipora Magnolia spp. Magnolia sprengeri Magnolia stellaia Michelia alba

Sida acuia Sida cordifolio L. Sida sp.

Moraceae Ficus bengalensis L

Musaceae Musa paradisica L.

Loranthaceae

Magnoliaceae

Malvaceae

Musa sapienium

Nandina domesiica

Hermidium alipes Wats.

Caiileya spp. Erin jarensis

Nandinaceae

N yctaginaceae

Orchidaceae

TY r TYr Hord Tyr, Oct

Phe, Tyr

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

EPh Phe, Eph, #Eph EPh

Phe, Tyr, nor-Epi, Dop

Nor-Epi

Hord

TY r N.N-DiMe-Phi

45 45 163 45

45 I08 40.41 I08 109 109 42 I09

109

41-43

1% 111 197 200 I98 110-113 . 156 199 113

295 44. 298 266

45

45, 90. 221,

219

45

183

114 59

222


TABLE V (Continued).


Papaveraceae Chelidonium majus L. Roemeria refracra DC.

PassiJlora quadrangularis L.

Piper amalago L.

Limonium vulgare Mill.

Eriogonum alarum Eriogonum annuum Eriogonum campanularum Eriogonum infatum

Portulaca oleracea L.

Aconirum napellus L. Aconitum nasutum Aconitum paniculatum Lam. Aconitum tanguticum

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

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

Citrus sinensis Osbeck Clausena brevistyla Evodia belahe

Passifloraceae

Piperaceae

Plumbaginaceae

Pol ygonaceae

Portulaceae

Ranunculaceae

Rosaceae

Rutaceae

Osbeck

Nor-Epi

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

Dop, nor-Epi

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

Phe Phe Phe Phe Tyr, Nor-Epi Phe Phe

Phe Phe Phe

Tyr

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

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

115 267

I05

109

116

423 423 423 423

8

117, 223 224 223 157

26 21 26 46 90 26 21 118 21 21 26

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

45, 90 234 232

(continued)

130 JAN LUNDSTROM

TABLE V (Continued)

Family and species Alkaloid' Reference(s)

Fagara hyemalis Fagara rubescens Fagara spp.

Phellodendron amurense Rupr. Pleiospermium alatum (Wight et

Am.) Swingle Teclea simplicifolia Zanthoxylum clava-herculis L. Zanthoxylum conspersipunctatum

Philadelphus delavayi

Atropa belladonna L. Capsicum frutescens L. Lycopersicon esculentum Mill. Nicotiana tabacum L. Solanum melongena L. Solanum tuberosum L.

Taxus baccata L.

Thea sinensis L.

Daucus carota L.

Stachytarpheta jamaicensis Vahl.

Vitis vinifera L.

Saxifragaceae

Solanaceae

Taxaceae

Theaceae

Umbelliferae

Verbenaceae

Vitaceae

Coryneine, tembamide Rubescamide Candicine, coryneine, tembamide

Candicine Alatamide, N-benzyl-CMeO-Tyr, N-

homoveratroyl-Homova N.N-DiMe-4-MeO-Phe, Hord Herclavin, candicine Tembamide

Phe

Phe Oct

Phe, Tyr

Tyr, Dop, nor-Epi

TYr

TYr

EPh

Phe

187, 235 239 187, 188.

235 159 243, 238

164 170, 171 236

21

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

269

50

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-PHENETHYLAMINES AND 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 phenyl- alkylamines 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, pre- parative 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 chromatography- mass 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

132 JAN LUNDSTROM

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). Alter- native methods for the synthesis of phenylethanolamines are exemplified by reduction of 2-aminoacetophenones (Method E) (313) or by reduction of cyano- hydrines (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 (+.)-norephedrine yields (*)-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. Re- duction of the N-protected amino ketone 5 with dimethylphenylsilane in trifluoroacetic acid (TFA) gave the N-protected amino alcohol 6 with high (>99%)

2. @-PHENETHYLAMINES AND EPHEDRINES 133

A. ArCHO + CH3N02 + ArCH=CHN02 LAH ArCH2CH2NH2

ArCH2CN * ArCH2CH2NH2 \u B. ArCH20H - ArCH2C1

f ArCH2NR1R2

ArCHZCONH2 ArCH2CH2NH2 2\

9

C. ArCOCl ArCOCHN

ArCOCH3 __t ArCH2C02H

ArCH2CH2NH2

ArCHCH2NH2

i' D. ArC02H d ArCOCl ArCOCN

I OH

E. ArCOCHzNR1R2 ArCHCH2NR1Rz I OH

F. ArCH-CN - ArCHCH2NH2 I I OH OH

G. ArCHO - ArCHCN - BH3'THF ArCHCH2NH2 I I OSiMe3 OH

K Co H. PhCHO + CH3CH2N02 -2 3- Ph-CH - CH-N02 - I 1 OH Me

+ Ph-CH - CH-NH2 Ph-CH - CH-NHMe I 1 I I OH Me OH Me

SCHEME 1. 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

&NHcooEt + HSiPh,Me -, TFA & NHCOOEt - 6

L-Ephedrine

Me,CHCH 4,&

Me2CHCH, 1. NaOI KMnO,

n-BuLi 1-BuOH

____* H o b & THF,-85"C I '

( E ) - I S , Z R - 8

o% ( Z ) - R - 7

Me0,C MeHN

- H O h- \ HO

2 S , 3 R - 9 e ephedrine ( 1 R , 2 S )


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)

HOOC- - - - Me - 1. PC1,

PhH,CH2C12

+Me __* KOH eMe NHC0,Me 2. *IC13 \ kHCOzMe \ NH,

s- 10 s- 11 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

0 CF,COOH HC1,EtzO

- - - HOOC vMe PhLi

HiC02-r-Bu HNCOZ-t-Bu NHL

s- 12 S- 13 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.

1) 2Eq.BuLi - - Me - - -

HOOC - Me

1 Eq. HNC0,- r- Bu 4

HNCO,-r-Bu

s- 12 S- 14

_____, CF,COOH 0"ii \ NH2

S-Merucathinone

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 -1 . P - HNC0,E t HNC0,E t

5- 15 5- 16

HNC0,E t

tS,ZRS- 17

4S,5R- 18

02 0-v Me

4s,5s- 18

KOH -

KOH ___*

3R.45-Merucathine

OH i

35,4S-Pseudo- -Merucathine

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

M e 0 MeovNHz HO

I O M e O M e

Mescaline 19


afforded the corresponding 4-demethylated analogs (e.g., 19) in high yield (412, 4 13). Finally, synthesis of specifically )H- and I4C-labeled phenethylamines 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 Tricho- cereuspachanoi (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. Alter- natively, 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

Homoveratry lamine 3-Methoxyt yramine

/

HO

I

Meo 1 19

M e 6

Mescaline

Ho 20 \

Hz M e 0

HO I 21 4

M e o w N R , R2O

R@ R,

Tetrahydroisoquinoline Cactus Alkaloids ( R = H o r M e )

SCHEME 2.

peyote alkaloids (10); however, this amino acid may be decarboxylated to phenethylamine, which is further N-methylated to N-methylphenethylamine in Dol- ichothele 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

‘HNPoH JNHN@oH Ho i Ho t

I ;“Do” H003

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 Phyrochemis- rty, Vol. 8, T. A. Wheaton and 1. Stewart, Biosynthesis of synephrine in citrus, Copyright 1969, Per- gamon Journals Ltd.)

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.

R2 OH OH

HO \ "'*mI HO Meo@NMeR M e 0

Tyramine Norepinephrine Normacromerine (R' = RZ = H) (R' = R3 = H) (R = H)

N-Methyltyramine Epinephrine Macromerine (R' = Me, R2 = H) (RI = Me, R3 = H) (R = Me)

Octopamine Normetanephrine (R1 = H, Rz = OH) (R1 = H, R3 = Me)

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]cinnamic acid 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).


WHY0" o"cooH L -Phenylalanine

1 I I 7

CHO COOH I

Shikimate - - - -

-p Methionine Forrnate - - - -

Aspartare ----;+ C,N 0

0 0

t-Ephedrine

SCHEME 4.

Several enzymes involved in the biosynthesis of phenethylamines in plants have been studied. A tyrosine carboxy-lyase (decarboxylase) isolated from barley seedlings and barley roots has been studied in considerable detail (347-349). The enzyme is rather specific for L-tyrosine and meta-tyrosine; ortho-tyrosine and L-dopa are decarboxylated slowly. Tyrosine carboxylase activity was also demonstrated in wheat and maize (348). Cytisus scoparius contains dopa carboxy-lyase which decarboxylates D- and L-dopa at about the same rate (350). Tyrosine is decarboxylated 15 times slower. A similar enzyme has been found in the alga Monostroma juscum ( 174).

An enzyme preparation isolated from the pulp of the banana fruit was shown to contain tyramine hydroxylase activity (351). Dopamine is the main product when tyramine serves as substrate. A similar enzyme oxidizing tyrosine to dopa has also been found in banana (352).

The peyote cactus contains an 0-methyltransferase that has been isolated and characterized (353). By using variously substituted phenolic phenethylamines as substrates for this enzyme, the previously postulated biosynthetic pathways to mescaline in this cactus could be verified (354, 327).

142 JAN LUNDSTROM

VI. Biological Effects

The most well known of the naturally occurring phenethylamine derivatives (Table I) are the transmitters of the sympathetic nervous system, epinephrine, norepinephrine, and dopamine. All these compounds are 3,4-dioxygenated in the aromatic nucleus and are collectively known as the catecholamines. Norepi- nephrine 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-Phenethylamine itself is produced endogenously from phenylalanine in mammalian tissue (365,366) and has been suggested to exert a neuromodulatory action 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 pene- trates 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-containing plants 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 MA0 inhibitors after ingestion of food containing tyramine (382, 383). Cheese, pickled herring, and red wine are commonly

2. B-PHENETHYLAMINES AND 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 Lopho- phora 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 north- ern Mexico as a medicine, an amulet, and.a hallucinogenic religious sacrament (390, 391). Another important natural source of mescaline is the huge column cactus Trichocereus pachanoi, 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 mil- lions 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 pseudomerucathine were found to have only weak dopamine-releasing effects and were therefore considered un- likely 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

2. L. Reti, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 3, p. 339. Academic Press, New

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).

York, 1953.

York, 1953.

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83977a.

-CHAPTER 3-

LYTHRACEOUS ALKALOIDS

KAORU FUJI

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 ofrepmducfion in any farm rrservcd.

156 KAORU FUJI

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

OMe OR

7

8 OH

1 , R H ( demethyllasublne I ) 2 , R = Me ( lasublnel)

OMe OMe

H oL@" OMe

4 ( subcosine I )

OMe

OMe

@OH

OH 3 ( 10-epidemethoxyabresollne )

6 , R = M e lasublne II )

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 Michael- type addition of the resulting enone 9 (6, 7) and (b) a Mannich-type reaction through 10 (8, 9), were proposed without any experimental evidence. Prepara- tion and cyclization studies of the intermediate 9, however, gave conclusive evidence to show that the pelletierine condensation proceeded through pathway a (10).

3. LYTHRACEOUS ALKALOIDS 157

cN& 0

9

Wo+ 8

ACHO c b

Ar a J 11

0 10

SCHEME I .

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 conditions even after 2 weeks.

0 H

0 H

15 16 12 R = BoC 14

13 R = CH(0H)Ph

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- AND Wan~-4-PHENYL-2-QUlNOLlZlDINONES (15 AND 16)

NaOH Reaction timeb Yield Ratio Entry" Solvent (equiv) (hr) (%) 15: 16

I Water 9 1 10 3.8 2 Water 9 14 69 0.67 3 Aq MeOH 9 1 62 3.4 4 Aq MeOH 9 16 79 0.20 5 Water 6 1 62 3.6 6 Water 6 16 66 1.1 1 Aq MeOH 6 I 61 2.9 8 Aq MeOH 6 17 62 0.14

Entries 1-4, Intramolecular cyclization of 9 (R = C,H,) (see Scheme I); entries 5-8 , normal

At 55°C. pelletierine condensation of 8 with benzaldehyde.

lecular 1,3-dipolar cycloaddition approach was applied by Takano and Shishido to the synthesis of two naturally occurring arylquinolizidine alkaloids, demethyl- lasubines 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 mes- ylation 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 18 19

OMe OMe OCHZPh

- OAC

22 H 23

C

21

r OM^ 1 OMe OMe OCHzPh OCHZPh

- OAC I 22 H 23

C

H

21

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


in 50% aqueous acetic acid to provide rrans-quinolizidine 22 (38%) and cis- quinolizidine 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 OMEM

OR H H

OCOPh H

24 25,R-Ac 27,R=Ac 26,R=H 28,R-H

0 0

‘“OD Me0 CHo MEMO OMEM 29 30

OMe OMe OMEM OMEM

OMe

OMEM 31 32

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 F U J I

formation of abresoline (7) were accomplished under Mitsunobu conditions, utilizing 3-methoxy-4-(~-methoxyethoxymethoxy)cinnamic acid to give 32. Abres- oline (7) was obtained by deprotection of 32 with trifluoroacetic acid in methylene chloride in 16% overall yield from 29 (12 , 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-tetrahydropyridine 1 -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. Ad- dition 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-dimethoxycinnamic anhydride provided subcosine I (4) in 48% yield.

The disadvantage of the intermolecular dipolar cycloaddition strategy is non- stereoselectivity. 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

b Me0 CHO ?-

Me0 _ E M B O D - Me0 + 0 - 19 33 34

3 5 a . R ~ p-H 36a,R= B-H 35b,R= a-H 36b,R= a-H

37

SCHEME 3. Reagents: a, Ph~P=cHCH=CH2/ether; b, toluene/reRux; c, HCUCHCI,; d, H2/Pd-C.


OMe

Me0 +C:H

0 38

c d &OMe

lasublnel(2)

N H OH

&OH ' - H 40 41

SCHEME 4. Reagents: a, PPh3/MeOOCN=NCOOMelTHF; b, NaB&/EtOH/-35 to -30°C; c, HCOOH; d, KOHlaq EtOH; e, LiAlH+/THF.

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 H 0

42 43

4. Lasubine I1 (6)

Lasubine I1 (6) was synthesized by three different routes. The first involves the traditional pelletierine condensation (15) , 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-dimethoxybenzaldehyde was 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 - a , b MeoflcHo - c , d

Me0 M e 0

ns O H NH2 S

45 46 47

0 OH NHBoc

f , g M e 0 , M e O F 40 49

e - ___)

i ' k lasublnefl(6)

O H H H

50 51

SCHEME 5. Reagents: a, ~-BUL~IBICH,CH(OM~)~; b, conc HCIITHF; c , CH2=C(OLi)CH2CH2- CH=CH2; d, PhCH2ONH2 . HClIpyridine; e , LiAIhfKOMe; f, Boc-S; g, NCS/AgN03; h, CF, COOH; i , LiAIhINaOMe; j, disiamylborane, then H202INaOH; k, TsClIpyridine.


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 spon- taneous 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 Me0

Me0 8-0 Me0 ?l a_ + OHC(CH&COOMe

53 54 55

MeoDCH:N 52

b _cc

OMe

i, lasublne I1 (6)

OH MeOOC

58 59 60

SCHEME 6. 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 tetrabutylam- monium 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 truns- quinolizidine structure. Unnatural 17-0-methyllythridine (63), a derivative of lythridine (a), was synthesized utilizing a new strategy for macrolide cyclization (23).

61 (vertaline) 62 (decallne) 63, R = Me 64 ,R=H

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

3. LYTHRACEOUS ALKALODS 165

H OH OCHO

68 65 66 67

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

X CHO, - + MeOOC(CH,),CH(OMe),- b

Me0 Me0 OMe

69b, X = I 6913, X = Br

OMe

Me0 OMe

OMe 70

C -

71

OMe

73 74

OMe Me0 Me0

+

OCHO

" 76

OMe Me0

+ H O ~ C H , C H , C O O M e

79

COoR2 OR'

OAc

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

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

SCHEME 8. Reagents: a, LiN(TMS)z/CH,-CHCHMgBr/THF b, 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 tetra- butylammonium 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-

Meo& Me0

82

+ 79

OMe

COOMe

Me0 (xi?< H COOL -

85

1 COOMe

OMe

86

SCHEME 9. Reagents: a, CuO/K2C03/Bu4NBr/pyridine; b, 19/toluene/reRux; c, MsCUpyridine; d, Zn/AcOH.

3. LYTHRACEOUS ALKALOlDS 167

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 phosphochlori- date 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 azodicarboxylate and 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-methyl- Iythrine (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 OCOCH,SiMe,

92 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 ,Cdimethoxybenz- aldehyde (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).


H o oMe

13

12 *. OH HO

7

94 (lythranldlne) 95, R 3: H (lythranceplne a) 96, R I Ac(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,.because it was known that N-nitroso- 2,6-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 KAORU F U J I

Meo oMe Meo oMe

P h 3 P = C H O C H = P P h 3 + / a_ 9 CHO OHC 98

97 \

Meo oMe Meo oMe 99

&X!+ A d ~ o A c ~ c ~ ~ o A c f , g , h , i

101 100

Meo oMe

H QH "* H lythranldlne (94)

102 103

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-diphosphetane 2,4-disulfide (Lawesson's reagent) gave the thiolactam 108 in 98% yield. The reaction of thiolactam 108 with ethyl bromoacetate was


108 109 110

- I IyulranCepiMtII (95) h

PhCH20'" 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 3- iodoanisaldehyde followed by successive reduction with lithium triethylborohy- dride 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

115 116 117

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 demethoxyabreso- line (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.

Incorporation of dl-[4,5-13C,,6-14C]1ysine via a symmetrical intermediate, ca- 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-quinolizi- dinones 123 and 124 were incorporated into vertine (119) (trans-quinolizidine ring) and lythrine (121) (cis-quinolizidine ring), respectively and specifically.

OMe OMe OMe al,, H

120, R = H (lylolh) 121, R = Me (lythrlne) 118 (demthoxyabresollne)


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 di- hydrothebaines 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-


ture-dependent I3C-NMR studies disclosed that a rather higher free energy of activation (- 15.6 kcal/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. (44) .

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.

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,

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).

Rodrigo. eds.), Vol. 18, p. 263. Academic Press, New York, 1981.

Can. J . Chem. 57, 1615 (1979).

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

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).

Series 215, p. 219. American Chemical Society, Washington, D.C., 1987.

176 KAORU FUJI

38. S. H. Hedges, R . B. Herbert, and P. C. Wordmald, J. Chem. Soc., Chem. Commun., 145

39. J. P. Ferris, C. B. Boyce, R . C. Briner, U. Weiss, 1. H. Qureshi, and N. E. Sharpless, J . Am.

40. K. Fuji, T. Yamada, E. Fujita, K. Kuriyama, T. Iwata, M. Shiro, and H. Nakai, Chem. Pharm.

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).

(1983).

Chem. Soc. 93, 2963 (1971).

Bull. 32, 55 (1984).

-CHAPTER 4-

DIBENZAZONINE ALKALOIDS

LUIS CASTEDO AND DOMINGO DOMINGUEZ

Departamento de Quimica Orgcinica Facultad de Quimica

Universidad de Santiago 15706 Santiago de Compostela, Spain

I. Introduction .......................................................... 11. Occurrence and Classification ............................................

111. Structure Determination . . . . . . . . . . . . . . . . . . . . . . . . . . A. TypeA Dibenzazonines .............................................

IV. Synthesis ............................................................ A. From Biphenyl Derivatives .......................................... B. Formation of the Biphenyl Bond .................... C. By Rearrangement ... ..........................................

A. From Bisphenethylamines ........................................... B. Via Morphinandienols ............................

VI. Pharmacological Properties . . . . . . . . . . . . . . ; ............................... VII. Related Alkaloids: Dibenzazecines ......................

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

B. Type B Dibenzazonines . . . .................

V. Biosynthesis .................... ........

C. Via Proerythrinadienones . . . . . . . . . . .

I77 179 I80 180 182 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) . Dibenza- zonines 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 Additional data

Erybidine (1)

Crassifolazonine (2)

Protostephanine (3)

Laurifonine (4)

Laurifine (5)

Laurifinine (6)

Neodihydrothebaine (7) and bractazonine (8)

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)

Stephania japoniru (16-21)

Cocculus laurifolius (22, 23)

Cocculus laurifolius

Cocrulus laurifolius (22, 23)

(22. 23)

Pupaver bracteatum (24)"

178- 180 (5)

160-162 (15)

90-95 (16) 73-74 (19)

(picrate) (18 )

(perchlorate) (23)

207 - 209

182- 185

Amorphous

243-245 (perchlorate) (23)

107 (24)

101 (24)

UV (15). IH NMR (IS), I3C NMR (15). MS ( 1 3 , (15)

UV (16, 21). IR (16, 21), 'H NMR (16, 18, 21, 24), MS (21, 24)

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)

'H NMR (24), MS (24)

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

4. DIBENZAZONINE ALKALOIDS 179

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 N-Me

Me0 Me0 Me0 5 Rl=H,R2=Me

OR2 6 Rl=Me,R2=H OMe OMe

Me0 OH

SCHEME 1.

180 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. TYPE A 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

9 R,=R2=Me N-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


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 nonoxy- genated 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).

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

B. TYPE B 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 'H- NMR 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. 'H NMR 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


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 (43 , 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) con- struction 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.

A. FROM BIPHENYL DERIVATIVES

Synthesis of dibenzazonines from biphenyl derivatives was first developed by Takeda (27), who carried out the synthesis of protostephanine (3) from poly- substituted 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 EXP~SITO AND DOMINGO DOMINGUEZ FRANCISCO

MeoQoMe Br CCILH

Me0 11 OMe

0

- -

Me0 OMe

W - R c d R=Me R=Et

e R=CHz-CHZH*

M e 0 Meop M m z M e O p

- - - - - - - - * / 0 0 ‘ ‘ ‘

Me0 15 Me0 Me0 4

OMe OMe 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.


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).

16 R=Br

Me0

hv * HO NaOW MeOH

Me0

I I

i 17 R=H(16%) I

Me0

Me0 p: OH .. . . . . . .

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) (15) .

186 LUIS CASTEDO EXP~SITO AND WMINGO WMINGUEZ FRANCISCO

OH HO

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

22 (2%) 23 (58%)

Me1

HO N-Me - HO

Me0 Me0 M e 0 8 (90%) (93%) (7 1 %)

6 NaOH hv I McOH ~ Ho \ & N - H + & N - H \

0 M e 0 0 Me0

M e 0 6N-H OH 26 (19%) OH 27 (38%)

i bractazonine (8) 24 R=Br 25 R=H(9%)

ScnmE 5 .


OH

""b N

HO

MeO 28 R=Br 29 R=H

-H hv NaOH I MeOH

w

P O M e OH

Me0 HO&

OH

+

30 (7%) 31 (10%)

i crassifolazonine (2 )

-H

SCHEME 6.

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).

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

d R4=OMe, Rl=R2=R3=R6=H, R5=Me g N-Me

32

/

\ e R3=OH, R,=R2=R4=R5=H, R,=Me

Ho /

R6° 33 Me0 '

OMe

2. Oxidative Coupling

Aryl-aryl bond formation by phenolic oxidative coupling of the bisarylethyla- mine 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 di- phenoquinone 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 (41) . 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% (41 ) (Scheme 8).

Me0

N-COCF3 D% N-COCF3

Me0 OR

M e 0 OR

37 R=H 38 R=Me

SCHEME 8.

39 R=H(11%) 40 R=Me(36%)

4. DIBENZAZONINE ALKALOIDS I89

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).

OMe

@ rKN-Me 41 OMe

OMe

Me0 OBz 43

OMC

Ni(Pph3), DMF $- 0

\

Ni(Pph3), DMF $- 0

\

OMe 42 (60%)

Ni(PPh3)3 M * g N-BZ b

PdK 0 0

Me0 \ Me0 OBz OH 44 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. 44) 44)

R=(CH,),-Ar (Ref. 45) HO & \ -Me

R=H (Ref. 46.47, and 24) R 41 Me0 '

SCHEME 10.

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


\ a R , 8R (+) -10' J

aS . 8R (+)-131° 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~SITO AND 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-phenyldihydrothebaine base of (+) -I3 I"; and (c) antipode of biphenyl (-)-35".


FIG. 2c.

45 - 49 hv t

OMe

SCHEME 12.

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

HO

Me0

MeMgI -Me -

Me 53

MeMgI

52

SCHEME 13.

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

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 (51) .

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 neospirinedienone 60, the iminium salt 61, whose catalytic reduction produces laurifonine (4) in excellent overall yield (55) (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 CASTEW EXPOSITO AND WMINGO DOMINGUEZ FRANCISCO

hand, when 75 was heated with BF,-OEt, in refluxing benzene and then hydroge- nated over Pt in methanol, the aporphine 67 (8%), the erybidine isomer 76 (35%), and the unnatural aporphine 77 (25%) were obtained (58) (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. (63) , 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 EXP~SITO AND 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). Inter- estingly, when 0-methylflavinantine (63) was heated in a steam bath with con- centrated 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 OH "-

SCHEME 16.

4. DIBENZAZONINE ALKALOIDS I97

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 competi- tive migration of alkyl and aryl groups to give proerythrinadienone and neo-

HO

67 (28%) Me0 Me0 OMe

Me0 -- - \ Me0

OMe

Me0 N-Me

0

\ 70 (8%) Me0 Me0

OMe OMe OMe SCHEME 17.

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 (59 ) (Scheme 18). In contrast,

OH

VOF, Me0 *

(40%) 1) NaOH

2) NaBH4

7 1 (40%) 35a (80%) OH OH OH

Me0 H+ M a p - *

Me0 Me0 M e 0 ’ *

(8.5%) \

OH OH OH

SCHEME 18.


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 (61) .

HO

M e 0 I\ - NaCH2SOCH, \

\ / Me0 ~ e o ' Me0 c I ~ OMe OMe OMe

I L

I HO

OMe

73b OMe

OH

' 74 OMe

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 CASTEW EXPOSITO AND WMINGO DOMINGUEZ FRANCISCO

hand, when 75 was heated with BF,-OEt, in refluxing benzene and then hydroge- nated over Pt in methanol, the aporphine 67 (8%), the erybidine isomer 76 (35%), and the unnatural aporphine 77 (25%) were obtained (58) (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. (63) , 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. DIBENZAZONINE ALKALOIDS 20 I

OMe 0

M e 0 $7 OMe

OMe Me0 I

Me0

-COH HCI

McOH

Me0 OMe

-COH

LiAlH,

Me0 OMe

Q-methylerybidine (9)

SCHEME 21

OMe

1) BrCN

2) LAH

81 Me0

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. (65) 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 O AND 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. (39) , 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)

4. DIBENZAZONINE ALKALOIDS

OH

203

M e 0

Me0 Me0 35a

N-Bz Me0 ‘OH

Me0 Me0

OH 89 R=Me M e 0

OBz 91 R, or R,=OEt 90 R=Et

SCHEME 23.

OH MflsoMT Ho 0

Me0 0

92

M e 0 “9 MeOH HCI

0

‘ OMe OMe

I I Me0

M e 0 OH 93 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 em- ploys a methyl chloroformate-induced ring expansion of the erythrinanone 98 (71) (Scheme 26). Compound 98 reacts with methyl chloroformate in refiuxing

204 LUIS CASTEW EXP~SITO AND WMINGO WMINGUEZ FRANCISCO

HO

Me0 OH 95

&e 9 R=Me

Me0

$"

Me1 I MeOH

OH I

' M*%N Me0 OH 97

SCHEME 25

OMe OMe

-Me

MeOCOCl

/

Me0 99 0

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. Inter- estingly, attempts to carry out the ring expansion of 98 using cyanogen bromide under various conditions failed (71 ).


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. FROM BISPHENETHYLAMINES

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 - 35a Me0 34 a

0 ,

Me0 OH OH

Erythrina i 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 EXP~SITO AND WMINGO DOMINGUEZ FRANCISCO

OH 0

.,IN-Me ,ol .,IN ''4- 1 %- 1 0 "para-para'' 0

~~0 \ 101R=OMe M e 0 ' 102 R=OH

OH OH 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 proeythrina- dienones, 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

M e 0

HO "para-ortho"

MeO Reticuline

0 Me0

- HO

Me0

Me0 8 :%&Me

Me0

N-Me - HO \ \

0 Me0 7 I

SCHEME 29.

(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

Me0 " q - M e OH

- MeO N-Me [HI

\

M e 0 OMe

Me0 "para-ortho" - M e 0 OH

protosinomenine HO HO

M e 0 Me0 ' SCHEME 31.

OH norprotosinomenine

N-Me MeO

Me0 104 MeO OMe

- - - - - - -

M e 0 105 M e 0 OH OH

SCHEME 32.

OH I [OI

M e 0

erythraline


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, antiap- petite 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).

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

/

Rl

109 RI=R,=H, R,=Et 110 Rl=Rz=H, R,=CH*=CH-CH,- RzF RZ R2 -R3

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 ( lH)] 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 N- methyl 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 33 - 135.4), four protonated aromatic carbons (107.5- 112.8), and five aliphatic

210 LUIS CASTEW EXP~SITO 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

\ 119 0

\

L o : 118 0 L O

116 R=Br i 117 R=H Dysazecine (1 14)

SCHEME 34.

4. DIBENZAZONINE ALKALOIDS 21 1

119 (26%). The latter was transformed to dysazecine (114) by the usual three- step 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 (41 ) (Scheme 35). A biogenetic type approach to dibenz[d,f]azecines has been de-

OMe OMe

N-COCF3 TIFA 60% ~ M*$ -COCF,

Me0 120 Me0 ' 121 OMe OMe

SCHEME 35.

OH

1) NaOH

2) NaBH4

Me0 D

Me0 124

A

OH :

OH OH OH

I

' Me0 I ___) ,ol ::v I I - C I C I ~ ~ ~ P H /

Me0 126 \ 127 Me0

125 0 Me0 OH OH

SCHEME 36.

scribed that starts from the phenethylisoquinoline 122, which by phenolic oxidative coupling leads to the homoproerythrinadienone intermediate 123. Subse- quent 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-acyltetrahydroquinoline 125 by oxidation to the di-

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 . Aca- demic 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, 121 1 (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, 161 I (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

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.,

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,

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

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,

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).

( 1980).

Tokyo, 1968. [Contains a list of references concerning protostephanine prior to 1966.1

1087 (1979).

R. J. I. C. Lousberg, Phytochemisrry 23, I157 (1984).

J . Org. Chem. 32, 1053 (1967).


34. H. G. Theuns, H. B. M. Lenting, C. A. Salemink, H. Tanaka, M. Shibata. K. Ito, and

35. H. G. Theuns, H. B. M. Lenting, C. A. Salemink, H. Tanaka, M. Shibata. K. Ito, and

36. H. Tanaka, M. Shibata, and K. Ito, Chem. Pharm. Bull. 32, 1578 (1984). 37. A. Mondon and M. Ehrhardt, Tefruhedron Leff.. 2557 (1966). 38. J. E. Gervay, F. McCapra, T. Money, G. M. Sharma, and A. 1. Scot, J. Chem. Soc.. Chem.

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.

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).

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).

R. J. J. C. Lousberg, Heterocycles 22, 2007 (1984).

R. J. J. C. Lousberg, Heterocycles 22, 1995 (1984).

Commun., 142 (1966).

J . Chem. Soc., Perkin Trans. I , 662 (1979).

43a. L. Small, L. J. Sargent, and J. A. Bralley, J . Org. Chem. 12, 839 (1947).

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 of (-)-35" from (aR,8R)-phenyIdihydrothebaine [(+)-a isomer of Small] for X-ray diffraction 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 elabo- rated 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 071 10. I . (aS,8R)-Phenyldihydrothebaine [HCI O4 (+) - 131°]:

CD (C 0.004 M , MeOH) [ ~ I ~ I s , 0; [61277. -4,125; [e]263. 0; [012s4, +1,250; [01247, 0; [elmr -18,250; [ O h . 0; [eh. +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 s . 0; [eho, +12,750; [eh. 0; [e1241, -18.950; [81234. -17,370; [ehl6, - 158,845; [eh,,,,, 0; [ehl, +342,960; [el,,, 0 (last).

CD ( c 0.005 M , MeOH) 0; +2,100; [ell98, 0; 1 ~ l l c 2 , - 34.500; [0lrs8. 0 (last).

3. (as)-Phenyltetrahydrothebaine [( -)-35']: -2,450; [eiZl5. - 1.200; [ei,,. 0; ieiZN.

- 19,800; [e1220, -7,600; [eizI3. - 12,000; [el,, 0; iei,,. + 14.000;

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)l and 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. La Vos, M. C. ten Noever de Brauw, and C. A. Salemink, Terruhedron

Lefi.. 4161 (1984).

214 LUIS CASTEW EXP~SITO AND WMINGO WMINGUEZ FRANCISCO

51. H. G. Theuns, R. H. A. M. Janssen, A. V. E. George, and H. W. A. Biessels, J. Chem. Res.

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.

54. A. R. Battersby, A. K. Bhatnagar, P. Hackett, C. W. Thornber, and J. Staunton, J. Chem.

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

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

63. V. Prelog, B. C. McKusick, J. R. Merchant, S. Julia, and M. Wilhelm, Helv. Chim. Acta 39,

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.

67. D. H. R. Barton, R. James, G. W. Kirby, D. W. Turner, and D. A. Widdowson, J. Chem. SOC.

68. D. H. R. Barton, R. D. Bracho, C. J. Potter, and D. A. Widdowson, J. Chem. SOC.. ferkin

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. Com-

74. A. R. Battersby, R. C. F. Jones, A. Minta, A. P. Ottridge, and J. Staunton, J. Chem. SOC.,

75. A. R. Battersby, R. C. F. Jones, R. Kazlankas, C. W. Thornber, S. Ruchirawat, and J. Staunton,

76. D. H. R. Barton, C. J. Potter, and D. A. Widdowson, J. Chem. SOC.. ferkin Trans. 1.

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

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).

(m) . 1458 (1985).

Soc., Chem. Commun., 1214 (1968).

SOC., ferkin Trans. 1. 2002 (1981).

(1974).

(1973).

498 (1956).

Struchkov, J. Chem. Soc.. Chem. Commun.. 150 (1974).

C. 1529 (1968).

Trans. 1. 2278 (1974).

mun.. 266 (1967).

ferk in Trans. I . 2030 (1981).

J . Chem. SOC.. ferk in Trans. I , 2016 (1981).

346 (1974).

(1984).

-CHAPTER 5-

NUPHAR ALKALOIDS

JACEK CYBULSKI AND 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

B. Mass Spectrometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. CircularDichroism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

A. NMR Spectroscopy . . .

VIII. Pharmacology . . . . . . . . . . . . . .

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.

216 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-NMR spectroscopy 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 concentrations were 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 (12 ) .

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 (14) . 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 (15) .

Nuphar variegatum Engelm. was used, among others, to examine microbial decomposition processes (16, 17) . 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 decom- positions 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 subtermi- nalis Torr., and Nuphar variegatum Engelm., the last undergoes decomposition most rapidly. In addition, the process of carbohydrate reduction (total nonstruc- tural) is greatest for N. variegatum (1 7 ) .

As the water plants exhibit different decomposition rates, it was deemed worth- while 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 sa- ponins was established (19). Forrest and Ray (20) isolated from N. variegatum caffeic acid, ferulic acid, and 3,4-dimethoxy-trans-cinnamic acid, 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


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 1,2,3,4,6- penta-0-galloyl-a-D-glucose, and 3 the structure 1,2,6-tri-O-galloy1-3,4-(S)- hexah ydroxydiphenyl-a-D-glucose.

1 2

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


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 C30 sulfur-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.

4 0

5

5 . NUPHAR ALKALOIDS 22 1

TABLE I NEW Nuphar ALKALOIDS

bl: Molecular Name Source Melting point (solvent) formula, M Reference(s)

5-(3-Furyl)-8-methyloctahydroindolizine (4)

7-Demethy ldeox y- nupharidine (5)

Nupharopumiline (6)

I-Epideoxynupharidine

I-Epi-7-epideoxynupharidine (8)

Nupharolidine (9)

(7)

lsocastoramine (10)

Secodihydrocastoramine

Nuphacristine (12) (11)

I-Epithiobinupharidine (1%

1'-Epithiobinupharidine (20)

1-Epi-1 '-epithiobinupharidine (21)

6'-Epihydroxythiobi- nupharidine (22)

Thiobinupharidine sulfoxide (syn) (23)

6-Hydroxythiobinuphari- dine sulfoxide (syn) (24)

6'-Hydroxythiobi- nupharidine sulfoxide (syn) (25)

nupharidine sulfoxide (syn) (26)

6.6'-Dihydroxythiobi-

6-Hydroxyneothiobi- nupharidine (27)

Castor fiber L.

Castor fiber L.

Nuphar pumila (Timm.) DC

Castor,fiber L.

Castor fiber L.

Nuphar lutea

Casror fiber L.

Nuphar japonicum

Nuphar lutea

Nuphar lutea

Nuphar lutea

Nuphar lutea

Nuphar lurea

Nuphar lutea

Nuphar lutea

Nuphar lutea

Nuphar lutea

Nuphar lutea

Amorphous

195- 197°C

Amorphous

Amorphous

110°C (hydrochloride) 240- 245°C (dec.)

109°C

Amorphous

Amorphous

- 124" (-) -

C14H21N0* 219

23 1

233

233

249

C,SH2INO7

C1SH23N0,

ISH23N0,

ISH23N02 9

C15H23N027 249

25 1

265

C15HZSN02*

c ISHdJO, *

Isolated as an inseparable mixture

- 30.9"

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

Amorphous -7.7"

- +3.4" (CHCl,)

26

27

26

26

28

26

29. 30

31

32

32

160- 165°C + 39" C ~ O H ~ ~ O S N ~ S . 36 (CHCI,) 542

Presence shown by spectral C,oH,20,N2S, 37, 38 data and reduction to 6 4 , derivative of neothiobinupharidine

510

(continued)


TABLE I (Continued)

14; Molecular Name Source Melting point (solvent) formula, M Reference(s)

6'-Hydroxyneothiobi- Nuphar /urea Presence shown by spectral C3,H,,0,N,S, 37. 38 nupharidine (28) data and reduction to 6'-d, 5 10

derivative of neothiobinupharidine

6.6'-Dihydroxyneothio- Nuphar /urea Presence shown by spectral C3,H,,0,N2S, 33 binupharidine (29) data and reduction to neo- 526

thiobinupharidine-6.6'-d2 Thionuphlutine B Nuphar /urea Presence shown by spectral C,,H,,O,N,S, 34, 39

sulfoxide (syn) (30) data and reduction to thio- 510 nuphlutine B

B. 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 (26) .


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. NU PH AROLI DIN E

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. (26) 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 (-)-7- epideoxynupharidine (15).

*OH Ag2C03- &:z Wolff -Kishner-

I “CH3 R1

10 0

mixture of

and M7-epi- H-deoxynupharidine 14

dcoxynupharidine 15

H. SECODIHYDROCASTORAMINE

Secodihydrocastoramine (1 1) 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.


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

t

HMPA

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).

H3C pH3 I \ 0

16 18

17

lT&.'* X

27 R2=R3=CH3 ;

28 Rz=R3=CH3 Z'=OH

29 R2=R3=CH3 Z = Z'=OH

Z=OH


22 : R ~ = R F R ~ = H ; R4=OH X = :

x = 0

x = o

x = o

2.4 : R1 =OH ,R2=R3=R&=W

25 : R1= R21R.4; R3=OH

26 : R1=R3=OH; RqrR4.H

J. THIOBINUPHARIDINE DERIVATIVES ( I-EPI, I '-EPI, AND ~-EPI-~'-EPI ISOMERS)

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-thiobinupharidine sulfoxide (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-NMR spectroscopy. 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


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’-dI thus 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 1 H-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 Transformations of Nuphur Alkaloids

The quinolizidine system in monomeric C,, alkaloids in some cases is suscep- tible 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.


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) (42 ) .

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-


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. Un- favorable 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 be- comes quaternary. Structures of this type are represented by thiobinupharidine monomethiodides 36 and 37 (43). In the dimethiodides the inversion was ob-


syn , naothiobinuphoridine sulfoxide (S oxiol

S oxiol or equatorial

SCHEME 1. Thermal transformation of syn-neothiobinupharidine sulfoxide.

3k 35

37

5 . NUPHAR ALKAMIDS 23 1

38

40

39

211-1

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 (45) (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-tetrahydrothiophene ring. The N+-CH3 group 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) (41 , 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


C-6’ and one of the protons on C-17 and, on the other, creation of an H-H 1,3- diaxial 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 enve- lope 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

5. NUPHAR ALKALOIDS 233

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


neothiobinupharidine

Raney nickel 1 #

Pummerer rearrangement

H

cis CP, a) a' B '

hydrolysis reduction

a' a'

Raney nickel

neothiobinupharidine

SCHEME 2. Chlorination and Pummerer rearrangement of 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.


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 influenc- ing 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%


S equatorial

face

S axial

D D

SCHEME 4. 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 6- hydroxythiobinupharidine syn-sulfoxide (24), 6’-hydroxythiobinupharidine syn- sulfoxide (25), and 6,6’-dihydroxythiobinupharidine syn-sulfoxide (26) follows a single steric mode (90% of deuterium incorporation) and introduces axial deuterium at both C-6 and 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-7 is controlling. No methyla-


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


OH

I

one steric mode C-6'dauterium C-6 deuterium 90% axial 100% 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


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-demethylodeoxy- nupharidine (5 ) from nonfunctionalized nitrones such as 64 (Scheme 9). Com- pound 65, after cyclization and removal of the ketone group, would furnish a synthesis of alkaloid 5.


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

1. CICO2CH3 2. A 500.

*'CH2OH

59

1.OsOklNaIO4 * b: 2 . H ~ l P d - c ~ 1. rnci3/py & 2. LiAIHb 3. resolv. KOH

5

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


yield 45-68% *-R1 1. NH2OH

2. PClgIether

II %O

0

A 61

NoHl benzene refl. under N2 t corresponding epoxides m- CI-C6H&03H

Bu Li I hexone

H

OH

II H 0

e~ (t)-nuphorolutine + (~)7-epinuphorolutine 50 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. Intra- molecular Diels-Alder condensation of l-Azadienes was shown (68) to be a stereoselective route to the total synthesis of (-)-deoxynupharidine (14). The key steps are shown in Scheme 12; from synthon A in four steps alkaloid 14 was obtained.

242 J A C K CYBULSKI AND JERZY T. WROBEL

0

- 1. NHzOH, 2. PC15

CH3 63

O X N l . H + L C H 3 2. A,CoO)

CH30CO

1. NoBHq k)-anhydronuphoromine 85% 62 2. chrornotogrophy~ nuphenine 15 %

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.


muta b

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

(i) -7- epideoxynupharidine (151

1.

2. Wolff - Kishner

+ kl -1 - epideoxynupharidine (81

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

1. A 2. H2I Pd-C 3. 3-lithiofuranC

(-1-deoxynupharidine (14 I &ACH3 0 U 4. BU3. sMe2

A

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


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 quinolizidine rings, deoxynupharidine (14), 7-epideoxynupharidine (lS), nupharolutine (50), and 7-epinupharolutine (60), and also for the synthetic model compounds 3(e)-methyL3(a)-rnethylthio- methylquinolizidine (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 7- epideoxynupharidine (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).


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+-methyl group, 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-


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-quinolizidinium ring 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 (41,43) (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 spirotetrahydrothiophene ring 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

A'B AB

SCHEME 13. I-Syn-diaxial interactions in ?runs-thiobinupharidine methiodides. w., CH3 H@< C-17' CH3 S CH3

N-J - c-17 c-8' c-17

H H A' 0' AB

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

+

5 . NUPHAR ALKALOlDS 247

c-7w c-17' H-H H/'-l7@'

c-9 H c-17 c-a c-7

C-6

H----- H a8 c-17' c-7 ;J,$s 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 trans- quinolizidinium system. In these compounds also, the carbon atom of the S- methyl 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


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 S- oxide (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 l 3 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, princi- pally 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


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 neothiobinupharidine S-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-sulfoxide 72 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 cis- quinolizidinium 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. MASS SPECTROMETRY

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, H20, SH, CH,S, and CH3S are


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

R=OH , R1 =H I- 176

\ R=D ; R1.H 1 7 1 7 9 !

178 \ R=H ; Rt=D

+H

SCHEME 16. Mass spectral fragmentation of thiohemiaminals of CN 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 five- membered 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 JACEK CYBULSKI AND JERZY T. WROBEL w$4c& I H

3F I 3F 1 lCH2SOl 1 @ neither

NCH2 m h 230 nor 'q@\ mlz 3F 231 m h 170

1

I

3F

rnlz 178 rnlz 230 rnlz 230

rnlz 170

SCHEME 18. Fragmentation of syn- and anti-sulfoxides of neothiobinupharidine.

mlz 178 and230 high intensity low intensity

mlz 170 and 230

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


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 a- thioiminium 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; 6- hydroxythionuphlutine 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’-dihydroxythiobinuphlutine B (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


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 Can- dida 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), Micro- sporum 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 mea- surable. 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 well- known active compound amphotericin B and derivative 90 (not containing the


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 a- thiohemiaminal90 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 in- dispensable 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.


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34. J. T. Wrobel, A. Iwanow, and K. Wojtasiewicz, Bull. Acad. Pol. Sci.. Ser. Sci. Chim. 24, 99

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50. R. T. LaLonde, C. F. Wong, A. I.-M. Tsai, J. T. Wrobel, J. Ruszkowska, K. Kabzinska,

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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 Com-

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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,

78. T. Nikaido, T. Ohmoto, H. Noguchi, T. Kinoshita, H. Saitoh, and U. Sankawa, Planra Med.

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-CHAPTER 6-

OXAZOLE ALKALOIDS

HELEN M. JACOBS

Department of Chemistry University of the West lndies Mona, Kingston 7 . Jamaica

AND

BASIL A. 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 MikamycinlStreptograminlVirginiamycin Family ........................

C. Oxalomycin, Neooxalomycin, Curromycin A, and Curromycin B . . . . . . . . . . .

E. Calcimycin (A23187) and actin .................................. F. Conglobatin ............................................

VI. Biological Activity ..................................................... VII. Isolation and Spectral Characteristics ......................................

D. Berniniamycin . . . . . . . . . . . . . . . . . . .

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

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

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

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

THE ALKALOIDS. VOL. 35 Copyright 8 1989 by Academic Ress. Inc.

All rights of reproduction in any form reserved

259

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 3,4- dimethoxycinnamoyl chloride (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. multi- florum 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 H 2 + e o C H 3

0 J. OCH3 2

wNp4-0cH3 0 0 - CHO3

l 4 POCl3

1

SCHEME 1. 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 radiolabeled precursors (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, pre- clude operation of the pathway phenylalanine (9) to cinnamic acid (12) to p- coumaric acid (13) to caffeic acid (14), as the observed incorporation of labeled cinnamic acid (12) could be construed as proof of this. Although neither ad- ministered 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 0- methylated 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 (vide infra), 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

wNom-0R N

vNo- CI @ Y CH3 A

16 Halfordinol R = H 17 Halfordine R = CH2CH(OH)C(OH)(CH3)2 18 Halfordinone R = CH2COCH(CH3)2 19 0-isopentenylhalfordinol R = CHzCH = C(CH3)2

21 0-geranylhalfordinol R = transgeranyl 22 0-methylhalfordinol R = CH3

20 R = CH2CH2-C( = CH2)CH3

23 N-methylhalfordinium chloride

6. OXAZOLE ALKALOIDS 263

(19) and its double bond isomer 20 (10-12, 17), 0-geranylhalfordinol(21) (13), 0-methylhalfordinol (22) (14) , N-methylhalfordinium chloride (23) (IS), 24

OCH3

-(o*OCH3

25 balsoxin 26 texamine

WN0&2 N

27 texaline

(13), balsoxin (25) (16) , 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 ISOLATION AND 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 Halfor- dia, 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)phenyloxazoles and the (3-phenylethylamides, none of which accumulate in Hulfordia. To account for oxazole formation these authors proposed two similar biogenetic pathways commencing with the a- hydroxy-P-phenylethylamide 28. 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 (32 to 33) and dehydrogenation- alkylation (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.

C e H HO

30

OH .1

H 33

31 34

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

SCHEME 4. Proposed biosynthetic pathway of oxazoles from P-phenylethylamides.


Although the biosynthesis of 2-pyridyl-5-phenyloxazoles has 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 ( I 1-13, 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 quinone- methene 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-meth- oxypheny1)ethylcinnamide (37), and N-2-methoxy-2-[(4-(3’,3’-dimethylallyl- oxy)phenyl]ethylcinnamide (38) ( 1 I). The coincidence in compounds 36, 37,

35 R = CH3 R‘ = H 36 R = CH3 R’ = CH3 37 R = CH3 R’ = CH2CH3 38 R = CH2CH:C(CH3)2; R’ = CH3 39 R = CH2CH:C(CH3)2; R‘ = H

1MHCI RT, 5 rnin

- 16

rnOJ-q--J N 19 OCH3 N

OH

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 (11) . 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 work- up, 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)ethylbenza- mide. Balsamide (40), on oxidation followed by treatment with phosphorus oxychloride yielded balsoxin (25) (16).


In addition to the oxazoles O-isopentenylhalfordinol (19) (12), O-geranylhalfordinol (21) (13), and 2-pyridyl-5-(3-methoxy-4,5-methylenedioxy)phenyl oxazole (24) (13), Amyris plumieri produces a number of novel chromenylated tyramides 41-43 and the P-styrylamide 44 (12-14, 18). The only other iso- lable 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 well- known and documented process (19). The mechanism of 02* addition and decomposition of peroxides of type 47 has been rigorously eluciated by Wasserman largely by IeOz isotope studies (20). This reaction has also found extensive synthetic application (21).

Breakdown of the transannular peroxide 47 via a route involving a Baeyer- Villiger-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 0- isopentenylhalfordinol (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


0 ’ 0

0 H i

CONHL o / /c I ‘OH + HO ‘-2

50 46 0 - +

45 N

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 ac- knowledged precursor to nicotinic acid in most organisms (23). The formation of the putative oxazole precursor 51 or its equivalent therefore constitutes a con- vergence of the two predominant modes of alkaloid biosynthesis in the family.

In the oxazole-containing species 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 ken- duck contains the quinoline alkaloid halfordamine (55) and the furanoquinoline halfordinine (56) (8, 22), while small quantities of dictamnine (57) occur in H.


HO qTC0’” NH2 54 OCH 3 OCH3

CH3O

57 C H ~ O I OCH,

OCH3 I

56 55

RO qJ2Q c H ; p T J OCH3 H \

58a R = H haplopine 59 58b R = CH3 skimmianine

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) (14) .

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 well- studied 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


Brossi and Wenis have prepared halfordinol(l6) by cyclodehydration of the a- amido ketone 60 followed by hydrolysis of the intermediate 0-benzyl derivative 61 (24) .

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

R M e 0 M e OAc

M e + & - - M e e M e 0 “h 0 II 0

M e R OAc M e 0

0 II

* N ~ H

62 R = =0 Ulapualide A

63 R = H,\o +Me Ulapualide B

O M e

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) (26) . 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-


MeO’ 64

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 0

68


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

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

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

SCHEME 6. Preparation of pimprinine (70).


a-pTcH3 \ N

" 76

ZDDQ, 50 min, THF argon reflux ~ 70

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

ZDDQ, THF - HzO *O-J!'~ - poci3 70 71

\N 72 a-firR \ N H RT H

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

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 P- hydroxytryptamine derivative 85, dehydrogenation-isomerization of which yields the P-keto compound 79 (32, 33).


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"

H 87 l l h / H (RC0)20, RCOzH

H 70 R = CH3 H

71 R = CH2CH3 72 R = CHzCgHg

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

B. GROUP A 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 no- menclatural 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


29 28 89

NAo 0 OH M e H

91

N'O 0 OH M e H

93

OH OH

34

0 OH M e H 30

33 32 31 90

0 +; \ OH M e H

94

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.


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).

08

0 N < 98 - N Y

97 - N Y 96 -

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 (47) . 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


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 griso- viridin (89) and virginiamycin MI (90) (whose absolute configurations are 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 re- sembling 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 ~ f - ~ Hlmethionine, D L - ~ - I4C]serine, ~ - [ 3 , 4 - ~ H,]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-


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 3 - l ~ Clserine. 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 [2J3 Clacetate. This, coupled with observed incorporation of [l-13C]acetate at 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, elimi- nating 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-[ 1- I4C]Alanine was also efficiently incorporated. These results and those from de-

tailed precursor product studies utilizing mixtures of DL-[~-' Hlalanine with L-[ 1- I4C]-, 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).


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-carboxyloxazoles

O Y N

103-105 (67-70). The remaining fragment

OH

7 N H 2

R O H R’

for griseoviridin (89) is the thiolactone 106; for madumycin I1 it is the ester of D- alanine 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 (53,69) , 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 103- 105. 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-


\’ \ NH2 OH OH H OH OH

103 110

CH3

113 R = H 114 R = E t

116 R = ~ B u 115 R = M e

OH O V - 111 112

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), 2,5- dimethyl-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 A = @ 118 A = 8

119 B = 0 120 B = e

121 122 123

The reaction of 2-methyl-4-carbethoxyoxazole (1 14) 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

124 125

H 3 C q x OEt H $ f > G O

'OEt 0

126 127

correspondence between the spectral data of 127 and that expected for 125 neces- sitated the application of chemical methods to establish the identity of 127 (75). In preliminary studies the methyl group of 2-methyl-4-carboxyoxazole 113 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 Corn- forth 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 for- mylated 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

128 0

129 130

OCH? I 1. LDA.THF

0 131

* 3. ZnCl2

O N


mediated ring closure affords the 2-substituted-4-carbalkoxyoxazole 11 1 as a mixture (67).

Initial attempts by Fujita et al. to effect alkylation at the methyl group of 2- methyl-4-carbo-tert-butoxylcarbonyloxazole (1 16) 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 halo-

OBut

116 tBuLi, THF

TMSCI I -98" - -78"

n-BuLi, THF Me,,/

0-7 0 CH 3

TMS 134

f OBut

o Y Y C H 3 OBut qe" L , T H F -98" . o*yCH3 0

tBu 0 NaH, 18-crown-6 135

THF TMS

133 Mel,RT \A 0 q 7 C H 3

116

genation-sulfonation of 116 to form compound 136,2-benzenesulfonylmethyl-4- tert-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-butoxycarbonyl- 1,3-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 145a- 14% in yields of 77-90% (77).

OBut O B u t NBS, CC14, hu

0 0 - 7 ~ ~ 3 $SOzNa.2H20

0 MeCN, 18-crown-6

2.5 tBuLi,THF -40"

STMSCI 116

2 tBuLi L i o 2 c ~ ~ CH2 - Li THF, -78"

E' TMS 143 TMS 144 a) E = CH3

b) E = X? OH

145 a) E = CH3

b) E = X? OH


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

OH

O Y O

O G 0 OH O\(

111 ( 1 : l mixt.) Ar

S O C H 3 /=&oc"3 146

O N O N Y Y

1 1 1 k, 147

Careful 'H-NMR analysis of the aldehyde 147derived from 146 by Swern oxidation established the syn relationship of 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 hydra- zine reduction followed by acid and then base treatment (78).


YY O Y O

147 Ar

A O C H 3

O N 9

+l-/Ho R

O Y O Ar

149 R = H 151 R = CH3

Pyr-HCI I E ( 1 5 : 1) z

I 52 153 II

/H2NNH2 2. HCI

103 3 . Base 105

II 0

R = H R = CH3


Model experiments geared 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-benzenesulfonylmethyl- 4-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

136 154 0

156 155

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-


N H

0 158 neooxalomycin

"i""VN H

0 159 R = CH20CH3 curromycinA 160 R = CH3 curromycin B

A d 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.


D. BERNINIAMYCIN

Berniniamycin, a complex peptide antibiotic substance produced by Strep- tomyces 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

oxazole A H3C- {

N q p 4 2 NH

/ co C I I

,c, c?

I HN CH2 NH

CH co I

/

H2C =i NH

/

C-NH HN-CO H2C4 I I

H C'CH2 / N \ /

\

co NH co \ / \

CH CO-C

CHr I

I CH3

H3C-C-OH

164

OH 165


166 R = CH3 167 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 hydroxyva- line, 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 (A23 187, 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. Cal- cimycin (A23 187, 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 R = H CO2R

169 R = CH3


(91). This was confirmed, and the relative configuration was determined by X- ray 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 pseudo- cyclically 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 0

1 72 173 COOH 171


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 5- hydroxyanthranilate (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 6- amino-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

NHCOCF3

COJCH 3 C02CH3 C02CH3

177 178 179

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


cohols in which the desired compound 182 was predominant. Treatment of 182 with oxalic acid yielded the dihydropyran 183 from which the silyl and tri- fluoroacetyl 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).

L iHzC<3?

NMeCOCF3

C02CH3 w

175 -100"

(COOH),, MeOH. * NMeCOCF3 25"

COzCHj

R35iw 4 I

CF3COMeN C02CH3

1. Bu~NF, THF. 2 5"

2. Collins *

N

C02CH 3

183 184 (Zinc enolate)

CH2CH3

Bu'OrC * * 6UtO2C

185 186

1 2 . HOHs

H + ion exch. resin

* 168 COrCH3


HO-N-COCH3

Nocobactin NA is the generic name given to a series of compounds obtained after dissociation of a ferric complex isolated from the bacterium Nocardia as- teroides 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

NaoH

HO- N -COCH3

(CH2)4 I I 0 CONH - CH - C 0 2 -CH - CH -CO-N

0" N &> 0 K H d n I I CH3 I

OH I CH3

n = mainly9and 1 1 H

187

I OH I - . . I

188 nocobactic acid NA H OH

I HCI

189 cobactin NA

n = mainly9and 1 1

HONH I I

CO2H (CH2)4

H2NCHCOzH + CH3C02H &> 0 CH3 -I-

190 asteroidic acid 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 ortho- acetate to afford 2-( o-hydroxy)phenyl-4-( 1 '-ethoxy)ethylidene-5-oxazolone (193). This product on treatment with base underwent Cornforth rearrangement,


192 193

via loss of ethanol, ring opening, and recyclization (98), to yield 190, identical to the naturally derived compound (97) . The neutral products from the initial base hydrolysis of the natural compounds were shown to be cobactin acid NA (189) (97 ) .

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 OH

194 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.


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

196 R = H R l = H 196a R = H R l = AC 196b R = CH2CC13 R l = H

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 N,

HO,C* II OLi 198 HO2C- 0 0 II I1 197 I 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

196 LiCH2-N = C 20 1 *

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).

6 . OXAZQLE ALKALOIDS 295

+ CI 3CCHzOzC-J

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) (1 1, 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 pur- ported 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 Tricho- phyton 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).


CH2 I CH2

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/virginiamycin series, 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 ,CH2

Me - CH - CONH - CH - CON - CH I I

0

I

CO I NR2 I

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 conformational change 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


( 1 14) as has the action of virginiamycin M on the peptidyltransferase ( 1 15). Re- sults 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 ( I 16, I I7 ). Vir- giniamycins have been demonstrated to enhance lactation in ruminants (118) and to protect HeLa cell monolayers infected with Herpes simplex type I virus (I 19).

Oxalomycin (157) and neooxalomycin (158) were obtained in an Ehrlich as- cites 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 structure- activity 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 gram- positive 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 toler- ates its own product has also been elucidated (121). Streptomyces bernensis has been found to possess ribosomal RNA methylases which effect specific pentose- methylation 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 DATA OF OXAZOLE ALKALOIDS

Melting point UV, nm (solvent) Alkaloid name Molecular formula (solvent) (reference) (reference)

Annuloline (1) C,,H,,NO,

Halfordinol (16) C,,H ,,,N,O,

N-Methylhalfor- C,H,,N20,CI dinium chloride (23

Halfordine (17) C,,H,,N,O,

Halfordinone (18) C ,,H ,8N203

0-Isopentenyl- C,,H,,N,O, halfordinol (19)

105-106°C (benzene- petroleum ether) ( I )

( 1 )

(EtOH) ( 1 )

HCI 174- 177°C (EtOH)

Picrate 216-218°C

255-256°C (MeOH) (6)

235°C (dec.) (6)

163-164°C (MeOH) (6)

132- 133°C (Me,CO-petroleum ether) (6)

115-118"C(MeOH)(12)

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

265 (log E 4.13 , 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)

Balsoxin (25) 17H ISN0, 99- 100°C (hexane) (18) 255 (log E 4.02). 323 (4.39) (EtOH) (16)

O-Methyl- C15H12N202 98-99°C (EtOH) (14) 266 (log E 3.92). 306 (sh, 3.90), 326 (4.14), 348 (3.61) (EtOH)

halfordinol (22)

(14)

0-Geranyl- C24H26NZO2 Oil halfordinol (21)

298

IR, cm-' (medium) IH-NMR, 6 (solvent) I3C-NMR Mass spectrum (reference) (reference) (solvent) ( 6) (reference)

966 ( 2 )

3400, 1620, 1610, 1510, -

1460, 1260 (nujol) (6) - -

1616, 1605, 1582, 1175, 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, 57 , 1.8 Hz), 8.52 (IH, d, J 5), 9.47 (IH. bs) (CDCI,) (12 )

1603, 1508 (CHCI,) (16) 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)

822 (CHCI,) ( 1 2 )

(CwI , ) (16) 1618, 1600, 1500, 1460,

1412, 1300, 1260, 1180 (CHCI,) (14)

3.83 (3H, s), 6.95 (2H. d, J 8.5 Hz), 7.32 (IH. s), 7.33 (IH, dd, 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)

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

-

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) (14)

-

299 (continued)



Compound 24 CI6Hl2N2O4

Texamine (26) Cl6HlINO,

Texaline (27) C15H10N203

Ulapualide A (62) C5,H,N,OI, Ulapualide B '51 H74N40 I6

(63). Ialo -21.7' (0.138, MeOH) (25)

(64). [a], +20° (0.1, CHCI,) (26)

Kabiramide C C4XH71N50i4

Pimprinine (70) C12Hl,N20

Pimprinethine C,,H12N20 (71)

Pimprinaphine C,,H 1 4 N 2 0 (72)

188-189T (13) 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 (EtOAc-hexane) (17) (4.39), 324 (4.63)

134- 137°C

(MeOH) (17)

171-174°C 202 (log E 4.64), 221 (EtOAc-hexane) (17) (sh), 257 (4.24). 331

(4.50) (MeOH), 264, 348 (MeOH-acid) (17)

Oil Oil

- 246 ( E 33,000) (25)

Colorless, noncrystalline 245 ( E 2600) (26) solid

205°C (30) 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) (MeOH- HCI) (31)

161°C (CHCI,) (31)

200-201°C (28) 225 (log E 4.44), 272 (4.19), 286 (sh, 4.15), 302 (sh, 4.10) (EtOH) (28)

300

IR, cm-' (medium) 'H-NMR, 6 (solvent) 13C-NMR Mass Spectrum (reference) (reference) (solvent) ( 6) (reference)

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) (17 )

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,) (17 )

1608, 1580, 1568, 1485, 1445, 1427, 1230,928 (KBr) (17)

6.00 (2H, s), 6.87 (IH, d, J 8 Hz), 7.14 (IH, d, J l.6), 7.21 (IH. 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 )

- -

- 7.41 (IH, d, J 1.5 Hz) 8.09(1H. s), 8.10 (IH, s) (25); oxazole signals only

7.55 (IH, d, J I Hz), 8.01 (lH, s ) , 8.07 (IH. s) (CDCI,) (26); oxazole signals only

3450, 3350, 3150, 1720, 1650 (26)

3150, 1640, 1630, 1590 2.54 (3H, s), 7.1-7.98 (nujol) (30) (6H, m), 8.40 (1H. s)

(CDCl,) (28)

3200, 1633, 1617, 1582, 1.43 (3H, t, 57.5 Hz), 2.90 (2H. q, J 7.5). 7.18 (IH. s), 7.25 (IH, m), 7.29 (IH, m), 7.44 (IH. m), 7.52 (IH, d, J 2.6). 7.85 (1H. m), 8.83 ( I H . bs) (CDCI,) (31)

(IlH. m), 8.55 (IH, s )

1572 (KBr) ( 3 l )

- 4.18 (2H, s), 7.1-7.96

(CDCl,) (28)

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,) (17)

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,) (17)

212.05 (25) 131-170 (9C) (25) ; OX-

azole signals only

129.9, 131.1, 135.5, 136.8, 137. I , 141.6, 155.5, 156.4, 163.2 (CDCI,) (26); oxazole signals only

-

11.5 (q), 22.2 (t), 105.0 (s), 112.5 (d), 118.1 (d), 120.1 (d), 121.0 (d), 123.1 (d), 123.4 (d), 125.0 (s), 137.8 ( s ) , 149.5 ( s ) , 164.5 (s) CDCl,) ( 3 1 )

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

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

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




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

Virginiamycin MI (90, ostreogrycin A),

(0.34, EtOH) (48)

Virginiamycin M2 (91, ostreogrycin G), [a], +78" (1.36, EtOH) (54)

(92, A2315A).

(0.375, MeOH) (58)

Madumycin l(93) A17002C (94).

[a], -218"

Madumycin I1

-132"

[aID -21" (0.95, MeOH) (59)

Oxalomycin (157)

Neooxalomycin (158)

Cummycin A (159)

Cummycin B (160) [QID

+35" (0. I , MeOH) (82)

Berniniamycin (164)

C51H50N 14'16'

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

203-205°C (EtOAc) (48)

122-127°C (dec.) (54)

Noncrystalline (58)

- 158°C (dec.) (59)

Amorphous (79)

>290"C (dec.) (85)

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

228 (log E 4.51), 272 (4.00) (EtOH); 303

(48) (4.20) (EtOH - HCI )

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

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

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

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

230, 265, 275, 285 (80)

288 ( E 19,000), 267 (sh, 15,600). 275 (19,000), 285 (sh, 14,400) (MeOH) (82)

absorption (~>15,000) (EtOH) (85)

210-280, intense broad


IR, cm-' (medium) 'H-NMR, 6 (solvent) ',C-NMR Mass spectrum (reference) (reference) (solvent) ( 6) (reference)

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

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

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

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

1825 (79)

1765 (SO)

3350, 1825, 1690, 1640 (KBr) (82)

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

7.84 ( I H , s) (DMF-d6) 131.8, 145.3, and one of (44); oxazole signal three signals between 366, 339, 322, 246, only 153.8 and 163.9 168, 141, 138, 136,

(DMF-d,) (44); OX-

7.84 ( I H , s) (CDCI,) 136. I or 137.2 (s), 145.4 (48); oxazole signal (d), 156.2 (s) (CDCI,) onty (45, 64); oxazole sig-

nals only

477 (M'), 459,441,

127, 110, 108 (100%). azole signals only 99 (44)

525, 507 (49)

8.01 ( I H , s) (CDCI,) - 527 (2%). 509 (54) (54); oxazole signal only

8.08 ( I H . s) (CDCI,) 135.6, 140.7, 162.2 503 (M', 7%), 485 (20). (58); oxazole signal (CDCI,) (64); oxazole 467 (14) (59) only signals only

- 8.38 ( 1 H . S) (DMSO-d,

-D,O) (59); oxazole signal only

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

7.81 ( I H , s) (CDCI,); oxazole signal of tri- acetate (80)

-

- -

135.4 (s), 141.1 (d), 487 (M', loo%), 469 159.5 (s) (DMSO-d6) (25) (59) (59)

122.4, 150.2, 160.7 - (CDCI,) (82); oxazole signals only

(CDCI,) (82); oxazole signals only

122.3, 149.8, 160.3 -

134.9, 135.5, 155.0, -

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

(continued)


TABLE 111 (Conrinued)


I8 1 - I 82°C (acetone) - Calcimycin C29H37N306 (A23187, 168). (91) [a], -56" (0.01. CHCl,) (94)

Nocobactin NA C3E-mH57-6,N509 124- 126°C (97) 256, 261, 267, 213, 279, (187) 309,318 (EtOH) (97)

Conglobatin C28H3EN206 124- 126°C 214 ( E 43,800) (EtOH) (19% [ a I D (ether-hexane) (99) (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 lipid- rich 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 domi- nate 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 reversed- phase chromatography, depending on the complexity of the mixture. The weak


IR, cm-' (medium) IH-NMR, 6 (solvent) I3C-NMR Mass spectrum (reference) (reference) (solvent) ( 6) (reference)

1640, 1696 (CHCI,) (91) - - 523 (M'), 318, 206, 123, 94 (91)

- - - 795, 767,430 (A1 complex) (97)

498 (M') (99) 1705, 1650, 1610, 1505, 6.78 (2H, s) 7.75 (2H. s) Fourteen peak spectrum 1275 (KBr) (99) oxazole signals only consistent with CZs di-

(99) meric structure (99)

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

B . ULTRAVIOLET SPECTROSCOPY

The UV and fluorescence characteristics of simple substituted oxazoles have been discussed in the early review, which also made mention of the utility of 2,5- diary1 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 0- isopentenylhalfordinol (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).


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-5 oxazole 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-NMR data 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. MASS SPECTROSCOPY

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


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. Spe- cial thanks go to Ms. Karen Long of PCRI for presenting the manuscript in its final form.

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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.

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

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

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

126. W. D. Crow, J. H. Hodgkin, and I. S. Shannon, Aust. J. Chem. 18, 1433 (1965).

Chem Absrr. 105, 167068g (1986).

( 1983).

Ther. 16.69 (1981).

( 1984).

references therein.

(1979).

CUMULATIVE INDEX OF TITLES

Aconitum alkaloids, 4. 275 (1954). 34. 95 (1988) diterpenoid. 7, 473 (1960) CI9 diterpenes, 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)

Cannabis sativa L.. 34, 77 (1988) the plant, 1, 15 (1950). 6, 1 (1960)

Ants and insects, 31, 193 (1987) Aspergillm, 29, 185 (1986) Rzuridiantha species, 30, 223 (1987) Tabemaemontma. 27, 1 (1986)

Alkaloids in

Alkaloids from

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

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

(1987)

simple, 8. 1 (1%5) simple indole, 10, 491 (1967)

311

312 CUMULATIVE INDEX OF TITLES

Benzophenanthridine alkaloids, 26, 185 (1985) Benzylisoquinoline alkaloids, 4, 29 (1954), 10, 402 (1967) Bisbenzylisoquinoline alkaloids, 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)

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)

chemistry, 3, 1 (1953)

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)

Dibenzopyrrocoline alkaloids, 31, 101 (1987) Diplomhynw alkaloids, 8, 336 (1%5) Clp-Diterpene alkaloids

Aconitum, 12, 2 (1970) Delphinium, 12, 2 (1970) Gunyu, 12, 2 (1970) structure, 17, 1 (1970) synthesis, 17, 1 (1979)

CUMULATIVE INDEX OF TITLES 313

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)


Indole bases, simple, 10, 491 (1967) Indolizidine, simple and quinolizidine alkaloids, 28, 183 (1986) 2,2'-Indolylquinuclidine alkaloids, 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-CarboIine alkaloids, 22, 1 (1983) Isolation of alkaloids, 1, 1 (1950) Isoquinoline alkaloids, 7, 423 (1960)

biosynthesis 4, 1 (1954)

simple isoquinoline alkaloids, 4, 7 (1954), 21, 255 (1983) 'T-NMR spectra, 18. 217 (1981)

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

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) Mifragynu alkaloids, 8. 59 (1%5), 10, 521 (1967). 14, 123 (1973) Monoterpene alkaloids, 16, 431 (1977)

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)

(1985)

glycosides, 17, 545 (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~u alkaloids, 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) Spirobenzylisoquinoline alkaloids, 13, 165 (1971) Sponges, isoquinolinequinones, 21, 55 (1983) Stemom alkaloids, 9, 545 (1%7)


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) Sohum 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)

respiratory, 5, 109 (1955) uterine, 5, 163 (1955)

Stimulants

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).

Tropoloisoquinoline alkaloids, 23, 301 (1984) ’Ifopolonic Colchicum alkaloids, 23, 1 (1984) lJ4ophom alkaloids, 9, 517 (1967)

Uterine stimulants, 5, 163 (1955)

K?mtrum alkaloids

33, 1 (1988)

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

A

A170002C. 273 Abresoline, 156. 157 N-Acetyl-3,4-dimethoxy-5-

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

hydroxyphenethylamine, 110

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 Benzylisoquinoline alkaloids, 14 Bernines, from Guaneria species, 28 Berniniamycinic acid, 288

INDEX

Bisbenzylisoquinolines, occurrence in

2,2'-Bisnorguattaguianine, 5, 9, 25 Bractazonine, 178, 179, 183

Guatteria species, 20

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 Demethyllasubine I, 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

Dihydromelsomine, 13, 39 Dihydroonychine, 52 3,4-Dihydroxy-5-methoxyphenethylamine, 98 6,6 '-Dihydroxyneothiobinupharidine,

6,6'-Dihydroxythiobinupharidine, biological

6,6 '-Dihydroxythiobinupharidine sulfoxide,

3.5-Dimethoxy-5-hydroxyphenethylamine, 99 O,ODimethylcurine, 5. 9, 27 Nfl-Dimethyl- 3,4-dimethoxy-5-

hydroxyphenethylamine, 99 Nfl-Dimethylhomoveratrylamine, 98 N,ODmethylliriodendronine, 4, 12, 36 N,ODimethyllythranidine. 174 Nfl-Dimethyl4methoxyphenethylamine, 93 Nfl-Dimethyl-3-methoxyt~~ne, 95 Nfl-Dimethylphenethylamine, Occurrence

4,5-Dioxoaporphineq subtype, 7, 38 Dioxymethylenecinnamic acid

phenethylamide, 109 Discoguattine, 4, 11, 33, 38 Dopamine, Occurrence of, 93 Dragabine, 47

conversion into dibenzazozines, 201

222, 227

activity of, 254

221, 227

of, 81

Duguespixine, 13, 44 Dysazecine, 209

from 1-phenethylisoquinolines, 211

E

Elmerrillicine, 7, 11, 33 Ephedralone, 116 Ephedrines, 106

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

Occurrence of, 113

F

Formouregine, 6, 10, 33 Formyldehydronuciferine, 44 N-Formyl-3,4-dimethoxy-5-

hydroxyphenethylamine, 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

INDEX 319

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,

6-Hydroxythiobinupharidine, 253 6-Hydroxythionuphlutine Ei, 253

227,253

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-hydroxyphenethyl-

N-Methylelmerrillicine, 7, 11, 33 N-Methylephedrine, 11 5 N-Methylepinephrine, 104 Methylflavinantine, 197 Methylflavinantinol, 194 N-Methylhalfordinium chloride, 262, 298 0-Methylhalfordinol, 262, 298 N-Methylhomoveratrylamine, occurrence

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

amine, 98

of, 97

N

Neodihydrothebaine, 178, 179, 183 Neooxalomycin, 285, 297, 302 Neothiobinupharidine, 224

derivatives of. 227, 247 syn-Neothiobinupharidine sulfoxide

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

INDEX 32 1

Oxyisocalycinine, 4, 12, 38 1,ll-Oxymethyleneaporphine, subtype, 18,45 Spiguetidine, 48

Skimmianine, 268

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

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%

alkaloids chemistry & pharmacology

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