Alkaloids: Chemical and Biological Perspectives

Alkaloids: Chemical and Biological Perspectives

Related Titles of Interest Books GAWLEY & AUBE: Principles of Asymmetric Synthesis GRIBBLE & GILCHRIST: Progress in Heterocyclic Chemistry, Volume 10 GRIBBLE & GILCHRIST: Progress in Heterocyclic Chemistry, Volume 11 SESSLER & WEGHORN: Expanded Contracted and Isomeric Porphyrins PELLETIER: Alkaloids: Chemical & Biological Abstracts, Volume 9 PELLETIER: Alkaloids: Chemical & Biological Abstracts, Volume 10 PELLETIER: Alkaloids: Chemical & Biological Abstracts, Volume 11 PELLETIER: Alkaloids: Chemical & Biological Abstracts, Volume 12 PELLETIER: Alkaloids: Chemical & Biological Abstracts, Volume 13 WONG & WHITESIDES: Enzymes in Synthetic Organic Chemistry

Major Reference Works BARTON, NAKANISHI, METH-COHN: Comprehensive Natural Products Chemistry KATRITZKY & REES: Comprehensive Heterocyclic Chemistry I CD-Rom KATRITZKY, REES & SCRIVEN: Comprehensive Heterocyclic Chemistry II

Journals BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) PHYTOCHEMISTRY TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON: LETTERS

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Alkaloids: Chemical and Biological Perspectives Volume Fourteen

Edited by

S. William Pelletier Institute for Natural Products Research and Department of Chemistry The University of Georgia, Athens

1999

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First edition 1999 Library of Congress Cataloging in Publication Data A catalog record from the Library of Congress has been applied for. British Library Cataloguing in Publication Data A catalogue record from the British Library has been applied for.

ISBN:

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Dedicated to the memory of

Roger Adams (1889-1971) Roger Adams was one of the great leaders who influenced the development of chemistry in the United States. He was born on June 2, 1889 (Boston), a member of the famous family which produced two presidents of the United States. After graduation (B.A., 1905) he obtained his Ph.D. (1912, Harvard) and spent three years (1913-1916) as an instructor in the Chemistry Department of Harvard University. During this period he spent some time in Germany to work with Richard Willstatter on the synthesis of some pyrrolomethanes related to the structure of chlorophyll. After returning from Germany, he joined the faculty of the University of Illinois in Urbana (1916) and served as chairman of the chemistry department from 1926-1954. Adams was interested in the study of natural products and established the correct structure of the pyrroloquinazoline alkaloid vasicine (1936). He contributed largely to the study of alkaloids of the Crotalaria and Senecio species which cause liver cirrhosis in grazing cattle. Other pyrrolidine alkaloids studied by him were: monocrotaline, seneciphylline, retrorsine, trichodesmine, jacobine and grantianine. He determined the structures of the "necic acids" such as monocrotic and monocrotalic acids, and the bases isolated by hydrolysis of the pyrrolidine alkaloids. He corrected the structure of riddellic acid, obtained by hydrolysis of riddelliine, an alkaloid from Senecio riddellii. Adams worked on the structures of gossypol from cotton seed meal, cannabinols from marijuana, and chalmoogra oil. He worked for three decades on the stereochemistry of molecules with restricted rotations about a single bond. Adams's contributions to the growth of organic chemistry are extraordinary. He published 425 papers, guided 184 Ph.D. students, 50 postdoctorals and consulted for many major chemical companies. Adams was solely responsible for starting the series of volumes of Organic Syntheses (1921) and later Organic Reactions (1942).

B. S. Joshi

v

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Contributors Toh-Seok Kam, Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, MALAYSIA. Jie Jack Li, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, U.S.A. Paul L. Schiff, Jr., Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pennsylvania 15261, U.S.A.

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Preface Volume 14 of this series presents three interesting reviews of research on alkaloids. Chapter 1, by Paul L. Schiff, Jr. is a monumental effort, presenting a selective, comprehensive tabular review of research on the bisbenzylisoquinoline alkaloids, with an analysis of the respective alkaloid types. The chapter should serve as a very useful tool for the bench research scientist who is involved in the isolation and elucidation of structures of bisbenzylisoquinoline alkaloids. Moreover, the data in these tables provides the botanical distribution and occurrence (family, genus, species) of the various classes of these alkaloids. The alkaloids are also categorized by their molecular weights and structural types. Chapter 2, by Toh-Seok Kam is a review of alkaloids derived from Malaysian flora. Malaysia's position near the Equator confers on it a tropical climate characterized by high temperatures, humidity, and rainfall, conditions favorable for plant life that has resulted in a rich flora of about 15,000 species of higher plants. This review concentrates on work published during the past twenty years and where appropriate compares the occurrence of alkaloids with studies of similar plants from countries neighboring to Malaysia, especially Thailand and Indonesia. Chapter 3 by Jie Jack Li presents a collection of very interesting total syntheses of naturally occurring indole alkaloids where palladium chemistry plays a central role in the syntheses. Five different types of palladium-mediated reactions are treated: (1) oxidative cyclization reactions promoted by palladium (II) species; (2) transmetallation reactions with organoboranes, organostannanes, and organozinc reagents; (3) inter- and intramolecular Heck reactions; (4) reactions with 7t-allylpalladium as the intermediate; and (5) reactions using C-N bond formation as the key step for the synthesis. Each chapter in this volume has been reviewed by at least one specialist in the field. The editor thanks these reviewers for their important contributions to this volume. Indexes for both subjects and organisms are provided. The editor invites prospective contributions to write him about topics for review in future volumes of this series. S. William Pelletier Athens, Georgia July 15, 1998 IX

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Contents of Previous Volumes Volume 1 1. The Nature and Definition of an Alkaloid S. William Pelletier 2. Arthropod Alkaloids: Distribution, Functions, and Chemistry Tappey H. Jones and Murray S. Blum

33

3. Biosynthesis and Metabolism of the Tobacco Alkaloids Edward Leete

85

4. The Toxicology and Pharmacology of Diterpenoid Alkaloids M. H. Benn and John M. Jacyno 5. A Chemotaxonomic Investigation of the Plant Families of Apocynaceae, Loganiaceae, and Rubiaceae by Their Indole Alkaloid Content M. Volkan Kisaburek, Anthony J.M. Leeuwenberg, and Manfred Hesse

153

211

Volume 2 1. Some Uses of X-ray Diffraction in Alkaloid Chemistry Janet Finer-Moore, Edward Arnold, and Jon Clardy 2. The Imidazole Alkaloids Richark K. Hill 3. Quinolizidine Alkaloids of the Leguminosae: Structural Types, Analyses, Chemotaxonomy, and Biological Properties A. Douglas Kinghorn and Manuel F. Balandrin

1

49

105

4. Chemistry and Pharmacology of Maytansinoid Alkaloids Cecil R. Smith, Jr. and Richard G. Powell 5.

13 C and Proton NMR Shift Assignments and Physical Constants of Ci9-Diterpenoid Alkaloids S. William Pelletier, Naresh V. Mody, Balawant S. Joshi, and Lee C. Schramm

149

XI

Contents of Previous Volumes

Volume 3 1. The Pyridine and Piperidine Alkaloids: Chemistry and Pharmacology Gabor B. Fodor and Brenda Colasanti 2. The Indolosesquiterpene Alkaloids of the Annonaceae Peter G. Waterman

9]

3. Cyclopeptide Alkaloids Madeleine M. Joullie and Ruth F. Nutt

113

4. Cannabis Alkaloids Mahmoud A. ElSohly

169

5. Synthesis of Lycopodium Alkaloids Todd A. Blumenkopf and Clayton H. Heathcock

185

6. The Synthesis of Indolizidine and Quinolizidine Alkaloids of Tylophora, Cryptocarya, Ipomoea, Elaeocarpus, and Related Species R. B. Herbert

241

7. Recent Advances in the Total Synthesis of Pentacyclic Aspidosperma Alkaloids Larry E. Overman and Michael Sworin

275

Volume 4 1. Amphibian Alkaloids: Chemistry, Pharmacology and Biology John W. Daly and Thomas F. Spande 2. Marine Alkaloids and Related Compounds William Fenical 3. The Dimeric Alkaloids of the Rutaceae Derived by Diels-Alder Addition Peter G. Watermann 4. Teratology of Steroidal Alkaloids Richard F. Keeler

275

331

389

Contents of Ftovious

Volume 5 1. The Chemistry and Biochemistry of Simple Indolizidine and Related Polyhydroxy Alkaloids Alan D. Elbein and Russell J. Molyneux 2. Structure and Synthesis of Phenanthroindiolizidine Alkaloids and Some Related Compounds Emery Gellert

1

55

3. The Aporphinoid Alkaloids of the Annonaceae Andre Cave, Michel Leboeuf, Peter G Waterman

133

4. The Thalictrum Alkaloids: Chemistry and Pharmacology Paul L Schiff, Jr.

271

5. Synthesis of Chephalotaxine Alkaloids Tomas Hudlicky, Lawrence D. Kwart, and Josephine W. Reed

639

Volume 6 1. Chemistry, Biology and Therapeutics of the Mitomycins William A. Remers and Robert T. Dorr

1

2. Alkaloids of Tabernaemontana Species Teris A. van Beek and Marian A.J.T. van Gessel

75

3. Advances in Alkaloid Total Synthesis via Iminium Ions, a-Aminocarbanions and a-Aminoradicals David J. Hart 4. The Biosynthesis of Protoberberine Alkaloids Christopher W. W. Beecher and William J. Kelleher 5. Quinoline, Acridone and Quinazoline Alkaloids: Chemistry, Biosynthesis and Biological Properties Michael F. Grundon

227

297

339

Contents of Previous Volumes

Volume 7 1. Homoerythrina and Related Alkaloids /. Ralph C. Bick andSirichai Panichanum 2. Carbon-13 NMR Spectroscopy of Steroidal Alkaloids Pawan K. Agrawal, Santosh K. Srivastava, and William Gaffleld 3. Carbon-13 and Proton NMR Shift Assignments and Physical Constants of Norditerpenoid Alkaloids S. William Pelletier and Balawant S. Joshi

1

43

297

Volume 8 1. Curare Norman G. Bisset 2. Alkaloid Chemistry and Feeding Specificity of Insect Herbivores James A. Saunders, Nichole R. O'Neill, and John T. Romero

151

3. Recent Advances in the Synthesis of Yohimbine Alkaloids Ellen W. Baxter and Patrick S. Mariano

197

4. The Loline Group of Pyrrolidine Alkaloids

320

Richard G. Powell and Richard J. Petroski Volume 9 1. Taxol M.E. Wall and M. C. Wani

1

2. The Synthesis of Macroline Related Sarpagine Alkaloids Linda K. Hamaker and James M. Cook

23

3. Erythrina Alkaloids Amrik Singh Chawla and Vijay K. Kapoor

85

4. Chemistry, Biology and Chemoecology of the Pyrrolizidine Alkaloids Thomas Hartmann and Ludger Witte

155

5. Alkaloids from Cell Cultures of Aspidosperma Quebracho-Bianco P. Obitz, J. Stockigt, L A. Mendonza, N Aimi and S.-i. Sakai

235

Contents of Previous Volumes

6. Fumonisins Richard G Powell and Ronald D. Planner

247

Volume 10 1. Alkaloids from Australian Flora /. R. C. Bick 2. Pyridine and Piperidine Alkaloids: An Update Marilyn J. Schneider

155

3. 3-Alkylpiperidine Alkaloids Isolated from Marine Sponges in the Order Haplosclerida Raymond J. Andersen, Rob W. M. Van Soest and Fangming Kong

301

4. P-Carboline and Isoquinoline Alkaloids from Marine Organisms Bill J. Baker

357

Volume 11 1.

The Thalictrum Alkaloids: Chemistry and Pharmacology (1985 - 1995) Paul L. Schiff, Jr.

2.

Taxine Giovanni Appendino

237

3.

The Alkaloids of South American Menispermaceae Mary D. Menachery

269

4.

The Chemistry and Biological Activity of Calystegines and Related Nortropane Alkaloids Russell J. Molyneux, Robert J. Nash, and Naoki Asano

303

5.

Polyhydroxylated Alkaloids that Inhibit Glycosidases Robert J. Nash, Naoki Asano, and Alison A. Watson

345

Contents of Previous Volumes Volume 12 1.

Acronycine-type Alkaloids: Chemistry and Biology Francois Tillequin, Sylvie Michel and Alexios-Uandros Skaltsounis

1

2.

Solarium Steroid Alkaloids — an Update Helmut Ripperger

103

3.

Synthesis and Structure-Activity Studies of Lissoclinum Peptide Alkaloids Peter Wipf

187

4.

Pyroglutamate as a Chiral Template for the Synthesis of Alkaloids Michael B. Smith

229

5.

Analysis of Alkaloids by Capillary Electrophoresis and Capillary Electrophoresis — Electrospray Mass Spectrometry Joachim Stockigt, Matthias Unger, Detlef Stockigt, and Detlev Belder

289

6.

Oxidation of Anthelmentic Marcofortine A, an Indole Alkaloid Byung H. Lee, Michael F. Clothier, and Gabe I Kornis

343

Volume 13 1.

Alkaloids from Amphibian Skins John W. Daly, H. Martin Garraffo and Thomas F. Spande

1

2.

Naturally Occurring Cyclotryptophans and Cyclotryptamines Uffe Anthoni, Carsten Christophersen and Per Halfdan Nielson

163

3.

Recent Research on Pyrrole Alkaloids Philip W. LeQuesne, Ying Dong and Todd A. Blythe

237

4.

Recent Developments in the Chemistry of Norditerpenoid and Diterpenoid Alkaloids Balawant S. Joshi and S. William Pelletier

289

5.

New Approaches to the Syntheses of Piperidine, Izidine, and Quinazoline Alkaloids by Means of Transition Metal Catalyzed Carbonylations Iwao Ojima and Donna M. Iula

371

Contents 1. The Bisbenzylisoquinoline Alkaloids - A Tabular Review Paul L Schiff, Jr. 2. Alkaloids from Malaysian Flora Toh-SeokKam 3. Applications of Palladium Chemistry to the Total Syntheses of Naturally Occurring Indole Alkaloids JieJackLi

437

Subject Index

505

Organism Index

529

1 235

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Chapter One

The Bisbenzylisoquinoline Alkaloids A Tabular Review Paul L. Schiff, Jr. Department of Pharmaceutical Sciences School of Pharmacy University of Pittsburgh Pittsburgh, Pennsylvania 15261 CONTENTS 1. 2. 3. 4. 5. 6. 7. 8. 9.

INTRODUCTION 3 AN ALPHABETICAL TABULAR COMPILATION OF THE BISBENZYLISOQUINOLINE ALKALOIDS 4 A NUMERIC TABULAR COMPILATION OF THE BISBENZYLISOQUINOLINE ALKALOIDS 36 AN ALPHABETICAL TABULAR COMPILATION OF THE BOTANICAL SOURCES (GENERA) OF THE BISBENZYLISOQUINOLINE ALKALOIDS 77 AN ALPHABETICAL TABULAR COMPILATION OF THE BOTANICAL SOURCES (FAMILIES) OF THE BISBENZYLISOQUINOLINE ALKALOIDS 112 A TABULAR COMPILATION OF THE CALCULATED MOLECULAR WEIGHTS OF THE BISBENZYLISOQUINOLINE ALKALOIDS 133 A TABULAR COMPILATION OF THE STRUCTURAL TYPES OF THE BISBENZYLISOQUINOLINE ALKALOIDS 147 ALKALOIDS WITH DUPLICATIVE NOMENCLATURE 165 AN ANALYSIS OF THE DISTRIBUTION OF THE BISBENZYLISOQUINOLINE ALKALOIDS BY STRUCTURAL TYPE 168 9.1. O n e Diphenyl Ether Linkage (Tail-to-Tail) 168 9.1.1. Typel(6,7,ll*,12-6,7,12*) 168 9.1.2. Type la (6,7,11*. 12-5,6,7,12*) 175 9.1.3. TVpeIb(6,7,10,ll*,12-6.7,12*) 176 9.1.4. Type 0 (6,7,10*,12,13-6,7,12*) 176 9.1.5. Type H a (6,7,10*,12,13-6,7,11,12*) 177 9.1.6. Type IIb(6,7,10*,l 1,12-6,7,11,12*) 177 9.1.7. Typeffl(5,6,7,ll*,12-5,6,7,12*) 178 9.2. O n e Diphenyl Ether Linkage (Head-to-Tail) 180 9.2.1. TypeV(6,7,ll*,12-6,7*,12) 180 9.2.2. TypeVa(6,7,10*,12,13-6,7*,ll,12) 180 9.2.3. TypeVb(6,7,10*,ll,12.13-6,7*,ll,12) 181 9.2.4. Type Vc (6,7,10,12*-6,7*,12) 181

2

P.L. Schiff, Jr. 9.2.5. TypeVd(6,7,12*-6,7*,8,12) 9.3. One Diphenyl Linkage (Tail-to-Tail) 9.3.1. TVpe XXVH [6,7,12-6,7,12(11-11)] 9.4. One Diphenyl Ether Linage (Head-to-Head) and One Diphenyl Linage (Tail-toTail) 9.4.1. Type IV [6,7,8M2-6,7*,12(11-11)] 9.5. One Diphenyl Ether Linage (Head-to-Head) and One Diphenyl Ether Linage (Tail-to-Tail) 9.5.1. TypeVI(6,7*,ir,12-6,7,8*,12*) 9.5.2. Type Via (6,7M0,11M2-6,7,8*,12*) 9.5.3. Type VII (6,7*,ir,12-5,6,7,8*,12*) 9.5.4. TypcVffl(6,7,8MlM2-6,7M2*) 9.5.5. TypeDC(5,6,7,8*,llM2-6,7*,12*) 9.5.6. Type X (6,7,8*,11*, 12,13-6,7*. 12*) 9.5.7. TypeXa(6,7,8*,10,llM2-6,7*,12+) 9.5.8. Type Xb (6,7*,8,10,1IV 2-6,7*, 12*) 9.5.9. TypeXI(6,7,8*,ll*,12-6*,7,12*) 9.5.10. TypeXn(6,7,8*,ir,12-5*,6,7,12*) 9.5.11. TypeXna(5,6,7,8*,llM2-5*,6,7,12+) 9.5.12. TypeXIII(5*,6,7,llU2-5,6,7,8*,12*) 9.5.13. Type XIV (6,7*,1 1*,12-5*,6,7,12*) 9.5.14. Type XlVa (5,6,7*, 1 lM2-5*,6,7f 12*) 9.5.15. Type XV (5*,6,7,11*, 12-6,7*. 12*) 9.5.16. Type XVI (5*,6,7,11M2-6*,7,12+) 9.5.17. Type XVII (5,6,7,8*,10,12,13*-6,7*,12*) 9.6. One Diphenyl Ether Linage (Head-to-Tail) and One Diphenyl Ether Linage (Head-to-Tail) 9.6.1. TypeXX(6,7,8*,12*-6,7,8U2*) 9.6.2. TypeXXI(6,7,8*,llM2-6,7M2*) 9.7. Two Diphenyl Ether Linkages (Head-to-Head) and One Diphenyl Linkage (Tail-to-Tail) 9.7.1. TypeXVm[6,7*,8U2-6*,7M2(l 1-11)] 9.7.2. Type XIX [5,6,7*,8M2-6*,7M2(11-11)] 9.7.3. Type XDCa[5,7*,8M2-6*,7M2(l 1-11)] 9.8. One Diphenyl Ether Linkage (Head-to-Tail) and One Benzylphenyl Ether Linkage (Head-to-Tail) 9.8.1. TypeXXn(6,7,8,12*-6,7,8*[7-12]) 9.8.2. Type XXHa(6,7,8,1 lM2-6,7*[7-12]) 9.9. Two Diphenyl Ether Linkages (Head-to-Head) and One Diphenyl Ether Linkage (Tail-to-Tail) 9.9.1. TypeXXni(6*,7MlM2-6,7*.8M2 i ) 9.9.2. TypeXXma(6*.7Ml#,12-5,6,7*,8M2#) 9.9.3. TypeXXIIIa(6,7*,8Mli.12-6,74.8*.12i) 9.9.4. TypeXXVin(6,7*,8Vl i ,12-6*,7\12 i ) 9.10. One Diphenyl Ether Linkage and One Benzylphenyl Ether Linkage (Head-to Head) and One Diphenyl Ether Linkage (Tail-to-Tail)

182

182 182 184 184 190 190 202 203 204 220 222 224 226 226 229 232 232 234 236 238 238 239 241 241 244 250 250 253 255 256 256 258 259 259 266 268 269 271

The Bisbenzylisoquinoline Alkaloids - A Tabular Review 9.10.1. Type XXV (6,7,8*,llM2,13-6,7*,12*[8-6]) 9.11. One Diphenyl Ether Linkage and One Benzylphenyl Ether Linkage (Head-to-Tail) and One Diphenyl Ether Linkage (Head-to-Tail) 9.11.1. Type XXVI (6,7,8*.12*-6,7,8M2*[11-7])

1.

3 271

272 272

INTRODUCTION*

Over the last twenty years, no less than five tabular reviews describing the bisbenzylisoquinoline alkaloids have appeared [1-5]. These works have detailed the botanical sources, as well as the physical and spectral data, for over 430 different alkaloids. Pharmacological activities, analytical methods, and significant biosynthetic pathways have also been featured. Since I have been the author of four of these reviews [2-5], it occurred to me that a collation of selective tables featured in these reviews into a single, defined chapter would perhaps serve as a contribution to those engaged in research in this field. Toward that end, I offer the reader a selective comprehensive tabular review of these alkaloids, with an analysis of the respective alkaloid types. This work should not be considered as a definitive academic treatise of the subject, but rather as a useful pragmatic tool for the bench research scientist who is actively involved in the isolation and elucidation of structure of bisbenzylisoquinoline alkaloids. A consideration of the data in these tables, as well as the analysis provided in the last section, permits the reader to understand the botanical distribution and occurrence (family, genus, species) of the various classes of bisbenzylisoquinoline alkaloids. In addition, the alkaloids are also categorized according to their molecular weights and structural types. In order to maintain a consistency between this chapter and the previous reviews [1-5], the work in this chapter continues to utilize the alkaloid numbering system and structural-type nomenclature presented in the first review of the series [1], and maintained throughout the next four reviews [2-5]. The numbering of the skeleton and the systematic numerical classification describing the oxygenation and dimerization patterns of the alkaloids generally follow the convention established by Shamma and Moniot [483], and Guinaudeau et al. [129], as exemplified by:.

This chapter is dedicated to my children: Anne-Marie, Elizabeth Anne, Paul Edmund, and Mary Denise. As you have been born, beginning in 1964 and concluding in 1992, I have been blessed with your presence. May God go with you all as you walk through His world.

4

P.L.Schiff,Jr.

In order to retain a sense of consistency that encompasses decades of work, the alkaloids in this chapter have been drawn such that the Ring C terminus of the diphenyl ether bridge between Ring C and Ring C is always at C-12\ This has resulted in the representation of four alkaloids that bear numbers in their names in a "flipped" position in comparison to the manner in which they were found in the original reviews [1-5]. These four alkaloids include: 1,2dehydrokohatamine (289), 1,2-dehydrokohatine (290), 5-hydroxyapateline (309), and 5hydroxytelobine (310). Each of these compounds has been drawn with the Ring C terminus of their Ring C - Ring C diphenyl ether bridge at C-12'. The appearance of the molecules is thus such that the numbers in their names should assume "prime" nomenclature, eg 1,2dehydrokohatamine (289) appears is if it really is 1',2'-dehydrokohatamine, etc. I have not chosen to make this nomenclature change in the tables because of the historic precedent involved, and the confusion that it would produce, particularly to the novice in this field. Finally, I have not undertaken the condensation of the spectral data in these tables into a focussed offering that would compliment the work here presented. It is not because I believe that such a work should not be done, but because this chapter is now very lengthy as it is, and also because I have simply "run of steam" for the present time. I hope that the reader will forgive me this failure. Finally, it has been almost forty years since my curiosity and interest in this group of alkaloids began, in those early years as a student of Professor Jack L. Beal in his course in Pharmacognosy in the College of Pharmacy at The Ohio State University in 1959-1960. This continued in my years as his graduate student, and then under the tutelage of Professor Raymond W. Doskotch during my doctoral studies. To these two men, I owe much, and I have learned that I can only partially repay that debt by passing on a little bit of them through me to my students. It is my hope that this spirit of tradition and integrity will continue to walk, hand-in-hand, from advisor to student, through the years and centuries to come.

2.

AN A L P H A B E T I C A L T A B U L A R B1SBENZYLISOQUINOLINE ALKALOIDS

COMPILATION

OF

THE

Table 1

272 Ambrimine C3gH44OsN2:656.3097 Hernandia nymphaeifolia (Presl) Kubirtzki [Biasoletlia nymphaeifolia Presl, Hernandia peltata (Meissn.)] (Hernandiaceae)[6] 394 Angchibangkine Pachygone dasycarpa Kurz (Menispermaceae)[7]

CJ5HM05N2:562.2468

225 Antioquine Pseudoxandra aff. lucida Fries (Annonaceae)[8]

C37H40O6N2:608.2886

The Blsbenzyllsoqnlnollne Alkaloids - A Tabular Review

5

Table 1. Continued 187 Apateline C34H3205N2:548.2311 Albertisia laurifolia (Menispermaceae)[9] Albertisia papuana Becc. (Menispermaceae)[10] Daphnandra apatela Schodde (Monimiaceae)[l 1] Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[ 12] Pachygone loyaltiensis Diels (Menispermaceae)[13] 273 Aquifoline Mahonia aquifolium (Pursh) Nutt. (Berberidaceac)[14] 31

C36H3lO6N2:594.2730

Aromoline (Thalicrine) CMH3gO6N2:594.2730 Abuta splendida Krukoff and Moldenkc (Menispermaceae)[15] Albertisia laurifolia (Menispermaceae)[9] Albertisia papuana Becc. (Menispermaceae)[16] Berberis aristata DC. (Berberidaceae) [see Berberis flohbunda Wall ex. Don (Berberidaceae)][17] Berberis boliviano Lechl. (Berberidaceae)[18] Berberis bumeliaefolia Schneid. (Berberidaceae)[ 18] Berberis cretica L. (Berberidaceae)[19] Berberis jloribunda Wall ex. Don (Berberidaceae)[also known as Berberis arisata DC. (Berberidaceae)] [ 17] Berberis koreana Palib. (Berberidaceae)[20] Berberis laurina (Thunb.) Billbg. (Berberidaceae)[18] Berberis nummularia Bge. (Berberidaceae)[21 ] Berberis orthobotrys Bienert ex Aitch. (Berberidaceae)[78] Berberis stolonifera (Berberidaceae)[23] Berberis turcomanica Kar. (Berberidaceae)[24] Berberis waziristanica (Berberidaceae)[25] Daphnandra aromatica F.M. Bailey (Monimiaceae)[26] Daphnandra tenuipes Perk. (Monimiaceae)[27] Doryphora aromatica Schodde (Monimiaceae)[28] Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[12] Mahonia aquifolium (Pursh) Nutt. (Berberidaceae)[29] Stephania cepharantha Hayata (Menispermaceae)[30-33] Stephania pierrii Diels (Menispermaceae)[34] Thalictrum cultratum Wall. (Ranunculaceae)[35] Thalictrum fortunei S. Moore (Ranunculaceae)[36] Thalictrum lucidum L. (Ranunculaceae)[37] Thalictrum minus L. var. microphyllum Boiss. (Ranunculaceae)[38] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)][39] Thalictrum thunbergii DC. (Ranunculaceae)[40,41] Triclisia patens Oliv. (Menispermaceae)[42]

P.L.SchifT,Jr. Table 1. Continued

171 Artifact (No. 16) Cyclea peltata Diels (Menispermaceae)[43]

C39H4406N2C12:707.2259

56 Atherospermoline Atherosperma moschatum L. (Monimiaceae)[44] Pachygone dasycarpa Kurz (Menispermaceae)[7]

C36H3gO6N2:594.2730

390 Auroramine C3gH40OgN2:652.2785 Gyrocarpus americanus Jacq. (Hernandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)] [45] 257 Baluchistanamine Berberis baluchistanica Ahrendt (Berberidaceae)[46]

C37H3gOgN2:638.2628

188 Baluchistine Berberis baluchistanica Ahrendt (Berberidaceae)[47]

C36H3gO6N2:594.2730

93

Belarine 03^0^:608.2886 Berberis laurina (Thunb.) Billbg. (Berberidaceae)[ 18,48]

218 Berbacolorflammine (1,2,3,4-Tetradehydrolimacine) C37H37O6N2*:605.2652 Pycnarrhena longifolia (Decne. ex Miq.) Becc. (Menispermaceae)[49,50] 57

Berbamine C37H40O6N2:608.2886 Atherosperma moschatum L. (Monimiaceae)[51 ] Berberis aggregata (Berberidaceae)[52] Berberis amurensis Rupr. (Berberidaceae)[53] Berberis aristata DC.. (Berberidaceae)[see Berberis floribunda Wall ex. Don (Berberidaceae)][ 17,54] Berberis aquifolium Pursch (Berberidaceae)[56] Berberis asiatica Roxb. ex DC. (Berberidaceae)[57] Berberis boliviano Lechl. (Berberidaceae)[18] Berberis brandisiana Ahrendt (Berberidaceae)[58] Berberis bumeliaefolia Schneid. (Berberidaceae)[18] Berberis chilensis Gill, ex Hook. (Berberidaceae)[59] Berberis cretica L. (Berberidaceae)[19] Berberis dictyoneura (Berberidaccae)[52] Berberis floribunda Wall ex. Don (Berberidaceae)[also known as Berberis arisata DC.. (Berberidaceae)][ 17,54] Berberis fortunei Lindl. (Berberidaceae)(See (Hort.) Fedde (Berberidaceae)[55]) Berberis fracisci-ferdinandi (Berberidaceae)[52] Berberis heterobotrys Wolf. (Berberidaceae)[60]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

7

Table 1. Continued

Berberis heteropoda Schrenk (Berberidaceae)[see Berberis vulgaris L. (Berberidaceae)][61 ] Berberis iliensis (Berberidaceae)[62] Berberisjaponic a R.Br. (Berberidaceae)(See Mahoniajaponica DC. (Berberidaceae)[55]) Berberis julianae Schneid. (Berberidaceae)[63] Berberis kawakamii Hayata (Berberidaceae)[64] Berberis koreana Palib. (Berberidaceae)[20] Berberis lambertii R.N. Parker (Berberidaceae)[65] Berberis lycium (Royle) (Berberidaceae)[66-68] Berberis mingetsensis Hayata (Berberidaceae)[69] Berberis morrisonensis Hayata (Berberidaceae)[69] Berberis oblonga (Regl.)(Berberidaceae)[70] Berberis orthobotrys Bienert ex Aitch. (Berberidaceae)[78] Berberis paucidentata Rusby. (Berberidaceae)[ 18] Berberis petiolaris Nail (Berberidaceae)[71] Berberis poiretii (Berberidaceae)[72,73] Berberis pseudothunbergii (Berberidaceae)[52] Berberis regeliana (Berberidaceae)[74) Berberis sibirica Pall. (Berberidaceae)[75] Berberis stolonifera (Berberidaceae)[23,76] Berberis swaseyi Buckey (Berberidaceae)[77] Berberis thunbergii DC. (Berberidaceae)[79,80] Berberis tinctoria Leschen (Berberidaceae)(also designated as Berberis aristata DC. (Berberidaceae)[81 ] Berberis virgetorum (Berberidaceae)[82] Berberis vulgaris L. (Berberidaceae)[also called Berberis heteropoda Schrenk (Berberidaceae)][61,83-86] Berberis wilsoniae Hemsl. et Wils. (Berberidacaeae)[87] Berberis zebiliana (Berberidaceae)[88] Cyclea barbata (Wall.) Miers (Menispermaceae)[89,90] Isopyrum thalictroides L. (Ranunculaceae)[91] Limaciopsis loangensis Engl. (Menispermaceae)[92] Mahonia aquifolium (Pursh) Nutt. (Berberidaceae)[29,93-95] Mahonia fortunei (Hort.) Fedde (Berberidaceae)[55] Mahonia griffithii Takeda (Berberidaceae)[96] Mahonia japonica DC. (Berberidaceae)[55] Mahonia lomariifolia Takeda (Berberidaceae)[97] Mahonia morrisonensis Takeda (Berberidaceae)[97] Mahonia philippinensis Takeda (Berberidaceae)[98) Mahonia swaseyi Fedde (Berberidaceae)(See Berberis swaseyi Buckey (Berberidaceae)[77]) Pycnarrhena australiana F. Muell. (Menispermaceae)[99]

P.L.Schiff,Jr. Table 1. Continued Pycnarrhena manillensis F. Muell. (Menispermaceae) or Vidal (Menispermaceae)[ 100,101 ]Pycnarrhena novoguineensis Miq. (Menispennaceae)[22] Stephania cepharantha Hayata (Menispermaceae)[30,32,102-105] Stephania sasakii Hayata (Menispermaceae)[106] Stephania tetrandra S. Moore (MenispermaceaeXdetected; not isolated)[107] Thalictrum foetidum L. (Ranunculaceae)[108] Thalictrum pedunculatum Edgew. (Ranunculaceae)[109] 274 Berbamine-2'p-N-Oxide Berberis brandisiana Ahrendt (Berberidaceae)[58]

C37H4o07N2:624.2836

1

0^^0^2:596.2886

Berbamunine Berberis amurensis Rupr. (Berberidaceae)[82,110] Berberis boliviano Lechl. (Berberidaceae)[18] Berberis brachypoda (Berberidaceae)[82] Berberis circumserrata (Berberidaceae)[82] Berberis cretica L. (Berberidaceae)[19] Berberis dasystachya (Berberidaceae)[82] Berberis diaphana (Berberidaceae)[82] Berberis dictyoneura (Berberidaceae)[82] Berberis dubia (Berberidaceae)[82] Berberis ferdinandi-coburgii (Berberidaceae)[82] Berberis gyalaica (Berberidaceae)[82] Berberis henryana (Berberidaceae)[82] Berberis heteropoda Schrenk (Berberidaceae)[l 11-113] Berberis iliensis (Berberidaceae)[62] Berberis integerrima Bge. (Berberidaceae)[114] Berberis jamesiana (Berberidaceae)[82] Berberis julianae Schneid. (Berberidaceae)[82] Berberis kansuensis (Berberidaceae)[82] Berberis nummularia Bge. (Berberidaceae)[21] Berberis oblonga (Regl.XBerberidaceae)[115] Berberis poiretii (Berberidaceae)[82] Berberis polyantha (Berberidaceae)[82] Berberis prattii (Berberidaceae)[82] Berberis sargentiana (Berberidaceae)[82] Berberis silva-taroucana (Berberidaceae)[82] Berberis soulieana (Berberidaceae)[82] Berberis stolonifera (Berberidaceae)[23,76] Berberis turcomanica Kar. (Berberidaceae)[116] Berberis valdiviana (Berberidaceae)[82] Berberis vernae (Berberidaceae)[82] Berberis vulgaris L. (Berberidaceae)[84,86]

The Blsbenzyllsoqoinoline Alkaloids - A Tabular Review Table 1. Continued

Pseudoxandra sclerocarpa Maas (Annonaceae)[117] Stephania pierhi Diels (Menispermaceae)[34] 275 Berbilaurine Berberis laurina (Thunb.) Billbg. (Berberidaceae)[ 18]

C36H38O6N2:594.2730

32

C34H3406N2:566.2417

N,N'-Bisnoraromoline Albertisia papuana Becc. (Menispermaceae)[10] Pachygone loyaltiensis Diels (Menispermaceae)[13] Pycnarrhena ozantha Diels (Menispermaceae)[ 118]

276 2,2'-Bisnorguattaguianine C36H38O6N2:594.2730 Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[ 119] 277 Bisnorobamegine Pycnarrhena ozantha Diels (Menispermaceae)[120]

C34H3406N2:566.2417

278 2,2'-Bisnorphaeanthine Albertisia papuana Becc. (Menispermaceae)[10]

C36H38O6N2:594.2730

279 Bisnorthalrugosine Pycnarrhena ozantha Diels (Menispermaceae)[ 120]

C35H36O6N2:580.2573

189 Calafatimine Berberis bwcifolia Lam. (Berberidaceae)[121]

C38H40O7N2:636.2836

190 Calafatine Berberis bwcifolia Lam. (Berberidaceae)[121-123] Berberis horrida (Berberidaceae)[124]

C39H4407N2:652.3149

226 Calafatine-2'a-N-Oxide Berberis bwcifolia Lam. (Berberidaceae)[125,126]

C39H44O8N2:668.3098

227 Calafatine-2'P-N-Oxide Berberis bwcifolia Lam. (Berberidaceae)[125,126]

€^0^2:668.3098

280 Candicusine C%H38O6N2:594.2730 Curarea candicans (L.C. Rich) Barneby and R Krukoff (Menispermaceae)[127-129] 281 Caryolivine C36H34O6N2:590.2417 Caryomene olivascens Bameby et Krukoff (Menispermaceae)[74]

10

P.L.SchifT,Jr. Table 1. Continued

33

Cepharanoline C36H3606N2:592.2573 Stephania cepharantha Hayata (Menispermaceae)[32,102,104] Stephania epigeae Diburong (Menispermaceae)[130]

34

Cepharanthine C37H3gO6N2:606.2730 Stephania cepharantha Hayata (Menispermaceae)[32J02,104,105,131] Stephania epigeae Diburong (Menispermaceae)[132,133] Stephania erecta Craib. (Menispermaceae)[134,135] Stephania pierrii Diels (Menispermaceae)[34] Stephania sasakii Hayata (Menispermaceae)[106] Stephania sinica Diels (Menispermaceae)[136] Stephania suberosa Forman (Menispermaceae)[137]

282 Cepharanthine-2'p-N-Oxide Stephania suberosa Forman (Menispermaceae)[137]

C37H3gO?N2:622.2679

258 Chenabine Berberis lycium (Royle) (Berberidaceae)[138]

C37H40O7N2:624.2836

228 Cheratamine C36H34O7N2:606.2366 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[ 139] 229 Chillanamine Berberis buxifolia Lam. (Berberidaceae)[123]

C37H4207N2:626.2992

129 Chondocurarine C3gH4406N2:624.3199 Chondodendron tomentosum Ruiz and Pavon (Menispermaceae)[140] 130 Chondocurine [Chondrocurine, (+)-Tubocurine] C3AH3gO6N2:594.2730 Chondodendron tomentosum Ruiz and Pavon (Menispermaceae)[141,142] Cyclea barbata (Wall.) Miers (Menispermaceae)[143] Cyclea madagascariensis Baill. (Menispermaceae)[144] Peruvian Curare [145] 131 Chondrofoline C37H40O6N2:608.2886 Chondodendron platiphyllum Miers (Menispermaceae)[146] Cleistopholis staudtii Engl, et Diels (Annonaceae)[147] Uvaria .»- a A. DC.. (Annonaceae)[148] 145 Cissampareine Cissampelos pareira L. (Menispermaceae)[149]

C37H38O6N2:606.2730

The BisbenzylisoquinoUne Alkaloids - A Tabular Review

11

Table 1. Continued 395 Cissampentin Cissampelos fasciculata Benth. (Menispermaceae)[ 150] 35

C37H40O6N2:608.2886

Coclobine C37H3gO6N2:606.2730 Anisocycla cymosa Troupin (Menispermaceae)[151] Cocculus trilobus D C (Menispermaceae)[152] Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[12)

396 Cocsiline C35H3406N2:578.2417 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[153] 397 Cocsilinine C33H30O6N2:550.2104 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[153] 152 Cocsoline C34H3205N2:548.2311 Albertisia laurifolia (Menispermaceae)[9] Albertisia papuana Becc. (Menispermaceae)[16,10] Anisocycla cymosa Troupin (Menispermaceae)[154] Cocculus leaebe DC. (Menispermaceae)[155] Cocculus pendulus (Forsk.) Diels (Mcnispermaceae)[139,153,156] Synclisia scabrida Miers (Menispermaceae)[157,158] 398 Cocsoline-2'P-N-Oxide Anisocycla cymosa Troupin (Menispermaceae)[ 159]

C34H32O6N2:564.2260

153 Cocsuline (Efirine, Trigilletine) C„H3405N2:562.2468 Albertisia laurifolia (Menispermaceae)[9] Albertisia papuana Becc. (Menispermaceae)[10,16] Anisocycla gradidieri H. Bn. (Menispermaceae)[165] Cocculus leaebe DC.. (Menispermaceae)[155] Cocculus pendulus (Forsk.) Diels (Menispermaceae)[139,153,156,161,166] erroneously identified as Andrachne cordifolia Muell., O.F. (Euphorbiaceae)[160]) Pachygone dasycarpa Kurz (Menispermaceae)[7] Synclisia scabrida Miers (Menispermaceae)[157,158] Triclisia dictyophylla Diels (Menispermaceae)[167] Triclisia gilletii (DeWild.) Staner (Menispermaceae)[168-170] Triclisia patens Oliv. (Menispermaceae)[168] 231 Cocsuline-N-2-Oxide Cocculus hirsutus Diels (Menispermaceae)[171]

C35H3406N2:578.2417

164 Cocsulinine ^5^0^:578.2417 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[153,156]

12

P.L.SchhT,Jr. Table 1. Continued

219 Colorflammine (r,2',3',4'-Tetradehydrolimacusine) C37H37O6N2+:605.2652 Pycnarrhena longifolia (Decne. ex Miq.) Becc. (Menispermaceae)[49,50] 283 Cordobimine Crematosperma sp. (Annonaceae)[172]

C36H3606N2:592.2573

284 Cordobine Crematosperma sp. (Annonaceae)[ 172]

C37H40O6N2:608.2886

399 Costaricine Nectandra salicifolia (H.B.K.) Nees (Lauraceae)[173]

C„H38O6N2:582.2730

285 Cultithalminine Thalictrum cultratum Wall. (Ranunculaceae)[35]

C36H36O7N2:608.2522

259 Curacautine Berberis buxifolia Lam. (Berberidaceae)[123]

C39H4209N2:682.2891

400 Curicycleatjenine Cyclea atjehensis Forman (Menispermaceae)[174]

C3lH3lO?N2:634.2679

401 Curicycleatjine Cyclea atjehensis Forman (Menispermaceae)[ 174]

C37H36O7N2:620.2523

132 (+)-Curine [Bebeerine, Chondodendrine] C36H3gO6N2:594.2730 A buta candicans Rich ex D C (Menispermaceae)[146] Buxus sempervirens L. (Buxaceae)[also called Buxus wallichiana Baill. (Buxaceae)][176] Buxus wallichiana Baill. (Buxaceae)[also called Buxus sempervirens L. (Buxaceae)][176] Chondodendron microphylum (Eichl.) Moldenke (Menispermaceae)[ 146] Cissampelos pareira L. (Menispermaceae)[(+/-)-Curine dimethiodide][476] Cyclea barbata (Wall.) Miers (Menispermaceae)(132 or 133)[177,178] Cyclea hainanensis Merr. (Menispermaceae)(132 or 133)[175] Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei (Lauraceae)][176] Ocotea rodiei (Lauraceae)[also known as Nectandra rodiei R. Schomb. (Lauraceae)][l 76] 133 (-)-Curine [(-)-Bebeerine] C36H3lO6N2:594.2730 Aristolochia indica L. (Aristolochiaceae)[179] Chondodendron platiphyllum Miers (Menispermaceae)[146] Chondodendron tomentosum Ruiz and Pavon (Menispermaceae)[ 141,142,200] Chondendron toxicoferum (Wedd.) Kruk. et Mold. (Menispermaceae)[201] Cissampelos pareira L. (Menispermaceae)[ 144,190,202,203]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

13

Table 1. Continued

Cleistopholis staudtii Engl, et Diels (Annonaceae)[147] Cyclea barbata (Wall.) Miers (Menispermaceae)[90] Cyclea barbata (Wall.) Miers (MenispermaceaeX132 or 133)[177,178] Cyclea hainanensis Merr. (Menispermaceae)(132 or 133)[175] Cyclea madagascahensis Baill. (Menispermaceae)[144] Isolona pilosa Diels (Annonaceae)[ 180,181 ] Paracyclea ochiaiana (Yamamoto) Kudo and Yamamoto (Menispermaceae)[ 182] Peruvian curare [145] Pleogyne australis Benth. (Menispermaceae)[also called Pleogyne cunninghamii Miers (Menispermaceae)][l 83] Pleogyne cunninghamii Miers (Menispermaceae)[also called Pleogyne australis Benth. (Menispermaceae)[183] Stephania epigeae Diburong (Menispermaceae)[130] 2

Cuspidaline C37H4206N2:610.3043 Limacia cuspidata Hook. f. and Thorns. (Menispermaceae)[ 184] Limacia oblonga Miers (Menispermaceae)[185]

402 Cycleabarbatine Cyclea barbata (Wall.) Miers (Menispermaceae)[90]

C37H40O6N2.608.2886

134 Cycleacurine Cyclea peltata Diels (Menispermaceae)[43]

€35*^0^2:580.2573

58

Cycleadrine Cyclea barbata (Wall.) Miers (Menispermaceae)[l] Cyclea peltata Diels (Menispermaceae)[43]

C37H40O6N2:608.2886

59

Cycleahomine Cyclea peltata Diels (Menispermaceae)[43]

C3,H4506N2+ :637.3278

286 Cycleaneonine Cyclea racemosa Oliv. (Menispermaceae)[187,188]

C3lH42O6N2:622.3043

403 (-)-Cycleaneonine Cyclea sutchuenensis Gagnep. (Menispermaceae)[ 188]

C38H42O6N2:622.3043

121 Cycleanine C3lH42O6N2:622.3043 Chondodendron tomentosum Ruiz and Pavon (Menispermaceae)[141,142] Cissampelos insularis Makino (Menispermaceae)(also called Paracyclea insularis (Makino) Kudo and Yamamoto (Menispermaceae)][131] Cissampelos pareira L. (Menispermaceae)[189,190] Cleistopholis staudtii Engl, et Diels (Annonaceae)[147]

14

P.L.Schiff,Jr. Table 1. Continued Cyclea hypoglauca (Menispermaceae)[ 191] Cyclea insularis (Makino) Diels (Menispermaceae)[192] Cyclea tonkinensis (Menispermaceae)[193] Epinetrum cordifolium Mangenot and Miege (Menispermaceae)[194] Epinetrum mangenotti Guill. and Debray (Menispermaceae)[194] Epinetrum villosum (Excell.) Troupin (Menispermaceae)[195] Heracleum wallichi (Umbelliferae)[197] lsolona hexaloba Engl. (Annonaceae)[181] Limaciopsis loangensis Engl. (Menispermaceae)[92] Paracyclea ochiaiana (Yamamoto) Kudo and Yamamoto (Menispermaceae)[182] Stephania capitata Spreng. (Menispermaceae)[204] Stephania cepharantha Hayata (Menispermaceae)[30,32,102,104,105,131] Stephania epigeae Diburong (Menispermaceae)[132] Stephania glabra (Roxb.) Miers (Menispermaceae)[205,206] Stephania pierrii Diels (Menispermaceae)[34] Stephania tetrandra S. Moore (Menispermaceae)[207J Synclisia scabrida Miers (Menispermaceae)[ 157,158,208]

232 Cycleanine N-Oxide Synclisia scabrida Miers (Menispermaceae)[158]

C38H40O7N2:636.2836

60

Cycleanorine Cyclea barbata (Wall.) Miers (Menispermaceae)[90] Cyclea peltata Diels (Menispermaceae)[43]

C37H40O6N2:608.2886

36

Cycleapeltine (Faralaotrine) Colubrina faralaotra (Rhamnaceae)[209] Cyclea barbata (Wall.) Miers (Menispermaceae)[210] Cyclea peltata Diels (Menispermaceae)[43]

C37H40O6N2.6O8.2886

404 Cycleatjehenine Cyclea atjehensis Forman (Menispermaceae)[211,212]

C37H36O6N2:604.2574

405 Cycleatjehine Cyclea atjehensis Forman (Menispermaceae)[211]

C%H34O6N2:590.2417

37

Daphnandrine C36H38O6N2:594.2730 Albertisia papuana Becc. (Menispermaceae)[10] Anisocycla cymosa Troupin (Menispermaceae)[151] Cyclea barbata (Wall.) Miers (Menispermaceae)[90] Daphnandra micrantha Benth. (Monimiaceae)[27] Doryphora aromatica Schodde (Monimiaceae)[28] Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[12]

The BisbenzyUsoquinoline Alkaloids - A Tabular Review

15

Table 1. Continued Pachygone loyaltiensis Diels (Menispermaceae)[13] Stephania erecta Craib. (Menispermaceae)[135] Stephania pierrii Diels (Menispermaceae)[34] 191 Daphnine C37H3207N2:616.2209 Daphnandra dielsii Perk. (Monimiaceae)[213] Daphnandra repandula F. Muell. (Monimiaceae)[214,215] 38

Daphnoline C35H36O6N2:580.2573 Albertisia laurifolia (Menispermaceae)[9] Albertisia papuana Becc. (Menispermaceae)[16,10] Cocculus pendulus (Forsk.) Diels (Menispermaceae)[139] Cocculus trilobus DC. (Menispermaceae)[216] Daphnandra aromatica F.M. Bailey (Monimiaceae)[26] Daphnandra micrantha Benth. (Monimiaceae)[27] Doryphora aromatica Schodde (Monimiaceae)[28] Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[12] Pachygone dasycarpa Kurz (Menispermaceae)[7] Pachygone loyaltiensis Diels (Menispermaceae)[13] Pycnarrhena longifolia (Decne. ex Miq.) Becc. (Menispermaceae)[49] Pycnarrhena ozantha Diels (Menispermaceae)[120]

406 Dauriciline Menispermum dauricum DC. (Menispermaceae)[217]

C36H40O6N2.596.2886

3

Dauricine C38H4406N2:624.3199 Cardiopetalum calophyllum Schlecht (Annonaceae)[218] Menispermum canadense L. (Menispermaceae)[219,220] Menispermum dauricum DC. (Menispermaceae)[221-228] Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

4

Dauricinoline C37H4206N2:610.3043 Menispermum dauricum DC. (Menispermaceae)[222,223]

5

Dauricoline C36H40O6N2:596.2886 Menispermum dauricum DC. (Menispermaceae)[221,223] Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

6

Daurinoline C37H4206N2:610.3043 Menispermum canadense L. (Menispermaceae)[220] Menispermum dauricum DC. (Menispermaceae)[221,223]

16

P.L.Schiff,Jr. Table 1. Continued

192 Daurisoline C37H4206N2:610.3043 Abuta pahni (Martius) Krukoff and Barneby (Menispermaceae)[230] Menispermum dauricum D C (Menispermaceae)[223,225,227] Polyalthia nitidissima Benth. (Annonaceae)[231 ] 287 Dehatridine Dehaasia triandra Merr. (Lauraceae)[232]

C35H32O6N2:576.2260

288 Dehatrine Beilschmiedia madang Bl. (Lauraceae)[474] Dehaasia triandra Merr. (Lauraceae)[232]

C37H3806N2.606.2730

193 1,2-Dehydroapateline C34H30O5N2:546.2155 Anisocycla cymosa Troupin (Menispermaceae)[154] Cocculus pendulus (Forsk.) Diels (Menispermaceae)[139] Daphnandra apatela Schodde (Monimiaceae)[ 11 ] Doryphora aromatica Schodde (Monimiaceae)[28] Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[ 12] Pachygone loyaltiensis Diels (Menispermaceae)[13] Stephania pierrii Diels (Menispermaceae)[34] 289 1,2-Dehydrokohatamine C35H32O6N2:576.2260 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[233] 290 1,2-Dehydrokohatine C34H10O6N3:562.2104 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[233] 154 1,2-Dehydromicranthine Daphnandra species unnamed (Monimiaceae)[234]

C34H30O,N2:546.2155

291 1,2-Dehydro-2-Norlimacusine C36H3606N2:592.2573 Caryomene olivascens Barneby et Krukoff (Menispermaceae)[74] 292 1,2-Dehydro-2'-Nortelobine C34H30O5N3:546.2155 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[233] 194 1,2-Dehydrotelobine C35H3205N2:560.2311 Albertisia papuana Becc. (Menispermaceae)[16] Anisocycla cymosa Troupin (Menispermaceae)[154] Anisocycla jolly ana (Pierre) Diels (Menispermaceae)[235] Daphnandra apatela Schodde (Monimiaceae)[ 11 ] Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[12] Pachygone loyaltiensis Diels (Menispermaceae)[13]

The Bisbenzylisoquinoline Alkaloids - A l abalar Review

17

Table 1. Continued Stephania erecta Craib. (Menispermaceae)[135] 39

Demerarine C36H38O6N2:594.2730 Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei (Lauraceae)][236]

293 12-O-Demethylcoclobine C36H3606N2:592.2573 Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[12] 195 7-O-Demethylisothalicberine C36H38O6N2:594.2730 Berberis chilensis Gill, ex Hook. (Berberidaceae)[237,238] Berberis lamina (Thunb.) Billbg. (Berberidaceae)[ 18] 294 12-O-Desmethyllauberine Berberis chilensis Gill, ex Hook. (Berberidaceae)[239]

C36H38O6N2:594.2730

60a 7-O-Demethylpeinamine C35H36O6N2:580.2573 Abuta grisebachii Triana and Planchon (Menispermaceae)[240] 155 12-O-Demethyltrilobine C34H3205N2:548.2311 Anisocycla gradidieri H. Bn. (Menispermaceae)[165] Cocculus pendulus (Forsk.) Diels (Menispermaceae)(designated by the authors as nortrilobine) [153] 233 N-Desmethylcycleanine Stephania glabra (Roxb.) Miers (Menispermaceae)[206] Stephania pierrii Diels (Menispermaceae)[34]

C37H40O6N2:608.2886

7

C 37 H 42 O A N 2 :6 10.3043

N'-Desmethyldauricine Menispermum canadense L. (Menispermaceae)[220]

196 N-Desmethylthalidasine Thalictrum cultratum Wall. (Ranunculaceae)[241] Thalictrum faberi Ulbr. (Ranunculaceae)[242,243]

C38H4207N2:638.2992

80

N-Desmethylthalidezine Thalictrum podocarpum Humb. (Ranunculaceae)[244]

C37H40O7N2:624.2836

16 N-Desmethylthalistyline Thalictrum baicalense Turcz. (Ranunculaceae)[245] Thalictrum longistylum DC. (Ranunculaceae)[246] Thalictrum podocarpum Humb. (Ranunculaceae)[244]

C40H46O8N2:682.3254

18

P.L.Schlfr,Jr. Table 1. Continued

197 N-Desmethylthalrugosidine Thalictrum alpinum L. (Ranunculaceae)[247]

C37H40O7N2:624.2836

260 Dihydrosecocepharanthine Stephania sasakii Hayata (Menispermaceae)[248]

C37H3gOgN2:638.2628

295 3',4'-Dihydrostephasubine C36H3606N2:592.2573 Stephania hernandifolia (Willd.) Walp. (Menispermaceae) [also called Stephania discolor Spreng. (Menispermaceae)][249] 198 Dihydrothalictrinine C38H3809N2:666.2577 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[250] 146 Dihydrowarifteine Cissampelos ovalifolia DC. (Menispermaceae)[251 ]

C36H38O6N2:594.2730

407 0,0'-Dimethylgrisabine 0^0^:638.3356 Phaeanthus vietnamensis Ban. (Menispermaceae)[252,253] 234 N,N'-Dimethyllindoldhamine[231] or 0^0^:596.2886 Guattegaumerine[254] Abuta pahni (Martius) Krukoff and Barneby (Menispermaceae)[230] Berberis stolonifera (Berberidaceae)[76] Caryomene olivascens Barneby et Krukoff (Menispermaceae)[74] Guatteria gaumeri Greenman (Annonaceae)[254] Polyalthia nitidissima Benth. (Annonaceae)[231 ] 156 N,0-Dimethylmicranthine Daphnandra micrantha Benth. (Monimiaceae)[255] Daphnandra species Dt-7 (Monimiaceae)[255] Daphnandra species unnamed (Monimiaceae)[234]

C36H360,N2:576.2624

135 0,0-Dimethylcurine Cyclea hypoglauca (Menispermaceae)[191] Guatteria megalophylla Dieis (Annonaceae)[196]

C37H40O6N2:608.2886

147 Dimethyldihydrowarifteine Cissampelos ovalifolia D C (Menispermaceae)[251]

C3gH42O6N2:622.3043

148 Dimethylwarifteine Cissampelos ovalifolia DC. (Menispermaceae)[251]

C3lH40O6N2:620.2886

the Bisbenzylisoquinoline Alkaloids - A Tabular Review

19

Table 1. Continued

114 Dinklacorine Tiliacora dinklagei Engl. (Menispermaceae)[256] Tiliacora triandra Diels (Menispermaceae)[257,258]

C36H3605N2:5 76.2624

172 Dinklageine - Undetermined Structure Stephania dinklagei Diels (Menispermaceae)[259]

C36H38O6N2:594.2730

19 Dirosine C37H4206N2:610.3043 Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei (Lauraceae)[236] 104 Dryadine C37H40O6N2:608.2886 Dryadodaphne novoguineensis (Perk.) A.C. Smith (Monimiaceae)[260] 105 Dryadodaphnine C36H38O6N2:594.2730 Dryadodaphne novoguineensis (Perk.) A.C. Smith (Monimiaceae)[260] 296 Efatine C38H44OgN2:656.3097 Hernandia nymphaeifolia (Presl) Kubirtzki [Biasoiettia nymphaeifolia Presl, Hernandia peltata (Meissn.)] (Hernandiaceae)[6] 199 Epinorhernandezine (Semisynthetic) C3IH4207N2:638.2992 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[250] 200 Epinorthalibrunine (Semisynthetic) C38H4208N2:654.2941 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[250] 40

(+)-Epistephanine C37H38O6N2:606.2730 Stephania capitata Spreng. (Menispermaceae)[261] Stephania hernandifolia (Willd.) Walp. (Menispermaceae) [also called Stephania discolor Spreng. (Menispermaceae)][249,262] Stephania japonica (Thunb.) Miers (Menispermaceae)[also called Cocculus japonicus (Menispermaceae)] [263,264] Stephania japonica (Thunb.) Miers var australis (Menispermaceae)[263,264]

41

(-)-Epistephanine Anisocycla gradidieri H. Bn. (Menispermaceae)[165]

8

Espinidine Berberis laurina (Thunb.) Billbg. (Berberidaceae)[265]

C37H38O6N2:606.2730

P.L.SchifT,Jr. Table 1. Continued

C36H40O6N2:596.2886

9

Espinine Berbehs chilensis Gill, ex Hook. (Berberidaceae)[239] Berberis laurina (Thunb.) Billbg. (Berberidaceae)[265]

61

Fangchinoline C37H40O6N2:608.2886 Cyclea barbata (Wall.) Miers (Menispermaceae)[266] Cyclea peltata Diels (Menispermaceae)[43,267] Daphnandra species Dt-7 (Monimiaceae)[255] Pachygone dasycarpa Kurz (Menispermaceae)[7] Stephania hernandifolia (Willd.) Walp. (Menispermaceae)[also called Stephania discolor Spreng. (Menispermaceae)] [ 199] Stephania tetrandra S. Moore (Menispermaceae)[107,207,269,270]([268] - detected, not isolated) Strychnopsis thouarsii Baill. (Menispermaceae)[271.272] Triclisia subcordata Oliv. (Menispermaceae)[ 168]

297 Fenfangjine A (Tetrandrine-2P-N-Oxide) C3gH4207N2:638.2992 Stephania tetrandra S. Moore (Menispermaceae)[207,273] 298 Fenfangjine B (Fangchinoline-2'a-N-Oxide) C37H40O7N2:624.2836 Stephania tetrandra S. Moore (Menispermaceae)[207,273] 299 Fenfangjine C (Fangchinoline-2'P-N-Oxide) C37H40O7N2:624.2836 Stephania tetrandra S. Moore (Menispermaceae)[207,273] 300 Fenfangjine D (1,3,4-Tridehydrofangchinolinium Hydroxide) C37H40O7N2:624.2836 Stephania tetrandra S. Moore (Menispermaceae)[207,274] 20

Funiferine C3gH42O6N2:622.3043 Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[ 119] Tiliacora dinklagei Engl. (Menispermaceae)[275] Tiliacora funifera Engl, ex Diels (Menispermaceae)[also known as Tiliacora warneckei Engl, ex Diels (Menispermaceae)][276]

201 Funiferine Dimethiodide C40H4gO6N2~:652.3512 (N,N-Dimethylfuniferine Iodide) Tiliacora funifera Engl, ex Diels (Menispermaceae)[also known as Tiliacora warneckei Engl, ex Diels (Menispermaceae)][277] 21

Funiferine N-Oxide C3SH4207N2:638.2992 Tiliacora funifera Engl, ex Diels (Menispermaceae)[also known as Tiliacora warneckei Engl, ex Diels (Menispermaceae)][278]

The Blsbenzyllsoqnlnoline Alkaloids - A Tabular Review

21

Table 1. Continued

301 Geraldoamine Aristolochia gigantea Mart. (Aristolochiaceae)[279]

C37H4206N2:610.3043

261 Gilgitine Berberis lycium (Royle) (Berberidaceae)[68]

C36H34OgN2:622.2316

202 Gilletine C35H3406N2:578.2417 Triclisia gilletii (DeWild.) Staner (Menispermaceae)[280,281] 302 Granjine Crematosperma sp. (Annonaceae)[ 172]

C39H4406N2:636.3199

10 Grisabine C37H4206N2:610.3043 Abuta ghsebachii Triana and Planchon (Menispermaceae)[240] Gyrocarpus americanus Jacq. (Hernandiaceae)(also known as Gyrocarpus jacquini Roxb. (Hcrnandiaceae)[282] Sciadotenia eichlericma Moldenke (Menispermaceae)[283] 303 Guattamine C37H40O6N2:608.2886 Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[l 19] 304 Guattaminone C37H36O7N2:620.2523 Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[ 119] 305 Gyroamericine C37H40O6N2:608.2886 Gyrocarpus americanus Jacq. (Hemandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)][282] 306 Gyrocarpine C37H40O6N2:608.2886 Gyrocarpus americanus Jacq. (Hernandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)][45,282] 307 Gyrocarpusine C37H40O6N2:608.2886 Gyrocarpus americanus Jacq. (Hernandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)][282] 308 Gyrolidine C38H4206N2:622 3043 Gyrocarpus americanus Jacq. (Hernandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)] [282] 136 Hayatidine Cissampelos pareira L. (Menispermaceae)[190]

C37H40O6N2:608.2886

P.L.Schifr,Jr. Table 1. Continued

137 Hayatine Cissampelos pareira L. (Menispermaceae)[ 144,190,202] Cyclea hainanensis Merr. (Menispermaceae)[175]

C36H3gO6H>:594.2730

138 Hayatinine Cissampelos pareira L. (Menispermaceae)[ 190,202]

€^0^:608.2886

81

Hernandezine (Thalicsimine) C39H4407N2:652.3149 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[161] Thalictrum alpinum L. (Ranunculaceae)[284,285] Thalictrum delavayi Franch. (Ranunculaceae)[286,287] Thalictrum fendleri Engelm. ex Gray (Ranunculaceae)[288] Thalictrum flavum L. (Ranunculaceae)[289] Thalictrum foetidum L. (Ranunculaceae)[290] Thalictrum glandulosissimum (Finet et Gagnep.) W.T. Wang et S.H. Wang (Ranunculaceae)[291,292] Thalictrum hernandezii Tausch (Ranunculaceae)[293] Thalictrum lankesteri Standi. (Ranunculaceae)[294] Thalictrum podocarpum Humb. (Ranunculaceae)[244] Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[295] Thalictrum simplex L. (Ranunculaceae)[296] Thalictrum sultanabadense Stapf. (Ranunculaceae)[297-300]

203 Hernandezine-N-Oxide Thalictrum sultanabadense Stapf. (Ranunculaceae)[299]

C39H44O8N2:668.3098

173 Himanthine - Undetermined Structure Berberis himalaica Ahrendt (Berberidaceae)[81 ]

C37H40O6N2:608.2886

42

Homoaromoline (Homothalicrine) C37H40O6N2:608.2886 A buta splendida Krukoff and Moldenke (Menispermaceae)[ 15] Albertisia papuana Becc. (Menispermaceae)[16] Anisocycla jolly ana (Pierre) Diels (Menispermaceae)[235] Arcangelisia flava (L.) Merr. (Menispermaceae)[301] Berberis boliviano Lechl. (Berberidaceae)[18] Berberis laurina (Thunb.) Billbg. (Berberidaceae)[18] Cyclea barbata (Wall.) Miers (Menispermaceae)[210,302,303] Doryphora aromatica Schodde (Monimiaceae)[28] Pseudoxandra sclerocarpa Maas (Annonaceae)fl 17] Pycnarrhena longifolia (Decne. ex Miq.) Becc. (Menispermaceae)[49] Stephania cepharantha Hayata (Menispermaceae)[30,32,104] Stephania erecta Craib. (Menispermaceae)[134,135] Stephania excentrica H-S. Lo (Menispermaceae)[304]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

23

Table 1. Continued

Thalictrum lucidum L. (Ranunculaceae)[37] Thalictrum minus L. var. microphyllum Boiss. (Ranunculaceae)[38] Thalictrum thunbergii DC. (Ranunculaceae)[40,41] The following plants yielded alkaloids that were formerly named thalrugosamine, but a reevlaution of the assignment of the structure of thalrugosamine published in 1972 [305] demonstrated an inconsistency in the structural representation (but not the actual work of the alkaloid [1,2] with the revelation that (+)-thalrugosmine was in reality (+)homoaromoline [38]: Limaciopsis loangensis Engl. (Menispermaceae)[92] Stephania pierrii Diels (Menispermaceae)[34] Stephania venosa Spreng. (Menispermaceae)[306] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)][305] 309 5-Hydroxyapateline C34H32O6N2:564.2260 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[233] 310 5-Hydroxytelobine C33H3406N2:578.2417 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[233] 311 5-Hydroxythalidasine Thalictrum cultratum Wall. (Ranunculaceae)[307]

C39H44OgN2:668.3098

312 5-Hydroxythalidasine-2ot-N-Oxide Thalictrum cultratum Wall. (Ranunculaceae)[35]

C3QH44O9N2:684.3046

313 5-Hydroxythalmine Thalictrum cultratum Wall. (Ranunculaceae)[307]

C37H40O7N2:624.2836

43

Hypoepistephanine (Pseudoepistephanine) C36H3606N,:592.2573 Stephania japonica (Thunb.) Miers (Menispermaceae)[also called Cocculus japonicus DC. (Menispermaceae)][263] Stephania japonica (Thunb.) Miers var australis (Menispermaceae)[263]

169 Insulanoline C37H3gO6N2:606.2730 Cyclea hypoglauca (Menispermaceae)[308J Cyclea insularis (Makino) Diels (Menispermaceae)[192] Cyclea sutchuenensis Gagnep. (Menispermaceae)[252,309] 170 Insularine Cissampelos pareira L. (Menispermaceae)[189] Cyclea hypoglauca (Menispermaceae)[308]

24

P.L.Schifr,Jr. Table 1. Continued Cyclea insularis (Makino) Diels (Menispermaceae)[ 192] Cyclea sutchuenensis Gagnep. (Menispermaceae)[252] Paracyclea ochiaiana (Yamamoto) Kudo and Yamamoto (Menispermaceae)[182] Stephania japonica (Thunb.) Micrs (Menispermaceae)[also called Coccuius japonicus (Menispermaceae)][310] Stephania japonica (Thunb.) Miers var australis (Menispermaceae)[310]

408 Insularine-2p-N-Oxide Cyclea sutchuenensis Gagnep. (Menispermaceae)[252]

C38H40O7N2:636.2836

409 Insularine-2'P-N-Oxide Cyclea sutchuenensis Gagnep. (Menispermaceae)[252]

C38H40O7N2:636.2836

174 (-)-Isochondocurarine - Undetermined Structure Curare [311]

C3„H4406N2++:624.3199

122 Isochondodendrine (Isobebeerine) C36H3gO6N2:594.2730 Abuta candicans Rich ex DC. (Menispermaceae)[146] Chondodendron limaciifolium (Diels) Moldenke (Menispermaceae)[312] Chondodendron microphylum (Eichl.) Moldenke (Menispermaceae)[146] Chondodendron platiphyllum Miers (Menispermaceae)[ 146] Chondodendron tomentosum Ruiz and Pavon (Menispermaceae)[ 141,142] Chondendron toxicoferum (Wedd.) Kruk. et Mold. (Menispermaceae)[201] Cissampelos mucronata A. Rich. (Menispermaceae)[313] Cissampelos pareira L. (Menispermaceae)[144,189,190] Cleistopholis staudtii Engl, et Diels (Annonaceae)[147] Cyclea barbata (Wall.) Miers (Menispermaceae)[303,314] Cyclea hainanensis Merr. (Menispermaceae)[175] Cyclea insularis (Makino) Diels (Menispermaceae)[315] Cyclea madagascariensis Baill. (Menispermaceae)[144] Cyclea peltata Diels (Menispermaceae)[267] Cyclea sutchuenensis Gagnep. (Menispermaceae)[309] Epinetrum cordifolium Mangenot and Miege (Menispermaceae)[194] Epinetrum mangenotti Guill. and Debray (Menispermaceae)[194] Epinetrum villosum (Excell.) Troupin (Menispermaceae)[195] Guatteria megalophylla Diels (Annonaceae)[196] Heracleum wallichi (Umbelliferae)[197] Isolona hexaloba Engl. (Annonaceae)[181] Isolona pilosa Diels (Annonaceae)[180] Paracyclea ochiaiana (Yamamoto) Kudo and Yamamoto (Menispermaceae)[182] Pleogyne cunninghamii Miers [Pleogyne australis Benth. (Menispermaceae)][183] Sciadotenia toxifera Krukoff and A.C. Smith (Menispermaceae)[198] Stephania erecta Craib. (Menispermaceae)[130]

The Bisbenzylisoqninoline Alkaloids - A Tabular Review

25

Table 1. Continued

Stephania hernandifolia (Willd.) Walp.(Menispermaceae)[also called Stephania discolor Spreng. (Menispermaceae)][199] 410 Isocuricycleatjenine Cyclea atjehensis Forman (Menispermaceae)[174]

C39H4606N2:634.2679

411 Isocuricycleatjine Cyclea atjehensis Forman (Menispermaceae)[174]

C37H36O7N2:620.2523

412 Isocycleaneonine Cyclea sutchuenensis Gagnep. (Menispermaceae)[188]

C38H42O6N2:622.3043

235 Isodaurisoline Polyalthia nitidissima Benth. (Annonaceae)[231 ]

C37H4206N2:610.3043

204 Isogilletine-N-Oxide C35H3407N2:594.2366 Triclisia gilletii (DeWild.) Staner (Menispermaceae)[281] 28

Isoliensinine Nelumbo nucifera Gaertn. (Nymphaceae)[316,317]

C37H4206N2:610.3043

87

Isotenuipine Daphnandra species (Monimiaceae)[318]

C38H40O7N2:636.2836

62

Isotetrandrine C38H42O6N2:622.3043 Atherosperma moschatum L. (Monimiaceae)[51] Berberis boliviano Lechl. (Berberidaceae)[ 18] Berberis brandisiana Ahrendt (Berberidaceae)[58] Berberis bumeliaefolia Schneid. (Berberidaceae)[ 18] Berberis cretica L. (Berberidaceae)[19] Berberis empetrifolia (Berberidaceae)[319] Berberis heteropoda Schrenk (Berberidaceae)[see Berberis vulgaris L. (Berberidaceae)][112] Berberis kawakamii Hayata (Berberidaceae)[64] Berberis koreana Palib. (Berberidaceae)[320] Berberis mingetsensis Hayata (Berberidaceae)[69] Berberis morrisonensis Hayata (Berberidaceae)[69] Berberis nummularia Bge. (Berberidaceae)[21,321 ] Berberis paucidentata Rusby. (Berberidaceae)f 18] Berberis poiretii (Berberidaceae)[72] Berberis stolonifera (Berberidaceae)[23] Berberis thunbergii D C (Berberidaceae)[79,80] Berberis valdiviana (Berberidaceae)[322]

26

P.L.Schiff,Jr. Table 1. Continued Berberis wilsoniae Hemsl. et Wils. (Berberidacaeae)[87] Cocculus pendulus (Forsk.) Diels (Menispermaceae)[153] Cyclea barbata (Wall.) Miers (Menispermaceae)[302] Doryphora aromatica Schodde (Monimiaceae)[28] Gyrocarpus americanus Jacq. (Hernandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)][282] Isopyrum thalictroides L. (Ranunculaceae)[91,323] Laurelia sempervirens R. et P. (Monimiaceae)[324,325] Limaciopsis loangensis Engl. (Menispermaceae)[92] Mahonia aquifolium (Pursh) Nutt. (Berberidaceae)[29,95] Mahonia japonica DC. (Berberidaceae)[55,326] Mahonia lomariifolia Takeda (Berberidaceae)[97] Mahonia morrisonensis Takeda (Berberidaceae)[97] Mahonia philippinensis Takeda (Berberidaceae)[98] Mahonia siamensis Takeda (Berberidaceae)[327] Pycnarrhena australiana F. Muell. (Menispermaceae)[99] Pycnarrhena manillensis F. Muell. or Vidal (Menispermaceae)[100,101] Stephania cepharantha Hayata (Menispermaceae)[30,32,103,104] Stephania erecta Craib. (Menispermaceae)[135] Stephania pierrii Diels (Menispermaceae)[34] Stephania tetrandra S. Moore (Menispermaceae)[269] Thalictrum foetidum L. (Ranunculaceae)[108] Tiliacora funifera Engl, ex Diels (Menispermaceae)[328] Triclisia gilletii (DeWild.) Staner (Menispermaceae)[168]

205 Isothalicberine C37H40O6N2:608.2886 Berberis chilensis Gill, ex Hook. (Berberidaceae)[237,238] 82

Isothalidezine C3IH4207N2:638.2992 Thalictrum delavayi Franch. (Ranunculaceae)[286] Thalictrum glandulosissimum (Finet et Gagnep.) W.T. Wang et S.H. Wang (Ranunculaceae)[292] Thalictrum podocarpum Humb. (Ranunculaceae)[244]

157 Isotrilobine (Homotrilobine) C36H3605N2:576.2624 Albertisia papuana Becc. (Menispermaceae)[16] Anisocycla jollyana (Pierre) Diels (Menispermaceae)[235] Cocculus hirsutus Diels (Menispermaceae)[329-331] Cocculus laurifolius DC.. (Menispermaccae)[329] Cocculus pendulus (Forsk.) Diels (Menispermaceae)[139,153] Cocculus sarmentosus Diels (Menispcrmaceae)[332] Cocculus trilobus DC. (Menispermaceae)[216,333] Pachygone dasycarpa Kurz (Menispermaceae)[7]

The BlsbenzylftsoqnlnoUne Alkaloids - A Tabular Review

27

Table 1. Continued Pachygone loyaltiensis Diels (Menispermaceae)[13] Pachygone pubescens Benth. (Menispermaceae)[334] Stephania hernandifolia (Willd.) WaIp.(Menispermaceae)[also called Stephania discolor Spreng. (Menispermaceae)][335] 262 Jhelumine Berberis lycium (Royle) (Berberidaceae)[138]

C36H3807N2:610.2679

206 Johnsonine Daphnandra johnsonii Schodde (Monimiaceae)[336]

C37H40O6N2:608.2886

314 Kohatamine C35H3406N2:578.2417 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[233] 236 Kohatine C34H32O6N2:564.2260 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[ 139,233] 63

Krukovine C36H3gO6N2:594.2730 Abuta splendida Krukoff and Moldenke (Menispermaceae)[15] Curarea candicans (L.C. Rich) Barneby and Krukoff (Menispermaceae)[ 127,128] Pycnarrhena longifolia (Decne. ex Miq.) Becc. (Menispermaceae)[49]

237 Kurramine C33H2805N2:532.1998 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[139] 106 Lauberine C37H40O6N2:608.2886 Berberis laurina (Thunb.) Billbg. (Berberidaceae)[ 18,337] C37H4206N2:610.3043

29

Liensinine Nelumbo nucifera Gaertn. (Nymphaceae)[338-341]

64

Limacine ^7^0^:608.2886 Anisocycla jollyana (Pierre) Diels (Menispermaceae)[235] Arcangelisia flava (L.) Merr. (Menispermaceae)[301] Colubrina faralaotra (Rhamnaceae)[209] Curarea candicans (L.C. Rich) Barneby and Krukoff (Menispermaceae)[ 127,128] Cyclea barbata (Wall.) Miers (Menispermaceae)[89,210) Gyrocarpus americanus Jacq. (Hernandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)][45,282] Limacia cuspidata Hook. f. and Thoms. (Menispermaceae)[ 184] Limacia oblonga Miers (Menispexmaceae)[185] Phaeanthus crassipetalus Becc. (Menispermaceae)[342]

28

P.L.SchiiT,Jr. Table 1. Continued Pycnarrhena longifolia (Decne. ex Miq.) Becc. (Menispermaceae)[49] Pycnarrhena novoguineensis Miq. (Menispermaceae)[22] Spirospermum penduliflorum Thou. (Menispermaceae)[271,272]

315 Limacine-2'ct-N-Oxide Curarea candicans (L.C. Rich) Barneby and Kmkoff (Menispermaceae)[ 127-129]

C37H40O7N2:624.2836

316 Limacine-2p-N-Oxide Curarea candicans (L.C. Rich) Barneby and Kmkoff (Menispermaceae)[ 127-129]

C37H40O7N2:624.2836

317 Limacine-2'P-N-Oxide C37H40O7N2:624.2836 Anisocycla jollyana (Pierre) Diels (Menispermaceae)[235] Curarea candicans (L.C. Rich) Barneby and Krukoff (Menispermaceae)[ 127-129] 44

Limacusine C37H40O6N2:608.2886 Curarea candicans (L.C. Rich) Barneby and Krukoff (Menispermaceae)[ 127-129] Limacia cuspidata Hook. f. and Thorns. (Menispermaceae)[ 184] Limacia oblonga Miers (Menispermaceae)[185]

413 Limacusine-2'P-N-Oxide C37H40O7N2:624.2836 Anisocycla jollyana (Pierre) Diels (Menispermaceae)[235] 11

Lindoldhamine C34H3606N2:568.2573 Abuta pahni (Martius) Krukoff and Barneby (Menispermaceae)[230] Albertisia papuana Becc. (Menispermaceae)[10,16] Lindera oldhamii Hemsl. (Lauraceae)[343] Polyalthia nitidissima Benth. (Annonaceae)[231 ]

44a Macolidine C36H3gO6N2:594.2730 Abuta grisebachii Triana and Planchon (Menispermaceae)[240] 44b Macoline C37H4206N2:610.3043 Abuta grisebachii Triana and Planchon (Menispermaceae)[240] 15

Magnolamine C37H4207N2:626.2992 Magnolia fuscata Andr. (Magnoliaceae)[344][also known as Michelia fuscata Blume (Magnoliaceae)]

The Bisbenzyllsoquinoline Alkaloids - A Tabular Review

29

Table 1. Continued 12 Magnoline (Grisabutine) C36H40O6N2:596.2886 Abuta grisebachii Triana and Planchon (Menispermaceae)[240] Magnolia fuscata Andr. (Magnoliaceae)[344](also known as Michelia fuscata Blume (Magnoliaceae)[475]) 238 Malekulatine C39H46O8N2:670.3254 Hernandia peltata Meissn. (Hernandiaceae)[345) Hernandia sonora L. (H. ovigera L.)(Hernandiaceae)[346,347] 391 Maroumine C37H3gOgN2:638.2628 Gyrocarpus americanus Jacq. (Hernandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)][45] 318 Medelline Pseudoxandra aff. lucida Fries (Annonaceae)[348]

C37H38O6N2:606.2730

165 Menisarine Cocculus leaebe DC. (Menispermaceae)[349] Cocculus sarmentosus Diels (Menispermaceae)[332]

C36H3406N2:590.2417

65

Menisidine Stephania tetrandra S. Moore (Menispermaceae)[350]

C37H40O6N2:608.2886

66

Menisine Stephania tetrandra S. Moore (Menispermaceae)[350]

C37H40O6N2:608.2886

207 N-Methylapateline Daphnandra johnsonii Schodde (Monimiaceae)[336]

C35H3405N2:562.2468

66a 2-N#-Methylberbamine Berberis oblonga (Regl.)(Berberidaceae)[351,352] Berberis turcomanica Kar. (Berberidaceae)f 116]

C38H4306N2*:623.3121

239 O-Methylcocsoline Albertisia papuana Becc. (Menispermaceae)[10,16] Pachygone loyaltiensis Diels (Menispermaceae)[13]

C35H3405N2:562.2468

414 12-0-Methylcocsoline-2'p-N-Oxide Anisocycla cymosa Troupin (Menispermaceae)[ 159]

C35H3406N2:578.2417

415 O-Methylcocsulinine C36H3606N2:592.2573 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[153]

30

P.L.Schifr,Jr. Table 1. Continued

139 4"-0-Methylcurine Cissampelos pareira L. (Menispermaceae)[203] Cyclea hainanensis Merr. (Menispermaceae)[175]

C37H40O6N2:608.2886

140 12'-OMethylcurine Guatteria megalophylla Diels (Annonaceae)[ 196]

C37H40O6N2:608.2886

240 7'-0-Methylcuspidaline Aristolochia elegans (Aristolochiaceae)[353]

C3gH4406N2:624.3199

12a O-Methyldauricine Colubrina asiatica Brogn. (Rhamnaceae)[354] Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C39H4606N2:638.3356

263 O-Methyldeoxopunjabine Stephania sasakii Hayata (Menispermaceae)[248]

C3AH3606N2:592.2573

66b N-Methyl-7-O-Demethylpeinamine C36H3gO6N2:594.2730 Abuta grisebachii Triana and Planchon (Menispermaceae)[240] Pachygone dasycarpa Kurz (Menispermaceae)[7] 149 Methyldihydrowarifteine Cissampelos ovalifolia DC. (Menispermaceae)[251 ]

C37H40O6N2:608.2886

416 2-N-Methylfangchinoline Stephania tetrandra S. Moore (Menispermaceae)[355]

C3gH43OftN2+:623.3121

417 7-O-Methylgrisabine Phaeanthus vietnamensis Ban. (Menispermaceae)[252]

C3gH4406N2:624.3199

319 N-2r-Methylisotetrandrine Berberis oblonga (RegI.)(Berberidaceae)[70J

C39H4506N2*:637.3278

94

O-Methylisothalicberine C3gH42O6N2:622.3043 Berberis chilensis Gill, ex Hook. (Berberidaceae)[237] Berberis laurina (Thunb.) Billbg. (Berberidaceae)[48,337]

320 O-Methyllimacusine C3gH42O6N2:622.3043 Gyrocarpus americanus Jacq. (Hernandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)][282] 321 2-N-Methyllindoldhamine C35H3gO6N2:582.2730 Abuta pahni (Martius) Krukoff and Barneby (Menispermaceae)[230]

The Blsbenzyllsoquinoline Alkaloids - A Tabular Review

31

Table 1. Continued 322 2'-N-MethyllindoIdhamine C35H38O6N2:582.2730 Abuta pahni (Martius) Krukoff and Barneby (Menispermaceae)[230] 241 7-O-MethylIindoldhamine Polyalthia nitidissima Benth. (Annonaceae)[231 ]

C35H38O6N2:582.2730

242 7-O-Methyllindoldhamine Polyalthia nitidissima Benth. (Annonaceae)[231 ]

C35H38O6N2:582.2730

158 O-Methylmicranthine Daphnandra micrantha Benth. (Monimiaceae)[255] Daphnandra species Dt-7 (Monimiaceae)[255] Daphnandra species unnamed (Monimiaceae)[234]

C35H3405N2:562.2468

208 N-Methylnorapateline Daphnandra johnsonii Schodde (Monimiaceae)[336]

C34H3205N2:548.2311

243 N-Methylpachygonamine C3
C36H34O7N2:606.2366

45

C3gH4,O6N2:622.3043

O-Methylrepandine Daphnandra dielsii Perk. (Monimiaceae)[27] Daphnandra johnsonii Schodde (Monimiaceae)[336] Daphnandra repandula F. Muell. (Monimiaceae)[27] Isopyrum thalictroides L. (Ranunculaceae)[323]

418 2-N-Methyltelobine Stephania erecta Craib. (Menispermaceae)[135]

C36H3605N2:576.2624

209 O-Methylthalibrine C39H4606N2:638.3356 Thalictrum faberi Ulbr. (Ranunculaceae)[359] Thalictrum glandulosissimum (Finet et Gagnep.) W.T. Wang et S.H. Wang [292] Thalictrum minus L. race B (Ranunculaceae)[360] 210 O-Methylthalibrunimine C39H42OgN2:666.2941 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[361]

P.L.SchhT,Jr. Table 1. Continued 95

O-Methylthalicbcrine (Thalmidine) C38H42O6N2:622.3043 Berberis chilensis Gill, ex Hook. (Berberidaceae)[238) Berberis turcomanica Kar. (Berberidaceae)[ 116] Thalictrum cultratum Wall. (Ranunculaceae)[307] Thalictrum faberi Ulbr. (Ranunculaceae)[359] Thalictrum flavum L. (Ranunculaceae)[289] Thalictrum foetidum L. (Ranunculaceae)[290] Thalictrum kuhistanicum Ovcz. (Ranunculaceae)[362] Thalictrum longipedunculatum E. Nik. (Ranunculaceae)[363] Thalictrum lucidum L. (Ranunculaceae)[37] Thalictrum minus L. (Ranunculaceae)[364-371] Thalictrum minus L. var. hypoleucum (Ranunculaceae)[372] Thalictrum minus L. var. majus (Ranunculaceae)[373] Thalictrum minus L. var. microphyllum Boiss. (Ranunculaceae)[38,374] Thalictrum minus L. var. minus (Ranunculaceae)[375] Thalictrum revolutum DC. (Ranunculaceae)[376,377] Thalictrum thunbergii DC. (Ranunculaceae)[378]

17 N-Methylthalistyline (Methothalistyline, Thalistyline Metho C4,H„08N2+*:712.3724 Salt) Thalictrum longistylum DC. (Ranunculaceae)[246] Thalictrum podocarpum Humb. (Ranunculaceae)[244] O-Methylthalmethine Thalictrum minus L. (Ranunculaceae)[364>368,371,379] Thalictrum minus L. var. minus (Ranunculaceae)[375] Thalictrum revolutum DC. (Ranunculaceae)[376]

C37H38O6N2:606.2730

244 O-Methylthalmine Thalictrum cultratum Wall. (Ranunculaceae)[307] Thalictrum sultanabadense Stapf. (Ranunculaceac)[380]

C38H42O6N2:622.3043

96

323 N-Methyltiliamosine C37H38O6N2:606.2730 Tiliacora racemosa Colebr. (Menispermaceae)[also called Tiliacora acuminata (Lam.) Miers (Menispermaceae)][381,382] 419 12-O-Methyltricordatine Pachygone dasycarpa Kurz (Menispermaceae)[7]

C35H3405N2:562.2468

150 Methylwarifteine Cissampelos ovalifolia DC. (Menispermaceae)[251 ]

C37H38O6N2:606.2730

ThetilisbenzylisoquinolineAlkaloids - A Tabular Review

33

Table 1. Continued

159 Micranthine Daphnandra micrantha Benth. (Monimiaceae)[27,255] Daphnandra species unnamed (Monimiaceae)[234]

C34H3205N,:548.2311

67

C39H4506N/:637.3278

Monomethyltetrandrinium Cyclea barbata (Wall.) Miers (Menispermaceae)[383]

324 Monterine Crematosperma sp. (Annonaceae)[172]

C38H42O6N2:622.3043

30

C38H4406N2:624.3199

Neferine Nelumbo nucifera Gaertn. (Nymphaceae)[317,339]

111 Nemuarine Nemuaron vieillardi Baill. (Monimiaceae)[384]

C37H40O6N2:608.2886

175 (+)-Neochondocurarine - Undetermined Structure Curare [311]

C38H4406N2":624.3199

123 Neoprotocuridine Curare [1]

C3AH38O6N::594.2730

420 Neosutchuenenine Cyclea sutchuenensis Gagnep. (Menispermaceae)[309]

C36H40O6N2:596.2886

211 Neothalibrine C38H4406N2:624.3199 Thalictrum alpinum L. (Ranunculaceae)[247] Thalictrum cultratum Wall. (Ranunculaceae)[35] Thalictrum revolutum DC. (Ranunculaceae)[377] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)][39] 325 Neothalibrine-2'a-N-Oxide Thalictrum cultratum Wall. (Ranunculaceae)[35] 68

C3gH44O7N2:640.3149

2-N-Norberbamine C36H3gO6N2:594.2730 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[ 139] Pycnarrhena australiana F. Muell. (Menispermaceae)[99] Pycnarrhena ozantha Diels (Menispermaceae)[120] Stephania pierrii Diels (Menispermaceae)[34]

326 2-Norcepharanoline Stephania pierrii Diels (Menispermaceae)[34]

C35H3406N2:578.2417

34

P.L.Schiff,Jr. Table 1. Continued

327 2-Norcepharanthine Stephania erecta Craib. (Menispermaceae)[ 135] Stephania suberosa Forman (Menispermaceae)[137]

C36H3606N2:592.2573

328 2'-Norcepharanthine Stephania pierrii Diels (Menispermaceae)[34)

C36H3606N2:592.2573

230 Nor-Nb-Chondrocurine Peruvian curare [145]

C35H3AO6N2:580.2573

421 2'-Norcocsoline Anisocycla cymosa Troupin (Menispermaceae)[159]

C33H30O5N,:534.2155

329 2'-Norcocsuline Albertisia papuana Becc. (Menispermaceae)[ 10] Pachygone dasycarpa Kurz (Menispermaceae)[7]

C34H3205N2:548.2311

422 N-Norcocsulinine C34H32O6N2:564.2260 Cocculus pendulus (Forsk.) Diels (Menispennaceae)[153] 124 (+)-Norcycleanine C37H40O6N2:608.2886 Chondodendron limaciifolium (Diels) Moldenke (Menispermaceae)[ 141,312] Chondodendron tomentosum Ruiz and Pavon (Menispermaceae)[141] Cyclea insularis (Makino) Diels (Menispermaceae)[ 192] Epinetrum villosum (Excell.) Troupin (Menispermaceae)[195] Sync Iis ia scabrida Miers (Menispermaceae)[158] 125 (-)-Norcycleanine Isolona hexaloba Engl. (Annonaceae)[181] Stephania cepharantha Hayata (Menispermaceae)[32]

C37H40O6N2:608.2886

330 2'-Nordaurisoline C36H40O6N2:596.2886 Abuta pahni (Martius) KrukofT and Barneby (Menispermaceae)[230] 331 2'-Norfuniferine C37H40O6N2:608.2886 Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)fl 19] 332 2'-Norguattaguianine C37H40O6N2:608.2886 Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[l 19] 212 N'-Norhernandezine C38H4207N2:638.2992 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[250]

The Bisbenzylisoqainoline Alkaloids - A Tabular Review

35

Table 1. Continued 333 2-Norisocepharanthine Stephania pierrii Diels (Menispermaceae)[34]

C36H3606N2:592.2573

334 2-Norisotetrandrine Stephania erecta Craib. (Menispermaceae)[135] Stephania pierrii Diels (Menispermaceae)[34]

C37H40O6N2:608.2886

213 Nor-2'-Isotetrandrine Limaciopsis loangensis Engl. (Menispermaceae)[92] Stephania pierrii Diels (Menispermaceae)[34]

C37H40O6N2:608.2886

335 Norisoyanangine Tiliacora triandra Diels (Menispermaceae)[385]

C35H3406N2:578.2417

336 2-Norlimacine C36H38O6N2:594.2730 Anisocycla jolly ana (Pierre) Diels (Menispermaceae)[235] Caryomene olivascens Barneby et KrukofT (Menispermaceae)[74] 423 2'-Norlimacine C36H3gO6N2:594.2730 Anisocycla jollyana (Pierre) Diels (Menispermaceae)[235] Cyclea barbata (Wall.) Miers (Menispermaceae)[90] 245 2-Norlimacusine C3AH3RO6N2:594.2730 Caryomene olivascens Barneby et KrukofT (Menispermaceae)[74] Sciadotenia eichleriana Moldenke (Menispermaceae)[283] 166 Normenisarine Cocculus trilobus DC. (Menispermaceae)[216]

C33H32O6N2:576.2260

337 2'-Norobaberine Stephania pierrii Diels (Menispermaceae)[34J

C37H40O6N2:608.2886

424 2-Norobaberine-2'p-N-Oxide Anisocycla cymosa Troupin (Menispermaceae)[151]

C37H40O7N2:624.2836

69

2-N-Norobamegine C35H36O6N2:580.2573 Pycnarrhena australiana F. Muell. (Menispermaceae)[99] Pycnarrhena ozantha Diels (Menispermaceae)[l 18,120]

338 2'-Noroxyacanthine Thalictrum cultratum Wall. (Ranunculaceae)[35]

C36H3SO6N2:594.2730

36

P.L.Schiff,Jr. Table 1. Continued

109 Norpanurensine A buta panurensis Eichl. (Menispermaceae)[386]

C36H3806N2:594.2730

246 Norpenduline C36H38O6N2:594.2730 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[139] 339 2'-Norpisopowiaridine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C36H40O6N2:596.2886

22 Norrodiasine C37H40O6N2:608.2886 Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei (Lauraceae)][236] 340 Norstephasubine Stephania suberosa Forman (Menispermaceae)[137]

C35H32O6N2:576.2260

88

(+)-Nortenuipine Daphrtandra johnsonii Schodde (Monimiaceae)[336] Daphnandra species Dt-7 (Monimiaceae)[255] Daphnandra tenuipes Perk. (Monimiaceae)[387]

C37H3g07N2:622.2679

89

(-)-Nortenuipine Daphnandra tenuipes Perk. (Monimiaceae)[27,387]

C37I l3807N2:622.2679

70

2-Nortetrandrine C37H40O6N2:608.2886 Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei][388]

13 Northalibrine C37H4206N2:610.3043 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[389] 341 Northalibroline Thalictrum minus L. var. minus (Ranunculaceae)[390]

C35H38O6N2:582.2730

214 N'-Northalibrunine C38H4208N2:654.2941 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[250,361] 342 2'-Northaliphylline Thalictrum cultratum Wall. (Ranunculaceae)[35,307]

C36H3806N2:594.2730

343 2-Northalmine Thalictrum cultratum Wall. (Ranunculaceae)[241]

C36H38O6N2:594.2730

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

37

Table 1. Continued

344 2-Northalrugosine Pycnarrhena ozantha Diels (Menispermaceae)[ 120] Stephania erecta Craib. (Menispermaceae)[135]

C36H38O6N2:594.2730

115 Nortiliacorine A (Isotiliarine) C35H340,N2:562.2468 Tiliacora funifera Engl, ex Diels (Menispermaceae)falso called Tiliacora warneckei Engl, ex Diels (Menispermaceae)][391] Tiliacora triandra Diels (Menispermaceae)[385] 116 Nortiliacorinine A (Pseudotiliarine) C35H3405N2:562.2468 Tiliacora dinklagei Engl. (Menispermaceae)[275] Tiliacora fumfera Engl, ex Diels (Menispermaceae)[also called Tiliacora warneckei Engl, ex Diels (Menispermaceae)][391] Tiliacora racemosa Colebr. (Menispermaceae)[also called Tiliacora acuminata (Lam.) Miers (Menispermaceae)][392-396] Tiliacora triandra Diels (Menispermaceae)[257,397.398] 117 Nortiliacorinine B C35H3405N2:562.2468 Tiliacora racemosa Colebr. (Menispermaceae)[also called Tiliacora acuminata (Lam.) Miers (Menispermaceae)][393] 345 2'-Nortiliageine C3ftH3RO6N2:594.2730 Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[ 119] 247 Nortrilobine (Bisnortrilobine) C34H320,N2:548.2311 Pachygone ovata (Poir.) Miers ex Hook (Menispermaceae)[399] 346 Noryanangine Tiliacora triandra Diels (Menispermaceae)[385]

C3,H3406N2:578.2417

46

C38H42O6N2:622.3043

Obaberine Albertisia papuana Becc. (Menispermaceae)[16] Berberis boliviano Lechl. (Berberidaceae)[ 18] Berberis cretica L. (Berberidaceae)[19] Berberis heterobotrys Wolf. (Berberidaceae)[60] Berberis iliensis (Berberidaceae)[62] Berberis koreana Palib. (Berberidaceae)[320] Berberis laurina (Thunb.) Billbg. (Berberidaceae)[337] Berberis paucidentata Rusby. (Berberidaceae)[18] Berberis pseudambalata (Berberidaceae)[230] Berberis tschonoskyana Regel (Berberidaceae)[400] Berberis vatdiviana (Berberidaceae)[322] Dehaasia triandra Merr. (Lauraceae)[232,401]

P.L.Schiff,Jr. Table 1. Continued Laurelia sempervirens R. et P. (Monimiaceae)[402] Mahonia repens (Lindl.) G. Don (Berberidaceae)[403] Pseudoxandra aff. lucida Fries (Annonaceae)[8] Pycnarrhena longifolia (Decne. ex Miq.) Becc. (Menispermaceae)[49] Stephania erecta Craib. (Menispermaceae)[135] Stephania pierrii Diels (Menispermaceae)[34] Stephania sasakii Hayata (Menispermaceae)[248] Thalictrum cultratum Wall. (Ranunculaceae)[35] Thalictrum lucidum L. (Ranunculaceae)[37] Thalictrum minus L. (Ranunculaceae)[404] Thalictrum minus L. var. majus (Ranunculaceae)[373J Thalictrum minus L. var. microphyllum Boiss. (Ranunculaceae)[374] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)][39] 71

Obamegine C36H3g06N2:594.2730 Berberis boliviano Lechl. (Berberidaceae)[ 18] Berberis cretica L. (Berberidaceae)[19] Berberis tschonoskyana Regel (Berberidaceae)[400] Mahonia aquifolium (Pursh) Nutt. (Berberidaceae)[29] Mahonia repens (Lindl.) G. Don (Berberidaceae)[403] Stephania cepharantha Hayata (Menispermaceae)[32] Stephania japonica (Thunb.) Miers (Menispermaceae)(also called Cocculus japonic us D C (Menispermaceae)[405] Thalictrum lucidum L. (Ranunculaceae)[37] Thalictrum minus L. var. microphyllum Boiss. (Ranunculaceae)[38] Thalictrum rugosum Ait. (Ranunculaceae)[406] Triclisia gilletii (DeWild.) Staner (Menipspermaceae)[281] Xanthorrhiza simplicissima Marsh (Ranunculaceae)[407]

47

Oblongamine Berberis oblonga (Regl.)(Berberidaceae)[l 15]

C38H4306N2*:623.3121

176 Ocodemerine - Undetermined Structure C37H4o06N2:608.2886 Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei (Lauraceae)][236] 23 Ocotine C37H4o06N2:608.2886 Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei (Lauraceae)][388] 24

Ocotosine C37H3lO6N2:606.2730 Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei (Lauraceae)][388]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

39

Table 1. Continued

248 Osornine Berbehs buxifolia Lam. (Berberidaceae)[123]

C38H4207N2:638.2992

177 Otocamine - Undetermined Structure C37H40O6N2:608.2886 Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei (Lauraceae)][236] 347 Oxandrine Pseudoxandra aff. lucida Fries (Annonaceae)[408]

C37H3807N2:622.2679

348 Oxandrinine Pseudoxandra aff. lucida Fries (Annonaceae)[408]

C38H40O7N2:636.2836

47a Oxoepistephanine C37H36O7N2:620.2523 Stephania hernandifolia (Willd.) Walp. (Menispermaceae)[also called Stephania discolor Spreng. (Menispermaceae)[409] 349 Oxofangchirine Stephania tetrandra S. Moore (Menispermaceae)[410]

C37H3
215 Oxothalibrunimine C38H3809N2:666.2577 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[250] 48

Oxyacanthine C37H40O6N2:608.2886 Albertisia papuana Becc. (Menispermaceae)[16] Berberis amurensis Rupr. (Berberidaceae)[l 10] Berberis aristata DC. (Berberidaceae)[also called Berberis floribunda Wall ex. Don (Berberidaceae)][ 17] Berberis chitria L. (Berberidaceae)[473] Berberis heterobotrys Wolf. (Berberidaceae)[60] Berberis heteropoda Schrenk (Berberidaceae)[also called Berberis vulgaris L. (Berberidaceae)][l 11-113,411] Berberis iliensis (Berberidaceae)[62] Berberis integerrima Bge. (Berberidaceae)[ 114,412,413] Berberis julianae Schneid. (Berberidaceae)[63] Berberis koreana Palib. (Berberidaceae)[20] Berberis lambertii R.N. Parker (Berberidaceae)[65] Berberis lycium (Royle) (Berberidaceae)[68] Berberis nummularia Bge. (Berberidaceae)[21,321,413] Berberis oblonga (Regl.)(Berberidaceae)[70,115,414] Berberis orthobotrys Bienert ex Aitch. (Berberidaceae)[78] Berberis paucidentata Rusby. (Berberidaceae)[18] Berberis pseudambalata (Berberidaceae)[415] Berberis sibirica Pall. (Berberidaceae)[75]

40

P.L.Schiff,Jr. Table 1. Continued Berberis thunbergii DC.. (Berberidaceae)[79] Berberis tschonoskyana Regel (Berberidaceae)[400] Berberis turcomanica Kar. (Berberidaceae)[24,116] Berberis vulgaris L. (Berberidaceae)[also called Berberis heteropoda Schrenk (Berberidaceae)][83-86,411] Cocculus leaebe DC. (Menispermaceae)[416] Dehaasia incrassata (Lauraceae)[417] Laurelia sempervirens R. et P. (Monimiaceae)[402] Magnolia compressa Maxim. (Magnoliaceae)[418] Mahonia acanthifolia Don. (Berberidaceae)[4l9] Mahonia aquifolium (Pursh) Nutt. (Berberidaceae)[95] Mahonia borealis Takeda (Berberidaceae)[420] Mahonia fortunei (Hort.) Fedde (Berberidaceae)[55] Mahonia griffithii Takeda (Berberidaceae)[96] Mahonia leschenaultii Takeda (Berberidaceae)[421 ] Mahonia manipurensis Takeda (Berberidaceae)[421] Mahonia repens (Lindl.) G. Don (Berberidaceae)[403] Mahonia sikkimensis Takeda (Berberidaceae)[421] Mahonia simonsii Takeda (Berberidaceae)[420] Thalictrum cultratum Wall. (Ranunculaceae)[35] Thalictrum lucidum L. (Ranunculaceae)[37] Thalictrum minus L. (Ranunculaceae)[379] Thalictrum minus L. var. majus [373] Xanthorrhiza simplicissima Marsh (Ranunculaceae)[407]

216 N-Oxy-2'-lsotetrandrine Limaciopsis loangensis Engl. (Menispermaceae)[92]

C38H4207N2:638.2992

350 N-2-Oxy-O-Methyldauricine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C39H46O7N2:654.3305

351 N-2'-Oxy-0-Methyldauricine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C39H46O7N2:654.3305

249 Pachygonamine C34H32O6N2:564.2260 Pachygone ovata (Poir.) Miers ex Hook (Menispermaceae)[356,357] 250 Pachyovatamine C34H3205N2:548.2311 Pachygone ovata (Poir.) Miers ex Hook (Menispermaceae)[357] 352 Pampulhamine Aristolochia gigantea Mart. (Aristolochiaceae)[279]

C36H40O6N2:596.2886

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

41

Table 1. Continued 353 Pangkoramine Albertisia papuana Becc. (Menispermaceae)[10]

C34H3406N2:566.2417

354 Pangkorimine Albertisia papuana Becc. (Menispermaceae)[10]

C34H32O6N2:564.2260

110 Panurensine Abuta panurensis Eichl. (Menispermaceae)[386]

C37H40O6N2:608.2886

355 Pedroamine Aristolochia gigantea Mart. (Aristolochiaceae)[279]

C35H38O6N,:582.2730

71a Peinamine C36H38O6N2:594.2730 Abuta grisebachii Triana and Planchon (Menispermaceae)[240] 425 Pendilinine C36H3606N2:592.2573 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[153] 178 Pendine - Undetermined Structure C3,H3406N2:578.2417 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[153,156] 72

Penduline C37H4(AN2:608.2886 Berberis brandisiana Ahrendt (Berberidaceae)[58] Cocculus leaebe DC. (Menispermaceae)[155] Cocculus pendulus (Forsk.) Diels (Menispermaceae)[ 139,153,156,161] (erroneously identified as Andrachne cordifolia Muell., O.F. (Euphorbiaceae)[ 160]) Pachygone dasycarpa Kurz (Menispermaceae)[7]

179 Pendulinine - Undetermined Structure C3,H3406N2:578.2417 Cocculus pendulus (Forsk.) Diels (Menispermaceae)[153,156] 73

Phaeantharine C38H3<S06R>:616.2573 Phaeanthus ebracteolatus (Presl) Merill. (Menispermaceae)[162,163]

74

Phaeanthine C3gH42O6N2:622.3043 Cyclea burmanni (DC.) Miers ex. Hook. f. & Thorns. (Menispermaceae)[164] Gyrocarpus americanus Jacq. (Hernandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)][45,282,422] Phaeanthus crassipetalus Becc. (Menispermaceae)[342] Phaeanthus ebracteolatus (Presl) Merill. (Menispermaceae)[423] Pycnarrhena australiana F. Muell. (Menispermaceae)[99] Pycnarrhena manillensis F. Muell. (Menispermaceae) or Vidal (Menispermaceae)[ 100,101 ]

42

P.L.Schiff,Jr. Table 1. Continued

Pycnarrhena novoguineensis Miq. (Menispermaceae)[22] Triclisia patens Oliv. (Menispermaceae)[ 168,424] 356 Phaeanthine-2'a-N-Oxide C3gH4207N2:638.2992 Pycnarrhena manillensis F. Muell. (Menispermaceae) or Vidal (Menispermaceae)[ 101] 25

Phlebicine C37H40O6N2:608.2886 Crematosperma polyphlebum (Diels) Fries (Annonaceae)[425]

357 Pisopowamine Popowia pisocarpa (BI.) Endl. (Annonaceae)[229]

C37H4206N2:610.3043

358 Pisopowetine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C3gH4406N2:624.3199

359 Pisopowiaridine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C37H4206N2:610.3043

360 Pisopowiarine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C3iH4406N2:624.3199

361 Pisopowidine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C3QH4606N2:638.3359

362 Pisopowine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

0^^0^2:652.3512

363 Popidine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C38H4406N2:624.3199

364 Popisidine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C38H4406N2:624.3199

365 Popisine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C38H4406N2:624.3199

366 Popisonine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C37H4206N2:610.3043

367 Popisopine Popowia pisocarpa (Bl.) Endl. (Annonaceae)[229]

C37H4206N2:610.3043

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

43

Table 1. Continued

180 Protochondocurarine - Undetermined Structure Curare [311]

C37H4IO6N/:609.3042

126 Protocuridine Curare [1]

C36H38O6N2:594.2730

167 Pseudorepanduline Daphnandra dielsii Perk. (Monimiaceae)[234] Daphnandra species unnamed (Monimiaceae)[234]

C37H38O6N2:606.2730

368 Pseudoxandrine Pseudoxandra aff. lucida Fries (Annonaceae)[408]

C37H3807N2:622.2679

369 Pseudoxandrinine Pseudoxandra aff. lucida Fries (Annonaceae)[408]

C3gH40O7N2:636.2836

265 Punjabine Berberis lycium (Royle) (Berberidaceae)[68]

C35H32O7N2:592.2210

392 Pycmanilline C38H40O,N2:668.2734 Pycnarrhena manillensis F. Muell. (Menispermaceae) or Vidal (Meni sperm aceae)[ 101] 75

Pycnamine C37H40O6N2:608.2886 Gyrocarpus americanus Jacq. (Hernandiaceae)[also called Gyrocarpus jacquini Roxb. (Hernandiaceae)][422] Pycnarrhena manillensis F. Muell. (Menispermaceae) or Vidal (Menispermaceae)f 100,101 ] Pycnarrhena novoguineensis Miq. (Menispermaceae)[22] Triclisia patens Oliv. (Menispermaceae)[168]

181 Pycnarrhenamine - Undetermined Structure C35H40O9N2:632.2734 Pycnarrhena manillensis F. Muell. (Menispermaceae) or Vidal (Menispermaceae)[100] 182 Pycnarrhenine - Undetermined Structure C36H42O9N2:646.2890 Pycnarrhena manillensis F. Muell. (Menispermaceae) or Vidal (Menispermaceae)[100] 370 Pycnazanthine Pycnarrhena ozantha Diels (Mensispermaceae)[120]

44

P.L.SchifT,Jr. Table 1. Continued

49

Repandine Cyclea barbata (Wall.) Miers (Menispermaceae)[90] Daphnandra johnsonii Schodde (Monimiaceae)[336] Daphnandra repandula F. Muell. (Monimiaceae)[426]

C37H40O6N2:608.2886

90

Repandinine Daphnandra dielsii Perk. (Monimiaceae)[27] Daphnandra johnsonii Schodde (Monimiaceae)[336] Daphnandra repandula F. Muell. (Monimiaceae)[27] Daphnandra tenuipes Perk. (Monimiaceae)[387]

C38H40O7N2:636.2836

168 Repanduline C37H36O7N2:620.2523 Daphnandra dielsii Perk. (Monimiaceae)[27] Daphnandra repandula F. Muell. (Monimiaceae)[27,426] Daphnandra tenuipes Perk. (Monimiaceae)[27] 266 Revolutinone Thalictrum revolutum DC. (Ranunculaceae)[427] 26

C3gH40OJ,N2:652.2785

Rodiasine C3gH42O6N2:622.3043 Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei (Lauraceae)][236,388]

127 Sciadenine C37H40OAN2:608.2886 Sciadotenia toxifera Krukoff and A.C. Smith (Menispermaceae)[ 198,428] 217 Sciadoferine C36H3606N2:592.2573 Sciadotenia toxifera Krukoff and A.C. Smith (Menispermaceae)[198] 128 Sciadoline C36H34O6N2:590.2417 Sciadotenia toxifera Krukoff and A.C. Smith (Menispermaceae)[ 198,429] 267 Secantioquine Pseudoxandra aff. lucida Fries (Annonaceae)[8,430]

C37H3gO,N2:638.2628

268 Secocepharanthine Stephania sasakii Hayata (Menispermaceae)[248]

C37H36OgN2:636.2472

432 Secohomoaromoline Anisocycla jolly ana Diels (Menispermaceae)[358]

C37H3lOlN2:638.2628

431 Secoisotetrandrine Laurelia sempervirens R. et P. (Monimiaceae)[325]

C38H40OlN2:652.2785

The Bisbeuzyllsoqulnoline Alkaloids - A Tabular Review

45

Table 1. Continued 433 Secojollyanine Anisocycla jollyana Diels (Menispermaceae)[358]

C36H36O7N2:608.2522

393 Secolucidine Pseudoxandra sclerocarpa Maas (Annonaceae)[l 17]

C36H34O7N2:606.2366

269 Seco-obaberine Pseudoxandra aff. lucida Fries (Annonaceae)[8]

C38H40OgN2:652.2785

50

Sepeerine (Ocoteamine) C36H38O6N2:594.2730 Nectandra rodiei R. Schomb. (Lauraceae)[also known as Ocotea rodiei (Lauraceae)][236] Ocotea rodiei R. Schomb. (Lauraceae)[also known as Nectandra rodiei R. Schomb. (Lauraceae)][236]

371 Siddiquamine C35H30O6N2:574.2104 Coccuius pendulus (Forsk.) Diels (Menispermaceae)[233] 372 Siddiquine C34H28O6N2:560.1947 Coccuius pendulus (Forsk.) Diels (Menispermaceae)[233] 270 Sindamine Berberis lycium (Royle) (Berberidaceae)[68] 51

C37H3808N2:638.2628

Stebisimine C36H34O6N2:590.2417 Anisocycla gradidieri H. Bn. (Menispermaceae)[165] Coccuius japonica DC. (Menispermaceae)[also called Coccuius japonic us Thunb.) Miers (Menispermaceae)][264,431 ] Stephania japonica (Thunb.) Miers (Menispermaceae)[also called Coccuius japonicus D C (Menispermaceae)][264,431] Stephania japonica (Thunb.) Miers var australis (Menispermaceae)[264] Triclisia gilletii (DeWild.) Staner (Menispermaceae)f 168,281]

373 Stephasubimine Stephania suberosa Forman (Menispermaceae)[137]

C35H30O6N2:574.2104

374 Stephasubine C36H34O6N2:590.2417 Stephania hernandifolia (Willd.) Walp. (Menispermaceae) [also called Stephania discolor Spreng. (Menispermaceae)][249] Stephania suberosa Forman (Menispermaceae)! 137] 375 Stephibaberine Stephania erecta Craib. (Menispermaceae)[135] Stephania pierrii Diels (Menispermaceae)[34]

C37H40O6N2:608.2886

46

P.L.SchifT,Jr. Table 1. Continued

376 Stepierrine Stephania pierrii Diels (Menispermaceae)[34]

C33H3206N2:5 76.2260

426 Sutchueneneonine Cyclea sutchuenensis Gagnep. (Menispermaceae)[309]

CJ6H40O6N2:596.2886

427 Sutchuenenine Cyclea sutchuenensis Gagnep. (Menispermaceae)[309)

C36H40O6N2:596.2886

271 Talcamine Berberis buxifolia Lam. (Berberidaceae)[123]

C40H44Ol0N2:712.2996

160 Telobine C35H3405N2:562.2468 Daphnandra apatela Schodde (Monimiaceae)[ 11 ] Daphnandra species Dt-7 (Monimiaceae)[255] Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[ 119] 251 Temuconine Berberis valdiviana (Berberidaceae)[432]

C37H4206N2:610.3043

91

(+)-Tenuipine Daphnandra species unnamed (Monimiaceae)[234] Daphnandra tenuipes Perk. (Monimiaceae)[387]

C3gH40O7N2:636.2836

92

(-)-Tenuipine Daphnandra dielsii Perk. (Monimiaceae)[27] Daphnandra tenuipes Perk. (Monimiaceae)[27]

C3lH40O7N2:636.2836

76

(+)-Tetrandrine C38H42O6N2:622.3043 Aristolochia debilis Sieb. & Zucch. (Aristolochiaceae)[433] Cocculus pendulus (Forsk.) Diels (Menispermaceae)[ 139,161] Cocculus sarmentosus Diels (Menispermaceae)[332] Cyclea barbata (Wall.) Miers (Menispermaceae)[210,303,314 - 76 or 77] Cyclea burmanni (DC.) Miers ex. Hook. f. & Thorns. (Menispermaceae)[ 164,434] Cyclea peltata Diels (Menispermaceae)[43,267] Isopyrum thalictroides L. (Ranunculaceae)[323] Pachygone dasycarpa Kurz (Menispermaceae)[7] Stephania hernandifolia (Willd.) Walp. (Menispermaceae)[also called Stephania discolor Spreng. (Menispermaceae)][199] Stephania tetrandra S. Moore (Menispermaceae)[ 107,207,269,270,435,436]; ([268] detected, not isolated) Strychnopsis thouarsii Baill. (Menispermaceae)[272] Triclisia subcordata Oliv. (Menispermaceae)[42]

The Blsbenzylisoquinoline Alkaloids - A Tabular Review

47

Table 1. Continued

77

(+/-)-Tetrandrine C3gH42O6N2:622.3043 Cyclea barbata (Wall.) Miers (Menispermaceae)[89][303 - 76 or 77] Cyclea peltata Diels (Menispermaceae)[267] Isopyrum thalictroides L. (Ranuncuiaceae)[323] Stephania hernandifolia (Willd.) Walp. (Menispermaceae)[also called Stephania discolor Spreng. (Menispermaceae)][199]

78 Tetrandrine Mono-N-2'-Oxide C38H4207N2:638.2992 Cyclea barbata (Wall.) Miers (Menispermaceae)(78)[143] 106a Thalabadensine C36H38O6N2:594.2730 Thalictrum minus L. (Ranunculaceae)[369] Thalictrum sultanabadense Stapf. (Ranunculaceae)[297-300] 102 Thalfine (Thalphine) Thalictrum foetidum L. (Ranunculaceae)[437,438] Thalictrum minus L. (Ranunculaceae)[404]

C38H3608N2:648.2472

103 Thalfinine (Thalphinine) Thalictrum foetidum L. (Ranunculaceae)[437,438] Thalictrum minus L. (Ranunculaceae)[404]

C39H42OgN2:666.2941

99

Thalfoetidine (Thalictrinine) C38H4207N2:638.2992 Thalictrum fargesii Fr. ex Fin. et Gagnep. (Ranunculaceae)[439,440] Thalictrum flavum L. (Ranunculaceae)[ 108,289] Thalictrum longipedunculatum E. Nik. (Ranunculaceae)[363]

14

Thalibrine C38H4406N2:624.3199 Thalictrum longistylum DC. (Ranunculaceae)[246] Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[389]

112 Thalibrunimine C38H40O8N2:652.2785 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[441,442] 113 Thalibrunine C39H44O8N2:668.3098 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[441,442] 97

Thalicberine C37H40O6N2:608.2886 Thalictrum longipedunculatum E. Nik. (Ranunculaceae)[363] Thalictrum lucidum L. (Ranunculaceae)[37] Thalictrum minus L. (Ranunculaceae)[364,368,370,371] Thalictrum minus L. var. majus (Ranunculaceae)[373] Thalictrum minus L. var. microphyllum Boiss. (Ranunculaceae)[38]

P.L.SchifT,Jr. Table 1. Continued Thalictrum minus L. var. minus (Ranunculaceae)[375] Thalictrum thunbergii DC. (Ranunculaceae)[378] 107 Thalictine C37H40O6N2:608.2886 Thalictrum cultratum Wall. (Ranunculaceae)[307] Thalictrum sultanabadense Stapf. (Ranunculaceae)[300,380] Thalictrum thunbergii DC. (Ranunculaceae)[443] 220 Thalictrinine C38H3609N2:664.2421 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[250] 100 Thalidasine C39H4407N2:652.3149 Thalictrum alpinum L. (Ranunculaceae)[247] Thalictrum cultratum Wall. (Ranunculaceae)[241 ] Vialictrum dasycarpum Fisch. and Lall. (Ranunculaceae)[444] Thalictrum faberi Ulbr. (Ranunculaceae)[242,243,445] Thalictrum fargesii Fr. ex Fin. et Gagnep. (Ranunculaceae)[439,440] Thalictrum flavum L. (Ranunculaceae)[289] Thalictrum foetidum L. (Ranunculaceae)[446] Thalictrum foliolosum DC. (Ranunculaceae)[447] Thalictrum longipedunculatum E. Nik. (Ranunculaceae)[363] Thalictrum lucidum L. (Ranunculaceae)[37] Thalictrum minus L. (Ranunculaceae)[404] Thalictrum revolutum DC. (Ranunculaceae)[376] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)] [406] Thalictrum squarrosum Steph. ex Willd. (Ranunculaceae)[448] 377 Thalidasine-2a-N-Oxide Thalictrum cultratum Wall. (Ranunculaceae)[35]

C3«,H44OgN2:668.3098

83 Thalidezine C38H4207N2:638.2992 Thalictrum delavayi Franch. (Ranunculaceae)[286] Thalictrum fendleri Engelm. ex Gray (Ranunculaceae)[288] Thalictrum flavum L. (Ranunculaceae)[289] Thalictrum foetidum L. (Ranunculaceae)[290] Thalictrum glandulosissimum (Finet et Gagnep.) W.T. Wang et S.H. Wang (Ranunculaceae)[291,292] Thalictrum minus L. (Ranunculaceae)[365] Thalictrum podocarpum Humb. (Ranunculaceae)[244] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)] [365] Thalictrum simplex L. (Ranunculaceae)[296]

The Bisbenzylisoqtiinoline Alkaloids - A Tabular Review

49

Table 1. Continued

428 Thalifortine Thalictrum fortune i S. Moore (Ranunculaceae)[36] 100a Thaligosidine C37H40O7N2:624.2836 Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)][449] 52a Thaligosine [see Thalisopine (54)] C38H4207N2:638.2992 The following alkaloids were named thaligosine, but the existence of an identical alkaloid, thalisopine, in the literature mandates the use of the latter designation [471] Thalictrum cultratum Wall. (Ranunculaceae)[35] Thalictrum foetidum L. (Ranunculaceae)[290] Thalictrum minus L. var. majus (Ranunculaceae)[373] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)] [449] 378 Thaligosine-2o>N-Oxide (Thalisopine-2a-N-Oxide) Thalictrum cultratum Wall. (Ranunculaceae)[35]

C38H4208N2:654.2941

52b Thaligosinine C38H4207N2:638.2992 Thalictrum fargesii Fr. ex Fin. et Gagnep. (Ranunculaceae)[439] Thalictrum foetidum L. (Ranunculaceae)[446] Thalictrum isopyroides C.A.M. (Ranunculaceae)[450] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)] [449] 252 Thaligrisine Pseudoxandra sclerocarpa Maas (Annonaceae)[ 117] Thalictrum minus L. var. microphyllum Boiss.[38]

C37H4206N2:610.3043

253 Thaliphylline Thalictrum cultratum Wall. (Ranunculaceae)[307] Thalictrum minus L. var. microphyllum Boiss.[38] Thalictrum minus L. var. minus (Ranunculaceae)[375]

C37H40O6N2:608.2886

379 Thaliphylline-2'p-N-Oxide Thalictrum cultratum Wall. (Ranunculaceae)[35]

C37H40O7N2:624.2836

17a Thalirabine Thalictrum baicalense Turcz. (Ranunculaceae)[245] Thalictrum minus L. (Ranunculaceae)[404]

C40H47OgN/:683.3332

50

P.L.Schifr,Jr. Table 1. Continued

14a Thaliracebine Thalictrum faberi Ulbr. (Ranunculaceae)[243] Thalictrum minus L. (Ranunculaceae)[404]

C39H4407N2:652.3149

17b Thalirugidine Thalictrum foliolosum DC. (Ranunculaceae)[451 ] Thalictrum rugosum Ait. (Ranunculaceae)[449]

C39H46O8N2:670.3254

14b Thalirugine C3lH44O7N2:640.3149 Thalictrum cultratum Wall. (Ranunculaceae)[35] Thalictrum minus L. var. microphyllum Boiss. (Ranunculaceae)[38] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf.(Ranunculaceae)] [449] 14c Thaiiruginine C3gH46O7N2:654.3305 Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf.(Ranunculaceae)][449] 84

Thalisamine Thalictrum simplex L. (Ranunculaceae)[296]

C38H4207N2:638.2992

53

Thalisopidine C37H40O7N2:624.2836 Thalictrum isopyroides C.A.M. (Ranunculaceae)[450,452,453]

54

Thalisopine C38H4207N2:638.2992 Thalictrum cultratum Wall. (Ranunculaceae)[35,307] Thalictrum faberi Ulbr. (Ranunculaceae)[359] Thalictrum foetidum L. (Ranunculaceae)[290] Thalictrum foliolosum DC. (Ranunculaceae)[451 ] Thalictrum isopyroides C.A.M. (Ranunculaceae)[452] Thalictrum javanicum Bl. (Ranunculaceae)[454] Thalictrum minus L. var. majus (Ranunculaceae)[373] Thalictrum minus L. var. microphyllum Boiss. (Ranunculaceae)[38,374] Thalictrum revolutum DC. (Ranunculaceae)[376] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)] [449]

221 Thalistine Thalictrum minus L. race B (Ranunculaceae)[360]

C3QH44O,N2:668.3098

18 Thalistyline Thalictrum longistylum DC. (Ranunculaceae)[246] Thalictrum podocarpum Humb. (Ranunculaceae)[244]

C4IH49OgN2+:697.3489

The Bisbenzyllsoquinoline Alkaloids - A Tabular Review

51

Table 1. Continued

380 Thalivarmine Thalictrum minus L. var. minus (Ranunculaceae)[375] 98

C36H3gO6N2:594.2730

Thalmethine C36H3606N2:592.2573 Thalictrum minus L. (Ranunculaceae))[364,368,369,371,379,455]

381 Thalmiculatimine Thalictrum cultratum Wall. (Ranunculaceae)[307]

C36H3606N,:592.2573

382 Thalmiculimine Thalictrum cultratum Wall. (Ranunculaceae)[307]

C37H3807N2:622.2679

383 Thalmiculine Thalictrum cultratum Wall. (Ranunculaceae)[307]

C38H4207N2:638.2992

108 Thalmine Thalictrum cultratum Wall. (Ranunculaceae)[241] Thalictrum kuhistanicum Ovcz. (Ranunculaceae)[362] Thalictrum minus L. (Ranunculaceae)[366,369,455]

C37H40O6N2:608.2886

222 Thalmirabine Thalictrum delavayi Franch. (Ranunculaceae)[286] Thalictrum minus L. race B (Ranunculaceae)[360]

C3QH44O8N2:668.3098

223 Thalpindione

C 3 7 H 3 6 O Q N 2 :652.2421

Thalictrum alpinum L. (Ranunculaceae)[247] 52

C37H40OAN2:608.2886 Thalrugosamine [see Homoaromoline (42)][3] The following alkaloids were formerly named thalrugosamine, but a reevlaution of the assignment of the structure of thalrugosamine published in 1972 [305] demonstrated an inconsistency in the structural representation (but not the actual work of the alkaloid [DF3,DG3] with the revelation that (+)-thalrugosmine was in reality (+)- homoaromoline [38]: Limaciopsis loangensis Engl. (Menispermaceae)[92] Stephania pierrii Diels (Menispermaceae)[34] Stephania venosa Spreng. (Menispermaceae)[306] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)] [3 05 ]

55 Thalrugosaminine (O-Methylthalisopine) Thalictrum alpinum L. (Ranunculaceae)[247] Thalictrum cultratum Wall. (Ranunculaceae)[35,307] Thalictrum foetidum L. (Ranunculaceae)[446]

C39H4407N2:652.3149

P.L.Schiff,Jr. Table 1. Continued Thalictrum foliolosum DC. (Ranunculaceae)[451] Thalictrum javanicum Bl. (Ranunculaceae)[454] Thalictrum minus L. (Ranunculaceae)[404] Thalictrum rugosum Ait. (Ranunculaceae)falso called Thalictrum glaucum Desf. (Ranunculaceae)][456] 384 Thalrugosaminine-2a-N-Oxide Thalictrum cultratum Wall. (Ranunculaceae)[35]

C3<,H44ORN2:668.3098

101 Thalrugosidine C3gH4207N2:638.2992 Thalictrum alpinum L. (Ranunculaceae)[247] Thalictrum cultratum Wall. (Ranunculaceae)[307] Thalictrum faberi Ulbr. (Ranunculaceae)[359] Thalictrum foliolosum DC. (Ranunculaceae)[447,451 ] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)] [406] 79

Thalrugosine (Thaligine, Isofangchinoline) C37H40O6N2:608.2886 Berberis boliviano Lechl. (Berberidaceae)[ 18] Berberis cretica L. (Berberidaceae)[19] Berberis laurina (Thunb.) Billbg. (Berberidaceae)[ 18] Berberis polymorpha (Berberidaceae)[457] Cyclea barbata (Wall.) Miers (Menispermaceae)[210,266] Laurelia sempervirens R. et P. (Monimiaceae)[402] Limaciopsis loangensis Engl. (Menispermaceae)[92] Mahonia repens (Lindl.) G. Don (Berberidaceae)[403] Pycnarrhena novoguineensis Miq. (Menispermaceae)[22] Stephania erecta Craib. (Menispermaceae)[135] Stephania japonica (Thunb.) Miers var australis (Menispermaceae)[458] Stephania sutchuenensis H.S. Lo (Menispermaceae)[459] Thalictrum lucidum L. (Ranunculaceae)[37] Thalictrum minus L. var. microphyllum Boiss. (Ranunculaceae)[374] Thalictrum minus L. race B (Ranunculaceae)[360] Thalictrum polygamum Muhl. (Ranunculaceae)[460] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)] [406] Thalictrum sachalinense Lecoyer. (Ranunculaceae)[461]

224 Thalrugosinone C38H3gO,N2:666.2577 Thalictrum cultratum Wall. (Ranunculaceae)[241] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. Ranunculaceae)] [ 3 9]

The Blsbenzylisoqninoline Alkaloids - A Tabular Review

53

Table 1. Continued

85

Thalsimidine (Thalcimidine) Thalictrum simplex L. (Ranunculaceae)[462]

86

Thalsimine (Thalcimine) C38H40O7N2:636.2836 Thalictrum rochebrunianum Franc, and Sav. (Ranunculaceae)[441] Thalictrum rugosum Ait. (Ranunculaceae)[also called Thalictrum glaucum Desf. (Ranunculaceae)][365] Thalictrum simplex L. (Ranunculaceae)[296,462,463]

385 Thalsivasine Thalictrum cultratum Wall. (Ranunculaceae)[307] Thalictrum minus L. var. minus (Ranunculaceae)[375]

C37H3807N2:622.2679

C36H3606N2:592.2573

183 Tiliacoridine - Undetermined Structure C39H40O8N2:664.2785 Tiliacora racemosa Colebr. (Menispermaceae)[also called Tiliacora acuminata (Lam.) Miers (Menispermaceae)][464] 118 Tiliacorine C36H3605N2:576.2624 Tiliacora funifera Engl, ex Diels (Menispermaceae)[also called Tiliacora warneckei Engl, ex Diels (Menispermaceae)][391] Tiliacora racemosa Colebr. (Menispermaceae)[also called Tiliacora acuminata (Lam.) Miers (Menispermaceae)][393] Tiliacora triandra Diels (Menispermaceae)[257,397,398] 119 Tiliacorinine C3«H3A0,N2:576.2624 Tiliacora dinklagei Engl. (Menispermaceae)[275] Tiliacora racemosa Colebr. (Menispermaceae)[also called Tiliacora acuminata (Lam.) Miers (Menispermaceae)][393,396] Tiliacora triandra Diels (Menispermaceae)[397,398] 254 Tiliacorinine-2'-N-Oxide Tiliacora triandra Diels (Menispermaceae)[385]

C36H3606N2:592.2573

79a Tiliafunimine C36H3606N2:592.2573 Tiliacora funifera Engl, ex Diels (Menispermaceae)[also called Tiliacora warneckei Engl, ex Diels (Menispermaceae)][465] 27

Tiliageine Guatteria guianensis (Aublet) R.E. Fries (Annonaceae)[119] Tiliacora dinklagei Engl. (Menispermaceae)[275] Tiliacora triandra Diels (Menispermaceae)[466]

54

P.L.SchilT,Jr. Table 1. Continued

120 Tiliamosine C36H3606N2:592.2573 Pachygone ovata (Poir.) Miers ex Hook (Menispermaceae)[356,357] Tiliacora racemosa Colebr. (Menispermaceae)[also called Tiliacora acuminata (Lam.) Miers (Menispermaceae)][382,392] 386 Tilianangine Tiliacora triandra Diels (Menispermaceae)[257]

C36H3606N2:592.2573

184 Tiliandrine - Undetermined Structure Tiliacora triandra Diels (Menispermaceae)[314]

C34H34O5N2:550.2468

429 Tiliaresine C36H3605N2:576.2624 Tiliacora racemosa Colebr. (Menispermaceae)[also called Tiliacora acuminata (Lam.) Miers (Menispermaceae)][382] 185 Tiliarine C35H3405N2:562.2468 Tiliacora racemosa Colebr. (Menispermaceae)[also called Tiliacora acuminata (Lam.) Miers (Menispermaceae)][395,467] 387 Tilitriandrine Tiliacora triandra Diels (Menispermaceae)[466]

C3AH38O6N2:594.2730

186 Tomentocurine - Undetermined Structure C36H3gO6N2:594.2730 Chondodendron tomentosum Ruiz and Pavon (Menispermaceae)[141] 141 Toxicoferine A 1:1 molecular complex of (-)-curine (133) and (-)-tubocurine (144)[201] Chondendron toxicoferum (Wedd.) Kruk. et Mold. (Menispermaceae)[201] 161 Tricordatine C34H3205N2:548.23ll Cocculus pendulus (Forsk.) Diels (Menispermaceae)[ 139] Pachygone dasycarpa Kurz (Menispermaceae)[7] Triclisia subcordata Oliv. (Menispermaceae)[169] 162 Trigilletimine C35H30O5N2:558.2155 Triclisia dictyophylla Diels (Menispermaceae)[167] Triclisia gilletii (DeWild.) Staner (Menispermaceae)[468] Triclisia patens Oliv. (Menispermaceae)[468] 163 Trilobine C35H3405N2:562.2468 Anisocycla cymosa Troupin (Menispermaceae)[154] Anisocycla gradidieri H. Bn. (Menispermaceae)[165] Anisocycla jolly ana (Pierre) Diels (Menispermaceae)[235]

i he Bisbenzylisoquinoline Alkaloids - A Tabular Review

55

Table 1. Continued

Cocculus hirsutus Diels (Menispermaceae)[329-331] Cocculus laurifolius DC. (Menispermaceae)[329] Cocculus pendulus (Forsk.) Diels (Menispermaceae)[153] Cocculus sarmentosus Diels (Menispermaceae)[332] Cocculus trilobus DC. (Menispermaceae)[216,333] Pachygone ovata (Poir.) Miers ex Hook (Menispermaceae)[399,469] 142 (+)-Tubocurarine C37H41O6N2:609.3043 Anomospermum grandifolium Eichl. (Menispermaceae)[470] Chondodendron tomentosum Ruiz and Pavon (Menispermaceae)[142] Peruvian curare [145] 143 (-)-Tubocurarine C37H41O6N2+:609.3043 Chondodendron tomentosum Ruiz and Pavon (Menispermaceae)[200] 144 (-)-Tubocurine C36H38O6N2:594.2730 Chondendron toxicoferum (Wedd.) Kruk. et Mold. (Menispermaceae)[201] 255 Vanuatine Hernandia peltata Meissn. (Hernandiaceae)[345]

C30H46O8N2:670.3254

256 Vateamine Hernandia peltata Meissn. (Hernandiaceae)[345]

C38H44O8N2:656.3097

430 Vateamine-2'p-N-Oxide C38H44O9N2:672.3047 Hernandia nymphaeifolia (Presl) Kubirtzki [Biasolettia nymphaeifolia Presl, Hernandia peltata (Meissn.)] (Hernandiaceae)[472] 151 Warifteine Cissampelos ovalifolia DC. (Menispermaceae)[251 ]

C36H3606N2:592.2573

388 Yanangcorinine Tiliacora triandra Diels (Menispermaceae)[398]

C36Hv,05N2:576.2624

389 Yanangine Tiliacora triandra Diels (Menispermaceae)[258]

C36H3606N2:592.2573

56

P.L.Schiff,Jr.

3.

A NUMERIC (1-5J COMPILATION OF THE BISBENZYLISOQUINOLINE ALKALOIDS Table 2

1

Berbamunine - 0 3 ^ 0 ^ : 5 9 6 . 2 8 8 6 [18,19,21,23,34,62,76,82,84,86,110-117]

2

Cuspidaline - C37H4206N2:610.3043 [184,185]

3

Dauricine - € 3 ^ 0 ^ : 6 2 4 . 3 1 9 9 [218-229]

4

Dauricinoline - C37H4206N2:610.3043 [222,223]

5

Dauricoline - C36H40O6N2:596.2886 [221,223,229]

6

Daurinoline - C37H4206N2:610.3043 [220,221,223]

7

N'-Desmethyldauricine - C37H4206N2:610.3043 [220]

8

Espinidine - C37H4206N2:610.3043 [265]

9

Espinine - C36H40O6N2:596.2886 [239,265]

10 Grisabine - C37H4206N2:610.3043 [240.282,283] 11

Lindoldhamine - C34H3606N2:568.2573 [10,16,230,231,343]

12 Magnoline (Grisabutine) - € ^ 0 ^ : 5 9 6 . 2 8 8 6 [240,475] 12a O-Methyldauricine - C„H4606N2:638.3356 [229,354] 13 Northalibrine - C37H4206N2:610.3043 [389] 14 Thalibrine - C3gH4406N2:624.3199 [246,389] 14a Thaliracebine - C39H4407N2:652.3149 [243,404] 14b Thalirugine - 0 3 , ^ 0 ^ : 6 4 0 . 3 1 4 9 [35,38,449] 14c Thaliruginine - C39H46O7N2:654.3305 [449] 15 Magnolamine - C37H4207N2:626.2992 [344] 16 N-Desmethylthalistyline - C40H46O8N2:682.3254 [244-246]

The Bisbenzylisoquinollne Alkaloids - A Tabular Review

57

Table 2. Continued 17 N-Methylthalistyline (Methothalistyline, Thalistyline Metho Salt) - C42H52OsN2":712.3724 [244,246] 17a Thalirabine - C40H47O8N/:683.3332 [245,404] 17b Thalirugidine - C39H46O8N2:670.3254 [449,451] 18 Thalistyline - C41H4908N/:697.3489 [244,246] 19 Dirosine - C37H4206N2:610.3043 [236] 20

Funiferine - C38H42O6N2:622.3043 [119,275,276]

21

Funiferine N-Oxide - C3gH4207N2:638.2992 [278]

22

Norrodiasine - C37H40O6N2:608.2886 [236]

23 Ocotine - C37H40O6N2:608.2886 [388] 24

Ocotosine - C37H38O6N2:606.2730 [388]

25

Phlebicine - C37H40O6N2:608.2886 [425]

26

Rodiasine - C38H42O6N2:622.3043 [236,388]

27 Tiliageine - C37H40O6N2:608.2886 [119,275,466] 28

Isoliensinine - C37H4206N2:610.3043 [316,317]

29

Liensinine - C37H4206N2:610.3043 [338-341]

30

Neferine - C38H4406N2:624.3199 [317,339]

31

Aromoline (Thalicrine) - C36H38O6N2:594.2730 [9,12,15-21,23-42,78]

32 N,N'-Bisnoraromoline - C34H3406N2:566.2417 [10,13,118] 33 Cepharanoline - C36H3606N2:592.2573 [32,102,104,130] 34

Cepharanthine - C37H38O6N2:606.2730 [32,34,102,104-106,131-137]

35

Coclobine - C37H38O6N2:606.2730 [12,151,152]

58

P.L.SchifT,Jr. Table 2. Continued

36

Cycleapeltine (Faralaotrine) - C37H4o06N2:608.2886 [43,209,210]

37

Daphnandrine - C36H38O6N2:594.2730 [10,12,13,27,28,34,90,135,151]

38

Daphnoline - C35H36O6N2:580.2573 [7,9,10,12,13,16,26-28,49,120,139,216]

39

Demerarine - € ^ 0 ^ : 5 9 4 . 2 7 3 0 [236]

40

(+)-Epistephanine - C37H38O6N2:606.2730 [249,261-264]

41

(-)-Epistephanine - C37H38O6N2:606.2730 [165]

42 Homoaromoline (Homothalicrine) - C37H4o06N2:608.2886 [15,16,18,28,30,32,37,38,40,41, 49,104,117,134,135,210,235,301-304] 43 Hypoepistephanine (Pseudoepistephanine) - C36H3606N2:592.2573 [263] 44

Limacusine - € 3 ^ 0 ^ : 6 0 8 . 2 8 8 6 [127-129,184,185]

44a Macolidine - C36H38O6N2:594.2730 [240] 44b Macoline - C37H4206N2:610.3043 [240] 45

O-Methylrepandine - C38H42O6N2:622.3043 [27,323,336]

46

Obaberine - C38H42O6N2:622.3043 [8,16,18,19,34,35,37,39,49,60,62,135,230,232,248,320, 322,337,373,374,400-404]

47

Oblongamine - C38H4306N/:623.3121 [ 115]

47a Oxoepistephanine - €^14*0^2:620.2523 [409] 48 Oxyacanthine - C37H40O6N2:608.2886 [16-18,20,21,24,35,37,55,60,62,63,65,68,70,75,78,79, 83-86,95,96,110-115,116,321,373,379,400,402,403,407,411-421,473] 49

Repandine - C ^ O J ^ .608.2886 [90,336,426]

50

Sepeerine (Ocoteamine) - C%H3806N2:594.2730 [236]

51 Stebisimine - 0 ^ , 0 ^ 2 : 5 9 0 . 2 4 1 7 [165,168,264,281,431] 52 Thalrugosamine [see Homoaromoline (42)][3] - € 3 ^ 0 ^ 3 : 6 0 8 . 2 8 8 6 [34,92,305,306]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

59

Table 2. Continued

52a Thaligosine [see Thalisopine (54)] - C38H4207N2:638.2992 [35,290,373,449] 52b Thaligosinine - C38H4207N2:63 8.2992 [439,446,449,450] 53 Thalisopidine - C37H40O7N2:624.2836 [450,452,453] 54

Thalisopine - C38H4207N2:638.2992 [35,38,290,307,359,373,374,376,449,451,452,454]

55

Thalrugosaminine (O-Methylthalisopine) - C39H4407N,:652.3149 [35,247,307,404,446,451, 454,456]

56

Atherospermoline - C36H38O6N2:594.2730 [7,44]

57

Berbamine - € ^ 0 ^ : 6 0 8 . 2 8 8 6 [17-20,22,23,29,51-109]

58

Cycleadrine - C37H40O6N2:608.2886 [1,43]

59

Cycleahomine - C39H4506N/:637.3278 [43]

60

Cycleanorine - C37H40O6N2:608.2886 [43,90]

60a 7-O-Demethylpeinamine - C35H36O6N2:580.2573 [240] 61

Fangchinoline - C37H40O6N2.608.2886 [7,43,107,168,199,207,255,266-272]

62 Isotetrandrine - C38H4,O6N,:622.3043 [18,19,21,23,28-30,32,34,51,55,58,64,69,72,79,80,87, 91,92,95,97-101,103", 104,108,112,135,153,168,269,282,302,319-328] 63

Krukovine - C36H3806N2.594.2730 [15,49,127,128]

64

Limacine - C37H40O6N2:608.2886 [22,45,49,89,127,128,184,185,209.210,235,271,272,282, 301,342]

65

Menisidine - C37H40O6N2:608.2886 [350]

66

Menisine - C37H40O6N2:608.2886 [350]

66a 2-N'-Methylberbamine - C38H4306N/:623.3121 [116,351,352] 66b N-Methyl-7-O-Demethylpeinamine - C%H3806N2:594.2730 [7,240] 67

Monomethyltetrandrinium - C39H4506N/:637.3278 [383]

#>

P.L.Schiff,Jr. Table 2. Continued

68

2-N-Norberbamine - C36H38O6N2:594.2730 [34,99,120,139]

69

2-N-Norobamegine - C33H36O6N2:580.2573 [99,118,120]

70

2-Nortetrandrine - C37H40O6N2:608.2886 [388]

71

Obamegine - C36H3iO6N2:594.2730 [18,19,29,32,37,38,281,400,403,405-407]

71a Peinamine - C36H38O6N2:594.2730 [240] 72 Penduline - C37H40O6N2:608.2886 [7,58,139,153,155,156,160,161] 73 Phaeantharine - C38H3606N2:616.2573 [ 162,163] 74

Phacanthine - C38H42O6N2:622.3043 [22,45,99-101,164,168,282,342,422-424]

75 Pycnamine - C37H4o06N2:608.2886 [22,100,101,168,422] 76 (+)-Tetrandrine - C38H42O6N2:622.3043 [7,42,43,107,139,161,164,199,207,210,267-270,272, 303,314,323,332,433-436] 77 (+/-)-Tetrandrine - C38H42O6N2:622.3043 [89,199,267,303,323] 78 Tetrandrine Mono-N-2'-Oxide - C38H4207N2:638.2992 [143] 79 Thalrugosine (Thaligine, Isofangchinoline) - 0 ^ 0 ^ 2 : 6 0 8 . 2 8 8 6 [ 18,19,22,37,92,135,210, 266,360,374,402,403,406,457-461] 79a Tiliafunimine - C36H3606N2:592.2573 [465] 80 N-Desmethylthalidezine - 0 ^ 0 ^ 2 : 6 2 4 . 2 8 3 6 [244] 81

Hernandezine (Thalicsimine) - C39H4407N2:652.3149 [ 161,244,284-300]

82

Isothalidezine - C38H4207N2:638.2992 [244,286,292]

83 Thalidezine - C38H4207N2:638.2992 [244,286,288-292,296,365] 84 Thalisamine - C38H4207N2:638.2992 [296] 85 Thalsimidine (Thalcimidine) - C37H3807N2:622.2679 [462] 86 Thalsimine (Thalcimine) - 0 ^ 0 ^ 2 : 6 3 6 . 2 8 3 6 [296,365,441,462,463]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

61

Table 2. Continued 87

Isotenuipine - C38H40O7N2:636.2836 [318]

88

(+)-Nortenuipine - C37H3807N2:622.2679 [255,336,387]

89

(-)-Nortenuipine - C37H3807N2:622.2679 [27,387]

90

Repandinine - C38H40O7N2:636.2836 [27,336,387]

91

(-f)-Tenuipine - C38H40O7N2:636.2836 [234,387]

92

(-)-Tenuipine - C38H40O7N2:636.2836 [27]

93

Belarine - C37H40O6N2:608.2886 [18,48]

94

O-Methylisothalicberine - C38H42O6N2:622.3043 [48,237,337]

95 O-Methylthalicberine (Thalmidine) - C38H42O6N2:622.3043 [37,38,238,116,307,359,289, 290, 362-378] 96

O-Methylthalmethine - C37H38O6N2:606.2730 [364,368,371,375,376,379]

97

Thalicberine - C37H40O6N2:608.2886 [37,38,363,364,368,370,371,373,375,378]

98

Thalmethine - C%H3606N2:592.2573 [364,368,369,371,379,455]

99

Thalfoetidine (Thalictrinine) - C38H4207N2:638.2992 [108,289,363,439,440]

100 Thalidasine-C39H4407N2:652.3149[37,241-243,247,289,363,376,404,406,439,440,444-448] lOOaThaligosidine - C37H40O7N2:624.2836 [449] 101 Thalrugosidine - C38H4207N2:638.2992 [247,307,359,406,447,451] 102 Thalfine (Thalphine) - C38H%08N2:648.2472 [404,437,438] 103 Thalfinine (Thalphinine) - C39H42OgN2:666.2941 [404,437,438] 104 Dryadinc - C37H40O6N2:608.2886 [260] 105 Dryadodaphnine - C36H38O6N2:594.2730 [260] 106 Lauberine - C37H40O6N2:608.2886 [18,337]

*2

P.L.Schiff,Jr. Table 2. Continued

106a Thalabadensine - C36H38O6N2:594.2730 [297-300,369] 107 Thalictine - C37H40O6N2:608.2886 [300,307,380,443] 108 Thalmine - C37H40O6N2:608.2886 [241,362,366,369,455] 109 Norpanurensine - C36H3gO6N2:594.2730 [386] 110 Panurensine - C37H40O6N2:608.2886 [386] 111 Nemuarine - C37H40O6N2:608.2886 [384] 112 Thalibrunimine - C38H40OgN2:652.2785 [441,442] 113 Thalibrunine - C39H44OgN2:668.3098 [441,442] 114 Dinklacorine - C36H3605N2:576.2624 [256-258] 115 Nortiliacorine A (Isotiliarine) - C35H3403N2:562.2468 [385,391] 116 Nortiliacorinine A (Pseudotiliarine) - C35H3405N2:562.2468 [257,275,391-398] 117 Nortiliacorinine B - C35H3405N2:562.2468 [393] 118 Tiliacorine - C36H3605N2:576.2624 [257,391,393,397,398] 119 Tiliacorinine - C36H3605N2:576.2624 [275,393,396-398] 120 Tiliamosine - C36H3606N2:592.2573 [356,357,382,392] 121 Cycleanine - C3gH42O6N2:622.3043 [30,32,34,92,102,104,105,131,132,141,142,147,157,158, 181,182,189-195,197,204-208] 122 Isochondodendrine(Isobebeerine)-C36H3gO6N2:594.2730[130,141,142,144,146,147,175,180183,189,190,194-199,201,267,303,309,312-315] 123 Neoprotocuridine - C36H3g06N2:594.2730 [1] 124 (+)-Norcycleanine - 0 ^ 0 ^ : 6 0 8 . 2 8 8 6 [141,158,192,195,312] 125 (-)-Norcycleanine - C37H40O6N2:608.2886 [32,181] 126 Protocuridine - C36H3g06N2:594.2730 [l]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

63

Table 2. Continued 127 Sciadenine - C37H40O6N2:608.2886 [198,428] 128 Sciadoline - C36H3406N2:590.2417 [198,429] 129 Chondocurarine - C3gH4406N2:624.3199 [140] 130 Chondocurine [Chondrocurine, (+)-Tubocurine] - C36H38O6N2:594.2730 [141-145] 131 Chondrofoline - C37H40O6N2:608.2886 [146-148] 132 (+)-Curine [Bebeerine, Chondodendrine] - C36H38O6N2:594.2730 [146,175-178,476] 133 (-)-Curine [(-)-Bebeerine] - C36H38O6N,:594.2730 [90,130,141,142,144-147,175,177-183, 190,200-203]

134 Cycleacurine - C35H36O6N2:580.2573 [43] 135 0,0-Dimethylcurine - C37H40O6N2:608.2886 [191,196] 136 Hayatidine - C37H40O6N2:608.2886 [190] 137 Hayatine - C36H38O6N2:594.2730 [144,175,190,202] 138 Hayatinine - C37H40O6N2:608.2886 [190,202] 139 4"-0-Methylcurine - C37H40O6N2:608.2886 [175,203] 140 12'-0-Methylcurine - C37H40O6N2:608.2886 [196] 141 Toxicoferine - A 1:1 molecular complex of (-)-curine (133) and (-)-tubocurine (144)[201] 142 (+)-Tubocurarine - C37H4,O6N2+:609.3043 [142,145,470] 143 (-)-Tubocurarine - C37H4lO6N2+:609.3043 [200] 144 (-)-Tubocurine - C36H38O6N2:594.2730 [201] 145 Cissampareine - C37H38O6N2:606.2730 [149] 146 Dihydrowarifteine - C36H38O6N2:594.2730 [251] 147 Dimethyldihydrowarifteine - C38H42O6N2:622.3043 [251]

64

P.L.Schiir,Jr. Table 2. Continued

148 Dimethylwariftcine - C38H40O6N2:620.2886 [251] 149 Methyldihydrowarifteine - C37H40O6N2:608.2886 [251] 150 Methylwarifteine - C37H38O6N2:606.2730 [251] 151 Warifteine - C36H36OeN2:592.2573 [251] 152 Cocsoline-C34H3205N2:548.2311 [9,10,16,139,153-158] 153 Cocsuline (Efirine, Trigilletine) - C33H3405N2:562.2468 [7,9,10,16,139,153,156-158,160, 161,165-170] 154 1,2-Dehydromicranthine - C34H30O5N2:546.2155 [234] 155 12-0-Demethyltrilobine-C34H3205N2:548.2311 [153,165] 156 N,0-Dimethylmicranthine - C36H3605N2:576.2624 [234,255] 157 Isotrilobine (Homotrilobine) - C36H3605N2:576.2624 [7,13,16,139,153,216,235,329-335] 158 O-Methylmicranthine - C35H3405N2:562.2468 [234,255] 159 Micranthine-C34H3205N2:548.2311 [27,234,255] 160 Telobine - C„H3405N2:562.2468 [11,119,255] 161 Tricordatine-C34H3205N2:548.2311 [7,139,169] 162 Trigilletimine - C35H30O5N2:558.2155 [167,468] 163 Trilobine - C35H3405N2:562.2468 [153,154,165,216,235,329-333,399,469] 164 Cocsulinine - € ^ 0 ^ : 5 7 8 . 2 4 1 7 [153,156] 165 Menisarine - C36H34O6N2:590.2417 [332,349] 166 Normenisarine - C35H3206N2:576.2260 [216] 167 Pseudorepanduline - C37H3lO6N2:606.2730 [234] 168 Repanduline - C37H36O7N2:620.2523 [27,426]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 2. Continued

169 Insulanoline - C37H3806N2.606.2730 [192,252,308,309] 170 Insularine - C38H40O6N2:620.2886 [182,189,192,252,308,310] 171 Artifact (No. 16) - C39H44O6N2Cl2:707.2259 [43] 172 Dinklageine - Undetermined Structure - C36H38O6N2:594.2730 [259] 173 Himanthine - Undetermined Structure - C37H40O6Ni:608.2886 [81] 174 (-)-Isochondocurarine - Undetermined Structure - C38H4406N2*+:624.3199 [311] 175 (+)-Neochondocurarine - Undetermined Structure - C38H4406N2+:624.3199 [311] 176 Ocodemerine - Undetermined Structure - C37H40O6N2:608.2886 [236] 177 Otocamine - Undetermined Structure - C37H40O6N2:608.2886 [236] 178 Pendine - Undetermined Structure - C33H3406N2:578.2417 [153,156] 179 Pendulinine - Undetermined Structure - C35H3406N2:578.2417 [153,156] 180 Protochondocurarine - Undetermined Structure - C37H4)06N2 :609.3042 [311] 181 Pycnarrhenamine - Undetermined Structure - C3,H40O9N2:632.2734 [100] 182 Pycnarrhenine - Undetermined Structure - C36H42O9N2:646.2890 [100] 183 Tiliacoridine - Undetermined Structure - C39H40O8N2:664.2785 [464] 184 Tiliandrine - Undetermined Structure - C34H34O5N2:550.2468 [314] 185 Tiliarine - C35H34OsN2:562.2468 [395,467] 186 Tomentocurine - Undetermined Structure - C36H38O6N2:594.2730 [141] 187 Apateline-C34H3205N2:548.231l [9-13] 188 Baluchistine - C36H38O6N2:594.2730 [47] 189 Calafatimine - C38H40O7N2:636.2836 [121] 190 Calafatine - C39H4407N2:652.3149 [121-124]

65

66

P.L.ScMfT,Jr. Table 2. Continued

191 Daphnine - C37H3207N2:616.2209 [213-215] 192 Daurisoline - C37H4206N2:610.3043 [223,225,227,230,231] 193 1,2-Dehydroapateline - C34H30O5N2:546.2155 [11-13,28,34,139,154] 194 1,2-Dehydrotelobine - C35H32O5N2:560.2311 [11-13,16,135,154,235] 195 7-O-Demethylisothalicberine - C36H3806N2:594.2730 [18,237,238] 196 N-Desmethylthalidasine - C38H4207N2:638.2992 [241-243] 197 N-Desmethylthalrugosidine - € 3 ^ 0 ^ 2 : 6 2 4 . 2 8 3 6 [247] 198 Dibydrothalictrinine - C38H3809N2:666.2577 [250] 199 Epinorhernandezine (Semisynthetic) - C38H4207N2:638.2992 [250] 200 Epinorthalibrunine (Semisynthetic) - C38H4208N2:654.2941 [250] 201 Funiferine Dimethiodide - C40H48O6N2~:652.3512 [277] (N,N-Dimethylfuniferine Iodide) 202 Gilletine - C35H3406N2:578.2417 [280,281] 203 Hernandezine-N-Oxide - C39H44O8N2:668.3098 [299] 204 Isogilletine-N-Oxide - C35H3407N2:594.2366 [281] 205 Isothalicberine - C37H40O6N2:608.2886 [237,238] 206 Johnsonine - 0,^,00^2:608.2886 [336] 207 N-Methylapateline - C35H3405N2:562.2468 [336] 208 N-Methylnorapateline-C34H3205N2:548.2311 [336] 209 O-Methylthalibrine - C39H4606N2:638.3356 [292,359,360] 210 O-Methylthalibrunimine - C39H42OgN2:666.2941 [361] 211 Ncothalibrine - 0 ^ 0 ^ 2 : 6 2 4 . 3 1 9 9 [24,35,39,377]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 2. Continued

212 N'-Norhernandezine - C3gH4207N2:638.2992 [250] 213 Nor-2'-Isotetrandrine - C37H40O6N2:608.2886 [34,92] 214 N'-Northalibrunine - C3gH42OgN2:654.2941 [250,361] 215 Oxothalibrunimine - C3gH3g09N2:666.2577 [250] 216 N-Oxy-2'-Isotetrandrine - C3gH4207N2:638.2992 [92] 217 Sciadoferine - C36H3606N2:592.2573 [198] 218 Berbacolorflammine (1,2,3,4-Tetradehydrolimacine) - C37H37O6N2*:605.2652 [49,50] 219 Colorflammine (r,2',3',4'-Tetradehydrolimacusine) - C37H37O6N/:605.2652 [49,50] 220 Thalictrinine - C3gH3609N2:664.2421 [250] 221 Thalistine - C39H44OgN2:668.3098 [360] 222 Thalmirabine - C39H44OgN2:668.3098 [286,360] 223 Thalpindione - C37H3609N2:652.2421 [247] 224 Thalrugosinone - C3gH3g09N2:666.2577 [39,241] 225 Antioquine - C37H40O6N2:608.2886 [8] 226 Calafatine-2'a-N-Oxide - C39H44OgN2:668.3098 [125,126] 227 Calafatine-2'P-N-Oxide - C39H44OgN2:668.3098 [125,126] 228 Cheratamine - C36H34O7N2:606.2366 [139] 229 Chillanamine - C37H4207N2:626.2992 [123] 230 Nor-Nb-Chondrocurine - C„H36O6N2:580.2573 [145] 231 Cocsuline-N-2-Oxide - C35H3406N2:578.2417 [171] 232 Cycleanine N-Oxide - C3gH40O7N2:636.2836 [158] 233 N-Desmethylcycleanine - C37H40O6N2:608.2886 [34,206]

67

o*

P.L.Schiff,Jr. Table 2. Continued

234 N,N'-Dimethyllindoldhamine [231] or Guattegaumerine [254] - 0 3 ^ 0 ^ 2 : 5 9 6 . 2 8 8 6 [74,76, 230,231,254] 235 Isodaurisoline - C37H4206N2:610.3043 [231] 236 Kohatine - C34H32O6N2:564.2260 [139,233] 237 Kurramine - C33H2805N2:532.1998 [139] 238 Malekulatine - C39H46OgN2:670.3254 [345-347] 239 O-Methylcocsoline - C35H3405N2:562.2468 [10,13,16] 240 7-O-Methylcuspidaline - C38H4406N2:624.3199 [353] 241 7-O-Methyllindoldhamine - C35H38O6N2:582.2730 [231] 242 7'-0-Methyllindoldhamine - C„H38O6N2:582.2730 [231] 243 N-Methylpachygonamine - C35H3406N2:578.2417 [356,357] 244 O-Methylthalmine - C38H42O6N2:622.3043 [307,380] 245 2-Norlimacusine - C36H38O6N2:594.2730 [74,283] 246 Norpenduline - C36H38O6N2:594.2730 [139] 247 Nortrilobine-C34H3205N2:548.2311 [399] 248 Osornine - C38H4207N2:638.2992 [123] 249 Pachygonamine - C34H32O6N2:564.2260 [356,357] 250 Pachyovatamine-C34H3205N2:548.2311 [357] 251 Temuconine - C37H4206N2:610.3043 [432] 252 Thaligrisine - C37H4206N2:610.3043 [38,117] 253 Thaliphylline - € ^ 0 ^ 2 . 6 0 8 . 2 8 8 6 [38,307,375] 254 Tiliacorininc-2'-N-Oxide - C36H3606N2:592.2573 [385]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 2. Continued

255 Vanuatine - C39H46O8N2:670.3254 [345] 256 Vateamine - C38H44O8N2:656.3097 [345] 257 Baluchistanamine - C37H3808N2:638.2628 [46] 258 Chenabine - C37H40O7N2:624.2836 [138] 259 Curacautine - C39H4209N2:682.2891 [123] 260 Dihydrosecocepharanthine - C37H3808N2:638.2628 [248] 261 Gilgitine - C36H34OgN2:622.2316 [68] 262 Jhelumine - C36H3807N2:610.2679 [138] 263 O-Methyldeoxopunjabine - C36H3606N2:592.2573 [248] 264 O-Methylpunjabine - C36H34O7N2:606.2366 [248,358] 265 Punjabine - C35H32O7N2:592.2210 [68] 266 Revolutinone - C38H40O8N2:652.2785 [427] 267 Secantioquine - C37H38OgN2:638.2628 [8,430] 268 Secocepharanthine - C37H36OgN2:636.2472 [248] 269 Seco-obaberine - C38H40O8N2:652.2785 [8] 270 Sindamine - C37H38OgN2:638.2628 [68] 271 Talcamine - C40H44Ol0N2:712.2996 [123] 272 Ambrimine - C38H44OgN2:656.3097 [6] 273 Aquifoline - C36H38O6N2:594.2730 [14] 274 Berbamine-2'P-N-Oxide - 0 ^ ^ 0 ^ 2 : 6 2 4 . 2 8 3 6 [58] 275 Berbilaurine - C36H38O6N2:594.2730 [18] 276 2,2'-Bisnorguattaguianine - C36H38O6N2:594.2730 [119]

69

70

P.L.Schiff,Jr. Table 2. Continued

277 Bisnorobamegine - C34H3406N2:566.2417 [120] 278 2,2'-Bisnorphaeanthine - C36H38O6N2:594.2730 [10] 279 Bisnorthalrugosine - C35H36O6N2:580.2573 [120] 280 Candicusine - C36H3gO6N2:594.2730 [127-129] 281 Caryolivine - C36H34O6N2:590.2417 [74] 282 Cepharanthine-2'P-N-Oxide - C37H3807N2:622.2679 [137] 283 Cordobimine - C36H3606N2:592.2573 [172] 284 Cordobine - C37H40O6N2:608.2886 [172] 285 Cultithalminine - C36H36O7N2:608.2522 [35] 286 Cycleaneonine - C38H42O6N2:622.3043 [187,188] 287 Dehatridine - C35H32O6N2:576.2260 [232] 288 Dehatrine - C37H38O6N2:606.2730 [232,474] 289 1,2-Dehydrokohatamine - C35H32O6N2:576.2260 [233] 290 1,2-Dehydrokohatine - C34H30O6N2:562.2104 [233] 291 l,2-Dehydro-2-Norlimacusine - C36H3606N2:592.2573 [74] 292 l,2-Dehydro-2'-Nortelobine - C34H30OsN2:546.2155 [233] 293 12-O-Demethylcoclobine - C36H3606N2:592.2573 [12] 294 12-O-Desmethyllauberine - C*H38O6N2:594.2730 [239] 295 3\4'-Dihydrostephasubine - C36H3606N2:592.2573 [249] 296 Efatinc - C38H44O8N2:656.3097 [6] 297 Fenfangjine A (Tetrandrine-2p-N-Oxide) - C38H4207N2:638.2992 [207,273] 298 Fenfangjine B (Fangchinoline-2'a-N-Oxide) - 0 3 ^ 0 ^ 2 : 6 2 4 . 2 8 3 6 [207,273]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 2. Continued 299 Fenfangjine C (Fangchinoline-2'p-N-Oxide) - C37H40O7N2:624.2836 [207,273] 300 Fenfangjine D (1,3,4-Tridehydrofangchinolinium Hydroxide) - C37H40O7N2:624.2836 [207,274] 301 Geraldoamine - C37H4206N2:610.3043 [279] 302 Granjine - C39H4406N2:636.3199 [172] 303 Guattamine - C37H40O6N2:608.2886 [119] 304 Guattaminone - C37H36O7N2:620.2523 [119] 305 Gyroamericine - C37H40O6N2:608.2886 [282] 306 Gyrocarpine - C37H40O6N2:608.2886 [45,282] 307 Gyrocarpusine - C37H40O6N2:608.2886 [282] 308 Gyrolidine - C3gH42O6N2:622.3043 [282] 309 5-Hydroxyapateline - C34H32O6N2:564.2260 [233] 310 5-Hydroxytelobine - C35H3406N2:578.2417 [233] 311 5-Hydroxythalidasine - C39H44O8N2:668.3098 [307] 312 5-Hydroxythalidasine-2a-N-Oxide - C39H44O9N2:684.3046 [35] 313 5-Hydroxythalmine - C37H40O7N2.624.2836 [307] 314 Kohatamine - C35H3406N2:578.2417 [233] 315 Limacine-2'a-N-Oxide - C37H40O7N2:624.2836 [127-129] 316 Limacine-2p-N-Oxide - C37H40O7N2:624.2836 [127-129] 317 Limacine-2'P-N-Oxide - 0 3 ^ 0 ^ : 6 2 4 . 2 8 3 6 [127,129,235] 318 Medelline - C37H38O6N2:606.2730 [348] 319 N-2'-Methylisotetrandrine - C39H4506N2^:637.3278 [70]

71

72

P.L.Schifr,Jr. Table 2. Continued

320 O-Methyllimaeusine - C38H42O6N2:622.3043 [282] 321 2-N-Methyllindoldhamine - C35H38O6N2:582.2730 [230] 322 2'-N-Methyllindoldhamine - C35H38O6N2:582.2730 [230] 323 N-Methyltiliamosine - C37H38O6N2:606.2730 [381,382] 324 Monterine - C38H42O6N2:622.3043 [172] 325 Neothalibrine-2'a-N-Oxide - C38H44O7N2:640.3149 [35] 326 2-Norcepharanoline - C35H3406N2:578.2417 [34] 327 2-Norcepharanthine - C36H3606N2:592.2573 [135,137] 328 2'-Norcepharanthine - C36H3606N2:592.2573 [34] 329 2'-Norcocsuline-C34H3205N2:548.2311 [7,10] 330 2'-Nordaurisoline - ( ^ ^ 0 ^ 2 : 5 9 6 . 2 8 8 6 [230] 331 2'-Norfuniferine - C37H40O6N2:608.2886 [119] 332 2'-Norguattaguianine - 0 3 ^ 0 ^ 2 : 6 0 8 . 2 8 8 6 [119] 333 2-Norisocepharanthine - C36H3606N2:592.2573 [34] 334 2-Norisotetrandrine - C37H40O6N2:608.2886 [34,135] 335 Norisoyanangine - C35H3406N2:578.2417 [385] 336 2-Norlimacine - C36H38O6N2:594.2730 [74.235] 337 2'-Norobaberine - C37H40O6N2:608.2886 [34] 338 2'-Noroxyacanthine - C36H38O6N2:594.2730 [35] 339 2'-Norpisopowiaridine - C36H40O6N2:596.2886 [229] 340 Norstephasubine - C35H32O6N2:576.2260 [137] 341 Northalibroline - C35H38O6N2:582.2730 [390]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 2. Continued

342 2'-Northaliphylline - C36H3806N2:594.2730 [35,307] 343 2-Northalmine - C36H38O6N2:594.2730 [241] 344 2-Northalrugosine - C36H38O6N2:594.2730 [120,135] 345 2'-Nortiliageine - C36H3806N2:594.2730 [119] 346 Noryanangine - C35H3406N2:578.2417 [385] 347 Oxandrine - C37H3807N2.622.2679 [408] 348 Oxandrinine - C38H40O7N2:636.2836 [408] 349 Oxofangchirine - C37H3407N2:618.2366 [410] 350 N-2-Oxy-O-Methyldauricine - C3gH46O7N2:654.3305 [229] 351 N-2'-Oxy-0-Methyldauricine - C39H46O7N2:654.3305 [229] 352 Pampulhamine - C36H40O6N2:596.2886 [279] 353 Pangkoramine - C34H3406N2:566.2417 [10] 354 Pangkoriminc - C34H32O6N2:564.2260 [10] 355 Pedroamine - C35H38O6N2:582.2730 [279] 356 Phaeanthine-2'a-N-Oxide - C38H4207N2:638.2992 [101] 357 Pisopowamine - C37H4206N2:610.3043 [229] 358 Pisopowetine - C38H4406N2:624.3199 [229] 359 Pisopowiaridine - C37H4206N2:610.3043 [229] 360 Pisopowiarine - C38H4406N2:624.3199 [229] 361 Pisopowidine - 0 3 9 ^ 0 ^ : 6 3 8 . 3 3 5 9 [229] 362 Pisopowine - C40H48O6N2:652.3512 [229] 363 Popidine - € ^ 0 ^ : 6 2 4 . 3 1 9 9 [229]

73

74

P.L.Sch!fr,Jr. Table 2. Continued

364 Popisidine - 0 ^ 0 ^ 2 : 6 2 4 . 3 1 9 9 [229] 365 Popisine - C3IH4406N2:624.3199 [229] 366 Popisonine - C37H4206N2:610.3043 [229] 367 Popisopine - C37H4206N2:610.3043 [229] 368 Pseudoxandrine - C37H3807N2:622.2679 [408] 369 Pseudoxandrinine - C38H40O7N2:636.2836 [408] 370 Pycnazanthine - 0 ^ 0 0 ^ 2 : 5 6 2 . 2 1 0 4 [120] 371 Siddiquamine - C35H30O6N2:574.2104 [233] 372 Siddiquine - C34H28O6N2:560.1947 [233] 373 Stephasubimine - C35H30O6N2:574.2104 [137] 374 Stephasubine - C36H34O6N2:590.2417 [137,249] 375 Stephibaberine - C37H40O6N2:608.2886 [34,135] 376 Stepierrine - C35H32O6N2:576.2260 [34] 377 Thalidasine-2a-N-Oxide - C39H44O8N2:668.3098 [35] 378 Thaligosine-2a-N-Oxide (Thalisopine-2a-N-Oxide) - 038H42O8N2:654.2941 [35] 379 Thaliphylline-2'p-N-Oxide - 0 ^ 0 ^ 2 : 6 2 4 . 2 8 3 6 [35] 380 Thalivarmine - C36H3lO6N2:594.2730 [375] 381 Thalmiculatimine - C36H3606N2:592.2573 [307] 382 Thalmiculimine - C37H3807N2:622.2679 [307] 383 Thalmiculine - C38H4207N2:638.2992 [307] 384 Thalrugosaminine-2a-N-Oxide - C39H44O8N2:668.3098 [35] 385 Thalsivasine - 0 ^ * 0 ^ 2 : 5 9 2 . 2 5 7 3 [307,375]

The Btsbenzylisoquinoline Alkaloids - A l abular Review Table 2. Continued 386 Tilianangine - C36H3606N2:592.2573 [257] 387 Tilitriandrine - C36H38O6N2:594.2730 [466] 388 Yanangcorinine - C36H3605N2:576.2624 [398] 389 Yanangine - C36H3606N2:592.2573 [258] 390 Auroramine - C38H40O8N2:652.2785 [45] 391 Maroumine - C37H3808N2:638.2628 [45] 392 Pycmanilline - C38H40O9N2:668.2734 [101] 393 Secolucidine - 0 ^ 0 ^ : 6 0 6 . 2 3 6 6 [117] 394 Angchibangkine - C35H3405N2:562.2468 [7] 395 Cissampentin - C37H40O6N2:608.2886 [150] 396 Cocsiline - C35H3406N2:578.2417 [153] 397 Cocsilinine - C33H30O6N2:550.2104 [153] 398 Cocsoline-2'p-N-Oxide-C34H32O6N2:564.2260[159] 399 Costaricine - C35H38O6N2:582.2730 [173] 400 Curicycleatjenine - C38H3807N2:634.2679 [174] 401 Curicycleatjine - 03^0,1^:620.2523 [174] 402 Cycleabarbatine - C37H40O6N2:608.2886 [90] 403 (-)-Cycleanconine - C38H42O6N2:622.3043 [188] 404 Cycleatjehenine - C37H36O6N2:604.2574 [211,212] 405 Cycleatjehine - 0 * ^ 0 ^ 2 : 5 9 0 . 2 4 1 7 [211] 406 Dauriciline - 0 ^ ^ 0 ^ 2 : 5 9 6 . 2 8 8 6 [217] 407 0,0'-Dimethylgrisabine - 0 ^ 0 ^ 2 : 6 3 8 . 3 3 5 6 [252,253]

75

76

P.L.SchifT,Jr. Table 2. Continued

408 Insularine-2p-N-Oxide - C38H4o07N2:636.2836 [252] 409 Insularine-2'p-N-Oxide - C38H40O7N2:636.2836 [252] 410 Isocuricycleatjenine - C39H4606N2:634.2679 [174] 411 Isocuricycleatjine - C37H36O7N2:620.2523 [174] 412 Isocycleaneonine - C3gH42O6N2:622.3043 [188] 413 Limacusine-2'p-N-Oxide - C37H40O7N2:624.2836 [235] 414 12-0-MethyIcocsoline-2'P-N-Oxide - C35H3406N2:578.2417 [159] 415 O-Methylcocsulinine - C36H%06N2:592.2573 [153] 416 2-N-Methylfangchinoline-C3gH4306N2+:623.3121 [355] 417 7-O-Methylgrisabine - € ^ 0 ^ : 6 2 4 . 3 1 9 9 [252] 418 2-N-Methyltelobine - C36H3605N2:576.2624 [135] 419 12-O-Methyltricordatine - C35H34OsN2:562.2468 [7] 420 Neosutchuenenine - C36H40O6N2:596.2886 [309] 421 2'-Norcocsoline - C33H30O5N2:534.2155 [159] 422 N-Norcocsulinine - C34H3206N2:564.2260 [153] 423 2'-Norlimacine - C36H38O6N2:594.2730 [90,235] 424 2-Norobaberine-2'p-N-Oxide - € ^ 0 ^ : 6 2 4 . 2 8 3 6 [151] 425 Pendilinine - C36H3606N2:592.2573 [153] 426 Sutchueneneonine - CwH40O6N2:596.2886 [309] 427 Sutchuenenine - 0 ^ ^ 0 ^ 2 : 5 9 6 . 2 8 8 6 [309] 428 Thalifortine - 0 3 7 ^ 0 ^ : 6 0 8 . 2 8 8 6 [36] 429 Tiliaresine - C36H3605N2:576.2624 [382]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

77

Table 2. Continued 430 Vateamine-2'P-N-Oxide - C3gH44O9N2:672.3047 [472] 431 Secoisotetrandrine - C38H40O8N2:652.2785 [325] 432 Secohomoaromoline - C37H3808N2:638.2628 [358] 433 Secojollyanine - C36H36O7N2:608.2522 [358] AN ALPHABETICAL TABULAR COMPILATION OF THE BOTANICAL SOURCES (GENERA) OF THE BISBENZYLISOQUINOLINE ALKALOIDS Table 3

Name of Plant

Plant Part*

Abuta candicans St Rich ex DC. (Menispermaceae) Abuta grisebachii St Triana and Planchon (Menispermaceae)

Abuta pahni St (Martius) Krukoff and Barneby (Menispermaceae)

Abuta panurensis Eichl. (Menispermaceae) Abuta splendida Krukoff and Moldenke (Menispermaceae) Albertisia laurifolia (Menispermaceae)

St St Rh

Alkaloid

Structural Type of Alkaloid

(+)-Curine(132)[146] (+)-lsochondodendrine (122)[146] Grisabine (10)[240] Magnoline (12)[240] 7-O-Demethylpeinamine (60a)[240] Macolidine (44a)[240] Macoline (44b)[240] N-Methyl-7-O-Demethylpeinamine (66b)[240] Peinamine (71a)[240] Daurisoline (192)[230] N,N'-Dimethyllindoldhamine (234)[230] Lindoldhamine(ll)[230] 2-N-Methyllindoldhamine(321)[230] 2'-N-Methyllindoldhamine(322)[230] 2'-Nordaurisoline (330)[230] Norpanurensine (109)[386] Panurensine (110)[386] Aromoline (31)[15] Homoaromoline (42)[15] Krukovine(63)[15] Apateline (187)[9] Aromoline (31)[9]

XXI XX I I VIII VI VI VIII VIII I

XV XV VI VI VIII XXIII VI

78

P.L.Schiff,Jr. Table 3. Continued

Albertisia papuana Becc. (Menispermaceae)

St

Anisocycla cymosa R Troupin (Menispermaceae)

Sd

Anisocycla gradidieri H. Bn. (Menispermaceae)

St

Anisocycla jolly ana L (Pierre) Diels (Menispermaceae)

Cocsoline (152)[9] XXIII Cocsuline (153)[9] XXIII VI Daphnoline (38)[9] XXIII N-Methylapateline (207)[9] XXIII Apateline (187)[10] VI Aromoline (31)[16] VI N,N'-Bisnoraromoline (32)[10] VIII 2,2'-Bisnorphaeanthine (278)[10] XXIII Cocsoline (152)[10,16] XXIII Cocsuline (153)[10,16] VI Daphnandrine (37)[10] VI Daphnoline (38)[ 16,10] 1,2-Dehydrotelobine (194)[16] XXIII Homoaromoline (42)[16] VI Isotrilobine(157)[16] XXIII Lindoldhamine (11)[16J0] I O-Methylcocsoline (239)[16,10] XXIII 2'-Norcocsuline (329)[10] XXIII Obaberine (46)[16] VI Oxyacanthine (48)[16] VI Pangkoramine (353)[ 10] VI Pangkorimine (354)[10] VI Cocsoline (152)[ 154] XXIII Cocsoline-2'p-N-Oxide (398)[159] XXIII XXIII 1,2-Dehydroapateline (193)[ 154] XXIII 1,2-Dehydrotelobine (194)[154] XXIII 12-0-Methylcocsoline-2'P-N-Oxide (414)[159] XXIII 2'-Norcocsoline(421)[159] XXIII Trilobine(163)[154] VI Coclobine(35)[151] VI Daphnandrine (37)[151] VI 2-Norobaberine (46 dvt)[151] VI 2-Norobaberine-2'p-N-Oxide (424) [151] 12-O-Demethyltrilobine (155)[165] XXIII VI (-)-Epistephanine (41)[165] VI Stebisimine (51)[165] XXIII Trilobine (163)[165] XXIII 1,2-Dehydrotelobine (194)[235] VI Homoaromoline (42)[235] XXIII Isotrilobine (157)[235] VIII Limacine (64)[235]

The Blsbenzylisoquinoline Alkaloids - A Tabular Review

79

Table 3. Continued

Anomospermum grandifolium St Eichl. (Menispermaceae) A rcangelisia flava R, St (L.) Merr. (Menispermaceae) Ahstolochia debt Iis R Sieb. & Zucch. (Aristolochiaceae) Aristolochia elegans L (Aristolochiaceae) Ahstolochia gigantea L Mart. (Aristolochiaceae) Aristolochia indica L. (Aristolochiaceae) Atherosperma moschatum L. (Monimiaceae)

L B

Atherosperma repandulum F. Muell. (Monimiaceae) W Beilschmiedia madang Bl. (Lauraceae) Berheris aggregata Unk (Berberidaceae) Berheris amurensis R,RB,StB,Sh Rupr. (Berberidaceae) St R Berheris aristata R DC. (Berberidaceae) [see Berheris florihunda RB Wall ex. Don (Berberidaceae)] R Berheris aquifolium Pursch (Berberidaceae) B,R,St Berheris asiatica Roxb. ex DC. (Berberidaceae)

Limacine-2'p-N-Oxide (317)[235] Limacusine-2'P-N-Oxide (413)[235] O-Methylpunjabine (264)[358] 2-Norlimacine (336)[235] 2'-Norlimacine (423)[235] Secohomoaromoline (432)[358] Secojollyanine (433)[358] Trilobine (163)[235] (+)-Tubocurarine (142)[470]

VIII VI XXIII VIII VIII VI XXIII XXIII XXI

Homoaromoline (42)[301] Limacine (64)[301] Tetrandrine (76)[433]

VI VIII VIII

7'-O-Methylcuspidaline(240)[353]

I

Geraldoamine (301)[279] Pampulhamine (352)[279] Pedroamine (355)[279] (-)-Curine(133)[179]

I I I XXI

Atherospermoline (56)[44] Berbamine (57)[51) Isotetrandrine (62)[51] See Daphnandra repandulum

VIII VIII VIII

Dehatrine (288)[474]

VIII

Berbamine (57)[52]

VIII

Berbamunine (1 )[82,110] Oxyacanthine (48)fl 10] Berbamine (57)[53] Berbamunine (1)[53] Berbamine (57)[54,17] Oxyacanthine (48)[54,17] Aromoline(31)[17]

I VI VIII I VIII VI VI

Berbamine (57)[56] Oxyacanthine (48)[56] Berbamine (57)[57]

VIII VI VIII

80

P.L.Schiff,Jr. Table 3. Continued

Berberis baluchistanica Ahrendt (Berberidaceae) Berberis boliviano Lechl. (Berberidaceae)

Unk R

St

Berberis brachypoda (Berberidaceae) Berberis brandisiana Ahrendt (Berberidaceae)

R,RB,StB

Baluchistanamine (257)[46] Baluchistine (188)[47] Aromoline (31)[18] Berbamine (57)[18] Homoaromoline (42)[18] Isotetrandrine (62)[18] Obaberine(46)[18] Obamegine (71)[18] Oxyacanthine (48)[18] Thalrugosine(79)[18] Aromoline (31)[18] Berbamine (57)[18] Berbamunine (1)[ 18] Isotetrandrine (62)[18] Obaberine(46)[18] Obamegine (71)[18] Oxyacanthine (48)[18] Berbamunine (1)[82]

Berbamine (57)[58] Berbamine-2'p-N-Oxide (274)[58] Isotetrandrine (62)[58] Penduline (72)[58] Berberis bumeliaefolia Aromoline (31)[18] R Schneid. (Berberidaceae) Berbamine (57)[ 18] Isotetrandrine (62)[18] Oxyacanthine (48)[18] R,StB Calafatine(190)[121,122] Berberis buxifolia Calafatimine(189)[121] Lam. (Berberidaceae) Unk Calafatine(190)[123] Chilianamine (229)[123] Curacautine (259)[123] Osornine (248)[123] Talcamine (271)[ 123] WP (minus L) Calafatine-2'a-N-Oxide (226) [125,126] Calafatine-2'P-N-Oxide (227) [125,126] L 12-O-Desmethyllauberine (294)[239] Berberis chilensis Gill, ex Hook. (Berberidaceae) Espinine (9)[239] L,St Berbamine (57([59] 7-O-DemethyIisothalicberine (195) [237,238] AP

VI VI VI VIII VI VIII VI VIII VI VIII VI VIII I VIII VI VIII VI I VIII VIII VIII VIII VI VIII VIII VI Xa Xa Xa lb Xa Via Xa Xa Xa XIV I VIII XI

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

81

Table 3. Continued

Berberis chitria D. Don (Berberidaceae) Berberis circumserrata (Berberidaceae) Berberis cretica L. (Berberidaceae)

WP

Isothalicberine (205)[237,238] O-Methylisothalicberine (94)[237] O-Methylthalicberine (95)[238] Oxyacanthine (48)[473]

XI XI XI VI

R,RB,StB

Berbamunine (1)[82]

I

WP

Aromoline (31)[19] Berbamine (57)[19] Berbamunine (1)[19] Isotetrandrine (62)[19] Obaberine(46)[19] Obamegine(71)[19] Oxyacanthine (48)[19] Thalrugosine (79)[19] Berbamunine (1)[82]

VI VIII I VIII VI VIII VI VIII

R,RB,StB Berberis dasystachya (Berberidaceae) R,RB,StB Berberis diaphana (Berberidaceae) Unk Berberis dictyoneura R,RB,StB (Berberidaceae) R,RB,StB Berberis dubia (Berberidaceae) Berberis empetrifolia R (Berberidaceae) Berberis ferdinandi-coburgii R,RB,StB (Berberidaceae) Berberis floribunda R Wall ex. Don (Berberidaceae) [also known as RB Berberis arisata DC.(Berberidaceae)] Berberis fortunei Lindl. (Berberidaceae) Berberis fracisci-ferdinandi Unk (Berberidaceae) Berberis gyalaica R,RB,StB (Berberidaceae) Berberis henryana R,RB,StB (Berberidaceae) Berberis heterobotrys L,Sh Wolf. (Berberidaceae)

I Berbamunine (1)[82] Berbamine (57)[52] Berbamunine (1)[82] Berbamunine (1)[82]

I VIII

I I

Isotetrandrine (62)[319]

VIII

Berbamunine (1)[82]

I

Berbamine (57)[54,17] Oxyacanthine (48)[54,17] Aromoline (31)[ 17]

VIII VI VI

See Mahonia fortunei Berbamine (57)[52] Berbamunine (1)[82] Berbamunine (1)[82]

VIII I I

Berbamunine (1 )[82]

I

Berbamine (57)[60] Obaberine (46)[60] Oxyacanthine (48)[60]

VIII VI VI

82

P.L.Schiff,Jr. Table 3. Continued

Berberis heteropoda Schrenk (Berberidaceae) [see Berberis vulgaris L. (Berberidaceae)]

L

StB StB

Aromline(31)[lll] Oxyacanthine (48)[111-113] Berbamine(57)[61] Oxyacanthine (48)[411,111-113] Berbamunine(l)[lll-U3] Isotetrandrine (62)[112] Oxyacanthine (48)[111-113] Himanthine(173)[81]

VI VI VIII VI I VIII VI -

L,St

Calafatine(190)[124]

Xa

Sh

Berbamine (57)[62] Berbamunine (1)[62] Obaberine (46)[62] Oxyacanthine (48)[62] Berbamunine (1)[114] Oxyacanthine (48)[ 114,412,413] See Mahonia japonica

VIII I VI VI I VI

R,RB,StB

Berbamunine (1)[82]

I

R R,RB,StB

Berbamine (57)[63] Oxyacanthine (48)[63] Berbamunine (1)[82]

VIII VI I

R,RB,StB

Berbamunine (1)[82]

I

R

Berbamine (57)[64] Isotetrandrine (62)[64] Isotetrandrine (62)[320] Obaberine (46)[320] Aromoline (31)[20] Berbamine (57)[20] Oxyacanthine (48)[20] Berbamine (57)[65] Oxyacanthine (48)[65] Aromoline (31)[18] Belarine(93)[18] Berbilaurine(275)[18] 7-O-Demethylisothalicberine (195) [18] Homoaromoline (42)[18] Lauberine(106)[18]

VIII VIII VIII VI VI VIII VI VIII VI VI XI XIV XI

R Sh

Berberis himalaica Ahrendt (Berberidaceae) Berberis horrida (Berberidaceae) Berberis iliensis (Berberidaceae) Berberis integerrima Bge. (Berberidaceae) Berberis japonica R.Br. (Berberidaceae) Berberis jamesicma (Berberidaceae) Berberis julianae Schneid. (Berberidaceae) Berberis kansuensis (Berberidaceae) Berberis kawakamii Hayata (Berberidaceae) Berberis koreana Palib. (Berberidaceae)

L

R T

Berberis lambertii R R.N. Parker (Berberidaceae) Berberis laurina R (Thunb.) Billbg. (Berberidaceae)

VI XIV

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

83

Table 3. Continued

RB R,TB

Berberis lycium (Royle) (Berberidaceae)

Berberis mingetsensis Hayata (Berberidaceae) Berberis morrisonensis Hayata (Berberidaceae) Berberis nummularia Bge. (Berberidaceae)

Berberis oblonga (Regl.)(Berberidaceae)

R

Unk R R,St L

Sh L,F,R,Sh R Unk

Berberis orthobotrys Bienert ex Aitch. (Berberidaceae) Berberis paucidentata Rusby. (Berberidaceae)

R

Berberis petiolaris Nail (Berberidaceae)

R

R,St

Thalrugosine(79)[18] Belarine (93)[48] Espinidine (8)[265] Espinine (9)[265] Lauberine (106)[337] O-Methylisothalicberine (94) [48,337] Obaberine (46)[337] Berbamine (57)[67,68] Chenabine(258)[138] Gilgitine (261)[68] Jhelumine (262)[138] Oxyacanthine (48)[68] Punjabine (265)[68] Sindamine (270)[68] Berbamine (57)[66] Berbamine (57)[69] Isotetrandrine (62)[69] Berbamine (57)[69] Isotetrandrine (62)[69] Aromoline(31)[21] Berbamunine (1)[21] Isotetrandrine (62)[21,321] Oxyacanthine (48)[21,321,413] Berbamine (57)[70] N-2'-Methylisotetrandrine (319)[70] Oxyacanthine (48)[70] Oxyacanthine (48)[414] 2'-N-Methylberbamine (66a)[352] Berbamunine (1)[115] 2'-N-Methylberbamine (66a)[351] Oblongamine (47)[115] Oxyacanthine (48)[115] Aromoline (31)[78] Berbamine (57)f78] Oxyacanthine (48)[78] Berbamine (57)[18] Isotetrandrine (62)[18] Obaberine (46)[ 18] Oxyacanthine (48)[18] Berbamine (57)[71]

VIII XI I I XIV XI VI VIII VIII XXIII VIII VI XXIII VIII VIII VIII VIII VIII VIII VI I VIII VI VIII VIII VI VI VIII I VIII VI VI VI VIII VI VIII VIII VI VI VIII

84

P.L.Schiff,Jr. Table 3. Continued

Berberis poiretii (Berberidaceae)

R,RB,StB RB

R,RB,StB Berberis polyantha (Berberidaceae) Berberis polymorpha St (Berberidaceae) Berberis prattii R,RB,StB (Berberidaceae) Berberis pseudambalata AP (Berberidaceae) Berberis pseudothunbergii Unk (Berberidaceae) Berberis regeliana Fr (Berberidaceae) Berberis sargentiana R,RB,StB (Berberidaceae) Berberis sibirica R Pall. (Berberidaceae) R,Sh Berberis silva-taroucana R,RB,StB (Berberidaceae) Berberis soulieana R,RB,StB (Berberidaceae) Berberis stolonifera Clt (Berberidaceae)

Berberis swaseyi Buckey (Berberidaceae) Berberis thunbergii DC. (Berberidaceae)

R Sd WP

Berberis tinctoria Leschen (Berberidaceae) (also designated as Berberis aristata DC. (Berberidaceae)

R

Berbamunine (1)[82] Berbamine (57)[72,73] Isotetrandrine (62)[72] Berbamunine (1)[82]

I VIII VIII I

Thalrugosine (79)[457]

VIII

Berbamunine (1)[82]

I

Obaberine (46)[230] Oxyacanthine (48)[415] Berbamine (57)[52]

VI VI VIII

Berbamine (57)[74]

VIII

Berbamunine (1)[82]

I

Berbamine (57)[75] Oxyacanthine (48)[75] Berbamunine (1)[82]

VIII VI I

Berbamunine (1)[82]

I

Aromoline (31)[23] Berbamine (57)[23,76] Berbamunine (1)[23,76] N,N'-Dimethyllindoldhamine (234) (Guattegaumerine) [76] Isotetrandrine (62)[23] 2-Norberbamunine (1 dvt)[23,76] Berbamine (57)[77]

VI VIII

Berbamine (57)[80] Isotetrandrine (62)[80] Berbamine (57)[79] Isotetrandrine (62)[79] Oxyacanthine (48)[79J Berbamine (57)[81]

VIII VIII VIII VIII VI VIII

I VIII I VIII

The Bisbenzylisoqulnoline Alkaloids - A Tabular Review

85

Table 3. Continued Berberis tschonoskyana Regel (Berberidaceae)

WP R,RB,StB

Obaberine (46)[400] Obamegine (71)[400] Oxyacanthine (48)[400] Aromoline (31)[24] Berbamunine (1)[ 116] 2'-N-Methylberbamine (66a)[l 16] O-Methylthalicberine (95)[ 116] Oxyacanthine (48)[24,116] Isotetrandrine (62)[322] Obaberine (46)[322] Temuconine (251)[432] Berbamunine (1 )[82]

VI VIII VI VI I VIII XI VI VIII VI I I

R,RB,StB

Berbamine (1)[82]

I

R

Berbamine (57)[61,84,86] Berbamunine (1)[84,86] Oxyacanthine (48)[84,411] Berbamine (57)[83,85] Oxyacanthine (48)[83,85] Oxyacanthine (48)[86] Aromoline (31)[25]

VIII I VI VIII VI VI VI

Berbamine (57)[87] Isotetrandrine (62)187] Berbamine (57)[88]

VIII VIII VIII

(+)-Curine(132)[176]

XXI

(+)-Curine(132)[176]

XXI

Dauricine (3)[218]

I

Caryolivine (281)[74] 1,2-Dehydro-2-Norlimacusine (291) [74]

VIII VI

St

Berberis turcomanica Kar. (Berberidaceae)

Berberis valdiviana (Berberidaceae) Berberis vernae (Berberidaceae) Berberis virgetorum (Berberidaceae) Berberis vulgaris L. (Berberidaceae) [also called Berberis heteropoda Schrenk (Berberidaceae)]

L,St

RB,StB

Sh Berberis waziristanica RB (Berberidaceae) AP Berberis wilsoniae Hemsl. et Wils. (Berberidacaeae) Unk Berberis zebiliana (Berberidaceae) Buxus sempervirens L L. (Buxaceae) (also called Buxus wallichiana Baill. (Buxaceae)] Buxus wallichiana L Baill. (Buxaceae) (also called Buxus sempervirens L. (Buxaceae)] Cardiopetalum calophyllum TB Schlecht (Annonaceae) Caryomene olivascens St Barneby et Krukoff (Menispermaceae)

86

P.L.Schiff,Jr. Table 3. Continued

Chondodendron candicans Sandwith (Menispermaceae) Chondodendron limaciifolium W (Diels) Moldenke (Menispermaceae) Chondodendron microphylum R (Eichl.) Moldenke (Menispermaceae) Chondodendron platiphyllum L Miers (Menispermaceae) L,R L,R,St Chondodendron tomentosum B,St Ruiz and Pavon (Menispermaceae)

L,St St Chondendron toxicoferum St (Wedd.) Krok. et Mold. (Menispermaceae) Cissampelos fasciculata AP Benth. (Menispermaceae) Cissampelos insularis R Makino (Menispermaceae) (also called Paracyclea insularis (Makino) Kudo and Yamamoto (Menispermaceae)] Cissampelos mucronata R A. Rich. (Menispermaceae) Cissampelos ovalifolia Unk DC. (Menispermaceae)

N,N'-Dimethyllindoldhamine (234) (Guattegaumerine) [74] 2-Norlimacine (336)[74] 2-Norlimacusine (245)[74] See Abuta candicans

VIII VI

Isochondodendrine (122)[312] (+)-Norcycleanine (124)[141,312] (Base B) (+)-Curine(132)[RVl] Isochondodendrine (122)[RV1]

XXI XX

Chondrofoline(131)[RVl] Isochondodendrine (122)[RV1] (-)-Curine(133)[RVl] Chondocurarine (129)[140] Chondocurine (130)[ 141,142] (-)-Curine (133)[ 141,142,200] Cycleanine(121)[141,142] Isochondodendrine (122)[141,142] (+)-Tubocurarine (142)[142] Tomentocurine (186)[ 141] (+)-Norcycleanine (124)[141] (-)-Tubocurarine (143)[200] (-)-Curine(133)[201] Isochondodendrine (122)[201] Toxicoferine (141)[201] Cissampentin (395)[150]

XXI XX XXI XXI XXI XXI XX XX XXI Unk XX XXI XXI XX XXI XXIIa

Cycleanine(121)[131]

XX

Isochondodendrine (122)[313]

XX

Dihydrowarifteine (146)[251] Dimethyldihydrowarifteine (147) [251] Dimethylwarifteine (148)[251] Methyldihydrowarifteine (149)[251] Methylwarifteine (150)[251] Warifteine(151)[251]

XXII XXII

XX XX

XXII XXII XXII XXII

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

87

Table 3. Continued

Cissampelos pareira L. (Menispermaceae)

L,R

Unk WP Cleistopholis staudtii StB Engl, et Diels (Annonaceae) Cocculus hirsutus Diels (Menispermaceae)

AP L R,St

Cocculus japonicus DC. (Menispermaceae) Cocculus laurifolius DC. (Menispermaceae) Cocculus leaebe DC. (Menispermaceae)

B,Tr L R

Cocculus pendulus L (Forsk.) Diels (Menispermaceae)

(-)-Curine(133)[144,190,202,203] Cycleanine (121)[189,190] Hayatidine (136)[190] Hayatine (137)[ 144,190,202] Hayatinine (138)[ 190,202] Insularine(170)[189] Isochondodendrine (122)[144,189] 4"-OMethylcurine (139)[203] (+/-)-Curine dimethiodide (N,N-Dimethyl-(+/-)-(132)[476] (N,N-Dimethylcurine iodide) Cissampareine (145)[149] (-)-Chondrofoline (131)[147] (-)-Curine(133)[147] (-)-Cycleanine(121)[147] (-)-Isochondodendrine (122)[147] Isotrilobine (157)[331] Trilobine(163)[331] Isotrilobine (157)[330] Trilobine (163)[330] Cocsuline-N-2-Oxide (231)[171] Isotrilobine (157)[329] Trilobine (163)[329] See Stephania japonica Isotrilobine (157)[329] Trilobine (163)[329] Menisarine (165)[349] Cocsoline(152)[155] Cocsoline(153)[155] Oxyacanthine (48)[416] Penduline(72)[155]

XXI XX XXI XXI XXI XXVI XX XXI XXI XXII XXI XXI XX XX XXIII XXIII XXIII XXIII XXIII XXIII XXIII

XXIII XXIII XXIV XXIII XXIII VI VIII

1,2-Dehydrokohatamine (289)[233] XXIIIa 1,2-Dehydrokohatine (290)[233] XXIIIa l,2-Dehydro-2'-Nortelobine (292) XXIII [233] 5-Hydroxyapateline (309)[233] XXIIIa 5-Hydroxytelobine (310)[233] XXIIIa Kohatamine (314)[233] XXIIIa Kohatine (236)[233] XXIIIa Siddiquamine (371)[233] XXIIIa Siddiquine (372)[233] XXIIIa

P.L.SchifT,Jr. Table 3. Continued

L,St

St

Unk

Cocsiline(396)[153] XXIV Cocsilinine(397)[153] XXIV Cocsoline(152)[156,153] XXIII XXIII Cocsuline (153)[156,153,16l] XXIV Cocsulinine(164)[156,153] XXIII 12-O-DemethyltriIobine (designated by the authors as nortrilobine)[153] XXIV 0,0-Dimethy lcocsulinine( 164)[ 153] Hernandezine (81)[161] IX Isotetrandrine (62)[153] VIII Isotrilobine(157)[153] XXIII O-Methylcocsulinine (415)[153] XXIV XXIV N-Norcocsulinine (422)[153] XXIV Pendilinine(425)[153] Unk Pendine (178)[156,153] VIII Penduline(72)[156J53,161] Unk Pendulinine(179)[153,156] XXIII Punjabine (265)[161] VIII Tetrandrine(76)[161] XXIII Trilobine (163)[153] XXIII Cocsuline (153)[ 160] (erroneously identified as Andrachne cordifolia Muell., O.F. (Euphorbiaceae)[160] Penduline(72)[160] VIII (erroneously identified as Andrachne cordifolia Muell., O.F. (Euphorbiaceae)[160] Cheratamine (228)[139] VIII Cocsoline(152)[139] XXIII Cocsuline (153)[ 139] XXIII Daphnoline(38)[139] VI 1,2-Dehydroapateline (193)[139] XXIII lsotrilobine(157)[139] XXIII Kohatine (236)[139] XXIIIa Kurramine (237)[139] XXIII XXIII N-Methylapateline (207)[139] VIII Norberbamine(68)[139] VIII Norpenduline (246)[139] VIII Penduline (72)[139] VIII Tetrandrine(76)[139] XXIII Tricordatine(161)[139] XXIII Cocsuline (153)[166] XXIII Trilobine (163)[333]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

89

Table 3. Continued

Isotrilobine (157)[332] Menisarine (165)[332] Tetrandrine (76)[332] Trilobine (163)[332] Isotrilobine (157)[333]

XXIII XXIV VIII XXIII XXIII

B

Coclobine(35)[152] Daphnoline(38)[216] Isotrilobine (157)[216] Normenisarine (I66)[216] Trilobine (163)[216] O-Methyldauricine (12a)[354]

VI VI XXIII XXIV XXIII I

L,StB,RB

Cycleapeltine (36)[209]

VI

Limacine (64)[209] Phlebicine (25)[425]

VIII IV

Cordobimine(283)[172] Cordobine(284)[172] Granjine(302)[172] Monterine(324)[172] (-)-Isochondocurarine [311] (+)-Neochondochrarine [311] Protochondocurarine [311] Candicusine (280)[127,128,129] Krukovine(63)[127,128] Limacine (64)[ 127J 28] Limacine-2'a-N-Oxide (315)[127,128,129] Limacine-2P-N-Oxide (316)[127,128,129] Limacine-2'P-N-Oxide (317)[127-129] Limacusine(44)[127-129] Curicycleatjenine (400)[ 174] Curicycleatjine (401)[ 174] Cycleatjehenine (404)[211,212] Cycleatjehine(405)[211] Isocuricycleatjenine (410)[174] Isocuricycleatjine (411)[ 174] Berbamine (57)[89] Chondocurine (130)[143]

IV IV IV IV Unk Unk Unk VI VIII VIII VIII

Cocculus sarmentosus Diels (Menispermaceae)

R

Cocculus trilobus DC. (Menispermaceae)

Unk WP

Colubrina asiatica Brogn. (Rhamnaceae) Colubrina faralaotra (Rhamnaceae)

Crematosperma polyphlebum B (Diels) Fries (Annonaceae) Crematosperma sp. StB (Annonaceae) Curare Curarea candicans R (L.C. Rich) Barneby and Krukoff (Menispermaceae)

Cyclea atjehensis L Forman (Menispermaceae)

Cyclea barbata Rh (Wall.) Miers (Menispermaceae)

VIII VIII VI XXI XXI XXIIa XXIIa XXI XXI VIII XXI

90

P.L.Schlff,Jr. Table 3. Continued

Unk Cyclea burmanni R (DC.) Miers ex. Hook. f. & Thorns. (Menispermaceae) Cyclea hainanensis L Merr. (Menispermaceae) Cyclea hypoglauca (Menispermaceae)

Unk R,Bb

Cyclea insularis Rh (Makino) Diels (Menispermaceae)

(+/-)-Fangchinoline (58)[266] Homoaromoline (42)[302] (+)-Isochondodendrine (122)[314] Isotetrandrine (62)[302] Limacine (64)[89] Monomethyltetrandrinium (67)[383] (+)-Tetrandrine (76)[314] (+/-)-Tetrandrine (77)[89] Tetrandrine Mono-N-2'-Oxide (78) [143] Thalrugosine (79)[266] Berbamine (57)[90] (-)-Curine (133)[90] Curine (132 or 133)[177,178] Cycleabarbatine (402)[90] Cycleanorine (60)[90] Cycleapeltine(36)[210] Daphnandrine (37)[90] Homoaromoline (42)[210,303] Isochondodendrine (122)[303] Limacine (64)[210] 2'-Norlimacine (423)[90] Repandine (49)[90] Tetrandrine (76)[210] Tetrandrine (76 or 77)[303] Thalrugosine (79)[210] Cycleadrine(58)[l] Phaeanthine (74)[164] Tetrandrine (76)[164,434]

VIII VI XX VIII VIII VIII VIII VIII VIII VIII VIII XXI XXI VIII VIII VI VI VI XX VIU VIII VI VIII VIII VIII VIII VIII VIII

Curine (132 or 133)[175] Hayatine(137)[175] (+)-Isochondodendrine (122)[175] (=)-4"-0-Methylcurine (139)[ 175] lnsulanoline (169)[308] Insularine (170)[308] Cycleanine(121)[191] 0,0-Dimethylcurine (I35)[191] Cycleanine (121)[192] lnsulanoline (169)[192] Insularine (170)[192] Isochondodendrine (122)[315] (+)-Norcycleanine (124)[192]

XXI XXI XX XXI XXVI XXVI XX XXI XX XXVI XXVI XX XX

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

91

Table 3. Continued Cyclea madagascariensis Baill. (Menispermaceae) Cyclea peltata Diels (Menispermaceae)

R Cyclea racemosa St Oliv. (Menispermaceae) R Cyclea sutchuenensis Gagnep. (Menispermaceae)

Cyclea tonkinensis (Menispermaceae) Daphnandra apatela Schodde (Monimiaceae)

Unk B

Daphnandra aromatica B F.M. Bailey (Monimiaceae) Daphnandra dielsii B Perk. (Monimiaceae)

Daphnandra Johnsonii Schodde (Monimiaceae)

B,L,St

Chondocurine (130)[144] (-)-Curine (133)[144] Isochondodendrine (122)[144] Cycleacurine (134)[43] Cycleadrine (58)[43] Cycleahomine (59)[43] Cycleanorine (60)[43] Cycleapeltine (36)[43] Fangchinoline (61)[43,267] Isochondodendrine (122)[267] (+)-Tetrandrine (76)[43,267] (+/-)-Tetrandrine (77)[267] Cycleaneonine (286)[187] Cycleaneonine (286)[188] (-)-Cycleaneonine (403)[188] Insulanoline (169)[252,309] Insularine (170)[252] Insularine-2p-N-Oxide (408)[252] Insularine-2'P-N-Oxide (409)[252] Isochondodendrine (122)[309] Isocycleaneonine (412)[188] Neosutchuenenine (420)[309] Sutchueneneonine (426)[309] Sutchuenenine (427)[309] Cycleanine(121)[193]

XXI XXI XX XXI VIII VIII VIII VI VIII XX VIII VIII XXII XXII XXII XXVI XXVI XXVI XXVI XX XXII V Vc Vd XX

Apateline (187)[11] 1,2-Dehydroapateline (193)[11] 1,2-Dehydrotelobine (194)[11] Telobine(160)[ll] Aromoline (31)[26] Daphnoline (38)[26] Daphnine(191)[213] O-Methylrepandine (45)[27] Repandinine (90)[27] (-)-Tenuipine (92)[27] Repanduline (168)[27] Pseudorepanduline (167)[234] Johnsonine (206)[336] N-Methyiapateline (207)[336] N-Methylnorapateline (208)[336] O-Methylrepandine (45)[336] (+)-Nortenuipine (88)[336]

XXIII XXIII XXIII XXIII VI VI Xb VI X X XXV XXV VI XXIII XXIII VI X

92

P.L.SchifT,Jr. Table 3. Continued

B,L B

Repandine (49)[336] Repandinine (90)[336] Daphnandrine (37)[27] N,0-Dimethylmicranthine (156)[255] O-Methylmicranthine (158)[255] Micranthine (159)[27,255] Daphnoline (38)[27] O-Methylrepandine (45)[27] Repandine (49)[426] Repandinine (90)[27] Repanduline (168)[27,426] Daphnine (191)[214,215] Isotenuipine (87)[318]

VI X VI XXIII XXIII XXIII VI VI VI X XXV Xa X

B

Fangchinoline (61)[255]

VIII

N,0-Dimethylmicranthine (156)[255] O-Methylmicranthine (158)[255] (+)-Nortenuipine (88)[255] Telobine (160)[255) 1,2-Dehydromicranthine (154)[234] N,0-Dimethylmicranthine (156)[234] O-Methylmicranthine (158)[234] Micranthine (159)[234] Pseudorepanduline (167)[234] (+)-Tenuipine (91)[234] Aromoline (31)[27] (+)-Nortenuipine (88)[387] Repandinine (90)[387] Repanduline (168)[27] (+)-Tenuipine (91)[387] (-)-Tenuipinc (92)[27] (-)-Nortenuipine (89)[27,387] Oxyacanthine (48)[417]

XXIII XXIII X XXIII XXIII XXIII XXIII XXIII XXV X VI X X XXV X X X VI

Dehatridine (287)[232] Dehatrine (288)[232] Obaberine(46)[232,401] Aromoline (31)[28] Daphnandrine (37)[28] Daphnoline (38)[28] 1,2-Dehydroapateline (193)[28] Homoaromoline (42)f281

VIII VIII VI VI VI VI XXIII VI

Daphnandra micrantha Benth. (Monimiaceae)

B

Daphnandra repandula F. Muell. (Monimiaceae)

B

Daphnandra species (Monimiaceae) Daphnandra species Dt-7 (Monimiaceae)

Daphnandra species unnamed L,St (Monimiaceae)

Daphnandra tenuipes Perk. (Monimiaceae)

Dehaasia incrassata (Lauraceae) Dehaasia triandra Merr. (Lauraceae) Doryphora aromatica Schodde (Monimiaceae)

B

L L L W B

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

93

Table 3. Continued

Dryadodaphne novoguineensis B (Perk.) A.C. Smith (Monimiaceae) Epinetrum cordifolium R Mangenot and Miege (Menispermaceae) Epinetrum mangenotti L,R Guill. and Debray (Menispermaceae) Epinetrum villosum (Excell.) Troupin (Menispermaceae) Guatteria gaumeri TB Greenman (Annonaceae) Guatteria guianensis StB (Aublet) R.E. Fries (Annonaceae)

Guatteria megalophylla Diels (Annonaceae)

StB

Gyrocarpus americanus Jacq. (Hernandiaceae) [also called Gyrocarpus jacquini Roxb. (Hernandiaceae)]

B,L L

StB

Isotetrandrine (62)[28] Dryadine (104)[260] Dryadodaphnine (105)[260] Cycleanine (121)[194] Isochondodendrine (122)[194] Norcycleanine (124)[ 194] Cycleanine (121)[194] Isochondodendrine (122)[ 194] Norcycleanine (124)[ 194] L,R,St Cycleanine (121)[195] Isochondodendrine (122)[ 195] (+)-Norcycleanine (124)[195] Guattegaumerine (234)[254]

VIII XIV XIV XX XX XX XX XX XX XX XX XX I

Apateline(187)[12] Aromoline(31)[12] 2,2'-Bisnorguattaguianine (276)[ 119] Coclobine(35)[12] Daphnandrine(37)[12] Daphnoline (38)[12] 1,2-Dehydroapateline (193)[12] 1,2-Dehydrotelobine (194)[12] 12-O-Demethylcoclobine (293)[ 12] Funiferine(20)[119] Guattamine(303)[119] Guattaminone (304)[119] 2'-Norfuniferine (331 )[119] 2'-Norguattaguianine (332)[ 119] 2'-Nortiliageine (345)[ 119] Telobine(160)[119] Tiliageine(27)[119] 0,0-Dimethylcurine (135)[ 196] Isochondodendrine (122)[196] 12'-0-Methylcurine (140)[196] Phaeanthine (74)[422] Pycnamine (75)[422] Auroramine (390)[45] Gyrocarpine (306)[45] Limacine (64)[45] Maroumine (391)[45] Phaeanthine (74)[45] Grisabine (10)[282] Gyroamericine (305)[282]

XXIII VI IV VI VI VI XXIII XXIII VI IV IV IV IV IV IV XXIII IV XXI XX XXI VIII VIII Seco VI VI VIII Seco VI VIII I VIII

94

P.L.SchJiT,Jr. Table 3. Continued

Heracleum wallichi R (Umbelliferae) Hernandia nymphaeifolia StB (Presl) Kubirtzki (Biasolettia nymphaeifolia Presl, TB Hernandia peltata (Meissn.) (Hernandiaceae) Hernandia peltata B Meissn. (Hernandiaceae) Hernandia sonora StB L. (H ovigera L.)(Hernandiaceae) TB Isolona hexaloba RB Engl. (Annonaceae) Isolona pilosa Diets (Annonaceae)

StB TB

lsopyrum thalictroides L. (Ranunculaceae)

Laurelia sempervirens R. et P. (Monimiaceae)

L StB

Limacia cuspidata Hook. f. and Thorns. (Menispermaceae)

WP

Gyrocarpine (306)[282] Gyrocarpusine (307)[282] Gyrolidine (308)[282] Isotetrandrine (62)[282] Limacine (64)[282] O-Methyllimacusine (320)[282] Phaeanthine (O-Methyllimacine) (74)[282] Cycleanine (121)[197] Isochondodendrine (122)[197J Ambrimine (272)[6] Efatine (296)[6] Vateamine-2'P-N-Oxide (430)[472]

VI VI VI VIII VIII VI VIII XX XX Vb Vb lib

Malekulatine (238)[345] Vanuatine (255)[345] Vateamine (256)[345] Malekulatine (238)[346]

Va Ha lib Va

Malekulatine (238)[347] Cycleanine (121)[181] Isochondodendrine (122)[ 181] (-)-Norcycleanine (125)[181] (-)-Curine(133)[181] Isochondodendrine (122)[181] Curine(133)[180] Isochondodendrine (122)[ 180] Berbamine(57)[91] Isotetrandrine (62)[91 ] Isotetrandrine (62)[323] O-Methylrepandine (45)[323] Tetrandrine (76)[323] (+/-)-Tetrandrine (77)[323] Isotetrandrine (62)[324,325] Secoisotetrandrine (431)[325] Obaberine (46)[402] Oxyacanthine (48)[402] Thalrugosine (79)[402] Cuspidaline (2)[ 184] Limacine (64)[ 184] Limacusine(44)[184]

XX XX XX XXI XX XXI XX VIII VIII VIII VI VIII VIII VIII VIII VI VI VIII I VIII VI

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

95

Table 3. Continued Limacia oblonga Miers (Menispermaceae)

WP

Limaciopsis loangensis Engl. (Menispermaceae)

Fr,L,R,St

L Lindera oldhamii Hemsl. (Lauraceae) B Magnolia compressa Maxim. (Magnoliaceae) L Magnolia fuscata Andr. (Magnoliaceae) [also known as Michelia fuscata Blume (Magnoliaceae)] R Mahonia acanthifolia Don. (Berberidaceae) Mahonia aquifolium BX (Pursh) Nutt. (Berberidaceae)

L,St,Fr Unk Mahonia borealis R Takeda (Berberidaceae) Mahonia fortunei Tr (Hort.) Fedde (Berberidaceae) Mahonia griffithii B Takeda (Berberidaceae) Mahonia japonica L, R,Tr DC. (Berberidaceae) R,Tr

,

Cuspidaline (2)[185] Limacine (64)[185] Limacusine (44)[185] Berbamine (57)[92] N-2'-Chloromethylisotetrandrine (N-2'-Chloromethyl-62)(artifact) [92] Cycleanine (121)[92] Isotetrandrine (62)[92] Nor-2'-Isotetrandrine (213)[92] N-Oxy-2'-Isotetrandrine (216)[92] Thalrugosamine (52)[92] Thalrugosine (79)[92] Lindoldhamine (11)[343]

XX VIII VIII VIII VI VIII I

Oxyacanthine(48)[418]

VI

Magnolamine (15)[344] Magnoline (12)[344]

II I

Oxyacanthine (48)[419]

VI

Aquifoline (273)[14] Aromoline (31)[29] Berbamine (57)[29,94] Isotetrandrine (62)[29] Obamegine (71)[29] Berbamine (57)[95] Isotetrandrine (62)[95] Oxyacanthine (48)[95] Berbamine (57)[93]

VIII VI VIII VIII VIII VIII VIII VI VIII

Oxyacanthine (48)[420]

VI

Berbamine (57)[55] Oxyacanthine (48)[55] Berbamine (57)[96] Oxyacanthine (48)[96] Isotetrandrine (62)[55,326] Berbamine (57)[55]

VIII VI VIII VI VIII VIII

VIII VI VIII VIII VIII

96

P.L.SchifT,Jr. Table 3. Continued

Mahonia leschenaultii R Takeda (Berberidaceae) Mahonia lomariifolia R Takeda (Berberidaceae) Mahonia manipurensis R Takeda (Berberidaceae) Mahonia morrisonensis R Takeda (Berberidaceae) Mahonia philippinensis R,Tr Takeda (Berberidaceae) Mahonia repens R,St (Lindl.) G. Don (Berberidaceae) Mahonia siamensis Takeda (Berberidaceae) Mahonia sikkimensis Takeda (Berberidaceae) Mahonia simonsii Takeda (Berberidaceae) Mahonia swaseyi Fedde (Berberidaceae) Menispermum canadense L. (Menispermaceae)

Menispermum dauricum D C (Menispermaceae)

Oxyacanthine (48)[421 ]

VI

Berbamine (57)[97] Isotetrandrine (62)[97] Oxyacanthine (48)[421 ]

VIII VIII VI

StB

Berbamine (57)[97J Isotetrandrine (62)[97] Berbamine (57)[98] Isotetrandrine (62)[98] Obaberine (46)[403] Obamegine (71)[403] Oxyacanthine (48)[403] Thalrugosine (79)[403] Isotetrandrine (62)[327]

VIII VIII VIII VIII VI VIII VI VIII VIII

StB

Oxyacanthine (48)[421]

VI

R

Oxyacanthine (48)[420]

VI

See Berberis swaseyi L Rh Rh,R,St R,Rh Rh

Clt Michelia Juscata Blume (Magnoliaceae) Nectandra rodiei R. Schomb. (Lauraceae) also known as Ocotea rodiei (Lauraceae)

B

B,Sd

No alkaloid [219] Daurinoline (6)[220] N'-Desmethyldauricine (7)[220] Dauricine (3)[219,220] Dauricine (3)[221,222,225-227] Dauriciline(406)[217] Dauricine (3)[223,224] Dauricinoline (4)[222,223] Dauricoline (5)[221,223] Daurinoline (6)[221,223] Daurisoline (192)[223] Dauricine (3)[228] Daurisoline (192)[225,227] See Magnolia fuscata Magnoiine (12)[475] Demerarine (39)[236] Dirosine (19)[236] Norrodiasine (22)[236] Ocodemerine (176)[236] Otocamine (177)[236] Ocotine (23)[388]

VI V V Unk Unk IV

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

97

Table 3. Continued

R Sd TB Nectandra salicifolia (H.B.K.) Nees (Lauraceae) Sd Nelumbo nucifera Gaertn. (Nymphaceae) Nemuaron vieillardi Baill. (Monimiaceae) Ocotea rodiei Pachygone dasycarpa Kurz (Menispermaceae)

B,L StB

Pachygone loyaltiensis Diels (Menispermaceae)

St

Pachygone ovata (Poir.) Miers ex Hook (Menispermaceae)

L L,St

R

Rodiasine (26)[236,388] Sepeerine (50)[236] (+)-Curine(132)[176] (+)-2-Nortetrandrine (70)[388] Ocotosine (24)[388] Costaricine(399)[173]

IV VI XXI VIII IV I

Isoliensinine (28)[316,317] Liensinine(29)[338-341] Neferine (30)[317,339] Nemuarine(lll)[384]

V V V XVI

See Nectandra rodiei Angchibangkine (394)[7] Atherospermoline (56)[7] Cocsuline (153)[7] Daphnoline (38)[7] Fangchinoline (61)[7] Isotrilobine (157)[7] N-Methyl-7-O-Demethylpeinamine (66b)[7] 12-O-Methyltricordatine (419)[7] 2'-Norcocsuline (329)[7] Penduline (72)[7] Tetrandrine (76)[7) Tricordatine(16!)[7] Apateline(187)[13] N,N'-Bisnoraromoline (32)[13] Daphnandrine(37)[13] Daphnoline (38)[ 13] 1,2-Dehydroapateline (193)[13] 1,2-Dehydrotelobine (194)[13] Isotrilobine (157)[ 13] O-Methylcocsoline (239)[13] Trilobine (163)[469] N-Methylpachygonamine (243) [356,357] Pachygonamine (249)[356,357] Pachyovatamine (250)[357] Tiliamosine (120)[356,357] Nortrilobine (247)[399] Trilobine (163)[399]

XXVIII VIII XXIII VI VIII XXIII VIII XXIII XXIII VIII VIII XXIII XXIII VI VI VI XXIII XXIII XXIII XXIII XXIII XIX XIX XVIII XIX XXIII XXIII

98

P.L.SchlfT,Jr. Table 3. Continued

Pachygone pubescens AP,R Benth. (Menispermaceae) Paracyclea insularis (Makino) Kudo and Yamamoto (Menispermaceae)] Paracyclea ochiaiana Rh,R,St (Yamamoto) Kudo and Yamamoto (Menispermaceae) Peruvian curare

Unk

Phaeanthus crassipetalus Unk Becc. (Menispermaceae) Phaeanthus ebracteolatus B (Presl) Merill. (Menispermaceae) L Phaeanthus vietnamensis L Ban. (Menispermaceae) R Pleogyne cunninghamii Miers (Pleogyne australis Benth. )(Menispermaceae) Polyalthia nitidissima StB Benth. (Annonaceae)

Isotrilobine (157)[334]

XXIII

See Cissampelos insularis (-)-Curine(133)[182] Cycleanine (121)[182] Insularine(170)[182] Isochondodendrine (122)[182] (/?.5)-Chondrocurine (130)[145] (R,R)-Cur'me (133)[145] (R, 5)-Nor-Nb-Chondrocurine (230)[145] (+)-Tubocurarine chloride (142)[145] Limacine (64)[342] Phaeanthine (74)[342] Phaeantharine (73)[162] Phaeanthine (74)[423] Phaeantharine (73)[163] O,O'-Dimethylgrisabine(407)[252,253] 7-O-Methylgrisabine (417)[253] (-)-Curine(133)[183] Isochondodendrine (122)[ 183]

XXI XX XXVI XX XXI XXI XXI XXI VIII VIII VIII VIII VIII I I XXI XX

Daurisoline(192)[231] N,N'-Dimethyllindoldhamine (234)[231]

Popowia pisocarpa (Bl.) Endl. (Annonaceae)

B and/or L

Isodaurisoline(235)[231] Lindoldhamine(U)[231] 7-O-Methyllindoldhamine (241)[231 ] 7'-0-Methyllindoldhamine (242)[231] Dauricine (3)[229] Dauricoline (5)[229] O-Methyldauricine (12a)[229] N-2-Oxy-O-Methyldauricine (350) [229] N-2'-Oxy-0-Methyldauricine (351) [229] 2'-Norpisopowiaridine (339)[229] Pisopowamine (357)[229] Pisopowetine (358)[229] Pisopowiaridine (359)[229] Pisopowiarine (360)[229]

1

XXVII XXVII XXVII XXVII XXVII

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

99

Table 3. Continued

Pseudoxandra aff. lucida Fries (Annonaceae)

StB

Pseudoxandra sclerocarpa Maas (Annonaceae)

StB

Pycnarrhena australiana WP F. Muell. (Menispermaceae)

Pycnarrhena longifolia (Decne. ex Miq.) Becc. (Menispermaceae)

R,St

Pycnarrhena manillensis R F. Muell. (Menispermaceae) or Vidal (Menispermaceae)

Pisopowidine (361)[229] XXVII Pisopowine (362)[229] XXVII Popidine (363)[229] I Popisidine (364)[229] I Popisine (365)[229] I Popisonine (366)[229] I Popisopine (367)[229] I Medelline (318)[348] XVIII Oxandrine (347)[408] IV Oxandrinine (348)[408] IV Pseudoxandrine (368)[408] IV Pseudoxandrinine (369)[408] IV Antioquine (225)[8] IV Obaberine (46)[8] VI Secantioquine (267)[8,430] IV Seco-obaberine (269)[8] VI Berbamunine (1)[117] I Homoaromoline (42)[ 117] VI Secolucidine (393)[ 117] Seco XVIII Thaligrisine (252)[ 117] I Berbamine (57)[99] VIII Isotetrandrine (62)[99] VIII 2-N-Norberbamine (68)[99] VIII 2-N-Norobamegine (69)[99] VIII Phaeanthine (74)[99] VIII Aromoline (31)f49] VI Berbacolorflammine (218)[50] VIII Colorfiammine (219)[50] VI Daphnoline (38)f49] VI Homoaromoline (42)[49] VI Krukovine (63)[49] VIII Limacine (64)[49] VIII Obaberine (46)[49] VI 1,2,3,4-Tetrahydrolimacine (218) VIII [49] l\2',3\4'-Tetrahydrolimacusine (219) VI [49] Berbamine (57)[100] VIII Isotetrandrine (62)[ 100] VIII Phaeanthine (74)[ 100] VIII Pycnamine (75)[100] VIII Pycnarrhenamine (181)[100] Unk Pycnarrhenine (182)[ 100] Unk

100

P.L.SchifT,Jr. Table 3. Continued R,St

Pycnarrhena novoguineensis St Miq. (Menispermaceae)

Pycnarrhena ozantha Diels (Menispermaceae)

B St

Sciadotenia eichleriana R,St Moldenke (Menispermaceae) Sciadotenia toxifera St Krukoff and A.C. Smith (Menispermaceae) W

Spirospermum penduliflorum StR Thou. (Menispermaceae) R Unk Stephania capitata Spreng. (Menispermaceae) Stephania cepharantha R Hayata (Menispermaceae)

RTb

Berbamine(57)[101] VIII Isotetrandrine (62)[101] VIII Phaeanthine (74)[ 101] VIII Phaeanthine-2'a-N-Oxide (356)[101] VIII Pycmanilline (392)[101] Seco VIII Pycnamine(75)[101] VIII Berbamine (57)[22] VIII Limacine (64)[22] VIII Phaeanthine (74)[22] VIII Pycnamine (75)[22] VIII Thalrugosine (79)[22] VIII N,N'-Bisnoraromoline (32)[ 118] VI 2-N-Norobamegine (69)[ 118] VIII Bisnorobamegine (277)[ 120] VIII VIII Bisnorthalrugosine (279)[ 120] Daphnoline(38)[120] VI VIII 2-Norberbamine (68)[ 120] 2-Norobamegine (69)[ 120] VIII 2-Northalrugosine (344)[ 120] VIII Pycnazanthine (370)[ 120] VI Grisabine (10)[283] I 2-Norlimacusine (245)[283] VI Sciadenine (127)[428] XX Sciadoline (128)[429] XX Isochondodendrine (122)[198] XX Sciadenine (127)[198] XX XX Sciadoferine (217)[ 198] XX Sciadoline (128)[ 198] Limacine (64)[271] VIII Limacine (64)[272] VIII Cycleanine (121)[204] XX VI (+)-Epistephanine (40)[261 ] Aromoline (31)[32,33] VI Berbamine (57)[32,104,105] VIII Cepharanoline (33)[32, 104] VI Cepharanthine (34)[32,104,105] VI Cycleanine (121)[32,104,105] XX Homoaromoline (42)[32,104] VI Isotetrandrine (62)[32,104] VIII (-)-Norcycleanine (125)[32] XX Obamegine (71)[32] VIII Berbamine (57)[102] VIII VI Cepharanoline (34)[ 102]

The Bisbenzylisoquinolinc Alkaloids - A Tabular Review

101

Table 3. Continued

R (Clt)

Sd Stephania dinklagei R,St Diets (Menispermaceae) Stephania discolor Spreng. Stephania epigeae Tb Diburong (Menispermaceae)

Stephania erecta Craib. (Menispermaceae)

Unk Tb

Stephania excentrica R H-S. Lo (Menispermaceae) Stephania glabra AP,Tb (Roxb.) Miers Rh (Menispermaceae) Stephania hernandifolia AP (Wiild.) Walp. R (Menispermaceae) [also called Stephania discolor Spreng. (Menispermaceae)]

Cepharanthine (33)[102,131] Cycleanine (121)[102,131] Isotetrandrine (62)[32,104] Aromoline(31)[30,31] Berbamine (57)[30] Cycleanine (121)[30] Homoaromoline (42)[30] Isotetrandrine (62)[30] Berbamine (57)[ 103] Isotetrandrine (62)[103] Dinklageine (172)[259]

VI XX VIII VI VIII XX VI VIII VIII VIII Unk

See Stephania hernandifolia Cepharanoline (33)[130] (-)-Curine(133)[130] Cepharanthine (34)[132,133] Cycleanine (121)[132] (-)-Curine Cepharanthine (34)[134,135] Daphnandrine (37)[135] 1,2-Dehydrotelobine (194)[135] Homoaromoline (42)[134.135] Isochondodendrine (122)[130] Isotetrandrine (62)[135] 2-N-Methyltelobine (418)[135] 2-Norcepharanthine (327)[135] 2-Norisotetrandrine (334)[135] 2-Norobaberine (46 dvt)[135] 2-Northalrugosine (344)[135] Obaberine(62)[135] Stephibaberine(375)[135] Thalrugosine(79)[135] Homoaromoline (42)[304]

VI VI XXIII VI XX VIII XXIII VI VIII VI VIII VI VI VIII VI

Cycleanine (121)[205] Cycleanine (121)[206] N-Desmethylcycleanine (233)[206] (+)-Epistephanine (40)[262] Fangchinoline (61)[199] Isochondodendrine (122)[199] Isotrilobine (157)[335] Oxoepistephanine (47a)[409]

XX XX XX VI VIII XX XXIII VI

VI XX VI XX

102

P.L.Schiff,Jr. Table 3. Continued

St

Stephania japonica AP,R (Thunb.) Miers (Menispermaceae) [also called Cocculus japonicus DC. (Menispermaceae)] L L,R,St L,St Stephania japonica AG,R (Thunb.) Miers var australis (Menispermaceae) L,St L,R,St R,St Stephania pierrii Tb Diels (Menispermaceae)

Stephania rotunda Lour. (Menispermaceae) Stephania sasakii R Hayata (Menispermaceae)

(+)-Tetrandrine (76)[199] (+/-)-Tetrandrine (77)[199] 3\4'-Dihydrostephasubine (295) [249] (+)-Epistephanine (40)[249] Stephasubine (374)[249] Hypoepistephanine (43)[263] Insularine(170)[310] Obamegine (71)[405] Stebisimine (51 )[431] Epistephanine (40)[263,264] Stebisimine (51)[264] Hypoepistephanine (43)[263] lnsularine(170)[310] Obamegine (71)[405] Stebisimine (51)[264] Epistephanine (40)[263,264] Thalrugosine (79)[458] Aromoline (31)[34] Berbamunine (1)[34] Cepharanthine (34)[34] Cycleanine (121)[34] Daphnandrine (37)[34] 1,2-Dehydroapateline (193)[34] N-Desmethylcycleanine (233)[34] Isotetrandrine (62)[34] 2-Norberbamine (68)[34] 2-Norcepharanoline (326)[34] 2'-Norcepharanthine (328)[34] 2-Norisocepharanthine (333)[34] 2-Norisotetrandrine (334)[34] 2'-Norisotetrandrine (213)[34] 2-Norobaberine (46 dvt)[34] 2'-Norobaberine (337)[34] Obaberine (46)[34] Stephibaberine (375)[34] Stepierrine (376)[34] Thalrugosamine (55)[34] See Stephania glabra Berbamine(57)[106] Cepharanthine (34)[106]

VIII VIII VI VI VI VI XXVI VIII VI VI VI VI XXVI VIII VI VI VIII VI I VI XX VI XXIII XXIII VIII VIII VI VI VI VIII VIII VI VI VI VI VIII VI VIII VI

The Bisbenzylisoquinoline Alkaloids - A tabular Review

103

Table 3. Continued

Unk

Stephania sinica Diels (Menispermaceae) Stephania suberosa Forman (Menispermaceae)

R Stephania sutchuenensis H.S. Lo (Menispermaceae) Stephania tetrandra AP,R S. Moore (Menispermaceae) R

Tb

Unk

Dihydrosecocepharanthine (260) [248] O-Methyldeoxopunjabine (263)[248] O-Methylpunjabine (264)[248] Obaberine (46)[248] Secocepharanthine (268)[248] Cepharanthine (34)[136] Cepharanthine (34)[137] Cepharanthine-2'P-N-Oxide (282) [137] 2-Norcepharanthine (327)[137] Norstephasubine (340)[137] Stephasubimine (373)[137] Stephasubine(374)[137] Thairugosine (79)[459] Tetrandrine (76)[270,436] Cycleanine(121)[207] Fangchinoline (61)[207,269,270] Fenfangjine A (Tetrandrine-2p-N-Oxide)(297) [207,273] Fenfangjine B (Fangchinoline-2'a-N-Oxide)(298) [207,273] Fenfangjine C (Fangchinoline-2'P-N-Oxide)(299) [207,273] Fenfangjine D (1,3,4-Tridehydrofangchinolinium Hydroxide (300)[207,274] Isotetrandrine (62)[269] 2-N-Methylfangchinoline(416)[355] Oxofangchirine (349)[410] Tetrandrine (76)[207,269,435] Fangchinoline (61)[268] Menisidine (65)[350] Menisine (66)[350] Tetrandrine (76)[268] Berbamine (57) (detected; not isolated)! 107]

VI XXIII XXIII VI VI VI VI VI VI VI VI VI VIII VIII VIII VIII VIII VIII VIII VIII VIII VIII VIII VIII VIII VIII VIII VIII VIII

104

P.L.SchifT,Jr. Table 3. Continued

Stephania venosa R Spreng. (Menispermaceae) Strychnopsis thouarsii L Baill. (Menispermaceae) R Synchosepalum microphyllum i Eichl. (Menispermaceae) R,St Synclisia scabhda Miers (Menispermaceae) St

Thalictrum alpinum L. (Ranunculaceae)

Thalictrum baicalense Turcz. (Ranunculaceae) Thalictrum cultratum Wall. (Ranunculaceae)

R

Unk R WP

Fangchinoline (61) (detected; not isolated)[ 107] Tetrandrine (76) (detected; not isolated)! 107] Thalrugosamine (42)[306]

VIII VIII VI

Fangchinoline (61)[271,272] Fangchinoline (61)[272] Tetrandrine (76)[272] See Chondodendron microphylum

VIII VIII VIII

Cocsoline(152)[157] Cocsuline(153)[157] Cycleanine(121)[157,208] Cocsoline(152)[158] Cocsuline(153)[158] Cycleanine(121)[158] Cycleanine N-Oxide (232)[158] (+)-Norcycleanine (124)[158] N-Desmethylthalrugosidine (197) [247] Neothalibrine(211)[247] Thalidasine (100)[247] Thalpindione (223)[247] Thalrugosaminine (55)[247] Thalrugosidine (101)[247] Hernandezine (Thalicsimine)(81)[284,285] N-Desmethylthalistyline (16)[245] Thalirabine (5-0-Desmethylthalistyline)(17a)[245] Aromoline (31)[35] Cultithalminine (28S)[35] N-Desmethylthalidasine (2-Northalidasine)(196)[241 ] 5-Hydroxythalidasine (311)[307] 5-Hydroxythalidasine-2a-N-Oxide (312)[35] 5-Hydroxythalmine (313)[307] O-Methylthalicberine (95)[307] O-Methylthalmine (244)[307] Neothalibrine(211)[35] Neothalibrine-2'a-N-Oxide(325)[35]

XXIII XXIII XX XXIII XXIII XX XX XX XII I XII XII VII XII IX III III VI XlVa XII Xlla Xlla XlVa XI XIV I I

The Bisbenzylisoquinoline Alkaloids - A Tabular Meview

105

Table 3. Continued

Thalictrum dasycarpum R Fisch. and Lall. (Ranunculaceae) Thalictrum delavayi R Franch. (Ranunculaceae)

Thalictrum faheri Ulbr. (Ranunculaceae)

WP R

Unk

2'-Noroxyacanthine (338)[35] 2'-Northaliphylline (342)[35,307] 2-Northalmine(343)[241] Obaberine (46)[35] Oxyacanthine (48)[35] Thalictine (107)[307] Thalidasine (100)[241] Thalidasine-2a-N-Oxide (377)[35] Thaligosine (Thalisopine) (52a)[35] Thaligosine-2p-N-Oxide (Thalisopine-2a-N-Oxide)(378)[35] Thaliphylline (253)[307] Thaliphylline-2'P-N-Oxide (379)[35] XI Thalirugine (14b)[35] Thalisopine (54)[307] Thalmiculatimine (381)[307] Thalmiculimine (382)[307] Thalmiculine (383)[307] Thalmine(108)[241] Thalrugosaminine (55)[307] Thalrugosaminine-2ct-N-Oxide (384) [35] Thalrugosidine (101)[307] Thalrugosinone (224)[241 ] Thalsivasine (385)[307] Thalidasine (100)[444J Hernandezine (81)[286] Isothalidezine (82)[286] Thalidezine (83)[286] Thalmirabine (222)[286] Hernandezine (81)[287] O-Methylthalibrine (209)[359] O-Methylthalicberine (95)[359] Thalisopine (Thaligosine) (54)[359] Thalrugosidine (101)[359] N-Desmethylthalidasine (196)[242,243] Thalfinine (103)[243] Thalidasine (100)[242,243,4451 Thaliracebine (14a)[243]

VI XI XIV VI VI XIV XII XII VII VII XI la VII XIV XlVa XlVa XIV VII VII XII XII XI XII IX IX IX XIII IX I XI VII XII XII XIII XII

106

P.L.SchifT,Jr. Table 3. Continued

Thalictrum fargesii R Fr. ex Fin. et Gagnep. (Ranunculaceae) Thalictrum fendleri WP Engelm. ex Gray (Ranunculaceae) Thalictrum flavum R L. (Ranunculaceae)

Thalictrum foetidum L. (Ranunculaceae)

AP R Unk UP

Thalictrum foliolosum DC. (Ranunculaceae)

UP UP R

WP? Thalictrum fortunei WP S. Moore (Ranunculaceae) Thalictrum glandulosissimum R (Finet et Gagnep.) W.T. R,Rh Wang et S.H. Wang (Ranunculaceae) Thalictrum glaucum Desf. (Ranunculaceae) Thalictrum hernandezii ? Tausch (Ranunculaceae) AP Thalictrum isopyroides C.A.M. (Ranunculaceae) R

Thalfoetidine (99)[439,440] Thalidasine (100)[439,440] Thaligosinine (52b)[439] Hernandezine (81)[288] Thalidezine (83)[288) Hernandezine (81)[289] O-Methylthalicberine (95)[289] Thalfoetidine (99)[289] Thalidasine (100)[289] Thalidezine (83)[289] Berbamine (57)[108] Isotetrandrine (62)[108] Thalfoetidine (99)[108] Thalfine (102)[437,438] Thalfmine (103)[437,438] Hernandezine (81)[290] O-Methylthalicberine (95)[290] Thalidasine (100)[446] Thalidezine (83)[290] Thaligosine (52a)[290] Thaligosinine (S2b)[446] Thalrugosaminine (55)[446] Thalirugidine(17b)[451] Thalisopine(54)[451] Thalrugosaminine (55)[451 ] Thalrugosidine(101)[451] Thalidasine (100)[447] Thalrugosidine (101)[447J Aromoline (31)[36] Thalifortine (428)[36] Isothalidezine (82)[292] O-Methylthalibrine (209)[292] Hernandezine (81)[291,292] Thalidezine (83)[291,292] See Thalictrum rugosum

XII XII VII IX IX IX XI XII XII IX VIII VIII XII XIII XIII IX XI XII IX VII VII VII III VII VII XII XII XII VI XIV IX I IX IX

Hernandezine (81)[293]

IX

Thalisopidine (53)[453] O-Methylthalisopine (55)[452] Thaligosinine (52b)[450] Thalisopidine (53)1452,4501

VII VII VII VII

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

107

Table 3. Continued

Thalictrum javanicum Bl. (Ranunculaceae) Thalictrum kuhistanicum Ovcz. (Ranunculaceae)

WP

AP Thalictrum lankesteri Standi. (Ranunculaceae) Thalictrum longipedunculatum AP E. Nik. (Ranunculaceae) Thalictrum longistylum DC. (Ranunculaceae) Thalictrum lucidum L. (Ranunculaceae)

Thalictrum minus L. (Ranunculaceae)

AP

Thalisopine (54)[452] Thalisopine (54)[454] Thalrugosaminine (55)[454] O-Methylthalicberine (Thalmidine) (95)[362] Thalmine (108)[362] Hernandezine (81)[294] O-Methylthalicberine (95)[363] Thalfoetidine (99)[363] Thalicberine (97)[363] Thalidasine (100)[363] N-Desmethylthalistyline (16)[246] N-Methylthalistyline (17)[246] Thalibrine (14)[246] Thalistyline (18)[246] Aromoline (31)[37] Homoaromoline (42)[37] O-Methylthalicberine (95)[37] Obaberine (46)[37] Obamegine (71)[37] Oxyacanthine (48)[37] Thalicberine (97)[37] Thalidasine (100)[37] Thalrugosine (79)[37] O-Methylthalicberine (95) [368,369,370,371] O-Methylthalmethine (96)[364,368,379,371] Oxyacanthine (48)[379] Thalabadensine (106a)[369] Thalicberine (97)[368,370,371] Thalmethine (99)[364,368,369,371, 379] Thalmine (108)[369] Obaberine (46)[404] Thalfine (102)[404] Thalfinine (103)[404] Thalicberine (97)[364] Thalidasine (100)[404] Thalidezine (83)[365] Thalirabine (17a)[404] Thaliracebine (14a)[404]

VII VII VII XI XIV IX XI XII XI XII III III I I VI VI XI VI VIII VI XI XII VIII XI XI VI XIV XI XI XIV VI XIII XIII XI XII IX III la

108

P.L. Setoff, Jr. Table 3. Continued

R,WP St WP Thalictrum minus L. var. hypoleucum (Ranunculaceae) AP Thalictrum minus UP L. var. majus UP (Ranunculaceae) AP AP Rh,R Thalictrum minus L. var. microphyllum Boiss (Ranunculaceae)

WP

Thalictrum minus L L. var. minus (Ranunculaceae)

R,Rh R Thalictrum minus L. race B (Ranunculaceae) Thalictrum pedunculatum Edgew. (Ranunculaceae) Thalictrum podocarpum Humb. (Ranunculaceae)

Unk R

Thalmethine (99)[455] Thalmine (108)[455) Thalrugosaminine (55)[404] O-Methylthalicberine (95)[364-367] O-Methylthalicberine (95)[369] Thalmethine (99)[369] Thalmine (108)[366] O-Methylthalicberine (95)[372]

XI XIV VII XI XI XI XIV XI

O-Methylthalicberine (95)[373] Obaberine (46)[373] Oxyacanthine (48)[373J Thalicberine (97)[373] Thaligosine (52a)[373] Aromoline (31)[38] Homoaromoline (42)[38] O-Methylthalicberine (95)[38] Obamegine (71)[38] Thalicberine (97)[38] Thaligrisine (252)[38] Thaliphylline (253)[38] Thalirugine (14b)[38] Thalisopine (Thaligosine) (54)[38] O-Methylthalicberine (95)[374] Obaberine (46)[374] Thalisopine (Thaligosine) (54)[374] Thalrugosine (79)[374] O-Methylthalicberine (95)[375] O-Methylthalmethine (96)[375] Thalicberine (97)[375] Thaliphylline (253)[375] Thalivarmine (380)[375] Thalmethine (98)[375] Thalsivasine (385)[375] Northalibroline (341)[390] O-Methylthalibrine (209)[360] Thalistine (221)[360] Thalmirabine (222)[360J Thalrugosine (79)[360] Berbamine (57)[109]

XI VI VI XI VII VI VI XI VIII XI I XI 1 VII XI VI VII VIII XI XI XI XI XI XI XI I I HI XIII VIII VIII

N-Desmethylthalidezine (80)[244] N-Desmethylthaiistyline (16)[244]

IX III

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

109

Table 3. Continued

Thalictrum polygamum Muhl. (Ranunculaceae) Thalictrum revolutum D C (Ranunculaceae)

Unk Fr R

Thalictrum rochebrunianum R Franc, and Sav. (Ranunculaceae)

Thalictrum rugosum AP Ait. (Ranunculaceae) R [also called Thalictrum glaucum Desf. (Ranunculaceae)]

Hernandezine (81)[244] Isothalidezine (82)[244] N-Methylthalistyline (17)[244] Thalidezine (83)[244] Thalistyline (18)[244] Thalrugosine (79)[460]

IX IX III IX HI VIII

O-Methylthalicberine (95)[377J Neothalibrine(211)[377] Revolutinone (266)[427] O-Methylthalicberine (95)[376] O-Methylthalmethine (96)[376] Thalidasine (100)[376] Thalrugosaminine (55)[376] Dihydrothalictrinine (198)[250] Epinorhernandezine (semisynthetic) (199)[250] Epinorthalibrunine (semisynthetic) (200)[250] Hernandezine (81)[295] O-Methylthalibrunimine (210)[361] N'-Norhernandezine (212)[250] Northalibrine (13)[389] N'-Northalibrunine (214)[250,361] Oxothalibrunimine (215)[250] Thalibrine (13)[389) Thalibrunimine (112)[441,442] Thalibrunine (113)[295,442] Thalictrinine (220)[250] Thai si mine (86) [441J Thalsimine (86)[365] Aromoline (31)[39] Neothalibrine (211)[39) Obaberine (46)[39] Obamegine (71)[406] Thalidasine (100)[406] Thalidezine (83)[365] Thaligosidine (100a)[449] Thaligosine (52a)[449] Thaligosinine (52b)[449] Thalirugidine (17a)[449] Thalirugine (14b)[449] Thaliruginine (14c)[449]

XI I XI XI XI XII VII XVII IX XVII IX XVII IX I XVII XVII I XVII XVII XVII IX IX VI I VI VIII XII IX XII VII VII III la la

P.L.Schiff,Jr.

no Table 3. Continued

Thalictrum sachalinense Lecoyer. (Ranunculaceae) Thalictrum simplex L. (Ranunculaceae)

R AP

AP,Sd Thalictrum squarrosum R Steph. ex Wilid. (Ranunculaceae) Thalictrum sultanabadense AP Stapf. (Ranunculaceae)

R+AP Thalictrum thunbergii D C (Ranunculaceae)

L,St

Tiliacora acuminata (Lam.) Miers (Menispermaceae) Tiliacora dinklagei R Engl. (Menispermaceae)

Tiliacora funifera L Engl, ex Diels (Menispermaceae) [also called Tiliacora warneckei Engl, ex Diels R (Menispermaceae))

Thalrugosamine (52)[305] Thalrugosaminine (55)[456J Thalrugosidine (101)[406] Thalrugosine (79)[406] Thalrugosinone (224)[39] Thalrugosine (79)[461 ]

VI VII XII VI11 XII VIII

Hemandezine (81)[296] Thalidezine (83)[296J Thalisamine (84)[296J Thalsimidine (85)[462] Thalsimine (86)[296,462,463] Thalidasine (100)[448]

IX IX IX IX IX XII

Hemandezine (81)[297-299] Hernandezine-N-Oxide (203)[299] O-Methylthaimine (244)[380] Thalabadensine (106a)f297-299] Thalictine (107)[380J Hemandezine (8I)[300] Thalabadensine (106a)[300] Thalictine (107)[300] O-Methylthalicberine (95)[378] Thalicberine (97)[378] Thalictine (107)[443] Aromo!ine(31)[40,41] Homoaromoline (42)[40,41 ] See Tiliacora racemosa

IX IX XIV XIV XIV IX XIV XIV XI XI XIV VI VI

Dinklacorine (114)[256] Funiferine (20)[275] Nortiliacorinine A (116){275] Tiliacorinine (119)[275] Tiliageine (27)[275J Isotetrandrine (62)[328] Thalrugosine (79)[328] Tiliafunimine (79a)[465] Funiferine (20)[276] Funiferine dimethiodide (201)[277] (Dimethylfuniferine iodide) Funiferine N-Oxide (21)[278] Nortiliacorine A (115)[391 ]

XVIII IV XVIII XVIII IV VIII VIII VI11 IV IV IV XV111

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

111

Table 3. Continued

Tiliacora racemosa L Colebr. (Meni spermaceae) [also called Tiliacora acuminata (Lam.) Miers (Menispermaceae)] R

Tiliacora triandra Diels (Menispermaceae)

L,R WP L,St

R

Tiliacora warneckei Engl, ex Diels (Menispermaceae) Triclisia dictyophylla WP Diels (Menispermaceae) Triclisia gilletii L (DeWild.) Staner (Menispermaceae)

Nortiliacorinine A (116)[391] Tiliacorine(118)[391] N-Methyltiliamosine (323)[382] Nortiliacorinine A (116)[396] Tiliacoridine (183)[464] Tiliacorinine (116)[396] Tiliamosine (120)[382,392] Tiliaresine (429)[382] N-Methyltiliamosine (323)[381] Nortiliacorinine A (116)[395] Nortiliacorinine B (117)[393] Tiliacorine(118)[393] Tiliacorinine (119)[393] Tiliarine (185)[395,467] Nortiliacorinine A (116)[392,393] Nortiliacorinine A (116)[394] Dinklacorine (114)[257.258] Nortiliacorinine A (116)[257,398] Nortiliacorine A (115)[385] Norisoyanangine (335)[385] Noryanangine (346)[385] Tiliacorine(118)[257,398] Tiliacorinine (119)[398] Tiiiacorinine-2'-N-Oxide (254)[385] Tiliageine (27)[466] Tilianangine (386)[257] Tilitriandrine (387)[466] Yanangcorinine (388)[398] Yanangine (389)[258] Nortiliacorinine A (116)[397] Tiliacorine(118)[397] Tiliacorinine (119)[397] Tiliacorinine 2'-N-Oxide (254)[397] Tiliandrine(184)[314] See Tiliacora funifera

XVIII XVIII XIX XVIII Unk XVIII XIX XlXa XIX XVIII XVIII XVIII XVIII XVIII XVIII XVIII XVIII XVIII XVIII XIX XIX XVIII XVIII XVIII IV XIX IV XVIII XIX XVIII XVIII XVIII XVIII Unk

Cocsuline(153)[167] Trigilletimine(162)[167] Gilletine (202)[280,281) lsogilletine-N-Oxide (204)(281] Obamegine(71)[281] Stebisimine (51)[ 168,281]

XXIII XXIII XXIV XXIV VIII VI

112

P.L.SchifT,Jr. Table 3. Continued R,St

Triclisia patens Oliv. (Menispermaceae)

Triclisia subcordata Oliv. (Menispermaceae)

Unk L R,St L,R,St R

Uvaria ovata L A. DC. (Annonaceae) Xanthorrhiza simplicissima Rh,R Marsh (Ranunculaceae)

Cocsuline (153)[168,169] Isotetrandrine (62)[168] Trigilletimine (162)[468] Cocsuline (Efirine)( 153)[ 170] Aromoline (31)[42] Cocsuline (153)[168] Pycnamine (75)[168] Trigilletimine (162)[468] Phaeanthine (74)[ 168,424] Fangchinoline (61)[168] Tetrandrine (76)[42] Tricordatine (161)[169] Chondrofoline (131)[148]

XXIII VIII XXIII XXIII VI XXIII VIII XXIII VIII VIII VIII XXIII XXI

Obamegine (71)[407] Oxyacanthine (48)[407]

VIII VI

a

AP = Aerial parts, B = Bark, Bb = Bulb, Clt = Culture, Fr = Fruits, L = Leaves, R = Roots, RB = Rootbark, Rh = Rhizomes, Sd = Seeds, Sh = Shoots, St = Stems, StB = Stembark, StR = Stemroots, Tb = Tubers, TB = Trunkbark, Tr = Trunk, Unk = Unknown, UP = Underground Parts, W = Wood, WP = Whole Plant 5.

AN ALPHABETICAL TABULAR COMPILATION OF THE BOTANICAL SOURCES (FAMILIES) OF THE BISBENZYLISOQUINOLINE ALKALOIDS Table 4

ANNONACEAE Cardiopetalum Dauricine(3)[218] Cleistopholis (-)-Chondrofoline (131)[147] (-)-Curine (133)[147] (-)-CycIeanine (121)[147] (-)-Isochondodendrine (122)[147] Crematosperma Cordobimine (283)[172] Cordobine (284)[172]

I he Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 4. Continued Granjine(302)[172] Monterine(324)[172] Phlebicine (25)[425] Guatteria Apateline (187)[12] Aromoline (31)fl2] 2,2'-Bisnorguattaguianine (276)[119] Coclobine (35)[12] Daphnandrine (37)[12] Daphnoline (38)fl2] 1,2-Dehydroapateline (193)[12] 1,2-Dehydroteiobine (194)[12] 12-O-Demethylcoclobine (293)[12] 0,0-Dimethylcurine (135)[196] Funiferine(2©)[lI9] Guattamine (303)[119] Guattaminone (304)[119] Guattegaumerine (234)[254] Isochondodendrine (122){196] 12'-0-MethyIcurine (140)[196] 2'-Norfuniferine (331)[ 119] 2'-Norguattaguianine (332)(119] 2'-Nortiliageine(345)[119] Telobine(160)[119] Tiliageine(27)[119] Isolona Curine (133)1180] (-)-Curine(133)[181) Cycleanine (121)[181] Isochondodendrine (122)[180,181] Norcycleanine (125)[18lj Polyalthia Daurisoline(192)[231] N,N'.Dimethyiiindoldhamine (234)f231] Isodaurisoline (235)[231J Lindoldhamine(ll)[231] 7-O-MethyHindoIdhamine (241)[231] 7'-0-Methy Wndoldhamine (242)[231 ]

113

114

P.L.ScWIT,Jr. Table 4. Continued

Popowia Dauricine (3)[229] Dauricoline (5)[229] O-Methyldauricine (12a)[229] N-2-Oxy-O-Methyldauricine(350)[229] N-2'-Oxy-0-Methyldauricine (351 )[229] 2'-Norpisopowiaridine (339)[229] Pisopowamine (357)[229] Pisopowetine (358)[229] Pisopowiaridine (359)[229] Pisopowiarine (360)[229] Pisopowidine (361)[229] Pisopowine (362)[229] Popidine (363)[229] Popisidine (364)[229] Popisine (365)[229] Popisonine (366)[229] Popisopine (367)[229] Pseudoxandra Antioquine (225)[8] Berbamunine (1)[86,117] Homoaromoline (42)[t 17] Medeiline (318)[348] Obaberine (46)[8] Oxandrine (347)[408] Oxandrinine (348)[408] Pseudoxandrine (368)[408] Pseudoxandrinine (369)[408] Secantioquine (267)[8,430] Secolucidine (393)[117] Seco-obaberine (269)[8] Thaligrisine(252)[117] Uvaria Chondrofoline(131)[148] ARISTOLOCH1ACEAE Ahstolochia (-)-Curine(133)[179] Geraldoamine (301)[279] 7'-0-Methylcuspidaline (240)[353]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 4. Continued Pampulhamine (352)[279] Pedroamine (355)[279] Tetrandrine (76)[433] BERBERIDACEAE Berberis Aromoline (31)[17-21,23-25,78,111] Baluchistanamine (257)[46] Baluchistine (188)[47] Belarine(93)[48,18] Berbamine (57)[ 17-19,20.23,52-54,56-74,76-88] Berbamine-2'P-N-Oxide (274)[58] Berbamunine(l)[18J9,21,23,53,76,82,84,n0-116] Berbilaurine(275)[18] Calafatimine (189)[121] Calafatine(190)[121-124] Calafatine-2'a-N-Oxide (226)[ 125,126] Calafatine-2'p-N-Oxide (227)[ 125,126] Chenabine(258)[138] Chillanamine(229)[123] Curacautine (259)[123] 7-O-Demethylisothalicberine (195)[ 18,237,238] 12-O-Desmethyllauberine (294)[239] Espinidine (8)[265] Espinine (9)[239,265] Gilgitine (261)[68] Guattegaumerine (N,N'-Dimethyllindoldhamine) [76](234) Himanthine(173)[81] Homoaromoline (42)[18] Isotetrandrine (62)[ 18,19,21,23,58,64,69,72,79,80,87,112,319-322] Isothalicberine (205)[237,238] Jhelumine(262)[138] Lauberine (106)[ 18,337] 2'-N-Methylberbamine (66a)[l 16,351,352] N-2'-Methylisotetrandrine (319)[70] 0-Methylisothalicberine(94)[48,237,337] O-Methylthalicberine (95)[116,238] 2-Norberbamunine (1 dvt)[23,76] Obaberine (46)[ 18,19,60,62,230,320,322,337,400] Obamegine (71)[ 18,19,400] Oblongamine (47)[115] Osornine (248)[123]

115

P.L.Schiff,Jr. Table 4. Continued Oxyacanthine (48)[ 17-19,20,21,24,54,56,60,62,63,65,68,70,75,78,79,83-86,110116,321,400,411-414,473] Penduline (72)[58] Punjabine (265)[68] Sindamine (270)[68] Talcamine (271)[123] Temuconine (251)[432] Thalrugosine (79)[ 18,19,457] Mahonia Aquifoline (273)[14] Aromoline (31)[29] Berbamine (57)[29,55,93-98] Isotetrandrine (62)[29,95,97,98,327] Obaberine (46)[403] Obamegine (71)[29,403] Oxyacanthine (48)[55,95,96,326,403,419-421 ] Thalrugosine (79)[403] BUXACEAE Buxus (+)-Curine(132)[176] HERNANDIACEAE Gyrocarpus Auroramine (390)[45] Grisabine (10)[282] Gyroamericine (305)[282] Gyrocarpine (306)[45,282] Gyrocarpusine (307)[282] Gyrolidine (308)[282] Isotetrandrine (62)[282] Limacine (64)[45,282] Maroumine (391)[45] O-Methyllimacusine (320)[282] Phaeanthine (74)[45,282,422] Pycnamine (75)[422] Hernandia Ambrimine (272)[6] Efatine (296)[6]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

117

Table 4. Continued Malekulatine (238)[345-347] Vanuatine (255)[345] Vateamine (256)[345] Vateamine-2'p-N-Oxide (430)[472] LAURACEAE Beilschmiedia Dehatrine (288)[474] Dehaasia Dehatridine (287)[232] Dehatrine (288)[232] Obaberine(46)[232,401] Oxyacanthine (48)[417] Undera Lindoldhamine (11)[343] Nectandra (see note below) Costaricine (399)[173] (+)-Curine(132)[176] Demerarine (39)[236] Dirosine (19)[236] Norrodiasine (22)[236] (+)-2-Nortetrandrine (70)[388] Ocodemerine (176)[236] Otocamine (177)[236] Ocotine (23)[388] Ocotosine (24)[388] Rodiasine (26)[236,388] Sepeerine (50)[236] Note: Ocotea rodiei is a synonym for Nectandra rodiei, although the latter may actually be Chlorocardium rodiei (M.R. Schomb)[Personal Communication: H Guinaudeau [Ann Missouri Bot Gard 78, 388 (1991)] MAGNOLIACEAE Michelia Magnolamine (15)[344] Magnoline (12)[344,475] Oxyacanthine (48)[418]

P.L.Schifr,Jr. Table 4. Continued MENISPERMACEAE Abuta Aromoline (31)[15] (+)-Curine (132)[146] Daurisoline (192)[230] 7-O-Demethylpeinamine (60a)[240] N,N'-Dimethyllindoldhamine(234)[230] Grisabine (10)[240] Homoaromoline (42)[ 15] (+)-lsochondodendrine (122)[146] Krukovine (63)[15] Lindoldhamine (11)[230] Macolidine (44a)[240] Macoline (44b)[240] Magnoline (12)[240] N-Methyl-7-O-Demethylpeinamine (66b)[240] 2-N-Methyllindoldhamine(321)[230] 2'-N-Methyllindoldhamine(321)[230] 2'-Nordauriso!ine (330)[230] Norpanurensine (109)[386] Panurensine (110)[386] Peinamine (71a)[240] Albertisia Apateline (187)[9,10] Aromoline (31)[9,16] N,N'-Bisnoraromoline (32)[10] 2,2'-Bisnorphaeanthine (278)[10] Cocsoline (152)[9,10,16] Cocsuline (153)[9,10,16] Daphnandrine (37)[10] Daphnoline (38)[9,10,16] 1,2-Dehydrotelobine (194)[16] Homoaromoline (42)[16] Isotrilobine (157)[16] Lindoldhamine (11)[10,16] N-Methylapateline (207)[9] O-Methylcocsoline (239)[10,16] 2'-Norcocsuline (329)[10] Obaberine (46)[16] Oxyacanthine (48)[16] Pangkoramine (353)[10]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 4. Continued

Pangkorimine (354)[10J Anisocycla Coclobine(35)[151] Cocsoline (152)[154J Cocsoline-2'P-N-Oxide (398)[159] Daphnandrine(37)[15J] 1,2-DehydroapateIine (193)[154] 1,2-Dehydrotelobine (194)[ 154,235] 12-O-DemethyItriiobine (155)[ 165] (-)-Epistephanine (41)[165] Homoaromoline (42)[235) Isotrilobine (157)[235] Limacine (64)[235] Limacine-2'p-N-Oxide (317)[235] Limacusine-2'p-N-Oxide (413)[235] 12-0'Methyicocsoline.2'P-N-Oxide (414)1159] O-Mcthylpunjabine (264)[358] 2'-Norcocsoline (421)[ 159] 2-Norlimacine (336)(235] 2'-Norlimacine (336)[235] 2-Norobaberine (46 dvt)[151] 2-Norobaberine-2'p-N-Oxide (424)[ 151] Secohomoaromoline (432)[358] Secojollyanine (433)[358] Stebisimine (51)[165] Trilobine (163)[154,165,235] Anomospermum (+)-Tubocurarine (142)[470] Arcangelisia Homoaromoline (42)[301] Limacine (64)[30l] Caryomene Caryolivine (281)[74] 1,2-Dehydro-2-Norlimacusine (291)[74) N,N'-Dimethyllindoldhamine (Guattegaumerine)(234)[74] 2-Norlimacine (336)[74] 2-Norlimacusine (245)[74]

119

120

P.L.Schiff,Jr. Table 4. Continued

Chondodendron Chondocurarine (129)[140] Chondocurine (130)[141,142,145] Chondrofoline (131)[146] (+)-Curine (132)[146] (-)-Curine (133)[ 141,142,145,200,201 ] Cycleanine(121)[141,142] (+)-Isochondodendrine (122)[ 141,142,146,201,312] (£S)-Nor-Nb-Chondrocurine(230)[145] (+)-Norcycleanine (124)[141,312] Tomentocurine (186)[141 ] Toxicoferine(141)[201] (+)-Tubocurarine (142)[142,145] (-)-Tubocurarine (143)[200] (-)-Tubocurine (144)[200] Cissampelos Cissampareine (145)[149] Cissampentin (395)[150] (-)-Curine (133)[ 144,190,202,203] (+/-)-Curine dimethiodide (N,N-Dimethyl-(+/-)-(132)(N,N-Dimethylcurine iodide)[EZ2] Cycleanine (121)[131,189,190] Dihydrowarifteine (146)[251] Dimethyldihydrowarifteine (147)[251 ] Dimethylwarifteine (148)[251] Hayatidine(136)[190] Hayatine (137)[ 144,190,202] Hayatinine (138)[ 190,202] Insularine (170)[189] Isochondodendrine (122)[ 144,189,313] 4"-OMethylcurine (139)[203] Methyldihydrowarifteine (149)[251 ] Methylwarifteine (150)[251] Warifteine(151)[251] Cocculus Cheratamine (228)[139] Coclobine(35)[152] Cocsiline(396)[153] Cocsoline(152)[139,155] Cocsilinine(397)[153] Cocsoline (152)[ 153,156]

The Blsbenzylisoqutnoline Alkaloids - A Tabular Review Table 4. Continued

Cocsuline(153)[139,153,156,161,165,166,169,170] Cocsuline-N-2-Oxide (231)[171] Cocsulinine(164)[153,156] Daphnoline (38)[ 139,216] 1,2-Dehydroapateline (193)[139] 1,2-Dehydrokohatamirte (289)[233] 1,2-Dehydrokohatine (290)[233] 1,2-Dehydro-2'-Nortelobine (292)[233] 12-O-Demethyltrilobine (designated by the authors as nortrilobine)[153] OtO-Dimethylcocsulinine( 164)[ 153] Hernandezine(81)[161] 5-Hydroxyapateline (309)[233J 5-Hydroxytelobine (310)[233] Isotetrandrine (62)[153] Isotri lobine (157)( 139,153,216,329-333] Kohatamine (314)[233] Kohatine (236)[ 139,233] Kurramine(237)[139] Menisarine (165)[332,349] N-Methylapateline (297)[139] O-Methylcocsulinine (415)[153] Norberbamine(68)[139] N-Norcocsulinine (422)[153] Normenisarine (166)[216] Norpenduline(246)[139] Oxyacanthine(48)[416] Pendilinine(425)fl53] Pendine(178)[153,156,161] Penduline(72)[139,155] Pendulinine(179)[153,156] Punjabine (265)[161] Siddiquamine (371)[233] Siddiquine (372)[233] Tetrandrine (76)[ 139,161,332] Tricordatine(161)[139] Trilobine (163)[153,216,329-333] Curarea Candicusine (280)[ 127-129] Kmkovine (63)[127,128] Limacine (64)[127,128] Limacine-2'a-N-Oxide (315)[ 127-129] Limacine-2p-N-Oxide (316)[ 127-129]

121

P.L. Schiff,Jr. Table 4. Continued Limacine-2'P-N-Oxide (317)[ 127-129] Limacusine (44)[127-129] Cyclea Berbamine (57)[89,90] Chondocurine (130)[143,144] Curicycleatjenine (400)[174] Curicycleatjine (401)[ 174] Curine(132orl33)[175] (-)-Curine (133)[90,144] Curine (132 or 133)[177,178] Cycleabarbatine (402)[90] Cycleacurine (134)[43] Cycleadrine(58)[l,43] Cycleahomine (59)[43] Cycleaneonine (286)[ 187J 88] (-)-Cycleaneonine (403)[188] Cycleanine(121)[191-193] Cycleanorine (60)[43,90] Cycleapeltine(36)[43,210] Cycleatjehenine (404)[211,212] Cycleatjehine(405)[211] Daphnandrine (37)[90] 0,0-Dimethylcurine (I35)[191] (+/-)-Fangchinoline(58)[43,266,267] Hayatine(137)[175] Homoaromoline (42)[210,302,303] Insulanoline (169)[ 192,252,308,309] Insularine (170)[ 192,252,308] Insularine-2p-N-Oxide (408)[252] Insularine-2'p-N-Oxide (409)[252] (+)-lsochondodendrine(122)[ 144,175,267,303,309,314,315] Isocuricycleatjenine (410)[174] Isocuricycleatjine (411)[174] Isocycleaneonine (412)[188] Isotetrandrine (62)[302] Limacine (64)[89,210] 4"-0-Methylcurine (139)[175] Monomethyltetrandrinium (67)[383] Neosutchuenenine (420)[309] (+)-Norcycleanine (124)[192] 2'-Noriimacine (423)[90] Phaeanthine (74)[164]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 4. Continued Repandine (49)[90] Sutchueneneonine (426)[309] Sutchuenenine (427)[309] (+)-Tetrandrine (76)[ 164,210,314,434] Tetrandrine (76 or 77)[43,267,303] (+/-)-Tetrandrine (77)[89,267] Tetrandrine mono-N-2'-Oxide (78)[143] Thalrugosine (79)[210,266] Epinetrum Cycleanine (121)[194,195] Isochondodendrine (122)[194,195] Norcycleanine (124)[194,195] Limacia Cuspidaline(2)[184,185] Limacine(64)[184,185] Limacusine(44)[184,185] Limaciopsis Berbamine (57)[92] Cycleanine (121)[92] Isotetrandrine (62)[92] Nor-2'-Isotetrandrine (213)[92] N-Oxy-2'-Isotetrandrine (216)[92] Thalrugosamine (52)[92] Thalrugosine (79)[92] Menispermum Daurinoline (6)[220] N'-Desmethyldauricine (7)[220] Dauricine (3)[219-228] Dauriciline (406)[217] Dauricinoline (4)[222,223] Dauricoline(5)[221,223] Daurinoline (6)[221,223] Daurisoline (192)[223,225,227] Pachygone Angchibangkine (394)[7] Atherospermoline (56)[7] Apateline (187)[13] N,N'-Bisnoraromoline (32)[13]

123

124

P.L.Schiir,Jr. Table 4. Continued

Cocsuline (153)[7] Daphnandrine (37)[13] Daphnoline (38)[7,13] 1,2-Dehydroapateline (193)[13] 1,2-Dehydrotelobine (194)[13] Fangchinoline (61)[7] Isotrilobine(157)[7,13,334] O-Methylcocsoline (239)[13] N-Methyl-7-O-Demethylpeinamine (66b)[7] N-Methylpachygonamine (243)[356,357] 12-O-Methyltricordatine (419)[7] 2'-Norcocsuline (329)[7] Nortrilobine (247)[399] Pachygonamine (249)[356,357] Pachyovatamine (250)[357] Penduline (72)[7] Tetrandrine (76)[7] Tiliamosine (120)[356,357] Tricordatine (161)[7] Trilobine (163)[399,469] Paracyclea (-)-Curine(133)[182] Cycleanine(121)[131,182] Insularine(170)[182] Isochondodendrine (122)[ 182] Phaeanthus O,O'-Dimethylgrisabine(407)[252,253] Limacine (64)[342] 7-O-Methylgrisabine (417)[253] Phaeantharine (73)[ 162,163] Phaeanthine (74)[342,423] Pleogyne (-)-Curine(133)[183] Isochondodendrine (122)[183] Pycnarrhena Aromoline (31)[49] Berbacolorflammine (218)[50] Berbamine(57)[22,99-101] N,N'-Bisnoraromoline (32)[118]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 4. Continued

Bisnorobamegine (277)[120] Bisnorthalrugosine (279)[120] Colorflammine (219)[50] Daphnoline (38)[49,120] Homoaromoline (42)[49] Isotetrandrine (62)[99-101] Krukovine (63)[49] Limacine (64)[22,49] 2-N-Norberbamine (68)[99,120] 2-N-Norobamegine (69)[99,118,120] 2-Northalrugosine (344)[120] Obaberine (46)[49] Phaeanthine (74)[22,99-101] Phaeanthine-2'ot-N-Oxide (356)[ 101] Pycmanilline(392)[101] Pycnamine (75)[22,100,101] Pycnarrhenamine (181)[100] Pycnarrhenine (182)[100] Pycnazanthine (370)[120] Thalrugosine (79)[22] Sciadotenia Grisabine (10)[283] 2-Norlimacusine (245)[283] Sciadenine(127)[198,428] Sciadoferine (217)[198] Sciadoline (128)[ 198,429] Isochondodendrine (122)[198] Sciadenine (127)[198] Sciadoline (128)[198] Spirospermum Limacine (64)[271,272] Stephania Aromoline (31)[30-34] Berbamine (57)[30,32,102-106,107'] Berbamunine (1)[34] Cepharanoline(33)[32,102,104,130,132,133] Cepharanthine (34)[32,102,104-106,131,134-137] Cepharanthine-2'P-N-Oxide (282)[ 137] (-)-Curine(133)[130] Cycleanine (121)[30,32,34,102,104,105,131,132,204-207]

125

P.L. SchifT,Jr. Table 4. Continued Daphnandrine (37)[34,135] 1,2-Dehydroapateline (193)[34] 1,2-Dehydrotelobine (194)[135] N-Desmethylcycleanine (233)[34,206] Dihydrosecocepharanthine (260)[248] 3',4'-Dihydrostephasubine (295)[249] Dinklageine (172)[259] (+)-Epistephanine (40)[249,261 -264] Fangchinoline (61)[ 107\ 199,207,268-270] Fenfangjine A (Tetrandrine-2P-N-Oxide)(297) Fenfangjine B (Fangchinoline-2'a-N-Oxide)(298)[207,273] Fenfangjine C (Fangchinoline-2'P-N-Oxide)(299)[207,273] Fenfangjine D (1,3,4-Tridehydrofangchinolinium Hydroxide (300)[207,274] Homoaromoline (42)[30,32,104,134,135,304] Hypoepistephanine (43)[263] Insularine (170)[310] Isochondodendrine (122)[130,199] Isotetrandrine (62)[30,32,34,103,104,135,269] Isotrilobine (157)[335] Menisidine (65)[350] Menisine (66)[350] O-Methyldeoxopunjabine (263)[248] 2-N-Methylfangchinoline(416)[355] O-Methylpunjabine (264)[248] 2-N-Methyltelobine (418)[135] 2-Norberbamine (68)[34] 2-Norcepharanoline (326)[34] 2-Norcepharanthine (327)[135,137] 2'-Norcepharanthine (328)[34] 2-Norisocepharanthine (333)[34] 2-Norisotetrandrine (334)[34] 2'-Norisotetrandrine (213)[34] 2-Norobaberine (46 dvt)[34] 2'-Norobaberine (337)[34] (-)-Norcycleanine (125)[32] 2-Norisotetrandrine (334)[135] 2-Norobaberine (46 dvt)[135] Norstephasubine (340)[137] 2-Northalrugosine (344)[135] Obaberine (62)[34,135,248] Obamegine (71)[32,405] * detected, not isolated

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 4. Continued Oxoepistephanine (47a)[409] Oxofangchirine (349)[410J Secocepharanthine (268)[248] Stebisimine(51)[264,431] Stephasubimine (373)[137] Stephasubine (374)[ 137,249] Stephibaberine (375)[34,135] Stepierrine (376)[34] (+)-Tetrandrine (76)[ 107\ 199,207,268-270,435,436] (+/-)-Tetrandrine (77)[199] Thalrugosamine (52)[34,306] Thalrugosine (79)[ 135,458,459] Strychnopsis Fangchinoline (61)[271,272] (+)-Tetrandrine (76)[272] Synchosepalum (+)-Curine(132)[146] Isochondodendrine (122)[146] Synclisia Cocsoline(152)[157] Cocsuline(153)[157] Cycleanine (121)[157,208] Cocsoline(152)[158] Cocsuline(153)[158] Cycleanine (121)[158] Cycleanine N-Oxide (232)[158] (-H)-Norcycleanine (124)[158] Tiliacora Dinklacorine (114)[256-258] Funiferine (20)[275,276] Funiferine dimethiodide (Dimethylfuniferine iodide)(201)[277] Funiferine N-Oxide (21)[278] Isotetrandrine (62)[328] N-Methyltiliamosine (323)[381,382] Norisoyanangine (335)[385] Nortiliacorine A (115)[385,391] Nortiliacorinine A (116)[257,275,39!-398] Nortiliacorinine B (117)[393] Noryanangine (346)[385]

127

P.L.Schi!T,Jr. Table 4. Continued Thalrugosine (79)[328] Tiliacoridine (183)[464] Tiliacorine(118)[257,391,393,397.398] Tiliacorinine(119)[275,393,396-398] Tiliacorinine-2'-N-Oxide(254)[385,397] Tiliafunimine (79a)[465] Tiliageine (27)[275,466] Tiliamosine (120)[382,392] Tilianangine (386)[257] Tiliandrine(184)[314] Tiliaresine (429)[382] Tiliarine (185)[395,467] Tilitriandrine (387)[466] Yanangcorinine (388)[398] Yanangine (389)[258J Triclisia Aromoline (31)[42] Cocsuline (153)[167,168] Fangchinoline (61)(168] Gilletine(202)[280,281] Isotetrandrine (62)[168] Isogilletine-N-Oxide (204)[281] Obamegine(71)[281] Phacanthinc (74)[ 168,424] Pycnamine (75)[168] Stebisimine (51)[ 168,281] Tetrandrine (76)[42] Tricordatine (161)[169] Trigilletimine (162)[ 167,468] MONIMIACEAE Atherosperma Atherospermoline (56)[44] Berbamine(57)[51] Isotetrandrine (62)[51] Daphnandra Aromoline (31)[26,27] Apateline (187)[11] Daphnandrine (37)[27] Daphnoline (38)[26,27]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 4. Continued Daphnine(191)[213-215] 1,2-Dehydroapateline (193)[11] 1,2-Dehydromicranthine (154)[234] 1,2-Dehydrotelobine (194)[ 11 ] N,0-Dimethylmicranthine (156)[234,255] Fangchinoline (61)[255] Isotenuipine (87)[318] Johnsonine (206)[336] N-Methylapateline (207)[336] 0-Methylmicranthine(158)[234,255] N-Methylnorapateline (208)[336] O-Methylrepandine (45)[27,336] Micranthine (159)[27,234,255] (+)-Nortenuipine(88)[255,336,387] (-)-Nortenuipine (89)[27,387J Pseudorepanduline (167)[234] Repandine (49)[336,426] Repandinine (90)[27,336,387] Repanduline (168)[27,426] Telobine (160)[ 11,255] (+)-Tenuipine (91)[234,387] (-)-Tenuipine (92)[27] Doryphora Aromoline (31)[28] Daphnandrine (37)[28] Daphnoline (38)[28) 1,2-Dehydroapateline (193)[28] Homoaromoline (42)[28] Isotetrandrine (62)[28] Dryadodaphne Dryadine (104)[260] Dryadodaphnine (105)[260] Lauretta Isotetrandrine (62)[324,325] Secoisotetrandrine (431)[325] Obaberine (46)[402] Oxyacanthine (48)[402] Thalrugosine (79)[402]

129

130

Table 4. Continued

Nemuaron Nemuarine (111)[384] NYMPHACEAE Nelumbo Isoliensinine (28)[316,317] Liensinine (29)[338-341] Neferine (30)[317,339]

RANUNCULACEAE Isopyrum Berbamine (57)[91] Isotetrandrine (62)[91] Isotetrandrine (62)[323] O-Methylrepandine (45)[323] Tetrandrine (76)[323] (+/-)-Tetrandrine (77)[323] Thalictrum Aromoline(31)[35-41] Berbamine (57)[ 108,109] Cultithalminine (285)[35] N-Desmethylthalidasine(2-Northalidasine)(196)[241-243] N-Desmethylthalidezine (80)[244] N-Desmethylthalistyline(16)[244-246] N-Desmethylthalrugosidine (197)[247] Dihydrothalictrinine (198)[250] Epinorhernandezine (semisynthetic)(199)[250] Epinorthalibrunine (semisynthetic)(200)[250] Hernandezine (81)[244,284-300] Hernandezine-N-Oxide (203)[299] Homoaromoline (42)[37,38,40,4lj 5-Hydroxythalidasine (311)[307] 5-Hydroxythalidasine-2a-N-Oxide(312)[35] 5-Hydroxythalmine (313)[307] Isotetrandrine (62)[108] Isothalidezine (82)[244,286,292] O-Methylthalibrine(209)[292,359,360] O-Methylthalibrunimine (210)[361] O-Methylthalicberine(Thalmidine)(95)[37,38,289,290,307,359,362-378] O-Methylthalisopine (55)[452]

The Bisbenzylisoqufnoline Alkaloids - A Tabular Review Table 4. Continued N-Methylthalistyline (17)[244,246] O-Methylthalmethine (96)[364,368,371,375,376,379] O-Methylthalmine (244)[307,380] Neothalibrine (211)[35,39,247,377] Neothalibrine-2,a-N-Oxide(325)[35] N'-Norhernandezine (212)[250] 2f-Noroxyacanthine (338)[35] Northalibrine (13)[389] Northalibroline (341)[390] N'-Northalibrunine (214)[250,361] 2'-Northaliphylline (342)[35,307] 2-Northalmine (343)[241] Obaberine(46)[35,37,39,373,374,404] Obamegine (71)[37,38,406] Oxothalibrunimine (215)[250] Oxyacanthine (48)[35,37,373,379] Revolutinone (266)[427] Thalabadensine(106a)[297-300,369] Thalfine (102)[404,437,438] Thalfinine(103)[243,404,437,438] Thalfoetidine (99)[ 108,289,363,439,440] Thalibrine (14)[246,389] Thalibrunimine (112)[441,442] Thalibrunine (113)[441,442] Thalicberine(97)[37,38,363,364,368,370,371,373,375,378] Thalictine(107)[300,307,380,443] Thalictrinine (220)[250] Thalidasine (100) [37,241-243,247,289,363,376,404,406,439,440,444-448] Thalidasinc-2a-N-Oxide (377)[35] Thalidezine(83)[244,286,288-292,296,365] Thalfoetidine (99)[363] Thalifortine (428)[36] Thaligosidine (100a)[449] Thaligosine (Thalisopine) (52a)[35,38,290,307,359,373,374,449,451,454] Thaligosine-2p-N-Oxide (Thalisopine-2a-N-Oxide)(378)[35] Thaligosinine(52b)[439,446,449,450] Thaligrisine (252)[38] Thaliphylline (253)[38,307] Thaliphylline-2'p-N-Oxide (379)[35] Thalirabine (5-O-Desmethylthalistyline)(17a)[245,404] Thaliracebine (14a)[243,404] Thalirugidine (17b)[449,451] Thalirugine (14b)[35,38,449]

131

132

P.L.SchifT,Jr. Table 4. Continued

Thaliruginine (14c)[449] Thalisamine (84)[296] Thalisopidine (53)[450,452,453] ThaIisopine(Thaligosine)(54)t35,38,290,307,359,373,374.449,451,452,454] Thalistine (221)[360] Thalistyline (18)[244,246] Thalmethine (99)[364,368,369,371,375,379,455] Thalmiculatiminc (381)[307] Thalmiculimine (382)[307] Thalmiculine (383)[307] Thalmine (108)[241,362,366,369,455] Thalmirabine (222)[286,360] Thalpindionc (223)[247] Thalrugosamine (52)[305] Thalrugosaminine (55)[247,307,3 76,404,446,451,454,456] Thalrugosaminine-2a-N-Oxide (384)[35] Thalrugosidine(101)[247,307,359,406,447,451] Thalrugosine (79)[37,360,374,406,460,461 ] Thalrugosinone (224)[39,241] Thalivannine (380)[375] Thalsimidine (85)[462] Thalsimine (86)[296,365,441,462,463] Thalsivasine (385)[307,375] Xanthorrhiza Obameginc (71)[407] Oxyacanthine (48)[407] RHAMNACEAE Colubrina Cycleapeltine (36)[209] Limacine (64)[209] O-Methyldauricine (12a)[354] UMBELLIFERAE Heracleum Cyclcaninc (121)[197] Isochondodcndrinc (122)[197] NONDESIGNATED SPECIES - Cunirc (-)-Isochondocurarine (174), (+)-Neochondocurarine (175), Protochondocurarine (180) - [311]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review 6.

133

A TABULAR COMPILATION OF THE CALCULATED MOLECULAR WEIGHTS OF THE BISBENZYLISOQUINOLINE ALKALOIDS Table 5

532.1998 C33H,805N2 Kurramine (237)[139] 534.2155 C33H30O,N, 2'-Norcocsoline (421)[159] 546.2155 C34H30O5N2 1,2-DehydroapateIine (193)[11-13,28,34,139,154] 1,2-Dehydromicranthine (154)[234] 1,2-Dehydro-2'-Nortelobine (292)[233] C34HrO,N, 548.2311 Apateline(187)[9-13] Cocsoline(152)[9.10,16,139,153-158] 12-O-Demethyltrilobine (155)[165](designated by the authors as nortrilobine [153]) N-Methylnorapateline (208)[336] Micranthine (159)[27,234,255] 2'-Norcocsuline (422)[t53] Nortrilobine (247)[399] Pachyovatamine (250)[357] Tricordatine (161)[7,139,169] C31H10O6N2 550.2104 Cocsilinine(397)[153] 550.2468 C34H340
P.L.SchifT,Jr. Table 5. Continued C34H30O6N2 562.2104 1,2-Dehydrokohatine (290)[233] Pycnazanthine (370)[120] 562.2468 C35H3405N2 Angchibangkine (394)[7] Cocsuline(153)[7,9,10,16,139,153,155-158,160,161,165-170] N-Methylapateline (207)[336] O-Methylcocsoline (239)[10,13,16] 0-Methylmicranthine(158)[234,255] 12-O-Methyltricordatine (419)[7] Nortiliacorine A (115)[385,391] Nortiliacorinine A (116)[257,275,391-398] Nortiliacorinine B (117)[393] Telobine (160)[11,119,255] Tiliarine (185)[395,467] Trilobine (163)[ 153,154,165,216,235,329-333,399,469] C 34 H r 0 6 N 2 564.2260 Cocsoline-2'p-N-Oxide (398)[159] 5-Hydroxyapateline (309)[233] Kohatine (236)[ 139,233] N-Norcocsulinine (422)[153] Pachygonamine (249)[356,357] Pangkorimine (354)[10] C34H34OftN2 566.2417 N,N'-Bisnoraromoline (32)[10,13,118] Bisnorobamegine (277)[120] Pangkoramine (353)[10] C34H3606N2 568.2573 Lindoldhamine (11)[ 10,16,230,231,343] 574.2104 C35H30O6N2 Siddiquamine (371)[233] Stephasubimine (373)[137] C35H3206N2 576.2260 Dehatridine (287)[23~2] 1,2-Dehydrokohatamine (289)[233] Normenisarine (166)[216] Norstephasubine (340)[137]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 5. Continued

Stepierrine (376)[34] 576.2624 C36H360,N2 N,0-Dimethylmicranthine (156)[234,255] Dinklacorine (114)[256-258] Isotrilobine (157)[7,13 , 1 6, 139,153,216,235,329-335] 2-N-Methyltelobine (418)[135] Tiliacorine (118)[257,391,393,397,398] Tiliacorinine(119)[275,393,396-398] Tiliaresine (429)[382] Yanangcorinine (388)[398] 578.2417 C35H3406N2 Cocsiline(396)[153] Cocsuline-N-2-Oxide (231)[171] Cocsulinine(164)[153,156] Gilletine(202)[280,281] 5-Hydroxytelobine (310)[233] Kohatamine (314)[233] 12-0-Methylcocsoline-2'-P-N-Oxide (414)[ 159] N-Methylpachygonamine (243)[356,357] 2-Norcepharanoline (326)[34] Norisoyanangine (335)[385] Noryanangine (346)[385] Pendine(178)[153,156] Pendulinine(179)[153,156] C35H3606N2 580.2573 Bisnorthalrugosine (279)[120] Cycleacurine (134)[43] Daphnoline (38)[7,9,10,12,13,16,26-28,49,120,139,216] 7-O-Demethylpeinamine (60a)[240] Nor-Nb-Chondrocurine (230)[145] 2-Norobamegine (69)[99,118,120] C35H3806N2 582.2730 Costaricine (399)[173] 2-N-MethyIl!ndoldhamine(321)[230] 2'-N-MethylIindoldhamine(322)[230] 7-0-Methyllindoldhamine(241)[231] 7'-0-Methyllindoldhamine (242)[231 ] Northalibroline (341)[390] Pedroamine (355)[279]

135

P.L.Schiff,Jr. Table 5. Continued 590.2417 C36H3406N2 Caryolivine (281)[74] Cycleatjehine(405)[211] Menisarine (165)[332,349] Sciadoline (128)[ 198,429] Stebisimine (51)[ 165,168,264,281,431 ] Stephasubine (374)[ 137,249] 592.2210 C35H3207N2 Punjabine (265)[68] C36H3606N2 592.2573 Cepharanoline (33)[32,102,104,130] Cordobimine(283)[172] 1,2-Dehydro-2-Norlimacusine (291)[74] 12-O-Demethylcoclobine (293)[12] 3',4'-Dihydrostephasubine (295)[249] Hypoepistephanine (43)[263] O-Methylcocsulinine (415)[153] O-Methyldeoxopunjabine (263)[248] 2-Norcepharanthine (327)[ 135,137] 2'-Norcepharanthine (328)[34] 2-Norisocepharanthine (333)[34] Pendilinine(425)[153] Sciadoferine(217)[198] Thalmethine (98)[364,368,369,371,379,455] Thalmiculatimine (381)[307] Thalsivasine (385)[307,375] Tiliacorinine-2'-N-Oxide(254)[385] Tiliafunimine (79a)[465] Tiliamosine(120)[356,357,382,392] Tilianangine (386)[257] Warifteine (151)[251] Yanangine (389)[258] 594.2366 C35H3407N2 Isogilletine-N-Oxide (204)[281] 594.2730 C36H3806N2 Aquifoline (273)[14] Aromoline (31 )[9,12,15-21,23-42,78] Atherospermoline (56)[7,44] Baluchistine (188)[47]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 5. Continued Berbiiaurine(275)[18] 2,2'-Bisnorguattaguianine (276)[119] 2,2'-Bisnorphaeanthine (278)[10] Candicusine (280)[127-129] Chondocurine (130)[141-145] (+)-Curine (132)[146.175-178] (-)-Curine (133)[90,130,141,142,144,145,147,175,177-183,190,200-203] (+/-)-Curine dimethiodide (132)[476] Daphnandrine (37)[ 10,12,13,27,28,34,90,135,151] Demerarine (39)[236] 7-0-Demethylisothalicberine(195)[18,237,238] 12-O-Desmethyllauberine (294)[239] Dihydrowarifteine (146)[251] Dinklageine (172)[259] Dryadodaphnine (105)[260] Hayatine (137)[ 144,175,190,202] Isochondodendrine(122)[130,141,142,144,146,147,175.180-183,189,190,194199,201,267,303,309.312-315] Krukovine (63)[15,49,127,128] Macolidine (44a)[240) N-Methyl-7-O-Demethylpeinamine (66b)[7,240] Neoprotocuridine (123)[ 1 ] 2-N-Norberbamine (68)[34,99,120,139] 2-Norlimacine (336)[74.235] 2'-Norlimacine (423)[90,235] 2-Norlimacusine (245)[74,283] 2'-Noroxyacanthine (338)[35] Norpanurensine (109)[386] Norpenduline(246)[139] 2'-Northaliphylline (342)[35,307] 2-Northalmine(343)[241] 2-Northalrugosine (344)[120,135] 2'-Nortiliageine(345)[119] Obamegine(71)[18,19,29,32,37,38,281,400,403,405-407] Peinamine (71a)[240] Protocuridine (126)[1] Sepeerine (50)[236] Thalabadensine(106a)[297-300,369] Thalivarmine (380)[375] Tilitriandrine (387)[466] Tomentocurine (186)[ 141] (-)-Tubocurine (144)[201]

137

138

P.L.Schiff,Jr. Table 5. Continued

C36H40O6N2 596.2886 Berbamunine (1)118,19,21,23,34,76,62,82,84,86,110-117] Dauriciline(406)[217] Dauricoline (5)[221,223,229] N,N'-DimethylIindoldhamine (Guattegaumerine)(234)[74,76,230,231,254] Espinine (9)[239,265] Magnoline (12)[240,344,475] Neosutchuenenine (420)[309] 2'-Nordaurisoline (330)[230] 2'-Norpisopowiaridine (339)[229] Pampulhamine (352)[279] Sutchueneneonine (426)[309] Sutchuenenine (427)[309] C37H3606N, 604.2574 Cycleatjehenine (404)[211,212] C37H3706N2+ 605.2652 Berbacolorflammine (218)[49,50] Colorflammine (219)[49,50] 606.2366 C36H3407N2 Cheratamine (228)[139] O-Methylpunjabine (264)[248,358] Secolucidine(393)[U7] 606.2730 C37H3g06N, Cepharanthine (34)[32,34,102,104-106,131 -137] Cissampareine (145)[149] Coclobine(35)[12,151,152] Dehatrine (288)[232,474] (+)-Epistephanine (40)[249,261 -264] (-)-Epistephanine (41)[165] Insulanoline (169)[ 192,252,308,309] Medelline (318)[348] 0-Methylthalmethine(96)[364,368,371,375,376,379] N-Methyltiliamosine (323)[381,382] Methylwarifteine (150)[251] Ocotosine (24)[388] Pseudorepanduline (167)[234]

The Bisbenzyllsoquinoline Alkaloids - A Tabular Review

139

Table 5. Continued 608.2522 C36H3607N2 Cultithalminine (285)[35] Secojollyanine (433)[358] 608.2886 C37H40O6N2 Antioquine (225)[8] Belarine (93)[ 18,48] Berbamine (57)[ 17-20,22,23,29,30,32,51 -84,86-109] Chondrofoline (131)[147,148,175] Cissampentin (395)[I50] Cordobine(284)[172] Cycleabarbatine (402){90] Cycleadrine (58)[K43] Cycleanorine (60)[43,90] Cycleapeltine (36)[43,90,209] N-Desmethylcycleanine (233)[34,206] 0,0-Dimethylcurine (135)[ 191,196] Dryadine (104)[260] Fangchinoline (61 )[7,43,107,168,199,207,255,266-272] Guattamine(303)[119] Gyroamericine (305)[282] Gyrocarpine (306)[45,282] Gyrocarpusine (307)[282] Hayatidine (136)[190] Hayatinine (138)[ 190.202] Himanthine(173)[81] Homoaromoline (42)[ 1,2,15,16,18,28,30,32,34,37,38,40,41,49,92,104,117,134,135,210, 235,301-306] Isothalicberine (205)[237,238] Johnsonine (206)[336] Lauberine (106)[ 18,337] Limacine (64)[22,45,49,89,127,128,184,185,209,210,235,271,272,282,301, 342] Limacusine (44)[ 127-129,184,185] Menisidine (65)[350] Menisine (66)[350] 4"-0-Methylcurine (139)[175,203] 12'-0-Methylcurine (140)[196] Methyldihyhdrowarifteine (149)[251 ] Nemuarine(lll)[384] (+)-Norcycleanine (124)[141,158,192,195,312] (-)-Norcycleanine (125)[32,181] 2'-Norfuniferine (331)[119]

P.L.Schiff,Jr. Table 5. Continued 2'-Norguattaguianine (332)[119] 2-Norisotetrandrine (334)[34,135] Nor-2'-Isotetrandrine (213)[34,92] 2'-Norobaberine (337)[34] Norrodiasine (22)[236] 2-Nortetrandrine (70)[388] Ocodemerine (176)[236] Ocotine (23)[388] Otocamine (177)[236] Oxyacanthine(48)[ 16-18,20,21,24,35,37,55,60,62,63,65.68,70,75,78,79,83-86,95,96,110116,321,373,379,400.402,403,407,411-421,473] Panurensine(110)[386] Penduline(72)[7,58,139,153,155,156,160,161] Phlebicine (25)[425] Pycnamine (75)[22,100,101,168,422] Repandine (49)[90,336,426] Sciadenine (127)[ 198,428] Stephibaberine (375)[34,135] Thalicberine(97)[37,38,363,364,368,370,371,373,375,378] Thalictine (107)[300,307,380,443] Thalifortine (428)[36] Thaliphylline (253)[38,307,375] Thalmine(108)[241,362,366,369,455] Thalrugosamine (52) - see Homoaromoline (42) Thalrugosine (79)[ 18,19,22.37,92,135,210,266,360,374,402,403,496,457-461 ] Tiliageine (27)[ 119,275,466] C37H4l06N2* 609.3042 Protochondocurarine (180)[311] (+)-Tubocurarine (142)[ 142,145,470] (-)-Tubocurarine (143)[200] C36H3S077N, 610.2679 Jhelumine(262)[138] C37H4206N2 610.3043 Cuspidaline (2)[ 184,185] Dauricinoline (4)[222.223] Daurinoline (6)[220,221,223] Daurisoline (192)[223,225,227,230,231 ] N'-Desmethyldauricine (7)[220] Dirosine (19)f236] Espinidine (8)[265]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 5. Continued Geraldoamine (301)[279] Grisabine (10)[240,282,283] Isodaurisoline (235)[231] Isoliensinine(28)[316,3l7] Liensinine(29)[338-341] Macoline (44b)[240] Northalibrine (13)[389] Pisopowamine (357)[229] Pisopowiaridine (359)[229] Popisonine (366)[229] Popisopine (367)[229] Temuconine (251)[432] Thaligrisine(252)[38,117] 616.2209 C37H3X>7N2 Daphnine(191)[213-215] C3gH3606N2 616.2573 Phaeantharine (73)[162,163] C37H3407N2 618.2366 Oxofangchirine (349)[410] 620.2523 C37H3607N2 Curicycleatjine (401)[174] Guattaminone (304)[119] Isocuricycleatjine (411)[174] Oxoepistephanine (47a)[409] Repanduline (168)[27,426] C38H40O6N2 620.2886 Dimethylwarifteine (148)[251] Insularine (170)[182,189,192,252,308,310] 622.2316 C36H34OgN2 Gilgitine (261)[68] C37H3gO?N2 622.2679 Cepharanthine-2'p-N-Oxide (282)[ 137] (+)-Nortenuipine(88)[255,387,336] (-)-Nortenuipine (89)[27,387] Oxandrine (347)[408] Oxandrinine (348)[408]

141

P.L.Schiff,Jr. Table 5. Continued Pseudoxandrine (368)[408] Thalmiculimine (382)[307] Thalsimidine (85)[462] C38H4206N2 622.3043 Cycleaneonine (286)[187,188] (-)-Cycleaneonine (403)[188] Cycleanine (121)[30,32,34,92,102,104,105,131,132,141,142,147,157,158,181,182,189, 190-195,197,204-208] Dimethyldihydrowarifteine (147)[251 ] Funiferine (20)[ 119,275,276] Gyrolidine (308)[282] Isocycleaneonine (412)[188] Isotetrandrine (62)[ 18,19,21,23,28-30,32,34,51,55,58,64,69,72,79,80,87,91,92,95, 97-100,101,103,104,108,112,135,153,168,269,282,302,319-328] 0-Methylisothalicberine(94)[48,237,337] O-Methyllimacusine (320)[282] 0-Methylrepandine(45)[27,323,336] O-Methylthalicberine (95)[37,38,116,238,289,290,307,359,362-378] O-Methylthalmine (244)[307,380] Monterine(324)[172] Obaberine (46)[8,16,18,19,34,35,37,39,49,60,62,135,230,232,248,320,322,337,373,374, 400-404] Phaeanthine (74)[22,45,99,100,101,164,168,282,342,422-424] Rodiasine (26)[236,388] (+)-Tetrandrine (76)[7,42,43,107,139,161,164,199,207,210,267-270,272,303,314,323, 332,433-436] (+/-)-Tetrandrine (77)[89,199,267,303,323] C3lH«306N2+ 623.3121 2-N'-Methylberbamine (66a)[l 16,351,352] 2-N-Methylfangchinoline(416)[355] Oblongamine (47)[115] C^H^N, 624.2836 Berbamine-2'P-N-Oxide (274)[58] Chenabine (258)[138] N-Desmethylthalidezine (80)[244] N-Desmethylthalrugosidine (197)[247] Fenfangjine B (Fangchinoline-2'a-N-Oxide) (298)[207,273] Fenfangjine C (Fangchinoline-2'P-N-Oxide) (299)[207,273] Fenfangjine D (1,3,4-Tridehydrofangchinolinium Hydroxide) (300)[207,274] 5-Hydroxythalmine (313)[307]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 5. Continued Limacine-2'a-N-Oxide (315)[ 127-129] Limacine-2p-N-Oxide (316)[ 127-129] Limacine-2'P-N-Oxide (317)[ 127-129] Limacusine-2'P-N-Oxide(413)[235] 2-Norobaberine-2'p-N-Oxide (424)[ 151] Thaligosidine (100a)[449] Thaliphylline-2'P-N-Oxide(379)[35] Thalisopidine (53)[453] C3gH44OftN2 624.3199 Chondocurarine (129)[140] Dauricine (3)[218-229] Isochondocurarine (174)(bisquaternary)[311] 7'-0-Methylcusidaline (240)[353] 7-O-Methylgrisabine (417)[252] Neferine (30)[317,339] (+)-Neochondocurarine (175)(bisquaternary)[311] Neothalibrine(211)[35,39,247,377] Pisopowetine (358)[229] Pisopowiarine (360)[229] Popidine (363)[229] Popisidine (364)[229] Popisine (365)[229] Thalibrine (14)[246,389] C37H4207N2 626.2992 Chillanamine (229)[123] Magnolamine (15)[344] 632.2734 C J6 H 4 AN 2 Pycnarrhenamine (181)[100] 634.2679 C37H3807N2 Curicycleatjenine (400)[174] Isocuricycleatjenine (410)[ 174] C37H3608N2 636.2472 Secocepharanthine (268)[248] 636.2836 C38H40O7N2 Calafatimine(190)[121] Cycleanine N-Oxide (232)[158] lnsularine-2p-N-Oxide (408)[252]

143

P.L.Schifr,Jr. Table 5. Continued Insularine-2'p-N-Oxide (409)[252] Isotenuipine (87)[318] O-Methylthalibrine(209)[292,359,360] Oxandrinine (348)[408] Pseudoxandrinine (369)[408] Repandinine (90)[27,336,387] (+)-Tenuipine (91)[234,387] (-)-Tenuipine (92)[27] Thalsimine (86)[296,365,441,462,463] C39H4406N, 636.3199 Granjine (302)[172] 637.3278 C39H4506N2* Cycleahomine (59)[43] N-2'-Methylisotetrandrine (319)[70] Monomethyltetrandrinium (67)[383] 638.2628 C37H3„OgN2 Baluchistanamine (257)[46] Dihydrosecocepharanthine (260)[248] Maroumine (391)[45] Secantioquine (267)[8,430] Secohomoaromoline (432)[358] Sindamine (270)[68] 638.2992 C38H4,07N, N-Desmethylthalidasine (196)[241 -243] Epinorhernandezine (199)[250] Fenfangjine A (Tetrandrine-2p-N-Oxide) (297)[207,273] Funiferine N-Oxide (21)[278] Isothalidezine (82)[244,286,292] N'-Norhernandezine (212)[250] Osornine (248)[123] N-Oxy-2'-Isotetrandrine (216)[92] Phaeanthine-2'a-N-Oxide (356)[101] Tetrandrine Mono-N2'-Oxide (78)[143] Thalfoetidine (99)[ 108,289,363,439,440] Thalidezine(83)[244,286,288-292,296,365] Thalisopine(Thaligosine)(54)[35,38,290,307,359,373,374,376,449,451,452,454,471] Thaligosinine(52b)[439,446,449,450] Thalisamine (84)[296] Thalmiculine (383)[307]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review Table 5. Continued

Thalrugosidine(101)[247,307,359,406,447,451] C39H4606N, 638.3356 O,O'-Dimethylgrisabine(~407)[252,253] O-Methyldauricine (12a)[229,354] Pisopowidine (361)[229] C38H4407N, 640.3149 Neothalibrine-2'a-N-Oxide(325)[35] Thalirugine (14b)[35,38,449] C38H40O8N2 646.2890 Pycnarrhenine (182)[100] 648.2472 C38H3608N, Thalfine (102)[404,437,438] C37H36OqN2 652.2421 Thalpindione (223)[247] 652.2785 C38H40O8N2 Auroamine (390)[45] Revolutinone (266)[427] Secoisotetrandrine (431)[325J Seco-obaberine (269)[8] Thalibrunimine (112)[441,442] C39H4407NU 652.3149 Calafatine(190)[121-124] Hernandezine (81)[161,244,284-300] Thalidasine(100)[37,241.243,247,289,363,376,404,406,439,440,445-448] Thaliracebine (14a)[243,404] Thalrugosaminine (55)[35,247,307,404,446,451,454,456] 652.3512 C40H48O6N2 Funiferine Dimethiodide (201)(bisquaternary)[277] Pisopowine (362)[229] C38H4208N2 654.2941 Epinortbalibrunine (200)[250] N'-Northalibrunine (214)[250,361] Thaligosine-2a-N-Oxide (Thalisopine-2a-N-Oxide) (378)[35]

14S

P.L.SchifT,Jr. Table 5. Continued 654.3305

CJOH^N,

N-2-Oxy-O-Methyldauricine(350)[229] N-2'-Oxy-0-Methyldauricine(351)[229] Thaliruginine (14c)[449] 656.3097 C38H4408N2 Ambrimine (272)[6] Efatine (296)[6] Vateamine (256)[345] 664.2421 C38H3609N2 Thalictrinine (220)[250] C39H40OgN2 664.2785 Tiliacoridine (183)[464] 666.2577 C3gH380QN2 Dihydrothalictrinine (198)[250] Oxothalibrunimine (215)[250] Thalrugosinone (224)[39,241] C39H4208N2 666.2941 O-Methylthalibrunimine (210)[361 ] Thalfinine (103)[404,437,438] 668.2734 C38H40O9N, Pycmanilline(392)[101] 668.3098 C39H4408N, Calafatine-2'a-N-Oxide (~226)[ 125,126] Calafatine-2'p-N-Oxide (227)[ 125,126] Hernandezine-N-Oxide (203)[299] 5-Hydroxythalidasine (311)[307] Thalibrunine (113)[441,442] Thalidasine-2a-N-Oxide (377)[35] Thalistine (221)[360] Thalmirabine (222)[286,360] Thalrugosaminine-2a-N-Oxide (384)[35] 670.3254 C39H46OgN2 Malekulatine (238)[345-347] Thalirugidine (17b)(449,451] Vanuatine (255)[345]

l he Bisbenzylisoquinoline Alkaloids - A Tabular Review

147

Table 5. Continued C38H44OqN, 672.3047 Vateamine-2'-P-N-Oxide(430)[472] 682.2891 C39H4209N2 Curacautine (259)[123] 682.3254 C40H46OgN2 N-Desmethylthalistyline (16)[244-246] 683.3332 C40H47O8N/ Thalirabine (17a)[245.404] 684.3046 C39H4409N2 5-Hydroxythalidasine-2a-N-Oxide (312)[35] C4lH49OgN/ 697.3489 Thalistyline (18)[244,246~] 712.2996 C40H44O,0NU Talcamine (271)[123] C42HoOgN2*4 712.3724 N-Methylthalistyline (17)[244,246] 7.

A TABULAR COMPILATION OF THE STRUCTURAL TYPES OF THE BISBENZYLISOQUINOLINE ALKALOIDS Table 6

I.

One Diphenyl Ether Linkage (Tail-to-Tail) Type I - 6,7,11\12-6,7,12* (XJt) Costaricine(399)[173] Cuspidaline(2)[l84,185] Dauriciline(406)[217] Dauricine (3)[218-228J Dauricinoline (4)[222,223] Dauricoline (5)[221,223,229] Daurinoline (6)[220,221,223] Daurisoline(192)[223,225,227,230,231]

H8

P.L.Schiff,Jr. Table 6. Continued N'-Desmethyldauricine (7)[220] N,N'-Dimethyllindoldhamine (Guattegaumerine)(234)[74,76,230,231,254] Geraldoamine (301)[279] Isodaurisoline (235)[231] Lindoldhamine (11)[ 10,16,230,231,343] 7'-O-Methylcuspidaline(240)[353] O-Methyldauricine (12a)[229,354] 2-N-Methyllindoldhamine (321 )[230] 2'-N-MethyIlindoldhamine(322)[230] 7-O-Methyllindoldhamine (241)[231 ] 7'-0-MethylIindoldhamine (242)[231 ] 2'-Nordaurisoline (330)[230] N-2-Oxy-O-Methyldauricine(350)[229] N-2'-Oxy-0-Methyldauricine(351)[229] Pampulhamine (352)[279] Pedroamine (355)[279] Popidine (363)[229] Popisidine (364)[229] Popisine (365)[229] Popisonine (366)[229] Popisopine (367)[229] (R,S) Berbamunine (1)[ 18,19,21,23,34,62,76,82,84.86,110-117] Espinidine (8)[265] Espinine (9)[239,265] Temuconine (251)[432] Thaligrisine(252)[38,117] (S,R) O,O'-Dimethylgrisabine(407)[252,253] Grisabine (10)[240,282,283] Magnoline (12)[240,344,475] 7-O-Methylgrisabine (417)[252] (S,S) O-Methylthalibrine(209)[292,359,360] Neothalibrine (211)[35,39,247,377]] Neothalibrine-2'a-N-Oxide(325)[35] Northalibrine (13)[389] Northalibroline (341)[390] Thalibrine (14)[246,389]

The Blsbenzylisoquinoline Alkaloids - A Tabular Review Table 6. Continued Type la - 6,7,11 ',12-5,6,7,12' Thaliracebine (14a)[243,404] Thalirugine (14b)[35,38,449] Thaliruginine (14c)[449] Type lb - 6,7,10,11\ 12-6,7,12* Chillanamine (229)[123] Type II - 6,7,10\12,13-6,7,12* Magnolamine (15)[344] Type Ha - 6,7,10M2,13-6,7,llM2 (S,S) Vanuatine (255)[345] Type lib - 6,7,10,11,12-6,7,11\12 (S,S) Vateamine (256)[345] Vateamine-2'.p-N-Oxide (430)[472] Type III - 5,6,7,1 1\12-5,6,7,12* (S,S) N-Desmethylthalistyline (16)[244-246] N-Methylthalistyline(17)[244,246] Thalirabine (17a)[245,404] Thalirugidine (17b)[449,451] Thalistine(221)[360] Thalistyline (18)[244,246] II.

One Diphenyl Ether Linkage (Head-to-Tail) Type V-6,7,11M2-6,7M2 <JW) Isoliensinine (28)[316,317] Liensinine(29)[338-341] Neferine (30)[317,339] Unknown stereochemistry Neosutchuenenine (420)[309]

149

150

P.L.Schitr,Jr. Table 6. Continued Type Va - 6,7,10\12,13-6,7\11,12 (S,S) Malekulatine (238)[345-347] Type Vb - 6,7,10\11,12-6,7\11,12 (S,S) Ambrimine (272)[6] Efatine (296)[6] Type Vc - 6,7\12-6,7,12* Unknown stereochemistry Sutchueneneonine (426)[309] Type Vd - 6,7\8,12-6,7,12* Unknown stereochemistry Sutchuenenine (427)[309]

III.

One Diphenyl Linkage (Tail-to-Tail) Type XXVII - 6,7,12-6,7,12(11-11) (R,R) 2'-Norpisopowiaridine (339)[229] Pisopowamine (357)[229] Pisopowetine (358)[229] Pisopowiaridine (359)[229] Pisopowiarine (360)[229] Pisopowidine (361)[229] Pisopowine (362)[229]

IV.

One Diphenyl Ether Linkage (Head-to-Head) and One Diphenyl Linkage (Tail-toTail) Type IV - 6,7,8\12-6,7\12(11-11) Cordobimine(283)[172] Guattamine (303)[119] Guattaminone (304)[119] Secantioquine (267)[8,430] (R,S) Cordobine (284)[172] Granjine (302)[172] Monterine(324)[172]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

151

Table 6. Continued

(S,R) Antioquine (225)[8] Funiferine (20)[119,275,276] Funiferine Dimethiodide (201)[277] Funiferine N-Oxide (21)[278] 2'-Norfuniferine(331)[119] Norrodiasine (22)[119,236] 2'-Nortiliageine(345)[H9] Phlebicine (25)[ 119,425] Rodiasine (26)[ 119,236,388] Tiliageine (27)[119,275,466] Tilitriandrine (387)[466] (5,5) 2,2'-Bisnorguattaguianine (276)[119] 2'-Norguattaguianine (332)[119] Ocotine(23)[ 119,388] Oxandrine (347)[408] Oxandrinine (348)[408] Pseudoxandrine (368)[408] Pseudoxandrinine (369)[408] Unknown stereochemistry Dirosine (19)[236] V.

One Diphenyl Ether Linkage (Head-to-Head) and One Diphenyl Ether Linkage (Tailto-Tail) Type VI - 6,7\11\12-6,7,8\12 + (-,-) Stebisimine (51)[ 165,168,264,281,431 ] Stephasubimine (373)[137] (*,-) Colorflammine (219)[49,50] 3',4'-Dihydrostephasubine (295)[249] (+)-Epistephanine (40)[249,261 -264] Hypoepistephanine (43)[263] Norstephasubine (340)[137] Oxoepistephanine (47a)[409] Pangkorimine (354)[10] Pycnazanthine (370)[120] Stephasubine (374)[ 137,249]

P.L.SchifT,Jr. Table 6. Continued

(-)-Epistephanine (41)[165] (-,*) Auroamine (390)[45] 1,2-Dehydro-2-Norlimacusine (291 )[74] Maroumine (391)[45] (-,S) CocIobine(35)[12,151,152] Baluchistanamine (257)[46] 12-O-Demethylcoclobine (293)[12] Dihydrosecocepharanthine (260)[248] Secocepharanthine (268)[248] Secohomoaromoline (432)[358] Seco-obaberine (269)[8] (*,*) Candicusine (280)[127-129] Gyrocarpusine (307)[282] Limacusine (44)[ 127-129,184,185] Limacusine-2'p-N-Oxide (413)[235] O-Methyllimacusine (320)[282] 2-Norlimacusine (245)[74,283] Pangkoramine (353)[10] (R,S) Aromoline (31)[ 1,9,12,15-21,23,24,26-42,78] Baluchistine (188)[47] N,N'-Bisnoraromoline (32)[10,13,118] Cepharanoline (33)[32,102,104,130] Cepharanthine (34)[32,34102,104-106,131 -137] Cepharanthine-2'p-N-Oxide (282)[ 137] Daphnandrine (37)[ 10,12,13,27,28,34,90,135,151] Daphnoline (38)[7,9,10,12,13,16,26-28,49,120,139,216] Homoaromoline (42)[ 1,2,15,16,18,28,30,32,34,37,38,40,41,49,92,104,117,134, 210,235,301-306] 2-Norcepharanoline (326)[34] 2-Norcepharanthine (327)[135,137] 2'-Norcepharanthine (328)[34] 2-Norisocepharanthine (333)[34] 2'-Norobaberine (337)[34] 2-Norobaberine-2'p-N-Oxide (424)[ 151]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

153

Table 6. Continued 2'-Noroxyacanthine (338)[35] Obaberine (46)[8,16,18,19,34,35,37.39,49,60.62,135,230,232,248,320.322,337,373, 374,400-404] Oxyacanthine(48)[ 16-18,20,21,24,35,37,55,60,62,63.65.68.70,75,78,79,83-86,95, 96,110-116,321,373,379,400,402,403,407,411.413-421,473] Sepeerine (50)[236] Stephibaberine (375)[34,135] Thalrugosamine (52) - see Homoaromoline (42) (S,R) Gyrocarpine (306)[45,282] Gyrolidine (308)[282] Macolidine (44a)[240] Macoline (44b)[240] (5,5) Cycleapeltine (36)[43.90,209] Demerarine (39)[236] Johnsonine (206)[336] 0-Methylrepandine(45)[27.323.336] Repandine (49)[90.336.426] Type Via - 6,7M0,llM2-6,7,8*,124 iS,R) Osornine (248)[123] Type VII - 5,6,7,8\12 + -6,7\U\12 (S,S) Thaligosine (52a) - see Thalisopine (54) Thaligosine-2a-N-Oxide - see Thalisopine-2a-N-Oxide Thaligosinine(52b)[439,446,449,450] Thalisopidine (53)[453] Thalisopine-2a-N-Oxide (378)[35] Thalisopine (54)[35,38,290,307,359,373,374.376,449.451.452,454,471] Thalrugosaminine (55)[35,247,307,404,446,451,454,456] Thalrugosaminine-2a-N-Oxide (384)[35] Type VIII - 6,7,8\11M2-6,7\12* Dehatrine (288)[232,474] Pycmanilline(392)[101] Secoisotetrandrine (432)[325]

154

P.L.Schiff,Jr. Table 6. Continued

Sindamine (270)[68] (-,*) Berbacolorflammine (218)[49,50] (-,5) Chenabine(258)[138] Cheratamine (228)[139] Dehatridine (287)[232] Fenfangjine D (1,3,4-Tridehydrofangchinolinium Hydroxide) (300) [207,274] Jhelumine (262)[138] Stepierrine (376)[34] Tiliafunimine (79a)[465]

(M Oxofangchirine (349)[410] (-,-) Phaeantharine (73)[162,163] (R,R) 2,2'-Bisnorphaeanthine (278)[10] Caryolivine (281)[74] Gyroamericine (305)[282] Krukovine (63)[ 15,49,127,128] Limacine (64)[22,45,49,89,127,128,184,185.209.210,235.271,272,282,301,342] Limacine-2'a-N-Oxide (315)[ 127-129] Limacine-2p-N-Oxide (316)[ 127-129] Limacine-2'P-N-Oxide (317)[ 127-129] 2-Norlimacine (336)[74,235] 2'-Norlimacine (423)[90,235] Phaeanthine (74)[22,45,99-101,164.168,282,342,422-424] Phaeanthine-2'a-N-Oxide (356)[ 101] Pycnamine (75)[22,100,101,168,422] (R,S) Aquifoline (273)[14] Berbamine (57)[ 17-20,22,23,29,30,32,51 -109] Berbamine-2'p-N-Oxide (274)[58] Bisnorobamegine (277)[120] Bisnorthalrugosine (279)[120]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

155

Table 6. Continued Cycleabarbatine (402)[90] Isotetrandrine (62)[ 18,19.21,23,28,29,30,32,34,51,55,58,64,69,72,79,80,87,91,92,95, 97-104,108, M 2,135,153,168,269,282,302,319-328] 2-N'-Methylberbamine (66a)[l 16,351,352] N-2'-Methyiisotetrandrine (319)[70] 2-N-Norberbamine (68)[34,99,120,139] 2-Norisotetrandrine (334)[34,135] Nor-2'-Isotetrandrine(213)[34,92] 2-Norobamegine (69)[99,118,120] 2-Northalrugosine (344)[120,135] Obamegine (71)[ 18,19,29,32,37,38,281,400,403,405,406,407] N-Oxy-2'-Isotetrandrine (216)[92] Thalrugosine (79)[ 18,19,22,37,92,135,210,266,360,374,402,403,406,457-461 ] (S,R) 7-O-Demethylpeinamine (60a)[240] Peinamine (71a)[240] (5,5) Atherospermoline (56)[7,44] Cycleahomine (59)[43] Cycleanorine (60)[43,90] Fangchinoline (61 )[7,43,107,168,199,207,255,266-272] Fenfangjine A (Tetrandrine-2P-N-Oxide) (297)[207,273] Fenfangjine B (Fangchinoline-2'a-N-Oxide) (298)[207.273] Fenfangjine C (Fangchinoline-2'P-N-Oxide) (299)[207,273] 2-N-Methylfangchinoline(416)[355] Monomethyltetrandrinium (67)[383] Norpenduline(246)[139] 2-Nortetrandrine (70)[388] Penduline (72)[7,58,139,153,155,156,160,161 ] (+)-Tetrandrine (76)[7,42,43,107,139,161,164,199,207,210.267-270,272,303,314, 323,332,433-436] Tetrandrine Mono-N2'-Oxide (78)[143] Racemate

Cycleadrine (Fangchinoline (61) racemate)(58)[l,43] (+/-)-Tetrandrine (77)[89,199,267,303,323] Isomorph Menisidine (65)(Isomorph of Fangchinoline (61))[350] Menisine (66)(Isomorph of (+)-Tetrandrine (76))[350]

P.L. Schiff, Table 6. Continued Type IX - 5,6,7,8\11M2-6,7M2+ Thalsimidine (85)[462] Thalsimine (86)[296,365,441,462,463] (S,R) Epinorhernandezine (semisynthetic)( 199)[250] Isothalidezine (82)[244,286,292] (S,S) N-Desmethylthalidezine (80)[244] Hernandezine (81)[ 161,244,284-300] Hernandezine-N-Oxide (203)[299] N'-Norhernandezine (212)[250] Thalidezine(83)[244,286,288-292,296,365] Thalisamine (84)[296] Type X - 6,7,8\11\12,13-6,7\12 + (R,R) (-)-Nortenuipine (89)[27,387] (-)-Tenuipine (92)[27] (R,S) Isotenuipine (87)[318] (S,S) (+)-Nortenuipine(88)[255,336,387] (+)-Tenuipine (91)[234,387] Racemate Repandinine (90)[Tenuipine (91) racemate] [27,3 36,3 87] Type Xa - 6,7,8\10,HM2-6,7\12* Calafatimine(189)[121] Curacautine (259)[123] Talcamine (271)[ 123] (S,R) Calafatine (190)[12M24] Calafatine-2'a-N-Oxide (226)[ 125,126] Calafatine-2'P-N-Oxide (227)[ 125,126]

The Bisbenzyllsoquinollne Alkaloids - A Tabular Review Table 6. Continued Type Xb - 6,7\8,11M2,13-6,7\12* (-,-) Daphnine(191)[213-215] Type XI - 6,7,8\11M2,-6\7,12 + (5,-) 0-Methylthalmethine(96)[364,368,371,375.376.379] Thalmethine(98)[364,368,369,371,379,455] Revolutinone (266)[427] Thalsivasine (385)[307.375] (R,S) Belarine (93)[ 18,48] 7-O-Demethylisothalicberine (195)[ 18,237,238] Isothalicberine (205)[237,238] 0-Methylisothalicberine(94)[48,237,337]

W5) O-Methylthalicberine (95)[37,38.116,238,289.290.307,359,363-378] 2'-Northaliphylline (342)[35,307] Thalicberine(97)[37,38,363,364,368,370,371,373.375,378] Thaliphylline (253)[38,307,375] Thaliphylline-2'p-N-Oxide(379)[35] Thalivarmine (380)[375] Type XII - 6,7,8\11+,12-5\6,7,124 (5,5) Thalfoetidine (99)[ 108,289,363,439,440] N-Desmethylthalidasine(196)[241-243] N-Desmethylthalrugosidine (197)[247] Thalidasine(100)[37,241-243,247,289,363,376,404,406,439,440,444-448] Thalidasine-2a-N-Oxide (377)[35] Thaligosidine (100a)[449] Thalpindione (223)[247] Thalrugosidine(101)[247,307,359,406,447,451] Thalrugosinone (224)[39,241 ] Type XHa - 5,6,7,8\H\12-5\6,7,12 + (5,5) 5-Hydroxythalidasine (311)[307] 5-Hydroxythalidasine-2a-N-Oxide (312)[35]

157

P.L. Schiff,Jr. Table 6. Continued Type XIII - 5\6,7,11M2,-5,6,7,8\12+ Thalfine (102)[404,437,438] (S,S) Thalfinine (103)[404,437,438] Thalmirabine (222)[286.360] Type XIV - 6,7\11+,12,-5\6,7,12+ (S,-) Thalmiculatimine (381)[307] (R,S) Berbilaurine(275)[18] 12-O-Desmethyllauberine (294)[239] Lauberine(106)[18,337] (S,R) Dryadine (104)[260] Dryadodaphnine (105)[260] Thalifortine (428)[36] (S,S) O-Methylthalmine (244)[307,380] 2-Northalmine(343)[241] Thalabadensine (106a)[297-300,369] Thalictine(107)[300,307,380,443] Thalmine (108)[241,363,366,369,455] Type XlVa - 5,6,7\11M2-5*,6,7,12* Cultithalminine (285)[35] Thalmiculimine (382)[307] (S,S) 5-Hydroxythalmine (313)[307] Thalmiculine (383)[307] Type XV - 5\6,7,U\12,-6,7\12 + (R,R) Norpanurensine (109)[386] Panurensine(110)[386]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

159

Table 6. Continued Type XVI - 5\6,7,11+,12,-6*,7,12+ (R,R) Nemuarine(lll)[384] Type XVII - 5,6,7,8*, 10M 1,12,-6,7\12+ Dihydrothalictrinine (198)[250] O-Methylthalibrunimine (210)[361] Oxothalibrunimine (215)[250] Thalibrunimine (112)[441,442] Thalictrinine (220)[250] (S,R) Epinorthalibrunine (semisynthetic)(200)[250] (S,S) N'-Northalibrunine (214)[250,361] Thalibrunine (113)[441,442] VI.

One Diphenyl Ether Linkage (Head-to-Tail) and One Diphenyl Ether Linkage (Headto-Tail) Type XX - 6,7,8\12+-6,7,8*12* Sciadoline (128)[ 198,429] Sciadoferine (217)[ 198] (R,R) Cycleanin«121)[30,32,34,92,102,104,105,131,132.141,142.147,157,158,181,182, 189-195,197,204-208] Cycleanine N-Oxide (232)[158] N-E>esmethylcycleanine (233)[34,206] Isochondodendrine(122)[ 144,146,312,141,142,201,313,189,190,175, 314,315,267,194,195,196,197,180,182,183,199.198,303,175,181, 147,130,309] (-)-Norcycleanine (125)[181,32] (S,R) Sciadenine (127)[428,198] (SfS) (+)-Norcycleanine (124)f312,141,192,195,158]

P.L.Schlff,Jr. Table 6. Continued Unknown stereochemistry Neoprotocuridine (123)[ 1 ] Protocuridine (126)[1] Type XXI - 6,7,8*,ll\12-6,r, 12* (R,R) (-)-Curine (133)[90,130,141,142,144,145,147,1 75-183,190.200-203] Cycleacurine (134)[43] 0,0-DimethyIcurine (135)[ 191,196] Isocuricycleatjenine (410)[I74] Isocuricycleatjine (411)[174] 12'-0-MethyIcurine (140)[196] (R,S) Chondocurarine (129)[140] Chondocurine (130)[141-145] (+)-Tubocurarine (142)[142,145,470] (-)-Tubocurine (144)[201] Nor-Nb-Chondrocurine (230)[145] (S,R) Curicycleatjenine (400)[174] Curicycleatjine (401)[ 174] Hayatidine(136)[190] (-)-Tubocurarine (143)[200] (S,S) Chondrofoline (131)[147,148,175] (+)-Curine (132)[146,175-178] 4"-0-Methylcurine (139)[ 175,203] Racemate

(+/-)-Curine dimethiodide (132)[476] Unknown stereochemistry Hayatine (137)[ 144,175,190,202] Hayatinine (138)[ 190,202] Mixture Toxicoferine (141)[201 ] -1:1 mixture of (-)-Curine (133) and (-)-Tubocurinc (144)

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

161

Table 6. Continued VII.

Two Diphenyl Ether Linkages (Head-to-Head) and One Diphenyl Linkage (Tail-toTail) Type XVIII - 6,7\8M2-6\7 + ,l 2(11-11) Secolucidine(393)[117J (R,S) Dinklacorine (114)[256-258] Nortiliacorine A (115)[385,391] Tiliacorine(118)[257,391,393,397,398] (S,R) Medelline (318)[348] (S,S) Nortiliacorinine A (116)[257,275,391-398] Nortiliacorinine B (117)[393] Pachyovatamine (250)[357] Tiliacorinine(119)[275,393,396-398] Tiliacorinine-2'-N-Oxide (254)[385] Yanangcorinine (388)[398] Type XIX - 5,6,7\8\12-6\7\12(11-11) (R,S) Norisoyanangine (335)[385] (S,S) N-Methyltiliamosine (323)[381,382] Ti!iamosine(120)[356,357,382,392] Noryanangine (346)[385] Tilianangine (386)[257] Yanangine (389)[258] Unknown stereochemistry N-Methylpachygonamine (243)[356,357] Pachygonamine (249)[356,357] Type XlXa - 5,7\8M2-6\7%12(11-11) Tiliaresine (429)[382]

P.L.SchifT,Jr. Table 6. Continued VIII. One Diphenyl Ether Linkage (Head-to-Tail) and One Benzylphenyl Ether Linkage (Head-to-Tail) Type XXII - 6,7\8,12+-6,7,8*[7-121 Cissampareine (145)[149] Dimethylwarifteine (148)[251] Methylwarifteine (150)[251] Warifteine(151)[251] Dihydrowarifteine (146)[251] Dimethyldihydrowarifteine (147)[251 ] Methyldihyhdrowarifteine (149)[251 ] (R,R) (-)-Cycleaneonine (403)[188] Isocycleaneonine (412)[188] Unknown stereochemistry (+)-Cycleaneonine (286)[ 187,188] Type XXIIa - 6,7,8,11 \12-6,7\12[7-121 Cycleatjehenine (404)[211,212] Cycleatjehine(405)[211] Unknown stereochemistry Cissampentin (395)[150] IX.

Two Diphenyl Ether Linkages (Head-to-Head) and One Diphenyl Ether Linkage (Tail-to-Tail) Type XXIII - 6\7\ll",12-6 f 7\8\12~ Trigilletimine (162)[ 167,468] 1,2-Dehydromicranthine (154)[234]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

163

Table 6. Continued

(-,S) 1,2-DehydroapateIine (193)[11-13,28,34,139.154] 1.2-Dehydro-2'-Nortelobine (292)[233] 1,2-Dehydrotelobine (194)[ 11 -13,16,135,154,235] Gilgitine (261)[68] Kurramine(237)[139] O-Methyldeoxopunjabine (263)[248] O-Methylpunjabine (264)[248,358] Punjabine (265)[68] Secojollyanine (433)[358] (R,R) N,0-Dimethylmicranthine (156)[234,255] 0-Methylmicranthine(158)[234,255] Micranthine (159)[27,234,255] (*,S) Apateline(l87)[9-13] N-Methylapateline (207)[336] N-Methylnorapateline (208)[336] 2-N-Methyltelobine (418)[135] Telobine(160)[l 1,119,255] (S,S) Cocsoline(152)[9,10,16,139,153-158] Cocsoline-2'P-N-Oxide (398)[159] Cocsuline(153)[7,9,10,16,139,153,155-158.160.161.165-170] Cocsuline-N-2-Oxide (231)[171] 12-O-Demethyltrilobine (155)[165](designated by the nortrilobine)[153] Isotriiobine(157)[7,13,16,139,153.216,235.329-335] O-Methylcocsoline (239)[ 10,13,16] 12-0-MethylcocsoIine-2'-P-N-Oxide (4I4)[159] 12-O-Methyltricordatine (419)[7] 2'-Norcocsoline (421)[159] 2'-Norcocsuline (329)[7,10] Nortrilobine (247)[399] Tricordatine (161)[7,139,169] Trilobine(163)[ 153,154,165,216,235,329-333,399,469]

authors

as

1^4

P.L. Schiff, Table 6. Continued Type XXIIIa - 5,6/7\8M2~-6\7M 1~,12 1,2-Dehydrokohatamine (289)[233] 1,2-Dehydrokohatine (290)[233] Siddiquamine (371)[233] Siddiquine (372)[233] (S,R) 5-Hydroxyapateline (309)[233] 5-Hydroxytelobine (310)[233] (S,S) Kohatamine (314)[233] Kohatine (236)[ 139,233] Type XXIV - 6,7\8\11~,12-6,7\8\12~ Menisarine (165)[332,349] Normenisarine (166)[216] (5,5) Cocsiline(396)[153] Cocsilinine(397)[153] Cocsulinine(164)[153,156] Gilletine(202)[280,281] O-Methylcocsulinine (415)[153] N-Norcocsulinine (422)[153] Unknown stereochemistry Isogilletine-N-Oxide (204)[281] Pendilinine(425)[153] Type XXVHI - 6 , 7 # f 8 \ l l 4 M M V \ 1 2 ~ (SfS) Angchibangkine (394)[7]

X.

One Diphenyl Ether Linkage plus One Benzyl Phenyl Ether Linkage (Head-to-Head) and One Diphenyl Ether Linkage (Tail-to-Tail) Type XXV - 6,7,8\H\12,13-6,7\12*[8-61 Unknown Pseudorepanduline (167)[234] Repanduline (168)[27,426]

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

165

Table 6. Continued XI.

One Diphenyl Ether Linkage plus One Benzyl Phenyl Ether Linkage (Head-to-Tail) and One Diphenyl Ether Linkage (Head-to-Tail) Type XXVI - 6,7,8\12+-6,7,8M2*|11-7| (RfR) Insulanoiine (169)[ 192,252,308,309] Insularine (170)[ 182,189.192,252,308,310] Insularine-2P-N-Oxide (408)[252] Insularine-2'P-N-Oxide(409)[252]

XII.

Undetermined Structure Dinklageine (172)[259] Himanthine(173)[81] Isochondocurarine (174)[311] (+)-Neochondocurarine (175)[311] Ocodemerine (176)[236] Otocamine (177)[236] Pendine(178)[153,156] Pendulinine(179)[153,156] Protochondocurarine (180)[311] Pycnarrhenamine (181)[100] Pycnarrhenine (182)[100] Tiliacoridine(183)[464] Tiliandrine (184)[314] Tiliarine (185)[395,467] Tomentocurine (186)[141]

8.

ALKALOIDS WITH DUPLICATIVE OR ERRONEOUS NOMENCLATURE

It is natural that over the years, a number of alkaloids that were believed to be novel and were being reported in the literature for the first time, were in fact not so. This most commonly happened when two groups submitted manuscripts for publication at approximately the same time. It can occur for other reasons, but notwithstanding these, it is important to include a section in this chapter dealing with duplicative or erroneous nomenclature. The following table and paragraphs are an attempt to summarize those alkaloids that have been subject to some confusion in nomenclature.

166

P.L. SchifT,Jr. Table 7: Alkaloids with Duplicative Nomenclature

Alkaloid First Literature Citation (Year)

Alkaloid Subsequent Literature Citation(s) (Year)

Aromoline (31)[478](1949)

Thalicrine (31)[40,471](1963)

Hernandezine (81)[293](1962)

Thalicsimine (Thaliximine) (81)[284,285] (1964)

Cocsuline(153)[166](1970)

Efirine (153)[170](1973), Trigilletine [169](153)(1973), N-Methyl-12'-0Desmethyltrilobine (153)[ 165]( 1972)

12-O-Demethyltrilobine (155) [165](1972)

2'-Norcocsuline (329)[10](1987)

Cycleapeltine (36)[43](1973)

Faralaotrine (36)[209](1975)

Guattegaumerine (234)[254] (September, 1983)(received November 15, 1982)

N,N'-Dimethyllindoldhamine (234)[231 ] (September, 1983Xreceived January 16, 1983)

2'-Nordaurisoline (330)[230] (July, 1987)(revised received October 1, 1986)

Pampulhamine (352)[279](September, 1987) (received March 16, 1987)

Dehatridine (287)[232](February, 1989)(received February 16,1988)

Stepierrine (376)[34](July, 1989) (received October 10, 1988)

Thalisopine (54) was first isolated from Thalictrum isopyroides C.A.M. (Ranunculaceae) in 1961 [471,482]. Some five years later, a detailed spectral analysis of the alkaloid resulted in its structural assignment as 54 [471]. However, it was not until 1978 that the structure of thalisopine was settled with certainity. At that time, extracts of Thalictrum rugosum Ait. (Ranunculaceae) furnished an alkaloid that was named thaligosine, but was later found to be identical with thalisopine [471]. It is therefore logical that the earlier name of thalisopine take precedent over thaligosine.

The bisbenzylisoquinoline Alkaloids - A Tabular Review

167

O-Methylthalicberine (95) was first isolated from Thalictrum thunbergii DC. [also known as T minus var. hypolecum (Ranunculaceae)] in 1959 [378] and its structure determined in the next decade [471]. The alkaloid thalmidine (95), first isolated from Thalictrum minus L. (Ranunculaceae) in 1950 [366] and later in 1956 [367], was shown to be identical with Omethylthalicberine in 1965 [479,480]. When the structure of thalicrine (31)[40,471] was revised to that of the hitherto known aromoline (31)[478], this resulted in the reassignment of homothalicrine (42) as homoaromoline (42)[40,41]. Homothalicrine had first been isolated in 1962 [40]. Thalrugosamine (42) was isolated in 1972, but a reevaluation of its structural assignment in 1984 demonstrated that thalrugosamine was identical with homoaromoline (42)[38]. Thalfoetidine (99) wasfirstisolated from Thalictrum foetidum L. (Ranunculaceae) in 1966 [108,481]. An alkaloid first named thalictrinine was isolated from Thalictrum longipedunculatum E. Nik. (Ranunculaceae) in 1968, but was later found to be identical with thalifoetidine (99)[471]. It is particularly important that this distinction be understood, because an alkaloid designated thalictrinine (220), and of different structure, was isolated from Thalictrum rochebrunianum Franc, and Sav. in 1980 [250]. Thalisamine was first isolated from Thalictrum simplex L. (Ranunculaceae) in 1967, and assigned as N-norhernandezine [296]. It was not until 1984 that Guinaudeau et al. [38] called attention to the close resemblance between thalisamine and N'-norhernandezine (212), the latter being isolated from Thalictrum rochebrunianum Franc, and Sav. in 1980 [250]. It was eventually concluded that the two alkaloids were identical. When the structure of cissampareine (145) was verified by X-ray crystallographic determination in 1978 [477], it was established that the compound known as methylwarifteine (150) was actually cissampareine. Finally, it should be noted that the prefix "nor-" has been erroneously used on several occasions. This prefix is traditionally employed in alkaloid chemistry to designate a lower homologue differing from the parent alkaloid in the loss of a N-methyl group ("N ohne Radikal")[184]. Within the bisbenzylisoquinoline alkaloid series, this prefix almost always suggests the loss of a N-methyl group from Ring B or Ring B\ with the generation of a secondary amine function (R,NH). However, this prefix has also been used to designated the loss of an O-methyl group (with a phenol usually resulting). There are no less than forty-six bisbenzylisoquinoline alkaloids that employ the prefix "nor-" (see Table 1). Five of these alkaloids use the prefix "nor-" to designate the loss of a methyl function from a methoxy group, thereby leaving a phenol. These five alkaloids are: (+)-norcycleanine (124), (-)-norcycleanine (125), normenisarine (166), (+)-nortenuipine (88), and (-)-nortenuipine (89).

168 9.

P.L.Schiff,Jr. AN ANALYSIS OF THE DISTRIBUTION OF THE BISBENZYLISOQUINOLINE ALKALOIDS BY STRUCTURAL TYPE

It is appropriate to present a few qualifying statements that pertain to the nomenclature used in the following analysis. First, when the terms "head" and "tail" are used, they refer to the isoquinoline portion and the benzyl portion, respectively, of the benzylisoquinoline ring. Second, the paired chiral centers that are designated refer to the C(l) and C(l') carbon atoms, respectively. Third, if in place of the term "JT or "5" when designating these centers there is a "-", then this indicates that the chirality of the carbon atom involved has been lost (likely due to the formation of an imine bond). Fourth, as stated in the Introduction, the alkaloids have been drawn such that the Ring C terminus of the diphenyl ether bridge between Ring C and Ring C is always at C-12'. In addition, the alkaloid numbering system and structural-type nomenclature generally follow those of earlier reviews in this series [1-5]. Fifth, there are very few references that are included as citations in the following analysis, because all of the conclusions presented have been drawn from the fully referenced tables in this chapter. Finally, the analysis that follows is consistent with the order in which the bisbenzylisoquinoline alkaloids are described by structural type in Table 6.

9.1.

One Diphenyl Ether Linkage (Tail-to-Tail)

The alkaloids of Types I, la, lb, II, Ila, lib, and III contain one diphenyl ether linkage and are linked tail-to-tail. There are no alkaloids in this group that are imines, with only a few secondary amines being found. 9.1.1. Type I (6,7,11\12-6,7,12#) (R,R) Alkaloids The largest subgroup (26 alkaloids) within Type I are those alkaloids with R,R stereochemistry at the C( 1) and C( 1') carbon atoms, respectively. There are seventeen alkaloids that are bis N-methyl compounds within this group. One of these alkaloids [O-Methyldauricine (12a)] is fully methylated at the available ether oxygen atoms [C(6), C(7), C(12), C(6'), C-(7')], while six of the alkaloids are monophenolic, seven are biphenolic, and three are triphenolic. The most common position that contains a phenolic group is C(12)(eight alkaloids), while the least common is C(6')(four alkaloids). There are three alkaloids that are secondary amines at N(2'), with each of these compounds having methoxy groups at C(6) and C(6') and phenolic hydroxy groups at C(12). Two of the three alkaloids are phenolic at C(7), while only one is phenolic at C(7'). 2'-Nordaurisoline (330) and pampulhamine (352) are identical, with both being published the same year and at about the same time [230,279]. However, since the former was received on October 1, 1986 and the latter on March 16, 1987, it is probably appropriate to use the former (2'-Nordaurisoline) as the official title of the alkaloid. There are four alkaloids that are bissecondary amines, and all of these compounds have methyl ethers at both C(6) and C(6'). Three of the alkaloids are phenolic at either C(7) or C(7'), with two of the compounds being biphenolic at these positions. It can be concluded that when bis secondary alkaloids are found within this

The Misbenzylisoquinoline Alkaloids - A tabular Kevlew

169

group, phenols when present are most commonly found at one or more of C(7)/C(7')/C(12). There are only two N-oxides within this group, and there are no alkaloids with unsaturation in the A or A' rings. The families Annonaceae (sixteen alkaloids) and Menispermaceae (fifteen alkaloids) are the most fruitful sources of these alkaloids, with the genera Popowia (ten alkaloids)(Annonaceae) and Menispermum (nine alkaloids)(Menispermaceae) being the most productive genera. The following is indicative of the distribution of alkaloids within these and other families: Annonaceae (Popowia - ten; Polyalthia - four; Cardiopetalum - one; Guatteha one); Menispermaceae (Menispermum - nine; Abuta - five; Albertisia - one; Caryomene - one); Aristolochiaceae (four)(all Aristolochia sp.); Berberidaceae (one)(Berberis sp.); Rhamnaceae (one)(Colubrina sp.).

H 3
Alkaloid

R,

E2

R3

8*

R5

Dauricine (3) 7'-0-Methylcuspidaline (240) O-Methyldauricine (12a) Popidine (363) Popisidine (364) Popisine (365)

CH3 CH3 CH3 H CH3 CH3

CH3 H CH3 CH3 CH3 CH3

H CH3 CH3 CH3 CH3 CH3

CH3 CH3 CH3 CH3 H CH3

CH3 CH3 CH3 CH3 CH3 H

P.L.Schifr,Jr.

170

.OR, H3C

.N^

WT*

s

R|0>

OR 2

R50'

"CH3

KT

^0R3 Alkaloid

R,

Cuspidaline (2) Dauricinoline (4) Daurinoline (6) Daurisoline (192) Isodaurisoline (235) Popisonine (366) Popisopine (367)

CH3 H CH3 CH, CH3 H H

&

E5

H CH3 CH3 H CH3 CH3 CH3

CH3 H H H H CH3 CH3

CH3 CH3 H CH3 CH3 H CH3

H CH3 CH3 CH3 H CH3 H

Alkaloid

E,

E2

E3

E*

E5

Dauriciline (406) Dauricoline (5) N,N'-Dimethyllindoldhamine (GuattegaumerineX234)

CH3 H CH3

H CH3 H

H H H

CH3 H CH3

H CH3 H

The Bisbeniylisoquinollne Alkaloids - A Tabular Review

H3C

H„.TR

171

.OR,

R40N

^OR2

R5O'

A "H *nH

^ORs Alkaloid

Ei

E2

£3

E«

Es

N'-Desmethyldauricine (7) Geraldoamine (301) 2'-Nordaurisoline (330) [same as Pampulhamine (352)] Pedroamine (355)

CH, CH, CH,

CH, H H

H CH, H

CH, CH, CH,

CH, CH, CH,

CH,

H

H

CH,

H

Alkaloid

R,

E2

E3

E4

E,

Costaricine (399) Lindoldhamine (11) 7-O-Methyllindoldhamine (241) T-O-Methyllindoldhamine (242)

CH, CH, CH, CH,

H H CH, H

CH, H H CH,

CH, CH, CH, CH,

H H H CH,

172

P.L.Schlff,Jr.

351

(5,5) Alkaloids There are only six alkaloids with the £,5 stereochemistry. Four of these six compounds are bis- N-methyl, while two of the alkaloids are secondary amines at N(2'). Five of the six alkaloids are monophenolic, with the sixth being triphenolic. The C(7) and C(7') positions are the most common sites for phenols, with C(12) being phenolic in only one instance. None of the alkaloids are phenolic at C(6) and C(6'). All of the alkaloids (O-Methylthalibrine (209), neothalibrine (211), northalibrine (13), northalibroline (341), and thalibrine (14) are restricted in their distribution to six species of the genus Thalictrum (Ranunculaceae).

The Bisbenzylisoquinoline Alkaloids - A Tabular Review „OCH3 H3C

H3C

CHjO^

^OR,

v

173

R 3 (T

OR2

Alkaloid

R.

E2

B3

E4

O-Methylthalibrine (209) Neothalibrine (211) Northalibrine (13) Northalilbroline (341) Thalibrine (14)

CH3 H CH3 H CH3

CH3 CH3 CH3 H CH3

CH3 CH3 H H H

CH3 CH3 H H CH3

H'

,OCH3

CH

OH

CHjO^^^

^OCH3 325

*°^^

•O^" S|'•••u

^H3

174

P.L.SchiflT,Jr.

(R,S) Alkaloids There are five alkaloids that are characterized by having R,S stereochemistry. Three of the bases are diphenolic and two are triphenolic, with each of the bases being bis N-methyl derivatives. Four of the five alkaloids are phenolic at C(7), while three of the bases are phenolic at either C(12) and/or C(7'). Only two of the alkaloids are phenolic at C(6'), and none of the compounds are phenolic at C(6). Berbamunine (1) has been isolated from thirty-one different Berbehs species (Berberidaceae), but only one Pseudoxandra species {P. sclerocarpa) (Annonaceae), and one Stephania species (5. pierr/z)(Menispermaceae). Espinidine (8) and espinine (9) have been isolated from Berberis laurina, while the latter alkaloid is also a constituent of B. chilensis. Temuconine (251) is a metabolite of only Berberis valdiviana, while thaiigrisine (252) has only been found in Pseudoxandra sclerocarpa (Annonaceae) and Thalictrum minus L. var. microphyllum (Ranunculaceae).

Alkaloid

E,

E2

E3

R«

Berbamunine (1) Espinidine (8) Espinine (9) Temuconine (251) Thaligrisine (252)

H H H CH3 H

H CH3 H H CH3

CH3 H H CH3 CH3

H CH3 CH3 H H

(S,R) Alkaloids There are four alkaloids with the S,R stereochemistry, each of which is a bis N-methyl compound with methoxy groups at both C(6) and C(6'). Three of the alkaloids are phenolic (one monophenol, one diphenol, one triphenol), with each of them being phenolic at C(7'). Two of the compounds are phenolic at C(7), while one is phenolic at C(12). 0,0'-Dimethylgrisabine (407) is only found in Phaeanthus vietnamensis (Menispermaceae), while grisabine (10) is found in Abuta grisebachii (Menispermaceae), Gyrocarpus americanus (Hernandiaceae), and Sciado tenia eichleriana (Menispermaceae). Magnoline (12) has only been isolated from Abuta grisebachii (Menispermaceae) and Magnolia fuscata (Magnoliaceae)(sometimes designated Michelia fuscata (Magnoliaceae), while 7-O-Methylgrisabine (417) is only found in Phaeanthus vietnamensis (Menispermaceae). The alkaloids of this group are mainly found in the Menispermaceae, and to lesser degrees in the Hernandiaceae and Magnoliaceae.

l hetiisbenzylisoquinolineAlkaloids - A tabular Review

175

H 3
Alkaloid

E3

0,0'-Dimetnylgrisabine (407) Grisabine (10) Magnoline (Grisabutine)(12) 7-O-MethyIgrisabine (417)

CH3 H H CH3

CH3 CH3 H CH3

CH3 H H H

9.1.2. Type la (6,7,11\12-5,6,7,12*) The three alkaloids of this type all possess the S,S stereochemistry and contain extra oxygenation at C(5'). Thaliracebine (14a), thalirugine (14b), and thaliruginine (14c) are restricted in distribution to four species and one variety of the genus Thalictrum (Ranunculaceae). Thaliracebine (14a) has been isolated from Thalictrum faberi and T minus, while thaliruginine (14c) has been found in T rugosum. Thalirugine occurs in three Thalictrum species; T cultratum, T minus var. microphyllum, and T rugosum.

14a

176

P.L.SchifT,Jr.

H3C

Alkaloid

R

Thalirugine (14b) Thaliruginine (14c)

H CH3

9.1.3. Type lb (6,7,10,H\12-6,7,12*) The sole alkaloid of this small group is chillanamine (229)(SfR) from Berberis buxifolia (Berberidaceae).

229

9.1.4. Type II (6,7,10\12,13-6,7,12-) The lone representative of this type is magnolamine (15)(5,£) from Magnolia fuscata (Magnoliaceae). Magnolamine differs from the Group I alkaloids in that magnolamine has a C(10) diphenyl ether terminus, instead of a C(ll) diphenyl ether terminus.

The Blsbenzylisoquinoline Alkaloids - A Tabular Review

177

9.1.5. Type Ha (6,7,1
9.1.6. Type lib (6,7,10\11,12-6,7,11,12*) The alkaloids of the Type lib series have oxygenation at C(l 1) instead of at C(13), as does vanuatine (255) of the Group Ha series. The only two alkaloids of the Type lib series are vateamine (256)(5,5) and vateamine-2'P-N-oxide (430) from Hernandia peltata. It is apparent that the distribution of both the Type Ha and Hb alkaloids is restricted to the genus Hernandia of the family Hernandiaceae.

178

P.L.Schiff,Jr.

430

9.1.7. Type III (5,6,7,11\12-5,6,7,12*) The alkaloids of this type are trioxygenated in both ring A and ring A'. There are five alkaloids within this group, each of which contains the S,S stereochemistry at C( 1) and C( 1'), and each of which has only been isolated from a Thalictrum species (Ranunculaceae). NDesmethylthalistyline (16) and thalistine (221) are bis-tertiary compounds, while thalirabine (17a) and thalistyline (18) are N(2) quaternary alkaloids, with N-Methylthalistyline (17) being a bisquaternary alkaloid. Extracts of both Thalictrum longistylum and T. podocarpum have furnished N-desmethylthalistyline (16), N-methylthalistyline (17), and thalistyline (18), while extracts of T. baicalense have yielded N-desmethylthalistyline (16) and thalirabine (17a). Thalirabine (17a) has been found as a constituent of T. minus, while thalistine (221) is an alkaloid of T. minus race B. It is quite evident that the alkaloids of this group are restricted in distribution to several species of the genus Thalictrum (Ranunculaceae).

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

179

Alkaloid

E

N-Desmethylthalistyline (16) Thalistine (221)

CH3 H

Alkaloid Thalirabine (17a) Thalistyline (18)

H CH,

OCH3

/ - ^

„OCH3 H3Cv H3C

+ I ^CH 3 ^OCHj

CH 3 0"

^OCH3 17

rs

CH3

180 9.2.

PL.Schiff,Jr. One Diphenyl Ether Linkage (Head-to-Tail)

The alkaloids in this group are characterized by a single diphenyl ether head-to-tail linkage. 9.2.1. Type V (6,7,11*,12-6,7\ 12) Three of the alkaloids of this type possess the R,R stereochemistry, and have only been found as metabolites of Nelumbo nucifera (Nymphaceae). Isoliensinine (28) and liensinine (29) are monophenolic, while neferine (30) is a trimethylether. Neosutchuenenine (420), an alkaloid of unknown stereochemistry, has only been found in Cyclea sutchuenensis (Menispermaceae).

Alkaloid

E,

R2

R3

Isoliensinine (28) Liensinine (29) Neferine (30)

H CH3

CH3 CH3

CH3 H

C-.H3

CH3

C-H3

9.2.2. Type Va (6,7,10\12,13-6,7\11,12) In comparison to Type V, the linkage of the alkaloid in Type Va is C(10) to C(7'), with additional oxygenation at C(13) and C(l 1'). The only alkaloid of this type is (3,5)-malekulatine (238) from Hernandia peltata and H. sonora (Hernandiaceae).

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

181

238 9.2.3. Type Vb (6,7,10\11,12,13-6,7\11,12) The two Type Vb alkaloids are both of the SfS stereochemistry and have the same linkage as the Va alkaloids, but the former have extra oxygenation at C( 11). Ambrimine (272) and efatine (296) are monophenolic in Ring C and have only been isolated from Hernandia nymphaeifolia (Hernandiaceae).

Alkaloid

R,

R2

Ambrimine (272) Efatine (296)

CH3 H

H CH3

9.2.4. Type Vc (6,7,10,12'-6,7', 12) The sole Type Vc alkaloid, sutchueneneonine (426) from Cyclea sutchuenensis (Menispermaceae), is linked from C(12) to C(7'). The stereochemistry of the chiral centers was not determined.

182

P.L. SchifT, Jr.

426

9.2.5. Type Vd (6,7,12*-6,r,8,12) The lone alkaloid from Type Vd is sutchuenenine (427) from Cyclea sutchuenensis (Menispermaceae). The stereochemistry is unknown, but the linkage is C(12) to C(7).

427

9.3.

One Diphenyl Linkage (Tail-to-Tail)

9.3.1. Type XXVII [6,7,12-6,7,12(11-11)1 These seven alkaloids are a recent and unique new group, and are characterized by having a single tail-to-tail diphenyl linkage, with no linkage in the top portion of the molecule. The alkaloids all possess the R,R stereochemistry and have only been reported to be present in one plant, Popowia pisocarpa (Annonaceae). Each of the alkaloids has two structural features in common; the presence of a N(2) methyl group and the presence of C(7) and C(7') methoxy groups. Two of the alkaloids, pisopowamine (357) and 2'-norpisopowiaridine (339), are secondary amines at N(2'). The alkaloids of this type differ by the number of phenolic hydroxy

183

The Bisbenzylisoqulnollne Alkaloids - A 1 abular Keview

groups and methoxy groups at positions C(6), C(12), C(6'), and C(12'), with pisopowine (362) being the fully methylated analog. Pisopowidine (361) is monophenolic at C(6), while pisopowiarine (360), pisopowetine (358), and pisopowamine (357) are biphenolic. Pisopowiaridine (359) and 2'-norpisopowiaridine (339) are triphenolic. The distribution of this new group of alkaloids is restricted, for the time being, to the genus Popowia of the family Annonaceae.

Alkaloid

E,

Pisopowiaridine (359) Pisopowiarine (360) Pisopowidine (361) Pisopowine (362)

H H H CH3

358

& H H CH3 CHj

H CH3 CH, CH3

184

P.L.Schiff,Jr.

Alkaloid 2'-Norpisopowiaridine (339) Pisopowamine (357)

9.4.

H CH3

R2

R3

CH3 H

H CH3

One Diphenyl Ether Linkage (Head-to-Head) and One Diphenyl Linkage (Tail-toTail)

9.4.1. Type IV (6,7,8\12-6,7\12(11-11)| The alkaloids in Type IV contain one diphenyl ether linkage and one diphenyl linkage, the former joining the rings head-to-head and the latter linking the rings tail-to-tail. Unlike the alkaloids in Types 1 through III, there are alkaloids in Type IV that are imines, thereby resulting in only one chiral carbon in these molecules. (/?,-) Alkaloid The imine cordobimine (283) has been isolated from Crematosperma sp. (Annonaceae), and is the only alkaloid of Group IV with singular chirality at C(l).

CH 3 '

The Blsbenzylisoquinoline Alkaloids - A Tabular Keview

\%$

(S,-) Alkaloids There are three alkaloids that constitute this small group. Guattamine (303) and guattaminone (304) are imine alkaloids isolated from Guatteha guianensis (Annonaceae), while secantioquine (267) is a seco- alkaloid isolated from Pseudoxandra aff. lucida (Annonaceae). Each of the three alkaloids is methoxylated at C(6) and C(6)\ with variations in numbers of methoxy or hydroxy groups at C(7), C(12), and C(12'). The imine alkaloids in Group IV appear to be restricted to a few genera of the Family Annonaceae.

186

P.L.Schiff,Jr.

(S,S) Alkaloids There are seven alkaloids in this group, including four which are compounds that possess a carbonyl function at the benzyl carbon of the benzylisoquinolne ring. Each of these seven alkaloids is methoxylated at both the C(6) and C(6') positions, with four of the seven compounds being characterized by C(12) hydroxy/C( 12') methoxy functions, and the other three alkaloids having C(12) methoxy/C(12') hydroxy groups. In those alkaloids bearing the C(a)-keto group, the aromatic ring containing this group is the likely site of hydroxylation at C(12), if hydroxylation occurs at all. Restating this in another fashion, the monomer that does not bear the carbonyl function will contain a benzyl ring in which C(12) is methoxylated. Six of the seven alkaloids of this small subgroup have been isolated from species of just two genera (Guatteria and Pseudoxandra) of the Family Annonaceae, while ocotine (23) has only been found in Nectandra rodiei (Lauraceae). Oxandrine (347) and oxandrinine (348) are characterized by the presence of a C(a') keto group, while pseudoxandrine (368) and pseudoxandrinine (369) contain a C(a) keto group. These four alkaloids have only been isolated from Pseudoxandra aff. lucida (Annonaceae). The last two alkaloids of this group are 2,2'-bisnorguattaguianine (276) and 2'-norguattaguianine (332), alkaloids that occur only in Guatteria guianensis (Annonaceae). With the exception of ocotine (23), the alkaloids of this subgroup are currently restricted in distribution to just two genera of the Annonaceae.

Alkaloid

R

Oxandrine (347) Oxandrinine (348)

H CH3

Alkaloid

E

Pseudoxandrine (368) Pseudoxandrinine (369)

H CH3

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

18/

Alkaloid

R,

R2

R3

2,2'-Bisnorguattaguianine (276) 2'-Norguattaguianine (332) Ocotine(23)

H CH3 CH3

H H CH3

CH3 CH3 H

{R,S) Alkaloids The three alkaloids of this subgroup are methoxylated at C(6), C(12), and C(6'), with two of the three compounds being phenolic at C(7). Cordobine (284), granjine (302), and monterine (324) were isolated from Crematospserma sp. (Annonaceae). Just as in the subgroups immediately preceding, the distribution of the alkaloids in this subgroup is restricted to the Annonaceae.

Cordobine (284) Granjine (302) Monterine (324)

H CH3 H

H CH3 CH3

188

P.L.SchifT,Jr.

{S,R) Alkaloids There are eleven alkaloids in this group, two of which are an oxide and the methoquaternary of funiferine (20), while a third alkaloid [norrodiasine (22)] is of incompletely determined structure. With the exception of phlebicine (25), all of these alkaloids are methoxylated at both C(6) and C(6)' [phlebicine is phenolic at C(6)'], while three are secondary at N(2'). The C(12) position is phenolic in six of the eleven alkaloids, with the other five compounds being phenolic at C(12'). There are no bisphenols at the C(12) and C(12') positions. These alkaloids occur in only five genera of three families; Pseudoxandra, Guatteria and Crematosperma of the Annonaceae; Tiliacora of the Menispermaceae; and Nectandra of the Lauraceae. There are four funiferine (20) analogs: funiferine (20) from Guatteria guianensis, Tiliacora dinklagei, and T funifera; 2'-norfuniferine (331) from Guatteria guianensis; funifierineN-oxide (21) from Tiliacora funifera; and funiferine dimethiodide (201) from T. funifera. Tiliageine (27) and 2'-nortiliageine (345) have been isolated from Guatteria guianensis, while tiliageine has also been found in Tiliacora dinklagei and Tiliacora triandra. Rodiasine (26) and norrodiasine (22) are metabolites of Nectandra rodiei, but the structure of norrodiasine is not fully known, as the position of the single N-methyl function has not been determined with certainty. The remaining alkaloids are antioquine (225) from Pseudoxandra aff. lucida, phlebicine (25) from Crematosperma polyphlebum, and tilitriandrine (387) from Tiliacora triandra.

Alkaloid

R,

E2

R3

R4

Rs

Antioquine (225) Funiferine (20) 2'-Norfuniferine (331) 2'-Nortiliageine (345) Phlebicine (25) Rodiasine (26) Tiliageine (27) Tilitriandrine (387)

H CH3 CH3 H CH3 CH3 H H

CH3 H H H CH3 CH3 H CH3

CH3 CH3 CH3 CH3 H CH3 CH3 H

H CH3 CH3 CH3 H H CH3 H

CH3 CH3 H H CH3 CH3 CH3 H

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

TH,

.CH3 TH3

Alkaloids of Unknown Structure There are two alkaloids of this type with unknown stereochemistry. One of the compounds, ocotosine (24) from Nectandra rodiei (Lauraceae), bears an imine function at N(2'). The structure of dirosine (19) was not determined with certainty, but it is thought to be an isomer of norrodiasine.

190

P.L.Schiff,Jr.

9.5.

One Diphenyl Ether Linkage (Head-to-Head) and One Diphenyl Ether Linkage (Tailto-Tail)

9.5.1. Type VI (6,7*, 11+, 12-6,7,8*, 12+) (-,-) Alkaloids Stebisimine (51) is a bisimino alkaloid that has been isolated entirely from genera of the Menispermaceae, including Anisocycla gradidieri, Cocculus japonica, Stephania japonica, Stephania japonica var. australis, and Thclisia gilletii. Stephasubimine (373), a partially oxidized ring B (imino) and a fully oxidized ring B' (I',2',3',4'-dehydro) alkaloid, has only been found in Stephania suberosa (Menispermaceae). There are but two bisimino alkaloids, and both have only been isolated from a combined total of four genera of the Menispermaceae.

373

191

The Bisbenzylisoquinoline Alkaloids - A Tabular Review (/?,-) Alkaloids

There are four alkaloids that are imino alkaloids in ring B' (that is 3,4dihydroisoquinolines): 3\4'-dihydrostephasubine (295) from Stephania hernandifolia (Menispermaceae), (-)-epistephanine (41) from Anisocycla gradidieri (Menispermaceae), hypoepistephanine (43) from Stephaniajaponica (Menispermaceae), and pangkorimine (354) from Albertisia papuana (Menispermaceae). These alkaloids differ in their phenolic nature at C(12) or C(7'), and one is a secondary amine at N(2). All three are methoxylated at C(6) and C(6'). These alkaloids are found in only three genera of the family Menispermaceae. There are four alkaloids that are fully oxygenated in ring B' (true isoquinolines): norstephasubine (340) from Stephania suberosa (Menispermaceae), pycnazanthine (370) from Pycnarrhena ozantha (Menispermaceae), stephasubine (374) from Stephania suberosa (Menispermaceae), and colorflammine (219) from Pycnarrhena longifolia (Menispermaceae). Each of these alkaloids is phenolic at C(7r) and varies in its phenolic nature at C(12). Pycnazanthine (370) is a norcompound at N(2), and colorflammine (219) is quaternary in ring B\ All four of these alkaloids are from two plants of the family Menispermaceae. „OCH3

CHaO,

Alkaloid 3',4'-Dihyhdrostephasubine (295) (-)-Epistephanine (41) Hypoepistephanine (43) Pangkorimine (354)

„OCH3

CH3 CH3

CHj

CHJ

H H

H

CH3ON

^OCH3 219

CHJ

H CHj CHJ

H

192

P.L.SchilT,Jr.

Alkaloid

R,

R2

Norstephasubine (340) Pycnazanthinc (370) Stephasubine (374)

H H CH3

CH3 H CH3

(-J?) Alkaloids There are three alkaloids in this group, two of which are the secobisbenzylisoquinolines auroramine (390) and maroumine (391). These two bases, that have only been found as metabolites of Gyrocarpus americanus (Hernandiaceae), differ only in the nature of their C(6') groups, with the former being a methoxy while the latter is a hydroxy. The remaining alkaloid is 1.2-dehydro-2-norlimacusine (291) from Caryomene olivascens (Menispermaceae).

Alkaloid

£

Auroramine (390) Maroumine (391)

CH3 H

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

193

291

(5,-) Alkaloids There are but two alkaloids in this small group, (+)-epistephanine (40) from three species (capitata, hernandifolia, and japonica) and one variety of these species (japonica var. australis) of Stephania (Menispermaceae), and oxoepistephanine (47a) from Stephania hernandifolia (Menispermaceae). The two compounds differ only in the presence of the carbonyl function at the a' carbon in oxoepistephanine. These alkaloids appear to be restricted in distribution to Stephania species.

47a

194

P.L.SchifT,Jr.

(-yS) Alkaloids There are seven alkaloids in this group, and these compounds may be combined into three smaller subgroups. One of these three subgroups is composed of two imino alkaloids: coclobine (35) from Anisocycla cymosa (Menispermaceae), Cocculus trilobus (Menispermaceae), and Guatteria guianensis (Annonaceae); and 12-O-demethylcoclobine (293) from Guatteria guianensis (Annonaceae). These two alkaloids differ in the constituent at C(12), with coclobine (35) being a methyl ether, while 12-O-demethylcoclobine (293) is phenolic.

Alkaloid

R

Coclobine (35) 12-O-Demethylcoclobine (293)

CH3 H

A second of the three subgroups is made up of three secobisbenzylisoquinoline alkaloids: baluchisanamine (257) from Berberis baluchistanica (Berberidaceae), secohomoaromoline (432) from Anisocycla jolly ana (Menispermaceae), and seco-obaberine (269) from Pseudoxandra aff. lucida (Annonaceae). Only the nature of the groups at C(12) and C(7f) differ in these three compounds, with some being phenolic and some being methyl ethers.

AMQJ4

E.

£2

Baluchistanamine (257) Secohomoaromoline (432) Seco-obaberine (269)

H CH3 CH3

CH3 H CH3

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

195

The third of the three subgroups is composed of two cepharanthine derivatives, dihydrosecocepharanthine (260) and secocepharanthine (268), both constituents of Stephania sasakii (Menispermaceae). The two alkaloids differ in the degree of oxidation of their side chain; formyl in secocepharanthine and hydroxymethyl in dihydrosecocepharanthine.

Alkaloid

R

Dihydrosecocepharanthine (260) Secocepharanthine (268)

CH2OH CHO

(R,R) Alkaloids There is one major structural group with seven alkaloids therein. These alkaloids differ according to the number of phenolic hydroxy and methoxy groups at C(12), C(6'), and C(7'). C(7') is more consistently phenolic (four of the six alkaloids), while C(12) and C(6') are more consistently substituted with methoxy groups (four-to-five of the six alkaloids). Other differences among these six alkaloids include one bis-secondary alkaloid [pangkoramine (353) from Albertisia papuana (Menispermaceae)] and one mono-secondary alkaloid [2-norlimacusine (245) from Caryomene olivascens (Menispermaceae)]. The remaining 4 alkaloids are candicusine (280) from Curarea candicans (Menispermaceae); gyrocarpusine (307) from Gyrocarpus amehcanus (Hernandiaceae); limacusine (44) from Curarea candicans (Menispermaceae), Limacia cuspidata (Menispermaceae), and Limacia oblonga (Menispermaceae); and O-methyllimacusine (320) from Gyrocarpus americanus (Hernandiaceae). These six alkaloids are distributed among one genus of the Hernandiaceae and two genera of the Menispermaceae. Finally, the one N-oxide alkaloid found in this group is limacusine-2'p-N-oxide (413) from Anisocycla joilyana (Menispermaceae).

196

P.L.SchifT,Jr.

Alkaloid

Ei

E2

Ej

Candicusine (280) Gyrocarpusine (307) Limacusine (44) O-Methyllimacusine (320)

H CH3 CH3 CH3

CH3 H CH3 CH3

H CH3 H CH3

W

H,C

^2

Alkaloid

E,

E2

2-Norlimacusine (245) Pangkoramine (353)

CH3 H

CH3 H

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

197

(R,S) Alkaloids There are two major structural groupings, each with corresponding N-oxides, that contain these twenty alkaloids. The first grouping contains twelve alkaloids, with the one common structural feature associated with all of these alkaloids being the presence of a C-6 methoxy group. Six of these alkaloids are bis N-methyl compounds; five are mono N(Me)/mono N(H) [three of these are secondary at N(2) and two are secondary at N(2')]; one is a bis secondary amine. The most consistently phenolic carbon atom is C(12)(seven alkaloids), followed by C(7)(five alkaloids) and C(6')(two alkaloids). There are four bisphenols, with three of these being bisphenolic at C-12 and C-7', and only one bisphenolic at C-12 and C-6'. The following families serve as rich sources of these alkaloids: Annonaceae, Berberidaceae, Menispermaceae, and Ranunculaceae. Aromoline (31) has been isolated from twenty-nine different species within ten genera. Those genera from within the Berberidaceae that contain species that furnish aromoline include Berberis (twelve species) and Mahonia aquifolium, while those from within the Menispermaceae include Abuta splendida, Albertisia laurifolia, Albertisia papuana, Stephania cepharantha, Stephaniapierrii, and Triclisia patens. Genera from within the Ranunculaceae include Thalictrum (six species); those from within the Monimiaceae include Daphnandra aromatica, Daphnandra tenuipes, and Doryphora aromatica; and those from within the Annonaceae include Guatteria guianensis. Baluchistine (188) has only been isolated from Berberis baluchistanica (Berberidaceae), while N,N'-Bisnoraromoline (32) has been isolated from three genera of the Menispermaceae including: Albertisia papauna, Pachygone loyaltiensis, and Pycnarrhena longifolia. Daphnandrine (37) has been isolated from five genera of the Menispermaceae including Albertisia, Anisocycla, Cyclea, Pachygone, and Stephania; two genera of the Monimiaceae (Daphnandra and Doryphora); and the genus Guatteria of the Annonaceae. Daphnoline (38) has been isolated from four genera of the Menispermaceae, including Albertisia, Cocculus, Pachygone, and Pycnarrhena; two genera of the Monimiaceae (Daphnandra and Doryphora); and the genus Guatteria of the Annonaceae. Homoaromoline (42) has been isolated from eight genera of the Menispermaceae, including Abuta, Albertisia, Anisocycla, Arcangelisia, Cylcea, Limaciopsis, Pycnarrhena, and Stephania. In addition, homoaromoline has been isolated from one genus of each of the following families: Annonaceae (Pseudoxandra), Berberidaceae (Berberis), Monimiaceae (Doryphora), and Ranunculaceae (Thalictrum). 2'-Norobaberine (337) has only been isolated from Stephania pierrii (Menispermaceae), while 2'-norobaberine-2'P-Noxide (424) has only been isolated from Anisocycla cymosa (Menispermaceae). 2'Noroxyacanthine (338) is only a metabolite of Thalictrum cultratum (Ranunculaceae). Obaberine (46) has been isolated from three genera of the Menispermaceae (Albertisia, Pycnarrhena, Stephania), two genera of the Berberidaceae (Berberis and Mahonia), and one genus from each of the following families: Lauraceae (Dehaasia), Monimiaceae (Laurelia), Annonaceae (Pseudoxandra), and Ranunculaceae (Thalictrum). Oxyacanthine (48) has been isolated from two genera of the following families: Menispermaceae (Albertisia, Cocculus), Berberidaceae (Berberis [twenty-one species], Mahonia [eleven species], and Ranunculaceae (Thalictrum [four species], Xanthorrhiza). The alkaloid has been isolated from a single genus of the following families: Lauraceae (Dehaasia), Monimiaceae (Laurelia), and Magnoliaceae (Magnolia). Seeperine (50) has only been isolated from one plant, Nectandra rodiei (Lauraceae), while stephibaberine (375)

198

P.L.Schlff,Jr.

has just been isolated from two Stephania species, S. erecta and S. pierrii. Only one N-oxide has been isolated from this large subgroup, 2-norobaberine-2'p-N-Oxide (424) from Anisocycla cymosa (Menispermaceae).

Alkaloid

E,

E2

E3

Aromoline (31) Baluchistine (188) Homoaromoline (42) Obaberine (46) Oxyacanthine (48) Stephibaberine (375)

H H CH3 CH3 H CH3

CH3 H CH3 CH3 CH3 H

H CH3 H CH3 CH3 CH3

^5

Alkaloid

Ei

E2

E3

N,N'-Bisnoraromoline (32) Daphnandrine (37) Daphnoline (38) 2'-Norobaberine (337) 2'-Noroxyacanthine (338) Sepeerine (50)

H H H CH3 CH3 H

H CH3 H CH3 H H

CH3 CH3 CH3 CH3 CH3 CH3

E5 H H H CH3 CH3 CH3

H CH3 CH3 H H CH3

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

199

W

424 The second major grouping of R,S alkaloids includes six alkaloids that bear a C(6')/C(7') methylenedioxy function and a C(6) methoxy group, and only occur in the genus Stephania (Menispermaceae). These compounds differ among each other as to whether they are mono- or bis-secondary amines, and whether they are phenolic at C(12). Cepharanoline (33) has been isolated from twc species of the genus Stephania, S. cepharantha and S. epigeae, while cepharanthine (34) has been isolated from seven species of the same genus, including S. cepharantha, S. epigeae, S. erecta, S. pierrii, S. sasakii. S. sinica, and S. suberosa. 2Norcepharanoline (326) has only been isolated from Stephania pierrii. 2-Norcepharanthine (327) has been isolated from Stephania erecta and S. suberosa, while 2'-Norcepharanthine (328) is only a metabolite of Stephania pierrii. Cepharanthine-2'P-N-Oxide (282) has only been found in Stephania suberosa.

Alkaloid

Ki

&

E3

Cepharanoline (33) Cepharanthine (34) 2-Norcepharanoline (326) 2-Norcepharanthine (327) 2'-Norcepharanthine (328)

CH, CH, H H CH,

H CH, H CH, CH,

CH, CH, CH, CH, H

200

P.L.SchifT,Jr. „OCH 3

282

(S,S) Alkaloids There are two small subgroups that contain alkaloids of the S,S stereochemistry. One subgroup contains five alkaloids, each of which bears a N(2') methyl group and a C(6) methoxy group. Four of these alkaloids are monophenolic, while the fifth is fully methylated at all of the ether oxygen atoms [O-methylrepandine (45)]. One of the alkaloids is secondary at N(2)[demerarine (39)]. Cycleapeltine (36) has been isolated from Colubrina faralaotra (Rhamnaceae) and from Cyclea barbata and Cyclea peltata (Menispermaceae), while demerarine (39), the epimer of seeperine, has only been isolated from Nectandra rodiei (Ocotea ro^/ez)(Lauraceae). Johnsonine (206) has only been found in Daphnandra johnsonii (Monimiaceae), while O-Methylrepandine (45), the epimer of obaberine, has been isolated from Daphnandra dielsii, D. johnsonii, D. repandula (all Monimiaceae) and Isopyrum thalictroides (Ranunculaceae). Repandine (49), the epimer of oxyacanthine, has been isolated from Cyclea barbata (Menispermaceae), Daphnandra johnsonii, D. repandula (Monimiaceae).

V

Mkatpid

Ri

R2

E3

E4

Cycleapeltine (36) Demerarine (39) Johnsonine (206) O-Methylrepandine (45) Repandine (49)

CH 3 H CH 3 OH 3 CH 3

CH 3 H CH 3 CH 3 H

CH 3 CH 3 H C^H3 CH 3

H CH 3 CH 3 C^H3 CH 3

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

201

The second subgroup has only one alkaloid, a cepharanthine epimer, 2-norisocepharanthine (333), an alkaloid of Stephania pierii (Menispermaceae).

333

(S,R) Alkaloids Each of the four alkaloids in this small group is a bis N-methyl compound with a C(6) methoxy group. The alkaloids differ by the presence of one or more phenolic hydroxy groups at C(12), C(6'), and C(7'). Gyrolidine (308) and gyrocarpine (306) have only been found in Gyrocarpus amehcanus (Hernandiaceae), while macolidine (44a) [an enantiomer of aromoline (31)] and macoline (44b) [a monoquaternary salt of macolidine (44a)] have only been isolated from Abuta grisebachii (Menispermaceae).

Alkaloid

E,

E2

R3

Gyrolidine (308) Gyrocarpine (306) Macolidine (44a)

CH3 CH3 H

CH3 H CH3

CH3 CH3 H

202

P.L.Schifr,Jr.

44b Unknown Oblongamine (47) is a N(2') monoquaternary analog of an oxyacanthine (48)-like substituted [C(12) is phenolic] compound. The stereochemistry is unknown. Oblongamine has been isolated from Berberis oblonga (Berberidaceae). ,OCH 3

CH 3 0 >

47

9.5.2. Type Via (6,7\10,H\12-6,7,8\12*) There is only one alkaloid in this group, (S,/?)-osornine (248), from Berberis bwcifolia (Berberidaceae). The substitution in Ring C is unusual due to the presence of C(10) oxygenation.

v

OCH 3 248

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

203

9.5.3. Type VII (6,7\11\12-5,6,7,8\12 + ) There are three parent alkaloids in this group, thalisopine (54)(thaligosine), thalisopidine (53) and thalrugosaminine (55), as well as the 2o>N-oxides of thalisopine and thalrugosaminine. The three parent alkaloids share the following characteristics: bis N-methylation, methoxylation at C(6), C(6), and C(7'). The compounds differ only in their potential phenolic nature at C(12) and C(5'). The five alkaloids of this group bear the 5,5 stereochemistry at their nitrogen atoms. These alkaloids have only been isolated from various species of the genus Thalictrum (Ranunculaceae), with thalisopine (54)(thaligosine) having been isolated from ten Thalictrum sp., thalisopidine only from T isopyroides, and thalrugosaminine from seven Thalictrum sp. The two N-oxides, thaligosine-2o>N-oxide [thalisopine-2a-N-oxide] (378) and thalrugosaminine-2a-Noxide (384) have only been isolated from T cultratum.

Alkaloid

E,

Rj

Thalisopine (54) Thalisopidine (53) Thalrugosaminine (55)

CH3 H CH3

H H CH3

Alkaloid

R

Thaligosine-2a-N-Oxide (378) Thalrugosaminine-2a-N-Oxide (384)

H CH3

204

P.L.Schiff,Jr.

9.5.4. Type VIII (6,7,8\11+,12-6,7M2*) (-,-) Alkaloids The sole alkaloid of this type that lacks chirality at both nitrogen atoms is phaeantharine (73), a bisquaternary alkaloid that is a true isoquinoline (not a tetrahydro- or dihydroisoquinoline), and only a metabolite of Phaeanthus ebracteolatus (Menispermaceae).

73 (/?,-) Alkaloids There are three alkaloids in this small subgroup, one of which is the N(2') imine dehatrine (288), and the other two are secobisbenzylisoquinoline derivatives at N(2'). Dehatrine (288), a nonphenolic alkaloid, has been isolated from two Lauraceous species, Beilschmiedia madang and Dehaasia triandra (Lauraceae). Pycmanilline (392) has only been isolated from Pycnarrhena manillensis (Menispermaceae), while secoisotetrandrine (431) has only been found in Laurelia sempervirens (Monimiaceae). These alkaloids differ in the level of oxidation of the carbon that was the methylene bridge and in the non-seco precursor. In the former (pycmanilline), that carbon is a carboxy group, while in the latter (secoisotetrandrine), that carbon is a formyl group. Either isotetrandrine (62) or phaeanthine (74) could have been the precursor of these bases. Only isotetrandrine (62) was reported in Laurelia sempervirens, but both isotetrandrine (62) and phaeanthine (74) were reported as constituents of Pycnarrhena manillensis.

288

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

205

AlkaloM

E

Pycmanilline (392) Secoisotetrandrine (431)

COOH CHO

(5,-) Alkaloids The secobisbenzylisoquinoline sindamine (270) from Berberis lycium (Berberidaceae) is the only representative of this very small subgroup. The rotation for naturally occurring sindamine was not reported, but sindamine prepared from berbamine had a positive rotation, even though the C( 1) atom of berbamine is of the R stereochemistry.

(-,/?) Alkaloids There are only two alkaloids that constitute this small subgroup, but both bear an identical oxygenation pattern. Berbacolorflammine (218) is monoquaternary benzylisoquinoline at N-2, while caryolivine (281) has a tertiary nitrogen atom in a benzyisoquinoline system. Each alkaloid has only been isolated from a single plant, berbacolorflammine (218) from Pycnarrhena longifolia (Menispermaceae) and caryolivine (281) from Caryomene olivascens (Menispermaceae).

206

PX.Schifr,Jr.

281 (-,S) Alkaloids There are seven alkaloids reported in this subgroup but two of them are identical, being given different names but being reported in the same year (1989): dehatridine (287) from Dehaasia triandra (Lauraceae) and stepierrine (376) from Stephania pierrii (Menispermaceae). The manuscript on dehatridine was received on February 16, 1988 and published in a February, 1989 journal [232]; while the manuscript on stepierrine was received on October 10, 1988 and published in a July, 1989 journal [34]. Dehatridine/stepierrine is a benzylisoquinolinebenzyltetrahydroisoquinoline dimer. Another benzylisoquinoline-benzyltetrahydroisoquinoline dimer is fenfangjine D (1,3,4-tridehydrofangchinolinium hydroxide)(300), which is fangchinolinelike N-2 quaternary alkaloid isolated from Stephania tetrandra (Menispermaceae). Tiliafunimine (79a) is an N-2 imine alkaloid (3,4-dihydrobenzylisoquinoline) isolated from Tiliacora fimifera (Menispermaceae). Possible precursors of tiliafunimine include fangchinoline (61) and cycleadrine (58), but neither of these compounds have been isolated from any of the Tiliacora species. However, both of these compounds have been isolated from genera of the Menispermaceae. Cheratamine (228) is a N-2 imine (3,4-dihydrobenzylisoquinoline) with a carbonyl group at the C-a carbon. It is the only alkaloid of its type and was isolated from Cocculus pendulus (Menispermaceae). The final two alkaloids of this subgroup are

The Misbenzylisoquinollne Alkaloids - A Tabular Review

207

secobisbenzylisoquinoline compounds, chenabine (258) and jheulmine (262), both being metabolites of Berberis lycium (Berberidaceae). These two alkaloids are unusual in that they lack the usual carbonyl group at C(l), instead simply possessing a simple methylene group. Both of the alkaloids have a formyl group at what would be the C(a) carbon, and both are methoxylated at C(6) and C(6'), with a phenolic group at what would be the C(12). Chenabine is methoxylated at C(7), while jheulmine is phenolic at C(12). All of the alkaloids in this subgroup are methoxylated at C(6) and C(6'), with varying degrees of methoxylation at C(7) and C(12). It can easily be observed that most of the alkaloids of this subgroup are from genera of the Menispermaceae and Berberidaceae.

79a

P.L. Schiff,Jr.

AMMd

E

Chcnabinc (258) Jhelumine (262)

CH3 H

(R,R) Alkaloids There are twelve alkaloids that possess the (R9R) stereochemistry, eight of which constitute a subgroup with characteristics to be discussed in the following paragraph. There is one bis secondary amine, 2,2'-bisnorphaeanthine (278), a metabolite of Albertisia papauana (Menispermaceae). There is one N-2 secondary amine, 2-norlimacine (336) from both Anisocycla jollyana (Menispermaceae) and Caryomene olivascens (Menispermaceae) and one N-2' secondary amine, 2'-Norlmacine from Anisocycla jollyana (Menispermaceae) and Cyclea barbata (Menispermaceae). Only one of the eight alkaloids is phenolic at C(6), gyroamericine (305) from Gyrocarpus americanus (Hernandiaceae). Three of the eight alkaloids are monophenolic at C(7), with one being monophenolic at C(12), and another being bisphenolic at both C(7) and C(12). Genera and families represented by the three phenolic alkaloids of this subgroup include: Gyroamericine (305) - Gyrocarpus sp. (Hernandiaceae); Krukovine (63)- Abuta, Curarea, Pycnarrhena (all Menispermaceae); Limacine (64) - Anisocycla, Arcangelisia, Curarea, Cyclea, Limacia, Phaeanthus, Pycnarrhena, Spirospermum (all Menispermaceae); Colubrina (Rhamnaceae); and Gyrocarpus (Hernandiaceae). It can be readily observed that these alkaloids are almost always methoxylated at C(6) and C(6), tend to occur in various Menispermaceous species, and that no imine nor benzylisoquinoline-benzyltetrahydroisoquinoline dimers of this subgroup have been isolated.

The Blsbenzylisoquinollne Alkaloids - A Tabular Review

209

Alkaloid

R,

Kj

R3

2,2'-Bisnorphaeanthine (278) 2-Norlimacine (336) 2'-Norlimacine (423)

H H CH3

CH3 H H

H CH3 H

HCHJ

Alkaloid

R,

R2

R3

Gyroamcricine (305) Krukovinc (63) Limacine (64) Phaeanthine (74) Pycnaminc (75)

H CH3 CH3 CH3 CH3

CH3 H H CH3 CH3

CH3 H CH3 CH3 H

The remaining four alkaloids that possess the (RfR) stereochemistry are mono-N-oxides, three of which are limacine derivatives: limacine-2'a-N-oxide (315) from Curarea candicans (Menispermaceae); limacine-2P-N-oxide (316) from Curarea candicans (Menispermaceae); limacine-2'P-N-oxide (317) from Curarea candicans (Menispermaceae) and Anisocycla jollyana (Menispermaceae). The fourth is phaeanthine-2'a-N-oxide (356) from Pycnarrhena manillensis (Menispermaceae). Thus, only two genera of the Menispermaceae are the source of the N-oxides of this small subgroup.

210

P.L.SchlfT,Jr. ,OCH3

CHjO,

Alkaloid

R

Limacine-2'a-N-Oxide (315) Phacanthine-2'a-N-Oxide (356)

H CH,

,OCH3 H

CHjO,

3Cv "CHj

,OCH3

CHjO,

317

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

211

(S,S) Alkaloids There are fourteen alkaloids that belong to this subgroup, and none of these compounds are N-oxides or quaternary bases. Three of the seven alkaloids are mono- secondary amines, two at N(2) and one at N(2'). AH of the seven alkaloids are methoxylated at C(6), while six are methoxylated at C(6'), the lone exception being atherospermoline (56) which is phenolic at C(6') and has been isolated from Atherosperma moschatum (Monimiaceae) and Pachygone dasycarpa (Menispermaceae). Six of the seven alkaloids are methoxylated at C(7), with the lone exception being fangchinoline (61) which is phenolic at that position and which has been isolated from species of the following families/genera: Menispermaceae - Cyclea, Pachygone, Stephania, Strychnopsis, and Triclisia; Monimiaceae - Daphnandra. Three of the seven alkaloids are phenolic at C( 12), including atherospermoline (56)fromAtherosperma moschatum (Monimiaceae) and Pachygone dasycarpa (Menispermaceae); norpenduline (246) from Cocculus pendulus (Menispermaceae); and penduline (72) from the following families/genera: Euphorbiaceae Andrachne; Berberidaceae - Berberis; and Menispermaceae - Cocculus, Pachygone. Three of the fourteen alkaloids are quaternary at N(2), including cycleahomine (59) from Cyclea peltata (Menispermaceae) and 2-N-Methylfangchinoline (416) from Stephania tetrandra (Menispermaceae). These two compounds differ by having a C(7) methoxy versus a C(7) phenolic hydroxy, respectively. The third alkaloid, monomethyltetrandrinium (67) from Cyclea barbata (Menispermaceae), is not completely characterized, because the position of the quaternary nitrogen atom is uncertain, being either N(2) or N(2'). Four of the fourteen alkaloids are monoN-oxides, with three of the four alkaloids bearing the N-oxide in the N(2') position. The only alkaloid with the N-oxide in the N-2 position is fenfangjine A (tetrandrine-2p-N-Oxide)(297), a compound isolated from Stephania tetrandra (Menispermaceae). Fenfangjine B (fangchinoline2'ct-N-Oxide)(298) and fenfangjine C (fangchinoIine-2'P-N-Oxide)(299) are also metabolites of Stephania tetrandra (Menispermaceae). The fourth alkaloid, tetrandrine mono-N-2'-oxide, does not have the stereochemistry of the oxide described, but was isolated from Cyclea barbata (Menispermaceae). Genera of the family Menispermaceae clearly dominate in the overall distribution of most of the 5,5 alkaloids of type VIII.

Alkaloid

£,

fc

&

Atherospermoline (56) Fangchinoline (61) Penduline (72) (+)-Tetrandrine (76)

CH3 H CH3 CH3

H CH3 H CH3

H CH3 CH3 CH3

212

P.L.Schifr,Jr. ^OCH3 H3C

90

„OCH3

CHaO^

R3

Alkaloid

E,

E2

E3

7-O-Demethylpeinamine (60) Norpenduline (246) 2-Nortctrandrinc (70)

CH, H H

CH3 H CH3

H CH, CH,

„OCH3

CH 3 0 >

Alkaloid

E

Cyclcahominc (59) 2-N-Methylfangchinolinc (416)

CH3 H

The Bisbenzylisoqnlnoline Alkaloids • A Tabular Review

213

„OCH3

CH3Ox

H3CV

,CH 3 ^2

Alkaloid

E,

Monomethyltetrandrinium (67)

H

CH3 or

CH3

H

78

OCH,

CHjO,

H3O1

^

297

214

P.L.SchlfT,Jr.

299 (R,S) Alkaloids There are thirteen alkaloids in this group, none of which are N-oxides or quaternary compounds. All of these alkaloids are methoxylated at C(6'). It can be observed that whichever side bears a C(7) phenylether bridge, the substituent at C(6) will be a methoxyl group. Eleven of the thirteen alkaloids are methoxylated at C-6 (two phenols), while only 7 are methoxylated at C(7) (six phenols). Seven of the thirteen alkaloids are methoxylated at C(12), with the remainder being phenolic. There are seven alkaloids that have one or two secondary nitrogen atoms. Four of these alkaloids are secondary at N(2) but tertiary at N(2'), while only one alkaloid is secondary at N(2') but tertiary at N(2) [nor-2'-isotetrandrine (213) from Limaciopsis loangensis (Menispermaceae) and Stephania pierrii (Menispermaceae)]. There are two alkaloids that are bis secondary compounds, bisnorobamegine (277) and bisnorthalrugosine (279), both having been isolated from Pycnarrhena ozantha (Menispermaceae). There are two alkaloids that are quaternary at N(2'): 2'-N-methylberbamine (66a) from Berberis oblonga and Berberis turcomanica (Berberidaceae), and N-2'-methylisotetrandrine from Berberis oblonga (Berberidaceae). Finally there are two N-oxide alkaloids: berbamine-2'P-NOxide (274) from Berberis brandisiana (Berberidaceae) and N-oxy-2'-isotetrandrine (216) from Limaciopsis loangensis (Menispermaceae).

215

The Blsbenzylisoquinoline Alkaloids - A Tabular Review .OR, H3C

v

H"'

CH 3 0 N .N.

OR2

ST'-H

^OR3 Alkaloid

E,

E2

E3

Aquifoline (273) Berbamine (57) Cycleabarbatine (402) Isotetrandrine (62) Obamegine (71) Thalrugosine (79)

H CH3 H CH3 CH3 CH3

CH3 CH3 CH3 CH3 H H

H H CH3 CH3 H CH3

Alkaloid

Ei

E2

E3

Bisnorobamegine (277) Bisnorthalrugosine (279)

CH3 CH3

H H

H CH3

XH3

216

P.L.Schifr,Jr. CH 3 0 N

W "H

Alkaloid

E,

2-N-Norberbamine (68) 2-Norisotetrandrine (334) 2-N-Norobamegine (69) 2-Northalrugosine (344)

CH, CH, CH, CH3

^OCH3

E3 CH3 CH3 H H

H CH, H CH3

CH3ON

213

^OCH3

CH 3 0 N

Aikajojd 2-N'-Methylbcrbaminc (66a) N-2'-Methylisotetrandrine (319)

H CH3

TH3

The Blsbenzylisoquinoline Alkaloids - A Tabular Review

217

(StR) Alkaloids There are only three alkaloids in this small subgroup, and all are derivatives of the monophenolic [C(12)j, monosecondary [N(2)] alkaloid peinamine (71a) which has only been isolated from A buta grisebachii (Menispermaceae). The other two alkaloids are 7-0demethylpeinamine (60a) and N-methyl-7-O-demethylpeinamime (66b), both being metabolites of the same plant as above. In addition, the latter has been isolated from Pachygone dasycarpa (Menispermaceae).

71a

218

P.L.SchifT,Jr.

66b Miscellaneous alkaloids

There are two alkaloids that are racemic mixtures: cycleadrine (58) [(+/-) - fangchinoline] from Cyclea barbata and C. peltata (Menispermaceae) and (+/-)-tetrandrine (77) from the same two plants, as well as from Isopyrum thalictroides (Ranunculaceae) and Stephania hernandifolia (Menispermaceae). Menisidine (65) is likely a fangchinoline isomer and menisine (66) is likely a (+)-tetrandrine stereoisomer. These latter two alkaloids were isolated from Stephania tetrandra (Menispermaceae). Oxofangchirine (349) is a benzyltetrahydoisoquinoline-benzylisoquinolone alkaloid from Stephania tetrandra (Menispermaceae). The stereochemistry at C( 1) is not defined.

58

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

219 CH^

OCH3

XH3

77 „OCH3

CH3ON

T>CH3 65

CfyO,

„OCH3

TH3

"OCH3 66 CH^

OCH3

^ OCH3 349

220

P.L.Schifr,Jr.

9.5.5. Type IX (5,6,7,8MlM2-6,7\l2+) (£,-) Alkaloids The only two alkaloids of this very small subgroup are thalsimidine (85), which has only been isolated from Thalictrum simplex (Ranunculaceae), and thalsimine (86), an alkaloid that has been isolated from three species of Thalictrum (T rochebrunianum, T rugosum, and T simplex). Thalsimine (86) is actually a 1:1 mixture of the two conformers of 5-O-methylthalsimidine.

Alkaloid

R

Thalsimidine (85) H Thalsimine (86) CH3 (a 1:1 mixture of the two conformers of 5-O-MethyIthalsimidine)

(S,S) Alkaloids There are four alkaloids and one alkaloid-N-oxide that constitute this subgroup. All of these alkaloids are methoxylated at C(6), C(7), C(12), and C(6'). Three of the five compounds are mono- secondary amines, one at N(2) and two at N(2'). Two of the alkaloids are phenolic at C(4), while the other three are methoxylated at that position. N-Desmethylthalidezine (80) has only been isolated from Thalictrum podocarpum (Ranunculaceae), while thalidezine (83) has been isolated from nine different Thalictrum species, including T podocarpum. Hernandezine (5-0methylthalidezine)(81) has been isolated from twelve different Thalictrum species (including T. podocarpum) as well as one other plant, Cocculus pendulus (Menispermaceae). Thalisamine (84) was subsequently shown to be identical with N'-norhernandezine (212). These alkaloids have been isolated from T simplex and T rochebrunianum, respectively. Hernandezine-N-oxide (203) has only been isolated from T sultanabadense (Ranunculaceae).

221

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

*R3

v

OCH3

Alkaloid

R,

E±2

*±3

N-Desmethylthalidezine (80) Hernandezine (81) Thalidezine (83) Thalisamine (84) [also called N'-Norhernandezine (212)]

H CH 3 CH 3 CH 3

H CH 3 H CH 3

CH3 C.H3 CH 3 H

OCH3

H3C

203 (S,R) Alkaloids Isothalidezine (82) is the only bisbenzylisoquinoline alkaloid of this group with the S,R stereochemistry that has been isolated from nature. This alkaloid was found in Thalictrum delavyi, T. glandulosissimum, and T. podocarpum (Ranunculaceae). Epinorhernandezine (199) is a semisynthetic product. With but one exception, all of the sources of the nine alkaloids of Type IX are Thalictrum species.

222

P.L.Schiff,Jr.

Alkaloid

R

Isothalidezine (82) Epinorhernandezine (199)

H CH3

9.5.6. Type X (6,7,8\ll\l2,13-6,7*42*) (R,R) Alkaloids There are two alkaloids that constitute this very small subgroup. (-)-Nortenuipine (89) has only been isolated from Daphnandra tenuipes (Monimiaceae), while (-)-tenuipine (92) has been isolated from both Daphnandra tenuipes and D. dielsii (Monimiaceae). The "nor" designation is misleading with regard to nortenuipine, because this prefix is usually reserved for secondary amines, but in this case refers to C(7) position which is phenolic in nortenuipine and methoxylated in tenuipine.

Alkajojd

R

(-)-Nortenuipine (89) (-)-Tcnuipine (92)

H CH3

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

223

(S,S) Alkaloids As with the (5,5) alkaloids, there are only two alkaloids in this subgroup; (+)-nortenuipine (88) from Daphnandra johnsonii, D. tenuipes, and Daphnandra species Dt-7 (Monimiaceae); and (+)-tenuipine (91) from Daphnandra tenuipes (Monimiaceae) and an unnamed Daphnandra species. The same misleading use of the prefix "nor" applies to (+)-nortenuipine as did to (-)nortenuipine above.

Alkaloid

£

(+)-Nortenuipine (88) (+)-Tenuipine (91)

H CH3

(R,S) Alkaloid The sole alkaloid of this stereochemical subgroup is isotenuipine (87), an alkaloid of a Daphnandra species (Monimiaceae).

224

P.L. Schiff, Jr.

Racemic Alkaloid There is only one racemic alkaloid in the type X alkaloid group. Repandinine [(+/-)tenuipine](90) has been isolated from four Daphnandra species, including D. dielsii, D. johnsonii, D. repandula, and D. tenuipes. It can be concluded that the alkaloids of this type are fundamentally of two groups; the nortenuipine (7-demethyltenuipine) type and the tenuipine type, each with differing stereochemistry. The C(12)/C(13) methylenedioxy group in these alkaloids is unusual in its occurrence, particularly within the bisbenzylisoquinoline alkaloids. The alkaloids of this group are restricted to the genus Daphnandra (Monimiaceae). 9.5.7. Type Xa (6,7,8M0,11M2-6,7*, 12*) These alkaloids are very unusual, in that they possess oxygenation at C(10). In each case, this oxygenation takes the form of a methoxyl group. (5,-) Alkaloids Calafatimine (189) is a nonphenolic N(2') imine alkaloid that has only been isolated from Berberis buxifolia (Berberidaceae). Curacautine (259) and talcamine (271) are two secobisbenzylisoquinoline alkaloids that have been isolated from the same plant and that contain ring B' in a higher oxidation state are. The ring C constituent in the former is a formyl group, while in the latter it is a carboxymethyl.

189

The Bisbenzylisoquinoline Alkaloids - A Tabular Review „OCH3

225

CH3Ox

Alkaloid

R

Curacautine (259) Talcamine (271)

CHO COOCH3

(S,R) Alkaloids Calafatine (190), the parent alkaloid of this small subgroup, has only been isolated from two Berberis species, B. buxifolia and B. horrida (Berberidaceae). The two N-oxides of calafatine, 2'ot (226) and 2'p (227), have only been isolated from Berberis buxifolia (Berberidaceae). „OCH3

CH 3 O v

190

„OCH3

CH 3 0^

^OCH3 Alkaloid Calafatine-2'ct-N-Oxide (226) Calafatine-2'P-N-Oxide (227)

R2 O* CH3

CH3 O

226

P.L.SchifT,Jr.

The alkaloids of this group are restricted to the genus Berberis of the family Berberidaceae. In fact, B. buxifolia has been the source of all the alkaloids, with B. horrida serving as an additional source of calafatine (190). 9.5.8. Type Xb (6,7\8,10,11*,12,13-6,7*, 12*) Daphnine (191), the highly conjugated N(2) zwitterionic alkaloid from Daphnandra dielsii and D. repandula (Monimiaceae), is the sole representative of this type of alkaloid. Daphnine is of very restricted distribution to the genus Daphnandra.

191

9.5.9. Type XI (6,7,8\11M2-6\7,12 + ) (5,-) Alkaloids There are four alkaloids that constitute this small subgroup. The mono imine [N(2')] alkaloids thalmethine (98) and O-methylthalmethine (96) have only been isolated from Thalictrum species (Ranunculaceae), with the former reported as a constituent of T. minus, while the latter has been found in T minus, T minus var. minus, and T revolutum. These two alkaloids differ at C(12), where thalmethine is monophenolic. A third N(2') imine alkaloid is thalsivasine (380), a constituent of Thalictrum cultratum and Thalictrum minus var. minus. This alkaloid is monophenolic at C(7), instead of C(12). The final alkaloid of this small group is the secobisbenzylisoquinoline alkaloid revolutionone (266) which has only been isolated from Thalictrum revolutum (Ranunculaceae). The alkaloids of this small subgroup appear to be restricted in distribution to the genus Thalictrum.

227

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

Alkaloid

R,

R2

O-Methylthalmethine (96) Thalmethine (98) Thalsivasine (385)

CH3 CH3 H

CH3 H CH3

266 (5,5) Alkaloids The six alkaloids of this subgroup differ in their substitution at C(7), C(12) and N(2'). In general, different combinations of phenolic and methoxyl groups vary at C(7) and C(12), with only one alkaloid of the group being a secondary amine at N(2'). Thalicberine (97) and O-methylthalicberine (95) differ in that the former is phenolic at C( 12). Thalicberine has been isolated from four species of Thalictrum, and from an additional three varieties of one of these species (T minus). This accounts for seven separate isolations of this alkaloid from species and varieties of the genus Thalictrum. O-Methylthalicberine (95) has been isolated from no less than ten species of this same genus, as well as an additional four varieties of one of these species (T minus). However, the latter has also been isolated from two species of the genus Berbehs (Berberidaceae). There are three alkaloids of the thaliphylline (253)-type that have been described: thaliphylline (253) from Thalictrum cultratum and two varieties of Thalictrum minus; 2'northaliphylline (342) from T cultratum; and thaliphylline-2'P-N-Oxide (379) also from T cultratum. The thaliphylline-type alkaloids are phenolic at C(7).

228

PL.Schiff,Jr.

The final alkaloid of this type is thalivarmine (380), an alkaloid that is bisphenolic at C(7) and C(12), having been isolated from only one plant, Thalictrum minus L. var. minus. It can be easily concluded that the alkaloids of this small subgroup are almost entirely restricted in distribution to the genus Thalictrum.

^3

Alkaloid

E,

O-Methylthalicberine (95) 2'-Northaliphylline (342) Thalicberine (97) Thaliphylline (253) Thalivarmine (380)

CH3 H CH3 H H

E3 CH3 CH3 H CH3 H

CH3 H CH3 CH3 CH3

«CH3

^OCHj 379

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

229

(R,S) Alkaloids The four alkaloids of this subgroup differ only in their substitution at C(7) and C(12). There are no nor-alkaloids in the series. The fully methoxylated alkaloid of the subgroup is Omethylisothalicberine (94), a compound that has only been isolated from two species of the genus Berberis (B. chilensis and B. laurina) (Berberidaceae). Monophenolic relatives of this alkaloid are belarine (93)[C(7) phenol] and isothalicberine [C(12) phenol], the former of which has only been isolated from Berberis laurina (Berberidaceae) while the latter has only been found as a metabolite of B. chilensis. Finally, the bisphenolic [C(7) and C(12)] alkaloid 7-0demethylisothalicberine (195) has been found in Berberis chilensis and B. laurina. It can be concluded that the alkaloids of this small subgroup appear to be restricted in their distribution to just two species of the genus Berberis (B. chilensis and B. laurina)( Berberidaceae).

Alkaloid

R,

R2

Belarine (93) 7-O-Demethylisothalicberine (195) Isothalicberine (205) O-Methylisothalicberine (94)

H H CH3 CH3

CH3 H H CH3

9.5.10. Type XII (6,7,8\llM2-5\6,7,12+) (S,S) Alkaloids All of the alkaloids of this group have identical stereochemistry (5,5), and differ only in their substitution at N(2), C(7), and C(12). Two of the alkaloids are secondary amines at N(2), while an additional two are N-formyl derivatives at that position. Four of the nine alkaloids are phenolic at C(7) (the rest being methoxylated), while only two of these alkaloids are phenolic at C(12). One alkaloid is phenolic at both positions [thaligosidine (100a)]. Thalidasine (100) analogs include N-desmethylthalidasine (196) and thalidasine-2o>Noxide (377). Thalidasine has been isolated from no less than fourteen species of the genus Thalictrum (including T. cultratum and T. faberi), while N-desmethylthalidasine (196) has been isolated only from Thalictrum cultratum and T. faberi. The N-oxide has been isolated from just one plant, T. cultratum. Thalrugosinone (224), the N(2)-formyl derivative of thalidasine, has

230

P.L.Schiff,Jr.

been isolated from T cultratum and T. rugosum. The occurrence of thalidasine (the fully methoxylated parent alkaloid of this series) and its analogs appears to be restricted to one genus, Thalictrum (Ranunculaceae). Furthermore, only one species, T cultratum, is the source of all four thalidasine-related alkaloids of this series. Thalrugosidine (101)(7-demethylthalidasine) has been isolated from five species of the genus Thalictrum (including Thalictrum alpinum), while its N(2)-demethyl derivative Ndesmethylthalrugosidine (197) has been isolated from only Thalictrum alpinum. Thalpindione (223), also known as N-2-formylthalrugosidine, is only a metabolite of Thalictrum alpinum. The occurrence of thalrugosidine and its derivatives is restricted to the genus Thalictrum, with all three alkaloids of this small subseries being isolated from just one species, T alpinum. Thalfoetidine (99)(12-demethoxythalidasine) has been isolated from Thalictrum fargesii, T.flavum,and T. longipedunculatum, and has not been isolated from any other source. The fully methoxylated parent alkaloid of this series, thalidasine (100) has also been isolated from these three species. Thaligosidine (100a)(7,12-demethoxythalidasine) has only been found in Thalictrum rugosum. Thalidasine has also been isolated from this species. It can be concluded that the distribution of the nine alkaloids of this Group are entirely restricted to species of the genus Thalictrum (Ranunculaceae).

Alkaloid

E,

£2

N-Desmethylthalidasine (196) N-Desmethylthalrugosidine (197)

CH3 H

CH3 CH3

The Bisbenzyllsoquinoline Alkaloids - A Tabular Review

Alkaloid

Ei

E2

Thalpindione (223) Thalrugosinonc (224)

H CH3

CH3 CH3

Alkaloid

Ei

E2

Thalfoctidinc (99) Thalidasine (100) Thaligosidinc (100a) Thalrugosidine (101)

CH3 CH3 H H

H CH3 H CH3

232

P.L.Schiff,Jr.

9.5.11. (Type Xlla

S&IJ&\\\%l2-f&l,\r)

There are only two alkaloids that comprise Type Xlla, 5-hydroxythalidasine (311) and 5hydroxythalidasine-2a-N-oxide (312). These two bases have the S£ stereochemistry and have only been found to date in Thalictrum cultratum.

312 9.5.12. Type XIII (5\6,7,llM2-5,6,7,8\12*) These alkaloids are somewhat unusual in that both sides bear 5,6,7-oxygenation. (5,5) Alkaloids The fully methoxylated parent alkaloid of this type group thalfinine (103), as well as its 5'-demethyl- analog thalmirabine (222), have both been isolated from just two plants, Thalictrum foetidum and T. minus (Ranunculaceae).

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

s

233

OCH 3

Alkaloid

R

Thalfinine (103) Thalmirabine (222)

CH3 H

(£,-) Alkaloid Thai fine (102), a benzyltetrahydroisoquinoline-benzylisoquinoline alkaloid, is the ring B' oxidized derivative of thalfinine (103). Thai fine (102) has also only been isolated from Thalictrum foetidum and Thalictrum minus.

H3C

^OCH3 102

It can be observed that the type XIII alkaloids are a very small group of compounds that are of restricted in distribution to the genus Thalictrum, and specifically within this genus to the species T. foetidum and T. minus.

234

P.L.SchifT,Jr.

9.5.13. Type XIV (6,7*,HM2-5*,6,7,12*) (5,-) Alkaloid Thalmiculatimine (381), isolated from Thalictrum cultraturn, is the only alkaloid of this small subgroup. It is a N-2'-demethyl derivative of thalictine (107), and because of the distribution of the alkaloids in the series to follow, it is most likely to have derived from thalictine (107). There are five different Thalictrum alkaloids in the S,S series, with each of these alkaloids having its distribution restricted to the genus Thalictrum. However, there are only three alkaloids in the S,R series, and only one of these compounds is found in the genus Thalictrum.

381 (RfS) Alkaloids The fully methoxylated parent alkaloid of this subgroup is lauberine (106), which is a metabolite ofBerberis laurina (Berberidaceae). Berbilaurine (275)(6-demethyllauberine) has also only been found in Berberis laurina, but 12-O-desmethyllauberine (294) has only been isolated from Berberis chilensis. It appears that the alkaloids of this small stereochemical subgroup are restricted in distribution to the genus Berberis (Berberidaceae).

Alkaloid

E.

S2

Berbilaurine (275) 12-O-Desmethyllauberine (294) Lauberine (106)

H CH3 CH3

CH3 H CH3

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

235

(S,R) Alkaloids Dryadine (104) and dryadodaphnine (12-demethyldryadine)( 105) have been isolated from Dryadodaphne novoguineensis (Monimiaceae), while thalifortine (6-Methyldryadodaphnine)(428) has only been isolated from Thaiictrum fortunei (Ranunculaceae).

Alkaloid

R,

R2

Dryadine (104) Dryadodaphnine (105) Thalifortine (428)

H H CH3

CH3 H H

(S,S) Alkaloids The fully methoxylated parent alkaloid of this series is O-methylthalmine (244), an alkaloid that has only been found in Thalictrum cultratum and Thalictrum sultanabadense (Ranunculaceae). The alkaloids in this small subgroup differ in their substitution at N(2), C(12), and C(6'). Thalictine (12-demethyl-O-methylthalmine)(107) has been isolated from three Thalictrum species; T cultratum, T. sultanabadense, and T thunbergii, while thalmine (108) has been isolated from T. cultratum, T. kuhistanicum, and T minus. There are two diphenolic alkaloids with the S,£ stereochemistry; 2-northalmine (343) and thalabadensine (12demethylthalmine)(106a), the former a metabolite of Thalictrum cultratum, while the latter has been found in Thalictrum minus and Thalictrum sultanabadense. It can be concluded that the alkaloids of this small subgroup are restricted in distribution to several species of the Thalictrum genus, with T cultratum and T sultanabadense being the most common sources. An interesting feature that may be observed concerning the distribution of the type XIV alkaloids is the effect of the stereochemistry of the chiral centers. The R,S alkaloids are confined to a single genus (Berberis) of the Berberidaceae, while the S,S alkaloids are similarly restricted to a single genus (Thalictrum) of the Ranunculaceae. The S,R alkaloids are found in both the Monimiaceae (Dryadodaphne) and the Ranunculaceae (Thalictrum). To date, no alkaloids with R,R stereochemistry have been found in nature.

236

P.L.Schlff,Jr.

H3C

Alkaloid

R.

E2

O-Methylthalmine (244) Thalabadensine (106a) Thalictine (107) Thalmine (108)

CH3 H H CH3

CH3 H CH3 H

X)CH3 343

9.5.14. Type XlVa (5,6,7*4l\12-5\6,7,12*) The alkaloids of this type differ from the parent Type XIV alkaloids in that the former have oxygenation at C(5). (5,-) Alkaloids The two alkaloids of this group are methoxylated at C(6), C(7'), and C(8'); hydroxylated at C(5); and are imines at N(2'). The two alkaloids differ only in their substitution at C(12), with cultithalminine (12-demethylthalmiculimine)(285) being phenolic and thalmiculimine (382) being a methylether. Both bases have only been found as metabolites of Thalictrum cultratum (Ranunculaceae).

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

237

H3C

Alkaloid

E

Cultithalminine (285) Thalmiculimine (382)

H CH3

(5,5) Alkaloids The two alkaloids of this very small subgroup are methoxylated at C(5), C(12), and C(7'), differing only by being phenolic [5-Hydroxythalmine (6-demethylthalmiculine)(313)] or methoxylated [thalmiculine (383)] at C(6). Both bases are tertiary amines with N-methyl functions, and both alkaloids have only been isolated from Thalictrum cultratum (Ranunculaceae).

OH

H3C

Alkaloid 5-Hydroxythalmine (313) Thalmiculine (383)

H CH3

The four type XlVa alkaloids are restricted in their distribution to the genus Thalictrum, and quite specifically to T. cultratum.

238

P.L.Schiff,Jr.

9.5.15. Type XV (5\6,7,HM2-6,7\12+) The two alkaloids of this group, panurensine (110) and norpanurensine (2'norpanurensine)(109), are monophenolic at C(6), and are methoxylated at C(7), C(12), and C(6'). Each of the compounds possesses the R,R stereochemistry. The alkaloids are restricted in their distribution to A buta panurensis (Menispermaceae).

9.5.16. Type XVI (5\6,7,llM2-6\7,12*) This highly unusual alkaloid type features a novel C(5) to C(6') ether bridge that joins the monomeric halves of the molecule. The only alkaloid in this group is (J?,l?)-nemuarine (111), a base isolated from Nemuaron vieillardi (Monimiaceae).

TH3

111

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

239

9.5.17. Type XVII (5,6,7,8\10,12,13+-6,7\12+) All of the alkaloids of this group are unusual in that they bear 10,12,13- trioxygenation in Ring C of their molecule. Six of the seven alkaloids are 10-hydroxy, 12-methoxy compounds, while one is a 10,12-dimethoxy compound. In addition, all seven of the alkaloids have only been isolated from one plant, Thalictrum rochebrunianum (Ranunculaceae), and thus these compounds are of very restricted distribution. (£,-) Alkaloids There are two subgroups of these type of alkaloids. The alkaloids of the first subgroup, thalictrinine (220) and dihydrothalictrinine (198), are characterized by being benzyltetrahydroisoquinoline-benzylisoquinoline dimers. Thalictrinine (220) is characterized by having a carbonyl group at the ct'-carbon, while dihydrothalictrinine (198) is the reduced form and bears a p-hydroxy group at the a'-carbon.

220

240

P.L. Schlff, Jr.

The second small subgroup is represented by three alkaloids that are benzyhetrahydroisoquinoline-benzyldihydroisoquinoline dimers; thalibrunimine (112), Omethylthalibrunimine (210), and oxothalibrunimine (215). Oxothalibrunimine bears a carbonyl group at the a'-carbon, while O-methylthalibrunimine is methylated at C(10). OCH3

H3C

N3CH3 Alkaloid

E,

O-Methylthalibrunimine (210) Oxothalibrunimine (215) Thalibrunimine (112)

CH3 H H

E2JLS3 H O H

(5,5) Alkaloids Thalibrunine (113) and N'-northalibrunine (214) are the representatives of this small group. Both are bisbenzyltetrahydroisoquinolines and are phenolic at C(10). OCH3

H3C

Alkaloid

E

N'-Northalibrunine (214) Thalibrunine (113)

H CH3

The Bisbenzylisoquinoline Alkaloids - A Tabular Review 9.6.

241

One Diphenyl Ether Linkage (Head-to-Tail) and One Diphenyl Ether Linkage (Headto-Tail)

9.6.1. Type XX (6,7,8\12+-6,7,8\12*) These are head-to-tail linked bases that tend to occur most commonly in the several genera of the Menispermaceae. (-,/?) Alkaloids The two alkaloids that constitute this small subgroup are sciadoferine (217) and sciadoline (128). These alkaloids differ in the degree of oxidation of their A rings, in that the former is a 3,4-dihydroisoquinoline, while the latter is a true isoquinoline. These alkaloids are metabolites of Sciadotenia toxifera (Menispermaceae).

217

128

242

P.L.SchifT,Jr.

(R,R) Alkaloids Four of the five alkaloids within this small subgroup are cycleanine (121) derivatives, including cycleanine-N-oxide (232), N-desmethylcycleanine (233)(the N(2') desmethyl derivative of cycleanine), and (-)-norcycleanine (125), the last of which is really not a "nor" derivative, but is a C(7') Odemethylcycleanine. Cycleanine (121) has been isolated from various species of no less than ten genera, but with eight of the genera being from the family Menispermaceae, while the remaining two are from the Umbelliferae [an extremely unusual alkaloid-bearing family] and the Annonaceae. Cycleanine-N-oxide (232) has only been isolated from Synclisia scabrida (Menispermaceae)(as has cycleanine itself). N-Desmethylcycleanine (233) has only been found in Stephania glabra and Stephania pierrii (Menispermaceae), both plants having also served as a source of cycleanine. (-)-Norcycleanine (125) has been isolated from two plants, Isolona hexaloba (Annonaceae) and Stephania cepharantha (Menispermaceae), both of which have also served as a source of cycleanine (121). All of the alkaloids of this subgroup are methylated at N(2), and are C(6)/C(6') bismethoxylated. Phenolic compounds may result by substitution at C(7) and/or C(7'). ^OCH3

-R3 CH3O'

Alkaloid

Ei

£2

£3

Cycleanine (121) N-Desmethylcycleanine (233) Isochondodendrine (122) (-)-Norcycleanine (125)

CH3 CH3 H CH3

CH3 CH3 H H

CH3 H CH3 CH3

CH3cr 232

1 he fiisbenzyllsoquinoline Alkaloids - A Tabular Review

243

(S,S) Alkaloid The only naturally occurring alkaloid of this small group is (+)-norcycleanine (124)[which is really 7'-0-demethylcycleanine). This alkaloid is not as widely distributed as its R,R diastereoisomer (-)-norcycleanine (125). The (+)-isomer has only been isolated from two plants: Isolona hexaloba (Annonaceae) and Stephania cepharantha (Menispermaceae), neither of which are a source of the (-)-isomer (which was found in four Menispermaceous genera; Chondodendron, Cyclea, Epinetrum, and Synclisia. The base tetra-O-demethylcycleanine (128a) has been reported, but data was not available.

Alkaloid

R,

E2

R3

(+)-Norcycleanine (124) Tetra-O-Demethylcycleanine (128a)

CH3 H

CH3 H

CH3 H

(StR) Alkaloid The only alkaloid of this group is sciadenine (127) which is solely a metabolite of Sciadotenia toxifera (Menispermaceae). Sciadenine (127) has the same substitution as sciadoline (128) and sciadoferine (217)[two other alkaloids of the same plant], except that sciadenine contains a fully reduced ring A, while ring A of the other two alkaloids is oxidized to different degrees.

127

244

P.L. SchifT,Jr.

(?,?) Alkaloids There are two alkaloids of incompletely determined structure, protocuridine (126) and neoprotocuridine (123). In the case of the former, only the stereochemisty of the chiral carbon atoms at C(l) and C(l') is unknown, but in the case of the latter, the positions of the phenolic hydroxy groups and methoxy groups have not been settled with certainty, nor has the stereochemistry at C(l) and C(l'). Both of these alkaloids were isolated from curare.

123

9.6.2. Type XXI (6,7,8*41+,12-6,7\12*) (R,R) Alkaloids There are four alkaloids in the (-)-curinc family: (-)-curine (133), cycleacurine (134), 0,0-dimethylcurine (135), and 12'-Omethylcurine (140). These alkaloids differ in the position of various phenolic hydroxy groups and methoxy groups among the C(7), C(12), and C(6') positions. (-)-Curine (133) has been isolated from six genera of the Menispermaceae including Chondodendron, Cissampelos, Cyclea, Paracyclea, Pleogyne, and Stephania. In addition, this

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

245

alkaloid has been isolated from two Annonaceous plants Cleistopholis staudtii and Isolona hexaloba, as well as one plant of the Umbelliferae, Heracleum wallichi. Cycleacurine (134) has only been isolated from Cyclea peltata (Menispermaceae), while 0,0-dimethylcurine (135) is only a metabolite of Cylcea hypoglauca (Menispermaceae) and Guatteria megalophylla (Annonaceae). Finally, 12'-0-methylcurine (140) has only been isolated from Guatteria megalophylla (Annonaceae).

Alkaloid

R,

R2

R,

(-)-Curine (133) Cycleacurine (134) 0,0-Dimethylcurine (135) 12'-0-Methylcurine (140)

H H CH3 H

H H CH3 CH3

CH3 H CH3 CH3

There are two alkaloids of this series that bear a methylenedioxy group at C(6)/C(7) and are acetylated at N(2'). These are isocuricycleatjenine (410) and isocuricycleatjine (411), two compounds that differ only by the presence of a 7-methoxy group in the former and a 7-hydroxy group in the latter. These alkaloids have only been found in Cyclea atjehensis (Menispermaceae).

Alkaloid

R

Isocuricycleatjenine (410) CH3 Isocuricycleatjine (410) H Although distribution within the Menispermaceae is favored for this subgroup, these alkaloids are also found in the Annonaceae and Umbelliferae.

246

P.L.Schlff,Jr.

(S,S) Alkaloids The three alkaloids of this small subgroup differ only in their substitution (phenolic hydroxy or methoxy groups) at C(7) and C(12)/C(4"). Chondrofoline (131) has been isolated from Chondodendron platiphyllum (Menispermaceae) and two Annonaceous plants (Cleistopholis staudtii and Uvaria ovata), while the bisphenol (+)-curine (132) has been isolated from varying genera in three different plant families, including the Buxaceae, the Lauraceae, and the Menispermaceae. (+)-Curine (132) is a metabolite of several Menispermaceous species, including Abuta candicans, Chondodendron microphyllum, Cyclea barbata and Cyclea hainanensis. In addition, the alkaloid is found in several Buxus species (Fam Buxaceae) and Ocotea rodiei (Lauraceae). 4"-0-Methylcurine (139) has been isolated from two Menispermaceous species, Cissampelos pareira and Cyclea hainanensis. Although distribution into the Menispermaceae tends to predominate in this subgroup, these alkaloids are also found in other plant families.

Alkaloid

Ri

R2

Chondrofoline (131) (+)-Curine (132) 4"-0-Methylcurine (139)

CH3 H H

H H CH3

(R,S) Alkaloids The two nonquaternary alkaloids of this small subgroup are chondocurine (130) and norNb-chondocurine (230), the latter being the N(2') nor- derivative of the former. Chondocurine (also called chondrocurine) has been isolated from Chondodendron tomentosum and 2 species of Cyclea, all three plants being of the family Menispermaceae. The nor-base 230 and chondocurine have both been isolated from what is only described as Peruvian curare.

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

247

Alkaloid

R

Chondocurine (130) Nor-Nb-Chondrocurine (230)

CH3 H

The two quaternary alkaloids in this small subgroup are the bisquaternary chondocurarine (129) and monoquaternary (+)-tubocurarine (142). The structures of these two compounds are identical, save for the lesser degree of quaternization in the latter. Chondocurarine has only been isolated from Chondodendron tomentosum (Menispermaceae), while (+)-tubocurarine has been isolated from the same plant, as well as from Anomospermum grandifolium (Menispermaceae) and Peruvian curare.

Alkaloid

R

Chondocurarine (129) (+)-Tubocurarine (142)

CH3 H

The alkaloids of this small subgroup seem to be solely distributed within Menispermaceaous plants, particularly of the genus Chondodendron.

248

P.L.Schifr,Jr.

(S,R) Alkaloids Two closely related alkaloids from this group are curicycleatjenine (400) and curicycleatjine (401), compounds that contain a methylenedioxy function at C(5)/C(6). These two alkaloids differ only in the nature of the C(12) function, whereas in the former it is methoxy group and in the latter a hydroxy group. These alkaloids have only been isolated from Cyclea atjehensis (Menispermaceae). Hayatidine (136), an alkaloid of Cissampelos pareira (Menispermaceae), is a diastereoisomer of 12'-0-methylcurine (140). (-)-Tubocurarine (143), a diastereoisomer of (+)tubocurarine (142), has only been isolated from Chondodendron tomentosum (Menispermaceae).

Alkaloid

R

Curicycleatjenine (400) Curicycleatjine (401)

CH3 H

136

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

249

143

Racemic Alkaloid (+/-)-Curine dimethiodide has been isolated from extracts of Cissampelos pareira (Menispermaceae).

Partially characterized alkaloids Hayatine (137) and hayatinine (12-methylhayatine)(138) are alkaloids that have both been isolated from Cissampelos pareira (Menispermaceae), with the latter alkaloid also having been found in Cyclea hainanensis (Menispermaceae). The chirality of the C( 1) and C( 1') carbon atoms in these alkaloids has not been determined, although the two compounds are identical in molecular structure to (-)-curine (133) and 12'-Omethylcurine (140), respectively. The compound reported as (-)-tubocurine (144)(thought to be enantiomeric with chondrocurine [(+)tubocurine]) was not isolated in a pure form, and hence the physical properties were not determined [1].

137

250

P.L.Schiff,Jr.

144

9.7.

Two Diphenyl Ether Linkages (Head-to-Head) and One Diphenyl Linkage (Tail-toTail)

9.7.1. Type XVIII |6,7\8\12-6\7\12(11-11)) The alkaloids of this group are dibenzodioxin compounds in the top portion of the dimeric system, but biphenyls (not biphenyl ethers) in the lower portion of the rings. (5,-) Alkaloid The only alkaloid of this group is secolucidine (393), which is a secobisbenzylisoquinoline that has only been found in Pseudoxandra sclerocarpa (Annonaceae). The precursor to this alkaloid could have been medelline (318) from Pseudoxandra aff. lucida (Annonaceae), found in another subgroup of this series.

393

251

The Bisbenzylisoquinoline Alkaloids - A Tabular Review (5,5) Alkaloids

The compounds in this subgroup differ among each other in the following two manners: first, the degree of N-methylation, with three of the alkaloids being monosecondary amines, and one a bis-secondary amine; second, the placement of methoxy and phenolic hydroxy groups at C(12) and C(12') positions. Four of the six alkaloids are C(12) methoxy/C(12') hydroxy compounds, while the other two are C(12) hydroxy/C(12') methoxy compounds. Tiliacorinine (119), an alkaloid of this group, is a diastereoisomer of tiliacorine (118) and medelline (318). Nortiliacorinine A (116) has been isolated from four species of the genus Tiliacora, including T. racemosa, while nortiliacorinine B (117) has only been isolated from T. racemosa. The bissecondary amine pachyovatamine (250) has only been isolated from Pachygone ovata (Menispermaceae). Tiliacorinine (119) has been isolated from three species of Tiliacora^ including T. triandra, while tiliacorinine-2'-N-oxide (254) has only been isolated from T. triandra. Tiliarine (185) is solely a metabolite of T. racemosa, while yanangcorinine (388) has only been found in T. triandra. It can be observed that with the exception of pachyovatamine (250), all of the other five alkaloids have been isolated from Tilacora species. The S,S alkaloids appear to be of restricted distribution to the family Menispermaceae.

^OCH3

V

"R4

Alkaloid

B,

&

&

&

Nortiliacorinine A (116) Nortiliacorinine B (117) Pachyovatamine (250) Tiliacorinine (119) Tiliarine (185) Yanangcorinine (388)

H CH, H CH, CH, CH,

CH3 CH, CH, CH, H H

H H H H CH, CH,

CH, H H CH, H CH,

252

P.L. Schiff, Jr.

254 (R,S) Alkaloids The two alkaloids of this series are tiliacorine (118) and nortiliacorine A (115). These alkaloids are both monophenolic at C(12'), but the position of the secondary amine at N(2) or N(2') in the latter has not been determined. Tiliacorine has only been isolated from three species of the genus Tiliacora: T funifera, T racemosa, and T. triandra, while the nor-base 115 has been isolated from T. funifera and T triandra. Tiliacorine (118) is a diastereoisomer of tiliacorinine (119) and medelline (318). The alkaloids of this group are only found in the genus Tiliacora of the Family Menispermaceae.

Alkali

£.

&

Nortiliacorine A (115)

CH3 H or H CH3

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

253

(S,R) Alkaloid Medelline (318) is the only alkaloid in this group. This compound has been isolated from just Pseudoxandra aff. lucida (Annonaceae). Medelline is a diastereoisomer of tiliacorine (118) and tiliacorinine (119). „OCH3

v

OCH 3 318

Unknown stereochemistry Dinklacorine (114) is likely a diastereoisomer of yanangcorinine (388), the latter of which has been isolated from Tiliacora triandra, while dinklacorine (114) has been found in both Tiliacora dinklagei and Tiliacora triandra. />CH 3

CH 3
9.7.2. Type XIX |5,6,7\8M2-6\7M2(11-11)I The alkaloids of this type are very similar to those of Type XVIII, but differ by bearing additional oxygenation (phenolic or methyl ether) at C(5). (R,S) Alkaloid The only alkaloid of this small subgroup is norisoyanangine (335) a secondary, biphenolic alkaloid from Tiliacora triandra (Menispermaceae)

254

P.L.Schiff,Jr.

335 (S,S) Alkaloids All of the alkaloids of this small subgroup are phenolic at C(5). Noryanangine (346) is the N(2') nor-derivative of yanangine (389), both alkaloids having been isolated only from Tiliacora triandra (Menispermaceae). Tilianangine (386) is a positional isomer of yanangine (389), in which the former contains a phenolic hydroxy group at C(12) and a methoxy group at C(12'), and the latter has these groups reversed.

Alkaloid

R,

Noryanangine (346) CH3 Tilianangine (386) H Yanangine (389) CH3

&

£3

H CH3 H

H CH3 CH3

{?,?) Alkaloids There are three alkaloids in this group, each of which bears a C(5) methoxy group, and is phenolic at C(12'). The stereochemistry of the chiral centers at N(2) and N(2') is unknown. Tiliamosine (120) has been isolatedfromboth Pachygone ovata (Menispermaceae) and Tiliacora racemosa (Menispermaceae), while pachygonamine (249) and N-methylpachygonamine (243) have only been isolated from the former plant.

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

255

OCH3

*R3

^OCH3

Alkaloid

E,

E2

R3

Tiliamosine (120) Pachygonamine (249) N-Methylpachygonamine (243)

CH, H CH3

CH3 H H

H H CH3

It can be concluded that most of the alkaloids of Type XIX are restricted in distribution to the genus Tiliacora, with a few of the bases coming from one species of the genus Pachygone. 9.7.3. Type XlXa |5,7\8\12-6\7\12(11-11)| The only alkaloid of this type is tiliaresine (429), a base that only occurs in Tiliacora racemosa (Menispermaceae). The most unusual feature of this alkaloid is the lack of oxygenation at C(6), which is extremely uncommon for a bisbenzylisoquinoline alkaloid.

OCH3

H3
v

OCH 3 429

256

P.L.Schift,Jr.

9.8.

One Diphenyl Ether Linkage (Head-to-Tail) and One Benzylphenyl Ether Linkage (Head-to-Tail)

9.8.1. Type XXII - (6,7,8,12*-6,7,8*[7-12]) The alkaloids of this group are characterized by two unusual features: an extremely uncommon methyleneoxy bridge between ring C and ring A, and oxygenation at C(8). All of the alkaloids have a N(2') methyl group, as well as methoxy groups at C(6) and C(6'). With but one exception [cycleaneonine (286)], all of the alkaloids in this group have been isolated from just three species of the genus Cissampelos (Menispermaceae). (-,/?) Alkaloids The three alkaloids of this small subgroup are characterized by the presence of an imine function in ring B. Warifteine (151) is biphenolic at C(8) and C(7'), while dimethylwarifteine (148) bears two methoxy groups at these positions. Cissampareine (145) is monophenolic, and has also been called methylwarifteine (7'-methylwarifteine). Warifteine and dimethylwarifteine have only been isolated from Cissampelos ovalifolia (Menispermaceae), while cissampareine has only been found in Cissampelos pareira (Menispermaceae). It can be observed that the occurrence of these alkaloids is confined to a single genus (Cissampelos) of the family Menispermaceae.

Alkaloid

E.

E2

Cissampareine (145) Dimethylwarifteine (148) Warifteine (151)

H CH3 H

CH3 CH3 H

(?,R) Alkaloids The three alkaloids of this small subgroup are very similar to the last subgroup, except that the imine function in ring B has been reduced. Each of these three alkaloids is a secondary amine at N(2), but the stereochemistry at C(l) is unassigned. Each of the alkaloids has only been

The Bisbenzylisoqiiinoline Alkaloids - A Tabular Review

257

isolated from Cissampelos ovalifolia (Menispermaceae). Dihydrowarifteine (146) is the 1,2dihydro-derivative of warifteine (151), while dimethyldihydrowarifteine (147) is the 8',7dimethylether of dihydrowarifteine. Methyldihydro warifteine (149) is the monomethyl-derivative of dihydrowarifteine, but lacking definite assignment of the methyl ether to either the C(8') or C(7) positions. These alkaloids are confined to a single genus (Cissampelos) of the family Menispermaceae.

Alkaloid

R,

R2

Dihydrowarifteine (146) Dimethyldihydrowarifteine (147) Methyldihydrowarifteine (149)

H CH3 CH3 or H

H CH3 H CH?

(RfR) Alkaloid The only alkaloid of this very small subgroup is (-)-cycleaneonine (403), a metabolite of Cissampelos sutchuenensis (Menispermaceae).

403

258

P.L.Schiff,Jr.

(RfS) Alkaloid The only alkaloid of this equally small subgroup is isocycleaneonine (412), also a metabolite of just one plant, Cissampelos sutchuenensis (Menispermaceae).

412 Unknown stereochemistry Cycleaneonine (286), an alkaloid of undesignated stereochemistry, has only been isolated from Cyclea racemosa (Menispermaceae). The alkaloid is strongly dextrorotatory (+377°,CHC13), in contrast to the weakly dextrorotatory isocycleaneonine (+5°,CHC13), and the levorotatory (-)cycleaneonine (-119°,CHC13).

286 9.8.2. Type XXIIa (6,7AllM2-6,7*|7-12|) The alkaloids of this type, just as those of type XXII, are characterized by two uncommon features: an unusual methyleneoxy bridge between ring C and ring A, and oxygenation at C(8). All three alkaloids have a N(2) methyl group, as well as methoxy groups at C(6) and C(6'), but the stereochemistry of the chiral centers has not been determined. Cycleatjehine (405) and cycleatjehenine (404), alkaloids of Cyclea atjehensis (Menispermaceae), are fully oxidized in ring B', and differ only in their substitution at C(12), with the former being a phenol and the latter a methylether. Cissampentin (395) is a true bisbenzyltetrahydroisoquinoline alkaloid having the same structure as cycleatjehine (405), with the exception of the reduced ring B' in the former. Cissampentin has only been found in Cissampelos fasciculata (Menispermaceae).

259

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

Alkaloid

R

Cycleatjehcnine (404) Cycleatjehine (405)

CH3 H

395 9.9.

Two Diphenyl Ether Linkages (Head-to-Head) and One Diphenyl Ether Linkage (Tail-to-Tail)

9.9.1. Type XXIII (6\7\11\12-6,7\8M2") The alkaloids of this group are characterized by three diphenyl ether linkages, two of which form the dibenzodioxin system that constitutes upper portion of the molecule (head-tohead), while the third forms the diphenyl ether portion that constitutes the lower portion of the molecule (tail-to-tail). Eleven of these alkaloids lack a chiral carbon atom at C(l), but rather are instead are imine derivatives (3,4-dihydroisoquinolines) or true isoquinolines. (£,-) Alkaloid The sole alkaloid of this type is trigilletimine (162), a base only isolated from Triclisia species (T. dictophyllay T. gilletti, and T. patens) of the Menispermaceae. Ring B' is in its fully oxidized state, and exists as a benzylisoquinoline.

260

P.L. Schiff, Jr.

162 (-,*) Alkaloid The single alkaloid in this small subgroup is 1,2-dehydromicranthine (154), a compound that has only been found in an unnamed Daphnandra sp. (Monimiaceae). The nitrogen atom in Ring B exists in its imine form.

154 (-,5) Alkaloids No less than nine alkaloids have been isolated that lack chirality at the C( 1) position in ring B. Four of these bases are imines at N(2), while the other five are secobisbenzylisoquinolines in various oxidation states. The imine bases vary in their substitution at C(12), C(6'), and N(2'). One of these alkaloids, kurramine (237), is biphenolic at C(12) and C(6'), while 1,2-dehydroapateline (193) is monophenolic at C(12). 1,2-Dehydro-2'-nortelobine (292) is a secondary amine at N(2'). Kurramine (237) and 1,2-dehydro-2'-nortelobine (292) only occur in Cocculus pendulus (Menispermaceae), while both 1,2-dehydroapateline (193) and 1,2dehydrotelobine (194) have been isolated from various species of the Menispermaceous genera Anisocycla, Pachygone, and Stephania. 1,2-Dehydroapateline (193) has also been isolated from a Cocculus species (Menispermaceae), while 1,2-dehydrotelobine (194) has been found in one Albertisia species (Menispermaceae). Both 193 and 194 have been isolated from Daphnandra apatela (Monimiaceae) and Guatteria guianensis (Annonaceae), while 193 has also been found in Doryphora aromatica (Monimiaceae). Plants of the families Menispermaceae, Annonacaeae, and Monimiaceae serve as sources of the alkaloids of this subgroup.

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

261

^3

Alkaloid 1,2-Dehydroapateline (193) l,2-Dehydro-2'-Nortelobine (292) 1,2-Dehydrotelobine (194) Kurramine (237)

H CH3 CH3 H

E2

R3

CH3 CH3 CH3 H

CH3 H CH3 CH3

The secobisbenzylisoquinolines vary in the oxidation state of the C(9) carbon in Ring C, with one alkaloid being fully reduced to a methyl group [O-methyldeoxopunjabine (263)], one existing as a hydroxymethyl-derivative [secojollyanine (433)], two with the anticipated formyl groups [Omethylpunjabine (264) and punjabine (265)], and one in the highest oxidation state of a carbomethoxy group [gilgitine (261)]. Gilgitine (261) and punjabine (265) are phenolic at C(12), and both have only been isolated from Berbehs lycium (Berberidaceae). O-Methylpunjabine (264) and O-Methyldeoxopunjabine (263) have both been found in Stephania sasakii (Menispermaceae). Anisocycla jolly ana (Menispermaceae) is the source of both (-)-secojollyanine (433) and O-methylpunjabine (264). It can be observed that a limited number of plants from the Berberidaceae and Menispermaceae serve as sources of these seco-alkaloids.

E2

A1MQJ4 Gilgitine (261)

O-Methyldeoxopunjabine (263) O-Methylpunjabine (264) Punjabine (265) Secojollyanine (433)

COOCH3 CH3 CHO CHO CH2OH

H CH3 CH3 H CH3

262

P.L.Schiff,Jr.

(R,R) Alkaloids There are just three alkaloids within this group, and each has only been isolated from species of the genus Daphnandra (Monimiaceae). The parent alkaloid of the group, micranthine (159), has been isolated from Daphnandra micrantha and an unnamed Daphnandra species, while Omethylmicranthine (158) and N,0-dimethylmicrantnine (156) have been found in Daphnandra micrantha, Daphnandra species Dt-7, and an unnamed Daphnandra species. The occurrence of these alkaloids appears to be strictly restricted to the genus Daphnandra.

Alkaloid

R,

R2

N,0-Dimethylmicranthine (156) O-Methylmicranthine (158) Micranthine (159)

CH3 H H

CH3 CH3 H

(R,S) Alkaloids The five alkaloids of this group differ via their substitution at N(2), C(12), and C(6'). Two of the alkaloids are the N(2) nor- compounds apateline (187) and telobine (160). Three of the alkaloids are phenolic at C(12); apateline (187), N-methylapateline (207), and Nmethylnorapateline (208). N-methylnorapateline (208) is also phenolic at C(6), even though the nor- designation is commonly reserved for the loss of a methyl group from a nitrogen atom, not an oxygen atom. N-Methylapateline (207) and N-methylnorapateline (208) have only been isolated from one plant, Daphnandra johnsonii (Monimiaceae), while N-methyltelobine has only been found in Stephania erecta (Menispermaceae). Telobine (160) has been isolated from two Daphnandra species, D. apatela and £>. species Dt-7 (Monimiaceae), as well as from Guatteria guianensis (Annonaceae). Apateline (187) has been isolated from two Menispermaceous plants, Albertisia laurifolia and A. papuana, as well as from the Annonaceous Guatteria guianensis. Apateline has only been isolated from one Daphnandra species, D. apatela (Monimiaceae). The occurrence of these alkaloids appears to be restricted to one genus each in the Annonaceae and the Monimiaceae, and two genera of the Menispermaceae.

263

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

Alkaloid

R,

R2

R,

Apateline (187) N-Methylapateline (207) N-Methylnorapateline (208) 2-N-Methyltelobine (418) Telobine (160)

H CH, CH, CH, H

H H H CH, CH,

CH, CH, H CH, CH,

(S,S) Alkaloids By far the largest subgroup of alkaloids within the Type XXIII bases is that subgroup in which the S,S stereochemistry exists at C(l)/C(l'). The thirteen alkaloids of this subgroup differ in their substitution at the N(2), C(12), C(6'), and N(2') positions. Six of the thirteen alkaloids are secondary amines at N-2, while five are secondary amines at N-2\ Two of the alkaloids, 2'norcocsoline (421) and 2'-norcocsuline (329), are bis secondary amines. Eight of the thirteen alkaloids are phenolic at C(12), but only two [12-O-methyltricordatine (419) and tricordatine (161) are phenolic at C(6')]. Isotrilobine (157) is the fully methylated parent alkaloid of the group. There are three N-oxide alkaloids within this group, including cocsuline-N-2-oxide (231), cocsoline-2'P-N-oxide (398), and 12-0-methylcocsoline-2'P-N-oxide (414). Cocsoline (152) and its analogs, O-methylcocsoline (239), 2'-norcocsoline (421), cocsoline-2'P-N-oxide (398), and 12O-methylcocsoline-2'p-N-oxide (414) have only been isolated from genera within the Menispermaceae, including Albertisia, Anisocycla, Cocculus, Pachygone, and Synclisia. Cocsuline (153)(N-methylcocsoline) has likewise only been isolated from Albertisia, Anisocycla, Cocculus, and Synclisia species, while 2'-norcocsuline (329) has been found in Albertisia and Pachygone species. Trilobine (163) has been isolated from Anisocycla, Cocculus, and Pachygone species, while isotrilobine (157) has been isolated from species of Albertisia, Anisocycla, Cocculus, Pachygone, and Stephania. Nortrilobine (247) has only been isolated from Pachygone ovata (Menispermaceae). Tricordatine (161) has been found in species of Cocculus, Pachygone, and Triclisia. In conclusion, all thirteen alkaloids of this subgroup have only been found in genera of the Menispermaceae. These genera include: Albertisia, Anisocycla, Cocculus, Pachygone, Stephania, and Synclisia. Only the occurrence of tricordatine (161) in Triclisia subcordata is from a different Menispermaceous genus.

264

P.L. Schiff, Jr.

Alkaloid

R,

R2

Cocsuline (153) Isotrilobine (157) 12-O-Methyltricordatine (419) Tricordatine (161)

H CH3 CH3 H

CH3 CH3 H H

Alkaloid

R

Cocsoline (152) O-Mcthylcocsolinc (239)

H CH3

AMo>d

E

12'-0-Demethyltrilobine (155) Trilobinc (163)

H CH3

265

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

W H'

Alkaloid

R

2'-Norcocsoline (421) Nortrilobine (247)

H CH,

H3C

231

W

H'

•«CH,

H'

^OCH3 414

266

P.L.Schlff,Jr.

9.9.2. Type XXIIIa (6*,7Ml\12-5,6,7\8*,12*) The alkaloids of this group are the same as those in Type XXIII with regard to their ether linkages, but differ by the presence of C(5') oxygenation in the form of a phenolic hydroxy group. (-,5) Alkaloids The four alkaloids of this group have only been found as metabolites of Cocculus pendulus (Menispermaceae). These compounds are characterized by unsaturation in ring B, with 1,2-dehydrokohatamine (289) and 1,2-dehydrokohatine (290) being 3,4-dihydrobenzylisoquinoline derivatives, while siddiquamine (371) and siddiquine (372) are benzylisoquinoline derivatives. 1,2-Dehydrokohatamine (289) and 1,2-dehydrokohatine (290) differ in the nature of substitution at C(12), with the former being a methyl ether while the latter is phenolic. A similar analogy is true for siddiquamine (371) and siddiquine (372).

Alkaloid

R

1,2-Dehydrokohatamine (289) 1,2-Dehydrokohatine (290)

CH3 H

AlKalpid

E

Siddiquamine (371) CH3 Siddiquine (372) H

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

267

(R,S) Alkaloids The two alkaloids of this small subgroup, 5-hydroxyapateline (309) and 5-hydroxytelobine (310), have only been found as constituents of Cocculus pendulus (Menispermaceae). These two alkaloids differ in their substitution at C(12), with the former being phenolic and the latter a methyl ether. Neither apateline (187) nor telobine (160) have been isolated from the genus Cocculus, but apateline (187) has been found in several other Menispermaceous genera, while telobine (160) has been isolated from genera of the Monimiaceae and Annonaceae.

Alkaloid

R

5-Hydroxyapateline (309) 5-Hydroxytelobine (310)

H CH3

(5,5) Alkaloids The two alkaloids of this subgroup, kohatamine (314) and kohatine (236) are the ring B fully reduced parent alkaloids of 1,2-dehydrokohatamine (289) and 1,2-dehydrokohatine (290), as described above. As with their oxidized counterparts, kohatamine (314) and kohatine (236) have only been isolated from one plant, Cocculus pendulus (Menispermaceae).

Alkaloid

E

Kohatamine (314) Kohatine (236)

CH3 H

268

P.L.Schifr,Jr.

9.9.3. Type XXIV - (6,r,8+,ll\12-6,7%8#,12#) The alkaloids of this group are characterized by two diphenyl ether bridges linking the dimer in a head-to-head fashion and one diphenyl ether bridge linking the dimer in a tail-to-tail manner. The head-to-head linkages are unusual in that they bond C-7 to C-8' and C-8 to C-7\ thereby producing a molecule with a very different spatial configuration than that found in the more traditional Type XXIII alkaloids (C-6 to C-7' and C-7 to C-8'). All of the alkaloids of Type XXIV share one structural feature - the presence of a C(6) methoxy group. (£,-) Alkaloids

Menisarine (165), a ring B' 3,4-dihydrobenzylisoquinoline alkaloid found in Cocculus leaebe and C. sarmentosus (Menispermaceae), is the only representative of this small subgroup whose structure has been firmly established. The structure of normenisarine has not been fully elucidated, but it is known that it is a derivative of menisarine, in which there is one phenolic group at one of the three ring substituted positions [C(6) or C(12) or C(6')]. As before, the prefix "nor-" is used incorrectly, and one would erroneously assume that normenisarine was in fact N-demethylmenisarine. Normenisarine has only been isolated from Cocculus thlobus (Menispermaceae). The two representatives of this small subgroup appear to be confined to a single genus (Cocculus) of the Menispermaceae.

165

(S,S) Alkaloids

The least substituted alkaloid of this subgroup is cocsilinine (397), which is a bissecondary amine that is also biphenolic at C(12) and C(6'). The other five alkaloids of this subgroup are derivatives of cocsilinine (397), in which varying numbers of methyl groups are found on the nitrogen atoms and the phenolic carbon atoms at C(12) and C(6'). The structure of cocsiline (396) has not been fully elucidated because the position of the single N-methyl group at either N(2) or N(2') has not been firmly established. Monosecondary amines in this subgroup include N-norcocsulinine (422)(N-2 nor-), and gilletine (202) (N-2r nor-). Five of the six alkaloids are phenolic at C(12) [the exception being gilletine (202)], while four of the six alkaloids are phenolic at C(6') [exceptions being O-methylcocsulinine (415) and cocsiline (396)].

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

269

With the exception of gilletine (202), the other five alkaloids, including cocsilinine (397), cocsiline (396), cocsulinine (164), N-norcocsulinine (422), and O-methylcocsulinine (415) have only been isolated from one plant, Cocculus pendulus (Menispermaceae). Gilletine (202) has been found as a metabolite of Triclisia gilletti (Menispermaceae).

„OCH3

'H

Alkaloid

R.

Cocsiline (396)

H

Cocsilinine (397) Cocsulinine (164) Gilletine (202) O-Methylcocsulinine (415) N-Norcocsulinine (422)

CH, H CH, CH, CH, H

R2 or H H H CH, H H

R3 CH,

CH,

CH, H H H CH, H

H H CH, H CH, CH,

It can be concluded that the occurrence of the alkaloids of this subgroup is almost completely restricted to one plant, Cocculus pendulus (Menispermaceae). Only one other Menispermaceous species, Triclisia gilletti, is known to contain an alkaloid of this type. Hence, the distribution of these bases is, for the time being, restricted to the Family Menispermaceae. 9.9.4. Type XXVIII ( 6 , 7 \ r f l l \ 1 2 - 6 \ 7 \ 1 2 i ) Angchibangkine (394), the sole member of this group of alkaloids, has only been found as a metabolite of Pachygone dasycarpa (Menispermaceae). This alkaloid is the prototype of a new group, in which the dibenzo-p-dioxin link in the top portion of the molecule is linked differently (C-7 to C-6' + C-8 to C-7') than in those more commonly occurring alkaloids of Group XXIII (C-6 to C-7' + C-7 to C-8'). The alkaloid possess the S,S stereochemistry at its chiral centers.

270

P.L. Schiff, Jr.

394 Incompletely characterized alkaloids Isogilletine-N-oxide (204), an alkaloid of Triclisia gilletti (Menispermaceae), is a compound of undefined stereochemistry. The molecular structure of isogilletine-N-oxide (204) is identical to that of gilletine (202), but with the addition of the oxide to the N(2) position. Pendilinine (425)[which may also be designated 6'-0-methylgilletine (425)], an alkaloid of Cocculuspendulus (Menispermaceae), is also an alkaloid of unestablished stereochemistry. The placement of these alkaloids in this subgroup is consistent with their plant sources being Menispermaceous plants of the genera Cocculus and Triclisia.

425

The Bisbenzylisoquinoline Alkaloids - A Tabular Review 9.10.

271

One Diphenyl Ether and One Benzylphenyl Ether Linkage (Head-to-Head) and One Diphenyl Ether Linkage (Tail-to-Tail)

9.10.1. Type XXV - (6,7,8\HM2,13-6,7\12*[8-6j) This very unique and quite small group of alkaloids is characterized by a head-to-head linkage that is accomplished by both a diphenyl ether and a benzylphenyl ether, with the tail-totail linkage being the more classical diphenyl ether. In addition, the C(8) position is unusual in that it is the ring A terminus for both the diphenyl ether link and the benzylphenyl ether link. This type of linkage is accompanied by the presence of a carbonyl group at C(7), thus altering the customary aromaticity of ring A. The parent alkaloid of the group is repanduline (168), a base that has only been isolated from three species of the genus Daphnandra; D. dielsii, D. repandula, and D. tenuipes. The other alkaloid of the group, pseudorepanduline (167), differs from repanduline in that the former has a methoxy group at C(12) and a hydroxy group at C(13),while the latter has a methylenedioxy group at those positions. Pseudorepanduline (167) has only been found in Daphnandra dielsii and an unnamed Daphnandra species. The chirality at C(l) and C(l') has not been established for these alkaloids.

272

P.L.Schifr,Jr.

9.11. One Diphenyl Ether and One Benzylphenyl Ether Linkage (Head-to-Tail) and One Diphenyl Ether Linkage (Head-to-Tail) 9.11.1. Type XXVI - (6,7,8\l2*-6,7,8*,12*lll-7)) There are only four alkaloids in this small group, with their distribution being restricted to only four genera of the family Menispermaceae. These alkaloids are characterized by head-to-tail linkages, with two diphenyl ether linkages and one benzylphenyl ether linkage. Each of the four alkaloids is characterized by R9R stereochemistry at the chiral C(l) and C(l') carbon atoms. There are two parent alkaloids for this subgroup; insulanoline (169) and insularine (7methylinsulanoline)(170). Insulanoline has been isolated from three Cyclea species (C. hypoglauca, C insularis, C sutchuenensis)(Memspcrmaceae), while insularine has been isolated from Cissampelos pareira, the same three Cyclea species that insulanoline has been isolated from, and from Paracyclea ochiaiana, Stephania japonica, and Stephania japonica var. australis (Menispermaceae). The other two alkaloids of this group are oxides of insularine, insuarine-2pN-oxide (408) and insularine-2'P-N-oxide (409), with both compounds only being reported as metabolites of Cyclea sutchuenensis (Menispermaceae). It appears that the alkaloids of this group have a very restricted distribution to several selected genera of the Menispermaceae.

Alkaloid

R

Insulanoline (169) Insularine (170)

H CH3

408

The Bisbenzylisoquinoline Alkaloids - A Tabular Review

273

409 Acknowledgements. The author would like to acknowledge the patience and assistance of many individuals who performed multiple duties, including filing, photocopying, and obtaining manuscripts from various libraries: Ms. Mary Birr, Ms. Beth Kitchen, Ms. Geraldine Robinson, Ms. Cathy Stevenson, Mr. Tawfeq Al-Howiriny, Dr. Adnan Al-Rehaily, and Dr. Maged Sharaf. A special debt of thanks goes to Dr. Al-Rehaily, who was so kind as to produce the structures. The efforts of Ms. Ruth Quimby and NAPRALERT (Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, The University of Illinois at Chicago) are deeply appreciated.

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382. 383. 384. 385. 386. 387. 388. 389. 390. 391. 392. 393. 394. 395. 396. 397. 398. 399. 400. 401. 402. 403. 404. 405. 406. 407. 408. 409.

410. 411. 412. 413. 414. 415. 416. 417. 418. 419. 420. 421. 422. 423. 424. 425.

The Bisbenzyllsoqutnoline Alkaloids - A Tabular Review 426. 427. 428. 429. 430. 431. 432. 433. 434. 435. 436. 437. 438. 439. 440. 441. 442. 443. 444. 445. 446. 447. 448. 449. 450. 451. 452. 453. 454. 455. 456. 457. 458. 459. 460. 461. 462. 463. 464. 465. 466. 467. 468. 469.

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472. 473. 474. 475. 476. 477. 478. 479. 480. 481. 482. 483.

Chapter Two

Alkaloids from Malaysian Flora Toh-Seok Kam Department of Chemistry University of Malaya 50603 Kuala Lumpur Malaysia

CONTENTS 1.1. INTRODUCTION 1.2. ALKALOID CONTAINING MALAYSIAN PLANTS 1.3. STRUCTURE ELUCIDATION AND CHEMISTRY 1.3.1. Isoquinoline and related alkaloids 1.3.2. Steroidal alkaloids 1.3.3. Monoterpene alkaloids 1.3.4. Indole alkaloids 1.3.5. Bisindole alkaloids 1.3.6. Miscellaneous nitrogenous natural products 1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants 1.4. BIOLOGICAL ACTIVITY 1.5. CONCLUSION 1.6. ADDENDUM REFERENCES

286 286 316 316 324 326 329 379 393 395 416 418 419 426

286

T.-S. Kara

1.1. INTRODUCTION Malaysia (incorporating the Malayan Peninsular and Malaysian Borneo) is located in the heart of South East Asia and constitutes part of the Malesian phytogeographical region. Its position near the Equator confers on it a typically tropical climate, characterized by high temperatures, humidity and rainfall throughout the year. Such conditions are conducive to plant life and have resulted in a rich and thriving flora. It is estimated that the country is home to some 15,000 species of higher plants [1,2]. The potential for botanical and chemical studies and for discovery of novel chemical constituents, especially those possessing useful bioactivities is therefore immense. The need for such studies has assumed a greater urgency in recent times in the wake of the threat posed by rapid development and with the growing concern that valuable plant substances which may present useful lead compounds for drug discovery may be lost. The study of alkaloids has always assumed a preeminent position in the early studies by investigators in the late 1960's and 70's. Perhaps this has to do with the easier isolation associated with this group of compounds due to their basic nature, or perhaps the fact that alkaloids invariably possess strong physiological properties presented an added incentive. The early studies were mainly dominated by phytochemical screening of plant samples for the presence of alkaloids, terpenes and saponins [3-10]. Interspersed between these studies were the occasional chemical studies of various plants, mainly with respect to the occurrence and structure of indole alkaloids and usually undertaken with collaboration of better equipped laboratories. With better facilities, the study of natural products and of alkaloids in particular attained greater momentum in the eighties which has continued through to the nineties. This review will concentrate on work published in the last 20 years or so with the exception of a few background papers, since this is the period when most of the work on the chemistry of alkaloids from Malaysian plants have emerged. In writing this review we are mindful of the fact that it is somewhat artificial to suppose that flora are respecters of national boundaries, hence the chemistry of the plants described in this chapter could very well be representative of similar flora found in other parts of the South East Asian region. In view of this, we will as far as possible and wherever appropriate, compare the occurrence of alkaloids with studies of similar plants from neighbouring countries, especially Thailand and Indonesia.

1.2. ALKALOID CONTAINING MALAYSIAN PLANTS There has been a number of phytochemical surveys of Malaysia that have been carried out in the period spanning the last three decades, especially during the earlier period of the sixties and seventies [3-17]. These surveys have provided useful information for subsequent

287

Alkaloids from Malaysian Flora

investigators in cataloging the results of tests for the presence of alkaloids and other constituents. Table 1 summarizes the alkaloid producing species found in Malaysia. The plants are listed systematically under family, genus and species. The alkaloids were detected by the Mayer or Dragendorff reagents or by TLC of an alkaloidal extract followed by detection with the Dragendorff reagent. The test results are cited as strong (s), medium (m), weak (w) or just (+) in cases where a positive result was obtained but no attempt was made to estimate the relative amount. The plant parts examined are abbreviated as follows: L (leaves), B (bark), S (stem), Wd (wood), Sd (seed), F (fruit), Fl (flowers), R (root) and W (whole plant). It is evident from examination of these results as well as from the subsequent chemical studies that have followed that alkaloid rich species predominate in the Families Annonaceae, Apocynaceae and Rubiaceae and to a lesser extent in Lauraceae, Menispermaceae, Verbanaceae, Euphorbiaceae and Rutaceae.

Table 1. Alkaloid-positive plants from phytochemical surveys

Plant Acanthaceae Acanthus ebracteatus Wall. Andrographis paniculata Nees Asystasia nemorum Nees Filetia glabra Ridl. Gendarusa vulgaris Justicia ptychostoma Nees Lepidagathis longifolia Wight Pseuderanthemum graciliflorum Nees Staurogyne lanceolata Kze Thunbergia alata Thunbergia natalensis Hk. f. Actinidiaceae Saurauia nudiflora Aizoacea Sesuvium portulacastrum (L.) L

Plant part

Alkaloid test

References

L,B W W W S,R W R W L,B W L W L W

w +

[in

w w s w s m w w m m + w

[11] [9] [4]

L

w

[16]

W

m

[7]

[6]

[11] [5] [9] [11] [10] [17] [11] [3] [9]

288

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Alangiaceae Alangium griffithii (Clarke) Harms. Amaranthaceae Celosia argentea Anacardiaceae Buchanania lucida Bl. Mangifera caesis Jack, ex Wall.

Melanorrhoea woodsiana Scort. Ancistrocladaceae Ancistrocladus tectorius (Lour.) Merr. Annonaceae Alphonsea cylindrica King Alphonseajohorensis J. Sinclair Alphonsea kinabaluensis J. Sinclair Anaxagorea javanica Bl. Artabotrys blumei Hk. f. & Thorns. Artabotrys crassifolius Hk.f. Artabotrys grandifolius King Artabotrys maingayi Hk. f. Artabotrys suaveolens Bl. Artabotrys venustus King Canangium odoratum Baill. Cyathocalyx pahangensis J. Sinclair

Plant part

Alkaloid test

References

F,Wd

w

[7]

L

+

[3]

S L S S S

w w w m +

[10] [7,9]

L,S

[7]

P] [6] [7]

L B L L B S L S L B B

s m m s m w w m w s m

B B L, S, Fl B B L B

s s +

[11] [11,12]

s + w s

[11] [6]

[11] [12] [11] [10] [10] [11] [11]

[6]

[H]

Alkaloids from Malaysian Flora

289

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Cyathocalyx scortechinii (King) J. Sinclair Cyathostemma excelsum J. Sinclair Cyathostemma hookeri Cyathostemma wrayi King Desmos chinensis Lour. Desmos dasymaschalus (Bl.) Saff. Desmos dasymaschalus Saff. var. wallichii Disepalum pulchrum (King) J. Sinclair Drepanthus pruniferus Maing. Enicosanthum congregatum (King) Airy-Shaw Enicosanthumfitscum(King) Airy-Shaw Enicosanthum membranifolium Fissistigma lanuginosum Merr. Fissistigma latifolium (Dun.) Merr. Fissistigma manubriatum Merr. Friesodielsia acuminata (Merr.) van Steenis Friesodielsia biglandulosa Friesodielsia calycina Friesodielsia korthalsiana Miq. Goniothalamus curtisii King

Plant part

Alkaloid test

References

B

w

[11]

L,B L S R B L S L,B L,B

w m w s s w m s m

[H] [12] [4] [11] [12] [11] [11]

[in F,S L B L

w w w m

[7] [11,14] [14]

,, Sd, R L B B L,S L,B L

s s m w w w s

[5] [11]

L L L L B L

w w w w m m

[14] [14]

[11]

[11] [12] [11] [H]

[11] [8,11] [8,11,13] [13]

290

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Goniothalamus fulvus Hk. f. Goniothalamus malayanus Hk. f. &Th. Goniothalamus ridleyi King

Goniothalamus rufus Miq. Goniothalamus subevenius King Goniothalamus suluensis Merr. Goniothalamus uvarioides King Meiogyne virgata (BI.) Miq. Mezzettia umbellata Becc. Miliusa longipes Mitrephora maingayii Monocarpia marginalis (Scheff.) J. Sinclair Oncodostigma monosperma J. Sinclair Orophea enterocarpa Maing Oxymitrafilipes Hk. f. Oxymitra kingii J. Sinclair Oxymitra latifolia Hk. f. Phaeanthus crassipetalus Becc.

Plant part

Alkaloid test

References

L B B

w m w

IU)

L L B S L,B S

s w m m s w

B B L L,B B B B,R B L B R B

s w w s m w s s s w s m

111] [11] [14]

B

s

[11]

L B B L B L B

m s s m s s s

[11]

[12] [5] [H] [9] [11] [10]

[11] [12] [12] [4] 15] [11] 14] [11]

[11] [11] [11,14] [11]

Alkaloids from Malaysian Flora

291

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Phaeanthus nutans Phaeanthus ophthalmicus (Roxb.) J. Sinclair Polyalthia affinis T. & B. Polyalthia cauliflora Hk. f.

Polyalthia cinnamomea Hk. f. & Th. Polyalthia clavigera King Polyalthia cunangiodes Polyalthia hookeriana Miq.

Polyalthia hypoleuca Hk. f. & Th. Polyalthia insignis (Hk. f.) Airy-Shaw

Polyalthia jenkensii Hk. f. et Th. Polyalthia macropoda Polyalthia microtus Miq. Polyalthia motleyana var. glabrescens Airy-Shaw Polyalthia rumphii (Bl.) Merr. Polyalthia stenopetala (Hk. f. & Th.) Ridley

Plant part

Alkaloid test

References

L,B L, S, F, R L,B R S L B S L B L L,B L L,B,R L,B L,B L,B,S

s s s s w w s m w s m w w s s m w

[4] [5] [4,11] [4] [10] [11,12]

L B L,B L B B L,B,R L B S,R L,B L

w s s m s w s w s s w w

[11]

L B

w s

[H]

[H] [12] [11] [14] [11] [15] [5] [11] [14] [12]

[12] [15] [14] [5] [11] [5] [11] [H]

292

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Polyalthia tenuipes Merrill Popowia odoardoi Diels Popowia perakensis King Popowia pisocarpa (Bl.) Endl.

Popowia ramosissima Popowia tomentosa Maingay ex Hk. f. & Th. Pseuduvaria macrophylla (Oliv.) Merr. Pseuduvaria monticola J. Sinclair Trivalvaria macrophylla (Bl.) Miq. Trivalvaria pumila J. Sinclair Uvaria lobbiana Hk.f. & Th. Uvaria sorzogonensis Presl. Xylopia caudata Hk. f. & Th.

Plant part

Alkaloid test

References

L,B L B B B,R,Sd L,B L L,B,R Sd,R L B L B B B S,R L R B L,S L B L,S L,B

w w s m s s m s s m s w m m s s m s s w m w w w

nil

Xylopia ferruginea Hk. f. & Th. Xylopia fusca Maing ex. Hk. f. &Th. L,B Xylopia stenopetala Oliv. Apocynaceae L Aganosma marginata (Roxb.) G. Don L,S Allamanda catharica L. L Alstonia angustifolia var. latifolia L L L Alstonia angustifolia Wall

tin nil [5] [4,U] [15] [4] [5] [11] [11] [11] [11] [4] [11] [4] [11] [12] [12] [7] [12] [12]

w w s m w m

[12] [7] [16]

[12]

AlkaloidsfromMalaysian Flora

293

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Alstonia angustifolia Wall Alstonia angustiloba Miq. Alstonia macrophylla Wall, ex G. Don Alstonia spathulata Bl.

Alstonia undulifolia K. M. Koschummen et K.M. Wong Chilocarpus costatus Chilocarpus obtusifolius Merr. Chilocarpus vernicosus Bl. Chonemorpha penangensis Dyera costulata Hk. f. Dyera laxiflora Hk. f. Dyera polyphylla (Miq.) Ashton Ervatamia coronaria (Wild.) Stapf. Ervatamia cylindrocarpa (King and Gamble) Corner Ervatamia macrocarpa Hk.f. Ervatamia malaccensis Ervatamia peduncularis Wall. Ervatamia polyneura (Scort. ex King and Gamble) Corner Hunteria zeylanica (Retz.) Gardn.ex Thw. Kibatalia maingayi Hk. f. R. E. Wood Kopsia arborea Bl.

Plant part

Alkaloid test

B L L,B L,B L L,B L B B

s m s s + s w s m

[11] [10,12]

R L

s m

[4]

L,B L,S R L L,S L L B L

w s s w + w s w w

[11] [4] [5] [12]

L,B L,S,R L L B L,B

s s s m s s

[11] [5] [11] [11]

L, B, R, Fl L L

s w s

[5] [12]

References

[11] [12] [7,11] [3]

[4] [11]

[11]

[6] [12] [11] [11]

[11]

[11,18]

294

T.-S. Kfttn

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Kopsia arborea Bl. Kopsia dasyrachis Ridl. KopsiafruticosaA. DC

Kopsia griffithii King and Gamble Kopsia lapidilecta van der Sleesen Kopsia larutensis King and Gamble Kopsia macrophylla Hk. f. Kopsia mitrephora van der Sleesen Kopsia pauciflora Hk. f. Kopsia profunda Markgraf

Plant part

Alkaloid test

References

S L B L,B L S L,B

m m s s m s s

[18]

L,B L,B

s s

[11] [1U8]

s s s s m s s w s + w w s s w s m w s s +

[11] [11] [11,19] [18]

L,B L,B L,B L S L,B Kopsia sleeseniana Markgraf & Bl. L,B Kopsia singapurensis Ridl. L S S L Kopsia tenuis Leenh. & Steenis B L,B Kopsia teoi L. Allorge L, Sd, B, R Leuconotis eugenifolia L,B Leuconotis griffithii Hk. f. L,S,R B B Leuconotis maingayi Dyer L,S Lochnera rosea Reichb. R L L Melodinus orientalis BL

w

[11] [11] [8] [11]

[12] [11]

m [6] [12,19] [19] [19] [5] [20] [4] [11,12] [11] [4,7] [4] [3] [12]

Alkaloids from Malaysian Flora

295

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Rauvolfia perakensis King and Gamble Rhynchodia verrucosa Tabernaemontana coronaria Tabernaemontana corymbosa Roxb. Tabernaemontana macrocarpa Jack Tabernaemontana malaccensis Hk. f. Tabernaemontana pandacaqui Lam Tabernaemontana peduncularis Tabernaemontana sphaerocarpa BI. Voacanga havilandii Ridl. Araceae Amorphophailus campanulatus Araliaceae Aralia montana Bl. Polyscias cf.javanica K. & V. Scheffierajunghuniana (Miq.) Harms Aristolochiaceae Apama corymbosa Soler. Asclepiadaceae Asclepias curassavica Calotropis gigantea Ait. Dischidia rqfflesiana Wall.

Plant part

Alkaloid test

References

S

+

[6]

R L,S L L L F L,S,R B L

s s s w w m s s w

[5]

L,R L B L B

s m s m s

Sd

W ["] [12] [12] [4] [11] [12] [4] [12] [12]

[5]

F S S

w w w

[7] [10]

L,S L

w w

[7] [10]

L S L,S

+ + +

[3] [6] [6]

[9]

296

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Bombacaceae Durio zibethinus Murr. Boraginaceae Heliotropium indicum Caesalpiniaceae Bauhinia purpurea L. Cassia spectabilis (cf. Corner) Saraca declinata (Jack) Miq. Campanulaceae Isotoma longiflora Presl. Laurentia longiflora (L.) Petermann Pratia begoniaefolia Lidl. Capparidaceae Capparis micracantha DC. Capparis scortechinii Cleome rutidosperma DC. Crataeva membranifolia Miq. Caricaceae Carica papaya Celastraceae Glyptopetalum quadrangulare Kurrimia paniculata Wall. Chloranthaceae Chloranthus brachystachys Bl. Clusiaceae Garcinia paTvifolia (Miq.) Miq. Compositae Adenostemma lavenia Ageratum conyzoides

Plant part

Alkaloid test

References

B, Wd, Sd

w

[7]

S

s

[4]

L,S L S S

w m w w

[10]

L,S,W L,F,R W

+ s s

[6] [4] [7]

W

w

[9J

L B L, B, Sd, R W B

w m s w w

[11]

L

+

[3]

L,B L

m s

[13] [8]

B

w

[11]

L,S

w

[7]

L L

+ +

[3] [3]

[8] [9]

[5] [8] [11]

Alkaloids from Malaysian Flora

297

Table 1. Alkaloid-positive plants from phytochemicai surveys (cont.)

Plant Blumea balsamifera Elephantopus tomentosus L. Erichtites valerianifolia Pluchea indica Synedrella nodiflora Vernonia arborea King Vernonia cineria Vernonia patula Connaraceae Cnestis palala var. palala Convolulaceae Erycibe stapfiana Jacquemontia tomentella Cornaceae Alangium unilcoulare King Aralidium pinnatifldum Miq. Mastixia cuspidata Cucurbitaceae Gymnopetalum integrifolium Trichosanthes wallichiana Trichosanthes wawraei Datiscaceae Octomeles sumatranum Miq. Dichapetalaceae Dichapetalum griffithii Dilleniaceae Tetracera scandens (L.) Merr Dioscoreaceae Dioscorea hispida Dioscorea scortechinii

Plant part

Alkaloid test

References

L W L L L L L L L

+

[31

w + + + w w + +

[7] [3] [3] [3]

R

s

[5]

F L

s +

[5] [3]

L S L L

w m w w

M [*] [16]

Sd R Sd

s s s

[5] [5] [5]

B

w

[H]

L,S,R

s

[5]

F

w

[7]

S,R B

s s

[4] [5]

[11] [17] [3] [3]

298

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Dipterocarpaceae Dipterocarpus crinitus Dyer. Shorea curtisii Dyer ex King Shorea glauca King Shorea resina-negra Foxw. Ebenaceae Diospyros discolor Willd. Diospyros subrhomboidea Elaeocarpaceae Elaeocarpus brevipes Elaeocarpus petiolatus (Jack.) Wall. Elaeocarpus robustus Roxb. Ericaceae Lyonia ovalifolia (Wall.) Drude Rhododendron jasminiflorum Hk. Rhododendron stenophyllum Vaccinium dialypetalum J. J. S. Vaccinium laurifolium (Bl.) Miq. var. ellipticum (Bl.) Sleum. Vaccinium viocifolium K.&G. var. bicalcaratum Sleum. Escalloniaceae Polyosma laete-virens Griff. Euphorbiaceae Acalypha grandis Benth. var. longi-acuminata Hayata Acalypha indica L. Agrostistachys gaudichaudi Mull. Antidesma cuspidatum Muell.-Arg. Antidesma pendulum Hook. Antidesma salicinum Ridl.

ant part

Alkaloid test

Referer

S L,B L,S L,B

w w w w

[8] [7] [7] [7]

L,S S,F

+ s

[6] [4]

L L,S

+ w

[3] [7]

L, S

w

[7]

B L L S L

w w + w w

[11] [11] [3] [11] [11]

S

w

[11]

L

w

in]

-,s

w

[8]

W B W L

w m w w m w

[10]

s s

[11] [9] [8] [10]

Alkaloids from Malaysian Flora

299

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Aporosa arborea (Bl.) M. A. Aporosa symplocoides Baccaurea lanceolata Baccaurea motleyana Bridelia ovata Decne. Bridelia stipularis (L.) Bl. Bridelia fomentosa Bl. Claoxylon longifolium (Bl.) Endl. ex Hassk. Croton argyratum Bl. Crotonjoufra Roxb. Elateriospermum tapos Bl. Emblica officinalis Gaertn. Euphorbia atoto Forst. f. Flueggea virosa Baill. Gelonium glomerulatum Glochidion cf brunneum Glochidion leiostylum Kurz Glochidion sericeum (Bl.) Hk.f. Glochidion wallichianum Mull. Jatropha gossypifolia L. Macaranga curtisii Macaranga hullettii King (male) Macaranga triloba Muell.-Arg. Mailotus cf. floribunda Mull. Mallotus philippinensis Muell.-Arg. Melanolepis multiglandulosa (Bl.) Rchb. f. & Zoll. Microdesmis ceasarifolia Omalanthus populnea (Geisel.) Pax.

Plant part

Alkaloid test

References

L L L,B F F S L,S,F L

w m m s +

[10] [14]

L,S W L B L,S S L,S Sd L,B S L F S L L,S L S F L

B,R L,S

w w m w + w w + m s s m w w w m w w + +

[15] [4] [6] [9] [7] [12] [7] [6] [11] [11] [6] [7] [7] [5] [13] [10] [11] [7] [7] [17] [7] [3] [6]

w w

[8] [9]

w

[10]

s w

[5] [7]

300

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Ostodes macrophylla Benth. Ptychopyxis caput-medusae Sapium baccatum Roxb. Fagaceae Castanopsis lucida Ficoidaceae Sesuvium portulacastrum (L.) L. Flacourtiaceae Casearia clarkei Homalium caryophyllaceum (Z. & M.) Benth. Flagellariaceae Flagellaria indica L. Geseriaceae Cyrtandromoea acuminata Bth. & Hk. Didymocarpus hispida Ridl. Gnetaceae Gnetum brunonianum Gnetum cuspidatum Bl. Gnetum latifolium Bl. Goodeniaceae Scaevola taccada (Gaertn.) Roxb. Gramineae Imperata cylindrica Hernandiaceae Hernandia ovigera L. Hippocrateaceae Salacia grandiflora Kurz Icacinaceae Gomphandra affinis

Plant part

Alkaloid test

References

L,S S B

w s s

[10]

L

w

[16]

W

m

[9]

S,Sd,R S

s w

[5] [9]

W

w

[7]

L S W

s w w

[9]

L L B L, B, S, R, Sd Wd

s w m s +

[5] [11]

L,S

s

[7]

L

+

[3]

L,S

w

[7]

L

w

[10]

L,B

s

[5]

[5] [11]

[9]

[5] [6]

Alkaloids from Malaysian Flora

301

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Gomphandra afflnis Gomphandra quadrifida (Bl.) Sleumer var. quadrifida Phytocrene bracteata Phytocrene oblonga Iridaceae Trimeza martinicensis (Jacq.) Herb. Labiatae Dysophylla auricularia Hyptis brevipis Ocimum basilicum L. Lauraceae Actinodaphne glomeratus Nees Actinodaphne montana Actinodaphne sesquipedalis Alseodaphne peduncularis Hk. f. Alseodaphne petiolare Beilschmiedia madang CassythafiliformisL. Cinnamomum iners Bl. Cinnamomum mollissimum Hk. f. Cinnamomum paraneuron Miq. Cinnamomum pubescens Ridl. Dehaasia caesia Dehaasia incrassata (Jack) Kostermans Eusideroxylon zwageri T. & B

Plant part

Alkaloid test

References

L,S,R L

s w

[4] [10]

F F

s s

[4] [4]

W

w

[7]

L L L,S L

+ +

[3] [3] [7] [10]

L,B B, F,R B,R L L,B L,S,R L, B, F, R L W B L B L,S B L B B L, F, S, R L,B

w w s s s s s s s w m s w s w s m s s s w

nu [5] [4,5] [4]

[HI [4] [4] [16] [7] [11] [17] [11] [7] [11] [15] [5,11,14] [5,14] [11]

302

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Lindera cubeba (Lour.) Pers. Lindera lucida (Bl.) Boerl. Lindera oxyphylla Hk. f. Lindera pentantha K. & V. Lindera pipericarpa Boerl. Lindera pipericarpa Boerl. Lindera spathacea Lindera spathacea var. tomentosa Litsea amara Litsea elliptibacea Litsea oppostifolia L.S. Gibbs Litsea spathacea Litsea tomentosa Bl. Litsea trunciflora Gamble

Plant part

Alkaloid test

References

L,B L,S,F B R S L R R R R L B B F B L

s w w m w w s s s s m

[i>] [7] [7]

L,S S L S L S B,R L, B, R, Fl L,B,R L,S,R L,B,R F

w s w

Fl L L

+ + s

s s s s m

[9] [11,16] [4] [4]

14] [5] [15J [11] [5] [11] [8]

c

Litsea umbellata (Lour.) Merr. Neolitsea cassiaefolia (Bl.) Merr. Neolitsea zeylanica Merr. Nothophoebe pahangensis Notaphoebe panduriformis Gamble Phoebe macrophylla Phoebe opaca Phoebe taroyna Stemmatodaphne perakensis Leguminosae Andira surinamensis Splitg. Cassia siamea Centrosema pubescens

s m s s s s s s s

[10] [8] [7] [16] [7] [5] [5] [4]

14] [4,5] [4] [6] [3] [17]

Alkaloids from Malaysian Flora

303

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant

Plant part

Alkaloid test

References

L

+

[3]

Crotalaria mucronata Desv.

W

w

Crotalaria

L

[11] [17]

L,F

s +

L

+

[3]

Crotalaria

anagyroides mucronata

Crotalaria striata DC.

[6]

Dialium platysepalum

Sd

s

[5]

Dracaena conferta

L

s

[4]

Enterolobium soman

L,S

s

[4]

Indigofera teysmanii

S

s

[4]

L,B,R

[6]

Millettia abiflora Mimosa sepiaria Benth.

B

s +

Pithecellobium dulce

L

+

[3]

Pithecellobium ellipticum

Sd

s

15]

Pithecellobium jiringa Prain

S

+

[6]

Pterocarpus indicus

L

s

[4]

Saraca declinata Miq.

B

w

[11]

Spatholobus gyrocarpus Bth.

B

[11]

Swartzia pinnata Willd.

S

m +

Sd

s

[5]

L

w

[7]

[5]

[6]

Liliaceae Dracaena congesta Liliaceae Roucheria griffithiana Planch.

S

s

Loganiaceae Fagraea blumei G. Don Fagraea crenulata Maing.

L

w

[11]

L,S,F

m

[7]

L,F

w

[7]

S

m

L

+

[3]

F

s

[7]

ex Clarke Fagraea fragrans Roxb.

Fagraea racemosa Jack. ex Wall. Gelsemium elegans Benth.

[6]

304

T.-S. Kim

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant part

Alkaloid test

References

Strychnos ignatii Bergius Strychnos ovalifolia Lythraceae Sonneratia acida L. Magnoliaceae Magnolia maingayi Talauma betongensis Craib. Talauma obovata Korthals

L,B S,R

s s

[H]

L

w

[10]

L B L

w s w

[16] [11] [11]

Talauma singapurensis Talauma villosa Malvaceae Hibiscus mutabilis Sida rhombifolia L. Melastomataceae Allomorphia malaccensis Ridl. Amplectrum divaricatum Triana. Dissochaeta cf. sagittata Bl. Melastoma schizocarpa Ridl. Memecylon oleaefolium Pternandra echinata Jack. Meliaceae Aglaia leucophylla Carapa guianensis Aubl.

,B,R L

s w

[5] [16)

L W

+ m

[3] [7]

L,S F

w m

[7,17]

S S L L,S

w w s w

[8] [7] [5] [7]

L S,Sd Sd L S S,F S Sd W

s w + w w w w +

[15] [7] [61 [16]

Plant

Chisocheton ceramicus Dysoxylum cauliflorum Hiem Melia azedarach L. Payena obscura Burck. Swietinia macrophylla King Turraea cf breviflora Ridl.

w

[4]

[7]

[9] [7] [10] [6] [10]

Alkaloids from Malaysian Flora

305

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Menispermaceae Albertisia crassa Forman Albertisia papuana Becc. Arcangelisia flava (L.) Merr. Arcangelisia loureiri (Pierre) Diels Coscinium blumeanum Miers ex Hk. f. Coscinium wallichianum Miers

Cyclea laxiflora Miers

Fibraurea chloroleuca Miers

Fibraurea tinctoria Lour. Hypserpa cuspidata Limacia oblonga Miers

Pericampylus glaucus (Lmk) Merr. Tinomiscium petiolare Tinospora crispa (L.) Miers. ex Hk. f. & Thorns. Mimosaceae Acacia auriculiformis A. Cunn. Adenanthera pavonina L. Moraceae Ficus annulata Bl.

Plant part

Alkaloid test

References

L,S B S S L,R B

w s m s s s

[11] [11] [11] [4,10]

B, Sd, R L,S S S,R B W S,R B,R L S L L,S R B W L S,R S

s s + s s s s s + s +

[5] [4] [6] [5]

s s s w s s m

L,S

w

[8]

S

w

[7]

L,S,F

w

[7]

[4] [11]

[11] [4] [5] [4] [6] [11] [3] [5] [4,5] [11] [9] [5] [4,5] [7]

306

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Ficus deltoidea Jack. Ficus fistulosa Ficus Julva Reinw. ex Bl. Ficus grossularioides Brum. f. Ficus hirta L. f. Ficus hispida L. Ficus indica L. Hullettia dumosa Myristicaceae Horsfleldia superba Warb. Knema communis J. Sinclair Myrsinaceae Ardisia colorata Roxb. Ardisia elliptica Thunb. Ardisia macrophylla Ardiceae serrata (Car.) Pers. Maesa impressinervia King Maesa ramentacea Wall. Myrtaceae Decaspermum fruticosum J. R. & G. Forst. Eugenia longiflora (Presl.) F. Vill. Nyctaginaceae Boerhavia diffusa L. Ochnaceae Gomphia serrata (Gaertn.) Kanis Olacaceae Lepionurus sylvestris Ochanostachys amentacea Mast. Strombosia multiflora King

Plant part

Alkaloid test

References

L,S,F L,B S L L L L L L

w w w w m m s m s

[7] [14]

L B L

s m s

[H]

L B B L L,B L B

w

[11]

s + m w m m

[6] [15] [11] [11] [7]

S S L,S

m w w

[8] [10] [7]

W

m

[11]

B

w

HI]

L,F L,S L

s w w

[5] [7]

[7] [10] [7] [11] [5] [8] [5] [11]

[U]

Alkaloids from Malaysian Flora

307

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Oleaceae Jasminum bifarium Linociera montana (Bl.) DC. Ligustrum sinense Lour. Olea brachiata (cf. Corner) Olea maritima Wall, ex DC. Osmanthus scortechinii King Oxalidaceae Averrhoa carambola L. Palmae Calamus javensis Plectocomiopsis geminiflorus

Plant part

Alkaloid test

References

L L,S L,B L,S S L,B

+

w m m w w

[3] [8]

[11]

w

[8]

s s s

[5] [5] [4,5]

m

[7]

w w w w w

[7]

w

l«]

L Sd F

Pandanaceae Pandanus recurvatus St. John Papilionaceae Dalbergia junghuhnii Benth. L,S Derris multiflora Benth. S Desmodium umbellatum (L.) DC. L,S Millettis decipiens Prain. L,S Moghania macrophylla (Willd.) O. K. F Passifloraceae W Passiflora foetida L. Passiflora laurifolia Passiflora quadrangularis L. Piperaceae Piper aduncum L. Piper magnibaccum C. DC. Piper porphyrophyllum Piper stylosum Miq. Polygalaceae Poly gala paniculata L.

L L W L,S L,S L,S,R

W

w

[>1] [10]

[9]

m

[7] [7] [7]

+ +

[3] 13]

m

[11]

w m s m

17] [10]

[4] [9] [7]

308

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Salomonia cantoniensis Lour. Xanthophyllum excelsum (Bl) Miq. Xanthophyllum palembanicum Miq. Pontederaceae Eichornia crassipes Ranunculaceae Naravelia laurifolia Wall, ex Hook. f. Thorns. Rhamnaceae Gouania javanica Miq. Smythea lanceata (Tul.) Summerh. Rhizophoraceae Bruguiera cylindrica (L.) Bl. Carallia brachiata Pellacalyx axillaris Korth.

Pellacalyx saccardianus Scort. Rubiaceae Anthocephalus chinensis (Lamk.) Rich, ex Walp. Argostemma involucratum Hemsl. Aulacodiscuspremnoides Hk. f. Canthium didymum Cephaelis psychotrioides Valeton triceps Ridl. Chasalia chartaceae Craib Chasalia pubescens Ridl. Chasalia curviflora Thw.

Plant part

Alkaloid test

References

W F1,B L,S L, B, R, Fl L S

w s m s s m

[8] [5] [9] [5] [8]

L

+

[3]

US

w

[8]

S L

w w

[9,10] [9]

S L L 3

w w m

[7] [16]

L B S

W

[9]

s m

[>U

s w w w w s w w m w

[11]

L B W L L W L S L,B L,B

[11]

[7]

[7] [10] [17] [11] [8] [11] [11]

Alkaloids from Malaysian Flora

309

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Chonemorpha penangensis Ridl. Cqffea canephora Pierre ex Froehner var. robusta (Linden ex De Wildem.) Chevalier Coptosapelta flavescens Coptosapelta tomentosa (Bl.) Val. ex K. Heyne Gardenia carinata Wall. Hedyotis capitellata lxora brunonis Ixora coccinea L. Ixora congesta Roxb. Ixora nigricans Ixora pendula Jack Ixora sticta Roxb. Ixora umbellata Valet. Morinda citrifolia L. Morinda elliptica Ridl. Nauclea maingayi Ophiorrhiza communis Ridl. Ophiorrhiza discolor R. Br. Ophiorrhiza tomentosa Jack Oxyceros curtisii (King and Gamble) K. M. Wong Oxyceros penangianus (King and Gamble) D. D. Tirvengadum Pavetta graciliflora Wall.

Plant part

Alkaloid test

References

L,S L

s w

[7] [9]

R S

s w

[4] [9]

B S R S L L L L L L B L S L S,R W

+

[6] [101

w w w L

w s + w w m w w w w w m w s m s w m m

[4] [6] [14] [8] [ID [14] [11] [11] [11] [7] [11] [4] [11] [11] [7] [11] [11] [11]

L F S

s s s

[4,5,11] [4,5] [4]

310

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant

Plant part

L L,S L,B Pavetta pauciflora Ridl. L,S Petungafloribunda Ridl. Pleiocarpidia capituligera (Ridl.) Brem. L,S L Porterandia anisophylla L,B Psychotria montana Bl. >,S,R L,B Psychotria rostrata L Randia anisophylla Jack. S S Randia densiflora Benth. S L,S Randia macrantha DC. L Randia macrophylla Hook. fil. S S Randia scortechinii King R Randia stenopetala S Tarennafragrans (Bl.) K. & V. L Tarenna mollis (Wall, ex Hk. f.) S B. L. Robinson L Uncaria acida Roxb. L S L Uncaria borneensis Havil L Uncaria callophylla Korth S L S S Uncaria cordata (Lour.) Merr. B Uncaria cordata (Lour.) Merr. var. Pavetta indica L.

cordata

Alkaloid test

References

s w s w w w s s s w s w

[4,11] [8] [11] [10] [12] [16,17]

+ +

m w w s m w m s w m s s w m w m s

[11] [4] [13,17] [8] [10] [6] [6] [8] [9] [4] [9] [12] [5] [8] [12,17,21 [21] [12] [7] [11,17]

Alkaloids from Malaysian Flora

311

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Uncaria cordata Men. forma sundaica Ridsd. Uncaria elliptica R. Br. ex G. Don Uncaria ferrea (Bl.) DC. Uncaria gambir (Hunt.) Roxb.

Uncaria lanosa Wall var. ferrea Ridsd. Uncaria longiflora var pteropoda (Miq.) Ridsd Uncaria ovalifolia Roxb. Uncaria parviflora Uncaria pteropoda Miq.

Uncaria roxburghiana Korth. Uncaria sclerophylla Roxb. Uncaria umbellatum Urophyllum macrophyllum Korth. Urophyllum trifurcum Pears. Urophyllum umbellatum Miq. Rutaceae Acronychia laurifolia Bl. Acronychia porteri Atalantia kwangtungensis Atalantia roxburghiana Euodia glabra Euodia latifolia DC.

Plant part

Alkaloid test

References

L B L L,S L,S S,R L B L

m w w w s s m w w

["]

L

s

[12,21]

S L,S,R L,B L,S R R, S, Sd S L L L B L,S

m s s s s +

[7] [4] [5,7] [4] [4,5]

L,B L S B L S S L

w w m s w m w s

m m s w w w

[12,21] [8] [7] [4] [12] [11]

[6] [9] [7] [4] [9] [11] [12] [11] [22] [5] [22] [22] [U,23]

312

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Euodia latifolia DC.

Euodia pilulifera King Glycosmis calcicola Glycosmis malayana Glycosmis pentaphylla Correa Glycosmis sapindoides Merrillia caloxylon Micromelum minutum (Forster F.) W. & A. Micromelum pubescens Muraya paniculata Jack Paramignya lobata Tetractomia tetrandra Craib. Triphasic* trifolia Xanthoxylum hirtellum Zanthoxylum myriacanthum Wall. Sapindaceae Allophylus cobbe Harpullia arborea Radik. Nephelium glabrum Sapotaceae Achras Sapota Linn. Madhuca korthalsii var. Lanceolata Madhuca mindanaensis Merr. Palaquium ridleyi King Scrophulariaceae Cyrtandromea acuminata

Plant part

Alkaloid test

B S R L,F B B R L,S L,R L,F1 S L S L,B L,B S B S L B,R S,B

w m s m w w s + s s m w m s + w m w w s w

References

[7] [4] [11,23] [22] [4] [6] [4] [22] [9] [5] [6] [22] [11] [22] [22] [5] [9,22]

L L,B Sd

m w s

[17]

S Sd B S

+

[6] [5]

s w w

[11] [5]

[HJ [7] [15]

Alkaloids from Malaysian Flora

313

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant

Plant part

Alkaloid test

References

Simarubaceae L

+

[3]

S,R

s

[4]

Brugmansia suaveolens (Humb.

W

m

[H]

and Bonpl. ex Wild.) Bercht and Presl

S

w

[9]

Capsicum frutescens

L

+

[3]

Datura mete!

L

+

[3]

Lycium Chinese Mill.

S

+

[6]

Brucea javanica Eurycoma apiculata Solanaceae

Solatium blumei

L

s

[5]

Solatium ferox L.

W

w

[11]

Solarium nigrum

L

+

[3]

L, B, F L,S,F

w +

[11] [6]

L

w

[8]

R

s

[4]

L

w

[16]

L,B

s

[13]

L,R

m

[14]

Byttneria maingayi Mast.

S

m

[10]

Commersonia barlramia (L.)

L

w

[7]

Me lochia corchorifolia L.

W

w

[9]

Pterospermum cf. elongatum

L

w

[8]

S

w

[9]

Symplocos anomala Brand

L,B

m

[H]

Symplocos fasciculata Zoll.

L

w

[11]

Symplocos ophirensis Clarke

B

w

[11]

Solanum torvum Sw. Solanum verboseifolium L. Staphyleaceae Turpinia ovalifolia Stemonaceae Stichoneuion caudatum Sterculiaceae

Merr.

Korth. Sterculia parviflora Roxb. Symplocaceae

314

T.-S. Kam

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Taccaceae Tacca pinnatifida Forst. Taxaceae Podocarpus teysmanni Miq. Ternstroemiaceae Eurya acuminata DC. Ploiarium alternifolium Tiliaceae Grewia tomentosa Juss. Triumfetta rhomboidea Jacq. Ulmaceae Gironniera nervosa Trema cannabina Lour. Gironniera subaequalis Urticaceae Villebrunea silvatica Bl. Verbenaceae Avicennia alba Bl. Clerodendron deflexum Wall Clerodendron deflexum Wall Clerodendron disparifolium Bl. Clerodendron indicum (L.) O. K. Clerodendron inerme Benth. Clerodendron inerme (L.) Gaertn. Clerodendron japonicum (Thunb.) Sweet. Clerodendron laevifolium Bl. Clerodendron laurifolium Clerodendron myrmecophilum Ridl.

Plant part

Alkaloid test

References

F

w

[7]

L

m

[7]

L L

w +

[8] [3]

L S L,S

w +

[8] [6]

w

17]

L,B US R

w w s

[13] [7] [5]

L,B

w

["]

S L W L W L,B L

+

[6]

w s w m w w

[11] [H] [11] [10]

L,S

w

[7]

S L W

+ s w

[6] [17] [9]

[11] [10]

Alkaloids from Malaysian Mora

315

Table 1. Alkaloid-positive plants from phytochemical surveys (cont.)

Plant Clerodendron serratum (L.) Moon. Clerodundron wallichii Merr. Duranta erecta L. Gmelina arborea L. Gmelina elliptica J. E. Smith Premna tomentosa Willd. Sphenodesma barbata Schauer Stachytarpheta indica Vahl.

Stachytarpheta jamaicensis (L.) Vahl. Stachytarpheta mutabilis (Jacq.) Vahl. Verbena bonariensis L. Vitex negundo L. Vitex ovata Thunb. Vitex pubescens Vitaceae Cayratia geniculata (Bl.) Gagn. Tetrastigma hookeri (Laws.) Planch. Zingiberaceae Globba pendula Roxb.

Plant part

Alkaloid test

References

L S S

s w w

[7]

L B,F L L,S L L,S W L

w w w w w m w +

[9] [7]

L,S

s

[7]

L

m

[7]

W L L,F L

w w w +

[H]

L

w

[9]

S

w

[9]

B

w

[11]

[9]

[8] [7]

["J [7] [11]

P]

[8] [7] [3]

316

T.-S. Kam

U . STRUCTURE ELUCIDATION AND CHEMISTRY

1.3.1. Isoquinoline and Related Alkaloids Isoquinoline and isoquinoline derived alkaloids are mainly distributed in the families Annonaceae, Lauraceae and Menispermaceae. Simple isoquinolines and derivatives. Ancistrocladus is the only genus of the Ancistrocladaceae and comprises some twenty species of lianas and shrubs found in the tropical rain forest of Asia and Africa. Examination of the bark extract of Ancistrocladus tectorius (Ancistrocladaceae) collected in Johore, Peninsular Malaysia, resulted in the isolation of a new simple isoquinoline, 6,8-dimethoxy-3hydroxymethyl-1-methylisoquinoline (1) and a new naphthylisoquinoline derivative, 4'-0demethylancistrocladine (4), together with the known isoquinolines, 6,8-dimethoxy-l,3dimethylisoquinoline (2) and (5)-6,8-dimethoxy-l,3-dimethyl-3,4-dihydroisoquinoline (3) [24J. Compound 1 was the major alkaloid present and compounds 2 and 3 were previously unknown as natural products. The related naphthylisoquinoline alkaloids ancistrocladine (5) and its atropisomer hamatine (6) were previously known from other Asian Ancistrocladus species [25] while the 7,3'-linked naphthyl-isoquinoline, ancistrotectorine (8), has been previously isolated from Ancistrocladus tectorius from Thailand [26]. The structure of 1 was deduced from spectral data (UV, MS, NMR) as well as by its ready conversion to the known 2 through successive mesylation and UAIH4 reduction. Likewise the structure and relative stereochemistry of 4 were established by spectral analysis (HMBC, NOESY) and by conversion to the known (-)-N-formyl-O-methylancistrocladine derivative 7 via successive formylation followed by methylation (Mel, NaH-DMF). Aporphines, Bisaporphines, Berberines, Azafluorenes, Aristolactams, seco-Benzyltetrahydroisoquinolines and Bisbenzylisoquinolines. The aporphine alkaloids constitute a large subgroup of alkaloids derived from isoquinoline and are widely distributed especially in the Annonaceae, Lauraceae, Magnoliaceae and Menispermaceae. Several new aporphine and berberine alkaloids which were uncovered in the period of the last ten years or so are from plants of the Annonaceae such as the 7-hydroxyaporphine, dasymachaline (9) from Desmos dasymachalus [27], the dioxoaporphine, 1,2,3-trimethoxy-4,5dioxo-6a,7-dehydroaporphine (10) from Pseuduvaria macrophylla [28], the tetrasubstituted

317

Alkaloids from Malaysian Flora Me

MeO

MeCX

OMe

OMe

Me

1

R = CH2OH

2

R = Me )Me

OMe

OR1

Me OMe

Me

4

R 1 = R 2 = R3 = H, V-S

5

R1 = Me, R2 = R3 = H, V-S

6

R1 = Me, R2 = R3 = H, V-fl

7

R1 = Me, R2 = Me, R3 = CHO, V-S

NMe

OMe 9

Me

10

318

T.-S. Kam MeO

MeOv

JV

MeO"

MeO' OH 11

14

OH MeO< MeO MeO H* .OMe

"OH 12

13 MeO.

MeO

OMe

OMe 15

319

Alkaloids from Malaysian Flora

17 R 1 =R2 =

H

18 R 1 = R 2 = Ac

19 R 1 = R 2 = H 20 R1 = R2 = Ac

aporphine, norisocorytuberine (11) from Trivalvaria macrophylla [29], the catecholic berberine, artavenustine (12) from Artabotrys venustus [30] and the tetrahydroprotoberberine, (-)-thaipetaline (13) from Polyalthia stenopetala [31]. In addition, the aporphine-derived phenanthrenoid, l-(N-acetyl-N-methylamino)ethyl-3,4,6-trimethoxy-7-hydroxyphenanthrene (14), was isolated from Aromadendron elegans of the Magnoliaceae family [32]. Trivalvaria macrophylla also furnished in addition to the known bisaporphine, N-methylurabaine (15), the new but related bisaporphine, trivalvone (16) [29].

320

T.-S. Kam

Examination of the stem-bark extract of Orophea enterocarpa led to the isolation of two new aristolactams, viz., enterocarpam-I (17) and enterocarpam-II (19), accompanied by the known enterocarpam-I acetate (18) and enterocarpam-II acetate (20) [33]. Two new azafluorene alkaloids kinabaline (21) and oncodine (22) were obtained from the annonaceous plants Meiogyne virgata and Oncodostigma monospermy respectively [34,35].

MeO,

MeO

21

22

MeO.

"TO

MeO

MeO

NMe

, ^R

OMe

MeO

23 R = H 24 R = OMe

Recently two jeco-benzyltetrahydroisoquinolines, polysignine (23) and methoxypolysignine (24), were obtained from Polyalthia insignis in addition to (-)-asimilobine, oxostephanine, O-methylmoschatoline and liriodenine [36]. The 'H NMR of polysignine showed two proton singlets at 6 6.67 and 6.58 due to the isolated H(2) and H(5) and another set of two 2H-doublets at 8 6.82 and 7.07 (J 8.8 Hz) due to H(2'), H(6') and H(3'), H(5') respectively. The aliphatic H(ot) and H(P) signals were observed

Alkaloids from Malaysian Flora

321

as multiplets centered at 8 2.44 and 2.71, respectively, while the H(a') and H(P') signals were overlapped as a broad singlet at 5 2.81. A possible pathway from a benzyltetrahydroisoquinoline precursor (25) was suggested involving N-methylation followed by either reductive cleavage of the C(\)-N bond or by stepwise P-elimination and reduction steps.

1 2 26 R = Me, R = H 1 2 27 R = H, R = Me

29 The bark of Phoebe grandis (Lauraceae) gave the known aporphines, boldine, norboldine, laurotetanine and lindecarpine while the leaves yielded two new alkaloids, phoebegrandines A (26) and B (27) [37], which belong to the rare proaporphine-tryptamine group of compounds exemplified by roehybridine (28) (syn series) and roemeridine (29) (anti series)fromRoemeria hybrida [38,39]. The structure of 29 was previously established by X-ray analysis [40].

T.-S. Kam

322

30

31

32

MeN

33

Alkaloids from Malaysian Flora

323

Four new bisbenzylisoquinolines, viz., (-)-2,2'-bisnorphaeanthine (30), (+)-pangkoramine (31), (+)-pangkorimine (32) and (+)-nor-2'-cocsuline (33), in addition to the known bisbenzylisoquinolines, (+)-lindoldhamine, (+)-daphnoline, (+)-dapnandrine, (+)-bisnoraromoline, (+)cocsuline, (+)-cocsoline, (+)-Omethyl cocsoline and (+)-apateline were obtained from the Menispermaceous plant Albertisia cf. A. papuana [41]. The Thai members of the Menispermaceae, especially from the genera Cyclea and Stephania, have received attention and were found to provide many bisbenzylisoquinoline alkaloids [42].

MeO

MeO

34

35

Hasubanan alkaloids The hasubanan alkaloids are a small group of about 30 compounds found mainly in Stephania species [43]. Two new alkaloids belonging to this class, (+)-clolimalongine (34) and (+)-limalongine (35) were isolated from the bark of Limacia oblonga (Menispermaceae) in addition to the known alkaloids (+)-stepharine (a proaporphine) and four aporphines, lysicamine, homomoschatoline, imenine and splendidine [44]. The two alkaloids 34 and 35 are structurally similar, the only difference being the presence of a chlorine atom in clolimalongine (34) as indicated by the mass-spectral data. These alkaloids are closely related to (-)-acutumine and (-)-acutumidine, two other chlorine containing compounds previously isolated from another Menispermaceous plant. The structure of clolimalongine is similar to that of acutumidine differing only by the absence of the alcoholic function and the presence of the methoxyl group at C(3) instead of at C(2) in clolimalongine, and this is reflected in the similarity of the spectral data of both compounds. The structure and absolute configuration of (-)-acutumidine have been previously determined by X-ray analysis.

324

T.-S. Kam

In the case of clolimalongine, the relative configuration at C(10) and the spiro carbon C(l I) were deduced from NOE experiments in which irradiation of the H(l) (methylene) signal resulted in enhancement of H(10) (geminal to chlorine) and vice versa, showing that the C(l) methylenes and the geminal H(10) are on the same side with respect to each other. The spectral data of (+)-limalongine (35) are in agreement with a structure in which the C(10) chlorine atom of clolimalongine has been replaced by hydrogen.

1.3.2. Steroidal alkaloids Steroidal alkaloids have been encountered only in one Malaysian species, viz., Holarrhena curtisii, from which holacurtine (36), the first aminoglycosteroid was obtained [45]. Previous studies of African and Indian Holarrhena showed that these plants provided mainly steroidal alkaloids of the aminopregnane-type [46-48]. The Indian species H. antidysenterica in particular has received considerable attention since the plant has a long history of being used in the treatment of dysentery [49,50]. A second study of the Malaysian H. curtisii was prompted by the observation that the chloroform and ethanol extracts of the leaves showed significant leishmanicidal activity which was subsequently traced to the basic fraction derived from these extracts. Further fractionation led to the isolation of several aminoglycosteroids, holacurtine (36), Af-demethylholacurtine (37), 17-e/?/-hoIacurtine (38), 17-e/?/-jV-demethylholacurtine (39), holacurtinol (40) and aminopregnanes, holamine (41), 3ot-amino-14P-hydroxypregnan-20-one (42) and 15oc-hydroxyholamine (43). Of these, compounds 38, 39, 40, 42 and 43 were new natural products [51]. The aminoglycosteroids 36 - 40, showed typical mass-spectra with the pregnane aglycone fragment invariably detected as the base peak, while the D-cymaropyranose sugar unit was readily identified from the l3C NMR spectra. The C(17) epimers of the known holacurtine and Af-demethylholacurtine, 38 and 39, respectively, showed changes in the 'H NMR spectra with respect to the H(17) signal. In holacurtine and N-demethylholacurtine, the H(17) signal appeared as a doublet of doublets at 5 2.9 with J 9 and 4.5 Hz indicative of an a-stereochemistry for H( 17) which has also been observed for other pregnane glucosides, whereas in compounds 38 and 39, the H(17) signal appeared as a triplet at 8 3.25 with J 9 Hz. Further confirmation of the change in stereochemistry at C(17) for 38 and 39 were provided by NOE experiments in which irradiation of the H(17) signal caused enhancement of the C(18) methyl signal and vice-versa. Holacurtinol (40) is a minor alkaloid. The mass-spectrum showed fragments attributable to successive losses of two molecules of H2O suggesting the presence of two hydroxyl groups. The NMR spectral data showed the presence of the same sugar unit (4-deoxy-4-amino-P-Dcymaropyranose) as in 37 and 39, while the pregnane aglycone portion was similar to that of

325

Alkaloids from Malaysian Flora

holamine (41), in which a C(5)-C(6) double bond is present. Comparison of the NMR spectra of holacurtinol with the aminopregnanes 41 and 42 indicated that the site of hydroxylation was in the five-membered ring of the aglycone moiety. In addition to the C(14) P-hydroxyl function M

18

V

M e

M 7 N

H H

14

is]

36 37 38 39

OH

H

H

OH

R1 R1 R1 R1

= Me, R2 = a-H = H, R2 = a-H = Me, R2 = p-H = H, R2 = p-H

OH HM*

42

40

41 43

R=H R = OH

Hoisr

(8 85), the presence of an adjacent hydroxyl substituent was indicated by a low-field oxymethine resonance at 5 82 while the COSY and HMQC data revealed the presence of a CH-CH2-CH-OH fragment corresponding to C(17)-C(16)-C(15). The stereochemistry of the

326

T.-S. Kam

C(15) hydroxyl function was deduced to be a from the observed NOE interaction between the H(15) oxymethine and the C(18) methyl. The mass-spectrum of the aminosteroid 42 showed the presence of a fragment ion due to loss of H 2 0 while the base peak at m/z 56 due to the fragment CH2=CHCH=NH2+ provided confirmation for the amino function at C(3). The ! H and ,3C NMR spectral data showed signals characteristic of a C2|-pregnane skeleton with an amino group at C(3), a P-acetyl group at C(17), and a (J-OH substituent on the quaternary centre at C(14). The a-orientation of the amino group was determined from consideration of the H(3) and C(3) signals [52]. Compound 43 had NMR spectral data which were similar to holamine but differed in the signals due to H(15) and C(15) which have undergone significant downfield shifts compared to holamine (41). The location of the hydroxyl function was supported by the 2-D NMR data and the observed NOE interaction between H(15) and the C(18) methyl indicated that the stereochemistry of the 15-hydroxy is a. These steroidal alkaloids also showed cytotoxic activity (vide infra).

1.3.3. Monoterpene alkaloids The monoterpene alkaloids constitute a relatively small group of compounds and their occurrence has been restricted to several species of the genus Kopsia, viz., K. pauciflora, K. macrophylla and K. dasyrachis, from which several new monoterpene alkaloids related to skytanthine have been recently isolated. The North Borneo species Kopsia pauciflora provided five such monoterpene alkaloids, viz., kinabalurines A - F which are hydroxyskytanthine derivatives [53,54]. The first alkaloid isolated was kinabalurine A (44), which was obtained as colorless plates. The mass spectrum showed a molecular ion at m/z 183 (CnH2jNO) accompanied by fragments due to loss of H, Me and OH, and other fragments at m/z 84, 58 and 44 characteristic of skytanthine-type alkaloids. The IR spectrum indicated the presence of a hydroxyl group (3357 cm"1) and this was supported by the presence of an OH absorption ca. 8 3.27 in *H NMR. The ,3C NMR spectrum accounted for all eleven carbon atoms and the presence of an oxymethine was confirmed by the resonance at 8 80.0. Other significant peaks in ! H NMR included a pair of 3-proton doublets at 8 0.97 and 1.06 corresponding to two CH3CH- groups and an Af-methyl singlet at 8 2.25. The spectral data thus suggested that kinabalurine A is a hydroxyskytanthine derivative and COSY and HETCOR experiments confirmed that hydroxy substitution is at C(7) and allowed the full assignments of the NMR spectral data. In addition the observed J\.9 value of 10 Hz required a trans ring junction. The NMR data however were insufficient to establish the stereochemistry completely and unequivocally and for this purpose X-ray diffraction analysis was undertaken which established the structure of kinabalurine A. Kinabalurine A was the second 7-hydroxyskytanthine reported, the first being incarvilline (50)

Alkaloids from Malaysian Flora

327

isolated from the Chinese plant Incarvillea sinensis. The structure of incarvilline was also established by X-ray analysis [55]. Kinabalurine A differs from incarvilline in having a transring junction, a 7-p-OH substituent and a 4-oc-methyl group. Kinabalurine B (45) is the 7-oxo derivative of kinabalurine A as shown by the spectral data as well by its ready formation via oxidation of kinabalurine A. Similarly kinabalurine C (46) was readily shown to be the Ndemethyl derivative of kinabalurine B from the spectral data (loss of the Af-methyl signal in 'H and ,3C NMR and the presence of a secondary amine absorption in IR, 3400 cm"1). The transring junction in kinabalurine C was clearly shown in the 600 MHz l H NMR spectrum which showed the H(9) signal as a quartet of doublets (^5p-9a - «/|p-9a = ^8p-9a = 12 Hz, J\a-9a = 4 Hz).

«Me

Ma,

Me,,,

44

45 R 46 R

Me H

47

OH ,.Me

Ma,

"*'H

48

49

50

The spectral data for kinabalurine D (47) showed it to be yet another 7-hydroxyskytanthine diastereomer but proved inadequate for definitive assignment of stereochemistry. To this end kinabalurine D was converted to the quaternary ammonium iodide salt which provided suitable crystals for X-ray analysis. Kinabalurine D differs from kinabalurines A - C in having a 4-p-methyl group and a trans ring junction in which the stereochemistry of H(5)

328

T.-S. Kam

and H(9) are now reversed. Kinabalurine E (48) is the 7-oxo derivative of kinabalurine D as shown by the spectral data and by chemical correlation (PCC oxidation) with 47. Kinabalurine F (49) was obtained in minute amounts and its structure elucidation relied mainly on analysis of the 600 MHz NMR data and by comparison with 44, 47 and incarvilline (50). The 7-hydroxy group of kinabalurine F was deduced to be (3 based on comparison of the observed C(7) shift (8 81) with those of 44 (5 80) and 47 (5 81) which also have 7-P-OH. The C(7) shift in incarvilline which has a 7-a-OH is shifted upfield to about 5 73. The observed NOE interaction from H(7oc) to 8-methyl and from H(6a) to H(5) fixed their respective stereochemistry. Likewise the observed H(lp)/H(8p) NOE interaction allowed the assignment of H(lot) which appeared as a triplet with J 10.5 Hz requiring H(9) and H(la) to be transdiaxial which is possible only if H(9) is p. The observed H(3) signals as a triplet with J 11 Hz and a doublet of doublets (J 11, 2 Hz) are only consistent with H(4p), resulting in H(4P) and H(3a) being /ra/w-diaxial to each other. The 4-methyl of kinabalurine F therefore has astereochemistry. The kinabalurines together with incarvilline provide a useful array of stereoisomers in this series with various ring junction, 7-hydroxy and 4- and 8-methyl group stereochemistry.

Me,

SCHEME 1

Alkaloids from Malaysian Flora

329

Kopsia macrophylla provided two more new monoterpene alkaloids, kopsilactone (51) and kopsone (52), in addition to the known compounds 5,22-dioxokopsane, dregamine, akuammiline, tabernaemontanine, deacetylakuammiline, norpleiomutine and kopsoffme [56]. The IR spectrum of kopsilactone indicated the presence of a ylactone unit (1770 cm"1) which was supported by the observation of a quaternary carbon resonance at 5 176. The observed J^ value of 11 Hz required a /ra/w-diaxial arrangement between H(3a) and H(4P), while the estimated J4.5 value of ca. 4 Hz suggested a c/s-relationship between H(4) and H(5). An equatorial H(5) requires a cis ring junction between the piperidine and the flve-membered ring which in turn fixes the stereochemistry of the lactone-piperidine ring junction. The second monoterpene alkaloid kopsone gave a molecular ion which analysed for C,,H,9NO. The IR (1720 cm'1) and ,3C NMR (8 218) spectral data indicated the presence of a ketone function. Other groups indicated by the NMR spectra were two CHMe groups, an Nmethyl, three methylenes (one deshielded at 8 56) and four methines (one deshielded at 8 72). These, as well as a postulated common origin of 51 and 52 from the hypothetical 9-hydroxyskytanthine precursor 53 (Scheme 1), led to the proposed structure for kopsone. The relative stereochemistry was deduced from analysis of the 'H NMR spectrum. The leaves of K. dasyrachis gave kopsirachine (54), which is constituted from union of the flavonoid, catechine and two units of skytanthine. The gross structure was deduced from spectral and chemical evidence but the stereochemistry of the skytanthine units in 54 remains to be firmly established [57].

54 1.3.4. Indole alkaloids The monoterpenoid indole alkaloids constitute a large group and careful investigation of plants, particularly from the Apocynaceae (Kopsia, Tabernaemontana, Alstonia, Leuconotis) and Rubiaceae (Uncaria, Mitragyna) have yielded many novel compounds.

330

T.-S. Kam

Simple indole and oxindole alkaloids and tryptamine oligomers The simple P-carboline compound harmane (55), although widely distributed in several families is rarely encountered in the Apocynaceae. It has been recently obtained for the first time from Kopsia from K. grifflthii [58]. A new P-carboline, harmicine (2,3,5,6,11,11bhexahydro-lH-indolizino[8,7-b] indole) (56), which has been previously synthesized in racemic form was also isolated for the first time as an opticatly active natural product from Kopsia grifflthii [58]. The observation of Wenkert-Bohlmann bands in the IR spectrum (2780 and 2835 cm"1) suggested that the stereochemistry of H(l lb) is a and also that the C/D ring junction is trans. Further confirmation of the trans-ring junction was obtained from NOE experiments. Thus irradiation of the H(l lb) signal at 5 4.26 resulted in NOE enhancements of NH (8 8.19), H(la) (8 2.29), H(2a) (8 1.91), H(3a) (8 2.92), and H(5ct) (8 3.09). Likewise, irradiation of the NH signal caused enhancement of the H(Ub) signal and vice versa. The observed NOE interaction between H(l lb) with H(3a) as well as H(5a) confirmed the trans-C/D ring junction of harmicine. A new simple oxindole alkaloid, (-)-horsfiline (57) was obtained from Horsfieldia superba (Myristicaceae), in addition to the known alkaloids 6-methoxy-2-methyl-l,2,3,4-tetrahydro-pcarboline (58) and 5-methoxy-N,Af-dimethyltryptamine [59]. Horsfiline is a simple spiropyrrolidinyloxindole, its structure was deduced from spectral data (MS & NMR) as well as by partial synthesis from 58 via oxidation with Pb(OAc)4 to the acetoxyindolenine 59, followed by acid catalysed rearrangement (MeOH/AcOH) to (±)-horsfiline (Scheme 2) [59].

56

55 NMe

Me

57

58

Alkaloids from Malaysian Mora

331

Pb(OAc)4

MeOH-AcOH •*

58

57

59 SCHEME 2

CO

*Et

steps

NH2.HCI

60

R = PhCH2OCO SEM = Me3SiCH2CH2OCH2 61

ii - iv

Reagents: i. Bu3SnH, AIBN, PhMe, A; ii, Bu4NF, (DMF)-H2NCH2CH2NH2, 80 °C; Hi, cyclohexa-1,4-diene, Pd-C. EtOH; iv, HC0 2 H, HCHO, A

SCHEME 3

332

T.-S. Kam

A synthesis of horsfiline has been achieved based on intramolecular cyclization of an aryl radical as the key step as shown in Scheme 3 [60]. Protection of the amide nitrogen in the unsaturated bromoamide precursor 61 (obtained in several steps from ethyl glycine hydrochloride 60) proved to be necessary in order to achieve a suitable conformation for effective cyclization; reaction (Bu3SnH) of the unprotected amide precursor led only to reduction. Furthermore, introduction of an SEM protecting group was found to give a favourable ratio of 5-exo to 6-endo cyclization. The remaining steps involved removal of the various protecting groups followed by Eschweiler-Clarke /V-methylation to give racemic horsfiline. Me N

f-BuOCI

62

57

NaOH, MeOH-H20 70 °C

SCHEME 4

NHCH3

63 57

Reagents: i, DMSO (3 eq.), 37% HCI (3 eq.), 80 °C; ii, (CH2Q)n (1.2 eq.), AcOH, A

SCHEME 5

333

Alkaloids from Malaysian Flora

65

66

(*M-)-57 Reagents: i, NBS, AcOH, THF-H20, -15 °C; ii, TMSCI, MeOH, A; iii, 36 % aq. CH 2 0 (1.5 eq.) NaBH3CN, AcOH; MeOH-2N HCI (5:1), A; iv, NH3, MeOH; (CF3CO)20, dioxane, pyridine; v, NaBH4, EtOH, pyridine, 12 h. 40 °C

SCHEME 6 This was followed by two other alternative syntheses of racemic horsfiline, one based on an oxidative rearrangement of the tetrahydro-y-carboline derivative 62 (Scheme 4) and another involving a spirocyclization between the 2-oxo-5-methoxytryptamine derivative 63 and formaldehyde (Scheme 5) [61].

334

T.-S. Kam /0 2 Me

XX)H Me< NH2.HCI N H

BOC

64

65

BOC = C(=0)OCMe 3

A recent synthesis of /?-(-)-horsfiline (57) has been reported starting from the commercially available (5)-5-hydroxytryptophan (Scheme 6) [62]. The key step involved a crucial diastereoselective oxidation-rearrangement sequence to the desired oxindole 66 from an optically pure tetrahydro-P-carboline compound 65, readily obtained from (S)-5hydroxytryptophan hydrochloride (64).

-Me K 1

N H

A

(CH 2 0) n , PhMe, A O R1 = COO-(-)-Menthyl

R = (-)-Menthyl (E)

69

67

-Me i. ii

Reagents: i, powdered KOH, 18-crown-6 (cat), THF; Dowex 50Wx8; ii, DCC, DMAP, 2-mercapto-pyridine N-oxide, CH 2 CI 2 ; Bu 3 SnH, AIBN, PhH, A

SCHEME 7

Alkaloids from Malaysian Flora

335

A non-biomimetic synthesis of rt-(-)-horsfiline (57) has also been recently reported which was based on a thermal intermolecular 1,3-dipolar cycloaddition reaction as outlined in Scheme 7 [63]. The reaction of the optically active menthyl ester 67 acting as a dipolarophile, with the JV-methylazomethine ylide 68 (thermally generated in situ from sarcosine and formaldehyde) proceeded with ft-facial diastereoselectivity to produce a chromatographically separable mixture of 69 and the unwanted diastereomer. Subsequent cleavage of the chiral auxiliary, followed by removal of the carboxylic acid group by the Barton radical method provided /?-(-)horsfiline. The calicanthine-type alkaloids as represented by calicanthine, the isomeric chimonanthine (70) and the dehydro derivative isocalycanthine (71) have been previously known from various genera of the Celastraceae, including Bhesa. The bark extract of the Malaysian species, Bhesa paniculata provided two new members of this group which are related to the previously known isocalycanthine (71) [64], viz., bhesine (72) and dehydrobhesine (73), bhesine being the iV-8a' dehydro derivative of isocalycanthine. The structure and relative configuration of bhesine were established by X-ray diffraction analysis [65].

Me 70

71

Me 72

Me 73

336

T.-S. Kam

The major alkaloidal component of Psychotria rostrata Bl., a common undergrowth tree shrub was the known tetrameric alkaloid, quadrigemine B, accompanied by four other minor alkaloids, hodgkinsine, (-)-calycanthine, (+)-chimonanthine and calycosidine [66]. The isolation of (+)-chimonanthine is noteworthy since previous isolations were of the levorotatory or meso isomers and the (+)-enantiomer has been previously obtained only from the skin of the Columbian dart frog [67]. Heteroyohimbines, yohimbines and related oxindoies Plants of the genus Uncaria (Rubiaceae), comprising some 34 species, are distributed mainly in tropical and subtropical Asia, Africa and tropical America. Of these about 14 species occur in Peninsular Malaysia. Early studies in the sixties by Chan yielded the pentacyclic oxindole alkaloids isopteropodine (74) and pteropodine (75) from Uncaria pteropoda [68-71].

75 Phillipson et al have also carried out an extensive survey of the alkaloidal content of this genus based on investigations of herbarium samples using TLC and GCMS [72]. Plants of this genus provide mainly heteroyohimbines, oxindoies and yohimbines. Chemical studies of several species from Thailand such as U. attenuata, U. canescans, U. elliptica, U. homomalla and V. macropylla have also been carried out by Phillipson and others [73-78]. A chemotaxonomic

337

Alkaloids from Malaysian Flora

study of the Malaysian members of this genus has been recently carried out and this complements the studies of the Thai plants [79].

76

78 R = H 79 R = OH

77

80 R = a-OH 81 R s P-OH

Two new tetracyclic heteroyohimbines, isogambirine (76) and gambireine (77), in addition to three new dimers (callophylline, callopylline A, callophylline B, vide infra) and the known alkaloids dihydrocorynantheine (78), gambirine (79), rotundifoline, yohimbine, pseudoyohimbine (80), a-yohimbine and P-yohimbine, were isolated from U. callophylla [79,80]. Isogambirine is an isomer of the more abundant gambirine and was readily shown to be the 10hydroxy analogue of gambirinefromthe 'H and ,3C NMR spectral data [79]. Gambireine on the other hand was shown to be the C(20) vinyl analogue of gambirine based on the observed molecular ion and the replacement of the ethyl group absorptions by vinyl group absorptions in !H and ,3C NMR [79]. The isolation of isogambirine represents the first instance of a 10-

338

T.-S. Kam

hydroxylated heteroyohimbine from an Uncaria species; hitherto only aromatic substitution at C(9) has been reported for heteroyohimbine alkaloids from Uncaria. V. callophylla appears to be unique in its ability to elaborate hydroxylated heteroyohimbine derivatives and dimeric alkaloids. Of special note is the result of a month-by-month monitoring of the alkaloidal composition of U. callophylla which revealed an interesting seasonal variation of the alkaloid content not recognised before in U. callophylla, in which the amount of the otherwise predominant gambirine diminishes drastically during thefloweringseason [79].

83

82

C0 2 Me OHC 84 R = OMe 85 R = H

C0 2 H

86 R = OMe 87 R = H

A detailed study of the previously uninvestigated U. borneensis was also carried out. The major alkaloids were the tetracyclic oxindoles isorhynchophylline, rhynchophylline, isocorynoxeine, and corynoxeine accompanied by minor yohimbine alkaloids, pseudoyohimbine, alloyohimbine and 3-e/w-P-yohimbine (81). The unique and predominant occurrence

Alkaloids from Malaysian Flora

339

of gambirine in U. callophylla has also allowed the development of a simple TLC method for distinguishing this species from the group of taxonomically related species which include besides U. callophylla, U. gambir, U. elliptica and U. acida which has caused some problems in the past. Roxburghines were also not detected in any of the Malaysian U. elliptica samples investigated [79], which is in agreement with the results of a previous study of the Thai species [76]. Only one species from the genus Mitragyna appears to have been investigated, v/z., Mitragyna speciosa which has received much attention in Thailand due to its widespread use as an opium substitute although the pharmacological basis of its narcotic effect remains unclear. A new heteroyohimbine, 3-dehydromitragynine (82) was isolated from fresh leaf samples, in addition to various alkaloids previously known from this species such as mitragynine (83), paynantheine, speciogynine, speciociliatine and mitraciliatine [81]. The 'H NMR spectrum indicated a 9-methoxylated tetracyclic heteroyohimbine and the UV spectrum suggested additional conjugation compared with mitragynine-like compounds, the observed bathochromic shift suggesting the presence of a quaternary nitrogen. Furthermore, the NMR spectrum showed downfield shifts for the H(15) methine and the H(5), H(14), and H(21) methylenes compared with those of mitragynine, suggesting the presence of an unsaturated bond in the vicinity. These observations led to the proposed structure 82 which was further supported by its ready reduction (NaBF^) to mitragynine (83) as well as by its facile formation via oxidation {Pb(OAc>4} of mitragynine. A subsequent study of very young leaf samples has resulted in the isolation of four additional new alkaloids which were the highly conjugated indoles, mitragynaline (84) and corynantheidinaline (85), and the related compounds mitragynalinic acid (86) and corynantheidinalinic acid (87) [82]. The NMR spectral data of 84 indicated the presence of a 9methoxy-substituted indole ring, methoxycarbonyl and ethyl side chains and an aldehyde function. The intense yellow color and the high wavelength maximum (490 nm) observed in the UV spectrum, indicated a highly conjugated system. The ,3C NMR spectrum showed five quaternary carbon resonances (including one amide carbonyl) which were additional to those of the indole system suggesting the presence of another aromatic ring. This observation together with the loss of the C(3) methine resonance when compared with mitragynine indicated that ring D is aromatic. The position of the aldehyde group was deduced from the observed NOE interaction between the aldehyde-H and H(12) as well as the ester OMe. The location of the aldehyde function is similar to that in the known compound nauclefidine which also has a similar UV spectrum as 84. As in the case of 84, the intense color and long wavelength absorption peaks in the UV spectrum of mitragynalinic acid (86) indicated the presence of a highly conjugated structure. The similarity of the NMR spectra with respect to the indole and ring C portions indicated similarity with mitragynaline (84). Notable differences were the absence of signals due to the ester methoxy and the amide carbonyl function and the appearance

340

T.-S. Kam

of new peaks attributable to another aldehyde and a carboxylic acid group. The 13C NMR showed another two additional signals at 5 S3 (methylene) and 5 35 (methine) and analysis of the COSY spectrum indicated these to be part of a CH2-CH-CH2 fragment corresponding to C(17)-C(16)-C(19). The spectral data also indicated the presence of another quaternary carbon at 5 122 which is ascribed to C(20) to which the aldehyde and acid groups are attached. Corynantheidinaline (85) and corynantheidinalinic acid (87) were readily shown to be the 9-demethoxy analogues of mitragynaline (84) and mitragynalinic acid (86), respectively, from the spectral data. The finding in the case of M. speciosa that the alkaloidal composition in young leaves can be significantly different from that in mature leaves raises the interesting possibility that similar variation may also be shown by many other plants for which chemical studies were mainly carried out on mature leaf samples.

88

89

Besides 3-e/?/-P-yohimbine (81) from Uncaria borneensis [79], another new yohimbine derivative is 19,20-dehydro-Oacetyl-yohimbine (88) which was obtained in minute amount from Alstonia angustifolia [83]. The spectral data suggested that it is a dehydro-derivative of the known O-acetyl-yohimbine (89) which was also present in the plant. The location of the additional unsaturation was deduced to be at C(19), C(20) instead of C(20), C(21) since the IR spectrum did not show any enamine band. Due to paucity of material however, the configuration at C(16) and C(17) could not be established. Ajmaline-sarpagine, strychnine and related alkaloids A new vincamajine ester, 4,-hydroxy-3,,5,-dimethoxybenzoylvincamajine (90) was obtained from the roots of Alstonia angustifolia, in addition to nine other known alkaloids, alstonerine, alstophylline, vincamajine, villalstonine, macralstonine, pleiocarpamine, macrocarpamine, norfluorocurarine and 11-methoxyakuammicine [84]. The UV spectrum of 90 was similar to

341

Alkaloids from Malaysian Flora

that of vincamajine (91) and the presence of a phenolic function was indicated by the observed bathochromic shift on addition of NaOH. The mass spectrum showed fragments typical of vincamajine esters (vicamajine and arylacyl fragments) and the ! H NMR spectrum was similar to that of vincamajine except for the presence of the aromatic (8 7.15) and methoxy resonances (8 3.92) due to the aromatic acid component and the downfield shift of H( 17) (8 5.58 versus 8 4.25 in vincamajine). The antiamoebic and antiplasmodial activities of the alkaloids were also investigated (vide infra).

90

91

In another study of the leaves of the same plant, several new monomeric alkaloids were obtained (in addition to bisindoles, vide infra) including the macroline alkaloid, 19,20-dehydro10-methoxytalcarpine(92) and 11-hydroxystrictamine (93) [83]. The spectral data of 92 were characteristic of a 10- or 11-methoxylated macroline and somewhat reminiscent of that of alstophylline (94). Both had the same composition and displayed similar mass-spectral fragmentation. As the 'H NMR spectrum gave broad signals, the location of the methoxy group at C(10) was deduced from the ,3C NMR data. The signal of H(21) (aldehyde) was observed as a singlet at 8 9.65 and that of the 18-methyl group as another singlet at 8 2.18. The proposed structure was in agreement with the COSY spectrum as well as the l3C NMR spectrum which was assigned by comparison with villalstonine. The structure of 11-hydroxystrictamine (93) was established by comparison of the spectral data with that of 10-hydroxystrictamine. A study of A. angustifolia from Indonesia resulted in the isolation of two new quaternary indole alkaloids, alstogustine (95) and 19-epialstogustine (96) from the water-soluble portion of the AcOH-MeOH extract of the stem-bark [85]. These alkaloids were characterized as their

342

T.-S. Kara

chlorides. The methanol-soluble portion gave four new alkaloids, AT(b)-demethylalstogustine (97) and the Af-oxides of pseudoakuammigine, akuammicine and jV(b)-demethylalstogustine (98)

92

93

94

95

98 A/(b)->0

Two new oxindoles, iVb-demethylalstophyllal oxindole (99) and alstonal (100), together with three known oxindoles jVb-demethylalstophylline oxindole (101), alstonisine (102), and talcarpine were isolated from Alstonia macrophylla occurring in Sabah, Malaysian Borneo [87]. Compound 99 is an isomer of the known 101. The NMR spectral data were similar to those of 101 except for the appearance of an aldehyde function and a vinylic methyl group in place of an

343

Alkaloids from Malaysian Mora

acyl group and the 19-vinylic hydrogen. Alstonal (100) was readily deduced to be the 11demethoxy derivative of compound 99 from the spectral data. A previous investigation of Alstonia macrophylla from Thailand gave vincorine, cathafoline and its /V-oxide, 11-methoxyakuammicine and its N-oxide, vincamajine, alstophylline, Af(4)-demethylalstophylline oxindole, vincamajine 17-0-veratrate and vincamajine Af(l)-tri-0-methylgallate [88], while a very recent study provided two new bisindoles [89].

99 R = OMe 100 R = H

101 R = OMe 102 R = H

Ervatamia polyneura provided a total of 23 alkaloids, mainly of the vobasine- and coronaridine-type. Of these, two represent new alkaloids of the vobasine-type, vobasenal (103) and 16-ep/-vobasenal (104) [90]. Vobasenal was obtained from the leaves while \6-epivobasenal was obtained from the stem-bark extract. Both compounds had similar composition and showed similar UV and IR spectral data. The NMR spectra of 103 showed besides the NH and aromatic signals, other signals characteristic of a vobasine skeleton except that the signals corresponding to an ethyl or ethylidene side chain and to H(21) were absent, being replaced instead by signals due to a vinylogous formamide unit (singlets at 8 7 and 9). The structures were in agreement with the ,3C NMR data which showed signals due to the vinylogous formamide unit at 5 185, 116 and 152 corresponding to C(19), C(20) and C(21), respectively. The configuration at C( 16) of the epimers was distinguished by the signal due to the ester methyl which was more shielded in vobasenal (5 2.82) compared with 16-epi-vobasenal (8 3.52). These compounds are notable for the loss of a carbon atom from the basic vobasinyl skeleton. Six new monomelic alkaloids were isolated from the root bark and leaves of Ervatamia hirta, of which five (105, 106, 109 - 111) possess the normacusine B-affmisine skeleton while the other (112), is the Af-oxide of norfluorocurarine [91]. Compounds 105 and 106 were readily identified as the C(16) epimers of normacusine B and affinisine, respectively, by comparison of their NMR spectral data with that of normacusine B (107) and affinisine (108). Similarly, compounds 109 and 110 were readily shown to be the O-acetyl derivative of 16-e/?i-affinisine and the N-oxide of affinisine, respectively. The remaining new alkaloid, dehydro-16-e/?/-

344

T.-S. Kam

affinisine (111), was shown to have a hexacyclic structure resulting from additional ring formation between C(6) and the C(17) oxygen of 16-epz-affinisine. This was supported by the observation of the oxymethine H(6) and C(6) signals at 6 5.6 and 71.4, respectively. Me0 2 C x

0 2 Me

H

CHO

CHO H 104

103 HOHoC

105 R = H 106 R = Me

H2OH

H

107 R = H 108 R = Me

H2OH

AcOH2Q

109

110 R = Me, A/(4HO

Alkaloids from Malaysian Flora

345

Kopsia deverrei in addition to providing several new aspidofractinine-type compounds (vide infra) also gave three other new indole alkaloids, the pleiocarpamine derivative, 16hydroxymethylpleiocarpamine (113), the akuammiline alkaloid, 16-e/?/-deacetylakuammiline (115) and the condylocarpine derivative, 14ot-hydroxy condylocarpine (117) [92]. The !H NMR spectrum of 113 was similar to that of pleiocarpamine (114) except for the absence of the H(16) signal. Instead, the presence of a pair of AB doublets at 8 4.5 and 4.2 with J 12 Hz and the observation of a M - 31 fragment in the mass-spectrum suggested the presence of a hydroxymethyl function at C(16). The C(16) configuration however could not be established due to the relative instability and paucity of material. Compound 115 had similar spectral data as deacetylakuammiline (116) and was readily identified as the C(16) epimer from the downfield shift of the H(17) signal (8 4.35) in !H NMR compared with the corresponding H(17) signal of deacetylakuammiline (8 2.91). Compound 117 was readily identified as 14ahydroxycondylocarpine based on comparison of its spectral data with that of condylocarpine (118). The ,3C NMR spectrum differed from that of condylocarpine in the signal for C(14) which appeared as a deshielded methine at 8 69.6. The stereochemistry of C(14) was deduced from the observed H(14)/H(3) and H(14)/H(15) coupling constants which are consistent with anaxialC(I5)-OH. The leaf extract of Alstonia scholar is gave in addition to the known alkaloids nareline methyl ether (120), picrinine and scholaricine (123), three new alkaloids, v/z., nareline ethyl ether (121), 5-e/?/-nareline ethyl ether (122) and scholarine-N-oxide (124) [93]. Compound 121 was obtained as colorless needles and the UV spectrum showed absorption maxima at 216 and 256 nm indicating the presence of an unsubstituted indolenine chromophore which was confirmed by the resonance at 8 184.5 in the ,3C NMR spectrum attributable to an imine carbon. The *H and ,3C NMR spectra were similar to those of the previously known nareline methyl ether except for the replacement of the C(5)-OMe signals with signals due to the ethyl ether function. The signal due to H(5) was observed as a singlet (8 3.91), which was also the case for the methyl ether derivative (8 3.82), indicating the absence of vicinal coupling due to

346

T.-S. Kam 17

MeOaC.

^HgOH

16)

hAeOzC^ '""R

113 R = CH20H 114 R = H HOHgC

115

jCOgMe

C02Me

117 R=:OH 118 R=rH

116

17

1"

C02Me

A.

r^f^

1 ^

14

21

\'=^'^'^^

^N 5

C02Me 0

119 120 121 122

R1=H,

R2=0H

R U H , R2=0Me R U H , R2=0Et R ^ = 0 Et, R2 . = H

123 R = OH 124 R = OMe,/V(4)-^

Alkaloids from Malaysian Flora

347

the H(5)/H(6) dihedral angle of ca. 90°, in agreement with the structure of nareline (119) previously established by X-ray analysis. Compound 122 had UV and mass-spectral data which were similar to that of 121. The *H NMR spectral data were also similar to that of 121 except for significant changes involving H(5) and the ethyl group resonances, suggesting a change in the configuration at C(5). This was also reflected in the ,3C NMR spectral data which were similar to those of 121 except for significant changes in the shifts associated with C(5) and C(6). The signal due to H(5) in 122 was a doublet with J 3 Hz and shifted to lower field at 8 5.14 which is consistent with the change in configuration of the C(5) ethoxy substituent resulting in a dihedral angle of ca. 45°. The signal due to the ethoxy group in 122 has also undergone a significant upfield shift to 5 0.45 as a result of anisotropy exerted by the aromatic ring due to the change in the stereochemistry of the ethyl ether substituent. Nareline (119) and its congeners were first isolated from an Indian sample of A. scholaris [94] and since then, have also been obtained from samples from Taiwan (cultivated) [95,96] and Thailand [96]. The alkaloidal composition of Alstonia scholaris from Pakistan [97,98], the Phillipines [96,99], and Thailand [96,100,101] have also been examined and comparison of the alkaloidal composition indicated affinity of the Indian-Thai-Malaysian species which are characterized by predominance of nareline- and akuammicine-picrinine-type alkaloids [93,94,96,102]. The alkaloidal pattern of the Phillipine-Indonesian samples appear different [96,99] and arc distinguished by the common occurrence of the 6,7-seco-angustilobine B-type compounds {e.g. 6,7-jeco-angustilobine B (125) and 6,7-5eco-19,20-epoxyangustilobine B (126)} which are not present in the Indian-Thai-Malaysian samples. In addition, the Indonesian A. scholaris also contains the ring-opened aspidosperma-type alkaloid, leuconolam (172), which is not present in any of the other Asian A. scholaris samples [96]. It is perhaps pertinent to note that similar 6,7-$eco-angustilobine B-type alkaloids have also been obtained from another Indonesian Alstonia (A. angustiloba) [103] although similar compounds were not detected from an examination of the Malaysian samples.

125

126

348

T.-S. Kam

Ervatamine and uleine alkaloids The ervatamine and uleine group of alkaloids are distinguished by their lack of the characteristic two-carbon tryptamine bridge, a feature they share in common with pericalline and ellipticine. Ervatamine-type alkaloids were first obtained from the Australian plant Ervatamia orientalis which yielded ervatamine (127), 20-e/H-ervatamine (128) and 19,20dehydroervatamine (129) [104]. Since then other ervatamine-type alkaloids have been obtained from other species of Tabernaemontana (Ervatamia) and Hazunta. The Malaysian E malaccensis gave in addition to dregamine, six other alkaloids of the ervatamine type, including 19,20-dehydroervatamine, 20-e/?/-ervatamine, methuenine (130), 16-epi-methuenine (131), 6oxo-methuenine (132), Af( 1 )-methoxy- 19,20-dehydroervatamine (133) and N( 1 )-methoxymethuenine (134) [105]. The last two compounds, which are N( 1 )-methoxylated derivatives of 19,20-dehydroervatamine and methuenine, respectively, were new alkaloids. These compounds showed UV (acyl indole chromophore) and NMR spectral data which were characteristic of the ervatamic skeleton but instead of signals due to the indole NH or NMe, there was present a low field 3H signal due to a Af-OMe group (SH 4.2; 5c 66). Substitution by methoxy on the indolic nitrogen was further confirmed by the observation of NOE between N-OMe and the aromatic H(12). The N(l)-methoxylated alkaloid 133 was first reported by Goh from a Tabernaemontana species identified as T corymbosa [106]. Compounds 129, 130, 133 and a new ervatamine alkaloid, 5-oxo-19,20-dehydroervatamine (135) were subsequently also reported from another sample identified as T corymbosa [107]. Compound 135 showed spectral data characteristic of the ervatamic skeleton except for the additional presence of an amide carbonyl (5c 167.7) which was located in the 7V(4)-containing ring D since the carbon resonances in this ring were significantly shifted whereas those of the rest remained essentially unchanged when compared with compound 129. The alternative location of the amide carbonyl function at C(21) was ruled out since the long-range coupling between Me(18) and H(21), which is a common feature of compounds 129,130 and 133, was also observed in the lH NMR spectrum of compound 135. The isolation of compound 135 represents the first instance of oxygenation at position 5 of the ervatamic skeleton, oxygenation at position 6 being previously the more common [107]. It is likely from the similar alkaloidal composition obtained, and considering the well known taxonomic difficulties associated with the Tabernaemontana (Ervatamia) [108], that all three samples belong to the same species. There has only been one reported instance of an uleine-type alkaloid from a Malaysian plant. Undulifoline (136), was obtained from the new Malayan Alstonia species, Alstonia undulifolia Kochummen and Wong, in addition to tetrahydrocantleyine, cantleyine, akuammicine, pieiocarpamine, echitamidine, 20-e/?M9£-echitamidine, echitamine and nor-echitamine [109].

349

Alkaloids from Malaysian Flora

130 R1 = H-p, R2 = H 2 131 R1 = H-a, R2 = H 2 132 R1 = H-P, R2 = 0

127 R = p-Et 128 R = a-Et 129 R = CHMe

Me

rV^i OMe O

133 R = C0 2 Me 134 R = H

135

The mass spectrum of 136 displayed besides a strong M+ ion (m/z 340), another intense peak at m/z 238 which arose from cleavage of the C(21)/N(4) bond followed by aromatization of ring C, in analogy to the mass-spectral fragmentation of uleine. The NMR spectral data were consistent with the proposed structure, showing an unsubstituted indole nucleus and presence of a methyl ester and of a N(4)-methyl group, while ethyl, vinyl or ethylidene side chains were absent. The ,3 C NMR spectrum showed two methyls, five methylenes (two oxymethylenes), three methines and one quaternary carbon. Analysis of the COSY spectrum revealed besides the presence of an isolated methylene, the existence of the partial structure OCH2CH2CH(CH)CHCH2CH2 which was consistent with the proposed structure of undulifoline. The relative configuration of C(16) and C(20) were fixed by the CH2OCH2 bridge between these two centres while the bridging of ring C in a 1,3 manner by piperidine and oxepane rings required these rings to be on opposite sides of the molecule. The presumed

350

T.-S. Kam

common origin of undulifoline and tubotaiwine from precondylcarpine allowed the tentative assignment of the absolute configuration of undulifoline as being similar to that of tubotaiwine (137).

136

137

Ebumane alkaloids Alkaloids of the ebumane group have been obtained only from the Apocynaceae and in the case of Malaysian plants, predominantly from plants of the genus Kopsia and Leuconotis. Kopsia larutensis gave predominantly alkaloids of the eburnane-type [110-112], including (+)eburnamonine (138), (+)-eburnamonine-N-oxide, (-)-ebumamine (139), (+)-isoeburnamine (142), (-)-O-ethyleburnamine (140), (+)-eburnamenine (145), (-)-kopsinine and two new alkaloids, larutensine [110] (larutenine [112]) and eburnaminol [110]. Larutensine (154) is isomeric with (+)-ebumamonine (138), the predominant alkaloid found in the leaves. The UV spectrum indicated an unsubstituted indole and the IR spectrum indicated absence of NH/OH functions and presence of an ether function. The ! H and ,3C NMR spectral data indicated an ebumane derivative oxygenated at C(16) (5c 77.5; 8H 5.83) but differing from the other ebumane alkaloids occurring in the plant in that the C(20) ethyl substituent was missing. The presence instead of carbon resonances at 6 58.5 (-CH20-) and 40.6 (-CH2CH20-) suggested that ring formation had occurred in which an ether oxygen now links C(18) to C(16). This was supported by the C(18) hydrogens which were shifted to 8 3.80 and 3.95. The proposed structure was in accord with the 2-D NMR data. The configuration at C(20) and C(21) were assumed to be similar to those in the other ebumane alkaloids isolated on biogenetic grounds. This being the case, the stereochemistry of the C(16) ether oxygen has to be p to permit formation of the six-membered ring. The likely precursor of larutensine, eburnaminol (155), was also isolated from K. larutensis, but as pointed out by Lounasmaa [113,114] and Kam [115], the original structure proposed {C(16)-a-OH} required amendment. The absolute configuration of C(16) of the ebumane group of alkaloids has also been established based on X-ray analysis of (-)-O-ethyleburnamine (140) and (+)-isoeburnamine (142), representing the ebumamine and

Alkaloids from Malaysian Mora

351

isoeburnamine (epieburnamine) series, respectively (Table 2) [115]. It has also been pointed out that the coupling constants for the H(16) doublet of doublets can be of diagnostic value since the pentacyclic compounds of the eburnamine series invariably have J 9 and 5 Hz, while the corresponding coupling constants in the diastereomeric isoeburnamine (epieburnamine) series are invariably 4 and 2 Hz due to H(16) being axial and equatorial, respectively, when ring E is in the preferred chair conformation [115]. Table 2. Absolute configuration of the eburnane alkaloids

(+)-eburnamonine (138) (-)-eburnamine (139) (-)-Oethyleburnamine (140) (-)-O-methyleburnamine (141) (+)-isoeburnamine (142) (+)-0-etnylisoeburnamine (143) (+)-0-methylisoeburnamine (144) (^)-eburnamenine (145)

138 139 140 141 142 143 144 145

R\R2 = 0 R1 = OH, R2 = H R1=OEt, R 2 = H R1= OMe, R2 = H R 1 =H, R2 = OH R 1 =H, R 2 =OEt R 1 =H,R 2 = OMe R 1 =H,R 2 = nil,A 16 ' 17

(-)-eburnamonine (146) (+)-eburnamine (147) (+)-0-ethyleburnamine (148) (+)-0-methyleburnamine (149) (-)-isoeburnamine (150) (-)-Oethylisoeburnamine (151) (-)-O-methylisoeburnamine (152) (-)-ebumamenine (153)

146 147 148 149 150 151 152 153

R\R2 = 0 R1 = H, R2 = OH R 1 =H, R2 = OEt R 1 =H, R2 = OMe R 1 =OH, R2 = H R1=OEt, R 2 =H R 1 =OMe, R2 = H R 1 =H,R 2 = nil,A 16 ' 17

352

T.-S. Kam

CH2OH 154

155

The structures of eburnaminol (155) and larutensine (154) have been confirmed by a synthesis reported by Lounasmaa from the previously available indoloquinolizidine ester 156 (Scheme 8). Successive reduction, acetylation and Fujii oxidation of 156 yielded the enamine 157 which was alkylated with iodoacetic ester followed by NaBH4 reduction to give a mixture of four products. Treatment of two of these, the epimeric esters 158, with ethanolic sodium ethoxide resulted in cyclization to 18-hydroxyeburnamonine (159) accompanied by its C(20) epimer. Reduction of 18-hydroxyeburnamonine furnished (±)-eburnaminol and 16-epieburnaminol (160) which on overnight treatment with acid gave (±)-larutensine [114]. Another new ebumane alkaloid recently obtained is (+)-19-oxoeburnamine (161) from Kopsia pauciflora [116]. The presence of the C(20)-acetyl side chain was indicated by the observed base peak due to loss of water and the acetyl side chain in the mass-spectrum and by the replacement of signals due to the C(20)-ethyl group by signals due to an acetyl group in the 'H and ,3C NMR spectra when compared with eburnamine. The configuration at C(21) and C(20) were assumed to be similar to that of (-)-eburnamine (139), (+)-isoeburnamine (142) and (+)-eburnamonine (138) which were also obtained, while the observed coupling constants for the H(16) doublet of doublets (J 9, 5 Hz) allowed the configuration at C(16) {C(16)-P-OH} to be established [116]. The Malaysian Borneo species, Kopsia dasyrachis, also furnished several ebumane alkaloids including (+)-ebumamonine (138), (+)-isoeburnamine (142) and (+)-19(/?)hydroxyeburnamine (162). The latter was a new alkaloid and X-ray diffraction was undertaken to establish the configuration at C(19) [117]. The occurrence of (+)-eburnamonine and (+)isoeburnamine in the same plant indicated that 162 belongs to the same enantiomeric group possessing the 20p, 21(3 configuration, and the observed coupling constants of the H(16) doublet of doublets of 10 and 5 Hz indicated that the C(16)-OH is p. This compound also occurs in K. pauciflora [118] and constitutes the ebumane half of the dimeric alkaloid kopsoffmol which also occurs in K. dasyrachis [117]. In view of the structure of 162, it would appear that an alternative and more likely structure for kopsoffinol is 312 in which the 19(/?)hydroxyeburnamine unit constitutes the ebumane half (vide infra).

Alkaloids from Malaysian Flora

i -in

EtQ2C

AcO

156

157

OAc 159

158

VII

155

16-POH

160

16-aOH

(±)-154

Reagents: i, LiAIH4, THF; ii, Ac20, py; Hi, EDTANa2, Hg(OAc)2, EtOH-H20, A; lv, ICH2C02Et; NaBH4; v, NaOEt/EtOH; vi, LiAIH4, THF; vii, 5% HCI, r.t. overnight

SCHEME 8

354

T.-S. Kam

HO^\"H 161

162

OH

T^K

k

163

164

Recently two new dihydroeburnane alkaloids, terengganensines A (163) and B (164), in addition to quebrachamine, isoebumamine, eburnaminol and larutensine were obtained from a new Kopsia species, Kopsia terengganensis [119]. The UV spectrum indicated the presence of dihydroindole chromophores and in common with eburnaminol and larutensine, the NMR spectra indicated absence of NH and ethyl groups, suggesting the presence of an oxidized ethyl side chain. The aromatic C(7) (8 ca. 78) and C(2) (8 ca. 92.5) in these two compounds were quaternary centres and the downfield shifts suggested that the former was a to an oxygen while the latter was linked to both an oxygen and nitrogen. The analysis of 2-D COSY and HMQC spectral data revealed fragments which were in accordance with the proposed structures while long range C-H correlations {H(18)/C(2), C(16)} in the HMBC spectrum of 163 supported the presence of the two ether bridges linking C(18)/C(2) and C(16)/C(2). The observation of Bohlmann bands in the IR and the observed NOE between H(19P) and H(21) indicated transfused C/D and cis fused D/E rings as in larutensine. The configuration at the centres C(21) and C(20) must be similar to the other eburnane compounds present and furthermore the formation of the ether bridges required the C(16)-0 and C(2)-0 bonds to be on the same side of ring E. Finally, a cis B/C junction was required to allow a chair conformation for ring C which fixed the

Alkaloids from Malaysian Flora

35*

stereochemistry of the C(7)-OH. Terengganensine B (164) showed similar NMR spectral data as terengganensine A except for absence of the C(16) and C(18) oxymethines. Instead an oxymethylene signal assigned to C(18) and signals due to two olefinic hydrogens typical of 16,17-dehydroeburnamine compounds were observed. This and the UV spectrum (228, 283 and 307 nm) which was consistent with the presence of an Af-arylenamine chromophore, supported the proposed structure of terengganensine B (164). It is of interest to compare the occurrence of the eburnane alkaloids in Malaysian Kopsia with that of the Chinese species [118]. From such a comparison, it would appear that the Malaysian Kopsia (and Leuconotis) species elaborate exclusively eburnane alkaloids of one enantiomeric group (20/?, 21/? or 20(3, 21(3 configuration) [18-20,58,110-112,115-119], while the Chinese species appear to elaborate eburnane alkaloids of the opposite enantiomeric group (20S, 215 or 20a, 21a configuration) [118,120-122]. Notable exceptions are the dimeric alkaloids kopsoffinol and kopsoffine isolated from the Malaysian Borneo species Kopsia pauciflora [124] which were reported to be constituted from union of kopsinine and dihydroeburnamenine units with the 20a, 21 a configuration (vide infra). Iboga alkaloids The iboga alkaloids, exemplified by coronaridine (165), abound in plants of the family Tabernaemontana (Ervatamia) [125]. Although many known iboga-type alkaloids such as for example coronaridine, voacristine, voacangine (166) and eglandine were obtained from examination of Malaysian Tabernaemontana plants, only two new monomelic iboga alkaloids, 3-oxo-19-ep/-heyneanine (167) and 3-hydroxy-3,4-secocoronaridine (168) have been reported, both of which were from E. polyneura (which also provided indole alkaloids of the vobasinetype, vide supra) [90]. The UV spectrum of 167 (227, 285, 293 nm) indicated an indole chromophore and the IR spectrum indicated the presence of NH (3320 cm"1), ester (1720 cm'1) and lactam carbonyls (1650 cm"1). The presence of the lactam function was also indicated by the carbon resonance at 8 173 and suggested a 3-oxo-coronaridine derivative. The NMR spectra were characteristic of coronaridine derivatives possessing the hydroxy ethyl side chain and assignment of the C(19) configuration as R was possible from the observed chemical shift of C(15) (8 28.0) and C(21) (8 53.1) by analogy with those of 19-
356

T.-S. Kara

structure 168, which can be considered as having arisen from coronaridine via cleavage of the C(3)-Af(4) bond followed by oxidation of the C(3) fragment.

165 R = H 166 R = OMe

167

168

169

Aspidospermine-aspidofractinine and related alkaloids The ring-opened aspidosperma alkaloid, rhazinilam (170), first isolated from the Indian plant, Rhazya stricta [126], has also been obtained from several genera of the Malaysian Apocynaceae including Leuconotis (L. griffithiU L. eugenefolia) [20,127,128] and Kopsia (K. singapurensis, K. teoi) [19,118,129-132]. A new oxo-derivative of rhazinilam, rhazinicine (171), has been recently obtained from the North Borneo species, Kopsia dasyrachis [133]. The UV spectrum and mass-spectral fragmentation of 171 were characteristic of rhazinilam alkaloids as were the ! H and ,3C NMR spectra. The ,3C NMR spectrum however showed the presence of an additional lactam carbonyl which must be at position 3 since the two adjacent aromatic-H of the pyrrole ring of a rhazinilam-type compound were still intact and furthermore, the characteristic H(3) resonances of rhazinilam were absent in 171 while the H(14) and C(14) signals have been shifted downfield. The location of the lactam function at position 3 was also consistent with the observed downfield shift of H(5) compared with 170

357

Alkaloids from Malaysian Flora

-A II

° ^

r^"^18

2

I H 170 171

R = H2 R=Q

172 173

R = p-OH R = a-OH

174

175

176

177

358

T.-S. Kam

due to anisotropy exerted by the proximate carbonyl function. Rhazinicine represents a new example of oxygenation of the rhazinilam skeleton. A previous example, 3-oxo-14,15dehydrorhazinilam, was obtained from cell suspension cultures of Aspidosperma quebracho W<wa?Schlecht[134]. Leuconotis griffithii gave in addition to eburnamine, 0-methyleburnamine, 0-methylisoeburnamine, kopsinine, norfluorocurarine and its TV-oxide, a new rhazinilam-type alkaloid, leuconolam (172), whose structure was established by X-ray analysis [135]. The X-ray structure revealed that leuconolam has the unusual structural feature in which the two N - O O planes are out of plane with the aromatic ring thus minimizing conjugation. Leuconolam was originally thought to be an artifact but its persistence during subsequent extraction of fresh plant material under neutral and alkaline conditions provided confirmation that it is indeed a natural product [128]. L. eugenefolia gave in addition to leuconolam and rhazinilam, two new alkaloids, epileuconolam (173) and 5,21-dihydrorhazinilam (174) [127,128]. The ready conversion of 174 to rhazinilam on standing indicated that 174 is the likely precursor of rhazinilam while epileuconolam is also likely to be an artifact since it was obtained only from acidic methanolic extracts but not from neutral or basic methanolic extracts of the plant material [128]. It is of interest to compare the alkaloidal composition of the Indonesian L. eugenefolia which gave besides leuconolam, 21 -0-methylleuconolam and rhazinilam-N-oxide, yohimbine, Pyohimbine, and the diazaspiroleuconolam compound, leuconoxine (175) [136], which has since then also been obtained from the North Borneo species, Kopsia tenuis [19]. A similar diazaspiroleuconolam derivative 176 has been obtained via a facile acid-induced ring-reclosure reaction of leuconolam, while the base-induced reaction gave the meloscine-type derivative 177 [127,128]. Tabernaemontana divaricata (double flower variety) provided an unusual minor alkaloid, voaharine (178), whose structure was established by X-ray analysis [137]. Voaharine is exceptional in being in all probability a tryptamine and secologariine derived alkaloid but possessing a 3-quinolone instead of an indole chromophore. Voaharine is probably derived from voaphylline (180) (which is also present in the plant) via oxidation and rearrangement and represents the first instance of a 3-quinolone-type alkaloid obtained from Tabernaemontana. Besides these, and the known alkaloids W-methylvoaphylline (181), pachysiphine (tabersoninep-epoxide) and apparicine, as well as two new bisindoles (vide infra), the plant also provided several new alkaloids of the aspidosperma-type including (-)-mehranine (179), voafinine (182), Af-methylvoafmine (183), voafinidine (184) and voalenine (185) which were obtained in minute amounts [138-140]. The spectral data of (-)-mehranine (179) [138], indicated that it is N( 1 )-methylaspidospermidine-epoxide which is similar to (+)-mehranine reported previously from E. coronaria grown in Pakistan [141]. However, the stereochemistry of the chiral centres of (+)-

Alkaloids from Malaysian Flora

359

mehranine were not defined in the previous study and since compound 179 had similar MS and ! H NMR spectra, except for the sign of the specific rotation, it was concluded that 179 was the enantiomer of (+)-mehranine. The stereochemistry of the 14,15-epoxide function was assigned the (3 configuration in common with those of the other alkaloids present in the plant as well as by the excellent agreement of the C(3), C(14), C(15), C(19) and C(20) carbon resonances when compared with those of tabersonine-P-epoxide [138]. Since (-)-mehranine constitutes one monomelic fragment of the bisindole, conofoline 305, these suppositions have since been vindicated by an X-ray analysis of conofoline (305) (vide infra) [142].

178

180 R = H 181 R = Me

179

182 R ^ H , R2 = OH 183 R1 = Me, R2 = OH

Voafmine (182) and N-methylvoafinine (183) were shown to be 16-hydroxy derivatives of voaphylline (180) and N-methylvoaphylline (181), respectively, from their spectral data [139]. The location of the hydroxy substituent on C(16) was deduced from the HMBC data which showed three-bond correlations from H(17) to C(19) and C(21). This was further confirmed by NOE experiments {NOE between N-Me/H(16), Me(18)/H(15)} which also allowed assignment

360

T.-S. Kam

of the stereochemistry of the C(16)-OH as well as the 14,15-epoxide function. In the case of the related alkaloid, voafinidine (184) [140], the NMR spectral data indicated a structure essentially similar to Af-methylvoaphylline but substantially modified in the piperidine ring. The presence of two oxymethines (5 70.8 and 80.8) suggested the presence of a 1,2-diol function at C(14) and C(15) which was supported by the COSY and HMQC data. The transdiaxial disposition of the C(14) and C(15) hydrogens were evident from the observed Jl4.l5 value (9 Hz) and the stereochemistry of the 14,15-substituents might be inferred as 14a and 150, assuming that the trans-dioi arose from nucleophilic attack by water on the 14,15-0epoxide function of N-methylvoaphylline, which would be anticipated to occur at the less hindered C(14). In the event, this was shown to be the case from NOE experiments {NOE between H(14P)/H(17P), Me(18)/H(15a)}. Voalenine (185) displayed spectral features typical of a hydroxyindolenine compound and detailed NMR analysis indicated that it is the 7-hydroxyindolenine of 16-oxo-voaphylline, which was, however, not obtained [140]. The structure of voalenine has been subsequently confirmed by X-ray analysis [143].

184

185

Plants of the genus Kopsia have proven to be a particularly rich source of aspidofractininetype alkaloids. Early studies in the sixties by Battersby [144,145] and Schmid [146,147] of Kopsiafruticosa,an ornamental Kopsia widely cultivated in Malaysia, yielded the heptacyclic bridged alkaloids, fruticosine (186), fruticosamine (187) and kopsine (188). Recently a new oxo-derivative of kopsine, kopsiflne (189) was obtained from K dasyrachis from Malaysian Borneo [133]. The ,3C NMR spectral data indicated the presence of a lactam carbonyl in addition to the ketonic carbonyl group bridging C(6) and C(16). The presence of the characteristic H(3) and H(21) resonances of kopsine-type compounds ruled out oxygenation at these positions. Oxygenation at position 5 was supported by the observation of H(6) as a singlet which had been shifted downfield as a result of anisotropy exerted by the proximate carbonyl function, as well as from the observed correlations in the HMBC spectrum

361

Alkaloids from Malaysian Flora

{H(6)/C(5), C(7), C(8), C(16), C(21), C(22); H(21)/C(5), C(6), C(7), C(8), C(17), C(19)}. Kopsifine (189) represents a rare instance of oxygenation of the kopsine skeleton. Previous examples of oxygenation of the kopsine skeleton include epikopsanol-10-lactam from Aspidosperma duckei and A. macrocarpon [148], and 5,22-dioxokopsane from various Kopsia species [56,120,121,149]. A derivative of fruticosine, jasminiflorine {12-methoxy-N( 1 )decarbomethoxyfruticosine (190)} has been reported from the Thai species, K jasminiflora [150].

OH 186 R 1 =OH, R2 = H 187 R^H, R2 = OH

188

« ^

OH 189

190

In 1959, Amarasingam and Kiang reported the isolation of kopsingine (191) and kopsaporine (12-demethoxykopsingine) (192) from Kopsia singapurensis [151,152]. The structure of kopsingine and kopsaporine were then established based on degradative experiments carried out on kopsingine, but the stereochemistry at C(17) could not be assigned with certainty [153]. Kopsingine and kopsaporine as well as many new aspidofractinines have been recently obtained from the new Malayan Kopsia species, K teoi. The stereochemistry at C(17) of kopsingine (and kopsaporine) can be established from the NMR spectrum which

362

T.-S. Kam

showed W-coupling between H(17) and H(21) (2 Hz), requiring H(17) to be a [154]. The structure has also been confirmed by an X-ray analysis [154].

191 192

R = OMe R= H

193 194

R = OH R = OMe

Several new derivatives of kopsingine or kopsaporine with different aromatic substitution which were recently obtained include 11-hydroxykopsingine (193) [131], 11-methoxykopsingine (194) [131] and 11,12-methylenedioxykopsaporine (195) [132]. Another new aspidofractinine, kopsinol (196) [130] was readily shown to be the N( 1 )-decarbomethoxy derivative of kopsaporine while compound 197 was assigned the structure 1 l-methoxy-12hydroxykopsinol from the spectral data [131]. The position of the aromatic methoxy group in 197 was established to be at C(l 1) from the observed NOE between H(10) and the aromatic OMe. Several kopsingine-type alkaloids with additional modification in the piperidine ring include 198 which was readily shown to be 14,15-P-epoxy kopsingine from the replacement of the characteristic olefinic signals by signals due to an epoxide function in the NMR spectra [131]. The stereochemistry of the epoxide function was deduced to be p from the observed NOE between H(21) and H(14ot). Another such alkaloid is kopsinganol (199) [130] which has additional hydroxy substitution at C(15). The position of hydroxy substitution was located at C(l 5) from the major product 200 {8 C(15) 209.0} obtained from oxidation (Collins reagent) of kopsinganol. The stereochemistry of the C(15)-OH was assigned the a configuration from the absence of NOE enhancement on irradiation of H(21) (irradiation of H(17) was not feasible due to overlap). Additional confirmation of this assignment was provided by the subsequent observation that reduction (NaBH4) of the oxo-bridged alkaloid kopsidine C (244) gave kopsinganol indicating that the C(15)-OH is a [168].

Alkaloids from Malaysian Flora

363

6H 199 200

R = 15-a-OH R = 15-oxo

Several other new aspidofractinines are characterized by departure in the substitution pattern of the C(16)/C(17) bridge compared with kopsingine or kopsaporine. Examples in this category include kopsinginine (201) [154], kopsinginol (202) [130] and 17-a-hydroxy-A14,15kopsinine (203) [154]. Kopsinginine (201) had M+ 440 (C24H2gN206) differing from kopsingine (191) by 16 mass units and indicating replacement of a hydroxyl function by H. This was confirmed by the 'H NMR spectrum which showed that the characteristic H(17) signal was absent and was replaced by a pair of broad doublets at 5 1.68 and 2.71. The ,3C NMR spectrum was also essentially similar to that of kopsingine except for C(17) which became a methylene shifted to higher field (8 41.2). Kopsinginol (202) on the other hand was shown to be modified in the C(16)/C(17) bridge by loss of both the C(16) carbomethoxy and hydroxyl substituents when compared with kopsinol (196). The NMR spectra showed C( 16) to be a methylene (8 39.5) and the W-coupIing observed between H(16P) and H(18a) (2 Hz) provided additional confirmation of the structure.

364

T.-S. Kam

201

202

H 203

C0 2 Me 204

Compound 203 (C21H24N2O3) had spectral data which indicated it was 17-a-hydroxyA -kopsinine. The NMR spectral data indicated an aspidofractinine-type compound with an unsubstituted aromatic ring, the presence of a C(16) methyl ester, C(17)-hydroxyl functions and unsaturation at C(14) and C(15), and absence of carbamate and C(16)-OH groups. The stereochemistry of the C(17)-OH was assigned the a configuration from the observed Wcoupling (2 Hz) between H(17p) and H(19a), while the absence of similar coupling between H(16) and one of the H(18) indicated that the C(16) methyl ester group was p which was also in accord with the observed H(16)/H(17) coupling of 7.5 Hz [154]. In another study of the same species, a compound 204 with similar spectral data was reported, but in which Wcoupling between H(16) and H(18) was apparently detected, requiring the methyl ester function to be a [132]. A reinvestigation of this compound has been carried out by detailed analysis (COSY, homonuclear decoupling, NOE) of the *H NMR spectrum obtained at 400 MHz which resolved the H(18) and H(16) signals as follows: 5 1.30, H(18p), ddd (J,8.|g 13 Hz,yI8p.l9jl 11 Hz, y,8p-i9o2.1 Hz); 8 1.88, H(\%a\dddd (JxlA% 13 Hz, J l8(rl9a 11 Hz, J18a.I9p 14,5

Alkaloids from Malaysian mora

365

7.5 Hz, and V, 8a ., 6 1.1 Hz); 8 2.77, H(16a), dd (J I6 ., 7 7.7 Hz and 4JlM%a 1.1 Hz). In addition, the observed NOE interaction between H(18p) and H(16) provided incontrovertible evidence for the stereochemistry of H(16) as a [155]. These results have vindicated the original assignment of this compound as 17-<x-hydroxy-A,4,5-kopsinine (203) [154]. Two new aspidofractinine compounds Af-carbomethoxy-17p-hydroxykopsinine (205) and Af-carbomethoxy-17p-hydroxy-A,4,l5-kopsinine (206) were obtained from K. deverrei and are characterized by the absence of the C(16) hydroxyl group when compared with kopsaporine. The assignments of the stereochemistry of the C(16) methyl ester and C(17) hydroxyl substituents as P were based on the absence of W-coupling between H(16) and H(17) to any of the C(18) and C(19) hydrogens respectively.

H 205 206 A 14 ' 15

211

207 208 209 210

R1 = R2 = H , A 1 4 1 5 R^H.R^OMe.A14'15 R1 = OMe, R2 = H, A 14 ' 15 R 1 =OMe,R 2 = H

m/z 280

366

T.-S. Kam

Kopsia deverrei is also notable for furnishing several 17-oxo-aspidofractinine alkaloids. Four such kopsinone derivatives were obtained, viz., kopsinone (207), 12-methoxykopsinone (208), 10-methoxykopsinone (209) and 14,15-dihydro-10-methoxykopsinone (210) [156,157]. A distinguishing feature of these compounds is the presence of the C(17) ketone resonance at 5 213. Reduction (LiAlH/THF) of kopsinone (207) gave the alcohol 211 which displayed the retro-Diels-Alder fragment at m/z 280 in its mass-spectrum, thus confirming the presence of the OH group on C(17) in the alcohol 211 [156]. Kopsia profunda and Kopsia dasyrachis are sources of new dehydropleiocarpine-type alkaloids which are characterized by the presence of a double bond across the C(16)/C(17) bridge. Alkaloids of this group include kopsidasine (212) and its N-oxide (213) from K. dasyrachis [158] and A^l)-methoxycarbonyl-ll,12-methylenedioxy-A,6J7-kopsinine (214), N(l)-methoxycarbonyl-12-methoxy-A,6,7-kopsinine (216), and Af(l)-methoxycarbonyl-12hydroxy-Al6,7-kopsinine (218), and the N-oxides of 214 and 216 (215 and 217, respectively) from K profunda [159,160]. These alkaloids show the typical olefinic carbon resonances as well as the vinylic-H resonance associated with the acrylic ester moiety. A similar compound, kopsijasmine (219) has also been obtained from the Thai species, K jasminiflora [150].

R1 = OMe. R2 = R3 = H, R4 = OH R1 = OMe, R2 = R3 = H, R4 = OH, A/(4)-»0 R1 = R4 = H, R2, R3 = OCH 2 0 R1 = R4 = H, R2, R3 = OCH2Of A/(4)->0 R1 = R 2 =R 4 = H, R3 = OMe, R1 = R 2 =R 4 = H, R3 = OMe, A/(4)->0 R1 = R 2 =R 4 = H, R3 = OH R1 = R 2 =R 3 = R4 = H

A new pilocarpine derivative, 12-methoxy pilocarpine (222) was obtained from Kopsia griffithii [58]. This plant furnished a diverse array of alkaloidal types which included the pcarboline compounds, harmane (55) and harmicine (56), the corynantheine alkaloids, tetrahydroalstonine and 16(/?)-19,20-£-isositsirikine (227), the aspidofractinine alkaloids, kopsilongine (223), kopsamine (224), kopsamine-N-oxide, pleiocarpine (221), kopsinine (220), A^(l)-methoxycarbonyl-12-methoxy-Al6,7-kopsinine (216), W-carbomethoxy-1 l-hydroxy-12methoxykopsinaline (225), A^-carbomethoxy-ll,12-dimethoxykopsinaline (226), the rare

Alkaloids from Malaysian Flora

367

kopsidasinine-type alkaloid, 12-methoxy-10-demethoxykopsidasinine (231), the eburnane alkaloids, (+)-eburnamonine (138), (-)-ebumamine (139), the ring-opened aspidosperma alkaloid, leuconolam (172), the quasidimer, buchtienine (228), the sarpagine alkaloids, rhazimol (deacetylakuammiline), 16-ep/-deacetylakuammiline, and the pentacyclic diazaspiro alkaloid, leuconoxine (175).

220 221 222

R1=R2 = H R1 = H, R2 = C0 2 Me R1 = OMe, R2 = C0 2 Me

228

223 224 225 226

R1 = H, R2 = OMe R 1 ,R 2 = OCH 2 0 R1 = OH, R2 = OMe R1 = R2 = OMe

368

T.-S. Kam

Three new compounds were obtained from the bark which were the TV-oxides of 16-e/wdeacetylakuammiline, akuammiline and 11,12-methylenedioxykopsinaline. Among the known alkaloids, the p-carboline alkaloid harmane, the quasidimer buchtienine and \6R-\9,20-Eisositsirikine, were found for the first time in Kopsia. Harmane and buchtienine constitute the major alkaloids in the leaves [58]. Kospsidasinine (229) was first isolated from Kopsia dasyrachis collected from Sabah in Malaysian Borneo. The structure was established by a combination of spectroscopy and chemical correlation, in particular, the key observation that the Hofmann degradation product of kopsidasinine, 232, was identical with the product obtained by treatment of kopsidasine (212) with methyl iodide [158]. Only two other kopsidasinine-type alkaloid have since been reported, 12-methoxy-10-demethoxykopsidasinine (230) from K pauciflora [116] and 10demethoxykopsidasinine (231) from the Thai species, K jasminiflora [161]. A distinguishing feature of these compounds is the presence of a relatively low field pair of AB doublets (5 4.0 and 3.5) due to an isolated CHCH unit {corresponding to C(16)-C(17)} and an unusually low field ketonic carbon resonance (5 214) due to C(21) [116, 161].

229 R1 = OMe, R 2 = H 230 R1 = H, R 2 = OMe 231 R1 = R2 = H

232

Two aspidofractinine-type compounds, lahadinines A (233) and B (234), obtained from Kopsia pauciflora are remarkable for having a cyano-substituent at C(21) [162]. The massspectra of these alkaloids are characterized by a strong molecular ion (usually also the base peak), with the odd mass indicating the presence of a third nitrogen. Fragments attributable to loss of CN and HON were also detected in the mass-spectrum and the IR spectrum showed a weak band at ca. 2250 cm*1. The characteristic H(21) signal was absent in the 'H NMR

Alkaloids from Malaysian Flora

369

spectrum and the 13C NMR spectrum showed an additional quaternary resonance at 8 118 due to the cyano group. The location of the cyano group at C(21) was supported by the observed three-bond correlations between C(21) and H(5), H(17) and H(19) in the HMBC spectrum. Alkaloids containing the unusual cyano group have previously been obtained from the Indonesian Alstonia angustiloba [103]. Lahadinines A and B are C(21)-cyano derivatives of kopsamine (Mmethoxycarbonyl-ll,12-methylenedioxykopsinaline) (224) and 7V-methoxycarbonyl-11,12-dimethoxykopsinaline (226) respectively, both of which also occur in the plant. The C(21)-hydroxy substituted derivative of 224, paucifmine (235) and its TV-oxide 236 were also isolated [162].

C0 2 Me \ ^ - C 0 2 l v 1 e OH 233 234

R 1 ,R 2 = OCH 2 0 R1 = R2 = OMe

235 236

237 238 239 240 241

A/(4)->0

R1 = R2 = H,R3=C02lv1e R1, R2 = OCH 2 0, R3 = C0 2 Me R1 = R2 = R3 = H R \ R 2 = OCH 2 0, R3 = H R1, R2 = OCH 2 0, R3 = H, A14-15

C0 2 Me

Kopsia arborea furnished several alkaloids belonging to the rare methyl chanofruticosinate group of compounds of which two (240 and 241) were new [163]. The parent compound methyl chanofruticosinate (237) was first obtained from fruticosine by Guggisberg et al [147]. It was isolated as a natural product relatively recently from the Chinese species, Kopsia

370

T.-S. Kam

officinalis together with two other derivatives, methyl 11,12-methylenedioxychanofruticosinate (238) and methyl jV-decarbomethoxychanofruticosinate (239). The structure was firmly established by an X-ray diffraction analysis performed on 238 [164]. The structures of the two new compounds, methyl 11,12-methylenedioxy-yV-decarbomethoxychanofruticosinate (240) and methyl ll,12-methylenedioxy-A^decarbomethoxy-Al4,,5-chanofruticosinate (241) obtained from K. arborea were readily established based on the spectral data and by reference to the previously known compounds 237 - 239 [163]. Several new heptacyclic alkaloids, kopsidines A, B, C and D (242 - 245) were obtained from Kopsia teoi which are characterized by formation of an oxygen bridge linking C( 17) to C(3) of the aspidofractinine framework [165,166]. The NMR spectra of these compounds indicated similarity to kopsingine except for departure of the piperidine ring signals. The 14,15 double bond was absent and two of the piperidine ring carbons were now oxygenated, of which one was substituted by a methoxy group (in the case of kopsidine A). The H(3) signal in these compounds appeared as a low field triplet at ca. 8 4.5 and LRCOSY showed long-range coupling between H(3) and H(17). Likewise, the H-C COLOC spectrum showed three-bond correlation between C(17) and H(3), further confirming the C(3) to C(17) linkage. The methoxy subsituent was thus at C(15) and the stereochemistry at this centre was deduced from the observed NOE interaction between H(15) and H(17), indicating that the C(15) alkoxy group was a. Formation of the additional ring has forced the piperidine ring into a boat conformation which was reflected in the observed coupling pattern of the H(3) (/, J3.14 2.5 Hz) and H(15) (dy J\4.\s 7.5 Hz) resonances. Several other alkaloids of the same type, singapurensines A - D, (246 - 249) have also been subsequently obtained from Kopsia singapurensis [167].

•C02Me ^H

242 243 244 245 246 247 248 249

R1 = H, R2 = OMe, R3 = a-OMe R1 = H, R2 = OMe, R3 = a-OEt R1 = H, R2 = OMe, R3 = a-OH R1 = H, R2 = OMe, R3 = p-OH R1 = R2 = H,R 3 =a-OH R1 = R2 = H,R 3 = a-OMe R1, R2 = OCH2Of R3 = a-OH R1, R2 = OCH 2 0, R3 = a-OMe

The 3-to-17oxo-bridged alkaloids kopsidines A - C (242 - 244) have been synthesized in high yields via the stable iminium salt obtained from electrochemical oxidation (Pt anode, 30% CH 2 Cl r MeCN, 0.1M EUNCIO^ of kopsingine (191) (Scheme 9) [168]. Electrooxidation of kopsingine resulted in stepwise loss of an electron, deprotonation, followed by loss of another

Alkaloids from Malaysian Flora

371

- 2e, - H +

OMe I

Vx
ROH OMG

io 2 M>^0 2 M H e

6H 191 252

'

OMe

6H

A14'15 (kopsingine) (dihydrokopsingine)

250

T \ ^ 'H io2MVc02Me OH 251 (242 - 245)

SCHEME 9

6Me

io2M>^2Me

0MG

io2M>^C02^

OH 253

OH 254

electron to yield the stable conjugated iminium salt, 250 as the main product of the electrochemical process. Addition of methanol resulted in conjugate addition of the nucleophile

372

T.-S. Kam

onto C(15) which was followed by an intramolecular 1, 2-addition of the 17-P-OH function of the resulting iminium ion intermediate 251 yielding kopsidine A. Similar electrochemical oxidation of the synthetic kopsingine derivative, dihydrokopsingine (252), on the other hand, gave the 17-to-5 and 17-to-3 oxo-bridged compounds 255 and 256 directly, presumably via the less stable iminium ions 253 and 254 [168]. A similar conversion from kopsingine via the Polonovsky-Potier reaction has also been reported [169]. 5 / ^

1 T OMe

<^1 ^ ^ r

/ ^ ^

H

1

b * ! ^

KV A

P]

N

C0 2 Me \ ^ - C 0 2 M e

OMe

C0 2 Me >^-C0 2 Me

6H

OH 256

255

257 258 259 260

R1 = C0 2 Me, R2 = A 1415 R1 = H, R2 = A 1 4 1 5 R 1 = H , R2 = 15-a-OH R1 = C0 2 Me, R2 = 15-a-OH

H

261 262 263

R1 = NH2, R2 = A 1415 R1 = NH 2 ,R 2 = 15-a-OH R1 = NHCOMe, R2 = A14'15

Yet another new group of alkaloids, kopsinitarines A - D (257 - 260), were obtained from Kopsia teoi which are characterized by formation of a cage-like structure as a consequence of formation of oxo and carbonyl bridges across C(17) and C(5) and across C(16) and C(6) respectively [170,171].

Alkaloids from Malaysian Flora

3/3

The distinguishing feature of the !H NMR spectra of these compounds was the significant downficld shift of the H(5) and H(6) resonances which were seen as a pair of AX doublets at 8 5.2 and 2.7 with a coupling constant of 4.9 Hz. The corresponding ,3C NMR resonances have also undergone a similar downfield shift to 8 95 {C(5)} and 57 {C(6)}. In addition, the carbon spectrum showed the presence of a ketonic function (8 207) corresponding to the C(22) carbonyl bridge. The proposed structure was supported by LRCOSY which showed long-range coupling between H(5) and H(17) and by HMBC which revealed three-bond correlations between C(5)/H(17) and C(17)/H(5), and two-bond correlations from C(22) to H(6). The subsequent isolation of kopsinitarine D (260) in sufficient amounts has allowed confirmation of the structure by X-ray analysis [171].

258 or 259 (R = A 1415 or15-a-OH)

264

261 or 262

265

(R«A 1 4 1 5 or15-a-OH) SCHEME 10

374

T.-S. Kam

In addition to the cage kopsinitarines, two other compounds, mersingine A (261) and B (262), were also obtained in trace amounts [171,172]. These compounds had NMR spectral data which indicated their structural affinity to the kopsinitarines but differed in possessing an additional nitrogen atom as shown by HRMS. Furthermore, these compounds gave positive tests with ninhydrin which indicated the presence of a primary amino group and 261 was also readily acetylated to the amide derivative 263. The stereochemistry of the C(15)-OH function was assigned the a configuration based on the observed NOE interaction between H(15) and H( 17). These compounds are probably artifacts which originated from the kopsinitarines in the basic media under which extraction of alkaloids were carried out. A possible genesis of these compounds derives from initial formation of an isokopsine-like precursor 264 formed under basic conditions via a reversible acyloin rearrangement of the kopsinitarine precursor (258 or 259). This could then be followed by a reversible condensation with ammonia resulting in the unstable imine 265, which could then subsequently rearrange back to the original kopsine-like alkaloid (261 or 262), which now incorporates a C(16)-amino function as shown in Scheme 10. Paucity of material in the case of kopsinitarines A - C prevented verification of the proposed pathway and in the case of kopsinitarine D, attempted reaction did not furnish the corresponding C(16)-amino compound, probably as a result of intramolecular H-bonding involving the C(16)-OH group and the proximate carbamate function which was detected in the solid state [171]. Two new alkaloids, paucidactine A (266) and B (267) were obtained from Kopsia pauciflora from Sabah, Malaysian Borneo which have as the novel feature, a novel heptacyclic ring system containing a lactone moiety [173]. The l3C NMR spectrum showed in addition to lactam carbonyl (8 166), another carbonyl signal due to a lactone function (5 169). A conspicuous feature of the 'H NMR spectrum was the presence of a low field one-H singlet at 8 4.74 which was attributed to H(6). The corresponding C(6) signal was also observed at 8 84, its downfield shift being consistent with its being a to both an oxygen and a carbonyl group of a lactam function. The 2-D COSY and HMQC data revealed the presence of an isolated methylene, an isolated oxymethine, a CH2CH2 unit and a CH2CH2CH2 fragment which were consistent with the proposed structure, especially the location of the lactam carbonyl at C(5) since the alternative location of the lactam carbonyl at C(3) would require the presence of two CH2CH2 fragments. The structure was supported by the HMBC data which showed threebond correlation from C(22) to H(6) and was also confirmed by an X-ray diffraction analysis. Kopsia pauciflora also provided several new alkaloids (268 - 271) [174] possessing a pentacyclic skeleton similar to that of kopsijasminilam (272), deoxykopsijasminilam (273) and 14,15-dehydrokopsijasminilam (274) from the Thai species Kopsia jasminiflora. The structure of 272 was established by X-ray analysis [150]. These rare alkaloids can be considered as being derived from an aspidofractinine-type precursor by cleavage of the C(21)-C(20) bond. In pauciflorine A (268) and B (269), the double bond is located between C(19) and C(20) while in

Alkaloids from Malaysian Flora

375

pauciflorine C (270) [19] the double bond is from C(15) to C(20). The structures of these alkaloids were established by detailed analysis of the NMR spectra. Pauciflorine A and B are remarkable for their ability to inhibit melanin biosynthesis (vide infra) [174]. In addition, another new compound, paucifoline (271) was obtained in minute amount. Paucifoline was shown to have a similar carbon skeleton as pauciflorines A - C, but differed in lacking the double bond and in having an additional ring in the form of a novel five-membered cyclic carbamate from N(\) to C(16). This structure is consistent with all the spectral data, especially the prominent but unusual M - CO2 fragment observed in the mass-spectrum. The presence of a cyclic carbamate function in paucifoline (271) constitutes the unusual and novel feature of this hexacyclic indole [19].

266 267

R = OH R= H

272 R = OH 273 R = H, 274 R = OH,A 14 ' 15

268 269 270

R1, R2 = OCH 2 0, A19'20 R1 = R2 = OMe, A19'20 R \ R 2 = OCH2Of A15-20

271

376

T.-S. Kam

Kopsia lapidilecta provided the novel pentacyclic alkaloid lapidilectine A (275), notable for having a novel carbon skeleton which incorporates a central eight-membered ring fused to an unsaturated five-membered ring [175,176]. Four other alkaloids related to lapidilectine A were also obtained, viz., isolapidilectine A (277), lapidilectam (278), lapidilectinol (279) and epilapidilectinol (280). In addition to these, another new hexacyclic alkaloid, lapidilectine B (276), was also obtained in which a five-membered ring lactone unit has been formed by loss of a methyl ester and a methyl from lapidilectine A. These alkaloids, which are related to kopsijasminilam and the pauciflorines, were obtained in amorphous form and their structure elucidation relied mainly on analysis of NMR spectral data.

275 R1 = C02Me, R2 = H 277 R1 = H, R2 = C02Me

278

276

279 R1 = OH, R2 = H 280 R1 = H, R2 = OH

The ,3C NMR spectrum of lapidilectine A (275) showed the presence of two methyl esters and a carbamate group. One of the ester methyls {C(16)-COOMe} was relatively shielded (8 2.93), as a result of being located above the aromatic plane in order to avoid steric hindrance. The ! H NMR spectrum showed the 3-carbon CH2CH=CH fragment corresponding

AlkaloidsfromMalaysian Flora

377

to the C(3)-C(14)-C(15) unit and the magnitude of Ju.\$ and J3.15 of 6 and 1 Hz, respectively, indicated the presence of a five-membered unsaturated ring, while the carbon resonance of C(20) at 8 67 supported its direct attachment to N(4). The proposed structure, incorporating the central eight-membered ring bearing two methyl ester groups was supported by the 2-D NMR data while the relative configuration of C(2), C(7) and C(20) were presumed to be similar to that of venalstonine (320) which was also isolated from the plant. Isolapidilectine A differed from lapidilectine A in the configuration at C(16) which was reflected in the downfield shift of the C(16) ester methyl signal to the normal value of ca. 8 3.5. The mass-spectral data of lapidilectam indicated incorporation of oxygen and loss of two hydrogens compared with lapidilectine A, while the NMR spectral data revealed the presence of a conjugated, fivemembered ring lactam consistent with the proposed structure (8c 171, 8H 6.0, 6.8). Lapidilectinol and its C(15) epimer were distinguished from lapidilectine A by loss of the C(14)-C(15) unsaturation and the presence of an alcohol function at C(15). These features were consistent with the NMR spectral data which showed absence of olefmic signals and the appearance instead of an oxymethine (8 81). The stereochemistry of the C(15)-OH in 279 and 280 were determined from the respective NOESY spectrum. The hexacyclic lapidilectine B (276) had a HRMS which indicated that it differed from lapidilectine A by loss of a methyl ester and a methyl group. The NMR spectral data was essentially similar to that of 275 except for loss of the two methyl ester signals, the appearance instead of a lactone carbonyl resonance (8 177), and the downfield shift of the C(7) resonance to 8 91, indicating its attachment to the lactone oxygen. The configurations at C(2), C(16) and C(7) follow from that of its probable progenitor, lapidilectine A. The Malaysian Borneo species, Kopsia tenuis, which is endemic to Sarawak, has not been previously investigated. Examination of its alkaloidal content provided novel monomelic as well as dimeric indoles. Three new alkaloids were obtained in minute amounts, lundurines A (281), B (282) and C (283) which possess a novel carbon skeleton incorporating a cyclopropyl unit [177]. The NMR spectral data of lundurine A (281) showed the presence of an aromatic methoxy group at C(10), a carbamate function, a lactam carbonyl at C(3), and a C(14)-C(15) double bond which was deduced to be part of a five-membered ring from the observed ./14.1s vicinal coupling constant of 6 Hz. The location of the lactam carbonyl at C(3) was indicated by the absence of signals normally attributed to H(3), the presence of an amide absorption at 8 170, as well as the substantial downfield shift of the H(l 5) olefmic resonance to 8 6.87 which is characteristic of a (3-proton of an a, ^-unsaturated carbonyl moiety. COSY and HMQC data revealed the remaining partial structures to be made up of two CH2CH2 and one CH2CH unit. A particularly conspicuous feature of the 'H NMR spectrum was the presence of a high field doublet at ca. 8 1.0 which was suggestive of cyclopropyl or cyclobutyl rings. This doublet was shown by COSY to be due to the methine of the CH2CH fragment. HMBC measurements allowed the structure as shown in 281 to be assembled which has the distinctive feature of

378

T.-S. Kam

having a cyclopropyl ring system fused to a dihydroindole unit at C(2) and C(7). Further support of the structure was provided by the observed three-bond correlation between C(15) and H(17) which was consistent with 281 but ruled out alternative structures with cyclobutyl rings (e.g., 284, 285) in place of the cyclopropylmethyl of 281. Finally, confirmation of the cyclopropyl unit was obtained from the measurement of the 'JC-H coupling constant for C(16) from the gated decoupled spectrum which yielded a large lyC-H value of 164.1 Hz. With the structure of lundurine A thus established, the structures of lundurine B and lundurine C follow from the spectral data. The cooccurrence of all three compounds in the leaves reflects the progressive stages in the oxidation level of the five-membered ring moiety in the lundurines. The novel lundurines can be envisaged to have arisen from the structurally related lapidilectine B (276) via decarboxylation followed by radical coupling.

C0 2 Me

C0 2 Me

281

282 A 1415 283

284

285

379

Alkaloids from Malaysian Flora 1.3.5. Bisindole alkaloids

Uncaria callophylla (Rubiaceae) is the only Uncaria species found to elaborate dimeric alkaloids. Three new bisindoles, viz., callophylline (286), callophylline A (287) and callophylline B (288) were isolated from the leaves [178,179]. All three compounds have the hydroxylated tetracyclic heteroyohimbine, gambirine (79), as the common unit present. Of the three compounds, callophylline [179] was relatively the more abundant, the other two being obtained in trace amounts from a large scale extraction [178]. Callophylline is constituted from gambirine (79) and pseudoyohimbine (80), while the second unit in callophylline B is 3-epi-$yohimbine (81). In both callophylline and callophylline A, the dimer is connected from C(10) of the gambirine unit to C(2T) of the yohimbine unit with the attachment at C(21') likely to be

286 287

17'-a-OH 17-p-OH

on the p-face due to steric factors. It is also likely that in both callophylline and callophylline A, intramolecular hydrogen bonding occurs between the phenolic hydrogen of the gambirine unit and the proximate N(4') atom of the yohimbine unit. An indication of this was the relative stability of these two dimers in air (compared to gambirine) as well as their resistance to acetylation with Ac20/pyridine. In contrast to the other two dimers, callophylline B (288) was relatively more unstable and prone to decomposition when exposed to air at room temperature. The FABMS showed a [MH]+ ion at m/z 753 corresponding to the formula C43H52N406, indicating the presence of an additional hydroxyl group compared to callophylline. The NMR data indicated that the other

380

T.-S. KADI

unit of the dimer was a C(9')-hydroxylated pseudoyohimbine and that the point of branching was fromC(21') of the substituted pseudoyohimbine moiety to C(ll) of gambirine. As in the other two related dimers the attachment is likely to be on the less hindered (3-face of C(2T) of the yohimbine unit. A possible origin of these dimeric compounds is through electrophilic attack of the yohimbine C(21') iminium ions on gambirine which is the predominant alkaloid in U. callophylla.

OMe

Me02C

288

Of a total of 31 alkaloids isolated from the leaves and stem-bark of Alstonia angustifolia, 11 were new and of these, eight were dimeric alkaloids, all of which possessed the macroline unit [83]. The predominant alkaloid present was the known dimeric alkaloid villalstonine (289).

289 290 291 292

Me0 2 C

R=H R = H, /V(4')->0 R = OMe R = OMe, W H O

Alkaloids from Malaysian Flora

381

Other villalstonine derivatives included 10-methoxyvilialstonine (291) and the jV-oxides of villalstonine 290 and 10-methoxyvillalstonine 292. Two of the new dimers were derivatives of macrocarpamine (293), viz., 10-methoxymacrocarpamine (294) and its N-oxide (295) while another three, angusticraline (296), alstocraline (297) and foliacraline (298) were constituted from union of methoxymacroline and cabucraline moieties.

382

T.-S. Kam

A possible biogenesis of the macroline-cabucraline (timers derives from a Michael reaction of the nucleophilic C(IO') of cabucraline (299) with the unsaturated aldehyde 300 (which may be regarded as an opened form of talcarpine) to give an addition product 301, which on subsequent hemiketalization or ketalization furnishes the dimeric compounds 296 and 297 [83].

297

298

383

Alkaloids from Malaysian Flora MeC MeQ 2 C v JH

300

Me0 2 C 302 299

MeO,

Me0 2 C 301

384

T.-S. Kara

A number of plants of the genus Tabernaemontana or Ervatamia have provided novel bisindoles. The root-bark of Ervatamia hirta in addition to several new monomelic alkaloids yielded one new dimeric alkaloid, viz., 16-decarbomethoxyvoacaminepseudoindoxyl (302) [91]. The mass spectrum showed an M+ at m/z 662 (C41H50N4O4) as well as fragments attributable to iboluteinyl and vobasinyl moieties. The compound showed an intense yellow-green fluorescent coloration in solution indicating a pseudoindoxyl chromophore. This was confirmed by the UV spectrum (228,272,294 and 417 nm) and an IR absorption band at 1660 cm"1. The structure was supported by the NMR data. The *H NMR spectrum was similar to that of voacamine except for the expected upfield shift of the iboluteinyl NH. The l3C NMR spectral data provided further support for the proposed structure, showing the presence of the vobasinyl unit as well as characteristic shifts of the iboluteinyl unit at 6 67.5 {C(2)} and 204.8 {C(7)}. The stereochemistry of H(3) is p, as in the related dimer voacamine, for steric reasons. The popular garden plant Tabernaemontana divaricata which is extensively grown in gardens in Malaysia as well as in India provided several novel bisindoles, one of which, viz., conophylline (303) has been shown to be a potent inhibitor of ras functions (vide infra). There are two distinct varieties, the single flower variety produces both conophylline (303) and conophyllidine (304) [137,180] while the double flower variety gives in addition, a third dimeric alkaloid, conofoline (305) [138] as well as several new aspidosperma-type compounds. Conophylline (303) [137,180] was obtained as light yellow prisms from ethyl acetate and showed an MH+ in the FABMS at m/z 795 (C44H50N4O10). The UV spectrum was characteristic of alkaloids with p-anilinoacrylate chromophores and the IR spectrum showed the presence of NH, OH and conjugated carbonyl functions. The !H and ,3C NMR spectral data indicated a bisindole constituted from highly oxygenated vincadifformine-tabersonine epoxide moieties. The !H NMR spectrum showed the presence of two indole NH, three isolated aromatic hydrogens one of which was significantly shielded (8 5.55), an OH function, four methoxy groups of which two were associated with the presence of two ester carbomethoxy functions and two ethyl groups. The presence of only three aromatic singlets indicated highly substituted indole rings, where one indole ring was substituted at the 10, 11, and 12 positions while the other was substituted at the 10' and 1V positions. This was confirmed by the NOE interactions observed between one of the indole NH and the aromatic MeO at C(12) and between the other indole NH' and the aromatic H(12'). The unusually low field aromatic MeO carbon absorptions (6C 60.5, 61.0) suggested that they were in an ortho arrangement and indicated that the other aromatic MeO group was at C(ll) with C(10) substituted by a OH group (8C 138.7), an arrangement reminiscent of that in the dimer pandicine [181]. Comparison of the spectral data with those of pandicine in fact revealed generally good agreement of the aromatic ,3 C shifts in particular, as well as those of the non-aromatic carbons with the exception of the piperidine ring D carbons. The other unit of the dimer was clearly shown to be a 10-alkyl-ll-oxy-

Alkaloids from Malaysian Flora

385

tabersonine-p-epoxide by the excellent correlation of the non-aromatic l3C shifts with those of tabersonine-p-epoxide and the aromatic 13C shifts with those of vandrikine and the dimeric alkaloid vincarubine. The general agreement of the carbon resonances with the exception of the ring D carbons in the pandicine-like 10-hydroxy-ll,12-dimethoxy-vincadifformine unit suggested an essentially similar structure but differing in the mode of attachment of the monomer units. The mode of attachment of the monomer units was deduced from examination of the H(3), H(14) and H(15) resonances of the piperidine ring of the vincadifformine unit, which were clear and well resolved in the region from ca 8 4 to 5. Analysis of the NMR spectral data revealed the partial structure for ring D of the vincadifformine unit and allowed the two monomeric entities to be connected.

303

R = P-0

304

R = A14'15'

305

The OH function was placed on C(15), since when exchanged with deuterium, the H(15) doublet *f doublets (J * 11.0, 3.7 Hz) collapsed to a doublet (J = 3.7 Hz). The mode of attachment of the monomeric units was thus via C(3) and C(14) of the vincadifformine unit to C(IO') and C(ll') of the tabersonine-epoxide unit, respectively, the C(14) to C(H') connection being mediated by an ether oxygen. The substitution at C(3) and C(14) has to be cfr, this being dictated by the fact that carbons 3 and 14 formed part of a dihydrofuran unit. The similarity of the C(3) shift to those in the dimers criophylline and pandicine [181] suggested that conophylline also has 3-a substitution which was further confirmed by the observation that

386

T.-S. Kam

H(9) of conophylline (8 5.55) was significantly shielded compared with H(9) of pandicine (5 6.34) in the *H NMR spectrum, owing to its being affected by the anisotropy of the aromatic ring of the tabersonine-epoxide unit, a feature which was only possible if the tabersonine epoxide unit was attached on the a-face at C(3) and C(14). The configuration of the remaining stereocenter, viz., that of the C(15)-OH was readily deduced to be P from the NOE interaction observed between H(15) and the C(18) hydrogens of the C(20) oc-ethyl substituent. The structure deduced from spectroscopic data [137] has been subsequently confirmed by X-ray analysis [180]. The second dimeric alkaloid conophyllidine (304) is identical in all respects with conophylline except for replacement of the epoxide function at positions 14' and 15' of the tabersonine epoxide unit by a double bond. Conophylline has also been subsequently isolated from the South American species, Tabernaemontana glandulosa [182], and from the Thai species, Ervatamia microphylla [183]. It has also been reported from another Malaysian species, Ervatamia polyneura, under the name polyervine [184]. The leaf extract of Ervatamia polyneura also yielded the related dimer, polyervinine (306), which is similar to conophylline except for the aromatic portion of the vincadifformine unit which now possesses an indoline dione chromophore, existing predominantly in its zwitterionic quinoniminium form.

306

307

Conofoline (305), which occurs only in the double flower variety of T. divaricata, has the same 10-hydroxy-ll,12-dimethoxy-tabersonine-P-epoxide unit as in conophylline, but differs

AlkaloidsfromMalaysian Flora

387

in the identity of the other monomelic unit as well as in the mode of attachment of the monomers [138]. This was shown by the *H and 13C NMR data which also revealed the other unit to be a 10-alkylmehranine moiety from the excellent agreement of the non-aromatic , 3 C NMR resonances with those of (-)-mehranine (179), which also occurs in the plant (vide supra). The NMR data also showed that the dimer was branched from C(3) of the oxygenated tabersonine-p-epoxide moiety to the aromatic C(IO') of the mehranine unit. The stereochemistry at C(3) was readily ascertained from the NMR signal attributed to H(3) (8 4.52) which was a singlet, requiring the H(3)/H(14) dihedral angle to be ca. 90°, an arrangement possible only if H(3) is p. The structure has also been subsequently confirmed by X-ray analysis [142]. Conofoline has also been isolated from another Malaysian Tabernaemontana species (Ervatamia pedunculahs) under the name pedunculine [185]. The same plant also furnished another dimeric alkaloid, peduncularidine (307), which shares the common oxygenated tabersonine-p-epoxide moiety of conofoline but differs in the second unit which is now an opened form of (-)-mehranine, with a trans diol functionality at position 14' and 15' instead of a P-epoxide function. The epoxide ring opening by a water molecule is anticipated to occur preferentially at the less hindered carbon (14') resulting in a H(14*P), H(15'a) configuration. This proposal was supported by the ROESY spectrum which showed correlations between the axial H(2') and H(l 7') with H(14'), indicating that the latter has p stereochemistry.

C0 2 R 308 309

R = Me R=H

C0 2 Me 310 311

R=H R = OH

388

T.-S. Kam

Kopsia pauciflora provided in addition to the known bisindoles, norpleiomutine (308) and kopsoffine (310), two related bisindole alkaloids, kopsoffmol (311) and demethylnorpleiomutine (309) [124]. These alkaloids are constituted from union of eburnane and kopsinine units and are remarkable in that while norpleiomutine and demethylnorpleiomutine incorporate eburnane units having the 20P, 21 p configuration, kopsoffine and kopsoffmol apparently incorporate eburnane units having the opposite (enantiomeric) configuration (20a, 21a). Since the monomelic eburnane precursors present in the plant are of the 20P, 21P configuration [19,116], it is surprising that the eburnane units in kopsoffine and kopsoffmol are of the opposite configuration. Furthermore considering that the likely precursor of the eburnane unit in kopsoffmol, (+)-19(/?)-hydroxyeburnamine (162) has been obtained from this plant [118], as well as from another Kopsia species from Malaysian Borneo (Kopsia dasyrachis\ and its structure has been established by X-ray analysis (vide supra) [117,234], an alternative and more likely structure of kopsoffmol is 312. The attachment of the kopsinine unit at C(16') is now P {H(16') a} as required by the observed coupling constants for the H(16') signal of 11 and 5 Hz for kopsoffmol [115,117,234].

C0 2 Me 312

Only one bisindole alkaloid, nitaphylline (313), was isolated from Kopsia teoi which otherwise provided a large number of new indoles. Nitaphylline [155,186] was shown to be a bisindole constituted from union of two kopsingine moieties. The mass-spectrum showed a molecular ion at m/z 910 with a significant peak at m/z 455 suggesting symmetrical cleavage of

AlkaloidsfromMalaysian Flora

C0 2 Me

314 315

R = a-H R = p-H

the parent ion along the bond bridging the monomelic moieties. This, together with the observation that the UV spectrum of nitaphylline was virtually superimposable with that of kopsingine provided an early indication that nitaphylline is constituted from union of two kopsingine units. This was further reinforced by the NMR spectral data. The , 3 C NMR spectrum accounted for only 33 peaks, indicating overlap of 15 carbon resonances. In addition, four pairs of signals although distinguishable were only just so, differing in chemical shift by only 0.1 or 0.2 ppm. The bulk of the overlapped signals were readily assigned to the aromatic portions of the alkaloid as well as the methoxy, carbamate and ester groups which were similar

390

T.-S. Kam

to those of kopsingine. The remaining signals could also be assigned based on 2-D NMR data and by comparison with kopsingine. The observation that the resonances of the piperidine ring carbons showed greater departure from kopsingine suggested that attachment of the monomelic entities involved the piperidine ring carbons. The ]H NMR spectrum showed six aromatic hydrogens, three olefinic hydrogens, two geminal hydrogens of an aminomethylene group and only one H due to an aminomethine, indicating branching of the dimer from C(3) of one kopsingine unit to the olefinic C(14') or C(15') of the other kopsingine unit. Since the geminal hydrogens of C(3') were doublets (J 16 Hz) with no evidence of coupling to any adjacent olefinic hydrogen, the dimer was therefore deduced to be bridged from C(3) of one kopsingine unit to C(14') of the other. The stereochemisty of the point of branching could not be ascertained directly from the NMR spectrum due to overlap of the aminomethylene signal and poor resolution of the olefinic signals but could be assigned by analogy to the bistabersonine alkaloids voafrine A (314) (pbranching)) and voafrine B (315) (cx-branching) which possess the same mode of attachment of the monomeric units [187]. In nitaphylline, the carbon shift of C(21) and C(21') are identical (overlapped) and is similar to the value in the monomer indicating that the substitution is (5, with the pseudoequatorially oriented second kopsingine unit pointing away from the first by analogy to voafrine A. In the a-branched voafrine B, the resulting greater spatial proximity between the two monomeric units is reflected in the very different shifts observed for C(21). Nitaphylline (313) represents the first example of an aspidofractinine-aspidofractinine type dimeric alkaloid [155,186]. Kopsia tenuis provided four novel bisindoles, tenuisines A, B, C (316 - 318) [188,189] and tenuiphylline (319) [189]. Tenuisines A, B and C are constituted from two identical monomeric units which are connected via carboxyl linkages from C(16) of one half to C(7) of the other. This arrangement results in the presence of a C2 axis passing through the two halves, irrespective of the conformation adopted due to free rotation of the carboxyl linkages. The C2 axis passes in between the two monomers and is orthogonal to the approximate plane defined by the central ten-membered ring. The EI mass-spectra of the tenuisines showed only the monomeric fragments as the base peaks (e.g. m/z 396 for tenuisine A) which can be misleading. The molecular ions (MH+) are more effectively detected by FABMS or API-LCMS (e.g. MH* m/z 793 for tenuisine A). The NMR spectra of these dimers were to some extent complicated by the existence of equilibrating rotamers due to the carbomethoxy substituent on the indole nitrogen which has been documented previously in other compounds but otherwise showed simplification of the spectra due to homotropic behaviour of the two halves. The molecular formula of tenuisine A (316), C44H48N4O10 was established by HRFABMS. The UV spectrum was that of a dihydroindole and somewhat reminiscent of that of lundurine B (282). The NMR spectral data showed the presence of an aromatic methoxy group at C(10), a carbamate function, an oxygenated quaternary carbon attributable to C(7), a lactone carbonyl

Alkaloids from Malaysian Flora

391

and a C(14)-C(15) double bond which was part of a five-membered ring. 2-D NMR experiments showed the presence of two CH2CH2 units corresponding to the C(5)-C(6) and C(18)-C(19) fragments and a CH-CH2 unit corresponding to the C(16)-C(17) fragment in addition to the CH2CH=CH unit corresponding to C(3)-C(14)-C(15). The NMR spectral data resembled that of lundurine B except that signals due to the cyclopropyl unit have been replaced by signals attributable to a lactone function. The spectral data for the non-aromatic portion of the molecule in fact resembled that of lapidilectine B (276), in which the lactone ring is part of a five-membered ring system involving carbons (7), (2) and (16). In the case of tenuisine A, HMBC experiments showed two bond correlations between the lactone carbonyl and H(16) as well as three bond correlations with the C(17) hydrogens. These observations, coupled with the observed molecular ion which indicated a dimeric compound and the simplification of the NMR spectra due to homotropic behaviour of the two halves, indicated the existence of an element of symmetry which is satisfied in the structure of tenuisine A (316).

316 317 318

R = C0 2 Me, R1 = OMe, R2 = H, R3 = H 2 R = C0 2 Me, R1 = R2 = OMe, R3 = H 2 R = C0 2 Me, R1 = OMe, R2 = H, R3 = O

The structures of the related compounds tenuisine B (317) and tenuisine C (318) follow from their respective spectral data. The tenuisines represent dimeric alkaloids of a novel structure type linked by carboxyl linkages and possessing a C2 axis giving rise to homotropic behaviour of the NMR spectra [188,189]. Tenuiphylline (319) [189] was obtained in minute amounts from Kopsia tenuis. The FABMS showed a MH+ peak at m/z 717 and high resolution measurements provided the formula C42H44N4O7. The UV spectrum indicated the presence of dihydroindole chromophores

392

T.-S. Kim

and the IR spectrum indicated the presence of hydroxyl, urethane, ester and lactone functions. In view of the small amount obtained, definitive structure elucidation of tenuiphy lline required resort to 600 MHz NMR spectra since extensive overlap was encountered with lower field instruments.

/ % C0 2 Me

/ 320

319

The NMR spectral data showed the presence of one carbamate and one methyl ester function. The aromatic region integrated for seven hydrogens indicating branching of the dimer from an aromatic carbon of one monomelic unit. Absence of a NH signal and the presence of only one urethane function indicated the dihydroindole nitrogen of the other monomelic moiety as the other site of attachment. The NMR spectral data also showed the presence of four oleftnic hydrogens, two associated with a six-membered ring and two with a five-membered ring. One unit of the dimer was readily deduced to be identical to lapidilectine B from the excellent correlation of the ,3C shifts, in particular the non-aromatic shifts, with that of lapidilectine B. The other monomelic unit can be considered as having a novel carbon skeleton or a rearranged venalstonine. The carbon shifts of this second unit generally resembled that of venalstonine (320) [190] except for changes involving carbons (2), (12), (16), (17), (18), (20) and (21). The COSY spectrum indicated the presence of the same groups as in venalstonine and the downfield shifts of C(20) and C(21) were reminiscent of those of the vindoline derivatives (e.g. M-methylvindoline [190]), suggesting a change in the connectivity involving the C(18)C(19) fragment. The presence of a hydroxyl group on C(2) was supported by its downfield shift at 5 99.8 due to its being linked to an oxygen and a nitrogen and by the observed threebond correlations from C(2) to H(6) and H(21) in HMBC. The presence of an OH on C(2) required that C(18) be now linked to C(16) which was consistent with the downfield shift of

AlkaloidsfromMalaysian Flora

393

C(16) when compared with venalstonine, as well as with the observed correlations from both C(18) and C(19) to H(17) in the HMBC spectrum. From the ! H NMR spectrum (COSY, NOE), it can be established that the aromatic portion associated with this unit was unsubstituted and furthermore the upfield shift of H(12) when compared with venalstonine was consistent with the change from NH in venalstonine to N-C(\ 1') in tenuiphylline. The attachment site on the lactone containing monomer can be at either C(IO') or C(ll') from the coupling pattern of the aromatic hydrogens. The observed NOE between the aromatic doublet at 8 7.33 and H(6'P), and a C(7)/H(9') correlation in HMBC allowed assignment of this signal to H(9') which must be coupled to H(IO') furnishing proof of C(ll') branching. The dimer is thus linked from N(\) of one unit to C(ll') of the other. Examination of models indicated that there should be restricted rotation about the N(\)C(l 1') bond due to steric congestion and the observed H(12)/H(10) and H(9'),H(10')/Me (ester) NOE interactions suggested a preferred conformation in which the approximately planar dihydroindole portions of the two monomers are nearly mutually orthogonal to each other. This proposal was also supported by the unusual upfield shift of the ester methyl which can be accounted for by the anisotropic influence of the other aromatic ring as a result of the methyl ester function being placed above the aromatic ring due to the preferred conformation adopted. The stereochemistry of the C(2)-OH was assigned the a configuration since had it been p, the ester function would have been too far removed to experience NOE with H(9') and H(IO') as well as the observed anisotropy from the other aromatic ring. An alkaloid corresponding to the novel venalstonine-like monomer in tenuiphylline has since then been obtained from another Malaysian Kopsia [191].

1.3.6. Miscellaneous nitrogenous natural products A number of novel nitrogenous derivatives have also been obtained in recent years from several Malaysian plants. An unusual nitrogenous compound angustimaline was obtained from Alstonia angustifolia [192]. The spectral data led to the structure 321 which showed that angustimaline retains all the features of the non-indole portion of a type-B macroline unit except for the presence of an additional oxygenated carbon. It is probably derived from fragmentation of a macroline-type precursor, possibly alstophylline or its oxindole. Monomargine (322), a new nitrogenous pigment was obtained from the annonaceous plant, Monocarpia marginalis [193]. Analysis of the spectral data led to a highly conjugated tetracyclic ring system with a seven-membered amide containing ring. The species Aglia argentea and Aglia forbesii of the Meliaceae family provided several new derivatives such as aglain A (323), B (324), C (325), aglaforbesin A (326) and B (327), which possess a new cyclopentatetrahydrobenzopyran-odorine type structure, and forbaglin A (328)

394

T.-S. Kam

and B (329) which have a benzoxepine-odorine type skeleton. The structure of forbaglin A (328) was established by X-ray analysis [194].

321

322

323 R1 = OAc, R 2 = H; H-3p, H-4a, 13S 324 R1 = H, R 2 = OH; H-3p, H-4a, 13S 325 R1 = H, R 2 = OH; H-3a, H-4p, 13S

Alkaloids from Malaysian mora

39S

Wi

?H MeO-

f\

MeO

R

V

HI

Vo

OMe OMe 326

R1 = OH, R 2 = H

328

13fl, 19S

327

R1 = H, R 2 = OH

329

13S

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants

Plant

Alkaloids [Reference]

Ancistrocladaceae

Ancistrocladus tectorius

6,8-Dimethoxy-3-hydroxymethyl-1 -methy lisoquinoline (1)[24] 6,8-Dimethoxy-l,3-dimethylisoquinoline (2) [24] (.S)-6,8-Dimethoxy-1,3-dimethy 1-3,4-dihydroisoquinoline (3)[24] (+)-4,-0-Demethylancistrocladine (4) [24]

Annonaceae Artabotrys grandifolius

A. maingayi

Atherospermidine [195] Liriodenine[195] (-)-Norstephalagine [ 195] (-)-Xylopinine [195] (-)-Norstephalagine [196] (-)-3-Hydroxynornuciferine [196] (-)-Anonaine [196] (-)-Nornuciferine [ 196]

396

T.-S. Kam

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

A. venustus

Desmos dasymaschalus (Bl.) Saff. D. dasymaschalus var. walichii Hk.

Disepalum pulchrum

Meiogyne virgata

Alkaloids [Reference] (-)-Ushinsunine [196] Atherospermidine [196] Liriodenine [196] Lysicamine [196] (-)-Discretamine[196] (-)-Artavenustine (12) [30] (-)-Nornuciferine [30] (-)-Asimilobine [30] (-)-Anonaine [30] (-)-Norstephalagine [30] (-)-Norushinsunine [30] (-)-Nuciferine [30] (-)-Lirinidine [30] (+)-(S)-Reticuline [30] (+)-Norcorydine [30] (-)-Discretamine [30] (-)-lO-ODemethyldiscretine [30] (-)-Dasymachaline (9) [27] Dicentrinone [27] O-Methylmoschatoline [197] Oxobuxifoline[197] Lanuginosine [ 197] Liriodenine [197] Oxocrebanine [ 197] (-Hsolaureline[197] (-)-Asimilobine [31 ] (-)-Anonaine [31] (-)-Norliridinc[31] Liriodenine [31] (-)-Scoulerine [31] Liriodenine [34] (-)-Norushinsunine [34] (-)-Anonaine [34]

AlkaloidsfromMalaysian Flora

397

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Oncodostigma monosperma

Orophea enterocarpa

Polyalthia insignis

Alkaloids [Reference] (-)-Asimilobine [34] (+)-Stepharine [34] (-)-Corydalmine [34] (-)-Discretamine [34] (-)-Stepholidine [34] Dehydrocorydalmine [34] (+)-Corytuberine [34] Cleistopholine [34] Kinabaline (21) [34] (+)-Corytuberine [35] (-)-Asimilobine [35] (-)-Nornuciferine [35] (-)-Anonaine [35] (-)-Norushinsunine [35] Liriodenine [35] Lysicaminc [35] Norcepharadione A [35] (+)-Stepharine [35] (-)-Discretamine [35] (-)-Stepholidine [35] Cleistopholine [35] Ursuline [35] Oncodine (22) [35] Enterocarpam-I (17) [33] Enterocarpam-I acetate (18) [33] Enterocarpam-II (19) [33] Enterocarpam-II acetate (20) [33] Polysignine (23) [36] Methoxypolysignine (24) [36] (-)-Asimilobine [36] Oxostephanine [36] O-Methylmoschatolinc [36] Liriodenine [36]

398

T.-S. Kara

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant P. macropoda

P. microtus

P. stenopetala

Pseuduvaria macrophylla

Trivalvaria macrophylla

Xylopiaferruginea Apocynaceae Alstonia angustilofolia

Alkaloids [Reference] (-)-OHveroline[31] (-)-Af-Oxyoliverine[31] Liriodenine [31] (-)-Coclaurine [31] Oxostephanine [36] OMethylmoschatoline [36] Liriodenine [36] Lanuginosine [36] Liriodenine [31 ] Oxostephanine [31 ] (-)-Discretamine [31 ] Isoursuline [31] (-)-Thaipetaline(13)[31] l,2,3-Trimethoxy-4,5-dioxo-6a,7-dehydroaporphine (10) [28] O-Methylmoschatoline [28] Isocorytuberine [29] (+)-Norcorydine [29] (+)-Laurolitsine [29] (+)-Boldine [29] (-)-Anonaine [29] (-)-Nornuciferine [29] Liriodenine [29] Lysicamine [29] Oxostephanine [29] (+)-Norisocorytuberine (11) [29] tf-Methylurabaine (15) [29] Trivalvone (16) [29] Liriodenine [198] Atheroline[198] (+)-Yohimbine [83] O-Acetyl yohimbine (89) [83]

Alkaloids from Malaysian Flora

399

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Alkaloids [Reference] (+)-P!eiocarpamine (114) [83,84] Fluorocarpamine [83] (-)-Cathafoline [83] (-)-Cabucraline (299) [83] (-)-N( 1)-Desmethylquaternine [83] (-)-Vincamajine (91) [83,84] (+)-Normacusine B (107) [83,192] (+)-Lochnerine [83] (-)-Akuammicine [83] (-)-Antirhine [83] (+)-Alstonisine (102) [83] (+)-Macralstonine [83,84] (+)-Villalstonine (289) [83,84,192] (+)-Tetrahydrocantleyine [83] (-)-19,20-Dehydro-10-methoxytalcarpine (92) [83,192] (+)-19,20-Dehydro-O-acetyl yohimbine (88) [83] (+)-l 1-Hydroxystrictamine (93) [83] (+)-Villalstonine W(4>oxide (290) [83] (+)-10-Methoxyvillalstonine (291) [83] (+)-10-Methoxyvillalstonine JV(4')-oxide (292) [83] 10-Methoxymacrocarpamine (294) [83] (-)-lO-Methoxymacrocarpamine Af(4>oxide (295) [83] (+)-Angusticraline (296) [83] (+)-Alstocra!ine (297) [83] (+)-Foliacraline (298) [83] (-)-Alstonerine (337) [83,84] (-)-Alstophylline (94) [83,84,192] (-)-Macrocarpamine (293) [84] (-)-Norfluorocurarine [84] (-)-l 1-Methoxyakuammicine [83,84] 4,-Hydroxy-3,,5,-dimethoxybenzoylvincamajine (90) [84] (+)-Affinisine (108) [83,192] (+)-Angustimaline (321) [192]

400

T.-S. Kam

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant A. macrophylla

A. scholaris

A. undulifolia

Holarrhena curtisii

Alkaloids [Reference] (+)-Ar(b)-Demethylalstophyllal oxindole (99) [87] (+)-Alstonal (100) [87,226] (+)-W(b)-Demethylalstophylline oxindole (101) [87] (+)-Alstonisine (102) [87] (-)-Talcarpine [87] (+)-Lochnerine [226] (-)-Cathafoline [226] (-)-Vincamajine (91) [226] (-)-Alstophylline (94) [226] (+)-Alstonisine (102) [226] (+)-10-Methoxyaffinisine (334) [226] (-)-lO-Methoxycathafoline (335) [226] (-)-Alstonerinal (336) [226] (-)-Alstonerine (337) [226] (-)-Nareline methyl ether (120) [93] (-)-Nareline ethyl ether (121) [93] (-)-5-£p/-Nareline ethyl ether (122) [93] (-)-Picrinine [93] (-)-Scholaricine(123)[93] (-)-Scholarine W(4)-oxide (124) [93] (+)-Tetrahydrocantleyine [109] (-)-Cantleyine [109] (-)-Akuammicine [109] (+)-Pleiocarpamine (114) [109] (-)-Echitamidine [109] (-)-20-£/>i-19£-echitamidine [109] (-)-Echitamine [109] (-)-Nor-echitamine [109] (-)-Undulifoline (136) [109] (+)-Holacurtine (36) [45,51] (+)-ALDemethylholacurtine (37) [51] (-)-17-£p/-Holacurtine (38) [51] (-)-17-£p/-A^Demethylholacurtine (39) [51]

401

Alkaloids from Malaysian Flora 1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Alkaloids [Reference] (+)-Holacurtinol(40)[51] (+)-Holamine(41)[51] (+)-3ct-Amino-14p-hydroxypregnan-20-one (42) [51] (+)-15a-Hydroxyholamine (43) [51]

Kopsia arborea

K. dasyrachis

(+)-Methy 1 11,12-methy lenedioxychanofruticosinate (238) [163] (+)-Methyl N( 1 )-decarbomethoxychanofruticosinate (239) [163] (+)-Methyl 11,12-methylenedioxy-Ar( 1 )-decarbomethoxychanofruticosinate (240) [163] (+)-Methyl 11,12-methylenedioxy- N(\)- decarbomethoxyA,4,5-chanofruticosinate (241) [163] (-)-Kopsidasine(212)[158] (-)-Kopsidasinine (229) [158] (-)-Kopsidasine /V(4)-oxide (213) [158] (+)-Kopsirachine (54) [57,223] (-)-Rhazinicine (171) [133,234] (+)-Kopsifine (189) [133,223,234] (+)-19(#)-Hydroxyeburnamine (162) [117,234] (+)-Ebumamonine (138) [117,234] (+)-Isoebumamine (142) [117,234] (+)-Kopsoffinol (311 or 312) [117,234] (-)-Norpleiomutine (308) [117,234] (-)-Demethylnorpleiomutine (309) [117,234] (-)-Kopsiflorine (350) [234] (-)-Kopsiflorine-M4)-oxide (351) [234] (-)-Kopsilongine (223) [234] (-)-Kopsamine (224) [223,234] (-)-Kopsamine tf(4)-oxide [223,234] (-)-l 1-Methoxykopsilongine (226) [223,234] (-)-l 1-Methoxykopsilongine tf(4)-oxide (352) [234] (-)-Kopsinine (220) [234] (-)-Kopsinine-M4)-oxide [234]

402

T.-S. Ktm

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Alkaloids [Reference] (-)-Pleiocarpine (221) [223,234] (-)-12-Methoxypleiocarpine (222) [223,234] (-)-l 1,12-Methylenedioxykopsinaline [234] (-)-Tetrahydroalstonine [234] (+)-Pleiocarpamine (114) [234] (+)-16-Hydroxymethylpleiocarpamine [234] (-)-Kopsine (188) [234] (+)-A^-Carbomethoxy-5,22-dioxokopsine[234] (-)-Leuconoxine (175) [234] (+)-Paucidactine B (267) [234] (+)-Decarbomethoxykopsifine (353) [234] (+)-Kopsinarine (354) [234] (-)-l 1,12-Methylenedioxykopsine (355) [234] (+)-Dasyrachine (356) [234] (-)-19(*)-Hydroxyisoebumamine (357) [117,234] (+)-Methyl chanofruticosinate (237) [223] (+)-Methyl 11,12-methylenedioxychanofruticosinate (238) [223]

K. deverrei

(+)-Methyl N-decarbomethoxychanofruticosinate (239) [223] (+)-Methy 1 11,12-methylenedioxy-Ar-decarbomethoxychanofruticosinate (240) [223] (+)-Kinabalurine G (330) [223] (-)-Danuphylline (358) [223,235,236] (-)-N-Carbomethoxy-17p-hydroxykopsinine (205) [ 156] (-)-JV-Carbomethoxy-17|3-hydroxy- A 14J 5-kopsinine (206) [156] (+)-Kopsinone (207) [156,157] (-)-lO-Methoxykopsinone (209) [157] (+)-12-Methoxykopsinone (208) [157] (-)-14,15-Dihydro-10-methoxykopsinone (210) [157] (+)-Pleiocarpamine (114) [92] (+)-l 6-Hydroxymethylpleiocarpamine (113) [92]

Alkaloids from Malaysian Flora

403

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Alkaloids [Reference] (+)-Deacetylakuammiline (116) [92] (+)-16-£p/-Deacetylakuammiline (115) [92] (+)-14a-Hydroxycondylocarpine (117) [92]

Kfruticosa

K. griffithii

(-)-Kopsine (188) [144,145] (+)-Fruticosamine (187) [144,145] (-)-Fruticosine (186) [144,145] Harmane (55) [58] (+)-Harmicine (56) [58] (-)-Tetrahydroalstonine [58] (-)-16(/?)-19,20-£-Isositsirikine (227) [58] (-)-Kopsilongine (223) [58] (-)-Kopsamine (224) [58] (-)-Kopsamine N(4)-oxide [58] (-)-Pleiocarpine(221)[58] (-)-12-Methoxy pilocarpine (222) [58] (-)-Kopsinine (220) [58] (-)-#( l)-Methoxycarbonyl-12-methoxy-A16,,7-kopsinine (216)[58] (-)-#( 1 )-Methoxycarbony 1-11 -hydroxy-12-methoxykopsinaline (225) [58] (-)-#( 1 )-Methoxycarbony 1-11,12-dimethoxykopsinaline (11-Methoxykopsilongine) (226) [58] (-)-12-Methoxy-10-demethoxykopsidasinine (231)[58] (+)-Ebumamonine (138) [58] (-)-Ebumamine (139) [212] (-)-Leuconolam(172)[58] (-)-Buchtienine (228) [58] (+)-Rhazimol (Deacetylakuammiline) [58] (-)-Leuconoxine (175) [58] (+)-16-£p/-Deacetylakuammiline [212] (-)-16-£/?/-Deacetylakuammiline-jV-oxide [212] (-)-Kopsinine W(4)-oxide [212]

404

T.-S. Kam

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

K. lapidilecta

K. larutensis

K. macrophylla

K. pauciflora

Alkaloids [Reference] (-)-Akuammiline Af(4)-oxide [212] (-)-Rhazinaline Af(4)-oxide [212] (-)-l 1,12-Methylenedioxykopsinaline Af(4)-oxide [212] (-)-Lapidilectine A (275) [175,176] (+)-Lapidilectine B (276) [175,176] (-)-Venalstonine (320) [176] (+)-Isolapidilectine A (277) [176] (+)-Lapidilectam (278) [176] (-)-Lapidilectinol (279) [176] (+)-Epilapidilectinol (280) [176] (+)-Eburnamonine (138) [110,112,115] (+)-Eburnamonine M4)-oxide [112,115] (-)-Eburnamine (139) [110,112,115] (+)-Isoeburnamine (142) (110,112,115] (-)-O-Ethyleburnamine (140) [115] (+)-Ebumamenine (145) [115] (-)-Kopsinine (220) [110,115] (+)-Larutensine (Larutenine) (154) [110,112,115] (-)-Eburnaminol(155)[110] (+)-Kopsilactone (51) [56] (+)-Kopsone (52) [56] (+)-5,22-Dioxokopsane [56] (-)-Dregamine [56] (-)-Tabernaemontanine [56] (+)-Akuammiline [56] (+)-Deacetylakuammiline [56] (-)-Norpleiomutine (308) [56] (+)-Kopsoffine (310) [56] (-)-Pauciflorine A (268) [174] (-)-Pauciflorine B (269) [174] (-)-Pauciflorine C (270) [19]

AlkaloidsfromMalaysian Flora

405

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Alkaloids [Reference] (+)-Paucifoline(271)[19] (+)-Paucidactine A (266) [173] (+)-Paucidactine B (267) [173] (-)-Kopsinine(220)[116) (-)-Eburnamine (139) [116] (+)-Isoeburnamine (142) [116] (+)-Ebumamonine (138) [116] (+)-19-Oxoeburnamine (161) [116] (-)-Norpleiomutine (308) [116,124] (-)-#( l)-Methoxycarbonyl-12-methoxy-A ' -kopsinine (216)[116] (-)-Kopsamine (N( 1 )-Methoxycarbony 1-11,12methylenedioxykopsinaline) (224) [116] (-)-Kopsamine Af(4)-oxide [116] (-)-#( 1 )-Methoxycarbonyl-11,12-dimethoxykopsinaline (226)[116] (-)-Kopsilongine (Af(l )-Methoxycarbonyl-12-methoxykopsinaline)(223)[116] (-)-12-Methoxy-10-demethoxykopsidasinine (230) [116] (-)-Lahadinine A (233) [162] (-)-Lahadinine B (234) [162] (-)-Paucifinine(235)[162] (-)-Paucifmine W(4)-oxide (236) [162] (+)-Kinabalurine A (44) [53,54] (-)-Kinabalurine B (45) [54] (+)-Kinabalurine C (46) [54] (-)-Kinabalurine D (47) [54] (+)-Kinabalurine E (48) [54] (+)-Kinabalurine F (49) [54] (+)-KopsoiTine(310)[124] (+)-Kopsoffinol (311 or 312) [124] (-)-Demethylnorpleiomutine (309) [124]

406

T.-S. Kara

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant K. profunda

Alkaloids [Reference] (-)-M 1 )-Methoxycarbony 1-11,12-methy lenedioxyA ,6l7 -kopsinine (214) [159,160] (-)-#( 1 )-Methoxycarbonyl-12-methoxy-A16''7kopsinine (216) [159,160] (-)-#( 1 )-Methoxycarbony 1-12-hydroxy-A'6'17kopsinine(218)[160] (-)-#( 1 )-Methoxycarbonyl-11,12-methy lenedioxy-A16''7kopsinine A^(4)-oxide (215) [160] (-)-#( 1 )-Methoxycarbony 1-12-methoxy-A] 6 '' 7 -

K. singapurensis

K. tenuis

K. teoi

kopsinine N(4)-ox\de (217) [160] (+)-Kopsingine (191) [ 151,152,153,167] (+)-Kopsaporine (192) [151,152,153,167] (-)-Rhazinilam (170) [167] 5,21-Dihydrorhazinilam (174) [167] (+)-l 1,12-Methylenedioxykopsaporine (195) [19,167] (-)-Singapurensine A (246) [167] (-)-Singapurensine B (247) [167] (-)-Singapurensine C (248) [167] (-)-Singapurensine D (249) [167] (-)-Lundurine A (281) [177] (-)-Lundurine B (282) [177] (-)-LundurineC(283)[177] (+)-Tenuisine A (316) [188,189] (+)-Tenuisine B (317) [188,189] (+)-Tenuisine C (318) [188,189] (-)-Tenuiphylline (319) [189] (-)-Tetrahydroalstonine [19] (-)-Leuconoxine (175) [19] (-)-Kopsinine(220)[19] (-)-Kopsinine Af(4)-oxide [19] (+)-Kopsingine (191) [132,154] (+)-Kopsaporine (192) [154] (+)-Kopsinginine (201) [19,154,165]

Alkaloids from Malaysian Flora

407

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Alkaloids [Reference] )-17-a-Hydroxy-A,4,5-kopsinine (203) [154,155,165] +)-Kopsidine A (242) [165,166] +)-Kopsidine B (243) [165,166] +)-Kopsidine C (244) [165,166] -)-Kopsidine D (245) [165,166] +)-Kopsinitarine A (257) [170,171] +)-Kopsinitarine B (258) [170,171]

K. terengganensis

)-Kopsinitarine C (259) [170,171] )-Kopsinitarine D (260) [171] +)-Mersingine A (261) [171,172] -)-Mersingine B (262) [171,172] +)-Kopsinol (196) [130,165] +)-Kopsinginol (202) [130,165] +)-Kopsinganol (199) [130,165] ;+)-! 1-Hydroxykopsingine (193) [131] -)-l 1-Methoxykopsingine (194) [131] +)-ll-Methoxy-12-hydroxykopsinol (197) [131] +)-14,15-P-Epoxykopsingine (198) [131] +)-11,12-Methylenedioxykopsaporine (195) 19,131,132] +)-Nitaphylline (313> [155,186] -)-Rhazinilam (170) [131,132] +)-Deacetylakuammiline [131] +)-16-£pi-DeacetyIakuammi!ine [131] +)-Akuammiline [131] )-Lonicerine [131,132] -)-Aspidodasycarpine [131] +)-Isoeburnamine (142) [132] 14,13 -)-16-Epi-17-a-Hydroxy-A -kopsinine(204)[132] +)-Quebrachamine [119] -)-Eburnamine(139)[119] +)-Isoeburnamine (142) [119] )-Eburnaminol(155)[119]

408

T.-S. Kam

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (com.)

Plant

Leuconotis griffithii

L. eugenifolia

Tabernaemontana corymbosa (Ervatamia corymbosa)

T. corymbosa

Alkaloids [Reference] (+)-Larutensine(154)[119] (-)-Terengganensine A (163) [119] (-)-Terengganensine B (164) [119] (-)-Leuconolam (172) [128,135] (-)-Norfluorocurarine [128,135] (-)-Norfluorocurarine tf(4)-oxide (112) [128,135] (-)-Eburnamine (139) [128,135] (-)-O-Methyleburnamine (141) [128,135] (+)-0-Methylisoeburnamine (144) [128,135] (-)-Kopsinine(220)[128] (-)-Leuconolam (172) [127,128] (+)-Epileuconolam (173) [127,128] (-)-Rhazinilam (170) [127,128] 5,21-Dihydrorhazinilam (174) [127,128] 5-Oxo-19,20-dehydroervatamine (135) [ 107] (-)-N( 1 )-Methoxy-19,20-dehydroervatamine (133) [ 107] (+)-19,20-Dehydroervatamine (129) [107] (+)-Methuenine (130) [107] (+)-Yohimbine [199] (-)-p-Yohimbine [199] (-)-P-Yohimbine pseudoindoxyl [199] (-)-P-Yohimbine oxindole [199] (+)-Normacusine B (107) [199] (-)-Modestanine [199] Vandrikine[199] (+)-Dippinine A (340) [227] (+)-Dippinine C (342) [228] (+)-Tronoharine (346) [231] (-)-Conodiparine A (362) [237] (-)-Conodiparine B (363) [237] (-)-Conodiparine C (364) [237] (-)-Conodiparine D (365) [237]

Alkaloids from Malaysian Flora

409

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant T. divaricata (single flower variety)

T. divaricata (double flower variety)

T. hirta (£. hirta)

Alkaloids [Reference] (-)-Voacangine(166)[180] (-)-Voacristine[180] (-)-Voacristine 7-hydroxyindolenine [180] (-)-Apparicine [180] (-)-19-Epi-Voacristine [ 180] (-)-Conophylline (303) [180] Conophyllidine(304)[180] (+)-Voaphylline (180) [137,138] (-)-AMvlethylvoaphylline (181) [137,138] (-)-Voaharine (178) [137,138] (-)-Pachysiphine [138] (-)-Apparicine[138] (-)-Mehranine(179)[138] (-)-Conophylline (303) [137,138] (-)-Conofoline(305)[138] (-)-Voafinine(182)[139] (-)-W-Methylvoafinine (183) [139] (+)-Voafinidine(184)[140] (-)-Voalenine(185)[140] (+)-(£> 16-£p/-Normacusine B (105) [91] (-)-(^-16-£p/-Affinisine (106) [91] (-)-0-Acetyl-16-ep/-affinisine (109) [91] (+)-Affinisine Af(4)-oxide (110) [91] (+)-Dehydro-16-«?pi-affinisine (111) [91] (-)-Norfluorocurarine-N(4)-oxide (112) [91] (-)-16-Decarbomethoxy voacaminepseudoindoxyl (302) [91] (-HE)- 16-£/?Msositsirikine (227) [91] (-)-p-Yohimbine [91] (+)-Yohimbine [91] (-)-19,20-Dehydro-P-yohimbine [91] (-)-p-Yohimbine-pseudoindoxyl [91 ] (-)-Isositsirikine [91]

410

T.-S. Kam

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Alkaloids [Reference] 19,20-Dihydroisositsirikine [91] (-)-P-Yohimbine-oxindole [91] (+)-Normacusine B (107) [91] (+)-Affinisine(108)[91] (-)-Vobasine[91] (-)-Dregamine[91] (-)-Tabemaemontanine [91 ] (-)-Norfluorocurarine [91] (-)-12-Hydroxynorfluorocurarine [91 ] (-)-Apparicine [91] 3,14-Dihydroellipticine [91] (-)-Antirhine[91] (-)-Voacristine[91] (-)-Ibogaine[91]

T. macrocarpa

T. malaccensis (E. malaccensis)

(-)-Iboxygaine [91] (+)-Iboxygaine-hydroxyindolenine [91 ] (-)-Iboluteine[91] (+)-4\ 17,( 17P)-Dihydrotchibangensine [91 ] (-)-16-Decarbomethoxy voacamine [91 ] (+)-19\20'-Dihydro-16-decarbomethoxyvoacamine[91] (-)-Coronaridine (165) [200] (+)-Voacangine hydroxyindolenine [200] (-)-3-Oxo-coronaridine [200] (-)-19(fl)-Heyneanine [200] (-)-Coronaridine pseudoindoxyl [200] (-)-Voacangine pseudoindoxyl [200] N( 1 )-Methoxymethuenine (134) [ 105 ] (-)-MO-Methoxy-19,20-dehydroervatamine (133) [105] (+)-19,20-Dehydrocrvatamine (129) [105] (-)-20-Epiervatamine (128) [105] (+)-Methuenine (130) [105] (-)-16-Epimethuenine (131) [105]

Alkaloids from Malaysian Flora

411

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

T. peduncularis (E. peduncularis)

T. polyneura {E. polyneura)

Alkaloids [Reference] (-)-6-Oxomethuenine (132) [105] (-)-Dregamine [ 105] (-)-Coronaridine (165) [185] (-)-Coronaridine hydroxyindolenine [185] (-)-Eglandine[185] (-)-Heyneanine [185] (-)-Eglandu!osine[185] (-)-Heyneanine hydroxyindolenine [185] (+)-Af( 1 )-Methylaspidospermidine [ 185] Pedunculine [185] {(-)-Conofoline (305) [138]} Peduncularidine (307) [185] (-)-Vobasenal (103) [90] (+)-16-Epivobasenal (104) [90] (-)-3-Oxo-19-epiheyneanine (167) [90] (-)-3-Hydroxy-3,4-secocoronaridine (168) [90] (+)-Pericyclivine [90] (-)-Vobasine [90] (-)-Vobasine-W(4)-oxide [90] (-)-16-Epivobasine [90] (+)-Vobasinol [90] (-)-Dregamine [90] (-)-Perivine [90] (-)-Anhydrovobasindiol [90] (-)-Apparicine [90] (+)-Tubotaiwine (137) [90] (+)-Voaphylline (180) [90] 3,14-Dihydroellipticine [90] (-)-Coronaridine (165) [90] (-)-Eglandine [90] (-)-Eglandulosine [90] (-)-Heyneanine [90] (-)-19-Epiheyneanine (169) [90] (-)-Voacangine (166) [90]

412

T.-S. Kam

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Alkaloids [Reference] (-)-Coronaridine hydroxyindolenine [90] Polyervinine (306) [184] Polyervine [184] {(-)-Conophylline (303) [137,180]}

Celastraceae Bhesa paniculata Euphorbiaceae Breynia coronata

Lauraceae Actinodaphne sesquipedalis Alseodaphne perakensis

Dehaasia incrassata

Lindera pipericarpa

Phoebe grandis

Magnoliaceae Aromadendron elegans

(+)-Bhesine (72) [65] (+)-Dehydrobhesine (73) [65] (+)-Viroallosecurinine [201] (+)-ewf-Phyllanthidine [201] (-)-Securinine [202] e/f/-Norsecurinine [202] (+)-Virosecurinine [202] (+)-Dicentrine [203] (+)-A^-Methyl-2,3,6-trimethoxymorphinandien-7-one [204] A^Methyl-2,3»6-trimethoxymorphinandien-7-oneW-oxide [205] (+)-lsocorydine [206] (+)-Norisocorydine [206] (+)-Oxyacanthine [206] (+)-W-Methyllaurotetanine [207] (+)-Isocorydine [207] (+)-Norisocorydine [207] Phoebegrandine A (26) [37] Phoebegrandine B (27) [37] (+)-Boldine [37] (+)-Norboldine [37] (+)-Laurotetanine [37] (+)-Lindecarpine [37] Liriodenine [32] Pontevedrine [32] (-)-N-Acetylnornuciferine [32]

Alkaloids from Malaysian Flora

413

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Talauma obovata

T. betongensis

Menispermaceae Albertisia cfA. papuana Becc.

Cyclea laxiflora Limacia oblonga

Alkaloids [Reference] -)-N-Acetylanonaine [32J +)-Predicentrine [32] Oxoglaucine [32] (A^-Acetyl-A^-methylamino)ethyl-3,4,6-trimethoxy7-hydroxyphenanthrene (14) [32] -)-Anolobine [11] Lanuginosine [11] -)-Asimilobine [11] -)-Xylopine[ll] -)-Anolobine [11] Liriodenine [11] -)-Norushinsunine [11] )-Asimilobine [11] )-Cuspidaline [11] -)-2,2'-Bisnorphaeanthine (30) [41] +)-Pangkoramine (31) [41] +)-Pangkorimine (32) [41] +)-Nor-2,-cocsuline (33) [41] +)-Lindoldhamine [41] ;+)-Daphnoline[41] +)-Daphnandrine [41] +)-Bisnoraromoline [41] [+)-Cocsuline[41] ;+)-Cocsoline[41] +)-0-Methyl cocsoline [41] ;+)-Apateline[41] ;+)-Dicentrine [208] +)-Clolimalongine (34) [44] '+)-Limalongine (35) [44] [+)-Stepharine [44] Lysicamine [44] Homomoschatoline [44]

414

T.-S. Kam

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

Alkaloids [Reference] Imenine [44] Splendidine [44]

Myristicaceae Horsfieldia superba

Rubiaceae Mitragyna speciosa

Ophiorrhiza communis O. tomentosa Psychotria rostrata

Uncaria borneensis

(-)-Horsfiline (57) [59] 6-Methoxy-2-methyl-1,2,3,4-tetrahydro-P-carboline (58)[59] S-Methoxy-A^N-dimethyltryptamine [59] 3-Dehydromitragynine (82) [81] (-)-Mitragynine (83) [81,82,225] (-)-Paynantheine [81,225] (+)-Speciogynine [81,225] (-)-Speciociliatine [81,225] Mitraciliatine [81] Mitragynaline (84) [82,225] Corynantheidinaline (85) [82] Mitragynalinic acid (86) [82] Corynantheidinalinic acid (87) [82] 7oc-Hydroxy-7//-mitragynine [225] (-)-3,4,5,6-Tetradehydromitragynine (331) [225] (-)-Mitralactonal (332) [225] (+)-Mitrasulgynine (333) [225] Harmane (55) [209] (-)-Strictosidinic acid [209] (-)-Strictosidinic acid [209] (+)-Quadrigemine B [66] (+)-Hodgkinsine [66] (-)-Calycanthine [66] (+)-Chimonanthine [66] (-)-Calycosidine [66] (+)-Isorhynchophylline [79] (-)-Rhynchophylline [79] Isocorynoxeine [79]

Alkaloids from Malaysian Flora

415

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

U. callophylla

U. cordata var. cordata f. sundaica U. cordata var. ferruginea f. ferruginea U. lanosa var. glabrata U. lanosa var. ferrea U. longiflora var. longiflora

U. longiflora var. pteropoda Rutaceae Euodia macrocarpa

Alkaloids [Reference] (-)-Corynoxeine [79] (-)-Alloyohimbine [79] (+)-Pseudoyohimbine (80) [79] 3-£p/-P-Yohimbine (81) [79] (+)-Dihyrocorynantheine (78) [79,80] (+)-Gambirine (79) [79,80] Isogambirine (76) [79] Gambireine (77) [79] (+)-Rotundifoline [79] Callophylline (286) [178,179] CallophyllineA(287)[178] Callophylline B (288) [178] (+)-Yohimbine [79] (+)-Pseudoyohimbine (80) [79,80] (-)-P-Yohimbine [79] (-)-<x-Yohimbine [79] (+)-Dihydrocorynantheine (78) [79] (+)-Dihydrocorynantheine (78) [79] (-)-Isopteropodine (74) [79] (-)-Pteropodine (75) [79] (-)-Isopteropodine (74) [79] (-)-Pteropodine (75) [79] (+)-Isorhynchophylline [79] (-)-Rhynchophylline [79] Isocorynoxeine [79] (-)-Corynoxeine [79] (-)-Isopteropodine (74) [68-70,79] (-)-Pteropodine (75) [68-70,79] Dictamine [23,210] Pteleine [23,210]

416

T.-S. Kam

1.3.7. Table 3. Alkaloid content of chemically investigated Malaysian plants (cont.)

Plant

E. roxburghiana

E. pachyphylla

E. pilulifera

E. euneura

Alkaloids [Reference] Evolitrine [23,210] Kokusaginine [23,210] Platydesmine [23,210] Dictamine [23,210] Evolitrine [23,210] Kokusaginine [23,210] Dictamine [23,210] Evolitrine [23,210] Kokusaginine [23,210] Skimmianine [23,210] Evolitrine [23,210] Kokusaginine [23,210] Skimmianine [23,210] Platydesmine [23,210] 4-Methoxy-1 -methy 1-2-quinolone [23,210] 5-Methoxy-2,2-dimethyl-2H-pyrano[2,3-b]-quinoline [23,210] 3,4-Dihydro-5-methoxy-2,2-dimethyl-2H-pyrano[2,3-b]-quinoline [23,210] 5,8,9-Trimethoxy-2,2-dimethyl-2H-pyrano[2,3-b]-quinoline [23,210] 3,4-Dihydro-5,8,9-trimethoxy-2,2-dimethyl2H-pyrano[2,3-b]-quinoline [23,210] Kokusaginine [23,210] Evellerine [23,210]

1.4. BIOLOGICAL ACTIVITY Three dimeric alkaloids from Alstonia angustifolia, macrocarpamine (293), macralstonine acetate and villalstonine (289) possess significant in vitro activity against Entamoeba histolytica and Plasmodium falciparum, protozoans causing amoebic dysentery and cerebral malaria, respectively [211]. The ED50/\iM of the compounds against E. histolytica were macrocarpamine

Alkaloids from Malaysian Flora

417

(8.12), macralstonine acetate (15.51), villalstonine (11.8) and against P. falciparum were macrocarpamine (9.36), macralstonine acetate (3.43), and villalstonine (2.92). These levels of activity were however found to be four to eight times less potent than the standard drug, emetine against E. histolytica and 1 5 - 5 0 times less potent than chloroquine against P falciparum although the results do provide some support for the use of A. angustifolia in traditional medicine for treatment of amoebic dysentery and malaria. The monomelic alkaloids from the plant (alstonerine, alstophylline, 11-methoxyakuammicine, norfluorocurarine, pleiocarpamine, vincamajine) were all considerably less active than the dimeric alkaloids. In screening for leishmanicidal activity (against Leishmania donovani), a number of plant extracts were found to show significant activity including Alstonia angustifolia, Kopsia griffithii and Holarrhena curtisii. The activity in all the cases were traced to the alkaloid containing basic fraction. In the case of K. griffithii, the strongest activity was shown by the quasidimer buchtienine (228) (0.39 < IC50 < 1.56 ^ig/ml) with harmane (55) and pilocarpine (221) showing weaker activity (6.25 < IC50 < 25 u^/ml) [58,212]. In the case of the steroidal alkaloids from H. curtisii, all eight compounds obtained were active with holacurtine (36), N-demethylholacurtine (37) and hoi amine (41) showing relatively higher activity [51]. Moreover, all these compounds were also found to be cytotoxic especially against HL-60 (IC50 0.01-2.6 |!g/ml). Of special note is the significant activity observed for the aminoglycosteroid, 17-ep/-holacurtine (38), especially when compared with that of the closely related epimer holacurtine (IC50 0.01 versus 0.86 u.g/ml), suggesting that a change in the configuration at C(17) has a profoundly beneficial effect on cytotoxic activity [51]. The heteroyohimbine alkaloids dihydrocorynantheine (78) and gambirine (79) were evaluated for anti-hypertensive effects in rats since the basic fraction from Uncaria callophylla showed activity in preliminary screening and plants of the genus Uncaria have been used in Asia for the treatment of various conditions including primary hypertension [179,213-215]. Gambirine, a major alkaloid of U. callophylla was found to be effective in reducing both systolic and diastolic pressures in anaesthetized normotensive rats [215]. The anti-hypertensive effects were shown to be dose-related, rapid in onset and were always accompanied by bradycardia at higher doses. The depressor response was also longer lasting compared to that of the structurally related dihydrocorynantheine [214]. A similar study of the anti-hypertensive activity of the alkaloids of Kopsia teoi were also carried out which were also prompted by positive results from preliminary screening of alkaloidal extracts. The major aspidofractinine alkaloid kopsingine (191) was found to produce dose-related decreases in mean arterial blood pressure and heart rate in anaesthetized spontaneously hypertensive rats (SHR) which were similar to those elicited in normotensive controls. The same depressor response was shown by the 12-demethoxy derivative (kopsaporine, 192) and the semisynthetic 14,15-dihydro derivative of kopsingine 252, indicating that minor modifications to the basic structure of kopsingine do not significantly alter

418

T.-S. Kam

the hypotensive responses. A more drastic change in the structure as in the heptacyclic kopsidine A (242) and the semisynthetic 3-to-17 oxobridged compound 256, resulted in an increase in blood pressure. Based on experiments involving pretreatment with various blockers such as hexamethonium, atropine, and phentolamine, it would appear that the depressor as well as the pressor effects produced by these compounds could be ascribed to both central and peripheral actions [216]. Rhazinilam (170) from Kopsia singapurensis was found to be active in vitro against KB cells and further studies showed that its action is on the disassembly process of tubulin. However it was later found to be inactive in vivo [118,129]. Of the three novel indoles from Kopsia tenuis, lundurines A, B and C, (281-283) which were tested against B16 melanoma, only lundurine B (282) was found to have significant activity (IC50 ca. 1.56 ug/ml) [19,217]. Other compounds which were active in the B16 melanoma assay were the bisindole alkaloids norpleiomutine (308) from K pauciflora [19], and conofoline (305) and conophylline quinone (semisynthetic) from Tabernaemontana divaricata [218,219]. In addition, conophylline (303) which is also present in the Thai Ervatamia microphylla has been shown to be a potent inhibitor of ras functions [183,220,221]. The nitrogenous pigment, monomargine (322) showed cytotoxic activity in vitro against KB and P388 cells (IC50 0.7 ug/ml) [193] while the known nitrogenous derivative, didesmethylrocaglamide from Aglaia argentea showed strong cytotoxic activity against KB cells (IC50 0.006 Ug/ml) [194]. Pauciflorines A (268) and B (269) from Kopsia pauciflora are notable for being rare examples of plant-derived indole alkaloids which showed potent inhibitory activity (equivalent to that of the commercial compound, arbutin) towards melanin biosynthesis in cultured B16 melanoma cells at concentrations of 13 and 25 ug/ml, respectively, without any cytotoxicity towards the cells [19,174,222].

1.5. CONCLUSION The study of alkaloids from Malaysian plants has proven to be a rewarding enterprise in view of the large number of new and intriguing alkaloid structures that have been discovered. The discovery of useful biological activities associated with some of these compounds, especially in the more recent studies, should present an added impetus for more intensified efforts in the future.

Alkaloids from Malaysian Flora

419

1.6. ADDENDUM A new monoterpene alkaloid, kinabalurine G (330) has been obtained from the leaf extract of Kopsia dasyrachis in addition to 11 known alkaloids and the novel pentacyclic indole, danuphylline (vide infra) [223]. Analysis of the spectral data allowed assignment of the gross structure as well as determination of the stereochemistry at the various centers. Kinabalurine G (330) is the Af-oxide of 9-hydroxy-5-skytanthine, which is unknown, although a 9-hydroxyskytanthine of unknown stereochemistry has been previously reported from Tecoma starts [224].

332

333

420

T.-S. Kara

Another investigation of Mitragyna speciosa has been carried out and three new alkaloids have been isolated from the leaves, viz., 3,4,5,6-tetradehydromitragynine (331), mitralactonal (332) and mitrasulgynine (333), the latter being notable for possessing an unprecedented sulfonate function [225]. The HR-FABMS spectrum of mitrasulgynine (333) provided the molecular formula C23H28N2O7S, as well as a fragment ion corresponding to loss of a sulfonate group. The stereochemistry at C(20) in mitralactonal (332), and at C(15) and C(20) in mitrasulgynine (333) were assigned as S, based on the assumption that these compounds are biogenetically related to the major compound mitragynine (83). 0 2 Me

H2OH

335

334

COMe

CHO 337

336

CH2OH

338

339a, 339b

Alkaloids from Malaysian Flora

421

The stem-bark extract of the Malayan Alstonia macrophylla provided in addition to seven known alkaloids, three new indole alkaloids, 10-methoxyafFmisine (334), 10-methoxycathafoline (335) and alstonerinal (336) [226]. The latter is a type A macroline and coeluted with the known type B macroline, alstonerine (337) during chromatography, and proved resistant to further resolution by chromatography or fractional crystallization. Eventually a pure sample was obtained by reduction of a mixture of 336 and 337 to yield the isomeric alcohols 338 and 339, followed by oxidation of 338 to yield alstonerinal (336).

340 R = OMe 341 R = H

342

343 R1 = R2 = OMe 344 R1 = R2 = H

345

Tabernaemontana corymbosa provided two new alkaloids, dippinines A (340) [227] and C (342) [228], which belong to the small group of novel indoles exemplified by chippiine (343) and 10,11 -demethoxy chippiine (344) previously obtained from T. chippii and T. markgraflana, respectively [229,230]. These alkaloids can be considered as having arisen from an ibogan-type precursor via cleavage of the N(4)-C(3) bond followed by formation of a new bond between C(3)and Af(l). Due to paucity of material, the configuration of C(3) in chippiine (p-OH) was originally assigned based on comparison of the chemical shift of H(3) with that of H(16) in the eburnamines and 16-descarbomethoxytacamines [229]. The observed NOE interactions

422

T.-S. Kam

between H(3) and H(15P), H(12) in the case of dippinines A (340) and C (342) however, indicated that the stereochemistry of the C(3)-OH function in these compounds should be a and not p. In the case of the hexacyclic derivative, dippinine C (342), an additional ring has been formed via insertion of a formyl group between C(19) and N(4). The configuration of C(19) was assigned as S which is consistent with the observed NOE interactions between H(19) and H(21), H(22). Since the hexacyclic tetrahydrooxazine derivatives (e.g. 342) are probably derived from the pentacyclic precursors such as 341, this in turn allowed the assignment of the C(19) configuration in dippinine A (340) as S [228]. The hexacyclic dippinine C (342) represents the first isolation of a chippiine-type compound which has incorporated an additional tetrahydrooxazine ring [228].

346

348

347

349

The stem-bark extract of Tabernaemontana corymbosa also yielded a minor alkaloid, tronoharine (346), which is characterized by an unprecedented hexacyclic carbon skeleton [231]. Tronoharine (346) can be considered as having arisen from an aspidospermatan-type

Alkaloids from Malaysian Flora

423

precursor (e.g. 347) via cleavage of the C(6)-C(7) bond followed by formation of a new bond between C(6) and C(16). A stepwise sequence initiated by protonation of C(16) of the aspidospermatan derivative 347, followed by a series of alkyl and hydride shifts involving several cationic intermediates has been suggested as a possible pathway to the tronoharine ring system [231]. The stereochemistry of the C(5)-C(6) ethylene bridge determines the absolute configuration of tronoharine, and based on the presumed biogenetic relationship of tronoharine with the aspidospermatan-type alkaloids, structure 346 is preferred over the enantiomer 348.

350 R1 = R 2 = H 351 R1 = R 2 = H, A/(4)-»0 352 R1 = R 2 = OMe, N(4)->0

353 R1, R 2 =OCH 2 0, R 3 = H, R 4 = O 354 R1 = R 2 = OMe, R 3 = C0 2 Me, R 4 = O 355 R\ R 2 =OCH 2 O f R 3 = C0 2 Me, R 4 = H 2

O 356

357

A new rhazinilam derivative, rhazinal (349) has been obtained from a Malayan Kopsia species [232]. The spectral data indicated that rhazinal is the 5-formyl derivative of rhazinilam. Rhazinal (349) represents the first instance of a naturally occurring rhazinilam derivative which

424

T.-S. Kam

has incorporated an additional carbon in the form of a formyl group, although semisynthetic formyl- and diformylrhazinilam derivatives have been recently reported in connection with a study of the antitubulin activity of rhazinilam analogues [233]. The stem extract of Kopsia dasyrachis furnished a total of 32 alkaloids. In addition to the new alkaloids mentioned earlier (vide supra), other new alkaloids include, the 7V(4)-oxides of kopsiflorine (351) and 11-methoxykopsilongine (352), decarbomethoxykopsifine (353), kopsinarine (354), 11,12-methylenedioxykopsine (355), dasyrachine (356), and (-)-19(tf)hydroxyisoeburnamine (357) [234]. The leaf extract of Kopsia dasyrachis provided a minor alkaloid, danuphylline (358) characterized by a novel pentacyclic skeleton [235,236]. The structure elucidation was based on spectral analysis of danuphylline as well as of the diol 359 derived from NaBH4 reduction of danuphylline. The structure of danuphylline represents a novel skeletal arrangement in which a new six-membered ring has been formed by cleavage of the C(5)-C(6) bond of the precursor compound 238, which was the predominant alkaloid present. Danuphylline (358) can thus be considered a "seco-methylchanofruticosinate" and represents the first member of this group isolated as a natural product. An unusual feature of the 'H NMR spectrum of danuphylline is the rather high field shift of the formamide-H (8 6.68), which is rationalized based on a preferred conformation in which the formamide carbonyl is directed away from the aromatic ring in order to avoid unfavorable repulsive interactions between the rc-electron density of the formamide C=0 as well as that of the lone pairs of the oxygen, and the 7C-electron density of the aromatic system, thus placing the formamide-H within the shielding zone of the aromatic ring current.

358

359

A possible origin of this ring-opened alkaloid is from the methyl chanofruticosinate (238) which on oxidation provides the iminium ion 360. Hydrolysis of this iminium ion gives the presumably unstable carbinol amine 361 which could then undergo a retro-aldol-type reaction

Alkaloids from Malaysian Mora

425

to provide the $eco-compound, danuphylline (358) (Scheme 11). An electrochemicallymediated semisynthesis based on such a biomimetic route has been successfully carried out [236]. The structure of danuphylline has also been subsequently confirmed by an X-ray analysis [223].

[O]

238 R = C0 2 Me

360

retro-aldol

H20

H2O 358

(-H+)

SCHEME 11

Tabernaemontana corymbosa also provided several new bisindole alkaloids, conodiparines A-D (362-365) which are constituted from union of iboga and vobasinyl moieties [237]. The spectral data indicated that in conodiparines A (362) and C (364), the dimers are branched from C(3) of the vobasinyl unit to C(IO') of the iboga unit whereas in conodiparines B (363) and D (365), the connection is from C(3) to C(12'). The configuration of C(19') in conodiparines A (362) and B (363) was determined to be S from examination of the carbon shifts of C(15') and C(2T) which corresponds to those of the iboga alkaloid heyneanine (345), exemplifying the 19(5) series in iboga alkaloids with a hydroxylethyl side chain [238].

426

T.-S. Kam

Me02(5

H

15

362 C(3)-C(10')bond 363 C(3)-C(12')bond

Me0 2 C

H

364 C(3) - C(10') bond 365 C(3)-C(12') bond

The initial discovery that the aspidofractinine alkaloid kopsiflorine (350) showed potential in reversing multidrug resistance (MDR) in vincristine-resistant KB cells prompted an evaluation of a series of aspidofractinine compounds [239]. In addition to kopsiflorine (350), the aspidofractinine compounds, 11-methoxykopsilongine (226), kopsamine (224), pilocarpine (221), lahadinine A (233) and M-methoxycarbonyl-11,12-methylenedioxy-A1617kopsinine (214) displayed promising levels of activity in reversing multidrug-resistance in the vincristine-resistant KB cells (KB/VJ300) when applied in the presence of vincristine, without manifesting any cytotoxicity towards the cells (IC50 1-5 fig/ml) [239]. The bisindole alkaloids, conodiparines A-D (362-365) also showed appreciable activity in reversing multidrug resistance in vincristine-resistant KB cells (KB/VJ300; IC50 1-5 fig/ml) with the highest activity shown by conodiparine A (362) (IC50 1.45 |Xg/ml) [237]. A study of the action of kopsiflorine (350) in reversing MDR has been carried out and the results indicate that kopsiflorine inhibits efflux of antitumour agents in the resistant cells by its direct interaction with P-glycoprotein [240].

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Chapter Three

Applications of Palladium Chemistry to the Total Syntheses of Naturally Occurring Indole Alkaloids JieJackLi Parke-Davis Pharmaceutical Research Division Warner-Lambert Company 2800 Plymouth Road Ann Arbor, Ml 48105 USA.

CONTENTS 1. 2. 3

4. 5. 6. 7. 8. 9.

INTRODUCTION OXIDATIVE CYCLIZATION USING Pd(II) SUZUKI, STILUS, AND NEGISHI REACTIONS 3.1. Suzuki Reaction 3.2. Stille Reaction 3.3. Negishi Reaction HECK AND INTRAMOLECULAR HECK REACTIONS 4.1. Heck Reaction 4.2. Intramolecular Heck Reaction TSUJI-TROST REACTION CARBON-NITROGEN BOND FORMATION REPRESENTATIVE EXPERIMENTAL PROCEDURES CONCLUDING REMARKS REFERENCES

438 438 446 446 455 464 469 469 474 485 491 494 499 499

438

JJ. LI

1. INTRODUCTION Since the monumental accomplishments of Woodward's total syntheses of strychnine in 1954 [1] and reserpine in 1958 [2], the arsenal of synthetic methods in indole alkaloid synthesis has greatly expanded. In the same time period, the use of palladium chemistry in organic syntheses h&> also witnessed tremendous growth with an ever-expanding repc Joire of synthetic methods and their applications to total synthesis. The use of palladium chemistry for the synthesis of indole alkaloids has been explored, and several examples have been included in recent reviews [3-6]. This account attempts to present a comprehensive collection of total syntheses of naturally occurring indole alkaloids where palladium chemistry plays a central role in the syntheses. This chapter is divided according to the five most popular types of palladium-mediated reactions: (1) oxidative cyclization reactions promoted by palladium(II) species; (2) reactions involving transmetallation with organoboranes (Suzuki), organostannanes (Stille), and organozinc reagents (Negishi); (3) inter- and intramolecular Heck reactions; (4) reactions involving nallylpalladium as the intermediate (Tsuji-Trost); and finally, (5) reactions that use the C-N bond formation as the key step for the total synthesis of naturally occurring indole alkaloids. 2. OXIDATIVE CYCLIZATION The oxidative coupling of aromatic compounds using Pd(OAc)2 was known in the 1960s. However, it was not until in 1975 when Akermark et al. revealed pioneering work on palladium(II)-promoted oxidative intramolecular cyclization of diphenylamines 1 to furnish carbazoles 2 [7, 8] (Scheme 1). Later, Itahara reported that intramolecular ring closure of 3benzoylindole 3 led to 5-methyl-5,10-dihydroindeno[l,2-&]indol-10-one (4) by refluxing 3 with 0.5 equivalent of palladium acetate in acetic acid [9]. When 2-methyl benzoylindole 5 was subjected to similar reaction conditions, poly cyclic indole 6, bridged at the peri position of the indole ring, was obtained as the major product in low yield. Furthermore, 6-oxo-6//isoindolo[2,l-a]indoles 8 were prepared by refluxing 7 with Pd(OAc)2 in acetic acid [10]. The role of acetic acid in such oxidative cyclization processes is to protonate the acetate ligand, making Pd(II) more electrophilic. The initial step in these oxidative cyclization reactions is electrophilic palladation of the aromatic ring. The total synthesis of ellipticine by Miller et al. [11] is one of the first syntheses of naturally occurring indole alkaloids using Pd(OAc)2 via the oxidative cyclization mechanism (Scheme 2). Exposure of 6-anilino-5,8-dimethylisoquinoline (9) to two equivalents of Pd(OAc)2 in TFA/AcOH facilitated the oxidative cyclization to the desired ellipticine (10). Recently, the same indole formation strategy that uses the Pd(OAc)2-mediated oxidative cyclization has been the cornerstone of several synthetic approaches directed toward ellipticine analogs. For instance, oxidative cyclization of diphenylamine 11 was carried out with Pd(OAc)2 in acetic acid to provide

Applications of Palladium Chemistry

R

439

2cqpj(oAch

O . J O '" N i X

. ""CXO

HOAc, reflux, ^0-80%

X 2

1

X = H, CH3; R = CH3, CH 3 0, Cl, Br, N0 2 , C0 2 H O

O HOAc, reflux, 60%

Ca^O N CH3

0.5 eq. Pd(OAc)2 i

HOAc, reflux, 30%

CH3 CH3

Pd(OAc)2 HOAc, reflux, 7-47%

R! = H, Cl, Me; R2 = H, Cl, Me Scheme 1. Early examples of oxidative cyclization of indoles an entry to carbazole 12 [12], which was then converted to 8,10-dimethoxyellipticine by the sulfonamide modification of the Pomeranz-Fritsch cyclization [13]. A similar oxidative cyclization was also used to synthesize carbazoles from novel «o-2-oxazolidinone dienes [14]. Another example is found in the synthesis of 14, an N-methylpyrazole analog of ellipticine, from diphenylamine 13 [15]. A remarkably concise synthesis of quindoline (16), an antimalarial agent isolated from a West African plant Cryptolepis sanguinolenta, was achieved in two steps in an

440

JJ . LI

overall 22% yield [16]. The precursor, 3-anilinoquinoline (15), was prepared by phenylation of 3aminoquinoline with Ph,Bi(OAc), in the presence of metallic copper. The crucial cyclization of 15 was then effected by Pd(OAc), in refluxing trifluoroacetic acid to afford quindoline (16).

Pd(OAc)2 10% CF3C02H, in HO Ac, 15-25%

CN Pd(OAc) 2 H

HOAc,32%

3co CH3 12

1.5 eq. Pd(OAc)2

H3CO

H3CO

•

HOAc, 20% 13

14

OXX) "

15

2 eq. Pd(OAc) 2 ^ CF,C0 2 H, 90*C,23%

H quindoline (16)

Scheme 2. Indole formation by palladium (Il)-promoted oxidative cyclization Hippadine (R\ R2 = -CH 2 -, 18a), pratorimine (R1 = H, R2 = CH,, 18b), pratorinine (R1 = CH,, R = H, 18c), and pratosinine (R1 = CH,, R2 = CH,, 18d, Scheme 3) belong to a family of pyrrolophenanthridone alkaloids isolated from the bulbs of Crinum pratense collected at 2

Applications of Palladium Chemistry

441

flowering time. Their biological importance emerged when they were found to exhibit reversible inhibition of fertility among male rats. Black et al. devised a short and effective synthesis of these

V ^

N

1.1 eq Pd(OAc>2, HOAc, 15-50% » 2. DDQ, quant.

^

OR* 17a-17d

18a-18d

Scheme 3. Direct, short and effective synthesis of pyrrolophenanthridone alkaloids

Pd(OAc)2 ||

HOAc

6-^ 19

O

21

Scheme 4. An 0-palladation gives five membered rings

442

JJ. U

pyrrolophenanthridone alkaloids and many of their analogs [17, 18]. The N-acylindoline (17) was derived from piperonyloyl chloride and indoline. Treatment of 17a with Pd(OAc)3 in glacial acetic acid at 115-120 °C afforded dihydrohippadine in 15% yield, along with 10% of the other regioisomer. Quantitative dehydrogenation of the cyclized in-.line, dihydrohippadine, gave hippadine (18a). Utilizing Itahara's mciiiodology [10], /V-piperonyl indole 19 was subjected to the same conditions. Palladium(II)-catalyzed intramolecular arylation of 19 occurred exclusively at the indole C(2) position to give a mixture of the two regioisomers 22 and 23 [17, 18]. As rationalized in Scheme 4, palladation intermediates 20 and 21 would be chelated and stabilized by the oxygen atom of the carbonyl group as in a typical o-palladation process. The intramolecular arylation at the C(2) position is favored because it gives a 5-membered palladium chelate 21 while palladation at the C(7) position gives a 6-membered intermediate 20.

H O^N (^

0

'taSs 1

Yv^TlT ji

/

\

^ N

CI

\\

N

O'ioH

CI 1

HO. NHMe Staurosporine (24)

\ OH OMe

Rebeccamycin (25)

1

Figure 1. Staurosporine and rebeccamycin are protein kinase C inhibitors Staurosporine (24) and rebeccamycin (25) (Figure 1), members of the indolo[2,3tfjcarbazole family, were isolated from Streptomyces staurosporeus [19, 20] in 1977 and from Saccharothrix aerococlonigens in 1985 [21], respectively. Like many indolo[2,3-a]carbazole alkaloids, they are protein kinase C (PKC) inhibitors. Their synthesis and those of their analogs have elicited great interest. Synthesis of the aglycone has also been the focus of many synthetic efforts because the aglycone fragment of staurosporine (24) is known to retain much of the activity of the parent. One example employing Pd(OAc)2-mediated oxidative cyclization for the C(2)-C(T) bond formation between the two indole rings was reported by Hill's group [22]. The precursor, arcyriarubin A (26), was easily prepared by condensation of dibromomaleimide with

Applications of Palladium Chemistry

443

four equivalents of indolylmagnesium bromide in refluxing benzene [23]. Treatment of 26 with one equivalent of Pd(OAc), in acetic acid at reflux for 18 hours led to the construction of the desired six-membered product as arcyriaflavin A (27, scheme 5).

Pd(OAc)2, AcOH 110°C,75% 27

26 Scheme 5. Synthesis of the aglycone of staurosporine

Reduction of imide 27 with LiAlH4 gave the corresponding hydroxylactam, which was then hydrogenolyzed to afford the desired aglycone as a lactam. In addition, the authors also examined the oxidative cyclization of other analogs of arcyriarubin A (26). In one scenario, when one of the two indole rings of 26 was replaced by a phenyl or 1-methylindole rings, Pd(OAc)2 was still the reagent of choice to effect the oxidative cyclization. Interestingly, when both indole rings were replaced by phenyl or 1-methylindole rings, no cyclization products were observed under the same conditions. Hill's oxidative cyclization strategy was also the key step for a new and efficient method to prepare pharmaceutically important bisindolylmaleimides [24].

PdCl2 BnO

*N N' H H 28aR=10-OH 28b R = 9-OH 28c R = H

DMF

BnO 29a 100% 29b 95% 29c 85%

Scheme 6. Remarkably high yields obtained in the oxidative cyclization of bisindole 28 In the synthesis of several arcyriaflavins (29a-c) [25], which are analogs of the staurosporine aglycone, the oxidative cyclization was realized by Ohkubo el al. in a remarkable 85-100% yield using PdCl, in DMF (Scheme 6). The original attempt to cyclize 28 using

JJ. LI Pd(OAc)2 in acetic acid by applying Hill's method [22] was unsuccessful because of the labile nature of the substrate under acidic conditions. This is the only reported example in which the cyclization was accomplished by using PdCl2 under neutral conditions instead of Pd(OAc)2 in acetic acid.

CH3

Pd(OAc)2,AcOH

H3C

reflux, 78%

H3»C C

H

II O

30

O II

kP°Sr

'CH 3 I

O pyrayaquinone- A (31)

CH3 H O

I OCH3

(l)Pd(OAc)2,AcOH reflux, 30 min. 84%

(2)BrCN,Et3N,DMAP,97% (3)Pyridine»HCl,200°C,42%

CN

32 O HO

f

CH3

7-deoxyprekinamycin (34)

VJT\

^=asx

~^~ ~CH3 1 N HO I O CN prekinamycin (35)

Scheme 7. Total synthesis of carbazolequinone alkaloids

OH

Applications of Palladium Chemistry

445

Indole formation by palladium-assisted intramolecular ring closure was the key step of the Furukawa group*s total synthesis of the carbazolequinone alkaloids, pyrayaquinones-A through C, and murrayaquinones -A through -D [26]. Murrayaquinone A has been found to show cardiotonic activity on guinea pig papillary muscxs. The synthetic route to pyrayaquinone-A (31) is highlighted here to showcase their strategy (Scheme 7). Treatment of 2-anilino-5-methyl-l,4benzoquinone 30, obtained via Michael addition of the corresponding arylamine to methyl-1,4benzoquinone, with one equivalent of Pd(OAc)2 in acetic acid at reflux afforded pyrayaquinone-A (31). Prekinamycin (35), like kinamycins A-F, was isolated from Streptomyces murayamaensis. Carbazole 33, a regioisomer of 7-deoxyprekinamycin (34), was synthesized in only four steps utilizing Pd(OAc)2 promoted oxidative cyclization as the pivotal step [27]. Similar to Furukawa's approach, the anilino-l,4-naphthoquinone 32 was obtained via Michael addition of the corresponding 2-methoxy-4-methyl-aniline to 1,4-naphthoquinone. Oxidative cyclization proceeded in 84% yield. The first oxidative cyclization using catalytic Pd(OAc)2 in the synthesis of naturally occurring indole alkaloids was published by Kn6lker's group [28]. As illustrated in Scheme 8, the reoxidization of palladium(O) to palladium(II) with cupric acetate makes the reaction catalytic with respect to palladium [29, 30]. Anilinobenzoquinone 36 was obtained via Michael addition of the corresponding arylamines to 2-methyl-3-methoxy-l,4-benzoquinonc. Catalytic oxidative cyclization of 36 provided 37, which was then treated with methyllithium to give carbazomycins G (38a) and H (38b), respectively. Recently, carbazoquinocin C and (±)-carquinostatin A have been synthesized using the same strategy [31, 32]. This finding is of great significance because Knolker et al. have demonstrated for the first time that the catalytic cycle for oxidative cyclization is viable, like most palladium-mediated reactions. An analogy can be made to the Wacker process which in principle would eliminate the consumption of a stoichiometric amount of expensive Pd(OAc)2, making the method a more practical one, especially on an industrial scale. In summary, oxidative cyclization using Pd(II) provides a direct, short, and effective method for preparing many naturally occurring indole alkaloids. Palladium acetate is the reagent of choice. In one example, PdCl2 was superior to Pd(OAc)2 because the substrate decomposed in acetic acid. Generally, PdCl2 oxidation only proceeds in the presence of a base. Alternatively, the oxidative cyclization process has been conducted by using a mixture of PdCl2 and NaOAc, or a mixture of PdCl2 and AgNO,. A catalytic process in which Pd(0) is reoxidized back to Pd(II) has been developed analogous to the Wacker process. This catalytic approach should be the direction of future application of the oxidative cyclization method. The methodology can provide facile access to complicated, functionalized indole alkaloids which are otherwise not easily synthesized in a concise manner.

446

R

J.J. Li

O Y^j \fYOCU3 ^^N^sArii H H CH3 36

0.1Pd(OAc)2, 25Cu(OAc \ AcOH, reflux,* 19 h, 71-73%

R

MeLi, THF », -78°Cto25°C

*y<^

O R V ^ _ J Y O C H

3

W N I ^ L A ™

^^

N Y 37

CH

3

O Jk^OCH,

^N^S C"CH3 H

HO CH3 38a, carbazomycin G, R =H, 71% 38b, carbazomycin H, R =OCH3, 41%

Scheme 8. Palladium-catalyzed oxidative cyclization 3. SUZUKI, STILLE, AND NEGISHI REACTIONS 3.1. Suzuki Reaction The Suzuki reaction is palladium-catalyzed cross-coupling between organoboranes and aryl or vinyl halides or triflates. There have been many elegant applications to the total syntheses of naturally occurring indole alkaloids. In the synthesis of aurantioclavine (44), Hegedus et al documented one of the first applications of the Suzuki reaction in the syntheses of indole natural products [33]. Aurantioclavine (44), isolated from Penicillium aurantiovirens, is an analog of clavicipitic acid which possesses the 3,4,5,6-tetrahydro-6-(2-methyl-l-propenyl)azepino[5,4,3a/]indole tricyclic system. The Hegedus total synthesis utilized a chemoselective Suzuki coupling between 3-iodo-4-bromo-l-tosylindole (39) and tri(2-ethoxyethenyl)borane to install the ethyl vinyl ether 40 (Scheme 9). Unfortunately, the process was very sensitive to the purity of the boron reagent and to the freshness of the catalyst, resulting in inconsistent yields. In contrast, the corresponding Ni(0)-catalyzed oxidative addition-transrnetallation from zirconium was a reliable method to produce 40 in 75-80% yields. After acetal formation from vinyl ether 40 to give 41, the tertiary allylic alcohol 42 was assembled by Heck olefination of the 4-bromoindole 41 with 2methy-3-buten-2-ol. The cyclization product 43 arises from the subsequent condensation of 42 with p-toluenesulfonamide in the presence of p-toluenesulfonic acid. Reductive detosylation of 43

447

Applications of Palladium Chemistry

using NaBH4 under photolytic conditions removed both tosylate groups and also reduced the enamine, yielding (±)-aurantioclavine (44).

OEt 1

J

PdL4 (cat.), NaOH,0-77%

BBr3, SMe2, then 1

B(^OE$;

EtOH, NaHC0 3 96%

Ts 39

40

OH EtCK ^.OEt

^foH

EUX ^OEt

Pd(OAc)2, (o-tolyl)3P Et3N, CH3CN, 100 °C 5 h, sealed tube, 92% 42

41

pTsNH2 CH3CN pTsOH 90 °C, 4 h 56%

NaBH4 DME/MeOH/H20 1

hv,94%

Scheme 9. Total synthesis of (i)-aurantioclavine Early examples of the total synthesis of naturally occurring indole alkaloids employing the Suzuki reaction include ellipticine (10) as reported by Miller et al. [34]. The aryl bromide, 6amino-7-bromo-5,8-dimethylisoquinoline (45) was derived from 2,5-dimethylaniline in nine steps. The Suzuki coupling of 45 with phenylboronic acid was carried out using catalytic tetrakis(triphenylphosphine)palladium in benzene and with Na3CO, serving as the base to furnish 6-amino-5,8-dimethyl-7-phenylisoquinoline (46, Scheme 10). The reaction conditions were compatible with a free amino group on the isoquinoline ring even though the Suzuki reaction of

448

JJ . Li

the corresponding acetyl derivative also proceeded in good yield. The amino group on 46 was converted to the corresponding azide by diazotization followed by treatment with NaN3. Solvent phase thermolysis of the resulting azidophenylisoquinoline in dodecane at 180 °C provided ellipticine (10) via a nitrene intermediate.

CH3 N

PhB(OH)2 Pd(Ph3P)4(cat.) aq. 2 M Na 2 C0 3 reflux, 99%

H2N

CHi

46

Pd(Ph3P)4, Na2C03/DME reflux, 40-49% B(OH)2 CHO 47a-b

R

^

V-o

49a-b

1. cat. Pd(Ph3P)4

N

>CL 51 OHC^^^B(OH)2 2. NaBH4,26%, 2 steps

Scheme 10. Application of Suzuki coupling in natural indole alkaloid synthesis Hippadine (18a), whose total synthesis employing the oxidative cyclization strategy is summarized in Section 2, was alternatively synthesized using a Suzuki reaction to form the C-C bond between the two benzene rings. Snieckus et al. described a short synthesis based on the onepot cross-coupling-cyclization sequence of halo indoline 47 and o-formyl arylboronic acids 48 [35]. For instance, 47a (R = H, X = I) and 48 underwent a cascade of reactions involving Suzuki

Applications of Palladium Chemistry

449

coupling, cyclization, and air oxidation of the intermediate carbinol amine to give lactam 49a, which was subsequently oxidized with DDQ to provide hippadine (18a). In an analogous fashion, 49b was obtained from 47b (R = OMs, X = Br). Reduction of 49b with excess Red-Al afforded ungermine, another member of the pyrrolophenanthridine alkaloid family. 1-Chloro-p-carboline (50) was prepared from tryptamine in three steps. It served as a common intermediate for palladium-catalyzed cross-coupling reactions that offered easy access to three natural indole alkaloids [36]. The Suzuki reaction of 50 with 5-formylfuranyl-2-boronic acid (51) formed the C-C bond between the pyridine and the furan rings. Reduction of the resulting adduct with NaBH4 yielded perlolyrine (52, Scheme 10). In the same manner, the Suzuki reaction

w

/7-NH 2

x ^

Q

"^i

-x1

\

N' ^ H

N H

nortopsentin A (53a, X] = X2 = Br) B (53b, X, = Br, X2 = H) C (53c, X, = H, X2 = Br) B(OH) B< 2

oi

I ^

55

N SEM 54

•N TBS

Pd(Ph3P)4, Na 2 C0 3 ,45%

TBS 56 B(OH)2

1.

£tf

Br

58

TBS 53c

2. H 2 0,74%

SEM

TBS 57

Scheme 11. Total synthesis of nortopsentin C

Pd(Ph3P)4,Na2C03 2.TBAF,50% 3.20% HC1,74%

450

Jjr. Li

with tri(m-propyl)phenylborate afforded komaroine. Alternatively, Stille coupling of 50 with tributylvinylstannane produced pavettine. A family of imidazole marine alkaloids, nortopsentins A-C (53a-c) were isolated from the marine sponge Spongosorites ruetzleri. They all possess a characteristic 2,4-bisindolylimidazole skeleton and exhibit cytotoxic and antifungal activities. Successive and regioselective diarylation via Suzuki coupling reactions using halogenated imidazole to make nortopsentins was disclosed by the Ohta group [37, 38]. The total synthesis of nortopsentin C is summarized here as a

Oo — ^ ^ N

2.B

OMe 59 NH2 1. NaN02, HCl N'

2.KI,84%

Ts 61 60, PdCl2(Ph3P)2,5 mol% THF, Ar, reflux, 38%

2 MeMgl, ether, rt ^N~

H

o:5

TBS i

Cr o

66

B r B r

65

toluene 110 °C, 20h946%

Scheme 12. Total synthesis of arcyriacyanin A

Applications of Palladium Chemistry

451

representative example. As depicted in Scheme 11, the JV-protected 2,4,5-triiodoimidazole (54) was coupled with one equivalent of the 3-indolylboronic acid 55 to give the adduct 56. The Suzuki reaction proceeded regioselectively at C(2) of the imidazole ring. A regioselective halogen-metal exchange reaction took place predominantly at C(5) to provide 57. A second Suzuki coupling reaction at C(4) of 57 with 6-bromo-3-indolylboronic acid 58 resulted in the assembly of the entire skeleton. Two consecutive deprotection reactions removed all three silyl groups to give the natural product (53c). This is a fine example of the chemoselectivity of the Suzuki reaction between an arylbromide and an aryliodide. The desired regioselectivity was achieved via an elegant manipulation of the substrate functionalities. A method developed by Ishikura et al [39-41] was the foundation of the synthetic endeavors towards the total synthesis of several indole natural products, including arcyriacyanin A (67) and structural analogs (e.g. 73) of yuechukene (74). The structural features of arcyriacyanin A (67) are different from that of the aglycone of staurosporine (24) and rebeccamycin (25). Besides the different indole orientations, the two indole rings on arcyriacyanin A (67) are connected by a seven- membered ring whereas staurosporine (24) and rebeccamycin (25) are tethered by a six-membered ring. In Ishikura*s methodology, the bis-aryl skeleton was assembled by Suzuki coupling between aryl halides and a novel indolylborate reagent, triethyl(lmethoxyindol-2-yl)borate (60), which is derived from regioselective deprotonation at C(2) of 59 with subsequent quenching by triethylborane. The crucial step in the total synthesis of arcyriacyanin A (67) by Tobinaga et al. [42] involved a Suzuki cross-coupling reaction between indoleborate 60 and 4-iodoindole (63). As outlined in Scheme 12, 4-iodo-l-tosyl-indole (62) was derived from 4-amino-l-tosyl-indole (61) by diazotization and iodination. Desulfonation of 62 with 40% NaOH in refluxing methanol led to 63. Employing the methodology developed by Ishikura, unsymmetrical bisindole 64 was prepared by Suzuki cross-coupling between 63 and 60. Protection of indole 63 at C(l) increased the yields for the Suzuki coupling (1-tosyl analog, 46%; 1-TBS analog, 51%, respectively). The bisindole 65 was treated with two equivalents of methylmagnesium iodide in ether and condensation of the resulting bisiodomagnesium salt with the TBS protected 3,4-dibromomaleimide (66) in refluxing toluene [23] furnished arcyriacyanin A (67). In the same PKC inhibitor arena, synthesis of staurosporine analogs using the Suzuki coupling reaction was also reported. For example, bromophthalimidine was coupled with pmethoxyphenylboronic acid to furnish bisphenyl phthalimidine as a staurosporine analog [43]. Utilizing the Suzuki coupling of l-tosylindolyl-2-boronic acid with an indolylmaleimide triflate to make a bisindolylmaleimide [44], Ishikura synthesized a structural analog (73, Scheme 13) of yuechukene (74) [45]. Yuechukene (74) was isolated from the root bark of Murraya paniculata and exhibits strong anti-implantation activity in rats, mice and pigs. Indolylborate 69, generated in situ from 1 -methylindole (68), underwent a palladium-catalyzed carbonylative cross-coupling reaction with vinyl triflate 70 to provide the desired 2-acylindole 71. Upon heating with acid

452

JJ. Li

(10% HC1), closure of the C ring was achieved with formation of inden[2,l-&]indole 72 with the requisite cis configuration at the C/Dringjuncture. Reduction of the carbonyl functionality in 72 with DIBAL provided the intrinsically unstable ally lie alcohol, which when treated with indole and BF,*OEt2 furnished the yuechukene analog 73.

Li©'

OQ^ Me

68

BuLi,THF

2. BEt3, THF

Me 69

PdCI2*(Ph3P)4 CO/THF,60% 1. DIBAL 1

2. Indole BF 3 OEt 2 65%

Scheme 13. Palladium-catalyzed cross-coupling reaction to synthesize yuechukene analogs Another use of the indolylborate reagent (69) was reported in the total synthesis of ellipticine analogs by the Ishikura group [46]. As illustrated in Scheme 14, vinylbromide 75 and indolylborate 69 underwent a tandem intramolecular Heck-Suzuki reaction to give hexatriene 76 which was then converted to the desired pyrido[4,3-fc]carbazoIe 77 using the well-known photocyclization protocol for styrylindole systems.

Applications of Palladium Chemistry

76

453

77

Scheme 14. Total synthesis of ellipticine analogs using indolylboronate Qugguiner's group has made great strides in the syntheses of naturally occurring indole alkaloids by using a combination of metallation of azines and diazines and cross-coupling strategies. The synergy between the directed metallation reaction and palladium-catalyzed crosscoupling reaction creates a powerful tool for the construction of unsymmetrical biaryl natural products. Application of this strategy has resulted in the total syntheses of more than a dozen natural indole alkaloids, including harm an, 2-ethyl-p-carboline, pavettine, 6-hydroxyharman, fascaplysin, lavendamycin derivatives, nitramarine, and 1-flouroellipticine. The aforementioned accomplishments were reviewed in 1995 by Qu6guiner et al. [5J. Only two representative examples of the total syntheses of naturally occurring indole alkaloids reported after their review are described here. One example employing their strategy that combines a directed metallation reaction with the Suzuki reaction is the total synthesis of bauerine B (84), a P-carboline natural product [47]. Bauerine B (84) was isolated from the terrestrial blue green alga Dachothrix baueriana GO-25-2. This cytotoxic alkaloid is active against herpes simplex virus type 2. As detailed in Scheme 15, 2,3-dichloroaniline (78) is protected as the corresponding pivaloylaminobenzene 79. Lithiation occurs regioselectively at the ortho position, and the resulting anion is quenched by trimethylborate to provide boronic acid 80 after hydrolysis. The Suzuki reaction between 80 and 3-fluoro-4-iodopyridine (81) leads to the desired biaryl product 82 contaminated with primary amine (ca. 30%). Indole formation to P-carboline 83 was accomplished by boiling the mixture with pyridinium chloride at 215 °C. Subsequent Nmethylation by using phase-transfer catalysis with methyl iodide completed the total synthesis of bauerine B (84). Another P-carboline natural product, the antibiotic eudistomin T (85), and a few other hydroxy p-carbolines were synthesized in the same fashion [48,49].

454

JJ. LI

PivCl, 10% Na 2 C0 3 C r ^y 'NH 2 CI

NHCOtBu

C1

CH2C12,1.5 h, rt, 92%

78 l.BuLi,THF -15 °C, 6 h

N

>T

Pd(Ph3P)4, 2M K 2 C0 3 1

toluene, reflux, 30 h

2.B(OMe) 3 ,-15°C,2h 3. hydrolysis, 65%

1. Pyridinium chloride, reflux, 15 min 2.NH4OH,ice,83% 82a, R = COtBu,60% 82b, R = H, 25%

•eXCO 83

CH31,50% NaOH HS04NBu4 Toluene, 2 d, rt, 97%

CI Me bauerine B (84)

Scheme IS. Total synthesis of bauerine B The total synthesis of an indoloquinoline natural product, quindoline (16), is summarized in Scheme 16 [50]. 2-Iodo-3-fluoro-quinoline (86) was prepared by treatment of 3-fluoro-4iodoquinoline with LDA followed by quenching with water. The fluoro-directed lithiation is a kinetic process and occurs at C(2), but an isomerization occurred (the so-called "halogen-dance" process) to give the more stable 4-lithioquinoline, which was protonated upon quenching with water to give 86. The Suzuki reaction of 86 with boronic acid 87 proceeded in a solution of ethanol and toluene and the resulting biaryl product 88 was then converted to quindoline (16) in a manner analogous to the synthesis of 83. An additional application of the Suzuki reaction is found in the total synthesis of cryptosanguinoline (92) by Timdri et al. [51]. The Suzuki reaction

Applications of Palladium Chemistry

455

between 3-bromoquinoline (89) and boronic acid 87 gave 90. Simple functional group transformations of the pivaloylamino group into the corresponding azido group provided 91, which was thermolyzed in 0-dichlorobenzene (180 °C) to furnish cryptosanguinoline (92) via a nitrene intermediate.

— i*OC N 86

I

B
^"'^NHCOtBu 87

NHCOtBu

Pd(Ph3P)4, EtOH toluene,94% reflux, Ar

*• Pyridinium chloride, reflux, 15 min 2.NH4OH,ice,83%

Br

quindoline (16)

87 Pd(Ph3P)4, EtOH, •

N

toluene, reflux, Ar,94%

89 1. o-dichlorobenzene 180°C,5h,75% 2. Me 2 S0 4 , CH3CN reflux, 5 h, K 2 C0 3 93% Scheme 16. Total synthesis of quindoline and cryptosanguinoline 3.2. Stille Reaction Among palladium-catalyzed reactions, the Stille reaction is unique because it proceeds under neutral conditions and is tolerant of a wide variety of functional groups. In addition, organostannane reagents enjoy ease of preparation and purification by standard synthetic techniques. The most frequently employed techniques for organostannane preparation include: (a) palladium(0)-catalyzed reaction between an aryl halide with hexaalkylditin; (b) halogen/metal exchange of an aryl halide followed by quenching with a stannyl electrophile; and (c) direct

456

JJ.LI

metallation of a substrate followed by quenching with a stannyl electrophile. Despite the toxicity of organostannanes, the Stille reaction has enjoyed many applications to the total syntheses of a plethora of natural products, including indole alkaloids.

Pd(0),(Me3Sn)2 » Xylene, 140 °C 24 h, 60%

O

W Br

B113S11

NH2

hippadine (18a)

49a

OEt ^.

Br

^^ 90%

OEt

Pd(PPh3)2Cl2 Et4NCI,MeCN 68%

(C02H)»2H20 tt

I

96%

94

Br 96

95

NaH,THF,72%

Pd(Ph3P)2Cl2 (Bu3Sn)2

COC1

H

Et4NBr, Li 2 C0 3 toluene, 68%

hippadine (18a)

& 97

98

Scheme 17. An intramolecular aryl dihalide tandem cyclization via the Stille reaction An attractive protocol using a Pd(0)/ditin catalyst system was utilized for two syntheses of hippadine (18a) via an intramolecular aryl dihalide tandem cyclization mechanism. In Grigg's approach [52], as depicted in Scheme 17, diiodide 93 was subjected to the Pd(0)/ditin catalyst system to form the C-C bond in lactam 49a. Oxidation of indoline moiety in 49a using DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone) completed the total synthesis of hippadine (18a). In a similar manner, another concise synthesis of hippadine was delineated by the Sakamoto group [53J. Their synthesis began with a Stille coupling of 2,6-dibromoaniline (94) with the masked carbonyl reagent, Z-l-tributylstannanyl-2-ethoxyethene, to provide 95. The phase-transfer agent,

Applications of Palladium Chemistry

457

tetraethylammonium chloride, provided a high concentration of chloride anions which stabilized and activated the palladium(O) complex during the Stille reaction. Cyclization of 95 was effected by oxalic acid to give 7-bromoindole (96). The TV-acylation of 96 with 2-bromo-3,4methylenedioxybenzoyl chloride (97) led to the 1-benzoylated indole 98. The intramolecular Stille coupling of 98, using the same protocol as Grigg's, delivered hippadine (18a). The Stille reaction was also pivotal to the convergent nature of Watanabe's synthesis of hippadine (18a) [54]. As illustrated in Scheme 18, the 7-stannylated indoline 100 was prepared by ortho-Utiaiion of 1-terf-butoxycarbonylindoline (99) followed by quenching with tributyltin chloride. The Stille coupling between 100 and 101 [Pd(OAc)2-P(o-Tol)3-Et3N (1:2:2) (10 mol%)/DMF/70 °C, 50 h] led to the adduct 102 in 63% yield. The more common palladium catalysts Pd(Ph3P)4 and Pd(PPh3)2Cl2 gave substantially inferior yields (8 and 14%, respectively). This is a good example of the functional group tolerance of the Stille reaction in which protection of the aldehyde was not required. Deprotection and basification of 102 provided the cyclized hemiaminal which was oxidized to anhydrolycorin-7-one. Dehydrogenation of anhydrolycorin-7one with DDQ completed the total synthesis of hippadine (18a). Pratosine (18b), oxoassoanine and kalbretorine were also synthesized in the same fashion.

Br

Q-J

,.,„.BuU,TMEDA ( V p LBoc 2-Bu,S„CI,6S%

BujSl

99

Af™

t

kc

qQT

100

1. cone. HCI 2.A g 2 0 » 3. DDQ 80%, 3 steps

Pd(OAc)2,P(o-ToI)3 » Et3N,DMF, 63% V-O

101

hippadine (18a)

102

Scheme 18. Application of 7-stannylated indoline in the synthesis of hippadine Carbazole alkaloids have drawn considerable attention from synthetic chemists due to their significant biological activities, including antimicrobial, antiviral, and cytotoxic properties.Two simple carbazole alkaloids, glycozolinine and glycozolidine (107) were

458

J.J. LI

synthesized by Watanabe et al. {55] via a tandem Stille and aryne-mediated cyclization sequence. The regiospecific synthesis of glycozolidine (107) is shown in Scheme 19. Stannane 104 was prepared by orf/io-lithiation of 103 followed by quenching with tributyltin chloride. The bromide 105, in turn, was derived in 96% yield from 2-chloro-6-methylphenol by sequential bromination

OMe

OMe l./-BuLi,THF . . 0 „ -78°Cto-20°C <\ / ~ S n B u 3 NH 2.Bu3SnCl Boc 103

MeO OMe NH Boc 106

NH

Br

Pd(Ph3P)2CI2 DMF,90°C

+

*-

Me 25 h, 56%

I

Boc 104 KNH2, liq. NH3 99%

H glycozolidine (107)

Scheme 19. Glycozolidine synthesis via consecutive Stille and aryne-mediated cyclization (PhCH2N Me,Br,\ CH2Cl2-MeOH, rt, 5 h) and methylation (Mel, K2CO,, acetone, reflux, 4 h). Stille coupling employing Pd(PPh,)2Cl2 as the catalyst provided the biphenyl 106. Upon treatment with amide in ammonia, 106 was cyclized via the aryne intermediate to furnish glycozolidine (107) in a remarkable 99% yield. 1-Chloro-P-carboline (50) not only was the precursor for Suzuki coupling to synthesize perlolyrine (52, Scheme 10), but was also the precursor for Stille reactions in the synthesis of several other indole alkaloids including pavettine [36], nitramarine, and annomontine [56]. Nitramarine was synthesized by Qulquiner et al. by applying their 0/7/10-lithiation and Suzuki combination strategy {vide supra). As depicted in Scheme 20 [56], the Stille reaction of 50 with tributyl(l-ethoxyvinyl)tin followed by acidic hydrolysis delivered 1-acetyl-p-carboline (108), which serves as a common intermediate for both nitramarine (110) and annomontine (112). The Friedlaender quinoline synthesis was accomplished by treating 108 with aminobenzaldehyde (109) in the presence of Triton B as the base to give nitramarine (110). Similarly, enamineketone 111, generated when 108 was treated with the Brederecks reagent [ferf-butoxy-bis(diamino)methane], was treated with guanidine carbonate to give annomontine (112). In yet another example, Stille coupling of tributyl(l-ethoxyvinyl)tin as a two-carbon building block was also an

Applications of Palladium Chemistry

459

1. Pd(Ph3P)2Cl2

Cu

Co

N EtO

CI

N'

S11B113 J

2.HC1,H 2 0,83%

so

a:

*0 108

CHO

H

109

NH2

Triton B, 49%

CgCJ^

BuOCH(NMe2)2

CuO N H

Me2N 108

H 111

guanidine carbonate 56%, 2 steps annomontine (112) Scheme 20. (Continued on next page)

460

jjr. Li

Continued from page 23

CH3 F catPd(Ph3P)4,95%

7 EtO

Cc H

S11B113

113

N

^OEt 114

CH3 F HC1, HOAc, Ac 2 0 > 54%

f

(T^r -r^r \KJ* H \KJ CH3

1

N1 1

l-fluoroellipticine (115) 1 Scheme 20. The Stille reaction using tributyK l-ethoxyvinyl)tin in alkaloid synthesis important tactic in Qulquiner's synthesis of l-fluoroellipticine (115). The 4-pyridylbromide 113 was assembled by applying their metallation/halogen-dance strategy starting from 2fluoropyridine [57]. Stille coupling of 113 with tributyK l-ethoxyvinyl)tin constructed the 4-(lethoxyethenyl)pyridine 114, which yielded l-fluoroellipticine (115) upon treatment with acid. Additional examples of carbazole alkaloid synthesis using the Stille coupling are found in Hibino's synthesis of polysubstituted carbazoles, including marine alkaloids carbazostatin, hyellazole, and carbazoquinocins B-F [58, 59]. The total syntheses of carbazostatin (123) and carbazoquinocin C (124) are summarized in Scheme 21. Carbazostatin (123) is a radical scavenger isolated from Streptomyces chromfuscus. Carbazoquinocin C (124), along with carbazoquinocins A, B, D, E, and F, is found in Streptomyces violaceus 2448-SVT2. They all have the
Applications of Palladium Chemistry

461

l.I 2 ,KOH,DMF N H

•CnC'

CHO 2.NaH,MOMCl DMF,94%

N' CHO MOM 117

116 OEt

r-BuOK, r-BuOH 90 °C, 92%

CnCTOMOM 120

OEt 9-BBN-C7H15 PdCl2(dppf) CHa

OTf

Pd(Ph3P)2Cl2, Et4N+CI',67%

**" • CnO° E t

MOM

OX<

OEt

l.HCCMgBr.THF

2.MOMC1,/ CH2C12:i,i-Pr , 2NEt 50 C 93% ' ° '

118

BujSns^fif^

NaOH, THF 85%

^ ^ t f ^ MOM r MOM119OMOM MHCl,/-PrOH,61%

TMSC1, Nal, MeCN, -20 °C 3. Tf 2 0, Pyr. 85%

O7QC,

121

CH3 C7HI5 122

BBr3, CH2C12 -78 °C to rt W%

(PhSeO)20 THF,50°C 95%

Scheme 21. Total synthesis of carazostatin and carbazoquinocin C 119. The protection was necessary in order to avoid the formation of the enone-type compounds during the generation of the allene intermediate. Heating 119 in the presence of potassium tbutoxide generated the allene intermediate which underwent an in situ electrocyclic cyclization to furnish the desired trisubstituted carbazole 120 after tautomerization. Triflate 121 was obtained

462

JJT. Li

Et3N, CH2CI2

«

lie

Br^ "*^ "COC1 Br"*^< 126

125

cvQr Br' 127

reflux, 84%

AcCl, CH2C12 reflux, 5 h, 42%

.N 128

i^^SnBua

Pd(Ph3P)4, toluene, DMF, 100°C,95%

O

N

CO (80 psi) Me4Sn Pd(Ph3P)4 m HMPA, LiCl 75°C,23%

Scheme 22. A bromopryridine as a common intermediate for Stille reactions

Applications of Palladium Chemistry

463

after exhaustive deprotection of the two MOM groups, followed by sulfonation. The Suzuki coupling of 121 with 9-heptyl-9-borabicyclo[3,3,l]nonane (easily derived from 1-heptene and 9BBN) provided 122. Subsequent removal of the ethyl ether furnished carbazostatin (123). Oxidation of 123 with benzeneselenic anhydride led to carbazoquinocin C (124). Hyellazole and other carbazoquinocin family members were also synthesized in a similar fashion. Additionally, in the synthesis of the novel p-carboline alkaloid oxopropaline G by Hibino et al. [60], a Stille reaction between 2-formyl-3-iodoindole and isopropenyl tributyltin as a three carbon building block was successfully applied. Several indolopyridine alkaloids were synthesized using the Stille reaction via a pyridylbromide [61]. Examples include angustine (129) and naucletine (130), which belong to the Vallasiachotaman class of monoterpenoid indole alkaloids. The synthesis began with the condensation of harman (125) with 3-bromonicotinoyl chloride hydrochloride (126) to give enamide 127 (Scheme 22). Treatment of 127 with acetyl chloride led to the formation of the pentacyclic lactam 128 through a sequence involving intramolecular nucleophilic addition of the enamide moiety to the y-position of the 7V-acyl-3,5-disubstituted pyridinium cation (formed from reaction of the pyridine nitrogen with AcCl) followed by autoxidation of the resulting 1,4dihydropyridine. The Stille reaction of 128 with tributylvinyltin gave angustine (129). Naucletine (130) was produced by a palladium-catalyzed carbonylation of 128 with tetramethyltin. As a side note, a palladium-mediated reduction of 128, using sodium methoxide as the hydrogen donor (Helquist method [62]), furnished nauclefine. Stille reaction has also enjoyed applications to the total synthesis of bis-indole alkaloids, including staurosporinone [63], didemnimide C [64], and the topsentins [65]. The total synthesis of staurosporinone (138) by Beccalli et al. is presented here as an example. The synthesis commenced with acylation of both NH and OH groups of the readily available 3-cyano-2hydroxy-3-(l//-indo-3-yl)-acrylic acid ethyl ester (131) followed by chemoselective deprotection of the carbonate to give 132 (Scheme 23). Following synthesis of vinyl triflate 133, the Culaccelerated Stille reaction employing indolylstannane 134 led to the construction of bis-indole 135, which was treated with Pd(OAc)2 in acetic acid to promote an oxidative cyclization to give pentacyclic bisindole 136. The two protecting groups, ethyl carbamate and benzenesuifonamide, were simultaneously removed using sodium ethoxide in refluxing ethanol to give 137. Reduction of the nitrile with sodium borohydride-cobaltous chloride completed the total synthesis of staurosporinone (138).

JJ. LI

464

-_.

CN

1. ClC02Et, Et3N CH2C12,90%

C0 2 Et OH

/ =

C02Et

•

OH

2. Me2NH, CH2C12 %

131 (CF 3 S0 2 ) 2 0

OTV

iPr2NEt,85%** \N i-U Et0 2 C

C02E< OTf

+

Or N"^

Ph0 2 S

SnBu3

Pd(Ph3P)4 CuI,LiCl THF, reflux 89%

Scheme 23. Total synthesis of staurosporinone c. Negishi Reaction The Negishi reaction is the palladium-catalyzed cross-coupling between organozinc reagents and aryl- or alkenyl halides or triflates. It is compatible with some functional groups that can tolerate the presence of the organozincs, including ketones, esters, amines and cyano groups.

Applications of Palladium Chemistry

465

However, because organozinc reagents are usually generated and used in situ by transmetallation of with Grignard or organolithium reagents with ZnCl2, which are not compatible with many functional groups. As a result, the Negishi reaction has met with limited applications in indole synthesis and has not been as widely used as the Stille or the Suzuki reactions.

a

j Q ^N^ S0 2 Ph

1.LDA,THF,0°C •

^

2.ZnCI 2 ,THF,25°C

N' ^ZnCl £Q ph 140

PdCl2(Ph3P)2, DIBAL THF, reflux

142

.Br 7 Sk-BuMe2 143

ZnCl 2. ZnCI2, THF, 25 °C

^^

N Sif-BuMe2 144

£>77X PdCl2(Ph3P)2, DIBAL THF, reflux

Me2f-BuSi

R2 145

Scheme 24. The Negishi reactions of 2- and 3-indolylzinc with 2-halopyridines (X = Br, or CI) The Negishi reactions of both 2- and 3-indolylzinc derivatives with diversely substituted 2-halopyridines resulted in the assembly of 2- and 3-(2-pyridyl)indoles, which became important intermediates in indole alkaloid synthesis [66-69]. As shown in Scheme 24, the 2-indolylzinc reagent 140 was easily prepared by metallation of l-(benzenesulfonyl)-indole (139) with LDA

JJ . Li

466

followed by treatment of the resulting 2-lithioindole with anhydrous zinc chloride. The Negishi reaction of 140 with 2-halopyridine 141 provided 2-(2-pyridyl)indole 142. Since 1(benzenesulfonyl)-3-lithioindole tends to isomerize into the corresponding 2-lithioindole analog, the silyl protected derivative, 3-bromo-l-(terf-butyldimethylsilyl)indole (143) is utilized to generate the 3-indolylzinc intermediate. Thus, 3-indolylzinc 144, prepared by halogen-metal exchange with terf-butyllithium followed by treatment with anhydrous zinc chloride, reacted with 2-halopyridine 141, resulting in formation of 3-(2-pyridyl)indole 145.

ZnCI N' Si/-BuMe2 144

C0 2 Me

141

1. PdCl2(Ph3P)2, DIBAL THF, reflux, 2.p-TsOH, EtOH, refux, 42% HH

HCI, MeOH, then H2, Pt0 2 , MeOH 60%

f j j

J"T

^

Et" H = H " C0 2 Me H

C02Me 145

Ba(OH)2, H 2 0 dioxane, reflux 1

then PPA 85-90 °C, 36%

146

LiAIH4, dioxane reflux, 33%

Cc& N H

148 Scheme 25. An application of 3-indolylzinc to the total synthesis of indole alkaloids Another application of this methodology is described above through the total synthesis of nordasycarpidone (147), which in turn serves as an intermediate for preparation of several other indole alkaloids [70, 71]. As depicted in Scheme 25, application of this well-developed methodology led to 3-(2-pyridyl)indole 145, which upon treatment with HCI and hydrogenation

Applications ot Falladium Chemistry

467

stereoselectively furnishes the all-cw-piperidine 146. Hydrolysis of ester 146 with Ba(OH)2 followed by cyclization of the resulting piperidine-4-carboxylic acid using PPA (polyphosphoric acid) led to the natural product (l)-nordasycarpidone (147). (±)-Nordasycarpidone (147) is an intermediate for uleine-type alkaloids, including dascarpidol, uleine, and 16,17-dihydrouleine. Reduction of (±)-nordasycarpidone (147) with LiAlH4 gave tetracycle 148, which constitutes a formal total synthesis of tubotaiwine, a Strychnos alkaloid with the aspidosermatan skeleton. Similarly, assembly of 3-(2-pyridyl)indole provided an alternative entry to tetracyclic ABCD substructures of akuammiline alkaloids [72]. The utility of 1-halo-p-carbolines as versatile building blocks was demonstrated by the applications to the total synthesis of perlolyrine (52) via a Suzuki coupling, nitramarine (110) and annomontine (112) via Stille coupling reactions {vide supra). The versatility of 1-halo-pcarbolines was further proven by the total synthesis of nitramarine (110) via a Negishi reaction [73]. Thus, 1-bromo-p-carboline (149) was sequentially treated with KH and terf-butyl lithium to give 1,9-dimetallated p-carboline 150, which was transmetallated to the corresponding organozinc reagent and then underwent a Negishi reaction with 2-chloroquinoline to provide an alternative access to nitramarine (110). In another example, Qu^guiner et al. synthesized eudistomin U (154) combining orf/to-lithiation and the Negishi reaction [74]. As depicted in Scheme 26, the organozinc reagent was prepared by regioselective ortho-\'\th\at\on of 151 with n-butyllithium followed by a transmetallation of the resulting lithio species with zinc chloride. Subsequent Negishi reaction of the organozinc reagent with 3-bromoindole 152 provided the corresponding trisubstituted pyridine 153. Ultimately, eudistomin U (154) was completed by boiling 153 with pyridinium chloride followed by a basic workup. In the synthesis of inverto-yuehchukene (160), an analog of yuehchukene (74), an intriguing extension of the Negishi reaction was employed [75]. The central transformation from acetate 158 and 2-indolylzinc 140 into bisindole 159 involves a cross-coupling of a nallylpalladium intermediate with an indolylzinc reagent. As delineated in Scheme 27, treatment of 3-indolylzinc with acid chloride 155 led to the formation of divinyl ketone 156 in 80% yield. The indolylzinc reagent was found to be superior here than the corresponding Grignard reagent for the coupling reaction with 155. Nazarov cyclization of the divinyl ketone 156 in refluxing HCl/1,4dioxane afforded the tetracycle 157 with the cis C/D ring juncture stereochemistry. The tetracycle 157 was converted to acetate 158. The pivotal reaction of 158 with 2-indolylzinc 140 in the presence of Pd(0) catalyst, derived in situ from PdCl2(PPh3)2 and DIBAL, gave 18% of the desired coupling product 159. Finally, reductive removal of the protecting groups afforded invertoyuehchukene (160).

468

JJ. LI

1. KH, THF B l n

2.2 eq. f-BuLi Br

149

1. ZnCl2 2.Pd(Ph3P)4 2-chloroquinoline 53%

1. BuLi, THF, -75 °C, 1 h 2. ZnCl2, -25 °C to rt F NHCOtBu 151

3. Pd(Ph3P)4

Br

NHCOtBu S02Ph

S0 2 Ph

153

1. pyridinium chloride reflux 2. NH4OH, ice, 80% Scheme 26. Synthesis of nitramarinc and cudistomin Uby using the Negishi reaction The Negishi reaction of oxazol-2-ylzinc chloride with 6-iodo partial ergoline alkaloid was also documented to synthesize potent 5-HTIA agonists [76].

Applications of Palladium Chemistry

469

EtMgBr, then ZnCl22

O

v /

cone. HCI, 1,4-dioxane *. reflux, 4 h 92%

H

156 1. BuLi, PhS02Cl, -78 °C 2. Superhydride, THF, 0 °C 15 min, 86% 3. Ac 2 0, DMAP, TEA CH2C12, rt, 0.5 h, 86%

' H S0 2 Ph 158

157

I

Na/Hg aq. NaH 2 P0 4

ZnCI

140 SQ2Ph

Et 2 OMeOH rt,78% |

•d(Ph3P)2CI2, DIBAL THF, reflux, 18% 159

A

160

Scheme 27. Synthesis of inverto-yuehchukene 4. INTER- AND INTRAMOLECULAR HECK REACTIONS 4.1. Heck Reaction In 1984, Hegedus and Harrington reported a synthesis of 3- and 4-substituted indoles [77] employing Heck's well-established process: Pd(0)-catalyzed functionalization of aryl halides by the oxidative addition-olefin insertion-P-hydride elimination. In this instance, 4-bromo-ltosylindole (161, Scheme 28) was converted to several diversely functionalized 4-substituted 1tosylindoles. Selective electrophilic substitutions at the C(3) position of 161 provided access to 3(chloromercurio)-l-tosylindole and 3-iodo-l-tosylindole (162), which then underwent a Heck

470

J.J. Li

reaction to give 3-substituted 1-tosylindoles. Another application of the Heck reaction involving 4-iodo-3-(2-nitrovinyl)indole and 3-buten-2-ol was documented by Somei etal [78, 79]. The most important applications of the intermolecular Heck reaction to indole alkaloid synthesis have been the total syntheses of ergot alkaloids, noticeably (±)-clavicipitic acid and (±)lysergic acid. The ergot alkaloids are metabolites of the parasitic fungus Claviceps with unique structures and pharmacological properties. Aside from the well-known hallucinogen lysergic acid diethylamide (LSD), many ergot alkaloids are biologically active and are in clinical use. The elegant total synthesis yV-acetyl-(±)-clavicipitic acid methyl ester by the Hegedus group is a classic example of the applications of organopalladium chemistry to indole alkaloid synthesis [80]. As shown in Scheme 28,4-bromo-l-tosylindole (161) was transformed into 4-bromo-3-

AcHN^,C0 2 Me

NHAc 1. Hg(OAc)2 cat. HCI04

l

!L J 2.12,97%

N ^ 5%Pd(OAc)2 Ts Et3N, MeCN 60% 162

N Ts

161

^k

OH

1

163

OH ,C02Me

AcHN^C0 2 Me || 15% 11 PdCI2(CH3CN)2

5% Pd(OAc)2/Et3N P(<j-Tol)3/MeCN 83%

CH3CN, 95% 165

NaBH4, Na 2 C0 3 4:2:1 MeOH/DME/H20 Av,-20°C

^(T H

Ac £0 2 Me

1

)

|" I T ^ H 166

AC2

\l

°

MeOH

H

N-

JL

f02H

1

\

y

\X 7 k^A ~N H

11 1

clavicipitic acid (167) 1

Scheme 28. An illustration of the efficacy of palladium chemistry in the total synthesis of Nacetyl-(±)-clavicipitic acid methyl ester

Applications of Palladium Chemistry

471

iodo-1-tosylindole (162) via a mercuration/iodination process. A chemoselective Heck reaction at the C(3) position of 162 with methyl a-acetamidoacrylate produced exclusively the Z-isomer 163, along with 15-20% of the deiodinated product 161. An additional Heck reaction at the C(4) position of 163 with 2-methyl-3-buten-2-ol proceeded under more forcing conditions [8 mol% palladium acetate and tri(o-toluene)phosphine) to install the tertiary allylic alcohol side-chain in 164. In general, use of tri(o-toluene)phosphine ligand is beneficial in Heck reactions involving arylbromides, whereas the Heck reactions involving aryliodides proceed smoothly without such ligands. Typically, phosphine ligands not only facilitate the oxidative additions of arylbromides, but also prevent Pd(0) from precipitating via chelation. The intramolecular aminopalladation of 164 was accomplished by a Pd(ll)-catalyzed process to give the tricyclic azepinoindole 165. The

OH AcHN, ,C0 2 Me 1. Rh(COD)2BF4/DIPAMP H2 (4 atm), MeOH, rt, 96 h

ACHNO^H

2. 0.1 eq. PdCl2(Ph3P)2/Ag2C03 100 °C in DMF-Et3N, 3 h, 83% 168

163

1. HCI, EtOAc 0 °C, 30 min » 2. Et3N, rt, 15 min 169 (29%)

Mg/MeOH 170

» rt, 1 h, 64-72%

Scheme 29. Synthesis of optically pure clavicipitic acid

170 (62%)

KOH MeOH-H2Q 79-80%

c,avicipitic add(167)

472

J.J. Li

mechanism of this interesting palladium-catalyzed cyclization may involve nucleophilic attack on a palladium(II)-alkene ic-complex, followed by preferential elimination of palladium(II) oxide [81]. Even though aminopalladation usually requires stoichiometric palladium, in this particular reaction, palladium(II) hydroxide (HO-Pd-Cl), instead of palladium hydride, was the ostensible elimination product, regenerating Pd(II). Therefore, no reoxidation of palladium(O) was required to maintain the catalytic activity. The p-toluenesulfonamide in 165 was cleaved by photochemical reduction, which also resulted in the stereoselective reduction the double bond to give the desired Af-acetyl-(±)-cIavicipitic acid methyl ester as two diastereomers (166), which were identical to those prepared from natural (±)-clavicipitic acid (167). An asymmetric version of the total synthesis of clavicipitic acid was reported by Yokoyama et al. [82-84]. As illustrated in Scheme 29 asymmetric hydrogenation of the known 4bromodehydrotryptophan 163 was best achieved (94% ee) using the optically active Monsanto bidentate phosphine, DIP AMP. The Heck vinylation in the presence of Ag2C03 gave the C(4)vinylated product 168 without racemization. Treatment of 168 with HCl-EtOAc effected the cyclization to give the tricyclic azepinoindole 170 (62%), air ig with diene 169 (29%). Cleavage of the sulfonamide (Mg/MeOH) afforded 171 which underwent saponification (KOH) to give optically active clavicipitic acid (167).

Scheme 30. Heck reaction in the synthesis of annonidine

473

Applications of Palladium Chemistry

Somei et al. also reported an early application of the Heck process in a total synthesis of the naturally occurring indole alkaloid annonidine (176), which was isolated from the stem bark of the west African medicinal plant, annonidium mannii [79J. As depicted in Scheme 30, the Heck reaction of 7-iodoindoline (172) with 2-methyl-3-buten-2-ol gave rise to 173. Additionally, 7-(3methyl-2-buten-l-yl)indole (174) was prepared from 173 by a three-step sequence that included hydrogenation (H2, 10% Pd/C), dehydration (p-TsOH, refluxing PhH), and oxidation (cat. salcomine, dioxygen, CH3OH, it). Condensation of 173 and 174 was facilitated by 2 N HCI in THF to afford 175 in a regiospecific fashion. Subsequent oxidation with catalytic salcomine and dioxygen afforded annonidine (176). In the total synthesis of (±)-lysergic acid (182) [85], the known Kornfeld's ketone (177) was converted to vinyl triflate 178 (Scheme 31). The Heck reaction between 178 and acrylate 179 furnished aminodienoate 180 with the desired E-geometry in 26% yield. Cleavage of the BOC group under acidic conditions followed by the treatment with NaHCO, produced the lysergic acid framework 181 as a mixture of two epimers. Since transformation of the major diastereomer of 181 to (±)-lysergic acid (182) is known, this work constitutes a formal total synthesis of (±)lysergic acid (182).

O

OTf

II

Me0 2 C

Boc

JU

Me

179

3 moI% Pd(OAc)2,6 mol% Ph3P 2.5 eq. Et3N, DMF, 60 °C, 24 h, 26%

C0 2 Me

C0 2 Me 2.5 N HCI AcOEt » 1.5 h, rt 60%

BzN

1 180

BzN 181

Scheme 31. Formal total synthesis of (±)-lysergic acid Two additional syntheses of indole alkaloids which utilize the Heck reaction are (±)-cistrikentrin A (185) and infractin (187). As outlined in Scheme 32,7-bromoindole 183 was coupled with an excess of methyl crotonate to give 184 under the Heck reaction conditions [86]. 184 was

474

J.J. Li

then converted to (±)-ci5-trikentrin A (185). The olefin geometry of the newly-formed trisubstituted double bond in the Heck reaction was inconsequential because k was subsequently reduced. In another case, P-carboline-1-triflate (186) was transformed into the naturally occurring P-carboline infractin (187) in two steps via a Heck reaction with methyl acrylate followed by a hydrogenation [87].

O

^A 183

4 mol% Pd(OAc)2 9 mol% P(o-toIyl)3 Et3N, CH3CN, 115 °C, 14h,61% O

1. Pd(OAc)2 P(o-Tol)3,18%

» 2.H 2 ,Pd-C,85% Scheme 32. Total synthesis of (±)-ci5-trikentrin A and infractin 4.2. Intramolecular Heck Reaction In the synthesis of the desethylibogamine alkaloid skeleton described by Trost and Genet [88], a mechanism similar to the Heck arylation (7-exo cyclization) was involved. As illustrated in Scheme 33, the dilithio indole 188 with a pendant olefin was treated sequentially with HgCl2, PdCl2, and then NaBH4 to give desethylibogamine (189). The difference from a common Heck reaction is that the last step is a simple reduction of the palladium intermediate instead of the usual reductive elimination. This method was also applied by Williams et al. in their total synthesis of (+)-paraberquamide B, where a heptacycle was synthesized from an indole ring with a pendant olefin using Trost's conditions [89]. An indole alkaloid synthesis employing a bona fide intramolecular Heck reaction was documented in Sundberg's preparation of 5,6-homoiboga derivatives [90]. Several attempts to construct 5,6-homoiboga derivative 191 using inter- or intramolecular Heck reaction conditions with phosphine ligands led to poor yields. Application of Jeffery's "ligand-free" phase-transfer

Applications of Palladium Chemistry

475

catalysis conditions [91] to the intramolecular Heck reaction (8-endo-cyclization) of 190 provided 191 in an exceptionally good yield.

^

Nl N LiLi 188

^

1. HgCI2 2.PdCl2,THF

N N H

1

3. NaBH4

C0 2 Et ^

Pd(OAc)2, I ^ \ A ' N 1 OCH3 «-BU 4 NC1, KOAC N^NA^/^CH, CH3 i o 2 C H 3

vx

f

^

DMF,80°C 89%

190

CH 3 C0 2 CH 3 191

Scheme 33. Examples of 1-exo and %-endo Heck cyclization reactions A 6-exo Heck cyclization plays a central role in Rawal's elegant total synthesis of strychnine (201). Strychnine is a member of Strychnos alkaloids, which were isolated from the seeds of Strychnos nux-vomica L., Loganiaceae and beans of S. ignitti, Berg. Its powerful biological activity (extremely poisonous) combined with the intriguing heptacyclic framework elicited tremendous efforts toward its synthesis. After Woodward's monumental accomplishment of a strychnine synthesis in 1954, it took nearly forty years to witness several additional total syntheses. Among those, Rawal's approach [92] is the most concise route, with an intramolecular Diels-Alder reaction and an intramolecular Heck cyclization as the key features. As illustrated in Scheme 34, commercially available o-nitrophenylacetonitrile (192) was converted to pyrroline 193 in 79% yield over five steps, including a Stevens' cyclopropyl iminium ion rearrangement [93J to prepare the pyrroline ring. In a manner analogous to Rawal's total synthesis of (±)dehydrotubifoline [94], 193 was transformed into dienamine 195 by condensation with aldehyde 194 (Z:E = 9:1) followed by quenching with methyl chloroformate. An intramolecular DielsAlder cyclization of 195 proceeded in quantitative yield with complete stereocontrol to give the desired tetracycle 196. Global demethylation using iodotrimethylsilane furnished the pentacyclic lactam 197. Alkylation of 197 with allylic bromide 198 (prepared in five steps from butynediol) resulted in substrate 199, a precursor for the pivotal intramolecular Heck cyclization. Employing Jeffery's phase-transfer catalysis modification of the Heck reaction, vinyl iodide 199 with a pendant olefin was converted into a hexacyclic strychnan 200 (74% yield).

476

JJ. LI

a

^ CCfi N

steps 55 steps

Mr*. "N02

^^^ ^s A>v V N -^C O j M e

-row* 79%

k^JL * 5 s ^ ! ^ NH MU 2

192

193

W Me0 2 C

m

** then ClC02Me, PhNEt2 85% ,C0 2 Me /—N

,N"C0 2 Me

l

J neat, 25 °C **^

PhH,185°C, 4 h, 99%

\^C02Me

Me0 2 C

k^COiMe 196

195 TMS-I (10 equiv.) CHC13, reflux,

K 2 C0 3 ,5:1 acetone:DMF 75%

CH3OH quench 90%

OTBS Pd(OAc)2 (0.3 eq.) ^. BU4NCI, DMF, K 2 C0 3 70°C,3h,74% OTBS 200

199

1.2N HC1, THF i

2. KOH,EtOH

Scheme 34. Rawal's total synthesis of strychnine

Applications of Palladium Chemistry

477

After the removal of the silyl protecting group, the resulting isostrychnine was subjected to a base-mediated isomerization and subsequent Michael addition to give strychnine (201). The longest linear sequence in Rawal's synthesis required 12 steps. If the synthesis of two fragments 197 and 201 are included, the total operations involved 21 steps [95]. The yield of 201 is about 9% (24% based on recovered isostrychnine that can be recycled). Considering there are 7 transfused rings with 6 contiguous asymmetric centers, the approach is remarkably efficient. The intramolecular Heck cyclization proceeded with complete stereocontrol, and the geometry of the olefin was kept intact. In contrast, in another case [96], an inversion of olefin geometry was observed when the carbamate protecting group of the indole ring was present. Rawal and coworkers speculated that the presence of a carbamate moiety intercepted the a-palladium Heck cyclization intermediate through coordination. Therefore, p-hydride elimination did not occur due to chelation after the normal ejro-cyclization. Instead, ejco-cyclization was followed by cyclopropane formation, rearrangement, and elimination to give the olefin with inversion of the double bond geometry.

OH 202

(±)-geissoschizal (203)

(±)-isogeissoschizal (204)

Pd(Ph3P)4 LiCN 26%

N02 O 206

Pd(OAc)2,Ph3P HC02Na, Et3N/CH3CN C0 2 Me 207

reflux, 12 h, 43% C02Me 208

Scheme 35. Applications of 6-exo Heck cyclization in indole alkaloid synthesis

478

J J. Li

The intramolecular Heck cyclization employed in Rawal's total synthesis of strychnine was a 6-exo cyclization. A similar strategy using a 6-exo Heck cyclization was applied to Rawal's total synthesis of the (±)-geissoschizine skeleton [97a], the biogenetic precursor to virtually all other families of monoterpenoid indole alkaloids. In contrast to strychnine, geissoschizine does not contain a bicyclic bridged system that would dictate the stereochemical outcome of the cyclization. As shown in Scheme 35, the "classical" Heck conditions [Pd(OAc)2, KjCO,, Et3N, PPhj] for substrate 202 favored (±)-isogeissoschizal 204, whereas Jeffery's "ligand-free" modification [Pd(OAc)2, K^CO,, Bu4NBr] produced the desired (±)-geissoschizal (203) as the predominant product. In contrast to the intramolecular Heck reaction conditions employed in the (±)-geissoschizal (203) synthesis, a very "non-polar" set of conditions [Pd(OAc)2, PPh3, proton sponge, K2C03, PhMe, 100 °C, 18 h] was found to be most suitable for the intramolecular Heck reaction in Rawal's synthesis of the apogeissoschizine skeleton [97b]. Other applications of the 6-exo Heck cyclization strategy can be found in the synthesis of pentacyclic Strychnos alkaloids by Bosch et ai [98] and tabersonine by Kuehne et al. [99]. As illustrated in Scheme 35, 6-exo Heck cyclization of substrate 205 was successful only when Grigg's [100] modified Heck conditions [Pd(OAc)2, LiCN] were employed to give the tricyclic intermediate 206. Another 6-exo reductive Heck reaction successfully cyclized tetracyclic substrate 207 into pentacyclic tabersonine (208). As shown in Scheme 36, a Heck polyannulation reaction was realized between dibromo(indolyl)maleimide 209 and diacetylenyl trifluoroacetanilide 210 to assemble indolo[2,3a]carbazole 211, the N-protected aglycone of rebeccamycin (25). Four bonds were formed in one step from a single monocyclic 1,3-diacetylene precursor [101] and the trifluoroacetyl protecting groups were readily cleaved during the workup.

Bn i

\=\ Br

209

Pd(Ph3P)4,K2C03 CH3CN,

Br

50 °C, 52% ^ W H NH

1

HN^V HN COCF3 COCF3 210

Scheme 36. Polyannulation Heck reaction for indolo[2,3-a]carbazole synthesis For intramolecular Heck reactions, the migratory insertion of the initial organopalladium species occurs not only with simple olefins, but also with dienes (e.g. 207 to 208) and aromatic rings. Examples of an aromatic ring as the migratory insertion recipient can be found in the bisindolylmaleimide field. For instance, an intramolecular Heck cyclization of inflate 212

Applications of Palladium Chemistry

479

furnished TV-methyl arcyriacynin A (213) through formation of C(2)-C(4*) bond linkage between the two indole rings (Scheme 37). The migratory insertion of the oxidative addition intermediate from 212 took place to an indole ring. In this particular case, the triflate was chosen because the bromide analog was unstable towards Grignard reagents and a reductive loss of the aromatic bromine atom was observed. When the triflate was used, successful intramolecular Heck reaction was achieved in 81% yield to give the desired product 213. Transformation of N-methyl arcyriacynin A (213) into arcyriacynin A (67) was accomplished by basic hydrolysis followed by acidic workup and treatment of the resulting anhydride with hexamethyldisilazane. In another approach to JV-methyl arcyriacyanin A (213), a domino intramolecular Heck was achieved between bromo(indolyl)maleimide 214 and 4-bromoindole (215, Scheme 37). Examples of migratory insertion to aromatic rings also include the total syntheses of anhydrolycorine-7-one (217) [102] and the E-azaeburnane series [103]. As illustrated in Scheme 38, an intramolecular Heck reaction of N-acylindoline 216 installed the six-membered lactam in anhydrolycorine-7-one (217). In a similar process, the tetracyclic pyrido-[2*,3*-^]pyridazino[2,3a]indole (219) was prepared from bromopyridine 218 under phase-transfer catalysis conditions. Pyridyl indole 219 is a precursor of the pentacyclic skeleton of the £-azaeburnane series.

CH, \_l

OTf

0.12% Pd(OAc)2, 0.14% dppp, Excess Et3N, DMF, 110 °C, 18h,81%

212

213

CH Pd(OAc)2, Ph3P, Et3N,CH3CN, 213

N Boc 214

80°C,3h, 10-30% 215

Scheme 37. Domino Heck cyclization

480

J.J. Li

Pd(OAc)2,K2C03

Q

DMA, 160-70 °C, 55%

°9X)

Pd(OAc)2,Ph3P, K 2 C0 3 , #tBu4NBr, » DMF, 120 °C, 92%

O 218 Scheme 38. Migratory insertions take place to aromatic rings An additional application of 1-exo Heck cyclization was found in Kelly's synthesis of maxonine (223), which was isolated from the root of a plant Simira maxonii endemic to the Costa Rican tropical forest. As shown in Scheme 39, the migratory insertion step of the intramolecular Heck cyclization of substrate 220 took place to both the pendant olefin and the benzene ring of the indole moiety simultaneously, giving rise to dihydropyridine 221 and seven-membered 222, respectively [104]. Oxidative cleavage of the stilbene double bond in 222 produced maxonine (223), which was identical to authentic maxonine. Kelly's synthesis of maxonine (223) revised the original structural assignment of the natural indole alkaloid. Aside from 8, 7, 6-endo, and 8, 7, 6-exo Heck cyclizations, 5-exo Heck cyclization is also feasible, although 5-endo cyclization is not favored. Kurihara et al. revealed a 5-exo Heck cyclization in their synthesis of the indole analog of magallanesine [105]. As depicted in Scheme 39, 5-exo Heck cyclization converted substrate 224 into 225, the indole analog of magallanesine (226) in 28% yield. The intermediate of the vinylic substitution was a palladium enolate, which underwent a syn P-hydride elimination after isomerization. (±)-Gelsemine (236) was isolated from Gelsemium sempervirens (Carolina jasmine) in 1870. Due to its intriguing bridged poly cyclic structure, (±)-gelsemine (236) has been a target of intensive synthetic endeavors. In fact, one of the first applications of intramolecular Heck reactions to form a quaternary center was documented by Overman et al. [106] in the synthetic studies towards (±)-gelsemine (236). As outlined in Scheme 40, when the cyclization precursor 227 was submitted to the "ligandless" conditions [Pd2(dba)3, Et3N] in the weakly coordinating solvent toluene, the quaternary center was formed as a 9:1 ratio of diasteromers (229:228 =

Applications of Palladium Chemistry

481

89:11). Addition of a silver salt in polar solvent THF completely reversed the sense of asymmetric induction in this cyclization reaction (229:228 = 3:97).

Pd(OAc)2

221 220

Os0 4 ,10 4 '

222

O

OMe OMe

Pd(OAc)2, Ph3P >TlOAc, D M F , 130 °C 28%

O

OMe ,OMe

Ph02S O

225

magallanesine (226)

Scheme 39. Total syntheses of maxonine and the indole analog of magallanesine In the total synthesis of (±)-gelsemine (236), Hiemstra and Speckamp [107J utilized Overman's "ligandless" intramolecular Heck conditions and achieved the synthesis of a spirooxindole in a 2:1 ratio favoring the desired stereoisomer. As depicted in Scheme 41, The key cyclization substrate 233 was derived from the carbonylation reaction between vinyltriflate 230

JJ. Li

482

-SEM

Pd2(dba)3,Et3N,PhCH3

r

110 °C, 80-95%

O SEM

V3o

Me0 2 C / Br

Me0 2 C

227

Pd2(dba)3,Ag3P04 THF,60°C,77%

Meo2c

Scheme 40. The stereochemical outcome is dependant on the choice of palladium catalyst and 2-bromoaniline (231). Since it is known that the Heck cyclization is low yielding with unprotected anilides, 232 was protected as its corresponding trimethylsilylethoxymethyl ether 233. Cyclization of 233 under the standard Heck arylation conditions produced a single spirooxindole product possessing the opposite spiro stereochemistry of (±)-gelsemine (236). When Overman's "ligandless" conditions were applied to substrate 233, a 2:1 ratio of the spiro-oxindole was obtained with desired product as the major isomer. Therefore, the desired spiro-oxindole 234 was obtained in 60% yield after removal of the TDS (thexyldimethylsilyl) protective group, along with 30% of the epimeric spiro-oxindole. With substrate 234 in hand, a mercury(II) triflate and /V,N-dimethylaniIine-initiated cyclization provided the tetrahydropyran ring formation and the resultant organomercurial intermediate was reduced with alkaline sodium borohydride. Removal of the SEM protective group delivered 21-oxogelsemine (235), which is a natural product itself. Selective reduction of the lactam moiety of 235 with alane in THF led to the formation of (±)gelsemine (236).

Applications of Palladium Chemistry

^

OTf

483

Pd(OAc)2,Ph3P,Et3N, CO,DMF,rt,24h,70%

O R

H2N-HT) OTDS 230

rxi 231

Br

232 R m H 233R = SEM 1. HgO, Tf 2 0, MeN0 2 , rt, N,N-dimethylaniline, 3 d

1. Pd2(dba)3, Et3N, PhMe, reflux, 4 h

».

^2. TBAF, THF, rt, 2 h Q 60% for 2 steps

OH 234

2. NaBH4, NaOH, CH2C12, EtOH, 3. TBAF, THF, 4 MS, reflux, 4 h, 43.2%

A1H3, THF, -65toO°C, 4 h, 50%

Scheme 41. Total synthesis of (±)-gelsemine At the early stage of Heathcock's biomimetic total syntheses of discorhabdins [108], a 5exo Heck cyclization was employed for the synthesis of 3,6,7-functionalized indole. As highlighted in Scheme 42, when precursor 237 was exposed to catalytic palladium acetate, tri-otolylphosphine, and stoichiometric base, indole 238 was smoothly produced in 89% yield. Subsequently, the total syntheses of discorhabdin C (239) and discorhabdin E (240) were accomplished using indole 238 as the common intermediate.

484

J.J.LI

NC 5 mol% Pd(OAc)2 •

(o-tol)3P, Et3N, CH3CN reflux, 3 h, 89 %

MeO

« N MeO" 71 H OBn 238

O Riv

-

R

discorhabdin C (239) R, = R2 = Br

2.

I N *1| N H

O

\ \ \ "N 1 H 1

discorhabdin E (240) R, = H, R2 = Br

Scheme 42. 5-exo Heck cyclization in the total synthesis of discorhabdins

COL

Br^

N I

CO,Me

Pd(Ph3P)3,KOAc dioxane, reflux, 91 %

\-6

241

1. L1AIH4 2. Dess-Martin 3. Mn0 2 4.RhCl(Ph3P)3

Scheme 43. An intramolecular "aryl-Heck" cyclization in the total synthesis of hippadine

Applications of Palladium Chemistry

485

One of the latest additions to the impressive repertoire of indole alkaloid total syntheses using intramolecular Heck strategy is the total synthesis of hippadine (18a) [109]. As depicted in Scheme 43, an intramolecular "aryl-Heck" cyclization of substrate 241 under normal Heck conditions gave the cyclized product 242, which was transformed into hippadine (18a) upon further manipulations. 5. TSUJI-TROST REACTION The Tsuji-Trost reaction is the Pd(0)-catalyzed allylation of nucleophiles [110]. Even though extensive applications of Tsuji-Trost reaction can be found in many areas, including heterocycles, applications to the indole field have been relatively rare. Nevertheless, several elegant total syntheses of indole alkaloids have used the Tsuji-Trost reaction as the key feature of the synthetic approaches to achieve great convergency.

?

AC

J! % ffS

f^. / Pd(Ph3P)4, Et3N CN 70 3 ' C,L5h (/ y—(

243

OCOtBu

\ , N

CH

244

i ^ c r t JI\

N H

OCOtBu

OCOtBu 245

246

Scheme 44. r|3-Allylpalladium intermediate in the synthesis of indole alkaloids In the total synthesis of desethylibogamine [88a], Trost and Gen6t transformed an allylacetate with a pendant secondary amine (243) into the desired isoquinuclidine 244 (Scheme 44). The cyclization took place via nucieophilic attack on a ft-allylpalladium intermediate by the secondary amine. An asymmetric version of the above transformation was accomplished by Trost, Godleski, and Genet [88b]. Such an operation involving the ft-allylpalladium intermediate appears to have proceeded with complete stereocontrol, since the ee (60%) remained constant throughout the transformation. Moreover, Trost, Godleski, and Belletire [88c] utilized the rc-allylpalladium method to achieve a formal synthesis of (±)-catharanthine. Under the same reaction conditions as

486

J J . Li

employed for the formation of 244, amino bis-pivalate 245 underwent a transformation sequence to isoquinuclidine 246 via formation of the r|3-allylpalladium intermediate and nucleophilic attack by the secondary amine (Scheme 44). Intermediate 246 was then manipulated to give (±)catharanthine. Many ergot alkaloids are important clinical agents for the treatment of hypertension, migraine attacks, Parkinson's disease, etc. Genet devised an efficient synthesis of ergoline precursors employing 7t-ally {palladium intermediate chemistry as the central step [111]. An ergoline synthon could be prepared from indole-4-carboxaldehyde (247) in six steps and 38-43% yield. The entire sequence proceeded without indole Af-protection. An asymmetric version was achieved by the addition of catalysts bearing different chiral ligands on the palladium [112]. The catalytic enantioselective carbocyclization via Tt-allylpalladium intermediates occurred with ee's ranging from 19% [(-)-CHIRAPHOS, THF, NaH at 65 °C] to 70% [R-CHIRAPHOS, DME, KF/alumina at 20 °C]. This methodology was used by Genet et al. in their asymmetric total synthesis of (-)chanoclavine (252) [113]. The Horner-Emmons olefination of indole-4-carboxaldehyde (247) with ethyl diethylphosphinoacetate, using potassium carbonate as the base, gave the a,f3unsaturated ester 248 with exclusive E geometry (Scheme 45). Reduction and acetylation of 248 produced allyl acetate 249. The installation of the nitroethyl side chain at C(3) could be accomplished by treatment of 249 with 1-dimethylamino-2-nitroethylene in the presence of TFA followed by sodium borohydride reduction to give nitroacetate 250. Alternatively, 250 could be synthesized via a classical three-carbon functionalization involving a Mannich condensation: treatment of 249 with di methyl ami ne/formaldehyde in acetic acid followed by treatment with methyl nitroacetate in refluxing toluene constructed 250 with concurrent decarbomethoxylation. The crucial intramolecular allylation was best achieved by employing Pd(OAc)2, and (£)-(-)BINAP in THF at room temperature, giving rise to 251 with up to 95% ee. The increase of diastereoselectivity and enantioselectivity using bidentate phosphine ligands, in comparison with other monodentate phosphine ligands, could be rationalized by the ligand pocket effect. With BINAP, the electrophilic rf-allylpalladium complex is a seven-membered ring. The steric effects cause an increase of the asymmetric induction during addition of the oc-anion to the nitro anion. With the tricyclic indole (251) in hand, straightforward transformations produced (-)chanoclavine (252) in 6 steps.

Applications of Palladium Chemistry

487

C0 2 Et 1. UAIH4, Et 2 0, 0°C,3h,9S%

CHO

60 N H

(EtO)2P(0)CH2C02Et K 2 C0 3 , THF, reflux, 24 h, 95%

N H 248

247

,OAc

»

2. Ac 2 0, Et3N, 0 °C, CH2C12 95%

1. Me2NCH=CHN02 TFA,CH2CI2,0°C 70%

,OAc

2. NaBH4, MeOH THF, 20 °C, 80%

Pd(OAc)2,3%, (S)-(-)-BINAP 6% 1

K 2 C0 3 , THF rt, 60%

6 steps 6% overall yield

Scheme 45. Asymmetric total synthesis of (-)-chanoclavine Godleski envisioned a unique way to assemble the D, E ring juncture of alloyohimbone (257) [114]. As summarized in Scheme 46, Diels-Alder adduct 253 was treated with tryptamine and the intermediate imine was reduced by NaBH, to give aminoallylic acetate 254. Acylation of the secondary amine on 254 provided the 7t-allylpalladium precursor 255. Anion formation with NaH and the subsequent reaction with Pd(diphos), gave 256 possessing exclusively the m-fused D, E-ring juncture. Notably, the Tsuji-Trost conditions afforded complete stereocontrol via the intermediacy of a n-allylpalladium complex. Desulfonylation of 256 using sodium amalgam in methanol in the presence of NaH,P04 (91%) followed by a Bischler-Napieralski reaction [POCI,, PhH, 80 °C, then CH,CI2. LiAl(OtBu),H, 72%] and an acid-facilitated hydrolysis (6 N HCI, CH,CN) of the vinyl sulfide provided alloyohimbone (257).

488

JJ . LI

9HO AcO^^*.

SPh 253

tryptamine, CH2C12, MgS0 4 , -23 °C, 11 h

^ \ — ^ ^ N

then, NaBH4, MeOH, -63°C,0.75h,85% 254

COCH2S02Tol, L A JJ°V ~~\^ :3N, -23X94% TJ^CO^

SPh

NaH, DME, 0 °C, then Pd(diphos)2, *• 85 °C, 10 min, 84%

SPh 255

O

j

J O ^ N.

N ^H w^ 1 v H ToI02S'

i. N a ( H g ) , 91 % K»H sph

2.BischIerNapieralski 84% 3.6 N HC1,64%

256 Scheme 46. Total synthesis of alloyohimbone The Tsuji-Trost reaction was also employed in the synthesis of a very intricate indole alkaloid, koumine (262). Koumine (262), possessing a particularly unique cage structure, is a principal Gelsemium alkaloid isolated from the Chinese toxic medicinal plant Hu-Mang-Teng. The Sakai group devised a biomimetic synthesis of koumine starting from naturally abundant 18hydroxygardnutine (258). Based on their successful partial synthesis of 11-methoxykoumine [115], 258 was transformed into 18-hydroxy-l 1-demethoxygardnerine (259) in 7 steps [116J. As shown in Scheme 47, treatment of 259 with methyl chloroformate resulted in carbamate 260 with concurrent C-N bond cleavage and C-O bond formation to install the tetrahydropyran ring. LiAIH4 reduction and acetylation furnished 18-O-acetyl-hydroxytaberpsychine analog (261). After generating the indole anion using NaH, the intramolecular Tsuji-Trost reaction of 261 was realized by the addition of Pd(OAc), and triphenylphosphine in DMF at 80-90 °C to tether C(7) and C(20), giving rise to koumine (262).

Applications of Palladium Chemistry

489

HO-

MeO

259

OH

2. LiAIH4, THF,

1. CIC02Me,

41%, 2 steps IF-H 20, THF-H rt, 2.5 h

H

3. Ac 2 0, pyr. rt, 1 h, 96% 260

Cud N H

, Me

NL

OH

NaH, D M F , rt, 10 min

then Pd(OAc)2, Ph3P » 90 °C, lh,80%

261 Scheme 47. Total synthesis of OAc koumine An ingenious extension of the Tsuji-Trost reaction was the cornerstone of Oppolzer's enantioselective synthesis of a heteroyohimbine alkaloid, (+)-3-isorauniticine (267) [117J. Substrate 263 was prepared from a commercially available glycinate equivalent by N-alkylation, installation of the sultam chiral auxiliary followed by a sultarn-directed C-alkylation. As illustrated in Scheme 48, the crucial double cyclization was accomplished by the treatment of 263 with Pd(dba)3, Bu,P, in the presence of carbon monoxide (1 atm) in acetic acid to give enone 264 and two other stereoisomers in a 67:22:11 ratio. In this case, an allyl carbonate, rather than an allyl acetate, was used as the allyl precursor. Since carbonate is an irreversible leaving group, formation of the 7C-allylpalladium complex occurs readily. In the presence of Pd(0), the allylic carbonate is converted into a rt-allylpalladium complex with concurrent release of CO, and

490

J JT. Li

Pd(dba)2,Bu3P,AcOH

p2 o

so2

Ar S02 -'-

O J1 ^ X*

CO,80°C,3h,45-53%

'

^H CH2

OC02Me 264

263 carbonylation, cyclization, & p-hydride elimination

oxidative addition

CSO

insertion

265

266

PdLn

Scheme 48. Enantioselective synthesis of (+)-3-isorauniticine alkoxide, which in turn serves as a base. Therefore, the allylation reaction can be conducted under neutral conditions without the addition of external bases. The transformation from 263 to 264 has been rationalized via the following mechanism: coordination of the K-allylpalladium complex with the pendant olefin to give 265 followed by an insertion reaction to provide 266. Subsequently, 266 underwent a carbonylation, a 5-exo Heck cyclization and finally P-hydride

Applications of Palladium Chemistry

491

elimination to furnish the desired exo-cnont 264. The natural product, (+)-3-isorauniticine (267), was obtained from 264 via several additional manipulations. 6. CARBON-NITROGEN BOND FORMATION In Section 5, the total syntheses of monoterpenoid alkaloids, alloyohimbone (257) and (+)3-isorauniticine (267) via palladium chemistry were reviewed. Two additional yohimbane alkaloids, 15,16,17,18,19,20-hexadehydroyohimbane and rutecarpine (273) were also synthesized using palladium chemistry. However, instead of the Tsuji-Trost reaction strategy as employed in the syntheses of 257 and 267, the syntheses of 15,16,17,18,19,20-hexadehydroyohimbane and rutecarpine (273) involved the formation of a carbon-nitrogen bond as the key feature. As illustrated in Scheme 49, the bromo-p-carboline substrate 268 was treated with Pd(OAc)2 and PPh, in the presence of /iBu3N under carbon monoxide atmosphere to assemble 21-oxoyohimbane 269. Subsequent reduction of 269 with LiAlH4 afforded 15,16,17,18,19,20hexadehydroyohimbane [118]. In the synthesis of rutecarpine (273) [119], N-carbomethoxy-oiodoaniline (271) and tryptamine (270) were allowed to react with carbon monoxide (1 atm) in the

Br

CSO Pd(OAc)2,Ph3P nBu3N, 100 °C, 76h,56%

268

Q O O N „ 2 • MK.!CNH.1 H

%J>

270

H »J T

HN

NW»^

K2CO3,120°C,77%

271

POCl3, CH2C12 • 60 °C, 3 h, 40%

272 Scheme 49. C-N bond formation with concurrent CO insertion

|

rutecarpine (273)

492

JJ.Li

presence of Pd(OAc)2, PPh3, and K^CO, as the base, to install quinazolinone derivative 272. Treatment of quinazolinone 272 with POC1, in dichloromethane at 60 °C for 3 hours furnished rutecarpine (273). As described in Section 4.1. (Scheme 29), in the frequently reviewed synthesis of Nacetyl-(±)-clavicipitic acid methyl ester (167) by Hegedus [80, 81], intramolecular aminopalladation of 164 was accomplished by a Pd(II)-catalyzed process to give the tricyclic azepinoindole 165. During the last few years, a novel Pd(0)-catalyzed method for C-N bond formation from amines and aryl halides has emerged largely due to contributions from the Buchwald and Hartwig groups [120, 121]. In one application, an intramolecular C-N bond linkage was realized using classic palladium catalysis condition in Buchwald's synthesis of tetrahydropyrroloquinoline

O

NMe2 NH2 Br

cAo^Me

3 steps

1. DCE, reflux

52%

2.EtOH,DCE, reflux, 83%

275

1

NHMe

"M

Me>.

10moI%Pd(Ph3P)4

t C02Me

Me

K 2 C0 3 , Et3N, tol, 200°C,81% 277

276

71 "Yt Me-N

1. BBr3 » 2. Mel 50%

CI

l

O L*NH7 111

MeO

dehydrobufotenine 1 (278) | Scheme SO. Synthesis of tetrahydropyrroloquinoline alkaloids

C02Me

Applications of Palladium Chemistry

493

alkaloids [122]. As shown in Scheme 50, tryptamine derivative 275 was prepared from 2-bromo4-methoxyaniline (274) using the intramolecular insertion reaction of zirconocene-stabilized benzyne complex [123]. Chemoselective demethylation of the tertiary amine was achieved by exposure of 275 to ACE-C1 (1-chloroethyl chloroformate) in DCE (dichloroethane) to provide secondary amine 276 while the methyl ether remained intact. Exposure of 276 to classic palladium catalysis conditions [Pd(OAc)2, I^CO,, Et,N, tol, 200 °C] led to the formation of tricyclic indole intermediate 277 in 81% yield. Buchwald's optimal intramolecular Pd-catalyzed aryl amination conditions [120, 124] were not compatible with this cyclization because the presence of NaO/Bu caused the cleavage of the carbamate, and none of the desired product was obtained. Finally, cleavage of the aryl methyl ether with concurrent removal of the carbamate using BBr3 followed by in situ quaternization by the addition of excess Mel and KHC03 produced the toad poison dehydrobufotenine (278) as its iodide salt. Using the same intramolecular C-N bond formation strategy as the crucial step, Buchwald also prepared tricyclic indole 279, a known intermediate in the total syntheses of makaluvamine C and damirones A and B.

^^N"^Br H 280 O

CH3I, reflux 70%

6H ° y ^ J V " 9

282 r*\ BOCNH/^° LiHMDS,SnCI4 -78°C,4h,57%

^ ^ N Br CH3 281

TFA/Me2S (1:3)

\ ^ x , A _ J„mn„ lh,rt,90% ? BrNHBOC CH3 283

O

^ ^ _ ^

a s

ILJCTX

O

X > ^dCdba^BINAP^ ^ Y ^ T ^ V ^

A 'BuONa,DMF,

N Br NH2 CH3 284

80°C,48h,51

«!VA A *k/° CH3 285

Scheme 51. Pd-catalyzed intramolecular C-N bond formation in a-carboline synthesis

494

JJ . LI

The Pd-catalyzcd C-N formation method developed by the Hartwig and Buchwald groups has also found applications to the synthesis of a-carboline 285, which contains the pyrido[2,36]indole skeleton of several naturally occurring alkaloids [125]. As illustrated in Scheme 51,2bromoindole-3-carboxaldehyde (280) was methylated to give 281. y-Lactone 282 was easily derived from 2[5//]-furanone in a two step sequence comprising a Michael addition of Nbenzylamine followed by a catalytic hydrogenation in the presence of di-ter/-butyl dicarbonate. The aldol condensation between 281 and 282 was conducted using lithium hexamethyldisilazide in the presence of stannic chloride to afford the aldol product 283 as a mixture of diastereomers. Simultaneous deprotection of the amino group and dehydration by treating 283 with trifluoroacetic acid and dimethyl sulfide gave the precursor 284. The intramolecular C-N bond formation was achieved by using Pd-catalyzed intramolecular C-N bond formation conditions [Pd(dba)3, sodium ferf-butoxide and BINAP] to assemble the desired a-carboline 285. 7. REPRESENTATIVE EXPERIMENTAL PROCEDURES 7.1. 2-Methyl-3,6-dimethoxycarbazoIe-l,4-quinone (37) [31J A solution of the benzo-1,4-quinone 36 (195 mg, 0.714 mmol), cupric acetate (324 mg, 1.78 mmol) and palladium(H) acetate (15.9 mg, 0.071 mmol) in glacial acetic acid (10 mL) was heated at reflux under air for 19 h. Silica gel (2 g) was added to the reaction mixture, the glacial acetic acid was evaporated in vacuum, and the resid»?e was purified by filtration over silica gel (EtOAcMeOH, 10:1). After removal of the solveiu, the residue was taken up in chloroform (5 mL), heated at reflux, and subsequently cooled to -30 °C. The resulting precipitate was isolated by filtration, washed with chloroform, and dried in a vacuum to afford the desired product 2-methyl3,6-dimethoxycarbazole-l,4-quinone (37) (142 mg, 73%) as a black-green solid.

OCH3

0.1 Pd(OAc)2, 2.5Cu(OAc)2

„ „3 "

AcOH, reflux, 19 h, 71-73%

c

O 36

Scheme 52. Catalytic oxidative cyclization using Pd(II)

Me

°

37

495

Applications of Palladium Chemistry 7.2. 2-[3-[l-(-/erf-Butyldimethylsilyl)indolyl]]-4,5-diiodo-l-[2-(trimethylsilyl)ethoxy-l//imidazole (56) [38]

A mixture of l-(-te^butyldimethylsilyl)indolyl-3-boronic acid (55, 0.5 mmol) and 2,4,5-triiodol-[[2-(trimethylsilyl)cthoxy]mcthyl]-l//-imidazole (54, 173 mg, 0.3 mmol), benzene (10 mL), methanol (2 mL), 2 M sodium carbonate (0.5 mL), and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) was refluxed for 8 h under N2 atmosphere. The reaction mixture was cooled to room temperature and anhydrous sodium sulfate was added. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude mixture. After purification by PTLC (AcOEt/w-hexane = 1/10), the product was recrystallized from EtOH-HaO to give 56 as colorless crystals (91 mg, 45%).

B(OH)2 "^

V

55 N SEM 54

TBS

Pd(Ph3P)4, Na 2 C0 3 ,45%

TBS 56

Scheme S3. The Suzuki coupling reaction in indole alkaloid synthesis 7.3.3-[l-[4-(l-Ethoxyethenyl)-2-nuoro-3-pyrldyl]ethyl]indole (114) [57] A mixture of (l-ethoxyvinyl)tributyltin (0.95 g, 3 mmol), bromide 113 (1.2 g. 3.3 mmol), and tetrakis(triphenylphospnine)palladium(0) (0.07 g, 0.06 mmol) in toluene (20 mL) was refluxed until precipitation of black palladium. Filtration and evaporation to dryness afforded a crude solid, which was crystallized from diethyl ether/hexane (1:1) to yield 95% of 114.

II

CH3 F EtO N Br H 113

SnBu3

catPd(Ph3P)4,95%

Scheme 54. The Stille reaction using (l-ethoxyvinyl)tributyltin

496

JJ.U

7.4. l-(te^.Butyldiinethylsilyl)-3-(2-pyridyl)indole (145a) [71] A solution of f-BuLi (1.7 M in pentane, 2.0 cquiv.) was slowly added to a 0.8 M solution of 3bromo-l-(terr-butyldimethylsilyl)indole (143) (2.0 g, 6.6 mmol) in anhydrous THF at -78 °C, and the resulting mixture was stirred for 10 min at this temperature. Then, a 0.3S M solution of ZnCl2 (1.1 equiv.) in THF was added to this solution, and the stirring was continued for 30 min at 25 °C to give 3-indolozinc 144. In a separates flask, a 0.54 M solution of 2-chloropyridine (141a) in anhydrous THF was added to 2 mol% of a catalyst prepared by reaction of a 0.014 M solution of Pd(Ph3P)2Cl2 in anhydrous THF with 2 equiv. of diisobutylaluminum hydride (1.0 M in hexane), and the mixture was stirred at 25 °C for 5 min. The resulting mixture was transferred via cannula to the solution of indolylzinc chloride 144 (1.5 equiv.) prepared as described above, and the solution was heated at reflux for 4 h, cooled and poured into saturated aqueous NajCO,. The aqueous phase was extracted with ether, and the organic extracts were dried and concentrated. The residue was chromatographed (CH2CI2) to afford 145a (1.1 g, 80%), along with l,T-bis(rer/butyldimethylsilyl)-3,3'-bisindole (200 mg, 13%), the homo-coupling product.

ca

B r

Z n C I

^ ^

1. /-BuLi, THF, -78 °C -»2. ZnCl2, THF, 25 °C

\ \ \

? Sif-BuMe2 144

Si/-BuMe2 143

TOPdCI2(Ph3P)2, DIBAL THF, reflux, 80%

if

OrO Me2*-BuSi 145a

Scheme 55. The Negishi reaction of 3-indolozinc with 2-chloropyridine 7.5.

4-(3-Methyl-2-buten-3-ol)-3-(2-acetylamido-2-carbomethoxyethen-l-yl)-l-tosylindole

(164) [80] A mixture of 3-[2-acetylamido-2-carbomethoxyethen-l-yl]-4-bromo-l-tosylindole (163) (0.219 g, 0.446 mmol), 2-methyl-3-buten-2-ol (0.171g, 2.0 mmol, 4.5 equiv.), palladium(II) acetate (0.008 g, 8 mol%), tri-0-tolylphosphine (0.027 g, 20 mol%), and triethylamine (0.068 g, 0.67 mmol, 1.5

Applications of Palladium Chemistry

497

equiv.) in 0.5 mL of acetonitrilc was heated at 100 °C in a sealed tube for 5 h. The mixture was cooled to room temperature, dissolved in 50 mL of dichloromethane, and filtered through Celite. The filtrate was evaporated under reduced pressure, leaving 0.36 g of a yellow oil which was purified by radial chromatography on silica gel. Hexane-ethyl acetate (1:1) eluted tri-otolylphosphine and Hexane-ethyl acetate (1:2) eluted the product. Evaporation of the solvent gave 0.184 g (83%) of 164 as a white solid. Recrystallization from hexane-ethyl acetate furnished the analytical sample.

AcHN^CC^Me ^

O

T

H

5% Pd(OAc)2/Et3N P(o-ToI)3/MeCN 83% 163

154

Scheme 56. Phosphine ligands can facilitate the Heck reaction of aryl bromides 7.6. The ferr-butyldimethylsilyl ether of isostrychnine (200) (92] A catalytic amount of Pd(OAc)2 (8.1 mg, 0.037 mmol) was added at room temperature to a mixture of vinyl iodide 199 (101 mg, 0.18 mmol), K^CO, (124 mg, 0.90 mmol) and n-Bu4NCl (75 mg, 0.27 mmol) in DMF (10 mL). The mixture was stirred at 70 °C for 3 h. The dark brown solution was cooled to room temperature, diluted with water, and extracted four times with ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (elution with 30% ethyl acetate in hexane) to afford the TBS ether of isostrychnine 200 as a colorless oil (60 mg, 74% yield).

OTBS 0.3 eq. Pd(OAc)2 >, Bu 4 NCl,DMF,K 2 C0 3 70°C,3h,74% OTBS 199 Scheme 57. Intramolecular Heck cyclization in Rawal's strychnine synthesis

200

498

JJ. Li

7.7. (4J?^J7)-4-Nitro-5-vinyl-l>39495-tetrahydrobenz[c>if]indole (251) [113] A mixture of K^CO, (9.58 g, 69.4 mmol)f Pd(OAc)2 (0.187 g, 0.83 mmol) and (5)-(-)-BINAP (1.048 g, 1.66 mmol) in dry THF (30 mL) was stirred at room temperature under argon. The mixture turned from light orange to dark red. A solution of (£)-3-[(2-nitroethyl)-4-indolyl]propenyl acetate 250 (8 g, 27.7 mmol) in dry THF (60 mL) was added dropwise, then stirred for 6 h. The reaction was filtered through silica gel, and the crude residue was washed with THF. The solvent was removed under reduced pressure. Flash chromatography (AcOEt/cyclohexane:l/9) yielded the titled product 251 as a white solid (3.6 g, 57%).

.OAc

N0 2

N02

Pd(OAc)2,3%, (5)-(-)-BIBAP,6% 1

K 2 C0 3 , THF rt,57% 250 Scheme 58. The Tsuji-Trost reaction in the synthesis of (-)-chanoclavine 7.8.

l-Carbomethoxy-5-methoxy-5-methyl-l,3,4,5-tetrahydropyrrolo[4,3,2-Je]quinoline

(277)[122J

To a mixture of 5-methoxy-4-iodo-3-(2-methylamino-ethyl)-l-carboethoxy-indole (276) (0.32 g, 0.80 mmol), Et,N (4 mL), and K^CO, (0.33 g, 2.4 mmol) in toluene (10 mL) was added Pd(Ph,P)4. The yellow mixture was heated to 200 °C for 15 h, cooled to room temperature, and poured into a separatory funnel containing Et^O (15 mL) and water (15 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over MgS04, and filtered, and the solvents were removed using a rotary evaporator. The product was purified by flash chromatography (4:1 hexane/ethyl acetate) to give the desired product 277 as a white powder (0.18 g, 82% yield).

NHMe

Me. 10mol%Pd(Ph3P)4

MeQ

K2C03,Et3N,tol, 200°C,81% 276 Scheme 59. Pd(0)-catalyzed intramolecular C-N bond formation

277

Applications of Palladium Chemistry

8.

499

CONCLUDING REMARKS

The maturation of palladium chemistry in organic synthesis has resulted in many applications to the total syntheses of naturally occurring indole alkaloids. Oxidative cyclization using Pd(II) is an efficient strategy for intramolecular aryl-aryl coupling. The development of processes to reoxidize Pd(0) to Pd(II) by using Cu(II) species, peroxides, and other oxidants, enables this transformation to be conducted with economy using catalytic palladium as manifested in Knttlker's synthesis of carbamycins. The Suzuki and the Stille reactions, in turn, are the two most popular methods for palladium-promoted coupling in indole alkaloid synthesis. Since the Suzuki reaction requires basic conditions to enable the transmetallation step, the Stille reaction is the method of choice for base sensitive substrates. Negishi's conditions can be applied to otherwise difficult substrates such as arylchlorides. On many occasions, the organozinc reagents react chemoselectively in the presence of organoboronic acids, providing a handle for further manipulations of the reaction products. However, due to the demanding reaction conditions to prepare organozinc reagents, limited success has been achieved in the application to indole alkaloid synthesis. Even though only limited applications of the intermolecular Heck reaction have been found in indole alkaloid synthesis, the intramolecular Heck reaction is a versatile strategy for C-C bond formation. The recipients for migratory insertion can be a double bond, a dicne, or an aromatic ring. The reaction generally proceeds with high regioselectivity. High stereoselectivities were also obtained when the substrates possess steric bias, as manifested in Rawal's strychnine synthesis. Quaternary carbon centers can be constructed via intramolecular Heck reactions, sometimes asymmetrically by using appropriate substrates or chiral ligands. In the total synthesis of naturally occurring indole alkaloids, applications of ft-allylpalladium intermediate and C-N bond formation are developing areas [126]. With the advent of new methodologies in these fields, especially with the successes of the Buchwald and Hart wig's chemistry, more syntheses using those strategies are to be expected. ACKNOWLEDGMENTS The author is indebted to Drs. Martin A. Berliner, Michael D. Kaufman, and Jessica E. Reed for proofreading the manuscript. Helpful comments and suggestions from Profs. Louis S. Hegedus, Viresh H. Rawal and Christian M. Rojas are greatly appreciated. 9. REFERENCES: 1.

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Subject Index

Note: Bold page numbers refer to illustrations, There are often textual references on the same pages. Acetoxyindolenine 330 (-)-N-Acetylanonaine 413 N-Acetyl-(±)-clavicipitic acid methyl ester 472,492,470 (-)-0-Acetyl-16-epi-affinisine 409 l-(A^Acetyl-A^methylamino)ethyl-3,4, 6trimethoxy-7-hydroxyphenanthrene 318319,413 (-)-N-Acetylnornuciferine 412 0-Acetyl yohimbine 340,398 Acrylic ester moiety 366 (-)-Acutumidine 323 (-)-Acutumine 323 W-Acylindoline 442,479 Acyloin rearrangement 374 (+)-Affinisine 343,344,399,410 Affinisine, C(16) epimer 343,344 Affinisine, M-oxide derivative 343,344 African medicinal plant 473 Aglaforbesin A, B 393,395 AglainA,B,C 393,394 Ajmaline-sarpagine 340 Akuammicine 342, 348 (-)-Akuammicine 399-400 Akuammicine-picrinine-type alkaloids 347 Akuammiline 329,345 (+)-Akuammiline 404,407 (-)-Akuammiline N(4)-oxide 404 Akuammiline, N-oxide 368 Aldol condensation 494 Alkyl and hydride shifts 423 10-Alkylmehranine moiety 387 Alloyohimbine 338,487,488,491 (-)-Alloyohimbine 415

r| -Allylpalladium intermediate 485 (+)-Alstocraline 381,382,399 Alstogustine 341,342 (+)-Alstonal 342,343,400 (-)-Alstonerinal 400,420,421 (-)-Alstonerine 340, 399-400,417,420,421 (+)-Alstonisine 342,343,399-400 (-)-Alstophylline 340-341,342,343, 399400,417 Ambrimine 4, 69,94, 116, 146, 150,181 6-Amino-5, 8-dimethyl-7phenylisoquinoline 447 Aminoglycosteroid 324,417 (+)-3ot-Amino-14p-hydroxypregnan-20one 324,325,401 Aminopregnanes 324-325 Amoebic dysentery 416-417 Ancistrocladine 316,317 Ancistrotectorine 316,317 Angchibangkine 4, 75,97,123, 134, 164, 269,270 (+)-Angusticraline 381,399 (+)-Angustimaline 393,394,399 Angustine 463,462 Anhydrolycorin-7-one 457,479 (-)-Anhydrovobasindiol 411 6-Anilino-5, 8-dimethylisoquinoline 438 P-Anilinoacrylate chromophores 384 3-Anilinoquinoline 440 Annomontine 458,467,459 Annonidine 473,472 (-)-Anolobine 413 (-)-Anonaine 395-398

506 Antiamoebic and antiplasmodial activities 341 Antibiotic 453 Antifungal activities 450 Anti-implantation activity 451 Antimalarial agent 439 Antimicrobial properties 457 Antioquine 4,67,99,114,139,151,188 Antioxidant properties 460 (-)-Antirhine 399,410 Antitubulin activity 424 Antitumour agents 426 Antiviral properties 457 Apateline 5,65,77-78,91,93,97,113,118, 123,128,133,163,262,263,267 (+)-Apateline 323,413 Apogeissoschizine skeleton 478 Aporphine alkaloid 316,321,323 Aporphine-derived phenanthrenoid 319 Apparicine 358 (-)-Apparicine 409-411 Aquifoline 5,69,95, 116, 136, 154,215 Arbutin 418 Arcyriacyanin A 450,451,479 Arcyriaflavins 443 Arcyriarubin A 442-443 Aristolactams 316,320 Aromoline 77-85,91-93,95,99,100-102, 104, 106-110, 112-113, 115-116, 118, 124, 125,128-130,136,152,166-167,197, 198,201 Artavenustine 318-319 (-)-Artavenustine 396 Artifact (No. 16) 6,65 Aryl radical, intramolecular cyclization 332 W-Arylenamine chromophore 355 (-VAsimilobine 320,396-397,413 (-)-Aspidodasycarpine 407 Aspidofractinines 345, 360,362-363, 365366,368,370,426 Aspidofractinine-aspidofractinine alkaloid, 356,390 Aspidosperma alkaloid 347,356, 384 Aspidospermatan skeleton 422-423,467 Atheroline 398

Atherospermidine 395-396 Atherospermoline 6,59,79,97,123,128, 136,155,211 Atropine 418 Atropisomer hamatine 316 Aurantioclavine 446,447 Auroramine 6, 75,93,116,145,152,192 Australian plant 348 £-azaeburnane series 479 Azafluorenes 316,320 Azepinoindole 471-472,492 Bl 6 melanoma 418 Baiuchistanamine 6,69, 80,115, 144,152, 194 Baluchistine 6,65, 80,115,136,152,197, 198 Barton radical method 335 Bauerine B 453,454 Belarine 6,61, 82-83,115,139,157,229 Benzoxepine-odorine type skeleton 394 3-Benzoylindole 438 Benzylisoquinoline 266 Benzyltetrahydroisoquinolinebenzyldihydroisoquinoline dimers 240 Benzyltetrahydroisoquinolinebenzylisoquinoline 218,233,240 Benzyltetrahydroisoquinoline precursor 320,321 Berbacolorflammine 99,124,138,154,205, 206 Berbamine 6, 59,79-85,89-90,94-96,99103,106,108,115-116,122-125, 128, 130,139,154,215,217 Berbamunine 8, 56, 79-85,99,102, 114115,125,138,148,174 Berberine alkaloid 316 Berbilaurine 9,69, 82, 115, 137, 158,234 (+)-Bhesine 335,412 Bisaporphine 319 Bisbenzylisoquinolines 316,323 Bisbenzyltetrahydroisoquinolines 240,258 Bischler-Napieralski reaction 487 Bisindole 359,443,451 Bisindole alkaloids 463

507 2,4-BisindolyIimidazole skeleton 450 Bisindolylmaleimides 443 N, JV-Bisnoraromoline 9,57,78,97,100, 118,123-124, 134, 152, 197,198 (+)-Bisnoraromoline 323 2,2'-Bisnorguattaguianine 9,69,93,113, 137,151,186,187 Bisnorobamegine 9, 70, 100, 125,134, 154, 214,215 2,2'-Bisnorphaeanthine 9, 70, 78,118,137, 154,208,209 (-)-2,2,-Bisnorphaeanthine 322, 323 Bisnorthalrugosine 9, 70, 100, 125,135, 154,214,215 Bistabersonine alkaloid 390 Blue green alga 453 Boldine 321 (+)-Boldine 398,412 Bradycardia 417 Brederecks reagent 458 Buchtienine 367, 368,417 (-)-Buchtienine 403 (-)-Cabucraline 382,383, 399 Calafatimine 9, 65, 80,115,143,156,224 Calafatinc 9,65, 80, 82,115,145,156, 225, 226 Calicanthine 335 Callophylline 337,415,379-380 Callopylline A 337 (-)-Calycanthine 336,414 Calycosidine 336 (-)-Calycosidine 414 Candicusine 9, 70, 89,121,137,152,195, 196 Cantleyine 348 (-)-Cantleyine 400 Carazostatin 461 Carbazole 438-439,445 Carbazole alkaloid synthesis 457,460 Carbazolequinone alkaloids 444,445 Carbazomycins 445,446 Carbazoquinocins A-F 460 Carbazoquinocin C 445,460,461,463 Carbazostatin 460,463

a-Carboline 493,494 P-Carboline 330,368,453,463,474 W-Carbomethoxy-11,12-dimethoxy kopsinaline 366,367 (+)-W-Carbomethoxy-5,22-dioxo kopsine 402 (-)-W-Carbomethoxy-17p-hydroxy kopsinine 365,402 (-)-AT-Carbomethoxy-l 7p-hydroxy-A14',5kopsinine 365,402 Af-Carbomethoxy-1 1-hydroxy-12-methoxy kopsinaline 366,367 Carbon-nitrogen bond formation 491,498 Carboxylic acid removal 335 Cardiotonic activity 445 (±)-Carquinostatin A 445 Caryolivine 9, 70, 85,119,136, 154,205, 206 Catalytic oxidative cyclization using Palladium(II) 494 Catecholic berberine 319 Cathafoline 343 (-)-Cathafoline 399-400 Cathafoline, W-oxide 343 (±)-Catharanthine 485-486 Cepharanoline 10, 57, 100-101,125, 136, 152,199 Cepharanthine 10, 57,100-103, 125,138, 152,199-200 Cerebral malaria 416 (-)-Chanoclavine 486,487 Chenabine 10,69, 83, 115,142,154, 207, 208 Cheratamine 10,67, 88, 120,138, 154, 206, 208 Chillanamine 10,67, 80,115,143,149 (+)-Chimonanthine 335,414 Chippiine 421,422 Chiral auxiliary 335 1-Chloro-P-carboline 449 Ar-2'-Chloromethylisotetrandrine 95 Chloroquine 417 Chondocurarine 10,63, 86,120,143,160, 247

508 Chondocurinc 10,63, 86, 89,91,120,122, 137,160,246,247,249 (R, 5>Chondrocurine 98 Chondrofoline 10,63, 86, 112, 114,120, 139,160,246 (-)-Chondrofoline 87,112 Cissampareine 10,63,87, 120,138,162, 167,256 Cissampentin 11, 75, 86,120,139,162, 258,259 (±)-Clavicipitic acid 446,470-471,472 Cleistopholine 397 (+)-Clolimalongine 323,324,413 (-)-Coclaurinc 398 Coclobine 11, 57, 78, 89,93,113,119-120, 138,152,194 Cocsiline 11, 75, 88, 120, 135, 164,268, 269 Cocsilinine 11, 75, 88,120,133,164,268, 269 Cocsolinc 11,64,78, 87-88,104,118-120, 127,133,163,263,264 (+)-Cocsoline 323,413 Cocsoline-2'p-Ar-Oxide 11, 75, 78,119,134, 163,263,265 Cocsuline (Efirine, Trigilletine) 11,64, 78, 88,97,104,111-112,116,118,121,124, 127-128,134,163,166 Cocsuline (#-methylcocsoline) 263,264 (+)-CocsuIine 323,413 Cocsuline-W-2-Oxide 11,67, 87,121,135, 163,263,265 Cocsulinine 11,64, 88,121,135,164,269 Colorflamminc 99,125,138,151,191 Columbian dart frog 336 Condylocarpine 345,346 (-)-Conodiparinc A, B, C, D 408,425,426 (-)-Conofolinc 384, 385,386-387,418,409 Conophyllidinc 384,385,386,409 (-)-Conophyllinc 385,409,418 Cordobiminc 12, 70,89,112,136,150,184 Cordobinc 12,70, 89,112,139,150,187 Coronaridine 355-356,356 (-)-Coronaridinc 410-411

(-)-Coronaridinehydroxyindolenine 411412 (-)-Coronaridine pseudoindoxyl 410 Coronaridine-type alkaloid 343 (-)-Corydalminc 397 Corynantheidinaline 338,339,340,414 Corynantheidinalinic acid 338,339-340, 414 Corynantheine alkaloids 366 Corynoxeine 338 (-)-Corynoxcine 415 (+)-Corytuberine 397 Costaricine 12, 75,97,117,135, 147,171 Criophyllinc 385 Cryptosanguinoline 454,455 Cultithalminine 12,70,104,130,139,158, 237 Curacautine 12,69, 80, 115,147, 156,224, 225 Curicycleatjenine 12, 75, 89, 122, 143, 160, 248 Curicycleatjinc 12, 75, 89, 122, 141, 160, 248 Curine 90,94,113,122, (+)-Curine 12,63,77, 85-86,97,116-118, 120,127,137,160,246 (-)-Curine 12,63, 79, 86-87,90-91,94,98, 101,112-114,120,122,124-125,137, 160,244,245,249 (R, £)-Curine 98 (±)-Curine dimethiodide 87 Cuspidaline 13, 56,94-95,123,140,147, 170 (-)-Cuspidaline 413 Cyano-substituent 368 Cycleabarbatine 13,75,90,122,139,155, 215 Cyclcacurine 13,63,91,122,135,160,244, 245 Cycleadrine [(±) - fangchinoline] 13, 59, 90-91,122,139,155,206,218 Cyclcahomine 13, 59,91,122,144,155, 211,212 Cyclcanconinc 13,70,91,122,142,256, 258

509 (-)-Cycleaneonine 13, 75,87,91,112,122, 142,162,257,258 (+)-Cycleaneonine 162 Cycleanine 13, 62, 86-87,90-91,93-95,98, 100-104,113,120,122-125,127,132, 142,159,242 Cycleanorine 14, 59,90-91,122,139,155 Cycleapeltine 89-91,122,132,139,153, 166,200 Cycleatjeheninc 14,75, 89,122,138,162, 258,259 Cyclcatjehine 14,75, 89,122,136,162, 258,259 Cyclization, aryne-mediated 458 Cyclization, Stille 458 Cyclopentatetrahydrobcnzopyran-odorine type structure 393 Cyclopropyl unit 377 D-Cymaropyranose sugar unit 324 Cytotoxic activity 326,417-418,426,450, 453, 457 Damirones A and B 493 (-)-Danuphylline 402,419,424,425 Daphnandrine 14,58,78,90,92-93,97, 101-102, 113, 118-119, 122, 124, 126, 128-129,137,152,197,198 (+)-Daphnandrine 413 Daphnine 15,66,91-92, 129, 141, 157,226 Daphnoline 15, 58, 78, 88-89, 91-93,97, 99-100, 113, 118, 121, 124-125, 128-129, 135,152,197,198 (+)-Daphnoline 323,413 (+)-Dapnandrine 323 Dascarpidol 467 Dasymachaline 316,317 (-)-Dasymachaline 396 (+)-Dasyrachine 402 Dasyrachine 423,424 Dauriciline 15, 75,96, 123, 138,147,170 Dauricine 15, 56, 85,96,98,112,114,123, 143, 147,169 Dauricinoline 15, 56,96,123,140,147,170 Dauricoline 15, 56,96,98,114,123,138, 147,170

Daurinoline 15, 56, 96,123,140,147,170 Daurisoline 16,66, 77,96,98,113,118, 123, 140, 147,170 (+)-Deacetylakuammiline 329,345,346, 367,403,404,407 (+)-Decarbomethoxykopsifine 402,423, 424 (-)-16-Decarbomethoxyvoacamine 410 (-)-16-Decarbomethoxyvoacaminepseudoindoxyl 383,384,409 Dehatridine 16, 70, 92,117, 134,154, 166, 206,207 Dehatrine 16, 70, 79,92, 117, 138, 153,204 19, 20-Dehydro-O-acetyl yohimbine 340, 399 1, 2-Dehydroapateline 16,66, 78, 88, 91-93, 97,102, 113, 119, 121, 124, 126, 129, 133, 163,260,261 (+)-Dehydrobhesine 335,412 Dehydrobufotenine 492,493 Dehydrocorydalmine 397 16, 17-Dehydroeburnamine compounds 355 (+)-Dehydro-16-epi-affinisine 343-344, 345,409 19,20-Dehydroervatamine 348,349 (+)-19,20-Dehydroervatamine 408,410 1,2-Dehydrokohatamine 16, 70, 87, 121, 134,164,266,267 1,2-Dehydrokohatine 4, 16, 70, 87, 121, 134,164,266,267 14, 15-Dehydrokopsijasminilam 374,375 (-)-19, 20-Dehydro-10-methoxy talcarpine 341,342,399 1, 2-Dehydromicranthine 16,64, 92,129, 133,162,260 3-Dehydromitragynine 338,339,414 1,2-Dehydro-2-norlimacusine 16, 70, 85, 119,136,152,192,193 1,2-Dehydro-2'-nortelobine 16, 70, 87,121, 133,163,260,261 Dehydropleiocarpine-type alkaloids 366 1,2-Dehydrotelobine 16,66, 78,91,93,97, 101,113,118-119,124, 126, 129,133, 163,260,261 (±)-Dehydrotubifoline 475

510 (-)-19,20-Dchydro-P-yohimbinc 409 Demerarine 17, 58,96,117,137,153,200 10,11-Demethoxychippiine 421 10-Demethoxykopsidasinine 368 12-Demethoxykopsingine (kopsaporine) 361,362 12-Demethoxythalidasine (Thalfoetidine) 230,231 7,12-Demethoxythalidasine (Thaligosidine) 230,231 N(b)-Demethylalstogustine 342 (+)-N(b)-Demethylalstophyllal oxindole 342,343,400 N(4)-Demethylalstophylline oxindole 343 (+)-N(b)-Demethylalstophylline oxindole 342,343,400 (+)-4,-0-Demethylancistrocladine 316,317, 395 12-0-Demethylcoclobine 17, 70,93,113, 136,152,194 7-ODemethylcycleanine [(+)Norcycleanine] 242,243 (-)-lO-0-Demethyldiscretine 396 12-Demethyldryadine (Dryadodaphnine) 235 (+)-W-Demethylholacurtine 324,325,400, 417 7-0-Demethylisothalicberine 17,66, 80, 82, 115,137,157,229 N-Demethylmenisarine 268 12-Demethyl-O-methylthalmine (Thalictine) 235 (-)-Demethylnorpleiomutine 387,388,401, 405 7-0-Demethylpeinamine 17, 59,77,118, 135,155,212,217,218 7-Demethyltenuipine (Nortenuipine) 224 7-Demethylthalidasine (Thalrugosidine) 230,231 5'-Demethylthalfinine (Thalmirabine) 232, 233 12-Demethylthalmiculimine (Cultithalminine) 236,237 6-Demethylthalmiculine (5-Hydroxythalmine) 237

12-Demethylthalmine (Thalabadensine) 235,236 12-aDemethyltrilobine 17,64,78, 88,119, 163,166 12'-0-Demethyltrilobine 264 4-Deoxy-4-amino-P-D-cymaropyranosc 324 Deoxykopsijasminilam 374,375 7-Deoxyprekinamycin 444,445 Depressor response 417,418 16-Descarbomethoxytacamines 421 Desethylibogamine 474,485 12-O-Desmethyllauberine 17, 70, 80,115, 137,158,234 Af-Desmethylcycleanine 17,67,101-102, 126,139,159,242 N'-Desmethyldauricine 17, 56,96,123,140, 148,171 (-)-N(l)-Desmethylquaternine 399 Ar-Desmethylthalidasine 17,66,230 A^-Desmethylthalidezine 17, 60, 108, 130, 142,156,220,221 Ar-Desmethylthalistyline 17, 56, 104, 107108,130,147,149,178,179 AT-Desmethylthalrugosidine 18,66,104, 130,142,157,230 Diastereoselective oxidationrearrangement 334 Diastolic pressures 417 Diazaspiroleuconolam compound 357,358 (+)-Dicentrine 412-413 Dicentrinone 396 Dictamine 415-416 DidemnimideC 463 Didesmethyl-rocaglamide 418 Diformylrhazinilam derivative 424 3,4-Dihydrobenzylisoquinoline 206,266 (+)-Dihydrocorynantheine 337,415,417 Dihydroeburnamenine 355 Dihydroeburnane alkaloids 354 (+)-19', 20'-Dihydro-16-decarbomethoxyvoacamine 410 3,14-Dihydroellipticinc 410-411 Dihydrohippadine 442 Dihydroindole 390 3,4-Dihydroisoquinolines 191,259

511 19,20-Dihydroisositsirikine 410 14, 15-Dihydrokopsingine derivative 417 Dihydrokopsingine 371,372 3,4-Dihydro-5-methoxy-2,2-dimethyl-2Hpyrano-[2, 3-b]-quinoline 416 (-H4, 15-Dihydro-10-methoxy kopsinone 365,366,402 5,21-Dihydrorhazinilam 357,406,408 Dihydrosecocepharanthine 18,69, 103,126, 144,152,195 3', 4'-Dihydrostephasubine 18,70,102,126, 136,151,191 (+)-4\ 17,(17p)-Dihydro tchibangensine 410 Dihydrothalictrinine 18,66, 109,130,146, 159,239 3,4-Dihydro-5, 8, 9-trimethoxy-2, 2dimethyl-2H-pyrano[2, 3-b]-quinoline 416 16, 17-Dihydrouleine 467 Dihydrowarifteine 18,63, 86, 120, 137, 162,257 Dimeric alkaloid 352, 384-385, 387, 390 Dimeric indoles 377 6, 8-Dimethoxy-l, 3-dimethyl isoquinoline 316,317,395 (S)-6, 8-Dimethoxy-l, 3-dimethyl-3,4dihydroisoquinoline 316,317,395 6, 8-Dimethoxy-3-hydroxymethyl-l -methyl isoquinoline 316,317, 395 8, 10-Dimethoxyellipticine 439 N, Af-Dimethyl-(±)-curine 87 O, O-Dimethylcocsulinine 88, 121 O, O-Dimethylcurine 18,63,90,93, 113, 122,139,160,244,245 N, N-Dimethylcurine iodide 87 Dimethyldihydrowarifteine 18,63, 86,120, 142,162,257 O, 0»-Dimethylgrisabine 18, 75,98,124, 145,148,174,175 Nt A^-Dimethyllindoldhamine (Guattegaumerine) 18,68,77,84,86,93, 98,113,118,166,170 Nt O-Dimethylmicranthine 18,64,92,129, 135,163,262

Dimethylwarifteine 18,64, 86,120,141, 162,256 Dinklacorine 19,62,110-111,127,135, 161,253 Dinklageine 19,101,126,137,165 Dioxoaporphine 316 5, 22-Dioxokopsane 329, 361 (+)-5,22-Dioxokopsane 404 Diphenylamine 438 1, 3-Dipolar cycloaddition reaction 335 (+)-Dippinine A, C 408,421,422 Dirosine 19, 57, 96, 117,140,151,189 Discorhabdins 483 Discorhabdin C, E 483,484 (-)-Discretamine 396-398 Domino Heck cyclization 479 DragendorfF or Mayer reagents 287 Dregamine 329 (-VDregamine 404,410-411 Dryadine 19,61,93, 129, 139, 158,235 Dryadodaphnine 19, 61, 93, 129,137, 158, 235 Dysentery, treatment of 324 (+)-Eburnamenine 350,351,404 (-)-Eburnamenine 351 Ebumamine 350, 352, 358,421 (-)-Eburnamine 350,351,352, 367,403405, 407-408 (+)-Eburnamine 351 Eburnaminol 352,350,353-354 (±)-Eburnaminol 352 (-)-Eburnaminol 404,407 (+)-Eburnamonine 351,352, 367,401,403405 (-)-Eburnamonine 351 (+)-Ebumamonine, isomer 350 (+)-Eburnamonine-^-oxidc 350 (+)-Eburnamonine N(4)-oxide 404 Eburnane 388 Eburnane alkaloids 350, 355, 367 Echitamidine 348 (-)-Echitamidine 400 Echitamine 348 (-)-Echitamine 400

512 Efatinc 19, 70,94,116, 146, 150,181 Efirine 166 Eglandine 355 (-)-Eglandine 411 (-)-Eglandulosine 411 Electrochemically-mediated semisynthesis 425 p-Elimination and reduction 321 Ellipticine 348,438,440,447-448,453 Emetine 417 Enantiomeric group elaboration of 355 Enterocarpam-I 319-320,397 Enterocarpam-I acetate 319-320,397 Enterocarpam-II 319-320,397 Enterocarpam-II acetate 319-320,397 (-)-(E)-16-Epi-affinisine 409 16-Epi-affinisine, 0-acetyl derivative 343, 344 19-Epialstogustine 341,342 16-Epi-deacetylakuammiline 345,346,367 (+)-16-Epi-Deacetylakuammiline 403,407 (-)-16-Epi-Deacetylakuammiline-Noxide 368,403 (-)-17-Epi-Af-Demethylholacurtinc 324,325, 400 16-Epieburnaminol 352,353 (-)-20-Epi-19e-cchitamidine 348,400 (-)-20-Epiervatamine 410 (-)-19-Epiheyneanine 411 Epikopsanol-10-lactam 361 20-Epi-ervatamine 348,349 19-Epi-heyneanine 355,356 (-)-17-Epi-holacurtine 324,325,400,417 (-)-16-Epi-17-a-hydroxy-AM*l5kopsinine 407 (-)-(E)-16-Epi-isositsirikine 409 (+)-Epilapidilectinol 376,404 (+)-Epileuconolam 357, 358, 408 16-Epi-methuenine 348,349 5-Epi-nareline ethyl ether 345,346 (-)-5-Epi-Nareline ethyl ether 400 (+)-(E)-16-Epi-Normacusine B 409 (-)-16-Epimethuenine 410 Epinorhernandezine 19,144,222

Epinorthalibrunine 19,145,159 Epistephanine 102 (+)-Epistephanine 19,58,100-102,126, 138, 151,193 (-)-Epistephanine 19, 58, 78,119,138,152, 191 (+)-16-Epivobasenal 343,344,411 (-)-16-Epivobasine 411 (-)-19-Epi-voacristine 409 3-Epi-p-yohimbine 337,338, 340, 379,415 (+)-14,15-P-Epoxykopsingine 362,363, 407 Equilibrating rotamers 390 Ergoline alkaloid 468 Ergoline precursors 486 Ergot alkaloids 470 Ervatamine 348,349 Ervatamine alkaloids 348 Espinidine 19, 56, 83,115, 140, 148,174 Espinine 20, 56, 80, 83, 115, 138, 148,174 2-Ethyl-p-carboline 453 Ethyl glycine hydro-chloride 331, 332 (-)-O-Ethyleburnamine 350,351,404 (+)-0-Ethyleburnamine 351 (+)-0-Ethylisoeburnamine 351 (-)-O-Ethylisoeburnamine 351 Eudistomin T 453,454 EudistominU 467,468 Evellerine 416 Evolitrine 416 £ro-2-oxazolidinone dienes 439 5-Exo to 6-endo cyclization 332 n-Facial diastereoselectivity 335 Fangchinoline 20, 59, 91-92, 97, 101, 103104, 112, 124, 126-129, 139, 155,206,211 (±)-Fangchinoline 90,122 Fangchinoline isomer 218 Fangchinoline-2,a-iV-Oxide (see Fenfangjine B) Fangchinoline-2'p-Ar-Oxide (see Fenfangjine C) Faralaotrine 166 Fascaplysin 453

513 Fenfangjine A (tetrandrine-2P-JV-Oxide) 20, 70,103,126,144,155,211,213 Fenfangjine B (Fangchinoline-2'a-AfOxide) 20, 70, 103, 126, 142,155,211, 214 Fenfangjine C (Fangchinoline-2'p-NOxide) 20, 71, 103,126,142,155, 211, 214 Fenfangjine D (1, 3, 4Tridehydrofangchinolinium Hydroxide) 20, 103,126, 142, 154,206, 207 Fluorocarpamine 399 l-Fluoroellipticine 453,460 Foliacraline 381,382 (+)-Foliacraline 399 ForbaglinA 393-394,395 ForbaglinB 394,395 Formaldehyde 333, 335 5-Formyl derivative of rhazinilam 423 (-)-M-Formyl-O-methylancistrocladine 316, 317 Formylrhazinilam derivative 424 N-2-Formylthalrugosidine (Thaipindione) 230,231 Friedlaender quinoline synthesis 458 (+)-Fruticosamine 360,361,403 (-)-Fruticosine 360,361,369,403 Funiferine 20, 57, 93, 110, 113, 127, 142, 151,188-189 Gambireine 337,415 Gambirine 337,338-339,379-380,417 (+)-Gambirine 415 Gauttegaumerine 170 (±)-Geissoschizal 477,478 (±)-Gelsemine 480-482,483 Gelsemium alkaloid 488 Geraidoamine 21, 71, 79, 114,141, 148, 171 Gilgitine 21,69,83,115,141,163,261 Gilletine 21,66, 111,128,135,164,268, 270,269 Glycinate 489 P-Glycoprotein 426

Glycozolidine 457,458 Glycozolinine 457 Granjine 21, 71, 89,113, 144, 150,187 Grisabine 21, 56, 77,93,100,116, 118, 125,141,148,174,175 Grisabutine 175 Guattamine 21, 71, 93, 113,139,150,185 Guattaminone 21,71,93, 113, 141, 150, 185 Guattegaumerine (see N, W-Dimethyl lindoldhamine) 86,93,113, 166 Gyroamericine 21, 71,93, 116, 139, 154, 208,209 Gyrocarpine 21,71,93-94,116, 139, 153, 201 Gyrocarpusine 21, 71,94, 116, 139, 152, 195,196 Gyrolidine 21, 71, 94, 116, 142, 153,201 Hallucinogen 470 Hamatine 316,317 Harman 453,463 Harmane 330,403,414,417 Harmicine (2, 3, 5, 6, 11, 11 p-hexahydrolH-indolizino[8, 7-b] indole) 330,366 (+)-Harmicine 403 Hasubanan alkaloids 323 Hayatidine 21, 63, 87, 120, 139, 160, 248 Hayatine 22,63, 87,90, 120, 122, 137, 160, 249 Hayatinine 22, 63, 87, 120, 139, 160, 250 Heck cyclization in indole alkaloid synthesis 477 Heck cyclization reactions, 1-exo and 8endo 475 Heck cyclization, Intramolecular 497 Heck olefination 446 Heck reaction 469,472,497 Hemiketaiization 382 Heptacyclic alkaloids 370,418 Heptacyclic bridged alkaloids 360 Heptacyclic ring system 374,475 Hemandezine 88, 105-107, 109-110, 121, 130,145,156,166,221 Herpes simplex virus type 2 453

514 Heteroyohimbines 336,339 Hexacyclic alkaloid 376 Hexacyclic carbon skeleton 344,422 Hexacyclic dippinine C 422 Hexacyclic indole 375 Hexacyclic tetrahydrooxazine derivatives 422 15, 16,17, 18,19,20-Hexadehydro yohimbane 491 2, 3, 5,6,11,1 lp-Hexahydro-lHindolizino[8, 7-b] indole (harmicine) 330 Hexamethonium 418 Hexatriene 452 Heyneanine 421,425 (-)-Heyneanine 411 (-)-19(K>Heyneanine 410 (-)-Heyneanine hydroxyindolenine 411 Himanthine 22, 82, 115, 139, 165 Hippadine 440,442,448-449,457,484,485 HL-60 417 (+)-Hodgkinsine 336,414 (+)-Holacurtine 324,325,400,417 (+)-Holacurtinol 324,325,401 (+)-Holamine 324,325,326,401,417 Homoaromoline 77-80, 82,90, 92,99-101, 107-108, 110,114-115,118-119,122,125126, 129-130, 139-140, 152-153, 167,197, 198 (+)-Homoaromoline 23 5,6-Homoiboga derivatives 474 Homomoschatoline 323,413 Homothalicrine 167 Homotropic behaviour 390-391 Horner-Emmons olefination 486 Horsfiline 332-333 R-(-)-Horsfiline 330-331,333,334-335,414 Horsfiline, racemic 332 10-Hydroxy-ll, 12-dimethoxyvincadifformine 385 10-Hydroxy-l 1,12-dimethoxy-tabersonineP-epoxide 386 4'-Hydroxy-3', S'-dimethoxybenzoyl vincamajine 340,341,399 (-)-3-Hydroxy-3,4-secocoronaridine 355, 356,411

9-Hydroxy-5-skytanthine, tf-oxide of 419 7a-Hydroxy-7H-mitragynine 414 (-)-17-o>Hydroxy-A14' 15-kopsinine 363, 364,407 17-p-Hydroxy-AMI5-kopsinine 365 7-Hydroxy-skytanthine 327 9-Hydroxy-skytanthine 328,329,419 5-Hydroxyapateline 4,23, 71, 87, 121, 134, 164,267 7-Hydroxyaporphine 316 (+)- 14a-Hydroxycondylocarpine 345,346, 403 (+)-19fly-Hydroxyeburnamine 352,354, 388,401 18-Hydroxyeburnamonine 352,353 18-Hydroxygardnutine 488 6-Hydroxyharman 453 (+)-15a-Hydroxyholamine 324,325,401 Hydroxyindolenine compound 360 7-Hydroxyindolenine of 16-oxovoaphylline 360 (-)-19fly-Hydroxyisoeburnamine 402,423, 424 (+)-l 1-Hydroxykopsingine 362,407 10-Hydroxylated heteroyohimbine 338 Hydroxylated heteroyohimbine derivatives 338 Hydroxylated tetracyclic heteroyohimbine 379 Hydroxylethyl side chain 425 16-Hydroxymethylpleiocarpamine 345,346 (+)-16-Hydroxymethylpleiocarpamine 402 (-)-12-Hydroxynorfluorocurarine 410 (-)-3-Hydroxynornuciferine 395 7-Hydroxyskytanthine 326 Hydroxyskytanthine derivatives 326 10-Hydroxystrictamine 341 (+> 11 -Hydroxystrictamine 341,342,399 5-Hydroxytelobine 4,23,71,87,121, 135, 164,267 5-Hydroxythalidasine 23,71,104,130,146, 157,232 5-Hydroxythalidasine-2a-JV-oxide 23,71, 104,130,147,157,232

515 5-Hydroxythalmine 23,71,104,130,142, 158,237 (5>5-Hydroxytryptophan hydrochloride 334 Hyellazole 460, 463 Hypertension 417-8,486 Hypoepistephanine 102,126,136,151,191 Iboga alkaloids 355,425 Ibogan-type precursor 421 (-)-Ibogaine 410 (-)-Iboluteine 410 (-)-Iboxygaine 410 (+)-Iboxygaine-hydroxyindolenine 410 Imenine 323,414 Imidazole marine alkaloids 450 Iminium ion 371,424 Incarvilline 326,327, 328 Inden[2, l-b]indole 452 Indian-Thai-Malaysian species 347 Indole alkaloids 329,345,421 Indole Alkaloids synthesis 437,466 Indole C(2), arylation 442 Indole chromophore 358 Indoleborate 451 Indoles 418,439-440,469 Indoline 442 Indolopyridine alkaloids 463 Indoloquinoline natural product 454 Indoloquinolizidine ester 352,353 Indolo[2, 3-a]carbazole 442, 478 Indolylboronate, use in synthesis 453 Indolylzinc 465-466 Indonesian species, alkaloidal composition 358 Infractin 473,474 Inhibit melanin biosynthesis 375 Inhibition of fertility 441 Inhibitory activity 418 Insulanoline 23,65,90-91, 122, 138, 165, 272 Insularine 23,65, 87,90-91,98,102,120, 122,124, 126, 141, 165,272-273 Insularine-2f)-Moxide 272 Intermolecular Heck reactions 469 Intramolecular "aryl-Heck" cyclization 485

Intramolecular 1, 2-addition 372 Intramolecular C-N bond formation 493 Intramolecular cyclization 332,456 Intramolecular hydrogen bonding 374, 379 Intramolecular Heck cyclization reaction 469,474,497 Inverto-yuehchukene 467,469 Isocalycanthine 335 Isochondocurarine 143,165 (-)-Isochondocurarine 24, 65, 89, 132 Isochondodendrine 86-87,90-91,93-94, 98, 100-101, 113, 120, 123-127,132, 137, 159,242 (+)-Isochondodendrine 77,90,118,120, 122 (-)-Isochondodendrine 87,112 (+)-Isocorydine 412 Isocorynoxeine 338,414-415 Isocorytuberine 398 Isocuricycleatjenine 25, 76, 89, 122, 143, 160,245 Isocuricycleatjine 25, 76, 89, 122, 141, 160, 245 Isocycleaneonine 25, 76, 91, 122, 142, 162, 258 Isodaurisoline 25,68, 98, 113, 141, 148, 170 Isoeburnamine (epieburnamine) 351, 354 (+)-Isoebumamine 350,351,352,401,404405,407 (-)-Isoeburnamine 351 Isogambirine 337,415 (±)-Isogeissoschizal 477,478 Isogilletine-N-oxide 25,66, 111, 128, 136, 164,270 Isokopsine-like precursor 373,374 Isolapidilectine A 376, 377 (+)-Isolapidilectine A 404 (-)-Isolaureline 396 Isoliensinine 25, 57,97,130,141,149,180 (-)-Isopteropodine 336,415 Isoquinoline derived alkaloids 316 Isoquinuclidine 485-486 (+)-3-Isorauniticine 489,490,491 Isorhynchophylline 338

516 (+)-Isorhynchophylline 414-415 (-)-Isositsirikine 409 16(K;-19,20-£-Isositsirikine 366,368 (-)-16#H9,20-£-Isositsirikine 367,403 Isostrychnine 477,497 Isotenuipinc 25,61,92, 129,144,156,223 Isotetrandrine 25, 59, 79-85, 88,90,93-96, 99-103,106, 110,112,115-116,121-123, 125-130,142,155,204,215 Isothalicberinc 26, 66, 81, 115,139, 157, 229 Isothalidezine 26,60, 105, 109, 130, 144, 156,221,222 Isotrilobine 78, 87-89,97-98, 101,118-119, 121,124,126,135,163,263,264 Isoursuline 398 Jasminiflorine (12-methoxy-N( 1 )decarbomethoxyfruticosine) 361 Jhelumine (Jheulmine) 27,69, 83, 115,140, 154,207,208 Johnsonine 27,66,91, 129, 139, 153,200 Kalbretorine 457 KB cells 418 Ketalization furnishes 382 Kinabaline 320,397 Kinabalurines 328 (+)-Kinabalurine A 326,327,405 Kinabalurine A, 7-oxo derivative 327 (-)-Kinabalurine B 327,405 Kinabalurine B, Af-demethyl derivative 327 (+)-Kinabalurine C 327,405 (-)-Kinabalurine D 405 Kinabalurine D, 7-oxo derivative 328 Kinabalurine D, quaternary ammonium iodide salt 327 (+)-Kinabalurine E 327-328,405 (+)-Kinabalurine F 328,405 (+)-Kinabalurine G 402,419 Kinamycins A-F 445 Kohatamine 27,71,87,121,135,164,267 Kohatine 27,68, 87-88, 121,134,164,267 Kokusaginine 416 Komaroine 450

Kopsamine 366 (->Kopsamine 367,401,403,426 (-)-Kopsamine-Methoxycarbonyl-ll, 12methylenedioxykopsinaline 405 (-)-Kopsamine N(4)-oxide 401,403,405 Kopsamine-iV-oxide 366 (+)-Kopsaporine 362,363,365,406,417 (-)-Kopsidasine 366,368,401 Kopsidasine, Af-oxide 366 (-)-Kopsidasinine 368,401 Kopsidines A, B, C, D 370 KopsidineA 372,418 (+)-Kopsidines A, B, C 407 Kopsidine C, reduction of 362 (-)-Kopsidine D 407 (+)-Kopsifine 360,361,401 (-)-Kopsiflorine 401,423,426 (-)-Kopsiflorine-N(4)-oxide 401,423,424 Kopsijasmine 366 Kopsijasminilam 375,376 (+)-Kopsilactone 328,329,404 (-)-Kopsilongine 366,367,401,403 (+)-Kopsinarine 423,424,402 (-)-Kopsine 360,361,402-403 (+)-Kopsinganol 362,363,407 Kopsinganol, oxdidation product 362,363 Kopsingine 361,362,363,370,417 A14' ,5-Kopsingine 371 (+)-Kopsingine 406 Kopsingine, iminium salt 371 (+)-Kopsinginine 363,364,406 (+)-Kopsinginol 363,364,407 Kopsinine 355, 358, 366,367,388 (-)-Kopsinine 350,401,403-406,408 (+)-Kopsinitarine A 372,407 (+)-Kopsinitarine B 372-373,407 (-)-Kopsinitarine C 372-373,407 (-)-Kopsinitarine D 372,373-374,407 Kopsinitarines 374 (+)-Kopsinol 362,363,407 (+)-Kopsinone 365,366,402 (+)-Kopsirachine 329,401 (+)-Kopsoffine 329,355,387,388,404-405

517 (+)-Kopsoffinol 352,355,387-388,401, 405 (+)-Kopsone 328,329,404 Kornfeld's ketone 473 Kospsidasinine 368 Koumine 488,489 Krukovine 27, 59, 77, 89,99,118,121,125, 137,154,208,209 Kurramine 27, 68, 88, 121, 133, 163,260, 261 (-)-Lahadinine A 368,369,405,426 (-)-Lahadinine B 368,369,405 Lanuginosine 396,398,413 (+)-Lapidilectam 376, 377,404 (-)-Lapidilectine A 376, 377,404 (+)-Lapidilectine B 376,378, 391-392,404 (-)-Lapidilectinol 376,377,404 Larutenine (larutensine) 350 Larutensine 350,354,352 (+)-Larutensine (Larutenine) 404,408 (±)-Larutensine 352 Lauberine 27,61, 82-83,115,139, 158,234 (+)-Laurolitsine 398 Laurotetanine 321 (+)-Laurotetanine 412 Lavendamycin derivatives 453 Leishmanicidal activity 324,417 (-)-Leuconolam 347,357,403, 408 (-)-Leuconoxine 357,358, 367,402-403, 406 Liensinine 27, 57,97, 130, 141, 149,180 Limacine 27, 59,78-79, 89-90, 93-95,98100,116,119, 121-125, 132,139,154, 208,209-210 Limacusine 28, 58, 89,94-95,122-123,139, 152,195,196 (+)-Limalongine 323,324,413 Lindecarpine 321,412 Lindoldhamine 28, 56, 77-78,95,98,113, 117-118,134,148,171 (+)-Lindoldhamine 323,413 (-)-Lirinidine 396 Liriodenine 320, 395-398,412-413 (+)-Lochnerine 399-400

(-)-Lonicerine 407 (-)-Lundurine A 378,406,418 (-)-Lundurine B 377,378,390,406,418 (-)-Lundurine C 377,378,406,418 (±)-Lysergic acid 470,473 Lysicamine 323, 396-398,413 Macolidine 28, 58, 77,118,137,153,201 Macoline 28, 58, 77, 118,141,153,201, 202 Macralstonine 340, 399 Macralstonine acetate 416-417 (-)-Macrocarpamine 340, 399 Macrocarpamine 381,416-417 Macroline alkaloid 341,380 Macroline-cabucraline dimers 382 Macroline-type precursor 393 Magallanesine 480, 481 Magnolamine 28, 56, 95, 117, 143, 149, 176,177 Magnoline 77,95-96, 117-118, 138, 148, 174,175 Makaluvamine C 493 Malaria 417 Malekulatine 29,68, 94, 117, 146,150, 180, 181 Marine sponge 450 Maroumine 29, 75, 93, 116, 144,152,192 Maxonine 480,481 Mayer or Dragendorff reagents 287 Medelline 29, 71, 99, 114,138, 161, 250252,253 (-)-Mehranine 358,359,387 (+)-Mehranine 358, 359,409 Melanin biosynthesis 418 Meloscine-type derivative 357 5-Memberedringlactone 376 5-Memberedrings,synthesis of 441 5-Membered unsaturated ring 376-377 5-Membered cyclic carbamate 375 5-Membered ring 391 8-Membered ring 377 8-Memberedringfused to 5-membered ring 376 7-Membered ring 393

518 10-Memberedring 390 Menisarine 29,64, 87,89,121,136, 164, 268 Menisidinc 29,59,103,126,139,155,218, 219 Menisinc 29, 59,103,126,139,155,218, 219 (+)-Mersingine A 372-373,374,407 (-)-Mcrsinginc B 372-373,374,407 (+)-10-Methoxyaffinisine 400 10-Mcthoxyaffinisinc 420,421 11-Methoxyakuammicine 340,343,417 (-)-11 -Methoxyakuammicine 3 99 Af-Methoxy-carbonyl-11,12-dimethoxy kopsinaline 369 (-)-N( 1 )-Methoxycarbony1-11,12-dimethoxy kopsinaline (11-Methoxy kopsilongine) 403,405 (-)-N( 1 )-Mcthoxycarbonyl-11 -hydroxy-12methoxy-kopsinaline 403 (-)-N( 1 )-Methoxycarbony I-12-methoxyA,6,7-kopsinine 403,405-406 N( 1 )-Methoxycarbonyl-12-methoxy-Al6nkopsinine 366 (-)-N(l)-Methoxycarbonyl-l 1, 12-methylene dioxy-A16,17-kopsininc 366,406,426 N( 1 )-Methoxycarbony 1-11,12-mcthy lenc dioxy-A16, l7-kopsinine, A^-oxide 366 W-Methoxycarbonyl-11,12-methylenedioxy kopsinaline (kopsamine) 369 (-)-lO-Methoxycathafoline 400,420,421 12-Methoxy-N( 1 )decarbomethoxyfruticosine (jasminiflorine) 361 (-)-N(l)-Methoxy-19,20dehydroervatamine 348,349,408,410 (-)-12-Methoxy-10-demethoxy kopsidasinine 367,368,403,405 5-Methoxy-W Af-dimethyltryptamine 330, 331,414 5-Methoxy-2,2-dimethyl-2H-pyrano-[2,3b]-quinoline 416 11-Methoxy-12-hydroxykopsinol 362,363 (+)-11 -Methoxy-12-hydroxykopsinol 407 (-)-11 -Methoxykopsilongine 401 11-Methoxykopsilongine 424,426

11-Methoxykopsilongine N(4)-oxide 423 (-)-ll-Methoxykopsingine 362,407 (-)-lO-Methoxykopsinone 365,366,402 (+)-12-Methoxykopsinone 365,366,402 11-Methoxykoumine 488 N(l)-Methoxylated derivative of 19,20dehydroervatamine 348 N(l)-Methoxylated derivative of methuenine 348 9-Methoxylated tetracyclic heteroyohimbine, nmr 339 10-Methoxymacrocarpamine 381,399 (-)-lO-Methoxymacrocarpamine N(4')oxide 399 Methoxymacroline 381 N( 1 )-Methoxymethuenine 348,349,410 6-Methoxy-2-methyl-l, 2, 3,4-tetrahydro-Pcarboline 330,414 4-Methoxy-l-methyl-2-quinolone 416 (-)-12-Methoxypleiocarpine 366,367,402403 Methoxypolysignine 320,397 (+)-10-Methoxyvillalstonine 380, 399 10-Methoxyvillalstonine, Moxide 380,399 (+)-Methuenine 348,349,408,410 tf-Methylapateline 29,66,78, 88,91,118, 121,129,134,163,262,263 A^-Methyl arcyriacynin A 479 N-Methylation 321 (+)-N(l)-Methylaspidospermidine 411 N( 1 )-Methyl-aspidospermidine-epoxide 358 W-Methylazomethine ylide 334,335 2-Methyl benzoylindole 438 2-tf'-Methylberbamine 29, 59,142,155, 216 2,-Ar-Methy!berbamine 83, 85,115,214 (+)-Methyl chanofruticosinate 369,402,424 (+)-0-Methyl cocsoline 323,413 O-Methylcocsoline 29,68,78,97,118,124, 134,163 12-0-Methylcocsoline-2'p-Ar-oxide 29, 76, 78,119,135,163,263,265 O-Methylcocsulinine 29,76, 88,121,136, 164,268,269 (^••-O-Methylcurine 90

519 4"-0-Methylcurine 30,63, 87,120,122, 139,160,246 n'-O-Methylcurine 30,63,93,113,139, 160,244,245,248-249 7-0-Methylcuspidaline 30,68,79,114, 143,148,169 O-Methyldauricine 30, 56, 89,98, 114,132, 145,148, 168,169 (+)-Methyl N(l)-decarbomethoxy chanofruticosinatc 369,370,401-402 Af-Methyl-7-O-demethylpeinamine 30,59, 77,97,118,124,137,217,218 O-Methyldeoxopunjabine 30, 69, 103,126, 136,163,261 Af-Methyl-U'-O-Desmethyltrilobine 166 5-Methyl-5,10-dihydroindeno[l, 2-b]indol10-one 438 Methyldihydrowarifteine 30, 64, 86, 120, 139,162,257 6-Methyldryadodaphnine (Thalifortine) 235 O-Methyleburnamine 358 (-)-O-Methyleburnamine 351,408 (+)-0-Methyleburnamine 351 11, 12-Methylenedioxykopsaporine 362, 363 (+)-ll, 12-Methylenedioxy kopsaporine 406-407 (-)-ll, 12-Methylenedioxykopsinaline 402 11,12-Methylenedioxykopsinaline, Noxide 368 (-)-ll, 12-Methylenedioxykopsine 402 11,12-Methylenedioxykopsine 424,423 2-#-Methylfangchinoline 30, 76, 103,126, 142,155,211,212 6'-0-Methylgilletine (Pendilinine) 270 7-O-Methylgrisabine 30, 76,98,124,143, 148,174,175 12-Methylhayatine (Hayatinine) 249,250 7-Methylinsulanoline (Insularine) 272 0-Methyl-isoeburnamine 358 (+)-0-Methylisoeburnamine 351,408 (-)-O-Methylisoeburnamine 351 A^-Methylisotetrandrine 30, 71, 83,115, 144,155,214,216

O-Methylisothalicberine 30,61, 81, 83,115, 142,157,229 (+)-A^Methyllaurotetanine 412 21-O-Methylleuconolam 358 O-Methyllimacusine 30, 72, 94,116,142, 152,195,196 2-tf-Methyllindoldhamine 30, 72,77,118, 135,148 2,-A^-Methyllindoldhamine 31, 72, 77,118, 135,148 7-0-Methyllindoldhamine 31, 68, 98, 113, 135,148,171 T-O-Methyllindoldhamine 31,68, 98,113, 135,148,171 (+)-Methyl 11,12-methylenedioxy chanofruticosinate 369,370,401,402, 425 (+)-Methyl 11, 12-methylenedioxy-N(l)decarbomethoxy-A14, ,5 chanofruticosinate 369, 370,401 (+)-Methyl 11, ^-methylenedioxy-Afdecarbomethoxy-chanofruticosinate 402 O-Methylmicranthine 31,64,92, 129, 134, 163,262 O-Methylmoschatoline 320, N-Methylnorapateline 31,66,91, 129, 133, 163,262,263 tf-Methylpachygonamine 31, 68,97,124, 135,161 O-Methylpunjabine 31,69,79,103,119, 126,138,163,261 O-Methylrepandine 31, 58,91-92,94,129130,142,153,200 2-W-Methyltelobine 31,76,101,126,135, 163,263 Af-Methyltelobine 262 O-Methylthalibrine 31,66, 105-106, 108, 130,144,148, 172,173 0-Methylthalibrunimine 31,66,109, 130, 146,159,240 O-Methylthalicberine 81,85,104-110,115, 142,157,167,227,228 5-0-Methylthalidezine (Hernandezine) 220 O-Methylthalisopine 106,130

520 tf-Methylthalistyline 107,109,131,147, 149,178,179 O-Methylthalmethine 32,61,107-109,131, 138,157,226,227 0-Methylthalmin 235,236 5-0-Methylthalsimidine (Thalsiminc) 220 #-Methyltiliamosine 32,72, 111, 127,138, 161 12-0-Methyltricordatine 32, 76,97,124, 134,163,263,264 (+)-AT-Methyl-2, 3,6trimethoxymorphinandien-7-one 412 Af-Methyl-2, 3, 6-trimethoxymorphinandien7-one-N-oxide 412 tf-Methylurabaine 318-319,398 tf-Methylvindoline 392 (-)-//-Methylvoafinine 358,359,409 (-)-#-Methylvoaphylline 358,409 Af-Methylvoaphylline, 16-hydroxy derivative 359 Methylwarifteine 32,64, 86, 120,138, 162, 167 Michael addition reaction 382,445 Michelia fuscata 95 Micranthine 33,64,92, 129,133, 163, 262 Migraine 486 Migratory insertions 480 Mitraciliatine 339,414 Mitragynaline 338,414 Mitragynalinic acid 338,339,414 (-)-Mitragynine 338,339,414,420 (-)-Mitralactonal 414,419,420 (+)-Mitrasulgynine 414,419,420 (-)-Modestanine 408 Monomargine 393,394,418 Monomethyltetrandrinium 33, 59,90,122, 144,155,211,213 Monoterpenoid alkaloids 326,329,419, 463,478,491 Monterine 33,72,89,113,142,150,187 Multidrug resistance (MDR) 426 Murrayaquinones (A-D) 445 Naphthylisoquinoline 316 Nareline 346,347

Nareline-type alkaloids 347 (-)-Nareline methyl ether 345,346,400 (-)-Nareline ethyl ether 346,347,400 Nauclefidine 339 Nauclefine 463 Naucletine 462,463 Nazarov cyclization 467 Neferine 33, 57,97,130,143,149,180 Negishi reaction 464,465,467,468,496 (R, *)-Nemuarine 33,62,97,130,139,159, 238 (+)-Neochondocurarine 33, 89,132,143, 165 Neoprotocuridine 33,62,137, 160,244 Neosutchuenenine 33,76,91,122,138, 149,180 Neothalibrine 33,66,104, 109,131,143, 148,172,173 (+)-Nitaphylline 388,389,390,407 Nitramarine 453,458,459,467,468 Nitrogenous pigment 393,418 NOE experiments 324 Norberbamine 88,121 2-Norberbamine 100,102,126 2-tf-Norberbamine 33,60,99,125,137, 155,216 2-Norberbamunine 84,115 Norboldine 321,412 Norcepharadione A 397 2-Norcepharanoline 33, 34,72,102,126, 135,152,199 2-Norcepharanthine 34,72,101,103,126, 136,152,199 2'-Norcepharanthine 34,72,102,126,136, 152,199 (R, 5)-Nor-Nb-chondrocurine 98,120 Nor-Nb-chondocurine 34,67,135,160, 246,247 2'-Norcocsoline 34,76,119,133,163,263, 265 2'-Norcocsuline 34, 72,78,97,118,124, 133,163,166 (+)-Nor-2'-cocsuline 322,323,413 tf-Norcocsulinine 34,76,88,121,134,164, 268,269

521 (+)-Norcorydine 396, 398 (-)-Norcycleanine 34,62,94,100,126,139, 159,167,242,243 (+)-Norcycleanine 34, 62, 86,90,93,104, 120, 122,127, 139, 159, 167,243 (±)-Nordasycarpidone 466-467 T-Nordaurisoline 34,72,77,118,138,148, 166,168,171 (-)-Norechitamine 348,400 (-VNorfluorocurarine 358,399,408,410, 417 (-)-Norfluorocurarine N(4)-oxide 343,345, 358,408-409 2'-Norfiiniferine 34, 72, 93, 113, 139,151, 188 2'-Norguattaguianine 34, 72, 93, 113, 140, 151,186,187 N -Norhernandczine (Thalisamine) 34,67, 109, 131, 144, 156, 167,220,221 2-Norisoccpharanthine 35,72, 102,126, 136,152,201 (+)-Norisocorydine 412 (+)-Norisocorytuberine 318,319,398 2-Norisotetrandrine 35, 72, 101-102, 126, 140,155,216 2,-Norisotctrandrine 102, 126 Nor-2'-Isotetrandrine 35, 67, 95, 123, 140, 155,214 Norisoyanangine 35, 72, 111, 127,135, 161, 253, 254 2-Norlimacine 35, 72, 79, 86,119, 137, 154, 208, 209 2'-Norlimacine 35, 76, 79,90, 119, 122, 137,154,208,209 2-Norlimacusine 35,68,86,100,119, 125, 137,152,195,196 (-)-Norliridine 396 (+)-Normacusine B 343,344, 399,408,410 Normacusinc B, C(16) cpimer 343,344 Normacusine B-affinisine 343 Normcnisarine 35,64, 89,121,134,164, 167,268 (-)-Nornucifcrinc 395-398 2-Norobaberine 78, 101-102, 119, 126,

2'-Norobaberine 35, 72,102,126,140, 152, 197,198 2-Norobaberine-2,p-Ar-Oxide 35, 76, 78, 119,143,152,198,199 2,-Norobaberine-2,p-W-oxide 197 2-Ar-Norobamegine (2-Norobamegine) 35, 60,99-100,125,135,155,216 2'-Noroxyacanthine 35,72,105,131, 137, 153,197,198 Norpanurensine (2'-Norpanurensinc) 36,62, 77,118,137,158,238 Norpendulinc 36,68, 88,121, 137,155, 211,212 2,-Norpisopowiaridine 36, 72, 98, 114, 138, 150,182-183,184 (-)-Norpleiomutine 329,387,388,401,404405,418 Norrodiasine 36, 57,96,117, 140, 151, 188189 ent-Norsecurinine 412 (-)-Norstephalagine 395-396 Norstephasubine 36, 72, 103, 126, 134, 151, 191,192 Nortenuipine (7-Demcthyltenuipinc) 224 (+)-Nortenuipine 36,61,91-92,129,141, 156,167,223 (-)-Nortenuipine 36,61,92, 129, 141, 156, 167,222 2-Nortetrandrine 36,60, 140, 155,212 (+)-2-Nortetrandrine 97, 117 Northalibrinc 36, 56,109,131, 141,148, 172,173 Northalibroline 36, 72,108,131, 135, 148, 172,173 AT-NorthaUbrunine 36,67, 109, 131, 145, 159,240 2,-Northaliphylline 36,73,105,131,137, 157,227,228 2-Northalmine 36, 73, 105,131, 137, 158, 235,236 2-Northalrugosine 37,73,100-101,125126,137,155,216 Nortiliacorinc A 110-111,127,134,161, 252

522 Nortiliacorininc A 110-111,127,134,161, 251 Nortiliacorininc B 37,62,111,127,134, 161,251 2,-Nortiliagcine 37, 73,93,113,137,151, 188 Nortopsentin C 449,450 Nortopsentins A-C 449,450 Nortrilobine 68, 88,97, 124, 133,163,263, 265 (-)-Norushinsuninc 396-397,413 Noryanangine 37, 73, 111, 127,135,161, 254 Novel carbon skeleton 376 (-)-Nuciferine 396 Obaberine 37, 58, 78, 80-85, 92,94, 96, 99, 101-103, 105, 107-109, 114-118,125-126, 129,131,142,153,197,198 Obamegine 38,60, 80-81, 85,95-96,100, 102, 107-109,111-112, 115-116, 126, 128, 131-132,137,155,215 Oblongamine 38, 58, 83, 115, 142,202 Ocodemerine 38,96,117,140,165 Ocotamine 117 Ocotine 38, 57, 96, 117, 140, 151, 186,187 Ocotosine 38, 57, 97, 117, 138,189 (-)-Oliveroline 398 Oncodine 320,397 Opium substitute 339 Optically active menthyl ester 334-335 Osornine 39,68, 80,115,144,153 (S, iO-Osornine 202 Otocamine 39, 96,117, 140, 165 Oxandrine 39, 73,99,114,141,151,186 Oxandrinine 39,73,99,114,141,144,151, 186 Oxepanering 349 Oxidative cyclization 438,439,446 17-Oxoaspidofractinine alkaloids 366 Oxoassoanine 457 3-to-17 Oxo-bridged alkaloids 370,418 17-to-5 Oxo-bridged compound 372 17-to-3 Oxo-bridged compound 372 Oxobuxifoline 396

Oxocrebanine 396 (-)-3-Oxocoronaridine 410 5-Oxo-19,20-dehydroervatamine 348,408, 349 3-Oxo-14,15-dehydrorhazinilam 358 (+)-19-Oxoeburnamine 405,354 (-)-3-Oxo-19-epiheyneanine 355,356,411 Oxoepistephanine 39,58,101,127,141, 151,193 Oxofangchirine 39,73, 103, 127, 141, 154, 218-219 21-Oxogelsemine 482,483 Oxoglaucine 413 6-Oxo-6H-isoindolo[2,1 -a]indoles 438 2-Oxo-5-methoxytryptamine derivative 332-333 (-)-6-Oxomethuenine 348,349,411 Oxopropaline G 463 Oxostephanine 320, 397-398 Oxothalibrunimine 39, 67, 109,131, 146, 159,240 Oxyacanthine 39, 58, 78-85, 87,92,94-96, 105,107-108,112,116-118, 121, 129, 131-132, 140,153,197,198,202 (+)-Oxyacanthine 412 Af-Oxy^-Isotetrandrine 40, 67, 95, 123, 144,155,214,217 W-2-Oxy-O-Methyldauricine 40, 73,98, 114,146,148,172 iV-2'-Oxy-0-Methyldauricine 40, 73,98, 114,146,148,172 (-)-W-Oxyoliverine 398 P388 cells 418 Pachygonamine 40,68,97, 124, 134, 161, 254,255 Pachyovatamine 40,68,97,124,133,161, 251 (-)-Pachysiphine (tabersonine-P-epoxide) 358,409 Palladium-catalyzed intramolecular carbonnitrogen bond formation 493,498 Palladium-catalyzed oxidative cyclization 446 Palladium-catalyzed cross-coupling 452

523 Pampulhaminc 40, 73, 79,115,138, 148, 166,168,171 Pandicine 384-386 Pangkoramine 41, 73, 78,118,134,152, 195,196 (+)-Pangkoramine 322,323,413 Pangkorimine 41, 73,78,119,134,151, 191 (+)-Pangkorimine 322,323,413 Panurensine 41, 62, 77,118, 140,158,238 (+)-Paraberquamide B 474 Parkinson's disease 486 (+)-Paucidactine A 374,375,405 (+)-Paucidactine B 374,375,402,405 (-)-Paucifinine 369,405 (-)-Paucifinine N(4)-oxide 369,405 (-)-Pauciflorine A, B, C 404 Pauciflorines 376 Pauciflorine A, B 374, 375,418 PauciflorineC 375 (+)-Paucifoline 375,405 Pavettine 450,453,458 Paynantheine 339,414 Pedroamine 41, 73, 79, 115, 135, 148,171 Peduncularidine 386,387,411 Pedunculine 387,411 Peinamine 41, 60, 77, 118, 137, 155,217 Pendilinine 41, 76, 88, 121, 136, 164,270 Pendine 41,88,121,135,165 Penduline 41, 60, 78, 80, 87-88,97, 116, 121,124,140,155,211 Pendulinine 41, 88, 121, 135, 165 Pentacyclic bisindole 463 Pentacyclic diazaspiro alkaloid 367 Pentacyclic indole 419 Pentacyclic oxindole alkaloids 336 Pentacyclic skeleton 374,424 Pericalline 348 (+)-Pericyclivine 411 (-)-Perivine 411 Perlolyrine 448,449 Phaeantharine 41, 60, 98, 124, 141, 154, 204

Phaeanthine 41,60,90,93, 98-100,112, 116,122,124-125,128,142,154,204, 209-210 Phenolic function, bathochromic shift 341 Phentolamine 418 Phillipine-Indonesian samples 347 Phlebicine 42, 57, 89,113, 140, 151,188 Phoebegrandine A 321,412 Phoebegrandine B 321,412 (+)-ent-Phyllanthidine 412 Phytochemical screening 286 (-)-Picrinine 345, 400 Piperidine ring 349, 362, 370 N-Piperonyl indole 442 Pisopowamine 42, 73,98, 114, 141,150, 182-183,184 Pisopowetine 42, 73, 98, 114, 143, 150,183 Pisopowiaridine 42, 73,98, 114, 141, 150, 183 Pisopowiarine 42, 73,98, 114, 143, 150, 183 Pisopowidine 42, 73, 98, 114, 145, 150,183 Pisopowine 42, 73, 99, 114, 145, 150,183 Platydesmine 416 Pleiocarpamine 340,346,348,417 (+)-Pleiocarpamine 399-400, 402 (-)-Pleiocarpine 366,367,402-403,417, 426 Polonovsky-Potier reaction 372 Polyervine 386,412 Polyervinine 386,412 Polysignine 320 Pomeranz-Fritsch cyclization 439 Pontevedrine 412 Popidine 42, 73,99, 114, 143,148,169 Popisidine 42, 74,99, 114, 143, 148,169 Popisine 42, 74,99,114,143,148,169 Popisonine 42, 74,99, 114,141, 148,170 Popisopine 42, 74, 99, 114, 141, 148,170 Pratorimine 440 Pratorinine 440 Pratosine 457 Pratosinine 440 (+)-Predicentrine 413 Pregnane aglycone 324

524 C2i-Pregnane skeleton 326 Prekinamycin 444,445 Pressor effects 418 Primary hypertension 417 Proaporphine 323 Af-Protected aglycone 478 Protein kinase C (PKC) inhibitors 442 Protein kinase C inhibitors 442 Protochondocurarine 43 Protocuridine 43,62, 137, 160,244 Pseudoakuammigine, #-oxides 342 Pseudoindoxyl chromophore 384 Pseudorepanduline 43,64,91-92,129,138, 164,271 Pseudoxandrine 43, 74, 99, 114, 142, 151, 186 Pseudoxandrinine 43,74, 99,114,144,151, 186 (+)-Pseudoyohimbine 337,338, 379-380, 415 Pteleine 415 (-)-Pteropodine 336,415 Punjabine 43, 69, 83, 88, 116, 121, 136, 163,261 Pycmanilline 43, 75, 100, 125, 146,153, 204,205 Pycnamine 43,60,93,99-100,112,116, 125,128,140,154,209 Pycnarrhenamine 43,99,125,143,165 Pycnarrhenine 43,99,125,145,165 Pycnazanthine 43, 74,100,125,134, 151, 191,192 Pyrayaquinone-A 444,445 Pyrayaquinones(A-C) 445 Pyrido-[2\ 3,-d,]pyridazino[2, 3-a] indole 479 Pyrido[2, 3-b]indole skeleton 494 Pyrido[4, 3-b]carbazoIe 452 Pyrroline ring 475 Pyrrolophenanthridine alkaloid 449 Pyrrolophenanthridone alkaloids 440, 441 Quadrigemine B 336,414 Quasidimer 367-368,417 Quaternary indole alkaloids 341

Quebrachamine 354,407 Quinazolinone 492 Quindoline 439,440,454,455 Quinoline 458 3-Quinolone chromophore 358 3-Quinolone-type alkaloid 358 Radical scavenger 460 Ras functions 418 Rebeccamycin 442,451,478 Repandine 44, 58, 90,92,123, 129,140, 153,200 Repandinine 44,61,91-92,129,144,156 Repanduline 44,64,91-92,129,141,164, 271 (+HS>Reticuline 396 Retro-aldol-type reaction 424 Revolutinone 44,69, 109, 131, 145, 157 Revolutionone 226,227 (+)-Rhazimol (deacetylakuammiline) 367, 403 Rhazinal 423,422 (-)-Rhazinaline N(4)-oxide 404 (-)-Rhazinicine 356,357,358,401 (-)-Rhazinilam 406-408 Rhazinilam 356,418,357 (-)-Rhynchophylline 338,414-415 Rodiasine 44, 57, 97, 117, 142, 151,188 Roehybridine 321 Roemeridine 321 Rotundifoline 337,415 Roxburghines 339 Rutecarpine 491-492 Salcomine 473 Sarcosine 335 Sarpagine alkaloids 367 (-)-Scholaricine 345,346,400 (-)-Scholarine N(4)-oxide 345,346,400 Sciadenine 44,63, 100,125,140,159,243 Sciadoferine 44,67, 100, 125,136, 159, 241,243 Sciadoline 44,63,100,125,136,159,241, 243 (-)-Scoulerine 396

525 Seasonal variation of the alkaloid content 338 Secantioquine 44, 69,99,114,144, 150, 185 6, 7-Seco-angustilobine B 347 Secobisbenzylisoquinoline 250 Secobisbenzylisoquinoline alkaloids 224, 226 Secobenzyltetrahydro-isoquinotines 316, 320 Secocepharanthine 44,69, 103, 127, 143, 152,195 6, 7-seco-19,20-epoxyangustilobine B 347 Secohomoaromoline 44, 77, 79, 119, 144, 152,194 Secoisotetrandrine 44, 77, 94,129,145, 153,204,205 Secojollyanine 45, 77,79, 119,139,163, 261 Secologanine derived alkaloid 358 Secolucidine 45, 75, 99,114,138, 161,250 Seco-methylchanofruticosinate 424 Seco-obaberine 45,69,99, 114, 145, 152, 194 (-)-Securinine 412 Seeperine (Sepeerine) 97, 117,137, 153, 197,198 SEM protecting group 332 Siddiquamine 45, 74, 87, 121, 134, 164,266 Siddiquine 45, 74, 87, 121, 133,164,266 Simple indole and oxindole alkaloids 330 Simple isoquinolines and derivatives. 316 Sindamine 45, 69, 83, 116, 144,154, 205 (-)-Singapurensines A, B, C, D 370,406 Skimmianine 416 Skytanthine 329 Speciociliatine 339,414 Speciogynine 339,414 Spiro-oxindole 481-482 Spiro-pyrrolidinyloxindole 330 Splendidine 323,414 7-StannyIated indoline 457 Staurosporine 451,442-443 Staurosporinone 463,464

Stebisimine 45, 58, 78,102, 111, 119,127128,136,151,190 (+)-Stepharine 323,397,413 Stephasubimine 45, 74,103,127,134,151, 190 Stephasubine 45, 74, 102-103, 127, 136, 151,191,192 Stephibaberine 45,74,101-102,127,140, 153, 197,198 (-)-Stepholidine 397 Stepierrine 46, 74, 102,127, 135, 154, 166, 206 Steroidal alkaloids 324,417 Stille reaction 455,456,460,495 (-)-Strictosidinic acid 414 Strychnan 475 Strychnine 340,475,476,477 Strychnos alkaloid 467 Styrylindole system 452 Sutchueneneonine 46, 76, 123, 138, 150, 181,182 Sutchuenenine 46,76,91, 123, 138, 150, 182 Suzuki coupling 446-447, 448,463, 495 Suzuki cross-coupling reaction 451 Tabernaemontanine 329 (-)-Tabernaemontanine 404,410 Tabersonine 478 Tabersonine-p-epoxide 385 Tabersonine-p-epoxide, 10-alkyl-l 1oxy 384 Talcamine 46,69, 80, 116, 147, 156,224, 225 Talcarpine 342, 382 (-)-Talcarpine 400 Tandem cyclization 456 Telobine 46, 64,91-93, 113, 129, 134, 163, 262,263,267 Temuconine 46,68, 85, 116, 141, 148,174 Tenuiphylline 390-391,392,393 (-)-Tenuiphylline 406 (+)-Tenuipine 46,61,92,129, 144, 156, 223

526 (-)-Tenuipine 46, 61,91-92,129,144,156, 222 Tenuipine (91) racemate 156 (±)-Tenuipine (Repandinine) 224 Tenuisine (A, B, C) 390,391,406 (+)-Tenuisines (A, B, C) 406 (-)-Terengganensine A 408 Terengganensine A 354,355 (-)-Terengganensine B 408 Terengganensine B 354,355 Tetracyclic heteroyohimbines 337 Tetracyclic oxindoles 338 Tetracyclic ring system, highly conjugated 393 (-)-3,4,5, 6-Tetradehydromitragynine 414, 419,420 Tetra-(9-demethylcycleanine 243 3,4, 5, 6-Tetrahydro-6-(2-methyl-lpropenyl)azepino[5, 4, 3-cd]indole 446 Tetrahydro-P-carboline compound 334 Tetrahydro-x-carboline derivative 332-333 (-)-Tetrahydroalstonine 366,402-403,406 (+)-Tetrahydrocantleyine 348, 399-400 1,2, 3,4-Tetrahydrolimacine 99 1\2\ 3', 4'-Tetrahydrolimacusine 99 Tetrahydrooxazine ring 422 Tetrahydroprotoberberine 319 Tetrahydropyrroloquinoline 492 Tetrandrine 79, 88-90,94,97, 103-104,112, 115,121,123,124,128,130,213 (+)-Tetrandrine 46,60,90-91, 102,123, 127,142,155,155,211,218 (±)-Tetrandrine 47,60,90-91,94,102,123, 127,130,142,155,218,219 Tetrandrine-2p-#-Oxide (see Fenfangjine A) Thai species 337,368,374,386 (-)-Thaipetaline 318-319,398 Thalabadensine 47,62,107,110,131,137, 158,236 Thalfine 106-107, 131, 145, 158,233 Thalfinine 105-107,131,146,158,232,233 Thalfoetidine 106-107,131,144,157,167, 231 Thalibrine 47, 56, 107, 109, 131,143,148, 172,173

Thalibrunimine 47,62,109,131, 145,159, 240 Thalibrunine 47,62,109,131, 146,159, 240 Thalicberine 47,61,107-108,110,131, 140,157,227,228 Thalicrine 166-167 Thalicsimine (Thaliximine) 166 Thalictine 48,62,105,110,131,140,158, 234,236 Thalictrinine 48,67, 109, 131, 146, 159, 167,239 Thalidasine 48,61,104-107,109-110, 131, 145,157,229-230,231 Thalidezine 48,60, 105-107, 109-110, 131, 144,156,220,221 Thalifoetidine 167 Thalifortine 49, 76, 106, 131, 140, 158,235 Thaligosidine 49,61, 109, 131, 143, 157, 231 Thaligosine 105-106, 108-109, 131, 153, 166,203 Thaligosinine 49,59, 106, 109, 131, 144, 153 Thaligrisine 49,68,99,108,114, 131,141, 148.174 Thaliphylline 49,68,105,108, 131, 140, 157,227,228 Thalirabine 49, 57,107, 147,149,178,179 Thaliracebine 50, 56,105, 107,131, 145, 149.175 Thalirugidine 50, 57, 109, 131, 146, 149 Thalirugine 50, 56, 105, 108-109, 131,145, 149,175,176 Thaliruginine 50, 56,109,132,146,149, 175.176 Thalisamine 50,60, 110, 132,144, 156, 167,221 Thalisopidine 50, 59,106,143,153,203 Thalisopine 50, 59,105-107,132,153,166, 203 Thalistine 50,67,108, 132, 146,149, 178, 179 Thalistyline 50,57,107,109,132,147,149, 178,179

527 Thalivarminc 51, 74, 108, 132, 137, 157, 228 Thalmethine 51,61,107-108,132,136, 157,226,227 Thalmiculatiminc 51, 74, 105, 132, 136, 158,234 Thalmiculimine 51,74,105,132,142,158, 236,237 Thalmiculine 51, 74, 105, 132,144, 158, 237 Thalmidine 167 Thalmine 51,62, 105,107-108,132, 140, 158,235,236 Thalmirabine 51,67, 105, 108, 132, 146, 158,233 Thalpindione 51,67, 104, 132, 145,157, 231 Thalrugosamine 23, 95, 102,104, 110, 123, 127, 132, 153, 167 Thalrugosaminine 104-110, 132, 145, 153, 203 Thalrugosidine 52,61, 104-106, 110, 132, 145, 157,231 Thalrugosine 80-81, 83-84, 90, 94-96, 100103, 107-110, 116, 123, 125, 127-129, 132,140,155,215 Thalrugosinone 52,67, 105, 110, 132, 146, 157,229,231 (+)-Thalrugosmine 23 Thalsimidine 110,132,142,156,220 Thalsimine 109-110, 132,144, 156,220 Thalsivasine 53, 74,105,108, 132, 136, 157,226,227 Tiliacoridinc 53, 111, 128,146, 165 Tiliacorinc 53,62, HI, 128, 135, 161,251, 252,253 Tiliacorinine 53, 62, 110-111, 128, 135, 161,251-252,253 Tiliafunimine 53,60, 128, 136, 154,206, 207 Tiliageinc 53, 57, 93, 110-111, 113,128, 140,151,188 Tiliamosinc 54,62,97, 111, 124,128,136, 161,254,255 Tilianangine 54, 75,111,128,136, 161,254

Tiliandrine 54, 111, 128, 133, 165 Tiliaresine 54, 76, 111, 128, 135,161, 255 Tiliarine 54,65, 111, 128,134,165,251 Tilitriandrine 54, 75, 111, 128,137,151, 188 Tin reagents in alkaloid synthesis 460 TLC 287 Toad poison 493 Tomentocurine 54, 86, 120, 137, 165 Topsentins 463 Toxicoferine 54, 86,120, 160 Tricordatine 54, 64, 88, 97, 112,121,124, 128,133,163,263,264 Tricyclic azepinoindole 471 1,3, 4-Tridehydrofangchinolinium hydroxide (Fenfangjine D) 206,207 Trigilletimine 54,64, 111-112, 128, 133, 162,259,260 Trigilletine 166 (±)-cw-Trikentrin A 473, 474 Trilobine 54, 64, 78-79, 87-89, 97, 119, 121,124,134,163,263,264 5, 8,9-Trimethoxy-2, 2-dimethyl-2Hpyrano-[2, 3-b]-quinoline 416 1, 2, 3-Trimethoxy-4, 5-dioxo-6a, 7-dehydro aporphine 316,317,398 Trivalvone 319,398 (+)-Tronoharine 408 Tronoharine 422,423 Tsuji-Trost reaction 485,487-489,498 Tryptamine 449 Tryptamine bridge 348 Tryptamine oligomers 330 (+)-Tubocurarine 55,63, 79, 86,119-120, 140,160,247,248 (-)-Tubocurarine 55,63, 86,120,140,160, 248,249 (+)-Tubocurarine chloride 98 (-)-Tubocurine 55,63, 120, 137,160,249, 250 (+)-Tubocurine (Chondrocurine) 249 (+)-Tubotaiwine 350,411,467 Tubulin 418 Type A macroline 421 Type B macroline 393,421

528 Uleinc 467 (-)-Undulifoline 400 Undulifoline 348,350 Ungermine 449 Ursuline 397 (-)-Ushinsunine 396 Vallasiachotaman class 463 Vandrikine 385,408 Vanuatinc 55,69, 94, 117,146, 149,177 Vateamine 55,69,94,117,146,149,177, 178 (-)-Venalstonine 377,392,393,404 (+)-Villalstonine 340,380,381, 399,416417 (+)-Villalstonine N(4')-oxide 380,399 Vincadifformin 385 (-)-Vincamajine 340,341,343, 399-400, 417 Vincarubine 385 Vincorine 343 Vincristine 426 Vindolinc 392 (+)-Viroallosecuriniiie 412 (+)-Virosecurinine 412 Voacamine 384 (-)-Voacangine 355,356,409,411 (+)-Voacangine hydroxyindolenine 410 (-)-Voacanginc pseudoindoxyl 410 (-)-Voacristine 355,409-410 (+)-Voafinidine 409 Voafinidine 358,360 (-)-Voafmine 358,359,409 Voafrine A 389,390 Voafrine B 389,390 (-)-Voaharinc 358,359,409 (-)-Voalcnine 358,360,409 (+)-Voaphylline 409,411 Voaphylline 358,359 (-)-Vobascnal 343,344,411 (-)-Vobasine 410-411 Vobasine-type alkaloid 343 (+)-Vobasinol 411 Vobasinyl moiety 384,425

Warifteine 55,64, 86,120, 136, 162,256 (-)-Xylopine 413 (-)-Xylopinine 395 Yanangcorinine 55, 75, 111, 128,135,161, 251,253 Yanangine 55,75, 111, 128,136,161,254 Yohimbane alkaloids 491 Yohimbine 336-338, 358 (+)-Yohimbine 398,408-409,415 a-Yohimbine 337,415 p-Yohimbine 337,358,408-409,415 Yuechukene 451,452 Zwitterionic quinoniminium form 386

529

Organism Index

Note: Tables containing organisms appear on pages 4-165, 287-315 and 393-416. Abuta 118,169,197,208 A. candicans 12,24, 77, 86 A. grisebachii 17, 21, 28-30,41, 77, 174, 201,217 A. pahni 16, 18, 28, 30-31, 34, 77 A. panurensis 36,41,77,238 A. splendida 5, 22, 27, 77, 197 Acacia auriculiformis 305 Acalypha grandis Benth. var. longiacuminata 298 A. indica 298 Acanthaceae 287 Acanthus ebracteatus 287 Achras Sapota 312 Acronychia laurifolia 311 A. porteri 311 Actinidiaceae 287 Actinodaphne glomeratus 301 A. montana 301 A. sesquipedalis 301,412 Adenanthera pavonina 305 Adenostemma lavenia 296 Aganosma marginata 292 Ageratum conyzoides 296 Aglaia argentea 418 A. leucophylla 304 Aglia argentea 393 A.forbesii 393 Agrostistachys gaudichaudi 298 Aizoacea 287 Alangiaceae 288 Alangium griffithii 288 A. unilcoulare 297 Albertisia 118, 169, 197, 260, 263, 323 A. crassa 305 A. laurifolia 5, 11, 15, 77, 197,262 A. papauana 208

A. papuana 11,14-16,22,26,28-29, 34, 37, 39,41, 78, 191, 195, 197,262,305, 323,413 Allamanda catharica 292 Allomorphia malaccensis 304 Allophylus cobbe 312 Alphonsea cylindrica 288 A.johorensis 288 A. kinabaluensis 288 Alseodaphne peduncularis 301 A. perakensis 412 A petiolare 301 ,4/sfowa 329, 347-348 if angustifolia 292-293, 339, 341, 380, 393,416-417 A. angustifolia var. latifolia 292 ^. angustiloba 293, 347, 369 i4. angustilofolia 398 A macrophylla 293, 342-343, 400,421 A scholaris 345, 347,400 A spathulata 293 A undulifolia 293, 348,400 Amaranthaceae 288 Amorphophallus campanulatus 295 Amplectrum divaricatum 304 Anacardiaceae 288 Anaxagoreajavanica 288 Ancistrocladaceae 288,316,395 Ancistrocladus 316 /I. tectorius 288, 316, 395 Andira surinamensis 302 Andrachne 116,211 A.cordifolia 11,41,78,88 Andrographis paniculata 287 Anisocycla 119, 197, 208,260, 263 A cymosa 11, 14,16, 29, 34-35, 54, 78, 194, 197-198

530 A. gradidieri 11,17, 19,45, 54, 78, 190191 A. jollyana 16,22,26-28,31,35,44-45, 54,78,194-195,208-209,261 Annonaceae 287-288,316,395 Annonaceous plants 320,393 Annonidium mannii 473 Anomospermum 119 A. grandifolium 55, 79, 247 Anthocephalus chinensis 308 Antidesma cuspidatum 298 A. pendulum 298 A. salicinum 298 Apama corymbosa 295 Apocynaceae 287,292, 329-330,350, 356, 398 Aporosa arborea 299 A. symplocoides 299 Araceae 295 Araliaceae 295 Araliaceae montana 295 Aralidium pinnatifidum 297 Arcangelisia 119,197, 208 A.flava 22,27,79,305 A loureiri 305 Ardiceae serrata 306 Ardisia colorata 306 if elliptica 306 if macrophylla 306 Argostemma irtvolucratum 308 Aristolochiaceae 295 Aristolochia 114, 169 A rfeftito 46, 79 A e/tgaitf 30, 79 if gigantea 21,40-41, 79 A /m/ica 12, 79 Aromadendron elegans 319,412 Artabotrys blumei 288 A. crassifolius 288 A. grandifolius 288, 395 if maingayi 288, 395 if suaveolens 288 if venustus 288, 319, 396 Asclepiadaceae 295 Asclepias curassavica 295 Aspidosperma duckei 361 if quebracho bianco 358

Asystasia nemorum 287 Atalantia kwangtungensis 311 ;f roxburghiana 311 Atherosperma 128 if moschatum 6,25, 79,211 ;f repandulum 79 Aulacodiscus premnoides 308 Averrhoa carambola 307 Avicennia alba 314 Baccaurea lanceolata 299 A motleyana 299 Bauhinia purpurea 296 Beilschmiedia 117 B.madang 16,79,204,301 Jferderfr 115,169, 174, 197,211,225-227, 229,234-235 A aggregata 6,79 A amurensis 6, 8, 39, 79 A aquifolium 6, 80 A arisata 5-6,81 A omtoto 5-7, 39, 79, 84 A asiatica 6, 80 A baluchistanica 6, 80, 194, 197 A boliviana 5-6, 8,22,25, 37-38, 52, 80 A brachypoda 8, 80 A brandisiana 6, 8,25,41, 80,214 A bumeliaefolia 5-6, 25, 80 A 6ta//o/fo 9-10,12, 39,46, 80,176,202, 224-226 A cM/e/tffc 6, 17,20,26, 30, 32, 80,174, 229,234 B.chitria 39,81 A circumserrata 8, 81 A cref/ai 5-6, 8,25, 37-38, 52, 81 A dasystachya 8, 81 A diaphana 8, 81 A dictyoneura 6, 8, 81 A c/uftia 8,81 A empetrifolia 25, 81 A ferdinandi-coburgii 8,81 B.floribunda 5-6,39,80-81 A fortunei 6,81 A fracisci-ferdinandi 6,81 B.gyalaica 8,81 A henryana 8, 81 A heterobotrys 6, 37, 39, 81

531 B. heteropoda 7-8,25, 39-40, 82, 85 B. himalaica 22, 82 B. horrida 9, 82, 225-226 B. iliensis 7-8, 37, 39, 82 B. integerrima 8, 39, 82 B. jamesiana 8, 82 B. japonica 7, 82 B.julianae 7-8,39,82 B. kansuensis 8, 82 B. kawakamii 7, 25, 82 B. koreana 5, 7, 25, 37, 39, 82 B. lambertii 7, 39, 82 B. laurina 5-6, 9, 17, 19-20, 22,27, 30, 37, 52,82,174,229,234 B lycium 7, 10,21,27, 39,43,45, 83, 205, 207, 261 B. mingetsensis 7, 25, 83 B. morrisonensis 7,25, 83 B. nummularia 5, 8, 25, 39, 83 B. oblonga 7-8, 29-30, 38-39, 83, 202, 214 B. orthobotrys 5, 7, 39, 83 B. paucidentata 7, 25, 37, 39, 83 B. petiolaris 7, 83 B. poiretii 7-8, 25, 84 B.polyantha 8,84 B. polymorpha 52, 84 B. prattii 8, 84 B. pseudambalata 37,39,84 B. pseudothunbergii 7, 84 B. regeliana 7, 84 B. repandula 226 B. sargentiana 8, 84 B. sibirica 7, 39, 84 B. silva-taroucana 8, 84 B soulieana 8, 84 B. stolonifera 5, 7-8, 18, 25, 84 B. swaseyi 7, 84, 96 B. thunbergii 7, 25, 40, 84 B. tinctoria 7, 84 B. tschonoskyana 37-38,40, 85 B. turcomanica 5, 8, 29, 32,40, 85, 214 B valdiviana 8,25, 37,46, 85,174 B. vernae 8, 85 B. virgetorum 7, 85 B. vulgaris 7-8,25, 39-40, 82, 85 B. waziristanica 5, 85 B. wilsoniae 7,26, 85

B. zebiliana 7, 85 Bhesa 335 B.paniculata 335,412 Biasolettia 94 B. nymphaeifolia 4, 19, 55 Blumea balsamifera 297 Boerhavia diffusa 306 Bombacaceae 296 Boraginaceae 296 Breynia coronata 412 Bridelia ovata 299 B. stipularis 299 B. tomentosa 299 Brucea javanica 313 Brugmansia suaveolens 313 Bruguiera cylindrica 308 Buchanania lucida 288 fluxw 116,246 £. sempervirens 12, 85 #. wallichiana 12,85 Byttneria maingayi 313 Caesalpiniaceae 296 Calamus javensis 307 Calotropis gigantea 295 Campanulaceae 296 Canangium odoratum 288 Canthium didymum 308 capitata 193 Capparidaceae 296 Capparis micracantha 296 C. scortechinii 296 Capsicum frutescens 313 Carallia brachiata 308 Carapa guianensis 304 Cardiopetalum 112,169 C. calophyllum 15,85 Caricaceae 296 Carica papaya 296 Carolina jasmine 480 Caryomene 119, 169 C. olivascens 9,16,18, 35, 85,192,195, 205,208 Casearia clarkei 300 Cassia siamea 302 C. spectabilis 296 Cassythafiliformis 301

532 Castanopsis lucida 300 Cayratia geniculata 315 Celastraceae 296,335,412 Celosia argentea 288 Centrosema pubescens 302 Cephaelis psychotrioides 308 Chasalia chartaceae 308 C. curviflora 308 C. pubescens 308 Chilocarpus costatus 293 C. obtusifolius 293 C vernicosus 293 Chisocheton ceramicus 304 Chloranthaceae 296 Chloranthus brachystachys 296 Chlorocardium rodiei 117 Chondendron toxicoferum 12, 24, 54-55, 86 Chondodendron 120,243-244,247 C candicans 86 C. limaciifolium 24, 34, 86 C microphyllum 246 C microphylum 12, 24, 86, 104 C platiphyllum 10, 12,24, 86,246 C tomentosum 10, 12-13, 24, 34, 54-55, 86, 246-248 Chonemorpha penangensis 293, 309 Cinnamomum iners 301 C. mollissimum 301 C. paraneuron 301 C. pubescens 301 Cissampelos 120,244,256-257 C. fasciculata 11,86,258 C insularis 13,86,98 C mucronata 24, 86 C ovalifolia 18, 30, 32, 55, 86,256-257 C /Nire/ra 10, 12-13, 21-24, 30, 87, 246, 248-249, 256,272 C. sutchuenensis 257-258 Claoxylon longifolium 299 Claviceps 470 Cleistopholis 112 C rfmidW 10, 13, 24, 87, 245-246 Cleome rutidosperma 296 Clerodendron deflexum 314 C disparifolium 314 C indicum 314 C inerme 314

C.japonicum 314 C. laevifolium 314 C. laurifolium 314 C myrmecophilum 314 C. serratum 315 Clerodundron wallichii 315 Clusiaceae 296 Cnestis palala var. pa/a/a 297 Cocculus 120,197,211,260,263,267-268, 270 C.hirsutus 11,26,55,87 C.japonica 45,190 C.japonicus 19,23-24,38,45, 87, 102 C. laurifolius 26, 55, 87 C/eaefe 11,29,40-41,87,268 C pendulus 10-11, 15-17,22-23,26-27, 29,33-34, 36,41,45-46, 54-55, 87,206, 211,220,260,266-267,269-270 C. sarmentosus 26,29,46, 55, 89, 268 C Jrr/otaf 11, 15,26, 35, 55, 89, 194, 268 Coffea canephora 309 Colubrina 132,169,208 C. asiatica 30, 89 C.faralaotra 14,27,89,200 Columbian dart frog 336 Commersonia barlramia 313 Compositae 296 Connaraceae 297 Convolulaceae 297 Coptosapeltaflavescens 309 C tomentosa 309 Comaceae 297 Coscinium blumeanum 305 C. wallichianum 305 Crataeva membranifolia 296 Crematosperma 12, 21, 33, 89, 112, 184, 187-188 C. polyphlebum 42, 89, 188 Crinum pratense 440 Crotalaria anagyroides 303 C. mucronata 303 C. rfriata 303 Croton argyratum 299 C.joufra 299 Cryptolepis sanguinolenta 439 Cucurbitaceae 297 Curare 33,43,132

533 Curarea 121,208 C candicans 9, 27-28, 89,195,209 Cyathocalyx pahangensis 288 C. scortechinii 289 Cyathostemma excelsum 289 C. hookeri 289 C way/ 289 Cyclea 122,197,208,211,243-244,246, 272,323 C. atjehensis 12, 14, 25, 89,245,248,258 C torfoita 7, 10,12-14,20, 22, 24, 26-27, 33, 35,44,46-47, 52, 89,200,208,211, 218,246 C burmanni 41,46,90 C. hainanensis 12-13,22,24, 30,90,246, 249 C. hypoglauca 14, 18, 23, 90, 245, 272 C tora/orfe 14,23-24, 34, 90, 272 C.laxiflora 305,413 C. madagascariensis 10, 13, 24,91 C pe/tafci 6, 13-14,20,24,46-47, 91, 200, 211,218,245 C racemosa 13,91,258 C. sutchuenensis 13, 23-25, 33, 46, 91, 180-182,272 C. tonkinensis 14, 91 Cyrtandromea acuminata 312 Cyrtandromoea acuminata 300 Dachothrix baueriana GO-25-2 453 Dalbergia junghuhnii 307 Daphnandra 16, 18, 36,43,92, 128, 197, 211,223-224,226,260,262,271 D. species Dt-7 20, 31,46,262 D. species 20, 25, 31, 33,46 D. apatela 5, 16,46, 91,260, 262 D. aromatica 5, 15, 91, 197 D. dielii 224 D. dielsii 15,31,43-44,46,91,200,222, 226,271 Djohnsonii 27,29, 31, 36,44, 91,200, 223-224,262 D. micrantha 14-15, 18, 31, 33,92,262 D. repandula 15, 31,44,92,200,224,271 D. repandulum 79 D. tenuipes 5, 36,44,46, 92, 197, 222224,271

Datiscaceae 297 Datura metel 313 Decaspermum fruticosum 306 Dehaasia 117, 197 D. caesia 301 D. incrassata 40, 92, 301,412 D. triandra 16, 37, 92,204,206 Derris multiflora 307 Desmodium umbellatum 307 Desmos chinensis 289 D. dasymachalus 316 D. dasymaschalus 289, 396 D. dasymaschalus Saff. var. wallichii 289 D. dasymaschalus var. walichii 396 Dialium platysepalum 303 Dichapetalaceae 297 Dichapetalum griffithii 297 Didymocarpus hispida 300 Dilleniaceae 297 Dioscoreaceae 297 Dioscorea hispida 297 D. scortechinii 297 Diospyros discolor 298 D. subrhomboidea 298 Dipterocarpaceae 298 Dipterocarpus crinitus 298 Dischidia rafflesiana 295 Disepalum pulchrum 289, 396 Dissochaeta cf. sagittata 304 Doryphora 129,197 Z). aromatica 5, 14-16,22,26, 92, 197, 260 Dracaena conferta 303 D. congesta 303 Drepanthus pruniferus 289 Dryadodaphne 129,235 £>. novoguineensis 19,93,235 Duranta erecta 315 Durio zibethinus 296 Dyera costulata 293 £>. laxiflora 293 D.polyphylla 293 Dysophylla auricularia 301 Dysoxylum cauliflorum 304 Ebenaceae 298 Eichornia crassipes 308

534 Elaeocarpaceae 298 Elaeocarpus brevipes 298 Epetiolatus 298 £ robustus 298 Elateriospermum tapos 299 Elephantopus tomentosus 297 Emblica officinalis 299 Enicosanthum congregatum 289 E.fuscum 289 £ membranifolium 289 Entamoeba histolytica 416-417 Enterolobium saman 303 Epinetrum 123,243 £ cordifolium 14, 24, 93 £ mangenotti 14,24,93 Evillosum 14,24,34,93 Ericaceae 298 Erichtites valerianifolia 297 Ervatamia 384 £ coronaria 293, 358 £ corymbosa 408 £ cylindrocarpa 293 £ Air/a 343, 384,409 £ macrocarpa 293 £ malaccensis 293, 348,410 £ microphylla 386,418 £ orientalis 348 £ peduncularis 293, 387,411 £ polyneura 293,343, 355, 386,411 Erycibe stapflana 297 Escalloniaceae 298 Eugenia longiflora 306 Euodia euneura 416 £ glabra 311 Elatifolia 311-312 £ macrocarpa 415 £ pachyphylla 416 Epilulifera 312,416 £ roxburghiana 416 Euphorbiaceae 287,298,412 Euphorbia atoto 299 Eurya acuminata 314 Eurycoma apiculata 313 Eusideroxylon zwageri 301 Fagaceae 300 Fagraea blumei 303

£ crenulata 303 F.fragrans 303 £ racemosa 303 Fibraurea chloroleuca 305 £ tinctoria 305 Ficoidaceae 300 Ficus annulata 305 £ deltoidea 306 Ffistulosa 306 Ffulva 306 £ grossularioides 306 £ A/rto 306 £ topiYfa 306 £ inrf/ai 306 Filetia glabra 287 Fissistigma lanuginosum 289 £ latifolium 289 £ manubriatum 289 Flacourtiaceae 300 Flagellariaceae 300 Flagellaria indica 300 Flueggea virosa 299 Friesodielsia acuminata 289 £ biglandulosa 289 £ calycina 289 £ korthalsiana 289 Froehner var. robusta 309 Garcinia parvifolia 296 Gardenia carinata 309 Gelonium glomerulatum 299 Gelsemium elegans 303 G. sempervirens 480 Gendarusa vulgaris 287 Geseriaceae 300 Gironniera nervosa 314 G. subaequalis 314 Globba pendula 315 Glochidion cf. brunneum 299 G. leiostylum 299 G. sericeum 299 G. wallichianum 299 Glycosmis calcicola 312 G. malayana 312 G. pentaphylla 312 G. sapindoides 312 Glyptopetalum quadrangulare 296

535 Gmelina arborea 315 G elliptica 315 Gnetaceae 300 Gnetum brunonianum 300 G. cuspidatum 300 G. latifolium 300 Gomphandra affinis 300-301 G quadriflda 301 Gomphia serrata 306 Goniothalamus curtisii 289 G.fulvus 290 G. malayanus 290 G. ridifey/ 290 G. rw/wj 290 G. subevenius 290 G. suluemis 290 G uvarioides 290 Goodeniaceae 300 Gouania javanica 308 Gramineae 300 Grewia tomentosa 314 Guatteha 113, 169, 186, 188, 197 G.gaumeri 18,93 G. guianensis 5, 9, 11, 14-17, 20-21, 34, 37,46,53,93, 185-186, 188, 194, 197, 260,262 G megalophylla 18, 24, 30, 93, 245 Gymnopetalum integrifolium 297 Gyrocarpus 116,208 G americanus 6, 21,26-27, 29-30,41, 43, 93,174,192,195,201,208 G jacquini 6, 21, 26-27, 29-30,41,43, 93 Harpullia arborea 312 Hazunta 348 Hedyotis capitellata 309 Heliotropium indicum 296 Heracleum 132 H.wallichi 14,24,94,245 Hernandiaceae 300 Hernandia 116,177 H.peltata 4 //. nymphaeifolia 4, 19, 55,94,181 //. ovigera 29, 94, 300 //. />e//a/a 19, 29, 55,94, 177, 180 H.sonora 29,94,180 Hernandifolia 193

Hibiscus mutabilis 304 Hippocrateaceae 300 Holarrhena 324 //. antidysenterica 324 K curtisii 324,400,417 Homalium caryophyllaceum 300 Horsfieldia superba 306,330,414 Hu-Mang-Teng 488 Hullettia dumosa 306 Hunteria zeylanica 293 Hypserpa cuspidata 305 Hyptis brevipis 301 Icacinaceae 300 Imperata cylindrica 300 Incarvillea sinensis 327 Indigofera teysmanii 303 Iridaceae 301 Isolona 113 /. hexaloba 14, 24, 34, 94, 242-243, 245 /.p/foja 13,24,94 Isopyrum 130 /. thalictroides 7,26, 31,46-47, 94, 200, 218 lsotoma longiflora 296 Ixora brunonis 309 /. coccinea 309 / congesta 309 /. nigricans 309 I.pendula 309 /. 5/ic/a 309 /. umbellata 309 Jacquemontia tomentella 297 Japonica 193 J. var. australis 193 Jasminum bifarium 307 Jatropha gossypifolia 299 Justicia ptychostoma 287 Kibatalia maingayi 293 Knema communis 306 Jfrprfa 326, 329-330, 350,354-356, 360361,368,388,393 tf. ar&orea 293-294, 369-370, 401 tf. dasyrachis 294, 326, 329, 352, 356, 360, 366, 368, 388,401, 419, 424

536 K. deverrei 345,365-366,402 K.fruticosa 294,360,403 K. griffithii 294,330,366,403,417 KJasminiflora 361,366,368,374 K. lapidilecta 294,376,404 K. larutensis 294, 350,404 K. macrophylla 294,329,404 K. mitrephora 294 K. officinalis 370 K. pauciflora 294,326, 352, 355,368, 374, 388,404,418 K. profunda 294, 366,406 K. singapurensis 294, 356, 361, 370,406, 418 K. sleeseniana 294 K. species 423 K. tenuis 294, 358, 377, 390-391,406,418 K. teoi 294, 356, 361, 370, 372, 388,406, 417 K. terengganensis 354,407 Kurrimia paniculata 296 Labiatae 301 Lauraceae 287, 301, 316,412 Laurelia 129,197 L. sempervirens 26, 38,40,44, 52, 94, 204 Laurentia longiflora 296 Leguminosae 302 Leishmania donovani 417 Lepidagathis longifolia 287 Lepionurus sylvestris 306 Leuconotis 329, 350,355-356 L. eugenefolia 356,358 L eugenifolia 294,408 L. griffithii 294,356,358,408 L maingayi 294 Lianas 316 Ligustrum sinense 307 Liliaceae 303 Limacia 123,208 L cuspidata 13,27-28,94,195 L. oblonga 13,27-28,95,195, 305,323, 413 Limaciopsis 123,197 L loangensis 7,14,23,26, 35,40, 51-52, 95,214 Linaceae 303

Undera 117 L. cubeba 302 L lucida 302 L oldhamii 28,95 L. oxyphylla 302 L.pentantha 302 L pipericarpa 302,412 L. spathacea 302 L spathacea var. tomentosa 302 Linociera montana 307 Litseaamara 302 L. elliptibacea 302 L. oppostifolia 302 L. spathacea 302 L. tomentosa 302 L. trunciflora 302 L. umbellata 302 Lochnera rosea 294 Loganiaceae 303 Lucida 43 Lycium Chinese 313 Lyonia ovalifolia 298 Lythraceae 304 Macaranga curtisii 299 M Au//tfft7 299 A/ irt/ofo 299 Madhuca korthalsii var. Lanceolata 312 A/, mindanaensis 312 Maesa impressinervia 306 A/, ramentacea 306 Magnoliaceae 304,316,319,412 Magnolia 197 A/, compressa 40,95 M.fuscata 28-29, 95-96, 174, 176 M maingayi 304 A/afemia 116,197 A/, acanthifolia 40,95 A/ aquifolium 5, 7,26, 38,40,95, 197 M borealis 40, 95 M.fortunei 7,40, 81,95 A/ £r#frA// 7,40,95 M.japonica 7,26, 82,95 A/, leschenaultii 40,96 A/, lomariifolia 7,26,96 A/, manipurensis 40,96 A/, morrisonensis 7, 26, 96

537 M. philippinensis 7,26,96 M. repens 38, 40, 52,96 M. siamensis 26, 96 M. sikkimensis 40, 96 M. simonsii 40, 96 M. swaseyi 7, 96 Mallotus cf. floribunda 299 M. philippinensis 299 Malvaceae 304 Mangifera caesis 288 Mastixia cuspidata 297 Meiogyne virgata 290, 320, 396 Melanolepis multiglandulosa 299 Melanorrhoea woodsiana 288 Melastoma schizocarpa 304 Melastomataceae 304 Meliaceae 304,393 Melia azedarach 304 Me lochia corchorifolia 313 Melodinus orientalis 294 Memecylon oleaefolium 304 Menispermaceae 287, 305, 316, 323,413 Menispermaceous plant 323 Menispermum 123, 169 M. canadense 15, 17, 96 A/, dauricum 15-16, 96 Merrillia caloxylon 312 Mezzettia umbellata 290 Michelia 117 M.fuscata 28-29,95-96, 174 Microdesmis ceasarifolia 299 Micromelum minutum 312 A/ pubescens 312 Miliusa longipes 290 Millettia abiflora 303 Millettis decipiens 307 Mimosaceae 305 Mimosa sepiaria 303 Mitragyna 329, 338 M speciosa 338-339,414,420 Mitrephora maingayii 290 Moghania macrophylla 307 Monocarpia marginalis 290,393 Moraceae 305 Morinda citrifolia 309 A/, elliptica 309 Muraya paniculata 312

Murraya paniculata 451 Myristicaceae 306, 330,414 Myrsinaceae 306 Myrtaceae 306 Naravelia laurifolia 308 Nauclea maingayi 309 Nectandra 117,188 M rafci 12,17,19, 36, 38-39, 44-45,9697,117,186,188-189,197,200 N. salicifolia 12,97 Nelumbo 130 M «i/c//era 25,27, 33, 97, 180 Nemuaron 130 AT. vieillardi 33, 97, 238 Neolitsea cassiaefolia 302 Af zeylanica 302 Nephelium glabrum 312 Notaphoebe panduriformis 302 Nothophoebe pahangensis 302 Nyctaginaceae 306 Nymphaeifolia 94 Ochanostachys amentacea 306 Ochnaceae 306 Ocimum basilicum 301 0cofea rorf/ei 12, 17, 19, 36, 38-39, 44-45, 96-97,117,200,246 Octomeles sumatranum 297 Olacaceae 306 Oleaceae 307 0/ea brachiata 307 0. maritima 307 Omalanthus populnea 299 Oncodostigma monosperma 290, 320, 397 Ophiorrhiza communis 309, 414 0. discolor 309 O. tomentosa 309,414 Orophea enterocarpa 290, 320, 397 Osmanthus scortechinii 307 Ostodes macrophylla 300 Oxalidaceae 307 Oxyceros curtisii 309 0. penangianus 309 Oxymitrafilipes 290 0. ftngtt 290 0 to/Jb/to 290

538 Pachygone 123, 197,211,255,260,263 P. dasycarpa 4,6, 11, 15,20,26,30, 32, 34,41,46,54,97,211,217,269 P. loyaltiensis 5,9,15-16,27,29,97,197 P. ovata 31, 37,40, 54-55,97,251,254, 263 P.pubescens 27,98 Palaquium ridleyi 312 Palmae 307 Pandanaceae 307 Pandanus recurvatus 307 Papilionaceae 307 Paracyclea 124,244 P. insularis 13,86,98 P. ochiaiana 13-14, 24,98, 272 Paramignya lobata 312 Passifloraceae 307 Passiflora foetida 307 P. laurifolia 307 P. quadrangularis 307 Pavetta graciliflora 309 P. indica 310 P. pauciflora 310 Payena obscura 304 Pellacalyx axillaris 308 P. saccardianus 308 Penicillium aurantiovirens 446 Pericampylus glaucus 305 Peruvian Curare 10, 13, 98 Petungafloribunda 310 Phaeanthus 124,208 P. crassipetalus 27,41,98,290 P. ebracteolatus 41,98,204 P. nutans 291 P. ophthalmicus 291 P. vietnamensis 18, 30, 98, 174 Phoebe grandis 321,412 P. macrophylla 302 P. 0/xmr 302 P. taroyna 302 Phytocrene bracteata 301 P. oblonga 301 Piperaceae 307 Piper aduncum 307 P. magnibaccum 307 P. porphyrophyllum 307 P. stylosum 307

Pithecellobium dulce 303 P. ellipticum 303 P.jiringa 303 Plasmodium falciparum 416-417 Plectocomiopsis geminiflorus 307 Pleiocarpidia capituligera 310 Pleogyne 124,244 P.australis 13,24,98 P. cunninghamii 13,24,98 Ploiarium alternifolium 314 Pluchea indica 297 Podocarpus teysmanni 314 Polyalthia 113,169 P. q#?w5 291 P. cauliflora 291 P. cinnamomea 291 P. clavigera 291 P. cunangiodes 291 P. hookeriana 291 P. hypoleuca 291 Pinsignis 291,320,397 P.jenkensii 291 P. macropoda 291,398 P. microtus 291,398 P. motleyana var. glabrescens 291 P. nitidissima 16, 18,25,28, 31, 98 P. rumphii 291 P. stenopetala 291, 319, 398 P. tenuipes 292 Polygalaceae 307 Polygala paniculata 307 Polyosma laete-virens 298 Polyscias cfjavanica 295 Pontederaceae 308 Popow/a 114,169,183 P. odoardoi 292 P. perakensis 292 P. pisocarpa 15, 30, 36, 40, 42, 98, 182, 292 P. ramosissima 292 P. tomentosa 292 Porterandia anisophylla 310 Pratia begoniaefolia 296 Premna tomentosa 315 Pseuderanthemum graciliflorum 287 Pseudoxandra 43, 114, 174, 186, 188, 197

539 P. aff. lucida 4, 29, 38-39,44-45,99,185186,188,194,250,253 P. sclerocarpa 9,22,45,49, 99, 174,250 Pseuduvaria macrophylla 292, 316, 398 P. monticola 292 Psychotria montana 310 P. rostrata 310,336,414 Pternandra echinata 304 Pterocarpus indicus 303 Pterospermum cf. elongatum 313 Ptychopyxis caput-medusae 300 Pycnarrhena 124,197,208 P. australiana 7, 26, 33, 35,41, 99 P. longifolia 6, 12, 15, 22, 27-28, 38, 99, 191,197,205 P. manillensis 8, 26,41-43, 99, 204, 209 P. novoguineensis 8,28,42-43, 52, 100 P ozantha 9, 15, 33,35, 37,43, 100, 191, 214 Randia anisophylla 310 R. densiflora 310 R. macrantha 310 R. macrophylla 310 R. scortechinii 310 R. stenopetala 310 Ranunculaceae 308 Rauvolfia perakensis 295 Rhamnaceae 308 Rhazya stricta 356 Rhizophoraceae 308 Rhododendron jasminiflorum 298 R. stenophyllum 298 Rhynchodia verrucosa 295 Roemeria hybrida 321 Roucheria grifflthiana 303 Rubiaceae 287,308,329,414 Rutaceae 287,311,415 Saccharothrix aerococlonigens 442 Salacia grandiflora 300 Salomonia cantoniensis 308 Sapindaceae 312 Sapium baccatum 300 Sapotaceae 312 Saraca declinata 296,303 Saurauia nudiflora 287

Scaevola taccada 300 Schefflerajunghuniana 295 Sciadotenia 125 5. eichleriana 21, 35, 100,174 5. /ojci/era 24,44, 100,241,243 Scrophulariaceae 312 Sesuvium portulacastrum 287, 300 Shorea curtisii 298 5. gfawca 298 S. resina-negra 298 shrubs 316 Sida rhombifolia 304 Simarubaceae 313 Simira maxonii 480 Sleumer var. quadriflda 301 Smythea lanceata 308 Solanaceae 313 Solatium blumei 313 S.ferax 313 5. nigrum 313 5. torvum 313 £ verbascifolium 313 Sonneratia acida 304 Spatholobus gyrocarpus 303 Sphenodesma barbata 315 Spirospermum 126, 208 S. penduliflorum 28, 100 Spongosorites ruetzleri 450 Stachytarpheta indica 315 S. jamaicensis 315 5. mutabilis 315 Staphyleaceae 313 Staurogyne lanceolata 287 Stemmatodaphne perakensis 302 Stemonaceae 313 Stephania 125,174, 193,197-199,211,244, 260,263, 323 5. capitata 14, 19, 100 5. cepharantha 5, 8,10,14,22,26, 34, 38, 100,197,199,242-243 £ dinklagei 19, 101 £ rffrco/or 18-20, 25, 27, 39,45-47, 101 S.epigeae 10,13-14,101,199 5. erecta 10,15,17,22,24,26, 31, 34-35, 37-38,45, 52, 101, 198-199, 262 5. excentrica 22, 101 S. glabra 14,17, 101-102,242

540 S. hernandifolia 18-20,25,27,39,45-47, 101,191,193,218 S.japonica 19,23-24, 38,45, 87,102, 190-191,272 S. japonica (Thunb.) Miers var. australis 19,23-24,45,52,102 5. japonica var. australis 190, 272 S. pierrii 5, 9-10, 14-17, 23,26, 33-35, 38, 45-46, 51, 102, 174,197-199,201,206, 214,242 & rotunda 102 S. sasakii 8, 10, 18, 30-31, 38,44,102, 195,199,261 S. sinica 10, 103, 199 S. suberosa 10, 34,36,45,103,190-191, 199 S. sutchuenensis 52, 103 S. tetrandra 8, 14,20,26,29-30,46, 103, 206,211,218 S. tetrandra S. Moore 39 S. venosa 23,51, 104 Sterculiaceae 313 Sterculia parviflora 313 Stichoneuion caudatum 313 Streptomyces chromfuscus 460 S. murayamaensis 445 S. staurosporeus 442 S. violaceus 2448-SVT2 460 Strombosia multiflora 306 Strychnopsis 127,211 S. thouarsii 20,46, 104 Strychnos ignatii 304,475 S. nux-vomica 475 S. ovalifolia 304 Swartzia pinnata 303 Swietinia macrophylla 304 Symplocaceae 313 Symplocos anomala 313 S. fasciculata 313 S. ophirensis 313 Synchosepalum Ml S. microphyllum 104 •Sywc/w/a 127,243,263 & sca&ri
Tabernaemontana 329,348, 355, 358, 384, 387 T. (Ervatamia) 348, 355 T. chippii 421 T. coronaria 295 r. corymbosa 295,348,408,421-422,425 T. divaricata 358, 384,386,409,418 r. glandulosa 386 T. A/r/a 409 7*. macrocarpa 295,410 T. malaccensis 295,410 T. markgraftana 421 T. pandacaqui 295 7*. peduncularis 295,411 T.polyneura 411 T. sphaerocarpa 295 Taccaceae 314 Tacca pinnatifida 314 Talauma betongensis 304,413 T. obovata 304,413 T. singapurensis 304 T. v/7/050 304

Tarenna fragrans 310 r. mo//w 310 Taxaceae 314 Tecomastans 419 Ternstrocmiaceae 314 Tetracera scandens 297 Tetractomia tetrandra 312 Tetrastigma hookeri 315 Thalictrum 130, 172, 175, 178, 197,203, 220-221,226-230,233-235,237 r. o/pmi/m 18,22, 33,48, 51-52, 104,230 T.baicalense 17,49,104,178 T. cultratum 5,12,17,23, 32-33,35-36, 38,40,48-53,104,175,197,203, 226227,229-230,232,234-237 T. dasycarpum 48, 105 T. delavayi 22,26,48, 51, 105 T. delavyi 221 T.faberi 17, 31-32,48, 50, 52,105, 175, 229 T.fargesii 47-49,106,230 T.fendleri 22,48,106 T.flavum 22,32,47-48,106,230 T.foetidum 8,22,26,32,47-51,106, 167, 232-233

541 T.foliolosum 48, 50, 52,106 T. fortune! 5,49,106,235 T. glandulosissimum 22,26, 31,48,106, 221 T. glaucum 5, 23, 33, 38,48-53,106,109 T. hernandezii 22, 106 T. isopyroides 49-50,106, 203 T.javanicum 50, 52,107 T. kuhistanicum 32, 51, 107, 235 T. lankesteri 22,107 T. longipedunculatum 32,47-48, 107, 167, 230 T. longistylum 17, 32,47, 50, 107, 178 T. Ipinum 230 T. lucidum 5, 23, 32, 38,40,47-48, 52, 107 T. minus 31-32, 38,40,47-52, 107, 167, 175, 178, 226-227, 232-233, 235 T. m. var. hypolecum 32, 108, 167 T. m. var. microphyllum 5,23, 32, 38,47, 49-50,52,108,174,175 T. m. var. majus 32, 38,40, 47, 49-50, 108 T. m. var. minus 32, 36, 48-49, 51, 53, 108, 226, 228 T. m. raceB. 108, 178 T. pedunculatum 8,108 T. podocarpum 17, 22, 26, 32, 48, 50, 108, 178,220-221 T. polygamum 52,109 T. revolutum 32-33,44, 48, 50, 109, 226 T. rochebrunianum 18-19, 22, 31, 34, 36, 47-48,53,109,167,220,239 T. rochebrunianum Franc. 39 T. rugosum 5, 23, 33, 38,48-53, 106, 109, 175,220,230 T. sachalinense 52, 110 T. simplex 22, 48, 50, 53,110, 167, 220 T. squarrosum 48, 110 T. sultanabadenst 22, 32,47-48, 110,220, 235 T. thunbergii 5,23, 32,48,110, 167,235 Thunbergia alata 287 T. natalensis 287 Tiliaceae 314 Tiliacora 127, 188, 206, 251-252, 255 T. acuminata 32, 37, 53-54, 110-111 T. dinkiagei 19-20, 37, 53,110,188,253

T.funifera 20,26, 37, 53, 110-111,188, 206,252 T. racemosa 32, 37, 53-54, 110-111,251252,254-255 T. triandra 19, 35, 37, 53-55,111, 188, 251-254 T. warneckei 20,37, 53,110-111 Tinomiscium petiolare 305 Tinospora crispa 305 Trema cannabina 314 Trichosanthes wallichiana 297 T. wawraei 297 Triclisia 128, 211,259,263,270 T. dictophylla 259 T. dictyophylla 11,54,111 r. gilletii 11,21, 25-26, 38,45, 54, 111, 190,259,269-270 T. patens 5, 11,42-43, 54, 112, 197, 259 T. subcordata 20, 46, 54, 112, 263 Trimeza martinicensis 301 Triphasia trifolia 312 Triumfetta rhomboidea 314 Trivaharia macrophylla 292, 319, 398 T. pumila 292 Turpinia ovalifolia 313 Turraea cf. breviflora 304 Ulmaceae 314 Uncaria 329,337,379,417 Uncaria (Rubiaceae) 336 U.acida 310,338 U. attenuata 336 U. borneensis 310, 337, 339,414 U. callophylla 310, 337-338, 379-380, 415,417 U. canescans 336 U. cordata 310 U. cordata Merr. var. cordata 310 U. cordata Merr. forma sundaica 311 U. cordata var. cordata f sundaica 415 U. cordata var. ferrugineaf ferrugine 415 U.elliptica 311,336,338 U.ferrea 311 U.gambir 311,338 U. homomalla 336 U. Iqnosa Wall var.ferrea 311 U. lanosavax.ferrea 415

542 U. longiflora var. longiflora 415 U. longiflora var. pteropoda 311,415 U. macropylla 336 U.ovalifolia 311 U.parviflora 311 U. pteropoda 311,336 U. roxburghiana 311 U. sclerophylla 311 U. umbellatum 311 undergrowth tree shrub 336 Urophyllum macrophyllum 311 (/. trifurcum 311 £/. umbellatum 311 Urticaceae 314 Uvaria 114 £/. /o^wj/wr 292 £/. ovata 10,112,246 £/. sorzogonensis 292 Vaccinium dialypetalum 298 K lauhfolium Miq. var. ellipticum 298 K viocifolium var. bicalcaratum 298 Verbanaceae 287,314 Verbena bonariensis 315 Vernonia arborea 297 K c/ntrfo 297 V.patula 297 Villebrunea silvatica 314 Vitaceae 315 Vitexnegundo 315 K ovfl/a 315 V. pubescens 315 Voacanga havilandii 295 Xanthophyllum excelsum 308 A! palembanicum 308 Xanthorrhiza 132,197 A. simplicissima 38,40, 112 Xanthoxylum hirtellum 312 Xylopia caudata 292 Xferruginea 292,398 A/use* 292 A! stenopetala 292 Zanthoxylum myriacanthum 312 Zingiberaceae 315