A Specialist Periodical Report The Alkaloids Volume 1 A Review of the Literature Published between January 1969 and June 1970 Senior Reporter J . E. Saxton, Department of Organic Chemistry, The University of Leeds Reporters A. R. Battersby, Cambridge University K. W. Bentley, Reckitt and Sons Ltd., Hull 0. E. Edwards, National Research Council of Canada, Ottawa R. Goutarel, Centre Nationale de la Recherche Scientifique, Gif-sur- Yvette, France A. Gorman, Manchester University R. B. Herbert, University of Leeds M. Hesse, University of Zurich W. H. Hopff, University of Zurich J. A. Joule, Manchester University E. Schlittler, Heidelberg University H. Schmid, University of Zurich V. A. Snieckus, University of Waterloo, Canada E. W. Warnhoff, University of Western Ontario, Canada P. G. Waser, University of Zurich SBN: 85186 257 8 0 Copyright 1971 The Chemical Society Burlington House, London, WIV OBN Set in Times on Monophoto Filmsetter and printed offset by J. W. Arrowsmith Ltd., Bristol, England Made in Great Britain Foreword This volume is the first in the series of annual Specialist Periodical Reports devoted to the chemistry of the Alkaloids. In preparing this first volume our aim has been not simply to record progress during a selected period, but also to include whatever background material and earlier references are necessary to enable the new work to be placed in perspective in its own particular area; in consequence we hope that the reader, whether the alkaloid specialist or the general reader, will be able to read and benefit from the discussions presented here with the minimum of reference to the standard monographs on the subject. The alkaloid literature has been reviewed up to the end of June 1970, but for convenience most authors have started their literature surveys from January 1969 ; this inaugural volume, therefore, properly represents a summary of developments in the subject during an eighteen-month period. The whole field of alkaloid chemistry has been reviewed with the exception of the steroidal alkaloids of the Solanum and Veratrum groups. It has not proved possible owing to limitations of space to include these sub-groups in the present volume, and it is therefore planned to include a review of developments in this area during a two-year period in the second volume. Although the Specialist Reports will normally consist of comprehensive annual reviews of alkaloid chemistry, we have included in this volume three chapters which, in view of their scope and character, are of a different type. The first of these is an authoritative statement on the biosynthesis of the terpenoid indole alkaloids, the main features of which are now reasonably well understood. It also seemed a most propitious moment in which to review the fascinating group of bisindole alkaloids and it will, I think, be generally agreed that the inclusion here of a definitive review by Professor Schmid and his Zurich colleagues fills a major gap in the alkaloid literature. The third non-recurrent review is by Dr. Schlittler, who has contributed a survey on the applications of alkaloids in the fields of pharmacology and clinical medicine during the last fifteen years, i.e. during the ‘post-reserpine’ period. In these Reports the pharmacology of the alkaloids will not normally be discussed, but it is appropriate to remember that the actual or reputed physiological activities of plant extracts and their wide- spread use in folk medicine have frequently provided the stimulus for the initial chemical investigations ; and while the fascinating chemistry subsequently iv A lkalo ids revealed has proved sufficient intellectual reward to the academician, the occa- sional discovery of substances of clinical value has provided a welcome bonus. This volume is the result of a cordial and enthusiastic collaboration between a team of alkaloid specialists in which I have done little more than plan the volume, plead for assistance, co-ordinate the final results, and exercise general editorial supervision. It is appropriate, therefore, that I should record here my gratitude to my collaborators for their eager participation and for the efforts they made to ensure the prompt submission of their contributions. Aside from the deliberate omission of part of the steroid field it is likely that there will also be inadvertent omission of some minor sub-groups of alkaloids, or of material from comparatively inaccessible journals. I shall be pleased to receive information concerning any such omissions, and constructive criticisms or suggestions concerning the preparation of future Reports will also be welcomed. J. E. SAXTON Contents Chapter 1 Biosynthesis-I. General By R. B. Herbert Pinidine and Coniine 1 Nicotiuna Alkaloids 3 N-Methy lpelletierine 4 Lycopodium Alkaloids 5 Lythraceae Alkaloids 6 Pyrrolizidine Group 8 Tropane and Fyrrolidine Alkaloids 9 Quinoline and Acridone Alkaloids 12 Benzodiazepine Alkaloids 15 Tyloplroru Alkaloids 15 Cactus Alkaloids 16 Ephedrine 18 Benzylisoquinoline Alkaloids 19 Homoaporphines 22 Erythrinu Alkaloids 22 Amaryllidaceae Alkaloids 24 Ergot 27 Indolmycin 30 Chapter 2 B iosynthesis-l I. Terpenoid I ndole Alkaloids 31 By A. R. Battersby Chapter 3 Pyrrolidine, Piperidine, and Pyridine Alkaloids By V. A. Snieckus 1 Pyrrolidine Alkaloids 48 2 Piperidine, Pyridine, and some Terpenoid Alkaloids 48 Piperidine and Pyridine Alkaloids 48 Mono- and Sesqui-terpenoid Alkaloids 52 vi Alkaloids Chapter 4 Tropane Alkaloids 55 By J. E. Saxton Chapter 5 The Pyrrolizidine Alkaloids By J. E. Saxton 1 Structure, Stereochemistry, and Reactions of the Necines 59 2 Simple Pyrrolizidine Alkaloids 63 3 The Ester Alkaloids 64 General 64 Monoester Alkaloids 64 Diester Alkaloids 68 4 Pharmacological Aspects 75 Chapter 6 The lndolizidine Alkaloids By J. E. Saxton 1 Zpomoea Alkaloids 76 2 Eheocarpus Alkaloids 76 3 The Tylophorine Group 81 Chapter 7 Quinolizidine Alkaloids By J. E. Saxton 1 LupineGroup 86 A Occurrence, and Isolation of New Alkaloids 86 B Bicyclic Alkaloids 88 C Tricyclic and Tetracyclic Alkaloids 89 2 Ormosia Alkaloids 92 3 Cryptopleurine Group 93 Chapter 8 Quinoline, Quinazoline, Acridone, and Related Alkaloids By V. A. Snieckus Quinoline Alkaloids 96 Quinazoline Alkaloids 100 Acridone Alkaloids 101 Contents vii Chapter 9 P-Phenethylamines and Simple lsoquinoline 103 A1 ka lo ids By V. A. Snieckus Chapter 10 The lsoquinoline Alkaloids By K. W. Bentley 1 Isoquinolines 106 2 Benzylisoquinolines and the Emetine Group 107 3 Pavine and Isopavine Alkaloids 110 4 BerberineProtopine Alkaloids 111 5 Spirobenzylisoquinolines 113 6 Bisbenzylisoquinolines 114 7 Aporphines and Proaporphines 117 8 Phenethylisoquinolines and Their Derivatives 120 9 Morphine Group 122 10 Other Alkaloids 135 Chapter 1 1 Amaryllidaceae Alkaloids 138 By V. A. Snieckus Chapter 12 Erythrina and Related Alkaloids By V. A. Snieckus Erythrina Alkaloids 145 Homoerythrina Alkaloids 148 Cephalotaxine Alkaloids 149 Chapter 13 lndole Alkaloids By J. A. Joule 1 Simple Indoles 150 Non-tryptamines 150 Non-isoprenoid Tryptamine Derivatives 153 2 Isoprenoid-tryptamineand -tryptophan Alkaloids 157 Non-terpenoid Bases 157 Monoterpene Bases 162 Yohimbine-Corynantheine (and Related 0xindoles)- 162 Picraline Group ... Vlll A lkaloids Strychnine-Akuammicine-Cond ylocarpine- 172 Uleine Group Sarpagine-Ajmaline Group 174 Aspidospermine-Aspidofractine Group 178 Eburnamine Group 185 Ibogamine Group 186 Secodine Group 189 Rearrangements of Iboga and Aspidosperma Types 193 3 Biogenetically Related Quinoline Alkaloids 197 Chapter 14 Bisindole Alkaloids By A. A. Gorman, M. Hesse, H. Schmid, P. G. Waser and W. H. Hopff 1 Calycanthaceous Alkaloids 20 1 Calycanthine 20 1 Folicanthine, Chimonanthine, meso-Chimonanthine, 202 and Calycanthidine Hodgkinsine 205 Quadrigemine A and Quadrigemine B 207 2 Alkaloids from Calabash-curare 209 Introduction and Interrelationships 209 Acid-catalysed Isomerisations of Calabash-curare 216 Alkaloids Anhydro-i socalebassine 216 The Ultracurines 219 3 Alkaloids with the Tubulosine Skeleton 223 4 Cinchophyllamine and Isocinchophyllamine 225 5 The Roxburghines 226 6 Haplophytine 228 7 Geissospermine and Geissolosimine 230 Geissospermine 230 Geissolosimine 236 8 The Secamines and Presecamines 237 The Secamines 237 The Presecamines 240 9 Alkaloids of the Voacamine Type 242 Voacamine 242 18'-Demethoxycarbonylvoacamine, Voacamine-N,,-oxide, and Voacamidine 246 ix Contents Voacorine and 20‘-Epivoacorine 247 Gabunine, Conodurine, and Conoduramine 247 Mass Spectral Behaviour 248 10 Alkaloids of the Vinblastine Type 250 Vinblastine and Vincristine 250 Leurosidine 253 Leurosine, Pleurosine ( = leurosine-Nhr(,,-oxide),and 254 ‘Tsoleurosine’( = 4’-desoxyvinblastine) Cathavine 257 Mass Spectra 257 11 The Pycnanthine Group 257 Pycnanthine and Pleiomutinine 257 ( + )-Pycnanthinine 264 12 Bisindole Alkaloids from Alstonia Species 265 Villalstonine 265 Macralstonine 269 Macralstonidine 275 13 Pleiomutine and Umbellamine 279 ( - )-Pleiomutine 279 ( -)-Umbellamine 282 14 Gabonine 286 15 Serpentinine 287 16 Alkaloids of the Vobtusine Type 293 Vo btusine 294 Owerreine, Goziline ( = desoxyvobtusine?), 304 and Amataine Vobtusine Lactone and Desoxyvobtusine Lactone 305 Voafoline, Isovoafoline, Voafolidine, and Folicangine 306 Callichiline 306 Recent Developments 314 17 General Remarks concerning Bisindole Alkaloids 315 U.V. Spectra and Ceric Sulphate Reactions 315 I.R. Spectra 320 N.M.R. Spectra 32 1 Mass Spectra 322 Transme t h yla tion 322 Retro-Diels-Alder Reactions 324 Further Pyrolysis Reactions 324 Molecular