THE PLANT ALKALOIDS BY THOMAS ANDERSON HENRY D.Sc.(Lond.), Formerly Director, Wellcome Chemical Research Laboratories and Superintendent of Laboratories, Imperial Institute, London. FOURTH EDITION THE BLAKISTON COMPANY Philadelphia • Toronto 1949 First edition . . .1913 Second edition . . 1924 Third edition . . . 1939 Fourth edition . . 1949 This book is copyright. It may not be reproduced by any means, in whole or in part, without permission. Application with regard, to copyright should be addressed to the Publishers. Printed in Great Britain and published in London by J. &• A. Churchill Ltd. 104 Gloucester Place, W.i. PREFACE TO THE FOURTH EDITION So much information concerning alkaloids has been published since the third edition of this book was issued in 1939, that the preparation of a new edition has involved re-writing a large part of the volume and adding considerably to its bulk. The material available has been dealt with, as in the previous edition, primarily on the.basis of a chemical classification according to nuclear structure, but as Nature does not produce alkaloids to meet the needs of either botanical or chemical systematists, strict observance of such a system would in some measure obscure those biological relationships among alkaloids which are at present attracting much attention from research workers. Accordingly this primary chemical classification has been modified, in cases where an extensive series, including several chemical types, occurs in one plant, or in closely related plants. When this results in a chemical group being dealt with in more than one place, cross references have been provided as a convenience to the reader. The author is, much indebted to Mr. L. G. Goodwin, B.Sc., B.Pharm., for reading certain of the pharmacological sections, and to Dr. S. Smith and Dr. A. C. White for advice on various points on which they are recognised experts. He also owes grateful thanks to Mrs. Henry for unstinted help in checking references, reading proofs and the maintenance of an index to the literature of alkaloids. The preparation of the type- script, and the typing of the numerous new and complicated graphic formulae, in a form suitable for photographic reproduction, was undertaken by Miss I. Bellis, to whom the author is greatly indebted for the untiring patience and meticulous care she has devoted to this task. He has also to thank the publishers for the kindly and sympathetic consideration they have given to all the technical problems raised in the course of printing the volume. Finally, the author owes to the customary generosity of the Wellcome Foundation Limited office accommodation and working facilities, without which this book could not have been prepared. T. A. HENRY. LONDON. PREFACE TO THE FIRST EDITION IN certain respects the plant alkaloids rank among the most interesting of naturally occurring substances. For the most part they are of complex structure, so that the determination of their constitution and the discovery of methods of producing them synthetically offer attractive problems to the chemist; and though a great deal has been accomplished, much still remains to be done in this direction. Their mode of origin and their function in plants are still unknown, and these two questions, with the more important one of correlating the structure of the alkaloids with their physiological action, form still almost untouched fields for combined work on the part of physiologists and chemists. Many of the alkaloids are of great importance in medicine, and the manufacture of these alkaloids and of products containing them constitutes an important branch of the " fine chemical " industry. In compiling this volume the author has kept in view these various aspects of the subject, and the articles on all the more important alkaloids describe not only the properties and the chemistry of these products, but also their occurrence, methods of estimation, and physiological action. In most cases the original memoirs have been consulted, and references to these are given in footnotes, but for descriptions of the physiological action of the better-known alkaloids Professor Cushny's " Textbook of Pharmacology and Therapeutics " has been largely utilised. The chemical nomenclature and the system of abbreviations used are, with a few unimportant exceptions, those employed in the " Abstracts " published by the Chemical Society of London, with which most English-speaking chemists are familiar. For much laborious work in checking formulae and references and in reading proofs, the author is indebted to Mrs. Henry, B.A., B.Sc. (Lond.), and to Miss A. Holmes, B.A. (Lond.). CONTENTS PAGE Introduction 1X Pyridine Group. Piperine, Piperovatine, Leucenol, Mimosine, Alkaloids of Ricinus communis, Foenugrec, Areca Nut, Hemlock, Lobelia, Tobacco (Nicotiana spp.), Anabasis aphylla, Pome- granate Root Bark . . . . . . .. 1 Tropane Group. Solanacedus Alkaloids, Convolvine and Allied Alkaloids, Dioscorine, Alkaloids of Coca Leaves (Erythroxylon coca) 64 Lupinane Group. Alkaloids of the Papilionacese: Lupinine, Lupam'ne, Sparteine, Anagyrine, Cytisine, Matrine and Asso- ciated Bases . . . . . . . • . . 116 isoQuinoline Group. Alkaloids of Cactaceas : Mezcaline, etc. . . . . . .. 154 Hydrastis canddensis: Hydrastine . . . . .162 Rhceadales 169 Opium (Papaver somniferum) : BenzyKsoquinolines ; Phthalide- t'soquinolines ; Morphine Sub-group, Sinomenium acutum . 175 Other Papaver spp. : Rhoeadine, etc. . . . .. 274 Other Papaveraceous Genera : a-Naphthaphenanthridines . 277 Corydalis and Allied Genera: Tetrahydroproioberberines; Cryptopine Sub-Group ; Aporphine Sub-group . . . 284 Anonaceae, Lauracese, Monimiacese; Anolobine, etc. . . 317 Berberis and Related Bases ; Berberine, Canadine, Palmatine, Coptisine, etc. . . . . . . . .. 3 28 BISBENZYLwoQUINOLINE SUB-GROUP Berbamine, Oxyacanthine . . . . . . . 346 Alkaloids of the Menispermacese; Coclaurine, Dauricine, Magnoline, Tetrandrine, Bebeerine, etc 349 Alkaloids of Curare ; Curine, Tubocurarine, Protocuridine, Calabash-curare I, etc., including Erythrina alkaloids . 371 Alkaloids of Ipecacuanha . . . . . . 394 Phenanthridine Group. Alkaloids of the Amaryllidacese ; Lycorine, etc 406 vii viii CONTENTS PAGE Quinoline Group. Dictamnine, Skimmianine, Fagarine. . . 413 Alkaloids of Cusparia Bark . . . . . . . .415 Cinchona spp. . . . . . . . 418 Indole Croup. Abrine, Gramine, Calycanthine . . .. 484 Alkaloids of Peganum harmala . . . . . .. 4 88 Evodia rutcecarpa . . . . . . . . 498 Yohimbe, Quebracho, etc. . . . . .. 5 00 Ergot 517 Calabar Bean 539 Strychnos spp. . . . . . . .. 5 53 Pyrrolidine Group 599 Pyrrolizidine Group . . . . . . . .. 6 01 Quinazoline Group . . . . . . . .. 6 17 Glyoxaline Group . . . . . . . .. 6 21 Alkaloidal Amines . 630 Steroidal Alkaloid Group 661 Alkaloids of Undetermined Constitution . . . .. 7 16 Minor Alkaloids 771 Recorded Occurrences of Alkaloids 779 Index 784 PLANT ALKALOIDS INTRODUCTION THE literature of alkaloids can conveniently be divided into five sections, dealing with (1) the occurrence and distribution of these substances in plants ; (2) biogenesis, or the methods by which alkaloids are produced in the course of plant metabolism; (3) analysis, ranging from the commer- cial and industrial estimation of particular alkaloids to the separation, purification and description of the individual components of the natural mixture of alkaloids, which normally occurs in plants ; (4) determination of structure ; and (5) pharmacological action. In the period that has elapsed since the third edition of this book was published there have been additions to each of these sections, and to some of them the new contributions have been numerous and important. Many new alkaloids have been described and new occurrences recorded. An interesting feature of this section of work is the operation of a number of what may be called alkaloidal surveys, ranging from searches for alkaloidal plants to investigations of plants of a particular botanical order, or of a selected botanical genus, or of geographical or other variants of a single species. In Soviet Russia, Massagetov 1 has made a preliminary examination of 113 species collected hi Central Asia, out of which he has found promising materials among lichens, mosses and liverworts, some varieties of maize, cotton and beans, certain species of Picea and Pinus, and a specially rich source in Dipsacus azureus belonging to the Dipsacaceae, a botanical family which like the allied Compositse, has not been a frequent source of alkaloids. In the same country, in 1939, Lazur'evskii and Sadikov 2 examined over 200 plants collected by various expeditions in Central Asia and recorded alkaloids in a number of species, including Aconitum talassicum and Convolvulus hamadce, the alkaloids of which have since then been investigated in detail as described later. Mention may also be made of the comprehensive volume on " The Poison Plants of New South Wales," compiled by Evelyn Hurst under the direction of the Poison Plants Committee of the University of Sydney. It includes numerous monographs on plants containing toxic alkaloids and should be of great value to research workers concerned with plant chemistry. In the course of the intensive campaign carried on in the United States of America during the war for the discovery of effective anti- malarial drugs, a team of workers 3 made anti-malarial tests on 600 different plants belonging to 123 families of phanerogams and three families of cryptogams, and it is recorded that the suppressive activity shown by some of these plants appeared to be associated with alkaloidal fractions of their extracts. x INTRODUCTION Of surveys with a narrower alkaloidal objective, mention may be made of the systematic work done by E. P. White and his collaborators in ascertaining the distribution of perloline in Lolium and allied grasses in New Zealand, and that of the same author in the examination of over 200 leguminous species, to ascertain the nature of their alkaloidal compo- nents and the effect of conditions on the alkaloidal content of various organs. Manske's work on alkaloids of Fumaraceous plants and of Lycopodium species also needs mention in this connection; it has not only resulted in new and interesting additions to the list of alkaloids, but the results, like those of White, have a bearing on the suggestion sometimes made that the nature of the substances present in plants may usefully be taken into account in some taxonomical problems. This suggestion is not as novel as is sometimes supposed, and Raymond-Hamet,4 in his paper maintaining the separation of Chevalier's genus Pseudocinchona from Corynanthe, on the ground that Pseudocinchona africana contains the alkaloids corynanthine and corynantheine, whereas Corynanthe paniculata yields yohimbine, makes the following statement: " Alphonse de Candolle a affirme que les phenomenes de physiologic (et par consequent les propriete's biochimiques et notamment la composition chimique) peuvent frtre envisages . . . comme caracteres d'une espece, d'un genre, d'une famille, d'une classe de vege'taux." 5 In this connection Manske 6 has suggested that the question whether Fumariacese and Papaveraceae, together forming the order Rhoeadales, should continue to be regarded as separate botanical families or be merged, can be settled in favour of the second alternative by a consideration of the nature of the alkaloids present in the plants, and he provides in support an interesting summary of existing information on this point. On the other hand, the number of cases of the occurrence of the same alkaloid in plants, which cannot be regarded as closely related botanically, justifies taxonomists in being cautious about freely accepting chemical evidence of this kind. Nicotine, for example, is found not only in the Solanaceous genera Nicotiana and Duboisia, but also in Asclepias (Asclepiadaceae), Equisetum (Equisetacese), Lycopodium (Lycopodiacese), Sedwn acre (Crassulacese) and Eclipta alba (Compositse), and as further instances, anabasine occurs both in Nicotiana glauca and Anabasis aphylla (Cheno- podiaceae), whilst ephedrine is not only present in Ephedra spp. (Ephe- dracese), but has also been recorded from Taxus baccata (Taxaceae) and Sida rhombifolia (Malvaceae) and its near relative d-nor-</i-ephedrine is the " cathine " of Catha edulis (Celastracese). More remarkable still is the case of berberine, which occurs in at least sixteen genera belonging to six different botanical families. Further, alkaloids of quite different types may occur in the same plant, for example in the opium poppy, and in Aconitum Napellus, in which ephedrine and sparteine have been recorded, as well as the typical aconite alkaloids. More information is in fact needed of the kind provided by the surveys undertaken by White and by Manske before chemical knowledge of plant constituents can be safely and generally applied to problems of plant classification. In the introduction to his INTRODUCTION xi series of papers on the alkaloids of the Leguminosse, White points out that although this order has been investigated perhaps more than any other for alkaloids, there is still uncertainty regarding the nature and distribution of alkaloids even in some common species, that little is known of the alka- loid content of common European plants grown under new conditions, for example in the Southern Hemisphere, that a large number of factors are capable of altering the alkaloidal content in quantity and nature, and that in much of the older European literature there is uncertainty due to incomplete chemical investigation. Although the number of alkaloids still in use in medicine is small, serious difficulty was caused by the war, due to the cutting-off of the usual sources of supply of the natural drugs which yield essential alkaloids, such as atropine, cocaine, hyoscine, morphine, emetine and ergometrine. Shortages were met as far as possible by new sources of supply and by local cultivation of the opium poppy, belladonna and other necessary drugs. This necessity provided new opportunities for the collection of experimental data regarding the possibility of plant selection and ot the effects of environment and of changes in cultural conditions on yield of alkaloids. An interesting account of the kind of work this involves will be found in the paper by W. O. James referred to below. One outcome of this work is the observation by workers in several countries that in solanaceous plants the tropane alkaloids are formed mainly in the roots.7 The plants generally used were belladonna, stramonium and Duboisia spp., and the necessary cultivation experiments were similar to those briefly described under the alkaloids of tobacco. The problem is, however, more complex than the results of these special observations seem to imply, and W. O. James,8 in the course of an account of work done by the Oxford Medicinal Plants Scheme on the biosynthesis of the belladonna alkaloids, states that alkaloids are first formed in the meristem of the radicle and can be detected when the radicles are 3 mm. long, but also shows that detached belladonna leaves can be induced to increase their alkaloidal content. He concludes that on the evidence available it is possible that the leaf alkaloids have a dual origin : by synthesis in situ and by translocation from the root. A curious observation, first made by Barnard and Finnemore 9 in the course of a systematic examination of Duboisia myoporoides in the whole range of its distribution in Australia, is that in this plant the relative proportions of the two main alkaloids is extremely variable, hyoscine being predominant in plants of the northern area and hyoscyamine in those of the southern region. Hills, Trautner and Rod well,9 continuing this work, confirmed this general result, but in the course of selection trials found that individual trees could exhibit the same variation ; the leaves of one specimen at Nambour, Queensland, contained in October about 3 per cent, of almost pure hyoscyamine and in April about the same amount of almost pure hyoscine. Trautner,10 in a paper dealing with these anomalies, and also discussing the possible modes of origin of the various amino- alcohols, tropine, 0-tropine, scopine, etc., and of the acids, tropic, benzoic, xii INTRODUCTION veratric, tiglic and wovaleric, which esterify them, suggests that in Duboisia and other solanaceous species two systems are in operation. The hyoscine system occurs alone in certain northern Duboisia myo- poroides, and forms scopine, ^r-tropine, dihydroxytropane and, in Datura meteloides, teloidine. Of these amino-alcohols, all the scopine is esterified by tropic acid and the minor bases by tiglic, methylbutyric or isovaleric acid, which contain the isoprene skeleton and are presumed to arise from that source. The hyoscyamine system is found alone in some adult Duboisia Leichhardtii and possibly in some southern D. myoporoides. It produces tropine and nortropine only, which are esterified with tropic acid, or as in opoatropine found in belladonna, with atropic acid, and to a small extent with the isoprene acids referred to above. Some tropine or nortropine may occur as such. Scopine, ^-tropine and dihydroxytropane are attsent. The hyoscine system occurs alone in all young plants and may continue throughout life in specimens in the northern area : it may represent the original alkaloid metabolism of the plant. The hyoscyamine system appears only at the age of four to six months, and in the southern area it replaces the hyoscine system almost completely ; it appears to be an adapted system and may represent the adult alkaloid metabolism of the plant. Usually both systems are present in varying proportions. It may be noted that Datura Metel, in which hyoscine is usually the predominant alkaloid, has been recorded in one instance by Libizov u as containing hyoscyamine, but no hyoscine, and a similar difference is mentioned for Scopolia lurida.11 In Robinson's now well-known suggestions,12 regarding the processes by which alkaloids may be produced in plants, two main reactions are used ; the aldol condensation and the similar condensation of carbinol- amines, resulting from the combination of an aldehyde or ketone with ammonia or an amine, and containing the group . C(OH) . N., with substances in which the group . CH . CO . is present. By these reactions it is possible to form the alkaloid skeleton, and the further necessary changes postulated include oxidations or reductions and elimination of water for the formation of an aromatic nucleus or of an ethylene derivative. This theory has stimulated activity in two main directions, suggestions for changes in detail in the steps of processes for particular alkaloids, and work on laboratory syntheses of known alkaloids, using the reactions specified and operated under conditions which might obtain in a plant, i.e., under what are now described as physiological conditions. All the results indicate that the theory is well-founded, and it seems possible that a technique may eventually be found by which the process may be observed in operation, directly or indirectly, in situ, say in a solanaceous plant. After determination of the seasonal variation in alkaloidal content of the leaves, stems and roots of belladonna and the production of evidence that there is a considerable movement of alkaloid upwards from root to leaves and a small transport in the opposite direction, Cromwell13 found that of a large number of amines injected, with or without glucose, into