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THE ALKALOIDS Chemistry and Physiology

VOLUME V I

This Page Intentionally Left Blank

THE ALKALOIDS Chemistry and Physiology Edited by

R. H. F. MANSKE Dominion Rubber Research Laboratory

Guelph. Ontario

VOLUME V I SUTPLEMENT TO VOLUMES I AND I1

1960

ACADEMIC PRESS

*

NEW YORK

*

LONDON

ACADEMIC PRESS INC. 111 FIFTHAVENUE NEWYORK3, NEWYORK U.K. Edition, Published by ACADEMIC PRESS INC. (LONDON) LTD. 40 PALLMALL, LONDON,S.W.l

Copyright @ 1960 by Academic Press Inc.

All rights reserved N O PART OF THIS BOOK MAY B E REPRODUCED IN A N Y FORM, B Y PHOTOSTAT, MICROFILM, OR A N Y OTHER MEANS, WITHOUT WRITTEN PERMISSION FROM THE PUBLISHERS.

Library of Congress Catalog Card Number: 50-5522

Printed in Great Britain by W. S. Cowell Ltd, Ipswich, SulTolk

PREFACE Since the publication of Volumes I through V of “The Alkaloids” remarkable advances have been made in all areas of research on alkaloid chemistry. The two volumes numbered as V I and VII have been organized on the same plan as the first five volumes and are designed to bring the chemistry of the alkaloids up to date by linking these new developments to the content of the earlier volumes. I n preparing all of these volumes the aim has been to bring together the important knowledge of the chemistry and pharmacology of the alkaloids. Since the appearance of Volume V many syntheses, bordering on the spectacular, have been achieved; new and hitherto unsuspected structures have been revealed; a surprisingly large number of new alkaloids have been discovered; many structural problems have been solved; and biogenetic pathways have been formulated, explored, and proved. In reviewing these advances the authors have keyed this new knowledge to the related material in the earlier volumes. Thus the reader will find in Volumes VI and VII notations of the numbers of the chapters in earlier volumes which the chapters in these volumes supplement. I n most cases the numbering of structural formulas is continuous with the sequence in the corresponding chapter in the original volume; in a few cases the numbering of such formulas starts with unity. The scheme followed for numbering references to the literature is not strictly uniform in all chapters. I n most cases the numbers are continuous with those cited in the related chapter of the earlier volume, but in some chapters the reference list in the supplementary material forms a new sequence. I n order to confine the subject index to a manageable length the entries have been limited to only the most important ones for each substance or group of substances. This means that the substance may not be named in the index if its mention is only incidental to the topic under discussion. The Editor once more is most grateful to the many authors who have contributed so conscientiously and to the chemists throughout the world who have so generously received the previous volumes.

R. H. F. MANSKE

June, 1959

V


CONTENTS PREFACE ................................................................ V CHAPTERS IN VOLUME VI AND THEIRCORRESPONDENCE TO CHAPTERS IN VOLUMES I AND I1.............................................................. X CONTENTSOF VOLUMES I. 11.111.AND IV ................................... xi CONTENTSOF VOLUME V .................................................. xii

.

Chapter 1

Alkaloids in the Plant

.

K MOTHES Halle. Germany

SUPPLEMENTARY TO VOLUME I. CHAPTER2

I. Introduction ..................................................... I1 Taxonomic Position of the Alkaloids in Plants ........................ I11. Genetics ......................................................... IV The Site ofFormation ............................................. V . Translocation. Distribution. and Accumulation ....................... VI Excretion and Degradation......................................... VII . Ontogeny ........................................................ VIII Biosynthssis and Breakdown ....................................... I X . External Factors Governing Alkaloid Formation ...................... X Metabolic Status.................................................. X I . Consequences of Alkaloid Synthesis ................................. XI1 References .......................................................

. . . . . .

Chapter 2

.

1 2 4 7 10 11 11 18 21 22 22 23

The Pyrrolidine Alkaloids LEO MNZION

National Research Council. Ottawa. Canada SUPPLEMENTARY TO VOLUMEI. CHAPTER3

I. Introduction ..................................................... I1 Hygrine ......................................................... I11 Hygroline ........................................................ IV Cuscohygrine ..................................................... V . Stachydrine...................................................... VI . Betonicino. Turicine ............................................... V I I References .......................................................

. . .

.

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Chapter 3

31 31 31 32 32 33 34

Senecio Alkaloids

.

NELSONJ LEONARD

University of Illinois. Urbana. Illinois SUPPLEMENTARY TO VOLUME I. CHAPTER4

I . Occurrence and Constitution ..................................... I1. Extractive and Degradative Procedure ............................ I11. Structure o f t h e Necines ......................................... vii

37 46 49

viii

CONTENTS

IV. Structurc of the Necic Acids ........................................

V . Structure of the Alkaloids .......................................... VI . Biosynthesis and Pharmacology ..................................... VII . References ....................................................... VIII Addendum ........................................................

.

Chapter 4

68 109 117 117 121

.

The Pyridine Alkaloids LEO MARION National Research Council. Ottuwa. Can& SUPPLEMENTARY TO VOLUME I. CHAPTER5

I . Introduction ..................................................... I1. The Pepper Alkaloids .............................................. I11. The Alkaloids of the Pomegranate Root Bark ........................ IV . Lobelia Alkaloids ................................................. V . Ricinine ......................................................... VI . Leucaenine ....................................................... VII . The Alkaloids of Hemlock .......................................... VIII The Tobacco Alkaloids ............................................ I X . Allraloids of Withania somnifera Dun ................................ X Gentianine ....................................................... X I . The Pinus Alkaloids ............................................... X I 1. Alkaloids of Tripterygium wilfordii Hook ............................. XI11. The Alkaloids of Sedum spp ......................................... XIV . Ammodendrine ................................................... XV . Alkaloids of Adenocarpus spp ....................................... XVI . Carpaine ......................................................... XVII . References .......................................................

. .

Chapter 5

123 124 125 126 126 126 127 128 133 133 133 134 136 137 138 140 142

.

The Tropane Alkaloids G. FODOR Stereochemical Research Team of the Hungarian Academy. Budapest SUPPLEMENTARY TO VOLUME I. CHAPTER 6

I . Introduction ..................................................... I1. Stereochemistry .................................................. 111. Total Syntheses .... ........................................... IV . The Structure of Dioscorine ........................................ V . Some New Physiological Aspects of Natural Tropanc Bases and of Their Synthetic Derivatives ............................................. VI . Some New Approaches to the Problem of Biogenesis in the Tropane Field VII . References .......................................................

145 146 163 169 171 172 174

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Chapter 6 The Strychnos Alkaloids J . B . HENDRICICSON Converse Mem.oria1 Laboratory. Harvard Uniuersity. Cambridge. Massachusetts SUPPLEMENTARY TO VOLUME I. CHAPTER7 AND VOLUME11. CHAPTER 18

. .

I Introduction ..................................................... I1 Reactions of Strychnine and Its Derivatives ..........................

179 182

CONTENTS

. . .

I11 Vomicine ........................................................ IV. Minor Alkaloids ................................................... V Biogenesis ....................................................... VI . Synthesis ........................................................ VII References ....................................................... Chapter 7

.

ix 195 204 206 211 215

The Morphine Alkaloids

GILBERTSTORK

Chandler Laboratory. Columbia University. New York. New York SUPPLEMENTARY TO VOLUME 11. CHAPTER 8

I. Introduction ..................................................... I1. The Reactions of Morphine and Codeine ............................. I11. The Reactions of Thebaine .........................................

IV . V VI . VII

Stereochemistry ..................................................

. Synthesis ........................................................ Biogenesis ....................................................... . Referencos ....................................................... Chapter 8. Colchicine and Related Compounds W . C. WILDMAN

219 220 228 233 23.5 242 243

National Heart Institute. Betheda. Maryland SUPPLEMENTARY TO VOLUME 11. CHAPTER 10

I . Introduction ..................................................... I1. Occurrence and Isolation ........................................... I11. Chemistry of Colchicine............................................ IV Lumicolchicincs ................................................... V . Minor Alkaloids ................................................... VI . Biosynthesis and Synthesis ......................................... VII References .......................................................

.

.

.

Chapter 9

247 248 257 274 276 283 284

Alkaloids of the Arnaryllidaceae

. .

W C WILDMAN

National Heart Institule. Bethesda. Maffjland SUPPLEMENTARY TO VOLUME 11. CHAPTER11

I . Gefieral Properties and Occurrence .................................. I1. Alkaloids Derived from the Pyrrolo[de]phenanthridine Nucleus ..........

I11. IV . V. VI . VII . VIII IX

Alkaloids Derived from [2]Benzopyrano[3.4g]indole.................... Alkaloids Derived from Dibenzofuran ................................ Alkaloids Derived from [2]Benzopyrano[3.4c]indole.................... Alkaloids Derived from 5.lOb.Ethanophenanthridine .................. Alkaloids Derived from N.Benzyl.N.(P.phenethylamine) ............... Biological Effects of the Amaryllidaceae Alkaloids ..................... Tables of Physical Constants ....................................... X . References .......................................................

. .

AUTHORINDEX ......................................................... SUBJECTINDEX .........................................................

290 312 329 338 343 354 373 374 409 409 415 435

x

CONTENTS

Chapters in Volume V I and Their Correspondence to Chapters in Volumes I and 11 CHAPTER 1. Alkaloids in the Plant . . 2. The Pyrrolidine Alkaloids . 3. Senecio Alkaloids . . 4. The Pyridine Alkaloids . 5. The Tropane Alkaloids . . 6. The Strychnos Alkaloids .

.

7.

8. 9.

SUPPLEMENTARY TO VOLUMECHAPTER PAQE

. . . . . .

. . . .

. . . . . . . . . .

The Morphine Alkaloids. . . . Colchicine and Related Compounds Alkaloids of the Amaryllidaceae .

. . . .

. . .

I I I I I I

. . . . . . . . .

I1 I1 I1 I1

.

. .

2 3 4 5 6 7 15 8 10 11

15 91 107 165 271 375 513 161 261 33 1

xi

CONTENTS

Contents of Volume I CRAPTER

.

. .

Sources of Alkaloids and their Isolation BY R . H . F. MANSKE Alkaloids in the Plant BY W 0 JAMES . . . . . . The Pyrrolidine Alkaloids BY LEOMARION . . . . . Senecio Alkaloids BY NELSONJ . LEONARD . . . . . The Pyridine Alkaloids BY LEOMARION . . . . . . The Chemistry of the Tropane Alkaloids BY H . L . HOLMES The Strychnos Alkaloids BY H . L . HOLMES. . . . .

. . . . . . . . .

1 The Morphine Alkaloids I BY H . L . HOLMES . . . . . . . . The Morphine Alkaloids.I1BY H . L .HOLMES AND (IN PART) GILBERTSTORK 161 Sinomenine BY H L HOLMES . . . . . . . . . . . . 219 Colchicine BY J . W COOKAND J . D LOUDON . . . . . . . . 261 Alkaloids of the Amaryllidaceae BY J . W . COOKAND J . D . LOUDON. . 331 Acridine Alkaloids BY J R . PRICE . . . . . . . . . . . 363 The Indole Alkaloids BY LEOMARION . . . . . . . . . . 369 The Erythrina Alkaloids BY LEOMARION . . . . . . . . . 499 The Strychnos Alkaloids Part 11BY H . L . HOLMES . . . . . . 613

1 2 3 4 5 6 7

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:

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.

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.

. . . . . .

1 15 91 107 166 271 376

Contents of Volume 11 8 8 9 10 11 12 13 14 15

.

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.

.

.

Contents of Volume 111

. 17. 18. 19. 20. 21. 22 . 23 . 24 . 16

The Chemistry of the Cinchona Alkaloids BY RICHARD B . TURNERAND R B WOODWARD . . . . . . . . . . . . . . . Quinoline Alkaloids. Other than Those of Cinchona BY H . T . OPENSHAW The Quinazoline Alkaloids BY H . T OPENSHAW. . . . . . . . Lupin Alkaloids BY NELSONJ . LEONARD . . . . . . . . . . The Imidazole Alkaloids BY A . R . BATTERSBY AND H . T . OPENSHAW . . The Chemistry of Solanum and Veratrum Alkaloids BY V PRELOG AND 0 JEGER . . . . . . . . . . . . . . . . . . . j3-Phenethylamines BY L RETI . . . . . . . . . . . . Ephreda Bases BY L . RETI . . . . . . . . . . . . . T h e Ipecac A l k a l o i d s ~MAURICE-MARIE ~ JANOT. . . . . . .

. .

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.

.

Contents of Volume I V 25 . The Biosynthesis of Isoquinolines BY R . H . F. MANSKE . . . . . 26 . Simple Isoquinoline Alkaloids B Y L . RETI. . . . . . . . . .

. . . . . .

27 28 29 30 31 32 33 34 35 36 37

. .

. .

.

1 65 101 119 201

247 313 339 363

1 7 Cactus Alkaloids BY L RETI . . . . . . . . . . . . . 23 The Benzylisoquinoline Alkaloids BY ALFRED BURGER. . . . . . 29 The Protoberberine Alkaloids BY R .H F MANSKEAND WALTERR .ASHFORD 77 The Aporphine Alkaloids BY R . H . F . MANSKE . . . . . . . . 119 The Protopine Alkaloids BY R . H . F . MANSKE . . . . . . . . 147 Phthalideisoquinoline Alkaloids BY JAROSLAV STANEK AND R .H F .MANSKE 167 Bisbenzylisoquinoline Alkaloids BY MARSHALLKULKA . . . . . . 199 The Cularine Alkaloids BY R . H . F. MANSKE . . . . . . . . 249 a-Naphthaphenanthridine Alkaloids BY R H . F . MANSKE 263 The Erythrophleum Alkaloids BY G . DALMA. . . . . . . . . 266 The Aconitum and Delphinium Alkaloids BY E. S STERN. . . . . 275

.

. .

.

.

. . . . .

.

xii

CONTENTS

Contents of Volume V CHAPTER 38. Narcotics and Analgesics BY HUGOKRUEGER . . . . 39 Cardioactive Alkaloids BY E . L MCCAWLEY. . . . . 40 . Respiratory Stimulants BY MARCELJ . DALLEMAGNE . . . 41 Antimalarials BY L . H . SCHMIDT. . . . . . . . 42 . Uterine Stimulants BY A . K . REYNOLDS. . . . . . 43 . Alkaloids as Local Anesthetics BY THOMAS P . CARNEY . 44 Pressor Alkaloids BY K K . CHEN . . . . . . . 45 . Mydriatic Alkaloids BY H R ING. . . . . . . . 46 . Curare-like Effects BY L . E CRAIG . . . . . . . 47 . The Lycopodium Alkaloids BY R H . F. MANSKE 48 . Minor Alkaloids of Unknown Structure BY R . H F . MANSKE

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1 79 109 141 163 211 229 243 265 295 301

CHAPTER 1

Alkaloids in the Plant K. MOTHES Halle, Germany

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

I. Introduction 11. Taxonomic Position of the Alkaloids in Plants.. 111. Genetics IV. The Site of Formation.. V. Translocation, Distribution, and Accumulation. VI. Excretion and Degradation.. ........................................ VII. Ontogeny ......................................................... VIII. Biosynthesis and Breakdown.. ...................................... 1. Ring Compounds ................................................ 2. Methylation .................................................... 3. Nuclear Syntheses ............................................... IX. External Factors Governing Alkaloid Formation.. X. Metabolic Status................................................... XI. Consequences of Alkaloid Synthesis.. XII. References

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

past 1 2 4 7 10 11 11 18 18 19 20 21 22 22 23

I. Introduction* This chapter is a supplement to the one by W. 0. James m Volume I of this series. The author has endeavored to take into consideration the most significant but by no means the whole of the literature published since 1948. There has been intense activity in this field within the last 20 years, and if important investigations have been overlooked this is in part due to the inaccessibility of the publications, often in languages not easily read. Whatever the cause of the omissions, the writer begs for indulgence. References to literature prior to 1948 are included only where it was felt necessary to supplement the earlier chapter. Some references have been omitted intentionally either because they did not seem germane to the limited scope of this chapter or because they seemed to be of minor significance only. The subjects specially emphasized are the biosynthesis, ontogeny, and inheritance of the plant alkaloids. Speculation is held to a minimum, and few of the theories of biosynthesis are mentioned because much work is in progress and it is confidently expected that the near future will witness important advances in this field. * This material is supplementary to Volume T, page 16. 1

2

K. MOTHES

II. Taxonomic Position of the Alkaloids in Plants*

It may be suggested that phylogenetical evolution not only involved morphological differentiation but that chemical differentiation is parallel to it and even forms its basis. It remains unproved that the evolution of higher plants requires the formation of more complex substances. The higher animal organism undoubtedly does require complex compounds that function in the hormonal system, but such compounds are often found in lower organisms where they seem to be of minor or of no obvious significance. The view that Gymnospermae, Pteridophytae, Fungi, etc., are not able to elaborate alkaloids because of their early phylogenetic age and their primitive status, has been shown to be erroneous by recent investigations. Equisetum and Lycopodium do in fact elaborate them. The Fungi, the chemistry of which has been extensively explored in the study of the so-called antibiotics, have been found to produce the most elementary protoalkaloids as well as a variety of extremely complicated substances. The following examples will illustrate these points: bufotenine, the specific poison from toads, has been isolated from Amanita species (Basidiomycetes) (176); aspergillic acid (1) from Aspergillus $avus, and picroroccelline (11)from Roccella fuciformis (Lichenes) are pyrazine derivatives which may be looked upon as derivatives of isoleucine and phenylalanine, respectively. The red pigment, pulcherrimine of Candida pulcherrima, is believed to be a polymeric iron complex of a dibutyldiketo-piperazine (177). The alkaloids of ergot represent a group of lysergic acid derivatives confined apparently to the genus Claviceps. Iodinine is a phenacine derivative from Chromobacterium iodinum. Cultures of Aspergillus glaucus have yielded echinuline (111);fusaric acid (IV) is elaborated by Fusarium heterosporum, a fungus which causes wilt in tomato seedlings; and viridicatine (V) is produced by Penicillium viridicatum (178). Since the greater majority of plants still remain to be examined, the taxonomic distribution of alkaloids cannot be fixed with any certainty, and their total number and occurrence can only be guessed. About one thousand are now known, the structures of many of them being still undetermined (179). The chemistry of the flora of only a few regions of the world has been intensively studied (Australia: Webb (180); Siberia: Sokolov (181) ). It is estimated that 10% to 20% of all plants contain alkaloids, but such estimates are uncertain to the extent that our analytical methods often fail to detect traces. Improved methods have led to the finding of nicotine in tomatoes (182) and of alkaloids in

* This material is supplementary to Volume I, pages 1-14.

3

ALKALOIDS I N THE PLANT

garden peas (Pisum sativum L.) in an amount of about 2% of those found in “sweet” lupines (183). The existence of larger quantities of alkaloids in plants depends not only upon the plant’s capacity to synthesize them but also upon its capacity to tolerate them. The widespread occurrence of nicotine has often been noted, but it frequently is present only in traces (Lycopersicon, Atropa, Lycopodium, Equisetum, Asclepim). When tomato or

OH

I

ocr Ph

CH,CYCHa.CH3

OH

OH

HOaC

IV

V

belladonna is grafted upon Nicotiana stock considerable quantities of nicotine migrate into the scion, and characteristic chlorosis and necrotic browning arise there undoubtedly as a result of the presence of nicotine (184). Hence tomato and belladonna do not differ from Nicotiana by their inability to produce nicotine but by their inability to tolerate it. Similarly, mutants of Nicotiana rustica L. and of Datura specially rich in nicotine were stunted (185). A remarkable example of tolerance to a considerable accumulation of nicotine is that of Zinnia elegans Jacq. (Compositae), which surprisingly grows well when grafted upon a tobacco root. Strangely enough, it also contains nicotine when grown on its own roots (186). Hegnauer (187) has discussed the resistance factor to alkaloids in plants. He notes the widespread occurrence of nicotine and regards it and anabasine, sedamine, cuscohygrine, hyoscyamine, the Lobelia and Punica alkaloids, and the pyrrolizidines and quinolizidines, as biochemically related and based upon similar syntheses. The widespread occurrence of nicotine (182, 158, 189) should be a warning to apply chemical structure cautiously to taxonomic problems. Sokolov (190) has sounded this warning, but he recognizes that with increasing morphological-anatomic advance the complexity of the alkaloids is

4

K. MOTHES

increased. However, in narrow taxonomic groups alkaloids are significant and characteristic features (191, 192). I n the Amaryllidaceae the alkaloids seem to be confined to the subfamily Amaryllidoidae. Though the structural types are not uniform they seem to be confined to these monocotyledons with one remarkable exception, namely, the phenolic cocculine present in the Caucasian variety of Cocculus laurifolius DC. (Menispermaceae).This base, which appears to be absent from the East Asiatic varieties of the same species, apparently has the same ring skeleton as has lycorine, which is remotely related to the isoquinolines so common in the Dicotyledonae (193). Our knowledge of alkaloids in animals is scant. The so-called protoalkaloids (biogenic amines and their derivatives) are widespread in lower animals (194, 195), and the parallelism between plant and animal metabolism is extensive. Betaines, methylated purines (e.g., paraxanthine (VI) ), derivatives of histidine (spinacine (VII) of the shark), and kynurenic acid (VIII) are not rare in animals. The animal alkaloids, with the exception of samandarine (Vol. V, p. 321), are characterized as weak bases; this is perhaps of importance for their excretion.

VI

VII

Vlll

Brief mention may be made of the phenoxazones, which in the form of the xanthommatins (196) are important pigments in the eyes of insects and as actinomycetins occur in some Actinomycetae (197). 111. Genetics I n general, plants that do elaborate alkaloids elaborate more than one. Only a few investigations with adequate plant material have been made to determine the limits of the alkaloid spectrum in hereditarily uniform material under a vaned environment. Ergot, the sclerotium of the fungus Claviceps purpurea, which grows on grasses and especially on rye, contains not only a number of amines derived from the amino acids but alkaloids which are derivatives of lysergic acid. Because of its probable haploid nature and its capacity for vegetative reproduction it is possible to study the constituents of homozygous populations occurring in a numher of geographical regions (198). The ergotoxine alkaloids predominate in the ergots of southwestern Europe, whereas those of the ergotamine type predominate in the middle and southeastern European ergots. I n East Asia and in Africa

5

ALKALOIDS IN THE PLANT

ergot races are found which elaborate simple lysergic acid derivatives, whereas ergots from northern regions often yield few or no alkaloids. Pure strains of C. purpurea have been selected from single-spore saprophytic cultures, and some of them yield only a single alkaloid aside from some water-soluble bases (199-203). Table 1 gives a resume of the alkaloid content of a number of strains studied by Groger (200, 201). Extensive investigations have shown that the nature of the alkaloids is influenced slightly or not at all by such variables as climate, the host plant, or the stage of development of the sclerotium (204, 205). During the prolonged cultivations of a single strain aberrant types occasionally appear. In most cases these variants may not be mutants but vegetative segregations of sclerotia formed from mycelia of different strains. Such mixed sclerotia may be formed experimentally (206, 207). TABLE

1

ALKALOID CONTENT O F THE ERGOT STRAINS SELECTED AT GATERSLEBEN

Strain Per cent total Caters- alkaloids (as leben ergotamine) No. (1956)

I11 IV V VI VII VIII X XI1

xx XXI XXII XXIV

xxv

XXVI XXVII XXVIII XXIX

xxx

XXXI XXXII

0.290 0.320 0.390 0.400 0.640 0.300 0.400 0.340 0.470 0.540 0.720 0.560 0.440 0.380 0.440 0.440 0.580 0.320 0.430 0.51 0

Key to the signs used:

Qualitat,ivecomposition of the alkaloid mixture

Ergonovine tr

* *

tr

*

* *

*

tr tr tr tr tr tr tr tr tr tr tr tr

Ergotamine

Ergosine

***

-

tr

tr tr

*

* * tr

* * *** *** ***

*

*

-

*

***

*** tr tr

***

- = not detectable. tr = only traces. = existent. ** = more than 5096 of total alkaloid. *** = more than 90% of total alkaloid.

Ergocristine

ErgoErgocornine kryptine

-

*** * ** ***

** -

-

** -

-

***

** **

-

** **

**

tr

tr

2.

6

K. MOTHES

Plant races which have limited geographical distribution and which are distinguished by their alkaloid content have been reported by a number of investigators. Some examples follow: Sokolov (190) described chemically distinguishable races of Salsola richteri Karel; Poethke (208) and Tomko (209) of Veratrum album L.; Annett (210), Rasilewskaja (211), and Heeger and Poethke (212) of Papaver somnijerum L.; Hills and Rodwell (213), Barnard (214), and Hills et al. (188) of Duboisia myoporoides R. Br., in which the total of 3% of alkaloids is either largely hyoscine or hyoscyamine; Marion et al. (215) found sedamine and nicotine in Sedum acre L. of Canadian origin, whereas material from Amsterdam and from Darmstadt examined by Beyerman and Muller (216) and by Schopf and Unger (217), respectively, yielded only sedridine. Different strains of barley show chemical differences in which hordenine may be replaced by N-methyltyramine (218). Exhaustive genetic analyses correlating alkaloid inheritance have been carried out only with Lupinus, the “sweet” variants of which have become economically important because of their selection and breeding by v. Sengbusch. According to him a number of genes control the alkaloid content (219-222). Less is known of the alkaloid heredity in tobacco, although the great variability in kind and amount has often been noted (223-225). I n spite of some efforts to do so the problem of the inheritance-dominance of nicotine and of anabasine has not been solved (226), partly because earlier analyses did not differentiate between anabasine and nornicotine. According to Valleau (227) and Griffith et al. (228) the deniethylation of nicotine to nornicotine is controlled by one gene. I n examining the dominance relations of nicotine and nornicotine inadequate attention has hitherto been paid to the stage of development of the plant (229), since there is no ‘(nornicotine” tobacco. The nornicotine in tobacco is produced in the leaves from nicotine often not before the aging of the leaf. The inherita,nce of alkaloids in Cinchona species has been the subject of an extensive program (230). If two Solanum species containing demissine and solanine, respectively, are hybridized a plant results which elaborates both alkaloids (231). Artificially induced mutations have not yet yielded alkaloid-free plants. Ergots exposed to X-rays and ultraviolet radiation yielded some types which lacked pigment. Such leucosclerotia in general contained less alkaloid than the original forms (201, 232-235). Evans and Menendez (236) obtained Datura tatula L. ( D . stramonium L.) mutants in which the ratio of hyoscine to hyoscyamine was altered. Similar results have been reported by Mothes and associates (185) in which


7

mutants of Datura and of Nicotiana containing more nicotine than their respective parents were obtained. Attempts to increase the alkaloid content by inducing polyploidy were not invariably successful (237, 238). Tetraploid Datura stramonium L. was richer in alkaloids than the diploid strain (239). The alkaloid content of the grafts in reciprocals of 4 n and 2n plants was that of the stock. The grafting of 2.n tomatoes on 4 n Datura inhibits alkaloid synthesis, as does the grafting of 4 n tomatoes on the same stock but to a lesser degree. Of special interest are the grafts of 2 n and 4 n Datura on the same 4n-Datura stock, the latter having the greater alkaloid concentration (240). Other authors are in substantial agreement with these results (238, 241, 242). Though it can be easily shown that the alkaloid-containing character of a genotypically alkaloid-free graft upon an alkaloid-containing stock is not inheritable, statements to the contrary have appeared frequently (243).

IV. The Site of Formation*

It is now generally recognized that the most intensively studied alkaloids (nicotine in tobacco; hyoscyamine in Datura, Atropa, and Hyoscyamus) are produced in quantity in the roots of intact plants, though other sites of formation are not entirely excluded. A fully developed tobacco leaf does not elaborate nicotine, but it has not yet been proved that this almost cosmopolitan alkaloid is produced only in the roots in all other plants. The differentiation of the metabolism in the different organs is a problem of the physiological development of that organ. A tobacco leaf resembles a defect-mutant as far as its ability to synthesize nicotine is concerned but since it can generate roots the capacity to synthesize nicotine is still there though latent. A variety of methods have played important roles in determining the site of formation of alkaloids, and all are subject to serious experimental and interpretational errors. The culture of isolated organs can lead to erroneous interpretations and the analysis of sap currents (xylem and phloem) is fraught with obvious inherent difficulties. I n grafts the shoot often forms adventitious roots which may not be visible when they grow into the stock. Such a graft is not only under the influence of the stock mot but under its own, and very short roots can show very great alkaloid synthesis activity (244, 245). It is not yet certain whether a shoot behaves differently on its own * This material is supplementary to Volume I, page 50.

8

K. MOTHES

root than on an alien one. Grafts of Atropa upon tomato roots produced mydriatic alkaloids which showed the Vitali reaction (246, 247), but the extent of synthesis was considerably dependent upon the tomato variety chosen as stock. Isolated organ culture under aseptic conditions yielding negative results indicates only that a root does not produce alkaloids under conditions of isolation. Isolation prevents the migration of metabolic products to and from the organ, and therefore the conditions are new. The plant is a very complicated organism, and it has not yet been possible to determine the exact site or sites of alkaloid syntheses, although there are indications that actively growing parts play the most important role (244, 248-251). It has been suggested that the primary nitrogen assimilation in the root is associated with alkaloid synthesis (252), but spraying the leaves with ammonium nitrate solutions cannot stimulate alkaloid formation in the leaves (253, 254). It should be noted that alkaloids are formed in tissue cultures of parenchyma and vascular parts of Hyoscyamus niger L. (255). The following are some examples of special interest. Betaines. The work of Csomwell and Rennie (256) indicates that glycine betaine is synthesized in the roots of Beta vulgaris L. and other plants, and its presence in other parts is a result of translocation but leaves are capable of oxidizing choline to betaine. No such oxidation occurs in etiolated seedlings of Triticum vulgare Vill. or in starving leaves of oats (257). Choline can accumulate in large amounts as phosphoryl choline in plant sap, and this seems to be an important storehouse of phosphorus (258). Ephedrine. Isolated sprouts of Ephedra distachya L. when fed with N16H, increase the absolute quantity of alkaloids and incorporate N16 (259). Gramine is elaborated from tryptophan in barley leaves (260). Coniine appears to be formed in the sprouts (261). Ricinine is largely produced in the young organs of Ricinus communis L., and the feeding of lysine increases the amount formed, especially in the roots (262). Nicotine. Malikovcev and Sirotenko (263) grafted very small shoots of tobacco on tomato and noted a relatively large increase in nicotine content. It is not clear, however, whether the nicotine originated in the tomato stock (182) or whether it had its origin in some adventitious roots. Pal and Nath (189) had already observed the formation of nicotine in young tobacco leaves on tomato stock. A number of recent experiments with compounds labeled with radioactive elements confirm the nicotine synthesis in the roots (264), and Hofstra (265) has shown that nicotine is still formed in the roots of vigorously growing plants


9

after these have been severed. The formation of anabasine in sprouts seems to be peculiar to Nicotiana gluuca R. Grah. (266). Tropane alkaloids. It is probable that hyoscyamine-like alkaloids are formed in shoots of Atropa and Datura and in ripening seeds of the latter (246, 267). Grafts of Datura on tomato yielded unidentified alkaloids, and Atropa grafts on tomato yielded cuscohygrine (268). Grafts of Nicotiana tabucum L. on Duboisia myoporoides yielded very little hyoscine or hyoscyamine but some nicotine and nornicotine and more than the normal amount of tropine (269). It was concluded that tropine and scopine are formed in the root and esterified in the leaf. Romeike (270) observed that leaves of Datura ferox L. can transform hyoscyamine into hyoscine. Lupinus alkaloids. I n lupines the alkaloids seem to be generated in the sprouts (271, 272), and a downward movement seems to be responsible for the appearance in the roots. Experiments with grafts indicate that low alkaloid yielding strains of lupines are able to metabolize these alkaloids to other substances (271), and Mothes and Engelbrecht (273) confirmed this by grafting lupines on other Leguminosae which do not elaborate alkaloids. They showed that the isolated roots in aseptic cultures synthesized no alkaloid when entirely free of hypocotyls. Wagenbreth (245) draws attention to errors that can result from unobserved adventitious roots, and others (183, 274) stress sources of error which may arise from inadequate analyses. Quinine.I n spite of extensive researches the site of the formation of alkaloids in Cinchona is not yet certain. The problem is complicated by the observation that the alkaloids in different parts of the plant are not the same. Synthesis in the roots seems to be improbable because scions of C. ledgeriana Moens. are rich in alkaloids when grafted on vigorously growing but low alkaloid yielding stocks of C. succirubra Pav. (275). Nevertheless there seems to be a definite mutual influence between stock and scion. According to van Leersum (276, 277) undoubted sites of formation are the leaves, but Dawson (278) has shown that the alkaloid content of the bark remains unchanged when a branch is defoliated and tip grafted with another species of Cinchona. Howard (279) believed that the alkaloids are formed in the cells on the surface of the cambium, and according to Moerloose (280, 281), who worked with C1402, syntheses take place independently in the bark and in the leaves, the bark producing cinchonine and cinchonidine and the leaves producing quinine and quinidine. Synthesis in the leaf seems to be inhibited in light, whereas increased light intensity increased the alkaloid content in the roots but not in the stems of C. ledgeriana. Similarly, heavy supplies of nitrogen increased the- alkaloid concentration in the roots,

10

K. MOTHES

but the sprout tips, the youngest roots, and the cambia were free of alkaloids. Vigorous growth promoted by a high temperature in the heatsensitive C. pubescens Vahl also increased the alkaloid content in the roots. Xolanum. The steroid alkaloids of this genus are mostly produced in the sprouts but also in the roots (281a, 281b).

V. Translocation, Distribution, and Accumulation* The translocation of the root alkaloids in the xylem can be observed by direct microchemical examination (251) but is best observed by bleeding of the sap. The quantity of the sap and its alkaloid concentration show daily periodicity (283), there being a maximum (based on crude fiber) in the morning (284) in Datura stramonium. Warren-Wilson (285) has shown that the downward migration of the Atropa alkaloids is via the phloem, and experiments with lupines confirm this (271). Here the root content is determined largely by that of the aerial portion, as was shown by grafting bitter lupines on sweet lupines and on non-alkaloid bearing legume stock (271, 273). A similar migration to the seeds of a Pisum has been reported by others (272). The speed of the migration from the leaves is probably dependent not only on the concentration gradient but also upon the regulating mechanism. Alkaloids have not been known to occur in sieve tubes, but aphids which suck only sieve tubes avoid tobacco leaves except those which are alkaloid-free growing on tomato stock. Why the parasitic plants Orobanche and Cuscuta are alkaloid-free even though growing on alkaloid-bearing plants is not clear (287, 288). Nicotine is mainly located in the intercostal areas of the leaf (247, 289, 290). Chojecki (291), by microchemical technique, has arrived at the following depots of nicotine in the tobacco plant given in the order of decreasing concentration : leaf epidermis, particularly at the base of the hairs, spongy mesophyll tissue of the leaves, primary cortex of roots, epidermis and parenchymatous tissue of the stem and palisade tissue of the leaves; small amounts in the phloem and xylem of the stem, in the veins of the leaves, and in the medulla of the stem; and traces in flowers and axial cylinders of the roots. The tropane alkaloids in Datura and Atropa are largely concentrated in the veins of the leaves (247, 292), but when Cyphomandra is grafted on Datura the greater amount of alkaloids is outside the veins. When Atropa is grafted on tobacco the nicotine is distributed as it is in tobacco leaves (247). Though most of the alkaloid in Nicotiana species (babacum, rustica) * This material is supplementary to Volume I, page 48.


11

is formed in the roots, it rapidly migrates to the aerial parts (286, 293). However, in N . alata the root is richer in alkaloids (294-297), and one may speculate on a possible breakdown of nicotine in the leaves. Fruits of Atropa and Nicotiana are comparatively rich in alkaloids, but tomatoes grown on Atropa or Nicotiana stock are almost devoid of alkaloids (298, 299), with the age of the stock seeming to have a slight effect (300). When mature or immature tomato fruits are injected with nicotine there is no apparent decrease with growth so that the lack of alkaloids in these fruits is not due to their breakdown (267). Potato tubers on Datura stock contain alkaloids but in lesser amount than the leaves.

VI. Excretion and Degradation The disappearance of alkaloids from plant tissue has been attributed to leaching (301-303), migration, excretion, or physiological degradation. The loss of volatile alkaloids (nicotine) by exhalation was observed by Ciamician and Ravenna (304) and by Chaze (305), who showed that nicotine can penetrate the epidermis (306). The loss of Ephedra alkaloids during the rainy season may be partly due to leaching (307). Isolated roots of Nicotiana, Atropa, and others excrete considerable amounts of alkaloid into the medium, but roots of intact plants excrete very little. The physiological degradation of alkaloids in ripening tobacco seeds was observed by Iljin (308); this degradation was also noted during starvation of tobacco particularly in detached leaves (263, 309). I n general, however, little degradation occurs in tobacco (310, 311) or in Datura (292). In lupines (271) and in seeds of Sarothamnus scoparius Koch (312) there appears to be some degradation of alkaloids. Steroid alkaloids in sprouting potatoes are decomposed by specific glycosidases (313), and they are also degraded in ripening fruits (282). This disappearance during ripening is a common phenomenon having been long known in Papaver somniferum (314, 3 15). Alkaloids disappear from Anabasis during autumnal frosts (190). VII. Ontogeny* The generation of alkaloids during the various stages of growth has been extensively investigated only in solanaceous plants. At the commencement of flowering alkaloid synthesis is either inhibited or entirely stopped (241, 316-319). This phenomenon is most striking in those plants the inflorescence of which is sharply separated from the stem, which then no longer elongates (Nicotiana,Hyoscyamus). I n sympodial * This material is supplementary to Volume I, pages 27-44.

12

K . MOTHES

perennials, particularly those with nonterminal inflorescences (Atropa), the effects of flowering are less evident. In any case this stage generally coincides with the decrease in alkaloid production paralleling decrease in growth due to diminished light and temperature. I n Nicotiana and Hyoscyamus the development of the inflorescence is accompanied by diminished root growth. It is possible that the supply of carbohydrates is the limiting factor, particularly since shading adversely affects alkaloid synthesis (286). When the triple graft, tobacco on potato on tobacco, produces tubers on the middle graft, the nicotine content of the leaves of the potato and tobacco is inversely proportional to the abundance of tubers (244, 264). Topping and pruning increase not only the relative but also the absolute amount of alkaloids in these species (244, 319-324) and bleeding sap analyses readily confirm this observation (265, 283). Photoperiodic prevention of flowering will also maintain the alkaloid synthetic activity of Nicotiana silvestris Speg. and Comes (Table 2). These findings are contradictory in part t o earlier ones (324, 325), but the discrepancy is probably due t o the fact that the earlier work paid inadequate attention to absolute rather than t o relative amounts of alkaloids. TABLE

2

Nicotiana silvestris PHOTOPERIODICAL EFFECT W O N

ALKALOID FORMATION

(250)

In one plant Dry weight (g.) Date

Nicotine (mg.)

Experiment State of development Root Shoot Total Root Shoot Total

2/29/56 Beginning Rosette 3/13/56 Long day Normal day Rosette Short day 3/22/56 Long day Elongationofaxes

0.21 1.46 1.25 1.72 5 .0 5.8 day Rosette 5.8 Short day 4/3/56 Long day Beginningofflowering 9 . 5 Normal day Rosette 11.0 Short day 13.1 4/16/56 Long day Flowering 7.8 15.6 day Rosette Short day 17.8

1 I

]

1.00 6.15 4.42 4.11 14.5 11.5 10.0 24.1 14.8 10.8 27.0 20.0 12.3

1.21 1.8 6.2 7.61 13.1 33.6 5.68 13.4 24.5 5.83 14.8 21.3 19.5 31.3 36.2 17.3 52.7 36.5 15.8 80.5 45.6 33.6 63.5 44.7 25.8 98.1 71.5 -23.9 141.3 58.7 34.8 62.4 26.1 35.6 179.0 79.2 30.1 264.3 94.4

8.0 46.7 37.9 36.3 67.6 89.2 126.1 108.2 169.6 200.0 88.6 258.2 358.7

In the early stages of germination nicotine is found in the tip of the radicle (248), and from there it migrates to the hypocotyl (326). It is


13

possible that nornicotine is first produced, since bleeding sap (265, 283) and isolated root cultures (297) frequently yield large amounts of it ( N . alata Link and Otto). But since demethylation is known to occur in the leaves, especially in some strains of N. tabacum, in N. silvestris, and in N. glutinosa L. (295, 327-332)) it may also occur in the roots, part,icularly since nicotine is never absent. The fate of the methyl group, or its origin, is not yet known but C140, is rapidly t,aken up by isolated leaves and the radiocarbon appears in the N-methyl group so that the methylation-demethylation process appears to be very labile (333). Iljin (264) and Dawson (334), however, maintain that the demethylation of nicotine in leaves of N. glutinosa is irreversible even in the presence of methionine, choline, and sodium formate, but this negative result may be ascribable to the age of the leaves or damage to them. In any case the demethylation lacks specificity because N. glutinosa leaves can dealkylate not only 1-nicotine but the dl-form as well as dl-N-ethylnornicotine, dl-N-methylanabasine, and dl-N-ethylanabasine (328).

All species or varieties do not bring about demethylation at the same stage. In some plants this process takes place before flowering, in some after flowering, in some only when the leaves show signs of aging, and in some not until the mature leaves undergo “curing” (266, 330, 335337). Long-day plants of N. silvestris have more nornicotine than short-day plants of the same species, but this does not appear to be a direct photoperiodic effect since the older the leaves, the greater the content of nornicotine. Short-day plants do not flower, remain in the rosette stage, and continually form new leaves, and consequently elaborate little nornicotine (250). Pyriki and Miiller (295) report an interesting example of what appears to be the transformation of anabasine into nicotine. When “Havanna Tobacco IIc” was grafted on N. glauca which produced anabasine almost exclusively the scion yielded nicotine and anabasine in about equal quantities. In our laboratory (Schroter) these grafts generally did not produce adventitious roots; thus the transformatioil, though still to be confirmed, seems to be authentic. The ontogeny of the tropane alkaloids is much like that of nicotine. The appearance and disappearance of alkaloid in Datura stramonium has been extensively studied by Guillon (338). In the leaves it appears first in the epidermis, then in the mesophyll, and finally in the parenchym of the vascular bundles. I n the root it makes its appearance in the outer parts on the sixth day, then spreading inward so that in one month it is present in the pith and the periderm. During aging of the root it disappears except for some in the central tube. The leaves of Atropa,

14

K . MOTHES

Datura, and Hyoscyamus contain alkaloids in the phloems of the vascular bundles (339). Flowering does not greatly inhibit alkaloid production in these genera, evidently because it is not a sharply differentiated stage of growth and indeed Scopolia japonica Maxim. has a maximum alkaloid content during flowering (317, 318, 321, 324). The alkaloid content of Atropa belladonna reaches a maximum in one-year-old plants at or shortly after flowering (340). Following this the alkaloid content fluctuates considerably, but generally inadequate attention has been paid to the alkaloid content of the roots (341).That such migration takes place was shown by Warren-Wilson (285), who grafted Atropa onto the nonalkaloid tomato, potato, and Physalis alkekengi L. ; in each case the stock roots contained alkaloids. Some attention has been given to the ratio of hyoscine to hyoscyamine, but the ratio seems t o be fairly constant in fully mature plants of the same species. In young plants, and especially in their roots, hyoscine often predominates even in typical hyoscyamine plants (247, 342-346). Evans and Partridge (342) have concluded that hyoscine is elaborated largely in the aerial portion of the plant, whereas hyoscyamine forms largely in the roots; James and Thewlis (347), however, believe that in Atropa and Datura inoxia Mill. ( D . fastuosa L.) synthesis takes place only in the roots. The extensive investigations of Romeike (270, 348) showed that grafts of genotypically non-alkaloid bearing plants on different alkaloid-bearing stocks always elaborated the alkaloids characteristic of the roots. Since the bleeding sap had the same composition, it was fairly evident that migration to the scion took place without change in alkaloids. However with Datura ferox grafts, a typical hyoscine plant, the alkaloid content was always predominantly hyoscine regardless of the nature of the stock (Fig. 1). When hyoscyamine was fed through the blade or the stalk of alkaloid-free Datura ferox growing on tomato, hyoscine was detectable in a short time. Not only did this experiment prove the conversion of hyoscyamine to hyoscine but its downward migration wag also noted. It was similarly demonstrated that meteloidine is degraded by Datura stramonium var. tatula. (Fig. 2). It is not entirely clear, however, which alkaloid is the f i s t to be synthesized, but Imaseki (349) and Shibata (259) concluded that it was hyoscyamine. Similarly Marion and co-workers (350, 351) using ornithine labeled with C14 in the a-position noted that the hyoscyamine in Datura stramonium was radioactive but that the hyoscine was not and that only the hyoscyamine was radioactive after feeding mature plants of the same species with methionine labeled with C14 in the methyl groupOn the other hand, the conversion of hyoscine into hyoscyamine

15


Datura ferox

Cyphomandra betacea

on Datura ferox S= hyoscine

on Datura ferox

H = hyoscyamine

Datura ferox

on Datstramon vac tatula M=meteloidine

Fig. I

Datstramonvac tatula on Datstramonvactatula

S=hyoscine

Cyphomandra betacea an Dat.stramon.vactatula

H=hyoscyamine Fig. It

Dat.stramon.var:tatula on Datura ferox

M=meteloidine

16

K. MOTHES

seems to take place in tomato grafts on Datura tatula (352). Furthermore in Duboisia the situation is complicated by a number of geographical strains which elaborate the alkaloids (hyoscyamine and hyoscine) in very different ratios, and indeed annual changes have been observed. For example, an individual plant in October contained 3% of alkaloid, almost all of which was hyoscyamine, and yet the same plant in April contained the same amount of almost pure hyoscine (346). The demethylation of nicotine which is present in small amounts in Duboisia takes place under the same conditions that maintain in tobacco. In ergot alkaloid synthesis does not become appreciable until the sphacelial stage gives rise to sclerotia. Unpublished experiments in the author’s laboratory (Groger) indicate that there is no change in the ratio of the alkaloids as the ergot matures. LEGUMINOSAE. In Leguminosae there is much variability in the alkaloid content not only seasonally but in the different organs (183, 274, 312). According to van der Kuy (274) seeds of Lupinus luteus L. contain mostly lupinine which disappears on germination and reappears during flowering but is absent from the roots. Pohm (353) believes that the cytisine in Cytisus laburnum L. is formed in the bast tissue and its transformation to N-methylcytisine takes place during its migration through the cambium into the wood, the ratio of the former to the latter changing from 32 to 1 to 1 to 1. The seed is rich in cytisine. Rjabinin and Iljina (354) record that Smirnovia turkestana Bge. contains mostly smirnovine in May, which gives place to smirnovinine and sphaerophysine in August. CHENOPODIACEAE. The alkaloid content in the twigs of Anabasis aphylla L. decreases toward the end of the vegetative period. When the aerial portion is severed the regenerated shoots are rich in alkaloid. Salsola richteri Karel similarly shows a decrease in alkaloid content at maturity and then salsoline predominates (355). CONIUM. y-Coniceine is the principal alkaloid in young plants of Conium maculatum L., especially in the leaves. It is still the chief constituent of leaves in two-year plants, but coniine dominates in the flowers and fruits. During ripening coniceine disappears and N-methylconiine is predominant (261, 356). SENECIO.Alkaloids accumulate in the roots of S. platyphyllzls DC. and reach a maximum at the flowering stage when they disappear from the aerial parts except from the seeds (357). During vigorous growth in spring they appear as N-oxides. PAPAVER. The physiology of the many alkaloids in P . somniferurn is far from clear. The almost alkaloid-free seeds on germination quickly


17

give rise to narcotine, codeine, morphine, and papaverine. I n the absence of a source of nutrient nitrogen narcotine is still produced but other alkaloids are wanting (358). According to Poethke and Arnold (359) the morphine content goes through the following changes during the vegetative period: decrease in the roots, increase in the stem followed by a decrease, and a slow but continuous increase in flowers and capsules and then a decrease. According to Wegner (360) morphine in seedlings is present in the roots only but there is an absolute increase in all organs followed by a decrease at maturity. The terminal capsules produce more opium but when lanced repeatedly all capsules rapidly yield less morphine, the nitrogen content remaining nearly the same (210). According to Saitzewa (361) the alkaloids are formed in the meristems and only stored in the latex tubes. Gadamer (362) and Klee (363) concluded that thebaine is the predominant constituent of P . orientale L. during growth and that isothebaine makes its appearance only in autumn. However, Dawson and James (364) feel that genotypically different strains are involved and that isothebaine is the major alkaloid. COLCHICUM. Neither the site of the formation nor the fate of colchicine or its congeners nor their ratio has been determined. All parts of the plant contain alkaloids but whether they arise by translocation, degradation, or transformation is still unknown in spite of a number of researches (365-369). SOLANUM. The steroid alkaloids in this genus arise mainly in the aerial portion, but the roots seem to be important as well (282). Young organs seem to have a greater facility for generating alkaloids, and the alkaloid content of tomatoes and potatoes continually increases (231, 313, 370, 371). I n the ripening plant alkaloid disappears from the roots, and the absolute content decreases partly in consequence of its translocation into the flowers, which in turn lose alkaloid as the seeds develop. When the plants are deprived of fruits there is an increase in alkaloid content in consequence of the loss of these organs of alkaloid breakdown (282). HORDEUM. Hordenine is not present in the fruit of barley but makes its appearance during germination. It is first demonstrable in meristematic root tissue. It is produced without an outside source of nitrogen and has its origin in tyrosine-clear proof that at least some of the building blocks of alkaloids are derivable from proteins. Its concentration rapidly reaches a maximum, and it disappears after one month (372). Seedlings of Panicum miliaceum L. behave in the same way (373). VERATRUM. The alkaloids of V . album L. vary considerably both in amount and in type in the different organs (208, 374). B

18

K. MOTHES

VIII. Biosynthesis and Breakdown* 1. RING COMPOUNDS

Alkaloids, defined in a limited sense, are heterocyclic nitrogen compounds, and the investigations into the mechanism leading to such ring systems have met with considerable success, particularly because of the use of isotopically labeled compounds. It has become evident that the theories of Trier (375) combined with the ingenious syntheses of Robinson (376) and of Schopf (377) under so-called physiological conditions are applicable with or without modifications to syntheses in the plant (378, 379). The synthesis of proline (X) from glutamic acid or from ornithine via the semialdehyde (IX)is an example of a type of ring closure involving an aldehyde and an amino group (380). This route has received strong experimental verification from work with Escherichia coli, Neurospora crassa, Torulopsis utilis, and mammals. The synthesis of pipecolic acid from the homologous lysine is strictly analogous but may involve different microorganisms (381, 382). Pipecolic acid (XII) may appear in large quantities in the metabolism of bacteria, fungi, and higher plants. L-Amino acid oxidase from Neurospora converts lysine into a-keto-E-aminocaproic acid (XI), which readily cyclizes and is convertible by Neurospora into pipecolic acid (383). Leete and co-workers (384)did not find radioactive stachydrine in Medicago sativa L. plants that had been fed with ornithine labeled in the a-position with (214. They concluded that ornithine was not the precursor of stachydrine, but they failed to demonstrate that stachydrine was formed at all in the duration of the experiment. CH, -CH,

I HC

t CHCQH

*o /

NH*

IX

CH, -CH,

I

CH,

I

CH.CQH

\NH'

X

XI

Xlll

The same ring systems but with different substituents arise from different sources, the pyrrol ring in protoporphyrins having its ultimate origin in glycine and succinic acid (385).

* This material is supplernenta,ry t o Volume I, pages 56-68.


19

The decarboxylated diamino acids seem to play a special role in the synthesis of simple pyrrolidines and piperidines (386, 387). For example, pea diaminooxydase converts putrescine into Al-pyrrolidine and cadaverine into dehydropiperidines. 2. METHYLATION

Many alkaloids have methyl groups on nitrogen or on oxygen or the equivalent methylene groups on two oxygens. It is notable that other alkyl groups are never present except in the rather special cases of the Aconite alkaloids, and therefore methylation is in a special position which as recent investigations have shown follows well-defined principles (186, 388-391).

The primary synthesis of methyl groups, which must be differentiated from their transfer, has its origin in active carbon fragments such as methanol, formaldehyde, formic acid, the 8-carbon of serine, the a-carbon of glycine, the a-carbon of histidine, and even acetone. The first stage in the formation of the methyl group is the attachment of a one-carbon fragment to the amino group on the p-aminobenzoyl moiety of tetrahydrofolic acid to form the formyl derivative. This derivative can transfer the carbon fragment, with or without previous reduction, to the sulfur atom of homocysteine forming methionine. The methyl groups of methionine, when activated by ATP, can be transferred, either as an oxidized fragment or whole, to methyl acceptors. Thus a large variety of N-methyl, 8-methyl, and 0-methyl groups are generated, such as in the betaines and in the alkylated thetines, which can function as methyl donors in turn. 0- and N-Methylations serve to detoxicate phytotoxic phenols and other compounds. For example, nicotinic acid in large quantities is toxic to plants but is readily methylated to the innocuous trigonelline (392). The formation of hordenine from tyrosine has already been noted. Its methylation to N-methyl derivatives can be achieved by feeding the barley with formate, choline, or methionine (218, 373, 393-396). The methyl group on the pyrrolidine nitrogen of nicotine is derivable from methionine, where it is transferred as such (397,398),from choline, which is probably first oxidized to betaine (399, 400), from formaldehyde (401), from glycine and from glycolic acid, of which the a-carbon is transferred (402, 403), and from serine (402) and from glycolic acid (403), from both of which the 8-carbon is transferred. Ricinus communis L. seedlings transfer the methyl from methionine to both oxygen and nitrogen of ricinine (404). The N-methyl as well as the methylene of the methylenedioxy groups in protopine can also originate in methionine (405). Similarly the methyl groups of the lignin

20

K. MOTHES

in barley and tobacco have been traced to methionine (403, 406). I n general C-methyl groups have their origin in the primary building blocks of the molecule, but the 5-methyl in thymine (XIII) has been traced to formate, serine, and glycine (407, 408). The source of the N-methyl groups in gramine was not identified, but it was shown by Bowden and Marion (260) and by Leete and Marion (409) that tryptophan is the source of gramine in barley leaves. By appropriate labeling it was also found that the bond between the aliphatic side chain and the pyrrol nucleus is not severed in this synthesis. 3. NUCLEAR SYNTHESES

It has been shown that the ring carbon between the nitrogens and the N-methyl group of ergothioneine can arise from the a-carbon of acetate during its synthesis by Neurospora or Claviceps. The N-methyl groups can also have their origin in methionine (410-412). The source of the pyridine nucleus in nicotine and in anabasine was somewhat of a mystery (413-415), particularly since it was not radioactive when synthesized in the plant in the presence of nicotinic acid labeled in the carboxyl (416). However, it was shown that nicotinic acid labeled in the nucleus with both H3 and C14 was incorporated into nicotine by isolated tobacco roots (417, 418). The origin of the pyrrolidine ring was traceable to ornithine (419-421). Labeled lysine, however, failed to yield radioactive nicotine (422), but it did contribute the piperidine ring in anabasine when supplied to growing plants of Nicotiana glauca (421). However, it did not give rise to anabasine when isolated leaves of the same plant were fed with it or with labeled hydroxylysine (423). The ring enlargement of pyrrolidine in nicotine to piperidine in anabasine could not be demonstrated (424). The origin of the tropane ring system had already been relegated to the arginine-ornithine-putrescine system (Vol. I, pp. 64-68) by experiments with isolated shoots and leaves (Atropa, Datura). I n view, however, of the known fact that the synthesis takes place largely in the roots it is evident that that, is the site of formation of the precursors. Young seedlings of Atropa first elaborate cuscohygrine along with large amounts of proline (425, 426), and scopolamine and hyoscyamine are formed only at a later stage. That cuscohygrine should also be formed by Erythroxylon coca Lam. is another convincing example of the fact that distantly related plants often end up with the same products if they have on hand the same starting materials. Parenthetically it might be remarked that the bellaradine of King and Ware (427) is in fact cuscohygrine (428).


21

When arginine, ornithine, or putrescine was fed to isolated roots of Atropa in sterile media there was an increase in growth and in alkaloid content and when the sucrose was increased from 2% to 4% still further increases in growth and alkaloid took place. The ratio of different alkaloids was not affected unless proline was introduced, in which case relatively large amounts of cuscohygrine were formed (268, 429). When cadaverine was introduced an unknown alkaloid appeared to be generated. Ornithine labeled at the a-carbon when fed to the roots of growing Datura stramonium yielded hyoscyamine labeled at the bridgehead carbons but scopolamine was not detected (409).

IX. External Factors Governing Alkaloid Formation* Though the literature on this subject is voluminous, there are very few examples in which the many variables were controlled sufficiently to justify the reaching of valid conclusions. I n general good cultural conditions promote good yields of alkaloids (240). Numerous workers have stressed adequate sources of nitrogen (ergot: (201, 206, 430); Papaver: (210);Nicotiana: (286, 301); Hyoscyamus: (316,431);Lupinus: (432) ), but excess nitrogen often lowers alkaloid formation in parallel with the diminished root growth (286, 433). Ergot cultivated on tetraploid rye produces larger sclerotia but the alkaloid content and the yield per unit area are essentially unchanged (434).

A deficiency of potassium has been reported to increase alkaloid formation (352) and indeed is credited with promoting putrescine formation to the point where it is thought to have induced chlorosis (435).

Reports that boron deficiency increased nicotine production (436, 437) could not be confirmed in the writer’s laboratory (Scholz, unpublished). Boron deficiency in SaZsoZu richteri (190) and in Atropa (438) seemed to decrease alkaloid formation. There is a report that extra manganese and cobalt lead to increased alkaloid yields in Datura (439).

The effects of rainfall and other climatic factors have not been extensively studied, but Duboisia seedlings tend to yield more hyoscyamine in a cool environment and more hyoscine at higher temperatures (346).

The degree of illumination seems to be important and in general the greater the light intensity, the greater the amount of alkaloid (205, 233, 282, 440-442). An interesting example is Solanum aviculare Forst., * This material is supplementary to Volume I, pages 68-81.

22

K. MOTRES

which under restricted illumination produced more diosgenin, presumably at the expense of solasodine, indicating a biogenetic relation between this steroid and the steroid alkaloid (443).

X. Metabolic Status* Those plants which elaborate alkaloids in the roots do so mostly in the actively growing parts thereof. Flower production, which inhibits root growth, can be circumvented by the culture of isolated rooted leaves. The absolute amount of alkaloid in such leaves can be as much as a hundred times that in the leaves on the plant and twenty times as much fractionally when based on dry weight (286). As has already been pointed out there is a positive and recognizable relation between amino acids and alkaloids, but we have searched in vain for one between proteins and alkaloids (250, 444). When tryptophan was injected into the internodes of rye infected with ergot there was a slight increase in the ergot alkaloids. If labeled tryptophan is injected, the lysergic acid of the alkaloids is radioactive (unpublished results of Groger and Griesebach). Other amino acids were without effect, and this is interpreted to mean either that they do not arrive at the site of synthesis or that there are other and unknown limiting factors (203, 445, 446). XI. Consequences of Alkaloid Synthesist It has not yet been demonstrated that alkaloids in any plant perform an essential function that cannot be performed otherwise. Their application from without often has pronounced effects, but such effects are not necessarily produced when the alkaloid is liberated inside the vacuoles. Toxicity is a relative term. Tomato leaves contain small amounts of nicotine (182), but they suffer toxic effects from nicotine when grafted on Nicotiana rustica. Even those plants which produce nicotine in fairly large quantities may show the ill effects of too much but N . rustica can tolerate a tenfold increase, whereas the growth of isolated roots of N . glauca is definitely retarded by additions of nicotine in concentrations of more than 200 mg./l. Grafts of Atropa, tomato, Cyphomandra, etc., on tobacco suffer typical nicotine damage if grown for some time in the sun but not in shade (184). The effect of alkaloids on chloroplasts has been repeatedly investigated (447-449), and their effect upon germination and normal nuclear division has often been noted (450-452). * This material is supplementary to Volume I, pages 52-56 and 81-83. t This material is supplementary to Volume I, pages 83-85.

ALKALOIDS I N T H E PLANT

23

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28

K . MOTHES

382. E. Work, in “Amino acid metabolism” (W. McElroy and B. Glass, eds.), pp. 462492. Johns Hopkins, Baltimore, 1955. 383. R. S. Schweet, J. T. Holden, and P. H. Lowy, in “Amino acid metabolism” (W. McElroy and B. Glass, eds.), pp. 496-506. Johns Hopkins, Baltimore, 1955. 384. E. Leete, L. Marion, and I. D. Spenser, J. Biol. Chem. 214, 71-77 (1955). 385. S. Granick, in “Chemical Pathways of Metabolism” (D. M. Greenberg, ed.), Vol. 2, pp. 287-342. Academic Press, New York, 1954. 386. K. Hasse and H. Maisack, Natururissewchaften 42, 627-628 (1955); Biochem. 2. 327, 296-304 (1955). 387. P. J. G. Mann and W. R. Smithies, Biochem. J. 61, 89-100, 101-105 (1955). 388. H. M. Bregoff and C. 0. Delwiche, J. Biol. Chem. 217, 819-828 (1955). 389. H. M. Rauen, in “Colloquium, 6, Gesellschaft fur Physiologische Chemie, Mosbach, Baden, Vergleichend biochemische Fragen,” pp. 132-164. Springer, Berlin, 1956. 390. H.-B. Schroter, in “Handbuch der Pflanzenphysiologie” (W. Ruhland, ed.), Vol. 8. Springer, Berlin, 1957. 391. V. du Vigneaud, “A Trail of Research in Sulfur Chemistry and Metabolism and Related Fields,” Cornell Univ. Press, Ithaca, New Pork, 1952. 392. F. C. J. Zeijlmaker, Acta Botan. N e e d 2, 123-143 (1953). 393. W. 0. James and V. S. Butt, Abhandl. deut. Akad. Wiss. Berlin K l . Chem. B e d . u. BWZ. (1957). 394. E. Leete, S. Kirkwood, and 1,. Marion, Can. J. Chem. 30, 749-60 (1952). 395. E. Leete and L. Marion, Can. J. Chem. 31, 126-133 (19.53). 396. T. J. Matchett, L. Marion, and S. Kirkwood, Can. J . Chem. 31, 488-92 (1953). 397. S. A. Brown and R. U. Byerrum, J. Am. Chem. SOC.74, 1523 (1952). 398. L. J. Dewey, R. U. Byerrum, and C. D. Ball, J. A m . Chem. SOC.76, 3997 (1954). 399. R. U. Byerrum, C. S. Sato, and Ch. D. Ball, Plant Physiol. 31, 374-77 (1956). 400. R. U. Byerrum and R. E. Wing, J . Biol. Chem. 205, 637-42 (1953). 401. R. U. Byerrum, R. L. Ringler, R. L. Hamill, and C. D. Ball, J. B i d . Chem. 216, 371 (1955). 402. R. U. Byerrum, R. L. Hamill, and C. D. Ball, J. Biol. Chem. 210, 645 (1954). 403. R. U. Byerrum, L. J. Dewey, R. L. Hamill, and C. D. Ball, J. Bwl. Chem. 219, 345-350 (1956). 404. M. Dubeck and S. Kirkwood, J. B i d . Chem. 199, 307-12 (1952). 405. M. Sribney and S. Kirkwood, Nature 171, 931 (1953). 406. R. U. Byerrurn, J. H. Flokstra, L. J. Dewey, and Ch. D. Ball, J . B i d . Chem. 210, 633-643 (1954). 407. D. Elwin and D. Sprinson, J. Am. Chem. SOC.72, 3317 (1950). 408. D. V. Rege and A. Sreenivasan, J. B i d . Chem. 208, 471-476 (1954). 409. E. Leete and L. Marion, Can. J. Chem. 31, 1195-1202 (1953). 410. H. Heath and J. Wildy, Nature 179, 196-197 (1957). 411. D. B. Melville, St. Eich, and M. L. Ludwig, J. B i d . Chem. 224, 871-877 (1967). 412. J. Wildy and H. Heath, Biochem. J. 65, 220-222 (1957). 413. K. Bowden, Nature 172, 768 (1953). 414. P. I. Mortimer, Nature 172, 74 (1953). 415. G. Petrosini, Tabacco, I1 58, 39-55 (1954). 416. R. F. Dawson, D. R. Christman, and C. Anderson, J. Am. Chem. SOC.75,51.14 (1953). 417. R . F. Dawson, D. R. Christman, and A. D’Adamo, Plant Physiol. 31, XXXVII ( 1956). 418. R. F. Dawson, D. R. Christman, R. Ch. Anderson, M. L. Solt, A. F. D. D’Adamo, and U. Weiss, J . A m . Chem. SOC.78, 2645-46 (1956).


29

419. L. J. Dewey, R. U. Byerrum, and C. D. Ball, Biochim. et Biophys. Acta 18, 141 (1955). 420. E. Leete, Chem. & Ind. (London),p . 537 (1955). 421. E. Leete, J. Am. Chem. SOC.78, 3520 (1956). 422. A. A. Bothner-By, R. F. Dawson, and D. R. Christman, Ezperientia 12, 151 (1956). 423. S. Aronoff, Plant Physiol. 31, 355-357 (1956). 424. H.-B. Schroter, 2. Naturforsch. 12 (1957). 425. P. Reinouts van Haga, Nature 173, 692 (1954). 426. P. Reinouts van Haga, Nature 174, 833 (1954). 427. H. King and L. Ware, J . Chem. SOC.139, 331 (1941). 428. E. Steinegger and G. Phokas, Pharm. Acta Helv. 30, 441-443 (1955). 429. P. Reinouts van Haga, Biochim. et Biophys. Acta 19, 562 (1956). 430. A. Silber and W. Bischoff, Pharmazie 9, 46 (1954). 431. L. J. Schermeister, R. F. Voigt, and F. T. MBher, J. Am. Pharm. Assoc. Sci. Ed. 39, 669-72 (1950). 432. Vogel and E. Weber, 2. PfZanzenerniihr. u. Dung. A 1, 85 (1922). 433. W. W. Garner, C. W. Bacon, J. D. Bowling, and D. E. Brown, Technical Bull. No. 414 (1934), quoted by A. Smirnow, “Biochemie des Tabaks,” p. 94. The Hague, 1940. 434. J. Deufel, Naturwissenschaften 39, 432 (1952); Arch. Pharm. 287, 329-32 (1954). 435. F. I. Richards and R. G. Coleman, Nature 170, 460 (1952). 436. R. A. Steinberg, Symposium o n Inorg. Nitrogen Metabolism, Baltimore, 1955, pp. 163-158 (1956); PZant Physiol. 30, 84-86 (1955). 437. R. A. Steinberg and R. N. Jeffrey, Plant Physiol. 31, 377-382 (1956). 438. J. M. P. Barcelo, J. B. A. Manrique, and C. L. Moreno, Bull. SOC. chim. biol. 34, 1106-1111 (1952). 439. A. Jindra, I. Syrovy, J. Boswart, V. JiraEek, and A. Majerova, Abhandl. deut. Akad. Wiss.Berlin, K l . Chem. Qeol. u. Biol. (1957). 440. H. Conner, Plant PhysioZ. 12, 79 (1937). 441. S. 0. Grebinskij, Doklady Akad. NaukS.S.S.R. 24, No. 5 (1939). 442. A. Renier, Ann. inst. exp. tabac Bergerac. 1 (Z), 145-162 (1951); 1 (3), 71-77 (1952). 443. K. Schreiber, Abhandl. deut. Akud. Wiss.Berlin, Kl. Chem. Geol. u. Biol. (1967). 444. H. Schmid and M. Serrano, Ezperientia 6, 311 (1948). 445. D. Groger and U. Mothes, Pharmazie 11, 323 (1956). J a p a n 71, 385 (1951). 446. T. Kawatani, M. Kataynagi, and S. Kiyooka, J. Pharm. SOC. 447. H. Larz, Flora (Jena) 135, 319 (1942). 448. K1. Mudrack, Protoplasma 46, 556 (1956). 449. H. H. Schmidt, Protoplasma 40, 209 (1951). 450. H. Lettrt5, Pharmazie 1, 145 (1946). 451. L. Recalde Martinez, Farmacognosia (Madrid) 9, 231-246 (1949). 452. G. T. Scarascia, Tabaceo, IZ 59, 133-153 (1955).


CHAPTER2

The Pyrrolidine Alkaloids LEO MARION National Research Council, Ottawa, Canada I. 11. 111. IV. V. VI. VII.

Introduction ..................................................... Hygrine .......................................................... Hygroline......................................................... Cusoohygrine...................................................... Strtohydrine....................................................... Betonicine, Turicine................................................ References........................................................

Page 31 31 31 32 32 33 34

I. Introduction* In the few years since the chapter on the pyrrolidine alkaloids was written they have not been the subject of much additional work. The recent investigations to be described relate to hygrine, hygroline, cuscohygrine, stachydrine, betonicine, and turicine. The structure of carpaine has also been fully elucidated, and this alkaloid has been shown to be a piperidine and not a pyrrolidine alkaloid and hence will be described under the heading “The Pyridine Alkaloids.” II. Hygrinet A number of additional syntheses of hygrine have been described. Borm (1) reported that the catalytic reduction of the product of the reaction of N-methylpyrrole and diazoacetone gave dl-hygrine. It was found by Galinovsky et al. (2) that the amino-aldehyde produced by the partial reduction of N-methyl-a-pyrrolidone with LiAlH,, on condensation with acetonedicarboxylic acid, gives rise to a mixture of dl-hygrine and cuscohygrine. The same material, when condensed with ethyl acetoacetate, produces a 60% yield of hygrine and no cuscohygrine (3). Racemic hygrine is resolved with tartaric acid, and the bitartrate of 1-hygrine melts at 69”, in the form of a hydrate, and at 130” when anhydrous. The recovered 1-hygrine has - 1.8” (water).

8A].[

III. Hygrolinej Hygroline has been synthesized by the catalytic reduction of 1-hygrine.

* This material is supplementary to Volume I, page 91. t This material is supplementary to Volume I, page 92. This material is supplementary to Volume I, page 94. 31

32

LEO MARION

The reduction product consists of a mixture of l-hygroline and Z-pseudohygroline which are separated by the fractional crystallization of their picrates. The base liberated from the more soluble picrate is converted to the benzoyl derivative and further purified by repeated crystallization of its chlorplatinate. Synthetic 1-hygroline melts at 34' and has [u]~'-84.1' (water), while Z-pseudohygroline, b.p. 80-90'/10-' mm., has [a]i4-113.7' (water) (3).

IV. Cuscohygrine* Recently, cuscohygrine has been detected in the fresh roots of

Atropa belladonna L., and also by paper chromatography in Datura strumonium L. (4). The alkaloid (XXV) had been synthesized by

Spath and Tuppy ( 5 ) , but the synthesis involved the dry distillation of a salt of (N-methyl-a-pyrry1)-acetic acid. The same synthesis was also reported by Rapoport and Jorgensen (6). A more convincing synthesis has since been described (2). It consists of the partial reduction of N-methyl-u-pyrrolidone with LiAlH, followed by the condensation of the resulting amino-aldehyde with acetonedicarboxylic acid. There is formed a mixture of hygrine and cuscohygrine. Another synthesis of cuscohygrine involves the condensation at pH 7 of acetonedicarboxylic acid with two molecular proportions of y-methylaminobutyraldehyde (7). Cuscohygrine, which is optically inactive, has been shown to be a naturally occurring meso form (3).

V. Stachydrinet It has been shown that the biogenetic precursor of the pyrrolidine ring in plants is ornithine (8).I n Medicago sativa L. the alkaloid stachydrine is stored in the seeds and appears to be actively synthesized only during the period of seed formation. At any rate, plants that are 19 weeks old are incapable of converting ornithine into stachydrine or even proline (9). Feeding the coenzyme pyridoxine together with labeled ornithine to the plant, however, results in the formation of radioactive proline, but no stachydrine is formed (10). The addition of methionine * This material is supplementary to Volume I, page 95. t This material is supplementary to Volume I, page 101.

THE PYRROLIDINE ALKALOIDS

33

to the ornithine and pyridoxine fed to the plant does not induce the formation of stachydrine, although in all other plants studied methionine was an effective methylating agent. Quite recently, it has been found that labeled methionine in the presence of a trace of folic acid when fed to the plant with pyridoxine does give rise to radioactive stachydrine (11). Hence before the stage of seed formation, although Medicago sativa does not synthesize stachydrine, it contains the amino acids required for the synthesis but lacks the coenzymes. Active synthesis takes place only after the requisite coenzymes are present.

VI. Betonicine, Turicine* The stereochemistry of the hydroxyproline betaines, betonicine and turicine, had not been previously established; this has now been done by the use of nonepimerizing methylating conditions on hydroxyprolines of known stereochemistry. Refluxing N-acetyl-0-p-tolylsulfonylhydroxy-L-proline in methyl ethyl ketone in the presence of anhydrous potassium carbonate causes the displacement of the toluenesulfonate ion by the carboxylate anion in an internal SN2 reaction, and leads to the lactone of N-acetylallohydroxy-L-proline (XXVI) with inversion. Hydroxy-L-proline belongs Ac

XXVI

t o the natural L,-series and its hydroxyl group is trans to the carboxyl (12, 13). The configuration at C, in hydroxy-L-proline can be related to L-glyceraldehyde while in the lactone XXVI it is related to D-glyceraldehyde; this is confirmed by the application of Hudson's rule. The lactone of allohydroxy-D-proline is obtained similarly from hydroxyD-proline (14). Hydrolysis of the lactone XXVI gave allohydroxy-Lproline. Methylation of hydroxy-L-proline with methyl iodide and silver oxide gave only betonicine, whereas methylation under the same H,C

CH,

"'\ Coo@

7,

4Y XXVlii

XXVll

* This material

is supplementary t o Volume

I, page 103.

34

LEO MARION

conditions of allohydroxy-D-proline produced pure turicine. Hence betonicine is represented by XXVII and turicine by XXVIII. Starting with betonicine or turicine, a base-catalyzed epimerization a t C, gives in each case a 60:40mixture of betonicine and turicine. This ease of epimerization raises some doubts about the natural occurrence of turicine, the betaine of allohydroxy-D-proline,which is perhaps more likely to arise from betonicine during isolation (14).

VII. References 1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

F. gorm, Collection Czechoslov. Chem. Cornmum. 12, 245 (1947). F. Galinovsky, A. Wagner, and R. Weiser, Monatsh. Chem. 82, 551 (1951). F. Galinovsky and H. Zuber, Monatsh. Chem. 84, 798 (1953). P. Reinouts van Haga, Nature 174, 833 (1953). E. Spiith and H. Tuppy, Monatsh. Chem. 79, 119 (1948). H. Rapoport and E. Jorgensen, J. Org. Chem. 14, 664 (1949). E. Anet, G. K. Hughes, and E. Ritchie, Nature 163, 289 (1949). E. Leete, L. Marion, and I. D. Spenser, Can. J. Chem. 32, 1116 (1954). E. Leete, L. Marion, and I. D. Spenser, J. Bwl. Chem. 214, 7 1 (1955). A. Morgan and L. Marion, Can. J. Chem. 34, 1704 (1956). G. Wiehler and L. Marion, J. B i d . Chem. 231, 799 (1958). A. Neuberger, J. Chem. Soc., p. 429 (1945). C. S. Hudson and A. Neuberger, J. Org. C h m . 15, 24 (1950). A. A. Patchett and B. Witkop, J. A m . Chem. SOC.79, 185 (1957).

CHAPTER3

Senecio Alkaloids NELSON J . LEONARD University of Illinois. Urbana. Illinois Page I Occurrence and Constitution (107-1 l6)* .............................. 37 I1. Extractive and Degradative Procedure (116-1 18)...................... 46 I11. Structure o f t h e Necines (118-138) ................................... 49 1. C.H.. NO Necines ................................................ 49 a . Trachelanthamidine (135-136) ................................. 49 b . Laburnine ................................................... 52 c . Lindelofidine ................................................ 53 2 C,H,, NO Necine ................................................ 56 a . Supinidine .................................................. 50 3. C.H,,NO. Necines ............................................... 60 a . Platynecine (118-135) ........................................ 60 4 C,H..NO, Necines ............................................... 63 a Heliotridine and Retronecine (118-135) ......................... 63 5 C.H15N0. Necine ................................................ 66 a . Rosmarinecine (137-138) ...................................... 66 6. Other Necines and Necine N.Oxides ............................... 67 IV Structure o f t h e Necic Acids ......................................... 68 1. C-5 Acids ....................................................... 68 a . Angelic Acid ................................................. 68 b S a ~ a c i n i cAcid .............................................. 68 2 C-6 Acids ....................................................... 69 a Dicrotalic Acid (138)......................................... 69 3 C-7 Acids ....................................................... 74 a Trachelanthic Acid (139)...................................... 74 b . Viridifloric Acid .............................................. 77 c . Echimidinic Acid (Macrotomic Acid) ............................ 78 4 C-8 Acids ....................................................... 79 a . Monocrotalic Acid (140-145) ................................... 79 b . Heliotrinic Acid (145-146) ..................................... 84 c Lasiocarpic Acid (146)........................................ 85 6. (3-10 Acids ...................................................... 86 a Mikanecic Acid .............................................. 86 b . Squalinecic Acid (148)........................................ 86 c . Sceleranecic Acid (148)........................................ 87 d . Seneciphyllic Acid (148)........................................ 89 e . Jacozinecic Acid ............................................. 92 f . Riddellic Acid (149).......................................... 92 94 g Grantianic Acid (149)......................................... h . Hastanecic Acid (149) ........................................ 95 * Numbers in parentheses following headings and subheadings in the contents and text refer to pages in Volume I. Chapter 4. to which this material is supplementary.

.

.

. . .

.

. . . . .

.

. .

.

35

.

36

NELSON J LEONARD

Integerrinecic Acid ........................................... Platynecic Acid (146-148) ..................................... Senecic Acid (146-148) Trichodesmic Acid ........................................... Usaramoensinecic Acid ........................................ Isatinecic Acid (149) ........................................... o. Jaconecic Acid (149) .......................................... p Junceic Acid ................................................ q Retronecic Acid (149) ......................................... r Miscellaneous Acids .......................................... Structure of the Alkaloids ........................................... 1 Monoesters of Necine and Monocarboxylic Acid ..................... a . Echinatine .................................................. b Europine .................................................... c . Heleurine ................................................... d Heliotrine ................................................... e Lindelofamine ............................................... f Lindelofine .................................................. g Macrotomine ................................................ h Supinine .................................................... i . Trachelanthamine (159-160) ................................... j . Viridiflorine ................................................. 2 . Diesters of Necine and Two Different Monocarboxylic Acids .......... a . Echimidine .................................................. b . Echiumine .................................................. c . Heliosupine ................................................. d . Lasiocarpine (154) ............................................ e . Sarracine .................................................... 3 . Cyclic Diesters of Necine and Dicarboxylic Acid ..................... a Dicrotaline (151) ............................................. b . Integerrimine (153) ........................................... c . Junceine ..................................................... d . Mikanoidine ................................................. e Monocrotaline (155) .......................................... f . Platyphylline (156) ........................................... g . Retrorsine (156) .............................................. h . Riddelliine (157) ............................................. i . Rosmarinine (158) ............................................ j . Sceleratine (158) ............................................. k Senecionine (159) ............................................. 1. Seneciphylline (159) .......................................... m . Spartioidine ................................................. n Trichodesmine (160) .......................................... o. Usaramoensine ............................................... 4 Other Alkaloids (for Which the Two Moieties May Be Known but Total Structures Cannot Be Written) ................................. Biosynthesis and Pharmacology ...................................... References ........................................................ Addendum ........................................................ i. j k 1. m n.

. . . . .

V

.

.

.

. . . . . .

.

.

.

.

.

.

VI VII. VIIT

.

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

pwe 95 96 97 100 101 102 105 108 109 109 109 109 109 110 110 110 110 110 111 111 111 111 111 111 112 112 112 112 112 112 113 113 113 114 114 114 114 115 115 115 115 116 116 116 116 117 117 121

SENECIO ALKALOIDS

37

I. Occurrence and Constitution* (107-1 16) Since the genus Xenecio still provides the greatest number of species containing alkaloids with a hydroxylated pyrrolizidine moiety, the term “Senecio alkaloids” (73) may be retained to describe this family of alkaloids. Alternatively, the term “pyrrolizidine alkaloids” (74-76) depicts the close chemical similarity of compounds which have been isolated from many different genera (Table 1) of the families Compositae, Leguminosae, and Boraginaceae. Excellent reviews by Adams (74, 76) and Warren (75) have brought to date periodically the general subject of the pyrrolizidine alkaloids, and significant advances in the structural chemistry of these compounds have been the result of the admirable and sustained investigations in the laboratories of these two chemists and of the Russian school centered in Men’shikov (77). In medicine, the Senecio, CrotaEaria, and Heliotropium plants and their alkaloids continue to be of interest and concern (75, 78). The structural interrelations of the Senecio alkaloids have been further refined since the first survey in these volumes (73). Specifically, the alkaloids fall into three main categories: monoesters of the “necine” (alkanolamineportion) with a monocarboxylic “necic acid,” diesters of the necine with two different monocarboxylic necic acids, and cyclic diesters of the necine with a dicarboxylic necic acid. The last category represents a highly interesting group of compounds, of wide natural occurrence, containing rings of medium size: the two ester groupings are part of a ring of eleven or twelve members. Since the gross structural features of many of the necines had been established earlier, accent in the past few years has been placed on the determination of the relative configurations of the asymmetric carbons in the necines and, more recently, on their absolute configurations. The status of the necic acids was not as favorable ten years ago (73), and impressive advances have been made in establishing their gross chemical structures, in recognizing the features common to related necic acids, and in making partial stereochemical configurational assignments. Untested theories of possible biogenetic pathways have provided interest and have promised some usefulness in applications to future structure problems. One feature relating to the constitution of the pyrrolizidine alkaloids which has assumed increased importance is the occurrence in the plant, now recognized as general (146), of the alkaloid N-oxides. Trachelanthamine N-oxide (trachelanthine) was the first such compound to be isolated and identified, along with trachelanthamine, from Trachelanthus korolkovi Lipsky (56-56c), and N-oxides have since been found *

See also Addendum, p. 121.

W

TABLE 1

00

Senecio ALKALOIDS* Alkaloid Aquaticine C18H25N06

Base 4 Brasilinecine Campestrine

Source

-

S. aquaticus Hill (79) [Characteristics similar to hieracifoline, which is a mixture of senecionine and seneciphylline (80) ] S. renardi Winkl. (81) S . brasiliensis D.C. (82) [Possibly a mixture of senecionine, seneciphylline, and jacobine (83) ]

(73)

M.p. ('C.)

220

176-178 171 (dec.)

[UlD

- 83'

-68.2O

a

93

C13H19N03

Carthamoidine Dicrotdine

[Mixture of seneciphylline and senecionine (84, 85) ] (73, 86)

170 (dec.) cl

C14H1klN06

Douglasiine Echimidine

[Mixture of seniciphylline, senecionine, riddelliine, and retrorsine (84, 85, 87) ] Echium plantagineum L. (88)

13.4'

Echinatine

Rindera echinata (89)

C15H25N06

Echiumine

Echium plantagineum L. ( 8 8 )

99-100

14.4

C20H81N06

Eremophiline Europine

[Mixture of senecionine, seneciphylline, and retrorsine (84, 85, 87) ] Heliotropium europaeum L. (90-92)

10.9 d

C16H27N06

Europine N-oxide

Heliotropium europaeum L. (90-92)

171

C16H27N07

* Where reference 73 is cited, the sonrre material in the original chapter may be considered complete. Other entries are additions or corrections. 0

Chloroform, b methanol, c water, d ethanol, e pyridine-solvent used in determination of speciflc rotation.

cw u

C20H31N07

25.3

TABLE I-(Continued)

Alkaloid Fuchsisenecionine

Source (73)

[aID

(73)

225-227 (HC1salt) 236

(73)

204-205 (dec.)

50.6’

(73)

170-171

- 72.3O

C12H21N03

Graminifoline

M.p. (‘C.)

C18H23N05

Grantianine

a

C16H23N07

Hastacine C18H27N05

Heleurine


67-68

- 12.0’ d

C16H27N04

Heleurine N-oxide

C16H27N05

Heliotrine N-oxide

E!

a 0


C16H27N05

Heliosupine C20H31N07 Heliotrine

W M

Heliotropium w p i n u m L. (88, 93a)

-4.3’

(73) Heliotropium europaeum L. (90-92) Helwtropium europaeum L. (90-92)

63.8’ a 128 171-172

17.6’ 26.6’

172-172.5

4.3O a

229-230

-28’

d

b

E8

W

C16H27N06

Hieracifoline Integerrimine C18H25N05

Isatidine “Isoheliotrine” Jacobine Cl*H25NOB

[Mixture of .senecionine and seneciphylline (80, 117, 1 IS)] (73) Crotalaria incana L. (93) [Identical with retrorsine N-oxide (94, 95)] [Identical with heliotrine (90, 96, 97)] Sene& brasiliensis D.C. (83) Senecio cineraria D.C. (98) Senecio jacobaea L. (99-102)

w W

I@

0

TABLE ~--(cOni?&W@d)

Alkaloid Jacodine Jacoline

Source [Identical with seneciphylline (loo)] Senecio jawbaea L. (99-102)

r alD

M.p. (OC.)

22 1

48'

a

C18H27N07

Jaconine

Senecio jacobaea L. (99, 100, 102)

146-147

C20H32C1N07

Jacozine Cl,H23NOO Junceine

Senecio jawbaea L. (99, 100) Crotalariu juncea L. (103, 104)

228 191-192

28' a 30' - 140'

-30

a

6

C18H27N07

Laburnine C8HlSNO Lanigerosine C18H27N08

Lasiocarpine C21H33N07

Lasiocarpine N-oxide

Cytisus laburnum L. (105) (Also a source of cytisine, a lupin alkaloid) Senecio pauciculyculatus Platt (106) Senecio retrorsus Benth. (107) (73) Heliotropium europaeum L. (90-92, 96, 97) Heliotropium europaeum L. (90-92)

15.5O

2

184 96.5-97 133 (dec.)

I-' -3.5O d 13.1'

LindeloBa anchusoides (108)

88

Limiklofia anchuaoides (108)

106-107

50°

[Identical with seneciphylline (85)] [Identical with retrorsine (87)] Senecio macrophyllus (109)

4244

34.5'

Macrotomia echoides Boiss. ( 1 10)

95-97

-6.9'

C20H33N06

Lindelofine C15H27N04

or-Longilobine 8-Longilobine iifacrophylline C,,H2lNO, Macrotomine C16H27N06

F M 0

?1 U

C21H33N08

Lindelofamine

3F

rA

d

Alkaloid Mikanoidine C18HZ,NO, Monocrotaline Cl,HZ,NO, Otosenine Cl,HZ,NO? Platyphylline C,,HZ,NO, Platyphylline N-oxide C18HZ7N0, Pterophine Renardine Cl,H,,NOS Retrorsine Cl,HZ,NOB

Retrorsine N-oxide C,,HZ,NO,

Source

M.p. ("C.)

Senecio mikanoides (Walp) Otto (73,111)

(73)

197-198

Senecio othonme Bieb. (81)

218-219 (dec.)

(73,112, 113) Nardomia laeVig& D.C. (114) Senecw hygrophilus Dyer and Sm. (116) Senecia platyphyllus D.C. (116) [Mixture of senecionine and seneciphylline (117,lls)] Nardosmia laewigata D.C. (114)

(73,95) Erechtites quadridentata D.C. (117) Senecw ambro8wides (83) Senecw ampullaceus Hook (84,87) Senecio bupleuroides D.C. (119) Senecio douglasii D.C. (84,87) Senecw eremphilus Richards (84,87) Senecio hatideus D.C. (115) Senecio Zongilobus Benth. (84,87, 120, 121) Senecio paueicalyculatus Platt (106) Senffiioriddellii T.and G . var. Parkaa'i Cory (76,84) Senecio ruderalw Harv. (122)

(94,95)

-64.7 a

129 180-181

-44.s"

a

B M

193-195 207-208 or 216-216.5 (?)

-2.2O

a

-48.6O a or -62.4O(?)

8

k

s

Ei

Ga

146

-8.2'

Erechtitw q d r i d e n t a t a D.C. (117) 1p

1-(Continued)

TABLE

Alkaloid

Riddelliine C18H23NoE

Rosmarinine C18H27NoE

Rosmarinine N-oxide C18H27N07

Ruwenine

Source

M.p. ("C.)

Senecio bupleuroides D.C. (119) Senecio isatideus D.C. (115, 123) Senecio paucicalyctdatus Platt (106) (73) Crotalaria juncea L. (103) Senecio douglasii D.C. (84) Senecio eremophilus Richards (84) Senecio longilobus Benth. (84) Senecio riddellii Tom. and Gray var. Parksii Cory (75, 84) (73) Senecio adnatus D.C. ( 1 15) Senecio brachypodus D.C. (115) Senecio hygrophilus Dyer and Sm. (115) Senecio adnatus D.C. (115) Senecio brachypodus D.C. (115) Senecio hygrophilus Dyer and Sm. (115) Senecio ruwenzoriensis S . Moore (124)

175.5-179 (dec.)

Senecio ruwenzoriensis S. Moore (124)

161-163 (dec.)

[=ID

195-196

- 109'

a

209

- 120'

a

M

- 94O d

C18H27N08

Sarracine

Senecio sarracenius L. (125-127)

51-52

-129.7'

Senecio sarracenius L. (125-127)

123-124

-81.6'

Senecio sceleratus Schweikerdt (73, 128-134)

178

54O

(73)

212

- 13.9'

C18H27N05

Sarracine N-oxide C18H27N08

Sceleratine

d

C18H27N07

Senecifolidine C18H26N07

2 er

C18H27N0B

Ruzorine

F

v1

TABLE

Alkaloid Senecifoline CISH27NO8 Senecine Senecionine

C,,H,,NO,

Seneciphylline

C,SH,,NO,

1-(Continued) Source

(73) (73, 84) (73) Crotalaria juncea L. (103) Erechtites hieracifolia (L.) Rafin. (80, 117, 118) Erechtites guadridentata D.C. (117, 118) Nardosmia laevigata D.C. (114) Senecio ambrosioides (83) Senecio ampullaceus Hook (84) Senecio brasiliensis D.C. (83) Senecio earthamoides Greene (84) Senecio cineraria D.C. (135) Senecio eremophilus Richards (84) Senecio ilicijolius Thunb. ( 117, 118) Senecio fwmonti Torr. and Gray (83) Senecio glabellus D.C. (93) Senecio jacobaea L. (80, 101) Senecio pterophorus D.C. (117, 118) Senecio tomentosus (140) (73) Crotalaria juncea L. (103) Erechtites hieracifolia (L.) Rafin. (80, 117, 118) Erechtites quadridentata D.C. (117, 118) Senecio ambrosioides (83) Senecio ampullaceus Hook (84, 85) Senecio brasiliensis D.C. (83)

M.p. ("C.) 194-195

236 (dec.)

[ah

28.1'

(I

-558'

v)

M

8

217-218 (dec.)

-134'4

TABLE

Alkaloid

Seneciphylline N-oxide C18H23N06

Senkirkine

+P. +P.

1-(Continued) Source

Senecio carthamoides Greene (84, 85) Senecio eremophilw, Richards (84, 86) Senecio frelnonti Torr. and Gray (83) Senecio ilicijolius Thunb. (117, 118) Senecio jawbaea L. (80, 94-101) Senecio Zongilobus Benth. (85, 120, 121) Senecio platyphyllw, D.C. (116) Senecio pterophorus D.C. (117, 118) Senecio renardi Winkl. (81) Senecio vulgaris L. (84, 85) Erechtites quadridsntata D.C. (117) Senecio platyphyllw, D.C. (116) Senecio kirkii Hook (136)

M.p.

[ah

(OC.)

3

F

$

ca. 120

4 197-198

- 6.2'

a

C18H25N06

Silvasenecine

(73)

Senecio spartioides Tom. and Gray (137)

178

-83.7'

(73)

169

-26.9'a

14s.149

-12O d

C16H23N05

Squalidine C18H25N05

Supinine C15H25N04

Supinine N-oxide C15H26N05

Tomentosine Cl,H2,NO,

M

1 U

C12H2,NOI

Spartioidine

l?

Heliotropium europaeum L . (90-92, 139) Heliotropium sup'num L. (93a, 138) Tournejorticl aarmentosa Lam. (139) Helwtropium europaeum L. (91, 92) Tourneforticl samnentosa Lam. (139) Senecio tomentom (140)

232

14'

a

Alkaloid Trachelanthamine

Source

M.p. (‘C.)

[.In

92-93

-18.1’

166-167

-22.5’

160-161

38’ d

Crotalaria usaramoensia E. G . Baker (93)

221 (dec.)

-25’

Cymglossum viridi@wum Willd. (144)

102.5-103.5

-11.7O

(73, 141)

C16H27N04

TrachelanthamineN-oxide

(73)

C15H2?N05

Trachelanthine aichodesmine C18HZ7N06

Turneforcine

[TrachelanthamineN-oxide (56a) ] (73)

Crotalaria juncea L. (103, 142) Tournejmtia sibiricu L. (143)

C18H21N03

Usaramoensine

a

C18HI,5N05

Viridi0orine C15H27N04 C5He”O C&H13N0

CBH15N02 C12H17(

qN04

Cl2Hl8N2O2 C13H21N03 C18H27N05 C18H27N05 18

27

No 6

(73) (73) (73)

Heliotropium europaeum L. (91) Crotalariu damarenais (145) (73) (73) (73) (73)

Cl,%NO,

Senecio tomentosus (140)

C20H17(1B)No6

(73)

158-159 (dec.)

222 169 175-176 237 (dec.)

-62.4’

46

NELSON J. LEONARD

in accompaniment with the corresponding alkaloids: europine, heleurine, heliotrine, lasiocarpine, platyphylline, retrorsine, rosmarinine, sarracine, seneciphylline, and supinine (Table 1). A study of the major alkaloids of Senecio paucicalyculatus Platt by Pretorius ( 106) indicated that the content of retrorsine increases, whereas that of retrorsine N-oxide decreases, with the age of the plant. A detailed investigation by Areshkina (147) into the relative amounts of seneciphylline and platyphylline and their respective N-oxides present in Senecio platyphyllus D.C. a t various stages of growth has established that the N-oxides greatly predominate during the vegetative period, reach a maximum just before flowering, and are substantially minor to the corresponding amine in the resting state (116). It is felt that the amine oxides, forming a convenient oxidation-reduction system, very likely play a significant role in the plant metabolism (146). Associated with this idea is the observation that the Senecio platyphyllus N-oxides are reduced by ascorbic acid, although fructose, glucose, and glycine are without effect (148, 149). Another novel structural feature has been discovered in a particular Senecio alkaloid: j aconine, from Senecio jacobaea, has been shown to contain chlorine (99, 100, 102), and the revised molecular formula is C,,H,,ClNO,.

II. Extractive and Degradative Procedure (1 16-1 18) With the recognition of the extensive occurrence of amine oxides as alkaloids in the plant there have been developed differential isolation procedures, to separate these from the amines, and reduction procedures, applied to crude extracts, to convert all the amine oxides to amines. For qualitative detection of amine oxides, the red or reddish brown coloration that these compounds give with acetic anhydride serves as a useful test (150). The problem of the separation of the naturally occurring amines from the amine oxides has been attacked in different ways. I n the first instance of isolation (56-56c), it was found that both trachelanthamine and its N-oxide could be extracted from an aqueous solution by dichloroethane. Sequences of organic extractants such as ether followed by chloroform (116) and chloroform followed by butanol (91) take advantage of the lower solubility of the N-oxide in the first solvent. Extraction at increasing pH levels has also been employed (91). If the isolation of the N-oxides is to be circumvented, the original aqueous solution of the combined alkaloids can be treated with zinc dust and acid, followed by alkalization of the solution and purification in the usual manner (113). This operation may lead to greatly enhanced yields of the known alkaloids (115, 117, 126). As an extreme illustration,

47

SENECIO ALKALOIDS

consider Senecio coronatus, which previously yielded only traces of alkaloid soluble in chloroform. The method of reduction prior to isolation gave increased yields of alkaloid commensurate with the toxic nature of the plant (115). Methods of chromatography have served admirably in the separation of both alkaloidal amines and amine oxides. Fractionation on alumina columns has been used extensively (84, 117, 120, 121), and Culvenor andothers ( 8 0 , 9 0 , 9 1 , 1 0 0 , 117, 118) have shown the efficacy ofpartition chromatography on buffered kieselguhr and on ground Pyrex glass (the latter for separation of senecionine and seneciphylline). The large number of artifacts previously reported which have now been shown to be mixtures of alkaloids (Table 1) testifies to the advances made in the separation of the pure compounds, mainly by chromatographic techniques. Countercurrent distribution using saturated aqueous sodium bicarbonate as the stationary phase and mixtures of chloroform and carbon tetrachloride as the mobile phase has also been employed by Culvenor (91). Paper chromatography has proved most useful for rapid determination of the alkaloidal components of a mixture and of the purity of each alkaloid at hand. When standardized conditions are used, values can be obtained which are highly reproducible and important properties for the alkaloids of this series, wherein the melting points and specific rotations are notoriously unselective. Recorded in Table la are the R, values obtained in the laboratories of Adams and of Culvenor with butanol-acetic acid (both descending (at 24" f 1") and ascending (at 17" lo)techniques) and butanol-ammonia (ascending, 17" lo)as the chromatographing solvents. Where Rf values for butanol-acetic acid are available by both techniques, the figures obtained using descending flow are consistently a little higher (average 0.06). By the use of ascending flow and comparison of the values obtained with the two solvent systems, it has been observed (90) that the Rf values of the N-oxides are altered only very slightly, if at all, when butanol-ammonia is substituted for butanol-acetic acid, whereas the tertiary amine alkaloids have much higher Rf values in the basic solvent. As employed by Culvenor et al. (go), comparison of Rf values using the two solvents provides a simple distinguishing test for the amine oxides. In further development, Bradbury and Mosbauer (101), employing a 5 x 100 cm. column packed tightly with about 1 kg. of powdered cellulose, have found that 10-15 g. of crude alkaloid from Senecio jacobaea L. can be separated cleanly into its five components using about 4 1. of solvent, butanol-acetic acid-water. Moreover, the same column can be used repeatedly without refilling.

*

*

48

NELSON J. LEONARD TABLE

af VALUES

Alkaloid

Echimidine Echiumine Europine Europine N-oxide Grantianine Heleurine Heliotrine Heliotrine N-oxide Integerrimine Jacobine Jacoline

FOR T H E

Senecw ALKALOIDS

Descending Butanol-5yo acetic acid (24') R, Reference

0.45

0.61 0.44

la

Ascending Butanol-5yo acetic acid (17') Rf Reference

Ascending Butmolammonia (17') R, Reference

0.59 0.67 0.28 0.37

0.78 0.33

0.48 0.42 0.52

0.90 0.85 0.52

(134)

(80) (80)

Jaconine Jacozine Junceine Lasiocarpine Lasiocarpine N-oxide Monocrotaline Retrorsine Riddelliine Senecionine

0.38

0.40 0.44 0.40 0.62

(134) (83, 104) (103, 104) (80, 104)

Seneciphylline

0.58

(80, 104)

Supinine Tomentosine Trichodesmine Usaramoensine

0.40 0.54 0.61

(140) (103, 104) (80)

0.39 0.26 0.27 0.43 0.32 0.34

(103, 104) 0.59 0.69

0.90 0.70

0.38 0.56 0.59 0.52 0.50 0.37

0.86

Spectral analysis serves as a useful adjunct to paper and column chromatography in the fast determination of the composition of alkaloidal mixtures. A comparative study of the IR-spectra of many pyrrolizidine alkaloids, all very similar to each other, has permitted the designation of a few bands of good intensity in the low-frequency region which are characteristic of certain of the alkaloids and therefore permit the detection of small amounts of impurities in a given sample (83, 84, 120). Thus, seneciphylline has a distinctive band at 902 cm.-l (9) and another at 992 cm.-l (m); senecionine (and its stereoisomers),a band at 757 cm.-l (m);riddelliine, 1120 cm.-1 (m);retrorsine, 1055 crn.-l (m).

49

SENECIO ALKALOIDS

The degradation of the Senecio alkaloids continues to be effected by saponification or hydrogenolysis. The use of alkali in the hydrolysis does not alter the necine moiety but it may cause a change in the geometrical configuration about an a,@-carbon-carbondouble bond in the necic acid. Hydrogenolysis provides important information as to the location of the esterified hydroxyl on the necine, and subsequent conversions permit a decision as to which end of a dicarboxylic necic acid (in the cyclic diesters) is attached to the allylic or primary hydroxyl of the necine.

III. Structure of the Necines (118-138) 1. C,H,,NO NECINES* a. Trachelanthumidine (135-136). Obtained by alkaline hydrolysis of the Senecio alkaloids, the necines of known structure are all hydroxysubstituted pyrrolizidines. Moreover, all the necines of presently known structure have a hydroxymethyl group attached at C, of the pyrrolizidine nucleus. It was recognized in the earlier chapter (73) that the simplest alkanolamine portion of a Senecio alkaloid is represented by trachelanthamidine, C,H,,NO, which is one of the four stereoisomers of 1-hydroxymethylpyrrolizidine (CVII) and a diastereoisomer of isoretronecanol (73, p. 131). One of the degradation sequences converted trachelanthamidine through chloropseudoheliotridane to a compound

CVI

CVll

CVlll

which was assumed to be a 1-methylpyrrolizidine (CVI), and since it would then be diastereoisomericwith heliotridane, it was named pseudoheliotridane, [a], -8.25' (homogeneous) (56a). Oxidation of trachelanthamidine with chromic acid in dilute sulfuric acid yielded an amino acid, [a], -43.3" (water), which was shown to be a pyrrolizidinecarboxylic acid and was assumed to have the carboxylic acid grouping at C, (56b). The gross structures of the three compounds were confirmed as correctly represented by CVI, CVII, and CVIII by the unequivocal synthesis of ( f)-pseudoheliotridane by Leonard and Felley (151, 152). The synthesis involved three steps: ( a ) the Michael addition of nitromethane to ethyl crotonate or diethyl ethylidenemalonate (CIX);

* See also Addendum, p. 121. D

50

NELSON J. LEONARD

( b ) the further reaction of the adduct (CX) with ethyllacrylate; and (c) reductive cyclization of the substituted pimelic ester (CXI). This sequence, with modifications, constitutes the most efficient general method for the synthesis of alkyl-substituted pyrrolizidines (151-156).

Applied as shown, it led to both diastereoisomeric racemates of l-methylpyrrolizidine (CVI), and was stereospecific, presumably in step ( b ) , in that the product CVI was 95% ( f)-pseudoheliotridane when the intermediate was (&)-CXa and 87%, from ( &)-CXb. The higher boiling racemate, b.p. 168-170' (748 mm.), was readily identified as ( f)-heliotridane by direct spectral comparison with ( -)-heliotridane, and the lower boiling racemate, b.p. 155-157" (748 mm.) was resolved for satisfactory identification as ( &)-pseudoheliotridane. The base liberated from the salt with (+)-tartaric acid had a specific rotation, [a], t6.94' (homogeneous), comparable in magnitude with that observed by Men'shikov and Eorodina (56a) for ( -)-pseudoheliotridane (mentioned above), and the corresponding derivatives of these enantiomorphs exhibited identical physical properties. The synthesis was extended to the preparation of l-hydroxymethylpyrrolizidine (CVII) (152) by effecting a Michael addition first of nitromethane t o ethyl y-acetoxycrotonate (CXII) and then of the intermediate ethyl P-nitromethyl-y-acetoxybutyrate (CXIII) to ethyl acrylate. Reductive cyclization of diethyl P-acetoxymethyl-y-nitropimelate (CXIV) furnished either 1-methylpyrrolizidine (CVI) or CH -CH,OAC

II

CHCOOC,H,

-

CH,-CH-CH,OAC

I

LO, CH,C00C2Hs

-+I

CH,-CH-CH-CH20AC

I

I

CH,

+ CVll

NO2 CHI

I

I

COOC,Hs COOC,Hs

CXll

CXlll

CXIV

1-hydroxymethylpyrrolizidine(CVII), depending upon the hydrogenation conditions employed. The properties of the synthetic CVII indicated that it was ( 5)-trachelanthamidine. Since ( f )-trachelanthamidine and ( & )-isoretronecanol are related as diastereoisomeric racemates, it followed that one pair of enantiomorphs (CXV and CXVI) must have ~

SENECIO ALKALOIDS

51

the hydrogens at C, and C, cis while the other pair (CXVII and CXVIII) must have these hydrogens in the trans relation. A decision as to the relative configurations of the asymmetric centers at C, and C, was reached on the following basis by Leonard and Felley (152). The structure of platynecine (optically active) was finally

cxv

CXVI

CXVll

CXVlll

determined as CXIX and that of anhydroplatynecine as CXX when the location of the secondary hydroxyl was established by Adams and Leonard (65) as being at the 7-position throughout the series of Senecio alkaloid products. Anhydroplatynecine (CXX) is readily formed from

&+&

cxx

CXIX

platynecine by treatment of CXIX with a variety of reagents (sulfuric acid, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, or phosphorus oxychloride). This ready dehydration with formation of the very stable cyclic ether demands that the hydrogen at C, be cis to the hydrogen at C, in anhydroplatynecine and in platynecine, but it does not necessarily define the relative configuration at C, in the precursor (CXIX) while requiring the hydrogen at C, to be cis to the C, hydrogen in the product (CXXI or its mirror image). Since various interconversions indicate that platynecine, ( -)-isoretronecanol,

CXXI

retronecanol, and ( -)-heliotridane maintain the same steric relation at C, and C,, (-)-isoretronecunol must therefore be either CXV or its mirror image CXVI. It follows that the necine trachelanthamidine,

62

NELSON J. LEONARD

being a diastereoisomer of isoretronecanol, possesses trans hydrogens at C, and C, and is accordingly represented as CXVII or its mirror image CXVIII. In retrospect, the synthesis of 1-methylpyrrolizidine (CIX+ CVI), which leads to a great predominance of ( -+)-pseudoheliotridane (trans-1,%hydrogens) over ( *)-heliotridane (cis-1&hydrogens) in the product, is stereochemically consistent with specificity being asserted in step (b) according to the principles of Curtin (157), Cram (158), and Prelog (159). Of corollary interest was the finding (56a) that the main course of the Hofmann degradation of pseudoheliotridane was different from that of heliotridane (73, p. 124).Thus, pseudoheliotridane (methiodide, m.p.>275') was converted via silver oxide and heat to des-Nmethylpseudoheliotridane, C,H,,N, b.p. 158-160", [a], -64" (homogeneous) (picrate, m.p. 127"), and thence by reduction with hydrogen and platinum in acid solution to a substituted N-methylpyrrolidine, C,HlgN, b.p. 165-167', [u], -1 1' (homogeneous) (picrate, 158-159"). The fact that the latter compound could be dehydrogenated to an optically active pyrrole derivative, CgH,,N, b.p. 189-191', [a], -5" (homogeneous), indicated that C,H,,N was 2-s-butyl-1-methylpyrrolidine (CXXIII) rather than 1,3-dimethyl-2-propylpyrrolidine, which had been obtained from heliotridane (73). The structures of the pyrrole derivative and of des-N-methylpseudoheliotridanewere defined as CXXIV and CXXII, respectively, by this sequence.

b. Laburnine. Surprisingly, the enantiomorph of trachelanthamidine has been found in a lupin alkaloid source (160). Thus, Galinovsky, Goldberger, and Pohm (161) isolated a C,H,,NO alkaloid, laburnine, from the seeds of Cytisus laburnum L. The colorless oil, [a], 15.5', forms a picrate, m.p. 172-173"; picrolonate, m.p. 181-182'; and methiodide, m.p. 307-309". The original report established the presence of a primary hydroxyl group and identified the ring system as pyrrolizidine. It was pointed out that this alkaloid, as a hydroxymethylpyrrolizidine, was probably the optical antipode of trachelanthamidine since their optical rotations are approximately equal and opposite and since the properties of derivatives of the two compounds are similar. Later work by Galinovsky et al. (162) has shown this hypothesis to be correct. The p-toluenesulfonic ester of laburnine was reduced with lithium aluminum

SENECIO ALKALOIDS

53

hydride to laburnane, or (+)-pseudoheliotridane (CVI, trans-l,8hydrogens), [ a ] , 17.1" (ethanol) (picrate, m.p. 234-235" (dec.); picrolonate, m.p. 165" (dec.) ). Direct comparison with derivatives of the synthetic, resolved (+)-pseudoheliotridane (152) established the identity. The same compound'was obtained by a second route from laburnine: conversion to bromolaburnane by treatment with hydrobromic acid in a sealed tube at loo", followed by hydrogenation using platinum oxide in strong ammonium hydroxide solution. Oxidation of laburnine with chromic acid (162) furnished laburninic acid (hydrate) (CVIII, trans-l,8-hydrogens), m.p. 215-216", [a], 44.2" (water, calculated for the water-free acid) (picrate, m.p. 175-176"), corresponding to the enantiomorph of trachelanthamidinic acid (73, p. 136). c. LindeloJdine. The fourth and remaining stereoisomer of l-hydroxymethylpyrrolizidine, C,H,,NO, is lindelofidine, the necine obtained from the alkaline hydrolysis of the alkaloids lindelofamine and lindelofine by Labenskii and Men'shikov (108). The properties of the necine and its derivatives showed that it was the optical antipode of isoretronecanol, that is, (+)-isoretronecanol: m.p. 40-41", [a], 79.1" (ethanol), b.p. 139140" (8mm.) (picrate, m.p. 193-1 94";picrolonate, m.p. 18 1-1 82"; methiodide, m.p. 281-282", [a], 32.5" (ethanol); benzoyllindelofidinehydrochloride, C,,H,,ClNO,, m.p. 180-1 81",[ a ] ,50.7"(ethanol);benzoyllindelofidine picrate, m.p. 130-131"). Replacement of the hydroxyl with chlorine by treatment of lindelofidine with thionyl chloride gave C8H,,C1N, b.p. 94-95", [ulD 123" (homogeneous) (picrate m.p. 185"; picrolonate, m.p. 205").The structural assignment was strikingly proved by the formation of a racemate picrate, m.p. 193-194", from a mixture of equal amounts of ( -)-isoretronecanol picrate and lindelofidine picrate. The base recovered from the picrate, ( &)-isoretronecanol, b.p. 115-1 16" (4 mm.), did not crystallize at -10". A solution (5%) in ethanol had zero rotation in a 1 dm. tube. The racemate picrolonate, made from equal amounts of the separate derivatives, melted at 176-177' alone and at 172-173" on admixture with ( -)-isoretronecanol picrolonate. The stereochemical interrelationships among all four of the 1hydroxymethylpyrrolizidines: isoretronecanol, lindelofidine, trachelanthamidine, and laburnine, have been determined, insofar as the C,, C, relative configurations are concerned, by the chromic acid oxidation studies of Labenskii, Serova, and Men'shikov (163). Repeating the oxidation of isoretronecanol originally reported by Adams and Hamlin (63), they were able to isolate two diastereoisomeric 1-pyrrolizidinecarboxylic acids in approximately equal amounts : the isoretronecanolic acid of Adams and Hamlin, m.p. 228-229" (dec.);[a],-71.4" (ethanol),(picrate, m.p. 219-220" (dec.) ), and trachelanthamidinic acid, m.p. 215-216",

54

NELSON J. LEONARD

-43.4' (water), -32.5' (ethanol) (picrate, m.p. 178-179"), obtained previously as the sole oxidation product of trachelanthamidine. Trachelanthamidine is therefore epimeric with isoretronecanol a t C,. Chromic acid oxidation of lindelofidine ( (+bisoretronecanol) produced two acids in approximately equal amounts: (+)-isoretronecanolic acid, m.p. 228229" (dec.), [u], 71.5" (ethanol) (picrate, m.p. 220-221" (dec.) ), and the optical antipode of trachelanthamidinic acid, or laburninic acid, m.p. 215-216", [u], 43.6" (water), 32.7" (ethanol) (picrate, m.p. 178-179'). Laburnine is therefore epimeric with lindelofidine. Each acid could be reduced to the stereochemically corresponding 1-hydroxymethylpyrrolizidine with lithium aluminum hydride. From these experiments, it is apparent that the more stable isomers of 1-pyrrolizidinecarboxylic acid are the two enantiomorphs having trans- 1,8-hydrogens. From partial formulas representing the folded structure of the bicyclic system possessing two, essentially cis-fused, five-membered rings, and by application of the principles of conformational analysis (164), it may be readily seen that in a l-pyrrolizidinecarboxylic acid possessing cis-1 ,8-hydrogens (CXXV) there will be repulsive interaction between the C,-COOH and the C,-H lying below the fold. Under epimerizing conditions at C,, the equilibrium should be [u],

cxxv

CXXVI

well on the side of the acid having the trans-l,8-hydrogens, since it has only H:H repulsive interaction and is undoubtedly thermodynamically more stable. The method employed for the oxidation of the l-hydroxymethylpyrrolizidines, i.e., heating in aqueous sulfuric acid on the steambath with a slight excess of chromium trioxide added in two portions (163), provides acidic epimerizing conditions (165), so that partial conversion of an acid CXXV, once formed, to CXXVI should be realized. Nearly total conversion (CXXV+CXXVI) might be feasible, given a sufficient period of time to reach equilibrium. These considerations explain the isolation of two 1-pyrrolizidinecarboxylic acids from the 1-hydroxymethylpyrrolizidines possessing cis- 1,8-hydrogens and one acid from the 1-hydroxymethylpyrrolizidines having trans-l,& hydrogens. The remaining stereochemical problem for the 1-hydroxymethylpyrrolizidine group (CXV-CXVIII)was the assignment of the absolute configurations at C, and C8, and this problem has been solved by

55

SENECIO ALKALOIDS

Warren and von Klemperer (166) as this chapter was going to press. The argument rests upon the three-stage Hofmann degradation of (-)heliotridane to (+)-3-methylheptane, of known absolute configuration (CXXVII) (167, 168). Thus, (-)-heliotridane, with cis hydrogens a t C,

CXXVll

and C,, is now fully defined as CXXVIII, lg-methyl-(8a)-pyrrolizidine (using the a$ convention of the steroids) or 1S,8S-l-methylpyrrolizidine (using the Cahn, Ingold and Prelog system) (169). Isoretronecanol therefore becomes 1/3-hydroxymethyl-(8a)-pyrrolizidine (CXV). The author (170), only shortly before, had deduced that t,he enantiomorphic structure (CXVI) was correct for isoretronecanol, on the basis of molecular rotational shifts relating isoretronecanol to one of the lupin alkaloids, ( -)-lupinine. The absolute configurations of the asymmetric

CXXVlll

carbons, with the C,,-H and the C,-CH,OH a, in (-)-lupinine (CXXIX) rest upon the basis indicated by Cooksoii (170) of the degradation of ( -)-lupinine to ( -)-4-methylnonane (170a) of known configuration. The close similarity of compounds in the lupin series, lupinine (CXXIX) and its epimer a t C,, with the corresponding stereoisomers of the ring-homologous 1-hydroxymethylpyrrolizidines, CXVI and CXV, encouraged a comparison of the rotational shifts (171) brought about by similar changes in substituents on both ring systems (169). The conformity in the molecular rotation shifts, as the grouping attached a t C, was changed from CH,OH to CH,, CH,OCOC,H, and CH,OH

CXXIX

CH,

cxxx

CH,Cl, suggested that the C,-C, stereochemistry in isoretronecanol was identical with the C,-C,, stereochemistry in the structure assigned to (-)-lupinine (CXXIX). Since the work of Warren and von Klemperer

56

NELSON J. LEONARD

(166) establishes isoretronecanol as CXV, with opposite stereochemistry, the basis for the consistent molecular rotation shifts (for the sodium D line in ethanol solution) for (-)-isoretronecanol ws. ( -)-lupinine is now unclear. The Warren assignment of the absolute configurations in isoretronecanol furnishes the key to the complete configurational assignments of all its stereoisomers. Thus, lindelofidine is CXVI; trachelanthamidine, the C, epimer of isoretronecanol, is CXVII; laburnine, the C, epimer of lindelofidine, is CXVIII. Chemical names which indicate the absolute configurational assignments can be given to the compounds described (using the steroid conventions ( 178) ) as follows : Isoretronecanol =lg-hydroxymethyl-(8a)-pyrrolizidine (CXV) Lindelofidine =1a-hydroxymethyl-(8/3)-pyrrolizidine(CXVI) Trachelanthamidinez 1a-hydroxymethyl-(8a)-pyrrolizidine(CXVII) Laburnine =lg-hydroxymethyl-( SP)-pyrrolizidine (CXVIII) This nomenclature system, with ( 8 g ) and ( 8 a )referring to the orientation of hydrogen on C,, and the absolute stereochemical structural assignments will be used in future discussion and depiction of the necines and their chemical relatives wherever possible. Stereochemical formulations which have been used prior to this time (74-76, 98, 152) for all the pyrrolizidine alkaloid products have been necessarily arbitrary. It is now possible to employ the complete stereochemical definitions of the pyrrolizidine products ( 166).

2. C,H,,NO NECINE

a. Supinidine. Thus far only one necine of molecular formula C,H,,NO, corresponding to the first group, C,HISNO, but containing a double bond, has been found. Men'shikov and Gurevich (138) isolated supinidine (Table 2) as a result of the alkaline hydrolysis of the alkaloid supinine, and Culvenor (91) later obtained the same necine from heleurine. Catalytic reduction of supinine with Raney nickel led to the absorption of 1 mole of hydrogen (double bond hydrogenation, but no hydrogenolysis (58) ), and alkaline hydrolysis of the intermediate ester led to ( -)-isoretronecanol (CXV),identified by direct comparison (138). The same product was obtained by the hydrogenation of supinidine with Raney nickel (91). The corroborative hydrogenations indicated that supinidine possessed a 1-hydroxymethyl group on a desaturated pyrrolizidine nucleus. When supinine was subjected to catalytic reduction using platinum in acid solution, 2 moles of hydrogen (double bond hydrogenation+ hydrogenolysis) were absorbed, and ( -)-heliotridane was the product. The attendant hydrogenolysis indicated that the double bond in supinidine originated at C,, and the fact that the necine was

2

TABLE

NECINES*

Necine CnHisNO Lindelofidine Trachelanthamidine

Chemical (and stereochemical) name

1a-Hydroxymethyl-(8g)-pyrrolizidine

1a-Hydroxymethyl-(8a)-pyrrolizidine

Parent alkaloid

[alu

M.p. ("C.)

Lindelofamine Lindelohe Macrotomine Trachelanthamine Viridaorine

40-41

Heleurine Supinine

b.p. 158-159 (10 mm.)

-10.3'

Hastacine Macrophylline Mikanoidine Platyphylline Sarracine Turneforcine

113-114 126-128 151-152

-

118.6-120

-10.5'

Echinatine Europine Heliosupine Heliotrine Lasiocarpine

117-1 18

31'

b.p. 139-140 (15 mm.)

79.1' -114.9'

C8H13N0

Supinidine

l-Hydroxymethyl-A1-dehydro-(8a). p yrrolizidine

CnHisNO, Hastanecine Macronecine Platynecine

Turneforcidine CnHiaNOz Heliotridine

(Structure not established) (Structure not established) 7P-Hydroxy-lg-hydroxymethyl(8a)-pyrrolizidine (Structure not established) 7 a-Hydroxy-1-hydroxymethyl- A* dehydro-(8a)-pyrrolizidine

Arranged in order of increasing unsaturation, oxygenation. Here", b , c, and refer to the 8ame solvents as listed in Table 1.

~

9.1' b 49.3O d -57.0' a

TABLE

Necine Retronecine

C,H,,NO3 Rosmarinecine C9H16N03 Otonecine

cn 00

2-(CO'dnued)

Chemical (and stereochemical) name 7p-Hydroxy- 1-hydroxymethyl-hldehydro-(8a)-pyrrolizidine

Parent alkaloid Dicrotaliiie Echiinidine Echiumine Grantianine Integerriniine Jacobine Jacoline Jaconine Junceine Monocrotaline Retrorsine Riddelliine , Sceleratine Senecifoline Senecionine Seneciphylline Spartioidine Squalidine Trichodesmine Usaramoensine

M.p. ('C.) 121-122

2a,7p-dihydroxy- 1/3-hydroxymethyl(8p)-pyrrolizidine

Rosmarinine

171-172

(Structure not established)

Otosenine

146-148 (HC1salt)

"ID

50.2'

-118.5'

TABLE

2-SUPPLEMENT

NECINE

N-Oxides as necines C8Hl6NO2 Trachelanthamidine N-oxide (Trachelanthidine)

Parent alkaloid

N-OXIDES M.p.

(OC.)

Derivatives

Lu1D

Hydrochloride, m.p. 107108', [aID - 19.9'

Trachelanthamine N-oxide (Trschelanthine)

C8H13N02

Supinidine N-oxide CaHiPO 3 Platynecine N-oxide

Heleurine N-oxide Supinine N-oxide Platyphylline N-oxide Sarracine N-oxide

21 7-2 18

Europine N-oxide Heliotrine N-oxide Lasiocarpine N-oxide Retrorsine N-oxide Seneciphylline N-oxide Senkirkine

201 (dec.)

Hydrochloride, m.p. 152-1 53' Picrate, m.p. 160-162' Anhydroplatynecine N+O, m.p. 101-102'; picrate, m.p. 190' (dec.)

C8H13N03

Heliotridine N-oxide

Retronecine N-oxide (Isatinecine) Unidentified necine or necine N-oxide

C,Hl,NO, Rosmarinecine N-oxide

Rosmarinine N-oxide

214-215

22.4'

C

Picrate, m.p. 147' Picrate, amorph., m.p. 175180' (dec.) Aurichloride, m.p. 165166' (dec.)

60

NELSON J. LEONARD

optically active fixed the double bond at the 1,2-position (138). Moreover, supinidine was thereby shown to be in the same stereochemical series as isoretronecanol (CXV) and ( -)-heliotridane (CXXVIII)with the absolute configuration at C, in isoretronecanol fixed as a (166), the complete representation of supinidine becomes CXXXI, l-hydroxymethyl-A1-dehydro-(8a)-pyrrolizidine. The hydrogenations of supinine

CXXXI

and supinidine are stereospecific, the hydrogen entering the molecules on top of the fold, which is the face offering less hindrance to approach of hydrogen on catalyst surface. Supinidine was also obtained indirectly by Men'shikov and Kuzovkov (172) from the alkaloid heliotrine (see later). With this alkaloid as a precursor, the secondary hydroxyl on the necine portion, heliotridine, was replaced by chlorine, the chlorine was stripped from the molecule using chromous chloride (64) and zinc, and the resulting intermediate was saponified to yield supinidine (picrate, m.p. 142-143"; methiodide, m.p. 112-113", [a], -10.1' (methanol) ). 3. C,H,,NO, NECINES a. Platynecine (118-135). For a discussion of the chemical conversions leading to the establishment of the gross structure of platynecine as one of the eight stereoisomers represented by 7-hydroxy-1-hydroxymethylpyrrolizidine (CXIX), one of the earlier reviews (73, 75, 76) will serve. The relative configurations of the C, and C, hydrogens in platynecine were shown to be cis (152), as described in Section 1, and that of the C, hydrogen in anhydroplatynecine was additionally defined as cis. In order to simplify discussion and to describe the absolute configurations in each molecule rather than to leave open the decision as to which enantiomorph of identical relative configurations is being considered, the recent absolute configurational assignments (166)will be transposed historically. Thus, being related stereochemicallyto ( -)-isoretronecanol a t C, and Cg, anhydroplatynecine is completely defined by the mirror image of CXXI (see ref. 152, formula XI11 therein). And now, in proper historical sequence, we may consider how the relative stereochemistry at the C, position in platynecine was decided, that is, whether the structure is CXXXII or the diastereoisomeric (epimeric) CXXXIII. One of these formulas corresponds to platynecine, the other to dihydroxyheliotridane (172) (see Section 4). The selective structural

SENECIO ALKALOIDS

CXXXll

61

CXXXlll

assignments have been corroborated in several laboratories. Adams and Van Duuren (76, 173, 174) operated on the assumption that platynecine possesses cis, cis-l,8,7-hydrogens not only because of the ease with which it forms anhydroplatynecine, but also because of the fact that many alkaloids of platynecine and retronecine ( “A1.2-dehydroplatynecine”) are found to be cyclic &esters, for which cis-7,s-hydrogens would dispose the two hydroxyls favorably for the formation of the eleven- and twelve-membered rings, whereas cyclic diester alkaloids of heliotridine (“A1.2-dehydrodihydroxyheliotridane”) are unknown. They found that heating platynecine with phosphorus oxychloride in benzene under reflux for 2 hours produced anhydroplatynecine, whereas dihydroxyheliotridane, treated with phosphorus oxychloride under identical conditions, did not yield any anhydroplatynecine. On the basis of the formation of cyclic sulfite esters from 1,2-diols (175, 176) and 1,3-diols (177), treatment of platynecine with thionyl chloride at 0” for 30 minutes gave platynecine sulfite hydrochloride, C,H,,NO,S.HCl, m.p. 197” (dec.), [u], -90” (ethanol) (platynecine sulfite picrate, m.p. 249” (dec.) ), in 99% yield, identified as a cyclic sulfite ester by analysis and characteristic IR-absorption. Hydrolysis of the cyclic sulfite with aqueous sodium hydroxide led to the recovery of platynecine. Scale molecular models indicate that a cyclic sulfite formed from CXXXII would be relatively strain-free; this is not the case from CXXIII. Moreover, the alkaline hydrolysis of the sulfite ester to the original platynecine indicates that the configuration at C, is unaltered in these processes or that there are two inversions. The latter possibility is unlikely. Therefore, formulation of platynecine sulfite as CXXXIV requires platynecine to be CXXXII-7p-hydroxy-l~-hydroxymethyl(8a)-pyrrolizidine. Treatment of dihydroxyheliotridane with thionyl chloride at 0” gave no cyclic sulfite ester but rather chlorohydroxyheliotridane hydrochloride, C,H,,ClNO-HCl, m.p. 158O, [a], - 5” 0

CXXXIV

cxxxv

62

NELSON J. LEONARD

(ethanol), as a result of the difference in stereochemistry. The corresponding base is probably CXXXV-l/3-chloromethyl-7a-hydroxy(8a)-pyrrolizidine. Platynecine and dihydroxyheliotridane may be acetylated readily by boiling with acetic anhydride for 30 minutes. The corresponding diacetates (picrate melting points 81" and 133-134", respectively) yielded the original bases quantitatively on alkaline hydrolysis. Warren and his co-workers (75, 178)rested their argument for the cis, cis-1,8,7-hydrogensin platynecine on the finding (experimental details were not offered, and apparently dihydroxyheliotridane was not compared) that p-toluenesulfonyl chloride and platynecine reacted to give anhydroplatynecine. If tosylation takes place preferentially at the primary hydroxyl, a 7~-hydroxyl(but not a 7a-hydroxyl) is favorably situated for an internal nucleophilic displacement at the primary carbon. Fodor (179)came to the same stereochemical conclusion, reasoning that thionyl chloride (at the boiling point) (39) would be expected to react first at the primary hydroxyl of platynecine, with the secondary hydroxyl then participating in nucleophilic displacement to effect closure of the tetrahydrofuran ring in anhydroplatynecine. The preservation of configuration at C, in the conversion finds analogy in a similar steric situation in the tropane series (180, 181). When acetylretronecanol, which is in the same relative and absolute configurational series with platynecine (152, 174) and may now be designated (166) as CXXXVI, 'was treated with ethyl iodoacetate, the quaternary salt (CXXXVIIa), m.p. 196O, was formed (98). Moist silver oxide converted CXXXVIIa to the corresponding betaine (CXXXVIIb), and hydrogen iodide converted this to the carboxymethyl quaternary salt 'H3C&

-

'& Grc>

CH COO

N

y+

p

CXXXVll

I-

04c-

CH2Y

CXXXVI

+

: ..CH:

-

CXXXVlll

a . Y-COOEt. I b. V-COOC.Y.COOH. I -

(CXXXVIIc), m.p. 203-204". Fodor and co-workers (98) consider, on the basis of earlier experience, that if the 7-acetoxyl group had been a, a six-membered lactone ring (CXXXVIII) would have been formed in this reaction sequence. Additional evidence is thus supplied for the correctness of the assignment of the 7fi-configuration of the hydroxyl in retronecanol, platynecine, retronecine, and related compounds.

SENECIO ALKALOIDS

63

Three other necines (Table 2) are isomeric, C8H15N02,with platynecine (m.p. 151-152", [a], -57" (chloroform); picrate, m.p. 184-185O (126) ): hastanecine, macronecine, and turneforcidine (111),all reported to be different (109, 143). None of these is enantiomorphic, on the basis of reported physical properties, with platynecine. Moreover, none is enantiomorphic or identical with dihydroxyheliotridane (CXXXIII) (m.p. 76-77", [a], -34" (ethanol); picrate, m.p. 157-158" (172) ). The remaining possible stereoisomers of 7-hydroxy-1-hydroxymethylpyrrolizidine are represented by CXXXIX and its mirror image (CXL), CXLI and its mirror image (CXLII). If indeed hastanecine and

CXXXIX

CXLI

CXL

CXLll

turneforcidine are nonidentical (75,143),it is impossible to accommodate all three necines, owing to their properties, as 7-hydroxy-1-hydroxymethylpyrrolizidines. Only two of the necines thus constituted could then be represented by two of the four stereoisomers CXXXIXCXLII. On the basis of the structure determined for rosmarinecine (see below) it is possible that one or more of the necines mentioned above could be a 2-hydroxy-1-hydroxymethylpyrrolizidine. Additional derivatives have been reported as follows: macronecine hydrochloride, m.p. 152-153", [a], 49.4" (ethanol) (109); turneforcine hydrochloride, m.p. 116" (143).

C8Hl,N0, NECINES a. Heliotridine and Retronecine (118-135). The complete structures, 4.

including absolute configurations at the asymmetric carbons, of the two necines in this group can now be provided: heliotridine, CXLIII, and retronecine, CXLIV (Table 2). First, the positions of the hydroxyls

CXLlll

CXLIV

64

NELSON J. LEONARD

and double bond in heliotridine were established by methods parallel to those used in the case of retronecine (73).Men'shikov and Kuzovkov in 1949 (172)found that the oxidation of hydroxyheliotridane (oxyheliotridane), the amine hydrogenolysis product of heliotrine, with chromic acid in acetic acid yielded an aminoketone, C,H,,NO (semicarbazone, m.p. 209", [a], -89.1" (ethanol); oxime, m.p. 165-167", [u], -76.8" (ethanol); picrate, m.p. 195" (dec.), identical with ( -)-retronecanone, obtained by Adams and Hamlin (63)from retronecanol and synthesized by Adams and Leonard (65)in an unequivocal manner. Retronecanol (CXLVI) and hydroxyheliotridane (CXLV) were thus confirmed as epimeric at C,. The question of the stereochemistry of retronecanone,

&(ycr3

-

N

CXLV 7a-hydroxy-ljJ rnethyl-@a)pyrrolizidine

-

tN

CXLVll

CXLVI

(a, 8 a - H . b . 8 / 3 - H )

7jJ-hydroxy-lpmethyl- ( E d pyrrolizidine

the ketone product produced by oxidation of the two secondary alcohols, was left open (CXLVII) by Adams and Leonard (65), since it was recognized that equilibration could easily occur at C, both in the degradative approach (63)to the compound, where aluminum t-butoxide, cyclohexanone, and toluene were employed at the reflux temperature, and in the synthetic approach (65), which utilized potassium in refluxing benzine for the Dieckmann cyclization and refluxing concentrated hydrochloric acid for the hydrolysis and decarboxylation. Equilibration could also have occurred in the chromic acidacetic acid method utilized by Men'shikov and Kuzovkov (172)for the oxidation of both hydroxyheliotridane and retronecanol. Although the aminoketone products may have been mixtures of CXLVIIa and CXLVIIb, the oximes and semicarbazone derivatives which were used for characterization in all cases probably represent pure stereochemical individuals. Epimerization of 1/3- methyl - 7- keto - (8a)- pyrrolizidine (CXLVIIa) to 1/3-rnethyl-7-keto-(8/3)-pyrrolizidine (CXLVIIb) is to be expected in the light of the epimerization (at C,) of isoretronecanolic

CXLVIIa'

CXLVIIV

65

SENECIO ALKALOIDS

acid to trachelanthamidinic acid (163). Formulas CXLVIIa' and CXLVIIb' serve to illustrate the conformational point. Moreover, if retronecanone were correctly represented by CXLVIIa, catalytic hydrogenation would have been expected to proceed stereospecifically (as with retronecine and esters of retronecine) to give retronecanol (hydrogen becoming attached to C, on top of the folded molecule). No retronecanol was produced either in neutral or acidic media using hydrogen and platinum, but rather product(s) more likely represented primarily by CXLVIII or secondarily by CXLIX (65).

CXLV 111

CXLIX

Be this as it may, the problem of the position of the secondary hydroxyl in heliotridine was solved. Turning to further characterization of structure CXLIII for heliotridine, the necine was reduced with hydrogen and nickel to dihydroxyheliotridane (CXXXIII), mentioned in Section 3. Treatment of this compound with benzoyl chloride furnished monobenzoyldihydroxyheliotridane, Cl5HlSNO3,m.p. 133-134', [a], -5.1' (chloroform) (picrate, m.p. 134-135"), which was converted without change in configurations a t C, and C, to benzoylisoretronecanol, Cl5HlSNO,(CLII) (hydrochloride, m.p. 180-181', [u], -49.6" (ethanol) ), of known structure (73), relative configuration (152), and now (166) absolute configuration. The structure of monobenzoyldihydroxyheliotridine is completely defined, then, by CL. The intermediate in this CH,OOCC,H,

CH,OOCC,H,

CH,OOCC,H,

pi' CL

CLI

CLll

sequence, obtained by treatment of monobenzoyldihydroxyheliotridane with thionyl chloride, C,,H,,NO, (hydrochloride, m.p. 147-148', [u], -91.7' (ethanol); picrate, m.p. 146-147'), is CLI. The final assignment of the C, hydroxyl as a in heliotridine and in retronecine is derivative of the ,%assignment in platynecine (CXXXII) (Section 3). It is interesting that, unlike platynecine, retronecine does not form a cyclic sulfite on treatment with thionyl chloride a t O', since the two hydroxyl groups are held away from each other. The preferred structure E

66

NELSON J. LEONARD

CLlll

of the product formed is that of 1-chloromethyl-7-hydoxy-A1-dehydropyrrolizidine, m.p. 152-153", [a], -65' (ethanol) (74, 174), which may now be represented configurationally as well: l-chloromethyl-7,3hydroxy- Al-dehydro-(8u)-pyrrolizidine (CLIII). 5. C,H,,NO,

NECINE

a. Rosmarinecine (137-138).The basic structure proposed by Richardson and Warren (73, see reference 43a) for rosmarinecine (CLIV) has been confirmed by degradation and partial synthesis by Dry et al. (178). Moreover, these workers were able to establish the relative configurations a t the four asymmetric centers in the necine. Absolute configurations may now be assigned (166), so that rosmarinecine is fully described as 2a,7,3-dihydroxy-l,3-hydroxymethyl-( Su)-pyrrolizidine

(CLV).

&OH CLIV -cLv-

The existence of three hydroxyl groups was established by the acetylation of rosmarinecine to give a tri-0-acetylrosmarinecine (picrate, m.p. 138-139"), and heating with thionyl chloride to give a trichloro compound (picrate, m.p. 194-196"). Benzoylation gave a dibenzoate, m.p. 179-180", formulated as resulting from esterification of the Cl-CH,OH and the C,-OH, by comparison of the structure postulated for rosmarinecine with that of platynecine. Further analogy was recognized in the conversion of rosmarinecine to anhydrorosmarinecine, C,H,,NO,, m.p. 63-66" (picrate, m.p. 183-185'; picrolonate, m.p. 232-234' ; dichloromethochloride (quaternary salt with chloroform), m.p. 198-200" (dec.); hydrochloride, m.p. 173-176"), by treatment with sulfuric acid. The anhydrorosmarinecine yielded a monoacetyl derivative (picrate, m.p. 190-192"), and produced chloroanhydroplatynecine with thionyl chloride (picrate, m.p. 265-268"). The last compound was named in this manner because it was reducible with hydrogen and Raney nickel to anhydroplatynecine (picrate, m.p. 264268"). These experiments established all but one of the structural

67

SENECIO ALKALOIDS

features in CLIV; moreover, they showed the relative configurations a t three of the asymmetric carbons, 1,8, and 7. The problem of the position and orientation of the remaining hydroxyl group was solved impressively by partial synthesis in the South African laboratory of Warren (178). The synthesis of rosmarinecine rested on the studied assumptions that the other secondary hydroxyl was 2a, that epoxyretronecine would have the 1,2-a-configuration (similar to the stereospecific catalytic hydrogenation of retronecine, which adds a la-hydrogen), and that one of the two possible products of catalytic reduction of the epoxide would be rosmarinecine. Retronecine CXLIV reacted readily with perbenzoic acid to give retronecine N-oxide (isatinecine)(CLVI),which then slowly took up another atom of oxygen to give epoxyretronecine-N-oxide (CLVII), C,H,,NO,, decomp. 200’, CH OH

’

c LVI

CLVll

+

J

cLv

CLVlll

-40.5’ (water). The epoxide-N-oxide CLVII was reduced readily with zinc dust or catalytically with platinum, to give epoxyretronecine (CLVIII), C,H,,NO,, m.p. 172-173’, [ a ] , -40.9’ (water) (di-0-acetyl derivative, picrate, m.p. 151-152’). Reduction of either CLVII or CLVIII with hydrogen and Raney nickel gave a semisolid gum. The bulk of the product, which contained no 1,2-glycol grouping, was rosmarinecine, since it readily gave derivatives (four) identical with those of the necine. 6. OTHERNECINES AND NECINEN-OXIDES No further information on the structure of otonecine, C,H,,NO,, is available since the previous review in these volumes (73), although the presence of the N-methyl group in this unusual necine has been confirmed by the report of an N-methyl in the parent alkaloid, otosenine (81). Another necine, “renarcine,” is of unknown structure and has had insufficient characterization. It is the alkaline hydrolysis product of the alkaloid renardine (81). “Mikanecine” has been shown to be identical with platynecine (73, 11l),and the name can be dropped. “Isatinecine” has been shown to be retronecine-N-oxide (94), and the latter name more clearly describes the compound. With the isolation of numerous alkaloids as N-oxides in this series, the necine N-oxides become important, since they are the hydrolysis products of the parents. Listed in the supplement to Table 2 are the necine N-oxides which have

[a],

68

NELSON J. LEONARD

been isolated thus far as hydrolysis products or as partial synthesis products from the related necines. The general configuration of the necine N-oxides is such that the oxygen will be cis to the C, hydrogen.

IV. Structure of the Necic Acids The necic acids are those acids which are bound in ester combination with the hydroxyl group or groups of the necines. Since the degradation of the alkaloids may lead to the isomerization or lactonization or partial cleavage of the original necic acids in ester form, the acid isolated may not always delineate the original, and some deduction as to the structure of the necic acid may be necessary. In Table 3 are assembled the necic acids with their chemical names, wherever structures have been established unequivocally, sources, and physical properties. Alkaloid N-oxides have been deliberately omitted as sources, since it will be recognized that the amine alkaloids and the corresponding amine oxide alkaloids contain the same acid moiety. 1. C-5 ACIDS

a. Angelic Acid. This acid, C5H,02, m.p. 45-46', is a necic acid found in at least eight Senecio alkaloids, bound in ester form. Since angelic acid (a-methyl-cis-crotonic acid or trans-a$-dimethylacrylic acid) (CLIX) isomerizes to tiglic acid (a-methyl-trans-crotonic acid or cisa,/3-dimethylacrylicacid) (CLX), m.p. 64', on boiling, or with concentrated sulfuric acid, or on boiling with dilute aqueous sodium hydroxide, it is necessary to select the alkaloid degradation conditions so that

isomerization is avoided and the original geometry of this C,H,O, acid is recognized. Angelic acid has an R, value of 0.29 using ascending butanol-ammonia (88) as the chromatographing solvent on paper; this value may be used to identify the acid. b. Sarracinic Acid was isolated along with angelic acid from the acid hydrolysis of sarracine (127). The molecular formula was shown by analysis of the silver salt and by difference between C,,H2,N0,+2H,0 and C,H,,NO, (platynecine)+C5H,0, (angelic acid) to be C,H,O,. Unsaturation was indicated by the analysis and by a positive Baeyer test, and the presence of one alcoholic hydroxyl group was also established. The hydroxyl was deduced to be in the a- or /3-position tQthe carboxyl since no lactone was formed on heating with 10% sulfuric acid.

SENECIO ALKALOIDS

69

Oxidation with lead dioxide in 5% phosphoric acid yielded acetaldehyde and formaldehyde. Catalytic reduction in the presence of platinum resulted in the absorption of 1.5 mole equivalents of hydrogen and the isolation, by its steam volatility, of nearly 0.6 mole of a-methylbutyric acid. The carbon skeleton of sarracinic acid was thus determined, and the accompanying hydrogenolysis (some nonvolatile acid was also obtained) established that the double bond and hydroxyl constituted an allylic alcohol moiety. Since further data (spectroscopic data would be especially valuable) were not available, Danilova and Kuzovkov (127) were limited to the conclusion that sarracinic acid could be represented by one of three possible structures (CLXIa-c):

The writer prefers structure CLXIc for this necic acid by analogy with other acids derived from alkaloids of Xenecio species, on the usual requirement of an a-hydroxyl for lead dioxide oxidation, and on the basis of possible biosynthesis (74). 2. G-6

ACIDS

u. Dicrotulic Acid (138).This acid, C,H,,O,, m.p. log', is optically inactive (monostrychnine salt, m.p. 162-164", [a],, -12.7' (chloroform); monobrucine salt, m.p. 198' (dec.), [a], -11.8 (chloroform)), has been shown by Adams and Van Duuren (86) to be /3-hydroxy-fl-methylglutaric acid (CLXII). One perceives immediately the close relation of

this acid to "mevalonic acid,'' DL-/3,8-dihydroxy-/3-methyl-Zi-valeric acid (182, 183). The IR-spectrum indicated hydroxyl and carboxylic acid; titration had previously shown that dicrotalic acid was dicarboxylic (73). Negative indication of a- and y-hydroxyls suggested that the hydroxyl was fl to the carboxyls. Acetic anhydride, with added acetyl chloride, in refluxing benzene produced acetyldicrotalic anhydride, m.p. 85", characterized by analysis, C,H,,O,, and IR-maxima at 1725, 1750, and 1800 cm.-l. This substance readily lost a molecule of acetic acid on heating at 100" for 12 hours, and the product, anhydrodicrotalic anhydride,

TABLE

4

3

0

NECIC ACIDS

Necic acid

Chemical name

Parent alkaloid

M.p. ("C.)

[UID

C-5 Acids

C5H802 Senecioic Angelic

C,H803 Sarracinic C-6 AG& C6HlOO5 Dicrotalic C-7 Acids

3-Methyl-2-butenoic acid a-Methyl-cis-crotonic acid or truns-a,B-dimethylacrylicacid

* Echimidine Echiumine Heliosupine Lasiocarpine Lindelofamine Macrophylline Sarracine Turneforcine

(Structure not established)

Sarracine

/3-Hydroxy-B-methylglutaric acid

Dicrotaline

C7H120S

(Partial necic acid)

Trichodesmine

C7H1404 Trachelanthic

(

+ )- Threo-3,4-dihydroxy-2methyl-3-pentanecarboxylicacid

~~~

Here b* c and d refer to the same solvents as listed in Table 1; f ethyl acetate. *Appears not to be in ester combination with a necine (73). t Lactone acid. tt Dilactone.

Echiumine Lindelofamine Lindelofine Supinine Trachelanthamine

45-46

109

93-94

0'

2.4'

3.7' d

TABLE

Necic acid Viridifloric

3-(Continued)

Chemical name ( + ) - or (-)-&ythro-3,4-

dihydroxy-2-methyl-3-pentanecarboxylic acid

Parent alkaloid Echinatine Viridiaorine

M.p. ('C.) 121

0'

C7H140b

Echimidinic (Macrotomic)

2-Methyl-2,3,4-trihydroxy-3-pentanecarboxylic acid

Echimidine Heliosupine Macrotomine

2,3-Dihydroxy-2,3,4-trimethylglutaric acid, 2(y)-lactone

Monocrotaline

( - )- Threo-3-hydroxy-4-methoxy2-methyl-3-pentanecarboxylic acid

He1eur ine Heliotrine

16.4'

C-8 Acids C8H1205

Monocrotalict C,H,llO4 Heliotrinic

181-182

-5.3'

94-95

-12'C

96-97

10.6'

CBH1605

Lasiocarpic

C-10 Acids ClOHl*O4 Mikanecic

2,3-Dihydroxy-4-methoxy-2-methyl-3Europine pentanecarboxylic acid Lasiocarpine

Mikanoidine

c10H1404

Squalinecic

Squalidine

129

Sceleratine

156

C10H1406

Carthamoidinecic-drop name a-and p-Longinecicdrop name Sceleranecictt

- 9.30C

TABLE

Necic acid

3-(continued)

Chemical name

Seneciphyllic ( 137)I isoSeneciphyllic (206) (Isomer of seneciphyllic) Cl,H,,O, Jacozinecic Riddellic

Parent alkaloid

2-Hydroxy-3-methylhepta-3,5-

Seneciphylline

[aln

M.p. ('C.)

115

- 13.2'

161 102-103

- 29.7' f - 2.60d

diene-2,5-dicarboxylic acid (Rpartioidine)

1,2-Dihydroxy-3-methylhcpta-3,5diene-2,5-dicarboxylic acid

Cl,H,,O, Grantianic:

Jacozine Riddell i ine

Grantianine

C10H1605

Hastanecic

Hastacine 4

C111H1605

Hieracinecic-drop Integerrinecic Platynecic Senecic

name

t3

2-Hydroxy-3-methylhept-5-enc-2,5dicarboxylic acid (trans) (Probably senecic acid integerrinecic acid) 2-Hydroxy-3-methylhept-5-ene-2,5dicarboxylic acid ( c i s )

+

Trichodesmicl

2,3-Dihydroxy-2,3-dimethyl-4-

Usaramoensiiiecic

isopropylglutaric acid, 2(y)-lactone 2-Hydroxy-3-methylhept-5-ene2,5-dicarboxylic acid

Cl,H,,O, Isatinecic

Integerrimine

151

Platyphylline

133-135

Rosmarinine Senecionine Senkirkine (?) Trichodesmine

147

11.8'

Usaramoensine

170

6.7'

146-147

- 9.1'C

1,2-Dihydroxy-3-methylhept-5-ene- Retrorsine 2,5-dicarboxylic acid (cis)

15.9'

M

0

2

0

t3

TABLE

Necic acid

3-(

Continued)

Chemical name

Jaconecic

Junceict

2,3-Dihydroxy-2-hydroxymethyl4-isopropyl-3-methylglutaric

Parent alkaloid Jacobine Jaconine Otosenine Tomentosine Junceine

r UID

M.p. ("C.) 182-183

30°d

180-182 (dec.)

acid, 2(y)-lactone Pterophinecic-drop name Retronecic

1,2-Dihydroxy-3-methylhept-5-ene- Retroraine (with isomerization) 2,5-dicarboxylicacid (trans) Senecifoline Jacoline

180-181.5

-11.4'

198-199

28.4'

148-149

- 8'

* ,%Hydroxy-DL-norvaline A

*(103) Renardine

74

NELSON J. LEONARD

C,H,O,, m.p. 85",had an IR-spectrum indicative of an unsaturated sixmembered ring (maxima at 1665, -1725,1735,1780,and -1800 cm.-l). Hydrolysis of the anhydride with alkali and subsequent acidification yielded anhydrodicrotalic acid, CeHs04, m.p. 149-150", which was shown to be cis-/3-methylglutaconic acid (CLXIII), m.p. 149-150", rather than trans-a-methylglutaconic acid, m.p. 145-146", by mixed

CLXlll

melting point determination with these two synthetic acids. Also, /3-methylglutaconic anhydride and anhydrodicrotalic anhydride were found to be identical. Finally, diethyl /3-hydroxy-/3-methylglutaratewas synthesized by a Reformatsky reaction using ethyl acetoacetate and ethyl chloroacetate and was hydrolyzed to /3-hydroxy-/3-methylglutaric acid, m.p. log", identical with dicrotalic acid. 3. G 7 ACIDS The acid C,H,,O, is not a necic acid per se but is a portion of the C-10 necic acid moiety of the alkaloid trichodesmine (73). a. Trachelanthic Acid (139).The structure of this acid, C,H&4, was shown satisfactorily by Men'shikov (73,see reference 56c) to be 3,4dihydroxy-2-methyl-3-pentanecarboxylicacid (CLXIV). Originally thought to be optically inactive, it was isolated in active form ,1I.[( 1.3" COOH

I

C(OH)CH CCHJ,,

I

CHOH

I

CH,

CLXIV

(water) ) from the alkaloid supinine under cleavage conditions not employing hot alkali (138).Culvenor (91)has provided a possible explanation of reported cases of trachelanthic acid lacking optical activity in the low specific rotation, coupled with a decrease in the rotation of trachelanthic acid in aqueous solution as the concentration is increased. He obtained a product of [u], 2.4" (water) from the hydrolysis of supinine employing 2.5 N sodium hydroxide at 100" for 2 hours. Moreover, refluxing the active acid with sodium hydroxide in water, aqueous ethanol, or amyl alcohol did not lower the specific rotation. I n paper chromatography, using ascending solvent, trachelanthic acid has an R, value of 0.76 for butanol-acetic acid, 0.33for butanol-ammonia.

75

SENECIO ALKALOIDS

The final structure proof for trachelanthic acid as CLXIV rests on syntheses of this acid, its diastereoisomer, viridifloric acid, and 8-methyl ether, heliotrinic acid, in the laboratories of Adams and of Warren. The latter has reached a conclusion as to whether the structure of trachelanthic acid is represented by one of the threo (CLXV) or erythro (CLXVI) forms of 3,4-dihydroxy-2-methyl-3-pentanecarboxylic acid, but not as to which threo form it is (CLXVa or b). That is, the absolute configurations in trachelanthic acid have not been determined; accordingly, formula CLXV will be used to designate the threo relative configurations at C-3 and C-4 with the intention of not signalizing a particular enantiomorph (UD,8L-dihydroxy (a)or aL, 8D-dihydroxy (b)). The synthesis of racemic trachelanthic acid is stereospecific, depending Coon

COOH

I

- C -OH

(CHXH

I

HO-C-H CH,

CLXV

(CH,LCH

-i. -OH I

H0DC-H CH,

(a)

FOOH WO-~-CHCCH,>,

I

H-F-OH CH,

tb)

thrro

COOH

I

(CH,),CH-C-OH

I

FOOH CCH,>~CHD~-OH

I

H-C-OR

HrCIOH

CH,

iH,

I

CLXVI

(a)

FOOH HOW~CHCCH,)~

I

HO*t*H

tH,

(b)

mm upon known mechanisms of cis- and trans-dihydroxylation of a double bond, upon analogy with the behavior of a lower homolog in synthesis (ethyl in place of isopropyl), and upon the stereochemical structure of the compound which is the important synthetic intermediate, a-isopropylcrotonic acid (CLXVII). If the geometry of this acid is indeed that of trans-crotonic acid rather than cis-crotonic acid (i.e., a-isopropylcrotonic acid rather than a-isopropylisocrotonic acid), as indicated by Dry and Warren (184),then trachelanthic acid may logically be assigned the threo structure (CLXV). No satisfactory proof of the geometrical structure of a-isopropylcrotonic acid, m.p. 53.5-54.5') has been provided. The UV-spectrum of the isomerically pure, solid a-isopropylcrotonic acid in 9574 ethanol exhibited a maximum at about 212 mp, ~=10,100(185).This molar extinction coefficient lies above the range usually observed for cis-a,P-unsaturated acids (186)and is therefore indicative of the trans relation between methyl and carboxyl

76

NELSON J. LEONARD

(187-1 89). The value is lower than the extinction coefficient observed for tiglic acid (CLX), 13,500at 212 mp in the same solvent (93) (for angelic acid (CLIX): 216 mp, ~=9500),but this diminution in extinction coefficient represents the effect to be expected in increasing the bulk of the a-substituent (190).Parallel greater stability and higher melting point are predictable for a-isopropyl-trans-crotonic,as for tiglic acid, on the basis of the finding by Turner and co-workers (191) that the difference between the heats of hydrogenation of 4-methyl-cis2-pentene and 4-methyl-trans-2-pentene (0.9 kcal./mole) is essentially identical with that recorded (1.0 kcal./mole) for the cis- and transbutenes. a-Isopropylcrotonic acid was made in the following way: catalytic reduction of ethyl isopropylacetoacetate gave ethyl /3-hydroxy-a-isopropylbutyrate, which on dehydration with phosphorus pentoxide yielded a mixture of a,P- and /3,y-unsaturated esters (maxima at 1718 and 1736 cm.-l) (187).Saponification of the ester mixture gave rise to a solid and a liquid fraction, each having the expected empirical formula. The solid acid, m.p. 53.5-54.5", was identified as a-isopropylcrotonic acid by IR-absorption spectrum (maxima at 1630 and 1685 cm.-l) and by ozonolysis, which yielded acetaldehyde. The liquid acid, by contrast, yielded some formaldehyde on ozonolysis.

CLXVll

CLXVlll

CLXIX

Model experiments (192, 193) on a-ethylcrotonic acid (structure CLXVIII strongly supported but not proved unequivocally) served as a guide for the homolog (CLXVII). Trans-dihydroxylation of a-ethylcrotonic acid using performic acid or pertungstic acid yielded erythro2,3-dihydroxy-3-pentanecarboxylic acid, m.p. 145",which is the same acid that is produced by cis-dihydroxylation, using permanganate, of a-ethylisocrotonic acid (CLXIX) (194).Adams and Herz (192)synthesized ( f)-trachelanthic acid, m.p. 119", by the oxidation of a-isopropylcrotonic acid (CLXVII) with alkaline potassium permanganate. Adams and Van Duuren (193)obtained the same acid by oxidation of methyl a-isopropylcrotonate with osmium tetroxide and hydrogen peroxide, another reaction known to give cis-dihydroxylation. It was pointed out by Dry and Warren (184)that the assignment of a-isopropylcrotonic acid as the trans-crotonic stereoisomer (CLXVII), coupled

SENECIO ALKALOIDS

77

with the known stereospecificity of the various dihydroxylation reactions, permitted the conclusion that ( f)-trachelanthic acid is ( &)-threo- 3,4-dihydroxy-2-methyl-3-pentanecarboxylicacid. The sequence may be illustrated for one of the enantiomorphs by CLXV1I-t CLXVb. Trachelanthic acid is thus (+)-thre0-3,4-dihydroxy-2-methyl-

CLXVll

CLXV b

3-pentanecarboxylic acid, since resolution (184, 193) of the ( &)-acid, m.p. 119", with brucine yielded a (+)-isomer, m.p. 89", [aID 2.9" f0.5" (water), identical with trachelanthic acid (brucine salt, m.p. 217-220", [a], -21" (chloroform); p-bromophenacyl ester, m.p. 99-99.5", [a], 3.9" (chloroform-ether)). The levorotatory form was also obtained (183, 193),m.p. 89", [a], -3.4" f 0.5" (water) (brucine salt, m.p. 182.5187.5", [a], -25" (chloroform)). Demethylation of the necic acid, heliotrinic acid (see below), produces trachelanthic acid and is therefore in the same (+)-threo stereochemical family (91, 195). b. Viridijloric Acid. The gross structure of viridifloric acid, C,H,,O,, was established by Men'shikov (144)as that of a stereoisomer-actually it is a diastereoisomer-of trachelanthic acid. Optical activity was not detected. Reduction of viridifloric acid with phosphorus and hydrogen iodide yielded ethylisopropylacetic acid (anilide, m.p. 116-1 17")--a conversion in which all the carbon atoms were preserved. The product of mercuric oxide oxidation of viridifloric acid was 4-methyl-2,3-pentanedione (b.p. 115-116'; osazone, m.p. 116-117"), just as from trachelanthic acid. Hence viridifloric acid can be named as a 3,4-dihydroxy-2methyl-3-pentanecarboxylic acid (CLXIV) (144). The relative configurations at the asymmetric carbons were decided through the stereospecific synthesis of ( +)-viridifloric acid, again on the assumption of CLXVII as the structure of the precursor a-isopropylcrotonic acid. Trans-dihydroxylation of a-isopropylcrotonic acid was effected by Dry and Warren (184) by conversion with perbenzoic acid to the epoxide (not isolated), which was hydrolyzed with aqueous sulfuric acid to ( f)-erythro-3,4-dihydroxy-2-methyl-3-pentanecarboxylic acid. The sequence may be illustrated for one of the enantiomorphs by CLXVII+CLXX+CLXVIb. Adams and Van Duuren (193) obtained the same racemate, m.p. 150" (p-phenacyl ester, m.p. 123124") by pertungstic acid oxidation of a-isopropylcrotonic acid. The

78

NELSON J. LEONARD

CLXX Ho%/i-pr HOI~#H /kOOH

tH,

CLXVlb

3,4-dihydroxy-2-methyl-3-pentanecarboxylic acid structure was confirmed by the ferric chloride test for an a-hydroxy acid, Criegee's glycol test with fuchsin, and oxidation with lead tetraacetate with the isolation of acetaldehyde (184, 193). The ( f ) - e r y t h r o acid was resolved with brucine in both laboratories. The less soluble brucine salt, m.p. 184186") [a], -22" (chloroform), furnished the (+)-erythro acid. There are discrepancies in the physical properties reported: m.p. 117-1 19" or 127.5", [a], 0" or 1.8" (water) (p-bromophenacyl ester, m.p. 110-11lo, [a], 3" (chloroform) ). The more soluble salt, m.p. 187-189" or 207-210°, [a], -23" (chloroform), gave the enantiomorphic acid, m.p. 118-122" or 127.5",[a], 0" or -1.6" (water). The melting points of both "optically active" forms were changed on admixture with the ( f)-erythro acid, and the melting point of a mixture of the two forms in nearly equivalent amounts was 140-143". With a sample of natural viridifloric acid on hand, along with the synthetic enantiomorphs, it would thus be simple to determine whether it is the (+)-or ( -)-erythro-3,4-dihydroxy-2methyl-3-pentanecarboxylic acid, despite the low or zero rotation. c. Echimidinic Acid (Macrotomic Acid). It appears that echimidinic acid, C,H,,O,, from echimidine (88) and heliosupine (88, 93a), and macrotomic acid, from macrotomine (1lo), are identical, although a direct comparison has not been realized. Their gross structures can be acid represented by 2-methyl-2,3,4-trihydroxy-3-pentanecarboxylic COOH

I c (OH)C(OH) I

(cH,),

CHOH

I

CH,

CLXXI

(CLXXI), but whether hydroxylated trachelanthic or viridifloric acid has not been decided. Men'shikov and Petrova (110) established the structure (of macrotomic acid) by periodate cleavage of macrotomine. A mole of oxygen was consumed per mole of alkaloid, and acetone, oxalic acid, and acetaldehyde were detected. The same products were

79

SENECIO ALKALOIDS

isolated from the periodate oxidation of heliosupine (93a) and echimidinic acid (Rf0.50 for ascending butanol-acetic acid chromatographing solvent; brucine salt, m.p. 209-210") (88). 4. G 8 ACIDS

a. Monocrotalic Acid (140-145). This acid, C,H,,O,, the hydrogenolysis product of monocrotaline, is a lactone acid and actually a conversion product of the dicarboxylic acid (C,H,,O,+H,O) which is the necic acid of the mother alkaloid. None of the postulated structures for monocrotalic acid given in the earlier review in these volumes (reference 73, p. 141) is correct in the light of the revisionary work of Adams and his school. The correct structure of monocrotalic acid (stereochemistry not indicated), established by degradation and synthesis, is represented acid, 2 (y )-1actone (CLXXII); by 2,3-dihydroxy-2,3,4-trimethylglutaric the precursor necic acid is therefore CLXXIII. The key to the new OH

CH,

CLXXll

CLXXlll

structural assignment lay in the reduction of methyl monocrotalate with lithium aluminum hydride. Adams and Govindachari (196) obtained a tetrahydroxy compound, C,H,,O,, m.p. 103", [a],,9.3" (ethanol), in 92% yield, which readily formed a dibenzoate (m.p. 107") and a di-p-nitrobenzoate (m.p. 115-1 16"). Two mole equivalents were consumed in periodate cleavage of the tetrol, and the products of the oxidation were formaldehyde, acetic acid, and 4-hydroxy-3-methyl-2butanone (CLXXV), the last two partially in combined form. 2,4-Diniand the trophenylhydrazones of both 4-hydroxy-3-methyl-2-butanone derived isopropenyl methyl ketone (CLXXVII) were isolated. The tetrol CH CH,

I ' I

CH,

I

HOCH,-CH-C(OH)-C(OH)-CH,OH

CLXXIV

y' 7% y,

C,H5COOCH,-CH- C(OH)-C(OH)-CH,OOC~H,

CLXXVI

-

CH CH,

CH,

I.

I ' I

HOCH,-CH-C=O+ COOH + CH20

CLXXV CH CH,

I -' CI = O (as dcrwative)

CHrC

CLXXVll

y. O= C

+

-C\OOCC6H, CLXXVlll

80

NELSON J. LEONARD

could therefore be formulated as 1,2,3,5-tetrahydroxy-2,3,4-trimethylpentane (CLXXIV). The dibenzoate (CLXXVI) reacted to the extent of 1 mole equivalent with lead tetraacetate. 2,4-Dinitrophenylhydrazones of isopropenyl methyl ketone (CLXXVII) and acetol benzoate (CLXXVIII) were identified and confirmed the structure CLXXVI. Formulation of the tetrol as CLXXVI requires the structure of monocrotalic acid t o be CLXXII, provided no rearrangement has occurred during the lithium aluminum hydride reduction. Methyl anhydromonocrotalate, which is obtained by heating methyl monocrotalate in vacuo, may be formulated as CLXXIX, and methyl dihydroanhydromonocrotalate as CLXXX. The UV-absorption spectrum of methyl anhydromonocrotalate (Agi:H 214 mp, E = 10,860) is $4 CH;C-C-COOCH,

I ).

CH;-C-C

-0

CLXXIX

$4 CH,-CH-C-COOCH,

I

CH;-Ck+C\

>O

' 0

CLXXX

consistent with the formulation CLXXIX. Lithium aluminum hydride reduction of methyl anhydromonocrotalate and methyl dihydroanhydromonocrotalate produced trihydroxy compounds, both of which consumed 1 mole equivalent of periodate and furnished 1 mole equivalent of formaldehyde in this process. It is only by placing the carboxyl group on the carbon atom involved in lactone formation as in structures CLXXII, CLXXIX, and CLXXX that the formation of formaldehyde from all three lithium aluminum hydride reduction products by periodate cleavage can be explained. The formation of dimethylmaleic anhydride by nitric acid oxidation of monocrotalic acid is readily explained on the basis of the new structure, involving a dehydration followed by oxidation. The formation of a,/?-dimethyllevulinic acid by treatment of monocrotalic acid with aqueous 0.4 N barium hydroxide at 100"for 1 hour (73, 197) may also be explained by structure CLXXII. The decarboxylation could take place by loss of carbon dioxide from the tertiary carboxylate anion with trans elimination of the 3-hydroxyl. The resulting a$-dimethyl- AP-angelicalactone would be the precursor, in basic solution, of the a,/?-dimethyllevulinic acid. An alternative pathway to the same product would be the /?-elimination (/?- to the lactone carboxyl) of the 3-hydroxyl under the hot alkali treatment. A 3,4double bond thus introduced is /?,y to the free carboxyl, and the latter might be expected (with double bond shift to the a,p-position) to lose carbon dioxide from the mono-anion of the ring-opened unsaturated hydroxy-dicarboxylic acid. These considerations may prove useful in

SENECIO ALKALOIDS

81

assigning relative configurations to the ring carbons of monocrotalic acid. The data gathered thus far with this goal in mind are not sufficient to make assured relative configurational assignments.

The structure of dihydroanhydromonocrotalic acid (CLXXXIII) was established by synthesis (of its enantiomorph) by Adams and Hauserman (198). The addition of hydrogen cyanide to +dimethyllevulinic acid (CLXXXI) yielded the cyanolactone (CLXXXII), which on hydrolysis furnished a mixture of the corresponding acids. Resolution with brucine gave a pure stereoisomer, m.p. 117.6-119.3', [u], +60.0" (ethanol), which was identical in IR-spectrum with the [u], -60.0" stereoisomer of dihydroanhydromonocrotalic acid and was therefore the mirror image of the product from the natural source. The p-bromophenacyl esters of the synthetic acid and that derived from monocrotalic acid had identical IR-spectra, melting points (107-108'), and exactly opposite rotations ([u]" *20" (acetone) ). Adams and Hauserman (198), in a study of various hydrolyses of methyl dihydroanhydromonocrotalate (CLXXX), found that whereas potassium cyanide treatment led to the [u], -60.0" dihydroanhydromonocrotalic acid, m.p. 117.6119.5", hydrochloric acid gave a stereoisomer, [u], 5.6', m.p. 132.4134.4'. Heating with base or acid causes an equilibration, and the specific rotation at equilibrium was found to be -56.0", indicating the predominance of the [u], -60.0" isomer and suggesting, on the basis of the hydrolysis conditions, that the methyl dihydroanhydromonocrotalate has the same configuration as the [u] 5.6" stereoisomer. The equilibration was explained logically as due to epimerization at C, (see CLXXXIII) by acid- or base-catalyzed enolization (198). The explanation was supported by a study of the action of acidic and basic reagents on optically active y-carboxy-y-valerolactone (CLXXXIV). The optically active acid, m.p. 88-89', [u], 15.4' (water),was recovered unchanged in rotation when refluxed with concentrated hydrochloric CHz-C-

I

COOH

>o

C H r C*o

CLXXXIV

F

82

NELSON J. LEONARD

acid or with 10% aqueous sodium hydroxide. If the carbon adjacent to the carboxyl group in dihydroanhydromonocrotalic acid were involved in the interconversion of its stereoisomers, then the optically active model lacking the 3- and 4-methyl groups (CLXXXIV)would have been expected to undergo racemization. From the predominance of the [u] -60.0' epimer at equilibrium, the author suggests that in the [u] 5.6' epimer of dihydroanhydromonocrotalic acid (CLXXXIV) the 3and 4-methyls are cis or eclipsed, and that they are trans in the thermodynamically more stable [a] -60.0' diastereoisomer. The synthesis of monocrotalic acid, fully proving the assigned structure (CLXXII),was achieved by Adams et al. (197) in the following manner. Pure diethyl 2,3-dimethylglutaconate (CLXXXV) was subjected to carbethoxylation with ethyl carbonate in the presence of sodium ethoxide. The sodio derivative was not isolated but was treated directly with 1 mole equivalent of methyl iodide. The product, diethyl 2,3,4-trimethyl-4-carbethoxyglutaconate (CLXXXVI), was obtained I

C- COOC,H,

CH,-C03C2Hs

ya

y.

Cn, CH,-C=

-

CH,-C=C-COOCJ4H,

CH,-C=

CH,-C-

CH,-CH-COOH

1

I

COOC,H,

I

C-COOH

COoCaHs

CLXXXV

CLXXXVI

CLXXXVll

4

CLXXll

pure and in good yield. The triester readily lost one carbethoxyl group in the presence of aqueous ethanolic sodium hydroxide, and further hydrolysis yielded a mixture of the stereoisomers, m.p. 127.5' (dec.) and m.p. 131.5-132', of 2,3,4-trimethylglutaconicacid (CLXXXVII). Stereochemical assignments were suggested on the basis that the lower melting acid melts with decomposition and loss of water and therefore has the -COOH and - HCOOH groupings so disposed (cis) as to form

7

CH, an anhydride. Trans-dihydroxylation of this acid (supposedly the form pictured in CLXXXVII; the melting point of the acid employed in this reaction is not given in the experimental section (197) ) was effected by means of pertungstic acid, and the product, which could not be crystallized, proved to be a mixture of diastereoisomeric racemates of 2,3dihydroxy-2,3,4-trimethylglutaricacid, 2(y)-lactone (CLXXII). Brucine treatment of the oil resulting from the pertungstic acid oxidation furnished a C,H,,O, acid, m.p. 180-182' (dec.), [u], -5.0" (ethanol), identical with monocrotalic acid, and another C,H,,05 acid of m.p. 180-182' (dec.),but [u], -G1' (ethanol),not identical with monocrotalic

83

SENECIO ALKALOIDS

acid. On the basis of the stereospecificity of the pertungstic acid oxidation and on the assumption of cis geometry in the substrate (CLXXXVII), the structures of these two synthetic acids may be assigned tentatively as having the 2- and %methyl groups in the cisrelation (197). All the y-lactones obtained in the study of monocrotalic acid exhibited characteristic lactone C=O stretching bands in the normal IRrange, 1774-1782 cm.-l, for solution (chloroform) spectra. By contrast, it was observed by Adams et al. (175) that the IR-spectrum of the alkaloid monocrotaline has only a single broad ester carbonyl band a t 1725 cm.-l with a shoulder at 1737 cm.-l and does not have any band in the five-memberedlactone carbonyl region. It was recognized that such an IR-spectrum could be more satisfactorily explained if the structure of the alkaloid, C,,H,,NO,, were represented as a bridged-ring cyclic diester (CLXXXVIII), with CLXXIII as the dicarboxylic acid moiety, and chemical evidence was supplied to indicate the correctness of this revised formulation. Monocrotaline sulfite, C,,H,,NO,S, m.p. 155.4-

CLXXXIX

O-C,H,(NH,),

I

Pd

H,

V

o=c.

cxc

d CXCl

84

NELSON J. LEONARD

155.8" (dec.), [a], 37.7" (ethanol) (hydrochloride, m.p. 226-226.5" (dec.), [a], 15.3" (water) ), was obtained by treatment of the alkaloid with thionyl chloride. Infrared spectra indicated the disappearance of the hydroxyls (3540, 3580 cm.-l) which were present in monocrotaline and the formation of a sulfite ester of a vicinal glycol grouping (1207, 1222 cm.-1) (CLXXXIX). Hydrogenolysis of monocrotaline sulfite using palladium on strontium carbonate was realized with the absorption of 1 mole equivalent of hydrogen and the formation of an amino acid (CXC), dihydromonocrotaline sulfite, C,,H,,NO,S, m.p. 169.5170" (dec.), [a], 23.7" (water) (hydrochloride, m.p. 185.8-186.2" (dec.), [a], -31.7" (ethanol) ). The IR-spectrum of this hydrogenolysis product showed the expected bands, but most significantly the ester band (1736 cm.-l) which is not found in the salt, deoxyretronecine monocrotalate (CXCI), m.p. 172.5-172.8" (dec.), [a], 9.7" (ethanol). This indicated clearly that the necic acid was originally joined to the necine by two ester links, one of which is easily cleaved by hydrogenolysis while the other survives only when the 2-hydroxyl is blocked, in the above case by the sulfite ester group. Therefore, when monocrotaline is hydrogenolyzed, the allylic ester is first cleaved, then an intramolecular transesterification takes place between the 2-hydroxyl and the remaining ester group (C, in the glutaric acid portion) with the formation of the lactone ring of monocrotalic acid. The presence of the two hydroxyls on the 2- and 3-positions of the necic acid was confirmed by oxidation of monocrotaline with lead tetraacetate and identification of a pyruvic acid ester in the reaction mixture by treatment with o-phenylenediamine hydrochloride and formation, in 80% yield, of 2-hydroxy-3-methylquinoxaline (CXCII). The 2,3-dihydroxycarboxylic grouping was thus required to be attached to the allylic hydroxyl of retronecine. Structure CLXXXVIII for monocrotaline also satisfactorily accounts for its transformations by the action of alkali into retronecine, a,P-dimethyllevulinic acid, ethyl methyl ketone, and carbon dioxide (142). Saponification of the alkaloid may follow or precede the breakdown of the necic acid portion of the molecule (74). b. Heliotrinic Acid (145-146). The gross structure of heliotrinic acid, C,H,,O,, was established as 3-hydroxy-4-methoxy-2-methyl-3-pentanecarboxylic acid by the work of Men'shikov (73, 172). Adams and Van Duuren (195) obtained trachelanthic acid on hydrolysis of heliotrinic acid with 48% hydrobromic acid-a finding which was confirmed by Culvenor (91). Thus, if the relative configurations of the asymmetric carbons in trachelanthic acid are correctly assigned as threo (184), heliotrinic acid is ( -)-threo-3-hydroxy-4-methoxy-2-methyl-3-pentanecarboxylic acid (CXCIII, absolute configurations not decided). The

SENECIO ALKALOIDS

85

COOH

I

tCH,&CH-C-OH CH,O-C-H

CH,

CXClll

synthesis of heliotrinic acid has not yet been achieved (195),although Dry and Warren have synthesized ( &)-erythro-a-hydroxy-p-methoxybutyric acid (p-phenylphenacyl ester, m.p. 137-138") (199)and (&)erythro-3-hydroxy-4-methoxy-2-methyl-3-pentanecarboxylic acid (200), m.p. ca. 40" (p-bromophenacyl ester, m.p. 138").Demethylation of the latter compound furnished ( f)-erythro-2,3-dihydroxy-4-methyl-3-pentanecarboxylic acid (CLXVI). c. Lasiocarpic Acid* (146).This acid, C8H1,05,has been investigated by Drummond (97),following the earlier demonstration by the Russian workers (73) that the acid possessed two hydroxyl groups and one methoxyl group. The two hydroxyls were shown to be present in an a-glycol grouping since 1 mole equivalent of periodate was consumed, and one hydroxyl was indicated as alpha to the carboxyl group since the acid gave a yellow color with ferric chloride and liberated carbon monoxide on warming with concentrated sulfuric acid. A structure similar to heliotrinic acid was suggested since Kuhn-Roth oxidation indicated 1.6 C-methyls for both lasiocarpic acid and heliotrinic acid (1 terminal methyl, 1 gem-dimethyl grouping). Acetone was identified as one of the products of periodate cleavage (90, 97) of lasiocarpic acid (Rf 0.25 for butanol-ammonia (91);p-phenylphenacyl ester, m.p. 145-145.5'), and Culvenor et al. (90) obtained both acetone and a C5Hl,0, acid, presumably a-hydroxy-p-methoxybutyric acid (CXCV) (p-phenylphenacyl ester, m.p. 115.5-116"), on heating the parent acid

in 30% aqueous potassium hydroxide. The supposition is that lasiocarpic acid is in the threo-series (CXCIV)along with heliotrinic acid and trachelanthic acid, but the relative and absolute configurations await determination. Designation of lasiocarpic acid is thus limited at the present time to 2,3-dihydroxy-4-methoxy-2-methyl-3-pentanecarboxylic acid.

* See also Addendum, p. 121.

86

NELSON J. LEONARD

5. C-~OACIDS a. Mikamecic Acid, C,,H,,O, (neutral equivalent = 100f2), was hydrogenated quantitatively using platinum to hexahydromikanecic acid (not analyzed), and the hydrogenated product was converted to the diethyl ester by diazoethane. Adams and Gianturco (1 1 l), who carried out this conversion on the original mikanecic acid of Manske (73), found that the “diethyl hexahydromikanecate” had an IR-spectrum identical with that of the product of a synthetic sequence. The spectral “identity” may have been fortuitous since the synthetic product, diethyl 5-ethyl-2,3-dimethyladipate (CXCVI ester), C14H2604, might have been isomerically pure, but was more likely a mixture of stereoisomers (n: 1.4350). The carbon skeleton was considered identical with

I COOH

CXCVI

I CH,

I

cow CXCVll

that of seneciphyllic acid (see below), and the suggestion was made that mikanecic acid may be a dehydrated seneciphyllic or isoseneciphyllic acid. The position of the UV-maximum for mikanecic acid in 95% ethanol (Amax. 216 mp, ~=8540)dictates a low degree of conjugation in the diacid supposed to contain three double bonds: one (on the basis of E) or each of two of the double bonds must be conjugated with one of the two carboxyl groups and no two of the double bonds may be at the same time conjugated with each other and with a carboxyl group. Of three structures conceived as possible, IR-evidence and other arguments were mustered in favor of CXCVII (111). The IR-spectrum of mikanecic acid excludes the presence of a cyclopropane ring. The spectrum (Nujol) contained the following bands indicative of certain of the groups present: 923 cm.-l (a-methylenic acid) (201);900 cm.-l C:( = CH,); 950 cm.-l (CH,C = CH-COOH) (202);960 cm.-l (carboxylic OH deformation); I 835 cm.-l (;C = C ~ H ) 1690, ; 1680 cm.-l, barely resolved (two carboxylic acids); 1650(s), 1638(sh) cm.-l (C = C’s); 2510, 2600 cm.-‘ (carboxylic O H stretching). Unfortunately, [ a ] , and C-methyl determinations are not available on the original acid and might be crucial in establishing the true structure. b. Sqiralinecic Acid (148). No further evidence has been provided toward devising a structure for squalinecic acid (73).

SENECIO ALKALOIDS

87

c. Sceleranecic Acid (148). The structure of sceleranecic acid, C,,H,,O,, remains undecided, although several possibilities have been put forward on the basis of information which one would wish to be more complete ( 7 4 7 5 , 133). The early data accumulated by de Waal and his co-workers in South Africa (73, 128-131) indicated that the hydrolysis and hydrogenolysis product of the alkaloid sceleratine was unchanged on further catalytic hydrogenation, had no carboxyl group, and was actually a dilactone, one ring of which was very stable. Thus, one lactone was opened in the cold with sodium hydroxide; the other lactone was opened on refluxing with alkali. De Waal and Van Duuren (133), in a reinterpretation of the early results, supplied the IR-absorption characteristics (5% solution in chloroform) of sceleranecic acid, also called "sceleranecic dilactone," and related compounds. The IR-maxima for sceleranecic dilactone a t 1775 and 1740 cm.-l were indicative of a y - and a 6(or larger)-lactone. The parent alkaloid sceleratine possessed no lactone band in this region, but only an ester band, a t 1715 cm.-l-a fact indicative that the alkaloid possessed similarity to monocrotaline (CLXXXVIII) in the occurrence of lactone formation on hydrolysis and hydrogenolysis. The function of the additional oxygen in the C,,H,,O, dilactone was shown to be hydroxylic (IR-maximum a t 3500 cm.-l) by the formation of a monoacetyl derivative, Cl,H,,O,(OCOCH,), m.p. 81", and a monobenzoyl derivative, C,,H,,O,(OCOC,H,), m.p. 155". Furthermore, oxidation with nitric acid showed it to be a primary alcohol group, by conversion of C,,H,,O, to Cl,Hl2O, (-CH,OH+ -COOH), m.p. 216" (methyl ester, m.p. 133'), which titrated immediately with 0.1 N potassium hydroxide for one carboxylic acid, 10 minutes later for a second acidic grouping, and only after refluxing for the third such grouping (131). Oxidation studies provided information concerning the juxtaposition of the primary hydroxyl and the lactonic hydroxyls (132). Thus, the potassium salt of sceleranecic acid yielded formaldehyde on periodate oxidation, and, with 2 mole equivalents of lead tetraacetate, formaldehyde, carbon dioxide, and a monolactonic acid, C8Hl2O4,m.p. loo", [u], 43.2" (water). The same acid was obtained (131) by oxidation with alkaline permanganate and by oxidation of the C,,H,,O, dilactonic acid described above with chromic acid-sulfuric acid. Acetaldehyde (actually disregarded in structural formulations) was also identified as a product of the alkaline permanganate oxidation, followed by acidification and steam-distillation. The C8H120,lactonic acid contains a five-membered ring lactone on the basis of titration (131) and IR-spectrum, which showed a maximum at 1760 cm.-l, along with one a t 1705 cm.-l for the acid grouping (133)

88

NELSON J. LEONARD

With the foregoing information, partial structures of the necic acid corresponding to sceleranecic dilactone and of the C,H,,O, oxidation product may be written as CXCVIII and CXCIX, respectively. Structure CXCVIII satisfies the 6- and y '-1actone formation, especially the I

-c-0,

-C -C-COOH

HOOC-C-&/

Id

HOOC-C

I

CHOH

-&-OH

18,

CXCVlll

I&?

18

c=o

I0 I= CXCIX

latter, where the y'-hydroxyl can transesterify the carboxyl attached to the secondary carbon of the necine moiety. The right-hand end of the same partial structure is satisfactory and necessary to explain the findings of the various oxidations. The y-lactonic acid oxidation product (CXCIX) places the remaining hydroxyl. The problem of locating the three methyl groups on these chains-the methyl groups should be on the same carbons in both CXCVIII and CXCIX-is a t present unresolved, largely as a result of the inconsistent Kuhn-Roth determinations originally reported (131, 133): 2.5 C-methyls for C,,H,,O,; 2.53 for CloHlzOa;1.46 for CsHl,O,. Indecision in this regard marked a point of departure of the structural postulates of Adams and Gianturco (134) and de Waal and Van Duuren (133), both schools agreeing on the partial structures CXCVIII and CXCIX. The former pair of workers, arguing on the basis of the close structural relation of sceleranecic acid with other acids in the series while admitting the inconsistency of the KuhnRoth determinations, support structure CC for this dilactone. The latter pair of workers, assuming that all the C-methyl values are low (203, 204) but indicate three such groupings, support structure CCI. Earlier postulates are not as satisfactory as either of these. Related in structure to sceleranecic acid (sceleranecic dilactone) is sceleratinic acid (sceleratinic dilactone), C1oH,,CIO,, found by de Waal and Louw (129) in Senecio sceleratus but apparently not a portion of an alkaloid. It was also obtained by de Waal et al. (132) by treatment of the potassium salt of sceleranecic acid with thionyl chloride or phosphorus pentachloride. On neutralization of sceleratinic dilactone ( vmax. 1765 cm.-l) with alkali, the compound behaved similarly to sceleranecic lactone, from which it was concluded that the two compounds possess the same dilactone structure. Moreover, oxidation of sceleratinic acid, potassium salt, yielded the same C,H,,O, monolactonic acid, m.p. IOO", on lead tetraacetate oxidation. A by-product of the treatment of sceleranecic acid, potassium salt, with thionyl chloride followed by alkali was a dicarboxylic acid, C,,H,,O,, m.p. 192", which was also obtainable from

89

SENECIO ALKALOIDS

sceleratinic dilactone after reaction with excess 2N potassium hydroxide, followed by acidification. This acid, which was shown to be a hydroxydicarboxylic acid by its conversion to a chlorodicarboxylic acid, CloH15C105, m.p. 231", reacted with concentrated hydrochloric acid to liberate formaldehyde and yield an acid C,H,,O,, m.p. 128". The interpretation of Adams and Gianturco of this chemistry is shown in Chart A; that of de Waal and Van Duuren, in Chart B (74). The compounds represented are as follows: CCII, C,,H,,O, dilactonic monocarboxylic acid; CCIII, sceleranecic acid, potassium salt; CCIV, C8Hl2O4monolactonic acid, m.p. 192"; CCV, CloHl,O, dicarboxylic acid, m.p. 192"; CCVI, sceleratinic dilactone; CCVII, CloH15C105chlorodicarboxylic acid; CCVIII, sceleratinic acid, potassium salt.

CClVa P b h )

c H, CCVlla

CCVlll a

d . Seneciphyllic Acid (148). If the necic acid which is part of the structure of seneciphylline is called seneciphyllic acid (originally a-longinecic), C10H1405,m.p. 115", [ a ] , -13.2' (water) (120, 121, 205), it must be recognized that this is the "isoseneciphyllic acid" of Konovalova and Danilova (m.p. 104-106", [ a ] , -8.6" (ethanol) (206) )

90

NELSON J. LEONARD CHART B

HNO,

.

c H J ~ c o o H CH,

0

CCI

CCllb

PbCOAc).

or KMno4 2 G T 2 0 KOOC OH

H

* HOOC

CCVb

CCVlb

CCVll b

CCVlllb

/

obtained from seneciphylline by hydrogenolysis followed by hydrolysis with 5%-18% aqueous potassium hydroxide. Treatment of seneciphyllic acid with 10% hydrochloric acid on the steam-bath (206) converted it to the thermodynamically more stable geometrical isomer, regarded later as being of the trans-crotonic acid type by Kropman and Warren (207) and by Adams and Gianturco (137). One mole of hydrogen was absorbed by either acid, with platinum as the catalyst, and the same dihydroseneciphyllic acid, m.p. 149-150”, [u], -8.0” (ethanol), was said to be obtained (206). The “trans”-isomeric acid was also obtained when seneciphylline was hydrogenolyzed and the intermediate retronecanol salt was heated with 5 yo alcoholic potassium hydroxide for 1.5 hours (206). The gross structure of seneciphyllic acid was established by Adams et al. (205). It was shown to be dibasic by direct titration and by formation of a dimethyl ester. The IR-maximum at 3452 cm.-l and a t 3497 cm.-l for the acid and its ester was indicative of a hydroxyl group, which because of its inertness was recognized as tertiary and because of the yellow color given by seneciphyllic acid with ferric chloride was

91

SENECIO ALKALOIDS

recognized as a to one of the carboxylic acid groups. The presence of two double bonds was deduced by quantitative hydrogenation. The IR-absorption spectrum (maxima at 1736 and 1717 cm.-l) showed that one of these was conjugated with one of the carboxyl groups, while the UV-spectrum (Ag\:H 214 mp, E = 8130) was also characteristic of an a,p-unsaturated acid, but not of the sorbic acid (Ag\:H 254 mp, E = 25,000) type (208). Chromic anhydride-sulfuric acid on the tetrahydroseneciphyllic acid, C,,H,,O,, gave a ketonic acid, CSHl6O3,which, on further oxidation with sodium hypobromite, yielded 2-ethyl-4methylglutaric acid (CCIX), identified as the jmide, m.p. 126-127" (mixture of isomers). Reversing the degradation series, it is possible to HOOCCH(CzHs)CH,CH (CH,)COOH

1

y'

I

5".

CCIX

NaOBr

HOOCCH(C,H~)CH,CH(CH,) CO

cro3 Haso.

HOOCCH(C2Hs)CH,CH(CH,)C-COOH

ccx

CCXl

OH

reconstruct the ketonic acid as CCX and the tetrahydroseneciphyllic acid as CCXI. Seneciphyllic acid reacted with lead tetraacetate with the loss of one carbon as carbon dioxide and the formation of an unsaturated ketonic acid, CsH,,03, which significantly showed no optical activity (2,4-dinitrophenylhydrazone,m.p. 184'; thiosemicarbazone, m.p. 163164') and gave a positive iodoform test indicative of a methyl ketone. Ozonization of seneciphyllic acid yielded acetaldehyde, and a KuhnRoth determination indicated three C-methyl groups (2.2 found). The combined information plus IR-evidence (maxima at 824 and 849 cm.-l) suggested that seneciphyllic acid possesses the double bond arrange"3,

'1C H

I

CH,

II I HOOC-'C-~H=~~CH,)-*C~OH)-COOH

CCXII

ment indicated in CCXII, 2-hydroxy-3-methylhepta-3,5-diene-2,5-dicarboxylic acid. The alternative structure with a methylenic double bond at C, was also considered by Adams et al. (205). The carbon skeleton corresponds to that found in senecic, isatinecic, and riddellic acids (see later),as originally postulated by Adams andGovindachari (120).The configuration of the 5-double bond was assigned by Kropman and Warren

92

NELSON J. LEONARD

(207) as being of the cis-crotonic acid type because of the possibility of isomerization to a more stable, higher melting acid. On heating seneciphyllic acid, water was evolved, presumably with the formation of a lactone (120); this would suggest that the configuration of the 3-double bond is cis with respect to the carbon chain. This conclusion is also reached by examination, using scale molecular models, of the C, c i s and C, trans possibilities with regard to closing the diester ring in the parent alkaloid, seneciphylline (75). Thus, a more refined representation of seneciphyllic acid becomes CCXIII, with the absolute configuration of C, undecided. Adams and Gianturco (137) have reached the conclusion

t.hat the acid portion (no name given) of the alkaloid spartioidine (XE:(H 215 mp, E = 10,170; V~;:,'J 1655 cm.-l) differs from seneciphyllic acid in configuration at both C, and C,. e. Jacozinecic Acid, CloH1,O,, has been obtained by Bradbury and Willis (102), by the alkaline hydrolysis of the alkaloid jacozine. It is a dicarboxylic acid, has a t least two C-methyls (1.9 found), and shows weak absorption in the ultraviolet 211 mp, E = 1138); the report of selected IR-maxima is not conclusive. Treatment of jacozinecic acid with acetyl chloride yielded a compound, C12H1406,m.p. 136", which contained one acetyl group and exhibited IR-bands typical of ester, anhydride, and hydroxyl groupings. f. Riddellic Acid (149).This acid, C,,,H,,O,, was partially characterized a t the time of the earlier review by the author (73). Complete characterization of the gross structure has been achieved by Adams and Van Duuren (176) using methods similar to those already described for other of the necic acids. A strong coloration of riddellic acid with ferric chloride indicated hydroxyl a to a carboxyl. A positive Criegee fuchsin test indicated the presence of a glycol, which was further confirmed by the reaction of bis-p-phenylphenacyl riddellate (m.p. 59-60", [a], -38.3" (ethanol) ) with thionyl chloride to produce a cyclic sulfite ester, bis-pphenylphenacyl riddellate sulfite (m.p. 78-80' (dec.), [u], -11.3" (ethanol), 1200-1250 cm.-l region (S = 0) ). The parent alkaloid riddelliine also formed a sulfite, Cl8H2,NO,S (m.p. 170" (dec.), [u], -17.4" (chloroform); hydrochloride, m.p. 215" (dec.), [ a ] , -41.5'

(Azz.

vz!'

93

SENECIO ALKALOIDS

vz!'

1230, 1240 cm.-l (S = 0) ), indicating that the (ethanol), glycolic moiety of the necic acid was intact in the parent. Riddellic acid consumed 2 moles of lead tetraacetate in oxidation, and the products were carbon dioxide, formaldehyde, and a C,H,,O, dibasic acid, m.p. 114", optically inactive. The IR-spectrum showed a single C = 0 stretching band at 1682 cm.-1, C = C stretching a t 1630 cm.-l, indicating only conjugated carboxylic acid, in contrast to riddellic acid, which had conjugated and unconjugated C = 0 bands at 1695 and 1720 cm.-1, C = C band at 1637 cm.-l. The C,H,,O, acid absorbed 2 moles of hydrogen using palladium on strontium carbonate as the catalyst. The product, C,H,,O,, m.p. 70-71°, was shown by direct comparison with synthetic material to be 2-ethyl-4-methylglutaric acid (CCIX),cis form. On the basis of these conversions and the overall similarity of the IR-spectra of seneciphylline and riddelliine, and of seneciphyllic acid and riddellic acid, with additional peaks due to hydroxyl in riddelliine and riddellic acid, guided Adams and Van Duuren in their formulation of riddellic acid as 1,2-dihydroxy-3-methylhepta3,5-diene-2,5-dicarboxylic acid (CCXIV). The IR-similarity and the

' f i

'cn,

.Icn

I

H00C-k

cn,

CH,OH

I

II

-tH=t(CH,>-'C(OH)

-COOH

in'

c

I coon

I C(OH)CH,OH I

COOH

CCXIV

ccxv

UV-similarity of seneciphyllic and riddellic acid 215 mp, E = 8300) further suggest identical geometrical configurations, cis-cis, at C, and C, (CCXV),but firmer evidence is not available. The orientation of riddellic acid in riddelliine, i.e., which carboxyl is esterified with the allylic primary alcohol of retronecine and which with the secondary alcoholic hydroxyl, was decided by hydrogenolysis and subsequent oxidation (176). Dihydroriddelliine, C18H,,N0,, m.p. 197", [a], 22.3" (water), was obtained with palladium on strontium carbonate and 1 mole equivalent of hydrogen. During this treatment one ester group, the allylic ester, was cleaved, and the maxima in the IR-spectrum of the product indicated the following distinctive structural features: I

= 0 (1707 cm.-l), 0 C = C (1655 cm.-l), C< (1635 cm.-l). One mole equivalent of 0-

-N+-H I

(2200-2500 cm.-l)? conjugated ester C

carbon dioxide was obtained in the lead tetraacetate oxidation of dihydroriddelliine, whereas no carbon dioxide was evolved with

94

NELSON J. LEONARD

riddelliine under identical conditions. These facts indicated that the carboxyl with the a-hydroxyl was free in dihydroriddelliine (CCXVII) and therefore that this carboxyl was esterified with the allylic alcohol in riddelliine (CCXVI).

H2

Pd

*

CCXVl

CCXVll

9. Grantianic Acid (149).This acid, C10H1407, not obtained in a pure state, is the hydrolysis product of grantianine, unique among the Crotahia alkaloids in containing a y-lactone grouping ( vmitx. 1765 cm.-l) as well as two ester linkages (1732 and 1717 cm.-l) and one hydroxyl (3520 cm.-l) (134). Hydrogenation of grantianine in ethanolacetic acid with platinum resulted in the absorption of 2 moles of hydrogen and the formation of tetrahydrograntianine, ClsH27N07, m.p. 242-242.5", [a], -56.8" (50% aqueous acetic acid) (with HCl present, [a], - 54.0°, unchanged on standing) (Rf 0.29, descending butanol-5% acetic acid; picrate, m.p. 195-196"). The IR-spectrum of the product exhibited bands characteristic of y-lactone (1767 cm.-l), OH (3380 cm.-'), unconjugated ester (1736 cm.,-l), COO- (1615 cm.-l), I

and -N+-H (2200-2400 cm.-1). A microtest devised by Adams and I Gianturco (134) for distinguishing between amine salts and amino acids (zwitterionic) in this series showed that tetrahydrograntianine was an amino acid and therefore that hydrogenolysis had occurred at only one, the allylic, ester linkage of grantianine. The working hypothesis put forward for the structure of grantianic acid is CCXVIII (134). Only the 0 CH

-'ck I

CH

I

HOOC

&0

- II

CH,

I

C-C(OH)-COOH CH,

CCXVlll

evidence given here has been provided in support, along with assumptions as to the structural relation of this acid to others (e.g., trichodesmic acid) in the series. Thus, no certainty can be ascribed to this

SENECIO ALKALOIDS

95

formulation, which, for example, does not necessarily explain the presence of the 1717 cm.-l ester carbonyl band in the IR-spectrum of grantianine. h. Hastanecic Acid (149).This acid is known to have the composition CloHl,O,, but characterization has not proceeded beyond that previously reviewed (73). i. Integerrinecic Acid, CloH,,O,, has been related as a geometrical isomer of senecic acid by Kropman and Warren (207). Thus, the lactone formed from senecic acid on evaporation with hydrochloric acid, CloHl,O,, m.p. 156", [u], 36.5" (ethanol) (117, 135, 207) was shown to be identical with the lactone formed from integerrinecic acid. Moreover, this "senecic acid lactone" should be renamed "integerrinecic acid lactone" to indicate the related stereochemistry, since a cautious ring opening of the lactone produced integerrinecic acid, m.p. 150" (bis-pphenylphenacyl ester, m.p. 144-145'). Senecic acid and integerrinecic acid gave the same dihydro acid (bis-p-phenylphenacyl ester, m.p. 98") on catalytic hydrogenation, confirming that their isomeric relation involves the sole double bond. The gross structure and the geometry of integerrinecic acid are thus derivative of the assignments in senecic acid (CCXIX), which was the first of these two acids investigated by Kropman and Warren (209) (see Section k). These workers regarded senecic acid, less stable and of lower melting point, as having the ciscrotonic acid structure and integerrinecic acid, the trans-crotonic acid

CCXIX

ccxx

structure (CCXX). They bolstered their argument with UV-data, and similar data have been used by Leisegang (122) and by Adams and Van Duuren (93) to support the same geometrical assignments. The following UV-maxima have been reported: senecic acid: A$:H\ 215 mp, E = 6195 (93); A$.! 215 mp, E = 4140 (209) or 218.5 mp, E = 4950 (122); integerrinecic acid: Agi:H 214 mp, E = 9021 (93); .A$: 218 mp, E = 9333 (207) or 218 mp, E = 9250 (122). The spectra of the parent alkaloids show the same relation: rosmarinine (senecic is the necic acid): 218 mp, E = 6100 (122); senecionine (senecic is the necic 215 mp, E = 2100 ( 2 ) (93); integerrimine: 212 acid):=: \ :A mp, E = 10,900; 216 mp, E = 8000. Integerrinecic acid lactone has AE\$H 222 mp, E = 12,000.

A$s,

Azsx.

96

NELSON J. LEONARD

Cason and Kalm (186)have criticized the assignments of Kropman and Warren, Leisegang, and Adams and Van Duuren, on the basis that the a-substituent (considering CCXIX and CCXX as derivatives of crotonic acid) is a bulky group, larger than carboxyl, and therefore steric interference would be "greater in the trans isomer in which this bulky a-substituent is on the same side as the /3-methyl group." They go on to state that they would expect the cis-crotonic acid type to have an extinction coefficient higher than the trans-crotonic acid type. No UV-data are available to support the argument of Cason and Kalm; the a-substituent under present consideration may be complicated, but it is not more bulky than an isobutyl group. An isobutyl group provides hindrance intermediate between that of ethyl and isopropyl (210).A comparison between cis and trans orientations of methyl and isopropyl groups about a double bond and similar orientations of methyl groups (191)has already been mentioned in the section on trachelanthic acid. Infrared spectra do not provide convincing evidence for either argument (93, 137, 186). The geometrical assignments of the Warren and Adams groups accordingly remain acceptable for senecic acid as cis (CCXIX) and for integerrinecic acid as trans (CCXX), and for other pairs of related acids as given (see below). However, Adams andVan Duuren (93) point, out that the acid isolated by the hydrolysis of any of the alkaloids need not occur in the same stereochemical form in the alkaloid. It has been suggested by Kropman and Warren (207)that squalinecic acid (73) from squalidine may actually be a mixture (m.p. 128")of integerrinecic acid and its lactone, but this would require identity of integerrimine and squalidine, which has been refuted by Adams and Van Duuren (93)on the basis of differences in specific rotation and picrate melting points (224"and 203", respectively). Adams and Van Duuren (93)have made decisions as to the positions of stereochemical difference in various pairs of necic acids. It is not apparent, however, that threo or erythro relative configurations may be assigned at this time to the C, and C, carbons of integerrinecic acid, 2-hydroxy-3-methylhept-5-ene-2,5-dicarboxyli~ acid (CCXX). j. Platynecic Acid (146-148). This acid, C,,H,,O, m.p. 133-135", obtained by alkaline hydrolysis of platyphylline (A%:. 219 mp, E = 6350 (122) ) by Danilova and Konovalova (211),along with senecic (senecionic) acid, was convertible to integerrinecic acid lactone (see Section i), m.p. 155-156". It would appear that this acid, m.p. 133135",could be a mixture of integerrinecic acid (CCXX) and senecic acid (CCXIX) rather than a pure chemical individual. This would explain more satisfactorily than other suggestions (93)the finding that platynecic acid and senecic acid, after absorption of two atoms of hydrogen

97

SENECIO ALKALOIDS

catalytically, are convertible to the same saturated lactonic acid as obtained from integerrinecic acid lactone by catalytic hydrogenation (211).Certain of the facts presented by Danilova and Konovalova (211) are valid for corroborating the senecic or integerrinecic structure: production of acetaldehyde and oxalic acid on permanganate or nitric acid oxidation, along with two isomeric acids, CsHloOj,with no lactonizable hydroxyl. Nevertheless, their representation of these acids as diastereoisomeric 3-hydroxy-2-methylglutaric acids is erroneous; in the light of other experience (207, 209) with senecic acid, the compounds acids. Platynecic acid are more likely 2,3-dimethyl-2-hydroxysuccinic is probably senecic acid in the alkaloid platyphylline. k. Senecic Acid (146-148). Senecic acid, C1,,HL6O5,is 2-hydroxy-3methylhept-fi-ene-2,5-dicarboxylic acid (cis) (CCXIX), geometrically isomeric with integerrinecic acid and convertible to integerrinecic acid lactone, C,,H,,O,, m.p. 156O, on evaporation with hydrochloric acid. The researches of Kropman and Warren (207, 209) and Adams and Govindachari (135), adding to the facts gathered at the time of the earlier review (73), led to the establishment of structure CCXIX for senecic acid. The dihydroacid lactone was reported by Adams and Govindachari (135) as having m.p. 118-120", whereas the melting point reported by Danilova and Konovalova was 133-134". The gross structure of senecic acid was determined by Kropman and Warren (209). A Kuhn-Roth determination indicated at least three C-methyls (2.9 found). The conditions of lactone formation suggested that the hydroxyl was 6 to one carboxylic acid, and the yellow color with ferric chloride indicated that it was a to the other. Acetaldehyde was identified as one product of the ozonization of senecic acid in ethyl acetate, and the other product was not isolated but was oxidized further with lead tetraacetate in aqueous solution. Carbon dioxide was collected, a product to be expected from an a-hydroxy acid. The other lead tetraacetate product, an oil, gave reactions typical of a methyl ket,one: solid formed with sodium bisulfite, purple color with dinitrobenzoic acid. Oxidation

1

HOOC-CHj-CH-COOH

CCXXI

NoOSr

HOOC

7

H,

- CH2-CH-

t

PbCOAc),

I

1'0. CCXIX Q

COC H,

CCXXll

98

NELSON J. LEONARD

with sodium hypobromite yielded methylsuccinic acid (CCXXI) and bromoform. One reconstruction sequence of the precursors is pictured in the accompanying formulas, proceeding through i3-methyllevulinic acid (CCXXII). To decide between this series and the other possibility embracing a-methyllevulinic acid, dihydrosenecic acid was subjected to lead tetraacetate cleavage. Carbon dioxide was evolved, and the methyl ketonic acid which was the other product was converted through sodium hypobromite oxidation followed by imide formation to cis-aethyl-y-methylglutarimide, m.p. 118-1 19". Mixture with an authentic specimen of the (i)-imide, m.p. 109-113", of Rydon (212), showed an intermediate melting point. This sequence established the relative positions of the ethyl and methyl groups in dihydrosenecic acid (CCXI) by showing their relative positions in the substituted glutaric acid (CCIX). The structures in the senecic acid oxidation sequence are thus correct as indicated (CCXXII, CCXXIII), and the gross structure of senecic acid is CCXIX. The geometry at the double bond is postulated as that of a cis-crotonic acid (207), as described in Section i above. Another stereochemical feature of interest is the absolute configuration of one representative asymmetric carbon in senecic acid. To return to the oxidative degradation products of senecic acid, it will be seen that the configuration of the asymmetric carbon in methylsuccinic acid, if this acid is optically active and not racemic, is related directly to the configuration of this carbon in senecic acid. The stages in the conversion of CCXIX to CCXXI preclude inversion of configuration at C, (CCXIX), but they do not preclude racemization. Interest lies, then, in whether the degradation product, methylsuccinic acid, possesses optical activity and, if so, of what sign. Kropman and Warren (209) state the following concerning this product: ". . . m.p. 103", undepressed when mixed with an authentic specimen of ( )-methylsuccinic acid. The available quantity did not permit the measurement of the specific rotation. It is almost certainly dextrorotatory since the methylsuccinic acid, obtained from isatinecic acid which contains the same basic structure as senecic acid, gave a hydrogen strychnine salt, m.p. 186"." Warren in his review article (75) is more definite: "The orientation of the methyl group a t G 3 is defined by the isolation by Kropman and Warren of (+)-methylsuccinic acid on oxidative degradation of senecic acid and must be the same in all acids." On reflection, it must be recognized that the melting point of the monostrychnine salt is not too valuable a criterion of which enantiomorph of methylsuccinic acid is on hand, since Ladenberg (213) used strychnine to resolve ( f)-methylsuccinic acid and the m.p. 186"-salt was the less soluble. Kropman and Warren's experience with

+

99

SENECIO ALKALOIDS

both the (+)- and the inactive-methylsuccinic acid was that the melting points vary considerably, depending upon rate of crystallization. Recorded earlier was the finding of Berner and Leonardsen (214) that a mixture of pure (+)-acid (m.p. 115") with (&)-acid, which is about 62% (+) and 38% (&) (81% (+),19% (-) ), forms a eutectic, m.p. 103". If indeed the senecic acid degradation product is (+)-methylsuccinic acid, the present author would point out that the absolute configuration at C, in senecic acid has actually been determined, since the correlation of Fredga (215, 216), confirmed by Eisenbraun and McElvain (217), relates sign of rotation to configuration (218). Thus (+)-methylsuccinic acid is D (CCXXIV), and this representation may $OOH

tn2coon CCXXIV

p k CCXXIV'

be turned (CCXXIV') so that it is in the correct relation to be incorporated in the chains of the necic acids as they are bound in our representation of the diester alkaloids. The absolute configurations at C, in senecic acid and integerrinecic acid would then be represented in the projections CCXIX' and CCXX'.

CCXIX'

CCXX'

Adams and Govindachari ( 1 35) established that the alkaloid senecionine is a cyclic diester from one molecule of retronecine (CXLIV and one of senecic acid, each of the two hydroxyls in retronecine being involved in ester formation. Thus, senecionine, C,,H,,NO, (methiodide, m.p. 243-245O; picrate, m.p. 190-191"), absorbed 2 mole equivalents of hydrogen in the presence of Raney nickel, yielding tetrahydrosenecionine, C,,H,,NO,, m.p. 197". This compound possessed the properties of an amino acid, including low solubility in organic solvents and a carboxylate IR-band at 1600 cm.-l, and yielded on hydrolysis retronecanol (CXLVI) and senecic acid. Tetrahydrosenecionine was easily converted to a crystalline methyl ester, m.p. 113", with diazomethane. I n the presence of platinum, 3 mole equivalents of hydrogen were absorbed, the last slowly, corresponding to the hydrogenation of the hindered double bond. The resulting amino acid (vmax. 1601 cm.-l) was hydrolyzed

100

NELSON J. LEONARD

to retronecanol and dihydrosenecic acid. The orientation of esterification in senecionine, i.e., the carboxyl having the a-hydroxyl esterified with the allylic primary alcohol, rests upon analogy with other alkaloids in the series, wherein the carboxyl group likely to have the stronger ionization constant is esterified with the primary hydroxyl group (75). Senecionine has been made by Koekemoer and Warren (115) from another alkaloid, rosmarinine, which contains the same necic acid moiety. The mono-p-toluenesulfonate ester of rosmarinine, m.p. 120" (tosyl group on C, of rosmarinecine (CLV) ), was heated under reflux with pyridine, and authenticated senecionine was the product. 1. Trichodesmic Acid. Portions of this acid were obtained from the alkaline hydrolysis of trichodesmine, C15H2,N06,by Men'shikov and Rubinstein, as reviewed in Volume I of this series (73), namely, isobutyl methyl ketone, (*)-lactic acid, and carbon dioxide. Adams and Gianturco (142) established the structure of trichodesmic acid after preliminary hydrogenation of trichodesmine 1735 cm.-l, indicating normal ester C = 0) using palladium on strontium carbonate. Two mole equivalents of hydrogen were absorbed yielding tetrahydrotrichodesmine, C,,H,,NO,, m.p. 182', [u], -20.4' (ethanol). The IRspectrum of tetrahydrotrichodesmine showed the complete absence of an ester carbonyl and carbon-carbon double bonds, but the presence of

(vz!'

0

bands at 1615 cm.-l ((ko-), 2400 cm.-' (-&+-H),

I

and 1765 cm.-l

(y-lactone).The anion and cation portions of this salt are thus separate, in the sense that no ester linkage is retained-a fact which can be verified by using a sulfonic ion exchanger (74). A similar result was obtained in the hydrogenolysis of monocrotaline, when the primary reduction product was isolated and purified (73, 142): tetrahydromonocrotaline, C1,HZ7NO5, m.p. 156', [a], -36.5' (ethanol), the salt of retronecanol (CXLVI), and monocrotalic acid (CLXXII). Tetrahydrotrichodesmine was recognized as the salt of retronecanol and trichodesmic acid, C,,,H,,O,, m.p. 209-21 1' (142). A glycol structure was indicated in trichodesmine by the consumption of 1 mole of periodate, incidentally at about half the rate for monocrotaline. The suggestion of Adams and Gianturco (142) that the two tertiary hydroxyls are cis (erythro) with respect to the eleven-membered ring of monocrotaline and truns (threo) with respect to the diester ring of trichodesmine may be correct, but such a rate factor could equally well be the result of a more hindered cis-glycol structure in the latter. Trichodesmine and thionyl chloride gave a colorless crystalline product, m.p. 172",with the correct analysis, C,5H,8C1N0,S, for the hydrochloride of an acid sulfite ester of the alkaloid. Under similar conditions, monocrotaline yielded a neutral

101

SENECIO ALKALOIDS

cyclic sulfite (CLXXXIX) as the hydrochloride. The difference in the product of thionyl chloride with the two alkaloids, parallel to the difference in their rates of oxidation with periodate, has been used by Adams and Gianturco to support their postulate of trans geometry of the two hydroxyls in trichodesmine (142).The IR-spectra of trichodesmine and monocrotaline, of trichodesmic acid and monocrotalic acid, are strikingly similar, which in this author's opinion is suggestive of similar relative configurations at the hydroxy-substituted carbons in these two acids. The stereochemistry of trichodesmic acid merits further attention. The gross structure of trichodesmic acid is well conceived as CCXXV, 2,3-dihydroxy-2,3-dimethyl-4-isopropylglutaric acid, 2(y)-lactone (or, OH II

CH,-C

.I

CH,-CH-CH

I

CH,

21

:.

-C-COOH -C+

0

cVH' I 1 I CH,

HOOC -CH

-C(OH)

CH,

-CGW-

COOH

CCXXVI

CH,

ccxxv

alternatively named, 2,3-dihydr~xy-3,5-dimethylhexane-2,4-dicarboxylic acid, 2(y)-lactone), on the basis of its similarity to monocrotalic acid and the similarity of the alkaline degradation products of trichodesmine and monocrotaline. Under the Men'shikov and Rubinstein conditions, Adams and Gianturco found that monocrotaline yielded ethyl methyl ketone, a$-dimethyllevulinic acid, and carbon dioxide. As mentioned above, trichodesmine yielded isobutyl methyl ketone-hence the conception of CCXXV as a homolog of CLXXII. The precursor of trichodesmic acid, as diesterified in the alkaloid, would then be CCXXVI. The formation of trichodesmic acid is parallel to that of monocrotalic acid, namely, hydrogenolysis of the allylic ester linkage followed by y-lactonization between the 2-hydroxyl and the 5-carboxylate ester attached to the C, hydroxyl of the retronecine (CXLIV) moiety. Mechanisms have been suggested (142) which account satisfactorily for the alkaline hydrolysis products. rn. Usaramoensinecic A c i d , C,,H,,O,, is stereoisomeric with senecic (CCXIX') and integerrinecic acid (CCXX'), as shown by Adams and Van Duuren (93).These three necic acids, in diester combination with retronecine (CXLIV), constitute the respective alkaloids: usaramoensine, senecionine, and integerrimine. Usaramoensinecic acid was obtained by the aqueous barium hydroxide hydrolysis of usaramoensine (picrate, with analysis for methanol of crystallization, m.p. 235" (dec.) ). Vacuum sublimation of usaramoensinecic acid at 120" and 1 mm. or evaporation with hydrochloric acid gave a lactone, C,,H,,O,, m.p.

102

NELSON J. LEONARD

151", [ a ] , 51" (ethanol), said to be identical in melting point and rotation

with integerrinecic acid lactone, but actually these are the lowest melting point and highest rotation ever reported for the "pure" lactone (135). The physical properties do not exclude identification of the Adams and Van Duuren product as a mixture of lactones, epimeric at C,. The conclusion of Adams and his co-workers (93, 137) was that integerrimine and usaramoensine have the same configuration about the carboncarbon double bond, probably trans, as in integerrinecic acid, and that they differ only in the configuration of asymmetric C,, being identical in configuration a t C,. The carbon-carbon stretching band in the IRspectra of integerrimine and usaramoensine, as determined in chloroform solution, appeared at 1665 cm.-l, whereas it was found at 1645 cm.-l for senecionine (137). The UV-extinction for the 200-215 mp region was reported to be similar for integerrimine and usaramoensine, but the extinction coefficient values for integerrinecic acid and usaramoensinecic acid (Xti'H 215 mp, E = 6000) were of a different order. This leaves open the questions of whether isomerization from trans- to cis-crotonic acid type is occurring as usaramoensine is hydrolyzed by aqueous alkali to usaramoensinecic acid (93, 137, 186) or whether cisto trans-isomerization is occurring as integerrimine is hydrolyzed by ethanolic alkali to integerrinecic acid, or whether geometrical configurations are retained in both cases. The data offered are not internally consistent, and the reviewer feels that it has not been decided whether the free acid, usaramoensinecic acid, is the C, epimer of senecic (CCXIX') or of integerrinecic acid (CCXX'). n. Lsatinecic Acid (149). This acid, C,,H,,O,, has been obtained by aqueous barium- or sodium-hydroxide hydrolysis of retrorsine and retrorsine N-oxide (isatidine) (95,117,120,121,219). The establishment of the structures of this acid and its stereoisomer, retronecic acid, is the result of a very effective investigation by Warren and his co-workers. Evaporation of isatinecic acid with anhydrous oxalic acid yielded retronecic acid lactone, CIOHIPOS, m.p. 185-186" (73, 95), the product of evaporation of retronecic acid with hydrochloric acid. Ozonization of either acid produced acetaldehyde. Hydrogenation of either acid produced the same dihydro acid (m.p. of bis-p-phenylphenacyl ester of dihydroisatinecic acid, 117-1 18"; of dihydroretronecic acid, 118-120'). The acids were thus shown to contain ethylidene groups and to be geometrical isomers about this double bond, with isatinecic acid less stable than its isomer, retronecic acid. Configurations were assigned on the basis of the facts given above plus interpretation of the UVspectra in terms of the higher maximum (E) in the 210-220 mp region representing the a-substituted trans-crotonic acid type. The subject of

103

SENECIO ALKALOIDS

assignments on the basis of thermodynamic stability and UV-absorption spectra has been treated more fully in Section i. The same conclusion is reached here: the Warren assignments are probably correct. Thus, 218 mp, E = 4720 (95); also reported, 218.5 mp, isatinecic acid [A%;. E = 5450 (122)]was assigned the &-configuration (just as senecic acid, CCXIX), and retronecic acid [A%:. 218 mp, E = 9400 (122, 195)], the trans-configuration (just as integerrinecic acid CCXX). The parent alkaloid, retrorsine, was considered to have cis-crotonic ester geometry (95)[A%;. 217.5 mp, E = 7100 (122)l. The glycol moiety in isatinecic acid was established by reaction with lead tetraacetate to produce formaldehyde and carbon dioxide, indicative of an a,fi-glycolic acid (219). The presence of the a-hydroxylic function was confirmed by the yellow color with ferric chloride and by production of 0.75 mole equivalent of carbon monoxide on treatment with concentrated sulfuric acid. Isatinecic acid furnished, as the other oxidation product, cis-2-ethylidene-4-methylglutaric acid (CCXXVIII), C8Hl,0,, m.p. 95". Oxidation of the isomeric retronecic acid with lead tetraacetate produced trans-2-ethylidene-4-methylglutaricacid (CCXXVIIIa), m.p. 151", which gave the trans-imide (CCXXIX), C8Hl,N0,, m.p. 90". The 2-ethylidene-4-methylglutaric acid from isatinecic acid was converted t o the same imide. Hydrolysis of the imide

ccxxx

CCXXVll

I

1 PbCOAcL H I

/c\c/cT /ens

H/cNc/ctc/cnl

CH

CH,

HOO!.

PbCOA:).

q

I

HOOC

O ,H !

I

COOH

CCXXVllla

CCXXVlll

".-' o H

CClX

CCXXIX

gave the 2-ethylidene-4-methylglutaricacid of m.p. 151". There is no doubt that the trans-a-ethylidene-a'-methylglutarimide(CCXXIX) is the more stable of two possible geometrical isomers and, since a single imide was isolated from two geometrically isomeric sources, that the imide of m.p. 90" is the "trans-crotonimide" type. The reconversion of

104

NELSON J. LEONARD

the imide by hydrolysis to the substituted glutaric acid of m.p. 151" is consistent with the description of this as the trans acid. Since retronecic acid is its precursor in a reaction which did not isomerize the double bond, retronecic acid is in the trans-crotonic acid series (CCXXVIIIa). The argument of Christie et al. (219) continued logically that the substituted glutaric acid of m.p. 95", since it underwent isomerization on imide formation (i.e., was not returned on hydrolysis of the imide), is in the cis-crotonic acid series (CCXXVIII), as is its precursor, isatinecic acid. The trans-2-ethylidene-4-methylglutaric acid was hydrogenated to 2-ethyl-4-methylglutaric acid (CCIX), which in turn was obtained directly by treatment of both dihydroretronecic acid and dihydroisatinecic acid with lead tetraacetate, and was characterized by conversion to cis-a-ethyl-a'-methylglutarimide,m.p. 120-121" (212). Hydrolysis of the saturated imide with concentrated hydrochloric acid acid, m.p. 72-73'. furnished "cis"-2-etl~yl-4-methylglutaric Further oxidation studies helped to establish the structures of isatinecic and retronecic acids. Thus, ozonolysis of either acid, followed by treatment with lead tetraacetate, furnished 2 mole equivalents of carbon dioxide, one of formaldehyde, and methylsuccinic acid. The products of the second oxidation stage are explicable in terms of the keto acid intermediate which would result from ozonolysis of either CCXXVII or CCXXX. The methyl-substituted carbon of methylsuccinic acid is asymmetric C, in the original acids and its configuration may have withstood the oxidative degradations. The rotation of the isolated methylsuccinic acid would be indicative of absolute configuration at this carbon, as discussed in Section k relating to senecic acid. Christie et al. (219) have provided no convincing evidence that the methylsuccinic acid they obtained from the two acids was the (+)-acid. The melting point of 109-110" was given for the methylsuccinic acid from retronecic acid, 98" for that from isatinecic acid. The fact that the derived hydrogen strychnine methylsuccinate melted at 185" may indicate only that a Ladenberg (213) resolution of the racemic acid was being accomplished. If further evidence appears which indicates that the oxidation product is actually (+)-methylsuccinic acid, the absolute configuration at C, in isatinecic and retronecic acids will conform to that pictured for senecic (CCXIX') and integerrinecic (CCXX') acids. Osmium tetroxide converted isatinecic acid Do a compound corresponding to dihydroxydihydroisatinecic acid, Cl0Hl8O8,m.p. 245O, which did not lactonize. Dihydroxylation at C, and C, in CCXXVII would account for such an acid; if the C, and C, substituents were exchanged in the structure of the original, the new dihydroxylated acid would have been capable of lactonization.

105

SENECIO ALKALOIDS

The compound obtained by de Waal(73, p. 154)following absorption by isatidine (retrorsine N-oxide) of 4 mole equivalents of hydrogen in the presence of platinum was recognized by Leisegang and Warren (123) as retronecanol (or -yl) dihydroisatinecate (CCXXXII). The

& Pt

A CCXXXI

I

n

.

CCXXXll

Dthydroiratinecic acid

orientation of the ester linkages in isatidine (CCXXXI) and therefore retrorsine was indicated by the lead tetraacetate products from retronecanol dihydroisatinecate. The evolution of carbon dioxide indicated that hydrogenolysis had occurred at the carboxyl esterified with the allylic hydroxyl of the retronecine moiety and that the glycol grouping was u,/3 to this carboxyl. By analogy, Leisegang and Warren (123)argued that similar ester orientation would be found in the alkaloids senecionine, integerrimine, platyphylline, and rosmarinine. On the basis of the structure-proof described in this section, isatinecic acid is 1,2-dihydroxy-3-methylhept-5-ene-2,5-dicarboxylic acid (cis) (CCXXVII) and retronecic acid is similar in all respects except in the geometry of the double bond ( t r a n s ) (CCXXX). 0. Jaconecic Acid* (149).Jaconecic acid, C1,,HI4O6, has been obtained by the alkaline hydrolysis of otosenine (73),jacobine, jaconine (220, 221), and tomentosine (140). It is dibasic (dimethyl ester, 1739 cm.-l, b.p. 120-124" (0.7mm.), [ u ] ~28" (ethanol); monoethyl ester, b.p. 142-143" (0.7mm.), [u], 34" (ethanol) (102)) and contains a hydroxyl group (acetyljaconecic acid, m.p. 195-196", [a], 9.1" (ethanol) (102)). The yellow color with ferric chloride was suggestive of hydroxyl u to carboxyl, confirmed by lead tetraacetate oxidation which furnished 1 mole equivalent of carbon dioxide (140,220). A negative reaction with periodate established the absence of a glycol structure, and the acid absorbed no hydrogen in the presence of either platinum oxide or Raney nickel. The IR-spectrum indicated the absence of C = 0 and C = C, but confirmed the presence of the carboxyl and hydroxyl. groups. Bradbury (220)accepts the presence of bands at 878,1153,1213, and 1266 cm.-l, which do not all appear in the spectra of other necic

YE:',

*

See also Addendum, p. 121.

106

NELSON J. LEONARD

acids (140), as indicative of the presence in the molecule of an epoxide grouping. Structures postulated thus far are based upon this assignment. Nevertheless, it must be recognized that this hypothesis is not supported by the facts that jaconecic acid is unchanged on refluxing with 15% hydrochloric acid, that hydrogen and a catalyst do not affect the molecule, and that the spectra of the mono- and diesters provide no strong support for the presence of the epoxide (102). The author therefore considers that postulates (102, 140) based upon the epoxide structure are premature, and only the positive information will be provided in this review. Readers are referred to the original papers of Bradbury (102, 220, 221) and Adams et ul. (74, 140) for more complete expositions supporting their representations (CCXXXIII and CCXXXIV, respectively) of jaconecic acid.

/”\

CH,-CH-C-C-CH-CH,OH HOO!

!H,

:H)

I

COOH

CCXXXlll

4HI

/O\ C,H,-CH-CH-C HOOC

-C-OH

I

I

CCXXXlV

Both laboratories agreed that three C-methyl groups are present in jaconecic acid. Bradbury (221) indicated that u,p-dimethylmalic acid was one of the nitric acid oxidation products of jaconecic acid, with its characterization depending upon isolation of dimethylmaleic anhydride. Bradbury and Willis (102) investigated a “tetrahydroxy reduction product,” C,,H,,O, (not analyzed), [u], 23.1’, which resulted from the lithium aluminum hydride reduction of dimethyl j aconecate. This compound formed a triacetate, C,,H2,0,, [u], 11.2’ (ethanol), which like its C,,H,,O, parent exhibited a C = C stretching band in the infrared. A tri-p-nitrobenzoate, C,lH,,N3013, m.p. 164O, was also obtained. Unlike jaconecic acid, the tetrahydroxy reduction product consumed 1 mole equivalent of periodate, with the production of formaldehyde. Formaldehyde was also obtained by lead tetraacetate oxidation. The crude reduction product thus contained an a-glycol grouping not present in jaconecic acid. The double bond was regarded as being formed by dehydrat,ion of a pentahydroxy intermediate formed by reduction and opening of an oxygen-containing ring (102). The relationship of the alkaloids jacobine and jaconine is important in further consideration of the chemistry of jaconecic acid. These alkaloids differ only by a molecule of HC1, and this is readily added or withdrawn with the interconversion of jacobine and jaconine. Treatment of jacobine with 1 mole equivalent of hydrochloric acid (0.1 N ) gave jaoobine hydrochloride, C,,H,,ClNO,, m.p. 220’, [u], -14.7’

SENECIO ALKALOIDS

107

alkali

(water). Further treatment with hydrochloric acid in hot ethanol solution gave jaconine hydrochloride, C,,H,,C1,N07, m.p. 204-205", [u], 12.4" (water), from which jaconine was recoverable by ammonia treatment. Hydrolysis of either alkaloid by prolonged refluxing with 15% hydrochloric acid yielded C10H13C104,m.p. 113", [u], -26" (chloroform), probably identical with the hydrolysis product of otosenine (73) and tomentosine (140). This compound, which is neutral and behaves like a lactone on titration, still contains three C-methyl groups and reverts to jaconecic acid on warming with excess alkali (220). The compound C,H,,C10, absorbed no hydrogen over platinum oxide, was found to contain no active hydrogen, and gave no selective UV-absorption. The IR-spectrum indicated no hydroxyl and no free acid C = 0 bands, while the C = 0 maximum at 1770 cm.-l (Nujol) or 1781 cm.-l (chloroform) was attributed to a y-lactone-actually, then, to a dilactone having two five-membered rings (140, 220). Further study of the alkaline hydrolysis of the Cl,Hl,C1O, compound indicated the formation, along with jaconecic acid, of iso-jaconecic acid, C,,H,,O,, m.p. 1131718, 1750 (?), 1773 cm.-1; bis-p-phenyl114", [u], 75" (ethanol) (u:::'~ phenacyl ester, m.p. 154-155"; a dibasic acid which gave a faint color with ferric chloride) and an oil, C,,H,,O,, [u], -10" (water), Rf 0.79, referred to as jaconecic monolactone (v:::'~ 1751 cm.-l). Hydrogenolysis of jacobine with 2 mole equivalents of hydrogen and a platinum catalyst yielded C,,H,,NO,, m.p. 212", an internal salt monoester, i.e., retronecanol jaconecate, which on hydrolysis with barium hydroxide gave retronecanol (CXLVI) and jaconecic acid. Tomentosine, on hydrogenation with palladium on strontium carbonate, absorbed 2 mole equivalents of hydrogen to produce tetrahydrotomentosine, ClBH3,NO7,m.p. 157-158", [u], -9.2" (chloroform) (140). The following selected IR-maxima have been reported for tetrahydrotomentosine: u ~ 3300-3100, ~ ~ ' 1745, 1705, 1616, and 875, 1155, 1210, and 1270 cm.-l; vE::'~ 3500-3000, 2400, 1740, 1705, 1608, 1400, and 1360 cm.-l (140). The action of hydrochloric acid on tomentosine produced a compound, Cl,H,,C1O,, with the same chemical properties and absorption spectrum as those found by Bradbury for the chloro compound from jacobine. Bradbury and Willis (102) state that "it is possible that jacoline and jaconine are the glycol and chlorohydrin, respectively, of

108

NELSON J. LEONARD

the epoxide jacobine." Hydrolysis of the alkaloid jacoline furnished an oily mixture of acids from which, on treatment with acetyl chloride, was obtained a compound referred to as jacolinecic dilactone acetate, ClZH1606, [ a ] , 16.5' (chloroform). From this was obtained by the sequence: 0.1 N sodium hydroxide at loo", concentrated hydrochloric acid, and ether extraction, a compound named jacolinecic monolactone, CloH1405, m.p. 47O,[u], -21.7" (water). The interrelations of these acid products and the structure of jaconecic acid have yet to be ascertained. p . Junceic Acid, ClOHl6O6, was obtained by Adams and Gianturco (104)by hydrogenation of the alkaloid junceine to tetrahydrojunceine, C1,H3,NO,, [u], -4.7" (ethanol) (~22~ 3220, 3340, 2300-2600, 1765, 1615 cm.-l), a salt of retronecanol, and the monobasic monolactonic 3340, 3480, 1710, 1725, 1740 cm.-l; v:: acid, junceic acid 1780 cm.-l). A close relation of junceic acid to trichodesmic and monocrotalic acids was thus indicated (104).Junceine was oxidized readily by periodic acid. One mole equivalent of the oxidant was consumed in 2 minutes and a total of 2 mole equivalents in 20 minutes, but no more reagent was used during a period of 3 hours. On the basis of the behavior of other alkaloids of known structure toward periodic acid, junceine was judged to have three hydroxyls on adjacent carbons, one of which was primary. By distilling the oxidized reaction mixture, formaldehyde was obtained, thus definitely establishing the presence of CH,OH adjacent to a potential hydroxyl function. Treatment of junceine with aqueous sodium hydroxide yielded isobutyl methyl ketone, indicating the close similarity of this alkaloid with trichodesmine, with which it is found in Crotalariajuncea (103,142).The structure of junceic acid (CCXXXV)which meets all the requirements is patterned after the structure of trichodesmic acid (CCXXV),and the chemical name, as a

(~22'

OH CH,-k-'C

I

.I

CYOH

I

\ --COOH

P

CH,

ccxxxv

substituted glutaric acid, would be 2,3-dihydroxy-2-hydroxymethyl-4isopropyl-3-methylglutaric acid, 2(y)-lactone. Trichodesmine and junceine are thus another pair of alkaloids differing from each other only y 3 3

by the two groups, -F-COOR OH

p o H

F

and - -COOR, OH

and showing the

SENECIO ALKALOIDS

109

same relationship as senecionine and retrorsine, seneciphylline and riddelliine. See Section n for an exposition of the formation of a lactonic acid of the trichodesmic, junceic acid type from the cyclic diester parent alkaloid. q. Retronecic Acid (149).This acid, C,,H,,O,, has been obtained along with its geometrical isomer, isatinecic acid, in the hydrolysis of retrorsine and its N-oxide with alcoholic sodium or potassium hydroxide. The necic acid is probably in the isomeric form (cis) in the parent alkaloid. Retronecic acid has the trans-crotonic acid arrangement about the 5,g-double bond in 1,2-dihydroxy-3-methylhept-5-ene-2,5-dicarboxylic acid (CCXXX). r. Miscellaneous Acids. The necic acid moiety of jacoline would appear to be a ClOH,,O, compound. Some of the conversion products have been noted in Section 0. Sceleratinic acid (sceleratinic dilactone), C,oH,,C1O,, has been discussed in Section c. The C,H,,NO, compound, not a necic acid, isolated from Crotalaria jzcncea, was identified as 8-hydroxy-DLnorvaline A by Adams and Gianturco (103). Other of the necic acids have not been sufficiently characterized to merit discussion.

V. Structure of the Alkaloids With a knowledge of the structures of the necines and necic acids and with the location of ester linkages ascertained, it is possible to write structural formulas to represent the pyrrolizidine alkaloids. Configurations (absolute and relative) at asymmetric carbons and double bonds are indicated when the author feels that these have been established with a reasonable degree of certainty. Structures have not been provided where the information is deemed insufficient, so that not all of the alkaloids listed in Table 1 will be given representations. The alkaloids are divided into three main categories: monoesters, diesters (two different necic acids), and cyclic diesters. The amine N-oxides are not given since their structures are obvious from the amines. 1. MONOESTERSOF NECINEAND MONOCARBOXYLIC ACID a. Echinatine (heliotridine and viridifloric acid).

0

II

OH OH

I

CH,

CCXXXVI

I

CH,

110

NELSON J. LE0NAR.D

b. Europine (heliotridine and lasiocarpic acid). 0 I1

CH,

CH,

CCXXXVll

c. Heleurine (supinidine and heliotrinic acid).

&

0

CH H

II

C%O- C

-C-I

I

CH,

-

C CH, OCH. I

C C = N < , also pointing to structure CCII (70).

H

Two new syntheses of myosmine have been described. The first started with l-(3-pyridyl)-3-dimethylaminopropanone-l hydrochloride which was condensed with excess nitromethane in the presence of sodium methoxide. The resulting 1-(3-pyridyl)-4-nitrobutanone-lon hydrogenation in the presence of Raney nickel gave an SO-SO% yield of myosmine (71). The second synthesis involved the condensation of potassium methyl nicotinylacetate with N - (2-bromoethyl)-phthalimide in boiling dimethylformamide solution followed by hydrolysis of the product (methyl-a-(2-phthalimidoethyl)-nicotinylacetate) with hydrochloric acid to myosmine (71). 6. NICOTELLINE Nicotelline, a solid base, m.p. 147-148’, was isolated a long time ago by Pictet and Rotschy (72a), who assigned to it the empirical formula C,,H,N,. It was later obtained again by Noga (72b), who described its picrate, m.p. 219”. Recently, Kuffner and Kaiser (73a), who had obtained Noga’s picrate, found that the analytical figures agreed better with the formula Cl,HllN3.2C,H,0,N3 and, therefore, corrected the formula of nicotelline to Cl,HllN3. Kuffner and Fader1 (73b) oxidized nicotelline and obtained nicotinic acid and pyridine-2,4-dicarboxylic acid, and concluded that the base must be 3,2’:4’,3”-terpyridyl (CCVI).

I

CH

+

CH6

I

CH.t-9

I

co

qco N

H

Q

C1Q

~

CClll

CCIV

ccv

CCVI

Nicotelline has since been synthesized by Thesing and Muller (73c), who condensed 3-acetylpyridine with nicotinic aldehyde and treated the resultant 3-pyridylethylidine-3-pyridylketone(CCIII) with N (aminoformylmethy1)-pyridiniumchloride (CCIV), thus obtaining the disubstituted pyrid-2-one (CCV). This pyridone when treated with phosphorus oxychloride and hydrogenated over Raney nickel gave CCVI, which was identical in every respect with nicotelline.

THE PYRIDINE ALKALOIDS

133

IX. Alkaloids of Withania somnifera Dun. The occurrence of nicotine in Witltania somnifera Dun. has been recorded (74). A number of other alkaloids were also isolated from the same plant as follows: somniferine, m.p. 185-187" (dec.), somniferinine, m.p. 120' (after decomposing 87-lOO'), somnine, m.p. 300°, withanine, m.p. 87-88' (dec.) (chloroaurate, m.p. 170-175'), withananine, m.p. 75-80' (picrate, m.p. 176-178"; chloroaurate, m.p. 115-119'), and pseudowithanine, m.p. 155-156' (dec.). Withanine is a chloroform addition compound, C,,H,,Ol,N,.CHC1,. When distilled with soda-lime i t yielded pyrrole and myosmine (?) (74). X. Gentianine Gentianine (Cl,HgO,N), m.p. 79-80', occurs in Gentiana kirilowi (75) and in the root of Dipsachus azureus Schrenk (76a). It forms salts such as the hydrochloride, m.p. 171-172', the nitrate, m.p. 238-240", the oxalate, m.p. 152-153", and the methiodide, m.p. 190-191". On catalytic hydrogenation it forms a dihydro derivative, m.p. 74-75', and on oxidation with potassium permanganate in acetone, gives rise to an acid lactone, CgH,O,N, m.p. 262-264' (76a), which on further oxidation with aqueous permanganate gives pyridine-3,4,5-tricarboxylicacid ( 75). More recently gentianine has been obtained from Enicostemma littorale Bl., and its further chemical examination has led to a synthesis (76b). The absence of a C-methyl led to a revision of the formula of the Russian authors to CCVII, and this formula was confirmed by a synthesis from 4-methyl-5-vinylnicotinic acid which readily condensed with formaldehyde to yield a base identical with gentianine.

CCVll

XI. The Pinus Alkaloids In a survey of a number of species of the genus Pinus for alkaloids it was discovered that three species, i.e., P . sabiniana Dougl., P . jeffreyi Balfour, and P . torreyana Parry contained appreciable quantities of an alkaloid that was named pinidine. These three species differed from others in not containing any bicyclic terpenes. P. sabiniana, which was chosen for a detailed study, was found to contain as well as pinidine a low-boiling alkaloid identified as (+)-a-pipecoline (77).

134

LEO MaRION

1. PINIDINE The main alkaloid, pinidine (C,H,,N), was separated from a-pipecoline by fractional distillation. It consists of a colorless oil, b.p. 176-177'/751 mm., n : ' . 1.4622, [u]:;, -23.4", [a]:&- 10.5 in absolute ethanol. It forms a hydrochloride, m.p. 244-246', and on treatment with methyl iodide gives an N-methyl hydriodide, m.p. 214-218". The base is therefore secondary, and this is confirmed by the presence of an NH band in its infrared spectrum. On catalytic hydrogenation, it absorbs 1 mole of hydrogen giving rise to dihydropinidine (C,H,,N, n:'" 1.4460, [a]:;,- 1.2" in absolute ethanol) which forms a hydrochloride, m.p. 244-246' depressed to 237-243" in admixture with pinidine hydrochloride. Ozonolysis of pinidine gives rise to acetaldehyde, thus indicating the presence in the alkaloid of the group CH,CH=C. The base also contains two C-CH, groups (77). Vapor-phase dehydrogenation of pinidine at 400-500" in the presence of palladium-charcoal gave an oil, C,H,,N, that formed a chlorplatinate (C,H,,N),.H,PtCl,, m.p. 193-195". By its infrared and ultraviolet spectra this oil was recognized as a pyridine derivative, and on oxidation it produced pyridine-2,6-dicarboxylicacid. All the evidence indicates that pinidine is probably one of the stereoisomers of 2-methyl-6-(2propeny1)-piperidineand, therefore, that the dehydrogenation product is 2-methyl-6-propylpyridine, and the latter was confirmed by synthesis. Catalytic hydrogenation of synthetic 2-methyl-6-propylpyridinegave a product assumed to be dl-cis-2-methyl-6-propylpiperidine, and its infrared absorption spectrum was identical with that of dihydropinidine. The most probable structure of pinidine, therefore, is that of ( -)-cis-2-methyl-6-(2-propenyl)-piperidine (78).

XII. Alkaloids of Tripterygium wilfordii Hook The alkaloid wilfordine isolated from the roots of Tripterygium wilfordii Hook (79)has been shown by countercurrent distribution to consist of a mixture (80)from which four ester alkaloids have been obtained by partition chromatography. These are wilforine, wilfordine, wilforgine, and wilfortrine (81,82). Upon saponification wilforine and wilfordine yielded 1 mole of benzoic acid, 5 moles of acetic acid, and 2 moles of acid nonvolatile in steam per mole of alkaloid. Wilforgine and wilfortrine yielded 1 mole of 3-furoic acid, 5 moles of acetic acid, and 2 moles of acid nonvolatile in steam per mole of alkaloid. I n addition the saponification of wilforine yielded a steam nonvolatile nitrogenous dibasic acid of molecular formula CI1H,,O,N, m.p. 195-196". From wilforgine, an identical acid was obtained.

135


A different nitrogenous dibasic acid, CllH1305N, m.p. 178-179" was obtained from both wilfordine and wilfortrine. The solutions remaining after removal of the acids in all four cases were evaporated and the residues extracted with hot methanol. Each of the extracts yielded the same polyhydroxy crystalline substance, Cl,H,,Ol,. This substance has no definite melting point but darkens when slowly heated to 240°, and it shows no absorption in the ultraviolet. Both dibasic nitrogenous acids when oxidized with alkaline potassium permanganate gave quinolinic, oxalic, and acetic acids, thus accounting for all the eleven carbon atoms. Since the acids do not give the test characteristic of a carboxyl group ortho to a pyridine nitrogen, only three possible formulas exist for the dibasic acid of wilforine (or wilforgine), and of these CCVIII is preferred (82).

acooH 7

CHiCH.CH.COOH

CCVIII. X= H CCIX. X=OH

I

CH,

CCIX

The dibasic acid of wilforine has an ultraviolet spectrum almost identical with that of the dibasic acid obtained from wilfordine, and in fact the latter appears to be the hydroxy derivative of the former. The infrared absorption spectra of wilfordine and wilfortrine show peaks in the hydroxyl region (3534 cm.-l) that are absent in the spectra of wilforine and wilforgine. The dibasic acid of wilfordine gives a positive test for an a-hydroxy acid, whereas the dibasic acid of wilforine does not. The hydroxy acid is, therefore, thought to have structure CCIX. Since wilforine, wilfordine, wilforgine, and wilfortrine contain 2, 3, 2, and 3 active hydrogens, respectively, the polyhydroxy nucleus Cl,H,,Ol, must contain 8 esterified hydroxyls and 2 free hydroxyls. The results obtained so far may be summarized by the following fragmentary representations of the alkaloids: Wilforine (C,,H,,O,,N): C,,H1,(0H),,+5CH,C00H+C,H5.C00H+

ClIH130,N -8HzO

+

Wilforgine (C,lH,,Ol,N) : C, ,HI,( OH),,+ 5CH3COOH C4H30.COOH

+

C11H1304N--sH20

Wilfordine (C,,H4,Ol9N): Cl,Hl,(OH),,+5CH,COOH+C,H,.COOH +C11H1305N

W7ilfortrine(C,,H,,O,,N)

-8HSo

: C,,H1,(OH),,+5CH3COOH+C,H3O.COOH t c l lH130ciN

-8HZo

136

LEO MARION

XIII. The Alkaloids of Sedum spp. Two species of Sedum have been examined for alkaloids, i.e., Sedum acre L. and Sedum sarmentosum Bunge. The first yielded the alkaloids sedamine (83) and sedridine (84, 85), whereas the other contained N-methyl isopelletierine and its dihydro derivative (86). 1. SEDAMINE This alkaloid is a crystalline solid, m.p. 89', [a],-56.75' (ethanol) that was first assigned the empirical formula C,,H,,O,N (83), which was later corrected to C,,H,,ON (87). It forms a hydrochloride, m.p. 205'. The infrared absorption spectrum of the base and that of one of the forms of the diastereoisomer of l-methyl-2-(/3-hydroxy-/3-phenylethy1)-piperidine, prepared from phenyl-(a-pyridy1)-acetylene,were identical (88). Another synthesis was reported which consisted in the reduction of the condensation product of a-picoline methiodide with benzaldehyde (89).The substance obtained, however, has a considerably lower melting point than dl-sedamine, and is probably a mixture of the two diastereoisomeric forms. Schopf (90) has reported that the condensation product of A'-piperideine with benzoylacetic acid, after N-methylation and resolution, gives rise to sedamine identical with the naturally occurring base. Another path of synthesis consists in condensing N-methyl-apiperidol with benzoylacetic acid at pH 5 . A 50% yield is thus obtained which is dehydrosedamine (91). of a-phenacyl-N-methylpiperidine A further synthesis was described (92) in which a-picolyl lithium is treated with benzaldehyde, and the resulting phenyl (a-picoly1)carbinol is converted to dl-sedamine by N-methylation followed by catalytic hydrogenation. From the mother liquors of the crystallization of dl-sedamine, the other diastereoisomer was obtained. It melts at 68-69" and has been named dl-isosedamine. 2. SEDRIDINE Whereas sedamine was the only base isolated from S. acre collected in Canada, the plant of European origin has yielded a new base named sedridine (84, 85). Sedridine (C,H,,ON), m.p. 72-73', [.It3+ 17.1'. It was found to occur together with (A)-sedridine, and the bases were separated by fractional crystallization of the phenylisothiocyanates, the dextro base derivative, C,,H,,ON,S, having m.p. 118-1 19'. From its analytical figures the base was assumed to be 1-(2-piperidyl)-2-propanol. This was synthesized by the reduction of 1-(2-pyridyl)-2-propanol. The reaction product was a mixture of the two diastereoisomeric racemates


137

which were separated by crystallization from petroleum ether. The crystalline racemate, m.p. 75", had an infrared absorption spectrum identical with that of sedridine. Hence, sedridine is the dextro enan(84, tiomorph of the racemate, m.p. 75", of 1-(2-piperidy1)-2-propanol 85). 3. N-METHYLDIHYDROISOPELLETIERINE S. sarmentosum contains two liquid alkaloids which are separated by fractional crystallization of the picrates. The least soluble picrate (C,,H,,O,N,), m.p. 159", proved to be identical with the picrate of synthetic dl-methylisopelletierine (86). The more soluble picrate (C,,H,,O,N,), m.p. 125", is that of an optically active base CsHlsON, [a], 25.0 (abs. ethanol). On the assumption that this new base was the dihydro derivative of N-methyl-isopelletierine (N-methyl-l-(2-piperidyl)-2-propanol), dl-methylisopelletierine was reduced with lithium aluminum hydride and the product converted to the picrate. The two diastereoisomeric forms separated into an oily picrate and a crystalline picrate, m.p. 126" (86). The base recovered from this picrate could not be resolved (93).

XIV. Ammodendrine* Isoammodendrine, an isomer of ammodendrine, has been found to occur in Ammodendron conollyi Bge., as well as ammodendrine, d-sparteine, anagyrine, and conolline (94). Isoammodendrine, C,,H2,0N2, m.p. 43-46", [a], 15.9" (ethanol) forms a hydrochloride, m.p. 193-194", [a], -27.4" (water), a hydriodide, m.p. 218-219", and a perchlorate, m.p. 202-203'. On hydrolysis it yields acetic acid. Conolline, Cl,H,,ON,, m.p. 192.5-193.5", forms a hydrochloride, m.p. 180-182O, a hydriodide, m.p. 195-196", and a perchlorate, m.p. 197198" (94). Catalytic hydrogenation converts isoammodendrine to a dihydro derivative, b.p. 175-185"/&9 mm., [a], 4". Dihydroisoammodendrine when saponified with methanolic potassium hydroxide produces dipiperidyl, which forms a dibenzoyl derivative, m.p. 151", [a], 181" (ethanol). Oxidation of the dipiperidyl with silver acetate gave rise to ag'-dipyridyl. Isoammodendrine warmed with benzyl chloride in benzene produced an oily benzyl derivative, the hydrochloride of which melted at 178-1 79". Hence, isoammodendrine has the same dipiperidyl-type skeleton as ammodendrine, with an acetyl group on one of its two nitrogen atoms (95). Ammodendrine has now been synthesized, and this synthesis has

* This material is supplementary to Volume I, page 256.

138

LEO MARION

made it possible to locate the double bond in the molecule. So far it had been identified only as a monoacetyl compound of tetrahydroanabasine. Acetylation of isotripiperideine (CCX) in an indifferent solvent with ketene gives an oily monoacetyl compound that is decomposed by

hydriodic acid to A'-piperideine and the monoacetyl derivative of the enamine form of tetrahydroanabasine (CCXI). The hydriodide (m.p. 221-222') is identical with ammodendrine hydriodide and the free base (m.p. 73-74') is identical with the alkaloid (96).

XV. Alkaloids of Adenocarpus spp. Various species of the genus Adenocarpus have been found to contain not only alkaloids belonging to the sparteine group but also others that are related to ammodendrine. Adenocarpus complicatus J. Gay contains d-adenocarpine, santiaguine (97), and iso-orensine (98). d-Adenocarpine also occurs in A . viscosus L. (99), in which it had previously been recorded as teidine (100). A . commutatus Juss. contains santiaguine, Z-adenocarpine, and orensiiie (101). The alkaloid decorticasine has been isolated from A. decorticans Bois (102), from A. argyrophyllus Rivas Goday (103) and from A. hispanicus D.C. (104). 1. ADENOCARPINE d-Adenocarpine (C,,H,,ON,), m.p. 65-66", [u]:'

+

30.9" (ethanol), is a monoacidic base from which a number of salts have been described such as the colored hydrochloride which when anhydrous starts to melt at 85" and decomposes at 133-147", the hydrobromide, m.p. 191-192" (anhydrous), the hydriodide, m.p. 204", the picrate, m.p. 213", the perchlorate, 1n.p. 159-160", the chloroaurate which melts partially at 95' and decomposes at 115-145", and the chlorplatinate, m.p. 176" (dec.) (97). Z-Adenocarpine, m.p. 64-65", [u]:' -30.1" (ethanol) (101). Adenocarpine is split by acid hydrolysis into cinnamic acid and a basic product C,,H,,N, which on catalytic hydrogenation takes up 1 mole of hydrogen and gives rise to racemic @-&piperidyl. When, however, this last base is prepared by hydrogenation of adenocarpine and hydrolysis of the product, the lev0 form is obtained. Adenocarpine is, therefore, an N-cinnamyltetrahydroanabasine(105).

139


2. ORENSINE

Orensine (C,,H,,ON,), m.p. 82-83", forms a hydrochloride, m.p. 208-210" (anhydrous), a hydriodide monohydrate, m.p. 133-134", and a picrate, m.p. 210-211". It is optically inactive and is the racemic form of adenocarpine. When oxidized with chromic acid orensine gives a substance C,,H,,O,N,, m.p. 227", which on hydrolysis with acid is split into oxalic acid and a diamine C,H,,ON, isolated as the dihydrochloride, m.p. 176175". These products locate the position of the double bond in orensine which must have structure CCXII. The oxidation and hydrolysis products would be represented by CCXIII and CCXIV, respectively (106).

CCXll

CCXlll

CCXIV

The structure of orensine, and therefore of adenocarpine, has been confirmed by synthesis. It is the same tetrahydro-anabasine as ammodendrine, except that instead of an N-acetyl group it carries an N-cinnamoyl group. Orensine was synthesized similarly by treating isotripiperideine with cinnamyl chloride and hydrolyzing the product at room temperature with 2N-hydriodic acid, whereby A'-piperideine and orensine hydriodide were obtained. The synthetic base liberated from its salt was identical with naturally occurring orensine (107). Orensine has been resolved into d- and l-adenocarpine with d- and l-camphorsulfonic acid (108). 3. ISO-ORENSINE Iso-orensine (C,,H,,ON,) forms a hydrochloride, m.p. 209-210°, a hydrobromide, m.p. 207-209", a hydriodide, m.p. 175-177", and a picrate, m.p. 204-205" (98). The base on hydrolysis gives trans-cinnamic acid and a base (C,,H,,N,) which on catalytic hydrogenation takes up 1 mole of hydrogen and is converted to aP'-dipiperidyl (CloH~oN~). Hence it seems that iso-orensine and orensine must be structural isomers. On the other hand, the methiodide of the hydrogenated iso-orensine is identical with that of the catalytic hydrogenation product of orensine, and, therefore, it is likely that the cinnamyl substituent is attached to the same nitrogen in both cases (109). (The methiodides are more likely hydriodides of N-methyl derivatives.)

140

LEO MARION

4. SANTIAGUINE Santiaguine was first assigned the structure C,,H,,ON, (97), but this was later doubled to C,,H,,O,N, (110). It melts at 235-236", has [.If +3.3", and forms a dihydrochloride hydrate, m.p. 241", a dihydrobromide hydrate, m.p. 24P253", a dihydroiodide hydrate, m.p. 241-242", a dipicrate, m.p. 285", a diperchlorate, m.p. 24&245", a chloroaurate, m.p. 150-151", and a chlorplatinate, m.p. 226-227". When hydrolyzed with acid santiaguine produces a-truxilic acid and a base C,,H,,N, which is hydrogenated catalytically to ag'-dipiperidyl. Consequently, the alkaloid is N,N'-a-truxil-bis (tetrahydro-anabasine), and Costa and Ribas (110)have assigned to it the partial structure CCXV.

ccxv 5. DECORTICASINE Decorticasine is an amorphous base (C,H,,ON,), [a];' +26.1" (ethanol), forming crystalline salts. The hydrochloride C,H,,ON,. 14.98" (water), the monopicrate, C,H,,ON,. 2HCl m.p. 308", C,H30,N3.3H,0, m.p. 227", the dipicrate, C,H,,0N,.2C,H30,N3.H20, m.p. 236-5237", the chloroaurate, m.p. 250-252", and the chlorplatinate which carbonizes at 250", have been described (102). No structural studies have yet been published. XVI. Carpaine It has now been demonstrated that carpaine, which was previously assumed to be a pyrrolidine derivative, is actually a piperidine alkaloid. The key to the skeleton previously suggested was provided by anitrogenfree hydroxy acid of probable composition C1,Hz8O3,m.p. 20-25", isolated from carpaine by a two-stage Hofmann degradation, followed by hydrogenation and hydrolysis (111). Rapoport and Baldridge (112)

+


141

have recently repeated the exhaustive methylation and Hofmann degradation, but they hydrogenated the material at each step rather than at the end of the process. Saponification of the final product gave a hydroxyl-free saturated acid C,,H,,O,, m.p. 52.3-53.1", identified a8 myristic acid. Hence, the carbon skeleton of carpaine must consist of a straight chain of 14 carbons, and, consequently, the Barger-Robinson formula is untenable. Carpaine when boiled in p-cymene with a 5% palladium-charcoal catalyst evolves 2 moles of hydrogen and gives rise to deoxycarpyrinic acid (C,,H,,O,N). The formation of this acid, since carpamic acid is C,,H,,O,N, involves the loss of the elements of water as well as 2 moles of hydrogen. A potentiometric titration showed the nitrogen to be basic, indicating that it could not be present in a substituted pyrrol, but rather in a substituted pyridine (112) so that the likely structure of deoxycarpyrinic acid is CCXVI and carpaine is a piperidine derivative.

CCXVl

Carpamic acid forms normal salts without loss of water and, therefore, the piperidine ring cannot be hydroxylated in either the a or a' positions. Methyl N-methylcarpamate methiodide was converted to the methocarbamate which was subjected to the Hofmann degradation. The product was hydrogenated and the process repeated to yield a nitrogenfree saturated material. This on oxidation with chromic oxide in glacial acetic acid yielded the dibasic dodecandioic acid, m.p. 125-126', and 12-ketotetradecanoic acid, m.p. 81.3-81.9'. Consequently, the structure of carpaine must be CCXVII (113). Recently, it has proved possible to

CCXVll

reconvert carpamic acid into carpaine by treating the hydrochloride of the acid with thionyl chloride and refluxing the crude product in a large volume of absolute ethylene dichloride (114). Carpaine can be methylated with formaldehyde and formic acid to N-methylcarpaine, m.p. 84". Since the hydroxyl group is resistant to dehydration and is readily replaced by chlorine and since the ethyl ester fails to epimerize, the 3-OH group of carpamic acid is assumed to have the equatorial configuration (115).

142

LEO MARION

XVII. References 1. A. D. Kuzovkov and G. P. Menshikov, J. Qen. Chem. 20, 1524 (1950); Chem. Abstr. 45, 2485 (1951). 2. E. Ott and F. Eichler, Ber. 55, 2653 (1922). 3. H. Lohaus and H. Gall, Ann. 517, 278 (1935). 4. K. Hess and A. Eichel, Ber. 50, 1192 (1917). 5. J. P. Wibaut and M. G. J. Beets, Rcc. trav. chim. 59, 653 (1940). 6. M. G. J. Beets and J. P. Wibaut, Rec. trav. chim. 60, 905 (1941). 7. M. A. Spielman, S. Swadesh, and C. W. Mortenson, J . Org. Chem. 6, 780 (1941). 8. F. Miller, J. A7n. Chem. Soc. 75, 4849 (1953). 9. J. A. King, V. Hofmann, and F. H. McMillan, J . Org. Chem. 16, 1100 (1951). 10. F. Galinovsky, 0. Vogl, and R. Weiser, Monatsh. Chem. 83, 114 (1952). 11. J. P. Wibaut and M. I. Hirschel, Rec. trav. chim. 7 5 , 225 (1956). 12. F. Galinovsky and 0. Vogl, Monatsh. Chem. 83, 1055 (1952). 13. F. Galinovsky, G. Bianchetti, and 0. Vogl, Monatsh. Chem. 84, 1221 (1953). 14. J. Chilton and M. W. Partridge, J . P h r m . and Phrmacol. 2, 784 (1950). 15. F. Galinovsky and R. Hollinger, Monatsh. Chem. 85, 1012 (1954). 16. K. Hess and A. Eichel, Ber. 50, 1386 (1917). 17. J. P. Wibaut, H. C. Beyerman, and P. H. Enthoven, Rec. trav.chim. 73, 102 (1954). 18. J. P. Wibaut, H. C. Beyerman, U. Hollstein, Y. M. F. Muller, and E. Greuell, Proc. Koninkl. Ned. Akad. Wetenschap. B58, 56 (1955). 19. K. V. Giri, J. Indian Inst. Sci. 37, 1 (1955). 20. U. Hollstein, Ph.D. Thesis, University of Amsterdam (1956). 21. E. Steinegger and F. Egger, Pharm. Acta Helv. 27, 113 (1952); Chem. Abstr. 47, 6954 (1953). 22. E. Steinegger and F. Egger, Pharm. Acta Helv. 27, 207 (1952); Chem. Abstr. 47, 12753 (1953). 23. E. Steinegger and H. Griitter, Pharm. Ackc Helv. 25, 49 (1950); Chem. Abstr. 44, 8601 (1950). 24. E. Rtcinegger and H. Griitter, Pharm. Ackc Helv. 25, 276 (1950); Chem. Abstr. 45, 3853 (1951). 25. C. von Plessing Baentsch, Farm. Chilenu 24,499 (1950);Chem. Abstr. 45,2152 (1951). 26. J. Gedeon and S. Gedeon, P h r m . Acta Helv. 29, 49 (1954); Chem. Abstr. 48, 10035 (1954). 27. J. Gedeon and S. Credeon, Pharm. Acta Helv. 30, 185 (1955); Ohem. Abstr. 50, 2918 (1956). 28. M. Dubeck and S. Kirkwood, J . Biol Chew 199, 307 (1952). 29a. S. Kirkwood and L. Marion, Can. J . Chem. 29, 30 (1951). 29b. E. Leete and F. H. B. Leitz, Chem. & I d . (London) p. 1572 (1957). 30. M. Mascr6, Compt. rend. 204, 890 (1937). 31. J. P. Wibaut and J. P. Schuhmacher, Rec. trav. chim. 71, 1017 (1952). 32. Sj. L. Bonting, Jr. and F. R. Schepman, Rec. trav. chim. 69, 1007 (1950). 33. E. Spath and E. Adler, Monatsh. Chem. 63, 127 (1933). 34. F. Galinovsky and H. Mulley, Monatsh. Chem. 79, 426 (1948). 35. E. Spath, F. Kuffner, and L. Ensfellner, Ber. 66, 591 (1933). 36. W. Griiber and K. Schlogl, Monatsh. Chem. 80, 499 (1943). 37. W. Griiber and K. Schlogl, Monatsh. Chem. 81, 83 (1950). 38. L. Marion and W. F. Cockburn, J . Am. Chem. SOC.71, 3402 (1949). 39. F. Sorm and J. Sicher, Collection Czechoslow. Chem. Communs. 14, 331 (1949). 40. K. Winterfeld and E. Muller, Arch. Pharm. 284, 269 (1951).


143

41. K. L. Hills, W. Bottomley, and P. I. Mortimer, Nature 171, 435 (1953). 42. D. N. Majumdar and G. B. Paul, Indian Pharmuckt 10, 79 (1954); Chem. Abatr. 49, 9881 (1955). 43. G. S. I l k , Biokhimiya 14, 552 (1949); Chem. Abstr. 44, 3575 (1950). 44. S. A. Brown and R. U. Byerrum, J . Am. Chem. SOC.74, 1523 (1952). 45. L. J. Dewey, R. U. Byerrum, and C. D. Ball, J . Am. Chem. SOC.76, 3997 (1954). 46. R. U. Byerrum and R. E. Wing, J . B i d . Chem. 205, 637 (1953). 47. M. Sribney and S. Kirkwood, Can. J. Chem. 32, 918 (1954). 48. R. U. Byerrum, R. L. Hamill, and C. D. Ball, J . Biol. Chem. 210, 645 (1954). 49. R. U. Byerrum, R. L. Ringles, and R. L. Hamill, Federation Proc. 14, 188 (1955). 50. R. U. Byerrum, J. D. Lovell, and C. D. Ball, Plant Physiol. Suppl. 30, xvi (1955. 51. E. Leete, Chem. & Ind. (London) p. 537 (1955). 52. L. J. Dewey, R.U. Byerrum, andC. D. Ball, Biochim. et Biophys. Acta 18,141 (1955). 53. E. Leete, J . A m . Chem. SOC.78, 3520 (1956). 54. A. A. Bothner-By, R. F. Dawson, and D. R. Christman, Ezperientia 12, 151 (1956). 55. P. I. Mortimer, Nature 172, 74 (1953). 56. K. Bowden, Nature 172, 768 (1953). 57. R. F. Dawson, D. R. Christman, and R. C. Anderson, J. A m . Chem. SOC.75, 5114 (1953). 58. R. F. Dawson, D. R. Christman, R. C. Anderson, M. L. Salt, A. F. O’Adams, and U. Weiss, J. A m . Chem. SOC.78, 2645 (1956). 59. A. I. Virtanen and S. Kari, Acta Chem. Scand. 9, 170 (1955). 60. C. Schopf, Angew. Chem. 61, 31 (1949). 61. H. Rapoport, M. Look, and G. J. Kelly, J . A m . Chem. SOC.74, 6293 (1952). 62. H. Rapoport and M. Look, J. Am. Chem. SOC.75, 4605 (1953). 63. M. L. Swain, A. Eisner, C. F. Woodward, and B. A. Brice, J. A m . Chem. SOC.71, 1341 (1949). 64. A. Pinner and R. Wolffenstein, Ber, 25, 1428 (1892). 65. P. G. Haines and A. Eisner, J . A m . Chem. SOC.72, 1719 (1950). 66. J. P. Wibaut and J. T. Hackmann, Rec. traw. chim. 61, 1157 (1932). 67. E. Spiith, J. P. Wibaut, and F. Kesztler, Ber. 71, 100 (1938). 68. J. P. Wibaut and H. C. Beyerman, Rec. traw. chim. 70, 977 (1951). 69. C. R. Eddy and A. Eisner, Anal. Chem. 26, 1428 (1954). 70. B. Witkop, J. A m . Chem. SOC.76, 5597 (1954). 71. M. L. Stein and A. Burger, J . A m . Chem. SOC.79, 154 (1957). 72s. A. Pictet and R. Rotschy, Ber. 34, 696 (1901). 72b. E. Noga, Fachliche Mitt. Osterr. Tabakregie 14, 1 (1914); Chemiches Zentralblatt, 1, 434 (1915). 73a. F. Kuffner and E. Kaiser, Monatsh. Chem. 85, 896 (1954). 73b. F. Kuffner and N. Faderl, Monatsh. Chem. 87, 71 (1956). 73c. J. Thesing and A. Miiller, Chem. Rer. 90, 711 (1957). 74. D. N. Majumdar, IndianJ. Pharm. 17, 158 (1955). 75. N. F. Proskurnina, J . Ben. Chem. (U.S.S.R.) 14, 1148 (1944); Chem. Abstr. 40, 7213 (1946). 76a. M. S. Rabinovich and R. A. Konovalova, J. Uen. Chem. (U.S.S.R.) 18, 1510 (1948); Chem. Abstr. 43, 2213 (1949). 76b. T. R. Govindachari, K. Nagarajan, and S. Rajappa, J . Chem. SOC.pp. 651, 2725 (1957). 77. W. H. Tallent, V. L. Stromberg, and E. C. Horning, J . Am. Chem. SOC.77, 6361 (1955).

144 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115.

LEO MARION

W. H. Tallent and E. C. Homing, J . Am. Chem. SOC.78, 4467 (1956). F. Acme and H. L. Haller, J. Am. Chem. SOC.72, 1608 (1950). M. Beroza, Anal. Chern. 22, 1507 (1950). M. Beroza, J. Am. Chem. SOC.73, 3656 (1951). M. Beroza, J. Am. Chem. SOC.74, 1585 (1952). D. J. Kolesnikovand A. G. Schwarzmann,J. Oen. Chem. (U.S.S.R.) 9, 2156 (1939); Chem. Abstr. 34, 4072 (1940). C. Schopf and R. Unger, Ezperientia 12, 19 (1956). H. C. Beyerman and Y. M. F. Muller, Rec. trav. chim. 74, 1568 (1955). L. Marion and M. Chaput, Can. J . Research B 27, 215 (1949). L. Marion, Can. J . Research B 23, 165 (1945). L. Marion, R. Lavigne, and L. Lemay, Can. J . C k m . 29, 347 (1951). J. StanBk, J. Hebkf, and V. ZvBrina, Collection Czechoslov. Chem. Communa. 18, 679 (1953); Chem. Abstr. 47, 12378 (1953). C. Schopf, Anales real SOC. espafi. fis. y quim. (Madrid) 51B, 247 (1955). H. C. Beyerman and P. H. Enthoven, Rec. trav. chim. 75, 82 (1956). H. C. Beyerman, W. Eveleens, and Y. M. F. Muller, Rec. trav. chim. 75, 63 (1956). L. Marion and A. Ayotte, unpublished results. N. F. Proskurnina and V. M. Merlis, J . Gen. Chem. (U.S.S.R.) 19, 1396 (1949); Chem. Abstr. 44, 1119 (1950). V. M. Merlis and N. F. Proskurnina, J . Gen. Chem. (U.S.S.R.) 20, 1722 (1950); Chem. Abstr. 45, 1302 (1951). C. Schopf and F. Braun, Naturwissenschaften 36, 377 (1949). I. Ribas and P. Taladrid, Anales real SOC. espafi. 3s.y quim. B 46, 489 (1950). I. Ribas and E. Rivera, Anales real SOC. espafi. fis. y quim. B 49, 707 (1953). I. Ribas, P. Taladrid, and R. Guitih, Anales real SOC. espafi. Jis. y quim. B 47, 533 (1951). A. G. Gonzalez and L. GalvBn, Anales real SOC. espaii. fis. y quim. B 47, 67 (1951). I. Ribas and L. Costa, Ann. pharm. franp. 10, 54 (1952); Chem. Abstr. 46, 6795 (1952). I. Ribas and J. Jorge, Anales asoc. puim. arg. 41, 27 (1953). J. M. Alonso de Lama and I. Ribas, Anales real SOC. espafi. Jis. y quim. B 49. 711 (1953). I. Ribas and J. M. Alonso de Lama, Farmacognosia (Madrid) 13, 367 (1954). I. Ribas, R. GuitiBn: and P. Taladrid, Anales real SOC. espafi.Jis. y quim. B 47, 715 (1951). J. Vega, J. Dominguez, and I. Ribas, Anales real SOC. espafi. Jis. y quim. B 50, 895 (1954). C. Schopf and K. Kreibich, Naturwissenschaften 41, 335 (1954). I. Ribas and M. del Rosario MBndez, Anales real SOC. espafi. 8s. y quim. B51, 55 (1955). E. Rivera and I. Ribas, Anales real SOC. espafi. 3s. y quim. B49, 777 (1953). L. Costa and I. Ribas, Anales real soc. espafi.Jis. y quim. B48, 699 (1952). G. Barger, R. Robinson, and T. S. W o r k , J . Chem. SOC.p . 711 (1937). H. Rapoport and H. D. Baldridge, Jr., J . Am. Chem. SOC.74, 5365 (1952). H. Rapoport, H. D. Baldridge, Jr., and E. J. Volcheck, Jr., J . Am. Chem. SOC.75, 5290 (1953). N. S. Narasimhan, Chem. & I n d . (London)p. 1526 (1956). T. R. Govindachari and N. S. Narasimhan, J . Chern. SOC. p. 1563 (1955).

CHAPTER5

The Tropane Alkaloids G. FODOR* Stereochemical Research Team of the Hungarian Academy, Budapest I. Introduction ...................................................... 11. Stereochemistry ................................................... 1. The Stereochemistry of the Tropeines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . a. The Configuration of the Ring Nitrogen Atom.. . . . . . . . . . . . . . . . . . 2. The Stereochemistry of the Ecgonines and Cocaines.. . . . . . . . . . . . . . . . a. Epimers of Cocaine and Their Derivatives.. . . . . . . . . . . . . . . . . . . . . . b. Absolute Configurations of the Nitrogen in Some Ecgoninol Derivatives 3. The Stereochemistry of Scopolamine, Valeroidine, and Teloidine. . . . . . a. Configuration of the Nitrogen Atom in Some Derivatives of 3a,6PDihydroxytropane and Scopoline . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Total Syntheses .................................................... 1. Total Syntheses of Scopolamine, Valeroidine, Scopoline, and Dihydrometeloidine ..................................................... a. Synthesis of Scopolamine.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . b. Synthesis of Scopoline (Oscine). .... . . . . .. . . . . .. . . . . .. . . . . . . . . . c. Synthesis of Valeroidine.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . d. Synthesis of Dihydrometeloidine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. The Structure of Dioscorine.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Some New Physiological Aspects of Natural Tropane Bases and of Their Synthetic Derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Some New Approaches t o the Problem of Biogenesis in the Tropane Field VII. References ........................................................

.

.

. .

.

.

.

.

..

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

Page 145 146 146 148 151 156 158 159 162 163 163 163 166 167 168 169 171 172 174

I. Introduction The rich field of the tropane alkaloids has been investigated intensively in the last five years.t The main features of this research work may be summarized as follows: ( I ) The steric structures of the naturally occurring representatives (except dioscorine) have been elucidated; ( 2 ) the total syntheses of scopolamine, oscine, valeroidine, and dihydrometeloidine serve as conclusive evidence for their structures; (3) the structure suggested for dioscorine in 1950 seems invalidated by more recent experimental facts; ( 4 ) a number of synthetic derivatives of the tropeines (e.g., quaternary tropanium salts and some derivatives of ecgonine) involving their pharmacological essays have been presented; * Formerly Professor of Organic Chemistry a t The University, Szeged.

t

K

Compare with Vol. I, chapter 6. 145

146

G. FODOR

( 5 ) the problem of biogenesis of the naturally occurring tropanes has been attacked from new angles. For detailed reviews in this field see Stoll and Jucker, Angew. Chem. 66, 376 (1954);Jucker, Chimia (Xwitz.) 9, 25 (1955); Fodor, Experientia 11, 129 (1955), Acta Chim. Acad. Sci. Hung. 5, 380 (1955) and Tetrahedron 1, 86 (1957).

11. Stereochemistry 1. THE STEREOCHEMISTRY OB THE TROPEINES

The epimers tropine and $-tropine are known to differ in the positions of the hydroxyl groups relative to the ring nitrogen only (1,2). Acyl migration experiments N-0 carried out with N-acetyl and N-benzoyl nor-tropine and nor- $-tropine, respectively, gave the first correct information as to their configurations (3, 4). Crystalline N-acetyl-nor+-tropine hydrochloride (I)(m.p. 150") (3) rearranges on heating to 150' quantitatively into O-acetyl-nor-$-tropine hydrochloride (11) (m.p. 21 3-214') (3), whereas the corresponding N-acetyl-nor-tropine hydrochloride (m.p. 163") (5) does not undergo isomerization. Benzoyl shift occurred easily with benzoyl nor-$-tropine as well, but failed with both N- and O-benzoyl nor-tropines (3, 4). This reaction has been shown to proceed only with neighboring nitrogen and hydroxyl groups (6, 7a), for it involves cyclic intermediates of the p-hydroxy oxazolidine* and oxazine types (111). Accordingly, the stereospecific behavior of the C,-epimeric tropanols represents decisive evidence for the syn-oriented hydroxyl group of $-nor-tropine including its derivatives, e.g., tropacocaine, as well as tigloidine, whereas nor-tropine and its alkyl derivative, tropine and its esters, e.g., atropine, hyoscyamine, convolamine, convolvine, poroidine, and iso-poroidine, all (IV) contain anti placed hydroxyl groups (3). The conclusions drawn from acyl migration experiments have been corroborated by a series of additional experimental facts. Nor- $tropine furnished a meta-oxazine derivative (V) (m.p. 101') (8) with p-nitrobenzaldehyde as contrasted with nor-tropine (IV; H instead of CH,), which gave only the N-p-nitrobenzoyl derivative (VI) (8) on similar treatment. The rates of hydrolysis of epimeric benzoyl and p-nitrobenzoyl-$tropeines and those of their methiodides have been determined (9). The bromo-magnesium salt of an intermediate of this type has been obtained recently by means of phenylniagnesium bromide from ~~-threo-3,4-diinethyl-5-phenyl-2-oxazolidone; G. Fodor, Chimin (Sw'itz.) 9, 179 (1954);K . Koczka and G . Fodor, Actu Chim. Acud. Sci. Hung. 13, 83 (1957).

147

THE TROPANE ALKALOIDS

IV

/

OAc

VI

V

Since tropine esters show smaller rates than +-tropeines and since boat conformations of the six-membered ring are postulated, these facts were attributed to the hydroxyl group hindered in the former case by a neighboring N-CH, group. Thus configurations opposite to those established by chemical means have been ascribed to the epimers. These views have been revised and corrected by the same workers (10). The benzilic ester of tropine showed a slower rate of hydrolysis than the tropine ester (11). Values of pK for tropine and +-tropine have been recorded and the higher basic strength of tropine was considered in favor of its trans configuration (12). More recently, however, it has been pointed out (13) that this difference is contrary to that observed for other cis-trans isomeric amino cyclanols. Consequently, the difference of basic strength can hardly be reconciled with the locations of the C,-hydroxyl groups only (13). TABLE 1

Tropine

PKB (at different ionic strength)

Dipole moments IR-bands cm.-l Density dz5

2.98 3.67 3.50 3.37 1.59 1040 1.001

$-Tropine 3.67 4.14 3.99 3.89 2.20 1057 0.998

Reference 12 13 13 13 14, 15 14, 16 14, 16

Dipole moments of the epimers have been measured (14, 15). Infrared data have been recorded (14, 16) as showing intramolecular H-bonding in +-tropine and an intermolecular one in the epimer.

148

G. PODOR

Reduction of tropinone with lithium aluminum hydride has been claimed to lead to +-tropine (17), whereas catalytic hydrogenation (18) furnished tropine selectively. This specificity, unfortunately, could not be confirmed later (19). On the assumption of boat conformation for the six-membered ring the formation of an equatorial, i.e., trans-OH group has been postulated for +-tropine (20). The conformation of the piperidine moiety has been reconsidered more recently by several authors (16, 21-23) who assume the predominance of the chair form. However, acyl migration (3),oxazine formation (sa),and intramolecular H-bonding (14, 16) can occur only in the boat form. Moreover, dipole moment data are also more consistent with this conformation. Infrared data have been reconsidered (16) in view of the Cole-Furst rule (24), according to which the position of the most intense bands in the 1000 cm.-l region can be correlated with the conformation of the hydroxyl groups. With +-tropine this band falls at 1057 cm.-l, whereas with tropine it falls at 1040 cm.-l; this indicates that equatorial bonding predominates in the former, which requires a chair form. In the reviewer’s opinion (25) the tropane skeleton might be considered as an endoethylenepiperidine or an endomethyliminocycloheptane with dynamic equilibrium between the two forms which would not preclude the chair form of the piperidine ring from prevailing in the ground state. As an important piece of evidence X-ray investigations of tropine hydrobromide crystals (26) indicated clearly the presence of this form only with the methyl group oriented towards the five-membered ring. All these findings could be fitted in with the concept of conformational analysis (21-25). The steric course of the reduction of tropinone using a variety of reagents has been extensively studied recently (120). A convention for the nomenclature has been suggested (3) based upon the N-methyl bridge as a reference group in the tropanes. Synplaced groups will hence be denoted by /3, anti-placed groups by a. Therefore, tropine will be 3a-tropanol and +-tropine will be 3jl-tropanol. This convention will be used throughout this chapter. a. The ConJiguration of the Ring Nitrogen Atom. Tropine (27, 28) and +-tropine (29) as well as their N-homologs (28) react with alkyl halides selectively, furnishing only one of the two possible N-epimers. Thus N-ethyl-nor-tropine methiodide is distinctly different (25) from tropine ethiodide as to melting point, crystal form, Debye-Sherer diagram, and IR-data (30). The same holds true for N-ethyl-nor-tropine propiodide and N-propyl-nor-tropine ethiodide, respectively (31). Similarly, the quaternary salt from +-tropine and ethyl iodoacetate proved to be the N-epimer of N-ethoxycarbonylmethyl-nor-+-tropinemethiodide. The


149

latter could be converted by hydrolysis into an anhydrous betaine (A), whereas the former furnished thereby a betaine-hydrate (B) difficult to dehydrate. The betaine (A) on treatment with hydriodic acid furnished a poor yield of a lactone salt. Consequently, definite configurations have been allotted (28c, 29) to the substituents of the ring nitrogen (VII and VIII). Furthermore, the group which enters first assumes with a greater likelihood the position towards the piperidine ring, thus predisposing the second alkyl group to be attached to the nitrogen near the ethylene bridge (25). The sequence of substitution and of quaternization of the nitrogen seems hence to lead to a certain, definite configuration. This steric selectivity has been explained (25, 33) in terms of the Pitzer strain (32) operating in the highly deformed five-membered ring of the tropanes, which may induce the acyclic substituent of the nitrogen to be shifted towards the piperidine ring-the more so since the latter in the chair form would avoid repulsion between the N-alkyl group and the C,-substituent. The limitations of this concept have been established on investigating the quaternization of a series of N-epimeric tropanols (33, 34). A further convention in describing positions of the substituents of the ring nitrogen has been suggested (33) in that those directed toward the six-membered ring be given the prefix a, and those adjacent to the five-membered cycle the prefix b. Accordingly, the lactone concerned may be designated as the lactone of N,-carboxymethyltropanium iodide (VII), and the epimeric N-acetic acid as N,-carboxymethyltropanium iodide (VIII). I n tropine hydrobromide crystals, however, owing to intermolecular lattice forces, the opposite position (Nb)of the methyl group has been found (26).

An interesting example of geometrical isomerism about the enolic double bond has been shown (35) recently for a-hydroxymethylenephenylacetyltropeine to which definite configurations (IX, X) could be ascribed on the basis of IR-spectra. Evidence has been presented for the bromination of tropinone to give

150

G . FODOR

,CHS

Ph,

s

'c=o I

0

C-H

RO'

II

I

C-

/

OR

H IX

X

rise to Zfl-brorno tropinone (XI) (hydrobromide, m.p. 192O) (36). Sodium borohydride reduction of this latter furnished a bromohydrine (XII) (m.p. 125.5'), hydrogenolysis of which over Pd-C led to 38tropanol whereas alkaline treatment yielded tropinone. This confirmatory piece of evidence points to the /?-placed hydroxyl as being cis to bromine. An interesting example of reversible ring opening is the conversion of 3/?-tropanol methohydroxide into 6-dimethylaminocyclohept-2-en-1-01 (XIIIa), the bromide (XIIIb) of which has been reconverted by sodium hydrogen carbonate into the methobromide of the same bromo-alcohol(m.p. 237", dec.) (36). Hence, the eliminated bromine must have been trans to the NMe, group, so the retained one is obviously cis-placed to the N-methyl bridge in the 2-bromo-tropanol concerned (36). 3-Chlorotropane underwent ring cleavage quite unexpectedly on the action of potassium cyanide, giving rise to N-methyl-2allyl-5-cyanopyrrolidine( 127). C,-epimeric tropanyl chlorides were chosen as models for studying the relationships between stereochemistry and reactivity in fragmentable systems (140).

THE TROPANE ALKALOIDS.

151

The synthesis of tropine and of its esters has been made practical because succinic dialdehyde has become easily available. Furane, now available commercially, gives on anodic oxidation in methanol with ammonium bromide as electrolyte good yields of 2,5-dimethoxy-2,5-2H-furane (37a). This mixed ketal of maleic dialdehyde could be hydrogenated readily and quantitatively over Raney nickel to 2,5-dimethoxy-4Hfurane (37b). The latter as a mixed ketal of succinic dialdehyde undergoes acid hydrolysis easily. Optimum conditions for the condensation of this dialdehyde formed in situ to tropinone have been recorded (38) with yield up t o 93% and at a higher rate than described earlier (18). The dihydrofurane derivative is a satisfactory starting material for the preparation of malic (39, 40, 61) and mesotartaric (40) dialdehydes, i.e., of key intermediates for the syntheses of valeroidine, scopolamine, and teloidine. Tropinone has been synthesized recently from an acetylenic precursor (124), such as hexa-l,&di-yne; Galinovsky (119) has made the interesting observation that Nmethylsuccinimide could be reduced by lithium aluminum hydride to a,a'-dihydroxy-N-methylpyrrolidineand this condensed with acetonedicarboxylic acid to tropinone. A number of 3a and 313 aminotropanes have been obtained by reductive amination of tropinone under various conditions, and they have been checked for physiological activity (126). Some new esters of tropine and their quaternary salts have been prepared recently (128). 2. THE STEREOCHEMISTRY OF THE ECQOXINES AXD COCAINES

The Willstatter synthesis of (-) ecgonine, (-) cocaine (42), (+) $-ecgonine (41), their antipodes, and a third racemic modification (42) of 2-carboxy-3-hydroxytropane (not resolved) involving reduction of the same methyltropinone-2-carboxylatehas supplied sufficient evidence for their chemical constitution but not for their configurations. An interesting new route to tropane derivatives, particularly to anhydroecgonine, has been outlined (122). Methylamine reacts with cycloheptatrienecarboxylic acid giving rise to ( &)-anhydroecgonine, that is, trop-2-enecarboxylic acid. This reaction may be looked upon as a reversal of the elimination reaction that takes place with tropinone methiodide and its hydroxy and bromo derivatives (121). The formation of ecgonine epimers depending on experimental conditions in reduction, analogous to the formation of C,-epimeric tropanols from tropinone, together with the seemingly close resemblance of the conversion of tropine into $-tropine to the epimerization of (-) ecgonine into (+)$-ecgonine by strong alkali (43), was originally (42,

152

0. FODOR

44, 45) considered as evidence that both pairs are C,-epimers. Recent investigations (46-48a), however, disproved this assumption. The elucidation of the configurations of these rather complex compounds has been realized essentially in four consecutive steps : (1). Determination of the relative steric position of the N-atom and of the C,-OH group in the ecgonines. (2). Establishment of the spatial interrelation of the C,-hydroxyl with the C,-carboxyl. (3). Determination of the location of the N-CH, bridge relative to the carboxylic group. (4). Correlation of (-) cocaine with one of the optically active series of known absolute configuration. ( 1 ) Nitrogen and C,-OH relationship. (a)N-Acetyl-nor-4-ecgonine ethyl ester (XIV) (m.p. 1 1 2 O ) underwent N-tO acyl migration easily and reversibly into XV (m.p. 229'; 119.4') (44, 45), thus indicating that these groups assume neighboring positions. N-Acetyl-nor-ecgonine ethyl ester, however, failed to rearrange under the same conditions (44, 45). Nevertheless, 0-benzoyl-nor-ecgonine (XVI) obtained on oxidative degradation of benzoyl ecgonine could be submitted (46) to 0 -+N acyl migration a t p H 11. The counterpart has been displayed in carrying out N-+O migration with N-benzoyl-nor-ecgonine (XVII) (47, 48b). Accordingly, ecgonine, $-ecgonine, and their esters all belong to the "pseudo"-tropine series, that is, they are 3/3-tropanols.

XIV

xv

XVI

XVll

( b ) A further important piece of evidence has been obtained from a study of the 2-methyl-3-tropanols, obta.ined from ( -) cocaine (XVIIIb) and (+)ybecgonine (XIX) methyl ester by the following route (47, 48).

153


They gave on hydrogenolysis two epimeric 2-hydroxymethyl-3-tropanols (XX and XXI), which could be chlorinated selectively to the

CHzOH '

N

xx'

,CHs

O

I

H

H

Nw CHzCl

OH

t

OH

OH

"NOH XXVlll

154

G . FODOR

2-chloromethyl derivatives (hydrochloride of XXII, m.p. 209"; [a]:' -60.2" and of XXIII, m.p. 263"; [a]:' +56.5'), which, in turn, led on hydrogenolysis to the 2-methyl-3-tropanol epimers (XXIV, XXV). Oximation of the methyl tropanol ([a]:' -58.2") derived from cocaine gave with aluminum isobutoxide as catalyst a ketone, XXVI, different from that (XXVII) prepared from +-ecgoninol on chromic acid oxidation. Oxidation carried out in alkaline medium, however, furnished in both cases the same oxime (XXVIII) ([a]:' -40.8'), which proved later to belong to the +-ecgonine series. Thus the C,-epimerism of (-) ecgonine and (+)+-ecgonine is evident (48). (c) Esters and a,mides of nor-2-methyl-3-tropanols, prepared by von Braun degradation, behaved completely analogously concerning N-0 acyl migrations, thus providing additional evidence for the /3-location of the tropanol C,-OH groups in both epimers (48). ( d ) Simultaneously it was shown that epimerization of cocaine into (+)4-ecgonine methyl ester proceeded by basic catalysis in methanol under very mild conditions, unlike those required for a C,-epimerization. Consequently, occurrence of racemization at C, (a to the carboxyl) has been suggested (46). In addition it could be demonstrated (49b) that the irreversible isomerization of 3a-tropanol into the 3/3-modificationin the presence of sodium amyloxide involves a half-cell oxidation-reduction (49a) mechanism (i) since it does not occur in nitrogen atmosphere and (ii) since it is catalyzed by oxygen and benzophenone, whereas the epimerization of cocaine is not at all sensitive to any of these reactants and conditions. (2) The positions of the carboxylic group relative to C,-OH in these C,-epimers have been established in different ways. (u) O-Benzoylecgonine and O-benzoyl-+-ecgonine have been converted by Curtius degradation into the epimeric 2-benzamido-3/3-tropanols (XXIX and XXX) (m.p. 163"; [a]: -So), which, in turn, were submitted to an acyl migration study (44, 45). I n acid medium the ecgonine derivative (m.p. 203" ; [a]:' +82') rearranged only into O-benzoyl-2-aminotropan-3/3-01(XXXI)while the $-ecgonine derivative did not give an amino ester salt. This has been regarded as evidence for the cis-relationship of C,-OH and C,-COOH in the former and for their trans-location in the latter (44, 45), provided Curtius degradation of the migrating group (i.e., in this case of the 3-hydroxy-2-tropanyl carbanion) proceeded with retention of configuration (50). ( b ) Of the two epimeric 2-hydroxymethyl-3/3-tropanols the ecgonine derivative gave a cyclic lsenzylidene acetal (XXXII) only, indicating a cis relationship of the functional groups in "ecgoninol" and consequently in cocaine (45).

155


XXlX

xxx

(c) A conclusive piece of evidence has been found in the spontaneous rearrangement of 2-chloromethyl-3/3-tropanol(XXII) derived from ecgonine into the isomeric hydrochloride of a four-membered ring ether base (XXXIII) (48).This structure has been proved by both chemical and IR-evidence (51). A cyclization of this type to a system of orthoanellated four- and six-membered rings can occur only with adjacent, i.e., equatorial-axial functional groups (51). On the basis of these facts, ecgonine must have the structure of 2/3-carboxymethyl-3/3-tropanol(XVIIIa), cocaine that of ( -) 2/3methoxycarbonyl-3/3-tropanol(XVIIIb), and (+) +-ecgonine that of (+) 2a-carboxymethyl-3/3-tropanol (XIX). (3)Despite the ample evidence presented above for the steric structure of cocaine, it seemed worth while to have a direct proof of the relationship of N to C,-COOR. This has been realized by hydration of N-cyano-nor-cocaine (XXXIV) into N-carbamyl-nor-cocaine followed by ring closure to yield the lactam of N-carbamyl-nor-ecgonine (XXXV) as well as N-carbamyl-nor-ecgonine methyl ester, the formation of which prove the proximity of the functional groups (47).

XXXIV

XXXV

156

G. FODOR

(4) The correlation of (-) cocaine, i.e., (-) 2p-methoxycarbonyl3p-tropanol, with L (+)glutamic acid, has been achieved via ecgoninic acid (see Volume I) recently as presented by the flow sheet ( 5 2 ) . Accordingly, the projectional formulas used in this chapter correctly depict the absolute configuration of the natural alkaloid.

b

a

COOH

I I CH2 I

YN-C-H

H

I

H I

t I

CH2

I

COOH L(+)glutomic ocid

Pyroglutomic ocid

To adopt the new convention outlined by Cahn et al. (113) the absolute configuration of (-) cocaine may be stated as 2(R)-methoxycarbonyl-3(S)-benzoxytropane and (+) pseudococaine as 2(S)-methoxycarbonyl-3(S)-benzoxytropane(114). a. Epimers of Cocaine and Their Derivatives. The so-called third racemate of ecgonine (42) has been converted recently into the methyl ester of the 0-benzoyl derivative, i.e., into a “third” cocaine (53a), not having any anesthetic effect, as expected. Mydriatic properties have not been recorded. Some efforts have been directed towards stereospecific synthesis of the hitherto unknown optically active ecgonine and cocaine epimers. “Ecgoninol” (XX) (45, 54) was converted into the four-membered ring ether (XXXIII) (47, 48), and this, in turn, was submitted to ring cleavage with inversion at C, to give 2~-hydroxymethyl-3~-tropanol (XXXVI) (51). This latter could be isomerized further by a half-cell oxidation-reduction process (51) into 2~-hydroxymethyl-3~-tropanol (XXXVII). Selective oxidation of these diols should lead to the expected new ecgonine epimers. Still more recently the synthesis of the fourth racemic ecgonine and cocaine has been reported in a preliminary paper (53b). Hydrogenation

157


XXll

XXXVII

H’

OH

Xxxlll

XXxVl

.

H‘

OH

over Adams Pt catalyst of 2-methoxycarbonyltropinone gave 80% of a “third” ecgonine methyl ester (m.p. 81.5-83.5”), which on benzoylation afforded a third racemic cocaine (m.p. 82-84”). Hydrolysis (supposedly in alkaline medium) furnished a mixture of ecgonines, one of which melted at 242” and the other at 237” (53b). The former has been reesterified to give a “fourth” (*) ecgonine methyl ester, m.p. SO’, which on benzoylation affords a “fourth” racemic cocaine, m.p. 98’ (53b). The “third” ( & ) ecgonine methyl ester prepared earlier (53a) on the lines of Willstatter (42) by hydrogenation of methyl tropinone 2-carboxylate with sodium amalgam has, however, m.p. 203-205’, whereas its benzoyl derivative, i.e., the “third” cocaine, shows m.p. 156-158” /53a), seemingly not identical with either of the compounds described by the American author (53b).The reasons for this discrepancy are still unknown. Configurations have been allotted (53b) to €he two racemates obtained by catalytic hydrogenation. Since the “fourth” modification arising from hydrolysis of the third one behaved like ecgonine towards methyl iodide, it may be depicted by the structure of ( j-) 28-methoxycarbonyl-3a-tropanol, whereas the third, not undergoing epimerization during quaternization, seems to represent ( &) 2a-carbomethoxy-3atropanol (53b). Furthermore, 2,4-dicarbomethoxytropinoneobtained according to the Robinson method (see Volume I) was saponified to (j-) 2-carbomethoxytropinone, whereas (+) pseudo-ecgonine methyl ester, i.e., (-f- ) 2a-methoxycarbonyl-3$tropanol, could be oxidized to the optically active 2a-methoxycarbonyl-3-tropanone (53b), which appears to

158

0. FODOR

undergo reduction into optically active (+) pseudo-ecgonine methyl ester together with its C,-epimer, 2a-methoxycarbonyl-3a-tropanol. The configuration of Willstatter’s “a”-cocaine has now been shown to be 3~-benzoyloxy-3a-methoxycarbonyltropane by adopting the method of oxazine formation of the nor derivative of “a”-ecgonine methyl ester. This latter had been obtained from tropinone by the cyanohydrin route. Obviously the cyanide ion attacks the ketone from the a-direction in contrast with metalloorganic compounds, which carry out nucleophilic attack from the nonhindered p-position (130). Tropane-3-carboxylic acid and its homologous 3-acetic acid have been described. Tropinone condensed with malononitrile gave the unsaturated dinitrile which was convertible to ethyl trop-2-enyl-3acetate by known reactions. Hydrogenation afforded the 3-acetic acid derivative. The cyanohydrin of tropinone on hydrolysis and esterification gave the expected hydroxy ester which on dehydration gave an unsaturated compound. Hydrogenation of it occurred stereospecifically giving rise to the anti ( a -) ester only which was epimerized by alkali to the more stable syn ( p - ) modification. The configuration of the latter follows from the fact that the derived chloromethyl compound (XXXVIIa) suffered intermolecular ring closure to N,Sp-endornethylenetropanium chloride (XXXVIIb). The epimeric 3-chloromethyl derivative failed to undergo ring closure. The chloromethyl compound was prepared from the corresponding carbinol, which was obtained by reduction of the ester (125).

XXXVll

0

XXXVll b

b. Absolute Configurations of the Nitrogen in Some Ecgoninol Derivatives. Ecgoninol (XX) gave with ethyl iodoacetate N,-ethoxycarbonylmethyl-2~-acetoxymethyl-3~-acetoxytropanium iodide (XXXVIII) (55), while “reverse” quaternization of nor-ecgoninol via methylation of N-ethoxycarbonylmethyl-nor-ecgoninolgave rise to the lactone of N,-carboxymethyl-2~-hydroxymethyl-3~-hydroxytropanium iodide (XXXIX) (55). Most of the success in learning the steric structure

159


of cocaines has been attained in the years 1951-1954 essentially in three laboratories (Szeged (University),Zurich (ETH), and Washington (NIH), ). , According to the recent conventions describing absolute configuration (113) ( -)ecgoninol (XX) is 2(S)-hydroxymethyl-3(S)-hydroxytropane ,CH3 CHzOH

‘

N

O H

xx

H

R0,CCHz N’‘

-

woH CH3

H

OH

XXXVlll

and XXXIX is the lactone of N-(R)-carboxymethyl-2(S)-hydroxymethyl-3(S)-hydroxytropaniumiodide while its N-epimeric carboxylic acid (XXXVIII) is N(R)-carboxymethyl-2(S)-hydroxymethyl-3(S)hydroxytropanium iodide ( 114). 3. THE STEREOCHEMISTRY OF SCOPOLAMINE, VALEROIDINE, AND TELOIDINE The spontaneous rearrangement of scopine (XL), i.e., the “true” alkamine of scopolamine, into scopoline (oscine) (56) has been interpreted (1952-1953) by several authors independently (23,44, 57) in terms of modern stereochemistry as an internal rearward nucleophilic attack (XLa-tXLI) of the C,-a-placed hydroxyl oxygen against C, end C,, i.e., against the bridgeheads of the epoxide group. This is possible only if the OH group in scopine assumes an a-, and the epoxide bridge a 8-, location. This deduction (44) has indeed been proved valid by hydrogenolysis of ( -) scopolamine affording the ( -) and (+)tropyl esters of ( & ) 3,6-dihydroxytropane (XLb-tXLII) (58). Hydrolysis and subsequent resolution by d-tartaric acid gave (-) and (+)3,6-dihydroxytropane (58), the levorotatory form thereof being identical with the alkamine (59) of natural valeroidine (XLIII) (60). Incidentally, the

160

G . FODOR

total synthesis of ( i)6-hydroxytropinone has been realized starting with malic dialdehyde on the Robinson-Schopf route (61). It was already known that valeroidine may be oxidized by potassium permanganate to a compound, the analytical data of which pointed to the structure of a cyclic urethan (XLIV) derived from nor-valeroidine (62). This could be formed only if the C,-OH and the ring nitrogen were adjacent in 3,6-dihydroxytropane. The conversion of scopolamine into dihydroxytropane ( 5 8 )supplied evidence for the /?-positionof the oxygen function at C,-C, in scopolamine (58). Hence, the structure of 3a-tropyloxy-6,7p-epoxytropane (XLb) deduced (44)for scopolamine and that of 3a-isovaleroxy-6~-hydroxytropane for valeroidine have been likewise confirmed. Conclusive evidence for the /?-locationof the C,-OH group has been obtained (63)by converting ( j-)3,6-dihydroxytropane by ethyl

x LV

XLll

XLlV

, i

f-4Hyo

w%

0-

161


iodoacetate into the lactone of N,-carboxymethyl-3a,6/3-dihydroxytropanium iodide (XLV) (47), which could also be converted into a betaine. Scopoline gave similarly a lactone salt with ethyl iodoacetate (XLVI) (33, 47, 63). In addition, nor-scopoline could be cyclized by the action of p-nitrobenzaldehyde into a meta-oxazine of type V (64), owing to the proximity of the N and 0 functions of scopoline. The exact correlation of the configuration of the C,-OH group in valeroidine and in scopolamine with that of tropine could be realized by converting scopolamine and valeroidine into tropine (65). Dehydration of ( *) 3~,6/3-dihydroxytropane(XLII) led to (&) “tropene oxide,”* i.e., 3a,6a-oxidotropane (XLVII), and this on acetobromolysis gave rise to 3u-acetoxy-6~-bromotropane (XLVIII). Dehydrobromination of the bromo-acetate led, in turn, to trop-6-en-3-yl acetate (XLIX), which afforded on hydrogenation acetyltropan-3a-01 (65). The synthesis of trop-6-en-3~-01served also as an intermediate in the total synthesis of scopolamine (66, 67a,b). The absolute configuration of valeroidine as (3R,6R) ( -)3,6-dihydroxytropane 3-isovalerate has been determined by reacting the optically active alkamine from valeroidine with ethyl iodoacetate and noting that

XLll

XLVll

,CH3

h h4

N

collidine or N(Et)j

Br

OAc

OAc

XLIX

XLVlll

* Levorotatory “tropene-oxide” has been prepared by Wolfes and Hromatka (69) by means‘of phosphoryl chloride from ( -)3.6-dihydroxy-tropane, obtained from Javaneae coca leaves. L

162

G . BODOR

the resulting strongly levorotatory compound ([a], -23.7’) is convertible into a dextrorotatory lactone ([a], +37.5’). The considerable shift, taking into consideration Hudson’s lactone rule, indicates that the hydroxyl concerned with the lactone formation belongs to the D, series (112). a. ConJiguration of the Nitrogen Atom in Some Derivatives of 3a,68Dihydroxytropane and Scopoline. The principle of “direct” and “reverse” quaternization of tropanes using ethyl iodoacetate and methyl iodide as consecutive reactants has been applied to both nor-3a,6jI-dihydroxytropane and nor-scopoline (33). N-Carboxymethyl-nor-3a,6/3-dihydroxytropane (La), its ethyl ester (Lb) and methiodide (LI) showed no tendency to lactonize-facts which point to the N, location of the carboxymethyl group even at the tertiary amine stage. nor-Scopoline (oscine), on the contrary, gave with ethyl iodoacetate an ester which readily lactonized into XLVIa subsequent to acid hydrolysis (33). With methyl iodide it furnished the lactone salt (XLVIb) besides an ester salt (LII) not undergoing cyclization (33). Hence, in this case the configurational stability of the tertiary base is decreased or in other terms the sequence of alkylations does not preclude the formation of the two possible epimers. The discrepancy in the behavior of bases derived from dihydroxytropane and of scopoline has been ascribed to the considerably less deformation of the pyrrolidine ring from coplanarity than in the case of the tetrahydrofurane derivative (33).

OH 11

Hob LII

The stereochemistry of teloidine, the alkamine of meteloidine, has been elucidated as far as the vicinal hydroxy groups are concerned by its Robinson synthesis from cis-dihydroxysuccinic dialdehyde (68). Their relative positions to the nitrogen, however, have been revealed only by

163


adopting the lactone salt method (25, 47). Indeed, reaction of ethyl iodoacetate with teloidine gave a lactone iodide, the chloride of which (LIIIa) withstood periodic acid oxidation (63). Hence evidence was presented in favor of the 8-positions of both C,- and C,-hydroxyls. Concerning the C,-OH group +-teloidine-6,7-acetonidehas been preSince this pared (81) and degraded into nor-+-teloidine-6,7-acetonide. latter afforded a metaoxazine derivative of type V with p-nitrobenzaldehyde, +-teloidine possesses a 8-placed hydroxyl group at C3, the reverse being true for teloidine (LIVa) and meteloidine (LIVb) (69).

HO m %

CH3

OR LIV

0 HO

111. Total Syntheses 1. TOTALSYNTHESES OF SCOPOLAMINE, VALEROIDINE, AND DIHYDROMETELOIDINE SCOPOLINE, a. Xynthesis of Scopolamine. Epoxysuccinic dialdehyde (LXI), the key intermediate for the suggested Robinson synthesis of the amino ketone scopinone, has been prepared both from furane (40)and by periodic acid oxidation of an epoxy-cyclitol, i.e., conduritoxide (70). Its conversion, however, into scopinone (LVI) failed (40,70).Another approach was aimed (71) at condensing maleic dialdeliyde into a tropenone (LVII) to be followed by selective reduction to trop-6-en-3-01 (XLIXa), which should be oxidized, in turn, into scopine (XLa). Unfortunately, no account of the realization of any further step on this route has been recorded so far, perhaps owing to the aromatization tendency of this ketone into tropone. Indeed, tropan-3-one methiodide is readily

a. FODOR

164

cleaved by alkali to a mixture of cycloheptadienones (dihydro-tropones) (72), but not to dihydrobenzaldehyde as believed earlier (73).

- +; H

\

N,cH3

H

c=o

LV

LV I ,CH3

Nh 0

LVll

OR XLlX

R = H (a) =Ac ( b )

To this assumption support has been lent by the fact that Hofmann elimination of 6-hydroxytropan-3-one methiodide involved dehydration giving rise to tropone directly. Similarly 2-bromotropan-%one methiodide underwent alkaline degradation into tropone by virtue of a concurrent or subsequent elimination of hydrogen bromide (121). In view of these and other negative experiments, the synthesis of tropenol has been attempted employing selective elimination reactions and on this diol itself, on some derivatives of 3~,6/3-dihydroxytropane j.e., on tropane derivatives of remarkable stability (65). Acetyl tropenol and hence tropenol have been obtained by two alternative routes: ( 1 ) from tropan-3~,6/3-diol(XLII) via “tropene oxide” (XLVII), as already outlined (p. 161) (65); (2) by starting with 6-hydroxytropan%one (39, 61) phenylurethan (LVIII) (65). Catalytic hydrogenation over Raney nickel led to tropan-3~,6/3-diol monophenylurethan (LIX), which could be acylated easily either with acetyl chloride or with isovaleryl chloride. Distillation in a vacuum of these mixed esters (LXa or b) proved sufficient to afford cleavage of the phenylcarbemyl group into phenyl isocyanate and the corresponding 3a-acyloxy-6/3hydroxytropane (LXI) (65); see also (143).

I65


Ph-N H-CO-C

m 0

LIX

LVlll

L XI

Ac = CHsCO

LX (0)

( j-) 3a-Acetoxy-6/3-hydroxytropane (LXIa) gave with p-toluenesulfonyl chloride the tosyl-ester (LXII), which underwent, in turn, elimination on action of collidine or triethylaniine, affording fairly good yields of acetyl-6-tropene-3a-01 (XLIXb) (65). Alkaline hydrolysis in acetone according to Kunz (76) furnished trop-6-en-3a-01 (XLIXa). Oxidation of acetyltropenol with monoperphthalic acid led essentially to the N-oxide (LXIII) (65), while a great excess of the same reactant afforded the appropriate N-oxide-epoxide (LXIV) (67b). The latter took up 2 moles of hydrogen giving rise to ( 5 )3a-acetoxy-6/3hydroxytropane (LXIa). Hence, the addition of the oxygen atom to the double bond at C,,, has taken an exo-steric course (67b), as expected by virtue of previous experience with similar systems (74). The formation of the N-oxide was avoided when trifluoroperacetic acid was reacted with the trifluoroacetate of acetyltropenol (67a, b). Recently it has been shown that hydrogen peroxide in formic acid gave a still better yield of epoxides without detectable N-oxides (671)). Acetylscopine (LXV) has been isolated as the picrate, (m.p. 212") (67a), identical with the sample obtained from scopine (XLa) (75) hydrochloride by acetyl chloride (67a). The conversion of acetylscopine into ( &) scopolamine (LXV-tXLb) has been realized (67b). Hydrolysis with N NaOH in acetone led to scopine (XLa), the hydrochloride of which was acylated, in turn, with acetyltropoyl chloride in nitrobenzene to acetylscopolamine besides a number of by-products. Separation was achieved using cellulose powder chromatography in butanol-N HC1. Acid hydrolysis of this ester with 2N HC1 led to (-J) scopolamine hydrochloride (XLb) (67b) identical with the natural

166

G . FODOR

product. Since scopolamine has already been resolved (77), the synthesis of hyoscine is complete. This may be considered as the last step in elucidating the structure of scopolamine and hyoscine.

TS =

- CH3 Cg H, SO2 Tr = tropoyl

OH

,CH3

N

An alternative route to scopolamine and hyoscine has been reported. When tropenol is acylated with either racemic or active acetyltropoyl chloride and the respective acetyldehydroatropine or acetyldehydrohyoscyamine is oxidized with performic acid, there is generated acetylscopolamine or acetylhyoscine, respectively (67b). The oxidation of scopine (LXXXIV) to scopinone (LXXXV) has been realized (133). b. Synthesis of Scopoline (Oscine). Several authors have chosen 3~,6~,7fi-trihydroxytropane as a possible intermediate in the synthesis of scopolamine and oscine. Hardegger and Furter (80a) converted (+) tartaric dianilide by lithium aluminum hydride reduction into

167

THE TROPANE ALXALOIDS

tJ

/ oxidoCion

. 0

'a

OQ-9 OH LXXXV

LXXXIV

(+) tartaric dialdehyde and condensed this to S(+)6,7-dihydroxytropan-3-one ( (+)6~,7~-dihydroxytropan-3-one). The same synthesis was reported by Stern and Wassermann (Sob), while Sheehan (SOc) reduced the above ketone to the triol. Racemic tartaric dialdehyde has been obtained by a third route by the neutral permanganate oxidation of fumaric dialdehyde tetramethyl acetal. It was convertible into allo-teloidinone by Robinson condensation and the ketone on reduction yielded allo-teloidine and pseudoallo-teloidine (129). Two syntheses of scopoline (oscine)have been reported. Teloidine carbonate has been submitted to thermolysis, giving rise to scopoline(131). The second synthesis took the way of ditosyl-teloidine. The last step involved hydrogenolysis of tosyl-scopoline by means of lithiumaluminum-hydride (132). c. Xynthesis of Valeroidine. ( j-)3~-Isovaleryl-6~-phenylcarbamyloxy tropane (LXIb) obtained from 6-hydroxytropinone phenylurethan in the manner described above (65) furnished on thermolysis (*) valeroidine (XLIII). The valeryl ester of levorotatory valeroidine had been synthesized earlier from ( -) tropan-3a, 68-diol (XLII) and isovaleryl chloride (78). Selective deacylation of this latter failed (78), however, to give the natural monoisovaleryl ester. Now, the racemic monophenylurethan of the diol could be resolved by d-tartaric acid and both antipodes have been converted-essentially on the same lines as the racemate-into (+)and (-) valeroidine (XLIII) (79). The latter proved to be identical with the natural (60) alkaloid.

d1st.h vocuo

Ph- N H- co' O

h Lx b

01 ',

H

O

h

168

G. FODOR

d . Synthesis of Dihydrometeloidine. 3a-Tigloyl-3a,6B,7B-trihydroxytropane (LXVI)63,64), meteloidine, gives on hydrogenation the dihydro derivative. This latter has now been synthesized (81) starting with teloidinone previously obtained by total synthesis (68). Benzylidene teloidinone (LXVII) afforded on hydrogenation over Raney nickel the 3a-hydroxy-derivative (LXIX) (with an axial hydroxy) exclusively. Benzylidene teloidine, in turn, could be acylated with a-methylbutyric anhydride into benzylidene dihydro meteloidine. The protecting ketal group could be split off by hydrogenolysis over 30% Pd-charcoal to give dihydro meteloidine (LXX) (81).Lithium aluminum hydride reduction of teloidinone acetonide, on the other hand, gave rise to $-teloidine acetonide (LXXI), while catalytic hydrogenation furnished the 3amodification (81).The synthesis of meteloidine, i.e., of the unsaturated alkaloid, is in progress (80).

ZH'/Pd

Ho

0-$LXVI

$=F

HO

H ,

O-C-CH-CHI

0 ChCY

LXXI

LXX

I l l

I

0 CHs CHI

OH

The kinetics of the hydrolysis of acylscopolamine methohalides and of acylscopolamines has been shown to involve dehydration to aposcopolamine while the nonacylated base does not suffer this change (117). An improved procedure for achieving the alkaline hydrolysis of scopolamine methobromide to salts of scopine has been reported (115). With methoxymethyl scopinium bromide alkaline hydrolysis followed by removal of the ketal-like protecting group gave still better yields of


169

scopine (116). The same protecting group, however, did not possess sufficient stability to serve in the oxidation of N-methoxymethyl-3acetoxytropenium chloride (65). A new alkaloid has recently been isolated from the roots of three species of Datura, namely, D. stramonium L., D. tatula L., and D. ferox L. On partial hydrolysis it yielded meteloidine and tiglic acid; hence it is ( f)3a,6/3-ditigloyloxy-7/3-hydroxytropane ( 111). ( -)3a,6/3-&tigloyloxy-tropane has been isolated from Datura roots (141). A new alkaloid is described from Datura ferox L. (142).

IV. The Structure of Dioscorine A tentative formula of the y-lactone of 2-(a-isopropylidene-carboxymethyl)-3-hydroxytropane (LXXII) has been suggested so far for dioscorine based merely upon positive Legal test indicating the presence of an a$-olefinic lactone grouping (82a) as well as on exhaustive methylation (82b) described in detail in Volume I of The Alkaloids. The isolation of the alkaloid from different sources (83) and its degradation have been recently (83) reinvestigated adopting modern experimental methods, including IR-spectroscopy (84). The base Cl3HZ1N obtained on first Hofmann degradation proved to break down when heated with palladized charcoal into trimethylamine, an unidentified base, and isobutylbenzene or p,p-dimethylstyrene, depending on the activity of the catalyst. Further exhaustive methylation of this base gave a hydrocarbon, CllHl,, IR-spectroscopic data of which support the structure of isobutenyl cycloheptatriene, LXXIII, containing a Ei>C

=

CH, linkage. Hydrogenation of this compound yields, how-

ever, a hydrocarbon C,,H,,, IR-data of which are very similar to but not identical with the curve of i-butylcycloheptane, obtained by synthesis (84) from 4-i-butylcyclohexanone by ring enlargement with diazomethane, followed by Kishner-Wolf reduction of the i-butylcycloheptanone. On the other hand, two of the possible structural isomers (LXXIV, LXXV) (1 :3, 1:4) of N,N-dimethyl-i-butylcycloheptylaminehave been synthesized. The IR-curves were very close to those of the saturated Hofmann base C13H,,N; none of them proved, however, to be identical with that of the base from dioscorine. Since configurations have not been taken into consideration, these data are not conclusive. Nevertheless, a new tentative formula has been suggested (84) which takes account of the formation of a >C = CH, group on decarboxylation of the hydroxy acid from dioscorine, i.e., that of the elactone of a tropine derivative with a /3-methyl-a,/3-butenoic acid side chain in

a. FODOR

170

LXXlV

position 2 (LXXVI) (84). Though these new investigations seem satisfactory in explaining the structural problem, it still requires synthetic confirmation in the reviewer’s opinion. As to stereochemical predictions the mydriatic effect of dioscorine supports strongly the presence of a 3a-placed hydroxyl group. Furthermore, Stuart-Briegleb models permit the existence of both cis and trans anellation of the sevenmembered unsaturated lactone ring to the piperidine ring of tropane. A more recent communication describes a somewhat different approach to the structural problem of dioscorine. Hydrogenolysis of the lactone led to a diol which on ozonolysis afforded glycolaldehyde and a hydroxy ketone. The latter underwent cleavage to acetone and another ketone, C,H1,ON, the IR-spectrum of which is more in accord with a five-membered than with a six-membered cyclic ketone. On this basis structure LXXVIa has been suggested for dioscorine (123). Racemic 6-oxotropane has been synthesized (135, 136) different from the ketone

LXXVI 0

LXXVl b


171

C,H,,ON obtained from dioscorine. Thus the alkaloid seems to be a 2-substituted tropane* (135) (LXXVIb).

V. Some New Physiological Aspects of Natural Tropane Bases and of Their Synthetic Derivativest The careful and extensive stereochemical investigations of the tropane bases rendered a reconsideration of their pharmacologicaleffects possible in correlating steric structure with physiological activity in a more precise manner than heretofore. Typical physiological effects exerted by tropane bases hitherto known are essentially as follows: ( I ) mydriatic, i.e., parasympathetic blocking, ( 2 ) anesthetic, (3) stimulating the central nervous system. Recently ( 4 ) ganglion blocking, i.e., curare-like activity, has been detected in some synthetic tropeines. Effect ( I ) proved to be based on tropanes with a C, a-placed esterified hydroxyl, e.g., atropine and hyoscyamine, as contrasted with (z), which seems to be specific for 3j3-tropanol esters only, such as tropacocaine, cocaine, and psicaine, whereas activities (3) and ( 4 ) seem to depend to a greater extent on the substituents of nitrogen and of the structure of the esterifying acid than of the a- or j3-location of the hydroxyl group at C, (89). Indeed, 0-benzoyl (instead of tropyl) esters of tropine were already known to have a reduced parasympathetic blocking activity, but this is more affected by the change of the substituent on nitrogen. All these effects point to a remarkable increase of the realm of therapeutic applicability, particularly for quaternary salts derived from tropine, e.g., in the therapy of collapse, of ulcus, in neuropathology, and so on. Quaternization of atropine has long been known (85) to result in a decrease in stimulating activity of the central nervous system with simultaneous maintenance of the parasympathetic blocking qualities. Mandelyltropine methobromide (“homatropine”) (86) has been found (1917) by Issekutz to have better therapeutic indices than the tropic ester derivative. In the last five years members of the staff of Issekutz, particularly Nador and Gyermek, contributed very much to this development. Replacement of alkyl groups by aralkyl in homatropine gave a strong decrease in parasympathetic blocking, i.e., antimuscarine effect, but a surprisingly great increase in synapsis blocking (antinicotine) activity (87, 88). The maximum of the antagonistic effect on * The ketone C,HI,ON proved now identical (144) with L( f) tropan-2-one prepared from natural cocaine (145). t This section is based mainly upon suggestions of Dr. K. NBdor and L. Gyermek (95, 134).

172

G. FODOR

vegetative ganglia has been reached by N,-p-xenylinethyl-3a-mandelyltropanium bromide (87, 88), while the p-aminobenzoyl ester of the same N-aralkyltropanium base proved three times as active as nicotine (89). Effect (a) emerged in other classes of bis-quaternary ammonium salts, i.e., decamethylene-bis-triethylammonium chloride (90) (“decamethonium”), the curare-like effect being ascribed to the interprosthetic distance of 13-15 d. of the two cationic centers (91, 92). However, Nb,N~p-xylylene-3a-benzoxytropaniumbromide (93) proved more active despite the fact that the two tropanium nitrogen atoms are considerably nearer than in decamethoniuin. Moreover, 0,O’-succinylbis-N,-benzyltropaniurn bromide (94) proved in frog tests five times as active, though the cationic centers are not as far from each other as in the N,N’-xylylene derivative. However, the N,-p-xylylene derivative is rather inactive, emphasizing the importance of the linear molecular shape for this type of physiological activity (95, 99). A number of 6-alkoxy tropeines have been synthesized (96, 97) recently in the search for new cholinegic compounds, and a brief account of their pharmacological properties has been given (98). According to this latter, 3~-benzoyl-6/3-( ?)-methoxytropanol (this alkoxy group was allocated (99) merely by the analogy of its synthesis leading to the 6p-hydroxy compound; however, 6-methoxytropine could be converted now into 3~~,6,4diacetoxytropane(137) ) is more active than scopolamine; the same holds true for the benzilic ester of the same synthetic alkamine (98). Nevertheless, N-butyl-scopolaminium bromide (“Buscopan”) seems to be superior in view of its blocking effect against acetylcholine esterase (100). 1-Substituted tropanols have been synthesized (101), e.g., 1 methoxymethyl-3a- and 3/3-tropanols, l-hydroxymethyltropan-3a-o1, and 1-methoxycarbonyltropines, which promise to have interesting physiological properties. A number of a-methyl-tropic esters of txopine and #-tropine, together with their methiodides and decamethylene di-iodides, have been prepared (102) showing some atropine-like effect. Derivatives of aecgonine methyl ester have also been synthesized, e.g., benzilic and p-aminobenzoyl esters and decamethylene salts. a-Ecgonine itself, if injected, proved a potent local anesthetic agent ( 1 03), at variance with earlier findings ( 104).

VI. Some New Approaches to the Problem of Biogenesis in the Tropane Field The formation of the tropane skeleton in the plant has been viewed as taking place in a manner similar to the successful Robinson-Schopf

173


synt,hesisof tropiiione (105) and of some of its derivatives as teloidinone (80) and 6-hydroxytropinone (39, 40, 61) from 1,4-dialdehydes under so-called physiological conditions ( 105).However, as mentioned already, epoxysuccindialdehyde failed to give scopinone under these circumstances (70). Furthermore the lack of enzymes in syntheses could hardly account for the occurrence of optically active 3~,6p-dihydroxytropane (59), valeroidine (go), cocaine, and ecgonine in the plant tissue. On the other hand, as discussed already in this monograph (Volume I, pp. 64-68) ornithine was suggested as a precursor of hyoscyamine. Recent feeding experiments on Datura stramonium with u-C14-labeledornithine (LXXVII) leading to C,-radioactive atropine (106) (LXXVIII) confirmed this view. It is peculiar, however, that scopolamine, which was formed simultaneously, was inactive.

\.

/CHa

t4.h

CHI C --,

I

H

CHI-CH~-"HI

COOH

-

LXXVll

% N

LXXVlll

OTI

,CHa

.

HOH

LXXIX

64 \

t H

LXXXl

4

OH LXXX

LXXXlll

This finding together with some plant geographical considerations (107) seemed to disprove the former assumption of a common precursor for these tropane bases, e.g., of tropenol (LXXIX) (108, log), which could be converted by enzymic reactions on the double bond (hydrogenation, hydration, oxidation, glycol formation, etc.) into the appropriate alkamines (LXXX-LXXXIII). More recently, however, it was recorded that a young Datura ferox plant, unable to produce hyoscine, gave hyoscine on feeding with hyoscyamine, identified by paper chromatography and isolated also as the picrate (110). An adult plant proved nevertheless unable to interconvert these alkaloids in agreement

174

a. FODOR

with the results of tracer studies (106). Dehydro hyoscyamine as well as (-) Sa,6fl-tropandiol 1-tropate both are converted by Datura ferox into hyoscine (138, 139). Hence, the central role of tropenol in the biosynthesis of tropariols might still be considered, though elucidation of these rather complicated problems requires further work.

VII. References R. Willstatter and A. Bode, Ber. 33, 1170 (1900). M. Barrowcliff and F. Tutin, J. Chem. SOC.95, 1966 (1909). G. Fodor and K. Nltdor, Nature 169, 462 (1952); J . Chem. SOC.p. 721 (1953). A. Nickon and L. F. Fieser, J . A m . Chem. Soc. 74, 5566 (1952). 5. M. Polonovski and M. Polonovski, Bull. SOC. chim. Frmce 43, 79 (1928). 6. L. H. Welsh, J . A m . Chcm. SOC.69, 71, 3500 (1949); G. Fedor and J. Kiss, Xature 163, 287 (1949) cf. A. P. Phillips and R. Baltzly, ibid. 69, 128 (1947). 7. G. Fodor and J . Kiss, J . A m . Chem. SOC.72, 3495 (1950). 8a. E. Hardegger and H. Ott, Helw. Chirn. Acta 36, 1186 (1953); b, 37, 685 (1954). 9. F. L. J. Sixma, C. M. Siegmann, and H. C. Beyermann, Konikl. Ned. Akad. Wcten schap. Ser. B . 54, 452 (1951). 10. C. M. Siegmann and J. P. Wibaut, Rec. traw. chim. 73, 203 (1954); H. C. Beyerman, C. M. Siegmann, F. L. J. Sixma, and J. H. Wisse, Rec. traw. chim. 75, 1445 (1956). 11. 0. Hromatka, C. Csoklich, and I. Hofbauer, Monatsh. Chem. 85, 1323 (1952). 12. Y.F. Smith and W. H. Hartung, J . A m . Chem. SOC.75, 3859 (1953). 13. T. A. Geismann, D. W. Burton, and R. B. Meclz, J . A m . Chem. SOC.76,4182 (1954). 14. B. L. Zenitz, C. M. Martini, M. Priznar, and F. C. Nachod, J . A m . Chem. SOC.74, 5564 (1952). 15. G. R. Clemo and K . H. Jack, Chem. & Ind. (London) p. 195 (1953). 16. S. Archer and T. R. Lewis, Chem. & I d . (London) p. 853 (1954). 17. Rafat Mirza, Nature 170, 730 (1952). 68, 1608 (1946). 18. L. C. Keagle and W. H. Hartung, J . A m . Chem. SOC. 19. 0. Kov4cs and I. Weisz, unpublished, quoted by G. Fodor, Acta Chim. A d . Sci. Hung. 5, 396 (1955). 20: N. L. Paddock, Chem. & Ind. (London) p. 63 (1953). 21. M. B. Sparke, Chem. & Ind. (London) p. 749 (1953). 22. A. K. Bose and R. Chaudhury, Nature 171, 652 (1952). 23. R. C. Cookson, Chem. & Ind. (London) p. 337 (1953). 24. A. R. H. Cole, R. N. Jones, and K. Dobriner, J . A m . Chem. SOC.74, 5571 (1952); A. Furst, H. H. Kuhn, R,. Scotoni Jr. and Hs. H. Gunt,hard, Helv. Chim. Acts 35, 951 (1952). 25. G. Fodor, Ezperientia 11, 129 (1955). 26. J. W. Visser, J. Manassen, and J. L. de Vries, Acta Cryst. 7, 288 (1954). 27. M. Scholtz and K. Bode, Arch. Pharm,. 242, 668 (1904). 28. J. T&h, Lecture, Meeting Hungarian Chem. Soc., Debrecen, Hungary, September, 1953; G. Fodor, J. T6th, J. LestyAn, and I. Vincze, Vegyipari Kutato lnltzetek Kozlemknyei 4, 293 (1954); G. Fodor, K . Koczka, and J. L e s t y h , J . C h m . SOC. p. 1411 (1956). 29. G. Fodor, II


CHAPTER 6

The Strychnos Alkaloids J. B. HENDRICKSON* Converse Memorial Laboratory, Harvard University, Cambridge, Massachusetts Page 179 11. Reactions of Strychnine and I t s Derivatives. .......................... 182 1. Strychnidine .................................................... 183 2. Permanganate Oxidation.. ....................................... 184 3. Bruciquinone .................................................... 185 4. Neostrychnine. ......................... ................. 186 5. Cyanogen Bromide Degradation. . . . . . . . . . . . . . . 187 6. Isostrychnine.. ............................ . . . . . . . . . . . . . . . . . 188 7. Pseudostrychnine. ............................................... 189 111. Vomicine.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195. 1. The Functional Groups.. ......................................... 19F 2. Fission around N b . . . . . . . . . . . . . ............................. 197 3. Deoxyvomicine and Isovomicine. ....................... IV. Minor Alkaloids.. ...................................... 1. The Australian Strychnos Alkaloids. ...................... 2. The Congo Strychnos Alkaloids.. ...................... 3. Nuz-vomicu Alkaloids ................ ... V. Biogenesis ........................................................ 206 VI. Synthesis.. . . . . . . . . ................................... 211 VII. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

I. Introduction ......................................................

I. Introduction The conquest of strychnine has finally been achieved, after almofit a century and a half of prodigious effort. The ultimate conclusion from the herculean assaults of the degradative chemistst has now been confirmed in full structural and stereochemical detail with the announcement of the complete delineation by X-ray crystallography (299, 300) and the total synthesis of the molecule (301, 302), which may be represented by the formula overleaf: * Present address, University of California, Los Angeles, California. t Compare with preceding chapters in “The Alkaloids.” I n accordance with previous practice in this series, the numbering of references and formulas in this chapter will follow consecutively from that of the previous two chapters, i.e., Volume I, Chapter 7, and Volume 11, Chapter 15. 179

180

J.

B. HI4:NDRICKSON

STRYCHNINE

Throughout virtually the entire historical span of organic chemistry the problem of the structure of strychnine has stood like a massive Everest amongst the challenging peaks of that field and was practically the last of the great classical problems of its kind to yield to the assaults directed against it. The immense amount of devoted effort on this problem has been broken down in terms of the number of contributions from each of the major laboratories (303), a compilation which totals 230 papers in this century alone. A cursory view of the development of the problem may lend perspective to its history and classical stature. The early period (1817-1910), featuring chiefly the work of Tafel, focused attack largely on the left side of the molecule, resulting in an expression for strychnine and the important correlation that brucine differed only in being dimethoxylated on the aromatic ring. In this and subsequent formulas the portion of the molecule which could be said to rest on unequivocal evidence is noted in heavy type as an indication of the course of the elucidation. The classical period (1910-1932) may be said to have started with the entrance into the battle of the English school, brilliantly headed by Sir Robert Robinson, and the forces of Hermann Leuchs in Berlin, who contributed the massive total of 225 papers of outstanding experimental work. The efforts of this period were largely devoted to oxidative incursions into the underside of the molecule. By 1932 the escalade had successfully taken the outer wall of the molecule’s defenses, leaving only the inaccessible and silent heart, which, with its singular intricacy of interlaced hydrocarbon rings, was to require sixteen more years of concentrated effort for solution. The formulas below accurately sum up the progress of these periods. The final period (1932-1948) was devoted to a search for entrke into the center of the molecule, which was

OH

Perkin and Robinson, 1910 (304a)

Perkin and Robinson, 1929 (304b)

181

THE STRYCHNOS ALKALOIDS

Qj N

0

Robinson, 1932 (304c)

0

Leuchs, 1932 (304d)

finally achieved in the clarification of the reactions of pseudostrychnine (303a, 303b), and the consequent demonstration of the structure of strychnine itself. Two relatively brief but excellent accounts of this history are available (303, 304). It will be advantageous, before proceeding, if we attempt to define what is meant by the title, “Strychnos Alkaloids,” of this series. Traditionally, it has referred only to those alkaloids isolated from Strychnos nirz-vomica, viz., strychnine, brucine, a- and 8-colubrine, vomicine, and pseudostrychnine, but in recent years investigations of a number of other Xtrychnos species have unearthed a quantity of new alkaloids, most of them very different from the structural family represented by the above. I n this chapter the traditional classification will generally be followed, but it is suggested that a more helpful and rigorous classification of these alkaloids will result from combining the traditional species classification with a biogenetic one. The basis for this classification will be taken up in more detail in the section dealing with biogenesis, but suffice it to say that the biogenetic relationships of the indole-derived alkaloids are on a firm enough footing to allow classification along these lines to be safely made. Furthermore, a biogenetic classification is essentially a structural one and so has the usefulness for chemists which that implies but escapes the objection of being purely arbitrary by having its basis in the reality of the plant’s modes of production of these substances. Combining taxonomic and biogenetic approaches to classification has the added advantage of pointing up the interrelations of the species in terms of their particular mechanisms for alkaloid generation. In addition to the known Strychnos alkaloids from the Asian species nux-vomica and ignatii, Strychnos species from three widely different geographical locales have recently been examined. The various Australian species yield strychnine and brucine as well as several new alkaloids of apparently the same structural family and biogenetic origin (305). The Congo Strychnos have been investigated by a Belgian group (306309) and found to yield strychnine, brucine, pseudostrychnine, and a series of new alkaloids, described in Section IV. On the other hand, the Xtrychnos plants from South America, a source of curare alkaloids, seem to contain no strychnine or any of its traditional family. Few of the

182

J. B. HENDRICKSON

many alkaloids from this source have been examined exhaustively enough even to yield provisional structures (although all seem to be derived from indoles, judging by ultraviolet absorption data), but no close structural or biogenetic relationship to the strychnine family has yet been shown and it seems reasonable at present to exclude them from consideration in this chapter. Several reviews of the curare alkaloids are available (310-3 12).

11. Reactions of Strychnine and Its Derivatives A number of degradative reactions on strychnine and its derivatives have been carried out since the writing of the last supplement (Vol. 11, Chap. 15). Before recounting these, however, it will be instructive to review momentarily the products of alkaline degradations on strychnine (cf. Vol. I, 380-382).* Eight products have been obtained in this way and identified, viz., carbazole, indole, skatole, 3-ethyl-indole, tryptamine, /3-picoline, /3-collidine, and a base, C,,H,,N (312a, slab), which, in the light of the correct strychnine formula, can now very likely be granted the structure CXCVIII. Also Kotake (313)has isolated, and demonstrated by synthesis, tryptophol ethyl ether (CXCIX) from alkaline degradation of ethoxymethyldihydroneostrychnine (see CLIII). I n view of the low esteem in which such violent degradations are often

_ .

CXCVlll

CXCIX

held in structural deductions and of the fact that all the old strychnine formulas involved cavalier neglect of at least one of these results, it is important to point out that not one of these products involves the rearrangement of any skeletal bond in strychnine, despite the apparently drastic nature of the conditions. The skeleton of CXCVIII is to be found intact (in heavy type) in the formula CC, which represents a

* References of this sort refer to the page numbers of the corresponding sections in the previous chapters, in Volume I and I1 of this mries.


183

simple first product of the action of base on strychnine. The remaining products are seen to be readily derived from CC by a simple dehydrogenation breaking the C,-C,, bond as in strychnone formation and hydrolyzing off acetic acid-cleavages shown by dotted lines in CC, to give CCI. This in turn can isomeriie to the indolenine tautomer CCII and be cleaved, as shown (arrows), to the hydroxy-aldehyde CCIII, ,?OH ,

I

‘I

I

CH,OH

CClll

which can now readily yield most of the above products. Thus, the hydroxymethyl-aldehyde CCIII can be isomerized to a methyl-acid (hydride transfer), decarboxylate, dehydrogenate to a pyridinium salt, and lose vinyl-indole to yield the /?-collidine and the nonbasic indole products (hydrolysis of the pyridinium moiety leads to tryptamine). Alternatively, the aldehyde side chain can cleave off and the hydroxymethyl group can be eliminated as formaldehyde ultimately to yield 8-picoline. An outline of changes of this sort, although not intended as a certain mechanism of alkaline degradation, can serve to indicate the possibility of simple alkali-induced changes which involve no great departures from known reactions and, most important, no skeletal rearrangements, thus serving to point up a reliability of this reaction for degradative studies which is not generally accepted. 1. STRYCHNIDINE~

The series of compounds arising from electrolytic reduction of the lactam to a methylene-amine (suffix “-idine”) has been of great service in degradative studies; thus it was only natural that attempts should recently have been made to replace this cumbersome reduction with lithium aluminum hydride. With strychnine, the colubrines, and dihydrobrucine the reaction went smoothly to the corresponding methylene bases (strychnidine, etc.) (314). Brucine, however, gave dehydrobrucidine in two polymorphic forms, formulated as AlO-ll-dehydrobrucidine, which was interconvertible with a methanol adduct (10methoxybrucidine) on recrystallization from methanol. All these products yielded dihydrobrucidine on catalytic hydrogenation (314317). The reaction of brucine with a series of Grignard reagents resulted


184

J. B. HENDRICKSON

analogously in the formation of the 10-substituted dehydrobrucidines (315) and comparable compounds from strychnine. These studies (315, 316) were undertaken in part in the hope that these reagents would also demethylate the aromatic ethers of brucine, but this hope was not realized. I n his thorough study of the N-methyl-pseudostrychnine derivat,es, Boit (318) investigated the reaction of lithium aluminum hydride on these compounds and showed that both N-methyl-sec-pseudostrychnine (CCIV, R =H) and N-methyl-sec-pseudostrychnidinegave the same product (CCV, R =H), which showed no carbonyl absorption in the infrared but did show- a band a t 3.0p, due to the hydroxyl group, which could be made to react with phenyl isocyanate to form a crystalline urethan. The same results were produced in the brucine series

ccv

CCIV

(R =OCH,), although in the iso-series, while N-methyl-sec-isopseudostrychnidine (CCVI, R =H) gave the corresponding alcohol, N-methylsec-isopseudostrychnine reduced only a t the lactam (and that only partially) to yield 10-hydroxy-sec-isopseudostrychnidine (CCVI, R=OH)-a result similar to that of brucine converted to dehydrobrucidine. It is noteworthy that lithium aluminum hydride succeeds in attacking the generally unreactive C,,-carbonyl in CCIV.

6H CCVI

2. PERMANGANATE OXIDATION*

Osmium tetroxide alone, or hydrogen peroxide with osmium tetroxide as catalyst, oxidizes strychnine to the expected glycol, CCVII, which * This 51 6-51 6.

material is supplementary to Volume I, pages 384-387; Volume 11, panes

185


yields strychninonic acid with permanganate (319), thus paralleling the oxidation with weakly acidic permanganate (319a). Lead tetraacetate oxidation of CCVII gives the expected aldehyde and the corresponding acid CCVIII. Like strychnine, strychnine N-oxide yields strychninonic and dihydrostrychninonic acids (320)and brucine N-oxide is completely analogous (321). The neutral permanganate oxidation of pseudostrychnine methyl ether gives the glycol di-lactam CCIX (benzal-derivative; monoacetate); this was cleaved with lead tetraacetate to pseudostrychninonal methyl ether (CCX), which yields a dioxime (321).

a:: * 0-CH,COOH

CCVll

CCVlll

0

0-CH,CHO

ccx

CCIX

3. BRUCIQUINONE* Investigations have been made on the phenoxazine formation from this quinone (XCIII) with ammonia. The product, called “Brucine Blue,” is formulated as CCXI and is said to be identical with a product

CCXl

CCXll

of Leuchs obtained by zinc reduction of the quinone oxime (322). The Frangois test for brucine is considered to involve a somewhat analogous dimeric coupling; the first product, a yellow precipitate from the action * This material is supplementary to Volume I, pages 392, 420-421.

186

J. B. HENDRICKSON

of bromine water, yields analyses for CCXII and the final brownish substance produced by the action of ammonium hydroxide on CCXII is formulated as CCXIII or a tautomer (323).

jzq:$d A. O

OH

X

\QI I H @ \ @ I N C="CN=C/ I /

H

I

0

CCXlll

CCXIV

4. NEOSTRYCHNINE* Neostrychnine (CL)is the isomer of strychnine produced by isomerization with Raney nickel, and thus is a vinylamine. Ordinary vinylamines form salts of the sort shown in CCXIV, but the cage structure of strychnine would lead us to suppose that neostrychnine could not form such a salt without violating Bredt's rule. I n a recent study of vinylamines it has been shown (324) that uncomplicated cases show a shift of the double-bond stretching frequency in the infrared spectrum on formation of the salt, but that, as anticipated, no such shift is observed on formation of the salts of neostrychnine. Hence access of the nitrogen's electrons at the 8-carbon as shown above-is not possible in neostrychnine without serious steric strain, so that the attack of nitrous acid (cf. Vol. 11, 520) and the reduced basicity of neostrychnine must be due primarily to inductive rather than resonance interaction of the nitrogen and the double bond. A rearrangement of some theoretical interest was discovered by Robinson (324a, 324b) in the course of studies on neostrychnine; the a.ction of acidic bromine water on this substance gave a base containing one additional oxygen as an aldehyde function. This aldehyde, oxodihydro-allostrychnine (CCXV), was said to hydrogenate to a primary alcohol as well as an isomer which reverted readily to neostrychnine in the presence of dilute acid. These changes were formulated as follows:

qL *2,

YO

0

-AH

o,:+

0

CL

* This material is supplementary to Volume I, pages 397-401; Volume 11, pages 518-520.

187


CHO

Dihydroisomer

cL

H,Oe+

ccxv Analogous changes were observed in other neo-bases, in one of which the compound corresponding to CCXV was reduced back to the neo-series by zinc and hydrochloric acid. If this sequence should prove correct, it would provide an interesting addition t o the known collection of acidcatalyzed rearrangements, but further experiment is clearly indicated before this scheme can be considered to be fully established. 5 . CYANOGEN BROMIDE DEGRADA4TION*

The position of cleavage by cyanogen bromide has now been established (325) with the isolation of two bromo-cyanamides, one crystalline and one not, from the reaction with strychnine, which previously had yielded only intractable gums. Dihydrostrychnine yielded only one product, which was identical with that produced by hydrogenating the crystalline strychnine derivative. This in turn was reduced with zinc, the cyano-group hydrolyzed off, and methylated to yield a base CCXVI which was different from the known allylic hydrogenolysis product (CCXVII) of methylstrychninium chloride. Accordingly, the crystalline W

H

,

4 1 ; ; N

N

0

0

CCXVI

0

0

CCXVll

CH, Br

CCXVlll

CCXIX

* This material is supplementary to Volume I, page 403.

188

J. B. HENDRICKSON

bromo-cyanamide was afforded structure CCXVIII and the noncrystalline, CCXIX. It is interesting to observe that the simple SN2displacement at C,, competes favorably with the normally more ready allylictype cleavage represented by CCXIX, while in the dihydro case, no N,-C,, cleavage occurs at all. This can presumably be taken as a measure of the greater steric accessibility of C,, over C,, to the attack of external reagents. 6. ISOSTRYCHNINE*

Isostrychnic (isostrychninic) acid is formed by the action of hot amyl-alcoholic alkali on strychnine and has been shown to possess, aside from the amino acid functions derived by opening the lactam, only one double bond and no hydroxyl group (325a). Hydrogenation with Adams’ catalyst was known to yield isotetrahydrostrychnine (325b) which possessed a readily dehydrated hydroxyl group. Assuming this hydroxyl group to be tertiary, Leuchs proposed the part structure CCXX for isostrychnic acid, indicating that its allylic hydrogenolysis and double-bond saturation would give rise to the corresponding isotetrahydrostrychnine with a tertiary alcohol at CI3. This has since been shown to be unjustified (326) since isotetrahydrostrychnidine (by electrolytic reduction of the lactam) is not readily dehydrated. Evidently,

ccxx

CCXXI

the structure of isostrychnic acid is CCXXI, the facile dehydration of the derived secondary alcohol at C,, being caused by its situation 8- to the lactam in isotetrahydrostrychnine (CCXXII). Since the acid is

n

f = J J & N H

HO,CH

CCXXll

‘0‘

Cti,

CCXXlll

* This material is supplementary to Volume I, pages 411-412;

Volume 11, page 621.


189

not identical with strychnic acid, the difference must lie in the configurations a t either or both of the centers C,, and CI3, these being the only asymmetric centers subject to epimerization in these alkaline conversions. Robinson (327) has since been able to build up isostrychnic acid from the reaction of acetic anhydride-sodium acetate on the Wieland-Gumlich aldehyde (327a, 327b) (CCXXIII; see also XXI; the aldehyde exists, as shown, as the hemiacetal, since it possesses no carbonyl absorption in the infrared (327c) ). He presents arguments to the effect that both C,, and C,, are inverted relative to their configurations in strychnine and strychnic acid. 7. PSEUDOSTRYCHNINE*

X new oxidation product of strychnine has been discovered, in a modified catalytic oxygenation, containing one more oxygen atoni than pseudostrychnine (328). This material, termed oxypseudostrychnine, is also formed by oxygenation of pseudostrychnine and enjoys the latter's easy etherification with alcohols to the corresponding alkyl structure. The compound is ether, thus suggesting the same C,,-OH not acetylatable and gives no carbonyl reactions, reduction in acidic media leaves it unchanged, hydrogenation only saturates the double bond, but reduction with sodium in wet chloroform yields pseudostrychnine. On the basis of the few assembled facts it seems hardly possible t o make a choice between the two alternative formulations of the author, viz., the N-oxide of pseudostrychnine and CCXXIV.

CCXXIV

ccxxv

It appears now that the formulation of the N-methyl-sec-pseudostrychnine metho-salts as N,N-dimethyl derivatives (CCXXVI) was quite unjustified and that the postulation of the facile and unique migration of a methyl group from nitrogen to oxygen and back (cf. c'ol. 11, 525-527) that was to account for their behavior may now be dispensed with, leaving us with a less remarkable story perhaps but one which is more in harmony with contemporary theory. * This material is supplrmentary to Volume I, pages' 412 418; \'olu~uo 11, pages 522 4 2 6 .

190

J. B. HENDRICKSON

CCXXVI

CCXXVll

The simplest argument that the metho-salts are t o be represented as CCXXVII, not as CCXXVI, derives from physical measurements: (CCXXVIII)* the infrared spectrum of N-methyl-sec-pseudostrychnine shows a carbonyl band at 5 . 9 5 ~which disappears in the methoperchlorate (329). A similar situation holds in the roughly analogous tenmembered-ring case of cryptopine (CCXXV) ( 5 . 9 7 ~ and ) its methoperchlorate (no carbonyl band). The same situation exists in protonation as in methylation, for the hydriodide of N-methyl-sec-pseudostrychnidine, in contrast to the free base, shows no carbonyl absorption. The keystone of the chemical proof for viewing the metho-salts as CCXXVI seems to have been, apart from one or two N-methyl determinations since proved incorrect, that methylation of pseudobrucine ethyl ether (CLXVI) and ethylation of pseudobrucine methyl ether give the same salt (CLXVII) via alkyl migration from oxygen to nitrogen. The experimental fact (329a),however, is that, while methylation of the ethyl ether gives the same mixed-alkyl salt as ethylation of N-methyl-sec-pseudobrucine (in agreement with CCXXVII), ethylation of the methyl derivative gives only the diethyl salt, the monoethyl hydriodides, and none of the mixed-alkyl salt found in the other experiment. Furthermore, even if CCXXVI and the postulated internal migrations were correct, the cross-alkylations described would not be expected to generate the same compound but rather to yield two salts epimeric a t the quaternary nitrogen, i.e., with the configurations of methyl and ethyl inverted in the one relative to the other. In a very thorough examination of these interesting pseudo-bases, Boit has conclusively demonstrated their behavior now by chemical means (330).The metho-salt in question (represented in its correct form, CCXXVII) can be prepared by methylation of either N-methyl-secpseudostrychnine (CCXXVIII) or 0-methyl-pseudostrychnine (pseudo-

* The prefix sec- (seco- from Latin secare, to cut) refers to the opened form of the ringchain tautomerism of the N-methylpseudo- series. Thus, N-methyl-sec-pseudostrychnine (CCXXVIII) and 0-methyl-pseudostrychnine (CCXXIX). This is to be distinguished from the prefix cham- (Greek chaos, chasm), which is reserved here for ring openings achieved by oxidative or reductive means, as in the sodium amalgam cleavages.

191


strychnine methyl ether) (CCXXIX). This in turn is interconvertible with the base N-methyl-sec-pseudostrychnine enol methyl ether (CCXXX) in acid or basic media as shown. If the methiodide of this base (CCXXXI) is now hydrolyzed (enol ether-ketone), one obtains a dimethyl salt which is isomeric with but different from the metho-salt in question. That the new substance is in fact CCXXVI is also demonstrated by its ready formation of an oxime. (Oxime formation occurs here and not in N-methyl-sec-pseudostrychnineowing to the absence here of an available electron pair on nitrogen to inactivate the carbonyl group.) Furthermore, unlike CCXXVII, CCXXVI gives no tertiary base on methoxide treatment. Hydrogenation of CCXXVII gives the known chano-base CCXVII (the hydrogenolysis of methoxy has been demonstrated in similar cases in vomicine chemistry by quantitative isolation of the methanol produced (330a), whereas CCXXVI takes up 3 moles of hydrogen to produce the alcohol CCXXXII. The same series

CCXXVlll

CCXXVll

J,

/

CCXXIX

&

I-'.=

ccxxx

I

OCH3 Q C ,H,CH,

0

0

0

CCXXVI

0

CCXXXI

CCXXXll

192

J . U. HENDRICKSON

of changes was also observed in the brucine, isostrychnine, and isobrucine analogs. The establishment of CCXXVII as the structure of the N-methyl-sec-pseudostrychnine metho-salts now allows the reactions of this salt with base and sodium amalgam (cf. CLXX) to be understood in a simple manner, without migrations. The consequences of this foriuulation in the vomicine series will be dealt with in that section. The extreme unreactivity of the C,,-carbonyl group in N-methylsec-pseudostrychnine has been the cause of much experiment and speculation. It forms no carbonyl derivatives and its infrared absorption has the long wavelength (over 5 . 9 ~ associated ) with inactivation in simpler systems like amides (329). That the cause of this inactivation is the presence of the electron-pair on N,, held rigidly in close proximity, is indicated by the low basicity (330b) and sluggish reactivity of that center. Furthermore, if the nitrogen electrons are taken up by methylation, as in CCXXVI, the carbonyl forms a normal oxime (330); alternatively, if the rigid proximity of the nitrogen is absent, as in the ketone corresponding to CCXXXII, it can also form an oxime (318). This state of affairs has often been ascribed t o resonance between the forms CCXXVIII and CCXXXIII (328, 330a). However, we must inquire as to

(y-gCH3 H c3/*

0

CCXXVlll

0

0

0

CCXXXlll

whether the two structures are not in fact tautomers. Thus, a primary definition of the difference between resonance and tautomerism in such syst,ems would state that the former involves shifts of electrons only, whereas the latter is distinguished by movements of atomic nuclei as well. Thus, in the classic case, a ketone differs from its enol not only in the movement of a hydrogen atom from carbon to oxygen but also in the change of the geometry of substituents at the a-carbon from a tetrahedral to a planar configuration, a change that involves a shift in the relative positions of several neighboring atoms. I n the enolate anion, on the other hand, although two forms can be written, with the charge residing either on carbon or oxygen, the geometry of the atomic nuclei is the same in each one (i.e., that of the planar enol without its hydrogen). It must be admitted that there is a twilight zone between the clear cases of resonance and of tautomerism; for example, neither of the two Kekul6 forms of benzene has exactly the geometry of the actual


193

molecule for each of them represents a structure of alternate long and short carbon-carbon bonds, whereas in benzene all the bonds are in fact of the same length. Thus benzene represents a case in which the gain in stabilization due to resonance more than offsets the energy required to distort the normal geometry of the two forms to the new symmetrical shape. Whereas benzene illustrates the case of two resonance forms which, but for the considerable stability derived from aromaticity, might be tautomers, a remarkable case of the existence of two tautomers strikingly close to this twilight zone has come to light in the strychnine series and may serve to illuminate the case in hand. Dihydrohydroxymethyldihydro(neo)strychnine (CCXXXIV) was made by cleavage of the C,,-N, bond of methylstrychnine by hydroxide, followed by hydrogenation of the double bond. This compound was oxidized with chromic acid to produce the corresponding aldehyde, but it was subsequently found that the substance produced was the tautomeric mixture CCXXXV-CCXXXVI (331). I n solution there is a rapid mobile equilibrium between the two compounds, but crystallization from water

I‘”‘o

ccxxxv

CCXXXVI

yields the less polar (hence less water-soluble) isomer, CCXXXV, as plates melting partially at 80°, then completely at 150°, whereas crystallization from benzene yields the more polar (less benzenesoluble) CCXXXVI as tiny prisms, melting at 165”. The infrared spectrum of solutions of either is the same, exhibiting a low-intensity 5.84,~ band, which is present and more intense in the solid spectrum of CCXXXV but disappears completely in the solid spectra of CCXXXVI N

194

J. B. HENDRICKSON

and of the salts derived by methylation (which must then be the 0-methyl salts derived from CCXXXVI). More evidence is also adduced, all in perfect accord with the independent existence of the two isomers. Thus we have here two tautomers which are distinguished from being simply resonance forms solely by the slight configurational difference a t the aldehyde carbon, planar in one case, tetrahedral in the other. It is, however, a difference representing a sufficient energy barrier to allow their separate existence! The application to the case of N-methylpseudostrychnine is inescapable. The open ketone, N-methyl-sec-pseudostrychnine (CCXXVIII), appears to be the isolated crystalline compound, judging by the solidstate infrared spectrum (329), but the tautomeric betaine, N-methylpseudostrychnine (CCXXXIII), formed virtually instantly on solution, is the more reactive to methylation and protonation, giving rise to products like CCXXVII. The dipolar tautomer is also responsible for the Emde cleavages discussed below. The nonreactivity of CCXXVIII to carbonyl reagents may be ascribed to a simple internal neutralization of the positive (carbonyl carbon) and negative (nitrogen) fields held in close proximity (330b), to a predominance of the betaine, CCXXXIII, at equilibrium, or to both. The latter explanation is probably much less likely, judging from the infrared solution spectra of vomicine derivatives (q.v.) which show a real, but shifted carbonyl band a t 6.02-6.06~. A series of very complete experiments have been made on the reductive cleavages of the methylated pseudo-bases. N-Methyl-sec-isopseudostrychnine (CCXXXVII, R = OH) takes up 4 moles of hydrogen on catalytic hydrogenation to give a tertiary chno-base (332) which is

CCXXXVll

F*.-H3

I

'

0 L

CCXL


195

identical with the product of hydrogenation of N-methyl-isostrychninium chloride (CCXXXVIII, R = OH) (333), and hence was formulated as CCXL (R = OH). Identical reactions were established in the deoxy series (R = H). It is clear that the first reaction is hydrogenolysis of the quaternary nitrogen of the betaine tautomer of CCXXXVII from its allylic site, yielding the carbinolamine CCXXXIX which then dehydrates and hydrogenates to CCXL. Similar allylic hydrogenolyses (Emde reductions) are general in the metho-salts, initiated by either hydrogen and catalyst or sodium amalgam. Thus, for example, N-methyl-isopseudobrucine methiodide (the isobrucine analog of CCXXVII) hydrogenates to CCXL (R =OH) (334), and the hydrogenations, previously mentioned, of methyl-strychninium chloride and N-methyl-pseudostrychnine methiodide to CCXVII follow a similar path. N-Methyl-sec-pseudobrucine enol methyl ether methiodide (brucine analog of CCXXXI) was reducible to the enol ether CCXLI (R=OCH,) either directly by catalytic hydrogenation or by sodium amalgam followed by saturation of the double bond, demonstrating the parallel course of the two reductions (335). Further investigations showed that the acid hydrolyses of CCXLI and of the direct product of sodium amalgam reduction both gave ketones which could

CCXLI

CCXLll

be hydrogenated to the same alcohol CCXLII, and that similar interconversions among the methiodides of the 21,22-dihydro bases supported the parallelism of the two types of reduction. An investigation on the analogous isobrucine series yielded comparable results (334).The sodium amalgam reduction of N-alkyl-pseudostrychninemetho-salts (cf. CCXXVII) generally cleaves the C,,-N, bond in preference to the allylic C,,-N, bond, yielding ether bases such as CLXX (329a), but in certain corresponding vomicine derivatives, two products are isolable, indicating a competition between the two reactions (vide infra).

III. Vomicine* I n view of the demonstrated identity of the nonaromatic portion of

* This material is 527-533.

supplementary to Volume

I, pages

426-436; Volume u[, pages

196

J. B. HENDRICKSON

vomicine with that of N-methyl-sec-pseudostrychnine (335a, 33513) and the reformulated interactions of the pseudo-bases described above, it is appropriate to recapitulate the chemistry of vomicine here in terms of the proper structures now assignable to its derivatives; the organization of Volume I will be retained. 1. THEFUNCTIONAL GROUPS* Vomicidine is phenolic, soluble in alkali, and capable of the ready oxidative destruction typical of o-aminophenols; the fact that vomicine itself appears not to be phenolic, on the other hand (not acylatable or soluble in alkali; no ferric chloride test), has been ascribed to a masking of the hydroxyl by internal attack on the lactam carbonyl (CIX) (336). Another explanation is that the hydroxyl is just very strongly

CIX

CCXLlll

CCXLIV

hydrogen-bonded to that carbonyl. The latter conception (vomicine, CCXLIII) has now been shown to be the correct one. The very close similarity of the ultraviolet spectrum of vomicine, not only with that of strychnine (337) but also with the spectra of alkaloids known to possess N-acetylindoline and 7-hydroxy-N-acetylindoline structures (338), rules out any actual destruction of the rr-electrons of the lactam carbony1 as in CIX. Furthermore, demethylaspidospermine (part structure CCXLIV) shows no hydroxyl band near 3p and lactam absorption at 6 . 1 2 in ~ the infrared, whereas the 0-acetyl derivative (which forms only with difficulty) has this band at the normal 6 . 0 1 ~position (338). Similarly, vomicine has no hydroxyl band and its lactam carbonyl absorbs at 6.12p, a band which disappears in the vomicidine series (339). Thus the existence of an intact carbonyl in the lactam is confirmed, the spectra showing further the effect on it of strong hydrogen-bonding forces in its considerable shift to longer wavelength. The unreactive carbonyl at C,, (strychnine numbering) of vomicine and vomicidine methyl ether (bz-OCH,) shows up in the infrared at 6 . 0 2 ~and 6.06p, respectively (in chloroform solution) (339). These bands are intense and suggest that the compounds exist largely as their ketone tautomers



197

in solution, but their considerable displacement to longer wavelength reflects the internal neutralization of the carbonyl by N,, which is rigidly held in close proximity by the structure of its environment. Conversely, the basicity of that nitrogen is markedly lowered t o pK 5.88 (330b). The case of internal neutralization in the protopines (cf. CCXXV), mentioned previously, is not nearly so marked as in vomicine owing to the more rigid structural adherence of the nitrogen close to the carbonyl in the latter; this is reflected in the greater carbonyl reactivity of the former as well as in the smaller displacement of its infrared absorption band from a normal position. 2. FISSION AROUND Nb*

The methyl-vomicinium salts must now be formulated as CCXLV in accord with the N-methylpseudostrychnine methiodides. On catalytic hydrogenation (330a) two stereoisomers of structure CCXLVI are formed as well as a mole of methanol, in accordance with the Emde cleavage described above. The sodium amalgam reductive cleavage

CCXLV

CCXLVI

yields two products, formerly inaccurately named N-methyl-vomicine I and 11. These compounds, as well as N-methyl-vomicidine I , yield analyses of one N-methyl and one 0-methyl group each (339a). One of these products must, on the grounds discussed above, be the normal Emde cleavage represented by CCXLVIII, so that the other is presumably the product of the competitive C,,-N, rupture (CCXLVII).

CCXLV II

CCXLV 111


198

J. B. HENDRICKSON

N-Methyl-vomicine I is demethylated to the corresponding secondary alcohol (cf. Vol. I, 432) by hydrogen bromide (339a), and so must be granted structure CCXLVII. N-Methyl-vomicine I1 (CCXLVIII) takes up 2 moles of hydrogen to yield a base, characterized only as its picrate, which should be one of the stereoisomers of CCXLVI, but this was not put to the test (339a).N-Methyl-vomicineI (for which the more accurate title 16-methoxy-vomicane is suggested) was converted by a second Emde reduction to the dimethylamino compound (“dimethylvomicine I”) which absorbs 1 mole of hydrogen and is degraded to trimethylamine by the Hofmann degradation. N-Methyl-vomicine I1 has been formulated as the corresponding neo-base (double bond shifted to A20--21) of CCXLVII, but this appears to have little to recommend it since the corresponding base in the deoxy series is unreactive to methylation, whereas N-methyl-vomicine I1 gives a methiodide which yields not only “dimethyl-vomicine 11” (different from I) on Emde reduction but also some N-methyl-vomicine I1 by splitting off methane (339a). Attempts have been made to interconvert the demethylated alcohol ( 16-hydroxy-vomicane) and vomicine by Oppenauer oxidation of the former and Meerwein-Ponndorf reduction of the latter (330a), but the failure of these attempts is not surprising in view of the internal nitrogen involvement with reactivity at CL6.I n view of Boit’s successful reduction a t that center with lithium aluminum hydride in the Nmethyl-sec-pseudostrychnine series (318), however, it is possible that this reagent may be effective on vomicine. 3. DEOXYVOMICINE AND ISOVOMICINE*

The products of halogen acids on vomicine are now seen to be those anticipated from the analogous strychnine cases, involving opening of ring VII. Thus isovomicine, from HBr, is CCXLIX (R = OH), the initial iodo product from HI is 12-iodo-12,13-dihydrodeoxyvomicine (CCXLIX, R = H; HI), and the stable, colorless deoxyvomicine is CCXLIX (R = H).

+

CCXLIX

CCL

* This material is supplementary t o Volume I, pages 433-436.

199


Two other deoxyvomicines are known: yellow deoxyvomicine, which readily isomerizes to the stable, colorless CCXLIX, still remains something of an enigma; neodeoxyvomicine is, however, now established as CCL (337) and will therefore be discussed first. Neodeoxyvomicine has been obtained in three ways: (1) by the action of potassium iodide in phosphoric acid on vomicine (339b); (2) as a side product in the reaction of methyl iodide with (colorless) deoxyvomicine (330a); and (3) as a second product of the isomerization of the yellow deoxyvomicine with sodium acetate in acetic acid (337). The vinylamine (neo-position) grouping is reflected in its lower basicity (pK 5.16; vomicine, pK 5.88) and unreacti‘vity to methylating agents. Furthermore, it generates no acetaldehyde on ozonolysis. Unlike deoxyvomicine,the neo-isomer forms no benzal derivative and, since its ultraviolet absorption is closely akin to that of N-crotonyl-o-aminophenol,has been assigned the a$-position of unsaturation in ring 111, shown in CCL. In contrast to the other deoxyvomicines, CCL takes up only 1 mole of hydrogen. Taken with its unreactivity to sodium amalgam, this result implies no allylic positioning of N,, previously discussed as mandatory for the characteristic Emde cleavages of these pseudo-bases. Yellow deoxyvomicine is formed by the direct action of HI on vomicine but is readily converted to the stable isomer with bases, zinc chloride, or heat. Accordingly, with benzaldehyde and base they both yield the same benzal derivative. Furthermore, the yellow isomer forms a yellow metho-salt which also undergoes ready transition with base to the metho-salt of the colorless species, and both salts as a result yield the same Emde product with sodium amalgam. That the allylic double bond remains at the C,,-,, position is shown by ozonolysis of both the deoxyvomicines (and the dihydro derivative of the yellow isomer) to significant yields of acetaldehyde (337, 3390). Thus yellow deoxyvomicine has been formulated as CCLI (337, 340), the isomerization to

CCLI

CCLll

the colorless isomer CCXLIX finding precedent in the formulation of the strychninolones. Reduction of the a,p-double bond in ring I11 either by zinc reduction of 12-iodo-12,13-dihydrodeoxyvomicineor

200

J. B. HENDRICKSON

partial hydrogenation of yellow deoxyvomicine gives the same dihydro derivative (m.p. 164-168'), which also appears to be identical with the anomalous lactamic dihydro product from electrolytic reduction of yellow deoxyvomicine (m.p. 161') (340a)-an interrelation which strongly supports the conjugated position of this double bond. The electrolytic reduction product (m.p. 161') yields CCLII on total hydrogenation, identical with the substance obtained by total hydrogenation of both deoxyvomicines. Extensive hydrogenation studies have been carried out on the deoxyvomicines. As noted above, both isomers absorb 4 moles to yield the anticipated CCLII, as does the metho-methylsulfate of deoxyvomicine with demonstrated loss of a mole of methanol (330a). Analogous to previous cases, this salt is CCLIII. In a parallel reaction the comparable metho-salt of the dihydrodeoxyvomicine (m.p. 164-168') discussed above also hydrogenates with loss of methanol to CCLII. Using special aged catalysts, Huisgen (337) was able to isolate a variety of partialhydrogenation products of yellow deoxyvomicine. Thus 1 mole yielded dihydrodeoxyvomicine (m.p. 164-168"), and 3 moles provided CCLIV, which yielded acetaldehyde on ozonolysis and CCLII on further hydrogenation. Dihydrodeoxyvomicine could be variously reduced to

CCLlll

CCLIV

CCLII, to CCLIV, and to an isomer of CCLIV which may involve a shift of the remaining double bond to the neighboring tetrasubstituted.position. Colorless deoxyvomicine, under similar conditions, gives a second isomer of CCLIV which can be formulated either as an epimer a t C,, or the isomer with a C,,-,, double bond (by preliminary isomerization of A21-22 and 1,4-addition). Finally, total hydrogenation of dihydrodeoxyvomicine or CCLIV in the presence of HC1 yields an isomer of CCLII which may involve epimerization a t any or all of the positions 13, 14, or 21. The above recapitulation satisfies most of the known facts about the yellow deoxyvomicine except its color. The ultraviolet absorption of this compound is strikingly unlike that of neodeoxyvomicine and in fact dissimilar to spectra of anything in the series (337), being more closely


20 1

akin to the a-pyridone spectra of dehydrostrychninolone or the model CCLXXVIII. A vinylamine formulation for yellow deoxyvomicine such as derived for “tetrahydro” vomicine A in the next paragraph (cf. CCLV, R = 0) must be rejected on two counts: that compound is colorless, and, although electrolytic reduction reduces the double bond in that situation, it also reduces the lactam carbonyl. On the other hand, that CCLI should reduce electrolytically only at the double bond but not at the lactam thereafter is unusual. Finally, it is difficult to rationalize the contrast of facile isomerization of the 11,12-double bond to A12-13 in yellow deoxyvomicine with its stability in neodeoxyvomicine (cf. no benzal derivative). Thus the structure CCLI of the yellow isomer cannot be said to rest on firm ground. Three isomers of tetrahydrodeoxyvomicidine have been prepared (339c, 340b) from deoxydihydrovomicine. (This substance, also referred to as dihydrodeoxyvomicine I, is obtained by HBr and zinc reduction on dihydrovomicine or zinc reduction of the HBr-addition product of deoxyvomicine, and involves reduction of the C2,-,, double bond as opposed to the ring 111-hydrogenateddihydrodeoxyvomicine previously discussed, which is also referred to as dihydrodeoxyvomicine 11.) Hydrogenation of deoxydihydrovomicine results in tetrahydrovomicines A and B, which are converted to the dibasic tetrahydrovomicidines A and B by electrolytic reduction. Conversely, electrolytic reduction of deoxydihydrovomicine followed by hydrogenation yields tetrahydrovomicidine C. A reasonable formulation of these products is possible if two experimental facts are brought into evidence. Firstly, tetrahydrovomicine A yields a colorless benzal derivative, typical of the 1 1-benzyl-a-pyridones similarly formed as “benzal derivatives” in the isostrychnine series (340c) and diagnostic of the presence of a double bond in ring 111. Secondly, tetrahydrovomicidine C, like the hydrogenation products of isovomicidine and deoxyvomicidine, does not give the typical color reactions of o-aminophenols with oxidizing agents in acidic media (340b). Woodward has suggested (footnote 26, reference 262) that this behavior indicates the presence of a double bond conjugated to N, so that in the acidic solution of the color tests it exists

+

as the nonoxidizable (p-N=C-CH

I

l

l

salts. Both pieces of evidence, then,

indicate (340) that none of the hydrogenations in this series have actually served to saturate the double bonds, but only to isomerize them catalytically to hindered tetrasubstituted positions. Accordingly, “tetrahydro” vomicine A is CCLV (R = 0),which then suffers reduction of the double bond electrolytically (owing to its conjugation with nitrogen) to tetrahydrovomicidine A (CCLVII), which gives normal

202

J. B. HENDRICKSON

oxidative colors in acid solution. (Tetrahydro” vomicidine B is then CCLVI, which also gives normal aminophenol color reactions, and “tetrahydro”vomicidine C is CCLV (R = Hz).Similarly the hydrogenation products of isovomicidine and deoxyvomicidine must be recognized as vinylamines like CCLV (R = Hz). (

CCLV

CCLVI

CCLVll

An intriguing situation exists in the formation of an isomeric methosalt from the methylation of deoxyvomicine. Inasmuch as this isomer is also formed in a partial isomerization of the normal metho-salt of deoxyvomicine (CCLIII) by iodine in methanol, it has been assumed that only a double-bond shift differentiates the salts and that the isomer was in fact the metho-salt of neodeoxyvomicine (A20-21)(330a). No direct comparison is possible, however, since the metho-salt of neodeoxyvomicine is unobtainable by direct methylation of the parent neo-base. The Emde reductions of this isomeric salt are remarkably uncharacteristic. Thus sodium amalgam gives two isomeric products, one of which yielded acetaldehyde on ozonolysis and gave a diacetyl derivative, suggesting the generation of a secondary hydroxyl group from a ketone at C16.Hydrogenation of the salt took up 3 instead of 4 moles to give a product with two N-methyl groups which could be reduced further with sodium amalgam to a dihydro product isomeric but not identical with the tetrahydro derivative obtained by hydrogenating one of the sodium amalgam products (the other does not hydrogenate). The vinylamine structure, as a neodeoxyvomicine methosalt, is not compatible with the Emde requirement of an allylic system


203

in this series, but the salient feature of this interesting metho-salt is the indication that it truly represents a member of the previously rejected family of N,N-dimethyl-seco- salts of the pseudo-bases with structures such as CCXXVI! A formulation which allows us to account for this singular behavior is given in CCLVIII in which the conjugated doublebond system, although not unduly strained in CCLVIII, would violate Bredt’s rule if a bond were formed between Nb and C,, as in the normal metho-salts. Sodium amalgam accomplishes normal allylic Emde

CCLV II I

CCLIX

reduction as well as simple reduction of the ketone (cf. oxime formation on CCXXVI), yielding the two dimethylamino bases CCLIX (doublebond shift; yields acetaldehyde) and its isomer with the unchanged conjugated double-bond system of CCLVIII; the latter, being hindered and conjugated, does not hydrogenate. Hydrogenation of the salt

CCLX

CCLXI

yields CCLX which is reduced to CCLXI by sodium amalgam. An epimer of CCLXI is obtained by hydrogenating CCLIX, differing in configuration at C,, or C,,. The relation between CCLXI and the comparable alcohol CCXXXII in a previous series (4.w.)should be noted. Finally, chromic acid oxidation of 21,22-dihydrodeoxyvomicidine (see Vol. I, 435) yields the pyridine base C,,H,,N,O (CCLXII), which contains one N-methyl group but dehydrogenates with loss of the elements CH,O to a base C,,H,,N, with no N-methyl which must presumably be formulated as CCLXIII (340).This same structure has been allotted to dehydroaponucidine (340d),obtained by oxidation and

204

J. B. HENDRICKSON

dehydrogenation of brucine. The interesting possibility that they might be identical, and so provide another link between vomicine and strychnine, has not yet been examined.

CCLXll

CCLXlll

IV. Minor Alkaloids 1. THE AUSTRALIAN Strychnos ALKALOIDS

Of the four species of Xtrychnos found in Australia, X . lucida R. Br. was found to contain strychnine (0.1yo)and brucine (1.3yo)as well as a further 0.5% of unresolved alkaloids (305). An alkaloid, lucidine-S, has been reported from the same source (341), but may be present only in the young plants, as its presence could not be confirmed in the older samples (305). The leaves of S. psilosperma F. Muell. were claimed to contain strychnine, brucine, and strychnicine (341); a later investigation (305) did not confirm this but resulted in the isolation of two new alkaloids, strychnospermine (0.9%) and spermostrychnine (0.5%). Strychnospermine, C,,H,,N,O,, was found to contain one methoxyl, at least two C-methyl groups, but no N-methyl groups (305). One nitrogen was tertiary, forming a methiodide; the other was present as N-acetyl, with an ultraviolet absorption very similar to that of p-colubrine, which yielded an N-nitroso derivative after hydrolytic

CCLXIV

deacetylation. The remaining oxygen atom was unreactive and assumed to be an ether bridge. It is a tribute to the elucidative power of the biogenetic mechanism that it sufficed, with these few data, to predict the formula (CCLXIV, R = OCH,) for strychnospermine (305))which has been virtually established by the experiments which follow (342). Spermostrychnine, C,,H,,N,O,, contains no methoxyl groups and shows


205

the ultraviolet spectrum of strychnine. It was felt that this alkaloid represented simply the demethoxylated derivative (CCLXIV, R = H) of strychnospermine (305); this was proved by oxidation of each alkaloid to the same C,,H,,,N,O, base with chromic acid. The chemical similarity to dioxonucidine in the strychnine series allowed formulation of this compound as CCLXV. Desacetyl-spermostrychnine was treated vigorously with hydrogen bromide in acetic acid and the crude product reduced with zinc and acetylated to yield deoxydihydrospermostrychnine (CCLXVI). The identical substance was produced by reduction of the Wieland-Gumlich aldehyde (CCXXIII) (327a, 327b) with potassium borohydride and hydrogen over palladium-charcoal, followed by the same hydrogen bromide, zinc dust, acetylation series as before. Thus the

CCLXV

CCLXVI

carbon skeletons of these two new alkaloids are established (342). The position of the methoxyl group in strychnospermine was further confirmed by rhodamine dye colors produced on fusion of phthalic anhydride with demethyldesacetyl-strychnospermineor N-ethyl-demethyldesacetyl-strychnospermine, which showed the presence of a metahydroxyaniline, and, more conclusively, by comparison of ultraviolet spectra with various model compounds (bz-methoxy-hexahydrocarbazoles) (342). Thus the relationship of spermostrychnine and strychnospermine corresponds to that of strychnine and 8-colubrine, respectively, and adds new data to the already strong evidence for the biogenetic schemes to be discussed in the next section. 2. THE CONGOStrychnos ALKALOIDS I n recent years a Belgian group has been examining the alkaloids of several species of Strychnos in this region, having identified strychnine in S. icuju in the amount of 6.6% in the branch bark, thus making this by far the richest source yet discovered (306). Two new alkaloids, “B” and “C,” were isolated by chromatography (309, 343). The formulas C,,H,,N,O, and C,,H,,N,O, were given as well as color reactions and ultraviolet spectra similar to those of brucine for both compounds. Methoxyl but no methylenedioxy groups were observed. S. angolensis

206

J. B. HENDRICKSON

also yielded strychnine and two other alkaloids by paper chromatography (308). From S . hobtii were separated four new alkaloids by chromatography: holstiine, holstiline, condensamine, and retuline (307). Holstiine, C2,H2,N,0,, m.p. 248-250°, [a]+268.9O, contains one N-methyl but no methoxyl group and is not catalytically hydrogenated (344). The ultraviolet spectrum is very similar to that of strychnine but significantly different from that of vomicine or isovomicine. The compound is reported to be soluble in excess 1% NaOH but not in NH,OH (307), but the ultraviolet spectrum, on the other hand, is unchanged in alkaline medium (344). The infrared spectrum shows a carbonyl doublet just above 6 . 0 ~ one ~ peak (or both) of which is presumably due to a lactam, probably located as in strychnine. The lower carbonyl of the doublet may be due to an unreactive C,,-carbonyl as in vomicine, but, compared with vomicine (pK 5.88) or strychnine (pK 7.37) (330b), holstiine possesses an unusually strong basicity at pK 8.8, which would seem to contravene this hypothesis. Holstiline, C,,H,,N,O,, m.p. 219-220°, has a similar ultraviolet absorption but has methoxyl and no N-methyl groups. Condensamine, C,,H,,N,O,, m.p. 262-265", also has methoxyl without N-methyl but shows an ultraviolet absorption similar to a-colubrine. Retuline, C,,H,,N,O,, m.p. 165-170°, has no N-methyl or methoxyl and shows an ultraviolet spectrum almost identical with strychnine. Its formula, solubilities, and melting point suggest it is identical with the tetrahydroneostrychnine of Robinson et d.(344a) (reported m.p. 167-168"), although the comparison has not been made. 3. Nux-vomica ALKALOIDS The alkaloid novacine has recently been isolated from S. nux-vomica and proved to be N-methyl-sec-pseudobrucine(345), thus establishing another biogenetic link between the strychnine and vomicine series and demonstrating that oxidation of the former to pseudostrychnine can actually occur in the plant and need not be simply an artifact of oxidation during isolation. This follows from the fact that strychnine metho-salts are not oxidized to the pseudo-series, so that oxidation followed by methylation must occur in the plant.

V. Biogenesis The simple basis for the biosynthesis of alkaloids in the plant cell is that a few common amino acids can be converted simply into reactive intermediates which may then condense spontaneously in variants of the Mannich reaction to yield, virtually a t a stroke, the fully elaborated nuclei of the alkaloids. More detailed accounts of the biogenetic concept


207

are available (346-348) but it will serve our purpose best here to examine only the indole-derived alkaloids. In particular, a vast number of indole and Strychnos alkaloids have been shown to be derivable from the amino acids tryptophan, dihydroxyphenylalanine, and glycine by variants of a simple major hypothesis. This tour de force in itself lends credence to the whole conception. Thus, tryptophan is considered to decarboxylate to tryptamine (CCLXVII), and glycine and dihydroxyphenylalanine are considered to oxidize with decarboxylation to formaldehyde and the aldehyde CCLXVIII or simple equivalents thereof. Since the indole component is known to possess anionoid reactivity at both the a- and p-positions, either of these centers may react with the aldehyde CCLXVIII and the primary amino group in a Mannich reaction, as shown below. The aerived products can then react again in an analogous reaction with formaldehyde to yield CCLXIX and

e)H

CCLXIX

CCLXX (349-351). I n these products can be seen the obvious progenitors of the Strychnos and Yohimbe alkaloids, and it will be shown that a variety of less obvious alkaloidal skeletons can also be handily derived from these two molecules. The further elaboration of strychnine from CCLXIX (349) postulates a second general biogenetic reaction in the cleavage (which is not necessarily oxidative) of the catechol ring between its oxygens. Since it is of course not possible to detail the intimate

208

J. B . HENDRICKSON

course of this cleavage in the plant, we must content ourselves with assuming (at least for the strychnine case) a product such as CCLXXI possessing oxygen functions in an oxidation state appropriate to easy further elaboration. This uncertainty does not invalidate the general scheme, however, since it is the construction of the carbon skeleton, not its ultimate oxidation state, which primarily concerns us here. In support of this view cases will later be brought into evidence of a wide variety of alkaloids with common skeletons but differing states of oxidation a t various key centers. If the molecule CCLXXI should now undergo a facile Mannich reaction to close ring I V and then be acetylated on N, (N,-acetyl-indoline alkaloids are known, cf. aspidospermine (338) and strychnospermine (342) ), there will be formed an intermediate,

n

CCLXXI

n

CCLXXll

CCLXXII, which can very easily condense and dehydrate to strychnine. Thus the seven-membered oxide ring contains all the former carbons of the oxygenated aromatic ring of CCLXIX; a similar situation is seen to exist in the comparable oxide ring of strychnospermine (q.v.), reflecting its parallel biogenesis. It will be noted that the Mannich reaction of CCLXXI, closing ring IV, yields in fact the WielandGumlich aldehyde (CCXXIII, vide supra), which Robinson has in fact converted to strychnine (360) with acetic anhydride in high yield, showing at least that a simple acetylation, not beyond the plant’s means, can yield the right product here. That the major condensation step of aldehyde CCLXVIII and tryptamine can in fact occur under “physiological conditions” has been amply demonstrated by Hahn (351) in a striking “physiological synthesis” of a base with the yohimbine skeleton (CCLXX). Hahn’s demonstration of spontaneous condensation at the indole a-position, however, casts doubt on the facility of the /3-condensation required for the Strychnos alkaloids and leads us to consider a variation of the scheme in which the a-position is oxidized first to an oxindole, thus forcing condensation only at the /3-position. That the /3-position of oxindoles is an adequate anionoid source is shown by the recent demonstration (352) that the oxindole CCLXXIII, on dehydrogenation, yields a base,


209

CCLXXIV, reminiscent of the strychnine progenitor above. The first step of this reaction must be formation of an anhydro salt CCLXXIIIa, the rapid condensation of which with the 8-position of the oxindole is in fact the previously invoked Mannich reaction! Further support for this biogenetic variation is to be found in the existence of an intact 8-disubstituted oxindole in gelsemine (353), an alkaloid which also appears to

I CH,

CCLXXlll

CCLXXllla

-

CCLXXIV

be derived from the same amino acid precursors as strychnine (354,355). The oxidation of carbon a- to nitrogen, required for oxindole formation here, is ably argued by Wenkert (355) to be another very widespread biogenetic mechanism, initiated by N-oxide formation and conversion of the N-oxide to a carbinol-amine or anhydro salt'. With slight variation it also explains the formation in plants of pseudostrychnine and vomicine. The ability of plants to utilize both the major biogenetic routes (to CCLXIX and CCLXX) is amply demonstrated by the various Strychnos species, some of which elaborate the strychnine family of alkaloids, some of which (the South American Strychnos) elaborate yohimbine types (curare alkaloids). Even more striking is the biosynthesis in the one plant Gelsemium sempervirens (not a Strychnos) of both gelsemine (353) and sempervirine (356), the former produced via CCLXIX, the latter via CCLXX. Other plants, not of Strychnos species, also appear to produce alkaloids structurally related to strychnine, cf. akuammicine (357).

Although it is of interest that no alkaloids have yet been found which possess an uncleaved carbocyclic ring derived from the oxygenated aromatic ring of CCLXIX in the strychnine-type biogenetic route, the Yohimbe alkaloids contain a wealth of examples both of intact E-rings (yohimbine and sempervirine (358) ) and E-rings which have been broken, always at the bond between the hydroxyls in the progenitor CCLXX. This E-ring rupture is evident in the skeletons of such a host of widely different alkaloids [e.g., corynantheine (347, 358), cinchonamine (358, 358a), ajmaline (359), and mavacurine (361)] that its generality as a mechanism cannot be doubted. In the appended formulas 0

210

J. B. HENDRICKSON

of these illustrative alkaloids, the six carbons of the original phenylalanine aromatic ring are indicated by heavy type; the location of the carbon from formaldehyde (glycine) is circled.

H

H

Gclecminc

Sempcrvirinc

Yohimbinc

d

Cor ynonthcinc

Akuammicine

CH3

Cinchonaminc

cyooc

C Y

OH

ow

T

H

Ajmaline

CH3

Mavacurinc

CH,

The simplicity and widespread applicability of the biogenetic hypothesis suggest its use as a basis for a classification of alkaloids, as mentioned in the introduction. The operation of the primary Mannich condensations can yield two groups of alkaloidal skeletons, provisionally titled the yohimboid (a-condensation) and strychnoid @-condensation) groups. The subgroups derived by operation as well of the aromatic ring cleavage can then be designated as the chanoyohimboid and chanostrychnoid alkaloids. Of the groups no true strychnoid alkaloids are known (present indications are that gelsemine may be), strychnine and its family are chanostrychnoid, reserpine is yohimboid, and cinchonamine, chanoyohimboid. Thus the present chapter is more accurately described as dealing with chanostrychnoid alkaloids from Strychnos species rather than simply with Strychnos species alkaloids. The names have the advantage that they can be viewed as purely structural classifications without committing the more cautious user to any endorsement of hypothetical biogenetic schemes. Finally, it should be noted that a simple extension of this classification can cover also the further great family of alkaloids of cinchona origin, a discussion of their


21 1

biogenesis from the same initial amino acids, via indolic intermediates, having been presented by Woodward (358a).

VI. Synthesis Now that the long course of degradative effort devoted to establishing the structure of strychnine has been crowned with confirmation with the announcement of the total synthesis of that substance by Woodward and his collaborators (301,302),it is appropriate that we review here the various synthetic assaults which have been made upon this redoubtable bastion. It is immediately apparent that, apart from the ultimately successful total synthesis, few attempts have been directed toward strychnine. This paucity of effort at total or even partial synthesis is almost unique in the history of major classical natural products and almost certainly reflects the appalling prospect this molecule presents to the synthetist. There is no proper place here to include syntheses of simple degradation products or ultraviolet absorption models, inasmuch as their purpose was merely one of confirmation for degradative results and the molecules so synthesized offer in general no worth-while starting point for elaboration of the entire skeleton. Apart from some fruitless attempts to emulate the biosynthesis with 8-oxindole-ethylamine and a substituted phenylacetaldehyde (362, 362a) (whichfoundered, not at the condensation step, but in the preparation of the amine, which, however, is now available synthetically (339)), all the early synthetic experiments were made in Robinson’s laboratories. The only partial synthesis of significance is the previously mentioned conversion of the WielandGumlich aldehyde to strychnine with acetic anhydride and malonic acid (360). The earliest efforts toward total synthesis (363, 363a, 363b), involved the forging of CCLXXV by a Fischer indole synthesis on the appropriate cyclohexanone-tri-acid. This synthesis was not carried beyond imine-reduction and lactamization and, since it was dedicated to an older, invalid strychnine formula, it is of little present interest.

HOOC

CCLXXV

CCLXXVI

More recently, a synthetic approach through the 2,3-benzpyrrocolines (CCLXXVI) took advantage of that system’s propensity for C-alkylation to achieve the crucial quaternary center at the indolic

212

J. B. HENDRICKSON

8-position (364). Thus, CCLXXVI was afforded by acid condensation of skatole with levulinaldehyde dimethyl acetal or its equivalent, 2-methylfuran, and then methylated with methyl iodide to furnish CCLXXVII, which could be oxidized with ferricyanide to CCLXXVIII. Other than the obtention by like means of CCLXXIX no further report

CCLXXVll

CCLXXVlll

q

HCOCHa

OJ-FH2 ' U c * C HI

C H,

CH20H

N

CCLXXIX

CCLXXX

has been forthcoming on the progress of this approach. I n 1953 Robinson advanced a very ingenious suggestion (365) for a strychnine synthesis in which the pyridine base CCLXXX might be hydrolyzed and reduced to the substituted glutaraldehyde CCLXXXI, which in turn could condense as shown (dotted lines) to yield the WielandGumlich aldehyde (CCXXIII)directly. However, a number of approaches (366) failed to produce CCLXXX, although it proved possible to prepare the simpler substance CCLXXXII. Unfortunately, the methiodide of the latter compound resisted the attempts made upon it to produce the corresponding glutaraldehyde and the work appears to have been abandoned at this stage. As no other synthetic approaches have seen the light of publication, we cam proceed to discussion of the Woodward synthesis (Chart I).

WJ0 &I

CCLXXXI

gCH2

N

CCLXXXll


213

The plan of attack was strongly influenced by the biogenetic considerations delineated above. Thus a tryptamine was to be condensed with an aldehyde to close ring V, but the necessity of blocking reactivity at the a-position of the indole first led to a decision to attach the oxygenated benzene ring to that position from the start. Then the Mannich condensation could be essayed with a two-carbon aldehyde, representing the remaining portion of the phenylacetaldehyde utilized by the synthesis in nature. I n accordance with this plan 2-veratrylindole (CCLXXXIII) was prepared by the Fischer indole synthesis and converted to 2-veratryltryptamine (CCLXXXV) via Mannich reaction to the gramine (CCLXXXIV), displacement of trimethylamine from its methiodide with cyanide ion, and reduction. The biogenetic condensation was next attempted with ethyl glyoxylate but only the Schiff base CCLXXXVI formed under simple acid or base catalysis, indicating perhaps some preference for the oxindole variant in the actual biosynthesis (vide supra). Toluenesulfonyl chloride and pyridine, however, closed ring V and the product (CCLXXXVII) was reduced and acetylated to CCLXXXVIII. Another feature of the biogenetic scheme was invoked at this stage, before closing ring IV, in the oxidative rupture of the oxygenated aromatic ring. This was achieved with vigorous ozonolysis to the diester CCLXXXIX, which rotated (at the arrow) and cyclized to the pyridone CCXC when subjected to methanolic acid; a double-bond shift also occurs. After the toluenesulfonyl residue had been replaced by acetyl (since Dieckmann conditions on CCXC had yielded a bizarre result tangential to the desired route), the Dieckmann reaction proceeded smoothly, closing ring I V to the pentacyclic CCXCI. This compound was reduced via the thio-enol benzyl ether (-SC,H, for -OH in CCXCI), Raney nickel, and catalytic hydrogenation to yield the acid CCXCII, which was resolved and found identical with the corresponding product produced by degradation of strychnine. The degradation from strychnine involved hydrogen peroxide-barium hydroxide cleavage of the keto-amide ring VI of dehydrostrychninone (CXLVIII) to the amino acid which was then N-acetylated. Both epimers at C,, of this acid were prepared for identification with CCXCII so that the stereochemistry shown is known to be correct (of the des-acetyl derivatives of the two epimers, that from CCXCII does not lactamize on sublimation, whereas its epimer does). Before proceeding we should note the elegant suitability of CCXCII for further construction toward strychnine, possessing as it does versatile reactivity at each of the three positions to which new bonds must be formed. The closure of ring VI, however, required an inordinate expenditure

214

J. B. HENDRICKSON

of effort, the simple reactions one would be tempted to try not having cooperated at all. Ultimately, the methyl ketone CCXCIII was prepared and oxidized to dehydrostrychninone (CXLVIII)with selenium dioxide. The construction of the final ring was begun by putting on the last two carbons in the form of sodium acetylide and reducing the ethinyl carbinol with Lindlar's partial hydrogenation. The resultant CCXCIV was reduced by lithium aluminum hydride both a t the ring V I lactam and in the pyridone ring, yielding in one step the strychnine progenitor CCXCV, which yielded isostrychnine I (CCXCVI) under vigorous acid conditions, and this was converted by base to strychnine, identical in all respects with the natural alkaloid. In conclusion, the completed X-ray crystallographic studies on the structure of strychnine salts from two laboratories have been published (299, 300) and find themselves in complete agreement with the formula derived by chemical means and now synthesized. The conformational conclusions from these sources are best summarized, and the singular intricacy of the strychnine architecture pictorialized, in the following expression:

CHART I THE SYNTHESIS OF STRYCHNINE

CCLXXXlll

ccLXXXVl

CCLXXXIV

CCLXXXVll

CCLXXXV

CCLXXXVlll

21 5


01_ CH$O

‘

COOCH,

c c L x XXlX

CCXCIV

\

COOCH,

/

0

CH2C0OCH,

’

ccxc

ccxcv

N \

COOCH,

0

CCXCI

bH CCXCVI

VII. References 299. J. H. Robertson and C. A. Beevers, Acta Cryst. 4, 270 (1951). 300. C. Bokhoven, J. C . Schoone, and J. M. Bijvoet, Acta Cryst. 4, 275 (1951). 301. R. R. Woodward, 111. P. Cava, W. D. Ollis, A. Hunger, H. U. Daeniker, and K. Schenker, J . Am. Chem. SOC.76, 4749 (1954). 302. R. B. Woodward, Ezperientia Suppl. 11, 213 (1955). 303. R. Huisgen, Angew. Chem. 62, 527 (1951); 63, 124 (1951). 303a. R. B. Woodward, W. J. Brehm, and A. L. Nelson, J . Am. Chem. SOC.69, 2250 (1947). 303b. R. B. Woodward and W. J. Brehm, J . Am. Chem. SOC.70, 2107 (1948). 304. R. Robinson, Progr. i n Org. Chem. 1, 1 (1952). 304a. W. H. Perkin and R. Robinson, J . Chem. SOC.p. 305 (1910). 304b. W. H. Perkin and R. Robinson, J . Chem. SOC.p. 964 (1929). 304c. K. N. Menon and R. Robinson, J. Chem. SOC.p. 780 (1932). 304d. H. Leuchs and W. Baur, Ber. 65, 1230 (1932). 305. F. A. L. Anet, G. K. Hughes, and E. Ritchie, AustraZian J. Chem. 6, 58 (1953). 306. A. Denoel, J. pharm. Belg. [N.S.] 5 , 59 (1950). 307. J. Body, J . pharm. Bdg. [N.S.] 6 , 150, 243 (1951). 308. A. Denoel, Fr. Jaminet, E. Philippot, M. J. Dallemagne, Arch. intern. physioZ. 59, 341 (1951). 309. Fr. Jaminet, J . pharm. Belg. [N.S.] 8, 339 (1953). 310. T. A. Henry, “The Plant AllraloidR,” 3rd ed., Blackiston, New York, 1939, p. 372. 311. H. King, J. Chem. Boc. p. 3263 (1949). 312. P. Karrer and H. Schmid, Angew. Chem. 67, 361 (1955).

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J. B. HENDRICKSON

312a. G. R. Clemo, J. Chem. SOC.p. 1695 (1936). 312b. G. R. Clemo and T. P. Metcalfe, J. Chem. SOC.p. 1518 (1937). 313. M. Kotake, T. Sakan, and T. Miwa, J. Chem. SOC. Japan 72, 245 (1951). 314. S. P. Findlay, J. Am. Chem. SOC.73, 3008 (1951). 315. A. Bertho and K. H. Loebmann, Ann. 588, 182 (1954). 316. A. Bertho and H. Bosch, Ann. 584, 23 (1953). 317. P. Karrer and H. Fleisch, Helv. Chim. Acta 36, 1529 (1953). 318. H. G. Boit end L. Paul, Chem. Ber. 87, 1859 (1954). 319. A. Kogure and M. Kotake, J. Inst. Polytech. Osaka City Univ. Ser. C 2, 39 (1952); Chem. Abstr. 46, 6131 (1952). 319a. V. Prelog and A. Kathriner, Helv. Chim. Acta 31, 505 (1948). 320. A. Kogure and M. Kotake, J . Inst. Polytech. Osaka City Univ. Ser. C 2, 45 (1952); Chem. Abstr. 46, 6131 (1952). 321. A. Kogure, T. Sakan, and M. Kotake, J . Inst. Polytech. Osaka City Univ. Ser. C 2, 49, 67 (1952); Chem. Abstr. 46, 6131 (1952); 47, 6959 (1953). 322. T. Pavolini, F. Gainbarin, and A. S. Godenigo, Gazz. chim. itul. 81, 527 (1951); Chem. Abstr. 46, 5593 (1952). 323. T. Pavolini and F. Gambarin, Gazz. chim. ital. 80, 220 (1950); Chem. Abstr. 45, 3854 (1951). 324. N. J. Leonard and V. W. Gash, J . A m . Chem. SOC.76, 2781 (1954). 324a. R. N. Chakravarti and R. Robinson, Nature 160, 18 (1947). 324b. R. N. Chakravarti, K. H. Pausacker, and R. Robinson, J. Chem. Soc. p. 1564 (1947). 325. H. G. Boit, Chem. Ber. 86, 133 (1953). 325a. H. Leuchs, Margarete Mengelberg, and Lieselotte Hemmann, Ber. 77, 737 (1944). 325b. H. Leuchs and Henda Schulte, Ber. 76, 1038 (1943). 326. H. G. Boit, Chem. Ber. 84, 16 (1951). 327. R. Robinson and J. E. Saxton, J . Chem. Soc. p. 982 (1952). 327a. H. Wieland and W. Gumlich, Ann. 494, 191 (1932). 32713. H. Wieland and K. Kaziro, Ann. 506, 60 (1933). 327c. S. Bloom, personal communication. 328. C. A. Friedmann, J. Chem. SOC.p. 1585 (1950). 329. F. A. L. Anet, A. S. Beiley, and R. Robinson, Chem. & Ind. (London)p. 944 (1953). 329a. H. G. Boit, Ber. 82, 303 (1949). 330. H. G. Boit and L. Paul, Chem. Ber. 88, 697 (1955). 330a. R. Huisgen, H. Wieland, and H. Eder, Ann. 561, 193 (1949). 330b. V. Prelog and 0. Hiifliger, Helv. Chim. Acta 32, 1851 (1949). 331. R. Hall, Thesis, Harvard University, Cambridge, Massachusetts, 1950. 332. H. G. Boit, Chem. Ber. 83, 217 (1950). 333. H. G. Boit, Chem. Ber. 85, 106 (1952). 334. H. G. Boit, Chem. Rer. 85, 19 (1952). 335. H. G. Boit, Chem. Ber. 84, 923 (1951). 3 3 5 ~ .0. Achmatowicz and C. Dybowski, J. Chem. SOC.p. 1483 (1938). 335b. R. Robinson, Sorninar, 1938. 336. H. Wieland and F. Calvet, Anit. 491, 117 (1931). 337. R. Huisgen, H. Eder, L. Blatzejewicz, and E. Morgentheler, Ann. 573, 121 (1951). 338. B. Wit,kop and J. B. Patrick, J . Am. Chem. SOC.76, 5603 (1954). 339. B. Witkop, personal communication. 339a. H. Wieland and W. Weisskopf, Ann. 555, 1 (1943). 33913. H. Wieland and M. Thiel, Ann. 550, 287 (1942).


217

339c. R. Huisgen and H. Wieland, Ann. 555, 9 (1943). 340. R. B. Woodward, lectures, 1946, as quoted by E. Crane, Thesis, Harvard University, Cambridge, Massachusetts, 1949. 340a. H. Wieland and G. Vargolis, Ann. 507, 82 (1933). 340b. H. Wieland and R. Huisgen, Ann. 556, 157 (1944). 340c. L. H. Briggs, H. T. Openshaw, and R. Robinson, J. Chem. SOC.p. 903 (1946). 340d. H. Wieland, R. Huisgen, and R. Bubenik, Ann. 559, 191 (1948). 341. F. H. Shaw and I. S. de la Lande, AustraZianJ. Exptl. B i d . Med. Sci.26, 199 (1948). 342. F. A. 1,. Anet and R. Robinson, J. Chem. SOC.p. 2253 (1955). 343. Fr. Jaminet, Lejeunia 15, 9 (1951). 344. M. Janot, R. Goutarel, and J. Bosly, Compt. rend. 232, 853 (1951). 344a. 0. Achmatowicz, G. R . Clemo, W. H. Perkin, and R. Robinson, J . Chem. SOC. p. 767 (1932). 345. W. F. Martin, H. R. Bentley, J. A. Henry, and F. S. Spring, J . Chem. SOC.p. 3603 (1952). 346. G. Schopf, Angew. Chem. 50, 779, 797 (1937). 347. R. Robinson, “Structural Relations of Natural Products,” Oxford Univ. Press, London and New York, 1955. 348. G. K. Hughes and E. Ritchie, Revs. Pure Appl. Chem. (Australia) 2, 125 (1962). 349. R. B. Woodward, Nature 162, 155 (1948). 350. G. Hahn and H. Ludewig, Ber. 67, 2031 (1934); G. Hahn and A. Hansel, Ber. 71, 2193 (1938). 351. G. Hahn and H. Werner, Ann. 520, 123 (1935). 362. B. Belleau, Chem. & Ind. (London) p. 229 (1955). 353. M. Kates and L. Marion, J . Am. Chem. SOC.72, 2308 (1950). 354. M. S. Gibson and R. Robinson, Chem. & Ind. (London) p. 93 (1951). 355. E. Wenkert, Experientia 10, 346 (1954). 356. V. Prelog. Helv. Chim. Acta 31, 588 (1948). 357. K. Aghoramurthy and R. Robinson, Tetrahedron 1, 172 (1957). 358. L. Marion, in “The Alkaloids” (R. H. F. Manske and H. L. Holmes, eds.), Academic Press, New York, 1952, Vol. 2, p. 369. 358a. R. B. Woodward, in “The Alkaloids” (R. H. F. Manske and H. L. Holmes, eds.), Academic Press, New York, 1953, Vol. 3, p. 54. 359. R. B. Woodward, Angew. Chem. 68, 13 (1956). 360. F. A. L. Anet and R. Robinson, Chem. & Ind. (London) p. 245 (1953). 361. P. Karrer, H. Schmid, and H. Bickel, Helw. Chim. Acta 38, 649 (1955). 362. E. Wenkert, Thesis, Harvard University, Cambridge, Massachusetts, 1951. 362e. J. Hendrickson, Thesis, Harvard University, Cambridge, Massachusetts, 1954. 363. H. T. Openshaw and R. Robinson, J. Chem. Lsoc. p. 941 (1937). 363a. H. L. Holmes, H. T. Openshaw, and R. Robinson, J. Chem. SOC.p. 910 (1946). 363b. R. N. Chakravarti and R. Robinson, J. Chem. SOC.p. 912 (1946). 364. J. T. Edward and R. Robinson, J. Chem. SOC.p. 1080 (1952). 365. R. Robinson and J. E. Saxton, J . Chem. SOC.p. 2598 (1953). 366. A. R. Katritsky, J . Chem. SOC.pp. 2581, 2586 (1955).


CHAPTER 7

The Morphine Alkaloids GILBERT STORK

Chandler Laboratory, Columbia Universityj New York, New York I. Introduction...................................................... 11. The Reactions of Morphine and Codeine.. ............................ 1. Reduction...................................................... 2. Oxidation...................................................... 3. Fission around the Nitrogen.. .................................... 4. Structure ofMetopon ............................................ 5. TheHalocodides ................................................ 111. The Reactions of Thebaine.. ........................................ 1. Reduction...................................................... 2. Phenyldihydrothebaine........................................... 3. Flavothebaone.................................................. IV. Stereochemistry................................................... V. Synthesis......................................................... VI. Biogenesis ........................................................ VII. References ........................................................

Page 219 220 220 222 226 226 226 228 228 230 230 233 235 242 243

I. Introduction The outstanding developments of the few years since the appearance of Volume 11* of this series have been mainly synthetic: The total synthesis of the morphine alkaloids was first achieved by Gates and Tschudi (377, 377a), and a second, quite different, synthesis was achieved by Elad and Ginsburg (378, 378a). Considerable experimentation has been done on stereochemical problems, mainly by Rapoport and by Bentley. Much of this work has displayed considerable ingenuity in a difficult area. It is not without some satisfaction, however, that we note that all the new evidence, including the detailed X-ray analysis of Mackay and Hodgkin (379), is in agreement with the structure which we deduced in Chapter 8, Part 11, of Volume 11. The structure of flavothebaone has finally been settled, and considerable interesting work has been done on its further degradation. A rather thorough survey of morphine chemistry (380) has been published since the appearance of Chapter 8, Part 11. This suffers to some extent, however, from its ‘unorthodox approach to reaction mechanisms. * This material is supplementary to Volume 11, Chapters 8 and 9. 219

220

GILBERT STORK

11. The Reactions of Morphine and Codeine 1. REDUCTION

The removal of the alcoholic hydroxyl by reaction of the corresponding toluene sulfonate with lithium aluminum hydride has been described: Codeine tosylate (CCCXXXVIII) thus leads to A7-deoxycodeine(381) and dihydrocodeine to dihydrodeoxycodeine (382). The former reduction may be contrasted with that of a-chlorocodide (CCCXXXIX), which leads to A6-deoxycodeinewith the same reagent (383). This is in

Wq+g

__L

+? /

CCCXXXVlll

CCCXXXIX

keeping with the generalization that bimolecular reactions requiring inversion can take place only in those codeine derivatives in which the back side is unhindered. The steric situation in codeine demands, ’ ) place, e.g., however, that displacement with rearrangement ( S N ~ take with a-chlorocodide and the other halocodides. The reduction of codeinone to codeine has been achieved in high yield with sodium borohydride (384), while it has been claimed that dihydrocodeinone gives mainly dihydroisocodeine under the conditions of the Meerwein-Ponndorf reduction (385). This is to be compared t o the unreactivity of dihydroisocodeine to the Oppenauer oxidation with potassium t-butoxide and benzophenone (386). Obviously the steric requirements are not the same for these two reagent systems. The interesting observations have been made by Perrine and Small (387) that the Wolff-Kishner reduction of dihydrocodeinone leads to A6-dihydrodeoxycodeine (CCCXL) while ethyl mercaptan in concentrated hydrochloric acid leads to dihydrothebainone (CCCXLI) apparently via its 5-thioethyl derivative.

THE MORPHTNE ALKALOIDS

22 1

CCCXL

CCCXLI

The generalization has previously been made (Vol. 11, p. 180) that morphine derivatives are always reduced catalytically to the natural series (C14hydrogen trans to the benzene ring):

Rapoport and Lavigne (388) have incorrectly claimed that there are “several exceptions” to this generalization. Of the two cases they mention, one (A8-thebainonemethine)is morphine alkaloid in name only: The molecule is in reality a simple phenanthrene derivative and the oourse of its hydrogenation is irrelevant. In the other purported

222

GILBERT STORK

exception, the reduction was that of thebaine with palladium on calcium carbonate, in aqueous hydrochloric acid solution (389). The product was mostly the normal dihydrothebainone together with a very small amount of ,6-dihydrothebainone isolated as its oxime. This is again irrelevant since its formation is easily accounted for by the expected formation of some thebainone-,6-thebainone mixture in the reduction medium. Further hydrogenation would of course give some dihydro ,6-thebainone (388a). 2. OXIDATION The aqueous sulfuric-chromic acid oxidation of codeine has long been known to give a hydroxycodeine in which the newly introduced hydroxyl is either a t position 9 or 10. From the fact that the methiodide of the substance (A) requires quite vigorous treatment with base to produce the ketonic methine, it was always clear that it could not be a carbinolamine: Such a substance would form a methiodide (B) that would merely be the hydriodide of the amino ketone and would thus be instantaneously transformed into free amino ketone upon treatment with dilute base: CH.

I n confirmation of the 10-hydroxycodeine structure it has now been found that the carbonyl of the ketonic methine base is conjugated with the aromatic ring: The ultraviolet absorption spectrum shows bands at 244 mp (log E 4.27), 284 mp (log E 4.06), and 323 mp (log E 3.69). The last band can be ascribed only to conjugation between the aromatic ring and the ketone since it is absent in 10-hydroxycodeine itself (390). I n a further study of the question, Rapoport and Masamune (391) have demonstrated that the C,, hydroxyl in 10-hydroxycodeine is trans to the nitrogen chain: I n the related 10-hydroxy dihydrodeoxycodeine (CCCXLII) the new hydroxyl group may be oxidized to a ketone with

THE MORPHINE ALKALOIDS

223

manganese dioxide in chloroform and the 10-ketocodeine gives with sodium borohydride a 10-hydroxycodeine which is different from the chromic acid product. The configuration of the two epimers was demonstrated by the fact that only the sodium borohydride product formed a cyclic oxazolidone when the urethan of the corresponding normethyl compound was treated with sodium ethoxide:

CCCXLll

A number of interesting observations were made: The rate of oxidation by the Oppenauer reagent, chromic acid, or manganese dioxide was greater with the cis amino alcohol while only the trans compound underwent hydrogenolysis back to dihydrodeoxycodeine. The rate of oxidation of axial alcohols is normally faster than that of the equatorial epimers (less hindrance of the (equatorial) hydrogen which must be removed in the rate-determining step), and yet the cis amino alcohol which is rapidly oxidized is here of necessity the equatorial isomer. One explanation of this reversal of the usual result which we would like to suggest follows from the fact that in allylic (or benzylic) alcohols overlap of the electrons of the C-H bond which must be broken in the oxidation and the T electrons of the allylic double bond is maximum when these are parallel-a situation which obtains in the isomer with the axial hydrogen and equatorial hydroxyl. This overlap should facilitate breaking of the C-H bond with the formation of an incipient anion, leading to the possible conclusion that equatorial allylic secondary alcohols may generally be oxidized more rapidly than their epimers:

224

GILBERT STORK

The synthesis of 10-hydroxymorphine has also been reported (392). Here it was necessary to protect the phenolic hydroxyl, and the ingenious device of preparing the allyl ether, followed after oxidation by removal of the allyl group with sodium and liquid ammonia, was used with success. Neopine, the A8-l4isomer of codeine, was also transformed to the 10-hydroxy derivative, but thebaine (CCCXLIII) merely gave the known 14-hydroxycodeinone (CCCXLIV) by attack of the en01 ether system (392).

CCCXLlll

CCCXLIV

The interesting observation has been made (393) that i n the presence of pyridine chromic acid oxidation follows a different course, leading to the oxidation of the N-methyl group : 6-Acetyldihydrocodeine (CCCXLV) gives 10% to 30% of N-formyl-6-acetyldihydronorcodeine (CCCXLVI):

CCCXLV

CCCXLVI

Among various mechanisms which can be written for this reaction are obvious ionic and radical varieties, but we believe that an internal rearrangement is worth considering:

Such a path would obviate the necessity of putting a double bond at a bridgehead in the related case of the oxidation of strychnine N-oxide to &strychnine (Chapter 15, Vol. 11):


225

The difficult oxidation of codeine to codeinone seems to be best carried out with anhydrous silver carbonate in refluxing benzene (394). Whether this reagent can oxidize other allylic alcohols remains to be determined. Perphthalic acid has been found to convert smoothly the (unsaturated) deoxycodeines to their N-oxides. In contrast to the situation with other peracids, the consumption of oxidizing agent stops cleanly after 1 mole (395). 3. FISSION AROUND

THE

NITROGEN

It has been known for a long time that the initial product of the degradation of codeine methiodide is rearranged to a more stable isomer on further treatment with strong alkali. The two methines, heretofore known as a- and 8-methylmorphimethine, respectively, have been renamed a- and 8-codeimethine-a logical simplification (396). More evidence has been adduced that the substances are indeed correctly represented by structures CCCXLVII and CCCXLVIII, respectively (396):

It has been noted that those morphine derivatives in which the nitrogen is allylic (A*.14compounds) can be degraded to dihydromethines by reduction of their methiodides with sodium in liquid ammonia. (397), and the important observation has been made that a useful alternative to the Hofmann degradation consists in the decomposition of tertiary amine oxides, especially in those cases in which the Hofmann elimination results in loss of the side chain. It will also be noted that double bonds are not isomerized in this process (398): P

226

QILBERT STORK

As illustrated previously (Vol. 11, p. 191), the corresponding Hofmann elimination results in loss of water and of the ethanamine side chain with the formation of methylmorphenol. 4. STRUCTURE OF METOPON

The reaction of enolic derivatives of dihydrocodeinone with methyl magnesium halides leads to two isomeric methyldihydrothebainones. One of these eventually leads to metopon, a derivative of morphine with favorable pharmacological properties. The efforts (399) to settle whether the added methyl group of metopon occupies position 5 or 7 have been successfully concluded (400) by showing that unambiguously synthesized 7-methyldihydrocodeinone (CCCXLIX) is identical with “isomethyldihydrocodeinone” and not with the methyl ether of metopon. The latter must then be CCCL, R = CH,, and metopon is the corresponding phenol (CCCL, R = H).

_c

CCCL

CCCXLIX

4

5. THE HALOCODIDES

We have previously discussed the structures and reactions of the halocodides (Vol. 11, pp. 180-185). Our assignment of structure and


227

stereochemistry implied, as we pointed out, the general occurrence of S N ~reactions ‘ in this series of allylic halides. The experimental evidence which establishes the correctness of our views has now been published (383). It has been shown that the kinetics of the reaction of piperidine with a-chlorocodide are second-order and that the reaction gives quantitatively the rearranged amine 8-piperidocodide (CCCLI) (383): n

‘OCH,

-OCH,

CCCLI

This confirms our previously expressed view that the halocodides can only undergo bimolecular displacement with rearrangement because of steric hindrance to S N attack ~ with inversion. It is interesting to note that the displacement reactions of the halocodides represent cases of clean-cut S N ~ reactions ’ which antedate the postulation of the theoretical possibility of such reactions. The assignment to /3-chlorocodide, bromocodide, and iodocodide of structure CCCLII (X=C1, Br, I) has been confirmed by a study of their infrared spectra, which are very similar to, but different from, that of a-chlorocodide (393).Normal S Ndisplacement ~ takes place with codeine tosylate and lithium chloride to give a-chlorocodide as would be expected, but the corresponding 6-brorno- and 6-iodocodide are not obtained in a similar manner: The substances are rearranged so rapidly that only the 8-bromo- and 8-iodocodide are obtained.

It is worth noting that even lithium aluminum hydride gives as the ’ by hydride ion: main isolatable substance the product of S N ~reduction

228

GILBERT STORK

/3-Chlorocodide, bromocodide, and iodocodide all give A7-deoxycodeine in contrast to a-chlorocodide, which leads to A6-deoxycodeine (383). An apparent exception to the above generalizations was the reported formation of some y-ethylthiocodide from the reaction of ethyl mercaptide ion with /&chlorocodide, in addition to the expected S N ~ ' product, a-ethylthiocodide. (See Vol. 11, p. 186.) This difficulty is not a real one as it has been shown long ago that so-called y-ethylthiocodide is spurious (401). 111. The Reactions of Thebaine 1. REDUCTION

Further work on the reduction of thebaine by chemical means has been published since Chapter 8 of Volume I1 was written. This supports the conclusions outlined previously (Vol. 11, pp. 199-203), (402, 403). A careful search of the mother liquors from the commercial hydrogenation of thebaine has led to the isolation of about 1% of neopine methyl ether (CCCLIII) (404). It is, of course, possible that more of this substance is formed than can be isolated since most of it might well be reduced further to tetrahydrothebaine which is also produced in the reduction.

CCCLlll

It has been proposed that the dihydrothebaine formed by sodium reduction of thebaine (so-called phenolic dihydrothebaine) be renamed dihydrothebainep (405). This substitution of a new trivial name for an older one does not appear legitimate once a structure is established beyond doubt. We would prefer the term A6.8(14)-dehydrothebainol methyl ether for the sodium-ethanol or sodium-ammonia reduction product (CCCLIV). The lithium aluminum hydride reduction product would then be A6.8(14)-dehydrothebainol methyl ether (CCCLV),and the third isomer, obtained by base-catalyzed rearrangement of codeine methyl ether, would be A5*7-dehydrothebaino1methyl ether (CCCLVI).


229

The course of the hydrolysis of A5*8'14)-dehydrothebainolmethyl ether has been reinvestigated by Bentley and co-workers (406, 407). It has been shown that the simple hydrolysis product, A8(I4) thebainone (CCCLVII), may be isolated by careful treatment of CCCLIV with aqueous alcoholic hydrobromic acid. The new substance is different from the product of the action of hot sulfurous acid on CCCLIV, the so-called a-thebainone of Small and Browning (408) and yields dihydrothebainone on catalytic hydrogenation. a-Thebainone, previously assumed to be CCCLVII, has been shown to be correctly represented by CCCLVIII (407). On the other hand, it is also known that aqueous potassium bisulfate leads to a mixture of A7-thebainone(CCCLIX)and A7 /3-thebainone (CCCLX)in which the latter is reported to predominate

CCCLIV

CCCLVll

(408). This is therefore not an equilibrium process, since Gates and Helg

(388a) have shown that the equilibrium between CCCLIX and CCCLX is greatly in favor of the former. The explanation of this unexpected result which has been given by Bentley is not satisfactory (407). [See, however (409).] Under the vigorous conditions of hot sulfurous acid hydrolysis the reasonable assumption has been made (407) that /3-elimination Qf the amine chain takes place, followed by readdition to yield a-thebainone (CCCLVIII).

230

GILBERT STORK

2. PHENYLDIHYDROTHEBAIE The experimental details on which the assignment of the structure of phenyldihydrothebaine was based have now been given. The crucial experiment was the oxidation of the exhaustive methylation product from the methyl ether of phenyldihydrothebaine to 5,6,5’-trimethoxydiphenic acid, also obtained by oxidation of acetylthebaol quinone with hydrogen peroxide and acetic acid, followed by methylation (410).

CH,O

p

bCoaH

CH 0

The mechanism by which phenyldihydrothebaine is formed (see Vol. 11, p. 198) implies that treatment of thebaine ’with magnesium iodide could lead to the salt CCCLXI. Some evidence for its presence as a product of that reaction was found in the further reaction of the unisolated intermediate with phenylmagnesium bromide to produce phenyldihydrothebaine. It was unfortunately not possible to isolate either CCCLXI or its reduction product (410).

t

1 0

CH,O

CCCLXI

3. FLAVOTHEBAONE It has been known for some time that thebaine behaves as a diene in the Diels Alder reaction. I n particular, its adduct with benzoquinone (CCCLXII) has been the object of considerable study (380). As is usual

231


with similar quinone adducts, aromatization to the hydroquinone (CCCLXIII) is easily brought about and the latter substance is transformed into a ketone, flavothebaone, upon treatment with acid.

CH,N

3 C

'

Z

N

3

IHF*' '00-H

OCH,

OCH,

CCCLXll

CCCLXlll

OCH,

CCCLXIV

The expected structure (CCCLXIV) for flavothebaone follows from the stereochemistry of the adduct, which allows easy pinacol-type rearrangement with migration of the phenyl ring. The structure CCCLXIV was recently proposed by Meinwald (411) and has been accepted by Bentley (412, 413)) who has adduced considerable further degradative evidence in its support. The interesting problem of the unexpected presence of a band a t 345 mp (log E 3.55) in the spectrum of flavothebaone has been ascribed to homoconjugation (411):

CH,N

It is in keeping with the mechanism of the rearrangement of flavothebaone that the maleic anhydride adduct of thebaine is unchanged by heating with concentrated hydrochloric or phosphoric acids (414). Excellent confirmation for structure CCCLXIV has come from two sources: I n the first place, it has been shown that the ultraviolet spectrum shows (after subtraction of the catechol contribution) an isolated a,p-unsaturated ketone. This was confirmed by the spectrum of its dinitrophenylhydrazone (411 ) . The dihydro derivative of CCCLXIII has also been found-contrary to early reports in the literature-to rearrange to dihydroflavothebaone, thus demonstrating that the double bond does not participate in the rearrangement (411,413). I n the second place, very elegant degradative work by Bentley et al. has provided further evidence on the problem (412, 413, 415): It has been found that

232

GILBERT STORK

the methine base (CCCLXV) from flavothebaone trimethyl ether is transformed on heating with alcoholic potassium hydroxide into a #-methine which, in contrast to its precursor, has its carbonyl group present as an unconjugated acetyl group. Structure CCCLXVI has been assigned (412, 413) to the #-methine, which is formed as a result of hydration of the enone double bond followed by reverse aldol and reverse

CH,-N

%rT'

C-CH,

CH,

CCCLXVI

Claisen reactions (loss of formic acid). The position of the double bond follows from the ultraviolet spectrum of CCCLXVI. Dry distillation of the methohydroxide of CCCLXVI led to a series of optically inactive compounds, the ultraviolet spectra of which resemble that of P-phenyl naphthalene. They were identified as 1,2,7,1O-tetramethoxychrysofluorene(CCCLXVII) and its 11-acetyl (CCCLXVIII) and 1 1-methyl (CCCLXIX) derivatives. The formation

CCCLXVlll

of CCCLXVIII is another illustration of the mechanism which was postulated for the formation of methylmorphenol from codeimethine methohydroxide (Vol. 11, p. 191). Reverse Claisen type cleavage of the acetyl group of CCCLXVIII gives the desacetyl compound CCCLXVII, while methylation of the anion of CCCLXVIII at the expense of some

233


quaternary salt leads to the 11-methyl derivative of CCCLXVIII, which is again cleaved as before to CCCLXIX. This path to CCCLXIX is preferable to that postulated by Bentley et al. (412) and is in keeping with the recovery of some #-methine (CCCLXVI).

CCCLXVll

CCCLXVlll

CCCLXIX

Some interesting Beckmann rearrangements have been carried out on the +methine (CCCLXVI) and some of its derivatives, and here again the results are in complete agreement with their assigned structures (415). IV. Stereochemistry The stereochemistry shown in CCCLXX which was considered established in Volume 11, Chapter 8, Part 11, has been further supported chemically, and has finally been completely verified by a detailed X-ray analysis. I n addition, the absolute configuration has been established,

OR

Codeine, R=Cn, Morphine.R= H

CCCLXX

and this is taken into account in all the structures written in this chapter . We will first consider some relevant additional chemical evidence bearing on the stereochemistry shown in CCCLXX. It has been shown that exhaustive methylation of dihydroisocodeine leads to a very small yield of the cyclic ether 6-codiran (CCCLXXI), whereas no cyclic ether can be obtained from dihydrocodeine under these circumstances (416).

CCCLXXI

234

GILBERT STORK

This result is in keeping with the cis arrangement of the secondary hydroxyl and the ethanamine chain in isocodeine and consequently with a trans relationship in codeine and morphine. I n agreement with the presence of a cis decalin system in the natural alkaloids it has been found that the cis amide acid derived from thebenone forms a cyclic imide on heating while the similar substance derived from 8-thebenone (epimeric at C14)does not cyclize under these conditions (388). A more conclusive chemical proof is given below in connection with absolute configuration.

The correctness of the stereochemistry shown in CCCLXX has now been verified by the X-ray analysis of the structure of morphine hydriodide by Mackay and Hodgkin (379), and the absolute configuration has been elegantly demonstrated by Jeger and co-workers (417), who were able to degrade dihydrocodeinone to optically active cis 2-methyl-2carboxy-cyclohexaneacetic acid of known absolute configuration. This work not only establishes the absolute configuration of the alkaloids but also gives a direct chemical demonstration of the cis fusion of the

235


decalin system in morphine and codeine. The same absolute configuration has also been deduced on other grounds (418, 419). It is of considerable interest that the equilibrium between thebainone (CCCLXXII) and 8-thebainone (CCCLXXIII) is in favor of the former to the extent of 84%, as determined polarimetrically (408). The two systems are closely similar but differ apparently by about 0.8 kcal. in favor of the natural configuration of CCCLXXII.

CCCLXXll

CCCLXXlll

The position of this equilibrium may be ascribed to two factors: There is considerably greater steric repulsion between the hydroxyl a t C, and the equatorial hydrogen at C, in CCCLXXIII than in CCCLXXJI (4%0),and one may further note that after canceling equivalent 1:3 interactions the (axial) electron pair on the nitrogen atom (421) (or the proton of the conjugate acid) interferes with the axial hydrogen at C,, in CCCLXXII while it is subject to the more serious interference with the similarly placed C, trigonal carbon in CCCLXXIII. These two fa,ctors can easily explain the observed difference in stability of the two epimers.

V. Synthesis The total synthesis of morphine was successfully completed in 1952 by Gates and Tschudi (377) along the lines which were indicated in Volume 11, pages 206-208. The full details have now been published

CN I

CCCLXXIV

236

GILBERT STORK

(377a). The starting material for the synthesis, 5,6-dimethoxy-4-cyanomethyl-l,2-naphthoquinone(CCCLXXIV), was prepared from 2,6dihydroxynaphthalene in a sequence of ten steps which were so well worked out that the overall yield was about 20%: Addition of butadiene to CCCLXXIV gave the tricyclic compound CCCLXXV in which the angular cyanomethyl group is correctly placed to serve as the progenitor of the ethanamine chain (422). Reduction over copper chromite a t 130"

ex@ /

NC

0

/

'

0%

00

,

$ Z-$ N C $

OCH,

OCH,

CCCLXXV

CCCLXXVI

OCH,

0

@

HN@

4

HN 0

and 27 atm. of hydrogen led to the crucial substance CCCLXXVI in which the basic skeleton of morphine has been established, although the configuration a t C,, is epimeric ("/?") with that of the natural alkaloids (vide infra).The path followed in this transformation is most likely that shown in A-D: reduction of the diketo form of CCCLXXV to a ketol which tautomerizes to an imino ether (C) which then rearranges homolytically to D (423). This last rearrangement is undoubtedly favored by the fact that the radical formed by rupture of the C-0 bond in the imino ether C is stabilized by the adjacent keto group. The ketonic function in CCCLXXVI was next removed by WolffKishner reduction a t temperatures low enough (ca. 150') that no demethylation took place, and the product (CCCLXXVII) was .hr-methylated with sodium hydride and methyl iodide, followed by

CCCLXXVll

CCCLXXVlll

237


lithium aluminum hydride reduction of the amide grouping. The substance (CCCLXXVIII) formed in this way was dl-/3-A6-dihydrodeoxycodeine methyl ether as shown by infrared comparison with the dsubstance obtained by degradation of p-dihydrothebainone. Resolution to the d-compound was effected via its dibenzoyl-L( )-tartrate, and introduction of a hydroxyl group at C, was finally achieved by hydration with dilute sulfuric acid to /3-dihydrothebainol methyl ether. Small

+

CCCLXXXlX

amounts of the 7-hydroxy compound are also formed. Demethylation of the more hindered C, methoxyl was achieved by heating with potassium hydroxide in diethylene glycol at 225', and oxidation with potassium t-butoxide-benzophenone gave the previously known /3-dihydrothebainone (CCCLXXIX). Inversion a t C,, to the natural dihydrothebainone series was then carried out, taking advantage of the previously discussed equilibration of /3-thebainone to thebainone (408). Dibromination of CCCLXXIX led to CCCLXXX which was transformed, on treatment with dinitrophenylhydrazine in acetic acid, to 1-bromothebainone 2,4-dinitrophenylhydrazone in which acid-catalyzed inversion at C,, had already taken place. Splitting with acetone-hydrochloric acid led to l-bromothebainone which could be reduced over platinum to l-bromodihydrothebainone (CCCLXXXI). It now was necessary to close the oxide ring and introduce a double bond in conjugation with the keto group.

Br' V O C H ,

CCCLXXX

B r'

OCH,

'OCH,

CCCLXXXI

This was achieved by dibromination of CCCLXXXI, followed by treatment of the tribromo compound with 2,4-dinitrophenylhydrazine in acetic acid, finally warming with pyridine, when 1-bromocodeinone

238

GILBERT STORK

dinitrophenylhydrazone was formed. This could be split to l-bromocodeinone (CCCLXXXII) with acetone-hydrochloric acid, but only with difficulty because of the well-known propensity of codeinone to rearrange in acid.

CCCLXXXll

CCCLXXXlll

ccc L x x x IV

Energetic reduction with lithium aluminum hydride led to the rednction of the carbonyl group with the formation of the correct alcohol epimer, as expected from the steric hindrance presented by the benzene ring, and to removal of the aromatic bromine. This last reaction is a noteworthy example of the removal of aromatically bound halogen without reduction of either an allylic hydroxyl or a double bond. The codeine so produced (CCCLXXXIII)was then demethylated to morphine (CCCLXXXIV) by short heating to 220' with pyridine hydrochloride. The first synthesis of morphine was thus brought to a successful conclusion (377, 377a). This synthesis of morphine is also a synthesis of thebaine rCCCLXXXVI), as the latter has recently been prepared from dihydrocodeinone by Rapoport et al. (424): Br

ccc LXXXV

CCCLXXXVl


239

These investigators succeeded in preparing codeinone dimethyl ketal (CCCLXXXV) starting with A6-dihydrothebaine, which can itself be prepared by methylation of dihydrocodeinone with sodium t-butoxide and dimethyl sulfate (425). Addition of bromine in methanol to the enol ether gave a bromoketal which was dehydrobrominated to CCCLXXXV with potassium t-amyloxide. Direct preparation of codeinone dimethyl ketal from codeinone was not successful. Thebaine was obtained by warming CCCLXXXV with p-toluenesulfonic acid in chloroform. It has also been pointed out that since thebaine can be transformed into neopine, the latter may be considered formally synthesized: 14-Bromocodeinone, which is readily obtained from the treatment of thebaine with brominating agents, can be reduced to the P,y-unsatixrated ketone, neopinone, and this gives neopine (CCCLXXXVII) on reduction with sodium borohydride (409).

9'

A second synthesis of 1-dihydrothebainone has been carried out by Ginsburg and Elad (378,378a). Taken together with Gates and Tschudi's conversion of I-dihydrothebainone to morphine, this may be considered another synthesis of the alkaloid itself. The path to dihydrothebainone followed by Elad and Ginsburg is quite different from that taken by Gates and Tschudi, but like the latter it involves an unusual reaction in the closure of the ethanamine chain. The starting material for the synthesis, 2-(2,3-dimethoxyphenyl)2cyclohexenone (CCCLXXXVIII), was prepared from the readily

CCCLXXXVlll

240

GILBERT STORK

available l-(2,3-dimethoxyphenyl)-cyclohexene (426). Michael addition of malonic ester to CCCLXXXVIII served to construct the third ring. Ketalization of the resulting keto malonic ester was necessary to prevent reversal of the Michael reaction during the hydrolysis to the keto malonic acid. The latter was directly cyclized to the diketone CCCLXXXIX with anhydrous hydrogen fluoride. The diketone CCCLXXXIX has a carbonyl group a t C, which will serve to introduce the carbon end of the ethanamine chain at 4a and a carbonyl a t C, which will be used to insert the nitrogen end of the chain a t C,, (phenanthrene numbering). Selective operations could be carried out by taking advantage of the fact that the C, carbonyl, which is conjugated with an aromatic ring, is notably sluggish towards ketal formation: Monoketalization readily forms the 4-ketal (427).

CCCLXXXlX

Treatment of the ketal with amyl nitrite and sodium ethoxide gave the expected oximino ketone which was reduced catalytically with palladium on charcoal in hydrochloric acid solution to furnish the corresponding amino diketone as its hydrochloride, the ketal being lost during the reaction. Building of the ethanamine chain was then continued via acylation with acetylglycollyl chloride to CCCXC.

cccxc

24 1


When the acetoxyacetamide (CCCXC) was treated with p-toluene sulfonic acid and ethylene glycol in benzene-toluene for 8 to 9 hours three surprising reactions were observed: Cyclization of the ethanamine chain took place, as well as demethylation of the more hindered methoxy group and ketalization of the carbonyl coiijugated with the aromatic ring. The latter reaction is presumably the result of the greater hindrance of the nonconjugated carbonyl after formation of the nitrogen ring.

-

4

OCH,

I

II

A ..

cccxc

C

CCCXCI

A possible mechanism for the cyclization is indicated in A-C. It will be noted that the stereochemistry of the product (CCCXCI)thus formed is that of the natural series of alkaloids a t C14:This results from the fact that the amino group of CCCXC must be equatorial since its adjacency to a ketone allows it to epimerize to the more stable configuration after its formation. The alkylation reaction can obviously form the new carbon-carbon bond only cis to the nitrogen atom, and the result is a cis decalin system in CCCXCI, even though the precursor (CCCXC) undoubtedly has a trans decalin system. Introduction of the necessary oxygen function a t C, was achieved by an interesting method which may prove generally useful: Nitrosation of CCCXCI was followed by controlled hydrolysis to remove the ketal grouping, and both keto groups of CCCXCII were then eliminated without damage to the oxime function by heating to 140’with hydrazine in diethylene glycol, in the absence of alkali. The resulting oxime was then hydrolyzed to the 6-keto compound, and the amide function wag reduced with lithium aluminum hydride. The resulting secondary amine was methylated with formaldehyde-formic acid and finally reoxidation of the mixture of epimeric C, alcohols was achieved with potassium t.-butoxide-benzophenone, leading to dl-dihydrothebainone which was then resolved with (+)tartaric acid to 1-dihydrothebainone (CCCXCIII) R

242

GILBERT STORK

identical with an authentic product (378, 378a). The conversion of this substance to morphine has been described by Gates (vide supra).

CCCXCll

CCCXClll

Before closing this section, mention should be made of the continued considerable activity in the field of morphinane chemistry (cf. Vol. 11, pp. 203-206), including development of further synthetic methods and resolution experiments (425-432).

VI. Biogenesis The original suggestion of Robinson and Sugasawa (433) t,hat the morphine alkaloids may originate via an oxidation of laudanine (CCCXCIV) or its derivatives has become even more compelling since

6CH,

CCCXClV

the elucidation by Barton et al. (434) of the course of the oxidation of p-cresol. This is illustrated below.

243


An analogous scheme for thebaine can be written from a partially demethylated laudanine (CCCXCV).

cccxcv

A number of interesting variants of this scheme have been proposed (435),while an ionic mechanism has been suggested (436) as another possibility which might yield sinomenine, the mirror image of CCCXCVI, directly from the same intermediate which normally gives benzyl isoquinolines such as laudanine itself. A variant is shown below.

I

CCCXCVI

VIII. References 377. M. Gates and G. Tschudi, J. Am. Chem. SOC.74, 1109 (1952). 377a. M. Gates and G. Tschudi, J . Am. Chem. SOC.7 8 , 1380 (1956). 378. D. Elad and D. Ginsburg, J . Am. Chem. SOC.76, 312 (1954). 378a. D. Elad and D. Ginsburg, J. Chem. SOC.p. 3052 (1954). 379. M. Mackay and D. C. Hodgkin, J . Chem. SOC.p. 3261 (1955). 380. K. W. Bentley, “The Chemistry of the Morphine Alkaloids,” Oxford Univ. Press, London and New York, 1954. 381. P. Karrer and G. Widmarlr, Helw. Chim. Actn 34, 34 (1951).

244

GILBERT STORK

P. Karrer and R. Saemann, Helv. Chim. Acta 36, 605 (1953). G. Stork and F. H. Clarke, J . Am. Chem. SOC.78, 4619 (1956). M. Gates, J. Am. Chern. SOC. 75, 4340 (1953). M. M. Baizer, A. Loter, K. S. Ellner, and D. R. Satriana, J . Org. Chem. 16, 643 (1951). 386. H. Rapoport, R. Naumann, E. R. Bissell, and R. M. Bonner, J. Org. Chem. 15, 1103 (1950). 387. T. D. Perrine and L. F. Small, J. Org. Chem. 17, 1540 (1952). 75, 5329 (1953). 388. H. Rapoport and J. B. Lavigne, J . Am. Chem. SOC. 388a. M. Gates and R. Helg, J . Am. Chem. SOC. 75, 379 (1953). 389. C. Schopf and L, Winterhalder, Ann. 452, 232 (1927). 76, 1796 (1964). 390. H. Rapoport and G. W. Stevenson, J . A m . Chem. SOC. 77, 4330 (1955). 391. H. Rapoport and S. Masamune, J . A m . Chem. SOC. 77, 6359 (1955). 392. H. Rapoport and S. Masamune, J . Am. Chem. SOC. 393. T. D. Perrine and L. F. Small, J . Org. Chem. 21, 111 (1956). 77, 490 (1955). 394. H. Rapoport and H. N. Reist, J . A m . Chem. SOC. 77, 5753 (1955). 395. H. Repoport and E. C . Galloway, J . Am. Chem. SOC. p. 3237 (1955). 396. K. W. Bentley and A. F. Thomas, J . Chem. SOC. p. 972 (1952). 397. K. W. Bentley and A. E. Wain, J . Chem. SOC. p. 1963 (1950). 398. K. W. Bentley, J. C. Ball, and J. P. Ringe, J . Chem. SOC. 58, 1467 (1936); 399. L. F. Small, H. M. Fitch, and W. E. Smith, J . Am. Chem. SOC. L. F. Small, S. G. Turnbull, and H. M. Fitch, J . Org. Chem. 3 , 204 (1938); L. J. Sargent and L. F. Small, i b i d . 16, 1031 (1951); R. I. Meltzer and J. A. King, J . Am. Chem. SOC. 75, 1355 (1953). 400. G. Stork and L. Bauer, J . Am. Chem. SOC. 75, 4373 (1953). 56, 2159 (1934). 401. D. E. Morris and L. Small, J . Am. Chem. SOC. 402. H. Schmid and P. Karrer, Helw. Chim. Acta 34, 1948 (1951). 74, 768 (1952). 403. G. Stork, J . A m . Chem. SOC. 404. L. F. Small, J . Org. Chem. 20, 953 (1955). 405. K. W. Bentley, R. Robinson, and A. E. Wain, J . Chem. SOC.p. 958 (1962). p. 967 (1952). 406. K. W. Bentley and A. E. Wain, J . Chem. SOC. p. 3245 (1955). 407. K. W. Bentley and H. M. E. Cardwell, J . Chem. SOC. 408. L. F. Smell and G. L. Browning, J . Org. Chem. 3, 618 (1939). 409. H. Conroy, J. A m . Chem. SOC. 77, 5960 (1955). 410. K. W. Bentley and R. Robinson, J . Chem. SOC.p. 947 (1952). 411. J. Meinwald and G. A. Wiley, Chem. & I d . (London)p. 957 (1956); J. Am. Chem. SOC.79, 2569 (1957). 412. K. W. Bentley, J. Dominguez, and J. P. Ringe, J. Org. Chem. 22, 409 (1957). 413. IS. W. Bentley, J. Dominguez, and J. P. Ringe, J . Org. Chem. 22, 418 (1957). p. 1863 (1956). 414. K. W. Bentley and A. F. Thomas, J . Chem. SOC. 415. K. W. Bentley and J. P. Ringe, J . Org. Chem. 22, 424 (1957). 74, 2630 (1952). 416. H. Rapoport and G. B. Payne, J . A m . Chem. SOC. 417. J. Kalvoda, P. Buchschacher, and 0. Jeger, HeZw. Chim. Acta 88, 1847 (1965). 418. K. W. Bentley and H. M. E. Cardwell, J . Chem. SOC.p. 3252 (1955). 419. I. R. C. Bick, Nature 169, 756 (1952). 420. A. K. Bose, Chem. & I d . (London)p. 130 (1954). 79, 495 (1957). 421. G. Stork and R. K. Hill, J . Am. Chem. SOC. 72, 228 (1950). 422. M. Gates, J. Am. Chem. SOC. 72, 423. M. Gates, R. B. Woodward, W. F. Newhall, and R. Kunzli, J . A m . Chem. SOC. 1141 (1950). 382. 383. 384. 385.


245

424. 425. 426. 427. 428. 429. 430. 431. 432.

H. Rapoport, H. N. Reist, and C. H. Lowell, J. Am. Chem. SOC.78, 5128 (1956). A. H. Homeyer, J. Org. Chem. 21, 370 (1956). D. Ginsburg and R. Pappo, J . Chek. SOC.p. 516 (1951). D. Ginsburg and R. Pappo, J. Chem. SOC.p. 938 (1951). R. Grewe, H. Pohlmann, and M. Schnoor, Ber. 84, 527 (1951). 0. Schnider and A. Grussner, Helv. Chim. Acta 34, 2211 (1951). H. Henecka, Ann. 583, 110 (1953). 0. Schnider, A. Brossi, and K. Vogler, Helv. Chim. Acta 37, 710 (1954). A. Grussner, J. Hellerbach, A. Brossi, and 0. Schnider, Helv. Chim. Acka 19,

433. 434. 435. 436.

R. Robinson and S. Sugasawa, J. Chem. SOC.p. 3163 (1931). D. H. R. Barton, A. M. Deflorin, and 0. E. Edwards, J . Chem. SOC.p. 530 (1956). K. W. Bentley, Ezperientiu 12, 251 (1956). T. Cohen, Chem. & I d . (London) p. 1391 (1956).

1371 (1956).


CHAPTER8

Colchicine and Related Compounds W. C. WILDMAN National Heart Institute. Bethesda. Maryland Page I . Introduction ...................................................... 247 I1. Occurrence and Isolation ............................................ 248 I11. Chemistry of Colchicine............................................. 257 1. Structure and Reactions of Colchicine.............................. 257 a . Structure of Ring B ........................................... 258 b . Structure of Ring C........................................... 259 c . X-Ray Studies............................................... 269 d . Miscellaneous Reactions ....................................... 269 2 . Stereochemistry of Colchicine..................................... 872 IV . Lumicolchicines .............................. ................. 274 276 V . Minor Alkaloids .................................................... .......... 276 1 . Substance B (N.Formyldesaretylco1chicine) . . . . . . . 276 2 . Substance C (3-Demeth 3. Substance D . . . . . . . . . . 277 277 4 . Substance El (Substanc 5. Substance F (Demecolcine, Colchamine N-Methyldesacetylcolchicine) 278 6. Substances GI, G , and H, ........................................ 279 279 7 . Substance I ..................................................... 219 8. Substance J .................................................... 9 . Substance K .............................. . . . . . . . . . . . . . . . 279 10. Substance M ............................... . . . . . . . . . . . . . . . 279 279 11. Substance N .................................................... 2d0 11. Substance 0 .................................................... 280 13. Substance P .................................................... 280 14. Substance R .................................................... 280 15. Substance S .................................................... 281 16. Substance T, ................................................... 17. Substance To................................. ......... 281 282 18. Substance U .................................................... 282 19. Sulfur-Containing Alkaloid ..................... 282 20. Colchicoside.................................................... 283 21. Gloriosine . . . . . . . . . . . . ....................... 283 22 . Unknown Alkaloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 23. Speciosine . . . . . . . . . . . ....................... 283 VI . Biosynthesis and Synthesis . . . . . . . . . . . . . . . . . . . . ....................... 284 VII . References . . . . . . . . . . . . . . . . ..............................

.

I . Introduction Although Colchicum has been known since the days of the early Egyptians and Greeks and the chemistry of colchicine has been studied 247

248

W. C. WILDMAN

for over half a century, the literature in the field has been voluminous for the past decade, indicating the complexity, scope, and interest of the problem. With the growing knowledge of the structure and reactions of the substances derived from Colchicum autumnale L., botanists, pharmacologists, and zoologists have been able to extend studies, once limited to the effects of colchicine, to the actions of a variety of new derivatives as well. The biological effects of colchicine were reviewed in Chapter 10, Volume 11, of this series, and Eigsti and Dustin (274) presented a comprehensive discussion in book form. These sources cover the major biological aspects and applications of colchicine. Since the more recent developments in this field appear to follow the earlier lines of research and represent extensions of established concepts, they will not be reviewed in this chapter. By chromatographic techniques, Santavp (274a, 275) has demonstrated the presence of a relatively large group of minor alkaloids which often accompany colchicine in the plant. The major component, colchicine, was designated Substance A, and subsequent minor materials were named B, C, etc. As the structures of these materials became known, chemical names derived from the parent alkaloid, colchicine, were assigned. I n the current literature, the chemical and alphabetical names often are used interchangeably. Many of these alkaloids contain the colchicine ring system, and the assignment of structures was simplified considerably by the chemical experience provided by colchicine. With the completion of Chapter 10, the gross structure of colchicine was known with certainty. The structure of ring A was secure, and strong evidence existed for the seven-membered nature of ring B. I n the addendum, decisive evidence that ring C is a tropolone methyl ether was advanced, and the seven-membered nature of ring B was shown by synthesis of key degradation products. Much of this later work was derived from preliminary communications, and for continuity and completeness some of the material of the addendum will be discussed in more detail. More recent work on the chemistry of colchicine, appearing since the addendum, has been concerned with the isolation and structure of minor alkaloids, the reactions of ring C, and the stereochemical aspects of the colchicine molecule.

11. Occurrence and Isolation* Toxic principles are quite common in the family Liliaceae. The better known poisonous genera include Rhodea of the subtribe Aspidistrinae, Urginea, Scilla, Muscari, Camassia, and Ornithogalum of the subfamily

* This material

is supplementary to Volume 11, pages 263-266.

249

COLCHICINE AND RELATED COMPOUNDS

Scilloideae, Fritillaria and Lloydia of the subfamily Liliodeae,Sabadilla, Zygadenus, and Veratrum of the tribe Veratreae, and Colclticum of the tribe Colchiceae. Many early, nonspecific alkaloid tests and toxicity studies of these genera have been carried over into recent literature as certain evidence for the presence of colchicine. Most of these errors have been corrected by the work of Santavjr (275), who, by modern techniques, reinvestigated many of the plants reported to contain colchicine. Proof of the presence of colchicine or related compounds was determined by at least one of four criteria, and usually a combination of tests was possible. These teats included: ( a )the actual isolation of colchicine or a related alkaloid, ( b )a positive ferric chloride test after acid hydrolysis of the crude alkaloid fraction, (c) polarographic determination of the presence of tropolones (275a-276), and ( d ) paper chromatographic isolation and identification (277-279). From these studies, colchicine and related compounds have been found only in the Colchicum, Merendera, Androcymbium, Gloriosa, and Littonia genera. No colchicinelike substances were detected in the plant materials listed in Table 3. TABLE

3

PLANT MATERIALS ERRONEOUSLY REPORTED TO CONTAIN COLCHICINE

Plant

Anthericum ramosum L. Asphodelus albus Willd. Chamaelirium carolinianum Willd. Chlorogallum pomeridianum Kth. Fritillaria montana Hoppe Hemerocallis f ulva L. Lloydia serotina Salisb. Muscari tenuijlorum Tausch. Narthecium ossifragrum L. Ornithogalum caudatum Ait. 0. comosum I,. 0.nutans L. 0. umbellatum L. Tofieldia calyculata Whlnd. T . glacialis Gaud. Tulipa ailvestris L. Veratrum album L. V . nigrum L. V . viride Ait. Xerophyllum eetifolium Mich. Zygadenus intermedius Rydb. (Zigadenus interntedius)

Reference reporting presence of colchicine 279a 279a 280 280 279a 279a 279a 279a 280 279a 279a 279a 279a 279a 279a 279a 279a 279a 279a 280 280

Reference containing evidence refuting original claim 275 275 275 275 275 275, 281 275 275 275 275, 277 275 275 275 275 275 275, 282 275 276 275 275 276

-

250

W. C. WILDMAK

All parts of C. autumnale have been found to contain colchicine or related compounds, and a considerable amount of information is available concerning the effect of environmental and seasonal factors on the alkaloid content. The relative content (based on per cent of dry weight of plant material) of colchicine is highest in the flowers and lowest in the leaves. However, by virtue of their greater weight, the corms contain the greatest amount of colchicine and the flowers, the least (283, 284). In the spring when the leaves first appear, the mature corms contain three times the percentage of colchicine-like material found present in the fall. During the next 14 days of development, the alkaloid content reaches a maximum amount. The mature corm atrophies gradually after this time, and its alkaloid content drops markedly. Simultaneously, a new corm is developing on the side of the parent, and a gradual increase in alkaloid content of the new corm begins. I n the developing corm, colchicine is the major alkaloid although Substance F is present. Although the highest percentage of alkaloids is not present in the fall, the maximum bulb weight is reached in this period and the greatest quantity of alkaloids may be obtained by processing the bulbs a t this time (285, 286). The quantity of colchicine present in the seeds of C. autumnale varies with the size of the seed (287), but it has been shown that mature seeds contain a higher percentage of colchicine than immature ones (283, 288). I n contrast, the content (on a dry-weight basis) of colchicine in the flowers decreases during their development (289). Environmental and seasonal factors affecting the alkaloid content of Gloriosa superba L. (290) and Colchicum speciosum Stev. (291, 292) have been reported. I n the case of the former plant, it was reported that the corms contained neither colchicine nor gloriosine but Substance B instead. It is a relatively recent observation that Colchicum species contain numerous chemical constituents of diverse chemical properties. Recognition of this fact has led to more efficient methods of isolation. I n addition to neutral, phenolic, and basic alkaloids, C . autumnale contains fatlike substances which are removed by a preliminary ligroin extraction of the pulverized, dry mat,erial. From such an extraction of the flowers of C. autumnale, Santav? and Herout (293) have isolated a m.p. 58-60'; an alcohol, CzzH,,OH, m.p. 66-67'; paraffin, C2,-z28H56-58, and a phytosterol, m.p. 139-140'. Benzoic, salicylic, and 2-hydroxy-6methoxybenzoic acids may be separated from the alkaloid mixture by virtue of their solubility in ether and aqueous base (294). The alkaloids themselves may be separated into neutral, phenolic, or basic fractions by standard extraction techniques. Pure alkaloids may be obtained from each fraction by fractional crystallization and chromatography on


25 1

alumina. Exact chromatographic procedures have been described in the literature, and extensive descriptions of these processes are not included in the experimental method presented below. From the existing literature it would appear that the basic alkaloids are eluted in the order F, S, and then U; neutral and phenolic alkaloids, in the order 0, I, J, R, colchicine, B, C, E,. Twenty kilograms of finely powdered, dry corms of C. autumnale were extracted first at room temperature and then a t higher temperatures (max. 70'). A total of 60 1. of ethanol was used in the series of extractions. The extract was concentrated on a water bath and finally under reduced pressure at looo. The oily concentrate was diluted to a volume of 4 1. with water and washed four times with 2-1. portions of ether. The ether extract was washed with 300-ml. portions of water, 3% hydrochloric acid, water, 4% sodium carbonate, and finally with two 300-ml. portions of water. The aqueous solution was acidified with hydrochloric acid t o p H 2-3 and extracted six times with 500-ml. portions of chloroform. Concentration of the chloroform extract afforded 48 g. of neutral and phenolic, chloroform-soluble materials. The aqueous solution was basified with ammonium hydroxide and extracted four times with 500-ml. portions of chloroform t o yield 14.4 g. of basic, chloroform-soluble substances. The remaining aqueous solution was neutralized t o p H 7 with hydrochloric acid (cooling) and concentrated t o a volume of 1 1. Five extractions of this concentrate with 500-ml. portions of chloroform-ethanol ( 2 : l ) afforded 4.5 g. of material, probably of glycosidic nature. The sodium carbonate extract of the ether-soluble fraction was acidified with dilute sulfuric acid and extracted with ethor. The ether extract was concentrated t o a mixture of benzoic, salicylic, and 2-hydroxy-6-methoxybenzoicacids, which were separated by the method of Clewer et al. (294a). The hydrochloric acid extract of the ether-soluble fraction was basified with ammonia and extracted with chloroform. Concentration of this chloroform solution gave 9.15 g. of basic, ether-soluble materials. To this fraction were added similar fractions derived from plant materials gathered at later dates. This material (16.51 g.) was dissolved in a minimum of ethanol and treated with wator until no further precipitate was formed. After 12 hours, the clear aqueous solution was decanted, and the water-soluble substances were extracted from the aqueous solution with chloroform. The water-insoluble precipitate was dissolved in ethanol and reprecipitated with water two times. In this manner there was obtained 4.0 g. of w-aterinsoluble and 10.5 g. of water-soluble material. The water-insoluble material, 111.p. 135-140°, could not be crystallized from the usual solvents and was methylated with diazomethane to give, after chromatography and recrystallization from ethyl acetateether, Substance H,, m.p. 183-185'. The water-soluble fraction was dissolved in the minimum amount of methanol, and after several hours at 3', the solution deposited 820 mg. of long, orange-yellow prisms of Substance T,. The filtrate was concentrated under reduced pressure and chromatographed on 250 g. of alumina (Brockmann's neutral). Elution with ether-chloroform (2:1) and chloroform afforded, after recrystallization from ethyl acetate, 5.42 g. of Substance F. Later fractions eluted with chloroform afforded a substance which melted a t 190-193' after recrystallization from ethyl acetate. When it was mixed with Suhstance F (m.p. 18&186'), no melting point depression was observed. The material was designated Substance L in case it proved to he different from Substance F. The 48.0 g. of neutral and phenolic, chloroform-soluble materials was dissolved in a minimum amount of ethanol and treated with 500 ml. of water end 10 g. of sodium

252

W. (?. WILDMAN

chloride. Apigenin (24.7 g.) precipitated from the solution as brown crystals and was identified as its acetyl derivative, m.p. 183-185'. The filtrate was extracted five times with 200-ml. portions of chloroform which were concentrated to give 22 g. of amorphous material. The aqueous solution was concentrated t o dryness, and the residue was extracted several times with chloroforni. The chloroform extract was concentrated and crystallized from ethyl acetate to afford colchiceine, m.p. 175-177'. The 22 g. of amorphous material was dissolved in a minimum quantity of hot ethyl acetate and then cooled t o 3' in the refrigerator. Over a period of six months, 3.2 g. of Substance To, m.p. 236-238', was deposited. I n a second experiment, 37 g. of neutral and phenolic, chloroformsoluble materials, freed of apigenin, was chromatographed directly on GOO g. of alumina. Elution with ether-chloroform (2:l and 1:l) afforded 16.54 g. of crude colchicine which was recrystallized from ethyl acetate and ether to give 14.0 g. of pure colchicine, m.p. 154-156'. Repeated chromatography and fractional crystallization of the noncrystalline residues from this column afforded a n additional 9.3 g. of colchicine and small quantities of Substances B, I, J, D, C, R, and P. From 10.5 g. of basic, chloroform-soluble material, 1.15 g. of Substance F was obtained by recrystallization from ethyl acetate. The mother liquors were chromatographed on 240 g. of alumina. Elution with ether-chloroform (2:l and 1:l) and chloroform followed by recrystallization from ethyl acetate afforded 5.0 g. of Substance F, m.p. 184-186'. Elution with chloroform-methanol (96:4 and 92:s) afforded 0.9 g. of nearly pure Substance S which was recrystallized from methanol-ether t o give 770 mg. of pure alkaloid, m.p. 136-138O. Elution with more polar solvents afforded amorphous materials from which 600 mg. of acetyl Substance C could be obtained by acetylation and chromatography (294).

Paper chromatography appears to be a most promising method for the detection and separation of alkaloids derived from colchicine. Either the ascending or descending technique appears to be satisfactory, and the latter is particularly effective with materials of low R, value. Materials containing the tropolone ring may be located by their fluorescence in ultraviolet light or by a phosphotungstic acid spray (295). I n addition, phenolic alkaloids may be identified by an intense color when sprayed with ferric chloride-potassium ferricyanide solution (296). A novel identification method involves spraying the dry, developed paper with 10% hydrochloric acid, heating the paper for 2 minutes at 110°C. in an oven, and then spraying with ferric chloride. Green spots indicate the location of tropolones produced by the acid hydrolysis of the tropolone ethers. Although many solvent systems have been used satisfactorily for these isolations, chromatography of the alkaloids on paper impregnated with 30% formamide in methanol or ethanol and development with benzene-chloroform (2:1 ) has been particularly successful (279). The information in Table 4 represents a summary of the occurrence of colchicine and related substances reported since 1946. The table includes only those isolations which have been shown to contain colchicine-like substances by at least one of the four criteria listed on page 249.

TABLE

4

BOTANICAL DISTRIBUTION

Substance Plant Androcymbiwm gramineum McBr.

Colchicum aggreinum Baker C. arenarium W.K.

C . autumnale L.

Source Corms Flowers and leaves Seeds corms Corms Flowers Leaves Seeds Seeds Seeds Seeds

Seeds

Colchicine

*

B

C

?

*

F

Substance El 4

*

*

*

0.15y0

* * * *

?

*

*

0.95y0

0.022%

0.55%

0.0075~0 0.025%

*

Seeds

0.45y0

Corms

0.084%

L

0.049y0

References 277. 279

*

*

Other

*

* * * *

Substance El Substance E,

Substance I (0.007%) Colchicoside (0.25%) 0.013y0 Substance K, Substance S (0.008%) Substance U (0.32%) * 0-Demethyl-N-methyldesacetylcolchicine (0.002yo) Compound C,,H,,N04S, (0.003%) 0.029y0 Colchiceine Substances El, I, D, J, R, P, Ha, Tap To, L, S Substance S (0.0037~0) Substance To (0.015%)

277

Q 0 F Q

279 282

3 G

279, 281 279 279 270 296s 297 298

k

299

1 td

i d

F

5 Q 0

5

5z e

v)

300 294. SOOa

E3

ol w

TABLE

N

&(Continued)

u1

Substance Plant

G. autumnale L.-(cont.)

G . autumnale var. album Hort. C. autumnale var. f i r e pleno Hort. C. autumnale var. majua Hort. G . autumnale var. minor Hort.

Source

Colchicine

Corms Flowers

0.034% 0.237%

Flowers

0.05y0

Pericarps Leaves Leaves and pericarps Corms corms

B

C

Other

0.114% Substance D (0.017%) Substance El (0.37%) Substance F (0.0027~0) Substance I (O.OO1~o) 0 . 0 0 0 6 ~ 0Substance D ( 0 . 0 0 2 ~ o ) Substance El (0.11%) Substance I (0.0006~0) Substance J (trace) Substance N ( 0 . 0 0 7 ~ 0 ) Substance 0 (0.0003~0) Substance S ( 0 . 0 0 5 ~ 0 ) Substance U (trace) Colchiceine Substance El(0.027%) * Substance El * Substance E,

0.0005~0

0.064% 8 8

* *

F

8

*

*

References 301 302

303

3 P

4

i:

tr 302 277 304 281

*

277

Corms

8

*

281

corns

8

*

281

P2

TABLE

4-(Continued

Substance Plant

Colchicum hybrids var. Lilac Wonder var. The Giant var. Violet Queen C. bornmiilleri Freyn. C. cilicum Hayelr. C. crocifolium Boiss. C. crocijlorum Schott and Kotschy (C. serpentinum Woronow ap. Mischenko) C . hierosolymnitanum Feinbr. C. lusitanum Brot. C . luteum Baker C. speciosum Stev.

C . ocrrirgatunl

I>.

C. w r n u m Ker-Gad.

Gloriosa rothschildiana O'Brien

Source

Colchicine

C

* * * * *

Corms

*

*

*

*

*

*

277, 305

*

* *

Corms

* *

*

* ?

*

*

Substance S Substance I

*

Speciosine Substance S Substance E, Substance S Substance E,

*

Substance I Substance J Substance I

* * *

References

281 281 281 281 281 275 281a

* *

* *

0.095%

Other

*

* * *

Lcsves Corms Corms

F

* *

* *

Corms Corms Corms Corms corms Corms Corms

Seeds Corms Corms corms corms corms Flowers

B

215 279 279 281, 291, 306 307 308 308 277 271 282 309, 310

-

TABLE

tQ

&Continued

-

Substance Plant

-

Source Corms Corms“ Cornisb

G . simplex L. a.superbn L.

Colchicine

B

C

F

*

*

*

*

0.23% 0.05%

Leavesb Flowersb Corms Corms Corms corn

L-ittonia rnodesta Hook. Merendera attica Boiss. e t Sprun.

corms corms

M . mucasica Spreng. M . sobolgera C.A.M. M . trigina Stapf. (C. mumsicurn Spreng. ) ___

a Of Czechoslovakian b Of Indian origin.

Corms Corms Corms

0.015% 0.03%

* 0.022%

*

*

0.0220,b 0.009~o

Trace Trace

* *

*

* *

*

* *

References

Substance I Substance I Substance I Substance GI Substance G , Substance E, Substance I Substance El

310 310, 310a 310a 310a 310a 310a 310a 310a 311

“New alkaloid,” m.p. 239-242’ (dec.) Gloriosine

o.10yo

0.13%

Other

* *

290, 312 313 314

Substance I, J

282 281a

*

277 277. 282 281a

*

~~

origin.

c

m n -.


257

The minor alkaloids occurring with C. autumnale are not always removed completely in the preparation of U.S.P. colchicine. Colchicine of Lhis purity has been reported to be contaminated with Substance B (315) and Substance C (316). 111. Chemistry of Colchicine* 1 . STRUCTURE AND REACTIONS OF COLCHICINE With the publication of Volume I1 of this series, studies on the structure of colchicine had progressed to the stage where only two formulas, XLI and XLII, seemed compatible with the accumulated chemical evidence. The pioneering efforts of Windaus left no doubt that the

XLI

XLll

structure of ring A was represented correctly. With the synthesis of colchinol methyl ether (XXXVII) and dihydrodeaminocolchinic acid anhydride (LXXII), the seven-membered nature of ring B in two series of degradation products was established, and there is little question that the B ring is seven-membered in colchicine as well. The concept of a tropoloid structure for ring C was proposed by Dewar in 1945, and with full knowledge of the inadequacies of the Windaus structure, investigators in many countries sought experimental evidence to confirm or

XXXVll

LXXll

reject the Dewar proposal. The chemical knowledge of tropolones and ring C of colchicine developed simultaneously and properties characteristic of one were sought, by analogy, in the other. This evidence by analogy is necessary for the acceptance of a tropoloid structure for colchicine, but it is not self-sufficient. Although X-ray diffraction This material is supplementary to Volume 11, pages 266-290, 325-329. 8

258

W. C . WILDMAN

studies support structure XLI for colchicine, complete chemical proof of the tropolone nature of ring C and the position of the carbonyl group within this ring has not been obtained. In this section, these problems will be considered in more detail. a. Structure of Riitg B. Proof of the seven-membered nature of ring B is derived from two distinct degradative routes. In one series, ring C had been converted by alkali to a benzenoid ring system before studies relative to the structure of ring B were begun. Degradative evidence for the structures of N-acetylcolchinol methyl ether, deaminocolchinol methyl ether, and isodeaminocolchinol methyl ether was presented in Chapter 10, and with the synthesis of Z-colchinolmethyl ether (XXXVII) (316a), dZ-colchinol methyl ether (316b, 317), and dihydrodeaminocolchinol methyl ether (XXXVII, H instead of NH,) (317), the sevenmembered nature of ring B in these degradation products was confirmed.

LXXIV

LXXlll

The second proof of the structure of ring B is derived from the structure of N-benzoylcolchinic acid anhydride (LXXIII), an oxidation product of N-benzoyltrimethylcolchicinic acid (LXXIV). The latter compound retains the intact ring system of colchicine. The oxidation of LXXIV to LXXIII and the degradation of the latter compound to deaminocolchinic acid anhydride (LXVI)* and dihydrodeaminocolchinic acid anhydride (LXXII) have been described in Chapter 10 (pp. 284, 326). By the synthesis (317a, 318) of dihydrodeaminocolchinic acid anhydride (LXXII) from LXVII,* it was shown that deaminocolchinic acid anhydride is a derivative of benzocycloheptatriene rather than naphthalene.

CHP

CH,O

0

LXVI

COOC,H,

LXVll

* Note that the formula given on page 327 of Volume I1 for LXVI is incorrect. Also, L X X I I was prepared from the diethyl ester of LXVII (Vol. 11,p. 327) rather than from the diacid.

COLCHICIN E AND RELATED COMPOUNDS

259

Frequent mention has been made in Chapter 10 of the many examples of molecular rearrangement of both rings B and C in the reactions of colchicine and colchicine derivatives. The course of the rearrangement which occurs when colchinol methyl ether is treated with nitrous acid has been elucidated (319). I n earlier work, Cohen et al. (319a) treated colchinol methyl ether with nitrous acid to obtain two isomeric carbinols: A, C19H2205, m.p. 115.5-116.5', and B, m.p. 157-160". Dehydration of the former afforded a mixture of deaminocolchinol methyl ether and isodeaminocolchinol methyl ether (319b). It was considered unlikely that these carbinols contained a seven-membered B ring (as in LXXV), since their ultraviolet spectra differed from those reported for dihydrodeaminocolchinol methyl ether, N-acetylcolchinol methyl ether, and colchinol methyl ether and resembled more closely that of a fluorene derivative (LXXVI) (319c). A synthesis of LXXV showed

LXXV

LXXVI

LXXVll

conclusively that it was not identical with either carbinol A or B. Since LXXVI, as an alternative, would be expected to yield a 9-vinyl derivative on dehydration, the carbinol LXXVII was considered the most likely structure for carbinol A. Lithium aluminum hydride reduction of methyl 9,10-dihydro-2,3,4,7-tetramethoxy-9-phenanthrenecarboxylate afforded synthetic LXXVII, identical in all respects with carbinol B, which was discovered at this time to be optically inactive. Carbinol A represented the levorotatory stereoisomer of LXXVII. Thus, the conversion of colchinol methyl ether to deaminocolchinol methyl ether via the carbinol A involves two Demjanow-type rearrangements; the first, conversion of colchinol methyl ether to the carbinols A and B, occurs with ring contraction. I n the second rearrangement, the sixmembered ring B of the carbinols A and B is re-expanded by phosphorus pentoxide to the seven-membered ring system of the deaminocolchinol methyl ethers (319). b. Structure of Ring C. As authentic tropolones became available, comparisons of the polarographic behavior (275a, 319d, 320) and infrared spectra (32Oa-32Oc) of these compounds with colchicine afforded more evidence for a tropoloid ring C. More detailed discussions of these

260

W. C. WILDMAN

and other physical properties with specific reference to simpler tropolones and tropones are included in several reviews (321-324). Many of the unusual transformations of colchicine have counterparts in the reactions of simpler tropolones. These similarities are so impressive that the tropoloid ring C has been accepted as fact by most workers in the field. However, Doering and Knox (320a), who were among the first to present this type of evidence, pointed out that whereas such a correspondence of properties is necessary to establish the presence of a tropoloid ring, it does not provide complete proof in itself. Tropolones form chelate complexes with many metals and similarly, colchiceine, but not colchicine, affords a crystalline copper salt (324a, 324b). Like tropolone methyl ether, which is more soluble in water than is tropolone, colchicine is more water-soluble than the free tropolone, colchiceine. Hydrolysis of colchicine with aqueous hydrochloric acid (324c, 324d) or with dilute alkali (324e) affords an acidic substance, colchiceine (XL), and methanol. On methylation with diazomethane, colchiceine is converted to colchicine and an isomeric compound, isocolchicine. The formation of two isomers under these conditions is consistent with the unsymmetrical substitution present in the C ring. Like colchicine, isocolchicine yields colchiceine on hydrolysis and allocolchicine (LXVIII) on isomerization with sodium methoxide in methanol (324f, 3248). The carbonyl and methoxyl groups of the tropolone ring C have been placed in the 9- and 10-positionsfrom mechanistic considerations of the reactions by which ring C becomes benzenoid in the presence of base. As yet, no unequivocal chemical evidence has been presented to indicate the specific positions of these groups. In keeping with the evidence which does exist, colchicine and other derivatives of the normal series will be considered to have the carbonyl group in position 9. Consistent with the view that colchicine and isocolchicine may be regarded as vinylogs of a methyl ester, the respective methoxyl groups of each may be replaced by amino, mercapto, or larger alkoxy groups through the action of amines, mercaptans, and alcohols, respectively. With guanidine or thiourea, derivatives of imidazole (325, 326) are produced. The products of these replacement reactions have been called “aminocolchicines,” “colchaminones” or “colchicine amides,” and “thiocolchicines.” A logical form of nomenclature based on the parent tropone colchicide (LXXVIII, R = COCH,, R, = CH,, Y = H) or isocolchicide (LXXIX, R = COCH,, R, = CH,, Y = H) has been suggested (327); this system will be followed in the present chapter. Many analogous examples of this type of substitution in simpler tropolones may be found in the literature (cj. (321),Table 6). A number

“q

COLCHICINE AND RELATED COMPOUNDS R CH,O

,

O

q

&

CH.0

‘

‘

CH.0

CH,O

+

LXXVlll

261

Y

LXXIX

of such derivatives of colchicine and isocolchicine have been prepared for pharmacological testing, and a summary of these preparations is given in Table 5 . TABLE

5

SUBSTITUTED COLCHICIDEB

R

Formula

LXXVIII

H

Rl

Y

References 328-333 328,330-332 330 327,328,330,332 330, 332,333 328, 330 330,333 330 330 330 332-334 332 332 332 332 332 332 328,331,332 332 332 333 328 328 328 335, 336 337 337 337 337 338 a39 337 337 339

2 62

W. C. WILDMAN TABLE

Formula

R

LXXVIII

CH,

5-(Continued)

Rl CH,

Y NHa NHCH, NHCH(CH,), NHC,H, NH(CH2)3CH3

LXXVIII

COCH,

H

NHCH2CH=CH, NHCH,CH,OH NHPh NWH,), N(CH,), N(CH,), N(CH,), SCH, NH, NHCH, NHC,H, NHCH,CH,CH, N H (CH,),CH, NH(CH2)4CH3

NH(CH2)5CH3 N(CH3)2

N(C,H,), N(CH2)5

LXXVIII

COCH,

CBHIIOS

“=,),O NHCH,CH,QH SCH, NH, NHCH, NHC,H, NHCH,CH,CH, NH(CH2)3CH3 NH(CH2)4CH3

NH(CH,),CH, N(CH3)2 N(C2H5)2

NHCH,CH,OH N(CH,CH,OH), NHCH,Ph NHCH( CH,) (CH,Ph) NHCH(Ph), NHNH, NHNHPh N(CH2)5

N(CHz),O NHPh SCH,

RefeIence8 340 340 340 340 340 340 340 340 3 40 340 340 340 337 341,342 341, 342 341,342 341,342 341,342 341,342 341,342 341, 342 341,342 341,342 341,342 341,342 335 343,344 343,344 343,344 343,344 343,344 343,344 343 343,344 343,344 343,344 343,344 343,344 343,344 343,344 343,544 343,344 343,344 343 344 337

263

COLCRICINE AND REJAATEDCOMPOUNDS TABLE 5-(Continued)

Formula LXXVIII LXXVIII LXXVIII LXXVIII LXXVIII LXXVIII LXXIX LXXIX

R

Y

Rl

CHO COPh COOC,H, CHO COPh COPh H COCH,

Reference8

SCH, SCH, SCH, SCH, SCH, SCH, NH, NH, NHCH,

337 337 337 337 337 337 338 334 329

These substitution reactions of colchicine proceed with a considerable degree of specificity (334). Thus, transetherification of colchicine by ethanol in the presence of acid afforded a 40% yield of ethoxycolchicide (LXXX, R = C,H,) and a 5 % yield of ethoxyisocolchicide (LXXXI, R = C,H,). Amination of either colchicine or ethoxycol-

LXXX

LXXXI

chicide affords aminocolchicide. Similar substitution reactions in the is0 series (LXXXI) proceed with the preservation of this isomerism, and derivatives of the is0 series are formed predominantly. Under acidic conditions, transetherification may be considered to take place by the mechanism shown below.

LXXXll

LXXXlll

'8.6

+ Ro-

OR'

LXXV

LXXIV

264

W. C. WILDMAN

The conversion of colchicine to aminocolchicides may be considered a direct nucleophilic replacement a t Cl0. I n more basic media such as methanolic sodium methoxide, colchicine and isocolchicine are converted

LXXXVl

LXXXvll

LXXXVlll

to allocolchicine (LXVIII; syn. colchicic acid methyl ester, colchicine methyl ester, methyl colchicicate) (324f, 3248) by attack of the methoxide anion a t the tropolone carbonyl group. From the structure of LXVIII and the mechanism by which it is formed, it is evident that the tropoloid ring of colchicine and isocolchicine is substituted in the 9and 10-positions. The drastic conditions required to convert colchiceine

LXXXIX

LXVlll

xc

to a derivative of benzoic acid (344a) may be explained by the electrostatic repulsion of the hydroxide anion by the negatively charged anion of colchiceine (XC) which is formed in the basic medium. Other conversions of the C ring of colchicine to a benzenoid system have been discussed in Chapter 10, Volume IT, in connection with the preparation of AT-acetylcolchinol (344b) and N-acetyliodocolchinol (344a, 344c). Many similar rearrangements have been reported for simpler tropolones. A table of these reactions and a detailed discussion of the possible mechanisms of such transformations have been presented (321). I n a comparison of colchicine and isocolchicine, Horowitz and Ullyot (334) and Santavf and Reichstein (296a) observed that isocolchicine and other compounds of the is0 series have more negative specific rotations than their counterparts in the normal series. Since there is no infallible method to distinguish between the two series by spectral methods, this method of comparison has been the basis of most of the assignments in the literature today. Spectral variations between the normal and is0 series have been found in a limited number of compounds.

COLCHICINE AND RELATED COMP0UNI)S

265

The ultraviolet absorption spectra of colchicine and isocolchicine differ in the respect that the longer wavelength band (-350 mp in ethanol) of isocolchicine and other alkoxyisocolchicides is shifted about 8 mp toward the violet from that observed in the corresponding alkoxycolchicide. This shift is less pronounced in the aminocolchicides. The absence of an active hydrogen in dialklylaminocolchicides and methylthiocolchioides causes a bathochromic shift of approximately 20 mp in the long wavelength absorption of these compounds (345). Studies of the infrared spectra of colchicides and isocolchicides have not been as useful. This may be attributed, in part, to the variations in resolution of the spectrophotometers used by various investigators and to the spectral variations caused by the choice of solvent and concentration. Scott and Tarbell (320b) reported that absorption at 6.17-6.19, 6.44-6.46, 7.76, and 7.89 p is characteristic of tropolones. The absorption band near 6.45 p appears to be associated with the tropolone carbonyl group. Bands specifically associated with the tricyclic colchicine ring structure were reported near 7.15, 7.43, 7.58, 8.78, 9.14, 9.58, 10.00, and 11.84 p (345) when the samples were examined at a concentration of 0.03-0.04 N in chloroform solution. I n a comparison of isomers in the normal and is0 series, it has been reported that compounds of the normal series have more fine structure in the 7-p region than do the is0 compounds (334). I n a limited number of examples, it appears that amide absorption for compounds of the normal series occurs in the range 5.97-5.99 p, whereas the is0 series shows absorption in the range 5.94-5.96 p (345). It has been reported that in the 3-p region the associated NH band of compounds in the is0 series is less intense and occurs at a lower wavelength than the same band in the normal series. Since colchiceine resembles the is0 compounds in the 7 - p region and has a specific rotation considerably more negative than that of colchicine, it would appear to be a nontautomeric, single species belonging to the is0 series. Horowitz and Ullyot postulate that colchiceine is stabilized in the is0 series by bonding of the hydrogen atom of the 9-hydroxyl to the carbonyl oxygen of the acetamido group. Although this involves a nine-membered ring, molecular models show that interaction of this type is quite possible. Compounds of the normal and is0 series differ considerably in biological activity. Those of the is0 series are much weaker in antimitotic activity and less toxic (346). Recognizing that the determination of the structure of ring C by physical and chemical analogies with simpler tropolones did not offer final chemical proof that this ring was tropoloid or that the carbonyl and methoxyl groups were in positions 9 and 10, respectively, recent

266

W. C. WILDMAN

workers have tried to design degradative and synthetic experiments which do not rely on the crutch of analogy. The total synthesis of colchicine offers one approach which will prove the tropoloid nature of ring C conclusively. However, total synthesis will not necessarily solve the problem of the relative positions of the carbonyl and methoxyl groups in ring C if, in the course of such a synthesis, ring C is maintained as a free tropolone (rather than as a tropolone methyl ether) to avoid base-induced rearrangements. A second approach has been concerned with the unambiguous degradation of colchicine to simpler compounds which contain a hydrogenated ring C. If ring C can be reduced in such a manner that the carbonyl group is retained in the position it occupies in colchicine, unequivocal evidence for this position may be obtained. Toward this end, a number of hydrogenation studies have been carried out on colchicine and its derivatives. An improved route to tetra- and hexahydrodemethoxycolcliicineinvolves the catalytic reduction of N,N-dimethylaminocolchicide (XCI) (327). Hydrolysis of XCI afforded colchiceine, which proved that the dimethylamino and carbonyl groups occupied the same two positions of ring C as were occupied by the methoxyl and carbonyl groups of colchicine. Dimethylaminocolchicide absorbed 3 moles of hydrogen rapidly and then, more slowly, an additional 2 moles. CHART I

choq +:q&+;QgH300 215-21 7 187-188 337 198 156-158 240 (dec.) 111-112 228 (dec.) 120-121 (.9H,O) 177-179 (.4HnO) 84 219 (dec.) (.H,O) 224-225 (dec.)

- 177.5' -324'

(CHC1,)

(CHCl,)

Crystal form

Needles (ether) Prisms (C,H,OH) Cubes (CH,OH-CHCl,) Needles

- 197' (CHCI,) - 1'74' (CHCI,)

- 181' (CHC1,) -89.8' (CHCI,) Plates (C,H,OH)

References

65 115 103 103 101 101 101 101 101 82 106 106 106 106 106 106 106

( - )-Anhydrolycorine

Methiodide Methocarbonate Methocarbonate Methochloride Methochloride

(-H,O) 226 (dec.) (*9H,O) 88-91 (.6H,O) 153 (dec.) (.4.5H20) 79-81 (.1.5H2O) 162 (dec.)

-56' -49'

(H,O) (HaO)

-63'

(H*O)

106 106 106 106 106

3 ?

d Y

F

z

Compound

M.p. or b.p. ("C.)

[ a ] (Solvent) ~ ~~

~

(

Picrate Anhydromethylpseudolycorinium chloride Base M Hydroperchlorate Caranine Hydroperchlorate a-Methiodide 8-Methiodide Caranine anhydromethine Bk-methiodide Picrate

~~~~~

References ~~

A

+)-Anhydrolycorine

Methiodide Methocarbonate Methocarbonate Methochloride Methochloride Anhydrolycorinium Chloride Iodide Nitrate Picrate Anhydromethylpseudolycorine

Crystal form

226 (dec.) ( .9HaO)87-90 ('6HaO) 152 (dec.)

$53' (HLO) +48O (HzO)

(-4.5HaO) 79-81 (*1.5HaO)163 (dec.)

+64' (H&)

280-285 (dec.) 304-305 (dec.) 270 (dec.) 260.5-261 (dec.) 145 (260-270) 174-177 234-252 (dec.) 226 (dec.)

B 221 (253-254 dec.) 286 (dec.) C 178-180 270 (dec.) 254-255 (dec.) 312-314 (dec.) 92-92.5 199-201 (dec.) 130-162

106 106 106 106 106

Needles (H,O) Needles (H,O) Prisms (CH,OH-acetone) Prisms (C,H,OH) Needles (C,H,OH) Needles (H,O)

106 108 108 108 93 87 93 87

r

2

F:

0 4

!i b-

Fw 3r

ij -40'

(DMF)

Prisms (acetone) Prisms (C,H,OH-ether)

- 196.6O (CHCl,)

Prisms (ethyl acetate)

- 111' (HSO-DMF) (H,O-DMF)

Needles (CaH,OH) Blades (HaO-CIH,OH) Flakes (CH,OH) Needles (CHJ)

+ 62'

90a 9Oa 65 65 115 116 116 116 115

$ i M

k

0 4

co

Compound

M.p. or b.p.

[ a ] (Solvent) ~

Cqatal form

References

Prisms (C,H,OH)

101 82 82 101 115

("(3 D Dehydrodihydrosewlycorine 226 Dehydromethylpseudolycorhe 226-229 Methiodide 242-246 Diacetyl-w-bromo-N-cyanodihy~oEewIycole 177-178 a-Dihydroacetylcaranine 193.5-195

- 71.6' (CHCI,) - 121' (CHC1,)

Picrate a-Dihydroacetylcaraninelactam

188-189 192-1 94

-171'

a-Dihydrooaranine Picrate

170.5-172

- 126' (CHCI,)

( 149-1 50)

8-Dihydrocaranine

172-173 (dec.) 166.5-168

Picrate

-181' (CHCI,) - 359' (CH,OH)

(CHC1,)

- 191' (CHCI,)

174-175 (dec.)

a-Dihydrocaranone 141-148 2,4-Dinitrophenylhydrazone 270 (dec.) Dihy~odiacetylnarciasidine 181-183 Dihydrodiacetylnarcissidine lactam 222.5-224 4,5.Dihydro-9,10-dimethoxypyrrolo[de]-7H- 272-274 phenanthridin-7-one 4,5-Dihydro-9-ethoxy-IO-methoxypyrrolo[de]-229-230 7H-phenanthridin-7-one 4,5-Dihydro-lO-ethoxy-9-methoxypyrrolo[de]-176-176 7H-phenanthridh-7-one

' 0 (CHC1,)

Needles (ethyl acetatecyclohexane) Plates (CHC1,-C,H,OH) Prisms (ethyl acetatecyclohexane) Prisms (ethyl acetate) Needles (C,H,OH-acetone) Prisms (ethyl ocetatecyclohexane) Spherulites (CHC1,C2H5OH) Prisms (CH,OH) Needles (CHCI,-C,H50H) Prisms (C,H,OH-H,O) Prisms (C,H,OH)

115 115 115 115 115 115 115 115 82 82 93 86

86

TABLE

Compound

5-(Gontitwed)

M.p. or b.p. ("C.1

[a]~ (Solvent)

Crystal form

References

D 128.5-129.5 146-148

Dihydr ofalcatine Dihydrogdanthine

Picrate 182-190 (dec.) 0-Acetyl hydroperchlorate 250-269 (dec.) Dihydrolycorine 250 (deo.) 2-Acetyl 170-171 1,2-Epoxide 148.5 196 (dec.) 2-Methyl ether 144-146 2-Tosylab 86-86 Dihydrolycorine anhydromethine Hydriodide 210 198-201 4,5-Dihydro-S(or ll)-methoxy-9,10-methylenedioxypyrrolo[de]- 7H-phenanthridin-7-one 4,5-Dihydro-9,l0-methylenedioxypyrrorrolo[de]- 232-234 7H-phenanthridin-7-one Dihydromethylpseudolycorine 192-196 Dihydronarciasidine 158.5-160 Methiodide 213 7-(3,4-Dihydroxy-6-methylphenyl) 1 159-161 methylindoline Hydrochloride 233-237 7-(3,4-Dimethoxy-6-methylphenyl)169-71 methylindoline Hydrobromide 197-199

--

- 57'

(C,H,OH)

Prisms (benzenecyclohexane)

Prisms (CH,OH) -215.4' - 85.7'

54 113 113 113 91 110 110 110 110 109 109 82 106

-65'

(DMF) Prisms (ethyl acetate) Prisms (acetone)

93 82 82 112,122

F

8

UI

0

w

ii P

F

a

5r

3P

0 M

k

112 112 112

w

m

r

TABLE

5-(Continued)

W

m

tc Compound -~

M.p. or b.p. ("C.)

[ a ] (Solvent) ~

Crystal form

References

E - 168' (CHCl,) +11.1 (C,H,OH)

o-Ethoxydihydrosecolycorine 167-168 1-Ethyl-7,8-methylenedioxy-10-methyl-5-0x0- 153-154 1,2,3,4-tetrahydrobenzo[f]pyrrocoline 4-Ethyl-8,9-methylenedioxyphenanthridine Methiodide 236 228 (dec.) Methobromide 4-Ethyl-5-methyl-8,9-methylenedioxy-6(5H)(106) 114 phenanthridone

101 101

109 109 109

3

F Falcatine 127-128 Hydrochloride 238-240 (dec.) Methiodide 250-255 (dec.) Picrate 182-185 (dec.) 0-Acetyl 201-202 1-( 10-Formy1-7,8-methylenedioxy-5-oxo212 (dec.) 1,2,3,4-tetrahydrobenzo[flpyrrocolyl)acetaldehyde Bis-ethylenemercaptole 255 Dioxime 252-253 (dec.) 2-Formyl-4,5-methylenedioxy-3-vinylbiphenyl215.5-216.5 2,4-dinitrophenylhydrazone Galanthine Hydriodide Hydrobromide

(H,O) 134-136 166-167 16&167 201-203

- 197.8'

+ 101'

(CHCl,)

Prisms (ether)

Prisms (C,H,OH) (C,H,OH)

54 54 54 54 54 101

101

Needles (CHC1,C*H,OH)

a -81.6'

(CgHbOH)

101 115

93 Prisms (H,O)

90 111

P

3

s

Pz

Compound

Galanthim-( Continued) Hydrochloride Hydroperchlorate

[ a ] (Solvent) ~

Crystal form

References

a 198-199 (211-213)280 (dec.)

+42.3" (C,H,OH)

199-200 (dec.)

Prisms (C,H,OH-ethyl acetate) Needles (CH,OH-H,O)

111 93 90

H

>400

A

8 *

1 -Hydroxyanhydrolycoriniurn Chloride

102 102 102 87

235-240 (dec.)

Prisms (H,O)

63-65 252-256 (dec.) 219-224 86-87

d

-

Lycorane Hydroperchlorate Picrolonate Lycor- 1(11b)-ene

m 0

3

Powder (H,O) Powder (HaO) Prisms (DMF) Needles (C,H,OH)

2

>300 270-280 (dec.) 275-280 (dec.) >300

e D

102

Picrate 2-Hydroxyanhydrolycorinium Chloride Nitrate Picrate 1-Hydroxyanhydromethylpseudolycoriniurn chloride 2-Hydroxyanhydromethylpseudolycoriniurn chloride 2-Hydroxymethyl-4,5-methylenedioxy-3'vinylbiphenyl

N

260-280 (dec.)

Powder (CH,OHCaHsOH) Prisms (DMF)

140 (0.03mm.)

102

93 115

ALKALOIDS OF THE AMARYLLIDACEAE

0

x

m

3

Picrate

M.p. or b.p. ("C.1

L

-52.3'

(CHCI,)

Prisms (hexane)

383

Prisms (C,H,OH-H,O)

- 226.7'

82 82 82 110

w

TABLE 5-(Continued)

00

t P

M.p. or b.p. ("C.1

Compound

[ a ] (Solvent) ~

Crystal form

References

L Lycor73(3a)-ene Methiodide Picrate Lycorine Hydrochloride Hydroperchlorate Picrate 1-Acetyl Hydrochloride 2-Acetyl 1,2-Diacetyl

120-121 294-296 (dec.) 174-176 (dec.) 270 (dec.) 212-214 (dec.) 245 (dec.) 196-197 (dec.) 215-216 266 (dec.) 231-232 219-221

Lycorine anhydrohydromethine Lycorine anhydromethine Hydriodide Hydrochloride Picrolonate

69-70 97 186 (dec.) 209 (dec.) 180 (dec.)

- 127' (CHCl,) (C,H50H-H,0)

Prisms (ether) Prisms (H,O)

-83.8' (C,H,OH) +44.9' (H,O)

Prisms (C,H,OH) Needles (C,H,OH) Plates (H,O) Leaflets Prisms (C,H,OH)

+ 124'

-69'

+26.6'

(C,H,OH)

(CHCl,)

Platelets (CH,OHether) Prisms (CH,OH)

82 82 82 92 92 91 92 103 103 103 72 106 106 109 106 106

M 2-Methoxyanhydromethylpseudolycorinium Nitrate Perchlorate 2-Methoxylycor-l( 11b)-ene 4,6-Methylenedioxy-2,3'-biphenyl dicarboxylic acid 7 - (3,4-Methylenedioxy-6-methylphenyl) 1 meth y lind o1e

-

-

240-255 (dec.) 300-302 (dec.) 156 262.5-263.6 65-67

Needles (H,O) Prisms (DMF)

-80' Prisms (ethyl acetatebenzene)

113 113 110 115 122

3 Q

4

E

Is

k

c c Compound

M.p. or b.p. ("C.1

[ a ](Solvent) ~

Crystal form

References

Needles (CH,OHCHCl,)

115

M 251-253 9,10-Methylenedioxy-1,2,3,3a,4,5,6,7 -0ctahydro- 1-oxopyrrolo[de]-7H-phenanthridin7-one 299-302 (dec.) 2,4-Dintrophenylhydrazone 160-163 9,1O-Methylenedioxypyrrolo[de]-7Hphenanthridine 216-218 9,l0-Methylenedioxypyrolo[de]-7Hphenanthridin-7 -one 216 (dec.) 8,9-Methylenedioxy-4-vinylphenanthridine methiodide 179-180 Methylpseudolycor-3(3a)-ene 234-242 (dec.) Methylpseudolycorine 230 (dec.) Hydroperchlorate 174-175 0,O-Diacetyl

-21.5'

(CHCl,)

*

F

Needles (DMF) Needles (CH,OH)

115 92

Needles (CH,OH)

92

E

109

- 133' (CHCl,) -40' (DMF)

Prisms (acetone) Prisms (C,H,OH)

82 93 93 93

-332'

Prisms (acetone) Prisms (H,O) Polyhedra (CH,OHacetone) Prisms (H,O) Prisms (H,O) Prisms (acetone-ether)

91 91 91

N Narcissidine Hydriodide Methiodide Picrate Picrolonate 0,O-Dimetyl

218-219 (dec.) 253-254 (dec.) 266-267 (dec.) 192 (dec.)

(mj204-205 (dec.) 170-172 (dec.)

(CHCl,)

91 91 91

0 1-0xyanhydrolycorinium betaine 2-Oxyanhydrolycorinium betaine

>400 260-270 (dec.)

Needles (C,H,OH)

102 102

u

Q:

vr

Compound

M.p. or b.p. ("C.)

[ a ] (Solvent) ~

Crystal form

References

0 I-Oxyanhydromethylpseudolycoriniumbetake >300 2-Oxyanhydromethylpseudolycorinium betaine 225-232 (dec.)

Needles (C,€&OH) P r k (H,O)

87 93

Prisms (acetone) Prisms (CH,OH) Prisms (H,O) Plates (H,O) Prisms (CH,OH) Polyhedra (H,O) Prisms (CH,OH) Needles (H,O) Needles (CH,OH) Prisms (CH,OH-acetone) Plates (CH,OH) Needles (CH,OH)

90 87 90 90 87

P Pluviine

225 (dec.)

Hydriodide Hydroperchlorate Methiodide Methoperchlorate 0-Acetyl Pseudolycorine Hydrochloride Methiodide 0-Triacetyl Hydrochloride

230 (dec.) 260 (dec.) 259-261 (dec.) 237-238 184 247-248 (dec.) 266 (dec.) 250-252 (dec.) 204-205 251 (dec.)

- 140' (CHC1,) - 170.5' (C,H,OH) -129'

-62'

(H,O)

(CaHSOH)

+34.6' (C,HsOH)

87 86 86 86 86 86

3 ?

d

E

!i

TABU

6

THE PHYSICAL CONSTANTS OF AMARYLLIDACEAE ALKALOIDS CONTAININQ THE [2]BENZOPYRANO[3,4g]INDOLE NUCLEUS AND THEIR PRODUCTS OF TRANSFORMATION AND DEQRADATION

Compound

M.p. or b.p.

[a]~ (Solvent)

Crystal form

References

("C.1

A Albomaculine Hydroperchlorate Methopicrate Picrate

180-181 285-289 (dec.) 244-246 (dec.) 189-198

Clivonine Hydrochloride Methopicrate Picrate 0-Acetyl

199-200 282-287 (dec.) 285 (dec.) 25&254 (dec.) 196196

9-Demethylhomolycorine a-Deoxydihydrolycorenine Dihydromethine Methine Methiodide 8-Deoxydihydrolycorenine Methine Methiodide Methiodide Deoxylycorenine Dihydroalbomaculine

213-214 m-169

+71.1' (CHC1,) Prisms (CH,OH) Prisms (C,H,OH-H,O)

89 69 69 69

C +41.2' (CHCI,) Prisms (CH,OH-ether)

69 69 69 69 69

D

Oil 101-103 26a270 125-127 73-76 234-236 (dec.) 281 (dec.) 117-1 18

Oil

+19.9'

(C,H,OH) -39.8' (CSHSOH) - 130° (C,HSOH)

Needles (acetone)

- 15.3'

Fine needles (CH,OH) Needles (ether)

+95'

(C,H,OH)

(C,H,OH)

86 116 116 116 116 116 116 116 116 118 69

W 00

TABLE 6-(Continued)

Compound ~_

M.p. or b.p. ("C.1

cx:

[ a ] (Solvent) ~

Crystal form

References

D Dihydrohippeastrine Hydroperchlorate Dihydrohomolycorine Dihydroneronine Picrate

Dihydronivaline

187-18s 269 (dec.) 188 157-168 (116-120) (158-160) 211-213 (dec.) Oil

+50° (CHCl,)

Rhombs (acetone) Prisms (H,O) Prisms (acetone)

Prisms (C,H,OH)

123 123 119 69

69 69

? Q

7-(3,4-Dihydroxy-6-rnethylphenyl)-l-methyl-159-161 indoline 7-(3,4-Dimethoxy-6-methylphenyl) 168-169 6-hydroxy-1-methylindole 7-(3,4-Dimethoxy-6-methylphenyl)-6-hydroxy126-128 l-methyl-5,6,7,7a-tetrahydroindoline 7-(3,4-Dimethoxy-6-methylphenyl)(98-99) 116-118 1-methylindole 7-( 3,4-Dimethoxy-6-methylphenyl)69-7 1 1-methylindoline Picrate 169 (dec.)

112, 122 122

- 146.8O (C,H,OH)

214-215 234-236 (dec.)

+ 160'

(CHCl,)

Cubes (ether)

122

Keedles (C,H,OH)

122

Prisms (acetone) Prisms (CH,OH-H,O)

Oil 260 (dec.)

122 122

H Hippeastrine Methopicrate 0-Acetyl Hydroperchlorate

Prisms (ether-ligroin)

Prisms (H,O)

63 63 66 66

5

s 5Z

TABLE

Compound

&(Continued)

M.p. or b.p. ("C.)

[ a ] (Solvent) ~

H Homolycorine

175

Chloroaurate Hydrochloride

137 278 (dec.)

Hydroiodide Hydroperchlora,te Methiodide Picrate

266 278 (dec.) 258 (dec.) 269 (dec.)

Methiodide 0-Acetyl Oxime Oxime hydrochloride

+

209.5-210 (dec.) 198-200 199-200 260 (dec.) 179-180 170-172 256 (dec.)

+ 234' + 180' + 152' -256O

(CHCl,) (CHCl,) (CH,OH)

180 209-210 (130-136) 196-197 260-265 (dec.) 205-209 (dec.) 201-202

+ 140'

Prisms (acetone) Xeedles (C,H,OH)

(C,H,OH)

+ 155'

(CHCl,) (CHCl,) (CHCI,)

+ 161.6'

References

118 120 84 118 118 84 84 84 84 69

Needles (C,H,OH-ether) Prisms (C,H,OH)

N Nerinine Neronine Methiodide Picrate 0-Acetyl

(H,O) 15' (CHCl,) P r i s m (H,O) Plates (H,O) Plates (CH,OH) Prisms (H,O)

iM Masonine

Plates

+ 100'

L Lycorenine

+

85' (C,H,OH) +93.60' (CHCl,)

K Krigeine

Crystal form

120 84 84 116 116 84 123a

Plates (acetone) Prisms (ethyl acetate) Prisms (H,O) Prisms (C,H,OH-H,O)

70 69 69 69 69

0

TABLE 6-(Continued)

Compound

M.p. or b.p. ("C.1

W

0

(Solvent)

[E]D

Crystal form

References

N Nivaline

131.5-132.5

0 Oduline Picrate Oxoneronine Picrate

168 221 (dec.) 14Cb150 175-178

Tetrahydroacetyllycorenine Tetraliydroalbomaculine Tetrahydroclivonine Tetrahydrohomolycorine 0,O-Diacetate Tetrahydrolycorenine Tetrahydroneronine

148-149

+268'

(C,H,OH)

+239'

(CHC1,)

69

Prisms (acetone) Plates (acetone-H,O)

88a 88a 69 69

T Oil 154.5 133-134 174-176 178-179

- 101'

U Urceoline Picrate Urminine

116 69

- 76.4' (C,H,OH)

Oil

189-1 90 188 (dec.) 177-179

(C,H,OH)

Plates (acetone)

69 118

3

s z

(C,H,OH)

Needles (acetone)

116 69

+ 180'

(CHCl,)

Prisms (acetone) Needles (CH,OH) Prisms (acetone)

68 68 68

(CHCl,)

0

118 -69.5'

-40°

3

F

TABLE

7

THE PHYSICAL CONSTANTS OF AMARYLLIDACEAE ALKALOIDS CONTAINING THE DIBENZOFURAN NUCLEUS AND THEIR PRODUCTS OF TRANSFORMATION AND DEQRADATION

Compound

K p . or b.p.

[a]D

(Solvent)

Crystal form

References

("C.) A Apogalanthamine Hydrobromide Hydroiodide

202-203 (dec.) 228-230 (dec.) 245.5-246.5

125 125 Flakes (H,O)

125

B Bromodemethyldeoxylycoramine Hydrobromide

180-190 215-217 (dec.)

124 124

C Chlidanthine Methiodide Methoperchlorate

238-239

- 140'

(C,H,OH)

263-264 (dec.) 255-256 (dec.)

Plates (CH,OH)

63

Prisms (H,O) Prisms (H,O)

63 63

D Demethyldeoxylycoramine Deoxylycoramine Hydroperchlorate Methiodide Dihydrochlidanthine Dihydrogalanthamine (lycoramine) 0,O-Dimethylapogalanthamine Hydrobromide Hydrochloride Methiodide Styphnate

228-229 (dec.) B.p. 150-160 (0.05 mm.) 219-220 274-275 (dec.) 215-216 120-121 -97.4'

Needles (C,H,OH)

(C,H,OH)

Leaflets (CH,OH) Needles (CH,OH) Prisms (acetone) Plates (acetone)

Oil 228-230 217-21 8 225-227 (dec.) 214-216

Cubes (acetone)

124 124 124 124 123 88 125 125 125 127 127

b F ?i

8

m

0

r

e

2

b-

F%

3

El

U b d M

cM

0 W

F

TABLE

w

$--(CO&nUed)

W

10

Compound

M.p. or b.p.

[ a ](Solvent) ~

Crystal form

References

( O W

D 0 .0-Dimethylapogalanthamine

173-175

125

dihydromethine hydrobromide Epigalanthamine (Base I X )

190

Galanthamic acid Galanthamine Chlorplatinate Hydrobromide Hydrochloride Hydriodide Hydronitrate Hydroperchlorate Methiodide 0-Acetyl Hydrobromide Galanthamine methine Hydroperchlorate Methiodide Picrate Galanthaminone Semicarbazone

205-207 127-129 216-217 246-247 4 5 2 . 6 2 5 3 (dec.) 260-261 (dec.) 224-225 236-237 (dec.) 279 (dec.) 129-1 30 246-247 80-82 221 5-222.5 188-189 148-151 188-192 230-240 (dec.)

Irenine

128

93

-121.4' -93.1'

(C,H,OH)

Prisms (acetone)

(H,O) Prisms (CH,OH) Prisms (H,O) Needles (CH,OH)

-94.5'

(H,O) Seedles (C,H,OH-H,O)

I

+ 120'

(CHC1,)

Prisms (ethyl acetate)

127 88 78 78 88 56 78 88 78 78, 88 78 78 78 78 78 93 93 YOa

r

0

3 U

z *z

TABLE 7-(Conddnued) ~

Compound

3I.p. or b.p. ('C.)

[ ~ J D (Solvent)

Crystal form

Referencea

L Lycoramine (dihydrogalanthamine) Chloroaurate Hydrobromide 0-Acetyl Lycoramine lactani 0-Acetyl Lycoraminone Semicarbazone Lycoraminone lactam p-Nitrophenylhydrazonr Oxinie Semicarbazone

120-1 2 1 193 (dec.) 221.5-223 93-95 251-252 130-131 130-132 114-116 (dec.) 218-219 259-260 257 238 (dec.)

0-Methylapogalanthaminc Hydrobromide

204-206 234

Xarcissamine

193-199 195-196 159-160

Hydriodide S-Methylniethiodide (galanthamine methiodide) >'-Methylmethoperchlorate (galanthamine methoperchlorate) O,N -Diacetyl Narwedine Methiodide Picrate Semicarbueonr:

2 i 9 - 2 5 2 (dec.)

-97.4'

(C,H,OH)

Prisms (C,H,OH) Needles (C,H,OH) Needles (C,H,OH) Needles (C,H,OH)

88 124 78 124 124 124 124 124 124 124 124 124

Needles (&H,OH) Prisms (C,H,OH)

125 127

Prisms (xylene) Prisms (benzene)

93 90 90 93

Prisms (H,O)

90

Needles (C,H,OH-H,O) Needles Needles (H,O-C,H,OH) Plates (C,H,OH)

M

N

-9.8" (CSH'OH) 0" (CHC1,) -93.2'

(C,H,OH)

278 (dee.)

208-209 188-190 195-196 (dec.) 123 240-241 (dec.)

Plates (acetone) Rhombs (CH,OH-H,O)

$-

19.3O (CHC1,) (CHCI,)

+ 100'

Prisnia (acetone) Prisms (CH,OH-acetone) Octahedra (H,O) Prisms (CH,OH)

93 90a 90a 9Oa

90a

TABLE

w tP

8

W

THE PHYSICAL CONSTANTS O F AMARYLLIDACEAE ALKALOIDS CONTAINING T E E [2]BENZOPYRANO[3,4C]INDOLENUCLEUS AWD THEIR PRODUCTS OF TRANSFORMATION A N D DEGRADATION

Compound

M.p. or b.p. ("C.)

[ a ] (Solvent) ~

Crystal form

References

B Bis-6-phenylpiperonylether (des base A)

99-100

Deoxyisotazettinol p-Nitrobenzoate Picrate Deoxytazettine Methiodide Deoxytazettine methine Methiodide Deoxytazettine neomethine Methiodide Deoxytazettinol p-Nitrobenzoate Picrate Deoxytazettinone oxime Dihydrodeoxytazettaminepicrate Dihydrodeoxytazettine Picrate Dihydrohomopseudotazettamine picrate 5,7-Dihydro-3,3-methylenedioxydibenzrceloxepine

122-123 185-186 203-206 135-136 231-233 (dec.) Oil 203-205 (dec.)

Needles (ether)

131

D +328'

(C,H,OH)

+225' + 139'

(C,H,OH) (C,H,OH) - 64.2' (C,H,OH) -72.1' (C,H,OH)

Oil 251 (dec.) 122-123 171-172 225 (dec.) 174-175 204-206 226-228 (dec.) 82-84 101 (dec.) 214-215 (dec.) 138-139

'0 (C,H,OH) $210' (C,H,OH)

+398' (C,H,OH)

+ 14.8'

(CH,OH)

$45.5'

(acetone)

55 66 65

55 55 55 55 56 55 55 55 55 55 55 55 55 55 140 56

9 0

3 5 F z

Compound

M.p. or b.p. ("C.)

[ a ](Solvent) ~

Crystal form

References

D 5,7-Dihydro-7-methylene-2,3-methylenedioxydibenz[ce]oxepine Dihydro-0-methyltazettine methine methiodide Dihydrotazettadiol Dihydrotazettamide Dihydrotazettamine Dihydrotazettine Methiodide Picrate Dihydrotazettine methine Picrate

147-151

Leaflets

238 (dec.)

Prisms (CH,OH-acetone)

55 136

c

%-

133.5-136 161-162 Oil 168-169 183 (dec.) 202 (dec.) Oil 136-137

-43' (CHCl,) +73.3' (CHCl,)

+ 15.8' (C,H,OH) + 11' (CHCl,)

140 140 65 136 55 Needles

76 55 140

H 6-(4-Hydroxypheny1)piperonylalcohol

P

55

186-188

I Isotazettinol (isotazettine) 0,O-Diacetyl Picrate

204-206 149-151 223-226 (dec.)

4'-Methoxy-3,4-methylenedioxy-6methylbiphenyl 4'-Methoxy-6,7-methylenedioxyspiro[cyclohexane-4,1'-isochroman] 6-(4-Methoxyphenyl)piperond

66-67

rn

0 4

i

P

Fw

s

E U

+26 1.7' +

(C,H,OH) 198' (C,H,OH) Nesdlea (C,H,OH)

55 55 55

5!

P

u

M 5658 105-107

Prisms (ether) 0' (C,H,OH)

136 55

Needles (CH,OH-ether)

134

0 CD 97

Compound

[aln (Solvent)

M.p. or b.p. (OC.)

Crystal form

References

M 147-149 6-(4-Methoxyphenyl)piperonyl alcohol (dea base D) 88-88.5 0-Acetyl 6-(4-Methoxyphenyl)piperonylicacid 225-226 251-252 4,5-Methylenedioxybiphenyl-2,2’-dicarboxylic acid 2,3-Methylenedioxydibenz[ee]oxepin-7( 5H)-one 151-152 0-Methylisotazettine Methiodide 204-205 Methopicrate B-Methyl-8,9-methylenedioxyphenanthridinium 274 (doc.) Chloride >310 Iodide 236-238 5H)5-Methyl-8,9-methylenedioxy-6( phenanthridone Oil 0-Methyltazettine 150-152 Methiodide 189-190 Methopicrate 188 Styphnate Oil 0-Methyltazettine methine 214-215 Methiodide

Prisms (ether)

136

Plates (acetone)

117 134 55

55

+ 143’ (CIH,OH)

55 55 56 55 55

f88.1’ (C,H,OH)

P r h s (CH,OH-metone)

55 55 55 55 131 131

P 6-Phenylpiperonyl Alcohol Chloride Iodide

102-103 58-59 120

128a 129, 130 129

TABLE 8-(Continued)

Compound

M.p. or b.p. ("C.)

[a]D

(Solvent)

+65'

(C,H,OH)

Crystal form

Referencm

T Tazettadiol Dipnitrobenzoate Tazettamide Tazettamine Tazettine Hydrochloride Hydroperchlorate Methiodide Methochloride Methoperchlorate Methopicrate Picrate Styphnate 0-Acetyl Methiodide Tazettine methine Methiodide Picrate

118-119 184-185 176-178 147- 148 208-210 217 (dec.) (100) 213 (dec.) 233 (dec.) 210 (dec.) 249 (dic.) 237-239 (dec.) 213 (dec.) 204 (dec.) 124-125 10S170

Tazettinol Picrate 0,O-Diacetyl

187-188 206-208 199-200

Oil

+ 106" (CHCl,) + 180" (CHC1,) + 160.4'

(CHCI,)

Prisms (C,H,OH) Prisms (C,H,OH-HCl) Needles (H,O) Prisms (acetone) Prisms (H,O)

+ 76.5'

(C,H,OH) Needles (acetone)

5 0 " (ma,)

182 178

+ 119" (C,H,OH) +65' (C,H,OH)

Hexagonal plates (acetone)

55 55 140 140 83 75 75 75 135 75 83 76 55 132 136 130 129 130

Y

E

55 56 55

0 W

4

TABLE

9

THE PHYSICAL CONSTANTS OF AMARYLLIDACEAE ALKALOIDS CONTAWWQ THE 5,10b-ETEANOPHENANTHRIDINENUCLEUS AND THEIR PRODUCTS OF TRANSFORMATION AND DEQRADATION

Compound

M.p. or b.p. ("C.1

[ a ] (Solvent) ~

Crystal form

References

B Buphanamine Hydroperchlorate 0-Acetyl hydroperchlorate Buphanidrine

-205' (CaHSOH) - 154' (C,H,OH)

184-186 232-234 131-132 88-89

(CHCl,) (C,H,OH) +5.6' (C,H,OH) +5.5' (C,H,OH) 8.1' (C,H,OH)

-6.93'

+ 1.8'

Oil 195-197 (dec.) 24G242 200-202 (dec.) 238-239

+

Buphanisine

122-124

-26'

(C,H,OH)

Crinamidine Methiodide 0-Acetyl hydroperchlorate 0,O-Diacetyl hydroperchlorate ( *)-Crinane Picrate (-)-Crinane Picrate

235-236 (dec.) 265 (dec.) 205-206 160-161 97-99 218-220 109-110 (206-7) 211-212

-24'

(CHC1,)

-6.3'

(CHCl,)

Hydrobromide Hydroperchlorate Hydrorhodanide Picrate

Prisms (acetone-ether) Prisms (ether)

60 60 59 148 60

Prisms (CH,OH-ether) Prisms (acetone-ether) Prisms (C,H,OHacetone) Prisms (ether)

60 6o 60 148 60

C Prisms (acetone) Prisms (H,O) Needles (HaO) Prisms (H,O)

70 70 85 85 148 148 148 148

s! ._ ?

a

n

t,

Ez

TABLE

Compound

9-(Continued)

M.p. or b.p.

[U]D

(Solvent)

Crystal form

References

("C.1 C

Crinine Hydroperchlorate Methiodide Picrate 0-Acetyl

209-210 135-137 198 237-239 145-146

(CHCl,)

-11.1'

Needles (acetone)

Prisms (H,O) Prisms (acetone-CH,OH)

+68'

(C,H,OH)

65 65 70 148 60

D Demethoxyepioxodihydroundulatine Dihydrobuphanamine Dihydrobuphanidrine Picrate ( - )-Dihydrobuphanisine Dihydrocrinamidine Dihydrocrinine Picrate Dihydroepicrinine Hydroperchlorate Picrate Dihydroepipowelline Dihydrooxobuphanamine Dihydrooxocrinine Dibenzylidene Dihydrooxocrinine methine Picrate (dihydrooxocrinine methopicrate) Dihydrooxopowelline Dihydropowelline a-Dihydroundulatine

206.5-209 200 Oil 281-283 (dec.) 95-96 260-261 220-221 266-267 (dec.) 103-108 135 202-204 107 137-138 158-159 125 150 (1 P ) 209-21 1 165-166 211-212 251-253

+9.8' (CHCl,)

-28' (CHC1,) $22.7' (C,H,OH) -28.8' (CHC1,) -23'

(CHCl,)

- 136' (CHC1,) -67.7' (CHCl,)

+ 138.7' - 20.6' -42.0' - 11.9' -37.0'

(CHCI,) (acetone-H,O) (CHCI,) (CHCI,) (CHCI,)

Prisms (ether)

67 59 148 148 82 149 148 149 148 148 148 148 147 148 148 148 148 148 148 67

400

TABLE %-(cOntintled)

Ip

s 0

Compound

[(LID (Solvent)

M.p. or b.p. ("C.)

Crystal form

References

E Epicrinine Picrate Epioxodihydroundulatine Picrate Epipowelline

- 142' (CHCl,)

209-209.5 227-229 219-223 (der.) 137-140 177-178

-51'

- 103'

148 148 67 67 148

(CHC1,) (CHC1,)

0

- 307' (CHCl,) '0 (CHC1,) - 15' (CHC1,)

(168-169) 183-185 109-110 Oil 234-236.5 177-178 132-133

- 258' (CHCl,) ' 0 (CHC1,)

Prisms (ether)

148 148 67 67 148 148

Needles (acetone) Prisms (CH,OH) Plates (C,H,OH-H,O)

148 148 56 56 56

P

+ )-Powellane

Picrate Powelline Methiodide Picrate

113.5-115 2 13-2 15 197-198 273-274 (dec.) 223-224

Tetrahydrooxocrinine methine Tetrahydrooxopowelliie methine

148-149 180 (It4

Undulatine Methiodide

148-149 267-268 (dec.)

(

+11.1' (CHC1,) +28.2' (CHC1,) ' 0 (CHCl,)

T ' 0 (CHCl,)

Prisms (C,H,OH)

148 148

Prisms (acetone) Needles (CH,OH)

85 66

0' (CHCl,)

U -22'

(CHCl,)

W. C. WILDMAN

Oxocrinine Oxocrinine methine Oxodihydroundulatine Picrate Oxopowelline Oxopowelline methine

W

TABm

Compound

9-( COflt'hued)

M.p. or b.p.

[a]~ (Solvent)

Crystal form

References

("C.1

V Vittatine Methiodide Picrate

207-208 198-199 234-235 (dec.)

$38' (CHCl,)

Prisms (acetone) Plates (CH,OH-acetone) Needles (CH,OH)

63 63 63 F

El TABLE

E

10

0 kj

THE PHYSICAL CONSTANTS O F AMARYLLIDACEAE ALKALOIDS CONTAINING THE

e

N-BENZYL-N-(,G-PHENETHYLAMINE) NUOLEUS AND THEIR

i?i

PRODUCTS O F TRANSFORMATION AND DEGRADATION

Compound

M.p. or b.p.

[.ID

(Solvent)

b-

Crystal form

References

2

("C.1 Belladine Hydroperchlorate Methiodide Piorate

Oil 128-129.5 224-225.5 13S139.5

0" (CHCl,) 0" (H,O-C,H,OH) ' 0 (H,O-DMF)

149h 149h 149h 149h

E

U

k M P M

TAELE 11

&I

0 E3

T H E PHYSICAL CONSTANTS OF AMARYLLIDACEAE ALKALOIDS O F UNDETERMINED STRUCTURE A N D THEIR PRODUCTS O F TRANSFORMATION A N D DEQRADATION

Compound

Formula

M.p. or b.p. ("C.)

Amaryllidine Hydroperchlorate Ambelline Hydrochloride Hydroperchlorate Methiodide Dihydro 0-Acetyl Oxalate Base I11 Hydrobromide Picrate Base D Base F Methiodide Base N Coccinine Hydroperchlorate Methiodide Picrate Dihydro Coruscine Hydriodide Methiodide Methoperchlorate

C17H19N05 B.HC104

204 134-135 260-261 (dec.) 227-230 (dec.) 200' (dec.) 297-298' (dec.) 198-199

C18H21N05

B.HCl.H,O B.HC10, B.CH,I CisHa,NO, CzoHa3NO.s C2oHa,NO.s.C,H,Op.H,O

C17H19-21N03

Cl8HZlNO5 (?I B.CH,I C18H19N05

C17H19N04 B.HC104 B.CH,I B.C6H,N,07 C17H21N04

C18H23N05

B.HI B.CH,I B.CH,.C104

[U]D

(Solvent)

Functional groups

$64" (CHC1,)

O,CH,,OCH,

+32.3' (CHCl,)

OaCH,,2OCH,,OH

+14.6' (H,O) - 13.0' (CHCl,)

Oil 163-164 2 12-213 174-175 217-219 228-229 (dec.)

0'

- 175'

(CHCl,)

20CH,

References 66 66 65 65 65 65 65 65 65 95 95 95 9oa 85

258 132-134 162-163 254-255 (dec.) 219-220 154-161 (dec.) Oil 170 179-180 (dec.) 311 (dec.) 278-280 (dec.)

-40' (CHCl,) - 189' (CaHSOH) -60.5'

OICH2,20CH, O,CH,,OCH,,OH

(H,O)

+70° (CHC1,)

O,CHS,20CH,,OH

85 63, 66 80 80 80 80 80 85 85 85 86

3 Q

1 P tr Is

4

Compound

Boit's crinine Methiodide Crispine Hydroperchlorate Methoperchlorate Picrate Criwelline Hydriodide Hydroperchlorate Daphnarcine Picrate Fiancine Picrate Galanthamidine Methiodide Haemanthine Hydrochloride Hydronitrate Methiodide Insularnine "Isotazettine" Hydrobromide Hydrochloride

Formula

C17H19N03

B.CH,I C18H%3N06

B.HC10, B.CH3.C10, B.C6H,N,07 C18H21N05

B.HI B.HC104 C16H17N04

B.C6H3N,0 C17HI,N0,.1/2 HZO C17H1,N0,.C,H3N,0; C18H23N05

B.CH31 C18H,lN05.1/2 H,O B.HC1.1.5 H,O B.HC1.1/2 H,O B.HN0, B.CH,I.H,O C18H17N03

Cl8H,lNO5 B.HBr B.HC1

M.p. or b.p. ("C.1 213-214 (dec.) 258-259 (dec.) 275 (dec.) 268-269 (dec.) 282-283 (dec.) 258 (dec.) 205-206 228-229 (dec.) 217-218 (dec.) 258-260 (dec.) 246 (dec.) 238-240 221-223 (dec.) 211-213 219 (dec.) 240 180 265 129-131 248 177-178 Oil 230-233 224-225

[ a ] (Solvent) ~

Functional groups

-89'

(CH,OH)

OCH,,NCH,,OH

-996'

(CHCI,)

O,CH,,BOCH,

+220' $40'

(CHC1,)

O,CH,,OCH,

(DMF)

References

70 70 63, 66 63 63 63 66 66 66 90e 9Oa

0" (CHCl,)

OaCH,,20CH, or O,CH,,OCH,,NCH,

89

-94.2'

OaCHe

77 77 61 61 61 58 61

(CHSOH)

-95' (CHCl,) +66.4O (CHCl,) +20.9' (H,O) +24.0° (H,O)

9Oa

68b 68b 68b

404

TABLE 11-(Continued)

Compound

Formula

M.p. or b.p.

[ a ] (Solvent) ~

Functional groups

- 18.4' (C,H,OH)

0,CH,,0CH3,20H

-26.6' -71.3' -97.9'

O,CH,,OCH,,OH O,CH,,BOCH, O,CH,,OCH,,OH

References

("(3

Q,

W

OZCH, O,CH2,2OCH,

(CHCI,) (CHC1,)

s

-89' -46'

qW m $

20CH,, NCH, O,CH,,OCH,

W

(CHCl,)

0' (CHCl,)

m 2

+ 110'

m

O,CH,,OCH,

m

(CHCl,)

W

-210'

95 95 95 95 80 80 80 80 80 80 80 80 80 80 89 89 89 89 89 63, 66 63 80a 90a 89 63, 66

W. C. WILDMAN

(CHCl,)

x 0 x" u,

m

-

;

0

B

0

0

I

OZCH,

m 3

C1SH23N05

I +

C20H23N06

-90'

O,CH,,OH

-

C~JLNOG

- 120' (CHCl,)

d a

C18H21N04

I

C17H19N04

B.HC10,

- 18.2' (CH,OH) + l l S" (H,O)

0

CZOHZ~NOG B.CH,I

(CHCl,) (CHCl,) (CHC1,)

-

C20H23N0G

B.CH,I B .CH,C104

I

C17H21N04

Ci,HziN01.CzHz04

I

Cl8H,lNOI C,,H,lNO* C17HlSNO4 B,.H,PtCl,.H,O B.HC10, B.CH,I B.C,H,0Q1/2 H,O B.C,H,N,07

185-186 122-123 195-197 201-202 269-270 114-116 Oil 220-221 (dec.) 249-250 (dec.) 252-254 (dec.) 227-229 (dec.) 225-226 (dec.) Oil 203-219 (dec.) 185-186 209-210 (151) 221 (dec.) 224-226 256-258 (dec.) 194-195 (120) 230-235 (dec.) 171-172 253-254 (dec.) 209-210 177-178

UYuaUYUY 0 0 0 0 0 0 0 0 0 0 m m m a m m a m a m m a c m w a c m m m a c m a c m w m ,w

C17H19N06

B.HC104 B.CH,I B.CpH,RT,O,

a_

Luteine Hydroperchlorate Methiodide Picrate Manthidine Manthine Montanine Chlorplatinate Hydroperchlorate Methiodide Oxalate Picrate Dihydro Oxalate Nartazine Methiodide Methoperchlorate Narzettine Methiodide Nerispine Hydroperchlorate Penarcine Petomine Poeticine Punicathine

TABLE

Compound

C17HZ1N03

C16H19N04 C18H%1N03

(C,H,OH)

O,CH,,OH,NCH, O,CH,,OH

-

0,

x

+23.7' (H,O)

+ 153.4'

(CH,OH)

+117' (CHCI,) 102' (H,O) 130.7' (H,O)

+ + + 103.8' (H,O) -29.3' (CH,OH) + 185' (CHCI,)

+57' (CHCLJ -53' (CHCl,) 100' (CHCI,)

+

0,CH2,0CH,,0H

O,CH,,OCH,

O&Ha OzCHII,NCH, O,CH,,BOCH,

References

9Oa 90a 90a 80a 95 95 95 95 95 95 96 96 96 96 96 96 96 96 96 96 68 63, 66 63, 66 68s 68a 68a 68a

b-

E

F

0,

U

m

0 H

3 b-

Fw 3

E

kM b

M

*

405

CIBHZlNO6 B.HI B.CH,I B.CeH,N,O 7

r:

Cl8HZINO6 C17H1DN06

+ 12.5' 0

C19H2SN06

+67' (CHCI,)

+ 1 + + 1 +

B.HBr B.HC1 B.HNO, B.CH,I CiDHasNOs

20CH,,NCH,

+

C19HZ3N06

Functional groups

(DMF)

-95'

m

B,.H,PtCl, B.HBr.H,O B.HC1 B.CH,I B.C6H,N,07 C,OHZSN04 B.CH,I CzzHz7NO6 Czo%7NO 4

Oil 24Cb241 (dec.) 248-249 (dec.) 186 231-232 192-193 226-226.5 181-182 20%203 227-228 20Cb201 179-1 SO 184-185 164-165 135-136 287-288 (dec.) 270-271 (dec.) 260 (dec.) 265-266 139 189-190 172-173 217-218 (dec.) 193 (dec.) 205-206 (dec.) 236 (dec.) 262-263 (dec.)

[ a ] (Solvent) ~


B.HI B.CH,I

M.p. or b.p. ("C.1

c.l

Robecine Hydriodide Methiodide Rulodine Sternine Chlorplatinate Hydrobromide Hydrochloride Methiodide Picrate Ungeridine Methiodide 0-Acetyl Dihydro Ungerine Hydrobromide Hydrochloride Hydronitrate Methiodide Dihydro Urceoline Vallotidine Vallotine Yemensine Hydriodide Methiodide Picrate

Formula

11-(Continued)

0

en

TABLE

rp 0

9 (ADDENDUM)

Q,

THE PHYSICAL CONSTANTS OF AMARYLLIDACEAE ALKALOIDS CONTAINING THE 6,lOb-ETHANOPHEXANTHRIDlNEXUCLEUS AND THEIR PRODUCTS OF TRANSFORMATION AND DEGRADATION

Compound

[all, (Solvent)

M.p. or b.p. ("C.)

Crystal form

References

A

Apohaemanthamine Apohaemanthidino

+208' (C,H,OH) 123' (CHCI,)

146-148 195-196 (doc.)

149b 146

+

B

Buphanamine Hydrochloride Hydronitrate

180 130

Crinamine Hydroperchlorate Picrate 0-Acetyl

198-199 201-201.5 273-274 (dec.) 161.5-163

C

+ 18.2' D

Dihydroapohaemanthemke Dihydroapohaemanthidino ( )-Dihydrobuphanisine Dihydrocrinamine Dihydrohaemanthamh Dihydrohaemanthidine Dihydrohaemultine Dihydrooxohaemmthamine Dihydrooxohaemanthaminemethino Hydroperchlorate

+

160-1 61 258-260 95-97 232-233 229-230 (140-150)204-207 218-220 179-180 202-207 (dec.)

+ 156.6'

(CHCI,)

(CHCI,)

+ 110' (C,H,OH) + 20.7' (CHCI,)

Prisms (C,H,OH-H,O)

149

Prisms (H,O)

149 65 65 65 65

(CHCI,) +272' (CHCI,)

149b 146 149 65 80 149 80b 149b

127.2 (5% NaOH)

149b

+27.9' (CHCI,)

+ 103' + 100'

(CHCI,)

3 0

sI4

s

E

6

z

TABLE

Compound

9

(ADDENDIJM)-(Cblt.&Ued)

M.p. or b.p. ("C.1

[a]~ (Solvent)

Crystal form

References

D Dihydrooxohaemanthidine 8-Dihydroundulatine

254-255 199-200.5

Epicrinamidine Epihaemanthamine Epoxyoxoisobuphanamine Epoxyoxopowelline Epoxypowelline Epoxyepipowelline Hydroperchlorate

114-116 216-217 246-248 199-200 195-195.5 Oil 153-155

Flexinine Hydroperchlorate Methiodide 0-Acetyl

221-222 260 (dec.) 223-224 206-207

Eaemanthamine (Natalensine)

203-203.5

146 67

+36' (CHCI,) $20' (CHCI,)

E -35' (CHCl,) -24.3' (CHCI,) 108' (CHC1,) -147' (CHCI,) -30.8' (CHC1,) -63' (CHCl,) -33' (C,H,OH)

+

Prisms (acetone) Prisms (ethyl acetate) Plates (C,H,OH) Prisms (C,H,OH) Prisms (ethyl acetate) Prisms (H,O)

149 149b 149 149 149 149 149

F -14'

H

Methiodide Methoperchlorate Picrate 0-Acetyl Hydroperchlorate 0-m-Nitrobenzoate

190-192 224-225 (dec.) 224-226 (dec.)

Oil 209 153-154

+

(CHCI,)

19.7' (CH,OH) +33' (CHCI,)

85 85 85 85

Prisms (acetone)

80 64 80 64 80 64 64 80

0

r

lb

TABLE 9 (ADDENDWM)-(CO7LhUed)

0 00

Compound

M.p. or b.p. ("C.)

[ aID (Solvent)

Crystal form

References

H Haemanthidine Picrate 0,O-Diacetyl Haemultine Hydriodide Methiodide Picrate 0-Acetyl hydroperchlorate

189-190 208 (dec.) 220-222' 174-175 102 263-264 (dec.) 208-210 (dec.) 192 (dec.)

-41'

+ 147'

(CHCl,)

(CHCl,)

Hydrochloride Hydronitrate 0,O'-Carbonate 0,O'-Diacetate

230-232 242-245 (dec.) 255 (dec.) 230-233 249-250 151-1 52

-108.8'

0

Oxoapohaemanthidine Oxocrinamidine Oxocrinamine Oxodihydrohaemultine Hydriodide Oxoflexinine hydroperchlorate Oxohaemanthamine Oxohaemanthidine Oxoisobuphanamine Oxonerbowdine

142-145 210-212 165-167 178 260 (dec.) 163-165 194-196 211-213 193-197

Prisms (acetone) Prisms (CH,OH) Plates (H,O) Prisms (H,O) Prisms (H,O)

N Nerbowdine

Polyhedra (acetone)

(CHCl,)

-86.1' -81.1' -146' -30.5'

(H,O) (H,O) (CHC1,) (CHCI,)

+230' -64.8' +203'

(CHCl,) (CHCl,) (C,H,OH)

+ 142O (CHCl,) -41.4" -42.9' -95.8'

(CHCI,) (CHC1,) (CHC1,)

Prisms (acetone) Prisms (C,H,OH) Needles (H,O) Needles (H,O) Prisms (ethyl acetate)

Prisms (ethyl acetate) Prisms (C,H,OH) Prisms (H,O) Prisms (H,O)

Prisms (ethyl acetate) Prisms (ethyl acetate)

64 64 149 80b 80b 80b 8Ob 80b 149 149 149 149 149 149 146 149 149 80b 149 149b 146 149 149

3 P U

F

z


409

anticholinesterase activity (161). A number of alkaloids of this family have been screened for cardiovascular activity by research workers at the National Heart Institute (162). Many of the alkaloids studied caused a fall in the blood pressure of dogs, but in general the effect was of a transient nature at relatively high dose levels. A summary of this work is given in Table 4. Although pharmacological studies of these alkaloids have not produced materials of promising therapeutic use, the work reported in this section represents a preliminary examination of less than one-fifth of the total number of known alkaloids in ,the family. Isolation of additional alkaloids and further testing may well produce fertile fields for pharmacological research.

IX. Tables of Physical Constants The alkaloids of Sections 11-VI and their transformation products are listed in alphabetical order in Tables 5-10. Derivatives have been listed in the order: ( a ) quaternary ammonium salts, ( b ) N-alkyl derivatives, and (c) 0-and N-acyl derivatives. Alkaloids of unknown structure, listed in Table 11, follow the same order, except that products of reduction are listed after the quaternary salts. Figures enclosed in parentheses designate melting points of polymorphic and/or solvated crystal modifications.

X. References 53. L. H. Briggs, L. D. Colebroolr, H. M. Fales, and W. C. Wildman, Anal. Chem. 29, 904 (1957). 54. W. C. Wildman and C. J. Kaufman, J. A m . Chem. SOC.77, 4807 (1955). 55. T. Ikeda, W. I. Taylor, Y. Tsuda, S. Uyeo, and H. Yajima, J. Chem. SOC.p. 4749 (1956). 56. H.-G. Boit and H. Ehmke, Chem. Ber. 88, 1590 (1955). 56e. K. Fragner, Ber. 24, 1498 (1891). 57. J. StanBk, Chem. & Ind. (London) p. 1557 (1955). 57a. F. Tutin, J. Chern. SOC.99, 1240 (1911). 57b. L. Lewin, Arch. exptl. Pathol. Pharmakol., Naunyn-Schmiedeberg's 68, 333 (1912). 58. J. K. Cooke and F. L. Warren, J. S. Ajrican Chem. Inst. 6 , 2 (1953). 59. L. G. Humber and W. I. Taylor, Can. J. Chem. 33, 1268 (1955). 60. J. Renz, D. Stauffacher, and E. Seebeck, Helv. Chim. Acta 38, 1209 (1955). 61. A. Goosen and F. L. Warren, Chem. & I d . (London) p. 267 (1957). 61a. A. N. Bates, J. K. Cooke, L. J. Dry, A. Goosen, H. Krusi, and F. L. Warren, J . Chem. SOC.p. 2537 (1957). 62. A. Goosen and F. L. Warren, personal communication, April 26, 1957. 63. H.-G. Boit, Chem. Ber. 89, 1129 (1956). 63a. F. A. Kincl, V. Troncoso, and G. Rosenkranz, J. Org. Chem.. 22, 574 (1957). 64. H.-G. Boit, Chem. Ber. 87, 1339 (1954).

410

W-.C. WILDMAN

65. L. H. Mason, E. R. Puschett, and W. C. Wildman, J. Am. Chem. SOC.7 7 , 1253 (1955). 66. H.-G. Boit and H. Ehmke, Chem. Ber. 89, 2093 (1956). 67. E. W. Warnhoff and W. C. Wildman, Chem. & Lnd. (London) p. 1293 (1958). 68. H.-G. Boit and W. Dopke, Chem. Ber. 90, 1827 (1957). 68a. H.-G. Boit, W. Dopke, and W. Stender, Chem. Ber. 90,2203 (1967). 68b. N. F. Proskurnina, Zhur. Obshchei Khim. 23, 3365 (1957). 69. Carol K. Briggs, P. F. Highet, R. J. Highet, and W. C. Wildman, J . Am. Chem. SOC.78, 2899 (1956). 70. H.-G. Boit, Chem. Ber. 87, 1704 (1954). 71. S. Rangaswami and E. V. Rao, Current Sci. ( I n d i a ) 23, 265 (1954). 72. A. Hunger and T. Reichstein, Helv. Chim. Acta 36, 824 (1953). 73. S. Rangaswami and M. Suryanarayana, I n d i a n J. Pharm. 17, 229 (1955). 74. J. R. Crowder and W. C. Wildman, unpublished data. 75. H.-G. Boit, Chem. Ber. 87, 724 (1954). 76. G. R. Clemo and D. G. I. Felton, Chem. & I n d . (London) p. 807 (1952). 77. N. F. Proskurnina and A. P. Yakovleva, Zhur. Obshchei Khim. 26, 172 (1956). 78. N. F. Proskurnina and A. P. Yakovleva, Zhur. Obshchea' Khim. 22, 1899 (1952). 79. H.-G. Boit, Chem. Ber. 87, 1448 (1954). 80. W. C. Wildman and Carol J. Kaufman, J. Am. Chem. SOC.7 7 , 1248 (1955). 80a. H.-G. Boit, W. Dopke, and W. Stender, Naturwisaewchaften 45, 262 (1958). Sob. H.-G. Boit and W. Dopke, Chem. Ber. 91, 1965 (1958). 80c. H.-G. Boit, W. Dopke, and W. Stender, Natumissenschaften 45, 390 (1958). 81. V. C. Mhquez, Bol. soc. quim. Peru 21, 141 (1955); Chem. Abstr. 50, 5243 (1956). 82. H. M. Fales and W. C. Wildman, J. Am. Chem. SOC.80, 4395 (1958). 82a. H.-G. Boit and W. Dopke, Naturwissenschaften45, 315 (1958). 83. W. C. Wildman and C. J. Kaufman, J . Am. Chem. SOC.76,5815 (1954). 84. H.-G. Boit, Chem. Ber. 87, 681 (1954). 85. H.-G. Boit and H. Ehmke, Chem. Ber. 90, 369 (1957). 86. S. Uyeo, personal communication. 87. H.-0. Boit, H. Ehmke, S. Uyeo, and H. Yajima, Chem. Ber. 90, 363 (1957). 88. S. Uyeo and S. Kobayashi, Pharm. Bull. (Tokyo) 1, 139 (1953). 88a. H.-G. Boit, W. Stender, and A. Beitner, Chem. Ber. 90, 725 (1957). 89. H.-G. Boit and W. Dopke, Chem. Ber. 89, 2462 (1956). 90. H.-G. Boit and H. Ehmke, Chem. Ber. 89, 163 (1956). 90a. H.-G. Boit, W. Dopke, and A. Beitner, Chem. Ber. 90, 2197 (1957). 91. H.-G. Boit and W. Stender, Chem. Ber. 87, 624 (1954). 92. J. W. Cook, J. D. Loudon, and P. McCloskey, J . Chem. SOC.p. 4176 (1954). 93. H. M. Fales, L. D. Giuffrida, and W. C. Wildman, J. Am. Chem. SOC.78, 4146 (1956). 94. N. F. Proskurnina, Zhur. Obshchei Khim. 25, 834 (1955). 95. N. F. Proskurnina and N. M. Ismailov, Zhur. Obshchei Khim. 23, 2056 (1953). 96. S. Yunusov and Kh. A. Abduazimov, Doklady Akad. Nauk Uzbek. S.S.R. 1958 (8). 44 (1953); Referat. Zhur. Khim. 1954, No. 27105 (1954); Chem. Abstr. 49, 1281 (1955); Zhur. Obshchei Khim. 27, 3357 (1957). 96a. H. Kondo and H. Katsura, Ber. 73, 1424 (1940). 97. E. J. Forbes, J. Harley-Mason, and R. Robinson, Chem. & I n d . (London) p. 946 (1953). 98. E. Wenkert, Chem. & I n d . (London) p. 1175 (1964). 99. R. B. Kelly, W. I. Taylor, and K. Wiesner, J . Chem. SOC.p. 2094 (1953).

ALKALOIDS O F THE AMARYLLIDACEAE

41 1

100. K. Wiesner, W. I. Taylor, and S. Uyeo, Chem. & Ind. (London) p. 46 (1954). 101. S. Takagi, W. I. Taylor, S. Uyeo, and H. Yajima, J. Chem. SOC.p. 4003 (1955). 102. H. M. Fales, E. W. Warnhoff, and W. C. Wildman, J. A m . Chem. SOC.77, 5885 (1955). 103. Y. Nakagawa, S. Uyeo, and H. Yajima, Chem. & Ind. (London) p. 1238 (1956). 104. T. R. Govindachari and B. S. Thyagarajan, Chem. & Ind. (London) p. 374 (1954). 105. W. I. Taylor, B. R. Thomas, and S. Uyeo, Chem. & I d . (London) p. 929 (1954). 106. L. E. Humber, H. Kondo, K. Kotera, S. Takagi, K. Takeda, W. I. Taylor, B. R. Thomas, Y. Tsuda, K. Tsukamoto, S. Uyeo, H. Yajima, and N. Yana,ihars, J. Chem. SOC.p. 4622 (1954). 106a. H. Kondo and S. Uyeo, Ber. 68, 1756 (1935). 106b. H. Kondo and S. Uyeo, Ber. 7 0 , 1087 (1937). 106c. H. Kondo and H. Katsura, Ber. 72, 2083 (1939). 106d. H. Kondo and K. Tomimura, J. Pharm. SOC.Japan 48, 36 (1928); Cheni. Zentr. 1928, 11, 157. 107. H. Kondo and K. Tomimura, J . Pharm. SOC. Japan 48, 223 (1928). 107a. H. Kondo and H. Katsura, J. Pharm. SOC.Japan 54, 194 (1934); Chem. Zentr. 1935, 11, 1181. 108. H. Kondo, K. Takeda, and K. Kotera, Ann. Rept. I T S U U Lab. (Tokyo)5,66 (1954). 109. T. Shingu, S. Uyeo, and H. Yajima, J . Chem. SOC.p. 3557 (1955). 109a. H. Kondo and H. Katsura, Ber. 73, 112 (1940). 110. K. Takeda and K. Kotera, Chem. & Ind. (London) p. 347 (1956); Pharm. Bull. (Tokyo) 5 , 234 (1957). 111. N. F. Proskurnina and L. Ya. Areshkina, Zhur. Obshchei Khim. 17, 1216 (1947). 112. N. F. Proskurnina, Doklady Akad. NaukS.S.S.R. 90, (4), 565 (1953). 113. H. M. Fales and W. C. Wildman, J. A m . Chem. SOC.7 8 , 4151 (1956). 114. E. W. Warnhoff and W. C. Wildman, Chem. & Ind. (London) p. 348 (1956). 115. E. W. Warnhoff and W. C. Wildman,J. A m . Chem. SOC.79, 2192 (1957). 115a. K. Takeda, K. Kotera, and S. Mizukami, J. A m . Chem. SOC.80, 2562 (1958). 116. H. Kondo-and T. Ikeda, Ann. Rept. I T S U U Lab. (Tokyo) 3, 55 (1952); J. Pharm. SOC.Jupa7~65, (9-10A), 5 (1945). 117. E. Wenkert and J. H. Hansen, Chem. & Ind. (London) p. 1262 (1954). 118. T. Kitigawa, W. I. Taylor, S. Uyeo, and H. Yajima, J. Chem. SOC.p. 1066 (1965). 119. H.-G. Boit, L. Paul, and W. Stender, Chem. Ber. 88, 133 (1955). 120. R. J. Highet and W. C. Wildman, J. A m . Chem. SOC.77,4399 (1955). 120a. H. Kondo and K. Tomimura, J. Pharm. SOC.Japan 49, 76 (1929); Chem. Zen&. 1929,11, 1013. 120b. H. Kondo and T. Ikeda, Ber. 73, 867 (1940). 121. G. R. Clemo and R. Robinson, Chem. & I d . (London) p. 1086 (1956). 122. S. Uyeo and H. Yajima, J. Chem. SOC.p. 3392 (1955). 123. H.-G. Boit and H. Ehmke, Chem. Ber. 90, 57 (1957). 123a. H.-G. Boit, Naturwksenschaften, 45, 85 (1958). 123b. H. Kondo, K. Tomimura, and S. Ishiwata, J. Pharm. SOC.Japan 52, 51 (1932); Chem. Zentr. 1932, 11, 877. 1230. H. Kondo and S. Ishiwata, Ber. 70, 2427 (1937). 124. S. Uyeo and J. Koizumi, Pharm. Bull. (Tokyo) 1, 202 (1953). 125. N. F. Proskurnina and A. P. Yakovleva, Zhur. Obshchei Khim. 25, 1035 (1965). 126. S. Kobayashi, T. Shingu, and S. Uyeo, Chem. & I d . (London) p. 177 (1956). 127. S. Kobayashi and S. Uyeo, J. Chem. Soc. p. 638 (1957).

412

W. C. WILDMAN

128. S. Uyeo, Congress Handbook, Intern. Congr. Pure and Appl. Chem., X V I t h Congr., Paris, 1957, p. 209. 128a. E. Spiith and L. Kahovec, Ber. 67, 1501 (1934). 129. G. R. Clemo and M. Hoggarth, Chem. & Ind. (London)p. 1046 (1954). 130. W. I. Taylor, S. Uyeo, and H. Yajima, J. Chem. SOC.p. 2962 (1955). 131. H. Kondo, T. Ikeda, and N. Okuda, Ann. Rept. I T S U U Lab. (Tokyo) 1, 21 (1950). 132. H. Kondo and T. Ikeda, Ann. Rept. I T S U U Lab. (Tokyo) 2, 55 (1951). 133. H. Kondo, T. Ikeda, and K. Takeda, Ann. Rept. I T S U U Lab. (Tokyo) 2,60 (1951). 134. H. Kondo, T. Ikeda, and J. Taga, Ann. Rept. I T S U U Lab. (Tokyo) 3, 65 (1952). 135. H. Kondo, T. Ikeda, and J. Taga, Ann. Rept. L T S U U Lab. (Tokyo) 4, 73 (1953). 136. H. Kondo, T. Ikeda, and J. Taga, Ann. Rept. I T S U U Lab. (Tokyo) 5 , 72 (1954). 137. E. Wenkert, Ezperientia 10, 476 (1954). 138. T. Ikeda, W. I. Taylor, and S. Uyeo, Chem. & Ind. (London) p. 1088 (1955). 139. T. Ikeda, W. I. Taylor, Y. Tsuda, and S. Uyeo, Chem. & Ind. (London)p. 411 (1956). 140. R. J. Highet and W. C. Wildman, Chem. & Ind. (London) p. 1159 (1955). 141. K. Wiesner and Z. Valenta, Chem. & Ind., Brit. In&. Fair Rev. p. R36 (1956). 142. W. C. Wildman, Chem. & Ind. (London) p. 123 (1956). 143. H.-G. Boit and W. Stender, Chem. Ber. 89, 161 (1956). 144. N. F. Proskurnina, Doklady Akad. Nauk S.S.S.R. 103, 851 (1955). 145. W. C. Wildman, J. A m . Chem. SOC.78, 4180 (1956). 146. S. Uyeo, H. M. Fales, R. J. Highet, and W. C. Wildman, J. A m . Chem. SOC.80, 2590 (1958). 147. W. C. Wildman, Chem. & Ind. (London) p. 1090 (1956). 148. W. C. Wildman, J. A m . Chem. SOC.80, 2567 (1958). 149. H. M. Fales and W. C. Wildman, unpublished data. 149a. E. W. Warnhoff, private communication, May 13, 1958. 149b. H. M. Fales and W. C. Wildman, Chem. & Ind. (London) p. 561 (1958). 149c. N. Sugimoto and H. Kugita, Pharm. Bull. (Tokyo) 5 , 378 (1957). 149d. K. Tanaka, J. Pharm. SOC.Japan 57, 139 (1937);Chem. Zentr., 1937,11, 3322. 149e. R. Robinson, “The Structural Relations of Natural Products,” Oxford Univ. Press, London and New York, 1955, p. 91. 149f. W. Steglich, Tetrahedron 1, 195 (1967). 149g. D. H. R. Barton and T. Cohen, “Festschrift Arthur Stoll,” Birkhauser, Basel, 1957, p. 117. 149h. E. W. Warnhoff, Chem. & Ind. (London) p. 1385 (1957). 150. K. Takeda, T. Minesita, S. Suda, and K. Yamaguchi, Ann. Rept. Shionogi Research Lab. 2, 100 (1952). 151. K. Yamaguchi and S. Suda, Folia Pharmacol. Japon. 48, ( l ) , Proc. 31-32 (1952); Chem. Abstr. 47, 1790 (1953). 152. T. Minesita, K. Yamaguchi, K. Takeda, and K. Kotera, Ann. Rept. Shionogi Research Lab. 6 , 119 (1956); Chem. Abstr. 51, 4560 (1957). 153. T. Minesita, K. Yamaguchi, K. Takeda, and K. Kotera, Ann. Rept. Shionogi Research Lab. 6, 131 (1956); Chem. Abstr. 51, 4560 (1957). 153a. K. Yarnamoto and T. Minesita, Ann. Rept. Shionogi Research Lab. 7, 81 (1957). 154. K. Takeda, T. Minesita, and Y. Kitadume, Ann. Rept. Shionogi Research Lab. 2, 107 (1952). 155. T. Minesita, K. Yamaguchi, and K. Takeda, Ann. Rept. Shionogi Research Lab. 5, 175 (1955). 156. D. B. Fitzgerald, J. L. Hartwell and J. Leiter, J. Natl. Cancer Inst. 20, 763 (1958).

ALKALOIDS OF THE A W Y L L I D A C E A E

413

157. M. Tomita, S. Uyeo, T. Yonezawa, and M. Nakanishi, Japan. J . Pharm. & Chem. 20, 8 (1948); Chem. Abstr. 45, 3565 (1951). 158. A. Tanaka and T. Minesita, Ann. Rept. Shionogi Research Lab. 5 , 164, 170 (1955). 159. N. B. Eddy, Caroline F. Touchberry, and J. E. Lieberman, J . Phurmacol. Exptl. Therap. 98, 121 (1950). 160. G . A. Mednikyan and B. G. Vinikova, Furmakol. i Toksikol. 18, ( 5 ) , 34 (1956); Chem. Abstr. 50, 10281 (1956). 161. M. D. Mashkovskii, Farmikol. i Toksikol. 18, (a), 21 (1955); Chem. Abatr. SO, 9626 (1956). 162. N. C. Moran, unpublished data, National Heart Institute, 1953-1956.


Author Index-Volume VI Nunihers in parentheses are reference numbers and are included to assist in locating refcrencea where the author's name is not mentioned in t.he text. Numbers in italics refer to the page of the article on which the reference is listed.

A Abd Elhafez, F. A., 52 (158), 119 Abduazimov, Kh. A., 311 (96), 405 (96), 410 Abe, M., 6 (232), 24 Achmatowicz, O., 196 (335a), 206 (344a), 216, 217 Ackermann, D., 4 (194), 23 Acree, F., 134 (79), 144 Adamcik, J., 75 (185), 120 Adams, R., 37 (74, 76), 38 (80, 83, 84, 85, 86, 87), 39 (80, 83, 93), 40 (85, 87, 103, 104), 41 (83, 84, 87, 111, 120, 121), 42 (84, 103, 134), 43 (80, 83, 84, 85, 93, 103, 135, 140), 44 (80, 83, 84, 85, 120, 121, 137, 140), 45 (93, 103, 140, 142), 47 (80, 84, 120, 121), 48 (80, 83, 84, 103, 104, 120, 134, l40), 51, 53, 56 (74, 76), 60 (76), 61 (76, 173, 174, 175, 176), 62 (174), 64, 65 (65), 66 (74, 174), 67 (lll), 69 (74, 86), 72 (137), 73 (103), 76 (93, 192, 193), 77 (193, 195), 78 (193), 79 (73), 80 (197), 81, 82, 83 (175, 197), 84 (74, 195), 85 (195), 86, 87 (74), 88, 89 (74, 120, 121, 205), 90, 91 (120, 205), 92 (120, 137, 176), 93 (176), 94 (134), 95 (93, 135), 96 (93, 137), 97, 99, 100 (74, 142), 101 (93, 142), 102 (93, 117, 121, 135, 137), 103 (195), 105 (140), 106 (74, 140), 107 (140), 108 (103, l04), 109 (113, 117), 117, 118,119, 120 Adler, E., 127 (33), 142 Aghoramurthy, K., 209 (357), 217 Ahmed, K., 271 (355d), 287 Ahmed, 2. F., 11 (316), 21 (316), 26 Alder, K., 54 (165), 119, 165 (74), 176 Alexander, E. R., 154 (50), 175 Allen, R. H., 274 (363), 288 Allinger, N. L., 76 (187), 120 Aniiard, G., 282 (378), 283 (378), 288 Anderson, C., 20 (416, 418), 28 Anderson, R. C., 129 (57, 58), 143 Andreadis, Th., 10 (289), 25

Anet, E., 32 (7), 34 Anet, F. A. L., 181 (305), 190 (329), 194 (329), 204 (305, 342), 205 (305, 342), 208 (342,360), 211 (360), 215, 216, 217 Annett, H. E., 6, 17 (210), 21 (210), 23 Archer, S., 147 (16), 148 (16), 150 (127), 151 (126), 171 (145), 174, 177 Areschkina, L. J . , 16 (357), 27 Areschkina, L. Ya., 46 (147, 148, lag), 102 (lag), 119, 121, 322, 382 ( l l l ) , 383 ( l l l ) ,411 Arnold, E., 17, 27 Arnold, H., 162 (68), 168 ( 6 8 ) , 175 Arnold, W., 173 (105), 177 Arnstein, H. R. V., 275 (366a), 288 Aronoff, S., 20 (423), 29 Ashley, J. N., 261 (328), 287 Ashner, T. C., 154 (49a), 175 Aulin-Erdtman, G., 259 (320c), 286 Awramowe, B., 14 (341), 27 Aycock, B. F., 88 (204), 120 Ayer, D. E., 170 (123), 171 (144), 177 Ayotte, A., 137 (93), 144

B Bacon, C. W., 21 (433), 29 Baizer, M. M., 220 (385), 244 Baldridge, H. D., Jr., 140, 141 (112, 113), 144 Ball, C. D., 19 (398, 399,401, 402,403), 20 (403, 406, 419), 28, 29, 129 (45, 48, 50, 52), 143 Ball, J. C., 225 (398), 244 Balon, A. D. J., 148 (120), 177 Baranova, V. Z., 6 (231), 17 (231), 24 Barcelo, J. M. P., 21 (438), 29 Barger, D., 159 (60), 167 (60), 173 (60),175 Barger, G., 140 ( l l I ) , 144 Barlow, R. B., 172 (91), 176 Barnard, C., 6, 24 Barrowcliff, M., 146 (2), 174 Bartek, J., 255 (310), 256 (310), 259 (320), 286 Barth, P., 151 (121), 164 (121), 177

415

416

AUTHOR INDEX-VOLUME

Barthel, W. P., 13 (332), 26 Barton, D. H. R., 54 (164), 119, 242, 245, 373 (149g), 412 Barton, G. M., 252 (296), 285 Barton, N., 259 (319b), 286 Bartosova, I., 249 (277, 278), 253 (277), 254 (277), 255 (277), 256 (277), 28ii Basilewskaja, N. A., 6, 23 Bates, A. N., 292 (61a), 296 (61a), 409 Bauer, L., 226 (400), 244 Baur, W., 181 (304d), 215 Beck, K. M., 50 (154), 119 Becker, B., 151 (61), 160 (61), 164 (61), 173 (61), 175 Eeckett, A. H., 149 (32), 177 Beckett, Ch. W., 148 (120), 174 Beer, A. A., 250 (291), 255 (291, 306), 278 (291, 368), 285, 286, 288 Beets, M. G. J., 125 (5, 6), 142 Beevers, C. A., 179 (299), 214 (299), 216 Beiley, A. S., 190 (329), 194 (329), 216 Beitner, A., 301 (90a), 302 (90a), 303 (9Oa), 304 (90a), 305 (90a), 306 (888, 90a), 307 (88a, SOa), 328 (90a), 329 (90a), 337 (88a), 342 (go&),343 (90a), 379 (90a), 390 (88% 90a), 393 (90a), 402 (90a), 403 (9Oa), 404 (90a), 405 (90a), 41 0 BBk&y, N.v., 5 (199), 6 (233), 21 (233), 23, 24

Bell, M. R., 171 (145), 177 Belleau, B., 208 (352), 217, 283, 288 Bellet, P., 253 (297, 299, 300), 262 (341, 343), 273 (359), 281, 282, 283 (378), 285, 287, 288

Benson, A. A., 8 (258), 25 Bentley, H. R., 206 (345), 217 Bentley, K. W., 219 (380), 225 (396, 397, 398), 228 (405), 229, 230 (380, 410), 231,232 (412,413), 233 (412,415), 235 (418), 243 (435), 243, 244, 245 Berner, E., 99, 120, 165 (75), 176 Beroza, M., 179 (80, 81, 82), 180 (82), 144 Bertho, A., 183 (315, 316), 184 (315, 316), 216

Beyerman, H. C., 6, 24, 125 (17, 18), 131, 136 (85, 91 92), 137 ( 8 5 ) , 142, 143, 144, 146 (9), 147 (lo), 174 Bianchetti, G., 125 (13), 142 Bick, I. R. C., 235 (419), 244

VI

Bickel, H., 209 (361), 217 Bijvoet, J. M., 214 (300), 215 Bischoff, W., 21 (430), 29 Bissell, E. R., 163 (81), 168 (81), 176 220 (386), 244 Blatzejewicz, L., 196 (337), 199 (337), 200 (337), 216 Blagek, Z., 6 (234), 11 (317), 14 (317), 24, 26

Bloom, B. M., 151 (40), 163 (40), 173 (40), 175, 189 (327c), 216 Boaz, H., 86 (210), 96 (210), 120 Bode, A., 146 (l),174 Bode, K., 148 (27), 174 Bogdasevskaja, 0. V., 8 (262), 25 Boit, H. G., 4 (193), 23, 184, 187 (325), 188 (326), 190 (329a, 330), 194 (332), 195 (329a, 333, 334, 335), 198 (318), 216, 292, 293 (63), 294 (64), 295 (66), 296 (63, 68, 68a, 70), 297 (56, 66, 68a, 70), 298 (56,68,75,79,80a, b), 299 (63,64, 68, 70, 80c, 82a), 300 (68, 68a, 82, 82a, 84), 301 ( ~ O C 85, , 87,90,90a), 302 (90, SOa), 303 (SOa), 304 (90, SO&), 305 (90, SOa), 306 (88a, 90, 90a), 307 (80% 88a, 90a), 308 (89), 309 (66, 84, 85, 89, 91), 310 (63, 66, 70, 85), 311 (56, 63, 68, ~ O C )312 , (56, 68a), 322 (go), 324 (87), 327 (87), 328 (87, 89, 90, go&), 329 (90a), 330 (119), 335, 336 (56, 70, 123), 337 (68,88a, 123), 338 (85,123a), 339 (64, 70), 342 (90a), 343 (63, 90, 90a, 123), 354 (143), 355 (56, 66, 70), 357 (56, 63, 66, 85), 360 (63, 66, 85), 361 (66, 70, 85), 362 (85), 365 (64), 368 80a, b,), 369 (56, 63, 64, 80a,b), 370 (64, 143). 379 (87, 90a), 381 (91), 382 (go), 383 (87, go), 384 (91), 385 (91), 386 (87, go), 388 (63, 66, 119, 123), 389 (70, 84, 123a), 390 (68, 88a), 391 (63, 123), 392 (56, 90a), 393 (90, SOa), 397 (75), 398 (70, 85), 399 (70), 400 (56, 66, 85), 401 (63), 402 (63, 66, 85, 90a), 403 (63, 66, 70, 89, 90a), 404 (63, 66, 80a, 89, 90a), 405 (63, 66, 68, 68a, 80a, 90a), 406 (Sob), 407 (64, 85), 408 (64, 80b),),409, 410, 411, 412 Bokhoven, C., 179 (300), 214 (300), 215 Bommer, M., 151 (4l), 175 Bonner, R. M., 220 (386), 244

AUTHOR INDEX-VOLUME

Bonting, Sj. L., Jr., 127 (32), 142 Borodina, G. M., 261 (333), 287 Borozdina, A., 6 (223), 24, 50 Borstelmann, P., 76 (194), 120 Bosch, H., 183 (316), 184 (316), 216 Bose, A. I

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