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ASPECTS of ALKALOID BIOSYNT7F,SIS a Thesis ASPECTS OF ALKALOID BIOSYNT7F,SIS a thesis subbitted by ROBERT HENRY HESSE in partial fulfilment of the requirements for the degree of DOCTOR OF PHILOSOPHY of THE UNIVERSITY OF LONDON Imperial College, London, S.W.7. December, 1964. (1) ABSTRACT Tracer experiments have shown that berberine is derived from reticuline, the N-methyl group of reticuline becoming the berberine ',bridge*. At least one step in this transformation is stereospecific. Reticuline has also been shown to be a precursor of protopine. An N-methyl cyclisation also takes place in this transformation and at least one step is stereospecific. Possible mechanisms for the N-methyl cyclisation are suggested and their implications in the biosynthesis of a variety of alkaloids are discussed. ACKNOWLEDGEMENTS I am deeply grateful to Professor D.H.R. Barton for the privilege of research under his guidance. I wish to thank Dr. Gordon Kirby for his constant encouragement and assistance, and in particular for the many stimulating discussions we have had. I am indebted to many members of the Imperial College staff for their assistance; among them in particular: Dr. D. Turner, Mr. D. Aldrich, Mr. R. Young, and Mrs. L. Brown. I acknowledge with gratitude the financial support of the National Science Foundation (U.S.A.). Finally, to Dr. Maurice M. Pechet who provided the opportunity, and to my wife, Lucille, who has shared the burdens, I dedicate these efforts. TABLE OF CONTENTS Eau_ Introduction 1 REVIE7 Synthesis of the Benzylisoquinoline Skeleton 5 Transformation of Larger Precursors 13 The Amaryllidaceae Alkaloids 16 Morphine 23 BERBER INE Introduction 28 One Carbon Metabolism 31 On the Origin of the Berberine Bridge 39 The Berberine Bridge in Otter Alkaloids 50 Protopine 54 OXIDATION OF AMINES Mechanistic Considerations 62 Alkaloids from Reticuline ... 75 SYNIfILSIS OF PRECURSORS 82 EXPERIMENTAL Precursors 100 Degradations 123 Tracer Experiments 126 REFERENCES.... 147 - 1 - Although proposals for the biosynthesis of alkaloids and "biologically-patterned." synthesis have been with us for nearly fifty years,1'2 the knowledge of how Nature effects the elaboration of these diverse and often complex natural products is much more recent and still in a state of rapid extension. Recent advances are primarily a result of the application of tracer techniques, which have enabled us to observe the fate of a substance interacting with a complex living system. Isotopic tracers are so fundamental to the study of alkaloid biosynthesis that it is desirable to recognize the assumptions and limitations inherent in their use. The basic assumption is that isotopically- labelled molecules are subject to the same fate as molecules composed of only the natural isotopes. Although this idea is qualitatively sound, quantitative differences are the rule rather than the exception.3 For most isotopes these differences are small and not important; for others, particularly hydrogen isotopes, they may be significant. Although isotope effects might constitute a snare for the naive, they provide a powerful tool for the sophisticated investigator.4 As our knowledge of alkaloid biosynthesis is refined, these 2 ONO subtle effects may well augment our understanding of the subject. Although we can label only individual atoms with isotopes, our interest for the most part is devoted to the transformation of molecules. In order to unequivocally follow these transformations, it is important that when we isolate a labelled substance, we provide evidence that it has been derived from its precursor in a specific fashion. This is a formidable problem. In the case of simple molecules degradation of products will often give evidence that the tracer atom has remained specifically attached to the various species involved in the transformation.5 In the case of complex substances, particularly those in which the tracer atom might be considered labile, it is often necessary to perform multiple-labelling experiments5,6 to insure that the appearance of radioactivity in the product is not the result of decomposition of the precursor followed by non-specific re-incorporation into the product. 'Multiple-labelling" experiments, as a rule, do not involve the preparation of a single molecular species containing all the requisite labels. These preparations are generally a mixture of singly- labelled species usually containing only small amounts of multiply-labelled species.7'8 The final distribution of labelling in the product is thus influenced by the nature of the isotopic species and by the rate at which each is incorporated. it is apparent, then, that this method is more susceptible to isotope effects than a method using a singly-labelled species. Observance of these criteria is basic to the proper pursuit of this method. Therefore, although details of degradations will not be presented in this review, it is to be understood that, withstanding evidence to the contrary, results are supported by proper degradations and, where applicable, multiple-labelling experiments. Since the use of tracers has become more widespread and since experience has inevitably led to a refinement of technique, the field of alkaloid biosynthesis is currently in a state of rapid flux. Because of the breadth of this topic and the rapid accrual of new information, any attempt by this author to exhaustively review this field would be presumptuous and of little value. A number of reviews have adequately covered various aspects of this subject. ,6,9,10 Our interest has for the most part been confined to the later 4 stages of biosynthesis, particularly those occurring in the benzylisoquinoline series, and an attempt has been made to introduce only material germane to this topic. REV IE7 5 Biosynthesis of the Benzylisoquinoline Skeleton The relationship of certain phenethylamine alkaloids such as hordenine (1), mescaline (2), or ephedrine (3) to the aromatic amino-acids, e.g.l phenylalanine (1k), tyrosine (5), and DOPA (6) was suggested more than fifty years ago.11 I I Ntle_ 2 OMe 1- CO,4H 14 HO' NH H2 2 3 4 5 OH GO2 1-' I-13 2 HOB NH NH 2 2 Subsequent experiments have confirmed this relationship. Rordenine (1) has been shown to be derived from [2_14-1ujphenylalanine 12 or [2-14C]tyrosine12 as well as from [a-14C]tyramine.13 Similarly, mescaline (2) has been shown to arise from tyrosine.14 In experiments using 13N. as a tracer Shibata and Imaseki have demonstrated that the nitrogen of ephedrine (3) is derived exclusively from the nitrogen of phenylalanine.15 Since rL3- 14 Cjphenylalaninei is a precursor of the closely 16 related norpseudoephedrine (7), it appears that in this instance phenylalanine is a direct precursor and does not undergo conversion to an aldehyde or a-keto acid. That the more complex benzylisoquinoline skeleton, as typified by tetrahydropapaveroline (8), could in principle be derived from amino-acid units was suggested by Robinson12 and Winterstein and Trier.11 In general Robinson reasoned that if the reaction outlined below were to take place in the plant it could participate in the formation of a variety of alkaloids. lz=r4 I I C C 0 NH C C —N I 1 - 7 - Variations as this theme are legion. The nucleophilic carbon could arise from an It&ctivated" carbon or an aromatic ring, and the two components might be provided by a preformed Schiffsf base. The reaction of this sort utilizing a phenethylamine and an aldehyde has become familiar to chemists as the 18 Pietet-Spengler synthesis of isoquinolines.171 The first evidence that this hypothesis was sound was provided by Battersby and Harper who isolated radioactive papaverine (9) from poppies fed [2- 40]- tyrosine .19 Degradation showed the labelling pattern indicated in figure 1. More recent investigations have shown that the more complex benzylisoquinolines such as morphine20 (10), berberine21 (ii), and hydrastine21 (12) as well as benzphenanthridine alkaloid, chelidonine22 (13), are derived from two units of tyrosine. In each case degradation showed the pattern of labelling to be that anticipated if two aromatic amino-acids were first to condense to form a simple benzylisoquinoline which then underwent further transformation. Phenylalanine has been reported to be a much less efficient precursor than tyrosine for berberine,21 hydrastine,21 and morphine.23 This is not unexpected. B Figure 1 I 1 HO H Me 0 3fric OH Otseie 8 9 H NH, • OH Label from dopamine 4". 1 3 Label from tyrosine • 9 Although in mammalian systems tyrosine is formed by, the hydroxylation of phenylalanine,21 in E.Co1i 25 and in certain higher plants this reaction is not important. 26,27 In these cases tyrosine is formed directly from prephenic acid28 (14). CO2H -0 CQH CO,H Calf 14 CO2H 2 Although it appears that a skeletal unit derived from two molecules of tyrosine is common to a number of the more complex alkaloids, the exact nature of the condensing units as well as the specific reactions involved in the formation of this skeleton remains unclear. It is apparent that the two amino-acid units from which the benzylisoquinoline skeleton is derived are probably not equivalent. The first evidence of this resulted from a study of the incorporation of tyrosine into hydrastine21'29 (12). In certain cases differential incorporation of tyrosine into the two - 10 - whalvesit of the molecule was observed. Although this effect was small, its presence strongly indicated that the apino-acid was being incorporated into the two halves via different paths. It now appears that one and only one of these paths involves dopamine. Recent investigations have shown that in the biosynthesis of morphine,3° berberine,31 hydrastine,32 and chelidonine33 only one unit of dopamine is incorporated. In each ease the position of labelling is consistent with the proposal that dopamine enters only the phenethylanine portion of the molecule and does not contribute to the formation of the C6-02 benzyl portion.
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