The first crude preparation of the alkaloid emetine was obtained in 1817 by Pelletier from the plant species Cephaelis ipecacuanha. Since that day many workers have turned their attentions to the structural problem presented by this alkaloid, among them being such famous chemists as Karrer, Pyman, Späth, and Reichstein. Their failure to complete the elucidation of the structure cannot be ascribed to a lack of time or to the substance being uninteresting in itself, for, during the century or so that emetine has been known, the structure of many alkaloids with considerably more complex molecules have been solved. Furthermore, emetine has always aroused considerable interest because of its unique position as therapeutic agent for the treatment of amoebic dysentery. It seems more probable that the great difficulty experienced by the early workers of obtaining pure emetine accounts partly for the slow rate of progress; the reluctance of the derivatives and degradation products of the alkaloid to crystallise, must also be taken in to account. Again, the oxidation technique, so powerful a weapon with many other alkaloidal problems, failed to cast any light on what might be called the core of the molecule. A knowledge of the structure of emetine will obviously be of considerable value in view of its pharmacological properties, and the present researches have been planned with that end in view. The mode of attack, different from these previously employed, will be described in this thesis. Part of the author's early work on the emetine problem was presented for a Higher Degree (M.Sc., Manchester), and will be described briefly in this historical survey.

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Thesis (M.Sc.)--York University, 2006. Graduate Programme in Biology. / Typescript. Includes bibliographical references (leaves 118-125). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR19667

Emetine is the principal alkaloid of ipecacuanha root which is obtained from the plant known botanically as Psychotria Ipecacuanha, also called Cephaelis Ipecacuanha, indigenous to Brazil, and from Psychotria Acuminata found in Colombia, both members of the Rubiaceous Order. In this root emetine is accompanied by cephaeline and, in much smaller amount, by psychotrine, 0=methylpsychotrine and emetamine, the five alkaloids being closely related to each other chemically. The two chief medicinal properties of ipecacuanha root, namely its emetic effect and its ability to alleviate dysentery, have long been known, the name “ipecacuanha” itself being derived through Portugese from a native word meaning “road-side sick-making plant”. It is with the investigations into the constitution of the ipecacuanha alkaloids, and particularly with the modern work in this field, that we are concerned in the present dissertation. From considerations of space, in the historical survey much must necessarily be disregarded which to the present author seems irrelevant to the main issue, and in particular on account of the work of many early investigators will be omitted because in no way do their results appear to have disclosed anything of fundamental importance. A chapter is to be included recording the development, scope and modern position of the technique of dehydrogenation, a technique which forms the basis of a large section of the present investigation of which this thesis is a record.

Sur la base de travaux précédemment réalisés au laboratoire concernant la réaction de Mannich vinylogue (RMV), nous avons continué le développement de cette réaction en mettant au point un protocole multi-composants. Nous avons ensuite étendu la gamme des substrats compatibles à différents hétérocycles azotés, de nouveaux électrophiles et nucléophiles avec des rendements généralement supérieurs à 80% et des rapports diastéréomériques supérieurs à 80/20. L’obtention de nombreux clichés de diffraction des rayons X a permis de confirmer que le diastéréomère majoritaire est toujours de configuration relative R*,R*. Nous avons ensuite valorisé ces produits en obtenant, en une étape, des structures tétracycliques complexes. Ces produits ont été synthétisés avec des rendements allant jusqu’à 87% et un rapport diastéréomérique supérieur à 95/5. Une étude de modélisation moléculaire a permis d’apporter une explication à cette diastéréosélectivité. La séquence RMV / cyclisation a conduit à la formation contrôlée de quatre centres stéréogéniques contigus. Ces structures tétracycliques ont ensuite servi de produits de départ vers la synthèse d’analogues d’une molécule naturelle antitumorale : l’émétine. Les intermédiaires de synthèse ont été testés pour leur activité cytotoxique. / On the basis of previous work done in the laboratory on the vinylogous Mannich reaction, we pursued the development of this reaction by devising a three component procedure. We then extended the scope of the reaction to different aza-heterocycles, to new electrophiles and nucleophiles with yields generally over 80% and diastereomeric ratios over 80/20. The numerous X ray structures obtained confirmed that the major diastereomer always present an R*,R* configuration. These substrates were then used to prepare complex tetracyclic structures in one step. These products were obtained with yield up to 87% and diastereomeric ratios up to 95/5. This diastereoselectivity was rationalized using molecular modeling. This vinylogous Mannich / cyclization reaction sequence allowed the controlled formation of four contiguous stereogenic centers. These tetracyclic structures were then used as starting points for the synthesis of analogues of emetine, a natural antitumor compound. The synthetic intermediates were tested for their cytotoxic activity.