Thesis advisor: Amir H. Hoveyda / In the course of a total synthesis of quebrachamine, we were faced with a late-stage enantioselective ring-closing metathesis that could not be promoted by any of the state-of-the-art chiral metathesis catalysts. To overcome this deficiency, we designed and developed a new class of catalysts based on mechanistic and theoretical principles. The new catalysts contain a stereogenic metal center and display unprecedented levels of reactivity and selectivity in enantioselective olefin metathesis, enabling us to complete our planned synthesis of quebrachamine. We have also discovered that non-productive metathesis reactions with stereogenic-at-Mo catalysts, generated and used in situ as a mixture of diastereomers, are crucial to the efficiency and enantioselectivity of the ring-closing metathesis reactions. Specifically, our studies have indicated that the two diastereomers of catalyst are in rapid equilibrium due to non-productive metathesis with ethylene, generated as the desired ring-closing reaction proceeds, thereby establishing a reaction manifold that is under Curtin-Hammett control. Finally, in our efforts to prepare air-stable precursors to stereogenic-at-Mo olefin metathesis catalysts, we have examined the addition of N,N-chelating ligands to Mo bis-pyrrolide complexes. Upon addition of 2,2′-bipyridyl to bis-dimethylpyrrolide Mo complexes, rather than the expected octahedral chelate, a five-coordinate monopyrrolide alkylidyne complex is generated. The complex displays good air-stability and efficiently serves as a precursor to stereogenic-at-Mo alkylidene catalysts; several alkylidyne complexes have been prepared. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Ce travail de thèse s’articule autour de la synthèse totale des alcaloïdes de la famille Rhazinilam, potentiels agents anticancéreux. Dans ce contexte, deux méthodologies clés ont été développées. Premièrement, une réaction de cyclisation-migration de groupements sulfonyles catalysée à l'or (I) conduisant à des sulfonates de pyrroles a été optimisée et le champ d'application a été largement étendu. En tirant profit de la carbophilie des catalyseurs d’or (I), une réaction en cascade comprenant une séquence de cyclisation-migration-hydrocarbonation a été mise en place, permettant la synthèse d’indolizines ou de pyrroloazépines dans un procédé en un seul pot. Deuxièmement, des conditions réactionnelles sans précèdent par catalyse au palladium ont été développées pour le couplage de Suzuki-Miyaura impliquant des substrats de types sulfonates de pyrroles. Ces conditions ont été appliquées de façon efficace sur divers types de partenaires (aryle, hétéroaryle, vinyle sulfonates ou analogues halogénés) mais également utilisées dans différents types de couplages (Sonogashira, Buchwald). Ces méthodologies ont ensuite été appliquées à la synthèse totale du Rhazinilam et permis d’ouvrir la voie à la synthèse des Kopsiyunnanines et du Leuconolam. En parallèle, de nouveaux complexes associant des polyoxométallates et des carbènes d'or (I) ont été synthétisés, caractérisés et utilisés en catalyse hétérogène. / This PhD work was articulated around the total synthesis of the Rhazinilam family alkaloids, potential anticancer agents. In this context, two key methodologies have been developed. Firstly, a gold(I)-catalyzed cyclization-sulfonyl migration reaction leading to pyrrole sulfonates has been optimized and the scope was largely extended. By taking advantage of the carbophilicity of gold(I) catalysts, a cascade reaction including a sequence of cyclization-migration-hydrocarbonation has been implemented, allowing the synthesis of indolizidines or pyrroloazepines in a one pot process. Secondly, unprecedented reaction conditions were developed for palladium-catalyzed Suzuki−Miyaura cross-coupling using pyrrole sulfonates as substrates. These conditions have been applied efficiently on various types of partners (aryl, heteroaryl, vinyl sulfonates or halogenated analogues) but also used in different types of cross-coupling (Sonogashira, Buchwald). These methodologies were then applied to the total synthesis of Rhazinilam and to open the way to the synthesis of Kopsiyunnanines and Leuconolam natural products. In parallel, new complexes combining polyoxometalates and gold(I) carbenes have been synthesized, characterized and used in heterogeneous catalysis.