Rubriflordilactones A and B are highly oxygenated nortriterpenoid natural products isolated from Schisandra rubriflora. The latter is of particular biological interest as it shows significant anti-HIV activity. Two transition metal-catalysed cascade cyclisation approaches for the formation of the CDE rings of the rubriflordilactones were developed. Palladium-catalysed cyclisation of bromoenediynes and cobalt-catalysed triyne cyclotrimerisation both transform acyclic precursors into 7,6,5-bisannelated arenes in a single step. Two enantioselective syntheses of the AB ring fragment common to both rubriflordilactones, with bromoene or alkyne functional groups required for the respective cyclisation methods, are described; along with the refinement of a route to the CDE diyne fragment of rubriflordilactone A. From these fully functionalised bromoenediyne and triyne substrates, both metal-catalysed cyclisation methods were successful; these strategies converged on a late-stage intermediate bearing the ABCDE ring system of rubriflordilactone A. Construction of the F ring, followed by attachment of the G ring by an intriguing oxo-carbenium ion addition reaction completed two enantioselective total syntheses of (+)-rubriflordilactone A.

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O objetivo deste trabalho foi desenvolver métodos para sintetizar o esqueleto carbônico básico de furanoeliangolidos. Goiazensolido é um típico exemplo destes produtos naturais, cujo núcleo estrutural podemos considerar como sendo de um biciclo[6.2.1]undecano. Imaginamos que este tipo de estrutura poderia ser preparado através da reação de Diels-Alder seguida da ruptura de uma ligação interna de um sistema policíclico. Na nossa primeira tentativa, fomos capazes de preparar o dimesilato 75, mas a clivagem da ligação C2-C7 não pôde ser efetivada, nem sob condições solvolíticas, nem por tratamento com base, somente misturas complexas foram obtidas em todas as tentativas. Nossa próxima abordagem foi baseada no possível rearranjo térmico de um sistema contendo dois anéis de ciclobutanos fundidos entre si (um sistema tetraciclo[6.2.1.02,7.03,6]undecano). Entretanto, embora tenhamos conseguido preparar os compostos 87 e 101 com bons rendimentos, o produto de fotocicloadição [2 + 2] não pôde ser obtido. Finalmente, em nossa terceira abordagem, baseada em uma reação de retro-aldol, conseguimos obter o sistema biciclo[6.2.1]undecano 117, pelo tratamento de 116 com NaH em tolueno aquecido até refluxo. O composto foi preparado por dois caminhos diferentes, ambos envolvendo reações de Diels-Alder. / The aim of this work was to develop methods to synthesize the main carbon skeleton of the furanoheliangolides. Goyazensolide is a typical example of these natural products, whose core structure is a bicyclo[6.2.1]undecane. We envisioned that this framework could be prepared through the Diels-Alder reaction followed by a cleavage of an internal bond of the polycyclic ring system. In our first attempt, we were able to prepare the dimesilate 75, but the desired cleavage of the C2-C7 bond could not be effected, neither under solvolytic conditions, nor by base treatment, complex mixtures being the result in all attempts. Our next approach was based in the possible thermal rearrangement of the system consisting of two fused cyclobutane rings (a tetracyclo[6.2.1.02,7.03,6]undecane ring system). However, although compounds 87 and 101 could be prepared in good yields, no photochemical [2 + 2] cycloaddition product could be obtained from them. Finally, in our third approach, based in a retro aldol reaction, we succeeded in preparing the desired bicyclo[6.2.1]undecane system 117 by treatment of 116 with NaH in refluxing toluene. Compound 116 was prepared by two different ways, both involving Diels-Alder reactions.

O objetivo deste trabalho foi desenvolver métodos para sintetizar o esqueleto carbônico básico de furanoeliangolidos. Goiazensolido é um típico exemplo destes produtos naturais, cujo núcleo estrutural podemos considerar como sendo de um biciclo[6.2.1]undecano. Imaginamos que este tipo de estrutura poderia ser preparado através da reação de Diels-Alder seguida da ruptura de uma ligação interna de um sistema policíclico. Na nossa primeira tentativa, fomos capazes de preparar o dimesilato 75, mas a clivagem da ligação C2-C7 não pôde ser efetivada, nem sob condições solvolíticas, nem por tratamento com base, somente misturas complexas foram obtidas em todas as tentativas. Nossa próxima abordagem foi baseada no possível rearranjo térmico de um sistema contendo dois anéis de ciclobutanos fundidos entre si (um sistema tetraciclo[6.2.1.02,7.03,6]undecano). Entretanto, embora tenhamos conseguido preparar os compostos 87 e 101 com bons rendimentos, o produto de fotocicloadição [2 + 2] não pôde ser obtido. Finalmente, em nossa terceira abordagem, baseada em uma reação de retro-aldol, conseguimos obter o sistema biciclo[6.2.1]undecano 117, pelo tratamento de 116 com NaH em tolueno aquecido até refluxo. O composto foi preparado por dois caminhos diferentes, ambos envolvendo reações de Diels-Alder. / The aim of this work was to develop methods to synthesize the main carbon skeleton of the furanoheliangolides. Goyazensolide is a typical example of these natural products, whose core structure is a bicyclo[6.2.1]undecane. We envisioned that this framework could be prepared through the Diels-Alder reaction followed by a cleavage of an internal bond of the polycyclic ring system. In our first attempt, we were able to prepare the dimesilate 75, but the desired cleavage of the C2-C7 bond could not be effected, neither under solvolytic conditions, nor by base treatment, complex mixtures being the result in all attempts. Our next approach was based in the possible thermal rearrangement of the system consisting of two fused cyclobutane rings (a tetracyclo[6.2.1.02,7.03,6]undecane ring system). However, although compounds 87 and 101 could be prepared in good yields, no photochemical [2 + 2] cycloaddition product could be obtained from them. Finally, in our third approach, based in a retro aldol reaction, we succeeded in preparing the desired bicyclo[6.2.1]undecane system 117 by treatment of 116 with NaH in refluxing toluene. Compound 116 was prepared by two different ways, both involving Diels-Alder reactions.

All Strychnos and Aspidosperma alkaloids possess a core pyrrolo[2,3-d]carbazole ABCE tetracycle. In order to develop an efficient and divergent methodology for the synthesis of Strychnos alkaloids, a streamlined synthetic sequence to the ABCE tetracycle has been developed. It features a Mitsunobu activation of an N-hydroxyethyl gramine intermediate and subsequent intramolecular aza-Baylis-Hillman reaction. This method was first applied in the total synthesis of (±)-alstolucine B. Additional key steps in the synthesis included (1) chemoselective intermolecular and intramolecular Michael additions and (2) a Swern indoline oxidation. The second application of this method was in the first total synthesis of (-)-melotenine A, a novel rearranged Aspidosperma alkaloid with potent biological activity. Additional key steps in the synthesis included (1) a Piers annulation of a vinyl iodide and a methyl ketone to prepare the D ring and (2) a site-selective intermolecular vinylogous aldol reaction / Chemistry

Ce projet de recherche se focalise sur les infections par mycobacterium ulcerans (maladie de l’ulcère de Buruli), une maladie de la peau dévastatrice caractérisée par la formation de lésions nécrotiques progressives et l’absence d’une réponse inflammatoire. Bien que négligée, cette infection est la troisième maladie mycobactérienne la plus répandue après la tuberculose et la lèpre et des cas sont rapportés dans plus de 30 pays à travers le monde. Mycobacterium ulcerans sécrète une toxine polycétidique complexe, appelée mycolactone A/B, qui est directement responsable des effets pathogènes de la maladie. Depuis sa découverte, les propriétés biologiques inhabituelles de la mycolactone A/B ont suscité de nombreux efforts de recherche dans différents domaines. Dans ce contexte, ce projet s’intéresse à l’élucidation du mécanisme d’action des mycolactones en utilisant la synthèse totale comme outil principal. Dans cette optique, notre équipe a mis en place une voie de synthèse permettant un accès facile et robuste à différents mimes de mycolactone. L’utilisation de cette méthode a conduit à la préparation de 13 mimes de la toxine au cours de cette thèse. D’autre part notre équipe s’intéresse également à la préparation de mimes possédant un ou plusieurs atomes de fluor. Ces derniers présentent un intérêt particulier pour améliorer la compréhension des interactions ayant lieu entre la toxine et sa cible cellulaire. Les travaux réalisés autours de la synthèse de mycolactones fluorés ont conduit à la mise au point d’une méthode générale et simple pour introduire un groupe trifluorométhyle sur un alcyne terminal, permettant ainsi des modulations inédites de la structure de la toxine. / This research project focuses on mycobacterium ulcerans infection (Buruli ulcer disease), a severe skin disease characterized by the formation of progressive necrotic lesions and the lack of an acute inflammatory response. Although neglected, this infection is the third most common mycobacteriosis after Mycobacterium tuberculosis and Mycobacterium leprae, and cases are reported in more than 30 countries worldwide. Mycobacterium ulcerans secretes a complex polyketidic macrolide, called mycolactone A/B, which is directly involved in the biological effects of the disease. Since its discovery, the unusual biology triggered by this toxin has spurred research efforts. In this context, this research project aims at a better understanding of mycolactone A/B molecular interactions by using total synthesis as main tool. To this end, our research team has developed an efficient synthetic pathway allowing the preparation of different mimetics of the toxin. This synthesis has been used to prepare thirteen new mycolactone mimetics during this thesis. Moreover our team has also been interested in the synthesis of fluorinated mycolactone analogs. Such fluorinated mycolactones are of great interest to improve the interactions that occur between the toxin and its biological binding site. Work in this field led to the development of a simple and general method to introduce a trifluoromethyl group onto a terminal alkyne, allowing novel modulation of the structure of the toxin.