Development of one-pot sequential cyclizations and applications towards the synthesis of complex alkaloids / Développement de cyclisations séquentielles monotopes et applications à la synthèse d'alcaloïdes complexes

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This research program is aimed at developing original strategies to efficiently synthesize complex natural products through new cascades of reactions. In this vein, the research proposed is divided into three orientations (see below). This proposed research program will have a significant impact in the community of organic chemists since it will provide innovative and efficient ways to access complex alkaloids and motifs that are hard to obtain using the currently available methods. Such a program is perfectly suited for the formation of highly qualified personnel destined to pharmaceutical industry and academia.1- Sequential Vilsmeier-Haack and organocatalyzed asymmetric Mannich cyclizations.In a previous project (published) on Vilsmeier-Haack and Mannich cyclizations cascade, we found serious limitations in the last step (Mannich), such as the low reactivity of the iminium ion as well as the absence of chiral induction. To address both of these issues, we plan to run the initial cyclization on substrates bearing an unreactive ketone or aldehyde. The addition of a catalytic amount of secondary amine will then trigger the second cyclization (Mannich) through an enamine intermediate. Catalyst loading, substrate scope as well as chiral induction with the use of asymmetric catalysts will be studied.2- New sequence of cyclizations using activated carbamates.We recently demonstrated that the same reactivity issue in the second (Mannich) cyclization could be addressed by starting from a carbamate. After activation and first cyclization, a rapid dealkylation generates an amide that is reactivated in situ in the presence of an excess of activating agent. The resulting triflyliminium ion is substantially more reactive than regular iminiums ions intermediates in the previous sequence. The second cyclization is thus greatly facilitated, which improves the applicability of this strategy. Substrate and nucleophile scope will be studied to access architecturally varied aza-bicyclic and aza-tricyclic compounds.3- Completion of the total synthesis of complex, polycyclic alkaloids using sequential Vilsmeier-Haack cyclization and intramolecular azomethine ylide cycloaddition.These syntheses exploit a sequential one-pot Vilsmeier-Haack cyclization and intramolecular azomethine ylide cycloaddition. We already proved that this strategy is highly efficient when applied to the synthesis of three classes of natural products, namely daphnanes, aspidospermans and aspidospermatans. In all cases, the key transformation generated an advanced intermediate. We now need to complete the syntheses of a series of targeted alkaloids in each of these families from the key step adducts to demonstrate the applicability our sequential cyclizations towards complex natural products.