Intermolecular Asymmetric Stetter Reaction Catalyzed by Nucleophilic Carbenes

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DESCRIPTION (provided by applicant): The discovery of new reactions facilitates the development of new drug entities and promising new therapeutics. This proposal will seek to apply novel chiral organic salts to catalyze the enantioselective formation of carbon-carbon bonds. Stereochemically dense functionality is associated with improved biological specificity for one target. The research plan involves investigating the Stetter mechanism in order to advance current methodology to induce the asymmetric intermolecular Stetter reaction. The Stetter reaction creates a new carbon-carbon bond between a Michael acceptor and an acyl anion equivalent derived from an aldehyde. A detailed mechanistic study of this reaction will provide insight into the intermediates and transformations within the catalytic cycle. This information will subsequently present the basis for the design of an intermolecular protocol. Approaches to intermolecular reactivity include the changing of substituents on our current triazolium salts to invoke enantioselectivity through both steric bulk and electronic effects. We also propose to affect the course of the reaction by using a variety of new substrates, such as imines as nucleophilic precursors and allenes as electrophilic acceptors. Lewis acid activation of the Michael acceptor is also proposed. Successful realization of these goals will allow a new reaction manifold and a novel strategy to solving problems of molecular complexity relevant to synthetic approaches to pharmaceutical targets.