Asymmetric Reactions with Bifunctional Organocatalysis

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Abstract: During the last several years our research program has made signiificant progress in the development and application of cinchona alkaloids as broadly useful chiral base/nucleophilic catalysts for asymmetric synthesis and in the elucidation of catalyst-substrate hydrogen bonding interaction as the basis for efficient and general asymmetric catalysis. The proposed work focuses on the design and development of novel cinchona alkaloids as tunable and practical acid-base bifunctional catalysts for synthetically important asymmetric C-C bond forming reactions. The specific aims are: 1) Development of catalytic asymmetric conjugate additions with trisubstituted carbon nucleophiles for direct and stereocontrolled construction of sole all carbon substituted quaternary stereocenter and adjacent quaternary-tertiary stereocenters; 2) Development of catalytic, asymmetric tandem conjugate addition-protonation reactions for one-step creation of 1,3-quaternary-tertiary stereocenters, a common structural motif in biologically important compounds that are now typically constructed by multistep process; 3) Development of catalytic enantioselective nucleophilic additions to ketones for the construction of oxygen-substituted tetrasubstituted carbon stereocenters (O-substituted quaternary stereocenters); 4) The design, synthesis and screening of novel C6'-OH cinchona alkaloid derivatives for the discovery and development of new and powerful bifunctional chiral catalysts. To illustrate the synthetic utility of these reactions, we outline concise and general synthetic routes which utilize these reactions for the preparation of various optically active chiral building blocks and biologically interesting compounds. Opening new and fundamentally important approaches for the construction of all carbon and oxygen-substituted quaternary centers, these new synthetic methods are expected to have a major impact on biomedical research by greatly facilitating the target-oriented as well as diversity-oriented synthesis of numerous biologically important compounds.