Catalytic Nucleophilic Glyoxylation: Asymmetric Derivatizations and Aldol/Oxidati

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DESCRIPTION (provided by applicant): a-Ketoesters play an important role in organic synthesis and are prevalent substructures of many biologically active natural products. The introduction of the a-ketoester structure is synthetically challenging and direct methods for the generation of this functionality are highly desirable. This proposal aims to develop practical new catalytic reactions that provide the synthetic equivalents of glyoxylate anions to allow the direct incorporation of this substructure into electrophiles. The proposed chemistry will utilize silyl glyoxylates, a unique versatile conjunctive reagent developed in the Johnson laboratory, to serve as a convenient nucleophilic glyoxylate donor in cyanide catalyzed additions to aldehydes. The development of a novel catalytic asymmetric addition/oxidation reaction cascade with acetoacetates and p-electrophiles is also proposed. This reaction will allow expedient access to enantioenriched a-ketoesters. PUBLIC HEALTH RELEVANCE: The synthesis of enantiopure biologically-relevant small molecules is an important area in the health sciences, as these compounds are used to probe structure-activity relationships in biological processes and can potentially serve as new chemotherapeutic agents. It is desirable to prepare these compounds as efficiently as possible and this grant aims to develop asymmetric reactions to incorporate the a-ketoester moiety. Chiral a-ketoesters are of particular interest due to their importance as intermediates in natural product synthesis and their roles in metabolic and biosynthetic pathways.