Ligand-promoted Enantioselective C-H Activation Reactions

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Project Summary While metal insertion into, and subsequent functionalization of, sp3 C−H bonds has the potential to afford transformative tools in synthesis, the impact of this approach on asymmetric catalysis has been moderate due to a number of unanswered challenges encountered in the development of asymmetric version of these reactions. This proposal centers on the development of two approaches for enantioselective C–H activation reactions of broadly useful substrates: (A) the design of bisdentate chiral ligands and (B) catalytic chiral directing groups. We will develop enantioselective C–H activation reactions of -methyl C–H bonds and methylene C–H bonds of carboxylic acids and carboxylate derived substrates, as well as -C–H bonds of amines and amine derived substrates. These reactions will provide novel and versatile methodologies for constructing -, -, and -chiral centers in asymmetric synthesis. The use of abundant and common substrates, as well as the diversity of the transformations will render palladium-catalyzed enantioselective C–H functionalization broadly useful for the synthesis of bioactive chiral molecules. Specifically, desymmetrization of isobutyric and pivalic acids via enantioselective C–H activation will be applied to the generation of a library of novel serine hydrolase inhibitors that can be evaluated by activity-based protein profiling to identify new drug leads for diabetes, cognitive dementia and bacterial infection.