Catalytic Asymmetric Reductive Coupling Reactions to Prepare Bioactive Molecules

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DESCRIPTION (provided by applicant): The overarching goal of this proposal is to develop new nickel-catalyzed enantioselective reductive cross- coupling reactions for applications in the synthesis and study of bioactive molecules. It is well established that the two enantiomers of a drug can exhibit remarkably different biological properties. As a result, the enantioselective synthesis of chiral small molecules has become an important area of research in both academic and industrial laboratories. Recently, Nickel-catalyzed reductive cross-coupling reactions have emerged as direct methods for carbon-carbon bond formation. These reactions typically tolerate an array of functional groups, occur under mild conditions, and employ inexpensive, earth abundant metals as stoichiometric reductants. Most importantly, they do not require the use of pre-generated organometallic reagents. In order to realize the full synthetic potential of Ni-catalyzed reductive cross-coupling reactions, it is critical to develop enantioselective variants o these transformations. This proposal describes the first significant progress toward this objective: the development of four new Ni-catalyzed enantioselective cross- coupling reactions. Preliminary results obtained for each transformation provide compelling evidence for the feasibility of this research. This research will be carried out by a team composed of the PI, three chemistry graduate students and one postdoctoral researcher. As part of this project, the graduate students and postdoctoral researchers will receive rigorous training in the theory, methods, and strategies of organic chemistry. The successful execution of this research will provide new tools to enable the synthesis of small molecules for the study and treatment of human disease.