Enantioselective Hydrochlorination of Alkenes enabled by Cooperative Catalysis and Enantioconvergent Dynamic Kinetic Resolution of Quaternary Stereocenters - Project Summary/Abstract The hydrochlorination of alkenes is a central reaction in introductory organic chemistry, illustrating fundamental concepts in organic mechanism and reactivity. Despite its pedagogical ubiquity, and the growing importance of alkyl chlorides in synthesis and drug discovery, enantioselective hydrochlorination of alkenes remains an unsolved challenge in organic synthesis. This proposal aims to develop a catalytic, enantioselective hydrochlorination reaction of simple olefins by employing hydrogen-bond-donor (HBD) organocatalysis to provide access to enantioenriched alkyl chlorides (K99). The research plan outlines specific strategies that will enable enantioselective hydrochlorination through identification of a suitable HBD catalyst framework and cooperative metal halide cocatalyst. A combination of mechanistic and computational investigations will provide insight into the critical non-covalent interactions and catalyst features necessary for enantioinduction. Subsequent investigations on the stereospecific displacement of the chiral alkyl chlorides will enable the asymmetric synthesis of diverse chiral motifs. These products are well poised for further synthetic derivatization or direct biological evaluation for small molecule-based drug discovery. By facilitating access to these value- added functional units, underexplored chemical matter will be interrogated in biological contexts, contributing to the discovery of new therapeutic technologies for the betterment of human health. In a second research area (R00), cooperative metal halide catalysis will be leveraged to enable the formal activation of canonically inert quaternary stereocenters for enantioconvergent coupling reactions. Dynamic covalent reactivity will be exploited in concert with chiral transition-metal complexes to promote enantioselective reactions from racemic precursors. Mechanistic and computational studies will provide insight on the origins of enantioselectivity and general design principles in cooperative asymmetric catalysis. The proposed career development project will serve as a platform for the teaching and mentoring of high school, undergraduate, and graduate students. The proposed development plan also outlines professional networking and conference opportunities focused on launching a successful independent research career.
