Nickel-Catalyzed Enantioconvergent Cross-Couplings of Racemic Silyl Electrophiles

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Project Summary The past decade has seen substantial progress in the enantioselective transition metal catalyzed cross couplings of alkyl halides with various organonucleophiles to form new C-C bonds. More importantly, earth abundant metals have been realized to be excellent catalysts for these processes compared to their precious metal counterparts. With the use of metals such as Ni, Cu and Fe, current mechanistic data has pointed to single electron pathways as important processes that provide new opportunities towards asymmetric catalysis. For example, recent studies from the Fu group have provided convincing evidence that radical intermediates are formed during Ni-catalyzed cross- couplings between alkyl halides and organometallic partners. This in turn has allowed an enantioconvergent approach using racemic starting materials and chiral catalysts to construct carbon-centered stereogenic centers. This proposal expands on this concept to discover and develop a novel enantioconvergent Ni-catalyzed cross-coupling between halosilanes and boronic acids to control silicon-centered stereogenic centers. The first specific aim will encompass two aspects. Initially the focus will be the discovery and development of this methodology using rapid assay using chiral GC analysis will be conducted to ascertain % conversion, % yield, and % ee. The second aspect will deal with applications towards known silicon incorporated biologically active compounds will then highlight this approach. Specifically, the first enantioselective total synthesis of a silicon analog of combretastatin A-4, a novel tumor cell growth inhibitor, will be achieved. The second specific aim will focus on systematic mechanistic studies will be performed to elucidate if this novel methodology is mechanistically related to previous enantioconvergent systems or has a unique operative pathway. Kinetic studies in combination with EPR, UV-vis and mass spectrometry will be invaluable tools for the success in this endeavor.