The Silyl-Directed Borylation of Aliphatic C-H Bonds

University Of California Berkeley, Berkeley CA

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Abstract

DESCRIPTION (provided by applicant): The creation of new and efficient methods for the synthesis of complex molecules is important to drug discovery and production. The development of methods for the direct, selective and catalytic functionalization of carbon-hydrogen (C-H) bonds to produce carbon-boron bonds (i.e. borylation) is especially critical. Organoboron reagents are arguably the most versatile synthetic intermediates in organic synthesis and medicine. Direct routes to organoboronates have been developed but are often limited by their selectivity. As a result, it becomes important to develop catalysts that promote reactivity at a single site. Toward this end, ordinary hydroxyl groups may be used as directing elements for transition metal-catalyzed C-H bond functionalization. This proposal focuses on the development of an efficient method for the silyl-directed borylation of unactivated primary C-H bonds. This method will increase the efficiency by which structurally complex molecules are made. The specific aims of this research are to: (i) identify a catalyst complex that catalyzes the borylation of aliphatic C-H bonds via silyl direction, (ii) evaluate the substrate scope and functional group tolerance of the developed method, (iii) provide a detailed mechanistic picture of how this process works, and (iv) apply this method to the synthesis of structurally complex, biologically active molecules. Thoughtful screening of various transition metal and ligand combinations will be done to identify a suitably active catalyst. The reaction will then be optimized with respect to catalyst loading, reagent identity and stoichiometry, solvent and temperature. The reaction's mechanism will then be established via the measurement of rate constants, thermodynamic parameters, as well as isotope and substituent effects. The long-term objectives of this proposal are to create a new synthetic methodology for drug discovery, enhance our molecular-level understanding of catalysis, and advance the field of natural products synthesis.