Enantioselective Synthesis of Secondary beta-Trifluoromethyl Alcoholsvia Catalytic Asymmetric Reductive Trifluoroalkylation and Diastereoselective Reduction

Fluorinated motifs are frequently encountered indrugs and agrochemicals. Incorporatingfluorine-containing motifsin drug candidates for lead optimization in pharmaceutical researchand development has emerged as a powerful tool. The constructionof molecules that feature a trifluoromethyl (CF3-) group on astereogenic carbon has accumulated broad research efforts. Unlike its well-explored, biologically active methyl counterpart,asymmetric construction of beta-trifluoromethylated alcohols bearing adjacent stereocenters still remains elusive. Throughretrosynthetic analysis, we posited that followed by sequential reduction of carbonyl, the initial construction of chiral alpha-trifluoromethylated ketones could render the desired product in a facile, one-pot fashion. Herein, we developed thefirst example ofnickel-catalyzed asymmtric reductive cross-coupling trifluoroalkylation of acyl chlorides for enantioselective synthesis of diverse alpha-trifluoromethylated ketones. The one-pot reduction of these alpha-trifluoromethylated ketones furnished corresponding alcohols bearing beta-CF3-substituted stereogenic carbons with excellent diastereoselectivity and complete enantioselective retention. High yields/enantioselectivity, mild conditions, and good functional group compatibility are shown in the system. Utilities of the method are alsoillustrated by applying asymmetric, late-stage trifluoroalkylation of biologically active complex molecules, revealing tremendouspotential for development of CF3-containing chiral drugs.