Enantioselective reduction of α-substituted ketones mediated by the boronate ester TarB-NO₂

A facile and mild reduction procedure is reported for the preparation of chiral secondary alcohols prepared from α-substituted ketones using sodium borohydride and the chiral boronate ester (l)-TarB-NO₂. Direct reduction of substituted ketones bearing Lewis basic heteroatoms generally provided secondary alcohols of only modest enantiomeric excess likely due to either competition between the target carbonyl and the functionalized sidechains at the Lewis acidic boron atom in TarB-NO₂ or the added steric bulk of the α-sidechain. As an alternative method, these substrates were synthesized using TarB-NO₂ via a two-step procedure involving the reduction of an α-halo ketone to a chiral terminal epoxide, followed by regioselective/regiospecific epoxide opening by various nucleophiles. This procedure provides access to a variety of functionalized secondary alcohols including β-hydroxy ethers, thioethers, nitriles, and amines with enantiomeric excesses of 94% and yields up to 98%.