Constructing Tertiary Alcohols with Vicinal Stereocenters: Highly Diastereo- and Enantioselective Cyanosilylation of α-Branched Acyclic Ketones and Their Kinetic Resolution

We report the first highly diastereo- and enantioselective C–C bond-forming reaction of racemic α-branched ketones to construct tertiary alcohols with adjacent stereocenters. Accordingly, a highly stereoselective cyanosilylation of racemic ketones is developed using our bifunctional cyanating reagent, Me₂(CH₂Cl)SiCN, giving C^α-tetrasubstituted silyl cyanohydrins with two vicinal stereocenters in up to >20:1 diastereomeric ratio (dr) and 90–98% enantiomeric excess (ee) values, which can undergo various diversification reactions by manipulating the chloromethyl group. A highly selective kinetic resolution of acyclic α-branched ketones is also developed that allows facile access to acyclic α-alkyl, allyl, and propargyl ketones with good recovery and excellent ee values. The synthetic value of this protocol is further demonstrated by the formal synthesis of the anti-obesity agent, taranabant (MK-0364). The activation of Jacobsen’s privileged catalyst (salen)AlCl by a suitable phosphorane plays a crucial role in the reaction. X-ray crystallographic analysis of single crystals of phosphorane–(salen)AlCl complexes and theoretical calculations help provide a working model. The present transformation opens a new path for the catalytic stereoselective synthesis of stereochemically complex tertiary alcohols featuring two stereocenters (adjacent or not) from racemic ketones.