Direct Catalytic Asymmetric Addition of Allyl Cyanide to Ketones via Soft Lewis Acid/Hard Bronsted Base/Hard Lewis Base Catalysis

We report that a hard Lewis base substantially affects the reaction efficiency of direct catalytic asymmetric gamma-addition of allyl cyanide (la) to ketones promoted by a soft Lewis acid/hard Bronsted base catalyst. Mechanistic studies have revealed that Cu/(R,R)-Ph-BPE and Li(OC6H4-p-OMe) serve as a soft Lewis acid and a hard Bronsted base, respectively, allowing for deprotonative activation of la as the rate-determining step. A ternary catalytic system comprising a soft Lewis acid/hard Bronsted base and an additional hard Lewis base, in which the basicity of the hard Bronsted base Li(OC6H4-p-OMe) was enhanced by phosphine oxide (the hard Lewis base) through a hard hard interaction, outperformed the previously developed binary soft Lewis acid/hard Bronsted base catalytic system, leading to higher yields and enantioselectivities while using one-tenth the catalyst loading and one-fifth the amount of la. This second-generation catalyst allows efficient access to highly enantioenriched tertiary alcohols under nearly ideal atom-economical conditions (0.5-1 mol % catalyst loading and a substrate molar ratio of 1:2).