Enantioselective Propargylic Substitution of Ketone Enolates with Propargylic Alcohol Derivatives through Cooperative B/Cu Catalysis

We present an asymmetric propargylic substitution reaction of ortho-hydroxy aryl ketones with propargylic acetates catalyzed by a B/Cu system. The reaction initiates with the activation of ortho-hydroxy aryl ketones via achiral borinic acid to form a tetracoordinated enol boronate complex, which then reacts with propargylic acetates catalyzed by copper salts with chiral P,N,N-ligand. This method is amenable to a broad range of substrates and delivers a series of chiral β-ethynyl ketones with high yields and remarkable enantioselectivity under mild conditions. The synthetic utility of the method is further demonstrated by a mmol-scale reaction and the synthesis of a key precursor to AMG 837, a potent GPR40 agonist.