Cooperative Activation of Alkyne and Thioamide Functionalities; Direct Catalytic Asymmetric Conjugate Addition of Terminal Alkynes to alpha,beta-Unsaturated Thioamides

摘要

A detailed study of the direct catalytic asymmetric conjugate addition of terminal alkynes to alpha,beta-unsaturated thioamides is described. A soft Lewis acid/hard Bronsted base cooperative catalyst, comprising [Cu(CH_(3)CN)_(4)]PF_(6), bisphosphine ligand, and Li(OC_(6)H_(4)-p-OMe) simultaneously activated both substrates to compensate for the low reactivity of copper alkynylide. A series of control experiments revealed that the intermediate copper-thioamide enolate functioned as a Bronsted base to generate copper alkynylide from the terminal alkyne, thus driving the catalytic cycle through an efficient proton transfer between substrates. These findings led to the identification of a more convenient catalyst using potassium hexamethyldisilazane (KHMDS) as the Bronsted base, which was particularly effective for the reaction of silylacetylenes. Divergent transformation of the thioamide functionality and a concise enantioselective synthesis of a GPR40 receptor agonist AMG-837 highlighted the synthetic utility of the present catalysis.