Chiral Bifunctional N, N, P-Ligand-Enabled Cooperative Cu Catalysis: One-Pot Two-Step Propargylic Substitution of Propargylic Alcohols

Abstract

Propargyl moieties are important structural features that are ubiquitously found in numerous natural products and pharmaceutical molecules. Due to the high reaction barrier, copper-catalyzed enantioselective propargylation with propargylic alcohol has not been reported so far. Herein, we describe the first example of copper catalytic asymmetric propargylic substitution reactions of propargylic alcohols. The N, N, P-ligand functioned as a bifunctional reagent, acting as a base catalyst to promote the esterification of propargylic alcohols and serving as a tridentate ligand to coordinate with copper salts, thereby forming the catalyst that activates propargylic esters. The methodology proceeds under mild reaction conditions and is tolerant of N-, C-, and O-nucleophiles, generating propargylic substitution products in good to excellent yields with high enantioselectivities (up to 95% yield, 97% ee). This methodology might open a new avenue for designing copper-catalyzed propargylic substitution reactions with propargylic alcohols.