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 units that are ubiquitous in numerous natural products and pharmaceutical molecules. Due to the high reaction barrier, copper-catalyzed enantioselective propargylation with propargylic alcohols has not been reported so far. Herein, we describe the first example of copper-catalyzed asymmetric propargylic substitution reactions of propargylic alcohols. The N,N,P-ligand functions 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 a catalyst that activates propargylic esters. The methodology proceeds under mild reaction conditions and is tolerant to 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.