Dual-Hydrogen-Bond Donor and Brønsted Acid Co-Catalysis Enables Highly Enantioselective Protio-Semipinacol Rearrangement Reactions

Abstract

A catalytic protio-semipinacol ring-expansion reaction has been developed for the highly enantioselective conversion of ter-tiary vinyl cyclopropanols into cyclobutanone products bearing alpha-quaternary stereogenic centers. The method relies on the co-catalytic effect of a chiral dual-hydrogen-bond donor (HBD) with hydrogen chloride. Experimental and computational evidence is provided for a stepwise mechanism proceeding through an enantiodetermining, HBD-promoted protonation of the alkene to generate a discrete carbocationic intermediate. This short-lived (20 ps), high-energy carbocation is generated in a chiral conformation in the presence of HBD catalyst and undergoes subsequent stereospecific C–C bond migration to the enantioenriched product. This research applies strong acid/chiral HBD co-catalysis to weakly basic olefinic substrates and lays the foundation for further investigations of enantioselective reactions involving high-energy cationic intermediates.