Dual-Hydrogen-Bond Donor and Brønsted Acid Cocatalysis Enables Highly Enantioselective Protio-Semipinacol Rearrangement Reactions
Melanie A. S. Blackburn, Corin Wagen, M. Raul Bodrogean, Pamela M. Tadross, Andrew J. Bendelsmith, Dennis A. Kutateladze, Eric N. Jacobsen
Abstract
A catalytic protio-semipinacol ring-expansion reaction has been developed for the highly enantioselective conversion of tertiary vinylic cyclopropyl alcohols into cyclobutanone products bearing α-quaternary stereogenic centers. The method relies on the cocatalytic effect of a chiral dual-hydrogen-bond donor (HBD) with hydrogen chloride. Experimental evidence is provided for a stepwise mechanism where protonation of the alkene generates a short-lived, high-energy carbocation, which is followed by C-C bond migration to deliver the enantioenriched product. This research applies strong acid/chiral HBD cocatalysis to weakly basic olefinic substrates and lays the foundation for further investigations of enantioselective reactions involving high-energy cationic intermediates.