Enantioselective Synthesis of Cyclopropanes via CuH-Catalyzed Intramolecular Hydroalkylation

Abstract

A Cu-catalyzed cyclopropanation of γ-bromocrotonate derivatives via a hydrocupration–alkylation sequence is described. This hydroalkylation process is of good generality and allows access to chiral cyclopropanes bearing aryl, heteroaryl, N-indole, alkenyl, and alkyl substituents, all with complete trans-diastereoselectivity, enantioselectivities up to >99:1 er, and good to high yields. An experimental and computational mechanistic analysis was undertaken, which provided a full understanding of the factors affecting the reaction’s diastereo- and enantioselectivity. More specifically, it was found that the Cu-catalyst drives both the conjugate hydride addition and alkylation steps and that the reaction enantioselectivity is governed by distortion effects of the metal coordination sphere at the diastereomeric TSs.