Enantioselective Arbuzov Reaction Enabled by Catalytic Ion-Pair Reorganization

Abstract

The stereocontrolled synthesis of stereogenic-at-phosphorus compounds is a long-standing challenge in organic chemistry that has received heightened research attention in recent years. None of the catalytic approaches taken to date have leveraged the rich manifold of transformations proceeding through nucleophilic dealkylation of phosphonium ion intermediates (e.g. Michaelis–Arbuzov, Pudovik, and Appel reactions). Here, we report enantioselective hydrogen-bond-donor-catalyzed Michaelis–Arbuzov reactions of dialkylphosphonites with hydrogen chloride to afford H-phosphinates, which are versatile P-chiral building blocks. Mechanistic and computational investigations reveal that the catalyst diminishes the reactivity of the chloride nucleophile, yet accelerates the rate-determining dealkylation step by preorganizing the phosphonium chloride resting state into a geometry that is primed to enter the SN2 transition state.