Regiodivergent Rhodium Catalysis: Enantioselective Hydroacylation of 2-Azetines

Abstract

In this article, we report a regio- and enantioselective Rh-catalyzed hydroacylation of 2-azetines, enabled by strategic ligand control. The choice of the bisphosphine ligand dictates whether the reaction yields chiral 2-acylazetidines or achiral 3-acylazetidines. Electron-rich Josiphos ligands promote selective formation of 2-acylazetidines with high enantioselectivity, while biaryl bisphosphines such as dppe favor the formation of the 3-acylazetidine isomer. This study pioneers the use of enecarbamates as viable coupling partners in hydroacylation, expanding the scope of strained heterocyclic functionalization. Mechanistic analysis using distortion–interaction models reveals that regiodivergence arises from distinct transition-state stabilization modes: dppe ligands allow regioselectivity to follow substrate electronics, while bulkier Josiphos ligands enforce steric and non-covalent interactions that override inherent reactivity.