Chiral pyrrolidines via an enantioselective Hofmann-Löffler-Freytag reaction

Abstract

Radical C–H aminations enable rapid access to the most common heterocycles in medicines (e.g., pyrrolidines), yet stereocontrol of these powerful transformations remains a challenge. Here, we report the discovery of the first enantio- and regioselective C–H imination, which readily converts ketones to enantioenriched pyrrolidines. This enantioselective Hofmann-Löffler-Freytag reaction mechanism entails iminyl radical generation from an oxime by a chiral Cu catalyst that facilitates 1,5-H-atom transfer (HAT) to form a remote C-radical regioselectively. The selective capture of this alkyl radical as an organocopper(III) complex then mediates highly stereoselective reductive elimination to unprotected pyrrolines. The broad steric and electronic scope of this remote C–H amination has been probed systematically, along with key mechanistic aspects of enantiodetermination, radical intermediacy, and atypical Cu(III) ligands that enable this uniquely selective C–N coupling. Importantly, either (1) reductions or (2) nucleophilic additions to these enantioenriched pyrrolines provide the most rapid syntheses of chiral pyrrolidines to date.