Chiral pyrrolidines via an enantioselective Hofmann-Löffler-Freytag reaction

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 regio- selective 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.