Scalable Enantioselective Oxidation of Aliphatic N-heterocycles via Catalytic Hydride Abstraction

Enantioselective C-H functionalization remains a highly desired yet challenging goal in organic synthesis. A prevailing strategy involves nonselective C-H cleavage followed by enantioselective functionalization of the resultant prochiral intermediate. A complementary but substantially less explored approach is direct asymmetric C-H activation (e.g., desymmetrization or kinetic resolution), which can generate multiple stereocenters and enable access to complex stereochemical arrays. Here, we report the enantioselective oxidation of N-protected cyclic amines to chiral lactams via asymmetric hydride abstraction by novel oxoammonium catalysts. This process employs a readily prepared amine catalyst precursor and is operationally simple, air-and water-tolerant, and highly selective across a broad substrate scope. This method streamlines the synthesis of key intermediates for bioactive molecules on preparative scale (up to 22 g lab scale and 10 kg plant scale) and provides rapid access to structural analogs of these medicinal agents. Mechanistic studies reveal hydride abstraction to be enantiodetermining and uncover stereoelectronic factors that underpin the observed high enantioselectivity.