Direct Access to Chiral Piperidines by Enantioselective HAT‐Initiated C( sp 3 )─H Oxidation

ABSTRACT Enantioselective C( sp 3 )─H functionalization reactions are appealing synthetic organic chemistry tools to streamline access to valuable chiral molecules from simple precursors. Chiral piperidines are ubiquitous motifs in pharmaceuticals and natural products, yet methods for their preparation from simple non‐chiral precursors remain limited. We report a catalytic strategy for the preparation of chiral piperidines by α‐C( sp 3 )─H oxidation of achiral piperidines using hydrogen peroxide as oxidant and an evolved manganese catalyst in 2,2,2‐trifluoroethanol. Piperidines are desymmetrized to afford chemically versatile chiral N,O ‐acetal products in good yields, with high enantio‐ and diastereoselectivity. The resulting products serve as key intermediates to access a diverse range of functionalized piperidines while retaining chirality. Mechanistic studies indicate that the reaction proceeds via a highly enantioselective hydrogen atom transfer (HAT) followed by an electron transfer to generate a chiral iminium cation that is rapidly hydroxylated. Statistical models correlating reaction performance to molecular features provide a mechanistic basis for the stereoselective dictating elements and offer a tool for future reaction development.