General Access to Chiral Piperidines via Enantioselective Catalytic C(sp3)-H Oxidation using Manganese Catalysts

Chiral piperidines are among the most prevalent amine scaffold in pharmaceuticals and natural products. Herein, we describe a catalytic method for the enantioselective synthesis of chiral piperidines via direct site-selective α-C(sp3)-H bond oxidation using hydrogen peroxide and an evolved manganese catalyst in trifluoroethanol media. The reaction enables the desymmetrization of piperidines, yielding chemically versatile chiral N,O-acetal products in good yields (up to 86%) with excellent enantioselectivity (up to 98% ee), and diastereoselectivity. The reaction is characterized by broad functional group compatibility, fast reaction times, and mild reaction conditions. Taking advantage of the versatility of the chiral N,O-acetal products, a range of substituted piperidines become readily available through various stereoretentive transformations. Mechanistic studies revealed that the reaction entails a highly enantioselective hydrogen atom transfer followed by electron transfer, generating an iminium cation that is subsequently trapped by a trifluoroethanol solvent molecule. Mechanistically informative statistical models provide valuable understanding that are guiding future reaction development.