Enantioselective β-C(sp3)–H Nucleophilic Tosylation of Native Amides: A Synthetic Platform for Chiral Methyl Stereocenters

Enantioselective oxygenation of unactivated C(sp3)-H bonds via asymmetric metalation remains an unsolved challenge. Herein we report the development of a Pd-catalyzed, enantioselective C(sp3)-H tosylation of native amides with NaOTs as the nucleophile, representing a rare example of enantioselective C-H functionalization with a nucleophilic coupling partner. High enantioselectivity in this reaction is achieved by chiral monoprotected amino sulfonamide (MPASA) ligands. Substantial enhancement of the enantioselectivity by silver salt additives was also observed. Through desymmetrization of the readily available isopropyl moiety, structurally diverse β-tosylated amides bearing an α-methyl stereocenter were obtained with high yield and enantioselectivity, which complements the current enzymatic method for making Roche ester chiral synthon. The tosylated products are highly versatile chiral building blocks for further diversifications with nitrogen, oxygen, and other nucleophiles, thus providing a platform for constructing chiral methyl stereocenters.