Synthesis of Chiral Saturated Heterocycles Bearing Quaternary Centers via Enantioselective β-C(sp3)-H Activation of Lactams

J Am Chem Soc. 2025 Jan 15;147(2):1427-1433. doi: 10.1021/jacs.4c15834. Epub 2024 Dec 31.

Abstract

The development of catalytic methods for the synthesis of enantiopure saturated heterocycles has been a long-standing challenge in asymmetric catalysis. We describe the first highly enantioselective palladium-catalyzed β-C(sp3)-H arylation and olefination of lactams for the preparation of various chiral N-heterocycles bearing quaternary carbon centers. The presence of strongly electron-withdrawing groups on the chiral bifunctional MPAThio ligand is crucial to the reactivity of weakly coordinating lactams. The resulting enantioenriched lactams are readily converted to a family of chiral piperidines and imides that are highly desirable in drug discovery.