Highly Enantioselective Ni(0)-Catalyzed Cascade Reductive Syn-Arylative Cyclization for Five-membered Heterocyclics Bearing Chiral Quaternary Carbon Stereocenters of Tetrasubstituted Allylic Alcohols

Construction of chiral quaternary carbon stereocenters is a significant challenge of asymmetric synthesis. Catalytic synthesis of these structures with trisubstituted allylic alcohols is highly important. However, most of reported methodologies required precious transition-metal catalyst. Herein we reported the first highly enantioselective synthesis of five-membered heterocyclics bearing chiral quaternary carbon stereocenters of tetrasubstituted allylic alcohols by cascade reductive syn-arylative cyclization of hetereo 1,6-alkynones with aryl boronic acids catalyzed by the earth-abundant Nickel catalysis Ni(cod)2 and P-chiral monophosphine ligand (S)-BIDIME applying proton solvent tert-butanol. Various multi-substituted functionalized pyrrolidines and tetrahydrofurans were achieved in high yield (up to 98%), excellent enantioselectivity (>99:1 er) with broad substrate scope. Totally thirty-seven examples were successfully applied for this transformation. The catalytic cycle and the role of proton solvent was proposed, modified and confirmed first time by detailed density functional theory (DFT) calculations, and further clarified the ligand-control for the excellent enantioselectivity initiated by Ni(0) precursor. Ligand effects, gram scale reaction and control experiments were carried out. New reaction design was proposed for further application of this methodology. This developed methodology and mechanism study is anticipated to find wider applications in organic synthesis and chemical biology.