Kinetic Resolution of Inherently Chiral Eight-Membered Azacycles via Chiral Phosphoric Acid-Catalyzed Asymmetric Transfer Hydrogenation of the Pending Alkenes

Conformationally inflexible medium-sized azacycles may be stable chiral molecules even when lacking conventional chiral elements, offering significant potential applications in chiral recognition and asymmetric synthesis. Herein, an efficient kinetic resolution of inherently chiral 10-vinyltribenzo[ b,d,f ]azocines through chiral phosphoric-acid-catalyzed (CPA) asymmetric transfer hydrogenation of the pending alkenyl moiety has been developed. Although the chirality in the hydrogenated products, 10-alkyltribenzo[ b,d,f ]azocines, is acid-labile, the recovered enantioenriched 10-vinyltribenzo[ b,d,f ]azocines are optically stable under both acidic and thermal conditions. This approach features mild reaction conditions, good functional group tolerance, good yields, and high enantioselectivity (up to 99% ee). Density functional theory (DFT) calculations reveal the reason for optical lability of the hydrogenated products in acid.