Enantioselective Synthesis of Chiral 1,4-Dihydroquinolines via Iridium-Catalyzed Asymmetric Partial Hydrogenation of Quinolines

Abstract

Chiral 1,4-dihydroquinolines are frequently found in natural products and pharmaceuticals, yet a generally useful route for their synthesis remains elusive. Here, we present an asymmetric partial hydrogenation strategy to access enantioenriched 1,4-dihydroquinolines from quinolines. Our strategy involves incorporating an ester group at position 3 of the quinoline ring, thereby enhancing the electronic deficiency and polarity of the C3–C4 double bond. Employing a chiral Ir-SpiroPAP catalyst facilitated the hydrogenation of a wide variety of 4-substituted 3-ethoxycarbonylquinolines, yielding chiral 1,4-dihydroquinolines in high yields (up to 95%) with exceptional enantioselectivity and efficiency (up to 99% ee and 1840 TONs). Noteworthy for its scalability and practicality, the method provides a robust avenue for the synthesis of valuable compounds such as 9-aryl aza-podophyllotoxins and melatonin MT₂ receptor modulators. Density functional theory calculations were performed to gain insights into the reaction mechanism and the origins of the enantioselectivity.