Dynamic Kinetic Resolution-Based Asymmetric Transfer Hydrogenation of Racemic 2-Substituted Quinolines

Abstract

The synthesis of chiral tetrahydroquinolines (THQs) has garnered significant interest from medicinal chemists due to their frequent presence as pharmacophores in bioactive compounds. While existing synthetic methods have primarily focused on THQs with single or multiple endocyclic chiral centers, the selective construction of THQs with both endo- and exo-cyclic chiral centers remains a significant challenge that requires further development. This study introduces a dynamic kinetic resolution (DKR)-based transfer hydrogenation of racemic 2-substituted quinolines, which yields structurally novel chiral THQs with consecutive endo- and exo-cyclic chiral centers in excellent yields and stereoselectivities (59 examples, with generally >20:1 dr and >90% ee, up to three consecutive stereocenters). Our approach offers a mechanistically novel method for the asymmetric transformation of electron-deficient aromatic N-heterocycles and presents an innovative way to expand the chiral N-heterocycle chemical space for medicinal chemistry.