Rh-Catalyzed Sequential Asymmetric Hydrogenations of 3-Amino-4-Chromones Via an Unusual Dynamic Kinetic Resolution Process

Rh-catalyzed sequential asymmetric hydrogenations of 3-amino-4-chromones have been achieved for the first time via an unprecedented dynamic kinetic resolution under neutral conditions, providing (S,R)-3-amino-4-chromanols in high yields (up to 98%) with excellent enantio- and diastereoselectivities (up to 99.9% ee and 20:1 dr). The mechanistic studies based on control experiments and density functional theory (DFT) calculations suggest that the dynamic kinetic resolution process for the intermediate enantiomers generated in the first hydrogenation step proceeded via a stereomutation (or called chiral assimilation) pathway from an undesired enantiomer to the desired enantiomer rather than via traditional racemization of the undesired enantiomer. The protocol can be performed on a gram scale with a relatively low catalyst loading and offers a practical and convenient pathway for synthesizing a series of bioactive chromanols and their derivatives.

Automated summary

Sequential asymmetric hydrogenation of 3-amino-4-chromones using Rh catalyst has been achieved for the first time. The process involves an unprecedented dynamic kinetic resolution under neutral conditions, resulting in high yields of (S,R)-3-amino-4-chromanols with excellent enantio- and diastereoselectivities. Mechanistic studies suggest that the process proceeds via stereomutation pathway rather than traditional racemization.