Ruthenium-Catalyzed Dynamic Kinetic Resolution Asymmetric Transfer Hydrogenation of β-Chromanones by an Elimination-Induced Racemization Mechanism

Abstract

Chiral chroman derivatives are important pharmacophores in natural and synthetic bioactive molecules. The discovery of catalytic asymmetric methods for the synthesis of these compounds is an important goal. Ruthenium-catalyzed asymmetric transfer hydrogenation under strongly basic conditions has been found to induce dynamic kinetic resolution of β-substituted chromanones, producing valuable chromanols in high yields and with high levels of stereocontrol. The reaction proceeds by base-catalyzed racemization of the β-stereocenter through a conjugate elimination/conjugate addition pathway in concert with a highly selective ketone transfer hydrogenation step. Computational analysis of the catalyst, substrate, and transition state structures has revealed the driving interactions for diastereoselectivity as well as unexpected CH–O stabilizing interactions between the catalyst sulfonamide and the reacting substrate.