Manganese-Catalyzed Asymmetric Hydrogenation of α-Substituted Tetralones via Dynamic Kinetic Resolution.

Abstract

Developing earth-abundant metal catalysts as alternatives to precious metals is highly appealing for asymmetric hydrogenation. However, low enantioselectivity and activity remain critical challenges. Herein, we disclose an efficient manganese-catalyzed asymmetric hydrogenation of α-substituted tetralones via dynamic kinetic resolution. A wide range of chiral tetrahydronaphthols containing two contiguous stereogenic centers were obtained in high yields and stereoselectivities (up to 99% yield, 99% ee, and >20:1 dr). The practicality of this protocol was demonstrated by a gram-scale synthesis of the key intermediate of (+)-elacestrant, a therapeutic agent for metastatic breast cancer, at a catalyst loading of 0.0038 mol %, with a TON (26 000) that was significantly higher than that achieved with the precious-metal catalysts for this hydrogenation.