Application of Biocatalytic Reductive Amination for the Synthesis of a Key Intermediate to a CDK 2/4/6 Inhibitor
Shengquan Duan, Daniel W. Widlicka, Michael P. Burns, Rajesh Kumar, Ian Hotham, Jean‐Nicolas Desrosiers, Paul Bowles, Kris Jones, Lindsay D. Nicholson, Michele T. Buetti-Weekly, Lu Han, Jeremy Steflik, Eric C. Hansen, Cheryl M. Hayward, Holly Strohmeyer, Sébastien Monfette, Scott C. Sutton, Christopher G. Morris
Abstract
Biocatalytic reductive amination catalyzed by engineered imine reductase (RedAms) is a new and powerful tool for the synthesis of substituted chiral amines. Herein, we describe a streamlined synthesis of compound 3, a key intermediate to a CDK 2/4/6 inhibitor 1, relying on the enzymatic reductive amination of a hydroxyketone to introduce the chiral secondary amine with high diastereoselectivity. The improved synthesis of the hydroxyketone precursor by a titanium-catalyzed reductive cyclization and the process development for two SNAr reactions en route to 3 are also presented.