Diastereoselective hydride transfer enables a synthesis of chiral 1,5-carboxamido-trifluoromethylcarbinols

Abstract

The deployment of fluorinated functional groups has become a widespread tool in medicinal chemistry due to the impact of fluorine on lipophilicity and metabolic stability. Among these compounds, enantiopure secondary trifluoromethylcarbinols are recurrent features in bioactive compounds. Herein, we present a diastereoselective redox-neutral process allowing the stereospecific synthesis of 1,5-carboxamido-trifluoromethylcarbinols through the formal reduction of a trifluoromethylketone into a trifluoromethylcarbinol. A combined experimental and computational investigation unveiled a network of interconnected equilibria leading to a key hydride transfer event.