Pyridoxal-Catalyzed Racemization of α-Aminoketones Enables the Stereodivergent Synthesis of 1,2-Amino Alcohols Using Ketoreductases

Abstract

Differentially substituted 1,2-amino alcohols are a prevalent motif in a variety of pharmaceutical and agrochemical molecules. Dynamic kinetic resolutions (DKRs) that involve the asymmetric reduction of α-amino ketones are attractive for preparing this motif; however, methods for racemizing the stereogenic α-carbon under mild conditions are underdeveloped. Here we report a chemoenzymatic DKR involving ketoreductases (KREDs), in which pyridoxal-5-phosphate (PLP) is used to catalyze racemization of the starting racemic α-aminoketone. This strategy enables access to a variety of 1,2-amino alcohols with high levels of diastereo- and enantioselectivity. Using commercially available KREDs, all four possible stereoisomers can be accessed, highlighting a benefit to this approach.