Selective Access to All Four Diastereomers of a 1,3‐Amino Alcohol by Combination of a Keto Reductase‐ and an Amine Transaminase‐Catalysed Reaction

Abstract

AbstractThe biocatalytic synthesis of chiral amines has become a valuable addition to the chemists’ toolbox. However, the efficient asymmetric synthesis of functionalised amines bearing more than one stereocentre, such as 1,3‐amino alcohols, remains challenging. By employing a keto reductase (KRED) and two enantiocomplementary amine transaminases (ATA), we developed a biocatalytic route towards all four diastereomers of 4‐amino‐1‐phenylpentane‐2‐ol as a representative molecule bearing the 1,3‐amino alcohol functionality. Starting from a racemic hydroxy ketone, a kinetic resolution using an (S)‐selective KRED provided optically active hydroxy ketone (86% ee) and the corresponding diketone. Further transamination of the hydroxy ketone was performed by either an (R)‐ or an (S)‐selective ATA, yielding the (2R,4R)‐ and (2R,4S)‐1,3‐amino alcohol diastereomers. The remaining two diastereomers were accessible in two subsequent asymmetric steps: the diketone was reduced regio‐ and enantioselectively by the same KRED, which yielded the (S)‐configured hydroxy ketone. Eventually, the subsequent transamination of the crude product with (R)‐ and (S)‐selective ATAs yielded the remaining (2S,4R)‐ and (2S,4S)‐diastereomers, respectively.magnified image