High Regio‐ and Stereoselective Multi‐enzymatic Synthesis of All Phenylpropanolamine Stereoisomers from β‐Methylstyrene

We present a one‐pot cascade for the synthesis of phenylpropanolamines (PPAs) in high optical purities (er and dr up to >99.5 %) and analytical yields (up to 95 %) by using 1‐phenylpropane‐1,2‐diols as key intermediates. This bioamination entails the combination of an alcohol dehydrogenase (ADH), an ω‐transaminase (ωTA) and an alanine dehydrogenase to create a redox‐neutral network, which harnesses the exquisite and complementary regio‐ and stereo‐selectivities of the selected ADHs and ωTAs. The requisite 1‐phenylpropane‐1,2‐diol intermediates were obtained from trans‐ or cis‐β‐methylstyrene by combining a styrene monooxygenase with epoxide hydrolases. Furthermore, in selected cases, the envisioned cascade enabled to obtain the structural isomer (1S,2R)‐1‐amino‐1‐phenylpropan‐2‐ol in high optical purity (er and dr >99.5 %). This is the first report on an enzymatic method that enables to obtain all of the four possible PPA stereoisomers in great enantio‐ and diastereo‐selectivity.