Enantio- and Diastereoselective Synthesis of Chiral Syn-Aryl β-Hydroxy α-Amino Esters via Biocatalytic Dynamic Reductive Kinetic Resolution

Development of an efficient, stereoselective, sustainable synthesis of chiral aryl beta-hydroxy alpha-amino acids and their derivatives is of paramount importance, owing to the broad utility of these molecules in pharmaceutical application and asymmetric synthesis. We report a systematic study on ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) of aryl alpha-amino beta-keto esters 6, furnishing 20 structurally diverse chiral syn-aryl beta-hydroxy alpha-amino esters (syn-(2S,3R)-7) in moderate-to-excellent isolated yield (up to 93%), along with moderate-to-excellent diastereoselectivity (up to >99 : 1 dr) and excellent enantioselectivity (mostly >99% ee). The practical synthesis potential of our developed method was showcased by the asymmetric, chemo-enzymatic total synthesis of thiamphenicol (1).

Automated summary

The study introduces an efficient, stereoselective method for synthesizing chiral aryl beta-hydroxy alpha-amino acids and their derivatives. The method, based on ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) of aryl alpha-amino beta-keto esters, shows promising results in terms of yield, diastereoselectivity, and enantioselectivity, demonstrating potential for practical synthesis applications such as the chemo-enzymatic total synthesis of thiamphenicol.