Enoate Reductase-Mediated Preparation of Methyl (S)-2-Bromobutanoate, a Useful Key Intermediate for the Synthesis of Chiral Active Pharmaceutical Ingredients

Enoate reductases belonging to the Old Yellow Enzyme (OYE) family were employed to develop a biocatalysed approach to methyl ( S )-2-bromobutanoate, a key intermediate for the introduction of a particular stereogenic unit into the molecular skeleton of a certain class of chiral drugs. Methyl ( Z )-2-bromocrotonate afforded, respectively, ( S )-2-bromobutanoic acid (ee = 97%) and methyl ( S )-2-bromobutanoate (ee = 97%) by baker’s yeast fermentation and by OYE1–3 biotransformations. The bioreductions of other methyl 2-haloalkenoates were also considered. It was observed that the ( Z )- and ( E )-diastereoisomers of α-bromo unsaturated esters afforded the same enantiomer of the corresponding reduced product.