Biocatalytic Asymmetric Reduction of a Sterically Hindered α‑Bromo Ketone for the Synthesis of Key Intermediates of Olodaterol

An efficient and selective biocatalytic process was developed for the reduction of highly bulky and hydrophobic α-bromo ketone 4a using ketoreductase from Lactobacillus kefiri. A fter the initial identification of this selective reductase, reaction conversion was increased from 25.7 to 94.3% and the substrate concentration increased from 5 to 85 g/L via detailed optimization. Through intramolecular epoxidation, the obtained α-bromohydrin 1a was transformed into epoxide 2 as the final product with >99.9% ee, 98.5% HPLC purity, and 90.2% yield over two steps. Eventually, a scale-up demonstration of the telescoped process was successfully performed at a 30 L scale showing excellent reproducibility and consistency, guaranteeing the obtainment of olodaterol with good quality. This biocatalytic process was further demonstrated as environmentally benign by a 50% reduction in process mass intensity (PMI) when compared to the reported (-)-DIP-Cl process.