Biocatalytic Asymmetric Reduction of a Sterically Hindered ?-Bromo Ketone for the Synthesis of Key Intermediates of Olodaterol

作者：Feng, Yahui; Wu, Shuming; Lu, Songquan; Pang, Xiaolei; Xia, Ke; He, Fang; Zhang, Qin; Yang, Hu; Wang, Zhongqing^*; Zhou, Zihong; Lin, Wei

来源：ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2023, 27(4): 640-648.

DOI：10.1021/acs.oprd.2c00371

• biocatalytic reduction
• KRED
• enzyme
• ?-bromo ketone
• olodaterol

An efficient and selective biocatalytic process was developed for the reduction of highly bulky and hydrophobic alpha- 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 alpha-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.

• 单位
  浙江大学