Duloxetine is a new-generation blockbuster antidepressant drug with annual sales of approx. $3.5 billion. It is a dual inhibitor of serotonin and norepinephrine reuptake and is used for systemic therapy that affects the body as a whole. In addition to its function in treatment of depressive disorders, duloxetine has been approved by the Food and Drug Administration to treat anxiety, diabetes-related pain, fibromyalgia and chronic musculoskeletal pain, including lower back pain and osteoarthritis.

The drug contains one stereocenter and only the (S)-enantiomer is pharmaceutically active. Retrosynthetic strategy revealed several chiral alcohol precursors that could act as the key intermediate for (S)-duloxetine. However, the typical enantiomericn excess (ee) achieved through these methods is merely ~90% ee, and this hampers their industrial application and additionally carries the risk of metal contamination. Another attractive approach is bioreduction which has made substantial contributions to industrial manufacturing of chiral pharmaceutical intermediates over the years. However, this system only tolerated the substrate at 1 g/l which significantly restricts its applications.

Prof. WU Zhongliu and coworkers from Chengdu Institute of Biology, Chinese Academy of Sciences, reported for the first time the whole-cell catalyzed bioreduction of N-methyl-3-oxo-3-(thiophen-2-yl)propanamide(MOTPA) to (S)-N-methyl-3-hydroxy-3-(2-thienyl) propionamide (MHTPA), which could be converted into N-methyl-3-hydroxy-(2-thienyl)-1-propanamine (MHTP), the immediate precursor of duloxetine, in a single step.The system was sufficiently robust and could tolerate the substrate at 30 g/l (164 mM) with excellent enantioselectivity (single enantiomer, >99.5% ee) and 95% conversion.

WU’s research entitled “Highly enantioselective bioreduction of N-methyl-3-oxo-3-(thiophen-2-yl) propanamide for the production of (S)-duloxetine” has been published in Biotechnol Lett (2011) 33:1435–1440 . This work was supported by the 100 Talents Program, the West Light Foundation, and the Knowledge Innovation Program (KSCX2-YW-G-075) of the Chinese Academy of Sciences, and National Natural Science Foundation of China (20802073 & 21072183).