Industrial production of chiral intermediate of cilastatin by nitrile hydratase and amidase catalyzed one-pot, two-step biotransformation
2014
Zheng, Ren-Chao | Yang, Zhong-Yi | Li, Cong-Cheng | Zheng, Yu-Guo | Shen, Yin-Chu
An industrial one-pot, two-step bioprocess catalyzed by nitrile hydratase (NHase) and amidase was developed for (S)-2,2-dimethylcyclopropanecarboxamide (1), the key chiral intermediate of cilastatin. The key unit operations of the whole process including fermentative production of enzymes, biotransformation, isolation of product, and recycling of by-product were reported for the first time. The volumetric enzyme activities of NHase and amidase in 1000-L fermentor were enhanced to 351,000 and 5880U/L, respectively. The two-step, one-pot biotransformation of rac-2,2-dimethylcyclopropanecarbonitrile (2) took full advantage of both enzymes, leading to accumulation of (S)-1 in 47% yield and 99.6% ee. (S)-1 and the by-product (R)-2,2-dimethylcyclopropanecarboxylic acid (3) were obtained with yields of 38% and 45%, respectively, by a novel macroporous resin adsorption chromatography. Moreover, the total yield of (S)-1 was further increased to 53% after one recycling of (R)-3. The new bioprocess dramatically improved process efficiency compared with the chemical route by elimination of six synthetic steps and proved to be a superior and more cost-effective approach towards (S)-1.
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