(S)-N-Boc-3-hydroxypiperidine ((S)-NBHP) is an important chiral intermediate for the synthesis of ibrutinib, an anticancer drug targeting B-cell malignancies. An NADPH-dependent reductase (YDR541C) from Saccharomyces cerevisiae was isolated and found to show excellent catalytic activity in the production of (S)-NBHP. The reductase YDR541C was cloned and overexpressed in Escherichia coil BL21 (DE3), purified to homogeneity, and its catalytic properties were studied. Furthermore, an ethyl caprylate-water (1:1, v/v) biphasic system was introduced to alleviate product inhibition. After optimization of the reaction, as much as 1200 mM N-Boc-piperidin-3-one (NBPO) (240 g/L) was asymmetrically reduced to (S)-NBHP within 6 h, resulting in a yield of 99%, an enantioselectivity of >99.5% ee, and a total turnover number (TTN) of 8000. These results indicate great potential for industrial application. (C) 2017 Elsevier Ltd. All rights reserved.
[1]East China Univ Sci & Technol, New World Inst Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China.
[2]Shanghai Univ Med & Hlth Sci, Sch Pharm, Shanghai 201318, Peoples R China.
(8.0+极速模式)