文献类型：期刊文献

英文题名：Development of a practical biocatalytic process for (S)-N-Boc-3-hydroxypiperidine synthesis

作者：Chen, Li-Feng[1];Fan, Hai-Yang[1];Zhang, Yi-Ping[1];Wu, Kai[2];Wang, Hua-Lei[1];Lin, Jin-Ping[1];Wei, Dong-Zhi[1]

机构：[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

年份：2017

卷号：58

期号：16

起止页码：1644

外文期刊名：TETRAHEDRON LETTERS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000399258300025)】；

基金：This work was supported by the National Natural Science Foundation of China (Grant No. 21406068/B060804), the Fundamental Research Funds for the Central Universities.

语种：英文

外文关键词：(S)-N-Boc-3-hydroxypiperidine; Carbonyl reductase; Asymmetric reduction; Biphasic system

摘要：(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.