Efficient bioreductive production of (S)-N-Boc-3-hydroxypiperidine using ketoreductase ChKRED03. Issue 7 (July 2016)

• Record Type: Journal Article
• Authors: Xu, Guang-Peng; Wang, Hai-Bo; Wu, Zhong-Liu
• Is Part Of: Process biochemistry. Volume 51:Issue 7(2016:Jul.)
• Page Start: 881
• Page End: 885
• Publication Date: 2016-07
• Subjects: (S)-N-Boc-3-hydroxypiperidine (PubChem CID: 1514399) -- N-Boc-piperidin-3-one (PubChem CID: 2756825); Carbonyl reductase -- Ketoreductase -- Asymmetric reduction -- Ibrutinib -- Chiral alcohol -- Biocatalysis; Biochemical engineering -- Periodicals; Biotechnology -- Periodicals; Biochemistry -- periodicals; Biotechnology -- periodicals; Chemical Engineering -- periodicals; Génie biochimique -- Périodiques; Biotechnologie -- Périodiques; Biochemical engineering; Biotechnology; Periodicals; 660.63
• DOI: 10.1016/j.procbio.2016.04.008
• Languages: English
• ISSNs: 1359-5113

Abstract

Graphical abstract: Highlights: Bioreduction of NBPO afforded the chiral intermediate of ibrutinib, ( S )-NBHP. The reaction was catalyzed with Ch KRED03 with excellent stereoselectivity. Using 3 g/L crude enzyme, 200 g/L substrate was completely reduced in 3 h. Abstract: Ibrutinib is an anticancer drug targeting B-cell malignancies. The key chiral intermediate for ibrutinib synthesis is the alcohol ( S )- N -Boc-3-hydroxypiperidine (( S )-NBHP), which can be produced via ketoreductase (KRED)-catalyzed bioreduction. After screening a small inventory of 27 KREDs mined from the genome of Chryseobacterium sp. CA49, Ch KRED03 was selected as the best performer, leading to the complete conversion of 100 g substrate/L within 10 h to yield ( S )-NBHP with high enantiomeric excess ( > 99% ee). The enzyme was NADPH dependent, and the highest enzymatic activity was observed at 30 °C in potassium phosphate buffer (pH 7.0). At a substrate/catalyst ratio of 66.7 (w/w), Ch KRED03 catalyzed the complete conversion of 200 g/L substrate within 3 h to yield ( S )-NBHP with >99% ee, demonstrating great potential for industrial application.