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Efficient synthesis of (S)-N-Boc-3-hydroxypiperidine using an (R)-specific carbonyl reductase from Candida parapsilosis

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Abstract

(S)-N-Boc-3-hydroxypiperidine (S-NBHP) is a critical chiral intermediate in the synthesis of pharmaceuticals, including ibrutinib, the active pharmaceutical ingredient of the new drug Imbruvica approved for the treatment of lymphoma. An (R)-specific carbonyl reductase from Candida parapsilosis (CprCR, also known as R-specific alcohol dehydrogenase) that catalyzes asymmetric reduction to produce (S)-N-Boc-3-hydroxypiperidine (S-NBHP) was identified for the first time. When co-expressed with a glucose dehydrogenase from Bacillus megaterium in Escherichia coli Rosetta (DE3), recombinant crude enzyme exhibited an activity of 9 U/mg with N-Boc-3-piperidone as the substrate and 12 U/mg with glucose as the substrate. The biocatalysis of N-Boc-3-piperidone to S-NBHP using recombinant whole-cell biocatalysts was processed in a water/butyl acetate system as well as an aqueous monophasic system without extra NAD+/NADH. This process showed great commercial potential, with a 100 g/l substrate concentration and a whole cells loading (w/v) of 10%, with the conversion of 97.8% and an e.e. of 99.8% in an aqueous monophasic system.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, No.30 Puzhu Road, Nanjing, 211816, People’s Republic of China

    Jingjing Chen, Ming Yan & Lin Xu

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  1. Jingjing Chen
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  2. Ming Yan
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  3. Lin Xu
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Correspondence to Ming Yan.

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Chen, J., Yan, M. & Xu, L. Efficient synthesis of (S)-N-Boc-3-hydroxypiperidine using an (R)-specific carbonyl reductase from Candida parapsilosis . World J Microbiol Biotechnol 33, 61 (2017). https://doi.org/10.1007/s11274-016-2189-y

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  • DOI: https://doi.org/10.1007/s11274-016-2189-y

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