Enantioselective synthesis of a chiral intermediate of himbacine analogs by Burkholderia cepacia lipase A
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ORIGINAL RESEARCH PAPER
Enantioselective synthesis of a chiral intermediate of himbacine analogs by Burkholderia cepacia lipase A Yanming Chen . Fei Gao . Guojun Zheng . Shuaihua Gao
Received: 15 January 2020 / Accepted: 13 July 2020 Ó Springer Nature B.V. 2020
Abstract The enantiomers of (4R/S)-4-hydroxy-N, N-diphenyl-2-pentynamide are key chiral synthons for the synthesis of thrombin receptor antagonists such as vorapaxar. In this paper, we report the enzymatic preparation of enantiomerically enriched (4R)-4-hydroxy-N, N-diphenyl-2-pentynamide using lipase A from Burkholderia cepacia ATCC 25416 as the catalyst. First, the lipase gene (lipA) and its chaperone gene (lipB) was cloned and expressed in Escherichia coli system. After purification, lipase A activation was performed with the assistance of foldase lipase B. Enzyme assay revealed that the activated lipase A showed the optimal catalytic activity at 60 8C and pH 7. The effects of various metals on the activity were Authors Yanming Chen and Fei Gao have contributed equally to this work. Y. Chen Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, People’s Republic of China Y. Chen F. Gao G. Zheng S. Gao State Key Laboratory of Chemical Resources Engineering, Beijing University of Chemical Technology, Beijing 100029, People’s Republic of China S. Gao (&) Department of Chemistry, and California Institute for Quantitative Biosciences, University of California, Berkeley 94720, USA e-mail: [email protected]
investigated and results demonstrated that most of the metals inhibited the activity. To further improve the catalytic outcome, two-phase reaction was studied, and n-hexane proved to be a good organic solvent for the combination system. Using the optimize conditions, (4R)-4-hydroxy-N, N-diphenyl-2-pentynamide with 94.5% ee value and 48.93% conversion ratio was achieved. Our investigation on this lipase reveals lipase A as a promising biocatalyst for producing chiral propargyl alcohol for preparation of novel himbacine analogs. Keywords Enantioselective hydrolysis Klebsiella oxytoca Lamivudine Oxathiolane Stereoselectivity
Introduction Vorapaxar (brand name Zontivity, formerly known as SCH 530348) is a thrombin receptor antagonist which was developed by Merck & Co based on the natural product himbacine to reduce the rate of combined endpoint cardiovascular death, stroke, and urgent coronary revascularization (Bailey and Campbell 2011; Chackalamannil 2006; Olivier et al. 2013; Tello-Montoliu et al. 2011). It is the first proteaseactivated receptor (PAR-1) inhibitor approved by the U.S. Food and Drug Administration (FDA) in 2014 (Chelliah et al. 2014). Vorapaxar can potently inhibit
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thrombin-induced platelet aggregation via a selective antagonism of the PAR-1, thus serving as a potent antiplatelet agent (Faraji et al. 2020; Goto and Goto 201
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