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Asymmetric Bio-oxidation Using Resting Cells of Rhodococcus rhodochrous ATCC 4276 Mutant QZ-3 for Preparation of (S)-Omeprazole in a Chloroform–Water Biphasic System Using Response Surface Methodology

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Abstract

(S)-Omeprazole is a very effective anti-ulcer medicine that is difficult to be prepared using whole cells at elevated substrate concentrations. In the chloroform–water biphasic system, resting cells of the mutant QZ-3 of Rhodococcus rhodochrous (R. rhodochrous) ATCC 4276 were used to catalyze the bio-oxidation of omeprazole sulfide for preparation of (S)-omeprazole. Using response surface methodology (RSM), the reaction was optimized to work at a substrate concentration of 180 mM and a cell concentration of 100 g/L. The optimal yield of (S)-omeprazole obtained was 92.9% with enantiomeric excess (ee) (> 99%), and no sulfone by-product was detected under the optimal working conditions; reaction temperature 37 °C, pH 7.3 and reaction time, 43 h. A quadratic polynomial model was established, which predicts the experimental data with very high accuracy (R2 = 0.9990). The chloroform–water biphasic system may contribute to the significant improvement in substrate tolerance because almost all substrates are partitioned in the organic phase (water solubility of omeprazole sulfide is only about 0.5 mg/mL), resulting in little damage and inhibition to cells by substrates. The mutant QZ-3 of R. rhodochrous ATCC 4276 exhibited high enantioselectivity, activity and substrate and product tolerance. The aerated flask provides enough oxygen for a high concentration of cells. Accordingly, bio-oxidation is thus more promising for efficient preparation of chiral sulfoxides.

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Acknowledgements

The authors gratefully acknowledge financial support from China Scholarship Council (Grant Number: 201908370079) and Shandong Provincial Key R&D Program [Grant Numbers 2019GSF107027, 2019GNC106028 and 2019GSF107033].

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Authors and Affiliations

  1. State Key Laboratory Base for Eco-Chemical Engineering in College of Chemical Engineering, Qingdao University of Science and Technology, 53 Zhengzhou Road, Mail Box 70, Qingdao, 266042, China

    Yuanyuan Zhang, Kuiying Lv, Yashan Deng, Huiling Li, Zhiyong Wang, Depeng Li, Xin Gao & Fanye Wang

  2. William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, 151 West Woodruff Avenue, Columbus, OH, 43210, USA

    Yuanyuan Zhang & Depeng Li

  3. Kekulé-Institutfür Organische Chemie Und Biochemie der Rheinischen Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Str., 153121, Bonn, Germany

    Huiling Li & Xin Gao

  4. Department of Pharmaceutical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, 53 Zhengzhou Road, Mail Box 70, Qingdao, 266042, China

    Yuanyuan Zhang, Kuiying Lv, Yashan Deng & Zhiyong Wang

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Zhang, Y., Lv, K., Deng, Y. et al. Asymmetric Bio-oxidation Using Resting Cells of Rhodococcus rhodochrous ATCC 4276 Mutant QZ-3 for Preparation of (S)-Omeprazole in a Chloroform–Water Biphasic System Using Response Surface Methodology. Catal Lett 151, 2928–2938 (2021). https://doi.org/10.1007/s10562-021-03531-w

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