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Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approach

Author

Listed:
  • Yajiao Zhang

    (Fudan University)

  • Minjie Liu

    (Fudan University)

  • Xianjing Zheng

    (Fudan University)

  • Liang Gao

    (Fudan University)

  • Li Wan

    (Fudan University)

  • Dang Cheng

    (Fudan University)

  • Fener Chen

    (Fudan University
    Jiangxi Normal University)

Abstract

Flow chemistry has many advantages over batch synthesis of organic small-molecules in terms of environmental compatibility, safety and synthetic efficiency when scale-up is considered. Herein, we report the 10-step chemo-biocatalytic continuous flow asymmetric synthesis of cyproterone acetate (4) in which 10 transformations are combined into a telescoped flow linear sequence from commercially available 4-androstene-3, 17-dione (11). This integrated one-flow synthesis features an engineered 3-ketosteroid-Δ1-dehydrogenase (ReM2)-catalyzed Δ1-dehydrogenation to form the C1, C2-double bond of A ring, a substrate-controlled Co-catalyzed Mukaiyama hydration of 9 to forge the crucial chiral C17α-OH group of D ring with excellent stereoselectivity, and a rapid flow Corey-Chaykovsky cyclopropanation of 7 to build the cyclopropyl core of A ring. By strategic use of these three key reactions and fully continuous-flow operations, cyproterone acetate (4) is produced in an overall yield of 9.6% in 3 h of total reaction time, this is the highest total number of chemical transformation performance in any other continuous-flow synthesis reported to date.

Suggested Citation

  • Yajiao Zhang & Minjie Liu & Xianjing Zheng & Liang Gao & Li Wan & Dang Cheng & Fener Chen, 2025. "Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approach," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56371-2
    DOI: 10.1038/s41467-025-56371-2
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    References listed on IDEAS

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    1. Sourav Chatterjee & Mara Guidi & Peter H. Seeberger & Kerry Gilmore, 2020. "Automated radial synthesis of organic molecules," Nature, Nature, vol. 579(7799), pages 379-384, March.
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