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Photoenzymatic enantioselective synthesis of fluorinated amides with remote stereocenter

Author

Listed:
  • Chaoqun Huang

    (Tianjin University
    Tianjin University
    Tianjin University)

  • Xuerui Jin

    (Tianjin University
    Tianjin University
    Tianjin University)

  • Zhenyu Liu

    (Tianjin University
    Tianjin University
    Tianjin University)

  • Can Cui

    (Tianjin University
    Tianjin University
    Tianjin University)

  • Yang Zhang

    (Sichuan University)

  • Binju Wang

    (Xiamen University)

  • Chun Zhang

    (Tianjin University)

  • Jianqiang Feng

    (Fuzhou University)

  • Dawen Niu

    (Sichuan University)

  • Yunzi Luo

    (Tianjin University
    Tianjin University
    Tianjin University
    Tianjin University)

Abstract

Fluorinated compounds are scarce in nature, albeit they are in high demand in pharmaceuticals, agrochemicals, and materials. Fluorinated amides serve as prevalent structural motifs in pharmaceuticals and bioactive molecules. However, enantioselective synthesis of fluorinated amides remains challenging. Herein, we develop a visible-light-driven ene-reductase system that effectively generates carbon-centered radicals from fluorine-containing brominated amides. The system further enables their enantioselective hydroalkylation with alkenes, achieving high stereocontrol. Diversified α-fluorinated amides with high yield (up to 91%) and distal chirality (γ-to F, up to 97% enantiomeric excess) are produced by optimizing the reaction system and performing enzyme engineering. This work advances photoenzymatic strategies for the integration of fluorinated chemical inputs and creates an opportunity for the asymmetric synthesis of valuable fluorinated compounds.

Suggested Citation

  • Chaoqun Huang & Xuerui Jin & Zhenyu Liu & Can Cui & Yang Zhang & Binju Wang & Chun Zhang & Jianqiang Feng & Dawen Niu & Yunzi Luo, 2025. "Photoenzymatic enantioselective synthesis of fluorinated amides with remote stereocenter," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60807-0
    DOI: 10.1038/s41467-025-60807-0
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    References listed on IDEAS

    as
    1. Haigen Fu & Jingzhe Cao & Tianzhang Qiao & Yuyin Qi & Simon J. Charnock & Samuel Garfinkle & Todd K. Hyster, 2022. "An asymmetric sp3–sp3 cross-electrophile coupling using ‘ene’-reductases," Nature, Nature, vol. 610(7931), pages 302-307, October.
    2. Xiaoqiang Huang & Binju Wang & Yajie Wang & Guangde Jiang & Jianqiang Feng & Huimin Zhao, 2020. "Photoenzymatic enantioselective intermolecular radical hydroalkylation," Nature, Nature, vol. 584(7819), pages 69-74, August.
    3. Tian-Ci Wang & Binh Khanh Mai & Zheng Zhang & Zhiyu Bo & Jiedong Li & Peng Liu & Yang Yang, 2024. "Stereoselective amino acid synthesis by photobiocatalytic oxidative coupling," Nature, Nature, vol. 629(8010), pages 98-104, May.
    4. Yuanyuan Xu & Hongwei Chen & Lu Yu & Xichao Peng & Jiawei Zhang & Zhongqiu Xing & Yuyan Bao & Aokun Liu & Yue Zhao & Changlin Tian & Yong Liang & Xiaoqiang Huang, 2024. "A light-driven enzymatic enantioselective radical acylation," Nature, Nature, vol. 625(7993), pages 74-78, January.
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