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Total syntheses of Tetrodotoxin and 9-epiTetrodotoxin

Author

Listed:
  • Peihao Chen

    (Peking University
    National Institute of Biological Sciences)

  • Jing Wang

    (National Institute of Biological Sciences
    Tsinghua University
    Tsinghua University)

  • Shuangfeng Zhang

    (National Institute of Biological Sciences)

  • Yan Wang

    (National Institute of Biological Sciences
    Tsinghua University
    Tsinghua University)

  • Yuze Sun

    (National Institute of Biological Sciences)

  • Songlin Bai

    (National Institute of Biological Sciences
    Tsinghua University
    Tsinghua University)

  • Qingcui Wu

    (National Institute of Biological Sciences)

  • Xinyu Cheng

    (National Institute of Biological Sciences
    Chinese Academy of Medical Sciences&Peking Union Medical College)

  • Peng Cao

    (National Institute of Biological Sciences
    Tsinghua University)

  • Xiangbing Qi

    (National Institute of Biological Sciences
    Tsinghua University)

Abstract

Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects. Here, we present a scalable asymmetric syntheses of Tetrodotoxin and 9-epiTetrodotoxin from the abundant chemical feedstock furfuryl alcohol. The optically pure cyclohexane skeleton is assembled via a stereoselective Diels-Alder reaction. The dense heteroatom substituents are established sequentially by a series of functional group interconversions on highly oxygenated cyclohexane frameworks, including a chemoselective cyclic anhydride opening, and a decarboxylative hydroxylation. An innovative SmI2-mediated concurrent fragmentation, an oxo-bridge ring opening and ester reduction followed by an Upjohn dihydroxylation deliver the highly oxidized skeleton. Ruthenium-catalyzed oxidative alkyne cleavage and formation of the hemiaminal and orthoester under acidic conditions enable the rapid assembly of Tetrodotoxin, anhydro-Tetrodotoxin, 9-epiTetrodotoxin, and 9-epi lactone-Tetrodotoxin.

Suggested Citation

  • Peihao Chen & Jing Wang & Shuangfeng Zhang & Yan Wang & Yuze Sun & Songlin Bai & Qingcui Wu & Xinyu Cheng & Peng Cao & Xiangbing Qi, 2024. "Total syntheses of Tetrodotoxin and 9-epiTetrodotoxin," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45037-0
    DOI: 10.1038/s41467-024-45037-0
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    References listed on IDEAS

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    1. Tie–Gen Chen & Lisa M. Barton & Yutong Lin & Jet Tsien & David Kossler & Iñaki Bastida & Shota Asai & Cheng Bi & Jason S. Chen & Mingde Shan & Hui Fang & Francis G. Fang & Hyeong-wook Choi & Lynn Hawk, 2018. "Building C(sp3)-rich complexity by combining cycloaddition and C–C cross-coupling reactions," Nature, Nature, vol. 560(7718), pages 350-354, August.
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