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Synthesis of (−)-Cotylenol, a 14-3-3 Molecular Glue Component

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Am. Chem. Soc. 2023, 145, 37, 20634-20645
    Article

    Synthesis of (−)-Cotylenol, a 14-3-3 Molecular Glue Component
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    • Stephen I. Ting
      Stephen I. Ting
      Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
      More by Stephen I. Ting
      Orcidhttps://orcid.org/0000-0002-6146-8112
    • Dylan W. Snelson
      Dylan W. Snelson
      Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
      Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
      More by Dylan W. Snelson
      Orcidhttps://orcid.org/0000-0003-2782-6243
    • Tucker R. Huffman
      Tucker R. Huffman
      Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
      Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
      More by Tucker R. Huffman
      Orcidhttps://orcid.org/0000-0002-6799-3057
    • Akihiro Kuroo
      Akihiro Kuroo
      Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
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    • Ryota Sato
      Ryota Sato
      Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
      More by Ryota Sato
    • Ryan A. Shenvi*
      Ryan A. Shenvi
      Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
      Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
      *Email: [email protected]
      More by Ryan A. Shenvi
      Orcidhttps://orcid.org/0000-0001-8353-6449
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2023, 145, 37, 20634–20645
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    https://doi.org/10.1021/jacs.3c07849
    Published September 8, 2023
    Copyright © 2023 American Chemical Society
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    Abstract

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    Small molecules that modulate the 14-3-3 protein–protein interaction (PPI) network represent valuable therapeutics and tool compounds. However, access has been lost to 14-3-3 PPI molecular glues of the cotylenin class, leading to investigations into the practical chemical syntheses of congeners and analogues. Here we report a concise synthesis of (−)-cotylenol via a 10-step asymmetric entry into a diversifiable 5-8-5 core. This route features a mild Liebeskind–Srogl fragment coupling that tolerates unprecedented steric hindrance to produce a highly congested ketone, and a tandem Claisen-ene cascade that establishes the 8-membered ring. Late-stage control of stereochemistry and functionality leads to (−)-cotylenol and sets the stage for focused library synthesis.

    Copyright © 2023 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c07849.

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    CCDC 2107502, 2127085, and 2163469 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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    Cited By

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    This article is cited by 2 publications.

    1. Bo-Yuan Xie, Zhi-Tao He. Chemodivergent Tandem Hydroalkylation and Hydroalkenoxylation of Conjugated Enynes. ACS Catalysis 2024, 14 (13) , 9742-9751. https://doi.org/10.1021/acscatal.4c02377
    2. Bolin Chen, Yufen Yang, Xijing Zhang, Dongdong Xu, Yuanjun Sun, Yue Chen, Liang Wang. Total Syntheses of Brassicicenes A, R, and T. Organic Letters 2023, 25 (48) , 8570-8574. https://doi.org/10.1021/acs.orglett.3c03355
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2023, 145, 37, 20634–20645
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.3c07849
    Published September 8, 2023
    Copyright © 2023 American Chemical Society
    Request reuse permissions

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