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Water-Compatible Staudinger–Diels–Alder Ligation
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    Water-Compatible Staudinger–Diels–Alder Ligation
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    • Masaru Tanioka*
      Masaru Tanioka
      Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
      *Email: [email protected]
    • Shohei Kanayama
      Shohei Kanayama
      Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
    • Fumino Kitamura
      Fumino Kitamura
      Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
    • Akinari Takano
      Akinari Takano
      Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
    • Yukiko Ikeda
      Yukiko Ikeda
      Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
      More by Yukiko Ikeda
    • Aki Kohyama
      Aki Kohyama
      Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
      More by Aki Kohyama
    • Tsuyoshi Yamada
      Tsuyoshi Yamada
      Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
    • Yuji Matsuya*
      Yuji Matsuya
      Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
      *Email: [email protected]
      More by Yuji Matsuya
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    The Journal of Organic Chemistry

    Cite this: J. Org. Chem. 2025, 90, 4, 1501–1506
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    https://doi.org/10.1021/acs.joc.4c02306
    Published January 12, 2025
    Copyright © 2025 American Chemical Society

    Abstract

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    The development of bioorthogonal reactions is expected to propel further advances in chemical biology. In this study, we demonstrate Staudinger–Diels–Alder (SDA) ligation as a candidate for a new bioorthogonal reaction. This reaction ligates two molecules via strong C–C bonds at room temperature. We found that the aryl substituent of azide-benzocyclobutene (azide-BCB) had a strong influence on the molecule’s tolerance to water. In particular, Cl-substituted azide-BCBs generated the ligated product in high yield, even in the presence of water. Mechanistic investigations using DFT methods revealed that hydrophobic electron-withdrawing substituents suppressed the side reactions of SDA ligation.

    Copyright © 2025 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/acs.joc.4c02306.

    • Experimental procedures, spectroscopic data, and NMR spectra for all compounds, and theoretical calculation (PDF)

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    The Journal of Organic Chemistry

    Cite this: J. Org. Chem. 2025, 90, 4, 1501–1506
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.joc.4c02306
    Published January 12, 2025
    Copyright © 2025 American Chemical Society

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