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C−F bond activation enables synthesis of aryl difluoromethyl bicyclopentanes as benzophenone-type bioisosteres

Author

Listed:
  • Mingshuo Chen

    (University of Chinese Academy of Sciences)

  • Yuang Cui

    (University of Chinese Academy of Sciences)

  • Xiaoping Chen

    (University of Chinese Academy of Sciences)

  • Rui Shang

    (The University of Tokyo)

  • Xiaheng Zhang

    (University of Chinese Academy of Sciences)

Abstract

Bioisosteric design has become an essential approach in the development of drug molecules. Recent advancements in synthetic methodologies have enabled the rapid adoption of this strategy into drug discovery programs. Consequently, conceptionally innovative practices would be appreciated by the medicinal chemistry community. Here we report an expeditous synthetic method for synthesizing aryl difluoromethyl bicyclopentane (ADB) as a bioisostere of the benzophenone core. This approach involves the merger of light-driven C−F bond activation and strain-release chemistry under the catalysis of a newly designed N-anionic-based organic photocatalyst. This defluorinative coupling methodology enables the direct conversion of a wide variety of commercially available trifluoromethylaromatic C−F bonds (more than 70 examples) into the corresponding difluoromethyl bicyclo[1.1.1]pentanes (BCP) arenes/difluoromethyl BCP boronates in a single step. The strategy can also be applied to [3.1.1]and [4.1.1]propellane systems, providing access to analogues with different geometries. Moreover, we have successfully used this protocol to rapidly prepare ADB-substituted analogues of the bioactive molecule Adiporon. Biological testing has shown that the ADB scaffold has the potential to enhance the pharmacological properties of benzophenone-type drug candidates.

Suggested Citation

  • Mingshuo Chen & Yuang Cui & Xiaoping Chen & Rui Shang & Xiaheng Zhang, 2024. "C−F bond activation enables synthesis of aryl difluoromethyl bicyclopentanes as benzophenone-type bioisosteres," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44653-6
    DOI: 10.1038/s41467-023-44653-6
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    References listed on IDEAS

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    1. Xiaheng Zhang & Russell T. Smith & Chip Le & Stefan J. McCarver & Brock T. Shireman & Nicholas I. Carruthers & David W. C. MacMillan, 2020. "Copper-mediated synthesis of drug-like bicyclopentanes," Nature, Nature, vol. 580(7802), pages 220-226, April.
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