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Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

Author

Listed:
  • Nils Frank

    (University of Oxford)

  • Jeremy Nugent

    (University of Oxford)

  • Bethany R. Shire

    (University of Oxford)

  • Helena D. Pickford

    (University of Oxford)

  • Patrick Rabe

    (University of Oxford)

  • Alistair J. Sterling

    (University of Oxford)

  • Tryfon Zarganes-Tzitzikas

    (Alzheimer’s Research UK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine)

  • Thomas Grimes

    (Alzheimer’s Research UK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine)

  • Amber L. Thompson

    (University of Oxford)

  • Russell C. Smith

    (Abbvie Drug Discovery Science & Technology (DDST))

  • Christopher J. Schofield

    (University of Oxford)

  • Paul E. Brennan

    (Alzheimer’s Research UK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine)

  • Fernanda Duarte

    (University of Oxford)

  • Edward A. Anderson

    (University of Oxford)

Abstract

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

Suggested Citation

  • Nils Frank & Jeremy Nugent & Bethany R. Shire & Helena D. Pickford & Patrick Rabe & Alistair J. Sterling & Tryfon Zarganes-Tzitzikas & Thomas Grimes & Amber L. Thompson & Russell C. Smith & Christophe, 2022. "Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane," Nature, Nature, vol. 611(7937), pages 721-726, November.
  • Handle: RePEc:nat:nature:v:611:y:2022:i:7937:d:10.1038_s41586-022-05290-z
    DOI: 10.1038/s41586-022-05290-z
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    Cited by:

    1. Yonghong Liu & Zhixian Wu & Jing-Ran Shan & Huaipu Yan & Er-Jun Hao & Lei Shi, 2024. "Titanium catalyzed [2σ + 2π] cycloaddition of bicyclo[1.1.0]-butanes with 1,3-dienes for efficient synthesis of stilbene bioisosteres," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    2. Wen-Biao Wu & Bing Xu & Xue-Chun Yang & Feng Wu & Heng-Xian He & Xu Zhang & Jian-Jun Feng, 2024. "Enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis," Nature Communications, Nature, vol. 15(1), pages 1-9, December.

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