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General access to cubanes as benzene bioisosteres

Author

Listed:
  • Mario P. Wiesenfeldt

    (Merck Center for Catalysis at Princeton University)

  • James A. Rossi-Ashton

    (Merck Center for Catalysis at Princeton University)

  • Ian B. Perry

    (Merck Center for Catalysis at Princeton University)

  • Johannes Diesel

    (Merck Center for Catalysis at Princeton University)

  • Olivia L. Garry

    (Merck Center for Catalysis at Princeton University)

  • Florian Bartels

    (Merck Center for Catalysis at Princeton University)

  • Susannah C. Coote

    (Lancaster University)

  • Xiaoshen Ma

    (Merck & Co., Inc.)

  • Charles S. Yeung

    (Merck & Co., Inc.)

  • David J. Bennett

    (Merck & Co., Inc.)

  • David W. C. MacMillan

    (Merck Center for Catalysis at Princeton University)

Abstract

The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity1–5. Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well suited as the ring strain imparts high bond strength and thus metabolic stability on their C–H bonds. Cubane is the ideal bioisostere as it provides the closest geometric match to benzene6,7. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings1–7. This is owing to the difficulty of accessing 1,3- and 1,2-disubstituted cubane precursors. The adoption of cubane in drug design has been further hindered by the poor compatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalysed valence isomerization8–11. Here we report expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C–H carboxylation reaction, respectively. Moreover, we leverage the slow oxidative addition and rapid reductive elimination of copper to develop C–N, C–C(sp3), C–C(sp2) and C–CF3 cross-coupling protocols12,13. Our research enables facile elaboration of all cubane isomers into drug candidates, thus enabling ideal bioisosteric replacement of ortho-, meta- and para-substituted benzenes.

Suggested Citation

  • Mario P. Wiesenfeldt & James A. Rossi-Ashton & Ian B. Perry & Johannes Diesel & Olivia L. Garry & Florian Bartels & Susannah C. Coote & Xiaoshen Ma & Charles S. Yeung & David J. Bennett & David W. C. , 2023. "General access to cubanes as benzene bioisosteres," Nature, Nature, vol. 618(7965), pages 513-518, June.
  • Handle: RePEc:nat:nature:v:618:y:2023:i:7965:d:10.1038_s41586-023-06021-8
    DOI: 10.1038/s41586-023-06021-8
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    Cited by:

    1. Davies, Jennifer & Sharifi, Hossein & Lyons, Andrew & Forster, Rick & Elsayed, Omar Khaled Shokry Mohamed, 2024. "Non-fungible tokens: The missing ingredient for sustainable supply chains in the metaverse age?," Transportation Research Part E: Logistics and Transportation Review, Elsevier, vol. 182(C).
    2. 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.

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