Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

General access to cubanes as benzene bioisosteres

Nature volume 618, pages 513–518 (2023)Cite this article

Subjects

Abstract

The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity1,2,3,4,5. 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 rings1,2,3,4,5,6,7. 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 isomerization8,9,10,11. 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cubanes in medicinal chemistry.
Fig. 2: Synthetic strategies towards nonlinear cubane precursors.
Fig. 3: Copper-mediated cross-coupling of cubane.
Fig. 4: Synthetic and medicinal applications of novel cubane isosteres.

Similar content being viewed by others

Data availability

All data are available in the main text or in the Supplementary information.

References

  1. Subbaiah, M. A. M. & Meanwell, N. A. Bioisosteres of the phenyl ring: recent strategic applications in lead optimization and drug design. J. Med. Chem. 64, 14046–14128 (2021).

    Article  CAS  PubMed  Google Scholar 

  2. Mykhailiuk, P. K. Saturated bioisosteres of benzene: where to go next? Org. Biomol. Chem. 17, 2839–2849 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Stepan, A. F. et al. Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor. J. Med. Chem. 55, 3414–3424 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Gianatassio, R. et al. Strain-release amination. Science 351, 241–246 (2016).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang, X. et al. Copper-mediated synthesis of drug-like bicyclopentanes. Nature 580, 220–226 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Eaton, P. E. Cubanes: starting materials for the chemistry of the 1990s and the new century. Angew. Chem. Int. Ed. 31, 1421–1436 (1992).

    Article  Google Scholar 

  7. Reekie, T. A., Williams, C. M., Rendina, L. M. & Kassiou, M. Cubanes in medicinal chemistry. J. Med. Chem. 62, 1078–1095 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. Cassar, L., Eaton, P. E. & Halpern, J. Silver(I)- and palladium(II)-catalyzed isomerizations of cubane. Synthesis and characterization of cuneane. J. Am. Chem. Soc. 92, 6366–6368 (1970).

    Article  Google Scholar 

  9. Cassar, L., Eaton, P. E. & Halpern, J. Catalysis of symmetry-restricted reactions by transition metal compounds. The valence isomerization of cubane. J. Am. Chem. Soc. 92, 3515–3518 (1970).

    Article  CAS  Google Scholar 

  10. Plunkett, S., Flanagan, K. J., Twamley, B. & Senge, M. O. Highly strained tertiary sp3 scaffolds: synthesis of functionalized cubanes and exploration of their reactivity under Pd(II) catalysis. Organometallics 34, 1408–1414 (2015).

    Article  CAS  Google Scholar 

  11. Toriyama, F. et al. Redox-active esters in Fe-catalyzed C–C coupling. J. Am. Chem. Soc. 138, 11132–11135 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Le, C., Chen, T. Q., Liang, T., Zhang, P. & MacMillan, D. W. C. A radical approach to the copper oxidative addition problem: trifluoromethylation of bromoarenes. Science 360, 1010–1014 (2018).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liang, Y., Zhang, X. & MacMillan, D. W. C. Decarboxylative sp3 C–N coupling via dual copper and photoredox catalysis. Nature 559, 83–88 (2018).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Feng, Y., Liu, L., Wang, J.-T., Zhao, S.-W. & Guo, Q.-X. Homolytic C–H and N–H bond dissociation energies of strained organic compounds. J. Org. Chem. 69, 3129–3138 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Levterov, V. V., Panasyuk, Y., Pivnytska, V. O. & Mykhailiuk, P. K. Water-soluble non-classical benzene mimetics. Angew. Chem. Int. Ed. 59, 7161–7167 (2020).

    Article  CAS  Google Scholar 

  17. Denisenko, A., Garbuz, P., Shishkina, S. V., Voloshchuk, N. M. & Mykhailiuk, P. K. Saturated bioisosteres of ortho-substituted benzenes. Angew. Chem. Int. Ed. 59, 20515–20521 (2020).

    Article  CAS  Google Scholar 

  18. Zhao, J.-X. et al. 1,2-Difunctionalized bicyclo[1.1.1]pentanes: long–sought-after mimetics for ortho/meta-substituted arenes. Proc. Natl Acad. Sci. USA 118, e2108881118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Epplin, R. C. et al. [2]-Ladderanes as isosteres for meta-substituted aromatic rings and rigidified cyclohexanes. Nat. Commun. 13, 6056 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. Iida, T. et al. Practical and facile access to bicyclo[3.1.1]heptanes: potent bioisosteres of meta-substituted benzenes. J. Am. Chem. Soc. 144, 21848–21852 (2022).

    Article  CAS  PubMed  Google Scholar 

  21. Kleinmans, R. et al. Intermolecular [2π+2σ]-photocycloaddition enabled by triplet energy transfer. Nature 605, 477–482 (2022).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Frank, N. et al. Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. Nature 611, 721–726 (2022).

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Rigotti, T. & Bach, T. Bicyclo[2.1.1]hexanes by visible light-driven intramolecular crossed [2 + 2] photocycloadditions. Org. Lett. 24, 8821–8825 (2022).

    Article  CAS  PubMed  Google Scholar 

  24. Eaton, P. E. & Cole, T. W. Cubane. J. Am. Chem. Soc. 86, 3157–3158 (1964).

    Article  CAS  Google Scholar 

  25. Falkiner, M. J., Littler, S. W., McRae, K. J., Savage, G. P. & Tsanaktsidis, J. Pilot-scale production of dimethyl 1,4-cubanedicarboxylate. Org. Process Res. Dev. 17, 1503–1509 (2013).

    Article  CAS  Google Scholar 

  26. Biegasiewicz, K. F., Griffiths, J. R., Savage, G. P., Tsanaktsidis, J. & Priefer, R. Cubane: 50 years later. Chem. Rev. 115, 6719–6745 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Kassiou, M., Coster, M. & Gunosewoyo, H. Polycyclic molecular compounds. Patent WO2008064432A1 (2008).

  28. Wlochal, J., Davies, R. D. M. & Burton, J. Cubanes in medicinal chemistry: synthesis of functionalized building blocks. Org. Lett. 16, 4094–4097 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Chalmers, B. A. et al. Validating Eaton’s hypothesis: cubane as a benzene bioisostere. Angew. Chem. Int. Ed. 55, 3580–3585 (2016).

    Article  CAS  Google Scholar 

  30. Houston, S. D. et al. The cubane paradigm in bioactive molecule discovery: further scope, limitations and the cyclooctatetraene complement. Org. Biomol. Chem. 17, 6790–6798 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. Bernhard, S. S. R. et al. Cubane cross-coupling and cubane–porphyrin arrays. Chem. Eur. J. 24, 1026–1030 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. Okude, R., Mori, G., Yagi, A. & Itami, K. Programmable synthesis of multiply arylated cubanes through C–H metalation and arylation. Chem. Sci. 11, 7672–7675 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Barborak, J. C., Watts, L. & Pettit, R. A convenient synthesis of the cubane system. J. Am. Chem. Soc. 88, 1328–1329 (1966).

    Article  CAS  Google Scholar 

  34. Brewer, C. R., Sheehan, N. C., Herrera, J., Walker, A. V. & McElwee-White, L. Photochemistry of (η4-diene)Ru(CO)3 complexes as precursor candidates for photoassisted chemical vapor deposition. Organometallics 41, 761–775 (2022).

    Article  CAS  Google Scholar 

  35. Pettit, R. & Henery, J. Cyclobutadieneiron tricarbonyl. Org. Synth. 50, 57–59 (1970).

    Google Scholar 

  36. Masamune, S., Nakamura, N. & Sapadaro, J. 1,2-Bis(β-tosylethoxycarbonyl)diazene. Its application to the 2,3-diazabicyclo[2.2.0]hexene system. J. Am. Chem. Soc. 97, 918–919 (1975).

    Article  CAS  Google Scholar 

  37. Britten, T. K., Akien, G. R., Kemmitt, P. D., Halcovitch, N. R. & Coote, S. C. An efficient preparation of 1,2-dihydropyridazines through a Diels–Alder/palladium-catalysed elimination sequence. Tetrahedron Lett. 60, 1498–1500 (2019).

    Article  CAS  Google Scholar 

  38. Altman, L. J., Semmelhack, M. F., Hornby, R. B. & Vederas, J. C. Photochemical isomerisation of dimethyl 1,2-dihydropyridazine-1,2-dicarboxylate. Chem. Commun. 1968, 686–687 (1968).

    Google Scholar 

  39. Britten, T. K., Kemmitt, P. D., Halcovitch, N. R. & Coote, S. C. 4-π-Photocyclization of 1,2-dihydropyridazines: an approach to bicyclic 1,2-diazetidines with rich synthetic potential. Org. Lett. 21, 9232–9235 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Bashir-Hashemi, A. Photochemical carboxylation of cubanes. Angew. Chem. Int. Ed. 32, 612–613 (1993).

    Article  Google Scholar 

  41. Collin, D. E., Kovacic, K., Light, M. E. & Linclau, B. Synthesis of ortho-functionalized 1,4-cubanedicarboxylate derivatives through photochemical chlorocarbonylation. Org. Lett. 23, 5164–5169 (2021).

    Article  CAS  Google Scholar 

  42. Chan, A. Y. et al. Metallaphotoredox: the merger of photoredox and transition metal catalysis. Chem. Rev. 122, 1485–1542 (2022).

    Article  CAS  PubMed  Google Scholar 

  43. Rodríguez, N. & Gooßen, L. J. Decarboxylative coupling reactions: a modern strategy for C–C-bond formation. Chem. Soc. Rev. 40, 5030–5048 (2011).

    Article  PubMed  Google Scholar 

  44. Ruiz-Castillo, P. & Buchwald, S. L. Applications of palladium-catalyzed C–N cross-coupling reactions. Chem. Rev. 116, 12564–12649 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherification of aryl halides. Acc. Chem. Res. 41, 1534–1544 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhao, W., Wurz, R. P., Peters, J. C. & Fu, G. C. Photoinduced, copper-catalyzed decarboxylative C−N coupling to generate protected amines: an alternative to the Curtius rearrangement. J. Am. Chem. Soc. 139, 12153–12156 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sodano, T. M., Combee, L. A. & Stephenson, C. R. J. Recent advances and outlook for the isosteric replacement of anilines. ACS Med. Chem. Lett. 11, 1785–1788 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sklyarova, A. S. et al. Preparation and testing of homocubyl amines as therapeutic NMDA receptor antagonists. Med. Chem. Res. 22, 360–366 (2013).

    Article  CAS  Google Scholar 

  49. Sakai, H. A., Liu, W., Le, C. & MacMillan, D. W. C. Cross-electrophile coupling of unactivated alkyl chlorides. J. Am. Chem. Soc. 142, 11691–11697 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Z. Dong, P. Sarver, Y. Liang, C. Oswood, W. Liu and M. Heilmann for discussions; I. Pelcer and K. Conover for assistance with NMR spectroscopy; R. Lambert for assistance with the preparation of this paper; J. Piesvaux, J. P. Imredy, R. L. Kraus and B. Lacey for help with biological profiling; and A. Beard, M. Darlak, S. McMinn, L. Nogle, M. Pietrafitta, D. Smith and Y. Ye (all Merck & Co., Inc.) for help with reverse-phase chromatography. The research was supported by the NIH National Institute of General Medical Sciences (NIGMS), the NIH (R35GM134897-03), the Princeton Catalysis Initiative, and kind gifts from Merck & Co., Inc., Bristol-Myers Squibb (BMS), Celgene, Genentech, Janssen Research and Development LLC, and Pfizer. M.P.W. was supported by the Deutsche Akademie der Naturforscher Leopoldina (LPDS 2018-16). F.B. was funded by the German Research Foundation (DFG) – 421436809, and J.D. was supported by an SNSF Early Postdoc.Mobility fellowship.

Author information

Author notes

  1. These authors contributed equally: Mario P. Wiesenfeldt, James A. Rossi-Ashton, Ian B. Perry

Authors and Affiliations

  1. Merck Center for Catalysis at Princeton University, Princeton, NJ, USA

    Mario P. Wiesenfeldt, James A. Rossi-Ashton, Ian B. Perry, Johannes Diesel, Olivia L. Garry, Florian Bartels & David W. C. MacMillan

  2. Lancaster University, Lancaster, UK

    Susannah C. Coote

  3. Department of Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA

    Xiaoshen Ma, Charles S. Yeung & David J. Bennett

Authors
  1. Mario P. Wiesenfeldt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James A. Rossi-Ashton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ian B. Perry
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Johannes Diesel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olivia L. Garry
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Florian Bartels
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Susannah C. Coote
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaoshen Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Charles S. Yeung
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David J. Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. David W. C. MacMillan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.P.W. and I.B.P. developed the route towards dimethyl cubane-1,3-dicarboxylate. O.L.G., M.P.W. and J.A.R.-A. developed the route towards 1-tert-butyl-2-methyl cubane-1,2-dicarboxylate. J.A.R.-A. and I.B.P. developed the amination reaction, J.D. and M.P.W. developed the alkylation reaction, M.P.W., F.B. and J.D. developed the arylation reaction, and J.A.R.-A. and F.B. developed the trifluoromethylation reaction. J.A.R.-A. applied the reactions to new cubane isomers and synthesized the drug analogues. Biological testing was conducted by X.M., C.S.Y. and D.J.B. D.W.C.M., S.C.C., X.M., C.S.Y. and D.J.B. provided advice. D.W.C.M., M.P.W., J.A.R.-A., I.B.P. and J.D. wrote the paper with contributions by all authors. D.W.C.M. directed the project.

Corresponding author

Correspondence to David W. C. MacMillan.

Ethics declarations

Competing interests

D.W.C.M. declares an ownership interest in the Penn PhD photoreactor, which is used to irradiate reactions in this work. The other authors declare no competing interests.

Peer review

Peer review information

Nature thanks Kaid Harper and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

This file contains general information, experimental procedures, characterization data, extended information, Supplementary Figs. 1–36, NMR spectra and references.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wiesenfeldt, M.P., Rossi-Ashton, J.A., Perry, I.B. et al. General access to cubanes as benzene bioisosteres. Nature 618, 513–518 (2023). https://doi.org/10.1038/s41586-023-06021-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41586-023-06021-8

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing