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General access to cubanes as benzene bioisosteres

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

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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.

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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.

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

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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.

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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

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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.

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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.

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

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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

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