General access to cubanes as benzene bioisosteres | Shijiazhuang AgilePeak Ventures Co.,Ltd

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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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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.

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

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

Lancaster University, Lancaster, UK

Susannah C. Coote

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

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

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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.

Correspondence to David W. C. MacMillan.

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.

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

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

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Received: 20 January 2023

Accepted: 27 March 2023

Published: 04 April 2023

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

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