TY - JOUR
T1 - General access to cubanes as benzene bioisosteres
AU - Wiesenfeldt, Mario P.
AU - Rossi-Ashton, James A.
AU - Perry, Ian B.
AU - Diesel, Johannes
AU - Garry, Olivia L.
AU - Bartels, Florian
AU - Coote, Susannah C.
AU - Ma, Xiaoshen
AU - Yeung, Charles S.
AU - Bennett, David J.
AU - MacMillan, David W.C.
N1 - Funding Information:
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.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/6/15
Y1 - 2023/6/15
N2 - The replacement of benzene rings with sp 3-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(sp 3), C–C(sp 2) 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.
AB - The replacement of benzene rings with sp 3-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(sp 3), C–C(sp 2) 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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UR - http://www.scopus.com/inward/citedby.url?scp=85160925818&partnerID=8YFLogxK
U2 - 10.1038/s41586-023-06021-8
DO - 10.1038/s41586-023-06021-8
M3 - Article
C2 - 37015289
AN - SCOPUS:85160925818
SN - 0028-0836
VL - 618
SP - 513
EP - 518
JO - Nature
JF - Nature
IS - 7965
ER -