General access to cubanes as benzene bioisosteres

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. MacMillan

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)513-518
Number of pages6
JournalNature
Volume618
Issue number7965
DOIs
StatePublished - Jun 15 2023

All Science Journal Classification (ASJC) codes

  • General

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