Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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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.
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 activity 1-5. 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 benzene 6,7. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings 1-7. 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 isomerization 8-11. 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-CF 3 cross-coupling protocols 12,13. 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 activity 1-5. 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 benzene 6,7. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings 1-7. 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 isomerization 8-11. 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-CF 3 cross-coupling protocols 12,13. Our research enables facile elaboration of all cubane isomers into drug candidates, thus enabling ideal bioisosteric replacement of ortho-, meta- and para-substituted benzenes.
KW - Multidisciplinary
U2 - 10.1038/s41586-023-06021-8
DO - 10.1038/s41586-023-06021-8
M3 - Journal article
C2 - 37015289
VL - 618
SP - 513
EP - 518
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7965
ER -