Abstract
“Escaping from flatland”, by increasing the saturation level and three‐dimensionality of drug‐like compounds, can enhance their potency, selectivity and pharmacokinetic profile. One approach that has attracted considerable recent attention is the bioisosteric replacement of aromatic rings, internal alkynes and tert‐butyl groups with bicyclo[1.1.1]pentane (BCP) units. While functionalisation of the tertiary bridgehead positions of BCP derivatives is well‐documented, functionalisation of the three concyclic secondary bridge positions remains an emerging field. The unique properties of the BCP core present considerable synthetic challenges to the development of such transformations. However, the bridge positions provide novel vectors for drug discovery and applications in materials science, providing entry to novel chemical and intellectual property space. This Minireview aims to consolidate the major advances in the field, serving as a useful reference to guide further work that is expected in the coming years.
Highlights
“Escaping from flatland”, by increasing the saturation level and positions
Introduction commented on this issue,[20] highlighting that abiotic scaffolds may prove important in the discovery of anticancer, anti
The BCP core is highly strained yet remarkably stable, with a strain energy of 65[17a]–68[21] kcal molÀ1 for the parent hydrocarbon and thermal stability up to ca. 300 8C.[17a,22] This strain primarily arises from significant destabilizing overlap of the rear lobes of bridgehead orbitals directed at substituent positions.[23]
Summary
The BCP core is highly strained yet remarkably stable, with a strain energy of 65[17a]–68[21] kcal molÀ1 for the parent hydrocarbon (cf. 27.5 kcal molÀ1 for cyclopropane[21]) and thermal stability up to ca. 300 8C.[17a,22] This strain primarily arises from significant destabilizing overlap of the rear lobes of bridgehead orbitals directed at substituent positions.[23]. Timothy Donohoe) working on cobalt-catalysed transformations of boronic acids He subsequently joined the GSK/University of Strathclyde Collaborative Industrial PhD Programme, where he is currently working under the supervision of Dr Darren Poole, Dr Nicholas Measom and Prof. Nicholas Measom completed his PhD in 2017 (GSK/University of Strathclyde Collaborative Industrial PhD programme, Dr David Hirst and Dr Craig Jamieson) working on the synthesis and application of bicyclo[1.1.1]pentanes within Lp-PLA2 inhibitors. He joined GSK as a synthetic medicinal chemist in 2017 and became an Investigator in 2020. Prefunctionalisation at the bridge positions is expected to be necessary for the divergent introduction of substituents
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