We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

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 review 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. Joseph Anderson completed his MChem in 2020 (University of Oxford, Prof. 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. John Murphy on bicyclo[1.1.1]pentane methodology. 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. Darren Poole completed his DPhil in 2014 (University of Oxford, Prof. Timothy Donohoe) where he worked on nucleophilic dearomatisation reactions, and hydrogen borrowing reactions of methanol. He joined GSK's Flexible Discovery Unit as a synthetic chemist in 2014, and is now a Scientific Leader and GSK Fellow in the Medicinal Chemistry department. His research interests are particularly focussed on the application of new synthetic methodologies and technologies in drug discovery. John Murphy was born in Dublin and educated at the University of Dublin (TCD) and the University of Cambridge. After Fellowships at Alberta and Oxford, he was appointed as Lecturer, then Reader, at the University of Nottingham. Since 1995, he has held the Merck-Pauson Professorship at the University of Strathclyde. His interests are in mechanism and synthesis.

Herein, we report the decarboxylative Minisci heteroarylation of bicyclo[1.1.1]pentane (BCP) and 2-oxabicyclo[2.1.1]hexane (oBCH) derivatives at the bridge positions. In an operationally simple, photocatalyst-free process, free bridge carboxylic acids are directly coupled with nonprefunctionalized heteroarenes to provide rare examples of polysubstituted BCP and oBCH derivatives in synthetically useful yields. Additionally, the impact of the BCP core on the physicochemical properties of a representative example compared to those of its all-aromatic ortho- and meta-substituted analogues is evaluated.

“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.

Herein we report the decarboxylative Minisci heteroarylation of bicyclo[1.1.1]pentane (BCP) derivatives at the C2 (bridge) position. The developed process directly couples free BCP C2-carboxylic acids with non-prefunctionalised heteroarenes to provide rare examples of polysubstituted BCPs in synthetically useful yields. An extension of the methodology to the related 2-oxa-bicyclo[2.1.1]hexane motif was also achieved. Finally, the impact of the BCP core on the physicochemical properties of a representative example compared to its all-aromatic ortho- and meta-substituted analogues was evaluated.

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