New methods for bicyclo[1.1.1]pentane synthesis and functionalization

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This project falls within the EPSRC Synthetic Organic Chemistry research area.Strained ring systems have always been of interest to chemists, whether it be strategies for ring formation, their intriguing structures, or their unique properties in materials science and medicine.Of the many strained ring systems, bicyclo[1.1.1]pentanes (BCPs) have recently stimulated significant interest due to their potential for applications in medicinal chemistry as saturated bioisosteres for 1,4-disubstituted benzene rings, alkynes and tert-butyl groups. Interestingly, BCP analogues of drug molecules such as Darapladib, Resveratrol and Avagacestat were all shown to have either, or both, improved activity and pharmacokinetic properties from their parent compounds.Although BCPs are beginning to be established as effective bioisosteres, their potential use as 'next generation' scaffolds for 3D chemical space exploration is often overlooked due to their challenging synthesis. However, computationally assisted drug discovery has had tremendous advancements over the last decade with regards to prediction and virtual screening. This, in the future will lead to the prediction of fixed saturated ring systems with multiple vectors, such as BCPs, as ideal candidates for Hit to Lead validation. Unfortunately, there is at present no suitable method for obtaining both bridge and bridgehead substituted BCPs in quantities sufficient for drug development.The focus of this research will be to investigate the strategies and limitations of the synthesis of bridge substituted BCPs. The Anderson group has already developed a mild method to achieve carbon/halogen-substituted BCP's via atom-transfer radical addition reactions with Tricyclo[1.1.1.0]pentane (TCP) to afford a diverse portfolio of bridgehead substituted BCPs. The first strategy will be to apply the above methodology to known TCP derivatives such as Tricyclo[2.1.0.0.]pentane (TCP'). This would then allow the possibility of having a substituent on each bridge, two of which that could either be further functionalised or removed, and would be the first example of a fully bridge substituted BCP. The second strategy will expand upon current functionality that has already been incorporated into the BCP bridge, such as the gem dichloro. The two main focuses of this are to develop a sufficient cross-coupling protocol, and to activate the bridge towards electrophiles through metal insertion of one, or both, of the chlorides. Enantioselective cross- coupling/desymmetrisation of BCPs will also be investigated, as it would provide the first example of enantiopure bridge substituted BCPs. Alongside this work, we will also further develop access to substituted bicyclobutanes, which represent 'known' precursors to BCPs via existing dichlorocarbene insertion chemistry.In summary, the work proposed in this project will contribute to knowledge of radical-initiated strain relief reactions, enantioselective cross-coupling and achieving access to new 3D templates which are of interest to the medicinal and agrochemical communities.