New methods for bicyclo[1.1.1]pentane synthesis and functionalization

Lead Research Organisation: University of Oxford


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[]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[]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.

Planned Impact

This programme is focused on a new cohort-driven approach to the training of next-generation doctoral scientists in the practice of novel and efficient chemical synthesis coupled with an in-depth appreciation of its application to biology and medicine.

This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.

We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.

The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.

We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.

We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).

Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.

The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.


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