Heterocyclic inflation - efficient routes to medium rings by migratory ring expansion of alkenes

Medium ring (8-12 membered) heterocycles form the core scaffold of a range of naturally occurring biologically active compounds, with the conformational constraints imposed by the cyclic structure attributed to improving the binding of medium ring-containing compounds to their target protein. Thus, these rings are attractive synthetic targets for medicinal chemistry. However, the synthesis of these scaffolds remains very challenging, due to the unfavourable transannular interactions upon ring closure; this is the likely reason for the marked underrepresentation of medium rings in drug discovery. Therefore, new methods are required to provide access to these structures, thereby enabling medicinal chemists to incorporate medium rings into fragment screening libraries and novel drug designs.

A ring expansion strategy is an appealing way to make medium-sized ring compounds, since this can partially reduce the entropic penalty in forming the medium-sized ring, and five- to seven-membered heterocycles are widely available. Previous work in the Clayden group has demonstrated that readily accessible arene-containing amide or urea substrates can undergo an intramolecular aryl migration to generate medium ring compounds. This research project aims to employ this powerful ring expansion strategy to achieve alkenyl migration, rather than aryl migration, which would broaden the scope and enrich the library of potentially bioactive medium ring scaffolds that could be accessed.

The project will begin with establishing a robust route to make a variety of alkene-containing starting materials. Some investigation into this has been carried out as part of an undergraduate's MSci research project, which will be further developed in this project to generate a more diverse set of substrates. The next stage will be to establish that the ring expansion via alkene migration is feasible on these types of substrates. It is envisaged that optimisation of this transformation could be carried out using Design of Experiments, which could be accelerated through use of Bristol Automated Synthesis Facility's Chemspeed platform. After robust conditions for the ring expansion have been found, they will be applied to a range of substrates, so as to investigate the functional group tolerance and scope of the process. This too could potentially be expedited using the Chemspeed robot to rapidly provide medium ring products that would be difficult to access by other methods.

The products of the ring expansion would have potential sites for further reaction, and therefore, we would like to showcase particular derivatisations that would demonstrate the versatility of medium ring products and their applicability to drug discovery. Regular meetings with Cancer Research UK throughout the project will guide the choice of scaffolds targeted and help ensure the transferability of this chemistry from academic laboratories to drug discovery research. The alkene migration is a very unusual reaction, and so we hope to undertake investigations its mechanism. The tools we could use to do this include experimental kinetic studies, in situ infrared spectroscopy measurements and computational modelling. The information gained from these studies could be valuable in developing further novel transformations.

1. PEOPLE: We will train students with skills that are in demand across a spectrum of industries from pharma/biotech to materials, as well as in academia, law and publishing. The enhanced experience they receive - through interactive brainstorming, problem and dragons' den type business sessions - will equip them with confidence in their own abilities and fast-track their leadership skills. 100% Employment of students from the previous CDT in Chemical Synthesis is indicative of the high demand for the skills we provide, but as start-ups and SMEs become increasingly important in the healthcare, medicine and energy sectors, training in IP, entrepreneurship and commercialisation will stimulate our students to explore their own ventures. Automation and machine learning are set to transform the workplace in the next 20 years, and our students will be in the vanguard of those primed to make best use of these shifts in work patterns. Our graduates will have an open and entrepreneurial mindset, willing to seek solution to problems that cross disciplines and require non-traditional approaches to scientific challenges.

2. ECONOMY: Built on the country's long history of scientific ingenuity and creativity, the >£50bn turnover and annual trade surplus of £5 bn makes the British chemical sector one of the most important creators of wealth for the national economy. Our proposal to integrate training in chemical synthesis with emerging fields such as automation/AI/ML will ensure that the UK maintains this position of economic strength in the face of rapidly developing competition. With the field of drug development desperately looking for innovative new directions, we will disseminate, through our proposed extensive industrial stakeholders, smarter and more efficient ways of designing and implementing molecular synthesis using automation, machine learning and virtual reality interfaces. This will give the UK the chance to take a world-leading position in establishing how molecules may be made more rapidly and economically, how compound libraries may be made broader in scope and accessed more efficiently, and how processes may be optimized more quickly and to a higher standard of resilience. Chemical science underpins an estimated 21% of the economy (>£25bn sales; 6 million people), so these innovations have the potential for far-reaching transformative impact.

3. SCIENCE: The science emerging from our CDT will continue to be at the highest academic level by international standards, as judged by an outstanding publication record. Incorporating automation, machine learning, and virtual reality into the standard toolkit of chemical synthesis would initiate a fundamental change in the way molecules are made. Automated methods for making limited classes of molecules (eg peptides) have transformed related biological fields, and extending those techniques to allow a wide range of small molecules to be synthesized will stimulate not only chemistry but also related pivotal fields in the bio- and materials sciences. Synthesis of the molecular starting points is often the rate-limiting step in innovation. Removing this hurdle will allow selection of molecules according to optimal function, not ease of synthesis, and will accelerate scientific progress in many sectors.

4. SOCIETY: Health benefits will emerge from the ability of both academia and the pharmaceutical industry to generate drug targets more rapidly and innovatively. Optimisation of processes opens the way for advances in energy efficiency and resource utilization by avoiding non-renewable, environmentally damaging, or economically volatile feedstocks. The societal impact of automation will extend more widely to the freeing of time to allow more creative working and also recreational pastimes. We thus aim to be among the pioneers in a new automation-led working model, and our students will be trained to think through the broader consequences of automation for society as a whole