This research proposal has its origin in the special properties of the selectively fluorinated molecule, all-cis-1,2,3,4,5,6-hexafluorocyclohexane, which we prepared and reported in 2015. This is cyclohexane ring system which emerges as the most polar aliphatic compound recorded and it has interesting properties such as the ability to associate with both cations and anions. The cyclohexane ring is highly unusual in that it has polarised faces. The fluorine face is negatively polarised and the hydrogen face is positively polarised. In 2015 this ring system was challenging to make, and particularly to make derivatives, however in 2017 a direct hydrogenation method was developed by Glorius's lab in Munster, which allows access to derivatived forms of the ring system directly from aromatic precursors. Relevant to this proposal will be the synthesis of a series of substituted pentafluorocyclohexanes, where all substituents are on the same side of the cyclohexane ring. With this development, this research programme aims to explore applications of these pentafluorocyclohexane ring systems, exploring properties relevant to medicinal and biological chemistry (interactions with amino acids and proteins) as well as in organic materials and we have selected a particular focus in the areas of liquid crystals. In the context of medicinal and biological chmeistry we want to explore how these ring systems will be expected to interact and bind with proteins. The negatively and positively polarised faces have the potential to make interactions with amino acid side chains with a complementary electrostatic profile. This will be explored by tagged 'pull-down' assays and proteins of high affinity will be identified by proteomics techniques. Candidate proteins will be progressed to co-crytsalisation structural (X-ray) studies for close structural analysis. In a complementary approach we will prepare tripeptides, from amino acid combinations that are known to be predisposed towards crystallinity. We will prepare a range of these with an amino acid with an all cis-2,3,4,5,6-pentafluorocyclohexyl side chain to explore how it interacts with other amino acid side chains. This study will extend to exploring the binding of this ring system to viral proteases, by making appropriate changes to drug molecules by replacing cyclohexyl or fluoroaromatic rings with the all cis-2,3,4,5,6-pentafluorocyclohexyl side chain. Structural biology(X-ray) analysis will allow us to determine how these ring systems interact with the protein, and this will inform medicinal chemists as to the potential of this motif. The programme will extend to CF3 containing cyclohexanes, but particulary rings with more than one CF3 and with a defined stereochemistry. We have recently demonstrated that cyclohexanes with multiple CF3 groups attached to the aliphatic ring can also be accessed efficiently by the direct hydrogenation of arylCF3 precursors. The programme will extend to exploring the preparation, properties and chemistry of cyclohexanes with two and three CF3 groups with defined stereochemistries. These are also highly polarised aliphatics and these novel motifs will be introduced into liquid crystal architectures to exemplify properties and potential. The liquid crystal aspect is supported by Merck Liquid Crystal Division in Darmstadt who will carry out detailed analysis of prpared materials. In overview the programme will explore an exciting class of organic chemistry motif which have potential to contribute new properties in a range of discovery chemistry arenas.

By 2025 targeted biological medicines, personalised and stratified, will transform the precision of healthcare prescription, improve patient care and quality of life. Novel manufacturing solutions have to be created if this is to happen. This is the unique challenge we shall tackle. The current "one-size-fits-all" approach to drug development is being challenged by the growing ability to target therapies to only those patients most likely to respond well (stratified medicines), and to even create therapies for each individual (personalised medicines). Over the last ten years our understanding of the nature of disease has been transformed by revolutionary advances in genetics and molecular biology. Increasingly, treatment with drugs that are targeted to specific biomarkers, will be given only to patient populations identified as having those biomarkers, using companion diagnostic or genetic screening tests; thus enabling stratified medicine. For some indications, engineered cell and gene therapies are offering the promise of truly personalised medicine, where the therapy itself is derived at least partly from the individual patient. In the future the need will be to supply many more drug products, each targeted to relatively small patient populations. Presently there is a lack of existing technology and infrastructure to do this, and current methods will be unsustainable. These and other emerging advanced therapies will have a critical role in a new era of precision targeted-medicines. All will have to be made economically for healthcare systems under extreme financial pressure. The implications for health and UK society well-being are profound There are already a small number of targeted therapies on the market including Herceptin for breast cancer patients with the HER2 receptor and engineered T-cell therapies for acute lymphoblastic leukaemia. A much greater number of targeted therapies will be developed in the next decade, with some addressing diseases for which there is not currently a cure. To cope, the industry will need to create smarter systems for production and supply to increasingly fragmented markets, and to learn from other sectors. Concepts will need to address specific challenges presented by complex products, of processes and facilities capable of manufacture at smaller scales, and supply chains with the agility to cope with fluctuating demands and high levels of uncertainty. Innovative bioprocessing modes, not currently feasible for large-scale manufacturing, could potentially replace traditional manufacturing routes for stratified medicines, while simultaneously reducing process development time. Pressure to reduce development costs and time, to improve manufacturing efficiency, and to control the costs of supply, will be significant and will likely become the differentiating factor for commercialisation. We will create the technologies, skill-sets and trained personnel needed to enable UK manufacturers to deliver the promise of advanced medical precision and patient screening. The Future Targeted Healthcare Manufacturing Hub and its research and translational spokes will network with industrial users to create and apply the necessary novel methods of process development and manufacture. Hub tools will transform supply chain economics for targeted healthcare, and novel manufacturing, formulation and control technologies for stratified and personalised medicines. The Hub will herald a shift in manufacturing practice, provide the engineering infrastructure needed for sustainable healthcare. The UK economy and Society Wellbeing will gain from enhanced international competitiveness.

This project aims to develop two recent discoveries from the St Andrews laboratory. Project 1: The first project develops from a recent syntheses of 1,2,3,4- and 1,2,4,5-tetrafluorocyclohexanes. Importantly the stereochemistry of the molecules has all of the fluorines on the same face of the cyclohexanes. We find that this makes these cyclohexanes very polar. TWhen cyclohexane adopts a chair conformation, then there are always two diaxial C-F bonds. This polarity renders these compounds crystalline solids, and NMR experiments reveal that the two faces are highly polarised. So the project aims now to incorporate this motif into more meaningful structures. We think that the all-syn tetrafluorocyclohexane motif can have wide ranging roles in developing performance molecules for pharmaceuticals and agrochemicals research. However in this project we will use liquid crystals as a background to explore their properties. Many liquid crystalline molecules that are used in modern displays for personal computers, smart phones and iPads etc contain fluorine atoms. This is because the C-F bond is polar, but it has low viscosity, and thus it can orientate and cycle very rapidly in changing electric fields. The all-syn tetraflurocyclohexane motifs appear to have exactly the correct caharacteristics for a particular class of LC's known as -ve dieletric anisotropic LC's. These are molecules where the dipole is orientated perpendicular to the molecular axis. The project requires that we develop chemistry around a phenyl derivative of the 1,2,4,5-tetrafluorocyclohexane. We plan to carry out a diversity of chemistry on this motif, and also to improve synthetic protocols. We want also to explore synthesis routes to other derivatives of the tetrafluorocyclohexane ring system eg. carboxylic acid and amine motifs we feel will be extremely attractive for medicinal chemistry research. One of the leading research companies and global suppliers of perfomance LC's, Merck in Darmstadt, Germany, have agreed to support the project by evaluating candidate compounds as LC's and they will assist in providing facilities to scale up the synthesis of these motifs. This aspect of the project will be successful if we can demonstrate a practical application of the all-syn tetrafluorocyclohexane and illustrate to the wider community its potential in the development of performance organic molecules. Project 2. The second project was stimulated by a new reaction carried out in the laboratory, which recognised that if an acetylenethioether is treated with an HF source, it generates a fluoroviny thioether (RS(F)=CH2). More significantly we find that the fluorovinyl thioether is a relatively stable entity. There is hardly any literature on this motif and in this research we want to explore its potential in the early stage design of enzyme inhibitors (fragment approach). We have recognised that the motif approximates the steric and electronic profile of an enol of a thioester. Thioester enols/ates are important intermediates in enzymology, eg. enzymes that process acetyl-CoA such citrate and malate synthase, acetyl-CoA carboxylase, and enoyl reductases of fatty acid biosynthesis are attractive. Therefore we want to assess if the fluorovinyl thioether moiety will be recognised and bind to these enzyme active sites by co-crystallisation X-ray studies. This requires that we synthesise appropriate motifs that represent truncated pantetheinyl moieties carrying the RS(F)=CH2 motif. These compounds will be co-crystallised with enzymes over-expressed in E. coli. In discussions with Syngenta they have suggested we explore such ligands for enoyl reductase, a target relevant to the agrochemical sector. A successful outcome will show that this motif binds to these enzyme active sites (by X-ray crystallography), and provides a starting poing for fragment based inhibitor development. The programme will introduce this motif to the wider research community.

Imagine materials that allow better protection against impact because they push back when hit, rather than getting thinner. Or optical materials that could make the next generation virtual and augmented reality vision devices energy efficient and fast enough to produce real-time holograms. Or new, non-toxic materials for that convert heat energy to electricity, and flow so provide the heat-exchanging medium. Such materials have come into existence in the last 5 years, and this proposal is designed to take them from early stage discovery, building a deep and comprehensive understanding of the physics, towards new applications. The proposal is founded on two of my discoveries in liquid crystals; the first synthetic auxetic material (a liquid crystal elastomer), and a novel electro-optic response in a rather esoteric liquid crystal state, the dark conglomerate phase. It also builds on my exploratory work of the electrocaloric effect in well-known ferroelectric LCs positioning me to examine the potential of newly discovered polar nematics. 1. Auxetic LC elastomers. Imagine a material that gets thicker when you stretch it rather than thinner! Such materials are known as auxetic and exist in nature in tendons, nacre, the cell nucleus and even cat skin. Auxetic materials are predicted to have extremely desirable properties including: high shock absorbance; tear resistance; high shear moduli; and to be acoustic meta-materials. Most existing synthetic auxetic materials involve porous geometries with typical dimensions of >10micrometres, limiting the possible device dimensions and introducing inherent weakness (it is easy to tear a sponge). I recently discovered the first synthetic molecular auxetic material offering a paradigm shift in developing materials for applications spaning automotive, aerospace, electronics and healthcare industries. My aim is to develop a deep understanding of the physics underpinning the phenomenon and engage academic and industrial collaborators. 2. Optically isotropic electro-optic modes. Liquid crystals have been a potential solution for switchable optics (and optical switches) for decades, but are inefficient and too slow for next generation devices. The dark conglomerate (DC) phase shows a remarkable electro-optic response, a large change in refractive index which is both fast and polarization-independent that could completely change the way in which switchable lenses and gratings could be designed. I plan to build on my work on the DC phase, understanding materials and mixtures that exhibit the phase, to take it from a scientific curiosity to one where the potential for new electro-optic devices is fully understood. 3. Polar nematic LCs for energy. This strand combines a recent discovery at York with my exploratory research into liquid crystals as electrocaloric materials. Electrocaloric materials convert heat into electricity (and vice versa) and having a fluid material that does this offers a new approach to device design. Unfortunately, fluid materials tend to have an electrical polarization that is orders of magnitude too small to be effective. The polarization in the splay nematic phase is reported to be three orders of magnitude bigger than other ferroelectric LCs - a real game changer! I will take the opportunity to explore this new nematic phase in great detail, with the aim of determining its potential in energy applications. My programme is timely, exciting and ambitious, designed to take fundamental understanding to a stage where engineers or industrial partners can begin to develop the ideas with the greatest potential.

Synthesis, the science of making molecules, is central to human wellbeing through its ability to produce new molecules for use as medicines and materials. Every new drug, whether an antibiotic or a cancer treatment, is based on a molecular structure designed and built using the techniques of synthesis. Synthesis is a complex activity, in which bonds between atoms are formed in a carefully choreographed way, and training to a doctoral level is needed to produce scientists with this expertise. Our proposed CDT is tailored towards training the highly creative, technologically skilled scientists essential to the pharmaceutical, biotech, agrochemical and materials sectors, and to many related areas of science which depend on novel molecules. Irrespective of the ingenuity of the synthetic chemist, synthesis is often the limiting step in the development of a new product or the advance of new molecular science. This hurdle has been overcome in some areas by automation (e.g. peptides and DNA), but the operational complexity of a typical synthetic route in, say, medicinal chemistry has hampered the wider use of the technology. Recent developments in the fields of automation, machine learning (ML), virtual reality (VR) and artificial intelligence (AI) now make possible a fundamental change in the way molecules are designed and made, and we propose in this CDT to engineer a revolution in the way that newly trained researchers approach synthetic chemistry, creating a new generation of pioneering innovators. Making use of Bristol's extensive array of automated synthetic equipment, flow reactors, peptide synthesisers, and ML Retrosynthesis Tool, students will learn and appreciate this cutting-edge technology-driven program, its potential and its limitations. Bristol has outstanding facilities, equipment and expertise to deliver this training. At its core will be a state-of-the-art research experience in our world-leading research groups, which will form the majority of the 4-year CDT training period. For the 8 months prior to choosing their project, students with complete a unique, multifaceted Technology & Automation Training Experience (TATE). They will gain hands-on experience in advanced techniques in synthesis, automation, modelling and virtual reality. In conjunction with our Dynamic Laboratory Manual (DLM), the students will also expand their experience and confidence with interactive, virtual versions of essential experimental techniques, using simulations, videos, tutorials and quizzes to allow them to learn from mistakes quickly, effectively and safely before entering the lab. In parallel, they will develop their teamworking, leadership and thinking skills through brainstorming and problemsolving sessions, some of them led by our industrial partners. Brainstorming involves the students generating ideas on outline proposals which they then present to the project leaders in a lively and engaging interactive feedback session, which invariably sees new and student-driven ideas emerge. By allowing students to become fully engaged with the projects and staff, brainstorming ensures that students take ownership of a PhD proposal from the start and develop early on a creative and collaborative atmosphere towards problem solving. TATE also provides a formal assessment mechanism, allow the students to make a fully informed choice of PhD project, and engages them in the use of the key innovative techniques of automation, machine learning and virtual reality that they will build on during their projects. We will integrate into our CDT direct interaction and training from entrepreneurs who themselves have taken scientific ideas from the lab into the market. By combining our expertise in synthesis training with new training platforms in automation, ML/AI/VR and entrepreneurship this new CDT will produce graduates better able to navigate the fast-changing chemical landscape.