Whilst traditional medicine largely depended on the serendipitous discovery of biologically active molecules, contemporary medicinal chemistry often involves the design of new molecules that may not exist already, based on a deep understanding of the interaction of the proposed drug molecule with its biological target. This process is frequently aided by computers, which can design drug molecules with the required characteristics for the desired biological activity based on an understanding of how the drug will operate. Thus, modern drug discovery relies heavily on the availability of efficient methods to prepare new drug molecules, as well as the precursors to the drug molecules themselves. Four-membered heterocycles are a class of rigid molecules that contain at least one heteroatom (an atom other than carbon - for example, oxygen, nitrogen or sulfur) arranged in a ring of four atoms. These molecules are of interest in drug discovery because their rigidity results in specific topologies that often interact better with biological targets than more "floppy" molecules. In particular, spirocyclic versions of these molecules (in which two rings of atoms are joined, sharing one atom in common) are especially promising as precursors to drug molecules. However, these molecules are very difficult to prepare, and the methods that do exist for their preparation are often specific to certain substitution (highly substituted examples are difficult to access), resulting in a limited range of these drug precursors being available. This project aims to streamline the preparation of these spirocyclic four-membered heterocycles, by developing new methodology that will be applicable across all of the classes of heterocycle (i.e. irrespective of the heteroatom(s) contained within the ring). Thus, a library of simple spirocyclic drug precursors will be generated, which can then be further "decorated" using existing chemistries to produce bespoke drug molecules for specific applications. The new methodology will make use of a reagent named cyclobutadiene, which is extremely versatile but has seen limited use previously. Cyclobutadiene is extremely reactive, so it cannot be stored and must be prepared immediately as it is to be used, and previously, no convenient precursors were available for its generation. This project will develop new precursors to cyclobutadiene that allow the generation of cyclobutadiene under mild conditions, with several different variants of essentially the same precursor being developed for different applications. As a result, a generally applicable, modular preparation of four-membered heterocycles will be enabled, making these molecules available as precursors to new drugs. To ensure that our methodology is broadly adopted, our products will be marketed in a timely fashion by our project partner Key Organics - a fine chemicals company with international reach. This will maximise the impact of our methodology, and ensure that our products are available not only to drug discovery researchers, but also to a wide variety of other sectors. Longer term, we aspire to develop further applications of our molecular scaffolds, not necessarily limited to drug discovery, but also in other areas requiring rigid, small-molecule motifs.

Commercially synthesised organic chemicals are crucial to industries as diverse as agriculture, medicine and electronics. The enormous global demand for these products is constantly rising in the face of innovations in drug design and everyday technology, such as mobile phones and solar panels. Set against this is the increasingly important need to conserve energy and raw materials, in the context of environmental concerns and diminishing natural resources. Catalysis is an extremely important tool in reconciling these competing demands. Using a catalyst lowers the energy barrier to carry out a given chemical reaction, allowing processes to function at lower temperatures and pressures, consuming less energy. Catalysts can also improve resource and time economy by promoting new reactions, reducing the number of reagents and steps required to obtain an end product. Catalysts are not consumed in these processes, but regenerated, making them a keystone of sustainable synthetic chemistry. This project will provide the fundamental research needed for development of low cost, efficient and accessible new catalysts. Currently, many of the catalysts most widely used in commercial organic synthesis are based on costly transition metals such as platinum, palladium, rhodium and gold, which have low natural abundance. Research into new catalysts is increasingly focused on replacing these with cheaper metals in existing catalytic processes. It is also desirable to develop catalysts for new processes, leading to improved reaction pathways and new products. While simple halides of main group elements have long been used as Lewis acid catalysts, these are generally corrosive and lack any tuneability. The development of catalysts based on organometallic main group derivatives is a nascent but rapidly growing area of study. Several important advances in recent years have challenged the idea that transition metals are necessary for the catalysis of organic bond forming reactions. Main group metals such as antimony (Sb) and bismuth (Bi) are abundant and inexpensive (more than 20 times cheaper than platinum, for example). The proposed research will develop straightforward synthetic routes to new molecules comprising organic and fluoride substituted Sb and Bi cations with weakly coordinating anions. Based on previous work, these molecules have the potential to be good catalysts for organic transformations because of their tuneable Lewis acidity and well-defined vacant binding sites. Organometallic compounds of heavy main group metals have until now received far less study than those of transition metals, and research into the organic fluorides of Sb and Bi has been particularly limited, despite these promising attributes. An important outcome of this project will be to understand the fundamental chemistry and bonding of these types of compound, and determine the most efficient ways to produce them. Investigation of their reactivity with Lewis bases and small organic molecules will help to identify potential catalysts which will be screened against a test set of key reactions. Establishing the basic chemistry governing the interaction of main group organometallic molecules with organic substrates is essential to reducing global dependence on expensive transition metal catalysts in the long term.

GSK is a global healthcare company that discovers, develops and manufactures medicines to treat a range of conditions including: respiratory diseases, cancer, heart disease, epilepsy, bacterial and viral infections (such as HIV and lupus), and skin conditions like psoriasis. GSK makes over 4 billion packs of medicines each year, with the goal of playing its part in meeting some of society's biggest healthcare challenges. Alongside a mission to provide transformative medicines to patients, GSK continually seeks to improve the efficiency and sustainability of our processes across the discovery, manufacturing, and delivery components of our supply chain. Indeed, GSK are committed to ambitious sustainability goals by 2050 that can only be achieved by making existing and future medicines via better routes, driving innovation all the way from the first design of the molecule through to patients in the clinic. This Prosperity Partnership aims to build on existing vibrant collaborations between GSK and the Universities of Nottingham and Strathclyde. The strengths of each partner will be leveraged to deliver a new suite of methods and approaches to tackle some of the major challenges in the discovery, development, and manufacture of medicines. Our vision is to increase efficiency in terms of atoms, energy, and time; resulting in transformative medicines at lower costs, reduced waste production, and shorter manufacturing routes. Key challenge areas, or themes, covered in our partnership include: 1. The development and application of Artificial Intelligence (AI) and Machine Learning to the efficient identification of next generation medicines: in Drug Discovery, many hundreds of candidate structures are designed, prepared, and tested to find the molecule with the right profile to take into the clinic. The development of AI informed decision making has the potential to deliver huge savings by minimising the number of compounds that need to be made at this stage. The software developed will incorporate green chemistry principles with the goal that the chemical methods employed are as efficient and sustainable as possible. 2. Next generation catalysis and synthesis: Chemists seeking to discover new medicines need new reactions that will allow them to make and investigate structures that are currently difficult, or even impossible, to make. A key objective of this proposal will be to develop new reagents, catalysts, and reactions to facilitate the more efficient preparation of drug-like molecules to accelerate drug discovery. Similarly, we will develop new ways of performing some of the most common chemical transformations in the synthesis of medicines whilst avoiding the use of carcinogenic reagents. 3. Sustainable processes that deliver efficiency and transition to scale-up from grammes to kilogrammes. Currently under-utilised approaches, such as electrochemistry, will be explored for their ability to catalyse reactions with cheaper and less environmentally impactful metals, such as replacing palladium with nickel. 4. A new Digital Design toolset for equipment will enable Digital Manufacturing of novel pharmaceutical processing equipment. Current development relies on existing traditional vessels and flow reactors that compromise our ability to deliver processes that operate at optimal performance. The research will couple advanced process models, state-of-the-art experimentation, and 3-D printing/additive manufacturing technologies to revolutionise how we develop, scale up, and operate chemical processes to supply new medicines. Integration of the projects and the expertise from the three partner institutions, and the successful prosecution of our research objectives, will make a major contribution to the wider pharmaceutical sector and, indeed, GSK's mission of discovering and developing transformative medicines faster to help people do more, feel better, and live longer.

Advanced economies are confronted with serious challenges that require us to approach problem solving in a completely different way. As the climate emergency deepens and our global population continues to rise, we must all consider several quite taxing philosophical questions, most pressingly we must address our addiction to economic growth, our expectation for longer, healthier lives and our insatiable need to collect more stuff! Societies demand for performance molecules, ranging from pharmaceuticals to fragrances or adhesives to lubricants, is growing year-on-year and the advent of competition in a globalised marketplace is generally forcing the market price downward, cutting margins and reducing the ability for some industry sectors to innovate. Feedstock to Function (F2F) is an exciting opportunity to forge a new philosophy that could underpin the next phase of sustainable growth for the chemicals manufacturing industry in the UK and further afield. An overarching driving force in the development of F2F was the desire to apply the knowledge and learning of Green and Sustainable Chemistry onto some of the biggest challenges that confront chemicals manufacture, from the smallest-scale, to the delivery of efficient and resilient processes that will future proof supply chains for the foreseeable future. Our CDT in resilient chemistry will deliver a sustainable pipeline of performance molecules, by moving towards circularity and resilience in feedstocks, and efficiency in processing and reaction chemistries . F2F will create an Integrated Approach to Sustainable Chemistry, promoting a culture of resilience in terms of materials and matter via industrially defined priorities: I. Sustainable routes to nitrogen containing molecules, avoiding Haber-Bosch fixed precursors: II. Non-petroleum routes to hydrocarbon feedstocks, particularly synthetic naphtha (C8-C30) III. Circular chemistries to manage the impact of phosphorus and other key inorganic materials; and IV. Enhanced circularity for technical materials including metals, catalysts, solvents and salts. F2F represents a multidisciplinary group of 45 academic advisors spanning 7 academic disciplines and two Universities, working together with a growing family of industrial partners who have expressed a common desire to develop Smarter products using Better chemistry to enable Faster processing and Shorter manufacturing routes. F2F will innovate by: 1 fostering a multidisciplinary, cohort-based approach to problem solving; 2 focus on challenge areas identified by our F2F partners such that sub-groups of our cohort can become immersed in research that impacts on industry; 3 embedding aspects of data-driven decision making in the day-to-day design and execution of high-quality research either on paper or indeed in the lab; 4 nurturing a vibrant and supportive community that allows PhD candidates to think 'outside of the box' in a relatively risk-free way; 5 developing 'next generation' synthesis using chemo- and bio-catalytic methods to drive efficiency, selectivity and productivity, underpinned by predictive in-silico methods and valorisation of big data; 6 streamlining the discovery process by enabling technologies: such as energy resilient photo/electrochemical methods, cleaner solvents and renewable materials 7 developing sustainable processes that deliver efficiency and transition to scale-up from g to Kg, applying state-of-the-art manufacturing including 3-D printing, fermentation, multiphase flow, in-line diagnostics to underpin rapid translation into industry; 8 applying robust reaction/process evaluation metrics such that comparative advantages can be quantified, providing evidence for real process decision making. F2F will train PhD graduates with the vision and skills to drive decarbonisation in the UK Chemicals using industries, securing innovation and future growth for this critical manufacturing sector.

Advanced economies are now confronted with a serious challenge that requires us to approach problem solving in a completely different way. As our global population continues to rise we must all consider several quite taxing philosophical questions, most pressingly we must address our addiction to economic growth, our expectation for longer, healthier lives and our insatiable need to collect more stuff! Societies demand for performance molecules, ranging from pharmaceuticals to fragrances or adhesives to lubricants, is growing year-on-year and the advent of competition in a globalised market place is generally forcing the market price downward, cutting margins and reducing the ability for some industry sectors to innovate. Atoms to Products (A2P) is an exciting opportunity to forge a new philosophy that could underpin the next phase of sustainable growth for the chemicals manufacturing industry in the UK and further afield. An overarching driving force in the development of A2P was the desire to apply the knowledge and learning of Green and Sustainable Chemistry to the creative phases embedded in the discovery and development of performance molecules that deliver function in applications as diverse as pharmaceuticals, agrochemicals and food. We propose a multi-disciplinary CDT in sustainable chemistry which aims to achieve a sustainable pipeline of performance molecules from design-to-delivery. A2P will create an Integrated Approach to Sustainable Chemistry, promoting a culture of waste minimisation, emphasising the development of a circular economy in terms of materials and matter replacing current modes of consumption and resource use. A2P represents a multidisciplinary group of 40 academic advisors spanning 7 academic disciplines, working together with a growing family of industrial partners spanning well-known multinationals including Unilever, GSK, AstraZeneca and Croda, and niche SMEs, including Promethean Particles, Sygnature and European Thermodynamics. Interestingly all partners have expressed a common desire to develop Smarter products using Better chemistry to enable Faster processing and Shorter manufacturing routes. A2P will drive innovation by: 1 fostering a multidisciplinary, cohort based approach to problem solving; 2 focussing on challenge areas identified by our A2P partners such that sub-groups of our cohort can become immersed in research at the "coal-face"; 3 embedding aspects of data-driven decision making in the day-to-day design and execution of high quality research either on paper or indeed in the lab; 4 nurturing a vibrant and supportive community that allows PhD candidates to think 'outside of the box' in a relatively risk- free way; 5 empowering the development of 'next generation' synthetic methods to drive efficiency, selectivity and productivity, underpinned my molecular modelling and the use of machine learning to extract additional value from experimental data; 6 developing sustainable processes that deliver efficiency and transition to scale-up from g to Kg, under-utilised approaches, including electrochemistry, will be investigated increase atom efficiency and reduce reliance on precious metals; 7 enabling efficient scale-up of new processes using flow-chemistry and 3-D printing technology to "print" the most efficient reactor system, thereby maximising throughput whilst efficiently managing mass transport and thermal factors; 8 applying robust reaction/process evaluation metrics such that comparative advantages can be quantified, providing evidence for real process decision making. Integration of outcomes from all A2P PhD projects, in combination with the expertise of all A2P partners, will deliver a major contribution to the health of the UK chemicals manufacturing industry. A2P will provide mentorship and training to the next generation of leaders securing innovation and future growth for this critical manufacturing sector.