Chiral amines are prevalent in natural products, which often display potent biological activity. Such chiral amine motifs are also frequently found in pharmaceutical drug compounds and chemical building blocks meaning that the development of environmentally benign and sustainable routes to produce these important motifs is extremely desirable. Nature synthesizes these complex and valuable molecules through the action of highly specialized enzymes. These natural catalysts enable an extremely efficient biosynthesis from simple starting materials, installing functional groups with exceptional levels of selectivity. Chemical catalysts are frequently designed to mimic the action of enzymes and are often capable of achieving impressive selectivity. However, unlike enzymes, processes involving these catalysts usually involve high temperatures, sub-optimal pH, organic solvent and complex purification methods. Enzymes called omega-transaminases (TAs) catalyze the conversion of commercially available or easily accessible starting materials to high-value amines. These biocatalysts require an additional donor molecule to provide the amine functional group. This donor is ultimately converted to a by-product and the desired amine product is formed. However, the reaction is freely reversible and unless this by-product is removed from the reaction, low yields of the desired amine will be isolated, as the enzyme will more readily catalyse the reverse reaction to regenerate starting materials. A number of elegant approaches have been reported which remove this ketone by-product and allow access to appreciable quantities of the chiral amine. These strategies include the addition of expensive enzymes or the use of extremely large quantities of the amine donor in combination with the technically challenging removal of ketone by-products. One such approach, which relies on an extensively modified TA, is currently used for the industrial synthesis of the antidiabetic drug compound, sitagliptin. However, the approach is far from efficient and the development of this heavily modified TA biocatalyst was enormously challenging, highlighting an immediate need for more sustainable strategies for performing these biotransformations and for developing suitable enzyme catalysts. This research will build upon recent work reported in our laboratory that describes arguably the most efficient approach to date for performing biotransformations involving TAs. The success of the approach is due to spontaneous precipitation of the by-product, which cannot regenerate starting materials. This polymer is also highly colored and has allowed the development of an effective high-throughput screening strategy that enables the rapid identification of active enzymes. Our focus now is to optimize the process further and make it more suitable for industrial application. Specifically, low cost amine donor molecules will be used that are spontaneously removed from the reaction in a similar way to our previously reported method. We will also apply a simple high-throughput screening strategy to assist in the genetic engineering of natural enzymes in order to increase the scope of the reactions that they can catalyze and make them suitable for industrial scale synthesis. The enzymes developed in this study will enable cost-effective, sustainable and environmentally neutral methods for the small/medium and industrial scale production of one of the most important compound classes.

The broad theme of the research training addresses the most rapidly developing parts of the bio-centred pharmaceutical and healthcare biotech industry. It meets specific training needs defined by the industry-led bioProcessUK and the Association of British Pharmaceutical Industry. The Centre proposal aligns with the EPSRC Delivery Plan 2008/9 to 2010/11, which notes pharmaceuticals as one of the UK's most dynamic industries. The EPSRC Next-Generation Healthcare theme is to link appropriate engineering and physical science research to the work of healthcare partners for improved translation of research output into clinical products and services. We address this directly. The bio-centred pharmaceutical sector is composed of three parts which the Centre will address:- More selective small molecule drugs produced using biocatalysis integrated with chemistry;- Biopharmaceutical therapeutic proteins and vaccines;- Human cell-based therapies.In each case new bioprocessing challenges are now being posed by the use of extensive molecular engineering to enhance the clinical outcome and the training proposed addresses the new challenges. Though one of the UK's most research intensive industries, pharmaceuticals is under intense strain due to:- Increasing global competition from lower cost countries;- The greater difficulty of bringing through increasingly complex medicines, for many of which the process of production is more difficult; - Pressure by governments to reduce the price paid by easing entry of generic copies and reducing drug reimbursement levels. These developments demand constant innovation and the Industrial Doctorate Training Centre will address the intellectual development and rigorous training of those who will lead on bioprocessing aspects. The activity will be conducted alongside the EPSRC Innovative Manufacturing Research Centre for Bioprocessing which an international review concluded leads the world in its approach to an increasingly important area .

USA

Aliphatic amines are central to the function of many biologically active molecules as evidenced by their prevalence in a large number of pharmaceutical agents. The groups appended to these nitrogen atoms are crucial in determining the physical properties of the amine and are linked to how well it interacts with a biological target. Despite the apparent simplicity of the aliphatic amine motif, the number of general methods available for the synthesis of this important feature is surprisingly small. Methods such as reductive amination, alkylative tactics, hydroamination and transamination have met the demand for many years, however the development of new straightforward methods for the synthesis of complex systems is essential for the continued advance of synthesis. A systematic method for the synthesis of complex aliphatic amines would be valuable to practitioners of drug discovery, and a streamlined approach to these molecules could involve a catalytic process capable of transforming simple, readily available aliphatic amines into complex variants via selective functionalization of their C-H bonds. Methods that enable the practical and selective functionalization of inert aliphatic C-H bonds have applications in fields that range from fine chemical production to drug discovery. Transition metal catalysis has emerged as a powerful tool to activate these traditionally unreactive C-H bonds. Several classes of functional group can direct C-H activation via a process called cyclometallation; coordination of the metal centre to a proximal Lewis basic atom steers the catalyst into position where the C-H bond can be cleaved. Reaction of the resulting C-metal bond with an external reagent leads to an overall transformation that sees a C-H bond converted into a versatile motif. Cyclometallation has led to a number of useful catalytic C-H functionalization processes that have expanded the chemists toolbox of available reactions; tailoring the electronic properties of directing functionalities has enabled cyclometallation in aliphatic hydrocarbons displaying carboxylic acid, hydroxyl groups, and derivatives of these motifs. Despite these advances, related transformations on aliphatic amines are rare and successful examples require the use of strongly electron withdrawing sulfonyl or bespoke directing groups to modulate the metal coordinating power of the nitrogen atom. As such, their synthetic intractability frequently precludes the wider application of strategic C-H bond activation in aliphatic amine systems. The overarching aim of this proposal is to establish aliphatic amines as viable feedstock molecules for C-H activation using a novel activation strategy. This will provide distinct C-H disconnections that will form part of a C-H activation road map for synthesis. The aliphatic amine motif is so ubiquitous in pharmaceutically relevant molecules that it is considered a 'privileged' feature and so we will investigate how the multi-faceted C-H activation platform can be translated into viable applications that have impact drug discovery and development.

Metamaterials are artificial materials with characteristics beyond those found in nature and that enable on-demand control of energy, waves and information to realise game-changing product performance, energy efficiency and functionality. Designed with structure and inclusions on the atom-to-wavelength scale, they underpin exciting emerging trends across a range of markets, e.g., telecommunications, aerospace, medical, sensors, automotive radar, imaging, anti-counterfeiting, camouflage, vibration suppression and more. Numerous market research studies predict significant growth, for example, by 2030 the metamaterial device market is expected to reach a value of over $10bn [e.g., Lux Research 2019]. Conventional metamaterials have a response or functionality that is fixed at the time of manufacture. Furthermore, metamaterials often suffer from functionality only over a relatively narrow band of frequencies, whereas many of today's applications require multifunctionality and reconfigurability, while reducing size, weight power and cost. The topic of this proposal, tunable, reconfigurable and programmable metamaterials and active devices, offers the potential of dynamic functionality in order to respond to external stimuli, or change functionality in real-time to meet specific application requirements. In our "A-Meta" collaboration we exploit synergies between the expertise and facilities of the University of Exeter's Centre for Metamaterial Research and Innovation (CMRI) in the UK, and the National Science Foundation Industry-University Cooperative Research Center for Metamaterials (CfM) in the USA. Together, we focus on three novel methods for enabling metamaterial tunability: phase-change-metasurfaces in the optical regime; photoexcitation of semiconductors for the microwave and THz; and polymer-loaded locally resonant meta-atoms for phononics and elastic waves. Our long list of project partners (Airbus, BAE Systems, Ball Aerospace, Bodkin Design, British Telecommunications, Dstl, Metamaterial Technologies, M.Ventures (Merck), NASA, Oxford Instruments, Phoebus Optoelectronics, QinetiQ, Thales, Transense Technologies, and Wave Optics) demonstrates the timely and strategic importance of active metamaterials and associated devices. Their letters of support detail strong relevance to applications such as wireless communication, sensing, filtering, imaging, consumer electronics, autonomous vehicles, RF devices, efficient and fast computing, high performance mechanical structures, manufacturing processes, and underwater sound control.