Increasing the Efficiency of Chemical Synthesis Using Asymmetric Transition Metal Catalysis

Organic molecules of all shapes and sizes are required for a multitude of applications in numerous settings, such as in the biomedical, pharmaceutical, and agrochemical industries, to name but a few. To meet this demand, organic synthesis is faced with the challenge of converting simple, readily available chemical building blocks into more complex structures in as rapid, efficient, and cost-effective a manner as possible. As such, increasing the efficiency of organic synthesis provides enormous benefits to society, quality of life, and a sustainable future. In this context, the use of catalysis to promote chemical reactions will play a vital role. The addition of small quantities of a catalyst to open up, accelerate, and fully control the outcome of complex chemical processes offers unparalleled opportunities for increasing the efficiency of organic synthesis. Of the catalysts available, those based upon transition metals are particularly valuable for the following reasons:1. Reactions catalysed by transition metals often proceed under very mild conditions.2. Transition metals exhibit a broad range of different behaviours, allowing their use in a tremendously diverse range of reactions. Simply replacing one transition metal catalyst with another can completely alter the course of a process, enabling a suite of powerful, complementary reactions to be developed.3. Transition metal-based catalysts are often comprised of an organic molecule called a ligand bound to a metal salt. This ligand fundamentally alters the steric and electronic characteristics of that catalyst, ultimately impacting chemical behaviour. Simply replacing one ligand with another can completely alter the outcome of a chemical reaction, allowing chemists to fine tune a catalyst to fit the purpose.In this proposal, we outline novel strategies to prepare useful chemical building blocks through a variety of reactions catalysed by transition metals. An important feature of the reactions is that the catalyst will control which particular enantiomer (non-superimposable mirror image) of the product is formed. This aspect is vital since different enantiomers of functional molecules (such as drugs) often display different behaviours. During the course of this research, we hope to be able to establish concepts that can be applied in initially unanticipated contexts, ultimately providing positive contributions to organic synthesis and society.

In addition to academic researchers, this research will benefit: - Chemists in the pharmaceutical and agrochemical industries. The development of new synthetic methodologies that enable more efficient access to in-demand molecules will streamline the process of developing new medicines and agrochemicals in several ways. First, new methodologies may be used to prepare large arrays of molecules that are employed in biological screening to identify new lead compounds for development. Second, advances in organic synthesis allow the large-scale synthesis of final drugs/agrochemicals in a more efficient and cost-effective fashion. - Chemical vendors. Compound vendors that embrace new synthetic methodologies will be able to increase their range of compounds offered for sale, which has broad implications since they underpin important activities conducted by pharmaceutical and agrochemical companies mentioned above. - Human health and farming. The ability of pharmaceutical companies to streamline their drug development effort through more efficient chemical synthesis can reduce the time interval between identification of potential therapeutic agents and their synthesis for biological evaluation, allowing for more efficient throughput of drugs into the market. Positive consequences for human health can result. Similar factors apply for agrochemical companies, for which more effective synthesis of crop protection agents will have widespread benefits for agriculture. - The UK economy. The ability to manufacture a greater range of drugs/agrochemicals more efficiently will enable pharmaceutical/agrochemical companies to operate more profitably. These sectors of the chemical industry are major players in the UK economy, being important for wealth creation and employment of thousands of skilled personnel. - The PDRA and PhD researchers on this project. The training of highly skilled personnel in synthetic chemistry is vital to maintain vibrant academic and industrial research communities, which are currently areas of strength in the UK's knowledge-based economy. - The environment. Industrial activities inevitably affect our environment in one way or another. The key to minimising these impacts to non-harmful and sustainable levels is to conduct these activities in the most efficient manner possible. In this context, reduction of time, labour, power consumption, processing of raw materials, and waste generation are desirable attributes. Advances in catalyst technology will assist in the effort to minimise damage to the environment by making previously lengthy, difficult-to-execute, and wasteful synthetic routes into more concise ones. To ensure that the potential beneficiary base is as broad as possible and that beneficiaries receive maximum gain, dissemination of this research will be conducted through the following channels: - Publication of the results in widely read high-impact international science or general chemistry journals. - Presentation of the results by the PI at national and internationally invited seminars/talks at universities, companies, and conferences. - Presentation of the results by the PDRA and PhD researchers orally or through pposters at international conferences or local/national meetings. - Regular contact with previous/current industrial collaborators to exchange information and to facilitate testing the latest developments arising from this research programme. Intellectual property that arises through the development of practical processes of industrial/commercial relevance will be exploited by the Principal Investigator and Edinburgh Research and Innovation (ERI). ERI is a wholly-owned subsidiary company of the University of Edinburgh, and was established to market and commercialise the University's research activities. ERI has extensive experience of working with external organisations and developing the commercial opportunities arising from new and innovative developments in academic research.