Increasing the Efficiency of Chemical Synthesis Using Asymmetric Transition Metal Catalysis

Lead Research Organisation: University of Nottingham
Department Name: Sch of Chemistry

Abstract

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.

Planned Impact

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.

Publications

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Best D (2014) C-N-containing azaarenes as activating groups in enantioselective catalysis. in The Journal of organic chemistry

 
Description This research has resulted in a range of new ways to make valuable chemical building blocks, primarily by the use of transition metal catalysis. Using catalysts based upon iridium, rhodium, copper, or nickel, we have uncovered a range of new synthetic methods that operate using novel modes of reactivity. A key point is that these methods generate chiral molecules, that is, molecules that are non-superimposable on their mirror images. By using chiral catalysts, we have been able to generate, in many cases, one particular mirror image of the products with high levels of selectivity (called "enantioselectivity"). This aspect is highly important, since the final function of molecules (e.g. their biological activity) often depends upon which particular mirror image they exist in. We have discovered: (1) Diastereo- and enantioselective iridium-catalysed arylative cyclisatons of alkynones. (2) New chiral ligands for the enantioselective rhodium-catalysed additions of arylboronic acids to alkenes activated by nitrogen-containing aromatic heterocycles. (3) A range of catalytic rhodium(III)-catalysed C-H functionalisation/oxidatve annulation reactions that form spirocyclic products. (4) The formation of bicyclo[3.n.1]alkanes by Michael cyclisations of substrates containing a cyclic 1,3-diketone tethered to an enone. By using chiral phosphoric acid catalysts, rather than catalysts based upon transition metals, we were able to develop a highly enantioselective version of this reaction. (5) New enantioselective rhodium(I)-catalysed nucleophilic allylations of imines. (6) Enantioselective nickel-catalysed cyclisations of alkynyl electrophiles that involve reversible E/Z isomerisation of alkenylnickel species. (7) Copper-catalysed multicomponent coupling reactions involving nitrogen-containing aromatic heterocycles.
Exploitation Route The findings from this research may stimulate other academic researchers to develop new methods to make important molecules with even greater efficiency. The methods we have developed may be adopted by synthetic chemists in the pharmaceutical and agrochemical industries to prepare biologically active molecules for use in new medicines or agrochemicals.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

 
Description This awarded funded research that resulted in a new chemical reaction developed in our laboratory; the enantioselective copper-catalysed reductive coupling of ketones with alkenes that are themselves connected to aromatic nitrogen heterocycles. This work was published in the following journal article: J. Am. Chem. Soc. 2012, 134, 8428. We have since become aware that similar chemistry was used in a patent application describing a process for the preparation of various antifungal agents (voriconazole and derivatives thereof): "Process for the preparation of voriconazole and analogues thereof" Patent number WO2014060900A1 However, although our paper is cited as relevant prior art in this patent, it may be the case that the chemistry used for this patent application was developed entirely independently and contemporaneously by industry scientists. The key point here is that the chemistry is industrially useful and applicable to the manufacture of pharmaceuticals.
First Year Of Impact 2014
Sector Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Marie Sklodowska-Curie Fellowships
Amount £126,099 (GBP)
Funding ID 702386 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 07/2016 
End 07/2018
 
Description Marie Sklowdowska-Curie Fellowships
Amount £128,290 (GBP)
Funding ID 657194 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 05/2015 
End 05/2017
 
Description Research Project Grants
Amount £180,351 (GBP)
Funding ID RPG-2016-341 
Organisation The Leverhulme Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 02/2020