alpha-Arylation and alpha-Vinylation of Enolates: New Reactivity from the Urea Linkage

Lead Research Organisation: University of Bristol
Department Name: Chemistry

Abstract

Amino acids are the simplest building blocks from which life is built. Most biological structures, and many of the molecules which allow life to function, are built in some way from amino acids. For this reason, when chemists design molecules to interact with life - new drugs for example - they often turn to amino acid structures. Although Nature typically uses just 20 amino acids, synthetic compounds can in principle be built from millions of possible alternatives, many of which may be made from the readily available natural versions. The problem is that the conversion of a natural amino acid to a modified synthetic one is subject to severe restrictions with regard to molecular structure and also the type of reagents that can be used. In this project, we propose to develop a conceptually new way of making synthetic amino acids from natural ones which avoids some of these problems. It allows ring structures to be introduced to the amino acids, and importantly it avoids using heavy metals, such as palladium, which are expensive, suffer from potential supply shortages, and cause problems if residues remain in molecules of potential use in medicine.
The chemistry we propose to explore makes use of a rather neglected and underestimated functional molecular fragment based on the structure of the famous waste product found in urine: urea. Linking the molecule of amino acid to the new fragment through a modified urea molecule brings the partners into close contact and allows them to react in ways that would be impossible under normal conditions. The reaction that results is so unusual that we shall need to investigate in detail the way that the reaction circumvents the usual well established rules of chemical reactivity.
The reaction will offer to chemists a new way of building simple structures efficiently, and will be useful in the design and production of molecules of potential value as drugs or in other fields of biomedicine.

Planned Impact

The central challenge in making organic molecules-a field of technology which underpins great tracts of national scientific and industrial endeavour-is to construct carbon-carbon bonds. Our work proposes to open up a new mode of reactivity allowing these bonds to be made, with consequent impacts for the way new molecules may be made efficiently - whether those molecules are actual or potential drugs to treat diseases, new materials, or tools for healthcare and bioscience. We aim to achieve a currently impossible transformation, but most comparable methods make use of expensive heavy metals (such as palladium) with erratic supply chains: we will avoid the use of palladium, and in its place use the much more abundant, cheap, light and non-toxic lithium. We will need proportionately more metal, but the environmental and economic impact will be much less.

Synthetic chemists work both in university and industrial labs to build new molecules for specific functions (as potential drugs, components of new materials, selective agrochemicals, new fragrances etc.) using a toolkit of techniques. Our work offers the possibility of expanding that toolkit with techniques specifically suitable for the construction of medicinal chemistry targets. Many drugs are made from the amino acid derivatives we target in this research, because these structures have properties that make them ideal for interactions with living systems. We therefore expect to have a direct impact on the efficiency with which new products are developed and manufactured, having an impact on the provision of new tools for healthcare.

Several areas of economic importance to the UK rely heavily on a supply of new molecular entities. These include not only the established pharmaceutical and healthcare sectors, but also the emerging biotechnology, organic electronics and materials sectors. Our proposed research is aligned with these needs, and with the capability themes of the EPSRC portfolio. For example, in the Healthcare Technologies area, our methods will allow streamlined routes to molecules of importance in the battle against disease by providing scientists in the field of biological chemistry and synthetic biology with efficient tools allowing them to construct and modify molecules with biological properties. In the Manufacturing the Future theme, our intended breakthroughs in reactivity, avoiding transition metals, open the possibility increasing cost-effectiveness by using much cheaper metals and of freeing manufacturing routes to drugs, fragrances, agrochemical and materials from reliance on overseas supplies of transition metals.

Breakthroughs in research in the molecular sciences-from materials to biology-require chemists skilled in the methods of making molecules. The project will deliver a highly trained PDRA capable of finding employment in several sectors of the economy where skills in the molecular sciences are required, or alternatively of entering academia as part of the next generation of inspiring academics training the next generation of leading researchers. The PDRA will gain skills in several areas of synthetic and analytical chemistry, but will also gain more general experience of organisation and management, critical and creative thinking, the use of IT, presentation skills.

Publications

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Atkinson RC (2015) Pseudoephedrine-Directed Asymmetric a-Arylation of a-Amino Acid Derivatives. in Angewandte Chemie (International ed. in English)

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Costil R (2017) Medium-Sized-Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion. in Angewandte Chemie (International ed. in English)

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Fernández-Nieto F (2015) Palladium Catalyzed C-Arylation of Amino Acid Derived Hydantoins. in Organic letters

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Hall J (2016) Medium-Ring Nitrogen Heterocycles through Migratory Ring Expansion of Metalated Ureas in Angewandte Chemie International Edition

Related Projects

Project Reference Relationship Related To Start End Award Value
EP/L018527/1 30/05/2014 29/06/2015 £293,777
EP/L018527/2 Transfer EP/L018527/1 30/06/2015 30/05/2018 £231,446
 
Description The research developed a new way of modifying amino acid for potential use in medicinal applications. A patent was filed and currently we are seeking to license this patent to fine chemical suppliers so that they can use our method to supply the modified amino acids as intermediates for the development of new drugs.
Exploitation Route The work facilitates the development of new protein or peptide structures, and will allow a wider range of simple molecules to be screened for potential use in the development of new drugs.
Sectors Agriculture, Food and Drink,Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description After continued research in the form of an IAA, some products from the research (Q4As) are now being marketed by a commercial biotech company.
First Year Of Impact 2020
Sector Chemicals,Pharmaceuticals and Medical Biotechnology
Impact Types Economic