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

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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.