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

Final Report Summary - ENOLAR (Arylation and Vinylation of Enolates: New Reactivity from the Urea Linkage)

The project aimed to develop new synthetic routes to quaternary alpha-arylated and vinylated amino acids, molecules which are of great value in medicinal, pharmaceutical and fine chemical industry. Principal objectives were:
1. Arylation and vinylation of amino acids: We will develop a methodology using strong bases to induce rearrangement of amino acid derives ureas, leading to the synthesis of quaternary amino acids and their derivatives.
2. Controlling absolute configuration: We aim to use chiral ligands or auxiliaries to induce enantioselective rearrangement, leading to quaternary amino acids as single enantiomers.
3. Mechanistic investigation: using NMR, in situ IR, and DFT calculations we will investigate the mechanism of the rearrangement, identifying intermediates along the reaction pathway.
4. Extending to other α-heterocarboxylic acid derivatives: Extension to reactions of carbamates and of thiocarbamates will allow the synthesis of a broad range of heterofunctionalised carboxylic acid derivatives.
5. Arylation and vinylation of ketones and aldehydes: Extension to the arylation of ketones and aldehydes allows synthesis of important structures with known biological activity.

1. We found that treatment of the urea derivatives of amino acids with strong base gave racemic hydantoin products which in certain cases could be converted to the amino acids.
2. By using a chiral auxiliary we were able to make single enantiomers of amino acids from their ephedrine amide derivatives. With chiral starting materials it proved possible to make derivatives of proline by stereoselective rearrangement. This work was published (J. Org. Chem. 2015, 80, 10757-10768 [doi 10.1021/acs.joc.5b01912])
3. Mechanistic studies by infra-red revealed the pathway of the reaction, but not the reason for its remarkable efficiency, so we turned to computation. Density functional theory calculations showed that the reaction relies of the conformation of the urea to proceed. These results were published (Eur. J. Org. Chem. 2015, 953-959 [doi 10.1002/ejoc.201403572])
4. Extension to heterosubstituted carboxylic acid derivatives was unsuccessful, so instead we investigated the rearrangement of heterocyclic structures with potential for use in the synthesis of medicinal candidates. We found that, remarkably, pyridyl groups were capable of stabilizing configurationally stable anions, allowing the synthesis of heterocyclic quaternary carbinamines. A publication on this work is in preparation.
5. Arylation of aldehydes and ketones provied unsuccessful, using a variety of conditions.
We additionally explored the vinylation and alkynylation of amino acids in parallel, with Julien Maury helping to supervise the work of a PhD student, Josep Mas Rosello. Vinylation proved successful and a paper on this work is in preparation. Alkynylation ran into difficulties with the synthesis of the starting materials, and we are still unable to find conditions to make the alkynylurea precursor.

Overall the project made excellent progress, with progress towards the stereoselective specific aspects of the reaction revealing key structural features allowing the efficient synthesis of heterocyclic (pyridyl, pyrrolidinyl) amino acids in particular. It also revealed key aspects of the mechanism that have allowed further developments and application to related structures.
The work led to further ongoing work in the hands of current research students Wojciech Zawodny on biocatalytic routes to starting materials, Josep Mas Rosello on amino acid vinylation, and Daniel Leonard on chiral memory in amino acid synthesis.
The work has potential impact to the pharmaceutical and fine chemical industry, and further research in this area has attracted interest from companies such as MerckSigma, Syngenta and AstraZeneca.
Details of the work (participants, publications) are found at