Gold-Catalysed Direct Allylic Etherification of Alcohols

The synthesis of complex molecules of the type produced by the fine chemicals industry (e.g. pharmaceuticals and agrochemicals) often involves a sequence of challenging chemical transformations. As such it is vital that each of these steps is as efficient as possible. This means giving consideration to the ease of access to reactants, minimizing energy usage, and also minimizing any side products. Ideally, the reaction will selectively produce a single chemical in the form of the target material. Combining these desirable features will ultimately reduce the financial cost and environmental impact of the synthetic process to a minimum.

A general solution to these demands is the development of suitable catalysts that will allow reactions to occur under mild conditions with reduced (or easily handled) waste. In this proposal we seek to implement these ideas for a key general process in chemical synthesis: the synthesis of allylic ethers.

Our approach will be to develop a new gold-catalysed methodology for allylic ether formation that uses simple allylic alcohols as the starting point for synthesis. Allylic alcohols are cheap and readily available starting materials that do not require complicated prior synthesis. Our method uses gold to promote the reaction of the allylic alcohol with a second (different) alcohol molecule to form a new allylic ether. Under these circumstances a new C-O bond is formed and the only side product is environmentally benign water. We have preliminary results that demonstrate the feasibility of this process and that it occurs under mild conditions that are tolerant of air and moisture, suggesting our methods can be developed for wide use in synthesis.

The initial aim of our work is first to fully understand the way in which the direct allylic etherification reaction works and we will achieve this through a combination of experimental chemistry and computational modeling. The insight gained will then allow us to extend our catalytic process to produce more elaborate allylic ethers, with control of selectivity of the reaction in terms of the regio-, stereo-(E/Z) and ultimately enantioselectivity of the products. Ideally we will be able to form a single chemically useful form of a wide range of allylic ethers. A particularly challenging aspect is the development of enantioselective processes. Such reactions are not well established in gold-catalysis and we expect the insight we gain into such reactions will be relevant to a range of other reactions well beyond the specific allylic etherification that we will study here. We will also seek to extend our methods to other nucleophiles, by replacing the alcohols with different species that will permit new C-N and C-C bond forming reactions to be developed, that run under the favourable tolerant conditions of gold-catalysis.

The project will provide the basis for a new tool, for both synthetic organic chemistry and the fine chemicals industry, that is clean, energy economic and broad ranging in its applicability.

Who will benefit from this research?

In addition to the academic beneficiaries describe in the previous section, the additional potential beneficiaries of the research described in this proposal can be split into four groups: a) researchers in industry working on catalysis, green chemistry and synthesis, b) industrial chemistry - especially the fine chemicals industry (e.g. pharmaceutical and agrochemical industry) which rely on new and efficient catalytic processes, c) the wider public, and d) PDRAs employed on this project.

How will they benefit from this research?

a) Researchers in industry working on catalysis will benefit from the insight gained into the mechanism of specific gold(I)-catalysed reactions of allylic alcohols. Furthermore, the general insight of what factors control enantioselectivity in gold-catalysis will be of more general interest and may suggest ways to incorporate this into a range of organic transformations. These insights should impact on a relatively short timescale (2-4 years). Industrial researchers involved in synthesis will greatly benefit from the availability of new and efficient synthetic routes with simplified, practical procedures and less waste. Synthetic chemists may therefore apply our methods to design and allow efficient synthesis of target molecules. Industrial researchers may very well adopt these methods in drug and pesticide discovery programmes on a relatively short timescale (3-5 years).

b) Industrial chemistry. More environmentally friendly processes are important throughout the chemical industry. Our proposed work will have a beneficial impact as it is designed to be efficient, atom-economical, practical and with reduced waste. The work is of particular relevance to the fine chemicals industry (e.g. pharmaceutical and agrochemical) and will therefore allow this sector to respond to the growing pressure for environmentally sustainable synthetic processes. Industry will also benefit from new methods which will allow for shorter synthetic sequences to target compounds, resulting in cost and time savings. Potential uptake of this methodology on an industrial scale is likely to be on a longer timescale (8-15 years).

c) Wider public. More efficient and environmentally friendly processes available for the chemical industry should also lead to benefits for the wider public. These benefits will be associated with a longer term improvement of quality of life through their potential application in the synthesis of fine chemicals such as pharmaceuticals and agrochemicals, as well as the lesser environmental impact of the processes associated with the production of such commodities.

d) PDRAs. The PDRAs on the project will experience immediate impact of the work by receiving excellent training in catalysis and synthetic chemistry or first class training in modern computational chemistry. Due to the nature of the project, both PDRAS will work in close collaboration such that the experimentalist will have the invaluable opportunity of working alongside computational chemists, and thus gaining insight into a different field (and vice versa). Both PDRAs will have the opportunity to develop transferrable and employability skills including communication and presentation skills (both oral and written), team working and organisational skills. Ultimately, the PDRAs trained during the course of this project will be in a position to play a significant future role, either academically or industrially.