Gold-Catalysed Direct Allylic Etherification of Alcohols

Lead Research Organisation: Heriot-Watt University
Department Name: Sch of Engineering and Physical Science

Abstract

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.

Planned Impact

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.

Publications

10 25 50
 
Description The main objective of the project was to develop a "Gold-Catalysed Direct Allylic Etherification of Alcohols", which has been successfully achieved. The reaction is of importance because it is very mild, produces only environmentally benign water as a by-product and minimises on waste. We have also successfully developed the reaction with efficient "chirality control", which allows us to selectively synthesise one mirror-image of the molecules over the other. Such control is of importance because the biological activity of one mirror-image can be vastly different to the other. More importantly, we also identified the factors that influence good "chirality control". Furthermore, we have successfully investigated and developed related reactions using molecules other than alcohols using gold and indium catalysis, thereby greatly expanding on the generality of the original aim. Throughout the project, computational studies were used in tandem with experimental studies in order to guide the development of the reaction, as well as to probe the mechanism of these newly developed reactions. The success of this project was down to the synergy between experimental and computational chemistry, which allowed us to gain a much deeper understanding of how our newly developed reactions work and also to guide our optimisation procedure. Our discoveries have led to 10 research publications so far, including a "Hot Article", "Cover Article" and "Feature Article". Our research has also been subject of a "Highlight" on the ChemistryViews website run by the publisher Wiley as well as being highlighted on Organic Chemistry Portal, and by independent international researchers in the journal Synfacts. There were also three invited articles in the area, including in the "New Talents" issue of Organic and Biomolecular Chemistry.
Exploitation Route The reactions and insights developed here are of potential benefit to other researchers in the field of catalysis, including researchers in industry working on catalysis, synthesis and fine chemicals industry (e.g. pharmaceuticals and agrochemical industry) which rely on new and efficient catalytic processes.
Sectors Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology

URL http://leegroup.eps.hw.ac.uk/
 
Description The work is one fundamental science, nevertheless various industrial companies have shown interest in the results of our research and the PI has been invited to give lectures and seminars on the work at various industrial companies: • 7th Biennial 'Celebration of Organic Chemistry' Symposium, Syngenta, Jealott's Hill, 19-20th September 2016. Organised by Syngenta and the Society of Chemical Industries Fine Chemicals Group. (Agrochemical industry) • AstraZeneca, Macclesfield, 18th November 2015. (Pharmaceutical industry) • GSK Emerging Academics Symposium, GlaxoSmithKline Research Centre, Stevenage, 20th Oct 2015. (Pharmaceutcial industry)
First Year Of Impact 2015
Sector Chemicals,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Leverhulme Trust Project Grant
Amount £106,832 (GBP)
Funding ID RPG-2014-345 
Organisation The Leverhulme Trust 
Sector Academic/University
Country United Kingdom
Start 05/2015 
End 05/2017
 
Description Dalton 2014 Joint Interest Groups Meeting, Warwick University 15-17 April 2014 (Attended by PDRA Dr Dave Johnson) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Attended a major chemistry conference with a focus on inorganic and organometallic chemistry, with several talks and posters covering gold chemistry.

Networking occurred throughout the conference, with discussions occurring not only with gold, organometallic and computational chemists, but also with discussions taking place around my own research during poster presentations.
Year(s) Of Engagement Activity 2014
 
Description Invited Lecture at GSK Emerging Academics Symposium (Returning Speaker), GlaxoSmithKline Research Centre, Stevenage, 20th Oct 2015. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Invited research lecture at GSK, which sparked questions and discussion afterwards.
Year(s) Of Engagement Activity 2015
 
Description Invited lecture AstraZeneca, Macclesfield, 18th November 2015. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Chemists from AstraZeneca attended the research talk and the talk was also transmitted to other AstraZeneca sites. The talk sparked questions and discussions afterwards.
Year(s) Of Engagement Activity 2015
 
Description Invited seminar, St Andrews University (EastChem Colloqium) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Invited seminar on our ongoing research work at St Andrews University (EastChem Colloqium), 22nd April 2015. Sparked questions and discussion afterwards.
Year(s) Of Engagement Activity 2015
 
Description Invited seminar, University of East Anglia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Invited seminar on our ongoing research work at University of East Anglia, 10th December 2014. Sparked questions and discussion afterwards, especially with postgraduate students and PDRAs.
Year(s) Of Engagement Activity 2014
 
Description Seminar at University of Otago, New Zealand, 26th July 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A research presentation at University of Otago, New Zealand, 26th July 2013.

This presentation lead to collaborations and a publication.
Year(s) Of Engagement Activity 2013
 
Description Seminar at University of Oxford 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Research seminar at University of Oxford, 30th October 2014 as part of a series of invited lectures for the Pfizer Graduate Symposium. Presented ongoing results from our research which sparked questions and discussion afterwards.

Increased interest in our research activities as well as useful suggestions and exchange of ideas for future research directions.
Year(s) Of Engagement Activity 2014
 
Description Seminar at University of Strathclyde, 10th April 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Research seminar at University of Strathclyde.

Increased interest in our research work and interesting ideas and suggestions.
Year(s) Of Engagement Activity 2013