Catalytic chemistry for methanol oxidation: a study into mechanism and utility

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry

Abstract

Chemistry is a dynamic subject that is at the centre of many different scientific advances. Organic chemistry is concerned with the reactivity of carbon in all its different forms and can be viewed as the chemistry taking place within living things. Chemists are constantly looking for new ways of designing and building molecules (synthetic chemistry is molecular architecture) and this proposal describes a short and powerful new way of making valuable molecules using a new type of catalyst. The molecules at the heart of the proposal are compounds containing a carbon-oxygen double bond (a carbonyl group) which have special properties and are the building blocks of many known pharmaceutical agents.

The novel chemistry proposed here will provide a new, efficient and powerful way of making carbonyl compounds using catalysis to control all aspects of the structures of the products formed: this will be of great benefit to both academia and industry who will be able to make interesting molecules (some that were otherwise inaccessible) in new ways. Plans have also been made to screen the compounds that we make for a wide range of biological activity.

Given all of the above, it is imperative that we have novel, efficient and powerful methods for making new carbonyl containing compounds so that we can study and use them. In addition, the development and application of new catalysts and catalytic systems is also important because catalysis makes chemical reactions run faster, and become cleaner with less waste: this is clearly a good thing for industry and also for the environment.

The Fellowship aspect of this proposal is designed to allow the principal investigator the time to study and develop a new research direction. Plans have been made to interact and collaborate with other academics who can provide specialist knowlege and also with two project partners (one a multi-national pharmaceutical company and the other a leading academic in the United States of America) so that industrial problems and mechanistic details can be identified and addressed at all stages of the project. Three post-doctoral assistants will be employed to carry out the exprimental work, and the project will provide a thorough and comprehensive training in science and the attendant areas of communication/ presentation and creativity. This will equip them very well for the job market afterwards.

Planned Impact

The first beneficiary to discuss (briefly) is academia, and it is my aim that the new chemistry described will find use in science labs around the world (primarily in chemistry and bioscience departments, indeed anywhere that new molecules are made). The beneficiaries outside of academia include: chemical industry including the pharmaceutical industry, the agrochemical industry and the fine chemicals industry. These beneficiaries will be able to exploit the chemistry described in this proposal to achieve the synthesis of biologically active compounds in a more efficient manner, and it will also allow chemical industry to make new molecules that were hitherto difficult to access. Organic molecule therapeutics are important and valuable molecules with many uses, especially in healthcare and this new science will allow industry to make the commercially valuable compounds of the future in a new and efficient way, giving them a competitive advantage. Each of the beneficiaries above improves the quality of life and the wealth of the nation, through the application of novel organic chemistry. Chemical industry plays a big role in the U.K. economy (2012 UK trade surplus in medicines was £5500 million) and the U.K. still has a very strong pharmaceutical industry, who all stand to benefit from this methodology.

Clearly, it is important that I engage with potential end-users of this chemistry so that I can ensure the project makes the maximum impact in the most relevant areas of research. I have several plans for publicising our work and for getting industry feedback on our routes to new molecules and library generation (and on the most worthwhile pharmaceutical targets to derivatise and open up new avenues of research). The easiest way to publicise our work is to deliver lectures in industrial laboratories, followed by a discussion of the potential applications (I have given 12 such lectures at pharmaceutical companies since 2008 and have invitations to speak at industial venues in 2014). Since appointment in 1994, I have had many CASE type collaborations (40) with industry and sent over 30 researchers to full-time employment in various industrial chemistry laboratories; so I have many relevant contacts within the industrial organic chemistry community. Other opportunities to publicise our work with the beneficiaries will come from the meetings that I have regularly with industry to discuss ongoing collaborations; I am also a consultant for several pharmaceutical companies which gives me another way to discuss this science. I have been, and will continue to be, very active in publicising our methodology and gaining feedback on useful applications of it.

I am keen to explore the possibility of large-scale operation of our new chemistry and will be in constant communication with the industrial project partner (AZ) in this regard. I was recently awarded the Society of Chemistry and Industry Prize for Process Research (2012), which is sponsored by four major chemical companies and which gives an indication of the high level of interaction that I have with the industrial end-users of my work.

The timescales involved in giving a benefit to the end-users of the research is short (months rather than years): as soon as new routes are developed and publicised then they can be used in industrial laboratories. Clearly, generating libraries of established drug candidates may take longer to make an impact in a medicinal chemistry setting. However, we expect that the new catalytic oxidation reactions that we develop will have such attendant improvements in efficiency and scalability that this will lead industry to use them. We also anticipate that the new compounds that we develop and the extra possibilities generated for derivatising complex molecules will have significant impact in a medicinal chemistry setting.

Details of our plans for future exploitation and collaboration are given in the full PIA plan.

Publications

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Armstrong RJ (2019) Catalytic Asymmetric Synthesis of Cyclohexanes by Hydrogen Borrowing Annulations. in Angewandte Chemie (International ed. in English)

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Reeves BM (2019) Transition-Metal-Free Reductive Hydroxymethylation of Isoquinolines. in Angewandte Chemie (International ed. in English)

 
Description We have discovered the role that substituted aromatic groups play in facilitating catalytic hydrogen borrowing reactions. This promises to have fundamental applications in organic chemistry in the future.
The role of higher alcohols in hydrogen borrowing has been uncovered and used to allow access to valuable and previously difficult to access compounds. Stereoselective processes have been discovered and applied in this context, which is an important breakthrough.
Aromatic systems have also been engaged in the hydrogen borrowing with methanol project and again difficult to access aromatic systems have been prepared.
Exploitation Route The application of pentasubstituted arenes could be widespread in chemistry applications. The hydrogen borrowing methodology that we have reported is likely to be used widely in both academia and the chemicals industry.
Sectors Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL http://donohoe.chem.ox.ac.uk/page-2/
 
Description CASE award with DTG support
Amount £32,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2014 
End 09/2018
 
Description EPSRC CASE
Amount £28,000 (GBP)
Organisation AstraZeneca 
Department Astra Zeneca
Sector Private
Country United States
Start 10/2018 
End 09/2022
 
Description EPSRC CASE
Amount £31,000 (GBP)
Organisation Eli Lilly & Company Ltd 
Sector Private
Country United Kingdom
Start 10/2015 
End 09/2018
 
Description Talk given to sixth form students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact I delivered a talk on scientific research and the topic of my EPSRC fellowship to 60 sixth form students who were undertaking a work experience week at GlaxoSmithKline.
Their questions afterwards were numerous and very interesting.
Year(s) Of Engagement Activity 2019
 
Description Talk on synthesis, catalysis and EPSRC fellowship to alumni 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact I have given two talks on synthetic organic chemistry, catalysis and my EPSRC Fellowship to audiences of alumni of Oxford Chemistry- most of whom no longer practise organic chemistry
Year(s) Of Engagement Activity 2016,2017
URL http://alumni.chem.ox.ac.uk/events.aspx