Organocatalytic Fluorinations with Fluoride Salts

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

Abstract

Fluorine is a unique element of the periodic table that impacts hugely on society because many pharmaceuticals, agrochemicals and anaesthetics owe their important properties to the presence of fluorine atoms within their structures. For example, the small and highly electronegative fluorine atom plays a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance molecular properties such as improved metabolic stability and enhanced membrane permeation. Fluorine substitution as a strategy to increase binding affinity of drug candidates to target protein has also been documented in a number of cases.

One of the challenges associated with the discovery and production of these compounds is the availability of highly efficient and cost effective catalytic methods for carbon-fluorine (C-F) bond formation. To date, many chemists worldwide have actively worked in this area of research, and developed a range of processes for this purpose, but the reactions discovered to date employ expensive fluorine source derived from F2, a gas yellow in colour that is highly reactive and corrosive. Only a minority of these processes make use of cheaper fluoride salts, but these then require expensive transition metal catalysts, and suffer from narrow substrate scope.

With this project, we propose to develop and study a novel catalytic reaction for carbon-fluorine bond formation, that benefits from the use of cost effective fluoride salts and cost effective catalysts made of purely organic materials and free from transition metal ions. The design of our system allows for easy chemical modification and hence simple coarse or fine-tuning of the catalysts structure and reactivity profile. The catalytic process that we have designed for fluoride activation is mechanistically unprecedented, and will be applied to the preparation of important fluorinated molecules for immediate application in medicinal chemistry. Accordingly these new catalytic fluorination and the products of these reactions will be of great value to chemists in industry and academia alike, and have the potential to impact widely on society by improving health and quality of life.

Planned Impact

Catalysis sciences are critically important to sustain many disciplines and to enable discoveries that impact on areas as diverse as health, supply, energy and advanced materials. More particularly, the development of catalytic methods for the preparation of fluorine-containing molecules is of considerable value, especially when the method features cost effective fluoride source and catalysts, combined with conceptual novelty that has the potential to be applied to processes other than carbon-fluorine bond construction.

Knowledge - The impact of the project on knowledge will take the form of scientific advances as the catalytic process proposed for carbon-fluorine bond formation is novel and will be examined thoroughly both for its synthetic value and mechanistically. Technically, the method that will emerge from this grant will benefit from its operational simplicity and cost efficiency, making it broadly applicable.

Society and Economy - The pharmaceutical industry contributes both to UK competitiveness and quality of life. The emergence of effective therapeutic solutions is an essential component of modern medicine to enhance the patient's quality of life and reduce the societal costs of healthcare. Many pharmaceutical drugs on the market and in drug discovery pipelines feature fluorine substitution, so methods for efficient and cost effective carbon-fluorine bond construction are urgently needed. This proposal offers a cost effective organocatalysed fluorination process from fluoride salt. The reaction is conceptually novel within the field of catalysis, and the principles could be applied to reactions beyond fluorination. Innovation in catalysis emerging from this project will therefore be significant and could have an immediate impact on society. Catalysis plays a central role in areas such as synthetic chemistry, physical chemistry, computational chemistry and materials science among others, and the outcome of this grant should contribute to maintain the strong international position of the UK in this area.

Pathway to dissemination - the applicants are committed to share broadly the results of this research with immediate publication and active participation at specialised workshops and (inter)national conferences. Presentation to non-chemistry scientists regarding applications of our work will take place, with widespread publicity of the success of our science and collaborations (e.g. press and electronic media). Both applicants have a strong track record demonstrating proactive dissemination of their research.

People - The two PDRAs on this grant will gain experience in fluorine chemistry, catalysis, synthesis of molecular entities important for pharmaceutical drug discovery, physical organic chemistry, and computational calculations. They will be strongly encouraged to attend advanced courses, including business and entrepreneurship, scientific writing and presentation skills offered by the University of Oxford. This will ensure that the project produces two fully experienced PDRAs, immediately employable in the scientific sector. Working at the frontiers of a project merging catalysis and translational applications in the medicinal chemistry sector is attractive, and in great demand for industrial, teaching and/or academic vacancies.

Publications

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Description Potassium fluoride (KF) is an ideal reagent for fluorination because it is safe, easy to handle and low-cost. However, poor solubility in organic solvents coupled with limited strategies to control its reactivity has discouraged its use for asymmetric C-F bond formation. Here, we demonstrate that hydrogen bonding phase-transfer catalysis with KF provides access to valuable ß-fluoroamines in high yields and enantioselectivities. This methodology employs a chiral N-ethyl bis-urea catalyst that brings solid KF into solution as a tricoordinated urea-fluoride complex. This operationally simple reaction affords enantioenriched fluoro-diphenidine (up to 50 g scale) using 0.5 mol % of recoverable bis-urea catalyst.
Exploitation Route Use of Potassium fluoride (KF) as a reagent for fluorination.
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

URL https://pubs.acs.org/doi/10.1021/jacs.8b12568?hootPostID=c3114c169c453b759eb64e52874e7b70
 
Description Patent Application entitled: Process for the multigram synthesis of tridentate bis-ureas hydrogen-bonding catalysts (in preparation) (Gouverneur Fluorination Catalysts)
First Year Of Impact 2020
Sector Chemicals,Manufacturing, including Industrial Biotechology
Impact Types Economic

 
Description Hydrogen Bonding Phase Transfer Catalysis
Amount € 2,499,070 (EUR)
Funding ID 832994 
Organisation European Research Council (ERC) 
Sector Public
Country Belgium
Start 07/2019 
End 06/2024
 
Description New Collaboration with Sanofi 
Organisation Sanofi
Department Sanofi Research Division
Country France 
Sector Private 
PI Contribution scale up of the fluorination on one of the aliphatic substrates described in J. Am. Chem. Soc., 2019, 141, 2878 (the one with a cyclohexyl on the backbone). Sanofi assisted with evaluating the thermal hazard of the reaction using DSC
Collaborator Contribution Sanofi were involved in evaluating the thermal hazard of the reaction using DSC
Impact evaluating the thermal hazard of the reaction using DSC
Start Year 2019
 
Description Dorothy Hodgkin Memorial Lecture, Somerville College, University of Oxford, Oxford (UK) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This lecture was part of the Oxford International Women's festival. Celebrating and relecting on the impact of the past years on the lives of women across Oxfordshire from all walks of life.
Year(s) Of Engagement Activity 2018
URL https://www.some.ox.ac.uk/event/fabulous-fluorine-the-dorothy-hodgkin-memorial-lecture/