Novel organofluorine motifs in the service of industry

Lead Research Organisation: University of St Andrews
Department Name: Chemistry

Abstract

This project aims to develop two recent discoveries from the St Andrews laboratory. Project 1: The first project develops from a recent syntheses of 1,2,3,4- and 1,2,4,5-tetrafluorocyclohexanes. Importantly the stereochemistry of the molecules has all of the fluorines on the same face of the cyclohexanes. We find that this makes these cyclohexanes very polar. TWhen cyclohexane adopts a chair conformation, then there are always two diaxial C-F bonds. This polarity renders these compounds crystalline solids, and NMR experiments reveal that the two faces are highly polarised. So the project aims now to incorporate this motif into more meaningful structures. We think that the all-syn tetrafluorocyclohexane motif can have wide ranging roles in developing performance molecules for pharmaceuticals and agrochemicals research. However in this project we will use liquid crystals as a background to explore their properties. Many liquid crystalline molecules that are used in modern displays for personal computers, smart phones and iPads etc contain fluorine atoms. This is because the C-F bond is polar, but it has low viscosity, and thus it can orientate and cycle very rapidly in changing electric fields. The all-syn tetraflurocyclohexane motifs appear to have exactly the correct caharacteristics for a particular class of LC's known as -ve dieletric anisotropic LC's. These are molecules where the dipole is orientated perpendicular to the molecular axis. The project requires that we develop chemistry around a phenyl derivative of the 1,2,4,5-tetrafluorocyclohexane. We plan to carry out a diversity of chemistry on this motif, and also to improve synthetic protocols. We want also to explore synthesis routes to other derivatives of the tetrafluorocyclohexane ring system eg. carboxylic acid and amine motifs we feel will be extremely attractive for medicinal chemistry research. One of the leading research companies and global suppliers of perfomance LC's, Merck in Darmstadt, Germany, have agreed to support the project by evaluating candidate compounds as LC's and they will assist in providing facilities to scale up the synthesis of these motifs. This aspect of the project will be successful if we can demonstrate a practical application of the all-syn tetrafluorocyclohexane and illustrate to the wider community its potential in the development of performance organic molecules.
Project 2. The second project was stimulated by a new reaction carried out in the laboratory, which recognised that if an acetylenethioether is treated with an HF source, it generates a fluoroviny thioether (RS(F)=CH2). More significantly we find that the fluorovinyl thioether is a relatively stable entity. There is hardly any literature on this motif and in this research we want to explore its potential in the early stage design of enzyme inhibitors (fragment approach). We have recognised that the motif approximates the steric and electronic profile of an enol of a thioester. Thioester enols/ates are important intermediates in enzymology, eg. enzymes that process acetyl-CoA such citrate and malate synthase, acetyl-CoA carboxylase, and enoyl reductases of fatty acid biosynthesis are attractive. Therefore we want to assess if the fluorovinyl thioether moiety will be recognised and bind to these enzyme active sites by co-crystallisation X-ray studies. This requires that we synthesise appropriate motifs that represent truncated pantetheinyl moieties carrying the RS(F)=CH2 motif. These compounds will be co-crystallised with enzymes over-expressed in E. coli. In discussions with Syngenta they have suggested we explore such ligands for enoyl reductase, a target relevant to the agrochemical sector.
A successful outcome will show that this motif binds to these enzyme active sites (by X-ray crystallography), and provides a starting poing for fragment based inhibitor development. The programme will introduce this motif to the wider research community.

Planned Impact

Who will benefit from this research?
Organofluorine compounds make up 20% of all pharmaceuticals products internationally and 30% or all agrochemical products on the market. The organic materials industry relies very heavily in selectively fluorinated organic compounds and polymers. So innovation in the selective incorporation of fluorine contributes substantially to products athat are designed to improve health, well being and the societal challenges of a growing population and a developing third world sector (BRIC Nations). That is the global perspective of who will benefit from this research. More tangibly this research prtogramme is focussed on two sectors. We will explore the introduction of the all-syn tetrafluorocyclohexane motif into candidate liquid crystalline molecules. This research will be partially guided by Merck Liquid crystals in Darmstadt, a global leader in innovation and supply of performance liquid crystals. So we have aligned directly with an industrial sector. This provides us with a platform in which to introduce this new motif and present it to a wide audience.
A second project takes a similar strategy in terms of Impact. We have discovered simple chemistry to a rather unusual structural motif, which has potential in binding to the active site of enzymes that utilise a a certain substrate class. It so happens that many of these enzymes are or clinical or agrochemical interest. For the purposes of this project we have aligned with the major agrochemical company Syngenta (Jealott's Hill), who have advised on some enzymes of relevance to the agrochemical sector. However we see this as an arena to profile the research and if successfull there could be much wider applications particularly in medicinal chemistry and enzymology.

How will they benefit?
They will benefit by being able to utilise these new motifs in their own research programmes. They will hopefully be stimuated by the design concepts and researchers in the area will take upo this design and modify it to their own purposes. Therefore the programme will stimulate thinking.

Staff working on this project will become expert in organo-fluorine chemistry and particularly the role of fluorine to influence the shape and efficacy of performance organic molecules. They will become specialist in the design strategy and execution of the preparation of particular molecules of interest (Dial a molecule; Grand Challenge).

The PDRA's will develop synthesis skills and know how in organic fluorine chemistry and will become a specialist in understanding the specific effects of fluorine in terms of modulating the properties of organic materials. Such a knowledge and understanding has relevance in a range of areas perfumery, pharma, agrochemicals, liquid crystal design etc..

St Andrews University are very proactive in developing IPR. This will be developed in consultation with the St Andrews Entrepreneurial Partnership (STEP) programme and Business Development Managers (BDMs) associated with the Department of Research Business Development & Contracts.

Beneficiaries within the wider public? Results from such a programme will be used in more general arenas for discussing the relevance of chemistry and molecular design to material properties, to interested lay audiences. This type of programme is particularly well suited to public interactions because it engages with societal products such as device displays and food production.

The research will be published and disemminated in leading journals and at appropriate international conferences.

Publications

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Al-Maharik N (2020) Probing the helical integrity of multivicinal all-syn-fluoro alkanes. in Organic & biomolecular chemistry

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Cormanich RA (2014) Analysis of CF···FC interactions on cyclohexane and naphthalene frameworks. in The journal of physical chemistry. A

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Durie AJ (2014) Synthesis and elaboration of all-cis-1,2,4,5-tetrafluoro-3-phenylcyclohexane: a polar cyclohexane motif. in Chemistry (Weinheim an der Bergstrasse, Germany)

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Fang Z (2016) Polar alicyclic rings: synthesis and structure of all cis-1,2,3,4-tetrafluorocyclopentane. in Chemical communications (Cambridge, England)

 
Description Two themes.
1. We have elaborated the tetrafluorocyclohexane motif towards a wide range of derivative as building blocks for pharmaceutical and agrochemicals discovery. We have also prepared amino acid derivatives and incorporated them into peptides.
2. We have developed synthesis methods to the fluorovinyl thio ether motif and have demonstrated efficiency and versatility, for the first time, in being able to access this motif. We have made a Co-enzyme A derivative and shown that it is an inhibitor of the enzyme citrate synthase.
Exploitation Route Further funding will be requested to develop the exploration of this motif with full Coenzyme-A derivatives and a wider range of enzymes, with a particular focus on enzymes relevant to agrochemicals research.
Sectors Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology

 
Description We are sharing the results with Syngenta and they are advising of relevant directions relevant to agrochemicals research. In 2018 a lab in Munster in Germany (led by prof Frank Glorius) improved our synthesis of 1,2,3,4,5,6-hexafluorocyclohexane and related derivatives, and this has made the material and its derivatives much easier to make. This work was patented (by the German lab), and a number of labs, including our own, are exploring their properties. For our part we are using the improved synthesis (fluoroaryl-hydrogenation) to prepare motifs on a much larger scale. We continue to work intensively on tehse selectively motifs. In particular we have opened up academic collaborations with scientists at the Frei University in Berlin and also at Heriot Watt University to build a pentafluorocyclohexane amino acid into peptides. It is perhaps too early for immediate commercial uptake, but the improved availability of our materials is stimulating activity and it will be interesting to see how they develop over the next few years.
First Year Of Impact 2017
Sector Agriculture, Food and Drink,Chemicals
Impact Types Economic

 
Title Data underpinning - Fluorine in fragrances: Exploring the difluoromethylene (CF2) group as a conformational constraint in macrocyclic musk lactones. 
Description  
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
 
Title Data underpinning - Polar alicyclic rings: Synthesis and structure of all cis-1,2,3,4-tetrafluorocyclopentane 
Description Computational data (Gaussian input and output files) 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes