Properties and applications of Janus faced fluorocyclohexanes

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

Abstract

This research proposal has its origin in the special properties of the selectively fluorinated molecule, all-cis-1,2,3,4,5,6-hexafluorocyclohexane, which we prepared and reported in 2015. This is cyclohexane ring system which emerges as the most polar aliphatic compound recorded and it has interesting properties such as the ability to associate with both cations and anions. The cyclohexane ring is highly unusual in that it has polarised faces. The fluorine face is negatively polarised and the hydrogen face is positively polarised. In 2015 this ring system was challenging to make, and particularly to make derivatives, however in 2017 a direct hydrogenation method was developed by Glorius's lab in Munster, which allows access to derivatived forms of the ring system directly from aromatic precursors. Relevant to this proposal will be the synthesis of a series of substituted pentafluorocyclohexanes, where all substituents are on the same side of the cyclohexane ring. With this development, this research programme aims to explore applications of these pentafluorocyclohexane ring systems, exploring properties relevant to medicinal and biological chemistry (interactions with amino acids and proteins) as well as in organic materials and we have selected a particular focus in the areas of liquid crystals.
In the context of medicinal and biological chmeistry we want to explore how these ring systems will be expected to interact and bind with proteins. The negatively and positively polarised faces have the potential to make interactions with amino acid side chains with a complementary electrostatic profile. This will be explored by tagged 'pull-down' assays and proteins of high affinity will be identified by proteomics techniques. Candidate proteins will be progressed to co-crytsalisation structural (X-ray) studies for close structural analysis. In a complementary approach we will prepare tripeptides, from amino acid combinations that are known to be predisposed towards crystallinity. We will prepare a range of these with an amino acid with an all cis-2,3,4,5,6-pentafluorocyclohexyl side chain to explore how it interacts with other amino acid side chains. This study will extend to exploring the binding of this ring system to viral proteases, by making appropriate changes to drug molecules by replacing cyclohexyl or fluoroaromatic rings with the all cis-2,3,4,5,6-pentafluorocyclohexyl side chain. Structural biology(X-ray) analysis will allow us to determine how these ring systems interact with the protein, and this will inform medicinal chemists as to the potential of this motif.
The programme will extend to CF3 containing cyclohexanes, but particulary rings with more than one CF3 and with a defined stereochemistry. We have recently demonstrated that cyclohexanes with multiple CF3 groups attached to the aliphatic ring can also be accessed efficiently by the direct hydrogenation of arylCF3 precursors. The programme will extend to exploring the preparation, properties and chemistry of cyclohexanes with two and three CF3 groups with defined stereochemistries. These are also highly polarised aliphatics and these novel motifs will be introduced into liquid crystal architectures to exemplify properties and potential. The liquid crystal aspect is supported by Merck Liquid Crystal Division in Darmstadt who will carry out detailed analysis of prpared materials.
In overview the programme will explore an exciting class of organic chemistry motif which have potential to contribute new properties in a range of discovery chemistry arenas.

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 on selectively fluorinated organic compounds and polymers. So innovation in the selective incorporation of fluorine contributes substantially to products that are designed to improve health, well being and the societal challenges of a growing population and a rapidy developing third world sector (BRIC Nations). That is the global perspective of who will benefit from this research. More tangibly this research programme is focussed on the medicinal and agrochemicals sectors and also on the organic materials industry (liquid crystals for displays).
Innovative thinking and the demonstration of new properties of organic compounds also impacts significantly on researchers within Univeristies including both experimentalists and theorists. New methods of synthesis and an exploration of the properties of organic fluorine compounds continue to attract attention in fundamental research environemnts, and there has been a notable increase in research activity in organic fluorine chemistry in publically funded institutes over the last decade.

How will they benefit?
Companies involved in the discovery of new bioactive organic molecules will benefit by being able to utilise these new motifs in their own research programmes. They will hopefully be stimuated by their unique properties and researchers in the area will be able to appliy or modify to their own purposes. Therefore the programme will stimulate thinking, and new approaches to current problems and challenges in drug and agrochemical discovery as well as in organic materials.

The St Andrews lab has a continual ongoing dialogue (conferences, lectures, hosting visitors, collaborations) with relevant individuals in the chemical industry, who have interests in the chemistry, properties and performance of fluorine.

The PDRAs will develop synthesis skills and know how in organic fluorine chemistry and they will become specialists in understanding the specific effects of fluorine in terms of modulating properties (Dial a molecule; Grand Challenge).

St Andrews University is proactive in developing IP. This will be developed in consultation with Business Development Managers (BDMs) associated with 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 behaviour and performance in the service of food security, health and communications (LC displays). This type of programme is particularly well suited to public interactions because it engages with these major societal concerns.

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

Publications

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