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Details of Grant 

EPSRC Reference: EP/S030506/1
Title: Properties and applications of Janus faced fluorocyclohexanes
Principal Investigator: O'Hagan, Professor D
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Merck KGaA
Department: Chemistry
Organisation: University of St Andrews
Scheme: Standard Research
Starts: 01 June 2019 Ends: 31 May 2022 Value (£): 482,983
EPSRC Research Topic Classifications:
Biological & Medicinal Chem. Chemical Biology
Chemical Synthetic Methodology
EPSRC Industrial Sector Classifications:
Chemicals Pharmaceuticals and Biotechnology
Related Grants:
Panel History:
Panel DatePanel NameOutcome
06 Mar 2019 EPSRC Physical Sciences - March 2019 Announced
Summary on Grant Application Form
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.
Key Findings
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Organisation Website: http://www.st-and.ac.uk