The CF2 group as a conformational tool in the olfactory receptor response

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This is a research proposal that aims to further our understanding of what makes good flavour and fragrance molecules. The programme will apply organo fluorine chemistry to the problem with the specific incorporation of the CF2 group into aliphatic rings. Certain large aliphatic rings (12 to 14 membered) and macrocyclic esters are important chemical constituents used in the perfumery industry. They have a musk fragrance. These compounds by the nature of their large ring, are subject to substantial conformational freedom and it is not clear what the important shape is for triggering the olfactory response. Also the structure of the olfactory receptor(s) is not known in any detail, and thus the fragrance molecules cannot be modelled into a well defined receptor binding site. Therefore structure activity relationships are not clear. Understanding the shape of the molecule that stimulates the olfactory receptor is important for the design of a new generation of unnatural fragrance molecules. This proposal aims to explore the active conformations of flexible musk macrocycles by incorporating the CF2 group in place of the CH2 group at strategic positions around the ring. We have recently shown [M. Skibinski, Y. Wang, A. M. Z. Slawin, T. Lebl, P. Kirsch, D. O'Hagan, 'Alicyclic ring structure: Conformational influence of the CF2 group in cyclododecanes' Angew. Chemie Int. Ed., 2011, 50, 10581 - 10584] that the CF2 group adopts (creates) corner positions in aliphatic ring. This is a consequence of some unexpected features of the CF2 groups, which changes the angles (hybridisation) at the carbon atom and avoids placing the C-F bond into the centre of the ring. Thus in this proposal we will use the CF2 group to manipulate the shape and limit the conformational dynamic of the rings. A clear advantage of this approach is that the CF2 group is approximately isosteric to the CH2 group, and it remains hydrophobic preserving that feature of CH2. Also the CF2 group does not form hydrogen bonds. We anticipate that this inert nature of the CF2 group will ensure that it does not independently stimulate the receptor in an adverse manner. The incorporation of two CF2 groups, strategically spaced will also be used as a design feature to put further constraints on ring flexibility. The research programme will prepare various different analogues of three important classes of fragrance macrocycles (muscone, civetone and (12R)-methyl-13tridecanolide). This will be achieved by the construction of the rings using modern methods of organic synthesis (eg metathesis, asymmetric conjugate addition) and also applying methodologies that have been used recently at St Andrews for incorporating the CF2 group into ring structures. These compounds will then be analysed structurally by X-ray crystallography and NMR. Importantly the resultant compounds will assayed for their similarity to their parent natural flavours and be subject to a series of psychophysical tests on human 'noses'. This will be carried out by experts at the Firmenich flavour and fragrance company (2nd largest company in this sector) in Geneva. The perfumery industry is an important global industry, with the top five companies in the sector generating sales in excess of $13 billion in 2011. Thus innovation in this area can lead directly to new product design.More generally we anticipate the concepts that emerge from this research programme will be applicaple to other research arenas where the shape of flexible molecules is important for performance eg. in the design of organic liquid crystalline display materials or in chemical biology eg. the design of lipids for specific functions such as inhibiting interactions with proteins.This research programme is ideally suited for promoting science in public interactions and with schools and it will be developed and incorporated into our outreach activities at St Andrews.