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

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.

The proposal focuses on an aspect of product development for the perfumery industry. Perfumery is a major UK market, which has a strong global presence. The Estimated value of the UK perfumery industry in 2009 = £1.4 bn with a growth of ~ 3.5% in the UK The global sales figures in 2011 of the worlds top five flavour and fragrance companies give some impression of the international scale of the industry; Givaudan ($4 billion), Firmenich ($3.0 billion), IFF ($2.7 billion), Symrise ($2.0 billion), Takasago ($1.4 billion). The top two companies are based in Europe (Switzerland).

The research programme has specifically engaged with the Research and Development arm of, Firmenich, the second largest company in this sector in the world. This interaction will ensure that the concepts from the research will link directly into the industry at the appropriate level.
More generally, organic fluorine compounds prevade every aspect of the organic chemicals industry from pharmaceuticals, agrochemicals to the entire fine chemicals industry, thus specific new insights and concepts involving organofluorine compounds, such as influencing molecular conformation with CF2, will be noticed and assimilated into all of those sectors, and will impact in product development, and thus the economy.

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 role of a CF2 group as proposed here, should be immediately noticed as a novel concept by researchers in a range of areas. But it is not complicated, and can easily be applied across a variety of research programmes demanding performance organic materials which rely on molecular conformation. The concept could have a significant impact in several product development programmes over a 10 year time scale particularly given the sterically small, unreactive and non hydrogen bonding (hydrophobic) nature of the CF2 group. Once the concept is in the collective consciousness of the research community it will remain there into the future.

The PDRA 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 smell and taste are associated with emotions, memory and the subconscious. Some funds are requested to promote that.
Linking shape to smell is a very straightforward example of an agonist/receptor response in neurotransmission. The same concepts extend to drug/target interactions, or even the concept of addiction and drug abuse. So this project has good prospects for the development of interesting and stimulating public engagement events, which we would seek to exploit through the Royal Society of Chemistry (Tay Side), and public engagement and extensive schools activities within our own environment, such as the Scottish National Chemistry Teachers Conference held each year in St Andrews.