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

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

Abstract

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.

Planned Impact

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 prodct 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.

Publications

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Ahmed L (2018) Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by ()-muscone and diverse other musk-smelling compounds. in Proceedings of the National Academy of Sciences of the United States of America

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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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Fujiwara T (2014) Successful fluorine-containing herbicide agrochemicals in Journal of Fluorine Chemistry

 
Description Research ongoing. We have prepared a range of musk lactones by advanced organic synthesis, and related musk fragrance compounds carrying CF2 groups. We have validated the hypothesis that the fluorine does not significantly change the fragrance but can significantly influence macrocyclic ring conformation.

Most recently these have been extended to working on pheromones of the Emerald Ash Borer, with the
Canadian Forest Service - New Brunswick

We have also explored muscone analogues carrying the CF2 group, and assessed a number of these on the human olfactory receptor (OR5AN1). In this process we discovered the most effective musk receptor agonist ever recorded. This was reported in PNAS in 2018.
Exploitation Route We are involved in close discussions with the major fragrance company Givaudan in Zurich, who are examining the olfactory properties of our compounds.
Our programme is moving towards insect pheromones and using the Cf2 group to make more powerful insect pheromone analogues to assist in monitoring the life cycle of insects and as a tool for pest control.

Or muscone studies involved a collaboration with groups in SUNY, Albany New York, Shanghai Jaitomng University, Yale and Duke Universities.
Sectors Chemicals,Environment,Leisure Activities, including Sports, Recreation and Tourism

 
Description Research ongoing. We have prepared a range of musk lactones by advanced organic synthesis, and related musk fragrance compounds carrying CF2 groups. We have validated the hypothesis that the fluorine does not significantly change the fragrance but can significantly influence macrocyclic ring conformation. Results have been exchanged with the two internationally leading fragrance companies, Givaudan and Firmenich Most recently we have prepared CF2 analogues of pheromones of the Emerald Ash Borer. This has been a collaboration with Dr Peter Silk, Insect Chemical Ecologist Canadian Forest Serivce - Atlantic Forestry Centre, Natural Resources Canada. Peter is based in New Brunswick. The Emerald Ash Borer is a major commercial pest of N. American forests. Our fluorinated pheromones aimed to identify improved compounds for traps. We have prepared 5 compounds and several of these are similar in efficacy to the natural pheromone. We have a paer in revision at Tetrahedron
First Year Of Impact 2016
Sector Chemicals,Environment,Leisure Activities, including Sports, Recreation and Tourism,Culture, Heritage, Museums and Collections
Impact Types Cultural,Economic

 
Title CCDC 1502954: Experimental Crystal Structure Determination 
Description Related Article: Mathew J. Jones, Ricardo Callejo, Alexandra M. Z. Slawin, Michael Bühl and David O'Hagan|2016|Beilstein J.Org.Chem.|12|2823| 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
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  
 
Description Dr Eric Block on olfactory receptors at SUNY 
Organisation State University of New York
Country United States 
Sector Academic/University 
PI Contribution Provided CF2 containing muscones for olfactory receptor studies
Collaborator Contribution They have over-expressed olfactory receptors and are able to measure the relative effacecies of our compounds on the human olfactory receptor
Impact Publication submitted
Start Year 2017