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

这是一项研究计划，旨在进一步了解是什么造就了好的风味和香味分子。该方案将应用有机氟化学来解决CF2基团具体并入脂肪环的问题。某些大脂肪环（12至14个成员）和大环酯是香水工业中使用的重要化学成分。它们有麝香的香味。这些化合物由于其大环的性质，具有很大的构象自由，并且尚不清楚触发嗅觉反应的重要形状是什么。此外，嗅觉受体的结构尚不清楚，因此芳香分子不能被建模为一个明确的受体结合位点。因此，构效关系尚不清楚。了解刺激嗅觉受体的分子的形状对于设计新一代的非天然香味分子非常重要。本提案旨在通过在环周围的战略位置加入CF2基团取代CH2基团来探索柔性麝香大环的活性构象。我们最近展示了[M]。Skibinski， A. M. Z. slain， T. Lebl， P. Kirsch， D. O' hagan，“环十二烷中CF2基团构象的影响”[j]。化学Int。编者，2011,50,10581 - 10584]，CF2基团在脂肪环上采用（产生）角位置。这是由于CF2基团的一些意想不到的特性造成的，这些特性改变了碳原子的角度（杂化），避免了将C-F键置于环的中心。因此，在本提案中，我们将使用CF2基团来操纵环的形状并限制环的构象动态。这种方法的一个明显的优点是CF2基团与CH2基团近似等构，并且它仍然是疏水的，保留了CH2的特征。而且CF2基团不形成氢键。我们预计CF2基团的惰性性质将确保它不会以不利的方式独立刺激受体。两个CF2组的合并，战略间隔也将被用作设计特征，以进一步限制环的灵活性。该研究计划将制备三种重要的香精大环（麝香酮、西维酮和(12R)-甲基-13三醇内酯）的各种不同的类似物。这将通过使用现代有机合成方法（如复分解，不对称共轭加成）构建环以及应用圣安德鲁斯最近用于将CF2基团纳入环结构的方法来实现。然后，这些化合物将通过x射线晶体学和核磁共振进行结构分析。重要的是，合成的化合物将被分析其与母体天然味道的相似性，并在人类“鼻子”上进行一系列心理物理测试。这将由日内瓦芬美意香精公司（该行业第二大公司）的专家进行。香水行业是一个重要的全球产业，2011年该行业前五大公司的销售额超过130亿美元。因此，这一领域的创新可以直接导致新产品的设计。更一般地说，我们预计从这个研究项目中产生的概念将应用于其他研究领域，在这些领域中，柔性分子的形状对性能很重要。在有机液晶显示材料的设计或在化学生物学，如。设计具有特定功能的脂质，如抑制与蛋白质的相互作用。这个研究项目非常适合在公共互动和学校中推广科学，它将被开发并纳入我们在圣安德鲁斯的推广活动中。

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.