Novel organofluorine motifs in the service of industry

该项目旨在开发圣安德鲁斯实验室的两项最新发现。项目1：第一个项目由最近合成的1，2，3，4-和1，2，4，5-四氟环己烷发展而来。重要的是，分子的立体化学使所有的氟都在环己烷的同一面上。我们发现这使得这些环己烷非常极性。当环己烷采用椅式构象时，总是存在两个双轴C-F键。这种极性使这些化合物成为结晶固体，核磁共振实验显示两面都是高度极化的。因此，该项目现在的目标是将这一主题纳入更有意义的结构中。我们认为，全正四氟环己烷基序在开发用于医药和农用化学品研究的性能分子方面可以发挥广泛的作用。然而，在这个项目中，我们将使用液晶作为背景来探索它们的性质。许多用于个人电脑、智能手机和iPad等现代显示器的液晶分子都含有氟原子。这是因为C-F键是极性的，但它的粘度很低，因此它可以在变化的电场中快速定向和循环。全同向四氟环己烷模体似乎完全符合一类特殊类型的液晶的特征，即介电各向异性液晶。这些分子的偶极方向垂直于分子轴。该项目要求我们围绕1，2，4，5-四氟环己烷的苯基衍生物开发化学。我们计划对这个基序进行多样化的化学研究，并改进合成方案。我们还想探索四氟环己烷环系其他衍生物的合成路线，例如。我们认为羧酸和胺基序在药物化学研究中将非常有吸引力。位于德国达姆施塔特的默克公司是性能LC的领先研究公司和全球供应商之一，该公司已同意通过评估候选化合物作为LC来支持该项目，他们将协助提供设施，以扩大这些主题的合成。如果我们能够展示全合成四氟环己烷的实际应用，并向更广泛的社区展示其在开发高性能有机分子方面的潜力，该项目的这一方面将是成功的。项目2.第二个项目受到实验室中进行的一项新反应的刺激，该反应认识到，如果乙酰亚硫醚用氢氟源处理，它会生成一种含氟硫醚(RS(F)=CH2)。更重要的是，我们发现氟乙烯基硫醚是一个相对稳定的实体。几乎没有任何关于这个基序的文献，在这项研究中，我们想要探索它在酶抑制剂的早期设计(片段方法)中的潜力。我们已经认识到，该基序类似于硫代酯的烯醇的空间和电子轮廓。硫代酯烯醇类化合物是重要的酶学中间体。处理乙酰辅酶A的酶，如柠檬酸和苹果酸合成酶、乙酰辅酶A羧基酶和脂肪酸生物合成的烯醇基还原酶，都是很有吸引力的。因此，我们希望通过共结晶X射线研究来评估氟乙烯基硫醚部分是否会被识别并与这些酶活性部位结合。这要求我们合成适当的基序，代表带有RS(F)=CH2基序的截短泛茶氨基基序。这些化合物将与在大肠杆菌中过度表达的酶共结晶。在与先正达的讨论中，他们建议我们探索与农化部门相关的目标--烯醇还原酶的这种配体。成功的结果将表明该基序与这些酶活性部位结合(通过X射线结晶学)，并为基于片段的抑制剂开发提供了起点。该方案将向更广泛的研究界介绍这一主题。

This project aims to develop two recent discoveries from the St Andrews laboratory. Project 1: The first project develops from a recent syntheses of 1,2,3,4- and 1,2,4,5-tetrafluorocyclohexanes. Importantly the stereochemistry of the molecules has all of the fluorines on the same face of the cyclohexanes. We find that this makes these cyclohexanes very polar. TWhen cyclohexane adopts a chair conformation, then there are always two diaxial C-F bonds. This polarity renders these compounds crystalline solids, and NMR experiments reveal that the two faces are highly polarised. So the project aims now to incorporate this motif into more meaningful structures. We think that the all-syn tetrafluorocyclohexane motif can have wide ranging roles in developing performance molecules for pharmaceuticals and agrochemicals research. However in this project we will use liquid crystals as a background to explore their properties. Many liquid crystalline molecules that are used in modern displays for personal computers, smart phones and iPads etc contain fluorine atoms. This is because the C-F bond is polar, but it has low viscosity, and thus it can orientate and cycle very rapidly in changing electric fields. The all-syn tetraflurocyclohexane motifs appear to have exactly the correct caharacteristics for a particular class of LC's known as -ve dieletric anisotropic LC's. These are molecules where the dipole is orientated perpendicular to the molecular axis. The project requires that we develop chemistry around a phenyl derivative of the 1,2,4,5-tetrafluorocyclohexane. We plan to carry out a diversity of chemistry on this motif, and also to improve synthetic protocols. We want also to explore synthesis routes to other derivatives of the tetrafluorocyclohexane ring system eg. carboxylic acid and amine motifs we feel will be extremely attractive for medicinal chemistry research. One of the leading research companies and global suppliers of perfomance LC's, Merck in Darmstadt, Germany, have agreed to support the project by evaluating candidate compounds as LC's and they will assist in providing facilities to scale up the synthesis of these motifs. This aspect of the project will be successful if we can demonstrate a practical application of the all-syn tetrafluorocyclohexane and illustrate to the wider community its potential in the development of performance organic molecules. Project 2. The second project was stimulated by a new reaction carried out in the laboratory, which recognised that if an acetylenethioether is treated with an HF source, it generates a fluoroviny thioether (RS(F)=CH2). More significantly we find that the fluorovinyl thioether is a relatively stable entity. There is hardly any literature on this motif and in this research we want to explore its potential in the early stage design of enzyme inhibitors (fragment approach). We have recognised that the motif approximates the steric and electronic profile of an enol of a thioester. Thioester enols/ates are important intermediates in enzymology, eg. enzymes that process acetyl-CoA such citrate and malate synthase, acetyl-CoA carboxylase, and enoyl reductases of fatty acid biosynthesis are attractive. Therefore we want to assess if the fluorovinyl thioether moiety will be recognised and bind to these enzyme active sites by co-crystallisation X-ray studies. This requires that we synthesise appropriate motifs that represent truncated pantetheinyl moieties carrying the RS(F)=CH2 motif. These compounds will be co-crystallised with enzymes over-expressed in E. coli. In discussions with Syngenta they have suggested we explore such ligands for enoyl reductase, a target relevant to the agrochemical sector. A successful outcome will show that this motif binds to these enzyme active sites (by X-ray crystallography), and provides a starting poing for fragment based inhibitor development. The programme will introduce this motif to the wider research community.