Novel organofluorine motifs in the service of industry

为工业服务的新型有机氟图案

• 批准号: EP/L017911/1
• 负责人: David O'Hagan
• 金额: $ 71.09万
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FL017911%2F1
• 关键词: Novel; organofluorine; motifs; service; industry

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.

该项目旨在开发圣安德鲁斯实验室最近的两项发现。项目1：第一个项目是从最近的1，2，3，4-和1，2，4，5-四氟环己烷的合成中开发的。重要的是，分子的立体化学在环己烷的同一面上具有所有的氟。我们发现，这使得这些环己烷非常极性。当环己烷呈椅式构象时，总是有两个二轴C-F键。这种极性使这些化合物结晶固体，NMR实验表明，这两个面是高度极化的。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。我们认为全顺式四氟环己烷基序在开发用于药物和农用化学品研究的性能分子中可以具有广泛的作用。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特性。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含有氟原子。这是因为C-F键是极性的，但它具有低粘度，因此它可以在变化的电场中非常快速地定向和循环。全顺式四氟环己烷基序似乎完全具有被称为-ve介电各向异性LC的特定类别的LC的正确的characteristics。这些分子中的偶极垂直于分子轴。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种化学研究，并改进合成方案。我们还想探索合成四氟环己烷环系的其他衍生物的路线。我们认为羧酸和胺基序对于药物化学研究将是非常有吸引力的。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，并将协助提供设施以扩大这些基序的合成。如果我们能够展示全顺式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.第二个项目是由实验室中进行的一个新反应激发的，该反应认识到，如果用HF源处理乙炔硫醚，它会生成氟乙烯基硫醚（RS（F）= CH 2）。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，我们想探索它在酶抑制剂的早期设计（片段方法）的潜力。我们已经认识到，该基序近似于硫酯的烯醇的空间和电子分布。硫代酯烯醇/酯是重要的酶学中间体，例如。加工乙酰辅酶A的酶如柠檬酸和苹果酸合酶、乙酰辅酶A羧化酶和脂肪酸生物合成的烯酰还原酶是有吸引力的。因此，我们希望通过共结晶X射线研究评估氟乙烯基硫醚部分是否会被识别并结合到这些酶活性位点。这要求我们合成代表携带RS（F）= CH 2基序的截短泛酰巯基乙胺基部分的适当基序。这些化合物将与在大肠杆菌中过表达的酶共结晶。杆菌在与先正达的讨论中，他们建议我们探索烯酰还原酶的配体，这是一个与农用化学品部门相关的目标。一个成功的结果将表明，该基序结合到这些酶的活性位点（通过X-射线晶体学），并提供了一个基于片段的抑制剂开发的起始波因。该方案将向更广泛的研究界介绍这一主题。

项目成果

Fluorovinyl Thioethers as Putative Steric and Electronic Thioester Enolate Mimetics: Chemoselective HF Addition to Acetylene Thioethers

氟乙烯基硫醚作为假定的空间和电子硫酯烯醇化物模拟物：化学选择性 HF 加成到乙炔硫醚

• DOI: 10.1071/ch14298
• 发表时间: 2015
• 期刊: Australian Journal of Chemistry
• 影响因子: 1.1
• 作者: Bello D

Fluorinated cyclohexanes: Synthesis of amine building blocks of the all-cis 2,3,5,6-tetrafluorocyclohexylamine motif.

• DOI: 10.3762/bjoc.13.72
• 发表时间: 2017
• 期刊: Beilstein journal of organic chemistry
• 影响因子: 2.7
• 作者: Bykova T;Al-Maharik N;Slawin AMZ;O'Hagan D
• 通讯作者: O'Hagan D

Supramolecular packing of alkyl substituted Janus face all-cis 2,3,4,5,6-pentafluorocyclohexyl motifs.

• DOI: 10.1039/d1sc02130c
• 发表时间: 2021-07-21
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Clark JL;Taylor A;Geddis A;Neyyappadath RM;Piscelli BA;Yu C;Cordes DB;Slawin AMZ;Cormanich RA;Guldin S;O'Hagan D
• 通讯作者: O'Hagan D