Properties and applications of Janus faced fluorocyclohexanes

Janus面氟环己烷的性能和应用

• 批准号: EP/S030506/1
• 负责人: David O'Hagan
• 金额: $ 61.54万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS030506%2F1
• 关键词: Properties; applications; Janus; faced; fluorocyclohexanes

This research proposal has its origin in the special properties of the selectively fluorinated molecule, all-cis-1,2,3,4,5,6-hexafluorocyclohexane, which we prepared and reported in 2015. This is cyclohexane ring system which emerges as the most polar aliphatic compound recorded and it has interesting properties such as the ability to associate with both cations and anions. The cyclohexane ring is highly unusual in that it has polarised faces. The fluorine face is negatively polarised and the hydrogen face is positively polarised. In 2015 this ring system was challenging to make, and particularly to make derivatives, however in 2017 a direct hydrogenation method was developed by Glorius's lab in Munster, which allows access to derivatived forms of the ring system directly from aromatic precursors. Relevant to this proposal will be the synthesis of a series of substituted pentafluorocyclohexanes, where all substituents are on the same side of the cyclohexane ring. With this development, this research programme aims to explore applications of these pentafluorocyclohexane ring systems, exploring properties relevant to medicinal and biological chemistry (interactions with amino acids and proteins) as well as in organic materials and we have selected a particular focus in the areas of liquid crystals. In the context of medicinal and biological chmeistry we want to explore how these ring systems will be expected to interact and bind with proteins. The negatively and positively polarised faces have the potential to make interactions with amino acid side chains with a complementary electrostatic profile. This will be explored by tagged 'pull-down' assays and proteins of high affinity will be identified by proteomics techniques. Candidate proteins will be progressed to co-crytsalisation structural (X-ray) studies for close structural analysis. In a complementary approach we will prepare tripeptides, from amino acid combinations that are known to be predisposed towards crystallinity. We will prepare a range of these with an amino acid with an all cis-2,3,4,5,6-pentafluorocyclohexyl side chain to explore how it interacts with other amino acid side chains. This study will extend to exploring the binding of this ring system to viral proteases, by making appropriate changes to drug molecules by replacing cyclohexyl or fluoroaromatic rings with the all cis-2,3,4,5,6-pentafluorocyclohexyl side chain. Structural biology(X-ray) analysis will allow us to determine how these ring systems interact with the protein, and this will inform medicinal chemists as to the potential of this motif. The programme will extend to CF3 containing cyclohexanes, but particulary rings with more than one CF3 and with a defined stereochemistry. We have recently demonstrated that cyclohexanes with multiple CF3 groups attached to the aliphatic ring can also be accessed efficiently by the direct hydrogenation of arylCF3 precursors. The programme will extend to exploring the preparation, properties and chemistry of cyclohexanes with two and three CF3 groups with defined stereochemistries. These are also highly polarised aliphatics and these novel motifs will be introduced into liquid crystal architectures to exemplify properties and potential. The liquid crystal aspect is supported by Merck Liquid Crystal Division in Darmstadt who will carry out detailed analysis of prpared materials. In overview the programme will explore an exciting class of organic chemistry motif which have potential to contribute new properties in a range of discovery chemistry arenas.

这一研究建议源于我们于2015年制备并报道的选择性氟化分子全顺-1，2，3，4，5，6-六氟环己烷的特殊性质。这是一种环己烷环体系，它是有记录以来最具极性的脂肪族化合物，它具有有趣的性质，如与阳离子和阴离子都能缔合。环己烷环非常不寻常，因为它有偏振面。氟面是负极化的，氢面是正极化的。2015年，这种环系的制造很有挑战性，特别是制造衍生物，然而在2017年，Glorius位于明斯特的实验室开发了一种直接加氢方法，允许直接从芳香前体获得环系的衍生形式。与这项提议相关的是合成一系列取代的五氟环己烷，其中所有取代基都在环己烷环的同一侧。随着这一进展，这项研究计划旨在探索这些五氟环己烷环系统的应用，探索与药物和生物化学(与氨基酸和蛋白质的相互作用)以及在有机材料中相关的性质，我们选择了液晶领域的特别重点。在药物和生物化学的背景下，我们想要探索这些环系统将如何与蛋白质相互作用和结合。负极化面和正极化面有可能与具有互补静电轮廓的氨基酸侧链相互作用。这将通过标记的“下拉”分析进行探索，并将通过蛋白质组学技术鉴定高亲和力的蛋白质。候选蛋白质将进行共结晶结构(X-射线)研究，以进行密切的结构分析。在一种互补的方法中，我们将从已知倾向于结晶度的氨基酸组合中制备三肽。我们将制备一系列具有全顺-2，3，4，5，6-五氟环己基侧链的氨基酸，以探索它如何与其他氨基酸侧链相互作用。这项研究将通过用全顺-2，3，4，5，6-五氟环己基侧链取代环己基或氟芳环，对药物分子进行适当的改变，来探索这个环系统与病毒蛋白酶的结合。结构生物学(X射线)分析将使我们能够确定这些环系统如何与蛋白质相互作用，这将使药物化学家了解这个基序的潜力。该方案将扩展到含有环己烷的CF3，但含有多于一个CF3的特殊环，并具有明确的立体化学。我们最近已经证明，脂肪环上带有多个CF3基团的环己烷也可以通过芳基CF3前体的直接氢化有效地获得。该方案将扩展到探索具有两个和三个CF3基团的具有明确立体化学的环己烷的制备、性质和化学。这些也是高度极化的脂肪族化合物，这些新的主题将被引入液晶结构中，以例证其性质和潜力。液晶方面由位于达姆施塔特的默克液晶部提供支持，该部门将对制备的材料进行详细分析。综上所述，该方案将探索一类令人兴奋的有机化学主题，这些主题有可能在一系列发现化学领域中贡献新的性质。

项目成果

Janus faced fluorocyclohexanes for supramolecular assembly: synthesis and solid state structures of equatorial mono-, di- and tri alkylated cyclohexanes and with tri-axial C-F bonds to impart polarity.

Janus 面临用于超分子组装的氟代环己烷：赤道单、二和三烷基化环己烷的合成和固态结构，并具有三轴 C-F 键以赋予极性。

• DOI: 10.1039/d2cc03010a
• 发表时间: 2022
• 期刊: Chemical communications (Cambridge, England)
• 作者: Poskin TJ

Does Perdeuteration Increase the Polarity of Janus Face Cycloalkanes?

全氘化是否会增加 Janus Face 环烷烃的极性？

• DOI: 10.1002/hlca.202200177
• 发表时间: 2023
• 期刊: Helvetica Chimica Acta
• 影响因子: 1.8
• 作者: Fang Z

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

The contribution of non-classical CHaxOC hydrogen bonds to the anomeric effect in fluoro and oxa-methoxycyclohexanes.

非经典 CHaxOC 氢键对氟代和氧杂甲氧基环己烷中异头效应的贡献。

• DOI: 10.1039/d0cp06646j
• 发表时间: 2021
• 期刊: PCCP
• 作者: Piscelli BA

Lateral dipole moments induced by all-cis-pentafluorocyclohexyl groups cause unanticipated effects in self-assembled monolayers

• DOI: 10.1007/s12274-023-5818-4
• 发表时间: 2023-06-26
• 期刊: NANO RESEARCH
• 影响因子: 9.9
• 作者: Fischer, Christian;Das, Saunak;Terfort, Andreas
• 通讯作者: Terfort, Andreas