Properties and applications of Janus faced fluorocyclohexanes

本课题源于我们在2015年制备并报道的选择性氟化分子全顺式-1,2,3,4,5,6-六氟环己烷的特殊性质。这是环己烷环系统，它是有史以来最具极性的脂肪族化合物，它有一些有趣的性质，比如能与阳离子和阴离子结合。环己烷环非常不寻常，因为它具有极化面。氟的面是负极化的氢的面是正极化的。2015年，这种环体系的制造具有挑战性，尤其是制造衍生物，然而，2017年，格洛瑞斯在明斯特的实验室开发了一种直接氢化方法，可以直接从芳香前体中获得环体系的衍生物。与这一建议相关的将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。随着这一发展，本研究计划旨在探索这些五氟环己烷体系的应用，探索与药物和生物化学（与氨基酸和蛋白质的相互作用）以及有机材料相关的特性，我们选择了液晶领域的特别重点。在医学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。负极性和正极性的面具有与具有互补静电剖面的氨基酸侧链相互作用的潜力。这将通过标记的“下拉”试验来探索，高亲和力的蛋白质将通过蛋白质组学技术来鉴定。候选蛋白将进行共结晶结构（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式-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。本研究将扩展到探索该环系统与病毒蛋白酶的结合，通过用全顺式-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。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，这将告知药物化学家该基序的潜力。该方案将扩展到含环己烷的CF3，但特别是含有一个以上CF3且具有明确立体化学的环。我们最近证明了与多个CF3基团连接到脂肪环上的环己烷也可以通过芳基CF3前体的直接氢化有效地获得。该计划将扩展到探索具有明确立体化学的两个和三个CF3基团的环己烷的制备、性质和化学性质。这些也是高度极化的脂肪族，这些新颖的图案将被引入液晶结构中，以举例说明其特性和潜力。液晶方面由位于达姆施塔特的默克液晶部门提供支持，该部门将对制备的材料进行详细分析。总的来说，该计划将探索一类令人兴奋的有机化学母题，这些母题有可能在一系列发现化学领域中贡献新的性质。

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.