Partially fluorinated alkyl motifs for pharmaceuticals and agrochemicals research

该研究旨在探索制备几种小的部分氟化基序，用于添加到小有机分子中以用于生物活性物质的发现。这项工作还将扩展到高性能有机材料，特别是用于显示器的液晶。氟通常在开发过程中引入分子中，以调整分子的物理性质，或者在药物的情况下，以改善体内性质（药代动力学）。这导致在药品和农用化学品领域进入市场的所有生物活性产品中约有20-30%引入了氟。氟具有高度极化的有趣特性（它是电负性最强的元素），并且它通过σ键拉动电子密度（称为感应效应），这具有改变分子整体极性的效果，或者改变相邻原子的性质，例如使氢比通常更具正电性。然而，氟原子本身与相邻分子的相互作用非常差（弱分子间相互作用）。它也相对较小，是氢之后的第二小原子，可以以稳定的形式与碳结合（C-F键是有机化学中最强的键）。这些特性的结合使得氟成为一种很好的工具，用于取代分子上的氢原子以调节其性质（通过将电子密度拉向氟），而不会过多地改变分子的形状，也不会改变分子间相互作用的性质。当引入一种以上的氟时，这可能成为问题。通常，工业界可能会引入CF 3基团。现在这已经变得相当大了。它是疏水性的，它排斥水，它赋予分子增加的亲油性。这可能有利于与特定蛋白质靶点结合，但该分子在水中的溶解度较低，在脂膜中的溶解度较高，并且它现在难以穿过膜并在血液中携带，直到它到达其靶点。因此，一个好的组合是增加对蛋白质靶点上疏水位点的亲和力，但保持合理的水溶性。理想地，如果可以引入相对于Et或CH 3稍大但不增加亲脂性（Log P）的有机取代基，则这样的有机取代基将是有吸引力的。在这个建议中，我们已经确定了四个图案是新的，并拥有这些极性疏水特性。基序1和2是氧和硫二氟乙基醚。我们已经设计了制备它们的方法，并希望探索将它们引入一系列建筑砌块和药用类似产品的化学方法。我们还将系统地探索它们的极性（Log Ps）和它们的代谢（如果有的话，身体如何改变它们）。基序3和4是携带三个氟的环丙烷。它们是极化的，因为它们有两个氢（亚甲基）和三个相邻的电负性氟原子。在基序4中，有一个额外的氧原子（也是电负性的），使该基序进一步极化。这些图案是非常新颖的，但我们已经证明，它们可以很容易地制备。该方案将探索其潜在的用途和特性，重点是生物活性发现方案，通过该方案，我们的目标是提请工业界和学术界的国际社会注意它们。基序5设想了三个氟，环丙烷环的三个碳上各有一个，并且具有所有氟指向的立体化学。这被认为是正在研究的基序中最极性的，并且将是生物活性研究之外的广泛科学家感兴趣的特殊结构，包括材料化学家和物理学家，因为它具有极不寻常的极性特性。

The proposed research aims to explore the preparation of several small partially fluorinated motifs for appending to small organic molecules for use in bioactives discovery. The work will also extend to performance organic materials, specifically liquid crystals for displays.Fluorine is often introduced into molecules during development to tune the physical properties of the molecule, or in the case of drugs, to improve in-vivo properties (pharmacokinetics). This has resulted in fluorine being introduced into about 20-30% of all bioactive products coming onto the market in the pharmaceuticals and agrochemicals sectors. Fluorine has the interesting property of being highly polarised (it is the most electronegative element) and it pulls electron density through sigma bonds (known as the inductive effect), and this has the effect of changing the overall polarity of the molecule, or changing the nature of neighbouring atoms eg making hydrogens more electropositive than usual. However the fluorine atom itself is very poor at interacting with adjacent molecules (weak intermolecular interactions). It is also relatively small and the next smallest atom after hydrogen that can be bound to carbon in a stable form (C-F bond is the strongest bond in organic chemistry). This combination of features makes fluorine an excellent tool for replacing hydrogen atoms on a molecule to tune its properties (by tugging electron density towards the fluorine), without changing the shape of the molecule too much, and without changing the nature of intermolecular interactions. When more than one fluorine is introduced, this can become problematic. Typically industry might introduce a CF3 group. This now is getting quite large. It is hydrophobic and it repels water, and it confers increased lipophilicity on the molecule. This can be good for binding to a particular protein target, but the molecule is less soluble in water and more soluble in lipid membranes, and it now has difficulty passing through membranes and being carried in the blood, until it gets to its target. So a good combination is to increase affinity for hydrophobic sites on a protein target, but to retain reasonable water solubility. Ideally if organic substituents can be introduced that are a little larger, but that do not increase lipophilicity (Log P), relative to Et or CH3, then such organic substituents would be attractive. In this proposal we have identified four motifs that are novel, and posess these polar hydrophobic characteristics. Motifs 1 and 2 are oxygen and sulfur difluoroethyl ethers. We have devised methods to prepare them, and want to explore chemistry for introducing them into a range of building bocks, and medicinal like products. We will also systematically explore their polarity (Log Ps) and their metabolism (how the body may modify them, if at all).Motifs 3 and 4 are cyclopropanes carrying three fluorines. They are polarised as they have two hydrogens (methylene group) with three electronegative fluorine atoms adjacent. In motif 4 there is an additional oxygen atom (also electronegative), polarising this motif further. These motifs are highly novel, but we have demonstrated that they can be readily prepared. The programme will explore their potential utility and properties with a focus on bioactive discovery programmes, and through this programme we would aim to bring them to the attention of the international community in industry and academia. Motif 5 envisages three fluorines, one each on the three carbons of a cyclopropane ring, and with a stereochemistry that has all of the fluorines pointing up. This is claculated to be the most polar of the Motifs under investigation, and would be a special structure of interest to a wide range of scientists beyond bioactives research, including materials chemists and physicists, as it would have highly unusual polar properties.