C-H Functionalisation of Cyclic Ethers: New Routes to 3-D Fragments, Scaffolds and Pharmaceuticals

环醚（含有一系列碳原子和至少一个氧原子的环化合物）是广泛的商业药物中非常常见的结构单元。含有吗啉环醚的一个例子是由辉瑞公司开发的用于治疗抑郁症的Roboxalone。其他两种常见的环醚是四氢呋喃（5-环）和四氢吡喃（6-环）。事实上，一项对1157种FDA批准的药物进行的最常用环系统的调查（2014年发表）报告说，四氢吡喃排在第6位，四氢呋喃排在第11位，吗啉排在第29位。这些非常有用的环系统在药物中没有更广泛地使用的原因之一是，从母体环结构开始，很少有方法在那些环中已经存在的碳原子上直接、容易地引入其他基团。特别地，获取碳-氢键并将其直接转化为新的碳-碳键的方法是高度期望的。另一个重要的方面是所谓的手性环醚的产生-这些是以镜像形式存在的化合物（就像我们的手一样）-药物需要用一种手性（称为单一对映体）制备，因为每种对映体可以具有不同的生物学特性。因此，为了应对这些挑战，在本项目中，我们将开发新的方法，将四氢呋喃，四氢吡喃和吗啉（输入）转化为手性药物片段，药物支架和药物（输出）。我们将通过使用市售的有机锂试剂将碳-氢键转化为各种新的碳-碳键来实现这一点。为了优化这些过程，我们将深入探索所涉及的机制，并采用各种技术，包括计算建模。然后，我们将探索使用我们的方法来合成手性化合物的可能性，并制备一系列只有一个手性的药物样化合物。我们的反应的催化版本也将被调查。该技术的全部范围将与一系列不同的底物含有四氢呋喃，四氢吡喃和吗啉环进行研究。我们还计划开发药物分子的短合成，如抗抑郁药，Robexalone。最后，我们确定了制药行业的两个工业项目合作伙伴-阿斯利康和YProTech。这些合作是开发对制药行业有用的方法的关键-药物化学家将指导我们选择底物，我们预计YProTech将扩大一些程序，并使选定的化合物商业化，以便更广泛地使用。总的来说，通过这个项目，我们将为药物化学提供新的合成工具，以及将引起学术兴趣的机械理解。该项目完全符合EPSRC“拨号分子”大挑战-我们将能够通过简单的C-H功能化以高效率随意拨号氧环系统。它还涉及EPSRC挑战主题的医疗保健技术和制造的未来，以及EPSRC优先领域催化。

Cyclic ethers (ring compounds that contain a series of carbon atoms and at least one oxygen atom) are very common structural units in a wide range of commercial pharmaceuticals. One example, that contains a morpholine cyclic ether, is Roboxetine which was developed by Pfizer for the treatment of depression. Two other common cyclic ethers are tetrahydrofuran (5-ring) and tetrahydropyran (6-ring). Indeed, a survey (published in 2014) of the most frequently used ring systems from a survey of 1157 FDA-approved drugs reported that tetrahydropyran was 6th, tetrahydrofuran was 11th and morpholine was 29th. One of the reasons that these very useful ring systems are not used even more widely in pharmaceuticals is that, starting from the parent ring structures, there are very few methods for the direct, easy introduction of other groups on the carbon atoms already present in those rings. In particular, methods which take a carbon-hydrogen bond and convert it directly into a new carbon-carbon bond are highly desirable. Another aspect that is important is the generation of so-called chiral cyclic ethers - these are compounds which exist in mirror image forms (just like our hands) - drugs need to be prepared with one handedness (known as single enantiomers) as each enantiomer can have different biological properties. Thus, to address these challenges, in this project, we will develop novel methodology for the conversion of tetrahydrofurans, tetrahydropyrans and morpholines (inputs) into chiral drug fragments, drug scaffolds and pharmaceuticals (outputs). We will do this by using commercially available organolithium reagents to convert a carbon-hydrogen bond into a wide range of new carbon-carbon bonds. In order to optimise the processes, we will make use of an in-depth exploration of the mechanisms involved and a variety of techniques will be employed, including computational modelling. We will then explore the possibility of using our methods to synthesise chiral compounds and prepare a range of drug-like compounds of just one handedness. Catalytic versions of our reactions will also be investigated. The full scope of the technology will be investigated with a range of different substrates containing tetrahydrofuran, tetrahydropyran and morpholine rings. We also plan to develop short syntheses of drug molecules such as the anti-depressant, Robexetine. Finally, we have identified two industrial project partners from the pharmaceutical industry - AstraZeneca and YProTech. These collaborations are key to developing methods that will be useful for the pharmaceutical industry - medicinal chemists will guide our choice of substrates and we anticipate that YProTech will scale up some of the procedures and make selected compounds commercially available to be more widely used. Overall, through this project, we will deliver new synthetic tools for medicinal chemistry as well as mechanistic understanding that will be of much academic interest. This project fits squarely within the EPSRC "Dial-a-Molecule" Grand Challenge - we will be able to dial-an-oxygen ring system at will via simple C-H functionalisations with high efficiency. It also relates to the EPSRC Challenge Themes of Healthcare Technologies and Manufacturing the Future, together with the EPSRC priority area catalysis.