New Catalytic Strategies for Metal-Free C-C Bond Formation

胺和n -杂环是药物化合物的关键组成部分，在所有小分子药物中占60%。然而，一个由大型制药公司组成的联盟最近发现，缺乏n -杂环合成的实用方法是药物开发的严重障碍（见Nature Chem. 2018, 10,383）。问题不在于这些结构在原则上不能被获取，而是现有的合成它们的技术是如此的费力和耗时，以至于化学家们经常被迫忽略那些很可能提供最佳候选药物的化学空间区域。本项目旨在寻找易于工业应用的胺和n -杂环合成新方法。我的研究将解决一些最受欢迎的n -杂环支架的上述挑战，包括那些只含有一个氮原子和包含两个氮原子的更奇特的环系统。我们的实验室最近发现了一种突破性的方法，可以在简单的含氮起始材料（称为伯胺）中功能化碳-氢（C-H）键，其中两种不同的催化剂在可见光照射下协调碳-碳（C-C）键的形成。我将利用这种新颖的反应性来设计新颖和创新的化学转化，以前所未有的效率组装重要的n -杂环，只需要一次合成操作。相比之下，目前针对这些目标的最新技术规定了多达五个（或更多）化学步骤的扩展线性序列，因此这里的贡献将是变革性的。我们正在进一步为自己设定挑战，确保我们所有的过程在一个过程规模上是潜在的可执行的，这需要大量的材料。为了实现这一目标，我将利用现代流动化学技术，在基于管道的反应器中运行化学反应，而不是传统的玻璃器皿。与我们的工业合作伙伴阿斯利康（AstraZeneca）一起，我还将探索使用自动化机器人平台与我们的化学技术相结合的潜力，以生成用于药物发现的高价值化合物的新文库。

Amines and N-heterocycles are key building blocks for pharmaceutical compounds, arising in 60% of all small-molecule drugs. However, a consortium of major pharmaceutical companies recently identified a lack of practical methods for N-heterocycle synthesis as a serious impediment to drug development (see Nature Chem. 2018, 10, 383). The problem is not that these structures cannot in principle be accessed, but that the existing technology to synthesise them is so laborious and time-consuming that chemists are often forced to overlook regions of chemical space that may well provide the most optimal drug candidates. The aim of this project is to find new synthetic methods for amine and N-heterocycle synthesis that can be easily applied in industry. My research will address the above challenges for some of the most highly sought-after N-heterocyclic scaffolds, including those containing only a single nitrogen atom and more exotic ring-systems comprising two nitrogen atoms.Our lab has recently discovered a ground-breaking process to functionalise carbon-hydrogen (C-H) bonds in simple, nitrogen-containing starting materials called primary amines, in which two different catalysts orchestrate a carbon-carbon (C-C) bond formation under visible-light irradiation. I will leverage this novel reactivity to design novel and innovative chemical transformations to assemble important N-heterocycles with unprecedented efficiency, requiring only a single synthetic operation. In contrast, the current state-of-the-art for these targets prescribes extended linear sequences of up to five (or more) chemical steps, so the contributions here are set to be transformative. We are further setting ourselves the challenge of ensuring that all of our processes are potentially executable on a process scale, which requires kilogram quantities of material. To achieve this goal, I will utilise modern flow chemistry techniques that run chemical reactions in tubing-based reactors, as opposed to conventional glassware. In conjunction with our industrial partner (AstraZeneca), I will also explore the potential for using automated robotic platforms in unity with our chemistry to generate novel libraries of high-value compounds for drug discovery.