Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates: A Transformative Disconnection for Drug Discovery

环状含氧和含氮化合物(含有一系列碳原子和一个氧或氮原子的环状化合物)是广泛的商业药物中非常常见的结构单元。一个例子是帕罗西汀，它是由葛兰素史克公司开发的，用于治疗抑郁症。制药行业中的药物化学家对手性药物结构的研究越来越感兴趣。手性分子是以镜像形式存在的化合物(就像我们的手一样)-药物需要用一只手(称为单一对映体)来制备，因为每个对映体可能具有不同的生物学特性。制药业最广泛使用的合成药物分子的工艺之一是铃木-宫浦交叉偶联反应，该反应的重要性在2010年的诺贝尔奖中得到了认可。然而，Suzuki-Miyaura反应还没有被直接用于制备手性药物基元--目前还没有一种方法来实现手性饱和杂环硼酸酯与芳基卤化物的一般Suzuki-Miyaura交叉偶联。该项目将提供这样一个过程，以实现变革性和非传统的断开，从根本上改变三维饱和含氮和含氧杂环的构建方式。自动化的高通量实验、丰富的数据分析和严格的机理研究将推动反应发现和合适催化方案的优化。FDA批准的药物中普遍存在的手性环状分子确保了该过程将成为制药业药物发现的一种使能和变革性技术。最后，将有机会使用我们的新方法来优化针对新冠肺炎治疗感兴趣的蛋白质的片段命中。

Cyclic oxygen- and nitrogen-containing compounds (ring compounds that contain a series of carbon atoms and an oxygen or nitrogen atom) are very common structural units in a wide range of commercial pharmaceuticals. One example is Paroxetine which was developed by GlaxoSmithKline for the treatment of depression. There is a growing interest for medicinal chemists in the pharmaceutical industry to work on chiral drug structures. Chiral molecules 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. One of the most widely used processes in the pharmaceutical industry to synthesise drug molecules is the Suzuki-Miyaura cross-coupling reaction, the importance of which was recognised with the award of the 2010 Nobel Prize. However, the Suzuki-Miyaura reaction has not been used to directly prepare chiral drug motifs - there is currently no method for the general Suzuki-Miyaura cross-coupling of chiral saturated heterocyclic boronates with aryl halides. This project will deliver such a process to enable transformative and non-traditional disconnections, fundamentally changing the way that three-dimensional saturated nitrogen- and oxygen-containing heterocycles are constructed. Reaction discovery and optimisation of suitable catalytic protocols will be driven by automated high throughput experimentation, rich data analysis and rigorous mechanistic studies. The ubiquity of chiral cyclic molecules containing in FDA-approved drugs ensures that the process will be an enabling and transformative technology for drug discovery in the pharmaceutical industry. Finally, there will be an opportunity to use our new methodology in the optimisation of fragment hits against proteins of interest for the treatment of covid-19.