Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates

含氧和含氮的环状化合物（含有一系列碳原子和一个氧或氮原子的环状化合物）是广泛的商业药品中非常常见的结构单元。其中一个例子是帕罗西汀，它是由葛兰素史克公司开发的治疗抑郁症的药物。制药行业的药物化学家对研究手性药物结构越来越感兴趣。手性分子是以镜像形式存在的化合物（就像我们的手一样）——药物需要用单手性（称为单对映体）来制备，因为每个对映体都有不同的生物学特性。制药行业合成药物分子最广泛使用的过程之一是Suzuki-Miyaura交叉偶联反应，其重要性被授予2010年诺贝尔奖。然而，Suzuki-Miyaura反应尚未被用于直接制备手性药物基序-目前还没有方法将手性饱和杂环硼酸盐与芳基卤化物进行一般的Suzuki-Miyaura交叉偶联。该项目将提供这样一个过程，实现变革性和非传统的断开连接，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的发现和合适的催化方案的优化。手性环分子在fda批准的药物中无处不在，这确保了该过程将成为制药行业药物发现的一项有利和变革性技术。最后，将有机会使用我们的新方法来优化针对治疗covid-19的感兴趣蛋白质的片段命中。有三个具体的研究目标：(i)通过高通量实验、丰富的数据分析和配体设计，对饱和含氧和含氮杂环的Suzuki-Miyaura交叉偶联反应进行优化；（ii）利用机理发现，探索饱和含氧和含氮杂环的Suzuki-Miyaura交叉偶联反应的范围和局限性（变化将包括不同的硼酸盐和芳基卤化物）；特别是对生产催化至关重要的步骤（iii）将新开发的方法应用于类似物和文库合成，包括与covid-19相关的片段命中

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. There are three specific research objectives:(i) to carry out the optimisation of Suzuki-Miyaura cross-coupling reactions of saturated oxygen- and nitrogen-containing heterocycles using high throughput experimentation, rich data analysis and ligand design(ii) to explore the scope and limitations of Suzuki-Miyaura cross-coupling reactions of saturated oxygen- and nitrogen-containing heterocycles (variations will include different boronates and aryl halides), drawing on mechanistic findings, particularly steps critical to productive catalysis(iii) to apply the newly developed methodology to analogue and library synthesis including covid-19-related fragment hits