Stereospecific Suzuki-Miyaura Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates: Programmable Exploration of 3-D Space

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化合物）是广泛的商业药物中非常常见的结构单元。在制药工业中，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。制药工业中最广泛使用的合成药物分子的方法之一是铃木-宫浦交叉偶联反应，其重要性获得了2010年诺贝尔奖的认可。然而，Suzuki-Miyaura反应尚未用于直接制备手性药物基序-目前还没有手性饱和杂环硼酸酯与芳基卤化物的一般Suzuki-Miyaura交叉偶联的方法。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。反应发现和合适的催化方案的优化将由自动化高通量实验、丰富的数据分析和严格的机理研究驱动。FDA批准的药物中所含的手性环状分子的普遍存在确保了该过程将成为制药行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目标蛋白质的片段命中，以治疗新冠肺炎。有三个具体的研究目标：（i）利用高通量实验、丰富的数据分析和配体设计，优化饱和含氧和含氮杂环的Suzuki-Miyaura交叉偶联反应;（ii）利用机理发现，特别是对生产性催化至关重要的步骤，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）;（iii）将新开发的方法应用于类似物和文库合成，包括Covid-19相关片段命中

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. 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