Accessing diverse saturated heterocycles via rhodium-catalysed intermolecular hydroacylation/cyclisation

本项目福尔斯属于EPSRC合成有机化学研究领域。含氮、氧和硫的饱和杂环化合物在天然和生物活性化合物中普遍存在。这些框架由于其增强的水溶性和3D结构而在治疗剂中变得越来越理想。具有杂芳烃附件的饱和杂环对于在药物发现中探测结合口袋相互作用特别重要。虽然杂芳族化合物的合成方法很多，但构建饱和N-、O-和S-杂环的方法有限。金属催化的炔加氢酰化反应，其中C-H键形式上加在π-键上，以原子经济的方式产生烯酮化合物。然后，这些化合物可以通过分子内共轭加成转化为不同的杂环。近年来，氢酰化反应已被证实为杂环组装的工具。2014年，Dong团队合成了α-芳基酮加氢酰化加合物，其通过环缩合环化为苯并呋喃。此外，我们的研究小组还分别报道了通过TFA脱保护环化和刘易斯酸催化的氮杂共轭加成反应合成喹啉和六氢喹啉。采用螯合金属的底物导向基团，有效地阻止了不希望的还原脱羰基途径。Lochow和米勒首先证明了这种所谓的螯合控制。从那时起，各种官能团已被证明在促进分子间加氢酰化方面是成功的。迄今为止，我们已经建立了一个强大的螯合物控制的分子间氢酰化方案，需要低催化剂负载量和温和的条件。在这个项目中，我们的目标是利用氢酰化来获得新的，合成有吸引力的饱和N-，O-和S-杂环。还期望合成具有多个立体中心的杂环，以探测环化的非对映选择性。此外，我们的小组最近报道了使用PNP（Cy）配体的支链选择性加氢酰化。我们提出，可以利用分支烯酮的分子内环化来获得更广泛的饱和杂环。此外，初步研究表明，环化反应的结果在一个单一的非对映异构体的优先形成。因此，我们也有兴趣设计一个对映选择性合成饱和杂环。最终，我们希望实现一种方法，为药物化学中寻求的各种新型支架提供原子经济，温和和有效的途径。

This project falls within the EPSRC Synthetic Organic Chemistry research area.Nitrogen-, oxygen and sulphur-containing saturated heterocycles are ubiquitous amongst natural and bioactive compounds. These frameworks are becoming increasingly more desirable in therapeutic agents owing to their enhanced aqueous solubility and 3D structure. Saturated heterocycles with heteroarene appendages are particularly important for probing binding pocket interactions in drug discovery. While a plethora of syntheses exist for heteroaromatics, there are limited methods for constructing saturated N-, O- and S-heterocycles. Approaches to these frameworks must be general, convenient and employ easily accessible starting materials.Metal-catalysed alkyne hydroacylation reactions, where a C-H bond is formally added across a pi-bond, generate enone compounds, in an atom-economical fashion. These compounds can then be transformed into diverse heterocycles via intramolecular conjugate addition. In recent years, hydroacylation reactions have been validated as a tool for heterocycle assembly. In 2014, the Dong group synthesised a- aryl ketone hydroacylation adducts, which were cyclised to benzofurans via cyclocondensation. Additionally, our group has reported syntheses of quinolines and hexahydroquinolines through TFA deprotection-cyclisation and Lewis acid-catalysed aza-conjugate addition, respectively.Intermolecular hydroacylation has advanced significantly over the past decade. The adoption of substrate directing groups, which chelate the metal, effectively thwarts an undesirable reductive-decarbonylation pathway. This so-called chelate control was first demonstrated by Lochow and Miller. Since then, a variety of functional groups have proven successful in promoting intermolecular hydroacylation. To date, our group have established a robust chelate controlled intermolecular hydroacylation protocol; requiring low catalyst-loadings and mild conditions.In this project, we aim to exploit hydroacylation to access novel, and synthetically attractive saturated N-,O-and S-heterocycles. Synthesis of heterocycles with multiple stereogenic centres is also desired, in order to probe the diastereoselectivity of cyclisation. Furthermore, our group has recently reported branched selective hydroacylation using PNP(Cy) ligand. We propose that intramolecular endo-cyclisation of branched enones, could be utilized to attain a much broader repertoire of saturated heterocycles. Moreover, preliminary investigations suggest the cyclisation reaction results in preferential formation of a single diastereomer. Consequently, we are also interested in designing an enantioselective synthesis of saturated heterocycles. Ultimately, we hope to realise a methodology that provides an atom-economical, mild and efficient route to a variety of novel scaffolds sought after in medicinal chemistry.