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

该项目属于EPSRC合成有机化学研究领域。含氮、氧和硫的饱和杂环在天然和生物活性化合物中普遍存在。这些骨架由于其更好的水溶性和3D结构，在治疗药物中变得越来越受欢迎。含杂芳烃的饱和杂环在药物发现中对于探测结合口袋相互作用特别重要。虽然合成杂芳烃的方法很多，但合成饱和的N-、O-和S杂环的方法有限。这些骨架的方法必须是通用的，方便的，并且使用容易获得的起始材料。金属催化的炔氢酰化反应，其中C-H键被正式地添加到pi键上，以原子经济的方式生成烯酮化合物。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是一种组装杂环的工具。2014年，董组合成了α-芳基酮氢酰化加合物，这些加合物通过环合反应环合成了苯并呋喃。此外，本课题组还报道了分别通过TFA去保护环化和Lewis酸催化的氮杂共轭加成反应合成喹啉和六氢喹啉。在过去的十年中，分子间氢酰化反应取得了显著的进展。采用底物导向基团来螯合金属，有效地阻止了不受欢迎的还原-脱碳途径。这种所谓的螯合控制最先是由Lochow和Miller证明的。从那时起，各种官能团已被证明在促进分子间氢酰化方面取得了成功。到目前为止，我们的团队已经建立了一个强大的螯合物控制的分子间氢酰化反应方案；需要低催化剂负载和温和的条件。在这个项目中，我们的目标是利用氢酰化反应来获得新颖的、合成上有吸引力的饱和N-、O-和S-杂环。为了探索环化反应的非对映选择性，还需要合成具有多个立体生成中心的杂环。此外，我们小组最近报道了使用PNP(Cy)配体的支化选择性氢酰化反应。我们认为，支链烯酮的分子内内环化可以用来获得更广泛的饱和杂环。此外，初步研究表明，环化反应导致优先形成单一的非对映异构体。因此，我们也有兴趣设计一种饱和杂环的对映选择性合成方法。最终，我们希望实现一种方法学，为药物化学中寻找的各种新型支架提供一种原子经济、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.