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

通过铑催化的分子间氢酰化/环化获得不同的饱和杂环

基本信息

批准号：
1923155
负责人：
金额：
--
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1923155
关键词：
Accessing diverse saturated heterocycles via

项目摘要

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.

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。由于水溶性和 3D 结构的增强，这些框架在治疗剂中变得越来越受欢迎。具有杂芳烃附属物的饱和杂环对于探索药物发现中的结合袋相互作用特别重要。虽然杂芳烃的合成方法很多，但构建饱和 N-、O- 和 S- 杂环的方法有限。这些框架的方法必须是通用的、方便的，并且使用易于获得的起始材料。金属催化的炔烃加氢酰化反应，其中C-H键正式加成到π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，加氢酰化反应已被验证为杂环组装的工具。 2014年，Dong课题组合成了α-芳基酮加氢酰化加合物，通过环缩合环化为苯并呋喃。此外，我们小组还报道了分别通过TFA脱保护环化和路易斯酸催化的氮杂缀合物加成来合成喹啉和六氢喹啉。分子间氢酰化在过去十年中取得了显着进展。采用螯合金属的底物导向基团，可有效阻止不良的还原脱羰途径。这种所谓的螯合物控制首先由 Lochow 和 Miller 证明。从那时起，多种官能团已被证明可以成功促进分子间加氢酰化。迄今为止，我们小组已经建立了强大的螯合物控制的分子间加氢酰化方案；需要低催化剂负载量和温和的条件。在这个项目中，我们的目标是利用加氢酰化来获得新颖且具有合成吸引力的饱和N-、O-和S-杂环。还需要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。我们建议，支链烯酮的分子内环化可用于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非对映体。因此，我们也有兴趣设计饱和杂环的对映选择性合成。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、温和且有效的途径。