Routes to Disubstituted Nitrogen and Oxygen Heterocycles: Stereoselective Functionalisation of 3- and 4-Substituted Piperidines and Tetrahydropyrans

双取代氮和氧杂环的途径：3-和4-取代哌啶和四氢吡喃的立体选择性官能化

• 批准号: 2107318
• 金额: --
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2107318
• 关键词: Routes; Disubstituted; Nitrogen; Oxygen; Heterocycles

IntroductionSaturated nitrogen and oxygen heterocycles such as piperidines and tetrahydropyrans are common sub-structures in blockbuster pharmaceuticals. In particular, arylated piperidines and tetrahydropyrans are motifs that are currently attracting the interest of medicinal chemists and, as a result, the development of new methods for sp3-sp2 carbon-carbon bond formation is topical. This new methodology will then be available to be incorporated into the toolkit of reactions for use in medicinal chemistry. Vision and ObjectivesDespite all of the advances in synthetic chemistry in the last 20 years, there are rather limited methods to access disubstituted piperidines and tetrahydropyrans. These are very important motifs that commonly occur in the development of potential pharmaceuticals. Therefore, we propose to work on these types of nitrogen and oxygen heterocycles in this project. We will be primarily involved in the development of novel organometallic chemistry - focusing on organolithium reactions and Negishi cross-coupling or organozinc species. Negishi cross-coupling requires the use of a Pd(0)/phosphine catalyst system. We plan to explore methods that will control where the lithiation occurs (regiochemistry) and also how the new bonds a related in space to each (stereochemistry). Since, chiral blockbuster drugs need need to be accessible as single enantiomers and diastereomers, these key aspects must be explored as part of general methodology development. In particular, there are few stereoselective routes (i.e. where the stereochemistry is controlled) to disubstituted piperidines and tetrahydropyrans that contain one aryl substitutent and one heteroatom substituent (e.g. fluoro-, alkoxy-, dialkylamino-). Hence, the primary aim of this project is to develop methodology for the arylation of 3- and 4-fluoro, alkoxy and dialkylamino-substituted piperidines and tetrahydropyrans which will allow access to particular substitution patterns with regio-, diastereo- and enantiocontrol. This will deliver new disubstituted 6-ring saturated heterocycles for use in medicinal chemistry. There are four reseach-specific objectives:(i) alpha-arylation of 4-substituted piperidines - diastereo- and enantioselectivity;(ii) alpha-arylation of 3-substituted piperidines - regio-, diastereo- and enantioselectivity;(iii) alpha-arylation of 4- and 3-substituted tetrahydropyrans;(iv) beta-arylation of 4- and 3-substituted piperidines and tetrahydropyrans.OverviewUsing nitrogen- or oxygen-directed alpha-lithiation followed by transmetallation to an organozinc species and Negishi coupling, the direct arylation of 3- and 4-substituted piperidines and tetrahydropyrans will be explored in this project. This will give access to disubstituted nitrogen and oxygen heterocycles in a regio-, diastereo- and enantiocontrolled way.

饱和氮氧杂环化合物如哌啶和四氢吡喃是畅销药物中常见的亚结构。特别地，芳基化哌啶和四氢吡喃是目前吸引药物化学家的兴趣的基序，因此，sp3-sp2碳-碳键形成的新方法的开发是热门的。这种新的方法将被纳入药物化学反应的工具包。愿景和目标尽管在过去的20年里，合成化学取得了很大的进步，但获得二取代哌啶和四氢吡喃的方法相当有限。这些是非常重要的基序，通常发生在潜在药物的开发中。因此，我们建议在本项目中对这些类型的氮和氧杂环进行研究。我们将主要参与新型有机金属化学的发展-专注于有机锂反应和根岸交叉偶联或有机锌物种。Negishi交叉偶联需要使用Pd（0）/膦催化剂体系。我们计划探索控制锂化发生的方法（区域化学）以及新键在空间中如何与每个键相关（立体化学）。由于手性重磅炸弹药物需要以单一对映异构体和非对映异构体的形式获得，因此这些关键方面必须作为一般方法学开发的一部分进行探索。特别地，对于含有一个芳基取代基和一个杂原子取代基（例如，氟-、烷氧基-、二烷基氨基-）的二取代的哌啶和四氢吡喃，几乎没有立体选择性途径（即，其中控制立体化学）。因此，本项目的主要目的是开发用于3-和4-氟、烷氧基和二烷基氨基取代的哌啶和四氢吡喃的芳基化的方法，这将允许获得具有区域、非对映体和对映体控制的特定取代模式。这将提供用于药物化学的新的二取代的6-环饱和杂环。具体研究目标有四个：（i）4-取代哌啶的α-芳基化-非对映体和对映体选择性;（ii）3-取代哌啶的α-芳基化-区域选择性、非对映体和对映体选择性;（iii）4-和3-取代四氢吡喃的α-芳基化;（iv）4-和3-取代的哌啶和四氢吡喃的β-芳基化。本项目将探索锂化，然后进行金属交换，形成有机锌物种和Negishi偶联，3-和4-取代哌啶和四氢吡喃的直接芳基化。这将以区域-、非对映体-和对映体控制的方式获得二取代的氮和氧杂环。