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

饱和氮氧杂环如哌啶和四氢吡喃是重磅药物中常见的亚结构。特别是芳基化哌啶和四氢吡喃是目前引起药物化学家兴趣的基序，因此，开发sp3-sp2碳-碳键形成的新方法是热门话题。这种新方法将被纳入药物化学反应工具包中。愿景与目标尽管在过去的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。这些都是非常重要的基序，通常出现在潜在药物的开发中。因此，我们建议在本项目中对这类氮氧杂环进行研究。我们将主要参与新型有机金属化学的发展-重点是有机锂反应和根岸交叉偶联或有机锌物种。根岸交叉耦合需要使用Pd(0)/磷化氢催化剂体系。我们计划探索控制锂化发生位置的方法（区域化学），以及新键如何在空间上相互关联（立体化学）。由于手性重磅药物需要以单对映体和非对映体的形式获得，因此必须将这些关键方面作为一般方法开发的一部分进行探索。特别是，含有一个芳基取代基和一个杂原子取代基（如氟-、烷氧基-、二烷基胺-）的二取代哌啶和四氢吡喃的立体选择途径很少（即立体化学受到控制的地方）。因此，该项目的主要目的是发展3-氟和4-氟、烷氧基和二氨基取代的哌啶和四氢吡喃的芳基化方法，以便获得具有区域、非映对和对映控制的特定取代模式。这将提供新的二取代6环饱和杂环用于药物化学。有四个特定的研究目标：(i) 4-取代哌啶的α -芳基化-非映对和对映选择性；（ii） 3-取代哌啶的α -芳基化-区域选择性、非映体选择性和对映体选择性；（iii） 4-和3-取代四氢吡喃的α -芳基化；（iv） 4-和3-取代哌啶和四氢吡喃的-芳基化。本项目将利用氮或氧定向α -锂化、金属转化为有机锌和根岸偶联，探索3-和4-取代哌啶和四氢吡喃的直接芳基化。这将以区域、非映对和对映控制的方式获得氮和氧的二取代杂环。

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.