New Routes to Substituted Nitrogen Heterocycles Using Negishi and Suzuki Cross-Coupling Reactions

利用 Negishi 和 Suzuki 交叉偶联反应制备取代氮杂环的新路线

• 批准号: 2267405
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2267405
• 关键词: New; Routes; Substituted; Nitrogen; Heterocycles

IntroductionSaturated nitrogen heterocycles such as piperidines, pyrrolidines, morpholines and piperazines are common parts of blockbuster pharmaceuticals. In particular, arylated nitrogen heterocycles 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 the advances in synthetic chemistry in recent years, there are limited methods that allow access to substituted piperidines, pyrrolidines, morpholines and piperazines in an asymmetric fashion starting from the parent heterocycle. These are important sub-structures that frequently occur in the development of potential pharmaceuticals. Therefore, we propose to work on these types of nitrogen heterocycles in this project. Two approaches are envisioned - Suzuki reactions from stereodefined boronate derivatives and Negishi reactions of stereodefined orgnaozinc reagents. Both types of cross-coupling reactions will be carried out using a Pd(0)/phosphine catalyst system. To achieve our aims and objectives, it will be necessary to screen a wide range of Pd catalysts and ligands. Since the development of blockbuster pharmaceuticals ultimately requires access to single enantiomers of chiral nitrogen heterocycles, the focus will be on diastereoselective and enantioselective methods. We will also work on substrates that contain functionality that is commonly found in drug molecules such as fluoro, amino, alkoxy and hydroxy groups. Our project will deliver a wide range of new building blocks for potential use in medicinal chemistry. The overall aim of the project is to develop new cross-coupling methodology for the asymmetric synthesis of nitrogen heterocycles. We will also aim to translate our new methodology to the pharmaceutical industry -this will be achieved using strongly established links that are already in place. There are three research-specific objectives:(i) arylation of piperidines and pyrrolidines using Suzuki reactions;(ii) arylation of piperidines using Negishi reactions;(iii) extension of methods from (i) and (ii) to arylation of morpholines and piperazines.OverviewUsing nitrogen-directed lithiation followed by transmetallation to an organozinc species and Negishi coupling, the direct arylation nitrogen heterocycles will be explored. Separately, an approach using boronate building blocks will be investigated so that a Suzuki cross-coupling approach can also be studied. This will give access to a wide range of building blocks of interest to medicinal chemists in the pharmaceutical industry.

引入饱和的氮杂环，例如哌啶，吡咯烷，吗啡和哌嗪是巨人药物的常见部分。特别是，芳基化的氮杂环目前正在吸引药物学家的兴趣，因此，SP3-SP2碳碳键形成的新方法的发展是局部的。然后，这种新方法将被纳入用于药物化学的反应工具包中。视觉和目标是尽管近年来合成化学的进步，但有限的方法可以从父母杂虫开始，以不对称的方式进入取代的哌啶，吡咯烷，吗啡和哌嗪。这些是潜在药物开发中经常发生的重要子结构。因此，我们建议在该项目中研究这些类型的氮异细胞。设想了两种方法 - 铃木反应来自立体构造的硼酸衍生物和立体构造的Orgnaozinc试剂的Negishi反应。两种类型的交叉偶联反应将使用PD（0）/磷酸催化剂系统进行。为了实现我们的目标和目标，有必要筛选广泛的PD催化剂和配体。由于大片药的发展最终需要访问手性氮异构体的单个对映异构体，因此重点将放在映选择性和对映选择性方法上。我们还将研究包含在氟，氨基，烷氧基和羟基等药物分子中通常发现的功能的底物。我们的项目将提供广泛的新构件，以便在药物化学中使用。该项目的总体目的是开发新的交叉偶联方法，以使氮异环的不对称合成。我们还将旨在将我们的新方法转化为制药行业 - 将使用已经建立的牢固链接来实现。有三个特定研究的目标：（i）使用铃木反应芳基芳基化和吡咯烷的芳基化；（ii）使用negishi反应芳基芳基化；（iii）（iii）从（i）和（ii）扩展（i）和（ii）到芳基的芳基和peperazines anderized and andiS and的芳基化的质地化岩性的芳基化的质地。耦合，将探索直接芳基化氮杂环。另外，将研究使用富有硼酸盐构建块的方法，以便还可以研究铃木交叉耦合方法。这将使制药行业的药物学家能够获得广泛的构建基础。