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

饱和氮杂环化合物如哌啶、吡咯烷、吗啉和哌嗪是畅销药物的常见组成部分。特别地，芳基化的氮杂环目前吸引了药物化学家的兴趣，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。尽管近年来在合成化学方面取得了进展，但允许以不对称方式从母体杂环开始获得取代的哌啶、吡咯烷、吗啉和哌嗪的方法有限。这些是在潜在药物开发中经常出现的重要子结构。因此，我们建议在本项目中对这些类型的氮杂环进行研究。设想了两种方法-来自立体定向的硼酸酯衍生物的Suzuki反应和立体定向的有机锌试剂的Negishi反应。两种类型的交叉偶联反应将使用Pd（0）/膦催化剂体系进行。为了实现我们的目的和目标，有必要筛选广泛的Pd催化剂和配体。由于重磅炸弹药物的开发最终需要获得手性氮杂环的单一对映体，因此重点将放在非对映体选择性和对映体选择性方法上。我们还将研究含有药物分子中常见的功能性的底物，如氟，氨基，烷氧基和羟基。我们的项目将提供广泛的新的构建模块，用于药物化学的潜在用途。该项目的总体目标是开发新的交叉偶联方法用于氮杂环的不对称合成。我们还将致力于将我们的新方法转化为制药行业-这将通过使用已经建立的牢固联系来实现。有三个具体的研究目标：（一）芳基化的哌啶和吡咯烷使用铃木反应;（二）芳基化的哌啶使用根岸反应;（三）从（一）和（二）的方法延伸到芳基化的吗啉和piperazine. Overview使用氮定向锂化，然后通过transmethalo的有机锌物种和根岸耦合，直接芳基化氮杂环将进行探讨。另外，将研究使用硼酸酯构建块的方法，以便也可以研究Suzuki交叉偶联方法。这将为制药行业的药物化学家提供广泛的基础知识。

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.