New Methods for Nitrogen and Oxygen Heterocycle Synthesis

项目摘要/摘要 有机小分子和化学过程的高效生产影响了制药研究， 包括药物发现和过程化学。手性化合物在生物活性小分子中占有相当大的比例 有机分子。它们的对映选择性合成最大限度地减少了手性分离技术的使用，这可以 时间和资源密集，以及生产不受欢迎的对映体，这通常被认为是 化学废物。新的铜催化的烯烃双功能化反应，使高效和 手性胺衍生物和醚，包括饱和杂环的立体选择性合成正在进行 发展起来的。这些反应的产物很容易映射到生物活性有机小分子中包含的结构上。 天然产物和药物等分子。在目标1中，对映体选择性好氧铜催化 为直接合成2-甲酰基吡咯烷和2-甲酰基，将探索烯烃氧化双官能化反应 四氢呋喃。这些有氧环化反应在生物活性天然产物合成中的应用 对药物发现有用的产品和小分子中间体将检验这些方法的实用价值。 目标2的重点是手性桥联双环对映体选择性合成方法的发展。 含有完全取代的碳立体中心的缩酮和其他饱和杂环。许多这样的 转变是由激进的群体转移策略实现的。这些反应的机械性方面将是 这将使它们的合理优化和可预测的应用成为可能。目标3的重点是 铜催化的醇胺偶联二组分和三组分反应的研究进展 含有苯乙烯或二烯和烷基的衍生物在原位形成。这些反应的机械性方面， 特别是与立体选择性有关的，将被研究。这些化学变化的发展将 使其在药物发现和化学生物学应用中的多步骤有机合成中得到应用。他们的 本发明为合成有机化学家提供了新的选择，这可能使不同的小分子 候选人需要有效地综合。从反应工程中学到的提高效率和选择性的经验 将适用于相关有用化学工艺的发明和开发。

Project Summary/Abstract The efficient production of small organic molecules and chemical processes impacts pharmaceutical research, both drug discovery and process chemistry. Chiral compounds make up a substantial portion of bioactive small organic molecules. Their enantioselective synthesis minimizes use of chiral separation technology, which can be time and resource intensive, and the production of undesired enantiomers, which are often considered chemical waste. New copper-catalyzed alkene difunctionalization reactions that enable efficient and stereoselective synthesis of chiral amine derivatives and ethers, including saturated heterocycles, are being developed. The products of these reactions readily map on to structures contained in bioactive organic small molecules such as natural products and pharmaceuticals. In Aim 1, enantioselective aerobic copper-catalyzed alkene oxidative difunctionalizations will be explored for the direct synthesis of 2-formyl pyrrolidines and 2-formyl tetrahydrofurans. Application of these aerobic cyclizations to the streamlined synthesis of bioactive natural products and small molecule intermediates useful to drug discovery will test the practical utility of the methods. The focus of Aim 2 is the development of methods for the enantioselective synthesis of chiral bridged bicyclic ketals and other saturated heterocycles that contain fully substituted carbon stereocenters. A number of these transformations are enabled by a radical group transfer strategy. Mechanistic aspects of these reactions will be explored, which will enable their rational optimization and predictable application. The focus of Aim 3 is on the development of copper-catalyzed 2- and 3-component reactions that involve the coupling of alcohol and amine derivatives with styrenes or dienes, and alkyl radicals formed in situ. Mechanistic aspects of these reactions, especially related to stereoselectivity, will be investigated. Development of these chemical transformations will enable their use in multi-step organic synthesis in drug discovery and chemical biology applications. Their invention enables new options for synthetic organic chemists, which may enable diverse small molecule candidates to be synthesized efficiently. Lessons learned in reaction engineering for efficiency and selectivity will be applicable to the invention and development of related useful chemical processes.