New Methods for Nitrogen and Oxygen Heterocycle Synthesis

项目总结/摘要 有机小分子和化学过程的有效生产影响了药物研究， 药物发现和工艺化学。手性化合物构成了生物活性小分子的相当大的一部分， 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， 是时间和资源密集型的，并且产生不希望的对映异构体，这通常被认为是 化学废物。新的铜催化的烯烃双官能化反应， 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， 开发这些反应的产物很容易映射到生物活性有机小分子中所含的结构上。 分子，如天然产物和药物。在目标1中，对映选择性好氧铜催化 将探索烯烃氧化双官能化以直接合成2-甲酰基吡咯烷和2-甲酰基吡咯烷。 四氢呋喃。这些有氧环化反应在生物活性天然产物的流线型合成中的应用 用于药物发现的产物和小分子中间体将测试该方法的实际效用。 目标2的重点是发展手性桥连双环的对映选择性合成方法 缩酮和其它含有完全取代的碳立构中心的饱和杂环。其中一些 通过基团转移策略实现转化。这些反应的机理方面将是 探索，这将使他们的合理优化和可预测的应用。目标3的重点是 铜催化的涉及醇和胺偶联的2-和3-组分反应的开发 具有苯乙烯或二烯的衍生物和原位形成的烷基。这些反应的机理方面， 特别是与立体选择性有关的问题。这些化学转化的发展将 使它们能够用于药物发现和化学生物学应用中的多步有机合成。他们的 本发明为合成有机化学家提供了新的选择， 候选人必须有效地合成。反应工程效率和选择性方面的经验教训 将适用于相关有用的化学方法的发明和开发。

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.