Administrative Equipment Supplement for 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着制药业的发展。 研究，包括药物发现和过程化学。手性化合物占了很大一部分 生物活性有机小分子。它们的对映选择性合成最大限度地减少了手性 分离技术，其可能是时间和资源密集型的，并且产生不期望的产物。 对映异构体，其通常被认为是化学废物。新型铜催化烯烃 能够有效和立体选择性合成手性胺的双官能化反应 正在开发包括饱和杂环的衍生物和醚。这些产品 反应很容易映射到生物活性有机小分子中所含的结构上， 产品和药品。目的1中，对映选择性好氧铜催化烯烃氧化 双官能化正被探索用于直接合成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化合物的流线型合成中的应用 对药物发现有用的天然产物和小分子中间体将测试实际效用 的方法。目标2的重点是发展对映选择性合成方法 手性桥连双环缩酮和其它含有完全取代的碳原子的饱和杂环 立体中心这些转变中的一些是通过激进的基团转移策略实现的。 将探讨这些反应的机理方面，这将使其合理的优化 可预测的应用。目标3的重点是开发铜催化的2-和3- 涉及醇和胺衍生物与苯乙烯或二烯偶联的组分反应， 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，将进行研究。这些化学转化的发展将使他们能够 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。在反应工程中获得的经验教训， 选择性应当适用于相关有用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 are being 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 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 should be applicable to the invention and development of related useful chemical processes.