Administrative Equipment Supplement for New Methods for Nitrogen and Oxygen Heterocycle Synthesis

项目摘要/摘要 有机小分子的高效生产和化学工艺对制药的影响 研究，包括药物发现和过程化学。手性化合物占相当大的比例。 具有生物活性的有机小分子。它们的对映选择性合成最大限度地减少了手性的使用 分离技术，这可能是时间和资源密集型的，并产生不需要的 对映体，通常被认为是化学废物。新型铜催化烯烃 手性胺高效立体选择性合成的双官能化反应 正在开发包括饱和杂环在内的衍生物和醚。这些产品的产品 反应很容易映射到生物活性有机小分子中包含的结构，如天然 产品和药品。在目标1中，对映体选择性好氧铜催化的烯烃氧化 人们正在探索直接合成2-甲酰基吡咯烷和2-甲酰基的双官能化方法 四氢呋喃。这些好氧环化反应在生物活性物质合成中的应用 对药物发现有用的天然产物和小分子中间体将检验其实用价值 方法上的差异。目标2的重点是对映选择性合成方法的发展。 含全取代碳的手性桥联双环酮和其他饱和杂环 立体中心。这些转变中的许多是通过激进的群体转移战略实现的。 将探索这些反应的机械方面，这将使它们能够进行合理的优化 和可预测的应用。目标3的重点是开发铜催化的2-和3- 涉及酒精和胺衍生物与苯乙烯或二烯偶联的组分反应， 和原位生成的烷基自由基。这些反应的机械性方面，尤其是与 立体选择性，将被调查。这些化学变化的发展将使它们能够 在药物发现和化学生物学应用中用于多步有机合成。他们的发明 为合成有机化学家提供新的选择，这可能使不同的小分子 候选人需要有效地综合。在反应工程中学到的提高效率和 选择性应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 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.