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

氮氧杂环合成新方法管理设备补充

• 批准号: 10380459
• 负责人: Sherry R Chemler
• 金额: $ 4.52万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380459
• 关键词: Aerobic; Alcohols; Alkenes; Amines; Biology; Biomedical Research; Carbon; Cardiovascular Diseases; Chemicals; Chemistry; Communicable Diseases; Copper; Coupling; Cyclization; Development; Diabetes Mellitus; Engineering; Equipment; Ethers; Human; In Situ; Malignant Neoplasms; Maps; Mental Health; Methods; Natural Products; Neurodegenerative Disorders; Nitrogen; Organic Synthesis; Oxygen; Pharmacologic Substance; Process; Production; Pyrrolidines; Reaction; Research; Resources; Structure; Styrenes; Technology; Testing; Time; bioactive natural products; diene; drug discovery; enantiomer; invention; ketal; method development; small molecule; tetrahydrofuran; wasting

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.

项目概要/摘要 小有机分子的高效生产和化学过程影响制药 研究，包括药物发现和过程化学。手性化合物占很大一部分 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 分离技术可能需要大量时间和资源，并且会产生不需要的物质 对映异构体，通常被认为是化学废物。新型铜催化烯烃 双官能化反应可高效、立体选择性地合成手性胺 衍生物和醚，包括饱和杂环，正在开发中。这些产品的 反应很容易映射到生物活性有机小分子（例如天然有机小分子）中包含的结构 产品和药品。在目标 1 中，对映选择性需氧铜催化烯烃氧化 正在探索双官能化用于直接合成 2-甲酰基吡咯烷和 2-甲酰基 四氢呋喃。这些有氧环化在生物活性物质的简化合成中的应用 对药物发现有用的天然产物和小分子中间体将测试实际用途 的方法。目标 2 的重点是开发对映选择性合成方法 手性桥联双环缩酮和其他含有完全取代碳的饱和杂环 立体中心。其中许多转变是通过激进的群体转移策略实现的。 将探索这些反应的机理，这将使它们能够合理优化 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它们 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，这可能使多样化的小分子成为可能 有效合成候选物。反应工程中汲取的经验教训，以提高效率和 选择性应适用于相关有用化学工艺的发明和开发。