New Methods for Nitrogen and Oxygen Heterocycle Synthesis

氮氧杂环合成新方法

基本信息

批准号：
10207659
负责人：
Sherry R Chemler
金额：
$ 33.28万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
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/10207659
关键词：
Aerobic Alcohols Alkenes Amines Biochemical Biochemical Process Biological Availability Biology Biomedical Research Carbon Carboxylic Acids Cardiovascular Diseases Catalysis Chemicals Chemistry Communicable Diseases Copper Coupling Cyclization Development Diabetes Mellitus Drug Industry Engineering Ethers Goals Human Hydrogenation In Situ Knowledge Ligands Malignant Neoplasms Maps Mental Health Methodology Methods Molecular Natural Products Neurodegenerative Disorders Nitrogen Organic Synthesis Oxidants Oxidases Oxygen Oxygenases Pharmaceutical Preparations Pharmacologic Substance Process Production Pyrrolidines Reaction Reagent Research Resources Stereoisomer Structure Styrenes Technology Testing Time Work bioactive natural products density diene drug development drug discovery enantiomer experimental analysis human disease invention ketal large scale production method development oxidation programs small molecule tetrahydrofuran theories tool wasting

项目摘要

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.

项目概要/摘要小有机分子和化学过程的高效生产影响着药物研究、药物发现和过程化学。手性化合物占生物活性小化合物的很大一部分有机分子。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，从而可以时间和资源密集，并且会产生不需要的对映体，这通常被认为是化学废物。新型铜催化烯烃双官能化反应可实现高效且手性胺衍生物和醚（包括饱和杂环）的立体选择性合成正在进行中发达。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。分子，例如天然产物和药物。在目标 1 中，对映选择性需氧铜催化将探索烯烃氧化双官能化直接合成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天然物质的简化合成中的应用对药物发现有用的产品和小分子中间体将测试这些方法的实际用途。目标2的重点是开发手性桥联双环的对映选择性合成方法缩酮和其他含有完全取代的碳立构中心的饱和杂环。其中一些激进的群体转移策略促成了转型。这些反应的机理方面将是探索，这将使其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 2 组分和 3 组分反应的开发，涉及醇和胺的偶联苯乙烯或二烯的衍生物，以及原位形成的烷基。这些反应的机理方面，特别是与立体选择性相关的，将进行研究。这些化学转化的发展将使其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，这可能使不同的小分子成为可能有效合成候选物。反应工程在效率和选择性方面的经验教训将适用于相关有用化学工艺的发明和开发。