New Methods for Nitrogen and Oxygen Heterocycle Synthesis

氮氧杂环合成新方法

基本信息

批准号：
10430185
负责人：
Sherry R Chemler
金额：
$ 33.27万
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/10430185
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.

项目摘要/摘要小型有机分子和化学过程的有效产生影响药物研究，药物发现和过程化学。手性化合物构成了大部分生物活性小有机分子。它们的对映选择性合成可最大程度地减少手性分离技术的使用，这可以是时间和资源密集型，以及不希望的对映异构体的产生，经常被认为化学废物。新的铜催化的烯烃的烷烃四官能化反应，可以有效和手性胺衍生物和醚（包括饱和杂环）的立体选择性合成正在发达。这些反应的产物很容易映射到生物活性有机小的结构天然产物和药物等分子。在AIM 1中，对映选择性有氧铜催化将探索烯烃氧化练习功能化，以直接合成2-甲甲基吡咯烷和2-甲基甲酰基四氢呋喃。将这些有氧环化的应用于生物活性天然的简化合成产品和小分子中间体对药物发现有用，将测试该方法的实际效用。 AIM 2的重点是开发手性桥接双环的对映选择性合成的方法酮和其他包含完全取代的碳立体中心的饱和杂环。其中一些激进的群体转移策略可以实现转换。这些反应的机械方面将是经过探索，这将使他们的理性优化和可预测的应用。目标3的重点是铜催化的2和3组分反应的发展，涉及酒精和胺的偶联带有静脉或二烯的衍生物，以及原位形成的烷基自由基。这些反应的机械方面，特别与立体选择性有关，将研究。这些化学转化的发展将启用它们在药物发现和化学生物学应用中的多步有机合成中的使用。他们的发明实现了合成有机化学家的新选择，这可能会导致多样化的小分子候选人有效合成。在反应工程方面汲取的经验教训以提高效率和选择性将适用于相关有用的化学过程的发明和开发。