New Methods for Nitrogen Heterocycle Synthesis

氮杂环合成新方法

• 批准号: 8185730
• 负责人: Sherry R Chemler
• 金额: $ 31.14万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185730
• 关键词: Adverse effects; Alcohols; Alkenes; Amination; Amines; Antipsychotic Agents; Basic Science; Benzazepines; Biological Factors; Biological Process; Carbon; Carboxylic Acids; Catalysis; Chemical Industry; Chemistry; Communities; Copper; Cyclization; Development; Diamines; Diuretics; Dopamine Receptor; Dose; Drug Industry; Free Radicals; Hydrogen Bonding; Knowledge; Ligands; Malignant Neoplasms; Marketing; Medical; Methodology; Methods; Nitrogen; Organic Synthesis; Oxygen; Pharmaceutical Preparations; Piperazines; Process; Pyrrolidines; Reaction; Reporting; Route; Series; Side; System; Technology; Testing; catalyst; chemical reaction; chemical synthesis; cost; design; drug development; drug discovery; enantiomer; functional group; hypertension treatment; indoline; oxindole; piperidine; programs; pyrrolidine; serotonin receptor; tool

DESCRIPTION (provided by applicant): New Methods for Nitrogen Heterocycle Synthesis New enabling technologies for the synthesis of nitrogen and oxygen heterocycles using copper-catalyzed reactions is proposed. The heterocycles formed can be useful for application as ligands and catalysts in the chemical industry and as modulators of biological function and intermediates in the synthesis of bioactive compounds in the pharmaceutical industry. One or more stereocenter is present in the products of most of the reactions and these stereocenters can be predictably formed with high enantio- and diastereoselectivity in most cases. The selective synthesis of chiral compounds impacts the pharmaceutical industry, enabling the optimization of activity while minimizing dosing and side-effects. Originating chirality from catalysts instead of stoichiometric amounts of chiral substrates is an efficient practice that greatly expands substrate scope while reducing cost. This proposal involves the optimization (reaction conditions, selectivity, catalyst loading), expansion (wide substrate scope and several new reactions proposed) and application (the synthesis of commercial drugs and bioactive natural products) of the new copper-catalyzed reactions. The starting compounds are stable, readily available amines, alcohols and alkenes. The reaction methodology enables the versatile stereoselective synthesis of various alkene difunctionalization products (diamination, carboamination, aminooxygenation, aminohalogenation, hydroamination, carboetherification) by judicious choice of reaction components. Several of the catalytic enantioselective methods being developed in this program are the first and only examples of such technology in the scientific community (e.g. the first and only catalytic enantioselective intramolecular alkene aminooxygenation, diamination and aminohalogenation reactions), and thus fill a recognized technology gap. PUBLIC HEALTH RELEVANCE: The efficient synthesis of chiral organic compounds is important to drug discovery and development. The discovery and development of the new synthetic methods described in this proposal will expand the tools available for drug discovery. Application of these methods in the synthesis of an anti-cancer natural product, an antipsychotic medication and a clinically used diuretic are proposed.

描述（由申请人提供）：提出了使用铜催化反应的氮杂环合成的新方法，用于合成氮和氧杂环的新启用技术。形成的杂环可用于化学工业中的配体和催化剂，以及作为生物活性化合物在制药行业合成的生物功能和中间体的调节剂。大多数反应的产物中都存在一个或多个立体中心，并且这些立体中心可以预见，在大多数情况下，可以用高对映选择性和非对映射性形成。手性化合物的选择性合成会影响制药行业，从而使活动优化，同时最大程度地减少剂量和副作用。来自催化剂而不是化学计量量的手性底物的手性是一种有效的实践，可以极大地扩展基板范围，同时降低成本。该建议涉及新铜催化反应的优化（反应条件，选择性，催化剂加载），扩展（较宽的底物范围和提出的几种新反应）以及应用（商业药物和生物活性天然产物的合成）。起始化合物是稳定的，容易获得的胺，醇和烯烃。反应方法可以通过明智地选择反应成分的选择。该程序中开发的几种催化对映选择性方法是科学界的第一个也是唯一的例子（例如，第一个也是唯一的催化催化对映体性分子内烯烃氨基化氨基化，胰岛胰蛋白和氨基分解反应），从而填补了公认的技术GAP。 公共卫生相关性：手性有机化合物的有效合成对药物发现和发育至关重要。本提案中描述的新合成方法的发现和开发将扩大可用于药物发现的工具。提出了这些方法在抗癌天然产物中的合成中的应用，抗精神病药和临床使用的利尿剂。