Application of New Amination Reactions to Natural Product and Nonnatural Heterocy

新胺化反应在天然产物和非天然杂性中的应用

• 批准号: 7658403
• 负责人: Jeffrey Nicholas Johnston
• 金额: $ 29.17万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658403
• 关键词: Acetylcholine; Acids; Aldehydes; Alkaloids; Alkynes; Amination; Amines; Amino Acids; Aziridines; Biological Factors; Carbon; Cerium; Class; DNA; Development; Drug Interactions; Equilibrium; Exhibits; Facility Construction Funding Category; Free Radicals; Grant; Imines; Indoles; Mediating; Metals; Methodology; Methods; Mitomycin; Pharmacologic Substance; Phase; Protocols documentation; Quinones; Reaction; Route; Skeletal system; Staging; Therapeutic; anticancer activity; aziridine; base; benzoquinone; chemical synthesis; chemotherapy; crosslink; esterase; indole; indoline; lycopodium alkaloid; member; method development; piperidine; programs; serratezomine A; small molecule

This program describes a chemical synthesis route to biologically active natural products. Mitomycin C is a clinically-used small molecule for chemotherapy that functions as a DNA cross-linking agent. No other known chemotherapeutic duplicates this mechanism of action. A short synthesis is being developed based on new reactions developed during the program¿s first phase: the aza-Darzens reaction of propargyl imines to produce the cis-aziridine diastereoselectively. A metal promoted amine-alkyne enamine synthesis is then paired with a quinone to conjoin the molecule¿s two halves. The completion of the synthesis will be accomplished via one of several intermediates this approach provides. Completion of the total synthesis of (+)-serratezomine A is also planned. Free radical-mediated vinyl amination is a key enabling reaction in this synthesis. Serratezomine A is a member of a class of lycopodium alkaloids that have exhibited acetylcholine esterase inhibition and anticancer activity. The synthesis route allows general access to these members and unnatural derivatives through a common skeletal construction. General methods development during this granting period will focus on new piperidine annulation methods. This heterocycle is common to numerous pharmaceuticals and biologically active natural products. Chemical synthesis of antitumor and potential Alzheimer¿s therapeutic leads will result from these studies. Additionally, new synthetic methods with broad application in pharmaceutical synthesis will be developed.

本程序描述了一种合成具有生物活性的天然产物的化学合成路线。丝裂霉素C 是一种临床上用于化疗的小分子，其功能是DNA交联剂。没有其他人了 已知的化疗复制了这种作用机制。正在开发一种简短的合成方法，基于 关于S计划第一阶段发展的新反应：炔丙基亚胺的氮杂-达尔森反应 非对映选择性地生产顺-氮杂环丙烷。然后金属催化胺-炔烯胺的合成 与一对苯二酚配对，将S分子连接成两半。合成的完成时间将是 通过这种方法提供的几种中间体之一来完成。完成全合成 (+)-serratezomine A也在计划中。自由基介导的乙烯基胺化反应是这一反应的关键 综合。Serratezomine A是一类表现出乙酰胆碱的石蒜生物碱的成员 抑制酯酶活性和抗癌活性。合成路线允许一般访问这些成员，并且 通过普通骨骼结构的非自然衍生品。在此过程中的一般方法开发 授权期将集中在新的哌啶环化方法上。这种杂环对许多人来说是常见的 药品和生物活性天然产品。 抗肿瘤和潜在的阿尔茨海默病S治疗线索的化学合成将由此产生 学习。此外，在药物合成中具有广泛应用的新的合成方法将是 发展起来的。