RADICAL REACTIONS FOR NATURAL PRODUCTS

天然产品的激进反应

• 批准号: 6385477
• 负责人: DENNIS P CURRAN
• 金额: $ 23.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-12-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6385477
• 关键词: alkaloids; antineoplastic antibiotics; antiviral agents; biological products; chemical addition; chemical structure function; chemical synthesis; chemical transfer reaction; combinatorial chemistry; cyclization; free radicals; protonation; silanes; solid state; stereochemistry

DESCRIPTION: (Applicant's Abstract) The development of new synthetic methods and reactions to synthesize drug candidates and other organic molecules of importance in health-related research is a continuing goal of great importance. In the next granting period, cascade radical reactions will be developed in two different directions: 1) solid phase radical reactions will be developed with the aim of synthesizing moderate sized (100-200) libraries of antitumor and antiviral agents, and 2) new radical cascade sequences will be studied with the aim of preparing complex tri- and tetracyclic ring systems in one step from acyclic precursors. The specific aims are: 1) To develop an efficient and practical solid phase synthesis of the mappicine family of alkaloids based on our current solution phase cascade radical annulation of isonitriles. 2) To develop a new o-halobenzyl linker for attaching alcohols to the solid phase, and to release substrates from this linker to provide quantitative information about radical competition kinetics on the solid phase. 3) To synthesize a library of 100-200 individual pure analogs of mappicine and mappicine ketone antiviral agents using the knowledge gained in Aims 2 and 3. 4) To synthesize in solution (20 member) and on the solid phase (100 member) libraries of E-ring expanded analogs of the antitumor agent camptothecin. These compounds will be assayed for their lactone stability and their ability to kill cancer cells. 5) To develop a short synthesis of the tricyclic natural product gymnomitrene starting from a readily available acyclic precursor through a triple cyclization in the "round trip" radical class. 6) To complete sequence of competent model studies that will light the way to a round trip radical cyclization approach to one of the crinipellin class of antibacterial agents. 7) To complete a concise total synthesis of one of the crinipellins in enantiomerically pure form by using a round trip radical reaction that forms the complete carbon skeleton and all four rings in a single step from a readily available acyclic precursor.

描述：（申请人摘要）新合成方法的开发 以及合成候选药物和其他有机分子的反应 健康相关研究的重要性是一个非常重要的持续目标。 在下一个授权期内，级联自由基反应将分为两个阶段发展 不同方向：1）固相自由基反应将发展为 合成中等规模（100-200）抗肿瘤和 抗病毒剂，以及2）新的自由基级联序列将与 一步制备复杂的三环和四环体系的目的 无环前体。具体目标是： 1) 开发高效实用的马匹碱固相合成方法 基于我们当前溶液相级联自由基的生物碱家族 异腈的环化。 2) 开发一种新的邻卤代苄基连接体，用于将醇连接到固体上 相，并从该接头释放底物以提供定量 有关固相激进竞争动力学的信息。 3) 合成包含 100-200 个马匹碱纯类似物的文库 利用目标 2 和 3 中获得的知识开发马匹辛酮抗病毒药物。 4) 溶液合成(20元)和固相合成(100元) 抗肿瘤剂喜树碱的 E 环扩展类似物文库。这些 将测定化合物的内酯稳定性和杀灭能力 癌细胞。 5) 开发三环天然产物gynomitrene的短合成 从容易获得的无环前体开始，通过三重 环化中的“往返”激进类。 6) 完成一系列有效的模型研究，为实现 一种crinipellin类化合物的往返自由基环化方法 抗菌剂。 7) 完成其中一种crinipellins的简明全合成 通过使用形成的往返自由基反应形成对映体纯形式 完整的碳骨架和所有四个环只需一步即可完成 可用的无环前体。