RADICAL REACTIONS FOR NATURAL PRODUCTS

天然产品的激进反应

• 批准号: 2908170
• 负责人: DENNIS P CURRAN
• 金额: $ 24.23万
• 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/2908170
• 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：（申请人的摘要）开发新合成方法 以及对合成候选药物和其他有机分子的反应 与健康相关的研究中的重要性是持续重要的目标。 在下一个授予期间，将在两个 不同的方向：1）将与 综合抗肿瘤和抗肿瘤库的中等尺寸（100-200）的目的 抗病毒药和2）将研究新的自由基级联序列 在距离一步的一步中准备复杂的三环环系统 无环前体。具体目的是： 1）开发映射的有效且实用的固相合成 基于我们当前溶液级联自由基的生物碱家族 异构体的一环。 2）开发一个新的O-甲苯二链接头，以将酒精固定在固体上 阶段，并从此接头释放底物以提供定量 关于固相的激进竞争动力学的信息。 3）综合一个由100-200个单独的纯种类似物的库和 使用AIM 2和3中获得的知识的Mappicine Ketone抗病毒药物。 4）在溶液中合成（20个成员）和固相（100个成员） 电子环的库扩展了抗肿瘤剂的类似物。这些 化合物将因其内酯稳定性和杀死能力而进行测定 癌细胞。 5）开发三环天然产品体操运动物的简短合成 从易于获得的无环前体开始，从三重 在“往返”激进类中的环化。 6）完成一系列有能力的模型研究的顺序 往返的根治性环化方法是Crinipellin类别之一 抗菌剂。 7）完成一个简明的总合成 通过使用形成的往返基本反应，对映体纯正形式 完整的碳骨架和所有四个戒指都可以轻松地从一个步骤中 可用的无环前体。