RADICAL REACTIONS FOR NATURAL PRODUCTS

天然产品的激进反应

• 批准号: 6179620
• 负责人: DENNIS P CURRAN
• 金额: $ 23.12万
• 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/6179620
• 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)新合成方法的发展 以及合成候选药物和其他有机分子的反应 在与健康相关的研究中的重要性是一个非常重要的持续目标。 在下一个授权期内，将在两个阶段中进行级联自由基反应 不同的方向：1)固相自由基反应将随着 目的是合成中等大小(100-200)的抗肿瘤和抗癌基因文库 抗病毒药物和2)新的自由基级联序列将用 目标是一步合成复杂的三环和四环体系 非环前体物。具体目标是： 1)建立了一种高效、实用的固相合成法。 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)开发了一种用于将醇连接到固体上的新的邻卤代苯基连接剂。 相，并从该连接物中释放底物以提供定量的 关于固相上的自由竞争动力学的信息。 3)合成100-200个Mappicine纯类似物文库 利用在AIMS 2和3中获得的知识使用Mappicine酮类抗病毒药物。 4)在溶液中合成(20个成员)和固相合成(100个成员) 抗肿瘤药物喜树碱的E-环扩展类似物文库。这些 将对化合物的内酯稳定性和杀灭能力进行检测 癌细胞。 5)开发三环天然产物裸子烯的短合成方法 从容易获得的非环前驱体开始，通过三元环 自行车运动在“往返”的激进班。 6)完成一系列称职的模型研究，为 Crinipellin类化合物之一的往返自由基环化方法 抗菌剂。 7)完成其中一种crinipellin的简明全合成 通过使用往返自由基反应形成的对映体纯形式 完整的碳骨架和所有四个环在一个步骤中从一个容易的 可用的无环前体。