TOTAL SYNTHESIS OF THE ANTILEUKEMIC AGENT BRYOSTATIN 1

抗白血病剂苔藓抑素 1 的全合成

• 批准号: 3175648
• 负责人: SATORU MASAMUNE
• 金额: $ 15.3万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1988-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3175648
• 关键词: alkenes; chemical structure function; diol; drug design /synthesis /production; drug metabolism; macrolide antibiotics; marine biology; neoplasm /cancer pharmacology; pyrans; stereochemistry

Although still largely untapped, the oceans have proven to be a source of several families of marine natural products possessing potentially useful pharmaceutical properties. For instance, several compounds isolated from Bugula neritina have shown promise in certain anticancer tests, and bryostatin 1, a representative member of this group, indeed extends the average lifetime of leukemic mice by 52-59%. This project is specifically aimed at the synthesis of bryostatin 1, C47H68O17, a 26-membered macrolide with 11 chiral centers comprising a series of 1,2-and 1,3-diol moieties, pyran rings, and olefinic linkages. The compound is retrosynthetically dissected into three major fragments, which will be assembled in the final stages of the proposed synthesis. Therefore, the entire scheme is highly convergent thus rendering the actual execution of the synthesis practical, despite the structural complexity of the target molecule. All of the structural units embedded in bryostatin 1 can be constructed through several methodologies developed recently in our or other laboratories. Stereochemical problems to be encountered during the course of the synthesis will be resolved with the proper application of the concept now termed multiple asymmetric induction. The importance of this concept in acyclic stereochemical control has now been fully recognized. The pursuit of this project will undoubtedly enhance our synthetic expertise and further help identify new fundamental problems yet to be investigated in the field of organic synthesis. Of primary benefit, however, would be the wealth of information which could answer many questions concerning the structure/activity relationship of bryostatin. It is definitely intended to submit adequate samples of this marine product and its derivative for biological screenings.

虽然海洋在很大程度上尚未开发，但已证明是一个 几种具有潜在用途的海洋天然产品 药物性质。 例如，几种化合物从 稻纵卷叶虫在某些抗癌试验中表现出了希望， 苔藓抑素1，这一组的代表性成员，确实延长了 白血病小鼠的平均寿命缩短52- 59%。 该项目具体为 目的是合成26元大环内酯苔藓抑素1，C47 H68 O 17， 其中11个手性中心包含一系列1，2-和1，3-二醇部分， 吡喃环和烯键。 该化合物是逆合成的， 被分解成三个主要的片段，这将在最后的组装， 拟议综合的各个阶段。 因此，整个方案高度 收敛从而使合成的实际执行变得实用， 尽管靶分子的结构复杂。 所有嵌入苔藓抑素1的结构单元都可以被构建 通过我们或其他机构最近开发的几种方法， laboratories. 课程中遇到的立体化学问题 的合成将得到解决的适当应用， 这个概念现在被称为多重不对称感应。 这一点的重要性 非环状立体化学控制中的概念现已得到充分认识。 对这个项目的追求无疑将提高我们的综合能力， 专业知识，并进一步帮助确定新的基本问题， 在有机合成领域的研究。 最主要的好处， 然而，将是丰富的信息，可以回答许多 关于苔藓抑素的结构/活性关系的问题。 它 一定会提交足够的海产品样本 及其衍生物用于生物筛选。