NEW SYNTHETIC REACTIONS FOR ACTIVE PRINCIPLES

活性原理的新合成反应

• 批准号: 6370887
• 负责人: SAMUEL J DANISHEFSKY
• 金额: $ 38.29万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-01-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6370887
• 关键词: alkaloids; antibacterial agents; biological products; cell growth regulation; chemical structure function; chemical synthesis; cyclization; cytotoxicity; enzyme activity; farnesyl compound; furans; heterocyclic polycyclic compound; phospholipase inhibitor; stereochemistry

DESCRIPTION: (provided by applicant) The broad objectives of our laboratory are four fold. (i) We seek to develop new strategies and new reaction modalities of value to organic synthesis. Enhancements in synthesis are, per se, of value to society since synthesis lies at the core of advances in the pharmaceutical, animal health and agricultural industries. (ii) We seek to direct these findings to achieve academic level total syntheses of natural products of significant structural complexity and promising biological profiles. In HL 25848-22-26 we focus on natural products of relevance to biological signaling, DNA replication and inflammation. (iii) While we emphasize completion of an academic level synthesis, where the situation is appropriate, we fine tune the synthesis with a view to optimization and possibly to scale up. (iv) Finally, we use our chemistry to help elucidate SAR profiles and with suitable collaborations, to deal with issues of mechanism. Our proposal is broadly divided into two components. The major thrust is toward a group of five new natural product objectives. Here, but for a few background experiments which will be described, we are starting essentially from the beginning. The first two total synthesis targets are phomactin A (1) and xestocyclamine (2). Phomactin A is a PAF antagonist and xestocyclamine is a highly active PKC inhibitor. While these structures are totally different from one another, we hope to use them to illustrate the emerging power of the B-alkyl Suzuki reaction in organic synthesis, particularly as a device for stereospecific macrocyclization. We hope to use this reaction to construct the ansa like bridges of both phomactin A and xestocyclamine. Another orienting target is guanacastepene (3), which is apparently active against vancomycin resistant bacteria. Along the way of its proposed synthesis we will undoubtedly learn much about the SAR profile of guanacastepene. While it's too early to conjecture on a mechanism of action we will certainly be seeking collaborations to deal with this problem. Moreover, the molecule provides opportunities for advances in synthetic strategy as well as key methodological advances (for instance, hydrazulene synthesis, bond reorganization reactions, activated cyclopropanes and oxidative furan disconnections. We then discuss the target alkaloid metabolite phalarine (4). The synthesis of this compound will occasion us to probe frontier issues in indole chemistry and more broadly carbon-carbon bond formation by cross coupling of complex systems. Still another target is cribrostatin IV (5). This compound is related to ecteinascidin 743 (6). A formal total synthesis of ET 743 is well advanced in our laboratory. While the mechanism of action of ET 743 has been suggested to involve inhibition of transcriptional activation, the mode of cytotoxicity of cybrostatin is unknown. Indeed, it will be of great interest to compare the mode of action of cribrostatin and ET 743. For this purpose we must achieve the synthesis of cribrostatin since it is currently available only with the greatest of difficulty from coral sources. In addition, we hope to complete the total synthesis of gelsemine (7), as well as ET 743 itself. Projects 6 and 7 have reached the point where our general route is clear. However, several significant issues and learning opportunities remain.

描述：（由申请人提供）我们实验室的主要目标是 四倍。(i)我们寻求制定新的战略和新的反应模式， 对有机合成的价值。合成方面的增强本身对以下方面具有价值： 社会，因为合成是制药， 动物健康和农业。(ii)我们试图引导这些 研究结果，以达到学术水平的天然产物的全合成 显著的结构复杂性和有前景的生物学特征。对HL 25848-22-26我们专注于与生物信号相关的天然产物， DNA复制和炎症。(iii)虽然我们强调完成一项 学术水平的综合，在适当的情况下，我们微调， 为了优化和可能的扩大规模而进行综合。(iv)最后， 我们使用我们的化学来帮助阐明SAR轮廓，并使用合适的 合作，解决机制问题。 我们的建议大致分为两部分。主要目标是 一组五个新的天然产品目标。在这里，但一些背景 实验将被描述，我们基本上是从 开始.前两个全合成靶点是根肌动蛋白A（1）和 （2）异戊环胺。Phomactin A是PAF拮抗剂，Xestocyclamine是PAF拮抗剂。 高活性PKC抑制剂。虽然这些结构完全不同于 彼此，我们希望用它们来说明新兴的力量， 有机合成中的B-烷基Suzuki反应，特别是作为 立体定向大环化。我们希望利用这种反应来构建 phomactin A和xestocyclamine两者的袢状桥。另一个定向 靶点是胍那甾烯（3），它对万古霉素有明显活性 耐药细菌沿着其建议的综合方式，我们无疑将 了解更多关于guanacastepene的SAR特征。虽然现在还为时过早 推测的行动机制，我们一定会寻求合作 来解决这个问题。此外，该分子提供了以下机会： 综合战略的进展以及关键方法的进展（ 例如，肼烯合成，键重组反应，活化 环丙烷和氧化呋喃断开。然后我们讨论目标 生物碱代谢产物法拉林（4）。这种化合物的合成 美国将探索吲哚化学和更广泛的碳-碳前沿问题 通过复杂系统的交叉耦合形成键。另一个目标是 Cribrostatin IV（5）。该化合物与海鞘素743（6）有关。一 ET 743的正式全合成在我们的实验室中进展良好。而 ET 743的作用机制已被认为涉及抑制 由于转录激活，cybrostatin的细胞毒性模式是未知的。 事实上，将其作用模式与 cribrostatin和ET 743。为此目的，我们必须实现综合 cribrostatin，因为它是目前只有最大的 珊瑚来源的困难。此外，我们希望完成总额 钩吻素（7）的合成以及ET 743本身。项目6和7有 到达了我们的大致路线清晰的地方但几 仍然存在重大问题和学习机会。