NEW SYNTHETIC REACTIONS FOR ACTIVE PRINCIPLES

描述：(申请人提供)我们实验室的总体目标有四个方面。(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 社会，因为合成是制药进步的核心， 动物健康和农业产业。(Ii)我们寻求指导这些措施 实现天然产物学术水平全合成的研究成果 显著的结构复杂性和前景看好的生物学特征。在HL 25848-22-26我们专注于与生物信号相关的天然产品， DNA复制和炎症。(Iii)虽然我们强调完成 学术水平综合，在情况适合的情况下，我们微调 综合，以期优化，并可能扩大规模。(四)最后， 我们使用我们的化学来帮助阐明SAR轮廓，并与适当的 合作，处理机制问题。 我们的建议大致分为两个部分。主要的推动力是 一组五个新的天然产品目标。在这里，但有几个背景 下面将描述的实验，我们基本上是从 开始了。前两个总的合成目标是鱼肌素A(1)和 己四环胺(2)。Phomactin A是PAF拮抗剂，xestcyclamine是一种 高活性蛋白激酶C抑制剂。虽然这些结构完全不同于 我们希望用它们来说明 B-烷基铃木反应有机合成中的B-烷基铃木反应，尤指作为一种装置 立体专一性大环化。我们希望利用这种反应来构建 ANSA喜欢由磷脂酰肌素A和己四环胺组成的桥梁。另一种定向 靶标是鸟粪碳内酯(3)，它显然对万古霉素有活性 耐药细菌。在它提出的合成的道路上，我们无疑将 了解更多有关鸟粪碳二烯的合成孔径雷达图谱。虽然现在下结论还为时过早 关于行动机制的猜测我们肯定会寻求合作 来处理这个问题。此外，该分子还为 合成策略的进展以及关键的方法学进展(用于 例如，肼合成，键重组反应，激活 环丙烷和氧化呋喃断开连接。然后我们讨论目标 生物碱代谢物Palarine(4)。这种化合物的合成将不失时机地 美国将探索吲哚化学和更广泛的碳-碳领域的前沿问题 通过复杂体系的交叉耦合而形成的键。还有一个目标是 新冠抑素IV(5)。该化合物与埃克西丁743(6)有关。一个 ET743的形式全合成在我们实验室取得了很好的进展。而当 ET 743的作用机制被认为涉及抑制 在转录激活方面，Cybrostatin的细胞毒作用机制尚不清楚。 事实上，比较联合国和欧洲联盟的行动模式将非常有意义。 Cribrostatin和ET 743。为此，我们必须实现……的合成 Cribrostatin，因为目前只有最好的 来自珊瑚来源的困难。此外，我们希望完成总的 钩吻(7)的合成，以及ET 743本身。项目6和7有 到达了我们的一般路线清晰的地方。然而，有几个 重大问题和学习机会依然存在。

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.