Synthesis and Properties of Nitrogen-Rich Polycycles

描述(由申请人提供)：本提案概述了探索两种新的天然生物碱类型的合成、结构和反应性的实验。每种情况下的长期目标都是了解它们的化学成分，并提供必要的工具来详细探讨它们的生化功能。1998年，开始研究海洋细胞毒素中的重氮酰胺家族。这项工作已经取得进展，现在可以对它们的结构/活性关系进行详细的研究。建议了进一步简化重氮酰胺多杂环结构的方法，以及精选的修饰，以促进对其在动物细胞培养中的抗有丝分裂作用的进一步研究。重氮酰胺二芳胺核是通过氧化引发的环化反应合成的，这一主题也存在于为帕劳胺及其近亲提出的研究中。帕劳胺周围的情况与几年前观察到的重氮胺类似。这种分子是一种新的结构类型，已被证明在实验室中特别难复制。它在体外具有强大的免疫抑制作用，并显示出广泛的抗菌活性。然而，既没有信息表明作用模式，也没有化合物供应来推动进一步的研究。概述了一种通过氧化螺环反应合成帕劳胺双胍阵列的方法。化学作用于二聚体底物，其对称和非对称形式产生非对映异构体产物。底物的选择决定了这条途径是通向帕劳胺还是它的非对映异构体之一。这样，就有可能以一种不同的方式解决问题--其中一个核心反应序列分支到更大的产品家族。大自然似乎也同样产生了这种结构类型。然而，合成方法提供了获取非天然同系物的宝贵途径，有助于从分子细节上探索它们对微生物和T细胞的影响。

DESCRIPTION (provided by applicant): This proposal outlines experiments to explore the synthesis, structure, and reactivity of two novel naturally occurring alkaloid types. The long term goal in each case is to understand their chemistry and to provide the tools necessary to probe their biochemical functions in detail. In 1998, studies began on the diazonamide family of marine cytotoxins. The work has advanced such that a detailed examination of their structure / activity relationships is now possible. Methods to further streamline construction of diazonamide polyhetereocycles are proposed as are selected modifications to facilitate additional research into their antimitotic effects on animal cell culture. The diazonamide diarylaminal core is synthesized via an oxidationinitiated cyclization event and this theme is also present in studies proposed for palau'amine and its relatives. The context surrounding palau'amine is similar to that observed for diazonamides several years ago. The molecule is a new structural type that has proven especially difficult to replicate in the laboratory. It is potently immunosuppressive in vitro and shows broad-based antimicrobial activity. However, there is neither information to suggest a mode of action nor a supply of compound to fuel further research. A strategy to synthesize the palau'amine bis-guanidine array via oxidative spiroannulation is outlined. The chemistry operates on a dimeric substrate whose symmetric and non-symmetric forms give rise to diastereomeric products. The choice of substrate dictates whether the pathway will lead to palau'amine or one of its diastereomeric relatives. In this way, it is possible to navigate the problem in a divergent manner - wherein one core reaction sequence branches out to reach to larger family of products. Nature seems to produce this structural type similarly. However, the synthetic approach gives access to non-natural congeners invaluable for probing their effects on microbes and T-cells in molecular detail.