NEW METHODS FOR ALKALOID SYNTHESIS

拟议研究的主要目标是开发方法 用于快速高效地生产多环氮 杂环化合物。尤其是吲哚利定和喹诺利定生物碱， 或者是包含这些环系的更大分子的目标。大号 许多生物活性化合物都包含在这些 结构类型。因此，有效和通用的合成方法是 对它们的建造来说是必要的。这将使科学家能够 人工合成自然界中稀有或不存在的生物碱， 但由于它们的生物活性，它们是理想的。所有的合成材料 所提出的方法是基于叠氮基团的化学。 叠氮化物与烯烃的分子内环加成反应生成双环 三唑啉，是热不稳定的杂环，可能会经历 某些类型的重新安排。特别是，他们有一种倾向 氮化排出氮素，产生氮杂环丙烷或亚胺部分内容 拟议的研究涉及到对这种化学物质的开发 产品形成另一个环。例如，叠氮的环化反应 某些1，3-二烯可导致吡咯里齐啶和 在一次合成操作中合成了吲哚咪啶类药物。一个更实用的版本是 最近开发的，其中叠氮化物与带有一个 远程离开小组。最初的三唑啉重排为亚胺， 它在分子内烷基化，得到有用的双环亚胺 离子。一种基于叠氮化学的完全不同的方法也 已经被开发出来了。某些醇和烯烃会被电离成 碳阳离子，可被叠氮化合物分子内捕获以形成 氨基重氮离子。邻碳原子上的基团之一 然后迁移到氮气中，取代氮素，留下一个 亚胺离子。可以通过以下方法制备各种各样的双环体系 这种方法原则上包括桥联双环。一位少校 该提案的一个方面是将这些方法应用于 利用这些化合物合成感兴趣的天然和非天然生物碱 方法：研究方法。卡索拉明等努帕尔生物碱是重要成分。 在香水行业。二氢辛可宁是金鸡纳属的一员 生物碱的一类，以抗疟疾活性著称。吲哚里西定209B 是尼古丁受体拮抗剂。单峰红素I是一种尾部信息素 法老蚂蚁，取暖建筑中的害虫，医院中的一个令人担忧的问题。 一些石蒜碱类生物碱具有抗肿瘤活性。 12B-环磷酰胺和伽马-石蒜素是这一类的成员 都是有针对性的。皮克塔明和棒曲霉是一个新类别的成员 显示出细胞毒活性的生物碱。芳基喹啉类生物碱 如Kayawongine和隐胸苷在生物学上也很有趣， 后者显示出细胞毒性、发泡剂和抗阿米巴杀伤力 活动。最后，一些重要的糖苷酶的类似物 抑制剂苦马豆素和苦参碱被提出。准备工作 喹诺利啶环类似物应提高选择性和效力 这些化合物中，正被研究为抗癌和 抗艾滋病毒药物。

The principle objective of the proposed research is to develop methods for the rapid and efficient production of polycyclic nitrogen heterocycles. In particular, indolizidine and quinolizidine alkaloids, or larger molecules containing these ring systems are targeted. A large number of biologically active compounds are encompassed by these structural types. Hence, efficient and general synthetic methods are necessary for their construction. This will allow scientists to synthetically prepare alkaloids that are rare or nonexistent in nature, but are desired due to their biological activity. All of the synthetic methods proposed are based on the chemistry of the azido group. Intramolecular cycloaddition of azides with alkenes produces bicyclic triazolines, which are thermally labile heterocycles that may undergo certain types of rearrangements. In particular, they have a propensity to extrude dinitrogen, producing aziridines or imines. Part of the proposed research involves the exploitation of the chemistry of such products to form another ring. For example, cyclization of an azide with certain 1,3-dienes leads to the formation of pyrrolizidines and indolizidines in one synthetic operation. A more practical version has recently been developed, where an azide cyclizes with an alkene bearing a remote leaving group. The initial triazoline rearranges to an imine, which is alkylated intramolecularly to give a useful bicyclic iminium ion. A completely different method based on azide chemistry has also been developed. Certain alcohols and alkenes undergo ionization to a carbocation, which may be captured intramolecularly by an azide to form an aminodiazonium ion. One of the groups on a neighboring carbon atom then migrates to the nitrogen, displacing dinitrogen and leaving an iminium ion. A wide variety of bicyclic ring systems may be prepared by this method in principle, including bridged bicyclic rings. A major aspect of the proposal is the application of these methods to the synthesis of natural and unnatural alkaloids of interest using these methods. Nuphar alkaloids such as castoramine are important components in the fragrance industry. Dihydrocinchonine is a member of the Cinchona class of alkaloids, famous for antimalarial activity. Indolizidine 209B is a nicotinic receptor antagonist. Monomorine I is a trail pheromone of the pharaoh ant, a pest in heated buildings and a concern in hospitals. Some alkaloids of the lycorine class exhibit antitumor activity. 12b-Epizephyranthine and gamma-lycorane are members of this class that are targeted. Pictamine and the clavepictines are members of a new class of alkaloids that show cytotoxic activity. Arylquinolizidine alkaloids such as kayawongine and cryptopleurine are also interesting biologically, with the latter showing cytotoxic, vesicant, and anti-amoebicidal activity. Finally, some analogues of the important glycosidase inhibitors swainsonine and castanospermine are proposed. Preparation of quinolizidine ring analogues should improve the selectivity and potency of these compounds, which are under investigation as anticancer and anti-HIV drugs.