NEW METHODS FOR ALKALOID SYNTHESIS

拟议研究的主要目标是制定方法， 用于快速有效地生产多环氮 杂环 具体地，吲哚里西啶和喹里西啶生物碱， 或含有这些环系统的较大分子作为目标。 大 这些化合物包括许多生物活性化合物 结构类型 因此，有效和通用的合成方法是 为他们的建设所必需。 这将使科学家能够 合成制备天然稀有或不存在的生物碱， 但由于它们的生物活性而被期望。 所有的合成 所提出的方法基于叠氮基的化学性质。 叠氮化合物与烯烃的分子内环加成反应生成双环 三唑啉，其是热不稳定的杂环， 某些类型的重组。 特别是他们有一种倾向 挤出二氮，产生氮杂环丙烷或亚胺。 的一部分 拟议的研究涉及利用这种化学物质， 形成另一个环。 例如，叠氮化物与 某些1，3-二烯导致吡咯烷的形成， 在一个合成操作中得到吲哚嗪。 更实用的版本有 最近开发了一种方法，其中叠氮化物与带有 远程离开组。 初始的三唑啉重排成亚胺， 其在分子内被烷基化，得到有用的双环亚胺鎓 离子。 一种基于叠氮化物化学的完全不同的方法也 开发了 某些醇和烯烃经过电离成 碳阳离子，其可以被叠氮化物分子内捕获以形成 氨基重氮离子。 相邻碳原子上的基团之一 然后迁移到氮气中，取代二氮， 亚胺离子 各种各样的双环系统可以通过以下方法制备： 这种方法原则上包括桥连双环。 一个主要 建议的一个方面是将这些方法应用于 使用这些合成感兴趣的天然和非天然生物碱 方法. 其中蓖麻胺等生物碱是重要成分 在香水行业。 二氢辛可宁是金鸡纳属的一员 生物碱类，以抗疟疾活性而闻名。 吲哚里西啶209B 是烟碱受体拮抗剂。Monomorine I是一种 食蚜蝇是供暖建筑物中的害虫，也是医院中的一个问题。 石蒜碱类的一些生物碱表现出抗肿瘤活性。 12 b-表菲兰和γ-石蒜烷是这类的成员， 是有针对性的。 Pictamine和clavepictine是一个新类别的成员 具有细胞毒活性的生物碱。 芳基喹里西啶生物碱 例如kayawongine和隐胸苷在生物学上也很有趣， 后者表现出细胞毒性、起泡性和抗阿米巴性 活动 最后，一些重要糖苷酶的类似物 提出了抑制剂苦马豆素和栗精胺。 制备 喹嗪环类似物应提高选择性和效力 在这些化合物中，它们正在被研究为抗癌药物， 抗艾滋病药物。

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.