ALKALOID SYNTHESIS VIA (3+2) CYCLOADDITIONS

描述：（主要研究者摘要） 建议的研究是继续开发通用和有效的方法， 具有生物学意义的含吡咯烷分子的合成。一 一般的合成方法可用于制备各种各样的 目标分子而不是单一类别。这项研究将试图 使用2-氮杂烯丙基阴离子与烯烃的阴离子（3+2）环加成， 甲亚胺叶立德与烯烃的1，3-偶极环加成反应 生物学相关靶分子的横截面的构建。的 2-氮杂烯丙基阴离子通过锡-锂交换制备， （2-氮杂烯丙基）锡烷。相同的（2-氮杂烯丙基）锡烷也是 几种新型的不稳定的甲亚胺叶立德，它们也能够 （3+2）环加成反应生成吡咯烷。这两种类型的反应 中间体被证明在它们的反应性上是互补的， 非对映选择性将这些方法应用于合成 提出了生物学上有趣的分子，以提供一个背景 方法学的发展。每个例子都是为了测试不同的方面 （3+2）方法。靶标包括：（1）单孢菌素1， 法老蚁信息素，（2）苦毒胺，一种新型喹啉嗪生物碱 从被囊动物中分离得到，具有抗菌、抗真菌和抗肿瘤活性， (3)Lundurines B和C，分离自Kopsia，其提取物发现 药用类风湿性关节炎，水肿，扁桃体炎在中国，（4） 7-epiaustraline，一种高度羟基化的吡咯里西啶生物碱， 羟甲基，羟甲基：一类具有活性的生物碱的成员 作为葡糖苷酶I抑制剂、抗病毒剂和抗逆转录病毒剂，（5） Scandine是一种中国民间药物的成分，用于治疗 风湿性心脏病，和（6）erycibelline，一个成员的托烷类 生物碱这些目标将允许检查2-氮杂烯丙基的范围， 阴离子和甲亚胺叶立德环加成方法的几种方式。比如说， 所需的阴离子或叶立德的类型是多种多样的（例如，简单的脂族 取代基，官能化侧链，杂取代的形式，更多 共轭形式和环状形式），每种形式都具有其独特的化学性质， 制备方法区域控制和立体控制的问题， 绝对的和相对的，都必须加以解决。串联过程涉及 （3+2）环加成的组合，随后是导致 到第二或第三环的形成或重排也在研究中。

DESCRIPTION: (Principal Investigator's Abstract) The principal objective of the proposed research is to continue to develop general and efficient methods for the synthesis of pyrrolidine-containing molecules of biological significance. A general synthetic method may be useful for the preparation of a wide variety of target molecules rather than a single class. The proposed research will attempt to use the anionic (3+2) cycloaddition of 2-azaallyl anions with alkenes and the 1,3-dipolar cycloaddition of azomethine ylides with alkenes for the construction of a cross-section of biologically relevant target molecules. The 2-azaallyl anions are prepared by tin-lithium exchange on (2-azaallyl)stannanes. The same (2-azaallyl)stannanes are also precursors of several novel types of non-stabilized azomethine ylides, which are also capable of (3+2) cycloadditions to produce pyrrolidines. These two types of reactive intermediates are proving to be complementary in their reactivity and diastereoselectivity. Applications of these methods to the synthesis of biologically interesting molecules is proposed in order to provide a context for methodology development. Each example is meant to test a different aspect of the (3+2) methodology. Targets include: (1) monomorine 1, the trail pheromone of the pharoah ant, (2) pictamine, a novel quinolizidine alkaloid isolated from tunicates with antimicrobial, antifungal, and antitumor activity, (3) lundurines B and C, isolated from Kopsia, the extracts of which find medicinal use for rheumatoid arthritis, dropsy, and tonsillitis in China, (4) 7-epiaustraline, a highly hydroxylated pyrrolizidine alkaloid with a unique hydroxymethyl group, a member of a class of such alkaloids that have activity as glucosidase I inhibitors, antiviral agents and antiretroviral agents, (5) scandine, a component of a Chinese folk medicine used for the treatment of rheumatic heart disease, and (6) erycibelline, a member of the tropane class of alkaloids. These targets will allow examination of the scope of the 2-azaallyl anion and azomethine ylide cycloaddition methods in several ways. For example, the types of anions or ylides required are diverse (e.g., simple aliphatic substituents, functionalized side chains, heterosubstituted versions, more conjugated versions, and cyclic versions), each with their unique chemistry and method of preparation. The issues of regiocontrol and stereocontrol, both absolute and relative, must be addressed. Tandem processes that involve the combination of (3+2) cycloaddition followed by additional reactions that lead to a second or third ring formation or a rearrangement are also being studied.