ALKALOID SYNTHESIS VIA (3+2) CYCLOADDITIONS

描述：(主要调查人员摘要) 拟议的研究是继续开发通用和有效的方法来 具有生物学意义的含吡咯烷分子的合成。一个 一般的合成方法可能适用于制备各种不同的 目标分子，而不是单一的类别。拟议的研究将尝试 利用2-氮杂烯丙基阴离子与烯烃的阴离子(3，2)环加成反应 甲亚胺叶立德与烯烃的1，3-偶极环加成反应 构建生物相关靶分子的横截面。这个 2-氮杂烯丙基阴离子是通过锡-锂交换制备的 (2-氮杂烯丙基)锡烷。相同的(2-氮杂烯丙基)锡烷也是 几种新型的非稳定化亚甲亚胺叶立德，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 事实证明，中间体的反应性和互补性 非对映选择性。这些方法在化合物合成中的应用 生物感兴趣的分子的提出是为了提供一种背景 用于方法论开发。每个示例都是为了测试不同的方面 (3)方法论。目标包括：(1)单峰1，小径 法老蚂蚁的信息素，(2)新的喹唑类生物碱苦参碱 从具有抗菌、抗真菌和抗肿瘤活性的衣状物中分离出来， (3)从Kopsia中分离出来的Lundurine B和C，其提取物发现 中国治疗类风湿性关节炎、水肿性扁桃体炎的药用，(4) 7-表奥司他林，一种高度羟化的吡咯里西丁生物碱，具有独特的 羟甲基，羟甲基：一类具有活性的此类生物碱的成员 作为葡萄糖苷酶I抑制剂、抗病毒药物和抗逆转录病毒药物，(5) 仙人掌，一种用于治疗糖尿病的中国民间药物的成分 风湿性心脏病，以及(6)红脑素，属于托烷类药物 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的几种方法。例如, 所需的阴离子或叶立德的类型是多样的(例如，简单的脂肪族 取代基、官能化侧链、杂取代形式等 共轭版本和循环版本)，每个版本都有其独特的化学和 制备方法。区域控制和立体控制的问题，都是 绝对的和相对的，必须加以解决。串联工艺，涉及 (3，2)环加成和随后的附加反应的组合 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.