NEW CYCLIZATION METHODS FOR NATURAL PRODUCT SYNTHESIS

天然产物合成的新环化方法

• 批准号: 3275907
• 负责人: RAYMOND L. FUNK
• 金额: $ 15.77万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3275907
• 关键词: Diels Alder reaction; antileukemic agent; carbopolycyclic compound; chemical structure function; cockroach; cyclic compound; cyclization; drug design /synthesis /production; heterocyclic compounds

The primary objective of this research is to continue to develop new strategies for the construction of complex carbocyclic or heterocyclic ring systems. It is expected that this new methodology will expedite the syntheses of biologically active com- pounds and, in addition, provide routes to important previously unsynthesized compounds. These new strategies are based on the further exploitation of a general carbocycle synthesis developed in these laboratories, namely, the ring contraction of macrocyclic lactones to carbo- or hetereocycles via Claisen rearrangement of ketene acetals. The targeted compounds are primarily comprised of medium and/or strained ring systems. For example, the strained in,out- bicyclo(4.4.1) undecan-7-one substructure of the ingenane class of compounds will be constructed by application of this methodology in a proposed synthesis of ingenol. Furthermore, analogs of the tumor promoter ingenol 3-hexadecanoate will be prepared for the purpose of testing and refining pharmacophore hypotheses which develop structural activity relationships for various tumor promoters. A long range goal is to discover tumor promoter analogs which elicit more specific biological responses and tumor promoter antagonists which retain the outstanding binding affinities for the tumor promoter binding site. An exceptionally short, efficient synthesis of the taxane ring system which exploits the Claisen-rearrangement-based methodology in the stereocontrolled construction of the central eight-membered ring will also be examined. The synthesis of taxinine, a member of this class of compounds, will initially be investigated and precedent the extension of this strategy to the synthesis of the antitumor agent taxol and analogs. The dibenzocyclooctadiene ring of the stegane class of compounds will also be assembled using this methodology. In particular, a synthesis of the antileukemic agent steganicin is planned. A sequential Claisen-Cope rearrangement is expected to facilitate the rapid construction of the bicyclic ring system of the very potent esperamicin and calichemic class of antitumor antibiotics. If this approach is successful, analogs will be prepared which may provide further insight into the intriguing proposed mechanism of action of this class of compounds and/or function as new chemotherapeutic agents. Finally, the cyclodecane ring system of the cockroach pheremones periplanone A and B will be assembled using an alicyclic Claisen rearrangement in projected syntheses.

这项研究的主要目的是继续发展 建造复杂碳环或的新策略 杂环环系统。 预计这个新的 方法学将加快生物活性综合的合成 磅，此外，还提供了以前通往重要的路线 非合成的化合物。 这些新策略是基于对 这些实验室中开发的一般碳循环合成， 也就是说，大环内酯的环收缩对碳水化合物或 通过酮乙烯的克莱森重排。 这 靶向化合物主要由培养基和/或 紧张的环系统。 例如，紧张，超出 Bicyclo（4.4.1）Undecan-7-Ingenane类的子结构 化合物将通过这种方法的应用来构建 在提议的ingenol合成中。 此外，类似 肿瘤启动子INGENOL 3-己二烷酸盐将为 测试和完善药效假设的目的 发展各种肿瘤的结构活动关系 发起人。 一个远距离目标是发现肿瘤启动子类似物 哪些引起更具体的生物学反应和肿瘤启动子 对抗者，保留了出色的结合亲和力 肿瘤启动子结合位点。 紫杉烷环的异常短而有效的合成 利用基于Claisen的方法的系统 在中央八人的立体控制中 还将检查戒指。 Taxinine的合成，成员 在这类化合物中，最初将进行研究，并且 先例将这种策略扩展到合成 抗肿瘤型紫杉醇和类似物。 Stegane化合物类别的二苯并杂志环 也将使用此方法组装。 特别是 计划了抗白血病药乙酰毒素的合成。 预计连续的Claisen-Cope重排有助于 迅速构造了非常的双环环系统 抗肿瘤抗生素的有效的厄充植物和卡利希血症类。 如果这种方法成功，将准备模拟 提供进一步了解有趣的提议的机制 这类化合物和/或作为新功能的作用 化学治疗剂。 最后，蟑螂状态的环烷环圆环系统 Periplanone A和B将使用Alicyclic Claisen组装 投影合成的重排。