Novel Syntheses of Heterocyclic and Aromatic Compounds

杂环和芳香族化合物的新合成

• 批准号: 6766138
• 负责人: JAMES W HERNDON
• 金额: $ 12.28万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6766138
• 关键词: alkenes; alkynes; aziridines; benzofurans; carbene; carbonyl group; chemical conjugate; chemical reaction; chemical structure function; chemical synthesis; drug design /synthesis /production; epoxides; heavy metals; heterocyclic compounds; intermolecular interaction; isoquinolines; morphine; pyrones; pyrroles; steroids

The research in this proposal focuses on the development of methods for the preparation of medicinally important heterocyclic ring systems and carbocyclic ring systems. The methodology utilizes the coupling of two very simple and highly accessible partners, highly conjugated acetylenes and transition metal carbene complexes, as the key elements for the design of new processes. New, efficient, and highly flexible synthetic route to a variety of target molecules utilizing these newly developed reactions have been proposed. Specific Aims 1-4 involve the tandem generation of isobenzofurans and/or pyrones and their subsequent cycloaddition reactions. Reliable protocols will be developed for the use of these reactions for the synthesis of ten-membered rings, partially hydrogenated phenanthrene ring systems, isoquinoline ring systems, and benzo-fused flve-membered ring heterocycles. These newly developed reaction processes will subsequently be used as cornerstones for incredibly short synthetic routes to the steroids, morphine alkaloids, hydrophenanthrene antibiotics, benzophenanthridine anti-cancer agents, and indole-containing phosphodiesterase inhibitors. The multicomponent nature of these couplings allows for a high degree of molecular diversity, a tremendous asset for long-term evaluation of structure-activity relationships of pharmaceutical analogs. Specific Aim 5 involves development of a novel synthetic route to the 1-aminopyrrole ring system based on the coupling of enyne-imines with carbene complexes. This reaction will serve as the cornerstone for the synthesis of unsymmetrical dipyrroles and a complementary method for the synthesis of partially hydrogenated phenanthrenes. This methodology will subsequently be employed in a short synthetic route to tanshinones, important components of then herb Dan Shen, and which display a diverse spectrum of biological activity. Specific Aim 6 involves extension of the above processes to the analogous epoxide or aziridine derivatives, and development of protocols for rapid assembly of the medicinally important 3-benzoxepine and 3-benzazepine ring systems.

本提案中的研究重点是开发制备具有重要药用价值的杂环系统和碳环系统的方法。该方法利用两个非常简单和容易获得的伙伴--高度共轭的乙炔和过渡金属卡宾络合物--的耦合，作为设计新工艺的关键要素。利用这些新开发的反应，已经提出了一种新的、高效的、高度灵活的合成路线来合成各种目标分子。具体目标1-4涉及异苯并呋喃和/或吡喃的串联生成及其随后的环加成反应 反应。这些反应将被用于合成十元环、部分氢化菲环系、异喹啉环系和苯并稠环杂环。这些新开发的反应过程随后将被用作合成类固醇、吗啡生物碱、氢菲抗生素、苯并菲抗癌剂和含吲哚的磷酸二酯酶抑制剂的极短路线的基石。这些偶联的多组分性质允许高度的分子多样性，这对于长期评估药物类似物的结构-活性关系是一种巨大的财富。具体目标5涉及开发一种新的合成1-氨基吡咯环系的路线，该路线基于烯-炔亚胺与卡宾络合物的偶联。该反应将作为合成不对称联吡咯的基石和合成部分氢化菲的补充方法。这种方法随后将用于合成丹参酮的短路线，丹参酮是当时草药丹参的重要成分，显示出不同的生物活性。 具体目标6涉及将上述方法扩展到类似的环氧化物或氮杂环丙烷衍生物，以及开发用于快速组装具有医学意义的3-苯并西平和3-苯并西平环系的方案。