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用于制备具有医学重要性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高度可及的合作伙伴，高度共轭乙炔和过渡金属卡宾配合物的耦合，作为设计新工艺的关键要素。已经提出了利用这些新开发的反应来合成各种靶分子的新的、有效的和高度灵活的合成路线。具体目标1-4涉及异苯并呋喃和/或吡喃酮的串联生成及其随后的环加成 反应.可靠的协议将开发使用这些反应的合成十元环，部分氢化菲环系统，异喹啉环系统，和苯并稠合的五元环杂环。这些新开发的反应过程随后将被用作类固醇、吗啡生物碱、氢化菲抗生素、苯并菲啶抗癌剂和含吲哚的磷酸二酯酶抑制剂的难以置信的短合成路线的基石。这些偶联的多组分性质允许高度的分子多样性，对于药物类似物的结构-活性关系的长期评估是巨大的资产。具体目标5涉及开发基于烯炔亚胺与卡宾络合物偶联的1-氨基吡咯环系统的新合成路线。该反应将作为合成不对称二吡咯的基础和合成部分氢化菲的补充方法。这种方法将随后在一个短的合成路线，丹参酮，当时草药丹参的重要组成部分，并显示出不同的生物活性谱。 具体目标6涉及将上述方法扩展到类似的环氧化物或氮丙啶衍生物，并开发用于快速组装医学上重要的3-苯并氧杂环庚三烯和3-苯并氮杂环庚三烯环系统的方案。