Novel Furan Cycloaddictions for Preparation of Medicinally Important Compounds

用于制备重要药用化合物的新型呋喃环化

• 批准号: 7426619
• 负责人: JAMES W HERNDON
• 金额: $ 21.21万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426619
• 关键词: Aldehydes; Alder plant; Alkaloids; Alkenes; Alkynes; Amides; Antineoplastic Agents; Apomorphine; Aporphines; Area; Biological Factors; Chemicals; Chromium; Complex; Coupling; Cyclization; Development; Diels Alder reaction; Dopamine Receptor; Electrons; Esters; Event; Furans; Goals; Hydrazones; Hypertension; Malignant Neoplasms; Marines; Methodology; Methods; Microtubule Polymerization; Microtubules; Parkinson Disease; Pattern; Phase; Population; Preparation; Procedures; Process; Protocols documentation; Pyrroles; Quality of life; Reaction; Relative (related person); Route; Scheme; Screening procedure; System; Testing; Variant; Work; analog; base; carbene; cycloaddition; design; diazene; eleutherobin; enantiomer; furan; hypertension treatment; nervous system disorder; nitrene; novel; preference; size; stereochemistry; tanshinone; undecane

DESCRIPTION (provided by applicant): The work in this proposal involves the development of new furan and pyrrole-based cycloaddition reactions that result in the formation of complex ring systems from simple and readily available components. The cycloaddition mode depends upon the synthetic route and the substitution pattern for the furan/pyrrole core. The [8+2]-cycloaddition mode occurs when alkynes couple with dienylfurans. This reaction assembles the core ring system (furan-bridged ten-membered ring) of the marine-derived experimental anti-cancer agent eleutherobin. The full synthetic potential of this reaction will be developed, including delineation of the scope, limit, and stereochemistry of the [8+2]-cycloaddition followed by a study of the reactivity profile for densely functionalized [8+2]-cycloadducts. These chemical processes will be employed in the design of new anti-cancer agents that structurally resemble eleutherobin. The ability of these compounds to promote microtubule polymerization will be tested, and active candidates will be further tested as anti-cancer agents. The coupling of chromium carbene complexes with ortho-alkynylbenzoyl derivatives leads to activated furan/pyrrole rings, which undergo efficient cycloaddition with a variety of alkenes and alkynes. A variant of this process will be developed where highly unsaturated chromium carbene complexes afford phenanthroid ring systems in a formal [5+5]-cycloaddition reaction. These reactions are the cornerstone for versatile and efficient synthetic approaches to tanshinones, useful for the treatment of hypertension, and to apomorphine, a dopamine receptor useful for the treatment of Parkinson's disease. Work in this proposal provides structurally complex and medicinally important compounds from simple and readily available components. The reaction process can conveniently provide compounds (or more importantly structural analogs) that have shown potent anti-cancer activity, anti-hypertension activity, and activity against neurologic disorders such as Parkinson's disease. These are all very common ailments that negatively impact the quality of life a large portion of the U.S. population.

描述（由申请人提供）：本提案中的工作涉及开发新的基于呋喃和吡咯的环加成反应，该反应可从简单且易于获得的组分形成复杂的环体系。环加成方式取决于呋喃/吡咯核心的合成路线和取代模式。[8+2]-环加成模式发生在炔与二烯呋喃偶联时。该反应组装了海洋来源的实验性抗癌剂刺柳皂苷的核心环体系（呋喃桥接十元环）。该反应的全部合成潜力将被开发，包括[8+2]-环加成的范围，限制和立体化学的描述，然后是密集功能化[8+2]-环加合物的反应性分布的研究。这些化学过程将被用于设计结构类似于刺柳皂苷的新型抗癌药物。这些化合物促进微管聚合的能力将被测试，活性候选物将被进一步测试作为抗癌剂。铬羰基配合物与邻炔基苯甲酰衍生物偶联形成活化的呋喃/吡咯环，并与多种烯烃和炔进行高效的环加成反应。该过程的一种变体将被开发出来，其中高度不饱和的碳铬配合物在正式的[5+5]-环加成反应中提供苯并杂环体系。这些反应是丹参酮（用于治疗高血压）和阿波啡（一种用于治疗帕金森氏病的多巴胺受体）多用途和高效合成方法的基础。