A fragmentation approach to large rings and polycyclic nitrogen heterocycles

大环和多环氮杂环的裂解方法

• 批准号: 7854711
• 负责人: MATTHIAS BREWER
• 金额: $ 29.11万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7854711
• 关键词: Acids; Address; Aldehydes; Alkaloids; Architecture; Area; Biological Factors; Biomedical Research; Complex; Development; Esters; Funding; Grant; Lead; Macrolides; Medicine; Methodology; Methods; Molecular; Nitrogen; One-Step dentin bonding system; Play; Preparation; Process; Reaction; Research; Role; Route; Scheme; Strategic Planning; Synthesis Chemistry; System; Work; aspidospermine; base; carbonyl compound; cycloaddition; functional group; improved; kinase inhibitor; novel; public health relevance; pyrroline; scaffold; stannic chloride; stem; tool

DESCRIPTION (provided by applicant): The overarching objective of this research is to develop new synthetic organic methodology that will provide efficient ways to prepare structurally-complex biomedically-relevant molecular scaffolds from simple starting materials. Polycyclic nitrogen containing heterocycles and medium or large ring systems are structural motifs that are ubiquitous in medicines and biologically active compounds. However, these structural motifs can be challenging to prepare, which can limit their use in biomedical studies. New methods to prepare these motifs would benefit biomedical research by providing synthetic routes to important compounds. Our proposed research is based on our recent discovery of a novel ring fragmentation that provides tethered aldehyde ynone products in high yield. Our central hypothesis is that this ring fragmentation will provide us with a unique and efficient way to prepare both polycyclic nitrogen containing heterocycles and medium or large ring systems. These synthetic methods will be directly applicable to the synthesis of biologically active natural products and we propose to prepare several natural products over the course of this grant period. The specific aims for this proposal are to study the fragmentation of fused bicyclic ?-silyloxy-?-hydroxy-?-diazo carbonyl compounds in which the ring fusion bond breaks as a way to prepare medium and large sized cyclic ynones and cyclic ynoates. To apply the ring fragmentation of fused bicyclic ?-diazo esters to the synthesis of (-)-phoracantholide I, (-)-diplodialide C, and the kinase inhibitor resorcylic macrolide L-783,277. To further develop the use of tethered aldehyde ynoate fragmentation products as substrates for intramolecular 1,3-dipolar cycloaddition reactions in order to prepare polycyclic 2,5-dihydropyrroles. To apply the ring fragmentation / 1,3-dipolar cycloaddition sequence to concise syntheses of the aeruginosin alkaloid core (choi), (-)-mesembrine, demissidine and (+)-aspidospermine. PUBLIC HEALTH RELEVANCE: The overarching objective of this research is to develop new synthetic organic methodology to efficiently prepare structurally-complex biomedically-relevant molecular scaffolds from simple starting materials. Advances in biomedical research depend to a great extent on chemists' abilities to prepare structurally-complex molecules and our research will provide new tools to efficiently prepare polycyclic heterocycles and macrocycles, which in turn will facilitate the use of these compounds in biomedical research and could lead to the discovery of new and improved medicinal agents.

描述（由申请人提供）：本研究的总体目标是开发新的合成有机方法，该方法将提供从简单起始材料制备结构复杂的生物医学相关分子支架的有效方法。多环含氮杂环和中或大环系统是在药物和生物活性化合物中普遍存在的结构基序。然而，这些结构基序的制备可能具有挑战性，这可能限制它们在生物医学研究中的应用。制备这些基序的新方法将通过提供重要化合物的合成路线而有益于生物医学研究。 我们提出的研究是基于我们最近发现的一种新的环断裂，提供栓系醛炔酮产品的高产率。我们的中心假设是，这种环断裂将为我们提供一种独特而有效的方法来制备多环含氮杂环和中型或大型环系统。这些合成方法将直接适用于生物活性天然产物的合成，我们建议在本授权期内制备几种天然产物。 该建议的具体目标是研究稠合双环？甲硅烷氧基-？-羟基-？-其中环稠合键断裂的重氮羰基化合物作为制备中等和大尺寸的环状炔酮和环状炔酸酯的方法。应用稠合双环的环断裂？重氮酯与（-）-phoracanthropine I、（-）-diplodialide C和激酶抑制剂resorcyclic macrolide L-783，277的合成有关。为了进一步开发栓系的炔酸醛酯片段化产物作为分子内1，3-偶极环加成反应的底物以制备多环2，5-二氢吡咯的用途。应用开环/1，3-偶极环加成程序，简洁地合成了Aerodosin生物碱核心（Choi）、（-）-mesembrine、demissidine和（+）-aspidospermine。 公共卫生相关性：本研究的总体目标是开发新的合成有机方法，从简单的起始材料有效地制备结构复杂的生物医学相关分子支架。生物医学研究的进展在很大程度上取决于化学家制备结构复杂分子的能力，我们的研究将提供有效制备多环杂环和大环的新工具，这反过来又将促进这些化合物在生物医学研究中的应用，并可能导致发现新的和改进的药物。