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: 8444688
• 负责人: MATTHIAS BREWER
• 金额: $ 25.88万
• 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/8444688
• 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.

描述（由申请人提供）：本研究的总体目标是开发新的有机合成方法，该方法将提供从简单的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。多环含氮杂环和中环或大环系统是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使用。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。 我们提出的研究基于我们最近发现的一种新型环断裂，该断裂可提供高产率的束缚醛炔酮产品。我们的中心假设是，这种环断裂将为我们提供一种独特且有效的方法来制备多环含氮杂环和中型或大环系统。这些合成方法将直接适用于生物活性天然产物的合成，我们建议在本资助期内制备几种天然产物。 本提案的具体目的是研究稠合双环α-甲硅烷氧基-α-羟基-α-重氮羰基化合物的裂解，其中环稠合键断裂，作为制备中型和大型环状炔酮和环状炔酸酯的一种方法。将稠合双环β-重氮酯的环断裂应用于(-)-佛棘内酯I、(-)-二倍二内酯C和激酶抑制剂间苯二酚大环内酯L-783,277的合成。进一步开发使用束缚醛炔酸酯裂解产物作为分子内 1,3-偶极环加成反应的底物，以制备多环 2,5-二氢吡咯。应用环断裂/1,3-偶极环加成序列来简明合成铜绿素生物碱核心 (choi)、(-)-mesembrine、demissidine 和 (+)-aspidospermine。