A fragmentation approach to large rings and polycyclic nitrogen heterocycles

描述(申请人提供)：这项研究的主要目标是开发新的合成有机方法学，为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提供有效的方法。多环含氮杂环和中环或大环体系是药物和生物活性化合物中普遍存在的结构基元。然而，这些结构基序的制备可能具有挑战性，这可能会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为生物医学研究提供重要化合物的合成路线。我们提出的研究是基于我们最近发现的一种新的环裂解方法，该方法可以高产率地提供栓系醛酮产品。我们的中心假设是，这种环裂解将为我们提供一种独特而有效的方法来制备含氮多环杂环和中或大环体系。这些合成方法将直接适用于合成具有生物活性的天然产品，我们建议在此授权期内制备几种天然产品。这项建议的具体目的是研究稠合双环-硅氧基-羟基-重氮羰基化合物中环熔键断裂的裂解，以此来制备中、大尺寸的环酮和环ynoates。将稠合双环-重氮酯的裂环反应应用于(-)-邻苯二酚内酯I、(-)-二聚二内酯C和酶抑制剂间苯二环大环内酯L-783,277的合成。进一步开发了以乙酸乙二醇酯裂解产物为底物进行分子内1，3-偶极环加成反应，合成多环2，5-二氢吡咯。将环断裂/1，3-偶极环加成序列应用于铜绿素生物碱核(CHAI)、(-)-中膜、去米西丁和(+)-天冬氨酸的简明合成。

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.