A fragmentation approach to large rings and polycyclic nitrogen heterocycles

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、大环体系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具有挑战性，这限制了它们在生物医学研究中的应用。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途径。我们提出的研究是基于我们最近发现的一种新的环碎片，它提供了高产量的系链醛醛产品。我们的中心假设是，这种环破碎将为我们提供一种独特而有效的方法来制备含杂环的多环氮和大中型环体系。这些合成方法将直接适用于生物活性天然产物的合成，我们建议在此资助期间制备几种天然产物。本提案的具体目的是研究熔融双环？-硅氧基- -羟基-？环熔合键断裂的重氮羰基化合物，可用于制备中、大尺寸环炔酮和环炔酸酯。应用熔合双环的环破碎？-重氮酯合成(-)-光棘烷内酯I、(-)-双双内酯C和激酶抑制剂间环大环内酯L-783,277。进一步开发利用栓接醛酸酯裂解产物作为底物进行分子内1,3-偶极环加成反应，制备多环2,5-二氢吡咯。应用环断裂/ 1,3-偶极环加成序列，简明合成铜绿苷类生物碱核心（choi）、(-)-膜膜、去米西啶和(+)-蜘蛛精胺。

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.