B-Lactones: Bioactive Target and Vehicles for Synthesis

描述(申请人提供)：本提案描述了几种新的天然产物的合成策略，重点是β-内酯(2-氧杂环己酮)的合成和应用。提出了未被充分利用的β-内酯的新的合成和转化方法，以简明地制备OMuralide和Salinosporamide衍生物，潜在的物种特异性蛋白酶体抑制剂，以及新型海洋大环内酯类细胞毒剂haterumalide。我们建议开发一种分子内亲核催化的羟醛-内酯化(NCAL)过程，它独特地结合了催化的不对称杂环合成和β-内酯的合成。提出了一种高度简明、通用的策略应用于欧穆拉利和盐孢酰胺衍生物，这两种衍生物在生物学中是研究蛋白酶体功能的非常有用的工具。开发一种用于合成四氢呋喃和四氢吡喃的新型串联的Mukaiyama羟醛内酯-内酯-环化-加成序列，通过硅烷化的β-内酯中间体进行，将应用于haterumalide、新的海洋、抗肿瘤大环内酯的收敛全合成。这项研究将扩大获得光学活性β-内酯的途径，并扩大它们作为合成中间体的用途，提供高度简明的策略，将OMuralide和盐孢酰胺衍生物作为潜在的抗寄生虫剂，作为研究蛋白酶体功能的普遍有用的工具，验证haterumalide的结构，并提供用于作用机制研究的衍生物。

DESCRIPTION (provided by applicant): This proposal describes several novel synthetic strategies to natural products focused on the synthesis and application of beta-lactones (2-oxetanones). New syntheses and transformations of underutilized beta-lactones are proposed for the concise preparation of Omuralide and salinosporamide derivatives, potential species-specific proteasome inhibitors, and the haterumalides, novel marine, macrolide cytotoxic agents. We propose development of an intramolecular, nucleophile-catalyzed, aldol-lactonization (NCAL) process, which uniquely merges catalytic, asymmetric heterocycle synthesis with beta-lactone synthesis. Applications to a highly concise, versatile strategy to Omuralide and salinosporamide derivatives, which are extremely useful tools in biology for study of proteasome function, are proposed. Development of a novel, tandem Mukaiyama aldol-lactonization-cyclization-addition sequence, proceeding through a silylated beta-lactone intermediate, for the synthesis of terahydrofurans and tetrahydropyrans will be applied to a convergent total synthesis of the haterumalides, new marine, antitumor macrolides. This research will expand access to optically active beta-lactones and expand their utility as synthetic intermediates, make available highly concise strategies to Omuralide and salinosporamide derivatives as potential anti-parasitic agents and as generally useful tools for study of proteasome function, verify the structure of the haterumalides and provide access to derivatives useful for mechanism of action studies.