B-Lactones: Bioactive Target and Vehicles for Synthesis

描述（由申请人提供）：本提案描述了几种新的天然产物合成策略，重点是β -内酯（2-奥西酮）的合成和应用。对未充分利用的β -内酯提出了新的合成和转化方法，以简化制备Omuralide和salinosporamide衍生物，潜在的物种特异性蛋白酶体抑制剂，以及haterumalides，新型海洋大环内酯类细胞毒性药物。我们提出了一个分子内，亲核催化，醛缩内酯化（NCAL）过程的发展，它独特地融合了催化，不对称杂环合成和β -内酯合成。本文提出了一种高度简洁、通用的方法来应用于Omuralide和salinosporamide衍生物，它们是生物学中研究蛋白酶体功能的非常有用的工具。开发一种新的，串联的Mukaiyama醛缩-内酯化-环化-加成序列，通过硅基化-内酯中间体，用于合成四氢呋喃和四氢吡喃，将应用于聚合全合成haterumalides，新的海洋抗肿瘤大环内酯。本研究将扩大对光学活性β -内酯的获取途径，扩大其作为合成中间体的用途，为Omuralide和salinosporamide衍生物作为潜在的抗寄生虫剂和研究蛋白酶体功能的普遍有用工具提供高度简明的策略，验证haterumalides的结构，并为作用机制研究提供有用的衍生物。

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.