B-Lactones: Bioactive Target and Vehicles for Synthesis

B-内酯：生物活性靶标和合成载体

基本信息

批准号：
7174186
负责人：
DANIEL ROMO
金额：
$ 21.73万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2009-01-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：该提案描述了几种新颖的天然产物合成策略，重点关注β-内酯（2-氧杂环丁酮）的合成和应用。提出了未充分利用的 β-内酯的新合成和转化，用于简洁制备 Omuralide 和 salinosporamide 衍生物、潜在的物种特异性蛋白酶体抑制剂和 hatrumalides（新型海洋大环内酯细胞毒剂）。我们建议开发一种分子内亲核试剂催化的羟醛内酯化 (NCAL) 工艺，该工艺独特地将催化不对称杂环合成与 β-内酯合成结合起来。提出了对 Omuralide 和 salinosporamide 衍生物高度简洁、通用的策略的应用，它们是生物学中用于研究蛋白酶体功能的非常有用的工具。开发一种新型串联Mukaiyama羟醛-内酯化-环化-加成序列，通过甲硅烷基化β-内酯中间体进行合成四氢呋喃和四氢吡喃，将应用于hatrarumalides（新的海洋抗肿瘤大环内酯）的聚合全合成。这项研究将扩大光学活性 β-内酯的获取范围并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作为研究蛋白酶体功能的常用工具提供高度简洁的策略，验证其结构哈特马利德并提供可用于作用机制研究的衍生物。