B-Lactones: Bioactive Target and Vehicles for Synthesis

B-内酯：生物活性靶标和合成载体

• 批准号: 7009943
• 负责人: DANIEL ROMO
• 金额: $ 22.38万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009943
• 关键词: antiparasitic agents; chemical structure; chemical synthesis; inhibitor /antagonist; lactones; proteasome; technology /technique development

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）：本提案描述了天然产物的几种新型合成策略，重点关注β-内酯（2-氧杂环丁酮）的合成和应用。未充分利用的β-内酯的新的合成和转化提出了用于Omuralide和salinosporamide衍生物，潜在的物种特异性蛋白酶体抑制剂，和haterumalides，新型海洋，大环内酯类细胞毒性剂的简明制备。我们提出了一个分子内，亲核催化，羟醛内酯化（NCAL）的过程，独特地合并催化，不对称杂环合成与β-内酯合成的发展。应用程序的一个高度简洁，通用的策略Omuralide和salinosporamide衍生物，这是非常有用的工具，在生物学研究的蛋白酶体功能，提出。开发一种新的，串联Mukaiyama醛醇-内酯化-环化-加成序列，通过甲硅烷基化的β-内酯中间体进行，用于合成四氢呋喃和四氢吡喃，将应用于收敛全合成的haterumalides，新的海洋，抗肿瘤大环内酯。这项研究将扩大获得光学活性β-内酯，并扩大其效用作为合成中间体，提供高度简洁的策略Omuralide和salinosporamide衍生物作为潜在的抗寄生虫剂，并作为一般有用的工具，用于研究蛋白酶体功能，验证的结构haterumalides和提供获得衍生物的作用机制研究有用。