STEREOCONTROLLED APPROACH TO PAMAMYCIN-607

PAMAMYCIN-607 的立体控制方法

• 批准号: 2183676
• 负责人: KEITH Thomas MEAD
• 金额: $ 10.76万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 1994-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2183676
• 关键词: antibiotics; chemical structure function; drug design /synthesis /production; ionophores; lactones; stereochemistry

Pamamycin-607, a polyether antibiotic, owes its pharmacological activity to its ability to disrupt bacterial cellular transport processes, once bound to the cell membrane. Precisely how this occurs at the molecular level is not known. However, its structure strongly suggests that it functions as an ionophore. A long-term objective of ours, therefore, is to use 1H and 13C NMR to study the binding properties of this molecule, and designed structural relatives of this molecule, with a variety of mono- and divalent cations. It is hoped that such an investigation will provide valuable insight into the mechanism by which normal bacterial cellular activity is disrupted by this agent. moreover, by measuring ion affinities in relation to structural variations, the design of more efficient membrane transport inhibitors, and hopefully more effective antibiotics, should be possible. For this project to be viable, an efficient entry into the complex pamamycin framework is essential. To this and, our immediate goal, as described in this application, is to develop a stereoselective synthesis of pamamycin607. The key step in our approach involves the addition of a 2-oxetanone enolate to a tetrahydrofuran acetaldehyde derivative with chelation control. We intend to explore the feasibility of this strategy by carrying out a series of reactions in which a simple 2-oxetanone enolate is generated from its alpha-silylated precursor, by treatment with fluoride, and added to a beta-alkoxy aldehyde in the presence of different potential chelating agents such as LiClO4 and ZnBr2. With this novel four-center diastereoselective process at our disposal, we then wish to use a carbonyl-directed reductive ring opening of these stereoselectively constructed units to provide a unique entry into cis 2,5-disubstituted tetrahydrofurans bearing multiple side chain asymmetry. Using a model system, the application of this strategy to pamamycin-607 will be demonstrated by controlled addition of the enolate of 4-(3-methyl-3butenyl)-2-oxetanone to syn alpha-methyl tetrahydrofuran acetaldehyde. From the aldol product, a carbonyl group for reductive cyclization will be unleashed from the terminal alkene moiety by low temperature ozonolysis. Plans have been made to apply methodology developed in the model system to the synthesis of the natural product.

帕霉素-607是一种聚醚类抗生素， 活性与其破坏细菌细胞转运的能力 过程，一旦结合到细胞膜上。 这是如何发生的， 分子水平是未知的。 然而，其结构强烈 表明它具有离子载体的功能。的长期目标 因此，我们采用1H和13 C NMR来研究结合性质 并设计了这个分子的结构相关物， 具有多种一价和二价阳离子。 希望这样一个 调查将提供宝贵的洞察机制， 正常的细菌细胞活性被该试剂破坏。此外，本发明还 通过测量与结构变化相关的离子亲合性， 设计更有效的膜转运抑制剂， 更有效的抗生素，应该是可能的。 为了使这个项目可行，有效地进入 复杂的帕霉素框架是必需的。 对此，我们的直接 如本申请中所述，目标是开发立体选择性的 帕霉素607合成 我们方法的关键步骤包括 将2-氧杂环丁烷酮烯醇化物加入到四氢呋喃乙醛中 螯合控制衍生物。 我们打算探讨 通过进行一系列的反应， 2-氧杂环丁烷酮烯醇化物由其α-甲硅烷基化的前体通过以下步骤产生： 用氟化物处理，并加入到β-烷氧基醛中， 存在不同的潜在螯合剂如LiClO 4和 ZnBr 2. 在我们的实验中， 处置，然后我们希望使用羰基定向的还原性开环 这些立体选择性构建的单元提供了一个独特的入口 转化为带有多个侧链的顺式2，5-二取代四氢呋喃 不对称。 使用一个模型系统，该策略的应用， 帕霉素-607将通过控制烯醇化物的加入来证明 4-（3-甲基-3-丁烯基）-2-氧杂环丁烷酮合成α-甲基四氢呋喃 乙醛 从羟醛产物中，用于还原的羰基基团 环化将从末端烯烃部分释放， 温度臭氧分解。 已制定计划， 在模型系统中开发的天然产物的合成。