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.

帕玛霉素-607，一种聚醚抗生素，归功于它的药理作用 其扰乱细菌细胞运输的能力的活性 突起，一旦结合到细胞膜上。准确地说这是如何在 分子水平尚不清楚。然而，它的结构强烈地 表明它起到了离子载体的作用。一个长期目标是 因此，我们用~1H和~(13)C核磁共振谱来研究其结合性质 并设计了这种分子的结构关系， 具有多种一价和二价阳离子。希望这样的一个 调查将提供宝贵的洞察机制，通过它 正常的细菌细胞活动会被这种试剂扰乱。此外， 通过测量与结构变化有关的离子亲和力， 设计更有效的膜转运抑制剂，希望 更有效的抗生素，应该是可能的。 为了使这个项目可行，一个有效的进入 复杂的帕玛霉素骨架是必不可少的。对此，我们的当务之急 正如本应用程序中所描述的，目标是开发一种立体选择性 帕马霉素607的合成。我们方法中的关键一步涉及 四氢呋喃乙醛加成2-氧乙酮烯醇酸 具有螯合控制的衍生物。我们打算探索一下可行性。 通过执行一系列反应，其中简单的 2-氧杂环丙酮烯醇酸是由其α-硅烷化的前体生成的，通过 用氟化物处理，并加入β-烷氧基醛 存在不同的潜在螯合剂，如LiClO4和 二溴化锌。通过这个新的四中心非对映选择过程在我们的 处理，然后我们希望使用一个羰基定向的还原开环 这些立体选择性构建的单元以提供唯一的入口 含多个侧链的顺式2，5-二取代四氢呋喃 不对称。利用模型系统，将该策略应用于 帕玛霉素-607将通过控制添加烯醇酸酯来证明 4-(3-甲基-3-丁烯基)-2-氧乙酮合成α-甲基四氢呋喃 乙醛。从羟醛的产物，一个还原的羰基 环化反应将从末端烯烃部分释放出来。 温度臭氧氧化。已经制定了应用方法论的计划 在模型体系中开发合成天然产物。