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.

Pamamycin-607 是一种聚醚类抗生素，其药理作用 其破坏细菌细胞运输能力的活性 一旦与细胞膜结合，就会发生过程。 具体是如何发生的 分子水平未知。 但其结构坚固 表明它起到离子载体的作用。长期目标是 因此，我们的方法是使用 1H 和 13C NMR 来研究结合特性 该分子的结构，以及该分子的设计结构相关物， 具有多种单价和二价阳离子。 希望这样的 调查将为了解这一机制提供宝贵的见解 该试剂会破坏正常的细菌细胞活性。而且， 通过测量与结构变化相关的离子亲和力， 设计更有效的膜转运抑制剂，并希望 更有效的抗生素应该是可能的。 为了使该项目可行，有效地进入 复杂的帕马霉素框架是必不可少的。 为此，我们立即 如本申请所述，目标是开发一种立体选择性 帕马霉素607的合成。 我们方法的关键步骤涉及 2-氧杂环丁酮烯醇化物与四氢呋喃乙醛的加成 具有螯合控制的衍生物。 我们打算探讨一下可行性 通过执行一系列反应来实现该策略，其中一个简单的反应 2-氧杂环丁酮烯醇化物是由其 α-硅烷化前体生成的，通过 用氟化物处理，并添加到β-烷氧基醛中 存在不同的潜在螯合剂，例如 LiClO4 和 溴化锌。 通过我们的这种新颖的四中心非对映选择性过程 处置，然后我们希望使用羰基定向还原开环 这些立体选择性构建的单元提供了独特的入口 转化为带有多个侧链的顺式2,5-二取代四氢呋喃 不对称。 使用模型系统，将该策略的应用 pamamycin-607 将通过烯醇化物的受控添加来证明 4-(3-甲基-3丁烯基)-2-氧杂环丁酮合成α-甲基四氢呋喃 乙醛。 从羟醛产物中，羰基用于还原 环化将从末端烯烃部分通过低 温度臭氧分解。 已制定应用方法的计划 在模型系统中开发了天然产物的合成。