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-607，一种多纤维抗生素，欠其药理 活性具有破坏细菌细胞转运的能力 过程，一旦结合到细胞膜。 恰恰是如何发生 分子水平尚不清楚。 但是，其结构强烈 表明它可以充当离子载体。一个长期目标 因此，我们的方法是使用1H和13C NMR研究结合特性 该分子，并设计了该分子的结构亲戚， 带有各种单阳离子和二价阳离子。 希望这样的 调查将对这种机制提供宝贵的见解 正常细菌细胞活性被该药物破坏。而且， 通过测量与结构变化相关的离子亲和力， 设计更高效的膜运输抑制剂，并希望 应该有可能进行更有效的抗生素。 为了使该项目可行，有效地进入 复杂的pamamycin框架至关重要。 对此，我们的直接 如本应用程序所述，目标是开发立体选择性 pamamycin607的合成。 我们方法的关键步骤涉及 添加2-氧甲酮在四氢呋喃乙醛中烯醇化 带有螯合控制的导数。 我们打算探索可行性 通过执行一系列简单的反应，来实现这种策略 由其α-硅胶的前体产生的2-氧甲酮，由 用氟化物处理，并在 存在不同潜在的螯合剂，例如Liclo4和 Znbr2。 有了这个新颖的四中心非映选择过程 然后，我们希望使用羰基定向的还原环开口 这些立体选择性构造的单元以提供独特的条目 进入带有多个侧链的四氢呋喃的顺式2,5二尿 不对称。 使用模型系统，将此策略应用于 帕木霉素607将通过控制的酸奶添加来证明 4-（3-甲基-3-丁基）-2-氧苯甲酮用于Synα-甲基四氢呋喃 乙醛。 来自Aldol产品，一个用于还原性的羰基 环化将通过低端子烯烃部分释放 温度臭氧分解。 已经制定了应用方法论 在模型系统中开发以合成天然产物。