SYNTHESIS OF ANTIBIOTIC AND ION TRANSPORT AGENTS

抗生素和离子传输剂的合成

• 批准号: 2175157
• 负责人: STEVEN D. BURKE
• 金额: $ 18.28万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2175157
• 关键词: X ray crystallography; amphiphilicity; antibiotics; chemical bond; chemical models; drug design /synthesis /production; ionophores; macrolide antibiotics; membrane channels; membrane reconstitution /synthesis; propionates; pyrans; stereochemistry

The goals of this research in synthetic organic and bioorganic chemistry are to synthesize natural antibiotics of the ionophore and macrolide classes and to design, synthesize, and study biomimetic hybrid molecules Incorporating macrocyclic hydropyran oligolides. Specific objectives are described below: 1 . Synthesis of 'second generation' macrocyclic hydropyran oligolides with directed functionality for the study of fundamental complexation, aggregation, and ion transport phenomena, including: (a) designed, structurally well-defined templates for assembling and characterizing amphiphilic helical peptide bundles as biomimetic transmembrane ion channels; (b) a conformationally favorable host for the water dimer, with potential as a self-assembling subunit in an extended, tubular supramolecular array; (c) other templates with self-complementary functionality for 'strict' (reversible) self-assembly into tubular supramolecules bound by ion pair or H-bonding interactions; (d) an ordered template Incorporating imidazole and sulfhydryl moieties to study two modes of self-assembly under physiological conditions, with potential application as a chiral proteinase mimic. 2. Total synthesis of the natural ionophore griseochelin (zincophorin), featuring: (a) a triply convergent route requiring only 19 linear steps for 17 stereogenic (13 asymmetric) centers; (b) direct comparison of anomeric radical and anionic hydropyran-to-vinylsulfone couplings in the context of acyclic stereocontrol. 3. Completion of a novel approach to polypropionate macrolides, exemplified by erythronolide B and erythronolide A, featuring: (a) exploitation of pseudosymmetrical C2->C6 and C8->C12 regions via a bis(dihydropyran) template; (b) double dioxanone-to-dihydropyran rearrangement to establish intact Cl->C13 array; (c) simultaneous multiple hydroborations to introduce several asymmetric centers at once; (d) a novel tactic for conformational restriction of the seco acid as an entropic aid to macrolactonization.

本研究的目标是合成有机和生物有机化学 是合成离子载体和大环内酯类天然抗生素 课程并设计、合成和研究仿生杂化分子 掺入大环氢吡喃低聚内酯。 具体目标是 描述如下： 1. “第二代”大环氢吡喃低聚内酯的合成 具有用于研究基本络合的定向功能， 聚集和离子传输现象，包括： (a) 设计的、结构明确的模板，用于组装和 将两亲性螺旋肽束表征为仿生 跨膜离子通道； (b) 水二聚体的构象有利宿主， 作为延伸的管状自组装子单元的潜力 超分子阵列； (c) 其他具有自我补充功能的模板 “严格”（可逆）自组装成管状超分子 离子对或氢键相互作用； (d) 包含咪唑和巯基的有序模板 研究生理条件下自组装的两种模式 条件下，具有作为手性蛋白酶模拟物的潜在应用。 2. 天然离子载体灰螯素（zincophorin）的全合成， 特色： (a) 三重收敛路线仅需要 19 个线性步骤即可实现 17 立体异构（13 个不对称）中心； (b) 异头自由基和阴离子的直接比较 无环背景下的氢吡喃与乙烯基砜偶联 立体控制。 3. 完成聚丙酸酯大环内酯的新方法， 以赤藓糖内酯B和赤藓糖内酯A为例，其特点是： (a) 利用伪对称 C2->C6 和 C8->C12 区域 双(二氢吡喃)模板； (b) 双二恶烷酮至二氢吡喃重排以建立 完整的 Cl->C13 阵列； (c) 同时进行多次硼氢化以引入几种 一次不对称中心； (d) 一种新的 Seco 酸构象限制策略 大环内酯化的熵助剂。

项目成果

Direct transacylation of 2,2,2-trihaloethyl esters with amines and alcohols using phosphorus (III) reagents for reductive fragmentation and in situ activation.

• DOI: 10.1021/jo991711m
• 发表时间: 2000-04
• 期刊: The Journal of organic chemistry
• 作者: J. Hans;R. Driver;S. D. Burke