A Concise, Convergent Approach to the Synthesis of (+)-Pleuromutilin

合成 ( )-截短侧耳素的简洁、收敛的方法

• 批准号: 9192694
• 负责人: Elliot Patrick Farney
• 金额: $ 5.43万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192694
• 关键词: Address; Alcohols; Anions; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Architecture; Bacteria; Bacterial Drug Resistance; Bacterial Proteins; Biological; Biological Availability; Biological Models; Biology; Carbon; Cell Nucleus; Chemicals; Chemistry; Coupling; Cyclization; Development; Diterpenes; Elements; Escherichia coli; Esters; Exhibits; FDA approved; Glycolates; Goals; Health; Human; Humanities; Investigation; Knowledge; Laboratories; Mediating; Metabolic; Modification; Molecular; Natural Products; Nature; Nickel; Parents; Peptidyltransferase; Pleurotus; Reporting; Research; Research Personnel; Resistance; Resort; Ribosomes; Samarium; Side; Staging; Structure; Time; Vancomycin; analog; base; carbon skeleton; chemical synthesis; design; drug discovery; forging; improved; large scale production; novel; open innovation; pleuromutilin; programs

PROJECT SUMMARY Antibiotic resistance is one of the greatest threats to human health. It is quickly becoming evident that current research efforts are unable to keep pace with the rate at which bacteria evolve inactivation mechanisms to last- resort antibiotics. The core structures of many of these last-resort compounds are small, flat, structurally sparse heterocycles amenable to rapid diversification by chemical semi-synthesis. However, recent major campaigns aimed at improving resistance have yielded only a small number of FDA-approved antibacterials derived from these molecules. Structurally-rich antibiotics, like vancomycin and pleuromutilin, have comparatively vast chemical and structural space that remains essentially unexplored. In particular, nearly 1200 derivatives of pleuromutilin have been synthesized since its discovery in 1951, but due to the sheer structural complexity of pleuromutilin, the majority of derivatives are semi-synthetic congeners of the glycolic acid side-chain. Much effort has been devoted to a total chemical synthesis of pleuromutilin, but only one such synthesis exists. The 34 linear steps required to prepare pleuromutuilin is both infeasible for large-scale production and does not allow for the rapid synthesis of congeners designed to probe fundamental questions regarding the metabolic degradation and biological activity of this important antibiotic. We propose the first highly convergent total chemical synthesis of pleuromutilin, in which two rapidly prepared building blocks are united by a regio- and stereospecific nickel-catalyzed reductive coupling at a late stage in the synthesis. A second key step leverages our expertise in organosamarium-mediated reductive cyclizations to forge a hindered carbon-carbon bond and establish three stereocenters. Taken together, these strategies will enable expedient access to pleuromutilin, allow for a much broader diversity of studies on the core carbon skeleton, facilitate derivatization efforts aimed at the much-needed development of new antibiotics, and contribute knowledge to the chemistry and biology of pleuromutilin.

项目摘要 抗生素耐药性是对人类健康的最大威胁之一。迅速变得很明显 研究工作无法与细菌进化的灭活机制的速度保持同步 度假村抗生素。许多这些最后一个度量化合物的许多核心结构在结构上很小，平坦 稀疏的杂环可以通过化学半合成而快速多样化。但是，最近的专业 旨在改善抵抗力的运动仅产生了少数FDA批准的抗菌作用 源自这些分子。结构丰富的抗生素，如万古霉素和胸膜素，具有 基本上未开发的化学和结构空间相对较大。特别是 自1951年发现以来，已合成了1200个胸膜素的衍生物，但由于纯粹 胸膜素的结构复杂性，大多数衍生物是糖溶质的半合成同源物 酸侧链。已经大量精力致力于胸膜素的总化学合成，但只有一种 存在合成。准备胸膜素蛋白所需的34个线性步骤对于大规模而言都是不可行的 生产，不允许迅速合成旨在探讨基本问题的同源物 关于这种重要抗生素的代谢降解和生物学活性。我们提出了第一个 高度收敛的胸膜素的总化学合成，其中两个快速制备的构件是 在合成的后期阶段，由区域和立体特异性镍催化的还原耦合结合。一个 第二个关键步骤利用了我们在有机氨基介导的还原环化中的专业知识来锻造 阻碍碳碳键并建立三个立体中心。综上所述，这些策略将实现 权宜获取胸膜素，可以在核心碳骨架上进行更广泛的研究， 促进旨在急需开发新抗生素的衍生化工作，并做出贡献 知识对胸膜素的化学和生物学。