Polyketides via Redox-Triggered Alcohol C-H Functionalization.

通过氧化还原触发的醇 C-H 官能化的聚酮化合物。

• 批准号: 9918890
• 负责人: MICHAEL J KRISCHE
• 金额: $ 31.11万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918890
• 关键词: Alcohols; Anti-Bacterial Agents; Ants; Area; Bacteria; Carbon; Collaborations; Complex; Data; Family; Fermentation; Funding; Glycols; Human; Industrialization; Laboratories; Mediating; Medicine; Methodology; Methods; Natural Products; Nature; Oxidation-Reduction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plants; Property; Research; Rifamycins; Route; Science; Site; Soil; Streptomyces; Structure; Technology; Tubulin; United States National Institutes of Health; analog; anti-cancer; bryostatin; cycloaddition; design; fungus; improved; innovation; novel; pathogen; professor; programs; small molecule

Polyketides are used extensively in human medicine and account for approximately 20% of the top-selling small molecule drugs. While the majority of polyketide drugs derive from soil bacteria, less than 5% of soil bacteria are amenable to culture. These data suggest that as methods for the culture of soil bacteria improve, the use of polyketides in human medicine will increase, as will the need for concise manufacturing routes to these complex structures and their functional analogues. Under the aegis of NIH support, we have developed a family of catalytic methods for the direct stereo- and site-selective conversion of lower alcohols to higher alcohols. These alcohol-mediated C-C couplings were conceived and developed exclusively in our laboratory and we remain the foremost group exploring this area of research. This technology has enabled total syntheses of diverse type I polyketides, including 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, cryptocaryol A, SCH 351448, swinholide, as well as formal syntheses of rifamycin S and scytophycin C. In all cases, our syntheses were significantly more concise than preexisting routes. These methods are finding increasingly frequent use across both academic and industrial laboratories. In the proposed funding period, two main objectives are proposed: (a) catalytic methods for type II polyketide construction will be developed and (b) simplified polyketide analogues possessing anti-cancer and anti-bacterial properties will be evaluated in ongoing collaborations. These studies advance an integrated program in which methodological innovation informs synthesis, and synthesis informs medicinal chemistry.

聚酮类化合物在人类医学中被广泛使用，约占 最畅销的小分子药物。虽然大多数聚酮类药物来自土壤细菌， 只有不到5%的土壤细菌适合培养。这些数据表明，作为 土壤细菌培养的改善，多酮类化合物在人类医学中的使用将增加，因为 是否需要为这些复杂的结构及其功能提供简洁的制造路线 类似物。在美国国立卫生研究院的支持下，我们开发了一系列催化方法 低级醇向高级醇的直接立体选择性转化。这些 酒精介导的C-C偶联是我们实验室独家构思和开发的， 我们仍然是探索这一研究领域的最重要的团队。这项技术使Total 不同类型I型聚酮的合成，包括6-脱氧赤藓内酯B，Bryostatin 7， 三线菌素A和F、氰化物A、罗沙菌素、隐甲花醇A、SCH 351448、Swinholide以及 利福霉素S和镰刀菌素C的合成在所有情况下，我们的合成都显著地 比先前存在的路线更简洁。这些方法的使用越来越频繁。 包括学术实验室和工业实验室。在拟议的供资期间，主要有两个 目标是：(A)第二类聚酮结构的催化方法将是 开发和(B)具有抗癌和抗细菌的简化聚酮类似物 物业将在持续的合作中进行评估。这些研究推进了一个完整的 方法学创新通知合成，合成通知医学的计划 化学反应。