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: 10394725
• 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/10394725
• 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.

聚酮化合物广泛用于人类医学，约占人类医学的20% 最畅销的小分子药物。虽然大多数聚酮化合物药物来自土壤细菌， 不到 5% 的土壤细菌适合培养。这些数据表明，作为方法 土壤细菌培养的改善，聚酮化合物在人类医学中的使用将会增加，因为 这些复杂结构及其功能是否需要简洁的制造路线 类似物。在 NIH 的支持下，我们开发了一系列催化方法 低级醇直接立体选择性和位点选择性转化为高级醇。这些 酒精介导的 C-C 偶联是在我们的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体。这项技术使总 多种 I 型聚酮化合物的合成，包括 6-deoxyerythronolide B、bryostatin 7、 三烯霉素 A 和 F、cyanolide A、roxaticin、cryptocaryol A、SCH 351448、swinholide 以及 利福霉素 S 和 scytophycin C 的正式合成。在所有情况下，我们的合成都显着 比现有路线更简洁。这些方法的使用越来越频繁 跨越学术和工业实验室。在拟议的资助期内，两个主要 提出的目标是： (a) II 型聚酮化合物构建的催化方法将 开发和（b）简化的具有抗癌和抗菌作用的聚酮化合物类似物 属性将在正在进行的合作中进行评估。这些研究推进了综合 方法创新为合成提供信息，合成为药物提供信息的计划 化学。