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20％ 最畅销的小分子药物。虽然大多数聚酮化合物来自土壤细菌，但 不到5％的土壤细菌可以与培养物相吻合。这些数据表明作为方法 土壤细菌的培养物可以改善，在人类医学中使用聚酮化合物会增加，因为 将需要简明的制造路线及其功能 类似物。在NIH的支持下，我们开发了一种催化方法的家族 低酒精的直接立体和现场选择性转化为较高的醇。这些 酒精介导的C-C耦合是在我们的实验室中构想和开发的， 我们仍然是探索这一研究领域的最重要小组。这项技术启用了总计 I型聚酮化合物的合成，包括6-脱氧醚醇B，Bryostatin 7， 三霉素A和F，Cyanolide A，roxaticin，cryptocaryol A，SCH 351448，Swinholide以及 利福米霉素S和Scytophycin C的形式合成。在所有情况下，我们的合成均显着 比先前存在的路线更简洁。这些方法发现越来越频繁地使用 在学术和工业实验室中。在拟议的资金期间，两个主要 提出了目标：（a）II型聚酮化合物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。这些研究推进了整合的 方法学创新为综合提供信息的程序，并合成为药用提供信息 化学。