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: 10207982
• 负责人: MICHAEL J KRISCHE
• 金额: $ 3万
• 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/10207982
• 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中，并且占约20%的聚酮化合物。 最畅销的小分子药物虽然大多数聚酮化合物药物来源于土壤细菌， 少于5%的土壤细菌适合培养。这些数据表明，作为 随着土壤细菌培养的改善，聚酮化合物在人类医学中的使用将增加， 将需要简洁的制造路线，这些复杂的结构和他们的功能 类似物在NIH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和位置选择性转化。这些 酒精介导的C-C偶联是在我们的实验室中构思和开发的， 我们仍然是探索这一研究领域的最早团体。这项技术使整个 合成不同的I型聚酮化合物，包括6-脱氧甘草酸B，苔藓抑素7， 三烯霉素A和F、氰草胺A、罗沙替星、隐花丁香酚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，我们的合成都显著 比现有的路线更简洁。这些方法的使用越来越频繁 在学术和工业实验室中。在拟议的供资期间，两个主要 提出的目标：（a）II型聚酮化合物的催化方法将是 开发和（B）简化的具有抗癌和抗菌活性的聚酮类似物 将在持续的合作中对财产进行评估。这些研究促进了一个综合的 一个程序，其中方法创新通知合成，合成通知医学 化学.