Supplement: Regio- and Site-Selective Processes Using Main Group and Transition Metal Catalysis

补充：使用主族和过渡金属催化的区域和位点选择性过程

• 批准号: 10388498
• 负责人: JOHN MONTGOMERY
• 金额: $ 6.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388498
• 关键词: Address; Biological; Biological Process; Biological Response Modifier Therapy; Biology; Biomedical Research; Boron; Carbohydrate Chemistry; Carbohydrates; Carbon; Catalysis; Chemical Structure; Chemicals; Chemistry; Complex; Coupling; Development; Elements; Evaluation; Fluorine; Foundations; Glycosides; Goals; High Pressure Liquid Chromatography; Hydrogen Bonding; Hydroxyl Radical; Methodology; Methods; Natural Products; Oligosaccharides; Outcome; Peptides; Play; Preparation; Process; Property; Reaction; Research; Role; Site; Speed; Structure; Therapeutic; Therapeutic Agents; Transcriptional Activation; Transition Elements; anti-cancer therapeutic; antimicrobial; catalyst; cost; design; dietary; functional group; glycosylation; improved; insight; instrument; interdisciplinary approach; multidisciplinary; novel

Project Summary / Abstract Rapid and reliable access to synthetically-derived chemical structures plays an essential role in many aspects of biomedical research. The underlying objective of this proposal is to provide fundamentally new strategies for highly selective bond formations that will enable more rapid and efficient access to biologically active compounds of potential therapeutic value. A suite of new reactions will be developed that rely on the boron-catalyzed coupling of organofluorine and organosilane substrates. Glycosylation reactions that rely on this reactivity paradigm will be developed in concert with catalyst design, mechanistic study, and computational evaluation. Robust methods that enable efficient assembly of glycosidic bonds with high degrees of stereocontrol and broad functional group tolerance will allow access to any desired stereochemical outcome while allowing a platform for iterative assembly of complex oligosaccharides. New late transition metal-catalyzed processes will be developed utilizing the framework of connecting organofluorine with organosilane substrates using boron co-catalysis. Methods where remote complexation of fluorine allows leaving groups to be activated on demand will developed as a general strategy for applications in carbohydrate chemistry and in carbon-carbon bond-forming methodology. Following the above focus on the development of new catalytic methods, approaches to the efficient assembly of glycosylated structures will be pursued to provide new methods for accessing novel chemical probes and potential therapeutic agents. This component will include developing new strategies for accessing rare carbohydrates and for the stereoselective glycodiversification of peptides, natural products, and complex synthetic intermediates. Methods for tailoring complex naturally occurring and synthetic structures will include derivatization of existing hydroxyl functionality or biocatalytic functionalization of unactivated C-H bonds. These capabilities will serve as a foundation for a broad array of collaborative studies including the discovery of new antimicrobial and anticancer therapeutic agents and new chemical probes to provide insight into diverse biological questions such as mechanisms of transcriptional activation and enzymatic degradation of host and dietary oligosaccharides. The synthetic approaches developed represent a merger of rarely combined fields of chemistry and biology: main group element catalysis, transition metal catalysis, carbohydrate chemistry, and biocatalysis. The unique multidisciplinary perspective allows examination of strategies that cannot be addressed by conventional approaches. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied.

项目摘要 /摘要 快速可靠地获得合成的化学结构在许多方面起着至关重要的作用 生物医学研究。该提案的基本目标是为从根本上提供新的策略 高度选择性的粘结形成将使能够更快有效地进入生物活性化合物 潜在的治疗价值。将开发一套新反应，依靠硼催化的耦合 有机氟和有机硅烷底物的。依赖于这种反应性范式的糖基化反应将 与催化剂设计，机械研究和计算评估一起开发。强大的方法 这样可以有效地组装糖苷键，并具有高度的立体控制和广泛的官能团 耐受性将允许访问任何所需的立体化学结果，同时允许迭代平台 复杂寡糖的组装。新的晚期过渡金属催化过程将利用 使用硼共催化的有机硅烷基板将有机氟氨酸连接起来的框架。方法 如果氟的远程络合允许按需激活小组作为一个 碳水化合物化学和碳碳键形成方法中应用的一般策略。 遵循上述侧重于开发新催化方法，采用有效组装的方法 将追求糖基化结构的糖基结构，以提供新的化学探针和 潜在的治疗剂。该组件将包括制定访问稀有的新策略 碳水化合物和用于肽，天然产物和复合物的立体选择性糖脂变化 合成中间体。定制复杂自然发生和合成结构的方法将包括 现有的羟基功能或未激活C-H键的生物催化功能化的衍生化。这些 能力将成为广泛协作研究的基础，包括发现新的 抗菌和抗癌治疗剂和新的化学探针，以洞悉多种多样 生物学问题，例如宿主的转录激活机制和酶促降解和 饮食寡糖。开发的合成方法代表了很少合并的领域的合并 化学和生物学：主要组元素催化，过渡金属催化，碳水化合物化学和 生物催化。独特的多学科观点允许检查无法解决的策略 通过常规方法。改进的生物医学重要结构的参赛作品使这可能成为可能 研究将使他们的生物学功能和治疗潜力更有效地研究。这 这项研究改善了生物医学重要的结构，这将使他们的生物学能够 功能和治疗潜力更有效地研究。