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

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: 10202252
• 负责人: JOHN MONTGOMERY
• 金额: $ 44.7万
• 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/10202252
• 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; 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; 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.

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获得生物活性 潜在治疗价值的化合物。将开发一系列新反应，依靠硼 有机氟和有机硅烷底物的催化偶联。依赖于此的糖基化反应 反应性范式将与催化剂设计，机械研究和计算一起开发 评估。强大的方法，可以有效地组装高度的糖苷键 立体控制和广泛的功能组公差将允许访问任何所需的立体化学结果 同时允许平台用于复杂的寡糖组装。新的晚过渡金属 - 利用有机硅硅烷连接有机氟的框架将开发催化过程 使用硼共列分析的底物。氟的远程络合允许离开组的方法 按需激活将作为碳水化合物化学应用的一般策略开发 碳碳键形成方法。遵循上述重点是开发新催化 将采用方法，有效组装糖基结构的方法以提供新的方法 获取新型化学探针和潜在治疗剂的方法。此组件将包括 制定新的策略来获取稀有碳水化合物和立体选择性糖化的策略 肽，天然产物和复杂的合成中间体。自然调整复合物的方法 发生和合成结构将包括现有羟基功能或生物催化的衍生化 未活化的C-H键的功能化。这些功能将成为一系列广泛的基础 合作研究，包括发现新的抗菌和抗癌治疗剂以及新的 化学探针可深入了解各种生物学问题，例如转录机制 宿主和饮食寡糖的激活和酶促降解。合成方法 开发代表了很少合并化学和生物学领域的合并：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 观点允许检查常规方法无法解决的策略。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。