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: 10610494
• 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/10610494
• 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; Derivation procedure; Development; Elements; Evaluation; Fluorine; Foundations; 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.

项目总结/摘要 快速可靠地获取合成衍生的化学结构在许多方面都起着至关重要的作用 生物医学研究。这项建议的基本目标是提供根本性的新战略， 高选择性键合形成将使得能够更快速和有效地获得生物活性物质， 具有潜在治疗价值的化合物。一系列新的反应将被开发出来，这些反应依赖于硼- 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、机理研究和计算方法相结合， 评价能够有效组装具有高度糖苷键的稳健方法 立体控制和宽官能团耐受性将允许获得任何期望的立体化学结果 同时允许用于复杂寡糖的迭代组装的平台。新型后过渡金属- 将利用有机氟与有机硅烷连接的框架开发催化过程 使用硼共催化的基质。其中氟的远程络合允许离去基团 按需激活将被开发为碳水化合物化学和生物化学中应用的一般策略。 碳-碳键形成方法。继上述重点开发新型催化剂 将寻求糖基化结构的有效组装的方法， 获得新的化学探针和潜在的治疗剂的方法。这一部分将包括 开发获取稀有碳水化合物和立体选择性糖多样化的新策略， 多肽、天然产物和复杂的合成中间体。自然裁剪复杂的方法 存在和合成的结构将包括现有羟基官能团的衍生化或生物催化的 未活化的C-H键的官能化。这些功能将成为广泛的 合作研究，包括发现新的抗微生物和抗癌治疗剂， 化学探针，以提供洞察各种生物学问题，如转录机制， 宿主和膳食寡糖的活化和酶促降解。综合方法 它代表了化学和生物学领域的融合：主族元素 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 透视允许检查无法通过常规方法解决的策略。的 这项研究使生物医学重要结构的改进条目成为可能， 功能和治疗潜力进行更有效的研究。