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Asymmetric Catalysis and Selective C-F Bond Functionalization with Organofluorines

有机氟的不对称催化和选择性 C-F 键官能化

基本信息

批准号：
10729601
负责人：
Christian Wolf
金额：
$ 45.87万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-10 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729601
关键词：
Address Alkenes Alkylation Aluminum Attention Biological Availability Carbon Catalysis Chemicals Chemistry Communities Community Medicine Complement Coumarins Coupled Coupling Development Educational Status Electrons Elements Exhibits Fluorides Fluorine Future Health Care Sector Health Sciences High School Student In Situ Investigation Metabolic Methodology Methods Modernization Modification Outcome Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Play Procedures Production Property Protocols documentation Reaction Research Resistance Role Science Scientist Side Stereoisomer Structure Synthesis Chemistry Thermodynamics Time Transition Elements analog chemical synthesis cryogenics drug discovery drug synthesis functional group graduate student innovation insight interest lipophilicity method development next generation oxindole pharmacologic pharmacophore scaffold tool undergraduate student

项目摘要

PROJECT ABSTRACT The ever-increasing demand for synthetic tools that expand currently available chemical space and provide efficient access to new biologically active compounds has shifted significant attention toward the development of methods that produce chemically versatile multifunctional fluorinated chiral compounds or accomplish carbon-fluorine bond functionalization in new ways that remove long-standing boundaries of traditional chemical synthesis. Despite considerable progress, in particular with hydrodefluorinations, these tasks remain quite difficult because the profound electron-withdrawing and stereoelectronic effects of fluorine often interfere with established synthetic protocols and dramatically alter reaction outcomes compared to nonfluorinated analogs. Given the abundance and diversity of readily available fluorinated building blocks that await chemical modification, the introduction of methodologies that overcome these challenges are expected to set the stage for new synthetic tools and possibilities that streamline or enable the production of current and future drugs. The proposed research aims to introduce carbon-fluorine bond activation chemistry and asymmetric methods that combine exceptional reaction control, scope and functional group tolerance. The C-F bond, typically considered chemically inert, will become a strategically useful entity that can be selectively activated under mild reaction conditions which will open the door to a variety of unprecedented applications including late-stage functionalization and stereoselective carbon-carbon bond formation. In addition, (organo)catalytic asymmetric methods that efficiently produce fluorinated structures exhibiting one or two elements of chirality, a wide range of functional groups, and pharmaceutically relevant motifs will be introduced. These efforts will afford a diverse pool of synthetically versatile structures with broad utility and respond to the rapidly increasing demand for high-yielding stereodivergent and atroposelective procedures among the synthetic and medicinal chemistry communities. While emphasis lies on the introduction of new synthetic methodologies and asymmetric catalysis development, the mechanistic underpinnings will be fully explored to guide optimization efforts and to stimulate similar efforts and discoveries in other research groups. The general feasibility and the corresponding prospects are supported by ample proof-of-concept results that show how organofluorines can be prepared and utilized in currently not possible ways. Finally, the suitability of the proposed transformations for the synthesis of biologically active compounds will be demonstrated.

项目摘要对扩大现有化学空间的合成工具的需求不断增长并有效获取新的生物活性化合物已引起人们的广泛关注致力于开发生产化学上通用的多功能氟化物的方法手性化合物或以新的方式实现碳-氟键功能化，消除传统化学合成的长期界限。尽管取得了相当大的进步，特别是加氢脱氟，这些任务仍然相当困难，因为氟的吸电子效应和立体电子效应经常干扰已建立的与非氟化类似物相比，合成方案并显着改变反应结果。鉴于现成的氟化建筑材料的丰富性和多样性，等待着化学修饰，克服这些挑战的方法的引入是预计将为新的合成工具和简化或启用的可能性奠定基础当前和未来药物的生产。拟议的研究旨在介绍碳-氟键活化化学和结合了特殊反应控制、范围和官能团的不对称方法宽容。通常被认为具有化学惰性的 C-F 键将成为一种战略上有用的键可以在温和反应条件下选择性激活的实体，这将为各种前所未有的应用，包括后期功能化和立体选择性碳-碳键的形成。此外，（有机）催化不对称方法可以有效地产生具有一种或两种手性元素的氟化结构，范围广泛将介绍官能团和药学相关基序。这些努力将提供具有广泛实用性并能快速响应的多种合成多功能结构对高产立体分歧和天体选择性程序的需求不断增加合成和药物化学社区。虽然重点在于引入新的合成方法和不对称催化发展，充分挖掘机理基础，指导优化努力并激发其他研究小组的类似努力和发现。将军可行性和相应的前景得到了充足的概念验证结果的支持，展示如何以目前不可能的方式制备和利用有机氟。最后，所提出的转化对于合成生物活性化合物的适用性将被证明。