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.

项目摘要对合成工具的不断增长的需求，这些工具扩大了当前可用的化学空间并有效地访问新的生物活性化合物已转移了很大的关注开发产生化学通用多功能氟化的方法手性化合物或以新的方式完成碳氟债券功能化传统化学合成的长期界限。尽管取得了很大进展，但特别是在水力发电上，这些任务仍然很困难，因为深刻氟氟的电子吸引和立体电代效应通常会干扰已建立的与非氟化类似物相比，合成方案和大大改变了反应结果。鉴于等待的易于使用的氟化构件的丰富性和多样性化学修改，克服这些挑战的方法的引入是有望为新的合成工具和可能性的可能性设定阶段当前和未来药物的生产。拟议的研究旨在引入碳氟键激活化学和不对称方法结合了特殊的反应控制，范围和官能团宽容。 C-F债券通常被认为是化学惰性的，将成为战略上有用的可以在轻度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程序，包括晚期功能和立体选择性碳碳键的形成。此外，（有机）催化不对称方法有效产生氟化的结构，表现出一个或两个元素的手性元素，范围很广将引入官能团和药物相关的基序。这些努力将负担得起具有广泛实用程序的多种合成结构池，并迅速响应对高收益的立体变态和肿瘤选择程序的需求不断增加合成和药物化学群落。而重点在于引入新的合成方法和不对称催化开发，机械基础将被充分探索以指导优化努力并刺激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充分的概念验证结果的支持展示如何以目前无法使用的方式准备和利用器官素氟。最后，提出的转化对于合成生物活性化合物的适用性将被证明。