Asymmetric Catalysis and Selective C-F Bond Functionalization with Organofluorines

项目摘要 对合成工具不断增长的需求，这些工具扩大了目前可用的化学空间 并提供有效获取新的生物活性化合物的途径已引起人们的极大关注 朝着生产化学上通用的多功能氟化物的方法的发展 手性化合物或以新的方式完成碳-氟键官能化 传统化学合成的边界由来已久。尽管取得了相当大的进展，但在 尤其是氢脱氟，这些任务仍然相当困难，因为深刻的 氟的电子抽离和立体电子效应经常干扰已建立的 与非氟化类似物相比，合成方案和显著改变了反应结果。 考虑到等待着的现成氟化建筑材料的丰富性和多样性 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可能性奠定基础，从而简化或使 生产当前和未来的药物。 拟议的研究旨在引入碳-氟键活化化学和 结合特殊反应控制、范围和官能团的不对称方法 宽容。通常被认为是化学惰性的C-F键将成为一种战略上有用的 可以在温和的反应条件下选择性地激活的实体，这将打开 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，高效的(有机)催化不对称方法 生产具有一种或两种手性元素的氟化结构，范围广泛 将介绍官能团和与药物相关的主题。这些努力将负担得起 具有广泛实用性和快速响应的综合多功能结构的多样化池 越来越多的人对高产量的立体定向手术和非选择性手术的需求 合成化学和药物化学社区。 而重点在于引入新的合成方法和不对称 催化开发，将充分挖掘机理基础，指导优化 并鼓励其他研究小组进行类似的努力和发现。这位将军 充分的概念验证结果支持了可行性和相应的前景 展示如何以目前不可能的方式制备和利用有机氟。最后， 所提出的转化方法对合成生物活性化合物的适用性 将会被证明。

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.