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，扩大了目前可用的化学空间 并提供新的生物活性化合物的有效途径， 致力于开发生产化学通用的多官能氟化的方法， 手性化合物或以新的方式实现碳-氟键官能化， 传统化学合成的长期边界。尽管取得了相当大的进展， 特别是在加氢脱氟方面，这些任务仍然相当困难，因为 氟的吸电子和立体电子效应经常干扰已建立的 合成方案，并显着改变反应结果相比，非氟化类似物。 考虑到现有氟化结构单元的丰富性和多样性， 化学修饰，引入克服这些挑战的方法， 预计将为新的合成工具和可能性奠定基础， 生产当前和未来的药物。 拟议的研究旨在介绍碳-氟键活化化学， 结合了联合收割机特殊反应控制、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键将成为战略上有用的键。 可以在温和的反应条件下选择性活化的实体，这将打开通往 各种前所未有的应用，包括后期官能化和立体选择性 碳-碳键形成。此外，（有机）催化不对称方法，有效地 制备显示一种或两种手性元素的氟化结构， 将引入官能团和药学相关的基序。这些努力将使 一个多样化的综合通用结构池，具有广泛的实用性，并迅速响应 对高产量立体分散和atroposelective程序的需求日益增加， 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，将充分探索机制基础，以指导优化 这是一个巨大的挑战，并鼓励其他研究小组进行类似的努力和发现。总 可行性和相应的前景得到了大量概念验证结果的支持， 显示了有机氟如何以目前不可能的方式制备和利用。最后， 拟定转化用于合成生物活性化合物的适用性 将被证明。

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.