Methods for the Functionalization of C-H Bonds

项目摘要 由于氟化小分子独特的物理化学性质，氟化物是一种 药物化学中最简单和最受欢迎的官能团。例如，氟化物中的氟 生物活性分子提高了亲脂性、生物利用度和氧化稳定性。这使得 药物化学家调整先导化合物的代谢稳定性和生物分布。的主要目标是 建议的研究是开发定向H原子提取作为一种通用的C-H氟化策略 综合。虽然已经为Csp2-H键的官能化开发了广泛的方法，但Csp3- H型债券仍具有挑战性。目前使用贵金属进行C-H活化的常用方法是 仅限于少数在特殊条件下运作的“特权”导演团体。化学反应 本文提出了利用定向氢原子转移来方便地获得Csp3-H键。引起的反应是 建议的化学将补充和扩展当前的C-H激活策略，通过扩展 定向基团相容和靶向Csp3-H键。在这个项目中，铁催化的反应将允许 选择性氟化分子中特定Csp3-H键的一系列导向基团。这一范例将是 用于活化的(目标1)和未活化的(目标2)Csp3-H键的氟化 氟化物起始材料。这些转化将在药物的合成和衍生化中得到应用。 候选、天然产物和生物探针。

Project Abstract Due to the unique physicochemical properties of fluorinated small molecules, fluorides stand as one of the simplest and sought after functional groups in medicinal chemistry. For example, the inclusion of fluorine in biologically active molecules increases the lipophilicity, bioavailability, and oxidative stability. This allows medicinal chemists to tune the metabolic stability and biodistribution of lead compounds. The primary goal of the proposed research is to develop directed H-atom abstraction as a versatile C–H fluorination strategy for synthesis. While extensive methodology has been developed for the functionalization of Csp2–H bonds, Csp3– H bonds remain challenging. The common approach of using noble metals for C–H activation is currently limited to only a few “privileged” directing groups that function under specialized conditions. The chemistry proposed here employs directed H-atom transfer to easily access Csp3–H bonds. The reactions arising from the proposed chemistry will complement and expand current C–H activation strategies through broadened directing-group compatibility and targetable Csp3–H bonds. In this project, iron-catalyzed reactions will allow a range of directing groups to selectively fluorinate specific Csp3–H bonds in a molecule. This paradigm will be employed in the fluorination of activated (Aim 1) and unactivated (Aim 2) Csp3–H bonds using readily available fluoride starting materials. These transformations will find application in the synthesis and derivatization of drug candidates, natural products, and biological probes.