Selective Oxidation of Primary C-H Bonds Using Late-Transition-Metal-Oxo Catalysts

项目摘要/摘要 有机合成方法学的进步可以深刻地影响新的和有用的开发 药物。例如，交叉偶联反应已经成为药物化学中不可或缺的工具， 提供了进入以前无法进入的化学空间的机会，并加强了药物发现工作。最近， C-H键的选择性官能化方法受到制药行业的重视 由于它们在药物类支架的多样化方面具有潜在的实用价值。为此，金属催化的C-H 利用极性官能团引导C-H位选择性活化的官能化反应 已经得到了广泛的探索。相比之下，避免使用预安装的定向组的方法，或者 “非定向”的C-H官能化反应是不发达的。具体地说，选择性的和非定向的 在存在较弱的C-H键的情况下，金属催化的强的初级C(SP3)-H键的活化代表 这是这一领域正在进行的挑战。值得注意的是，这种技术将为化学家提供有用的合成工具。 在生物活性分子的远程位置安装功能。虽然针对非定向选择的方法 最近出现了甲基的催化官能化以形成C-C、C-B和C-Cl键 未活化的初级C(SP3)-H键的催化氧化(C-O键形成)未知。 金属稳定的卡宾、硝烯和恶烯是有用的活性中间体，可以插入碳或 杂原子官能团转变为具有配体控制选择性的强C(SP3)-H键。虽然早-中- 对第一排过渡金属氧合物进行了深入的研究，第一排后过渡金属氧合物 物种(LTM-oxo)尽管对C-H氧化具有潜在的效用，但被探索得较少。事实上，合成LTM- 氧代络合物是利用这些高活性物种作为有用的氧化剂的主要挑战。 这项拟议的研究旨在开发一种模块化路线，以获得一系列LTM-oxo络合物，该络合物具有一种新颖的 立体大体积的三三烯取代的联苯并吡喃配体支架。这一配体架构预计将强制 络合物的动力学稳定性有助于分离和表征工作。配体支架也将 促进高自旋电子构型，这应该会削弱M-O键并使络合物 对C(SP3)-H氧化反应更活跃。最后，暂态形成和空间受阻的反应性 LTM-oxo络合物将被利用来实现空间上的选择性和非定向催化氧化 不受阻碍的甲基。这种方法论也将适用于选择性后期功能化 与医学相关的支架。这些努力将导致第一个通用的催化不定向方法 初级C(SP3)-H键的氧化。此外，这些研究将提供第一个明确的描述 并验证了它们在催化C-H氧化反应中的合成效用。

Project Summary/Abstract Advances in organic synthetic methodology can profoundly impact the development of new and useful medicines. For example, cross-coupling reactions have become indispensable tools in medicinal chemistry, provided entry to previously inaccessible chemical space, and enhanced drug discovery efforts. Recently, methods for the selective functionalization of C–H bonds have gained attention from the pharmaceutical industry due to their potential utility in the diversification of drug-like scaffolds. Toward this end, metal-catalyzed C–H functionalization reactions that take advantage of polar functional groups to direct site-selective C–H activation have been extensively explored. In comparison, methods that avoid the use of pre-installed directing groups, or “undirected” C–H functionalization reactions, are underdeveloped. Specifically, the selective and undirected metal-catalyzed activation of strong primary C(sp3)–H bonds in the presence of weaker C–H bonds represents an ongoing challenge in the field. Notably, such technologies would provide chemists with useful synthetic tools to install functionality at remote sites on bioactive molecules. Though methods for the undirected selective catalytic functionalization of methyl groups to forge C–C, C–B, and C–Cl bonds have recently emerged, a general catalytic oxidation (C–O bond formation) of unactivated primary C(sp3)–H bonds is unknown. Metal-stabilized carbenes, nitrenes, and oxenes are useful reactive intermediates that can insert carbon or heteroatom functionality into strong C(sp3)–H bonds with ligand-controlled selectivities. Although early- and mid- first-row transition-metal-oxo complexes have been intensively studied, first-row late-transition-metal-oxo species (LTM-oxo) are less explored despite their potential utility for C–H oxidation. Indeed, synthesizing LTM- oxo complexes represents a major challenge toward harnessing these highly reactive species as useful oxidants. The proposed research aims to develop a modular route toward a series of LTM-oxo complexes bearing a novel sterically-bulky triptycene-substituted dipyrrin ligand scaffold. This ligand architecture is expected to enforce kinetic stability of the complexes to facilitate isolation and characterization efforts. The ligand scaffold will also promote high-spin electronic configurations, which should weaken the M–O bond and render the complexes more reactive toward C(sp3)–H oxidation. Finally, the reactivity of transiently-formed and sterically encumbered LTM-oxo complexes will be harnessed to enable the selective and undirected catalytic oxidation of sterically unhindered methyl groups. This methodology will also be applied toward the selective late-stage functionalization of medicinally-relevant scaffolds. These efforts will result in the first general method for the catalytic undirected oxidation of primary C(sp3)–H bonds. Moreover, these studies will provide the first unambiguous characterization of high-spin LTM-oxo complexes and validate their synthetic utility for catalytic C–H oxidation.