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

使用后过渡金属氧合催化剂选择性氧化初级 C-H 键

• 批准号: 10555189
• 负责人: Timothy Bartlett Boit
• 金额: $ 6.91万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555189
• 关键词: Acceleration; Alcohols; Architecture; Area; Attention; Binding; Carbon; Chemicals; Complex; Coupling; Derivation procedure; Development; Disparity; Drug Industry; Electronics; Health; Human; Hydrogen Bonding; In Situ; Industry; Kinetics; Ligands; Medicine; Metals; Methodology; Methods; Natural Products; Organic Chemistry; Organometallic Compounds; Oxidants; Oxygen; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Physical condensation; Preparation; Production; Reaction; Research; Role; Route; Series; Site; Structure; Structure-Activity Relationship; Synthesis Chemistry; Technology; Transition Elements; analog; carbene; catalyst; chemical property; chemical synthesis; comparative; drug discovery; electronic structure; forging; functional group; hydroxyl group; improved; innovation; insight; methyl group; next generation; nitrene; novel; oxene; oxidation; prevent; scaffold; small molecule; tool; trend

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.

项目总结/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有机合成方法的发展。 药例如，交叉偶联反应已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途径，并加强了药物发现工作。最近， 用于C-H键的选择性官能化的方法已经得到制药工业的关注 这是由于它们在药物样支架多样化中的潜在用途。为此，金属催化的C-H 利用极性官能团来指导位点选择性C-H活化的官能化反应 已经被广泛地研究过了。相比之下，避免使用预安装的定向组的方法， “无向”C-H官能化反应是不发达的。具体来说，选择性和无方向性 在较弱的C-H键存在下，金属催化的强初级C（sp3）-H键的活化代表了 这是该领域的一个持续挑战。值得注意的是，这些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。虽然方法的无向选择 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）是未知的。 金属稳定的卡宾、氮宾和氧杂环己烯是有用的反应性中间体，其可以插入碳或氧杂环己烯。 杂原子官能团转化为强C（sp3）-H键，具有配体控制的选择性。虽然早中期 第一行过渡金属-氧代配合物已被深入研究，第一行后过渡金属-氧代配合物 尽管它们对于C-H氧化具有潜在的效用，但较少探索LTM-氧代物种。事实上，合成LTM- 氧代络合物代表了利用这些高反应性物质作为有用氧化剂的主要挑战。 拟议的研究旨在开发一种模块化路线，以获得一系列具有新颖结构的LTM-氧代复合物。 空间大体积三蝶烯取代的二吡咯啉配体支架。这种配体结构预计将加强 复合物的动力学稳定性，以促进分离和表征工作。配体支架还将 促进高自旋电子构型，这将削弱M-O键并使络合物 对C（sp3）-H氧化反应性更强。最后，瞬时形成的和空间受阻的 LTM-氧代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方法，催化无定向 初级C（sp3）-H键的氧化。此外，这些研究将提供第一个明确的特征， 的高自旋LTM-氧代配合物，并验证其催化C-H氧化的合成效用。