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.

项目概要/摘要 有机合成方法的进步可以深刻影响新的和有用的产品的开发 药物。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机会，并加强了药物发现工作。最近， C-H键选择性功能化的方法引起了制药行业的关注 由于它们在类药物支架多样化方面的潜在用途。为此，金属催化的C-H 利用极性官能团直接进行位点选择性 C–H 激活的官能化反应 已被广泛探索。相比之下，避免使用预装指导组的方法，或 “非定向”C-H 官能化反应尚不发达。具体来说，选择性的和无向的 在较弱的 C-H 键存在下，金属催化强伯 C(sp3)-H 键的活化代表 该领域持续存在的挑战。值得注意的是，此类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。尽管无向选择性的方法 最近出现了甲基基团的催化功能化以形成 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）尚不清楚。 金属稳定的卡宾、氮宾和氧烯是有用的反应中间体，可以插入碳或 杂原子官能团形成具有配体控制选择性的强 C(sp3)–H 键。虽然早中期 第一行过渡金属氧配合物已得到深入研究，第一行后过渡金属氧配合物 尽管 LTM-oxo 具有 C-H 氧化的潜在用途，但对其研究较少。事实上，合成LTM- 氧配合物代表了利用这些高活性物质作为有用氧化剂的重大挑战。 拟议的研究旨在开发一种模块化路线，用于一系列具有新颖特征的 LTM-oxo 复合物 空间庞大的三蝶烯取代的二吡啉配体支架。这种配体架构预计将强制执行 复合物的动力学稳定性，以促进分离和表征工作。配体支架也将 促进高自旋电子构型，这会削弱 M-O 键并使配合物 对 C(sp3)–H 氧化更具反应性。最后，瞬时形成和空间阻碍的反应性 LTM-氧代配合物将用于实现空间选择性和非定向催化氧化 不受阻碍的甲基。该方法也将应用于选择性后期功能化 医学相关支架。这些努力将产生第一个催化无向催化的通用方法。 伯C(sp3)–H键的氧化。此外，这些研究将提供第一个明确的特征 高自旋LTM-氧配合物的合成并验证其催化C-H氧化的合成效用。