Mechanistic Insights into Catalytic Acyl C-O and C-N Activation and Cross Coupling

催化酰基 C-O 和 C-N 活化及交叉偶联的机理见解

• 批准号: 10713753
• 负责人: Caitlyn Rose Kennedy
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713753
• 关键词: 3-Dimensional; Address; Amides; Area; Benign; Catalysis; Computer Analysis; Coupling; Crystallography; Development; Environment; Esters; Face; Goals; Health; Human; Investigation; Kinetics; Ligands; Metals; Methodology; Methods; Mission; Molecular Probes; Nickel; Palladium; Pharmaceutical Preparations; Play; Public Health; Reaction; Reaction Time; Research; Research Personnel; Role; Source; Structure; Temperature; Transition Elements; Translating; United States National Institutes of Health; catalyst; design; experience; functional group; human disease; improved; innovation; insight; invention; next generation; programs; small molecule; small molecule therapeutics; tool; translational potential

PROJECT SUMMARY/ABSTRACT Transition metal-catalyzed cross-coupling methods are important in the context of human health because they play a central role in the synthesis of small-molecule therapeutics and molecular probes. Although cross-coupling methodologies are dominated by palladium catalysis, newer methodologies utilizing terrestrially abundant 3d metals (such as nickel) enable cross-coupling with polar C–O and C–N electrophiles. This feature is important because O- and N-containing functional groups are common in bioderived and bioactive small molecules and could therefore offer a greatly expanded scope of sustainably sourced cross-coupling partners. However, nickel catalyzed methodologies for cross-coupling with acyl C–O and C–N electrophiles remain in early stages, and (i) face practical limitations due to a pronounced sensitivity to changes in substrate structure, (ii) generally require high precatalyst loadings, and (iii) often utilize high reaction temperatures or long reaction times. Attempts to address these limitations are stymied by a lack of detailed mechanistic into the features responsible. This proposal addresses these ambiguities through systematic mechanistic investigation of three distinct classes of nickel-catalyzed cross-coupling with biologically important acyl C–O and C–N electrophiles with a specific focus on (i) C–X activation steps, (ii) selectivity-determining features, and (iii) speciation of key organometallic intermediates. This approach leverages ligand design and organometallic synthesis, structure elucidation through spectroscopic and crystallographic studies, and reaction kinetics, supported by state-of-the-art computational analysis to derive insights into the reactivity and selectivity-determining features of catalytic reactions. These insights will be leveraged to elucidate key reactivity and selectivity relationships and to offer methodological improvements that address current inefficiencies. As an Early-Stage Investigator (ESI), the PI is uniquely suited to build this research program due to their extensive prior experience working across the organic– inorganic and synthetic–mechanistic axes to interrogate, improve, and invent methodologies with translational potential. The PI’s program will build on this expertise to offer conceptually innovative, mechanism-driven, strategies to meet key synthetic needs. Successful completion of the proposed research will result in detailed insight into the mechanisms and limiting features of nickel-catalyzed acyl C–N and C–O activation and cross coupling. These insights will be translated into development of a suite of single-component precatalysts with enhanced activity and selectivity along with a practical “user’s guide to catalyst selection” to enable expanded application to the synthesis and elaboration of biologically important small molecules. The ultimate goal of this project area is to achieve mechanism-driven improvements bringing these methodologies—which use terrestrially abundant metals to elaborate biologically abundant functional groups—to a level competitive with or superior to established, palladium-catalyzed cross-coupling alternatives.

项目摘要/摘要 过渡金属催化的交叉耦合方法在人类健康的背景下很重要，因为它们 在小分子疗法和分子问题的合成中起着核心作用。虽然交叉耦合 方法以钯催化为主，较新的方法利用陆层丰富的3D 金属（例如镍）可以与极性C – O和C – N电力物进行交叉耦合。此功能很重要 因为在生物调节和生物活性的小分子中常见含O和N的官能团，并且 因此，可以提供大大扩展的可持续采购的交叉耦合伙伴的范围。但是，镍 与酰基C – O和C – N亲电的交叉偶联的催化方法保留在早期阶段，（i） 由于对底物结构变化的明显敏感性而面临实际限制，（ii）通常需要 高催化剂载荷，（iii）通常会使用高反应温度或较长的反应时间。尝试 解决这些局限性因缺乏详细的机制而受到阻碍。 提案通过三个不同类别的系统机械投资解决这些歧义 与具有特定焦点的生物学上重要的酰基C – O和C – N电力的镍催化的交叉偶联 在（i）C – x激活步骤，（ii）选择性确定的特征和（iii）关键有机物的规范 中间人。这种方法利用配体设计和有机合成，结构阐明 通过光谱学和晶体学研究以及反应动力学，由最新的 计算分析以洞悉催化性的反应性和选择性确定特征 反应。这些见解将被利用以阐明关键的反应性和选择性关系，并提供 解决当前效率低下的方法学改进。作为早期研究员（ESI），PI是 非常适合构建该研究计划，因为它们在有机遍布的经验丰富的经验 无机和合成机械轴以转化的质疑，改进和发明方法 潜在的。 PI的计划将以这一专家为基础，以提供概念上的创新，机制驱动的， 满足关键合成需求的策略。成功完成拟议的研究将详细介绍 深入了解镍催化的酰基C – N和C – O激活的机理和限制特征 耦合。这些见解将转化为与单一组件预催化剂的开发 增强的活动和选择性以及实用的“催化剂选择指南”，以促进扩展 应用于生物学上重要的小分子的合成和阐述。最终目标 项目领域是为了实现机构驱动的改进，带来了这些方法 陆层丰富的金属以详细培训生物学丰富的功能组，以与或 优于已建立的，钯催化的交叉偶联替代方案。