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

项目总结/摘要 过渡金属催化的交叉偶联方法在人类健康的背景下是重要的，因为它们 在小分子治疗剂和分子探针的合成中发挥核心作用。虽然交叉耦合 钯催化是主要的方法，利用地球上丰富的三维 金属（例如镍）能够与极性C-O和亲电体和C-N亲电体交叉偶联。该特征是重要的 因为含O和N的官能团在生物衍生的和生物活性的小分子中是常见的， 因此，可以大大扩大可持续来源的交叉耦合合作伙伴的范围。然而，镍 与酰基C-O和C-N亲电体交叉偶联的催化方法仍处于早期阶段，以及（i） 由于对衬底结构变化的显著敏感性而面临实际限制，（ii）通常需要 高的预催化剂负载量，和（iii）经常利用高的反应温度或长的反应时间。试图 解决这些局限性是由于缺乏详细的机制到负责的功能。这 建议通过对三种不同类别的 镍催化的交叉偶联与生物学上重要的酰基C-O和C-N亲电试剂， （i）C-X活化步骤，（ii）选择性决定特征，（iii）关键有机金属的形态 中间体的这种方法利用配体设计和有机金属合成，结构解析 通过光谱学和晶体学研究以及反应动力学， 计算分析，以深入了解催化剂的反应性和选择性决定特征， 反应.这些见解将被用来阐明关键的反应性和选择性关系， 改进方法，解决目前的效率低下问题。作为早期研究者（ESI），PI是 独特的适合建立这个研究计划，由于他们广泛的工作经验，在整个有机- 无机和合成机械轴，以询问，改进和发明翻译方法 潜力PI的计划将建立在这种专业知识的基础上，提供概念创新，机制驱动， 满足关键合成需求的战略。成功完成拟议的研究将导致详细的 深入了解镍催化的酰基C-N和C-O活化和交叉的机制和限制特征 偶合器.这些见解将转化为一套单组分预催化剂的开发， 提高活性和选择性沿着实用的“催化剂选择用户指南”， 应用于生物学上重要的小分子的合成和加工。这个项目的最终目标 项目领域的目标是实现机制驱动的改进， 地球上丰富的金属，以阐述生物丰富的功能团-到一个水平的竞争，或 上级于已建立的钯催化的交叉偶联替代物。

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.