Regiodivergent Palladium-Catalyzed Decarboxylative Coupling of Stabilized Benzylic Nucleophiles

稳定的苄基亲核试剂的区域发散钯催化脱羧偶联

• 批准号: 10731034
• 负责人: Raul Navarro
• 金额: $ 34.18万
• 依托单位: OCCIDENTAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731034
• 关键词: Acids; Address; Alkylation; Anions; Carbon; Carbon Dioxide; Chemicals; Chemistry; Coupling; Data; Decarboxylation; Development; Drug Industry; Esters; Family; Fluorenes; Goals; Health; Human; Investigation; Kinetics; Ligand Binding; Ligands; Mediating; Medicine; Metals; Methods; Modernization; Organic Chemistry; Palladium; Pathway interactions; Pharmacologic Substance; Play; Preparation; Prevalence; Reaction; Reagent; Reporting; Research; Role; System; Transition Elements; Work; bioactive natural products; catalyst; computer studies; cyclopropane; drug development; enolate; forging; improved; novel strategies; pharmacophore; small molecule; success; tool; undergraduate student

Project Summary Transition metal-catalyzed carbon-carbon bond formation plays a critical role in bioactive small molecule synthesis, both in academic and pharmaceutical industry settings. A particularly attractive tool is the palladium-catalyzed decarboxylative allylic alkylation (DAA) reaction, which facilitates carbon-carbon bond formation via the extrusion of a single byproduct, carbon dioxide. Despite its extensive applications in the preparation of medicinally relevant molecules, existing strategies to engage carbon-centered nucleophiles in DAA chemistry is limited to stabilized enolate-based and related nucleophiles whose conjugate acid pKa is less than 25. On the other hand, the reaction of less stabilized nucleophiles (conjugate acid pKa of > 25) is less well documented, in part due the energetic barriers associated with promoting their decarboxylation. Additionally, the majority of Pd-catalyzed decarboxylative couplings proceed through a mechanism in which the intermediate nucleophile and allylpalladium species react to predominantly deliver allylation products. In contrast, reports that detail the formation of the regioisomeric cyclopropanation product remain relatively scarce. To address these limitations, we have devised a new approach that relies on the use of aromatic anions as a means to stabilize and engage otherwise recalcitrant nucleophiles in decarboxylative coupling chemistry. Specifically, we recently demonstrated that allyl ester-substituted phthalides undergo efficient allylation in the presence of a Pd/Xantphos catalyst, delivering a variety of functionalized phthalides in excellent yield. Interestingly, when Xantphos is replaced with the bisamino ligand tetramethylethylenediamine (TMEDA), a cyclopropanated phthalide is isolated in high regioselectivity. The goal of Aim 1 is to significantly expand on these preliminary findings by applying our optimal Pd/Xantphos DAA catalyst to access a variety of biologically relevant motifs, including functionalized isoindolinone and fluorene derivatives. Alternatively, Aim 2 seeks to exploit the reactivity Pd/TMEDA-based catalyst to develop a general decarboxylative cyclopropanation of phthalide-based nucleophiles. Finally, the goal of Aim 3 is to elucidate the mechanistic basis of the regioselectivity for allylation versus cyclopropanation chemistry via structural, kinetic, and computational studies. The successful implementation of this proposal constitutes a significant expansion of the breadth of Pd-catalyzed decarboxylative coupling, establishing access to a wider family of bioactive structural motifs while engaging undergraduates in impactful yet practical research endeavors.

项目摘要 过渡金属催化的碳碳键形成在生物活性小分子中起关键作用 在学术和制药行业环境中的合成。一个特别有吸引力的工具是 钯催化的脱羧烯丙基烷基化（DAA）反应，促进碳碳键 通过挤出单个副产品二氧化碳形成。尽管在 制备药物相关的分子，现有的策略，使以碳为中心的亲核试剂参与 DAA化学仅限于稳定基于烯醇的和相关的亲核试剂，其结合酸PKA为 另一方面，少于25。 不太有记录的部分，部分原因是与促进其脱羧相关的能量障碍。 另外，大多数PD催化的脱羧耦合通过一种机制进行 中间的亲核试剂和烯丙基丙酰亚胺物种对主要传递烯丙基化产物反应。在 对比，报道了详细介绍区域异构环丙谁的形成相对较高的 稀缺。为了解决这些限制，我们设计了一种依赖于芳香的新方法 阴离子作为稳定和参与的一种手段 化学。具体而言，我们最近证明了烯丙基酯取代的邻苯二甲酸酯会有效 在存在PD/Xantphos催化剂的情况下，烯丙基化在 出色的产量。有趣的是，当Xantphos用二氨基配体四甲基甲基二胺代替时 （TMedA），在高区域选择性中分离了环丙烷的邻苯二甲酸酯。目标1的目标是显着 通过应用我们的最佳PD/Xantphos DAA催化剂来访问各种各样的初步发现 生物学相关的基序，包括功能化的异丁酮和氟衍生物。或者， AIM 2试图利用基于PD/TMEDA的反应性催化剂来开发一般的脱羧 基于邻苯二甲酰的亲核试剂的环丙烷化。最后，目标3的目标是阐明机械 通过结构，动力学和 计算研究。该提案的成功实施构成了重大扩张 PD催化的脱羧耦合的广度，建立了更广泛的生物活性系列 结构性图案在吸引有影响力但实用的研究工作的同时。