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着关键作用 合成，无论是在学术和制药行业的设置。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，其促进碳-碳键 通过挤出单一的副产物二氧化碳来形成。尽管它在世界上有着广泛的应用， 医药相关分子的制备，现有的策略，使碳中心的亲核试剂， DAA化学仅限于稳定的基于烯醇化物的亲核试剂和相关的亲核试剂，其共轭酸pKa为 少于25。另一方面，较不稳定的亲核试剂（共轭酸pKa> 25）的反应是 文献记载较少，部分原因是与促进其脱羧相关的能量障碍。 此外，大多数Pd催化的脱羧偶联通过以下机制进行： 中间体亲核试剂和烯丙基钯物质反应以主要提供烯丙基化产物。在 相比之下，详细描述区域异构环丙烷化产物形成的报道仍然相对较少。 稀少。为了解决这些局限性，我们设计了一种新的方法， 阴离子在脱羧偶联中作为稳定和与其它不稳定亲核试剂结合的手段 化学.具体来说，我们最近证明，烯丙基酯取代的苯酞进行有效的 在Pd/Xantphos催化剂的存在下进行烯丙基化，从而以 很好的产量。有趣的是，当Xantphos被双氨基配体四甲基乙二胺取代时， （TMEDA），以高区域选择性分离环丙烷化苯酞。目标1的目标是， 通过应用我们的最佳Pd/Xantphos DAA催化剂来扩展这些初步发现， 生物学相关的基序，包括官能化的异吲哚啉酮和芴衍生物。可选择地， 目标2旨在利用Pd/TMEDA基催化剂的反应性来开发通用脱羧剂 基于苯酞的亲核试剂的环丙烷化。最后，目标3的目标是阐明 通过结构、动力学和化学方法研究烯丙基化与环丙烷化化学的区域选择性基础 计算研究。这一建议的成功实施， Pd催化脱羧偶联的广度，建立了更广泛的生物活性 结构的主题，同时从事有影响力的，但实际的研究工作的本科生。