Regiodivergent Palladium-Catalyzed Decarboxylative Coupling of Stabilized Benzylic Nucleophiles

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至关重要的作用 在学术和制药行业环境中的合成。一个特别吸引人的工具是 钯催化的脱羧烯丙基烷基化(DAA)反应，促进碳-碳键 通过挤出单一的副产品二氧化碳而形成。尽管它广泛应用于 制备与医学相关的分子，现有的策略使以碳为中心的亲核分子 DAA化学仅限于稳定的烯醇基和相关的亲核剂，其共轭酸pKA为 不到25人。另一方面，较不稳定的亲核试剂(~gt；25的共轭酸pKa)的反应为 较少的文献记载，部分原因是与促进其脱羧基有关的能量障碍。 此外，大多数Pd催化的脱羧偶联都是通过一种机制进行的，在这种机制中 中间亲核试剂和烯丙基钯物种主要反应生成烯丙化产物。在……里面 相比之下，详细说明区域异构体环丙烷化产物形成的报道仍然相对较多。 少之又少。为了解决这些限制，我们设计了一种依赖于芳香族化合物使用的新方法 阴离子作为稳定和吸引其他顽固亲核分子进行脱羧基偶联的手段 化学反应。具体地说，我们最近证明了烯丙基酯取代的邻苯二甲酸酯经历了有效的 在Pd/Xantphos催化剂存在下的烯丙化反应，提供了多种功能化的邻苯二甲酸酯 产量极高。有趣的是，当黄磷被双氨基配体四甲基乙二胺取代时 (TMEDA)，以较高的区域选择性分离了一种环丙烷化邻苯二甲酸酯。目标1的目标是显著地 通过应用我们最优的Pd/Xantphos DAA催化剂来获取各种 生物相关的基序，包括官能化的异吲哚和荧衍生物。或者， 目标2旨在开发反应性Pd/TMEDA催化剂以开发一种通用脱羧剂 苯基亲核试剂的环丙烷化反应。最后，目标3的目标是阐明 烯丙化与环丙烷化化学的区域选择性基础通过结构、动力学和 计算研究。这项提议的成功实施构成了对 钯催化的脱羧偶联的广度，建立了获得更广泛的生物活性家族的途径 结构主题，同时让本科生参与有影响力但实际的研究努力。

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.