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

基本信息

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
项目类别：
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

项目摘要

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.

项目概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，无论是在学术界还是制药业环境中。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-碳键通过挤出单一副产品二氧化碳而形成。尽管其广泛应用在药物相关分子的制备、以碳为中心的亲核试剂参与的现有策略 DAA 化学仅限于稳定的烯醇基和相关亲核试剂，其共轭酸 pKa 为小于 25。另一方面，稳定性较差的亲核试剂（共轭酸 pKa > 25）的反应为文献记载较少，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：中间亲核试剂和烯丙基钯物质反应主要产生烯丙基化产物。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缺。为了解决这些限制，我们设计了一种新方法，该方法依赖于芳香族化合物的使用阴离子作为脱羧偶联中稳定和接合其他顽固亲核试剂的手段化学。具体来说，我们最近证明烯丙基酯取代的苯并呋喃类化合物可以有效地在 Pd/Xantphos 催化剂存在下进行烯丙基化，在其中提供各种官能化的苯酞优良的产量。有趣的是，当 Xantphos 被双氨基配体四甲基乙二胺取代时 (TMEDA) 是一种以高区域选择性分离的环丙烷苯酞。目标 1 的目标是显着通过应用我们的最佳 Pd/Xantphos DAA 催化剂来扩展这些初步发现，以获得各种生物学相关的基序，包括功能化异吲哚酮和芴衍生物。或者，目标 2 寻求利用基于 Pd/TMEDA 的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 的目标是阐明其机制烯丙基化与环丙烷化化学的区域选择性的基础，通过结构、动力学和计算研究。该提案的成功实施将显着扩大 Pd 催化脱羧偶联的广度，建立了更广泛的生物活性家族结构主题，同时让本科生参与有影响力且实用的研究工作。