Asymmetric Nucleophilic Aromatic Substitution Enabled by Hydrogen-Bonding Catalysis

氢键催化实现不对称亲核芳香取代

• 批准号: 9907565
• 负责人: Gabriel J Lovinger
• 金额: $ 6.46万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-10 至 2023-01-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907565
• 关键词: Address; Affinity; Aniline; Area; Binding; Biological; Biological Testing; Catalysis; Centenarian; Chemical Structure; Chemicals; Complex; Computer Models; Coupling; Data; Development; Electrons; Elements; Enzymes; Goals; Grant; Health; High temperature of physical object; Human; Hydrogen Bonding; Knowledge; Libraries; Light; Measures; Medicine; Methodology; Methods; Modernization; Molecular; National Institute of General Medical Sciences; Nature; Organic Synthesis; Outcome; Pharmaceutical Chemistry; Pharmacologic Substance; Phenols; Pollution; Preparation; Production; Reaction; Reagent; Research; Site; Structure; Structure-Activity Relationship; Surface; Surveys; System; Techniques; Titrations; Transition Elements; Validation; Work; aryl halide; catalyst; cost; design; enantiomer; enolate; functional group; improved; inorganic phosphate; insight; novel; novel strategies; scaffold; small molecule; success; therapeutic target; trend; wasting

Project Summary/Abstract: Asymmetric Nucleophilic Aromatic Substitution Enabled by Hydrogen-Bonding Catalysis Nucleophilic aromatic substitution (SNAr) is one of the most broadly utilized reactions in pharmaceutical and medicinal chemistry, allowing access to aromatic and heterocyclic molecules. Despite its enormous importance, the scope of this reaction class remains constrained by its intrinsic mechanistic features. As a result, the diversity of structures that can be explored in medicinal chemistry research using SNAr is relatively limited. Existing methods suffer from several limitations: 1) reliance on harsh reaction conditions and powerful stoichiometric reagents, which limits functional group compatibility, 2) required use of aryl substrates with strongly electron withdrawing groups, which inherently restricts the scope of accessible products, 3) reliance on aryl electrophiles with halide leaving groups, precluding the use of inexpensive phenol, anisole, and aniline feedstock chemicals and producing large quantities of halogenated waste. Alternative cross coupling approaches often rely on expensive transition metal catalysts that must be removed assiduously before biological testing. The use of SNAr to generate medicinally valuable enantioenriched structures is largely unexplored. An attractive new approach would be to use an organocatalyst to promote an asymmetric SNAr reaction in which tertiary or even quaternary enantioenriched stereocenters might be generated by coupling unactivated aryl electrophiles and prochiral nucleophiles such as enolates. This approach would address each of the previously mentioned key limitations. Hydrogen-bond donor (HBD) organocatalysts are known to activate neutral organic molecules via leaving group binding while also controlling the stereochemical outcome of nucleophilic trapping of these species. By leveraging the powerful transition state stabilization and synergistic dual nucleophilic and electrophilic activation capabilities unique to HBD catalysts, this approach should enable previously unfeasible SNAr reactions to be accomplished with exquisite site- and enantioselectivity. The goal of this proposal is to design a leaving group binding organocatalyst that will catalyze the first general and synthetically useful asymmetric SNAr reaction capable of merging unactivated aryl electrophiles and prochiral nucleophiles. The research plan outlines a strategy to develop such a catalyst system guided by hypothesis-driven experimentation, computational modeling, and structure-activity studies. To add to the information gained in the reaction development, a detailed mechanistic study of HBD organocatalyst activation of simple aryl electrophiles such as anisole, analine, and phenol derivatives, as well as more traditional aryl halides will be undertaken using data-intensive multi-dimensional correlation. This study will enable simple and inexpensive bench-stable feedstock aryl electrophiles to be utilized to produce medicinally relevant enantioenriched compounds in a novel manner and will have enormous importance to medicinal research and catalyst development, substantially contributing to scientific knowledge.

项目摘要/摘要：氢键实现的不对称亲核芳香族取代 催化作用 亲核芳香族取代反应(SNAR)是医药和化工领域应用最广泛的反应之一。 药物化学，允许获得芳香族和杂环分子。尽管它非常重要，但 这个反应类的范围仍然受到其内在机理特征的限制。因此，物种的多样性 使用SNAR在药物化学研究中可以探索的结构相对有限。现有方法 受到几个限制：1)依赖苛刻的反应条件和强大的化学计量试剂，这 限制官能团的兼容性，2)需要使用具有强吸电子基团的芳基底物， 这固有地限制了可获得产品的范围，3)依赖于卤化物离开的芳基亲电化合物 禁止使用廉价的苯酚、苯甲醚和苯胺类原料化学品，并生产大量 大量的卤化废物。另一种交叉耦合方法通常依赖昂贵的过渡金属 在进行生物测试之前必须认真移除的催化剂。SNAR在医药生产中的应用 有价值的富含对映体的结构在很大程度上还没有被探索。 一种有吸引力的新方法是使用有机催化剂来促进不对称Snar反应，在该反应中 通过偶联未活化的芳基，可以生成三级甚至四级对映体富集型立体中心 亲电性和亲手性亲核剂，如烯醇酸盐。这种方法将解决以前的每一个 提到了关键限制。 氢键供体(HBD)有机催化剂通过离开基团来激活中性有机分子 结合，同时也控制这些物种的亲核诱捕的立体化学结果。通过利用 强大的过渡态稳定化和协同亲核亲电双重活化能力 HBD催化剂的独特之处在于，这种方法应该能够实现以前不可行的SNAR反应 精致的位置和对映体选择性。 这项提议的目标是设计一种离开基团结合的有机催化剂，它将催化第一个一般的和 合成有用的不对称Snar反应，可将未活化的芳基亲电体和前手性化合物合并 亲核主义者。研究计划概述了在假设驱动的指导下开发此类催化剂系统的策略 实验、计算建模和结构-活性研究。要添加到在 反应进展--HBD有机催化剂活化简单芳基亲电化合物的详细机理研究 如苯甲醚、苯丙氨酸和苯酚衍生物，以及更传统的芳基卤化物，将使用 数据密集型多维关联。这项研究将使简单和廉价的基础上稳定的原料 利用芳基亲电试剂以新的方式生产与药物相关的对映体富集物，以及 将对药物研究和催化剂开发具有巨大的重要性，大大有助于 科学知识。