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: 10311063
• 负责人: Gabriel J Lovinger
• 金额: $ 6.76万
• 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 2023-07-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311063
• 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.

项目概要/摘要：通过氢键实现的不对称亲核芳香取代 催化 亲核芳族取代（SNAr）是制药和制药中最广泛使用的反应之一， 药物化学，允许获得芳香族和杂环分子。尽管它非常重要， 这类反应的范围仍然受到其内在机理特征的限制。因此， 在药物化学研究中使用SNAr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化学计量试剂， 限制了官能团的相容性，2）需要使用具有强吸电子基团的芳基底物， 其固有地限制了可获得的产品的范围，3）依赖于具有卤化物离去的芳基亲电体 组，排除了使用廉价的苯酚，苯甲醚和苯胺原料化学品，并产生大量 大量的卤化废物。替代的交叉耦合方法通常依赖于昂贵的过渡金属 催化剂必须在生物测试之前被仔细去除。使用SNAr产生药用 有价值的对映体富集的结构在很大程度上未被探索。 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，其中 叔或甚至季对映体富集的立体中心可以通过偶联未活化的芳基 亲电试剂和前手性亲核试剂如烯醇化物。这种方法将解决以前的每一个问题， 提到了关键限制。 氢键给体（HBD）有机催化剂通过离去基团活化中性有机分子 结合，同时还控制这些物质的亲核捕获的立体化学结果。通过利用 强大过渡态稳定和协同双重亲核和亲电活化能力 独特的HBD催化剂，这种方法应该能够实现以前不可行的SNAr反应， 精确的位点和对映体选择性。 该提案的目标是设计一种结合离去基团的有机催化剂，其将催化第一个通用和 能够合并未活化的芳基亲电试剂和前手性试剂的合成有用的不对称SNAr反应 亲核试剂该研究计划概述了一种策略，以开发这样一种催化剂系统， 实验、计算建模和结构活性研究。为了补充在 反应发展，HBD有机催化剂活化简单芳基亲电试剂的详细机理研究 例如苯甲醚、苯胺和苯酚衍生物，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工作台稳定的原料 芳基亲电试剂，用于以新的方式生产药用相关的对映体富集的化合物， 将对药物研究和催化剂开发具有巨大的重要性， 科学知识。