New Catalysts and Strategies for Selective C–H Functionalization and Cycloaddition Reactions

选择性 C–H 官能化和环加成反应的新催化剂和策略

• 批准号: 10622182
• 负责人: Michael Kenneth Hilinski
• 金额: $ 50.79万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622182
• 关键词: Acceleration; Acids; Address; Amination; Amines; Area; Biological; Catalysis; Chemicals; Chemistry; Diels Alder reaction; Foundations; Future; Goals; Hydrogen Bonding; Hydroxylation; Investments; Laboratories; Medical; Metals; Methods; Nitrogen; Organic Synthesis; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Reaction; Research; Site; Sodium Chloride; Structure; Variant; cancer therapy; catalyst; cycloaddition; direct application; driving force; drug discovery; flexibility; invention; novel; novel drug class; programs; small molecule; small molecule therapeutics; success; virtual

Project Summary/Abstract Organic synthesis is a rate-limiting factor in drug discovery, and consequently, advances in synthetic methods relevant to bioactive molecule preparation can be a powerful driving force to accelerate the discovery of new small molecule therapeutics for unmet medical needs. Research in the Hilinski laboratory is focused on addressing unsolved challenges in catalysis and synthesis that have immediate relevance to the contemporary practice of drug discovery, and that have the potential for broad impact as widespread platforms for new reaction discovery and/or synthetic planning. We are also invested in the direct application of small molecule synthesis to drug discovery, in collaborative projects that use small molecules to engage new biological targets for cancer treatment. This MIRA application outlines our recent endeavors and future plans in two areas: (1) catalytic, selective C–H functionalization, and (2) novel cycloaddition reactions. In the first area, research in the field of intermolecular, site selective C(sp3)–H hydroxylation and amination has advanced considerably in recent years, but has reached a major barrier in the desire to transition from substrate-controlled selectivity to catalyst controlled selectivity. To address these and other challenges, we have established a program in organocatalytic atom-transfer C–H functionalization and over the past several years have shown that our catalytic platform, focused on iminium salt and amine catalysts, competes with or exceeds metal-catalyzed methods in reactivity and selectivity, and also that it has the flexibility to enable multiple types of atom transfer (i.e. both hydroxylation and amination). Having established this foundation, we are now beginning to better understand the unique mechanistic details of these reactions and the influence of catalyst structure on reactivity and selectivity. Our goals over the next five years are to use amine catalysis to override substrate control of C–H hydroxylation site selectivity and to develop enantioselective C–H hydroxylation methods, and to use iminium catalysis to expand both the scope and selectivity among benzylic, unactivated tertiary, and unactivated secondary C–H bonds in late-stage C–H amination applications. Distinct from our research on C–H functionalization, we have also established a program on the invention of new regioselective and stereoselective cycloaddition reactions targeting nitrogen-containing heterocycles and carbocycles appended to nitrogen-containing heterocycles, two major structural motifs in drug discovery. Described in this application is our recent discovery of Lewis acid catalysis of a virtually unexplored variant of the Diels-Alder reaction – one that uses vinylazaarenes as dienophiles. Over the next five years, we intend to pursue our long-term goal of establishing this as a strategy- level synthetic approach by expanding this chemistry to include hetero Diels-Alder reactions to form azaarene- appended aliphatic nitrogen heterocycles, and by developing enantioselective variants. The results of these future research plans will enable an expansion of the chemical space that can be explored for drug discovery.

项目概要/摘要 有机合成是药物发现的速率限制因素，因此合成方法的进步 与生物活性分子制备相关的可以成为加速新发现的强大驱动力 满足未满足的医疗需求的小分子疗法。希林斯基实验室的研究重点是 解决与当代直接相关的催化和合成方面尚未解决的挑战 药物发现实践，并且有可能作为新反应的广泛平台产生广泛影响 发现和/或综合规划。我们还投资于小分子合成的直接应用 药物发现，在使用小分子参与癌症新生物靶点的合作项目中 治疗。此 MIRA 应用概述了我们最近在两个领域的努力和未来计划：(1) 催化、 选择性 C-H 官能化，以及 (2) 新颖的环加成反应。在第一个领域，研究领域 分子间、位点选择性 C(sp3)–H 羟基化和胺化近年来取得了相当大的进展， 但在从底物控制选择性向催化剂过渡的愿望上遇到了主要障碍 受控选择性。为了应对这些和其他挑战，我们制定了有机催化计划 原子转移 C–H 功能化以及过去几年的研究表明，我们的催化平台， 专注于亚胺盐和胺催化剂，在反应活性方面可与金属催化方法竞争或超过 和选择性，而且它还具有灵活性，可以实现多种类型的原子转移（即羟基化 和胺化）。建立了这个基础后，我们现在开始更好地了解独特的 这些反应的机理细节以及催化剂结构对反应性和选择性的影响。我们的 未来五年的目标是利用胺催化来超越 C-H 羟基化位点的底物控制 选择性并开发对映选择性 C-H 羟基化方法，并使用亚胺催化来扩展 苄基、未活化的叔键和未活化的仲 C-H 键之间的范围和选择性 后期C-H胺化应用。与我们对C-H官能化的研究不同，我们还 制定了新的区域选择性和立体选择性环加成反应发明计划 靶向含氮杂环和附加到含氮杂环的碳环，两个 药物发现中的主要结构基序。本申请描述的是我们最近发现的路易斯酸 狄尔斯-阿尔德反应的一种几乎未经探索的变体的催化——一种使用乙烯基氮杂芳烃作为 亲二烯体。在接下来的五年里，我们打算追求我们的长期目标，将其作为一项战略—— 通过扩展这种化学反应以包括杂狄尔斯-阿尔德反应以形成氮杂芳烃，实现了水平合成方法 附加脂肪族氮杂环，并通过开发对映选择性变体。这些结果 未来的研究计划将扩大可用于药物发现的化学空间。