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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要/摘要有机合成是药物发现的限制因素，因此，合成方法的进展与生物活性分子制备相关的可能是加速新发现的强大驱动力针对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有直接相关的催化和合成中未解决的挑战药物发现的实践，并且有可能作为新反应的宽度平台产生广泛影响发现和/或合成计划。我们还投资于小分子合成的直接应用在药物发现中，在使用小分子参与癌症的新生物学目标的协作项目中治疗。此MIRA应用程序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功能化和（2）新型的环加成反应。在第一个领域，该领域的研究近年来，分子间的位点选择性C（SP3） - H羟基化和分析已仔细提前，但在从基材控制的选择性过渡到催化剂的愿望方面已经达到了重大障碍控制性的选择性。为了应对这些挑战，我们已经建立了一个有机催化的计划 Atom-Transfer C – H功能化以及过去几年都表明我们的催化平台，专注于亚米盐和胺催化剂，与金属催化的方法竞争反应性和选择性，并且具有启用多种原子转移的灵活性（即两者都羟基化和胺化）。建立了这个基础后，我们现在开始更好地理解独特的这些反应的机械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覆盖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，并使用亚米米催化来扩展在二苯基，未激活的第三纪和未激活的次级C – H键之间的范围和选择性晚期C – H胺化应用。与我们对C – H功能化的研究不同，我们也有建立了有关新调节性选择性和立体选择性环加成反应的计划靶向含氮的杂环和碳纤维的靶向附加到含氮的杂环上的药物发现中的主要结构基序。在此应用中描述的是我们最近发现的刘易斯酸催化了Diels-Alder反应的几乎意外变体 - 一种使用乙烯基芳族作为一种二磷。在接下来的五年中，我们打算实现我们的长期目标，以确立这一战略 - 通过扩展该化学的水平合成方法，包括杂型主教 - alder反应以形成偶氮加入脂肪族氮杂环，并通过开发对映选择性变体。这些结果未来的研究计划将使可以探索用于药物发现的化学空间扩展。