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

项目总结/摘要 有机合成是药物发现的限速因素，因此，合成方法的进步 与生物活性分子制备相关的技术可以成为加速发现新的生物活性分子的强大动力。 用于未满足的医疗需求的小分子治疗剂。希林斯基实验室的研究重点是 解决催化和合成方面尚未解决的挑战，这些挑战与当代直接相关 药物发现的实践，并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 到药物发现，在合作项目中使用小分子来参与癌症的新生物靶点， 治疗这个MIRA应用程序概述了我们最近的努力和未来的计划在两个领域：（1）催化， 选择性C-H官能化，和（2）新的环加成反应。在第一个领域， 近年来，分子间位点选择性C（sp3）-H羟基化和胺化已经有了相当大的进展， 但是在从底物控制的选择性向催化剂的转变的期望方面已经达到了主要障碍 控制选择性。为了应对这些和其他挑战，我们已经建立了一个有机催化的计划， 原子转移C-H官能化，并且在过去几年中已经表明我们的催化平台， 专注于亚胺盐和胺催化剂，在反应性方面与金属催化方法竞争或超过金属催化方法 和选择性，并且还具有能够进行多种类型的原子转移（即， 和胺化）。在建立了这个基础之后，我们现在开始更好地了解 这些反应的机理细节和催化剂结构对反应性和选择性的影响。我们 未来五年的目标是使用胺催化来克服C-H羟基化位点的底物控制 选择性和发展对映选择性的C-H羟基化方法，并使用亚胺催化扩大 苄基，未活化的叔，和未活化的仲C-H键的范围和选择性， 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 建立了一个新的区域选择性和立体选择性环加成反应的发明计划 靶向含氮杂环和附加到含氮杂环上的碳环， 药物发现中的主要结构基序。在本申请中描述的是我们最近发现的刘易斯酸 Diels-Alder反应的一个几乎未探索的变体的催化-一个使用乙烯基氮杂芳烃作为 亲二烯体在未来五年，我们打算追求我们的长期目标，将其确立为一项战略， 水平的合成方法，将这种化学反应扩展到包括杂狄尔斯-阿尔德反应以形成氮杂芳烃- 附加的脂肪族氮杂环，并通过开发对映选择性变体。的结果予以 未来的研究计划将扩大可用于药物发现的化学空间。

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.