Construction of Heteroarenes Through Single Atom Insertion Strategies

项目摘要 该建议涉及新试剂的开发和用于 通过单原子插入制备碱性、芳香族、含氮杂环 反应.这些结构（吡啶，嘧啶， 哒嗪）是很难夸大的-在三十个新的小分子药物批准， 2019年，其中10个包含一个或多个这些图案，它们在 药物相关化合物是一个长期的趋势。这种特权地位 这促使了各种合成策略的发展， 可以在很大程度上细分为杂芳核的从头组装（通常 缩合），以及通过交叉偶联连接预先形成的杂芳烃， 亲核芳族取代方法。这些战略使 这类化合物的扩散用于广泛的医药应用，但它们的 然而，实施远非微不足道，需要继续开发 新的战略。 概念上的中点存在于从头合成和连接之间，其中 一个杂环结构被转化成另一个。这种做法限制了 历史先例，但由于正交反应性， 优选性（例如亲核相对于亲电）和5-相对于6-的反应相容性。 元杂环。我们在此提出了一组试剂，其将使这种方法成为可能。 转换以合成的直接方式实现。 我们对单原子变化的关注是经过计算的：重排反应，虽然 由于其逆合成的复杂性，很少用于合成。通过 开发在逆合成意义上容易识别的转化（例如， “去除这个氮原子”）我们希望为药物化学家提供用户友好的工具 雇用。此外，将吡咯、吡唑和咪唑转化为 各种6元环杂环天然地进入后期骨架编辑， 药物，允许生物活性支架的多样化，以获得更有效的结构- 活性关系测定和位点特异性同位素标记。因此，在本发明中， 成功实现本文列举的目标将提高化学家的能力， 通过提供一个强大的， 一套新的综合工具。

Project Abstract This proposal concerns the development of new reagents and strategies for the preparation of basic, aromatic, nitrogenous heterocycles through single-atom insertion reactions. The medicinal importance of such structures (pyridines, pyrimidines, pyridazines) is difficult to overstate – of the thirty new small molecule drugs approved in 2019, ten of them contain one or more of these motifs and their prevalence among medicinally-relevant compounds is a long-standing trend. This privileged status has prompted the development of a variety of synthetic strategies for their preparation, which can largely be subdivided into de novo assembly of the heteroaromatic nucleus (typically condensations), and attachment of preformed heteroarenes via cross-coupling and nucleophilic aromatic substitution approaches. These strategies have enabled the proliferation of such compounds for wide-ranging medicinal applications, but their implementation is nonetheless far from trivial, necessitating the continuing development of novel strategies. A conceptual mid-point exists between de novo synthesis and attachment wherein one heterocyclic structure is converted into another. Such an approach has limited historical precedent but holds substantial promise due to the orthogonal reactivity preferences (e.g. nucleophilic vs. electrophilic) and reaction compatibility of 5- vs. 6- membered heterocycles. We propose herein a set of reagents which will enable such transformations to be realized in a synthetically straightforward manner. Our focus on single-atom changes is calculated: rearrangement reactions, though lauded, are rarely employed in synthesis due to their retrosynthetic complexity. By developing transformations that are easy to recognize in a retrosynthetic sense (e.g. “remove this nitrogen atom”) we hope to provide user-friendly tools for medicinal chemists to employ. Moreover, the ability to transform pyrroles, pyrazoles, and imidazoles into a variety of 6-membered ring heterocycles feeds naturally into late-stage skeletal editing of pharmaceuticals, allowing diversification of bioactive scaffolds for more efficient structure- activity relationship determination and for site-specific isotopic labeling. As such, successful realization of the goals enumerated herein will advance the ability for chemists to interrogate biological function of heteroaromatic compounds by affording a powerful new set of tools for their synthesis.