Construction of Heteroarenes Through Single Atom Insertion Strategies

项目摘要 这项建议涉及开发新的试剂和战略，用于 单原子插入法制备碱性、芳香、含氮杂环 反应。此类结构的药用价值(吡啶、嘧啶、 在年批准的30种新的小分子药物中，很难夸大 2019年，其中10个主题包含一个或多个这样的主题，它们在 与药物相关的化合物是一个长期的趋势。这一特权地位具有 促使开发了各种合成战略来制备它们，这 大体上可以细分为杂芳核的从头组装(通常 缩合)，以及通过交叉偶联和连接预制杂芳烃 亲核芳香族取代方法。这些战略使 这类化合物的扩散可用于广泛的医疗用途，但它们的 然而，执行远远不是微不足道的，需要继续发展 新奇的策略。 在从头合成和依附之间存在一个概念性的中间点，其中 一种杂环结构转化为另一种结构。这种方法已经限制了 历史上的先例，但由于正交反应性而具有实质性的前景 5-与6-的偏好(如亲核性与亲电性)和反应相容性 成员杂环。我们在此提出一套试剂，它将使这种 以综合直截了当的方式实现转换。 我们对单原子变化的关注是经过计算的：重排反应 由于它们的逆合成复杂性，很少用于合成。通过 开发易于在逆向合成意义上识别的转换(例如 《去除这个氮原子》)我们希望为药物化学家提供方便使用的工具 雇佣。此外，将吡咯、吡唑和咪唑转化为 各种6元环杂环自然地进入后期骨架编辑 药物，允许生物活性支架的多样化，以实现更有效的结构- 活度关系的测定和特定部位的同位素标记。因此， 成功地实现这里列举的目标将提高化学家的能力 通过提供一种强有力的方法来探讨杂环化合物的生物学功能 一套用于合成它们的新工具。

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.