Department of Chemistry, Colorado State University, Fort Collins, CO, USA.
Nature. 2024 Jul;631(8019):87-93. doi: 10.1038/s41586-024-07474-1. Epub 2024 May 2.
Structure-activity relationship (SAR) studies are fundamental to drug and agrochemical development, yet only a few synthetic strategies apply to the nitrogen heteroaromatics frequently encountered in small molecule candidates. Here we present an alternative approach in which we convert pyrimidine-containing compounds into various other nitrogen heteroaromatics. Transforming pyrimidines into their corresponding N-arylpyrimidinium salts enables cleavage into a three-carbon iminoenamine building block, used for various heterocycle-forming reactions. This deconstruction-reconstruction sequence diversifies the initial pyrimidine core and enables access to various heterocycles, such as azoles. In effect, this approach allows heterocycle formation on complex molecules, resulting in analogues that would be challenging to obtain by other methods. We anticipate that this deconstruction-reconstruction strategy will extend to other heterocycle classes.
构效关系（SAR）研究是药物和农用化学品开发的基础，但只有少数合成策略适用于小分子候选物中经常遇到的含氮杂芳烃。在这里，我们提出了一种替代方法，我们将含嘧啶的化合物转化为各种其他含氮杂芳烃。将嘧啶转化为相应的 N-芳基嘧啶鎓盐可以裂解为三碳亚氨基烯胺砌块，用于各种杂环形成反应。这种解构-重建序列使初始嘧啶核心多样化，并能够获得各种杂环，如唑类。实际上，这种方法允许在复杂分子上形成杂环，得到用其他方法难以获得的类似物。我们预计这种解构-重建策略将扩展到其他杂环类别。
