A deconstruction-reconstruction strategy for pyrimidine diversification

• 成果类型: Article
• 署名作者: Uhlenbruck, Benjamin J. H.; Josephitis, Celena M.; de Lescure, Louis; Paton, Robert S.; McNally, Andrew
• 署名单位: Colorado State University System; Colorado State University Fort Collins
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4613
• DOI: 10.1038/s41586-024-07474-1
• 发表日期: 2024-07-04
• 页码: 87-+
• 关键词: functionalization; drugs; atom

摘要

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(1-3). 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(4). 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.