Ghosh Bidhan, Kafle Prakash, Mukherjee Rishav, Welles Randall, Herndon Deacon, Nicholas Kenneth M, Shao Yihan, Sharma Indrajeet
Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, USA.
Science. 2025 Jan 3;387(6729):102-107. doi: 10.1126/science.adp0974. Epub 2025 Jan 2.
Given the prevalence of nitrogen-containing heterocycles in commercial drugs, selectively incorporating a single nitrogen atom is a promising scaffold hopping approach to enhance chemical diversity in drug discovery libraries. We harness the distinct reactivity of sulfenylnitrenes, which insert a single nitrogen atom to transform readily available pyrroles, indoles, and imidazoles into synthetically challenging pyrimidines, quinazolines, and triazines, respectively. Our additive-free method for skeletal editing employs easily accessible, benchtop-stable sulfenylnitrene precursors over a broad temperature range (-30 to 150°C). This approach is compatible with diverse functional groups, including oxidation-sensitive functionalities such as phenols and thioethers, and has been applied to various natural products, amino acids, and pharmaceuticals. Furthermore, we have conducted mechanistic studies and explored regioselectivity outcomes through density functional theory calculations.
鉴于含氮杂环在商业药物中的普遍性，选择性地引入单个氮原子是一种很有前景的骨架跃迁方法，可增强药物发现库中的化学多样性。我们利用硫烯基氮宾的独特反应性，它能插入单个氮原子，分别将易得的吡咯、吲哚和咪唑转化为合成上具有挑战性的嘧啶、喹唑啉和三嗪。我们用于骨架编辑的无添加剂方法在很宽的温度范围（-30至150°C）内使用易于获得、在台面稳定的硫烯基氮宾前体。这种方法与多种官能团兼容，包括对氧化敏感的官能团，如酚类和硫醚类，并且已应用于各种天然产物、氨基酸和药物。此外，我们进行了机理研究，并通过密度泛函理论计算探索了区域选择性结果。
