Ruos Madeline E, Romer Natalie P, Deichert Julie A, Alabanza Lady Mae, Gandhi Shivaani S, Brown Giselle Z, Walroth Richard C, Cruz Karissa, Gosselin Francis, Hong Allen Y, Sigman Matthew S, Doyle Abigail G
Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, California 90095, United States.
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.
J Am Chem Soc. 2025 Jul 23;147(29):25815-25824. doi: 10.1021/jacs.5c07548. Epub 2025 Jul 9.
We report the discovery and development of several new (hetero)aryl sulfonyl fluoride reagents that have enhanced deoxyfluorination reactivity, improved physical properties, and excellent safety profiles compared to those of PyFluor and other fluorination reagents such as PBSF and DAST. To select structurally diverse reagents, we computed a virtual library of (hetero)aryl sulfonyl fluorides and leveraged training set design principles to broadly survey structure-activity relationships in a model deoxyfluorination reaction. We developed predictive models to optimize sulfonyl fluoride reagents for the deoxyfluorination of a key intermediate used in the synthesis of RIPK1 inhibitor GDC-8264. The top-performing reagents demonstrated broad applicability across diverse alcohol substrate classes, including complex natural products and active pharmaceutical ingredients, highlighting the power of data science-enabled approaches in reagent development.
我们报告了几种新型（杂）芳基磺酰氟试剂的发现与开发，与PyFluor以及其他氟化试剂（如PBSF和DAST）相比，这些试剂具有更高的脱氧氟化反应活性、更优的物理性质以及出色的安全性。为了筛选出结构多样的试剂，我们计算了（杂）芳基磺酰氟的虚拟文库，并运用训练集设计原则广泛研究了模型脱氧氟化反应中的构效关系。我们开发了预测模型，以优化用于RIPK1抑制剂GDC - 8264合成中关键中间体脱氧氟化反应的磺酰氟试剂。性能最佳的试剂在各类醇底物中均表现出广泛的适用性，包括复杂的天然产物和活性药物成分，这凸显了数据科学驱动方法在试剂开发中的强大作用。
