Site-Divergent C–H Bond Functionalization of Free Phenols Enables Hydroxyflavanones

A solvent-controlled strategy to regulate the site-selectivity of free phenols and stereospecificity of 1,4-addition is presented, thereby divergently producing 4'-hydroxyflavanone and 2'-hydroxyflavanone <i>via</i> site-specific C-H bond functionalization. This protocol is applicable to a diverse range of free phenols. Furthermore, this strategy efficiently accesses natural product-like frameworks, including Eriodictyol, Narigenin, (+)-Anastatins A, (+)-Anastatins B, and (+)-Cycloaltilisin 7 with high selectivity. Late-stage modifications of pharmaceuticals, such as Ethinylestradiol, <i>β</i>-Estradiol, Ezetimibe, and Estrone, are certainly enabling. Importantly, the IC₅₀ values of the newly synthesized compounds <b>4o</b> and <b>5m</b> were determined to be in the submicromolar range, indicating a notably potent inhibitory effect. This finding for the synthesis of hydroxyflavanones marks a significant stride in overcoming the extraction challenges of natural products.