Stereoselective <i>O</i> -Furanosylation of Phenols by Cooperative Effect of Lewis Acid and Nickel Complex

High Resolution Image Download MS PowerPoint Slide Despite the biological significance of stereodefined phenolic O-glycosides, their efficient synthesis remains challenging. Here, we report the stereoselective O -furanosylation of phenols toward bench-stable glycosyl fluorides by cooperative activation of a Lewis acid and transition-metal complex, proceeding in high yields at room temperature. The novel glycosylation strategy is demonstrated to be effective for a wide substrate scope of acceptors, including small molecules, natural products, and commercial drugs. Mechanistic studies, supported by TEMPO-trapping and DFT simulations, established a radical-mediated pathway for this glycosylation. To demonstrate the utility of this strategy for bioactive molecule diversification, we focused on phenolic compounds with known anti-inflammatory properties (e.g., sesamol). Their ribofuranose conjugates were synthesized and evaluated, leading to the discovery that glycosylation could potentiate the parent compounds’ ability to inhibit IL-6 production in LPS-stimulated macrophages, thereby demonstrating the potential of this glycosylation strategy to improve the pharmacological profiles of bioactive phenols.