Iridium Photoredox-Catalyzed Stereoselective C-Glycosylation with Tetrafluoropyridin-4-yl Thioglycosides: A Facile Synthesis of C-α/β-Glucogallins and Their Antioxidant Activity

Abstract

We demonstrate an efficient, scalable, and stereoselective C-glycosylation with thioglycosides possessing a unique photoactive tetrafluoropyridin-4-yl (TFPy) thio radical leaving group, affording editable and medicinally and biologically essential C-α-glucogallin derivatives. In the presence of silyl enol ether acceptors, the desulfurative coupling reaction performs smoothly under mild conditions upon exposure to blue light irradiation. This versatile protocol permits the synthesis of sugar-drug chimeras by C1 ketonylation of complex drug-derived silyl enol ethers. The scale-up synthesis, anomeric epimerization, and post-C-glycosylation modification of ketone sugars showcase the reaction’s potential utilities. Furthermore, the reaction could be applied to direct carbohydrate skeleton editing by equipping the leaving group on the nonanomeric position. The ketonylation is viable for unprotected TFPy thioglycoside, affording a direct route to unprotected ketonyl sugars. The concise six-step assembly of both configurated C-glucogallins from commercially cheap glucose pentaacetate and their antioxidant reactivity investigations underline the promising medicinal relevance of our current protocols. The reaction mechanism was investigated through a radical trapping experiment, an oxocarbenium trapping experiment, a fluorescence quenching experiment, and Stern–Volmer analysis, confirming that the major glycosyl radical intermediates are generated from the thioglycoside donors, whose tetrafluoropyridin-4-yl thio group could effectively quench the fluorescence of excited Ir(ppy)₃ through an oxidative quenching process, and C-glycosylation with oxocarbenium is a complementary route to the product, accounting for examples with moderate selectivities.