Free-radical and ionic routes towards hydrolytically stable and bioactive C-glycosyl compounds

Photo-initiated addition of glycopyranosyl radicals to such radical acceptors as allyltributyltin, acrylonitrile, or diethyl vinylphosphonate was efficiently achieved to afford stereoselectively alpha-configured C-glycosyl compounds. With acrylonitrile or diethyl vinylphosphonate, catalytic amounts of organotin were used with NaBH3CN in excess. C-I Sugar dihalides may be converted into the beta-configured C-glycosyl analogues in two radical steps (C-C bond formation, reduction), or into bis-C,C-glycosides (two C-C bond forming reactions in one pot). These dihalides also opened the first access to C-glycodienes. C-Glycosyl-ethylphosphonic acids were elaborated into non-isosteric C-glycosyl mimics of natural sugar nucleotide diphosphates, which were evaluated as inhibitors of glycosyl transferases. In another approach, aromatic electrophilic substitution of 1,4-dimethoxybenzene by D-glycopyranosylium ions gave access to C-glycosyl derivatives of 1,4-dimethoxybenzene hydroquinone, and 1,4-benzoquinone. Some were found to inhibit protein tyrosine phosphatase 1B (PTP1B) and glycogen phosphorylase (GP), as shown by enzymatic and crystallographic studies. Extension of the synthetic work led to C-glycosyl-chromanols and C-glycosyl-tocopherols, which have been studied as anti-oxidants.