Improved Synthesis of 1‐Glycosyl Thioacetates and Its Application in the Synthesis of Thioglucoside Gliflozin Analogues

An improved method to synthesize 1‐glycosyl thioacetates was developed, where per‐O‐acetylated glycoses were allowed to directly react with potassium thioacetate (KSAc) in the presence of BF3 ⋅ Et2O in ethyl acetate under mild conditions. This method not only overcomes the disadvantage of the traditional one‐step method, which is that the odorous and toxic thioacetic acid has to be used, but also overcomes the disadvantage of the traditional two‐step method, which is that the unstable intermediate, glycosyl halide, has to be synthesized from the per‐O‐acetylated glycose in advance. Based on this, the per‐O‐acetylated glucosyl disulfide and the per‐O‐acetylated glucosyl 1‐thiol were efficiently synthesized in high yields (91 % and 90 % respectively) starting from per‐O‐acetylated glycoses in two‐step without the need to isolate intermediate products. Through metal‐catalyzed cross‐coupling of per‐O‐acetylated glucosyl 1‐thiol with aryl‐iodide under very mild conditions, two thioglucoside gliflozin analogues were efficiently synthesized in high yields for the first time. These two thioglucoside gliflozin analogues were further confirmed to be stable to hydrolysis of β‐glucosidase. We reported relative green synthesis of 1‐thioglycosides by straightforward reaction of per‐O‐acetylated glycoses with KSAc in EtOAc. Furthermore, the highly efficient method to synthesize per‐O‐acetylated glycosyl disulfide and glycosyl 1‐thiol were developed. Based on this, the synthesis of auranofin was improved and two thioglucoside gliflozin analogues (possible SGLT inhibitors) were efficiently synthesized in high yields.