Stereoselective Synthesis of 1,2-cis-α-Glycosyl Thiols and Trehalose-Type α,α'-Thiodisaccharides by Cryo Thiol-Ene Photocoupling - Thio-Click Reaction in Frozen State.

Abstract

α-Glycosyl thiols are key building blocks for the formation of stable thioglycoside mimetics of widespread and biologically relevant α-O-glycosides, which urges their efficient synthesis. Here, we demonstrate that the photoinitiated radical-mediated addition of thioacetic acid to 2-substituted glycals followed by selective S-deacetylation is a generally applicable and fully stereoselective method for the synthesis of 1,2-cis-α-glycosyl thiols. The low reactivity of thioacetic acid in the radical reaction was overcome by carrying out the reaction in AcOH at -80 °C, in frozen state, with UVA irradiation, achieving high yields irrespective of the sugar configurations. For effective irradiation and simultaneous effective cooling, a self-made spiral vessel reactor was used, which also enables large-scale synthesis. By subjecting 1,2-cis-α-1-thiosugars to a second thiol-ene coupling reaction with 2-substituted glycals, 34 trehalose-type symmetrical and unsymmetrical α,α'-thiodi- and oligosaccharides were obtained with full stereoselectivity. Moreover, the oxidation of α-1-thiosugars provided an easy access to α,α'-diglycosyl disulfides.