Photoinitiated thiol-ene reactions of glycals: Effect of C2-substitution on reactivity and regio- and stereoselectivity

The photoinitiated thiol-ene reaction is a metal-free click chemistry method for the synthesis of thioglycosides and sulfur-linked glycomimetics. Here we present a comparative study on the thiol-ene reactions of C2-substituted and unsubstituted glycals with some selected thiols, such as thioacetic acid, tert-butyl mercaptan, and per-O-acetylated 1-thio-β-d-galactose and 1-thio-β-d-lactose derivatives at -80 °C in the presence of 2,2-dimethoxy-2-phenylacetophenone photoinitiator. 2-Acetoxyglycals gave the 1,2-cis-α-thioglycosides with complete regio- and stereoselectivity, in high yields with all thiols tested, except for tert-butyl mercaptan. Unsubstituted glucal and galactal gave the 1-deoxy-2-thiolated products regioselectively, and in most cases as a mixture of C2 epimers. Hydrothiolation of galactal always yielded the galacto-isomer in greater proportion than the talo-isomer. In hydrothiolation of glucal, either manno- or gluco-selectivity prevailed, depending on the thiol size and reaction temperature. Remarkably, unsubstituted glycals showed higher reactivity towards thiols than C2-substituted glycals.