Exploiting σ-hole activation to achieve stereoselective synthesis of deoxy glycosides from glycals

A versatile method for the direct stereoselective synthesis of both O-, N- and C-deoxyglycosides from glycals in high yield and stereocontrol using a chalcogenonium is described. The reaction follows an unprecedented sigma-hole activation pathway distinct to previously reported chalcogen-bond-mediated glycal-catalysed glycosylations. Experimental evidence supports a stepwise mechanism whereby the reaction commences by the chalcogenonium activation of the enol ether to generate the key reactive intermediate, that is rapidly intercepted by the incoming nucleophile. The nucleophile is in tandem activated by the catalyst and further stabilized via a hydrogen bond interaction with the triflate counter ion to give either -O-glycosides via a syn>anti addition, or -indolyl C- and N-glycosides following an anti>syn addition route. The reaction proceeds under mild conditions and is compatible with most common protecting groups. Its utility in oligosaccharide synthesis is demonstrated in the synthesis of a tetrasaccharide in 62% overall yield.