Cu(I)-Catalyzed Stereoselective Glycosylation of "Electron-Deficient" Glycals

An efficient and mild Cu(I)-catalyzed Michael-type conjugate addition for 2-nitro glycals to access O-, S-, and C-glycosides with high stereoselectivity is reported. Under optimized conditions, nitrogalactals achieved high α-selectivity, whereas nitroglucal predominantly gave β-selective glycosides. The method is further demonstrated with other Michael-type substrates, including 2-formyl glycals and 3-keto glycals. Initial mechanistic investigations using NMR and supported by DFT calculations suggest that the reaction proceeds via a preorganized complex that positions the nucleophile close to the double bond to promote the Michael-type addition, in a manner analogous to enzyme-catalyzed processes. Moreover, the versatility of this synthetic approach was exemplified in the stereoselective synthesis of a mucin-type glycopeptide and the chemoselective one-pot synthesis of a trisaccharide.