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

Abstract

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.

1. Cu­(I)-Catalyzed Activation of Glycals (Top Left) and Michael-Type Addition on Olefins (Top Right) and Activation of Electron-Deficient Glycals (Bottom)

2. (A) Synthesis of Mucin-Type Core 5 7 and (B) One-Pot Synthesis of Trisaccharide 8

3. Primary and Secondary KIE Study of the Donor 1a with Methanol and Deuterated Methanol (CH₃OD and CD₃OH)

4. (A) Proposed Mechanism and (B) Lowest Energy DFT-Calculated Transition States for 1a α- and β-Selective Routes, and 1e β-Selective Pathway