A Stereoselective Glycosylation Approach to the Construction of 1,2-trans-β-D-Glycosidic Linkages and Convergent Synthesis of Saponins.

Conventional syntheses of the 1,2-trans-β-D- or α-L-glycosidic linkages rely mainly on the neighboring group participation in the glycosylation reactions. The requirement of a neighboring participation group (NPG) excludes direct glycosylation with (1→2)-linked glycan donors, thus only allowing stepwise assembly of glycans and glycoconjugates containing this type of common motif. Here we disclose a robust glycosylation protocol for the synthesis of 1,2-trans-β-D- or α-L-glycosidic linkages without resorting to NPG, which employs an optimal combination of glycosyl N-phenyltrifluroacetimidates as donors, FeCl3 as promoter, and CH2Cl2/nitrile as solvent. A broad substrate scope has been demonstrated by glycosylations with twelve (1→2)-linked di- and trisaccharide donors and thirteen alcoholic acceptors including eight complex triterpene derivatives. Most of the glycosylation reactions are high yielding and exclusively 1,2-trans selective. Ten representative naturally occurring triterpene saponins are thus synthesized in a convergent manner after deprotection of the coupled glycosides. Intensive mechanistic studies indicate that the present glycosylation proceeds via a SN2-type substitution of the glycosyl α-nitrilium intermediates. Importantly, FeCl3 dissociates and coordinates with nitrile into [Fe(RCN)nCl2]+ and [FeCl4]-, and the ferric cationic species coordinates with the alcoholic acceptor to provide a protic species which activates the imidate, meanwhile the poor nucleophilicity of [FeCl4]- ensures a non-interruptive role for the glycosidation.