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

Abstract

Conventional syntheses of 1,2-trans-β-d- or α-l-glycosidic linkages rely mainly on neighboring group participation in the glycosylation reactions. The requirement for 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, a robust glycosylation protocol for the synthesis of 1,2-trans-β-d- or α-l-glycosidic linkages without resorting to NPG is disclosed; it employs an optimal combination of glycosyl N-phenyltrifluroacetimidates as donors, FeCl3 as promoter, and CH2 Cl2 /nitrile as solvent. A broad substrate scope has been demonstrated by glycosylations with 12 (1→2)-linked di- and trisaccharide donors and 13 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 were thus synthesized in a convergent manner after deprotection of the coupled glycosides. Intensive mechanistic studies indicated that this glycosylation proceeds by SN 2-type substitution of the glycosyl α-nitrilium intermediates. Importantly, FeCl3 dissociates and coordinates with nitrile into [Fe(RCN)n Cl2 ]+ and [FeCl4 ]- , and the ferric cationic species coordinates with the alcoholic acceptor to provide a protic species that activates the imidate, meanwhile the poor nucleophilicity of [FeCl4 ]- ensures an uninterruptive role for the glycosidation.