Solvent-Dependent Mechanism and Stereochemistry of Mitsunobu Glycosylation with Unprotected Pyranoses

An S(N)2 mechanism was proposed for highly stereoselective glycosylation of benzoic acid with unprotected alpha-D-oglucose under Mitsunobu conditions in dioxane, while an S(N)1 mechanism was indicated for nonstereoselective glycosylation in DMF. The S(N)2-type stereoselective Mitsunobu glycosylation is generally applicable to various unprotected pyranoses as glycosyl donors in combination with a wide range of acidic glycosyl acceptors such as carboxylic acids, phenols, and imides, retaining its high stereoselectivity (33 examples). Glycosylation of a carboxylic acid with unprotected alpha-D-mannose proceeded also in an S(N)2 manner to directly afford a usually less accessible 1,2-cis-mannoside. One- or two-step total syntheses of five simple natural glycosides were performed using the glycosylation strategy presented here using unprotected alpha-D-glucose.