Anionic Additions to Glycosyl Iodides: Highly Stereoselective Syntheses of β C-, N-, and O-Glycosides1

Abstract

Classically, glycosyl halides are activated as glycosyl donors by metal chelation under Koenigs−Knorr or Helferich conditions. These reactions often proceed through oxonium formation, and the stereochemical outcome is dictated by the anomeric effect and/or the nature of the protecting group on the C2 hydroxyl. Alternatively, glycosyl halides may undergo direct displacement of the halide by an incoming nucleophile in an SN2 mechanism. The latter reaction is far less common, and before this study it was primarily performed with glycosyl bromides. Having recently shown that both α and β glycosyl iodides could be efficiently generated, we embarked upon an investigation of nucleophilic additions to glycosyl iodides. The studies reported herein show that additions of stabilized anions to α-glycosyl iodides proceed with inversion of stereochemistry to give β-glycosides, even in the absence of a C2 participatory group. Glucosyl, galactosyl, and mannosyl iodides were studied, and the combined results indicate that the reactivity of 2,3,4,6-tetra-O-benzyl-α-d-galactosyl iodide > 2,3,4,6-tetra-O-benzyl-α-d-glucosyl iodide > 2,3,4,6-tetra-O-benzyl-α-d-mannosyl iodide. Both the glucosyl and galactosyl iodides are susceptible to E-2 elimination when treated with highly basic anions. In contrast, the mannosyl iodide undergoes substitution to give the 1,2 cis configuration. The overall sequence involves reaction of an anomeric acetate with trimethylsilyl iodide with in vacuo removal of the resulting trimethylsilyl acetate. The iodide is then treated with a nucleophile without further characterization. A variety of nucleophiles were stereoselectively added to the glycosyl halides providing β-, C-, N-, and O-glycosides.