Stereoselective C-glycoside formation with 2-O-benzyl-4,6-O-benzylidene protected 3-deoxy gluco- and mannopyranoside donors: comparison with O-glycoside formation

Abstract

Unlike alcohols, the reaction of C-nucleophiles with 2-O-benzyl-4,6-O-benzylidene-protected 3-deoxy-gluco- and mannopyranosyl thioglycosides is highly stereoselective providing the α-C-glycosides in the gluco-series and the β-C-glycosides in the manno-series. Conformational analysis of nucleophilic attack of putative intermediate glycosyl oxocarbenium ions suggests that the observed selectivities for C-glycoside formation can be explained by preferential attack on the opposite face of the oxocarbenium to the C2-H2 bond and that eclipsing interactions with this bond are the main stereodetermining factor. It is argued that the steric interactions in the attack of alcohols (sp(3)-hybridized O) and of typical carbon-based nucleophiles (sp(2) C) on oxocarbenium ions are very different, with the former being less severe, and thus that there is no a priori reason to expect O- and C-glycosylation to exhibit parallel stereoselectivities for attack on a given oxocarbenium ion.

Figure 1

Influence of the 3-O-benzyl ether on glycoside formation in the gluco- and manno- series.

Figure 2

Newman projections about C1-C2 showing alternative modes of attack on the 4,6-O-benzyidene-protected mannosyl and glucosyl oxocarbenium ions, indicating torsional interactions present in the disfavored modes.

Figure 3

Representations of the transition states for antiperiplanar attack by π-type C-nucleophiles, and alcohols on the disfavored face of the glycosyl oxocarbenium ions (cf Figure 2, α-for manno- and β-for gluco) highlighting the influence of the C2-H2 bond. Of the two unhindered staggered conformations available for O-glycoside formation only the one taking account of any developing exo-anomeric effect is illustrated.

Scheme 1

Rationale for the stereoselective formation of 9 and 14.

Scheme 2

Nucleophilic attack on the B_2,5 conformation of the 4,6-O-benzylidene-protected mannopyranosyl (X = OBn) and 3-deoxymannopyranosyl (X = H) oxocarbenium ions.

Scheme 3

Nucleophilic attack on the ⁴H₃ conformation of the 4,6-O-benzylidene-protected glucopyranosyl (X = OBn) and 3-deoxyglucopyranosyl (X = H) oxocarbenium ions.

Scheme 4. Alternative pathway for the formation of α-O-mannopyranosides