The effect of a 4,6-O-alkylidene acetal on the rate of acid-catalyzed hydrolysis of methyl galactopyranosides and of spontaneous hydrolysis of 2,4-dinitrophenyl galactopyranosides has been studied through the synthesis and hydrolysis of analogs in which O6 is replaced by a methoxymethylene unit in which the methoxy group adopts either an equatorial or an axial position according to the configuration. Consistent with earlier studies under both acid-catalyzed and spontaneous hydrolysis conditions the alkylidene acetal, or its 7-carba analog, retards hydrolysis with respect to comparable systems lacking the cyclic protecting group. The configuration at C7 in the 7-carba analogs does not influence the rate of acid-catalyzed hydrolysis but has a minor influence on the rate of spontaneous hydrolysis of the 2,4-dinitrophenyl galactosides, confirming earlier studies on the role played by the hydroxymethyl group conformation on glycoside reactivity. The benzylidene acetal is found to stabilize the α-anomer of galactopyranose derivatives relative to monocyclic analogs. Reasons for the α-selectivity of 4,6-O-benzylidene-protected galactopyranosyl donors bearing neighboring group-active protecting groups at O2 are discussed.

The synthesis of oligomeric glycocomimetics has been performed for targeting the Pseudomonas aeruginosa PA-IIL lectin, which is of therapeutical interest for anti-adhesive treatment. The disaccharide alpha-L-Fucp-(1-->4)-beta-D-GlcNAc, which is a high-affinity ligand of the lectin, has been coupled to dimeric and trimeric linkers with various lengths and geometries. A series of linear dimers displayed an efficient clustering effect and a very strong affinity, with a lower dissociation constant of 90 nM. The trimeric compound was less efficient in inhibition assays but displayed high affinity in solution. Titration microcalorimetry and molecular modeling allowed in-depth analysis and rationalization of the binding data. These glycoclusters could act by crosslinking the lectins present on the surface of bacteria and therefore interfere with host recognition or biofilm formation.

Unlike alcohols, the reaction of C-nucleophiles with 2-O-benzyl-4,6-O-benzylidene-protected 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 (sp3-hybridized O) and of typical carbon-based nucleophiles (sp2 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.

2-(2-Pyridyldithio-3-butenyl) glycosides react with carbohydrate-based thiols in a two step process involving sulfenyl transfer followed by desulfurative 2,3-allylic rearrangement, promoted by either triphenylphosphine or silver nitrate, to give novel saccharide mimetics. In an alternative embodiment of the same chemistry anomeric thiols are coupled with carbohydrates derivatized in the form of 2-(2-pyridyldithio-3-butenyl) ethers. This new method of glycoligation does not require protection of hydroxyl groups and is compatible with the presence of acetamides, azides, trichloroethoxycarbamates, and thioglycosides. Variations on the general theme enable the preparation of mimetics of reducing and non-reducing oligosaccharides as well as of non-glycosidically linked systems.