Synthesis of the C-linked disaccharide alpha-D-Man-(1-->4)-D-Man employing a SmI(2)-mediated C-glycosylation step: en route to cyclic C-oligosaccharides.

Investigations are reported on the assembly of the C-linked disaccharide alpha-D-Man-(1-->4)-D-Man, representing the first steps in our projected synthesis of a cyclic C-oligomer containing repeating units of this C-dimer. The key step in this synthesis uses a SmI(2)-mediated coupling of 2,3,4,6-tetra-O-benzyl-alpha-D-mannopyranosyl 2'-pyridyl sulfone with a C4-formyl branched mannopyranoside unit, affording the C-disaccharide derivative with complete stereocontrol at the two new stereogenic centers. Subsequently, a modified tin hydride based deoxygenation produced the target carbohydrate analogue. The synthesis of the C4-formyl monosaccharide makes use of a stereoselective radical-based allylation followed by double bond migration and ozonolysis.

Conformation of glycomimetics in the free and protein-bound state: structural and binding features of the C-glycosyl analogue of the core trisaccharide alpha-D-Man-(1 --> 3)-[alpha-D-Man-(1 --> 6)]-D-Man.

The conformational properties of the C-glycosyl analogue of the core trisaccharide alpha-D-Man-(1 --> 3)-[alpha-D-Man-(1 --> 6)]-D-Man in solution have been carefully analyzed by a combination of NMR spectroscopy and time-averaged restrained molecular dynamics. It has been found that both the alpha-1,3- and the alpha-1,6-glycosidic linkages show a major conformational averaging. Unusual Phi ca. 60 degrees orientations for both Phi torsion angles are found. Moreover, a major conformational distinction between the natural compound and the glycomimetic affects to the behavior of the omega(16) torsion angle around the alpha-1 --> 6-linkage. Despite this increased flexibility, the C-glycosyl analogue is recognized by three mannose binding lectins, as shown by NMR (line broadening, TR-NOE, and STD) and surface plasmon resonance (SPR) methods. Moreover, a process of conformational selection takes place, so that these lectins probably bind the glycomimetic similarly to the way they recognize the natural analogue. Depending upon the architecture and extension of the binding site of the lectin, loss or gain of binding affinity with respect to the natural analogue is found.

Application of the anomeric samarium route for the convergent synthesis of the C-linked trisaccharide alpha-D-Man-(1-->3)-[alpha-D-Man-(1-->6)]-D-Man and the disaccharides alpha-D-Man-(1-->3)-D-Man and alpha-D-Man-(1-->6)-D-Man.

Studies are reported on the assembly of the branched C-trisaccharide, alpha-D-Man-(1-->3)-[alpha-D-Man-(1-->6)]-D-Man, representing the core region of the asparagine-linked oligosaccharides. The key step in this synthesis uses a SmI(2)-mediated coupling of two mannosylpyridyl sulfones to a C3,C6-diformyl branched monosaccharide unit, thereby assembling all three sugar units in one reaction and with complete stereocontrol at the two anomeric carbon centers. Subsequent tin hydride-based deoxygenation followed by a deprotection step produces the target C-trimer. In contrast to many of the other C-glycosylation methods, this approach employes intact carbohydrate units as C-glycosyl donors and acceptors, which in many instances parallels the well-studied O-glycosylation reactions. The synthesis of the C-disaccharides alpha-D-Man-(1-->3)-D-Man and alpha-D-Man-(1-->6)-D-Man is also described, they being necessary for the following conformational studies of all three carbohydrate analogues both in solution and bound to several mannose-binding proteins.