No abstract

The stereodirecting effect of the glycosyl C-5 substituent has been investigated in a series of d-pyranosyl thioglycoside donors and related to their preferred positions in the intermediate (3)H(4) and (4)H(3) half-chair oxacarbenium ions. Computational studies showed that an axially positioned C-5 carboxylate ester can stabilize the (3)H(4) half-chair oxacarbenium ion conformer by donating electron density from its carbonyl function into the electron-poor oxacarbenium ion functionality. A similar stabilization can be achieved by a C-5 benzyloxymethyl group, but the magnitude of this stabilization is significantly smaller than for the C-5 carboxylate ester. As a result, the preference of the C-5 benzyloxymethyl to occupy an axial position in the half-chair oxacarbenium ions is much reduced compared to the C-5 carboxylate ester. To minimize steric interactions, a C-5 methyl group prefers to adopt an equatorial position and therefore favors the (4)H(3) half-chair oxacarbenium ion. When all pyranosyl substituents occupy their favored position in one of the two intermediate half-chair oxacarbenium ions, highly stereoselective glycosylations can be achieved as revealed by the excellent beta-selectivity of mannuronate esters and alpha-selectivity of 6-deoxygulosides.

Glycosylations of mannuronate ester donors proceed highly selectively to produce the 1,2-cis-linked products. We here forward a mechanistic rationale for this counterintuitive selectivity, based on the remote stereodirecting effect of the C5-carboxylate ester, which has been demonstrated using pyranosyl uronate ester devoid of ring substituents other than the C5- carboxylate ester. It is postulated that the C5-carboxylate ester prefers to occupy an axial position in the oxacarbenium intermediate, thereby favoring the formation of the (3)H4 half-chair over the (4)H3 conformer. Nucleophilic attack on the (3)H4 half-chair intermediate occurs in a beta-fashion, providing the 1,2-cis-mannuronates with excellent stereoselectivity. The potential of the mannuronate ester donors in the formation of the beta-mannosidic linkage has been capitalized upon in the construction of a mannuronic acid alginate pentamer using a convergent orthogonal glycosylation strategy.

A facile synthesis route toward beta-linked mannuronic acid oligomers using the corresponding 1-thiomannuronic acid esters in combination with the Ph2SO/Tf2O or NIS/TMSOTf reagent combinations is presented. The presence of the remotely attached carboxylic ester sufficiently influences the electronic environment to allow good to excellent beta-selectivities.

This Microreview covers some general strategies for the preparation of uronic acid residues and their incorporation into anionically charged oligosaccharides. Two distinct strategies can be recognized: (1) glycosylation followed by oxidation, and (2) oxidation of the monosaccharide building