Stereoselective conjugate addition of nitrogen and carbon nucleophiles to sugar-derived enones: Synthesis of sialic acid analogues

The conjugate addition of benzylamine to three polyalkoxy alpha,beta-enones derived from D-glyceraldehyde, D-erythrose, and D-mannose, whose carbonyls were flanked by the thiazole ring, proceeded with modest to good syn-selec tivity. The resulting polyalkoxy beta-amino ketones were converted by ketal ization into methyl 1-(2-thiazolyl)-pyranosides that in turn were transform ed into 4-amino-3,4-dideoxy-ulosonic acids by sequential cleavage of the th iazole ring into the formyl group and oxidation of the latter to carboxylat e. Thus, starting from the enone derived from D-mannose, the 4-acetamido-no nulosonic acid iso-Neu4Ac, a positional isomer of sialic acid Neu5Ac, was p repared. Because of some unsatisfactory reactions, a more efficient synthes is of iso-Neu4Ac was carried out by the use of trimethylsilyl azide as a ni trogen nucleophile in the initial conjugate addition reaction. Also, in the presence of DBU the addition of nitromethane to the same enones proceeded with good syn-selectivity and chemical yield. The cyclization of the result ing ketones afforded methyl 3-nitromethyl-1-(2-thiazolyl)-pyranosides. Furt hermore, the pyranoside derived from the enone incorporating the D-mannose moiety afforded after reduction of the nitro to the amino group and carboxy late generation from the thiazole ring, a 4-acetamidomethyl-3, 4-dideoxy-ul osonic acid, which is a branched one-carbon higher homologue of iso-Neu4Ac.