Advances in the synthesis of homochiral (-)-1-azafagomine and (+)-5-epi-1-azafagomine. 1-N-phenyl carboxamide derivatives of both enantiomers of 1-azafagomine: Leads for the synthesis of active α-glycosidase inhibitors.

A new expeditious preparation of homochiral (-)-1-azafagomine and (+)-5-epi-1-azafagomine has been devised. Stoodley's diastereoselective cycloaddition of dienes bearing a 2,3,4,6-tetraacetyl glucosyl chiral auxiliary to 4-phenyl-1,2,4-triazole-3,5-dione was merged with Bols's protocol for functionalizing alkenes into molecules bearing a glucosyl framework. Homochiral (+)-5-epi-1-azafagomine was synthetized for the first time. Partial reductive cleavage of the phenyltriazolidinone moiety afforded new homochiral 1-N-phenyl carboxamide derivatives of 1-azafagomine. Both enantiomers of these derivatives were synthetized and tested, displaying a very good enzymatic inhibition toward baker's yeast α-glucosidase. The molecular recognition mechanism of the 1-N-phenyl carboxamide derivative of 1-azafagomine by α-glucosidase from baker's yeast was studied by molecular modeling. The efficient packing of the aromatic ring of the 1-N-phenyl carboxamide moiety into a hydrophobic subsite (pocket) in the enzyme's active site seems to be responsible for the improved binding affinity in relation to underivatized (-)-1-azafagomine and (+)-1-azafagomine.

Diels-Alder cycloaddition in the synthesis of 1-azafagomine, analogs, and derivatives as glycosidase inhibitors.

This comprehensive review deals with the synthesis of 1-azafagomine, analogs, and derivatives having the Diels-Alder cycloaddition as the key step. Most of the compounds referred are racemic or have been resolved by lipase transesterification. There are two asymmetric cycloadditions leading to 1-azafagomine or to an analog. In one case both enantiomers of 1-azafagomine were prepared together with a pair of derivatives. The study comprises glycosidase inhibition studies of the target compounds to a set of glycosidic enzymes, and evidenced molecular features that enhance or diminish their activity as glycosidase inhibitors.