Advances in the synthesis of Homochiral (-)-1-azafagomine and (+)-5-epi-1-azafa...

• Author(s): Alves, M. José ; Costa, Flora Teixeira e ; Duarte, Vera C. M. ; Fortes, A. Gil ; Martins, J. A. R. ; Micaelo, N. M.
• Date: 2011
• Persistent ID: http://hdl.handle.net/1822/15141
• Origin: RepositóriUM - Universidade do Minho
• Subject(s): Diels-Alder; Iminosugars; 1-azafagomine derivatives; Glycosidase inhibitors; Synthesis
• Document Type: Article
• Language: English

Description

- 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 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 towards 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 modelling. The efficient packing of the aromatic ring of the 1-N-phenyl carboxamide moiety into a hydrophobic sub-site (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.