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

• Autor(a) principal: Alves, M. José
• Data de Publicação: 2011
• Outros Autores: Costa, Flora Teixeira e, Duarte, Vera C. M., Fortes, A. Gil, Martins, J. A. R., Micaelo, N. M.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/1822/15141
• topic: Diels-Alder; Iminosugars; 1-azafagomine derivatives; Glycosidase inhibitors; Synthesis; Science & Technology

- 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.