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

• Published in: Journal of organic chemistry Vol. 76; no. 23; pp. 9584 - 9592
• Main Authors: Alves, M. José, Costa, Flora T, Duarte, Vera C. M, Fortes, Antonio Gil, Martins, José A, Micaelo, Nuno M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 02.12.2011
• Subjects: Amides - chemistry; Binding Sites - drug effects; Carbohydrates with 4, 5, 6, ... C atoms, dissacharides and oligosaccharides; Carbohydrates. Nucleosides and nucleotides; Chemistry; Crystallography, X-Ray; Cyclization; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Exact sciences and technology; Glycoside Hydrolases - antagonists & inhibitors; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Indolizines - chemical synthesis; Indolizines - chemistry; Indolizines - pharmacology; Kinetics and mechanisms; Models, Molecular; Molecular Conformation; Organic chemistry; Preparations and properties; Reactivity and mechanisms; Stereoisomerism; Structure-Activity Relationship; Nitrogen heterocycle; Active site; Chiral compound; 1,2,4-Triazole derivative; Saccharomyces; Fungi; Chemical reduction; Chiral auxiliary; Alkene; Binding capacity; Enantiomer; Force field method; Reaction mechanism; Cleavage; Aromatic compound; Baker yeast; Chemical synthesis; Ascomycota; Stacking sequence; Enzyme; Enzyme inhibitor; Hydrophobic compound; Diketone; Dienic compound; Diastereoselectivity; Glycosylases; Cycloaddition; α-Glucosidase; Glycosidases; Molecular recognition; Hydrolases; Carboxamide; Ethylenic compound
• DOI: 10.1021/jo201486q
• ISSN: 0022-3263

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.