title: Efficient atropodiastereoselective access to 5,5'-bis-1,2,3-triazoles: studies on 1-glucosylated 5-halogeno 1,2,3-triazoles and their 5-substituted derivatives as glycogen phosphorylase inhibitors.
abstract: Whereas copper-catalyzed azide-alkyne cycloaddition (CuAAC) between acetylated β-D-glucosyl azide and alkyl or phenyl acetylenes led to the corresponding 4-substituted 1-glucosyl-1,2,3-triazoles in good yields, use of similar conditions but with 2 equiv CuI or CuBr led to the 5-halogeno analogues (>71 %). In contrast, with 2 equiv CuCl and either propargyl acetate or phenyl acetylene, the major products (>56 %) displayed two 5,5'-linked triazole rings resulting from homocoupling of the 1-glucosyl-4-substituted 1,2,3-triazoles. The 4-phenyl substituted compounds (acetylated, O-unprotected) and the acetylated 4-acetoxymethyl derivative existed in solution as a single form (d.r.>95:5), as shown by NMR spectroscopic analysis. The two 4-phenyl substituted structures were unambiguously identified for the first time by X-ray diffraction analysis, as atropisomers with aR stereochemistry. This represents one of the first efficient and highly atropodiastereoselective approaches to glucose-based bis-triazoles as single atropisomers. The products were purified by standard silica gel chromatography. Through Sonogashira or Suzuki cross-couplings, the 1-glucosyl-5-halogeno-1,2,3-triazoles were efficiently converted into a library of 1,2,3-triazoles of the 1-glucosyl-5-substituted (alkynyl, aryl) type. Attempts to achieve Heck coupling to methyl acrylate failed, but a stable palladium-associated triazole was isolated and analyzed by (1)H NMR and MS. O-Unprotected derivatives were tested as inhibitors of glycogen phosphorylase. The modest inhibition activities measured showed that 4,5-disubstituted 1-glucosyl-1,2,3-triazoles bind weakly to the enzyme. This suggests that such ligands do not fit the catalytic site or any other binding site of the enzyme.
authors.affiliation: Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2, Glycochimie, UMR 5246, Université Claude Bernard Lyon 1 and CNRS, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne (France), Fax: (+33) 472-432-752.
authors.forename: David
authors.initials: D
authors.lastname: Goyard
authors.forename: Aikaterini S
authors.initials: AS
authors.lastname: Chajistamatiou
authors.forename: Anastasia I
authors.initials: AI
authors.lastname: Sotiropoulou
authors.forename: Evangelia D
authors.initials: ED
authors.lastname: Chrysina
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Praly
authors.forename: Sébastien
authors.initials: S
authors.lastname: Vidal
mesh_terms: D000818:Animals; D057930:Click Chemistry; D061565:Cycloaddition Reaction; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006031:Glycosylation; D054879:Halogenation; D007536:Isomerism; D008958:Models, Molecular; D011817:Rabbits; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014230:Triazoles; D024981:Glycogen Phosphorylase
keywords: atropisomerism; carbohydrates; click chemistry; cross-coupling; cycloaddition