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.

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.