Synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives from amino acids

Abstract

A versatile method for the synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives starting from easily accessible naturally occurring D-or L-amino acids as chiral synthons is described. The amino acids were converted into azido alcohols, followed by copper catalyzed [3+2] cycloaddition reactions between the azido alcohols and methyl propiolate and subsequent ester aminolysis with primary and secondary amines furnished the target compounds, which were obtained in excellent yields with no racemization. Docking of selected target compounds shows that the chiral 1,4-disubstituted-1,2,3-triazoles derivatives has the potential of mimicking the binding mode of known purine analogues.

Figure 1

(a) Docked binding mode of (R)-3 (yellow) compared to X-ray structure (1R6A) of ribavirin-5’-triphosphate (blue) 1 in the active site of the NS5MTase_DV in the dengue virus; (b) The docking shows that the NH2-groups of compound (R)-3 and ribavirin-5’-monophosphate are almost superimposed and makes the same important interaction with the carbonyl functions of Leu17 and Leu20 in the protein; (c) Docked binding mode of (R)-3 (yellow) compared to x-ray structure (1v7a) of inhibitor 2 in the active site of the ADA enzyme; (d) The imidazole part of compound (R)-3 is almost superimposed over compound 2 and the phenyl ring points in (R)-3 in the same direction as the naphtyl ring in 2.

Figure 2

Retrosynthetic strategy for the generation of chiral 1,4-disubstituted-1,2,3-triazole derivatives.

Scheme 1

Derivatisation of ester functionality with different amides. i. Amines, NaOMe, MeOH, 15 h, RT.