Mimetics of ADP-Ribosylated Histidine through Copper(I)-Catalyzed Click Chemistry.

A convergent synthesis provided nearly perfect τ-ADP-ribosylated histidine isosteres (His*-τ-ADPr) via a copper(I)-catalyzed cycloaddition between an azido-ADP-ribosyl analogue and an oligopeptide carrying a propargyl glycine. Both α- and β-configured azido-ADP-ribosyl analogues have been synthesized. The former required participation of the C-2 ester functionality during glycosylation, while the latter was obtained in high stereoselectivity from an imidate donor with a nonparticipating -methoxy benzyl ether. Four His*-τ-ADPr peptides were screened against a library of human ADP-ribosyl hydrolases.