Direct and Stereoselective Protecting-Group-Free N-ADP-Ribosylation through Traceless Staudinger Ligation

Adenine diphosphate (ADP)-ribosylation catalyzed by bacterial toxins is the addition of an ADP-ribose moiety to specific amino acid residues in target proteins such as arginine, asparagine, glutamine, and histidine through 1,2-cis(alpha)-glycosidic bond formation. ADP-ribosylation modifies host cell functions, altering normal cellular processes to facilitate their survival, and replication. Despite the development of click chemistry and solid-phase peptide synthesis-based approaches, the synthesis of structurally well-defined naturally occurring N-linked ADP-ribosyl molecules remains challenging. Herein, we report a direct and alpha-selective N-ADP-ribosylation using unprotected beta-ADP-ribosyl azide and triphenylphosphine esters through traceless Staudinger ligation. The stereoselectivity of this protecting-group-free N-ADP-ribosylation was validated by enzymatic degradation experiment and high-performance liquid chromatography, referencing synthetic standards. This method facilitated the facile and rapid synthesis of N-ADP-ribosyl acetamide, biotin, fluorescent dye, amino acids, and tripeptide with complete alpha-selectivity and moderate yields (37-55 %).