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

• Published in: European journal of organic chemistry 2024-06, Vol.27 (22), p.n/a
• Main Authors: Hagino, Rui, Komura, Naoko, Imamura, Akihiro, Ishida, Hideharu, Ando, Hiromune, Tanaka, Hide‐Nori
• Format: Article
• Language: English
• Subjects: Adenine; ADP-ribosylation; Amino acids; Biotin; Chemical synthesis; Esters; Fluorescent dyes; Glutamine; Histidine; Liquid chromatography; N-glycosidic bond formation; protecting-group-free reactions; Ribose; Stereoselectivity; traceless Staudinger ligation
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202400251

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(α)‐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 α‐selective N‐ADP‐ribosylation using unprotected β‐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 α‐selectivity and moderate yields (37–55 %). A direct and α‐selective protecting‐group‐free N‐ADP‐ribosylation through traceless Staudinger ligation is successfully developed. The stereoselectivity of this protecting‐group‐free N‐ADP‐ribosylation is comfirmed by an enzymatic degradation experiment and HPLC analysis using synthetic standards. This method enables the facile and rapid synthesis of N‐linked ADP‐ribosyl molecules with complete α‐selectivity and moderate yields.