Protecting‐Group‐Free Synthesis of ADP‐Ribose and Dinucleoside Di‐/Triphosphate Derivatives via P(V)‐P(V) Coupling Reaction

Abstract

AbstractBiomolecules containing adenosine di‐ or triphosphate (ADP or ATP) are crucial for diverse biological processes. Synthesis of these biomolecules and development of their chemical probes are important to elucidate their functions. Enabling reproducible and high‐yielding access to these ADP‐ and ATP‐containing molecules via conventional P(III)‐P(V) and P(V)‐P(V) coupling reactions is challenging owing to water content in highly polar phosphate‐containing substrates. Herein, we report an efficient and reliable method for protecting‐group‐free P(V)‐P(V) coupling reaction through in situ activation of phosphates using hydrolysis‐stable 2‐[N‐(2‐methylimidazoyl)]‐1,3‐dimethylimidazolinium chloride (2‐MeImIm‐Cl), providing the corresponding electrophilic P(V) intermediates for subsequent nucleophilic attack using their coupling partners. This P(V)‐P(V) coupling reaction proceeded even in a wet reaction medium and showed a broad substrate scope, accommodating protecting‐group‐free synthesis of ADP‐ribose and nicotinamide adenine diphosphate analogs, ATP‐containing biomolecules, and ADP‐ribosyl peptides.