Functionalization of amino acids with aryl fluorosulfate for prodrug construction by SuFEx chemistry

Abstract Sulfur (VI) Fluoride Exchange (SuFEx) chemistry is proposed as a new generation of click chemistry with potential in drug discovery and biological study. Herein we report a simple and convenient approach to synthesize amino acid derivatives functionalized with aryl fluorosulfonyl group from a simple building block. Promoted by 1,1′-Carbonyldiimidazole (CDI), methyl protected amino acids and other amines were efficiently functionalized with SO2F by the reaction with 4-((fluorosulfonyl)oxy)benzoic acid giving fluorosulfonylated amides (FSAs) as products. We also demonstrated that FSAs are useful building blocks in drug discovery. The conjugation of FSA with pharmaceutical phenols by SuFEx efficiently introduced amino acid moiety into target molecule, providing a series of prodrugs with diverse property.