Functionalization Of Amino Acids With Aryl Fluorosulfate For CA-4 Prodrug Construction By SuFEx Chemistry

Objective:Sulfur?VI?Fluoride Exchange?SuFEx?chemistry is proposed as a new generation of click chemistry with potential in organic chemistry and medicinal chemistry.Herein,we hope to design a simple and convenient approach to synthesize amino acid with aryl fluorosulfate derivatives by using 4-??fluorosulfonyl?oxy?benzoic acid as a simple building block and amino acids as substrates.Methods:Promoted by N,N?-Carbonyldiimidazole?CDI?,methyl protected amino acids and other amines were efficiently functionalized with SO₂F via the reaction with 4-??fluorosulfonyl?oxy?benzoic acid giving fluorosulfonylated amides?FSAs?as products.Results:With 4-??fluorosulfonyl?oxy?benzoic acid as fluorosulfonylation reagent,the coupling reaction of amino group and carboxyl group were achieved by using N,N?-Carbonyldiimidazole.The optimal condition of the reaction was obtained by screening.In this report,25 new compounds were synthesized and determined by nuclear magnetic resonance?NMR?,high resolution mass spectrometry?HRMS? and IR spectra.Conclusion:we have successfully developed a two-step,one-pot strategy for introduction of aryl fluorosulfate into amino acids by employing CDI as an efficient coupling reagent.The reaction conditions are mild,the operation is simple and the raw materials are cheap and easy to obtain.The application of fluorosulfonyl amides?FSAs?was further explored,and the corresponding Combretastatin A-4 prodrugs were obtained by SuFEx reaction.