A modular flow platform for sulfur(VI) fluoride exchange ligation of small molecules, peptides and proteins

Sulfur(VI) fluoride exchange click chemistry is a formidable tool to rapidly and effectively link chemical structures. Despite advances in the field in recent years, the installation of the sulfonyl fluoride handle still requires the use of purpose-designed, expensive and non-atom-economic reagents. The use of the SO2F2 for sulfonyl fluoride synthesis has been thwarted by the difficulties associated with the manipulation and dosage of this toxic gas, and by its apparent low reactivity with amino functionalities. Here we report a modular flow platform that can generate on demand, and efficiently dose, gaseous SO2F2. The use of flow technologies allows many lingering limitations of this transformation to be overcome, resulting in reduced reaction times, efficient reactivity and broad substrate scope. The effectiveness of the process was demonstrated by the successful synthesis of a diverse set of fluorosulfates and sulfamoyl fluorides, including those derived from biorelevant compounds, peptides and proteins. The use of gaseous sulfuryl fluoride in sulfur(VI) fluoride exchange reactions is a challenge. Now, a flow set-up for the on-demand generation and onward reaction of sulfuryl fluoride, from sulfuryl chloride, is reported. The process produces fluorosulfate and sulfamoyl fluoride analogues of small molecules, peptides and proteins.