A modular flow platform enables selective and fast SuFEx ligation of small molecules, peptides, and proteins

SuFEx click chemistry has established itself as a formidable tool to rapidly and effectively link chemical structures. Despite tremendous advancements in the field in recent years, the installment of the crucial -SO2F handle still requires the use of purposely designed, expensive, and non-atom economical reagents. However, the use of the most obvious reagent, SO2F2, has been twarthed by the difficulties associated with the manipulation and dosage of this toxic gas, as well as its apparent low reactivity with amino functionalities. Herein, we disclose a modular flow platform, which is able to generate on demand, and safely dose, gaseous SO2F2. Due to the use of flow technology, many lingering limitations of this transformation could be overcome, resulting in significantly reduced reaction times, high reactivity and exceptional reaction 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.