Streamlining SuFEx Inhibitor Development: A Unified Approach Using Orthogonal Sulfinate Protecting Groups

Sulfonyl fluorides have gained significant importance due to their classification as a click reaction and therefore have seen increased use in drug discovery and biochemistry. Their use, however, is complicated by the methods by which they are synthesized and their general synthetic instability. This results in sulfonyl fluorides being introduced late in a synthetic route with minimal structural diversity. Masking the reactivity of a sulfonyl fluoride by protecting the parent sulfinate is one method to ameliorate these issues. This study outlines discovery and selection of sulfinate protecting groups (SPGs) based on their overall stability, ease of synthesis, and simple deprotection conditions. This includes the discovery of two novel, photolabile sulfinate protecting groups (SPGs), para¬-methoxybenzyl Rongalite and ortho-nitrobenzyl Rongalite that can be directly converted to the sulfonyl fluoride using light and selectfluor. Along with known SPG, 2-trimethylsilylethyl sulfone (SES), all three SPGs were found to possess broad stability when exposed to numerous common synthetic conditions and are easily coupled to aryl halides from their sulfinate salt precursor. Overall, having access to a wide range of stable, easily functionalized SPGs will aid in increasing the structural diversity of sulfonyl fluorides.