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

Sulfonyl fluorides (SFs) 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 SFs 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. Current sulfinate protecting groups (SPGs), however, possess limited stability. This study outlines the discovery and selection of SPGs based on their overall stability, ease of synthesis, and simple deprotection conditions. This includes the discovery of two novel, photolabile 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. Their utility is then demonstrated in the synthesis of SPG containing building blocks that are incorporated into several bioactive small molecules.