Taming sulfur – From radical alkylations to covalent sulfonyl fluoride inhibitors
The incorporation of sulfur into value added products is a vital segment of organic and medicinal chemistry. Harnessing the reactivity of sulfur is critical for the use in novel bond forming reactions whether in the context of synthetic organic methodology, biochemistry, or drug discovery. From a methodology standpoint, this involves controlling the reactivity of sulfinates, thiols, and sulfones to form new carbon-carbon or carbon-sulfur bonds through environmentally friendly and accessible means. This includes controlling desulfination of sulfinates for the radical alkylation of azine heterocycles mediated by electron donor acceptor complexes and the incorporation of functionality that protects and masks the reactivity of sulfonyl fluorides. Sulfonyl fluorides are a subset of covalent warheads that can selectively react with lysine, tyrosine, and histidine residues on proteins. 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. We have developed novel sulfinate protecting groups (SPGs) that have exceptional stability in harsh conditions such as high temperature and basic 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. They can also be incorporated onto various structures using cross coupling and photocatalysis and can be used in the development of complex SF based small molecule probes. On the drug discovery and biochemistry side, these small molecule sulfonyl fluoride libraries are used to discover lead covalent inhibitors and probes for understudied protein targets via both ligand- and electrophile-first approaches.
Hosted by Professor Spencer Knapp