Synthetic Organic Chemistry
One method to achieve covalent inhibitors is through sulfur fluoride exchange chemistry (SuFEx), which was identified by Sharpless in 2014. SuFEx chemistry relies upon the exchange of an incoming nucleophile with fluoride on a hexavalent sulfur forming an irreversible, covalent bond. This exchange, however, must occur under catalytic conditions whereby both the sulfonyl group and departing fluoride group are stabilized by hydrogen bonding. This imparts a degree of stability and selectivity on sulfonyl fluorides not seen with other electrophilic groups such as sulfonyl chloride, epoxides, and acrylamides. SuFEx chemistry can be categorized as “click reaction” as it operates rapidly under mild conditions in the presence of water and air.
In general, 53% of covalent inhibitors target cysteine. Cysteine, however, is the least commonly found nucleophilic residue in active sites. On the other hand, tyrosine and lysine are more abundant both in active sites and at protein-protein interfaces, yet the covalent warheads available to react with these residues selectively are quite limited. Sulfonyl fluorides are one of the rare electrophilic warheads known to react with both lysine and tyrosine. Our lab targets enzymes and proteins by targeting reactive lysine and tyrosine residues present in the active site or binding site of interest. Our small molecule libraries of sulfonyl fluorides provide a starting point for development of covalent small molecule inhibitors and probes of various protein targets.
The use of SFs is restricted by the methods by which they are synthesized. Most SFs are synthesized from the corresponding sulfonyl chloride, which in turn is either commercially available or made from sulfonylation under harsh, acidic conditions. Ultimately most SF containing small molecules are formed by coupling a pendant preformed SF to a core structure at the end of a synthetic sequence. This ultimately restricts the diversity of the obtainable structures. More useful are methods by which late stage coupling or C-H activation directly yields the SF. he use of sulfonyl fluorides in drug discovery is complicated by their synthesis. Our lab develops novel methods to forge new carbon-sulfur bonds on complex small molecule scaffolds. Efforts include the sulfonylation of heterocycles and arenes via a multitude of methods including photocatalysis, organometallic cross coupling, and organocatalysis.
Heterocyclic ring systems are found in numerous important products ranging from bioactive drug molecules, polymers, and organic materials. The ability to forge new bonds through metal-free organic reactions is critical to sustainable access to value added products. When developing new methodologies, the ability to control the reactivity of a single functional group is critical to determining the types of bond formations possible. Sulfinate salts are an example of a functional group that under varying conditions can give vastly different products. In general sulfate salts are reactive at sulfur and can be alkylated for form sulfones or can be oxidizes to form sulfonyl halides or sulfonamides. However, under radical-generating conditions alkyl sulfinates a known to be unstable and lose sulfur dioxide forming alkyl radicals, which can be further trapped by various heterocycles. This provides an efficient method to access substituted heterocycles from a similar starting material.