Exploring chemoselective S-to-N acyl transfer reactions in synthesis and chemical biology

C hemoselectivity refers to the preferential reaction of a single chemical reagent with one of two or more different functional groups1. One of the most formidable challenges presented to synthetic chemists involves achieving high levels of chemoselectivity and regioselectivity amongst the myriad of reactive functionalities present in biological systems. Despite the onerous challenges, chemists continue to discover and develop robust and efficient chemical ligation methodologies that enable exquisitely high levels of selectivity2–4. The chemoselective formation of amide bonds is a critical reaction in biology for protein synthesis and post-translational modification of proteins (PTMs), it is also widely utilized in organic synthesis and medicinal chemistry5–7. Amide bond formation requires chemoselective ligations that can furnish specific amide products in the presence of functional groups such as unprotected amines, carboxylic acids and alcohols6,7. The chemoselectivity of the S-to-N acyl transfer process arises from the unique reactivity of thioesters that renders them ideal intermediates for acyl transfer processes. Thioesters have been found to be more reactive then the corresponding oxoesters towards most nucleophiles (with the notable exception of hydroxide and alkoxides). The enhanced reactivity of thioesters may be due to a poor C-S p overlap that lowers the overall thermodynamic stability of the thioester relative to the oxoester8–10. Thioesters have been exploited as reactive intermediates by chemists to perform sophisticated ligation reactions under neutral conditions in an aqueous environment and have inspired a recent surge in the development of synthetic and biosynthetic ligation methodologies11–15. Efficient cascade processes involving thioester formation and subsequent acyl transfer to N-, Oor Segroups are at the core of several critical biological processes14. For example, Acetoacetyl-CoA functions as an efficient acyl transfer reagent in the Krebs cycle16. Thioesters are also key intermediates in protein ubiquitination17,18, intein splicing19,20 and the covalent modification of bacterial cell-surface proteins21,22. Thioesters are formed in transglutamination and in glutathione (GSH) biosynthesis. The abundance of thioester mediated processes in nature has led to speculation regarding the role of these derivatives in the origin of life23. In this review we DOI: 10.1038/ncomms15655 OPEN