Rapid peptide synthesis using a methylimidazolium sulfinyl fluoride salt.

Abstract

Peptide couplings have been a subject of investigation for over a century, with modern research seeking to discover new methodologies that minimize purification steps, minimize reagent expense, and/or decrease reaction times. Of the numerous coupling reagents available, sulfur(IV) fluorides have potential as they can effectively transform carboxylic acids to reactive intermediates, and the sulfite by-products can be removed through aqueous washes. Here we demonstrate the formation and capture of key acyl fluorosulfite intermediates for peptide couplings in 15 min total, without epimerization or column chromatography for purification. Dipeptides were obtained in 40-94% yields. This approach was expanded to longer chains through iterative couplings, with oligopeptides obtained in 24-57% yields, each within 2 days. Mechanistic studies indicate the reaction does not proceed through acyl fluoride intermediates, and instead involves nucleophilic catalysis. The mild conditions are tolerant of a wide range of protecting groups of canonical and non-canonical amino acids.