Solid phase synthesis of peptide C-terminal thioesters by Fmoc/t-Bu chemistry

Peptide C-terminal thioesters are key intermediates in a variety of applica tions, most notably the recently developed native chemical ligation methods for the total chemical synthesis of proteins. So far they have been prepar ed only by the use of the least prevalent Boc/benzyl solid-phase method on ad hoc prepared resin supports. We describe here a novel method for the sol id phase synthesis of thioesters by the most prevalent Fmoc/t-Bu method. Th e method is based on the use of a 3-carboxypropanesulfonamide safety-catch linker, which is fully stable to repetitive exposure to the basic condition s needed for Fmoc cleavage. Activation with diazomethane or iodoacetonitril e followed by displacement with a suitable thiol produces the thioester in good to excellent yields. The method is also compatible with Boc/benzyl che mistry. Moreover, ail the necessary reagents are commercially available.