A Photolabile Backbone Amide Linker for the Solid-Phase Synthesis of Cyclic Peptides and C-terminal Thioesters

Introduction: A new backbone amide linker has been developed for the synthesis of cyclic and C-terminally modified peptides that permits photochemical detachment of the synthesized peptide from the solid support, thus avoiding problems associated with acid deprotection conditions. Methods: An initial survey of known photolabile motifs for their ability to produce a linker-bound model dipeptide in high yield and their ability to undergo efficient photochemical detachment of the model dipeptide found that the 6-nitroveratryl (Nve) motif afforded the most efficient release of the dipeptide. The problematic acylation of Nve-bound amino esters was solved through the development of the 2-hydroxy-4-carboxy-6-nitrobenzyl (Hcnb) linker, which utilizes an O-to-N transacylation to afford efficient acylation of even sterically hindered, linker-bound amino esters. Two different approaches were carried out to avoid/minimize diketopiperazine formation. This methodology was then used to synthesize cyclic peptides and peptide thioesters. Results: The Hcnb linker was found to afford high yields of amino acid loading, acylation, and photolytic cleavage of model tripeptides. Attachment of the Hcnb linker to the aminomethyl TG resin permitted the solid phase synthesis of representative cyclic peptides and C-terminal thioesters in high overall yield and purity. Conclusion: Hcna is a new photolabile backbone amide linker that has been used to synthesize cyclic peptides and peptide thioesters. It was found that the linker efficiently released the synthesized peptides when UV light was shed on it. This linker is also stable to acids meaning global deprotections can be done on resin and can be washed to remove by-products, releasing only the peptide upon its photocleavage from the resin.