Cyanosulfurylides (CSY): Carboxylic Acid Protecting Groups That Prevent Aspartimide Formation During Peptide Synthesis
2019-09-06T15:50:31Z (GMT) by
Peptide chemistry has made great progress in the last decades but the frequent occurrence of aspartimide formation during peptide synthesis remains a formidable challenge. Aspartimide formation leads to low yields in addition to costly purification steps or even inaccessible peptide sequences, hindering both academic research and industrial applications. Here, we report a new alternative approach to address this longstanding challenge of solid phase peptide synthesis by utilizing cyanosulfurylides to mask carboxylic acids by a stable C–C bond. These functional groups – formally zwitterionic species – are exceptionally stable to all common manipulations and impart improved solubility and processing during peptide synthesis. Deprotection is readily and rapidly achieved under mild, aqueous conditions with electrophilic halogenating agents via a highly selective C–C bond cleavage reaction. This new protecting group was employed for the synthesis a range of peptides and proteins including teduglutide, ubiquitin, and LDLa – a peptide that was not accessible on solid-phase peptide synthesis before due to three aspartimide-prone motifs. This protecting group strategy has the potential to overcome one of the most difficult aspects of modern peptide chemistry.