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.
A Tetrazine-Labile Vinyl Ether Benzyloxycarbonyl Protecting Group (VeZ): An Orthogonal Tool for Solid-Phase Peptide Chemistry
