pNZ Removal Aided Aqueous Solid-Phase Peptide Synthesis: A Gateway to Sustainable Synthesis of Complex Peptides

For decades, chemists have followed Nature's lead, developing methods to make peptides in water. For the aqueous variant of the ubiquitous solid-phase peptide synthesis (ASPPS) in particular, significant advances have been reported, albeit with scope restricted to simple linear peptides. We report the aqueous removal of a p-nitrobenzyloxycarbonyl (pNZ) amino protecting group (PG) as an entry to the ASPPS of ε-Lys branched peptides. Using this new ASPPS approach, a bis-ε-Lys-amino acid (AA)-functionalized peptide resin was obtained, which upon FeCl₃/AcOH cleavage furnished a bis-ε-Lys peptide in a manner comparable to cleavage with the standard reagent TFA. This result demonstrates compatibility of ASPPS of complex peptides with PFAS-free resin cleavage, opening a new area within the realms of sustainable peptide synthesis.