Neutral-pH pNZ Removal Enables Fully Aqueous Solid-Phase Synthesis of Linear and ε-Lys-Branched Peptides

Aiming to emulate Nature by synthesizing peptides in water, we report pH ∼ 7 Na2S2O4/DIEA-induced pNZ removals as a means of enabling fully aqueous solid-phase peptide synthesis (SPPS). Furthermore, pNZ removal in water was applied to SPPS of ε-Lys-branched peptides and hybrid pNZ/Fmoc SPPS. Finally, combining our methods for SPPS in water with TFA-free resin cleavages opens the door to fully aqueous, PFAS-free approaches to a variety of complex peptides.