N- to C-Peptide Synthesis, Arguably the Future for Sustainable Production

The advancement of peptide production was revolutionized by the introduction of solid-phase synthesis in the C- to N-direction, from carboxylate to amine. This foundational technique in modern peptide science has facilitated numerous academic and industrial applications. However, C- to N-solid-phase peptide synthesis (C-N-SPPS) is associated with high process mass intensity and poor atom economy. A major drawback of C-N-SPPS is its dependence on atom-intensive protecting groups, such as fluorenylmethyloxycarbonyl (Fmoc), along with the excessive use of protected amino acids and coupling reagents. In contrast, synthesizing peptides in the N- to C-direction, from amine to carboxylate, presents an opportunity to reduce reliance on protective strategies and could offer a more efficient approach to peptide manufacturing. Notably, effective amide bond formation in the N- to C-direction has been achieved through techniques involving thioesters, vinyl esters, and transamidation, allowing for peptide synthesis with minimal epimerization. This review explores N- to C-peptide synthesis, highlighting its advantages as a more sustainable alternative for peptide production.