The advent of epimerization-free methods for coupling in N- to C-direction synthesis offers improved atom economy for sustainable peptide synthesis.
ABSTRACT
A revolution in peptide production arrived from the innovation of carboxylate to amine C– to N-direction solid-phase synthesis. This cornerstone of modern peptide science has enabled multiple academic and industrial applications; however, the process of C– to N-solid phase peptide synthesis (C-N-SPPS) has extreme process mass intensity and poor atom economy. Notably, C-N-SPPS relies upon the use of atom-intensive protecting groups, such as the fluorenylmethyloxycarbonyl (Fmoc) protection and wasteful excess of protected amino acids and coupling agents. On the other hand, peptide synthesis in the amine to carboxylate N– to C-direction offers potential to minimize protection and may arguably enable more efficient means for manufacturing peptides. For example, efficient amide bond formation in the N– to C-direction has been accomplished using methods employing thioesters, vinyl esters, and transamidation to achieve peptide synthesis with minimal epimerization. This review aims to provide an overview of N– to C-peptide synthesis indicating advantages in taking this avenue for sustainable peptide production.
