On the other hand, Nto C-direction peptide synthesis has strong potential to impact on "green" manufacturing approaches. As de la Torre and Albericio have noted, "A major reduction in atom economy will call for major efforts to be channelled into the development of a totally new concept of peptide synthesis. This concept is likely to consist of minimizing the presence of protecting groups following a similar approach to that used for native chemical ligation." In this context, activation of the carboxylate as thioacid offers significant potential for minimizing protection and mimicking the advantages of native chemical ligation. Combined with methods, such as mechanochemistry, which reduce solvent use and have shown promise for Cterminal activation of peptide fragments in couplings without racemization, Nto C-direction peptide synthesis offers significant potential for reducing PMI. Improvements in product purification after Nto C-direction peptide synthesis may similarly arise from application of soluble supports for N-terminal anchoring. The notably improved overall yield compared to the Cto N-approaches in the synthesis of the active pharmaceutical ingredient (API) carfilzomib using vinyl ester activation bears well for the application of Nto C-direction strategies in the future. Further investment and research into enabling strategies for peptide anchoring, purification, and elongation under conditions that minimize the use of environmentally benign solvent and reagents are likely to complement advances in amido acid coupling without epimerization with minimal side chain protection to solidify the advantages of Nto C-direction peptide synthesis. Examining the recent achievements and the potential of this atom economical approach, the arguments indicate strongly that Nto C-peptide synthesis merits future application for sustainable production N-to C-SPPS Ghosh and Lubell