The reason for the difference in racemization rates was elegantly examined by Benoiton, who in the 1980's, reported on the optical integrity of the 2-alkoxy-5(4H)-oxazolones, which were used in coupling reactions without racemization. In head-to-head comparisons, "the chiral stability" of the 2-alkoxy-5(4H)-oxazolones (e.g., S-19a and S-19b) contrasted with that of the 2-alkyl-5(4H)-oxazolones (e.g., S-19c and S-19d) which could not "be coupled without extensive racemization". In other words, both carbamate and amide protected amino acids underwent oxazolone formation; however, the 2-alkoxy-was less prone than the 2-alkyl-5(4H)oxazolone to form the hydroxy-oxazole intermediate (e.g., 20) and epimerize prior to coupling (Figure ). Notably, under basic conditions, both oxazolones were susceptible to epimerization but at different rates. Inspired by reports that alternative activation methods could avoid racemization of amide protected amino acids, especially the conditions of Honzl and Rudinger for preparing and coupling N-protected amino azides without side product from Curtius rearrangement, Felix and Merrifield examined N-C-SPPS in 1970 using peptide azides (Scheme 3). In a proof of concept synthesis, tetrapeptide 10 (H-Leu-Ala-Gly-Val-OH) was prepared using N-C-SPPS with acyl azide activation and shown to possess identical properties as material made by C-N-SPPS. Scheme 3. Azide activation in N-C-SPPS after N'-protected hydrazide couplings and deprotections.