After much refinement, C-N-SPPS remains the contemporary paradigm for peptide production, because sequential elongation enables use of N-protected amino acids without the need for purification after each coupling and deprotection step. Immobilization of the growing peptide chain on an insoluble polymer resin simplified the purification process by eliminating the isolation of intermediates and paved the way for the construction of longer and more complex peptides. Scheme 2. Letsinger Nto C-direction solid-phase peptide synthesis In 1963, Letsinger and Kornet introduced Nto C-solid-phase peptide synthesis (N-C-SPPS), stating that the "recent publication by Merrifield describing the synthesis of a tetrapeptide on polymer beads prompt us to report at this time experiments carried out independently which demonstrate the feasibility of using a modified 'popcorn' polymer as a supporting matrix in repetitive-step syntheses." The "popcorn" polymer was, in fact, a variant of the reticulated polystyrene that Merrifield had employed except that it was converted into chloroformate 12 for introducing the first residue as an amino ester (Scheme 2). In contrast to the tetrapeptide prepared by C-N-SPPS, a dipeptide was made in the Nto C-direction using ester saponification, mixed anhydride coupling, and resin cleavage with strong acid. Commenting on the N-C-SPPS in 1965, Merrifield stated that although "a dipeptide was synthesized in this way, the danger of racemization might limit the usefulness of this procedure for longer peptides". The so-called "danger of racemization" was known at the time based on various pioneering studies. For example, as reviewed by Neuberger, Bergmann and Zervas hypothesized in 1929 that amide protected amino acids could undergo racemization by way of oxazolone intermediates. By the early sixties, various researchers including Bodanszky, Goodman, Williams and Young, all had confirmed the problem of racemization of oxazolone intermediates in carboxylate activation of peptides and noted faster rates of epimerization compared with carbamate protected amino acid counterparts. For example, 84fold higher rates of racemization were observed in the coupling to valine methyl ester of N-Cbz-glycyl-L-methionine pentafluorophenyl ester compared to N-Cbz-L-methionine counterpart in THF using triethylamine as base.