The DIC/HOBt conditions provide product of better configurational integrity but poorer yield compared to those featuring TBTU with N-methyl morpholine (NMM) as base, which gave product in higher yield but with increased degrees of epimerization. The employment of bis(1-hydroxybenzotriazole) copper complex [Cu(OBt)2] diminished epimerization significantly in the DIC coupling protocol. In the synthesis of Leu-enkephalin (39, H-Tyr-Gly-Gly-Phe-Leu-NH2), the combination of Cu(OBt)2 and DIC afforded product of higher purity (57% vs 21% HPLC purity) without racemization compared to that obtained using HATU and diisopropylamine (DIEA) which gave 5% of a diastereomer. In a related approach employing a photo-cleavable carbamate linker on a TentaGel resin, five tripeptides were synthesized with minimal epimerization by N-C-SPPS using amino acid tritert-butoxysilyl esters, HATU and 2,4,6-trimethylpyridine (TMP, collidine) as base without pre-activation. A notably higher level of epimerization occurred in the coupling of the silyl ester of isoleucine to the resin-bound Asp(Fm)-Ser(t-Bu)-OH dipeptide. Cupric chloride was found to suppress epimerization at the expense of causing resin cleavage and lower loading.