Preparation of peptides containing a reduced bond isostere reveals that the solid-phase procedure introduced by D.H. Coy is prone to generate significant levels of peptide diastereomers. A systematic study was conducted analyzing reaction conditions and reagents for causes of this epimerization. These studies show that trapping of the intermediate imine is the major contributor to generation of peptide diastereomers in the final product. These studies also suggest that careful adjustments of solvent and pH are necessary to suppress epimerization. Thus, an improved solid-phase procedure has been devised that efficiently traps the intermediate imine, resulting in extremely low levels of peptide diastereomers. These improved procedures have been successfully used in synthesis from 0.25 mmol to > 50 mmol batch sizes.