The Hosoya group previously reported that a copper(I) salt, tetrakis(acetonitrile)copper(I) tetrafluoroborate or (MeCN)4CuBF4, could reversibly protect cyclooctynes from reacting with azides. This strategy builds on the finding that various metals can form complexes with cycloalkyne rings, which led us to examine copper as an additive to prevent the acid-mediated 5-endo-dig cycloisomerization of DBCO. Guided by the methodology reported by the Hosoya group, initial attempts at protecting peptides 1a and 2a were performed by treating peptide resins with ~3 equiv. (MeCN)4CuBF4 in dimethylformamide (DMF) for 1 h. The resin was then washed with DMF and dichloromethane (DCM) before cleavage in the standard cocktail at rt for 3 h. Standard ether precipitation and air drying produced the crude DBCO peptides. As envisioned, a transient DBCO-Cu complex was protected from acid-promoted ring rearrangement, and the resultant DBCO peptide product 1a was able to react with excess 6-azidohexanoic acid (Figure ). However, we discovered that (MeCN)4CuBF4 caused premature cleavage of peptides assembled on 2-chlorotrityl chloride resin. Additionally, the Cu(I) salt reacted with the C-terminal hydrazide-containing peptide 2a to form undesired side products (Figure ). Switching the solvents used to dissolve (MeCN)4CuBF4 (DCM, N-methylpyrrolidone, methanol, and MeCN) did not overcome these side reactions (Figures ).