Peptide with C-terminal aldehyde is of interest due to its property as a transition-state analogue toward numerous classes of proteolytic enzymes; aspartyl-, and cysteine protease are inhibited by peptide aldehyde. Since leupeptin is produced by actinomycetes, which inhibit a variety of proteases potently, natural peptide aldehydes are attractive targets for drug discovery. Peptide aldehyde can also be used as a key intermediate in the syntheses of pseudo-peptides, particularly in the synthesis of reduced peptide by reduced fragment condensation. Though several methods for solid phase synthesis of peptide aldehyde have been reported, there is a restriction to prepare a variety of peptide sequences.

     We prepared several peptide aldehydes on a solid support since the aldehyde group seems to be effective for the thiol functional group of cysteine protease. At that time, we found that the conversion of an acetal to an aldehyde was quite slow but that the thioacetal can be efficiently converted into the desired aldehyde by treatment with N-bromo succinimide (NBS). In the presentation, we report a practical synthetic route for the preparation of several peptide aldehydes with different amino acids and commercially available linkers on a solid support. Although treatment of resin with EtSH and catalytic BF₃-Et₂O followed by the addition of NBS as a one-pot reaction afforded the corresponding peptide, the yields markedly depended on the nature of the sequence, especially C-terminal amino acid. On the other hand, stepwise conversion was effective to obtain the designed peptide aldehyde using isolated thioacetal.