The Pseudoproline Approach to Peptide Cyclization

Abstract

The development of efficient methods for the synthesis of cyclic peptides is of interest because of the many potential applications of this class of molecule. Pseudoprolines are derived from serine, threonine, and cysteine and can be used as traceless turn-inducers to facilitate the cyclization of a wide range of linear peptide precursors. The incorporation of a pseudoproline into the peptide to be cyclized generally results in a cyclization reaction that proceeds more quickly and with higher yield than that of an analogous sequence without the pseudoproline. Installation of a pseudoproline at the C-terminal position of a linear peptide sequence has also been shown to eliminate any epimerization of this residue during the reaction. Following pseudoproline-mediated cyclization, these turn-inducers can be removed on treatment with acid in a similar manner to other protecting groups to provide the native peptide sequence, and in the case of cysteine-derived pseudoprolines, the resulting cysteine can be readily converted into alanine through desulfurization. These traceless turn-inducers have been successfully used in the synthesis of cyclic peptides containing either serine, threonine, cysteine or alanine residues.