Hydroxproline peptides are a rich source of drug-like molecules. Small and medium-sized proline containing cyclo-peptides can be attributed to their low molecular weight, favorable pharmacokinetic characteristics, and structural support for a wide range of functional groups. These cyclic peptides, however, are underrepresented in clinical use due to synthetic challenges, most notably the cyclization of a corresponding linear peptide. This is primarily due to the difficulty inherent in bringing the termini sufficiently close together allowing cyclization to induce. In order to overcome these challenges, we have formulated a methodology in which Salicylaldehyde ester-induced chemoselective ligation lactamization with hydroxyproline as a novel ring-closing/contraction method. In addition, this methodology will provide an efficient and powerful tool for the synthesis of medium-sized cyclic peptides, currently too difficult to synthesize with traditional synthetic methods, by bypassing the high energy barrier needed to overcome backbone strain with a quick and chemoselective ring-closing capture, followed by ring contraction.

New coupling and cyclization strategy for peptide synthesis via chemoselective three-fragment hydroxyproline ligation

249th National Meeting (2015)

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