Strategies for the Solid-Phase Diversification of Poly-l-proline-Type II Peptide Mimic Scaffolds and Peptide Scaffolds Through Guanidinylation

A strategy for the solid-phase diversification of PPII mimic scaffolds through guanidinylation is presented. The approach involves the synthesis <i>N</i>-Pmc-<i>N</i>′-alkyl thioureas as diversification reagents. Analogues of Fmoc-Orn(Mtt)-OH can be incorporated into a growing peptide chain on Wang resin. Side chain deprotection with 1% TFA/CH<sub>2</sub>Cl<sub>2</sub> followed by EDCI-mediated reaction of <i>N</i>-Pmc-<i>N</i>′-alkyl thioureas with the side chain amine affords arginine analogues with modified guanidine head groups. The scope, limitations, and incidental chemistry are discussed.