On-resin synthesis of novel arginine-isostere peptides bearing substituted amidine headgroups

A methodology is presented for the facile synthesis of Arg-containing peptides modified at the guanidine headgroup as substituted amidine cores. This process allows for the iterative construction of these Arg isosteres while the peptide is being built out on the solid support, providing a high potential for diversity in substitution pattern in the resulting peptide. A series of N-Pmc-substituted thioamides were condensed with deprotected δ-N Orn-bearing peptides while attached to the solid support using Mukaiyama's reagent as coupling reagent, yielding isosteric Arg-containing analogs. Peptides were cleaved using trimethylsilyl trifluoromethanesulfonate/TFA and analyzed in their crude form in order to illustrate the amenability of this process toward production of peptide isolates in high crude purity. Arg-containing peptides having a single Arg isostere were utilized to show the general utility of this approach as well as a multiple-Arg-containing construct, illustrating the amenability of this method toward stepwise construction of differently substituted amidine headgroups within the same peptide. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.