Synthesis of N-Methylated Peptides: On-Resin Methylation and Microwave-Assisted Couplings

N-Methylation may positively influence the pharmacokinetic properties of peptides by improving oral availability and in vivo half-life. Additionally, target affinity and specificity may be improved. Here, we describe the solid-phase N-methylation of peptides using direct alkylation. This method allows a rapid N -methyl scan of synthetic, bioactive peptides. Additionally, a microwave-enhanced method for the difficult coupling onto the methylated N terminus is provided.