On-resin microwave-assisted copper-catalyzed azide-alkyne cycloaddition of H1-relaxin B single chain ‘stapled’ analogues

The development of conformationally constrained analogues of bioactive peptides is a relevant goal in peptide medicinal chemistry. Among the several classes of conformationally constrained peptides, the so-called stapled peptides, which bear a side-chain-to-side-chain bridge, are particularly interesting since they offer the possibility to stabilize specific conformational elements, such as α-helices or β-turns. We describe an efficient and reproducible microwave-assisted strategy to prepare side- chain-to-side-chain clicked peptides, performing the copper-catalyzed azide-alkyne cycloaddition on solid phase, using as a model peptide a portion of the H1-relaxin B chain, which contains the binding cassette motif of this important bioactive peptide. All the relevant parameters, that is, resin, solvent, catalytic system, microwave energy and reaction time were optimized using a systematic one-factor-at-a-time (OFAT) approach. This method will be useful for the preparation of libraries of conformationally constrained relaxin analogues.