Toward solid-phase peptide fragment ligation by a traceless-Ugi multicomponent reaction approachElectronic supplementary information (ESI) available: Detailed experimental procedures, analytical and characterization data for all compounds. See DOI: 10.1039/c6ob02342h

A new methodology to couple peptide fragments on solid support using a traceless isocyanide-based multicomponent reaction is described. The approach uses a microwave-assisted on-resin Ugi four-component reaction to attach a carboxyl free peptide to a supported peptide bearing a free N-terminal amine via the formation of an N -protected amide bond at the ligation site. Afterward, the generated backbone amide protecting group can be efficiently removed by microwave-assisted acidolysis with trifluoroacetic acid to afford a fully deprotected peptide. This straightforward Ugi reaction/deprotection approach was applied to condense various fragment lengths and provided a variety of oligopeptides. Peptide fragments have been efficiently condensed by sequential on-resin Ugi four-component reaction and microwave-assisted backbone amide deprotection.