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.
To increase the chemical diversity accessible with peptoids and peptide-peptoid hybrids, N-alkylated arylsulfonamides were used to prepare side chain protected N-substituted glycines compatible with solid-phase synthesis. The described procedures give access to peptoid monomers bearing a wide variety of functional groups from commercially available amines in four straightforward steps. The prepared N-substituted N-arylsulfonylglycines were used as monomers in solid-phase synthesis to introduce relevant functionalized side chains into peptoid oligomers and peptide-peptoid hybrids.
A new one‐pot methodology to anchor peptides by their backbone to a solid support using an isocyanide‐based multicomponent reaction is described. The approach uses a microwave‐assisted Ugi four‐component reaction to simultaneously condense and bind an N‐protected amino acid and an amino ester to a supported aldehyde. Afterward, the generated backbone anchored dipeptide can be used in solid‐phase peptide synthesis to prepare head‐to‐tail cyclic peptides. Moreover, we also show that peptide fragment ligation can be performed with the described one‐pot anchoring. The backbone anchored peptides can be efficiently released from the resin by microwave‐assisted acidolysis with trifluoroacetic acid. This straightforward one‐pot anchoring approach was also applied to condense fragments and prepare a variety of linear and macrocyclic peptides.
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