Toward solid-phase peptide fragment ligation by a traceless-Ugi multicomponent reaction approach

Abstract

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.

Convenient two-step synthesis of highly functionalized benzo-fused 1,4-diazepin-3-ones and 1,5-diazocin-4-ones by sequential Ugi and intramolecular S N Ar reactions

“…Lower conversion rates and yields were observed with shorter reaction times (entries 1 and 2). MW irradiations have been shown to accelerate and improve Ugi-4CR 33,51,52,67,68 but in our case no significant improvement was observed after 1 or 2 h of MW heating at 60°C (entries 4 and 5). For this reason and based on the possibility to perform parallel synthesis more efficiently, the room temperature condition was selected to conduct the next experiments.…”

Improved Stability and Tunable Functionalization of Parallel β‐Sheets via Multicomponent N‐Alkylation of the Turn Moiety

“…Thus, we aimed at finding out whether the turn-inducing capacity of the N-alkylated peptidomimetic fragment is sufficient to fold the peptides into parallel b-sheets without the positive influence of the Thorpe-Ingold effect provided by the geminal methyl substituents. The versatility of the MCR method also enabled the facile synthesis of the non-N-alkylated b-sheet, peptide 8, using the acid-labile 2,4-dimethoxyphenyl substituent [17] (arising from the aldehyde component), which allows the cleavage at that specific position. Scheme 2 B (upper panel) shows a comparison of the circular dichroism (CD) spectra in acetate buffer (AcB) of the N-alkylated peptides 5 a, 6 a, and 7 a with the non-N-alkylated one (8), all based on the DADME residue.…”

Development of a solid‐phase traceless‐Ugi multicomponent reaction for backbone anchoring and cyclic peptide synthesis

“…Our strategy was based on a traceless‐Ugi multicomponent reaction we have recently described to efficiently couple peptide fragments on solid support (Figure a) . Because it involves the reaction of isocyanide, carboxylic acid, amine and carbonyl compounds to afford a α‐acylamino amide, the Ugi four‐component reaction (Ugi‐4CR) is a very attractive approach to form N ‐substituted peptide bonds and perform one‐pot backbone anchoring.…”

“…Because it involves the reaction of isocyanide, carboxylic acid, amine and carbonyl compounds to afford a α‐acylamino amide, the Ugi four‐component reaction (Ugi‐4CR) is a very attractive approach to form N ‐substituted peptide bonds and perform one‐pot backbone anchoring. In this previous study, an on‐resin Ugi‐4CR was used 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 was efficiently removed by microwave‐assisted acidolysis with trifluoroacetic acid (TFA) to afford a fully deprotected peptide.…”