Tripodal amine ligands for accelerating Cu-catalyzed azide–alkyne cycloaddition: efficiency and stability against oxidation and dissociation

Abstract

Ancillary ligands, especially the tripodal ligands such as tris(triazolylmethyl)amines, have been widely used to accelerate the Cu-catalyzed azide-alkyne cycloaddition (CuAAC, a “click” reaction). However, the relationship between the activity of these Cu(I) complexes and their stability against air oxidation and ligand dissociation/exchange was seldom studied, which is critical for the applications of CuAAC in many biological systems. In this work, we synthesized twenty-one Cu(I) tripodal ligands varying in chelate arm length (five to seven atoms), donor groups (triazolyl, pyridyl and phenyl), and steric hindrance. The effects of these variables on the CuAAC reaction, air oxidation, and ligand dissociation were evaluated. Reducing the chelate arm length to five atoms, decreasing steric hindrance, or using a relatively weakly-binding ligand can significantly increase the CuAAC reactivity of the Cu(I) complexes, but the concomitant higher degree of oxidation cannot be avoided, which leads to rapid degradation of a histidine-containing peptide as a model of proteins. The oxidation of the peptide can be reduced by attaching oligo(ethylene glycol) chains to the ligands as sacrificing reagents. Using electrospray ionization mass spectrometry (ESI-MS), we directly observed the tri- and di-copper(I)-acetylide complexes in CuAAC reaction in the [5,5,5] ligand system and a small amount of di-Cu(I)-acetylide in the [5,5,6] ligand system. Only the mono-Cu(I) ligand adducts were observed in the [6,6,6] and [5,6,6] ligand systems.

Bioinspired complexes confined in well-defined capsules: getting closer to metalloenzyme functionalities

“…Moreover, it was previously reported that the addition of only 2 equivalents of GSH was sufficient to inhibit the catalytic activity of common tris(triazole)-based CuAAC catalysts. 64 This behaviour also highlights the benefits of the hemicryptophane flexibility–rigidity balance, since Cu-catalysts encapsulated in azacryptand caged ligands were found to be too structurally flexible to efficiently prevent the GSH-induced deactivation of the confined catalysts. 65…”

A Brief Guide to Preparing a Peptide–Drug Conjugate

“…The use of accelerating ligands (e. g., tris-hydroxypropyltriazolylmethylamine, THPTA) in Cucatalysed azide-alkyne cycloaddition (CuAAC) to increase the kinetics and the conversion in case of slow reactions has been described. [19] As the use of metal catalyst could represent a problem from both a biological and an environmental point of view, strained cyclooctynes have been studied as starting materials to overcome the issues associated with the use of metal catalysts, in the so-called strain-promoted azide-alkyne cycloaddition (SPAAC) reactions. [20,21] Due to the intramolecular strain, the cyclooctyne reacts readily with azide without metal catalyst at ambient temperature affording high yields of triazole product.…”

Macrocyclization strategies for cyclic peptides and peptidomimetics

“…296 Furthermore, by stabilizing the Cu I species, the ligands accelerate the reaction. 297,298 A selection of reported reaction conditions can be found in ESI † Tables S5 and S6.…”