Multicopper Clusters Enable Oxidative Phenol Macrocyclization (OxPM) of Peptides.

The biosynthesis of glycopeptide antibiotics such as vancomycin and other biologically active biaryl-bridged and diaryl ether-linked macrocyclic peptides includes key enzymatic oxidative phenol macrocyclization(s) of linear precursors. However, a simple and step-economical biomimetic version of this transformation remains underdeveloped. Here, we report highly efficient conditions for preparing biaryl-bridged and diaryl ether-linked macrocyclic peptides based on multicopper(II) clusters. The selective syntheses of ring models of vancomycin and the arylomycin cyclic core illustrate the potential of this technology to facilitate the assembly of complex antibiotic macrocyclic peptides, whose syntheses are considered highly challenging. The unprecedented ability of multicopper(II) clusters to chelate tethered diphenols and promote intramolecular over intermolecular coupling reactions demonstrates that copper clusters can catalyze redox transformations that cannot be accessed by smaller metal catalysts.

Mechanistic Insights into the FeCl3-Catalyzed Oxidative Cross-Coupling of Phenols with 2-Aminonaphthalenes.

The selective FeCl3-catalyzed oxidative cross-coupling reaction between phenols and primary, secondary, and tertiary 2-aminonaphthalene derivatives was investigated. The generality of this scalable method provides a sustainable alternative for preparing N,O-biaryl compounds that are widely used as ligands and catalysts. Based on a comprehensive kinetic investigation, a catalytic cycle involving a ternary complex that binds to both the coupling partners and the oxidant during the key oxidative coupling step is postulated. Furthermore, the studies showed that the reaction is regulated by off-cycle acid-base and ligand exchange processes.

Synthesis of Biaryl-Bridged Cyclic Peptides via Catalytic Oxidative Cross-Coupling Reactions.

Biaryl-bridged cyclic peptides comprise an intriguing class of structurally diverse natural products with significant biological activity. Especially noteworthy are the antibiotics arylomycin and its synthetic analogue G0775, which exhibits potent activity against Gram-negative bacteria. Herein, we present a simple, flexible, and reliable strategy based on activating-group-assisted catalytic oxidative coupling for assembling biaryl-bridged cyclic peptides from natural amino acids. The synthetic approach was utilized for preparing a number of natural and unnatural biaryl-bridged cyclic peptides, including arylomycin/G0775 and RP 66453 cyclic cores.