Multicopper Clusters Enable Oxidative Phenol Macrocyclization (OxPM) of Peptides

Abstract

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.

Hexafluoroisopropanol as a Bioconjugation Medium of Ultrafast, Tryptophan-Selective Catalysis

“…HFIP and other fluorinated alcohols such as trifluoroethanol have been known to induce a certain secondary structure in peptide (formation of a helicoidal structure) due to their hydrogen-bonding capability, increased acidity of their hydroxyl group, and a high dielectric constant . In addition, there has been considerable growth in synthetic chemistry using HFIP with its unique molecular capabilities, which include stabilization of cationic species. , …”

Crafting Unnatural Peptide Macrocycles via Rh(III)-Catalyzed Carboamidation

“…25 Pappo and colleagues have recently published a Cu-catalyzed oxidative coupling of Tyr residues to form biaryl bridges. 26 In addition, Waser and colleagues have demonstrated a Au-catalyzed C(sp 2 )−H activation strategy that couples unprotected Trp residues with hypervalent iodine functional groups to generate fluorescent cyclic peptides. 27 Each of these methods takes a distinct elegant approach to producing macrocyclic structures while installing a variety of functional motifs.…”

“…MacMillan and colleagues have reported a selective Ir-catalyzed photoredox method of macrocyclization to form γ-amino acid linkages from Giese additions of carbon-centered radicals into electron deficient olefins . Pappo and colleagues have recently published a Cu-catalyzed oxidative coupling of Tyr residues to form biaryl bridges . In addition, Waser and colleagues have demonstrated a Au-catalyzed C­(sp 2 )–H activation strategy that couples unprotected Trp residues with hypervalent iodine functional groups to generate fluorescent cyclic peptides .…”

Dynamic Thermodynamic Resolution of Racemic 1,1′-Binaphthyl-2,2′-diol (BINOL)

“…In contrast, with the Nakajima catalyst, [Cu 2 (tmeda) 2 (μ-OH) 2 ]­Cl 2 [ tmeda Cu 2 Cl , 5 mol % (Figure A, green triangles)], in combination with ( R )-BINOL in acetonitrile, a slow racemization took place (60% ee after 3 h). While the [Cu 2 (tmeda) 2 (μ-OH) 2 (OTf) 2 ]­(OTf) complex ( tmeda Cu 2 OTf , blue squares) displayed an improved activity (20% ee after 3 h), a substantial rate enhancement was observed with the [Cu 2 (tmeda) 2 (μ-OH) 2 ]­Br 2 complex ( tmeda Cu 2 Br , red circles), resulting in the complete racemization of ( R )-BINOL in less than 50 min.…”