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

Abstract

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.

Oxidative Photocatalytic Homo- and Cross-Coupling of Phenols: Nonenzymatic, Catalytic Method for Coupling Tyrosine

“…Our final endeavor aimed to achieve the direct catalytic coupling of tyrosine. Although a highly efficient oxidative and catalytic method for coupling tyrosine derivatives was recently reported, a tert- butyl group positioned ortho to the phenol was required to obtain a high conversion, which we had also observed independently (Figure , 2r, 2s, 2t ). While this group can be readily removed in excellent yield, its use is not ideal due to the decrease in step-economy.…”

“…Remarkably, electron-poor CF 3 -aryl-substituted phenols ( 2l, 2o ) provided higher conversion and yield than electron-rich MeO-aryl-substituted phenols ( 2j , 2m ), which is an unexpected outcome, as electron-poor phenols are typically less easily oxidized (vide infra). Additionally, the ortho-tert -butyl-substituted tyrosine substrate ( 2r ) afforded the highest isolated yield, indicating the synthetic utility of this method as found independently by Pappo and co-workers . In certain cases, 1,2-dichloroethane was added as a cosolvent with HFIP to ensure complete solubility of reaction components over the time course of the reaction.…”

“…More recently, in 2020, the Pappo group leveraged the presence of a tert-butyl activating group on tyrosine, which had been reported by us and others as a removable group that activates phenols toward oxidative coupling and blocks additional reactive sites, 29−32 to effect the synthesis of several arylomycin analogues via an intermolecular iron-catalyzed tyrosine coupling (Scheme 1d). 33 Herein, we disclose a photocatalytic process to accomplish such couplings without the aid of a directing group (Scheme 1e). 34 Our initial approach involved screening our library of oxidizing transition metal catalysts in the coupling of tyrosine and related phenols but revealed no reactivity and recovery of starting material.…”

Advances in C(sp2)−H/C(sp2)−H Oxidative Coupling of (Hetero)arenes Using 3d Transition Metal Catalysts

“…In addition to the synthesis of biphenols and binaphthols, Pappo has explored the iron‐catalyzed protocol to synthesize cyclic peptides via oxidative cross‐coupling of phenol derivatives (Scheme 17). [40] Thus, the biologically important cyclic peptides containing biaryl‐bridges were achieved using Fe[TPP]Cl ( 11 ) as a catalyst and m ‐CPBA oxidant in dichloromethane. The reaction generally involves oxidative coupling, macrolactonization and removal of activating group (AG) to obtain the desired peptides.…”

Carrier Protein‐Free Enzymatic Biaryl Coupling in Arylomycin A2 Assembly and Structure of the Cytochrome P450 AryC**

“…This elegant approach, however, requires two equivalents of the copper reagent. Most recent work achieved catalytic oxidative cross‐coupling using iron(tetraphenylporphyrinato) chloride (FeCl[TPP]), which in turn necessitates the application of removable tert ‐Butyl ( t Bu) activating groups at the phenolic residues [16] . Taken together, despite the tremendous developments in arylomycin synthesis, there is still no catalytic route available that employs non‐activated aromatic amino acids, in analogy to the natural pathway.…”