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.

M[TPP]Cl (M = Fe or Mn)-Catalyzed Oxidative Amination of Phenols by Primary and Secondary Anilines

“…The coupling between 2,6-dimethoxyphenol ( 1a , 1.5 equiv) and 3,4-dimethoxyaniline ( 2a , 1 equiv) was chosen as a model reaction; we commenced by examining catalytic conditions based on meso -tetraphenylporphyrin iron(III) chloride complex [Fe[TPP]Cl (1 mol %), t -BuOOH (2 equiv), HFIP, rt] that were developed in our group for the oxidative cross-coupling of phenols. 16 Under these conditions, benzoquinone anil 3 was obtained in 78% yield (entry 3). Other oxidants were examined; whereas urea hydrogen peroxide (UHP) afforded product 3 in a similar yield (79% yield, entry 4), meta -chloroperbenzoic acid (mCPBA) resulted in the complete decomposition of the aniline (entry 5), and dioxygen molecule (1 atm) afforded the product in poor yield (entry 6).…”

Solid-Phase Synthesis of Biaryl Cyclic Lipopeptides Derived from Arylomycins

“…The structural features of arylomycins in conjunction with their significant biological activities have prompted scientists to develop efficient methods to obtain these compounds and a diversity of analogues. 4 − 6 , 13 − 21 In particular, Romesberg and co-workers reported the total synthesis of arylomycin A 2 in solution. 4 They proposed two strategies that differed in the macrocyclization step for the formation of the biaryl macrocyclic tripeptide core.…”

“… 19 , 20 More recently, the Pappo group has devised a three-step synthesis for the cyclic core involving an activating-group-assisted catalytic oxidative coupling for the formation of the biaryl bond followed by macrolactamization. 21 …”

Carrier Protein-Free Chemo-Enzymatic Synthesis of Arylomycin A2 and Structural Characterization of the Cytochrome P450 AryC

“…Most recent work achieved catalytic oxidative cross-coupling using Fe[TPP]Cl, which in turn necessitates the application of removable tBu activating groups at the phenolic residues. 19 Taken together, despite the tremendous developments in arylomycin synthesis, there is still no catalytic route towards these antibiotics that employs un-activated aromatic amino acids, in analogy to the natural pathway. The biosynthetic machinery of the arylomycins was discovered in 2011 by Moore, Dorrestein and coworkers combining imaging mass spectrometry and genome mining.…”