Macrolactamization Approaches to Arylomycin Antibiotics Core

Lim, Ngiap‐Kie; Linghu, Xin; Wong, Nicholas; Zhang, Haiming; Sowell, C. Gregory; Gosselin, Francis

doi:10.1021/acs.orglett.8b03603

Cited by 23 publications

(16 citation statements)

References 29 publications

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“…Whereas approach A relies on the macrocyclic coupling of phenol‐based linear peptides, approach B requires chemoselective cross‐coupling between two discrete phenol‐based amino acids, followed by a macrolactamization step. For example, the Romesberg group prepared the arylomycin cyclic core 4 in 14 synthetic steps using a palladium‐catalyzed cross‐coupling strategy according to approach A, whereas the Lim group reported an improved synthesis based on approach B . The total synthesis of other bioactive dityrosine‐containing macrocyclic peptides, such as RP 66453 ( 3 , Figure A) has also been achieved using various palladium‐catalyzed cross‐coupling strategies .…”

Section: Figurementioning

confidence: 99%

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

et al. 2020

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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.

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Section: Figurementioning

confidence: 99%

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

et al. 2020

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“…The first total syntheses relied on the preparation of linear peptide precursors followed by macrocyclization by Suzuki‐Miyaura reaction [10–12] . Further work provided elevated yields to the macrocyclic arylomycin core by macrolactamization [13] and improved Suzuki‐Miyaura macrocyclization [14] . Romesberg and Baran enabled access to the macrocycle by C−H functionalization of the unmodified aromatic amino acids by copper‐mediated oxidative phenol coupling [15] .…”

Section: Figurementioning

confidence: 99%

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

Aldemir

Shu

Schaefers

et al. 2021

Chemistry A European J

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The arylomycin antibiotics are potent inhibitors of bacterial type I signal peptidase. These lipohexapeptides contain a biaryl structural motif reminiscent of glycopeptide antibiotics. We herein describe the functional and structural evaluation of AryC, the cytochrome P450 performing biaryl coupling in biosynthetic arylomycin assembly. Unlike its enzymatic counterparts in glycopeptide biosynthesis, AryC converts free substrates without the requirement of any protein interaction partner, likely enabled by a strongly hydrophobic cavity at the surface of AryC pointing to the substrate tunnel. This activity enables chemo‐enzymatic assembly of arylomycin A2 that combines the advantages of liquid‐ and solid‐phase peptide synthesis with late‐stage enzymatic cross‐coupling. The reactivity of AryC is unprecedented in cytochrome P450‐mediated biaryl construction in non‐ribosomal peptides, in which peptidyl carrier protein (PCP)‐tethering so far was shown crucial both in vivo and in vitro.

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“…Fmoc removal (14) with DBU and attachment of Fmoc-L-HPG with COMU/NEt3 in DMF furnished tripeptide 15. Removal of the Fmoc protection group (16) and installation of an N-ortho-nitrobenzenesulfonyl (NBS) group (17) set the stage for selective mono N-methylation to 18 following Kessler's protocol. 23 Removal of NBS using mercaptoethanol liberated the amine 19, permitting installation of the lipopeptide chain 11b directly on resin to give 20b.…”

mentioning

confidence: 99%

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

Aldemir

Shu

Schaefers

et al. 2021

Preprint

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Most antibiotics in clinical use are inspired by natural products. Prominent examples are the glycopeptides, such as vancomycin. These compounds contain biaryl-and biaryl-ether bonds that are crucial for biological activity and biosynthetically get installed by dedicated cytochrome P450 enzymes. The application of these biocatalysts in the chemo-enzymatic synthesis of novel glycopeptides has been impeded by their strict requirement for peptidyl carrier-protein (PCP) bound substrates and additional X domain interactions. This necessitates equimolar amounts of protein tethers, precluding truly catalytic applications. We describe the functional and structural evaluation of AryC, the cytochrome P450 performing biaryl coupling in biosynthetic arylomycin assembly, and its application in the chemo-enzymatic synthesis of arylomycin A2. AryC efficiently converts free substrates without the requirement of any protein interaction partner, likely enabled by a strongly hydrophobic cavity at the surface of AryC pointing to the substrate tunnel. The resulting reactivity of AryC is unprecedented in cytochrome P450-mediated biaryl construction in non-ribosomal peptides, in which PCP-tethering so far was crucial both in vivo and in vitro. Our work thus provides a basis for the development of general biocatalytic platforms for the efficient biocatalytic synthesis of biaryl peptide antibiotics.

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Macrolactamization Approaches to Arylomycin Antibiotics Core

Cited by 23 publications

References 29 publications

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

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

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

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

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