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

Invited for the cover of this issue are Sabine Schneider, Tobias A. M. Gulder and co-workers at Technical University of Dresden, Technical University of Munich and Ludwig-Maximillians-University Munich. The image depicts the crystal structure of the cytochrome P450 AryC from arylomycin biosynthesis. Read the full text of the article at 10.1002/chem.202103389.

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

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.

Chemoenzymatic Total Synthesis of Sorbicatechol Structural Analogues and Evaluation of Their Antiviral Potential.

Sorbicillinoids are fungal polyketides characterized by highly complex and diverse molecular structures, with considerable stereochemical intricacy combined with a high degree of oxygenation. Many sorbicillinoids possess promising biological activities. An interesting member of this natural product family is sorbicatechol A, which is reported to have antiviral activity, particularly against influenza A virus (H1N1). Through a straightforward, one-pot chemoenzymatic approach with recently developed oxidoreductase SorbC, the characteristic bicyclo[2.2.2]octane core of sorbicatechol is structurally diversified by variation of its natural 2-methoxyphenol substituent. This facilitates the preparation of a focused library of structural analogues bearing substituted aromatic systems, alkanes, heterocycles, and ethers. Fast access to this structural diversity provides an opportunity to explore the antiviral potential of the sorbicatechol family.

Chemo-enzymatic total synthesis of the spirosorbicillinols.

The natural product class of the sorbicillinoids is composed of structurally diverse molecules with many strong, biomedically relevant biological activities. Owing to their complex structures, the synthesis of sorbicillinoids is a challenging task. Here we show the first total synthesis of the fungal sorbicillinoids spirosorbicillinols A-C. The convergent route comprises the chemo-enzymatic transformation of sorbicillin to the highly reactive sorbicillinol and the assembly of scytolide and isomers starting from shikimic and quinic acid analogs. The key step in the total synthesis is the fusion of both building blocks in a Diels-Alder cycloaddition leading to the straightforward formation of the characteristic sorbicillinoid bicyclo[2.2.2]octane backbone. This work provides unifying access to all natural spirosorbicillinols and unnatural diastereomers.

One-pot synthesis of functionalized bis(trifluoromethylated)benziodoxoles from iodine(I) precursors.

Bis(trifluoromethylated)benziodoxoles (Bx) are broadly used cyclic hypervalent iodine reagents due to their stability and unique chemical properties. However, current methods to access them require several steps and long reaction times, making their synthesis tedious. Herein, a direct one-pot synthesis of bis(trifluoromethylated) Bx reagents from iodine(I) precursors is reported, enabling the synthesis of functionalized reagents.

Antibiotic Potential of the Ambigol Cyanobacterial Natural Product Class and Simplified Synthetic Analogs.

The ambigols are cyanobacterial natural products characterized by three polychlorinated aromatic building blocks connected by biaryl and biaryl ether bridges. All ambigols known to date possess promising biological activities. Most significantly, ambigol A was reported to have antibacterial activity against Gram-positive bacteria, such as Bacillus megaterium and B. subtilis. We established a diverse compound library for in-depth biological evaluation building on our previous bio- and total synthetic research on this natural product family. To explore the antimicrobial potential in detail and to determine initial structure-activity relationships of this product class, a large set of dimeric and trimeric compounds were screened against selected bacterial and Candida target strains. Our results reveal exceptional antibiotic activity of the ambigols, especially against challenging clinical isolates.

Total Synthesis of the Ambigols: A Cyanobacterial Class of Polyhalogenated Natural Products.

The first total synthesis of all members of the cyanobacterial natural product class of the ambigols is described. Key steps of the synthetic strategy are the formation of sterically demanding mono- and bis-iodonium salts to install the required biaryl ether structural elements and Suzuki cross-coupling giving straightforward access to the biaryl bonds. The synthetic methods are also utilized to construct unnatural or hypothetical ambigols that are still awaiting discovery from Nature.

Bypassing Biocatalytic Substrate Limitations in Oxidative Dearomatization Reactions by Transient Substrate Mimicking.

Enzymatic oxidative dearomatization is an efficient way to generate chiral molecules from simple arenes. One example is the flavin-dependent monooxygenase SorbC involved in sorbicillinoid biosynthesis. However, SorbC requires a long-chain keto substituent at its phenolic substrate, thus preventing its application beyond the synthesis of natural sorbicillinoids or close structural analogues. This work describes an approach to broaden the accessible product spectrum of SorbC by employing an ester functionality mimicking the natural substrate structure during enzymatic oxidation.