Engineered Cytochrome P450-Catalyzed Oxidative Biaryl Coupling Reaction Provides a Scalable Entry into Arylomycin Antibiotics

We report herein the first example of a cytochrome P450-catalyzed oxidative carbon–carbon coupling process for a scalable entry into arylomycin antibiotic cores. Starting from wild-type hydroxylating cytochrome P450 enzymes and engineered Escherichia coli, a combination of enzyme engineering, random...

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Bibliographic Details
Published inJournal of the American Chemical Society Vol. 144; no. 32; pp. 14838 - 14845
Main Authors Molinaro, Carmela, Kawasaki, Yukie, Wanyoike, George, Nishioka, Taiki, Yamamoto, Tsuyoshi, Snedecor, Brad, Robinson, Sarah J., Gosselin, Francis
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 17.08.2022
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Multidisciplinary
Physical Sciences
Science & Technology
BACTERIAL SIGNAL PEPTIDASE
STREPTOMYCES SP TU-6075
VANCOMYCIN
BIOSYNTHESIS
ENZYMES
ESCHERICHIA-COLI
HYDROXYLATION
BOND FORMATION
P450
EXPRESSION
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Summary:We report herein the first example of a cytochrome P450-catalyzed oxidative carbon–carbon coupling process for a scalable entry into arylomycin antibiotic cores. Starting from wild-type hydroxylating cytochrome P450 enzymes and engineered Escherichia coli, a combination of enzyme engineering, random mutagenesis, and optimization of reaction conditions generated a P450 variant that affords the desired arylomycin core 2d in 84% assay yield. Furthermore, this process was demonstrated as a viable route for the production of the arylomycin antibiotic core on the gram scale. Finally, this new entry affords a viable, scalable, and practical route for the synthesis of novel Gram-negative antibiotics.
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ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.2c06019