Fu W,
Fu Y,
Zhao Y,
Wang H,
Liu P,
*,
Yang Y.
*
University of California, Santa Barbara and University of Pittsburgh, USA
A Metalloenzyme Platform for Catalytic Asymmetric Radical Dearomatization.
Nat. Chem. 2024;
DOI:
10.1038/s41557-024-01608-8
Key words
radical dearomatization - electron-rich arenes - cytochrome P450 - directed evolution
- enantioconvergent - enantiodivergent
Significance
Yang, Liu and co-workers developed a new-to-nature enzymatic strategy for the asymmetric
intramolecular dearomatization of electron-rich arenes. By employing directed evolution,
they engineered several P450 radical dearomatases (P450rad) based on cytochrome P450 enzymes, thereby achieving stereocontrol for the intramolecular
radical dearomatization of indoles, pyrroles, phenols, and naphthols. Mechanistically,
the redox-active haem cofactor initiated the enzyme-controlled radical formation of
the α-bromocarbonyl substrates. The highly reactive radical then undergoes dearomative
cyclization and the dearomatized spirocyclic products are obtained after an oxidative-radical
crossover and proton transfer.
Comment
By developing a metalloenzyme platform for a new-to-nature asymmetric radical dearomatization,
the authors expanded the repertoire of (bio)catalytic reactions and gained control
over a challenging stereoselective radical mechanism. In addition to the enantioselective
dearomatization of indoles, the enantioconvergent conversion of phenols and the enantiodivergent
consumption of pyrroles were also achieved. The obtained chiral (hetero)spirocyclic
dearomatized products represent valuable motives that are found in several bioactive
compounds and feature adjacent quarternary–quarternary carbon atoms.
