Biocatalytic Stereoselective Oxidation of 2‑Arylindoles

3-Hydroxyindolenines can be used to access several structural
motifs
that are featured in natural products and pharmaceutical compounds,
yet the chemical synthesis of 3-hydroxyindolenines is complicated
by overoxidation, rearrangements, and complex product mixtures. The
selectivity possible in enzymatic reactions can overcome these challenges
and deliver enantioenriched products. Herein, we present the development
of an asymmetric biocatalytic oxidation of 2-arylindole substrates
aided by a curated library of flavin-dependent monooxygenases (FDMOs)
sampled from an ancestral sequence space, a sequence similarity network,
and a deep-learning-based latent space model. From this library of
FDMOs, a previously uncharacterized enzyme, Champase, from the Valley
fever fungus, Coccidioides immitis strain
RS, was found to stereoselectively catalyze the oxidation of a variety
of substituted indole substrates. The promiscuity of this enzyme is
showcased by the oxidation of a wide variety of substituted 2-arylindoles
to afford the respective 3-hydroxyindolenine products in moderate
to excellent yields and up to 95:5 er.