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.

Nature-Inspired Radical Pyridoxal-Mediated C-C Bond Formation.

Pyridoxal-5'-phosphate (PLP) and derivatives of this cofactor enable a plethora of reactions in both enzyme-mediated and free-in-solution transformations. With few exceptions in each category, such chemistry has predominantly involved two-electron processes. This sometimes poses a significant challenge for using PLP to build tetrasubstituted carbon centers, especially when the reaction is reversible. The ability to access radical pathways is paramount to broadening the scope of reactions catalyzed by this coenzyme. In this study, we demonstrate the ability to access a radical PLP-based intermediate and engage this radical intermediate in a number of C-C bond-forming reactions. By selection of an appropriate oxidant, single-electron oxidation of the quinonoid intermediate can be achieved, which can subsequently be applied to C-C bond-forming reactions. Through this radical reaction pathway, we synthesized a series of α-tertiary amino acids and esters to investigate the substrate scope and identify nonproductive reaction pathways. Beyond the amino acid model system, we demonstrate that other classes of amine substrates can be applied in this reaction and that a range of small molecule reagents can serve as coupling partners to the semiquinone radical. We anticipate that this versatile semiquinone radical species will be central to the development of a range of novel reactions.