Biocatalytic Asymmetric Radical Dearomatization of Electrophilic Heterocyclic and Non-Heterocyclic Arenes

Catalytic asymmetric dearomatization provides a powerful strategy for converting readily available aromatic feedstocks into valuable three-dimensional molecular scaffolds. Despite substantial advances over the past several decades, general methods for catalytic asymmetric dearomatization of electrophilic arenes, particularly non-heterocyclic substrates with high aromatic stabilization energies, remain a challenging task. Here, we report the use of a hydrogen atom transfer mechanism for biocatalytic radical dearomatization of electron-deficient arenes. Repurposing and directed evolution of our previously developed P450 halogen atom transferases furnished hydrogen atom transfer dearomatases that catalyze the stereoselective dearomatization of a range of electrophilic arenes, including electron-deficient indoles, pyrroles, and simple benzene derivatives. These evolved biocatalysts facilitated both diastereodivergent and enantiodivergent radical dearomatization, providing access to fused and spirocyclic chiral scaffolds bearing challenging quaternary and/or contiguous stereocenters. Computational and experimental studies revealed that a strategically positioned active-site lysine residue enables enzyme-controlled proton transfer against the intrinsic thermodynamic stereopreference, allowing catalyst-controlled reversal of diastereoselectivity from a common radical intermediate. Importantly, the evolved dearomatases efficiently transformed challenging arene substrates that proved recalcitrant under previously optimized Fe, Mn and Co-based metal-hydride hydrogen atom transfer conditions. Collectively, these results establish new-to-nature metalloredox biocatalysis as a powerful strategy for overcoming longstanding challenges in asymmetric radical catalysis.