Biocatalytic Asymmetric Radical Dearomatization of Electrophilic Heterocyclic and Non-Heterocyclic Arenes
- 1University of California Santa Barbara
Abstract
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.
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BibTeX
@misc{lin2026biocatalytic,
title = {{Biocatalytic Asymmetric Radical Dearomatization of Electrophilic Heterocyclic and Non-Heterocyclic Arenes}},
author = {K. Lin and P.-P. Xie and Y. Tian and H. Chen and H. Chen and P. Liu and Y. Yang},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.07.764688},
url = {https://www.biorxiv.org/content/10.64898/2026.11.07.764688v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Biocatalytic Asymmetric Radical Dearomatization of Electrophilic Heterocyclic and Non-Heterocyclic Arenes
AU - K. Lin
AU - P.-P. Xie
AU - Y. Tian
AU - H. Chen
AU - H. Chen
AU - P. Liu
AU - Y. Yang
PY - 2026
DA - 2026/11/07
PB - bioRxiv
DO - 10.64898/2026.11.07.764688
UR - https://www.biorxiv.org/content/10.64898/2026.11.07.764688v1
AB - 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.
ER -