Regiodivergent Biocatalytic Rearrangement of Indoles: Enantioselective Access to 2- and 3-Oxindoles Bearing Quaternary Stereocenters
Abstract
Chiral oxindoles bearing a quaternary stereocenter are prevalent scaffolds across a wide range of biologically active natural products and pharmaceutical agents, yet their enantioselective synthesis via oxidative 1,2-shift reactions remains largely underdeveloped, particularly within the realm of biocatalysis. Herein, we report the first biocatalytic asymmetric semipinacol-type rearrangement of indoles with C–C bond migration, mediated by engineered flavin-dependent styrene monooxygenases (StyAs), enabling the enantioselective synthesis of both 3,3-dialkyl-substituted 2-oxindoles and 2,2-dialkyl-substituted 3-oxindoles. Screening of an extensive library of flavin-dependent monooxygenases, comprising wild-type StyAs, Pseudomonas StyA variants and Baeyer-Villiger monooxygenases, against a pyrano-[2,3]-fused indole model substrate identified the double mutant PsStyA-Q4 (V48N/Y73V) as the optimal biocatalyst, delivering the (R)-configured spiro-2-oxindole with up to full conversion and excellent enantioselectivity (>99% ee) under mild aqueous conditions. Substrate scope evaluation confirmed broad generality across methyl- and halogen-substituted indoles, while a set of 3-allyl- and 3-benzyl-substituted indoles, converted by PsStyA-Q4 or wild-type SwStyA, gave access to the complementary 2,2-dialkyl-3-oxindole scaffold with equally excellent enantiocontrol. Quantum chemical calculations suggest that both substrate classes share the same intrinsic migratory preference, so that the exclusive formation of spiro-2oxindoles from the pyrano-fused indoles cannot be traced back to substrate control alone. These observations indicate that the styrene monooxygenases exert control not merely over the initial oxygen transfer, but throughout the rearrangement itself.
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BibTeX
@misc{li2026regiodivergent,
title = {{Regiodivergent Biocatalytic Rearrangement of Indoles: Enantioselective Access to 2- and 3-Oxindoles Bearing Quaternary Stereocenters}},
author = {Jingyi Li and Jingsong Song and Jan Deska and J. D. Rolfes and Jinhui Feng and Xuejie Qi and Yuchang Liu and Qiaqing Wu and Dunming Zhu},
howpublished = {ChemRxiv},
year = {2026},
month = aug,
doi = {10.26434/chemrxiv.15008133/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008133/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Regiodivergent Biocatalytic Rearrangement of Indoles: Enantioselective Access to 2- and 3-Oxindoles Bearing Quaternary Stereocenters
AU - Jingyi Li
AU - Jingsong Song
AU - Jan Deska
AU - J. D. Rolfes
AU - Jinhui Feng
AU - Xuejie Qi
AU - Yuchang Liu
AU - Qiaqing Wu
AU - Dunming Zhu
PY - 2026
DA - 2026/08/31
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008133/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008133/v1
AB - Chiral oxindoles bearing a quaternary stereocenter are prevalent scaffolds across a wide range of biologically active natural products and pharmaceutical agents, yet their enantioselective synthesis via oxidative 1,2-shift reactions remains largely underdeveloped, particularly within the realm of biocatalysis. Herein, we report the first biocatalytic asymmetric semipinacol-type rearrangement of indoles with C–C bond migration, mediated by engineered flavin-dependent styrene monooxygenases (StyAs), enabling the enantioselective synthesis of both 3,3-dialkyl-substituted 2-oxindoles and 2,2-dialkyl-substituted 3-oxindoles. Screening of an extensive library of flavin-dependent monooxygenases, comprising wild-type StyAs, Pseudomonas StyA variants and Baeyer-Villiger monooxygenases, against a pyrano-[2,3]-fused indole model substrate identified the double mutant PsStyA-Q4 (V48N/Y73V) as the optimal biocatalyst, delivering the (R)-configured spiro-2-oxindole with up to full conversion and excellent enantioselectivity (>99% ee) under mild aqueous conditions. Substrate scope evaluation confirmed broad generality across methyl- and halogen-substituted indoles, while a set of 3-allyl- and 3-benzyl-substituted indoles, converted by PsStyA-Q4 or wild-type SwStyA, gave access to the complementary 2,2-dialkyl-3-oxindole scaffold with equally excellent enantiocontrol. Quantum chemical calculations suggest that both substrate classes share the same intrinsic migratory preference, so that the exclusive formation of spiro-2oxindoles from the pyrano-fused indoles cannot be traced back to substrate control alone. These observations indicate that the styrene monooxygenases exert control not merely over the initial oxygen transfer, but throughout the rearrangement itself.
ER -