Direct Asymmetric Hydroalkoxylation of Styrenes Through Flavin Brønsted Acid Biocatalysis
5 affiliations
- 1Faculty of Chemistry
- 2Bielefeld University
- 3Institut de Química Computacional i Catàlisi, and Departament de Química, Universitat de Girona
- 4ICREA
- 5Pg. Lluís Companys
Abstract
Direct addition of free alcohols across alkenes would provide a concise route to chiral ethers, but controlling alkene activation, nucleophile capture, and stereochemistry remains difficult. We evolved an oleate hydratase, an enzyme that naturally adds water across alkenes, to favor alcohol addition instead. The resulting enzyme catalyzes intermolecular hydroalkoxylation of electron-rich styrenes in aqueous solution, reaching up to 80% yield and >99% enantiomeric excess. Evolution reshaped an alcohol-binding pocket around a conserved flavin-centered core, allowing alcohol to compete with water. Mechanistic studies support a redox-neutral cycle in which protein-bound neutral FADH 2 acts as a Brønsted acid to protonate the alkene. By placing direct asymmetric hydroalkoxylation within an engineerable enzyme scaffold, this work opens a route to expand both alkene and nucleophile scope through protein engineering.
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BibTeX
@misc{jain2026direct,
title = {{Direct Asymmetric Hydroalkoxylation of Styrenes Through Flavin Brønsted Acid Biocatalysis}},
author = {Shubhanshu Jain and Raúl Lago-Saavedra and Jill McLachlan and Axel Jeibmann and Matúš Gajdoš and Silvia Dehne and Lara Huppertz and Ferran Feixas and Tilman Kottke and Marc Garcia-Borràs and Stephan Christian Hammer},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15009728/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009728/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Direct Asymmetric Hydroalkoxylation of Styrenes Through Flavin Brønsted Acid Biocatalysis
AU - Shubhanshu Jain
AU - Raúl Lago-Saavedra
AU - Jill McLachlan
AU - Axel Jeibmann
AU - Matúš Gajdoš
AU - Silvia Dehne
AU - Lara Huppertz
AU - Ferran Feixas
AU - Tilman Kottke
AU - Marc Garcia-Borràs
AU - Stephan Christian Hammer
PY - 2026
DA - 2026/10/01
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009728/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009728/v1
AB - Direct addition of free alcohols across alkenes would provide a concise route to chiral ethers, but controlling alkene activation, nucleophile capture, and stereochemistry remains difficult. We evolved an oleate hydratase, an enzyme that naturally adds water across alkenes, to favor alcohol addition instead. The resulting enzyme catalyzes intermolecular hydroalkoxylation of electron-rich styrenes in aqueous solution, reaching up to 80% yield and >99% enantiomeric excess. Evolution reshaped an alcohol-binding pocket around a conserved flavin-centered core, allowing alcohol to compete with water. Mechanistic studies support a redox-neutral cycle in which protein-bound neutral FADH 2 acts as a Brønsted acid to protonate the alkene. By placing direct asymmetric hydroalkoxylation within an engineerable enzyme scaffold, this work opens a route to expand both alkene and nucleophile scope through protein engineering.
ER -