Enzymatic control over reactive intermediates enables direct oxidation of alkenes to carbonyls by a P450 iron-oxo species

Soler J, Gergel S, Hammer S, Garcia-Borràs M (2022)
ChemRxiv.

Preprint | Veröffentlicht | Englisch
 
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Autor*in
Soler, Jordi; Gergel, SebastianUniBi; Hammer, StephanUniBi; Garcia-Borràs, Marc
Abstract / Bemerkung
The oxidation of alkenes by high-valent iron-oxo active species normally leads to the formation of the corresponding epoxides. Rarely, carbonyl compounds are observed as a side product of the reaction. However, the selective formation of carbonyl compounds from alkenes using iron-oxo species and small molecule catalysts has not yet been achieved. Recently, a new P450-based enzyme (aMOx) has been engineered through laboratory directed evolution to directly oxidize styrenes to their corresponding aldehydes. This transformation uses an enzymatic iron-oxo species as catalytic oxidant and generates aldehydes with high activity and selectivity while suppressing epoxidation. Here, we combine extensive computational modelling together with experimental mechanistic investigations to study the reaction mechanism and unravel the molecular basis behind the selectivity achieved by the laboratory evolved aMOx enzyme. We found that alkene epoxidation and carbonyl formation pathways diverge from a common covalent radical intermediate generated after the first C–O bond formation. Although both pathways are accessible and very similar in energy, intrinsic dynamic effects determine the strong preference for epoxidation. We discovered that aMOx overrides these intrinsic dynamic preferences by controlling the accessible conformations of the covalent radical intermediate. This disfavors epoxidation and facilitates the formation of a key carbocation intermediate that generates the aldehyde product through a fast 1,2-hydride migration. Computations predicted that the hydride migration is stereoselective due to the conformational control over the intermediate species when formed in the enzyme active site. These predictions were corroborated by experiments using deuterated styrene substrates, which proved that the hydride migration is cis- and enantioselective. Our results demonstrate that directed evolution tailored a highly specific active site that imposes strong steric control over key fleeting biocatalytic intermediates, which is essential for accessing the carbonyl forming pathway and preventing competing epoxidation.
Erscheinungsjahr
2022
Zeitschriftentitel
ChemRxiv
eISSN
2573-2293
Page URI
https://pub.uni-bielefeld.de/record/2962552

Zitieren

Soler J, Gergel S, Hammer S, Garcia-Borràs M. Enzymatic control over reactive intermediates enables direct oxidation of alkenes to carbonyls by a P450 iron-oxo species. ChemRxiv. 2022.
Soler, J., Gergel, S., Hammer, S., & Garcia-Borràs, M. (2022). Enzymatic control over reactive intermediates enables direct oxidation of alkenes to carbonyls by a P450 iron-oxo species. ChemRxiv. https://doi.org/10.26434/chemrxiv-2022-6lpjf
Soler, J., Gergel, S., Hammer, S., and Garcia-Borràs, M. (2022). Enzymatic control over reactive intermediates enables direct oxidation of alkenes to carbonyls by a P450 iron-oxo species. ChemRxiv.
Soler, J., et al., 2022. Enzymatic control over reactive intermediates enables direct oxidation of alkenes to carbonyls by a P450 iron-oxo species. ChemRxiv.
J. Soler, et al., “Enzymatic control over reactive intermediates enables direct oxidation of alkenes to carbonyls by a P450 iron-oxo species”, ChemRxiv, 2022.
Soler, J., Gergel, S., Hammer, S., Garcia-Borràs, M.: Enzymatic control over reactive intermediates enables direct oxidation of alkenes to carbonyls by a P450 iron-oxo species. ChemRxiv. (2022).
Soler, Jordi, Gergel, Sebastian, Hammer, Stephan, and Garcia-Borràs, Marc. “Enzymatic control over reactive intermediates enables direct oxidation of alkenes to carbonyls by a P450 iron-oxo species”. ChemRxiv (2022).

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Preprint: 10.26434/chemrxiv-2022-6lpjf

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