Issue 48, 2022

Biocatalytic approach to chiral fluoroaromatic scaffolds

Abstract

Ten different fluorinated aromatic epoxides have been tested as potential substrates for halohydrin dehalogenase (HHDH) HheC. The majority of investigated epoxides are useful building blocks in synthetic chemistry applications, with a number of them being polysubstituted. Moderate to high enantioselectivities (ER = 15 → 200) were observed in azidolysis, allowing the synthesis of enantioenriched (R)-azido alcohols containing fluorine in the molecule. In the case where a reaction runs over 50% conversion, enantiopure (S)-epoxides are also available. While o-F-styrene oxide was easily converted into a product, a sterically challenging o-CF3-derivative was not accepted by HheC. In silico probing of the binding site indicates that, in order to accommodate an o-CF3-derivative in the HheC active site, it is necessary to eliminate steric hindrance. Hence, we extended our research by probing several available HheC variants containing relevant modifications in the active site. The active mutant P84V/F86P/T134A/N176A (named HheC-M4) was identified, showing not only high activity towards o-CF3-styrene oxide, but also inverted enantioselectivity (ES = 27). Since (S)-enantioselective HHDHs are rare and therefore valuable for their synthetic application, this enzyme was screened on the initial panel of substrates. The observed (S)-enantioselectivity (ES = 1–111) is ascribed to the formation of the additional space by introduced mutations in HheC-M4, which is also confirmed by classical MD simulations. Successive molecular docking demonstrated that this newly formed tunnel located close to the protein surface is a critical feature of HheC-M4, representing a novel binding site.

Graphical abstract: Biocatalytic approach to chiral fluoroaromatic scaffolds

Supplementary files

Article information

Article type
Paper
Submitted
25 10 2022
Accepted
18 11 2022
First published
21 11 2022

Org. Biomol. Chem., 2022,20, 9734-9741

Biocatalytic approach to chiral fluoroaromatic scaffolds

I. Dokli, Z. Brkljača, P. Švaco, L. Tang, V. Stepanić and M. Majerić Elenkov, Org. Biomol. Chem., 2022, 20, 9734 DOI: 10.1039/D2OB01955H

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements