# Enantioselective electrophilic α-fluorination catalyzed by an artificial metalloenzyme

## TL;DR

Scientists engineered an artificial enzyme to perform a rare chemical reaction that adds fluorine to molecules with high precision and selectivity.

## Contribution

A novel artificial metalloenzyme enables enantioselective electrophilic α-fluorination with up to 95% ee through targeted mutagenesis and cofactor design.

## Key findings

- An artificial metalloenzyme achieved enantioselective α-fluorination with up to 95% ee.
- Mutagenesis of residues S112 and K121 improved reactivity and selectivity.
- Molecular simulations explained how cofactor positioning and steric shielding control enantioselectivity.

## Abstract

Fluorine incorporation profoundly influences the properties of pharmaceuticals and imaging agents, yet enzymatic C–F bond formation remains exceedingly rare. Here we report an enantioselective electrophilic α-fluorination catalyzed by an artificial metalloenzyme assembled from a biotinylated Cu(ii) Lewis acid cofactor embedded in streptavidin. Targeted mutagenesis of residues S112 and K121 yielded variants delivering up to 95% ee. Substrate scope studies revealed distinct steric and electronic influences on both reactivity and selectivity. Docking and molecular dynamics simulations indicate that precise cofactor positioning and steric shielding from K121Q govern the approach of the electrophilic fluorinating reagent, accounting for the observed enantioselectivity. These findings demonstrate that electrophilic fluorination chemistry can be engineered into protein environments and highlight the broader potential of artificial metalloenzymes to enable new-to-nature biotransformations.

Enantioselective electrophilic α-fluorination was achieved using a Sav–biotin-based artificial metalloenzyme with moderate to high yields and enantioselectivities.