Site-selective Chlorination of Pyrrolic Heterocycles by Flavin Dependent Enzyme PrnC

01 November 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Halogenation of pyrrole requires strong electrophilic reagents and often leads to undesired polyhalogenated products. Biocatalytic halogenation is a highly attractive approach given its chemoselectivity and benign reaction conditions. Whilst there are several reports of enzymatic phenol and indole halogenation in organic synthesis, corresponding reports on enzymatic pyrrole halogenation has been lacking. Here we describe the first in vitro functional and structural characterization of PrnC, a flavin-dependent halogenase that can act on free-standing pyrroles. Computational modelling and site mutagenesis studies identified three key residues in the catalytic pocket. Moderate resolution map using single-particle cryogenic electron microscopy (CryoEM) reveals PrnC to be a dimer. This native PrnC can halogenate a library of structurally diverse pyrrolic heterocycles in a site-selective manner and was applied in the chemoenzymatic synthesis of a chlorinated analog of the agrochemical fungicide, Fludioxonil.

Keywords

biocatalysis
halogenation
pyrrole
chlorination
halogenase

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