Toby J. Nash¹, Scott Wharry², Thomas S. Moody^2,3*, Simon E. Lewis¹*
*Corresponding author
1. Department of Chemistry, University of Bath, United Kingdom
2. Department of Biocatalysis and Isotope Chemistry, Almac Group Ltd, Craigavon, United Kingdom
3. Arran Chemical Company Limited, Athlone, Ireland

Abstract

The enzyme benzoate dioxygenase (BZDO) from Ralstonia eutropha B9 is able to dihydroxylate benzoic acids in a dearomative process that proceeds with a different regioselectivity than other known dioxygenase enzymes. Here we show that 4-fluorobenzoic acid is oxidised by BZDO to give an enantiopure diol that can be rapidly elaborated to highly oxygenated homochiral building blocks with quaternary centres. Notably, the diol produced in this biotransformation displays reactivity which is distinct from that of the more extensively studied non-fluorinated analogue.

INTRODUCTION

The dearomatising dihydroxylation of an aromatic ring is a reaction which is very difficult to perform by conventional chemistry (1). However, arene dioxygenase enzymes are able to effect this chemistry with great stereo- and regioselectivity (2-8). Arene dioxygenases are produced by various microorganisms and the most extensively studied enzymes to date have been toluene dioxygenase (TDO), naphthalene dioxygenase (NDO) and biphenyl dioxygenase (BPDO). All of these possess a wide substrate scope, and their selectivity towards substituted arenes has been studied (9). Thus, a monosubstituted arene 1 will typically be oxidised to give a cyclohexadiene cis-diol of type 2, wherein hydroxylation has occurred ortho and meta to the original substituent, and with the absolute stereochemistry as shown (Scheme 1a). In contrast, benzoate dioxygenase (BZDO) exhibits a distinct selectivity and is able to effect the oxidation of benzoic acids 3 to give products of type 4. In cis-diols 4, the hydroxylation occurs ipso and ortho to the carboxylic acid substituent (Scheme 1b), and with the absolute stereochemistry as shown (i.e ...