Synthesis and stereoselective reduction of α-fluoro-β-ketoesters by ketoreductases

Abstract

Using commercially available ketoreductase (KRED) enzymes, α-fluoro-β-hydroxy esters were stereoselectively synthesized from racemic α-fluoro-β-keto esters through dynamic reductive kinetic resolution (DYRKR). The α-fluoro-β-keto esters were synthesized via Reformatsky reactions between an aromatic aldehyde and ethyl bromofluoroacetate and subsequent oxidation with Dess Martin Periodinane (DMP). Two enzymes were selected for their ability to yield either syn or anti diastereomers. Three aromatic substrates were reduced in high diastereomeric and enantiomeric excess and good yields. The KRED products were derivatized with (R)- and (S)-α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) and analyzed via ¹⁹F NMR spectroscopy to determine their absolute stereochemistry via Mosher ester analysis. For the three substrates, KRED 110 yielded the anti 2S,3S isomer. KRED 130 predominantly yielded the syn 2S,3R isomer but with less specificity. The use of these commercially available KRED enzymes provides access to enantio- and diastereomerically pure α-fluoro-β-hydroxy esters from readily accessible racemic substrates. Optically pure α-fluoro-β-hydroxy esters may serve as useful intermediates in the synthesis of medicinally relevant compounds such as fluorinated amino acids or fluorinated sphingolipid derivatives.