β-Fluorinated Paraconic Acid Derivatives: Synthesis and Fluorine Stereoelectronic Effects

New methods for the introduction of fluoro substituents are in great demand, owing to the present importance of fluorinated bioactive compounds. Here we report a simple strategy for the synthesis of a new class of β-fluorinated paraconic acid derivatives. Methyl and ethyl hexanoyl succinates were fluorinated by Selectfluor®, then reduced by a mild reducing agent in acidic medium, thus partially suppressing the HF elimination reaction. The diastereomeric β-fluoro-γ-lactones afforded by lactonization of the fluorinated hydroxydiesters were separated by column chromatography. Their stereochemistry was assessed by means of 19F{1H}-HOESY NMR measurements. The relationship between the remarkable 19F chemical shift difference (20 ppm) and configuration difference was elucidated by two-component relativistic DFT calculations. Both the quick survey of conformers stability based on molecular mechanics in the RDKit environment and the DFT geometry optimizations at the scalar ZORA TZ2P/BLYP level, revealed that for the (2R,3R) diastereomer the γ-lactone ring adopts one prevalent envelope conformation, whereas for the (2R,3S) one both envelope conformations must be taken into consideration.