Chiral fluoroacetic acid: synthesis of (R)- and (S)-[2H1]-fluoroacetate in high enantiopurity

A two-step synthesis of (R)- and (S)-[2H1]-fluoroacetate (sodium salts) in high enantioselectivity is reported. The synthesis is the development of a previous one in which the enantioselectivity has been increased from ∼38% ee to >95% ee. The improvement in enantioselectivity applied Bio's methodology, which involved a deoxyfluorination reaction with DAST on either enantiomer of [2H1]-benzyl alcohol, adding TMS-morpholine to the reaction. The additive promotes an SN2 inversion process, and suppresses a competing non-stereospecific SN1 reaction course, and as a result significantly improves the stereointegrity of the C-F bond formation. The intermediate [2H1]-benzyl alcohols, [2H1]-benzyl fluorides and the product [2H1]-fluoroacetates as their hexyl esters were separately assayed for their stereochemical integrity, using the Courtieu method. This method involved measuring their 2H NMR spectra in a chiral matrix of poly-γ-benzyl l-glutamate. The chiral assay demonstrated that there was no significant loss in stereointegrity during the deoxyfluorination reaction and showed that the enantiomers of [2H1]-fluoroacetate were generated with high enantiomeric purity (95% ee).