Chiral fluoroacetic acid: synthesis of (R)- and (S)-[2H1]-fluoroacetate in high enantiopurity |
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Authors: | Rudy DP Wadoux Xiaowei Lin Neil S Keddie David O’Hagan |
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Institution: | 1. School of Chemistry and Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife KY16 9ST, UK;2. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Ling Ling Road 345, Shanghai 200032, China |
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Abstract: | 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). |
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