Determination of the absolute configuration of (+)- and (?)-N-CBZ-3-fluoropyrrolidine-3-methanol using vibrational circular dichroism and confirmation of stereochemistry by conversion to (R)-tert-butyl 3-fluoro-3-(((R)-1-phenylethyl)carbamoyl)pyrrolidine-1-carboxylate

Article abstract of DOI:10.1016/j.tetasy.2016.09.008

Racemic N-CBZ-3-fluoropyrrolidine-3-methanol (±)-1 was resolved by preparative chiral HPLC. The absolute configuration of the enantiomers of 1 was identified by vibrational circular dichroism and confirmed by chemical synthesis, which involved exchanging the CBZ protecting group of (?)-1 with Boc, followed by oxidation with RuCl₃, NaIO₄, activation of the resulting acid with carbonyl diimidazole and reaction with (R)-α-methylbenzylamine to give (R)-tert-butyl 3-fluoro-3-(((R)-1-phenylethyl)carbamoyl) pyrrolidine-1-carboxylate 7. The latter was compared with authentic (S)-tert-butyl 3-fluoro-3-(((R)-1-phenylethyl)carbamoyl)pyrrolidine-1-carboxylate 6 and its diastereomer 7; the configuration of diastereomer 6 was obtained by an X-ray diffraction study. This established that the enantiomer (?)-1 had an (R)-configuration.