Resolution of 5-oxo-1-phenylpyrazolidine-3-carboxylic acid and synthesis of novel enantiopure amide derivatives

Abstract

Dedicated to Bruce E. Maryanoff and Cynthia A. Maryanoff, in appreciation for their active role in the promotion of chemical science AbstractThe synthesis is reported of (±)-5-oxo-1-phenylpyrazolidine-3-carboxylic acid, (±)-3, via nucleophilic addition of phenylhydrazine to dimethyl maleate, followed by cyclization of the resulting hydrazine-diester. The resolution of (±)-3 was achieved via diastereomeric salts employing (R)-and (S)-α-methylbenzylamine as resolving agent. Preferential crystallization of the like (R,R)-and (S,S)-salts allowed the isolation of the desired enantiomerically pure (R)-and (S)-target compounds in up to 87-89 % of the theoretical yield. An X-ray structure of the (S,S)-salt allowed secure assignment of its relative configuration, and thus unequivocal assignment of the absolute configuration in the enantiomeric heterocycles.

New Advances in the Synthetic Application of Enantiomeric 1-Phenylethylamine (α-PEA): Privileged Chiral Inducer and Auxiliary

“…Cavalluzzi and collaborators obtained (−)-(R)-2-(pentafluorophenoxy)-2-(phenyl-d5)acetic acid (Scheme 21a) of (98% ee) by resolution of a racemate with (−)-(R)-α-PEA. The obtained chiral CSA was successfully used for the direct 1 H NMR determination of enantiomeric excess of Highly demanded chiral fluoro-compounds find application as chiral solvating agents (CSAs) in 1 H and 19 F NMR. Cavalluzzi and collaborators obtained (−)-(R)-2-(pentafluorophenoxy)-2-(phenyl-d 5 )acetic acid (Scheme 21a) of (98% ee) by resolution of a racemate with (−)-(R)-α-PEA.…”

“…Similarly, Béni's group resolved α-(nonafluoro-tert-butoxy)carboxylic acid using enantiomeric (S)-α-PEA (Scheme 21b) [33]. The enantioenriched fluoro-derivatized CSA gave 19 F NMR chemical shift differences (Δδ) 0.006-0.028 ppm in CDCl3 and 0.010 and 0.014 ppm in apolar C6D6 with biologically active amines [33]. A different synthetic approach was used for the resolution of racemic salicylaldehydes containing an isobornyl substituent.…”