Stereoselective Synthesis of the Diunsaturated Metabolites of Valproic Acid

Two diene metabolites of valproic acid (VPA),(E)-2-n-propyl-2, 4-pentadienoic acid (1) and(E)-2-(1′-propenyl)-(E)-2-pentenoic acid (2), were stereoselectively synthesized. Mesylate elimination in the final step to produce the unsaturation at position 2 was stereospecific for the(E)-configuration in the case of 2. Gas chromatography-mass spectroscopy and NMR were used to confirm the configuration of each diene including the minor isomers,(Z)-2-n-propyl-2, 4-pentadienoic acid (9) and(Z)-2-(1′-propenyl)-(E)-2-pentenoic acid (18). Analysis of the dienes, as PFB derivatives by negative chemical ionization GC-MS from a serum extract of a patient on VPA therapy, revealed the presence of four peaks that in order of elution correspond to 9,18,1, and 2.