Asymmetric synthesis and teratogenic activity of (R)- and (S)-2-ethylhexanoic acid, a metabolite of the plasticizer di-(2-ethylhexyl)phthalate

Abstract

The stereoselectivity of the teratogenic activity of 2-ethylhexanoic acid (EHXA), a metabolite of the widely-used plasticizer di-(2-ethylhexyl)phthalate, was investigated. The enantiomers of EHXA were prepared via asymmetric synthesis with the aid of the chiral auxiliaries (R)- and (S)-1-amino-2-(methoxymethyl)pyrrolidine (RAMP, SAMP). The aqueous solutions of the sodium salts of (R)- and (S)-EHXA and the racemic EHXA [+/- )-EHXA) were injected each morning and evening of day 7 and 8 of gestation in the NMRI mouse (500 mg/kg, i.p.), a period highly sensitive in regard to the production of neural tube defects (exencephaly) by branched-chain carboxylic acids. (S)-EHXA did not yield any teratogenic or embryotoxic response in this model, while (R)-EHXA was highly teratogenic (59% of living fetuses exhibited exencephaly) and embryotoxic (as indicated by embryolethality and fetal weight retardation); the exencephaly rate induced by (+/- )-EHXA was between those of the two enantiomeres (32%). It is therefore likely that stereoselective interactions of the enantiomers of EHXA with chiral molecules in the embryo are decisive in regard to the teratogenic response. This first example of the stereoselectivity of the teratological activity of an environmental pollutant suggests that the safety of man-made chemicals can be improved by the use of pure enantiomers instead of racemates.