Stereochemistry of piperazine-2,5-dione formation by self-condensation of DL-amino acid esters

‘Racemic’ piperazine-2,5-diones (diketopiperazines, dkps) have been synthesized by the self-condensation of DL-amino acid esters without solvent. It was found that ‘racemic’ dkps consisted of cis- and trans-isomers, and that cis-dkp was preferentially formed in the early stage of the self-condensation, the cis : trans ratios gradually decreasing with increasing reaction time. These results may be attributed to the difference in the rates of cyclization of two kinds of diastereoisomeric dipeptide esters, intermediates in the formation of dkps from DL-amino acid esters. It was further confirmed that the pre-cis-dipeptide ester, which formed cis-dkp, cyclized faster than the pre-trans-dipeptide ester in methanol. Differences in steric hindrance in the cyclization reaction of pre-cis- and pre-trans-isomers may be an important factor in the stereochemistry of self-condensation.