( S)- N-Benzyl-3(6)-methylpiperazine-2,5-diones as chiral solvating agents for N-acylamino acid esters

Abstract

Three closely related diketopiperazines, ( S)-1-benzyl-6-methylpiperazine-2,5-dione ( S)- 1a, ( S)-1-benzyl-3-methylpiperazine-2,5-dione ( S)- 1b, and ( S)-6-methyl-1-(pentafluorobenzyl)piperazine-2,5-dione ( S)- 1c, were prepared and screened as potential chiral solvating agents in NMR spectroscopy. The 1H NMR spectra of 13 racemic α-amino acid derivatives ( RS)- 5a– 5m were taken in CDCl 3 in the presence of equimolar amounts of enantiopure diketopiperazines ( S)- 1a– 1c at 29 °C, 0 °C, and −20 °C. Compound ( S)- 1a exhibited the strongest chiral solvating properties for racemic α-amino acid derivatives ( RS)- 5a– 5m and was recognized as a suitable CSA for the determination of their enantiomer composition. Weaker interactions of diketopiperazines ( S)- 1b and ( S)- 1c with compounds ( RS)- 5a– 5m indicate that the position and properties of substituents play an important role in the binding affinity of diketopiperazines 1 towards amino acid derivatives 5. Association constants for binding of ( S)- 1a to each enantiomer of the leucine derivative ( RS)- 5d in CDCl 3 at −20 °C were also determined by NMR titration.