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

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 CDCl3 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 CDCl3 at −20 °C were also determined by NMR titration.

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(S)-6-Methyl-1-(pentafluorobenzyl)piperazine-2,5-dioneC12H9F5N2O2Ee = 100%[α]D28=+4.2 (c 0.15, CHCl3)Source of chirality: (S)-alanine methyl esterAbsolute configuration: (S)