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The effect of substituents on the chiral solvating properties of 13 different (S)-1,6-dialkylpiperazine-2,5-diones (S)-1a–m and five (3S,6S)-1,3,6-trialkyl analogues (S,S)-1n–r was studied by NMR in CDCl3 with methyl (RS)-N-benzoylleucinate (RS)-2a as the model analyte. Most diketopiperazines exhibited typical resolution, Δ Δ δ RS - 20 ∼0.1 ppm. Increased performance was observed with 6-CH2R substituted compounds (S)-1h–j. The best resolution of the NH protons of (R)-2a and (S)-2a, Δ Δ δ RS - 20 = 0.227 ppm, was obtained with (S)-1-isopropyl-6-(4-nitrobenzyl)piperazine-2,5-dione (S)-1j. An additional syn-oriented substituent at the C(3) position decreased the enantioselectivity. Association constants for the binding of (S)-1j to each enantiomer of (RS)-2a in CDCl3 at −20 °C were determined by NMR titration.

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) α-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction.

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.

In CDCl 3 solution, enantiopure ( S )-1-benzyl-6-methylpiperazine-2,5-dione ( S )- 1a formed diastereomeric C O ⋯ H –N hydrogen-bonded associates with racemic ( RS , Z )-1-benzyl-3-[(dimethylamino)methylidene]piperazine-2,5-diones 2a and 2b , ( RS )- tert -butyl pyroglutamate ( RS )- 2c and ( RS )- N -benzoylalanine methyl ester ( RS )- 2d . This resulted in splitting (doubling) of the characteristic signals in the 1 H NMR and 13 C spectra of racemic compounds 2a – d in the presence of 1 equiv of ( S )- 1a . The formation of hydrogen-bonded dimers in CDCl 3 solution was studied by 1 H NMR, 13 C NMR and 2D NMR and confirmed by the intermolecular NOE observed between the hydrogen-bonded amide protons from each of the monomeric units, ( S )- 1a and 2a – c . On the other hand, a slightly different binding mode was proposed for association of ( S )- 1a with alaninamide ( RS )- 2d . Enantiomer compositions of known (weighed) mixtures of both enantiomers of tert -butyl pyroglutamate 2c were re-determined by 1 H NMR in the presence of ( S )- 1a in CDCl 3 . The experimental values were in good agreement with the theoretical values, thus indicating the potential applicability of ( S )- 1a and related diketopiperazines as chiral solvating agents in NMR spectroscopy.