The effect of substituents on the chiral solvating properties of (S)-1,6-dialkylpiperazine-2,5-diones

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, ΔΔδRS-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, ΔΔδRS-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.

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(S)-N-Butyl-3-(1-isopropyl-2,5-dioxopiperazin-6-yl)propanamideC14H25N3O3[α]D27=+94.6 (c 0.5, CH2Cl2)Ee = 82%Source of chirality: dimethyl (S)-glutamateAbsolute configuration: (S)