Synthesis and application of amino alcohol imides as NMR solvating agents for chiral discrimination of carboxylic acids

A series of amino alcohol imides 2–8 have been synthesized from commercially available starting materials by regioselective ring opening reaction of epoxides with chiral amines. Compounds 2–8 were tested as chiral solvating agents (CSAs) for enantiomeric discrimination of biological important carboxylic acids. C2-Symmetric (S,R,R,S)-3 was found to be a satisfactory CSA for mandelic acid with ΔΔδ of 24.8 Hz. CSA (S,S)-5 exhibited the best enantiomeric discrimination for α-phenyl-α-methoxyacetic acid with ΔΔδ of 32 Hz. Enantiomeric differentiated values found for mandelic acid, o-chloro mandelic acid, ibuprofen and naproxen are 7.2, 4.4, 2 and 3 Hz respectively.

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(1R,2R)-Bis[(R)-2-hydroxy(2-phenyl)ethyl]-1,2-diaminocyclohexane (2)C22H30N2O2[α]D20 = −52.2° (c = 1, CHCl3)Source of chirality: (R,R)-1,2-diaminocyclohexane, (R)-styrene oxideAbsolute configuration: R,R,R,R

N,N′-Dibenzyl-N,N′-bis[(S)-2-hydroxy-3-phtalimido]-(1R,2R)-1,2-diaminocyclohexane (3)C42H44N4O6[α]D20 = −14.2° (c = 1, CHCl3)Source of chirality: (1R,2R)-N,N′-dibenzyl-1,2-diaminocyclohexane, (R)-N-(2,3-epoxypropyl)phthalimideAbsolute configuration: S,R,R,S

2-[(2S)-2-Hydroxy-3-[[(1R)-α-cyclohexylethyl]amino]propyl]isoindoline-1,3-dione (4)C19H26N2O3[α]D20 = 14° (c = 1, CHCl3)Source of chirality: (R)-α-cyclohexylethylamine, (R)-N-(2,3-epoxypropyl)phthalimideAbsolute configuration: R,S

2-[(2S)-2-Hydroxy-3-[[(1S)-α-cyclohexylethyl]amino]propyl]isoindoline-1,3-dione (5)C19H26N2O3[α]D20 = +7.2° (c = 1, CHCl3)Source of chirality: (S)-α-cyclohexylethylamine, (R)-N-(2,3-epoxypropyl)phthalimideAbsolute configuration: S,S

2-[(2S)-2-Hydroxy-3-[N-benzyl-[(1S)-α-cyclohexylethyl]amino]propyl]isoindoline-1,3-dione (6)C26H32N2O[α]D20 = +9.8° (c = 1, CHCl3)Source of chirality: (S)-α-cyclohexylethylamine, (R)-N-(2,3-epoxypropyl)phthalimideAbsolute configuration: S,S

2-[(2S)-2-Hydroxy-3-[[[(1S)-α-phenylethyl]amino]propyl]isoindoline-1,3-dione (7)C19H20N2O3[α]D20 = 10.7° (c = 1, CHCl3)Source of chirality: (S)-α-phenylethylamine, (R)-N-(2,3-epoxypropyl)phthalimideAbsolute configuration: S,S

2-[(2S)-2-Hydroxy-3-[[(1S)-1-naphthylethyl]amino]propyl]isoindoline-1,3-dione (8)C23H22N2O3[α]D20 = +16.9° (c = 0.5, DMSO).Source of chirality: (S)-1-(1-naphthyl)ethylamine, (R)-N-(2,3-epoxypropyl)phthalimideAbsolute configuration: S,S