Preparation of pyridino-crown ether-based new chiral stationary phases and preliminary studies on their enantiomer separating ability for chiral protonated primary aralkylamines

This paper reports the preparation and testing of three new pyridino-18-crown-6 ether-based chiral stationary phases (S,S)-CSP-12, (S,S)-CSP-17 and (S,S)-CSP-20. Secondary amine (S,S)-7 was first transformed to triethoxysilyl derivative (S,S)-11, which contains a urea unit by treating the former with 3-(triethoxysilyl)propyl isocyanate. Next, (S,S)-11 was heated with spherical HPLC quality silica gel in toluene to obtain (S,S)-CSP-12. In order to acetylate the 3-aminopropylsilyl groups bonded to the silica gel during immobilization of the triethoxysilyl derivative (S,S)-11, we pumped acetic anhydride and triethylamine in DMF through the column to give the modified chiral stationary phase (S,S)-CSP-20.Triflate (S,S)-13 was first transformed to a pyridino-18-crown-6 ether derivative (S,S)-15, which contains a 4-(methoxycarbonyl)phenyl substituent at the 4-position of the pyridine ring by a Suzuki carbon–carbon coupling reaction. The hydrolysis of ester (S,S)-15 gave carboxylic acid (S,S)-21. Carboxylic acid (S,S)-21 was reacted with an excess of thionyl chloride to form the appropriate acyl chloride, which was treated with 3-(triethoxysilyl)propylamine in the presence of triethylamine in THF to furnish triethoxysilyl derivative (S,S)-16 containing an amide unit. Triethoxysilyl derivative (S,S)-16 was heated with spherical HPLC quality silica gel in toluene to give the chiral stationary phase (S,S)-CSP-17.The enantiomer separating ability of chiral stationary phases (S,S)-CSP-12, (S,S)-CSP-17 and (S,S)-CSP-20 were tested by using mixtures of enantiomers of 1-(1-naphthyl)ethylamine hydrogen perchlorate (1-NEA), 1-(2-naphthyl)ethylamine (2-NEA), 1-(4-bromophenyl)ethylamine (Br-PEA) and 1-(4-nitrophenyl)ethylamine hydrogen chloride (NO2-PEA). Chiral stationary phase (S,S)-CSP-17 showed the best enantiomer separating ability for the mixtures of enantiomers of amine compounds amongst the pyridino-crown ether-based CSPs ever synthesized. The high enantioselectivity is probably due to the strong π–π interaction of the extended π system of the aryl–substituted pyridine unit.

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(4S,14S)-(+)-N-Butyl-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21)-17,19-triene-19-amineC21H36N2O5Ee >97%[α]D25=+15.3 (c 0.91, dichloromethane)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: (4S,14S)

(4S,14S)-(−)-N-Butyl-4,14-diisobutyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21)-17,19-triene-19-amineC27H48N2O5Ee >97%[α]D25=-11.3 (c 0.73, dichloromethane)Source of chirality: (S)-(+)-leucineAbsolute configuration: (4S,14S)

(4S,14S)-(−)-N-Benzyl-4,14-diisobutyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21)-17,19-triene-19-amineC30H46N2O5Ee >97%[α]D25=-17.6 (c 0.91, dichloromethane)Source of chirality: (S)-(+)-leucineAbsolute configuration: (4S,14S)

1-Butyl-1-[(4S,14S)-(+)-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,19-triene-19-yl]-3-(3-(triethoxysilyl)propyl)ureaC31H57N3O9SiEe >97%[α]D25=+3.6 (c 1.91, dimethoxyethane)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: (4S,14S)

(4S,14S)-(+)-4,14-Dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,19-triene-19-yl trifluoromethanesulfonateC18H26F3NO8SEe >97%[α]D25=+11.8 (c 2.46, dichloromethane)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: (4S,14S)

(4S,14S)-(+)-19-Iodo-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,19-trieneC17H26INO5Ee >97%[α]D25=+13.4 (c 2.09, dichloromethane)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: (4S,14S)

Methyl 4-[(4S,14S)-(−)-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,19-triene-19-yl]-benzoateC25H33NO7Ee >97%[α]D25=-1.7 (c 1.21, dichloromethane)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: (4S,14S)

4-[(4S,14S)-(−)-4,14-Dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,19-triene-19-yl]-N-(3-(triethoxysilyl)propyl)benzamideC33H52N2O9SiEe >97%[α]Hg(365)25=-2.0 (c 1.23, dichloromethane)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: (4S,14S)

4-[(4S,14S)-(+)-4,14-Dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-1(21),17,19-triene-19-yl]-benzoic acidC24H31NO7Ee >97%[α]D25=+19.9 (c 1.86, MeOH)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: (4S,14S)