Acylative kinetic resolution of racemic heterocyclic amines using N-phthaloyl-(S)-amino acyl chlorides with alkyl side chains

A comparative study of the acylative kinetic resolution of racemic 2-methyl-1,2,3,4 tetrahydroquinoline and 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine using N-phthaloyl-(S)-amino acyl chlorides with alkyl side chains has been carried out. The influence of steric factors on the stereoselectivity of the acylation was demonstrated. The (S)-enantiomers of the heterocyclic amines (ee >99%) were obtained in good yields via a kinetic resolution protocol using N-phthaloyl-(S)-leucyl chloride.

Figure optionsDownload as PowerPoint slide

N-Phthaloyl-(S)-tert-leucyl chlorideC14H14ClNO3[α]D20=-86.0 (c 1.2, C6H6)Source of chirality: N-phthaloyl-(S)-tert-leucineAbsolute configuration: (2S)

N-Phthaloyl-3-cyclohexyl-(S)-alanyl chlorideC17H18ClNO3[α]D20=-73.9 (c 1.2, C6H6)Source of chirality: N-phthaloyl-3-cyclohexyl-(S)-alanineAbsolute configuration: (2S)

(2S)-2-Methyl-1-[N-phthaloyl-(S)-valyl]-1,2,3,4-tetrahydroquinolineC23H24N2O3[α]D20=+406 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-(S)-valineAbsolute configuration: (2S,2′S)

(2R)-2-Methyl-1-[N-phthaloyl-(S)-valyl]-1,2,3,4-tetrahydroquinolineC23H24N2O3[α]D20=-241 (c 0.7, CHCl3)Source of chirality: N-phthaloyl-(S)-valineAbsolute configuration: (2R,2′S)

(2S)-2-Methyl-1-[N-phthaloyl-(S)-tert-leucyl]-1,2,3,4-tetrahydroquinolineC24H26N2O3[α]D20=+252 (c 0.9, CHCl3)Source of chirality: N-phthaloyl-(S)-tert-leucineAbsolute configuration: (2S,2′S)

(2R)-2-Methyl-1-[N-phthaloyl-(S)-tert-leucyl]-1,2,3,4-tetrahydroquinolineC24H26N2O3[α]D20=-219 (c 0.5, CHCl3)Source of chirality: N-phthaloyl-(S)-tert-leucineAbsolute configuration: (2R,2′S)

(2S)-2-Methyl-1-[N-phthaloyl-3-cyclohexyl-(S)-alanyl]-1,2,3,4-tetrahydroquinolineC27H30N2O3[α]D20=+416 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-3-cyclohexyl-(S)-alanineAbsolute configuration: (2S,2′S)

(3S)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-valyl]-2H-[1,4]benzoxazineC22H22N2O4[α]D20=+163 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-(S)-valineAbsolute configuration: (3S,2′S)

(3R)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-valyl]-2H-[1,4]benzoxazineC22H22N2O4[α]D20=-256 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-O-methyl-(S)-tyrosineAbsolute configuration: (3R,2′S)

(3S)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-tert-leucyl]-2H-[1,4]benzoxazineC23H24N2O4[α]D20+77.8 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-(S)-tert-leucineAbsolute configuration: (3S,2′S)

(3R)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-tert-leucyl]-2H-[1,4]benzoxazineC23H24N2O4[α]D20=-266 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-(S)-tert-leucineAbsolute configuration: (3R,2′S)

(3S)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-leucyl]-2H-[1,4]benzoxazineC23H24N2O4[α]D20+370 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-(S)-leucineAbsolute configuration: ((3S,2′S)

(3R)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-leucyl]-2H-[1,4]benzoxazineC23H24N2O4[α]D20-216 (c 0.2, CHCl3)Source of chirality: N-phthaloyl-(S)-leucineAbsolute configuration: (3R,2′S)

(3S)-3,4-Dihydro-3-methyl-1-[N-phthaloyl-3-cyclohexyl-(S)-alanyl]-2H-[1,4]benzoxazineC26H28N2O4[α]D20+344 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-3-cyclohexyl-(S)-alanineAbsolute configuration: (3S,2′S)

(3R)-3,4-Dihydro-3-methyl-1-[N-phthaloyl-3-cyclohexyl-(S)-alanyl]-2H-[1,4]benzoxazineC26H28N2O4[α]D20-183 (c 0.4, CHCl3)Source of chirality: N-phthaloyl-3-cyclohexyl-(S)-alanineAbsolute configuration: (3R,2′S)