Substituent effect on the stereoselectivity of acylation of racemic heterocyclic amines with N-phthaloyl-3-aryl-(S)-alanyl chlorides

The acylative kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and 2,3-dihydro-3-methyl-4H-1,4-benzoxazine using acyl chlorides of N-phthaloyl-(S)-phenylalanine, N-phthaloyl-3-(4-nitrophenyl)-(S)-alanine and N-phthaloyl-O-methyl-(S)-tyrosine as chiral resolving agents has been carried out. It is shown that the effectiveness of an acylative kinetic resolution depends on the electronic effects of substituents in the phenyl fragment of the acylating agent and increases as the electron-donating properties of the para-substituent (OMe > H > NO2) in phenyl fragment of N-phthaloyl-3-aryl-(S)-alanyl chlorides increase; conducting the process at a reduced temperature also contributes to an enhancement of the kinetic resolution.

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(2S)-2-Methyl-1-[3-(4-nitrophenyl)-N-phthaloyl-(S)-alanyl]-1,2,3,4-tetrahydroquinolineC27H23N3O5[α]D20=+383 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-3-(4-nitrophenyl)-(S)-alanineAbsolute configuration: (2S,2′S)

(3S)-2,3-Dihydro-3-methyl-4-[3-(4-nitrophenyl)-N-phthaloyl-(S)-alanyl]-4H-1,4-benzoxazineC26H21N3O6[α]D20=+339 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-3-(4-nitrophenyl)-(S)-alanineAbsolute configuration: (3S,2′S)

(2S)-2-Methyl-1-[O-methyl-N-phthaloyl-(S)-tyrosyl]-1,2,3,4-tetrahydroquinolineC28H26N2O4[α]D20=+369 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-O-methyl-(S)-tyrosineAbsolute configuration: (2S,2′S)

(3S)-2,3-Dihydro-3-methyl-4-[O-methyl-N-phthaloyl-(S)-tyrosyl]-4H-1,4-benzoxazineC27H24N2O5[α]D20=+305 (c 1.0, CHCl3)Source of chirality: N-phthaloyl-O-methyl-(S)-tyrosineAbsolute configuration: (3S,2′S)