Synthesis and circular dichroism of optically active 1,3-disubstituted isochromans of dopamine D4 antagonist activity

The C-1 epimers of the 3-methyl-6,7-dimethoxy analogues of the D4 antagonist sonepiprazole 1b and 5-HT1D agonist PNU-109291 1a containing both the isochroman and p-methoxyphenylpiperazine chromophores were prepared in order to study the applicability of circular dichroism for the assignment of the configuration of 1,3-disubstituted isochromans and test their dopamine D4 antagonist activity.

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(+)-Ethyl-[(1S,3S)-6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-yl]acetateC16H22O5[α]D20=+30.2 (c 1.25, CHCl3)Source of chirality: bioreductionAbsolute configuration: (1S,3S)

(+)-[(1S,3S)-6,7-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-yl]acetic acidC14H18O5[α]D20=+21.1 (c 0.88, CH2Cl2)Source of chirality: bioreductionAbsolute configuration: (1S,3S)

(+)-1-{[(1S,3S)-6,7-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-yl]acetyl}-4-(4-methoxyphenyl)piperazineC25H32N2O5[α]D20=+6.4 (c 1.35, CHCl3)Source of chirality: bioreductionAbsolute configuration: (1S,3S)

(+)-1-{2-[(1S,3S)-6,7-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-yl]ethyl}-4-(4-methoxyphenyl)piperazineC25H34N2O4[α]D20=+14.9 (c 0.11, CHCl3)Source of chirality: bioreductionAbsolute configuration: (1S,3S)

(+)-Ethyl-[(1R,3S)-6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-yl]acetateC16H22O5[α]D20=+108.2 (c 1.27, CHCl3)Source of chirality: bioreductionAbsolute configuration: (1R,3S)

(+)-[(1R,3S)-6,7-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-yl]acetic acidC14H18O5[α]D20=+117.5 (c 1.28, CH2Cl2)Source of chirality: bioreductionAbsolute configuration: (1R,3S)

(+)-1-{[(1R,3S)-6,7-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-yl]acetyl}-4-(4-methoxy-phenyl)piperazineC25H32N2O5[α]D20=+79.5 (c 1.47, CHCl3)Source of chirality: bioreductionAbsolute configuration: (1R,3S)

(+)-1-{2-[(1R,3S)-6,7-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-yl]ethyl}-4-(4-methoxyphenyl)piperazineC25H34N2O4[α]D20=+67.1 (c 0.54, CHCl3)Source of chirality: bioreductionAbsolute configuration: (1R,3S)