An enantiodivergent and formal synthesis of paroxetine enantiomers by asymmetric desymmetrization of 3-(4-fluorophenyl)glutaric anhydride with a chiral SuperQuat oxazolidin-2-one

The asymmetric desymmetrization of 3-(4-fluorophenyl)glutaric anhydride 9 with lithiated chiral oxazolidin-2-one 8 has been studied. The desymmetrized product was formed with >90% de and converted into known intermediates for both (+)- and (−)-paroxetines.

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Methyl ester of (3′R,4S)-5,5-di(2-methoxy-5-methylphenyl)-3-[3-(4-fluorophenyl)-4-methoxycarbonyl-1-oxobutyl]-4-isopropyloxazolidin-2-oneC34H38NO7F[α]D23=-173.1 (c 0.84, MeOH)Source of chirality: asymmetric induction, (S)-valineAbsolute stereochemistry: (3′R,4S)

(3′R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-3-[3-(4-fluorophenyl)-4-benzylcarbamoyl-1-oxobutyl]-4-isopropyloxazolidin-2-oneC40H43FN2O6[α]D23=-192 (c 0.5, CHCl3)Source of chirality: asymmetric induction, (S)-valineAbsolute stereochemistry: (3′R,4S)

(S)-4-(Benzylcarbamoyl)-3-(4-fluorophenyl)butanoic acidC18H18FNO3[α]D23=+1.8 (c 1.1, MeOH)Source of chirality: asymmetric inductionAbsolute stereochemistry: (S)

(R)-N-Benzyl-3-(4-fluorophenyl)-5-hydroxypentanamideC18H20FNO2[α]D23=-12.5 (c 0.4, CHCl3)Source of chirality: asymmetric inductionAbsolute stereochemistry: (R)

(R)-1-Benzyl-4-(4-fluorophenyl)piperidin-2-oneC18H18FNO[α]D27+7.8 (c 0.9, CHCl3)Source of chirality: asymmetric inductionAbsolute stereochemistry: (S)

(3S,1′S)-3-(4-Fluorophenyl)-5-oxo-5-(1′-phenylethylamino)pentanoic acidC19H20FNO3[α]D26=-74 (c 1, MeOH)Source of chirality: asymmetric inductionAbsolute stereochemistry: (3S,1′S)

(3′R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-3-[3-(4-fluorophenyl)-5-hydroxypentyl]-4-isopropyloxazolidin-2-oneC33H38FNO6[α]D26=-152 (c 0.84, CHCl3)Source of chirality: asymmetric induction, (S)-valineAbsolute stereochemistry: (3′R,4S)

(S)-1-Benzyl-4-(4-fluorophenyl)piperidin-2-oneC18H18FNO[α]D25=-30 (c 0.4, CHCl3)Source of chirality: asymmetric inductionAbsolute stereochemistry: (S)