Biocatalytic preparation of optically active 4-(N,N-dimethylamino)pyridines for application in chemical asymmetric catalysis

4-Chloro-2-(1-hydroxybenzyl)pyridine and 4-chloro-2-(1-hydroxyalkyl)pyridines were obtained with moderate to excellent enantiomeric excesses and high isolated yields by bioreduction with Baker’s yeast of the corresponding ketones. The resulting optically active alcohols were transformed into adequate DMAP derivatives, which have been applied in asymmetric catalytic processes as nucleophilic catalysts in the stereoselective chemical alkoxycarbonylation of 1-phenylethanol or as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde.

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(S)-(−)-4-Chloro-2-(1-hydroxyethyl)pyridineC7H8NOClEe 99% (HPLC, Chiralcel OB-H)[α]D20=-36.1 (c 2, CHCl3)Source of chirality: bioreductionAbsolute configuration: S

(S)-(−)-4-Chloro-2-(1-hydroxypropyl)pyridineC8H10NOClEe 99% (HPLC, Chiralcel OB-H)[α]D20=-29.4 (c 2, CHCl3)Source of chirality: bioreductionAbsolute configuration: S

(S)-(−)-4-Chloro-2-(1-hydroxybutyl)pyridineC9H12NOClEe 99% (HPLC, Chiralcel OB-H)[α]D20=-41.7 (c 2, CHCl3)Source of chirality: bioreductionAbsolute configuration: S

(S)-(−)-4-Chloro-2-(1-hydroxypentyl)pyridineC10H14NOClEe 99% (HPLC, Chiralcel OB-H)[α]D20=-45.8 (c 2, CHCl3)Source of chirality: bioreductionAbsolute configuration: S

(R)-(−)-4-Chloro-2-(1-hydroxybenzyl)pyridineC12H10NOClEe 97% (HPLC, Chiralcel OD)[α]D20=-43.4 (c 2, CHCl3)Source of chirality: bioreductionAbsolute configuration: R

(S)-(−)-4-(N,N-Dimethylamino)-2-(1-hydroxyethyl)pyridineC9H14N2OEe 99% (HPLC, Chiralcel OD)[α]D20=-31.5 (c 1, EtOH)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(S)-(−)-4-(N,N-Dimethylamino)-2-(1-hydroxypropyl)pyridineC10H16N2OEe 99%[α]D20=-19.9 (c 1, EtOH)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(S)-(−)-4-(N,N-Dimethylamino)-2-(1-hydroxybutyl)pyridineC11H18N2OEe 99%[α]D20=-26.7 (c 1, EtOH)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(S)-(−)-4-(N,N-Dimethylamino)-2-(1-hydroxypentyl)pyridineC12H20N2OEe 99%[α]D20=-21.8 (c 1, EtOH)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(R)-(−)-4-(N,N-Dimethylamino)-2-(1-hydroxybenzyl)pyridineC14H16N2OEe 97% (HPLC, Chiralcel OD)[α]D20=-24.1 (c 1, EtOH)Source of chirality: bioreductionAbsolute configuration: R

(S)-(−)-4-(N,N-Dimethylamino)-2-[(1-methoxyethyl)pyridine]C10H16N2OEe 99%[α]D20=-100.2 (c 2.1, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(S)-(−)-4-(N,N-Dimethylamino)-2-[(1-methoxypropyl)pyridine]C11H18N2OEe 99%[α]D20=-80.6 (c 1.1, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(S)-(−)-4-(N,N-Dimethylamino)-2-[(1-methoxybutyl)pyridine]C12H20N2OEe 99%[α]D20=-73.9 (c 1.1, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(S)-(−)-4-(N,N-Dimethylamino)-2-[(1-methoxypentyl)pyridine]C13H22N2OEe 99% (HPLC, Chiralcel OD)[α]D20=-77.5 (c 1, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(R)-(−)-4-(N,N-Dimethylamino)-2-[(1-methoxybenzyl)pyridine]C15H18N2OEe 97% (HPLC, Chiralcel OD)[α]D20=-62.9 (c 1.5, CHCl3)Source of chirality: bioreductionAbsolute configuration: R

(S)-(−)-4-(N,N-Dimethylamino)-2-[(1-butoxyethyl)pyridine]C13H22N2OEe 99%[α]D20=-107.3 (c 2.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S