Enzymatic resolution of (±)-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester and its transformations into polyfunctionalised amino acids and dipeptides

Enantiomerically pure (5R)-(−)-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester was obtained via enzymatic resolution of the corresponding racemic mixture using a lipase from hog pancreas (PPL). The following reduction of the ester group to the corresponding alcohol and the oxidation of the latter led to (5R)-(−)-5-phenyl-4,5-dihydroisoxazole-3-carbaldehyde, and the reaction between this and Schöllkopf’s reagent, (2R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine, gave mixtures of adducts with a good syn/anti ratio. The steric configurations of the major diastereoisomer were assigned on the basis of spectroscopic data and X-ray analysis. The subsequent controlled hydrolysis of the pyrazine ring led to β-(5-phenyl-4,5-dihydroisoxazol-3-yl)-serine methyl esters and the corresponding dipeptides with (R)-valine. Finally, reductive cleavage of the 4,5-dihydroisoxazole ring under hydrolytic conditions made it possible to obtain the corresponding polyfunctionalised dipeptides.

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(5R)-5-Phenyl-4,5-dihydroisoxazole-3-carbaldehydeC10H9NO2Ee = 96% [HPLC][α]D20=-459 (c 1.29, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (R)

(5R)-5-Phenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl esterC12H13NO3Ee = 96% [HPLC][α]D20=-285.3 (c 0.95, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (R)

[(5R)-5-Phenyl-4,5-dihydroisoxazole-3-yl]-methanolC10H11NO2Ee = 96% [HPLC][α]D20=-166.3 (c 1.05, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (R)

(S)-[(2S,5R)-5-Isopropyl-3,6-dimethoxy-2,5,dihydropyrazin-2-yl]-[(5R)-5-phenyl-4,5-dihydroisoxazol-3-yl]-methanolC19H25N3O4Dr = >98% [NMR][α]D20=-149.35 (c 0.96, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (2S, 5R, 1′S)

(R)-[(2R,5R)-5-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]-[(5R)-5-phenyl-4,5-dihydroisoxazol-3-yl]-methanolC19H25N3O4Dr = >98% [NMR][α]D20=-78.7 (c 1.41, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (2R,1′R)

(R)-[(2S,5R)-5-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]-[(5R)-5-phenyl-4,5-dihydroisoxazol-3-yl]-methanolC19H25N3O4Dr = >98% [NMR][α]D20=-51.2 (c 0.65, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (2S,1′R)

(S)-[(2R,5R)-5-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]-[(5R)-5-phenyl-4,5-dihydroisoxazol-3-yl]-methanolC19H25N3O4Dr = >98% [NMR][α]D20=-41.4 (c 0.45, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (2R,1′S)

(2S)-Amino-(3S)-hydroxy-3-[(5R)-phenyl-4,5-dihydroisoxazol-3-yl]-propionic acid methyl esterC13H16N2O4Dr = >98% [NMR][α]D20=-54.1 (c 0.77, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (2S,3S)

(2S)-[(2R)-Amino-3-methyl-butyrylamino]-(3S)-hydroxy-3-[(5R)-5-phenyl-4,5-dihydroisoxazol-3-yl]-propionic acid methyl esterC18H25N3O5Dr = >98% [NMR][α]D20=-80.7 (c 0.32, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (2S,3S)

(2R)-Amino-[(3R)-hydroxy-3-(5R)-5-phenyl-4,5-dihyroisoxazol-3-yl]-propionic acid methyl esterC13H16N2O4Dr = >98% [NMR][α]D20=-99.7 (c 0.30, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (2R,3R)

(2R)-[(2R)-Amino-3-methyl-butyrylamino]-(3R)-hydroxy-3-[(5R)-5-phenyl-4,5-dihydroisoxazol-3-yl]-propionic acid methyl esterC18H25N3O5Dr = >98% [NMR][α]D20=-35.3 (c 0.15, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (2R,3R)

(2S,3S,6R)-2-[(2R)-2-Amino-3-methyl-butyrylamino]-3,6-dihydroxy-4-oxo-6-phenyl-hexanoic acid methyl esterC18H26N2O6Dr = >98% [NMR][α]D20=+60.6 (c 0.42, CHCl3)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (2S,3S)