Stereoselective synthesis of δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids

Enantiomerically pure δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids were stereoselectively synthesized starting from (2R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Schöllkopf’s reagent) and suitable β-heteroaryl-α,β-unsaturated aldehydes. The stereocontrolled addition gave a mixture of two diastereoisomers whose configurations were assigned on the basis of spectroscopic data and the accepted model for aldol condensation of the Schöllkopf’s reagent. Upon controlled hydrolysis the adducts were transformed into the corresponding methyl esters of δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids.

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(1′R,2S,5R)-(E)-3-Furan-2-yl-1-(5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-prop-2-en-1-olC16H22N2O4Dr = >99% [NMR][α]D20=-73.65 (c 0.72, Et2O)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (1′R,2S,5R)-(E)

(1′S,2S,5R)-(E)-3-Furan-2-yl-1-(5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-prop-2-en-1-olC16H22N2O4Dr = >99% [NMR][α]D20=+58.2 (c 0.74, Et2O)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (1′S,2S,5R)-(E)

(1′S,2R,5S)-(E)-3-Furan-2-yl-1-(5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-prop-2-en-1-olC16H22N2O4Dr = >99% [NMR][α]D20=+68.9 (c 0.83, Et2O)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (1′S,2R,5S)-(E)

(1′R,2R,5S)-(E)-3-Furan-2-yl-1-(5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-prop-2-en-1-olC16H22N2O4Dr = >99% [NMR][α]D20=-49.9 (c 0.57, Et2O)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (1′R,2R,5S)-(E)

(1′R,2S,5R)-(E)-1-(5-Isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-3-thiazol-2-yl-prop-2-en-1-olC15H21N3O3SDr = >99% [NMR][α]D20=-99.1 (c 0.89, Et2O)Source of chirality: Schöllkopf’s reagentAbsolute configuration: (1′R,2S,5R)-(E)

(1′S,2S,5R)-(E)-1-(5-Isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-3-thiazol-2-yl-prop-2-en-1-olC15H21N3O3SDr = >99% [NMR][α]D20=+82.9 (c 0.57, Et2O)Source of chirality:Schöllkopf’s reagentAbsolute configuration:(1′S,2S,5R)-(E)

(1′R,2S,5R)-(E)-1-(5-Isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-3-thiophen-2-yl-prop-2-en-1-olC16H22N2O3SDr = >99% [NMR][α]D20=-28.4 (c 1.2, Et2O)Source of chirality:Schöllkopf’s reagentAbsolute configuration:(1′R,2S,5R)-(E)

(1′R,2S,5R)-(E)-1-(5-Isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-3-(5-p-tolyl-isoxazol-3-yl)-prop-2-en-1-olC22H27N3O4Dr = >99% [NMR][α]D20=-82.4 (c 0.66, Et2O)Source of chirality:Schöllkopf’s reagentAbsolute configuration:(1′R,2S,5R)-(E)

(1′S,2S,5R)-(E)-1-(5-Isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazin-2-yl)-3-(5-p-tolyl-isoxazol-3-yl)-prop-2-en-1-olC22H27N3O4Dr = >99% [NMR][α]D20=+63.5 (c 0.20, Et2O).Source of chirality:Schöllkopf’s reagentAbsolute configuration:(1′S,2S,5R)-(E)

(2S,3R)-(E)-2-Amino-5-furan-2-yl-3-hydroxy-pent-4-enoic acid methyl esterC10H13NO4Dr = >99% [NMR][α]D20=+27.0 (c 0.45, CH3COCH3)Source of chirality:asymmetric synthesisAbsolute configuration: (2S,3R)-(E)

(2S,3R)-(E)-2-Amino-3-hydroxy-5-thiazol-2-yl-pent-4-enoic acid methyl esterC9H12N2O3SDr = >99% [NMR][α]D20=+14.5 (c 0.54, CH3COCH3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R)-(E)

(2S,3S)-(E)-2-Amino-3-hydroxy-5-thiazol-2-yl-pent-4-enoic acid methyl esterC9H12N2O3SDr = >99% [NMR][α]D20=+14.0 (c 0.5, CH3COCH3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)-(E)