Practical and efficient synthesis of chiral 2,4-disubstituted oxazolines from β-phosphonoamides

Herein we report a practical and efficient method for the synthesis of optically active 2,4-disubstituted oxazolines (S)-1a–h in good to excellent yields. The target compounds were prepared in good yield through the Horner–Wadsworth–Emmons reaction of β-phosphonoamide 3 bearing l-phenylalaninol with commercially available aryl aldehydes followed by the cyclodehydration of the corresponding N-(cinnamoyl)-(S)-phenylalaninol derivatives (S)-2a–h. Additionally, the cyclodehydration of β-phosphonoamide (S)-3 followed by the Horner–Wadsworth–Emmons reaction of β-phosphono-oxazoline (S)-4 with aryl aldehydes also gave the 2,4-disubstituted oxazolines (S)-1a–h.

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N-(p-Fluorocinnamoyl)-(S)-phenylalaninolC18H18FNO2De >98%[α]D28 = −88.3 (c 1.6, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

N-(p-Chlorocinnamoyl)-(S)-phenylalaninolC18H18ClNO2De >98%[α]D28 = −1.3 (c 3.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

N-(p-Bromocinnamoyl)-(S)-phenylalaninolC18H18BrNO2De >98%[α]D28 = −110.8 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

N-(p-Methoxycinnamoyl)-(S)-phenylalaninolC19H21NO3De >98%[α]D28 = −95.7 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

N-(p-Benzyloxycinnamoyl)-(S)-phenylalaninolC25H25NO3De >98%[α]D28 = −83.35 (c 1.0, DMSO)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

N-(p-Carbomethoxycinnamoyl)-(S)-phenylalaninolC20H21NO4De >98%[α]D28 = −116.0 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

N-(Furan-2-yl-acryloyl)-(S)-phenylalaninolC16H17NO3De >98%[α]D28 = −116.0 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(4S)-4-Benzyl-2-(p-fluorocinnamoyl)-2-oxazolineC18H16FNODe >98%[α]D28 = +17.7 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(4S)-4-Benzyl-2-(p-chlorocinnamoyl)-2-oxazolineC18H16ClNODe >98%[α]D28 = +4.0 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(4S)-4-Benzyl-2-(p-bromocinnamoyl)-2-oxazolineC18H16BrNODe >98%[α]D28 = +8.0 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(4S)-4-Benzyl-2-(p-methoxycinnamoyl)-2-oxazolineC19H19NO2De >98%[α]D28 = +16.3 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(4S)-4-Benzyl-2-(p-benzyloxycinnamoyl)-2-oxazolineC25H23NO2De >98%[α]D28 = +23.4 (c 1.0, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(4S)-4-Benzyl-2-(p-carbomethoxycinnamoyl)-2-oxazolineC20H19NO3De >98%[α]D28 = +4.0 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(4S)-4-Benzyl-2-(furan-2-yl-vinyl)-2-oxazolineC16H15NO2De >98%[α]D28 = +16.0 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-2-(2-Diethoxyphosphoryl)acetamide-3-phenylbromoprapaneC15H23BrNO4PDe >98%[α]D28 = −12.9 (c 1.0, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)

(S)-Diethyl ((4-benzyl-4,5-dihydrooxazol-2-yl)methyl)phosphonateC15H22NO4PDe >98%[α]D28 = −42.9 (c 4.7, CH3OH)Source of chirality: Asymmetric synthesisAbsolute configuration: (S)