An efficient approach to enantiomeric isoxazolidinyl analogues of tiazofurin based on nitrone cycloadditions

An efficient synthetic route to isoxazolidinyl analogues of tiazofurin has been developed. The strategy involves, as a key step, a 1,3-dipolar cycloaddition between acrylonitrile and chiral nonracemic nitrones. An opposite diastereofacial induction was observed when the chiral group was placed at either the carbon atom or the nitrogen one of the nitrone function. The 2-cyano isoxazolidines obtained were further converted into the enantiomeric target compounds by constructing the thiazole ring via condensation with l-cysteine.

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(3S,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-cyanoisoxazolidineC16H20N2O3[α]D25=+43 (c 0.22, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 4′S,3S,5S

(3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-cyanoisoxazolidineC16H20N2O3[α]D25=-50 (c 0.27, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 4′S,3S,5R

(3R,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-cyanoisoxazolidineC16H20N2O3[α]D25=+11 (c 0.37, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 4′S,3R,5R

(3R,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-cyanoisoxazolidineC16H20N2O3[α]D25=+32 (c 0.25, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 4′S,3R,5S

(3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-[(4S)-4-(methoxycarbonyl)-2-thiazolin-2-yl]isoxazolidineC20H26N2O5S[α]D25=-4 (c 0.10, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 4′S,4′′S,3S,5R

(3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-[4-(ethoxycarbonyl)-2-thiazolyl]isoxazolidineC21H26N2O5S[α]D25=-16 (c 0.39, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 4′S,3S,5R

(3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-[4-(methoxycarbonyl)-2-thiazolyl]isoxazolidineC20H24N2O5S[α]D25=-23 (c 0.12, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 4′S,3S,5R

(3S,5R)-2-Benzyl-3-(hydroxymethyl)-5-[4-(ethoxycarbonyl)-2-thiazolyl]isoxazolidineC17H20N2O4S[α]D25=-2 (c 0.55, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 3S,5R

(3S,5R)-2-Benzyl-3-(hydroxymethyl)-5-[4-(methoxycarbonyl)-2-thiazolyl]isoxazolidineC16H18N2O4S[α]D25=-11 (c 0.21, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 3S,5R

(3S,5R)-2-Benzyl-3-(hydroxymethyl)-5-[4-(aminocarbonyl)-2-thiazolyl]isoxazolidineC15H17N3O3S[α]D25=-28 (c 0.20, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 3S,5R

(3S,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolon-4-yl]-5-[(4S)-4-(methoxycarbonyl)-2-thiazolin-2-yl]isoxazolidineC20H26N2O5S[α]D25=-18 (c 0.10, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 4′S,4″S,3S,5S

(3S,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-[4-(ethoxycarbonyl)-2-thiazolyl]isoxazolidineC21H26N2O5S[α]D25=-3 (c 0.68, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration:4′S,3S,5S

(3S,5S)-2-Benzyl-3-(hydroxymethyl)-5-[4-(ethoxycarbonyl)-2-thiazolyl]isoxazolidineC17H20N2O4S[α]D25=-29 (c 0.65, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 3S,5S

(3S,5S)-2-Benzyl-3-(hydroxymethyl)-5-[4-(aminocarbonyl)-2-thiazolyl]isoxazolidineC15H17N3O3S[α]D25=-44 (c 0.40, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 3S,5S

(3R,5S)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-isopropylidene-β-d-ribofuranosyl)-3-(tert-butyldiphenylsiloxymethyl)-5-cyanoisoxazolidineC45H56N2O6Si2[α]D25=-7 (c 0.62, CHCl3)Source of chirality: d-riboseAbsolute configuration: 3R,5S

(3R,5S)-2-Benzyl-3-(hydroxymethyl)-5-cyanoisoxazolidineC12H14N2O2[α]D25=+76 (c 0.23, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 3R,5S

(3R,5S)-2-Benzyl-3-(tert-butoxydiphenylsiloxy-methyl)-5-cyanoisoxazolidineC28H32N2O2Si[α]D25=+60 (c 0.19, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: 3R,5S

(3R,5S)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-isopropylidene-β-d-ribofuranosyl)-3-(tert-butyldiphenylsiloxymethyl)-5-[(4S)-4-(ethoxycarbonyl)-2-thiazolyl]isoxazolidineC50H62N2O8SSi2[α]D25=-19 (c 0.24, CHCl3)Source of chirality: d-riboseAbsolute configuration: 3R,5S

(3R,5S)-3-(Hydroxymethyl)-5-[4-(aminocarbonyl)-2-thiazolyl]isoxazolidineC8H11N3O3S[α]D25=+20 (c 0.17, MeOH)Source of chirality: d-riboseAbsolute configuration: 3R,5S