Towards the development of oxadiazinanones as chiral auxiliaries: synthesis and application of N3-haloacetyloxadiazinanones

Oxadiazinanones derived from (1R,2S)-ephedrine and (1R,2S)-norephedrine were employed in the asymmetric α-halo aldol reaction. The optimized yields and diastereoselectivities for the ephedrine based oxadiazinanone aldol reaction ranged from fair to good. The ephedrine based aldol adducts were hydrolyzed to afford the α-bromo-β-hydroxycarboxylic acids. The absolute stereochemistry and enantiomeric purity of these products were determined by chiral HPLC and specific rotation measurements.

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(4R,5S,6R)-3-(2-Chloroacetyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC13H15ClN2O3[α]D25=-28.3 (c 0.53, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (4R,5S,6R)

(4R,5S,6R)-3-(2-Bromoacetyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC13H15BrN2O3[α]D25=-19.6 (c 0.58, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-(2-Chloro-3-hydroxy-3-phenylpropanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC20H21N2O4Cl[α]D25=-20.3 (c 0.48, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-[2-Chloro-3-(4-chlorophenyl)-3-hydroxypropanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC20H21N2O4Cl2[α]D25=-17.2 (c 0.31, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-(2-Chloro-3-hydroxy-3-naphthalen-2-yl-propanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC24H23N2O4Cl[α]D25=-30.0 (c 0.33, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-(2-Chloro-3-hydroxy-4-methylpentanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC17H23N2O4Cl[α]D25=-31.9 (c 0.25, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-(2-Chloro-3-hydroxy-4,4-dimethylpentanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC18H25N2O4Cl[α]D25=-20.5 (c 0.48, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-(2-Bromo-3-hydroxy-3-phenylpropanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC20H21N2O4Br[α]D25=-22.7 (c 0.29, CH3OH)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-[2-Bromo-3-hydroxy-3-(4-methoxyphenyl)propanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC21H23N2O5Br[α]D25=-16.5 (c 0.53, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-[2-Bromo-3-hydroxy-3-(4-chlorophenyl)propanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC20H20N2O4BrCl[α]D25=-27.4 (c 0.49, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-(2-Bromo-3-hydroxy-3-naphthalen-2-yl-propanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC24H23N2O4Br[α]D25=-27.4 (c 0.32, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-(2-Bromo-3-hydroxy-3-m-tolylpropanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC21H23N2O4Br[α]D25=-19.6 (c 0.30, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-[2-Bromo-3-hydroxy-3-(4-nitrophenyl)propanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC20H21N3O6Br[α]D25=-23.2 (c 0.38, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-[2-Bromo-3-(4-cyanophenyl)-3-hydroxypropanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC21H21N3O4Br[α]D25=-16.5 (c 0.40, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-[2-Bromo-3-hydroxy-3-(4-benzyloxyphenyl)propanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-oneC27H27BrN2O5[α]D25=-16.8 (c 0.27, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

(2′S,3′R,4R,5S,6R)-3-(2-Bromo-3-hydroxy-4-methylpentanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-oneC17H23N2O4Br[α]D25=-25.6 (c 0.30, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2′S,3′R,4R,5S,6R)

Methyl (2R,3R)-phenylglycidateC10H10O3[α]D = +10.0 (c 0.25, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2R,3R)

Methyl (2R,3S)-2-Bromo-3-hydroxy-3-phenylpropanoateC10H11BrO3[α]D = +29.1 (c 0.42, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (2R,3S)