Synthesis of chiral 1,5-disubstituted pyrrolidinones via electrophile-induced cyclization of 2-(3-butenyl)oxazolines derived from (1R,2S)- and (1S,2R)-norephedrine

Starting from (1R,2S)- and (1S,2R)-norephedrine, enantiomers of the corresponding 2-(3-butenyl)oxazolines were prepared in a two-step process. The cyclization of the intermediate alkenylamides with phenylselenyl bromide afforded cyclic imidates instead of the expected pyrrolidinones. The electrophile-induced cyclizations of 2-alkenyloxazolines with bromine or iodine produced diastereomeric mixtures of chiral 1,5-disubstituted pyrrolidinones. The ring closure of the all-cis (1R,2S,5R)-diastereomer 7 with NaH resulted in the tetrahydropyrrolo[2,1-b]oxazol-5-one derivative 18, which was alternatively prepared by the cyclocondensation of (1R,2S)-norephedrine with levulinic acid.

Starting from (1R,2S)-norephedrine 1, chiral 1,5-disubstituted pyrrolidinones were prepared via electrophile-induced cyclization. The ring closure of 2 resulted in chiral tetrahydropyrrolo[2,1-b]oxazol-5-one derivative 3, which was alternatively prepared by cyclocondensation of 1 with levulinic acid.Figure optionsDownload as PowerPoint slide

N-[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]-4-pentenamideC14H19NO2[α]D20=-110.7 (c 1.5, CH2Cl2)Source of chirality: (1R,2S)-(−)-norephedrineAbsolute configuration: (1S,2R)

(4S,5R)-2-(3-Butenyl)-4-methyl-5-phenyl-4,5-dihydro-1,3-oxazoleC14H17NO[α]D20=-170 (c 0.1, MeOH)Source of chirality: (1R,2S)-(−)-norephedrineAbsolute configuration: (4S,5R)

(1S,2R,5R)-5-Bromomethyl-1-(2-hydroxy-1-methyl-2-phenylethyl)-2-pyrrolidinoneC14H18BrNO2[α]D20=-42.3 (c 1.0, CH2Cl2)Source of chirality: (1R,2S)-(−)-norephedrineAbsolute configuration: (1S,2R,5R)

(1S,2R,5S)-5-Bromomethyl-1-(2-hydroxy-1-methyl-2-phenylethyl)-2-pyrrolidinoneC14H18BrNO2[α]D20=-37.6 (c 1.05, CH2Cl2)Source of chirality: (1R,2S)-(−)-norephedrineAbsolute configuration: (1S,2R,5S)

(1S,2R,5R)-5-Iodomethyl-1-(2-hydroxy-1-methyl-2-phenylethyl)-2-pyrrolidinoneC14H18INO2[α]D20=-74 (c 1.0, CH2Cl2)Source of chirality: (1R,2S)-(−)-norephedrineAbsolute configuration: (1S,2R,5R)

(1S,2R,5S)-5-Iodomethyl-1-(2-hydroxy-1-methyl-2-phenylethyl)-2-pyrrolidinoneC14H18INO2[α]D20=-49.1 (c 1.1, CH2Cl2)Source of chirality: (1R,2S)-(−)-norephedrineAbsolute configuration: (1S,2R,5S)

(2R,3S,7aS)-3,7a-Dimethyl-2-phenyl-pyrrolo[2,1-b]oxazol-5(6H)-oneC14H17NO2[α]D20=-25 (c 0.25, MeOH)Source of chirality: (1R,2S)-(−)-norephedrineAbsolute configuration: (2R,3S,7aS)