Chiral oxaziridines in the enantioselective synthesis of isoxazolidines

The stereoselective synthesis of oxaziridines with three stereogenic centres is presented in this paper. The chirality is provided by asymmetric induction, and a possible mechanism for the induced stereoselectivity is also discussed. These small heterocycles undergo the [3+2] cycloaddition reaction with aryl ethenes to afford enantiomerically pure isoxazolidines of controlled configurations. This class of heterocycles is present in the structure of various compounds of biological and pharmacological interest, which can undergo further synthetic modifications.

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(−)-(1′S,2S,3S)-3-Phenyl-2-(1-phenylethyl)oxaziridineC15H15NOEe = 100%[α]D21.0=-61.1 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2S,3S)

(+)-(1′S,2R,3R)-3-Phenyl-2-(1-phenylethyl)oxaziridineC15H15NOEe = 100%[α]D21.0=+81.5 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2R,3R)

(+)-(1′R,2R,3R)-3-Phenyl-2-(1-phenylethyl)oxaziridineC15H15NOEe = 100%[α]D21.0=+60.2 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2R,3R)

(−)-(1′R,2S,3S)-3-Phenyl-2-(1-phenylethyl)oxaziridineC15H15NOEe = 100%[α]D21.0=-79.9 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2S,3S)

(−)-(1′S,2S,3S)-2-(1-Phenylethyl)-3-p-tolyloxaziridineC16H17NOEe = 100%[α]D21.3=-55.0 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2S,3S)

(+)-(1′S,2R,3R)-2-(1-Phenylethyl)-3-p-tolyloxaziridineC16H17NOEe = 100%[α]D21.3=+60.1 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2R,3R)

(+)-(1′R,2R,3R)-2-(1-Phenylethyl)-3-p-tolyloxaziridineC16H17NOEe = 100%[α]D21.3=+56.7 (c 0.03, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2R,3R)

(−)-(1′R,2S,3S)-2-(1-Phenylethyl)-3-p-tolyloxaziridineC16H17NOEe = 100%[α]D21.3=-61.1 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2S,3S)

(−)-(1′S,2S,3S)-3-(4-Methoxyphenyl)-2-(1-phenylethyl)oxaziridineC16H17NO2Ee = 100%[α]D25.0=-41.9 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2S,3S)

(+)-(1′S,2R,3R)-3-(4-Methoxyphenyl)-2-(1-phenylethyl)oxaziridineC16H17NO2Ee = 100%[α]D25.0=+90.6 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2R,3R)

(+)-(1′R,2R,3R)-3-(4-Methoxyphenyl)-2-(1-phenylethyl)oxaziridineC16H17NO2Ee = 100%[α]D25.0=+43.0 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2R,3R)

(−)-(1′R,2S,3S)-3-(4-Methoxyphenyl)-2-(1-phenylethyl)oxaziridineC16H17NO2Ee = 100%[α]D25.0=-89.1 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2S,3S)

(−)-(1′S,2S,3S)-3-(4-Chlorophenyl)-2-(1-phenylethyl)oxaziridineC15H14ClNOEe = 100%[α]D22.1=-44.1 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2S,3S)

(+)-(1′S,2R,3R)-3-(4-Chlorophenyl)-2-(1-phenylethyl)oxaziridineC15H14ClNOEe = 100%[α]D22.1=+97.3 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2R,3R)

(+)-(1′R,2R,3R)-3-(4-Chlorophenyl)-2-(1-phenylethyl)oxaziridineC15H14ClNOEe = 100%[α]D22.1=+44.6 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2R,3R)

(−)-(1′R,2S,3S)-3-(4-Chlorophenyl)-2-(1-phenylethyl)oxaziridineC15H14ClNOEe = 100%[α]D22.1=-96.1 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2S,3S)

(−)-(1′S,2S,3S)-2-[2-(1-Phenylethyl)oxaziridin-3-yl]pyridineC14H14N2OEe = 100%[α]D24.0=-78.1 (c 0.03, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2S,3S)

(+)-(1′S,2R,3R)-2-[2-(1-Phenylethyl)oxaziridin-3-yl]pyridineC14H14N2OEe = 100%[α]D24.0=+91.8 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2R,3R)

(+)-(1′R,2R,3R)-2-[2-(1-Phenylethyl)oxaziridin-3-yl]pyridineC14H14N2OEe = 100%[α]D24.0=+77.3 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2R,3R)

(−)-(1′R,2S,3S)-2-[2-(1-Phenylethyl)oxaziridin-3-yl]pyridineC14H14N2OEe = 100%[α]D24.0=-92.2 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2S,3S)

(−)-(1′S,2S,3S)-4-[2-(1-Phenylethyl)oxaziridin-3-yl]pyridineC14H14N2OEe = 100%[α]D22.3=-103.9 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2S,3S)

(+)-(1′S,2R,3R)-4-[2-(1-Phenylethyl)oxaziridin-3-yl]pyridineC14H14N2OEe = 100%[α]D22.3=+37.4 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2R,3R)

(+)-(1′R,2R,3R)-4-[2-(1-Phenylethyl)oxaziridin-3-yl]pyridineC14H14N2OEe = 100%[α]D22.3=+102.1 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2R,3R)

(−)-(1′R,2S,3S)-4-[2-(1-Phenylethyl)oxaziridin-3-yl]pyridineC14H14N2OEe = 100%[α]D22.3=-38.1 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2S,3S)

(−)-(1′S,2S,3S)-4-Methyl-2-[2-(1-phenylethyl)oxaziridin-3-yl]thiazoleC13H14N2OSEe = 100%[α]D23.0=-60.2 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2S,3S)

(+)-(1′S,2R,3R)-4-Methyl-2-[2-(1-phenylethyl)oxaziridin-3-yl]thiazoleC13H14N2OSEe = 100%[α]D23.0=+84.6 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2R,3R)

(+)-(1′R,2R,3R)-4-Methyl-2-[2-(1-phenylethyl)oxaziridin-3-yl]thiazoleC13H14N2OSEe = 100%[α]D23.0=+58.8 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2R,3R)

(−)-(1′R,2S,3S)-4-Methyl-2-[2-(1-phenylethyl)oxaziridin-3-yl]thiazoleC13H14N2OSEe = 100%[α]D23.0=-84.1 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2S,3S)

(−)-(1′S,2S,3S)-2-[2-(1-Phenylethyl)oxaziridin-3-yl]benzothiazoleC16H14N2OSEe = 100%[α]D21.0=-55.6 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2S,3S)

(+)-(1′S,2R,3R)-2-[2-(1-Phenylethyl)oxaziridin-3-yl]benzothiazoleC16H14N2OSEe = 100%[α]D21.0=+80.3 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,2R,3R)

(+)-(1′R,2R,3R)-2-[2-(1-Phenylethyl)oxaziridin-3-yl]benzothiazoleC16H14N2OSEe = 100%[α]D21.0=+56.0 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2R,3R)

(−)-(1′R,2S,3S)-2-[2-(1-Phenylethyl)oxaziridin-3-yl]benzothiazoleC16H14N2OSEe = 100%[α]D21.0=-80.7 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,2S,3S)

(−)-(1′R,3R,5R)-(trans)-2-[3-Phenyl-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC22H22N2OEe = 100%[α]D24.0=-50.1 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,3R,5R)

(+)-(1′R,3R,5S)-(cis)-2-[3-Phenyl-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC22H22N2OEe = 100%[α]D24.0=+70.4 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,3R,5S)

(+)-(1′S,3S,5S)-(trans)-2-[3-Phenyl-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC22H22N2OEe = 100%[α]D24.0=+50.0 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,3S,5S)

(−)-(1′S,3S,5R)-(cis)-2-[3-Phenyl-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC22H22N2OEe = 100%[α]D24.0=-70.2 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,3S,5R)

(+)-(1′R,3S,5S)-(trans)-2-[3-Phenyl-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC22H22N2OEe = 100%[α]D24.0=+21.2 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,3S,5S)

(−)-(1′R,3S,5R)-(cis)-2-[3-Phenyl-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC22H22N2OEe = 100%[α]D24.0=-26.0 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,3S,5R)

(−)-(1′S,3R,5R)-(trans)-2-[3-Phenyl-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC22H22N2OEe = 100%[α]D24.0=-21.0 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,3R,5R)

(+)-(1′S,3R,5S)-(cis)-2-[3-Phenyl-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC22H22N2OEe = 100%[α]D24.0=+26.3 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,3R,5S)

(−)-(1′R,3R,5R)-(trans)-2-[3-(4-Methoxyphenyl)-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC23H24N2O2Ee = 100%[α]D21.0=-55.3 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,3R,5R)

(−)-(1′S,3S,5R)-(cis)-2-[3-(4-Methoxyphenyl)-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC23H24N2O2Ee = 100%[α]D21.0=-65.6 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,3S,5R)

(+)-(1′S,3S,5S)-(trans)-2-[3-(4-Methoxyphenyl)-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC23H24N2O2Ee = 100%[α]D21.0=+55.1 (c 0.02, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,3S,5S)

(+)-(1′R,3R,5S)-(cis)-2-[3-(4-Methoxyphenyl)-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC23H24N2O2Ee = 100%[α]D21.0 = +64.9 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,3R,5S)

(−)-(1′S,3R,5R)-(trans)-2-[3-(4-Methoxyphenyl)-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC23H24N2O2Ee = 100%[α]D21.0=-15.1 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,3R,5R)

(+)-(1′S,3R,5S)-(cis)-2-[3-(4-Methoxyphenyl)-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC23H24N2O2Ee = 100%[α]D21.0=+30.3 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′S,3R,5S)

(+)-(1′R,3S,5S)-(trans)-2-[3-(4-Methoxyphenyl)-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC23H24N2O2Ee = 100%[α]D21.0=+15.5 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,3S,5S)

(−)-(1′R,3S,5R)-(cis)-2-[3-(4-Methoxyphenyl)-2-(1-phenylethyl)isoxazolidin-5-yl]pyridineC23H24N2O2Ee = 100%[α]D21.0=-31.3 (c 0.01, CHCl3)Source of chirality: asymmetric inductionAbsolute configuration: (1′R,3S,5R)