Asymmetric [2,3]-Wittig rearrangement of the dienolates of chiral secondary alcohol-substituted β-pyrrolidinyl-γ-allyloxyl-α,β-unsaturated esters: total synthesis of (+)-eldanolide

The asymmetric [2,3]-Wittig rearrangement of the dienolates of various chiral β-pyrrolidinyl-γ-allyloxyl-α,β-unsaturated esters was investigated using different chiral secondary alcohol substitutions. When (1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2,2,1]heptane-1-carboxylic acid diisopropylamide was used as chiral auxiliary, it provided the best enantioselectivity in the rearrangement. When various γ-allyloxy substitutions underwent temperature and additive studies, 1,1-dimethylpropenoxy substitution was found to give the best enantioselectivity. The methodology was applied to the total synthesis of (+)-eldanolide.

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4-Allyloxy-3-oxo-butyric acid (1S,2R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl esterC17H26O4[α]D26=-26.4 (c 0.39, CH2Cl2)Source of chirality: [(1S)-endo]-(−)-BorneolAbsolute configuration: 1S,2R

4-Allyloxy-3-oxo-butyric acid (1R,2R)-1-(hydroxy-diphenyl-methyl)-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC29H34O5[α]D26=+63.6 (c 1.4, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-Allyloxy-3-oxo-butyric acid (1R,2R)-1-diethylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC21H33NO5[α]D26=-20.3 (c 0.37, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-Allyloxy-3-oxo-butyric acid (1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC23H37NO5[α]D26=-35.0 (c 0.5, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-Allyloxy-3-oxo-butyric acid (1R,2R)-1-dicyclohexylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC29H45NO5[α]D26=-19.8 (c 0.3, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-Allyloxy-3-pyrrolidin-1-yl-but-2-enoic acid (1S,2R)-1,7,7-trimethyl-bicyclo[2.2.1]hept 2-yl esterC21H33NO3[α]D26=-34.7 (c 0.4, CH2Cl2)Source of chirality: [(1S)-endo]-(−)-BorneolAbsolute configuration: 1S,2R

4-Allyloxy-3-pyrrolidin-1-yl-but-2-enoic acid (1R,2R)-1-(hydroxy-diphenyl-methyl)-7,7-trimethyl-bicyclo[2.2.1]hept 2-yl esterC21H33NO3[α]D26=-48.2 (c 0.14, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-Allyloxy-3-pyrrolidin-1-yl-but-2-enoic acid (1R,2R)-1-diethylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC25H40N2O4[α]D26=-48.0 (c 0.8, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-Allyloxy-3-pyrrolidin-1-yl-but-2-enoic acid (1R,2R)-1-diisopropylcarbamoyl-7,7-di-methyl-bicyclo[2.2.1]hept-2-yl esterC27H44N2O4[α]D26=-15.9 (c 0.15, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-Allyloxy-3-pyrrolidin-1-yl-but-2-enoic acid (1R,2R)-1-dicyclohexylcarbamoyl-7,7-di-methyl-bicyclo[2.2.1]hept-2-yl esterC26H43NO5[α]D26=-40.9 (c 0.15, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

(5S)-5-Allyl-4-pyrrolidin-1-yl-5H-furan-2-oneC11H15NO2Ee = 86%[α]D26=+26.9 (c 0.39, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

4-(1-Methyl-allyloxy)-3-oxo-butyric acid (1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC24H39NO5[α]D26=-37.9 (c 0.21, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-(1-Methyl-allyloxy)-3-pyrrolidin-1-yl-but-2-enoic acid (1R,2R)-1-diisopropylcarbamo-yl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC28H46N2O4[α]D26=-44.8 (c 0.2, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

3-Oxo-butyric acid (1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC20H33NO4[α]D26=-16.9 (c 0.19, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-Bromo-3-oxo-butyric acid (1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC20H32BrNO4[α]D26=-20.9 (c 0.2, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-(1,1-Dimethyl-allyloxy)-3-oxo-butyric acid (1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC25H41NO5[α]D26=-29.0 (c 0.47, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-(3-Methyl-but-2-enyloxy)-3-oxo-butyric acid (1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC25H41NO5[α]D26=-26.5 (c 0.6, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-(1,1-Dimethyl-allyloxy)-3-pyrrolidin-1-yl-but-2-enoic acid (1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC29H48N2O4[α]D26=-23.7 (c 0.2, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

4-(3-Methyl-but-2-enyloxy)-3-pyrrolidin-1-yl-but-2-enoic acid (1R,2R)-1-diisopropylcarbamoyl-7,7-di-methyl-bicyclo[2.2.1]hept-2-yl esterC29H48N2O4[α]D26=-32.1 (c 0.18, CH2Cl2)Source of chirality: (1S,2R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1R,2R

(5S)-5-(3-Methyl-but-2-enyl)-4-pyrrolidin-1-yl-5H-furan-2-oneC13H19NO2Ee = 95%[α]D26=+26.1 (c 0.45, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

3-Oxo-butyric acid (1S,2S)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC20H33NO4[α]D26=+16.8 (c 0.19, CH2Cl2)Source of chirality: (1R,2S)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1S,2S

4-Bromo-3-oxo-butyric acid (1S,2S)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC20H32BrNO4[α]D26=+21.0 (c 0.39, CH2Cl2)Source of chirality: (1R,2S)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1S,2S

4-(1,1-Dimethyl-allyloxy)-3-oxo-butyric acid (1S,2S)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC25H41NO5[α]D26=+28.9 (c 0.32, CH2Cl2)Source of chirality: (1R,2S)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1S,2S

4-(1,1-Dimethyl-allyloxy)-3-pyrrolidin-1-yl-but-2-enoic acid (1S,2S)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl esterC29H48N2O4[α]D26=+23.7 (c 0.22, CH2Cl2)Source of chirality: (1R,2S)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane-1-carboxylic acidAbsolute configuration: 1S,2S

(5R)-5-(3-Methyl-but-2-enyl)-4-pyrrolidin-1-yl-5H-furan-2-oneC13H19NO2Ee = 93%[α]D26=-25.8 (c 0.42, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(5R)-5-(3-Methyl-but-2-enyl)-5H-furan-2-oneC9H12O2Ee = 93%[α]D26=-125.2 (c 1.15, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(5R)-Dihydro-4-methyl-5-(3-Methyl-but-2-enyl)furan-2(3H)-oneC10H16O2Ee = 93%[α]D26=+46.5 (c 1.02, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (R)