Preparation of enantiopure 3,5,5-trialkyl-γ-butyrolactones by diastereospecific 5-endo halo lactonizations

A new preparation of 3,5,5-trialkyl-γ-butyrolactones of defined absolute configuration is reported. This method involves the diastereoselective alkylation of 3,4-ethylenic acids after incorporation of a chiral Evans auxiliary, and then after separation of the two diastereomers and hydrolysis of the auxiliary, stereospecific halo lactonizations. This method was applied to the preparation of a natural product, present in a sponge.

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(R)-3-((E)-4-Phenylpent-3-enoyl)-4-phenyloxazolidin-2-oneC20H19NO3Ee = 100%[α]D25=-85.9 (c 1.6, CH2Cl2)Source of chirality:enantiomerically pure starting materialAbsolute configuration:(R)

(R)-3-((R,E)-2-Methyl-4-phenylpent-3-enoyl)-4-phenyloxazolidin-2-oneC21H21NO3Ee = 100%[α]D20=-149.0 (c 0.96, CH2Cl2)Source of chirality:diastereoselective alkylationAbsolute configuration:(2R,3R)

(R,E)-2-Methyl-4-phenylpent-3-enoic acidC12H14O2Ee = 100%[α]D20=-53.1 (c 1.15, CH2Cl2)Source of chirality:enantiomerically pure starting materialAbsolute configuration:(R)

(3S,4R,5S)-Dihydro-4-iodo-3,5-dimethyl-5-phenylfuran-2(3H)-oneC12H13IO2Ee = 100%[α]D20=-45.9 (c 0.90, CH2Cl2)Source of chirality:diastereospecific iodo lactonizationAbsolute configuration:(3S,4R,5S)

(R,E)-2-Benzyl-4-phenylpent-3-enoic acidC18H18O2Ee = 100%[α]D20=-154.1 (c 1.08, CH2Cl2).Source of chirality:enantiomerically pure starting materialAbsolute configuration:(R)

(R)-3-((Z)-4-Phenylpent-3-enoyl)-4-phenyloxazolidin-2-oneC20H19NO3Ee = 100%[α]D20=-30.7 (c 1.2, CH2Cl2)Source of chirality:enantiomerically pure starting materialAbsolute configuration:(R)

(R,Z)-2-Methyl-4-phenylpent-3-enoic acidC12H14O2Ee = 100%[α]D20=-252.8 (c 1.2, CH2Cl2)Source of chirality:diastereoselective alkylationAbsolute configuration:(2S,3R)

(3S,4R,5S)-4-Bromo-dihydro-3,5-dimethyl-5-phenylfuran-2(3H)-oneC12H13BrO2Ee = 100%[α]D20=-25.4 (c 3, CH2Cl2)Source of chirality:diastereospecific bromo lactonizationAbsolute configuration:(3S,4R,5S)

(3S,4R,5R)-Dihydro-4-iodo-3,5-dimethyl-5-phenylfuran-2(3H)-oneC12H13IO2Ee = 100%[α]D20=-66.3 (c 0.9, CH2Cl2)Source of chirality:diastereospecific iodo lactonizationAbsolute configuration:(3S,4R,5R)

(R)-3-((R,E)-2-Benzyl-4-phenylpent-3-enoyl)-4-phenyloxazolidin-2-oneC27H25NO3Ee = 100%[α]D20=-196.8 (c 1.33, CH2Cl2)Source of chirality:diastereoselective alkylationAbsolute configuration:(2R,3R)

(R,E)-4-Phenyl-2-propylpent-3-enoic acidC14H18O2Ee = 100%[α]D20=-54.8 (c 1.98, CH2Cl2).Source of chirality:enantiomerically pure starting materialAbsolute configuration:(R)

(3S,4R,5S)-3-Benzyl-4-bromo-dihydro-5-methyl-5-phenylfuran-2(3H)-oneC18H17BrO2Ee = 100%[α]D20=-11.0 (c 1.07, CH2Cl2)Source of chirality:diastereospecific bromo lactonizationAbsolute configuration:(3S,4R,5S)

(3S,4R,5S)-3-Benzyl-4-iodo-dihydro-5-methyl-5-phenylfuran-2(3H)-oneC18H17IO2Ee = 100%[α]D20=+4.2 (c 1.25, CH2Cl2)Source of chirality:diastereospecific iodo lactonizationAbsolute configuration:(3S,4R,5S)

(R)-3-((R,E)-4-Phenyl-2-propylpent-3-enoyl)-4-phenyloxazolidin-2-oneC23H25NO3Ee = 100%[α]D20=-128.1 (c 0.99, CH2Cl2)Source of chirality:diastereoselective alkylationAbsolute configuration:(2R,3R)

(R)-3-(2-((E)-2-Phenylprop-1-enyl)pent-4-enoyl)-4-phenyloxazolidin-2-oneC23H23NO3Ee = 100%[α]D20=-151.0 (c 1.1, CH2Cl2)Source of chirality:diastereoselective alkylationAbsolute configuration:(2R,3R)

(3S,4R,5S)-Dihydro-4-iodo-5-methyl-5-phenyl-3-propylfuran-2(3H)-oneC14H17IO2Ee = 100%[α]D20=-18.9 (c 0.75, CH2Cl2)Source of chirality:diastereospecific iodo lactonizationAbsolute configuration:(3S,4R,5S)

(R)-3-((R,Z)-2-Methyl-4-phenylpent-3-enoyl)-4-phenyloxazolidin-2-oneC21H21NO3Ee = 100%[α]D20=-100.3 (c 0.5, CH2Cl2)Source of chirality:diastereoselective alkylationAbsolute configuration:(2R,3R)

(R)-2-((E)-2-Phenylprop-1-enyl)pent-4-enoic acidC14H16O2Ee = 100%[α]D20=-80.2 (c 2.1, CH2Cl2)Source of chirality: enantiomerically pure starting materialAbsolute configuration: (R)

(3S,4R,5S)-3-Allyl-dihydro-4-iodo-5-methyl-5-phenylfuran-2(3H)-oneC14H15IO2Ee = 100%[α]D20=-30.1 (c 0.9, CH2Cl2)Source of chirality: diastereospecific iodo lactonizationAbsolute configuration: (3S,4R,5S)

(R)-2,4-dimethylpent-3-enoic acidC7H12O2Ee = 100%[α]D20=-310.0 (c 2.0, CH2Cl2)Source of chirality: enantiomerically pure starting materialAbsolute configuration: (R)

(R)-3-((R)-2,4-Dimethylpent-3-enoyl)-4-phenyloxazolidin-2-oneC16H19NO3Ee = 100%[α]D20=-157.0 (c 2.0, CH2Cl2)Source of chirality: diastereoselective alkylationAbsolute configuration: (2R,3R)

(3R,5R)-Dihydro-5-(hydroxymethyl)-3,5-dimethylfuran-2(3H)-oneC7H12O3Ee = 100%[α]D20=-4.9 (c 0.90, EtOH)Source of chirality: enantiomerically pure starting materialAbsolute configuration: (3R,5R)

(3S,4R)-Dihydro-4-iodo-3,5,5-trimethylfuran-2(3H)-oneC7H11IO2Ee = 100%[α]D20=-16.7 (c 2.0, CH2Cl2)Source of chirality: diastereospecific iodo lactonizationAbsolute configuration: (3S,4R)

(3R,5R)- Dihydro-3,5-dimethyl-5-phenylfuran-2(3H)-oneC12H14O2Ee = 100%[α]D20=-32.0 (c 0.33, CH2Cl2)Source of chirality: enantiomerically pure starting materialAbsolute configuration: (3R,5R)

(3R,5S)-Dihydro-3,5-dimethyl-5-(11-phenylundecyl)furan-2(3H)-oneC24H38O2Ee = 100%[α]D20=-8.5 (c 0.2, MeOH)Source of chirality: enantiomerically pure starting materialAbsolute configuration: (3R,5S)