Enantioselective synthesis of γ-substituted-γ-butyrolactone and δ-substituted-δ-valerolactone

Abstract

The invention belongs to the field of chemical technology and relates to a method for enantioselective synthesis of gamma-substituted-gamma-butyrolactone and delta-substituted-delta-valerolactone. A cu-chiral phosphine catalyst is used to promote the reaction of silicon hydride, methacrylates, 3-acyl propionate or 4-acyl butyrate in an organic solvent to synthesize chiral gamma-alkoxyl formyl methyl-gamma-butyrolactone and delta-alkoxyl formyl methy-delta-valerolactone with important biological activity. Compared with the prior art, the method provided by the invention has enantioselectivity, the ee value of the product is up to 84%, and any one isomer of enantiomers can be preferentially obtained by adjusting the configuration of the ligand; the target compound obtained according to the invention contains a chiral ring-lactone structure and has application value.

Description

technical field

[0001] The invention belongs to the technical field of chemical industry, and relates to a method for enantioselectively synthesizing γ-substituted-γ-butyrolactone and δ-substituted-δ-valerolactone, more specifically to γ-(1-methyl-1- Oxygenylethyl)-γ-butyrolactone and δ-(1-methyl-1-hydrocarbyloxyethyl)-δ-valerolactone. Background technique

[0002] Chiral compounds widely exist in nature and many medicines. Compounds with the same atomic connection sequence but different configurations, that is, enantiomers, often show different activities in organisms. In order to ensure drug safety, when using chiral When making drugs, it is necessary to be aware of the difference in activity of these isomers or to be cautious, to use a single enantiomer to avoid possible toxic side effects of its enantiomers.

[0003] The structures of γ-butyrolactone and δ-valerolactone widely exist in natural products and have important biological activities. Compounds with such struct...

Examples

Embodiment 1

[0025] Under nitrogen protection, add (R)-(+)-SEGPHOS(L6,R 5 =Ph)(7.4mg), Cu(OAc) 2 ·H 2 O (2.2 mg), toluene (1.0 mL), and polymethylhydrogensiloxane (48 μL) was added while stirring well. Add methyl methacrylate (85 μL) and methyl 3-benzoylpropionate (77 mg) in toluene (2.0 mL) dropwise under stirring, and stir at room temperature for 4 h, then add saturated NH 4F in water (2 mL), and stirring was continued for 30 min. The phases were separated, and the aqueous phase was extracted with dichloromethane (3×5mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain a colorless solid γ-phenyl - γ-(1-methyl-1-methoxyformylethyl)-γ-cyclobutyrolactone (102 mg, yield 97%). The product was analyzed by chiral HPLC, and the ee value was 84%.

Embodiment 2

[0027] Under nitrogen protection, add (R)-MeO-BIPHEP (L5,R 5 =Ph) (7.5mg, Cu(OAc) 2 ·H 2 O (2.2mgl), benzene (1.0mL), stir well, add polymethylhydrogensiloxane (48μL), add methyl methacrylate (85μL), 3-benzoylpropionic acid dropwise under stirring at room temperature A solution of the methyl ester (77 mg) in benzene (2.0 mL) was stirred for another 4 h. Add saturated NH to the reaction mixture 4 F in water (2 mL), and stirring was continued for 30 min. The phases were separated, and the aqueous phase was extracted with dichloromethane (3×5mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain a colorless solid γ-phenyl - γ-(1-methyl-1-methoxyformylethyl)-γ-cyclobutyrolactone (94 mg, yield 90%, enantiomeric ratio ee 82%).

Embodiment 3

[0029] Under nitrogen protection, add (S,S)-Ph-BPE(L7,R 6 =Ph)(2.0mg,), Cu(OAc) 2 ·H 2 O (2.2 mg), toluene (1.0 mL), stirred well, and polymethylhydrogensiloxane (30 μL) was added. Cool to 0°C, add methyl methacrylate (53 μL), methyl 3-benzoylpropionate (77 mg) in toluene (2.0 mL), stir at 0°C for 24 h, then add saturated NH 4 F aqueous solution (2mL), and continue to stir for 30min, separate the phases, extract the aqueous phase (3×5mL) with dichloromethane, wash the combined organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and pass through the column Chromatographic separation gave γ-phenyl-γ-(1-methyl-1-methoxyformylethyl)-γ-cyclobutyrolactone (80 mg, yield 76%, ee 78%) as a colorless solid.

technical field

[0001] The invention belongs to the technical field of chemical industry, and relates to a method for enantioselectively synthesizing γ-substituted-γ-butyrolactone and δ-substituted-δ-valerolactone, more specifically to γ-(1-methyl-1- Oxygenylethyl)-γ-butyrolactone and δ-(1-methyl-1-hydrocarbyloxyethyl)-δ-valerolactone. Background technique

[0002] Chiral compounds widely exist in nature and many medicines. Compounds with the same atomic connection sequence but different configurations, that is, enantiomers, often show different activities in organisms. In order to ensure drug safety, when using chiral When making drugs, it is necessary to be aware of the difference in activity of these isomers or to be cautious, to use a single enantiomer to avoid possible toxic side effects of its enantiomers.

[0003] The structures of γ-butyrolactone and δ-valerolactone widely exist in natural products and have important biological activities. Compounds with such struct...

Examples

Embodiment 1

[0025] Under nitrogen protection, add (R)-(+)-SEGPHOS(L6,R 5 =Ph)(7.4mg), Cu(OAc) 2 ·H 2 O (2.2 mg), toluene (1.0 mL), and polymethylhydrogensiloxane (48 μL) was added while stirring well. Add methyl methacrylate (85 μL) and methyl 3-benzoylpropionate (77 mg) in toluene (2.0 mL) dropwise under stirring, and stir at room temperature for 4 h, then add saturated NH 4F in water (2 mL), and stirring was continued for 30 min. The phases were separated, and the aqueous phase was extracted with dichloromethane (3×5mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain a colorless solid γ-phenyl - γ-(1-methyl-1-methoxyformylethyl)-γ-cyclobutyrolactone (102 mg, yield 97%). The product was analyzed by chiral HPLC, and the ee value was 84%.

Embodiment 2

[0027] Under nitrogen protection, add (R)-MeO-BIPHEP (L5,R 5 =Ph) (7.5mg, Cu(OAc) 2 ·H 2 O (2.2mgl), benzene (1.0mL), stir well, add polymethylhydrogensiloxane (48μL), add methyl methacrylate (85μL), 3-benzoylpropionic acid dropwise under stirring at room temperature A solution of the methyl ester (77 mg) in benzene (2.0 mL) was stirred for another 4 h. Add saturated NH to the reaction mixture 4 F in water (2 mL), and stirring was continued for 30 min. The phases were separated, and the aqueous phase was extracted with dichloromethane (3×5mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain a colorless solid γ-phenyl - γ-(1-methyl-1-methoxyformylethyl)-γ-cyclobutyrolactone (94 mg, yield 90%, enantiomeric ratio ee 82%).

Embodiment 3

[0029] Under nitrogen protection, add (S,S)-Ph-BPE(L7,R 6 =Ph)(2.0mg,), Cu(OAc) 2 ·H 2 O (2.2 mg), toluene (1.0 mL), stirred well, and polymethylhydrogensiloxane (30 μL) was added. Cool to 0°C, add methyl methacrylate (53 μL), methyl 3-benzoylpropionate (77 mg) in toluene (2.0 mL), stir at 0°C for 24 h, then add saturated NH 4 F aqueous solution (2mL), and continue to stir for 30min, separate the phases, extract the aqueous phase (3×5mL) with dichloromethane, wash the combined organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and pass through the column Chromatographic separation gave γ-phenyl-γ-(1-methyl-1-methoxyformylethyl)-γ-cyclobutyrolactone (80 mg, yield 76%, ee 78%) as a colorless solid.

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