Marine natural product (+)-(4E, 15Z)-4, 15-docosadienoic-1- alkyne-3-alcohol and synthetic method of enantiomer thereof

Abstract

The invention discloses a marine natural product (+)-(4E, 15Z)-4, 15- docosadienoic-1- alkyne-3-alcohol and a synthetic method of an enantiomer thereof, and belongs to the field of chemical synthesis. With propargyl alcohol as an initial raw material, the method provided by the invention comprises multiple reactive synthesis steps, such as coupling, triple bond transposition, oxidation, selective reduction, asymmetric alkynylation, esterification and hydrolysis and the like, and the key step is to carry out an asymmetric addition reaction on trimethylsilylacetylene and aldehyde to directly obtain a chiral propargyl alcohol structure. The synthetic method disclosed by the invention has the advantages of simple steps, high total yield and high optical purity of the product.

Description

technical field

[0001] The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing marine natural product (+)-(4E,15Z)-4,15-docosadiene-1-yn-3-ol and its enantiomer . Background technique

[0002] In the past two decades, marine natural products have been extensively studied due to their unique structures and biological activities (Nat.Prod.Rep.2013,30,237-323.; .), has become an emerging research field and research hotspot. (4E,15Z)-docosa-4,15-dien-1-yn-3-ol is a kind of sponge natural product (J.Org.Chem.1990,55,6223-5.), the structure of the natural product There is a chiral carbon atom, and there are a pair of enantiomers with different biological activities. Studies have shown that this natural product has unique effects in antiviral, anti-inflammatory, anti-tumor and other aspects (J.Nat.Prod.1992,55,1275-80.). Therefore, how to efficiently and economically synthesize such products has extremely high innovation and applicat...

Examples

Embodiment 1

[0023] Embodiment 1 prepares 2-dodecyn-1-alcohol

[0024] Under nitrogen protection, add anhydrous THF (50 mL), freshly distilled propynyl alcohol (3.36 g, 60 mmol) and hexamethylphosphoric triamide (42 mL, 240 mmol) into a 250 mL Shrek tube, and stir well. The mixture was cooled to -78°C, and n-butyllithium solution (48 mL, 2.5 mol / L in hexane, 120 mol) was slowly added dropwise. After the dropwise addition, the mixture was stirred at -78°C for 30min, then warmed up to -30°C, and stirred for 3h. Iodo-n-nonane (16.8 g, 66 mmol) was slowly added to the mixture, and the stirring reaction was continued for 12 h, and the reaction liquid was naturally warmed to room temperature. After the reaction, add saturated NH 4 Aqueous Cl (5 mL) was used to quench the reaction. The aqueous phase was extracted with ether (40mL×3), the organic phases were combined, anhydrous Na 2 SO 4 After drying, the solvent was removed under reduced pressure to obtain a crude product. Finally, it was p...

Embodiment 2

[0025] Example 2 Preparation of 2-(11-dodecynyloxy)tetrahydropyran

[0026] Under nitrogen protection, in a 500mL four-neck flask equipped with mechanical stirring, a thermometer and a reflux condenser, add 1,3-propanediamine (150mL), add NaH (4.6g, 60% in mineral oil, 115mmol), the mixture was heated to 70°C, and stirring was continued for 1h after a large number of bubbles emerged. Then the mixture was cooled to room temperature, 2-dodecyn-1-ol (5.0 g, 27.5 mmol) was slowly added dropwise, the reaction solution was heated to raise the temperature to 55°C, and the reaction was continued to stir for 12 h. After the reaction was complete, a small amount of ice water (3 mL) was added to quench the reaction. The organic phase was extracted with ether (50mL×3), the organic phases were combined, anhydrous Na 2 SO 4 After drying and concentrating under reduced pressure, a colorless viscous liquid terminal acetylenic alcohol crude product was obtained, which could be directly used...

Embodiment 3

[0028] Embodiment 3 prepares 2-(11-octadecynyloxy group) tetrahydropyran

[0029] Under nitrogen protection, add anhydrous THF (30mL), 2-(11-dodecynyloxy)tetrahydropyran (1.3g, 5mmol) and hexamethylphosphoric triamide (3.5mL) into a 100mL Shrek bottle mL, 20mol), stir well. The mixture was cooled to -78°C, and n-butyllithium (4 mL, 2.5mol / L in hexane, 10 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at -78°C for 30 min. Then the temperature was raised to -30°C and stirring was continued for 3h. Then bromo-n-hexane (0.9 g, 5.5 mmol) was added slowly, and the stirring reaction was continued for 12 h, and the reaction liquid was naturally warmed to room temperature. After the reaction, add saturated NH 4 Aqueous Cl solution (1 mL) quenched the reaction. The aqueous phase was extracted with ether (40mL×3), the organic phases were combined, anhydrous Na 2 SO 4 After drying, the solvent was removed under reduced pressure to obtain a ...

technical field

[0001] The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing marine natural product (+)-(4E,15Z)-4,15-docosadiene-1-yn-3-ol and its enantiomer . Background technique

[0002] In the past two decades, marine natural products have been extensively studied due to their unique structures and biological activities (Nat.Prod.Rep.2013,30,237-323.; .), has become an emerging research field and research hotspot. (4E,15Z)-docosa-4,15-dien-1-yn-3-ol is a kind of sponge natural product (J.Org.Chem.1990,55,6223-5.), the structure of the natural product There is a chiral carbon atom, and there are a pair of enantiomers with different biological activities. Studies have shown that this natural product has unique effects in antiviral, anti-inflammatory, anti-tumor and other aspects (J.Nat.Prod.1992,55,1275-80.). Therefore, how to efficiently and economically synthesize such products has extremely high innovation and applicat...

Examples

Embodiment 1

[0023] Embodiment 1 prepares 2-dodecyn-1-alcohol

[0024] Under nitrogen protection, add anhydrous THF (50 mL), freshly distilled propynyl alcohol (3.36 g, 60 mmol) and hexamethylphosphoric triamide (42 mL, 240 mmol) into a 250 mL Shrek tube, and stir well. The mixture was cooled to -78°C, and n-butyllithium solution (48 mL, 2.5 mol / L in hexane, 120 mol) was slowly added dropwise. After the dropwise addition, the mixture was stirred at -78°C for 30min, then warmed up to -30°C, and stirred for 3h. Iodo-n-nonane (16.8 g, 66 mmol) was slowly added to the mixture, and the stirring reaction was continued for 12 h, and the reaction liquid was naturally warmed to room temperature. After the reaction, add saturated NH 4 Aqueous Cl (5 mL) was used to quench the reaction. The aqueous phase was extracted with ether (40mL×3), the organic phases were combined, anhydrous Na 2 SO 4 After drying, the solvent was removed under reduced pressure to obtain a crude product. Finally, it was p...

Embodiment 2

[0025] Example 2 Preparation of 2-(11-dodecynyloxy)tetrahydropyran

[0026] Under nitrogen protection, in a 500mL four-neck flask equipped with mechanical stirring, a thermometer and a reflux condenser, add 1,3-propanediamine (150mL), add NaH (4.6g, 60% in mineral oil, 115mmol), the mixture was heated to 70°C, and stirring was continued for 1h after a large number of bubbles emerged. Then the mixture was cooled to room temperature, 2-dodecyn-1-ol (5.0 g, 27.5 mmol) was slowly added dropwise, the reaction solution was heated to raise the temperature to 55°C, and the reaction was continued to stir for 12 h. After the reaction was complete, a small amount of ice water (3 mL) was added to quench the reaction. The organic phase was extracted with ether (50mL×3), the organic phases were combined, anhydrous Na 2 SO 4 After drying and concentrating under reduced pressure, a colorless viscous liquid terminal acetylenic alcohol crude product was obtained, which could be directly used...

Embodiment 3

[0028] Embodiment 3 prepares 2-(11-octadecynyloxy group) tetrahydropyran

[0029] Under nitrogen protection, add anhydrous THF (30mL), 2-(11-dodecynyloxy)tetrahydropyran (1.3g, 5mmol) and hexamethylphosphoric triamide (3.5mL) into a 100mL Shrek bottle mL, 20mol), stir well. The mixture was cooled to -78°C, and n-butyllithium (4 mL, 2.5mol / L in hexane, 10 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at -78°C for 30 min. Then the temperature was raised to -30°C and stirring was continued for 3h. Then bromo-n-hexane (0.9 g, 5.5 mmol) was added slowly, and the stirring reaction was continued for 12 h, and the reaction liquid was naturally warmed to room temperature. After the reaction, add saturated NH 4 Aqueous Cl solution (1 mL) quenched the reaction. The aqueous phase was extracted with ether (40mL×3), the organic phases were combined, anhydrous Na 2 SO 4 After drying, the solvent was removed under reduced pressure to obtain a ...

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