CN112608296B - Synthesis method of Brazilane natural product Brazilane - Google Patents
Synthesis method of Brazilane natural product Brazilane Download PDFInfo
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Abstract
The invention relates to a method for synthesizing Brazilane, which utilizes glycol compounds to carry out reactions such as single protection by acetic anhydride, mitsunobu reaction, dess-Martin oxidation reaction and intramolecular Prins/Friedel-Crafts tandem reaction under the catalysis of p-toluenesulfonic acid (p-TsOH), and constructs a key indenopyran ring skeleton structure by a one-pot method, thus synthesizing Brazilane, a Brazilane natural product. The invention uses the conventional chemical reagents as reagents, has mild reaction conditions, simple operation, relatively high speed and fewer reaction byproducts, and greatly shortens the synthesis steps, thereby reducing the synthesis cost.
Description
Technical Field
The invention relates to a method for synthesizing a key intermediate of an anticancer active compound, in particular to a method for synthesizing Brazilane which is a brazilin natural product.
Background
Brazilane belongs to the Brazilian class of natural products. Brazilin natural products are a special compound in traditional Chinese medicine sappan wood, are mainly separated from sappan wood, are sequentially discovered from the beginning of the 50 th 20 th century, and are mainly separated and identified by the following 6 compounds: brazilin, brazilein, brazilide A, haematoxylin, haematoxylane and Brazilane. The compounds have similar chemical structures and are a class of homoisoflavone derivatives, and all have a chroman ring. The structure of Brazilane represents the basic framework structure of brazilin-like natural products, on the basis of which other compounds are oxidized. Brazilane and its cognate compounds possess a variety of biological activities and are therefore of interest to many researchers. Such as chemists find that the composition has various biological activities of reducing blood sugar, resisting blood platelets, resisting inflammation, resisting bacteria, resisting tumors, protecting liver, resisting cancers and the like. Because of the unique structure and remarkable biological activity of Brazilane, many chemical researchers have attracted attention and struggle towards synthesizing this molecule.
The chemical structure of Brazilane is as follows:
the chemical methods reported in the literature for synthesizing the natural product Brazilane mainly comprise: (1) F. Morsingh et al in 1970 entitled The synthesis of Brazilin and Haematoxylin to Tetrahedron; (2) Jinzhu Xu et al 1996 published a research paper entitled First Synthesis of (+) -Brazilane from (+) -Brazilin on tetrahedron letters; (3) A research paper titled Gold-Catalyzed Deoxygenative Nazarov Cyclization of2,4-Dien-1-als for Stereoselective Synthesis of Highly Substituted Cyclopentenes published by Lee et al in 2008 on j Am. chem. Soc; (4) Jhillu Singh Yadav et al, 2014, published a research paper on Tetrahedron entitled Formalsynthesis of (+) -brazilin and total synthesis of (+) -brazizalane; (5) The study paper titled Design and synthesis of a hybrid framework of indanone andchromane: total synthesis of a homoisoflavanoid, brazilane, published by Jinwoo Kim et al in 2018 on org. Biomol. Chem. In view of the synthetic routes of synthesizing target molecules by scientific researchers at home and abroad, we carefully analyze and find that the currently reported synthetic routes have the problems of long synthetic steps, difficult individual reactions, expensive reagents and high toxicity due to the semisynthetic route taking a few natural products as raw materials. Therefore, the main research direction for synthesizing Brazilane is established by searching a complete synthesis route which shortens the synthesis step, is common and easy to obtain raw materials and has more efficient reaction, and the urgent need is met.
Disclosure of Invention
The invention aims to provide a brand-new synthesis method of Brazilian hematoxylin natural products Brazilian, which has fewer synthesis steps, common and easily available raw materials and efficient reaction.
In order to achieve the above purpose, the invention adopts the following technical scheme: a method for synthesizing Brazilian hematoxylin natural products Brazilian comprises the following steps:
step one, 3, 4-dimethoxy benzyl alcohol as an initial raw material of a compound shown in a formula 1 is taken as a solvent, triethylamine is added into the initial raw material, methanesulfonyl chloride is added into the initial raw material, and a methanesulfonylation reaction is carried out to protect a hydroxyl group, so that a compound shown in a formula 2 is obtained;
dissolving sodium hydride in tetrahydrofuran and N, N-dimethylformamide solution, dropwise adding diethyl malonate into the solution, dropwise adding a compound of formula 2 into the reaction solution, and reacting to obtain a compound of formula 3;
step three, dropwise adding the compound of the formula 3 dissolved in the tetrahydrofuran solution into the tetrahydrofuran solution of lithium aluminum hydride to perform a reduction reaction to obtain a compound of the formula 4;
step four, reacting the compound shown in the formula 4 with acetic anhydride under the condition of taking anhydrous acetonitrile as a solvent to obtain a compound shown in the formula 5;
step five, dissolving the compound of formula 5 and 3-methoxyphenol in tetrahydrofuran, and adding the compound to the mixture of ADDP and Bu 3 In the presence of P, a Mitsunobu reaction occurs to provide a compound of formula 6;
step six, dissolving the compound of the formula 6 in methanol, and adding K 2 CO 3 Reacting at room temperature, and performing deacetylation protection reaction to obtain a compound of formula 7;
step seven, adding a dess-Martin oxidizer DMP into the compound of the formula 7 at normal temperature, and carrying out oxidation reaction by taking methylene dichloride as a solvent to obtain a compound of the formula 8;
step eight, adding p-toluenesulfonic acid into a compound of formula 8, and taking dichloromethane as a solvent to perform Prins/Friedel-Crafts tandem reaction in one-pot molecules to obtain a compound of formula 9;
step nine, dissolving a compound of formula 9 in dichloromethane, adding boron tribromide into the dichloromethane, and removing methyl ether for protection to obtain a target product Brazilane;
the reaction formula is as follows:
in the first step, under the protection of 0 ℃ and nitrogen, the compound of the formula 1 is dissolved in a dichloromethane solvent, triethylamine and methanesulfonyl chloride are sequentially added dropwise, the solution is gradually changed into light yellow after being moved to room temperature for reaction, dichloromethane is used for extraction, an organic phase is collected, reduced pressure concentration is carried out, and the compound of the formula 2 is obtained after separation and purification.
In the second step, sodium hydride is dissolved in anhydrous tetrahydrofuran and N, N-dimethylformamide solution with equal amounts of substances under the protection of nitrogen at the temperature of 0 ℃, diethyl malonate solution dissolved in tetrahydrofuran solvent is slowly added dropwise into the solution to react for 30min at the temperature of 0 ℃, tetrahydrofuran solution of the compound of the formula 2 is added dropwise into the solution, the reaction is continued after the solution is moved to room temperature, saturated ammonium chloride solution is added to quench the solution, and the compound of the formula 3 is obtained after extraction by ethyl acetate, decompression concentration and separation and purification.
Further, in the third step, lithium aluminum hydride is dissolved in an anhydrous tetrahydrofuran solvent under the protection of nitrogen at the temperature of 0 ℃, and then a solution of the compound of the formula 3 dissolved in the tetrahydrofuran solvent is added and stirred; then moving to room temperature for reaction, then adding methanol, 15% sodium hydroxide solution, water and 2M hydrochloric acid solution for quenching, extracting with ethyl acetate, concentrating under reduced pressure, separating and purifying to obtain the compound of formula 4.
In the fourth step, tetrabutylammonium acetate and acetic anhydride are added into the compound of the formula 4 under the conditions of normal temperature and nitrogen protection and the condition of anhydrous acetonitrile as a solvent, and the compound of the formula 5 is obtained after complete reaction at 40 ℃, filtration, reduced pressure concentration and separation and purification.
In the fifth step, azodicarbonyl dipiperidine (ADDP) is dissolved in anhydrous tetrahydrofuran under the protection of 0 ℃ and nitrogen, the anhydrous tetrahydrofuran is placed in an ice bath for stirring, tributylphosphine is dropwise added into the solution under the condition that the solution is yellow, after the solution becomes colorless, the compound of the formula 5 dissolved in THF and 3-methoxyphenol dissolved in THF are dropwise added into the solution respectively, the reaction solution is moved to 70 ℃ for reflux, mitsunobu reaction is carried out, the concentration is carried out under reduced pressure, and the compound of the formula 6 is obtained after separation and purification.
In the sixth step, the compound of formula 6 is dissolved in methanol solvent at normal temperature, potassium carbonate is added, the reaction is complete at room temperature, the concentration is carried out under reduced pressure, and the compound of formula 7 is obtained after separation and purification.
In the seventh step, the compound of formula 7 is dissolved in dichloromethane, and then the dess-martin oxidant DMP is added, the reaction is complete at normal temperature, the concentration is carried out under reduced pressure, and the compound of formula 8 is obtained after separation and purification.
In the eighth step, the compound of formula 8 is dissolved in dichloromethane, 5.0 times of equivalent of p-toluenesulfonic acid is added into the solution under the protection of nitrogen, the reaction is complete at room temperature, the concentration is carried out under reduced pressure, and the compound of formula 9 is obtained after separation and purification.
Further, in the step nine, dropwise adding boron tribromide into a solution of a compound of formula 9 dissolved in anhydrous dichloromethane at the temperature of-78 ℃, reacting for 1 hour at the temperature of-78 ℃, then moving the solution to room temperature for continuous reaction, concentrating under reduced pressure after the reaction is completed, and separating and purifying to obtain a final product Brazilane.
The invention utilizes the diol compound to build key indenopyran ring skeleton structure and other reactions through acetic anhydride single protection, mitsunobu reaction, dess-Martin oxidation reaction and intramolecular Prins/Friedel-Crafts tandem reaction under the catalysis of p-toluenesulfonic acid (p-TsOH), and the like, and synthesizes Brazilane, a brazilin natural product.
The invention uses the conventional chemical reagents as reagents, has mild reaction conditions, simple operation, relatively high speed and fewer reaction byproducts, and greatly shortens the synthesis steps, thereby reducing the synthesis cost.
Drawings
Fig. 1 to 12 are NMR charts of the following compounds, respectively.
FIG. 1 is a compound of formula 3 -1 H, FIG. 2 is a compound of formula 4 -1 H, FIG. 3 is a compound of formula 5 -1 H, FIG. 4 is a compound of formula 5 - 13 C, FIG. 5 is a compound of formula 6 -1 H, FIG. 6 is a compound of formula 6 -13 C, FIG. 7 is a compound of formula 7 -1 H, FIG. 8 is a compound of formula 7 -13 C, FIG. 9 is a compound of formula 9 -1 H, FIG. 10 is a compound of formula 9 -13 C, FIG. 11 shows Brazilane -1 H, FIG. 12 is Brazilane -13 C。
Detailed Description
According to the synthesis method of Brazilane, which is a brazilin natural product provided by an exemplary embodiment, the reaction formula is as follows:
according to the above reaction route, the natural product Brazilane is synthesized by taking the known compound 1 as a starting material, carrying out an upper protecting group reaction, a lithium aluminum hydride reduction reaction, an acetyl group selective protecting one hydroxyl group, a Mitsunobu reaction, a dess-Martin oxidation reaction, a one-pot cascade Prins/Friedel-Crafts reaction under an acidic condition, and the like.
The reaction steps of the synthesis method provided in the present embodiment are:
step one, 3, 4-dimethoxy benzyl alcohol as an initial raw material of a compound shown in a formula 1 is taken as a solvent, triethylamine is added into the initial raw material, methanesulfonyl chloride is added into the initial raw material, and a methanesulfonylation reaction is carried out to protect a hydroxyl group, so that a compound shown in a formula 2 is obtained;
step two, the compound of the formula 2 reacts with sodium hydride and diethyl malonate to obtain a compound of the formula 3;
step three, in the presence of lithium aluminum hydride, the compound of the formula 3 undergoes a lithium aluminum hydride reduction reaction to obtain a compound of the formula 4;
step four, reacting the compound shown in the formula 4 with acetic anhydride in the presence of tetrabutylammonium acetate to obtain a compound shown in the formula 5;
step five, the compound of formula 5 is mixed with 3-methoxyphenol, at ADDP and Bu 3 In the presence of P, carrying out Mitsunobu reaction to obtain a compound of a formula 6;
step six, the compound of formula 6 is reacted with K in methanol 2 CO 3 Reacting to remove acetyl protecting group to obtain a compound of formula 7;
step seven, adding an oxidant DMP into the compound of the formula 7, and carrying out an oxidation reaction by taking methylene dichloride as a solvent to obtain a compound of the formula 8;
step eight, the compound of the formula 8 reacts with p-toluenesulfonic acid by taking methylene dichloride as a solvent to obtain a compound of the formula 9;
step nine, the compound of formula 9 reacts with boron tribromide in methylene dichloride, and the product Brazilane is obtained after the dimethyl ether is removed for protection.
The method provided by the embodiment realizes the synthesis of the natural product Brazilane, and has the advantages of relatively high reaction rate, fewer byproducts and high reaction yield; the reagents used in the whole route are all conventional chemical reagents, and are low in cost and easy to obtain, so that the production cost is greatly reduced; the whole reaction condition is mild, the operation process is simple, and the method is suitable for industrial production.
The synthesis process claimed in the present invention will be further clarified and fully described by the following examples.
Example 1
Synthesis of compounds of formula 2 and 3:
the compound of formula 1 (0.5 g,2.97 mmol) was dissolved in dichloromethane solvent under nitrogen protection, triethylamine (0.83 ml,5.95 mmol) was added dropwise thereto at 0 ℃, methanesulfonyl chloride (0.35 ml,4.46 mmol) was added thereto, and then the reaction time was allowed to reach room temperature for 12 hours. After TLC monitoring the completion of the reaction, water was added to quench the reaction, and anhydrous Na was used 2 SO 4 Drying, rotating the organic solvent under reduced pressure, separating and purifying the product (ethyl acetate: petroleum ether=1:10) by column chromatography, and concentrating the eluent to obtain pale yellow liquid 2 (0.59 g). Yield: 80%.
Dissolving sodium hydride (60% in minor oil; 0.0513 g,1.28 mmol) in anhydrous tetrahydrofuran (2 ml) and DMF (2 ml) under the protection of nitrogen at 0 ℃ and stirring for 30 minutes at 0 ℃ by dropwise adding diethyl malonate (0.24 ml,1.60 mmol) dissolved in tetrahydrofuran (2 ml) into the reaction system, then dropwise adding a compound (0.2 g,1.07 mmol) of formula 2 dissolved in tetrahydrofuran (2 ml) into the reaction system, transferring to room temperature for reaction for about 12 hours, cooling the reaction solution to 0 ℃ after TLC detection reaction is completed, quenching with saturated ammonium chloride solution, extracting with ethyl acetate (3×5 mL), combining organic phases, and anhydrous Na 2 SO 4 Drying, filtering to remove solid impurities, separating and purifying the product (ethyl acetate: petroleum ether 1:15) by column chromatography after reduced pressure distillation, and concentrating the eluent to obtain colorless oily substance 3 (0.3 g). Yield: 90%. 1 H NMR (400 MHz, CDCl3): δ 6.74 (dd,J= 8.7, 4.9 Hz, 2H), 6.71 (s, 1H), 4.19-4.09 (m, 4H), 3.83 (s, 3H), 3.82 (s, 3H), 3.60 (dd,J= 17.0, 9.2 Hz, 1H), 3.14 (d,J= 7.8 Hz, 2H), 1.30 – 1.14 (m, 6H)。
Synthesis of compounds of formula 4:
dissolving lithium aluminum hydride (0.0053 g,0.14 mmol) in anhydrous tetrahydrofuran (1 ml) under the protection of 0 ℃ and nitrogen, dropwise adding a compound (0.0218 g,0.07 mmol) of the formula 3 dissolved in tetrahydrofuran (1 mL) into the solution, stirring the solution for 30 minutes at 0 ℃, then transferring the solution to room temperature for reaction for 4 hours, cooling the reaction system to 0 ℃ after TLC detection reaction is completed, quenching the reaction system by methanol, 15% sodium hydroxide solution, water and 2M hydrochloric acid solution, extracting the solution by ethyl acetate (3X 10 mL), and extracting the solution by anhydrous Na 2 SO 4 Drying, filtering to remove solid impurities, separating and purifying the product by column chromatography (methanol: dichloromethane=1:20) after reduced pressure distillation, and concentrating the eluent to obtain white solid powder 4 (0.014, g). Yield: 87%. 1 H NMR (400 MHz, CDCl 3 ) δ 6.79 (d,J= 9.9 Hz, 1H), 6.72 (d,J= 4.9 Hz, 2H), 3.86 (dd,J= 3.7, 1.6 Hz, 6H), 3.83 – 3.78 (m, 2H), 3.7.-3.65 (m, 2H), 2.57 (dd,J= 7.4, 2.7 Hz, 2H), 2.35 – 2.12 (m, 2H), 2.07-2.02 (m, 1H), 1.30 – 1.20 (m, 1H)。
Synthesis of compounds of formula 5:
the compound (0.3 g,1.33 mmol) of formula 4 was dissolved in anhydrous acetonitrile (3 ml) solvent, and the weighed tetrabutylammonium acetate (0.28 g,0.93 mmol) was added thereto, and acetic anhydride (0.19 ml,1.99 mmol) was added to the above mixed solution, and the temperature was raised to 40 ℃ and the reaction was stirred for 10 hours. After TLC monitoring the completion of the reaction, quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (3×10 mL), the organic phase was collected, the product was purified by column chromatography after distillation under reduced pressure (ethyl acetate: petroleum ether=1:4), and finally the eluate was concentrated to give a pale yellow oil 5 (0.26 g, 73% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 6.77 (d,J= 8.1 Hz, 1H), 6.70 (d,J=5.73Hz, 2H), 4.16 (dd,J= 11.2, 4.6 Hz, 1H), 4.06 (dd,J= 11.2, 6.5 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.58 (dd,J= 11.3, 4.6 Hz, 1H), 3.50 (dd,J= 11.3, 6.1 Hz, 1H), 2.59 (m, 3H), 2.07 (s, 4H). 13 C NMR (100 MHz, CDCl 3 ): δ 171.90, 149.02, 147.99, 131.98, 121.16, 112.28, 111.35, 64.16, 62.12, 56.04, 55.97, 42.64, 34.01,21.07. HRMS (ESI) calcd for C 14 H 21 O 5 [M+H] + 269.1389, found 269.1388。
Synthesis of compounds of formula 6:
under the protection of 0 ℃ and nitrogen, ADDP (0.6827 g,2.71 mmol) is dissolved in tetrahydrofuran (6 ml), tributylphosphine (0.77 ml,3.07 mmol) is slowly and dropwise added, after the solution turns from yellow to colorless, a compound (0.33 g,1.23 mmol) of formula 5 dissolved in tetrahydrofuran (6 ml) and 3-methoxyphenol (0.1 ml,1.00 mmol) dissolved in tetrahydrofuran (6 ml) are dropwise added into a reaction system in sequence, then reflux heating is carried out for 12 hours at 70 ℃ until TLC detection reaction is completed, after reduced pressure distillation, a column chromatography separation and purification product (ethyl acetate: petroleum ether=1:5) is used, and finally eluent is concentrated to obtain pale yellow liquid 6 (0.3620 g). Yield: 87%. 1 H NMR (400 MHz, CDCl 3 ): δ 7.16 (t,J= 8.2 Hz, 1H), 6.78 (d,J=6.57Hz, 1H), 6.71 (dd,J= 8.1, 1.9 Hz, 1H), 6.67 (d,J= 1.9 Hz, 1H), 6.52 – 6.44 (m, 3H), 4.23-4.13(m, 2H), 3.91 – 3.83 (m, 5H),3.78 (s, 3H), 3.75 (s, 3H), 2.81 – 2.70 (m, 2H), 2.42 – 2.35 (m, 1H), 2.07 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 171.23, 161.01, 160.25, 149.00, 147.64, 131.57, 130.07, 121.26,112.42, 111.36,106.85,106.53, 101.13, 66.65, 64.48,56.05, 55.85, 55.45, 40.15, 34.15, 21.13. HRMS (ESI) calcd. for C 21 H 27 O 6 [M+H] + 375.1808, found 375.1808。
Synthesis of compounds of formula 7:
the compound (0.2746 g,0.81 mmol) of formula 6 was dissolved in methanol (5 ml) at room temperature, potassium carbonate (0.1683 g,1.22 mmol) was added thereto, and the reaction was stirred at room temperature for 4 hours, after completion of TLC detection, water quenching was added thereto, ethyl acetate (3×5 mL) was extracted, and after distillation under reduced pressure, the purified product was separated by column chromatography (ethyl acetate: petroleum ether=1:3), and finally the eluent was concentrated to give pale yellow liquid 7 (0.2401 g). Yield: 89%. 1 H NMR (400 MHz, CDCl 3 ): δ 7.16 (t,J= 8.2 Hz, 1H), 6.78 (d,J= 8.0 Hz, 1H), 6.72 (dd,J= 10.4, 2.2 Hz, 2H), 6.52 – 6.44 (m, 3H), 3.97 (dd,J= 9.2, 4.5 Hz, 1H), 3.91 (dd,J= 9.2, 5.9 Hz, 1H), 3.84 (s, 3H), 3.80 – 3.71 (m, 8H), 2.74 (d,J= 7.0 Hz, 2H), 2.29 – 2.19 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 160.97, 160.17, 148.96, 147.51, 132.25, 130.08, 121.17, 112.40, 111.31, 106.85, 106.59,101.09, 68.36, 63.88, 56.02, 55.84, 55.42, 42.90, 34.01. HRMS (ESI) calcd for C 19 H 25 O 5 [M+H] + 333.1702, found 333.1702。
Synthesis of compounds of formula 8:
the compound of formula 7 (0.1484 g,0.45 mmol) was dissolved in dichloromethane (3 ml) at room temperature, followed by the addition of sodium bicarbonate (0.1313 g,1.56 mmol), dess-martin oxidant (0.38 g,0.9 mmol), stirring at room temperature for 4 hours, quenching with saturated aqueous sodium chloride after TLC detection, extracting with dichloromethane (3×10 mL), mixing the obtained organic phases, adding anhydrous Na 2 SO 4 Drying, filtering to remove solid impurities, separating and purifying the product (ethyl acetate: petroleum ether 1:5) by column chromatography after reduced pressure distillation, and concentrating the eluent to obtain deep yellow thick liquid 8 (0.1224 g). Yield: 83%.
Synthesis of compounds of formula 9:
the compound (0.47 g,1.43 mmol) of the formula 8 was dissolved in methylene chloride (6 ml) at room temperature, and p-toluenesulfonic acid (1.35 g,7.11 mmol) was added to the reaction mixture and reacted at room temperature for 1 hour. After completion of the TLC detection reaction, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (3X 10 mL), the organic phase was collected, washed with saturated brine, the organic solvent was spun off under reduced pressure, the purified product was separated by column chromatography (ethyl acetate: petroleum ether 1:10), and finally the eluent was concentrated to give white solid 9 (0.24 g). Yield: 51%. 1 H NMR (400 MHz, CDCl 3 ): δ 7.32 (d,J= 8.5 Hz, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 6.60 (dd,J= 8.4 , 2.6 Hz, 1H), 6.43 (d,J= 2.5 Hz, 1H), 4.23 (d,J= 6.5 Hz, 1H), 4.13 (dd,J= 10.9, 4.4 Hz, 1H), 3.87 – 3.84 (m, 6H), 3.77 (s, 3H), 3.63 (t,J= 10.6 Hz, 1H), 3.18 (dd,J= 15.7, 7.2 Hz, 1H), 2.92 (tdd,J= 6.4, 4.2, 2.0 Hz, 1H), 2.60 (dd,J= 15.7, 2.1 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 199.31, 155.73, 148.99, 148.38, 137.45, 132.80, 130.87, 116.08,108.56, 108.15, 108.01, 102.00, 67.04, 56.29, 56.24, 55.50, 43.40, 37.07, 34.22, 29.91. HRMS (ESI) calcd forC 19 H 21 O 4 [M+H] + 313.1440, found 313.1440。
Synthesis of Brazilane:
the compound of formula 9 (0.1 g) was dissolved in dichloromethane (3 ml) and boron tribromide (1.53 ml) was added at-78 °c，1.53 mmol，1M in CH 2 Cl 2 ) Slowly dropwise adding the mixture, reacting at this temperature for 1 hr, shifting to room temperature for 1 hr, quenching with water solution after TLC detection reaction is complete, extracting with ethyl acetate (3×10 mL), mixing the obtained organic phases, adding anhydrous MgSO 4 Drying, filtering to remove solid impurities, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether: dichloromethane=1:1:1) after reduced pressure distillation, and concentrating the eluent to obtain red solid Brazilane (0.055 g). Yield: 63%. 1 H NMR (400 MHz, MeOD): δ 7.07 (d,J= 8.3 Hz, 1H), 6.64 (s, 1H), 6.51 (s, 1H), 6.31 (dd,J= 8.3, 2.5 Hz, 1H), 6.11 (d,J= 2.5 Hz, 1H), 4.00 – 3.89 (m, 2H), 3.36 (t,J= 10.6 Hz, 1H), 2.93 (dd,J= 15.6, 7.1 Hz, 1H), 2.69 – 2.62 (m, 1H), 2.35 (dd,J= 15.6, 1.9 Hz, 1H), 1.89 (s, 1H), 1.15 (t, J=7.1 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 157.73, 156.79, 145.47, 145.20, 138.37, 133.25, 132.16, 116.76, 112.98, 112.63, 109.67, 104.33, 67.88, 44.28,38.43, 34.63. HRMS (ESI) calcd for C 16 H 15 O 4 [M+H] + 271.0970, found 271.0968。
Claims (10)
1. A method for synthesizing Brazilian hematoxylin natural products Brazilian is characterized in that: the method comprises the following steps:
step one, 3, 4-dimethoxy benzyl alcohol as an initial raw material, methylene dichloride as a solvent, dropwise adding triethylamine into the initial raw material, adding methanesulfonyl chloride, and performing methanesulfonylation reaction to protect a hydroxyl group to obtain a compound of formula 2;
dissolving sodium hydride in tetrahydrofuran and N, N-dimethylformamide solution, dropwise adding diethyl malonate into the solution, dropwise adding a compound of formula 2 into the reaction solution, and reacting to obtain a compound of formula 3;
step three, dropwise adding the compound of the formula 3 dissolved in the tetrahydrofuran solution into the tetrahydrofuran solution of lithium aluminum hydride to perform a reduction reaction to obtain a compound of the formula 4;
step four, reacting the compound shown in the formula 4 with acetic anhydride under the condition of taking anhydrous acetonitrile as a solvent to obtain a compound shown in the formula 5;
step five, dissolving the compound of formula 5 and 3-methoxyphenol in tetrahydrofuran, and adding the compound to the mixture of ADDP and Bu 3 In the presence of P, a Mitsunobu reaction occurs to provide a compound of formula 6;
step six, dissolving the compound of the formula 6 in methanol, and adding K 2 CO 3 Reacting at room temperature, and performing deacetylation protection reaction to obtain a compound of formula 7;
step seven, adding a dess-Martin oxidizer DMP into the compound of the formula 7 at normal temperature, and carrying out oxidation reaction by taking methylene dichloride as a solvent to obtain a compound of the formula 8;
step eight, adding p-toluenesulfonic acid into a compound of formula 8, and taking dichloromethane as a solvent to perform Prins/Friedel-Crafts tandem reaction in one-pot molecules to obtain a compound of formula 9;
step nine, dissolving a compound of formula 9 in dichloromethane, adding boron tribromide into the dichloromethane, and removing methyl ether for protection to obtain a target product Brazilane;
the reaction formula is as follows:
2. the method for synthesizing Brazilane, a brazilin natural product, according to claim 1, wherein: in the first step, under the protection of 0 ℃ and nitrogen, the compound of the formula 1 is dissolved in dichloromethane solution, then triethylamine and methanesulfonyl chloride are sequentially added dropwise, the solution is moved to room temperature for reaction, the solution gradually turns to light yellow, dichloromethane is used for extraction, an organic phase is collected, reduced pressure concentration is carried out, and the compound of the formula 2 is obtained after separation and purification.
3. The method for synthesizing Brazilane, a brazilin natural product, according to claim 1, wherein: in the second step, sodium hydride is dissolved in anhydrous tetrahydrofuran and N, N-dimethylformamide solution with equal amounts of substances under the protection of 0 ℃ and nitrogen, diethyl malonate solution dissolved in tetrahydrofuran solvent is slowly added dropwise into the anhydrous tetrahydrofuran and N, N-dimethylformamide solution to react for 30min under the condition of 0 ℃, tetrahydrofuran solution of the compound of the formula 2 is added dropwise into the solution, then the solution is moved to room temperature to continue to react, saturated ammonium chloride solution is added to quench the solution, and the compound of the formula 3 is obtained after extraction by ethyl acetate, decompression concentration and separation and purification.
4. The method for synthesizing Brazilane, a brazilin natural product, according to claim 1, wherein: step three, dissolving lithium aluminum hydride in an anhydrous tetrahydrofuran solvent under the protection of nitrogen at the temperature of 0 ℃, adding a solution of a compound of formula 3 dissolved in the tetrahydrofuran solvent, and stirring; then moving to room temperature for reaction, then adding methanol, 15% sodium hydroxide solution, water and 2M hydrochloric acid solution for quenching, extracting with ethyl acetate, concentrating under reduced pressure, separating and purifying to obtain the compound of formula 4.
5. The method for synthesizing Brazilane, a brazilin natural product, according to claim 1, wherein: in the fourth step, tetrabutylammonium acetate and acetic anhydride are added into the compound of the formula 4 under the conditions of normal temperature and nitrogen protection and with anhydrous acetonitrile as a solvent, and the compound of the formula 5 is obtained after complete reaction at 40 ℃ and filtration, reduced pressure concentration, separation and purification.
6. The method for synthesizing Brazilane, a brazilin natural product, according to claim 1, wherein: in the fifth step, azodicarbonyl dipiperidine (ADDP) is dissolved in anhydrous tetrahydrofuran under the protection of 0 ℃ and nitrogen, the anhydrous tetrahydrofuran is placed in an ice bath for stirring, tributylphosphine is dropwise added into the solution under the condition that the solution is yellow, after the solution becomes colorless, the compound of the formula 5 dissolved in THF and 3-methoxyphenol dissolved in THF are dropwise added into the solution respectively, the reaction solution is moved to 70 ℃ for reflux, mitsunobu reaction is carried out, the concentration is carried out under reduced pressure, and the compound of the formula 6 is obtained after separation and purification.
7. The method for synthesizing Brazilane, a brazilin natural product, according to claim 1, wherein: in the sixth step, the compound of the formula 6 is dissolved in a methanol solvent at normal temperature, potassium carbonate is added, the reaction is complete at room temperature, the concentration is carried out under reduced pressure, and the compound of the formula 7 is obtained through separation and purification.
8. The method for synthesizing Brazilane, a brazilin natural product, according to claim 1, wherein: in the seventh step, the compound of the formula 7 is dissolved in dichloromethane, then the dess-Martin oxidizer DMP is added, the reaction is complete at normal temperature, the concentration is carried out under reduced pressure, and the compound of the formula 8 is obtained after separation and purification.
9. The method for synthesizing Brazilane, a brazilin natural product, according to claim 1, wherein: in the eighth step, the compound of formula 8 is dissolved in methylene dichloride, 5.0 times of equivalent of p-toluenesulfonic acid is added into the solution under the protection of nitrogen, the reaction is complete at room temperature, the concentration is carried out under reduced pressure, and the compound of formula 9 is obtained after separation and purification.
10. The method for synthesizing Brazilane, a brazilin natural product, according to claim 1, wherein: in the step nine, dropwise adding boron tribromide into a solution of a compound of formula 9 dissolved in anhydrous dichloromethane at the temperature of-78 ℃, reacting for 1 hour at the temperature of-78 ℃, then moving the solution to room temperature for continuous reaction, concentrating under reduced pressure after the reaction is completed, and separating and purifying to obtain a final product Brazilane.
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| CN110776488A (en) * | 2019-12-04 | 2020-02-11 | 山西省肿瘤研究所 | Method for synthesizing (-) -Brazilin |
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