CN112574163A - Method for synthesizing Brazilin natural product (+) -Brazilin - Google Patents

Method for synthesizing Brazilin natural product (+) -Brazilin Download PDF

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CN112574163A
CN112574163A CN202110124695.4A CN202110124695A CN112574163A CN 112574163 A CN112574163 A CN 112574163A CN 202110124695 A CN202110124695 A CN 202110124695A CN 112574163 A CN112574163 A CN 112574163A
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reaction
brazilin
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CN112574163B (en
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杨喜花
黄双平
常宏宏
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Shanxi Tumour Hospital
Shanxi Tumour Institute
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Shanxi Tumour Institute
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention relates to a method for synthesizing Brazilin natural product (+) -Brazilin, which takes 3, 4-dimethoxy benzyl alcohol of a compound shown in a formula 1 as an initial raw material, and synthesizes the natural product (+) -Brazilin through nucleophilic substitution reaction, lithium aluminum hydride reduction reaction, asymmetric reaction catalyzed by Lipase PS enzyme, Mitsunobu reaction, dess-Martin oxidation reaction, one-pot Prins/Friedel-Crafts series reaction under acidic condition and the like. The method uses conventional chemical reagents, has mild reaction conditions, simple operation, relatively high speed and less reaction byproducts, and greatly shortens the synthesis steps, thereby greatly reducing the synthesis cost.

Description

Method for synthesizing Brazilin natural product (+) -Brazilin
Technical Field
The invention relates to a synthesis method of a key intermediate of a compound with anticancer activity, in particular to a synthesis method of Brazilin natural product (+) -Brazilin.
Background
The natural product Brazilin (Brazilin) is a specific compound in the traditional Chinese medicine sappan wood, which is discovered successively from the beginning of the 50 th 20 th century, and the following 6 compounds are mainly identified and separated at present: (+) -Brazilin, (-) -Brazilein, (+) -Brazilide A, (+) -Haematoxylin, (+) -Haematoxyline and (+) -Brazilane. The compounds have similar chemical structures, are homoisoflavone derivatives and have chroman rings. The structure of Brazilin has a variety of biological activities and has received attention from numerous researchers. The red biological stain is originally used as a natural red biological stain, and with the progress of research, chemists find that the red biological stain has various biological activities of reducing blood sugar, resisting blood platelet, resisting inflammation, resisting bacteria, resisting tumors, protecting liver, resisting cancers and the like, and even is a DNA cutting agent. Nowadays, an important criterion for judging the traditional Chinese medicine sapanwood is the content of Brazilin. According to the regulation in Chinese pharmacopoeia published in 2010, the content of Brazilin in the sappan wood serving as a medicinal material is not less than 0.5%. Due to its unique structure and remarkable biological activity, it has attracted the attention of many chemical researchers and has been struggling towards the synthesis of this molecule. The chemical structure of Brazilin is as follows:
Figure 42019DEST_PATH_IMAGE002
the chemical methods for synthesizing the natural product reported in the literature mainly include: (1) heller and Tamm were published in 1980Chemistry of Organic Natural ProductsA research paper on Fortschritte Der Chemie Organischer Naturstoffe; (2) kirkiacharian et al 1975Bull.Soc.Chim.Fr.A research paper entitled, novel Method Of Synthesis Of 2' -Hydroxybenzylic acids Esters; (3) lee et al, 2010 published inBioorg.Med.Chem.LetA research paper entitled Total Synthesis and evaluation of branched and analogies as anti-inflammatory and cytoxic agents; (4) davis, F.A et al, 1993J.Org.ChemA research paper titled Enantioselective synthesis of (+) -O-trimethylapalone B and (+) -O-trimethybrazilin; (5) merlin et al, 1995, published inJ.Chem.Soc., Perkin TransEntitled Synthesis and Sweet Ta-ste of optical Active (-) -Haematoxin and of Some (+ -) -Haematoxylin Derivativ-es; (5) suzuk et al 2012 published inBioorg. Med. Chem. LetA research paper entitled Synthesis and biological evaluation of deoxy-hemoglobin derivatives as a novel class of anti-HIV-1 agents; (6) jahng et al, 2014 published inTetrahedron：AsymmetrA research paper entitled Enantioselective syntheses of (+) -and (-) -broozilin; (7) pettus et al, published in 2005Org. LetA research paper on Synthesis of (+ -) -Brazilin Using IBX; (8) liu et al, 2008 published inJ. Am. Chem. SocA research paper on Gold-Catalyzed deoxygenetic catalysis of 2,4-Dien-1-als for Stereoselective Synthesis of high purity substitated cycles; (9) zhang, H, B, et al, published in 2011SynlettOn a research paper entitled Design and Synthesis of Brazilin-Like Compounds; (10) zhang, H, B, et al, published in 2013Chem．CommunA research paper entitled Enantioselective total synthesis of (+) -blazein, (-) -blazein and (+) -blazeide A; (11) qin, H.B et al, 2013Tetrahedron Lett.A research paper on the subject of Total Synthesis of (+ -) -brazilin and formal Synthesis of (+ -) -brazilein, (+ -) -brazilide A using m-CPBA; (12) yadav et al, 2014 published inTetrahedronA research article entitled Formal synthesis of (+ -) -brazilin and total synthesis of (+ -) -brazilane; (13) kim et al were published in 2015J. Title on org. Chem is Total A research paper of Synthesis of Brazilin; (14) vranken et al 2019, published in j.org. ChemSubject matter of Total Synthesis of (+ -) -Brazilin Using [4+1 ]]A research paper of Palladium-catalysis annular analysis; huang, S.P et al, published in 2020Tetrahedron Lett.A research paper entitled A Total Synthesis of (+) -Brazilin. Through the research on the synthesis routes of target molecules synthesized by the researchers at home and abroad, the detailed analysis shows that most of the currently-used synthesis routes have long synthesis steps, individual reactions are not easy to carry out, and reagents are expensive and have high toxicityThe characteristics of (1). Therefore, a total synthesis route which shortens the synthesis steps, is common and easily available in raw materials and more efficient in reaction is sought, and the important research direction for synthesizing Brazilin in future is formed. Therefore, the need for a general, efficient, and low-cost synthetic route is urgent.
Disclosure of Invention
The invention aims to provide a method for synthesizing Brazilin natural product (+) Brazilin with fewer synthetic steps and more efficient reaction.
In order to solve the technical problems, the invention adopts the technical scheme that: a method for synthesizing Brazilin natural product (+) Brazilin is disclosed, wherein the reaction formula is as follows:
Figure 631263DEST_PATH_IMAGE004
the synthetic route comprises the following steps:
step one, taking 3, 4-dimethoxybenzyl alcohol which is a compound shown in formula 1 as an initial raw material, taking dichloromethane as a solvent, adding 4-Dimethylaminopyridine (DMAP) and p-toluenesulfonyl chloride into the initial raw material, then dropwise adding triethylamine into the initial raw material, reacting at room temperature, and carrying out p-toluenesulfonylation reaction to obtain a monohydroxy protection product; then, under the condition of 0 ℃, dissolving sodium hydride in tetrahydrofuran and N, N-dimethylformamide solution, slowly dropwise adding diethyl malonate into the solution, dropwise adding the obtained monohydroxy protection product into the reaction solution, and moving the reaction solution to room temperature for reaction to obtain a compound shown in a formula 2;
dissolving the compound shown in the formula 2 in a tetrahydrofuran solvent, adding elemental iodine and sodium acetate into the tetrahydrofuran solvent, and oxidizing a hydroxyl group from a quaternary carbon position to obtain a compound shown in the formula 3;
thirdly, carrying out lithium aluminum hydride reduction reaction on the compound of the formula 3 in the presence of lithium aluminum hydride to obtain a compound of a formula 4;
step four, the compound of the formula 4 is subjected to glycol asymmetric reaction under the catalytic action of Liase PS enzyme by using vinyl acetate as an acetyl donor, so as to form a chiral quaternary carbon center, and obtain a chiral precursor compound of the formula 5;
fifthly, the compound shown in the formula 5 and p-toluenesulfonyl chloride are subjected to a p-toluenesulfonylation reaction under the action of 4-dimethylaminopyridine and triethylamine to form a protecting group on a hydroxyl group, so as to obtain a compound shown in a formula 6;
step six, dripping the compound shown in the formula 6 into a reaction system of 3-methoxyphenol and cesium carbonate dissolved in a DMF solvent to perform nucleophilic substitution reaction to obtain a compound shown in the formula 7;
step seven, dissolving the compound shown in the formula 7 in methanol, and then adding K2CO3Carrying out a reaction of removing acetyl protection to obtain a compound of a formula 8;
step eight, adding N, N-diisopropylethylamine, dimethyl sulfoxide and sulfur trioxide pyridine compound into the compound in the formula 8, and carrying out an oxidation reaction by using dichloromethane as a solvent to obtain a compound in a formula 9;
step nine, adding trifluoroacetic acid into the compound shown in the formula 9, and carrying out one-pot intramolecular Prins/Friedel-Crafts serial cyclization reaction by taking dichloromethane as a solvent to obtain the compound shown in the formula 10;
dissolving the compound shown in the formula 10 in dichloromethane, and performing boron tribromide to remove ether protection to obtain a product compound (+) Brazilin;
preferably, in the first step, under the protection of nitrogen, the compound of formula 1 is dissolved in dichloromethane, then 4-dimethylaminopyridine and p-toluenesulfonyl chloride are added, triethylamine is added dropwise, the reaction is carried out at room temperature until the solution becomes light yellow, dichloromethane is used for extraction, an organic phase is collected, reduced pressure concentration is carried out, and separation and purification are carried out to obtain a monohydroxy protected product; dissolving sodium hydride in an anhydrous tetrahydrofuran and N, N-dimethylformamide solvent at 0 ℃ under the protection of nitrogen, slowly dropwise adding a diethyl malonate solution dissolved in the tetrahydrofuran, reacting at 0 ℃, slowly dropwise adding a tetrahydrofuran solution of a monohydroxy protection product into a reaction system, moving to room temperature for reaction, adding a saturated ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, concentrating under reduced pressure, and separating and purifying to obtain the compound of the formula 2.
Preferably, in the second step, under an open condition, the compound of formula 2 dissolved in a tetrahydrofuran solvent, elemental iodine and sodium acetate are exposed to the air at 35 ℃ for reaction, after the reaction is completed, a saturated sodium thiosulfate aqueous solution is added for quenching, and the compound of formula 3 is obtained by extraction with dichloromethane, reduced pressure concentration, separation and purification.
Preferably, in the third step, under the protection of 0 ℃ and nitrogen, dissolving lithium aluminum hydride in tetrahydrofuran, slowly dropping the compound of formula 3 into the reaction system, and stirring at the temperature; 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.
Preferably, in the fourth step, under the protection of nitrogen and at room temperature, vinyl acetate is added into the compound of the formula 4, then Lipase PS enzyme is added, and the compound 5 can be obtained after room temperature reaction, filtration, reduced pressure concentration, separation and purification.
Preferably, in the fifth step, under the protection of nitrogen and at 0 ℃, 4-dimethylaminopyridine, p-toluenesulfonyl chloride and triethylamine are sequentially added into a dichloromethane solution of the compound of the formula 5, the mixture is moved to room temperature for reaction, water is added for quenching, dichloromethane is used for extraction, reduced pressure concentration and separation and purification are carried out, so that the compound of the formula 6 is obtained.
Preferably, in the sixth step, under the protection of nitrogen, cesium carbonate and 3-methoxyphenol are dissolved in a DMF solvent, a heating reaction is performed at 60 ℃, then the compound of formula 6 is dropwise added into the reaction system, the temperature is continuously increased to 85 ℃ for reaction, an aqueous solution is added for quenching, the ethyl acetate is used for extraction, the concentration is performed under reduced pressure, and the compound of formula 7 is obtained through separation and purification.
Preferably, in step seven, potassium carbonate is added into the methanol solution of the compound of formula 7 at room temperature, and after the reaction is completed, the mixture is concentrated under reduced pressure, separated and purified to obtain the compound of formula 8.
Preferably, in the eighth step, under the protection of 0 ℃ and nitrogen, the compound of N, N-diisopropylethylamine, dimethyl sulfoxide and sulfur trioxide pyridine is sequentially added into the anhydrous dichloromethane solution of the compound of formula 8, reacted at 0 ℃, extracted with dichloromethane, concentrated under reduced pressure, separated and purified to obtain the compound of formula 9.
Preferably, in the ninth step, the compound of formula 9 is dissolved in dichloromethane, trifluoroacetic acid is added dropwise to the solution under the protection of nitrogen, the reaction is carried out at room temperature, then the concentration is carried out under reduced pressure, and the compound of formula 10 is obtained after separation and purification.
Preferably, in the tenth step, the compound shown in the formula 10 is dissolved in dichloromethane, the temperature is reduced to-78 ℃, boron tribromide is dropwise added into an anhydrous dichloromethane solution dissolved in the compound 10, the reaction is carried out at-78 ℃, and then the reaction is carried out at room temperature to continue the reaction, so that a (+) Brazilin product is obtained.
The invention successfully realizes the asymmetric synthesis of the natural product Brazilin by utilizing Lipase PS enzyme catalytic reaction, Mitsunobu reaction, dess-Martin oxidation reaction, intramolecular Prins/Friedel-Crafts series reaction under the catalysis of trifluoroacetic acid (TFA) and the like.
The whole synthesis route of the invention has novel and unique design, the used reagents are all conventional chemical reagents, the reaction condition is mild, the operation is simple, the speed is relatively high, the reaction byproducts are less, and the synthesis steps are greatly shortened, thereby greatly reducing the synthesis cost.
Drawings
Fig. 1 to 12 are NMR charts of the following compounds, respectively. FIG. 1 shows a compound of formula 2-1H, FIG. 2 is a compound of formula 3-1H, FIG. 3 is a compound of formula 4-1H, FIG. 4 is a compound of formula 5-1H, FIG. 5 is a compound of formula 7-1H, FIG. 6 is a compound of formula 7-13C, FIG. 7 is a compound of formula 8-1H, FIG. 8 is a compound of formula 8-13C, FIG. 9 is a compound of formula 9-1H, FIG. 10 is a compound of formula 9-13C, FIG. 11 is a compound of formula 10-1H, FIG. 12 is a compound of formula 10-13C, FIG. 13 is (+) -Brazilin-1H, FIG. 14 is (+) -Brazilin-13C。
Detailed Description
The invention provides a synthesis method of Brazilin natural product (+) Brazilin, which has the following reaction formula:
Figure DEST_PATH_IMAGE005
according to the reaction formula, the invention provides a brand new synthetic route for synthesizing the natural product Brazilin, the compound 3, 4-dimethoxy benzyl alcohol in the formula 1 is used as an initial raw material, and the natural product (+) Brazilin is synthesized through nucleophilic substitution reaction, lithium aluminum hydride reduction reaction, desymmetry reaction catalyzed by Lipase PS enzyme, Mitsunobu reaction, dess-Martin oxidation reaction, one-pot Prins/Friedel-Crafts series reaction under an acidic condition and the like; the reaction steps of the synthesis method are as follows:
step one, taking 3, 4-dimethoxybenzyl alcohol of the compound shown in the formula 1 as an initial raw material, dichloromethane as a solvent and triethylamine as an acid-binding agent, and reacting with sodium hydride and diethyl malonate after protecting a hydroxyl group by p-toluenesulfonyl chloride to obtain the compound shown in the formula 2.
And step two, under the action of the elemental iodine and sodium acetate, oxidizing the compound in the formula 2 to obtain a compound in a formula 3. More specifically, the compound of formula 2 is dissolved in tetrahydrofuran solvent, and elemental iodine and sodium acetate are added to oxidize a hydroxyl group from the quaternary carbon position to obtain the compound of formula 3.
Thirdly, carrying out lithium aluminum hydride reduction reaction on the compound of the formula 3 in the presence of lithium aluminum hydride to obtain a compound of a formula 4;
step four, the compound of the formula 4 is subjected to glycol asymmetric reaction under the catalytic action of Liase PS enzyme by using vinyl acetate as an acetyl donor, so as to form a chiral quaternary carbon center, and obtain a chiral precursor compound of the formula 5;
fifthly, the compound shown in the formula 5 and p-toluenesulfonyl chloride are subjected to a p-toluenesulfonylation reaction under the action of 4-dimethylaminopyridine and triethylamine to form a protecting group on a hydroxyl group, so as to obtain a compound shown in a formula 6;
step six, dripping the compound shown in the formula 6 into a reaction system of 3-methoxyphenol and cesium carbonate dissolved in a DMF solvent to perform nucleophilic substitution reaction to obtain a compound shown in the formula 7;
step seven, dissolving the compound shown in the formula 7 in methanol, and then adding K2CO3To perform a reaction for removing acetyl protection to obtain formula 8A compound;
step eight, adding N, N-diisopropylethylamine, dimethyl sulfoxide and sulfur trioxide pyridine compound into the compound in the formula 8, and carrying out an oxidation reaction by using dichloromethane as a solvent to obtain a compound in a formula 9;
step nine, adding trifluoroacetic acid into the compound shown in the formula 9, and carrying out one-pot intramolecular Prins/Friedel-Crafts serial cyclization reaction by taking dichloromethane as a solvent to obtain the compound shown in the formula 10;
and step ten, dissolving the compound shown in the formula 10 in dichloromethane, and performing demethyl ether protection through the action of boron tribromide to obtain a product compound (+) Brazilin.
The whole route provided by the invention is novel and unique in design, single selective synthesis of a natural product Brazilin is realized, the reaction rate is relatively high, byproducts are less, and the reaction yield is high; the used reagents are conventional chemical reagents, are cheap and easy to obtain, and greatly reduce the production cost; the whole reaction condition is mild, the operation process is simple, and the method is suitable for industrial production.
The claimed solution is further illustrated by the following examples. However, the examples are intended to illustrate embodiments of the invention without departing from the scope of the subject matter of the invention, and the scope of the invention is not limited by the examples. Unless otherwise specifically indicated, the materials and reagents used in the present invention are available from commercial products in the art.
Synthesis of compounds of formula 2:
the compound of formula 1 (0.2 g, 1.19 mmol) was dissolved in dichloromethane (5 ml) under nitrogen, 4-dimethylaminopyridine (0.0872 g, 0.71 mmol) and p-toluenesulfonyl chloride (0.2720 g, 1.43 mmol) were added sequentially, and triethylamine (0.17 ml, 1.19 mmol) was added. After TLC detection reaction was completed, the system was quenched with water, extracted with dichloromethane (3X 6 mL), and the organic phase was collected and dried over anhydrous Na2SO4Drying, filtering to remove solid impurities, distilling under reduced pressure to remove organic solvent, purifying by column chromatography to obtain product (ethyl acetate: petroleum ether 1: 10), and concentrating eluate to obtain light yellow oily monohydroxy compoundProtecting the product. Yield: 83 percent.
Dissolving sodium hydride (60% in mineral oil; 0.0513 g, 1.28 mmol) in anhydrous tetrahydrofuran (2 mL) and DMF (2 mL) under the protection of 0 ℃ and nitrogen, dropwise adding diethyl malonate (0.24 mL, 1.60 mmol) dissolved in tetrahydrofuran (2 mL) into a reaction system, stirring at 0 ℃ for 30 minutes, then dropwise adding monohydroxy protection products (0.34 g, 1.07 mmol) dissolved in tetrahydrofuran (2 mL) into the reaction system, then transferring to room temperature for reaction for about 12 hours, after TLC detection reaction is finished, cooling the reaction liquid to 0 ℃ and quenching with saturated ammonium chloride solution, extracting with ethyl acetate (3X 5 mL), combining organic phases, and anhydrous Na2SO4Drying, filtering to remove solid impurities, distilling under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether 1: 15), and concentrating the eluate to obtain the compound of formula 2 (0.3 g) as colorless oil. Yield: 90 percent.1H 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 3:
dissolving a compound (0.1 g, 0.32 mmol) of the formula 2 in a tetrahydrofuran (3 ml) solvent, sequentially adding elemental iodine (0.082 g, 0.32 mmol) and sodium acetate (0.044 g, 0.32 mmol), heating to 35 ℃, and exposing to air for stirring reaction for 48 hours. After TLC detection, add saturated sodium thiosulfate aqueous solution to quench the reaction, extract with dichloromethane (3X 5 mL), collect the organic phase, use anhydrous Na2SO4Drying, removing the organic solvent under reduced pressure, purifying the crude product by column chromatography to obtain a separated product (ethyl acetate: petroleum ether =1: 4), and concentrating the eluate to obtain the compound of formula 3 (0.1 g) as colorless oil. Yield: 98 percent.1H NMR (400 MHz, CDCl3) δ 6.80 (s, 1H), 6.75 (s, 2H), 4.23 (q, J = 6.8 Hz, 4H), 3.83 (s, 6H), 3.74 (s, 1H), 3.28 (s, 2H), 1.27 (t, J = 7.1 Hz, 6H)。
Synthesis of compounds of formula 4:
under the protection of 0 ℃ and nitrogen, dissolving lithium aluminum hydride (0.048 g, 1.23 mmol) in anhydrous tetrahydrofuran (3 mL), dropwise adding a compound 3 (0.2 g, 0.61 mmol) dissolved in tetrahydrofuran (3 mL), stirring at 0 ℃ for 30 minutes, then moving to room temperature for reaction for 4 hours, after TLC detection reaction is completed, cooling the reaction system to 0 ℃, quenching with methanol, 15% sodium hydroxide solution, water and 2M hydrochloric acid solution, extracting with ethyl acetate (3 × 10 mL), and extracting with anhydrous Na2SO4Drying, filtering to remove solid impurities, distilling under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether =2: 1), and finally concentrating the eluate to obtain the compound of formula 4 (0.094 g) as colorless oil. Yield: and 63 percent.1H NMR (400 MHz, CDCl3) δ 6.80 (dd, J = 4.9, 3.1 Hz, 2H), 6.76 (dd, J = 8.2, 1.7 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.57 (q, J = 11.2 Hz, 4H), 2.74 (s, 2H), 2.55 (s, 2H), 1.81 (s, 1H)。
Synthesis of compounds of formula 5:
dissolving the compound of formula 4 (0.32 g, 1.32 mmol) in vinyl acetate (12 ml) at room temperature, adding Lipase PS enzyme (0.32 g), reacting at room temperature for 6 hours, filtering to remove enzyme after TLC detection reaction is completed, distilling under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether =1: 1), and finally concentrating the eluent to obtain a light yellow liquid, namely the compound of formula 5 (0.587 g). Yield: 95% and an er value of 2.6: 1. HPLC { SHIMADZU LC-10A VP, hexane/2-propanol = 7:3 (v/v) }.1H NMR (400 MHz, CDCl3) δ 6.81 (dd, J = 8.6, 4.9 Hz, 2H), 6.76 (dd, J = 8.1, 1.9 Hz, 1H), 4.08 (d, J = 11.5 Hz, 1H), 4.00 (d, J = 11.5 Hz, 1H), 3.87 (s, 3H), 3.87 (s, 3H), 3.47 (q, J = 11.5 Hz, 2H), 2.79 (s, 2H), 2.39 (s, 1H), 2.14 (s, 3H)。
Synthesis of compounds of formula 6 and compounds of formula 7:
under the protection of nitrogen, the compound of the formula 5(0.3 g, 1.06 mmol) is dissolved in dichloromethane (5 mL) solvent, the temperature is reduced to 0 ℃, 4-dimethylaminopyridine DMAP (0.064 g, 0.53 mmol), p-toluenesulfonyl chloride (0.2414 g, 1.27 mmol) and triethylamine (0.3 mL, 2.11 mmol) are sequentially added, the mixture is moved to room temperature and stirred for reaction for 10 hours, after the TLC monitoring reaction is finished, water is added for quenching reaction, dichloromethane (3X 8 mL) is extracted, organic phases are combined, and anhydrous Na2SO4Drying, removing the organic solvent under reduced pressure, purifying the crude product by column chromatography (ethyl acetate: petroleum ether =1: 2), collecting the eluate containing the desired product, and concentrating under reduced pressure to obtain the compound of formula 6 (0.35 g) as a pale yellow oil. Yield: 75 percent.
Dissolving 3-methoxyphenol (0.025 ml,0.23 mmol) and cesium carbonate (0.744 g, 2.3 mmol) in an N, N-dimethylformamide (1 ml), heating to 60 ℃, stirring for reaction for 30 minutes, adding a compound 6 (0.1 g, 0.23 mmol) into the solution, continuously heating to 85 ℃, and stirring for reaction for 30 minutes. After TLC monitoring of the completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate (3X 5 mL), the organic phases were combined, washed with saturated aqueous NaCl, anhydrous Na2SO4Drying, removing the organic solvent under reduced pressure, separating and purifying the obtained crude product (ethyl acetate: petroleum ether =1: 10), and concentrating the eluent to obtain colorless liquid, namely the compound of formula 7 (0.055 g). Yield: 68 percent.1H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 8.2 Hz, 1H), 6.80 – 6.72 (m, 3H), 6.55 – 6.47 (m, 3H), 3.85 (s, 3H), 3.82 (s, 1H), 3.79 (s, 3H), 3.74 (dd, J = 12.2, 7.5 Hz, 2H), 3.67 (s, 1H), 3.65 (s, 3H), 2.99 – 2.88 (m, 2H), 1.63 (s, 3H). ; 13C NMR (100 MHz, CDCl3): 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。
Synthesis of compounds of formula 8:
the compound of formula 7 (0.2746 g, 0.70 mmol) was dissolved in methanol (4 ml) at room temperature, and potassium carbonate (0.1457 g,1.06 mmol) at room temperature, stirring and reacting for 4 hours, adding water to quench the reaction after TLC detection reaction is finished, extracting with ethyl acetate (3X 5 mL), distilling under reduced pressure, and separating and purifying the product by column chromatography (ethyl acetate: petroleum ether =1: 3), and finally concentrating the eluent to obtain a light yellow liquid, namely the compound (0.2132 g) of the formula 8. Yield: 87 percent.1H NMR (400 MHz, CDCl3) δ 7.11 (t, J = 8.4 Hz, 1H), 6.69 (d, J = 7.4 Hz, 3H), 6.46 (dd, J = 13.6, 6.8 Hz, 3H), 3.77 (s, 3H), 3.74 (s, 1H), 3.70 (s, 3H), 3.69 – 3.64 (m, 2H), 3.59 (s, 1H), 3.55 (s, 3H), 2.87 (q, J = 13.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 160.73, 159.46, 148.54, 147.65, 129.84, 128.43, 122.29, 113.59, 111.05, 106.60, 100.99, 74.14, 68.85, 65.526, 55.65, 55.32, 55.06, 39.60. HRMS (ESI): m/z calcd. for C19H25O6, [M+H]+ 349.1646, found 349.1648。
Synthesis of a compound of formula 9:
under the protection of nitrogen, dissolving the compound of formula 8 (2.0 g, 5.75 mmol) in anhydrous dichloromethane (30 mL), cooling to 0 ℃, adding N, N-diisopropylethylamine (2.23 g, 17.24 mmol, 3 eq.) sequentially, dimethyl sulfoxide (4.49 g, 57.47 mmol, 10 eq.) and sulfur trioxide pyridine complex (2.75 g, 17.24 mmol, 3 eq.) sequentially, and stirring at the temperature for reaction for 1 hour. TLC detection when the raw materials completely reacted, adding dilute hydrochloric acid solution to neutralize excess N, N-diisopropylethylamine, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated brine, and adding anhydrous Na2SO4And (5) drying. And (3) carrying out suction filtration to remove solid impurities, carrying out column chromatography separation and purification on the crude product after vacuum concentration (petroleum ether: ethyl acetate = 8: 1), and carrying out vacuum concentration on the obtained eluent containing the target product to obtain a colorless viscous liquid, namely the compound (1.81 g) shown as the formula 9. Yield: 91 percent.1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.13 (t, J = 8.2 Hz, 1H), 6.73 (dd, J = 9.6, 7.6 Hz, 3H), 6.57 – 6.48 (m, 1H), 6.43 (d, J = 7.1 Hz, 2H), 4.10 (d, J = 9.4 Hz, 1H), 3.89 (d, J = 9.4 Hz, 1H), 3.80 (s, 3H), 3.73 (d, J= 6.1 Hz, 6H), 3.61 (s, 1H), 3.02 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 203.248, 161.31, 159.73, 149.24, 148.69, 130.42, 126.84, 122.88, 114.16, 111.66, 107.67, 107.06, 101.68, 79.95, 70.77, 56.23, 56.16, 55.66, 39.24. HRMS (ESI): m/z calcd. for C19H23O6, [M+H]+ 347.1489, found 347.1492。
Synthesis of compound 10 of formula:
under nitrogen protection, the compound of formula 9 (1.81 g, 5.23 mmol) was dissolved in anhydrous dichloromethane (50 mL), and trifluoroacetic acid (2.40 g, 21.40 mmol, 4 eq.) was added dropwise to the reaction system, and the reaction was stirred for 1 hour. After completion of the TLC detection reaction, the reaction was quenched by addition of an appropriate amount of saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL. times.3), the resulting organic phases were combined, washed with saturated brine and then with anhydrous Na2SO4The organic phase was dried to remove water. The crude product obtained by suction filtration and concentration under reduced pressure was purified by silica gel column separation (petroleum ether: ethyl acetate = 6: 1), and the eluate was concentrated under reduced pressure to obtain a white solid compound of formula 10 (1.42 g). Yield: 83 percent.1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.4 Hz, 1H), 6.78 (s, 1H), 6.73 (s, 1H), 6.64 (dd, J = 8.4, 2.3 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 4.07 (s, 1H), 4.01 (d, J = 11.3 Hz, 1H), 3.83 (d, J = 3.9 Hz, 6H), 3.79 (d, J = 11.3 Hz, 1H), 3.74 (s, 3H), 3.21 (d, J = 15.8 Hz, 1H), 2.85 (d, J = 15.8 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 159.40, 154.38, 148.73, 148.45, 136.19, 130.65, 114.46, 108.84, 108.52, 107.80, 101.98, 77.45, 70.26, 56.12, 56.08, 55.32, 50.48, 41.43. HRMS (ESI): m/z calcd. for C19H21O5 [M+H]+ 329.1384, found 329.1385。
Synthesis of (+) -Brazilin:
under the protection of nitrogen, the compound is mixed10 (1.42 g, 4.34 mmol) is dissolved in anhydrous dichloromethane (85 mL), the temperature is reduced to-78 ℃, and boron tribromide (21.7 mL, 21.70 mmol, 1M in CH)2Cl25 eq.) was added dropwise to the reaction system, reacted at-78 ℃ for 2 hours, and then transferred to room temperature for 16 hours. After TLC detection, water quenching was added to complete the reaction, and after removal of dichloromethane by concentration under reduced pressure, the mixture was extracted with ethyl acetate (30 mL. times.3), and the organic phases obtained were combined, washed with saturated brine, and then with anhydrous Na2SO4Drying to remove water from the solution. The solid impurities were removed by suction filtration, and the crude product obtained by concentration under reduced pressure was purified by column chromatography (petroleum ether: ethyl acetate =1: 1), and the resulting eluate containing the target product was concentrated under reduced pressure to give an amber solid product (1.03 g). Yield: 83 percent.1H NMR (400 MHz, CD3OD) δ 7.16 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 6.60 (s, 1H), 6.47 (dd, J = 8.3, 2.3 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 3.96 (s, 1H), 3.92 (d, J = 11.5 Hz, 1H), 3.67 (d, J = 11.3 Hz, 1H), 3.01 (d, J = 15.6 Hz, 1H), 2.75 (d, J = 15.7 Hz, 1H). 13C NMR (100 MHz, CD3OD) δ 157.73, 155.68, 145.57, 145.25, 137.51, 132.29, 131.46, 115.63, 113.00, 112.53, 110.06, 104.35, 78.15, 70.86, 51.05, 49.96, 42.86. HRMS (ESI): m/z calcd. for C16H15O5, [M+H]+ 287.0914, found 287.0914。
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, so that any modifications, equivalents and improvements made within the spirit of the present invention are included in the scope of the present invention.

Claims (11)

1. A method for synthesizing Brazilin natural product (+) Brazilin is characterized in that the reaction formula is as follows:
Figure DEST_PATH_IMAGE001
the synthetic route comprises the following steps:
step one, taking 3, 4-dimethoxybenzyl alcohol which is a compound shown in formula 1 as an initial raw material, taking dichloromethane as a solvent, adding 4-Dimethylaminopyridine (DMAP) and p-toluenesulfonyl chloride into the initial raw material, then dropwise adding triethylamine into the initial raw material, reacting at room temperature, and carrying out p-toluenesulfonylation reaction to obtain a monohydroxy protection product; then, under the condition of 0 ℃, dissolving sodium hydride in tetrahydrofuran and N, N-dimethylformamide solution, slowly dropwise adding diethyl malonate into the solution, dropwise adding the obtained monohydroxy protection product into the reaction solution, and moving the reaction solution to room temperature for reaction to obtain a compound shown in a formula 2;
dissolving the compound shown in the formula 2 in a tetrahydrofuran solvent, adding elemental iodine and sodium acetate into the tetrahydrofuran solvent, and oxidizing a hydroxyl group from a quaternary carbon position to obtain a compound shown in the formula 3;
thirdly, carrying out lithium aluminum hydride reduction reaction on the compound of the formula 3 in the presence of lithium aluminum hydride to obtain a compound of a formula 4;
step four, the compound of the formula 4 is subjected to glycol asymmetric reaction under the catalytic action of Liase PS enzyme by using vinyl acetate as an acetyl donor, so as to form a chiral quaternary carbon center, and obtain a chiral precursor compound of the formula 5;
fifthly, the compound shown in the formula 5 and p-toluenesulfonyl chloride are subjected to a p-toluenesulfonylation reaction under the action of 4-dimethylaminopyridine and triethylamine to form a protecting group on a hydroxyl group, so as to obtain a compound shown in a formula 6;
step six, dripping the compound shown in the formula 6 into a reaction system of 3-methoxyphenol and cesium carbonate dissolved in a DMF solvent to perform nucleophilic substitution reaction to obtain a compound shown in the formula 7;
step seven, dissolving the compound shown in the formula 7 in methanol, and then adding K2CO3Carrying out a reaction of removing acetyl protection to obtain a compound of a formula 8;
step eight, adding N, N-diisopropylethylamine, dimethyl sulfoxide and sulfur trioxide pyridine compound into the compound in the formula 8, and carrying out an oxidation reaction by using dichloromethane as a solvent to obtain a compound in a formula 9;
step nine, adding trifluoroacetic acid into the compound shown in the formula 9, and carrying out one-pot intramolecular Prins/Friedel-Crafts serial cyclization reaction by taking dichloromethane as a solvent to obtain the compound shown in the formula 10;
and step ten, dissolving the compound shown in the formula 10 in dichloromethane, and performing demethyl ether protection through the action of boron tribromide to obtain a product compound (+) Brazilin.
2. The method for synthesizing the Brazilin natural product (+) Brazilin of claim 1, wherein: in the first step, under the protection of nitrogen, dissolving the compound shown in the formula 1 in dichloromethane, then adding 4-dimethylaminopyridine and p-toluenesulfonyl chloride, then dropwise adding triethylamine, reacting at room temperature until the solution gradually becomes light yellow, extracting with dichloromethane, collecting an organic phase, concentrating under reduced pressure, and separating and purifying to obtain a monohydroxy protected product; dissolving sodium hydride in an anhydrous tetrahydrofuran and N, N-dimethylformamide solvent at 0 ℃ under the protection of nitrogen, slowly dropwise adding a diethyl malonate solution dissolved in the tetrahydrofuran, reacting at 0 ℃, slowly dropwise adding a tetrahydrofuran solution of a monohydroxy protection product into a reaction system, moving to room temperature for reaction, adding a saturated ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, concentrating under reduced pressure, and separating and purifying to obtain the compound of the formula 2.
3. The method for synthesizing the Brazilin natural product (+) Brazilin of claim 1 or 2, wherein: and in the second step, under an open condition, exposing the compound of the formula 2 dissolved in a tetrahydrofuran solvent, elementary iodine and sodium acetate to the air at 35 ℃ for reaction, adding a saturated sodium thiosulfate aqueous solution after the reaction is finished, quenching, extracting with dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound of the formula 3.
4. The method for synthesizing the Brazilin natural product (+) Brazilin of claim 3, wherein: in the third step, under the protection of 0 ℃ and nitrogen, dissolving lithium aluminum hydride in tetrahydrofuran, slowly dripping the compound shown in the formula 3 into the reaction system, and stirring at the temperature; 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 the Brazilin natural product (+) Brazilin of claim 1 or 4, wherein: and in the fourth step, adding vinyl acetate into the compound shown in the formula 4 at room temperature under the protection of nitrogen, then adding Lipase PS enzyme, reacting at room temperature, filtering, concentrating under reduced pressure, separating and purifying to obtain the compound 5.
6. The method for synthesizing the Brazilin natural product (+) Brazilin of claim 5, wherein: and in the fifth step, under the protection of nitrogen and at the temperature of 0 ℃, sequentially adding 4-dimethylaminopyridine, p-toluenesulfonyl chloride and triethylamine into a dichloromethane solution of the compound shown in the formula 5, moving to room temperature for reaction, adding water for quenching, extracting with dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound shown in the formula 6.
7. The method for synthesizing the Brazilin natural product (+) Brazilin of claim 1 or 6, wherein: in the sixth step, under the protection of nitrogen, cesium carbonate and 3-methoxyphenol are dissolved in a DMF solvent, the mixture is heated at 60 ℃ for reaction, then the compound shown in the formula 6 is dropwise added into a reaction system, the temperature is continuously increased to 85 ℃ for reaction, aqueous solution is added for quenching, the ethyl acetate is used for extraction, the concentration is carried out under reduced pressure, and the compound shown in the formula 7 is obtained through separation and purification.
8. The method for synthesizing the Brazilin natural product (+) Brazilin of claim 7, wherein: and seventhly, adding potassium carbonate into the methanol solution of the compound shown in the formula 7 at room temperature, performing reduced pressure concentration after the reaction is finished, and separating and purifying to obtain the compound shown in the formula 8.
9. The method for synthesizing the Brazilin natural product (+) Brazilin of claim 8, wherein: in the eighth step, under the protection of 0 ℃ and nitrogen, sequentially adding the compound of N, N-diisopropylethylamine, dimethyl sulfoxide and sulfur trioxide pyridine into an anhydrous dichloromethane solution of the compound of the formula 8, reacting at 0 ℃, extracting with dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound of the formula 9.
10. The method for synthesizing the Brazilin natural product (+) Brazilin of claim 9, wherein: and step nine, dissolving the compound shown in the formula 9 in dichloromethane, dropwise adding trifluoroacetic acid into the solution under the protection of nitrogen, reacting at room temperature, concentrating under reduced pressure, and separating and purifying to obtain the compound shown in the formula 10.
11. The method for synthesizing the Brazilin natural product (+) Brazilin of claim 10, wherein: and step ten, dissolving the compound shown in the formula 10 in dichloromethane, cooling to-78 ℃, dropwise adding boron tribromide into an anhydrous dichloromethane solution dissolved in the compound shown in the formula 10, reacting at-78 ℃, and then moving to room temperature for continuous reaction to obtain a product (+) Brazilin.
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CN115215830A (en) * 2022-08-17 2022-10-21 山西省肿瘤医院 C-8 hydroxyl substituted brazilein analogue and preparation method and application thereof

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