CN110776488B - Method for synthesizing (-) -Brazilin - Google Patents
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Abstract
The invention relates to a method for synthesizing (-) -Brazilin, which takes a format reagent as an initial raw material, constructs a chiral carbon atom connected with a hydroxyl group through Mitsunobu Coupling Reaction and Sharpless Asymmetric dehydration Reaction, and constructs a tetracyclic framework as a key Reaction step in the synthesis process through double Friedel-crafts alkylation one-step Reaction, and finally realizes the Asymmetric total synthesis of a natural product (-) -Brazilin. The reaction process has the advantages of mild reaction conditions, simplicity, high efficiency, less side reactions, simple and convenient operation, less linear steps and suitability for industrial preparation.
Description
Technical Field
The invention relates to a synthesis method of various bioactive natural product molecules with functions of dyeing, resisting tumors, reducing blood sugar, resisting inflammation, resisting bacteria and the like, in particular to a total synthesis method of a natural product (-) -Brazilin.
Background
Brazilin is a crystalline compound first isolated from sappan wood by Chevreul in 1808, however its molecular formula and molecular structure have been controversial until Libermann and Burg identified C 16 H 14 O 5 And partial structures of three phenolic hydroxyl groups and one alcoholic hydroxyl group. Brazilin is one of Brazilin natural product molecules, the structures of the compounds are similar, the compounds all have chroman rings, and the compounds are homoisoflavonoid derivatives, and the chemical structures of (+) -Brazilin and (-) -Brazilin are as follows:
in particular, compared with other Brazilin natural product molecules, Brazilin is widely applied and is used as a natural red coloring agent at first, and researchers find that Brazilin has various biological activities of resisting tumors, inflammation, bacteria, protecting livers, resisting oxidation, reducing blood sugar and the like and can also be used as a DNA cutting agent.
Due to various biological activities and unique tetracyclic framework structures, the method attracts the attention of a plurality of synthetic chemists. The chemical methods reported in the Brazilin literature for synthesizing the natural product are mainly as follows: davis research group was published in 1993J. Org. ChemThe research paper titled Enantiosective Synthesis of (+) -O-Trimethypsapanone B and (+) -O-Trimethybrazilin realizes the first asymmetric Synthesis of Brazilin trimethyl etherified derivatives; pettus topic group was published in 2005Org. LettThe research paper titled Synthesis of (+/-) -Brazilin Using IBX totally goes through 9 steps of reaction, and the complete Synthesis of Brazilin racemization is really completed for the first time with the total yield of 8.5%; the Qinhong Bo research group was published in 2013Tetrahedron LettTopic of above is Total Synthesis oThe research paper of f (+/-) -Brazilin and formal synthesis of (+/-) -brazilein and (+/-) -brazilide A using m-CPBA, completes the racemization total synthesis of Brazilin by a method similar to the construction of a four-ring framework by an Qin red wave research group, and the total yield is 23 percent; fifthly, Jahng et al published in 2014Tetrahedron: AsymmetryThe research paper titled Enantioselective syntheses of (+) -and (-) -brocilin completed Brazilin synthesis in 9 steps, however, its ee value was low, only 63%.
By carefully analyzing the known synthetic routes, we find that many researchers at home and abroad use various methods to synthesize target molecules, and the problems of the design and the methods of the synthetic routes mainly include: the synthesis steps are longer, and the yield is lower; only racemization synthesis is carried out, and the ee value is lower; the synthesis strategy is single, the individual reaction is not easy to operate, the reagent is expensive and the toxicity is large. Very few asymmetric syntheses have been reported for (-) -Brazilin.
Disclosure of Invention
The invention aims to solve the technical problems of long route, low yield, high synthesis cost and the like of the existing synthesis method, and provides a novel synthesis method of a natural product (-) -Brazilin.
In order to solve the technical problems, the invention adopts the technical scheme that: a method of synthesizing (-) -Brazilin, comprising the steps of:
step one, taking tetrahydrofuran as a solvent and iodine as an initiator, heating and refluxing at 45-55 ℃, dropwise adding 4-bromo veratrole of a compound of formula 1 dissolved in tetrahydrofuran into a reaction system, and reacting with magnesium to generate a Grignard reagent, namely a compound of formula 2;
step two, taking the compound shown in the formula 3 as an initial raw material, dissolving the compound in tetrahydrofuran at normal temperature, sequentially adding cuprous iodide and lithium chloride, and moving a reaction system to an ice-water bath at 0 ℃; then dropwise adding the compound shown in the formula 2 into a reaction system, and carrying out a coupling reaction between a Grignard reagent and a halogenated hydrocarbon under the concerted catalysis of lithium chloride and cuprous iodide to obtain a compound shown in the formula 4;
dissolving the compound shown in the formula 4 in dichloromethane, and carrying out ester reduction reaction with diisobutylaluminum hydride at 0 ℃ to obtain a compound shown in the formula 5;
dissolving the compound shown in the formula 5 and the compound shown in the formula 6 in toluene, adding triphenylphosphine, moving to an ice water bath at 0 ℃, adding diisopropyl azodicarboxylate, and carrying out Mitsunobu Coupling Reaction to obtain a compound shown in the formula 7;
step five, the compound of formula 7 is dissolved in tert-butanol and water, the reaction system is moved to 0 ℃ in an ice-water bath, and then potassium ferricyanide, potassium carbonate, potassium osmate and ligand (DHQ) are added in sequence 2 PHAL, undergoing Sharpless Asymmetric Dihydroxylation reaction, (Sharplesi Asymmetric Dihydroxylation reaction) to yield the compound of formula 8;
step six, dissolving the compound shown in the formula 8 in dichloromethane, moving the reaction system to an ice-water bath at 0 ℃, and then sequentially addingN,N-diisopropylethylamine, dimethyl sulfoxide and sulfur trioxide pyridine complex, reacting to obtain a compound of formula 9;
seventhly, dissolving the compound shown in the formula 9 in dichloromethane, adding trifluoroacetic acid, and performing a double Friedel-crafts alkylation reaction to obtain a compound shown in a formula 10;
step eight, dissolving the compound shown in the formula 10 in dichloromethane, moving to a reaction system at-78 ℃, adding boron tribromide, and reacting to obtain a compound shown in the formula 11;
the reaction formula is as follows:
preferably, in the first step, the conditions for preparing the format reagent are as follows: adding ground magnesium strips into a three-neck flask filled with nitrogen protection at normal temperature, taking tetrahydrofuran as a solvent and iodine as an initiator, slowly dropwise adding the compound of the formula 1 dissolved in the tetrahydrofuran into a reaction system at 45 ℃, and reacting for 0.5 h to obtain a Grignard reagent, namely the compound of the formula 2.
Step two is a coupling reaction of the aryl format reagent compound of formula 2 and the starting material halohydrocarbon compound of formula 3, and the reaction conditions are preferably as follows: slowly dripping the compound shown in the formula 2 into a reaction system, after adding, moving to room temperature for reaction for 2 h after 1 h, adding a proper amount of water for quenching, extracting with ethyl acetate, concentrating under reduced pressure, separating and purifying to obtain the compound shown in the formula 4.
Step three reduces the ester to an alcohol, preferably, the step formula is: under the condition of room temperature and under the protection of nitrogen, dissolving the compound shown in the formula 4 in dichloromethane, moving a reaction system to an ice-water bath at 0 ℃, and then slowly dropwise adding diisobutyl aluminum hydride into the reaction system to react for 1 h; adding methanol and sodium potassium tartrate to quench, stirring at room temperature for 1-2 hours for layering, extracting with dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound shown in the formula 5.
Step four is etherification, preferably, the Mitsunobu Coupling Reaction condition of the compound shown in the formula 5 and the compound shown in the formula 6 is as follows: under the protection of nitrogen at room temperature, dissolving the compound of the formula 5 and the compound of the formula 6 in toluene, adding triphenylphosphine, moving to an ice water bath at 0 ℃, then slowly dropwise adding diisopropyl azodicarboxylate, moving to room temperature for reaction for 8 hours after the addition is finished, adding water for quenching, extracting with dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound of the formula 7.
Step five is a non-symmetrical double hydroxylation reaction, and preferably, the conditions for the Sharpless Asymmetric Dihydroxylation reaction in the step are as follows: under the protection of nitrogen at room temperature, the compound of formula 7 is dissolved in tert-butanol and water, the reaction system is placed in an ice water bath at 0 ℃, and then potassium ferricyanide, potassium carbonate, potassium osmate and ligand (DHQ) are added in sequence 2 And reacting for 7 hours by using PHAL, quenching by using a saturated aqueous solution of sodium thiosulfate, extracting by using dichloromethane, concentrating under reduced pressure, and separating and purifying to obtain the compound shown in the formula 8.
Step six is to oxidize the hydroxyl group in the compound of formula 8 to aldehyde, and the preferred reaction conditions are: dissolving the compound shown in the formula 8 in dichloromethane under the protection of nitrogen at room temperature, moving a reaction system to an ice water bath at 0 ℃, and then sequentially addingN,NReacting the compound of-diisopropylethylamine, dimethyl sulfoxide and sulfur trioxide pyridine for 4 hours, adding water for quenching, extracting by using dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound of the formula 9.
And seventhly, carrying out double Friedel-crafts alkylation on the compound of the formula 9 to construct a tetracyclic framework structure. The conditions under which the compound of formula 9 undergoes a double Friedel-crafts alkylation reaction are: under the protection of nitrogen at room temperature, the compound of the formula 9 is firstly dissolved in dichloromethane, then trifluoroacetic acid is added, the reaction is carried out for 8 hours at room temperature, dichloromethane is used for extraction, reduced pressure concentration, separation and purification are carried out, and the compound of the formula 10 is obtained.
Step eight is demethylating the compound of formula 10, preferably under the reaction conditions: dissolving the compound of the formula 10 in dichloromethane, moving to a reaction system at-78 ℃, slowly dropwise adding boron tribromide dissolved in dichloromethane into the reaction system, reacting for 2 hours, transferring to room temperature for reaction for 12 hours, adding water for quenching, carrying out reduced pressure concentration to remove dichloromethane, extracting by ethyl acetate, carrying out reduced pressure concentration, separating and purifying to obtain the final product, namely the compound of the formula 11.
The invention takes a compound shown in a formula 2 as an initial raw material, chiral carbon atoms connected with hydroxyl groups are constructed through Mitsunobu Coupling Reaction and Sharpless Asymmetric Dihydroxylation Reaction, a tetracyclic skeleton is constructed through one-step double Friedel-crafts alkylation Reaction as a key Reaction step in the synthesis process, and finally, the Asymmetric total synthesis of a natural product (-) -Brazilin is realized through only 8 steps of Reaction.
The design of the whole route provided by the invention is unique and novel, the (-) -Brazilin is obtained by single selective synthesis in theory, the reaction process is mild in reaction condition, simple and efficient, less in side reaction, simple and convenient to operate, less in linear steps and suitable for industrial preparation. The total yield is up to 39%, and the ee value is 93.6%.
The conventional chemical reagents are utilized in the route, the raw materials and the reagents are cheap and easy to obtain, and the synthesis cost can be greatly reduced.
In conclusion, the method for synthesizing the natural product (-) -Brazilin provided by the invention has good universality, and can be further used for synthesizing Brazilin and analogues thereof, thereby providing a material basis for medicinal chemical research and related medicinal application development.
Drawings
FIG. 1 is hydrogen and carbon spectra data for a compound of formula 4;
FIG. 2 is hydrogen and carbon spectra data for the compound of formula 5;
FIG. 3 is hydrogen and carbon spectra data for the compound of formula 7;
FIG. 4 is hydrogen and carbon spectra data for the compound of formula 8;
FIG. 5 is hydrogen and carbon spectra data for the compound of formula 9;
FIG. 6 is hydrogen and carbon spectra data for compounds of formula 10;
FIG. 7 is hydrogen and carbon spectra data for compounds of formula 11.
Detailed Description
Synthesis of compounds of formula 2:
a250 mL three-necked flask was evacuated and purged with nitrogen, and milled magnesium rods (2.06 g, 84.64 mmol) and THF (40 mL) were added in that order. Starting stirring, heating to 45-55 ℃, refluxing and adding one iodine particle to obtain a reddish brown solution. The compound of formula 1 (9.2 g, 42.32 mmol) is dissolved in 26 mL tetrahydrofuran, then 20 drops are slowly dropped into the reaction system, when the solution of the reaction system is reddish brown and turns into yellow emulsion until it turns into white solution, the solution of the reaction system continues to slowly drop, and as the reaction proceeds, the solution of the reaction system becomes clear and transparent liquid. After the addition, the reaction is carried out for 0.5 h to obtain the compound shown in the formula 2.
Synthesis of compounds of formula 4:
a500 mL round-bottomed flask was evacuated under nitrogen, the compound of formula 3 (5.00 g, 27.93 mmol), THF (80 mL), CuI (8.38 mmol, 1.60 g) and LiCl (55.86 mmol, 2.37 g) were added in this order, and the reaction was placed in an ice-water bath at 0 ℃. And (3) dropwise adding the compound of the formula 2 obtained by the reaction into the reaction system, reacting for 0.5 h after the addition is finished, moving to room temperature for reacting for 2 h, and detecting the reaction process by TLC. After the reaction, an appropriate amount of water was added, followed by extraction three times with ethyl acetate (40 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, and separation and purification of the crude product by silica gel column (eluent petroleum ether: ethyl acetate = 30: 1) gave the compound of formula 4 (5.39 g, yield 82%) as a colorless oily liquid.
FIG. 1 is hydrogen and carbon spectra data for compounds of formula 4, 1 H NMR (400 MHz, CDCl 3 ) δ 6.75 (d, J = 8.7 Hz, 1H), 6.69 (dd, J = 6.3, 1.8 Hz, 2H), 6.17 (s, 1H), 5.43 (d, J = 1.4 Hz, 1H), 3.80 (d, J = 2.5 Hz, 6H), 3.69 (s, 3H), 3.53 (s, 2H). 13 C NMR (400 MHz, CDCl 3 ) δ 168.94, 150.42, 149.13, 141.92, 132.75, 127.54, 122.59, 113.85, 112.79, 57.40, 57.34, 53.41, 39.21。
synthesis of compounds of formula 5:
a250 mL round-bottom flask was evacuated and purged with nitrogen, the compound of formula 4 (2.16 g, 9.15 mmol) and 46 mL of dichloromethane were added sequentially, and the reaction was placed in an ice-water bath at 0 ℃. 15.3 mL of diisobutylaluminum hydride (1 mol/L) is added into the reaction system dropwise, and the reaction progress is detected by TLC after the dropwise addition is finished. After the reaction is finished, slowly dropwise adding methanol and saturated sodium potassium tartrate solution for quenching, gradually changing the reaction system into a cementing solid, vigorously stirring for 1-2 h, when the system is obviously layered, filtering by using kieselguhr, adding proper amount of water, then extracting for three times by using dichloromethane (30 mL multiplied by 3), combining organic phases, washing by using saturated saline solution, and drying by using anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, and separation and purification of the crude product by silica gel column (eluent petroleum ether: ethyl acetate = 5: 1) gave the compound of formula 5 (1.876 g) in 99% yield.
Figure 2 is hydrogen and carbon spectral data for the compound of formula 5, 1 H NMR (400 MHz, CDCl 3 ) δ 6.58 (q, J = 7.9 Hz, 3H), 4.95 (s, 1H), 4.70 (s, 1H), 3.84 (s, 2H), 3.64 (d, J = 2.9 Hz, 6H), 3.48 (s, 1H), 3.16 (s, 2H). 13 C NMR (400 MHz, CDCl 3 ) δ 150.30, 150.02, 148.90, 133.29, 122.52, 113.78, 112.78, 112.31, 66.18, 57.30, 57.21, 40.83。
synthesis of compounds of formula 7:
a250 mL round-bottom flask was evacuated and purged with nitrogen, followed by addition of compound of formula 5 (1.83 g, 8.79 mmol), 44 mL toluene, compound of formula 6 (1.20 g, 9.67 mmol), and triphenylphosphine (4.61 g, 17.59 mmol), and the reaction was placed in an ice-water bath at 0 deg.C with stirring. Diisopropyl azodicarboxylate (3.56 g, 17.30 mmol) was added dropwise and the mixture was allowed to cool to room temperature for 8 h, followed by TLC detection of the progress of the reaction. After the reaction, an appropriate amount of water was added, followed by extraction with ethyl acetate (40 mL. times.3) three times, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, and separation and purification of the crude product by silica gel column (eluent petroleum ether: ethyl acetate = 30: 1) gave the compound of formula 7 (2.70 g, yield 98%) as a colorless transparent liquid.
Figure 3 is hydrogen and carbon spectral data for the compound of formula 7, 1 H NMR (400 MHz, CDCl 3 ) δ 7.16 (s, 1H), 6.86 – 6.66 (m, 3H), 6.48 (dd, J = 7.7, 5.0 Hz, 3H), 5.21 (s, 1H), 5.05 (s, 1H), 4.39 (s, 2H), 3.91 – 3.72 (m, 9H), 3.44 (s, 2H). 13 C NMR (400 MHz, CDCl 3 ) δ 162.41, 161.88, 161.57, 150.49, 149.36, 149.16, 148.30, 146.10, 145.51, 132.87, 131.44, 122.62, 115.35, 113.74, 112.80, 108.62, 107.97, 102.88, 71.58, 57.50, 57.35, 56.84, 41.25。
synthesis of compounds of formula 8:
a250 mL round-bottom flask was evacuated and purged with nitrogen, and the compound of formula 7 (3.00 g, 9.55 mmol), 49 mL of water and 49 mL of t-butanol were added in this order, and the reaction system was placed in an ice-water bath at 0 ℃. Potassium ferricyanide (9.43 g, 28.65 mmol), potassium carbonate (3.96 g, 28.65 mmol), potassium osmate (14.4 mg, 0.04 mmol) and ligand (DHQ) were added sequentially 2 PHAL (78 mmg, 0.10 mmg) is added into the reaction system in a dropwise manner, after the dropwise addition is finished, the reaction is carried out for 7 hours, and the reaction progress is detected by TLC. After the reaction was complete, quench with sodium thiosulfate and filter through celite. Then, the mixture was extracted three times with methylene chloride (40 mL. times.3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure concentration of the filtrate, and silica gel column separation and purification of the crude product (eluent petroleum ether: ethyl acetate = 5: 1) gave the compound of formula 8 (3.032 g, yield 91%) as a colorless transparent liquid.
FIG. 4 is hydrogen and carbon spectra data for the compound of formula 8, 1 H NMR (400 MHz, CDCl 3 ) δ 7.08 (s, 1H), 6.67 (d, J = 5.8 Hz, 3H), 6.44 (dd, J = 12.3, 7.9 Hz, 3H), 3.85 – 3.61 (m, 9H), 3.60 – 3.48 (m, 4H), 3.43 – 3.21 (m, 2H), 2.85 (d, J = 11.4 Hz, 2H). 13 C NMR (400 MHz, CDCl 3 ) δ 162.44, 161.20, 150.18, 149.29, 131.61, 130.21, 124.05, 115.23, 112.65, 108.33, 108.27, 102.67, 75.99, 70.35, 67.22, 57.36, 57.02, 56.81, 41.28。
synthesis of compounds of formula 9:
a100 mL round-bottom flask was evacuated and purged with nitrogen, and the compound of formula 8 (1.07 g, 3.07 mmol) and 15 mL of dichloromethane were added in this order, and then the reaction was transferred to an ice-water bath at 0 ℃. Then dimethyl sulfoxide (2.40 g, 30.7 mmol) is added in turn,N, NDiisopropylethylamine (3.97 g, 30.7 mmol) and sulfur trioxide pyridine complex (1.941 g, 9.21 mmol) were reacted for 4 h, TLC checked for progress, and after completion of the reaction, an appropriate amount of water was added. Then, the mixture was extracted three times with methylene chloride (40 mL. times.3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, and separation and purification of the crude product by silica gel column (eluent petroleum ether: ethyl acetate = 10: 1) gave the compound of formula 9 (1.02 g, yield 96%) as a pale yellow oily solid.
Figure 5 is hydrogen and carbon spectral data for the compound of formula 9, 1 H NMR (400 MHz, CDCl 3 ) δ 9.82 (s, 1H), 7.21 – 7.12 (m, 1H), 6.77 (d, J = 3.0 Hz, 3H), 6.58 – 6.51 (m, 1H), 6.49 – 6.41 (m, 2H), 4.17 – 4.11 (m, 1H), 3.96 – 3.90 (m, 1H), 3.85 (s, 3H), 3.77 (d, J = 2.5 Hz, 6H), 3.55 – 3.46 (m, 1H), 3.06 (s, 2H). 13 C NMR (400 MHz, CDCl 3 ) δ 202.84, 160.87, 159.26, 148.76, 148.21, 130.03, 126.31, 122.41, 113.57, 111.09, 107.24, 106.57, 101.18, 70.31, 55.82, 55.29, 38.83。
synthesis of compounds of formula 10:
a25 mL round-bottom flask was evacuated and purged with nitrogen, followed by addition of the compound of formula 9 (0.14 g, 0.40 mmol), 4 mL dichloromethane and trifluoroacetic acid (0.09 g, 0.81 mmol), stirring, reaction at room temperature for 8 h and TLC check of the progress of the reaction. After the reaction is finished, adding a proper amount of water. Then, the mixture was extracted three times with methylene chloride (10 mL. times.3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, and separation and purification of the crude product by silica gel column (eluent petroleum ether: ethyl acetate = 10: 1) gave the compound of formula 10 (0.112 g, yield 86%) as a white powdery solid.
Figure 6 is hydrogen and carbon spectral data for the compound of formula 10, 1 H NMR (400 MHz, CDCl 3 ) δ 6.96 (d, J = 8.4 Hz, 1H), 6.49 (s, 1H), 6.42 (s, 1H), 6.33 (d, J = 8.3 Hz, 1H), 6.14 (s, 1H), 3.76 (s, 1H), 3.71 (d, J = 11.2 Hz, 1H), 3.59 – 3.46 (m, 8H), 3.43 (s, 3H), 2.87 (s, 1H), 2.57 (s, 1H). 13 C NMR (400 MHz, CDCl 3 ) δ 160.87, 155.96, 150.27, 149.97, 137.92, 132.58, 116.22, 110.23, 109.50, 103.53, 71.67, 57.67, 57.62, 56.82, 51.90, 43.19。
synthesis of compounds of formula 11:
a25 mL round-bottom flask was evacuated and purged with nitrogen, and the compound of formula 10 (85 mg, 0.26 mmol) and 5mL of dichloromethane were added in this order, and then the reaction was transferred to-78 ℃. Dissolving boron tribromide (326 mmg, 1.30 mmol) in 6.5 mL dichloromethane, slowly dropwise adding into the reaction system, reacting for 2 h after adding, moving to room temperature for reacting for 12 h, and detecting the reaction process by TLC. After the reaction was completed, the reaction mixture was quenched with an appropriate amount of water, concentrated under reduced pressure to remove methylene chloride, and then extracted three times with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, and separation and purification of the crude product through silica gel column (eluent petroleum ether: ethyl acetate: dichloromethane = 1.5: 1: 1) gave the compound of formula 11 (48.5 mg, yield 65%) as a red solid.
Figure 7 is hydrogen and carbon spectral data for the compound of formula 11, 1 H NMR (400 MHz, CD 3 OD) δ 7.25 – 7.13 (m, 1H), 6.77 – 6.66 (m, 1H), 6.64 – 6.56 (m, 1H), 6.51 – 6.41 (m, 1H), 6.37 – 6.20 (m, 1H), 4.04 – 3.83 (m, 2H), 3.80 – 3.62 (m, 1H), 3.40 – 3.21 (m, 1H), 3.10 – 2.94 (m, 1H), 2.86 – 2.68 (m, 1H). 13 C NMR (400 MHz, CD 3 OD) δ 157.80, 155.64, 145.57, 145.25, 137.34, 132.18, 131.27, 115.50, 112.82, 112.38, 109.90, 104.18, 77.99, 70.77, 50.96, 42.83。
the above description is intended to be illustrative of the present invention and should not be taken as limiting the invention, as the invention is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
Claims (9)
1. A method for synthesizing (-) -Brazilin, which is characterized by comprising the following steps:
step one, taking tetrahydrofuran as a solvent and iodine as an initiator, heating and refluxing at 45-55 ℃, dropwise adding 4-bromo veratrole dissolved in tetrahydrofuran and shown in a formula 1 into a reaction system, and reacting with magnesium to generate a Grignard reagent, namely a compound shown in a formula 2;
step two, taking the compound shown in the formula 3 as an initial raw material, dissolving the compound in tetrahydrofuran at normal temperature, sequentially adding cuprous iodide and lithium chloride, and moving a reaction system to an ice-water bath at 0 ℃; then dropwise adding the compound shown in the formula 2 into a reaction system, and carrying out a coupling reaction between a Grignard reagent and a halogenated hydrocarbon under the concerted catalysis of lithium chloride and cuprous iodide to obtain a compound shown in the formula 4;
dissolving the compound shown in the formula 4 in dichloromethane, and carrying out ester reduction reaction with diisobutylaluminum hydride at 0 ℃ to obtain a compound shown in the formula 5;
dissolving the compound shown in the formula 5 and the compound shown in the formula 6 in toluene, adding triphenylphosphine, moving to an ice water bath at 0 ℃, adding diisopropyl azodicarboxylate, and carrying out Mitsunobu Coupling Reaction to obtain a compound shown in the formula 7;
step five, the compound of formula 7 is dissolved in tert-butanol and water, the reaction system is moved to 0 ℃ in an ice-water bath, and then potassium ferricyanide, potassium carbonate, potassium osmate and ligand (DHQ) are added in sequence 2 PHAL, undergoing a Sharpless Asymmetric Dihydroxylation reaction to give a compound of formula 8;
step six, dissolving the compound shown in the formula 8 in dichloromethane, moving the reaction system to an ice-water bath at 0 ℃, and then sequentially addingN,N-diisopropylethylamine, dimethyl sulfoxideAnd sulfur trioxide pyridine complex to obtain a compound of formula 9;
seventhly, dissolving the compound shown in the formula 9 in dichloromethane, adding trifluoroacetic acid, and performing a double Friedel-crafts alkylation reaction to obtain a compound shown in the formula 10;
step eight, dissolving the compound shown in the formula 10 in dichloromethane, moving to a reaction system at-78 ℃, adding boron tribromide, and reacting to obtain a compound shown in the formula 11;
the reaction formula and each compound are as follows:
2. the method of synthesis according to claim 1, characterized in that: in the first step, a ground magnesium strip is added into a three-neck flask filled with nitrogen protection at normal temperature, tetrahydrofuran is used as a solvent, iodine is used as an initiator, the compound of the formula 1 dissolved in the tetrahydrofuran is slowly dripped into a reaction system at the temperature of 45 ℃, and the reaction is carried out for 0.5 h to obtain a Grignard reagent, namely the compound of the formula 2.
3. The method of synthesis according to claim 1, characterized in that: and in the second step, slowly dropwise adding the compound shown in the formula 2 into the reaction system, after adding, moving to room temperature for reaction for 2 h after 1 h, adding a proper amount of water for quenching, extracting with ethyl acetate, concentrating under reduced pressure, separating and purifying to obtain the compound shown in the formula 4.
4. The method of synthesis according to claim 1, characterized in that: in the third step, under the protection of nitrogen at room temperature, the compound of the formula 4 is dissolved in dichloromethane, the reaction system is moved to an ice-water bath at 0 ℃, and then diisobutylaluminum hydride is slowly dripped into the reaction system to react for 1 h; adding methanol and potassium sodium tartrate for quenching, stirring at room temperature for 1-2 hours for layering, extracting with dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound shown in the formula 5.
5. The method of synthesis according to claim 1, characterized in that: in step four, the Mitsunobu Coupling Reaction conditions between the compound of formula 5 and the compound of formula 6 are as follows: under the protection of nitrogen at room temperature, dissolving the compound of the formula 5 and the compound of the formula 6 in toluene, adding triphenylphosphine, moving to an ice water bath at 0 ℃, then slowly dropwise adding diisopropyl azodicarboxylate, moving to room temperature for reaction for 8 hours after the addition is finished, adding water for quenching, extracting with dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound of the formula 7.
6. The method of synthesis according to claim 1, characterized in that: in step five, the conditions for the Sharpless Asymmetric hydrolysis reaction to occur are as follows: under nitrogen protection at room temperature, the compound of formula 7 is first dissolved in tert-butanol and water and the reaction system is placed in an ice-water bath at 0 deg.C, then potassium ferricyanide, potassium carbonate, potassium osmate and ligand (DHQ) are added in sequence 2 And reacting for 7 hours by using PHAL, quenching by using a saturated aqueous solution of sodium thiosulfate, extracting by using dichloromethane, concentrating under reduced pressure, and separating and purifying to obtain the compound shown in the formula 8.
7. The method of synthesis according to claim 1, characterized in that: in the sixth step, under the condition of room temperature and under the protection of nitrogen, the compound shown in the formula 8 is dissolved in dichloromethane, then the reaction system is moved to an ice-water bath at 0 ℃, and then the compound is sequentially addedN,NReacting the compound of-diisopropylethylamine, dimethyl sulfoxide and sulfur trioxide pyridine for 4 hours, adding water for quenching, extracting by using dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound of the formula 9.
8. The method of synthesis according to claim 1, characterized in that: in the seventh step, the conditions for the double Friedel-crafts alkylation reaction of the compound of formula 9 are as follows: under the protection of nitrogen at room temperature, the compound of the formula 9 is firstly dissolved in dichloromethane, then trifluoroacetic acid is added, the reaction is carried out for 8 hours at room temperature, dichloromethane is used for extraction, reduced pressure concentration, separation and purification are carried out, and the compound of the formula 10 is obtained.
9. The method of synthesis according to claim 1, characterized in that: and step eight, dissolving the compound of the formula 10 in dichloromethane, moving to a reaction system at-78 ℃, slowly dropwise adding boron tribromide dissolved in dichloromethane into the reaction system, reacting for 2 hours, transferring to room temperature, reacting for 12 hours, adding water for quenching, carrying out reduced pressure concentration to remove dichloromethane, extracting by ethyl acetate, carrying out reduced pressure concentration, and carrying out separation and purification to obtain the final product, namely the compound of the formula 11.
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| FR2939654A1 (en) * | 2008-12-12 | 2010-06-18 | Oreal | A CAPILLARY COLORING PROCESS USING A HEMATOXYLINE, HEMATEINE, BRAZILINE OR BRAZILEINE DERIVATIVE, A METAL SALT, HYDROGEN PEROXIDE AND (BI) CARBONATE |
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| CN101045046A (en) * | 2006-03-31 | 2007-10-03 | 上海安普生物科技有限公司 | Use of Brazil hemoatoxy type compound for preparing antineoplastic |
| FR2939654A1 (en) * | 2008-12-12 | 2010-06-18 | Oreal | A CAPILLARY COLORING PROCESS USING A HEMATOXYLINE, HEMATEINE, BRAZILINE OR BRAZILEINE DERIVATIVE, A METAL SALT, HYDROGEN PEROXIDE AND (BI) CARBONATE |
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