CN113135932B - Synthesis method of cytochalasin compound flaviperine B - Google Patents
Synthesis method of cytochalasin compound flaviperine B Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a cytochalasin compound flaviperine B, wherein the structural formula of the compound is as follows:
the synthesis method provided by the invention is novel, efficient and economical, reagents used in the whole synthesis process can be purchased at low cost, and the reaction strategy is also suitable for synthesis of similar intermediate product derivatives of other types of cytochalasin, so that a foundation is laid for structure modification, structure-activity relationship research, new drug development and mass preparation of the alkaloids.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing a cytochalasin compound flaviperine B.
Background
Although natural products have abundant structures, natural products are often limited in natural sources, and it is difficult to carry out deep research on chemical properties and biological activities of the natural products, so how to simply, efficiently and massively obtain natural products and analogues thereof with specific structures becomes an important research content of natural product chemical synthesis, biosynthesis and organic synthesis methodologies.
Cytochalasin (cytochalasan) is a kind of fungus polyamino acid hybrid secondary metabolite with significant biological function. To date, over 400 different compounds of this family have been successfully isolated and identified. The cytochalasin name originated from the greek kyto-meaning "cell" and chalasis-meaning "relax", which discloses that an important biological function of this class of compounds is to inhibit the activity of actin microfilaments. The structural diversity of cytochalasin compounds makes them have a wide range of biological effects. Since cytochalasin has a major role in filaggrin, and its specific mechanism of action interferes with several cellular processes, such as cytokinesis, intracellular movement, and endocytosis, it exhibits potent cytotoxic and antibacterial activities. Biological activities of cytochalasin have been reported to include nematicidal, antifouling, and anti-inflammatory activities, as well as inducing apoptosis in leukemic cells, inhibiting angiogenesis, and against multidrug-resistant bacteria. Even some cytochalasin has anti-HIV and phytotoxic effects, which do not appear to be directly associated with microfilaments. Due to the potent anti-tumor properties of cytochalasin-like compounds, cytochalasin has attracted considerable interest as a candidate natural product for anti-cancer drugs. However, due to severe and non-selective cytotoxicity, no such compounds have been used as actin-targeting agents in clinical trials to date.
Therefore, it is desirable to modify cytochalasin to improve its biological activity and toxic side effects. However, the currently reported methods for synthesizing cytochalasin have the disadvantages of multiple steps, low yield, high reagent toxicity, high price and the like, and are not enough to meet the requirement of modifying and improving cytochalasin.
At present, no feasible chemical synthesis method is reported for cytochalasin skeleton compounds, and the existing biological fermentation extraction method has the defects of high cost, low yield, long period, difficult separation of products, low purity and the like. The separation method reported in the literature is basically that only milligram-level products can be finally separated from dozens or even hundreds of grams of crude extract, and the efficiency of the biological fermentation method is low.
Therefore, the technical problem to be solved by those skilled in the art is how to provide a simple, efficient and economical method for synthesizing a cytochalasin compound, which can rapidly complete the synthesis of cytochalasin, and realize the preparation of gram-level quantity.
Disclosure of Invention
In view of the above, the invention provides an efficient and economic synthesis method of cytochalasin compound flaviperine B, compared with the prior art, the method is low in cost, short in production period, capable of preparing high-purity products in gram-scale mode and high in production efficiency.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing a cytochalasin compound flavipesine B, wherein the structural formula of the compound flavipesine B is as follows:
the synthesis route is as follows:
the method comprises the following specific steps:
(1) dissolving the compound B in anhydrous pyridine, adding p-toluenesulfonic anhydride, stirring at room temperature for 1-2h, then quenching with 1mol/L hydrochloric acid aqueous solution for reaction, extracting with ethyl acetate, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering under reduced pressure, concentrating under reduced pressure in vacuum to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain a compound C;
(2) dissolving the compound C in anhydrous tetrahydrofuran, adding zinc powder and ammonium acetate, stirring at 40-50 deg.C for 2-3h, cooling to room temperature, filtering with diatomite, vacuum concentrating to obtain crude product, and purifying with silica gel column chromatography to obtain compound D;
(3) dissolving the compound D in anhydrous tetrahydrofuran, adding scandium trifluoromethanesulfonate, stirring at room temperature for 2-3h, then quenching the reaction by using a saturated sodium bicarbonate aqueous solution, extracting by using ethyl acetate, washing by using a saturated sodium chloride aqueous solution, drying by using anhydrous sodium sulfate, filtering under reduced pressure, concentrating under reduced pressure in vacuum to obtain a crude product, and purifying the crude product by using a silica gel column chromatography to obtain a compound E;
(4) dissolving a compound E in tetrahydrofuran, sequentially adding manganese (II) acetylacetonate and phenylsilane, continuously introducing oxygen into the solution, reacting for 10-20min, continuing to react for 18-20h under the oxygen atmosphere, quenching by using a saturated sodium thiosulfate aqueous solution, extracting by using ethyl acetate, washing by using a saturated sodium chloride aqueous solution, drying by using anhydrous sodium sulfate, filtering under reduced pressure, concentrating under reduced pressure in vacuum to obtain a crude product, and purifying the crude product by using a silica gel column chromatography to obtain a compound F;
(5) adding selenium dioxide into the stirred 1, 4-dioxane solution of the compound F, then continuing stirring for 1-2h at 50-65 ℃, cooling to room temperature, then quenching by saturated sodium thiosulfate aqueous solution, then extracting by ethyl acetate, washing by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, filtering under reduced pressure, and concentrating under reduced pressure under vacuum to obtain a crude compound;
(6) dissolving the crude product compound obtained in the step (5) in methanol at 0 ℃, adding cerium trichloride heptahydrate, stirring for 10-20min, then adding sodium borohydride, stirring for 10-20min, quenching by saturated sodium bicarbonate aqueous solution at 0 ℃, extracting by ethyl acetate, washing by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, filtering under reduced pressure, concentrating under reduced pressure under vacuum to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain the compound A.
The synthesis of compound B in the present invention can be found in Long, X; ding, Y; deng, j.angelw.chem., int.ed.2018,130, 14417-14420.
Preferably, in the step (1), the molar ratio of the compound B to the p-toluenesulfonic anhydride is (1: 1.5) - (1: 2.5), and the concentration of the solution of the compound B dissolved in the anhydrous pyridine is 0.01-0.5 mol/L.
Preferably, the molar ratio of the compound C, the zinc powder and the ammonium acetate in the step (2) is (1: 10: 12) - (1: 20: 22), and the concentration of the solution of the compound C dissolved in the anhydrous tetrahydrofuran is 0.01-0.5 mol/L.
Preferably, in the step (3), the molar ratio of the compound D to the scandium trifluoromethanesulfonate is (1: 1.2) - (1: 2.5), and the concentration of the solution of the compound D dissolved in the anhydrous tetrahydrofuran is 0.01-0.5 mol/L.
Preferably, in the step (4), the molar ratio of the compound E, the manganese (II) acetylacetonate and the phenylsilane is (1: 0.1: 1.5) - (1: 0.2: 2.5), and the concentration of the solution of the compound E dissolved in tetrahydrofuran is 0.01-0.5 mol/L.
Preferably, the molar ratio of the compound F to selenium dioxide in the step (5) is (1: 3) to (1: 6), and the 1, 4-dioxane solution concentration of the compound F is 0.01 to 0.5 mol/L.
Preferably, the molar ratio of the crude compound, cerium trichloride heptahydrate and sodium borohydride in step (6) is (1: 3: 1.2) - (1: 3: 1.6), and the concentration of the solution of the crude compound dissolved in methanol is 0.01-0.5 mol/L.
Preferably, the quenching time in the quenching reaction in any one of the steps (1) to (6) is 10-15 min; the vacuum degree of the reduced pressure filtration is 50-600 mbar; vacuum degree of reduced pressure concentration is 50-600 mbar.
Preferably, the eluent used for the silica gel column chromatography purification in any one of the steps (1) to (3) is ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is (20: 80) - (90: 10).
Preferably, the eluent used for the silica gel column chromatography purification in steps (4) and (6) is dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is (99: 1) - (85: 15).
According to the technical scheme, compared with the prior art, the synthesis method of the novel, efficient and economical cytochalasin compound flavipesine B is provided. Reagents used in the whole synthesis process can be purchased at low cost in a commercial mode, and the reaction strategy is also suitable for synthesis of derivatives of similar intermediate products of other types of cytochalasin, so that a foundation is laid for structural modification, structure-activity relationship research, new drug development and large-scale preparation of the alkaloids.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a chart showing a hydrogen spectrum of compound C prepared in example 2 of the present invention;
FIG. 2 is a carbon spectrum of Compound C prepared in example 2 of the present invention;
FIG. 3 is a chart showing a hydrogen spectrum of compound D prepared in example 2 of the present invention;
FIG. 4 is a carbon spectrum diagram of compound D prepared in example 2 of the present invention;
FIG. 5 is a chart showing a hydrogen spectrum of a compound E prepared in example 2 of the present invention;
FIG. 6 is a carbon spectrum of compound E prepared in example 2 of the present invention;
FIG. 7 is a chart showing a hydrogen spectrum of compound F prepared in example 2 of the present invention;
FIG. 8 is a carbon spectrum of compound F prepared in example 2 of the present invention;
FIG. 9 is a hydrogen spectrum of flaviperine B, a compound prepared in example 2 of the invention;
FIG. 10 is a carbon spectrum diagram of flaviperine B, a compound prepared in example 2 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Example 1 of the present invention provides a method for synthesizing compound B used in the present invention, specifically as follows:
p-toluenesulfonic acid (2.27mmol) and 2,2,6, 6-tetramethylpiperidine oxide (2.34mmol) were mixed in 15mL of dichloromethane solution at 0 deg.C, stirring (400rpm) was continued for 10min under ice bath, the dichloromethane solution of this mixture was added to 7mL of dichloromethane solution of Compound G (0.38mmol), stirring (400rpm) was continued for 1h under ice bath, then the reaction was quenched with 10mL of saturated aqueous sodium bicarbonate solution at 0 deg.C (10min), extracted with ethyl acetate at 25 deg.C, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered under reduced pressure (500mbar), and concentrated under reduced pressure (150mbar) to give crude product, which was purified by silica gel column chromatography (V ethyl acetate: V petroleum ether ═ 30: 70) to give Compound B (143mg, 94% yield)
The assay data for compound B is as follows:
1 H NMR(400MHz,CDCl 3 ):δ＝8.25(d,J＝16.3Hz,1H),7.87(s,1H),6.46(d,J＝16.3Hz,1H),6.29(d,J＝11.2Hz,1H),5.40(s,1H),4.72(t,J＝7.2Hz,1H),3.70(d,J＝7.2Hz,1H),3.10(d,J＝4.3Hz,2H),2.69(d,J＝11.0Hz,1H),2.63–2.47(m,1H),2.33(d,J＝8.7Hz,2H),1.86–1.76(m,2H),1.77(s,3H),1.56–1.51(m,1H),1.29–1.25(m,2H),1.21(d,J＝7.3Hz,3H),1.18(s,3H),0.90(d,J＝6.5Hz,3H),0.79(d,J＝6.5Hz,3H)ppm；
13 C NMR(101MHz,CDCl 3 ):δ＝205.13,195.49,173.68,141.64,138.69,136.21,126.48,126.42,124.55,74.58,69.16,51.95,48.31,47.39,41.54,39.77,34.82,32.35,25.06,23.72,20.85,20.21,15.43,13.81ppm；
HRMS(m/z):[M+Na] + calcd for C 24 H 33 NO 4 Na + 422.2307,found 422.2302.
example 2
(1) Compound B (0.25mmol) was dissolved in 2.5mL of anhydrous pyridine at room temperature, and p-toluenesulfonic anhydride (0.50mmol) was added. Stirring (450rpm) for 1h, then quenching the reaction with 1mol/L aqueous hydrochloric acid (5mL) (10min), followed by extraction with ethyl acetate, washing with saturated aqueous sodium chloride, drying over anhydrous sodium sulfate, filtration under reduced pressure (500mbar), and concentration under reduced pressure (150mbar) to give crude which is purified by silica gel column chromatography (V ethyl acetate: V petroleum ether ═ 20: 80) to give compound C (131.7mg, 95% yield);
(2) compound C (0.216mmol)) was dissolved in 4.5mL of anhydrous tetrahydrofuran at room temperature, zinc powder (2.60mmol) and ammonium acetate (3.2mmol) were added, then the temperature was raised to 40 ℃ and stirred (300rpm) for 2h, then cooled to room temperature, filtered through celite (500mbar), concentrated under reduced pressure (150mbar) to give the crude product, which was purified by silica gel column chromatography (V ethyl acetate: v petroleum ether 50: 50) compound D (60.9mg, 73% yield) was obtained;
(3) compound D (0.13mmol) was dissolved in 2mL of anhydrous tetrahydrofuran at room temperature, scandium triflate (0.195mmol) was added, stirring (500rpm) for 2h, then the reaction was quenched with 2mL of saturated aqueous sodium bicarbonate solution (10min), extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered under reduced pressure (500mbar), and concentrated under reduced pressure (150mbar) to give crude product, which was purified by silica gel column chromatography (ethyl acetate: V petroleum ether 75: 25) to give compound E (43.7mg, yield 87%);
(4) dissolving the compound E (0.104mmol) in 0.3mL tetrahydrofuran at room temperature, adding manganese (II) acetylacetonate (0.01mmol) and phenylsilane (0.208mmol) sequentially, reacting for 10min under oxygen bubbling, reacting for 18h under oxygen atmosphere, quenching with 0.5mL saturated aqueous sodium thiosulfate (10min), extracting with ethyl acetate, washing with saturated aqueous sodium chloride, drying over anhydrous sodium sulfate, filtering under reduced pressure (500mbar), and concentrating under reduced pressure (150mbar) to obtain a crude product, which is purified by silica gel column chromatography (V dichloromethane: V methanol 92: 8) to obtain compound F (20.6mg, yield 49%);
(5) adding selenium dioxide (0.186mmol) into 0.3mL1, 4-dioxane solution of compound F (0.0372mmol) at 25 ℃, then stirring (500rpm) for 1h at 50 ℃, cooling to room temperature, quenching (10min) with 0.5mL saturated sodium thiosulfate aqueous solution, extracting with ethyl acetate, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering under reduced pressure (500mbar), and concentrating under reduced pressure (150mbar) to obtain crude compound which can be directly used in the next step without purification;
(6) the crude compound obtained in step (5) was dissolved in 0.3mL of methanol at 0 ℃ and cerium trichloride heptahydrate (0.111mmol) was added and stirred (400rpm) for 10 min. Then adding sodium borohydride (0.052mmol), continuously stirring (400rpm) for 10min, quenching the reaction with 0.5mL of saturated aqueous sodium bicarbonate solution at 0 ℃ for 10min, extracting with ethyl acetate, washing with saturated aqueous sodium chloride solution, drying with anhydrous sodium sulfate, filtering (500mbar), and concentrating under reduced pressure (150mbar) to obtain a crude product, and purifying the crude product by silica gel column chromatography (V dichloromethane: V methanol ═ 90: 10) to obtain the compound A, namely the compound flaviperine B (11.2mg, the yield of the two steps is 71%).
Example 3
(1) Compound B (0.25mmol) was dissolved in 0.5mL of anhydrous pyridine at room temperature, and p-toluenesulfonic anhydride (0.375mmol) was added. Stirring (450rpm) for 1h, then quenching the reaction with 1mol/L aqueous hydrochloric acid (5mL) (10min), followed by extraction with ethyl acetate, washing with saturated aqueous sodium chloride, drying over anhydrous sodium sulfate, filtration under reduced pressure (500mbar), and concentration under reduced pressure (150mbar) to give crude which is purified by silica gel column chromatography (V ethyl acetate: V petroleum ether ═ 20: 80) to give compound C (120mg, 86% yield);
(2) dissolving compound C (0.216mmol) in 0.43mL of anhydrous tetrahydrofuran at room temperature, adding zinc powder (2.17mmol) and ammonium acetate (2.6mmol), stirring (300rpm) at 40 ℃ for 2h, cooling to room temperature, filtering through celite (500mbar), concentrating under reduced pressure (150mbar) to give a crude product, which is purified by silica gel column chromatography (V ethyl acetate: V petroleum ether ═ 50: 50) to give compound D (49mg, 58% yield);
(3) dissolving compound D (0.13mmol) in 0.26mL of anhydrous tetrahydrofuran at room temperature, adding scandium trifluoromethanesulfonate (0.155mmol), stirring (500rpm) for 2h, then quenching the reaction with 2mL of saturated aqueous sodium bicarbonate solution (10min), extracting with ethyl acetate, washing with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, filtering under reduced pressure (500mbar), and concentrating under reduced pressure (150mbar) to give a crude product, which is purified by silica gel column chromatography (ethyl acetate: V petroleum ether: 75: 25) to give compound E (41mg, 82% yield);
(4) dissolving compound E (0.104mmol) in 0.2mL of tetrahydrofuran at room temperature, adding manganese (II) acetylacetonate (0.01mmol) and phenylsilane (0.155mmol) in this order, reacting for 10min under bubbling of oxygen, reacting for 18h under an oxygen atmosphere, then quenching with 0.5mL of saturated aqueous sodium thiosulfate (10min), extracting with ethyl acetate, washing with saturated aqueous sodium chloride, drying over anhydrous sodium sulfate, filtering under reduced pressure (500mbar), and concentrating under reduced pressure (150mbar) to give a crude product, which is purified by silica gel column chromatography (V dichloromethane: V methanol 92: 8) to give compound F (15mg, yield 36%);
(5) adding selenium dioxide (0.11mmol) into 0.1mL of 1, 4-dioxane solution of compound F (0.0372mmol) at 25 ℃, stirring (500rpm) for 1h at 50 ℃, cooling to room temperature, quenching (10min) with 0.5mL of saturated sodium thiosulfate aqueous solution, extracting with ethyl acetate, washing with saturated sodium chloride aqueous solution, drying over anhydrous sodium sulfate, filtering under reduced pressure (500mbar), and concentrating under reduced pressure (150mbar) to obtain crude compound which can be used in the next step without purification;
(6) dissolving the crude compound obtained in the step (5) in 0.3mL of methanol, adding cerous chloride heptahydrate (0.111mmol) and stirring at 0 ℃ for 10min (400rpm), then adding sodium borohydride (0.045mmol), continuously stirring at 400rpm for 10min, then quenching the reaction with 0.5mL of saturated aqueous sodium bicarbonate solution at 0 ℃ for 10min, extracting with ethyl acetate at room temperature, washing with saturated aqueous sodium chloride solution, drying with anhydrous sodium sulfate, filtering under reduced pressure (500mbar), and concentrating under reduced pressure (150mbar) to obtain a crude product, and purifying the crude product by silica gel column chromatography (V dichloromethane: V methanol is 90: 10) to obtain a compound A, namely the compound flavipesine B (9mg, the yield of the two steps is 60%).
Example 4
(1) Compound B (0.25mmol) was dissolved in 25mL of anhydrous pyridine at room temperature, and p-toluenesulfonic anhydride (0.625mmol) was added. Stirring (450rpm) for 1h, then quenching the reaction with 1mol/L aqueous hydrochloric acid (5mL) (10min), extracting with ethyl acetate, washing with saturated aqueous sodium chloride, drying over anhydrous sodium sulfate, filtering under reduced pressure (500mbar), and concentrating under reduced pressure (150mbar) to give crude product which is purified by silica gel column chromatography (V ethyl acetate: V petroleum ether ═ 20: 80) to afford compound C (100mg, yield 72%);
(2) compound C (0.216mmol)) was dissolved in 22mL of anhydrous tetrahydrofuran at room temperature, zinc powder (4.33mmol) and ammonium acetate (4.77mmol) were added, stirred (300rpm) at 40 ℃ for 2h, cooled to room temperature, filtered through celite (500mbar), concentrated under reduced pressure (150mbar) to give the crude product, which was purified by silica gel column chromatography (V ethyl acetate: v petroleum ether 50: 50) to give Compound D (55mg, 66% yield)
(3) Compound D (0.13mmol) was dissolved in 13mL of anhydrous tetrahydrofuran at room temperature, scandium triflate (0.33mmol) was added, stirring (500rpm) was continued for 2h, then the reaction was quenched with 2mL of saturated aqueous sodium bicarbonate solution (10min), extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered under reduced pressure (500mbar), and concentrated under reduced pressure (150mbar) to give a crude product, which was purified by silica gel column chromatography (ethyl acetate: V petroleum ether 75: 25) to give compound E (42mg, 84% yield);
(4) compound E (0.104mmol) was dissolved in 10mL of tetrahydrofuran at room temperature, manganese (II) acetylacetonate (0.02mmol) and phenylsilane (0.26mmol) were added in this order, the mixture was reacted under bubbling of oxygen for 10min, then reacted under oxygen for 18h, then quenched with 0.5mL of saturated aqueous sodium thiosulfate solution (10min), extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered under reduced pressure (500mbar), and concentrated under reduced pressure (150mbar) to give a crude product, which was purified by silica gel column chromatography (V dichloromethane: V methanol: 92: 8) to give Compound F (5mg, yield 12%)
(5) Adding selenium dioxide (0.22mmol) into 3.72mL of 1, 4-dioxane solution of compound F (0.0372mmol) at 25 ℃, stirring at 50 ℃ for 1h at 500rpm, cooling to room temperature, quenching with 0.5mL of saturated aqueous sodium thiosulfate solution (10min), extracting with ethyl acetate, washing with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, filtering under reduced pressure (500mbar), and concentrating under reduced pressure (150mbar) to obtain crude compound which can be used in the next step without purification
(6) The crude compound obtained in step (5) was dissolved in 0.3mL of methanol at 0 ℃ and cerium trichloride heptahydrate (0.111mmol) was added and stirred (400rpm) for 10 min. Then adding sodium borohydride (0.059mmol), continuing stirring (400rpm) for 10min, then quenching the reaction with 0.5mL saturated aqueous sodium bicarbonate solution at 0 ℃ (10min), extracting with ethyl acetate at room temperature, washing with saturated aqueous sodium chloride solution, drying with anhydrous sodium sulfate, filtering under reduced pressure (500mbar), and concentrating under reduced pressure (150mbar) to obtain a crude product, and purifying the crude product by silica gel column chromatography (V dichloromethane: V methanol ═ 90: 10) to obtain compound A, namely compound flaviperine B (8.5mg, the yield of the two steps is 57%).
Example 5
Each compound synthesized in example 2 was tested, and the test data is as follows:
wherein, the detection data of the compound C are as follows:
fig. 1 is a hydrogen spectrum of compound C, with specific peaks: 1 H NMR(400MHz,Chloroform-d):δ＝8.30(d,J＝16.5Hz,1H),7.80(d,J＝8.0Hz,2H),7.33(d,J＝7.8Hz,2H),6.77(brs,1H),6.30(d,J＝11.8Hz,1H),6.25(d,J＝16.6Hz,1H),5.50(d,J＝8.1Hz,1H),5.37(s,1H),3.18(t,J＝4.5Hz,1H),3.12(dd,J＝10.0,4.7Hz,1H),2.66(d,J＝11.2Hz,1H),2.42(s,3H),2.38–2.21(m,3H),2.03–1.95(m,1H),1.92–1.81(m,1H),1.77(s,3H),1.60–1.50(m,1H),1.41–1.26(m,2H),1.22(d,J＝7.2Hz,3H),1.14(s,3H),0.91(d,J＝5.4Hz,3H),0.90(d,J＝5.0Hz,3H)ppm；
fig. 2 is a carbon spectrum of compound C, with specific peaks: 13 C NMR(101MHz,Chloroform-d):δ＝197.26,195.55,172.87,145.07,141.78,139.96,135.25,133.21,129.93,128.07,127.50,126.49,124.29,79.38,68.87,51.71,48.28,47.44,41.34,38.81,34.72,29.31,25.26,23.76,21.71,21.24,20.18,15.30,13.86ppm；
[α]26D＝-53.7(c＝0.62in CHCl 3 )；
IR(film):ν max ＝3411,3246,2959,2931,2870,1691,1617,1442,1368,1295,1190,1176,1034,898cm -1 ；
HRMS(m/z):[M+Na] + calcd for C 31 H 39 NO 6 SNa + 576.2390,found 576.2390.
the assay data for compound D are as follows:
fig. 3 is a hydrogen spectrum of compound D, with specific peaks: 1 H NMR(400MHz,Chloroform-d):δ＝6.55(s,1H),6.21(d,J＝10.7Hz,1H),5.36(s,1H),3.85(ddd,J＝17.5,11.5,2.6Hz,1H),3.14(brs,1H),2.99(d,J＝10.6Hz,1H),2.79(ddd,J＝14.0,11.5,2.8Hz,1H),2.70(ddd,J＝13.6,8.1,2.5Hz,1H),2.64–2.50(m,3H),2.39(ddd,J＝17.6,8.2,2.8Hz,1H),2.31–2.19(m,1H),2.20–2.11(m,1H),2.07(dd,J＝17.0,7.8Hz,1H),1.96(td,J＝13.0,3.9Hz,1H),1.73(s,3H),1.65–1.47(m,2H),1.34(s,3H),1.25–1.07(m,2H),1.18(d,J＝6.9Hz,3H),0.91(d,J＝3.9Hz,3H),0.89(d,J＝3.9Hz,3H).ppm；
fig. 4 is a carbon spectrum of compound D, with specific peaks: 13 C NMR(101MHz,Chloroform-d):δ＝208.40,208.24,176.04,139.81,137.69,125.93,124.43,67.14,52.66,50.82,48.73,43.34,41.31,39.20,38.04,37.66,35.37,25.14,23.76,21.54,20.07,19.98,14.84,13.52ppm；
[α]26D＝-70.3(c＝0.69in CHCl 3 )；
IR(film):ν max ＝3434,3202,2957,2928,2871,1690,1440,1416,1385,1222,1143,1125,1051,913cm -1 ；
HRMS(m/z):[M+H] + calcd for C 24 H 36 NO 3 + 386.2690,found 386.2697.
the assay data for compound E is as follows:
fig. 5 is a hydrogen spectrum of compound E, with specific peaks: 1 H NMR(400MHz,Methanol-d 4 ):δ＝5.47(s,1H),4.84(s,1H),4.39(s,1H),3.27–3.22(m,1H),3.20(dt,J＝4.4,2.6Hz,1H),2.56(t,J＝7.3Hz,1H),2.33–2.20(m,2H),2.19–2.08(m,3H),2.08–1.99(m,2H),1.91(ddd,J＝12.5,9.8,5.0Hz,1H),1.84–1.78(m,3H),1.75–1.72(m,1H),1.74(s,3H),1.67–1.56(m,1H),1.44(td,J＝12.7,4.5Hz,1H),1.34–1.17(m,2H),1.24(d,J＝7.2Hz,3H),0.93(d,J＝4.3Hz,3H),0.91(d,J＝4.4Hz,3H)ppm；
fig. 6 is a carbon spectrum of compound E, with specific peaks: 13 C NMR(101MHz,Methanol-d 4 ):δ＝179.17,149.62,138.77,127.56,109.40,107.10,84.64,60.55,52.50,51.06,48.51,47.90,38.41,38.24,37.67,36.98,35.36,30.86,25.87,25.30,24.15,22.11,20.11,13.69ppm；
[α]26D＝+86.2(c＝0.63in CHCl 3 )；
IR(film):ν max ＝3444,3272,2956,2933,2865,1678,1465,1384,1288,1264,1143,1060,908,890cm -1 ；
HRMS(m/z):[M+H] + calcd for C 24 H 36 NO 3 + 386.2690,found 386.2696.
the assay data for compound F are as follows:
fig. 7 is a hydrogen spectrum of compound F, with specific peaks: 1 H NMR(400MHz,Methanol-d 4 ):δ＝6.28(s,1H),3.15(dt,J＝9.7,3.5Hz,1H),2.96(d,J＝11.7Hz,1H),2.52(t,J＝7.1Hz,1H),2.33–2.25(m,1H),2.22–2.11(m,2H),2.08(dd,J＝5.5,2.7Hz,1H),1.86(ddd,J＝15.0,12.5,3.8Hz,1H),1.79–1.71(m,2H),1.75(s,3H),1.70–1.67(m,2H),1.67–1.51(m,5H),1.32–1.15(m,2H),1.23(d,J＝7.1Hz,3H),1.06(s,3H),0.92(d,J＝5.1Hz,3H),0.91(d,J＝5.2Hz,3H)ppm；
fig. 8 is a carbon spectrum of compound F, with specific peaks: 13 C NMR(151MHz,Methanol-d 4 ):δ＝179.34,138.23,127.84,106.96,84.35,74.45,60.66,52.46,51.71,50.35,48.21,44.67,39.34,39.23,36.57,35.42,33.17,25.90,24.22,22.05,21.95,21.09,20.45,13.78ppm；
[α]26D＝+44.8(c＝0.25inMeOH)；
IR(film):ν max ＝3436,2959,2933,2867,1673,1459,1448,1383,1296,1120,1061,1014,985,833cm -1 ；
HRMS(m/z):[M+Na] + calcd for C 24 H 37 NO 4 Na + 426.2615,found 426.2615.
the detection data of the compound flaviperine B are as follows:
fig. 9 is a hydrogen spectrum of compound flaviperine B, and the specific peak values are: 1 H NMR(400MHz,Methanol-d 4 ):δ＝6.51(s,1H),4.04(s,2H),3.28(dd,J＝6.4,3.6Hz,1H),3.00(d,J＝11.7Hz,1H),2.59(t,J＝7.5Hz,1H),2.31(dd,J＝11.8,4.3Hz,1H),2.25–2.10(m,2H),2.08(dd,J＝5.6,2.7Hz,1H),1.86(ddd,J＝14.6,12.3,3.7Hz,1H),1.81–1.71(m,2H),1.70–1.51(m,6H),1.35–1.25(m,1H),1.31(d,J＝7.1Hz,3H),1.19(ddd,J＝13.4,9.4,4.0Hz,1H),1.06(s,3H),0.92(d,J＝4.3Hz,3H),0.90(d,J＝4.3Hz,3H)ppm；
fig. 10 is a carbon spectrum of the compound flaviperine B, and the specific spectrum peak values are as follows: 13 C NMR(151MHz,Methanol-d 4 ):δ＝179.05,141.82,131.00,106.97,84.33,74.45,64.20,60.84,52.58,51.49,50.26,48.14,44.57,39.31,39.21,36.05,35.39,33.15,25.98,24.23,22.16,21.97,21.09,12.93ppm；
[α]26D＝+25.5(c＝0.17inMeOH)；
IR(film):ν max ＝3422,2957,2931,2867,1674,1461,1382,1294,1222,1145,1059,1013,985,820cm -1 ；
HRMS(m/z):[M+Na] + calcd for C 24 H 37 NO 5 Na + 442.2564,found 442.2567.
the embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other. The device disclosed by the embodiment corresponds to the method disclosed by the embodiment, so that the description is simple, and the relevant points can be referred to the method part for description.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (9)
1. A method for synthesizing a cytochalasin compound flaviperine B, wherein the structural formula of the compound flaviperine B is as follows:
the method is characterized in that the synthesis path is as follows:
the method comprises the following specific steps:
(1) dissolving the compound B in anhydrous pyridine, adding p-toluenesulfonic anhydride, stirring at room temperature for 1-2h, then quenching with 1mol/L hydrochloric acid aqueous solution for reaction, extracting with ethyl acetate, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering under reduced pressure, concentrating under reduced pressure in vacuum to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain a compound C;
(2) dissolving the compound C in anhydrous tetrahydrofuran, adding zinc powder and ammonium acetate, stirring at 40-50 deg.C for 2-3h, cooling to room temperature, filtering with diatomite, vacuum concentrating to obtain crude product, and purifying with silica gel column chromatography to obtain compound D;
(3) dissolving the compound D in anhydrous tetrahydrofuran, adding scandium trifluoromethanesulfonate, stirring at room temperature for 2-3h, then quenching the reaction by using a saturated sodium bicarbonate aqueous solution, extracting by using ethyl acetate, washing by using a saturated sodium chloride aqueous solution, drying by using anhydrous sodium sulfate, filtering under reduced pressure, concentrating under reduced pressure in vacuum to obtain a crude product, and purifying the crude product by using a silica gel column chromatography to obtain a compound E;
(4) dissolving a compound E in tetrahydrofuran, sequentially adding manganese (II) acetylacetonate and phenylsilane, continuously introducing oxygen into the solution, reacting for 10-20min, continuing to react for 18-20h under the oxygen atmosphere, quenching by using a saturated sodium thiosulfate aqueous solution, extracting by using ethyl acetate, washing by using a saturated sodium chloride aqueous solution, drying by using anhydrous sodium sulfate, filtering under reduced pressure, concentrating under reduced pressure in vacuum to obtain a crude product, and purifying the crude product by using a silica gel column chromatography to obtain a compound F;
(5) adding selenium dioxide into the stirred 1, 4-dioxane solution of the compound F, then continuing stirring for 1-2h at 50-65 ℃, cooling to room temperature, then quenching by saturated sodium thiosulfate aqueous solution, extracting by ethyl acetate, washing by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, filtering under reduced pressure, and concentrating under reduced pressure under vacuum to obtain a crude compound;
(6) and (3) dissolving the crude product compound obtained in the step (5) in methanol at 0 ℃, adding cerium trichloride heptahydrate, stirring for 10-20min, then adding sodium borohydride, stirring for 10-20min, then quenching by using a saturated sodium bicarbonate aqueous solution, extracting by using ethyl acetate, washing by using a saturated sodium chloride aqueous solution, drying by using anhydrous sodium sulfate, filtering under reduced pressure, concentrating under reduced pressure in vacuum to obtain a crude product, and purifying the crude product by using a silica gel column chromatography to obtain the compound A.
2. The method for synthesizing the cytochalasin compound flaviperine B as claimed in claim 1, wherein the molar ratio of the compound B to the p-toluenesulfonic anhydride in the step (1) is (1: 1.5) - (1: 2.5), and the concentration of the solution of the compound B dissolved in the anhydrous pyridine is 0.01-0.5 mol/L.
3. The method for synthesizing the cytochalasin compound flaviperine B as claimed in claim 1, wherein the molar ratio of the compound C to the zinc powder to the ammonium acetate in the step (2) is (1: 10: 12) - (1: 20: 22), and the concentration of the solution of the compound C dissolved in the anhydrous tetrahydrofuran is 0.01-0.5 mol/L.
4. The method for synthesizing the cytochalasin compound flaviperine B as claimed in claim 1, wherein the molar ratio of the compound D to the scandium trifluoromethanesulfonate in the step (3) is (1: 1.2) - (1: 2.5), and the concentration of the solution of the compound D dissolved in the anhydrous tetrahydrofuran is 0.01-0.5 mol/L.
5. The method for synthesizing the cytochalasin compound flaviperine B as claimed in claim 1, wherein the molar ratio of the compound E to the manganese (II) acetylacetonate to the phenylsilane in step (4) is (1: 0.1: 1.5) - (1: 0.2: 2.5), and the concentration of the solution of the compound E dissolved in the tetrahydrofuran is 0.01-0.5 mol/L.
6. The method for synthesizing the cytochalasin compound flavipesine B as claimed in claim 1, wherein the molar ratio of the compound F to the selenium dioxide in the step (5) is (1: 3) - (1: 6), and the concentration of the 1, 4-dioxane solution of the compound F is 0.01-0.5 mol/L.
7. The method for synthesizing the cytochalasin B as claimed in any one of claims 1-6, wherein the quenching time in the quenching reaction in any one of steps (1) and (3) - (6) is 10-15 min; the vacuum degree of the reduced pressure filtration is 50-600 mbar; vacuum degree of reduced pressure concentration is 50-600 mbar.
8. The method for synthesizing the cytochalasin compound flaviperine B as claimed in any one of claims 1-6, wherein the eluent used for the silica gel column chromatography purification in any one of steps (1) - (3) is ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is (20: 80) - (90: 10).
9. The method for synthesizing the cytochalasin B as claimed in any one of claims 1-6, wherein the eluents used for silica gel column chromatography purification in steps (4) and (6) are dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is (99: 1) - (85: 15).
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| Biomimetic Synthesis of (+)‐Aspergillin PZ;Julius R. Reyes,et al;《Angewandte Chemie International Edition》;20181231;第57卷(第47期);第15587-15591页 * |
| Biosynthetically Inspired Divergent Syntheses;Xianwen Long, et al;《Chem》;20210114;第7卷(第1期);第212–223页 * |
| Flavipesines A and B and Asperchalasines E-H: Cytochalasans and Merocytochalasans from Aspergillus flavipes;Xiaotian Zhang,et al;《Journal of Natural Products》;20191231;第82卷(第11期);第2994-3001页 * |
| Total Syntheses of Asperchalasines A–E;Ruiyang Bao,et al;《Angewandte Chemie》;20181231;第130卷(第43期);第14412-14416页 * |
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