CN108101879B - Polycyclic lactone compound and preparation method thereof - Google Patents
Polycyclic lactone compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a polycyclic lactone compound and a preparation method thereof, wherein the polycyclic lactone compound has a chemical structure shown in a formula 9:
wherein: r is selected from hydrogen or C1～C8An alkyl group. The polycyclic lactone compounds can be used for synthesizing the benastatin compounds with polycyclic lactone structures and derivatives thereof or other natural products with similar structures; in addition, the preparation method of the polycyclic lactone compound has the advantages of simple operation, safety, no pollution, no special requirement on equipment, low production cost and the like, and has extremely high practical value for realizing the industrial preparation of the polycyclic lactone compound.
Description
Technical Field
The invention relates to a polycyclic lactone compound and a preparation method thereof, belonging to the technical field of pharmaceutical chemistry.
Background
Has the advantages of
(dotted line indicates optional double bond) structure of polycyclic lactones generally have good biological activity, such as: the research shows that the compound has the activity of preventing malignant cell diffusion, and the research shows that the compound has the activity of preventing malignant cell diffusionThe structural formulas are respectively as follows:
at present, the synthesis has
(dotted line indicates optional double bond) structure of polycyclic lactones have been reported less, and no synthesis of polycyclic lactones having such a structure has been reported
(dotted line represents optional double bond) structure of benastatin compound or derivative, and research finds that application of benastatin compound or derivative with optional double bond structure
(R is hydrogen or C1～C8Alkyl) structure, and can obtain Benastatin (Benastatin) medicaments or derivatives thereof through simple chemical reaction
(R is hydrogen or C1～C8Alkyl, dotted line represents an optional double bond), and
the existence of the alkyne bond also lays a foundation for finally synthesizing the Benastatin (Benastatin) medicaments or derivatives thereof, and simultaneously
The site which can be transformed is more, and a new way is provided for synthesizing other compounds with similar structures or natural products.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a polycyclic lactone compound and a preparation method thereof.
The polycyclic lactone compound has a chemical structure shown in a formula 9:
Preferably, R is selected from hydrogen or C1～C4Alkyl (preferably methyl, ethyl or propyl).
A method for preparing a polycyclic lactone compound shown as a formula 9 comprises the following steps of h, g-h, f-g-h, e-f-g-h, d-e-f-g-h, c-d-e-f-g-h, b-c-d-e-f-g-h, a-b-c-d-e-f-g-h or a-b-c-d-e-f-g-h in the following synthetic route:
wherein: ra is selected from C1～C8Alkyl (preferably C)1～C4Alkyl, preferably methyl, ethyl or propyl).
Preferably, step a is carried out by reacting the compound of formula 1 with an Ra alkylating agent in the presence of a base to obtain the compound of formula 2.
In a further preferred embodiment, in step a, the base is an inorganic base or an organic base, and the inorganic base is selected from any one or a mixture of more than two of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and barium hydroxide; the organic base is selected from one or a mixture of more than two of sodium alkoxide, triethylamine, diisopropylethylamine, pyridine, 2-hydroxypyridine, piperidine, N-methylpiperidine, morpholine and N-methylmorpholine.
In a further preferable embodiment, in the step a, the reaction temperature is 50 to 70 ℃, and the reaction solvent is any one selected from N, N-dimethylformamide, acetone, tetrahydrofuran, acetonitrile and dioxane.
As a further preferred embodiment, in step a, a compound of formula 1: alkali: molar ratio of Ra alkylating agent 1: (1-2): (1-2).
Preferably, step b is to selectively remove the Ra alkyl protection from the compound of formula 2 in the presence of a dealkylating agent to obtain the compound of formula 3.
As a further preferred embodiment, in step b, the dealkylating agent is a lewis acid, such as: aluminum trichloride, boron trichloride, ferric chloride and antimony pentafluoride, wherein boron trichloride is preferred.
In a further preferred embodiment, in step b, the reaction solvent is selected from any one of dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane.
In a further preferable embodiment, in the step b, the molar ratio of the compound of formula 2 to the dealkylating agent is 1:1 to 1: 2.
Preferably, the step c is to perform sonogashira coupling reaction of the compound of formula 3 and triisopropyl silyl acetylene to obtain the compound of formula 4.
As a further preferred solution, the operation of step c is as follows: the compound of the formula 3 is subjected to sonogashira coupling reaction with triisopropyl silyl acetylene at 75-85 ℃ in a mixed solvent of an organic solvent and an organic base under the catalysis of a palladium catalyst and cuprous iodide to obtain the compound of the formula 4.
In a further preferable mode, in the step c, the volume ratio of the organic solvent to the organic base in the mixed solvent is (4-6): 1.
As a further preferable mode, in the step c, the organic solvent is N, N-dimethylformamide.
In a further preferred embodiment, in step c, the organic base is selected from one or a mixture of more than two of triethylamine, diisopropylethylamine, pyridine, 2-hydroxypyridine, piperidine, N-methylpiperidine, morpholine and N-methylmorpholine.
As a still further preferred embodiment, in step c, the palladium catalyst is bis triphenylphosphine palladium dichloride.
In a further preferable mode, in the step c, the molar ratio of the compound shown in the formula 3 to the triisopropylsilylacetylene is 1: 1-1: 2.
Preferably, said step d is to react the compound of formula 4 with trifluoromethanesulfonic anhydride in the presence of a base to obtain the compound of formula 5.
In a further preferred embodiment, in step d, the base is an inorganic base or an organic base, and the inorganic base is selected from any one or a mixture of more than two of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and barium hydroxide; the organic base is selected from one or a mixture of more than two of sodium alkoxide, triethylamine, diisopropylethylamine, pyridine, 2-hydroxypyridine, piperidine, N-methylpiperidine, morpholine and N-methylmorpholine.
As a further preferred embodiment, in step d, a compound of formula 4: trifluoromethanesulfonic anhydride: the molar ratio of the alkali is 1: (1-2): (2-4).
In a further preferred embodiment, in step d, the reaction solvent is selected from any one of dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane.
Preferably, said step e is performed by reacting a compound of formula 5 with
Carrying out the sonogashira coupling reaction to obtain the compound of formula 6.
As a further preferred solution, the operation of step e is as follows: the compound of formula 5 is reacted with organic base in the mixed solvent of organic solvent and organic base under the catalysis of palladium catalyst and cuprous iodide
Carrying out sonogashira coupling reaction at 75-85 ℃ to obtain the compound of formula 6.
In a further preferable mode, in the step e, the volume ratio of the organic solvent to the organic base in the mixed solvent is (4-6): 1.
As a further preferable mode, in the step e, the organic solvent is N, N-dimethylformamide.
In a further preferred embodiment, in step e, the organic base is selected from one or a mixture of more than two of triethylamine, diisopropylethylamine, pyridine, 2-hydroxypyridine, piperidine, N-methylpiperidine, morpholine and N-methylmorpholine.
As a still further preferred embodiment, in step e, the palladium catalyst is bis triphenylphosphine palladium dichloride.
As a further preferred embodiment, in step e, the compound of formula 5 is reacted with
The molar ratio of (a) to (b) is 1:1 to 1: 2.
Preferably, the compound of formula 7 is obtained by cyclization reaction of the compound of formula 6 in the presence of an indium catalyst in step f.
In a further preferred embodiment, in step f, the reaction solvent is a mixed solvent of 1, 2-dichloroethane and trifluoroacetic acid.
In a further preferred embodiment, in step f, the volume ratio of 1, 2-dichloroethane to trifluoroacetic acid is (3-5): 1.
As a further preferable scheme, in the step f, 1mmol of the compound of the formula 6 needs to be added with (5-15) mL of a mixed solvent of 1, 2-dichloroethane and trifluoroacetic acid.
As a further preferable embodiment, in step f, the indium catalyst is indium tribromide.
In a further preferable embodiment, in the step f, the molar ratio of the compound of formula 6 to the indium catalyst is 2:1 to 4: 1.
Preferably, the step g is to remove the TIPS (i.e., triisopropylsilyl) protection on alkyne from the compound of formula 7 in the presence of quaternary ammonium salt to obtain the compound of formula 8.
In a further preferred embodiment, in step g, the quaternary ammonium salt is tetrabutylammonium fluoride.
In a further preferable embodiment, in the step g, the molar ratio of the compound of formula 7 to the quaternary ammonium salt is 1:1 to 1: 2.
In a further preferred embodiment, in step g, the reaction solvent is selected from any one of acetone, tetrahydrofuran, acetonitrile, and dioxane.
Preferably, step h is performed by removing the Ra alkyl protection from the compound of formula 8 in the presence of a dealkylating agent to obtain the compound of formula 9.
As a further preferred embodiment, in step h, the dealkylating agent is a lewis acid, such as: aluminum trichloride, boron trichloride, ferric chloride and antimony pentafluoride, wherein boron trichloride is preferred.
In a further preferred embodiment, in step h, the reaction solvent is any one selected from dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane.
In a further preferable embodiment, in the step h, the molar ratio of the compound of formula 8 to the dealkylating agent is 1:1 to 1: 2.
Compared with the prior art, the invention has the following remarkable beneficial effects:
the polycyclic lactone compounds of the invention can be modified at more sites, and provide a new chemical synthesis way for synthesizing benastatin compounds and derivatives thereof and other natural products with similar structures; in addition, the preparation method of the polycyclic lactone compound has the advantages of simple operation, safety, no pollution, no special requirement on equipment, low production cost and the like, and has extremely high practical value for realizing the industrial preparation of the polycyclic lactone compound.
Detailed Description
The technical scheme of the invention is further detailed and completely explained by combining the embodiment.
Example 1: preparation of the polycyclic lactone compounds
Step a: preparing a compound represented by formula 2:
the compound of formula 1 (8.08g,25.58mmol) was dissolved in N, N-dimethylformamide (64mL), potassium carbonate (7.78g,56.27mmol) and dimethyl sulfate (5.09mL,53.72mmol) were added, and then reacted at 60 ℃ for 21.5 hours to terminate the reaction, the reaction solution was cooled to room temperature, quenched with a saturated ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, the resulting organic phase was washed twice with water, once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (5% ethyl acetate/petroleum ether) to give the compound of formula 2 (7.74g, yield 88%) with Rf 0.56 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(300MHz,CDCl3)δ6.46(s,2H),3.91(s,3H),3.83(s,6H)ppm；
13C NMR(100MHz,CDCl3δ165.45,158.06(2C),151.22,118.61(q,J＝320.8Hz),112.81,97.85(2C),56.39(2C),52.69ppm；
HRMS–EI(m/z):[M]+calcd for C11H11F3O7S,344.0178；found,344.0176。
step b: preparing a compound represented by formula 3:
the compound of formula 2 (7.77g,22.58mmol) was dissolved in dichloromethane (113mL), an n-hexane solution of boron trichloride (1.0M, 22.58mL) was dropwise added at-78 ℃ under nitrogen protection, the reaction was terminated after completion of the dropwise addition, reaction was carried out at room temperature for 10.5 hours, the reaction was terminated, saturated ammonium chloride was quenched, extraction was carried out with ethyl acetate, the organic phases were combined, the resulting organic phase was dried over anhydrous sodium sulfate, filtration and concentration were carried out, and the residue was separated by column chromatography (2% ethyl acetate/petroleum ether) to obtain a compound of formula 3 (5.21g, yield 70%) having Rf of 0.63 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,CDCl3)δ11.88(s,1H),6.52(d,J＝2.4Hz,1H),6.31(d,J＝2.4Hz,1H),3.95(s,3H),3.88(s,3H)ppm；
13C NMR(125MHz,CDCl3)δ170.82,164.89,162.28,153.75,118.60(q,J＝320.7Hz),102.94,102.92,96.18,56.56,52.76ppm；
HRMS–EI(m/z):[M]+calcd for C10H9F3O7S,330.0021；found,330.0019。
step c: preparing a compound represented by formula 4:
dissolving the compound of formula 3 (5.21g,15.80mmol) in a mixed solvent of N, N-dimethylformamide (65mL) and triethylamine (15mL), adding bis-triphenylphosphine palladium dichloride (554.5mg,0.79mmol) and cuprous iodide (150.5mg,0.79mmol), freezing with liquid nitrogen to remove oxygen three times, adding triisopropylsilylacetylene (7.08mL,31.60mmol), reacting at 80 ℃ for 0.5 hour, finishing the reaction, cooling the reaction solution to room temperature, adding saturated ammonium chloride to quench, extracting with ethyl acetate, combining the organic phases, washing the obtained organic phases three times with distilled water, washing once with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating, separating the residue with column chromatography (2% ethyl acetate/petroleum ether) to obtain the compound of formula 4 (5.47g, 96% yield), Rf ═ 0.63 (5% ethyl acetate/petroleum ether).
Through the test:1H NMR(300MHz,CDCl3)δ11.52(s,1H),6.72(s,1H),6.47(s,1H),3.95(s,3H),3.87(s,3H),1.13(s,21H)ppm；
13C NMR(100MHz,CDCl3)δ171.22,163.22,160.48,129.88,113.86,105.91,105.46,103.16,94.28,56.29,52.55,18.62(6C),11.23(3C)ppm；
HRMS–EI(m/z):[M]+calcd for C20H30O4Si,362.1913；found,362.1914。
step d: preparing a compound represented by formula 5:
dissolving the compound of formula 4 (5.45g, 15.04mmol) in dry dichloromethane (75mL), adding triethylamine (6.25mL,45.12mmol) at 0 ℃ under nitrogen protection, stirring for 5 minutes, dropwise adding trifluoromethanesulfonic anhydride (2.54mL,18.05mmol), reacting at room temperature for 4 hours after completion of dropwise addition, terminating the reaction, quenching the reaction solution with saturated ammonium chloride, extracting with ethyl acetate, combining the organic phases, washing the resulting organic phase with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering, concentrating, and separating the residue by column chromatography (2% ethyl acetate/petroleum ether) to obtain the compound of formula 5 (6.95g, yield 94%), Rf 0.42 (5% ethyl acetate/petroleum ether).
Through the test:1H NMR(300MHz,CDCl3)δ6.99(s,2H),3.93(s,3H),3.90(s,3H),1.15–1.10(m,21H)ppm；
13C NMR(125MHz,CDCl3)δ163.01,158.01,146.53,127.54,118.42(t,J＝317.5Hz,1C),117.37,117.02,114.43,104.11,95.63,56.65,52.84,18.60(6C),11.20(3C)ppm；
HRMS–EI(m/z):[M]+calcd for C21H29O6SiSF3,494.1406；found,494.1404。
step e: preparing a compound represented by formula 6:
dissolving the compound of formula 5 (6.95g,14.06mmol) in a mixed solvent of N, N-dimethylformamide (60mL) and triethylamine (12mL), adding bis triphenylphosphine palladium dichloride (986.9mg,1.41mmol) and cuprous iodide (267.8mg,1.41mmol), freezing with liquid nitrogen to remove oxygen three times, adding 1-pentyne (2.77mL, 28.12mmol), then reacting at 80 ℃ for 1 hour, cooling the reaction solution to room temperature, adding saturated ammonium chloride to quench, extracting with ethyl acetate, combining the organic phases, washing the obtained organic phases twice with distilled water, washing once with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating, and separating the residue by column chromatography (2% ethyl acetate/petroleum ether) to obtain the compound of formula 6 (5.30g, yield 91%), Rf ═ 0.42 (5% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,CDCl3)δ7.14(d,J＝1.2Hz,1H),6.88(d,J＝1.3Hz,1H),3.90(s,3H),3.82(s,3H),2.35(t,J＝7.0Hz,2H),1.58(h,J＝7.2Hz,2H),1.12(s,21H),1.01(t,J＝7.4Hz,3H)ppm；
13C NMR(100MHz,CDCl3)δ167.15,155.82,128.07,126.05,125.53,122.96,113.42,105.55,94.71,92.37,77.03,56.01,52.39,21.95,21.35,18.59(6C),13.41,11.19(3C)ppm；
HRMS–EI(m/z):[M]+calcd for C25H36O3Si,412.2434；found,412.2432。
step f: preparing a compound represented by formula 7:
dissolving the compound of formula 6 (2.0g, 4.85mmol) in a mixed solvent of 1, 2-dichloromethane (20mL) and trifluoroacetic acid (5mL), adding indium tribromide (516.0mg,1.46mmol), reacting at room temperature for 4 days to terminate the reaction, slowly pouring the reaction solution into a saturated sodium bicarbonate solution to quench, extracting with ethyl acetate, combining the organic phases, washing the obtained organic phases with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering, concentrating, and separating the residue by column chromatography (5% -10% ethyl acetate/petroleum ether) to obtain the compound of formula 7 (1.86g, 96% yield), Rf ═ 0.50 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,CDCl3)δ6.98(d,J＝1.3Hz,1H),6.89(d,J＝1.3Hz,1H),6.09(s,1H),3.99(s,3H),2.44(t,J＝7.5Hz,2H),1.70(h,J＝7.4Hz,2H),1.17–1.12(m,21H),0.96(t,J＝7.4Hz,3H)ppm；
13C NMR(125MHz,CDCl3)δ161.22,159.37,159.14,140.41,130.58,120.73,112.01,108.56,105.57,102.42,95.34,56.38,35.17,20.02,18.62(6C),13.43,11.22(3C)ppm；
HRMS–EI(m/z):[M]+calcd for C24H34O3Si,398.2277；found,398.2284。
step g: preparing a compound represented by formula 8:
dissolving the compound of formula 7 (1.83g,4.58mmol) in dry tetrahydrofuran (23mL), adding tetrabutylammonium fluoride (1M tetrahydrofuran, 4.82mL) under nitrogen protection, then reacting at room temperature for 1 hour, ending the reaction, adding methanol to the reaction solution and quenching, adding calcium carbonate (2.29g,22.9mmol) and ion exchange resin (3.03g) and stirring for 15 minutes, filtering with celite, concentrating, and separating the residue with column chromatography (10% -20% ethyl acetate/petroleum ether) to obtain the compound of formula 8 (841.9mg, yield 77%) with Rf of 0.24 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,CDCl3)δ7.00(d,J＝1.4Hz,1H),6.94(d,J＝1.4Hz,1H),6.09(d,J＝0.9Hz,1H),3.99(s,3H),3.26(s,1H),2.45(t,J＝7.5Hz,2H),1.83–1.65(m,2H),0.97(t,J＝7.4Hz,3H)ppm；
13C NMR(125MHz,CDCl3)δ161.24,159.38,159.24,140.52,129.23,120.71,112.27,109.03,102.39,82.36,80.59,56.40,35.20,20.07,13.46ppm；
HRMS–EI(m/z):[M]+calcd for C15H14O3,242.0943；found,242.0942。
step h: preparing a polycyclic lactone compound shown as a formula 9:
dissolving a compound (750mg,3.10mmol) shown in the formula 8 in dry dichloromethane (15mL), dropwise adding a boron trichloride solution (1M n-hexane, 3.41mL) at-78 ℃ under the protection of nitrogen, reacting at room temperature for 0.5 hour after dropwise adding, finishing the reaction, adding saturated ammonium chloride into the reaction liquid, quenching, extracting with ethyl acetate, combining organic phases, washing the obtained organic phases with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating, and separating residues by column chromatography (5% -10% ethyl acetate/petroleum ether) to obtain a polycyclic lactone compound (688.8mg, yield 97%) shown in the formula 9, wherein Rf is 0.75 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,CDCl3)δ10.98(s,1H),6.99(d,J＝1.3Hz,1H),6.92(d,J＝1.3Hz,1H),6.21(s,1H),3.26(s,1H),2.49(t,J＝7.5Hz,2H),1.72(q,J＝7.4Hz,2H),0.99(t,J＝7.4Hz,3H)ppm；
13C NMR(100MHz,CDCl3)δ166.37,161.19,158.19,137.84,130.80,118.82,117.68,105.85,103.62,82.19,80.88,35.14,20.10,13.43ppm；
HRMS–EI(m/z):[M]+calcd for C14H12O3,228.0786；found,228.0787。
example 2: application of polycyclic lactone compounds in preparation of benastatin G
Step 1): preparing a compound of formula 11:
dissolving a compound of formula 10 (3.51g,19.49mmol) in N, N-dimethylformamide (20mL), slowly adding phosphorus oxychloride (2.68mL,29.23mmol) dropwise at 0 ℃ under nitrogen protection, stirring at 90 ℃ for 3 hours after the dropwise addition is completed, finishing the reaction, slowly pouring the reaction liquid into ice water after cooling to room temperature, adjusting the pH of the obtained mixed solution to 10 with 20 wt% sodium hydroxide solution, extracting with diethyl ether, combining organic phases, washing the obtained organic phase with saturated sodium bicarbonate solution and saturated saline solution once respectively, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until no solution is distilled off, and separating the residue by column chromatography (8% ethyl acetate/petroleum ether) to obtain a compound of formula 11 (2.74g, 68% yield), wherein Rf is 0.30 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(300MHz,CDCl3)δ10.49(s,1H),6.53(d,J＝2.3Hz,1H),6.31(d,J＝2.3Hz,1H),4.10(hept,J＝6.8Hz,1H),3.87(s,6H),1.19(d,J＝6.8Hz,6H)ppm；
13C NMR(100MHz,CDCl3)δ190.80,165.25,164.78,155.48,116.16,103.53,94.94,55.77,55.30,28.41,23.45(2C)ppm；
HRMS–EI(m/z):[M]+calcd for C12H16O3,208.1099；found,208.1101。
step 2): preparing a compound of formula 13:
the compound of formula 11 (472.3mg, 2.27mmol) was placed in a dry photoreaction tube (quartz tube) under nitrogen protection, 47mL (10mg/mL) of dry, oxygen-removed 1, 4-dioxane was added and mixed well, adding tetraisopropoxytitanate (1.32mL,13.61mmol) and the compound of formula 12 (1.94mL,6.81mmol) in sequence, mixing well, irradiating in a photoreactor with wavelength of 300nm for 8.5 h, after the reaction, the reaction mixture was poured into a saturated sodium bicarbonate solution and stirred for half an hour, and extracted with ethyl acetate, the organic phases were combined, the obtained organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until no solution was distilled off, and the residue was separated by column chromatography (10% ethyl acetate/petroleum ether) to obtain the compound of formula 13 (444.5mg, yield 64%), and Rf 0.28 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,CDCl3)δ6.50(d,J＝2.3Hz,1H),6.36(d,J＝2.3Hz,1H),5.07(dd,J＝6.8,2.8Hz,1H),3.84(s,3H),3.82(s,3H),3.16–3.13(m,1H),3.09(d,J＝6.1Hz,1H),2.80(ddd,J＝16.2,12.2,7.7Hz,1H),2.53–2.39(m,2H),2.17–2.00(m,1H),1.85–1.75(m,3H),1.43(s,3H),1.15(s,3H)ppm；
13C NMR(125MHz,CDCl3)δ213.90,160.23,158.46,145.47,117.62,102.23,95.87,62.10,55.44,55.24,49.71,46.55,41.29,36.68,33.77,27.59,24.31,21.88ppm；
HRMS–EI(m/z):[M]+calcd for C18H24O4,304.1675；found,304.1677。
step 3): preparing a compound of formula 14:
the compound of formula 13 (600mg, 1.97mmol) was dissolved in dry tetrahydrofuran (20mL), 2-iodoxybenzoic acid (728.3mg,2.56mmol) was added under nitrogen protection at 0 ℃, the addition was completed, the reaction was refluxed for 13 hours, the reaction was completed, the reaction solution was naturally cooled to room temperature and then filtered through a short silica gel column, the filtrate was concentrated, and the residue was separated by column chromatography (10% ethyl acetate/petroleum ether) to obtain the compound of formula 14 (499.0mg, yield 84%), Rf ═ 0.28 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,CDCl3)δ16.75(s,1H),6.53(d,J＝2.1Hz,1H),6.37(d,J＝2.1Hz,1H),3.88(s,3H),3.84(s,3H),2.50(dd,J＝11.7,4.8Hz,1H),2.36–2.33(m,2H),1.97–1.90(m,2H),1.63–1.46(m,1H),1.35–1.27(m,4H),0.94(s,3H)ppm；
13C NMR(125MHz,CDCl3)δ186.90,181.75,163.88,162.11,156.39,113.20,106.97,101.46,96.29,55.99,55.18,41.41,37.96,31.01,24.27,23.59,23.22,20.65ppm；
HRMS–EI(m/z):[M]+calcd for C18H22O4,302.1518；found,302.1519。
step 4): preparing a compound of formula 15:
the compound of formula 14 (909.6mg,2.99mmol) was dissolved in a mixed solvent of N, N-dimethylformamide (15mL) and water (3mL), potassium iodate (2.56g,11.96mmol) and iodine (2.66g, 10.5mmol) were sequentially added, and the mixture was stirred at 150 ℃ for 2.5 hours to terminate the reaction, the reaction mixture was naturally cooled to room temperature, saturated sodium bisulfite was added and stirred for 20 minutes, followed by ethyl acetate extraction, the organic phases obtained were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure until no solution was distilled off, and the residue was separated by column chromatography (10% ethyl acetate/petroleum ether) to give the compound of formula 15 (747.1mg, yield 59%), Rf ═ 0.28 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,CDCl3)δ14.78(s,1H),7.87(d,J＝8.4Hz,1H),6.84(d,J＝8.4Hz,1H),6.72(d,J＝2.3Hz,1H),6.46(d,J＝2.3Hz,1H),3.97(s,3H),3.92(s,3H),1.65(s,6H)ppm；
13C NMR(100MHz,CDCl3)δ187.31,165.01,163.75,161.63,155.88,150.74,143.86,118.02,115.98,112.35,103.87,96.89,82.77,56.38,55.50,39.01,33.92(2C)ppm；
HRMS–EI(m/z):[M]+calcd for C18H17O4I,424.0172；found,404.0170。
step 5): preparing a multi-compound of formula 16:
dissolving the compound of formula 15 (796.4mg,1.88mmol) in acetone (19mL), adding potassium carbonate (518.9mg,3.76mmol) and dimethyl sulfate (0.19mL,2.25mmol), stirring at 60 ℃ for 10.5 hours to complete the reaction, naturally cooling the reaction solution to room temperature, after the solvent is dried by spinning, adding water for dilution, extracting with ethyl acetate, combining the organic phases, washing the obtained organic phases with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating, and separating the residue with column chromatography (10% -20% ethyl acetate/petroleum ether) to obtain the compound of formula 16 (563.4mg, yield 68%) and Rf ═ 0.18 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.4Hz,1H),7.08(d,J＝8.4Hz,1H),6.66(d,J＝2.2Hz,1H),6.41(d,J＝2.2Hz,1H),3.94(s,3H),3.89(s,3H),3.86(s,3H),1.61(s,6H)ppm；
13C NMR(100MHz,CDCl3)δ183.20,163.35,160.98,158.36,152.93,150.80,141.57,129.46,121.76,117.15,101.69,96.56,92.08,62.66,56.19,55.38,39.31,32.19(2C)ppm；
HRMS–EI(m/z):[M]+calcd for C19H19O4I,438.0328；found,438.0330。
step 6): preparing a compound of formula 17:
the compound of formula 16 (907mg,2.07mmol) was dissolved in a mixed solvent of N, N-dimethylformamide (5mL) and diisopropylamine (3mL), tetratriphenylphosphine palladium (239.2mg, 0.207mmol) and cuprous iodide (19.7mg,0.104mmol) were added, frozen in liquid nitrogen to remove oxygen, 2.5mL of a frozen deoxygenated solution of the compound of formula 9 (496.2mg,2.17mmol) in N, N-dimethylformamide was added, then, the reaction was carried out at 45 ℃ for 3 hours to terminate the reaction, the reaction mixture was cooled to room temperature, and then, saturated ammonium chloride was added thereto to quench the reaction mixture, ethyl acetate was extracted, the organic phases were combined, the obtained organic phase was washed twice with distilled water, once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (20% ethyl acetate/petroleum ether) to obtain a compound of formula 17 (837.0mg, yield 75%) with Rf of 0.5 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,CDCl3)δ11.00(s,1H),7.59(d,J＝8.2Hz,1H),7.34(d,J＝8.3Hz,1H),7.05(d,J＝1.4Hz,1H),6.97(d,J＝1.4Hz,1H),6.69(d,J＝2.2Hz,1H),6.45(d,J＝2.2Hz,1H),6.24(s,1H),4.16(s,3H),3.93(s,3H),3.89(s,3H),2.49(t,J＝7.5Hz,2H),1.73(q,J＝7.4Hz,2H),1.66(s,6H),0.99(t,J＝7.4Hz,3H)ppm；
13C NMR(125MHz,CDCl3)δ183.20,166.34,163.29,161.12,160.99,160.65,158.01,152.84,151.29,137.79,135.69,132.08,129.04,119.64,118.15,117.22,116.81,116.14,105.26,103.65,101.73,96.53,92.58,89.30,62.70,56.11,55.31,39.44,35.06,32.11(2C),20.02,13.36ppm；
HRMS–EI(m/z):[M]+calcd for C33H30O7,538.1992；found,538.2005。
step 7): preparing a compound of formula 18:
dissolving a compound (53.6mg,0.10mmol) of a formula 17 in tetrahydrofuran (2mL), adding 10% palladium/carbon (10.7mg,0.02mmol) under the protection of nitrogen, introducing hydrogen, reacting at room temperature for 6 hours, finishing the reaction, filtering the reaction solution by using kieselguhr, and concentrating to obtain a hydrogenated intermediate product; dissolving the intermediate product in dichloroethane (1mL), adding iodine (50.1mg,0.39mmol) and tetramethylethylenediamine copper oxychloride (46.0mg,0.20mmol), reacting at 50 ℃ under an oxygen atmosphere for 24 hours to terminate the reaction, cooling the reaction solution to room temperature, adding saturated sodium bisulfite, stirring for 20 minutes, extracting with ethyl acetate, combining the organic phases, drying the resulting organic phase with anhydrous sodium sulfate, filtering, concentrating, and separating the residue by column chromatography (20% ethyl acetate/petroleum ether) to obtain the compound of formula 18 (58.7mg, yield 89%), Rf ═ 0.1 (30% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,CDCl3)δ11.98(s,1H),7.32(d,J＝8.1Hz,1H),7.27(d,J＝8.1Hz,1H),6.75(s,1H),6.71(d,J＝2.2Hz,1H),6.45(d,J＝2.2Hz,1H),6.19(s,1H),3.95(s,3H),3.93(s,3H),3.90(s,3H),3.24–3.06(m,2H),3.04–2.88(m,2H),2.47(t,J＝7.4Hz,2H),1.70(p,J＝7.5Hz,2H),1.64(s,6H),0.98(t,J＝7.4Hz,3H)ppm；
13C NMR(125MHz,CDCl3)δ184.75,166.05,163.14,160.79,160.47,158.06,157.44,154.75,153.34,148.72,137.30,132.89,132.78,128.18,119.43,117.87,116.31,103.70,103.61,101.60,96.50,87.47,62.65,56.16,55.36,42.53,39.26,35.14,32.29(2C),29.95,20.02,13.40ppm；
HRMS–ESI(m/z):[M+Na]+calcd for C33H33INaO7,691.1163；found,691.1166。
step 8): preparing a compound of formula 19:
placing a compound (87.5mg,0.131mmol) shown in formula 18 in a 15mL photoreaction tube, adding deoxygenated acetonitrile (13.1mL) and 2, 6-lutidine (140.3mg,1.31mmol) under the protection of nitrogen, shaking uniformly, placing in a 366nm photoreactor for illumination for 3 hours to finish the reaction, adding 1N hydrochloric acid into the reaction solution for neutralization, extracting with dichloromethane, combining organic phases, drying the obtained organic phases with anhydrous sodium sulfate, filtering, concentrating, and separating residues by using column chromatography (50% ethyl acetate/petroleum ether) to obtain a benastatin intermediate: a compound of formula 19 (50.3mg, 71% yield), Rf ═ 0.3 (30% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,CDCl3)δ12.24(s,1H),8.60(s,1H),6.77(s,1H),6.74(d,J＝2.3Hz,1H),6.45(d,J＝2.3Hz,1H),6.26(s,1H),3.94(s,3H),3.92(s,3H),3.90(s,3H),2.92(dd,J＝8.6,5.1Hz,2H),2.82(dd,J＝8.5,5.1Hz,2H),2.53(t,J＝7.5Hz,2H),1.80–1.74(m,2H),1.73(s,6H),1.01(t,J＝7.4Hz,3H)ppm；
13C NMR(125MHz,CDCl3)δ183.95,167.51,163.05,161.03,159.21,157.99,155.55,153.77,150.11,147.61,137.23,135.56,130.01,126.77,120.40,120.08,117.70,114.84,105.00,104.14,101.76,96.60,62.16,56.13,55.33,39.43,35.12,32.57(2C),30.67,20.55,20.13,13.42ppm；
HRMS–EI(m/z):[M]+calcd for C33H32O7,540.2148；found,540.2152。
step 9): preparing a compound represented by formula 20:
the compound of formula 19 (46.7mg,0.086mmol) was dissolved in a mixed solvent of glacial acetic acid (9mL) and 55 wt% aqueous hydroiodic acid (3mL), reacted at 120 ℃ for 6 hours, the reaction was terminated, the reaction solution was cooled to room temperature and poured into ice water, chloroform was extracted, the organic phases were combined, the obtained organic phase was washed once with distilled water, saturated sodium bicarbonate, and saturated sodium chloride, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (15% ethyl acetate/petroleum ether) to obtain the compound of formula 20 (40.7mg, yield 95%), Rf ═ 0.6 (40% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,THF-d8)δ13.06(s,1H),12.89(s,1H),12.50(brs,1H),9.59(brs,1H),8.43(brs,1H),6.89(s,1H),6.66(d,J＝2.3Hz,1H),6.45(s,1H),6.23(d,J＝2.2Hz,1H),2.87(s,4H),2.55(t,J＝7.5Hz,2H),1.77–1.74(m,2H),1.71(s,6H),1.02(t,J＝7.3Hz,3H)ppm；
13C NMR(125MHz,THF-d8)δ191.56,168.21,167.32,166.73,160.95,159.83,159.55,156.23,151.47,149.86,140.01,139.22,123.95,120.52,118.71,116.15,113.19,108.57,107.54,106.20,104.97,102.14,39.81,35.95,34.56(2C),31.42,21.19,20.53,13.89ppm；
HRMS–EI(m/z):[M]+calcd for C30H26O7,498.1679；found,498.1688。
step 10): preparation of benastatin G:
the compound of formula 20 (11mg,0.022mmol) was dissolved in a mixed solvent of tetrahydrofuran (0.25mL) and water (0.25mL), potassium hydroxide (12.4mg, 0.221mmol) was added, and then the reaction was terminated by reacting at 70 ℃ for 7 hours, the reaction solution was cooled to room temperature, then pH was adjusted to 5 with 1N diluted hydrochloric acid, ethyl acetate was extracted, the organic phases were combined, the resulting organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated with a preparative silica gel plate (10% methanol/dichloromethane), to give benstatin G (7mg, yield 62%), and Rf to 0.5 (10% methanol/dichloromethane).
Through the test:1H NMR(500MHz,THF-d8)δ13.02(s,1H),12.93(s,1H),8.47(s,1H),6.69(s,1H),6.66(d,J＝2.2Hz,1H),6.22(d,J＝2.2Hz,1H),2.85(m,2H),2.79(m,2H),2.11(t,J＝8.0Hz,2H),1.70(s,6H),1.57(m,2H),0.95(t,J＝7.4Hz,3H)ppm；
13C NMR(125MHz,THF-d8)δ191.42,167.07,166.42,159.60,156.09,149.41,140.83,140.31,123.55,121.14,118.62,112.70,108.39,107.27,101.93,43.97,39.61,34.41(2C),30.76,20.48,17.76,14.38ppm；
HRMS–ESI(m/z):[M-H]-calcd for C30H27O7,515.1711；found,515.1686。
example 3: application of polycyclic lactone compounds in preparation of benastatin J
Step 1) to step 8) are the same as step 1) to step 8) of example 2.
Step 9): preparing a compound of formula 21:
the compound of formula 19 (37.2mg,0.0689mmol) was dissolved in dry dichloromethane (0.7mL), and trimethylsilyl iodide (37.2mg,0.186mmol) was added under nitrogen atmosphere at 0 ℃, followed by reaction at room temperature for 24 hours to terminate the reaction, the reaction solution was quenched by adding methanol, the solvent was directly dried by rotary evaporation, and the residue was separated by column chromatography (50% dichloromethane/petroleum ether) to give the compound of formula 21 (33.3mg, yield 94%), Rf ═ 0.81 (40% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,CDCl3)δ13.15(s,1H),13.06(s,1H),12.31(s,1H),8.37(s,1H),6.77(s,1H),6.69(d,J＝2.4Hz,1H),6.41(d,J＝2.3Hz,1H),6.26(s,1H),3.89(s,3H),2.92–2.88(m,2H),2.88–2.84(m,2H),2.53(t,J＝7.4Hz,2H),1.78–1.73(m,2H),1.72(s,6H),1.01(t,J＝7.4Hz,3H)ppm；
13C NMR(125MHz,CDCl3)δ190.59,167.48,166.21,165.91,159.79,158.65,158.35,154.48,150.56,148.76,138.94,137.79,122.97,119.72,117.65,115.04,112.26,108.38,106.17,105.04,104.14,98.72,55.54,38.91,35.16,34.06(2C),30.56,20.14,19.45,13.45ppm；
HRMS–EI(m/z):[M]+calcd for C31H28O7,512.1835；found,512.1838。
step 10): preparation of benastatin J:
dissolving the compound of formula 21 (26.0mg,0.0508mmol) in N, N-dimethylformamide (1mL), adding potassium carbonate (7.0mg,0.0508mmol) and methyl iodide (7.2mg,0.0508mmol), then reacting at room temperature for 64 hours to terminate the reaction, neutralizing the reaction solution with 1N hydrochloric acid, extracting with dichloromethane, combining the organic phases, washing the resulting organic phase twice with distilled water, washing with saturated sodium chloride once, drying with anhydrous sodium sulfate, filtering, concentrating, and separating the residue with preparative silica gel plate (dichloromethane) to obtain benastatin J (18.7mg, yield 70%), Rf ═ 0.73 (30% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,CDCl3)δ13.13(s,1H),13.11(s,1H),8.39(s,1H),7.05(s,1H),6.68(d,J＝2.4Hz,1H),6.41(d,J＝2.4Hz,1H),6.19(s,1H),3.89(s,3H),3.73(s,3H),2.94–2.89(m,2H),2.89–2.83(m,2H),2.50(t,J＝7.5Hz,2H),1.79-1.73(m,2H),1.71(s,6H),1.01(t,J＝7.3Hz,3H)ppm；
13C NMR(125MHz,CDCl3)δ190.67,166.37,165.94,160.75,159.59,159.42,158.80,154.44,149.26,149.16,140.18,138.72,126.76,123.87,120.34,117.58,112.82,112.57,108.33,106.23,102.74,98.84,61.57,55.57,38.96,35.29,33.92(2C),30.28,20.13,19.65,13.51ppm.
HRMS–EI(m/z):[M]+calcd for C32H30O7,526.1992；found,526.1987。
the invention can be made with reference to the preparation described in example 1, by selecting other alkylating agents instead of the methylating agent in step a of example 1: dimethyl sulfate, by selecting others
The reagent replaces 1-pentyne in step e of example 1, so that the polycyclic lactone compounds of the invention, wherein R is alkyl, can be prepared; the method for preparing the compound with the structure similar to that of the benastatin G or the benastatin J from the polycyclic lactone compounds can refer to the contents in example 2 or example 3.
In conclusion, the invention provides a novel polycyclic lactone compound, and the polycyclic lactone compound can be used for preparing the compound with the structure of
(the dotted line represents an optional double bond) or other natural products or compounds with similar structures, thereby providing a new synthetic route for synthesizing the benastatin derivatives or other natural products with similar structures; in addition, the preparation method of the polycyclic lactone compound has the advantages of simple operation, safety, no pollution, no special requirements on equipment, low production cost and the like, and has important significance for realizing large-scale production.
Finally, it should be pointed out here that: the above is only a part of the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention, and the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above description are intended to be covered by the present invention.
Claims (7)
1. A method for preparing a polycyclic lactone compound, wherein the polycyclic lactone compound has a chemical structure shown in formula 9:
wherein: r is selected from hydrogen or C1～C8An alkyl group;
the preparation method comprises the following steps a-b-c-d-e-f-g-h in the synthetic route:
wherein: ra is selected from C1～C8An alkyl group; said step b is a selective dealkylation of the compound of formula 2 in the presence of a dealkylation agentRemoving Ra alkyl for protection to obtain a compound shown in a formula 3, wherein the dealkylation reagent is Lewis acid; and the step f is to perform cyclization reaction on the compound shown in the formula 6 in the presence of an indium catalyst to obtain a compound shown in a formula 7, wherein the indium catalyst is indium tribromide.
2. The method of claim 1, wherein: the step a is to react the compound of the formula 1 with an Ra alkylating agent in the presence of a base to obtain the compound of the formula 2.
3. The method of claim 1, wherein: and the step c is to carry out sonogashira coupling reaction on the compound shown in the formula 3 and triisopropyl silyl acetylene to obtain the compound shown in the formula 4.
4. The method of claim 1, wherein: and the step d is to react the compound of the formula 4 with trifluoromethanesulfonic anhydride in the presence of a base to obtain a compound of the formula 5.
5. The method of claim 1, wherein: said step e is performed by reacting a compound of formula 5 with
Carrying out the sonogashira coupling reaction to obtain the compound of formula 6.
6. The method of claim 1, wherein: and g, removing the TIPS protection on alkyne from the compound of the formula 7 in the presence of quaternary ammonium salt to obtain the compound of the formula 8.
7. The method of claim 1, wherein: and h, removing Ra alkyl protection from the compound of the formula 8 in the presence of a dealkylating agent to obtain the compound of the formula 9.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0449051A1 (en) * | 1990-03-16 | 1991-10-02 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Novel, physiologically active substances, benastatins A and B, and production and use thereof |
| CN103951647A (en) * | 2014-03-27 | 2014-07-30 | 华东师范大学 | Xanthone compound and preparation method thereof |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0449051A1 (en) * | 1990-03-16 | 1991-10-02 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Novel, physiologically active substances, benastatins A and B, and production and use thereof |
| CN103951647A (en) * | 2014-03-27 | 2014-07-30 | 华东师范大学 | Xanthone compound and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| Benastatin,Anthrabenzoxocinone以及Naphthacemycin类天然抗生素的全合成研究;辛坤云;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20190115(第1期);第B016-1903页 * |
| Seijiro Hosokawa等.TOTAL SYNTHESIS OF AN ENDOTHELIN CONVERTING ENZYME INHIBITOR, TMC-66.《HETEROCYCLES》.2008,第76卷(第1期), * |
| Synthesis and Biological Evaluation of Cytogenin Derivatives;NAOKI MATSUMOTO等;《THE TOURNAL OF ANTIBIOTICS》;20010331;第54卷(第3期);第287页左栏第1行-第288页左栏第1行，第292页右栏第1-20行，Scheme 2 * |
| Synthesis and Biological Evaluation of Kibdelone C and Its Simplified Derivatives;Janjira Rujirawanich等;《J. Am. Chem. Soc.》;20160726;第138卷;第10561-10570页 * |
| TOTAL SYNTHESIS OF AN ENDOTHELIN CONVERTING ENZYME INHIBITOR, TMC-66;Seijiro Hosokawa等;《HETEROCYCLES》;20080421;第76卷(第1期);第701页第1行-第703页第1行,第708页第10-20行，Scheme 4 * |
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