CN113735875A - Preparation method of guaiane sesquiterpene dimer - Google Patents
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Abstract
The invention provides a preparation method of guaiane sesquiterpene dimer, belonging to the technical field of medicines. The preparation method comprises the steps of taking arglabin (arglabin) or derivatives thereof as a raw material, carrying out epoxy isomerization to obtain a diene body, and carrying out Diels-Alder reaction/deprotection on the diene body and another molecule of arglabin or dehydroleucodin to obtain lavindolide I and artemimatrilide F; the lavondiolide I is subjected to C-10 hydroxyl configuration isomerization under an acidic condition to prepare lavondiolide H; and the lavandiolide H is reduced to prepare lavandiolide I.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method and application of guaiane sesquiterpene dimer Lavandiiides H, I, K and artermatrilide F.
Background
Guaiane sesquiterpenes are important natural products, widely present in Asteraceae (Asteraceae) plants, and distributed in Umbelliferae (Apiaceae), Acoraceae (Acoraceae) and other family plants, and Russulaceae (Russulaceae) and other fungi. Guaiane sesquiterpenes are structurally diverse, and over 2600 compounds have been reported to possess a wide range of biological activities, in particular their antitumor activities, which have attracted a wide range of attention from many medicinal chemists. Such as arglabin pairs isolated from plants of the genus ArtemisiaThe tumor cell strain has better inhibitory activity (IC)500.9-5.9 mug/mL), the anti-cancer action mechanism is inhibition of farnesyl transferase, and dimethylamino hydrochloride of the farnesyl transferase is developed into an anti-cancer drug which is sold in the republic of Kazakhstan and mainly used for treating breast cancer, colon cancer, ovarian cancer, lung cancer and liver cancer. The michelia lactone separated from michelia plants can regulate and control the expression of B-cell lymphoma-2 (B-cell lymphoma, Bcl-2) to target and kill leukemia stem cells by increasing Reactive Oxygen Species (ROS) in the cells, has small toxic and side effects on normal stem cells, and the dimethylamino hydrochloride of the michelia lactone can be used as a prodrug to be used as a novel drug for resisting glioblastoma 1.1 to be clinically researched in Australia. Polyoxygen substituted sesquiterpene lactone thapsigargin isolated from Mediterranean plant thapsigargin (Thapsia garganica) is a highly effective inhibitor of intracellular calcium ion transport enzyme, can induce apoptosis and autophagy of cancer cells, and its C-8 ester derivative mipsaggin (G-202) is currently used as a prodrug in the U.S. phase III clinical trials, mainly for treating prostate cancer, kidney cancer, liver cancer and brain tumor.
Guaiane sesquiterpene multimers are a class of structurally complex natural products with a 30-60 carbon backbone formed by the linkage of two or more guaiane sesquiterpene units. According to different connection modes, sesquiterpene monomers of the same or different types can be connected to form sesquiterpene dimers mainly through cyclization ([4+2], [2+2], [3+2]), carbon-carbon single bonds, ester bonds and the like. Among them, sesquiterpene dimers formed based on Diels-Alder reaction are more common types, the components are mainly formed by [4+2] Diels-Alder addition of an electron-donating diene body containing conjugated double bonds and another electrophilic double bond segment, the most common diene body is guaiane sesquiterpene with C5/C7/C5 ring system, and the dienophile is mainly sesquiterpene containing relevant alpha-methylene-gamma-lactone segment.
In the earlier stage of the invention, a series of sesquiterpene dimers which have spirolactone structural units and are obtained by Diels-Alder reaction are separated from artemisia apiacea, and the compounds have cytotoxic activity on human hepatoma cell strains HepG2, Huh7 and SMMC-7721 and have activity which is higher than that of a monomerThe compound is remarkable. In particular, the IC of lavandiolide H on three hepatoma cells50Values of 3.8, 4.6 and 4.5 μm, stronger than the positive drug sorafenib, and inhibited cell invasion, migration and induced cell withering (Su, l.; Zhang, x.; Ma, y.; Geng, c.; Huang, x.; Hu, j.; Li, t.; Tang, s.; Shen, c.; Gao, z.; Zhang, x.; Chen, j. -j. acta pharmaceutical Sinica B2021, 11, 1648-. Representative compound structural formulas are shown below.
However, the content of the dimers in plants is low, so that the research on the structure-activity relationship, the action mechanism, the in-vivo efficacy evaluation and the like of the dimers is restricted. The guaiane dimers have a highly condensed seven-ring framework and more than 10 chiral centers, and the complex structure makes the total synthesis difficult and large-scale preparation difficult. The synthesis of guaiane sesquiterpene dimers reported at present is carried out by taking the eudesmane sesquiterpene as a raw material in mountain years, and the industrial application of the guaiane sesquiterpene dimers is restricted by the factors of long reaction steps, high cost and the like.
The synthesis of guaiane dimer with spirolactone structural unit is not reported in literature at present.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method of a guaiane dimer, lavandiolides H, I, K and artemimatrilide F, which have spirolactone structural units. The method has the advantages of easily obtained raw materials, easy operation and suitability for industrial production, and provides a new synthetic method for the industrial preparation of the guaiane sesquiterpene polymer.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
a process for preparing the guaiane dimer lavandiolides H, I, K and artomatrolide F includes such steps as epoxy isomerizing arglabin or its derivative to obtain diene, Diels-Alder reaction/deprotection of diene and arglabin or dehydroleucodin to obtain Lavandiolide I and artomatrolide F, isomerizing Lavandiolide I via 10-position hydroxy configuration under acidic condition to obtain Lavandiolide H, reducing Lavandiolide H to obtain Lavandiolide I,
wherein R is methyl, (dimethylamino) methylene, (diethylamino) methylene, piperidylmethylene, morpholinylmethylene, phenylselenomethylene, substituted phenylselenomethylene, phenylthiomethylene, substituted phenylthiomethylene, and the like.
The synthesis of lavondiolide I and artomatrolide F mainly comprises the following two key reaction steps:
a first reaction step: reacting arglabin (arglabin) or a derivative thereof with a proper isomerization reagent in a proper reaction solvent to obtain a diene, wherein the isomerization reagent is 2,2,6, 6-tetramethyl piperidyl diethyl aluminum or dicyclo amino aluminum or diisopropyl amino diethyl aluminum or 2,2,6, 6-tetramethyl piperidyl dimethyl aluminum, and the reaction solvent is toluene or benzene or diethyl ether or tetrahydrofuran; or the isomerization reagent is titanocene monochloride, and the reaction solvent is toluene, benzene, diethyl ether or tetrahydrofuran.
And a second reaction step: carrying out Diels-Alder reaction/deprotection on diene and arglabin or dehydroleucodin under a proper condition to prepare a sesquiterpene dimer, wherein the Diels-Alder reaction is carried out under a proper condition that benzene, toluene, xylene and tetrahydrofuran are used as solvents, and the diene and the arglabin or the dehydroleucodin react under a heating condition; or 2, 6-di-tert-butyl-4-methylphenol is taken as an antioxidant, benzene, toluene, xylene and tetrahydrofuran are taken as solvents, and diene reacts with arglabin or dehydroleucodin under the heating condition; or the diene reacts with the arglabin or dehydroleucodin at room temperature under the condition of no solvent; or the diene and the arglabin or dehydroleucodin are heated to react under the condition of no solvent.
The invention provides a step of preparing lavondiolide H from lavondiolide I under the action of proper acid, wherein the proper acid is nitro salicylic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid and perchloric acid;
the invention also provides a step of preparing the lavandriolide I by reducing the lavandriolide H with a proper reducing agent, wherein the proper reducing agent is sodium borohydride/methanol, sodium borohydride/ethanol, sodium borohydride/tetrahydrofuran, sodium borohydride/dioxane.
Compared with the prior art, the invention has the following advantages: provides a novel preparation method of guaiane dimer lavandiolides H, I, K and artemiroll F with spironolactone structural units. The method comprises the steps of taking arglabin (arglabin) or derivatives thereof as a raw material, carrying out epoxy isomerization to obtain a diene body, and carrying out Diels-Alder reaction/deprotection on the diene body and another molecule of arglabin or dehydroleucodin to obtain lavandrolide I and artemimatrilide F. The Lavandiolide I is subjected to isomerization by a 10-position hydroxyl configuration under an acidic condition to obtain Lavandiolide H, and the Lavandiolide H is subjected to reduction to obtain the Lavandiolide I. The method has the advantages of easily obtained raw materials, easy operation and suitability for industrial production, and provides a new synthetic method for the industrial preparation of the guaiane sesquiterpene polymer.
Drawings
FIG. 1 is a flow chart of the process for the preparation of guaiane dimer lavandiolides H, I, K and artemiatrilide F of the present invention.
Detailed Description
For the understanding of the present invention, the following description will further illustrate the essence of the present invention by referring to the specific embodiments thereof with reference to the accompanying drawings, but the present invention is not limited thereto.
Example 1
The diene is prepared by taking arglabin or derivatives thereof as raw materials.
The method comprises the following steps:
2,2,6, 6-tetramethylpiperidine (113mg,0.8mmol) was dissolved in 4mL of dry toluene under an argon atmosphere, n-butyllithium (1.6M,0.40mL,0.8mmol) was slowly added thereto after cooling in an ice bath to 0 ℃ and 0.89mL of a diethyl aluminum chloride solution (0.9M heptane solution, 0.8mmol) was added to the reaction mixture after reacting for half an hour. After the reaction was continued for 0.5h, a toluene solution (1.5mL) of arborecin (49.6mg,0.2mmol) was added to the reaction mixture. After 2 hours of reaction, the reaction was quenched by addition of 5mL of saturated sodium potassium tartrate solution, extracted with ethyl acetate (5 mL. times.3), the organic phases were combined, concentrated under reduced pressure to remove the solvent, and the crude product was separated by silica gel column chromatography (ethyl acetate-petroleum ether, 20:80) to give diene I (26mg yield 52%).
Diene compound I
The molecular formula is as follows: c15H20O3
Molecular weight: 248.32
The characteristics are as follows: oily liquid
HRMS(ESI,m/z):[M+H-H2O]+[C15H19O2]+Calculated 231.1380, test value 231.1350.
1H NMR(400MHz,CDCl3)δ6.55(s,1H,H-2),6.10(s,1H,H-3),3.49(t,J＝10.4Hz,1H,H-6),3.03(d,J＝10.8Hz,1H,H-5),2.24-2.19(m,1H,H-11),2.15(s,3H,H-15),2.01-1.91(m,2H,H-7,H-9a),1.86-1.81(m,2H,H-8a,H-9b),1.66-1.59(m,1H,H-9b),1.48(s,3H,H-14),1.25(d,J＝6.8Hz,H-13)；13C NMR(100MHz,CDCl3)δ178.7(C-12),152.0(C-1),147.6(C-4),131.3(C-2),128.3(C-3),84.4(C-6),72.8(C-10),58.9(C-5),55.1(C-7),41.9(C-11),40.7(C-9),34.2(C-14),22.9(C-8),17.5(C-15),12.6(C-13).
The second method comprises the following steps:
dicyclohexylamine (145mg,0.8mmol) was dissolved in 4mL of dry toluene under protection of argon, n-butyllithium (1.6M,0.40mL,0.8mmol) was slowly added thereto after cooling in an ice bath to 0 deg.C, and 0.89mL of a diethyl aluminum chloride solution (0.9M in heptane, 0.8mmol) was added to the reaction mixture after reacting for half an hour. After the reaction was continued for half an hour, a toluene solution (1.5mL) of arborecin (49.6mg,0.2mmol) was added to the reaction mixture. After 2 hours of reaction, the reaction was quenched by addition of 5mL of saturated sodium potassium tartrate solution, extracted with ethyl acetate (5 mL. times.3), the organic phases were combined, concentrated under reduced pressure to remove the solvent, and the crude product was isolated by silica gel column chromatography (ethyl acetate-petroleum ether, 20:80) to give diene I (15mg, yield 31%).
The third method comprises the following steps:
diisopropylamine (81mg,0.8mmol) was dissolved in 4mL of dry toluene under an argon atmosphere, n-butyllithium (1.6M,0.40mL,0.8mmol) was slowly added thereto after cooling to 0 ℃ in an ice bath, and 0.89mL of a diethyl aluminum chloride solution (0.9M in heptane, 0.8mmol) was added to the reaction mixture after reacting for half an hour. After the reaction was continued for half an hour, a toluene solution (1.5mL) of arborecin (49.6mg,0.2mmol) was added to the reaction mixture. After 2 hours of reaction, the reaction was quenched by addition of 5mL of saturated sodium potassium tartrate solution, extracted with ethyl acetate (5 mL. times.3), the organic phases were combined, concentrated under reduced pressure to remove the solvent, and the crude product was separated by silica gel column chromatography (ethyl acetate-petroleum ether, 20:80) to give 20 mg of diene I, 40% yield.
The method four comprises the following steps:
under the protection of argon, titanocene dichloride (99.6mg,0.4mmol) is dissolved in 2mL of strictly deoxidized tetrahydrofuran, 78mg of zinc powder (1.2mmol) is added into the solution under stirring, 49.6mg of arboresin (0.2mmol) is added into the solution after the reaction solution turns from red to green after 15min, and the reaction is carried out for 12h at room temperature. The reaction was quenched with 5mL of saturated sodium bicarbonate, stirred for 30min, extracted with ethyl acetate (5 mL. times.3), the organic phases combined, concentrated under reduced pressure to remove the solvent, and the crude product was separated by silica gel column chromatography (ethyl acetate-petroleum ether, 20:80) to give diene I (33mg, yield 67%) and diene II (7mg, yield 15%).
Diene II
The molecular formula is as follows: c15H20O3
Molecular weight: 248.32
The characteristics are as follows: white solid
Melting point: 118.0-118.9 deg.C
And (3) optical rotation: [ alpha ] to]D 2431.37(c 0.102, methanol)
IRνmax 3479,2914,1751,1180,1150,879cm-1；
HRMS(ESI,m/z):[M+HCOO]-[C16H21O5]-Calculated 293.1386, test value 293.1367.
1H NMR(500MHz,CDCl3)δ6.04(t,J＝1.8Hz,1H,H-2),5.36-5.33(m,1H,H-6),2.86-2.84(m,2H,H-3),2.33-2.67(m,1H,H-11),2.16(d,J＝2.4Hz,3H,H-15),2.02(dt,J＝14.5,3.5Hz,1H,H-7),1.96-1.82(m,2H,H-9a,H-8a),1.76-1.71(m,1H,H-9b),1.58(s,3H,H-14),1.57-1.52(m,1H,H-8a),1.48(s,1H,-OH),1.23(d,J＝7.0Hz,3H,H-13)；13C NMR(125MHz,CDCl3)δ179.1(C-12),151.0(C-1),137.5(C-1),135.0(C-5),124.6(C-2),83.1(C-6),70.9(C-10),52.5(C-7),45.7(C-3),41.6(C-11),40.0(C-9),31.0(C-14),26.0(C-8),15.1(C-15),12.9(C-14)；
The method five comprises the following steps:
under the protection of argon, dichlorotitanocene (99.6mg,0.4mmol) is dissolved in 2mL of strictly deoxidized tetrahydrofuran, 66mg of manganese powder (1.2mmol) is added thereto under stirring, 49.6mg of arboresin (0.2mmol) is added thereto after the reaction solution turns from red to green after 15min, and the reaction is carried out at room temperature for 12 h. The reaction was quenched with 5mL of saturated sodium bicarbonate, stirred for 30min, extracted with ethyl acetate (5 mL. times.3), the organic phases combined, concentrated under reduced pressure to remove the solvent, and the crude product was separated by silica gel column chromatography (ethyl acetate-petroleum ether, 20:80) to give diene I (32mg, yield 64%) and diene II (8mg, yield 16%).
The method six:
under the protection of argon, dichlorotitanocene (99.6mg,0.4mmol) is dissolved in 2mL of strictly deoxidized tetrahydrofuran, 78mg of zinc powder (1.2mmol) is added into the solution under stirring, 49.2mg of arglabin (0.2mmol) is added into the solution after the reaction solution changes from red to green after 15min, and the reaction is carried out for 12h at room temperature. The reaction was quenched with 5mL of saturated sodium bicarbonate, stirred for 30min, extracted with ethyl acetate (5 mL. times.3), the organic phases were combined, concentrated under reduced pressure to remove the solvent, and the crude product was separated by silica gel column chromatography (ethyl acetate-petroleum ether, 20:80) to give diene I (27mg, yield 55%) and diene II (4mg, yield 9%)
The method comprises the following steps:
under the protection of argon, dichlorotitanocene (99.6mg,0.4mmol) is dissolved in 2mL of strictly deoxidized tetrahydrofuran, 78mg of zinc powder (1.2mmol) is added into the solution under stirring, after 15min, 58.2mg of dimethylamino arglabin (0.2mmol) is added into the solution after the color of the reaction solution changes from red to green, and the reaction is carried out for 72h at room temperature. The reaction was quenched with 5mL of saturated sodium bicarbonate, stirred for 30min, extracted with ethyl acetate (5 mL. times.3), the organic phases combined, concentrated under reduced pressure to remove the solvent, and the crude product was chromatographed on silica gel (triethylamine-ethyl acetate-petroleum ether, 1:20:80) to give diene III (45mg, yield 77%).
Diene III
The molecular formula is as follows: c17H25NO3
Molecular weight: 291.39
The characteristics are as follows: light yellow powder
And (3) optical rotation: [ alpha ] to]D 236.35(c 0.145, methanol);
IRνmax 3434,2934,1772,1458,1369,964cm-1；
HRMS(ESI,m/z):[M+H]+[C17H26NO3]+calculated 293.1907, test value 293.1889.
1H NMR(500MHz,CDCl3)δ5.98-5.97(m,1H,H-2),5.35-5.33(m,1H,H-6),2.80-2.79(m,2H,H-3),2.70-2.66(m,1H,H-13a),2.50-2.47(m,1H,H-13b),2.40-2.35(m,1H,H-11),2.24-2.22(m,1H,H-7),2.16(s,6H,N-Me2),2.10(d,J＝1.5Hz,3H,H-15),2.03-1.88(m,4H,H-8a,H-8b,H-9a,H-9b),1.51(s,1H,H-14)；13C NMR(125MHz,CDCl3)δ177.9(C-12),151.1(C-4),136.9(C-1),135.1(C-5),124.1(C-2),82.9(C-6),70.5(C-10),58.5(C-13),49.7(C-7),45.8(N-Me2),45.5(C-3),44.8(C-11),40.1(C-9),30.8(C-14),26.2(C-8),14.9(C-15).
Example 2:
and preparing lavondiolide I-DMA by Diels-Alder reaction.
The method comprises the following steps:
diene III (59mg,0.24mmol) and arglabin (58mg,0.2mmol) were dissolved in 1mL of toluene and heated under reflux for 24 h. After the reaction, the solvent was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography to give lavondiolide I-DMA (46mg, 43% yield).
lavandiolide I-DMA
The molecular formula is as follows: c32H43NO6
Molecular weight: 537.70
The characteristics are as follows: white solid
Melting point: 105.4-106.6 deg.C
And (3) optical rotation: [ alpha ] to]D 2391.89(c 0.111, methanol)
IRνmax 3468,2936,1768,1457,1228,1095,1013cm-1；
HRMS(ESI,m/z):[M+H]+[C32H44NO6]+Calculated 538.3162, test value 538.3190.
1H NMR(500MHz,CDCl3)δ5.47-5.43(m,2H,H-3′,H-6),3.88(dd,J＝10.0,10.0Hz,1H,H-6′),2.91(d,J＝3.5Hz,1H,H-2),2.79-2.59(m,4H,H-7,H-2′a,H-5′,H-13a),2.47(m,1H,H-13b),2.31-2.26(m,1H,H-11),2.15-1.98(m,11H,N-Me2,H-8a,H-9a,H-9′a,H-9′b,H-2′b),1.95-1.82(m,8H),1.95-1.78(m,7H,H-9′a,H-7′,H-8b,H-9b,H-15),1.70-1.59(2H,H-8′b,H-3b),1.51-1.47(m,2H,H-13′b,H-3b),1.28(s,6H,H-14,H-15),1.24(s,1H,H-14′)；13C NMR(125MHz,CDCl3)δ180.9(C-12′),177.5(C-12),150.5(C-1),144.6(C-5),140.6(C-4′),125.0(C-3′),83.9(C-6),79.9(C-7′),72.1(C-10),71.9(C-1′),61.9(C-10′),60.1(C-4),58.5(C-13),55.8(C-11′),53.3(C-4),52.3(C-5′),52.0(C-7′),47.7(C-7),45.8(N-Me2),45.5(C-11),42.5(C-2),39.0(C-2′),38.9(C-9),34.5(C-13′),32.6(C-9′),27.7(C-14),25.4(C-8),22.4(C-14′),20.8(C-8′),18.4(C-15′),17.8(C-15)；
The second method comprises the following steps:
diene III (59mg,0.24mmol), arglabin (58mg,0.2mmol) and 2, 6-di-tert-butyl-4-methylphenol (22mg,0.1mmol) were dissolved in 2mL of toluene and heated under reflux for 24 h. After the reaction, the solvent was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to give lavondiolide I-DMA (52mg, yield 48%).
The third method comprises the following steps:
diene III (59mg,0.24mmol) and arglabin (58mg,0.2mmol) were dissolved in 2mL of dichloromethane at room temperature, and the resulting solution was concentrated under reduced pressure to remove the solvent, followed by solvent-free reaction for 5 days. The product was isolated by silica gel column chromatography to give lavandiolide I-DMA (90mg, 84% yield).
The method four comprises the following steps:
diene III (59mg,0.24mmol) and arglabin (58mg,0.2mmol) were dissolved in 2mL of dichloromethane at room temperature, concentrated under reduced pressure to remove the solvent, and reacted at 50 ℃ for 60 hours without solvent. The product was isolated by silica gel column chromatography to give lavandiolide I-DMA (93mg, yield 87%).
Example 3
And preparing lavondiolide I.
Lavondiolide I-DMA (10.7g,20mmol) was dissolved in 200mL of methanol, 6.2mL of iodomethane (100mmol) was added thereto, stirred overnight, concentrated under reduced pressure to remove the solvent, and 200mL of 10% NaHCO was added3And 200mL of ethyl acetate, the mixture was transferred to a separatory funnel and mixed until the solid was completely dissolved. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (2X 100mL), the organic phases were combined, the solution was removed by concentration under reduced pressure, and the crude product was separated by silica gel column chromatography (triethylamine-ethyl acetate-petroleum ether, 1:20:80) to give lavindolide I (9.4g, yield 95%).
lavandiolide I
The molecular formula is as follows: c30H36O6
Molecular weight: 492.61
The characteristics are as follows: white solid
Melting point: 88.1-89.2 deg.C
And (3) optical rotation: [ alpha ] to]D 2363.39(c 0.136, methanol);
IRνmax3469,2938,1764,1447,1317,1231,1152,972cm-1；
HRMS(ESI,m/z):[M+H]+calcd for[C30H37O6]+493.2585,found 493.2610.
1h NMR and13the C NMR data are shown in tables 1 and 2.
Example 4
Preparation of lavondiolide H.
In a 50mL round-bottomed flask, 1.48g of lavandiolide I (3mmol) was dissolved in a mixed solvent of 5mL acetonitrile and 1mL water, 137mg of 3, 5-dinitrosalicylic acid (0.6mmol) was added thereto with stirring, after reacting at room temperature for 2 hours, 20mL of saturated sodium bicarbonate was added to quench the reaction, ethyl acetate was extracted (2X 25mL), the organic phases were combined, the solvent was removed by concentration under reduced pressure, and the crude product was separated by silica gel column chromatography (ethyl acetate-petroleum ether, 25:75) to give lavandiolide I (605mg, yield 41%)
lavandiolide H
The molecular formula is as follows: c30H36O6
Molecular weight: 492.61
The characteristics are as follows: white solid
Melting point: 208.1-210.2 deg.C
And (3) optical rotation: [ alpha ] to]D 2469.5(c 0.124, methanol);
IRνmax 2962,1766,1446,1314,1245,971cm-1；
HRMS(ESI,m/z):[M+HCOO]-[C31H37O8]-calculated 537.2494, test value 537.2451.
1H NMR and13the C NMR data are shown in tables 1 and 2.
Example 5
Preparation of lavandiolide K.
At room temperature, lavondiolide H (49.2mg,0.1mmol) was dissolved in 5mL of tetrahydrofuran, and 4.6mg of NaBH was added thereto with stirring4(0.12mmol), after reacting for two hours, the reaction was quenched by pouring the reaction mixture into 5mL of water, extracted with ethyl acetate (2X 5mL), the organic phases were combined, concentrated under reduced pressure to remove the solution, and the crude product was isolated by silica gel column chromatography (ethyl acetate-petroleum ether, 25:75) to give lavindolide K (32mg, yield 65%).
lavandiolide K
The molecular formula is as follows: c30H38O6
Molecular weight: 494.63
The characteristics are as follows: white solid
Melting point: 101.5-102.9 deg.C
And (3) optical rotation: [ alpha ] to]D 2472.08(c 0.144, methanol)
IRνmax 3446,2933,1770,1454,1312,1169,1002,736cm-1；
HRMS(ESI,m/z):[M+HCOO]-[C31H39O8]-Calculated 539.2650, test value 539.2612.
1H NMR and13c NMR data are shown in tables 1 and 2
Example 6
Preparation of artomatrolide F.
Diene III (58mg,0.20mmol) and dehydroleu were reacted at room temperaturecodin (58.6mg,0.2mmol) was dissolved in 2mL of dichloromethane, concentrated under reduced pressure to remove the solvent, and then reacted at 50 ℃ for 60 hours without solvent. The product was dissolved in 5mL of methanol, 62. mu.L of methyl iodide (1mmol) was added thereto, after stirring overnight, the solvent was removed by concentration under reduced pressure, and 5mL of 10% NaHCO was added3And 5mL of ethyl acetate, the mixture was transferred to a separatory funnel and mixed until the solid was completely dissolved. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (2X 5mL), the organic phases were combined, the solution was removed by concentration under reduced pressure, and the crude product was separated by silica gel column chromatography (ethyl acetate-petroleum ether, 25:75) to give artemiroll F (53mg, yield 54%).
artematrolide F
The molecular formula is as follows: c30H34O6
Molecular weight: 490.60
The characteristics are as follows: white solid
Melting point: 148.7-149.8 deg.C
And (3) optical rotation: [ alpha ] to]D 24 100.0(c 0.106,MeOH)
HRMS(ESI,m/z):[M+HCOO]-[C31H35O8]-Calculated 535.2337, test value 535.2351.
1H NMR and13c NMR (DEPT) data are shown in tables 1 and 2
TABLE 1 Lavandiiolides H, I, K and artemiroll F1H NMR data
a1H NMR is measured by a 500MHz nuclear magnetic resonance instrument;b1h NMR is measured by a 150MHz nuclear magnetic resonance instrument;cused as CD3An OD solvent;dusing CDCl3As a solvent
TABLE 2 Lavandiiolides H, I, K and artemimatolide F13C NMR data
a13C NMR was measured on a 125MHz NMR spectrometer;b13c NMR is measured by a 600MHz nuclear magnetic resonance instrument;cusing CD3OD is a solvent;dusing CDCl3As a solvent
From the above examples, it can be seen that the present invention provides methods for preparing lavandiolides H, I, K and artemimatrilide F. The foregoing is only a preferred embodiment of the present invention, and it should be noted that modifications can be made by those skilled in the art without departing from the principle of the present invention, and these modifications should also be construed as the protection scope of the present invention.
Claims (6)
1. The preparation method of guaiane sesquiterpene dimer lavandiolides H, I, K and artemimatrilide F comprises the steps of taking arglabin or derivatives thereof as a raw material, obtaining a diene body through epoxy isomerization, obtaining the diene body and another molecule of arglabin or dehydroleucodin through Diels-Alder reaction/deprotection to obtain lavandiolide I and artemimatrilide F; under the acidic condition, the lavondiolide I is subjected to C-10 hydroxyl configuration isomerization to obtain lavondiolide H; the lavandiolide H is reduced to obtain lavandiolide I,
in the formula (I), R is methyl, (dimethylamino) methylene, (diethylamino) methylene, piperidyl methylene, morpholinyl methylene, phenylselenomethylene, substituted phenylselenomethylene, thiophenylmethylene and substituted thiophenylmethylene.
2. The method for preparing guaiane sesquiterpene dimer lavandiolides H, I, K and artomatrolide F according to claim 1, wherein the step of preparing the diene compound by reacting arglabin or a derivative thereof as a raw material with an isomerization reagent in a reaction solvent, wherein the isomerization reagent is 2,2,6, 6-tetramethylpiperidyldiethylaluminum or dicyclo-amino-aluminum or diisopropylamino-diethylaluminum or 2,2,6, 6-tetramethylpiperidyldiethylaluminum; the reaction solvent is toluene or benzene or diethyl ether or tetrahydrofuran; or the isomerization reagent is titanocene monochloride, and the reaction solvent is toluene, benzene, diethyl ether or tetrahydrofuran.
3. The method for preparing lavandrolides H, I, K and artmatrilide F as claimed in claim 1, wherein the step of preparing lavandrolides I and artmatrilide F by Diels-Alder reaction/deprotection of diene and arglabin or dehydroleucodin is carried out, wherein Diels-Alder reaction takes benzene, toluene, xylene and tetrahydrofuran as solvents, and diene and arglabin or dehydroleucodin react under heating condition; or 2, 6-di-tert-butyl-4-methylphenol is taken as an antioxidant, benzene, toluene, xylene and tetrahydrofuran are taken as solvents, and diene reacts with arglabin or dehydroleucodin under the heating condition; or the diene reacts with the arglabin or dehydroleucodin at room temperature under the condition of no solvent; or the diene and the arglabin or dehydroleucodin are heated to react under the condition of no solvent.
4. The method for preparing lavondiolides H, I, K and artomatrolide F as claimed in claim 1, wherein said lavondiolide I is prepared under the action of acid to obtain lavondiolide H, wherein the acid is nitro salicylic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, perchloric acid.
5. The method for preparing lavondiolides H, I, K and artmatrilide F as claimed in claim 1, wherein the reducing agent used in the step of preparing lavondiolide I by reducing lavondiolide H is sodium borohydride/methanol, sodium borohydride/ethanol, sodium borohydride/tetrahydrofuran, sodium borohydride/dioxane.
6. The preparation method of guaiane sesquiterpene dimer lavandiolides H, I, K and artemimatrilide F comprises the steps of taking arglabin or derivatives thereof as a raw material, obtaining a diene body through epoxy isomerization, obtaining the diene body and another molecule of arglabin or dehydroleucodin through Diels-Alder reaction/deprotection to obtain lavandiolide I and artemimatrilide F; under the acidic condition, the Lavandiolide I is subjected to C-10 hydroxyl configuration isomerization to obtain Lavandiolide H; the lavandiolide H is reduced to obtain lavandiolide I,
in the formula (I), R is methyl, (dimethylamino) methylene, (diethylamino) methylene, piperidylmethylene, morpholinylpiperidylmethylene, phenylselenomethylene, substituted phenylselenomethylene, phenylthiomethylene, substituted phenylthiomethylene;
in the step of preparing the diene by reacting arglabin or a derivative thereof serving as a raw material with an isomerization reagent in a reaction solvent, wherein the isomerization reagent is 2,2,6, 6-tetramethyl piperidyl diethyl aluminum or dicyclo amino aluminum or diisopropyl amino diethyl aluminum or 2,2,6, 6-tetramethyl piperidyl dimethyl aluminum; the reaction solvent is toluene or benzene or diethyl ether or tetrahydrofuran; or the isomerization reagent is titanocene monochloride, and the reaction solvent is toluene, benzene, diethyl ether or tetrahydrofuran;
in the step of preparing lavendiolide I and artemimatride F by Diels-Alder reaction/deprotection of the diene body and the arglabin or the dehydroleucodin, wherein the Diels-Alder reaction takes benzene, toluene, xylene and tetrahydrofuran as solvents, and the diene body and the arglabin or the dehydroleucodin react under the heating condition; or 2, 6-di-tert-butyl-4-methylphenol is taken as an antioxidant, benzene, toluene, xylene and tetrahydrofuran are taken as solvents, and diene reacts with arglabin or dehydroleucodin under the heating condition; or, the diene reacts with the arglabin or dehydroleucodin at room temperature under the condition of no solvent; or the diene and the arglabin or dehydroleucodin are heated to react under the condition of no solvent;
in the step of preparing the lavondiolide H under the action of acid, the acid is nitro salicylic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid and perchloric acid;
in the step of preparing the lavondioide I by reducing the lavondioide H, the reducing agents used are sodium borohydride/methanol, sodium borohydride/ethanol, sodium borohydride/tetrahydrofuran and sodium borohydride/dioxane.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585841A (en) * | 2008-05-22 | 2009-11-25 | 北京大学 | Guaianolide sesquiterpene dimers, preparation method thereof and use thereof |
| CN104311572A (en) * | 2014-09-11 | 2015-01-28 | 中国科学院成都生物研究所 | Ainsliatrimer B preparation method |
| CN106459078A (en) * | 2014-04-24 | 2017-02-22 | 北京生命科学研究所 | Sesquiterpenoids |
| CN110343116A (en) * | 2018-12-21 | 2019-10-18 | 中山大学 | A kind of Flos Chrysanthemi Indici extract and preparation method thereof and the application in preparation treatment medicine for nasopharyngeal |
| CN112225746A (en) * | 2020-11-15 | 2021-01-15 | 中国科学院昆明植物研究所 | Artemisia sphaerocephala lactone A-R and pharmaceutical composition and application thereof |
-
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585841A (en) * | 2008-05-22 | 2009-11-25 | 北京大学 | Guaianolide sesquiterpene dimers, preparation method thereof and use thereof |
| CN106459078A (en) * | 2014-04-24 | 2017-02-22 | 北京生命科学研究所 | Sesquiterpenoids |
| CN104311572A (en) * | 2014-09-11 | 2015-01-28 | 中国科学院成都生物研究所 | Ainsliatrimer B preparation method |
| CN110343116A (en) * | 2018-12-21 | 2019-10-18 | 中山大学 | A kind of Flos Chrysanthemi Indici extract and preparation method thereof and the application in preparation treatment medicine for nasopharyngeal |
| CN112225746A (en) * | 2020-11-15 | 2021-01-15 | 中国科学院昆明植物研究所 | Artemisia sphaerocephala lactone A-R and pharmaceutical composition and application thereof |
Non-Patent Citations (10)
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115010719A (en) * | 2022-04-11 | 2022-09-06 | 中国科学院昆明植物研究所 | Guaiane sesquiterpene dimer and derivative thereof and application of guaiane sesquiterpene dimer and derivative thereof in pharmacy |
| CN115010719B (en) * | 2022-04-11 | 2023-09-05 | 中国科学院昆明植物研究所 | Guaiane sesquiterpene dimer and derivative thereof and application of guaiane sesquiterpene dimer and derivative in pharmacy |
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