CN110845512A - Total synthesis method of triterpenoid natural product (+) -Arisugacins F/G - Google Patents
Total synthesis method of triterpenoid natural product (+) -Arisugacins F/G Download PDFInfo
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract
The invention discloses a total synthesis method of a natural product (+) -ArisugacinSF/G of heteroterpenoids, belonging to the field of organic synthesis. Oleanolic acid is used as a chiral source starting material, and chiral intermediate aldehyde is obtained through active group protection, free radical elimination, ring opening reaction, cis-trans isomerization and oxidative hydrolysis; then carrying out a [3+3] cycloaddition reaction on the raw materials and pyrone, and carrying out hydrogenation reduction to generate (+) -Arisugacins F; subsequent oxidation gives (+) -Arisugacin G. In the invention, the chiral source starting material oleanolic acid is commercially available, the reaction conditions of each unit in the reaction process are mild and controllable, the stereoselectivity of the key reaction is strong, and the method has potential application value in the total synthesis of natural product of the terpenoids and the discovery of medicines.
Description
Technical Field
The invention relates to a method for totally synthesizing a natural heteroterpenoid compound, in particular to (+) -Arisugacins F and (+) -Arisugacins G, belonging to the technical field of organic synthesis.
Background
Alzheimer's disease is a degenerative neurological disorder characterized primarily by cognitive impairment involving alterations and abnormalities of the cholinergic system, the dopamine system, the adenosine receptor system, the adrenergic receptor system, and the like. The Arisugacins series of compounds are natural products extracted from Penicillium FO-4259, are typical acetylcholinesterase (AChE) inhibitors, and therefore their research and synthesis are advantageous for the screening and discovery of new drugs.
Arisugasins F and G, which are relatively simple structures in the Arisugasins series of compounds, are considered as important intermediates for the biosynthesis of the series of compounds, and have the following structural formulas:
in 1995
The group determined the structure, and the study found that this class of compounds exhibited significant AChE inhibitory activity. In 2003, the group reported a method for synthesizing the racemates aristuccins F and G (j.antiblock., 2003,56, 730).
Because the natural product has a plurality of chiral centers and the chiral centers have the specificity, the total synthesis research is few, and the further application of the natural product of the hetero terpenoids in the drug development is limited.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a total synthesis method of a natural product of the terpenoids, in particular (+) -Arisugacins F and (+) -Arisugacins G. Taking commercially available oleanolic acid as a chiral source starting material, and carrying out active group protection, free radical elimination, ring-opening reaction, cis-trans isomerization and oxidative hydrolysis to obtain a chiral intermediate aldehyde 6; then the intermediate and pyrone 7 undergo [3+3] cycloaddition reaction and hydrogenation reduction to generate (+) -Arisugacins F; (+) -Arisugcins F undergoes an oxidation reaction to produce (+) -Arisugcins G. The synthesis method has the advantages of easily obtained commercial chiral source starting materials, mild and controllable reaction conditions of each unit in the reaction process, and strong stereoselectivity of key reaction. Has important application value in the complete synthesis of the natural product of the hetero terpenoids and the discovery of medicaments.
The total synthesis method of (+) -Arisugacin F and (+) -Arisugacin G comprises the following steps: from oleanolic acid 1, sequentially carrying out active group protection, free radical elimination, ring opening reaction, cis-trans isomerization, oxidative hydrolysis, 3+3 cycloaddition reaction and hydrogenation reduction to obtain (+) -Arisugacins F, and then carrying out oxidation reaction to obtain (+) -Arisugacins G. The following equation is used:
the reaction specifically comprises the following steps:
first step, active group protection:
reacting oleanolic acid 1, alkali and a methylating agent in a polar aprotic solvent, and then reacting with acetic anhydride or acetyl chloride to obtain an intermediate 2;
wherein the methylating agent is selected from dimethyl carbonate, dimethyl sulfate, methyl iodide, etc. The base is selected from inorganic base (such as potassium carbonate, sodium carbonate, cesium carbonate, etc.) or organic base (such as triethylamine, diisopropylethylamine, etc.), preferably potassium carbonate or cesium carbonate. The polar aprotic solvent is selected from DMF, DMSO, dioxane, etc.
Further, under the reaction conditions, the molar ratio of the oleanolic acid 1 to the methylating agent to the alkali is 1: 0.8-1.5: 1-3; the preferred molar ratio is 1: 1-1.2: 1.5-2.
The typical operation of this step is as follows: sequentially adding oleanolic acid 1, alkali and a polar aprotic solvent into a reaction kettle, dropwise adding a methylation reagent, and reacting at room temperature; after the reaction is finished, adding saturated solution of ammonium chloride for quenching, extracting and separating liquid, washing and drying an organic layer, removing solvent and concentrating, and then adding acetic anhydride for reflux reaction; after the reaction is finished, adding saturated sodium chloride solution for quenching, extracting and separating liquid, washing and drying an organic layer, and then performing desolventizing and concentrating.
Second step, eliminating free radicals:
reacting the intermediate 2 with a brominating agent in a chlorohydrocarbon solvent in the presence of a free radical initiator to generate an intermediate 3;
wherein the brominating agent is selected from N-bromosuccinimide (NBS), dibromohydantoin and the like. The free radical initiator is selected from Azobisisobutyronitrile (AIBN), Benzoyl Peroxide (BPO), etc. The halogenated hydrocarbon solvent is selected from carbon tetrachloride, chloroform, dichloroethane, etc.
Further, under the reaction conditions, the molar ratio of the intermediate 2, the brominating agent and the radical initiator is 1: 0.8-2: 0.01-0.2; the preferred molar ratio is 1: 2: 0.05.
the typical operation of this step is as follows: sequentially adding the intermediate 2 and a halogenated hydrocarbon solvent into a reaction kettle, heating and refluxing, and adding a bromization reagent and a free radical initiator in batches; and after the reaction is finished, adding saturated salt solution for quenching, extracting, separating liquid, washing and drying an organic layer, removing solvent, concentrating, adding alkane, crystallizing and purifying to obtain an intermediate 3.
Step three, ring opening reaction:
carrying out a light irradiation reaction on the intermediate 3 in an alcohol solvent to generate an intermediate cis-4;
wherein the alcohol solvent is selected from ethanol, isopropanol, n-propanol, etc., preferably ethanol. The light irradiation adopts a high-pressure mercury lamp.
The typical operation of this step is as follows: sequentially adding the intermediate 3 and an alcohol solvent into the reaction kettle, and irradiating by a high-pressure mercury lamp for reaction; after the reaction is finished, desolventizing and concentrating, and purifying by silica gel column chromatography to obtain a cis-form intermediate 4.
Fourthly, configuration inversion reaction:
heating the intermediate cis-4 and an acid catalyst in an organic solvent in the presence of a palladium catalyst to react to generate an intermediate trans-5;
wherein the palladium catalyst is selected from Pd (PPh)3)4、Pd2(dba)3Or Pd (t-Bu)3P)2At least one of them. The acid catalyst is selected from AgOTf, Sc (OTf)3Camphor sulfonic acid, and the like. The reaction solvent is selected from common solvents such as toluene, dioxane, DMF, THF, etc.
Further, under the above reaction conditions, the molar ratio of the intermediate 4, the palladium catalyst and the acid catalyst is 1: 0.01-0.20: 0.01-0.20; the preferred molar ratio is 1: 0.05-0.10: 0.05-0.10.
The typical operation of this step is as follows: sequentially adding the intermediate 4, a palladium catalyst, an acid catalyst and a reaction solvent into a reaction kettle, and heating for reaction; and after the reaction is finished, adding saturated sodium bicarbonate for quenching, extracting, separating liquid, washing and drying an organic layer, desolventizing and concentrating, and purifying by fast silica gel column chromatography to obtain a trans-form intermediate 5.
Step five, oxidizing hydrolysis:
reacting the intermediate trans-5 with sodium periodate in a mixed solvent in the presence of ruthenium trichloride, and then reacting with lithium hydroxide to generate an intermediate 6;
under the reaction conditions, the molar ratio of the intermediate 5, the ruthenium trichloride catalyst, the sodium periodate and the lithium hydroxide is 1: 0.01-0.20: 2-30: 2-30; the preferred molar ratio is 1: 0.05-0.10: 10-20: 10-20.
The typical operation of this step is as follows: sequentially adding the intermediate (5), acetone, a ruthenium trichloride catalyst, sodium periodate and water into a reaction kettle, and reacting at room temperature; after the reaction is finished, extracting and separating liquid, washing and drying an organic layer, then desolventizing and concentrating, dissolving in a methanol-water system, adding lithium hydroxide, reacting at room temperature, adding ethyl acetate after the reaction is finished, extracting and drying, and then desolventizing and concentrating. And performing silica gel column chromatography to obtain chiral intermediate aldehyde 6.
Sixth step, cycloaddition of [3+3]
Dissolving the intermediate 6 and the intermediate 7 in a solvent, adding ethylenediamine diacetate, and heating for reaction to obtain a cyclized intermediate 8.
Under the reaction conditions, the molar ratio of the intermediate 6 to the intermediate 7 to the ethylenediamine diacetate is 1: 1-3: 1-3; the preferred molar ratio is 1: 2-2.5: 1-1.5.
Wherein the reaction solvent is selected from common solvents such as toluene, dioxane, DMF, tetrahydrofuran, etc. The reaction temperature may be controlled at 60 to 120 deg.C, preferably 80 to 100 deg.C.
The typical operation of this step is as follows: sequentially adding the intermediate 6, the intermediate 7 and a reaction solvent into a reaction kettle, then adding ethylenediamine diacetate, and heating for reaction; after the reaction is finished, desolventizing and concentrating, and separating the product mixture by a silica gel column chromatography to obtain an intermediate 8.
Seventh step, hydrogenation reduction
Reacting the cyclization intermediate 8 in an organic solvent in the presence of palladium carbon and hydrogen to obtain (+) -Arisugacins F;
under the above reaction conditions, the mass ratio of the intermediate 8 to Pd/C was 1: 0.05-0.3; the preferable mass ratio is 1: 0.1-0.25; the pressure of hydrogen is 1atm to 5atm, preferably 1atm to 3 atm.
Wherein the reaction solvent is selected from common solvents such as methanol, ethanol, ethyl acetate, tetrahydrofuran, etc.
The typical operation of this step is as follows: sequentially adding the intermediate 8, a reaction solvent and Pd/C into a reaction kettle, then replacing the reaction system with hydrogen, and reacting at room temperature; after the reaction is finished, desolventizing and concentrating, and separating the product mixture by a silica gel column chromatography to obtain a product (+) -Arisugacins F.
Eighth step, oxidation reaction
Adding N-methylmorpholine oxide (NMO) and tetrapropyl ammonium homoruthenate (TPAP) into an organic solvent to react to obtain (+) -Arisugacins G.
Under the above reaction conditions, the molar ratio of (+) -Arisugacins F, NMO and TPAP is 1: 1-10: 0.2-0.8; the preferred molar ratio is 1: 3-6: 0.3-0.6.
Wherein the reaction solvent is selected from common solvents such as dichloromethane, acetonitrile and the like.
The typical operation of this step is as follows: sequentially adding (+) -Arisugacin F, an organic solvent, NMO and TPAP into a reaction kettle, and reacting at room temperature; and after the reaction is finished, adding saturated saline solution for washing, drying the organic phase, performing desolventizing concentration, and separating the product by a silica gel column chromatography to obtain a product (+) -Arisugcins G.
Wherein, in the whole synthesis scheme, the synthesis operation of the compound 7 is as follows: dissolving ethyl acetoacetate in an ether solvent, adding LDA and TMEDA, reacting for a period of time, adding methyl 4-methoxybenzoate, and after the reaction is finished, generating an intermediate 7 at high temperature under reduced pressure. Expressed as the following equation:
under the reaction conditions, the molar ratio of ethyl acetoacetate, LDA, TMEDA and 4-methoxy-methyl benzoate is 1: 1-3: 1-3: 0.8 to 2; the preferred molar ratio is 1: 1.5-2.5: 1-2: 1-1.5.
The typical operation of this step is as follows: dissolving ethyl acetoacetate in an organic solvent, sequentially dropwise adding LDA and TMEDA under a low-temperature condition, reacting for a period of time, and dropwise adding methyl 4-methoxybenzoate; after the reaction is finished, adding acetic acid for quenching, extracting and separating liquid after concentration, washing and drying an organic layer, desolventizing and concentrating, performing reduced pressure condensation under a high temperature condition after silica gel column chromatography and purification, and adding ethyl acetate for recrystallization to obtain an intermediate 7.
Advantageous effects of the invention
The invention provides a full synthesis method of natural products (+) -Arisugacin F and (+) -Arisugacin G for the first time, the synthesis method has the advantages that the initial raw materials of chiral sources are commercially available, the reaction conditions of all units in the reaction process are mild and controllable, and the stereoselectivity of key reaction is strong. Has important application value in the complete synthesis of the natural product of the hetero terpenoids and the discovery of medicaments.
Detailed Description
The technical solution of the present invention will be described in further detail with reference to specific examples.
Example 1
1) The intermediate 2 is synthesized by the following specific steps:
45.7g of oleanolic acid 1(0.1mol), 27.6g of potassium carbonate (0.2mol) and 400g of DMF are sequentially put into a dry 1L four-mouth bottle, 21.3g of methyl iodide (0.15mol) is slowly dripped at 0 ℃, after the dripping is finished, the mixture is stirred and reacted for 24 hours at room temperature, and the reaction raw material oleanolic acid is completely converted by TLC detection.
Cooling to room temperature after the reaction is finished, adding 500g of saturated sodium chloride to quench the reaction, stirring for 0.5h, adding ethyl acetate to extract and separate layers, keeping an organic phase, washing the organic phase twice with 2 x 250g of water, adding anhydrous sodium sulfate to the organic phase, drying, filtering and concentrating to obtain a white solid, dissolving the white solid in 200g of acetic anhydride, heating and refluxing for 24h, cooling to room temperature, adding 400g of saturated saline and 400g of ethyl acetate to extract and separate the liquid, keeping the organic phase, washing the organic phase twice with 2 x 250g of water, adding anhydrous sodium sulfate to the organic phase, drying, filtering and concentrating to obtain 48.0g of the white solid, namely the target intermediate 2, the yield is 93.6%, the melting point is 218 ℃., [ α ]]25 D＝+71.6(c 1,CHCl3).1H NMR(500MHz,CDCl3)δ5.29(t,J＝3.5Hz,1H),4.57–4.42(m,1H),3.63(s,3H),2.87(dd,J＝13.8,4.2Hz,1H),2.05(s,3H),2.02–1.86(m,3H),1.76–1.25(m,15H),1.23–1.15(m,2H),1.13(s,3H),1.10–1.02(m,2H),0.94(s,3H),0.93(s,3H),0.91(s,3H),0.87(s,3H),0.86(s,3H),0.73(s,3H).13C NMR(125MHz,CDCl3)δ178.3,171.0,143.8,122.3,80.9,55.3,51.5,47.6,46.7,45.8,41.6,41.3,39.3,38.1,37.7,36.9,33.9,33.1,32.6,32.4,30.7,28.0,27.7,25.9,23.6,23.5,23.4,23.1,21.3,18.2,16.8,16.7,15.4.HRMS(ESI):m/z(M+Na)+calcd for:C33H52NaO4 +:535.3763；found:535.3760.
2) The intermediate 3 is synthesized by the following specific steps:
a dry 1L four-mouth bottle is charged with 46.1g of intermediate 2(0.09mol) and 500g of carbon tetrachloride in sequence, heated to reflux, and slowly added with a mixture of 16.02g of NBS (0.09mol) and 1.18g of AIBN (0.0072mol) in portions, after the charging, the reaction is refluxed for 24 hours, and TLC detection is carried out, so that the conversion of the reaction intermediate 2 is complete.
After the reaction, adding 200g of saturated sodium chloride solution to quench the reaction, adding dichloromethane to extract and separate layers, keeping an organic phase, washing the organic phase twice with 2 x 100g of saturated common salt water, adding anhydrous sodium sulfate to the organic phase, drying, filtering and concentrating to obtain a light yellow solid, adding n-hexane to recrystallize to obtain 39.7g of a white solid, wherein the white solid is the target intermediate 3, the yield is 86.3%, the melting point is 206 ℃., [ α ], [ 208 ]]25 D＝+188(c 0.1,CHCl3).1H NMR(500MHz,CDCl3)δ5.57(q,J＝5.8Hz,2H),4.52(dd,J＝11.5,5.0Hz,1H),3.64(s,3H),3.02(dd,J＝13.5,4.0Hz,1H),2.06(s,3H),2.05–1.90(m,2H),1.79–1.25(m,14H),1.24–1.16(m,5H),1.15–1.06(m,1H),1.01(s,3H),0.95(s,3H),0.94(s,3H),0.91(s,3H),0.90(s,3H),0.88(s,3H).13C NMR(125MHz,CDCl3)δ178.3,171.0,154.2,145.2,120.5,115.8,80.5,51.7,51.2,46.1,45.8,42.3,40.7,39.6,38.7,37.8,36.8,33.7,33.0,32.2,32.1,30.7,28.1,26.9,25.2,25.1,24.2,23.7,23.6,21.3,20.2,20.1,18.1,16.7.HRMS(ESI):m/z(M+H)+calcd for:C33H51O4 +:511.3787；found:511.3776.
3) The intermediate 4 is synthesized by the following specific steps:
35.8g of intermediate 3(0.07mol) and 1200g of ethanol were sequentially charged into a dry 2L four-necked flask, and the reaction was carried out at room temperature by irradiation with a 500W high-pressure mercury lamp, and the intermediate 3 was completely converted by TLC detection.
After the reaction is finished, the system is subjected to desolventizing and concentration to obtain yellow viscous liquid, and the yellow viscous liquid is purified by silica gel column chromatography to obtain 31.3g of light yellow syrupy compound serving as a target intermediate 4 with the yield of 87.6 percent [ α ]]25 D＝+231(c 0.1,CHCl3).1H NMR(500MHz,CDCl3)δ6.02(d,J＝12.5Hz,1H),5.83(d,J＝12.5Hz,1H),4.55(dd,J＝11.5,4.5Hz,1H),3.65(s,3H),2.82(dd,J＝13.0,4.0Hz,1H),2.35-2.15(m,2H),2.06(s,3H),2.00-1.80(m,4H),1.75-1.52(m,7H),1.50(s,3H),1.48-1.40(m,3H),1.35-1.25(m,5H),1.20-1.15(m,1H),1.13(s,3H),0.914(s,3H),0.907(s,3H),0.90(s,3H),0.88(s,3H).13C NMR(125MHz,CDCl3)δ178.3,171.0,137.7,134.4,132.8,129.6,127.9,127.2,80.9,51.6,50.5,45.3,43.0,38.5,37.9,37.1,35.5,34.1,32.9,32.8,30.7,29.8,28.2,26.9,24.9,24.3,22.6,21.9,21.5,21.3,20.8,18.7,16.7.HRMS(ESI):m/z(M+H)+calcd for:C33H51O4 +:511.3787；found:511.3782.
4) The intermediate 5 is synthesized by the following specific steps:
into a dry 1L four-necked flask, 28.1g of intermediate 4(0.055mol) and 3.17g of Pd (PPh) were charged in this order3)4(0.00275mol), 0.71g AgOTf (0.00275mol) and 500g toluene, replaced by nitrogen and heated to 90 ℃ under the protection of nitrogen for 24h, and detected by TLC, the intermediate 4 is completely converted.
After the reaction, 300g of saturated aqueous sodium bicarbonate solution is added to quench the reaction, extraction and liquid separation are carried out, anhydrous sodium sulfate is dried, filtered and concentrated to obtain light yellow oily liquid, silica gel column chromatography purification is carried out to obtain 24.0g of light yellow syrup which is the target intermediate 5, and the yield is 85.5% [ α ]]25 D＝+110(c 0.1,CHCl3).1H NMR(400MHz,CDCl3)δ6.15(d,J＝16.2Hz,1H),5.95(d,J＝16.2Hz,1H),4.49(dd,J＝12.0,4.0Hz,1H),3.60(s,3H),3.19-3.05(m,1H),2.21-2.04(m,4H),2.03(s,3H),1.90-1.81(m,1H),1.76-1.67(m,4H),1.66(s,3H),1.63(s,3H),1.59-1.05(m,10H),1.03(s,3H),0.98(s,3H),0.88(s,3H),0.876(s,3H),0.87(s,3H).13C NMR(100MHz,CDCl3)δ178.3,171.1,141.3,132.4,131.4,129.6,126.8,123.0,81.0,51.7,50.7,45.7,42.2,37.9,36.2,34.1,33.6,33.3,32.9,32.1,30.9,30.7,28.1,24.2,24.1,22.4,21.5,21.4,20.5,19.1,18.6,16.6.HRMS(APCI):m/z(M+H)+calcdfor:C33H51O4 +:511.3787；found:511.3786.
5) The intermediate 6 is synthesized by the following specific steps:
into a dry 2L four-necked flask were charged 23.0g of intermediate 5(0.045mol), 500g of acetone, and 0.59g of RuCl in this order3·3H2O (0.0025mmol), 96.2g NaIO was added dropwise at room temperature4(0.45mol)/1L of the aqueous solution, and reacting at room temperature for 1h after the dropwise addition.
After the reaction is finished, desolventizing and concentrating, adding dichloromethane and saline water for extraction and liquid separation, drying and concentrating the organic phase, directly dissolving 500g of methanol/water with the volume ratio of 1/1 in the residue, then adding 10.8g (0.45mol) of lithium hydroxide, and reacting for 24 hours at room temperature.
After the reaction, 200g of saturated saline solution is added for quenching, ethyl acetate is added for extraction and liquid separation, anhydrous sodium sulfate is added for drying, filtration and concentration, silica gel column chromatography is carried out on the kettle residue to obtain 3.0g of light yellow solid, the yield is 28.2 percent, and the product is confirmed to be an intermediate 6 through nuclear magnetism, the melting point is 104 ℃, the temperature is 106 ℃, and the temperature is α]25 D＝-16(c 0.1,CHCl3).1H NMR(400MHz,CDCl3)δ10.03(s,1H),3.24(dd,J＝11.2,5.2Hz,1H),2.64(dt,J＝13.6,3.6Hz,1H),2.31-2.24(m,2H),2.03(s,3H),1.75-1.44(m,5H),1.16(s,3H),1.13-1.03(m,1H),1.01(s,3H),0.82(s,3H).13C NMR(100MHz,CDCl3)δ192.3,154.7,143.2,78.7,51.1,39.0,37.4,36.9,34.3,28.3,27.82,20.0,19.0,18.1,15.6.HRMS(ESI):m/z(M+H)+calcd for:C15H25O2 +:237.1855；found:237.1850.
6) The intermediate 7 is synthesized by the following specific steps:
13.0g (0.1mol) of ethyl acetoacetate and 400g of tetrahydrofuran were put into a dry 1L four-necked flask in this order, the temperature was lowered to-78 ℃ and 125.0mL (0.25mol) of a 2M LDA solution was added dropwise, and after the addition, 11.6g of TMEDA (0.1mol) was added dropwise. The reaction mixture was reacted at-78 ℃ for 3 hours, 16.6g of methyl 4-methoxybenzoate (0.1mol) was added dropwise, and the reaction mixture was allowed to return to room temperature and reacted for 24 hours.
After the reaction is finished, adding 20mL of acetic acid for quenching, stirring for 0.5h, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography. The intermediate product obtained is heated to 150 ℃ under high vacuum (0.5mmHg) and reacted for 3 h. The system was cooled to room temperature, 30mL of ice ethyl acetate was added, stirred for 30min, filtered and the resulting yellow solid washed with cold ethyl acetate (5mL × 2) to give 7.2g of yellow solid as intermediate 7 in 33.0% yield. Melting point 204-206 ℃.1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),7.76(d,J＝8.4Hz,2H),7.02(d,J＝8.4Hz,2H),6.60(s,1H),5.29(d,J＝1.2Hz,1H),3.79(s,3H).13CNMR(100MHz,DMSO-d6)δ171.3,163.7,161.9,160.8,127.8,124.0,115.0,97.2,89.2,56.0.HRMS(ESI):m/z(M+H)+calcd for:C12H11O4 +:219.0657；found:219.0652.
7) The intermediate 8 is synthesized by the following specific process:
a dry 250mL four-necked flask was charged with 2.4g of intermediate 6(0.01mol), 4.4g of intermediate 7(0.02mol), 100g of toluene, and 1.8g of ethylenediamine diacetate (0.01mmol) in this order, and the mixture was heated at 90 ℃ for reaction for 24 hours.
After the reaction is finished, cooling, desolventizing and concentrating, carrying out silica gel column chromatography on the residue in the kettle to obtain 1.3g of off-white solid, wherein the off-white solid is confirmed to be an intermediate 8 through nuclear magnetism, the yield is 29.8%, the melting point is 200-]25 D＝+65(c 0.04,CHCl3).1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),6.33(s,1H),6.25(s,1H),3.84(s,3H),3.24(dd,J＝11.5,4.5Hz,1H),2.28-2.15(m,1H),2.05-1.60(m,7H),1.50(s,3H),1.27-1.22(m,1H),1.15(s,3H),1.02(s,3H),0.82(s,3H).13C NMR(100MHz,CDCl3)δ162.8,162.4,161.8,159.8,146.2,127.3,124.0,114.4,109.4,100.2,96.1,81.9,78.4,77.3,55.5,51.3,41.3,39.2,39.2,36.3,28.2,27.6,27.1,23.8,19.1,15.6.HRMS(ESI):m/z(M+H)+calcd for:C27H33O5 +:437.2328；found:437.2326.
8) The synthesis of (+) -Arisugacin F comprises the following specific steps:
into a dry 250mL four-necked flask, 0.87g of intermediate 8(0.002mol), 100g of tetrahydrofuran and 0.087g of 10% Pd/C were sequentially charged, and the reaction system was replaced with hydrogen gas and reacted at room temperature under hydrogen gas for 4 hours.
After the reaction, filtering, desolventizing and concentrating the organic phase, carrying out silica gel column chromatography on the residue to obtain 0.335g of off-white solid, wherein the yield is determined as (+) -Arisugacins F by nuclear magnetism, the melting point is 254 ℃., [ α ]]25 D＝+61(c 0.1,CHCl3).1H NMR(500MHz,CDCl3)δ7.73(d,J＝8.5Hz,2H),6.93(d,J＝8.5Hz,2H),6.25(s,1H),3.85(s,3H),3.24(dd,J＝11.5,4.5Hz,1H),2.51(dd,J＝16.5,4.5Hz,1H),2.28-2.18(m,1H),2.15-2.10(m,1H),1.84-1.77(m,2H),1.72-1.66(m,3H),1.49(dd,J＝13.0,5.0Hz,1H),1.46-1.42(m,1H),1.26(s,3H),1.15-1.08(m,1H),1.03(s,3H),1.02-0.98(m,1H),0.91(s,3H),0.82(s,3H).13C NMR(125MHz,CDCl3)δ164.7,163.5,161.5,158.3,127.0,124.0,114.2,98.4,96.7,80.6,78.5,55.4,55.0,51.6,40.4,38.8,37.5,36.9,28.1,27.2,20.7,19.4,17.2,15.5,15.1.HRMS(ESI):m/z(M+H)+calcd for:C27H35O5 +:439.2484；found:439.2480.
9) The synthesis of (+) -Arisugacin G comprises the following specific steps:
to a dry 100mL four-necked flask, 0.13g of (+) -Arisugcins F (0.0003mol), 30g of dichloromethane, 0.21g of NMO (0.0018mol), and 0.53g of TPAP (0.0015mol) were sequentially charged and reacted at room temperature for 4 hours.
After the reaction is finished, adding saturated saline solution for extraction and liquid separation, washing an organic phase twice by using the saturated saline solution, drying the organic phase, desolventizing and concentrating, and carrying out silica gel column chromatography on kettle residues to obtain 0.12G of off-white solid, wherein the yield is determined as (+) -Arisugacin G through nuclear magnetism, the melting point is 155-]25 D＝+114(c 0.1,CHCl3).1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.9Hz,2H),6.93(d,J＝8.9Hz,2H),6.25(s,1H),3.84(s,3H),2.62-2.41(m,3H),2.33-2.23(m,1H),2.18-2.12(m,1H),2.10-2.01(m,1H),1.78-1.69(m,2H),1.63-1.50(m,4H),1.30(s,3H),1.12(s,3H),1.06(s,3H),1.03(s,3H).13C NMR(125MHz,CDCl3)δ216.1,164.6,163.5,161.6,158.6,127.0,124.0,114.3,98.2,96.6,80.2,55.4,54.7,51.0,47.3,39.8,37.9,36.7,33.8,26.6,21.3,20.6,20.5,17.3,14.7.HRMS(APCI):m/z(M+H)+calcd for:C27H33O5 +:437.2328found:437.2320.
Example 2
1) The intermediate 2 is synthesized by the following specific steps:
4.57g of oleanolic acid 1(0.01mol), 2.76g of potassium carbonate (0.02mol) and 400g of DMF are sequentially put into a dry 100mL four-mouth bottle, 1.9g of dimethyl sulfate (0.015mol) is slowly dripped at 0 ℃, after the dripping is finished, the reaction is stirred at room temperature for 24 hours, and TLC detection is carried out, so that the oleanolic acid serving as a reaction raw material is completely converted.
After the reaction is finished, cooling to room temperature, adding 50g of saturated sodium chloride to quench the reaction, stirring for 0.5h, adding ethyl acetate to extract and stratify, and keeping an organic phase; washing the organic phase with 2 × 25g of water, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a white solid, dissolving the white solid in 20g of acetic anhydride, heating and refluxing for reaction for 24 hours, cooling to room temperature, adding 40g of saturated saline and 40g of ethyl acetate, extracting and separating the liquid, and keeping the organic phase; the organic phase was washed with 2 × 25g of water, dried over anhydrous sodium sulfate, filtered and concentrated to give 4.3g of a white solid as the target intermediate 2 in 84.0% yield.
2) The intermediate 3 is synthesized by the following specific steps:
4.1g of intermediate 2(0.008mol) and 50g of 1, 2-dichloroethane are sequentially put into a dry 100mL four-necked flask, heated and refluxed, and a mixture of 1.4g of NBS (0.008mol) and 0.12g of AIBN (0.00072mol) is gradually added in portions, and after the addition is finished, the reaction is refluxed for 24 hours, and TLC detection is carried out, so that the conversion of the reaction intermediate 2 is completed.
After the reaction is finished, adding 20g of saturated sodium chloride solution to quench the reaction, extracting and separating liquid, washing 2 x 10g of organic phase saturated salt water, drying with anhydrous sodium sulfate, filtering and concentrating; a pale yellow solid was obtained, and n-hexane was added to recrystallize, to obtain 3.5g of a white solid, which was the target intermediate 3, with a yield of 85.3%.
3) The intermediate 4 is synthesized by the following specific steps:
a dry 250mL four-necked flask was charged with 3.5g of intermediate 3(0.007mol) and 100g of ethanol in this order, and the reaction was carried out at room temperature using a 500W high-pressure mercury lamp, followed by TLC detection, whereby the conversion of the starting material, intermediate 3, was complete.
After the reaction is finished, the system is desolventized and concentrated; a yellow viscous liquid was obtained and purified by silica gel column chromatography to obtain 3.0g of a pale yellow syrupy compound as the objective intermediate 4 in a yield of 85.7%.
4) The intermediate 5 is synthesized by the following specific steps:
a dry 100mL four-necked flask was charged with 2.8g of intermediate 4(0.0055mol) and 0.32g of Pd (PPh) in this order3)4(0.000275mol)、0.14g Sc(OTf)3(0.000275mol) and 50g of toluene, replaced by nitrogen, heated to 90 ℃ under the protection of nitrogen, reacted for 24h, detected by TLC, and the conversion of the reaction raw material, namely the intermediate 4, is complete.
After the reaction is finished, adding 30g of saturated sodium bicarbonate aqueous solution to quench the reaction, extracting and separating liquid, drying the organic phase anhydrous sodium sulfate, filtering and concentrating; a pale yellow oily liquid was obtained, which was purified by silica gel column chromatography to obtain 2.3g of a pale yellow syrupy compound as the objective intermediate 5 in a yield of 82.1%.
5) The intermediate 6 is synthesized by the following specific steps:
a dry 250mL four-necked flask was charged with 2.3g of intermediate 5(0.0045mol), 50g of acetone, and 0.059g of gGluCl in that order3·3H2O (0.00025mmol), 14.4g NaIO was added dropwise at room temperature4(0.00675mol)/100mL of the aqueous solution, after the dropwise addition, the reaction was carried out at room temperature for 1 h.
After the reaction, the mixture was desolventized and concentrated, dichloromethane and brine were added to extract and separate the liquid, the organic phase was dried and concentrated, and the residue was directly dissolved in 50g of methanol/water at a volume ratio of 1/1, and then 1.1g (0.045mol) of lithium hydroxide was added to the solution, and the reaction was carried out at room temperature for 24 hours.
After the reaction is finished, adding 20g of saturated saline solution for quenching, adding ethyl acetate for extraction and liquid separation, drying with anhydrous sodium sulfate, filtering and concentrating; performing silica gel column chromatography on the residue to obtain light yellow solid 0.33g as an intermediate 6 with the yield of 31.1%,
6) the intermediate 8 is synthesized by the following specific process:
a dry 50mL three-necked flask was charged with 0.31g of intermediate 6(0.0013mol), 0.57g of intermediate 7(0.0026mol), 10g of toluene, and 0.234g of ethylenediamine diacetate (0.0013mmol) in this order, and the mixture was heated at 90 ℃ for reaction for 24 hours.
After the reaction, the temperature was reduced, the solvent was removed, the reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.17g of an off-white solid, which was intermediate 8, with a yield of 30.0%.
7) The synthesis of (+) -Arisugacin F comprises the following specific steps:
a dry 50mL four-necked flask was charged with 0.17g of intermediate 8(0.00039mol), 10g of tetrahydrofuran and 0.003g of 10% Pd/C in this order, and the reaction system was replaced with hydrogen to conduct a reaction at room temperature under hydrogen for 6 hours.
After the reaction, the mixture is filtered, the organic phase is desolventized and concentrated, and the residue is subjected to silica gel column chromatography to obtain 0.07g of off-white solid with the yield of 41.2 percent.
8) The synthesis of (+) -Arisugacin G comprises the following specific steps:
to a dry 10mL single-neck flask, 0.07g of (+) -Arisugcins F (0.16mmol), 3g of dichloromethane, 0.075g of NMO (0.64mmol), and 0.02g of TPAP (0.064mmol) were charged in this order, and reacted at room temperature for 4 hours.
After the reaction is finished, adding saturated saline solution for extraction and liquid separation, washing an organic phase twice by using the saturated saline solution, drying the organic phase, carrying out desolventizing and concentration, and carrying out silica gel column chromatography on kettle residues to obtain 0.067G of off-white solid, wherein the yield is 95.7% of (+) -Arisugacin G determined by nuclear magnetism.
The foregoing embodiments describe the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, but that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (10)
1. The total synthesis method of the triterpenoid natural product (+) -Arisugacins F is characterized by comprising the following steps: from oleanolic acid 1, sequentially carrying out active group protection, free radical elimination, ring opening reaction, cis-trans isomerization, oxidative hydrolysis, 3+3 cycloaddition reaction and hydrogenation reduction to obtain (+) -Arisugacins F; the reaction equation is expressed as follows:
2. the total synthesis process of (+) -arisugins F according to claim 1, characterized in that:
first step, active group protection
Reacting oleanolic acid 1, alkali and a methylating agent in a polar aprotic solvent, and then reacting with acetic anhydride or acetyl chloride to obtain an intermediate 2;
second step, radical elimination
Reacting the intermediate 2 with a brominating agent in a chlorohydrocarbon solvent in the presence of a free radical initiator to generate an intermediate 3;
third step, Ring opening reaction
Carrying out a light irradiation reaction on the intermediate 3 in an alcohol solvent to generate an intermediate cis-4;
the fourth step, cis-trans isomerization
Heating the intermediate cis-4 and acid in an organic solvent in the presence of a palladium catalyst to react to generate an intermediate trans-5;
the fifth step, oxidizing hydrolysis
Reacting the intermediate trans-5 with sodium periodate in a mixed solvent in the presence of ruthenium trichloride, and then reacting with lithium hydroxide to generate an intermediate 6;
sixth step, cycloaddition of [3+3]
Heating the intermediate 6 and the intermediate 7 to react in the presence of ethylenediamine diacetate to obtain a cyclized intermediate 8;
seventh step, hydrogenation reduction
The cyclization intermediate 8 reacts in an organic solvent in the presence of palladium carbon and hydrogen to obtain (+) -Arisugacins F.
3. The process for the total synthesis of (+) -arisugins F according to claim 2Characterized in that: in the first step, the methylating agent is selected from dimethyl carbonate, dimethyl sulfate or methyl iodide; the base is selected from potassium carbonate or cesium carbonate; in the second step, the bromization reagent is selected from N-bromosuccinimide or dibromohydantoin, and the free radical initiator is selected from azobisisobutyronitrile or benzoyl peroxide; in the third step, a high-pressure mercury lamp is adopted for illumination; in the fourth step, the palladium catalyst is selected from Pd (PPh)3)4、Pd2(dba)3Or Pd (t-Bu)3P)2At least one acid catalyst selected from AgOTf, Sc (OTf)3Or camphorsulfonic acid.
4. The total synthesis process of (+) -arisugins F according to claim 2, characterized in that: in the first step, the molar ratio of oleanolic acid 1 to the methylating agent to the alkali is 1: 1-1.2: 1.5-2; in the second step, the molar ratio of the intermediate 2, the brominating agent and the radical initiator is 1: 0.8-2: 0.01-0.2; in the fourth step, the molar ratio of the intermediate 4, the palladium catalyst and the acid catalyst is 1: 0.05-0.10: 0.05-0.10; in the fifth step, the molar ratio of the intermediate 5, ruthenium trichloride, sodium periodate and lithium hydroxide is 1: 0.05-0.10: 10-20: 10-20 parts of; in the sixth step, the molar ratio of the intermediate 6 to the intermediate 7 to the ethylenediamine diacetate is 1: 2-2.5: 1-1.5; in the seventh step, the mass ratio of the intermediate 8 to the palladium-carbon is 1: 0.1-0.25.
5. The total synthesis process of (+) -arisugins F according to claim 2, characterized in that: in the first step, the polar aprotic solvent is selected from DMF, DMSO or dioxane; in the second step, the halogenated hydrocarbon solvent is selected from carbon tetrachloride, chloroform or 1, 2-dichloroethane; in the third step, the alcohol solvent is selected from methanol, ethanol, isopropanol or n-propanol; in the fourth step, the reaction solvent is selected from toluene, dioxane, DMF or THF; in the fifth step, the mixed solvent is selected from acetone/water or methanol/water mixture; in the sixth step, the reaction solvent is selected from toluene, dioxane, DMF or tetrahydrofuran; in the seventh step, the reaction solvent is selected from methanol, ethanol, ethyl acetate or tetrahydrofuran.
6. The total synthesis process of (+) -arisugins F according to claim 2, characterized in that: in the sixth step, the reaction temperature is controlled to be 80-100 ℃; in the seventh step, the pressure of the reaction hydrogen is 1-3 atm.
7. The total synthesis method of the diterpenoid natural product (+) -Arisugacin G is characterized in that: a total synthesis process comprising (+) -Arisugacin F according to any of claims 1-6 further comprising oxidation of (+) -Arisugacin F to yield (+) -Arisugacin G, the reaction equation being:
8. the total synthesis of (+) -arisugins G as claimed in claim 7, wherein: the oxidation reaction operation is that (+) -Arisugacin F is mixed with organic solvent, N-methylmorpholine oxide and tetrapropyl ammonium homoruthenate are added for reaction, and (+) -Arisugacin G is obtained.
9. The total synthesis of (+) -arisugins G as claimed in claim 8, wherein: in the eighth step, the mol ratio of (+) -Arisugacin F, N-methylmorpholine oxide and tetrapropyl ammonium homoruthenate is 1: 3-6: 0.3-0.6; the reaction solvent is selected from dichloromethane or acetonitrile.
10. The total synthesis of (+) -Arisugacins F/G according to any one of claims 1-9, wherein: the preparation method of the compound 7 comprises the steps of reacting ethyl acetoacetate with LDA and TMEDA in an ether solvent, then adding 4-methoxy methyl benzoate, and after the reaction is finished, carrying out reduced pressure distillation at high temperature to obtain an intermediate 7; wherein the molar ratio of the ethyl acetoacetate, the LDA, the TMEDA and the methyl 4-methoxybenzoate is 1: 1.5-2.5: 1-2: 1-1.5.
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