CN111087405B - Method for asymmetrically synthesizing amaryllidaceae alkaloid (+) -gamma-lycorane - Google Patents
Method for asymmetrically synthesizing amaryllidaceae alkaloid (+) -gamma-lycorane Download PDFInfo
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract
The invention discloses a convenient and efficient method for asymmetrically synthesizing amaryllidaceae alkaloid (+) -gamma-lycorane. The method takes a lactone compound shown in formula (2) as an initial raw material, and prepares the amaryllidaceae alkaloid (+) -gamma-lycorane through six reactions such as condensation reaction, decarboxylation reaction, reduction reaction and the like. The method starts from cheap and easily-obtained raw materials, is simple and convenient in operation process and short in synthetic route, and provides good technical support for realizing large-scale production of lycorine-like lycorinae-series molecules and researching structure-activity relationship subsequently.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis process application, and particularly relates to a method for asymmetrically synthesizing amaryllidaceae alkaloid (+) -gamma-lycorane.
Background
The monocotyledon of the lycoris family is an important ornamental economic plant, the plant can be divided into 13 families, 85 genera are totally 1200 varieties globally, and 14 genera of 140 varieties of lycoris family are present in China alone. The amaryllidaceae alkaloid separated from amaryllidaceae plant is always the object of great scientists' attention due to its good biological activity (anti-tumor, anti-bacterial, anti-virus, etc.). The lycorine alkaloid has an important composition classification in lycorine alkaloid categories, namely lycorine alkaloid, and has the distinct characteristics on the skeleton structure: containing a natalkane ring system-a pyrrolo [ d, e ] phenanthridine ring system. From the successful separation of the first lycorine alkaloid of lycorinae in 1877, the lycorine alkaloid of lycorinae shows wide biological activities such as: antiviral activity, antitumor activity, inhibition of protein synthesis, etc.
Many of the existing synthetic methods are racemic synthesis, and the asymmetric synthetic method has complicated steps or uses expensive metal reagents, which are not favorable for the research of the synthesis and the biological activity of the alkaloid.
Disclosure of Invention
The invention provides a convenient and efficient method for asymmetrically synthesizing amaryllidaceae alkaloid (+) -gamma-lycorane. The method can start from cheap and easily-obtained raw materials, is simple and convenient in operation process and short in synthesis route, completes asymmetric synthesis of (+) -gamma-lycorane without using an expensive transition metal catalyst in the synthesis process, and provides good technical support for realizing scale production of lycorine lycoris family molecules and researching structure-activity relationship in the follow-up process.
The invention provides a novel asymmetric synthesis method for preparing an amaryllidaceae alkaloid (+) -gamma-lycorane compound shown in a formula (1), which is prepared by taking lactone of a compound shown in a formula (2) as an initial raw material through six reactions such as condensation reaction, decarboxylation reaction, reduction reaction and the like.
The method specifically comprises the following steps:
a step (a): dissolving the compound of the formula (2) in trifluoroacetic acid to carry out a first substitution reaction, then dissolving the product in an organic solvent, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxy-7-azobenzotriazol, triethylamine and 2-iodopiperonylbenzoic acid to carry out a second substitution reaction, and obtaining the compound of the formula (3).
Step (b): dissolving a compound shown in a formula (3), iodobenzene acetate and iodine in an organic solvent, and carrying out elimination reaction to obtain an imine cation intermediate compound; then adding trifluoroacetic acid and triethyl hydrosilyl to carry out addition reaction to obtain the compound shown in the formula (4).
A step (c): dissolving the compound shown in the formula (4), 2, 6-di-tert-butyl-p-cresol and potassium fluoride in an organic solvent, and carrying out elimination reaction to obtain the compound shown in the formula (5).
A step (d): dissolving the compound shown in the formula (5) in an organic solvent, adding palladium acetate, 1 '-binaphthyl-2, 2' -bis-diphenylphosphine and alkali, and carrying out addition reaction to obtain the compound shown in the formula (6).
A step (e): dissolving the compound shown in the formula (6) in an organic solvent, adding raney nickel and hydrogen, and carrying out reduction reaction to obtain the compound shown in the formula (7).
A step (f): dissolving the compound shown in the formula (7) in a first organic solvent, adding lithium aluminum hydride, and carrying out reduction reaction; then, adding raney nickel and hydrogen into a second organic solvent, and carrying out a second reduction reaction to obtain the compound of amaryllidaceae alkaloid (+) -gamma-lycorane shown in the formula (1).
The reaction is shown in scheme (I):
route (I)
In the step (a), the temperature of the first substitution reaction is room temperature; preferably, it is 25 ℃.
In the step (a), the time of the first substitution reaction is 3 to 5 hours; preferably, 3 hours, 4 hours, 5 hours; further preferably, it is 3 hours.
In the step (a), trifluoroacetic acid is used for removing Boc and t-Bu in the first substitution reaction, the removal of Boc is used for preparing the synthesis of the compound shown in the formula (3) in the step (a), and the removal of t-Bu is used for preparing the synthesis of the compound shown in the formula (4) in the step (b).
In the step (a), the organic solvent is one or more of acetonitrile, toluene, dichloromethane and the like; preferably, it is acetonitrile.
In the step (a), the temperature of the second substitution reaction is room temperature; preferably, it is 25 ℃.
In the step (a), the time of the second substitution reaction is 36 to 48 hours; preferably, 36 hours, 42 hours, 48 hours; further preferably, it is 48 hours.
In the step (a), in the second substitution reaction, the molar ratio of the compound shown in the formula (2) to the 2-iodopiperonylic acid, the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and the N-hydroxy-7-azobenzotriazol is 1: (1-2): (1-5): (1-5); preferably 1:1.5:4: 4.
In the step (b), the organic solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, acetonitrile and the like; preferably, dichloromethane.
In the step (b), the temperature of the elimination reaction is-20 ℃ to 25 ℃; preferably, the temperature is-20 ℃,0 ℃, 25 ℃; further preferably, it is 0 ℃.
In the step (b), the elimination reaction time is 0.5-2 hours; preferably, 0.5 hour, 1 hour, 1.5 hours, 2 hours; further preferably, it is 2 hours.
In the step (b), the elimination reaction is carried out under the irradiation of an incandescent lamp of 8W-200W; preferably, 8W, 25W, 50W, 100W, 150W, 200W; further preferably, the elimination reaction is carried out under irradiation of a 200W incandescent lamp.
In the step (b), the temperature of the addition reaction is 0-40 ℃; preferably, at 0 deg.C, 25 deg.C, 40 deg.C; further preferably, it is room temperature (25 ℃).
In the step (b), the time of the addition reaction is 1-2 hours; preferably, 1 hour, 1.5 hours, 2 hours; further preferably, it is 2 hours.
In the step (b), the molar ratio of the compound shown in the formula (3) to iodobenzene acetate, iodine and triethylsilylhydride is 1:2 (0.1-0.5): 5; preferably 1:2:0.1:5, 1:2:0.2:5, 1:2:0.3:5, 1:2:0.4:5, 1:2:0.5: 5; further preferably, the optimal molar ratio is 1:2:0.2: 5.
In the step (c), the organic solvent is one or more of toluene, benzene, 1, 2-dichlorobenzene and the like; preferably, it is toluene.
In step (c), the elimination reaction is preferably carried out in a microwave reactor, the model of which is Microsynth.
In the step (c), the temperature of the elimination reaction is 110-160 ℃; preferably, the temperature is 110 ℃, 130 ℃, 150 ℃ and 160 ℃; further preferably 150 deg.c.
In the step (c), the elimination reaction time is 2-6 hours; preferably, 2 hours, 4 hours, 6 hours; further preferably, it is 4 hours.
In the step (c), the molar ratio of the compound in the formula (5) to the 2, 6-di-tert-butyl-p-cresol and the potassium fluoride in the elimination reaction is 1 (6-7) to 3-4; preferably 1:6.6: 3.3.
In the step (d), the organic solvent is one or more selected from benzene, toluene, 1, 2-dichlorobenzene, tetrahydrofuran and the like; preferably, it is toluene.
In the step (d), the temperature of the addition reaction is 50-100 ℃; preferably, the temperature is 50 ℃,60 ℃, 70 ℃, 80 ℃,90 ℃ and 100 ℃; further preferably 100 deg.c.
In the step (d), the time of the addition reaction is 6 to 18 hours; preferably, 6 hours, 12 hours, 18 hours; further preferably, it is 12 hours.
In the step (d), the alkali is selected from one or more of potassium carbonate, cesium carbonate, sodium hydroxide and the like; preferably, cesium carbonate.
In the step (d), the molar ratio of the compound of formula (5), palladium acetate, 1 '-binaphthyl-2, 2' -bis-diphenylphosphine and a base is 1: (0.1-1): (0.1-1): (1-5); preferably, 1: 0.18: 0.36: 2.
in the step (e), the organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, toluene and the like; preferably, it is ethanol.
In the step (e), the temperature of the reduction reaction is 0-25 ℃; preferably, it is 25 ℃.
In the step (e), the time of the reduction reaction is 0.5 to 2 hours; preferably, 0.5 hour, 1 hour, 1.5 hours, 2 hours; further preferably, it is 1 hour.
In step (e), the molar ratio of the compound of formula (6) to raney nickel is 1: (0.5-2); preferably, it is 1:1.
In the step (f), the first organic solvent is selected from one or more of diethyl ether, tetrahydrofuran, acetonitrile and the like; preferably, diethyl ether.
In the step (f), the temperature of the first reduction reaction is 25-60 ℃; preferably, 25 ℃, 40 ℃,60 ℃; further preferably 40 ℃.
In the step (f), the time of the first reduction reaction is 0.5 to 2 hours; preferably, 0.5 hour, 1 hour, 1.5 hours, 2 hours; further preferably, 1 hour.
In the step (f), the second organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, toluene and the like; preferably, ethanol.
In the step (f), the temperature of the second reduction reaction is 0-25 ℃; preferably, it is 25 ℃.
In the step (f), the time of the second reduction reaction is 6 to 24 hours; preferably 6 hours, 12 hours, 24 hours, 2 hours; further preferably, 12 hours.
In the step (f), the molar ratio of the compound of formula (7), lithium aluminum hydride and raney nickel is 1: (1-10): (1-5); preferably, 1: 5: 1.
the invention also provides a compound of amaryllidaceae alkaloid (+) -gamma-lycorane, the structural formula of which is shown as the formula (1):
in a specific embodiment, the specific steps include:
and (a'), dissolving the compound of the formula (2) in trifluoroacetic acid, and reacting the reaction device for 3 hours at room temperature. And (2) carrying out reduced pressure rotary evaporation to remove trifluoroacetic acid, dissolving the trifluoroacetic acid by using dry acetonitrile, sequentially adding the dry acetonitrile into a mixed solvent of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxy-7-azobenzotriazol, triethylamine and 2-iodopiperonylbenzoic acid in acetonitrile, and reacting for 2d at room temperature. The organic solvent was removed, ethyl acetate was added to dissolve the compound, saturated copper sulfate was added thereto and stirred for 10 minutes, followed by extraction with ethyl acetate three times, and the organic phases were combined and purified by column chromatography (petroleum ether: ethyl acetate 1:10) to obtain a white solid compound of formula (3).
And (b'), dissolving the compound shown in the formula (3) in dry dichloromethane, sequentially adding iodobenzene acetate and iodine into a reaction system, placing the reaction device in an ice bath at 0 ℃, reacting for 2 hours under the illumination condition of a 200W tungsten filament lamp, adding trifluoroacetic acid and triethylhydrosilane into the system, and moving the reaction device to the room temperature for reacting for 2 hours. The dichloromethane was removed by rotary evaporation under reduced pressure, and column chromatography purification was carried out to obtain a white solid of the compound of formula (4).
And (c'), dissolving the compound shown in the formula (4) in toluene, and adding an antioxidant 2, 6-p-di-tert-butyl-p-cresol and potassium fluoride into the system. The reaction is placed under the condition of microwave for reaction for 4 hours at 150 ℃. And (3) cooling the reactor to room temperature, carrying out vacuum spin-drying on toluene, and carrying out column chromatography purification to obtain a light yellow solid compound of the formula (5).
And (d ') dissolving the compound of formula (5) in toluene (30ml), and adding palladium acetate, 1' -binaphthyl-2, 2' -bis-diphenylphosphine, and cesium carbonate to the system in this order. The air in the system was purged with nitrogen, and the reaction was carried out at 100 ℃ for 12 hours. And (3) removing toluene in the system by rotation, and performing column chromatography purification to obtain a yellow solid compound of the formula (6).
And (e') dissolving the compound of formula (6) in ethanol, adding raney nickel into the reaction solution, and reacting at room temperature for 1h in a hydrogen atmosphere. And (3) directly filtering the reaction liquid by using kieselguhr, washing the reaction liquid by using ethyl acetate for three times, combining the solvents, decompressing, spinning out the solvent, and directly performing column chromatography purification to obtain a white solid compound shown as the formula (7).
Step (f'), in which the formula (7) is dissolved in tetrahydrofuran, and the resulting solution is added to LiAlH at 0 deg.C 4 With tetrahydrofuran. The reaction was carried out at 40 ℃ for 1 hour, quenched by addition of 1ml of water at 0 ℃ and the reaction solution was dried over anhydrous magnesium sulfate, filtered and spun dry. Dissolving the spun-out mixture by using ethanol, adding raney nickel into the system, and reacting the reaction solution for 12 hours in a hydrogen atmosphere. Directly filtering the reaction solution, decompressing, spinning out the solvent, and directly carrying out column chromatography alcoholization to obtain the yellow oily alkaloid (+) -gamma-lycorane of the formula (1) amaryllidaceae.
In a particular embodiment, the reaction scheme for the synthesis of the compound of formula (1) is shown in scheme (I'):
route (I')
Drawings
FIG. 1 is a H-NMR spectrum of example 6 of the present invention.
FIG. 2 is a C-NMR spectrum of example 6 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and the accompanying drawings. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1
Synthesis of Compound of formula (3)
The compound of formula (2) (4.0g,10.95mmol,1.0equiv) was dissolved in trifluoroacetic acid (5ml), and the reaction apparatus was left to react at room temperature for 3 hours. Trifluoroacetic acid was removed by rotary evaporation under reduced pressure, and then dissolved in dry acetonitrile (110ml), and added to the system in sequence in a mixed solvent of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.2g,21.90mmol, 2.0equiv) and N-hydroxy-7-azobenzotriazol (2.96g,21.90mmol,2.0equiv) and 2-iodopiperylbenzoic acid (4.80g,16.43mmol, 1.5equiv) in acetonitrile, followed by reaction at room temperature for 2 d. The organic solvent was removed, dissolved in ethyl acetate, and saturated copper sulfate was added thereto and stirred for 10min, followed by extraction with ethyl acetate three times, and the organic phases were combined and purified by column chromatography (petroleum ether: ethyl acetate 1:10) to give a white solid compound of formula (3) (2.65g, 50%).
The assay data for the compound of formula (3) is as follows: data for compounds 2-79: 1 H NMR(400MHz,CDCl 3 )δ7.16(s,1H),7.13(br s,1H),6.67(s,1H),6.63–6.60(m,1H),6.54–6.51(m,1H),6.06–5.96(m,2H),5.03(s,1H),4.53(d,J＝3.7Hz,1H),4.39(br s,1H),2.88(dd,J＝18.8,9.4Hz,1H),2.60–2.50(m,1H),2.22(dd,J＝13.3,8.9Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ174.4,172.2,171.3,149.5,148.2,134.4,134.0,131.4,118.9,109.1,102.2,75.2,64.9,59.7,43.9,41.2,29.1,27.8.MS(ESI)[M+H] + Calcd for C 18 H 145 INO 7 484,Found 484.
example 2
Synthesis of Compound of formula (4)
Dissolving formula (3) (2.26g,4.68mmol,1.0equiv) in dry dichloromethane (200ml), adding iodobenzene acetate (3.01g,9.36mmol,2.0equiv) and iodine (237.6mg,0.936mmol,0.2equiv) to the reaction system in sequence, placing the reaction device in an ice bath at 0 ℃ and reacting for 2h under the illumination condition of a tungsten filament lamp of 200W, adding trifluoroacetic acid (4ml) and triethylsilylhydride (2.72g,23.4mmol,5.0equiv) to the system, and moving the reaction device to the room temperature condition for reacting for 2 h. Dichloromethane was removed by rotary evaporation under reduced pressure and column chromatography was performed (petroleum ether: ethyl acetate 1:1) to obtain the compound of formula (4) (1.37g, 67%) as a white solid.
The detection data for the compound of formula (4) are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.15(s,1H),6.71(s,1H),6.60(m,1H),6.48(m,1H),5.96(s,2H),5.12(d,J＝4.8Hz,1H),4.59(dd,J＝9.1,3.5Hz,1H),4.27–4.25(m,1H),3.36–3.25(m,2H),2.76(t,J＝9.5Hz,1H),2.28–2.17(m,1H),2.05–2.00(m,1H)； 13 C NMR(100MHz,CDCl 3 )δ171.7,168.9,148.9,148.4,135.9,134.1,130.5,118.3,107.8,102.1,102.0,80.1,78.4,56.8,49.4,44.4,42.1,27.4.HRMS(EI)[M] + Calcd for C 17 H 14 INO 5 438.9917,Found 438.9920.
example 3
Synthesis of Compound of formula (5)
The compound of formula (4) (440.0mg,1.0mmol,1.0equiv) was dissolved in toluene (5ml), and the antioxidants 2, 6-p-di-tert-butyl-p-cresol (1.45g,6.6mmol,6.6equiv) and potassium fluoride (191.73mg,3.3mmol,3.3equiv) were added to the system. The reaction is placed under the condition of microwave for reaction for 4 hours at 150 ℃. The reactor was cooled to room temperature, toluene was spin-dried in vacuo and purified by column chromatography (petroleum ether: ethyl acetate: 2:1) to give compound of formula (5) (217.45mg, 55%) as a pale yellow solid.
The assay data for the compound of formula (5) is as follows: a rotamer A: 1 H NMR(400MHz,CDCl 3 )δ7.19(s,1H),6.74(s,1H),6.09–5.76(m,6H),5.05–5.03(m,1H),3.61–3.55(m,1H),3.12–3.06(m,1H),2.90–2.77(m,1H),2.16–2.09(m,1H),2.01–1.90(m,1H)； 13 C NMR(100MHz,CDCl 3 )δ168.4,148.6,148.5,137.1,127.6,124.1,122.7,122.6,118.5,107.3,101.9,80.9,55.6,46.2,36.3,31.8.rotamer B: 1 H NMR(400MHz,CDCl 3 )δ7.19(s,1H),6.79(s,1H),6.09–5.56(m,6H),5.24(d,J＝9.2Hz,1H),4.47(d,J＝9.8Hz,1H),3.2–3.06(m,1H),2.90–2.77(m,1H),2.25–2.18(m,1H),2.01–1.90(m,1H)； 13 C NMR(100MHz,CDCl 3 )δ169.0,148.6,148.3,136.7,128.5,124.9,123.8,122.1,118.5,108.0,102.0,80.9,57.8,43.9,37.5,30.0.HRMS(EI)[M] + Calcd for C 16 H 14 INO 3 395.0018,Found 395.0023.
example 4
Synthesis of Compound of formula (6)
The compound of formula (5) (120.0mg,303.7umol,1.0equiv) was dissolved in toluene (30ml), and palladium acetate (12.3mg,18 umol%), 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (68.1mg,36 umol%), cesium carbonate (198.0mg,0.60mmol,2.0equiv) were sequentially added to the system. The reaction was carried out overnight at 100 ℃ by purging the system with nitrogen. Toluene in the system was removed by rotation, and column chromatography purification was performed (petroleum ether: ethyl acetate: 2:1) to obtain a compound of formula (6) (73.1mg, 90%) as a yellow solid.
The detection data for the compound of formula (6) are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.46(s,1H),6.84(s,1H),6.04(dd,J＝5.6,1.8Hz,1H),6.00–5.95(m,3H),5.90(dd,J＝9.6,4.8Hz,1H),4.61(d,J＝13.6Hz,1H),3.94(dd,J＝11.4,7.4Hz,1H),3.18–3.08(m,1H),3.07–3.00(m,1H),2.23–2.17(m,1H),1.63–1.54(m,1H)； 13 C NMR(100MHz,CDCl 3 )δ161.8,150.6,148.0,132.0,127.7,124.4,121.2,116.1,107.8,102.6,101.6,55.2,41.0,38.1,32.1；HRMS(EI)[M]+Calcd for C 16 H 13 NO 3 267.0895,Found 267.0892.
example 5
Synthesis of Compound of formula (7)
The compound of formula (6) ((60.0mg,224.5umol,1.0equiv) was dissolved in ethanol (5ml), raney nickel (13.2mg,224.5umol,1.0equiv) was added to the reaction solution and reacted at room temperature under an atmosphere of hydrogen for 1h the reaction solution was directly filtered with celite and washed three times with ethyl acetate, the solvents were combined and the solvent was spun off under reduced pressure to directly column chromatographe (petroleum ether: ethyl acetate ═ 2:1) to give the compound of formula (7) (36.2mg, 60%) as a white solid.
The detection data for the compound of formula (7) are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.80(s,1H),6.87(s,1H),6.05(s,2H),4.36(dd,J＝12.1,8.4Hz,1H),3.81(td,J＝11.9,5.8Hz,1H),3.01(m,1H),2.69(dd,J＝16.2,6.7Hz,1H),2.53–2.44(m,1H),2.41–2.34(m,1H),2.24–2.18(m,1H),1.81–1.64(m,1H),1.38–1.25(m,1H)； 13 C NMR(100MHz,CDCl 3 )δ160.0,151.7,146.6,141.2,135.2,121.1,106.6,105.9,101.6,99.9,46.9,40.2,31.0,28.0,22.8,22.1.HRMS(ESI)[M+H] + Calcd for C 16 H 16 NO 3 270.1125,Found 270.1125.
example 6
Synthesis of compound of formula (1), Amaryllidaceae alkaloid (+) -gamma-lycorane
The compound of formula (7) (15.0mg,55.7umol,1.0equiv) was dissolved in tetrahydrofuran (2ml), andthe resulting solution was added to LiAlH at 0 deg.C 4 (11.6mg,278.5umol,5.0equiv) with tetrahydrofuran (3 ml). The reaction was carried out under reflux for 1h, quenched by addition of 1ml of water at 0 deg.C, dried over anhydrous magnesium sulfate and filtered, and spun dry. The spun-out mixture was dissolved in ethanol (3ml), raney nickel (3.3mg,55.7umol,1.0equiv) was added to the system, and the reaction solution was reacted under an atmosphere of hydrogen for 12 hours. The reaction solution was directly filtered, the solvent was spun off under reduced pressure, and column chromatography was directly performed to give (+) - γ -lycorane (10.5mg, 73%) which is a compound of formula (1) as a yellow oil.
The assay data for the compound of formula (1) is as follows: 1 H NMR(400MHz,CDCl 3 )δ6.61(s,1H),6.49(s,1H),5.89(d,J＝2.8Hz,2H),4.02(d,J＝14.4Hz,1H),3.40–3.35(m,1H),3.21(d,J＝14.3Hz,1H),2.77–2.71(m,1H),2.37(t,J＝4.7Hz,1H),2.21–2.13(m,2H),2.05–1.99(m,1H),1.78–1.61(m,3H),1.52–1.24(m,5H)； 13 C NMR(100MHz,CDCl 3 )δ146.0,145.6,133.2,127.3,108.3,106.2,100.6,62.9,57.1,53.7,39.5,37.4,31.7,30.4,29.3,25.2.HRMS(EI)[M] + Calcd for C 16 H 19 NO 2 257.1416,Found 257.1418.
the protection content of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (7)
1. A preparation method of asymmetrically synthesized amaryllidaceae alkaloid (+) -gamma-lycorane is characterized by comprising the following steps:
a step (a): dissolving the compound of the formula (2) in trifluoroacetic acid to perform a first substitution reaction, then dissolving the product in an organic solvent, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxy-7-azobenzotriazol, triethylamine and 2-iodopiperonylbenzoic acid to perform a second substitution reaction, and obtaining the compound of the formula (3);
a step (b): dissolving the compound shown in the formula (3), iodobenzene acetate and iodine in an organic solvent, and carrying out elimination reaction to obtain an imine cation intermediate compound; then adding trifluoroacetic acid and triethyl hydrosilyl to carry out addition reaction to obtain a compound shown in a formula (4);
a step (c): dissolving a compound shown in a formula (4), 2, 6-p-di-tert-butyl-p-cresol and potassium fluoride in an organic solvent, and carrying out elimination reaction to obtain a compound shown in a formula (5);
a step (d): dissolving the compound shown in the formula (5) in an organic solvent, adding palladium acetate, 1 '-binaphthyl-2, 2' -bis-diphenylphosphine and alkali, and carrying out addition reaction to obtain a compound shown in the formula (6);
a step (e): dissolving the compound shown in the formula (6) in an organic solvent, adding raney nickel and hydrogen, and carrying out reduction reaction to obtain a compound shown in the formula (7);
step (f): dissolving a compound shown in a formula (7) in a first organic solvent, adding lithium aluminum hydride, and carrying out a first reduction reaction; then, adding raney nickel and hydrogen into a second organic solvent to perform a second reduction reaction to obtain a compound of amaryllidaceae alkaloid (+) -gamma-lycorane (1) shown as a formula (1);
the reaction is shown in scheme (I):
2. the method of claim 1, wherein in step (a),
the organic solvent is one or more of acetonitrile, toluene and dichloromethane;
the temperature of the first substitution reaction is room temperature;
the time of the first substitution reaction is 3 to 5 hours;
the temperature of the second substitution reaction is room temperature;
the time of the second substitution reaction is 36 to 48 hours;
the molar ratio of the compound shown in the formula (2) to 2-iodopiperylbenzoic acid, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxy-7-azobenzotriazole is 1: (1-2): (1-5): (1-5).
3. The method of claim 1, wherein in step (b),
the temperature of the elimination reaction is-20 ℃ to 25 ℃;
the elimination reaction time is 0.5-2 hours;
the organic solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane and acetonitrile;
the elimination reaction is carried out under the irradiation of an incandescent lamp of 8W-200W;
the temperature of the addition reaction is 0-40 ℃;
the time of the addition reaction is 1-2 hours;
the molar ratio of the compound shown in the formula (3), iodobenzene acetate, iodine and triethylsilylhydride is 1:2 (0.1-0.5): 5.
4. The method of claim 1, wherein in step (c),
the organic solvent is one or more of toluene, benzene and 1, 2-dichlorobenzene;
the temperature of the elimination reaction is 110-160 ℃;
the elimination reaction time is 2-6 hours;
the molar ratio of the compound shown in the formula (5) to the 2, 6-p-di-tert-butyl-p-cresol to the potassium fluoride is 1 (6-7) to 3-4.
5. The method of claim 1, wherein in step (d),
the temperature of the addition reaction is 50-100 ℃;
the alkali is selected from one or more of potassium carbonate, cesium carbonate, sodium carbonate and sodium hydroxide;
the organic solvent is selected from one or more of benzene, toluene, 1, 2-dichlorobenzene and tetrahydrofuran;
the time of the addition reaction is 6 to 18 hours;
the molar ratio of the compound of the formula (5), palladium acetate, 1 '-binaphthyl-2, 2' -bis-diphenylphosphine and a base is 1: (0.1-1): (0.1-1): (1-5).
6. The method of claim 1, wherein in step (e),
the organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile and toluene;
the temperature of the reduction reaction is 0-25 ℃;
the time of the reduction reaction is 0.5 to 2 hours;
the molar ratio of the compound of formula (6) to raney nickel is 1: (0.5-2).
7. The method of claim 1, wherein in step (f),
the first organic solvent is selected from one or more of diethyl ether, tetrahydrofuran and acetonitrile;
the temperature of the first reduction reaction is 25-60 ℃;
the time of the first reduction reaction is 0.5 to 2 hours;
the second organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile and toluene;
the temperature of the second reduction reaction is 0-25 ℃;
the time of the second reduction reaction is 6 to 24 hours;
the molar ratio of the compound of formula (7), lithium aluminum hydride and Raney nickel is 1: (1-10): (1-5).
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| （±）-γ-Lycorane 的立体选择性合成;邵志会，等;《合成化学》;20041231;第12卷(第2期);111-114 * |
| Asymmetric Hydrogenation of a,a-Disubstituted Cycloketones through Dynamic Kinetic Resolution: An Efficient Construction of Chiral Diols with Three Contiguous Stereocenters;Chong Liu, 等;《Angewandte Chemie-International Edition》;20131231;第52卷(第2期);593-596 * |
| Chong Liu, 等.Asymmetric Hydrogenation of a,a-Disubstituted Cycloketones through Dynamic Kinetic Resolution: An Efficient Construction of Chiral Diols with Three Contiguous Stereocenters.《Angewandte Chemie-International Edition》.2013,第52卷(第2期),593-596. * |
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| Novel synthetic approach to nine-membered diallylic amides: stereochemical behavior and utility as chiral building block;Katsuhiko Tomooka，等;《SYNLETT》;20080822(第16期);2518-2522 * |
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