CN106008164A - Stereoselectivity synthetic method of radix bupleuri alkynol and (2Z,8E,10E)-pentadecane-2,8,10-triene-4,6-diyne-1-ol thereof - Google Patents
Stereoselectivity synthetic method of radix bupleuri alkynol and (2Z,8E,10E)-pentadecane-2,8,10-triene-4,6-diyne-1-ol thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical synthesis, and relates to a stereoselectivity synthetic method of radix bupleuri alkynol and (2Z,8E,10E)-pentadecane-2,8,10-triene-4,6-diyne-1-ol thereof. The method comprises the steps that (2E,8Z)-10-t-((butyl diphenyl)alkoxy)-2,8-decadiene-4,6-diyne aldehyde and 5-(R-base sulphone)-1-phenyl-1H-tetrazole are dissolved into tetrahydrofuran according to the molar equivalent ratio being 1:(1.3-3.0), cooling is performed till the temperature is subzero 40 to subzero 78 DEG C, a 1.0 mol/L organic base tetrahydraofuran solution is added under the temperature of subzero 40 to subzero 78 DEG C, a stirring reaction is performed for 30-60 min, then, continuous stirring is performed under the room temperature for a reaction for 6-12 h, a Julia-Kocienski high-stereoselectivity reaction is performed to generate a trans-target product (2E,8Z,10E)-10-((tertiary butyl diphenyl)alkoxy)-pentadecatrien-4,6-diyne, the compound (2E,8Z,10E)-10-((tertiary butyl diphenyl)alkoxy)-pentadecatrien-4,6-diyne is dissolved into tetrahydrofuran, triethylamine trihydrofluoride with the molar equivalent being 1:15-20 is added, a reaction is performed for 12-24 h, and radix bupleuri alkynol and (2Z,8E,10E)-pentadecane-2,8,10-triene-4,6-diyne-1-ol are obtained respectively.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of natural product bupleurynol with antidepressant activity and (2Z, 8E, 10E)-ten five carbon-2,8,10-triolefin-4, the Stereoselective synthesizing process of 6-diine-1-alcohol (RB-2).
Background technology
Polyacetylene compound is the natural product that a class is important, is distributed widely in plant, fungus and animal, especially in Marine microorganism.Even if also with the presence of the polyacetylene compound of trace in human body.This compounds has the cytoprotection that multifarious biological activity is the most multi-level, neurotoxicity, sedative activity, immunosuppressive activity, hPPAR δ inhibitory activity.In our early-stage Study, the strategy applying anti-phase pharmacokinetics (reverse pharmacokinetic) finds that from classical antidepressant recipe-XIAOYAO POWDER bupleurynol and the like can pass through blood brain barrier gathering in brain, and experiment proves that bupleurynol and the like can suppress the rat brain synaptosomes reuptake to monoamine neurotransmitter in vitro.The most efficiently and economically synthesize such product u-0 thing and there is high novelty and using value.Bupleurynol has been carried out efficiently synthesizing research by Organ professor seminar at present, but its reaction yield is relatively low, substantial amounts of substrate dimer byproducts is generated in cardiot-chodkiewicz reacts, then they have developed the synthetic route of an efficient bupleurynol, but employ the reagent such as n-BuLi and cyclopentadienyl group hydrogen zirconium thing in this method, condition is harsh, is unfavorable for that this type of has the preparation of two acetylenic natural products of notable biological activity and industrialized production.
Development and design new drug tool can be of great significance by this kind of natural product and analog as Small-molecule probe or the lead compound of new drug development.But owing to the natural content of this compounds is rare, limit its systematic study and extensively use, so, the present invention is to asymmetric synthesis two acetylenic natural product compounds, and tool is of great significance.
Summary of the invention
It is an object of the invention to provide bupleurynol and the Stereoselective synthesizing process of (2Z, 8E, 10E)-ten five carbon-2,8,10-triolefin-4,6-diine-1-alcohol (RB-2) thereof.
The technical scheme that the present invention takes for achieving the above object is:
nullA kind of bupleurynol and (2Z thereof,8E,10E)-ten five carbon-2,8,10-triolefin-4,The Stereoselective synthesizing process of 6-diine-1-alcohol，(2E,8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine aldehyde and 5-(R base sulfone)-1-phenyl-1H-tetrazole are dissolved in oxolane with the molar equivalent ratio of 1:1.3～3.0，It is cooled to-40～-78 DEG C，And at-40～-78 DEG C, add the organic base tetrahydrofuran solution of 1.0mol/L，Stirring reaction 30～60 minutes，Then stirring reaction 6～12 hours is continued under room temperature，The reaction of Julia Kocienski highly-solid selectively is occurred to generate trans target product (2E,8Z,10E)-10-((tert-butyl diphenyl) epoxide)-pentadecane triolefin-4,6-diine，Compound (2E,8Z,10E)-10-((tert-butyl diphenyl) epoxide)-pentadecane triolefin-4,6-diine is dissolved in oxolane，Add 1:15～the triethylamine trihydrofluoride of 20 molar equivalents，React 12～24 hours，Respectively obtain bupleurynol and (2Z,8E,10E)-ten five carbon-2,8,10-triolefin-4,6-diine-1-alcohol.
The synthesis step of (2E, 8Z) of the present invention-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine aldehyde is as follows:
nullMethyl propiolate and lithium iodide carry out Stereoselective reaction and obtain (Z)-3-iodo-2-acrylic acid methyl ester.，(Z)-3-iodo-2-acrylic acid methyl ester. occurs Sonagashia coupling reaction to generate (Z)-5-(TMS)-4-alkynes-2-alkene-methyl valerate with the acetylene of the silica-based protection of trimethyl under the catalysis of dichloro triphenyl phosphorus palladium and Hydro-Giene (Water Science).，Compound (Z)-5-(TMS)-4-alkynes-2-alkene-methyl valerate is reduced to hydroxy compounds (Z)-5-(TMS)-2-amylene-3-alkynes-1-alcohol under going back original reagent diisopropyl aluminum hydride effect，(Z) reaction under DMAP is catalyzed obtains compound (Z)-tert-butyl diphenyl ((5-(trimethyl silyl)-2-amylene-4-alkynes-1-base) epoxide) silane to-5-(TMS)-2-amylene-3-alkynes-1-alcohol with tert-butyl diphenyl chlorosilane and triethylamine，(Z)-tert-butyl diphenyl ((5-(trimethyl silyl)-2-amylene-4-alkynes-1-base) epoxide) silane generates terminal alkyne compound (Z)-tert-butyl ester-(2-amylene-4-alkynes-1-oxygen) diphenyl silane under potassium carbonate effect，(Z)-tert-butyl ester-(2-amylene-4-alkynes-1-oxygen) diphenyl silane and N-bromo-succinimide are generating compound (Z)-(tert-butyl group) ((5-bromo-2-amylene-4-alkynes-1-base) epoxide) diphenyl silane under silver nitrate is catalyzed，(Z) under Hydro-Giene (Water Science). is catalyzed, there is cardiot-chodkiewicz reacting generating compound (2E with (E)-amyl group-2-alkene-4-alkynes-1-alcohol in-(tert-butyl group) ((5-bromo-2-amylene-4-alkynes-1-base) epoxide) diphenyl silane,8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine-1-alcohol，(2E,8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine-1-alcohol generates aldehyde compound (2E under Dai Si-Martin's oxidant effect,8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine aldehyde.
The synthesis step of 5-of the present invention (R base sulfone)-1-phenyl-1H-tetrazole is as follows: the reaction under diethyl azodiformate and triphenyl phosphorus are catalyzed of ROH Yu 1-phenyl-1H-TETRAZOLE-5-mercaptan generates 5-(R base sulfenyl)-1-phenyl-1H-tetrazole, 5-(R base sulfenyl)-1-phenyl-1H-tetrazole and hydrogen peroxide under ammonium molybdate tetrahydrate is catalyzed, generate 5-(R base sulfone)-1-phenyl-1H-tetrazole.
R base in 5-of the present invention (R base sulfone)-1-phenyl-1H-tetrazole is amyl group or heptyl.
ROH of the present invention is n-amyl alcohol or n-heptanol.
Organic base of the present invention is potassium hexamethyldisilazide, LHMDS or sodium hexamethyldisilazide.
Accompanying drawing explanation
Fig. 1 is the structural formula of the present invention；
Fig. 2 is the reaction equation that the present invention prepares (2E, 8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine aldehyde；
Fig. 3 is the reaction equation that the present invention prepares 5-(amyl group sulfone)-1-phenyl-1H-tetrazole；
Fig. 4 is the reaction equation that the present invention prepares 5-(heptyl sulfone)-1-phenyl-1H-tetrazole；
Fig. 5 is that the present invention prepares bupleurynol and the reaction equation of (2Z, 8E, 10E)-ten five carbon-2,8,10-triolefin-4,6-diine-1-alcohol thereof；
Fig. 6 is the hydrogen spectrogram of the embodiment of the present invention 1 preparation (Z)-3-iodo-2-acrylic acid methyl ester.；
Fig. 7 is the carbon spectrogram of the embodiment of the present invention 1 preparation (Z)-3-iodo-2-acrylic acid methyl ester.；
Fig. 8 is the hydrogen spectrogram of the embodiment of the present invention 2 preparation (Z)-5-(TMS)-4-alkynes-2-alkene-methyl valerate；
Fig. 9 is the carbon spectrogram of the embodiment of the present invention 2 preparation (Z)-5-(TMS)-4-alkynes-2-alkene-methyl valerate；
Figure 10 is the hydrogen spectrogram of the embodiment of the present invention 3 preparation (Z)-5-(TMS)-2-amylene-3-alkynes-1-alcohol；
Figure 11 is the carbon spectrogram of the embodiment of the present invention 3 preparation (Z)-5-(TMS)-2-amylene-3-alkynes-1-alcohol；
Figure 12 is the hydrogen spectrogram of the embodiment of the present invention 4 preparation (Z)-tert-butyl diphenyl ((5-(trimethyl silyl)-2-amylene-4-alkynes-1-base) epoxide) silane；
Figure 13 is the carbon spectrogram of the embodiment of the present invention 4 preparation (Z)-tert-butyl diphenyl ((5-(trimethyl silyl)-2-amylene-4-alkynes-1-base) epoxide) silane；
Figure 14 is the hydrogen spectrogram of the embodiment of the present invention 5 preparation (Z)-tert-butyl ester-(2-amylene-4-alkynes-1-oxygen) diphenyl silane；
Figure 15 is the carbon spectrogram of the embodiment of the present invention 5 preparation (Z)-tert-butyl ester-(2-amylene-4-alkynes-1-oxygen) diphenyl silane；
Figure 16 is the hydrogen spectrogram of the embodiment of the present invention 6 preparation (Z)-(tert-butyl group) ((5-bromo-2-amylene-4-alkynes-1-base) epoxide) diphenyl silane；
Figure 17 is the carbon spectrogram of the embodiment of the present invention 6 preparation (Z)-(tert-butyl group) ((5-bromo-2-amylene-4-alkynes-1-base) epoxide) diphenyl silane；
Figure 18 is the hydrogen spectrogram of the embodiment of the present invention 7 preparation (Z)-(tert-butyl group) ((5-bromo-2-amylene-4-alkynes-1-base) epoxide) diphenyl silane；
Figure 19 is the hydrogen spectrogram of the embodiment of the present invention 8 preparation (2E, 8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine aldehyde；
Figure 20 is the carbon spectrogram of the embodiment of the present invention 8 preparation (2E, 8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine aldehyde；
Figure 21 is the hydrogen spectrogram of 5-(the pentylthio)-1-phenyl-1H-tetrazole of the embodiment of the present invention 9 preparation；
Figure 22 is the carbon spectrogram of 5-(the pentylthio)-1-phenyl-1H-tetrazole of the embodiment of the present invention 9 preparation；
Figure 23 is the hydrogen spectrogram of 5-(amyl group the sulfone)-1-phenyl-1H-tetrazole of the embodiment of the present invention 10 preparation；
Figure 24 is the carbon spectrogram of 5-(amyl group the sulfone)-1-phenyl-1H-tetrazole of the embodiment of the present invention 10 preparation；
Figure 25 is the hydrogen spectrogram of the embodiment of the present invention 11 preparation (2E, 8Z, 10E)-10-((tert-butyl diphenyl) epoxide)-pentadecane triolefin-4,6-diine；
Figure 26 is the hydrogen spectrogram of the embodiment of the present invention 12 preparation (2Z, 8E, 10E)-pentadecane triolefin-4,6-diine-1-alcohol；
Figure 27 is the carbon spectrogram of the embodiment of the present invention 12 preparation (2Z, 8E, 10E)-pentadecane triolefin-4,6-diine-1-alcohol；
Figure 28 is the hydrogen spectrogram of 5-(heptyl the sulfenyl)-1-phenyl-1H-tetrazole of the embodiment of the present invention 13 preparation；
Figure 29 is the carbon spectrogram of 5-(heptyl the sulfenyl)-1-phenyl-1H-tetrazole of the embodiment of the present invention 13 preparation；
Figure 30 is the hydrogen spectrogram of 5-(heptyl the sulfone)-1-phenyl-1H-tetrazole of the embodiment of the present invention 14 preparation；
Figure 31 is the carbon spectrogram of 5-(heptyl the sulfone)-1-phenyl-1H-tetrazole of the embodiment of the present invention 14 preparation；
Figure 32 is the hydrogen spectrogram of the embodiment of the present invention 15 preparation (2E, 8Z, 10E)-10-((tert-butyl diphenyl) epoxide)-heptadecane triolefin-4,6-diine；
Figure 33 is the hydrogen spectrogram of the embodiment of the present invention 16 preparation (2Z, 8E, 10E)-heptadecane triolefin-4,6-diine-1-alcohol；
Figure 34 is the carbon spectrogram of the embodiment of the present invention 16 preparation (2Z, 8E, 10E)-heptadecane triolefin-4,6-diine-1-alcohol.
Detailed description of the invention
Embodiment 1 prepares (Z)-3-iodo-2-acrylic acid methyl ester. (4)
Methyl propiolate 15g (178mmol) and lithium iodide 26.3g (196mmol) is dissolved in acetic acid 178mL, stirs 11h at 70 DEG C, under agitation adds water 900mL cancellation reaction, reactant liquor K2CO3It is neutralized to without CO2Till gas produces, extract three times with ether, merge organic facies, wash three times with saturated common salt, anhydrous sodium sulfate is dried, and filters, and filtrate concentrates gained residue through column chromatography (petroleum ether: ethyl acetate=30:1), obtain pale yellow oily liquid body (Z)-3-iodo-2-acrylic acid methyl ester. (4) 32.4g, productivity 89%.Reaction equation is shown in Fig. 2.
1H-NMR(600MHz,CDCl3) δ 7.37 (d, J=8.4Hz, 1H), 6.79 (d, J=8.4Hz, 1H), 3.64 (s, 3H), see Fig. 6；
13C-NMR(150MHz,CDCl3) δ 164.8,129.4,95.0,51.5, see Fig. 7.
In hydrogen spectrum, there are two doublets in chemical shift 7.37 and 6.79, illustrates to generate alkene, and coupling constant is 8.4Hz, illustrates to generate cis-form olefin.
Embodiment 2 prepares (Z)-5-(TMS)-4-alkynes-2-alkene-methyl valerate (5)
31.5g (149mmol) compound (Z)-3-iodo-2-acrylic acid methyl ester. (4) is dissolved in dry tetrahydrofuran 372mL, under the conditions of 0 DEG C, adds PdCl2(PPh3) 21.0g (1.5mmol), Hydro-Giene (Water Science). 28.5mg (0.15mmol), triethylamine 41.2mL (297.4mmol), then in 20min, slowly drip trimethyl silicane ethyl-acetylene 23.8mL (178.4mmol), reactant liquor is stirred at room temperature 18h, add saturated ammonium chloride solution 100mL cancellation reaction, reactant liquor ether extracts three times, merge organic facies, wash three times with saturated common salt, anhydrous sodium sulfate is dried, filter, filtrate concentrates gained residue through column chromatography (petroleum ether: ethyl acetate=100:1), obtain pale yellow oily liquid body (Z)-5-(TMS)-4-alkynes-2-alkene-methyl valerate (5) 23.5g, productivity 87%.Reaction equation is shown in Fig. 2.
1H-NMR(600MHz,CDCl3) δ 6.12 (d, J=11.4Hz, 2H), 6.07 (d, J=12Hz, 1H), 3.75 (s, 3H), 0.19 (s, 9H), see Fig. 8；
13C-NMR(150MHz,CDCl3) δ 164.9,129.1,122.7,108.2,100.6,51.3,0.5, see Fig. 9.
In hydrogen spectrum, chemical shift 0.19 occurs that 9 hydrogen are unimodal, illustrates to occur coupling reaction to generate yne compounds, and in carbon spectrum, chemical shift 129.1 and 122.7 is the peak of alkynyl carbon simultaneously, illustrates to generate yne compounds.
Embodiment 3 prepares (Z)-5-(TMS)-2-amylene-3-alkynes-1-alcohol (6)
4.77g (26.2mmol) (Z)-5-(TMS)-4-alkynes-2-alkene-methyl valerate (5) is dissolved in dry methylene chloride 130mL, is cooled to-78 DEG C, under stirring, slowly drips 1.0mol L-1DIBAL-H 105mL (105mol), about need 1.5h, stir 4h at this temperature, after the sodium potassium tartrate solution 50mL cancellation reaction that the lower addition of stirring is saturated, until bubble-free produces, mixture is stirred at room temperature 3h again, mixture dichloromethane extracts three times, merging organic facies, wash three times with saturated common salt, anhydrous sodium sulfate is dried, filter, filtrate concentration gained residue, through column chromatography (petroleum ether: ethyl acetate=10:1), obtains colourless oil liquid 3.71g, productivity 92%.Reaction equation is shown in Fig. 2.
1H-NMR(600MHz,CDCl3) δ 6.09 (dt, J=11.1,6.3Hz, 1H), 5.57 (d, J=11.0Hz, 1H), 4.38 (d, J=6Hz, 2H), 0.17 (s, 9H), see Figure 10；
13C-NMR(150Hz,CDCl3) δ 142.7,110.3,100.8,100.5,60.9,0.2, see Figure 11；
In hydrogen spectrum, reaction substrate methylester portion is positioned at the peak disappearance of chemical shift 3.75 methyl, and 4.38 the doublet of 2 hydrogen occur, illustrate that ester group is reduced to alcoholic extract hydroxyl group
Embodiment 4 prepares (Z)-tert-butyl diphenyl ((5-(trimethyl silyl)-2-amylene-4-alkynes-1-base) epoxide) silane (7)
nullUnder argon shield，4.69g (30mmol) compound (Z)-5-(TMS)-2-amylene-3-alkynes-1-alcohol (6) is dissolved in 63.0mL dichloromethane，TEA 12.7g (99mol) it is sequentially added under room temperature，DMAP 0.37g(3mmol)，The most slowly dropping TBDPSCl 8.7mL (33mmol) is dissolved in the solution that the dichloromethane of 12mL is formed，Finish，It is stirred at room temperature reaction 13h，Stop stirring，Add 15mL saturated ammonium chloride to terminate reaction，Then extraction three times it is extracted with ethyl acetate，Merge organic facies，Wash three times by saturated NaCl solution，Anhydrous sodium sulfate is dried，Filter，Filtrate concentrates gained residue and obtains pale yellow oil (Z)-tert-butyl diphenyl ((5-(trimethyl silyl)-2-amylene-4-alkynes-1-base) epoxide) silane (7) 10.7g through column chromatography (petroleum ether: ethyl acetate=100:1)，Yield 91%.Reaction equation is shown in Fig. 2.
1H-NMR(600MHz,CDCl3) δ 7.70-7.69 (m, 4H), 7.43-4.40 (m, 6H), 6.16-6.14 (m, 1H), 5.50 (d, J=10.8Hz, 1H), 4.54 (d, J=6.0Hz, 2H), 1.08 (s, 9H), 0.10 (s, 9H), Figure 12 is seen；
13C-NMR(150MHz,CDCl3)δ143.7,135.5,133.6,129.6,127.7,109.1,100.7,100.3,
62.6,26.8,19.2,0.2, see Figure 13.
Hydrogen spectrum occurs at chemical shift 7.70-7.69 and 7.43-4.40 the multiplet of 10 hydrogen, illustrates to generate oxygen silicon key.
Embodiment 5 prepares (Z)-tert-butyl ester-(2-amylene-4-alkynes-1-oxygen) diphenyl silane (8)
Under argon shield; 10.38g (26.4mmol) compound (Z)-tert-butyl diphenyl ((5-(trimethyl silyl)-2-amylene-4-alkynes-1-base) epoxide) silane (7) is dissolved in the methanol that 332mL is dried; it is stirred vigorously lower addition Anhydrous potassium carbonate 0.62g (4.5mmol); room temperature reaction 12h; reacting liquid filtering; filtrate concentrates gained residue and obtains pale yellow oily liquid body 8.0g, productivity 95% through column chromatography (petroleum ether: ethyl acetate=1:0).Reaction equation is shown in Fig. 2.
1H-NMR(600Hz,CDCl3) δ 7.73-7.72 (m, 4H), 7.46-7.40 (m, 6H), 6.23-6.19 (m, 1H), 5.49 (d, J=10.8Hz, 1H), 4.54 (d, J=4.8Hz, 2H), 3.03 (s, 1H), 1.10 (s, 9H), Figure 14 is seen；
13C-NMR(600Hz,CDCl3) δ 144.5,135.6,133.5,129.6,127.7,108.0,82.9,79.3,62.4,26.8,19.2, see Figure 15.
In hydrogen spectrum, the chemical shift 3.03 in the unimodal disappearance of 9 hydrogen of chemical shift 0.10, hydrogen spectrum of reaction substrate trimethyl silicane part occurs unimodal, shows to remove trimethyl silicane base section, generates terminal alkyne.
Embodiment 6 prepares (Z)-(tert-butyl group) ((5-bromo-2-amylene-4-alkynes-1-base) epoxide) diphenyl silane (9)
Under argon shield, by NBS 2.03g (11.4mmol), AgNO30.18mg (1.0mmol) is dissolved in the acetone that 8.0mL is dried, then it is slowly added dropwise 3.33g (10.4mmol) compound (Z)-tert-butyl ester-(2-amylene-4-alkynes-1-oxygen) diphenyl silane (8) and is dissolved in the solution that 1mL acetone is formed, it is stirred at room temperature reaction 3h, the normal hexane adding 2mL terminates reaction, the water washing of organic facies 8mL, then aqueous phase is extracted with ethyl acetate three times, merge organic facies (normal hexane phase and ethyl acetate extraction phase), anhydrous sodium sulfate is dried, filter, filtrate concentrates gained residue and obtains colourless oil liquid 3.2g through column chromatography (petroleum ether: ethyl acetate=1:0), productivity 78.0%.Reaction equation is shown in Fig. 2.
1H-NMR(600MHz,CDCl3) δ 7.71-7.70 (m, 4H), 7.47-7.40 (m, 6H), 6.14 (dt, J=11.4,6.6Hz, 1H), 5.46 (d, J=10.4Hz, 1H), 4.46 (d, J=6.0Hz, 1H), 1.07 (s, 9H), are shown in Figure 16；
13C-NMR(150MHz,CDCl3) δ 144.1,135.6,133.4,129.7,127.7,108.7,76.1,62.3,54.5,26.8,19.1, see Figure 17；
In hydrogen spectrum, reaction substrate terminal alkyne disappears at chemical shift 3.03 peak, illustrates bromo-reaction, generates end group bromo compound.
Embodiment 7 prepares (2E, 8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine-1-alcohol (10)
nullUnder argon shield，2-amylene-4-alkynes-1-the alcohol of 0.46g (6.1mmol) is mixed in the piperidines that 4mL is dried with 80.4mg (0.4mmol) CuI，Ice-water bath is cooled to 0 DEG C，It is slowly added dropwise 0.67g (1.7mmol) compound (Z)-(tert-butyl group) ((5-bromo-2-amylene-4-alkynes-1-base) epoxide) diphenyl silane (9) under stirring and is dissolved in the solution that 0.2mL piperidines is formed，It is to slowly warm up to room temperature，At room temperature react 3.5h，Stop stirring，Add 2mL saturated ammonium chloride solution to terminate reaction，Then three times it are extracted with ethyl acetate，Merge organic facies，Saturated NaCl solution is washed three times，Anhydrous sodium sulfate is dried，Filter，Filtrate concentrates gained residue and obtains colourless oil liquid (2E through column chromatography (petroleum ether: ethyl acetate=5:2),8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine-1-alcohol (10) 0.61g，Productivity 91%.Reaction equation is shown in Fig. 2.
1H-NMR(600Hz,CDCl3) δ 7.70-7.69 (m, 4H), 7.46-7.39 (m, 6H), 6.39 (dt, J=15.6,4.8Hz, 1H), 6.23 (dt, J=11.4,6.0Hz, 1H), 5.85 (d, J=16.2Hz, 1H), 5.56 (d, J=11.4Hz, 1H), 4.49 (d, J=6.0Hz, 2H), 4.25 (d, 4.8Hz, 2H), 1.61 (s, 1H), 1.07 (s, 9H), are shown in Figure 18；
There are two peaks in chemical shift 6.39 and 5.85 in hydrogen spectrum, and in chemical shift 4.25, doublet occurs, illustrate coupling reaction.
Embodiment 8 prepares (2E, 8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine aldehyde (11)
By 0.47g (1.17mmol) compound (2E, 8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine-1-alcohol (10) is dissolved in the dichloromethane that 7.2mL is dried, and is slowly added dropwise 1.5g (3.53mmol) Dai Si-Martin's oxidant and is dissolved in the solution that 2mL dichloromethane is formed under stirring.Finish, at room temperature react 1.2h, add 2mL saturated ammonium chloride solution to terminate reaction, then extracting three times with dichloromethane, merge organic facies, saturated NaCl solution is washed three times, anhydrous sodium sulfate is dried, filtering, filtrate concentrates gained residue and obtains colourless oil liquid 0.43g, productivity 91% through column chromatography (petroleum ether: ethyl acetate=60:1).Reaction equation is shown in Fig. 2.
1H-NMR(600MHz,CDCl3) δ 9.59 (d, J=7.2Hz, 1H), 7.69-7.68 (m, 4H), 7.44-7.43 (m, 6H), 6.64 (d, J=15.6Hz, 1H), 6.53 (dd, J=15.0,6.6Hz, 1H), 6.34 (d, J=6.0Hz, 1H), 5.61 (d, J=11.4Hz, 1H), 4.4-9-4.48 (m, 2H), 1.07 (s, 9H), are shown in Figure 19；
13C-NMR(150MHz,CDCl3) δ 192.6,148.3,141.3,135.6,133.3,130.8,129.8,127.8,107.5,87.8,84.0,78.2,78.1,62.7,26.8,19.2, see Figure 20.
There is doublet in chemical shift 9.59 in hydrogen spectrum, illustrates that alcoholic extract hydroxyl group is oxidized to aldehyde.
Embodiment 9 prepares 5-(pentylthio)-1-phenyl-1H-tetrazole (13)
Being dissolved in the oxolane that 130mL is dried by 0.7g (7.94mmol) n-amyl alcohol, ice-water bath is cooled to 0 DEG C, is then sequentially added into PPh35.21g (19.9mmol), 1-phenyl-1H-TETRAZOLE-5-mercaptan 2.83g (15.9mmol), diethyl azodiformate 3.13mL (19.9mmol), react 1h with this understanding, under agitation add the diluted ethyl acetate of 40mL, add 30mL saturated ammonium chloride to terminate reaction, then extraction three times it is extracted with ethyl acetate, merge organic facies, saturated NaCl solution is washed three times, anhydrous sodium sulfate is dried, filter, filtrate concentrates gained residue and obtains colourless oil liquid 5-(pentylthio)-1-phenyl-1H-tetrazole (13) 1.77g through column chromatography (petroleum ether: ethyl acetate=20:1), productivity 90%.Reaction equation is shown in Fig. 3.
1H-NMR(600MHz,CDCl3) δ 7.57-7.49 (m, 5H), 3.36 (t, J=7.4Hz, 2H), 1.83-1.76 (m, 2H), 1.36-1.28 (m, 2H), 0.87 (t, J=7.3Hz, 3H), see Figure 21；
13C-NMR(150MHz,CDCl3) δ 154.4,133.6,129.9,129.6,123.7,33.2,30.6,28.7,22.0,13.8, see Figure 22.
There is multiplet at chemical shift 7.57-7.49 in hydrogen spectrum, illustrates to generate sulfide compound.
Embodiment 10 prepares 5-(amyl group sulfone)-1-phenyl-1H-tetrazole (14)
Compound 5-(pentylthio)-1-phenyl-1H-tetrazole (13) of 0.5g (2.0mmol) is dissolved in 16mL ethanol, ice-water bath is cooled to 0 DEG C, then ammonium molybdate tetrahydrate 0.25g (20.1mmol), the H of 30% it are sequentially added into2O22.4mL (10mmol), react 12h with this understanding, add sodium sulfite solution saturated for 9mL to terminate reaction, then being extracted with ethyl acetate three times, merge organic facies, saturated NaCl solution is washed three times, anhydrous sodium sulfate is dried, filtering, filtrate concentrates gained residue and obtains white solid 5-(amyl group sulfone)-1-phenyl-1H-tetrazole (14) 0.51g, productivity 92% through column chromatography (use petroleum ether: ethyl acetate=1:15)., reaction equation is shown in Fig. 3.
1H-NMR(600Hz,CDCl3) δ 7.67 (d, J=7.5Hz, 2H), 7.63-7.51 (m, 3H), 3.77-3.64 (m, 2H), 1.97-1.87 (m, 2H), 1.51-1.41 (m, 2H), 1.36 (dt, J=14.8,7.3Hz, 2H), 0.90 (t, J=7.3Hz, 3H), see Figure 23；
13C-NMR(150Hz,CDCl3) δ 153.4,133.0,131.3,129.6,125.0,55.9,30.0,21.9,21.5,13.5, see Figure 24.
There is multiplet at chemical shift 3.77-3.64 in hydrogen spectrum, illustrates to generate sulfone-based compound
Embodiment 11 prepares (2E, 8Z, 10E)-10-((tert-butyl diphenyl) epoxide)-pentadecane triolefin-4,6-diine (18)
nullBy 50mg (0.13mmol) compound 5-(amyl group sulfone)-1-phenyl-1H-tetrazole (14) and 47mg (0.17mmol) compound (2E,8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine aldehyde (11) is dissolved in the oxolane that 5mL is dried，It is subsequently cooled to-78 DEG C，It is slowly added dropwise 1.0mol/L KHMDS 0.16mL (0.17mmol) at this temperature,Stirring reaction 30min at this temperature，Then reaction 12h it is warmed to room temperature，The saturated ammonium chloride of 3mL is added to terminate reaction at 0 DEG C，Then three times it are extracted with ethyl acetate，Merge organic facies，Saturated NaCl solution is washed three times，Anhydrous sodium sulfate is dried，Filter，Filtrate concentrates gained residue and obtains pale yellow oily liquid body (2E through column chromatography (petroleum ether: ethyl acetate=1:0),8Z,10E)-10-((tert-butyl diphenyl) epoxide)-pentadecane triolefin-4,6-diine (18) 49mg，Productivity 86%.Reaction equation is shown in Fig. 5.
1H-NMR(600MHz,CDCl3) δ 7.71-7.68 (m, 4H), 7.43-7.41 (m, 6H), 6.23-6.17 (m, 1H), 6.25-6.20 (m, 1H), 6.13 (dd, J=15.0,10.9Hz, 1H), 5.91-5.84 (m, 1H), 5.55 (t, J=13.4Hz, 2H), 4.48 (dd, J=6.0Hz, 1.2Hz, 2H), 2.13 (d, J=7.2Hz, 2H), 1.55 (s, 1H), 1.43-1.35 (m, 2H), 1.36-1.28 (m, 2H), 1.06 (s, 10H), 0.90 (t, J=7.2Hz, 3H), see Figure 25.
The aldehyde radical hydrogen of chemical shift 9.59 disappears, and many 4 thiazolinyl hydrogen in alkene region, thus there occurs coupling reaction, and judges to generate trans olefins by coupling constant.
Embodiment 12 prepares (2Z, 8E, 10E)-pentadecane triolefin-4,6-diine-1-alcohol (2)
By 0.15g (0.34mmol) compound (2E, 8Z, 10E)-10-((tert-butyl diphenyl) epoxide)-pentadecane triolefin-4, 6-diine (18) is dissolved in the oxolane that 4.5mL is dried, under agitation it is slowly added dropwise 0.68mL (4.2mmol) triethylamine trihydrofluoride, at room temperature react 18h, add the water of 2mL to terminate reaction, then three times it are extracted with ethyl acetate, merge organic facies, wash three times by saturated NaCl solution, anhydrous sodium sulfate is dried, filter, filtrate concentrates gained residue and obtains pale yellow oily liquid body (2Z through column chromatography (petroleum ether: ethyl acetate=4:1), 8E, 10E)-pentadecane triolefin-4, 6-diine-1-alcohol (2) 66.7mg, productivity 92%.Reaction equation is shown in that Fig. 5, structural formula are shown in Fig. 1.
1H-NMR (600MHz, CDCl3) δ 6.70 (dd, J=15.5,10.8Hz, 1H), 6.28-6.18 (m, 1H), 6.11 (dd, J=14.9,11.1Hz, 1H), 5.92-5.84 (m, 1H), 5.68 (d, J=11.0Hz, 1H), 5.56 (d, J=15.6Hz, 1H), 4.43 (d, J=6.1Hz, 2H), 2.13 (d, J=7.2Hz, 2H), 1.58 (s, 1H), 1.38 (dd, J=14.8Hz, 2H), 1.32 (dd, J=14.7,7.3Hz, 2H), 0.90 (t, J=7.2Hz, 4H), see Figure 26；
13C-NMR (150MHz, CDCl3) δ 145.7,144.9,140.5,129.4,109.7,107.0,83.1,79.9,77.6,75.1,61.2,32.6,31.0,22.2,13.9, see Figure 27.
In hydrogen spectrum, the hydrogen in the aryl domains of chemical shift 7.43-7.41 and 7.71-7.68 disappears, and illustrates that oxygen silicon key ruptures, and generates alcoholic extract hydroxyl group.
Radix Bupleuri polyacetylene experimental section
Embodiment 13 prepares 5-(heptyl sulfenyl)-1-phenyl-1H-tetrazole (16)
Being dissolved in the oxolane that 70mL is dried by 0.5g (4.30mmol) n-heptanol, ice-water bath is cooled to 0 DEG C, is then sequentially added into PPh32.82g (10.7mmol), 1-phenyl-1H-TETRAZOLE-5-mercaptan 1.53g (8.58mmol), diethyl azodiformate 1.69mL (10.7mmol), react 1h with this understanding, under agitation add the diluted ethyl acetate of 30mL, add 15mL saturated ammonium chloride to terminate reaction, then three times it are extracted with ethyl acetate, merge organic facies, saturated NaCl solution is washed three times, anhydrous sodium sulfate is dried, filter, filtrate concentrates gained residue and obtains colourless oil liquid 5-(heptyl sulfenyl)-1-phenyl-1H-tetrazole (16) 1.1g through column chromatography (petroleum ether: ethyl acetate=30:1), productivity 91%.Reaction equation is shown in Fig. 4.
1H-NMR(600MHz,CDCl3) δ 7.59-7.48 (m, 5H), 3.38 (t, J=7.4Hz, 2H), 1.83-1.73 (m, 2H), 1.45-1.37 (m, 2H), 1.36-1.17 (m, 6H), 0.86 (t, J=6.9Hz, 3H), is shown in Figure 28；
13C-NMR (150MHz, CDCl3) δ 154.5,133.7,130.0,129.7,123.8,33.3,31.6,29.0,28.6,28.5,22.5,14.0, see Figure 29.
There is multiplet at chemical shift 7.59-7.48 in hydrogen spectrum, illustrates to generate sulfide compound.
Embodiment 14 prepares 5-(heptyl sulfone)-1-phenyl-1H-tetrazole (17)
Being dissolved in 25mL ethanol by the compound 16 of 0.88g (3.2mmol), ice-water bath is cooled to 0 DEG C, is then sequentially added into ammonium molybdate tetrahydrate 0.4g (0.32mmol), the H of 30%2O23.8mL, (32.0mmol), reacting 12h with this understanding, sodium sulfite solution saturated for addition 15mL, to terminate reaction, is then extracted with ethyl acetate three times, merge organic facies, saturated NaCl solution is washed three times, and anhydrous sodium sulfate is dried, and filters, filtrate concentrates gained residue and obtains colorless oil solid 5-(heptyl sulfone)-1-phenyl-1H-tetrazole (17) 0.88g, productivity 90% through column chromatography (petroleum ether: ethyl acetate=20:1).Reaction equation is shown in Fig. 4.
1H-NMR (600MHz, CDCl3) δ 7.69 (d, J=7.4Hz, 2H), 7.60 (dt, J=14.5,4.7Hz, 3H), 3.75-3.69 (m, 2H), 1.04 (dt, J=12.1,7.8Hz, 2H), 1.53-1.45 (m, 2H), 1.38-1.22 (m, 6H), 0.88 (t, J=6.8Hz, 3H), see Figure 30；
13C-NMR(150MHz,CDCl3) δ 153.4,132.9,131.3,129.5,125.0,55.8,31.2,28.4,27.9,22.3,21.8,13.9, see Figure 31.
There is multiplet at chemical shift 3.75-3.69 in hydrogen spectrum, illustrates to generate sulfone-based compound
Embodiment 15 prepares (2E, 8Z, 10E)-10-((tert-butyl diphenyl) epoxide)-heptadecane triolefin-4,6-diine (19)
70mg (0.23mmol) compound 17 and 68mg (0.17mmol) compound 11 is dissolved in the oxolane that 5mL is dried, it is subsequently cooled to-78 DEG C, it is slowly added dropwise 1.0mol/L KHMDS 0.22mL (0.22mmol) at this temperature, stirring reaction 30min at this temperature, then reaction 12h it is warmed to room temperature, the saturated ammonium chloride of 3mL is added to terminate reaction at 0 DEG C, then three times it are extracted with ethyl acetate, merge organic facies, saturated NaCl solution is washed three times, anhydrous sodium sulfate is dried, filter, filtrate concentrates gained residue and obtains pale yellow oily liquid body 71mg through column chromatography (petroleum ether: ethyl acetate=1:0), productivity 91%.Reaction equation is shown in Fig. 5.
1H-NMR(600MHz,CDCl3) δ 7.69-7.68 (m, 4H), 7.45-7.39 (m, 6H), 6.71-6.65 (m, 1H), 6.25-6.20 (m, 1H), 6.09-6.11 (m, 1H), 5.85-5.91 (m, 1H), 5.55 (t, J=13.2Hz, 2H), 4.49 (d, J=5.9Hz, 2H), 2.12 (q, J=7.2Hz, 2H), 1.55 (s, 1H), 1.39 (dd, J=14.0,6.8Hz, 2H), 1.35-1.22 (m, 8H), 1.06 (s, 9H), 0.91-0.85 (m, 3H), is shown in Figure 32.
The aldehyde radical hydrogen of chemical shift 9.59 disappears, and many 4 thiazolinyl hydrogen in alkene region, thus there occurs coupling reaction, and judges to generate trans olefins by coupling constant.
Embodiment 16 prepares (2Z, 8E, 10E)-heptadecane triolefin-4,6-diine-1-alcohol (1)
By 60mg (0.13mmol) compound (2E, 8Z, 10E)-10-((tert-butyl diphenyl) epoxide)-heptadecane triolefin-4, 6-diine (19) is dissolved in the oxolane that 1.6mL is dried, under agitation it is slowly added dropwise 0.25 μ L (1.54mmol) triethylamine trihydrofluoride, finish, at room temperature react 18h, add the water of 1mL to terminate reaction, then three times it are extracted with ethyl acetate, merge organic facies, wash three times by saturated NaCl solution, anhydrous sodium sulfate is dried, filter, filtrate concentrates gained residue and obtains pale yellow oily liquid body 28mg through column chromatography (petroleum ether: ethyl acetate=4:1), productivity 93%.Structural formula is shown in Fig. 1.Reaction equation is shown in Fig. 5.
1H-NMR(600MHz,CDCl3) δ 6.71 (dd, J=15.6,10.8Hz, 1H), 6.24-6.22 (m, 1H), 6.11 (dd, J=15.6,11.4Hz, 1H), 5.91-5.87 (m, 1H), 5.68 (d, J=10.8Hz, 1H), 5.56 (d, J=15.6Hz, 1H), 4.43 (d, J=6.0Hz, 2H), 2.12 (q, J=7.2Hz, 2H), 1.58 (s, 2H), 1.39 (dd, J=13.8,6.6Hz, 2H), 1.28 (td, J=13.8,7.2Hz, 6H), 0.22 (t, J=6.6Hz), is shown in Figure 33；
13C-NMR(150MHz,CDCl3) δ 145.7,144.9,140.6,129.4,109.7,107.0,83.1,79.9,77.6,75.1,61.2,32.9,31.6,28.9,22.6,14.1, see Figure 34.
In hydrogen spectrum, the hydrogen in the aryl domains of chemical shift 7.69-7.68 and 7.45-7.39 disappears, and illustrates that oxygen silicon key ruptures, and generates alcoholic extract hydroxyl group.
Claims (6)
- null1. a bupleurynol and (2Z thereof,8E,10E)-ten five carbon-2,8,10-triolefin-4,The Stereoselective synthesizing process of 6-diine-1-alcohol，It is characterized in that: (2E,8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine aldehyde and 5-(R base sulfone)-1-phenyl-1H-tetrazole are dissolved in oxolane with the molar equivalent ratio of 1:1.3～3.0，It is cooled to-40～-78 DEG C，And at-40～-78 DEG C, add the organic base tetrahydrofuran solution of 1.0mol/L，Stirring reaction 30～60 minutes，Then stirring reaction 6～12 hours is continued under room temperature，The reaction of Julia Kocienski highly-solid selectively is occurred to generate trans target product (2E,8Z,10E)-10-((tert-butyl diphenyl) epoxide)-pentadecane triolefin-4,6-diine，Compound (2E,8Z,10E)-10-((tert-butyl diphenyl) epoxide)-pentadecane triolefin-4,6-diine is dissolved in oxolane，Add 1:15～the triethylamine trihydrofluoride of 20 molar equivalents，React 12～24 hours，Respectively obtain bupleurynol and (2Z,8E,10E)-ten five carbon-2,8,10-triolefin-4,6-diine-1-alcohol.
- A kind of bupleurynol the most according to claim 1 and (2Z thereof, 8E, 10E)-ten five carbon-2,8,10-triolefin-4, the Stereoselective synthesizing process of 6-diine-1-alcohol, it is characterized in that: described (2E, 8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4, the synthesis step of 6-diine aldehyde is as follows:nullMethyl propiolate and lithium iodide carry out Stereoselective reaction and obtain (Z)-3-iodo-2-acrylic acid methyl ester.，(Z)-3-iodo-2-acrylic acid methyl ester. occurs Sonagashia coupling reaction to generate (Z)-5-(TMS)-4-alkynes-2-alkene-methyl valerate with the acetylene of the silica-based protection of trimethyl under the catalysis of dichloro triphenyl phosphorus palladium and Hydro-Giene (Water Science).，Compound (Z)-5-(TMS)-4-alkynes-2-alkene-methyl valerate is reduced to hydroxy compounds (Z)-5-(TMS)-2-amylene-3-alkynes-1-alcohol under going back original reagent diisopropyl aluminum hydride effect，(Z) reaction under DMAP is catalyzed obtains compound (Z)-tert-butyl diphenyl ((5-(trimethyl silyl)-2-amylene-4-alkynes-1-base) epoxide) silane to-5-(TMS)-2-amylene-3-alkynes-1-alcohol with tert-butyl diphenyl chlorosilane and triethylamine，(Z)-tert-butyl diphenyl ((5-(trimethyl silyl)-2-amylene-4-alkynes-1-base) epoxide) silane generates terminal alkyne compound (Z)-tert-butyl ester-(2-amylene-4-alkynes-1-oxygen) diphenyl silane under potassium carbonate effect，(Z)-tert-butyl ester-(2-amylene-4-alkynes-1-oxygen) diphenyl silane and N-bromo-succinimide are generating compound (Z)-(tert-butyl group) ((5-bromo-2-amylene-4-alkynes-1-base) epoxide) diphenyl silane under silver nitrate is catalyzed，(Z) under Hydro-Giene (Water Science). is catalyzed, there is cardiot-chodkiewicz reacting generating compound (2E with (E)-amyl group-2-alkene-4-alkynes-1-alcohol in-(tert-butyl group) ((5-bromo-2-amylene-4-alkynes-1-base) epoxide) diphenyl silane,8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine-1-alcohol，(2E,8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine-1-alcohol generates aldehyde compound (2E under Dai Si-Martin's oxidant effect,8Z)-10-((tert-butyl diphenyl) epoxide)-2,8-decadinene-4,6-diine aldehyde.
- A kind of bupleurynol the most according to claim 1 and (2Z thereof, 8E, 10E)-ten five carbon-2, 8, 10-triolefin-4, the Stereoselective synthesizing process of 6-diine-1-alcohol, it is characterized in that: the synthesis step of described 5-(R base sulfone)-1-phenyl-1H-tetrazole is as follows: the reaction under diethyl azodiformate and triphenyl phosphorus are catalyzed of ROH Yu 1-phenyl-1H-TETRAZOLE-5-mercaptan generates 5-(R base sulfenyl)-1-phenyl-1H-tetrazole, 5-(R base sulfenyl)-1-phenyl-1H-tetrazole and hydrogen peroxide ammonium molybdate tetrahydrate be catalyzed under generate 5-(R base sulfone)-1-phenyl-1H-tetrazole.
- A kind of bupleurynol the most according to claim 1 and (2Z thereof, 8E, 10E)-ten five carbon-2,8,10-triolefin-4, the Stereoselective synthesizing process of 6-diine-1-alcohol, is characterized in that: the R base in described 5-(R base sulfone)-1-phenyl-1H-tetrazole is amyl group or heptyl.
- A kind of bupleurynol the most according to claim 3 and (2Z, 8E, 10E)-ten five carbon-2,8,10-triolefin-4, the Stereoselective synthesizing process of 6-diine-1-alcohol, is characterized in that: described ROH is n-amyl alcohol or n-heptanol.
- A kind of bupleurynol the most according to claim 1 and (2Z thereof, 8E, 10E)-ten five carbon-2,8,10-triolefin-4, the Stereoselective synthesizing process of 6-diine-1-alcohol, is characterized in that: described organic base is potassium hexamethyldisilazide, LHMDS or sodium hexamethyldisilazide.
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