CN106831693A - Complete synthesis method of griseoviridin A and analogues - Google Patents
Complete synthesis method of griseoviridin A and analogues Download PDFInfo
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- CN106831693A CN106831693A CN201710050127.8A CN201710050127A CN106831693A CN 106831693 A CN106831693 A CN 106831693A CN 201710050127 A CN201710050127 A CN 201710050127A CN 106831693 A CN106831693 A CN 106831693A
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- aspergiolide
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- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 title abstract 4
- UXWOXTQWVMFRSE-SXTNSRNPSA-N griseoviridin Chemical compound C([C@H](OC1=O)C)\C=C(C(NC/C=C\C=C/[C@@H](O)C[C@@H](O)C2)=O)/SC[C@H]1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-SXTNSRNPSA-N 0.000 title abstract 4
- 108010033580 griseoviridin Proteins 0.000 title abstract 4
- 238000001308 synthesis method Methods 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000006257 total synthesis reaction Methods 0.000 claims abstract description 17
- -1 9-anthrone lactone compounds Chemical class 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 150000004434 1-hydroxyanthraquinones Chemical class 0.000 claims abstract description 6
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 5
- 238000003786 synthesis reaction Methods 0.000 claims abstract 2
- XDYWIHGBFULPRQ-UHFFFAOYSA-N 16-(2,4-dihydroxy-6-methylbenzoyl)-4,6,10-trihydroxy-12-methyl-14-oxatetracyclo[7.7.1.02,7.013,17]heptadeca-1(16),2(7),3,5,9,11,13(17)-heptaene-8,15-dione Chemical compound CC1=CC(O)=CC(O)=C1C(=O)C(C(O1)=O)=C2C3=C1C(C)=CC(O)=C3C(=O)C1=C(O)C=C(O)C=C12 XDYWIHGBFULPRQ-UHFFFAOYSA-N 0.000 claims description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 230000000977 initiatory effect Effects 0.000 claims description 5
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims description 5
- 229960001180 norfloxacin Drugs 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 3
- 150000004718 beta keto acids Chemical class 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000010933 acylation Effects 0.000 abstract description 3
- 238000005917 acylation reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- MNPDVZORKLLUAB-UHFFFAOYSA-N C1=COC=2C=CC=C3C=2C1=C1C=CC=CC1=C3 Chemical compound C1=COC=2C=CC=C3C=2C1=C1C=CC=CC1=C3 MNPDVZORKLLUAB-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 3
- 241000132177 Aspergillus glaucus Species 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 150000005204 hydroxybenzenes Chemical class 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- CDNFREJAKMEVKD-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yl)-5-phenylfuro[3,2-g]chromen-7-one Chemical compound C12=CC=3C(C=4C=C5OCOC5=CC=4)=COC=3C=C2OC(=O)C=C1C1=CC=CC=C1 CDNFREJAKMEVKD-UHFFFAOYSA-N 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- 229940076442 9,10-anthraquinone Drugs 0.000 description 1
- UEBLTUIPNYZESL-UHFFFAOYSA-N C12=CC=CC=C2CC2=CC=CC1=C2 Chemical compound C12=CC=CC=C2CC2=CC=CC1=C2 UEBLTUIPNYZESL-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 208000008342 Leukemia P388 Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000238370 Sepia Species 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 125000005577 anthracene group Chemical group 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 210000004043 pneumocyte Anatomy 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis, and relates to a total synthesis method of griseoviridin A and analogues thereof; 1-hydroxyanthraquinone compounds are used as starting materials, hydroxyl groups are protected through acylation, the 1-hydroxyanthraquinone compounds and beta-keto ester undergo Knoevenagel cyclization reaction to generate 9-anthrone lactone compounds, and finally demethylation reaction is carried out to obtain final products of griseoviridin A and analogues; the total synthesis method has the advantages of easily available raw materials, simple reaction steps, mild reaction conditions, convenient post-treatment, wide adaptability and the like, and the synthesized griseoviridin A and the like can be used for developing novel antitumor drugs.
Description
Technical field：
The invention belongs to chemosynthesis technical field, it is related to a kind of total synthesis method of aspergiolide A and the like；Pass through
1- hydroxy anthraquinones compound is initiation material, is finally produced through acylation, Knoevenagel Norfloxacin Reactions and demethylation
Thing aspergiolide A and the like.
Background technology：
Aspergiolide A is the secondary metabolite produced by ocean Aspergillus glaucus (Aspergillus glaucus) HB1-19
A kind of isolated compound with novel anthraquinone lactone skeleton structure, the cytotoxic activity with wide spectrum is more to human body
Plant cancer cell, such as typeⅡ pneumocyte, human leukemia HL-60 cell, human hepatocellular carcinoma BEL-7402 cell, mouse leukemia P388
Cell has stronger inhibited proliferation, as a kind of antitumor primer of brand-new anthraquinone class formation, it is possible in drug effect, the heart
Dysentery aspect shows the characteristics different from the anthracene ring antitumor medicinal such as adriamycin；Because aspergiolide A is in original strain
In content it is extremely small, greatly constrain to its activity in vivo evaluation and structure activity study, therefore, being ground by each side
Study carefully, by the research of biosynthesis pathway, optimization, metabolic regulation, shearing and dissolving oxygen environment to Aspergillus glaucus condition of culture
Control, greatly improves the yield of aspergiolide A, and is amplified to 30L to 500L, is respectively increased the yield of aspergiolide A
37mg and 30mg.But up to the present, the chemical fully synthetic of aspergiolide A yet there are no document report, therefore seek a kind of system
Standby simple, raw material is easy to get, and the total synthesis method of friendly aspergiolide A of preparation condition and the like has good social benefit
And economic benefit.
The content of the invention：
It is an object of the invention to the shortcoming for overcoming prior art to exist, seek to provide a kind of aspergiolide A and the like
Total synthesis method；With 1- hydroxy anthraquinones compounds as initiation material, through being acylated protection hydroxyl, then passed through with beta-ketoester
Knoevenagel Norfloxacin Reactions generate 9- anthrone lactone compounds, and last demethylating reaction obtains final product aspergiolide A
And the like.
To achieve these goals, the synthetic route of the total synthesis method of aspergiolide A of the present invention and the like
Reaction equation is：
The specific steps of the fully synthetic technique of aspergiolide A of the present invention and the like:
(1)：Control temperature tries 1- hydroxy anthraquinones compound II at 0-50 DEG C under the effect of the first alkali with acylation
Agent is reacted 1-24 hours in the first reaction dissolvent, obtains compound III, and its reaction equation is：
Wherein, the mol ratio of 1- hydroxy anthraquinones compound and acylting agent is 1:1-1:3, acylting agent and alkali
Mol ratio is 1:2-1:5；R in compound III1It is one or more in hydrogen atom, hydroxyl, methyl or methoxy, R1It is hydrogen
The number of atom is 0-7；1- hydroxy anthraquinones compounds II is initiation material, and its chemical constitution is：
Wherein R1It is one or more in hydrogen atom, hydroxyl, methyl or methoxy, R1For the number of hydrogen atom is 0-6；
(2)：Control temperature at 20-100 DEG C by obtained compound III in step (1) under the effect of the second alkali with β-
Keto ester, through Knoevenagel Norfloxacin Reactions 12-72 hours, generates compound IV in the second reaction dissolvent, and its reaction equation is：
Wherein, wherein the mol ratio of compound III and beta-ketoester is 1:1.5-1:The mol ratio of 3, compound III and alkali
It is 1:3-1:10；Beta-ketoester chemical structural formula is：
Wherein R2It is one or more in hydrogen atom, hydroxyl, methyl or methoxy, R2For the number of hydrogen atom is 0-5,
R " is alkyl CnH2n+1, and wherein n is the number of carbon atom, and the size of n is 1,2 or 3；
(3)：Control temperature is at -40-20 DEG C by obtained compound IV in step (2) and Boron tribromide solution the 3rd
Compound I, i.e. aspergiolide A and the like were obtained through demethylation reaction 1-12 hours in reaction dissolvent, its reaction equation is：
Wherein, compound IV and the mol ratio of Boron tribromide are 1:15-1:30.
The present invention relates to the step of (1) in the first reaction dissolvent be dichloromethane, chloroform, ethyl acetate, tetrahydrochysene
One or more in furans or N,N-dimethylformamide.
The present invention relates to the step of (1) in acylting agent be chlorobenzoyl chloride, acyl chlorides R ' COCl or acid anhydrides (R ' CO)2O
In one or more；Wherein R ' is the alkyl of carbon number 1-2.
The present invention relates to the step of (1) in the first alkali be the one kind or many in triethylamine, piperidines, potassium carbonate or sodium carbonate
Kind.
The present invention relates to the step of (2) in the second alkali be the one kind or many in triethylamine, piperidines, potassium carbonate or sodium carbonate
Kind；
The present invention relates to the step of (2) in the second reaction dissolvent for acetone, tetrahydrofuran, N,N-dimethylformamide or
One or more in dimethyl sulfoxide (DMSO).
The present invention relates to the step of (3) in the 3rd reaction dissolvent be in dichloromethane, chloroform or tetrahydrofuran one
Plant or various.
The present invention relates to the step of (3) in Boron tribromide solution in solvent for concentration for 0.1-2.0mol/L dichloro
One or more of methane, normal heptane or n-hexane.
The present invention compared with prior art, its with 1- hydroxy anthraquinones compounds as initiation material, through be acylated,
Knoevenagel Norfloxacin Reactions, demethylation obtains final product aspergiolide A and the like；Its total synthesis method has original
Material is easy to get, and reactions steps are simple, and reaction condition is gentle, and convenient post-treatment, synthetic method has the advantages that extensive adaptability, closes
Into aspergiolide A and the like can be used for developing new type antineoplastic medicine.
Specific embodiment：
Below by embodiment, the invention will be further described.
Embodiment 1：The preparation of 4- methoxyl group -1- acetoxyl group -9,10- anthraquinones
1- hydroxyl -4- methoxyl group -9,10- anthraquinones (2.0g, 7.87mmol) are dissolved in 100mL dichloromethane, ice bath is stirred
Mix down and sequentially add triethylamine (6.04mL, 43.29mmol) and chloroacetic chloride (2.23mL, 31.48mmol), be warmed to room temperature and continue to stir
After mixing reaction 1 hour, it is concentrated under reduced pressure, dichloromethane extraction filtering, extract is washed through saturated common salt, anhydrous sodium sulfate drying,
Filtering, after being concentrated under reduced pressure, residue rapid column chromatography separates (V (petroleum ethers (60~90 DEG C)：V (ethyl acetate)=2:1, Rf=
0.275) 4- methoxyl group -9,10- anthraquinone -1- acetic acid esters 2.0g, yield 86%, are obtained.Orange/yellow solid, M.p.：185 DEG C,1H
NMR(CDCl3,400MHz,23℃),δ8.2(m,1H),8.1(m,1H),7.7(m,2H),7.3(m,2H),4.0(s,3H),2.5
(s, 3H)；MS(APCI)for C17H12O5(M+H+)：297.1.
Embodiment 2：The preparation of 4- methoxyl group -1- benzoyloxy -9,10- anthraquinones
1- hydroxyl -4- methoxyl group -9,10- anthraquinones (2g, 7.87mmol) are dissolved in 100mL dichloromethane, under ice bath according to
Secondary addition triethylamine (6.04mL, 43.3mmol) and chlorobenzoyl chloride (3.63mL, 31.5mmol), after room temperature continues to react 2 hours,
Washed with saturated common salt, be concentrated under reduced pressure, residue rapid column chromatography separates (V (petroleum ethers (60~90 DEG C)：V (ethyl acetate)=
2：1, Rf=0.35), obtain 2.45g orange/yellow solid 4- methoxyl group -1- benzoyloxy -9,10- anthraquinones, yield 87%.It is orange
Color solid, M.p.：214 DEG C,1H NMR(CDCl3, 400MHz, 23 DEG C), δ 8.31 (dd, 2H), 8.25 (d, 1H), 8.11 (d,
1H),7.78(m,3H),7.61(m,2H),7.52(d,1H),7.45(d,1H),4.10(s,3H)；MS(APCI)for C22H14O6
(M+H+):358.9。
Embodiment 3：The preparation of 6- methoxyl groups-(1- benzoyls) naphtho- [1,2,3-de] chromene -2,7- diketone
Under nitrogen, sequentially add Anhydrous potassium carbonate (120mg, 0.85mmol), ethyl benzoylacetate (43 μ L,
0.225mmol), 1- acetic acid -4- methoxy anthraquinones ester (50mg, 0.17mmol) and DMSO (2.0mL), 40 DEG C are reacted 24 hours
Afterwards, 10mL water, dichloromethane (3 × 30mL) extraction, combining extraction liquid is added through anhydrous sodium sulfate drying, to filter, depressurize dense
Contracting, residue rapid column chromatography separates (V (petroleum ethers (60~90 DEG C)：V (ethyl acetate)=2:1, Rf=0.13) 6- first, is obtained
Oxy-1-benzoyl naphthalene [1,2,3-de] chromene-2,7- diketone 72mg, yield is 55%.Sepia solid, M.p.：
224 DEG C,1H NMR(CDCl3,400MHz,23℃),δ8.47(dd,1H),8.07(d,2H),7.85(d,1H),7.73(m,3H),
7.55(m,2H),7.47(m,2H),4.14(s,3H)；MS(APCI)for C24H14O5(M+H+)：383.1.
Embodiment 4：6- methoxyl groups-(1- is to anisoyl base) naphtho- [1,2,3-de] chromene -2,7- diketone
Prepare
Under nitrogen, sequentially add Anhydrous potassium carbonate (60mg, 0.43mmol), to methoxybenzoyl ethyl acetate (79 μ L,
0.34mmol), 4- methoxyl groups -1- benzoyloxy -9,10- anthraquinones (50mg, 0.17mmol) and DMF (4mL), 50 DEG C of reactions 24
After hour, 10mL water is added, extracted with dichloromethane (3 × 30mL), extract depressurizes dense through anhydrous sodium sulfate drying, filtering
Contracting, residue rapid column chromatography separates (V (petroleum ethers (60~90 DEG C)：V (ethyl acetate)=2：1, Rf=0.11), obtain 6- first
Oxy-1-and to anisoyl base naphthalene [1,2,3-de] chromene-2,7- diketone 27mg, yield is 37%.Brown solid,
M.p.：180 DEG C,1H NMR(CDCl3,400MHz,23℃),δ8.46(d,1H),8.03(m,2H),7.95(m,1H),7.72(m,
1H),7.67(m,1H),7.46(m,2H),6.99(m,2H),4.17(s,3H),3.89(s,3H)；MS(APCI)for C25H16O6
(M+H+)：413.2.
Embodiment 5：The preparation of 6- hydroxyls-(1- benzoyls) naphtho- [1,2,3-de] chromene -2,7- diketone
Under nitrogen, by 6- methoxyl group -1- benzoyls naphtho- [1,2,3-de] chromene -2,7- diketone (50mg,
0.13mmol) it is dissolved in dichloromethane (2ml), after ice bath cooling, is added dropwise over the two of Boron tribromide (0.91mL, 0.91mmol)
Chloromethanes solution, after being warmed to room temperature reaction 3 hours, adds methanol/water (5mL) mixed solution, dichloromethane (3 × 10mL) extraction
Take, through anhydrous sodium sulfate drying, filter, after being concentrated under reduced pressure, residue column chromatography for separation (V (petroleum ethers (60~90 DEG C)：V (second
Acetoacetic ester)=3：1, Rf=0.45), obtain 6- hydroxyl -1- benzoyls naphtho- [1,2,3-de] chromene -2,7- diketone
43mg, yield is 89%；Orange/yellow solid,1H NMR(CDCl3,400MHz,23℃),δ13.24(s,1H),8.58(dd,1H),
8.08(dd,2H),7.95(d,1H),7.73(m,3H),7.71(m,3H),7.69(m,1H)；MS(APCI)for C23H12O5(M+
H+):369.1。
Embodiment 6：The system of 6- hydroxyls-(1- para hydroxybenzenes formoxyl) naphtho- [1,2,3-de] chromene -2,7- diketone
It is standby
Under nitrogen, by 6- methoxyl group -1- to anisoyl base naphtho- [1,2,3-de] chromene -2,7- diketone
(50mg, 0.12mmol) is dissolved in dichloromethane (2mL), ice bath cooling after, be added dropwise over Boron tribromide (1.82mL,
Dichloromethane solution 1.82mmol), after being warmed to room temperature reaction 2 hours, adds methanol/water (10mL) mixed solution, dichloromethane
Alkane (3 × 20mL) is extracted, and through anhydrous sodium sulfate drying, is filtered, after being concentrated under reduced pressure, residue column chromatography for separation (V (petroleum ethers (60
~90 DEG C)：V (ethyl acetate)=2：1, Rf=0.20) obtain 6- hydroxyls-(1- para hydroxybenzenes formoxyl) naphtho- [1,2,3-de] benzene
And pyrans -2,7- diketone 25mg, yield 54%；Orange/yellow solid,1H NMR(CDCl3,400MHz,23℃),δ13.07(s,
1H),10.74(s,1H),8.47(d,1H),8.00(d,2H),7.92(t,2H),7.83(t,1H),7.75(d,1H),7.50
(d,1H),6.89 (d,2H)；MS(APCI)for C23H12O6(M+H+)：385.1.
Claims (9)
1. the total synthesis method of a kind of aspergiolide A and the like, it is characterised in that synthetic route reaction equation is：
。
2. a kind of total synthesis method of aspergiolide A according to claim 1 and the like, it is characterised in that its synthesis work
The specific steps of skill include:
(1)：Control temperature exists 1- hydroxy anthraquinones compound II at 0-50 DEG C under the effect of the first alkali with acylting agent
Reacted 1-24 hours in first reaction dissolvent, obtain compound III, its reaction equation is：
Wherein, the mol ratio of 1- hydroxy anthraquinones compound and acylting agent is 1:1-1:3, acylting agent and alkali mole
Than being 1:2-1:5；R in compound III1It is one or more in hydrogen atom, hydroxyl, methyl or methoxy, R1It is hydrogen atom
Number be 0-7；1- hydroxy anthraquinones compounds II is initiation material, and its chemical constitution is：
Wherein R1It is one or more in hydrogen atom, hydroxyl, methyl or methoxy, R1For the number of hydrogen atom is 0-6；
(2)：With beta-keto acid under controlling temperature that obtained compound III in step (1) is acted in the second alkali at 20-100 DEG C
Ester, through Knoevenagel Norfloxacin Reactions 12-72 hours, generates compound IV in the second reaction dissolvent, and its reaction equation is：
Wherein, wherein the mol ratio of compound III and beta-ketoester is 1:1.5-1:The mol ratio of 3, compound III and alkali is 1:
3-1:10；Beta-ketoester chemical structural formula is：
Wherein R2It is one or more in hydrogen atom, hydroxyl, methyl or methoxy, R2For the number of hydrogen atom is 0-5, R " is
Alkyl CnH2n+1, wherein n are the number of carbon atom, and the size of n is 1,2 or 3；
(3)：Control temperature is at -40-20 DEG C by obtained compound IV in step (2) and Boron tribromide solution in the 3rd reaction
Compound I, i.e. aspergiolide A and the like were obtained through demethylation reaction 1-12 hours in solvent, its reaction equation is：
Wherein, compound IV and the mol ratio of Boron tribromide are 1:15-1:30.
3. a kind of total synthesis method of aspergiolide A according to claim 2 and the like, it is characterised in that the step
(1) the first reaction dissolvent in is in dichloromethane, chloroform, ethyl acetate, tetrahydrofuran or N,N-dimethylformamide
One or more.
4. a kind of total synthesis method of aspergiolide A according to claim 2 and the like, it is characterised in that the step
(1) acylting agent in is chlorobenzoyl chloride, acyl chlorides R ' COCl or acid anhydrides (R ' CO)2One or more in O；Wherein R ' is carbon
The alkyl of atomicity 1-2.
5. a kind of total synthesis method of aspergiolide A according to claim 2 and the like, it is characterised in that the step
(1) the first alkali in is one or more in triethylamine, piperidines, potassium carbonate or sodium carbonate.
6. a kind of total synthesis method of aspergiolide A according to claim 2 and the like, it is characterised in that the step
(2) the second alkali in is one or more in triethylamine, piperidines, potassium carbonate or sodium carbonate.
7. a kind of total synthesis method of aspergiolide A according to claim 2 and the like, it is characterised in that the step
(2) the second reaction dissolvent in is for one or more in acetone, tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide (DMSO).
8. a kind of total synthesis method of aspergiolide A according to claim 2 and the like, it is characterised in that the step
(3) the 3rd reaction dissolvent in is for one or more in dichloromethane, chloroform or tetrahydrofuran.
9. a kind of total synthesis method of aspergiolide A according to claim 2 and the like, it is characterised in that the step
(3) solvent in Boron tribromide solution in is the one of the dichloromethane that concentration is 0.1-2.0mol/L, normal heptane or n-hexane
Plant or various.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108329291A (en) * | 2018-01-31 | 2018-07-27 | 青岛理工大学 | Synthesis method of ionic liquid catalyzed 9-anthrone lactone compound |
| CN109096239A (en) * | 2017-06-20 | 2018-12-28 | 中国海洋大学 | Application of the preparation route of 9- anthrone lactone skeleton compound and the like in anti-tumor aspect |
-
2017
- 2017-01-23 CN CN201710050127.8A patent/CN106831693A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 高利明: "海洋天然产物灰绿霉素A全合成方法研究", 《中国优秀硕士论文全文数据库 工程科技I辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109096239A (en) * | 2017-06-20 | 2018-12-28 | 中国海洋大学 | Application of the preparation route of 9- anthrone lactone skeleton compound and the like in anti-tumor aspect |
| CN109096239B (en) * | 2017-06-20 | 2022-02-11 | 中国海洋大学 | Preparation route of 9-anthrone lactone framework compound and application of analogue thereof in antitumor aspect |
| CN108329291A (en) * | 2018-01-31 | 2018-07-27 | 青岛理工大学 | Synthesis method of ionic liquid catalyzed 9-anthrone lactone compound |
| CN108329291B (en) * | 2018-01-31 | 2021-07-09 | 青岛理工大学 | Synthesis method of ionic liquid catalyzed 9-anthrone lactone compound |
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