CN106831693A - Complete synthesis method of griseoviridin A and analogues - Google Patents

Complete synthesis method of griseoviridin A and analogues Download PDF

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Publication number
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
synthesis method
total synthesis
reaction
compound
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谭伟强
夏岩
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Qingdao University of Technology
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D311/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02Heterocyclic 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
    • C07D311/78Ring systems having three or more relevant rings

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  • 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

A kind of total synthesis method of aspergiolide A and the like
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.
CN201710050127.8A 2017-01-23 2017-01-23 Complete synthesis method of griseoviridin A and analogues Pending CN106831693A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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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