CN113336731A - Flavaginess natural product asymmetric diversity guide synthesis method - Google Patents

Flavaginess natural product asymmetric diversity guide synthesis method Download PDF

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CN113336731A
CN113336731A CN202010137149.XA CN202010137149A CN113336731A CN 113336731 A CN113336731 A CN 113336731A CN 202010137149 A CN202010137149 A CN 202010137149A CN 113336731 A CN113336731 A CN 113336731A
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methoxyphenyl
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陆海华
曹梦月
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Westlake University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
    • B01J31/2414—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/44—Allylic alkylation, amination, alkoxylation or analogues
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Abstract

The invention discloses an asymmetric synthesis method of Flavivines natural products, which comprises the steps of carrying out palladium-catalyzed asymmetric decarboxylation allylation on an allylation precursor (III) to obtain a first intermediate, carrying out end-position selective Wacker oxidation on the first intermediate to obtain a second intermediate, carrying out intramolecular benzoin condensation on the second intermediate to obtain a third intermediate, carrying out dehydrogenation and Michael addition on the third intermediate to construct three continuous chiral centers to obtain a fifth intermediate, and finally carrying out functional group synthesis on the fifth intermediate to obtain a plurality of Flavivines natural products, wherein the Flavivines natural products are shown in formula (I). The invention creatively researches the diversity-oriented Flavagines natural product asymmetric synthesis method, realizes the establishment of a novel compound library of the natural product, and effectively promotes the drug activity test and the anti-cancer of the natural productSimilar to the development of clinical trials.
Figure DDA0002397738000000011

Description

Flavaginess natural product asymmetric diversity guide synthesis method
Technical Field
The invention belongs to the technical field of chemical preparation, relates to a method for preparing a natural compound, and particularly relates to an asymmetric diversity-oriented synthesis method for a Flavaginess natural product.
Background
Flavaginess is a natural product which is separated from a tree orchid plant and has a special structural framework and important physiological activity. The main physiological activities include: anticancer, anti-inflammatory, neuroprotective and cardioprotective effects, etc. Among them, Flavaginess has remarkable anticancer activity, which has attracted research interest of a great number of scientists. Structurally, Flavaginess mostly has a polycyclic core backbone of benzofurocyclopentane. Among them, cyclopentane has five consecutive chiral centers, which brings some challenges to the asymmetric synthesis of such natural products.
Figure RE-GDA0002555365570000011
In 1990, the Trost project group reported the first asymmetric total synthesis of rocaglamide by substrate-induced, palladium-catalyzed [3+2 ]]And performing cycloaddition to construct a Flavaginess chiral cyclopentane skeleton. In 2006, the Porco subject group combines the chiral auxiliary agent and the photocatalysis to realize the high-efficiency biomimetic synthesis of the natural products. In 2015, the Tius group completed the first example of catalytic asymmetric synthesis of Flavagliness family natural products using a palladium and ligand catalyzed Nazarov cyclization reaction. Despite the potential anticancer cell activity and the reported multiple synthetic strategies, the Flavagliness natural product has not met the clinical trial requirements in the aspect of drug development. Meanwhile, the current work and the known synthetic methods are limited to the change of the substituent on the aromatic ring and cannot relate to the synthesis of alkyl substituted Flavaginess (R)1,R2＝ alkyl)。
Therefore, the targeted synthesis of Flavaginess natural products based on asymmetric diversity is carried out, a compound library is established by synthesizing a plurality of similar natural products, and a deep drug activity test is carried out, so as to screen out the novel anti-cancer drugs with the most cancer cell growth inhibition and selective toxicity.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a diversity-oriented asymmetric synthesis method aiming at the dilemma of clinical tests of Flavaginess natural products, and the invention also aims to provide the Flavaginess natural products prepared by the method.
The technical scheme is as follows: the invention relates to an asymmetric diversity guided synthesis method of Flavivines natural products, which comprises the steps of carrying out palladium-catalyzed asymmetric decarboxylation allylation on allylation precursors prepared from aromatic furanones to obtain first intermediates, carrying out end position selective Wacker oxidation on the first intermediates to obtain second intermediates, carrying out intramolecular benzoin condensation on the second intermediates to obtain third intermediates, carrying out dehydrogenation and Michael addition on the third intermediates to construct three continuous chiral centers to obtain fifth intermediates, and finally synthesizing Flavivines natural products from the fifth intermediates, wherein the Flavivines natural products are shown as a formula (I);
Figure RE-GDA0002555365570000031
wherein:
Figure RE-GDA0002555365570000032
R2is one of H, methyl, ethyl, isopropyl, vinyl, isopropyl, benzyl, cyclohexyl, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl;
R3is one of H, methyl, ethyl, isopropyl, vinyl, isopropyl, benzyl, cyclohexyl, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl;
R4is H, CO2Me，CO(NMe)2One of (1);
R5is H, CO2Me，CO(NMe)2One of (1);
R6is hydroxy or H;
R7is hydroxy or H;
R8is a hydroxyl group.
Further, as a preferred embodiment, R2Is H; r3Is methyl, ethyl, isopropyl, vinyl, isopropylOne of benzyl, cyclohexyl, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl;
R4is H; r5Is H, CO2Me，CO(NMe)2One kind of (1).
Further, as a preferred embodiment, R2Is one of methyl, ethyl, isopropyl, vinyl, isopropyl, benzyl, cyclohexyl, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl; r3Is H;
R4is H, CO2Me，CO(NMe)2One of (1); r5Is H.
Further, as a preferred embodiment, the method specifically comprises the following steps:
(1) adding aromatic furanone derived allyl carbonate into a reaction bottle, adding a solvent, a catalyst and a ligand, reacting at-20 to-15 ℃ for 40 to 50 hours, removing the solvent after the reaction is finished, and performing column chromatography separation by using n-hexane/ethyl acetate to obtain a first intermediate, wherein the formula is shown In (IV);
(2) adding a solvent into the first intermediate, adding a metal catalyst, reacting at room temperature for 20-30 h in an oxygen atmosphere, adding a quenching agent after the reaction is finished, extracting, drying, removing the solvent, and performing column chromatography separation by using n-hexane/ethyl acetate to obtain a second intermediate shown as a formula (V);
(3) and adding a solvent into the second intermediate, adding a carbene precursor and alkali, and reacting at room temperature for 4-5 h. After the reaction is finished, removing the solvent, and performing column chromatography separation by using n-hexane/methyl tert-butyl ether to obtain a third intermediate, wherein the third intermediate is shown as a formula (VI);
(4) adding a solvent into the third intermediate, adding a catalyst, reacting for 20-30 h at 70-90 ℃ in an oxygen atmosphere, adding a quenching agent after the reaction is finished, extracting, drying, removing the solvent, and performing column chromatography separation by using n-hexane/methyl tert-butyl ether to obtain a fourth intermediate, wherein the formula is (VII);
(5) adding a solvent, a catalyst and a Grignard reagent into the fourth intermediate, reacting at-80 to-75 ℃ for 2 to 3 hours, heating to 0 ℃ and continuing to react for 1 hour. Adding a quenching agent after the reaction is finished, extracting, drying, removing the solvent, and performing column chromatography separation by using n-hexane/ethyl acetate to obtain a fifth intermediate, wherein the formula is shown as a formula (VIII);
(6) and adding a solvent into the fifth intermediate, adding an esterification reagent, and adding a quenching agent after the reaction is finished. After extraction, drying and solvent removal, adding a solvent into the obtained intermediate product, adding a condensing agent and amine, reacting for 3-5 hours at 100 ℃, and directly removing the solvent after the reaction is finished. Continuously adding a solvent into the obtained intermediate amide, adding a reducing agent, reacting at 20-30 ℃ for 3h, adding a quenching agent after the reaction is finished, extracting, drying, removing the solvent, and performing column chromatography separation by using n-hexane/ethyl acetate to obtain a Flavaglines natural product shown in the formula (I);
the specific reaction process is as follows:
Figure RE-GDA0002555365570000051
further, as a preferred embodiment, in the step (1), the solvent is tetrahydrofuran, and the catalyst is Pd2(dba)3The ligand is a cycloheptane Trost ligand, and the structure of the cycloheptane Trost ligand is shown as a formula L1:
Figure RE-GDA0002555365570000061
wherein: ar (Ar)2Is 4-CH3-C6H4-；
The preparation method of the cycloheptane Trost ligand specifically comprises the following steps: performing addition reaction on cycloalkenyl methyl formate and diaryl phosphine oxide to obtain a first intermediate, performing one-pot reduction and boronization on the first intermediate to obtain a second intermediate, hydrolyzing the second intermediate to obtain a third intermediate, and performing condensation reaction on the third intermediate and cycloheptane chiral diamine to obtain the novel Trost ligand L1.
Further, as a comparisonIn a preferred embodiment, the solvent in the step (2) is tert-butyl alcohol or nitromethane; the catalyst is PdCl2(PhCN)2,CuCl2·2H2O,AgNO2(ii) a The quenching agent is water.
Further, as a preferred embodiment, the solvent in the step (3) is tetrahydrofuran; the condensing agent is an azacarbene reagent, and the structure of the azacarbene reagent is shown as a formula L2:
Figure RE-GDA0002555365570000062
further, as a preferred embodiment, the solvent in the step (4) is dimethyl sulfoxide; the dehydrogenation reagent is palladium acetate; the Lewis acid catalyst is trifluoroacetic acid; the quenching agent is ice-water mixed liquid.
Further, as a preferred embodiment, the solvent in the step (5) is tetrahydrofuran; the Lewis acid catalyst is CuBr. Me2S; the quenching agent is saturated ammonium chloride;
the solvent in the step (6) is N, N-dimethylformamide, methanol, toluene, acetonitrile or acetic acid; esterification reagent is Stile's reagent and trimethylsilyldiazomethane, amidation reagent is 4-dimethylaminopyridine and dimethylamine, and reducing agent is Me4NBH(OAc)3The quenching agent is dilute hydrochloric acid and saturated sodium carbonate.
The invention also provides a Flavoglies natural product prepared by the synthesis method, which is shown as the formula (I);
Figure RE-GDA0002555365570000071
wherein:
Figure RE-GDA0002555365570000072
R2is H, methyl, ethyl, isopropyl, ethenyl, isopropyl, benzyl, cyclohexyl, 1-propenyl, p-methylOne of oxyphenyl, o-methoxyphenyl and m-methoxyphenyl;
R3is one of H, methyl, ethyl, isopropyl, vinyl, isopropyl, benzyl, cyclohexyl, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl;
R4is H, CO2Me，CO(NMe)2One of (1);
R5is H, CO2Me，CO(NMe)2One of (1);
R6is hydroxy or H;
R7is hydroxy or H;
R8is a hydroxyl group.
Has the advantages that: the invention creatively researches the synthetic method of the Flavivines natural products, provides an asymmetric synthetic strategy for the diversity synthesis of the natural products, and effectively promotes the further development of the Flavivines natural products in the aspect of the pharmaceutical activity test; in the invention, through the research of the inventor on the characteristics of raw materials, novel ligands are designed in a targeted manner, a carbene catalyst, an oxidation/reduction agent, a condensing agent and the like are selected and matched with corresponding solvents, so that the smooth proceeding of the reaction process is ensured, and the stereoselectivity and the yield of the product are improved.
Drawings
FIG. 1 is a drawing of the product of example 11H NMR spectrum;
FIG. 2 is a drawing of the product of example 113C NMR spectrum;
FIG. 3 is the product of example 21H NMR spectrum;
FIG. 4 is a graph of the product of example 213C NMR spectrum;
FIG. 5 is a photograph of the product of example 31H NMR spectrum;
FIG. 6 is a graph of the product of example 313C NMR spectrum;
FIG. 7 is a graph of the product of example 41H NMR spectrum;
FIG. 8 is a graph of the product of example 413C NMR spectrum;
FIG. 9 is a photograph of the product of example 51H NMR spectrum;
FIG. 10 is the product of example 513C NMR spectrum;
FIG. 11 is a photograph of the product of example 61H NMR spectrum;
FIG. 12 is a graph of the product of example 613C NMR spectrum.
Detailed Description
The technical solution of the present invention is described in detail below with reference to the accompanying drawings, but the scope of the present invention is not limited to the embodiments.
Example 1: preparation of the first intermediate
Figure RE-GDA0002555365570000091
Under the protection of argon atmosphere, 36.6mg of Pd2(dba)331.4mg of cycloheptane Trost ligand L1 was added to 15mL of anhydrous tetrahydrofuran, stirred at room temperature for 5min, and then the reaction system was cooled to-20 ℃ and stirred under nitrogen. And adding 6.2g of 20mmol of allyl carbonate (IIIa) into 60mL of anhydrous tetrahydrofuran in a 200-mL round-bottom flask under the protection of nitrogen, cooling the reaction system to-20 ℃, dropwise adding the precooled catalyst/tetrahydrofuran solution, and reacting for 48 hours at-20 ℃ after dropwise adding. After the reaction is finished, the solvent is directly removed under reduced pressure to obtain a crude product, column chromatography is carried out, the eluent, namely n-hexane and ethyl acetate, is 20: 1-15: 1, and the crude product is purified to obtain 4.97g of a first intermediate compound, wherein the yield is 94% and the ee value is 91%.
The structural characterization data for the product obtained in example 1 are shown below:
1H NMR(400MHz,CDCl3):δ7.36–7.22(m,2H),7.21–6.80(m,7H),6.00–5.78(m, 1H),5.39–5.16(m,2H),4.64(d,J＝5.8Hz,2H),4.00(s,2H).
13C NMR(101MHz,CDCl3):δ203.39,171.78,138.09,134.45,130.67,130.45,128.07, 126.94,124.11,121.59,121.54,119.94,113.11,91.93,41.81,40.18.
the successful synthesis of the first intermediate is proved by the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the product.
The specific optical rotation of the compound of formula (IVa) [ alpha ]]D 20＝50.0(c＝0.10,MeOH).
HRMS:calculated for C18H17O2[M+H]+:265.1229,found:265.1236.
The specific structure of the cycloheptane Trost ligand in the embodiment is as follows:
Figure RE-GDA0002555365570000092
the preparation method comprises the following steps: (1) at room temperature and N2Under protection, 693mg of (R) -H8-BINOL，27μL H2Adding O into 15mL of anhydrous tetrahydrofuran, vigorously stirring at room temperature for 5min, dropwise adding 1.5mmol of dibutyl magnesium (1M) dissolved in heptane into a reaction system, then adding 3.45g and 15mmol of di (p-tolyl) phosphine oxide into the reaction system, vigorously stirring at room temperature for 5min, cooling the reaction system to-20 ℃ after stirring, dropwise adding 2.4g and 15.75mmol of cycloheptene methyl formate after stirring at the temperature for 5min, and reacting at-20 ℃ for 48h after dropwise adding; after the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution, the solvent was removed under reduced pressure, the aqueous phase was extracted three times with chloroform, the organic phase obtained by the extraction was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a crude product, and column chromatography was performed to obtain 5.4g of a first intermediate of the compound, the yield was 95%, the ee value was 95%, and the dr value was 6.3:1, by eluting with dichloromethane and ethyl acetate 2: 1.
(2) At room temperature and N2Under protection, 3g,7.8mmol of the first intermediate and 2.62g,23.4mmol of cycloheptanediamine are dissolved in 80mL of anhydrous toluene, the mixture is stirred at room temperature, the reaction system is cooled to 0 ℃, and 1.6mL of 15.6mmol of trichlorosilane is added dropwise. Stirring the mixture at 80 ℃ for 18 hours, then transferring the obtained suspension to an ice bath for cooling, dropwise adding 39mL of 39mmol borane tetrahydrofuran complex, and reacting at room temperature for 1 hour after dropwise adding; quenching with methanol solution after the reaction is finished, and then using a drainThe white solid was removed by funnel filtration and washed with ethyl acetate. The solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography using ethyl acetate 15:1 as eluent to give 1.6g of the second intermediate of the compound in 47% yield over two steps.
At-10 ℃ and N2Under protection, adding 30mL of dimethyl sulfide into 5.2g and 38.7mmol of aluminum trichloride, then dissolving 1.49g and 3.9mmol of a second intermediate into 10mL of dimethyl sulfide, slowly injecting the mixed solution of the second intermediate into the solution of aluminum trichloride (20mL/h) by using a syringe pump, and stirring the mixture for 18-20 h at-10 ℃. Then cooling the reaction system to 0 ℃, taking out the reaction solution by using an injector, slowly dropwise adding the reaction solution into 50mL of vigorously stirred ice-water mixture, quickly injecting 30mL of dichloromethane by using the injector, vigorously stirring, standing for layering, taking out the solution at the lower layer by using the injector, repeatedly injecting dichloromethane, and taking out the organic phase solution for three times; the combined organic phase solution was dried over anhydrous sodium sulfate in N2Filtration at protected low temperature and removal of the solvent under reduced pressure gave 1.2g of the third intermediate in a crude yield of 87% without further purification. The solvents in the step are all cooled in advance at the temperature of minus 20 ℃ and N is used2Degassing and deoxidizing.
At 0 ℃ and N2Under protection, 20mL of anhydrous dichloromethane were added to 1.2g,3.4mmol of the third intermediate, 128mg, 1.13mmol of (1R,2R) - (-) -1, 2-cyclohexanediamine, 753mg, 3.94mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 137mg, 1.13mmol of 4-dimethylaminopyridine, and the mixture was stirred at room temperature overnight. Then cooling the mixture to 0 ℃, dropwise adding 20mL of 1M hydrochloric acid cold solution under vigorous stirring, standing for layering, sucking out the organic phase by using an injector, then injecting 20mL of dichloromethane, repeatedly injecting dichloromethane, and taking out the organic phase solution for three times; combined organic phase solution in N2Drying with anhydrous sodium sulfate under protection, and then adding N2The crude product was purified by filtration at 0 ℃ under reduced pressure to give the crude product, which was purified by column chromatography in a glove box using n-pentane over ether and acetone at 15:4:1 as eluent to give 183mg of the final product in 26% yield over two steps. The solvents in the step are all cooled in advance at the temperature of minus 20 ℃ andwith N2Degassing and deoxidizing.
Example 2: preparation of the second intermediate
Figure RE-GDA0002555365570000111
At room temperature and O2Under protection, 828.5mg Pd (PhCN)2Cl2、368.2mg CuCl2·2H2O、166.2mg AgNO2Added to 180mL of t-butanol and 12mL of nitromethane and bubbled with oxygen for 15 min. Dropwise adding 4.75g of 18mmol of allyl product (IVa), and reacting for 24 hours at 23 ℃ after dropwise adding; after the reaction was completed, the solvent was removed under reduced pressure, 100mL of water was added, and extraction was performed three times with methyl t-butyl ether. The organic phase obtained by extraction was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a crude product, column chromatography was performed, and the crude product was purified with n-hexane and methyl t-butyl ether as eluent at a ratio of 10:1 to 4:1 to obtain 3.78g of a second intermediate compound in a yield of 75%.
The structural characterization data for the product obtained in example 2 are shown below:
1H NMR(500MHz,CDCl3):δ9.63(s,1H),7.58–7.47(m,2H),7.19–7.08(m,5H), 7.04–6.93(m,2H),3.10(d,J＝1.8Hz,2H),2.50–2.09(m,4H).
13C NMR(126MHz,CDCl3):δ203.04,200.33,171.59,138.36,133.97,130.33,128.07, 127.01,124.14,121.89,121.34,113.14,91.39,42.20,37.66,27.98.
the successful synthesis of the second intermediate is proved by the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the product.
The specific optical rotation of the compound of formula (Va) [ alpha ]]D 20＝63.0(c＝0.10,MeOH).
HRMS:calculated for C18H17O3(M+H)+:281.1178,found:281.1182.
Example 3: preparation of third intermediate
Figure RE-GDA0002555365570000112
In N2Under protection, 2.26g of azacarbene reagent, 738.3mg of sodium acetate were added to 300mL of tetrahydrofuran, and 8.4g,30mmol of the second intermediate (Va) were slowly injected into the reaction system using a syringe pump (the duration of the dropwise addition was 2h), and after the dropwise addition, the mixture was stirred at room temperature for 2 h. And (3) after the reaction is finished, removing the solvent under reduced pressure to obtain a crude product, performing column chromatography, and purifying the crude product to obtain 6.72g of a third intermediate compound with the yield of 80% by using an eluent, namely n-hexane and methyl tert-butyl ether, wherein the eluent is 5: 1-3: 1.
The structural characterization data for the product obtained in example 3 are shown below:
1H NMR(500MHz,CDCl3):δ7.40–7.11(m,7H),6.92–6.77(m,2H),3.18(d,J＝ 14.2Hz,1H),3.01(dd,J＝14.3,1.6Hz,1H),2.43–2.28(m,1H),2.27–2.08(m,1H),2.06 –1.75(m,2H).
13C NMR(126MHz,CDCl3):δ213.31,213.29,159.46,135.65,131.67,130.67,128.37, 126.95,126.37,124.42,121.63,111.18,95.46,86.43,38.55,34.28,30.55.
the successful synthesis of the third intermediate is proved by the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the product.
The specific optical rotation of the compound of formula (VIa) [ alpha ]]D 20＝247.0(c＝0.10,MeOH).
HRMS:calculated for C18H16NaO3(M+Na)+:303.0997,found:303.0980.
Example 4: preparation of the fourth intermediate
Figure RE-GDA0002555365570000121
136.9mg of palladium acetate, 45uL of trifluoroacetic acid, 1.7g, 6.1mmol of the third intermediate (VIa) were added to 6.1mL of dimethyl sulfoxide under oxygen protection, and blown with an oxygen balloon for 10 min. The reaction was then warmed to 80 ℃ for 24h and, after completion of the reaction, the system was poured slowly into 30mL of ice-water mixture and extracted three times with methyl tert-butyl ether. The organic phase obtained by extraction was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a crude product, column chromatography was performed, and the crude product was purified with n-hexane and ethyl acetate at a ratio of 20:1 to 10:1 to obtain 1.5g of a fourth intermediate of the compound in 92% yield.
The structural characterization data for the product obtained in example 4 are as follows:
1H NMR(500MHz,CDCl3):δ7.45–7.27(m,7H),7.22(d,J＝6.1Hz,1H),6.97(t,J＝ 7.5Hz,1H),6.89(d,J＝8.2Hz,1H),6.32(d,J＝6.1Hz,1H),3.47(d,J＝14.6Hz,2H), 3.08(d,J＝14.6Hz,1H).
13C NMR(126MHz,CDCl3):δ202.93,158.46,158.13,135.20,132.81,131.79,130.55, 128.53,127.10,126.33,124.68,121.81,111.31,94.56,84.56,38.87.
the successful synthesis of the fourth intermediate is proved by the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the product.
The specific optical rotation of the compound of formula (VIIa) [ alpha ]]D 20＝162.2(c＝0.10,MeOH).
HRMS:calculated for C18H15O3[M+H]+:279.1021,found:279.1004.
Example 5: preparation of the fifth intermediate
Figure RE-GDA0002555365570000131
4.1g of cuprous bromide dimethylsulfide complex, 2.78g, 10mmol of fourth intermediate (VIIa) were added to 100mL of anhydrous tetrahydrofuran under nitrogen, and the reaction was cooled to-78 ℃. Stirring at the temperature for 5min, dropwise adding 3.5mL isopropyl magnesium bromide (3mol/L in THF) into the reaction system, reacting at-78 deg.C for 2h after dropwise addition, heating to 0 deg.C, and continuing to react for 1 h. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution and the aqueous phase was extracted three times with ethyl acetate. The organic phase obtained by extraction was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a crude product, column chromatography was performed, the crude product was purified using n-hexane and ethyl acetate at a ratio of 15:1 to 10:1 as eluent, to obtain 2.9g of a fourth intermediate of the compound with a yield of 90%.
The structural characterization data for the product obtained in example 5 are shown below:
1H NMR(500MHz,CDCl3):δ7.31–7.20(m,2H),7.18–7.05(m,4H),7.01(dd,J＝7.5, 1.4Hz,1H),6.79–6.61(m,2H),3.42(s,1H),3.11(s,2H),2.30–2.10(m,2H),2.10–2.01 (m,1H),1.73–1.62(m,1H),0.83(d,J＝6.8Hz,3H),0.69(d,J＝6.7Hz,3H).
13C NMR(126MHz,CDCl3):δ212.04,160.34,136.07,131.42,130.90,127.97,126.58, 126.52,123.88,121.13,110.06,95.70,87.71,49.21,40.81,36.67,27.93,23.28,19.99.
the successful synthesis of the fifth intermediate is proved by the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the product.
The specific optical rotation of the compound of formula (VIIIa) < alpha > [ alpha ]]D 20＝52.0(c＝0.10,MeOH).
HRMS:calculated for C21H22NaO3[M+Na]+:345.1467,found:345.1463.
Example 6: preparation of Flavaginess Natural product (Ia)
Figure RE-GDA0002555365570000132
322mg, 1.0mmol of the fifth intermediate (VIIIa) were added to 1mL of N, N-dimethylformamide under nitrogen, and 1.5mL of methylmethoxymagnesium carbonate (Stile's reagent, 2.0mol/L in DMF) were added dropwise. After the dropwise addition, the temperature is raised to 100 ℃ for reaction for 12 hours. After the reaction is finished, the mixture is moved to an ice water bath for cooling, is diluted by adding 5mL of ether, is quenched by a cold 6mol/L hydrochloric acid solution, and is extracted by ether for three times. And drying the organic phase obtained by extraction with anhydrous sodium sulfate, and decompressing and removing the solvent to 3.0mL under the low-temperature condition (0-5 ℃) to obtain a methanol solution of a crude product. 0.5mL (trimethylsilyl) diazomethane (2.0mol/L in hexane) was added to the methanol solution of the crude product obtained above. After the addition, the reaction was carried out at 0 ℃ for 1 hour. After the reaction is finished, the solvent is directly removed under reduced pressure to obtain an esterification crude product.
The crude product obtained above, 36.6mg of 4-dimethylaminopyridine and 5mL of dimethylamine (2mol/L in THF) were added to 12.55mL of anhydrous toluene, and the temperature was raised to 100 ℃ to react for 3 hours. After the reaction is finished, the solvent is removed under reduced pressure to obtain a crude product.
The crude product obtained above, 1.3g Me4NBH(OAc)3The mixture was added to 5mL of acetonitrile and 0.5mL of acetic acid, and reacted at 25 ℃ for 3 hours. After the reaction is finished, quenching the reaction by saturated sodium carbonate, extracting the reaction product for three times by ethyl acetate, drying an organic phase obtained by extraction by anhydrous sodium sulfate, removing a solvent under reduced pressure, carrying out column chromatography, and purifying a crude product to obtain 210mg of a Flavaginess natural product (I), wherein the yield is 53% in three steps, and an eluent is n-hexane and ethyl acetate which are 1: 1-1: 2.
The structural characterization data for the product obtained in example 6 are as follows:
1H NMR(500MHz,CDCl3):δ7.50(dd,J＝7.6,1.1Hz,1H),7.38(d,J＝6.9Hz,2H), 7.23–7.07(m,4H),6.84(t,J＝6.9Hz,1H),6.76(d,J＝8.1Hz,1H),4.46(d,J＝10.5Hz, 1H),3.16(d,J＝14.2Hz,1H),3.03(d,J＝14.2Hz,1H),2.89(d,J＝11.0Hz,6H),2.62(t,J ＝10.9Hz,1H),2.51(dd,J＝11.3,3.9Hz,1H),1.40–1.26(m,1H),0.53(dd,J＝11.3,6.8 Hz,6H).
13C NMR(126MHz,CDCl3):δ174.44,160.25,136.76,131.09,130.64,127.95,127.48, 127.31,126.41,120.58,109.75,95.48,89.11,81.72,52.13,45.33,42.15,37.59,36.41,27.26, 23.22,20.16.
the success of synthesizing the Flavaginess natural product (Ia) is proved by the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the product.
The specific optical rotation of the compound of formula (Ia) [ alpha ]]D 20＝-23.0(c＝0.10,MeOH).
HRMS:calculated for C24H29NNaO4[M+Na]+:418.1994,found:418.2023.
The invention creatively completes the research on asymmetric synthesis of various oriented Flavaginess natural products, successfully constructs the chiral cyclopentane of an alkyl substituent based on the key strategy of Pd catalysis asymmetric decarboxylation allylation, expands the test range of the pharmaceutical activity of the natural products, and has guiding significance for the synthetic research and the pharmaceutical research and development of the Flavaginess natural products.
As noted above, while the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limited thereto. Various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (10)

1. A Flavaginess natural product asymmetric diversity guide synthesis method is characterized in that: an allylation precursor prepared from aromatic furanone is subjected to palladium-catalyzed asymmetric decarboxylation allylation to obtain a first intermediate, the first intermediate is subjected to end position selective Wacker oxidation to obtain a second intermediate, intramolecular benzoin condensation is performed on the second intermediate to obtain a third intermediate, the third intermediate is subjected to dehydrogenation and Michael addition to construct three continuous chiral centers to obtain a fifth intermediate, and finally a Flavaglines natural product is synthesized from the fifth intermediate, wherein the Flavaglines natural product is shown as a formula (I);
Figure FDA0002397737970000011
wherein:
Figure FDA0002397737970000012
R2is one of H, methyl, ethyl, isopropyl, vinyl, isopropyl, benzyl, cyclohexyl, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl;
R3is one of H, methyl, ethyl, isopropyl, vinyl, isopropyl, benzyl, cyclohexyl, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl;
R4is H, CO2Me，CO(NMe)2One of (1);
R5is H, CO2Me，CO(NMe)2One of (1);
R6is hydroxy or H;
R7is hydroxy or H;
R8is a hydroxyl group.
2. The Flavaginess natural product asymmetric diversity-directed synthesis method according to claim 1, characterized in that:
R2is H; r3Is one of methyl, ethyl, isopropyl, vinyl, isopropyl, benzyl, cyclohexyl, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl;
R4is H; r5Is H, CO2Me，CO(NMe)2One kind of (1).
3. The Flavaginess natural product asymmetric diversity-directed synthesis method according to claim 1, characterized in that:
R2is one of methyl, ethyl, isopropyl, vinyl, isopropyl, benzyl, cyclohexyl, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl; r3Is H;
R4is H, CO2Me，CO(NMe)2One of (1); r5Is H.
4. The Flavaginess natural product asymmetric diversity-directed synthesis method according to claim 1, which is characterized by comprising the following steps:
(1) adding aromatic furanone derived allyl carbonate into a reaction bottle, adding a solvent, a catalyst and a ligand, reacting at-20 to-15 ℃ for 40 to 50 hours, removing the solvent after the reaction is finished, and performing column chromatography separation by using n-hexane/ethyl acetate to obtain a first intermediate, wherein the formula is shown In (IV);
(2) adding a solvent into the first intermediate, adding a metal catalyst, reacting at room temperature for 20-30 h in an oxygen atmosphere, adding a quenching agent after the reaction is finished, extracting, drying, removing the solvent, and performing column chromatography separation by using n-hexane/ethyl acetate to obtain a second intermediate shown as a formula (V);
(3) and adding a solvent into the second intermediate, adding a carbene precursor and alkali, and reacting at room temperature for 4-5 h. After the reaction is finished, removing the solvent, and performing column chromatography separation by using n-hexane/methyl tert-butyl ether to obtain a third intermediate, wherein the third intermediate is shown as a formula (VI);
(4) adding a solvent into the third intermediate, adding a catalyst, reacting for 20-30 h at 70-90 ℃ in an oxygen atmosphere, adding a quenching agent after the reaction is finished, extracting, drying, removing the solvent, and performing column chromatography separation by using n-hexane/methyl tert-butyl ether to obtain a fourth intermediate, wherein the formula is (VII);
(5) adding a solvent, a catalyst and a Grignard reagent into the fourth intermediate, reacting at-80 to-75 ℃ for 2 to 3 hours, heating to 0 ℃ and continuing to react for 1 hour. Adding a quenching agent after the reaction is finished, extracting, drying, removing the solvent, and performing column chromatography separation by using n-hexane/ethyl acetate to obtain a fifth intermediate, wherein the formula is shown as a formula (VIII);
(6) and adding a solvent into the fifth intermediate, adding an esterification reagent, and adding a quenching agent after the reaction is finished. After extraction, drying and solvent removal, adding a solvent into the obtained intermediate product, adding a condensing agent and amine, reacting for 3-5 hours at 100 ℃, and directly removing the solvent after the reaction is finished. Continuously adding a solvent into the obtained intermediate amide, adding a reducing agent, reacting at 20-30 ℃ for 3h, adding a quenching agent after the reaction is finished, extracting, drying, removing the solvent, and performing column chromatography separation by using n-hexane/ethyl acetate to obtain a Flavaglines natural product shown in the formula (I);
the specific reaction process is as follows:
Figure FDA0002397737970000031
Figure FDA0002397737970000041
5. the Flavaginess natural product asymmetric diversity-directed synthesis method according to claim 4, characterized in that: in the step (1), the solvent is tetrahydrofuran, and the catalyst is Pd2(dba)3The ligand is a cycloheptane Trost ligand, and the structure of the cycloheptane Trost ligand is shown as a formula L1:
Figure FDA0002397737970000042
wherein: ar (Ar)2Is 4-CH3-C6H4-；
The preparation method of the cycloheptane Trost ligand specifically comprises the following steps: performing addition reaction on cycloalkenyl methyl formate and diaryl phosphine oxide to obtain a first intermediate, performing one-pot reduction and boronization on the first intermediate to obtain a second intermediate, hydrolyzing the second intermediate to obtain a third intermediate, and performing condensation reaction on the third intermediate and cycloheptane chiral diamine to obtain the novel Trost ligand L1.
6. The Flavaginess natural product asymmetric diversity-directed synthesis method according to claim 4, characterized in that: the solvent in the step (2) is tert-butyl alcohol and nitromethane; the catalyst is PdCl2(PhCN)2,CuCl2·2H2O,AgNO2(ii) a The quenching agent is water.
7. The Flavaginess natural product asymmetric diversity-directed synthesis method according to claim 4, characterized in that: in the step (3), the solvent is tetrahydrofuran; the condensing agent is an azacarbene reagent; the structure of the azacarbene reagent is shown as a formula L2:
Figure FDA0002397737970000051
8. the Flavaginess natural product asymmetric diversity-directed synthesis method according to claim 4, characterized in that: the solvent in the step (4) is dimethyl sulfoxide; the dehydrogenation reagent is palladium acetate; the Lewis acid catalyst is trifluoroacetic acid; the quenching agent is ice-water mixed liquid.
9. The Flavaginess natural product asymmetric diversity-directed synthesis method according to claim 4, characterized in that: in the step (5), the solvent is tetrahydrofuran; the Lewis acid catalyst is CuBr. Me2S; the quenching agent is saturated ammonium chloride;
the solvent in the step (6) is N, N-dimethylformamide, methanol, toluene, acetonitrile or acetic acid; esterification reagent is Stile's reagent and trimethylsilyldiazomethane, amidation reagent is 4-dimethylaminopyridine and dimethylamine, and reducing agent is Me4NBH(OAc)3The quenching agent is dilute hydrochloric acid and saturated sodium carbonate.
10. A Flavaglines natural product prepared by the synthesis method of any one of claims 1 to 9, represented by formula (I);
Figure FDA0002397737970000061
wherein:
Figure FDA0002397737970000062
R2is one of H, methyl, ethyl, isopropyl, vinyl, isopropyl, benzyl, cyclohexyl, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl;
R3is H, methyl, ethyl, isopropyl, vinyl, isopropyl, benzyl, cyclohexylOne of a group, 1-propenyl, p-methoxyphenyl, o-methoxyphenyl and m-methoxyphenyl;
R4is H, CO2Me，CO(NMe)2One of (1);
R5is H, CO2Me，CO(NMe)2One of (1);
R6is hydroxy or H;
R7is hydroxy or H;
R8is a hydroxyl group.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60246302A (en) * 1984-05-16 1985-12-06 バイエル・アクチエンゲゼルシヤフト Use of amides for improving cultural plant resistance of herbicidal heteroaryloxyacetamides
DE19622284A1 (en) * 1996-05-23 1997-11-27 Hoechst Schering Agrevo Gmbh New benzofuranone derivatives useful as herbicides,
US20080182031A1 (en) * 2007-01-15 2008-07-31 Fujifilm Corporation Ink composition and inkjet recording method using the same
CN109071482A (en) * 2016-01-15 2018-12-21 汉堡大学 Carry the flavonoids type compound of O- rhamnopyranosyl residue

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60246302A (en) * 1984-05-16 1985-12-06 バイエル・アクチエンゲゼルシヤフト Use of amides for improving cultural plant resistance of herbicidal heteroaryloxyacetamides
DE19622284A1 (en) * 1996-05-23 1997-11-27 Hoechst Schering Agrevo Gmbh New benzofuranone derivatives useful as herbicides,
US20080182031A1 (en) * 2007-01-15 2008-07-31 Fujifilm Corporation Ink composition and inkjet recording method using the same
CN109071482A (en) * 2016-01-15 2018-12-21 汉堡大学 Carry the flavonoids type compound of O- rhamnopyranosyl residue

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