CN115197058A - Anticancer natural product Dysideanone B analogue and preparation method thereof - Google Patents

Anticancer natural product Dysideanone B analogue and preparation method thereof Download PDF

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CN115197058A
CN115197058A CN202110388630.0A CN202110388630A CN115197058A CN 115197058 A CN115197058 A CN 115197058A CN 202110388630 A CN202110388630 A CN 202110388630A CN 115197058 A CN115197058 A CN 115197058A
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鲁照永
张海明
种传可
张群龙
柯佳
杨旭东
匡扬
马巨伟
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Nankai University
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Abstract

The invention provides a dysideanone B analogue shown in formulas (II) and (III) and a preparation method thereof. The method uses the derivative 1 of Wieland-Miescher ketone as a starting material, simply and efficiently completes the first total synthesis of the sesquiterpene quinone anticancer natural product dysideanone B, synthesizes a series of analogues, and simultaneously proves that the ethoxy group of the dysideanone B can be derived from solvent ethanol. The invention has short synthetic reaction route and higher total yield, is beneficial to the mass synthesis of the dysianone B and the analogues thereof, and provides sufficient raw materials for the evaluation of the biological activity and the research of the structure-activity relationship.

Description

Anticancer natural product Dysideanone B analogue and preparation method thereof
Technical Field
The invention belongs to the technical field of synthesis of sesquiterpene quinone compounds, and particularly relates to a dysidenone B analogue and a preparation method thereof.
Background
Sesquiterpene quinones are one of the most important natural products of the heteroterpenes, and structurally, are sesquiterpene fragments composed of isoprene units linked to a quinone moiety composed of polyketones. The natural products of the series show a series of remarkable biological activities, such as antibacterial activity, antifungal activity, anti-HIV activity, anti-inflammatory activity, antioxidant activity, antitumor activity and inhibitory activity on protein tyrosine phosphatase 1B (PTP 1B).
Dysideanone B is a sesquiterpene quinone marine natural product with interesting structure and good biological activity. In 2014, the compound is obtained by separating secondary metabolites of Dysidea catarrhalis (Dysidea avara) which is a south China sea animal. The chemical structure was also determined by methods such as HRMS, IR, NMR and 2D NMR. Structurally, the natural product dysianone B contains an unprecedented 6/6/6/6 fused tetracyclic all-carbon skeleton, the molecular skeleton is crowded, and the molecule contains 5 continuous chiral centers, wherein 2 are quaternary carbon centers. Biological tests show that the dysianone B has good antitumor activity and IC (integrated Circuit) on human cervical cancer cell line HeLa and liver cancer cell line HepG2 50 The values were 7.1. Mu.M and 9.4. Mu.M, respectively.
Figure BDA0003015601560000011
The good biological activity and interesting structural characteristics have prompted chemists to develop a full synthetic study on the natural product, dysianone B. The dense chiral centers and the crowded tetracyclic backbone make their synthesis highly challenging. The synthesis of this natural product has been studied by chemists to date only in a limited amount, and no group of subjects has completed its total synthesis. Based on the research, the inventor develops a total synthesis research on the natural product dysideanone B, designs and synthesizes an analogue on the basis of the research, researches the structure-activity relationship of the natural product, and provides a new idea for treating cancers.
Disclosure of Invention
The invention aims to simply and efficiently complete the total synthesis of the dysianone B by utilizing a chemical synthesis method and through cheap and easily available raw materials, and synthesize a series of analogues of the natural product on the basis.
In order to achieve the above object, the present invention provides the following technical solutions:
provides a dysideanone B analogue shown as a formula (I),
Figure BDA0003015601560000021
in the formula (I), A ring is a benzene ring or p-benzoquinone;
R 1 and R 4 Can be the same or different and are respectively hydrogen atom, oxygen atom, hydroxyl and substituted hydroxyl;
R 2 and R 3 Can be the same or different and is respectively hydrogen atom, hydroxyl, substituted hydroxyl, amino, substituted amino, sulfydryl, substituted sulfydryl, heterocyclic radical and substituted heterocyclic radical;
R 5 is carbon atom, oxygen atom;
the structural formula is selected from all isomeric forms, such as enantiomers, diastereomers and geometric isomers (or conformational isomers): for example, the R, S configuration containing an asymmetric center.
The dysianone B analogue provided by the invention is selected from the compounds shown in a formula (II),
Figure BDA0003015601560000022
wherein R is 1 And R 4 Can be the same or different and are respectively hydrogen atom, hydroxyl and substituted hydroxyl;
R 2 and R 3 May be the same or different and is each a hydrogen atom, a hydroxyl group, a substituted hydroxyl group, an amino group, a substituted amino group, a heterocyclic group or a substituted heterocyclic group;
R 5 is a carbon atom or an oxygen atom.
The dysideanone B analogue provided by the invention is also selected from the compounds shown in the formula (III),
Figure BDA0003015601560000023
wherein R is 2 And R 3 The hydroxyl group, the substituted hydroxyl group, the amino group, the substituted amino group, the mercapto group, the substituted mercapto group, the heterocyclic group and the substituted heterocyclic group may be the same or different.
The dysianone B analogue provided by the invention comprises one of the following compounds:
Figure BDA0003015601560000031
the invention also provides a preparation method of the dysianone B and the analogues thereof, which is characterized in that the synthetic route is as follows:
Figure BDA0003015601560000032
wherein R is 2 Is a hydrogen atom or an ethoxy group;
R 3 is a hydrogen atom or an ethoxy group;
R 6 and R 7 May be the same or different and is a chlorine atom, a bromine atom or an iodine atom.
The invention also provides a preparation method of the compound 10, which is characterized in that tetrahydrofuran is used as a solvent, the compound 9 reacts with a methyleneation reagent to generate the compound 10, and the methyleneation reagent is a Wittig reagent, a Peterson reagent, a Nysted reagent, a Tebbe reagent and a Julia reagent.
The invention also provides a preparation method of the compound 1, which is characterized in that toluene is used as a solvent, the compound 12 reacts with tri-n-butyltin hydride and azobisisobutyronitrile to generate the compound 1, and the molar ratio of the compound 13 to the azobisisobutyronitrile is (1).
The invention also provides a preparation method of the dysianone B and the compound 4, which is characterized in that under the action of oxygen, the compound 3 reacts with alkali in ethanol solvent to generate the dysianone B and the compound 4, wherein the alkali is N, N-diisopropylethylamine, triethylamine, pentamethylpiperidine, potassium carbonate, sodium bicarbonate, potassium phosphate, sodium hydride, lithium tert-butoxide, potassium tert-butoxide, N-butyllithium and bis (trimethylsilyl) amino potassium,
Figure BDA0003015601560000041
wherein R is 2 Is a hydrogen atom or an ethoxy group;
R 3 is a hydrogen atom or an ethoxy group.
The method has the advantages of mild synthesis reaction conditions, short reaction route, high yield, cheap and easily-obtained raw materials, is favorable for the mass synthesis of the dysianone B and the analogues thereof, and provides important material basis and guarantee for the evaluation of the biological activity and the research of the structure-activity relationship.
Drawings
FIG. 1 is a synthetic route for the natural product dysianone B and its analogs.
FIG. 2. Synthetic route for compounds 5 and 6.
Detailed Description
The present invention is further illustrated by the following specific examples, which are provided only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1: synthesis of Dysideanone B
The specific synthetic route is shown in figure 1, and the specific steps are as follows:
(1) Preparation of ketone 9:
t-BuOK (47.5mL, 47.5mmol,1.0M in THF, 1.1equiv) was added dropwise to a THF (40 mL) solution of enone 7 (10.2g, 43.2mmol,1.0 equiv) at 0 ℃ and the reaction mixture was heated to 23 ℃ and stirred for 1 hour. Then, a solution of bromide 8 (16.1g, 51.8mmol, 1.2equiv) in THF (10 mL) was added dropwise to the above solution at 0 ℃ and stirred for 10 minutes, after which the reaction mixture was heated to 40 ℃ and reacted for 1 hour. After the reaction is completed, saturated NH is used 4 Aqueous Cl (80 mL) was diluted and extracted with EtOAc (50 mL) 3 times. The combined organic phases were washed with saturated brine (50 mL) and anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography (PE: etOAc = 8). White solid, M.P. 153-155 deg.C，R f ＝0.35(silica gel，PE:EtOAc＝2:1)，FT-IR(KBr):ν max ＝3084,2971,2941,2885,2833,1700,1576,1477,1263,1208,1040,799,720,668cm -1 ， 1 H NMR(400MHz,C 6 D 6 ):δ＝6.31(s,2H),6.02(dd,J＝4.9,2.8Hz,1H),3.68(d,J＝13.9Hz,1H),3.63(d,J＝13.9Hz,1H),3.56–3.47(m,4H),3.30(s,3H),3.24(s,3H),3.14–2.97(m,1H),2.64–2.48(m,2H),2.39(dddd,J＝18.1,11.4,7.0,2.8Hz,1H),2.04(dddd,J＝17.8,6.1,4.9,1.3Hz,1H),1.84(ddd,J＝13.3,11.4,6.9Hz,1H),1.76–1.65(m,1H),1.54–1.47(m,1H),1.50(s,3H),1.16(s,3H)ppm， 13 C NMR(101MHz,C 6 D 6 ):δ＝211.4,152.7,150.8,150.4,128.5,121.2,118.7,112.1,110.4,109.3,65.1,64.8,56.2,54.8,53.3,42.8,42.3,34.2,26.5,24.6,24.6,23.3,23.2ppm，HRMS(ESI-TOF):calcd for C 23 H 29 BrO 5 Na + [M+Na] + 487.1091,found 487.1096.
(2) Preparation of tricyclic diene 10:
adding TiCl dropwise to a solution of Nysted reagent (48.9g, 41.2mL,107mmol,20wt% in THF, 10equiv) in THF (20 mL) at 0 deg.C 4 (96.5mL, 96.5mmol,1.0M in toluene,9.0 equiv), and the reaction mixture was stirred at this temperature for 0.5 hour. Then, a solution of ketone 9 (4.99g, 10.7mmol,1.0 equiv) in THF (20 mL) was added dropwise to the above solution, and after 10 minutes, the reaction solution was heated to 40 ℃ and reacted for 6 hours. After the reaction is completed, saturated NaHCO is used 3 Aqueous (200 mL) was quenched and extracted 3 times with EtOAc (100 mL). The combined organic phases were washed with brine (50 mL) and anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography (PE: etOAc = 20. White solid, M.P. 134-136 deg.C, R f ＝0.56(silica gel，PE:EtOAc＝5:1)，FT-IR(KBr):ν max ＝2958,2925,2853,1731,1507,1287,1258,1123,1065,1038,796,723cm -1 ， 1 H NMR(400MHz,C 6 D 6 ):δ＝6.35(s,2H),6.06(dd,J＝4.9,2.9Hz,1H),4.82–4.76(m,1H),4.54(t,J＝1.9Hz,1H),3.63(d,J＝13.3Hz,1H),3.62–3.54(m,5H),3.33(s,3H),3.22(s,3H),3.14–3.01(m,1H),2.59–2.35(m,3H),2.11(dddd,J＝17.5,6.5,4.7,1.6Hz,1H),1.94(ddd,J＝13.1,11.2,6.8Hz,1H),1.71(ddd,J＝13.0,8.6,4.2Hz,1H),1.56(ddt,J＝13.3,7.0,1.4Hz,1H),1.50(s,3H),1.47(s,3H)ppm， 13 C NMR(101MHz,C 6 D 6 ):δ＝153.8,152.6,151.2,150.8,130.1,120.2,119.1,112.7,110.0,109.0,108.5,65.1,64.7,56.2,54.7,46.9,43.7,42.3,28.9,27.1,26.6,26.2,25.7,24.6ppm，HRMS(ESI-TOF):calcd for C 24 H 32 BrO 4 + [M+H] + 463.1478,found 463.1475.
(3) Preparation of tricyclenone 11:
to a mixed solution of tricyclodiene 10 (758mg, 1.64mmol,1.0 equiv) in THF (6 mL) and acetone (2 mL) was added dropwise 3M HCl (5.46mL, 16.4mmol, 1.0 equiv) at 0 ℃ and the reaction solution was warmed to 23 ℃ and reacted for 2 hours. After the reaction is completed, saturated NaHCO is used 3 Aqueous (20 mL) diluted and extracted 3 times with EtOAc (10 mL). The combined organic phases were washed with saturated brine (10 mL) and anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography (PE: etOAc =10: 1) finally yielded tricycloalkenone 11 (672mg, 1.60mmol, 98%). Colorless oil, R f ＝0.46(silica gel，PE:EtOAc＝2:1)，FT-IR(KBr):ν max ＝3661,3638,2943,2834,1707,1574,1474,1258,1069,1038,795,724cm -1 ， 1 H NMR(400MHz,C 6 D 6 ):δ＝6.35(d,J＝8.9Hz,1H),6.30(d,J＝8.9Hz,1H),5.30(dd,J＝5.2,3.6Hz,1H),4.85–4.80(m,2H),3.42(d,J＝13.1Hz,1H),3.33(s,3H),3.20(s,3H),3.09(d,J＝13.1Hz,1H),2.82–2.70(m,1H),2.41(dq,J＝12.0,6.6Hz,3H),2.21–1.97(m,3H),1.94–1.84(m,1H),1.44(s,3H),1.18(s,3H)ppm， 13 C NMR(101MHz,C 6 D 6 ):δ＝212.7,153.7,152.1,150.9,148.1,129.9,119.9,118.7,110.2,109.3,108.9,56.3,55.2,48.2,47.2,40.8,34.3,27.7,27.5,26.3,25.6,24.2ppm，HRMS(ESI-TOF):calcd for C 22 H 27 BrO 3 Na + [M+Na] + 441.1036,found 441.1031.
(4) Preparation of tricyclic ketone 12:
(PPh) in the presence of hydrogen at 23 ℃, (PPh) 3 ) 3 RhCl (719mg, 0.777mmol, 0.5equiv) in tolueneThe solution was stirred (10 mL) for 0.5 h. Then, a solution of tricyclenone 11 (652mg, 1.55mmol,1.0 equiv) in toluene (5 mL) was added dropwise to the above solution, and after 10 minutes, the reaction mixture was heated to 40 ℃ and reacted for 4 hours. After completion of the reaction, the reaction was filtered through celite, and the filtrate was concentrated and purified by column chromatography (PE: etOAc =10, 1) to finally obtain tricyclic ketone 12 (550mg, 1.31mmol, 84%). White solid, M.P. 137-139 deg.C, R f ＝0.55(silica gel，PE:EtOAc＝2:1)，FT-IR(KBr):ν max ＝2998,2928,2845,1699,1476,1460,1433,1263,1242,1064,1040,808,716cm -1 ， 1 H NMR(400MHz,C 6 D 6 )δ:＝6.33(s,2H),5.71(dd,J＝6.6,2.5Hz,1H),3.49(d,J＝13.2Hz,1H),3.32(s,3H),3.28(d,J＝13.2Hz,1H),3.25(s,3H),2.43–2.30(m,1H),2.18–2.02(m,4H),1.98–1.81(m,2H),1.63–1.53(m,1H),1.41–1.33(m,1H),1.30(s,3H),1.16(s,3H),0.69(d,J＝6.8Hz,3H)ppm， 13 C NMR(101MHz,C 6 D 6 )δ:＝213.7,153.7,151.1,150.3,132.3,122.4,118.6,109.8,109.4,56.2,55.3,48.7,45.2,43.8,38.0,34.4,31.0,27.5,26.4,24.4,23.0,19.9ppm，HRMS(ESI-TOF):calcd for C 22 H 30 BrO 3 + [M+H] + 421.1373,found 421.1375.
(5) Preparation of tetracyclic ketone 1:
to a solution of tricyclic ketone 12 (363mg, 0.861mmol,1.0 equiv) in toluene (8 mL) at 23 ℃ were added n-Bu in this order 3 SnH (501mg, 462. Mu.L, 1.72mmol,2.0 equiv) and AIBN (14.2mg, 86.1. Mu. Mol,0.1 equiv), the reaction mixture was heated to 80 ℃ and reacted for 1.5 hours. After completion of the reaction, the solution was concentrated and then purified by column chromatography (PE: etOAc =35: 1) to finally obtain tetracyclic ketone 1 (180mg, 0.525mmol, 61%). White solid, M.P. 208-209 deg.C, R f ＝0.42(silica gel，PE:EtOAc＝8:1)，FT-IR(KBr):ν max ＝3649,2997,2944,2899,2833,1700,1473,1457,1252,1085,958,798,717cm -1 ， 1 H NMR(400MHz,C 6 D 6 ):δ＝6.47(s,2H),3.46–3.35(m,7H),3.25(d,J＝16.6Hz,1H),3.15(ddt,J＝12.3,6.7,2.6Hz,1H),2.65(td,J＝14.4,6.7Hz,1H),2.40(ddd,J＝14.7,4.6,2.3Hz,1H),2.13(d,J＝16.6Hz,1H),1.90(dt,J＝14.0,3.3Hz,1H),1.76(td,J＝13.4,4.5Hz,1H),1.40(d,J＝11.1Hz,1H),1.30–1.16(m,3H),1.14–1.03(m,1H),0.94(s,3H),0.83(d,J＝6.6Hz,3H),0.63(s,3H)ppm， 13 C NMR(101MHz,C 6 D 6 ):δ＝212.9,152.5,152.1,128.8,126.7,107.8,107.7,55.2,54.9,54.4,48.5,43.3,41.1,38.5,35.8,34.3,33.2,32.6,26.6,18.7,15.8,14.7ppm，HRMS(ESI-TOF):calcd for C 22 H 30 O 3 Na + [M+Na] + 365.2087,found 365.2082.
(6) Preparation of Tetracycloalkene 2:
to Ph at 0 DEG C 3 PCH 3 Br (1.88g, 5.26mmol,10 equiv) in toluene (15 mL) was added dropwise t-BuOK (4.73mL, 4.73mmol,1.0M in THF,9.0 equiv), and the reaction was warmed to 23 ℃ and stirred for 1 hour. Then, a solution of tetracycloketone 1 (180mg, 0.526mmol,1.0 equiv) in toluene (5 mL) was added dropwise to the above solution, and after 10 minutes, the reaction mixture was heated to 50 ℃ and reacted for 6 hours. After the reaction is completed, saturated NH is used 4 Aqueous Cl (30 mL) was diluted and extracted with EtOAc (20 mL) 3 times. The combined organic phases were washed with saturated brine (20 mL) and anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography (PE: etOAc =60 1) yielded tetracycloolefin 2 (156mg, 0.457mmol, 87%) finally. White solid, M.P. 143-145 deg.C, TLC R f ＝0.61(silica gel，PE:EtOAc＝10:1)，FT-IR(KBr):ν max ＝2985,2931,2858,2832,1633,1475,1433,1251,1089,887,790,715cm -1 ， 1 H NMR(400MHz,C 6 D 6 ):δ＝6.49(dd,J＝9.0,2.1Hz,2H),4.70(d,J＝6.3Hz,2H),3.44(s,3H),3.43(s,3H),3.40–3.35(m,1H),3.30–3.24(m,1H),3.29(d,J＝16.6Hz,1H),2.79(td,J＝13.7,4.8Hz,1H),2.38(dt,J＝13.8,3.4Hz,1H),2.23(d,J＝16.6Hz,1H),1.71(dt,J＝12.8,3.4Hz,1H),1.61(td,J＝12.8,4.1Hz,1H),1.43(d,J＝11.2Hz,1H),1.39–1.17(m,4H),1.12(s,3H),0.91(d,J＝6.7Hz,3H),0.72(s,3H)ppm， 13 C NMR(101MHz,C 6 D 6 ):δ＝159.8,152.7,152.1,130.2,126.8,107.8,107.4,103.8,55.7,55.2,54.9,43.9,41.7,40.1,38.5,35.4,35.3,34.6,34.3,27.4,20.8,16.0,14.5ppm，HRMS(ESI-TOF):calcd for C 23 H 33 O 2 + [M+H] + 341.2475,found 341.2470.
(7) Preparation of tetracyclic quinone 3:
6M HNO was added to a solution of tetracycloene 2 (156mg, 0.458mmol, 1.0equiv) in 1, 4-dioxane (4 mL) in this order at 23 deg.C 3 (382. Mu.L, 2.29mmol,5.0 equiv) and AgO (170mg, 1.37mmol,3.0 equiv), and the reaction mixture was reacted at this temperature for 10 minutes. After completion of the reaction, it was diluted with water (5 mL) and extracted 3 times with EtOAc (5 mL). The combined organic phases were washed with brine (5 mL) and anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography (PE: etOAc =40: 1) finally yielded tetracyclic quinone 3 (122mg, 0.394mmol, 86%). Yellow foam, R f ＝0.61(silica gel，PE:EtOAc＝9:1)，FT-IR(KBr):ν max ＝2977,2923,2861,1649,1599,1458,1384,1293,1137,892,873,438cm -1 ， 1 H NMR(400MHz,C 6 D 6 ):δ＝6.11(s,2H),4.59(d,J＝1.8Hz,2H),2.92–2.83(m,1H),2.75–2.68(m,1H),2.74(d,J＝18.7Hz,1H),2.49(tdt,J＝13.9,5.0,1.8Hz,1H),2.15(ddd,J＝13.9,4.2,2.5Hz,1H),1.61(dd,J＝19.1,4.2Hz,1H),1.55(dt,J＝12.8,3.6Hz,1H),1.48–1.37(m,1H),1.29–1.16(m,2H),1.03–0.90(m,3H),0.88(s,3H),0.73(d,J＝6.8Hz,3H),0.43(s,3H)ppm， 13 C NMR(101MHz,C 6 D 6 ):δ＝187.3,187.1,158.7,144.4,141.0,136.8,135.5,104.0,53.8,43.7,40.3,39.4,37.8,34.7,34.1,33.4,33.4,27.1,20.5,15.7,14.2ppm，HRMS(ESI-TOF):calcd for C 21 H 27 O 2 + [M+H] + 311.2006,found 311.2001.
(8) Preparation of Dysideanone B:
23 ℃ and O 2 In the presence of Et, et (5 mL) was added to a solution of tetracycloquinone 3 (41.4mg, 0.133mmol,1.0 equiv) in EtOH (5 mL) 3 N (135mg, 185. Mu.L, 1.33mmol,10 equiv), the reaction mixture was heated to 45 ℃ and reacted for 3 hours. After the reaction is completed, saturated NH is used 4 Aqueous Cl (5 mL) was diluted and extracted with EtOAc (5 mL) 3 times. The combined organic phases were washed with saturated brine (5 mL) and anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography (PE: etOAc =20: 1) finally yielded dsideanone B (25.0 mg,70.7mmol, 53%). Light yellow solid, M.P. 151-153 deg.C, R f ＝0.43(silica gel，PE:EtOAc＝4:1)，FT-IR(KBr):ν max ＝3545,3083,2958,2926,2860,1728,1650,1605,1460,1380,1221,1036,891cm -1 ， 1 H NMR(400MHz,CDCl 3 ):δ＝5.81(s,1H),4.56(s,1H),4.54(s,1H),4.05–3.89(m,2H),2.94–2.84(m,1H),2.72(d,J＝19.0Hz,1H),2.62–2.54(m,1H),2.53–2.46(m,1H),2.22(dd,J＝11.7,3.9Hz,1H),1.81(dd,J＝19.1,4.0Hz,1H),1.72(dt,J＝12.4,3.2Hz,1H),1.64–1.52(m,1H),1.48–1.43(m,2H),1.47(t,J＝7.0Hz,3H),1.30–1.21(m,1H),1.11(s,3H),1.10(d,J＝10.6Hz,1H),1.01(td,J＝13.0,12.2,4.0Hz,1H),0.93(d,J＝6.7Hz,3H),0.67(s,3H)ppm， 13 C NMR(101MHz,CDCl 3 ):δ＝187.8,182.4,158.9,158.3,143.0,141.7,107.0,103.8,65.1,54.1,43.7,40.2,39.4,37.6,34.8,33.9,33.1,33.1,27.0,20.7,15.9,14.4,14.0ppm，HRMS(ESI-TOF):calcd for C 23 H 31 O 3 + [M+H] + 355.2268,found 355.2263.
Example 2: synthesis of Compound 4
The specific synthetic route is shown in figure 1, and the specific steps are as follows:
23 ℃ and O 2 In the presence of Et, et was added to a solution of tetracycloquinone 3 (41.4 mg,0.133mmol,1.0 equiv) in EtOH (5 mL) 3 N (135mg, 185. Mu.L, 1.33mmol, 10equiv), the reaction mixture was heated to 45 ℃ and reacted for 3 hours. After the reaction is completed, saturated NH is used 4 Aqueous Cl (5 mL) was diluted and extracted with EtOAc (5 mL) 3 times. The combined organic phases were washed with brine (5 mL) and anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography (PE: etOAc =20: 1) finally yielded compound 4 (17.0 mg,48.0 μmol, 36%). Yellow oil, R f ＝0.47(silica gel，PE:EtOAc＝4:1)，FT-IR(KBr):ν max ＝3649,3629,3182,2922,2852,2360,2342,1671,1650,1605,1222,1108,1035cm -1 ， 1 H NMR(400MHz,C 6 D 6 ):δ＝5.52(s,1H),4.61(d,J＝1.7Hz,2H),3.10(q,J＝7.0Hz,2H),3.05–2.96(m,1H),2.92(ddt,J＝11.2,5.3,2.7Hz,1H),2.79(d,J＝18.5Hz,1H),2.63–2.52(m,1H),2.21(ddd,J＝13.9,4.3,2.5Hz,1H),1.66(dd,J＝18.6,3.9Hz,1H),1.57(dt,J＝12.9,3.3Hz,1H),1.45(td,J＝12.2,5.8Hz,1H),1.30–1.17(m,2H),1.11(dtd,J＝13.8,11.7,4.2Hz,1H),1.00–0.93(m,1H),0.98(d,J＝10.9Hz,1H),0.92(s,3H),0.91(t,J＝7.0Hz,3H),0.73(d,J＝6.8Hz,3H),0.49(s,3H)ppm， 13 C NMR(101MHz,C 6 D 6 ):δ＝187.3,182.1,158.8,157.7,144.7,139.0,108.3,104.0,64.3,53.9,43.7,40.2,39.5,37.8,34.8,34.8,33.6,33.5,27.1,20.6,15.8,14.2,13.8ppm，HRMS(ESI-TOF):calcd for C 23 H 31 O 3 + [M+H] + 355.2268,found 355.2269.
Example 3: synthesis of Compound 5
The specific synthetic route is shown in figure 2, and the specific steps are as follows:
to a solution of dsideanone B (12.6 mg, 35.5. Mu. Mol,1.0 equiv) in AcOH (2 mL) at 0 ℃ was added p-TsOH. H 2 O (1.4 mg, 7.11. Mu. Mol,0.2 equiv), the reaction solution was heated to 23 ℃ and reacted for 9 hours. After completion of the reaction, it was diluted with ice water (5 mL) and extracted 3 times with EtOAc (5 mL). The combined organic phases were washed with brine (5 mL) and anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography (PE: etOAc = 20) finally yielded compound 5 (11.6 mg,32.7 μmol, 92%). Yellow oil, R f ＝0.43(silica gel，PE:EtOAc＝4:1)，FT-IR(KBr):ν max ＝2957,2925,2875,2853,1716,1698,1650,1605,1418,1142,1123,1087,946,806cm -1 ， 1 H NMR(400MHz,C 6 D 6 ):δ＝5.59(s,1H),5.15–5.12(m,1H),3.11(qd,J＝7.0,4.5Hz,2H),3.04(d,J＝18.3Hz,1H),3.07–2.97(m,2H),1.73(dd,J＝18.5,3.2Hz,1H),1.68–1.58(m,1H),1.55(t,J＝3.2Hz,1H),1.52(d,J＝1.8Hz,3H),1.26(d,J＝10.9Hz,1H),1.21–1.17(m,2H),1.09–0.98(m,2H),0.92(t,J＝7.0Hz,3H),0.86(s,3H),0.79(d,J＝6.7Hz,3H),0.52(s,3H)ppm， 13 C NMR(101MHz,C 6 D 6 ):δ＝187.3,181.9,158.3,143.3,143.0,140.6,120.6,107.2,64.4,52.2,43.5,39.8,37.9,37.1,34.5,33.5,29.8,27.3,19.3,17.7,15.7,14.5,13.8ppm，HRMS(ESI-TOF):calcd for C 23 H 31 O 3 + [M+H] + 355.2268,found 355.2262.
Example 4: synthesis of Compound 6
The specific synthetic route is shown in figure 2, and the specific steps are as follows:
to a solution of Compound 4 (10.2mg, 28.8. Mu. Mol,1.0 equiv) in AcOH (2 mL) at 0 ℃ was added p-TsOH. H 2 O (1.1mg, 5.75. Mu. Mol,0.2 equiv), and the reaction mixture was heated to 23 ℃ and reacted for 9 hours. After completion of the reaction, it was diluted with ice water (5 mL) and extracted 3 times with EtOAc (5 mL). The combined organic phases were washed with brine (5 mL) and anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography (PE: etOAc = 20) yielded compound 6 (9.6 mg,27.1 μmol, 94%) finally. Yellow oil, R f ＝0.47(silica gel,PE:EtOAc＝4:1)，FT-IR(KBr):ν max ＝2961,2925,2853,1671,1650,1635,1605,1457,1222,1034,850,789cm -1 ， 1 H NMR(400MHz,C 6 D 6 ):δ＝5.55(s,1H),5.24–5.21(m,1H),3.21–3.04(m,2H),3.11(q,J＝6.9Hz,2H),2.90(d,J＝18.0Hz,1H),1.75(ddt,J＝16.7,10.8,2.4Hz,1H),1.66(dd,J＝18.1,3.4Hz,1H),1.57(t,J＝3.3Hz,1H),1.54(dt,J＝2.9,1.6Hz,3H),1.26(d,J＝10.8Hz,1H),1.22–1.15(m,2H),1.10–0.98(m,2H),0.92(t,J＝7.0Hz,3H),0.89(s,3H),0.75(d,J＝6.8Hz,3H),0.51(s,3H)ppm， 13 C NMR(101MHz,C 6 D 6 ):δ＝187.3,182.2,157.9,145.0,143.4,138.2,120.8,108.1,64.3,52.0,43.4,39.5,37.9,37.1,34.4,34.1,30.0,27.3,19.4,17.8,15.7,14.5,13.8ppm，HRMS(ESI-TOF):calcd for C 23 H 31 O 3 + [M+H] + 355.2268,found 355.2262.
It should be noted that the above examples are only preferred embodiments of the present invention and are not intended to limit the present invention. It will be appreciated by those skilled in the art that changes in these embodiments may be made without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims.

Claims (8)

1. A dysianone B analogue shown in formula (I),
Figure FDA0003015601550000011
in the formula (I), A ring is a benzene ring or p-benzoquinone;
R 1 and R 4 May be the same or different and is a hydrogen atom, an oxygen atom, a hydroxyl group or a substituted hydroxyl group;
R 2 and R 3 Can be the same or different and are respectively hydrogen atom, hydroxyl, substituted hydroxyl, amino, substituted amino, sulfydryl, substituted sulfydryl, heterocyclic radical and substituted heterocyclic radical;
R 5 is carbon atom or oxygen atom;
the structural formula is selected from all isomeric forms, such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, the R, S configuration containing an asymmetric center.
2. The dysianone B analog of claim 1 having formula (II)
Figure FDA0003015601550000012
Wherein R is 1 And R 4 Can be the same or different and are respectively hydrogen atom, hydroxyl and substituted hydroxyl;
R 2 and R 3 May be the same or different and is a hydrogen atom, a hydroxyl group, a substituted hydroxyl group, an amino group, a substituted amino group, a heterocyclic group or a substituted heterocyclic group;
R 5 is a carbon atom or an oxygen atom.
3. The dysidenone B analog of claim 1 having formula (III)
Figure FDA0003015601550000013
Wherein R is 2 And R 3 May be the same or different and is each a hydrogen atom, hydroxyl group, substituted hydroxyl group, amino group, substituted amino group, mercapto group, substituted mercapto group, heterocyclic group or substituted heterocyclic group.
4. The compound of claim 1, comprising a compound of one of:
Figure FDA0003015601550000021
5. the process for preparing dysianone B and analogs thereof according to claim 1, wherein the synthetic route is:
Figure FDA0003015601550000022
wherein R is 2 Is a hydrogen atom or an ethoxy group;
R 3 is a hydrogen atom or an ethoxy group;
R 6 and R 7 May be the same or different and is a chlorine atom, a bromine atom or an iodine atom.
6. The method of claim 5, wherein compound 9 is reacted with a methylenating agent selected from the group consisting of Wittig reagent, peterson reagent, nysted reagent, tebbe reagent, julia reagent, to form compound 10 in tetrahydrofuran as a solvent.
7. The method for preparing compound 1 according to claim 5, wherein compound 12 is reacted with tri-n-butyltin hydride and azobisisobutyronitrile in toluene as a solvent to form compound 1, wherein the molar ratio of compound 12 to azobisisobutyronitrile is 1.
8. The process for preparing dysideanone B and compound 4 according to claim 5, wherein compound 3 is reacted with a base in ethanol as a solvent under the action of oxygen to produce dysideanone B and compound 4, wherein the base is N, N-diisopropylethylamine, triethylamine, pentamethylpiperidine, potassium carbonate, sodium hydrogencarbonate, potassium phosphate, sodium hydride, lithium tert-butoxide, potassium tert-butoxide, N-butyllithium, potassium bis (trimethylsilanyl) amide,
Figure FDA0003015601550000031
wherein R is 2 Is a hydrogen atom or an ethoxy group;
R 3 is a hydrogen atom or an ethoxy group.
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