CN115197058B - 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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CN115197058B
CN115197058B CN202110388630.0A CN202110388630A CN115197058B CN 115197058 B CN115197058 B CN 115197058B CN 202110388630 A CN202110388630 A CN 202110388630A CN 115197058 B CN115197058 B CN 115197058B
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dysideanone
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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 dysideanone B analogues shown in formulas (II) and (III) and a preparation method thereof. The method takes Wieland-Miescher ketone derivative 1 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 of dysideanone B can be derived from solvent ethanol. The invention has short synthetic reaction route and higher total yield, is favorable for mass synthesis of dysideanone B and analogues thereof, and provides sufficient raw materials for biological activity evaluation and research of structure-activity relationship thereof.

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 dysideanone B analogues and a preparation method thereof.
Background
Sesquiterpene quinones are one of the most important natural products of the class of the hetero terpenes, structurally, in which a sesquiterpene fragment consisting of isoprene units is linked to a quinone moiety consisting of polyketides. The series of natural products exhibit a range of significant biological activities such as antibacterial, antifungal, anti-HIV, anti-inflammatory, antioxidant, antitumor, and inhibitory activity against protein tyrosine phosphatase 1B (PTP 1B).
Dysideanone B is a sesquiterpene quinone marine natural product with interesting structure and good biological activity. In 2014, lin Houwen et al separated from the secondary metabolite of the greedy and drool sponge (DYSIDEA AVARA) of south China sea animals. Lin Houwen et al also determined their chemical structure by HRMS, IR, NMR and 2D NMR methods, among others. Structurally, natural products dysideanone B contain an unprecedented 6/6/6/6 fused tetracyclic all-carbon backbone, a more crowded molecular backbone, and 5 consecutive chiral centers in the molecule, 2 of which are quaternary carbon centers. Biological tests show that dysideanone B shows good anti-tumor activity on a human cervical cancer cell line HeLa and a liver cancer cell line HepG2, and the IC 50 value is 7.1 mu M and 9.4 mu M respectively.
The good bioactivity and interesting structural features have prompted chemists to develop total synthesis studies on natural products dysideanone B. The dense chiral centers and the crowded tetracyclic backbones make their synthesis very challenging. Until now, there have been few studies on the synthesis of this natural product by chemists, and there has been no subject group to complete the complete synthesis thereof. Based on the above investigation, the inventors will develop a total synthesis study on the natural product dysideanone B, and design and synthesize analogues based thereon, study the structure-activity relationship of the natural product, and provide a new idea for cancer treatment.
Disclosure of Invention
The invention aims to simply and efficiently complete dysideanone B full synthesis by using a chemical synthesis method 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 of the present invention, the present invention provides the following technical solutions:
there is provided an analogue dysideanone B as shown in formula (I),
In the formula (I), the A ring is benzene ring or p-benzoquinone;
r 1 and R 4 may be the same or different and are each a hydrogen atom, an oxygen atom, a hydroxyl group or a substituted hydroxyl group;
R 2 and R 3 are the same or different and are each a hydrogen atom, a hydroxyl group, a substituted hydroxyl group, an amino group, a substituted amino group, a mercapto group, a substituted mercapto group, a heterocyclic group or a substituted heterocyclic group;
R 5 is a carbon atom or an oxygen atom;
the structural formula is selected from all isomeric forms, such as enantiomers, diastereomers and geometric isomers (or conformations): such as R, S configurations containing asymmetric centers.
The dysideanone B analogue provided by the invention is selected from compounds shown in a formula (II),
Wherein R 1 and R 4 can be the same or different and are respectively a hydrogen atom, a hydroxyl group and a substituted hydroxyl group;
R 2 and R 3 may be the same or different and each 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.
The dysideanone B analogue provided by the invention is also selected from compounds shown in a formula (III),
Wherein R 2 and R 3 may be the same or different and each is a hydrogen atom, a hydroxyl group, a substituted hydroxyl group, an amino group, a substituted amino group, a mercapto group, a substituted mercapto group, a heterocyclic group, or a substituted heterocyclic group.
The dysideanone B analogs provided by the invention comprise a compound that is one of the following:
The invention also provides a preparation method of dysideanone B and analogues thereof, which is characterized in that the synthetic route is as follows:
wherein R 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 each 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, and the compound 9 reacts with a methylene reagent to generate the compound 10, wherein the methylene 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 taken as a solvent, the compound 12 reacts with tri-n-butyltin hydride and azodiisobutyronitrile to generate the compound 1, and the molar ratio of the compound 13 to the azodiisobutyronitrile is 1:0.01-1:1.
The invention also provides a preparation method of dysideanone B and a compound 4, which is characterized in that under the action of oxygen, the compound 3 reacts with alkali in solvent ethanol to generate dysideanone 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 potassium bis (trimethylsilyl) amide,
Wherein R 2 is a hydrogen atom or an ethoxy group;
R 3 is a hydrogen atom or an ethoxy group.
The invention has the advantages of mild synthesis reaction condition, short reaction route, higher yield, low-cost and easily-obtained raw materials, is favorable for mass synthesis of dysideanone B and analogues thereof, and provides important substance basis and guarantee for biological activity evaluation and research of structure-activity relationship thereof.
Drawings
FIG. 1. Synthetic route for natural products dysideanone B and analogs thereof.
FIG. 2. Synthetic routes for compounds 5 and 6.
Detailed Description
The present invention will be further described in detail by the following specific examples, which are only for illustrating the present invention, and do not limit the scope of the present invention thereto.
Example 1: dysideanone B Synthesis
The specific synthetic route is shown in figure 1, and the specific steps are as follows:
(1) Preparation of ketone 9:
To a solution of enone 7 (10.2 g,43.2mmol,1.0 equiv) in THF (40 mL) at 0deg.C was added dropwise t-BuOK (47.5mL,47.5mmol,1.0M in THF,1.1equiv), and the reaction was warmed to 23deg.C and stirred for 1 hour. Then, a solution of bromo 8 (16.1 g,51.8mmol,1.2 equiv) in THF (10 mL) was added dropwise to the above solution at 0 ℃, and after stirring for 10 minutes, the reaction solution was heated to 40 ℃ and reacted for 1 hour. After completion of the reaction, it was diluted with saturated aqueous NH 4 Cl (80 mL) and extracted 3 times with EtOAc (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2SO4, filtered, concentrated and purified by column chromatography (PE: etoac=8:1) to finally give ketone 9 (14.4 g,31.1mmol, 72%). White solid ,M.P.:153–155℃,Rf＝0.35(silica gel,PE:EtOAc＝2:1),FT-IR(KBr):νmax＝3084,2971,2941,2885,2833,1700,1576,1477,1263,1208,1040,799,720,668cm-1,1H NMR(400MHz,C6D6):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,13C NMR(101MHz,C6D6):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 C23H29BrO5Na+[M+Na]+ 487.1091,found 487.1096.
(2) Preparation of tricyclic diene 10:
TiCl 4 (96.5mL,96.5mmol,1.0M in toluene,9.0equiv) was added dropwise to a solution of Nysted reagent (48.9g,41.2mL,107mmol,20wt%in THF,10equiv) in THF (20 mL) at 0deg.C, and the reaction was stirred at this temperature for 0.5 hours. A solution of ketone 9 (4.99 g,10.7mmol,1.0 equiv) in THF (20 mL) was then added dropwise to the solution, and after 10 minutes the reaction was heated to 40℃and reacted for 6 hours. After completion of the reaction, it was quenched with saturated aqueous NaHCO 3 (200 mL) and extracted 3 times with EtOAc (100 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2SO4, filtered, concentrated and purified by column chromatography (PE: etoac=20:1) to finally give tricyclodiene 10 (1.54 g,3.32mmol, 31%) and starting ketone 9 (2.69 g,5.78mmol, 54%). White solid ,M.P.:134–136℃,Rf＝0.56(silica gel,PE:EtOAc＝5:1),FT-IR(KBr):νmax＝2958,2925,2853,1731,1507,1287,1258,1123,1065,1038,796,723cm-1,1H NMR(400MHz,C6D6):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,13C NMR(101MHz,C6D6):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 C24H32BrO4 +[M+H]+ 463.1478,found 463.1475.
(3) Preparation of tricycloenone 11:
To a mixed solution of tricyclodiene 10 (758 mg,1.64mmol,1.0 equiv) in THF (6 mL) and acetone (2 mL) at 0deg.C was added 3M HCl (5.46 mL,16.4mmol,10 equiv) dropwise, the reaction solution was warmed to 23deg.C and reacted for 2 hours. After completion of the reaction, it was diluted with saturated aqueous NaHCO 3 (20 mL) and extracted 3 times with EtOAc (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na 2SO4, filtered, concentrated and purified by column chromatography (PE: etoac=10:1) to finally give tricycloenone 11 (67 mg,1.60mmol, 98%). Colorless oil ,Rf＝0.46(silica gel,PE:EtOAc＝2:1),FT-IR(KBr):νmax＝3661,3638,2943,2834,1707,1574,1474,1258,1069,1038,795,724cm-1,1H NMR(400MHz,C6D6):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,13C NMR(101MHz,C6D6):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 C22H27BrO3Na+[M+Na]+ 441.1036,found 441.1031.
(4) Preparation of tricyclic ketone 12:
A solution of (PPh 3)3 RhCl (719 mg,0.777mmol,0.5 equiv) in toluene (10 mL) was stirred for 0.5 h at 23℃in the presence of hydrogen, then a solution of tricycloketone 11 (652 mg,1.55mmol,1.0 equiv) in toluene (5 mL) was added dropwise to the above solution, after 10 min the reaction was heated to 40℃and reacted for 4 h, after completion of the reaction was filtered with celite, the filtrate was concentrated and purified by column chromatography (PE: etOAc=10:1), finally tricycloketone 12 (550 mg,1.31mmol, 84%) was obtained as a white solid ,M.P.:137–139℃,Rf＝0.55(silica gel,PE:EtOAc＝2:1),FT-IR(KBr):νmax＝2998,2928,2845,1699,1476,1460,1433,1263,1242,1064,1040,808,716cm-1,1H NMR(400MHz,C6D6)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,13C NMR(101MHz,C6D6)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 C22H30BrO3 +[M+H]+ 421.1373,found 421.1375.
(5) Preparation of tetracyclic ketone 1:
To a toluene (8 mL) solution of tricyclic ketone 12 (803 mg,0.861mmol,1.0 equiv) at 23℃were added n-Bu 3 SnH (501 mg, 462. Mu.L, 1.72mmol,2.0 equiv) and AIBN (14.2 mg, 86.1. Mu. Mol,0.1 equiv) in this order, and the reaction solution 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 give tetracyclic ketone 1 (180 mg,0.525mmol, 61%). White solid ,M.P.:208–209℃,Rf＝0.42(silica gel,PE:EtOAc＝8:1),FT-IR(KBr):νmax＝3649,2997,2944,2899,2833,1700,1473,1457,1252,1085,958,798,717cm-1,1H NMR(400MHz,C6D6):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,13C NMR(101MHz,C6D6):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 C22H30O3Na+[M+Na]+ 365.2087,found 365.2082.
(6) Preparation of tetracycloalkene 2:
To a solution of Ph 3PCH3 Br (1.88 g,5.26mmol,10 equiv) in toluene (15 mL) at 0deg.C was added t-BuOK (4.73mL,4.73mmol,1.0M in THF,9.0equiv) dropwise, the reaction was warmed to 23deg.C and stirred for 1 hour. A solution of tetracyclic ketone 1 (180 mg,0.526mmol,1.0 equiv) in toluene (5 mL) was then added dropwise to the above solution, and after 10 minutes the reaction solution was heated to 50deg.C and reacted for 6 hours. After completion of the reaction, it was diluted with saturated aqueous NH 4 Cl (30 mL) and extracted 3 times with EtOAc (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na 2SO4, filtered, concentrated and purified by column chromatography (PE: etoac=60:1) to finally give tetracycloalkene 2 (156 mg,0.457mmol, 87%). White solid ,M.P.:143–145℃,TLC:Rf＝0.61(silica gel,PE:EtOAc＝10:1),FT-IR(KBr):νmax＝2985,2931,2858,2832,1633,1475,1433,1251,1089,887,790,715cm-1,1H NMR(400MHz,C6D6):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,13C NMR(101MHz,C6D6):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 C23H33O2 +[M+H]+ 341.2475,found 341.2470.
(7) Preparation of tetracyclic quinone 3:
To a solution of tetracycloolefin 2 (156 mg,0.458mmol,1.0 equiv) in 1, 4-dioxane (4 mL) at 23℃were successively added 6M HNO 3 (382. Mu.L, 2.29mmol,5.0 equiv) and AgO (170 mg,1.37mmol,3.0 equiv), and the reaction solution 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 saturated brine (5 mL), dried over anhydrous Na 2SO4, filtered, concentrated and purified by column chromatography (PE: etoac=40:1) to finally give tetracyclic quinone 3 (122 mg, 0.390 mmol, 86%). Yellow foam ,Rf＝0.61(silica gel,PE:EtOAc＝9:1),FT-IR(KBr):νmax＝2977,2923,2861,1649,1599,1458,1384,1293,1137,892,873,438cm-1,1H NMR(400MHz,C6D6):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,13C NMR(101MHz,C6D6):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 C21H27O2 +[M+H]+ 311.2006,found 311.2001.
(8) Dysideanone B preparation:
To a solution of tetracyclic quinone 3 (41.4 mg,0.133mmol,1.0 equiv) in EtOH (5 mL) at 23℃and in the presence of O 2 was added Et 3 N (135 mg, 185. Mu.L, 1.33mmol,10 equiv), and the reaction was heated to 45℃and reacted for 3 hours. After completion of the reaction, it was diluted with saturated aqueous NH 4 Cl (5 mL) and extracted 3 times with EtOAc (5 mL). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous Na 2SO4, filtered, concentrated and purified by column chromatography (PE: etoac=20:1) to finally give dysideanone B (25.0 mg,70.7mmol, 53%). Pale yellow solid ,M.P.:151–153℃,Rf＝0.43(silica gel,PE:EtOAc＝4:1),FT-IR(KBr):νmax＝3545,3083,2958,2926,2860,1728,1650,1605,1460,1380,1221,1036,891cm-1,1H NMR(400MHz,CDCl3):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,13C NMR(101MHz,CDCl3):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 C23H31O3 +[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:
To a solution of tetracyclic quinone 3 (41.4 mg,0.133mmol,1.0 equiv) in EtOH (5 mL) at 23℃and in the presence of O 2 was added Et 3 N (135 mg, 185. Mu.L, 1.33mmol,10 equiv), and the reaction was heated to 45℃and reacted for 3 hours. After completion of the reaction, it was diluted with saturated aqueous NH 4 Cl (5 mL) and extracted 3 times with EtOAc (5 mL). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous Na 2SO4, filtered, concentrated and purified by column chromatography (PE: etoac=20:1) to finally give compound 4 (17.0 mg,48.0 μmol, 36%). Yellow oil ,Rf＝0.47(silica gel,PE:EtOAc＝4:1),FT-IR(KBr):νmax＝3649,3629,3182,2922,2852,2360,2342,1671,1650,1605,1222,1108,1035cm-1,1H NMR(400MHz,C6D6):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,13C NMR(101MHz,C6D6):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 C23H31O3 +[M+H]+ 355.2268,found 355.2269.
Example 3: synthesis of Compound 5
The specific synthetic route is shown in fig. 2, and the specific steps are as follows:
To a solution of dysideanone 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), and the reaction mixture was warmed 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 saturated brine (5 mL), dried over anhydrous Na 2SO4, filtered, concentrated and purified by column chromatography (PE: etoac=20:1) to finally give compound 5 (11.6 mg,32.7 μmol, 92%). Yellow oil ,Rf＝0.43(silica gel,PE:EtOAc＝4:1),FT-IR(KBr):νmax＝2957,2925,2875,2853,1716,1698,1650,1605,1418,1142,1123,1087,946,806cm-1,1H NMR(400MHz,C6D6):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,13C NMR(101MHz,C6D6):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 C23H31O3 +[M+H]+ 355.2268,found 355.2262.
Example 4: synthesis of Compound 6
The specific synthetic route is shown in fig. 2, and the specific steps are as follows:
To an AcOH (2 mL) solution of Compound 4 (10.2 mg, 28.8. Mu. Mol,1.0 equiv) at 0deg.C was added p-TsOH.H 2 O (1.1 mg, 5.75. Mu. Mol,0.2 equiv), and the reaction mixture was warmed to 23deg.C 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 saturated brine (5 mL), dried over anhydrous Na 2SO4, filtered, concentrated and purified by column chromatography (PE: etoac=20:1) to finally give compound 6 (9.6 mg,27.1 μmol, 94%). Yellow oil ,Rf＝0.47(silica gel,PE:EtOAc＝4:1),FT-IR(KBr):νmax＝2961,2925,2853,1671,1650,1635,1605,1457,1222,1034,850,789cm-1,1H NMR(400MHz,C6D6):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,13C NMR(101MHz,C6D6):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 C23H31O3 +[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. Various alternatives and modifications to these embodiments will be apparent to those skilled in the art without departing from the principles and spirit of the invention.

Claims (4)

1. A preparation method of dysideanoneB and analogues thereof is characterized in that the synthetic route is as follows:
wherein R 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 each is a chlorine atom, a bromine atom or an iodine atom.
2. The process for preparing dysideanoneB and analogues thereof according to claim 1, wherein tetrahydrofuran is used as solvent, and compound 9 is reacted with a methyleneating reagent, which is a Wittig reagent, peterson reagent, nysted reagent, tebbe reagent, julia reagent, to form compound 10.
3. The preparation method of dysideanoneB and analogues thereof according to claim 1, wherein toluene is used as solvent, compound 12 reacts with tri-n-butyltin hydride and azodiisobutyronitrile to form compound 1, and the molar ratio of compound 12 to azodiisobutyronitrile is 1 (0.01-1).
4. The process for preparing dysideanoneB and analogues thereof as claimed in claim 1, wherein the reaction of compound 3 with a base in solvent ethanol under the action of oxygen gives dysideanoneB and compound 4, the base being N, N-diisopropylethylamine, triethylamine, pentamethylpiperidine, potassium carbonate, sodium bicarbonate, potassium phosphate, sodium hydride, lithium t-butoxide, potassium t-butoxide, N-butyllithium, potassium bis (trimethylsilyl) amide.
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CN109384675A (en) * 2017-08-14 2019-02-26 南开大学 The Enantioselective total synthesis method of needle juniper celery alkane type diterpene and the like
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