CN118184675A - Mugwort lactone I derivative and pharmaceutical composition thereof, and preparation method and application thereof - Google Patents

Mugwort lactone I derivative and pharmaceutical composition thereof, and preparation method and application thereof Download PDF

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CN118184675A
CN118184675A CN202410295603.2A CN202410295603A CN118184675A CN 118184675 A CN118184675 A CN 118184675A CN 202410295603 A CN202410295603 A CN 202410295603A CN 118184675 A CN118184675 A CN 118184675A
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mugwort
lactone
derivative
derivatives
reaction
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陈纪军
王星
李天泽
马云保
马文静
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Kunming Institute of Botany of CAS
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Kunming Institute of Botany of CAS
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Abstract

The invention provides 33 mugwort lactone I derivatives 1-33 shown in a structural formula (I), a pharmaceutical composition thereof, a preparation method and application thereof, and belongs to the technical field of medicines. The mugwort lactone I derivative 1-33 has obvious inhibition activity on human liver cancer cell lines (HepG 2, huh7, SK-Hep-1), can form a pharmaceutical composition with a pharmaceutically acceptable carrier, and can be used for preparing anti-liver cancer drugs.

Description

Mugwort lactone I derivative and pharmaceutical composition thereof, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a medicinal composition taking mugwort lactone I derivatives 1-33 as active ingredients, a preparation method thereof and application of the derivatives and the medicinal composition thereof in preparing medicines for resisting liver cancer.
Background
Liver cancer is classified into primary and secondary, is a global disease, the number of newly increased patients in 2020 is 90.5 ten thousand worldwide, the number of deaths reaches 83 ten thousand, and the incidence rate is continuously increased, and is expected to exceed 100 ten thousand in 2025. Hepatocellular carcinoma accounts for about 90% of primary liver cancer, and has complex pathogenesis and is affected by a plurality of factors including non-alcoholic fatty liver, hepatitis B, liver cirrhosis caused by hemochromatosis or primary cholangitis, etc. The medicines for treating liver cancer which are marketed at present are five small molecule synthetic medicines of the amino acid kinase inhibitors sorafenib, lenvatinib, regorafenib, cabozantinib and dorafinib, and 8 monoclonal antibody medicines of the ramucirumab and the PD-1 inhibitor palboc Li Zhushan and the nano Wu Liyou monoclonal antibody. Recently, the national drug administration has approved alcaladine for the treatment of hepatocellular carcinoma. The medicine for treating liver cancer has greatly progressed, but has the defects of obvious toxic and side effects, intolerance, high price and the like, and a novel anti-liver cancer medicine still needs to be developed. Natural products and derivatives thereof play an important role in the development of new drugs in various structures and biological activities, and in recent years, many reports have shown that various sesquiterpenes have cytotoxic activities on liver cancer cells.
In previous studies by the present inventors, mugwort lactone I (lavandiolide I) isolated from mugwort has inhibitory activity on three liver cancer cells of HepG2, huh7 and SK-Hep-1, and IC 50 values are 12.1±0.9, 18.4±1.1, 17.6±1.2 μm, respectively. To date, the prior art has no report on the mugwort lactone I derivatives and the pharmacological activity thereof, no report on the mugwort lactone I derivatives and the pharmacological activity thereof as pharmaceutical compositions, and no report on the mugwort lactone I derivatives and the pharmaceutical compositions thereof in preparing anti-liver cancer drugs.
Disclosure of Invention
The invention aims to provide a novel mugwort lactone I derivative (1-33) with medicinal value, a preparation and synthesis method thereof, and a medicinal composition taking the mugwort lactone I derivative as an active ingredient, and application of the mugwort lactone I derivative in medicaments for treating liver cancer. The invention synthesizes a new derivative by carrying out structural modification on mugwort lactone I, and provides a new anti-liver cancer active compound.
In order to achieve the above object, the present invention provides the following technical solutions:
Mugwort lactone I derivatives 1-33 (compounds 1-33) shown in structural formula (I),
The molecular structure of the mugwort lactone I derivative 1-33 shown in the figure 1 is that the mugwort lactone I derivative 1-33 or a pharmaceutically acceptable salt thereof refers to pharmaceutically acceptable salts, including salts formed with organic acid or inorganic acid, wherein the organic acid is citric acid, maleic acid and fumaric acid, and the inorganic acid is hydrochloric acid, sulfuric acid and phosphoric acid.
The invention also provides a method for preparing the mugwort lactone I derivatives 1-33 (compounds 1-33), which comprises the following steps:
Preparation of mugwort lactone I derivative 1-2:
The coupling of benzene rings and exocyclic double bonds is realized by taking mugwort lactone I as a substrate, palladium acetate as a catalyst and iodobenzene as a benzene ring source, so that mugwort lactone I derivative 1 is obtained; in tetrahydrofuran solution, sodium hypochlorite is used as oxidant to carry out addition polymerization with 4-methylbenzaldehyde oxime through 1, 3-dipolar ring to obtain oxazoline derivative 2 of the mugwort lactone I.
Preparation of mugwort lactone I derivative 1-2:
Coupling mugwort lactone I with iodobenzene under the catalysis of palladium acetate to obtain mugwort lactone I derivative 1; the field mugwort lactone I and 4-methyl benzaldehyde oxime are subjected to 1, 3-dipolar cycloaddition to obtain the oxazoline derivative 2 of the field mugwort lactone I.
Preparation of mugwort lactone I derivatives 3-10:
Using mugwort lactone I as a substrate, and obtaining mugwort lactone I derivative 3 through esterification; using mugwort lactone I as a substrate, and reacting with alcohol (methanol and phenethyl alcohol) under an acidic condition to obtain mugwort lactone I derivatives 4, 5, 6 and 7 respectively; dehydrating mugwort lactone I under the action of HF.Py to obtain a derivative 8; the mugwort lactone I is reduced by carbocation under the acidic condition to obtain mugwort lactone I derivatives 9 and 10.
Preparation of mugwort lactone I derivatives 11-21:
Sesquiterpenes 3α,4α-epoxy-arglabin,3,4-hydro-arglabin,kauniolide,8-deoxyrupicolin B,1-hydroxy-10-methoxy-arglabin,1,10-epi-arglabin,11,13-dehydrodesacetylmatricarin,1β,10β-epoxy-2α-hydroxykauniolide and 14-hydroxykauniolide are respectively used as reaction substrates, and the mugwort lactone I derivative 11-21 is obtained through Diels-Alder reaction and removal of dimethylamino protecting groups under the conditions of no solvent and 50 ℃.
Preparation of mugwort lactone I derivatives 22-33:
Taking the mugwort lactone I derivative 21 as a reaction raw material, and oxidizing by using a dess-martin reagent to obtain a mugwort lactone I derivative 22; the mugwort lactone I derivative 22 takes sodium chlorite as an oxidant, naH 2PO4 is taken as a reaction acid-base buffer, and 2-methylbut-2-ene is added at the same time, so as to obtain a mugwort lactone I derivative 23; the mugwort lactone I derivative 23 is esterified and condensed with phenol under the action of DCC and DMAP to obtain mugwort lactone I derivative 24; the mugwort lactone I derivative 21 is respectively esterified and condensed with acetic anhydride and benzoic anhydride under the action of DCC and DMAP to obtain mugwort lactone I derivatives 25 and 26; taking a mugwort lactone I derivative 21 as a substrate, adding DPPA and DBU, and reacting in an alkaline environment through S N to obtain an azido derivative 27 of mugwort lactone I; firstly, a slight excess triphenylphosphine is used for reducing the mugwort lactone I derivative 27 through Shi Dingge reaction (Staudinger reaction) to obtain an intermediate amino derivative, and then the intermediate amino derivative is reacted with benzoic anhydride to obtain an amide derivative 28 of mugwort lactone I; taking the intermediate amino derivative as a substrate, and obtaining carbamate derivative 29 of the mugwort lactone I under the action of benzyl alcohol and CDI; adding 2-phenethyl isocyanate under alkaline condition by taking an intermediate amino derivative as a substrate to obtain a urea-containing compound 30; the mugwort lactone I derivative 21 is used as a reaction substrate, sodium hydride provides an alkaline environment, and the sodium hydride and benzyl bromide are subjected to Williamson ether synthesis reaction to obtain a compound 31; the method comprises the steps of taking a mugwort lactone I derivative 27 as a substrate, and respectively carrying out Click reaction on the mugwort lactone I derivative 27 and a terminal alkynyl compound (phenylacetylene and 4-methyl phenylacetylene) in a reaction system of cuprous iodide and triethylamine to obtain triazole derivatives 32 and 33 of mugwort lactone I; then, pharmaceutically acceptable carriers are added separately.
The invention also provides application of the mugwort lactone I derivative (1-33) in preparing an anti-liver cancer inhibitor and in preparing an anti-liver cancer medicament.
In addition, the invention provides a pharmaceutical composition which comprises a therapeutically effective amount of at least one of the derivatives (1-33) of mugwort lactone and a pharmaceutically acceptable carrier.
Meanwhile, a method for preparing the pharmaceutical composition containing the active ingredients of the mugwort lactone I derivatives (1-33) is provided, wherein the mugwort lactone I compounds are used as reaction raw materials to synthesize the mugwort lactone I derivatives (1-33), and pharmaceutically acceptable carriers are respectively added.
And provides the application of the pharmaceutical composition in preparing anti-liver cancer inhibitors and in preparing anti-liver cancer drugs.
When the compound of the present invention is used as a medicament, it may be used as it is or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99%, preferably 0.5-90%, of the compound of the invention, the balance being pharmaceutically acceptable, non-toxic and inert pharmaceutically acceptable carriers for humans and animals.
The pharmaceutically acceptable carriers are one or more of solid, semi-solid and liquid diluents, fillers and pharmaceutical formulation adjuvants. The pharmaceutical composition of the present invention is used in the form of a unit weight dose. The medicine of the present invention may be administered via injection (intravenous injection, intramuscular injection) and orally.
Compared with the prior art, the invention has the following advantages:
1. The invention provides a series of novel mugwort lactone I derivatives 1-33 (compounds 1-33), which fills the blank of the prior art.
2. The invention provides a method for preparing novel compounds 1-33, the content of the preparation raw materials in plants is high, a large amount of the preparation raw materials can be separated and extracted from the plants, the synthetic route is short, the yield is high, and the industrial production is easy.
3. The invention provides a pharmaceutical composition with novel compounds 1-33 as active ingredients, and provides a novel medicament with better medicinal effect for novel anti-liver cancer medicaments.
4. The compounds 1-33 have stronger activity on the inhibition activities of three liver cancer cells (HepG 2, huh7 and SK-Hep-1); 13 compounds (4,12,14,22,24,26-33) have stronger inhibitory activity than sorafenib and mugwort lactone I on three liver cancer cells; in particular compound 24, IC 50 values of 5.2 (HepG 2), 5.4 (Huh 7) and 5.8. Mu.M (SK-Hep-1), 2.3, 3.4 and 3.0 times higher than that of mugwort lactone I, 2.5, 1.6 and 2.0 times stronger than that of bissorafenib; and the compound 6,22,24,28-33 shows better safety, better selectivity to normal liver cells (THLE-2) and SI value range of 1.3-4.4.
5. The mugwort lactone I derivatives 1-33 can be used as medicines for treating liver cancer related diseases.
Drawings
FIG. 1 is a schematic diagram of the structures of the mugwort lactone I derivatives 1-33 (compounds 1-33) of the present invention.
Detailed Description
In order to better understand the gist of the present invention, the synthesis method and pharmacological effect results of the mugwort lactone I derivatives 1-33 of the present invention will be further described with reference to the accompanying drawings, but the present invention is not limited thereto.
Nuclear magnetic resonance spectra (1H and 13 C) were determined on 400MHz,500MHz and 600MHz nuclear magnetic resonance spectrometers (Bruker, bremerhaven, germany) with TMS (tetramethylsilane) as internal standard. HRMS was determined on an LC/MS-IT-TOF mass spectrometer (Shimadzu, kyoto, japan). All compounds were purified by silica gel column chromatography (200-300 mesh, qingdao Megao group Co., ltd.). All reagents and solvents were purchased from regular manufacturers.
Example 1
Preparation of Compound 1:
To a solution of mugwort lactone I (40 mg,0.08mmol,1.0 eq) in DMF (2 mL) at-40℃were added Et 3 N (34. Mu.L, 3.0 eq) and iodobenzene (20 mg,1.2 eq), pd (OAc) 2 (2 mg,0.05 eq), after which the reaction was heated to 80℃for 16 hours. After the reaction was quenched with saturated NaHCO 3 solution, extracted with DCM (10 mL), the organic phase was washed with saturated brine, dried over anhydrous Na 2SO4 and the solvent was recovered under reduced pressure. The crude product was purified by silica gel column chromatography [ petroleum ether-acetone, 20:1 (v/v) ] to give compound 1 (white solid, yield 57%).
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 30H36O5[M+H]+ 569.2898, found 569.2908.
IRνmax 3451,1756,1653,1461,1378,1262,1096,1022,802,737,698cm-1
1 H-NMR and 13 C-NMR data ：1H NMR(500MHz,CDCl3)δH 7.62(d,J＝3.6Hz,1H,H-13),7.43–7.29(m,5H,H-2",3",4",5",6"),5.62(d,J＝9.4Hz,1H,H-6),5.58–5.54(m,1H,H-3'),3.99(dd,J＝10.2,10.2Hz,1H,H-6'),3.29–3.22(m,1H,H-7),3.03(br s,1H,H-2),2.83(d,J＝10.5Hz,1H,H-5'),2.79–2.73(m,1H,H-9a),2.25–2.19(m,2H,H-8a,H-13'a),2.18–2.10(m,2H,H-9b,H-9'a),2.06–1.98(m,1H,H-9'b),1.98–1.93(m,1H,H-7'),1.92–1.91(s,3H,H-15'),1.72–1.63(m,2H,H-2'a,H-8'a),1.63–1.55(m,4H,H-8'b,H-2'b,H-3a),1.49(dd,J＝12.2,2.6Hz,1H,H-13'b),1.45(s,3H,H-15),1.40(s,3H,H-14),1.38-1.35(m 1H,H-3b),1.3(s,3H,H-14');13C NMR(125MHz,CDCl3)δC 180.8(C-12'),171.6(C-12),150.1(C-1),145.5(C-5),140.9(C-4'),137.1(C-13),134.2(C-11),130.6(C-1"),129.4(C-2",C-3"),129.1(C-4"),128.4(C-5",C-6"),125.1(C-3'),83.2(C-6),79.9(C-6'),72.6(C-10),72.1(C-1'),62.0(C-10'),60.1(C-4),55.9(C-11'),54.0(C-3),52.5(C-7'),52.2(C-5'),46.3(C-7),42.5(C-2),39.1(C-9),38.4(C-2'),35.2(C-13'),32.8(C-9'),27.0(C-14),23.1(C-8),22.5(C-14'),20.9(C-8'),18.5(C-15'),17.1(C-15)
Example 2
Preparation of compound 2:
Mugwort lactone I (50 mg,0.17mmol,1.0 eq) was weighed into a 10mL three-necked round bottom flask under Ar protection, then NaOCl (0.75 mL) and 4-methylbenzaldehyde oxime (25 mg,1.5 eq) were added in sequence and reacted at room temperature for 8 hours. After the reaction was quenched by addition of saturated NaHCO 3 solution, then extracted with DCM (10 ml×3), the organic phases were combined, washed once with saturated NaCl solution, H 2 O and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was isolated by column chromatography [ petroleum ether-acetone, 85:15 (v/v) ] to give compound 2 (white solid, yield 90%). .
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 38H43NO7[M+H]+ 626.3112, found 626.3123.
IRνmax 3491,1780,1757,1613,1457,1378,1261,1161,1095,1020,804cm-1；
1 H-NMR and 13 C-NMR data ：1H NMR(500MHz,CDCl3)δH 7.54(d,J＝8.0Hz,2H,H-3",H-4"),7.21(d,J＝7.9Hz,2H,H-5",H-6"),5.90(d,J＝9.6Hz,1H,H-6),5.64–5.52(m,1H,H-3'),4.00(dd,J＝10.1,10.1Hz,1H,H-6'),3.90(d,J＝17.0Hz,1H,H-13a),3.18(d,J＝16.9Hz,1H,H-13b),3.05(br s,1H,H-2),2.84(d,J＝10.5Hz,1H,H-3a),2.76(dd,J＝17.8,2.3Hz,1H,H-2'a),2.38(s,3H,H-8"),2.25–2.08(m,5H,H-13'a,H-7a,H-8a,H-9'a,H-2'b),2.07–1.96(m,1H,H-9'b),1.95–1.90(m,6H,H-15',C-7'a,H-9'b,H-7'b),1.80–1.63(m,2H,H-9),1.61–1.56(m,2H,H-8b,H-8'a),1.56–1.49(m,2H,H-13'b,H-3a),1.42(s,3H,H-15),1.38(s,3H,H-14),1.34(s,3H,H-14'),1.30(d,J＝2.3Hz,1H,H-3b);13C NMR(125MHz,CDCl3)δC 180.7(C-12'),173.4(C-12),155.9(C-1"),151.8(C-1),143.7(C-5),140.9(C-4'),140.8(C-7"),129.5(C-5",C-6"),126.8(C-3",C-4"),125.6(C-2"),125.1(C-3'),86.4(C-11),84.0(C-6),80.0(C-6'),72.5(C-1'),72.1(C-10),62.0(C-10'),60.2(C-4),56.0(C-11'),53.4(C-3),52.4(C-5'),52.3(C-7'),51.7(C-7),42.7(C-2),40.1(C-13),39.1(C-2'),38.5(C-9),34.9(C-13'),32.8(C-9'),26.9(C-14),22.5(C-14'),21.5(C-8"),20.8(C-8'),18.5(C-15'),17.3(C-8),17.1(C-15);
Example 3
Preparation of compound 3:
Lavandiolide I (50 mg,0.1mmol,1.0 eq) was weighed into a 10mL round bottom flask, dissolved by adding DCM (5 mL), then DMAP (13 mg,0.1mmol,1.0 eq) and acetic anhydride (21 mg,0.2mmol,2.0 eq) were added, reacted for 15 hours, after the reaction was completed saturated NaHCO 3 solution was added to quench the reaction, then extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, washed once with saturated NaCl solution, H 2 O and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography [ petroleum ether-acetone, 85:15 (v/v) ] to give compound 3 (white solid, yield 38%).
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 32H38O7[M+H]+ 557.2510, found 557.2500;
IRνmax 1769,1737,1618,1462,1378,1262,1097,1022,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.16(d,J＝3.4Hz,1H,H-13a),5.56–5.53(m,1H,H-3'),5.51(d,J＝10.3Hz,1H,H-6),5.44(d,J＝3.2Hz,1H,H-13b),3.98(dd,J＝10.1,10.1Hz,1H,H-6'),2.92–2.89(br s,1H,H-2),2.81–2.71(m,3H,H-2'a,H-7,H-7'),2.18–2.06(m,6H,H-8a,H-9a,H-13'a,H-2'a),2.01–1.97(m,1H,H-9'a),1.96(s,3H,H-2"),1.92(s,3H,H-14'),1.90–1.87(m,1H,H-9b),1.71(s,3H,H-14),1.63–1.55(m,3H,H-3a,H-8'),1.38(s,3H,H-15),1.36–1.33(m,1H,H-3b),1.33(s,3H,H-15');13C NMR(125MHz,CDCl3)δC 179.2(C-12'),170.1(C-12),169.9(C-1"),147.7(C-1),147.3(C-5),141.1(C-4'),139.8(C-11),124.8(C-3'),118.8(C-13),83.6(C-6),81.4(C-10),79.5(C-6'),72.1(C-10'),61.8(C-1'),59.5(C-4),55.7(C-11'),55.1(C-3),52.5(C-5'),52.3(C-7'),46.5(C-7),42.9(C-2),39.1(C-2'),36.5(C-13'),33.6(C-9),32.8(C-9'),25.3(C-14),24.6(C-8),22.5(C-14'),21.9(C-2"),20.9(C-8'),18.6(C-15'),16.9(C-15);
Example 4
Preparation of Compounds 4-7:
Lavandiolide I (60 mg,0.12mmol,1.0 eq) was weighed into a 10mL round bottom flask, dissolved in DCM (5 mL) and then TFA (40. Mu.L, 0.24mmol,2.0 eq) and MeOH/phenethyl alcohol (0.1 mL/0.1mL,10.0 eq) were added, reacted for 12 hours, after the reaction was completed, saturated NaHCO 3 solution was added to quench the reaction, followed by extraction with dichloromethane (10 mL. Times.3), the organic phases combined and washed once with saturated NaCl solution, H 2 O and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography [ petroleum ether-acetone, 95:5 (v/v) ] to give compounds 4,5 and 6,7.
Compound 4 structural data:
Traits: white solid
Yield: 25 percent of
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 31H38O6[M+H]+ 507.2741, found 507.2741.
IRνmax 1765,1664,1458,1378,1095,1024,864,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.12(d,J＝3.6Hz,1H,H-13a),5.58–5.53(m,1H,H-3'),5.42(d,J＝3.3Hz,1H,H-13b),5.37(d,J＝10.2Hz,1H,H-6),4.00(dd,J＝10.1,10.1Hz,1H,H-6'),3.27(s,3H,H-1"),3.20–3.09(m,1H,H-7),3.03-1.97(br s,1H,H-2),2.83(d,J＝10.5Hz,1H,H-3a),2.80–2.72(m,1H,H-2'a),2.29–2.09(m,4H,H-2'b,H-13'a,H-9'a,H-13'b),2.07–2.01(m,1H,H-9'b),2.01–1.93(m,1H,H-9a),1.92(s,3H,H-15'),1.83(m,1H,H-9b),1.64–1.59(m,2H,H-8),1.59–1.49(m,1H,H-5'),1.47(m,1H,H-7'),1.45(s,3H,H-15),1.34(s,3H,H-14'),1.31(m,1H,H-9b),1.30(s,3H,H-14);13C NMR(125MHz,CDCl3)δC 180.2(C-12'),170.5(C-12),149.3(C-5),148.5(C-1),140.8(C-4'),140.4(C-11),125.1(C-3'),118.8(C-13),84.4(C-6),79.9(C-6'),76.4(C-10),72.1(C-1'),61.9(C-10'),60.2(C-4),56.0(C-11'),52.8(C-3),52.4(C-5'),52.3(C-7'),50.6(C-1"),46.5(C-7),44.1(C-2),39.1(C-2'),36.1(C-9),34.2(C-13'),32.7(C-9'),24.0(C-14),23.4(C-8),22.5(C-14'),20.9(C-8'),18.5(C-15'),17.1(C-15);
Compound 5 structural data:
Traits: white solid
Yield: 13%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 31H38O6[M+H]+ 507.2741, found 507.2721.
IRνmax 1768,1620,1461,1378,1262,1096,1022,863,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.14(d,J＝3.5Hz,1H,H-13a),5.57(d,J＝10.2Hz,1H,H-6),5.56–5.52(m,1H,H-3'),5.41(d,J＝3.2Hz,1H,H-13b),4.00(dd,J＝10.1,10.1Hz,1H,H-6'),3.07(s,3H,H-1"),2.87-2.85(br s,1H,H-2),2.83–2.72(m,3H,H-2'a,H-7,H-5'),2.18–2.11(m,2H,H-2'b,H-13'a),2.11–1.94(m,6H,H-9'a,H-9'b,H-8a,H-8b,H-9a,H-7'),1.92(s,3H,H-15'),1.79–1.74(m,1H,H-9b),1.63-1.56(m,3H,H-8',H-13'b,H-3a),1.38(s,3H,H-15),1.37-1.34(m,1H,H-3b),1.33(s,3H,H-14'),1.32(s,3H,H-14);13C NMR(125MHz,CDCl3)δC 179.5(C-12'),170.3(C-12),149.1(C-5),147.6(C-1),141.0(C-4'),140.3(C-11),124.9(C-3'),118.6(C-13),83.1(C-6),79.7(C-6'),76.5(C-10),72.1(C-1'),61.9(C-10'),59.3(C-4),55.7(C-11'),55.6(C-3),52.5(C-5'),52.4(C-7'),50.9(C-16),46.6(C-7),42.7(C-2),39.1(C-2'),35.3(C-9),33.7(C-13'),32.8(C-9'),24.2(C-14),23.9(C-8),22.5(C-14'),20.9(C-8'),18.6(C-15'),16.9(C-15);
Compound 6 structural data:
Traits: white solid
Yield: 14%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 38H44O6[M+H]+ 597.3211, found 597.3205.
IRνmax 1767,1621,1460,1378,1262,1096,1023,863,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(600MHz,CDCl3)δH 7.25–7.21(m,2H,H-4",H-5"),7.19–7.13(m,3H,H-6",H-7",H-8"),6.04(d,J＝3.5Hz,1H,H-13a),5.55(m,1H,H-3'),5.28–5.24(m,2H,H-13b,H-6),3.98(dd,J＝10.1,10.1Hz,1H,H-6'),3.74–3.69(dt,J＝13.8,6.7Hz,1H,H-1"a),3.56(dt,J＝14.2,6.5Hz,1H,H-1"b),2.95–2.93(m,1H,H-7),2.84–2.80(m,3H,H-2",H-5'),2.79–2.73(m,2H,H-2'a,H-2),2.18–2.10(m,3H,H-13'a,H-2'b,H-9'a),2.09–1.99(m,2H,H-8a,H-9'b),1.95–1.92(m,1H,H-7'),1.91(s,3H,H-15'),1.89–1.86(m,1H,H-9a),1.80–1.73(m,1H,H-9b),1.62–1.57(m,2H,H-8'),1.54–1.51(m,1H,H-3a),1.43–1.40(m,4H,H-15,H-3b),1.34(s,3H,H-14'),1.32–1.28(m,4H,H-14,H-13'b);13CNMR(150MHz,CDCl3)δC 180.4(C-12'),170.8(C-12),149.6(C-1),148.7(C-5),141.0(C-4'),140.8(C-11),139.7(C-3"),129.1(C-6",C-7"),128.5(C-4",C-5"),126.3(C-8"),125.3(C-3'),118.3(C-13),84.4(C-6),80.1(C-6'),75.9(C-10),72.3(C-1'),64.1(C-1"),62.1(C-10'),60.2(C-4),56.1(C-11'),52.9(C-3),52.6(C-5'),52.5(C-7'),46.2(C-7),44.4(C-2),39.3(C-2'),37.3(C-2"),36.9(C-9),34.3(C-13'),32.9(C-9'),24.9(C-14),23.2(C-8),22.7(C-14'),21.0(C-8'),18.7(C-15'),17.2(C-15);
Compound 7 structural data:
Traits: white solid
Yield: 12%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 38H44O6[M+H]+ 597.3211, found 597.3219.
IRνmax 1767,1623,1460,1378,1262,1096,1022,863,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(600MHz,CDCl3)δH 7.23(m,4H,H-4",H-5",H-6",H-7"),7.18–7.14(m,1H,H-8"),6.13(d,J＝3.4Hz,1H,H-13a),5.59–5.55(m,2H,H-3',H-6),5.39(d,J＝3.2Hz,1H,H-13b),3.98(dd,J＝10.1,10.1Hz,1H,H-6'),3.37(dt,J＝13.8,6.7Hz,1H,H-1"a),3.31(dt,J＝14.2,6.5Hz,1H,H-1"b),2.87–2.80(m,2H,H-2"a,H-5'),2.79–2.69(m,3H,H-2"b,H-2,H-7,H-2'a),2.18–2.00(m,5H,H-2'b,H-9',H-13'a,H-8a),1.98(s,3H,H-15'),1.96–1.89(m,3H,H-8b,H-13'a,H-7'),1.80–1.74(m,1H,H-9b),1.758–1.56(m,3H,H-8'a,H-3a),1.51–1.47(m,1H,H-8'b),1.38(s,3H,H-15),1.35–1.32(m,4H,H-14',H-3b),1.28(s,3H,H-14);13C NMR(150MHz,CDCl3)δC 179.5(C-12'),170.6(C-12),149.6(C-1),147.5(C-5),141.3(C-4'),140.5(C-11),139.5(C-3"),129.5(C-6",C-7"),128.3(C-4",C-5"),126.2(C-8"),125.1(C-3'),118.6(C-13),83.6(C-6),79.8(C-6'),76.5(C-10),72.3(C-1'),64.0(C-1"),62.1(C-10'),59.3(C-4),55.9(C-11'),55.4(C-3),52.6(C-5'),52.6(C-7'),46.8(C-7),42.9(C-2),39.3(C-2'),37.1(C-2"),36.2(C-9),34.1(C-13'),33.0(C-9'),24.5(C-14),24.3('C-8),22.7(C-14'),21.0(C-8'),18.8(C-15'),17.0(C-15);
Example 5
Preparation of Compound 8:
lavandiolide I (100 mg,0.34mmol,1.0 eq) was weighed into a 10mL round bottom flask, dissolved by adding DCM (5 mL), then HF. Py (30. Mu.L, 0.51mmol,1.5 eq) was added, the reaction was allowed to proceed for 12 hours, after the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, then extracted with dichloromethane (10 mL. Times.3), the organic phases combined, washed once with saturated NaCl solution, H 2 O and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography [ petroleum ether-acetone, 95:5 (v/v) ] to give compound 8.
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H34O5[M+H]+ 475.2479, found 475.2470.
IRνmax 1766,1624,1461,1378,1096,1023,862,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.13(d,J＝3.5Hz,1H,H-13a),5.59–5.52(m,2H,H-6,H-3'),5.41(d,J＝3.3Hz,1H,H-13b),5.15(d,J＝1.6Hz,1H,H-14a),5.10(d,J＝1.6Hz,1H,H-14b),4.01(dd,J＝10.1,10.1Hz,1H,H-6'),3.07–2.96(m,2H,H-2,H-7),2.88–2.80(m,1H,H-7'),2.81–2.72(m,1H,H-2'a),2.46–2.37(m,2H,H-13'),2.20–2.09(m,3H,H-9'a,H-9a,H-2'b),2.08–1.94(m,1H,H-9b),1.91(m,4H,H-5',H-14),1.76–1.66(m,1H,H-8a),1.64–1.60(m,1H,H-8'),1.60–1.57(m,1H,H-3a),1.47(m,1H,H-3b),1.45(s,3H,H-15'),1.34(s,3H,H-14'),1.31–1.25(m,1H,H-9'b);13C NMR(125MHz,CDCl3)δC 180.3(C-12'),170.5(C-12),148.0(C-1),146.8(C-5),141.9(C-10),140.9(C-4'),140.2(C-11),125.1(C-3'),118.6(C-13),115.8(C-14),84.1(C-6),79.9(C-6'),72.1(C-1'),62.0(C-10'),59.6(C-4),56.7(C-11'),52.5(C-5'),52.3(C-7'),51.8(C-3),47.1(C-7),43.8(C-2),39.1(C-2'),34.1(C-13'),33.4(C-9'),32.7(C-9),27.3(C-8),22.5(C-14'),20.8(C-8'),18.5(C-15'),16.2(C-15);
Example 6
Preparation of Compounds 9-10:
Lavandiolide I (80 mg,0.27mmol,1.0 eq) was weighed into a 10mL three-necked round bottom flask under Ar protection, dissolved in DCM (5 mL) and cooled to-40℃followed by slow dropwise addition of TFA (120. Mu.L, 1.35mmol,5.0 eq) and reaction for 15 min, quenched by addition of saturated NaHCO 3 solution after completion of the reaction, extracted with dichloromethane (10 mL. Times.3), the organic phases combined and washed once with saturated NaCl solution, H 2 O and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography [ petroleum ether-acetone, 95:5 (v/v) ] to give compounds 9 and 10.
Compound 9 structural data:
Traits: white solid
Yield: 35%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H36O5[M+H]+ 477.2636, found 477.2628.
IRνmax 1769,1620,1461,1378,1262,1097,1023,863,803cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(600MHz,CDCl3)δH 6.13(d,J＝3.5Hz,1H,H-13a),5.57–5.53(m,1H,H-3'),5.49–5.45(m,1H,H-6),4.02–3.95(dd,J＝10.3,10.1Hz,1H,H-6'),2.91(m,1H,H-7),2.85–2.80(m,2H,H-2,H-5'),2.79–2.73(m,1H,H-2'a),2.68(m,1H,H-10),2.21–2.09(m,4H,H-13'a,H-2'b,H-9a,H-8a),2.06–1.98(m,1H,H-8b),1.93(s,3H,H-15'),1.78(m,1H,H-7'),1.72–1.64(m,2H,H-9'a,H-8'b),1.63–1.56(m,3H,H-9a,H-9'b,H-3a),1.53(m,1H,H-8'b),1.40(s,3H,H-15),1.38–1.34(m,2H,H-3b,H-13'b),1.34(s,3H,H-14'),1.08(d,J＝7.3Hz,3H,H-14);13C NMR(150MHz,CDCl3)δC 180.1(C-11'),170.6(C-11),151.2(C-1),143.8(C-5),141.0(C-4'),140.5(C-12),125.0(C-3'),118.8(C-13),85.0(C-6),79.7(C-6'),72.1(C-1'),61.9(C-10'),59.5(C-4),55.5(C-11'),53.4(C-3),52.4(C-7′),52.4(C-5'),46.9(C-7),45.2(C-2),39.1(C-2'),34.5(C-13'),33.3(C-10),33.0(C-9′),32.8(C-8),25.5(C-9),22.5(C-14'),20.9(C-8'),18.7(C-14),18.5(C-15'),16.8(C-15);
Compound 10 structural data:
Traits: white solid
Yield: 16%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H36O5[M+H]+ 477.2636, found 477.2616;
IRνmax 1768,1632,1461,1377,1261,1095,1023,862,803cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(600MHz,CDCl3)δH 6.16(d,J＝2.9Hz,1H,H-13a),5.48–5.44(m,1H,H-3'),5.42(d,J＝2.5Hz,1H,H-6),5.35(d,J＝2.5Hz,1H,H-13b),3.84(dd,J＝10.2Hz,1H,H-6'),3.32–3.21(m,1H,H-7),2.80–2.63(m,2H,H-2,H-5'),2.62–2.53(m,1H,H-10),2.51(m,1H,H-2'a),2.05(m,3H,H-13'a,H-2'b,H-8a),1.95–1.88(m,1H,H-8b),1.84(s,3H,H-15'),1.78(m,1H,H-7'),1.67(m,3H,H-9'a,H-8'a),1.53(m,4H,H-9'b,H-9b,H-3a,H-13'b),1.42–1.33(m,2H,H-3b,H-8'b),1.29(s,3H,H-15),1.26(s,3H,H-14'),0.94(d,J＝7.1Hz,3H,H-14);13C NMR(150MHz,CDCl3)δC 178.9(C-12'),170.6(C-12),148.3(C-1),141.4(C-5),140.6(C-4'),139.1(C-11),124.6(C-3'),120.2(C-13),79.0(C-6'),78.1(C-6),72.2(C-1'),61.9(C-10'),58.8(C-4),55.2(C-11'),55.2(C-3),52.2(C-7'),51.9(C-5'),45.1(C-7),45.0(C-2),39.1(C-2'),35.9(C-10),35.3(C-13'),32.9(C-9'),31.3(C-8),26.8(C-9),22.5(C-14'),21.2(C-8'),18.8(C-14),18.6(C-15'),15.9(C-15);
Example 7
Preparation of Compounds 11-21:
The corresponding sesquiterpenes (0.2 mmol,1.0 eq) were weighed separately into a 150mL round bottom flask, diene (0.2 mmol,1.0 eq) was added, and 10mL dichloromethane was added again to dissolve, concentrated under reduced pressure to a solvent-free state, reacted at 50 ℃ for 24h, and the crude product was isolated by column chromatography and used for the next reaction. The sample was dissolved in 15mL of methanol at room temperature, methyl iodide (1.0 mmol,5.0 eq) was added with stirring, the reaction was quenched by adding saturated NaHCO 3 solution after 3H, then extracted with dichloromethane (10 mL. Times.3), the organic phases were mixed, washed once with saturated NaCl solution, H 2 O and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography to give compounds 11-21.
Compound 11 structural data:
Traits: white solid
Yield: 45%
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 30H36O7[M+Na]+ 531.2353, found 531.2330;
IRνmax 3447,1768,1628,1445,1383,1320,1261,1232,1149,1091,1007,817cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.14(d,J＝3.5Hz,1H,H-13a),5.53(d,J＝10.1Hz,1H,C-6),5.43(d,J＝3.2Hz,1H,H-13b),4.11(dd,J＝10.2,10.0Hz,1H,H-6'),3.28(m,1H,H-3'),3.03–2.99(m,1H,H-2),2.84–2.75(m,1H,H-7),2.38(d,J＝10.2Hz,1H,H-5'),2.33(dd,J＝15.5,1.5Hz,1H,H-2'a),2.19(dd,J＝12.3,3.6Hz,1H,H-13'a),2.15–2.03(m,2H,H-8,H-9'a),2.02–1.95(m,1H,H-9a),1.95–1.91(m,2H,H-7',H-9'b),1.90–1.87(m,1H,H-2'b),1.86–1.83(m,1H,H-8a),1.80–1.74(m,1H,H-9b),1.62(s,3H,H-15'),1.55–1.50(m,2H,H-8'),1.50–1.47(m,2H,H-13'b,H-3a),1.40(s,3H,H-15),1.39(s,3H,H-14),1.35–1.31(m,1H,H-3b),1.26(s,3H,H-14');13C NMR(125MHz,CDCl3)δC180.6(C-12'),170.2(C-12),150.7(C-1),145.1(C-5),140.0(C-11),118.9(C-13),83.9(C-6),77.8(C-6'),72.4(C-10),69.2(C-10'),65.8(C-4'),62.6(C-3'),60.2(C-4),58.8(C-1'),56.1(C-11'),53.6(C-3),51.7(C-7'),50.0(C-5'),46.8(C-7),42.7(C-2),38.4(C-9),36.0(C-2'),34.8(C-13'),32.7(C-9'),27.7(C-14),23.7(C-8),22.5(C-14'),20.6(C-8'),18.9(C-15'),17.1(C-15);
Compound 12 structural data:
Traits: white solid
Yield: 23%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H38O6[M+H]+ 495.2741, found 495.2722;
IRνmax 3479,1763,1620,1461,1378,1262,1096,1023,863,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.14(d,J＝3.5Hz,1H,H-13a),5.52(d,J＝10.1Hz,1H,H-6),5.42(d,J＝3.2Hz,1H,H-13b),3.86(dd,J＝10.1Hz,1H,H-6'),3.70(m,1H,H-4'),3.01(m,1H,H-2),2.80(m,1H,H-7),2.32(m,1H,H-9'a),2.19(dd,J＝12.2,3.6Hz,1H,H-13′a),2.09(m,3H,H-8a,H-3'a,H-7'),2.05–1.82(m,4H,H-9'b,H-9a,H-5',H-8b),1.78–1.70(m,2H,H-3'b,H-9b),1.66–1.61(m,1H,H-2'a),1.53(m,2H,H-2'b,H-8'a),1.50–1.46(m,2H,H-8'b,H-13'a),1.40(s,3H,H-14),1.38(s,3H,H-15),1.31(s,3H,H-14'),1.23(m,2H,H-3),1.18(d,J＝6.4Hz,3H,H-15');13C NMR(125MHz,CDCl3)δC181.1(C-12'),170.2(C-12),150.6(C-1),145.1(C-5),140.0(C-11),118.8(C-13),83.9(C-6),81.5(C-6'),73.6(C-10'),72.4(C-10),62.5(C-1'),60.3(C-4),56.3(C-11'),53.6(C-3),52.9(C-7'),51.3(C-5'),46.8(C-7),42.7(C-2),39.2(C-4'),38.4(C-9),34.8(C-13′),32.8(C-9'),32.8(C-2'),31.3(C-3'),27.6(C-14),23.7(C-8),23.2(C-14'),21.3(C-15'),21.1(C-8'),17.3(C-15);
Compound 13 structural data:
Traits: white solid
Yield: 30%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H38O6[M+H]+ 495.2741, found 495.2738;
IRνmax 3442,1767,1621,1461,1378,1096,1020,804cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.15(d,J＝3.5Hz,1H,H-13a),5.52(d,J＝10.1Hz,1H,H-6),5.43(d,J＝3.2Hz,1H,H-13b),3.91(dd,J＝10.3,10.1Hz,1H,H-6'),3.04–3.00(m,1H,H-2),2.85–2.75(m,1H,H-7),2.52(m,1H,H-4'),2.21(dd,J＝12.2,3.6Hz,1H,H-13′a),2.17–2.07(m,4H,H-8a,H-3'a,H-9'a,H-7'),2.02–1.94(m,3H,H-9'b,H-9a,H-5'),1.91–1.85(m,1H,H-8b),1.80–1.74(m,2H,H-3'b,H-9b),1.73–1.66(m,1H,H-2'a),1.63–1.59(m,1H,H-2'b),1.55(m,1H,H-8′a),1.50(m,2H,H-8′b,H-13′a),1.40(s,6H,H-14,H-15),1.35–1.31(m,1H,H-3b),1.31(s,3H,H-14'),1.06(d,J＝7.0Hz,3H,H-15');13CNMR(125MHz,CDCl3)δC181.3(C-12'),170.2(C-12),150.4(C-1),145.4(C-5),140.0(C-11),118.9(C-13),84.0(C-6),78.7(C-6'),72.5(C-10),71.2(C-10'),60.7(C-1'),60.5(C-4),56.7(C-11'),53.6(C-3),50.8(C-7'),50.5(C-5'),46.9(C-7),42.7(C-2),38.5(C-9),36.4(C-4'),34.9(C-13′),33.3(C-9'),30.7(C-2'),30.3(C-3'),27.7(C-14),23.7(C-14′),23.7(C-8),21.2(C-8′),17.4(C-15),14.9(C-15');
Compound 14 structural data:
Traits: white solid
Yield: 43%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H36O5[M+H]+ 477.2636, found 477.2624;
IRνmax 3340,1764,1633,1455,1378,1261,1094,1022,804cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.13(d,J＝3.4Hz,1H,H-13a),5.52(d,J＝10.1Hz,1H,H-6),5.50–5.47(m,1H,H-3'),5.42(d,J＝3.2Hz,1H,H-13b),3.55(dd,J＝10.0,10.0Hz,1H,H-6),3.31(d,J＝10.0Hz,1H,H-5'),3.02–2.99(m,1H,H-2),2.95–2.91(m,2H,H-2'),2.85–2.76(m,1H,H-7),2.46(dt,J＝12.6,3.1Hz,1H,H-7'),2.31-2.26(m,1H,H-9'a),2.15–2.04(m,3H,H-13'a,H-8a,H-9'b),1.98(ddd,J＝12.7,10.0,5.8Hz,1H,H-9a),1.88(s,3H,H-15),1.69(s,3H,H-14'),1.51-1.45(m,4H,H-13'b,H-15'),1.46–1.40(m,1H,H-3a),1.38(s,3H,H-14),1.35–1.31(m,1H,H-3b);13C NMR(125MHz,CDCl3)δC 180.8(C-12'),170.1(C-12),150.9(C-1),144.9(C-5),141.3(C-4'),140.1(C-11),135.5(C-10'),131.5(C-1'),126.2(C-3'),118.7(C-13),83.8(C-6),82.3(C-6'),72.4(C-10),60.1(C-4),56.3(C-11'),55.8(C-5'),54.2(C-7'),53.5(C-3),46.7(C-7),42.7(C-2),38.3(C-9),37.0(C-2'),35.0(C-13'),33.6(C-9'),27.4(C-14),25.8(C-8'),23.6(C-8),22.3(C-14'),18.0(C-15'),17.1(C-15);
Compound 15 structural data:
Traits: white solid
Yield: 55%
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 30H36O6[M+HCOO]- 537.2494, found 537.2486;
IRνmax 3485,1767,1623,1460,1384,1261,1097,1025,803cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.15(d,J＝3.5Hz,1H,H-13a),5.58–5.55(m,1H,H-3'),5.51(d,J＝10.1Hz,1H,H-6),5.43(d,J＝3.0Hz,1H,H-13b),3.72(dd,J＝10.5,10.1Hz,1H,H-6'),3.06–3.02(m,1H,H-2),2.85–2.76(m,2H,H-2'a,H-7),2.55(d,J＝10.8Hz,1H,H-5'),2.33(dt,J＝10.8,3.0Hz,1H,H-7'),2.27(m,1H,H-9'a),2.19–2.10(m,3H,H-13'a,H-8a,H-2'b),1.99(m,1H,H-9a),1.94–1.92(m,3H,H-15'),1.85–1.74(m,2H,H-9b,H-8'a),1.53(m,1H,H-9'b),1.51(m,1H,H-13'b),1.48(m,1H,H-8'b),1.45(s,3H,H-15),1.39(s,3H,H-14),1.38–1.35(m,1H,H-3),1.33(s,3H,H-14');13C NMR(125MHz,CDCl3)δC180.3(C-12'),170.0(C-12),150.7(C-1),145.0(C-5),141.7(C-4'),139.9(C-11),124.6(C-3'),118.9(C-13),83.7(C-6),81.9(C-6'),72.5(C-10),71.7(C-1'),62.6(C-10'),60.3(C-4),56.9(C-5'),56.4(C-11'),53.5(C-3),52.7(C-7'),46.7(C-7),42.7(C-2),38.4(C-9),37.8(C-2'),37.0(C-9'),35.0(C-13'),27.5(C-14),23.6(C-8),23.0(C-8'),20.0(C-14′),18.1(C-15'),17.1(C-15);
Compound 16 structural data:
Traits: white solid
Yield: 46%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 31H40O7[M+H]+ 525.2847, found 525.2836;
IRνmax 3500,1743,1621,1462,1377,1261,1096,1022,802cm-1；；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.15(d,J＝3.5Hz,1H,H-13a),5.54(d,J＝10.1Hz,1H,H-6),5.44(d,J＝3.2Hz,1H,H-13b),5.41–5.37(m,1H,H-3'),4.11(dd,J＝10.4,10.4Hz,1H,H-6'),3.28–3.24(m,1H,H-7'),3.24(s,3H,H-1"),3.04–3.01(m,1H,H-2a),2.89–2.83(m,1H,H-2'),2.82–2.76(m,1H,H-7),2.72-2.65(m,1H,H-7'),2.19-2.14(m,2H,H-13'a,H-8a),2.05–1.96(m,3H,H-9'a,H-9a,H-2a),1.94–1.87(m,1H,H-8b),1.86–1.83(m,4H,H-8'a,H-15),1.80–1.74(m,1H,H-9b),1.73–1.68(m,1H,H-8'b),1.68–1.64(m,1H,H-9'a),1.58–1.55(m,1H,H-3a),1.47(s,3H,H-15'),1.40(s,3H,H-14),1.34–1.30(m,1H,H-3b),1.25(d,J＝1.2Hz,1H,H-9'b),1.19(s,3H,H-14');13C NMR(125MHz,CDCl3)δC 182.1(C-12'),170.2(C-12),149.9(C-1),145.9(C-5),141.9(C-4'),139.9(C-11),122.1(C-3'),118.8(C-13),89.2(C-10'),84.2(C-6),82.0(C-6'),78.3(C-1'),72.4(C-10),61.1(C-4),55.8(C-11'),54.5(C-5'),53.6(C-3),48.6(C-1"),47.0(C-7),43.9(C-2'),43.0(C-7'),42.9(C-2),38.5(C-9),34.3(C-13'),29.5(C-9'),28.0(C-14),23.9(C-8),23.0(C-8'),22.5(C-14'),17.8(C-15'),17.5(C-15);
Compound 17 structural data:
Traits: white solid
Yield: 53%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H36O6[M+H]+ 493.2585, found 493.2596;
IRνmax 3439,1762,1634,1460,1378,1262,1096,1023,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.15(d,J＝3.5Hz,1H,H-13a),5.55–5.52(m,1H,H-3'),5.50(d,J＝10.1Hz,1H,H-6),5.43(d,J＝3.2Hz,1H,H-13b),5.15(br s,1H,H-14'a),5.06(br s,1H,H-14'b),3.66(dd,J＝10.1,10.1Hz,1H,H-6'),3.05–3.00(m,1H,H-2),2.93(m,1H,H-2'a),2.84–2.77(m,1H,H-7),2.64(d,J＝10.3Hz,1H,H-5'),2.56(dt,J＝12.1,4.9Hz,1H,H-7'),2.45–2.41(m,2H,H-9'),2.41–2.34(m,1H,H-2'),2.20–2.15(m,1H,H-13'a),2.15–2.08(m,1H,H-8'a),2.08–2.05(m,1H,H-8a),2.02–1.94(m,3H,H-8b,H-9a),1.92(s,3H,H-15'),1.86–1.73(m,2H,H-8'b,H-9b),1.48(s,3H,H-15),1.44–1.40(m,1H,H-13'b),1.43–1.36(m,1H,H-3a),1.38(s,3H,H-14),1.34–1.30(m,1H,H-3b);13C NMR(125MHz,CDCl3)δC 180.6(C-12'),170.1(C-12),151.8(C-10'),150.8(C-1),144.7(C-5),140.9(C-4'),139.9(C-11),124.4(C-3'),118.9(C-13),114.9(C-15'),84.7(C-1'),83.8(C-6),80.0(C-6'),72.4(C-10),63.1(C-5'),60.4(C-4),56.0(C-11'),53.2(C-3),50.5(C-7'),46.8(C-7),43.8(C-2'),42.9(C-2),38.5(C-9),35.1(C-13'),30.8(C-9'),30.5(C-8),27.7(C-14),23.7(C-8'),18.5(C-15'),17.2(C-15);
Compound 18 structural data:
Traits: white solid
Yield: 56%
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 30H36O7[M+Na]+ 503.2353, found 503.2348;
IRνmax 3495,1770,1749,1639,1462,1374,1261,1158,1028,814cm-1；；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.15(d,J＝3.5Hz,1H,H-13a),5.48(d,J＝10.1Hz,1H,H-6),5.43(d,J＝3.2Hz,1H,H-13b),4.86–4.81(m,2H,H-15'),3.80(dd,J＝10.1,10.1Hz,1H,H-6'),3.34(br s,1H,H-3'),3.04-3.01(m,1H,H-1'),2.90–2.84(m,1H,H-2),2.84–2.76(m,1H,H-7),2.55-2.48(m,1H,H-7'),2.42–2.33(m,2H,H-5',H-9'a),2.22(dd,J＝12.3,3.8Hz,1H,H-13'a),2.20-2.15(m,1H,H-2'a),2.15–2.04(m,1H,H-9'b),2.04–1.97(m,1H,H-9),1.90–1.82(m,2H,H-8a,H-8'a),1.80–1.73(m,2H,H-2'b,H-13'b),1.59(s,3H,H-14'),1.49–1.46(m,1H,H-8'b),1.46(s,3H,H-15),1.40(s,3H,H-14),1.39–1.38(m,1H,H-3a),1.33–1.29(m,1H,H-3b);13C NMR(125MHz,CDCl3)δC 180.7(C-12'),170.1(C-12),150.7(C-1),148.5(C-10'),144.6(C-5),139.9(C-11),118.9(C-13),112.7(C-14'),83.7(C-6),78.1(C-6'),72.5(C-10),65.9(C-4'),62.8(C-3'),61.0(C-4),55.5(C-11'),53.1(C-3),49.9(C-5'),49.0(C-7'),46.8(C-7),43.2(C-2),43.0(C-1'),38.5(C-9),35.5(C-13'),32.3(C-9'),32.1(C-2'),29.7(C-8'),27.9(C-14),23.7(C-8),19.3(C-15'),17.2(C-15);
Compound 19 structural data:
Traits: white solid
Yield: 35%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H36O7[M+H]+ 503.2377, found 503.2373;
IRνmax 3434,1765,1692,1646,1461,1378,1262,1097,1022,463,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.19–6.14(m,2H,H-13a,H-3'),5.56(d,J＝10.1Hz,1H,H-6'),5.45(d,J＝3.2Hz,1H,H-13b),3.86(td,J＝10.2,2.2Hz,1H,H-8'),3.55(t,J＝10.1Hz,1H,H-6'),3.47–3.40(m,1H,H-7'),3.02–2.94(m,2H,H-2,H-9'a),2.87–2.78(m,1H,H-7),2.70(t,J＝10.0Hz,1H,H-8a),2.41–2.39(m,3H,H-14'),2.37(dd,J＝8.9,1.6Hz,1H,H-3b),2.33(d,J＝2.3Hz,1H,H-9'a),2.29(t,J＝1.1Hz,3H,H-15'),2.21(dd,J＝12.0,3.6Hz,1H,H-9a),2.15–2.09(m,1H,H-8a),2.07–1.93(m,1H,H-13'a),1.85(m,2H,H-8b),1.77(dt,J＝13.3,5.5Hz,1H,H-13'b),1.60(s,3H,H-15),1.57(d,J＝2.5Hz,1H,H-9b),1.40(s,3H,H-14');13C NMR(125MHz,CDCl3)δC 195.2(C-2'),179.5(C-12'),171.0(C-12),150.5(C-1),149.7(C-10'),146.1(C-1'),144.4(C-5),140.1(C-11),136.0(C-3'),133.7(C-4'),118.9(C-13),84.3(C-6),79.3(C-6'),72.5(C-10),64.8(C-8'),61.7(C-4),59.0(C-5'),58.6(C-12'),54.3(C-3),51.0(C-7'),49.0(C-9'),46.8(C-7),42.9(C-2),38.3(C-13'),35.6(C-9),27.7(C-14),23.9(C-8),20.6(C-14'),20.2(C-15'),16.8(C-15);
Compound 20 structural data:
Traits: white solid
Yield: 30%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H36O7[M+H]+ 509.2550, found 509.2534;
IRνmax 3438,1765,1623,1461,1378,1262,1096,1023,864,803cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.15(d,J＝3.5Hz,1H,H-13a),5.79(q,J＝1.2Hz,1H,H-3'),5.52(d,J＝10.1Hz,1H,H-6),5.44(d,J＝3.1Hz,1H,H-13b),4.32–4.24(m,1H,H-2'),3.92(dd,J＝10.2,10.2Hz,1H,H-6'),3.11(dt,J＝10.5,2.0Hz,1H,H-5'),3.04–3.01(m,1H,H-2),2.80(dt,J＝13.2,5.2Hz,1H,H-7),2.20(dd,J＝12.2,3.6Hz,1H,H-13'a),2.16–2.08(m,3H,H-8a,H-9'a,H-9'b),2.04–2.00(m,1H,H-9a),1.99–1.98(s,3H,H-15'),1.98–1.95(m,1H,H-7'),1.87(s,1H,H-8b),1.80–1.74(m,1H,H-9b),1.63–1.57(m,3H,H-8',H-3a),1.53(s,3H,H-14'),1.48(dd,J＝12.2,2.6Hz,1H,H-13'b),1.42(s,3H,H-15),1.40(s,3H,H-15'),1.37–1.33(m,1H,H-3b);13C NMR(125MHz,CDCl3)δC180.8(C-12'),170.1(C-12),150.5(C-1),149.4(C-4'),145.4(C-5),139.9(C-11),128.7(C-3'),119.0(C-13),83.9(C-6),80.0(C-6'),79.9(C-2'),73.2(C-10'),72.5(C-10),63.8(C-1'),60.4(C-4),55.8(C-11'),53.6(C-3),51.9(C-7'),50.4(C-5'),46.8(C-7),42.7(C-2),38.5(C-9),34.9(C-13'),33.5(C-9'),27.7(C-14),23.7(C-8),22.8(C-14'),21.0(C-8'),18.8(C-15'),17.2(C-15);
Compound 21 structural data:
Traits: white solid
Yield: 63%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H34O5[M+H]+ 475.2479, found 475.2495;
IRνmax 3452,1766,1617,1461,1378,1262,1096,1023,864,802cm-1；；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.12(d,J＝3.5Hz,1H,H-13a),5.56(d,J＝9.7Hz,1H,H-6),5.51–5.48(m,1H,H-3'),5.41(d,J＝3.3Hz,1H,H-13b),5.15–5.08(m,2H,H-15),4.16–4.07(m,2H,H-15'),3.65(dd,J＝10.0,10.0Hz,1H,H-6'),3.41(d,J＝10.0Hz,1H,H-5'),3.13–3.03(m,2H,H-2'),3.03–2.96(m,2H,H-2,H-7),2.56–2.48(m,2H,H-9'a,H-7'),2.43–2.33(m,2H,H-13'),2.24-2.17(m,1H,H-9'b),2.17–2.09(m,2H,H-8a,H-9a),1.93-1.87(m,4H,H-14,H-8'a),1.73–1.66(m,1H,H-8b),1.52(s,3H,H-15),1.51–1.41(m,3H,H-3,H-8'b),1.27–1.23(m,1H,H-9b);13C NMR(125MHz,CDCl3)δ179.8(C-12'),170.5(C-12),148.0(C-1),146.6(C-5),141.9(C-4'),141.0(C-1'),140.2(C-10),140.0(C-11),134.6(C-10'),125.8(C-3'),118.5(C-13),115.8(C-14),84.1(C-6),81.6(C-6'),64.9(C-14'),59.6(C-4),57.1(C-11'),56.0(C-5'),54.5(C-7'),51.7(C-3),47.1(C-7),44.0(C-2),35.9(C-2'),34.2(C-13'),33.5(C-9),28.9(C-9'),27.2(C-8),26.5(C-8'),17.9(C-15),16.2(C-15');
Example 8
Preparation of compound 22:
Compound 21 (50 mg,0.1mmol,1.0 eq) was weighed into a 10mL three-necked round bottom flask under Ar protection, dissolved in DCM (3 mL), cooled to 0 ℃, then slowly added Dess-Martin periodinane (70 mg,0.2mmol,2.0 eq) and allowed to react for 8 hours after natural warming to room temperature. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography [ petroleum ether-acetone, 85:15 (v/v) ] to give compound 22 (white solid, 82%).
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H34O6[M+H]+ 491.2418, found 491.2428;
IRνmax 3445,1765,1668,1449,1379,1229,1153,1108,1013,816cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 9.91(s,1H,H-14'),6.15(d,J＝3.5Hz,1H,H-13a),5.62–5.57(m,1H,H-3'),5.52(d,J＝10.1Hz,1H,H-6),5.43(d,J＝3.2Hz,1H,H-13b),3.69(d,J＝10.2Hz,1H,H-5'),3.63(dd,J＝9.9,9.9Hz,1H,H-6'),3.71–3.58(m,3H,H-5',C-6',H-2'),3.17(ddd,J＝14.5,6.2,1.8Hz,1H,H-9'a),3.04–2.98(m,1H,H-2),2.85–2.78(m,1H,H-7),2.59(dt,J＝12.5,3.0Hz,1H,H-7'),2.16–2.07(m,2H,H-8a,C-13'a),2.02–1.96(m,1H,H-9a),1.95(s,3H,H-15'),1.93–1.85(m,2H,H-9'b,H-8'a),1.84–1.69(m,2H,H-8b,C-2'b),1.50(s,3H,H-15),1.45–1.40(m,2H,H-13'b,H-3a),1.39(s,3H,H-14),1.37-1.34(m,1H,H-3b),1.30–1.24(m,1H,H-8'b);13C NMR(125MHz,CDCl3)δC190.8(C-14'),179.9(C-12'),170.1(C-12),164.6(C-1'),150.9(C-1),144.9(C-5),140.0(C-4'),139.9(C-11),136.2(C-10'),125.2(C-3'),118.9(C-13),83.7(C-6),80.4(C-6'),72.5(C-10),60.2(C-4),58.4(C-5'),56.2(C-11'),54.2(C-7'),53.5(C-3),46.7(C-7),42.8(C-2),38.4(C-9),35.4(C-2'),34.9(C-13'),27.5(C-14),25.6(C-8'),23.6(C-8),22.5(C-9'),17.6(C-15'),17.1(C-15);
Example 9
Preparation of compound 23:
Compound 22 (40 mg,0.08mmol,1.0 eq) was weighed into a 10mL three-necked round bottom flask under Ar protection, t-BuOH/H 2 O/THF (1:1:4) (6.0 mL) was added to dissolve, naH 2PO4 (40 mg) was added in sequence, 2-methylbut-2-ene (80 μl) was cooled to 0 ℃, then NaClO 2 (40 μl) was slowly added, and the reaction was carried out after naturally warming to room temperature for 8 hours. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with methylene chloride (10 ml. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was isolated by column chromatography [ petroleum ether-acetone, 75:25 (v/v) ] to give compound 23 (white solid, 63%).
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 30H34O7[M+H]+ 507.2373, found 507.2377;
IRνmax 3437,1768,1702,1638,1460,1378,1262,1096,1022,865,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.15(d,J＝3.5Hz,1H,H-13a),5.60–5.56(m,1H,H-3'),5.52(d,J＝10.1Hz,1H,H-6),5.43(d,J＝3.2Hz,1H,H-13b),3.63–3.55(m,2H,H-5',H-6'),3.54–3.40(m,2H,H-2'),3.14–3.07(m,1H,H-8'),3.04–3.00(m,1H,H-2),2.87–2.78(m,1H,H-7),2.60(dt,J＝12.6,3.5Hz,1H,H-7'),2.20(dt,J＝13.2,3.5Hz,1H,H-8'b),2.14–2.08(m,2H,H-8a,H-13'a),2.02-1.95(m,1H,H-9a),1.93(s,3H,H-15'),1.91–1.86(m,1H,H-9'a),1.83–1.75(m,2H,H-8b,H-9b),1.50(s,3H,H-15),1.49–1.47(m,1H,H-13'b),1.45–1.40(m,2H,H-9'b,H-3a),1.39(s,3H,H-14),1.37–1.34(m,1H,H-3b);13C NMR(125MHz,CDCl3)δC 180.1(C-12'),172.4(C-14'),162.6(C-1'),170.1(C-12),151.2(C-1),144.5(C-5),140.0(C-11),139.1(C-4'),127.3(C-10'),126.7(C-3'),119.0(C-13),83.6(C-6),80.4(C-6'),72.6(C-10),60.0(C-4),58.3(C-5'),56.3(C-11'),54.5(C-7'),53.5(C-3),46.7(C-7),42.8(C-2),40.3(C-2'),38.3(C-9),34.9(C-13'),27.3(C-14),27.1(C-8'),25.9(C-9'),23.5(C-8),17.7(C-15'),17.1(C-15);
Example 10
Preparation of compound 24:
Compound 23 (20 mg,0.04mmol,1.0 eq) was weighed into a 10mL three-necked round bottom flask, dissolved in DCM (3 mL) and reacted for 8 hours at room temperature after EDC (16 mg,0.08mmol,2.0 eq), DMAP (2 mg,0.01mmol,0.25 eq) and phenol (8 mg,0.08mmol,2.0 eq) were added. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography [ petroleum ether-acetone, 85:15 (v/v) ] to give compound 24 (white solid, 87%).
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 36H38O7[M+H]+ 583.2690, found 583.2684;
IRνmax 3439,1767,1637,1460,1378,1262,1096,1022,864,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(600MHz,CDCl3)δH 7.43–7.39(m,2H,H-4",H-5"),7.26–7.23(m,1H,H-6"),7.14–7.10(m,2H,H-4",H-5"),6.18(d,J＝3.5Hz,1H,H-13a),5.61(d,J＝2.7Hz,1H,H-6),5.57(d,J＝10.1Hz,1H,H-3'),5.46(d,J＝3.2Hz,1H,H-13b),3.74–3.65(m,2H,H-6',H-5'),3.62–3.48(m,2H,H-2'),3.26(dd,J＝14.7,6.5Hz,1H,H-13'a),3.05(br s,1H,H-2),2.88–2.80(m,1H,H-7),2.66(dt,J＝12.5,3.5Hz,1H,H-7'),2.34(dt,J＝13.4Hz,1H,H-9a),2.20(dd,J＝12.1,3.7Hz,1H,H-13'b),2.18–2.11(m,1H,H-8a),2.04–1.99(m,1H,H-2'a),1.97(s,3H,H-15'),1.88–1.77(m,3H,H-8'a,H-8b,H-2'b),1.59–1.55(m,1H,H-9b),1.54(s,3H,H-15),1.53–1.51(m,1H,H-8'b),1.47–1.45(m,7 1H,H-3a),1.42(s,3H,H-14),1.40–1.38(m,1H,H-3b);13C NMR(150MHz,CDCl3)δC 180.2(C-12'),170.3(C-12),166.1(C-14'),161.9(C-1"),151.1(C-1'),150.9(C-1),145.0(C-5),140.2(C-11),139.3(C-4'),129.7(C-4",C-5"),127.5(C-10'),126.8(C-3'),126.1(C-6"),121.9(C-2",C-3"),119.2(C-13),83.9(C-6),80.6(C-6'),72.8(C-10),60.4(C-4),58.5(C-5'),56.5(C-11'),54.8(C-7'),53.7(C-3),46.9(C-7),43.0(C-2),40.4(C-2'),38.7(C-9),35.2(C-13'),27.8(C-9'),27.7(C-14),26.2(C-8'),23.8(C-8),17.9(C-15'),17.3(C-15);
Example 11
Preparation of Compounds 25-26:
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compound 21 (50 mg,0.08mmol,1.0 eq) was weighed into a 10mL three-necked round bottom flask, dissolved in DCM (3 mL) and DMAP (4 mg,0.02mmol,0.25 eq) was added sequentially and acetic anhydride/benzoic anhydride (15. Mu.L/28.0 mg,0.12mmol,1.5 eq) was reacted at room temperature for 5 hours. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography [ petroleum ether-acetone, 85:15 (v/v) ] to give compounds 25-26.
Compound 25 structural data:
Traits: white solid
Yield: 99 percent of
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 32H38O7[M+H]+ 535.2690, found 535.2673;
IRνmax 3479,1767,1743,1619,1460,1378,1262,1097,1022,864,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.13(d,J＝3.5Hz,1H,H-13a),5.51(d,J＝10.1Hz,1H,H-6),5.50–5.47(m,1H,H-3'),5.42(d,J＝3.2Hz,1H,H-13b),4.57–4.47(m,2H,H-14'),3.59(dd,J＝10.0,10.0Hz,1H,H-6'),3.39(d,J＝10.0Hz,1H,H-5'),3.13–3.04(m,2H,H-2'),3.03–2.99(m,1H,H-2),2.84–2.76(m,1H,H-7),2.49(dt,J＝12.8,3.1Hz,1H,H-7'),2.30(dt,J＝14.8,1.9Hz,1H,H-9'a),2.15–2.08(m,3H,H-9'b,H-8a,H-13'a),2.06(s,3H,H-2"),1.98(dt,J＝11.3,4.2Hz,1H,H-9a),1.88(s,3H,H-15'),1.85–1.72(m,2H,H-8b,H-9b),1.53–1.48(m,1H,H-13'b),1.47(s,3H,H-15),1.44(dd,J＝8.7,1.6Hz,1H,H-3a),1.38(s,3H,H-14),1.33(dd,J＝8.7,2.1Hz,1H,H-3b);13C NMR(125MHz,CDCl3)δC 180.4(C-12'),171.1(C-1"),170.1(C-12),150.9(C-1),144.9(C-5),143.0(C-10'),140.8(C-4'),140.0(C-11),130.3(C-1'),125.8(C-3'),118.8(C-13),83.7(C-6),81.5(C-6'),72.4(C-10),66.5(C-14'),60.1(C-4),56.2(C-11'),56.2(C-5'),54.2(C-7'),53.5(C-3),46.7(C-7),42.7(C-2),38.4(C-9),36.2(C-2'),35.0(C-13'),29.4(C-9'),27.5(C-14),26.1(C-8'),23.6(C-8),21.0(C-2"),18.0(C-15'),17.1(C-15);
Compound 26 structural data:
Traits: white solid
Yield: 98 percent of
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 37H40O7[M+H]+ 597.2847, found 597.2843;
IRνmax 3447,1766,1719,1603,1459,1377,1262,1098,1023,862,803cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 8.05-8.00(m,2H,H-3",H-4"),7.59–7.54(m,1H,H-7"),7.47–7.42(m,2H,H-5",H-6"),6.15(d,J＝3.4Hz,1H,H-13a),5.53(m,2H,H-6,H-3'),5.43(d,J＝3.1Hz,1H,H-13b),4.85–4.73(m,2H,H-14'),3.64(dd,J＝10.0,10.0Hz,1H,H-6'),3.44(d,J＝10.0Hz,1H,H-5'),3.18(dd,J＝4.4,2.3Hz,2H,H-2'),3.04–2.99(m,1H,H-2),2.85–2.77(m,1H,H-7),2.53(dt,J＝12.6,3.1Hz,1H,H-7'),2.45(m,1H,H-9'a),2.33–2.24(m,1H,H-9'b),2.16–2.08(m,2H,H-13'a,H-8a),2.03–1.96(m,1H,H-9a),1.91(s,3H,H-15'),1.80(m,3H,H-8'a,H-8b,H-9b),1.53–1.49(m,1H,H-13'b),1.49(s,3H,H-15),1.45–1.41(m,2H,H-8'b,H-3a),1.39(s,3H,H-14),1.36–1.32(m,1H,H-3b);13C NMR(125MHz,CDCl3)δC 180.5(C-12'),166.6(C-1"),170.1(C-12),150.8(C-1),145.0(C-5),143.1(C-10'),140.8(C-4'),140.0(C-11),133.1(C-7"),130.4(C-1'),130.1(C-2"),129.6(C-3",C-4"),128.6(C-5",C-6"),125.8(C-3'),118.8(C-13),83.7(C-6),81.6(C-6'),72.5(C-10),66.9(C-14'),60.2(C-4),56.3(C-11'),56.2(C-5'),54.2(C-7'),53.6(C-3),46.8(C-7),42.8(C-2),38.4(C-9),36.3(C-2'),35.0(C-13'),29.5(C-9'),27.5(C-14),26.1(C-8'),23.6(C-8),17.9(C-15'),17.1(C-15);
Example 12
Preparation of compound 27:
compound 21 (50 mg,0.1mmol,1.0 eq) was weighed into a 10mL three-necked round bottom flask under Ar gas protection, dissolved in dry THF (3 mL) and DPPA (34 μl,0.15mmol,1.5 eq), DBU (23 μl,0.15mmol,1.5 eq) were added sequentially and reacted at room temperature for 5 hours. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography [ petroleum ether-acetone, 85:15 (v/v) ] to give compound 27 (white solid, 52%).
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 30H35N3O5[M+H]+ 518.2649, found 518.2651;
IRνmax 3517,3433,2101,1769,1759,1620,1460,1377,1262,1095,862,803cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 6.16(d,J＝3.5Hz,1H,H-13a),5.55(d,J＝10.1Hz,1H,H-6),5.52(m,1H,H-3'),5.44(d,J＝3.2Hz,1H,H-13b),3.91(d,J＝12.9Hz,1H,H-14'a),3.63(dd,J＝10.0,10.0Hz,1H,H-6'),3.69(d,J＝12.9Hz,1H,H-14'b),3.45(d,J＝9.9Hz,1H,H-5'),3.17–3.06(m,2H,H-2'),3.06–3.01(m,1H,H-2),2.85–2.78(m,1H,H-7),2.53(dt,J＝12.8,3.2Hz,1H,H-7'),2.35–2.31(m,2H,H-9'a,H-8a),2.21(d,J＝13.1Hz,1H,H-9'b),2.24–2.08(m,2H,H-9a,H-8b),2.03–1.94(m,1H,H-13'a),1.92(s,3H,H-15'),1.90–1.74(m,4H,H-8'a,H-13'b,H-8'b),1.50(s,3H,H-15),1.47–1.44(m,2H,H-9b,H-3a),1.41(s,3H,H-14),1.39–1.34(m,1H,H-3b);13C NMR(125MHz,CDCl3)δC180.2(C-12'),170.1(C-12),150.8(C-1),145.1(C-5),143.5(C-10'),141.2(C-4'),140.0(C-11),129.6(C-1'),125.5(C-3'),118.8(C-13),83.8(C-6),81.6(C-6'),72.5(C-10),60.1(C-4),56.2(C-5'),56.2(C-11'),55.5(C-14'),54.0(C-7'),53.5(C-3),46.8(C-7),42.8(C-2),38.5(C-9),36.6(C-2'),35.0(C-13'),30.6(C-9'),27.6(C-14),25.9(C-8'),23.6(C-8),17.9(C-15'),17.1(C-15);
Example 13
Preparation of Compound 28:
Compound 27 (200 mg,0.4mmol,1.0 eq) was weighed into a 25mL three-necked round bottom flask under Ar protection, THF-H 2 O (6 mL:0.6 mL) was added to dissolve, PPh 3 (200 mg,0.8mmol,2.0 eq) was added and reacted at room temperature for 12 hours. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was isolated by column chromatography [ Petroleum ether-acetone, 75:25 (v/v) ] to give the crude amino derivative (180 mg).
The crude amino derivative (30 mg,0.06mmol,1.0 eq) was weighed into a 10mL three-necked round bottom flask under Ar protection, dissolved in DCM (3 mL) and then Et 3 N (42. Mu.L, 0.3mmol,5.0 eq) and benzoic anhydride (20 mg,0.09mmol,1.5 eq) were added and reacted at room temperature for 5 hours. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography [ petroleum ether-acetone, 75:25 (v/v) ] to give compound 28 (white solid, 75%).
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 37H41NO6[M+Na]+ 618.2826, found 618.2818;
IRνmax 3419,1765,1643,1534,1460,1378,1262,1096,1023,865,803cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 7.79–7.74(m,2H,H-3",H-4"),7.53–7.47(m,1H,H-7"),7.44–7.39(m,2H,H-5",H-6"),6.41–6.35(m,1H,NH),6.11(d,J＝3.5Hz,1H,H-13a),5.54–5.49(m,2H,H-3',H-6),5.41(d,J＝3.2Hz,1H,H-13b),4.15(dd,J＝14.3,6.4Hz,1H,H-15'a),3.96(dd,J＝14.2,5.1Hz,1H,H-15'b),3.63(dd,J＝10.0,10.0Hz,1H,H-6'),3.39(d,J＝10.0Hz,1H,H-5'),3.20–3.07(m,2H,H-2'),2.99–2.97(br s,1H,H-2),2.83–2.75(m,1H,H-7),2.48(dt,J＝12.6,3.1Hz,1H,H-7'),72.37–2.31(m,1H,H-9'a),2.24–2.17(m,1H,H-9'b),2.12–2.09(m,2H,H-8a,H-13'a),2.01–1.94(m,1H,H-9a),1.89(s,,3H,H-15'),1.83–1.74(m,3H,H-8b,H-8'b,H-9b),1.47(dd,J＝12.1,2.5Hz,1H,H-13'b),1.44(s,3H,H-15),1.42–1.39(m,1H,H-3a),1.37(s,3H,H-14),1.33–1.29(m,1H,H-3b);13C NMR(125MHz,CDCl3)δC 180.4(C-12'),170.2(C-12),167.8(C-1"),150.9(C-1),144.9(C-5),141.0(C-1'),140.8(C-4'),140.0(C-11),134.4(C-10'),131.9(C-7"),131.5(C-2"),128.6(C-5",C-6"),126.9(C-3",C-4"),125.9(C-3'),118.9(C-13),83.9(C-6),81.6(C-6'),72.4(C-10),60.6(C-4),56.3(C-11'),56.2(C-5'),54.2(C-7'),53.5(C-3),46.7(C-7),43.9(C-14'),42.7(C-2),38.4(C-9),36.4(C-2'),34.9(C-13'),29.5(C-9'),27.5(C-14),26.3(C-8'),23.6(C-8),18.0(C-15'),17.1(C-15);
Example 14
Preparation of compound 29:
Compound 27 (200 mg,0.4mmol,1.0 eq) was weighed into a 25mL three-necked round bottom flask under Ar protection, THF-H 2 O (6 mL:0.6 mL) was added to dissolve, PPh 3 (200 mg,0.8mmol,2.0 eq) was added and reacted at room temperature for 12 hours. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was isolated by column chromatography [ Petroleum ether-acetone, 75:25 (v/v) ] to give the crude amino derivative (180 mg).
The crude amino derivative (30 mg,0.06mmol,1.0 eq) was weighed into a 10mL round bottom flask, dissolved in DCM (3.0 mL) and the triazole product VI (9. Mu.L, 0.09mmol,1.5 eq) was added and reacted at room temperature for 12 hours. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was isolated by column chromatography [ petroleum ether-acetone, 85:15 (v/v) ] to give compound 29 (white solid, 56%).
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 38H43NO7[M+H]+ 626.3112, found 626.3117;
IRνmax 3425,1765,1722,1619,1520,1459,1378,1261,1096,1022,864,803cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 7.38–7.29(m,5H,H-4",H-5",H-6",H-7",H-8"),6.14(d,J＝3.5Hz,1H,H-13a),5.53(d,J＝10.1Hz,1H,H-6),5.49(br s,1H,H-3'),5.43(d,J＝3.2Hz,1H,H-13b),5.11(s,2H,H-2"),3.86–3.71(m,2H,H-14'),3.60(dd,J＝10.0,10.0Hz,1H,H-6'),3.36(d,J＝10.0Hz,1H,H-5'),3.14–3.02(m,2H,H-2'),3.02-2.98(br s,1H,H-2),2.85–2.76(m,1H,H-7),2.48(dt,J＝10.6Hz,1H,H-7'),2.31–2.24(m,1H,H-9'a),2.21–2.07(m,3H,H-9'b,H-8a,H-13'a),2.02–1.95(m,1H,H-9a),1.89(s,3H,H-15'),1.85–1.75(m,3H,H-8b,H-8'a,H-9b),1.47(s,3H,H-15),1.45(m,1H,H-13'b),1.43–1.40(m,1H,H-3a),1.39(s,3H,H-14),1.36–1.32(m,1H,H-3b);13C NMR(125MHz,CDCl3)δC 180.5(C-12'),170.2(C-12),156.7(C-1"),150.8(C-1),145.0(C-5),141.0(C-4'),140.5(C-1'),140.0(C-11),131.9(C-10'),128.9(C-4",C-5",C-6",C-7"),128.2(C-3"),128.1(C-8"),125.8(C-3'),118.9(C-13),83.8(C-6),81.7(C-6'),72.5(C-10),66.8(C-2"),60.1(C-4),56.2(C-11'),56.1(C-5'),54.1(C-7'),53.5(C-3),46.7(C-7),45.1(C-14'),42.7(C-2),38.4(C-9),36.3(C-2'),35.0(C-13'),29.4(C-9'),27.5(C-14),26.4(C-8'),23.6(C-8),17.9(C-15'),17.1(C-15);
Example 15
Preparation of compound 30:
The crude amino derivative (35 mg,0.06mmol,1.0 eq) was weighed into a10 mL round bottom flask under Ar protection, dry THF (3 mL) was added for dissolution, PHENETHYL ISOCYANATE (6.5. Mu.L, 0.07mmol,1.2 eq) was added, and Et 3 N (7.6. Mu.L, 0.09mmol,1.5 eq) was reacted at room temperature for 8 hours. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was isolated by column chromatography [ petroleum ether-acetone, 75:25 (v/v) ] to give compound 30 (white solid, 86%).
Specific rotation: [ alpha ] +51.52 (c 0.099, CHCl 3);
high resolution mass spectrometry (ESI, m/z) calculated C 39H46N2O6[M+H]+ 639.3429, found 639.3434;
IRνmax 3402,3084,1766,1651,1556,1458,1378,1262,1096,1022,865,802cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 7.31–7.25(m,2H,H-5",H-6"),7.23–7.18(m,1H,H-9"),7.18–7.14(m,2H,H-7",H-8"),6.11(d,J＝3.4Hz,1H,H-13a),5.53(d,J＝10.1Hz,1H,H-6),5.49–5.45(m,1H,H-3'),5.42(d,J＝3.2Hz,1H,H-13a),4.59(m,2H,NH),3.76(dd,J＝14.3,6.1Hz,1H,H-14'a),3.64(dd,J＝14.2,5.3Hz,1H,H-14'b),3.56(dd,J＝10.0,10.0Hz,1H,H-6'),3.51–3.36(m,2H,H-2"),3.32(d,J＝10.0Hz,1H,H-5'),2.99(m,2H,H-2'a,H-2),2.79(m,2H,H-2'b,H-7),2.45(dt,J＝12.7,3.1Hz,1H,H-7'),2.33–2.25(m,1H,H-9'a),2.13–2.07(m,3H,H-8a,H-13'a,H-9'a),1.98(dt,J＝15.0,4.0Hz,1H,H-9a),1.88(s,3H,H-15'),1.78(m,3H,H-8b,H-8'a,H-9b),1.47(m,1H,H-13'b),1.45(s,3H,H-15),1.43-1.40(m,1H,H-3a),1.38(s,3H,H-14),1.34(m,2H,H-3b,H-8'b);13C NMR(125MHz,CDCl3)δC 180.4(C-12'),170.3(C-12),158.5(C-1"),151.0(C-1),144.8(C-5),140.9(C-4'),140.0(C-11),139.8(C-1'),139.1(C-4"),132.8(C-10'),128.8(C-7",C-8"),128.6(C-5",C-6"),126.5(C-9"),125.9(C-3'),118.9(C-13),83.9(C-6),81.7(C-6'),72.4(C-10),60.1(C-4),56.2(C-11'),56.1(C-5'),54.2(C-7'),53.5(C-3),46.7(C-7),44.3(C-14'),42.7(C-2),41.6(C-2"),38.4(C-9),36.4(C-2'),36.2(C-3"),34.9(C-13'),29.2(C-9'),27.5(C-14),26.3(C-8'),23.6(C-8),18.0(C-15'),17.1(C-15);
Example 16
Preparation of Compound 31:
NaH (5 mg,0.2mmol,1.2 eq) was added to a 10mL three-necked round bottom flask under Ar protection and placed in DMF (4 mL) to form a suspension, then Compound 21 (50 mg,0.17mmol,1.0 eq) and benzyl bromide (10. Mu.L, 0.34mmol,2.0 eq) were weighed and dissolved in DMF, and the reaction system was added by injection and reacted at room temperature for 7 hours. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was isolated by column chromatography [ petroleum ether-acetone, 85:15 (v/v) ] to give compound 31 (white solid, yield 83%).
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 37H42O6[M+H]+ 583.3054, found 583.3046;
IRνmax 3434,1765,1621,1459,1378,1262,1096,1023,864,803cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(400MHz,CDCl3)δH 7.43–7.27(m,5H,H-3",H-4",H-5",H-6",H-7"),6.16(d,J＝3.5Hz,1H,H-13a),5.55(d,J＝10.1Hz,1H,H-6),5.51–5.47(m,1H,H-3'),5.44(d,J＝3.2Hz,1H,H-13b),4.47(m,2H,H-1"),4.04–3.91(m,2H,H-14'),3.65(dd,J＝10.0,10.0Hz,1H,H-6'),3.42(d,J＝10.0Hz,1H,H-5'),3.07-2.98(m,3H,H-2',H-2),2.88–2.77(m,1H,H-7),2.57–2.48(m,2H,H-9'a,H-7'),2.23–2.10(m,3H,H-9'b,H-13'a,H-8a),2.05–1.93(m,1H,H-8b),1.90(s,3H,H-15'),1.88-1.74(m,3H,H-9a,H-8'a,H-13'a),1.50(s,3H,H-15),1.49–1.43(m,2H,H-9b,H-3a),1.40(s,3H,H-14),1.38-1.33(m,1H,H-3b);13C NMR(100MHz,CDCl3)δC 180.6(C-12'),170.1(C-12),150.7(C-1),145.1(C-5),141.1(C-4'),141.0(C-1'),140.0(C-11),138.3(C-10'),132.5(C-2"),128.4(C-5",C-6"),127.7(C-7"),127.7(C-3",C-4"),125.8(C-3'),118.8(C-13),83.8(C-6),81.8(C-6'),72.5(C-10),72.1(C-14'),71.7(C-1"),60.2(C-4),56.2(C-5'),54.2(C-7'),53.5(C-3),46.8(C-7),42.8(C-2),38.4(C-9),36.2(C-2'),35.0(C-13'),29.1(C-9'),27.6(C-14),26.2(C-8'),23.6(C-8),17.9(C-15'),17.1(C-15).
Example 17
Preparation of Compounds 32-33:
under Ar protection, compound 35 (40 mg,0.08mmol,1.0 eq) was weighed into a 10mL three-necked round bottom flask, added MeCN-H 2 O (1.8 mL:0.2 mL) was dissolved, and CuI (2 mg,0.008mmol,0.1 eq), et 3 N (11. Mu.L, 0.08mmol,1.0 eq), phenylacetylene/4-methylphenylene (11.0. Mu.L/12.0. Mu.L, 0.08mmol,1.0 eq) was added in sequence to react at room temperature for 12 hours. After the reaction was completed, the reaction was quenched by adding saturated NaHCO 3 solution, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed once with saturated NaCl solution, H 2 O, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography [ petroleum ether-acetone, 85:15 (v/v) ] to give compounds 32,33, respectively.
Compound 32 structural data:
Traits: white solid
Yield: 78%
Specific rotation:
High resolution mass spectrometry (ESI, m/z) calculated C 38H41N3O5[M+H]+ 620.3119, found 620.3132;
IRνmax 3446,3133,1764,1613,1460,1377,1261,1228,1096,1020,804cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(500MHz,CDCl3)δH 7.84–7.80(m,2H,H-4",H-5"),7.71(s,1H,H-1"),7.44-7.40(m,2H,H-6",H-7"),7.36–7.31(m,1H,H-8"),6.13(d,J＝3.5Hz,1H,H-13a),5.58-5.55(m,1H,H-3'),5.52(d,J＝10.1Hz,1H,H-6),5.42(d,J＝3.1Hz,1H,H-13b),5.05–4.88(m,2H,H-14'),3.66(dd,J＝10.0,10.0Hz,1H,H-6'),3.47(d,J＝10.0Hz,1H,H-5'),3.34–3.19(m,2H,H-2'),2.99-2.95(br s,1H,H-2),2.83-2.75(m,1H,H-7),2.48(dt,J＝12.6,3.0Hz,1H,H-7'),2.27–2.16(m,2H,H-9'),2.14-2.05(m,2H,H-8a,H-13'a),2.00-1.96(m,1H,H-13'a),1.93(s,3H,H-15'),1.86–1.79(m,1H,H-8b),1.79-1.76(m,1H,H-13'b),1.74(m,1H,H-8'a),1.46(dd,J＝12.2,2.5Hz,1H,H-13'b),1.43(s,3H,H-15),1.37(s,3H,H-14),1.36–1.28(m,2H,H-3),1.27–1.23(m,1H,H-8'b);13C NMR(125MHz,CDCl3)δC 180.3(C-12'),170.1(C-12),150.7(C-1),148.2(C-2"),145.0(C-5),144.0(C-10'),141.4(C-4'),139.9(C-11),130.4(C-1'),129.4(C-3"),128.9(C-6",C-7"),128.3(C-8"),125.7(C-4",C-5"),125.3(C-3'),119.3(C-1"),118.9(C-13),83.8(C-6),81.2(C-6'),72.5(C-10),60.2(C-4),56.4(C-5'),56.1(C-11'),54.3(C-14'),54.0(C-7'),53.5(C-3),46.7(C-7),42.7(C-2),38.4(C-9),36.8(C-2'),35.0(C-13'),29.5(C-9'),27.6(C-14),25.9(C-8'),23.7(C-8),17.9(C-15'),17.1(C-15);
Compound 33 structural data:
Traits: white solid
Yield: 82%
Specific rotation:
high resolution mass spectrometry (ESI, m/z) calculated C 39H43N3O5[M+H]+ 634.3275, found 634.3277;
IRνmax 3446,1766,1672,1461,1378,1261,1096,1022,803cm-1；
1 H-NMR and 13 C-NMR data :1H NMR(600MHz,CDCl3)δH 7.74–7.70(m,2H,H-4",H-5"),7.67(s,1H,H-1"),7.26-7.23(m,2H,H-6",H-7"),6.15(d,J＝3.5Hz,1H,H-13a),5.59–5.56(m,1H,H-3'),5.53(d,J＝10.1Hz,1H,H-6),5.44(d,J＝3.2Hz,1H,H-13b),5.05–4.89(m,2H,H-14'),3.67(dd,J＝10.0,10.0Hz,1H,H-6'),3.48(d,J＝10.0Hz,1H,H-5'),3.35-3.21(m,2H,H-2'),2.98(br s,1H,H-2),2.85-2.77(m,1H,H-7),2.50(dt,J＝12.7,3.0Hz,1H,H-7'),2.38(s,3H,H-9"),2.27–2.17(m,2H,H-9'),2.15–2.06(m,2H,H-8a,H-13'a),2.01–1.96(m,1H,H-9a),1.94(s,3H,H-15'),1.83(m,1H,H-8b),1.76(m,2H,H-9b,H-8'a),1.47(dd,J＝12.2,2.5Hz,1H,H-13'b),1.45(s,3H,H-15),1.39(s,3H,H-14),1.37-1.31(m,2H,H-3),1.31-1.27(m,1H,H-8'b);13C NMR(150MHz,CDCl3)δC 180.5(C-12'),170.3(C-12),150.9(C-1),148.5(C-2"),145.2(C-5),144.1(C-10'),141.6(C-4'),140.1(C-11),138.4(C-1'),129.8(C-6",C-7"),129.6(C-8"),127.8(C-3"),125.8(C-4",C-5"),125.5(C-3'),119.1(C-1"),118.9(C-13),84.0(C-6),81.4(C-6'),72.7(C-10),60.4(C-4),56.6(C-5'),56.3(C-11'),54.5(C-14'),54.2(C-7'),53.7(C-3),46.9(C-7),42.9(C-2),38.6(C-9),37.0(C-2'),35.2(C-13'),29.9(C-9'),27.8(C-14),26.1(C-8'),23.9(C-8),21.5(C-9"),18.1(C-15'),17.3(C-15).
Example 18
Inhibition activity of mugwort lactone I derivative 1-33 on HepG2, huh7 and SK-Hep-1 liver cancer cells.
1. Materials and methods
1.1 Materials
SK-Hep-1, huh-7 and HepG2 cells were purchased from Shanghai Ji Ning Biotechnology Inc., THLE-2 cells were purchased from the American ATCC biological Standard resource center and stored in liquid nitrogen. SK-Hep-1 and HepG2 cells were cultured in MEM (VivaCell, shanghai, china) medium, huh-7 cells were cultured in DMEM (VivaCell, shanghai, china) medium, THLE-2 cells were cultured in BEBM (Lonza, brazil, switzerland) medium at 37℃under 5% CO 2, 10% fetal bovine serum (Gibco, # 10099141) and 1% penicillin and streptomycin (Gibco, # 15070-063) were added. MTT was purchased from the state racing biotechnology limited (china, guangzhou). CCK-8 was purchased from Shanghai plum Biotechnology Co., ltd (Shanghai, china). DMSO was purchased from beijing solibao technologies limited (beijing, china). The absorbance was recorded using a microplate reader (Varioskan Lux, sammer femto science and technology, su zhou, china). FlexStation III bench type multifunctional ELISA reader (Bio-RAD 6080) was purchased from Bio-Rad Laboratories (Calif., U.S.A.). Analytical balance (AG 135) was purchased from Metler Toledo (Shanghai, china). Incubator (DHP-9082) was purchased from Mitsui technology (Shanghai).
1.2 Instruments
Flex Station 3 bench-top multifunctional microplate reader (Bio-RAD 680, USA); analytical balances (AG 135, metler Toledo, china); incubator (DHP-9082, shanghai).
1.3 Experimental procedure
1.3.1MTT Experimental method
1) Taking liver cancer cells growing in log phase, discarding old culture medium, washing twice with PBS, discarding PBS;
2) Digesting the cells with 0.25% trypsin, and rapidly absorbing trypsin when the outline of the cells is deepened and the rounding trend is observed under a microscope;
3) Stopping digestion and resuspending cells with DMEM complete medium containing 10% FBS, taking 10 μl of cell suspension, counting with a cell counter, adjusting cell concentration to 1×10 4/mL with medium, inoculating onto 96-well plates, adding 100 μl of cell suspension per well, incubating in an incubator at 37 ℃ with 5% CO 2 for 24h, and allowing cells to adhere;
4) Sucking the culture medium, adding diluted samples into the plate, adding 100 mu L of the diluted samples into each hole, setting 3 compound holes for each concentration, and continuously incubating in an incubator for 48 hours;
5) Sucking out the culture medium, adding the prepared MTT solution (1 mg/mL), adding 100 mu L of the solution into each hole, and incubating in an incubator for 4 hours;
6) Sucking MTT solution, adding DMSO, adding 100 μl per well, and incubating in incubator for 10min;
7) Absorbance values were measured at 490nm wavelength using a microplate reader by the formula: inhibition ratio = (negative-experimental group)/(negative-blank group) ×100% the cell inhibition ratio was calculated, IC 50 was calculated with statistical software GRAPHPAD PRISM, and the experiment was repeated 3 times.
1.3.2CCK-8 experimental method
CCK-8 assays were used to assess the effect of synthetic compounds on THLE-2 cell proliferation. THLE-2 cells in the logarithmic growth phase were seeded at 6000 cells/well (90 μl per well) in 96-well plates for 24 hours, and then treated with KGA-6006 and sorafenib (Solarbio, beijing, china) at different concentrations for 48 hours. Optical Density (OD) values were then measured at a wavelength of 450 nm.
2. Results
The inhibitory activity of all derivatives on HepG2, huh7 and SK-Hep-1 hepatoma cells was evaluated, and the IC 50 values are shown in Table 1. The synthesized compounds have certain inhibitory activities on HepG2, huh7 and SK-Hep-1, and 13 compounds (4,12,14,22,24,26-33) have stronger inhibitory activities than sorafenib and mugwort lactone I on three liver cancer cells; in particular compound 24, IC 50 values of 5.2 (HepG 2), 5.4 (Huh 7) and 5.8 (SK-Hep-1) μM, 2.3, 3.4 and 3.0 times higher than that of mugwort lactone I, 2.5, 1.6 and 2.0 times stronger than that of sorafenib; and the compound 6,22,24,28-33 shows better safety, better selectivity to normal liver cells (THLE-2) and SI value range of 1.3-4.4.
TABLE 1 cytotoxic Activity of mugwort lactone I derivatives 1-33 against liver cancer cells
aIC50 Values are expressed as mean ± table difference (n=3); b Sorafenib as positive control
TABLE 2 cytotoxicity of mugwort lactone I, sorafenib and select Compounds against THLE-2
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3. Conclusion(s)
The synthesized compounds have certain inhibitory activities on HepG2, huh7 and SK-Hep-1, and 13 compounds (4,12,14,22,24,26-33) have stronger inhibitory activities than sorafenib and mugwort lactone I on three liver cancer cells; in particular compound 24, IC 50 values of 5.2 (HepG 2), 5.4 (Huh 7) and 5.8 (SK-Hep-1) μM, 2.3, 3.4 and 3.0 times higher than that of mugwort lactone I, 2.5, 1.6 and 2.0 times stronger than that of sorafenib; and the compound 6,22,24,28-33 shows better safety, better selectivity to normal liver cells (THLE-2) and SI value range of 1.3-4.4. The results show that the artemisine derivatives 1-33 can be used as medicines for liver cancer related diseases.
Pharmaceutical formulation examples 1-5:
In the following application examples, conventional reagents are selected and preparation is performed according to the conventional methods, and the application examples only show that at least one of the florfenicol derivatives 1-33 (compounds 1-33) or pharmaceutically acceptable salts thereof according to the present invention can be prepared into different preparations, and specific reagents and operations are not specifically limited:
1. Dissolving at least one of the compounds 1-33 or pharmaceutically acceptable salts thereof with DMSO, adding water for injection according to conventional method, fine filtering, packaging, and sterilizing to obtain injection with concentration of 0.5-5mg/Ml.
2. Dissolving at least one of the compounds 1-33 or pharmaceutically acceptable salts thereof with DMSO, dissolving in sterile water for injection, stirring to dissolve, filtering with sterile suction filter funnel, sterile fine filtering, packaging in ampoule, freeze drying at low temperature, and sealing under sterile condition to obtain powder for injection.
3. At least one of the compounds 1-33 or the pharmaceutically acceptable salts thereof is added with excipient according to the mass ratio of the compound to the excipient of 9:1 to prepare powder.
4. At least one of the compounds 1-33 or the pharmaceutically acceptable salts thereof is added with excipient according to the mass ratio of 5:1 of the excipient, and the mixture is granulated and tableted.
5. At least one of the compounds 1-33 or the pharmaceutically acceptable salts thereof is prepared into oral liquid according to the conventional oral liquid preparation method.
6. Adding excipient into at least one of compounds 1-33 or pharmaceutically acceptable salt thereof at a mass ratio of 5:1, and making into capsule.
7. Adding excipient into at least one of the compounds 1-33 or pharmaceutically acceptable salts thereof according to the mass ratio of the compound to the excipient of 5:1, and preparing into granules.
From the above examples, the present invention provides a florfenicol derivative 1-33, a preparation method and application thereof, a pharmaceutical composition and application thereof. The 33 mugwort lactone I derivatives provided by the invention have different degrees of cytotoxic activity on HepG2, huh7 and SK-Hep-1 liver cancer cells, can be combined with a medicinal carrier or excipient to form a medicinal composition, and can be used for preparing anti-liver cancer medicaments.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (9)

1. Mugwort lactone I derivative 1-33 shown in structural formula (1) or pharmaceutically acceptable salt thereof
2. The mugwort lactone I derivative 1-33 or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt, including a salt with an organic acid, such as citric acid, maleic acid, fumaric acid, or an inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid.
3. A pharmaceutical composition comprising any one of the mugwort lactone I derivatives 1-33 or pharmaceutically acceptable salts thereof as claimed in claim 1, or any combination thereof, and a pharmaceutically acceptable carrier.
4. A process for the preparation of mugwort lactone I derivatives 1-33 of formula (I) according to claim 1, characterized in that the process comprises the steps of:
Preparation of mugwort lactone I derivative 1-2: coupling mugwort lactone I with iodobenzene under the catalysis of palladium acetate to obtain mugwort lactone I derivative 1; obtaining oxazoline derivative 2 of the mugwort lactone I through 1, 3-dipolar cycloaddition of the mugwort lactone I and 4-methylbenzaldehyde oxime;
Preparation of mugwort lactone I derivatives 3-10: using mugwort lactone I as a substrate, and obtaining mugwort lactone I derivative 3 through esterification; using mugwort lactone I as a substrate, and reacting with alcohol (methanol and phenethyl alcohol) under an acidic condition to obtain mugwort lactone I derivatives 4, 5, 6 and 7 respectively; dehydrating mugwort lactone I under the action of HF.Py to obtain a derivative 8; obtaining mugwort lactone I derivatives 9 and 10 by reducing mugwort lactone I with carbocation under acidic condition;
Preparation of mugwort lactone I derivatives 11-21: sesquiterpenes 3α,4α-epoxy-arglabin,3,4-hydro-arglabin,kauniolide,8-deoxyrupicolin B,1-hydroxy-10-methoxy-arglabin,1,10-epi-arglabin,11,13-dehydrodesacetylmatricarin,1β,10β-epoxy-2α-hydroxykauniolide and 14-hydroxykauniolide are respectively used as reaction substrates for diene reaction, and a Diels-Alder reaction is carried out, and dimethylamino protecting groups are removed to obtain mugwort lactone I derivatives 11-21;
Preparation of mugwort lactone I derivatives 22-33: the mugwort lactone I derivative 21 is oxidized by a dess-martin reagent to obtain a mugwort lactone I derivative 22; the mugwort lactone I derivative 22 takes sodium chlorite as an oxidant, naH 2PO4 is taken as a reaction acid-base buffer, and 2-methylbut-2-ene is added at the same time, so as to obtain a mugwort lactone I derivative 23; the mugwort lactone I derivative 23 is esterified and condensed with phenol under the action of DCC and DMAP to obtain mugwort lactone I derivative 24; the mugwort lactone I derivative 21 is respectively esterified and condensed with acetic anhydride and benzoic anhydride under the action of DCC and DMAP to obtain mugwort lactone I derivatives 25 and 26; taking a mugwort lactone I derivative 21 as a substrate, adding DPPA and DBU, and reacting in an alkaline environment through S N to obtain an azido derivative 27 of mugwort lactone I; firstly, a slight excess triphenylphosphine is used for reducing the mugwort lactone I derivative 27 through Shi Dingge reaction (Staudinger reaction) to obtain an intermediate amino derivative, and then the intermediate amino derivative is reacted with benzoic anhydride to obtain an amide derivative 28 of mugwort lactone I; taking the intermediate amino derivative as a substrate, and obtaining carbamate derivative 29 of the mugwort lactone I under the action of benzyl alcohol and CDI; adding 2-phenethyl isocyanate under alkaline condition by taking an intermediate amino derivative as a substrate to obtain a urea-containing compound 30; the mugwort lactone I derivative 21 is used as a reaction substrate, sodium hydride provides an alkaline environment, and the sodium hydride and benzyl bromide are subjected to Williamson ether synthesis reaction to obtain a compound 31; mugwort lactone I derivative 27 is taken as a substrate and respectively reacts with terminal alkynyl compounds (phenylacetylene and 4-methyl phenylacetylene) in a reaction system of cuprous iodide and triethylamine through Click to obtain triazole derivatives 32 and 33 of mugwort lactone I.
5. A process for preparing a pharmaceutical composition according to claim 3, which comprises synthesizing the mugwort lactone I derivatives 1 to 33 from mugwort lactone I as a reaction raw material, and adding a pharmaceutically acceptable carrier, characterized in that the process comprises the steps of:
Preparation of mugwort lactone I derivative 1-2: coupling mugwort lactone I with iodobenzene under the catalysis of palladium acetate to obtain mugwort lactone I derivative 1; obtaining oxazoline derivative 2 of the mugwort lactone I through 1, 3-dipolar cycloaddition of the mugwort lactone I and 4-methylbenzaldehyde oxime;
Preparation of mugwort lactone I derivatives 3-10: using mugwort lactone I as a substrate, and obtaining mugwort lactone I derivative 3 through esterification; using mugwort lactone I as a substrate, and reacting with alcohol (methanol and phenethyl alcohol) under an acidic condition to obtain mugwort lactone I derivatives 4, 5, 6 and 7 respectively; dehydrating mugwort lactone I under the action of HF.Py to obtain a derivative 8; obtaining mugwort lactone I derivatives 9 and 10 by reducing mugwort lactone I with carbocation under acidic condition;
Preparation of mugwort lactone I derivatives 11-21: sesquiterpenes 3α,4α-epoxy-arglabin,3,4-hydro-arglabin,kauniolide,8-deoxyrupicolin B,1-hydroxy-10-methoxy-arglabin,1,10-epi-arglabin,11,13-dehydrodesacetylmatricarin,1β,10β-epoxy-2α-hydroxykauniolide and 14-hydroxykauniolide are respectively used as reaction substrates for diene reaction, and a Diels-Alder reaction is carried out, and dimethylamino protecting groups are removed to obtain mugwort lactone I derivatives 11-21;
Preparation of mugwort lactone I derivatives 22-33: the mugwort lactone I derivative 21 is oxidized by a dess-martin reagent to obtain a mugwort lactone I derivative 22; the mugwort lactone I derivative 22 takes sodium chlorite as an oxidant, naH 2PO4 is taken as a reaction acid-base buffer, and 2-methylbut-2-ene is added at the same time, so as to obtain a mugwort lactone I derivative 23; the mugwort lactone I derivative 23 is esterified and condensed with phenol under the action of DCC and DMAP to obtain mugwort lactone I derivative 24; the mugwort lactone I derivative 21 is respectively esterified and condensed with acetic anhydride and benzoic anhydride under the action of DCC and DMAP to obtain mugwort lactone I derivatives 25 and 26; taking a mugwort lactone I derivative 21 as a substrate, adding DPPA and DBU, and reacting in an alkaline environment through S N to obtain an azido derivative 27 of mugwort lactone I; firstly, a slight excess triphenylphosphine is used for reducing the mugwort lactone I derivative 27 through Shi Dingge reaction (Staudinger reaction) to obtain an intermediate amino derivative, and then the intermediate amino derivative is reacted with benzoic anhydride to obtain an amide derivative 28 of mugwort lactone I; taking an intermediate amino derivative as a substrate, and obtaining carbamate derivative 29 of mugwort lactone I under the action of benzyl alcohol and CDI; adding 2-phenethyl isocyanate under alkaline condition by taking an intermediate amino derivative as a substrate to obtain a urea-containing compound 30; mugwort lactone I derivative 21 is used as a reaction substrate, sodium hydride provides an alkaline environment, and the alkaline environment and benzyl bromide are subjected to Williamson ether synthesis reaction to obtain a compound 31; the method comprises the steps of taking a mugwort lactone I derivative 27 as a substrate, and respectively carrying out Click reaction on the mugwort lactone I derivative 27 and a terminal alkynyl compound (phenylacetylene and 4-methyl phenylacetylene) in a reaction system of cuprous iodide and triethylamine to obtain triazole derivatives 32 and 33 of mugwort lactone I; then, pharmaceutically acceptable carriers are added separately.
6. Use of mugwort lactone I derivatives 1-33 or pharmaceutically acceptable salts thereof as claimed in claim 1 in the manufacture of an anti-liver cancer inhibitor.
7. Use of the pharmaceutical composition of claim 3 for the preparation of an anti-liver cancer inhibitor.
8. Use of mugwort lactone I derivatives 1-33 or pharmaceutically acceptable salts thereof as claimed in claim 1 in the manufacture of a medicament for the treatment of liver cancer.
9. Use of the pharmaceutical composition of claim 3 in the preparation of a medicament for treating liver cancer.
CN202410295603.2A 2024-03-15 2024-03-15 Mugwort lactone I derivative and pharmaceutical composition thereof, and preparation method and application thereof Pending CN118184675A (en)

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