A method for synthesizing 3-oxa terpenes by oxonium ion-initiated cascade polyene cyclization reaction

Abstract

The application relates to a method for synthesizing 3-oxacyclic terpene through an oxonium ion initiated tandem polyene cyclization reaction, discloses that (E)-(6-(benzyloxy))-4-methylhex-3-en-1-yl) benzene and derivatives thereof are used as substrates, zinc bromide is used as a catalyst, T + BF4 ‑ As an oxidant, 1,2-dichloroethane is used as a solvent, and activated molecular sieve is used as a water removing agent, and 3-oxacyclic terpene compounds are obtained under the condition of 70 DEG C. The method has good functional group tolerance, and provides an efficient and novel preparation method for 3-oxacyclic terpene compounds.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 3-oxaterpenes through a tandem polyene cyclization reaction initiated by oxonium ions. Background Art

[0002] Polycyclic compounds, such as steroids and terpenes, are widely found in nature and possess significant physiological and pharmaceutical activity. Therefore, the facile and efficient synthesis of terpenes and steroids with polycyclic backbones, chiral centers, and quaternary carbon centers has been a research hotspot in recent years. Among the numerous methods for synthesizing polycyclic molecules from chain molecules through selective C-C bonds, polyene cyclization is considered a unique and efficient method for synthesizing polycyclic compounds due to its advantages of short synthesis steps and high atom economy. Oxonium ions are highly reactive but extremely unstable transient species, susceptible to a range of reactions including cycloadditions, nucleophilic substitutions, carbene transfers, and migratory rearrangements. Oxonium ions are often used as intermediates in key transformations in the construction of specific ring systems. In recent years, the research and application of oxonium ions in synthesis has made significant progress. The excellent reactivity of oxonium ions has enabled the construction of a variety of specialized ring systems, making the synthesis of complex natural product molecules possible. Designing suitable oxonium ion precursors also allows for highly selective reactions between species. However, further research is still needed to "controllably" and "efficiently" utilize the high reactivity of oxonium.

[0003] As one of the most widely distributed natural products, 3-oxapods have attracted significant interest from biologists and chemists due to their bioactivity and medicinal potential. For example, tinocapillins A, a natural product isolated from the plant Tinocapillary genus of the Menispermaceae family, exhibits significant inhibitory activity against the proliferation of A549, Hep G2, Hela, and OS-RC-2 cancer cells. Pharmacological studies of salvinorin A have demonstrated that this natural product binds to and activates peptidergic G protein-coupled receptors (GPCRs) in a novel manner. Furthermore, salvinorin A acts as a selective κ-opioid receptor agonist and is expected to be clinically useful through further research and modification. Compound C exhibits significant cytotoxic activity (100% growth inhibition at 10 μg / mL), and compound D is mildly toxic to brine shrimp. Therefore, developing green and efficient synthetic methods is crucial for the research and application of this promising class of 3-oxapods. Summary of the Invention

[0004] The purpose of the present invention is to improve the deficiencies of existing preparation and synthesis methods and to provide a method for synthesizing 3-oxaterpenes through a tandem polyene cyclization reaction initiated by an oxonium ion, which has efficient and simple reaction conditions, a wide range of substrate applicability, and convenient operation.

[0005] The technical solution of the present invention is: a substrate, an oxidant, and a catalyst are placed in a test tube, a solvent is added, and a 3-oxaterpenoid compound is obtained under argon protection and room temperature. The reaction formula is as follows:

[0006]

[0007] (1)R 1 is selected from the group consisting of phenyl, vinyl, styryl, biphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-cyanophenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-iodo-phenyl;

[0008] (2)R 2 is selected from a chlorine atom, a methoxy group, a methyl group, a thienyl group, and a phenyl group;

[0009] (3) The organic solvent used is selected from 1,2-dichloroethane, dichloromethane, chloroform, toluene, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, preferably 1,2-dichloroethane;

[0010] (4) The oxidizing agent used is selected from 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium tetrafluoroborate, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), ceric ammonium nitrate, tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide, potassium persulfate, tetrachlorobenzoquinone, preferably 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium tetrafluoroborate;

[0011] (5) The heating temperature used is selected from 25-90°C, preferably 70°C;

[0012] (6) The Lewis acid used is selected from indium trichloride, copper acetate, zinc chloride, and zinc bromide, preferably zinc bromide;

[0013] (7) The molar mass ratio of each substance in the reaction is preferably: (E)-(6-(benzyloxy))-4-methylhex-3-en-1-yl)benzene: zinc bromide: 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium tetrafluoroborate = 1:0.1:2. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The following are the conditions for the synthesis of 3-oxaterpenes:

[0015] Figure 2 is the preparation reaction formula of compound 2a;

[0016] Figure 3 is the preparation reaction formula of compound 2b;

[0017] Figure 4 is the preparation reaction formula of compound 2c;

[0018] Figure 5 is the preparation reaction formula of compound 2d;

[0019] Figure 6 is the preparation reaction formula of compound 2e;

[0020] Figure 7 is the preparation reaction formula of compound 2f;

[0021] Figure 8 is the preparation reaction formula of compound 2g;

[0022] Figure 9 is the reaction formula for the preparation of compound 2h;

[0023] Figure 10 is the preparation reaction formula of compound 2i;

[0024] Figure 11 is the preparation reaction formula of compound 2j;

[0025] Figure 12 is the preparation reaction formula of compound 2k;

[0026] Figure 13 is the preparation reaction formula of compound 21;

[0027] Figure 14 is the reaction formula for the preparation of compound 2m;

[0028] Figure 15 is the preparation reaction formula of compound 2n;

[0029] Figure 16 is the reaction formula for the preparation of compound 2o;

[0030] Figure 17 is the reaction formula for the preparation of compound 2p;

[0031] Figure 18 is the preparation reaction formula of compound 2q;

[0032] Figure 19 This is the reaction formula for the preparation of compound 2r. DETAILED DESCRIPTION

[0033] The present invention is further described below through specific examples, but this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0034] Example 1: Using substrate (1a) as raw material (Reaction Formula 1)

[0035]

[0036] Under argon, substrate 1a (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain product 2a.

[0037] Product testing data are as follows:

[0038] 1 H NMR (400MHz, CDCl3) δ7.36–7.30(m,4H),7.27–7.23(m,1H),7.20–7.14(m,1H),7.11(td,J=7.3,1 .5Hz,1H),7.03(dd,J=7.5,1.4Hz,1H),4.37(d,J=10.3Hz,1H),4.16–4.09(m,1H),4.08–3.99(m,1 H),2.84–2.76(m,1H),2.76–2.65(m,1H),2.17–2.12(m,1H),2.05(td,J=12.8,4.8Hz,1H),1.90(d dd,J=13.4,10.3,3.3Hz,1H),1.59–1.45(m,1H),1.34(s,3H),1.19(ddt,J=13.6,8.1,2.8Hz,1H); 13 C NMR (101MHz, CDCl3) δ135.21,129.42,128.50,128.00,127.51,125.93,125.87,123.99,80.43,64.46,46.77,38.02,35.79,27.98,21.96,19.75.

[0039] Implementation Case 2

[0040] Using substrate (1b) as raw material (reaction formula 2)

[0041]

[0042] Under argon, substrate 1b (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain product 2b.

[0043] Product testing data are as follows:

[0044] 1 H NMR (400MHz, CDCl3) δ7.24–7.19(m,1H),7.19–7.15(m,1H),7.14–7.10(m,1H),7.10–7.06(m,1H),5.81(ddd,J=17. 2,10.3,7.6Hz,1H),5.31(ddd,J=17.2,1.8,0.9Hz,1H),5.26(ddd,J=10.3,1.8,0.6Hz,1H),4.04(ddd,J=11.9,5.2 ,1.8Hz,1H),3.94(ddd,J=12.7,11.9,2.4Hz,1H),3.87(dd,J=9.6,7.6Hz,1H),2.93–2.87(m,2H),2.08(dt,J=13.1 ,2.1Hz,1H),1.95–1.85(m,1H),1.75(dddd,J=10.8,6.9,4.2,2.3Hz,1H),1.66–1.48(m,2H),1.26(d,J=0.8Hz,3H); 13 C NMR (101MHz, CDCl3) δ138.05,135.14,129.41,125.89,125.85,123.96,118.20,78.83,63.74,45.18,37.86,35.26,28.17,22.01,19.74.

[0045] Implementation Case 3

[0046] Using substrate (1c) as raw material (reaction formula 3)

[0047]

[0048] Under argon, substrate 1c (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain product 2c.

[0049] Product testing data are as follows:

[0050] 1 H NMR (400MHz, CDCl3) δ7.44–7.39(m,2H),7.36–7.29(m,2H),7.27–7.20(m,2H),7.15(s,0H),7 .15–7.10(m,1H),7.07(dd,J=7.3,1.8Hz,1H),6.65(dd,J=16.0,2.3Hz,1H),6.17(ddd,J=16. 0,7.8,2.3Hz,1H),4.11–3.94(m,3H),2.89(dd,J=9.1,5.0Hz,2H),2.11(dt,J=13.2,2.3Hz,1 H),1.95(td,J=12.8,5.3Hz,1H),1.82–1.67(m,2H),1.65–1.52(m,1H),1.29(d,J=2.4Hz,3H); 13 C NMR (101MHz, CDCl3) δ146.99,136.87,135.16,133.35,129.46,129.37,128.68,127.8 6,126.71,125.94,125.89,124.00,63.91,45.77,37.89,35.42,28.18,22.07,19.95.

[0051] Implementation Case 4

[0052] Using substrate (1d) as raw material (reaction formula 4)

[0053]

[0054] Under argon, substrate 1d (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain product 2d.

[0055] Product testing data are as follows:

[0056] 1 H NMR (400MHz, CDCl3) δ7.65–7.58(m,4H),7.45(qd,J=6.7,6.1,1.9Hz,4H),7.39–7.33(m,1H),7.29(dd,J=7.8,1.5Hz,1H) ,7.21(td,J=7.5,1.6Hz,1H),7.15(td,J=7.3,1.5Hz,1H),7.07(dd,J=7.5,1.4Hz,1H),4.45(d,J=10.3Hz,1H),4.20–4.15 (m,1H),4.09(td,J=12.2,2.5Hz,1H),2.91–2.82(m,1H),2.81–2.72(m,1H),2.19(dt,J=13.2,2.3Hz,1H),2.11(dd,J=12 .7,5.2Hz,1H),1.97(ddd,J=13.4,10.3,3.3Hz,1H),1.59(tdd,J=13.2,10.1,8.1Hz,1H),1.39(s,3H),1.36–1.28(m,1H); 13 C NMR (101MHz, CDCl3) δ147.06,140.32,129.43,128.85,127.92,127.34,127.23,127. 20,125.94,125.88,123.98,80.13,64.46,46.74,38.02,35.79,27.98,21.95,19.79.

[0057] Implementation Case 5

[0058] Using substrate (1e) as raw material (Reaction Formula 5)

[0059]

[0060] Under argon, substrate 1e (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2e.

[0061] Product testing data are as follows:

[0062] 1 H NMR (400MHz, CDCl3) δ7.25 (dq, J=7.9, 2.1, 1.2Hz, 3H), 7.20–7.14 (m, 1H), 7.11 (td, J=7.3, 1.5Hz, 1H), 7.03 (dd, J= 7.5, 1.5Hz, 1H), 6.88 (d, J = 8.6Hz, 1H), 4.33 (d, J = 10.3Hz, 1H), 4.10 (ddd, J = 11.9, 5.3, 1.8Hz, 1H), 4.02 (td, J = 12. 2,2.5Hz,1H),3.80(s,3H),2.86–2.65(m,2H),2.14(dt,J=13.2,2.3Hz,1H),2.03(td,J=12.7,5.2Hz,1H),1.87(dd d,J=13.4,10.3,3.3Hz,1H),1.49(tdd,J=13.2,10.0,8.0Hz,1H),1.33(s,3H),1.21(ddt,J=13.6,7.9,2.8Hz,1H); 13 C NMR (101MHz, CDCl3) δ135.23,133.53,129.41,128.59,125.90,125.86,123. 98,113.86,79.86,64.42,55.38,46.78,38.03,35.82,28.01,21.93,19.80.

[0063] Implementation Case 6

[0064] Using substrate (1f) as raw material (Reaction Formula 6)

[0065]

[0066] Under argon, substrate 1f (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2f.

[0067] Product testing data are as follows:

[0068] 1 H NMR(400MHz, CDCl3)δ7.37(d,J=8.3Hz,2H),7.29–7.24(m,3H),7.19(td,J=7.6,1.8Hz,1H),7.1 3(td,J=7.3,1.5Hz,1H),7.05(dd,J=7.3,1.5Hz,1H),4.36(d,J=10.3Hz,1H),4.15–4.08(m,1H) ,4.04(td,J=12.1,2.5Hz,1H),2.82–2.73(m,2H),2.18–2.12(m,1H),2.09–2.02(m,2H),1.94(d dd,J=13.4,10.3,3.3Hz,1H),1.57–1.47(m,1H),1.37(s,3H),1.32(s,10H),1.30–1.24(m,1H); 13 C NMR (101MHz, CDCl3) δ147.17,138.09,135.28,129.42,127.13,125.88,125.83,125.41 ,123.98,80.12,64.43,46.40,38.00,35.78,34.65,31.49,31.20,27.98,21.97,19.75.

[0069] Implementation Case 7

[0070] Using substrate (1g) as raw material (reaction formula 7)

[0071]

[0072] Under argon, 1 g (1.0 equiv., 35 mg) of substrate, activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4- The oxidant (2.0 equiv., 61 mg) was added, and then 1 mL of ultra-dry DCE solvent was added. The reaction was placed in an oil bath at 70°C for 4 h. After the reaction was completed, TLC (petroleum ether / ethyl acetate = 8:1) was used to detect the completion of the reaction. The reaction was quenched with saturated sodium thiosulfate solution and the reaction system was extracted with dichloromethane three times (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain 2 g of the product.

[0073] Product testing data are as follows:

[0074] 1 H NMR(400MHz, CDCl3)δ7.29–7.08(m,8H),7.05–7.00(m,1H),4.33(d,J=10.3Hz,1H), 4.12–4.07(m,1H),4.02(td,J=12.2,2.5Hz,1H),2.75(qdd,J=17.7,9.2,5.2Hz,2H), 2.34(s,3H),2.14(dt,J=13.1,2.2Hz,1H),2.07–1.99(m,1H),1.88(ddd,J=13.3,10 .3,3.3Hz,1H),1.50(tdd,J=13.2,10.1,8.0Hz,1H),1.33(s,3H),1.24–1.16(m,1H); 13 C NMR (101MHz, CDCl3) δ138.22,137.51,129.35,129.09,127.33,125.83,125. 79,123.92,80.14,64.36,46.65,37.99,35.74,27.95,21.89,21.26,19.73.

[0075] Implementation Case 8

[0076] Using substrate (1h) as raw material (Reaction formula 8)

[0077]

[0078] Under argon, substrate 1h (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, the reaction was detected by TLC (petroleum ether / ethyl acetate = 8:1). The reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2h.

[0079] Product testing data are as follows:

[0080] 1 H NMR (400MHz, CDCl3) δ7.28–7.09(m,8H),7.04(d,J=7.3Hz,1H),4.34(d,J=10.3Hz,1H),4.13(ddd,J =12.0,5.3,1.8Hz,1H),4.04(td,J=12.2,2.5Hz,1H),2.81(ddd,J=17.6,8.1,2.1Hz,1H),2.72(dd, J=17.3,9.6Hz,1H),2.35(s,3H),2.15(dt,J=13.2,2.3Hz,1H),2.06(td,J=12.8,5.1Hz,1H),1.91( ddd,J=13.4,10.2,3.3Hz,1H),1.52(tdd,J=13.3,10.0,8.2Hz,1H),1.34(s,3H),1.26–1.17(m,1H); 13 C NMR (101MHz, CDCl3) δ147.10,141.10,138.10,135.19,129.36,128.70,128.24,128.01,125. 86,125.80,124.68,123.92,80.44,64.40,46.58,38.00,35.72,27.90,21.86,21.54,19.74.

[0081] Implementation Case 9

[0082] Using substrate (1i) as raw material (reaction formula 9)

[0083]

[0084] Under argon, substrate 1i (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2i.

[0085] Product testing data are as follows:

[0086] 1 H NMR (400MHz, CDCl3δ7.45(d,J=7.5Hz,1H),7.30–7.25(m,1H),7.24–7.10(m,5H),7.05(dd,J=7. 5,1.4Hz,1H),4.78(d,J=10.2Hz,1H),4.14(ddd,J=11.9,5.2,1.7Hz,1H),4.06(td,J=12.3,2.4H z,1H),2.85–2.77(m,1H),2.76–2.67(m,1H),2.39(s,3H),2.17(dt,J=13.1,2.2Hz,1H),2.06(td ,J=12.8,5.2Hz,1H),1.95(t,J=11.4Hz,1H),1.65–1.56(m,1H),1.39(s,3H),1.25–1.22(m,1H); 13 C NMR (101MHz, CDCl3) δ147.05,139.78,135.65,135.13,129.92,129.47,127.42,126.68,1 26.37,125.93,125.90,124.14,64.69,47.84,38.17,35.97,28.37,22.24,19.90,19.21.

[0087] Implementation Case 10

[0088] With substrate (1j) (reaction formula 10)

[0089]

[0090] Under argon, substrate 1j (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2j.

[0091] Product testing data are as follows:

[0092] 1 HNMR (400MHz, CDCl3) δ7.65(d,J=8.3Hz,2H),7.45(d,J=8.2Hz,2H),7.24(d,J=1.5Hz,1H),7.18(ddd,J=8.6,7.3,1.6Hz ,1H),7.13(td,J=7.3,1.6Hz,1H),7.04(dd,J=7.4,1.4Hz,1H),4.42(d,J=10.3Hz,1H),4.14(ddd,J=12.0,5.2,1.7Hz,1 H),4.04(td,J=12.4,2.4Hz,1H),2.86–2.78(m,1H),2.69(dd,J=17.5,8.9Hz,1H),2.20–2.16(m,2H),2.09–2.00(m,1H) ,1.81(ddd,J=13.3,10.3,3.2Hz,1H),1.56(qd,J=7.9,6.7,3.6Hz,2H),1.34(s,3H),1.12(ddt,J=13.3,8.1,2.4Hz,1H); 13 C NMR (101MHz, CDCl3) δ146.50,134.81,132.32,129.43,128.25,126.12,126.03,123.95,111.79,64.45,47.02,37.81,35.71,27.77,21.87,19.66.

[0093] Implementation Case 11

[0094] Using substrate (1k) as raw material (reaction formula 11)

[0095]

[0096] Under argon, substrate 1k (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4- The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2k.

[0097] Product testing data are as follows:

[0098] 1 H NMR (400MHz, CDCl3) δ7.35–7.28(m,2H),7.27–7.24(m,1H),7.18(td,J=7.6,1.6Hz,1H),7.13(td,J=7.3,1.6Hz ,1H),7.09–7.00(m,3H),4.37(d,J=10.3Hz,1H),4.12(ddd,J=12.1,5.2,1.8Hz,1H),4.04(td,J=12.3,2.4Hz,1H ),2.88–2.78(m,1H),2.72(ddd,J=17.8,10.1,8.3Hz,1H),2.16(dt,J=13.2,2.2Hz,1H),2.05(td,J=12.8,5.3H z,1H),1.85(ddd,J=13.4,10.3,3.3Hz,1H),1.57–1.45(m,1H),1.34(s,3H),1.18(ddt,J=13.5,8.1,2.8Hz,1H); 13 CNMR (101MHz, CDCl3) δ146.96,135.11,129.45,129.11,129.03,123.99,79.69,64.48,47.01,38.00,35.81,27.94,21.92,19.76.

[0099] Implementation Case 12

[0100] Using substrate (1l) as raw material (reaction formula 12)

[0101]

[0102] Under argon, substrate 1L (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2l.

[0103] Product testing data are as follows:

[0104] 1 H NMR (400MHz, CDCl3) δ7.33–7.21(m,5H),7.20–7.14(m,1H),7.11(td,J=7.2,1.5Hz,1H),7.03(d,J=7 .6Hz,1H),4.34(d,J=10.3Hz,1H),4.16–4.08(m,1H),4.02(td,J=12.3,2.4Hz,1H),2.87–2.76(m,1H ),2.70(dt,J=17.8,9.1Hz,1H),2.15(dt,J=13.3,2.2Hz,1H),2.03(td,J=12.9,5.2Hz,1H),1.82(dd d,J=13.2,10.2,3.3Hz,1H),1.51(tdd,J=13.3,10.2,7.9Hz,1H),1.17(ddt,J=13.7,8.4,2.7Hz,1H); 13 C NMR (101MHz, CDCl3) δ146.88,139.89,135.06,133.63,129.45,128.86,128.66,1 26.02,125.96,123.98,79.71,64.46,46.99,37.97,35.78,27.92,21.91,19.73.

[0105] Implementation Case 13

[0106] Using substrate (1m) as raw material (reaction formula 13)

[0107]

[0108] Under argon, substrate 1m (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2m.

[0109] Product testing data are as follows:

[0110] 1 HNMR (400MHz, CDCl3) δ7.48(d,J=8.4Hz,2H),7.26–7.24(m,2H),7.22(d,J=8.4Hz,2H),7.20–7.16(m,1H),7.13(td,J= 7.3,1.5Hz,1H),7.04(dd,J=7.5,1.4Hz,1H),4.35(d,J=10.3Hz,1H),4.13(ddd,J=12.0,5.2,1.7Hz,1H),4.03(td,J=1 2.3,2.4Hz,1H),2.82(ddd,J=17.6,8.0,2.1Hz,1H),2.77–2.65(m,1H),2.16(dt,J=13.1,2.2Hz,1H),2.04(td,J=12.9 ,5.2Hz,1H),1.83(ddd,J=13.3,10.3,3.2Hz,1H),1.58–1.46(m,1H),1.34(s,3H),1.18(ddt,J=13.5,8.2,2.7Hz,1H); 13 C NMR (101MHz, CDCl3) δ146.84,140.39,135.04,131.59,129.44,129.21,126. 02,125.95,123.97,79.75,64.45,46.95,37.95,35.76,27.91,21.92,19.71.

[0111] Implementation Case 14

[0112] Using substrate (1n) as raw material (reaction formula 14)

[0113]

[0114] Under argon, substrate 1n (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4- The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2n.

[0115] Product testing data are as follows:

[0116] 1 H NMR (400MHz, CDCl3) δ7.67(d,J=8.4Hz,2H),7.25–7.21(m,1H),7.19–7.14(m,1H),7.14–7.09(m,1H),7.08(d ,J=8.3Hz,2H),7.03(dd,J=7.4,1.4Hz,1H),4.31(d,J=10.2Hz,1H),4.12–4.08(m,1H),4.01(td,J=12.3,2.4 Hz,1H),2.80(ddd,J=17.7,8.0,2.1Hz,1H),2.75–2.67(m,1H),2.15(dt,J=13.2,2.2Hz,1H),2.05–1.97(m,1 H),1.81(ddd,J=13.3,10.3,3.3Hz,1H),1.54–1.47(m,1H),1.32(s,3H),1.18(ddt,J=13.5,8.2,2.7Hz,1H); 13 C NMR (101MHz, CDCl3) δ146.72,140.93,137.44,134.93,129.36,129.32,125. 90,125.83,123.85,79.73,64.31,46.79,37.82,35.64,27.79,21.80,19.59.

[0117] Implementation Case 15

[0118] Using substrate (1o) as raw material (reaction formula 15)

[0119]

[0120] Under argon, substrate 1o (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2o.

[0121] Product testing data are as follows:

[0122] 1 H NMR (400MHz, CDCl3) δ7.39–7.28(m,5H),7.21(d,J=2.2Hz,1H),7.08(dd,J=8.2,2.2Hz,1H) ,6.99–6.94(m,1H),4.36(d,J=10.3Hz,1H),4.13(ddd,J=12.0,5.0,1.9Hz,1H),4.02(td,J =12.0,2.9Hz,1H),2.75(ddd,J=17.8,8.1,2.1Hz,1H),2.70–2.60(m,1H),2.14–1.98(m,2H ),1.84(ddd,J=13.3,10.2,3.2Hz,1H),1.54–1.42(m,1H),1.33(s,3H),1.24–1.14(m,1H); 13 C NMR (101MHz, CDCl3) δ148.87,140.99,133.61,130.76,128.53,128.09,127. 45,126.03,124.25,80.30,64.30,46.50,37.85,36.00,27.40,21.88,19.55.

[0123] Implementation Case 16

[0124] Using substrate (1p) as raw material (reaction formula 16)

[0125]

[0126] Under argon, substrate 1p (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2p.

[0127] Product testing data are as follows:

[0128] 1 H NMR (400MHz, CDCl3) δ7.43–7.27(m,10H),7.00(d,J=8.3Hz,1H),6.97(d,J=8.4Hz,1H),6.80(dd,J=7.6,2.7Hz,2H),6.71(dt,J=8.4, 1.8Hz,2H),6.36(dd,J=9.5,3.2Hz,1H),5.22(dd,J=9.6,2.6Hz,1H),4.59(d,J=11.0Hz,1H),4.37(d,J=10.3Hz,1H),4.24–4.16(m,1 H),4.14–4.10(m,1H),4.09–4.06(m,1H),4.05–3.99(m,1H),2.83–2.57(m,3H),2.20(dt,J=12.8,6.3Hz,1H),2.15–1.98(m,4H),1.8 9(ddd,J=13.3,10.3,3.2Hz,1H),1.50(tdd,J=13.2,10.2,8.0Hz,1H),1.35(s,3H),1.25(s,3H),1.18(ddt,J=13.6,8.2,2.8Hz,1H); 13 C NMR (101MHz, CDCl3) δ159.51,157.83,148.33,141.24,140.18,130.20,128.65,128.49,128.33,128.19,128.03,128.00,127.61,127.51,126.2 3,124.43,111.16,110.20,110.01,109.58,80.44,64.52,64.44,55.43 ,47.52,46.79,38.00,36.55,36.00,35.55,27.16,21.88,19.86,18.08.

[0129] Implementation Case 17

[0130] Using substrate (1q) as raw material (Reaction formula 17)

[0131]

[0132] Under argon, 1q (1.0 equiv., 35 mg) of substrate, activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2q.

[0133] Product testing data are as follows:

[0134] 1 H NMR (400MHz, CDCl3) δ7.42–7.28(m,6H),7.19–7.14(m,1H),7.05–6.98(m,1H),6.92–6.86(m,1H),4.39 (d,J=10.3Hz,1H),4.14(ddd,J=12.0,5.3,1.8Hz,1H),4.05(td,J=12.2,2.5Hz,1H),2.83–2.74(m,1H) ,2.74–2.64(m,1H),2.30(s,3H),2.16(dt,J=13.1,2.2Hz,1H),2.09–2.02(m,1H),1.90(ddd,J=13.3,1 0.3,3.2Hz,1H),1.53(tdd,J=13.2,10.1,8.0Hz,1H),1.35(s,3H),1.20(ddt,J=13.5,7.9,2.8Hz,1H); 13 C NMR (101MHz, CDCl3) δ144.23,141.27,135.36,135.04,129.97,128.45,127.94,127. 48,126.68,123.91,80.39,64.44,46.96,38.10,35.44,27.93,21.97,21.00,19.76.

[0135] Implementation Case 18

[0136] Using substrate (1r) as raw material (reaction formula 18)

[0137]

[0138] Under argon, substrate 1r (1.0 equiv., 35 mg), activated Molecular sieves, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - The oxidant (2.0 equiv., 61 mg) was added, followed by the addition of 1 mL of ultra-dry DCE solvent, and the reaction was placed in an oil bath at 70°C for 4 h. After completion of the reaction, as detected by TLC (petroleum ether / ethyl acetate = 8:1), the reaction was quenched with saturated sodium thiosulfate solution, and the reaction system was extracted three times with dichloromethane (1.5 mL × 3). The organic phases were combined and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain the product 2r.

[0139] Product testing data are as follows:

[0140] 1 H NMR(400MHz, CDCl3) δ7.34(d,J=3.8Hz,4H),7.31–7.27(m,1H),7.17–7.07(m,2H),7.01(dd,J=7.0,1.6 Hz,1H),4.37(d,J=10.3Hz,1H),4.12(ddd,J=12.0,5.2,1.8Hz,1H),4.03(td,J=12.3,2.4Hz,1H),2.62 (ddd,J=18.0,7.8,1.5Hz,1H),2.49(ddd,J=18.2,10.4,8.4Hz,1H),2.14(s,4H),2.08–1.98(m,1H),1. 88(ddd,J=13.3,10.3,3.0Hz,1H),1.53(tdd,J=13.3,10.5,7.8Hz,1H),1.34(s,3H),1.31–1.21(m,1H); 13 C NMR (101MHz, CDCl3) δ146.96,141.30,136.77,128.47,127.97,127.55,127.51, 125.63,121.78,80.39,64.50,46.31,38.34,35.78,25.86,22.27,19.89,19.69.

Claims

1. A method for synthesizing 3-oxaterpenes by tandem polyene cyclization reactions initiated by oxonium ions, characterized in that: (E)-(6-(benzyloxy))-4-methylhex-3-en-1-yl)benzene and its derivatives as substrates, zinc bromide as catalyst, T + BF4 - as oxidant, 1,2-dichloroethane as solvent, activated Molecular sieves were used as dehydrating agents to react at 70°C to obtain 3-oxaterpenoid compounds. The reaction formula is as follows: Where: R 1 is selected from the group consisting of phenyl, vinyl, styryl, biphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-cyanophenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-iodo-phenyl; R 2 Selected from chlorine atom, methoxy group, methyl group.

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