Method for synthesizing 3-oxaterpene by oxonium ion-initiated tandem polyene cyclization reaction

Abstract

The invention relates to a method for synthesizing 3-oxaterpenoids through serial polyene cyclization reaction initiated by oxonium ions, and discloses a method for synthesizing 3-oxaterpenoids by taking (E)-(6-(benzyloxy))-4-methylhex-3-ene-1-yl) benzene and derivatives thereof as substrates, zinc bromide as a catalyst, T + BF4-as an oxidizing agent, 1, 2-dichloroethane as a solvent and an activated # imgabs0 # molecular sieve as a dewatering agent. And reacting at the temperature of 70 DEG C to obtain the 3-oxa-terpenoids. The method has good functional group tolerance, and an efficient and novel preparation method is provided for the 3-oxa-terpenoids.

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, widely exist in nature, and most of them have good physiological and pharmaceutical activities. Therefore, the simple and efficient synthesis of terpenes and steroidal compounds with polycyclic skeletons, chiral centers, and quaternary carbon centers has been a research hotspot in recent years. Among the many methods for synthesizing polycyclic molecules by selective CC bonds of chain molecules, polyene cyclization reaction is considered to be one of the unique and efficient methods for synthesizing polycyclic compounds because of its outstanding advantages of short synthesis steps and high atom economy. Oxonium ion is a highly reactive but extremely unstable transient species, which is prone to a series of reactions such as cycloaddition, nucleophilic substitution, carbene transfer, and migration rearrangement. Oxonium ion is often used as an intermediate for key transformation when constructing some specific ring system structures. In recent years, the research and application of oxonium ion in synthesis has made great progress. With the help of the excellent reactivity of oxonium ion, the construction of a variety of special ring systems can be realized, and the synthesis of some complex natural product molecules becomes possible. By designing suitable oxonium ion precursors, highly selective reactions between species can also be achieved. 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-oxadipenes have attracted great interest from biologists and chemists for their biological activity and medicinal potential. For example, the natural product molecule tinocapillins A (Scheme 1, A) isolated from the plant of the genus Tinocapillary of the Menispermaceae family has obvious inhibitory activity on the proliferation of A549, Hep G2, Hela and OS-RC-2 cancer cells; pharmacological studies of salvinorin A (Scheme 1, B) have shown that this natural product can bind to and activate peptide-ergic G protein-coupled receptors (GPCRs) in a completely new mode. In addition, salvinorin A can be used as a selective κ-opioid receptor agonist and is expected to be put into clinical application through further research and transformation; compound C has obvious cytotoxic activity (100% growth inhibition at 10ug / mL); compound D is slightly toxic to brine shrimp. Therefore, the development of green and efficient synthetic methods is of great significance for the research and application of this type of 3-oxadipenes with broad application prospects. Summary of the invention

[0004] The purpose of the present invention is to improve the shortcomings of existing preparation and synthesis methods and provide a method for synthesizing 3-oxaterpenes by 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 scheme 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 chlorine atom, methoxy group, methyl group, thienyl group and 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 oxidant used is selected from 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium tetrafluoroborate, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), cerium 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 synthesis conditions 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 4is 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] Fig. 9 is the preparation reaction formula of compound 2h;

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

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

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

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

[0027] Fig.14 is the preparation reaction formula of compound 2m;

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

[0029] Fig.16 is the preparation reaction formula of compound 2o;

[0030] Fig.17 is the preparation reaction formula of compound 2p;

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

[0032] Fig.19 This is the reaction formula for preparing compound 2r. DETAILED DESCRIPTION

[0033] The present invention is further described below through specific embodiments, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following embodiments, and all technologies implemented based on the above content of the present invention belong to 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 sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain product 2a.

[0037] The 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 sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain product 2b.

[0043] The product testing data are as follows:

[0044] 1 HNMR (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 sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, and the reaction was placed in an oil bath at 70°C for 4 h. After the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), and then quenched with saturated sodium thiosulfate solution. The reaction system was extracted with dichloromethane three times (1.5 mL×3), and the organic phases were combined and concentrated under vacuum to obtain a crude product, which was purified by silica gel column chromatography to finally obtain product 2c.

[0049] The 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 conditions, substrate 1d (1.0 equiv., 35 mg), activated Molecular sieve, 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, it was detected by TLC (petroleum ether / ethyl acetate = 8:1). It was quenched with a 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2d.

[0055] The 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 Using substrate (1e) as raw material (Reaction Formula 5)

[0058]

[0059] Under argon conditions, substrate 1e (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4- Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, and the reaction was placed in an oil bath at 70°C for 4 h. After the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), and then quenched with saturated sodium thiosulfate solution. The reaction system was extracted with dichloromethane three times (1.5 mL×3), and the organic phases were combined and concentrated under vacuum to obtain a crude product, which was purified by silica gel column chromatography to finally obtain the product 2e.

[0060] The product testing data are as follows:

[0061] 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.

[0062] Implementation Case 6 Using substrate (1f) as raw material (Reaction Formula 6)

[0063]

[0064] Under argon, substrate 1f (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2f.

[0065] The product testing data are as follows:

[0066] 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.

[0067] Implementation Case 7

[0068] Using substrate (1g) as raw material (reaction formula 7)

[0069]

[0070] Under argon conditions, 1 g (1.0 equiv., 35 mg) of substrate and activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain 2 g of the product.

[0071] The product testing data are as follows:

[0072] 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.

[0073] Implementation Case 8 Using substrate (1h) as raw material (reaction formula 8)

[0074]

[0075] Under argon conditions, substrate 1h (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed by TLC (petroleum ether / ethyl acetate = 8:1), it 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2h.

[0076] The product testing data are as follows:

[0077] 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.

[0078] Implementation Example 9 Using substrate (1i) as raw material (Reaction Formula 9)

[0079]

[0080] Under argon conditions, substrate 1i (1.0 equiv., 35 mg), activated Molecular sieve, 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, and the reaction was placed in an oil bath at 70 ° C for 4 h. After the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), and then quenched with saturated sodium thiosulfate solution. The reaction system was extracted with dichloromethane three times (1.5 mL×3), and the organic phases were combined and concentrated under vacuum to obtain a crude product, which was purified by silica gel column chromatography to finally obtain product 2i.

[0081] The product testing data are as follows:

[0082] 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.

[0083] Implementation Case 10

[0084] With substrate (1j) (reaction formula 10)

[0085]

[0086] Under argon, substrate 1j (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain product 2j.

[0087] The product testing data are as follows:

[0088] 1 H NMR (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,1H ),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.

[0089] Example 11 Using substrate (1k) as raw material (reaction formula 11)

[0090]

[0091] Under argon conditions, substrate 1k (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2k.

[0092] The product testing data are as follows:

[0093] 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 C NMR (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.

[0094] Example 12 Using substrate (11) as raw material (reaction formula 12)

[0095]

[0096] Under argon conditions, 1 l of substrate (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70°C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2l.

[0097] The product testing data are as follows:

[0098] 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.

[0099] Implementation Case 13 Using substrate (1m) as raw material (reaction formula 13)

[0100]

[0101] Under argon conditions, substrate 1m (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2m.

[0102] The product testing data are as follows:

[0103] 1 H NMR (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.

[0104] Example 14: Using substrate (1n) as raw material (reaction formula 14)

[0105]

[0106] Under argon conditions, substrate 1n (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2n.

[0107] The product testing data are as follows:

[0108] 1 HNMR(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. 4Hz,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, 1H),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.

[0109] Example 15 Using substrate (1o) as raw material (reaction formula 15)

[0110]

[0111] Under argon conditions, substrate 1o (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2o.

[0112] The product testing data are as follows:

[0113] 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.

[0114] Example 16 Using substrate (1p) as raw material (reaction formula 16)

[0115]

[0116] Under argon, the substrate 1p (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 -Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2p.

[0117] The product testing data are as follows:

[0118] 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.

[0119] Implementation Case 17 Using substrate (1q) as raw material (Reaction Formula 17)

[0120]

[0121] Under argon conditions, 1q of substrate (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70 ° C for 4 h, and after the reaction was completed by TLC (petroleum ether / ethyl acetate = 8:1), it 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2q.

[0122] The product testing data are as follows:

[0123] 1 HNMR(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),4.3 9(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, 10.3,3.2Hz,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.

[0124] Example 18 Using substrate (1r) as raw material (reaction formula 18)

[0125]

[0126] Under argon, substrate 1r (1.0 equiv., 35 mg), activated Molecular sieve, zinc bromide (0.1 equiv., 2.8 mg), T + BF4 - Oxidant (2.0 equiv., 61 mg), then 1 mL of ultra-dry DCE solvent was added, the reaction was placed in an oil bath at 70°C for 4 h, and after the reaction was completed, it was detected by TLC (petroleum ether / ethyl acetate = 8:1), 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 a crude product, which was purified by silica gel column chromatography to finally obtain the product 2r.

[0127] The product testing data are as follows:

[0128] 1 H NMR (400 MHz, CDCl3) δ7.34(d,J=3.8 Hz,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=10.3 Hz,1H),4.12(ddd,J=12.0,5.2,1.8 Hz,1H),4.03(td,J=12.3,2.4 Hz,1H),2.62(ddd,J=18.0,7.8,1.5 Hz,1H),2.49(ddd,J=18.2,10.4,8.4 Hz,1H),2.14(s,4H),2.08–1.98(m,1H),1.88(ddd,J=13.3,10.3,3.0 Hz,1H),1.53(tdd,J=13.3,10.5,7.8 Hz,1H),1.34(s,3H),1.31–1.21(m,1H); 13 C NMR(101 MHz, 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 reaction initiated by oxonium ions, characterized in that (E)-(6-(benzyloxy))-4-methylhex-3-en-1-yl)benzene and its derivatives are used as substrates, zinc bromide is used as a catalyst, T + BF4 - as oxidant, 1,2-dichloroethane as solvent, activated Molecular sieves were used as dehydrating agents to obtain 3-oxaterpenoid compounds at 70°C. The reaction formula is as follows: in: 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, thienyl group and phenyl group.

2. The method for synthesizing 3-oxaterpenes by tandem polyene cyclization reaction initiated by an oxonium ion according to claim 1, characterized in that: The organic solvent used is selected from 1,2-dichloroethane, dichloromethane, chloroform, toluene, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, preferably 1,2-dichloroethane.

3. The method for synthesizing 3-oxaterpenes by tandem polyene cyclization reaction initiated by an oxonium ion according to claim 1, characterized in that: The oxidant used is selected from 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium tetrafluoroborate, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), cerium ammonium nitrate, tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide, potassium persulfate, tetrachlorobenzoquinone, preferably 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium tetrafluoroborate.

4. The method for synthesizing 3-oxaterpenes by tandem polyene cyclization reaction initiated by an oxonium ion according to claim 1, characterized in that: The heating temperature used is selected from 25-90°C, preferably 70°C.

5. The method for synthesizing 3-oxaterpenes through a tandem polyene cyclization reaction initiated by an oxonium ion according to claim 1, characterized in that: The Lewis acid used is selected from indium trichloride, copper acetate, zinc chloride, zinc bromide, preferably zinc bromide.

6. The method for synthesizing 3-oxaterpenes by tandem polyene cyclization reaction initiated by oxonium ions according to claim 1, characterized in that: 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.

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