A chiral cyclic monoterpene derivative and its synthesis method

Abstract

The present invention relates to a method for synthesizing chiral cyclic monoterpene derivatives. Specifically, an aromatic heterocyclic compound reacts with isoprene under the action of a zero-valent nickel catalyst and a chiral N-heterocyclic carbene ligand. The present invention obtains a series of chiral cyclic monoterpene derivatives through simple and safe steps.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing non-natural chiral cyclic monoterpene derivatives. Background Art

[0002] Terpenoids are the largest family of plant secondary metabolites, widely distributed in nature, and are compounds and their derivatives composed of several isoprene units. In nature, isopentenyl pyrophosphate and dimethylallyl pyrophosphate are used by various terpene synthases to synthesize various monoterpenes and their derivatives. Although nature has evolved for millions of years, there are only seven representative cyclic monoterpene skeletons, which restricts the development of compound diversity. As a cheap bulk chemical, isoprene has attracted extensive attention in the scientific research community and the industrial community as a raw material for the synthesis of fine chemicals. The direct conversion of isoprene into terpenoids not only helps the effective selective conversion of the bulk chemical isoprene, but also provides guidance for the diverse synthesis of terpenoids.

[0003] Compared with the traditional synthesis of monoterpene derivatives, the route used in the present invention is concise, the raw materials are cheap and easily available, the target product can be obtained in one step, and the product has excellent enantioselectivity, regioselectivity and chemoselectivity. The generated cyclic monoterpene skeleton is a non-natural skeleton, which not only enriches the diversity of terpenoids, but also lays a foundation for the biomimetic synthesis of terpenoids.

[0004] In summary, a method for enantioselectively synthesizing non-natural cyclic monoterpenes with simple steps and mild conditions is described herein. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for synthesizing non-natural chiral cyclic monoterpene derivatives.

[0006]

[0007] Reaction Equation 1: Method for Synthesizing Chiral Cyclic Monoterpene Derivatives

[0008] The specific operation steps are as follows:

[0009] The reaction is carried out in a reactor. Under the protection of an inert gas, an aromatic heterocyclic compound 1, isoprene 2, a nickel catalyst, a N-heterocyclic carbene ligand, an additive, and a solvent are sequentially added, and the reaction is carried out at 100 °C for 24 hours; after the reaction is completed, the chiral cyclic monoterpene derivative 3 is separated.

[0010] Among them, the aromatic heterocyclic compound includes one or two of purine derivatives or imidazole derivatives. The specific structures are:

[0011]

[0012]

[0013] The molar ratio of the aromatic heterocyclic compound to isoprene is 1:8 - 1:4, and the preferred ratio is 1:6 - 1:4.

[0014] The nickel catalyst is one or more of bis(1,5-cyclooctadiene)nickel, nickel acetylacetonate, nickel chloride, nickel bromide, nickel fluoride; preferably bis(1,5-cyclooctadiene)nickel; the amount of the nickel catalyst is 1 - 10% molar equivalent (relative to the aromatic heterocyclic compound), preferably 1 - 5% molar equivalent.

[0015] The additive is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium tert-butoxide, lithium methoxide, sodium isopropoxide, potassium carbonate; preferably sodium ethoxide, sodium tert-butoxide, sodium isopropoxide; the amount of the additive is 10 - 100% molar equivalent (relative to the aromatic heterocyclic compound), preferably 80 - 100% molar equivalent.

[0016] The solvent is changed to one or more of toluene, n-hexane, dichloromethane, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, ethyl acetate, trifluorotoluene; preferably toluene, N-methylpyrrolidone, n-hexane and trifluorotoluene, and the amount of the solvent is 5 - 10 mL of the solvent per millimole of the aromatic heterocyclic compound 1, preferably 5 - 6 mL.

[0017] The N-heterocyclic carbene ligand is one or two of the following, and the structures of L1, L2, L3, L4, L5, L6, L7 are shown as follows. Preferably L7, and the amount of the N-heterocyclic carbene ligand is 1 - 10% molar equivalent (relative to the aromatic heterocyclic compound), preferably 1 - 5% molar equivalent.

[0018]

[0019] The present invention has the following advantages:

[0020] First, the reaction raw materials, the aromatic heterocyclic compound and isoprene, are both simple and easily available. Second, the reaction conditions are mild and safe, and the reaction steps are simple and efficient. Finally, the obtained product is a novel class of non-natural chiral cyclic monoterpene derivatives with excellent yield and enantioselectivity. Specific Embodiments

[0021] To better understand the present invention, it is described through the following examples, and the reaction raw materials and results of Examples 1 - 40 are shown in Table 1.

[0022] Table 1 Reaction Results of Different Aromatic Heterocyclic Compounds

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031] As can be seen from the results in Table 1: Different aromatic heterocyclic compounds can all be converted into chiral cyclic monoterpene derivatives in high yields and high enantioselectivities under the action of nickel catalyst and chiral N-heterocyclic carbene ligand with isoprene.

[0032] Example 1

[0033] The reaction was carried out in a reactor. Aromatic heterocyclic compound 1a (0.2 mmol), isoprene 2a (0.8 mmol), bis(1,5-cyclooctadiene)nickel Ni(COD)2 (0.01 mmol), N-heterocyclic carbene L7 (0.01 mmol), sodium ethoxide (0.2 mmol), and toluene (1.0 mL) were successively added and reacted at 100 °C for 24 hours. After the reaction was completed, chiral cyclic monoterpene derivative 3a was obtained by column chromatography separation with a yield of 96% and an ee value of 93%. The structure of the compound was identified by nuclear magnetic resonance (1H NMR and 13C NMR) and high-resolution mass spectrometry.

[0034] Compound 3a has good activity in inhibiting monoamine oxidase B, with an IC50 value of 5.43 ± 1.32 μM. The specific operation is as follows: Potassium phosphate buffer (concentration 100 mM, pH 7.4) is used as the medium solution for the enzymatic reaction. Compound 3a is dissolved in DMSO with a concentration gradient range of 0.003 - 100 μM (samples are taken at 0.01, 0.1, 1.0, 10.0, and 100.0 μM respectively), and then transferred to the above medium solution so that the final mass fraction of DMSO is 4% as the co-solvent for the enzymatic reaction. The reaction medium contains kynurenine as the substrate (1.0 M), and the concentration of monoamine oxidase B is 30 μM. The reaction (500 μL) is carried out at 37 °C for 30 minutes, and 400 μL of sodium hydroxide solution (2 M) and 1000 μL of water are added to terminate the reaction. The 4-hydroxyquinoline catalyzed by monoamine oxidase B is measured by fluorescence spectroscopy (excitation wavelength 310 nm, emission wavelength 400 nm). Finally, the IC50 value is obtained by fitting the calibration curve (ordinate is the reaction rate (i.e., the formation rate of the product), abscissa is the logarithm of the concentration of 3a).

[0035] The test data is as follows:

[0036] 3a: white solid, melting point: 128 - 129 °C, 63.1 mg, 96% yield, 93% ee, [α] 20 D = +26.00 (c 1.05, CHCl3), R f = 0.51 (PE / EA = 1:1). 1 1H NMR (400 MHz, Chloroform - d) δ 5.29 (s, 1H), 3.89 (s, 3H), 3.55 (s, 3H), 3.38 (s, 3H), 2.80 - 2.60 (m, 2H), 2.06 - 1.84 (m, 3H), 1.85 - 1.73 (m, 1H), 1.70 - 1.56 (m, 5H), 1.46 (t, J = 6.4 Hz, 2H), 0.96 (s, 3H). 13 13C NMR (100 MHz, Chloroform - d) δ 155.29, 154.97, 151.71, 147.98, 132.94, 119.25, 107.32, 38.68, 37.41, 33.72, 31.64, 31.04, 29.74, 27.85, 27.46, 24.03, 23.34, 21.65. HRMS calculated for C 18 H 27 N4O2 [M + H] + 331.2134, found 331.2128. HPLC: Chiralpak IE column, 254 nm, 30 °C, n Hexane / i PrOH = 80 / 20, flow = 1.0 mL / min, retention time 40.9 min (maj.) and 47.5 min.

[0037] Example 2:

[0038] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the difference in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N - methylpyrrolidone (volume ratio 10 / 1), the dosage is 1.1 mL, the yield of product 3b is 88%, the ee value is 93%, and the structure of the compound is identified by nuclear magnetic resonance (1H - NMR and 13C - NMR) and high - resolution mass spectrometry.

[0039] Example 3:

[0040] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), the dosage is 1.1 mL, the yield of product 3c is 73%, the ee value is 93%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0041] Example 4:

[0042] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), the dosage is 1.1 mL, the yield of product 3d is 96%, the ee value is 94%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0043] Example 5:

[0044] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), the dosage is 1.1 mL, the yield of product 3e is 87%, the ee value is 94%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0045] Example 6:

[0046] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), the dosage is 1.1 mL, the yield of product 3f is 96%, the ee value is 94%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0047] Example 7:

[0048] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / trifluorotoluene (volume ratio 10 / 1), the dosage is 1.1 mL, the additive is sodium tert-butoxide, the dosage is 0.2 millimolar equivalent, the yield of product 3g is 22%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0049] Example 8:

[0050] The operation process and conditions are the same as those in Example 1. The differences from Example 1 are as follows: Except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / trifluorotoluene (volume ratio 10 / 1), with a dosage of 1.1 mL, the additive is sodium tert-butoxide, with a dosage of 1.0 millimolar equivalent, the yield of the product after 3 h is 57%, the ee value is 93%, and the compound is characterized by nuclear magnetic resonance (proton spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0051] Example 9:

[0052] The operation process and conditions are the same as those in Example 1. The differences from Example 1 are as follows: Except for the differences in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, with a dosage of 100% millimolar equivalent (relative to aromatic heterocyclic compound 1i), the yield of the product 3i is 90%, the ee value is 93%, and the structure of the compound is identified by nuclear magnetic resonance (proton spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0053] Example 10:

[0054] The operation process and conditions are the same as those in Example 1. The differences from Example 1 are as follows: Except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), with a dosage of 1.1 mL, the yield of the product 3j is 40%, the ee value is 93%, and the structure of the compound is identified by nuclear magnetic resonance (proton spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0055] Example 11:

[0056] The operation process and conditions are the same as those in Example 1. The differences from Example 1 are as follows: Except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), with a dosage of 1.1 mL, the yield of the product 3k is 72%, the ee value is 93%, and the structure of the compound is identified by nuclear magnetic resonance (proton spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0057] Example 12:

[0058] The operation process and conditions are the same as those in Example 1. The differences from Example 1 are as follows: Except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), with a dosage of 1.1 mL, the yield of the product 3l is 93%, the ee value is 92%, and the structure of the compound is identified by nuclear magnetic resonance (proton spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0059] Example 13:

[0060] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), the dosage is 1.1 mL, the yield of product 3m is 87%, the ee value is 91%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0061] Example 14:

[0062] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, the dosage is 100% millimolar equivalent (relative to aromatic heterocyclic compound 1n), the yield of product 3n is 51%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0063] Example 15:

[0064] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), the dosage is 1.1 mL, the yield of product 3o is 96%, the ee value is 93%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0065] Example 16:

[0066] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), the dosage is 1.1 mL, the yield of product 6a is 92%, the ee value is 94%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0067] Example 17:

[0068] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that the aromatic heterocyclic compounds described in Table 1 are different. The yield of product 6b is 76%, the ee value is 93%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0069] Example 18:

[0070] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that the aromatic heterocyclic compounds described in Table 1 are different. The yield of product 6c is 91%, the ee value is 95%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum and fluorine spectrum) and high-resolution mass spectrometry.

[0071] Example 19:

[0072] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, and the dosage is 100% millimole equivalent (relative to aromatic heterocyclic compound 5d). The yield of product 6d is 75%, and the ee value is 95%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0073] Example 20:

[0074] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is the different aromatic heterocyclic compounds described in Table 1. The yield of product 6e is 43%, and the ee value is 94%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0075] Example 21:

[0076] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the additive is sodium isopropoxide, and the dosage is 100% millimole equivalent (relative to aromatic heterocyclic compound 5f). The yield of product 6f is 71%, and the ee value is 94%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0077] Example 22:

[0078] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, and the dosage is 100% millimole equivalent (relative to aromatic heterocyclic compound 5g). The yield of product 6g is 74%, and the ee value is 93%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0079] Example 23:

[0080] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is the different aromatic heterocyclic compounds described in Table 1. The yield of product 6h is 80%, and the ee value is 94%. The structure of the compound was identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0081] Example 24:

[0082] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the additive is sodium isopropoxide, and the dosage is 100% millimole equivalent relative to aromatic heterocyclic compound 5i). The yield of product 6i is 54%, and the ee value is 93%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0083] Example 25:

[0084] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the difference in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, and the dosage is 100% milliequivalent relative to the aromatic heterocyclic compound 5j). The yield of the product 6j is 46%, and the ee value is 93%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0085] Example 26:

[0086] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the difference in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, and the dosage is 100% milliequivalent relative to the aromatic heterocyclic compound 5k). The yield of the product 6k is 98%, and the ee value is 94%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0087] Example 27:

[0088] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the difference in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, and the dosage is 100% milliequivalent relative to the aromatic heterocyclic compound 5l). The yield of the product 6l is 90%, and the ee value is 94%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0089] Example 28:

[0090] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the difference in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, and the dosage is 100% milliequivalent relative to the aromatic heterocyclic compound 5m). The yield of the product 6m is 92%, and the ee value is 93%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0091] Example 29:

[0092] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the difference in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, and the dosage is 100% milliequivalent relative to the aromatic heterocyclic compound 5n). The yield of the product 6n is 98%, and the ee value is 93%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0093] Example 30:

[0094] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, and the dosage is 100% millimolar equivalent relative to the aromatic heterocyclic compound 5o). The yield of product 6o is 86%, and the ee value is 93%. The structure of the compound was identified by infrared spectroscopy, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0095] Example 31:

[0096] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is the different aromatic heterocyclic compounds described in Table 1. The yield of product 8a is 91%, and the ee value is 94%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0097] Example 32:

[0098] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the additive is sodium tert-butoxide, and the dosage is 100% millimolar equivalent (relative to the aromatic heterocyclic compound 7b). The yield of product 8b is 65%, and the ee value is 94%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0099] Example 33:

[0100] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), and the dosage is 1.1 mL. The yield of product 8c is 75%, and the ee value is 93%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0101] Example 34:

[0102] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is the different aromatic heterocyclic compounds described in Table 1. The yield of product 8d is 45%, and the ee value is 93%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0103] Example 35:

[0104] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences in the aromatic heterocyclic compounds described in Table 1, the solvent is changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), and the dosage is 1.1 mL. The yield of product 8e is 36%, and the ee value is 94%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0105] Example 36:

[0106] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, except for the difference in the aromatic heterocyclic compounds described in Table 1, the solvent was changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), with a dosage of 1.1 mL. The yield of product 8f was 45%, and the ee value was 93%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR) and high-resolution mass spectrometry.

[0107] Example 37:

[0108] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, except for the difference in the aromatic heterocyclic compounds described in Table 1, the solvent was changed to toluene / N-methylpyrrolidone (volume ratio 10 / 1), with a dosage of 1.1 mL. The yield of product 8g was 64%, and the ee value was 93%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR) and high-resolution mass spectrometry.

[0109] Example 38:

[0110] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that the aromatic heterocyclic compounds described in Table 1 were different. The yield of product 8h was 95%, and the ee value was 94%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR) and high-resolution mass spectrometry.

[0111] Example 39:

[0112] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, except for the difference in the aromatic heterocyclic compounds described in Table 1, the solvent was changed to toluene / trifluorotoluene (volume ratio 10 / 1), with a dosage of 1.1 mL, and the temperature was 120 °C. The yield of product 8i was 83%, and the ee value was 95%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR) and high-resolution mass spectrometry.

[0113] Example 40:

[0114] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, except for the difference in the aromatic heterocyclic compounds described in Table 1, the additives were sodium tert-butoxide with a dosage of 100% millimolar equivalent (relative to aromatic heterocyclic compound 7j) and iron(III) chloride with a dosage of 50% millimolar equivalent (relative to aromatic heterocyclic compound 7j). The yield of product 8j was 97%, and the ee value was 96%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR) and high-resolution mass spectrometry.

[0115] Comparative Example 1:

[0116] The raw materials, operation process and conditions were the same as those in Example 1. The difference from Example 1 was that no nickel catalyst was added, and product 3a was not obtained.

[0117] Comparative Example 2:

[0118] The raw materials, operation procedures and conditions are the same as those in Example 1. The difference from Example 1 is that sodium ethoxide as an additive is not added, and product 3a is not obtained.

[0119] Comparative Example 3:

[0120] The raw materials, operation procedures and conditions are the same as those in Example 1. The difference from Example 1 is that the nickel catalyst is changed to nickel carbonate, and the dosage is 5% millimole equivalent (relative to aromatic heterocyclic compound 1a), and product 3a is not obtained.

[0121] Comparative Example 4:

[0122] The raw materials, operation procedures and conditions are the same as those in Example 1. The difference from Example 1 is that sodium ethoxide as an additive is changed to sodium carbonate, and the dosage is 100% millimole equivalent (relative to aromatic heterocyclic compound 1a), and product 3a is not obtained.

Claims

1. A method for synthesizing a chiral cyclic monoterpene derivative, characterized in that: An aromatic heterocyclic compound and isoprene are used as raw materials to produce a chiral cyclic monoterpene derivative; Among them, the specific structure of the aromatic heterocyclic compound is as follows: , The following aromatic heterocyclic compound 1 and isoprene 2 are used as raw materials to produce a chiral cyclic monoterpene derivative 3, and the reaction formula is as follows: ， Among them, the structural formula of the aromatic heterocyclic compound 1 is shown as follows in 1a: , The nickel catalyst used is one or more of bis(1,5-cyclooctadiene)nickel, nickel acetylacetonate, nickel chloride, nickel bromide, nickel fluoride; The additive is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium tert-butoxide, lithium methoxide, sodium isopropoxide, potassium carbonate.

2. The method according to claim 1, wherein: The specific operation steps are as follows: The reaction is carried out in a reactor. Under the protection of an inert atmosphere, an aromatic heterocyclic compound, isoprene, a nickel catalyst, a N-heterocyclic carbene ligand, an additive, and a solvent are added in sequence, and the reaction is carried out at 100 - 120 °C for 12 - 24 hours; after the reaction is completed, the chiral cyclic monoterpene derivative is separated.

3. According to the method described in claim 1 or 2, characterized in that: The molar ratio of the aromatic heterocyclic compound to isoprene is 1:8 - 1:

4.

4. According to the method described in claim 1 or 2, characterized in that: The nickel catalyst used is bis(1,5-cyclooctadiene)nickel; the amount of the nickel catalyst is 1 - 10% molar equivalent relative to the aromatic heterocyclic compound.

5. According to the method described in claim 1 or 2, characterized in that: The additive is one or more of sodium ethoxide, sodium tert-butoxide, sodium isopropoxide; the amount of the additive is 10 - 100% molar equivalent relative to the aromatic heterocyclic compound.

6. According to the method described in claim 1 or 2, characterized in that: The solvent is one or more of toluene, n-hexane, dichloromethane, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, ethyl acetate, trifluorotoluene; the amount of the solvent is 5 - 10 mL of the solvent per millimole of the aromatic heterocyclic compound.

7. According to the method described in claim 1 or 2, characterized in that: The molar ratio of the aromatic heterocyclic compound to isoprene is 1:6 - 1:4, The amount of the nickel catalyst is 1 - 5% molar equivalent relative to the aromatic heterocyclic compound; The amount of the additive is 80 - 100% molar equivalent relative to the aromatic heterocyclic compound; The solvent is one or more of toluene, N-methylpyrrolidone, n-hexane, and trifluorotoluene, and the amount of the solvent is 5 - 6 mL of the solvent per millimole of the aromatic heterocyclic compound.

8. According to the method described in claim 1 or 2, characterized in that: The N-heterocyclic carbene ligand is one or more of the compounds shown in the following L1, L2, L3, L4, L5, L6, L7 structures; the amount of the N-heterocyclic carbene ligand is 1 - 10% molar equivalent relative to the aromatic heterocyclic compound, 。 9. The method according to claim 8, characterized in that: The amount of the N-heterocyclic carbene ligand is 1 - 5% molar equivalent relative to the aromatic heterocyclic compound.

10. A chiral cyclic monoterpene compound, characterized in that: The structural formula of the chiral cyclic monoterpene compound is as follows: 。

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