An enantioselective synthesis method of a diterpene derivative and the diterpene derivative

Abstract

The present invention relates to an enantioselective synthesis method of diterpene derivatives. Specifically, coffee reacts with conjugated dienes under the action of a nickel catalyst and a chiral N-heterocyclic carbene ligand. A series of chiral diterpene, triterpene, and tetraterpene derivatives are obtained through concise and safe steps.

Description

Technical Field

[0001] The present invention relates to a method for the enantioselective synthesis of diterpene derivatives. Background Art

[0002] Terpenoids are widely distributed in nature and play a crucial role in human daily life. According to the number of carbon atoms, terpenoids can be divided into monoterpenes (10 carbon atoms), sesquiterpenes (15 carbon atoms), diterpenes (20 carbon atoms), triterpenes (30 carbon atoms), and polyterpenes, etc. Since most terpenoid molecules have different numbers of carbon rings, they can also be divided into acyclic terpenes, monocyclic terpenes, bicyclic terpenes, tricyclic terpenes, etc. Caffeine, as an important alkaloid, has important physiological and pharmacological activities. However, there are very few reports on the diverse transformation of caffeine, and the synthesis of polyterpenoid compounds using caffeine and conjugated dienes and their derivatives has not been reported yet. Herein, we used cheap and readily available conjugated dienes and their derivatives such as myrcene, and through a strategy of biomimetic catalysis, a series of diterpenes, triterpenes, tetraterpenes and their derivatives were prepared. This not only enriches the diversity of polyterpene derivatives, but also lays a foundation for the research of the functions of terpenoid compounds in the scientific community.

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

[0004] In summary, a method for the enantioselective synthesis of polyterpene derivatives with simple steps, mild conditions is described herein. Summary of the Invention

[0005] The object of the present invention is to provide a method for the enantioselective synthesis of polyterpene derivatives.

[0006]

[0007] Reaction Equation 1: Method for the enantioselective synthesis of polyterpene 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, caffeine, conjugated diene, nickel catalyst, N-heterocyclic carbene ligand, additive, and solvent are sequentially added, and the reaction is carried out at 100 °C for 24 hours; after the reaction is completed, the polyterpene derivative 3 is separated.

[0010] Among them, the conjugated diene includes one or two of myrcene and its derivatives, ocimene, and other conjugated dienes. Specifically:

[0011]

[0012] The molar dosage ratio of caffeine to conjugated diene is 1:8 - 1:4, and the preferred ratio is 1:6 - 1:4.

[0013] 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 dosage of the nickel catalyst is 1 - 10% molar equivalent (relative to caffeine), preferably 1 - 5% molar equivalent.

[0014] 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 dosage of the additive is 10 - 100% molar equivalent (relative to caffeine), preferably 80 - 100% molar equivalent.

[0015] 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 dosage of the solvent is 5 - 10 mL of solvent per millimole of aromatic heterocyclic compound 1, preferably 5 - 6 mL.

[0016] The N-heterocyclic carbene ligand is one or two of the following, and the structures of L1, L2, L3, and L4 are shown as follows. Preferably L4, and the dosage of the N-heterocyclic carbene ligand is 1 - 10% molar equivalent (relative to caffeine), preferably 1 - 5% molar equivalent.

[0017]

[0018] The present invention has the following advantages:

[0019] Firstly, the reaction raw materials caffeine and conjugated diene are both simple and easily available. Secondly, 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 terpene derivatives with excellent yield and enantioselectivity. Detailed implementation mode

[0020] To better understand the present invention, it is illustrated by the following examples, and the reaction raw materials and results of Examples 1 - 5 are shown in Table 1.

[0021] Table 1 Reaction results of different conjugated dienes

[0022]

[0023] Specifically:

[0024]

[0025]

[0026] As can be seen from the results in Table 1: Caffeine reacts with conjugated diene under the action of a nickel catalyst and a chiral N-heterocyclic carbene ligand. The present invention obtains a series of chiral diterpenes, triterpenes, and tetraterpene derivatives through simple and safe steps.

[0027] Example 1

[0028] The reaction was carried out in a reactor. Caffeine 1 (0.2 mmol), conjugated diene 2a (0.8 mmol), bis(1,5-cyclooctadiene)nickel Ni(COD)2 (0.01 mmol), N-heterocyclic carbene L4 (0.01 mmol), sodium tert-butoxide (0.2 mmol), and n-hexane (1.0 mL) were successively added and reacted at 100 °C for 24 hours. After the reaction, chiral cyclic monoterpene derivative 3a was obtained by column chromatography separation with a yield of 83% and an ee value of 97%. The structure of the compound was identified by nuclear magnetic resonance (1H NMR and 13C NMR) and high-resolution mass spectrometry.

[0029] Compound 3a has good activity against monoamine oxidase A type, with an IC50 value of 59.4 ± 10.0 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 (0.01, 0.1, 1.0, 10.0, 100.0 μM are sampled 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), the concentration of monoamine oxidase A is 30 μM, and the reaction (500 μL) is carried out at 37 °C for 30 minutes. 400 μL of sodium hydroxide solution (2 M) and 1000 μL of water are added to terminate the reaction. 4-Hydroxyquinoline produced by the catalysis of monoamine oxidase A 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 production rate of the product), abscissa is the logarithm of the concentration of 3a).

[0030] The detection data are as follows:

[0031] 3a: colorless oil, 38.9 mg, 83% yield (0.1 mmol scale), 97% ee. [α] 20 D = +7.90 (c 0.72, CHCl3), Rf = 0.69 (PE / EA = 1:1). 1 H NMR (400 MHz, Chloroform-d) δ 5.30 (s, 1H), 5.14 - 4.98 (m, 2H), 3.89 (s, 3H), 3.54 (s, 3H), 3.37 (s, 3H), 2.71 - 2.59 (m, 2H), 2.11 - 2.03 (m, 2H), 2.01 - 1.90 (m, 6H), 1.90 - 1.85 (m, 2H), 1.78 - 1.69 (m, 1H), 1.69 - 1.62 (m, 6H), 1.61 - 1.57 (m, 6H), 1.55 - 1.45 (m, 2H), 1.42 - 1.33 (m, 1H), 1.32 - 1.17 (m, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 155.27, 154.97, 151.70, 148.00, 136.69, 131.39, 131.37, 124.70, 124.22, 118.88, 107.29, 37.44, 36.34, 36.01, 34.18, 33.60, 31.62, 31.57, 29.70, 27.83, 26.40, 25.70, 25.68, 25.40, 21.99, 21.30, 17.68, 17.66. HRMS calculated for C 28 H 43 N4O2 [M + H] + 467.3386, found 467.3387. HPLC: Chiralcel OX-3 column, 254 nm, 35 °C, n Hexane / EtOH / Et2NH = 95 / 5 / 0.1, flow = 1.0 mL / min, retention time 51.1 min (maj.) and 54.3 min.

[0032] Example 2:

[0033] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the conjugated diene difference described in Table 1, the solvent is changed to toluene with a dosage of 1.0 mL. The yield of product 3b is 82%, and the ee value is 92%. The structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0034] Example 3:

[0035] 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 conjugated dienes described in Table 1, the solvent is changed to toluene with a dosage of 1.0 mL. The yield of product 3c is 76%, the dr is >20:1, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0036] Example 4:

[0037] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is the conjugated diene described in Table 1. The yield of product 3d is 96%, and the ee value is 93%. The structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0038] Example 5:

[0039] 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 conjugated dienes described in Table 1, the solvent is changed to tetrahydrofuran with a dosage of 1.0 mL. The yield of product 3e is 68%, and the dr value is 1:1. The structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0040] Comparative Example 1:

[0041] The raw materials, operation process and conditions are the same as those in Example 1. The difference from Example 1 is that no nickel catalyst is added, and product 3a is not obtained.

[0042] Comparative Example 2:

[0043] The raw materials, operation process and conditions are the same as those in Example 1. The difference from Example 1 is that no N-heterocyclic carbene is added, and product 3a is not obtained.

[0044] Comparative Example 3:

[0045] The raw materials, operation process and conditions are the same as those in Example 1. The difference from Example 1 is that the nickel catalyst bis(1,5-cyclooctadiene)nickel is changed to nickel iodide with a dosage of 5% millimole equivalent (relative to caffeine 1), and product 3a is not obtained.

[0046] Comparative Example 4:

[0047] The raw materials, operation process and conditions are the same as those in Example 1. The difference from Example 1 is that the additive sodium tert-butoxide is changed to triethylamine with a dosage of 100% millimole equivalent (relative to caffeine 1), and product 3a is not obtained.

Claims

1. An enantioselective synthesis method of a diterpene derivative, characterized in that: Using caffeine and conjugated diene as raw materials to generate chiral diterpene, triterpene, and tetraterpene derivatives; Using the aromatic heterocyclic compound caffeine 1 and conjugated diene 2 shown in the following formula as raw materials to generate chiral cyclic diterpene derivatives 3, and the reaction formula is as follows: ， wherein the substituent R is: , The nickel catalyst used is one or more of bis(1,5-cyclooctadiene)nickel, nickel acetylacetonate, nickel chloride, nickel bromide, and nickel fluoride; The additive is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium tert-butoxide, lithium methoxide, sodium isopropoxide, and potassium carbonate; The N-heterocyclic carbene ligand is one or more of the compounds shown in the following L1, L2, L3, and L4 structures, 。 2. The method according to claim 1, characterized in that: Among them, the conjugated diene 2 includes one or more of the following structural formulas: 。 3. The method according to claim 1, wherein: The specific operation steps are as follows: React in a reactor. Under the protection of an inert gas, add caffeine, conjugated diene, nickel catalyst, N-heterocyclic carbene ligand, additive, and solvent in sequence, and react at 100-120 °C for 12-24 hours; after the reaction is completed, separate to obtain the diterpene derivative 3.

4. The method according to claim 1 or 3, characterized in that: The molar ratio of caffeine to conjugated diene is 1:8 - 1:

4.

5. The method according to claim 4, characterized in that: The molar ratio of caffeine to conjugated diene is 1:6 - 1:

4.

6. The method according to claim 1 or 3, 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 caffeine.

7. The method according to claim 6, characterized in that: The amount of the nickel catalyst is 1-5% molar equivalent relative to caffeine.

8. The method according to claim 1 or 3, characterized in that: The additive is one or more of sodium ethoxide, sodium tert-butoxide, and sodium isopropoxide; the amount of the additive is 10-100% molar equivalent relative to caffeine.

9. The method according to claim 8, wherein: The amount of the additive is 80-100% molar equivalent relative to caffeine.

10. The method according to claim 1 or 3, characterized in that: The solvent is one or more of toluene, n-hexane, dichloromethane, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, ethyl acetate, and trifluorotoluene; the amount of the solvent is 5-10 ml of solvent per millimole of caffeine 1.

11. The method according to claim 10, wherein: 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 solvent per millimole of caffeine 1.

12. The method according to claim 1 or 3, characterized in that: The N-heterocyclic carbene ligand is L4; the amount of the N-heterocyclic carbene ligand is 1-10% molar equivalent relative to caffeine.

13. The method according to claim 12, characterized in that: The amount of the N-heterocyclic carbene ligand is 1-5% molar equivalent relative to caffeine.

14. A diterpene derivative, characterized in that: The structural formula of the chiral cyclic diterpene derivative 3 is shown as follows: , the substituent R is: .

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