Asymmetric synthesis method of (R)-muscone

Abstract

The invention discloses an asymmetric synthesis method of (R)-muscone, specifically, a novel chiral catalyst generated by coordination of a chiral ligand and a copper salt is used for catalyzing asymmetric synthesis of (R)-muscone, and the reaction selectivity and yield are both very high. According to the novel chiral catalyst, expensive metal is not used, and a satisfactory catalytic effect can be achieved by using a very low amount of chiral ligand, so that the production cost is greatly saved. The asymmetric synthesis method is simple in route and convenient to operate, and satisfactory selectivity and yield can be achieved without extremely low reaction temperature.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and provides an asymmetric synthesis method of (R)-musk ketone. Background Art

[0002] Musk is a secretion from the glandular sac under the abdomen of male musk deer, which is in the form of blocks or particles. Musk can open up all the orifices, open up the meridians, and penetrate the muscles and bones. It is mainly used to treat wind phlegm, typhoid fever, plague, summer heat, dryness, qi stagnation, sores, eye diseases and many other diseases. In the catalog of Chinese patent medicines in my country, there are 298 kinds of Chinese patent medicines that need to be compatible with musk. Musk is not only a precious Chinese medicinal material, but also a precious animal fragrance. It has a sweet, strong and rich musk aroma, an extremely low aroma threshold, and a long-lasting fragrance. It can be well blended with various spices and is an indispensable additive for various high-end flavors and high-end cosmetics.

[0003] Musk ketone is the main fragrance component of natural musk, and its content in natural musk is 0.5-2.0%. The chemical structure of musk ketone is 3-methylcyclopentadecanone. Natural musk ketone is in the (R) configuration, but the commercially available product is mainly a racemate, that is, an equal mixture of (R) and (S) configurations. Comparing the aroma of (R)-musk ketone and (S)-musk ketone, (R)-musk ketone has a full, strong, and highly diffusible aroma (threshold: 3ppm); (S)-musk ketone has an unfull aroma and a weak aroma (threshold 10ppm). In terms of aroma intensity, (R)-musk ketone is three times that of (S)-musk ketone, so people are more inclined to obtain (R)-musk ketone.

[0004] In 1951, Stallberg-stenhagen and Ark Kemi first synthesized musk ketone. Since then, new synthetic methods of musk ketone have continued to emerge. However, there are still few reports in the literature on the asymmetric synthesis of (R)-musk ketone.

[0005] In 1990, Tanaka et al. used chiral amino alcohol ligands and CuI and MeLi to perform asymmetric Michael addition on 2-cyclopentadecenone in toluene solution, and obtained (R)-musk ketone with an optical purity of 99% and a yield of 80% (J. Chem. Soc., Chem. Commun., 1990, 795; J. Chem. Soc. Perkin. Trans. 1. 1993, 153). This asymmetric synthesis method has high yield and optical purity, but the method has extremely high requirements for refrigeration equipment (-78°C), and the reaction process requires repeated cooling and heating. The reaction is time-consuming and complicated to operate. In addition, the chiral inducing agent used in the reaction is difficult to synthesize and has no commercial source, so it cannot be industrialized.

[0006]

[0007] In recent years, olefin metathesis has been widely used in the synthesis of small molecules. In 2000, the Hagiwara group of Niigata University in Japan reported the synthesis of (R)-musk ketone by using citronellal as a chiral methyl source and constructing a 15-membered ring using the RCM reaction (J. Chem. Soc. Perkin. Trans. I. 1998, 2253; Tetrahedron. 2000, 56, 4397). This method is relatively long and has no practical value.

[0008]

[0009] In 2002, Yamamoto et al. obtained 3-methylcyclopentadecenone from 2,15-hexadecanedione through intramolecular Aldol condensation reaction, and then asymmetric hydrogenation was performed under the catalysis of p-tolyl-BINAP-Ru(II) complex to obtain (R)-musk ketone product. This method has good yield and stereoselectivity (Tetrahedron, 2002, 58, 9209). However, the catalyst used in this method is expensive, and the E / Z selectivity of 3-methylcyclopentadecenone obtained by Aldol condensation is also not ideal.

[0010]

[0011] In 2004, Takasago Fragrances of Japan reported the use of chiral phosphinamide or phosphinite ligands and copper salts, dimethyl zinc in toluene solution for asymmetric Michael addition of 2-cyclopentadecenone, and the obtained (R)-musk ketone had an optical purity of up to 95% and a yield of 92% (CN101056843B). This asymmetric synthesis method has high yield and optical purity, but the method uses dimethyl zinc as a methylating agent, which is flammable and has no stable commercial reagent source, so it cannot be mass-produced industrially.

[0012]

[0013] In 2005, Takabe et al. used a chiral separation method to separate racemic 3-methylpentadecanone into (R)-musk ketone and (S)-musk ketone under the action of tartaric acid derivatives. The enantioselectivity of (R)-musk ketone obtained by this method was above 98%, and the diastereoselectivity was greater than 99:1 (Tetrahedron Letters, 2005, 46, 3457). However, the yield of this method was low (the theoretical maximum yield did not exceed 50%) and caused waste of the other enantiomer.

[0014]

[0015] In 2006, Pfaltz et al. oxidized cyclopentadecanone to form 2,13-cyclopentadecadienone by IBX, and then reacted it with dimethylzinc for asymmetric conjugate addition to obtain a product with an optical purity of up to 98%. The addition product was hydrogenated to obtain (R)-musk ketone (Synlett, 2006, 7, 1031). This route uses an excess of oxidant IBX, which is not only very expensive, but also has the risk of explosion.

[0016]

[0017] In 2007, Knopff et al. used chiral amino alcohols to induce intramolecular asymmetric Aldol condensation to produce a chiral methyl center, and then carried out Eschenmoser cleavage and hydrogenation to obtain (R)-musk ketone with 76% ee (Angew. Chem. Int. Ed. 2007, 46, 1307). However, the enantioselectivity of this method was too low.

[0018]

[0019] In 2010, Ye Jinxing et al. from East China University of Science and Technology used cyclopentadecenone and bissulfone methane as raw materials, and carried out asymmetric Michael addition under the catalysis of chiral cinchona alkaloid derivatives. The addition product was then subjected to carbonyl protection, and the steps of removing the bissulfone group and decarbonyl protection with magnesium metal were used to synthesize (R)-musk ketone (CN101982451B). This reaction route has mild conditions and simple operation, but the synthesis route is long and the production cost is high.

[0020]

[0021] Natural musk resources are extremely limited and expensive, so artificially synthesizing (R)-musk ketone to replace natural musk has important economic value. At present, the synthesis route of musk ketone generally has many steps and high costs, and most of them are synthesized racemic musk ketone. There are few methods for asymmetric synthesis of (R)-musk ketone. The existing methods for asymmetric synthesis of (R)-musk ketone also face the problem of expensive chiral catalysts and difficulty in recycling. Therefore, it is very necessary to develop a low-cost, efficient technology for artificial synthesis of (R)-musk ketone suitable for industrial production. Summary of the invention

[0022] In view of this, the object of the present invention is to provide a method for asymmetric synthesis of (R)-musk ketone, aiming to solve the problem of difficulty in asymmetric synthesis of (R)-musk ketone.

[0023] To achieve the above object, the present invention provides the following technical solutions:

[0024] 1. A chiral catalyst having a structure shown in general formula (I):

[0025]

[0026] Wherein, X is N or P; Y is trifluoromethanesulfonate anion, trifluoroacetic acid anion, acetylacetone anion, acetate anion, sulfate anion, perchlorate anion, chloride anion, bromide anion, iodine anion, cyanide anion, tetrafluoroborate anion;

[0027] R1a, R2a, R1b and R2b are each independently C1-10 chain alkyl, 5-8 membered unsaturated carbocyclic or heterocyclic ring, saturated heterocyclic ring, phenyl or phenyl substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino or halogen; or, R1a and R2a, R1b and R2b are linked together in a ring;

[0028] R3a is hydrogen, deuterium, halogen, C1-6 alkoxy, C1-6 alkylamino, C1-10 chain alkyl, 5-8 membered unsaturated carbocyclic or heterocyclic ring, saturated heterocyclic ring, phenyl, or phenyl substituted by the following groups: C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, diphenyl or di-p-tolyl substituted phosphino or halogen.

[0029] As one of the preferred technical solutions, X is N or P; Y is a trifluoromethanesulfonic acid anion or a sulfate anion;

[0030] R1a and R2a are the same and are tert-butyl, cyclohexenyl, phenyl or methyl;

[0031] R1b and R2b are the same and are cyclohexenyl, phenyl or trifluoromethyl substituted phenyl;

[0032] R3a is methyl or diphenylphosphinophenyl.

[0033] As one of the further preferred technical solutions, X is N or P; Y is a trifluoromethanesulfonic acid anion or a sulfate anion;

[0034] R1a and R2a are the same and are cyclohexenyl, phenyl or methyl;

[0035] R1b and R2b are the same and are cyclohexenyl, phenyl or trifluoromethyl substituted phenyl;

[0036] R3a is methyl or diphenylphosphinophenyl.

[0037] 2. An asymmetric synthesis method of (R)-musk ketone based on the aforementioned chiral catalyst, comprising the steps of:

[0038] (1) adding a chiral ligand and a copper salt into a solvent, stirring and mixing, and obtaining a solution containing the chiral catalyst;

[0039] (2) adding a methyl Grignard reagent and 2-cyclopentadecenone to the solution obtained in step (1) to carry out an asymmetric Michael addition reaction to obtain (R)-musk ketone;

[0040] The reaction formula is as follows:

[0041]

[0042] As one of the preferred technical solutions, the molar ratio of the chiral ligand, copper salt, methyl Grignard reagent, and 2-cyclopentadecenone is 0.1-2:0.1-1:1-5:1, the mass volume ratio of 2-cyclopentadecenone to the solvent is 1 g:10-20 mL, and the molar ratio of the chiral ligand to the copper salt is further preferably 0.1-0.5:0.5-1.

[0043] As one of the preferred technical solutions, in step (1), the structural formula of the chiral ligand is selected from the structure shown in general formula (II);

[0044]

[0045] Wherein, X is N or P;

[0046] R1a, R2a, R1b and R2b are each independently C1-10 chain alkyl, 5-8 membered unsaturated carbocyclic or heterocyclic ring, saturated heterocyclic ring, phenyl or phenyl substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino or halogen; or, R1a and R2a, R1b and R2b are linked together in a ring;

[0047] R3a is hydrogen, deuterium, halogen, C1-6 alkoxy, C1-6 alkylamino, C1-10 chain alkyl, 5-8 membered unsaturated carbocyclic or heterocyclic ring, saturated heterocyclic ring, phenyl, or phenyl substituted by the following groups: C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, diphenyl or di-p-tolyl substituted phosphino or halogen.

[0048] As one of the further preferred technical solutions, X is N or P; Y is a trifluoromethanesulfonic acid anion or a sulfate anion;

[0049] R1a and R2a are the same and are tert-butyl, cyclohexenyl, phenyl or methyl;

[0050] R1b and R2b are the same and are cyclohexenyl, phenyl or trifluoromethyl substituted phenyl;

[0051] R3a is methyl or diphenylphosphinophenyl.

[0052] As one of the further preferred technical solutions, X is N or P; Y is a trifluoromethanesulfonic acid anion or a sulfate anion;

[0053] R1a and R2a are the same and are cyclohexenyl, phenyl or methyl;

[0054] R1b and R2b are the same and are cyclohexenyl, phenyl or trifluoromethyl substituted phenyl;

[0055] R3a is methyl or diphenylphosphinophenyl.

[0056] As one of the further preferred technical solutions, in step (1), the chiral ligand is selected from one of the following structures:

[0057]

[0058] As one of the further preferred technical solutions, the chiral ligand is selected from one of the following structures:

[0059]

[0060] As one of the preferred technical solutions, in step (1), the copper salt is a monovalent copper salt or a divalent copper salt, selected from any one of copper trifluoromethanesulfonate, cuprous trifluoromethanesulfonate, copper trifluoroacetate, copper acetylacetonate, copper acetate, copper sulfate, copper perchlorate, cupric chloride, cuprous chloride, cupric bromide, cuprous bromide, copper iodide, cuprous iodide, cuprous cyanide, and copper tetrafluoroborate, and further selected from one of copper trifluoromethanesulfonate, cuprous trifluoromethanesulfonate, and copper sulfate.

[0061] As one of the preferred technical solutions, in step (1), the solvent is selected from any one of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, toluene, ethylene glycol dimethyl ether, and methyl tert-butyl ether, and is further selected from one of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

[0062] As one of the preferred technical solutions, in step (2), the methyl grignard reagent is methylmagnesium bromide or methylmagnesium chloride.

[0063] As one of the preferred technical solutions, in step (2), the solution is cooled to -30 to 20°C, methyl grignard reagent is added, the reaction is stirred and kept warm for the first time, 2-cyclopentadecenone is added, the reaction is stirred and kept warm for the second time until 2-cyclopentadecenone disappears, and post-treatment is performed to obtain (R)-musk ketone.

[0064] As one of the further preferred technical solutions, the first heat preservation and stirring reaction time is 1 hour, and the second heat preservation and stirring reaction time is 1 hour.

[0065] As one of the further preferred technical solutions, 2-cyclopentadecenone is dissolved in a solvent and then slowly added dropwise, and the mass volume ratio of 2-cyclopentadecenone to the solvent is 1 g: 10 to 20 mL.

[0066] As one of the further preferred technical solutions, the solvent is selected from any one of tetrahydrofuran, ether, 2-methyltetrahydrofuran, toluene, ethylene glycol dimethyl ether, and methyl tert-butyl ether, and is further selected from one of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

[0067] As one of the further preferred technical solutions, the solution is cooled to -30 to 0°C.

[0068] As one of the further preferred technical solutions, the post-treatment includes: quenching the reaction, separating the organic phase, concentrating the organic phase under reduced pressure, and distilling.

[0069] As one of the further preferred technical solutions, the reaction is quenched with a saturated ammonium chloride solution, an ethyl acetate aqueous solution is added to the reaction solution, the organic phase is separated, concentrated under reduced pressure, and distilled.

[0070] The beneficial effects of the present invention are:

[0071] (1) The present invention uses cheap chiral ligands and copper salts to form a novel chiral catalyst for catalytic asymmetric synthesis of (R)-musk ketone. The selectivity of the reaction can reach an optical purity of more than 99% according to the calculation method in the reference (J. Chem. Soc. Perkin. Trans. 1. 1993, 153), and the yield after distillation can reach 84%. The optical purity and yield are not lower than the catalytic effect reported in the existing literature. In addition, the novel chiral catalyst avoids the use of expensive metals, and the chiral ligand can achieve a satisfactory catalytic effect when used in 0.1 equivalents, which greatly saves production costs.

[0072] (2) The present invention is the first to use methylmagnesium bromide or methylmagnesium chloride to carry out an asymmetric Michael addition reaction to synthesize (R)-musk ketone. The reaction effect is basically consistent with the dimethylzinc reagent commonly used in the literature. In addition, methylmagnesium bromide and methylmagnesium chloride are commercial methyl metal reagents (dimethylzinc reagent cannot be commercially supplied in large quantities), have a stable source and are inexpensive, which is convenient for industrial production.

[0073] (3) This asymmetric synthesis method solves the current problem of (R)-musk ketone being difficult to produce industrially. The route is simple and easy to operate, and satisfactory selectivity and yield can be achieved without strict ultra-low temperature conditions.

[0074] Other advantages, objectives and features of the present invention will be described in the following description to some extent, and to some extent, will be obvious to those skilled in the art based on the following examination and study, or can be taught from the practice of the present invention. The objectives and other advantages of the present invention can be realized and obtained through the following description. DETAILED DESCRIPTION

[0075] The present invention will be further described below in conjunction with specific implementation modes.

[0076] Optical rotation analysis

[0077] The optical rotation of the product was measured using an IP-digi300 / 3+FD polarimeter from Shanghai Yimai Instrument Technology Co., Ltd. The optical rotation of the self-made standard reference substance tested using the above instrument is [α] 24 D -11.3 (c 0.02, methanol). The preparation method of the standard reference substance is based on the literature (J.Chem.Soc.Perkin.Trans.1.1993,153). The optical purity and optical rotation of the musk ketone sample prepared in the literature are [α] 24 D -11.3, ee>99%.

[0078] Example 1

[0079] Add chiral ligand L1 (4.0 g, 6.8 mmol, (R)-(-)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine, CAS: 158923-09-2, purchased from Adamas reagent), cuprous trifluoromethanesulfonate (2.9 g, 13.5 mmol) and 150 mL of ethylene glycol dimethyl ether to a 500 mL three-necked flask. Cool the reaction solution to -30 ° C, add 3M methylmagnesium bromide (78.8 mL, 236.3 mmol) dropwise thereto for 0.5 hours, and after the addition is complete, keep the mixture at -30 ° C and stir for 1 hour. Dissolve 2-cyclopentadecenone (15.0 g, 67.5 mmol) in 100 mL of ethylene glycol dimethyl ether and slowly add dropwise to the above reaction system for 1 hour, after the addition is complete, keep the mixture at -30 ° C and react for 1 hour.

[0080] After the reaction is completed, 20 mL of saturated ammonium chloride solution is added dropwise to the reaction solution to quench the reaction, and the temperature is slowly raised to room temperature under stirring. 100 mL of ethyl acetate and 50 mL of water are added to the reaction solution, and the organic phase is separated and concentrated under reduced pressure to obtain crude musk ketone. The crude musk ketone is distilled (distillation conditions: 180°C, 2 mm Hg) to obtain musk ketone, 13.5 g of colorless liquid, with a yield of 84%, and an optical rotation [α] 24 D -11.2 (c 0.02, methanol). 1H NMR (600MHz, CDCl3) δ2.47-2.36(m,3H),2.18(dd,J=15.1,5.2Hz,1H),2.10-2.06(m, 1H), 1.73-1.64 (m, 1H), 1.64-1.55 (m, 1H), 1.45-1.14 (m, 20H), 0.94 (d, J = 6.8Hz, 3H).

[0081] Example 2

[0082] Add chiral ligand L3 (23.2 g, 27.2 mmol, (R)-(-)-1-{(Sp)-2-[bis(3,5-di-trifluoromethylphenyl)phosphino]ferrocenyl}ethyldicyclohexylphosphine, CAS: 292638-88-1, purchased from Adamas reagent), copper sulfate (8.8 g, 54 mmol) and 200 mL of anhydrous toluene to a 500 mL three-necked flask. Cool the reaction solution to -20°C, add 3M methylmagnesium bromide (78.8 mL, 236.3 mmol) dropwise thereto for 0.5 hours, and stir at -20°C for 1 hour after the addition is complete. Dissolve 2-cyclopentadecenone (15.0 g, 67.5 mmol) in 100 mL of anhydrous toluene and slowly dropwise add it to the above reaction system for 1 hour after the addition is complete, and react at -20°C for 1 hour.

[0083] After the reaction is completed, 20 mL of saturated ammonium chloride solution is added dropwise to the reaction solution to quench the reaction, and the temperature is slowly raised to room temperature under stirring. 100 mL of ethyl acetate and 50 mL of water are added to the reaction solution, and the organic phase is separated and concentrated under reduced pressure to obtain crude musk ketone. The crude musk ketone is distilled (distillation conditions: 180°C, 2 mm Hg) to obtain musk ketone, 12.2 g of colorless liquid, with a yield of 76%, and an optical rotation [α] 24 D -11.3 (c 0.02, methanol).

[0084] Example 3

[0085] Add chiral ligand L6 (15g, 34mmol, (R)-N,N-dimethyl-1-[(Sp)-2-bis(diphenylphosphino)ferrocenyl]ethylamine, CAS: 55700-44-2, purchased from Adamas reagent), copper trifluoromethanesulfonate (25g, 67.5mmol) and 200mL tetrahydrofuran to a 500mL three-necked flask. Cool the reaction solution to -30°C, add 3M methylmagnesium bromide (112.5mL, 337.5mmol) dropwise thereto for 0.5 hours, and stir at -30°C for 1 hour after the addition is complete. Dissolve 2-cyclopentadecenone (15.0g, 67.5mmol) in 100mL tetrahydrofuran and slowly dropwise add it to the above reaction system for 1 hour after the addition is complete, and react at -30°C for 1 hour.

[0086] After the reaction is completed, 20 mL of saturated ammonium chloride solution is added dropwise to the reaction solution to quench the reaction, and the temperature is slowly raised to room temperature under stirring. 100 mL of ethyl acetate and 50 mL of water are added to the reaction solution, and the organic phase is separated and concentrated under reduced pressure to obtain crude musk ketone. The crude musk ketone is distilled (distillation conditions: 180°C, 2 mm Hg) to obtain musk ketone, 13.2 g of colorless liquid, with a yield of 82%, and an optical rotation [α] 24 D -11.4 (c 0.02, methanol).

[0087] Example 4

[0088] Add chiral ligand L7 (4.7 g, 6.8 mmol, (R, Rp)-1-[α-(dimethylamino)-2-(diphenylphosphino)benzyl]-2-diphenylphosphinoferrocene, CAS: 1003012-96-1, purchased from Adamas reagent), copper chloride (0.9 g, 6.8 mmol) and 150 mL 2-methyltetrahydrofuran to a 500 mL three-necked flask. Cool the reaction solution to 0°C, add 3M methylmagnesium bromide (78.8 mL, 236.3 mmol) dropwise thereto for 0.5 hours, and keep the mixture at 0°C and stir for 1 hour. Dissolve 2-cyclopentadecenone (15.0 g, 67.5 mmol) in 50 mL 2-methyltetrahydrofuran and slowly add dropwise to the above reaction system for 1 hour, and keep the mixture at 0°C and react for 1 hour.

[0089] After the reaction is completed, 20 mL of saturated ammonium chloride solution is added dropwise to the reaction solution to quench the reaction, and the temperature is slowly raised to room temperature under stirring. 100 mL of ethyl acetate and 50 mL of water are added to the reaction solution, and the organic phase is separated and concentrated under reduced pressure to obtain crude musk ketone. The crude musk ketone is distilled (distillation conditions: 180°C, 2 mm Hg) to obtain musk ketone, 13.1 g of colorless liquid, with a yield of 81%, and an optical rotation [α] 24D -11.2 (c 0.02, methanol).

[0090] Example 5

[0091] Add chiral ligand L7 (2.35 g, 3.4 mmol, (R, Rp)-1-[α-(dimethylamino)-2-(diphenylphosphino)benzyl]-2-diphenylphosphinoferrocene, CAS: 1003012-96-1, purchased from Adamas reagent), copper chloride (0.45 g, 3.4 mmol) and 150 mL 2-methyltetrahydrofuran to a 500 mL three-necked flask. Cool the reaction solution to 0°C, add 3M methylmagnesium bromide (78.8 mL, 236.3 mmol) dropwise thereto for 0.5 hours, and keep the mixture at 0°C and stir for 1 hour. Dissolve 2-cyclopentadecenone (15.0 g, 67.5 mmol) in 50 mL 2-methyltetrahydrofuran and slowly dropwise add the mixture to the above reaction system for 1 hour, and keep the mixture at 0°C and react for 1 hour.

[0092] After the reaction is completed, 20 mL of saturated ammonium chloride solution is added dropwise to the reaction solution to quench the reaction, and the temperature is slowly raised to room temperature under stirring. 100 mL of ethyl acetate and 50 mL of water are added to the reaction solution, and the organic phase is separated and concentrated under reduced pressure to obtain crude musk ketone. The crude musk ketone is distilled (distillation conditions: 180°C, 2 mm Hg) to obtain musk ketone, 13.7 g of colorless liquid, with a yield of 84%, and an optical rotation [α] 24 D -10.2 (c 0.02, methanol).

[0093] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution, which should be included in the scope of the claims of the present invention.

Claims

1. A chiral catalyst, characterized in that It has the structure shown in the general formula (I): Wherein, X is N or P; Y is trifluoromethanesulfonate anion, trifluoroacetic acid anion, acetylacetone anion, acetate anion, sulfate anion, perchlorate anion, chloride anion, bromide anion, iodine anion, cyanide anion, tetrafluoroborate anion; R1a, R2a, R1b and R2b are each independently C1-10 chain alkyl, 5-8 membered unsaturated carbocyclic or heterocyclic ring, saturated heterocyclic ring, phenyl or phenyl substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino or halogen; or, R1a and R2a, R1b and R2b are linked together in a ring; R3a is hydrogen, deuterium, halogen, C1-6 alkoxy, C1-6 alkylamino, C1-10 chain alkyl, 5-8 membered unsaturated carbocyclic or heterocyclic ring, saturated heterocyclic ring, phenyl, or phenyl substituted by the following groups: C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, diphenyl or di-p-tolyl substituted phosphino or halogen.

2. A method for asymmetric synthesis of (R)-musk ketone based on the chiral catalyst of claim 1, characterized in that: Includes steps: (1) adding a chiral ligand and a copper salt into a solvent, stirring and mixing, and obtaining a solution containing the chiral catalyst; (2) adding a methyl Grignard reagent and 2-cyclopentadecenone to the solution obtained in step (1) to carry out an asymmetric Michael addition reaction to obtain (R)-musk ketone; The reaction formula is as follows:

3. The method according to claim 2, characterized in that The molar ratio of the chiral ligand, the copper salt, the methyl Grignard reagent and 2-cyclopentadecenone is 0.1-2:0.1-1:1-5:1, and the mass volume ratio of 2-cyclopentadecenone to the solvent is 1 g:10-20 mL.

4. The method according to claim 2, characterized in that: In step (1), the structural formula of the chiral ligand is selected from the structure shown in general formula (II); Wherein, X is N or P; R1a, R2a, R1b and R2b are each independently C1-10 chain alkyl, 5-8 membered unsaturated carbocyclic or heterocyclic ring, saturated heterocyclic ring, phenyl or phenyl substituted by C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino or halogen; or, R1a and R2a, R1b and R2b are linked together in a ring; R3a is hydrogen, deuterium, halogen, C1-6 alkoxy, C1-6 alkylamino, C1-10 chain alkyl, 5-8 membered unsaturated carbocyclic or heterocyclic ring, saturated heterocyclic ring, phenyl, or phenyl substituted by the following groups: C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, diphenyl or di-p-tolyl substituted phosphino or halogen.

5. The method according to claim 2, characterized in that: In step (1), the copper salt is a monovalent copper salt or a divalent copper salt, selected from any one of copper trifluoromethanesulfonate, cuprous trifluoromethanesulfonate, copper trifluoroacetate, copper acetylacetonate, copper acetate, copper sulfate, copper perchlorate, cupric chloride, cuprous chloride, cupric bromide, cuprous bromide, copper iodide, cuprous iodide, cuprous cyanide, and copper tetrafluoroborate.

6. The method according to claim 2, characterized in that In step (1), the solvent is selected from any one of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, toluene, ethylene glycol dimethyl ether, and methyl tert-butyl ether.

7. The method according to claim 2, characterized in that: In step (2), the methyl grignard reagent is methylmagnesium bromide or methylmagnesium chloride.

8. The method according to claim 2, characterized in that: In step (2), the solution is cooled to -30 to 20°C, methyl grignard reagent is added, the reaction is stirred for the first time, 2-cyclopentadecenone is added, the reaction is stirred for the second time until the 2-cyclopentadecenone disappears, and post-treatment is performed to obtain (R)-musk ketone.

9. The method according to claim 8, characterized in that The first heat-insulating stirring reaction time was 1 hour, and the second heat-insulating stirring reaction time was 1 hour.

10. The method according to claim 8, characterized in that 2-cyclopentadecenone is dissolved in a solvent and then slowly added dropwise, and the mass volume ratio of 2-cyclopentadecenone to the solvent is 1 g: 10-20 mL.

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