Synthesis method of Z-configuration chiral olefin

Abstract

The invention relates to a synthesis method of Z-configuration chiral olefin, which comprises the following steps: uniformly mixing chain-shaped racemic allyl benzyl ether, a Grignard reagent, a phosphoramidite ligand, a catalyst, boron trifluoride diethyl etherate and a solvent, and carrying out asymmetric allyl alkylation reaction to prepare a chain-shaped Z-configuration chiral olefin compound, the structural formula of the Z-configuration chiral olefin is as follows: # imgabs0 #, R1 is a primary alkyl group, R2 is a primary alkyl group or a secondary alkyl group, and R3 is a primary alkyl group. According to the invention, chain racemic allyl benzyl ether is used as a substrate to carry out asymmetric allyl alkylation reaction, and chain Z-configuration chiral olefin with optical activity is constructed. The chain racemic allyl benzyl ether serving as a raw material not only has excellent reaction activity and enantioselectivity, but also is high in stability, not easy to deteriorate and easy to store.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing Z-configuration chiral olefins. Background Art

[0002] The construction method of chiral carbon-carbon bonds is an important research direction in organic synthetic chemistry. The Cu-catalyzed asymmetric allylic alkylation reaction of racemic compounds is an important tool for constructing chiral carbon-carbon bonds. However, since the racemic compound is a mixture of two equal enantiomers, its asymmetric allylic alkylation process is more complicated and challenging than that of prochiral substrates. Especially for the racemic compound of l, since there is no ring rigid structure in its molecule, there is a phenomenon of single bond rotation in the molecule. Therefore, there are two different conformations of pro-Z and pro-E in the chain racemic compound molecule. In the asymmetric allylic alkylation reaction of the chain racemic compound, the substrate molecule will react with the nucleophile in the form of pro-Z or pro-E, and the reaction process is relatively complicated. Therefore, it is particularly difficult to synthesize alkylated products with high enantioselectivity through the asymmetric allylic alkylation reaction of the chain racemic compound as a substrate. Previous research work was mainly limited to using highly sensitive compounds such as allyl chloride as substrates to improve the yield of the reaction. However, due to their high sensitivity, these substrates are extremely difficult to synthesize, purify and store.

[0003] Although the asymmetric alkylation reaction of inert chain racemic allyl methyl ether has been conquered in recent years (application number 202410434888.3), this method is limited to the synthesis of chiral olefins containing Z / E mixtures, and the Z / E mixture as the product cannot be separated by subsequent steps.

[0004] Currently, the Cu-catalyzed asymmetric allylic alkylation of linear racemic allylic ethers to synthesize chiral Z-configured olefins with high selectivity remains unexplored.

[0005] The main reason is that the racemic compound is a mixture containing two equal amounts of enantiomers. The synthesis of chiral olefins with high selectivity of Z configuration through its asymmetric alkylation reaction needs to consider three factors, namely, the enantioselectivity, regioselectivity and Z / E selectivity of the reaction.

[0006] Specifically, Figure 1 and Figure 2 As shown in the figure, there are 8 reaction pathways for this type of reaction, which may produce up to 6 products with different structures, and the reaction system is particularly complex. Therefore, it is extremely challenging in the field of chemical synthesis to achieve the synthesis of highly selective Z-configured chiral olefins with high enantioselectivity by designing an efficient catalytic system. Summary of the invention

[0007] Based on this, it is necessary to provide a method for the asymmetric alkylation reaction of chain racemic allyl ethers to synthesize Z-configuration chiral olefin compounds, aiming to solve the technical problem that the method of the prior art through the asymmetric alkylation reaction of chain racemic allyl ethers can only obtain chiral olefins containing Z / E mixtures, but cannot obtain chiral olefins with high selectivity Z configuration.

[0008] Therefore, the present invention successfully synthesized a series of chiral olefins with high selectivity of Z configuration by designing a kinetic resolution process so that the reaction only produces products of Z configuration and inhibits the production pathway of products of E configuration. It is worth noting that the reaction is a kinetic resolution process of racemic compounds, and the maximum yield of the product in the reaction must be controlled below 50% to ensure that the product has a high Z / E selectivity.

[0009] To achieve the above object, the present invention provides a technical solution:

[0010] A method for synthesizing a Z-configuration chiral olefin compound comprises the following steps:

[0011] The chain racemic allyl benzyl ether, Grignard reagent, phosphoramidite ligand, catalyst, boron trifluoride etherate and solvent are uniformly mixed to undergo an asymmetric alkylation reaction to obtain a Z-configuration chiral olefin compound;

[0012] The structural formula of the Z-configuration chiral olefin compound is as follows:

[0013]

[0014] Among them, R 1 is a primary alkyl group, R 2 is a primary alkyl group or a secondary alkyl group, R 3 It is a primary alkyl group.

[0015] Preferably, the method for the asymmetric alkylation reaction of the chain racemic allyl ether comprises the following specific steps:

[0016] Under the protection of an inert gas, adding the phosphoramidite ligand, the catalyst and the solvent into a container and mixing them evenly to obtain a first mixed solution;

[0017] adding the chain racemic allyl benzyl ether to the first mixed liquid to obtain a second mixture;

[0018] Adding the boron trifluoride etherate and the Grignard reagent to the second mixed solution, and keeping the mixture warm for 0.5 to 4 hours after the addition is complete;

[0019] The reaction is quenched by using a quenching agent, and then the organic phase is extracted and washed, dried and concentrated to obtain the Z-configuration chiral olefin compound.

[0020] Preferably, the quenching agent includes any one of saturated ammonium chloride solution, saturated hydrochloric acid solution, ethanol and methanol.

[0021] Preferably, the reaction temperature of the insulation reaction is -20 to -78°C.

[0022] Preferably, the ligand comprises at least one of the following phosphoramidite ligand molecular structures:

[0023]

[0024] Preferably, the Grignard reagent includes at least one of methylmagnesium bromide, ethylmagnesium bromide, n-butylmagnesium bromide, isobutylmagnesium bromide, n-heptylmagnesium bromide, 4-methyl-3-n-pentenylmagnesium bromide, phenethylmagnesium bromide, isopropylmagnesium bromide, cyclobutylmagnesium bromide, cyclohexylmagnesium bromide, cycloheptylmagnesium bromide, cyclopentylmagnesium bromide, methylmagnesium chloride, ethylmagnesium chloride, n-butylmagnesium chloride, isobutylmagnesium chloride, n-heptylmagnesium chloride, 4-methyl-3-n-pentenylmagnesium chloride, phenethylmagnesium chloride, isopropylmagnesium chloride, cyclobutylmagnesium chloride, cyclohexylmagnesium chloride, cycloheptylmagnesium chloride and cyclopentylmagnesium chloride.

[0025] Preferably, the catalyst comprises at least one of cuprous bromide dimethyl sulfide, cuprous chloride, cuprous iodide, cuprous thiophene-2-carboxylate and cupric trifluoromethanesulfonate.

[0026] Preferably, the Grignard reagent is dissolved in diethyl ether.

[0027] Preferably, the solvent comprises at least one of toluene, dichloromethane, ether, tetrahydrofuran and p-xylene.

[0028] Preferably, in terms of molar amount, the chain racemic allyl benzyl ether: the phosphoramidite ligand: the catalyst: the boron trifluoride etherate: the Grignard reagent = 1: (0.05-0.20): (0.05-0.20): (1.00-3.00): (1.00-3.00).

[0029] The beneficial effects of the asymmetric alkylation reaction method provided by the embodiment of the present invention are as follows:

[0030] The invention uses chain racemic allyl benzyl ether as a substrate to carry out an asymmetric alkylation reaction. By designing and using benzyl ether with large steric hindrance as a reaction substrate, the reaction rate is successfully controlled, a kinetic resolution process is caused in the reaction, only a product with a Z configuration is produced, and a reaction pathway for producing a product with an E configuration is suppressed. A series of chiral olefins with a highly selective Z configuration are successfully synthesized, and the problem that only chiral olefins containing a Z / E mixture can be obtained in the asymmetric alkylation reaction method of chain racemic allyl substrates in the prior art is successfully solved. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 A synthetic route for asymmetric alkylation reaction in the prior art;

[0032] Figure 2 Products with different structures synthesized by asymmetric alkylation reactions in the prior art;

[0033] Figure 3 It is the structural formula of a Z-configuration chiral olefin compound. DETAILED DESCRIPTION

[0034] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0035] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials and reagents used in the following examples are all commercially available unless otherwise specified. The quantitative tests in the following examples were performed in triplicate, and the data are the average or average ± standard deviation of the triplicate experiments.

[0036] In addition, the "and / or" in the full text includes three solutions. Taking A and / or B as an example, it includes technical solution A, technical solution B, and a technical solution that satisfies both A and B. In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the ability of ordinary technicians in the field to implement. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0037] An embodiment of the present invention provides a method for synthesizing a Z-configuration chiral olefin compound, comprising the following steps:

[0038] The chain racemic allyl benzyl ether, Grignard reagent, phosphoramidite ligand, catalyst, boron trifluoride etherate and solvent are uniformly mixed to undergo an asymmetric allylic alkylation reaction to obtain a Z-configuration chiral olefin compound;

[0039] As shown in 3, the structural formula of the Z-configuration chiral olefin compound is as follows:

[0040]

[0041] Among them, R 1 is a primary alkyl group, R 2is a primary alkyl group or a secondary alkyl group, R 3 The present invention uses chain racemic allyl benzyl ether as a substrate to carry out an asymmetric alkylation reaction. The ring chain racemic allyl benzyl ether as a raw material not only has excellent reaction activity and enantioselectivity, but also has high stability, is not easy to deteriorate, and is easy to store.

[0042] Specifically, the asymmetric alkylation of chain racemic allyl ether is a nucleophilic substitution reaction, and the reaction rate is positively correlated with the leaving ability of the substituent in the substrate. The rates of different reaction paths in the reaction can be effectively regulated by adjusting the type of the substituent in the substrate. Preferably, by designing a leaving group using a benzyloxy group as a substrate, the reaction can undergo a kinetic resolution process, so that only a Z-configuration product is produced in the reaction, and the production of an E-configuration product in the reaction is suppressed.

[0043] It is worth noting that the maximum yield of the product in the reaction must be controlled below 50% to ensure that the product has a high Z / E selectivity. This is because the racemic compound contains two enantiomers in a 1:1 ratio. When the reaction occurs, one isomer will be converted into a Z-configuration product, while the other isomer will be converted into an E-configuration product (doi:10.1002 / anie.201005373). The present invention designs a kinetic resolution process, which can suppress the generation of E-configuration products and obtain Z-configuration products by controlling the reaction rate of a pair of enantiomers in the substrate. In the ideal kinetic resolution process, the reaction conditions only selectively react one of the enantiomers, so that only one of the enantiomers (i.e., 50% of the compound) can be converted into the product to the maximum extent. Therefore, when one enantiomer reacts completely, the other enantiomer hardly reacts, and the remaining enantiomer will not be further converted, so the highest theoretical yield is only 50%.

[0044] Preferably, the synthesis method of the Z-configuration chiral olefin compound comprises the following specific steps:

[0045] S1. Under the protection of inert gas, add the ligand, catalyst and solvent into a container and mix them evenly to obtain a first mixed solution.

[0046] Preferably, the ligand comprises at least one of the following phosphoramidite ligand molecular structures:

[0047]

[0048] Preferably, the catalyst includes at least one of cuprous bromide dimethyl sulfide, cuprous chloride, cuprous iodide, cuprous thiophene-2-carboxylate and cupric trifluoromethanesulfonate.

[0049] Preferably, the solvent includes at least one of toluene, dichloromethane, ethyl ether, tetrahydrofuran and p-xylene.

[0050] Preferably, the container is a dry Schlenk reaction tube equipped with a stirring bar.

[0051] Preferably, the Grignard reagent is dissolved in ether. Specifically, the Grignard reagent is prone to chemical reaction when it encounters water, acid or air, and releases flammable gas. Therefore, the Grignard reagent is dissolved in ether and needs to react under the protection of an inert gas.

[0052] S2. Add 0.2 mmol of linear racemic allyl benzyl ether to the first mixed liquid to obtain a second mixture.

[0053] Specifically, in step S200, the temperature is -78°C.

[0054] S3. Add boron trifluoride etherate and Grignard reagent to the second mixed solution, and keep warm for 0.5 to 4 hours to obtain a third mixed solution.

[0055] Specifically, the reaction temperature of the insulation reaction is -20 to -78°C.

[0056] Preferably, the Grignard reagent includes at least one of methylmagnesium bromide, ethylmagnesium bromide, n-butylmagnesium bromide, isobutylmagnesium bromide, n-heptylmagnesium bromide, 4-methyl-3-n-pentenylmagnesium bromide, phenethylmagnesium bromide, isopropylmagnesium bromide, cyclobutylmagnesium bromide, cyclohexylmagnesium bromide, cycloheptylmagnesium bromide, cyclopentylmagnesium bromide, methylmagnesium chloride, ethylmagnesium chloride, n-butylmagnesium chloride, isobutylmagnesium chloride, n-heptylmagnesium chloride, 4-methyl-3-n-pentenylmagnesium chloride, phenethylmagnesium chloride, isopropylmagnesium chloride, cyclobutylmagnesium chloride, cyclohexylmagnesium chloride, cycloheptylmagnesium chloride and cyclopentylmagnesium chloride.

[0057] Specifically, the reaction formula of the asymmetric allylic alkylation reaction in one embodiment is as follows:

[0058]

[0059] Where L is the phosphoramidite ligand, R 1 is a primary alkyl group, R 2 is a primary alkyl group or a secondary alkyl group, R 3 It is a primary alkyl group.

[0060] More specifically, the Z-configuration chiral olefin compound is one of the following compounds 3a to 3j:

[0061]

[0062] Preferably, the molar ratio of the chain racemic allyl benzyl ether, the phosphoramidite ligand, the catalyst, the boron trifluoride etherate and the Grignard reagent is 1:(0.05-0.20):(0.05-0.20):(0.50-3.00):(0.50-3.00).

[0063] S4. The third mixed solution is quenched with a quenching agent, and then the organic phase is extracted and washed, dried and concentrated to obtain the Z-configuration chiral olefin compound.

[0064] Preferably, the quenching agent includes any one of saturated ammonium chloride solution, saturated hydrochloric acid solution, ethanol and methanol.

[0065] Preferably, the extractant is ethyl acetate.

[0066] Preferably, the detergent is a mixture of water and salt water.

[0067] Preferably, the desiccant is anhydrous magnesium sulfate.

[0068] The following are specific examples. Unless otherwise specified, the raw materials in the examples are all commercially available products.

[0069] Example 1

[0070] Synthesis of Z-configuration Chiral Olefin Compound a

[0071] S1. Add 0.02 mol of phosphoramidite ligand L8 and 0.01 mmol of cuprous chloride into a dry schlenk reaction tube equipped with a stirring bar and mix well. Replace the argon gas three times with a vacuum pump. Add 2.0 mL of dichloromethane (DCM) under the protection of argon gas and stir at 25°C for 15 min to obtain a first mixed solution.

[0072] S2, adding 0.2 mmol (E)-5-benzyloxy-3-heptene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0073] S3, adding 0.3 mmol of boron trifluoride etherate and 0.3 mL of butyl magnesium chloride solution (1 mol / L, solvent is ether) to the second mixed solution by using a syringe pump, after the addition is completed, heat-retaining and reacting at -78°C for 1 hour to obtain a third mixed solution;

[0074] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound a.

[0075] The expected product was purified by silica gel column chromatography with an isolation yield of 46%, Z / E=97:3, and the Z configuration ee value was 99%.

[0076] The NMR data of compound a are as follows:

[0077] 1 H NMR (400MHz, Chloroform-d) δ5.39 (dt, J=10.9, 7.3Hz, 1H), 4.98 (tt, J=10.5, 1.6Hz, 1H), 2.18 (qt, J=9. 1,4.6Hz,1H),2.10–1.96(m,2H),1.45–1.09(m,8H),0.95(t,J=7.5Hz,3H),0.85(dt,J=17.9,7.2Hz,6H).

[0078] Example 2

[0079] Synthesis of Z-configuration chiral olefin compound b

[0080] S1. Add 0.02 mol of phosphoramidite ligand L8 and 0.01 mmol of cuprous chloride into a dry schlenk reaction tube equipped with a stirring bar and mix well. Replace the argon gas three times with a vacuum pump. Add 2.0 mL of dichloromethane (DCM) under the protection of argon gas and stir at 25°C for 15 min to obtain a first mixed solution.

[0081] S2, adding 0.2 mmol (E)-7-benzyloxy-5-undecene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0082] S3, adding 0.5 mmol of boron trifluoride etherate and 0.5 mL of isopropyl magnesium chloride solution (1 mol / L, solvent is ether) to the second mixed solution by using a syringe pump, after the addition is complete, heat-retaining the mixture at -78°C for 0.5 h to obtain a third mixed solution;

[0083] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound b.

[0084] The expected product was obtained by purification through silica gel column chromatography with an isolation yield of 51%, Z / E=96:4, and the ee value of Z configuration was 99%.

[0085] The NMR data of compound b are as follows:

[0086] 1H NMR(400MHz,Chloroform-d)δ5.41(dt,J=11.0,7.2Hz,1H),5.18–5.01(m,1H),2.16–2.05(m,1H)2.05–1.95(m,2H),1.56–1. 47(m,1H),1.44–1.35(m,1H),1.34–1.29(m,4H),1.28–1.24(m,3H),1.20–1.09(m,2H),0.92–0.85(m,9H),0.84–0.79(m,3H).

[0087] Example 3

[0088] Synthesis of Z-configuration Chiral Olefin Compound c

[0089] S1. Add 0.02 mol of phosphoramidite ligand L8 and 0.01 mmol of cuprous chloride into a dry schlenk reaction tube equipped with a stirring bar and mix well. Replace the argon gas three times with a vacuum pump. Add 2.0 mL of dichloromethane (DCM) under the protection of argon gas and stir at 25°C for 15 min to obtain a first mixed solution.

[0090] S2, adding 0.2 mmol (E)-4-benzyloxy-2-pentene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0091] S3, adding 0.2 mmol of boron trifluoride etherate and 0.2 mL of phenethyl magnesium chloride solution (1 mol / L, solvent is ether) to the second mixed solution using a syringe pump, and after the addition is completed, the mixture is kept at -78°C for 1 hour to obtain a third mixed solution;

[0092] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound c.

[0093] The expected product was obtained by purification through silica gel column chromatography with an isolation yield of 44%, Z / E=95:5, and the ee value of Z configuration was 99%.

[0094] The NMR data of compound c are as follows:

[0095] 1H NMR(400MHz,Chloroform-d)δ7.31–7.22(m,2H),7.20–7.13(m,3H),5.50–5.38(m,1H),5 .20(tt,J=11.2,1.8Hz,1H),2.69–2.43(m,3H),1.71–1.47(m,5H)0.97(d,J=6.7Hz,3H).

[0096] Example 4

[0097] Synthesis of Z-configuration Chiral Olefin Compound d

[0098] S1. Add 0.02 mol of phosphoramidite ligand L8 and 0.01 mmol of cuprous chloride into a dry schlenk reaction tube equipped with a stirring bar and mix well. Replace the argon gas three times with a vacuum pump. Add 2.0 mL of dichloromethane (DCM) under the protection of argon gas and stir at 25°C for 15 min to obtain a first mixed solution.

[0099] S2, adding 0.2 mmol (E)-4-benzyloxy-2-pentene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0100] S3, adding 0.2 mmol of boron trifluoride etherate and 0.2 mL of p-fluorophenethyl magnesium chloride solution (1 mol / L, solvent is ether) to the second mixed solution using a syringe pump, and after the addition is complete, heat-retaining the mixture at -78°C for 1 hour to obtain a third mixed solution;

[0101] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound d.

[0102] The expected product was purified by silica gel column chromatography with an isolation yield of 35%, Z / E=97:3, and the Z configuration ee value was 99%.

[0103] The NMR data of compound d are as follows:

[0104] 1 H NMR(400MHz,Chloroform-d)δ7.11(dd,J=8.4,5.7Hz,2H),6.95(t,J=8.7Hz,2H),5.51–5.40(m,1H ),5.20(ddq,J=11.3,9.6,1.8Hz,1H),2.71–2.31(m,3H),1.68–1.43(m,5H),0.97(d,J=6.7Hz,3H).

[0105] Example 5

[0106] Synthesis of Z-configuration Chiral Olefin Compound e

[0107] S1. Add 0.04 mol of phosphoramidite ligand L8 and 0.02 mmol of cuprous chloride into a dry schlenk reaction tube equipped with a stirring bar and mix well. Replace the argon gas three times with a vacuum pump. Add 2.0 mL of dichloromethane (DCM) under the protection of argon gas and stir at 25°C for 15 min to obtain a first mixed solution.

[0108] S2, adding 0.2 mmol (E)-5-benzyloxy-3-octene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0109] S3, adding 0.3 mmol of boron trifluoride etherate and 0.3 mL of phenethyl magnesium chloride solution (1 mol / L, solvent is ether) to the second mixed solution by using a syringe pump, after the addition is complete, heat-retaining and reacting at -78°C for 1 hour to obtain a third mixed solution;

[0110] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound e.

[0111] The expected product was purified by silica gel column chromatography with an isolation yield of 48%, Z / E=94:6, and the Z configuration ee value was 99%.

[0112] The NMR data of compound e are as follows:

[0113] 1 H NMR(400MHz,Chloroform-d)δ7.30–7.22(m,2H),7.21–7.10(m,3H),5.46(dt,J=11.0 ,7.3Hz,1H),5.20–5.03(m,1H),2.64(ddd,J=15.5,10.7,5.1Hz,1H),2.48(ddd,J=13. 8,10.6,6.1Hz,1H),2.26(qt,J=9.4,4.6Hz,1H),2.07–1.92(m,2H),1.77–1.65(m,1H ),1.50–1.31(m,4H),1.26–1.14(m,1H),0.91(t,J=7.4Hz,3H),0.84(t,J=7.4Hz,3H).

[0114] Example 6

[0115] Synthesis of Z-configuration Chiral Olefin Compound f

[0116] S1, add 0.022 mol of phosphoramidite ligand L8 and 0.02 mmol of cuprous bromide dimethyl sulfide into a dry schlenk reaction tube equipped with a stirring bar and mix well, replace argon three times with a vacuum pump, add 2.0 mL of dichloromethane (DCM) under the protection of argon, and stir at 25°C for 15 min to obtain a first mixed solution;

[0117] S2, adding 0.2 mmol (E)-7-benzyloxy-5-decene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0118] S3, adding 0.3 mmol of boron trifluoride etherate and 0.3 mL of ethyl magnesium bromide solution (1 mol / L, solvent is ether) to the second mixed solution using a syringe pump, and after the addition is complete, heat-retaining the mixture at -78°C for 1 hour to obtain a third mixed solution;

[0119] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound f.

[0120] The expected product was obtained by purification through silica gel column chromatography with an isolation yield of 49%, Z / E=95:5, and the ee value of Z configuration was 98%.

[0121] The NMR data of compound f are as follows:

[0122] 1 H NMR(400MHz,Chloroform-d)δ5.39(dt,J=11.0,7.3Hz,1H),5.02(ddt,J=11.4,10.1,1.6Hz,1H),2.19(ddq,J=13.8,9.1,4.7Hz,1H),2.00(qd,J= 7.3,1.6Hz,2H),1.44–1.32(m,4H),1.26(d,J=6.2Hz,4H),1.19–1.12(m, 2H), 0.91 (t, J = 7.3Hz, 3H), 0.86 (d, J = 7.0Hz, 3H), 0.83 (t, J = 7.4Hz, 3H).

[0123] Example 7

[0124] Synthesis of Z-configuration chiral olefin compound g

[0125] S1, add 0.022 mol of phosphoramidite ligand L8 and 0.02 mmol of cuprous bromide dimethyl sulfide into a dry schlenk reaction tube equipped with a stirring bar and mix well, replace argon three times with a vacuum pump, add 2.0 mL of dichloromethane (DCM) under the protection of argon, and stir at 25°C for 15 min to obtain a first mixed solution;

[0126] S2, adding 0.2 mmol (E)-6-benzyloxy-4-decene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0127] S3, adding 0.3 mmol of boron trifluoride etherate and 0.3 mL of ethyl magnesium bromide solution (1 mol / L, solvent is ether) to the second mixed solution using a syringe pump, and after the addition is complete, heat-retaining the mixture at -78°C for 1 hour to obtain a third mixed solution;

[0128] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound g.

[0129] The expected product was obtained by purification through silica gel column chromatography with an isolation yield of 49%, Z / E=94:6, and the ee value of Z configuration was 99%.

[0130] The NMR data of compound g are as follows:

[0131] 1 H NMR(400MHz,Chloroform-d)δ5.39(dt,J=10.9,7.2Hz,1H),5.04–4.96(m,1H),2.21(qt,J=8.9,4.3Hz,1H),2.01(dtq,J=6.5,4.2, 2.1Hz,2H),1.43–1.34(m,2H),1.33–1.28(m,4H),1.26–1.20(m,2H),1.18–1.09(m,2H),0.92–0.85(m,6H),0.83(t,J=7.4Hz,3H).

[0132] Example 8

[0133] Synthesis of Z-configuration chiral olefin compound h

[0134] S1. Add 0.02 mol of phosphoramidite ligand L8 and 0.01 mmol of cuprous chloride into a dry schlenk reaction tube equipped with a stirring bar and mix well. Replace the argon gas three times with a vacuum pump. Add 2.0 mL of dichloromethane (DCM) under the protection of argon gas and stir at 25°C for 15 min to obtain a first mixed solution.

[0135] S2, adding 0.2 mmol (E)-7-benzyloxy-5-decene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0136] S3, adding 0.3 mmol of boron trifluoride etherate and 0.3 mL of isopropyl magnesium chloride solution (1 mol / L, solvent is ether) to the second mixed solution using a syringe pump, and after the addition is complete, heat-retaining the mixture at -78°C for 1 hour to obtain a third mixed solution;

[0137] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound h.

[0138] The expected product was purified by silica gel column chromatography with an isolation yield of 49%, Z / E=97:3, and the Z configuration ee value was 97%.

[0139] The NMR data of compound h are as follows:

[0140] 1 H NMR(400MHz,Chloroform-d)δ5.42(dt,J=11.2,7.2Hz,1H),5.10(tt,J=10.7,1.7Hz,1H),2.19–2.06(m,1H),2.05–1. 93(m,2H),1.59–1.48(m,1H),1.38(dt,J=14.8,7.7Hz,3H),1.30–1.23(m,3H),1.20–1.07(m,2H),0.93–0.81(m,12H).

[0141] Example 9

[0142] Synthesis of Z-configuration chiral olefin compound i

[0143] S1. Add 0.04 mol of phosphoramidite ligand L8 and 0.02 mmol of cuprous chloride into a dry schlenk reaction tube equipped with a stirring bar and mix well. Replace the argon gas three times with a vacuum pump. Add 2.0 mL of dichloromethane (DCM) under the protection of argon gas and stir at 25°C for 15 min to obtain a first mixed solution.

[0144] S2, adding 0.2 mmol (E)-5-benzyloxy-3-octene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0145] S3, adding 0.3 mmol of boron trifluoride etherate and 0.3 mL of cyclobutylmagnesium chloride solution (1 mol / L, solvent is ether) to the second mixed solution by using a syringe pump, after the addition is complete, heat-retaining and reacting at -78°C for 1 hour to obtain a third mixed solution;

[0146] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound i.

[0147] The expected product was obtained by purification through silica gel column chromatography with an isolation yield of 49%, Z / E=95:5, and the ee value of Z configuration was 98%.

[0148] The NMR data of compound i are as follows:

[0149] 1 H NMR(400MHz,Chloroform-d)δ5.44(dt,J=11.0,7.3Hz,1H),4.95(ddt,J=11.4,10.0,1.7Hz,1H),2.23–1.93 (m,5H),1.91–1.81(m,1H),1.81–1.52(m,4H),1.47–1.32(m,3H),1.01–0.87(m,4H),0.81(t,J=7.4Hz,3H).

[0150] Example 10

[0151] Synthesis of Z-configuration Chiral Olefin Compound j

[0152] S1. Add 0.04 mol of phosphoramidite ligand L8 and 0.02 mmol of cuprous chloride into a dry schlenk reaction tube equipped with a stirring bar and mix well. Replace the argon gas three times with a vacuum pump. Add 2.0 mL of dichloromethane (DCM) under the protection of argon gas and stir at 25°C for 15 min to obtain a first mixed solution.

[0153] S2, adding 0.2 mmol (E)-5-benzyloxy-3-octene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0154] S3, adding 0.3 mmol of boron trifluoride etherate and 0.3 mL of cyclopentylmagnesium chloride solution (1 mol / L, solvent is ether) to the second mixed solution using a syringe pump, and after the addition is complete, heat-retaining the mixture at -78°C for 1 hour to obtain a third mixed solution;

[0155] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound j.

[0156] The expected product was purified by silica gel column chromatography with an isolation yield of 43%, Z / E=97:3, and the Z configuration ee value was 98%.

[0157] The NMR data of compound j are as follows:

[0158] 1 H NMR(400MHz,Chloroform-d)δ5.46–5.35(m,1H),5.08(tt,J=10.8,1.7Hz,1H),2.12–1.93(m,3H),1.78–1.68( m,1H),1.67–1.44(m,7H),1.42–1.31(m,2H),1.20–1.03(m,3H),0.91(t,J=7.3Hz,3H),0.82(t,J=7.4Hz,3H).

[0159] Embodiment 11

[0160] Synthesis of Z-configuration Chiral Olefin Compound f

[0161] S1, add 0.022 mol of phosphoramidite ligand L1 and 0.02 mmol of cuprous bromide dimethyl sulfide into a dry schlenk reaction tube equipped with a stirring bar and mix well, replace argon three times with a vacuum pump, add 2.0 mL of dichloromethane (DCM) under the protection of argon, and stir at 25°C for 15 min to obtain a first mixed solution;

[0162] S2, adding 0.2 mmol (E)-7-benzyloxy-5-decene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0163] S3, adding 0.3 mmol of boron trifluoride etherate and 0.3 mL of ethyl magnesium bromide solution (1 mol / L, solvent is ether) to the second mixed solution using a syringe pump, and after the addition is complete, heat-retaining the mixture at -78°C for 1 hour to obtain a third mixed solution;

[0164] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound f.

[0165] The NMR yield was less than 10%, Z / E=96:4, and the ee value of the Z configuration was -36%.

[0166] Example 12

[0167] Synthesis of Z-configuration Chiral Olefin Compound f

[0168] S1, add 0.022 mol of phosphoramidite ligand L2 and 0.02 mmol of cuprous bromide dimethyl sulfide into a dry schlenk reaction tube equipped with a stirring bar and mix well, replace argon three times with a vacuum pump, add 2.0 mL of dichloromethane (DCM) under the protection of argon, and stir at 25°C for 15 min to obtain a first mixed solution;

[0169] S2, adding 0.2 mmol (E)-7-benzyloxy-5-decene to the first mixed liquid, cooling to -78°C, and maintaining for 10 minutes to obtain a second mixture;

[0170] S3, adding 0.3 mmol of boron trifluoride etherate and 0.3 mL of ethyl magnesium bromide solution (1 mol / L, solvent is ether) to the second mixed solution using a syringe pump, and after the addition is complete, heat-retaining the mixture at -78°C for 1 hour to obtain a third mixed solution;

[0171] S4. After the third mixed solution was quenched with 2.0 mL of saturated NH4Cl aqueous solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with a mixed solution of water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound f.

[0172] The NMR yield is less than 10%, Z / E=90:10, and the ee value of Z configuration is -90%.

[0173] Comparative Example 1

[0174] The difference between Comparative Example 1 and Example 3 is that an equal amount of the reaction substrate (E)-4-benzyloxy-2-pentene is replaced by an equal amount of (E)-4-chloro-2-pentene, and no boron trifluoride etherate is added. The separation yield is 86%, Z / E=52:48, and the Z configuration ee value is 88%.

[0175] This comparative example shows that this technical method overcomes the technical difficulty in the previously disclosed method of using highly sensitive compounds such as allyl chloride as substrates, and the Z / E mixture of the product cannot be separated through subsequent steps.

[0176] Comparative Example 2

[0177] The difference between Comparative Example 2 and Example 6 is that the raw material of the reaction is replaced with a similar chain racemic allyl methyl ether in the disclosed method (application number 202410434888.3), and when the experiment is carried out under its optimal conditions, the product Z / E is 55:45, the yield is 98%, and the Z configuration ee value is 89%. When it is expected to achieve kinetic resolution of the substrate by adding 0.5 equivalents of nucleophilic reagent to synthesize Z-configured olefins with high selectivity, the product Z / E is 89:11, and the separation yield under this condition is only 13%, and the Z configuration ee value is 96%.

[0178] This comparative example illustrates that the reaction system of asymmetric alkylation of chain racemic allyl methyl ether in the previously disclosed method is not suitable for synthesizing highly selective Z-configuration chiral olefins. Even if it is expected to achieve the synthesis of highly selective Z-configuration products at the expense of yield by adjusting the equivalent of the nucleophilic reagent, the Z / E of the product under this condition is only 89:11 and the yield is too low. This method is not a simple extension of the previously disclosed method, but a key regulation of the substrate structure in the original reaction system, which expands the reaction rate difference of a pair of enantiomers in the substrate, so as to achieve the kinetic resolution of the substrate and synthesize highly selective Z-configuration chiral olefins.

[0179] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0180] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for synthesizing a Z-configuration chiral olefin compound, characterized in that: The steps include: The chain racemic allyl benzyl ether, Grignard reagent, phosphoramidite ligand, catalyst, boron trifluoride etherate and solvent are uniformly mixed to undergo an asymmetric allylic alkylation reaction to obtain a Z-configuration chiral olefin compound; The structural formula of the Z-configuration chiral olefin compound is as follows: Among them, R 1 is a primary alkyl group, R 2 is a primary alkyl group or a secondary alkyl group, R 3 It is a primary alkyl group.

2. The method for synthesizing a Z-configuration chiral olefin according to claim 1, characterized in that: The synthesis method of the Z-configuration chiral olefin compound specifically comprises the following steps: Under the protection of an inert gas, adding the phosphoramidite ligand, the catalyst and the solvent into a container and mixing them evenly to obtain a first mixed solution; adding the chain racemic allyl benzyl ether to the first mixed liquid to obtain a second mixture; Adding the boron trifluoride etherate and the Grignard reagent to the second mixed solution, and keeping the mixture warm for 0.5 to 4 hours after the addition is complete; The reaction is quenched by using a quenching agent, and then the organic phase is extracted and washed, dried and concentrated to obtain the Z-configuration chiral olefin compound.

3. The method for synthesizing a Z-configuration chiral olefin compound according to claim 2, characterized in that: The quenching agent includes any one of saturated ammonium chloride solution, saturated hydrochloric acid solution, ethanol and methanol.

4. The method for synthesizing a Z-configuration chiral olefin compound according to claim 2, characterized in that: The reaction temperature of the insulation reaction is -20°C to -78°C.

5. The method for synthesizing a Z-configuration chiral olefin compound according to claim 1, characterized in that: The ligand includes at least one of the following phosphoramidite ligand molecular structures:

6. The method for synthesizing a Z-configuration chiral olefin compound according to claim 1, characterized in that: The Grignard reagent includes at least one of methylmagnesium bromide, ethylmagnesium bromide, n-butylmagnesium bromide, isobutylmagnesium bromide, n-heptylmagnesium bromide, 4-methyl-3-n-pentenylmagnesium bromide, phenethylmagnesium bromide, isopropylmagnesium bromide, cyclobutylmagnesium bromide, cyclohexylmagnesium bromide, cycloheptylmagnesium bromide, cyclopentylmagnesium bromide, methylmagnesium chloride, ethylmagnesium chloride, n-butylmagnesium chloride, isobutylmagnesium chloride, n-heptylmagnesium chloride, 4-methyl-3-n-pentenylmagnesium chloride, phenethylmagnesium chloride, isopropylmagnesium chloride, cyclobutylmagnesium chloride, cyclohexylmagnesium chloride, cycloheptylmagnesium chloride, cyclopentylmagnesium chloride, methylmagnesium chloride, ethylmagnesium chloride, n-butylmagnesium chloride, isobutylmagnesium chloride, n-heptylmagnesium chloride, 4-methyl-3-n-pentenylmagnesium chloride, phenethylmagnesium chloride, isopropylmagnesium chloride, cyclobutylmagnesium chloride, cyclohexylmagnesium chloride, cycloheptylmagnesium chloride and cyclopentylmagnesium chloride.

7. The method for synthesizing a Z-configuration chiral olefin compound according to claim 1, characterized in that: The catalyst includes at least one of cuprous bromide dimethyl sulfide, cuprous chloride, cuprous iodide, cuprous thiophene-2-carboxylate, and copper trifluoromethane sulfonate.

8. The method for synthesizing a Z-configuration chiral olefin compound according to claim 1, characterized in that: The Grignard reagent was dissolved in diethyl ether.

9. The method for synthesizing a Z-configuration chiral olefin compound according to claim 1, characterized in that: The solvent includes at least one of toluene, dichloromethane, ether, tetrahydrofuran and p-xylene.

10. The method for synthesizing a Z-configuration chiral olefin compound according to claim 1, characterized in that: In terms of molar amount, the chain racemic allyl benzyl ether: the phosphoramidite ligand: the catalyst: the boron trifluoride etherate: the Grignard reagent = 1: (0.05-0.20): (0.05-0.20): (0.50-3.00): (0.50-3.00).

Images