A method for desymmetrization reaction of meso-allyl ether

Abstract

The present invention relates to a method for the desymmetrization reaction of meso allyl ether, comprising the following steps: uniformly mixing cyclic meso allyl methyl ether, a Grignard reagent, a ligand, a catalyst, boron trifluoride etherate and a solvent, causing a desymmetrization reaction, and obtaining an asymmetric allyl alkyl compound; the structural formula of the asymmetric allyl alkyl compound is as follows: wherein R is a primary alkyl group or a secondary alkyl group, and n is 0 or 1. The present invention utilizes cyclic meso allyl methyl ether as a substrate to carry out a desymmetrization reaction, eliminates the symmetry factor in the raw material, and directly constructs a product molecule with two chiral centers. The cyclic meso allyl methyl 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.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a method for a desymmetrization reaction of meso-allyl ether. Background Art

[0002] Desymmetrization reactions with meso compounds as substrates are an important method for constructing chiral carbon-carbon bonds, and have many applications in the synthesis of natural products and biologically active compounds. Meso compounds refer to compounds with two or more chiral centers. At the same time, due to the presence of a planar symmetry factor in the molecule, they are not optically active and cannot be separated into optically active compounds. Desymmetrization reactions can effectively remove the symmetry factor in the molecule and construct compounds with two or more chiral centers.

[0003] In the past, the research on the desymmetrization reaction of meso-allylic substrates still has certain limitations. In the previous methods, organometallic reagents are usually used as nucleophiles to undergo nucleophilic substitution reactions with meso-allylic substrates to achieve the purpose of removing symmetry factors in the molecule and constructing optically active products. However, most of the meso-allylic substrates selected in the past are highly active allyl halides or phosphoesters, etc., but because these highly active substrates are more sensitive, have poor stability, and have harsh storage conditions, and they are very easy to react with nucleophiles, thereby removing halogens or phosphoesters from the substrates, the application of such substrates in multi-step reactions is limited. Compared with the substrates used in the past, the leaving ability of the alkoxy group in the meso-allylic ether substrate is several orders of magnitude worse than that of the halides and phosphoesters. Therefore, the meso-allyl methyl ether substrate is more stable than the meso-allyl halide or phosphoester substrate, is not easy to deteriorate, is easy to store, and is more challenging. Summary of the invention

[0004] Based on this, it is necessary to provide a method for the desymmetrization reaction of meso-allyl ether, aiming to solve the technical problem of reaction substrate sensitivity in the desymmetrization reaction method of meso-allyl ether in the prior art.

[0005] To achieve the above object, the present invention provides a technical solution:

[0006] A method for the desymmetrization reaction of meso-allyl ether comprises the following steps:

[0007] The cyclic meso-allyl methyl ether, the Grignard reagent, the ligand, the catalyst, the boron trifluoride etherate and the solvent are uniformly mixed to cause a desymmetrization reaction to obtain an asymmetric allyl alkyl compound;

[0008] The structural formula of the asymmetric allyl alkyl compound is as follows:

[0009]

[0010] Wherein, R is a primary alkyl group or a secondary alkyl group, and n is 0 or 1.

[0011] Preferably, the method for the desymmetrization reaction of meso-allyl ether comprises the following specific steps:

[0012] Under the protection of inert gas, adding the ligand, the catalyst and the solvent into a container and mixing them evenly to obtain a first mixed solution;

[0013] adding the cyclic meso-allyl methyl ether to the first mixed liquid to obtain a second mixture;

[0014] Adding the boron trifluoride etherate and the Grignard reagent to the second mixed solution, and keeping the mixture warm for 0.5 to 1.5 hours;

[0015] The reaction is quenched with a quenching agent, and then the organic phase is extracted and washed, dried and concentrated to obtain the asymmetric allyl alkyl compound.

[0016] Preferably, the quenching agent includes any one of saturated ammonium chloride solution, saturated hydrochloric acid solution, ethanol and methanol.

[0017] Preferably, the reaction temperature of the insulation reaction is -20 to -78°C.

[0018] Preferably, the ligand comprises at least one of the following phosphoramidite ligand molecular structures:

[0019]

[0020] 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 and cyclopentylmagnesium bromide.

[0021] Preferably, the catalyst comprises at least one of cuprous bromide dimethyl sulfide, cuprous chloride, cuprous thiophene-2-carboxylate and copper trifluoromethanesulfonate.

[0022] Preferably, the Grignard reagent is dissolved in diethyl ether.

[0023] Preferably, the solvent comprises at least one of toluene, dichloromethane, ether, tetrahydrofuran and p-xylene.

[0024] Preferably, in terms of molar amount, the cyclic meso-allyl methyl ether: the 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).

[0025] The beneficial effects of the method for the desymmetrization reaction of meso-allyl ether provided in the embodiment of the present invention are as follows:

[0026] The present invention uses cyclic meso allyl methyl ether as a substrate to carry out a desymmetrization reaction. The cyclic meso allyl methyl 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, thereby solving the technical problem of reaction substrate sensitivity in the desymmetrization reaction method of meso allyl ether in the prior art. DETAILED DESCRIPTION

[0027] The following will be combined with 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.

[0028] 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.

[0029] 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.

[0030] An embodiment of the present invention provides a method for the desymmetrization reaction of a meso-allyl ether, comprising the following steps:

[0031] The cyclic meso-allyl methyl ether, the Grignard reagent, the ligand, the catalyst, the boron trifluoride etherate and the solvent are uniformly mixed to cause a desymmetrization reaction to obtain an asymmetric allyl alkyl compound;

[0032] The structural formula of the asymmetric allyl alkyl compound is as follows:

[0033]

[0034] Wherein, R is a primary alkyl group or a secondary alkyl group, and n is 0 or 1.

[0035] The present invention uses cyclic meso allyl methyl ether as a substrate to carry out a desymmetrization reaction. The cyclic meso allyl methyl 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.

[0036] Specifically, the desymmetrization reaction of meso-allyl ether is a nucleophilic substitution reaction, and the reaction rate is positively correlated with the leaving ability of the substituent in the substrate. Most of the substrates used in the past are meso-allyl halides or phosphoesters, and the leaving ability of the alkoxy group in meso-allyl ether substrates is several orders of magnitude worse than that of halides and phosphoesters. Therefore, meso-allyl methyl ether substrates are more stable than meso-allyl halides or phosphoester substrates, are not easy to deteriorate, are easier to store, and are more challenging.

[0037] Preferably, the method for the desymmetrization reaction comprises the following specific steps:

[0038] S100. Under the protection of an inert gas, a ligand, a catalyst and a solvent are added into a container and mixed evenly to obtain a first mixed solution.

[0039] Preferably, the ligand comprises at least one of the following phosphoramidite ligand molecular structures:

[0040]

[0041] Preferably, the catalyst includes at least one of cuprous bromide dimethyl sulfide, cuprous chloride, cuprous thiophene-2-carboxylate and copper trifluoromethanesulfonate.

[0042] Preferably, the solvent includes at least one of toluene, dichloromethane, ethyl ether, tetrahydrofuran and p-xylene.

[0043] Preferably, the container is a dry Schlenk reaction tube equipped with a stirring bar.

[0044] 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.

[0045] S200. Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid to obtain a second mixture.

[0046] Specifically, in step S200, the temperature is room temperature.

[0047] S300. Add boron trifluoride etherate and Grignard reagent to the second mixed solution, and keep warm for 0.5 to 1.5 hours after the addition.

[0048] Specifically, the reaction temperature of the insulation reaction is -20 to -78°C.

[0049] 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 and cyclopentylmagnesium bromide.

[0050] Specifically, the reaction formula of the desymmetrization reaction in one embodiment is as follows:

[0051]

[0052] Wherein L is a phosphoramidite ligand, and R is a primary alkyl group or a secondary alkyl group.

[0053] More specifically, the asymmetric allyl alkyl compound is one of the following compounds 3a to 31 and 4a:

[0054]

[0055] Preferably, in terms of molar amount, cyclic meso-allyl methyl ether: ligand: catalyst: boron trifluoride etherate: Grignard reagent = 1: (0.05-0.20): (0.05-0.20): (1.00-3.00): (1.00-3.00).

[0056] S400. The reaction is quenched with a quenching agent, and then the organic phase is extracted and washed, and then dried and concentrated to obtain an asymmetric allyl alkyl compound.

[0057] Preferably, the quenching agent includes any one of saturated ammonium chloride solution, saturated hydrochloric acid solution, ethanol and methanol.

[0058] Preferably, the extractant is ethyl acetate.

[0059] Preferably, the detergent is water or salt water.

[0060] Preferably, the desiccant is anhydrous magnesium sulfate.

[0061] The following are specific examples. Unless otherwise specified, the raw materials in the examples are all commercially available products.

[0062] Example 1

[0063] Synthesis of compound 3a

[0064] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0065] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0066] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L n-heptylmagnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0067] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate, washed with water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 3a.

[0068] The expected product was purified by silica gel column chromatography with an isolated yield of 86% and an ee value of 99%.

[0069] The NMR data of compound 3a are as follows:

[0070] 1 HNMR(400MHz,Chloroform-d)δ5.68–5.61(m,1H),5.60–5.48(m,1H),3.38(s,3H),3.13(ddd,J=8.6,6.0,2.7Hz,1H),2.20–2.05 (m,2H),2.03–1.85(m,2H),1.65–1.57(m,1H),1.57–1.47(m,1H),1.45–1.36(m,1H),1.31–1.24(m,10H),0.88(t,J=6.7Hz,3H). 13 C NMR (100MHz, Chloroform-d) δ129.3,126.0,80.0,56.1,41.1,33.3,31.9,29.9,29.3,26.8,24.5,23.2,22.7,14.1.

[0071] Example 2

[0072] Synthesis of compound 3b

[0073] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0074] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0075] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L isobutylmagnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0076] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate and extracted, washed with water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 3b.

[0077] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 75% and an ee value of 95%.

[0078] The NMR data of compound 3b are as follows:

[0079] 1 H NMR(400MHz,Chloroform-d)δ5.68–5.61(m,1H),5.60–5.51(m,1H),3.37(s,3H),3.11(ddd,J=7.9,5.3,2.6Hz,1H),2.23–2.08 (m,2H),2.03–1.91(m,1H),1.89–1.80(m,1H),1.78–1.57(m,2H),1.42–1.29(m,1H),1.17–1.07(m,1H),0.91(t,J=6.5Hz,6H). 13 CNMR(100MHz,Chloroform-d)δ129.0,126.0,80.4,56.1,43.2,38.5,25.2,23.9,23.6,22.7,22.1.

[0080] Example 3

[0081] Synthesis of compound 3c

[0082] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0083] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0084] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L n-butylmagnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0085] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate and extracted, and washed with water and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 3c.

[0086] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 78% and an ee value of 96%.

[0087] The NMR data of compound 3c are as follows:

[0088] 1 H NMR(400MHz,Chloroform-d)δ5.68–5.60(m,1H),5.59–5.50(m,1H),3.37(s,3H),3.13(ddd,J=8.6,6.0,2.7 Hz,1H),2.20–2.04(m,2H),2.04–1.85(m,2H),1.67–1.47(m,2H),1.40–1.25(m,5H),0.90(t,J=6.9Hz,3H). 13 C NMR (100MHz, Chloroform-d) δ129.3,126.0,80.0,56.1,41.1,33.0,29.0,24.5,23.2,23.0,14.1.

[0089] Example 4

[0090] Synthesis of compound 3d

[0091] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0092] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0093] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L ethyl magnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0094] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate, extracted, and washed with water and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3d.

[0095] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 72% and an ee value of 99%.

[0096] The NMR data of compound 3d are as follows:

[0097] 1 H NMR(400MHz,Chloroform-d)δ5.69–5.62(m,1H),5.58–5.51(m,1H),3.38(s,3H),3.13(ddd,J=8.8,6.2,2.7Hz,1H),2 .21–2.09(m,1H),2.08–1.96(m,2H),1.95–1.86(m,1H),1.62–1.52(m,2H),1.38–1.28(m,1H),0.93(t,J=7.5Hz,3H). 13 C NMR (100MHz, Chloroform-d) δ129.0,126.3,79.6,56.2,42.7,25.7,24.7,23.3,11.1.

[0098] Example 5

[0099] Synthesis of compound 3e

[0100] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0101] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0102] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L methylmagnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0103] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, the mixture was diluted and extracted with 10 mL of ethyl acetate, washed with water and brine, and then the organic phase was dried over anhydrous magnesium sulfate. Since the reaction product had a low boiling point and was very volatile, the separation yield could not be obtained. The reaction conversion rate was determined by GCMS and GC, and the conversion rate was 83% and the ee value was 90%.

[0104] Example 6

[0105] Synthesis of compound 3f

[0106] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0107] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0108] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L 4-methyl-3-n-pentenylmagnesium bromide solution (solvent: ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0109] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate and extracted, and washed with water and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 3f.

[0110] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 77% and an ee value of 98%.

[0111] The NMR data of compound 3f are as follows:

[0112] 1 H NMR(400MHz,Chloroform-d)δ5.70–5.62(m,1H),5.60–5.52(m,1H),5.18–5.07(m,1H),3.37(s,3H),3.14(ddd,J=8.6, 6.0,2.8Hz,1H),2.19–1.85(m,6H),1.69(s,3H),1.68-1.61(m,1H),1.61(s,3H),1.58–1.51(m,1H),1.36–1.27(m,1H). 13 C NMR (100MHz, Chloroform-d) δ131.5,129.0,126.2,124.6,80.0,56.2,40.7,33.4,25.7,25.3,24.5,23.2,17.7.

[0113] Example 7

[0114] Synthesis of compound 3g

[0115] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0116] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0117] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L phenethyl magnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0118] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate and extracted, and washed with water and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 3g.

[0119] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 92% and an ee value of 98%.

[0120] The NMR data of compound 3g are as follows:

[0121] 1 H NMR(400MHz,Chloroform-d)δ7.31–7.26(m,2H),7.23–7.15(m,3H),5.74–5.67(m,1H),5.66–5.58(m,1H),3.37(s,3H),3.17 (ddd,J=8.8,6.2,2.7Hz,1H),2.81–2.71(m,1H),2.69–2.58(m,1H),2.24–2.10(m,2H),2.08–1.84(m,3H),1.65–1.57(m,2H). 13 C NMR (100MHz, Chloroform-d) δ142.6,128.7,128.3,128.3,126.6,125.6,80.0,56.1,41.0,35.2,33.2,24.7,23.3.

[0122] Example 8

[0123] Synthesis of compound 3h

[0124] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0125] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0126] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L isopropyl magnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0127] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate and extracted, and washed with water and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 3h.

[0128] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 70% and an ee value of 94%.

[0129] The NMR data of compound 3h are as follows:

[0130] 1 H NMR(400MHz,Chloroform-d)δ5.79–5.64(m,1H),5.56–5.45(m,1H),3.37(s,3H),3.22(ddd,J=9.9,7.0,2.8H z,1H),2.19–2.07(m,1H),2.05–1.88(m,4H),1.59–1.47(m,1H),0.96(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H). 13 C NMR (100MHz, Chloroform-d) δ127.2,126.6,78.0,56.1,47.5,28.1,25.6,23.6,21.0,18.0.

[0131] Example 9

[0132] Synthesis of compound 3i

[0133] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0134] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0135] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L cyclobutylmagnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0136] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate and extracted, washed with water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 3i.

[0137] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 77% and an ee value of 97%.

[0138] The NMR data of compound 3i are as follows:

[0139] 1H NMR(400MHz,Chloroform-d)δ5.76–5.66(m,1H),5.61–5.53(m,1H),3.35(s,3H),3.12(ddd,J=7.3,4.5,2.9Hz,1H) ,2.29–2.18(m,1H),2.16–2.05(m,2H),2.04–1.89(m,3H),1.88–1.80(m,2H),1.80–1.75(m,2H),1.74–1.62(m,2H). 13 C NMR (100MHz, Chloroform-d) δ126.7,126.4,78.1,56.0,46.4,39.4,27.2,26.3,23.8,22.3,18.4.

[0140] Example 10

[0141] Synthesis of compound 3j

[0142] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0143] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0144] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L cyclopentylmagnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0145] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate, washed with water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 3j.

[0146] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 80% and an ee value of 97%.

[0147] The NMR data of compound 3j are as follows:

[0148] 1H NMR(400MHz,Chloroform-d)δ5.75–5.67(m,1H),5.61–5.52(m,1H),3.37(s,3H),3.26(ddd,J=7.7,5.2,2.7Hz,1H) ,2.18–2.01(m,2H),2.00–1.81(m,3H),1.80–1.63(m,3H),1.63–1.45(m,4H),1.35–1.26(m,1H),1.23–1.13(m,1H). 13 C NMR (100MHz, Chloroform-d) δ127.7,126.9,79.1,56.1,45.4,42.5,30.8,29.3,25.4,25.3,24.0,22.5.

[0149] Embodiment 11

[0150] Synthesis of compound 3k

[0151] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0152] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0153] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L cyclohexylmagnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0154] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate and extracted, and washed with water and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 3k.

[0155] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 80% and an ee value of 95%.

[0156] The NMR data of compound 3k are as follows:

[0157] 1H NMR(400MHz,Chloroform-d)δ5.72–5.63(m,1H),5.56–5.48(m,1H),3.37(s,3H),3.28(ddd,J=9.4,6.6,2.8Hz,1H),2.17–2.06(m,1H) ,2.04–1.90(m,3H),1.78–1.69(m,2H),1.69–1.62(m,2H),1.61–1.50(m,3H),1.33–1.22(m,2H),1.20–1.09(m,2H),1.08–0.93(m,1H). 13 C NMR (100MHz, Chloroform-d) δ127.4,126.7,77.4,56.1,47.0,38.9,31.4,28.9,26.8,26.7,26.7,25.5,23.3.

[0158] Example 12

[0159] Synthesis of compound 3l

[0160] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0161] Add 0.2 mmol of cyclic meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0162] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L cycloheptylmagnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0163] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate, extracted, and washed with water and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 31.

[0164] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 82% and an ee value of 95%.

[0165] The NMR data of compound 3l are as follows:

[0166] 1H NMR(400MHz,Chloroform-d)δ5.71–5.62(m,1H),5.53–5.41(m,1H),3.37(s,3H),3.18(ddd,J=10.4,7.5,3.0Hz,1H),2.17–2. 06(m,2H),2.05–1.94(m,2H),1.86–1.76(m,1H),1.74–1.63(m,2H),1.62–1.52(m,4H),1.51–1.32(m,6H),1.24–1.12(m,1H). 13 C NMR (100MHz, Chloroform-d) δ127.4,127.1,78.2,56.2,48.9,39.3,33.4,29.7,28.3,28.0,27.8,27.5,26.0,24.0.

[0167] Embodiment 13

[0168] Synthesis of compound 4a

[0169] 0.012 mmol phosphoramidite ligand 0.01 mmol of cuprous bromide dimethyl sulfide was added to a dry schlenk reaction tube equipped with a stirring bar and mixed evenly, and the argon gas was replaced three times with a vacuum pump. Under the protection of argon gas, 2.0 mL of dichloromethane was added, and the mixture was stirred at 25° C. for 15 minutes to obtain a first mixed solution;

[0170] Add 0.2 mmol of five-membered ring meso-allyl methyl ether to the first mixed liquid, cool to -78°C, and keep for 10 minutes to obtain a second mixture;

[0171] Add 0.5 mmol of boron trifluoride etherate and 0.5 mL of 1 mol / L n-heptylmagnesium bromide solution (solvent is ether) to the second mixed solution using a syringe pump. After the addition is complete, heat and react at -78°C for 1 hour.

[0172] Use 2.0 mL saturated NH 4 The reaction was quenched with aqueous Cl solution, and the mixture was diluted with 10 mL of ethyl acetate, washed with water and brine, and then the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 4a.

[0173] The expected product was obtained by purification through silica gel column chromatography with an isolated yield of 71% and an ee value of 95%.

[0174] The NMR data of compound 4a are as follows:

[0175] 1H NMR(400MHz,Chloroform-d)δ5.71–5.66(m,1H),5.66–5.61(m,1H),3.65(dt,J=6.4,3.1Hz,1H) ,3.32(s,3H),2.67–2.53(m,2H),2.36–2.23(m,1H),1.39–1.24(m,12H),0.88(t,J=6.8Hz,3H). 13 C NMR (100MHz, Chloroform-d) δ133.3,127.5,86.6,56.3,51.6,38.1,33.8,31.8,29.8,29.3,27.7,22.6,14.1.

[0176] It should be noted that in the above examples, when the nucleophilic reagent is a methyl-containing Grignard reagent, the product is highly volatile and no separation yield is obtained. The conversion rate is determined by gas phase, and the regioselectivity is S N 2': S N 2=78:22. The regioselectivity of the products in the remaining examples is S N 2': S N 2>19:1.

[0177] The above description is only a preferred embodiment of the present invention, and does not limit the patent scope of the present invention. All equivalent structural changes made by using the contents of the present invention specification under the inventive concept of the present invention, or direct / indirect application in other related technical fields are included in the patent protection scope of the present invention.

Claims

1. A method for the desymmetrization reaction of a meso-allyl ether, characterized in that: The steps include: The cyclic meso-allyl methyl ether, the Grignard reagent, the ligand, the catalyst, the boron trifluoride etherate and the solvent are uniformly mixed to cause a desymmetrization reaction to obtain an asymmetric allyl alkyl compound; The structural formula of the cyclic meso-allyl methyl ether is as follows: ； Where n is 0 or 1; The structural formula of the asymmetric allyl alkyl compound is as follows: ； Wherein, R is a primary alkyl group or a secondary alkyl group, and n is 0 or 1; The ligand is a phosphoramidite ligand molecular structure as follows: ； The catalyst includes at least one of cuprous bromide dimethyl sulfide, cuprous chloride, cuprous thiophene-2-carboxylate, and copper trifluoromethanesulfonate.

2. The method for the desymmetrization reaction of meso-allyl ether according to claim 1, characterized in that: The method for the desymmetrization reaction specifically comprises the following steps: Under the protection of inert gas, adding the ligand, the catalyst and the solvent into a container and mixing them evenly to obtain a first mixed solution; adding the cyclic meso-allyl methyl ether to the first mixed liquid to obtain a second mixture; Add the boron trifluoride etherate and the Grignard reagent to the second mixed solution, and keep the mixture warm for 0.5 to 1.5 hours. The reaction is quenched with a quenching agent, and then the organic phase is extracted and washed, dried and concentrated to obtain the asymmetric allyl alkyl compound.

3. The method for the desymmetrization reaction of meso-allyl ether 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 the desymmetrization reaction of meso-allyl ether according to claim 2, characterized in that: The reaction temperature of the insulation reaction is -20~-78°C.

5. The method for the desymmetrization reaction of meso-allyl ether 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 and cyclopentylmagnesium bromide.

6. The method for desymmetrization of meso-allyl ether according to claim 1, characterized in that: The Grignard reagent was dissolved in diethyl ether.

7. The method for desymmetrization of meso-allyl ether according to claim 1, characterized in that: The solvent includes at least one of toluene, dichloromethane, ether, tetrahydrofuran and p-xylene.

8. The method for desymmetrization of meso-allyl ether according to claim 1, characterized in that: In terms of molar amount, the cyclic meso-allyl methyl ether: the 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).

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