Chiral dienyl-substituted carboxylate compounds and asymmetric preparation methods thereof

Abstract

The present application discloses a chiral dienyl-substituted carboxylate compound and an asymmetric preparation method thereof, wherein the chiral dienyl-substituted carboxylate compound is an optically active compound with the structure shown in the following formula I, including stereoisomers with the same chemical formula: in the formula, * represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1‑10 alkyl or aryl; Ar is an aromatic ring or a substituted aromatic ring; R 1 , R 2 , R 3 , R 4 , R 5 are independently selected from hydrogen, halogen, C 1‑10 alkyl or alkoxy; R 6 is independently selected from C 1‑10 alkyl or aryl; R 7 is independently selected from C 1‑10 alkyl or aryl. The present application applies a chiral isothiourea catalytic electrochemical synthesis system to precisely and quickly synthesize the chiral dienyl-substituted carboxylate compound in a high yield and high stereoselectivity and in a gram-scale. The preparation method of the present application is simple, and has biomedical practicability and industrial application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of asymmetric organic synthesis, and particularly relates to a chiral dienyl-substituted carboxylate compound and an asymmetric preparation method thereof. BACKGROUND

[0002] Carboxylic acid is an important chemical raw material, and functionalization reaction of the carbonyl alpha-position thereof is an important reaction in organic synthesis chemistry, which can rapidly and efficiently convert simple carboxylic acid derivatives into important compounds with diverse structures, and has been widely used in the fields of medicinal chemistry, polymer chemistry and material chemistry. On the other hand, 1,3-diene is a unique and important skeleton, which is widely present in natural products, bioactive molecules, drugs and functional organic materials. So far, although a large number of asymmetric catalytic methods have been established, the construction of chiral carboxylic acid compounds containing diene skeleton from simple carboxylic acid derivatives through asymmetric catalytic synthesis method is still a hot and difficult point in the field of organic synthesis. Therefore, it is a scientific hotspot to develop an efficient catalytic system to realize the enantioselective synthesis of chiral dienyl-substituted carboxylate compounds, and to create more abundant three-dimensional molecular structures.

[0003] Electrochemical synthesis strategy is a kind of green and sustainable synthesis method. Electrochemical synthesis realizes chemical reaction through electron gain or loss of reactants on the electrode, and in principle does not use other reagents, thereby greatly reducing material consumption and environmental pollution. In recent years, with the vigorous development of electrochemical asymmetric synthesis strategy, asymmetric electrochemical functionalization reactions of chiral amines, chiral metal complex catalyzed aldehyde compounds, acylimidazole compounds and benzoxazole carbonyl compounds have been realized. However, the development of more types of asymmetric electrochemical catalytic system, and then the realization of asymmetric electrochemical reaction of simple carboxylic acid derivatives and the stereochemical control of the process still face great challenges. SUMMARY

[0004] The purpose of the present application is to provide a chiral dienyl-substituted carboxylate compound and an asymmetric preparation method thereof, so as to solve the above problems existing in the prior art.

[0005] The chiral dienyl-substituted carboxylate compound of the present application is an optically active compound having the structure shown in the following formula I, including stereoisomers thereof having the same chemical formula:

[0006]

[0007] In the formula, * represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1-10 alkyl or aryl; Ar is an aromatic ring or a substituted aromatic ring; R 1 , R 2 , R3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, C 1-10 alkyl or alkoxy; R 7 is independently selected from C 1-10 alkyl or aryl.

[0008] The asymmetric preparation method of the chiral dienyl-substituted carboxylate compound of the application uses substituted diallyl silane 1 and carboxylate derivative 2 as starting materials, alcohol 3 as a quenching reagent, chiral isothiourea as a reaction catalyst, and obtains the target product I through asymmetric alkylation under electrochemical reaction conditions after separation and purification.

[0009] The synthetic route is shown as follows:

[0010]

[0011] In the above formula: * represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1-10 alkyl or aryl; Ar is an aromatic ring or a substituted aromatic ring; R 1 , R 2 , R 3 , R 4 , R 5 are independently selected from hydrogen, halogen, C 1-10 alkyl or alkoxy; R 6 is independently selected from C 1-10 alkyl or aryl; R 7 is independently selected from C 1-10 alkyl or aryl; R 8 is independently selected from C 1-10 alkyl or aryl.

[0012] Specifically includes the following steps:

[0013] Under a nitrogen atmosphere, substituted diallyl silane 1, carboxylate derivative 2, alcohol 3, chiral isothiourea catalyst and electrolyte are added in a reaction bottle equipped with an electrode, and an organic solvent is added for dissolution, a current is applied at -20 to 70°C for 2-48 hours, and the reaction endpoint is determined by thin layer chromatography point plate; after the reaction is complete, the solvent is removed by reduced pressure distillation, and finally the residue is separated by column chromatography to obtain the target product I.

[0014] In the preparation process of the application:

[0015] The chiral isothiourea catalyst is selected from the following structure:

[0016]

[0017] wherein: * is a carbon chiral center; n is 0 or 1; R 9 , R 10 , R 11 , and R 12 are each independently selected from hydrogen, halogen, a substituted or unsubstituted group selected from C 1-10 alkyl, C 3-10 cycloalkyl, 2-furyl, or C 6-20 aryl; R 13 is independently selected from C 1-10 alkyl or aryl.

[0018] the organic solvent is 1,4-dioxane, dichloromethane, dichloroethane, dimethyl sulfoxide, N -methylpyrrolidone, N , N -dimethylformamide, N , N -dimethylacetamide, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, toluene, ethylbenzene, fluorobenzene, chlorobenzene, bromobenzene, xylene, or mesitylene.

[0019] the electrode is one or two of carbon, carbon cloth, carbon felt, carbon paper, platinum, nickel, reticulated vitreous carbon (RVC), glassy carbon (GC), boron-doped diamond (BDD) electrode.

[0020] the electrolyte is tetrabutylammonium hexafluorophosphate, tetraethylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, tetrabutylammonium perchlorate, or tetrabutylammonium bromide.

[0021] wherein: the molar ratio of chiral isothiourea catalyst and substituted diallylsilyl 1 is 0.025:1-1:1; the molar equivalent ratio of substituted diallylsilyl 1 and carboxylate derivative 2 is 1:1-1:5; the molar equivalent ratio of substituted diallylsilyl 1 and alcohol 3 is 1:1-1:100; the molar ratio of substituted diallylsilyl 1 and electrolyte is 1:0.1-1:5.

[0022] The application provides a synthesis method of chiral dienyl-substituted carboxylate compounds by electrochemical catalytic asymmetric reaction. The application takes substituted diallyl silane 1 and carboxylate derivative 2 as starting materials, alcohol 3 as a quenching reagent, and chiral isothiourea as a reaction catalyst, and the target product I is obtained through asymmetric alkenyl reaction under electrochemical reaction conditions and after separation and purification. The application successfully develops a synthesis method of chiral dienyl-substituted carboxylate compounds, and chiral dienyl-substituted carboxylate compounds with high yield and high optical purity can be easily prepared. The electrochemical synthesis method is used to replace the traditional oxidant with electrons, so that the synthesis of chiral dienyl-substituted carboxylate compounds can be realized in a green and atom economy manner, which is beneficial to industrial production. Meanwhile, 1,3-diene is a unique and important skeleton, which is widely present in natural products, bioactive molecules and functional organic materials (Harned, A. M., Volp, K. A. The sorbicillinoid family of natural products: Isolation, biosynthesis, and synthetic studies. Nat. Prod. Rep. 2011, 28 , 1790.). Chem. Rev. 2015, 115 , 5301-5365.). Therefore, it is of great research value and significance to realize the synthesis of chiral molecules containing diene skeleton, which reflects the practicability of the preparation method. DETAILED DESCRIPTION

[0023] The specific embodiments of the application are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the application, and are not used to limit the application.

[0024] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0025] Example 1: Preparation of chiral dienyl-substituted carboxylic acid ester compound 4a

[0026]

[0027] Take a dry 10 mL reaction tube equipped with a magnetic stir bar, and set it with a carbon electrode as the anode and a platinum electrode as the cathode. Under a nitrogen atmosphere, weigh and add the corresponding compounds 1a (0.1 mmol), 2a (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), and tetrabutylammonium hexafluorophosphate (…). n Bu4NPF6 (0.3 mmol) was added, followed by the addition of a 2:1 THF / MeCN mixture (3 mL) to dissolve it. Electrolysis was then performed at a constant current (1 mA) at 25 °C for 12 hours. After the reaction was complete, the solvent was removed directly by vacuum distillation. Finally, the dienated product 4a (55% yield, 97% ee) was obtained by column chromatography using a 50:1 volume ratio of petroleum ether / ethyl acetate as the eluent.

[0028] 1 H NMR (400 MHz, CDCl3)δ 7.26 – 7.16 (m, 7H), 7.13 – 7.06 (m, 2H), 5.56 (dd, J = 6.8, 1.4 Hz, 1H), 5.46 (d, J = 1.6 Hz, 1H), 4.83 (d, J = 1.6Hz, 1H), 4.28 (d, J = 1.4 Hz, 1H), 3.56 (s, 3H), 2.30 (s, 3H), 1.59 (dd, J =6.8, 1.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.7, 145.8, 139.3, 137.6, 137.0,136.0, 129.3, 129.2, 128.3, 127.2, 126.4, 126.0, 115.2, 57.1, 52.0, 21.2,14.9.ESI-MS: calculated [C 21 H 22 O2 + Na] + : 329.1512, found: 329.1510. [α] 20 D = +89.4 (c = 0.98, CH2Cl2). The product was analyzed by HPLC to determine theenantiomeric excess: 97% ee (CHIRALPAK IBN-5, n -hexane / i -PrOH = 95 / 5, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 3.9min, t2(major) = 4.4 min.

[0029] Example 2: Preparation of chiral dienyl-substituted carboxylic acid ester compound 4b

[0030]

[0031] Take a dry 10 mL reaction tube equipped with a magnetic stir bar, and set it with a carbon electrode as the anode and a platinum electrode as the cathode. Under a nitrogen atmosphere, weigh and add the corresponding compounds 1b (0.1 mmol), 2a (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), and tetrabutylammonium hexafluorophosphate (…). n Bu4NPF6 (0.3 mmol) was added, followed by the addition of a 2:1 THF / MeCN mixture (3 mL) to dissolve it. Electrolysis was then performed at a constant current (1 mA) at 25 °C for 12 hours. After the reaction was complete, the solvent was removed directly by vacuum distillation. Finally, the dienated product 4b (56% yield, 97% ee) was obtained by column chromatography using a 50:1 volume ratio of petroleum ether / ethyl acetate as the eluent.

[0032] 1H NMR (500 MHz, CDC13) δ 7.67 - 7.56 (m, 4H), 7.52 - 7.43 (m, 4H), 7.41 - 7.27 (m, 6H), 5.69 (dd, J = 6.8, 1.4 Hz, 1H), 5.64 (d, J = 1.5 Hz, 1H), 5.00 (d, J = 1.5 Hz, 1H), 4.41 (t, J = 1.4 Hz, 1H), 3.66 (s, 3H), 1.70 (dd, J = 6.8, 1.3 Hz, 3H). 13 C NMR (125 MHz, CDC13) δ 172.7, 145.6, 140.8, 140.6, 139.1, 137.9, 136.9, 129.3, 128.8, 128.4, 127.4, 127.3, 127.2, 127.0, 126.9, 126.4, 116.0, 57.2, 52.0, 15.0. ESI-MS: calculated [C 26 H 24 O2 + Na] + : 391.1669, found: 391.1661. [a] 20 D = +94.3 (c = 0.80, CH2CI2). The product was analyzed by HPLC to determine the enantiomeric excess: 97% ee (CHIRALCEL AD, n -hexane / i -PrOH = 95 / 5, detector: 254 nm, T = 25 °C, flow rate: 1 mL / min), t1(minor) = 4.6 min, t2(major) = 5.0 min.

[0033] Example 3: Preparation of chiral dienyl-substituted carboxylate compound 4c

[0034]

[0035] A dry 10 mL reaction tube equipped with a stirring magnet and dried was taken, equipped with a carbon electrode as anode and platinum electrode as cathode. Under nitrogen atmosphere, the corresponding compounds 1c (0.1 mmol), 2a (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (Bu4NPF6, 0.3 mmol) were weighed and added sequentially, then THF / MeCN = 2:1 mixed solution (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by reduced pressure distillation, and finally column chromatography was used for separation with petroleum ether / ethyl acetate mixed as eluent according to the volume ratio of 50:1 to obtain the dienylated product 4c (61% yield, 92% ee). n Bu4NPF6, 0.3 mmol), then THF / MeCN = 2:1 mixed solution (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by reduced pressure distillation, and finally column chromatography was used for separation with petroleum ether / ethyl acetate mixed as eluent according to the volume ratio of 50:1 to obtain the dienylated product 4c (61% yield, 92% ee).

[0036] 1 H NMR (400 MHz, CDCl3) δ 7.29 – 7.15 (m,7H), 6.98 – 6.89 (m, 2H),5.56 (dd, J = 6.8, 1.4 Hz, 1H), 5.42 (d, J = 1.4 Hz, 1H), 4.87 (d, J = 1.4Hz, 1H), 4.25 (d, J = 1.5 Hz, 1H), 3.55 (s, 3H), 1.56 (dd, J = 6.8, 1.3 Hz,3H). 13 C NMR (101 MHz, CDCl3) δ 172.62, 162.58 (d, J = 246.7 Hz), 145.07,138.97, 136.75, 135.09, 129.23, 128.36, 128.26, 128.18, 127.34, 126.44,115.89, 115.42, 115.21, 57.21, 52.02, 14.93. 19 F NMR (376 MHz, CDCl3) δ -114.7.ESI-MS: calculated [C 20 H 19 FO2 + Na] + : 333.1261, found: 333.1265. [α] 20 D=+36.9 (c = 0.67, CH2Cl2).The product was analyzed by HPLC to determine theenantiomeric excess: 92% ee (CHIRALPAK IBN-5, n -hexane / i -PrOH = 98 / 2, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(major) = 4.6 min, t2(mior) = 5.3 min.

[0037] Example 4: Preparation of chiral dienyl-substituted carboxylic acid ester compound 4d

[0038]

[0039] Take a dry 10 mL reaction tube equipped with a magnetic stir bar, and set it with a carbon electrode as the anode and a platinum electrode as the cathode. Under a nitrogen atmosphere, weigh and add the corresponding compounds 1d (0.1 mmol), 2a (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), and tetrabutylammonium hexafluorophosphate (…). n Bu4NPF6 (0.3 mmol) was added, followed by the addition of a 2:1 THF / MeCN mixture (3 mL) to dissolve it. Electrolysis was then performed at 25°C with a constant current (1 mA) for 12 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the dienated product 4d (65% yield, 97% ee) was obtained by column chromatography using a 50:1 volume ratio of petroleum ether / ethyl acetate as the eluent.

[0040] 1 H NMR (400 MHz, CDCl3) δ 7.26 – 7.02 (m, 9H), 5.58 (dd, J = 6.8, 1.3Hz, 1H), 5.48 (d, J = 1.7 Hz, 1H), 4.87 (d, J = 1.6 Hz, 1H), 4.28 (d, J = 1.8Hz, 1H), 3.57 (s, 3H), 2.29 (s, 3H), 1.60 (dd, J = 6.8, 1.3 Hz, 1H). 13C NMR(100MHz, CDCl3) δ 172.7, 146.0, 139.3, 138.8, 138.0, 137.0, 129.2, 128.6,128.4, 128.3, 127.2, 126.1, 123.7, 115.9, 57.0, 52.0, 21.5, 14.9.ESI-MS:calculated [C 21 H 22 O2 + Na] + : 329.1512, found: 329.1517. [α] 20 D = +54.6 (c =0.76, CH2Cl2). The product was analyzed by HPLC to determine the enantiomericexcess: 97% ee(CHIRALCEL OJ-H, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T =25 ℃, flow rate: 1 mL / min), t1(major) = 5.2 min, t2(minor) = 9.6 min.

[0041] Example 5: Preparation of chiral dienyl-substituted carboxylic acid ester compound 4e

[0042]

[0043] Take a dry 10 mL reaction tube equipped with a magnetic stir bar, and set it with a carbon electrode as the anode and a platinum electrode as the cathode. Under a nitrogen atmosphere, weigh and add the corresponding compounds 1e (0.1 mmol), 2a (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), and tetrabutylammonium hexafluorophosphate (…). n Bu4NPF6 (0.3 mmol) was added, followed by the addition of a 2:1 THF / MeCN mixture (3 mL) to dissolve it. Electrolysis was then performed at a constant current (1 mA) at 25 °C for 12 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the dienated product 4e (67% yield, 94% ee) was obtained by column chromatography using a 50:1 volume ratio of petroleum ether / ethyl acetate as the eluent.

[0044] 1H NMR (400 MHz, CDC13) δ 7.34 - 7.21 (m, 5H), 7.01 - 6.89 (m, 3H), 5.63 (dd, J = 6.7, 1.3 Hz, 1H), 5.52 (d, J = 1.7 Hz, 1H), 4.89 (d, J = 1.7 Hz, 1H), 4.32 (d, J = 1.3 Hz, 1H), 3.62 (s, 3H), 2.30 (s, 6H), 1.66 (dd, J = 6.7, 1.3 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 172.8, 146.0, 139.4, 138.8, 137.9, 137.1, 129.5, 129.2, 128.3, 127.2, 126.0, 124.4, 115.7, 57.0, 52.0, 21.4, 14.9. ESI-MS: calculated [C 22 H 24 O2 + Na] + : 343.1669, found: 343.1660. [a] 20 D = +82.2 (c = 0.64, CH2CI2). The product was analyzed by HPLC to determine the enantiomeric excess: 94% ee (CHIRALCEL OJ-H, n -hexane i -PrOH = 70 / 30, detector: 254 nm, T = 25 °C, flow rate: 1 mL / min), t1(major) = 4.0 min, t2(mior) = 4.9 min.

[0045] Example 6: Preparation of chiral dienyl-substituted carboxylate compound 4f

[0046]

[0047] A dry 10 mL reaction tube equipped with a stirring magnet and dried was taken, equipped with a carbon electrode as anode and platinum electrode as cathode. Under nitrogen atmosphere, the corresponding compounds 1f (0.1 mmol), 2a (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (Bu4NPF6, 0.3 mmol) were weighed and added sequentially, then THF / MeCN = 2:1 mixed solution (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by reduced pressure distillation, and finally column chromatography was used for separation with petroleum ether / ethyl acetate mixed as eluent according to the volume ratio of 50:1 to obtain the dienylated product 4f (63% yield, 97% ee). n Bu4NPF6, 0.3 mmol), then THF / MeCN = 2:1 mixed solution (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by reduced pressure distillation, and finally column chromatography was used for separation with petroleum ether / ethyl acetate mixed as eluent according to the volume ratio of 50:1 to obtain the dienylated product 4f (63% yield, 97% ee).

[0048] 1 H NMR (400 MHz, CDCl3) δ 7.85 – 7.76 (m, 4H), 7.52 – 7.28 (m, 8H),5.52 (dd, J = 6.8, 1.4 Hz, 1H), 5.41 (d, J = 1.4 Hz, 1H), 4.85 (d, J = 1.4Hz, 1H), 4.27 (d, J = 1.3 Hz, 1H), 3.65 (s, 3H), 1.53 (dd, J = 6.8, 1.3 Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 173.8, 146.5, 140.1, 139.1, 136.4, 131.4,130.7, 128.2, 127.1, 126.4, 126.1, 125.7, 125.4, 124.7, 124.7, 124.1, 123.0,116.3, 57.7, 52.5, 15.3.ESI-MS: calculated [C 24 H 22 O2 + Na] + : 365.1512, found:365.1510. [α] 20 D= +52.9 (c = 0.69, CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess: 97% ee (CHIRALPAK IBN-5, n -hexane / i -PrOH =95 / 5, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(major) = 4.5 min, t2(mior) = 5.1 min.

[0049] Example 7: Preparation of 4g of a chiral dienyl-substituted carboxylic acid ester compound

[0050]

[0051] Take a dry 10 mL reaction tube equipped with a magnetic stir bar, and set it with a carbon electrode as the anode and a platinum electrode as the cathode. Under a nitrogen atmosphere, weigh and add the following compounds sequentially: 1 g (0.1 mmol), 2a (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), and tetrabutylammonium hexafluorophosphate (…). n Bu4NPF6 (0.3 mmol) was added, followed by the addition of a 2:1 THF / MeCN mixture (3 mL) to dissolve it. Electrolysis was then performed at a constant current (1 mA) at 25 °C for 12 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and finally, using a 50:1 volume mixture of petroleum ether and ethyl acetate as eluent, 4 g of the dienylated product (60% yield, 94% ee) was obtained by column chromatography.

[0052] 1 H NMR (500 MHz, CDCl3) δ 7.34 – 7.29 (m, 2H), 7.27 – 7.15 (m, 8H), 5.51 (d, J = 1.3 Hz, 1H), 5.44 (d, J = 1.6 Hz, 1H), 4.84 (d, J = 1.6 Hz, 1H), 4.26 (s, 1H), 3.56 (s, 3H), 1.99 (d, J = 7.4 Hz, 2H), 1.29 (q, J = 7.4 Hz, 2H), 0.77 (t,J = 7.4 Hz, 3H). 13 C NMR (125 MHz, CDCl3) δ 172.7, 146.2, 139.0,138.2, 137.0, 132.0, 129.3, 128.4, 128.3, 127.8, 127.2, 126.6, 115.9, 57.0,51.9, 31.2, 22.9, 13.9.ESI-MS: calculated [C 22 H 24 O2 + Na] + : 343.1669, found:343.1665. [α] 20 D = +75.7 (c = 0.70, CH2Cl2). The product was analyzed by HPLCto determine the enantiomeric excess: 94% ee(CHIRALPAK IBN-5, n -hexane / i -PrOH= 95 / 5, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 3.9min, t2(major) = 4.4 min.

[0053] Example 8: Preparation of chiral dienyl-substituted carboxylate compound 4h

[0054]

[0055] A dry 10 mL reaction tube equipped with a stirring magnet, a carbon electrode as anode and a platinum electrode as cathode was charged with the corresponding compound 1h (0.1 mmol), 2a (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (0.3 mmol) and then THF / MeCN = 2:1 (3 mL) was added to dissolve the mixture. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 h. After the reaction was completed, the solvent was removed directly by distillation under reduced pressure and the dienylated product 4h was isolated by column chromatography using petroleum ether / ethyl acetate (50:1 by volume) as eluent (50% yield, 93% ee). n Bu4NPF6, 0.3 mmol), and then THF / MeCN = 2:1 (3 mL) was added to dissolve the mixture. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 h. After the reaction was completed, the solvent was removed directly by distillation under reduced pressure and the dienylated product 4h was isolated by column chromatography using petroleum ether / ethyl acetate (50:1 by volume) as eluent (50% yield, 93% ee).

[0056] 1 H NMR (400 MHz, CDCl3) δ 7.31 – 7.07 (m, 13H), 7.02 – 6.94 (m, 2H),5.53 (dd, J = 7.3, 1.3 Hz, 1H), 5.39 (d, J = 1.6 Hz, 1H), 4.71 (d, J = 1.6Hz, 1H), 4.22 (d, J = 1.2 Hz, 1H), 3.56 (s, 3H), 2.57 (t, J = 7.2 Hz, 2H),2.39 – 2.29 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 172.6, 146.0, 141.6, 138.9,138.8, 136.8, 131.1, 129.3, 128.7, 128.5, 128.3, 128.2, 127.8, 127.3, 126.6,125.8, 116.0, 56.9, 52.0, 36.0, 31.3.ESI-MS: calculated [C 27 H 26 O2 + Na] + :405.1825, found: 405.1820. [α] 20 D = +80.4 (c = 0.75, CH2Cl2). The product wasanalyzed by HPLC to determine the enantiomeric excess: 93% ee(CHIRALPAK IBN-5, n -hexane / i -PrOH = 90 / 10, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 4.3 min, t2(major) = 4.9 min.

[0057] Example 9: Preparation of chiral dienyl-substituted carboxylate compound 4i

[0058]

[0059] A dry 10 mL reaction tube equipped with a stirring magnet and dried was taken, equipped with a carbon electrode as anode and platinum electrode as cathode. Under nitrogen atmosphere, the corresponding compounds 1a (0.1 mmol), 2b (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (Bu4NPF6, 0.3 mmol) were weighed and added sequentially, then THF / MeCN = 2:1 mixed solution (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by reduced pressure distillation, and finally dienylated product 4i was obtained by column chromatography with petroleum ether / ethyl acetate mixed as eluent in the volume ratio of 50:1 (68% yield, 92% ee). n Bu4NPF6, 0.3 mmol), then THF / MeCN = 2:1 mixed solution (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by reduced pressure distillation, and finally dienylated product 4i was obtained by column chromatography with petroleum ether / ethyl acetate mixed as eluent in the volume ratio of 50:1 (68% yield, 92% ee).

[0060] 1 H NMR (400 MHz, CDCl3) δ 7.38 – 7.28 (m, 5H), 7.25 – 7.20 (m, 2H),7.03 – 6.93 (m, 2H), 5.65 (dd, J = 6.9, 1.4 Hz, 1H), 5.55 (d, J = 1.5 Hz,1H), 4.91 (d, J = 1.5 Hz, 1H), 4.31 (s, 1H), 3.64 (s, 3H), 1.68 (dd, J = 6.8,1.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 172.66, 162.16 (d, J = 245.6 Hz),145.81, 139.23, 138.88, 130.93, 130.85, 128.56, 127.90, 126.57, 126.10,116.34, 115.29, 115.08, 56.37, 52.10, 14.99. 19 F NMR (376 MHz, CDCl3) δ -115.43.ESI-MS: calculated [C 20 H 19 FO2 + Na] + : 333.1261, found: 333.1267.[α] 20 D= 44.9 (c = 0.98, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 92% ee (CHIRALCEL AD-H, n - hexane i - PrOH = 99 / 1, detector: 254 nm, T = 25 °C, flow rate: 1 mL / min), t1(minor) = 12.6 min, t2(major) = 14.6 min.

[0061] Example 10: Preparation of chiral dienyl-substituted carboxylate compound 4j

[0062]

[0063] A dry 10 mL reaction tube equipped with a stirring magnet, a carbon electrode as anode and a platinum electrode as cathode was charged. Under nitrogen atmosphere, the corresponding compound la (0.1 mmol), 2c (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (Bu4NPF6, 0.3 mmol) were weighed and added sequentially, then dissolved by adding a mixture of THF / MeCN = 2:1 (3 mL). Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by distillation under reduced pressure, and finally the dienylated product 4j was isolated by column chromatography using a mixture of petroleum ether / ethyl acetate in the ratio 50:1 by volume as eluent (58% yield, 90% ee). n Bu4NPF6, 0.3 mmol), then dissolved by adding a mixture of THF / MeCN = 2:1 (3 mL). Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by distillation under reduced pressure, and finally the dienylated product 4j was isolated by column chromatography using a mixture of petroleum ether / ethyl acetate in the ratio 50:1 by volume as eluent (58% yield, 90% ee).

[0064] 1 H NMR (400 MHz, CDCl3) δ 7.45 – 7.38 (m, 2H), 7.37 – 7.28 (m, 5H),7.18 – 7.11 (m, 2H), 5.66 (dd, J = 6.8, 1.4 Hz, 1H), 5.55 (d, J = 1.5 Hz,1H), 4.91 (d, J = 1.5 Hz, 1H), 4.29 (d, J = 1.4 Hz, 1H), 3.63 (s, 3H), 1.68(dd, J= 6.8, 1.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 172.3, 145.7, 138.9,138.8, 136.0, 131.5, 131.1, 128.6, 127.9, 126.6, 126.4, 121.4, 116.5, 56.5,52.2, 15.0.ESI-MS: calculated [C 20 H 19 BrO2 + Na] + : 393.0461, found: 393.0465.[α] 20 D = +70.6 (c = 0.75, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 90% ee (CHIRALPAK IA, n -hexane / i -PrOH =99 / 1, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(major) = 9.8 min, t2(minor) = 11.1 min.

[0065] Example 11: Preparation of chiral dienyl-substituted carboxylic acid ester compound 4k

[0066]

[0067] Take a dry 10 mL reaction tube equipped with a magnetic stir bar, and set it with a carbon electrode as the anode and a platinum electrode as the cathode. Under a nitrogen atmosphere, weigh and add the corresponding compounds 1a (0.1 mmol), 2d (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), and tetrabutylammonium hexafluorophosphate (…). n Bu4NPF6 (0.3 mmol) was added, followed by the addition of a 2:1 THF / MeCN mixture (3 mL) to dissolve it. Electrolysis was then performed at a constant current (1 mA) at 25 °C for 12 hours. After the reaction was complete, the solvent was removed directly by vacuum distillation. Finally, the dienated product 4k (66% yield, 94% ee) was obtained by column chromatography using a 50:1 volume ratio of petroleum ether / ethyl acetate as the eluent.

[0068] 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.28 (m, 5H), 7.19 – 7.08 (m, 4H),5.62 (dd, J = 6.8, 1.4 Hz, 1H), 5.56 (d, J = 1.5 Hz, 1H), 4.97 (d, J = 1.5Hz, 1H), 4.31 (s, 1H), 3.61 (s, 3H), 2.33 (s, 3H), 1.65 (dd, J = 6.8, 1.3 Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 172.9, 146.0, 139.2, 139.0, 136.9, 133.8,129.1, 128.5, 127.7, 126.5, 126.1, 116.1, 56.7, 51.9, 21.1, 14.9.ESI-MS:calculated [C 21 H 22 O2 + Na] + : 329.1512, found: 329.1516. [α] 20 D = +77.1 (c =0.80, CH2Cl2).The product was analyzed by HPLC to determine the enantiomericexcess: 94% ee (CHIRALPAK IA, n -hexane / i -PrOH = 90 / 10, detector: 254 nm, T =25 ℃, flow rate: 1 mL / min), t1(minor) = 7.2 min, t2(major) = 7.7 min.

[0069] Example 12: Preparation of chiral dienyl-substituted carboxylate compound 4l

[0070]

[0071] A dry 10 mL reaction tube equipped with a stirring magnet and dried was taken, equipped with a carbon electrode as anode and platinum electrode as cathode. Under nitrogen atmosphere, the corresponding compounds 1a (0.1 mmol), 2e (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (Bu4NPF6, 0.3 mmol) were weighed and added sequentially, then THF / MeCN = 2:1 mixed solution (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by reduced pressure distillation, and finally column chromatography was used for separation with petroleum ether / ethyl acetate mixed as eluent in the volume ratio of 50:1 to obtain the dienylated product 4l (64% yield, 96% ee). n Bu4NPF6, 0.3 mmol), then THF / MeCN = 2:1 mixed solution (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by reduced pressure distillation, and finally column chromatography was used for separation with petroleum ether / ethyl acetate mixed as eluent in the volume ratio of 50:1 to obtain the dienylated product 4l (64% yield, 96% ee).

[0072] 1 H NMR (400 MHz, CDCl3) δ 7.41 – 7.29 (m, 7H), 7.22 – 7.18 (m, 2H),5.63 (dd, J = 6.8, 1.3 Hz, 1H), 5.58 (d, J = 1.6 Hz, 1H), 4.99 (d, J = 1.5Hz, 1H), 4.32 (d, J = 1.4 Hz, 1H), 3.61 (s, 3H), 1.65 (dd, J = 6.8, 1.3 Hz,3H), 1.31 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 171.4, 148.6, 144.7, 137.7,132.3, 127.4, 127.0, 126.3, 125.1, 124.8, 123.8, 114.5, 55.3, 50.4, 29.9,13.5.ESI-MS: calculated [C 24 H 28 O2 + Na] + : 371.1982, found: 371.1980. [α] 20 D= +47.5 (c = 0.67, CH2Cl2). The product was analyzed by HPLC to determine theenantiomeric excess: 96% ee(CHIRALCEL AD-H, n -hexane / i -PrOH = 90 / 10, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) =6.5 min, t2(major) = 7.0 min.

[0073] Example 13: Preparation of chiral dienyl-substituted carboxylic acid ester compound 4m

[0074]

[0075] Take a dry 10 mL reaction tube equipped with a magnetic stir bar, and set it with a carbon electrode as the anode and a platinum electrode as the cathode. Under a nitrogen atmosphere, weigh and add the corresponding compounds 1a (0.1 mmol), 2f (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), and tetrabutylammonium hexafluorophosphate (…). n Bu4NPF6 (0.3 mmol) was added, followed by the addition of a 2:1 THF / MeCN mixture (3 mL) to dissolve it. Electrolysis was then performed at a constant current (1 mA) at 25 °C for 12 hours. After the reaction was complete, the solvent was removed directly by vacuum distillation. Finally, the dienated product 4m (59% yield, 91% ee) was obtained by column chromatography using a 50:1 volume ratio of petroleum ether / ethyl acetate as the eluent.

[0076] 1 H NMR (400 MHz, CDCl3)δ 7.64 – 7.51 (m, 4H), 7.48 – 7.28 (m, 10H), 5.71 (dd, J = 6.8, 1.3 Hz, 1H), 5.59 (d, J = 1.5 Hz, 1H), 5.00 (d, J = 1.5Hz, 1H), 4.40 (d, 1H), 3.65 (s, 3H), 1.69 (dd, J = 6.8, 1.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.2, 144.5, 139.3, 138.7, 137.6, 137.5, 134.5, 128.2,127.3, 127.0, 126.3, 125.8, 125.6, 125.6, 125.1, 124.9, 114.7, 55.4, 50.6,13.5.ESI-MS: calculated [C 26 H 24 O2 + Na] + : 391.1669, found: 391.1666. [α] 20 D = +89.6 (c = 0.55, CH2Cl2).The product was analyzed by HPLC to determine theenantiomeric excess: 91% ee(CHIRALCEL AD-H, n -hexane / i -PrOH = 90 / 10, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 8.8 min, t2(major) = 9.8 min.

[0077] Example 14: Preparation of chiral dienyl-substituted carboxylic acid ester compound 4n

[0078]

[0079] Take a dry 10 mL reaction tube equipped with a magnetic stir bar, and set it with a carbon electrode as the anode and a platinum electrode as the cathode. Under a nitrogen atmosphere, weigh and add the corresponding compounds 1a (0.1 mmol), 2 g (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), and tetrabutylammonium hexafluorophosphate (…). n Bu4NPF6 (0.3 mmol) was added, followed by the addition of a 2:1 THF / MeCN mixture (3 mL) to dissolve it. Electrolysis was then performed at a constant current (1 mA) at 25 °C for 12 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the dienated product 4n (71% yield, 91% ee) was obtained by column chromatography using a 50:1 volume ratio of petroleum ether / ethyl acetate as the eluent.

[0080] 1H NMR (400 MHz, CDC13) δ 7.43 - 7.27 (m, 5H), 7.24 - 7.17 (m, 1H), 7.13 - 7.03 (m, 3H), 5.62 (dd, J = 6.8, 1.4 Hz, 1H), 5.57 (d, J = 1.6 Hz, 1H), 4.99 (d, J = 1.5 Hz, 1H), 4.32 (d, J = 1.5 Hz, 1H), 3.62 (s, 3H), 2.33 (s, 3H), 1.66 (dd, J = 6.8, 1.4 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 172.8, 146.1, 139.1, 139.0, 137.9, 136.7, 129.9, 128.5, 128.2, 128.1, 127.8, 126.5, 126.3, 126.3, 116.1, 57.1, 52.0, 21.5, 14.9. ESI-MS: calculated [C 21 H 22 O2 + Na] + : 329.1512, found: 329.1510. [a] 20 D = +73.9 (c = 0.64, CH2CI2). The product was analyzed by HPLC to determine the enantiomeric excess: 91% ee (CHIRALPAK IB, n -hexane / i -PrOH = 99 / 1, detector: 254 nm, T = 25 °C, flow rate: 1 mL / min), t1(minor) = 7.1 min, t2(major) = 8.8 min.

[0081] Example 15: Preparation of chiral dienyl-substituted carboxylate compound 4o

[0082]

[0083] A dry 10 mL reaction tube equipped with a stirring magnet and dried was charged with a carbon electrode as anode and a platinum electrode as cathode. Under nitrogen atmosphere, the corresponding compounds 1a (0.1 mmol), 2h (0.3 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (Bu4NPF6, 0.3 mmol) were weighed and added sequentially, then THF / MeCN = 2:1 (3 mL) was added to dissolve them. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by distillation under reduced pressure, and finally dienylated product 4o (54% yield, 92% ee) was obtained by column chromatography with petroleum ether / ethyl acetate mixed as eluent at a volume ratio of 50:1. n Bu4NPF6, 0.3 mmol), then THF / MeCN = 2:1 (3 mL) was added to dissolve them. Subsequently, electrolysis was carried out at 25 °C under constant current (1 mA) for 12 hours. After the reaction was completed, the solvent was directly removed by distillation under reduced pressure, and finally dienylated product 4o (54% yield, 92% ee) was obtained by column chromatography with petroleum ether / ethyl acetate mixed as eluent at a volume ratio of 50:1.

[0084] 1 H NMR (400 MHz, CDCl3) δ 7.85 – 7.76 (m, 3H), 7.68 (s, 1H), 7.52 –7.28 (m, 8H), 5.68 (dd, J = 6.8, 1.4 Hz, 1H), 5.55 (d, J = 1.5 Hz, 1H), 4.98(d, J = 1.6 Hz, 1H), 4.52 (s, 1H), 3.65 (s, 3H), 1.68 (dd, J = 6.8, 1.3 Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 172.8, 146.0, 139.1, 139.1, 134.4, 133.4,132.7, 128.6, 128.1, 128.0, 127.9, 127.7, 127.4, 126.7, 126.7, 126.1, 126.0,116.3, 57.3, 52.1, 15.0.ESI-MS: calculated [C 24 H 22 O2 + Na] + : 365.1512, found:365.1514. [α] 20 D= +73.4 (c = 0.69, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 92% ee (CHIRALPAK IA, n - hexane i - PrOH = 99 / 1, detector: 254 nm, T = 25 °C, flow rate: 1 mL / min), t1(minor) = 12.9 min, t2(major) = 15.1 min.

Claims

1. An asymmetric preparation method of chiral dienyl-substituted carboxylate compounds, characterized in that: under a nitrogen atmosphere, a reaction bottle equipped with electrodes is added with substituted diallyl silyl 1, carboxylate derivative 2, alcohol 3, chiral isothiourea catalyst and electrolyte, and an organic solvent is added for dissolution, a current is applied for electrolysis at -20-70℃ for 2-48 hours, and a reaction end point is determined by thin layer chromatography point plate; after the reaction is completed, the solvent is directly removed by reduced pressure distillation, and finally the residue is separated by column chromatography to obtain the target product I; the synthesis route is as shown below: The structure of the chiral isothiourea catalyst is as shown below:

2. The asymmetric preparation method according to claim 1, characterized in that: ； in the above formulae: * represents a chiral carbon atom; the substituents R are C 1-10 alkyl; R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl or C 1-10 alkoxy; R 6 is C 1-10 aryl; R 7 is selected from the group consisting of C 1-10 alkyl; R 8 is selected from the group consisting of C 1-10 aryl; The electrolyte is tetrabutylammonium hexafluorophosphate, tetraethylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, tetrabutylammonium perchlorate or tetrabutylammonium bromide. 。 3. The asymmetric preparation method according to claim 1, characterized in that: The molar ratio of chiral isothiourea catalyst to substituted diallyl silyl 1 is 0.025:1-1:1; the molar equivalent ratio of substituted diallyl silyl 1 to carboxylate derivative 2 is 1:1-1:5; the molar equivalent ratio of substituted diallyl silyl 1 to alcohol 3 is 1:1-1:100; and the molar ratio of substituted diallyl silyl 1 to electrolyte is 1:0.1-1:

5.

4. The asymmetric preparation method according to claim 1, characterized in that: The organic solvent is 1,4-dioxane, dichloromethane, dichloroethane, dimethyl sulfoxide, N-methyl pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, toluene, ethylbenzene, fluorobenzene, chlorobenzene, bromobenzene, xylene or mesitylene. ​ ​

Images