Chiral dicarbonyl compound and asymmetric preparation method thereof

Abstract

The present application discloses a kind of chiral dicarbonyl compound and its asymmetric preparation method, wherein chiral dicarbonyl compound is optical active compound with the structure shown in the following formula I, including its stereoisomer with the same chemical general formula: formula I in wherein: * represent chiral carbon atom;N is 0, 1 or 2;Ar is aromatic ring or substituted aromatic ring;R 1 、R 2 、R 3 、R 4 、R 5 Respectively independently selected from hydrogen, halogen, C 1‑10 Hydrocarbon group or hydroxyl group;R 6 Independently selected from C 1‑10 Alkyl or aryl;R 7 Independently selected from C 1‑10 Alkyl or aryl.The present application applies small molecule chiral isothiourea catalyst, catalyzes a class of electrochemical asymmetric alkylation reaction as key step, with high yield, high stereoselectivity and accurately, quickly synthesized chiral dicarbonyl compound with k-class scale.The preparation method of the present application is simple, has biomedical practicability and industrial application prospect.

Description

TECHNICAL FIELD

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

[0002] Carboxylate structures are widely present in biology, chemistry and material science. In the field of organic synthesis, it is particularly important to modify the functional groups at the asymmetric alpha position of simple ester compounds. At the same time, compounds containing chiral dicarbonyl structures are important components of many intermediates of biologically active natural products and drug molecules. Therefore, the asymmetric synthesis of such compounds has always been a research focus. Although a variety of asymmetric catalytic methods have been successfully developed, it is still a challenging task to efficiently synthesize chiral dicarbonyl compounds from simple carboxylic acid derivatives through asymmetric catalysis. Therefore, it is of great research value in organic synthesis chemistry to develop an efficient catalytic system to realize the high enantioselective synthesis of chiral dicarbonyl compounds.

[0003] With the rapid development of science and technology and the continuous in-depth research of scientific researchers, the field of electrochemical synthesis is full of vitality and has gradually become the frontier of modern organic chemical synthesis. Compared with traditional organic chemical synthesis, electrochemical synthesis has many advantages: 1. Mild reaction conditions, energy saving. 2. Avoid using a large amount of toxic and dangerous oxidizing agents and reducing agents, reducing environmental pollution, in line with the strategy of green development. 3. During the reaction process, the reaction rate and reaction progress can be changed by controlling the current and voltage. In recent years, with the vigorous development of electrochemical asymmetric synthesis strategies, asymmetric electrochemical functionalization reactions involving chiral amines, chiral metal complex-catalyzed aldehyde compounds, acylimidazole compounds, and benzoxazole carbonyl compounds have been realized. However, developing new types of electrocatalytic asymmetric synthesis strategies, promoting the generation of key active radical intermediates and achieving stereoselective control, has extremely high synthesis difficulty and far-reaching research value.

[0004] Chiral dicarbonyl compounds are a class of key intermediates that can be used to construct biologically active molecules, have biological and pharmaceutical synthesis value, and can realize the asymmetric synthesis of chiral natural products calyxolane A and ent Calyxolane B through simple transformation. However, the direct synthesis of chiral dicarbonyl compounds through one-step reaction is still a scientific problem that has not been solved. Therefore, it is urgent to develop a new type of catalytic system to directly synthesize chiral dicarbonyl compounds, starting from simple and readily available carboxylic acid derivatives, to realize a general strategy for the synthesis of structurally diverse chiral dicarbonyl compounds with high yield and high enantioselectivity in a precise and rapid manner, and to be applied to the asymmetric synthesis of chiral natural products calyxolane A and entThe precise synthesis of calyxolane B embodies the practicability of the preparation method, and provides a new synthesis platform for exploration and development of bioactive molecules. SUMMARY

[0005] The present application aims to provide a chiral dicarbonyl compound and an asymmetric preparation method thereof, so as to solve the above problems existing in the prior art.

[0006] The chiral dicarbonyl 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:

[0007]

[0008] In the formula, * represents a chiral carbon atom; n is 0, 1 or 2; Ar is an aromatic ring or a substituted aromatic ring; R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, C 1-10 alkyl or alkoxy; R 6 is independently selected from hydrogen, C 1-10 alkyl or aryl; R 7 is independently selected from C 1-10 alkyl or aryl.

[0009] The asymmetric preparation method of the chiral dicarbonyl compound of the present application uses carboxylate derivative 1 and enol silyl ether compound 2 as starting materials, alcohol 3 as a quenching reagent, and chiral isothiourea as a reaction catalyst, and the target product I is obtained after asymmetric alkylation reaction under electrochemical reaction conditions, separation and purification.

[0010] The synthesis route is shown as follows:

[0011]

[0012] In the formula, * represents a chiral carbon atom; n is 0, 1 or 2; Ar is an aromatic ring or a substituted aromatic ring; R 1 , R 2 , R 3 , R 4 , R 5 are each 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.

[0013] Specifically comprising the following steps:

[0014] Under a nitrogen atmosphere, in a reaction bottle equipped with electrodes, add carboxylate derivative 1, enol silyl ether compound 2, alcohol 3, chiral isothiourea catalyst and electrolyte, and add an organic solvent for dissolution, apply current electrolysis at -40℃ to 80℃ for 2-60 hours, determine the reaction endpoint by thin layer chromatography point plate; after the reaction is complete, directly remove the solvent by reduced pressure distillation, and finally separate the residue by column chromatography to obtain the target product I.

[0015] In the preparation process of the application:

[0016] The chiral isothiourea catalyst is a commercially available catalyst, selected from the following structures:

[0017]

[0018] In the formula: * 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.

[0019] The electrolyte is one of tetrabutylammonium hexafluorophosphate, tetraethylammonium hexafluorophosphate, tetramethylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium perchlorate, tetraethylammonium perchlorate, tetraethylammonium tetrafluoroborate, tetrabutylammonium chloride, tetrabutylammonium bromide.

[0020] The organic solvent is one of 1,4-dioxane, dichloromethane, dichloroethane, dimethyl sulfoxide, N -methylpyrrolidone, N , N dimethylformamide, N , N dimethylacetamide, ethyl acetate, chloroform, methanol, tetrahydrofuran, acetonitrile, toluene, ethylbenzene, fluorobenzene, chlorobenzene, bromobenzene, xylene or mesitylene.

[0021] 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.

[0022] Wherein: the molar ratio of the chiral isothiourea catalyst to the enol silyl ether compound 2 is 0.03:1-1:1; the molar equivalent ratio of the enol silyl ether compound 2 to the carboxylate derivative 1 is 1:0.5-1:5; the molar equivalent ratio of the enol silyl ether compound 2 to the alcohol 3 is 1:1-1:100; and the molar ratio of the enol silyl ether compound 2 to the electrolyte is 1:0.1-1:5.

[0023] The present invention provides a method for synthesizing chiral dicarbonyl compounds through the key step of electrochemical catalytic asymmetric reaction. The present invention uses carboxylate derivatives 1 and enol silyl ether compounds 2 as starting materials, alcohol 3 as quenching reagent, and chiral isothiourea as reaction catalyst. Under electrochemical reaction conditions, an asymmetric alkylation reaction is carried out, and the target product I is obtained after separation and purification. The present invention successfully develops a method for synthesizing chiral dicarbonyl compounds, which can easily produce chiral dicarbonyl compounds with high yield and high optical purity. In addition, starting from this type of compound, through multi-step transformation, the natural product calyxolane A and ent The asymmetric total synthesis of -calyxolane B demonstrates the practicality of this preparation method and provides a new synthetic platform for the exploration and development of bioactive molecules. DETAILED DESCRIPTION

[0024] The following is a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention and are not intended to limit the present invention.

[0025] The endpoints of the ranges and any values ​​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 endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0026] Example 1: Preparation of Chiral Dicarbonyl Compound 4a

[0027]

[0028] Take a 10 mL dry reaction tube equipped with a stirring magnet, equip it with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, weigh and add the corresponding compounds 1a (0.3 mmol), 2a (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( nBu4NPF6, 0.3 mmol), then a mixture of THF / MeCN = 2:1 (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1.0 mA) for 8 h. After the reaction was completed, the solvent was directly removed by distillation under reduced pressure, and finally the corresponding chiral dicarbonyl compound 4a (57% yield, 95% ee) was isolated by column chromatography with petroleum ether / ethyl acetate mixed as eluent at a volume ratio of 50:1.

[0029] 1 H NMR (500 MHz, CDCl3) δ 8.00-7.94 (m, 2H), 7.70-7.52 (m, 1H), 7.48-7.41 (m, 2H), 7.31-7.21 (m, 2H), 7.19-7.10 (m, 2H), 4.26 (dd, J = 10.3, 4.1Hz, 1H), 3.93 (dd, J = 18.0, 10.3 Hz, 1H), 3.69 (s, 3H), 3.25 (dd, J = 18.0,4.1 Hz, 1H), 2.33 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 197.9, 174.2, 137.4,136.6, 135.5, 133.4, 129.7, 128.7, 128.2, 127.8, 52.5, 46.1, 43.0, 21.2. ESI-MS: calculated [C 18 H 18 O3 + Na] + : 305.1148, found: 305.1145. [α] 20 D = +97.5 (c =0.53, CH2Cl2). The product was analyzed by HPLC to determine the enantiomericexcess: 95% ee (CHIRALPAK IC, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T =25 ℃, flow rate: 1 mL / min), t1 (minor) = 7.4 min, t2 (major) = 8.2 min.

[0030] Example 2: Preparation of chiral dicarbonyl compound 4b

[0031]

[0032] 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 1b (0.3 mmol), 2a (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (Bu4NPF6, 0.3 mmol) and then THF / MeCN = 2:1 (3 mL) was added to dissolve the reagents. Subsequently, electrolysis was carried out at 25 °C under constant current (1.0 mA) for 8 h. After the reaction was completed, the solvent was removed directly by distillation under reduced pressure, and finally the corresponding chiral dicarbonyl compound 4b was isolated by column chromatography using petroleum ether / ethyl acetate (50:1 by volume) as eluent (67% yield, 97% ee). n Bu4NPF6, 0.3 mmol), and then THF / MeCN = 2:1 (3 mL) was added to dissolve the reagents. Subsequently, electrolysis was carried out at 25 °C under constant current (1.0 mA) for 8 h. After the reaction was completed, the solvent was removed directly by distillation under reduced pressure, and finally the corresponding chiral dicarbonyl compound 4b was isolated by column chromatography using petroleum ether / ethyl acetate (50:1 by volume) as eluent (67% yield, 97% ee).

[0033] 1 H NMR (500 MHz, CDCl3) δ 7.98-7.95 (m, 2H), 7.58-7.53 (m, 1H), 7.45(m, 2H), 7.30-7.23 (m, 2H), 7.22-7.18 (m, 2H), 4.27 (dd, J = 10.4, 4.0 Hz,1H), 3.94 (dd, J = 18.0, 10.4 Hz, 1H), 3.69 (s, 3H), 3.25 (dd, J = 18.0, 4.0Hz, 1H), 2.89 (d, J = 6.9 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H). 13 C NMR (100 MHz,CDCl3) δ 197.9, 174.2, 148.3, 136.5, 135.7, 133.4, 128.7, 128.2, 127.8,127.1, 52.4, 46.0, 43.1, 33.9, 24.1. ESI-MS: calculated [C 20 H 22 O3 + Na] +:333.1461, found: 333.1455. [α] 20 D = +67.4 (c = 0.66, CH2Cl2). The product wasanalyzed by HPLC to determine the enantiomeric excess: 97% ee (CHIRALPAK IC, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1 (minor) = 6.5 min, t2 (major) = 7.3 min.

[0034] Example 3: Preparation of Chiral Dicarbonyl Compound 4c

[0035]

[0036] A 10 mL dry reaction tube equipped with a stirring magnet was prepared, equipped with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, the corresponding compounds 1c (0.3 mmol), 2a (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, the corresponding chiral dicarbonyl compound 4c (80% yield, 96% ee) was isolated by column chromatography using a 50:1 v / v mixture of petroleum ether and ethyl acetate as the eluent.

[0037] 1 H NMR (500 MHz, CDCl3) δ 8.00-7.94 (m, 2H), 7.62-7.53 (m, 1H), 7.49-7.42 (m, 2H), 7.39-7.29 (m, 2H), 7.10-6.98 (m, 2H), 4.29 (dd, J = 10.0, 4.4Hz, 1H), 3.91 (dd, J = 18.0, 9.9 Hz, 1H), 3.70 (s, 3H), 3.27 (dd,J = 18.0,4.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 197.55, 173.89, 162.32 (d, J = 246.4Hz), 136.43, 134.18 (d, J = 3.1 Hz), 133.55, 129.58 (d, J = 8.1 Hz), 128.78,128.21, 115.92 (d, J = 21.3 Hz), 52.55, 45.70, 42.86. 19 F NMR (471 MHz, CDCl3)δ -114.9. ESI-MS: calculated [C 17 H 15 FO3 + Na] + : 309.0897, found: 309.0899. [α] 20 D = +76.6 (c = 0.68, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (CHIRALPAK IC, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 5.4 min, t2(major) = 6.5 min.

[0038] Example 4: Preparation of Chiral Dicarbonyl Compound 4d

[0039]

[0040] A 10 mL dry reaction tube equipped with a stirring magnet was prepared, equipped with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, the corresponding compounds 1d (0.3 mmol), 2a (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( nBu4NPF6, 0.3 mmol), then a mixture of THF / MeCN = 2:1 (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1.0 mA) for 8 hours. After the reaction was completed, the solvent was directly removed by distillation under reduced pressure, and finally column chromatography was performed using a mixture of petroleum ether / ethyl acetate = 50:1 by volume as the eluent to obtain the corresponding chiral dicarbonyl compound 4d (71% yield, 94% ee).

[0041] 1 H NMR (500 MHz, CDCl3) δ 8.01-7.92 (m, 2H), 7.62-7.54 (m, 1H), 7.51-7.42 (m, 2H), 7.36-7.26 (m, 4H), 4.28 (dd, J = 9.9, 4.4 Hz, 1H), 3.91 (dd, J = 18.0, 9.9 Hz, 1H), 3.70 (s, 3H), 3.27 (dd, J = 18.0, 4.5 Hz, 1H). 13 C NMR(125 MHz, CDCl3) δ 197.4, 173.6, 136.9, 136.4, 133.6, 133.6, 129.4, 129.2,128.8, 128.2, 52.6, 45.8, 42.7, 29.8. ESI-MS: calculated [C 17 H 15 ClO3 + Na] + :325.0602, found: 325.0594. [α] 20 D = +29.9 (c = 0.70, CH2Cl2). The product wasanalyzed by HPLC to determine the enantiomeric excess: 94% ee (CHIRALPAK IC, n -hexane / i -PrOH = 90 / 10, detector: 240 nm, T = 25 ℃, flow rate: 1 mL / min),t1(minor) = 9.8 min, t2(major) = 10.6 min .

[0042] Example 5: Preparation of chiral dicarbonyl compound 4e

[0043]

[0044] 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 1e (0.3 mmol), 2a (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (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 (1.0 mA) for 8 h. After the reaction was completed, the solvent was removed directly by distillation under reduced pressure, and finally the corresponding chiral dicarbonyl compound 4e was isolated by column chromatography using petroleum ether / ethyl acetate (50:1 by volume) as eluent (71% yield, 95% 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 (1.0 mA) for 8 h. After the reaction was completed, the solvent was removed directly by distillation under reduced pressure, and finally the corresponding chiral dicarbonyl compound 4e was isolated by column chromatography using petroleum ether / ethyl acetate (50:1 by volume) as eluent (71% yield, 95% ee).

[0045] 1 H NMR (400 MHz, CDCl3) δ 8.00-7.90 (m, 2H), 7.64-7.53 (m, 1H), 7.52-7.39 (m, 4H), 7.30-7.19 (m, 2H), 4.27 (dd, J = 9.9, 4.5 Hz, 1H), 3.90 (dd, J = 18.0, 9.9 Hz, 1H), 3.69 (s, 3H), 3.27 (dd, J = 18.0, 4.5 Hz, 1H). 13 C NMR(100 MHz, CDCl3) δ 197.4, 173.6, 137.5, 136.4, 133.6, 132.1, 129.7, 128.8,128.2, 121.7, 52.6, 45.9, 42.6. ESI-MS: calculated [C 17 H 15 BrO3 + Na] + :369.0097, found: 369.0100. [α] 20 D= +76.2 (c = 0.78, CH2Cl2). The product wasanalyzed by HPLC to determine the enantiomeric excess: 95% ee (CHIRALPAK IC, n -hexane / i -PrOH = 90 / 10, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 10.5 min, t2(major) = 11.3 min.

[0046] Example 6: Preparation of Chiral Dicarbonyl Compound 4f

[0047]

[0048] Take a 10 mL dry reaction tube equipped with a stirring magnet, equip it with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, weigh and add the corresponding compound 1f (0.3 mmol), 2a (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, column chromatography using a 50:1 v / v mixture of petroleum ether and ethyl acetate as the eluent afforded the corresponding chiral dicarbonyl compound 4f (75% yield, 97% ee).

[0049] 1 H NMR (500 MHz, CDCl3) δ 8.02-7.94 (m, 2H), 7.60-7.53 (m, 1H), 7.49-7.42 (m, 2H), 7.28-7.21 (m, 1H), 7.18-7.13 (m, 2H), 7.13-7.07 (m, 1H), 4.27(dd, J = 10.4, 3.9 Hz, 1H), 3.95 (dd, J = 18.0, 10.4 Hz, 1H), 3.70 (s, 3H), 3.25 (dd, J= 18.0, 4.0 Hz, 1H), 2.36 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ197.8, 174.1, 138.8, 138.4, 136.5, 133.4, 129.0, 128.7, 128.6, 128.5, 128.2,125.0, 52.5, 46.4, 43.0, 21.6. ESI-MS: calculated [C 18 H 18 O3 + Na] + : 305.1148, found: 305.1148. [α] 20 D = +74.3 (c = 0.68, CH2Cl2). The product was analyzed byHPLC to determine the enantiomeric excess: 97% ee (CHIRALPAK IC, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(major) =7.7 min, t2(minor) = 8.4 min.

[0050] Example 7: Preparation of 4g of chiral dicarbonyl compounds

[0051]

[0052] Take a 10 mL dry reaction tube equipped with a stirring magnet, equip it with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, weigh and add the corresponding compound 1g (0.3 mmol), 2a (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, column chromatography using a 50:1 mixture of petroleum ether and ethyl acetate as the eluent afforded 4 g (56% yield, 96% ee) of the corresponding chiral dicarbonyl compound.

[0053] 1 H NMR (500 MHz, CDCl3) δ 8.02-7.93 (m, 2H), 7.60-7.51 (m, 1H), 7.50-7.41 (m, 2H), 7.31-7.22 (m, 1H), 6.96-6.86 (m, 2H), 6.86-6.80 (m, 1H), 4.27(dd, J = 10.4, 3.9 Hz, 1H), 3.94 (dd, J = 18.0, 10.4 Hz, 1H), 3.81 (s, 3H),3.70 (s, 3H), 3.26 (dd, J = 18.0, 4.0 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ197.7, 173.8, 160.1, 140.0, 136.5, 133.5, 130.1, 128.7, 128.2, 120.2, 113.7,113.0, 55.4, 52.5, 46.5, 42.9 ESI-MS: calculated [C 18 H 18 O4 + Na] + : 321.1097,found: 321.1102. [α] 20 D = +80.9 (c = 0.56, CH2Cl2). The product was analyzed byHPLC to determine the enantiomeric excess: 96% ee (CHIRALPAK IE, n -hexane / i -PrOH = 80 / 20, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(major) =12.2 min, t2(minor) = 13.0 min.

[0054] Example 8: Preparation of chiral dicarbonyl compound 4h

[0055]

[0056] 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 argon atmosphere, the corresponding compounds 1h (0.3 mmol), 2a (0.1 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 (1.0 mA) for 8 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 corresponding chiral dicarbonyl compound 4h (67% yield, 90% 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 (1.0 mA) for 8 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 corresponding chiral dicarbonyl compound 4h (67% yield, 90% ee).

[0057] 1 H NMR (500 MHz, CDCl3) δ 8.02-7.93 (m, 2H), 7.61-7.54 (m, 1H), 7.51-7.41 (m, 2H), 7.35-7.27 (m, 1H), 7.17-7.11 (m, 1H), 7.10-7.05 (m, 1H), 7.02-6.95 (m, 1H), 4.30 (dd, J = 10.2, 4.2 Hz, 1H), 3.93 (dd, J = 18.0, 10.1 Hz,1H), 3.71 (s, 3H), 3.29 (dd, J = 18.0, 4.2 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ197.39, 173.49, 163.07 (d, J = 247.2 Hz), 140.76 (d, J = 7.4 Hz), 136.33,133.59, 130.54 (d, J = 8.3 Hz), 128.79, 128.22, 123.75 (d, J = 2.8 Hz),115.02 (d, J = 22.1 Hz), 114.71 (d, J = 21.1 Hz), 52.64, 46.17, 42.67. 19F NMR(471 MHz, CDCl3) δ -112.21. ESI-MS: calculated [C 17 H 15 FO3 + Na] + : 309.0897, found: 309.0896. [α] 20 D = +82.3 (c = 0.64, CH2Cl2). The product was analyzed byHPLC to determine the enantiomeric excess: 90% ee (CHIRALPAK IB, n -hexane / i -PrOH = 90 / 10, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) =8.0 min, t2(major) = 9.1 min.

[0058] Example 9: Preparation of Chiral Dicarbonyl Compound 4i

[0059]

[0060] Take a 10 mL dry reaction tube equipped with a stirring magnet, equip it with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, weigh and add the corresponding compound 1i (0.3 mmol), 2a (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, column chromatography using a 50:1 v / v mixture of petroleum ether and ethyl acetate as the eluent afforded the corresponding chiral dicarbonyl compound 4i (63% yield, 90% ee).

[0061] 1 H NMR (400 MHz, CDCl3) δ 8.01-7.94 (m, 2H), 7.62-7.53 (m, 1H), 7.51-7.42 (m, 2H), 7.36 (m, 1H), 7.30-7.20 (m, 3H), 4.28 (dd,J = 10.1, 4.2 Hz,1H), 3.93 (dd, J = 18.1, 10.1 Hz, 1H), 3.71 (s, 3H), 3.27 (dd, J = 18.0, 4.2Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 197.3, 173.4, 140.4, 136.3, 134.8, 133.6,130.3, 128.8, 128.2, 128.1, 128.0, 126.3, 52.6, 46.1, 42.6. ESI-MS:calculated [C 17 H 15 ClO3 + Na] + : 325.0602, found: 325.0598. [α] 20 D = +84.9 (c =0.63, CH2Cl2). The product was analyzed by HPLC to determine the enantiomericexcess: 90% ee (CHIRALPAK IB, n -hexane / i -PrOH = 90 / 10, detector: 254 nm, T =25 ℃, flow rate: 1 mL / min), t1(minor) = 8.3 min, t2(major) = 9.3 min.

[0062] Example 10: Preparation of chiral dicarbonyl compound 4j

[0063]

[0064] 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 1j (0.3 mmol), 2b (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (0.1 mmol) and dry dichloromethane (1 mL) under an argon atmosphere. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent: dichloromethane / MeOH = 95 / 5) to give the product 4j as a white solid (0.1 mmol, 100% yield). nBu4NPF6, 0.3 mmol), then a mixed solution of THF / MeCN = 2:1 (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1.0 mA) for 8 hours. After the reaction was completed, the solvent was directly removed by distillation under reduced pressure, and finally column chromatography was performed using petroleum ether / ethyl acetate mixed at a volume ratio of 50:1 as the eluent to obtain the corresponding chiral dicarbonyl compound 4j (85% yield, 97% ee).

[0065] 1 H NMR (400 MHz, CDCl3) δ 7.91-7.83 (m, 2H), 7.39-7.31 (m, 4H), 7.31-7.26 (m, 1H), 7.26-7.25 (m, 1H), 7.24-7.22 (m, 1H), 4.29 (dd, J = 10.3, 4.1Hz, 1H), 3.92 (dd, J = 17.9, 10.3 Hz, 1H), 3.70 (s, 3H), 3.25 (dd, J = 17.9,4.1 Hz, 1H), 2.40 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 197.4, 174.1, 144.3,138.6, 134.1, 129.4, 129.0, 128.3, 128.0, 127.7, 52.5, 46.5, 42.8, 21.8.ESI-MS: calculated [C 18 H 18 O3 + Na] + : 305.1148, found: 305.1151. [α] 20 D = +94.3 (c =0.80, CH2Cl2). The product was analyzed by HPLC to determine the enantiomericexcess: 97% ee (CHIRALPAK IB, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T =25 ℃, flow rate: 1 mL / min), t1(minor) = 5.7 min, t2(major) = 7.2 min。

[0066] Example 11: Preparation of Chiral Dicarbonyl Compound 4k

[0067]

[0068] A 10 mL dry reaction tube equipped with a stirring magnet was prepared, equipped with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, the corresponding compounds 1j (0.3 mmol), 2c (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, column chromatography using a 50:1 v / v mixture of petroleum ether and ethyl acetate as the eluent afforded the corresponding chiral dicarbonyl compound 4k (77% yield, 98% ee).

[0069] 1 H NMR (400 MHz, CDCl3) δ 8.01-7.90 (m, 2H), 7.45-7.31 (m, 4H), 7.31-7.26 (m, 1H), 6.96-6.88 (m, 2H), 4.29 (dd, J = 10.3, 4.1 Hz, 1H), 3.97 – 3.83(m, 4H), 3.69 (s, 3H), 3.23 (dd, J = 17.8, 4.1 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 196.2, 174.1, 163.8, 138.6, 130.5, 129.6, 129.0, 128.0, 127.6,113.9, 55.6, 52.4, 46.6, 42.6. ESI-MS: calculated [C 18 H 18 O4 + Na] + : 321.1097, found: 321.1093. [α] 20 D= +54.6 (c = 0.76, CH2Cl2). The product was analyzed byHPLC to determine the enantiomeric excess: 98% ee (CHIRALPAK IC, n -hexane / i -PrOH = 90 / 10, detector: 260 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) =32.3 min, t2(major) = 34.1 min.

[0070] Example 12: Preparation of Chiral Dicarbonyl Compound 41

[0071]

[0072] A 10 mL dry reaction tube equipped with a stirring magnet was prepared, equipped with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, the corresponding compounds 1j (0.3 mmol), 2d (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, column chromatography using a 50:1 v / v mixture of petroleum ether and ethyl acetate as the eluent afforded the corresponding chiral dicarbonyl compound 41 (75% yield, 97% ee).

[0073] 1 H NMR (400 MHz, CDCl3) δ 7.97-7.88 (m, 2H), 7.48-7.45 (m, 2H), 7.39-7.32 (m, 4H), 7.31-7.26 (m, 1H), 4.31 (dd, J = 10.3, 4.2 Hz, 1H), 3.93 (dd, J = 18.0, 10.2 Hz, 1H), 3.69 (s, 3H), 1.34 (s, 9H). 13C NMR (100 MHz, CDCl3) δ197.4, 174.0, 157.2, 138.6, 134.0, 129.0, 128.2, 128.0, 127.6, 125.7, 52.4,46.5, 42.8, 35.3, 31.2. ESI-MS: calculated [C 21 H 24 O3 + Na] + : 347.1618, found:347.1614. [α] 20 D = +80.4 (c = 0.75, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 97% ee (CHIRALPAK IC, n -hexane / i -PrOH =90 / 10, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 12.7min, t2(major) = 15.3 min.

[0074] Example 13: Preparation of Chiral Dicarbonyl Compound 4m

[0075]

[0076] A 10 mL dry reaction tube equipped with a stirring magnet was prepared, equipped with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, the corresponding compounds 1j (0.3 mmol), 2e (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, column chromatography using a 50:1 v / v mixture of petroleum ether and ethyl acetate as the eluent afforded the corresponding chiral dicarbonyl compound 4m (82% yield, 98% ee).

[0077] 1H NMR (400 MHz, CDC13) δ 8.07-8.02 (m, 2H), 7.70-7.65 (m, 2H), 7.65-7.59 (m, 2H), 7.49-7.43 (m, 2H), 7.43-7.33 (m, 5H), 7.33-7.27 (m, 1H), 4.33(dd, J = 18.0, 10.3 Hz, 1H), 3.71 (s, 3H),3.30 (dd, J = 18.0, 10.3 Hz, 1H), 3.71 (s, 3H),3.30 (dd, J = 18.0, 10.3 Hz, 1H), 3.71 (s, 3H),3.30 (dd, 13 C NMR (125 MHz, CDC13) δ 197.4, 174.0, 146.1, 139.9, 138.5, 135.2, 129.1, 128.8, 128.4, 128.0, 127.7, 127.4, 127.4, 52.5, 46.5, 43.0. ESI-MS: calculated [C 23 H 20 O3 + Na] + : 367.1305, found: 367.1306. [a] 20 D = +75.7 (c = 0.70, CH2CI2). The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (CHIRALPAK IC, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T = 25 °C, flow rate: 1 mL / min), t1(major) = 9.8 min, t2(minor) = 12.1 min.

[0078] Example 14: Preparation of chiral dicarbonyl compound 4n

[0079]

[0080] 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 argon atmosphere, the corresponding compounds 1j (0.3 mmol), 2f (0.1 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, constant current electrolysis (1.0 mA) was carried out at 25 °C for 8 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 corresponding chiral dicarbonyl compound 4n (68% yield, 95% ee). n Bu4NPF6, 0.3 mmol), then THF / MeCN = 2:1 mixed solution (3 mL) was added to dissolve it. Subsequently, constant current electrolysis (1.0 mA) was carried out at 25 °C for 8 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 corresponding chiral dicarbonyl compound 4n (68% yield, 95% ee).

[0081] 1 H NMR (400 MHz, CDCl3) δ 8.05-7.95 (m, 2H), 7.42-7.32 (m, 4H), 7.32-7.27 (m, 1H), 7.15-7.08 (m, 2H), 4.29 (dd, J = 10.4, 4.0 Hz, 1H), 3.92 (dd, J = 17.9, 10.4 Hz, 1H), 3.70 (s, 3H), 3.23 (dd, J = 17.9, 4.0 Hz, 1H). 13 C NMR(100 MHz, CDCl3) δ 196.21, 173.96, 166.03 (d, J = 255.2 Hz), 138.35, 132.98(d, J = 3.1 Hz), 130.88 (d, J = 9.5 Hz), 129.10, 127.93, 127.76, 115.87 (d, J = 22.0 Hz), 52.52, 46.48, 42.85. 19 F NMR (376 MHz, CDCl3) δ -104.8. ESI-MS:calculated [C 17 H 15 FO3 + Na] + : 309.0897, found: 309.0898. [α] 20D = +82.2 (c =0.64, CH2Cl2). The product was analyzed by HPLC to determine the enantiomericexcess: 95% ee (CHIRALPAK IC, n -hexane / i -PrOH = 90 / 10, detector: 254 nm, T =25 ℃, flow rate: 1 mL / min), t1(major) = 9.1 min, t2(mior) = 10.3 min.

[0082] Example 15: Preparation of Chiral Dicarbonyl Compound 4o

[0083]

[0084] A 10 mL dry reaction tube equipped with a stirring magnet was prepared, equipped with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, the corresponding compounds 1j (0.3 mmol), 2g (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, column chromatography using a 50:1 v / v mixture of petroleum ether and ethyl acetate as the eluent afforded the corresponding chiral dicarbonyl compound 4o (63% yield, 95% ee).

[0085] 1 H NMR (500 MHz, CDCl3) δ 7.94-7.88 (m, 2H), 7.46-7.40 (m, 2H), 7.38-7.32 (m, 4H), 7.32-7.27 (m, 1H), 4.29 (dd, J = 10.1, 3.7 Hz, 1H), 3.91 (dd, J = 17.9, 10.3 Hz, 1H), 3.70 (s, 3H), 3.22 (dd, J = 17.9, 3.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 196.6, 173.9, 139.9, 138.3, 134.8, 129.6, 129.1, 129.1,127.9, 127.8, 52.5, 46.4, 42.9. ESI-MS: calculated [C 17 H 15 ClO3 + Na] + :325.0602, found: 325.0609. [α] 20 D = +73.9 (c = 0.64, CH2Cl2). The product wasanalyzed by HPLC to determine the enantiomeric excess: 95% ee (CHIRALPAK IG, n -hexane / i -PrOH = 90 / 10, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 14.6 min, t2(major) = 16.1 min.

[0086] Example 16: Preparation of Chiral Dicarbonyl Compound 4p

[0087]

[0088] A 10 mL dry reaction tube equipped with a stirring magnet was prepared, equipped with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, the corresponding compounds 1j (0.3 mmol), 2h (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, the corresponding chiral dicarbonyl compound 4p was isolated by column chromatography using a 50:1 v / v mixture of petroleum ether and ethyl acetate as the eluent to obtain 4p (56% yield, 95% ee).

[0089] 1H NMR (400 MHz, CDCl3) δ 7.86-7.78 (m, 2H), 7.58-7.50 (m, 1H), 7.50-7.40 (m, 2H), 7.39-7.27 (m, 5H), 6.97-6.82 (m, 2H), 3.79 (dd, J = 8.3, 7.0Hz, 1H), 3.68 (s, 3H), 3.16-3.04 (m, 1H), 2.84-2.72 (m, 1H). 13 C NMR (100 MHz,CDCl3) δ 190.7, 173.5, 145.3, 138.0, 137.7, 132.9, 129.0, 128.7, 128.7,128.1, 128.0, 127.8, 52.4, 50.6, 36.6. ESI-MS: calculated [C 19 H 18 O3 + Na] + :317.1148, found: 317.1144. [α] 20 D = +52.0 (c = 0.55, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 95% ee (CHIRALPAK IC, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 9.0 min, t2(major) = 10.1 min.

[0090] Example 17: Preparation of chiral dicarbonyl compound 4q

[0091]

[0092] 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 1j (0.3 mmol), 2i (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (0.1 mmol) and dry dichloromethane (1 mL) under an argon atmosphere. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent: dichloromethane / ethanol 95 / 5) to give the product 4q as a white solid (0.1 mmol, 100% yield). nBu4NPF6, 0.3 mmol), then a mixed solution of THF / MeCN = 2:1 (3 mL) was added to dissolve it. Subsequently, electrolysis was carried out at 25 °C under constant current (1.0 mA) for 8 hours. After the reaction was completed, the solvent was directly removed by distillation under reduced pressure, and finally column chromatography was performed using petroleum ether / ethyl acetate mixed at a volume ratio of 50:1 as an eluent to isolate the corresponding chiral dicarbonyl compound 4q (51% yield, 97% ee).

[0093] 1 H NMR (400 MHz, CDCl3) δ 7.96-7.90 (m, 2H), 7.70-7.61 (m, 4H), 7.54-7.45 (m, 2H), 7.44-7.36 (m, 2H), 7.35-7.27 (m, 4H), 6.96-6.91 (m, 2H), 3.81(dd, J = 8.3, 7.0 Hz, 1H), 3.69 (s, 3H), 3.19-3.01 (m, 1H), 2.92-2.75 (m,1H). 13 C NMR (100 MHz, CDCl3) δ 190.1, 173.5, 145.7, 145.2, 140.0, 138.0,136.4, 129.3, 129.1, 129.0, 128.3, 128.1, 128.0, 127.8, 127.4, 127.3, 52.4,50.6, 36.6. ESI-MS: calculated [C 25 H 22 O3 + Na] + : 393.1461, found: 393.1460. [α] 20 D = +22.4 (c = 0.63, CH2Cl2). The product was analyzed by HPLC to determinethe enantiomeric excess: 97% ee (CHIRALPAK IC, n -hexane / i -PrOH = 70 / 30,detector: 300 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 13.6 min, t2(major) = 16.5 min.

[0094] Example 18: Preparation of chiral dicarbonyl compound 4r

[0095]

[0096] 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 1j (0.3 mmol), 2j (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (0.3 mmol), THF / MeCN = 2:1 (3 mL) and stirred at 25 °C under an argon atmosphere. The electrolysis was carried out at constant current (1.0 mA) for 8 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure and the corresponding chiral dicarbonyl compound 4r was isolated by column chromatography using petroleum ether / ethyl acetate 50:1 as eluent (76% yield, 93% ee). n Bu4NPF6, 0.3 mmol), and then dissolved in THF / MeCN = 2:1 (3 mL). The electrolysis was carried out at constant current (1.0 mA) for 8 h at 25 °C. After the reaction was completed, the solvent was removed by distillation under reduced pressure and the corresponding chiral dicarbonyl compound 4r was isolated by column chromatography using petroleum ether / ethyl acetate 50:1 as eluent (76% yield, 93% ee).

[0097] 1 H NMR (400 MHz, CDCl3) δ 7.39-7.14 (m, 9H), 6.59 (dt, J = 15.8, 6.8Hz,1H), 6.47 (dt, J = 15.8, 1.2 Hz, 1H), 3.74 (t, J = 7.7 Hz, 1H), 3.67 (s,3H), 3.10-2.98 (m, 1H), 2.80-2.68 (m, 1H), 2.33 (s, 3H) 13 C NMR (100 MHz,CDCl3) δ 196.4, 173.4, 146.7, 138.6, 137.9, 137.1, 132.6, 131.3, 130.6,129.0, 128.3, 128.0, 127.8, 125.4, 52.4, 50.5, 36.4, 20.3. ESI-MS: calculated[C 20 H 20 O3 + Na] + : 331.1305, found: 331.1298. [α] 20 D= +62.0 (c = 0.78, CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee(CHIRALPAK IC, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T = 25 ℃, flowrate: 1 mL / min), t1(minor) = 9.0 min, t2(major) = 10.9 min.

[0098] Example 19: Preparation of Chiral Dicarbonyl Compound 4s

[0099]

[0100] A 10 mL dry reaction tube equipped with a stirring magnet was prepared, equipped with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, the corresponding compounds 1j (0.3 mmol), 2k (0.1 mmol), methanol 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, column chromatography using a 50:1 v / v mixture of petroleum ether and ethyl acetate as the eluent afforded the corresponding chiral dicarbonyl compound 4s (40% yield, 97% ee).

[0101] 1 H NMR (400 MHz, CDCl3) δ 9.51 (d, J = 7.9 Hz, 1H), 7.39-7.24 (m, 6H), 7.06-6.95 (m, 1H), 6.39-6.23 (m, 1H), 6.19-6.01 (m, 2H), 3.72-3.68 (m, 1H), 3.67 (s, 3H), 3.04-2.92 (m, 1H), 2.75-2.63 (m, 1H). 13C NMR (100 MHz, CDCl3) δ193.9, 173.5, 151.9, 142.5, 138.0, 131.1, 130.8, 129.0, 127.9, 127.8, 52.4,51.0, 36.9. ESI-MS: calculated [C 15 H 16 O3 + Na] + : 267.0992, found: 267.0995. [α] 20 D = +75.4 (c = 0.31, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 97% ee (CHIRALPAK IC, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T = 25 ℃, flow rate: 1 mL / min), t1(minor) = 12.5 min, t2(major) = 13.8 min.

[0102] Example 20: Preparation of Chiral Dicarbonyl Compound 4t

[0103]

[0104] A 10 mL dry reaction tube equipped with a stirring magnet was prepared, equipped with a carbon electrode as the anode and a platinum electrode as the cathode. Under an argon atmosphere, the corresponding compounds 1j (0.3 mmol), 2a (0.1 mmol), ethanol 3b (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate ( n Bu4NPF6, 0.3 mmol), was then dissolved in a 2:1 THF / MeCN mixture (3 mL). Electrolysis was then carried out at 25°C with a constant current (1.0 mA) for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. Finally, column chromatography using a 50:1 v / v mixture of petroleum ether and ethyl acetate as the eluent afforded the corresponding chiral dicarbonyl compound 4t (73% yield, 94% ee).

[0105] 1H NMR (500 MHz, CDC13) δ 8.00-7.94 (m, 2H), 7.63-7.53 (m, 1H), 7.50-7.42 (m, 2H), 7.40-7.32 (m, 4H), 7.32-7.26 (m, 1H), 4.28 (dd, J = 10.4, 4.0 Hz, 1H), 4.20 (dq, J = 10.8, 7.2 Hz, 1H), 4.11 (dq, J = 10.8, 7.1 Hz, 1H), 3.95 (dd, J = 18.0, 10.4 Hz, 1H), 3.26 (dd, J = 18.0, 4.0 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDC13) δ 197.8, 173.5, 138.6, 136.5, 133.4, 129.0, 128.7, 128.2, 127.9, 127.6, 61.2, 46.6, 42.9, 14.2. ESI-MS: calculated [C 18 H 18 O3 + Na] + : 305.1148, found: 305.1148. [α] 20 D = +52.9 (c = 0.69, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 94% ee (CHIRALPAK IC, n -hexane / i -PrOH = 70 / 30, detector: 254 nm, T = 25 °C, flowrate: 1 mL / min), t1(minor) = 6.7 min, t2(major) = 8.2 min.

[0106] Example 21: Asymmetric preparation of the natural products calyxolane A and ent calyxolane B

[0107]

[0108]

[0109] A dry 10 mL reaction tube equipped with a stirring magnet and dried was equipped with a carbon electrode as anode and a platinum electrode as cathode. Under argon atmosphere, the corresponding compounds 1j (0.3 mmol), 2a (0.1 mmol), 3a (0.5 mmol), chiral isothiourea catalyst (0.01 mmol), tetrabutylammonium hexafluorophosphate (Bu4NPF6, 0.3 mmol) were weighed and added successively, then a mixture solution of THF / MeCN = 2:1 (3 mL) was added to dissolve them. Subsequently, electrolysis was carried out at 25 °C under constant current (1.0 mA) for 8 hours. After the reaction was completed, the solvent was removed directly by distillation under reduced pressure, and finally the corresponding chiral biscarbonyl compound 4u was obtained by column chromatography using petroleum ether / ethyl acetate (50:1 by volume) as eluent (75% yield, 96% ee). n Bu4NPF6, 0.3 mmol), then a mixture solution of THF / MeCN = 2:1 (3 mL) was added to dissolve them. Subsequently, electrolysis was carried out at 25 °C under constant current (1.0 mA) for 8 hours. After the reaction was completed, the solvent was removed directly by distillation under reduced pressure, and finally the corresponding chiral biscarbonyl compound 4u was obtained by column chromatography using petroleum ether / ethyl acetate (50:1 by volume) as eluent (75% yield, 96% ee).

[0110] 1 H NMR (400 MHz, CDCl3) δ 8.02-7.90 (m, 2H), 7.68-7.50 (m, 1H), 7.52-7.43 (m, 2H), 7.39-7.31 (m, 4H), 7.32-7.27 (m, 1H), 4.30 (dd, J = 10.4, 4.0Hz, 1H), 3.96 (dd, J = 18.0, 10.3 Hz, 1H), 3.70 (s, 3H), 3.28 (dd, J = 18.1,4.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 197.7, 174.0, 138.5, 136.5, 133.4,129.1, 128.7, 128.2, 128.0, 127.7, 52.5, 46.5, 42.9. ESI-MS: calculated[C 17 H 16 O3 + Na] + : 291.0992, found: 291.0991. [α] 20 D= +89.4 (c = 0.98, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (CHIRALPAK IC, n - hexane i - PrOH = 70 / 30, detector: 254 nm, T = 25 °C, flowrate: 1 mL / min), t1(minor) = 7.6 min, t2(major) = 8.2 min.

[0111]

[0112] BH3THF (0.9 mol / L, 0.56 mL, 5.0 eq) was added to a Schlenk tube containing 4u (96% ee, 26.8 mg, 0.1 mmol) and the solution was stirred at 25 °C for 8 h, then carefully quenched with MeOH. The resulting mixture was concentrated and dissolved in DCM (2.0 mL), then the solution was treated with BF3Et2O (25 µL, 2.0 eq) at 25 °C for 2 h. The reaction was quenched with saturated NH4Cl and extracted with DCM (3 x 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. Column chromatography separation with petroleum ether / ethyl acetate mixed as eluent in the ratio of 20:1 by volume gave the natural product calyxolane A (6, 31% yield, 95% ee) and ent calyxolane B (7, 41% yield, 96% ee).

[0113] Calyxolane A: 1 H NMR (400 MHz, CDCl3) δ 7.70-6.91 (m, 10H), 5.16 (dd, J = 7.8, 5.8 Hz, 1H), 4.44-4.35 (m, 1H), 3.87 (t, J = 8.2 Hz, 1H), 3.46 (p, J =7.8 Hz, 1H), 2.41 (dt, J = 12.4, 7.7 Hz, 1H), 2.32-2.19 (m, 1H). 13C NMR (100 MHz, CDC13) δ 143.7, 142.2, 128.8, 128.5, 127.5, 127.3, 126.8, 125.6, 80.7, 75.3, 44.5, 42.8. ESI-MS: calculated [C 16 H 16 O + Na] + : 247.1093, found: 247.1088. [α] 20 D = +35.4 (c = 0.23, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 95% ee (CHIRALPAK IB, n -hexane / i -PrOH = 99 / 1, detector: 210.1 nm, T = 25 °C, flow rate: 1 mL / min), t1(major) = 9.4 min, t2(minor) = 11.0 min.

[0114] ent -calyxolane B: 1 H NMR (400 MHz, CDC13) δ 7.77-6.94 (m, 9H), 5.04-4.89 (m, 1H), 4.28 (ddt, J = 8.4, 5.8, 2.8 Hz, 1H), 3.94 (ddt, J = 8.5, 5.9, 2.9 Hz, 1H), 3.61-3.52 (m, 1H), 2.68 (tq, J = 9.7, 3.0 Hz, 1H), 2.01-1.87 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 142.8, 141.8, 128.8, 128.6, 127.6, 127.4, 126.8, 125.9, 82.0, 75.2, 46.2, 43.9. ESI-MS: calculated [C 16 H 16 O + Na] +:247.1093, found: 247.1093. [α] 20 D = +43.9 (c = 0.30, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (CHIRAL OD, n - hexane i - PrOH = 90 / 10, detector: 210.3 nm, T = 25 °C, flow rate: 1 mL / min), t1(major) = 6.5 min, t2(minor) = 8.2 min.

Claims

1. An asymmetric preparation method of chiral dicarbonyl compounds, characterized in that: under a nitrogen atmosphere, a carboxylate derivative 1, an enol silyl ether compound 2, an alcohol 3, a chiral isothiourea catalyst, and an electrolyte are added into a reaction bottle equipped with electrodes, and an organic solvent is added for dissolution, a current is applied at -40 to 80℃ for 2-60 hours, and a reaction end point is determined by a thin layer chromatography spot 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 a target product I; and a synthesis route is as shown below: The structure of the chiral isothiourea catalyst is as shown below:

2. The preparation method according to claim 1, characterized in that: ； In the above formula: * represents a chiral carbon atom; n is 0, 1 or 2; R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen; R 6 is selected from C 1-10 alkyl; R 7 is selected from C 1-10 alkyl; R 8 is selected from C 1-10 aryl; The electrolyte is one of tetrabutylammonium hexafluorophosphate, tetraethylammonium hexafluorophosphate, tetramethylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium perchlorate, tetraethylammonium perchlorate, tetraethylammonium tetrafluoroborate, tetrabutylammonium chloride, and tetrabutylammonium bromide. 。 3. The preparation method according to claim 1, characterized in that: The molar ratio of the chiral isothiourea catalyst to the enol silyl ether compound 2 is 0.03:1-1:1; the molar equivalent ratio of the enol silyl ether compound 2 to the carboxylate derivative 1 is 1:0.5-1:5; the molar equivalent ratio of the enol silyl ether compound 2 to the alcohol 3 is 1:1-1:100; and the molar ratio of the enol silyl ether compound 2 to the electrolyte is 1:0.1-1:

5.

4. The 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, methanol, tetrahydrofuran, acetonitrile, toluene, ethylbenzene, fluorobenzene, chlorobenzene, bromobenzene, xylene, or mesitylene.

5. The preparation method according to claim 1, characterized in that: The electrode is one or two of carbon, carbon cloth, carbon felt, carbon paper, platinum, nickel, reticular glassy carbon, glassy carbon, and boron-doped diamond electrode. ​ ​ ​

Images