A method for synthesizing chiral alpha-hydroxy-beta-keto acid ester compounds

Abstract

This invention provides a method for synthesizing chiral α-hydroxy-β-keto esters. The method involves dissolving β-keto esters, a chiral catalyst, and an EDA electron acceptor in an organic solvent, and then conducting an asymmetric α-hydroxylation reaction at 0-50°C for 1-12 h under visible light induction and an oxygen atmosphere. After the reaction, the resulting reaction solution is post-treated to obtain the chiral α-hydroxy-β-keto esters. This method is highly efficient and mild, with high yield, good asymmetric selectivity, and a broad substrate range. The prepared product can serve as an important organic intermediate in pharmaceuticals, pesticides, and other fields, demonstrating significant application value.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, specifically to a chiral synthesis method driven by a photoinduced EDA complex. α -hydroxy- β - Synthesis methods for keto ester compounds. Background Technology

[0002] Chirality α -hydroxy- β Ketoesters have significant practical value in drug development and agricultural chemistry because their skeletons are present in many bioactive molecules, drugs, and pesticide molecules, such as Indoxacarb, Kjellmanianone, Epicoconigrone B, and Vindoline analogue, as shown in the figure below:

[0003] Due to chirality α -hydroxy- β The application value of keto esters has been extensively studied. β - Ketoester asymmetry α Hydroxylation reactions have been developed, and while reported catalytic systems (such as small organic molecule catalysis, phase transfer catalysis, and metal catalysis) can achieve high enantioselectivity, they still have significant limitations in terms of atom economy and environmental friendliness. For example, traditional chemical oxidants (such as cumene hydroperoxide and tert-butyl hydroperoxide) are used in reported patents (CN202111358738.1 and CN201910178985.X), resulting in low atom utilization and poor environmental friendliness. In recent years, visible light-induced asymmetric synthesis has become a powerful strategy for constructing chiral molecules due to its advantages such as mild reaction conditions, environmental friendliness, and clean energy. A previously reported (CN201810466329.5) photo-induced... β - Ketoester α In the hydroxylation reaction, an external photosensitizer (such as tetraphenylporphyrin, phthalocyanine and rose red) is needed to activate molecular oxygen. However, these photosensitizers generally have drawbacks such as complex structure, high synthesis and use cost, easy photobleaching, and difficulty in separation and purification. Summary of the Invention

[0004] This invention aims to overcome the limitations of current photocatalytic synthesis techniques for chiral materials. α -hydroxy- β The shortcomings of keto ester compounds led to the proposal of a chiral approach based on an EDA strategy. α -hydroxy- β Synthetic methods for keto ester compounds.

[0005] This mechanism is based on the non-covalent interaction between electron-rich molecules, which act as electron donors, and electron-deficient molecules, which act as electron acceptors. Under ground state conditions, the two molecules can form an EDA complex through non-covalent bonding. The EDA complex formed by the combination of the two molecules has characteristic absorption in the visible light region. When the EDA complex is excited by visible light, an intermolecular electron transfer process occurs, generating highly reactive free radical species under mild conditions. These free radical species can further participate in subsequent reactions, thereby driving the entire catalytic cycle to proceed efficiently.

[0006] β - Ketoester substrate molecules α The hydrogen atom at the carbon atom is relatively reactive. Under the electron-withdrawing effect of the carbonyl group, the hydrogen atom on the methyl group easily dissociates, forming an electron-rich carbanion intermediate. Simultaneously, the electron-donating conjugation effect of the ester group and aromatic ring further increases the electron cloud density of the substrate molecule, giving it electron-rich properties. This electron-rich property makes… β - Ketoesters can act as excellent electron donors, forming photoactive EDA complexes with electron-deficient o-dinitrobenzene in the ground state. Under visible light irradiation, this complex undergoes an intermolecular single-electron transfer process, with electrons transferring from the electron-rich ketone... β The keto ester donor is transferred to the o-dinitrophenyl acceptor, thereby enabling the electron-rich substrate to generate a key radical intermediate under mild conditions. The electrons gained by the o-dinitrophenyl are then captured by molecular oxygen to form a superoxide radical ion. Ultimately, under the stereoselective control of a chiral catalyst, the desired effect is achieved. β -Asymmetric ketoester compounds α -Hydration conversion.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] This invention provides a method for synthesizing chiral α-hydroxy-β-keto ester compounds as shown in formula (II), the method being as follows: The β-keto ester compound, chiral catalyst, and EDA electron acceptor shown in formula (I) are dissolved in an organic solvent and subjected to an asymmetric α-hydroxylation reaction at 0-50°C under visible light induction and an oxygen atmosphere. After the reaction, the resulting reaction solution is post-treated to obtain the chiral α-hydroxy-β-keto ester compound shown in formula (II). The molar ratio of the β-keto ester compound, chiral catalyst, and EDA electron acceptor shown in formula (I) is 1:0.01-0.10:0.01-0.10. The EDA complex electron acceptor is one or more of o-dinitrobenzene, m-dinitrobenzene, p-dinitrobenzene, or nitrobenzene. The chiral catalyst is a chiral complex formed by a chiral oxazoline shown in formula (III) or (IV) and a nickel salt, and the molar ratio of the chiral oxazoline to the nickel salt is 0.5-2:1 (preferably 1:1).

[0009] In formula (I), R1 is H, alkyl, alkoxy, nitro or halogen; R2 is adamantyl or C1-C10 alkyl; n is 1 or 2, x is C or O; R1 in formula (II) is the same as R1 in formula (I), R2 in formula (II) is the same as R2 in formula (I), n in formula (II) is the same as n in formula (I), and x in formula (II) is the same as x in formula (I); In formula (III) or formula (IV), marked with The carbon atom is a chiral carbon atom; In formula (III), R3 is simultaneously a C1-C10 alkyl group; R4 is simultaneously H, a C1-C10 alkyl group, a C6-C12 aryl group, or a substituted C6-C12 aryl group; R5 is simultaneously a C1-C10 alkyl group, a benzyl group, a C6-C12 aryl group, or a substituted C6-C12 aryl group. In Formula IV, R6 can be H, a C1-C10 alkyl group, a C6-C12 aryl group, or a substituted C6-C12 aryl group.

[0010] Furthermore, the organic solvent is one or more selected from toluene, methyl tert-butyl ether, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, or 1,2-dichloroethane.

[0011] Furthermore, the volume of the organic solvent is 1.0-30.0 mL / mmol (preferably 10.0-20.0 mL / mmol) in molar ratio to the β-keto ester compound.

[0012] Furthermore, the electron acceptor of the EDA complex is o-dinitrobenzene.

[0013] Furthermore, the post-processing method is as follows: the reaction solution is concentrated under reduced pressure to remove the solvent, and the residue is separated by column chromatography using 200-300 mesh silica gel (the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10:1). The eluent containing the target compound is collected, the solvent is evaporated and dried to obtain the chiral α-hydroxy-β-keto ester compound.

[0014] Furthermore, the reaction time is 1-12 hours.

[0015] Furthermore, the chiral catalyst is a chiral complex formed by a chiral oxazoline and a nickel salt, wherein the chiral oxazoline and the nickel salt are dissolved in the organic solvent and stirred until homogeneous before being added.

[0016] Furthermore, the nickel salt is one or more of nickel acetylacetonate, nickel bromide, or nickel bis(triphenylphosphine) chloride.

[0017] Furthermore, the chiral oxazoline is one of the following:

[0018] Furthermore, the chiral α-hydroxy-β-keto ester compound is one of the following:

[0019] The method of this invention uses visible light as an inducer and is based on an EDA complex strategy. β The keto ester substrate serves as the electron donor, o-dinitrobenzene as the electron acceptor, and the metal-chiral bisoxazoline ligand complex as the chiral catalyst. This preparation method utilizes electron-rich... β - Ketoesters and electron-deficient o-dinitrobenzene form a photoactive electron donor-acceptor (EDA) complex in the ground state. This complex undergoes intermolecular electron transfer (SET) under visible light irradiation, thereby efficiently generating a key radical intermediate under mild conditions, based on a chiral bisoxazoline ligand nickel salt complex. β - The superior chiral induction of keto esters can achieve α -hydroxyl β Highly efficient asymmetric catalytic preparation of keto esters.

[0020] The synthesis method of this invention is highly efficient and mild, with high yield, environmentally friendly, good asymmetric selectivity, and a wide range of reaction substrates. At the same time, the prepared product can be used as an important organic intermediate in the fields of medicine and pesticides, and has important application value.

[0021] Therefore, the present invention has the following beneficial effects: the synthesis method of the present invention is efficient and mild, with high yield, good asymmetric selectivity, and a wide range of reaction substrates. At the same time, the product prepared can be used as an important organic intermediate in the fields of medicine, pesticides and other fields, and has important application value. Detailed Implementation

[0022] The present invention will be further described below with reference to specific embodiments.

[0023] Example 1:

[0024] The reaction formula is:

[0025] Dissolve 0.01 mmol of oxazoline ligand (III)-e and 0.01 mmol of nickel acetylacetone in 2 mL of methyl tert-butyl ether. Stir at room temperature for 0.5 h. Then add 0.1 mmol of 1-adamantyl (1-Ad) indanone carboxylate and 0.003 mmol of o-dinitrobenzene to a quartz tube. Evacuate the system and replace the gas with oxygen. Stir the reaction under 450 nm-10 W blue LED visible light for 3 h. Concentrate the reaction solution under reduced pressure and separate it on a 200-300 mesh silica gel column. Use a gradient elution with petroleum ether and ethyl acetate in a volume ratio of 1-10:1. Collect the eluent and evaporate the solvent to obtain a white solid product (yield 96%). of ), [α] 20 D = 27 (c = 1, CHCl3). 1 H NMR (400MHz, Chloroform- d ) δ 7.77 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.0 Hz, 1H), 7.46(d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 4.04 (s, 1H), 3.64 (d, J =17.1 Hz, 1H), 3.20 (d, J = 17.1 Hz, 1H), 2.10 (s, 3H), 1.95 (s, 6H), 1.58 (s, 6H). 13 C NMR (101 MHz, Chloroform- dδ 201.25, 169.99, 152.14, 135.59, 133.76, 127.67, 126.04, 124.81, 83.68, 80.31, 40.68, 39.35, 35.63, 30.58. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm). R = 13.421 min, 22.770 min. 96% oh. HRMS: m / z = 349.1415 [M+Na] +

[0026] Example 2-16:

[0027] Using the same reactants and operating procedures as in Example 1, ligand (III)-e was replaced with ligands of 0.01 mmol or less, and asymmetric reactions were performed in different organic solvents. α The results of the hydroxylation reaction are shown in the table below:

[0028] Example 17:

[0029] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 5-chloro-1-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 95%, 92%). of ). [α] 20 D = 59 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ7.72 (d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 4.02 (s,1H), 3.62 (d, J = 17.3 Hz, 1H), 3.19 (d, J = 17.3 Hz, 1H), 2.12 (s, 3H), 1.96(d, J= 2.9 Hz, 6H), 1.60 (s, 6H). 13 C NMR (101 MHz, Chloroform- d δ 199.83, 169.63, 153.51, 142.21, 132.26, 128.61, 126.34, 125.91, 84.11, 80.31, 40.74, 39.07, 35.65, 30.63. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 14.342 min, 25.246 min. 92% oh. HRMS: m / z = 383.1029 [M+Na] + .

[0030] Example 18:

[0031] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 6-fluoro-1-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a colorless oily product (yield 92%, 91%). of ). [α] 20 D = 19 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ7.44 (dd, J = 7.1, 3.3 Hz, 1H), 7.43-7.39 (m, 1H), 7.35 (td, J = 8.5, 2.6 Hz,1H), 4.06 (s, 1H), 3.60 (d, J = 16.9 Hz, 1H), 3.17 (d, J = 16.9 Hz, 1H), 2.12(s, 3H), 1.95(d, J = 3.0 Hz, 6H), 1.59 (s, 6H). 13 C NMR (101 MHz, Chloroform- d)δ 200.78, 169.94, 163.73 (d, J = 249.5), 147.91, 135.86(d, J = 8.1), 127.85(d, J = 8.1), 123.73 (d, J = 24.2), 110.99 (d, J = 22.2), 84.35, 81.30, 41.05, 39.16, 35.96, 30.94. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 11.256 min, 21.463 min. 91% oh. HRMS: m / z = 367.1319 [M+Na] + .

[0032] Example 19:

[0033] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 5-fluoro-1-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 83%, 94%). of ). [α] 20 D = 52 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ7.79 (dd, J = 8.4, 5.3 Hz, 1H), 7.13 (d, J = 6.4 Hz, 1H), 7.09 (d, J = 8.6Hz, 1H), 4.06 (s, 1H), 3.63 (d, J = 17.4 Hz, 1H), 3.19 (d, J = 17.3 Hz, 1H), 2.11 (s, 3H), 1.99-1.90 (m, 6H), 1.59 (s, 6H). 13C NMR (101 MHz, Chloroform- d )δ 199.63, 169.98, 169.08 (d, J = 259.6), 155.46 (d, J = 10.1), 130.49 (d, J =2.02), 127.61, 116.54 (d, J = 24.2), 113.34 (d, J = 23.2), 84.27, 80.75, 41.03, 39.52, 35.94, 30.92. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 10.452 min, 16.792 min. 94% oh. HRMS: m / z = 367.1319[M+Na] +

[0034] Example 20:

[0035] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 4-bromo-1-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 81%, 87%). of ). [α] 20 D = 67 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ7.64 (d, J = 9.4 Hz, 2H), 7.55 (d, J = 8.2 Hz, 1H), 4.03 (s, 1H), 3.62 (d, J = 17.3 Hz, 1H), 3.19 (d, J = 17.3 Hz, 1H), 2.12 (s, 3H), 1.96 (s, 6H), 1.60 (s, 6H). 13C NMR (101 MHz, Chloroform- d δ 200.40, 169.92, 153.90, 132.96, 131.77, 131.44, 129.74, 126.27, 84.44, 80.53, 41.05, 39.32, 35.96, 30.95. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 15.108 min, 26.641 min. 87% oh. HRMS: m / z = 427.0518 [M+Na] +

[0036] Example 21:

[0037] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 6-bromo-1-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a colorless oily product (yield 87%, 88%). of ). [α] 20 D = 92 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d δ7.90 (s, 1H), 7.74 (d, J = 10.1 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 4.03 (s,1H), 3.59 (d, J = 17.3 Hz, 1H), 3.14 (d, J = 17.3 Hz, 1H), 2.12 (s, 3H), 1.96(d, J = 3.0 Hz, 6H), 1.60 (s, 6H). 13 C NMR (101 MHz, Chloroform- dδ 200.23, 169.87, 150.98, 138.65, 135.94, 127.96, 127.93, 122.12, 84.48, 80.87, 41.09, 39.35, 35.98, 30.98. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 12.793 min, 26.180 min. 88% oh. HRMS: m / z = 427.0519 [M+Na] +

[0038] Example 22:

[0039] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 6-methyl-1-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 96%, 93%). of ). [α] 20 D = 17 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform-d) δ7.57 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 4.00 (s,1H), 3.60 (d, J = 17.0 Hz, 1H), 3.14 (d, J = 17.0 Hz, 1H), 2.40 (s, 3H), 2.11(s, 3H), 1.96 (d, J = 2.9 Hz, 6H), 1.59 (s, 6H). 13 C NMR (101 MHz, Chloroform- dδ 201.59, 170.46, 149.91, 137.98, 137.19, 134.22, 126.03, 125.04, 83.91, 80.94, 41.05, 39.36, 36.00, 30.94, 21.21. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 10.077 min, 17.59 min. 93% oh. HRMS: m / z = 363.1577 [M+Na] +

[0040] Example 23:

[0041] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 5-methyl-1-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a yellow solid product (yield 96%, 93%). of ). [α] 20 D = 37 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ7.70 (d, J = 7.8 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 4.01 (s,1H), 3.63 (d, J = 17.1 Hz, 1H), 3.18 (d, J = 17.1 Hz, 1H), 2.48 (s, 3H), 2.14(s, 3H), 1.99 (d, J = 3.0 Hz, 6H), 1.62 (s, 6H). 13 C NMR (101 MHz, Chloroform- dδ 200.86, 170.40, 152.88, 147.30, 131.65, 129.20, 126.63, 124.91, 83.81, 80.69, 40.93, 39.39, 35.89, 30.82, 22.28. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 15.976 min, 31.268 min. 93% oh. HRMS: m / z = 363.1580 [M+Na] +

[0042] Example 24:

[0043] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 4-methoxy-1-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 94%, 96%). of ). [α] 20 D = 32 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d )δ 7.37 (d, J = 1.3 Hz, 1H), 7.36 (s, 1H), 7.14-7.03 (m, 1H), 3.99 (s, 1H), 3.91 (s, 3H), 3.58 (d, J = 17.6 Hz, 1H), 3.06 (d, J = 17.6 Hz, 1H), 2.11 (s, 3H), 1.97 (d, J = 2.9 Hz, 6H), 1.59 (s, 6H). 13 C NMR (101 MHz, Chloroform- dδ213.24, 182.01, 168.26, 153.00, 146.94, 141.02, 128.13, 127.64, 95.51, 91.94, 67.22, 52.57, 48.03, 47.53, 42.47. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20:80, flow rate 1.0 mL / min, 254 nm; t R = 25.822 min, 32.300 min. 96% oh. HRMS: m / z = 379.1520 [M+Na] +

[0044] Example 25:

[0045] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 5-methoxy-1-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 72%, 77%). of ). [α] 20 D = 39 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d )δ 7.70 (d, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 4.01 (s,1H), 3.63 (d, J = 17.1 Hz, 1H), 3.18 (d, J = 17.1 Hz, 1H), 2.48 (s, 3H), 2.14(s, 3H), 1.99 (d, J = 2.8 Hz, 6H), 1.62 (s, 6H). 13 C NMR (101 MHz, Chloroform- dδ 200.99, 170.53, 153.00, 147.42, 131.78, 129.32, 126.75, 125.04, 83.94, 80.82, 41.05, 39.52, 36.01, 30.94, 22.41. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 6.750 min, 9.021 min. 77% oh. HRMS: m / z = 379.1518 [M+Na] +

[0046] Example 26:

[0047] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 5,6-dimethoxy-1-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a yellow solid product (90% yield, 85% yield). of ). [α] 20 D = 67 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ 7.19 (s, 1H), 6.88 (s, 1H), 4.00 (s, 1H), 3.99 (s, 3H), 3.92(s, 3H), 3.57 (d, J = 16.8 Hz, 1H), 3.11 (d, J = 16.9 Hz, 1H), 2.13 (s, 3H), 1.99 (d, J = 2.9 Hz, 6H), 1.60 (s, 6H). 13 C NMR (101 MHz, Chloroform- dδ 199.96, 170.68, 156.52, 149.88, 148.37, 128.81, 126.88, 107.29, 105.38, 83.92, 56.49, 56.26, 41.10, 39.41, 36.03, 30.96. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 25.820 min, 32.227 min. 85% oh. HRMS: m / z = 409.1628 [M+Na] +

[0048] Example 27:

[0049] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 2-adamantyl (1-Ad) indanone carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 95%, 87%). of ). [α] 20 D = 49 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ 7.80(d, J = 7.7 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.42(t, J = 7.5 Hz, 1H), 4.95 (s, 1H), 4.04 (s, 1H), 3.70 (d, J = 17.0 Hz, 1H), 3.29 (d, J = 17.0 Hz, 1H), 1.84-1.54 (m, 10H), 1.36-1.20 (m, 4H). 13 C NMR (101MHz, Chloroform- dδ 200.47, 169.98, 151.34, 135.29, 133.41, 127.40, 125.59, 124.38, 80.33, 79.10, 38.90, 36.39, 35.39, 35.30, 31.05, 30.80, 30.78, 30.60, 26.13, 25.99. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol: hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 8.934 min, 11.486 min. 87% oh. HRMS: m / z = 349.1416 [M+Na] +

[0050] Example 28:

[0051] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate used was replaced with 1-adamantyl 1-tetrahydronaphthone-2-carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 80%, 83%). of ). [α] 20 D = 23 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ 8.06(d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 4.26 (s, 1H), 3.19-3.06 (m, 2H), 2.66 (dt, J = 13.4, 5.2Hz, 1H), 2.31 -2.20 (m, 1H), 2.14 (s, 3H), 2.03 (d, J = 2.3 Hz, 6H), 1.63 (s, 6H). 13 C NMR (101 MHz, Chloroform-d δ 195.04, 169.81, 143.96, 134.17, 130.86, 128.91, 128.08, 126.97, 83.59, 77.95, 41.13, 36.07, 32.98, 30.95, 25.88. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 9.615 min, 14.817 min, 83% oh. HRMS: m / z = 363.1569 [M+Na] +

[0052] Example 29:

[0053] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate was replaced with methyl 1-indanone-2-carboxylate, while the other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 82%, 46%). of ). [α] 20 D = 13 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ 7.79 (d, J =7.7 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.43 (t, J =7.5 Hz, 1H), 4.04 (s, 1H), 3.72 (d, J = 9.7 Hz, 4H), 3.25 (d, J = 17.3 Hz, 1H). 13 C NMR (101 MHz, Chloroform- dδ 200.97, 172.05, 152.33, 136.33, 133.63, 128.29, 126.60, 125.46, 80.49, 53.61, 39.39. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak OD-H, 2-propanol : hexane = 10 : 90, flow rate 1.0 mL / min, 254 nm; t R = 12.730 min, 15.254 min. 46% oh. HRMS: m / z = 229.0477 [M+Na] +

[0054] Example 30:

[0055] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate was replaced with ethyl 1-indanone-2-carboxylate, while the other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 81%, 45%). of ). [α] 20 D = 16 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ 7.79 (d, J = 7.7Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.42 (t, J = 7.5Hz, 1H), 4.19 (ddq, J = 10.7, 7.1, 3.6 Hz, 2H), 4.06 (s, 1H), 3.71 (d, J =17.3 Hz, 1H), 3.24 (d, J = 17.2 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H). 13 C NMR (101MHz, Chloroform- dδ 201.08, 171.57, 152.40, 136.22, 133.70, 128.21, 126.56, 125.37, 80.42, 62.87, 39.42, 14.07. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak OD-H, 2-propanol : hexane = 10 : 90, flow rate 1.0 mL / min, 254 nm; t R = 19.346 min, 34.046 min. 45% oh. HRMS: m / z = 243.0633 [M+Na] +

[0056] Example 31:

[0057] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate was replaced with methyl 5-chloro-1-indanone-2-carboxylate. All other reaction conditions and steps were the same as in Example 1, yielding a white solid product (yield 92%, 37%). of ). [α] 20 D =35 (c=1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ 7.72 (d, J =8.2 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J = 9.6 Hz, 1H), 4.07 (s, 1H), 3.74 (s,3H), 3.69 (d, J = 17.5 Hz, 1H), 3.23 (d, J = 17.5 Hz, 1H). 13 C NMR (101 MHz, Chloroform- dδ 199.54, 171.65, 153.66, 142.98, 132.09, 129.19, 126.88, 126.51, 80.55, 53.74, 39.09. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak OD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 324 nm; t R =12.730 min, 15.254 min. 37% oh. HRMS: m / z = 263.0085 [M+Na] +

[0058] Example 32:

[0059] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate was replaced with isopropyl 1-indanone-2-carboxylate, while the other reaction conditions and steps were the same as in Example 1, yielding a yellow oily product (yield 83%, 63%). of ). [α] 20 D = 57 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ 7.78 (d, J =7.7 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.41 (t, J =7.5 Hz, 1H), 5.05 (p, J = 6.3 Hz, 1H), 4.04 (s, 1H), 3.68 (d, J = 17.2 Hz, 1H), 3.22 (d, J = 17.2 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H), 1.11 (d, J = 6.2Hz, 3H). 13 C NMR (101 MHz, Chloroform- dδ 201.13, 171.12, 152.45, 136.13, 133.76, 128.15, 126.51, 125.30, 80.40, 70.97, 39.40, 21.43. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak OD-H, 2-propanol: hexane = 10 : 90, flow rate 1.0 mL / min, 254 nm; t R = 12.058 min, 21.450 min. 63% oh. HRMS: m / z = 257.0786[M+Na] +

[0060] Example 33:

[0061] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylate was replaced with 3-oxo-2,3-dihydrobenzofuran-2-carboxylate tert-butyl ester. All other reaction conditions and steps were the same as in Example 1, yielding a yellow solid product (yield 84%, 90%). of ). [α] 20 D = 37 (c = 1.0, CHCl3). 1 H NMR (400 MHz, DMSO- d 6) δ7.77 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 1.33 (s, 9H). 13 C NMR (101 MHz, DMSO- d 6) δ 195.36, 170.76, 164.33, 139.40, 124.76, 122.81, 118.58, 113.33, 100.07, 83.22, 27.32. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R= 12.862 min, 15.786 min. 90% oh. HRMS: m / z = 273.0738[M+Na] +

[0062] Example 34:

[0063] The difference from Example 1 is that the 1-adamantyl (1-Ad) indanone carboxylic acid ester used was replaced with 1-indanone-2-carboxylic acid tert-butyl ester. All other reaction conditions and steps were the same as in Example 1, yielding a yellow oily product (yield 90%, 85%). of ). [α] 20 D = 59 (c = 1.0, CHCl3). 1 H NMR (400 MHz, Chloroform- d ) δ 7.79 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 4.00 (s, 1H), 3.65 (d, J = 17.1 Hz, 1H), 3.22 (d, J = 17.1 Hz, 1H), 1.36 (s, 9H). 13 C NMR (101 MHz, Chloroform- d δ 201.34, 170.54, 152.32, 135.83, 133.93, 127.93, 126.27, 125.06, 83.93, 80.55, 39.44, 27.70. Analysis was performed by chiral HPLC under the following conditions: Daicel Chiralpak AD-H, 2-propanol : hexane = 20 : 80, flow rate 1.0 mL / min, 254 nm; t R = 5.882 min, 7.632 min. 85% oh. HRMS: m / z = 271.0945 [M+Na] +

Claims

1. A method for synthesizing a chiral α-hydroxy-β-keto ester compound as shown in formula (II), characterized in that, The method is as follows: The β-keto ester compound, chiral catalyst, and EDA electron acceptor shown in formula (I) are dissolved in an organic solvent and subjected to an asymmetric α-hydroxylation reaction at 0-50°C under visible light induction and an oxygen atmosphere. After the reaction is completed, the resulting reaction solution is post-treated to obtain the chiral α-hydroxy-β-keto ester compound shown in formula (II). The molar ratio of the β-keto ester compound, chiral catalyst, and EDA electron acceptor shown in formula (I) is 1:0.01-0.10:0.01-0.

10. The EDA complex electron acceptor is one or more of o-dinitrobenzene, m-dinitrobenzene, p-dinitrobenzene, or nitrobenzene. The chiral catalyst is a chiral complex formed by a chiral oxazoline shown in formula (III) or (IV) and a nickel salt, and the molar ratio of the chiral oxazoline to the nickel salt is 0.5-2:

1. In formula (I), R1 is H, alkyl, alkoxy, nitro or halogen; R2 is adamantyl or C1-C10 alkyl; n is 1 or 2, x is C or O; R1 in formula (II) is the same as R1 in formula (I), R2 in formula (II) is the same as R2 in formula (I), n in formula (II) is the same as n in formula (I), and x in formula (II) is the same as x in formula (I); In formula (III) or formula (IV), marked with The carbon atom is a chiral carbon atom; In formula (III), R3 is simultaneously a C1-C10 alkyl group; R4 is simultaneously H, a C1-C10 alkyl group, a C6-C12 aryl group, or a substituted C6-C12 aryl group; R5 is simultaneously a C1-C10 alkyl group, a benzyl group, a C6-C12 aryl group, or a substituted C6-C12 aryl group. In Formula IV, R6 can be H, a C1-C10 alkyl group, a C6-C12 aryl group, or a substituted C6-C12 aryl group.

2. The method for synthesizing chiral α-hydroxy-β-keto ester compounds as described in claim 1, characterized in that, The organic solvent is one or more of toluene, methyl tert-butyl ether, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, or 1,2-dichloroethane.

3. The method for synthesizing chiral α-hydroxy-β-keto ester compounds as described in claim 1, characterized in that, The volume of the organic solvent is 1.0-30.0 mL / mmol in molar ratio to the β-keto ester compound.

4. The method for synthesizing chiral α-hydroxy-β-keto ester compounds as described in claim 1, characterized in that, The electron acceptor of the EDA complex is o-dinitrobenzene.

5. The method for synthesizing chiral α-hydroxy-β-keto ester compounds as described in claim 1, characterized in that, The post-processing method is as follows: the reaction solution is concentrated under reduced pressure to remove the solvent, the residue is separated by column chromatography using 200-300 mesh silica gel, the eluent containing the target compound is collected, the solvent is evaporated and dried to obtain the chiral α-hydroxy-β-keto ester compound.

6. The method for synthesizing chiral α-hydroxy-β-keto ester compounds as described in claim 1, characterized in that, The reaction time is 1-12 hours.

7. The method for synthesizing chiral α-hydroxy-β-keto ester compounds as described in claim 1, characterized in that, The chiral catalyst is a chiral complex formed by a chiral oxazoline and a nickel salt, which is added after being dissolved in the organic solvent and stirred until homogeneous.

8. The method for synthesizing chiral α-hydroxy-β-keto ester compounds as described in claim 7, characterized in that, The nickel salt is one or more of nickel acetylacetonate, nickel bromide, or nickel bis(triphenylphosphine) chloride.

9. The method for synthesizing chiral α-hydroxy-β-keto ester compounds as described in claim 7, characterized in that, The chiral oxazoline is one of the following: 。 10. The method for synthesizing chiral α-hydroxy-β-keto ester compounds as described in claim 1, characterized in that, The chiral α-hydroxy-β-keto ester compound is one of the following: 。

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