A method for preparing an indole-acetic acid compound containing a 3-position chiral quaternary carbon center

Abstract

This invention discloses a method for preparing indole-acetic acid compounds containing a 3-chiral quaternary carbon center, belonging to the field of organic synthesis technology. The method specifically includes the following steps: adding a catalyst, ligand, base, and reducing agent to a reaction vessel; then adding the reaction substrate and solvent under a CO2 atmosphere; stirring the reaction at room temperature for 0.1–96 h; followed by acidification; and then separating and purifying the reaction product to obtain the indole-acetic acid compounds containing a 3-chiral quaternary carbon center. This invention, based on the transition metal-catalyzed CO2-mediated carbon-carboxylation reaction of olefins in a reduction system, achieves for the first time the efficient construction of indole-acetic acid compounds containing a 3-chiral quaternary carbon center. It has advantages such as a wide range of reaction substrates, good selectivity, good functional group compatibility, mild reaction conditions, and low cost.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing an indole-acetic acid compound containing a 3-position chiral quaternary carbon center. Background Technology

[0002] Indoline and oxidized indole structures containing chiral quaternary carbon centers are widely found in natural products. These alkaloids possess excellent physiological activities, such as antitumor, antiviral, anti-anxiety, anti-inflammatory, antihypertensive, antipyretic, analgesic, and cathepsin inhibitory effects. Therefore, the efficient construction of these structures has attracted widespread attention in organic chemistry, medicinal chemistry, and biochemistry. Oxidized indole-acetic acid compounds containing a 3-position chiral quaternary carbon center are important synthetic precursors for a large class of alkaloids. The efficient construction of these compounds will promote the rapid synthesis of (spiro)heterocyclic fused indole alkaloids and enrich their molecular library, providing a material basis for research on the physiological properties of these molecules in medicinal chemistry and biochemistry.

[0003] Traditional synthetic methods for oxidized indole-acetic acid compounds containing a 3-position chiral quaternary carbon center have significant limitations, including cumbersome procedures, the need for toxic CO gas or highly toxic cyano compounds as carboxyl sources, and the requirement for noble metals. Furthermore, the direct and efficient chiral synthesis of these molecules has remained difficult to achieve. Therefore, exploring efficient chiral synthesis of these molecules has significant academic and practical value.

[0004] Carbon dioxide, as a cheap, readily available, non-toxic, renewable, and abundant carbon-1 resource, has attracted significant attention in the fields of materials science and chemical engineering in recent years. Therefore, developing efficient CO2 conversion methods has important academic significance and potential industrial value. Recently, the use of CO2 in the construction of carboxylic acids has received considerable attention from organic chemists. Among these methods, CO2 participation in the functionalization of unsaturated hydrocarbons is an important pathway for constructing carboxylic acid products. Furthermore, CO2 participation in the carbon-carboxyl bifunctionalization of alkenes can simultaneously introduce two carbon functional groups, providing a convenient route for the rapid construction of multi-substituted complex carboxylic acids. However, to date, transition metal-catalyzed CO2-mediated carbon-carboxylation of alkenes remains rarely reported. Transition metal-catalyzed CO2-mediated carbon-carboxylation of alkenes based on reduction systems has not been reported, and its asymmetric carbon-carboxylation reaction is an even greater challenge.

[0005] Therefore, it is urgently needed in this field to develop a novel CO2-involved asymmetric carbon-carboxylation reaction of alkenes to provide a method for the efficient synthesis of optically pure oxidized indole-acetic acid compounds, replacing expensive and toxic carboxyl sources (CO or cyano). Summary of the Invention

[0006] In view of the shortcomings or defects of the prior art, the purpose of this invention is to provide a method for preparing indole-acetic acid compounds containing a 3-position chiral quaternary carbon center. This method can effectively solve the problems of cumbersome steps and the use of toxic CO gas or highly toxic cyano compounds as carboxyl sources in existing preparation methods. At the same time, this method has the advantages of high yield, high selectivity, mild reaction conditions, low toxicity of reaction reagents, and low cost.

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

[0008] This invention provides a method for preparing oxidized indole-acetic acid compounds containing a 3-position chiral quaternary carbon center, specifically comprising the following steps:

[0009] The catalyst, ligand, base, and reducing agent were added to a reaction vessel, and then the reaction substrate and solvent were added under a CO2 atmosphere. The reaction was stirred at room temperature for 0.1–96 h, followed by acidification. The reaction products were then separated and purified to obtain indole-acetic acid compounds containing a chiral quaternary carbon center at the 3-position. The molar ratio of the reaction substrate, catalyst, ligand, base, and reducing agent was 1:0.001–0.30:0.002–0.60:1–4:1–4.

[0010] The reaction substrate is an amide-bridged aryl (pseudo)halogenated compound, whose general structural formula is shown below:

[0011]

[0012] Wherein, X is a chlorine, bromine, or trifluoromethanesulfonate group; R 1 and R 2 All are alkyl groups.

[0013] Based on the above technical solution, the present invention can be further improved as follows.

[0014] Furthermore, the molar ratio of the reaction substrate, catalyst, ligand, base, and reducing agent is 1:0.05–0.15:0.15–0.30:2:2.

[0015] Furthermore, the reaction time is 48–96 hours.

[0016] Furthermore, when adding the catalyst, ligand, base, and reducing agent to the reaction vessel, magnesium chloride is added together; wherein the molar ratio of magnesium chloride to the reaction substrate is 1 to 4:1, preferably 2:1.

[0017] Furthermore, the catalyst is a nickel catalyst, preferably nickel dimethyl ether bromide of ethylene glycol, nickel dimethyl ether chloride of ethylene glycol, nickel acetylacetone, or bis-(1,5-cyclooctadiene) nickel.

[0018] Further, the ligands are (S)-4-isopropyl-2-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydrooxazole, (S)-(-)-2-[2-(diphenylphosphine)phenyl]-4-isopropyl-4,5-dihydrooxazole, (4S,4'S)-4,4'-di-tert-butyl-4,4',5,5'-tetrahydro-2,2'-bisoxazole, and (S)-1-(diphenylphosphine)-2-[(S)-4-isopropyloxazole]. [Zazoline-2-yl]ferrocene, (6S,9S)-6,9-dimethyl-6,7,8,9-tetrahydro-[1,6]dioxadecan[3,2-b:4,5-b']bipyridine, (1R,2R)-(+)-1,2-diaminocyclohexyl-N,N'-bis(2'-diphenylphosphobenzoyl), (S)-binaphthyl(3,5-dimethyl)phosphine, or (2S,4S)-(-)-2,4-bis(diphenylphospho)pentane.

[0019] Furthermore, the base is lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium carbonate, or potassium phosphate.

[0020] Furthermore, the reducing agent is a metal reducing agent, preferably zinc or manganese.

[0021] Furthermore, the carbon dioxide pressure is 0.5-5 atm, preferably 1 atm; and the solvent concentration is 0.05-1 M.

[0022] Furthermore, the solvent is N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, or acetonitrile.

[0023] Furthermore, the acidification reagent is dilute hydrochloric acid with a concentration of 2N.

[0024] In this invention, the synthetic reaction equation for oxidized indole-acetic acid compounds containing a 3-position chiral quaternary carbon center is as follows:

[0025]

[0026] The reaction principle is as follows Figure 1As shown. First, Ni(0)L* species I coordinated with a chiral ligand undergoes oxidative addition with an aryl (pseudo)halogenated compound to obtain Ar-Ni(II)L* species II. It may undergo Zn-mediated single-electron reduction to generate Ar-Ni(I)L* species III (path A), followed by enantioselective cyclization to obtain alkyl-Ni(I)L* intermediate IV. At the same time, Ar-Ni(II)L* species II may also undergo direct cyclization to obtain alkyl-Ni(II)L* intermediate V, which can be reduced by Zn to generate intermediate IV (path B). IV then undergoes nucleophilic attack on CO2 to obtain Ni(I)-carboxylate VI, which further undergoes reduction and transmetalation to generate carboxylate VII, and regenerates Ni(0)L*. VII is then treated with acid hydrolysis to obtain the desired product VIII.

[0027] The present invention has the following advantages:

[0028] 1. This invention provides a method for preparing oxidized indole-acetic acid compounds containing a 3-chiral quaternary carbon center. Based on the transition metal catalysis of a reduction system, CO2 participates in the carbon-carboxylation reaction of olefins, achieving for the first time the efficient construction of oxidized indole-acetic acid compounds containing a 3-chiral quaternary carbon center. Specifically, carbon dioxide is used as the carboxylic acid source, effectively avoiding the problem of using toxic CO gas or highly toxic cyano compounds as carboxyl sources in traditional preparation methods.

[0029] 2. This invention has a wide range of reaction substrates, good selectivity, good functional group compatibility, mild reaction conditions, and is easy to scale up and undergo subsequent derivatization and transformation. This invention overcomes the shortcomings of existing technologies, such as high reagent toxicity and harsh reaction conditions. The raw materials used are inexpensive and readily available, and it has good prospects for industrial application. Attached Figure Description

[0030] Figure 1 This is a schematic diagram illustrating the synthesis mechanism of the oxidized indole-acetic acid compounds containing a 3-position chiral quaternary carbon center according to the present invention. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention; that is, the described embodiments are merely some embodiments of the invention, and not all embodiments.

[0032] Therefore, the following detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0033] It should be noted that relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0034] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0035] Example 1

[0036] The synthesis of (R)-2-(1-benzyl-3-methyl-2-oxoindol-3-yl)acetic acid methyl ester 2a' from N-benzyl-N-(2-bromophenyl)methacrylamide 1a includes the following steps:

[0037] S1: In a glove box under N2 atmosphere, add nickel catalyst (0.010 mmol, 5 mol%), chiral ligand (0.030 mmol, 15 mol%), activated Zn powder (0.4 mmol, 2.0 equivalent), MgCl2 (0.4 mmol, 2.0 equivalent), and base (0.4 mmol, 2.0 equivalent) to a dry Schlenk tube (10 mL) containing a stir bar.

[0038] S2: After sealing the Schlenk tube, take it out of the glove box and connect it to the double-row tube connected to the CO2 cylinder. Loosen the cap and pump and replace the CO2 in the double-row tube 3 times to fill the tube with CO2 gas.

[0039] S3: Add solvent (4 mL) under CO2 atmosphere, then add N-benzyl-N-(2-bromophenyl)methacrylamide 1a (0.2 mmol) into the reaction tube, seal it and stir the reaction at room temperature for 48 h;

[0040] S4: Add MeI (0.8 mmol, 4.0 equivalent) to the reaction mixture and react at 65 °C for 4 h;

[0041] S5: Quench the reaction mixture with 15 mL of water and extract with EtOAc (about 10 mL, 3 times). Concentrate the combined organic phases under vacuum to obtain the crude product.

[0042] S6: The crude product was purified by rapid silica gel column chromatography (silica gel: 200-300 mm; eluent: PE:EA = 10:1) to obtain the desired pure product 2a'. Its chemical yield and optical rotation were calculated, and its enantiomeric purity was determined by normal-phase chiral HPLC.

[0043] The specific reaction conditions are shown in Table 1 below, and the reaction formulas are as follows:

[0044]

[0045] Table 1. Reaction conditions for N-benzyl-N-(2-bromophenyl)methacrylamide 1a

[0046]

[0047]

[0048] Note: In Table 1, NR represents no reaction; w / o represents no addition; Trace represents <1%; the structural formula of ligand L* is shown below:

[0049]

[0050]

[0051] As shown in Table 1, the reaction can proceed smoothly without the addition of magnesium chloride; the addition of magnesium chloride can further improve the yield of the product; magnesium chloride, as a Lewis acid, plays a role in activating CO2.

[0052] Example 2

[0053] The synthesis of oxyindole-acetic acid compounds containing a 3-position chiral quaternary carbon center from aryl bromides involves the following steps:

[0054] S1: In a glove box under N2 atmosphere, add Ni(COD)2 (0.015 mmol, 5 mol%) and (S)-1-(diphenylphosphino)-2-[(S)-4-isopropyloxazoline-2-yl]ferrocene ((S,S) p )- i Pr-FOXAP (0.045 mmol, 15 mol%), activated Zn powder (0.6 mmol, 2.0 equivalents), MgCl2 (0.6 mmol, 2.0 equivalents), LiO t Bu (0.6 mmol, 2.0 equivalent);

[0055] S2: After sealing the Schlenk tube, take it out of the glove box and connect it to the double-row tube connected to the CO2 cylinder. Loosen the cap and pump and replace the CO2 in the double-row tube 3 times to fill the tube with CO2 gas.

[0056] S3: Add 6 mL of ultra-dry solvent DMSO under a CO2 atmosphere, then add 0.3 mmol of reaction substrate 1 into the reaction tube, seal it, and stir at room temperature;

[0057] S4: After complete conversion (TLC monitoring), the reaction mixture was quenched with 5 mL of 2N HCl aqueous solution, washed with water (about 20 mL), and extracted with EtOAc (about 10 mL, 3 times). The combined organic phases were concentrated under vacuum to obtain the crude product.

[0058] S5: The crude product was purified by rapid silica gel column chromatography (silica gel: 200-300 mm; eluent: PE:EA = 4:1, containing 0.1% AcOH) to obtain the desired pure product 2. Its chemical yield and optical rotation were calculated.

[0059] S6: Treat the carboxylation product with a MeOH / Et2O solution of TMSCHN2 (v / v = 1:1). Perform normal-phase chiral HPLC on the esterified compound to determine its enantiomeric purity.

[0060] The specific reaction formulas, product structures, yields, and enantiomeric excess values ​​are as follows:

[0061]

[0062] Note: In the table above, b represents Ni(COD)2 (10 mol%), L4 (30 mol%); c represents NiBr2·DME (10 mol%), L4 (30 mol%).

[0063] Example 3

[0064] The synthesis of indole-acetic acid oxides containing a chiral quaternary carbon center at the 3-position from aryl trifluoromethanesulfonates follows the same steps as those for substrate 1, differing only in the starting materials. The specific reaction formulas, compound structures, yields, and enantiomeric excess values ​​are as follows:

[0065]

[0066] Example 4

[0067] The synthesis of oxyindole-acetic acid compounds containing a chiral quaternary carbon center at the 3-position from aryl chlorides follows the same steps as those for substrate 1, differing only in the starting materials. The specific reaction formulas, compound structures, yields, and enantiomeric excess values ​​are as follows:

[0068]

[0069] The products obtained in Examples 1-4 were characterized and analyzed in this invention. The characterization data results are consistent with the obtained products. Specific characterization data are as follows:

[0070] (R)-2-(1-Benzyl-3-methyl-2-oxoindol-3-yl)acetic acid (2a)

[0071] The structural formula is:

[0072]

[0073] Example 2: White solid, mass 93.8 mg, yield 88%, R f =0.2 (PE / EA = 1:2);

[0074] 1 H NMR(400MHz,Chloroform-d)δ7.25-7.14(m,5H),7.10(dd,J=7.3,1.2Hz,1H),7.05(td,J=7.7,1.3Hz,1H),6.92(td,J=7.6,1.0Hz,1H ),6.61(d,J=7.8Hz,1H),4.91(d,J=15.8Hz,1H),4.78(d,J=15.8Hz,1H),3.02(d,J=16.6Hz,1H),2.81(d,J=16.6Hz,1H),1.34(s,3H); 13 CNMR(101MHz,Chloroform-d)δ180.16,174.62,142.34,135.71,132.69,128.75 ,128.17,127.55,127.18,122.72,122.24,109.54,45.40,43.97,41.04,24.88;

[0075] HRMS(ESI+,m / z) for C 18 H 17 NO3[M+Na] + :Calcd.318.1101,Found:318.1099;

[0076] Enantiomeric excess=94%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =6.7min(major),t R = 18.5min (minor); [α] D 25 = +23.18° (c = 1.0, CHCl3);

[0077] Example 3: White solid, mass 51 mg, yield 57%, enantioselective excess = 93.5%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 85:15, flow rate 1.0 mL / min, T = 30 °C, λ = 210 nm):t R =6.8min(major),t R =19min (minor);

[0078] Example 4: White solid, mass 86 mg, yield 96%, enantioselective excess = 95%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 85:15, flow rate 1.0 mL / min, T = 30 °C, λ = 210 nm):t R =6.6min(major),t R = 17.6min (minor)

[0079] (R)-2-(1-(4-methoxybenzyl)-3-methyl-2-oxoindol-3-yl)acetic acid (2b)

[0080] The structural formula is:

[0081]

[0082] White solid, weighing 77 mg, yield 79%, R f =0.2 (PE / EA = 1:2);

[0083] 1H NMR(400MHz,Chloroform-d)δ7.25-7.18(m,2H),7.17-7.09(m,2H),6.97(td,J=7.5,1.0Hz,1H),6.85-6.77(m,2H),6.69(dt,J=7.8, 0.8Hz,1H),4.92(d,J=15.5Hz,1H),4.76(d,J=15.5Hz,1H),3.75(s,3H),3.06(d,J=16.7Hz,1H),2.85(d,J=16.7Hz,1H),1.38(s,3H); 13 CNMR(101MHz,Chloroform-d)δ180.06,174.78,158.92,142.31,132.64,128.55,12 8.10,127.73,122.61,122.16,114.08,109.52,55.22,45.32,43.39,40.99,24.79;

[0084] HRMS(ESI+,m / z) for C 19 H 19 NO4[M+Na] + :Calcd.348.1206,Found:348.1183;

[0085] Enantiomeric excess=94%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =9.8min(major),t R = 25.5min (minor); [α] D 25 = +22.08° (c = 1.0, CHCl3)

[0086] (R)-2-(3-methyl-2-oxo-1-(4-(trifluoromethyl)benzyl)indol-3-yl)acetic acid (2c)

[0087] The structural formula is:

[0088]

[0089] White solid, weighing 88 mg, yield 80%, R f =0.2 (PE / EA = 1:2);

[0090] 1 H NMR(400MHz,Chloroform-d)δ7.53(d,J=8.1Hz,2H),7.40(d,J=8.1Hz,2H),7.17-7.08(m,2H),6.98(td,J=7.5,1.0Hz,1H),6.6 0(d,J=7.7Hz,1H),5.14(d,J=16.1Hz,1H),4.76(d,J=16.1Hz,1H),3.12(d,J=17.0Hz,1H),2.88(d,J=17.0Hz,1H),1.38(s,3H); 13 C NMR(101MHz,Chloroform-d)δ179.92,175.22,142.02,139.82(d,J=1.5Hz),132.57,129.70(q,J=3 2.4Hz),128.15,127.49,125.67(q,J=3.8Hz),122.84,122.18,109.11,45.30,43.45,40.79,25.13; 19 F NMR(376MHz,Chloroform-d)δ-62.47;

[0091] HRMS(ESI+,m / z) for C 19 H 16 F3NO3[M+Na] + :Calcd.386.0974,Found:386.0974

[0092] Enantiomeric excess=94%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =6.7min(major),t R = 20.5min (minor); [α] D 25 = +12.46° (c = 1.0, CHCl3)

[0093] (R)-2-(1-(3-fluorobenzyl)-3-methyl-2-oxoindol-3-yl)acetic acid (2d)

[0094] The structural formula is:

[0095]

[0096] White solid, mass 65 mg, yield 69%, R f = 0.2 (PE / EA = 1:2);

[0097] 1 H NMR (400 MHz, Chloroform-d) (400 MHz, Chloroform-d) δ 7.28 - 7.20 (m, 1H), 7.19 - 7.11 (m, 2H), 7.07 (dt, J = 7.7, 1.2 Hz, 1H), 7.03 - 6.97 (m, 2H), 6.96 - 6.89 (m, 1H), 6.65 (d, J = 8.1 Hz, 1H), 4.98 (d, J = 16.0 Hz, 1H), 4.82 (d, J = 16.0 Hz, 1H), 3.09 (d, J = 16.7 Hz, 1H), 2.88 (d, J = 16.7 Hz, 1H), 1.40 (s, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 180.08, 174.76, 162.95 (d, J = 246.6 Hz), 142.10, 138.31 (d, J = 7.2 Hz), 132.65, 130.32 (d, J = 8.3 Hz), 128.12, 122.80, 122.69 (d, J = 2.8 Hz), 122.24, 114.47 (d, J = 21.0 Hz), 114.10 (d, J = 22.1 Hz), 109.28, 45.39, 43.42 (d, J = 1.9 Hz), 40.92, 25.01; 19 F NMR (376 MHz, Chloroform-d) δ -112.45;

[0098] HRMS (ESI+, m / z) for C 18 H 16 FNO3 [M+Na] + : Calcd. 336.1006, Found: 336.0992;

[0099] Enantiomeric excess = 92.5%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 90:10, flow rate 1.0 mL / min, T = 30 °C, λ = 210 nm): t R = 7.4 min (major), t R = 21.1 min (minor); [α]D 25 = +4.94° (c = 1.0, CHCl3)

[0100] (R)-2-(3-methyl-2-oxo-1-(4-(trifluoromethoxy)benzyl)indol-3-yl)acetic acid (2e)

[0101] The structural formula is:

[0102]

[0103] White solid, weighing 91 mg, yield 80%, R f =0.2 (PE / EA = 1:2);

[0104] 1 H NMR(400MHz,Chloroform-d)δ7.36-7.31(m,2H),7.15(ddt,J=11.1,8.1,1.6Hz,4H),7.00(td,J=8.0,1.0Hz,1H),6.66(d, J=7.7Hz,1H),5.08(d,J=15.9Hz,1H),4.75(d,J=15.9Hz,1H),3.12(d,J=16.9Hz,1H),2.89(d,J=17.0Hz,1H),1.40(s,3H); 13 CNMR(101MHz,Chloroform-d)δ179.98,174.98,148.55,142.16,134.50,132.67 ,128.64,128.19,122.83,122.21,121.19,109.21,45.32,43.21,40.85,25.07; 19 F NMR(376MHz,Chloroform-d)δ-57.81;

[0105] HRMS(ESI+,m / z) for C 19 H 16 F3NO4[M+H] + :Calcd.380.1104,Found:380.1103;

[0106] Enantiomeric excess=92%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R=6.2min(major),t R = 21.7min (minor); [α] D 25 = +21.43° (c = 1.0, CHCl3)

[0107] (R)-2-(1-(4-cyano-2-fluorobenzyl)-3-methyl-2-oxoindol-3-yl)acetic acid (2f)

[0108] The structural formula is:

[0109]

[0110] White solid, weighing 43 mg, yield 42%, R f =0.2 (PE / EA = 1:2);

[0111] 1 H NMR(400MHz,Chloroform-d)δ7.42-7.32(m,2H),7.26(dd,J=8.0,1.5Hz,1H),7.20-7.13(m,2H),7.03(td,J=7.5,1.0Hz,1H),6. 65(d,J=7.4Hz,1H),5.18(d,J=16.8Hz,1H),4.81(d,J=16.8Hz,1H),3.17(d,J=17.3Hz,1H),2.94(d,J=17.3Hz,1H),1.37(s,3H); 13 C NMR (101MHz, Chloroform-d) δ179.91, 175.54, 159.77 (d, J = 249.9Hz), 141.59, 132.44, 130.33 (d, J = 4.3Hz), 128.94 (d, J = 14.2Hz), 128.59 (d, J = 3.8Hz), 128.35,123.13,122.21,118.94(d,J=25.0Hz),117.49(d,J=2.8Hz),112.69 (d,J=9.5Hz),108.66(d,J=1.5Hz),45.28,40.73,37.03(d,J=5.0Hz),25.39; 19 F NMR(376MHz,Chloroform-d)δ-115.22;

[0112] HRMS(ESI+,m / z) for C 19 H 15 FN2O3[M+H] +:Calcd.339.1139,Found:339.1138;

[0113] Enantiomeric excess=92%, determined by HPLC (Daicel Chiralpak AD-HColumn, n-Hexane:i-PrOH=95:5, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =29.8min(major),t R = 31.7min (minor); [α] D 25 = +25.64° (c = 1.0, CHCl3)

[0114] (R)-2-(3-methyl-1-(naphth-1-ylmethyl)-2-oxoindol-3-yl)acetic acid (2g)

[0115] The structural formula is:

[0116]

[0117] White solid, 90 mg in mass, yield 87%, R f =0.2 (PE / EA = 1:2);

[0118] 1 H NMR (400MHz, Chloroform-d) δ8.10-8.01(m,1H),7.85(dd,J=8.1,1.5Hz,1H),7.75(dd,J=7.2,2. 2Hz,1H),7.52(dddd,J=14.8,8.1,6.9,1.5Hz,2H),7.39-7.28(m,2H),7.20(dd,J=7.2,1.2Hz,1H) ,7.08(td,J=7.7,1.3Hz,1H),6.99(td,J=7.5,1.0Hz,1H),6.64(dd,J=7.8,0.9Hz,1H),5.47(d,J= 16.4Hz,1H),5.34(d,J=16.4Hz,1H),3.16(d,J=16.6Hz,1H),2.93(d,J=16.6Hz,1H),1.46(s,3H); 13C NMR(101MHz,Chloroform-d)δ180.17,174.87,142.59,133.74,132.63,130.87,130.36,128.90,128.20 ,128.13,126.40,125.85,125.42,124.30,122.75,122.72,122.15,109.90,45.50,42.11,41.06,25.05;

[0119] HRMS(ESI+,m / z) for C 22 H 19 NO3[M+H] + :Calcd.346.1438,Found:346.1437;

[0120] Enantiomeric excess=94.5%, determined by HPLC (Daicel Chiralpak AD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =16.1min(major),t R = 19.3min (minor); [α] D 25 = +3.7° (c = 1.0, CHCl3)

[0121] (R)-2-(1,3-dimethyl-2-oxindol-3-yl)acetic acid (2h)

[0122] The structural formula is:

[0123]

[0124] Example 2: White solid, mass 44.7 mg, yield 68%, R f =0.1 (PE / EA = 1:2);

[0125] 1 H NMR(400MHz,Chloroform-d)δ7.27(td,J=7.7,1.3Hz,1H),7.18(dd,1H),7.05(td,J=7.5,1.0Hz,1H), 6.85(dd,J=7.8,0.9Hz,1H),3.21(s,3H),2.97(d,J=16.4Hz,1H),2.78(d,J=16.4Hz,1H),1.38(s,3H); 13C NMR (101MHz, Chloroform-d) δ180.45,173.45,142.99,132.66,128.35,122.90,122.31,108.49,45.24,41.34,26.50,23.87;

[0126] HRMS(ESI+,m / z) for C 12 H 13 NO3[M+H] + :Calcd.220.0968,Found:220.0967;

[0127] Enantiomeric excess=94.5%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =8.3min(major),t R = 15.4min (minor); [α] D 25 = +16.4° (c = 1.0, CHCl3)

[0128] Example 4: White solid, mass 55 mg, yield 83%, enantioselective excess = 94.5%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 90:10, flow rate 1.0 mL / min, T = 30 °C, λ = 210 nm):t R =8.3min(major),t R = 15.4min (minor)

[0129] (R)-2-(1-Ethyl-3-methyl-2-oxindol-3-yl)acetic acid (2i)

[0130] The structural formula is:

[0131]

[0132] A colorless, oily liquid, weighing 50 mg, with a yield of 71%, R f =0.2 (PE / EA = 1:2);

[0133] 1H NMR(400MHz,Chloroform-d)δ7.26(td,J=7.7,1.3Hz,1H),7.17(dd,J=7.4,1.2Hz,1H),7.03(td,J=7.5,1.0Hz,1H),6.85(d,J=7.8Hz,1H),3. 83(dq,J=14.5,7.3Hz,1H),3.67(dq,J=14.2,7.1Hz,1H),2.98(d,J=16.6Hz,1H),2.79(d,J=16.6Hz,1H),1.34(s,3H),1.21(t,J=7.2Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ179.85,174.30,142.22,132.95,128.16,122.48,122.36,108.49,45.17,41.26,34.73,24.10,12.05;

[0134] HRMS(ESI+,m / z) for C 13 H 15 NO3[M+Na] + :Calcd.256.0944,Found:256.0941;

[0135] Enantiomeric excess=93%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=95:5, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =9.1min(major),t R = 14.8min (minor); [α] D 25 = +9.00° (c = 1.0, CHCl3)

[0136] (R)-2-(3-methyl-1-(2-methylallyl)-2-oxindol-3-yl)acetic acid (2j)

[0137] The structural formula is:

[0138]

[0139] A colorless, oily liquid, weighing 57 mg, with a yield of 73%, R f =0.2 (PE / EA = 1:2);

[0140] 1H NMR(400MHz,Chloroform-d)δ7.23-7.13(m,2H),7.01(t,J=7.4Hz,1H),6.82(d,J=7.8Hz,1H),4.87(d ,J=8.0Hz,2H),4.24(s,2H),3.01(d,J=16.7Hz,1H),2.81(d,J=16.7Hz,1H),1.69(s,3H),1.36(s,3H); 13 C NMR (101MHz, Chloroform-d) δ180.02,174.56,142.52,139.06,132.60,128.11,122.65,122.13,112.56,109.45,46.02,45.25,40.98,24.80,19.87;

[0141] HRMS(ESI+,m / z) for C 15 H 17 NO3[M+H] + :Calcd.260.1281,Found:260.1281;

[0142] Enantiomeric excess=93.5%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =4.9min(major),t R = 11.7min (minor); [α] D 25 = +26.22° (c = 1.0, CHCl3)

[0143] (R)-2-(3-methyl-1-(3-methylbut-2-en-1-yl)-2-oxindol-3-yl)acetic acid (2k)

[0144] The structural formula is:

[0145]

[0146] A colorless, oily liquid, weighing 73 mg, with a yield of 89%, R f =0.2 (PE / EA = 1:2);

[0147] 1H NMR(400MHz,Chloroform-d)δ7.24(td,J=7.7,1.3Hz,1H),7.18(dd,J=7.4,1.2Hz,1H),7.03(td,J=7.5,1.0Hz,1H),6.80(d,J=7.8Hz,1H), 5.12(td,J=6.4,3.1Hz,1H),4.32(t,J=5.8Hz,2H),2.97(d,J=16.5Hz,1H),2.80(d,J=16.5Hz,1H),1.81(s,3H),1.71(s,3H),1.37(s,3H); 13 C NMR(101MHz,Chloroform-d)δ179.88,174.37,142.45,136.62,132.84,128.2 0,122.62,122.33,118.12,109.15,45.24,41.34,38.27,25.64,24.02,18.16;

[0148] HRMS(ESI+,m / z) for C 16 H 19 NO3[M+Na] + :Calcd.296.1257,Found:296.1253;

[0149] Enantiomeric excess=91%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =4.7min(major),t R = 12.5min (minor); [α] D 25 = +22.24° (c = 1.0, CHCl3)

[0150] (R)-2-(1-Cinnamyl-3-methyl-2-oxindol-3-yl)acetic acid (2l)

[0151] The structural formula is:

[0152]

[0153] A colorless, oily liquid, weighing 53 mg, with a yield of 55%, R f =0.2 (PE / EA = 1:2);

[0154] 1 H NMR(400MHz,Chloroform-d)δ7.35-7.25(m,4H),7.23-7.13(m,3H),7.01(td,J=7.5,1.0Hz,1H),6.88(d,J=7.8Hz,1H),6.64-6.56(m,1H),6.14(dt,J= 15.9,5.9Hz,1H),4.54(ddd,J=16.1,5.7,1.7Hz,1H),4.44(ddd,J=16.1,6. 2,1.6Hz,1H),3.01(d,J=16.6Hz,1H),2.81(d,J=16.6Hz,1H),1.38(s,3H);

[0155] 13 C NMR(101MHz,Chloroform-d)δ179.97,174.13,142.37,136.24,132.90,132.73,128.49 ,128.21,127.78,126.48,122.86,122.70,122.29,109.34,45.25,42.15,41.20,24.34;

[0156] HRMS(ESI+,m / z) for C 20 H 19 NO3[M+Na] + :Calcd.344.1257,Found:344.1256;

[0157] Enantiomeric excess=84.5%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =9.2min(major),t R = 11.8min (minor); [α] D 25 = +12.32° (c = 1.0, CHCl3)

[0158] (R)-2-(1-Benzyl-3-ethyl-2-oxoindol-3-yl)acetic acid (2m)

[0159] The structural formula is:

[0160]

[0161] A colorless, oily liquid, weighing 91 mg, with a yield of 98%, R f =0.2 (PE / EA = 1:2);

[0162] 1 H NMR(400MHz,Chloroform-d)δ7.34-7.20(m,5H),7.13(ddt,J=6.0,4.7,1.9Hz,2H),7.00(t,J=7.5Hz,1H),6.67(d,J=7.6Hz, 1H), 4.89 (q, 2H), 3.06 (d, J = 16.5Hz, 1H), 2.87 (d, J = 16.5Hz, 1H), 1.86 (ddt, J = 31.3, 13.5, 7.1Hz, 2H), 0.60 (t, J = 7.3Hz, 3H); 13 C NMR(101MHz,Chloroform-d)δ179.46,174.91,143.35,135.78,130.58,128.67,12 8.13,127.46,127.24,122.59,122.48,109.24,49.97,43.99,40.66,31.53,8.09;

[0163] HRMS(ESI+,m / z) for C 19 H 19 NO3[M+H] + :Calcd.310.1438,Found:310.1437;

[0164] Enantiomeric excess=92.5%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =6.4min(major),t R = 16.8min (minor); [α] D 25 = +27.88° (c = 1.0, CHCl3)

[0165] (R)-2-(1,3-bis(3-methylbut-2-en-1-yl)-2-oxoindol-3-yl)acetic acid (2n)

[0166] The structural formula is:

[0167]

[0168] A colorless, oily liquid with a mass of 94 mg and a yield of 95%, R f =0.2 (PE / EA = 1:2);

[0169] 1 H NMR(400MHz,Chloroform-d)δ7.20(td,J=7.7,1.2Hz,1H),7.12(dd,J=7.4,1.2Hz,1H),6.98(td,J=7 .5,0.9Hz,1H),6.74(d,J=7.8Hz,1H),5.04(tt,J=6.4,1.5Hz,1H),4.74(tt,1H),4.37(dd,J=15.5,6 .5Hz,1H),4.18(dd,J=15.6,6.6Hz,1H),2.97(d,J=16.5Hz,1H),2.80(d,J=16.5Hz,1H),2.42(d,J=7 .7Hz,1H),1.78(d,J=1.3Hz,3H),1.68(d,J=1.4Hz,3H),1.53(d,J=1.3Hz,3H),1.41(d,J=1.3Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ179.19,174.20,143.01,136.31,136.27,130.96,128.07,122. 78,122.24,118.35,116.61,108.75,49.50,39.92,38.12,36.17,25.78,25.61,18.09,17.91;

[0170] HRMS(ESI+,m / z) for C 20 H 25 NO3[M+Na] + :Calcd.350.1727,Found:350.1728;

[0171] Enantiomeric excess=93%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=95:5, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =5.8min(major),t R = 9.0min (minor); [α] D 25 = +21.48° (c = 1.0, CHCl3)

[0172] (R)-2-(1,3-Dibenzyl-2-oxindol-3-yl)acetic acid (2o)

[0173] The structural formula is:

[0174]

[0175] Example 2: White solid, mass 103 mg, yield 92%, R f =0.2 (PE / EA = 1:2);

[0176] 1 H NMR(400MHz,Chloroform-d)δ7.20(dd,J=7.1,1.5Hz,1H),7.17-7.11(m,4H),7.09-6.97(m,4H),6.78(ddd,J=9.8,7.8,1.7Hz,4H),6.36 (d,J=7.1Hz,1H),4.74(d,J=16.0Hz,1H),4.60(d,J=16.0Hz,1H),3.23(d,J=16.5Hz,1H),3.14(d,J=3.0Hz,2H),2.99(d,J=16.5Hz,1H); 13 C NMR(101MHz,Chloroform-d)δ178.55,174.66,143.23,135.22,134.58,130.12,129.81,128.52 ,128.34,127.79,127.10,126.85,126.61,123.06,122.31,109.39,51.20,43.82,43.73,40.84;

[0177] HRMS(ESI+,m / z) for C 24 H 21 NO3[M+H] + :Calcd.372.1594,Found:372.1594;

[0178] Enantiomeric excess=95%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =9.27min(major),t R = 11.4min (minor); [α]D 25 = -53.96° (c = 1.0, CHCl3)

[0179] Example 4: White solid, mass 100 mg, yield 90%, enantioselective excess = 95%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 90:10, flow rate 1.0 mL / min, T = 30℃, λ = 210 nm):t R =9.2min(major),t R = 11.3min (minor)

[0180] (R)-2-(1-benzyl-3-(3-fluorobenzyl)-2-oxoindol-3-yl)acetic acid (2p)

[0181]

[0182] White solid, 90 mg in mass, yield 77%, R f =0.2 (PE / EA = 1:2);

[0183] 1 H NMR(400MHz,Chloroform-d)δ7.20(dd,J=7.1,1.5Hz,1H),7.18-7.11(m,3H),7.09-6.94(m,3H),6.85-6.77(m,3H),6.57(dt,J=7.6,1.2 Hz,1H),6.45(dt,1H),6.38(dd,J=7.5,1.2Hz,1H),4.65(q,J=16.0Hz,2H),3.19(d,J=16.6Hz,1H),3.11(q,2H),2.98(d,J=16.6Hz,1H); 13 C NMR (101MHz, Chloroform-d) δ178.22, 174.33, 163.32, 160.88, 143.19, 137.01 (d, J = 7.3Hz), 135.16, 129.43, 129.18, 129.10, 128.59, 128. 54,127.24,126.65,125.84(d,J=2.8Hz),122.94,122.49,116.85(d,J=21.3Hz),113.81(d,J=20.9Hz),109.48,50.98,43.79,43.32,40.79; 19F NMR(376MHz,Chloroform-d)δ-113.65;

[0184] HRMS(ESI+,m / z) for C 24 H 20 FNO3[M+H] + :Calcd.390.1500,Found:390.1496;

[0185] Enantiomeric excess=91.5%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =8.9min(major),t R = 12.4min (minor); [α] D 25 = -34.2° (c = 0.6, CHCl3)

[0186] (R)-2-(1-benzyl-3-(naphth-1-ylmethyl)-2-oxindol-3-yl)acetic acid (2q)

[0187] The structural formula is:

[0188]

[0189] White solid, weighing 78 mg, yield 62%, R f =0.2 (PE / EA = 1:2);

[0190] 1 H NMR(400MHz,Chloroform-d)δ7.93-7.87(m,1H),7.76-7.72(m,1H),7.66(d,J=8.2Hz ,1H),7.34(tt,J=6.8,5.2Hz,2H),7.17-7.04(m,4H),7.01-6.92(m,3H),6.72-6.65(m ,2H),6.33(d,J=7.7Hz,1H),4.72(d,J=15.9Hz,1H),4.52(d,J=15.9Hz,1H),3.67(d,J =13.7Hz,1H),3.57(d,J=13.7Hz,1H),3.34(d,J=16.6Hz,1H),3.03(d,J=16.6Hz,1H); 13C NMR(101MHz,Chloroform-d)δ179.28,173.88,142.97,135.18,133.58,132.31,131.01,129.94,128.89,128.49,128.30 ,128.28,127.79,127.17,126.65,125.57,125.43,124.64,124.33,123.71,122.15,109.27,50.96,43.85,40.60,38.99;

[0191] HRMS(ESI+,m / z) for C 28 H 23 NO3[M+H] + :Calcd.422.1751,Found:422.1751;

[0192] Enantiomeric excess=90%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=95:5, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =23.4min(major),t R = 28.6min (minor); [α] D 25 = -84.12° (c = 1.0, CHCl3)

[0193] (R)-2-(1-benzyl-3-((((tert-butyldimethylsilyl)oxy)methyl)-2-oxindol-3-yl)acetic acid(2r)

[0194] The structural formula is:

[0195]

[0196] Yellow liquid, mass 100 mg, yield 78%, R f =0.2 (PE / EA = 1:2);

[0197] 1H NMR (400MHz, Chloroform-d) δ7.32-7.19(m,6H),7.14-7.08(m,1H),6.96(t,J=7.5Hz,1H),6.62(d,J=7.8Hz,1H),4.99(d,J=15.9H z,1H),4.80(d,J=15.9Hz,1H),3.84(d,J=9.3Hz,1H),3.69(d,J=9.3Hz,1H),3.06(s,2H),0.76(s,9H),-0.09(s,3H),-0.15(s,3H); 13 C NMR(101MHz,Chloroform-d)δ177.65,175.49,143.39,135.68,129.86,128.65,128.22,127. 38,127.09,123.39,122.21,109.14,68.05,51.84,43.93,36.82,25.65,18.13,-5.61,-5.80;

[0198] HRMS(ESI+,m / z) for C 24 H 31 NO4Si[M+Na] + :Calcd.448.1915,Found:448.1911;

[0199] Enantiomeric excess=89.5%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =4.9min(major),t R = 5.4min (minor); [α] D 25 = -27.00° (c = 1.0, CHCl3)

[0200] (R)-2-(1-Benzyl-3-(3-Methoxypropyl)-2-oxoindol-3-yl)acetic acid (2s)

[0201] The structural formula is:

[0202]

[0203] White solid, mass 92 mg, yield 86%, R f =0.2 (PE / EA = 1:2);

[0204] 1 H NMR(400MHz,Chloroform-d)δ7.33-7.19(m,5H),7.17-7.07(m,2H),6.97(td,J=7.5,1.0Hz,1H),6.65(d,J=7.7Hz,1H),4.95(d,J=15.7Hz,1H),4.8 1(d,J=15.7Hz,1H),3.18(d,J=2.2Hz,5H),3.04(d,J=16.5Hz,1H),2.86(d ,J=16.5Hz,1H),1.95-1.74(m,2H),1.36-1.24(m,1H),1.18-1.03(m,1H); 13 C NMR(101MHz,Chloroform-d)δ179.33,174.32,143.19,135.73,130.66,128.67,128.22,1 27.48,127.26,122.70,122.54,109.29,71.99,58.32,49.17,44.02,40.86,34.96,23.65;

[0205] HRMS(ESI+,m / z) for C 21 H 23 NO4[M+Na] + :Calcd.376.1520,Found:370.1521;

[0206] Enantiomeric excess=92.5%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =7.6min(major),t R = 9.3min (minor); [α] D 25 = +26.68° (c = 1.75, CHCl3)

[0207] (R)-2-(3-benzyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e]indol-1-yl)acetic acid (2t)

[0208] The structural formula is:

[0209]

[0210] White solid, 90 mg by mass, yield 87%, R f =0.2 (PE / EA = 1:2);

[0211] 1 H NMR(400MHz,Chloroform-d)δ7.77(dd,J=8.1,5.1Hz,2H),7.66(d,J=8.6Hz,1H),7.49-7.44(m,1H),7.31-7 .19(m,6H),6.96(d,J=8.7Hz,1H),5.06(d,J=16.0Hz,1H),4.92(d,J=16.0Hz,1H),3.33(q,2H),1.61(s,3H); 13 C NMR(101MHz,Chloroform-d)δ181.13,174.55,140.27,135.82,130.48,129.80,129.43,128.92 ,128.72,127.47,127.22,126.99,123.71,123.56,121.31,110.69,47.00,43.99,41.25,24.37;

[0212] HRMS(ESI+,m / z) for C 22 H 19 NO3[M+H] + :Calcd.346.1438,Found:346.1439;

[0213] Enantiomeric excess>99.8%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=254nm): t R = 14.28 min (major); [α] D 25 = +7.80° (c = 0.4, CHCl3)

[0214] (R)-2-(1-Benzyl-3,5-dimethyl-2-oxindol-3-yl)acetic acid (2u)

[0215] The structural formula is:

[0216]

[0217] Example 2: White solid, mass 62 mg, yield 67%, R f =0.2 (PE / EA = 1:2);

[0218] 1 H NMR(400MHz,Chloroform-d)δ7.30-7.22(m,5H),7.00(d,J=1.6Hz,1H),6.93(dt,J=8.1,1.3Hz,1H),6.57(d,J=7.9Hz,1H) ,4.97(d,J=15.8Hz,1H),4.84(d,J=15.8Hz,1H),3.09(d,J=16.7Hz,1H),2.87(d,J=16.7Hz,1H),2.28(s,3H),1.42(s,3H); 13 CNMR(101MHz,Chloroform-d)δ180.21,174.36,139.80,135.73,132.73,132.31,12 8.68,128.42,127.45,127.12,123.00,109.26,45.36,43.93,41.05,24.89,21.11;

[0219] HRMS(ESI+,m / z) for C 19 H 19 NO3[M+Na] + :Calcd.310.1438,Found:310.1438;

[0220] Enantiomeric excess=92%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =6.2min(major),t R = 13.6min (minor); [α] D 25 = +33.34° (c = 1.0, CHCl3)

[0221] Example 3: White solid, mass 43 mg, yield 46%, enantioselective excess = 93.5%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 85:15, flow rate 1.0 mL / min, T = 30 °C, λ = 210 nm):t R =6.4min(major),t R = 14.6min (minor)

[0222] Example 4: White solid, mass 90 mg, yield 97%, enantioselective excess = 94%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 90:10, flow rate 1.0 mL / min, T = 30 °C, λ = 210 nm):t R =6.4min(major),t R = 14.4min (minor)

[0223] (R)-2-(1-Benzyl-3,6-dimethyl-2-oxindol-3-yl)acetic acid (2v)

[0224] The structural formula is:

[0225]

[0226] Example 2: White solid, mass 73 mg, yield 78%, R f =0.2 (PE / EA = 1:2);

[0227] 1 H NMR(400MHz,Chloroform-d)δ7.33-7.20(m,5H),7.05(d,J=7.5Hz,1H),6.80(d,J=7.4Hz,1H),6.50(d,J=1.4Hz,1H),4. 95(d,J=15.8Hz,1H),4.83(d,J=15.8Hz,1H),3.05(d,J=16.6Hz,1H),2.85(d,J=16.6Hz,1H),2.24(s,3H),1.38(s,3H); 13C NMR(101MHz,Chloroform-d)δ180.49,174.91,142.41,138.22,135.84,129.74,12 8.70,127.43,127.05,123.27,121.96,110.30,45.17,43.84,41.12,24.94,21.78;

[0228] HRMS(ESI+,m / z) for C 19 H 19 NO3[M+Na] + :Calcd.310.1438,Found:310.1436;

[0229] Enantiomeric excess=90%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =7.2min(major),t R = 19.8min (minor); [α] D 25 = +15.88° (c = 1.0, CHCl3)

[0230] Example 3: White solid, mass 49.5 mg, yield 53%, R f =0.2 (PE / EA=1:2), Enantioselective excess=90%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =7.6min(major),t R = 21.5min (minor)

[0231] Example 4: White solid, mass 86 mg, yield 93%, enantioselective excess = 94.5%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 90:10, flow rate 1.0 mL / min, T = 30 °C, λ = 210 nm):t R=7.5min (major),t R =21min (minor)

[0232] (R)-2-(1-Benzyl-3,7-dimethyl-2-oxindol-3-yl)acetic acid (2w)

[0233] The structural formula is:

[0234]

[0235] Example 2: White solid, mass 71 mg, yield 76%, R f =0.2 (PE / EA = 1:2);

[0236] 1 H NMR(400MHz,Chloroform-d)δ7.32-7.17(m,5H),7.06(dd,J=6.4,2.3Hz,1H),6.99-6.91(m,2H), 5.19(q,J=17.0Hz,2H),3.12(d,J=16.7Hz,1H),2.89(d,J=16.7Hz,1H),2.25(s,3H),1.44(s,3H); 13 C NMR(101MHz,Chloroform-d)δ181.32,174.27,140.31,137.71,133.49,132.18,128.79,127. 09,125.63,122.89,120.15,120.02,45.17,44.68,41.23,25.52,18.70; HRMS(ESI+,m / z)for C 19 H 19 NO3[M+Na] + :Calcd.310.1438,Found:310.1438;

[0237] Enantiomeric excess=85%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =6.8min(major),t R = 14.6min (minor); [α] D 25 = +14.02° (c = 1.0, CHCl3)

[0238] Example 4: White solid, mass 70 mg, yield 75%, enantioselective excess = 86%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 90:10, flow rate 1.0 mL / min, T = 30 °C, λ = 210 nm):t R =6.7min(major),t R = 14.2min (minor)

[0239] (R)-2-(1-Benzyl-7-fluoro-3-methyl-2-oxindol-3-yl)acetic acid (2x)

[0240] The structural formula is:

[0241]

[0242] A colorless, oily liquid, weighing 72 mg, with a yield of 76%, R f =0.2 (PE / EA = 1:2);

[0243] 1 H NMR (400MHz, Chloroform-d) δ7.44-7.17(m,5H),7.03-6.76(m,3H),5.15-4.91(m,2H),3.10(d,J=16.9Hz,1H),2.88(d,J=16.9Hz,1H),1.39(s,3H); 13 C NMR(101MHz,Chloroform-d)δ177.23(d,J=485.3Hz),147.49(d,J=244.6Hz),137.03,135.70(d,J=3.1Hz),129.01(d,J=8.5Hz),128.45,127 .36,127.24(d,J=1.5Hz),123.39(d,J=6.4Hz),117.96(d,J=3.1Hz),116.49,116.29,45.68(d,J=1.9Hz),45.39(d,J=4.6Hz),40.93,25.17; 19 F NMR(376MHz,Chloroform-d)δ-133.60;

[0244] HRMS(ESI+,m / z) for C 18 H 16 FNO3[M+H] +:Calcd.314.1187,Found:314.1188;

[0245] Enantiomeric excess=85.5%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =6.9min(major),t R = 30.2min (minor); [α] D 25 = +8.84° (c = 1.0, CHCl3)

[0246] (R)-2-(1-Benzyl-5-methoxy-3-methyl-2-oxindol-3-yl)acetic acid (2y)

[0247] The structural formula is:

[0248]

[0249] A colorless, oily liquid, weighing 80 mg, with a yield of 82%, R f =0.2 (PE / EA = 1:2);

[0250] 1 H NMR(400MHz,Chloroform-d)δ7.35-7.17(m,5H),6.81(d,J=2.4Hz,1H),6.65(ddd,J=8.4,2.5,1.0Hz,1H),6.58(dd,J=8.5,1.5Hz,1 H),4.97(d,J=15.7Hz,1H),4.84(dd,J=15.7,1.8Hz,1H),3.73(s,3H),3.09(d,J=16.7Hz,1H),2.87(d,J=16.7Hz,1H),1.43(s,3H); 13 C NMR(101MHz,Chloroform-d)δ179.96,174.08,156.05,135.68,135.57,134.10,128. 70,127.50,127.13,112.12,109.88(d,J=1.1Hz),55.66,45.72,44.01,41.03,24.79;

[0251] HRMS(ESI+,m / z) for C 19 H 19NO4[M+H] + :Calcd.326.1387,Found:326.1389;

[0252] Enantiomeric excess=90%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =8.1min(major),t R = 20.6min (minor); [α] D 25 = +32.98° (c = 1.0, CHCl3)

[0253] (R)-2-(5-methoxy-1,3-dimethyl-2-oxindol-3-yl)acetic acid (2z)

[0254] The structural formula is:

[0255]

[0256] Example 2: White solid, mass 56 mg, yield 75%, R f =0.2(EA);

[0257] 1 H NMR(400MHz,Chloroform-d)δ6.79(d,J=2.4Hz,1H),6.78-6.74(m,1H),6.72(d,J=8.3Hz,1 H),3.75(s,3H),3.15(s,3H),2.93(d,J=16.5Hz,1H),2.75(d,J=16.5Hz,1H),1.32(s,3H); 13 C NMR (101MHz, Chloroform-d) δ180.05,173.75,156.10,136.56,134.14,112.18,110.03,108.72,55.72,45.71,41.24,26.55,23.99;

[0258] HRMS(ESI+,m / z) for C 13 H 15 NO4[M+H] + :Calcd.250.1074,Found:250.1072;

[0259] Enantiomeric excess=90%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =10.9min(major),t R = 17.8min (minor); [α] D 25 = +29.44° (c = 1.0, CHCl3)

[0260] Example 4: A colorless oily liquid, mass 49 mg, yield 65%, enantioselective excess = 92%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 90:10, flow rate 1.0 mL / min, T = 30℃, λ = 210 nm):t R =11min(minor),t R = 18min (major)

[0261] (R)-2-(1-Benzyl-6-methoxy-3-methyl-2-oxindol-3-yl)acetic acid (2aa)

[0262] The structural formula is:

[0263]

[0264] Example 2: A colorless oily liquid, weighing 69 mg, with a yield of 71%, R f =0.2 (PE / EA = 1:2);

[0265] 1 H NMR(400MHz,Chloroform-d)δ7.41-7.16(m,5H),7.06(d,J=8.2Hz,1H),6.48(dd,J=8.2,2.2Hz,1H),6.26(d,J=2.2Hz,1H) ,4.94(d,J=15.8Hz,1H),4.80(d,J=15.8Hz,1H),3.68(s,3H),3.04(d,J=16.5Hz,1H),2.84(d,J=16.5Hz,1H),1.38(s,3H); 13CNMR(101MHz,Chloroform-d)δ180.66,174.85,159.90,143.55,135.63,128.72,1 27.51,127.16,124.61,122.80,106.21,97.72,55.34,44.92,43.95,41.22,24.99;

[0266] HRMS(ESI+,m / z) for C 19 H 19 NO4[M+H] + :Calcd.326.1387,Found:326.1389;

[0267] Enantiomeric excess=92.5%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =9.7min(major),t R = 26.6min (minor); [α] D 25 = +17.50° (c = 1.0, CHCl3)

[0268] Example 3: A colorless oily liquid, with a mass of 42 mg, yield of 43%, and enantioselective excess of 92%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 90:10, flow rate 1.0 mL / min, T = 30℃, λ = 210 nm):t R =10.1min(major),t R = 28.4min (minor)

[0269] Example 4: A colorless oily liquid, with a mass of 78 mg, yield of 80%, enantioselective excess of 93.5%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH = 90:10, flow rate 1.0 mL / min, T = 30 °C, λ = 210 nm):t R =9.9min(major),tR = 27.7min (minor)

[0270] (R)-2-(1-Benzyl-3-methyl-2-oxo-5-(trifluoromethoxy)indol-3-yl)acetic acid (2ab)

[0271] The structural formula is:

[0272]

[0273] White solid, weighing 67 mg, yield 59%, R f =0.2 (PE / EA = 1:2);

[0274] 1 H NMR(400MHz,Chloroform-d)δ7.37-7.24(m,5H),7.08(d,J=2.3Hz,1H),7.00(dd,J=8.4,2.3Hz,1H),6.65(d,J=8.5H z,1H),4.98(d,J=15.8Hz,1H),4.84(d,J=15.8Hz,1H),3.12(d,J=17.0Hz,1H),2.90(d,J=17.0Hz,1H),1.42(s,3H); 13 C NMR(101MHz,Chloroform-d)δ179.68,174.39,144.72,141.02,135.21,134.18 ,128.81,127.70,127.13,121.14,116.26,109.81,45.65,44.07,40.71,24.74; 19 F NMR(376MHz,Chloroform-d)δ-58.30;

[0275] HRMS(ESI+,m / z) for C 19 H 16 F3NO4[M+H] + :Calcd.380.1104,Found:380.1103;

[0276] Enantiomeric excess=85%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =5.6min(major),t R= 16.7min (minor); [α] D 25 = +8.38° (c = 1.0, CHCl3)

[0277] (R)-2-(6-benzyl-8-methyl-7-oxo-2,3,7,8-tetrahydro-6H-[1,4]dioxa[2,3-f]indol-8-yl)acetic acid (2ac)

[0278] The structural formula is:

[0279]

[0280] White solid, mass 92 mg, yield 86%, R f =0.2 (PE / EA = 1:2);

[0281] 1 H NMR(400MHz,Chloroform-d)δ7.33-7.18(m,5H),6.72(s,1H),6.22(s,1H),4.89(d,J=15.7Hz,1H) ,4.76(d,J=15.7Hz,1H),4.15(s,4H),3.02(d,J=16.6Hz,1H),2.80(d,J=16.6Hz,1H),1.37(s,3H); 13 C NMR(101MHz,Chloroform-d)δ180.20,174.34,143.11,139.28,136.13,135.63,12 8.72,127.52,127.19,125.22,112.06,99.58,64.44,64.03,45.25,44.04,24.95;

[0282] HRMS(ESI+,m / z) for C 20 H 19 NO5[M+Na] + :Calcd.376.1156,Found:376.1150;

[0283] Enantiomeric excess=92%, determined by HPLC (Daicel Chiralpak OD-HColumn, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30°C, λ=210nm): t R =13.8min(major),t R= 40.1min (minor); [α] D 25 = +28.44° (c = 1.0, CHCl3)

[0284] (R,E)-2-(1-(3,6-dimethylhept-2,5-dien-1-yl)-3-methyl-2-oxindol-3-yl)acetic acid (5c)

[0285] The structural formula is:

[0286]

[0287] A colorless oily liquid with a mass of 87 mg and a yield of 89%, Rf = 0.2 (PE / EA = 1:2);

[0288] 1 H NMR (400MHz, Chloroform-d) δ7.26-7.12(m,2H),7.00(t,J=7.5Hz,1H),6.77(d,J=7.8Hz,1H),5.10(t,J=6.8Hz,1H),5.00(t,J=6.8Hz,1H),4.32(t, J=5.9Hz,2H),2.95(d,J=16.6Hz,1H),2.78(d,J=16.6Hz,1H),2.01(dq,J= 16.0,9.0,8.3Hz,2H),1.78(s,3H),1.60(s,3H),1.54(s,3H),1.34(s,3H); 13 C NMR(101MHz,Chloroform-d)δ179.73,174.74,142.48,139.88,132.78,131.64,128.10,123.79, 122.49,122.29,118.14,109.18,45.25,41.22,39.37,38.22,26.20,25.69,24.04,17.71,16.47;

[0289] HRMS(ESI+,m / z) for C 20 H 25 NO3[M+Na] + :Calcd.328.1908,Found:328.1907;

[0290] Enantioselective excess=94%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =4.3min(major),t R = 8.3min (minor); [α] D 25 = +19.54° (c = 1.0, CHCl3)

[0291] (R)-2-(1-Benzyl-6-fluoro-3-methyl-2-oxindol-3-yl)acetic acid (5i)

[0292] The structural formula is:

[0293]

[0294] A colorless, oily liquid, weighing 82 mg, with a yield of 87%, R f =0.2 (PE / EA = 1:2);

[0295] 1 H NMR (400MHz, Chloroform-d) δ7.33-7.21 (m, 5H), 7.10 (dd, J=8.2, 5.2Hz, 1H), 6.67 (ddd, J=9.5, 8.2, 2.3Hz, 1H), 6.41 (dd, J= 8.9,2.3Hz,1H),4.96(d,J=15.8Hz,1H),4.80(d,J=15.8Hz,1H),3.10(d,J=16.8Hz,1H),2.88(d,J=16.8Hz,1H),1.39(s,3H); 13 CNMR(101MHz,Chloroform-d)δ180.22,174.97,162.73(d,J=244.7Hz),143.88(d,J=11.7Hz),135.18,128.81,127.91(d, J=2.9Hz),127.68,127.12,123.09(d,J=9.9Hz),108.68(d,J=22.5Hz),98.31(d,J=27.6Hz),45.01,44.06,40.95,25.02; 19 F NMR(376MHz,Chloroform-d)δ-112.00;

[0296] HRMS(ESI+,m / z) for C 18 H 16 FNO3[M+H] + :Calcd.314.1187,Found:314.1191;

[0297] Enantioselective excess=91%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =6.5min (major),t R = 17.7min (minor); [α] D 25 = +9.98° (c = 1.0, CHCl3)

[0298] (R)-2-(1-Benzyl-3-methyl-2-oxo-6-(trifluoromethyl)indol-3-yl)acetic acid (5j)

[0299] The structural formula is:

[0300]

[0301] A colorless, oily liquid with a mass of 74.5 mg and a yield of 68%;

[0302] 1 H NMR(400MHz,Chloroform-d)δ7.41-7.17(m,7H),6.88(s,1H),5.00(d,J=15.8Hz,1H) ,4.86(d,J=15.8Hz,1H),3.14(d,J=17.1Hz,1H),2.93(d,J=17.1Hz,1H),1.40(s,3H); 13 C NMR(101MHz,Chloroform-d)δ179.65,174.80,143.13,136.64(d,J=1.5Hz),134.98,130.52(q,J=32.4Hz),12 8.84,127.76,127.10,125.13,122.30,119.78(t,J=4.0Hz),105.96(q,J=3.8Hz),45.35,44.05,40.59,24.83; 19 F NMR(376MHz,Chloroform-d)δ-62.41;

[0303] HRMS(ESI+,m / z) for C 19 H 16 F3NO3[M+H] + :Calcd.386.0975,Found:386.0971;

[0304] Enantioselective excess=84.5%, determined by HPLC (Daicel ChiralpakOD-H Column, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =7.3min(major),t R = 23.7min (minor); [α] D 25 = +3.6° (c = 1.0, CHCl3)

[0305] (R)-2-(1-Benzyl-4-methoxy-3-methyl-2-oxindol-3-yl)acetic acid (5k)

[0306] The structural formula is:

[0307]

[0308] A colorless, oily liquid with a mass of 72.5 mg and a yield of 74%;

[0309] 1 H NMR(400MHz,Chloroform-d)δ7.30-7.18(m,5H),7.06(t,J=8.1Hz,1H),6.52(d,J=8.3Hz,1H),6.31(d,J=7.8Hz,1H),4. 96(d,J=15.8Hz,1H),4.80(d,J=15.8Hz,1H),3.77(s,3H),3.24(d,J=16.6Hz,1H),3.07(d,J=16.6Hz,1H),1.44(s,3H); 13 C NMR(101MHz,Chloroform-d)δ180.42,175.72,155.65,143.66,135.94,129.17,12 8.64,127.35,127.05,117.98,105.74,102.86,55.36,45.59,44.02,39.43,22.59;

[0310] HRMS(ESI+,m / z) for C 19 H 19 NO4[M+H] + :Calcd.348.1207,Found:348.1203;

[0311] Enantioselective excess=80%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH=85:15, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =6.8min(major),t R =21min (minor); [α] D 25 = +29.44° (c = 1.0, CHCl3)

[0312] (R)-2-(1,3-Dibenzyl-6-methoxy-2-oxindol-3-yl)acetic acid (5m)

[0313] The structural formula is:

[0314]

[0315] White solid, weighing 109 mg, yield 90%, R f =0.2 (PE / EA = 1:2);

[0316] 1 H NMR(400MHz,Chloroform-d)δ7.17-7.09(m,4H),7.06(td,J=8.2,1.9Hz,3H),6.83-6.78(m,2H),6.74(dd,J=7.4,2.1Hz,2H),6.49(dd,J=8.2,2.3Hz, 1H),5.94(d,J=2.3Hz,1H),4.71(d,J=16.1Hz,1H),4.55(d,J=16.1Hz,1H) ,3.62(s,3H),3.18(d,J=16.4Hz,1H),3.08(s,2H),2.95(d,J=16.4Hz,1H); 13C NMR(101MHz,Chloroform-d)δ179.06,174.85,159.97,144.45,135.15,134.77,130.18,128.54,12 7.84,127.12,126.80,126.64,123.71,121.61,106.08,97.42,55.23,50.70,43.83,43.78,41.06;

[0317] HRMS(ESI+,m / z) for C 25 H 23 NO4[M+H] + :Calcd.424.1520,Found:424.1522;

[0318] Enantioselective excess=94%, determined by HPLC (Daicel Chiralpak OD-H Column, n-Hexane:i-PrOH=90:10, flow rate 1.0mL / min, T=30℃, λ=210nm): t R =8.5min (major),t R = 10.1min (minor); [α] D 25 = -54.48° (c = 1.0, CHCl3)

[0319] The above content is merely an example and illustration of the structure of the present invention. Any modifications or additions to the specific embodiments described, or substitutions made by those skilled in the art without creative effort, shall still fall within the scope of protection of this patent.

Claims

1. A method for preparing an indole-acetic acid compound containing a chiral quaternary carbon center at the 3-position, characterized in that, Includes the following steps: The catalyst, ligand, base, and reducing agent were added to a reaction vessel, and then the reaction substrate and solvent were added under a CO2 atmosphere. The reaction was stirred at room temperature for 0.1–96 h, followed by acidification. The reaction products were then separated and purified to obtain indole-acetic acid compounds containing a chiral quaternary carbon center at the 3-position. The molar ratio of the reaction substrate, catalyst, ligand, base, and reducing agent was 1:0.001–0.30:0.002–0.60:1–4:1–4. The reaction substrate is an amide-bridged aryl (pseudo)halogenated compound, with the following general structural formula: Wherein, X is a chlorine, bromine, or trifluoromethanesulfonate group; R 1 and R 2 All are alkyl groups; The catalyst is nickel ethylene glycol dimethyl ether bromide, nickel ethylene glycol dimethyl ether chloride, nickel acetylacetone, or bis-(1,5-cyclooctadiene) nickel; The ligand is , , , , , ; The solvent is N,N -Dimethylformamide, dimethyl sulfoxide; The alkali is lithium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium carbonate, or potassium phosphate; The reducing agent is zinc or manganese.

2. The method for preparing the indole-acetic acid compound containing a chiral quaternary carbon center at the 3-position as described in claim 1, characterized in that, The molar ratio of the reaction substrate, catalyst, ligand, base and reducing agent is 1:0.05~0.15:0.15~0.30:2:2, and the reaction time is 48~96 h.

3. The method for preparing oxidized indole-acetic acid compounds containing a 3-position chiral quaternary carbon center as described in claim 1, characterized in that, When adding the catalyst, ligand, base, and reducing agent to the reaction vessel, magnesium chloride is added at the same time; wherein the molar ratio of magnesium chloride to the reaction substrate is 1~4:1.

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