阅读说明：本技术 一种氮杂环卡宾催化的含吲哚骨架手性螺环化合物的制备方法及用途 (preparation method and application of chiral spiro compound containing indole skeleton and catalyzed by N-heterocyclic carbene ) 是由 池永贵 刘雍贵 蒋仕春 金智超 于 2019-09-16 设计创作，主要内容包括：本发明涉及氮杂环卡宾有极小分子催化高对映选择性合成含吲哚骨架螺环化合物(R)-1-芳基-1’H-螺[二氢吲哚-3,3’-恶唑并[3,4-α]吲哚]-1’,2二酮衍生物的制备方法及良好的生物活性用途。结构通式如下：<Image he="292" wi="405" file="DDA0002202821980000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中R<Sup>1</Sup>是吲哚-2-甲醛的取代基,R<Sup>2</Sup>是吲哚-2,3-二酮的取代基,R<Sup>3</Sup>是吲哚-2,3-二酮的不同保护基,甲基,苄基,三苯基甲基。本发明公开的吲哚-2-甲醛和吲哚-2,3-二酮的不对称环化反应制备吲哚骨架手性螺环化合物(R)-1-芳基-1’H-螺[二氢吲哚-3,3’-恶唑并[3,4-α]吲哚]-1’,2二酮衍生物,其衍生物普适性好,具有优异的产率高达98％、对映选择性高达99％和良好的生物活性。(The invention relates to a preparation method of azacyclo-carbene which has a very small molecular catalysis and high enantioselectivity for synthesizing spiro compound (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ] indole ] -1',2 dione derivatives containing indole skeleton and good bioactivity application, wherein the structural general formula is as follows: , wherein R 1 is a substituent of indole-2-formaldehyde, R 2 is a substituent of indole-2, 3-dione, R 3 is different protecting groups of indole-2, 3-dione, methyl, benzyl and triphenylmethyl.)

1. A chiral indole skeleton spiro compound (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ] indole ] -1',2 dione derivative is represented by the following general formula (1):

Wherein the carbon atom marked by is a chiral carbon atom, R¹Is a halogen atom, methyl, methoxy or 5, 7-dichloro), R²Is a halogen atom, methyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, 4-bromo-5-methyl, 4, 7-dichloro, 4, 6-difluoro or 5, 6-difluoro), R³Is methyl, benzyl or triphenylmethyl.

2. The chiral indole skeleton spiro compound (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ] indole ] -1',2 dione derivative according to claim 1, which is characterized in that: the halogen atom is fluorine, chlorine, bromine, or iodine.

3. a process for the preparation of chiral indole skeleton spiro compound (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3,4- α ] indole ] -1',2 dione derivative according to claim 1, comprising the steps of:

(1) Reacting substituted indole-2-formaldehyde with a chiral carbene catalyst to obtain a Breslow intermediate I, oxidizing the intermediate into an acylazolium intermediate in the presence of an oxidant, and using tetrahydrofuran as a reaction solvent;

(2) Deprotonating N-H in the intermediate molecule obtained in the step (1) under the condition of N, N-diisopropylethylamine DIEA, losing one proton H to generate an intermediate II, forming an azafulvene intermediate III, having nucleophilicity, and reacting at the temperature of 10 ℃ in a solvent of tetrahydrofuran;

(3) Carrying out [3+2] cyclization reaction on the nucleophilic azafulvene intermediate and electrophilic body substituted indole-2, 3-diketone, leaving a carbene catalyst, participating in the next cycle process, and continuously catalyzing to generate a chiral spiro-structured compound (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ] indole ] -1', 2-diketone derivative, wherein the reaction solvent is tetrahydrofuran;

The reaction general formula and the process are as follows:

4. A preparation method of chiral indole skeleton spiro compound (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ] indole ] -1',2 dione derivative according to claim 1, which is characterized by comprising the following steps: the synthetic route of the reaction substrate indole-2-formaldehyde is as follows: dissolving substituted indole-2-ethyl formate S1 in tetrahydrofuran, slowly adding lithium aluminum hydride powder in an ice water bath, monitoring the reaction, slowly adding ethyl acetate and ice water after TLC monitoring reaction is finished, quenching the reaction, carrying out suction filtration, extracting ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, and carrying out spin drying to obtain a product S2 which is directly subjected to the next step; dissolving S2 in appropriate amount of dichloromethane, adding manganese dioxide, heating and refluxing, monitoring reaction condition, after the reaction is finished, performing suction filtration, and purifying filtrate by column chromatography with dry petroleum ether and ethyl acetate (10:1) to obtain S3;

。

5. A preparation method of chiral indole skeleton spiro compound (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ] indole ] -1',2 dione derivative according to claim 1, which is characterized by comprising the following steps: the synthetic route of the reaction substrate substituted indole-2, 3-diketone is as follows: dissolving substituted indole-2, 3-diketone S4 in a proper amount of N, N-dimethylformamide, adding 60% sodium hydride under the condition of ice-water bath, stirring for 20 minutes, adding halogenated hydrocarbon, monitoring the reaction, adding ice water to quench the reaction after the reaction is finished, slowly separating out a solid, extracting with dichloromethane, drying, spin-drying, recrystallizing with absolute ethyl alcohol, and performing suction filtration to obtain a product S5;

Technical Field

The invention relates to a preparation method and application of a chiral spiro compound containing an indole skeleton by using N-heterocyclic carbene organic micromolecule as a catalyst

background

Organic heterocyclic molecules are widely present in medicines, pesticides, ligands, natural products and other functional molecules, nitrogen atoms of indole molecules of heterocyclic compounds can perform addition reaction with active ketones to form N, O-acetal products, namely indole skeleton chiral spiro compounds, and great challenges exist in conversion and enantioselectivity control of the products. N, O-acetals are building blocks which are widely present in functional molecules (Angew. chem. int. Ed.,2013,52, 3250-. Breakthrough progress in the field of transition metal and chiral phosphoric acid catalysis has been made by Antilla (J.Am.chem.Soc.,2008,130, 12216-containing 12217), List (Angew.chem.int.Ed.,2010,49, 9749-containing 9752) and other researchers, but there has been little research in the field of N-heterocyclic carbene catalysis, and the problem of synthesizing N, O-acetal indole framework chiral spiro compounds with excellent yield and high enantioselectivity has been studied all the time by using N-heterocyclic carbene to activate the nitrogen atom of indole to perform addition reaction with active ketone.

Disclosure of Invention

The invention aims to design and synthesize an indole framework chiral spiro compound with novel structure, good substrate universality and high enantioselectivity, and further explore the application of the chiral spiro compound in the aspect of biological activity.

The spiro compound (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ] indole ] -1',2 dione derivative with indole skeleton is represented by the following general formula (1):

Wherein the carbon atom marked by is a chiral carbon atom, R¹Is a halogen atom, methyl, methoxy or 5, 7-dichloro), R²Is a halogen atom, methyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, 4-bromo-5 methyl, 4, 7-dichloro, 4, 6-difluoro or 5, 6-difluoro), R³Is methyl, benzyl or triphenylmethyl.

The halogen atom is fluorine, chlorine, bromine or iodine; .

The specific preparation method of the invention is illustrated as follows:

(1) reacting 1.5 molar equivalent of indole-2-formaldehyde with 0.05 molar equivalent of chiral carbene catalyst to obtain Breslow intermediate I, oxidizing the intermediate into acyl azolium intermediate in the presence of 1.7 molar equivalent of oxidant, wherein the reaction temperature is 10 ℃, and the reaction solvent is tetrahydrofuran;

(2) Deprotonating N-H in the intermediate molecule obtained in the step (1) under the condition of 1.5 molar equivalent of alkali N, N-diisopropylethylamine DIEA, losing one proton H to generate an intermediate II, and forming an azafulvene intermediate III, wherein the intermediate III has nucleophilicity, the reaction temperature is 10 ℃, and the reaction solvent is tetrahydrofuran;

(3) carrying out [3+2] cyclization reaction on the nucleophilic azafulvene intermediate and 1.0 molar equivalent of electrophilic indole-2, 3-dione, leaving a carbene catalyst, participating in the next cycle process, and continuously catalyzing to generate a chiral spiro-structured compound (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ] indole ] -1', 2-dione derivative, wherein the reaction temperature is 10 ℃, and the reaction solvent is tetrahydrofuran;

The reaction general formula and the process are as follows:

The synthetic route of the reaction substrate substituted indole-2-formaldehyde is as follows: dissolving substituted indole-2-ethyl formate S1 in tetrahydrofuran, slowly adding lithium aluminum hydride powder in an ice water bath, monitoring the reaction, slowly adding ethyl acetate and ice water after TLC monitoring reaction is finished, quenching the reaction, carrying out suction filtration, extracting ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, and carrying out spin drying to obtain a product S2 which is directly subjected to the next step; dissolving S2 in appropriate amount of dichloromethane, adding manganese dioxide, heating and refluxing, monitoring reaction condition, after the reaction is finished, performing suction filtration, and purifying filtrate by column chromatography of dried petroleum ether and ethyl acetate (10:1) to obtain S3;

dissolving substituted indole-2, 3-diketone S4 in a proper amount of N, N-dimethylformamide, adding 60% sodium hydride under the condition of ice-water bath, stirring for 20 minutes, adding halogenated hydrocarbon, monitoring the reaction, adding ice water to quench the reaction after the reaction is finished, slowly separating out a solid, extracting with dichloromethane, drying, spin-drying, recrystallizing with absolute ethyl alcohol, and performing suction filtration to obtain a product S5;

The invention has the positive effects that: the (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ] indole ] -1', 2-dione derivatives can be efficiently prepared under the catalysis of N-heterocyclic carbene by using reactant molecules with simple structure units, namely substituted indole-2-formaldehyde and substituted indole-2, 3-dione, and have the advantages of good universality, excellent yield, high enantioselectivity and the like.

Detailed description of the preferred embodiments

The following describes the examples of the present invention, and 36 preparation examples and bacteriostatic activity tests are described.

General examples

The synthetic route of the reaction substrate substituted indole-2-formaldehyde is as follows: dissolving substituted indole-2-ethyl formate S1 in tetrahydrofuran, slowly adding lithium aluminum hydride powder in an ice water bath, monitoring the reaction, slowly adding ethyl acetate and ice water after the reaction is finished, quenching the reaction, performing suction filtration, extracting ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, and performing spin drying to obtain a product S2 which is directly subjected to the next step; dissolving S2 in a proper amount of dichloromethane, adding manganese dioxide, heating and refluxing, monitoring the reaction condition, after the reaction is finished, performing suction filtration, and performing spin-drying and column-passing purification on the filtrate to obtain S3;

the synthetic route of the reaction substrate substituted indole-2, 3-diketone is as follows: dissolving substituted indole-2, 3-diketone S4 in a proper amount of N, N-dimethylformamide, adding sodium hydride under the condition of ice-water bath, adding halogenated hydrocarbon after 20 minutes, monitoring the reaction by TLC, adding water to quench the reaction after the reaction is finished, separating out a solid, extracting by dichloromethane, drying, spin-drying, recrystallizing by absolute ethyl alcohol, and performing suction filtration to obtain a product S5;

Synthetic route for the preparation of (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ] indole ] -1', 2-dione derivatives (I):

The preparation implementation method and conditions are as follows:

0.15mmol of substituted indole-2-carbaldehyde 1, 0.1mmol of substituted indole-2, 3-dione 2, 0.05mmol (2.1mg) of N-heterocyclic carbene catalyst E and 0.17mmol (69.5mg) of oxidizing agent DQ were weighed out separately and added to a 10mL Schlenk reaction tube equipped with a magnetic stirrer, 1mL of tetrahydrofuran THF as a solvent was added, followed by 0.15mmol (25. mu.L) of N, N-diisopropylethylamine DIEA, and the reaction wall was gently shaken to mix them well. The bottle cap is covered, and the mixture is placed in an isopropanol water bath at 10 ℃ to be fully stirred and reacted for 24 hours. After TLC monitoring reaction is finished, 1mL of 1N hydrochloric acid is added into a reaction tube, stirring is carried out for 5 minutes at room temperature, ethyl acetate is used for extracting an organic layer, spinning is carried out, a small amount of dichloromethane is fully dissolved, wet-process sample loading is carried out, column chromatography separation is carried out, eluent polar petroleum ether and ethyl acetate are 10:1, a target compound I is obtained, corresponding yield is calculated after weighing, and the compound is characterized by a melting point instrument, a polarimeter, a nuclear magnetic resonance spectrometer NMR, a high resolution mass spectrometer HRMS and a high performance liquid chromatograph HPLC.

Preparation of example 1

Substituent R¹Is H, R²Is H, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

0.15mmol (23.73mg) of indole-2-carbaldehyde 1, 0.1mmol (21.86mg) of indole-2, 3-dione 2, 0.05mmol (2.1mg) of N-heterocyclic carbene catalyst E and 0.17mmol (69.5mg) of oxidizing agent DQ were weighed out separately and added to a 10mL Schlenk reaction tube equipped with a magnetic stirrer, 1mL of tetrahydrofuran THF as a solvent was added, 0.15mmol (25. mu.L) of base N, N-diisopropylethylamine DIEA was added thereto, and the reaction wall was gently shaken to mix them well. The bottle cap is covered, and the mixture is placed in an isopropanol water bath at 10 ℃ to be fully stirred and reacted for 24 hours. After TLC monitoring reaction is finished, 1mL of 1N hydrochloric acid is added into a reaction tube, stirring is carried out for 5 minutes at room temperature, ethyl acetate is used for extracting an organic layer, spinning is carried out, a small amount of dichloromethane is fully dissolved, wet-method sample loading is carried out, column chromatography separation is carried out, and the target compound I is obtained by eluting polar petroleum ether and ethyl acetate which are 10:1₁The corresponding yields were calculated after weighing and characterized as in general example I.

(R) -1-benzyl-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₁)

(dddd,J＝21.4,15.3,7.4,0.9Hz,3H),6.98(d,J＝8.0Hz,1H),6.51(dd,J＝8.3,0.9Hz,1H),5.12(d,J＝15.4Hz,1H),4.83(d,J＝15.4Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ167.9,159.0,143.4,134.1,133.1,132.8,131.9,128.7,128.0,127.3,125.8,125.6,124.4,124.0,123.9,122.1,120.2,110.4,109.8,102.8,87.8,44.3；

HRMS(ESI,m/z)calcd.for C₂₄H₁₆O₃N₂ H⁺:381.1233,found:318.1225；

Chiral analysis by HPLC, with the specific conditions of 96:4er (OD-H column, 25 ℃, hexans-ⁱPrOH＝85/15,0.5mL/min,λ＝254nm),Rt(minor)＝30.9min,Rt(major)＝34.6min.

Preparation of example 2

substituent R¹Is 4-Br, R²Is H, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-8 '-bromo-1' H-spiro [ dihydroindoleIndole-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₂)

7.07–6.92(m,2H),6.44(d,J＝8.4Hz,1H),5.11(d,J＝15.4Hz,1H),4.83(d,J＝15.4Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ166.9,157.7,142.7,133.3,132.8,132.6,131.1,128.0,127.3,126.6,125.6,125.1,124.3,124.0,123.3,119.1,116.7,109.7,108.2,102.4,87.1,43.7；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃Br H⁺:459.0338,found:459.0332；

Chiral analysis by HPLC, with the specific conditions 97:3er (U-IC column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝17.3min,Rt(major)＝14.3min.

Preparation of example 3

Substituent R¹Is 4-OCH₃,R²Is H, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-8 ' -methoxy-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₃)

1H),5.11(d,J＝15.5Hz,1H),4.82(d,J＝15.5Hz,1H),3.95(s,3H)；

¹³C NMR(101MHz,CDCl₃)δ167.9,158.9,155.2,143.4,134.1,133.0,128.7,127.9,127.3,126.9,125.7,124.3,123.9,122.9,120.3,110.3,102.5,101.0,100.8,87.6,55.1,44.3；

HRMS(ESI,m/z)calcd.for C₂₅H₁₈N₂O₄ H⁺:411.1339,found:411.1329；

Chiral analysis by HPLC, with the specific conditions 97:3er (U-IC column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝41.9min,Rt(major)＝32.9min.

Preparation of example 4

Substituent R¹Is 5-F, R²Is H, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-7 ' -fluoro-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₄)

J＝9.0,2.5Hz,1H),6.42(dd,J＝9.1,4.3Hz,1H),5.12(d,J＝15.4Hz,1H),4.82(d,J＝15.4Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ168.1(s),158.9(s),158.8(d,J＝241.3Hz),143.7(s),134.5(s),133.62(d,J＝8.0Hz),129.1(s),128.9(s),128.4(s),127.7(s),126.4(s),126.1(s),124.4(s),120.3(s),115.3(d,J＝27.3Hz),111.2(d,J＝10.1Hz),110.8(s),108.8(d,J＝23.2Hz),102.9(d,J＝5.5Hz),88.1(s),44.7(s).

¹⁹F NMR(377MHz,CDCl₃)δ-119.6；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃FH⁺:399.1139,found:399.1134；

Chiral analysis by HPLC, with the specific conditions of 96:4er (U-IB column, 25 ℃, hexans-ⁱPrOH＝95/5,0.3mL/min,λ＝254nm),Rt(minor)＝23.2min,Rt(major)＝25.4min.

Preparation of example 5

Substituent R¹Is 5-Cl, R²Is H, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-7 ' -chloro-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₅)

(m,2H),6.93(d,J＝8.0Hz,1H),6.33(d,J＝8.8Hz,1H),5.05(d,J＝15.4Hz,1H),4.74(d,J＝15.4Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ167.7,158.6,143.5,134.2,133.4,130.2,129.1,128.9,128.2,128.1,127.4,127.2,126.3,125.9,124.2,123.3,119.9,111.0,110.6,102.2,87.9,44.5；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃ClH⁺:415.0844,found:415.0839；

Chiral analysis by HPLC, with the specific conditions 99:1er (IA column, 25 ℃, hexans-ⁱPrOH＝85/15,0.5mL/min,λ＝254nm),Rt(minor)＝41.7min,Rt(major)＝53.1min.

preparation of example 6

Substituent R¹Is 5-Br, R²is H, R³for Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-7 ' -bromo-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₆)

J＝7.6,0.8Hz,1H),7.00(d,J＝8.0Hz,1H),6.36(d,J＝8.8Hz,1H),5.12(d,J＝15.4Hz,1H),4.82(d,J＝15.4Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ165.6,156.4,141.3,132.2,132.0,131.3,128.3,126.8,126.6,126.1,125.3,124.4,123.7,123.5,122.0,117.8,113.4,109.2,108.5,99.9,85.8,42.4；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃BrH⁺:459.0338,found:459.0335；

Chiral analysis by HPLC, specific conditions were:>99:1er (U-IC column, 25 ℃, hexans @ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝21.9min,Rt(major)＝16.7min.

Preparation of example 7

Substituent R¹Is 5-OH₃,R²Is H, R³for Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-7 ' -methoxy-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₇)

(dd,J＝9.0,2.4Hz,1H),6.39(d,J＝9.0Hz,1H),5.12(d,J＝15.4Hz,1H),4.81(d,J＝15.4Hz,1H),3.83(s,3H)；

¹³C NMR(101MHz,CDCl₃)δ168.3,159.3,155.7,143.7,134.5,133.9,133.4,129.1,128.3,127.7,126.1,125.2,124.3,120.6,117.9,111.1,110.7,103.9,102.6,88.1,55.6,44.7；

HRMS(ESI,m/z)calcd.for C₂₅H₁₈N₂O₄ H⁺:411.1339,found:411.1334；

Chiral analysis by HPLC, with the specific conditions 91:9er (U-IA column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝38.0min,Rt(major)＝41.2min.

preparation of example 8

Substituent R¹is 6-Cl, R²Is H, R³for Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-6 ' -chloro-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₈)

(td,J＝7.6,0.7Hz,1H),6.99(d,J＝8.0Hz,1H),6.62–6.43(m,1H),5.17(d,J＝15.5Hz,1H),4.80(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ168.0,158.8,143.7,134.3,133.8,132.2,132.2,131.7,129.3,128.4,127.5,126.1,125.5,125.3,124.5,123.6,120.1,111.0,110.1,103.2,88.1,44.7；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃Cl H⁺:415.0844,found:415.0841；

Chiral analysis by HPLC, with the specific conditions being 87:13er (U-IA column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝17.5min,Rt(major)＝19.9min.

Preparation of example 9

Substituent R¹Is 6-Br, R²Is H, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-6 ' -bromo-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₉)

6.84–6.60(m,1H),5.18(d,J＝15.5Hz,1H),4.78(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ168.0,158.8,143.7,134.3,133.8,132.6,132.0,129.3,128.4,127.4,126.2,126.1,125.5,125.4,124.5,120.0,113.1,111.0,103.3,88.2,44.7；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃BrH⁺:459.0338,found:459.0332；

Chiral analysis by HPLC, with the specific conditions 96:4er (U-IC column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝18.7min,Rt(major)＝14.9min.

Preparation of example 10

Substituent R¹Is 6-CH₃,R²Is H, R³for Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-6 ' -methyl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]indoles]-1', 2-dione (I)₁₀)

(dd,J＝8.4,1.0Hz,1H),6.99(d,J＝8.0Hz,1H),6.28(s,1H),5.19(d,J＝15.5Hz,1H),4.77(d,J＝15.5Hz,1H),2.25(s,3H)；

¹³C NMR(101MHz,CDCl₃)δ168.4,159.4,143.6,136.6,134.6,133.3,132.7,131.1,129.0,128.3,127.7,126.1,124.6,124.3,124.1,123.9,120.7,110.7,109.7,103.2,88.0,44.6,21.9；

HRMS(ESI,m/z)calcd.for C₂₅H₁₈N₂O₃H⁺:395.1390,found:395.1383；

Chiral analysis by HPLC, with the specific conditions 95:5er (U-IA column, 25 ℃, hexans-ⁱPrOH＝95/5,0.3mL/min,λ＝254nm),Rt(minor)＝20.9min,Rt(major)＝23.7min.

preparation of example 11

Substituent R¹Is 6-OCH₃,R²Is H, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-6 ' -methoxy-1 ' H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₁₁)

(d,J＝7.9Hz,1H),6.85(dt,J＝13.2,6.6Hz,1H),5.85(d,J＝2.1Hz,1H),5.19(d,J＝15.5Hz,1H),4.77(d,J＝15.5Hz,1H),3.46(s,3H)；

¹³C NMR(101MHz,CDCl₃)δ168.4,159.3,159.1,143.7,134.7,133.4,133.2,129.1,128.3,127.7,127.4,126.2,125.1,124.3,123.4,120.5,113.4,110.5,103.7,92.3,55.2,44.7；

HRMS(ESI,m/z)calcd.for C₂₅H₁₈N₂O₄H⁺:411.1339,found:411.1336；

chiral analysis by HPLC, with the specific conditions 97:3er (U-IC column, 25 ℃, hexans-ⁱPrOH＝90/10,0.5mL/min,λ＝254nm),Rt(minor)＝33.1min,Rt(major)＝27.0min.

Preparation of example 12

Substituent R¹Is 5, 7-bicl, R²Is H, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-5 ',7' -dichloro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-. alpha. ]]indoles]-1', 2-dione (I)₁₂)

4.86(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ168.3,158.0,144.2,135.4,134.1,133.3,129.3,129.0,128.4,128.3,,127.9,126.5,125.0,124.1,123.2,122.0,117.5,110.6,103.1,90.0,45.0；

HRMS(ESI,m/z)calcd.for C₂₄H₁₄N₂O₃Cl₂H⁺:449.0454,found:449.0442；

Chiral analysis by HPLC, with the specific conditions being 99:1er (IB column, 25 ℃, hexans @)ⁱPrOH＝90/10,0.5mL/min,λ＝254nm),Rt(minor)＝28.6min,Rt(major)＝31.0min.

Preparation of example 13

Substituent R¹is H, R²is 4-Cl, R³for Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-4-chloro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]indoles]-1', 2-dione (I)₁₃)

6.53(dd,J＝8.2,0.9Hz,1H),5.13(d,J＝15.5Hz,1H),4.86(d,J＝15.4Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ167.6,159.1,145.2,134.3,134.2,133.7,133.0,132.0,129.2,129.1,128.5,127.7,126.0,125.1,124.8,124.5,122.4,117.5,109.7,109.0,103.4,44.9；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃ClH⁺:415.0844,found:415.0840；

Chiral analysis by HPLC, with the specific conditions 98:2er (U-IB column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝12.4min,Rt(major)＝15.6min.

Preparation of example 14

Substituent R¹Is H, R²Is 4-Br, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-4-bromo-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]indoles]-1', 2-dione (I)₁₄)

＝15.5Hz,1H),4.86(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ167.6,159.2,145.5,134.4,134.1,132.9,132.0,129.2,128.5,128.1,127.6,126.0,125.0,124.5,122.4,121.4,119.1,109.7,109.5,103.4,88.2,44.8；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃BrH⁺:459.0338,found:459.0333；

Chiral analysis by HPLC, with the specific conditions being 99:1er (U-IC column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝38.9min,Rt(major)＝23.9min.

Preparation of example 15

Substituent R¹Is H, R²Is 5-F, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-5-fluoro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₁₅)

(m,1H),5.10(t,J＝11.9Hz,1H),4.81(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ168.2(s),159.6(d,J＝247.4Hz),159.0(s),139.6(d,J＝3.0Hz),134.2(s),133.2(s),132.2(s),129.20(s),128.5(s),127.7(s),126.2(s),124.5(s),124.4(s),122.6(s),122.1(d,J＝8.0Hz),120.1(d,J＝23.2Hz),114.1(d,J＝25.2Hz),111.8(d,J＝7.0Hz),110.1(s),103.6(s),87.8(s),44.9(s).

¹⁹F NMR(377MHz,CDCl₃)δ-116.7；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃FH⁺:399.1139,found:399.1133；

Chiral analysis by HPLC, with specific conditions of 99:1er (U-IC column),25℃,hexans/ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝22.3min,Rt(major)＝27.4min.

preparation of example 16

Substituent R¹Is H, R²is 5-Cl, R³for Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-5-chloro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]indoles]-1', 2-dione (I)₁₆)

Hz,1H),5.11(d,J＝15.5Hz,1H),4.81(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ167.9,158.9,142.2,134.1,133.3,132.2,129.9,129.6,129.4,129.2,128.5,127.7,126.4,126.2,124.5,122.6,122.2,111.9,110.1,103.7,87.6,44.9；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃ClH⁺:415.0844,found:415.0839；

Chiral analysis by HPLC, with the specific conditions 96:4er (IA column, 25 ℃, hexans-ⁱPrOH＝90/10,0.5mL/min,λ＝254nm),Rt(minor)＝43.8min,Rt(major)＝50.3min.

Preparation of example 17

Substituent R¹Is H, R²is 5-Br, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-5-bromo-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]indoles]-1', 2-dione (I)₁₇)

6.86(d,J＝8.4Hz,1H),6.53(dd,J＝8.2,0.9Hz,1H),5.11(d,J＝15.5Hz,1H),4.81(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ167.8,158.8,142.7,136.3,134.0,133.2,132.1,129.2,128.5,127.6,126.2,124.5,124.4,122.6,122.5,117.0,112.2,110.1,103.7,87.52,44.8；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃BrH⁺:459.0338,found:459.0331；

Chiral analysis by HPLC, with the specific conditions 95:5er (IA column, 25 ℃, hexans-ⁱPrOH＝90/10,0.5mL/min,λ＝254nm),Rt(minor)＝44.4min,Rt(major)＝53.3min.

Preparation of example 18

Substituent R¹Is H, R²Is 5-I, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-5-iodo-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]indoles]-1', 2-dione (I)₁₈)

0.9Hz,1H),5.11(d,J＝15.5Hz,1H),4.80(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ167.6,158.8,143.4,142.2,134.7,134.0,133.2,132.1,129.2,128.5,127.6,126.2,124.5,124.4,122.7,122.6,112.7,110.1,103.6,86.5,44.8；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃IH⁺:507.0200,found:507.0195；

Chiral analysis by HPLC, with the specific conditions 94:6er (AD-H column, 25 ℃, hexans-ⁱPrOH＝85/15,0.5mL/min,λ＝254nm),Rt(minor)＝46.2min,Rt(major)＝56.2min.

Preparation of example 19

Substituent R¹Is H, R²Is 5-OCH₃，R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-5-methoxy-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₁₉)

6.55(dd,J＝8.2,0.9Hz,1H),5.09(d,J＝15.4Hz,1H),4.80(d,J＝15.4Hz,1H),3.69(s,3H)；

^{1 3}C NMR(101MHz,CDCl₃)δ168.1,159.3,157.0,136.7,134.6,133.2,132.2,129.0,128.3,127.7,125.9,124.7,124.4,122.4,121.6,118.7,112.0,111.5,110.3,103.21,8.43,55.8,44.8；

HRMS(ESI,m/z)calcd.for C₂₅H₁₈N₂O₄H⁺:411.1339,found:411.1335；

Chiral analysis by HPLC, with the specific conditions 97:3er (U-IA column, 25 ℃, hexans-ⁱPrOH＝80/20,0.3mL/min,λ＝254nm),Rt(minor)＝15.9min,Rt(major)＝13.0min.

Preparation of example 20

Substituent R¹Is H, R²Is 5-OCF₃，R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-5-trifluoromethoxy-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₂₀)

Hz,1H),4.83(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ168.2,158.8,145.7,142.3,134.0,133.3,132.2,129.2,128.6,127.7,126.5,126.3,124.6,124.4,122.7,122.1,119.9,111.6,109.9,103.8,87.5,44.9；.

¹⁹F NMR(377MHz,CDCl₃)δ-58.4；

HRMS(ESI,m/z)calcd.for C₂₅H₁₅N₂O₄F₃H⁺:465.1056,found:465.1053；

chiral analysis by HPLC, with the specific conditions 97:3er (AD-H column, 25 ℃, hexans-ⁱPrOH＝85/15,0.3mL/min,λ＝254nm),Rt(minor)＝32.8min,Rt(major)＝38.6min.

preparation of example 21

Substituent R¹Is H, R²is 5-CH₃，R³To Bn, preparationThe procedure and conditions were as in general example I;

(R) -1-benzyl-5-methyl-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]indoles]-1', 2-dione (I)₂₁)

1H),4.81(d,J＝15.4Hz,1H),2.24(s,3H)；

¹³C NMR(101MHz,CDCl₃)δ168.2,159.4,141.3,134.6,134.3,133.7,133.2,132.2,129.0,128.3,127.7,126.7,125.8,124.8,124.3,122.4,120.5,110.5,110.3,103.0,88.3,44.7,20.8；

HRMS(ESI,m/z)calcd.for C₂₅H₁₈N₂O₃H⁺:395.1390,found:395.1393；

Chiral analysis by HPLC, with the specific conditions 95:5er (U-IC column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝32.5min,Rt(major)＝26.7min.

preparation of example 22

Substituent R¹Is H, R²Is 6-F, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-6-fluoro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₂₂)

(d,J＝8.3Hz,1H),5.10(d,J＝15.5Hz,1H),4.79(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ168.6,165.9(d,J＝253.5Hz),159.1(s),145.8(d,J＝12.2Hz),134.0(s),133.25(s),132.2(s),129.2(s),128.6(s),128.0(d,J＝10.5Hz),127.6(s),126.1(s),124.7(s),124.5(s),122.5(s),116.0(d,J＝3.3Hz),110.9(d,J＝23.3Hz),110.1(s),103.4(s),99.9(d,J＝28.2Hz),87.6(s),44.9(s)；

¹⁹F NMR(376MHz,CDCl₃)δ-102.4；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃FH⁺:399.1139,found:399.1132；

chiral analysis by HPLC, with the specific conditions of 96:4er (AD-H column, 25 ℃, hexans-ⁱPrOH＝80/20,0.5mL/min,λ＝254nm),Rt(minor)＝38.6min,Rt(major)＝45.1min.

Preparation of example 23

Substituent R¹Is H, R²Is 6-Cl, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-6-chloro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₂₃)

J＝3.3Hz,1H),6.53(dd,J＝8.2,0.9Hz,1H),5.10(d,J＝15.5Hz,1H),4.79(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ168.3,159.0,144.9,139.6,134.0,133.2,132.2,129.2,128.6,127.6,127.1,126.1,124.6,124.5,124.4,122.6,118.9,111.5,110.1,103.5,87.5,44.8；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃ClH⁺:415.0844,found:415.0838；

Chiral analysis by HPLC, with the specific conditions 97:3er (AD-H column, 25 ℃, hexans-ⁱPrOH＝85/15,0.5mL/min,λ＝254nm),Rt(minor)＝42.1min,Rt(major)＝49.4min.

Preparation of example 24

Substituent R¹is H, R²Is 6-Br, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-6-bromo-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₂₄)

Hz,1H),4.72(d,J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ166.3,157.1,143.0,132.0,131.2,130.2,127.3,126.6,125.7,125.7,125.4,125.4,124.2,122.6,122.5,120.7,117.5,112.3,108.2,101.66,85.6,42.9；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃BrH⁺:459.0338,found:449.0332；

Chiral analysis by HPLC, with the specific conditions 96:4er (U-IC column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝22.3min,Rt(major)＝27.4min.

Preparation of example 25

substituent R¹Is H, R²is 6-OCH₃，R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-6-methoxy-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₂₅)

1H),3.80(s,3H)；

¹³C NMR(101MHz,CDCl₃)δ168.9,164.0,159.6,145.4,134.6,133.1,132.2,129.1,128.3,127.6,127.5,125.8,125.0,124.3,122.3,111.8,110.3,107.7,102.96,98.9,88.3,55.7,44.7；

HRMS(ESI,m/z)calcd.for C₂₅H₁₈N₂O₄H⁺:411.1339,found:411.1335；

Chiral analysis by HPLC, with the specific conditions 95:5er (U-IB column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝6.4min,Rt(major)＝9.9min.

preparation of example 26

Substituent R¹Is H, R²is 7-F, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-7-fluoro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]indoles]-1', 2-dione (I)₂₆)

6.46(dd,J＝8.3,0.8Hz,1H),5.21(d,J＝15.2Hz,1H),5.01(dd,J＝15.1,1.2Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ168.2(s),158.9(s),147.8(d,J＝248.4Hz),135.6(s),133.1(s),132.1(s),130.3(d,J＝10.1Hz),128.8(s),128.3(s),128.0(d,J＝2.0Hz),126.11(s),125.3(d,J＝6.0Hz),124.4(s),123.3(d,J＝2.8Hz),122.57(s),122.0(d,J＝3.5Hz),121.8(s),121.6(s),110.1(s),103.5(s),87.6(s),46.4(s).

¹⁹F NMR(377MHz,CDCl₃)δ-130.4；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃FH⁺:399.1139,found:399.1129；

Chiral analysis by HPLC, with the specific conditions 96:4er (U-IC column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝24.6min,Rt(major)＝19.7min.

Preparation of example 27

Substituent R¹Is H, R²is 7-Cl, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-7-chloro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₂₇)

(m,1H),5.53–5.32(m,2H)；

¹³C NMR(101MHz,CDCl₃)δ169.1,158.9,139.9,136.0,136.0,133.2,132.2,128.8,127.9,127.0,126.2,125.3,124.8,124.6,124.5,123.6,122.6,117.1,110.2,103.6,87.1,45.8；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃ClH⁺:415.0844,found:415.0836；

Chiral analysis by HPLC, with the specific conditions 97:3er (U-IA column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝10.7min,Rt(major)＝7.1min.

preparation of example 28

Substituent R¹Is H, R²Is 7-Br, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-7-bromo-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₂₈)

–6.48(m,1H),5.49–5.34(m,2H)；

¹³C NMR(101MHz,CDCl₃)δ169.1,158.9,139.9,136.0,136.0,133.2,132.2,128.8,127.9,127.0,126.2,125.1,124.8,124.6,124.5,123.6,122.6,117.1,110.1,103.6,87.1,45.8；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₂O₃BrH⁺:459.0338,found:459.0668；

Chiral analysis by HPLC, specific conditions were:>99:1er (U-IA column, 25 ℃, hexans @ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝18.8min,Rt(major)＝12.2min.

Preparation of example 29

substituent R¹Is H, R²Is 7-CF₃，R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-7-trifluoromethyl-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₂₉)

＝16.1Hz,2H)；

¹³C NMR(101MHz,CDCl₃)δ167.5(s),157.1(s),139.7(s),137.6(s),134.1(s),131.4(s),130.4(s),127.0(s),126.0(s),125.1(s),124.4(s),123.8(s),123.6(s),122.8(s),122.7(s),122.1(s),120.8(s),108.4(s),102.2(s),101.8(s),85.3(s),43.6(s)；

¹⁹F NMR(377MHz,CDCl₃)δ-54.8；

HRMS(ESI,m/z)calcd.for C₂₅H₁₅N₂O₃F₃H⁺:449.1107,found:449.1157；

Chiral analysis by HPLC, specific conditions were:>99:1er (ID column, 25 ℃, hexans @)ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝59.4min,Rt(major)＝64.8min.

Preparation of example 30

Substituent R¹Is H, R²Is 7-NO₂，R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-7-trifluoromethyl-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₃₀)

7.20(dd,J＝8.3,7.4Hz,1H),7.16–7.07(m,2H),6.67–6.54(m,1H),5.29–5.18(m,2H)；

¹³C NMR(101MHz,CDCl₃)δ169.4,158.4,137.0,136.9,133.3,132.1,132.1,130.0,129.2,129.1,128.6,127.9,126.5,124.7,124.4,124.3,124.3,122.9,110.0,104.2,85.9,46.6；

HRMS(ESI,m/z)calcd.for C₂₄H₁₅N₃O₅H⁺:426.1084,found:426.1077；

Chiral analysis by HPLC, with the specific conditions 97:3er (U-IC column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝13.7min,Rt(major)＝10.9min.

Preparation of example 31

Substituent R¹Is H, R²is 4-Br-5-CH₃，R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-4-bromo-5-methyl-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₃₁)

＝8.2,0.8Hz,1H),5.11(d,J＝15.4Hz,1H),4.84(d,J＝15.4Hz,1H),2.24(s,3H)；

¹³C NMR(101MHz,CDCl₃)δ167.5,159.3,143.0,134.5,134.2,134.1,132.7,131.8,128.9,128.2,127.5,125.7,125.1,124.2,123.5,122.1,119.0,109.6,109.2,103.0,88.5,44.6,21.3；

HRMS(ESI,m/z)calcd.for C₂₅H₁₇N₂O₃BrH⁺:473.0495,found:473.0489；

chiral analysis by HPLC, specific conditions were:>99:1er (OD-H column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝80.6min,Rt(major)＝72.7min.

Preparation of example 32

Substituent R¹Is H, R²Is 4, 6-di F, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-4, 6-difluoro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₃₂)

J＝15.5Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ168.01(s),165.48(d,J＝12.6Hz),162.03(d,J＝14.7Hz),159.45(d,J＝15.0Hz),158.65(s),146.43(dd,J＝14.0,8.6Hz),133.79(s),133.20(s),132.13(s),129.35(s),128.78(s),127.69(s),126.19(s),124.67(s),124.28(s),122.61(s),109.74(s),103.87(s),100.74–99.58(m),96.32(d,J＝28.3Hz),86.44(s),45.33(s)；

¹⁹F NMR(377MHz,CDCl₃)δ-97.9,-110.6；

HRMS(ESI,m/z)calcd.for C₂₄H₁₄N₂O₃F₂H⁺:417.1045,found:417.1040；

Chiral analysis by HPLC, with the specific conditions 92:8er (U-IA column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝10.7min,Rt(major)＝13.3min.

Preparation of example 33

Substituent R¹Is H, R²Is 4, 7-bicl, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-4, 7-dichloro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-. alpha. ] -]Indoles]-1', 2-dione (I)₃₃)

(m,2H)；

¹³C NMR(101MHz,CDCl₃)δ168.5,158.8,141.3,136.7,135.7,132.9,132.6,132.0,128.9,128.1,127.0,126.2,126.0,124.7,124.6,122.6,119.9,115.5,109.6,103.8,86.8,45.8；

HRMS(ESI,m/z)calcd.for C₂₄H₁₄N₂O₃Cl₂H⁺:449.0454,found:449.0454；

chiral analysis by HPLC, specific conditions were:>99:1er (U-IC column, 25 ℃, hexans @ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝20.5min,Rt(major)＝12.3min.

Preparation of example 34

Substituent R¹is H, R²Is 5, 6-di F, R³For Bn, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-benzyl-5, 6-difluoro-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₃₄)

white solid, yield 93%; melting point: 158 ℃ and 160 ℃;

¹³C NMR(101MHz,CDCl₃)δ166.42(s),156.95(s),151.89(dd,J＝256.0,13.9Hz),145.76(dd,J＝248.6,13.6Hz),138.77(d,J＝9.8Hz),131.95(s),131.50(s),130.40(s),127.56(s),126.96(s),125.87(s),124.52(s),122.86(s),122.64(s),120.97(s),114.40(d,J＝1.9Hz),114.19(q,J＝4.2Hz),108.20(s),102.08(s),99.76(d,J＝23.5Hz),85.59(s),43.25(s).

¹⁹F NMR(377MHz,CDCl₃)δ-126.8,-141.4.

HRMS(ESI,m/z)calcd.for C₂₄H₁₄N₂O₃F₂H⁺:417.1045,found:417.1044；

chiral analysis by HPLC, with the specific conditions 97:3er (U-IA column, 25 ℃, hexans-ⁱPrOH＝90/10,0.3mL/min,λ＝254nm),Rt(minor)＝12.5min,Rt(major)＝15.1min.

Preparation of example 35

Substituent R¹is H, R²is H, R³Is CH₃The preparation method and conditions were the same as in general example I;

(R) -1-methyl-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₃₅)

1H),3.33(s,3H)；

¹³C NMR(101MHz,CDCl₃)δ168.0,159.3,144.7,133.6,133.1,132.2,126.1,126.0,124.8,124.4,124.3,122.4,120.5,110.0,109.7,103.1,88.1,27.0；

HRMS(ESI,m/z)calcd.for C₁₈H₁₂N₂O₃H⁺:305.0920,found:305.0916；

Chiral analysis by HPLC, with the specific conditions 92:8er (U-IB column, 25 ℃, hexans-ⁱPrOH＝95/5,0.3mL/min,λ＝254nm),Rt(minor)＝26.5min,Rt(major)＝21.7min.

Preparation of example 36

substituent R¹Is H, R²Is H, R³For Trt, the preparation was carried out under the same conditions and conditions as in general example I;

(R) -1-triphenylmethyl-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-alpha ]]Indoles]-1', 2-dione (I)₃₆)

(dd,J＝8.3,0.7Hz,1H)；

¹³C NMR(101MHz,CDCl₃)δ167.2,157.2,142.7,138.9,130.9,130.1,129.9,126.9,125.8,125.2,123.5，123.4,123.1,122.0,121.6,120.0,118.7,115.2,108.3,100.7,86.1,73.6；

HRMS(ESI,m/z)calcd.for C₃₆H₂₄N₂O₃H⁺:533.1859,found:533.1857；

Chiral analysis by HPLC, with the specific conditions being 99:1er (OD-H column, 25 ℃, hexans-ⁱPrOH＝98/2,0.3mL/min,λ＝254nm),Rt(minor)＝44.0min,Rt(major)＝36.9min.

The following provides 34 preparation examples of (R) -1-aryl-1 ' H-spiro [ indoline-3, 3' -oxazolo [3,4- α ] indole ] -1', 2-dione derivatives of the invention for their bacteriostatic activity:

(1) Test method

The inhibition activity of a target compound on pseudomonas solanacearum (R.solaNacerarium) is tested by adopting a turbidity method, and the specific operation steps are as follows:

A. Adding 1000mL of sterilized distilled water into a 2000mL beaker, sequentially adding 5.0g of peptone, 1.0g of yeast powder, 10.0g of glucose and 3.0g of beef extract under electromagnetic stirring, and after uniformly stirring, adjusting the pH value to be neutral (7.2 +/-0.2) by using a sodium hydroxide aqueous solution;

B. Cleaning and sterilizing the test tubes, placing the test tubes on a test tube rack, transferring 4.0mL of the solution obtained in the first step (1) into each test tube by using a liquid transferring gun, adding a rubber plug, packaging every 6 test tubes, and sterilizing for 20min at 121 ℃ by using a sterilizing pot for later use;

C. Weighing 0.008g of a compound sample to be detected in a centrifuge tube, dissolving the compound sample in 150 mu L of DMSO, transferring 80 mu L and 40 mu L of the DMSO into the centrifuge tube which is numbered after sterilization respectively, additionally adding 40 mu L of DMSO into the centrifuge tube filled with 40 mu L of sample solution, adding 4mL of Tween-20 into each centrifuge tube, and simultaneously setting thiabendazole copper or bismerthiazol as a control agent and DMSO as a blank control;

D. 1mL to 3 solutions in each centrifugal tube are transferred and contained in the second step (2) of pilot tube (operation before an alcohol lamp is carried out, other bacteria are prevented from being polluted);

E. Taking a blank 96-well plate, measuring a blank OD value, excluding holes with OD values larger than 0.05, adding 200 mu L (4) of solution in each available hole to measure the OD value and record, finally, inoculating 40 mu L of activated ralstonia solanacearum strain into each test tube, wrapping the test tube with newspaper, carrying out shake culture in a constant temperature shaking table at 28 ℃ and 180rpm for 24 hours, measuring the OD value of the solution in the test tube during the period to track the growth state of bacteria, and taking 200 mu L of solution in the test tube to measure the OD value and record after the culture is finished;

F. The calculation formula of the inhibition rate of the compound on bacteria is as follows,

Corrected OD value-bacteria-containing medium OD value-sterile medium OD value

(2) Test results of biological activity against plant pathogens

Table 1 example I₁-I₃₆Inhibition rate a of prepared compound on ralstonia solanacearum respectively under set concentration

The inhibition activity of the target compound on the ralstonia solanacearum is tested by a turbidity method by taking commercial medicaments comprising the benziothiazolinone and the bismerthiazol as positive controls at a test concentration of 100 and 50 mu g/mL (see table 1). The test results show that: all compounds had a certain inhibitory rate against the plant bacteria tested. Wherein, when the concentration is 100 mu g/mL, the compound I₁,I₃,I₄,I₈,I₉,I₁₀,I₁₃,I₁₄The inhibition rates of the compound are all higher than those of the benziothiazolinone (46.82%) and the bismerthiazol (62.42%); when the concentration is 50. mu.g/mL, the compound I₁,I₃,I₈,I₉,I₁₀,I₁₃,I₁₄The preparation rate of the product exceeds that of the benziothiazolinone (28.58 percent) and the bismerthiazol (53.25 percent). As the above experimental activity data indicate, (R) -1-aryl-1 'H-spiro [ indoline-3, 3' -oxazolo [3, 4-. alpha. ]]Indoles]-1', 2-diketonesthe derivative has a certain inhibiting effect on plant pathogenic bacteria, namely ralstonia solanacearum, wherein part of target compounds have excellent inhibiting activity on the plant pathogenic bacteria, can be used as potential plant pathogenic bacteria inhibiting medicines, and has a good application prospect.

In summary, the present invention is only a preferred embodiment, and is not limited to any form, and any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention are still within the scope of the technical solution of the present invention without departing from the technical solution of the present invention.