CN114160206B

CN114160206B - Catalyst for catalytic synthesis of optically active indole compound, application and synthesis method thereof, and optically active indole compound

Info

Publication number: CN114160206B
Application number: CN202111517733.9A
Authority: CN
Inventors: 汪志勇; 孙翔
Original assignee: University of Science and Technology of China USTC
Current assignee: University of Science and Technology of China USTC
Priority date: 2021-12-13
Filing date: 2021-12-13
Publication date: 2023-03-10
Anticipated expiration: 2041-12-13
Also published as: CN114160206A

Abstract

The invention provides a catalyst for catalytically synthesizing an optically active indole compound, application, a synthesis method and the optically active indole compound. The catalyst provided by the invention can prepare the 3-alkenyl-3-substituted oxindole compound with optical activity through the high enantioselectivity and diastereoselectivity direct asymmetric olefination reaction of the 3-alkenyl indole compound on the isatin-like compound, and simultaneously obtain higher enantioselectivity and diastereoselectivity; the enantioselectivity is more than 91 percent ee, the diastereoselectivity dr is more than 20:1, and the product yield is more than 81 percent.

Description

Catalyst for catalytic synthesis of optically active indole compound, application and synthesis method thereof, and optically active indole compound

Technical Field

The invention relates to the field of organic synthesis, and particularly relates to a catalyst for catalytically synthesizing an optically active indole compound, application, a synthesis method and an optically active indole compound.

Background

3-alkenyl-2-oxoindoles are among the most abundant and important structural motifs in organic synthesis. They are widely found in biologically active molecules and drugs. For example, spirotrpostatin B alkaloids exhibit cytotoxic activity. JP-8g has the potential to treat cancer and inflammation. Furthermore, chiral alcohols and chiral amines in the allylic position are widely present in many biologically active compounds, such as prostaglandin A1 and fosstriicin. Meanwhile, 3-substituted 3-aminooxindole unit analogs have great medicinal value, SSR-1494153 is a VIb receptor antagonist used for treating anxiety and depression, and NITD609 is an excellent candidate drug of an antimalarial drug. Therefore, the development of a novel C3 indole compound is of great significance, and the construction of optically active allyl alcohol and allylamine at the C3 position of the oxindole has attracted wide attention chemically.

Isatin and its analogues have been widely used in synthetic chemistry due to their excellent pharmaceutical value and ready availability of raw materials. While asymmetric alkenylation of isatin has been rarely reported before. In 2010, the Zhou project group reported that cinchona alkaloid catalyzed asymmetric synthesis of isatin and acrolein, resulting in high yield and enantioselectivity. In 2016, the Zhao topic group reported that chiral CoI 2-bisphosphine complexes undergo an asymmetric olefination reaction of isatin with arylboronic acids at 70 ℃ to give 93% ee. However, since the reactivity of the naked alkenyl group is poor, an appropriate substituent is required at the alkenyl reaction site to enhance the reactivity thereof. Therefore, how to successfully realize direct alkenylation of isatin and analogues thereof and obtain better synthetic effect still needs further research.

Disclosure of Invention

In view of the above, the present invention aims to provide a catalyst for catalytic synthesis of an optically active indole compound, applications thereof, a synthesis method thereof, and an optically active indole compound. The catalyst and the synthesis method provided by the invention can be used for catalytically synthesizing optically active C3 indole compounds with high enantioselectivity and diastereoselectivity, and have high yield.

The catalyst provided by the invention can prepare the 3-alkenyl-3-substituted oxindole compound with optical activity through the high enantioselectivity and diastereoselectivity direct asymmetric olefination reaction of the 3-alkenyl indole compound on the isatin-like compound, and simultaneously obtain higher enantioselectivity and diastereoselectivity; the enantioselectivity reaches more than 91 percent ee, the diastereoselectivity dr is more than 20:1, the product yield reaches more than 81 percent, and the purity reaches more than 99.9 percent. Compared with the conventional catalysts such as Lewis acid and the like, the catalyst provided by the invention has obviously improved selectivity and yield.

The invention provides application of a catalyst in catalytic synthesis of an optically active indole compound, which is represented by a formula (C) for the first time ₁ ) Compound and/or formula (C) ₂ ) The compound is used as a catalyst for catalytically synthesizing an optically active indole compound, and particularly, the optically active 3-alkenyl-3-substituted oxindole compound is prepared by asymmetric direct olefination reaction of the 3-alkenyl indole compound on high enantioselectivity and diastereoselectivity of an isatin compound, and a good preparation effect is obtained.

The synthesis method of the optically active indole compound provided by the invention can obtain the optically active 3-alkenyl-3-substituted oxindole compound with high enantioselectivity and diastereoselectivity, the enantioselectivity reaches more than 91% ee, the diastereoselectivity dr is more than 20:1, the product yield reaches more than 81%, and the purity reaches more than 99.9%. The stereoselectivity of the product can still be maintained when the reaction is scaled up to gram scale.

The optical activity indole compound provided by the invention is a novel optical activity indole compound which is not disclosed in the prior art, the oxidation indole compound has potential medicinal value and a natural product precursor, so that the optical activity indole compound has practical value for the research of the skeleton structure, and the optical activity indole compound provided by the invention is a 3-alkenyl-3 substituted oxindole compound, enriches the variety of C3 position indole compounds and provides more indole skeleton precursors.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.

FIG. 1 shows intermediate S obtained in preparation example 1 of the starting Material ₁ The nuclear magnetic resonance hydrogen spectrum of (a);

FIG. 2 shows intermediate S obtained in preparation example 1 of the starting Material ₁ Nuclear magnetic resonance carbon spectrum of (a);

FIG. 3 shows the product L obtained in preparation example 1 of the starting material _1b The nuclear magnetic resonance hydrogen spectrum of (a);

FIG. 4 shows the product L obtained in preparation example 1 of the starting material _1b Nuclear magnetic resonance carbon spectrum of (a);

FIG. 5 shows a chiral copper-based catalyst C in example 1 of the present invention _1b The structure of the single crystal of (1);

FIG. 6 shows a NMR chart of a product of formula III-1 a obtained in example 1 of the present invention;

FIG. 7 shows a NMR chart of a product of formula III-1 a obtained in example 1 of the present invention;

FIG. 8 is a HPLC chromatogram of the product of formula III-1 a obtained in example 1 of the present invention;

FIG. 9 shows a NMR chart of a product of formula III-1 b obtained in example 2 of the present invention;

FIG. 10 shows a NMR chart of a product of formula III-1 b obtained in example 2 of the present invention;

FIG. 11 shows the NMR spectrum of the product of the formula III-1 c obtained in example 3 of the present invention;

FIG. 12 shows a NMR chart of a product of formula III-1 c obtained in example 3 of the present invention;

FIG. 13 is a NMR chart of the product of example 4 of the present invention, formula III-1 d;

FIG. 14 shows the NMR chart of the product of example 4 of the present invention, formula III-1 d;

FIG. 15 is a NMR chart of the product of example 5 of the present invention, formula III-1 e;

FIG. 16 is a NMR chart of the product of example 5 of the present invention, formula III-1 e;

FIG. 17 shows a NMR chart of a product of the formula III-2 a obtained in example 6 of the present invention;

FIG. 18 shows a NMR chart of a product of the formula III-2 a obtained in example 6 of the present invention;

FIG. 19 is a HPLC chromatogram of the product of formula III-2 a obtained in example 6 of the present invention;

FIG. 20 is a NMR chart of the product of example 7 of the present invention, formula III-2 b;

FIG. 21 shows a NMR carbon spectrum of a product of formula III-2 b obtained in example 7 of the present invention;

FIG. 22 shows a NMR chart of a product of the formula III-2 c obtained in example 8 of the present invention;

FIG. 23 shows a NMR chart of a product of the formula III-2 c obtained in example 8 of the present invention.

Detailed Description

The invention provides a catalyst for catalytically synthesizing an optically active indole compound, which is a chiral copper-based catalyst;

the chiral copper-based catalyst is represented by the formula (C) ₁ ) Compound and/or formula (C) ₂ ) A compound:

wherein:

Ar ¹ 、Ar ² each independently selected from: substituted or unsubstituted aryl. The aryl group is preferably phenyl or naphthyl. In the substituted aryl group, the substituent is preferably an alkyl group, a haloalkyl group, or an alkoxy group. Wherein the alkyl is preferably C1-C6 alkyl; more preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl or n-hexyl. The alkyl group in the halogenated alkyl group is the same as the above-mentioned one, and the description thereof is omitted; halogen as a substituent is preferably fluorine, chlorine, bromine or iodine. The alkoxy is preferably C1-C6 alkoxy; more preferably methoxy, ethoxy or isopropoxy. Preferably, ar is ¹ And Ar ² The same is true.

In the present invention, preferably, the chiral copper-based catalyst is selected from one or more of the following compounds:

the invention also provides a preparation method of the catalyst for catalytically synthesizing the optically active indole compound in the technical scheme, which comprises the following steps:

mixing and reacting a cupric salt, a nitrogen-containing organic base and a ligand to form a catalyst;

the ligand is of formula (L) ₁ ) A compound and/or formula (L) ₂ ) A compound:

wherein Ar is ¹ 、Ar ² The types of the above-mentioned components are the same as those in the above-mentioned technical solutions, and are not described in detail herein.

In the present invention, the ligand is represented by the above formula (L) ₁ ) A compound and/or formula (L) ₂ ) A compound is provided. Compared with other ligands such as BOX ligand and the like, the catalyst obtained by adopting the ligand can catalyze the subsequent synthesis reaction to obtain the optically active indole compound.

More preferably, the ligand is selected from one or more of the following compounds:

in the present invention, ligand L is used ₁ For example, it can be prepared by the following method:

a) L-phenylalanine, SOCl ₂ Mixing with ethanol for reaction to form a compound A;

b) Reacting the compound A with bromide to form an intermediate S1;

the bromide is Ar ¹ Br and Ar ² Br；

c) The intermediate S1 reacts with a salicylaldehyde derivative B to form a ligand L ₁ 。

The synthetic route of the above process is as follows:

ligand L ₂ The synthesis process of (2) and the above ligand L ₁ The synthesis process is similar, and only the L-phenylalanine raw material is adaptively replaced by the corresponding raw material.

In the invention, the cupric salt is preferably one or more of cupric bromide, cupric fluoride, cupric chloride, copper trifluoromethanesulfonate, cupric nitrate, cupric sulfate and cupric acetate. In the present invention, the molar ratio of the divalent copper salt to the ligand is preferably (0.95 to 1.00) to 1.

In the invention, the nitrogen-containing organic base is preferably one or more of N-ethylmorpholine, triethylamine, piperidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-diisopropylethylamine and triethylene diamine. In the present invention, the molar ratio of the nitrogen-containing organic base to the ligand is preferably (2.00 to 2.05): 1.

In the invention, the reaction temperature is preferably 0-25 ℃, and more preferably 10-20 ℃; the reaction time is preferably 2 to 4 hours. In the present invention, stirring is preferably accompanied during the reaction.

In the present invention, the step of preparing the catalyst preferably specifically comprises:

and (2) mixing and reacting a cupric salt, a nitrogen-containing organic base, a ligand and a solvent to obtain the chiral copper-based catalyst compound.

In the present invention, the kind of the solvent is not particularly limited, and may be any solvent that is conventional in the art, and in the present invention, one or more of toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, acetone, ethyl acetate, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol, isopropanol and water are preferred; ethanol is more preferred. In the present invention, the concentration of the ligand in the solvent is preferably 0.10 to 0.11mol/L.

In a solvent medium, after the reaction, a chiral copper-based catalyst is generated in the system, and a compound containing the chiral copper-based catalyst, namely the chiral copper-based catalyst compound (namely the system also comprises other components such as a solvent besides the generated catalyst) is obtained.

In the invention, the chiral copper-based catalyst and the chiral copper-based catalyst compound can be used for catalyzing the synthesis of the optically active indole compound, namely the invention can catalyze the synthesis of the optically active indole compound in two ways. The first mode is as follows: the chiral copper-based catalyst compound is directly put into a preparation system for subsequently synthesizing the optically active indole compound to catalyze the synthesis of the optically active indole compound. The second way is: and (2) separating and extracting the chiral copper-based catalyst compound, separating the chiral copper-based catalyst, and putting the chiral copper-based catalyst serving as a catalyst into a preparation system for subsequently synthesizing the optically active indole compound to catalyze the synthesis of the optically active indole compound. In the second aspect, the means for separating and extracting is preferably: and (2) stirring the catalyst system for 2-3 hours by using acetone as a solvent, then carrying out centrifugal sedimentation, taking the filtrate, carrying out spin drying, adding methanol, washing and drying to obtain the chiral copper-based catalyst.

About applications：

The invention also provides application of the catalyst in the technical scheme in catalytic synthesis of the optically active indole compound. Corresponding to the foregoing, the above application includes two ways: the chiral copper-based catalyst compound containing the chiral copper-based catalyst is used for catalytically synthesizing the optically active indole compound; secondly, a pure chiral copper-based catalyst is used for catalyzing and synthesizing the optically active indole compound.

The invention also provides a synthetic method of the optically active indole compound, which comprises the following steps:

under the action of a catalyst, reacting the 3-alkenyl indole compound shown in the formula (I) with an isatin-like compound to form an optically active 3-alkenyl-3 substituted oxindole compound;

the isatin-like compound is a compound of a formula (II-1) and/or a compound of a formula (II-2);

the optically active 3-alkenyl-3 substituted oxindole compound is a compound shown in a formula (III-1) and/or a compound shown in a formula (III-2);

the catalyst is the catalyst in the technical scheme;

wherein:

R ¹ selected from: hydrogen, alkyl or halogen;

R ² 、R ⁴ each independently selected from: hydrogen, alkyl, halogen, nitro, trifluoromethyl;

R ³ selected from: allyl, phenyl, substituted or unsubstituted benzyl.

In the present invention, the term "under the action of a catalyst" means that the chiral copper-based catalyst complex described above may be directly put into a system to catalyze a synthesis reaction in the presence of a catalyst, or the chiral copper-based catalyst separated and extracted as described above may be put into a system to catalyze a synthesis reaction, as long as the catalyst is present.

In order to simplify the operation, the first mode is preferably adopted in the invention, and the chiral copper-based catalyst compound is directly used for catalyzing the synthesis reaction. Namely, after the chiral copper-based catalyst compound is obtained according to the preparation steps, the chiral copper-based catalyst compound is directly used for catalytic synthesis reaction without separation and extraction.

In the invention, the 3-alkenyl indole compound is shown as the following formula (I):

wherein R is ¹ Selected from: hydrogen, alkyl or halogen. The alkyl is preferably C1-C6 alkyl; more preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl or n-hexyl. The halogen is preferably fluorine, chlorine, bromine or iodine.

In the invention, more preferably, the 3-alkenyl indole compound shown in the formula (I) is selected from one or more of the following compounds:

in the invention, the isatin-like compound is a compound of a formula (II-1) and/or a compound of a formula (II-2):

wherein:

R ² 、R ⁴ each independently selected from: hydrogen, alkyl, halogen, nitro, trifluoromethyl. The alkyl group is preferablyC1-C6 alkyl; more preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl or n-hexyl. The halogen is preferably fluorine, chlorine, bromine or iodine.

R ³ Selected from: allyl, phenyl, substituted or unsubstituted benzyl. In the substituted benzyl group, the substituents are preferably: F. cl, br, me, OMe or CF ₃ 。

In the formula (II-2), the group Boc-means t-butoxycarbonyl; the radical Bn-is benzyl.

In the invention, more preferably, the isatin-like compound is selected from one or more of the following compounds:

in the invention, the molar weight of the catalyst is 5-30% of that of the isatin-like compound. In the invention, the molar ratio of the isatin-like compound to the 3-alkenyl indole compound shown in the formula (I) is 1: 1-1.5.

In the present invention, as described above, in order to simplify the operation, the first mode is preferably adopted in the present invention, and the synthesis reaction is directly catalyzed by the chiral copper-based catalyst composite. After the chiral copper-based catalyst compound is obtained according to the preparation steps, the chiral copper-based catalyst compound is directly used for catalytic synthesis reaction without separation and extraction. Specifically, after the chiral copper-based catalyst compound is obtained according to the preparation steps, the 3-alkenyl indole compound shown in the formula (I) and the isatin-like compound are directly added into the chiral copper-based catalyst compound for reaction. In the invention, the initial concentration of the 3-alkenyl indole compound shown in the formula (I) in the system is preferably 0.1-0.5 mol/L, and more preferably 0.1-0.3 mol/L; the initial concentration refers to the concentration of the 3-alkenyl indole compound shown in the formula (I) when the compound is added into the chiral copper-based catalyst compound.

In the invention, the reaction temperature is preferably 0-25 ℃, and more preferably 10-20 ℃; in some embodiments of the invention, the temperature of the reaction is 15 ℃ or 20 ℃. The reaction time is preferably 24 to 48 hours. After the reaction, the optically active 3-alkenyl-3 substituted oxindole compound is formed in the system.

In the invention, the obtained optically active 3-alkenyl-3 substituted oxindole compound is a compound shown in a formula (III-1) and/or a compound shown in a formula (III-2):

wherein R is ¹ 、R ² 、R ² 、R ⁴ The types of the above-mentioned components are the same as those in the foregoing technical solutions, and are not described in detail here.

In the invention, more preferably, the obtained optically active 3-alkenyl-3 substituted oxindole compound is selected from one or more of the following compounds:

in the present invention, after the above reaction, separation and purification treatment is preferably further performed. In the present invention, the method of separation and purification is not particularly limited, and may be any conventional method known to those skilled in the art, and in the present invention, a liquid-liquid separation method such as column chromatography, liquid chromatography, distillation, or the like, or a solid-liquid separation method such as recrystallization, or the like is preferable, and column chromatography is more preferable. In the column chromatography, the eluent adopted is preferably a mixed solvent of ethyl acetate and petroleum ether; the volume ratio of the ethyl acetate to the petroleum ether is preferably 1: 2-10. In the present invention, it is more preferable that the reaction solution obtained by the reaction is extracted with ethyl acetate, then back-extracted with a saturated saline solution, and then spin-dried, followed by column chromatography. After the post-treatment, the 3-alkenyl-3 substituted oxindole compound with optical activity is obtained.

In the invention, the raw material of the formula (II-1) corresponds to obtain a product of the formula (III-1), and the raw material of the formula (II-2) corresponds to obtain a product of the formula (III-2). When the starting material of formula (II-1) is fed separately, the product of formula (III-1) is obtained; when the starting material of formula (II-2) is fed separately, the product of formula (III-2) is obtained; when the starting material of formula (II-1) and the starting material of formula (II-2) are simultaneously charged, the product of formula (III-1) and the product of formula (III-2) are simultaneously obtained.

The invention also provides an optically active indole compound, which has a structure shown in a formula (III-1) and/or a structure shown in a formula (III-2):

wherein R is ¹ 、R ² 、R ² 、R ⁴ The types of the above-mentioned components are the same as those in the above-mentioned technical solutions, and are not described in detail herein.

In the invention, more preferably, the optically active 3-alkenyl-3 substituted oxindole compound is selected from one or more of the following compounds:

the technical scheme provided by the invention has the following beneficial effects:

1. the catalyst provided by the invention can prepare the 3-alkenyl-3-substituted oxindole compound with optical activity through the high enantioselectivity and diastereoselectivity direct asymmetric olefination reaction of the 3-alkenyl indole compound on the isatin-like compound, and simultaneously obtain higher enantioselectivity and diastereoselectivity; the enantioselectivity reaches more than 91 percent ee, the diastereoselectivity dr is more than 20:1, the product yield reaches more than 81 percent, and the purity reaches more than 99.9 percent. Compared with the conventional Lewis acid and other catalysts, the catalyst provided by the invention has obviously improved selectivity and yield.

2. The invention provides a preparation method of the catalyst, which can effectively synthesize the chiral copper-based catalyst and obtain high yield and high purity.

3. The invention provides application of a catalyst in catalytic synthesis of an optically active indole compound, which is represented by a formula (C) for the first time ₁ ) Compound and/or formula (C) ₂ ) The compound is used as a catalyst for catalytically synthesizing an optically active indole compound, and particularly, the optically active 3-alkenyl-3-substituted oxindole compound is prepared by asymmetric direct olefination reaction of the 3-alkenyl indole compound on high enantioselectivity and diastereoselectivity of an isatin compound, and a good preparation effect is obtained.

4. The synthesis method of the optically active indole compound provided by the invention can obtain the optically active 3-alkenyl-3-substituted oxindole compound with high enantioselectivity and diastereoselectivity, the enantioselectivity reaches more than 91% ee, the diastereoselectivity dr is more than 20:1, the product yield reaches more than 81%, the purity reaches more than 99.9%, the obtained product is single chirality, and the chirality reaches more than 91%. The stereoselectivity of the product can still be maintained when the reaction is scaled up to gram scale.

5. The optical activity indole compound provided by the invention is a novel optical activity indole compound which is not disclosed in the prior art, the oxidation indole compound has potential medicinal value and a natural product precursor, so that the optical activity indole compound has practical value for the research of the skeleton structure, and the optical activity indole compound provided by the invention is a 3-alkenyl-3 substituted oxindole compound, and enriches the category of C3 position indole compounds. In addition, natural products and drug molecules are generally single chirality, and the chirality of the synthesized optically active indole compound reaches more than 91%, so that the method has important significance.

For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the invention, and not to limit the scope of the claims.

In the following examples, the solvents were purchased from the national pharmaceutical group and the pharmaceutical raw materials were purchased from Shanghai Bigdi pharmaceutical science and technology Co. In HPLC analysis, silica gel plate was purchased from Nicotiana Xinno chemical Co., ltd, and pure n-hexane and isopropanol for chromatography were purchased from TEDIA. The room temperature means 25 ℃.

Raw material preparation example 1: ligand L _1b Preparation of (2)

S1, preparing an intermediate S1:

to a suspension of L-phenylalanine (3.0 g) in ethanol as a solvent at 0 ℃ was added dropwise SOCl ₂ . Then reacted for a period of time and the solvent evaporated to give a white solid which was further saturated with Na ₂ CO ₃ The aqueous solution is treated until the pH reaches 8-9. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with anhydrous Na ₂ SO ₄ Drying and removal of the solvent under reduced pressure gave pure (S) -ethyl-2-amino-3-phenylpropionate (3.395g, 96%). A thoroughly dried two-necked round bottom flask was equipped with a reflux condenser, an additional funnel and a nitrogen inlet. Magnesium powder (1.5g, 62mmol) and 15mL of tetrahydrofuran were then placed in the apparatus. A solution of p-bromotoluene (4.34mL, 42mmol) in tetrahydrofuran (25 mL) was added slowly. After the addition was complete, the mixture was refluxed for another 1 hour. After cooling to 0 ℃, a solution of ethyl (S) -2-amino-3-phenylpropionate (2g, 10.4 mmol) in tetrahydrofuran (10 mL) was slowly added and the reaction mixture was further refluxed for 2 hours. The reaction was quenched with saturated aqueous NH4Cl at 0 ℃. The solution was filtered and extracted with dichloromethane (25 mL. Times.3). The combined organic phases were washed with anhydrous Na ₂ SO ₄ Dried and evaporated under reduced pressure to give a yellow solid. The crude product was purified by crystallization from methanol to give intermediate S as a white solid ₁ (2.65g, 81% yield).

S2, preparing ligand L _1b ：

To intermediate S ₁ To a solution of (0.5 mmol) in methanol (5 mL) was added the salicylaldehyde derivative (0.5 mmol). The solution was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petrol/ethyl acetate =10/1 as eluent) to quantitatively give the corresponding schiff base ligand (L) _1b )。

The synthetic route of the steps S1 to S2 is as follows:

sample characterization:

(1) Characterization of intermediate S1:

preparation of intermediate product S from raw Material preparation example 1 by Nuclear magnetic resonance ₁ The nuclear magnetic resonance hydrogen spectrum of the sample was obtained by analysis, as shown in FIG. 1. ¹ H NMR(400MHz,CDCl ₃ ):δ7.51-7.45(m,4H),7.30-7.26(m,2H),7.22-7.16(m,3H),7.13-7.10(m,4H),4.13-4.10(m,1H),2.66(d,J＝13.7Hz,1H),2.46-2.39(m,1H),2.29(s,3H),2.28(s,3H),1.21(br,2H)；

Preparation of intermediate product S from raw Material preparation example 1 by Nuclear magnetic resonance ₁ The nuclear magnetic resonance carbon spectrum of the sample was obtained by analysis, as shown in FIG. 2. ¹³ C NMR(100MHz,CDCl ₃ ):δ144.3,141.8,140.0,136.4,136.1,129.3,129.2,129.1,128.8,126.5,125.8,125.4,78.5,58.3,37.0,21.1,21.0；IR(film):3436,3391,3025,2923,2869,1602,1510,1453,1377,1174,813,782,734；

Using mass spectrometers (Waters) ^TM Q-TOF Premier) on intermediate product S obtained in preparation example 1 of starting Material ₁ The analysis was carried out to obtain results HRMS (ESI) m/z, calcd for C ₂₃ H ₂₅ NO 331.1936,found 331.1933

(2) Ligand L _1b The characterization of (1):

preparation of the product L obtained in example 1 from the starting Material by means of Nuclear magnetic resonance _1b The nuclear magnetic resonance hydrogen spectrum of the sample was obtained by analysis, as shown in FIG. 3. ¹ H NMR(400MHz,CDCl ₃ ):δ13.97(br,1H),7.55-7.48(m,4H),7.32(d,J＝8.3Hz,2H),7.20-7.10(m,5H),7.05-6.97(m,5H),6.76(t,J＝7.6Hz,1H),4.32(dd,J＝10.3Hz,1.8Hz,1H),3.04(dd,J＝13.8Hz,1.6Hz,1H),2.84(dd,J＝13.8Hz,10.3Hz,1H),2.80(s,1H),2.33(s,3H),2.22(s,3H)；

Preparation of the product L obtained in example 1 from the starting Material by means of Nuclear magnetic resonance _1b The nuclear magnetic resonance hydrogen spectrum of the sample was obtained by analysis, as shown in FIG. 4. ¹³ C NMR(100MHz,CDCl ₃ ):δ165.8,160.4,142.4,141.3,138.9,136.9,136.8,135.3,130.1,129.8,129.4,129.2,128.5,126.6,126.1,125.9,119.0,117.3,79.6,78.6,37.5,21.1,21.0；IR(film):3584,3430,3027,2925,1634,1508,1455,1332,1154,1120,1078,817,753,733；

Using mass spectrometers (Waters) ^TM Q-TOF Premier) on product L obtained in preparation example 1 of starting Material _1b The analysis was carried out to obtain results HRMS (ESI) m/z, calcd for C ₃₁ H ₂₈ F ₃ NO ₂ 503.2072,found 503.2069。

Example 1

Copper bromide (2.2mg, 0.01mmol) and ligand (L) were added to a 10mL reaction tube in this order _1b 5.0mg, 0.01mmol), ethanol (1.0 ml) and N-ethylmorpholine (2.5 μ l,0.02 mmol) at room temperature, and stirring at room temperature for 2 hr to obtain chiral copper-based catalyst composite (wherein the chiral copper-based catalyst C is _1b Yield of (2) is 100%, purity is 100%). Then, 3-alkenylindole (formula I-1, 33.0mg, 0.15mmol) and N-benzyl isatin (formula II-1a,23.7mg, 0.1mmol) were added to the complex system in this order at 20 ℃ to obtain a reaction solution containing an optically active indole compound after completion of the reaction (TLC follow-up detection). Extracting with ethyl acetate, back-extracting with saturated brine, drying with anhydrous sodium sulfate, and spin-drying the obtained residue, and purifying with petroleum ether/ethyl acetate system (volume ratio of ethyl acetate to petroleum ether is 1: 5) as eluent to obtain pale yellow solid of formula III-1 a (40.6 mg,91% ee>20, 1; yield 89%, purity 100%).

In the preparation process, the synthesis route of the catalyst is as follows:

in the obtained chiral copper-based catalyst compound, a chiral copper-based catalyst C _1b The single crystal structure of (a) is shown in fig. 5, and the structural parameter information corresponding to the single crystal structure of fig. 5 is shown in table 1 below.

TABLE 1 chiral copper-based catalyst C obtained in example 1 _1b Single crystal structure information of

Molecular formula	C ₆₂ H ₅₂ Cu ₂ F ₆ N ₂ O ₄
		Molecular weight	1130.14
Space group	P.1
		Z	4
a,A°	23.8750(9)
		b,A°	15.9632(4)
c,A°	16.7720(5)
		a,°	90.00
β,°	111.60
		γ,°	90.00
V,A ^°3	5943.1(3)
		T，K	293
p,g/cm ³	1.328

In the preparation process, the synthetic route of the optically active indole compound is as follows:

the product obtained in example 1, formula III-1 a, was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a hydrogen nuclear magnetic resonance spectrum, as shown in FIG. 6. ¹ H NMR(500MHz,CD ₃ OD)δ7.88(d,J＝7.9Hz,1H),7.35(dd,J＝7.3,3.1Hz,2H),7.29–7.23(m,4H),7.21(ddd,J＝8.4,5.6,2.4Hz,1H),7.14(ddd,J＝7.9,3.2,2.1Hz,2H),7.11–7.05(m,2H),7.05–7.00(m,2H),6.97(t,J＝7.4Hz,1H),6.78(s,1H),6.65(d,J＝7.1Hz,2H),6.50(s,1H),6.40(d,J＝7.8Hz,1H),4.75(d,J＝15.8Hz,1H),3.84(d,J＝15.8Hz,1H)。

The product of formula III-1 a obtained in example 1 was analyzed by NMR to obtain a NMR carbon spectrum, as shown in FIG. 7. ¹³ C NMR(125MHz,CD ₃ OD)δ178.2,142.1,139.5,138.7,137.5,135.7,133.6,129.2,128.7,128.3,127.2,127.0,127.0,126.7,125.8,124.8,124.4,124.3,122.8,121.5,120.0,119.5,118.0,111.3,109.3,75.9,43.0。

Using mass spectrometers (Waters) ^TM Q-TOF Premier) analysis of the product of formula III-1 a obtained in example 1 gave the result HRMS (ESI) m/z for C ₃₁ H ₂₄ N ₂ O ₂ [M+Na] ⁺ 479.1735 and measured 479.1728.

Wherein, the chirality of the obtained product III-1 a is characterized by high performance liquid chromatography (TLC method), and the result is shown in figure 8, and the chirality reaches 91%.

Example 2

A chiral copper-based catalyst composite was prepared as in example 1. Then, 3-alkenylindole (formula I-1, 33.0mg, 0.15mmol) and N-allylisatin (formula II-1b,18.7mg, 0.1mmol) were added to the complex system in this order at 20 ℃ to obtain a reaction solution containing an optically active indole compound after completion of the reaction (TLC follow-up detection). The residue obtained by the subsequent extraction with ethyl acetate, back extraction with saturated brine, drying over anhydrous sodium sulfate and spin-drying was subjected to column chromatography using a petroleum ether/ethyl acetate system (volume ratio of ethyl acetate to petroleum ether: 1: 5) as an eluent to give a pale yellow solid of formula III-1 b (37.7mg, 91% ee, dr 20; yield 93%, purity 100%).

the product obtained in example 2, formula III-1 b, was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a hydrogen nuclear magnetic resonance spectrum, as shown in FIG. 9. ¹ H NMR(500MHz,CD3OD)δ7.85(d,J＝8.0Hz,1H),7.35(dd,J＝10.9,7.7Hz,2H),7.22–7.05(m,4H),7.01(dd,J＝13.4,7.2Hz,3H),6.74(s,1H),6.63(d,J＝7.1Hz,2H),6.51(d,J＝7.8Hz,1H),6.49(s,1H),5.76–5.50(m,1H),5.13(ddd,J＝13.8,11.6,1.2Hz,2H),4.13–3.94(m,1H),3.41(dd,J＝16.4,5.9Hz,1H)。

The product of formula III-1 b obtained in example 2 was analyzed by NMR to obtain a NMR carbon spectrum, as shown in FIG. 10. ¹³ C NMR(125MHz,CD3OD)δ177.7,142.2,139.4,138.8,137.5,133.7,131.3,129.2,128.8,127.0,126.7,125.7,124.8,124.5,124.2,122.8,121.5,120.0,119.5,118.0,116.3,111.3,109.2,75.9,41.7。

Using mass spectrometers (Waters) ^TM Q-TOF Premier) analysis of the product of formula III-1 b obtained in example 2 gave the result HRMS (ESI) m/z for C ₂₇ H ₂₂ N ₂ O ₂ [M+Na] ⁺ 425.1579 and measured 429.1576.

Example 3

A chiral copper-based catalyst composite was prepared as in example 1. Then, 3- (4-methoxyphenyl) vinyl indole (formula I-3, 38.0mg, 0.15mmol) and N-allyl isatin (formula II-1b,18.7mg, 0.1mmol) were added to the complex system in this order at 20 ℃ to obtain a reaction solution containing an optically active indole compound after completion of the reaction (TLC follow-up). The residue obtained by the subsequent extraction with ethyl acetate, back extraction with saturated brine, drying over anhydrous sodium sulfate and spin-drying was subjected to column chromatography using a petroleum ether/ethyl acetate system (volume ratio of ethyl acetate to petroleum ether: 1: 5) as an eluent to give a pale yellow solid of formula III-1 c (40.5mg, 91% ee, dr >.

the product obtained in example 3, formula III-1 c, was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a hydrogen nuclear magnetic resonance spectrum, as shown in FIG. 11. ¹ H NMR(500MHz,MeOD)δ7.82(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,2H),7.17(t,J＝7.6Hz,1H),7.12(t,J＝7.4Hz,1H),7.07(t,J＝7.4Hz,1H),7.02(t,J＝7.4Hz,1H),6.70(s,1H),6.66–6.31(m,6H),5.65(ddd,J＝22.0,10.4,5.2Hz,1H),5.19(d,J＝17.3Hz,1H),5.12(d,J＝10.3Hz,1H),4.08(dd,J＝16.3,4.4Hz,1H),3.74(s,3H),3.54(dd,J＝16.3,5.5Hz,1H).

The product of formula III-1 c obtained in example 3 was analyzed by NMR to obtain a NMR carbon spectrum, as shown in FIG. 12. ¹³ C NMR(125MHz,MeOD)δ177.7,158.6,142.3,139.1,137.5,133.8,131.4,131.2,130.4,128.8,125.7,124.9,124.6,124.2,122.8,121.4,120.1,119.5,118.3,116.4,112.4,111.3,109.1,75.9,54.3,41.8.

Using mass spectrometers (Waters) ^TM Q-TOF Premier) analysis of the product of formula III-1C obtained in example 3 gave the result HRMS (ESI) m/z for C ₂₈ H ₂₄ N ₂ O ₃ [M+Na] ⁺ 459.1685, found 459.1688.

Example 4

A chiral copper-based catalyst composite was prepared as in example 1. Then, 3-vinyl indole (formula I-1, 33.0mg, 0.15mmol) and 5-methyl-N-benzyl isatin (formula II-1c,20.1mg, 0.1mmol) were added to the complex system in this order at 20 ℃ to obtain a reaction solution containing an optically active indole compound after the reaction was completed (TLC follow-up). The residue obtained by the subsequent extraction with ethyl acetate, back-extraction with saturated brine, drying over anhydrous sodium sulfate and spin-drying was subjected to column chromatography using a petroleum ether/ethyl acetate system (volume ratio of ethyl acetate to petroleum ether: 1: 5) as an eluent to give a pale yellow solid of formula III-1 d (38.0 mg,92% ee, dr 20; yield 81%, purity 100%).

the product obtained in example 4, formula III-1 d, was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a hydrogen nuclear magnetic resonance spectrum, as shown in FIG. 13. ¹ H NMR(500MHz,MeOD)δ7.85(d,J＝7.9Hz,1H),7.35(d,J＝8.0Hz,1H),7.29-7.24(m,4H),7.23-7.20(m,1H),7.16–7.11(m,3H),7.09(t,J＝7.5Hz,1H),7.02(t,J＝7.4Hz,2H),6.87(d,J＝7.9Hz,1H),6.75(s,1H),6.67(d,J＝7.3Hz,2H),6.53(s,1H),6.32(d,J＝8.0Hz,1H),4.72(d,J＝15.7Hz,1H),3.91(d,J＝15.7Hz,1H),2.23(s,3H).

The product of formula III-1 d obtained in example 4 was analyzed by NMR to obtain a NMR carbon spectrum, as shown in FIG. 14. ¹³ C NMR(125MHz,MeOD)δ178.1,139.7,139.4,138.9,137.5,135.9,133.2,132.5,129.2,128.9,128.3,127.1,127.1,127.0,126.9,125.7,125.1,124.9,124.4,121.5,120.0,119.5,118.1,111.3,109.0,76.1,43.0,19.7.

Using mass spectrometers (Waters) ^TM Q-TOF Premier) analysis of the product of formula III-1 d obtained in example 4 gave the result HRMS (ESI) m/z for C ₃₂ H ₂₆ N ₂ O ₂ [M+Na] ⁺ 493.1892 and measured 493.1885.

Example 5

A chiral copper-based catalyst composite was prepared as in example 1. Then, 3-vinylindole (formula I-1, 33.0mg, 0.15mmol) and 5-methoxy-N-benzylisatin (formula II-1d,20.1mg, 0.1mmol) were added to the complex system in this order at 20 ℃ and after the reaction was completed (TLC follow-up detection), a reaction solution containing optically active indole compounds was obtained. Extraction with ethyl acetate, back-extraction with saturated brine, drying over anhydrous sodium sulfate, and spin-drying the resulting residue, which was passed through a column using a petroleum ether/ethyl acetate system (volume ratio of ethyl acetate to petroleum ether 1: 5) as eluent, gave a pale yellow solid of formula III-1 e (40.8 mg,96% ee, dr > -20, 84% yield, 100% purity).

the product obtained in example 5, formula III-1 e, was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a hydrogen nuclear magnetic resonance spectrum, as shown in FIG. 15. ¹ H NMR(500MHz,MeOD)δ7.86(d,J＝7.9Hz,1H),7.35(d,J＝8.0Hz,1H),7.29–7.23(m,4H),7.23–7.18(m,1H),7.16–7.06(m,3H),7.01(t,J＝7.6Hz,2H),6.95(d,J＝2.5Hz,1H),6.76(s,1H),6.69(d,J＝7.2Hz,2H),6.59(dd,J＝8.6,2.5Hz,1H),6.53(s,1H),6.31(d,J＝8.6Hz,1H),4.73(d,J＝15.7Hz,1H),3.88(d,J＝15.7Hz,1H),3.67(s,3H).

The product of formula III-1 e obtained in example 5 was analyzed by NMR to obtain a NMR carbon spectrum, as shown in FIG. 16 ¹³ C NMR(125MHz,MeOD)δ178.0,156.6,139.6,138.8,137.5,135.8,135.4,134.4,129.2,128.3,127.1,127.1,127.0,126.7,125.8,124.9,124.3,121.5,120.1,119.6,118.1,113.6,111.3,111.2,109.8,76.3,54.9,43.1.

Using mass spectrometers (Waters) ^TM Q-TOF Premier) analysis of the product of formula III-1 e obtained in example 5 gave the result HRMS (ESI) m/z,for C ₃₂ H ₂₆ N ₂ O ₃ [M+Na] ⁺ 509.1841 and measured 509.1838.

Example 6

A chiral copper-based catalyst composite was prepared as in example 1. Then, 3- (4-methylphenyl) vinyl indole (formula I-2, 35.0mg, 0.15mmol) and N-benzyl isatin imine (formula II-2a,33.6mg, 0.1mmol) are added into the complex system in sequence at 15 ℃, and after the reaction is finished (TLC tracking detection), a reaction solution containing the optically active indole compound is obtained. The residue obtained by the subsequent extraction with ethyl acetate, back extraction with saturated brine, drying over anhydrous sodium sulfate and spin-drying was subjected to column chromatography using a petroleum ether/ethyl acetate system (volume ratio of ethyl acetate to petroleum ether: 1: 5) as an eluent to give a pale yellow solid of formula III-2 a (55.7 mg,97% ee, dr 20; yield 98%, purity 100%).

the product obtained in example 6, formula III-2 a, was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a hydrogen nuclear magnetic resonance spectrum, as shown in FIG. 17. ¹ H NMR(500MHz,CDCl ₃ )δ8.44(s,1H),7.57(d,J＝7.9Hz,1H),7.34(d,J＝7.3Hz,2H),7.29(d,J＝8.0Hz,2H),7.27(d,J＝7.3Hz,2H),7.22–7.18(m,1H),7.14(t,J＝7.4Hz,1H),7.09–7.01(m,2H),6.98(q,J＝8.0Hz,4H),6.90(t,J＝7.4Hz,1H),6.55(d,J＝2.6Hz,1H),6.44(d,J＝5.6Hz,1H),6.17(s,1H),5.44(s,1H),4.73(s,1H),4.34(s,1H),2.34(s,3H),1.25(s,9H).

The product obtained in example 6, formula III-2 a, was analyzed by NMR to obtain the NMR carbon spectrum, as shown in FIG. 18. ¹³ C NMR(125MHz,CDCl ₃ )δ176.1,153.8,142.3,139.4,137.1,136.9,135.8,135.3,132.4,129.6,128.8,128.7,128.4,128.3,127.4,125.6,125.0,124.0,122.8,122.3,121.6,120.5,120.4,119.7,111.6,109.0,80.1,63.6,44.1,28.1,21.3.

Using mass spectrometers (Waters) ^TM Q-TOF Premier) analysis of the product of formula III-2 a obtained in example 6 gave the result HRMS (ESI) m/z for C ₃₇ H ₃₅ N ₃ O ₃ [M+Na] ⁺ 592.2576 and measured 592.2579.

Wherein, the chirality of the obtained product III-2 a is characterized by high performance liquid chromatography (TLC method), and the result is shown in figure 19, and the chirality reaches 91%.

Example 7

A chiral copper-based catalyst composite was prepared as in example 1. Then, 3- (4-methoxyphenyl) vinyl indole (formula I-3, 38.0mg, 0.15mmol) and N-benzyl isatin imine (formula II-2a,33.6mg, 0.1mmol) are added into the complex system in sequence at 15 ℃, and after the reaction is finished (TLC tracking detection), a reaction solution containing the optically active indole compound is obtained. The residue obtained by the subsequent extraction with ethyl acetate, back-extraction with saturated brine, drying over anhydrous sodium sulfate and spin-drying was subjected to column chromatography using a petroleum ether/ethyl acetate system (volume ratio of ethyl acetate to petroleum ether: 1: 5) as an eluent to give a pale yellow solid of formula III-2 b (57.9mg, 97% ee, dr 20; yield 99%, purity 100%).

the product obtained in example 7, formula III-2 b, was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a hydrogen nuclear magnetic resonance spectrum, as shown in FIG. 20. ¹ H NMR(500MHz,CDCl ₃ )δ8.51(s,1H),7.55(d,J＝7.8Hz,1H),7.37(d,J＝7.4Hz,2H),7.31(d,J＝8.1Hz,2H),7.28(d,J＝7.2Hz,2H),7.22(t,J＝7.2Hz,1H),7.15(t,J＝7.2Hz,1H),7.11–7.03(m,2H),7.01(d,J＝8.5Hz,2H),6.93(t,J＝7.4Hz,1H),6.71(d,J＝8.7Hz,2H),6.59(d,J＝2.6Hz,1H),6.49(d,J＝6.2Hz,1H),6.17(s,1H),5.48(s,1H),4.77(s,1H),4.44(s,1H),3.81(s,3H),1.27(s,9H).

Examples using nuclear magnetic resonanceThe product of formula III-2 b obtained in FIG. 7 was analyzed to obtain its NMR carbon spectrum, as shown in FIG. 21. ¹³ C NMR(126MHz,CDCl ₃ )δ176.1,159.0,153.8,142.3,139.2,136.9,135.8,132.4,131.0,130.6,128.7,128.4,127.5,127.5,125.5,125.1,124.0,122.8,122.3,120.4,120.4,119.9,113.4,113.1,111.7,109.0,80.2,63.5,55.3,44.1,28.2.

Using mass spectrometers (Waters) ^TM Q-TOF Premier) analysis of the product of formula III-2 b obtained in example 7 gave the result HRMS (ESI) m/z for C ₃₇ H ₃₅ N ₃ O ₄ [M+Na] ⁺ 608.2525, found 608.2520.

Example 8

A chiral copper-based catalyst composite was prepared as in example 1. Then, 3-vinylindole (formula I-1, 33.0mg, 0.15mmol) and 5-methyl N-benzyl isatin imine (formula II-2b,35.0mg, 0.1mmol) were added to the above complex system in this order at 15 ℃ to obtain a reaction solution containing an optically active indole compound after the reaction was completed (TLC follow-up detection). The residue obtained by the subsequent extraction with ethyl acetate, back-extraction with saturated brine, drying over anhydrous sodium sulfate and spin-drying was subjected to column chromatography using a petroleum ether/ethyl acetate system (volume ratio of ethyl acetate to petroleum ether: 1: 5) as an eluent to give a pale yellow solid of formula III-2 c (54.0 mg,99% ee, dr >.

the product obtained in example 8, formula III-2 c, was analyzed by nuclear magnetic resonance (Bruker AC-300 FT) to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 22. ¹ H NMR(500MHz,CDCl ₃ )δ8.42(s,1H),7.62(d,J＝7.9Hz,1H),7.40–7.30(m,4H),7.25–7.20(m,3H),7.17(t,J＝7.4Hz,3H),7.13–7.06(m,2H),7.00(d,J＝7.1Hz,2H),6.81(d,J＝7.8Hz,1H),6.54(d,J＝2.6Hz,1H),6.32(d,J＝7.0Hz,1H),6.29(s,1H),5.45(s,1H),4.72(s,1H),4.29(s,1H),2.19(s,3H),1.30(s,9H).

The product of formula III-2 c obtained in example 8 was analyzed by NMR to obtain a NMR carbon spectrum, as shown in FIG. 23. ¹³ C NMR(125MHz,CDCl ₃ )δ175.6,153.6,139.5,139.2,138.0,136.6,135.6,131.8,131.5,129.2,128.4,128.3,127.8,127.3,127.1,127.1,127.0,125.3,124.8,124.6,122.1,120.1,119.7,119.3,111.3,108.5,79.9,63.2,43.7,27.9,20.7.

Using mass spectrometers (Waters) ^TM Q-TOF Premier) analysis of the product of formula III-2C obtained in example 8 gave the result HRMS (ESI) m/z for C ₃₇ H ₃₅ N ₃ O ₃ [M+Na] ⁺ 592.2576 and measured 592.2572.

The foregoing examples are provided to facilitate an understanding of the principles of the invention and their core concepts, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The scope of the invention is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that approximate the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

Claims

1. A synthetic method of an optically active indole compound is characterized by comprising the following steps:

under the action of a catalyst, 3-alkenyl indole compounds shown in formula (I) react with isatin-like compounds to form 3-alkenyl-3 substituted oxindole compounds with optical activity;

wherein:

R ¹ selected from: hydrogen, alkyl or halogen;

R ³ selected from the group consisting of: allyl, phenyl, substituted or unsubstituted benzyl;

the catalyst is a chiral copper-based catalyst;

wherein:

Ar ¹ 、Ar ² each independently selected from: substituted or unsubstituted aryl.

2. The synthesis method as claimed in claim 1, wherein the 3-alkenyl indole compound shown in the formula (I) is selected from one or more of the following compounds:

3. the synthesis method according to claim 1, characterized in that the temperature of the reaction is 0-25 ℃.

4. The synthesis method according to claim 1, wherein the molar amount of the catalyst is 5 to 30% of the molar amount of the isatin-like compound.

5. The synthesis method according to claim 1, wherein the molar ratio of the isatin-like compound to the 3-alkenyl indole compound shown in the formula (I) is 1: 1-1.5.

6. The method of synthesis of claim 1, wherein Ar ¹ 、Ar ² Wherein said aryl is phenyl or naphthyl; in the substituted aryl, the substituent is selected from alkyl, alkoxy or halogenated alkyl.

7. The synthesis method according to claim 1, wherein the chiral copper-based catalyst is selected from one or more of the following compounds:

8. an optically active indole compound prepared by the synthesis method of any one of claims 1 to 7, wherein the optically active indole compound has a structure of formula (III-1) and/or a structure of formula (III-2);

wherein:

R ¹ selected from: hydrogen, alkyl or halogen;

R ³ selected from: allyl, phenyl, substituted or unsubstitutedA benzyl group.