CN114276288B - Synthesis method and application of chiral α-propargyl-3-indole compounds and their derivatives - Google Patents

Abstract

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a synthesis method and application of chiral alpha-propargyl-3-indole compounds and derivatives thereof, wherein the compounds and the derivatives thereof take diazo compounds, alcohols and indolypropanol as raw materials, rh ₂ (esp) ₂ Chiral phosphoric acid is used as a catalyst, a molecular sieve is used as a water absorbent, and the catalyst is prepared by one-step three-component reaction in an organic solvent. The method has the advantages of high atom economy, good selectivity, mild reaction conditions, high yield, simple and safe operation and the like. The chiral alpha-propargyl-3-indole compounds and the derivatives thereof have a lot of biological activities, and indole frameworks and indolinone frameworks contained in the compounds are important structural fragments of a lot of complex natural products with biological activities, so that the compounds can be used as important pharmaceutical and chemical intermediates and have wide application prospects in the pharmaceutical field.

Description

A method for synthesizing chiral α-propargyl-3-indole compounds and their derivatives and their applications

Technical Field

The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a synthesis method and application of a chiral α-propargyl-3-indole compound and its derivatives.

Background Art

Chiral α-propargyl-3-indole compounds are widely present in natural products and drug molecules. They are an important skeleton structure for building natural products and drugs, and are also important intermediates for organic synthesis and drug synthesis. Due to their high biological activity, the synthesis of this type of compound is one of the important areas of organic chemistry research, but their asymmetric synthesis is still very challenging.

At present, the method of synthesizing propargyl heterocyclic skeleton compounds using propargyl alcohol as raw material has made certain research progress. There are two main methods for synthesizing propargyl heterocyclic skeleton compounds. One is to use propargyl alcohols to directly asymmetric replace nucleophilic heterocyclic compounds to construct propargyl heterocyclic skeleton compounds; the other is to use the nucleophilic addition of allenyl reagents to unsaturated nucleophiles to construct substituted propargyl heterocyclic skeleton compounds. However, the substrates used in the existing methods are limited to some relatively simple structures and lack structural diversity, resulting in the synthesized propargyl heterocyclic skeleton compounds having defects such as a narrow scope of substrate application and poor selectivity. Therefore, it is necessary to develop a new method for synthesizing propargyl heterocyclic skeleton compounds to improve its defects such as a narrow scope of substrate application and poor selectivity.

Summary of the invention

In order to overcome the above-mentioned deficiencies of the prior art, the primary purpose of the present invention is to provide a chiral α-propargyl-3-indole compound and its derivatives.

The second object of the present invention is to provide a method for synthesizing the chiral α-propargyl-3-indole compounds and their derivatives. The method of the present invention has the advantages of high atom economy, good step economy, good regioselectivity and enantioselectivity, wide substrate applicability, mild reaction conditions, high yield, simple and safe operation, etc.

The third object of the present invention is to provide the use of the chiral α-propargyl-3-indole compounds and their derivatives. The chiral α-propargyl-3-indole compounds and their derivatives of the present invention can be used as important pharmaceutical and chemical intermediates and have broad application prospects in the pharmaceutical field. For example, they can be used to prepare anti-colon cancer drugs.

The above first object of the present invention is achieved by the following technical solutions:

A chiral α-propargyl-3-indole compound or a derivative thereof, wherein the structure of the compound or the derivative thereof is as shown in syn-5 or anti-5 of formula (I):

In the formula, Ar ¹ is independently selected from phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, alkoxy-substituted phenyl, naphthyl, alkyl-substituted naphthyl, alkoxy-substituted naphthyl;

Ar ² is independently selected from phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, alkoxy-substituted phenyl, naphthyl, alkyl-substituted naphthyl, alkoxy-substituted naphthyl, thienyl, furanyl;

R ¹ is independently selected from hydrogen, alkyl, benzyl, halobenzyl, tert-butyloxycarbonyl, acetyl;

^R2 is independently selected from alkyl, benzyl, C2 alkyl-substituted benzyl, C2 alkoxy-substituted benzyl, 2-naphthylmethyl, allyl, cinnamyl, nerol, phenylpropargyl;

R is independently selected from alkyl, alkylsilyl, and phenyl.

Preferably, ^Ar1 is phenyl, 5-methylphenyl, 5-chlorophenyl, 6-chlorophenyl, 6-bromophenyl, 6-methoxyphenyl, 7-methylphenyl, naphthyl, 2-methylnaphthyl or 2-methoxynaphthyl; ^Ar2 is phenyl, 5-chlorophenyl, 5-methoxyphenyl, 6-methoxyphenyl, 7-methylphenyl, naphthyl, 2-methylnaphthyl, 2-methoxynaphthyl, thienyl or furanyl; ^R1 is hydrogen, _C1-3 alkyl, benzyl, halogenated benzyl, acetyl or tert-butyloxycarbonyl; ^R2 is methyl, ethyl, propyl, isopropyl, ethyl substituted by trimethylsilyl, methyl substituted by cyclohexyl, benzyl, 2-methoxy substituted benzyl, 2-methyl substituted benzyl, 2-naphthylmethyl, allyl, cinnamyl, phenyl propargyl, nerol; R is trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, methyl, tert-butyl, phenyl.

Furthermore, Ar ¹ is phenyl or 7-methylphenyl; Ar ² is phenyl or 6-methoxyphenyl; R ¹ is methyl or benzyl; R ² is phenyl, 2-naphthylmethyl, ethyl, cinnamyl, phenylpropargyl or nerol; R is trimethylsilyl, tert-butyl or phenyl.

The above second object of the present invention is achieved through the following technical solutions:

The preparation method of the chiral α-propargyl-3-indole compound or its derivative is specifically as follows: according to reaction formula (II), the alcohol of formula (1), the diazo compound of formula (2) and the indole propargyl alcohol of formula (3) are used as raw materials, Rh ₂ (esp) ₂ and chiral phosphoric acid are used as catalysts, and molecular sieves are used as water absorbents, and the chiral α-propargyl-3-indole compound or its derivative is prepared by a one-step three-component reaction in an organic solvent:

In order to overcome the defects of the prior art in the preparation method of chiral α-propargyl-3-indole compounds, such as the narrow scope of substrate application and poor selectivity, the present invention proposes a method for efficiently synthesizing α-propargyl-3-indole compounds and their derivatives with two chiral centers in one step by using an indole imine-chiral phosphate ion pair to capture the active intermediate, hydroxyl ylide. The method of the present invention has the advantages of high atom economy, good step economy, regioselectivity and enantioselectivity, wide substrate applicability, mild reaction conditions, high yield, simple and safe operation, etc. Moreover, the chiral α-propargyl-3-indole compounds and their derivatives prepared by the present invention have good inhibitory activity on human colon cancer cells, and can be used as important intermediates in medicine and chemical industry, and have broad application prospects in the field of medicine.

The chemical reaction mechanism of the present invention is shown in Figure 1: first, the diazo compound of formula (1) decomposes under the catalysis of metal _Rh2 (esp) ₂ to form metal carbene (I) and release nitrogen, and the generated metal carbene (I) then interacts with the nucleophilic reagent alcohol of formula (2) to generate active intermediate hydroxyl ylide (II, III), and then the indole propargyl alcohol of formula (3) is dehydrated under the action of chiral phosphoric acid to form ion pair active intermediate (V, VI), and then the ion pair active intermediate (VI) is used as an electrophilic reagent to capture the active intermediate hydroxyl ylide (II, III), and a 1,4-addition reaction occurs to generate the product of the three-component reaction, a chiral α-propargyl-3-indole compound or its derivative.

Preferably, the reaction temperature is -30 to 25°C, and the reaction time is 2 to 6 hours. Specifically, the reaction temperature is -30°C, and the reaction time is 4 hours.

Preferably, the structure of the chiral phosphoric acid is as shown in formula (5):

In the formula, R is 1-pyrene.

Preferably, the molar ratio of the alcohol of formula (1), the diazo compound of formula (2) and the indole propargyl alcohol of formula (3) is 1.0-2.0:1.0-2.0:1.0. Specifically, the molar ratio of the alcohol of formula (1), the diazo compound of formula (2) and the indole propargyl alcohol of formula (3) is 1.5:1.5:1.0.

Preferably, based on the indole propargyl alcohol of formula (3), the amount of catalyst Rh ₂ (esp) ₂ is 2.0 mol% of the indole propargyl alcohol, and the amount of chiral phosphoric acid is 5.0-10 mol% of the indole propargyl alcohol. Specifically, the amount of chiral phosphoric acid is 10 mol% of the indole propargyl alcohol.

Preferably, the molecular sieve (MS) includes but is not limited to Molecular sieves, Molecular sieves, Molecular sieve. Specifically, the molecular sieve is Molecular sieve.

Preferably, based on the indole propargyl alcohol of formula (3), the feeding amount of the molecular sieve is 100 mg/mmol.

Preferably, the organic solvent includes but is not limited to dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene. Specifically, the organic solvent is 1,2-dichloroethane.

Preferably, the reaction further includes a separation and purification step; the separation and purification is performed by column chromatography using a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:5 to 30.

The above second object of the present invention is achieved through the following technical solutions:

Application of the chiral α-propargyl-3-indole compounds or their derivatives in the preparation of drugs for preventing colon cancer.

Preferably, the anti-colon cancer drug is a drug that inhibits colon cancer cells.

Preferably, the chiral α-propargyl-3-indole compound or its derivative is syn-5 of formula (I).

The present invention also provides a drug for resisting colon cancer or a drug for inhibiting colon cancer cells, wherein the drug has the drug for inhibiting colon cancer cells as a main active ingredient.

Preferably, it also includes other anti-tumor active ingredients that can synergistically enhance the effect with the above-mentioned chiral α-propargyl-3-indole compounds or their derivatives.

Preferably, the medicament further comprises a pharmaceutically acceptable carrier and/or excipient.

Furthermore, the excipient refers to diluents, adhesives, lubricants, disintegrants, solubilizers, stabilizers and other pharmaceutical matrices that can be used in the pharmaceutical field. The carrier is an acceptable functional pharmaceutical excipient in the pharmaceutical field, including surfactants, suspending agents, emulsifiers and some new pharmaceutical polymer materials, such as cyclodextrin, chitosan, polylactic acid (PLA), polyglycolic acid polylactic acid copolymer (PLGA), hyaluronic acid, etc.

Preferably, the above-mentioned drugs can be prepared into clinically acceptable dosage forms. The dosage forms are injections, tablets, capsules, etc. commonly used in clinical practice. The drug preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically). If some drugs are unstable under gastric conditions, they can be prepared into enteric-coated tablets.

Compared with the prior art, the present invention has the following beneficial effects:

The present invention discloses a chiral α-propargyl-3-indole compound and its derivatives, wherein the compound and its derivatives are prepared by a one-step three-component reaction in an organic solvent using a diazo compound, an alcohol, and an indole propargyl alcohol as raw materials, _Rh2 (esp) ₂ and chiral phosphoric acid as catalysts, and a molecular sieve as a water absorbent. The present invention has the following advantages:

(1) For the first time, a method for synthesizing chiral α-propargyl-3-indole compounds was proposed using an indole imine-chiral phosphate ion pair to capture the active intermediate, hydroxyl ylide;

(2) The method for synthesizing chiral α-propargyl-3-indole compounds and their derivatives by a one-step three-component reaction has the advantages of high flexibility, high selectivity, high atom economy, wide substrate applicability, easy product purification, mild reaction conditions, high yield, simple and safe operation, etc.;

(3) The α-propargyl-3-indole compounds and their derivatives containing an indole skeleton of the present invention can be used as important intermediates in medicine and chemical industry, and have broad application prospects in the pharmaceutical field. Moreover, with the increasing development of the concept of atom economy in recent years, the method of the present invention will also receive more and more attention, and will surely have broad application prospects in the field of drug synthesis.

(4) The chiral α-propargyl-3-indole compounds and their derivatives involved in the present invention not only have many biological activities (such as showing good inhibitory activity against human colon cancer cells), but also the indole skeleton and 2-indolone skeleton contained in the compounds are important structural fragments of many complex natural products with biological activities. Therefore, the compounds can be used as important intermediates in medicine and chemical industry and have broad application prospects in the field of medicine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a diagram showing the synthesis mechanism of chiral α-propargyl-3-indole compounds and their derivatives;

FIG2 is a ¹ H NMR schematic diagram of product 5a;

FIG3 is a schematic diagram of ¹³ C NMR of product 5a;

FIG4 is a ¹ H NMR schematic diagram of product 5b;

FIG5 is a schematic diagram of ¹³ C NMR of product 5b;

FIG6 is a ¹ H NMR schematic diagram of product 5c;

FIG7 is a schematic diagram of ¹³ C NMR of product 5c;

FIG8 is a ¹ H NMR schematic diagram of product 5d;

FIG9 is a schematic diagram of ¹³ C NMR of product 5d;

FIG10 is a ¹ H NMR schematic diagram of product 5e;

FIG11 is a schematic diagram of ¹³ C NMR of product 5e;

FIG12 is a ¹ H NMR schematic diagram of product 5f;

FIG13 is a schematic diagram of ¹³ C NMR of product 5f;

FIG14 is a ¹ H NMR schematic diagram of product 5g;

FIG15 is a schematic diagram of ¹³ C NMR of product 5g;

FIG16 is a ¹ H NMR schematic diagram of product 5h;

FIG17 is a schematic diagram of ¹³ C NMR of product 5h;

FIG18 is a ¹ H NMR schematic diagram of product 5i;

FIG19 is a schematic diagram of ¹³ C NMR of product 5i;

FIG20 is a ¹ H NMR schematic diagram of product 5j;

FIG21 is a schematic diagram of ¹³ C NMR of product 5j;

FIG22 is a ¹ H NMR schematic diagram of product 5k;

FIG. 23 is a schematic diagram of ¹³ C NMR of product 5k.

DETAILED DESCRIPTION

The specific embodiments of the present invention are further described below. It should be noted that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation of the present invention. In addition, the technical features involved in each embodiment of the present invention described below can be combined with each other as long as they do not conflict with each other.

The experimental methods in the following examples are conventional methods unless otherwise specified, and the experimental materials used in the following examples are commercially available unless otherwise specified.

Example 1 A chemical synthesis method of chiral α-propargyl-3-indole compounds and their derivatives

According to reaction formula (II), the diazo compound of formula (1), the alcohol of formula (2) and the indole propargyl alcohol of formula (3) are used as raw materials, Rh ₂ (esp) ₂ and chiral phosphoric acid are used as catalysts, Molecular sieve is a water-absorbing additive. Through a one-step three-component reaction in an organic solvent, the chiral α-propargyl-3-indole compounds or their derivatives (syn-5 and anti-5) are obtained with high selectivity:

In the reaction formula, Ar ¹ is independently selected from phenyl, 5-methylphenyl, 5-chlorophenyl, 6-chlorophenyl, 6-bromophenyl, 6-methoxyphenyl, 7-methylphenyl, naphthyl, 2-methylnaphthyl or 2-methoxynaphthyl; Ar ² is independently selected from phenyl, 5-chlorophenyl, 5-methoxyphenyl, 6-methoxyphenyl, 7-methylphenyl, naphthyl, 2-methylnaphthyl, 2-methoxynaphthyl, thienyl, furanyl or pyridyl; R ¹ is independently selected from hydrogen, C _1-3 alkyl, benzyl, halogenated benzyl, acetyl or tert-butyloxycarbonyl; R ^R is independently selected from methyl, ethyl, propyl, isopropyl, ethyl substituted by trimethylsilyl, methyl substituted by cyclohexyl, benzyl, 2-methoxy substituted benzyl, 2-methyl substituted benzyl, 2-naphthylmethyl, allyl, cinnamyl, phenylpropargyl, nerol or menthol; R is independently selected from trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyl or phenyl.

The structure of the chiral phosphoric acid is shown in formula (5):

R is 1-pyrene.

The molecular sieve (MS) is Molecular sieve, the organic solvent is 1,2-dichloroethane.

The specific synthesis is as follows:

(1) Synthesis of compounds syn-5a and anti-5a

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-benzyl isatin diazo (0.3 mmol), benzyl alcohol (0.3 mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is dissolved in deuterated chloroform and the dr value is determined using ¹ H NMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereoisomers, the structures of which are shown in formulas (syn-5a) and (anti-5a), and the total yield is: 83%, syn:anti = 58:42. The NMR data of the product are as follows:

Compound syn-5a: ¹ H NMR (500MHz, Chloroform-d) δ8.14 (d, J＝6.5Hz, 1H), 7.48–7.42 (m, 3H), 7.36 (t, J＝7.5Hz, 2H), 7.31(d,J＝7.4Hz,1H),7.26(d,J＝8.3Hz,1H),7.21–7.15(m,3H),7.11(t,J＝7.5Hz,1H),7.02–6.95(m ,3 H),6.47(s,1H),6.33(d,J＝7.1Hz,1H),6.25(d,J＝7.6Hz,2H),4.99(s,1H),4.93(d,J＝15.9Hz, 1H),4.47(d,J＝11.1Hz,1H),4.35(d,J＝11.1Hz,1H),4.17(d,J＝15.9Hz,1H),3.50(s,3H),0.30(s, 9H). ¹³ C NMR (125MHz, CDCl ₃ ) δ174.6,144.1,138.0,136.3,134.9,130.1,128.9,128.2,128.0,127.4,127.4,126.9,126.6,126.2,126.1,125.4,122.2,1 21.4,119.8,119.06,109.08 ,108.7,107.2,105.3,87.8,83.6,67.6,43.5,38.0,32.5,0.0.Peak overlapping was observed.

Compound anti-5a: ¹ H NMR(400MHz,Chloroform-d)δ7.82(d,J＝8.1Hz,1H),7.39–7.31(m,6H),7.28–7.22(m,5H),7.21–7.16(m,2H),7.02–6.96(m,2H),6.90(t,J＝7.4Hz,1H),6.75(t . 4Hz,9H). ^13C NMR (100MHz, CDCl3) δ175.6,144.4,137.7,137.1,136.0,130.3,129.8,128.9128.1,128.0,127.71,127.67,127.5,127.4,126.2,125.0,122.1,122.0, 121.5,118.8,108.8,108.3,88.2,84.7,68.2,44.2,38.7,33.0,0.0.Peak overlapping was observed.

(2) Synthesis of compounds syn-5b and anti-5b

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-benzyl isatin diazo (0.3 mmol), 2-naphthalene methanol (0.3 mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is dissolved in deuterated chloroform and the dr value is determined using ¹ H NMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereomers, the structures of which are shown in formulas (syn-5b) and (anti-5b), and the total yield is: 75%, syn:anti = 55:45. The NMR data of the product are as follows:

Compound syn-5b: ¹ H NMR (400MHz, Chloroform-d) δ8.01–7.94 (m, 1H), 7.67–7.58 (m, 4H), 7.38 (d, J = 8.4Hz, 1H), 7.32–7.25 (m,2H),7.08–7.03(m,2H),7.01–6.93(m,3H),6.92–6.87(m,1H),6.80–6.74(m,3H),6 .28(s,1H),6.15–6.08(m,1H),6.03(d,J＝7.6Hz,2H),4.81(s,1H),4.67(d,J＝16.0Hz,1H),4.41( d,J＝11.2Hz,1H),4.33(d,J＝11.1Hz,1H),3.88(d,J＝16.0Hz,1H),3.29(s,3H),0.11(s,9H). ¹³ C NMR (125MHz, CDCl ₃ ) δ174.6,144.1,136.2,135.3,134.9,133.1,132.9,130.1,128.9,128.2,127.8,127.6,127.5,126.8,126.6,126.2,126.13, 126.07,125.82,125.77,125.6 ,125.3,122.2,121.4,119.8,119.0,109.1,108.7,107.2,105.3,87.8,83.6,67.8,43.4,38.0,32.4,0.0.Peak overlapping was observed.

Compound anti-5b: ¹ H NMR (500MHz, Chloroform-d) δ7.81 (d, J＝8.0Hz, 1H), 7.74–7.70 (m, 1H), 7.63 (d, J＝8.4Hz, 1H), 7.57–7.53(m,1H),7.45(s,1H),7.39–7.35(m,2H),7.33–7.26(m,5H),7.25–7.21(m,1H),7.20–7.15(m,3H ),6.95–6.89(m,2H),6.82(t,J＝7.5Hz,1H),6.69(t,J＝7.8Hz,2H),5.24(d,J＝15.6Hz,1H),4.90(s ,1H),4.61(d,J＝15.6Hz,1H),4.43(d,J＝11.1Hz,1H),4.13(d,J＝11.1Hz,1H),3.72(s,3H),0.00(s ,9H). ¹³ CNMR (125MHz, CDCl3) δ175.7,144.4,137.1,136.0,135.2,133.1,132.8,130.2,129.9,128.9,128.2,128.0,127.7,127.6,127.5,126.2,126.1,12 5.8,125.7,124.9,122.0,121.5 ,119.0,108.9,108.8,108.5,103.2,88.1,84.9,68.2,44.2,38.5,32.9,0.0. Peak overlapping was observed.

(3) Synthesis of compounds syn-5c and anti-5c

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-benzyl isatin diazo (0.3 mmol), ethanol (0.3 mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is dissolved in deuterated chloroform and the dr value is determined using ¹ H NMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereomers, the structures of which are shown in formulas (syn-5c) and (anti-5c), and the total yield is: 89%, syn:anti = 55:45. The NMR data of the product are as follows:

Compound syn-5c: ¹ H NMR (500MHz, Chloroform-d) δ8.11–8.02(m,1H),7.41(d,J＝8.2Hz,1H),7.26–7.22(m,1H),7.20–7.08 (m,4H),7.01–6.92(m,3H),6.45(s,1H),6.34–6.22(m,3H),4.91–4.82(m,2H),4.19(d,J＝16.0Hz,1H ), 3.49 (s, 3H), 3.41–3.29 (m, 2H), 1.27 (t, J = 6.8Hz, 3H), 0.27 (s, 9H). ¹³ C NMR (125MHz, CDCl ₃ )δ175.1,144.0,136.3,135.0,129.9,128.9,128.2,126.9,126.6,126.2,125.9,122.1,121.4,120.0,119.0,109.0,108.7,107.4,105.4,87.883 .6,61.4,43.4,38.1,32.5 ,15.4,0.0.Peak overlapping was observed.

Compound anti-5c: ¹ H NMR (500MHz, Chloroform-d) δ7.93 (d, J＝8.1Hz, 1H), 7.32–7.27 (m, 5H), 7.26–7.22 (m, 1H), 7.22–7.15 (m,2H),7.06(t,J＝7.5Hz,1H),6.92(s,1H),6.81(t,J＝7.5Hz,1H),6.68(d,J＝7.8H z,1H),6.54(d,J＝7.4Hz,1H),5.31(d,J＝15.6Hz,1H),4.78(s,1H),4.56(d,J＝15.6Hz,1H),3.76( s,3H),3.24(p,J＝7.4Hz,1H),2.96(p,J＝7.4Hz,1H),1.06(t,J＝7.0Hz,3H),0.00(s,9H). ¹³ C NMR (125MHz, CDCl3) δ176.1,144.2,137.2,136.0,130.2,129.5,128.8,128.4,127.6,127.4,126.1,125.2,122.3,121.8,121.4,118.7,108.9,10 8.8,108.7,103.2,88.0, 84.7,61.6,44.1,38.6,32.9,15.4,0.0.Peak overlapping was observed.

(4) Synthesis of compounds syn-5d and anti-5d

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-benzyl isatin diazo (0.3 mmol), 3-phenyl propargyl alcohol (0.3 mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is dissolved in deuterated chloroform and the dr value is determined using ¹ H NMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereomers, the structures of which are shown in formulas (syn-5d) and (anti-5d), and the total yield is: 78%, syn:anti = 53:47. The NMR data of the product are as follows:

Compound syn-5d: ¹ H NMR (500MHz, Chloroform-d) δ8.12–8.07 (m, 1H), 7.37–7.33 (m, 3H), 7.28–7.25 (m, 3H), 7.21–7.18 (m, 1H), 7.18–7.14 (m, 2H), 7.10 (t, J＝7.6Hz, 1H), 7.02 (t, J＝7.5Hz, 1H), 6.91 –6.86(m,3H),6.43(s,1H),6.27–6.22(m,1H),6.10(d,J＝7.6Hz,2H),4.87(s,1H),4.82(d,J＝16.1Hz,1H),4.41–4.31(m,2H),3.94(d,J＝16.0Hz,1H),3 .44(s,3H),0.22(s,9H). ¹³ C NMR (125MHz, CDCl ₃ ) δ174.7,144.4,136.3,134.9,131.7,130.3,129.0,128.3,128.13,128.08,126.8,126.6,126.1,124.3,122.6,122.0,121.4 ,119.9,119.0,109.3,108.7,107.1,105.1,88.3,86.4,84.9,83.3,55.0,43.7,38.3,32.5,0.0.Peak overlapping was observed.

Compound anti-5d: ¹ H NMR (400MHz, Chloroform-d) δ7.96 (d, J＝8.1Hz, 1H), 7.34–7.29 (m, 3H), 7.26–7.17 (m, 10H), 7.05 (t ,J＝7.0Hz,1H),6.98(s,1H),6.83(t,J＝7.0Hz,1H),6.70–6.63(m,2H),5.19(d,J＝15.7Hz,1H),4.86 (s,1H),4.63(d,J＝15.7Hz,1H),4.09(q,J＝15.1Hz,2H),3.77(s,3H),0.00(s,9H). ¹³ C NMR (100MHz, CDCl3) δ175.3,144.5,137.23,135.9,131.7,130.5,130.0,128.9,128.32,128.25,128.2,127.6,127.4,126.7,124.0,122.7,122.3,122. 0,121.5,119.0,108.97,108.95, 108.3,102.9,88.4,86.4,85.0,84.5,55.0,44.4,39.0,33.0,0.00. Peak overlapping was observed.

(5) Synthesis of compounds syn-5e and anti-5e

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-benzyl isatin diazo (0.3 mmol), cinnamyl alcohol (0.3 mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is dissolved in deuterated chloroform and the dr value is determined using ¹ H NMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereomers, the structures of which are shown in formulas (syn-5e) and (anti-5e), and the total yield is: 75%, syn:anti = 57:43. The NMR data of the product are as follows:

Compound syn-5e: ¹ H NMR (500MHz, Chloroform-d) δ8.04–8.00(m,1H),7.32(d,J＝8.2Hz,1H),7.29–7.27(m,1H),7.25–7.22 (m,2H),7.19–7.13(m,3H),7.12–7.09(m,2H),7.05(t,J＝7.7Hz,1H),6.99(t,J＝7.4Hz,1H), 6.85(t,J＝7.6Hz,3H),6.42–6.35(m,2H),6.26–6.16(m,2H),6.07(d,J＝7.6Hz,2H),4.82(s,1H),4.76 (d,J＝16.0Hz,1H),4.00(d,J＝6.0Hz,2H),3.88(d,J＝16.0Hz,1H),3.39(s,3H),0.19(s,9H). ¹³ C NMR (125MHz, CDCl ₃ ) δ175.2,144.1,136.7,136.3,134.9,132.1,130.0,128.9,128.4,128.1,127.5,126.8,126.6,126.4,126.2,126.1,125.8,1 25.3,122.1,121.3,119.8 ,119.0,109.1,108.7,107.2,105.3,87.9,83.3,67.0,43.5,38.2,32.4,0.0.Peak overlapping was observed.

Compound anti-5e: ¹ H NMR (500MHz, Chloroform-d) δ7.92 (d, J＝8.1Hz, 1H), 7.35–7.28 (m, 5H), 7.27–7.21 (m, 4H), 7.20–7.15 (m,4H),7.06(t,J＝7.5Hz,1H),6.96(s,1H),6.85(t,J＝7.5Hz,1H),6.69(dd,J＝15.3,7.6Hz,2H) ,6 .26(d,J＝15.9Hz,1H),6.06(dt,J＝16.0,5.5Hz,1H),5.21(d,J＝15.6Hz,1H),4.85(s,1H),4.62(d, J＝15.6Hz,1H),3.94(dd,J＝12.4,5.7Hz,1H),3.78(s,3H),3.67(dd,J＝12.4,5.2Hz,1H),0.00(s,9H). ¹³ C NMR (125MHz, CDCl3) δ176.0,144.4,137.2,136.9,136.0,131.5,130.3,129.8,128.9,128.5,128.3,127.7,127.54,127.47,126.5,126.3,125.6, 124.9,122.1,122.0,121.6, 119.0,109.0,108.8,108.6,103.2,88.1,84.6,66.7,44.3,38.6,33.0,0.0. Peak overlapping was observed.

(6) Synthesis of compounds syn-5f and anti-5f

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-benzyl isatin diazo (0.3 mmol), nerol (0.3 mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is taken and dissolved in deuterated chloroform to determine the dr value using ¹ H NMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereomers, the structures of which are shown in formulas (syn-5f) and (anti-5f), with a total yield of 84%, syn:anti = 55:45. The NMR data of the product are as follows:

Compound syn-5f: ¹ H NMR (400MHz, Chloroform-d) δ8.13–8.04 (m, 1H), 7.39 (d, J = 8.1Hz, 1H), 7.23 (d, J = 8.2Hz, 1H), 7.19–7.15(m,2H),7.14–7.06(m,2H),7.01–6.90(m,3H),6.45(s,1H),6.33–6.26(m,1H),6.24(d,J＝7.2 Hz,2H),5 .44(t,J＝6.1Hz,1H),5.09–5.00(m,1H),4.90(d,J＝16.0Hz,1H),4.85(s,1H),4.15(d,J＝16.0Hz, 1H),3.84(d,J＝7.3Hz,2H),3.48(s,3H),2.03–1.92(m,4H),1.75(s,3H),1.66(s,3H),1.56(s,3H ),0.26(s,9H). ¹³ C NMR (100MHz, CDCl ₃ ) δ175.2,144.1,140.8,136.3,135.1,131.7,129.9,128.9,128.2,126.9,126.7,126.21,126.17,125.7,123.9,122.1,121.4 ,121.4,120.0,119.0,109.0 ,108.7,107.5,105.4,87.9,83.3,62.4,43.5,38.2,32.5,32.1,26.7,25.6,23.5,17.6,0.0.Peak overlapping was observed.

Compound anti-5f: ¹ H NMR (500MHz, Chloroform-d) δ7.88 (d, J＝8.1Hz, 1H), 7.32–7.25 (m, 5H), 7.25–7.22 (m, 1H), 7.20–7.14 (m,2H),7.02(t,J＝7.6Hz,1H),6.93(s,1H),6.80(t,J＝7.5Hz,1H),6.68(d,J＝7.8Hz,1H),6.55 (d,J＝7.4Hz,1H),5.29(d ,J＝15.6Hz,1H),5.22(t,J＝6.6Hz,1H),4.85(t,J＝6.9Hz,1H),4.78(s,1H),4.57(d,J＝15.6Hz,1H ),3.75(s,3H),3.73–3.68(m,1H),3.48–3.42(m,1H),1.88–1.69(m,4H),1.62(s,3H),1.52(s,3H), 1.40(s,3H),0.00(s,9H). ¹³ C NMR (125MHz, CDCl3) δ176.0,144.3,139.7,137.2,136.1,131.6,130.3,129.6,128.8,128.2,127.6,127.5,126.2,125.0,124.0,122.4,121.8,12 1.5,121.4,118.7,108.8, 108.64,108.59,88.0,84.4,62.7,44.1,38.7,32.9,32.2,26.5,25.6,23.4,17.6,0.0.Peak overlapping was observed.

(7) Synthesis of compounds syn-5g and anti-5g

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-benzyl-6-methoxyisatin diazo (0.3 mmol), ethanol (0.3 mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is dissolved in deuterated chloroform and the dr value is determined using ¹ H NMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereomers, the structures of which are shown in formulas (syn-5g) and (anti-5g). Total yield: 87%, syn:anti = 58:42. The NMR data of the product are as follows:

Compound syn-5g: ¹ H NMR (400MHz, Chloroform-d) δ7.94 (d, J＝8.4Hz, 1H), 7.50–7.45 (m, 1H), 7.26–7.22 (m, 1H), 7.17–7.13 (m,1H),7.10–7.06(m,1H),7.00–6.94(m,3H),6.69–6.64(m,1H),6. 45(s,1H),6.25(d,J＝7.6Hz,2H),5.91(s,1H),4.88–4.81(m,2H),4.16(d,J＝15.9Hz,1H),3.73(s ,3H),3.50(s,3H),3.38–3.25(m,2H),1.25(t,J=6.9Hz,1H),0.26(s,9H). ¹³ C NMR (100MHz, CDCl ₃ ) δ175.6,161.4,145.4,136.2,135.0,128.8,128.2,126.9,126.7,126.3,121.3,119.9,119.0,117.7,108.7,107.6,105.7,97. 1,87.4,83.2,61.1 ,55.3,43.4,37.9,32.5,15.4,0.0.Peak overlapping was observed.

Compound anti-5g: ¹ H NMR (500MHz, Chloroform-d) δ7.91 (d, J＝8.1Hz, 1H), 7.30–7.25 (m, 5H), 7.24–7.20 (m, 1H), 7.18 (t ,J＝7.6Hz,1H),7.04(t,J＝7.5Hz,1H),6.91(s,1H),6.39(d,J＝8.1Hz,1H),6.32–6 .22(m,2H),5.27(d,J＝15.6Hz,1H),4.73(s,1H),4.49(d,J＝15.6Hz,1H),3.75(s,3H),3.67(s, 3H), 3.18 (p, J = 7.1Hz, 1H), 2.94 (p, J = 7.2Hz, 1H), 1.03 (t, J = 6.9Hz, 3H), 0.00 (s, 9H). ¹³ C NMR (125MHz, CDCl3) δ176.6,161.1,145.6,137.2,136.0,130.1,128.8,128.3,127.6,127.4,126.9,122.3,121.4,118.6,117.0,108.9,108.8,10 5.4,103.4,96.8,87.8, 84.4,61.3,55.4,44.1,38.5,32.9,15.4,0.0. Peak overlapping was observed.

(8) Synthesis of compounds syn-5h and anti-5h

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-methyl indigo carmine diazo (0.3 mmol), ethanol (0.3 mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is dissolved in deuterated chloroform and the dr value is determined using ¹ H NMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereomers, the structures of which are shown in the formulas (syn-5h) and (anti-5h), and the total yield is: 82%, syn:anti = 64:36. The NMR data of the product are as follows:

Compound syn-5h: ¹ H NMR (500MHz, Chloroform-d) δ7.91 (d, J = 7.3Hz, 1H), 7.37 (d, J = 8.1Hz, 1H), 7.28 (d, J = 5.4Hz, 1H),7.18(t,J＝7.5Hz,1H),7.12(d,J＝8.2Hz,1H),7.10–7.06(m,1H),6.91(t,J＝7.5Hz,1H),6.49( s,1H),6.43(d,J＝7.7Hz,1H),4.73(s,1H),3.57(s,3H),3.35–3.25(m,2H),2.61(s,3H),1.24(t ,J＝7.0Hz,3H),0.25(s,9H). ¹³ C NMR (125MHz, CDCl ₃ ) δ175.0,144.5,136.2,129.8,128.9,126.5,126.0,125.5,122.0,121.0,119.8,118.6,108.5,107.5,107.4,105.1,87.7,84.2,6 1.8,38.7,32.5,25.4 ,15.4,0.0.Peak overlapping was observed.

Compound anti-5h: ¹ H NMR (500MHz, Chloroform-d) δ7.94 (d, J＝8.1Hz, 1H), 7.35–7.28 (m, 2H), 7.22 (t, J＝7.6Hz, 1H), 7.07(t,J＝7.5Hz,1H),6.91(s,1H),6.87–6.81(m,2H),6.46(d,J＝7.3Hz,1H),4.73(s,1H),3.80(s ,3H),3.27(s,3H),3.17(p,J＝7.2Hz,1H),2.94(p,J＝7.2Hz,1H),1.06(t,J＝6.9Hz,3H),0.00(s ,9H). ¹³ C NMR (125MHz, CDCl3) δ176.2,145.1,137.2,130.2,129.6,128.4,126.1,125.0,122.4,121.7,121.4,118.7,108.8,108.8,107.5,103.0,87.7,85.1,61. 8,38.6,33.026.1, 15.4,0.0.Peakoverlapping was observed.

(9) Synthesis of compounds syn-5i and anti-5i

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-benzyl isatin diazo (0.3 mmol), ethanol (0.3 mmol) and indole-3-phenylpropargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is dissolved in deuterated chloroform and the dr value is determined using ¹ H NMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereomers, the structures of which are shown in formulas (syn-5i) and (anti-5i), and the total yield is: 84%, syn:anti = 47:53. The NMR data of the product are as follows:

Compound syn-5i: ¹ H NMR (500MHz, Chloroform-d) δ8.05 (t, J＝4.4Hz, 1H), 7.53–7.48 (m, 2H), 7.46 (d, J＝8.1Hz, 1H), 7.33–7.28(m,3H),7.22(d,J＝8.3Hz,1H),7.17–7.10(m,3H),7.06(t,J＝7.4Hz,1H),6.94(t,J＝7.5 Hz,3H),6.46(s,1H),6.30(t,J＝4.4Hz,1H),6.25(d,J＝7.6Hz,2H),5.03(s,1H),4.88(d,J＝15.7 Hz,1H),4.17(d,J＝15.9Hz,1H),3.46(s,3H),3.33(dp,J＝26.8,7.5Hz,2H),1.26(t,J＝6.3Hz,3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ175.3,144.1,136.4,135.1,131.7,130.0,129.0,128.31,128.26,127.8,127.0,126.8,126.3,126.2,126.0,124.0,122.5 ,121.5,119.9,119.3,109.1 ,108.9,107.9,89.2,84.1,83.3,61.6,43.6,37.9,32.6,15.6.Peak overlapping was observed.

Compound anti-5i: ¹ H NMR (500MHz, Chloroform-d) δ8.02 (d, J＝8.1Hz, 1H), 7.30–7.25 (m, 3H), 7.23–7.16 (m, 5H), 7.12–7.05 (m,4H),7.03–6.99(m,3H),6.85(t,J＝7.5Hz,1H),6.69(d,J＝7.9Hz, 1H),6.60(d,J＝7.4Hz,1H),5.03(s,1H),4.98(d,J＝15.7Hz,1H),4.89(d,J＝15.7Hz,1H),3.75(s, 3H), 3.26 (p, J = 7.2Hz, 1H), 2.98 (p, J = 7.2Hz, 1H), 1.09 (t, J = 6.9Hz, 3H). ¹³ C NMR (125MHz, CDCl3) δ176.3,144.3,137.2,135.7,131.8,130.2,129.7,128.7,128.4,128.1,127.9,127.4,127.3,126.2,125.3,123.3,122.3,12 2.0121.5,118.9,109.4,108.91, 108.88,86.9,84.8,83.6,61.6,44.2,38.0,32.9,15.4. Peak overlapping was observed.

(10) Synthesis of compounds syn-5j and anti-5j

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-benzyl isatin diazo (0.3 mmol), ethanol (0.3 mmol) and indole-3-tert-butyl propargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is taken and dissolved in deuterated chloroform to determine the dr value using ¹ HNMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereomers, the structures of which are shown in formulas (syn-5j) and (anti-5j), and the total yield is: 80%, syn:anti = 67:33. The NMR data of the product are as follows:

Compound syn-5j: ¹ H NMR (500MHz, Chloroform-d) δ8.01 (d, J = 7.1 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.26–7.22 (m, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.17–7.03 (m, 4H), 6.95 (t, J = 7.5 Hz, 2H), 6.89 (t, J = 7.6 Hz, 1H), 6.44 (s ,1H),6.25(d,J＝8.1Hz,2H),4.82(d,J＝16.0Hz,1H),4.76(s,1H),4.18(d,J＝16.0Hz,1H),3.47(s,3H),3.36(p,J＝7.5Hz,1H),3.27(p,J＝7.4,7.0Hz,1H) ,1.30(s,9H),1.23(t,J=6.9Hz,3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ175.5,144.0,136.4,135.2,129.7,128.9,128.3,126.92,126.85,126.4,126.3,126.0,122.1,121.3,120.2,118.8,109.0 ,108.7,108.6,91.5,84.0,77.4,61.3,43.5,37.2,32.5,31.2,27.7,15.5.Peak overlapping was observed.

Compound anti-5j: ¹ H NMR (500MHz, Chloroform-d) δ7.97 (d, J＝8.1Hz, 1H), 7.34–7.27 (m, 5H), 7.27–7.24 (m, 1H), 7.22–7.15 (m,2H),7.06(t,J＝7.6Hz,1H),6.91(s,1H),6.81(t,J＝7.5Hz,1H),6.70(d,J＝7.8Hz, 1H),6.52(d,J＝7.4Hz,1H),5.40(d,J＝15.6Hz,1H),4.71(s,1H),4.51(d,J＝15.6Hz,1H),3.78(s, 3H), 3.25 (p, J = 6.6, 6.1Hz, 1H), 2.95 (p, J = 7.2Hz, 1H), 1.06 (t, J = 6.9Hz, 3H), 1.01 (s, 9H). ¹³ C NMR (125MHz, CDCl3) δ176.3,144.2,137.2,136.1,130.1,129.3,128.8,128.5,127.6,127.5,126.0,125.5,122.5,121.7,121.3,118.5,110.0,10 8.7,108.5,91.9,84.9, 75.4,61.6,44.0,37.3,32.9,31.0,27.2,15.4.Peak overlapping was observed.

(11) Synthesis of compounds syn-5k and anti-5k

1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and Molecular sieves (20 mg) were added to a dry 10 mL test tube, and then 2.0 mL of 1.2-dichloroethane was added and the temperature was cooled to -30 °C;

2) N-benzyl isatin diazo (0.3 mmol), ethanol (0.3 mmol) and 7-methylindole-3-trimethylsilyl propargyl alcohol (0.2 mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use a peristaltic pump to pump the mixed solution in step 2) into a test tube within 2 hours, and continue stirring for 2 hours after pumping. After the reaction solution is decompressed to remove the solvent, a sample is dissolved in deuterated chloroform and the dr value is determined using ¹ H NMR. Finally, all the solutions are mixed and separated and purified using column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to obtain a pair of diastereomers, the structures of which are shown in formulas (syn-5k) and (anti-5k), and the total yield is: 83%, syn:anti = 55:45. The NMR data of the product are as follows:

Compound syn-5k: ¹ H NMR(400MHz,Chloroform-d)δ8.06–8.00(m,1H),7.30–7.27(m,1H),7.22–7.16(m,2H),7.13(t,J＝7.5Hz,1H),6.99(t,J＝7.6Hz,2H),6.85–6.79(m,2H),6.38–6 .31(m,3H),6.23(s,1H),4.91(d,J＝15.8Hz,1H),4.82(s,1H),4.19(d,J＝15.9Hz,1H),3.70(s,3H),3.44–3.25(m,2H),2.73(s,3H),1.27(t,J＝7.0Hz, 3H),0.26(s,9H). ¹³ CNMR (100MHz, CDCl ₃ ) δ175.2,144.1,135.2,135.0,130.6,129.9,128.2,127.9,127.0,126.6,126.2,126.0,124.2,122.1,120.4,119.3,118.0,109. 0,107.2,105.6,87.6,83.5,61.4,43.6,37.8,36.5,19.8,15.5,0.1.Peak overlapping was observed.

Compound anti-5k: ¹ H NMR (400MHz, Chloroform-d) δ7.78 (d, J＝7.9Hz, 1H), 7.34–7.29 (m, 4H), 7.26–7.24 (m, 1H), 7.18 (t ,J＝7.7Hz,1H),6.93–6.86(m,2H),6.84(d,J＝7.5Hz,1H),6.79(s,1H),6.69(d,J＝7.8Hz,1H), 6.61(d,J＝7.3Hz,1H),5.32(d,J＝15.7Hz,1H),4.75(s,1H),4.57(d,J＝15.6Hz,1H),4.04(s,3H), 3.23(p,J＝7.1Hz,1H),2.96(p,J＝7.1Hz,1H),2.78(s,3H),1.06(t,J＝6.9Hz,3H),0.00(s,9H). ¹³ C NMR (100MHz, CDCl3) δ176.1,144.3,136.1,135.9,132.0,129.5,128.8,127.6,127.5,126.2,125.2,124.2,121.8,120.6,120.4,118.9,108.7,10 8.6,103.4,87.8,84.8, 61.6,44.1,38.4,37.0,19.9,15.4,0.0.Peak overlapping was observed.

Example 2 Antitumor Activity Test of Chiral α-propargyl-3-indole Compounds and Their Derivatives

Human colon cancer HCT116 p53 Wild Type cell line and HCT116 p53 Knockout cell line were inoculated in a culture medium (RPMI1640 culture medium) containing 10% serum and 1% penicillin-streptomycin solution, placed in a 37°C, 5% _CO2 incubator, passaged every 2-3 days, and cells in the logarithmic growth phase were used for testing.

The cell viability was detected by MTS method, that is, the culture medium of cells in logarithmic growth phase was aspirated, and after trypsin digestion, RPMI1640 culture medium (containing 10% serum and 1% penicillin-streptomycin) was added to terminate the digestion, and the cells were gently blown and counted, and 100uL was inoculated in a 96-well plate at 3000 cells/well, and then compounds (syn-5a to syn-5k) were added. A concentration gradient (50uM half-dilution, 8 concentrations) was set for each compound, and triplicate wells were set for each concentration. Each concentration was added to the corresponding wells, and cultured in a 5% CO ₂ , 37°C incubator for 72 hours. After adding 20uL MTS, the cells were incubated at 37°C for 2 hours, and then the light absorption value at 490nm (L1) was measured using SpectraMAX340, and the reference wavelength was 690nm (L2). The (L1-L2) value was plotted against different compound concentrations, and the IC ₅₀ was obtained by fitting the formula.

During the test, the activity of the sample was first screened under a single concentration condition (e.g., 20 μg/mL). For samples that showed activity under certain conditions (inhibition rate %Inhibition greater than 50), the activity dose-dependency relationship was tested, i.e., IC ₅₀ /EC ₅₀ value. The test was obtained by nonlinear fitting of the sample activity to the sample concentration. The software used for calculation was Graphpad Prism 4, and the model used for fitting was sigmoidal dose-response (varibleslope). For most inhibitor screening models, the bottom and top of the fitting curve were set to 0 and 100. In general, each test had a reported compound as a reference. The test results are shown in Table 1.

As can be seen from Table 1, compared with p53knockoutHCT116, most of the chiral α-propargyl-3-indole compounds and their derivatives prepared by the present invention show a higher growth inhibitory effect on p53WTHCT116 cells. For mice with colon cancer in which the tumor suppressor gene p53 is knocked out, the IC ₅₀ (i.e., the half inhibition rate of cancer cells) is about 6uM, showing a good activity of inhibiting cancer cells. It can be seen that the compounds and their derivatives of the present invention have good medical application prospects.

Table 1 Inhibitory effects of representative chiral α-propargyl-3-indole compounds and their derivatives on human colon cancer HCT116 cells

Sample No. Sample No. Molecular formula Molecular weight (MW) weight IC ₅₀ (uM) 1 syn-5a C ₃₇ H ₃₆ N ₂ O ₂ Si 568.79 1.66 6.42 2 syn-5b C ₄₁ H ₃₈ N ₂ O ₂ Si 618.85 1.44 6.41 3 syn-5c C ₃₂ H ₃₄ N ₂ O ₂ Si 506.72 1.82 6.74 4 syn-5d C ₃₉ H ₃₆ N ₂ O ₂ Si 592.81 1.59 6.13 5 syn-5e C ₃₉ H ₃₈ N ₂ O ₂ Si 594.83 1.97 5.94 6 syn-5f C ₄₀ H ₄₆ N ₂ O ₂ Si 614.91 1.68 5.31 7 syn-5g C ₃₃ H ₃₆ N ₂ O ₃ Si 536.75 1.36 5.42 8 syn-5h C ₂₆ H ₃₀ N ₂ O ₂ Si 430.62 1.52 4.81 9 syn-5i C ₃₅ H ₃₀ N ₂ O ₂ 510.64 1.58 4.63 10 syn-5j C ₃₃ H ₃₄ N ₂ O ₂ 490.65 1.62 4.52 11 syn-5k C ₃₃ H ₃₆ N ₂ O ₂ Si 520.75 1.57 5.12

The embodiments of the present invention are described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions and variations of these embodiments are made without departing from the principles and spirit of the present invention, and still fall within the protection scope of the present invention.

Claims (8)

1. A chiral α-propargyl-3-indole compound, characterized in that the structure of the compound is as shown in syn-5: In the formula, Ar ¹ is phenyl, 6-methoxyphenyl, Ar ² is phenyl, 7-methylphenyl, R ¹ is benzyl, methyl, R ² is benzyl, 2-naphthylmethyl , ethyl, phenyl propargyl, R is trimethylsilyl, phenyl, tert-butyl. 2. A chiral α-propargyl-3-indole compound, characterized in that the compound is selected from at least one of the following structural formulas: 3. The preparation method of chiral α-propargyl-3-indole compounds according to claim 1, characterized in that, according to reaction formula (II), the alcohol of formula (2), the alcohol of formula (1) Diazo compounds and indole propargyl alcohol of formula (3) are used as raw materials, Rh ₂ (esp) ₂ and chiral phosphoric acid are used as catalysts, and molecular sieves are used as water absorbing agents. Chiral α-propargyl-3-indole compounds are prepared through component reactions: In the reaction formula, Ar ¹ is phenyl, 6-methoxyphenyl, Ar ² is phenyl, 7-methylphenyl, R ¹ is benzyl, methyl, R ² is benzyl, 2-naphthylmethyl base, ethyl, phenyl propargyl, R is trimethylsilyl, phenyl, tert-butyl; The structure of the chiral phosphoric acid is shown in formula (5): In the formula, R is 1-pyrene group. 4. The preparation method of chiral α-propargyl-3-indole compounds according to claim 3, characterized in that the temperature of the reaction is -30~25°C, and the reaction time is 2-6h . 5. The preparation method of chiral α-propargyl-3-indole compounds according to claim 3, characterized in that the alcohol of formula (2), the diazo compound of formula (1) and the formula (3 ), the molar ratio of indole propargyl alcohol is 1.0~2.0:1.0~2.0:1.0. 6. The preparation method of chiral α-propargyl-3-indole compounds according to claim 3, characterized in that, based on the indole propargyl alcohol of formula (3), the catalyst Rh ₂ (esp ) ₂ is used in an amount of 2.0 mol% of indole propargyl alcohol, and chiral phosphoric acid is used in an amount of 5.0 to 10 mol% of indole propargyl alcohol. 7. The preparation method of chiral α-propargyl-3-indole compounds according to claim 3, characterized in that, based on the indole propargyl alcohol of formula (3), the feeding of the molecular sieve The amount is 100mg/mmol. 8. Use of the chiral α-propargyl-3-indole compound according to claim 1 or 2 in the preparation of anti-colon cancer drugs.