CN114276288A - Synthetic method and application of a kind of chiral α-propargyl-3-indole compounds and derivatives thereof - Google Patents

Abstract

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a synthesis method and application of a chiral α-propargyl-3-indole compound and derivatives thereof. and indole propargyl alcohol as raw materials, Rh ₂ (esp) ₂ , chiral phosphoric acid as catalyst, molecular sieve as water absorbing agent, and prepared by one-step three-component reaction in organic solvent. The method of the invention has the advantages of high atom economy, good selectivity, mild reaction conditions, high yield, simple and safe operation and the like. Moreover, the chiral α-propargyl-3-indole compounds and their derivatives of the present invention not only have many biological activities themselves, but also have many indole skeletons and indolinone skeletons contained in the compounds. Important structural fragments of complex natural products with biological activity, therefore, such compounds can be used as important intermediates in medicine and chemical industry, and have broad application prospects in the field of medicine.

Description

Synthetic method and application of a kind of chiral α-propargyl-3-indole compounds and derivatives thereof

technical field

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a synthesis method and application of a chiral α-propargyl-3-indole compound and a derivative thereof.

Background technique

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

At present, certain research progress has been made in the synthesis of propargyl-containing heterocyclic skeleton compounds from propargyl alcohol. There are two main methods for synthesizing the existing propargyl-containing heterocyclic skeleton compounds. One is to construct the propargyl-containing heterocyclic skeleton compound by using the method of direct asymmetric substitution of the nucleophilic heterocyclic compound by propargyl alcohols. ; 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, which leads to the defects of the synthesized propargyl-containing heterocyclic skeleton compounds having a limited range of substrates and poor selectivity. Therefore, it is necessary to develop a new synthesis method for propargyl-containing heterocyclic skeleton compounds to improve the defects such as the limited 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 above-mentioned chiral α-propargyl-3-indole compounds and derivatives thereof. The method of the invention has the beneficial effects of high atom economy, good step economy, regioselectivity and enantioselectivity, wide substrate applicability, mild reaction conditions, high yield, simple and safe operation and the like.

The third object of the present invention is to provide the application of the above-mentioned chiral α-propargyl-3-indole compounds and derivatives thereof. The chiral α-propargyl-3-indole compounds and derivatives of the present invention can be used as important intermediates in medicine and chemical industry, and have wide application prospects in the field of medicine. For example, the preparation of anti-colon cancer drugs.

The above-mentioned first purpose of the present invention is achieved through the following technical solutions:

A chiral α-propargyl-3-indole compound or a derivative thereof, the structure of the compound or its derivative is shown as 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, t-butoxycarbonyl, acetyl;

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

R is independently selected from alkyl, silyl, phenyl.

Preferably, the Ar ¹ is phenyl, 5-methylphenyl, 5-chlorophenyl, 6-chlorophenyl, 6-bromophenyl, 6-methoxyphenyl, 7-methylphenyl , naphthyl, 2-methylnaphthyl or 2-methoxynaphthyl; Ar ² is phenyl, 5-chlorophenyl, 5-methoxyphenyl, 6-methoxyphenyl, 7-methyl phenyl, naphthyl, 2-methylnaphthyl, 2-methoxynaphthyl, thienyl or furyl; R ¹ is hydrogen, C _1-3 alkyl, benzyl, halobenzyl, acetyl or tert-butoxycarbonyl; R ² is methyl, ethyl, propyl, isopropyl, trimethylsilyl substituted ethyl, cyclohexyl substituted methyl, benzyl, 2-methoxy substituted benzyl base, 2-methyl substituted benzyl, 2-naphthylmethyl, allyl, cinnamyl alcohol, phenyl propargyl, nerol; R is trimethylsilyl, triisopropylsilyl , tert-butyldimethylsilyl, methyl, tert-butyl, phenyl.

Further, the Ar ¹ is phenyl, 7-methylphenyl; Ar ² is phenyl, 6-methoxyphenyl; R ¹ is methyl, benzyl; R ² is phenyl, 2-naphthalene Methyl, ethyl, cinnamyl alcohol, phenyl propargyl, nerol; R is trimethylsilyl, tert-butyl, phenyl.

The above-mentioned second purpose of the present invention is achieved through the following technical solutions:

The preparation method of the above-mentioned chiral α-propargyl-3-indole compound or its derivative is specifically: according to the reaction formula (II), the alcohol of the formula (1), the diazo compound of the formula (2) and The indole propargyl alcohol of formula (3) is used as raw material, Rh ₂ (esp) ₂ and chiral phosphoric acid are used as catalysts, and molecular sieve is used as water absorbing agent, and the chiral α-propargyl group is prepared by one-step three-component reaction in an organic solvent -3-Indole compounds or derivatives thereof:

In order to overcome the defects in the preparation methods of chiral α-propargyl-3-indole compounds in the prior art, the substrate application range is not wide and the selectivity is poor. One-step efficient synthesis of α-propargyl-3-indole compounds with two chiral centers and their derivatives by ion-pair-active intermediate-hydroxyylide capture strategy. The method of the invention has the beneficial effects of high atom economy, good step economy, regioselectivity and enantioselectivity, wide substrate applicability, mild reaction conditions, high yield, simple and safe operation and the like. In addition, the chiral α-propargyl-3-indole compounds and derivatives thereof prepared by the present invention have good inhibitory activity on human colon cancer cells, and can be used as important pharmaceutical and chemical intermediates. It has broad application prospects in the field of medicine.

The chemical reaction mechanism of the present invention is shown in Figure 1: first, the diazonium compound of formula (1) is decomposed under the catalysis of metal Rh ₂ (esp) ₂ to form metal carbene (I) and release nitrogen gas, the generated metal carbene (I) Subsequently, it interacts with the nucleophile alcohol of formula (2) to form an active intermediate hydroxyylide (II, III), and then the indole propargyl alcohol of formula (3) is dehydrated under the action of chiral phosphoric acid to form an ion-pair active intermediate (V, VI), then the ion-pair active intermediate (VI) acts as an electrophile to capture the active intermediate hydroxyl ylide (II, III), and a 1,4-addition reaction occurs to generate a three-component reaction product hand α-propargyl-3-indole compounds or derivatives thereof.

Preferably, the temperature of the reaction is -30-25°C, and the reaction time is 2-6h. Specifically, the reaction temperature was -30°C, and the reaction time was 4 h.

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

In the formula, R is 1-pyrene group.

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 consumption of catalyst Rh ₂ (esp) ₂ is 2.0 mol% of indole propargyl alcohol, and the consumption of chiral phosphoric acid is 5.0 mol% of indole propargyl alcohol ~10 mol%. Specifically, the amount of chiral phosphoric acid used is 10 mol% of indole propargyl alcohol.

分子筛、

分子筛、

分子筛。具体地，所述分子筛为

分子筛。Preferably, the molecular sieve (MS) includes but is not limited to

molecular sieve,

molecular sieve,

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, and toluene. Specifically, the organic solvent is 1,2-dichloroethane.

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

The above-mentioned second purpose of the present invention is achieved through the following technical solutions:

Application of the above-mentioned chiral α-propargyl-3-indole compounds or derivatives thereof in the preparation of medicines against 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 an anti-colon cancer drug or a drug for inhibiting colon cancer cells, wherein the drug takes the drug for inhibiting colon cancer cells as the main active ingredient.

Preferably, other antitumor active ingredients that can synergize with the above-mentioned chiral α-propargyl-3-indole compounds or derivatives thereof are also included.

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

Further, the excipients refer to diluents, binders, lubricants, disintegrants, co-solvents, stabilizers and some other pharmaceutical bases that can be used in the pharmaceutical field. The carrier is functional pharmaceutical excipients acceptable 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 medicaments can be prepared into clinically acceptable dosage forms. The dosage forms are injections, tablets, capsules and the like commonly used in clinical practice. Pharmaceutical formulations may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically), and if certain drugs are unstable under gastric conditions, they may be prepared as enteric-coated tablets.

Compared with the prior art, the beneficial effects of the present invention are:

The invention discloses a chiral α-propargyl-3-indole compound and a derivative thereof. The compound and its derivative are made of a diazo compound, an alcohol and an indole propargyl alcohol as raw materials, and Rh ₂ ( esp) ₂ and chiral phosphoric acid are used as catalysts, and molecular sieves are water-absorbing agents, which are prepared in an organic solvent through a one-step three-component reaction. The present invention has the following advantages:

(1) For the first time, a method for the synthesis of chiral α-propargyl-3-indole compounds was proposed by using the indoleimine-chiral phosphate ion pair to capture the active intermediate-hydroxyylide;

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

(3) The indole skeleton-containing α-propargyl-3-indole compounds and derivatives thereof of the present invention can be used as important pharmaceutical and chemical intermediates, and have broad application prospects in the field of medicine. 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 themselves (for example, they have good inhibitory activity on human colon cancer cells), Moreover, the indole skeleton and 2-indolinone skeleton contained in these compounds are important structural fragments of many complex natural products with biological activity. Therefore, such compounds can be used as important pharmaceutical and chemical intermediates and have broad application prospects in the field of medicine.

Description of drawings

Fig. 1 is the synthetic mechanism diagram of chiral α-propargyl-3-indole compounds and derivatives thereof;

Fig. 2 is the schematic diagram of ¹ H NMR of product 5a;

Fig. 3 is the schematic diagram of ¹³ C NMR of product 5a;

Fig. 4 is the schematic diagram of ¹ H NMR of product 5b;

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

Fig. 6 is the schematic diagram of ¹ H NMR of product 5c;

Fig. 7 is the schematic diagram of ¹³ C NMR of product 5c;

Figure 8 is a schematic diagram of the ¹ H NMR of the product 5d;

Figure 9 is a schematic diagram of the ¹³ C NMR of the product 5d;

Figure 10 is a schematic diagram of the ¹ H NMR of the product 5e;

Figure 11 is a schematic diagram of the ¹³ C NMR of the product 5e;

Figure 12 is a schematic diagram of the ¹ H NMR of the product 5f;

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

Figure 14 is a schematic diagram of the ¹ H NMR of the product 5g;

Figure 15 is a schematic diagram of the ¹³ C NMR of the product 5g;

Figure 16 is a schematic diagram of the ¹ H NMR of the product 5h;

Figure 17 is a schematic diagram of the ¹³ C NMR of the product 5h;

Figure 18 is a schematic diagram of the ¹ H NMR of the product 5i;

Figure 19 is a schematic diagram of the ¹³ C NMR of the product 5i;

Figure 20 is a schematic diagram of ¹ H NMR of product 5j;

Figure 21 is a schematic diagram of ¹³ C NMR of product 5j;

Figure 22 is a schematic diagram of the ¹ H NMR of the product 5k;

Figure 23 is a schematic diagram ^of13C NMR of product 5k.

Detailed ways

The specific embodiments of the present invention will be further described below. It should be noted here that the descriptions of these embodiments are used to help the understanding of the present invention, but do not constitute a limitation of the present invention. In addition, the technical features involved in the various embodiments 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 can be purchased through conventional commercial channels unless otherwise specified.

Embodiment 1 A kind of chemical synthesis method of chiral α-propargyl-3-indole compounds and derivatives thereof

分子筛为吸水的添加剂，在有机溶剂中经过一步三组分反应高选择性地得到产物手性α-炔丙基-3-吲哚类化合物或其衍生物(syn-5和anti-5)：According to reaction formula (II), with the diazo compound of formula (1), the alcohol of formula (2) and the indole propargyl alcohol of formula (3) as raw materials, Rh ₂ (esp) ₂ and chiral phosphoric acid as catalysts,

Molecular sieve is a water-absorbing additive, and the product chiral α-propargyl-3-indole compound or its derivatives (syn-5 and anti-5) can be obtained with high selectivity through a one-step three-component reaction in an organic solvent:

In the reaction formula, Ar ¹ is independently selected from phenyl, 5-methylphenyl, 5-chlorophenyl, 6-chlorophenyl, 6-bromophenyl, 6-methoxyphenyl, 7-methylphenyl Phenyl, naphthyl, 2-methylnaphthyl or ² -methoxynaphthyl; Ar is independently selected from phenyl, 5-chlorophenyl, 5-methoxyphenyl, 6-methoxybenzene radical, 7-methylphenyl, naphthyl, 2-methylnaphthyl, 2-methoxynaphthyl, thienyl, furyl or pyridyl; R ¹ is independently selected from hydrogen, C _1-3 alkyl , benzyl, halobenzyl, acetyl or tert-butoxycarbonyl; R ² is independently selected from methyl, ethyl, propyl, isopropyl, trimethylsilyl substituted ethyl, cyclohexyl substituted Methyl, 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为1-芘基。

R is 1-pyrene.

分子筛，所述有机溶剂为1，2-二氯乙烷。The molecular sieve (MS) is

Molecular sieves, and the organic solvent is 1,2-dichloroethane.

The specific synthesis situation is as follows:

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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

2) N-benzylisatin diazonium (0.3mmol), benzyl alcohol (0.3mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2mmol) were mixed and dissolved in 2.0mL of 1.2-dipropargyl alcohol In chloroethane;

3) Use the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After the reaction solution was decompressed to remove the solvent, the sample was dissolved in deuterated chloroform, and the dr value was measured by ¹ H NMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 5: 1). 1) to obtain a pair of diastereomers, the structures are shown in formulas (syn-5a) and (anti-5a), 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 ,3H),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 )δ174.6,144.1,138.0,136.3,134.9,130.1,128.9,128.2,128.0,127.4,127.4,126.9,126.6,126.2,126.1,125.4,1282.2,9 , 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, J=17.4Hz, 1H), 5.31 (d, J=15.8Hz, 1H) ,4.93(s,1H),4.69(d,J＝15.6Hz,1H),4.33(d,J＝10.8Hz,1H),4.07(d,J＝11.2Hz,1H),3.80(s,3H) ,0.09(d,J＝1.4Hz,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 , 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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

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

3) Use the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After the reaction solution was decompressed to remove the solvent, the sample was dissolved in deuterated chloroform, and the dr value was measured by ¹ H NMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 5: 1). 1) to obtain a pair of diastereomers, the structures are shown in formulas (syn-5b) and (anti-5b), 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) δ 8.01-7.94(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) ^.13CNMR (125MHz,CDCl3)δ175.7,144.4,137.1,136.0,135.2,133.1,132.8,130.2,129.9,128.9,128.2,128.0,127.7,127.6,127.5,126.2,125.1,124.8. ,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.Peakoverlapping was observed.

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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

2) N-benzylisatin diazonium (0.3mmol), ethanol (0.3mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2mmol) were mixed and dissolved in 2.0mL of 1.2-dichlorohydrin in ethane;

3) Use the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After the reaction solution was decompressed to remove the solvent, the sample was dissolved in deuterated chloroform, and the dr value was measured by ¹ H NMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 5: 1). 1) to obtain a pair of diastereomers, the structures are shown in formula (syn-5c) and (anti-5c), 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, 136.3,135.0,129.9,128.9,128.2,126.9,126.6,126.2,125.9,122.1,121.4,120.0,119.0,109.0,108.7,107.4,105.4,87.883.6,61.4,4,3.4,38.1 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=7.8Hz, 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) δ176.1,144.2,137.2,136.0,130.2,129.5,128.8,128.4,127.6,127.4,126.1,125.2,122.3,121.8,121.4,118.7,108.1,108.8,108.7,10,3.2,6,48.0,8.8 32.9, 15.4, 0.0. Peak overlapping was observed.

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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

2) N-benzylisatin diazonium (0.3mmol), 3-phenylpropargyl alcohol (0.3mmol) and indole-3-trimethylsilylpropargyl alcohol (0.2mmol) were mixed and dissolved in 2.0 mL of 1.2-dichloroethane;

3) Use the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After the reaction solution was decompressed to remove the solvent, the sample was dissolved in deuterated chloroform, and the dr value was measured by ¹ H NMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 5: 1). 1) to obtain a pair of diastereomers, the structures are shown in formulas (syn-5d) and (anti-5d), 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, 128.3,128.13,128.08,126.8,126.6,126.1,124.3,122.6,122.0,121.4,119.9,119.0,109.3,108.7,107.1,105.1,88.3,86.4,84.9,30.3.,32.5,43 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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

2) N-benzylisatin diazonium (0.3mmol), cinnamyl alcohol (0.3mmol) and indole-3-trimethylsilyl propargyl alcohol (0.2mmol) were mixed and dissolved in 2.0mL of 1.2-bismuth In chloroethane;

3) Use the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After the reaction solution was decompressed to remove the solvent, the sample was dissolved in deuterated chloroform, and the dr value was measured by ¹ H NMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 5: 1). 1) to obtain a pair of diastereomers, the structures are shown in formulas (syn-5e) and (anti-5e), 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 )δ175.2,144.1,136.7,136.3,134.9,132.1,130.0,128.9,128.4,128.1,127.5,126.8,126.6,126.4,126.2,126.1,125.8,121.3,122.1 109.1, 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, 121.6, 2.0, 9 119.0,109.0,108.8,108.6,103.2,88.1,84.6,66.7,44.3,38.6,33.0,0.0.Peak overlapping was observed.

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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

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

3) Use the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After removing the solvent under reduced pressure, the reaction solution was sampled and dissolved in deuterated chloroform to measure the dr value using ¹ H NMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1-5 : 1) to obtain a pair of diastereomers, whose structures are shown in formulas (syn-5f) and (anti-5f), total yield: 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, 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, 129.6,128.8,128.2,127.6,127.5,126.2,125.0,124.0,122.4,121.8,121.5,121.4,118.7,108.8,108.64,108.59,88.0,84.4,62.7,44.1,38.7,32 23.4, 17.6, 0.0. Peak overlapping was observed.

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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

2) N-benzyl-6-methoxyisatin diazonium (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 the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After the reaction solution was decompressed to remove the solvent, the sample was dissolved in deuterated chloroform, and the dr value was measured by ¹ H NMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 5: 1). 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) δ 7.94(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 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) δ 176.6, 161.1, 145.6 ,137.2,136.0,130.1,128.8,128.3,127.6,127.4,126.9,122.3,121.4,118.6,117.0,108.9,108.8,105.4,103.4,96.8,87.8,84.4,61.3,54,5.4,5.1 ,0.0.Peakoverlapping was observed.

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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

2) N-methylisatin diazonium (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-dichlorohydrin in ethane;

3) Use the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After the reaction solution was decompressed to remove the solvent, the sample was dissolved in deuterated chloroform, and the dr value was measured by ¹ H NMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 5: 1). 1) to obtain a pair of diastereomers, the structures are shown in formula (syn-5h) and (anti-5h), 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) δ 7.91 (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, 61.8, 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)δ176.2,145.1,137.2,130.2,129.6,128.4,126.1,125.0,122.4,121.7,121.4,118.7,108.8,108.8,107.5,103.0,8,7.7,85. 38.6, 33.026.1, 15.4, 0.0. Peakoverlapping was observed.

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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

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

3) Use the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After the reaction solution was decompressed to remove the solvent, the sample was dissolved in deuterated chloroform, and the dr value was measured by ¹ H NMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 5: 1). 1) to obtain a pair of diastereomers, the structures are shown in formula (syn-5i) and (anti-5i), 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=7.5Hz) ,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＝15.7Hz ,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, 121.9.5, 122.5, 121.9 108.9, 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 Peaklapping was observed.

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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

2) N-benzylisatin diazonium (0.3mmol), ethanol (0.3mmol) and indole-3-tert-butylpropargyl alcohol (0.2mmol) were mixed and dissolved in 2.0mL of 1.2-dichloroethane middle;

3) Use the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After removing the solvent under reduced pressure, the reaction solution was sampled and dissolved in deuterated chloroform to measure the dr value using ¹ HNMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether:ethyl acetate=30:1～5: 1) to obtain a pair of diastereomers, the structures are shown in formulas (syn-5j) and (anti-5j), 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=7.1Hz, 1H), 7.39(d, J=8.1Hz, 1H), 7.26-7.22(m, 1H), 7.19(d,J=8.2Hz,1H),7.17–7.03(m,4H),6.95(t,J=7.5Hz,2H),6.89(t,J=7.6Hz,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 )δ175.5,144.0,136.4,135.2,129.7,128.9,128.3,126.92,126.85,126.4,126.3,126.0,122.1,121.3,120.2,118.8,109.0,108.4,108 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)δ176.3,144.2,137.2,136.1,130.1,129.3,128.8,128.5,127.6,127.5,126.0,125.5,122.5,121.7,121.3,118.5,110.0,108.7,108.5,91.6,84 37.3, 32.9, 31.0, 27.2, 15.4. Peak overlapping was observed.

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

分子筛(20mg)加入干燥的10mL试管中，再加入2.0mL 1.2-二氯乙烷后降温至-30℃；1) Under nitrogen protection, Rh ₂ (esp) ₂ (0.004 mmol), chiral phosphoric acid (0.02 mmol) and

Molecular sieves (20mg) were added to a dry 10mL test tube, then 2.0mL of 1.2-dichloroethane was added, and the temperature was lowered to -30°C;

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

3) Use the peristaltic pump to pump the mixed solution in step 2) into the test tube within 2 hours, and continue stirring for 2 hours after the beating. After the reaction solution was decompressed to remove the solvent, the sample was dissolved in deuterated chloroform, and the dr value was measured by ¹ H NMR. Finally, all solutions were mixed and separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 5: 1). 1) to obtain a pair of diastereomers, the structures are shown in formulas (syn-5k) and (anti-5k), 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=15.8 Hz, 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, 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) δ176.1,144.3,136.1,135.9,132.0,129.5,128.8,127.6,127.5,126.2,125.2,124.2,121.8,120.6,120.4,118.9,108.7,108,.6,108.7,108,.6,108.8,6.4. , 44.1, 38.4, 37.0, 19.9, 15.4, 0.0. Peak overlapping was observed.

Example 2 Measurement of antitumor activity 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, cells were seeded in medium (RPMI1640 medium) containing 10% serum and 1% penicillin-streptomycin solution at 37°C, 5% CO ₂ In an incubator, passage every 2-3 days, and take cells in the logarithmic growth phase for testing.

The MTS method was used to detect the cell viability, that is, the medium of the cells in the logarithmic growth phase was drawn, and after trypsinization, RPMI1640 medium (containing 10% serum and 1% penicillin-streptomycin) was added to terminate the digestion, and the digestion was stopped by gently pipetting and counting. , take 100uL and inoculate 3000 cells/well in a 96-well plate, then add compounds (syn-5a to syn-5k), each compound is set to a concentration gradient (50uM fold and half dilution, 8 concentrations), each concentration is set to three Duplicate wells, each concentration was added to the corresponding well, 5% CO ₂ , incubated in a 37°C incubator for 72 hours, added 20uL MTS and then incubated at 37°C for 2 hours, and then measured the light at 490nm (L1) using SpectraMAX340 Absorption value, the reference wavelength is 690nm (L2), the (L1-L2) value is plotted against the concentration of different compounds, and IC ₅₀ is obtained by formula fitting.

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

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

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

Sample serial number Sample serial number Molecular formula (Formula) Molecular weight (MW) weight IC₅₀(uM) 1 syn-5a C₃₇H₃₆N₂O₂Si 568.79 1.66 6.42 2 syn-5b C₄₁H₃₈N₂O₂Si 618.85 1.44 6.41 3 syn-5c C₃₂H₃₄N₂O₂Si 506.72 1.82 6.74 4 syn-5d C₃₉H₃₆N₂O₂Si 592.81 1.59 6.13 5 syn-5e C₃₉H₃₈N₂O₂Si 594.83 1.97 5.94 6 syn-5f C₄₀H₄₆N₂O₂Si 614.91 1.68 5.31 7 syn-5g C₃₃H₃₆N₂O₃Si 536.75 1.36 5.42 8 syn-5h C₂₆H₃₀N₂O₂Si 430.62 1.52 4.81 9 syn-5i C₃₅H₃₀N₂O₂ 510.64 1.58 4.63 10 syn-5j C₃₃H₃₄N₂O₂ 490.65 1.62 4.52 11 syn-5k C₃₃H₃₆N₂O₂Si 520.75 1.57 5.12

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

Claims (10)

1. a chiral α-propargyl-3-indole compound or its derivative, is characterized in that, the structure of described compound or its derivative is as shown in syn-5 of formula (I) or anti-5 Show:

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, t-butoxycarbonyl, acetyl; R2 is independently selected from alkyl, benzyl, C2 alkyl substituted benzyl, C2 alkoxy substituted benzyl, ² -naphthylmethyl, allyl, cinnamyl, nerol, phenyl propargyl; R is independently selected from alkyl, silyl, phenyl. 2. The chiral α-propargyl-3-indole compound or its derivative according to claim 1, wherein the Ar ¹ is phenyl, 5-methylphenyl, 5-chloro Phenyl, 6-chlorophenyl, 6-bromophenyl, 6-methoxyphenyl, 7-methylphenyl, naphthyl, 2-methylnaphthyl or 2-methoxynaphthyl; Ar ² is phenyl, 5-chlorophenyl, 5-methoxyphenyl, 6-methoxyphenyl, 7-methylphenyl, naphthyl, 2-methylnaphthyl, 2-methoxynaphthyl , thienyl or furyl; R ¹ is hydrogen, C _1-3 alkyl, benzyl, halobenzyl, acetyl or tert-butoxycarbonyl; R ² is methyl, ethyl, propyl, isopropyl , trimethylsilyl substituted ethyl, cyclohexyl substituted methyl, benzyl, 2-methoxy substituted benzyl, 2-methyl substituted benzyl, 2-naphthylmethyl, allyl, Cinnamyl alcohol group, phenyl propargyl group, nerol group; R is trimethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, methyl group, tert-butyl group, phenyl group. 3. The preparation method of the chiral α-propargyl-3-indole compound or its derivative according to claim 1 or 2, characterized in that, 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 raw materials, Rh ₂ (esp) ₂ and chiral phosphoric acid are catalysts, and molecular sieves are water absorbing agents. The reaction is prepared to obtain chiral α-propargyl-3-indole compounds or derivatives thereof:

4. The preparation method of chiral α-propargyl-3-indole compounds or derivatives thereof according to claim 3, wherein the reaction temperature is -30～25°C, and the reaction time 2-6h. 5. the preparation method of chiral α-propargyl-3-indole compound or its derivative according to claim 3, is characterized in that, the structure of described chiral phosphoric acid is as shown in formula (5):

In the formula, R is 1-pyrene group. 6. The preparation method of chiral α-propargyl-3-indole compounds or derivatives thereof according to claim 3, wherein the alcohol of formula (1), the diazo compound of formula (2) The molar ratio with the indole propargyl alcohol of the formula (3) is 1.0 to 2.0:1.0 to 2.0:1.0. 7. the preparation method of chiral α-propargyl-3-indole compounds or derivatives thereof according to claim 3, is characterized in that, based on the indole propargyl alcohol of formula (3), catalyst The dosage of Rh ₂ (esp) ₂ is 2.0 mol % of indole propargyl alcohol, and the dosage of chiral phosphoric acid is 5.0-10 mol % of indole propargyl alcohol. 8. The preparation method of chiral α-propargyl-3-indole compounds or derivatives thereof according to claim 3, characterized in that, based on the indole propargyl alcohol of formula (3), the The feeding amount of the molecular sieve is 100 mg/mmol. 9. The preparation method of chiral α-propargyl-3-indole compounds or derivatives thereof according to claim 3, wherein the organic solvent comprises dichloromethane, 1,2-dichloromethane Ethane, tetrahydrofuran, toluene. 10. Use of the chiral α-propargyl-3-indole compound or its derivative according to claim 1 or 2 in the preparation of an anti-colon cancer medicament.

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