阅读说明：本技术 一种合成手性色氨酸衍生物的方法 (Method for synthesizing chiral tryptophan derivative ) 是由 高洪银 王敏 刘笑 王丽英 于 2021-10-09 设计创作，主要内容包括：本发明涉及一种合成手性色氨酸衍生物的方法,该手性色氨酸衍生物具有式(Ⅲ)所示结构。将化合物(I)、化合物(II)、Zn(OTf)-(2)、金催化剂、银催化剂混合,在氮气氛围下加入溶剂,于氮气氛围下反应,待反应完成后,提纯,即得。本发明具有良好的官能团兼容性,并且以良好的产率和高区域选择性制备了多种手性色氨酸的衍生物。(The invention relates to a method for synthesizing chiral tryptophan derivatives, wherein the chiral tryptophan derivatives have a structure shown in a formula (III). Mixing compound (I), compound (II), Zn (OTf) 2 Mixing the gold catalyst and the silver catalyst, adding a solvent in the nitrogen atmosphere, reacting in the nitrogen atmosphere, and purifying after the reaction is finished to obtain the catalyst. The invention has good functional group compatibility, and prepares a plurality of chiral tryptophan derivatives with good yield and high regioselectivity.)

1. A chiral tryptophan derivative, wherein the chiral tryptophan derivative has a structure represented by formula (iii):

in the formula (III), R¹Is one of hydrogen atom, alkyl, alkenyl, aryl (including various substituted phenyl, naphthyl, heteroaromatic ring substituent groups and the like), oxygen trifluoromethyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, sulfur trifluoromethyl, ester group, indolyl and carbazolyl;

R²is one of alkyl, alkenyl and aryl;

R³is one of alkyl, alkenyl and aryl;

PG is one of alkyl, alkenyl, aryl, benzoyl, acetyl, pivaloyl, ester, tert-butyloxycarbonyl, benzyloxycarbonyl, trifluoroacetyl and 9-fluorenylmethoxycarbonyl.

2. The method for synthesizing chiral tryptophan derivatives as claimed in claim 1, comprising the steps of:

mixing compound (I), compound (II), Zn (OTf)₂Mixing the gold catalyst and the silver catalyst, adding a solvent in a nitrogen atmosphere, reacting in the nitrogen atmosphere, and purifying after the reaction is finished to obtain a target compound (III);

3. the method for synthesizing chiral tryptophan derivatives according to claim 2, wherein the purification method comprises the following steps:

after the reaction is finished, the reaction mixture is decompressed and concentrated, the crude product is subjected to column chromatography, and the eluent after the column chromatography is petroleum ether: ethyl acetate 7:1 to obtain the target compound (III).

4. The method for synthesizing chiral tryptophan derivatives according to claim 2, wherein the molar ratio of the compound (I) to the compound (II) is 1: (1-3).

5. The method for synthesizing chiral tryptophan derivative according to claim 2, wherein the gold catalyst is Ph₃PAuCl，Cy₃PAuCl, IpruCl or (ArO)₃PAuCl(Ar＝2,4-di-tert-butylphenyl)。

6. The method for synthesizing chiral tryptophan derivative according to claim 2, wherein the amount of the gold catalyst is 5 to 20 mol% of the compound (I).

7. The method for synthesizing chiral tryptophan derivative according to claim 2, wherein the silver catalyst is AgOTf or AgNTf₂。

8. The method for synthesizing chiral tryptophan derivative according to claim 2, wherein the amount of the silver catalyst is 5 to 20 mol% of the compound (I).

9. The method for synthesizing chiral tryptophan derivatives according to claim 2, wherein the solvent is toluene or 1, 2-dichloroethane.

10. The method for synthesizing chiral tryptophan derivatives according to claim 2, wherein the reaction time is 10 to 20 hours;

preferably, the reaction temperature is 60-80 ℃.

Technical Field

The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a chiral tryptophan derivative and a synthesis method thereof.

Background

Amino acid is a chiral molecule with biological activity, and the amino acid and the derivatives thereof have very wide application in the fields of medicine and food and have great market demand, so the synthesis of the chiral amino acid derivatives becomes a hot point of research in the synthesis field.

L-tryptophan is an amino acid discovered and separated by Hopkins and Kole in 1901, is one of essential amino acids for human body, and occupies a unique position in aspects of regulating the synthesis of human protein, enhancing the immune function of the body and the like. Many studies have shown that L-methyltryptophan has antitumor activity and tumor chemotherapeutic effect as a tryptophan derivative as well as an IDO inhibitor. Therefore, the search for other tryptophan analogs as antitumor agents has become a hot spot for the chemists to study. In addition, certain L-tryptophan derivatives can react with certain monoterpene compounds having aldehyde groups or hemiacetal hydroxyl groups to form monoterpene indole alkaloids by the Pictet-Spengler reaction. The compounds have strong antitumor bioactivity, and thus attract great attention of scientific workers in pharmaceutical, chemical, biological, medical and other fields.

Since few literature reports exist on the synthesis of L-tryptophan derivatives, it is of certain significance to modify the structure of L-tryptophan to obtain tryptophan derivatives with different structures. The prior art mainly relates to a biological method for preparing L-tryptophan derivatives, and the L-tryptophan derivatives are prepared by microorganisms, such as: US5275940A, JP1985034192A etc.

However, few chemical syntheses of L-tryptophan derivatives have been reported.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a novel method for synthesizing chiral tryptophan derivatives. A series of derivatives of chiral tryptophan are synthesized with high regioselectivity through the reaction of aryl hydroxylamine and chiral alkyne under the concerted catalysis of gold and zinc.

The technical scheme of the invention is as follows:

a chiral tryptophan derivative has a structure shown in a formula (III):

in the formula (III), R¹Is one of hydrogen atom, alkyl, alkenyl, aryl (including various substituted phenyl, naphthyl, heteroaromatic ring substituent groups and the like), oxygen trifluoromethyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, sulfur trifluoromethyl, ester group, indolyl and carbazolyl;

R²is alkyl, alkenyl, aryl (including each)A substituted phenyl, naphthyl, heteroaryl ring substituent group, etc.);

R³is one of alkyl, alkenyl and aryl (including various substituted phenyl, naphthyl and heteroaromatic ring substituent groups and the like);

PG is one of alkyl, alkenyl, aryl (including various substituted phenyl, naphthyl, heteroaromatic ring substituent groups and the like), benzoyl, acetyl, pivaloyl, ester group, tert-butyloxycarbonyl, benzyloxycarbonyl, trifluoroacetyl and 9-fluorenylmethoxycarbonyl.

According to the present invention, the method for synthesizing the chiral tryptophan derivative comprises the following steps:

mixing compound (I), compound (II), Zn (OTf)₂Mixing the gold catalyst and the silver catalyst, adding a solvent in a nitrogen atmosphere, reacting in the nitrogen atmosphere, and purifying after the reaction is finished to obtain a target compound (III);

during the reaction, the progress of the reaction can be followed by TLC.

According to the present invention, preferably, the purification method is as follows:

after the reaction is finished, the reaction mixture is decompressed and concentrated, the crude product is subjected to column chromatography, and the eluent after the column chromatography is petroleum ether: ethyl acetate 7:1 to obtain the target compound (III).

According to the invention, it is preferred that the molar ratio of compound (I) to compound (II) is 1: (1-3), and more preferably 1: 1.5.

According to the invention, preferably, the gold catalyst is Ph₃PAuCl，Cy₃PAuCl, IpruCl or (ArO)₃PAuCl (Ar ═ 2,4-di-tert-butylphenyl), most preferably Cy₃PAuCl；

Preferably, the gold catalyst is used in an amount of 5 to 20%, most preferably 10%, based on the molar amount of compound (I).

According to the invention, preferably, the silver catalyst is AgOTf or AgNTf₂Most preferably AgOTf;

preferably, the amount of silver catalyst used is 5 to 20%, most preferably 10%, of the molar amount of compound (I).

According to the present invention, preferably, the solvent is toluene or 1, 2-dichloroethane, most preferably toluene.

According to the present invention, the reaction time is preferably 10 to 20 hours, and more preferably 12 hours.

According to the invention, the reaction temperature is preferably 60 to 80 ℃ and most preferably 80 ℃.

According to the invention, said compound (I) has the following structure: take PG as Bz for example

The compounds (I) can be prepared according to the prior art route, which is as follows:

the preparation method comprises the following steps: in N₂The nitro compound (1.0 eq) and 5% Rh/C (0.30 mol% Rh) were dissolved in THF (0.324M) under an atmosphere, and the reaction was subsequently cooled to 0 ℃ and hydrazine hydrate (1.2 eq) was added dropwise. The reaction mixture was stirred at 0 ℃ for 1 hour, then slowly warmed to 45 ℃ and stirred at 45 ℃ for 4 hours, after the reaction was complete, the reaction mixture was filtered through celite, concentrated by rotary evaporation, recrystallized and the crude hydroxylamine obtained was used directly in the next step.

To a solution of hydroxylamine in ether (0.5M), saturated NaHCO was added₃Aqueous solution, then the solution is cooled to 0 ℃, acid chloride (1.1 eq) is added dropwise, after stirring at 0 ℃ for 10 seconds, the reaction is quenched with saturated NH₄Quenching with aqueous Cl, extracting the reaction mixture with dichloromethane, washing the organic layer with brine and drying over sodium sulfate, removing the solvent in vacuo, subjecting the crude product to column chromatography with an eluent for the column chromatography being dichloromethane: ethyl acetate 80:1 to give compound (I).

According to the invention, said compound (II) has the following structure:

the compound (II) can be prepared according to the prior art route, which is as follows: with R³For example, isopropyl

To a solution of glycine (4.50g, 60.0mmol) in isopropanol (150mL) at-10 ℃ was added thionyl chloride (14.0mL, 192mmol) dropwise, stirring at-10 ℃ for 10 minutes, then the reaction was heated to 40 ℃ and after 4h of reaction, the reaction mixture was cooled to room temperature and evaporated to remove the solvent, yielding the crude product, isopropyl glycinate.

The crude product isopropyl glycinate is dissolved in DCM (60mL), benzophenone imine (10.8mL, 60mmol) is added, the reaction is stirred for 24h at room temperature, the suspension is filtered through kieselguhr, the filtrate is washed with water and brine in sequence, the solvent is removed by evaporation and concentration, and the crude product is purified by recrystallization (PE/EtOH) to obtain the compound S1.

The bromide of the alkyne (2.6mL,30.0mmol) was added dropwise to a mixed solvent of N- (diphenylmethylene) glycine isopropyl ester S1(1.69g,6.0mmol) and catalyst (270mg,0.6mmol) in toluene/chloroform (7:3,30 mL). The reaction was then cooled to-20 ℃, 50% aqueous KOH (9mL) was added, and the reaction mixture was stirred at-20 ℃ until the starting material was consumed. Diluting the suspension with ethyl acetate, washing with water, drying with anhydrous sodium sulfate, evaporating to remove the solvent, subjecting the crude product to column chromatography, and eluting with petroleum ether: ethyl acetate 20:1 gave compound S2.

S2(5mmol, 1.67g) was dissolved in MeOH (30mL) followed by 2.0mL concentrated hydrochloric acid dropwise at room temperature. After stirring the reaction mixture at room temperature for 12h, the solvent was removed by evaporation and concentration, the residue was diluted with water and extracted 3 times with EtOA. The aqueous layer was concentrated by evaporation to give crude product S3.

Adding Et₃N (7.5mmol, 0.9mL) was added dropwise to a solution of crude S3(5.0mmol, 0.82g) and phthalic anhydride (5.0mmol, 1.1g) in toluene (15mL) and the reaction was stirred at reflux for 2 h. The reaction mixture was extracted with EtOAc and the organic layer was washed with brine and over Na₂SO₄Drying, evaporating and concentrating to remove the solvent, and purifying the crude product by column chromatography, wherein the eluent of the column chromatography is petroleum ether: ethyl acetate 10:1 to give compound (II).

The technical route of the invention is as follows:

the invention has the beneficial effects that:

according to the invention, a series of derivatives of chiral tryptophan are synthesized in a high regioselectivity manner through the reaction of aryl hydroxylamine and chiral alkyne under the concerted catalysis of gold and zinc. The invention has good functional group compatibility, and prepares a plurality of chiral tryptophan derivatives with good yield and high regioselectivity.

Drawings

FIG. 1 shows the preparation of isopropyl (S) -3- (1-benzoyl-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate obtained in example 1¹H-NMR spectrum;

FIG. 2 shows the preparation of isopropyl (S) -3- (1-benzoyl-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate obtained in example 1¹³A C-NMR spectrum;

FIG. 3 is an HPLC chromatogram of isopropyl (S) -3- (1-benzoyl-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate prepared in example 1;

FIG. 4 shows the preparation of isopropyl (S) -3- (1-benzoyl-2, 5-dimethyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate obtained in example 2¹H-NMR spectrum;

FIG. 5 shows the preparation of isopropyl (S) -3- (1-benzoyl-2, 5-dimethyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate obtained in example 2¹³A C-NMR spectrum;

FIG. 6 is an HPLC chromatogram of isopropyl (S) -3- (1-benzoyl-2, 5-dimethyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate prepared in example 2;

FIG. 7 shows the preparation of isopropyl (S) -3- (1-benzoyl-2-methyl-5- (trifluoromethoxy) -1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate obtained in example 3¹H-NMR spectrum;

FIG. 8 shows the preparation of isopropyl (S) -3- (1-benzoyl-2-methyl-5- (trifluoromethoxy) -1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate obtained in example 3¹³A C-NMR spectrum;

FIG. 9 shows the preparation of isopropyl (S) -3- (1-benzoyl-2-methyl-5- (trifluoromethoxy) -1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate obtained in example 3¹⁹F-NMR spectrum;

FIG. 10 is an HPLC chromatogram of isopropyl (S) -3- (1-benzoyl-2-methyl-5- (trifluoromethoxy) -1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate prepared in example 3;

FIG. 11 shows the preparation of isopropyl (S) -3- (1-benzoyl-5-chloro-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate obtained in example 4¹H-NMR spectrum;

FIG. 12 shows the preparation of isopropyl (S) -3- (1-benzoyl-5-chloro-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate obtained in example 4¹³A C-NMR spectrum;

FIG. 13 is an HPLC chromatogram of isopropyl (S) -3- (1-benzoyl-5-chloro-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate prepared in example 4;

FIG. 14 is a schematic view ofPreparation of isopropyl (S) -3- (1-benzoyl-2, 7-dimethyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate prepared in example 5¹H-NMR spectrum;

FIG. 15 shows the preparation of isopropyl (S) -3- (1-benzoyl-2, 7-dimethyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate obtained in example 5¹³A C-NMR spectrum;

FIG. 16 shows the HPLC chromatogram of isopropyl (S) -3- (1-benzoyl-2, 7-dimethyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate prepared in example 5.

Detailed Description

The present invention is further illustrated by, but is not limited to, the following specific examples.

EXAMPLE 1 Synthesis of isopropyl (S) -3- (1-benzoyl-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate

Coupling N-hydroxy-N-phenylbenzamide (0.2mmol, 43mg), (S) -isopropyl 2- (1, 3-dioxaisoindolin-2-yl) hex-4-yne (0.3mmol, 90mg), Zn (OTf)₂(0.02mmol，5.6mg)、Cy₃PAuCl (0.02mmol, 10mg), AgOTf (0.02mmol, 5.2mg) were mixed, the solvent toluene (2mL) was added under nitrogen atmosphere, reaction was carried out at 80 ℃ for 12H, after completion of the reaction, the solvent was removed by evaporation concentration, and the crude product was subjected to column chromatography (eluent: petroleum ether: ethyl acetate ═ 7:1) to give (S) -3- (1-benzoyl-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid isopropyl ester as an oily product in 92% yield and 92% ee value.

¹H NMR(500MHz,CDCl3):δ7.81-7.75(m,2H),7.71-7.66(m,2H),7.56(t,J＝7.6Hz,3H),7.49(d,J＝7.8Hz,1H),7.39(t,J＝7.6Hz,2H),7.08(t,J＝7.4Hz,1H),,7.03-6.94(m,2H),5.22–5.06(m,2H),3.62(qd,J＝14.9,7.9Hz,2H),2.19(s,3H),1.28(d,J＝6.3Hz,3H),1.24(d,J＝6.3Hz,3H)；

¹³C NMR(126MHz,CDCl3):δ169.6,168.3,167.4,136.4,135.6,134.9,134.2,132.8,131.7,129.7,129.4,128.7,123.5,123.2,122.5,117.8,114.4,114.2,69.9,52.1,24.1,21.8,21.7,13.2；

HPLC:the ee value was determined by HPLC analysis(Chiralcel ODH,i-PrOH/Hexane＝5/95,1.0mL/min,227nm),retention time:tmajor＝9.614min,tminor＝13.339min,ee＝92％；[α]D²⁵＝-267.4(c＝1.97,CHCl₃).

EXAMPLE 2 Synthesis of isopropyl (S) -3- (1-benzoyl-2, 5-dimethyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate

Coupling N-hydroxy-N- (p-tolyl) benzamide (0.2mmol, 45mg), (S) -isopropyl 2- (1, 3-dioxaisoindolin-2-yl) hex-4-yne (0.3mmol, 90mg), Zn (OTf)₂(0.02mmol，5.6mg)、Cy₃PAuCl (0.02mmol, 10mg), AgOTf (0.02mmol, 5.2mg) were mixed, the solvent toluene (2mL) was added under nitrogen atmosphere, reaction was carried out at 80 ℃ for 12H, after completion of the reaction, the solvent was removed by evaporation concentration, and the crude product was subjected to column chromatography (eluent: petroleum ether: ethyl acetate ═ 7:1) to give (S) -3- (1-benzoyl-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid isopropyl ester as an oily product in 76% yield and 92% ee.

¹H NMR(500MHz,CDCl₃):δ7.72-7.67(m,2H),7.65-7..57(m,2H),7.48(t,J＝6.9Hz,3H),7.31(t,J＝7.6Hz,2H),7.13(s,1H),6.77(d,J＝8.4Hz,1H),,6.67(d,J＝8.4Hz,1H),5.15-4.98(m,2H),3.51(ddd,J＝25.6,14.9,7.8Hz,2H),2.20(s,3H),2.10(s,3H),1.20(d,J＝6.3Hz,3H),1.17(d,J＝6.3Hz,3H).

¹³C NMR(126MHz,CDCl₃):δ169.6,168.3,167.4,135.7,134.9,134.6,134.1,132.6,132.0,131.7,129.7,129.6,128.6,124.3,123.3,117.8,114.3,113.9,69.9,52.1,24.0,21.8,21.7,21.2,13.2.

HPLC:the ee value was determined by HPLC analysis(Chiralcel ODH,i-PrOH/Hexane＝5/95,1.0mL/min,227nm),retention time:t_major＝9.527min,t_minor＝13.679min,ee＝92％；[α]_D ²⁵＝-261.5(c＝1.60,CHCl₃).

EXAMPLE 3 Synthesis of isopropyl (S) -3- (1-benzoyl-2-methyl-5- (trifluoromethoxy) -1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate

Coupling N-hydroxy-N- (p-trifluoromethoxy) benzamide (0.2mmol, 59mg), (S) -isopropyl 2- (1, 3-dioxaisoindolin-2-yl) hex-4-yne (0.3mmol, 90mg), Zn (OTf)₂(0.02mmol，5.6mg)、Cy₃PAuCl (0.02mmol, 10mg), AgOTf (0.02mmol, 5.2mg) were mixed, the solvent toluene (2mL) was added under nitrogen atmosphere, reaction was carried out at 80 ℃ for 12H, after completion of the reaction, the solvent was removed by evaporation concentration, and the crude product was subjected to column chromatography (eluent: petroleum ether: ethyl acetate ═ 7:1) to give (S) -3- (1-benzoyl-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid isopropyl ester as an oily product in 76% yield and 92% ee.

¹H NMR(500MHz,CDCl₃):δ7..81-7.75(m,2H),7.73-7.65(m,2H),7.63-7.53(m,3H),7.47-7.37(m,2H),7.29(s,1H),7.06(d,J＝8.9Hz,1H),6.83(d,J＝8.9Hz,1H),5.21-5.12(m,1H),5.11-5.04(m,1H),3.60(d,J＝7.9Hz,2H),2.21(s,3H),1.28(d,J＝6.3Hz,3H),1.24(d,J＝6.2Hz,3H).

¹³C NMR(126MHz,CDCl₃):δ169.4,168.1,167.4,144.8,136.8,135.1,134.5,134.2,133.1,131.5,130.3,129.7,128.8,123.5,121.6,119.5,116.4,114.9,114.3,110.3,70.1,51.9,23.9,21.7,21.6,13.4.

¹⁹F NMR(471MHz,CDCl₃):δ-58.0.

HPLC:the ee value was determined by HPLC analysis(Chiralcel ADH,i-PrOH/Hexane＝5/95,1.0mL/min,227nm),retention time:t_major＝6.884min,t_minor＝9.890min,ee＝92％；[α]_D ²⁵＝-222.5(c＝1.27,CHCl₃).

EXAMPLE 4 Synthesis of isopropyl (S) -3- (1-benzoyl-5-chloro-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate

Coupling N- (4-chlorophenyl) -N-hydroxybenzamide (0.2mmol, 50mg), (S) -isopropyl 2- (1, 3-dioxaisoindolin-2-yl) hex-4-yne (0.3mmol, 90mg), Zn (OTf)₂(0.02mmol，5.6mg)、Cy₃PAuCl (0.02mmol, 10mg), AgOTf (0.02mmol, 5.2mg) were mixed, the solvent toluene (2mL) was added under nitrogen atmosphere, reaction was carried out at 80 ℃ for 12H, after completion of the reaction, the solvent was removed by evaporation concentration, and the crude product was subjected to column chromatography (eluent: petroleum ether: ethyl acetate ═ 7:1) to give (S) -3- (1-benzoyl-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid isopropyl ester as an oily product in 67% yield and 92% ee.

¹H NMR(500MHz,CDCl₃):δ7..74-7.67(m,2H),7.67-7.59(m,2H),7.55-7.43(m,3H),7.33(dd,J＝9.2,4.7Hz,3H),6.84(dt,J＝8.8,5.3Hz,2H),5.09(hept,J＝6.3Hz,1H),4.99(dd,J＝10.6,5.0Hz,1H),3.49(qd,J＝15.0,7.8Hz,2H),2.09(s,3H),1.21(d,J＝6.3Hz,3H),1.17(d,J＝6.3Hz,3H).

¹³C NMR(126MHz,CDCl₃):δ169.4,168.1,167.4,136.3,135.2,134.2,133.1,131.6,130.7,129.7,128.8,128.3,123.4,123.2,117.5,115.1,113.9,70.1,51.9,24.0,21.8,21.7,13.2.

HPLC:the ee value was determined by HPLC analysis(Chiralcel ADH,i-PrOH/Hexane＝5/95,1.0mL/min,227nm),retention time:t_major＝10.533min,t_minor＝15.490min,ee＝92％；[α]_D ²⁵＝-223.9(c＝2.07,CHCl₃).

EXAMPLE 5 Synthesis of isopropyl (S) -3- (1-benzoyl-2, 7-dimethyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate

Coupling N-hydroxy-N- (o-tolyl) benzamide (0.2mmol, 45mg), (S) -isopropyl 2- (1, 3-dioxaisoindolin-2-yl) hex-4-yne (0.3mmol, 90mg), Zn (OTf)₂(0.02mmol，5.6mg)、Cy₃PAuCl (0.02mmol, 10mg), AgOTf (0.02mmol, 5.2mg) were mixed, the solvent toluene (2mL) was added under nitrogen atmosphere, reaction was carried out at 80 ℃ for 12H, after completion of the reaction, the solvent was removed by evaporation concentration, and the crude product was subjected to column chromatography (eluent: petroleum ether: ethyl acetate ═ 7:1) to give (S) -3- (1-benzoyl-2-methyl-1H-indol-3-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid isopropyl ester as an oily product in 62% yield and 94% ee.

¹H NMR(500MHz,CDCl₃):δ7..69-7.63(m,2H),7.61-7.54(m,2H),7.51-7.44(m,1H),7.40(d,J＝7.2Hz,2H),7.32(d,J＝7.8Hz,1H),7.26(t,J＝7.7Hz,2H),,6.97(t,J＝7.6Hz,1H),6.77(d,J＝7.3Hz,1H),5.14-5.01(m,2H),3.69-3.44(m,2H),1.98(s,3H),1.85(s,3H),1.20(d,J＝6.3Hz,3H),1.16(d,J＝6.3Hz,3H).

¹³C NMR(126MHz,CDCl₃):δ171.2,168.4,167.4,136.1,135.7,134.3,134.1,133.7,131.7,130.2,129.5,128.8,125.9,123.3,122.6,122.2,115.8,111.6,69.8,52.2,24.2,21.8,21.7,20.2,12.1.

HPLC:the ee value was determined by HPLC analysis(Chiralcel ADH,i-PrOH/Hexane＝5/95,1.0mL/min,227nm),retention time:t_major＝12.596min,t_minor＝19.444min,ee＝94％；[α]_D ²⁵＝-206.7(c＝0.90,CHCl₃).

Test example 1

Taking N-hydroxy-N-phenyl benzamide and 2- (1, 3-dioxy isoindoline-2-yl) hexyl-4-acetylenic acid isopropyl ester as raw materials, the using amount of a gold catalyst and a silver catalyst is 10 mol%, Zn (OTf)₂10mol percent, toluene as a solvent, and 60 ℃ in a nitrogen atmosphere for 12h, and the influence of the types of the gold catalyst and the silver catalyst on the reaction is researched, as shown in Table 1

TABLE 1 influence of the kind of gold catalyst and silver catalyst on the reaction

As can be seen from the experimental results in Table 1, Cy₃PAuCl and AgOTf are the best gold and silver catalysts for this reaction, other gold and silver catalysts can lead to reduced yields.

Test example 2

Using N-hydroxy-N-phenyl benzamide and 2- (1, 3-dioxide isoindoline-2-yl) hexyl-4-acetylenic acid isopropyl ester as raw materials, Cy₃PAuCl and AgOTf as catalysts, Cy₃The amounts of PAuCl and AgOTf are 10% mol, Zn (OTf)₂The reaction is carried out for 12 hours in the nitrogen atmosphere with the dosage of 10 mol% and the toluene as the solvent, the influence of the temperature on the reaction is researched, and when the reaction temperature is increased from 60 ℃ to 80 ℃, the reaction yield is increased from 71% to 96%. From the experimental results, the yield of the reaction was the best when the reaction temperature was 80 ℃.

Test example 3

With N-hydroxy-N-benzenePhenylbenzamide and isopropyl 2- (1, 3-dioxoisoindolin-2-yl) hex-4-ynoate as starting materials, Cy₃PAuCl and AgOTf as catalysts, Cy₃The amounts of PAuCl and AgOTf are 10% mol, Zn (OTf)₂The reaction is carried out for 12 hours at 80 ℃ in the nitrogen atmosphere by taking toluene as a solvent, the influence of the use amounts of the gold catalyst and the silver catalyst on the reaction is researched, and when the use amount of the catalyst is reduced from 10 mol% to 5 mol%, the reaction yield is reduced from 96% to 79%. From the experimental results, it was found that the yield of the reaction was the best when the amount of the gold catalyst and the silver catalyst was 10 mol%.

Test example 4

Taking phenyl hydroxylamine compounds carrying different substituent groups (or protecting groups) and 2- (1, 3-dioxoisoindoline-2-yl) hexyl-4-propargyl as raw materials, and Cy₃PAuCl and AgOTf as catalysts, Cy₃The amounts of PAuCl and AgOTf are 10% mol, Zn (OTf)₂The method is characterized in that the reaction is carried out for 12 hours at 80 ℃ in a nitrogen atmosphere by taking toluene as a solvent, and the functional group compatibility and the high regioselectivity of a plurality of phenyl hydroxylamine compounds carrying different substituent groups (or protective groups) in the reaction are researched. The corresponding chiral tryptophan derivatives were obtained in 92% and 92% ee, 76% and 92% ee, 67% and 92% ee, 62% and 94% ee, respectively, of N-hydroxy-N- (p-tolyl) benzamide, N-hydroxy-N- (p-trifluoromethoxy) benzamide, N- (4-chlorophenyl) -N-hydroxybenzamide, N-hydroxy-N- (o-tolyl) benzamide. From experimental results, the synthetic method has good functional group compatibility and high regioselectivity.

Test example 5

According to research reports, the chiral tryptophan and the analogue thereof in the synthesis method have the effects of bacteriostasis, cancer resistance and the like, and have great application prospects in the fields of medicine synthesis and the like. Based on¹⁸F, it has been confirmed in the study of the tryptophan tracerMing 2¹⁸F]L-FEHTP has pharmacological characteristics that can accumulate in endocrine and non-endocrine tumor models through LAT transport, but is not decarboxylated by AADC. In addition, the naturally-occurring 2, 5-diketopiperazine compound Brevia amide F not only can be used as a novel natural plant growth inhibitor, but also is a precursor of a plurality of complex indole diketopiperazine alkaloids, and the analogue obtained by changing the amino acid structure shows various biological activities such as bacteriostasis, cancer resistance and the like.