CN109970753B

CN109970753B - Xanthone skeleton spliced oxoindole or benzofuranone compound and preparation method and application thereof

Info

Publication number: CN109970753B
Application number: CN201910343265.4A
Authority: CN
Inventors: 刘雄利; 汪军鑫; 常顺琴; 左雄; 周英; 袁伟成
Original assignee: Guizhou University
Current assignee: Guizhou University
Priority date: 2019-04-26
Filing date: 2019-04-26
Publication date: 2022-05-10
Anticipated expiration: 2039-04-26
Also published as: CN109970753A

Abstract

The invention discloses a xanthone skeleton spliced oxoindole or benzofuranone compound, which is prepared by reacting various substituted bifunctional oxoindole/benzofuranone-chromone synthons and various substituted 3-alkene benzofuranones in an organic solvent under the action of an organic small molecular catalyst to obtain the xanthone skeleton spliced oxoindole compound or the xanthone skeleton spliced benzofuranone compound, and the compound contains a potential bioactive xanthone skeleton and a spiro oxoindole or spiro benzofuranone skeleton, can provide a compound source for biological activity screening, and has important application value for the screening of medicaments and the pharmaceutical industry. The method has the advantages of simple and easy operation, cheap and easily obtained raw material synthesis, capability of being carried out in various organic solvents, better air stability, wide applicability and good compatibility for various substituent groups. And the skeleton compound has the function of inhibiting the tumor growth of human leukemia cells (K562).

Description

Xanthone skeleton spliced oxoindole or benzofuranone compound and preparation method and application thereof

Technical Field

The invention relates to the technical field of chemistry and pharmacy, in particular to a xanthone skeleton spliced oxoindole or benzofuranone compound and a preparation method and application thereof.

Background

According to the active scaffold splicing and migration principle of drug design, splicing two or more scaffolds with biological activity into a multi-scaffold molecule with potential biological activity is an extremely important research field in organic chemistry and medicinal chemistry. (1) The xanthone skeleton is also ubiquitous in natural products and drug molecules. For example, the natural product molecules Ergochrome DD, Diversonol, Desoxydigersonol, Aplantin B and Isoochlioquinone A share one xanthone molecular unit, and the compounds play an important role in relieving pain and realizing economic development. (2) Spiro six-membered carbocyclic oxindole is widely available in natural products and synthetic drug molecules, for example, as shown in figure 8, natural products or active small molecules of spiro six-membered carbocyclic oxindole Satavaptan and provenance receptor agonist II show obvious biological activity. (3) Spiro six-membered carbocyclic benzofuranone compounds are also found in a wide range of natural products and synthetic drug molecules, for example, fig. 8, where natural products or active small molecules of spiro six-membered carbocyclic benzofuranones rosmeadial and ferrubitolide exhibit significant biological activity.

The xanthone skeleton, the spiro six-membered carbocyclic oxoindole skeleton and the spiro six-membered carbocyclic benzofuranone have potential biological activity. Therefore, the spiro six-membered carbocyclic ring oxoindole skeleton or spiro six-membered carbocyclic ring benzofuranone is spliced to the xanthone skeleton to synthesize a series of novel xanthone skeleton spliced oxoindole or benzofuranone compounds with potential multi-active functional groups, so that a compound source can be provided for biological activity screening, and the spiro six-membered carbocyclic ring oxoindole or benzofuranone compound has important application value for the drug screening and pharmaceutical industry (as shown in figure 8).

Disclosure of Invention

The purpose of the invention is: the xanthone skeleton spliced oxindole or benzofuranone compound is an important medical intermediate analogue and a drug molecule analogue, has important application value to drug screening and pharmaceutical industry, and is very economical and simple in synthesis method.

The invention also discloses the application of the compounds in preparing the medicines for preventing and treating tumor diseases.

The invention is realized by the following steps: a xanthone skeleton splicing oxoindole or benzofuranone compound has a structure shown in the following general formula (I):

in the formula, R¹Is methyl or chlorine or fluorine or hydrogen; r²Is methyl or fluoro or isopropyl or hydrogen;R³is methyl or hydrogen; r⁴Is an ester group or a benzoyl group; x is nitrogen substitution or oxygen substitution.

A preparation method of a xanthone skeleton spliced oxoindole or benzofuranone compound comprises the step of carrying out Michael/Michael cycloaddition reaction on various substituted bifunctional oxoindole/benzofuranone-chromone synthons and various substituted 3-alkene benzofuranones in an organic solvent under the action of an organic small molecular catalyst to obtain the xanthone skeleton spliced oxoindole or benzofuranone compound 3 or 5.

The synthetic route is exemplified as follows:

wherein the substituents of the compounds in the synthetic route satisfy R¹Is methyl or chlorine or fluorine or hydrogen; r²Is methyl or fluoro or isopropyl or hydrogen; r³Is methyl or hydrogen; r⁴Is an ester group or a benzoyl group.

The reaction mechanism is exemplified as follows:

the organic solvent is acetonitrile, toluene, dichloromethane or chloroform.

The organic micromolecule alkaline catalyst is thiourea or aromatic amide derived from chiral difunctional cinchona alkaloid, thiourea or aromatic amide derived from cyclohexyl diamine and thiourea or aromatic amide derived from 1, 2-diphenyl diamine.

The organic small molecule basic catalyst is exemplified as follows:

the reaction temperature of various substituted bifunctional oxoindole/benzofuranone-chromone synthons and various substituted 3-alkene benzofuranones in an organic solvent is-10 ℃ to 40 ℃, and the reaction time is 1 to 5 days.

The application of xanthone skeleton spliced oxoindole or benzofuranone compounds in preparing medicines for preventing and treating tumor diseases is provided.

By adopting the technical scheme, various substituted bifunctional oxoindole/benzofuranone-chromone synthons and various substituted 3-alkene benzofuranones are subjected to Michael/Michael cycloaddition reaction in an organic solvent under the action of an organic small molecule catalyst to obtain the xanthone skeleton spliced oxoindole or benzofuranone compound 3 or 5, wherein the compound contains a potential bioactive xanthone skeleton and a spiro oxoindole or spiro benzofuranone skeleton, can provide a compound source for bioactive screening, and has important application value for the screening of medicaments and the pharmaceutical industry. And the novel skeleton compound has an inhibitory activity on human leukemia cells (K562). The method has the advantages of simple and easy operation, cheap and easily obtained raw material synthesis, capability of being carried out in various organic solvents, better air stability, wide applicability and good compatibility for various substituent groups.

Drawings

FIGS. 1 and 2 are data of the spectrum of compound 3a according to an embodiment of the present invention;

FIG. 3 is a liquid chromatogram data of Compound 3 a;

FIGS. 4 and 5 are data of the spectra of compound 5a according to the example of the invention;

FIG. 6 is a liquid phase chromatogram data of Compound 5 a;

FIG. 7 is a single crystal diagram of

compounds

3a,3c and 5a of an embodiment of the present invention;

FIG. 8 is an inventive design of the compounds of the present invention.

Detailed Description

The embodiment of the invention comprises the following steps: adding bifunctional oxoindole-chromone synthon 2a (0.12mmol), 3-ethylenic benzofuranone 1a (0.10mmol), quinine-derived thiourea catalyst C2(10 mol%, 0.01mmol) and 3.0mL of newly distilled ether solution into a reaction tube in sequence, stirring and reacting for 3 days at room temperature, detecting by TLC to be basically complete, directly loading the sample through a column layerThe product was purified by chromatography (eluent: V (petroleum ether): V (ethyl acetate): 5:1) to give compound 3a as a white solid, melting point: 191.8 to 192.4 ℃; the yield is 90%; the content of the solid is 99% ee,>20:1dr,[α]_D ²⁰＝136.7(c 0.44,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝36.83min；τ_minor21.49 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.72(s,9H),1.67(s,9H),2.48-2.54(m,1H),2.62-2.68(m,1H),3.82-3.90(m,1H),4.04(s,1H),5.84(d,J＝14.4Hz,1H),6.72(d,J＝8.4Hz,1H),6.95-6.99(m,1H),7.14-7.21(m,3H),7.26-7.38(m,4H),7.77-7.83(m,3H)；¹³C NMR(CDCl₃,100MHz)δ:26.7,28.1,32.0,38.6,47.2,53.2,56.1,79.9,82.7,84.5,110.0,115.0,117.9,120.1,121.5,121.9,124.7,124.9,126.8,126.9,127.7,128.8,129.8,132.5,136.0,139.3,148.9,154.5,159.7,165.9,177.6,178.7,192.3；HRMS(ESI-TOF)m/z:Calcd.for C₃₇H₃₅NNaO₉[M+Na]⁺:660.2204；Found:660.2207.

the production methods of the compounds 3b to 3t and the compounds 5a to 5k were carried out in the same manner as the production method of the compound 3a, and the compounds 3b to 3t and the compounds 5a to 5k were obtained at the same charge ratio as the compound 3a, and the reaction yields and dr values, ee values, are shown in tables 1 to 3, but it should be emphasized that the compounds of the present invention are not limited to those shown in tables 1 to 3.

Table 1 shows the chemical structure of a preparation method of xanthone skeleton-spliced oxoindole compounds

Table 2 shows the chemical structure of xanthone skeleton spliced oxoindole compounds

Table 3 shows the chemical structure of a preparation method of xanthone skeleton-spliced benzofuranone compounds

This example prepares compound 3b as a white solid, melting point: 115.4-116.2 ℃; the yield is 90%; the content of the solid is 99% ee,>20:1dr,[α]_D ²⁰＝135.7(c 0.28,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝36.12min；τ_minor22.20 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.57-0.60(m,3H),1.69(s,9H),2.50-2.57(m,1H),2.66-2.72(m,1H),3.24-3.32(m,1H),3.39-3.47(m,1H),3.83-3.91(m,1H),4.14(s,1H),5.86(d,J＝14.0Hz,1H),6.75(d,J＝8.4Hz,1H),6.98-7.02(m,1H),7.16-7.23(m,3H),7.31-7.39(m,4H),7.76-7.84(m,3H)；¹³C NMR(CDCl₃,100MHz)δ:12.9,28.1,31.5,38.6,47.2,53.2,55.2,61.4,79.9,84.6,109.9,115.1,117.9,120.2,121.6,122.0,124.9,125.1,126.8,127.0,127.2,129.1,129.9,132.3,136.1,139.4,148.9,154.3,159.7,167.3,177.7,178.7,192.2；HRMS(ESI-TOF)m/z:Calcd.for C₃₅H₃₁NNaO₉[M+Na]⁺:632.1891；Found:632.1897.

this example prepares compound 3c as a white solid, melting point: 135.4-136.2 ℃; the yield is 91%; the total content of the solid matter was 97% ee,>20:1dr,[α]_D ²⁰＝160.7(c 0.18,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IC column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝13.32min；τ_minor21.20 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.73(s,9H),1.67(s,9H),2.31(s,3H),2.47-2.54(m,1H),2.63-2.69(m,1H),3.82-3.90(m,1H),4.02(s,1H),5.87(d,J＝14.4Hz,1H),6.73(d,J＝8.0Hz,1H),6.95-6.98(m,1H),7.05(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.17-7.21(m,1H),7.29-7.38(m,3H),7.58(s,1H),7.79-7.84(m,2H)；¹³C NMR(CDCl₃,100MHz)δ:21.2,26.6,28.1,31.9,38.6,47.2,53.3,56.4,79.9,82.6,84.3,109.6,114.9,117.9,120.2,121.5,121.8,124.9,126.5,126.9,128.0,128.9,130.1,132.4,134.0,135.9,139.4,149.1,152.4,159.8,165.9,177.8,178.4,192.4；HRMS(ESI-TOF)m/z:Calcd.for C₃₈H₃₇NNaO₉[M+Na]⁺:674.2361；Found:674.2365.

this example prepares compound 3d as a white solid, melting point: 108.7 to 109.3 ℃; the yield is 93%; the total content of the solid matter was 97% ee,>20:1dr,[α]_D ²⁰＝84.1(c 0.41,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝24.18min；τ_minor35.47 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.59-0.62(m,3H),1.69(s,9H),2.33(s,3H),2.50-2.57(m,1H),2.65-2.71(m,1H),3.25-3.33(m,1H),3.40-3.48(m,1H),3.83-3.91(m,1H),4.12(s,1H),5.86(d,J＝14.0Hz,1H),6.76(d,J＝8.0Hz,1H),6.97-7.01(m,1H),7.05-7.08(m,1H),7.15(d,J＝8.0Hz,1H),7.19-7.23(m,1H),7.31-7.40(m,3H),7.53(s,1H),7.83(d,J＝8.4Hz,2H)；¹³C NMR(CDCl₃,100MHz)δ:12.9,21.3,28.1,31.5,38.6,47.2,53.3,55.4,61.4,79.9,84.4,109.5,115.1,117.9,120.2,121.7,122.0,124.3,125.0,126.6,127.0,127.5,129.1,130.2,132.2,134.3,136.0,139.5,149.0,152.3,159.8,167.3,177.9,178.5,192.3；HRMS(ESI-TOF)m/z:Calcd.for C₃₆H₃₃NNaO₉[M+Na]⁺:646.2048；Found:646.2045.

this example prepares compound 3e as a white solid, melting point: 199.3-200.1 ℃; the yield is 89%;>99％ee,>20:1dr,[α]_D ²⁰＝139.0(c 0.44,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝51.35min；τ_minor25.04 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,500MHz)δ:0.71(s,9H),1.66(s,9H),2.23(s,3H),2.46-2.53(m,1H),2.59-2.65(m,1H),3.78-3.86(m,1H),4.03(s,1H),5.77(d,J＝14.4Hz,1H),6.62(d,J＝8.4Hz,1H),7.13-7.20(m,4H),7.25-7.35(m,3H),7.58(s,1H),7.76-7.83(m,1H)；¹³C NMR(CDCl₃,100MHz)δ:20.5,26.8,28.2,32.2,38.7,47.3,53.4,56.2,80.1,82.8,84.7,110.1,115.1,117.8,119.9,121.6,124.8,125.1,126.6,127.0,127.8,129.0,129.9,131.5,132.8,137.2,139.4,149.1,154.6,158.0,166.1,177.8,178.9,192.7；HRMS(ESI-TOF)m/z:Calcd.for C₃₈H₃₇NNaO₉[M+Na]⁺:674.2361；Found:674.2362.

this example prepared compound 3f as a white solid, melting point: 141.5-142.3 ℃; the yield is 93%;>99％ee,>20:1dr,[α]_D ²⁰＝142.7(c 0.39,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝42.40min；τ_minor19.73 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.55-0.58(m,3H),1.67(s,9H),2.24(s,3H),2.48-2.54(m,1H),2.61-2.68(m,1H),3.21-3.29(m,1H),3.37-3.45(m,1H),3.78-3.87(m,1H),4.11(s,1H),5.79(d,J＝14.4Hz,1H),6.62(d,J＝8.4Hz,1H),7.13-7.21(m,4H),7.28-7.36(m,3H),7.59(s,1H),7.74-7.78(m,2H)；¹³C NMR(CDCl₃,100MHz)δ:13.1,20.5,28.3,32.1,38.7,47.3,53.4,55.4,61.5,80.0,84.7,110.0,115.2,117.8,119.9,121.8,124.9,125.2,126.7,127.0,127.3,129.2,129.9,131.6,132.5,137.2,139.5,149.0,154.5,158.0,167.5,177.8,178.8,192.5；HRMS(ESI-TOF)m/z:Calcd.for C₃₆H₃₃NNaO₉[M+Na]⁺:646.2048；Found:646.2047.

this example prepares compound 3g, white solid, melting point: 132.4-133.0 ℃; the yield is 85%; the content of the solid is 99% ee,>20:1dr,[α]_D ²⁰＝146.7(c 0.34,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IC column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝9.11min；τ_minor19.14 min); nuclear magnetic resonanceThe results of vibration and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.72(s,9H),1.66(s,9H),2.24(s,3H),2.31(s,3H),2.46-2.52(m,1H),2.59-2.66(m,1H),3.78-3.86(m,1H),4.00(s,1H),5.80(d,J＝14.4Hz,1H),6.64(d,J＝8.8Hz,1H),7.03(d,J＝8.0Hz,1H),7.11-7.14(m,1H),7.16-7.20(m,2H),7.25-7.32(m,2H),7.57-7.58(m,2H),7.802-7.82(m,1H)；¹³C NMR(CDCl₃,100MHz)δ:20.5,21.4,26.8,28.3,32.2,38.8,47.4,53.5,56.5,80.0,82.7,84.4,109.7,115.0,117.9,120.0,121.7,125.1,126.6,126.8,128.2,129.0,130.2,131.5,132.7,134.1,137.1,139.6,149.3,152.6,158.1,166.1,178.0,178.6,192.8；HRMS(ESI-TOF)m/z:Calcd.forC₃₉H₃₉NNaO₉[M+Na]⁺:688.2517；Found:688.2514.

this example prepares compound 3h as a white solid, melting point: 198.1-198.9 ℃; the yield is 77%; the total of the two solid phases is 98% ee,>20:1dr,[α]_D ²⁰＝214.6(c 0.21,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝33.32min；τ_minor27.91 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.56-6.00(m,3H),1.67(s,9H),2.24(s,3H),2.31(s,3H),2.48-2.54(m,1H),2.60-2.67(m,1H),3.23-3.71(m,1H),3.38-3.44(m,1H),3.783.86(m,1H),4.09(s,1H),5.79(d,J＝14.4Hz,1H),6.63(d,J＝8.4Hz,1H),7.02(d,J＝8.4Hz,1H),7.11-7.14(m,1H),7.16-7.20(m,2H),7.28-7.32(m,2H),7.51-7.52(m,1H),7.58-7.59(m,1H),7.80(d,J＝8.0Hz,1H)；¹³C NMR(CDCl₃,100MHz)δ:13.1,20.5,21.4,28.3,32.0,38.7,47.3,53.5,55.6,61.4,80.0,84.5,109.6,115.2,117.8,119.9,121.8,125.1,126.7,126.8,127.6,129.2,130.3,131.5,132.5,134.4,137.2,139.6,149.2,152.4,158.0,167.5,178.1,178.6,192.6；HRMS(ESI-TOF)m/z:Calcd.for C₃₇H₃₅NNaO₉[M+Na]⁺:660.2204；Found:660.2209.

this example prepares compound 3i as a white solid, melting point: 106.9-107.5 ℃; the yield is 91%; the total content of the two amino acids in the total amino acid is 98 percent ee,>20:1dr,[α]_D ²⁰＝115.4(c 0.34,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝29.28min；τ_minor18.21 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.69(s,9H),1.64(s,9H),2.44-2.51(m,1H),2.56-2.63(m,1H),3.77-3.85(m,1H),3.99(s,1H),5.81(d,J＝14.4Hz,1H),6.68-6.71(m,1H),7.03-7.09(m,1H),7.12-7.19(m,3H),7.26-7.34(m,3H),7.41-7.43(m,1H),7.74-7.79(m,2H)；¹³C NMR(CDCl₃,100MHz)δ:26.7,28.1,31.5,38.6,47.2,53.1,56.1,80.2,82.8,84.7,110.0,111.9(d,J_CF＝21.4Hz),115.1,119.6,121.5,123.4,124.9(d,J_CF＝22.7Hz),126.7,127.7,128.9,129.9,132.4,139.3,148.9,154.5,155.8,157.2(d,J_CF＝245.1Hz),165.8,177.6,178.8,191.6；HRMS(ESI-TOF)m/z:Calcd.for C₃₇H₃₄FNNaO₉[M+Na]⁺:678.2110；Found:678.2107.

this example prepares compound 3j as a white solid, melting point: 129.7-130.4 ℃; the yield is 86%; the content of the solid is 96% ee,>20:1dr,[α]_D ²⁰＝116.3(c 0.40,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝20.20min；τ_minor12.85 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.51-0.55(m,3H),1.64(s,9H),2.46-2.52(m,1H),2.58-2.64(m,1H),3.20-3.26(m,1H),3.34-3.42(m,1H),3.77-3.85(m,1H),4.07(s,1H),5.81(d,J＝14.4Hz,1H),6.67-6.70(m,1H),7.04-7.09(m,1H),7.11-7.19(m,3H),7.26-7.34(m,3H),7.41-7.44(m,1H),7.70-7.75(m,2H)；¹³C NMR(CDCl₃,100MHz)δ:12.9,28.1,31.7,38.5,47.2,53.0,55.2,61.4,80.1,84.7,109.9,111.7,112.0(d,J_CF＝20.3Hz),115.1,119.6,120.5,121.6,123.3(d,J_CF＝23.5Hz),124.9,125.1,126.7,127.1,129.1,129.9,132.1,139.4,148.8,154.3,156.0,157.4(d,J_CF＝225.6Hz),167.2,177.6,178.7,191.5；HRMS(ESI-TOF)m/z:Calcd.for C₃₅H₃₀FNNaO₉[M+Na]⁺:650.1797；Found:650.1797.

this example prepares compound 3k as a white solid, melting point: 116.3 to 117.0 ℃; the yield is 90%; the content of the solid is 99% ee,>20:1dr,[α]_D ²⁰＝93.4(c 0.43,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝37.23min；τ_minor46.24 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.69(s,9H),1.63(s,9H),2.28(s,3H),2.44-2.50(m,1H),2.56-2.62(m,1H),3.77-3.85(m,1H),3.97(s,1H),5.83(d,J＝14.4Hz,1H),6.68-6.72(m,1H),7.01(d,J＝8.0Hz,1H),7.04-7.12(m,2H),7.14-7.18(m,1H),7.25-7.29(m,2H),7.39-7.43(m,1H),7.53(s,1H),7.78(d,J＝8.4Hz,1H)；¹³C NMR(CDCl₃,100MHz)δ:21.2,26.6,28.1,31.8,38.6,47.2,53.2,56.4,80.1,82.7,84.4,109.7,112.1(d,J_CF＝22.6Hz),115.0,120.9,121.5,123.3(d,J_CF＝23.1Hz),125.0,126.4,128.1,128.9,130.2,132.3,134.1,139.4,149.0,152.4,156.0,157.2(d,J_CF＝244.1Hz),165.8,177.8,178.5,191.8；HRMS(ESI-TOF)m/z:Calcd.for C₃₈H₃₆FNNaO₉[M+Na]⁺:692.2266；Found:692.2269.

this example prepares compound 3l as a white solid, melting point: 167.3-168.1 ℃; the yield is 84%; the total of the two solid phases is 98% ee,>20:1dr,[α]_D ²⁰＝100.4(c 0.39,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝19.52min；τ_minor11.39 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.76(s,9H),1.68(s,9H),2.45-2.52(m,1H),2.64-2.70(m,1H),3.81-3.89(m,1H),3.99(s,1H),5.82(d,J＝14.0Hz,1H),6.74(d,J＝8.4Hz,1H),6.98-7.05(m,2H),7.07-7.09(m,1H),7.16-7.20(m,2H),7.36-7.41(m,2H),7.78-7.83(m,3H)；¹³C NMR(CDCl₃,100MHz)δ:26.8,28.1,31.9,38.5,47.5,53.2,55.9,79.9,83.0,84.8,109.1(d,J_CF＝25.0Hz),110.0,115.3(d,J_CF＝23.3Hz),116.5,117.9,120.1,122.0,124.8,126.7,127.0,127.6,129.9,134.5,136.1,148.8,154.5,159.7,160.1(d,J_CF＝242.2Hz),165.8,177.6,178.3,192.1；HRMS(ESI-TOF)m/z:Calcd.for C₃₇H₃₄FNNaO₉[M+Na]⁺:678.2110；Found:678.2113.

this example prepares compound 3m as a white solid, melting point: 112.5-113.2 ℃; the yield is 81%; the total content of the solid matter was 97% ee,>20:1dr,[α]_D ²⁰＝115.8(c 0.36,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝20.97min；τ_minor13.87 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.58-0.62(m,3H),1.68(s,9H),2.47-2.53(m,1H),2.67-2.73(m,1H),3.26-3.34(m,1H),3.43-3.51(m,1H),3.82-3.90(m,1H),4.07(s,1H),5.84(d,J＝14.0Hz,1H),6.75(d,J＝8.4Hz,1H),6.98-7.07(m,3H),7.16-7.20(m,2H),7.36-7.42(m,2H),7.74(d,J＝7.6Hz,1H),7.78-7.84(m,2H)；¹³C NMR(CDCl₃,100MHz)δ:12.9,28.1,31.6,38.5,47.4,53.1,55.1,61.6,79.8,84.8,109.4(d,J_CF＝25.4Hz),110.0,115.6(d,J_CF＝23.1Hz),116.6,117.9,120.1,122.1,124.9,126.7,127.0,130.0,134.1,136.1,148.8,154.4,159.7,160.1(d,J_CF＝235.7Hz),167.2,177.6,178.2,192.0；HRMS(ESI-TOF)m/z:Calcd.for C₃₅H₃₀FNNaO₉[M+Na]⁺:650.1797；Found:650.1798.

this example prepares compound 3n as a white solid, melting point: 128.6-129.3 ℃; the yield is 83%; the total content of the solid matter was 97% ee,>20:1dr,[α]_D ²⁰＝116.2(c 0.37,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝26.29min；τ_minor32.74 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.77(s,9H),1.67(s,9H),2.32(s,3H),2.44-2.51(m,1H),2.64-2.70(m,1H),3.81-3.89(m,1H),3.97(s,1H),5.83(d,J＝14.4Hz,1H),6.76(d,J＝8.0Hz,1H),6.97-7.02(m,2H),7.04-7.09(m,2H),7.15-7.17(m,1H),7.37-7.41(m,1H),7.56(s,1H),7.80-7.85(m,2H)；¹³C NMR(CDCl₃,100MHz)δ:21.2,26.7,28.1,31.8,38.5,47.5,53.2,56.1,79.8,82.9,84.6,109.2(d,J_CF＝25.2Hz),109.7,115.3(d,J_CF＝23.4Hz),116.4,116.5,118.0,120.1,121.9,126.5,127.0,128.0,130.2,134.2,136.0,149.0,152.5,159.8,160.1(d,J_CF＝243.5Hz),165.8,177.8,178.0,192.2；HRMS(ESI-TOF)m/z:Calcd.for C₃₈H₃₆FNNaO₉[M+Na]⁺:692.2266；Found:692.2267.

this example prepared compound 3o a white solid, melting point: 109.8-110.4 ℃; the yield is 78%; the content of the solid is 96% ee,>20:1dr,[α]_D ²⁰＝94.2(c 0.25,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝20.38min；τ_minor29.56 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.59-0.63(m,3H),1.68(s,9H),2.33(s,3H),2.46-2.53(m,1H),2.66-2.72(m,1H),3.28-3.33(m,1H),3.44-3.50(m,1H),3.80-3.89(m,1H),4.05(s,1H),5.83(d,J＝14.4Hz,1H),6.76(d,J＝8.4Hz,1H),6.98-7.07(m,4H),7.15-7.17(m,1H),7.35-7.42(m,1H),7.50(s,1H),7.81-7.85(m,2H)；¹³C NMR(CDCl₃,100MHz)δ:12.9,21.3,28.1,31.3,38.5,47.4,53.2,55.3,61.6,79.8,84.6,109.4(d,J_CF＝26.1Hz),115.6(d,J_CF＝23.4Hz),116.5,117.9,120.1,122.0,126.4,127.0,127.4,130.3,134.3,136.1,149.0,152.3,159.7,160.1(d,J_CF＝239.9Hz),167.2,177.8,192.1；HRMS(ESI-TOF)m/z:Calcd.for C₃₆H₃₂FNNaO₉[M+Na]⁺:664.1953；Found:664.1958.

this example prepares compound 3p as a white solid, melting point: 115.1-115.9 ℃; the yield is 77%;>99％ee,>20:1dr,[α]_D ²⁰＝136.6(c 0.24,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝29.65min；τ_minor16.97 min); the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.69(s,9H),1.61(s,9H),2.36-2.43(m,1H),2.54-2.60(m,1H),3.76-3.81(m,1H),3.94(s,1H),5.72(d,J＝14.4Hz,1H),6.67(d,J＝8.4Hz,1H),6.90-6.94(m,1H),7.08-7.14(m,3H),7.18-7.20(m,1H),7.28-7.33(m,2H),7.70-7.75(m,2H),7.80(s,1H)；¹³C NMR(CDCl₃,100MHz)δ:26.8,28.1,31.9,38.6,47.1,53.2,56.0,79.9,83.0,85.1,110.0,115.9,117.9,120.2,122.0,122.4,124.8,124.9,126.8,127.0,127.6,129.9,131.1,134.6,136.1,140.3,148.7,154.6,159.8,165.9,177.6,178.2,192.2；HRMS(ESI-TOF)m/z:Calcd.for C₃₇H₃₄ClNNaO₉[M+Na]⁺:694.1814；Found:694.1817.

this example prepares compound 3q as a white solid, melting point: 119.7-120.5 ℃; the yield is 80%; the total of the two solid phases is 98% ee,>20:1dr,[α]_D ²⁰＝128.8(c 0.33,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝39.02min；τ_minor22.89 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.50-0.53(m,3H),1.61(s,9H),2.38-2.44(m,1H),2.56-2.62(m,1H),3.17-3.25(m,1H),3.34-3.42(m,1H),3.74-3.82(m,1H),4.01(s,1H),5.74(d,J＝11.4Hz,1H),6.67(d,J＝8.4Hz,1H),6.91-6.94(m,1H),7.08-7.14(m,3H),7.18(d,J＝8.8Hz,1H),7.28-7.32(m,2H),7.63-7.65(m,1H),7.73-7.76(m,1H),7.80(s,1H)；¹³C NMR(CDCl₃,100MHz)δ:13.0,28.1,31.6,38.5,47.0,53.1,55.2,61.6,79.8,85.2,110.0,116.0,117.9,120.2,122.1,122.6,124.9,125.1,126.7,127.0,127.1,130.0,130.7,134.8,136.1,140.4,148.6,154.4,159.7,167.3,177.6,178.2,192.0；HRMS(ESI-TOF)m/z:Calcd.for C₃₅H₃₀ClNNaO₉[M+Na]⁺:666.1501；Found:666.1507.

this example prepares Compound 3r as a white solid, meltPoint: 121.9-122.4 ℃; the yield is 73%;>99％ee,>20:1dr,[α]_D ²⁰＝125.3(c 0.25,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝45.28min；τ_minor57.22 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.69(s,9H),1.60(s,9H),2.25(s,3H),2.36-2.42(m,1H),2.54-2.60(m,1H),3.73-3.81(m,1H),3.92(s,1H),5.73(d,J＝14.4Hz,1H),6.68(d,J＝8.4Hz,1H),6.89-6.94(m,1H),6.99(d,J＝8.4Hz,1H),7.08-7.14(m,2H),7.18-7.20(m,1H),7.28-7.33(m,1H),7.47(s,1H),7.74(d,J＝6.8Hz,1H),7.84(s,1H)；¹³C NMR(CDCl₃,100MHz)δ:21.2,26.8,28.1,31.8,38.6,47.1,53.3,56.2,79.9,82.9,84.9,109.7,115.8,118.0,120.2,122.0,122.4,124.9,126.5,127.0,128.0,130.2,131.0,134.2,134.6,136.1,140.4,148.9,152.5,159.8,165.9,177.8,178.0,192.3；HRMS(ESI-TOF)m/z:Calcd.for C₃₈H₃₆ClNNaO₉[M+Na]⁺:708.1971；Found:708.1970.

this example prepares compound 3s as a white solid, melting point: 132.8-133.3 ℃; the yield is 88%;>99％ee,>20:1dr,[α]_D ²⁰＝106.4(c 0.38,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝41.43min；τ_minor19.71 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.68(s,9H),1.61(s,9H),2.18(s,3H),2.36-2.42(m,1H),2.52-2.58(m,1H),3.70-3.79(m,1H),3.93(s,1H),5.67(d,J＝14.4Hz,1H),6.56(d,J＝8.8Hz,1H),7.08-7.13(m,4H),7.18(d,J＝7.6Hz,1H),7.24-7.31(m,2H),7.52(s,1H),7.71(d,J＝7.2Hz,1H),7.80(s,1H)；¹³C NMR(CDCl₃,100MHz)δ:20.3,26.8,28.1,32.0,38.5,47.0,53.2,55.9,79.9,83.0,85.1,110.0,115.9,117.7,119.8,122.4,124.8,124.9,126.5,126.9,127.6,129.8,131.2,131.5,134.5,137.2,140.3,148.7,154.6,157.9,165.9,177.6,178.2,192.4；HRMS(ESI-TOF)m/z:Calcd.for C₃₈H₃₆ClNNaO₉[M+Na]⁺:708.1971；Found:708.1976.

this example prepares compound 3t as a white solid, melting point: 148.2-148.9 ℃; the yield is 85%; the total of the two solid phases is 98% ee,>20:1dr；The ee was determined by HPLC analysis using a Chiralpak IA column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝27.28min；τ_minor10.71 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,500MHz)δ:1.74(s,9H),2.58-2.63(m,1H),2.83-2.87(m,1H),3.96-4.01(m,1H),5.08(s,1H),6.07(d,J＝11.5Hz,1H),6.66-6.70(m,2H),6.99-7.02(m,1H),7.13-7.18(m,5H),7.20-7.22(m,2H),7.26-7.29(m,1H),7.36-7.41(m,3H),7.62-7.63(m,1H),7.81(d,J＝6.5Hz,1H),7.85-7.87(m,1H)；¹³C NMR(CDCl₃,125MHz)δ:28.3,31.3,38.7,47.8,52.8,57.6,80.0,84.6,109.4,115.4,117.9,120.4,121.1,122.0,125.0,125.1,127.2,127.6,128.6,129.0,129.6,132.5,133.4,136.0,149.2,153.6,159.8,178.4,179.2,192.3,196.3；HRMS(ESI-TOF)m/z:Calcd.for C₃₉H₃₁NNaO₈[M+Na]⁺:664.1942；Found:664.1947.

this example prepares compound 5a as a white solid, melting point: 109.2-110.8 ℃; the yield is 68 percent; 96% ee,92:8dr, [ alpha ]]_D ²⁰＝124.0(c 0.08,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝39.01min；τ_minor28.25 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.74(s,9H),2.55-2.61(m,1H),2.69-2.75(m,1H),3.83-3.91(m,1H),4.02(s,1H),5.70(d,J＝14.0Hz,1H),6.74(d,J＝8.0Hz,1H),6.97-7.02(m,1H),7.12-7.15(m,1H),7.17-7.21(m,3H),7.30-7.33(m,2H),7.35-7.41(m,2H),7.71-7.73(m,1H),7.81-7.83(m,1H)；¹³C NMR(CDCl₃,100MHz)δ:26.9,31.5,38.6,46.0,53.1,56.1,79.9,83.6,110.2,110.9,118.1,120.2,122.1,122.3,124.9,125.1,126.5,127.2,127.5,129.8,130.2,132.1,136.3,153.0,154.6,159.8,166.1,177.5,179.9,192.0；HRMS(ESI-TOF)m/z:Calcd.for C₃₂H₂₆NaO₈[M+Na]⁺:561.1520；Found:561.1525.

this example prepares compound 5b as a white solid, melting point: 139.2 to 140.1 ℃; the yield is 62%; 99% ee,91:9dr, [ alpha ]]_D ²⁰＝102.6(c 0.23,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝19.04min；τ_minor16.98 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,500MHz)δ:0.74(s,9H),1.16(s,3H),1.18(s,3H),2.55-2.61(m,1H),2.67-2.73(m,1H),2.79-2.86(m,1H),3.80-3.89(m,1H),4.02(s,1H),5.66(d,J＝14.4Hz,1H),6.67(d,J＝8.4Hz,1H),7.12-7.21(m,5H),7.30-7.36(m,3H),7.67(d,J＝2.5Hz,1H),7.70-7.72(m,1H)；¹³C NMR(CDCl₃,100MHz)δ:23.9,26.8,31.6,33.4,38.6,46.0,53.1,56.1,79.9,83.5,110.2,110.9,117.9,122.1,124.1,124.9,125.0,129.8,130.1,135.1,142.9,153.0,154.6,158.2,166.2,177.4,179.9；HRMS(ESI-TOF)m/z:Calcd.for C₃₅H₃₂NaO₈[M+Na]⁺:603.1989；Found:603.1994.

this example prepares compound 5c as a white solid, melting point: 141.3-142.1 ℃; the yield is 66%;>99％ee,90:10dr,[α]_D ²⁰＝106.4(c 0.24,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝35.13min；τ_minor25.15 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.74(s,9H),2.25(s,3H),2.54-2.61(m,1H),2.66-2.72(m,1H),3.80-3.88(m,1H),4.01(s,1H),5.65(d,J＝14.0Hz,1H),6.63(d,J＝8.8Hz,1H),7.11-7.20(m,5H),7.30-7.36(m,3H),7.60(d,J＝2.0Hz,1H),7.71-7.73(m,1H)；¹³C NMR(CDCl₃,100MHz)δ:20.5,26.8,31.6,38.6,46.0,53.1,56.0,79.9,83.5,110.2,110.9,117.8,122.1,124.9,125.0,126.7,127.5,129.8,130.1,131.8,137.4,153.0,154.6,157.9,166.2,177.5,179.9,192.3；HRMS(ESI-TOF)m/z:Calcd.for C₃₃H₂₈NaO₈[M+Na]⁺:575.1676；Found:575.1678.

this example prepares compound 5d as a white solid, melting point: 219.8-220.0 ℃; the yield is 58%; the total content of the two amino acids in the total amino acid is 98 percent ee,>20:1dr,[α]_D ²⁰＝135.8(c 0.29,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝34.77min；τ_minor25.05 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.74(s,9H),2.55-2.61(m,1H),2.66-2.72(m,1H),3.82-3.90(m,1H),4.01(s,1H),5.69(d,J＝14.4Hz,1H),6.71-6.75(m,1H),7.09-7.21(m,5H),7.30-7.40(m,3H),7.45-7.48(m,1H),7.70-7.72(m,1H)；¹³C NMR(CDCl₃,100MHz)δ:26.8,31.4,38.6,46.0,53.0,56.1,80.1,83.6,110.3,110.9(d,J_CF＝2.8Hz),112.2(d,J_CF＝23.2Hz),122.0,123.8(d,J_CF＝25.3Hz),125.0,125.1,126.4,127.5,129.9,130.3,131.9,153.0,154.6,156.0,157.7(d,J_CF＝242.5Hz),166.0,177.4,179.9,191.4；HRMS(ESI-TOF)m/z:Calcd.for C₃₂H₂₅FNaO₈[M+Na]⁺:579.1426；Found:579.1419.

this example prepares compound 5e as a white solid, melting point: 152.3-153.1 ℃; the yield is 64%; 95% ee,94:6dr, [ alpha ]]_D ²⁰＝118.9(c 0.13,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝43.88min；τ_minor37.45 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.75(s,9H),2.31(s,3H),2.53-2.59(m,1H),2.71-2.77(m,1H),3.82-3.91(m,1H),4.01(s,1H),5.71(d,J＝14.4Hz,1H),6.75(d,J＝8.0Hz,1H),6.97-7.01(m,1H),7.06(d,J＝8.4Hz,1H),7.12-7.21(m,3H),7.30-7.41(m,3H),7.49(d,J＝1.2Hz,1H),7.81-7.83(m,1H)；¹³C NMR(CDCl₃,100MHz)δ:21.3,26.8,31.3,38.6,46.1,53.1,56.1,79.8,83.5,109.8,110.9,118.1,122.1,122.2,124.9,127.2,127.7,129.8,130.5,134.7,136.3,152.5,153.0,159.9,166.2,177.7,179.8,192.1；HRMS(ESI-TOF)m/z:Calcd.for C₃₃H₂₈NaO₈[M+Na]⁺:575.1676；Found:575.1678.

this example prepares compound 5f as a white solid, melting point: 148.6-149.1 ℃; the yield is 76%; the content of the solid is 96% ee,>20:1dr,[α]_D ²⁰＝61.9(c 0.24,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(98/2hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝59.96min；τ_minor41.19 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.75(s,9H),2.31(s,3H),2.53-2.60(m,1H),2.68-2.74(m,1H),3.81-3.89(m,1H),3.99(s,1H),5.70(d,J＝14.4Hz,1H),6.72-6.75(m,1H),7.05-7.21(m,5H),7.30-7.35(m,2H),7.45-7.48(m,2H)；¹³C NMR(CDCl₃,100MHz)δ:21.3,26.8,31.2,38.6,46.1,53.0,56.2,80.1,83.5,109.9,110.9,112.2(d,J_CF＝23.1Hz),119.8(d,J_CF＝2.8Hz),122.1,123.7(d,J_CF＝24.3Hz),124.9,127.7,129.8,130.5,131.9,134.8,152.5,153.0,156.1,157.6(d,J_CF＝242.3Hz),166.1,177.7,179.8,191.4；HRMS(ESI-TOF)m/z:Calcd.for C₃₃H₂₇FNaO₈[M+Na]⁺:593.1582；Found:593.1589.

this example prepares compound 5g as a white solid, melting point: 152.4-153.2 ℃; the yield is 77%; 93% ee,93:7dr, [ alpha ]]_D ²⁰＝135.7(c 0.23,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IF column(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝21.22min；τ_minor20.21 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.75(s,9H),1.16(s,3H),1.18(s,3H),2.30(s,3H),2.53-2.60(m,1H),2.69-2.75(m,1H),2.80-2.86(m,1H),3.80-3.88(m,1H),4.00(s,1H),5.67(d,J＝14.4Hz,1H),6.68(d,J＝8.4Hz,1H),7.06(d,J＝8.4Hz,1H),7.12-7.21(m,3H),7.25-7.34(m,3H),7.48(s,1H),7.67(d,J＝2.0Hz,1H)；¹³C NMR(CDCl₃,100MHz)δ:21.2,23.8,23.9,31.3,33.3,38.5,45.9,53.0,56.0,79.7,83.3,109.7,110.7,117.8,122.0,124.0,124.7,127.6,129.6,130.3,134.9,142.7,152.4,152.8,158.1,166.0,177.6,179.7,192.3；HRMS(ESI-TOF)m/z:Calcd.for C₃₆H₃₄NaO₈[M+Na]⁺:617.2146；Found:617.2152.

this example prepared compound 5h as a white solid, melting point: 151.3-152.1 ℃; the yield is 80%; 99% ee,94:6dr, [ alpha ]]_D ²⁰＝104.20(c 0.25,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝22.92min；τ_minor30.03 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:1.59(s,3H),2.01(s,3H),2.23-2.29(m,1H),2.38-2.44(m,1H),3.49-3.58(m,1H),3.70(s,1H),5.36(d,J＝14.4Hz,1H),6.35(d,J＝8.4Hz,1H),6.76(d,J＝8.4Hz,1H),6.82-6.91(m,4H),7.00-7.03(m,2H),7.19(s,1H),7.30(s,1H)；¹³C NMR(CDCl₃,100MHz)δ:20.3,21.2,26.7,31.3,38.5,45.9,53.0,56.0,79.7,83.3,109.7,110.0,110.7,117.7,122.0,124.7,126.6,127.6,129.6,130.3,131.6,132.0,137.1,152.4,152.8,157.8,166.0,177.6,179.7,192.2；HRMS(ESI-TOF)m/z:Calcd.forC₃₄H₃₀NaO₈[M+Na]⁺:589.1833；Found:589.1838.

this example prepares compound 5i as a white solid, melting point: 148.7-149.2 ℃; the yield is 77%;>99％ee,>20:1dr,[α]_D ²⁰＝+71.71(c 0.14,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IC column(98/2hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝39.88min；τ_minor36.93 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.56-0.59(m,3H),2.31(s,3H),2.53-2.60(m,1H),2.73-2.79(m,1H),3.27-3.35(m,1H),3.43-3.51(m,1H),3.82-3.90(m,1H),4.09(s,1H),5.71(d,J＝14.4Hz,1H),6.74(d,J＝8.4Hz,1H),6.98-7.01(m,1H),7.05(d,J＝8.0Hz,1H),7.12-7.21(m,3H),7.28-7.42(m,4H),7.82(d,J＝7.6Hz,1H)；¹³C NMR(CDCl₃,100MHz)δ:13.0,21.3,31.2,38.6,46.1,53.1,55.3,61.9,79.7,109.8,110.9,118.1,120.2,122.2,122.3,125.0,127.1,127.3,130.0,130.6,136.3,152.4,153.0,159.8,167.4,177.7,179.7,191.9；HRMS(ESI-TOF)m/z:Calcd.for C₃₁H₂₄NaO₈[M+Na]⁺:547.1363；Found:547.1367.

this example prepares compound 5j as a white solid, melting point: 132.0 to 133.1 ℃; the yield is 67%;>99％ee,>20:1dr,[α]_D ²⁰＝+105.33(c 0.22,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IC column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝23.35min；τ_minor27.05 min); the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.56-0.59(m,3H),2.25(s,3H),2.31(s,3H),2.53-2.59(m,1H),2.71-2.77(m,1H),3.27-3.35(m,1H),3.42-3.50(m,1H),3.79-3.88(m,1H),4.08(s,1H),5.67(d,J＝9.6Hz,1H),6.64(d,J＝8.4Hz,1H),7.04(d,J＝8.4Hz,1H),7.12-7.15(m,2H),7.17-7.21(m,2H),7.28-7.35(m,2H),7.42(s,1H),7.60(s,1H)；¹³C NMR(CDCl₃,100MHz)δ:13.0,20.5,21.3,31.4,38.6,46.1,53.1,55.2,61.8,79.7,109.8,110.9,117.8,122.2,125.0,126.8,127.1,129.9,130.5,131.8,134.7,137.3,152.4,153.0,158.0,167.4,177.7,179.7,192.2；HRMS(ESI-TOF)m/z:Calcd.for C₃₂H₂₆NaO₈[M+Na]⁺:561.1520；Found:561.1524.

this example prepared compound 5k a white solid, melting point: 146.7-147.7 ℃; the yield is 76%; the content of the solid is 96% ee,>20:1dr,[α]_D ²⁰＝+101.49(c 0.20,CH₂Cl₂)；The ee was determined by HPLC analysis using a Chiralpak IA column(95/5hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τ_major＝23.75min；τ_minor31.32 min); the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:¹H NMR(CDCl₃,400MHz)δ:0.56-0.59(m,3H),2.31(s,3H),2.54-2.60(m,1H),2.70-2.76(m,1H),3.27-3.35(m,1H),3.42-3.51(m,1H),3.81-3.89(m,1H),4.08(s,1H),5.71(d,J＝10.4Hz,1H),6.72-6.75(m,1H),7.05(d,J＝8.4Hz,1H),7.09-7.18(m,3H),7.20(d,J＝7.6Hz,1H),7.28(d,J＝6.8Hz,1H),7.32-7.36(m,1H),7.41(s,1H),7.45-7.48(m,1H)；¹³C NMR(CDCl₃,100MHz)δ:13.0,21.3,31.2,38.6,46.1,53.0,55.3,61.9,80.0,109.8,111.0,112.1,112.4,122.2,125.1,126.2,127.1,130.0,130.6,131.6,134.8,152.4,153.0,156.1,156.5,158.9,167.3,177.6,179.7,191.3；HRMS(ESI-TOF)m/z:Calcd.for C₃₁H₂₃FNaO₈[M+Na]⁺:565.1269；Found:565.1270.

the compound of formula (1) of the present invention has important biological activity, and cytotoxicity test in vitro against human leukemia cells (K562) shows that: the xanthone skeleton splicing oxoindole or benzofuranone compound with the structure shown in the formula (1) has an inhibiting effect on the growth of tumor cells, and can be possibly developed into a new tumor prevention and treatment drug. It is emphasized, however, that the compounds of the invention are not limited to the cytotoxicity indicated by human leukemia cells (K562).

Pharmacological examples: cytotoxicity of Compounds 3m,3q and 5d on K562 cells

K562 (human chronic myelogenous leukemia cells) was cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells were added to 96 wells at a concentration of 5000 cells per well and 5% CO at 37 deg.C₂Incubate in a humidified air incubator for 24 hours.

The cell viability was determined by the modified MTT method. After 24 hours incubation of the cells, solutions of the newly formulated compounds 3m,3q and 5d in dimethylsulfoxide were added to each well in a concentration gradient such that the final concentration of the compounds in the wells was 5, 10, 20, 40 and 80 μmol/L, respectively. After 48 hours, 10. mu.L of MTT (5mg/mL) in phosphate buffer was added to each well, and after further incubation at 37 ℃ for 4 hours, the unconverted MTT was removed by centrifugation for 5 minutes, and 150. mu.L of dimethyl sulfoxide was added to each well. The OD value was measured at 490nm wavelength with a microplate reader by dissolving reduced MTT crystal formazan (formazan). Wherein the compounds 3m,3q and 5d are pairedK562 cell half inhibitory concentration IC₅₀Analyzed by the sps software (version 19). IC of compound 3m on K562 tumor cells₅₀47.41 mu mol/L; IC of compound 3q on K562 tumor cells₅₀46.52 mu mol/L; IC of Compound 5d on K562 tumor cells₅₀54.07 mu mol/L; IC of positive control cisplatin on PC-3 tumor cells₅₀It was 24.01. mu. mol/L.

And (4) experimental conclusion: k562 cells are an effective tool and an evaluation index for testing the cytotoxicity of compounds on tumor cells. The experiment shows that the xanthone skeleton splicing oxoindole or benzofuranone compound shown in the formula (1) has stronger cytotoxicity on K562 cells and is likely to be developed into a new medicine with an anti-tumor effect.

From the pharmacological examples, the xanthone skeleton spliced oxindole or benzofuranone compounds have the potential of being developed into antitumor drugs and are worthy of further research.

Claims

1. A xanthone skeleton splicing oxidized indole or benzofuranone compound is characterized in that: the compound has one of the structures shown below:

in the formula, R¹Is methyl or chlorine or fluorine or hydrogen; r²Is methyl or fluoro or isopropyl or hydrogen; r³Is methyl or hydrogen; r is⁴Is benzoyl.

2. The preparation method of the xanthone skeleton-spliced oxoindole or benzofuranone compound as claimed in claim 1, wherein the synthetic route is as follows:

in the formula，R¹Is methyl or chlorine or fluorine or hydrogen; r²Is methyl or fluoro or isopropyl or hydrogen; r is³Is methyl or hydrogen; r⁴Is benzoyl.

3. An application of the xanthone skeleton-spliced oxindole or benzofuranone compound as defined in claim 1 in preparing medicines for preventing and treating leukemia.