A method for synthesizing chiral azepine compounds by gold-catalyzed asymmetric cycloaddition and kinetic resolution

Abstract

The application provides a method for synthesizing chiral azepine compounds through gold-catalyzed asymmetric cycloaddition and kinetic resolution. The method comprises the following steps: through asymmetric [4+4] cycloaddition and kinetic resolution, an alkynyl cyclopropanone compound I and an aminoanthranilic anhydride compound II are subjected to asymmetric cycloaddition in a solvent A under the catalysis of a gold catalytic system to obtain a chiral azepine compound III; the gold catalytic system is composed of a chiral gold catalyst and silver trifluoromethanesulfonate, and the chiral gold catalyst has a structure shown in formula IV; the chiral azepine compound is synthesized through gold-catalyzed asymmetric cycloaddition, and the method has the advantages of convenient operation, simplicity, high yield, low cost of catalyst, low cost of raw materials, wide application range of substrates, good diastereoselectivity, high enantioselectivity and the like.

Description

Technical Field

[0001] The invention relates to a method for synthesizing chiral nitrogen eight-membered ring compounds through gold-catalyzed asymmetric cycloaddition reaction and kinetic resolution, and belongs to the technical field of organic synthesis. Background Art

[0002] Chiral aza-octane backbones are widely found in active natural products and pharmaceutical molecules, such as the antibacterial FR-900482, the anti-cancer Manzamine A, and the analgesic indole alkaloid natural product Apparicine. However, these backbone compounds are difficult to obtain solely through isolation from nature and suffer from drawbacks such as low availability and high cost. Therefore, asymmetric synthesis is a promising approach for obtaining these natural products. In recent decades, transition-metal-catalyzed dipolar ion cycloadditions have become a versatile method for constructing a wide range of cyclic compounds, offering high atom and step economies by allowing the formation of multiple carbon-carbon or carbon-heteroatom bonds in a single reaction. This reaction, often utilizing only simple building blocks, allows for the efficient construction of multiple rings in a single step. In chirality control, the combination of chiral ligands and transition metals allows for the efficient and asymmetric construction of natural product core backbones through a single reaction.

[0003] Based on a literature review, we found that in recent years, strategies for constructing aza-octacyclic compounds have primarily relied on palladium- or iridium-catalyzed allylation reactions. However, methods for constructing aza-octacyclic compounds using novel catalytic systems and catalytic modes have yet to be reported. Therefore, the design and development of novel catalytic reactions for constructing aza-octacyclic compounds is of great practical significance. Kinetic resolution can transform racemic compounds into highly optically active chiral molecules and is an efficient and widely used asymmetric synthetic strategy. However, the low efficiency and limited substrate applicability of kinetic resolution have significantly hampered its development and application. Over the past few decades, with the rapid development of chiral catalysts and chiral ligands, kinetic resolution strategies have become widely used in asymmetric catalysis, resulting in the acquisition of chiral compounds of excellent optical purity. Combining the advantages of kinetic resolution with asymmetric dipolar cycloaddition, the 1,3-dipolar cycloaddition reaction has been developed to achieve efficient kinetic resolution of chiral heterocyclic compounds (Chin. J. Org. Chem. 2022, 42, 3322-3334). However, there are few reports on the construction of chiral heterocycles via 1,4-dipolar cycloaddition reactions under kinetic resolution. In 2012, Zhang Junliang's group reported the first gold-catalyzed asymmetric [4+3] cycloaddition of 2-(1-alkynyl)-2-alkyl-1-ones with nitrones, constructing a seven-membered nitrogen heterocycle and simultaneously achieving kinetic resolution of racemic 1-(1-alkynyl)cyclopropyl ketone (Chem. Commun., 2012, 48, 4710-4712). However, the gold-catalyzed [4+4] cycloaddition to obtain chiral nitrogen-containing eight-membered rings and simultaneously achieving efficient kinetic resolution of racemic 1-(1-alkynyl)cyclopropyl ketone has not yet been reported.

[0004] Anthranils are a very active and important intermediate due to their unique conjugated structure and strong aromatization driving force. They are widely used in the construction of natural product skeletons and the synthesis of drug molecules. In previous work, our group has completed the palladium-catalyzed asymmetric [4+4] cycloaddition reaction of γ-methylene-δ-valerolactone and anthranils (ACS Catal., 2021, 11, 2684-2690). Therefore, using 1-(1-alkynyl)cyclopropyl ketone to generate a 1,4-dipole ion as a quaternary synthon, and then completing the [4+4] cycloaddition reaction under kinetic resolution with anthranils, the asymmetric and efficient construction of furan-fused benzazazepine octahedral ring is achieved, and chiral aza-octahedral rings with different skeletons can be prepared through further structural modification, which is of great significance. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention provides a method for synthesizing chiral nitrogen-containing octahedral ring compounds via a gold-catalyzed asymmetric cycloaddition reaction and kinetic resolution. Using a simple chiral gold complex as the catalytic system, the present invention completes the [4+4] cycloaddition reaction under kinetic resolution, achieving efficient asymmetric synthesis of chiral nitrogen-containing octahedral rings.

[0006] Terminology Notes:

[0007] Room temperature has the commonly known meaning in the art, which refers to 25±5°C.

[0008] The technical solutions of the present invention are as follows:

[0009] A method for synthesizing chiral nitrogen-containing octahedral compounds by gold-catalyzed asymmetric cycloaddition reaction and kinetic resolution comprises the following steps:

[0010] In solvent A, an alkynyl cyclopropanone compound I and anthranilic anhydride compound II undergo an asymmetric [4+4] cycloaddition reaction and kinetic resolution under the catalysis of a gold catalyst system to obtain a chiral nitrogen eight-membered ring compound III; the gold catalyst system comprises a chiral gold catalyst and silver trifluoromethanesulfonate, and the chiral gold catalyst has a structure shown in Formula IV;

[0011]

[0012] Wherein, in the structural formula of the compound of formula I, R1 is phenyl or halogen-substituted phenyl; R2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heteroatom of the heteroaryl is O, N or S, and the aromatic ring of the substituted aryl or substituted heteroaryl is substituted by one or more substituents R5, each substituent R5 is independently selected from halogen, methoxy, and cyano; R3 is methyl or ethyl;

[0013] In the structural formula of the compound of formula II, R4 is halogen, C1-C3 alkyl, C1-C3 alkoxy, benzoyl, nitro or ester;

[0014] In the structural formula of the compound of formula III, the substituents R1, R2, and R3 are the same as those in the structural formula of the compound of formula I; and the substituent R4 is the same as that in the structural formula of the compound of formula II.

[0015] According to a preferred embodiment of the present invention, in the structural formula of the compound of formula I, R1 is phenyl or 4-bromophenyl, R2 is phenyl, 4-fluorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-fluorophenyl, thienyl, and R3 is methyl;

[0016] In the structural formula of the compound of formula II, R4 is halogen, benzoyl or nitro.

[0017] Preferably, according to the present invention, the solvent A is dichloromethane; the ratio of the volume of the solvent A to the molar number of the alkynylcyclopropanone compound I is 5-20 mL:1 mmol; and the solvent A is anhydrous.

[0018] Preferably, according to the present invention, the molar ratio of the alkynyl cyclopropanone compound I to the anthranilic anhydride compound II is 1:0.5-0.8.

[0019] Preferably, according to the present invention, the molar ratio of the chiral gold catalyst to silver trifluoromethanesulfonate in the gold catalyst system is 1:2 to 2.6; and the molar ratio of the chiral gold catalyst to the alkynyl cyclopropanone compound I is 0.01 to 0.05:1.

[0020] According to the preferred embodiment of the present invention, the reaction system in which the alkynyl cyclopropanone compound I and the anthranilic anhydride compound II undergo asymmetric [4+4] cycloaddition reaction and kinetic resolution is further added Molecular sieve; The ratio of the mass of the molecular sieve to the molar number of the alkynyl cyclopropanone compound I is 1 to 3 g:1 mmol, and its function is to further remove trace amounts of water in the reaction system.

[0021] According to the present invention, preferably, the cycloaddition reaction and kinetic resolution are carried out under the protection of a protective gas, and the protective gas is nitrogen or argon.

[0022] According to the present invention, preferably, the temperature of the cycloaddition reaction and kinetic resolution is -20 to 30°C, more preferably 20 to 30°C.

[0023] According to the present invention, the time for the cycloaddition reaction and kinetic resolution is preferably 12 to 48 hours, more preferably 12 to 24 hours; the reaction progress is monitored by HPLC during the reaction, and the reaction is terminated when the ee value of the chiral raw material alkynylcyclopropanone compound obtained in the system is greater than 80%.

[0024] According to the present invention, after an alkynyl cyclopropanone compound I and an anthranilic anhydride compound II undergo an asymmetric [4+4] cycloaddition reaction and kinetic resolution, the product can be separated and characterized according to a conventional separation and purification method. The specific post-reaction treatment steps are as follows: removing the solvent from the reaction solution, and separating the obtained crude product by silica gel column chromatography to obtain a chiral nitrogen eight-membered ring compound III, wherein the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the mixed solvent is 0.02 to 0.2:1.

[0025] According to the present invention, a preferred embodiment comprises the following steps:

[0026] Under protective gas, chiral gold catalyst, silver trifluoromethanesulfonate (AgOTf) and solvent A were added to a dry reaction flask, stirred for 15 to 20 minutes and filtered, and the filtrate was added to a mixture containing alkynyl cyclopropanone compound I, anthranilic anhydride compound II and In a reaction flask with molecular sieves, an asymmetric [4+4] cycloaddition reaction and kinetic resolution were carried out; after the reaction was completed, the solvent was removed, and the resulting crude product was separated by silica gel column chromatography to obtain chiral nitrogen eight-membered ring compound III.

[0027] The present invention also provides a chiral nitrogen eight-membered ring compound prepared by the above method. The structural formula of the obtained chiral nitrogen eight-membered ring compound is shown in Formula III.

[0028]

[0029] According to the present invention, the chiral nitrogen eight-membered ring compound is used in the preparation of anti-gastric cancer and esophageal cancer drugs.

[0030] According to the present invention, the alkynyl cyclopropanone compound I is obtained from an α,β-unsaturated ketone as a starting material by a known method (see reference: Chem. Eur. J. 2009, 15, 8975-8978.), and the reaction scheme is as follows:

[0031]

[0032] In the above formula, the substituents R1, R2 and R3 are as described above.

[0033] According to the present invention, the anthranilic anhydride compounds II are synthesized from the corresponding substituted nitroaryl formaldehydes by known methods (see literature: Angew. Chem. Int. Ed. 2019, 58, 5739-5743.), and the reaction scheme is shown below:

[0034]

[0035] In the above formula, the substituent R4 is as described above.

[0036] According to the present invention, the preparation method of the chiral gold catalyst is an existing technology and can be prepared with reference to the literature (J.Am.Chem.Soc.2005,127,18002-18003; J.Am.Chem.Soc.2007,129,12638-12639).

[0037] The technical features and beneficial effects of the present invention are as follows:

[0038] The present invention creatively provides a novel method for constructing nitrogen-containing eight-membered ring compounds through a gold-catalyzed asymmetric cycloaddition reaction and kinetic resolution. The method of the present invention has the following advantages: (1) a chiral gold catalyst with a simple structure is used as the catalytic system, which has the advantages of low catalyst cost, high efficiency, and low catalyst usage; (2) a high reaction yield, good diastereoselectivity (dr>20:1), and high enantioselectivity (95% ee); (3) the reaction raw materials are inexpensive and readily available, the atom economy is good, and the substrate has a wide range of applicability; (4) the reaction conditions are mild, and the operation is convenient and simple; (5) the chiral nitrogen-containing eight-membered ring compounds obtained by the present invention have excellent inhibitory effects on gastric cancer cells and esophageal cancer cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 The inhibition rate of the chiral nitrogen eight-membered ring compounds prepared in Examples 1-7 in Application Example 1 on gastric cancer cells (SGC-7901).

[0040] Figure 2 The inhibition rate of different concentrations of compound IIIec on gastric cancer cells (SGC-7901) in Application Example 2 and the concentration-inhibition rate curve are shown.

[0041] Figure 3 The inhibition rate of different concentrations of compound IIIfc on gastric cancer cells (SGC-7901) in Application Example 3 and the concentration-inhibition rate curve are shown.

[0042] Figure 4 The inhibition rate of compound IIIfc at different concentrations on esophageal cancer cells (KYSE150) in Application Example 4 and the concentration-inhibition rate curve are shown. DETAILED DESCRIPTION

[0043] The present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited thereto.

[0044] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and raw materials can be obtained from commercial channels or prepared according to known methods unless otherwise specified.

[0045] The solvents used in the examples were treated with anhydrous solvents, and the treatment method was based on the prior art.

[0046] The yields described in the examples are molar yields.

[0047] The preparation method of the chiral gold catalyst used in the embodiment is as follows:

[0048] In a dry reaction flask, chiral bisphosphine ligand V (0.5 mmol), dimethyl sulfide gold chloride (1.0 mmol) and 5 mL of dichloromethane were added, and the reaction was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure to obtain a chiral gold catalyst.

[0049] The reaction scheme is as follows:

[0050]

[0051] Example 1

[0052] Synthesis of (5S,6R,11R)-9-bromo-3-methyl-1,5-diphenyl-4,5-dihydro-11H-6,11-epoxybenzo[b]furo[3,4-e]azooctane (Ⅲaa)

[0053] The reaction route is as follows:

[0054]

[0055] The steps are as follows:

[0056] Under nitrogen protection, chiral gold catalyst (6.0 μmol, 9.9 mg), AgOTf (14.4 μmol, 3.7 mg) and 1.0 mL of dichloromethane were added to a dry 5 mL reaction bottle. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a flask containing substrate Ia (0.2 mmol, 52.0 mg), substrate IIa (0.14 mmol, 27.7 mg) and The reaction was then stirred at room temperature for 16 hours. HPLC analysis revealed that the enantioselectivity of the resulting chiral raw material, alkynylcyclopropanone (Ia′), was greater than 80%. The solvent was then removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02-0.1:1, v / v) to afford the target product IIIaa (41 mg, 45% yield).

[0057] The characterization data of the obtained product (IIIaa) are as follows:

[0058] White solid, mp = 236-238 ° C; 41 mg, 45% yield; 87% ee; [Daicel Chiralpak IC-3 (0.45cm×25cm), n-hexane / tetrahydrofuran=90 / 10, v=1.0mL·min -1 ,λ=254nm, t(major)=5.9min, t(minor)=6.7min];

[0059] 1 HNMR (400MHz, CDCl3) δ2.27(s,3H),2.73(dd,J=16.2,4.3Hz,1H),3.00(dd,J=16.1,2.7Hz,1H),4.67(dd,J=5.2,2.6Hz,1H),6. 24(s,1H),7.01-7.12(m,1H),7.27(t,J=7.3Hz,1H),7.35(t,J=7.6Hz,3H),7.44(dd,J=11.3,7.5Hz,4H),7.57(d,J=7.1Hz,4H);

[0060] 13 CNMR(100MHz, CDCl3)δ11.6,25.5,71.3,77.6,115.3,117.8,118.4,124.2,125.4,126. 0,127.5,127.9,128.2,128.4,128.9,130.5,131.6,137.4,139.9,145.7,147.6,148.5;

[0061] HRMS(ESI)m / z calcd.for C 26 H 21 BrNO2[M+H] + :458.0750,found:458.0754.

[0062] The characterization data of the obtained chiral raw material alkynylcyclopropanone (Ia') are as follows:

[0063] 1-((1S,2R)-2-phenyl-1-(phenylethynyl)cyclopropyl)ethan-1-one (1a′)

[0064] Yellow oil, 25.5 mg, 48% yield; 90% ee; [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=254nm, t(major)=6.6min, t(minor)=6.3min];

[0065] 1HNMR (400MHz, CDCl3) δ1.87 (dd, J=8.0, 4.2Hz, 1H), 2.22 (dd, J=9.1, 4.3Hz, 1H), 2.60 ( s,3H),3.07(t,J=8.5Hz,1H),6.90-6.97(m,2H),7.10-7.15(m,2H),7.27-7.43(m,5H);

[0066] 13 CNMR(100MHz, CDCl3)δ26.5,29.7,33.4,39.2,84.4,87.4,123.0,127.3,128.0,128.1,128.3,128.7,131.4,135.9,205.0.

[0067] HRMS(ESI)m / z calcd.for C 19 H 187 O[M+H] + :261.1279,found:261.1280.

[0068] Example 2

[0069] Synthesis of (5S,6R,11R)-1-(4-chlorophenyl)-3-methyl-8-nitro-5-phenyl-4,5-dihydro-11H-6,11-epoxybenzo[b]furo[3,4-e]azooctane (Ⅲbb)

[0070] The reaction route is as follows:

[0071]

[0072] The steps are as follows:

[0073] Under nitrogen protection, chiral gold catalyst (6.0 μmol, 9.9 mg), AgOTf (14.4 μmol, 3.7 mg) and 1.0 mL of dichloromethane were added to a dry 5 mL reaction bottle. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a flask containing substrate Ib (0.2 mmol, 59 mg), substrate IIb (0.14 mmol, 23.0 mg) and 300 mg The reaction mixture was stirred at room temperature for 24 hours. HPLC analysis revealed that the enantioselectivity of the chiral raw material alkynylcyclopropanone (Ib′) was greater than 80%. The solvent was then removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIbb (33 mg, 36% yield).

[0074] The characterization data of the obtained product (IIIbb) are as follows:

[0075] Yellow solid, mp = 180-182 ° C; 33 mg, 36% yield; 88% ee; [Daicel Chiralpak IB-3 (0.45cm×25cm), n-hexane / tetrahydrofuran=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(major)=6.9min, t(minor)=7.6min];

[0076] 1 H NMR (400MHz, CDCl3) δ2.20(s,3H),2.63(ddd,J=16.2,5.1,1.5Hz,1H),3.03(dd,J=16.2,3.1Hz,1H),4.71(dd,J=5.2,3.1Hz,1H),6.24(s,1H),7.21-7 .27(m,1H),7.30(dd,J=8.3,6.6Hz,2H),7.32-7.39(m,3H),7.42-7.46(m, 2H),7.47-7.53(m,2H),7.94(d,J=1.9Hz,1H),7.99(dd,J=8.2,2.0Hz,1H);

[0077] 13 C NMR (100MHz, CDCl3) δ11.6,26.0,71.7,77.6,109.3,118.3,121.2,122.5,123.9,127.1 ,127.8,128.0,128.6,128.9,129.2,133.9,139.5,141.6,144.6,148.3,148.9,150.8;

[0078] HRMS(ESI)m / z calcd.for C 26 H 20 ClN2O4[M+H] + :459.1106,found:459.1109.

[0079] The characterization data of the obtained chiral raw material alkynylcyclopropanone (Ib′) are as follows:

[0080] 1-((1S,2R)-1-((4-chlorophenyl)ethynyl)-2-phenylcyclopropyl)ethan-1-one (Ib′)

[0081] Yellow crystals, 23 mg, 39% yield; 83% ee; [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=254nm, t(major)=7.6min, t(minor)=6.5min];

[0082] 1 H NMR (400MHz, CDCl3) δ1.86 (dd, J=7.9, 4.3Hz, 1H), 2.20 (dd, J=9.0, 4.3Hz, 1H), 2.57 (s ,3H),3.05(t,J=8.5Hz,1H),7.00-7.05(m,2H),7.17-7.22(m,2H),7.26-7.39(m,5H);

[0083] 13 C NMR (100MHz, CDCl3) δ26.5,29.7,33.3,39.3,83.3,88.5,121.5,127.4,128.1,128.6,128.7,132.6,134.1,135.8,204.6;

[0084] HRMS(ESI)m / z calcd for C 19 H 16 ClO[M+H] + :295.0884,found:295.0880.

[0085] Example 3

[0086] Synthesis of (5S,6R,11R)-9-chloro-5-(4-fluorophenyl)-3-methyl-1-phenyl-4,5-dihydro-11H-6,11-epoxybenzo[b]furo[3,4-e]azooctane (Ⅲcc)

[0087] The reaction route is as follows:

[0088]

[0089] The steps are as follows:

[0090] Under nitrogen protection, chiral gold catalyst (6.0 μmol, 9.9 mg), AgOTf (14.4 μmol, 3.7 mg) and 1.0 mL of dichloromethane were added to a dry 5 mL reaction bottle. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a flask containing substrate Ic (0.2 mmol, 55.7 mg), substrate IIc (0.14 mmol, 21.5 mg) and 300 mg The reaction mixture was stirred at room temperature for 24 hours. HPLC analysis revealed that the enantioselectivity of the chiral raw material alkynylcyclopropanone (Ic′) was greater than 80%. The solvent was then removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIcc (35 mg, 40% yield).

[0091] The characterization data of the obtained product (IIIcc) are as follows:

[0092] White solid, mp = 192-194 ° C; 35 mg, 40% yield; 88% ee; [Daicel Chiralpak IB-3 (0.45cm×25cm), n-hexane / tetrahydrofuran=90 / 10, v=1.0mL·min -1 ,λ=254nm, t(major)=9.2min, t(minor)=12.8min];

[0093] 1 H NMR(400MHz, CDCl3) δ2.26(s,3H),2.72(dd,J=16.3,5.0Hz,1H),3.00(dd,J=16.2,2.7Hz,1H),4. 67(dd,J=5.3,2.6Hz,1H),6.15(s,1H),7.06-7.20(m,3H),7.23-7.39(m,5H),7.49-7.63(m,4H);

[0094] 13 C NMR (100MHz, CDCl3) δ11.6,25.3,71.3,77.6,114.8,116.0(d,J=21.8Hz),118.4,122.4,124.0,126.9(d,J=3.5Hz) ,127.5,127.8(d,J=8.1Hz),128.1,128.4,128.8,130.4,136.9,139.9,144.8,147.5,148.0,162.4(d,J=248.0Hz);

[0095] HRMS(ESI)m / z calcd.for C 26 H 20 ClFNO2[M+H] + :432.1161,found:432.1164.

[0096] The characterization data of the obtained chiral raw material alkynylcyclopropanone (Ic') are as follows:

[0097] ((1S,2R)-1-((4-Fluorophenyl)ethynyl)-2-phenylcyclopropyl)methanone (Ic′)

[0098] Yellow oil, 28.4 mg, 38% yield; 92% ee; [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=254nm, t(major)=7.5min, t(minor)=6.9min];

[0099] 1 H NMR (400MHz, CDCl3) δ1.96 (dd, J=7.9, 4.8Hz, 1H), 2.50 (dd, J=9.1, 4.7Hz, 1H), 3.02 (t, J=8.5Hz, 1H),6.86(t,J=8.7Hz,2H),6.95(dd,J=8.6,5.6Hz,2H),7.31-7.45(m,7H),8.01(d,J=8.6Hz,2H);

[0100] 13 C NMR (100MHz, CDCl3) δ23.7, 32.0, 38.3, 84.1, 87.5, 115.5 (d, J = 22.1Hz), 118.9 (d, J = 3.5Hz), 127.6, 128.2, 128.4, 128.7, 130.7, 133.1 (d, J = 8.4Hz), 135.1, 135.6, 139.1, 162.3 (d, J = 249.3Hz), 195.5;

[0101] HRMS(ESI)m / z calcd.for C 24 H 17 ClFO[M+H] + :279.1185,found:279.1181.

[0102] Example 4

[0103] Synthesis of (5S,6R,11R)-1-(3-bromophenyl)-9-chloro-3-methyl-5-phenyl-4,5-dihydro-11H-6,11-epoxybenzo[b]furo[3,4-e]azooctane (Ⅲdc)

[0104] The reaction route is as follows:

[0105]

[0106] The steps are as follows:

[0107] Under nitrogen protection, chiral gold catalyst (6.0 μmol, 9.9 mg), AgOTf (14.4 μmol, 3.7 mg) and 1.0 mL of dichloromethane were added to a dry 5 mL reaction bottle. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a flask containing substrate Id (0.2 mmol, 67.8 mg), substrate IIc (0.14 mmol, 21.5 mg) and 300 mg The reaction mixture was stirred at room temperature for 24 hours. HPLC analysis revealed that the enantioselectivity of the chiral raw material alkynylcyclopropanone (Id′) was greater than 80%. The solvent was then removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIdc (35 mg, 36% yield).

[0108] The characterization data of the obtained product (IIIdc) are as follows:

[0109] White solid, mp = 182-184 ° C; 35 mg, 36% yield; 94% ee; [Daicel Chiralpak IB-3 (0.45cm×25cm), n-hexane / tetrahydrofuran=90 / 10, v=1.0mL·min -1 ,λ=254nm, t(major)=6.6min, t(minor)=9.6min];

[0110] 1H NMR (400MHz, CDCl3) δ2.27(s,3H),2.71(dd,J=16.1,5.1,1.5Hz,1H),3.00(dd,J=16.1,2.8Hz,1H),4.66(dd,J =5.1,2.7Hz,1H),6.22(s,1H),7.10(d,J=8.2Hz,1H),7.25-7.39(m,7H),7.40-7.45(m,1H),7.52-7.61(m,3H); 13 C NMR (100MHz, CDCl3) δ11.6,25.4,71.3,77.4,114.8,118.7,122.4,123.8,125.2,125.9,127.6 ,127.8,128.1,128.5,128.8,130.1,130.5,132.2,134.9,136.6,139.8,144.0,148.0,148.2;

[0111] HRMS(ESI)m / z calcd.for C 26 H 20 BrClNO2[M+H] + :492.0360,found:492.0363.

[0112] The characterization data of the obtained chiral raw material alkynylcyclopropanone (Id') are as follows:

[0113] 1-((1S,2R)-1-((3-bromophenyl)ethynyl)-2-phenylcyclopropyl)ethan-1-one

[0114] Yellow oily liquid, 40mg, 43% yield; 83% ee; [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=254nm, t(major)=6.2min, t(minor)=5.9min];

[0115] 1H NMR (400MHz, CDCl3) δ1.86 (dd, J=8.0, 4.3Hz, 1H), 2.20 (dd, J=9.1, 4.3Hz, 1H), 2.57 (s, 3H), 3.06 (t, J=8.5Hz, 1H), 7.0 2(dt,J=7.8,1.3Hz,1H),7.08(t,J=7.8Hz,1H),7.23(t,J=1.7Hz,1H),7.27(dd,J=7.9,1.6Hz,2H),7.30-7.39(m,4H);

[0116] 13 C NMR (100MHz, CDCl3) δ26.5,29.7,33.3,39.4,82.9,89.1,122.0,125.0,127.5,128.1,128.7,129.7,129.9,131.2,134.2,135.7,204.4;

[0117] HRMS(ESI)m / z calcd for C 19 H 16 BrO[M+H] + :339.0379,found:339.0377.

[0118] Example 5

[0119] Synthesis of (5S,6R,11R)-9-chloro-3-methyl-5-phenyl-1-(thien-3-yl)-4,5-dihydro-11H-6,11-epoxybenzo[b]furo[3,4-e]azooctane (Ⅲec)

[0120] The reaction route is as follows:

[0121]

[0122] The steps are as follows:

[0123] Under nitrogen protection, chiral gold catalyst (6.0 μmol, 9.9 mg), AgOTf (14.4 μmol, 3.7 mg) and 1.0 mL of dichloromethane were added to a dry 5 mL reaction bottle. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a flask containing substrate Ⅰe (0.2 mmol, 53.3 mg), substrate Ⅱc (0.14 mmol, 21.5 mg) and 300 mg The reaction mixture was stirred at room temperature for 24 hours. HPLC analysis revealed that the enantioselectivity of the chiral raw material alkynylcyclopropanone (Ie′) was greater than 80%. The solvent was then removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIec (31 mg, 37% yield).

[0124] The characterization data of the obtained product (IIIec) are as follows:

[0125] White solid, mp = 180-182 ° C; 31 mg, 37% yield; 90% ee; [Daicel Chiralpak IC-3 (0.45cm×25cm), n-hexane / tetrahydrofuran=90 / 10, v=1.0mL·min -1 ,λ=254nm, t(major)=6.3min, t(minor)=7.1min];

[0126] 1 H NMR (400MHz, CDCl3) δ2.24(s,3H),2.71(ddd,J=16.2,5.1,1.5Hz,1H),2.99(dd,J=16.1,2.8Hz,1H),4.67(dd,J=5.2,2.8Hz,1H),6.22 (s,1H),7.10(d,J=8.3Hz,1H),7.25(d,J=4.3Hz,1H),7.27-7.32(m,2H),7.31-7.38(m,3H),7.38-7.43(m,2H),7.56(d,J=7.6Hz,2H);

[0127] 13 C NMR (100MHz, CDCl3) δ11.6,25.5,71.5,77.6,114.8,118.0,120.5,122.4,123.5,125.4 ,126.6,127.5,128.2,128.4,128.7,130.4,131.6,137.0,140.0,142.1,147.0,148.0;

[0128] HRMS(ESI)m / z calcd.for C 24 H 19 ClNO2S[M+H] + :420.0820,found:420.0818.

[0129] The characterization data of the obtained chiral raw material alkynylcyclopropanone (Ie') are as follows:

[0130] 1-((1S,2R)-2-phenyl-1-(thiophen-3-ylethynyl)cyclopropyl)ethan-1-one

[0131] Yellow oily liquid, 40mg, 39% yield; 82% ee; [DaicelChiralpak IJ-3 (0.45cm×25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=254nm, t(major)=9.5min, t(minor)=8.5min];

[0132] 1 H NMR(400MHz, CDCl3) δ1.83(dd,J=8.0,4.2Hz,1H),2.19(dd,J=9.1,4.2Hz,1H),2.57(s,3H),3.02(t,J=8.5Hz,1H),6.81 (dd,J=4.9,1.2Hz,1H),7.13(dd,J=3.0,1.2Hz,1H),7.17(dd,J=4.9,3.0Hz,1H),7.24-7.31(m,3H),7.31-7.39(m,2H);

[0133] 13 C NMR (100MHz, CDCl3) δ26.5,29.7,33.4,39.2,79.5,86.9,122.0,125.2,127.3,128.0,128.4,128.7,129.7,135.9,204.9;

[0134] HRMS(ESI)m / z calcd for C 17 H 15 OS[M+H]+:267.0838,found:267.0835.

[0135] Example 6

[0136] Synthesis of (5S,6R,11R)-9-chloro-1-(2-fluorophenyl)-3-methyl-5-phenyl-4,5-dihydro-11H-6,11-epoxybenzo[b]furo[3,4-e]azooctane (Ⅲfc)

[0137] The reaction route is as follows:

[0138]

[0139] The steps are as follows:

[0140] Under nitrogen protection, chiral gold catalyst (6.0 μmol, 9.9 mg), AgOTf (14.4 μmol, 3.7 mg) and 1.0 mL of dichloromethane were added to a dry 5 mL reaction bottle. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a flask containing substrate IF (0.2 mmol, 55.7 mg), substrate Ⅱc (0.14 mmol, 21.5 mg) and 300 mg The reaction mixture was stirred at room temperature for 24 hours. HPLC analysis revealed that the enantioselectivity of the chiral raw material alkynylcyclopropanone (IF') was greater than 80%. The solvent was then removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIfc (27 mg, 31% yield).

[0141] The characterization data of the obtained product (IIIfc) are as follows:

[0142] White solid, mp = 202-204 ° C; 27 mg, 31% yield; 94% ee; [Daicel Chiralpak IC-3 (0.45cm×25cm), n-hexane / tetrahydrofuran=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(major)=10.0min, t(minor)=11.2min];

[0143] 1 H NMR (400MHz, CDCl3) δ2.28(s,3H),2.76(ddd,J=16.1,5.1,1.5Hz,1H),2.98(dd,J=16.1,2.4Hz,1H),4.68(dd,J=4.8,1.9Hz,1H),6.03(d ,J=4.2Hz,1H),7.10(d,J=8.3Hz,1H),7.14-7.24(m,2H),7.26-7.31(m,2H),7.31-7.39(m,3H),7.43(d,J=2.0Hz,1H),7.55-7.63(m,3H);

[0144] 13C NMR (100MHz, CDCl3) δ11.6, 25.0, 71.1, 78.0 (d, J = 10.3Hz), 114.5, 116.1 (d, J = 22.6Hz), 118.4, 118.7 (d, J = 13.8Hz), 123.5 (d, J = 9.2Hz), 124.7 (d, J = 3.3Hz),126.5,127.5,128.1,128.4,128.6,129.6(d,J=3.3Hz),129.7(d,J =7.3Hz),130.6,136.7,139.2,139.8,147.9,148.8,158.2(d,J=245.5Hz);

[0145] HRMS(ESI)m / z calcd.for C 26 H 20 ClFNO2[M+H] + :432.1161,found:432.1165.

[0146] The characterization data of the obtained chiral raw material alkynylcyclopropanone (IF') are as follows:

[0147] 1-((1S,2R)-1-((2-fluorophenyl)ethynyl)-2-phenylcyclopropyl)ethan-1-one

[0148] Yellow oily liquid, 40mg, 38% yield; 90% ee; [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=254nm, t(major)=5.7min, t(minor)=5.3min];

[0149] 1 H NMR (400MHz, CDCl3) δ1.89 (dd, J=8.0, 4.3Hz, 1H), 2.22 (dd, J=9.1, 4.2Hz, 1H), 2.61 (s, 3H), 3 .06(t,J=8.5Hz,1H),6.95-7.09(m,3H),7.18-7.24(td,J=7.3,5.1Hz,1H),7.25-7.37(m,5H);

[0150] 13C NMR (100MHz, CDCl3) δ26.7, 29.7, 33.5, 39.3, 78.2, 92.7 (d, J = 3.3Hz), 111.6 (d, J = 15.0Hz), 115.4 (d, J = 20.8Hz), 12 3.9(d,J=3.7Hz),127.4,128.1,128.7,129.7(d,J=8.0Hz),133.2(d,J=1.5Hz),135.7,162.9(d,J=251.2Hz),204.7;

[0151] HRMS(ESI)m / z calcd for C 19 H 16 FO[M+H] + :279.1180,found:279.1177.

[0152] Example 7

[0153] Synthesis of (5S,6R,11R)-5-(4-bromophenyl)-9-chloro-3-methyl-1-phenyl-4,5-dihydro-11H-6,11-epoxybenzo[b]furo[3,4-e]azooctane (Ⅲgc)

[0154] The reaction route is as follows:

[0155]

[0156] The steps are as follows:

[0157] Under nitrogen protection, chiral gold catalyst (6.0 μmol, 9.9 mg), AgOTf (14.4 μmol, 3.7 mg) and 1.0 mL of dichloromethane were added to a dry 5 mL reaction bottle. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a flask containing substrate Ⅰg (0.2 mmol, 67.8 mg), substrate Ⅱc (0.14 mmol, 21.5 mg) and 300 mg The reaction mixture was stirred at room temperature for 24 hours. HPLC analysis revealed that the enantioselectivity of the chiral raw material alkynylcyclopropanone (Ig′) was greater than 80%. The solvent was then removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIgc (37 mg, 38% yield).

[0158] The characterization data of the obtained product (IIIgc) are as follows:

[0159] White solid, mp = 176-178 ° C; 37 mg, 38% yield; 86% ee; [Daicel Chiralpak IC-3 (0.45cm×25cm), n-hexane / tetrahydrofuran=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(major)=8.5min, t(minor)=7.1min];

[0160] 1 H NMR (400MHz, CDCl3) δ2.26(s,3H),2.73(ddd,J=16.3,5.1,1.6Hz,1H),2.94(dd,J=16.2,2.6Hz,1H),4.62(dd ,J=5.2,2.6Hz,1H),6.23(s,1H),7.08-7.14(m,1H),7.30-7.37(m,3H),7.41-7.51(m,6H),7.54-7.59(m,2H);

[0161] 13 C NMR (100MHz, CDCl3) δ11.6,25.3,70.7,77.6,114.8,118.0,121.6,122.6,124.0,126.1 ,128.0,128.8,128.9,130.0,130.4,130.6,131.5,137.0,138.9,145.9,147.6,147.7;

[0162] HRMS(ESI)m / z calcd.for C 26 H 20 BrClNO2[M+H] + :492.0360,found:492.0365.

[0163] The characterization data of the obtained chiral raw material alkynylcyclopropanone (Ig') are as follows:

[0164] 1-((1S,2R))-2-(4-bromophenyl)-1-(phenylethynyl)cyclopropyl)ethan-1-one

[0165] Yellow oil, 40mg, 41% yield; 88%ee; [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=254nm, t(major)=6.2min, t(minor)=5.9min];

[0166] 1 H NMR (400MHz, CDCl3) δ1.78 (dd, J=7.9, 4.4Hz, 1H), 2.18 (dd, J=9.1, 4.4Hz, 1H), 2.58 (s, 3H), 2.98(t,J=8.4Hz,1H),7.09-7.21(m,4H),7.26(dd,J=5.5,2.1Hz,3H),7.46(d,J=8.2Hz,2H);

[0167] 13 C NMR (100MHz, CDCl3) δ26.6,29.7,33.2,38.2,84.8,86.9,121.2,122.8,128.3,128.4,130.4,131.1,131.4,135.1,204.7.

[0168] Comparative Example 1

[0169] The synthesis of (5S,6R,11R)-9-bromo-3-methyl-1,5-diphenyl-4,5-dihydro-11H-6,11-epoxybenzo[b]furo[3,4-e]azooctane (IIIaa) was as shown in Example 1, except that no gold catalyst was added.

[0170] In this comparative example, no gold catalyst was added and no reaction occurred.

[0171] Comparative Example 2

[0172] The synthesis of (5S,6R,11R)-9-bromo-3-methyl-1,5-diphenyl-4,5-dihydro-11H-6,11-epoxybenzo[b]furo[3,4-e]azooctane (IIIaa) was as shown in Example 1, except that AgOTf was not added.

[0173] In this comparative example, no AgOTf was added and no reaction occurred.

[0174] Application Example 1: Inhibitory activity of the compounds synthesized in Examples 1-7 against gastric cancer cells (SGC-7901)

[0175] The CKK8 colorimetric assay was used to test the inhibitory effects of the compounds synthesized in Examples 1-7 on gastric cancer cell (SGC-7901) cell proliferation.

[0176] The gastric cancer cells (SGC-7901) used were purchased from Shanghai Saibaikang Biotechnology Co., Ltd. The culture medium used was a complete cell culture medium prepared in a ratio of (culture medium: fetal bovine serum = 9:1), and the culture medium type was RPMI1640.

[0177] The specific steps are as follows:

[0178] (1) Sample solution preparation: The test compound was dissolved in DMSO, sterilized by 0.22 μm filtration, and prepared into a stock solution with a concentration of 100 μM. The stock solution was diluted with culture medium to a total drug concentration of 5 μM to obtain the sample solution. At the same time, the culture medium to which an equal volume of DMSO was added was used as the control solution.

[0179] (2) Gastric cancer cells (SGC-7901) in the logarithmic growth phase were counted and the cell concentration was adjusted to 6×10 3 The cells were inoculated into 96-well plates at a density of 100 cells / well and cultured in a 37°C, 5% CO2 incubator.

[0180] (3) After the cells have been attached and grown for 24 hours, the cell culture medium was discarded and 100 μL of sample solution and control solution were added to each well. After incubation at 37°C and 5% CO2 for 72 hours, the culture medium was removed and each well was washed three times with PBS. 100 μL / well of culture medium containing 10% CCK-8 was added and the cells were incubated in a 37°C constant temperature incubator containing 5% CO2 for 2 hours. The absorbance at 450 nm was measured with a microplate reader and the cell viability was calculated. The experiment was repeated three times and the average value was taken. The results are shown in the figure. Figure 1 .

[0181] Depend on Figure 1 As can be seen, the chiral nitrogen-containing eight-membered ring compounds of the present invention inhibit the proliferation of gastric cancer cells (SGC-7901). In particular, compounds IIIec and IIIfc exhibited inhibition rates exceeding 80% against gastric cancer cells (SGC-7901), providing a scientific basis for the development of new anti-gastric cancer drug candidates. We further determined the IC50 values ​​of IIIec and IIIfc against gastric cancer cells (SGC-7901).

[0182] Application Example 2: IC50 of the half-maximal inhibitory concentration of the synthetic compound IIIec on gastric cancer cells (SGC-7901)

[0183] The specific test steps are as described in Application Example 1, except that: Step (1) Preparation of sample solution: Dissolve the test compound IIIec in DMSO, filter and sterilize through 0.22 μm to obtain a 100 μM sample stock solution, and then dilute it with complete culture medium to concentrations of 0.5, 1, 2, 3, 4, 5, and 20 μM, respectively, to obtain sample solutions.

[0184] The absorbance values ​​of each group were input into Excel and the relative activity was calculated (relative activity % = (OD value of experimental group - background OD value) / (mean OD value of control group - background OD value) × 100), where the background OD value is the absorbance of only adding CCK8 reagent and culture medium. The relative activity values ​​were input into GraphPad Prism for plotting. The test results were plotted in Figure 2 As shown in Figure 2 As shown, the synthetic compound IIIfc of the present invention exhibited excellent inhibitory activity against gastric cancer cells (SGC-7901), with an IC50 value of 1.49 μM.

[0185] Application Example 3: IC50 of the synthetic compound IIIfc against gastric cancer cells (SGC-7901)

[0186] The specific test steps are as described in Application Example 2, except that the concentrations of the sample solutions in step (1) are 0.01, 0.05, 0.1, 0.5, 1, and 5 μM, respectively.

[0187] The test results are in Figure 3 As shown in Figure 3 As shown, the synthetic compound IIIfc of the present invention exhibited excellent inhibitory activity against gastric cancer cells (SGC-7901), with an IC50 value of 0.46 μM.

[0188] Application Example 4: IC50 of the synthetic compound IIIfc against esophageal cancer cells (KYSE150)

[0189] Esophageal cancer cells (KYSE150) were purchased from Shanghai Saibaikang Biotechnology Co., Ltd.

[0190] The specific test steps are as described in Application Example 2, except that the gastric cancer cells (SGC-7901) are replaced by esophageal cancer cells (KYSE150), and the concentrations of the sample solution in step (1) are 0.1, 0.5, 1, 2, 5, and 20 μM.

[0191] The test results are in Figure 4 As shown in Figure 4 As shown, the synthetic compound IIIfc of the present invention exhibited excellent inhibitory activity against esophageal cancer cells (KYSE150), with an IC50 value of 2.69 μM.

[0192] The above are only some embodiments of the present invention and do not limit the present invention in any form. Any simple modification, equivalent change or modification of the above embodiments based on the invention shall fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing chiral nitrogen-containing eight-membered ring compounds by gold-catalyzed asymmetric cycloaddition reaction and kinetic resolution, comprising the following steps: In solvent A, an alkynyl cyclopropanone compound I and anthranilic anhydride compound II undergo an asymmetric [4+4] cycloaddition reaction and kinetic resolution under the catalysis of a gold catalyst system to obtain a chiral nitrogen eight-membered ring compound III; the gold catalyst system comprises a chiral gold catalyst and silver trifluoromethanesulfonate, and the chiral gold catalyst has a structure shown in Formula IV; ； in, In the structural formula of the compound of formula I, R1 is phenyl or halogen-substituted phenyl; R2 is phenyl, 4-fluorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-fluorophenyl or thienyl; R3 is methyl or ethyl; In the structural formula of the compound of formula II, R4 is halogen, C1-C3 alkyl, C1-C3 alkoxy, benzoyl or nitro; In the structural formula of the compound of formula III, the substituents R1, R2, and R3 are the same as those in the structural formula of the compound of formula I; the substituent R4 is the same as that in the structural formula of the compound of formula II; The solvent A is dichloromethane; a 4Å molecular sieve is also added to the reaction system for the asymmetric [4+4] cycloaddition reaction and kinetic resolution of the alkynyl cyclopropanone compound I and the anthranilic anhydride compound II; the temperature of the cycloaddition reaction and kinetic resolution is -20~30°C.

2. The method for synthesizing chiral nitrogen eight-membered ring compounds according to claim 1, wherein In the structural formula of the compound of formula I, R1 is phenyl or 4-bromophenyl, and R3 is methyl; In the structural formula of the compound of formula II, R4 is halogen, benzoyl or nitro.

3. The method for synthesizing chiral nitrogen eight-membered ring compounds according to claim 1, wherein The ratio of the volume of the solvent A to the molar number of the alkynyl cyclopropanone compound I is 5-20 mL:1 mmol; the solvent A is treated with anhydrous solvent.

4. The method for synthesizing chiral nitrogen eight-membered ring compounds according to claim 1, wherein The molar ratio of the alkynyl cyclopropanone compound I to the anthranilic anhydride compound II is 1:0.5-0.

8.

5. The method for synthesizing chiral nitrogen eight-membered ring compounds according to claim 1, wherein The molar ratio of the chiral gold catalyst to silver trifluoromethanesulfonate in the gold catalytic system is 1:2-2.6; and the molar ratio of the chiral gold catalyst to the alkynyl cyclopropanone compound I is 0.01-0.05:

1.

6. The method for synthesizing chiral nitrogen eight-membered ring compounds according to claim 1, wherein The ratio of the mass of the 4Å molecular sieve to the molar number of the alkynyl cyclopropanone compound I is 1-3 g:1 mmol; The cycloaddition reaction and kinetic resolution are carried out under the protection of a protective gas, which is nitrogen or argon.

7. The method for synthesizing chiral nitrogen eight-membered ring compounds according to claim 1, wherein The temperature of the cycloaddition reaction and kinetic resolution is 20-30° C.; the time of the cycloaddition reaction and kinetic resolution is 12-48 h.

8. The method for synthesizing chiral nitrogen eight-membered ring compounds according to claim 1, wherein The cycloaddition reaction and kinetic resolution take 12 to 24 hours.

9. The method for synthesizing chiral nitrogen eight-membered ring compounds according to claim 1, wherein After the alkynyl cyclopropanone compound I and the anthranilic anhydride compound II undergo an asymmetric [4+4] cycloaddition reaction and kinetic resolution, the specific post-reaction treatment steps are as follows: the solvent is removed from the reaction solution, and the resulting crude product is separated by silica gel column chromatography to obtain a chiral nitrogen-containing eight-membered ring compound III. The eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the mixed solvent is 0.02~0.2:

1.

10. A chiral nitrogen eight-membered ring compound, characterized in that: Its structural formula is shown in Formula III; ； In formula III, the substituents R1, R2, R 3、 R4 is as described in claim 1.

11. Use of the chiral nitrogen eight-membered ring compound according to claim 10 in the preparation of drugs for treating gastric cancer and esophageal cancer.

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