Chiral spiro-oxoindole compound and synthesis method thereof

Abstract

The invention belongs to the field of organic chemistry, and relates to a chiral spiro-oxoindole compound and a synthesis method thereof. The chiral spiro-oxoindole compound is a compound with a structure as shown in a formula (1), or an epoxide or a hydrogenation product thereof: # imgabs0 # in the formula (1), R1 is methyl or benzyl; r2 is at least one of hydrogen, alkyl of C1-C4, alkoxy of C1-C4 and halogen; r3 is phenyl, substituted phenyl, naphthyl or phenyl (C1-C4) alkyl, and preferably, the substituent group of the substituted phenyl is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen. A series of chiral spiro-oxoindole derivatives are efficiently constructed by using oxoindole ketene generated by a simple and easily available diazo compound under the illumination condition and alkenyl oxygen heterocyclic propane under the conditions of a metal catalyst and a chiral ligand, and a simple and efficient new method is provided for synthesizing bioactive molecules containing the skeleton.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry, and in particular relates to a chiral spirocyclic oxidized indole compound and a synthesis method thereof. Background Art

[0002] The spirocyclic oxidized indole skeleton is the core structural unit of many natural products and pharmacologically active molecules. Because it contains highly electronegative heteroatoms such as oxygen and nitrogen, it has strong intermolecular forces with many biological macromolecules. Therefore, they are a class of active compounds with special structures. They are known as "advantageous structures" in drug design and are widely concerned by chemists. In the past decade, scientists have continued to deepen their research on spirocyclic oxidized indole and gradually found that such compounds generally have pharmacological activities such as anti-cancer, anti-inflammatory, antibacterial, antiviral, and antimalarial. Among these activities, anti-tumor activity has attracted widespread attention from researchers because of its most outstanding performance. In fact, oxidized indole chemistry is closely related to life sciences, materials science, medicinal chemistry, pesticide chemistry, etc. Therefore, its chemical synthesis and selective modification have become an important research direction of modern organic synthetic chemistry.

[0003] In the past few decades, organic chemists have developed many practical strategies for the synthesis of spirocyclic oxidized indoles, mainly focusing on organic small molecule catalysis and metal-catalyzed cyclization reactions. However, these strategies must use oxidized indoles or their analogs as reaction substrates, and in most cases, racemic products are obtained. There are relatively few strategies for catalytic asymmetric synthesis of spirocyclic oxidized indoles. Therefore, finding new reaction substrates and developing diverse chiral spirocyclic oxidized indoles synthesis strategies have important practical significance and application value.

[0004] CN106986815A discloses an optically active indole cyclopentenone and its derivatives and a synthesis method, specifically disclosing a series of optically active indole cyclopentenones synthesized from indole-2-one-3-diazo compounds and trans-2-trimethylsiloxane-4-methoxy-1,3-butadiene as raw materials. However, it requires the use of a special chiral carboxylic acid rhodium catalyst and the selected optimal solvent carbon tetrachloride is highly toxic, and the reaction needs to be carried out at 0 degrees Celsius and requires complex post-treatment. The most important thing is that it is difficult to control the enantioselectivity of the reaction, and optically pure products can only be obtained through recrystallization. Summary of the invention

[0005] Based on the above analysis and the previous work of this research group, the present invention plans to develop a new type of asymmetric metal-catalyzed dipolar cycloaddition reaction and establish a universal method for synthesizing chiral spirocyclic indole oxides. It is hoped that starting from simple and readily available substrates, chiral spirocyclic indole oxide products with diverse structures and rich functional groups can be quickly and effectively synthesized, which can lay a material foundation for the biological activity screening of such heterocyclic compounds, and also provide a new method for the development of total synthesis of spirocyclic indole natural products.

[0006] In order to achieve the above object, the first aspect of the present invention provides a chiral spirocyclic oxidized indole compound, wherein the chiral spirocyclic oxidized indole compound is a compound having a structure shown in formula (1), or an epoxide or hydrogenation product thereof:

[0007]

[0008] In formula (1), R 1 is methyl or benzyl; R 2 is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen; R 3 It is phenyl, substituted phenyl, naphthyl or phenyl(C1-C4)alkyl. Preferably, the substituent of the substituted phenyl is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen.

[0009] The second aspect of the present invention provides a method for synthesizing the chiral spirocyclic oxidized indole compound, comprising the following steps:

[0010] Step (a): Under a first inert gas protection condition and in the presence of a first solvent, a diazo compound having a structure represented by formula (VII) is subjected to light treatment to obtain an oxidized indole ketone;

[0011] Step (b): under the protection of a second inert gas and in the presence of a second solvent, the oxidized indole ketone, the alkenyl oxirane having the structure of formula (VI), the chiral ligand and the metal catalyst are mixed to undergo a dipolar cyclization reaction to obtain a compound having the structure shown in formula (1);

[0012]

[0013] and, optionally, step (c) or step (d);

[0014] Step (c): subjecting the compound having the structure represented by formula (1) to epoxidation reaction to obtain epoxide;

[0015] Step (d): subjecting the compound having the structure represented by formula (1) to a hydrogenation reaction to obtain a hydrogenation product.

[0016] The present invention utilizes the indole enone oxide produced by simple and readily available diazo compounds under light conditions and reacts with alkenyl oxirane under the conditions of a metal catalyst and a chiral ligand to efficiently construct a series of structurally diverse chiral spirocyclic indole oxide derivatives through an asymmetric dipolar cyclization reaction, thereby providing a simple and efficient new method for synthesizing bioactive molecules containing such skeletons.

[0017] Other features and advantages of the present invention will be described in detail in the following detailed description. DETAILED DESCRIPTION

[0018] The preferred embodiments of the present invention will be described in more detail below. Although the preferred embodiments of the present invention are described below, it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments set forth herein.

[0019] In order to achieve the above object, the first aspect of the present invention provides a chiral spirocyclic oxidized indole compound, wherein the chiral spirocyclic oxidized indole compound is a compound having a structure shown in formula (1), or an epoxide or hydrogenation product thereof:

[0020]

[0021] In formula (1), R 1 is methyl or benzyl; R 2 is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen; R 3 It is phenyl, substituted phenyl, naphthyl or phenyl(C1-C4)alkyl. Preferably, the substituent of the substituted phenyl is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen.

[0022] According to the present invention, preferably, the chiral spirocyclic oxidized indole compound is selected from at least one of the compounds having structures represented by formula (I) to formula (V);

[0023]

[0024] (I) to (V), R 1 Each is independently methyl or benzyl; R 2 is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen; R 4 It is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen.

[0025] According to the present invention, preferably, R 2 is hydrogen, 1-methyl, 1-fluoro, 2-methyl, 2-methoxy, 3-methyl or 4-methyl; R 4is hydrogen, 6-methoxy, 7-methyl, 7-chloro, 7-bromo, 7-fluoro or 6,7-dichloro.

[0026] The second aspect of the present invention provides a method for synthesizing the chiral spirocyclic oxidized indole compound, comprising the following steps:

[0027] Step (a): Under a first inert gas protection condition and in the presence of a first solvent, a diazo compound having a structure represented by formula (VII) is subjected to light treatment to obtain an oxidized indole ketone;

[0028] Step (b): under the protection of a second inert gas and in the presence of a second solvent, the oxidized indole ketone, the alkenyl oxirane having the structure of formula (VI), the chiral ligand and the metal catalyst are mixed to undergo a dipolar cyclization reaction to obtain a compound having the structure of formula (1);

[0029]

[0030] and, optionally, step (c) or step (d);

[0031] Step (c): subjecting the compound having the structure represented by formula (1) to epoxidation reaction to obtain epoxide;

[0032] Step (d): subjecting the compound having the structure represented by formula (1) to a hydrogenation reaction to obtain a hydrogenation product.

[0033] According to the present invention, preferably, in step (a), the first inert gas is selected from argon and / or nitrogen; the first solvent is dichloromethane and / or 1,2-dichloroethane.

[0034] According to the present invention, preferably, in step (a), the light treatment uses visible light, the wavelength of the visible light is 350-400nm, the light intensity is 8-15W, the light temperature is 0-40°C, and the light time is 2-6h.

[0035] According to the present invention, preferably, in step (b), under the protection of a second inert gas, the chiral ligand and the metal catalyst are first dissolved in a second solvent, stirred and mixed at 0 to 40° C. for 20 to 30 minutes, and then mixed with the oxidized indole ketone and the alkenyl oxirane having the structure of formula (VI).

[0036] According to the present invention, preferably, in step (b), the second inert gas is argon and / or nitrogen; the metal catalyst is selected from at least one of tris(dibenzylideneacetone)dipalladium chloroform adduct and / or tris(dibenzylideneacetone)dipalladium; and the second solvent is selected from at least one of dichloromethane, acetonitrile, benzyl cyanide and 1,2-dichloroethane.

[0037] The chiral ligand is selected from at least one of the compounds having structures represented by formula (VIII) to (XI);

[0038]

[0039] In the present invention, all the ligands shown have been reported in the literature, and the synthesis methods and characterizations are all in the literature (J.Am.Chem.Soc.2021,143,1038.; Angew.Chem.Int.Ed.2024,e202319728). In the present invention, the compound with the structure shown in formula (VIII) is preferably used.

[0040] The molar ratio of the oxidized indole ketone, the alkenyl oxirane having the structure of formula (VI), the chiral ligand and the metal catalyst is 40-50:20-25:2-2.4:1;

[0041] The conditions of the dipolar cyclization reaction include: temperature of 0 to 40° C. and time of 8 to 20 hours.

[0042] According to a specific embodiment of the present invention, the synthesis method is as follows:

[0043]

[0044] In the reaction formula, Pd2(dba)3·CHCl3: tris(dibenzylideneacetone)dipalladium chloroform adduct; DCM: dichloromethane; MeCN: acetonitrile; PhCN: benzonitrile; 370nm, 10W kessil lamp: kessil lamp with a wavelength of 370nm and a light intensity of 10W; yield: yield; ee: enantiomeric excess.

[0045] According to another specific embodiment of the present invention, the synthesis method is as follows:

[0046]

[0047] In the reaction formula, Pd2(dba)3·CHCl3: tris(dibenzylideneacetone)dipalladium chloroform adduct; DCM: dichloromethane; MeCN: acetonitrile; PhCN: benzonitrile; 370nm, 10W kessil lamp: kessil lamp with a wavelength of 370nm and a light intensity of 10W; yield: yield; ee: enantiomeric excess.

[0048] According to another specific embodiment of the present invention, the synthesis method is as follows:

[0049]

[0050] In the reaction formula, Pd2(dba)3·CHCl3: tris(dibenzylideneacetone)dipalladium chloroform adduct; DCM: dichloromethane; MeCN: acetonitrile; PhCN: benzonitrile; 370nm, 10W kessil lamp: kessil lamp with a wavelength of 370nm and a light intensity of 10W; yield: yield; ee: enantiomeric excess.

[0051] According to the present invention, preferably, in step (c), the epoxidation reaction is carried out under the protection of a third inert gas in the presence of a third solvent and an epoxidation reagent; the third inert gas is argon and / or nitrogen; the third solvent is selected from dichloromethane and / or 1,2-dichloroethane; the epoxidation reagent is m-chloroperbenzoic acid; the molar ratio of the compound having the structure shown in formula (1) to the epoxidation reagent is 2-5:1;

[0052] The conditions of the epoxidation reaction include: temperature of 20 to 40° C. and time of 10 to 15 hours.

[0053] According to a specific embodiment of the present invention, the synthesis method is as follows:

[0054]

[0055] In the reaction formula, m-CPBA: meta-chloroperbenzoic acid; DCM: dichloromethane; yield: yield; ee: enantiomeric excess; dr value: diastereoisomer ratio.

[0056] According to the present invention, preferably, the addition reaction is carried out under the protection of a fourth inert gas in the presence of hydrogen, a fourth solvent and a catalyst; the fourth inert gas is argon and / or nitrogen; the catalyst is palladium / carbon and / or palladium hydroxide; the fourth solvent is ethyl acetate and / or methanol; the molar ratio of the compound having the structure shown in formula (1) to the catalyst is 1-10:1;

[0057] The conditions of the addition reaction include: temperature of 0 to 40° C. and time of 5 to 15 hours.

[0058] According to a specific embodiment of the present invention, the synthesis method is as follows:

[0059]

[0060] In the reaction formula, Pd / C: palladium / carbon; EtOAc: ethyl acetate; H2: hydrogen; rt: room temperature; yield: yield; ee: enantiomeric excess; dr value: diastereoisomer ratio.

[0061] In the embodiments of the present invention, all reaction substrates are prepared according to published literature. Formula VI-1 to 9 (Org. Lett, 2019, 21, 214.), Formula VII-1 to 8 (Chem. Commun., 2019, 55, 5239.).

[0062] The chiral ligand of Examples 1-18 is a compound of the structure shown in formula (VIII), and the chiral ligand of Example 23 is a compound of the structure shown in formula (XI).

[0063] The structural formulas of the reaction substrates VI-1 to VI-9 are as follows:

[0064]

[0065] The structural formulas of the reaction substrates VII-1 to VII-8 are as follows:

[0066]

[0067] Example 1

[0068] Synthesis of Compound I-1

[0069]

[0070] Under argon protection, add substrate VII-1 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and MeCN (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-1 (0.1mmol, 1.0eq.) and PhCN (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-1 with a yield of 60% and an ee value (enantiomeric excess) of 93%, as determined by separating the pure product via chiral high performance liquid chromatography.

[0071] 1H NMR (400MHz, CDCl3) δ (ppm) 7.58 (d, J = 7.4Hz, 1H), 7.44-7.28 (m, 6H), 7.12 (t, J = 7.6Hz, 1H), 6.86 (d ,J=7.8Hz,1H),6.29(t,J=8.8Hz,1H),4.63(s,2H),3.25(d,J=1.1Hz,3H),3.09(s,2H),2.95(s,2H).

[0072] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.4, 171.4, 143.8, 143.2, 142.8, 129.3, 128. 5,127.5,126.7,126.6,125.5,122.8,108.3,70.2,62.9,37.5,34.1,26.5.

[0073] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=38.05min, t2=16.45min

[0074] High resolution: Calculated value: [M+H] + :334.1438, measured value:334.14383.

[0075] Optical rotation: [α] D 25 =49.93 (c = 1.00 in CHCl3)

[0076] Example 2

[0077] Synthesis of Compound I-2

[0078]

[0079] Under argon protection, add substrate VII-1 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and MeCN (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-2 (0.1mmol, 1.0eq.) and PhCN (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-2 with a yield of 63% and an ee value (enantiomeric excess) of 95%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0080] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.57 (d, J = 7.4Hz, 1H), 7.34 (t, J = 7.8Hz, 1H), 7.28 (d, J = 7.7Hz, 2H), 7.21-7.05 (m, 3H), 6.8 6(d,J=7.8Hz,1H),6.26(t,J=8.8Hz,1H),4.61(s,2H),3.24(d,J=1.6Hz,3H),3.07(s,2H),2.92(s,2H),2.36(s,3H)..

[0081] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.2,171.3,1431,142.5,140.8,137.2,129.1,1 29.1,126.0,126.3,125.6,125.4,122.7,108.2,62.8,37.4,33.9,26.5,21.1.

[0082] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =85:15, flow rate 1.0mL / min, λ=254nm, t1=40.83min, t2=15.09min

[0083] High resolution: Calculated value: [M+H] + :348.1594, measured value:348.1598.

[0084] Optical rotation: [α] D 25 =55.93 (c = 1.00 in CHCl3)

[0085] Example 3

[0086] Synthesis of Compound I-3

[0087]

[0088] Under argon protection, add substrate VII-1 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and MeCN (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-3 (0.1mmol, 1.0eq.) and PhCN (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-3 with a yield of 74% and an ee value (enantiomeric excess) of 93%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0089] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.58 (d, J = 7.5Hz, 1H), 7.44-7.32

[0090] (m,3H),7.26(d,J=1.6Hz,1H),7.13(t,J=7.7Hz,2H),7.08-7.00(m,1H),6.87(d,J=7.8Hz,1H),6.26(s,1H),4.60(d,J=

[0091] 25.7Hz, 2H), 3.25 (t, J = 1.6Hz, 3H), 2.98 (s, 4H).

[0092] 13 C NMR (100MHz, CDCl3) δ (ppm) 171.4, 170.2, 163.6, 161.1, 143.2, 139.8 (0), 139.7 (7), 129.3, 128.41 (d ,J=8.0Hz),126.7,126.2,125.3,122.8,115.29(d,J=21.4Hz),108.4,70.18,62.9,37.3,34.2,26.5.

[0093] 19 F NMR(377MHz,CDCl3)δ(ppm)-115.1

[0094] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇=90:10, flow rate 1.0mL / min, λ=254nm, t1=42.43min, t2=22.31min

[0095] High resolution: Calculated value: [M+H] + :352.1343, measured value:352.1336.

[0096] Optical rotation: [α] D 25 =57.27 (c = 1.00 in CHCl3)

[0097] Example 4

[0098] Synthesis of Compound I-4

[0099]

[0100] Under argon protection, add substrate VII-1 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and MeCN (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-4 (0.1mmol, 1.0eq.) and PhCN (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-4 with a yield of 75% and an ee value (enantiomeric excess) of 92%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0101] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.56 (d, J = 7.5Hz, 1H), 7.38-7.33 (m, 1H), 7.31 (s, 4H), 7.14 -7.12(m,1H),6.86(d,J=7.7Hz,1H),6.30(t,J=8.8Hz,1H),4.60(d,J=30.2Hz,2H),3.25(s,3H),2.99(s,4H).

[0102] 13C NMR (100MHz, CDCl3) δ (ppm) 172.4,171.4,143.2,142.2,141.6,133.5,129.4,1 28.6,128.1,127.3,126.2,125.3,122.8,108.4,70.1,62.9,37.3,34.0,26.5.

[0103] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =85:15, flow rate 1.0mL / min, λ=254nm, t1=31.69min, t2=17.14min

[0104] High resolution: Calculated value: [M+H] + :368.1048, measured value:368.1049.

[0105] Optical rotation: [α] D 25 =73.93 (c = 1.00 in CHCl3)

[0106] Example 5

[0107] Synthesis of Compound I-5

[0108]

[0109] Under argon protection, add substrate VII-1 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and MeCN (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-5 (0.1mmol, 1.0eq.) and PhCN (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction is completed, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-5 with a yield of 53% and an ee value (enantiomeric excess) of 90%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0110] 1H NMR (400MHz, CDCl3) δ (ppm) 7.56 (d, J = 7.5Hz, 1H), 7.50-7.44 (m, 2H), 7.37-7.33 (m, 1H), 7.29-7.23 (m, 2H), 7.12 (t,J=7.6Hz,1H),6.86(d,J=7.8Hz,1H),6.30(t,J=8.8Hz,1H),4.60(d,J=28.4Hz,2H),3.25(s,3H),2.98(s,4H)

[0111] 13 C NMR(100MHz,CDCl3)δ(ppm)172.3,171.4,143.2,142.7,141.6,131.6,129.4,1 28.4,127.4,126.2,125.3,122.8,121.6,108.4,70.2,62.9,37.3,33.9,26.5.

[0112] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =85:15, flow rate 1.0mL / min, λ=254nm, t1=35.04min, t2=18.77min

[0113] High resolution: Calculated value: [M+H] + :412.0534, measured value:412.0538.

[0114] Optical rotation: [α] D 25 =41.83 (c = 1.00 in CHCl3)

[0115] Example 6

[0116] Synthesis of Compound I-6

[0117]

[0118] Under argon protection, add substrate VII-1 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and MeCN (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-6 (0.1mmol, 1.0eq.) and PhCN (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-6 with a yield of 86% and an ee value (enantiomeric excess) of 93%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0119] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.57 (d, J = 7.4Hz, 1H), 7.37-7.32 (m, 1H), 7.27 (t, J = 7.9Hz, 1H), 7.13-7.09 (m, 1H), 7.00-6.95 (m, 1H), 6.91(t,J=2.1Hz,1H),6.88-6.80(m,2H),6.30(t,J=8.8Hz,1H),4.63(s,2H),3.84(s,3H),3.24(s,3H),3.10(s,2H),2.92(s,1H).

[0120] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.3,171.4,159.6,145.3,143.2,142.7,129.5,129.2,126 .6,126.4,125.5,122.8,119.3,112.8,112.6,108.3,70.2,62.9,55.3,37.5,34.1,26.5.

[0121] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=81.58min, t2=27.62min

[0122] High resolution: Calculated value: [M+H] + :364.1543, measured value:364.1539.

[0123] Optical rotation: [α] D 25 =53.90(c=1.00 in CHCl3)

[0124] Example 7

[0125] Synthesis of Compound I-7

[0126]

[0127] Under argon protection, add substrate VII-1 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and MeCN (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-7 (0.1mmol, 1.0eq.) and PhCN (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-7 with a yield of 78% and an ee value (enantiomeric excess) of 80%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0128] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.55 (d, J = 7.5Hz, 1H), 7.44 (d, J = 2.1Hz, 1H), 7.41 (d, J = 8.4Hz, 1H), 7.35 (t, J = 7.8Hz, 1H), 7.22 (dd, J = 8 .3,2.2Hz,1H),7.12(t,J=7.6Hz,1H),6.87(d,J=7.8Hz,1H),6.34(t,J=8.7Hz,1H),4.61(d,J=40.9Hz,2H),3.25(s,3H),2.97(s,4H)

[0129] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.4, 171.3, 143.7, 143.2, 140.5, 132.5, 131.6, 130. 4,129.4,128.5,126.3,126.0,125.2,122.9,108.4,69.9,62.9,37.2,33.8,26.5.

[0130] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=37.12min, t2=20.68min

[0131] High resolution: Calculated value: [M+H] + :402.0658, measured value:402.0651.

[0132] Optical rotation: [α] D 25 =52.03(c=1.00 in CHCl3)

[0133] Example 8

[0134] Synthesis of Compound I-8

[0135]

[0136] Under argon protection, add substrate VII-2 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and MeCN (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-1 (0.1mmol, 1.0eq.) and PhCN (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-8 with a yield of 81% and an ee value (enantiomeric excess) of 94%, which was determined by separating the pure product through chiral high performance liquid chromatography.

[0137] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.59 (d, J = 7.4Hz, 1H), 7.42-7.33 (m, 4H), 7.33-7.19 (m, 7H), 7.12-7.03 (m, 1H) ,6.74(d,J=7.8Hz,1H),6.34(t,J=8.6Hz,1H),4.95(d,J=1.6Hz,2H),4.64(d,J=21.6Hz,2H),3.02(s,4H).

[0138] 13C NMR (100MHz, CDCl3) δ (ppm) 172.5, 171.4, 143.7, 142.2, 135.5, 129.1, 128.8, 128.4, 127. 7,127.5,127.3,126.7,126.5,126.2,125.4,122.7,109.3,70.3,62.9,43.9,37.5,34.0.

[0139] Chiral HPLC: Chiral AS column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=28.16min, t2=22.62min

[0140] High resolution: Calculated value: [M+H] + :410.1751, measured value:410.1743.

[0141] Optical rotation: [α] D 25 =56.37 (c = 1.00 in CHCl3)

[0142] Example 9

[0143] Synthesis of Compound I-9

[0144]

[0145] Under argon protection, add substrate VII-3 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and DCM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-1 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction is completed, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-9 with a yield of 72% and an ee value (enantiomeric excess) of 81%, which was determined by separating the pure product through chiral high performance liquid chromatography.

[0146] 1H NMR (400MHz, CDCl3) δ (ppm) 7.43-7.33 (m, 5H), 7.29 (t, J = 7.0Hz, 1H), 7.14 (d, J = 7.9Hz, 1H), 6. 75(d,J=7.8Hz,1H),6.31(t,J=8.8Hz,1H),4.64(s,2H),3.23(s,3H),3.02(s,4H),2.38(s,3H).

[0147] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.4,171.6,143.9,142.6,140.8,132.4,129.5,128 .5,127.5,126.8,126.7,126.4,126.1,108.1,70.3,63.0,37.4,34.1,26.6,21.3.

[0148] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=47.58min, t2=20.08min

[0149] High resolution: Calculated value: [M+H] + :348.1594, measured value:348.1589.

[0150] Optical rotation: [α] D 25 =45.17 (c = 1.00 in CHCl3)

[0151] Example 10

[0152] Synthesis of Compound I-10

[0153]

[0154] Under argon protection, add substrate VII-3 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and DCM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-4 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction is completed, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-10 with a yield of 48% and an ee value (enantiomeric excess) of 89%, which was determined by separating the pure product through chiral high performance liquid chromatography.

[0155] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.30 (s, 1H), 7.24 (s, 4H), 7.14-7.02 (m, 1H), 6.68 (d, J = 7.9Hz, 1H), 6.24 (t, J = 8.7Hz, 1H), 4.53 (d, J = 39.9Hz, 2H), 3.15 (s, 3H), 2.92 (s, 4H), 2.30 (s, 3H).

[0156] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.5, 171.5, 142.2, 141.4, 140.8, 133.4, 132.4, 129. 6,128.6,128.2,127.5,126.1,125.9,108.1,70.1,63.0,37.38,34.0,26.5,21.3.

[0157] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=36.42min, t2=19.72min

[0158] High resolution: Calculated value: [M+H] + :382.1204, measured value:382.1203.

[0159] Optical rotation: [α] D 25 =43.07 (c = 1.00 in CHCl3)

[0160] Embodiment 11

[0161] Synthesis of Compound I-11

[0162]

[0163] Under argon protection, add substrate VII-3 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and DCM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-6 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction is completed, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-11 with a yield of 90% and an ee value (enantiomeric excess) of 84%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0164] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.40-7.32 (m, 4H), 7.32-7.27 (m, 1H), 7.21 (d, J = 2.6Hz, 1H), 6.87 (dd, J = 8.5, 2.6Hz, 1H), 6.76

[0165] (d,J=8.5Hz,1H),6.29(t,J=8.5Hz,1H),4.63(s,2H),3.82(s,3H),3.23(s,3H),3.05(s,4H).

[0166] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.1, 171.4, 156.0, 143.8, 142.8, 136.8, 128.5, 127.5,126.7,126.5,113.3,113.2,108.5,70.3,63.2,56.0,37.5,34.1,26.6.

[0167] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇=90:10, flow rate 1.0mL / min, λ=254nm, t1=63.23min, t2=33.73min

[0168] High resolution: Calculated value: [M+H] + :364.1543, measured value:364.1535.

[0169] Optical rotation: [α] D 25 =83.47 (c = 1.00 in CHCl3)

[0170] Example 12

[0171] Synthesis of Compound I-12

[0172]

[0173] Under argon protection, add substrate VII-4 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and DCM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-1 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction is completed, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-12 with a yield of 88% and an ee value (enantiomeric excess) of 84%, which was determined by separating the pure product through chiral high performance liquid chromatography.

[0174] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.44-7.32 (m, 4H), 7.32-7.27 (m, 1H), 7.21 (d, J = 2.6Hz, 1H), 6.87 (dd, J = 8.5, 2. 6Hz,1H),6.76(d,J=8.5Hz,1H),6.29(t,J=8.5Hz,1H),4.63(s,2H),3.82(s,3H),3.23(s,3H),3.05(s,4H).

[0175] 13C NMR (100MHz, CDCl3) δ (ppm) 172.1, 171.4, 156.0, 143.8, 142.8, 136.8, 128.5, 127.5,126.7,126.5,113.3,113.2,108.5,70.3,63.2,56.0,37.5,34.1,26.6.

[0176] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=63.23min, t2=33.71min

[0177] High resolution: Calculated value: [M+H] + :364.1543, measured value:364.1535.

[0178] Optical rotation: [α] D 25 =38.87 (c = 1.00 in CHCl3)

[0179] Example 13

[0180] Synthesis of Compound I-13

[0181]

[0182] Under argon protection, add substrate VII-4 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and DCM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-2 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction is completed, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-13 with a yield of 85% and an ee value (enantiomeric excess) of 69%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0183] 1H NMR (400MHz, CDCl3) δ (ppm) 7.34-7.23 (m, 2H), 7.21 (d, J = 2.5Hz, 1H), 7.16 (d, J = 7.9Hz, 2H), 6.87 (dd, J = 8.5, 2.6Hz, 1H), 6.76(d,J=8.5Hz,1H),6.26(t,J=8.8Hz,1H),4.61(s,2H),3.82(s,3H),3.22(s,3H),3.00(d,J=37.8Hz,4H),2.36(s,3H).

[0184] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.0, 171.3, 156.0, 142.7, 140.8, 137.3, 136.7, 129.2, 127.7,126.6,125.7,113.3,113.2,108.5,70.3,63.2,56.0,37.5,34.0,26.6,21.2.

[0185] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=76.43min, t2=29.74min

[0186] High resolution: Calculated value: [M+H] + :378.1700, measured value:378.1696.

[0187] Optical rotation: [α] D 25 =51.63 (c = 1.00 in CHCl3)

[0188] Embodiment 14

[0189] Synthesis of Compound I-14

[0190]

[0191] Under argon protection, add substrate VII-5 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), CM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-1 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction is completed, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-14 with a yield of 54% and an ee value (enantiomeric excess) of 86%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0192] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.45 (d, J = 7.6Hz, 1H), 7.41-7.33

[0193] (m,4H),7.32-7.27(m,1H),7.07-6.91(m,1H),6.69(d,J=1.4

[0194] Hz,1H),6.28(s,1H),4.62(s,2H),3.23(s,3H),3.01(d,J=59.9

[0195] Hz,4H),2.40(s,3H).

[0196] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.7, 171.6, 143.8, 143.3, 142.6, 139.6, 128.5, 127.5, 126.7(3),126.6(6),125.2,123.5,123.3,109.3,70.2,62.8,37.5,34.1,26.5,21.9.

[0197] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=46.44min, t2=17.37min

[0198] High resolution: Calculated value: [M+H] +:348.1594, measured value:348.1587.

[0199] Optical rotation: [α] D 25 =22.73 (c = 1.00 in CHCl3)

[0200] Embodiment 15

[0201] Synthesis of Compound I-15

[0202]

[0203] Under argon protection, add substrate VII-6 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and DCM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-1 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction is completed, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-16 with a yield of 49% and an ee value (enantiomeric excess) of 66%, which was determined by separating the pure product through chiral high performance liquid chromatography.

[0204] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.51-7.36 (m, 4H), 7.35-7.27 (m, 1H), 7.11 (d, J = 7.7Hz, 1H), 7.03 (t, J = 7.6Hz, 1H), 6.33 (t, J =

[0205] 8.8Hz,1H),4.66(s,2H),3.57(s,3H),3.23-2.86(m,4H),2.62(s,3H).

[0206] 13 C NMR (100MHz, CDCl3) δ (ppm) 173.2, 171.6, 143.9, 142.7, 141.0, 133.0, 128.5, 127.5,126.8,126.8,123.4,122.6,119.9,70.4,62.4,37.7,34.1,29.9,19.2.

[0207] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=46.44min, t2=17.37min

[0208] High resolution: Calculated value: [M+H] + :348.1594, measured value:348.1587.

[0209] Optical rotation: [α] D 25 =22.73 (c = 1.00 in CHCl3)

[0210] Example 16

[0211] Synthesis of Compound I-16

[0212]

[0213] Under argon protection, add substrate VII-7 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and DCM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-1 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-16 with a yield of 50% and an ee value (enantiomeric excess) of 97%, which was determined by separating the pure product through chiral high performance liquid chromatography.

[0214] 1H NMR (400MHz, CDCl3) δ (ppm) 7.42-7.38 (m, 2H), 7.36-7.31 (m, 2H), 7.30-7.27 (m, 1H), 7.25-7.20 (m, 1H), 6.91-6.89 (m, 1H), 6.70 (d, J = 7.7Hz, 1H), 6 .41(t,J=8.7Hz,1H),4.72-4.64(m,1H),4.55-4.52(m,1H),3.40(d,J=11. 3Hz,1H),3.24(s,3H),3.15-3.05(m,1H),3.03-2.85(m,2H),2.57(s,3H).

[0215] 13 C NMR (100MHz, CDCl3) δ (ppm) 173.0,172.1,144.1,144.0,141.3,136.7,129.0,128 .4,128.1,127.3,126.7,126.4,123.7,106.1,70.6,64.7,34.4,34.3,26.6,20.6.

[0216] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=50.47min, t2=18.42min

[0217] High resolution: Calculated value: [M+H] + :348.1594, measured value:348.1589.

[0218] Optical rotation: [α] D 25 =9.13 (c = 1.00 in CHCl3)

[0219] Embodiment 17

[0220] Synthesis of Compound I-17

[0221]

[0222] Under argon protection, add substrate VII-7 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and DCM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-2 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-17 with a yield of 42% and an ee value (enantiomeric excess) of 98%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0223] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.34 (d, J = 1.6Hz, 2H), 7.31-7.24

[0224] (m,1H),7.18(d,J=7.9Hz,2H),6.94(d,J=7.8Hz,1H),6.73(d,

[0225] J=7.7Hz,1H),6.41(t,J=8.7Hz,1H),4.71-4.65(m,1H),4.60

[0226] -4.55(m,J=10.8,5.5,3.1Hz,1H),3.43-3.34(m,1H),3.28(s,3H),3.15-3.06(m,1H),3.03-2.90(m,2H),2.60(s,3H),2.39(s,3H).

[0227] 13 C NMR (100MHz, CDCl3) δ (ppm) 173.0,172.01,144.1,141.2,141.1,137.1,136.8,129.1 ,129.0,127.3,126.6,126.4,123.8,106.1,70.6,64.8,3456,34.3,26.6,21.2,20.7.

[0228] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇=90:10, flow rate 1.0mL / min, λ=254nm, t1=48.28min, t2=19.60min

[0229] High resolution: Calculated value: [M+H] + :362.1751, measured value:362.1750.

[0230] Optical rotation: [α] D 25 =28.20 (c = 1.00 in CHCl3)

[0231] Embodiment 18

[0232] Synthesis of Compound I-18

[0233]

[0234] Under argon protection, add substrate VII-8 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and DCM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-1 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-17 with a yield of 58% and an ee value (enantiomeric excess) of 70%, which was determined by separating the pure product through chiral high performance liquid chromatography.

[0235] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.45-7.17 (m, 6H), 6.88-6.83 (m, 1H), 6.68 (dd, J = 7.8, 0.8Hz, 1H), 6.28-6.22 (td, 1H), 4.67 (t, J

[0236] =10.4Hz,1H),4.49-4.44(m,1H),3.65-3.25(m,2H),3.25(s,3H),2.81(d,J=15.4Hz,2H).

[0237] 13C NMR (100MHz, CDCl3) δ (ppm) 171.2, 169.9, 160.7, 158.2, 145.4 (d, J

[0238] =8.9Hz),144.1,142.4,142.4,131.1(d,J=9.0Hz),128.4,127.3,127.1,127.1,126 .9,126.9,111.2(d,J=22.4Hz),104.5,104.4,69.9,63.3(3),63.2(9),34.1,27.1.

[0239] 19 F NMR(377MHz, CDCl3)δ(ppm)-62.9.

[0240] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm, t1=28.68min, t2=15.78min

[0241] High resolution: Calculated value: [M+H] + :352.1343, measured value:352.1337.

[0242] Optical rotation: [α] D 25 =25.20 (c = 1.00 in CHCl3)

[0243] Embodiment 19

[0244] Synthesis of compound II

[0245]

[0246] Under argon protection, add substrate VII-1 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and MeCN (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate Ⅵ-8 (0.1mmol, 1.0eq.) and PhCN (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯=20:3 column chromatography to obtain the target product of formula II, with a yield of 60% and an ee value (enantiomeric excess) of 93%, which was determined by separating the pure product through chiral high performance liquid chromatography.

[0247] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.96-7.84 (m, 4H), 7.65 (d, J = 7.4Hz, 1H), 7.59-7.46 (m, 3H), 7.43-7.34 (m, 1H), 7.16 (t ,J=7.3Hz,1H),6.90(d,J=7.8Hz,1H),6.47(t,J=8.8Hz,1H),4.73(s,2H),3.30(s,3H),3.22(s,2H),3.11(s,2H)..

[0248] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.4, 171.5, 143.2, 142.7, 141.1, 133.4, 132.7, 129.3, 128.2, 128. 2,127.6,127.1,126.4,126.0,125.5,125.3,125.1,122.8,108.4,70.3,63.0,37.6,34.1,26.6.

[0249] Chiral HPLC: Chiral OD column, V 正己烷 / V 异丙醇 =90:10, flow rate 0.7mL / min, λ=254nm, t1=48.73min, t2=58.51min

[0250] High resolution: Calculated value: [M+H] + :384.1594, measured value:384.1597.

[0251] Optical rotation: [α] D 25 =46.03 (c = 1.00 in CHCl3)

[0252] Embodiment 20

[0253] Synthesis of compound III

[0254]

[0255] Under argon protection, add substrate VII-1 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and MeCN (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-9 (0.1mmol, 1.0eq.) and PhCN (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product of formula III with a yield of 77% and an ee value (enantiomeric excess) of 90%, as determined by chiral high performance liquid chromatography.

[0256] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.40 (d, J = 7.3Hz, 1H), 7.37-7.27 (m, 3H), 7.24-7.18 (m, 3H), 7.10-7. 06(m,1H),6.87-6.81(m,1H),5.84(t,J=8.6Hz,1H),4.55(s,2H),3.22(s,3H),3.12-2.26(m,8H).

[0257] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.3, 171.5, 143.0, 142.3, 141.4, 129.0, 128.4, 128.3, 126.6,125.9,125.5,122.9,122.6,108.2,70.0,62.9,41.9,37.0,34.5,33.6,26.4.

[0258] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =90:10, flow rate 0.7mL / min, λ=254nm, t1=23.13min, t2=17.07min

[0259] High resolution: Calculated value: [M+H] + :362.1751, measured value:362.1755.

[0260] Optical rotation: [α] D 25=50.03 (c = 1.00 in CHCl3)

[0261] Embodiment 21

[0262] Synthesis of compound IV

[0263]

[0264] Under argon, compound I-1 (0.1 mmol, 1.0 equiv.) was dissolved in DCM (1.5 mL), and m-CPBA (0.5 mmol, 5 equiv.) was added to the mixture. The temperature was raised to 30° C. and the reaction was carried out for 12 hours until the reaction was complete as detected by TLC. The mixture was quenched with a saturated sodium thiosulfate solution, extracted three times with ethyl acetate, and the organic phase was collected and back-extracted with a saturated saline solution, dried over anhydrous sodium sulfate, desolvated, and V 石油醚 / V 乙酸乙酯 =10:1 column chromatography to directly obtain the target product of formula IV, with a yield of 65%; ee value (enantiomeric excess): 92%, determined by separating the pure product by chiral high performance liquid chromatography; dr value (diastereoisomer ratio): 6:1, determined by H NMR spectrum of the reaction mixture.

[0265] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.57-7.53 (m, 3H), 7.44-7.28 (m, 4H), 7.12 (td, J = 7.6, 1.0Hz, 1H), 6.88 (d, J = 7.8Hz, 1H), 4.88 (t, J=12.2Hz,1H),4.28-4,24(m,1H),4.07(dd,J=10.7,4.5Hz,1H),3.28(s,3H),2.58(dd,J=13.4,4.4Hz,2H),2.51-2.25(m,2H).

[0266] 13 C NMR(100MHz,CDCl3)δ(ppm,major+minor)173.3,172.2,143.5,140.4,129.6,129.6,128.6,128.5,128.2(2),128.1 (7),127.6,127.5,125.2,125.1,124.5,123.1,109.4,108.0,66.1,62.8,57.7,57.3,57.1,38.3,37.5,26.6,26.5.

[0267] Chiral HPLC: Chiral IE columns, V 正己烷 / V 异丙醇=80:20, flow rate 0.7mL / min, λ=254nm, t1=28.35min, t2=41.49min

[0268] High resolution: Calculated value: [M+H] + :372.1207, measured value:372.1206.

[0269] Optical rotation: [α] D 25 =-22.3 (c = 1.00 in CHCl3)

[0270] Embodiment 22

[0271] Synthesis of Compound V

[0272]

[0273] Under argon conditions, compound I-1 (0.1 mmol, 1.0 equiv.) and 10% Pd / C (1 mmol, 10 equiv.) were dissolved in EtOAc (1 mL), and a hydrogen balloon was bubbled. The reaction was carried out at room temperature for 8 hours until the reaction was complete as detected by TLC. The organic phase was collected by filtration through diatomaceous earth, and the solvent was removed. 石油醚 / V 乙酸乙酯 =25:1 column chromatography to directly obtain the target product of formula V, with a yield of 84%; ee value (enantiomeric excess): 90% / 90%, determined by separating the pure product by chiral HPLC; dr value (diastereoisomer ratio): 2:1, determined by H NMR spectrum of the reaction mixture.

[0274] V-1 (major diastereomer):

[0275] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.59 (dd, J = 7.5, 1.2Hz, 1H), 7.40-7.24 (m, 3H), 7.22-7.17 (m, 3 H),7.12(td,J=7.6,1.0Hz,1H),6.84(d,J=7.8Hz,1H),4.72(dd,J=10.9,5.8Hz,1H),4.38(d dd,J=12.3,10.8,4.4Hz,1H),3.23(s,3H),2.77(d,J=9.7Hz,1H),2.67(dd,J=15.7,9.1Hz, 2H),2.53-2.39(m,1H),2.34-2.19(m,1H),2.12-1.97(m,1H),1.86(dd,J=14.6,4.4Hz,1H).

[0276] 13C NMR (100MHz, CDCl3) δ (ppm) 174.0, 172.2, 149.9, 143.2, 129.1, 128.8, 127.4, 126.3,126.0,124.6,122.8,108.2,67.3,57.2,45.6,40.6,38.2,33.0,26.4.

[0277] Chiral HPLC: Chiral IE columns, V 正己烷 / V 异丙醇 =80:20, flow rate 0.7mL / min, λ=254nm, t1=29.98min, t2=24.25min

[0278] High resolution: Calculated value: [M+H] + :358.1414, measured value:358.1414.

[0279] Optical rotation: [α] D 25 =-10.27 (c = 1.00 in CHCl3)

[0280] V-2 (minor diastereomer):

[0281] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.68 (dd, J=7.5, 1.2Hz, 1H), 7.44-7.27 (m, 3H), 7.20 (d, J=7.4Hz ,3H),7.14(td,J=7.6,1.0Hz,1H),6.87(d,J=7.8Hz,1H),4.71(td,J=11.7,4.0Hz,1H),4.63

[0282] -4.48(m,1H),3.25(s,3H),3.00-2.84(m,1H),2.72-2.43(m,2H),2.34-2.10(m,3H),1.95(dd,J=14.6,4.0Hz,1H).

[0283] 13 C NMR (100MHz, CDCl3) δ (ppm) 173.0,171.9,149.4,143.1,129.0,128.8,128.1,126 .38,126.3,126.1,125.4,122.7,108.4,67.9,58.2,44.1,40.4,38.4,34.3,26.6.

[0284] Chiral HPLC: Chiral IE columns, V 正己烷 / V异丙醇 =80:20, flow rate 0.7mL / min, λ=254nm, t1=33.03min, t2=28.51min

[0285] High resolution: Calculated value: [M+H] + :358.1414, measured value:358.1407.

[0286] Optical rotation: [α] D 25 =-2.13 (c = 1.00 in CHCl3)

[0287] Embodiment 23

[0288] Synthesis of Compound I-19

[0289] The difference between this embodiment and embodiment 4 is that the chiral ligand used is the compound with the structure shown in (XI) and the reaction solvent is DCM (dichloromethane).

[0290] Under argon protection, add substrate VII-1 (0.2mmol, 2.0eq.) and DCM (1mL) to a 10mL Shrek tube, and illuminate at room temperature for 3 hours under a 10W Kessil lamp at 370nm. Then, add Pd2(dba)3·CHCl3 (5% mol), chiral ligand L (12% mol), and DCM (1mL) to another 10mL Shrek tube under argon protection, and stir at room temperature for 20-30 minutes. Then, add the reaction solution (after illumination) in the first Shrek tube, substrate VI-4 (0.1mmol, 1.0eq.) and DCM (1mL) to the second Shrek tube, stir at room temperature, and react for 12 hours. After the reaction is completed, evaporate the solvent and use V 石油醚 / V 乙酸乙酯 =20:3 column chromatography gave the target product I-19 with a yield of 46% and an ee value (enantiomeric excess) of 80%, as determined by separating the pure product by chiral high performance liquid chromatography.

[0291] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.56 (d, J = 7.5Hz, 1H), 7.38-7.33 (m, 1H), 7.31 (s, 4H), 7.14 -7.12(m,1H),6.86(d,J=7.7Hz,1H),6.30(t,J=8.8Hz,1H),4.60(d,J=30.2Hz,2H),3.25(s,3H),2.99(s,4H).

[0292] 13C NMR (100MHz, CDCl3) δ (ppm) 172.4,171.4,143.2,142.2,141.6,133.5,129.4,1 28.6,128.1,127.3,126.2,125.3,122.8,108.4,70.1,62.9,37.3,34.0,26.5.

[0293] Chiral HPLC: Chiral AD column, V 正己烷 / V 异丙醇 =85:15, flow rate 1.0mL / min, λ=254nm, t1=31.69min, t2=17.14min

[0294] High resolution: Calculated value: [M+H] + :368.1048, measured value:368.1049.

[0295] Optical rotation: [α] D 25 =73.93 (c = 1.00 in CHCl3)

[0296] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and changes will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments.

Claims

1. A chiral spirocyclic indole compound, characterized in that: The chiral spirocyclic oxidized indole compound is a compound having a structure shown in formula (1), or an epoxide or hydrogenation product thereof: In formula (1), R 1 is methyl or benzyl; R 2 is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen; R 3 It is phenyl, substituted phenyl, naphthyl or phenyl(C1-C4)alkyl. Preferably, the substituent of the substituted phenyl is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen.

2. The chiral spirocyclic indole compound according to claim 1, wherein The chiral spirocyclic oxidized indole compound is at least one compound selected from the group consisting of compounds having structures represented by formula (I) to formula (V); In formula (I) to formula (V), R 1 Each is independently methyl or benzyl; R 2 is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen; R 4 It is at least one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen.

3. The chiral spirocyclic indole compound according to claim 2, wherein: R 2 is hydrogen, 1-methyl, 1-fluoro, 2-methyl, 2-methoxy, 3-methyl or 4-methyl; R 4 is hydrogen, 6-methoxy, 7-methyl, 7-chloro, 7-bromo, 7-fluoro or 6,7-dichloro.

4. The method for synthesizing the chiral spirocyclic oxidized indole compound according to any one of claims 1 to 3, characterized in that: The steps include: Step (a): Under a first inert gas protection condition and in the presence of a first solvent, a diazo compound having a structure represented by formula (VII) is subjected to light treatment to obtain an oxidized indole ketone; Step (b): under the protection of a second inert gas and in the presence of a second solvent, the oxidized indole ketone, the alkenyl oxirane having the structure of formula (VI), the chiral ligand and the metal catalyst are mixed to undergo a dipolar cyclization reaction to obtain a compound having the structure of formula (1); and, optionally, step (c) or step (d); Step (c): subjecting the compound having the structure represented by formula (1) to epoxidation reaction to obtain epoxide; Step (d): subjecting the compound having the structure represented by formula (1) to a hydrogenation reaction to obtain a hydrogenation product.

5. The synthesis method according to claim 4, wherein In step (a), the first inert gas is argon and / or nitrogen; The first solvent is dichloromethane and / or 1,2-dichloroethane.

6. The synthesis method according to claim 4, wherein In step (a), the light treatment uses visible light, the wavelength of the visible light is 350-400nm, the light intensity is 8-15W, the light temperature is 0-40°C, and the light time is 2-6h.

7. The synthesis method according to claim 4, wherein In step (b), under the protection of a second inert gas, the chiral ligand and the metal catalyst are first dissolved in a second solvent, stirred and mixed at 0 to 40° C. for 20 to 30 minutes, and then mixed with the oxidized indole ketone and the alkenyl oxirane having the structure of formula (VI).

8. The synthesis method according to claim 4, wherein In step (b), the second inert gas is argon and / or nitrogen; The metal catalyst is tris(dibenzylideneacetone)dipalladium chloroform adduct and / or tris(dibenzylideneacetone)dipalladium; The second solvent is selected from at least one of dichloromethane, acetonitrile, benzyl cyanide and 1,2-dichloroethane; The chiral ligand is selected from at least one of the compounds having structures represented by formula (VIII) to (XI); The molar ratio of the oxidized indole ketone, the alkenyl oxirane having the structure of formula (VI), the chiral ligand and the metal catalyst is 40-50:20-25:2-2.4:1; The conditions of the dipolar cyclization reaction include: temperature of 0 to 40° C. and time of 8 to 20 hours.

9. The synthesis method according to claim 4, wherein In step (c), the epoxidation reaction is carried out under a third inert gas protection condition in the presence of a third solvent and an epoxidation reagent; The third inert gas is argon and / or nitrogen; The third solvent is dichloromethane and / or 1,2-dichloroethane; The epoxidation reagent is m-chloroperbenzoic acid; The molar ratio of the compound having the structure shown in formula (1) to the epoxidation reagent is 2-5:1; The conditions of the epoxidation reaction include: temperature of 20-40° C. and time of 10-15 h.

10. The synthesis method according to claim 4, wherein The addition reaction is carried out under a fourth inert gas protection condition in the presence of hydrogen, a fourth solvent and a catalyst; The fourth inert gas is argon and / or nitrogen; The catalyst is palladium / carbon and / or palladium hydroxide; The fourth solvent is ethyl acetate and / or methanol; The molar ratio of the compound having the structure shown in formula (1) to the catalyst is 1-10:1; The conditions of the addition reaction include: temperature of 0 to 40° C. and time of 5 to 15 hours.

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