A chiral spirooxindole compound and its preparation method

Abstract

The present invention discloses a chiral spirooxindole compound and a diastereodivergent preparation method thereof. The chiral spirooxindole compound is an optically active compound having the structure shown in Formula I below, including its stereoisomers having the same chemical general formula: #imgabs0#In the formula: * represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1‑10 alkyl or aryl; Ar is an aromatic ring or a substituted aromatic ring; Ar' is an aromatic ring or a substituted aromatic ring; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are each independently selected from hydrogen, halogen, a C 1‑4 hydrocarbyl or hydrocarbyloxy group. The present invention applies a combined catalytic system of a chiral rhodium complex and a chiral N-heterocyclic carbene to catalyze a class of asymmetric [3+3] cycloaddition reactions as the key step, and synthesizes the chiral spirooxindole compound with high yield, high stereoselectivity and on a gram scale accurately and rapidly. The preparation method of the present invention is simple and has biomedical practicability and industrial application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of asymmetric organic synthesis, and particularly relates to a chiral spirooxindole compound and a diastereodivergent preparation method thereof. Background Art

[0002] Spirooxindole compounds widely exist in natural products and drug molecules, and have broad-spectrum biological activities. Their efficient construction is of great significance for drug research and development, and has attracted extensive attention from chemists and pharmacologists. In recent years, the method of asymmetric catalysis to synthesize chiral spirooxindole compounds with high stereoselectivity has gradually become a research hotspot among organic chemists.

[0003] Chirality is one of the essential properties of nature. There are a large number of chiral molecules in nature and living organisms. Many biological macromolecules that are important bases of life activities, such as proteins, polysaccharides, and nucleic acids, are basically chiral. The research on chirality plays an important role in life sciences, pharmaceuticals, and food science. There are significant differences in the pharmacology and toxicity of chiral drugs. For example, Thalidomine was widely used as a sedative in Europe. Many pregnant women who took this drug gave birth to deformed fetuses because only the R-isomer has a sedative effect while the S-isomer is teratogenic. Developing new, rapid, efficient, and sensitive chiral separation and analysis methods is of great significance for the stereoselective synthesis of enantiomers, the pharmacological research of chiral drugs, the purity analysis of enantiomers, environmental monitoring, and human healthy life. Therefore, developing new synthetic methodologies to obtain all stereoisomers of fragments with multiple chiral elements is a field with important scientific research value and high challenges.

[0004] The cooperative control strategy of dual catalytic systems has been proven to be a simple and effective solution. In recent years, chemists have successively developed various types of cooperative control strategies to efficiently achieve stereodivergent syntheses with diverse structural types, and precisely and controllably achieve the collective asymmetric synthesis of multiple diastereoisomers of multi-chiral center molecules under unified raw materials, synthetic routes, and reaction conditions, providing an important guarantee for the synthesis of multiple chiral isomers of natural products with important physiological activities and the study of structure-activity relationships.

[0005] The wide application of chiral spirooxindole compounds prompts us to search for an efficient synthesis method for different isomers of such compounds. However, there has been no report on the diastereodivergent synthesis of chiral spirooxindole-derived compounds. Therefore, there is an urgent need to develop a general strategy for the diastereodivergent synthesis of structurally diverse chiral spirooxindole compounds with high yield and high enantioselectivity in a precise and rapid manner starting from simple and readily available skeletons. Summary of the Invention

[0006] The object of the present invention is to provide a chiral spirooxindole compound and a diastereodivergent preparation method thereof, so as to solve the above problems existing in the prior art.

[0007] The chiral spirooxindole compound provided by the present invention is an optically active compound having the structure shown in Formula I below, including its stereoisomers having the same chemical general formula:

[0008]

[0009] In the formula: * represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1-10 alkyl or aryl; Ar is an aromatic ring or a substituted aromatic ring; Ar' is an aromatic ring or a substituted aromatic ring; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, halogen, C 1-4 hydrocarbyl or hydrocarbyloxy groups.

[0010] The diastereodivergent preparation method of the chiral spirooxindole compound of the present invention uses an α,β-unsaturated aldehyde 1 derived from oxindole and a 1,4-dihydro-1,4-epoxynaphthalene compound 2 as starting materials, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate as a metal catalyst, a chiral phosphine reagent as a ligand, and a chiral N-heterocyclic carbene as an organocatalyst. After an asymmetric [3+3] cycloaddition reaction assisted by a base, the target product I is obtained after separation and purification.

[0011] The synthesis route is as follows:

[0012]

[0013] In the above formula: * represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1-10 alkyl or aryl; Ar is an aromatic ring or a substituted aromatic ring; Ar' is an aromatic ring or a substituted aromatic ring; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, halogen, C 1-4 hydrocarbyl or hydrocarbyloxy groups.

[0014] Specifically, it includes the following steps:

[0015] Under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate metal catalyst and a chiral phosphine ligand are mixed and pre-stirred in an organic solvent for 1 hour. Subsequently, under nitrogen protection, a chiral N-heterocyclic carbene catalyst, an indole-derived α,β-unsaturated aldehyde 1, a 1,4-dihydro-1,4-epoxynaphthalene compound 2, a base, and an organic solvent are added to the mixed system, and the reaction is carried out at 10 - 60 °C for 4 - 72 hours. The end point of the reaction is determined by thin-layer chromatography spotting; then the reaction system is diluted with ethyl acetate and extracted with water, and then the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure, and finally, the asymmetric spirooxindole product I is obtained by column chromatography separation.

[0016] In the preparation process of the present invention:

[0017] The base is potassium phosphate, potassium monohydrogen phosphate, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethylethylenediamine or N-methylmorpholine.

[0018] The organic solvent is 1,4-dioxane, dichloromethane, dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, toluene, ethylbenzene, fluorobenzene, chlorobenzene, bromobenzene, xylene or trimethylbenzene.

[0019] The chiral phosphine ligand is selected from

[0020] wherein: R 7 , R 8 , R 9 , R 10 , R 11 are each independently selected from hydrogen, halogen, or the following substituted or unsubstituted groups: C 1-10 alkyl, C 3-10 cycloalkyl, 2-furyl or C 6-20 aryl.

[0021] The chiral N-heterocyclic carbene catalyst is selected from:

[0022]

[0023] wherein: R 12 , R 13 , R 14 are each independently selected from hydrogen, halogen, or the following substituted or unsubstituted groups: C 1-10 alkyl, C 3-10 cycloalkyl, 2-furyl or C 6-20 aryl.

[0024] During the preparation process of the present invention, the (R,R,R), (R,S,S), (S,R,R), and (S,S,S) configurations of the target product I can be selectively obtained by changing the configurations of the chiral phosphine ligand and the chiral N-heterocyclic carbene.

[0025] Among them:

[0026] The molar ratio of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate to the α,β-unsaturated aldehyde 1 derived from oxindole is 0.025:1 - 1:1; the molar ratio of the chiral phosphine ligand to the α,β-unsaturated aldehyde 1 derived from oxindole is 0.025:1 - 1:1; the molar ratio of the chiral N-heterocyclic carbene catalyst to the α,β-unsaturated aldehyde 1 derived from oxindole is 0.025:1 - 1:1; the molar equivalent ratio of the α,β-unsaturated aldehyde 1 derived from oxindole to the 1,4-dihydro-1,4-epoxynaphthalene compound 2 is 1:1 - 1:5; the molar ratio of the α,β-unsaturated aldehyde 1 derived from oxindole to the base is 1:0.1 - 1:5.

[0027] Furthermore, the molar ratio of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate to the chiral phosphine ligand is 1:1 - 1:4.

[0028] The present invention provides a method for synthesizing chiral spirooxindoles through the key steps of an asymmetric reaction. The present invention uses the α,β-unsaturated aldehyde 1 derived from oxindole and the 1,4-dihydro-1,4-epoxynaphthalene compound 2 as starting materials, bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate as a metal catalyst, a chiral phosphine reagent as a ligand, and a chiral N-heterocyclic carbene as an organocatalyst. Through an asymmetric reaction assisted by a base, the chiral spirooxindole compound I is precisely and rapidly synthesized in high yield, high stereoselectivity, and gram-scale. The present invention has not only successfully developed a method for synthesizing chiral spirooxindole compounds, and it is easy to obtain chiral spirooxindole compounds with high yield and high optical purity. At the same time, this compound also has biological activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 are the test results of the activities of different chiral spirooxindole compounds against Hela cells.

[0030] Figure 2 are the imaging test results of the activities of different chiral spirooxindole compounds against Hela cells. DETAILED DESCRIPTION OF THE INVENTION

[0031] Example 1: Preparation of the chiral spirooxindole compound (R,R,R)-3aa

[0032]

[0033] Under an atmosphere of nitrogen at 25 °C, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, the chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1a (18.7 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction endpoint was determined by thin layer chromatography spotting. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,R,R)-3aa (31.8 mg, 96% yield, 95:5 d.r., >99% e.e.), as a white solid.

[0034] 1 H NMR (400 MHz, CDCl3) δ 7.74–7.67 (m, 1H), 7.38 (td, J = 7.5, 1.7 Hz, 1H), 7.32 (td, J = 7.6, 1.4 Hz, 1H), 7.28–7.23 (m, 1H), 7.21–7.11 (m, 2H), 7.05 (dd, J = 7.4, 1.3 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.42 (dd, J = 9.6, 3.0 Hz, 1H), 6.31 (d, J = 13.9 Hz, 1H), 5.05 (dd, J = 9.6, 2.1 Hz, 1H), 3.28 (s, 3H), 3.15 (dt, J = 14.0, 2.5 Hz, 1H), 3.06 (d, J = 17.5 Hz, 1H), 2.84 (d, J = 17.5 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 177.47, 169.13, 143.67, 133.51, 131.73, 130.93, 130.09, 129.56, 128.59, 128.15, 126.50, 123.84, 123.70, 122.87, 121.81, 108.68, 75.50, 47.30, 44.08, 37.36, 26.59. HRMS (ESI) m / z (M+H) + : calculated for (C 21 H 18 NO3) + : 332.1281, found: 332.1288; [α] 20 D = -90.3 (c = 0.59, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK OD-H, hexane / i-PrOH = 80 / 20, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 20.73 min, t R (major) = 22.66 min.

[0035] Example 2: Preparation of chiral spirooxindole compound (R,S,S)-3aa

[0036]

[0037] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (R)-1-[(Sp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 1.0 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1a (18.7 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 1.0 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction endpoint was determined by thin-layer chromatography spotting. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,S,S)-3aa (31.8 mg, 96% yield, 86:14 d.r., >99% e.e.), which was a white solid.

[0038] 1 H NMR (500 MHz, CDCl3) δ 7.71 (dd, J = 7.6, 1.3 Hz, 1H), 7.39 (td, J = 7.8, 1.2 Hz, 1H), 7.34 (td, J = 7.6, 1.3 Hz, 1H), 7.31–7.24 (m, 2H), 7.12 (td, J = 7.5, 1.0 Hz, 1H), 7.05 (dd, J = 7.4, 1.3 Hz, 1H), 7.01–6.96 (m, 1H), 6.35 (dd, J = 9.6, 3.0 Hz, 1H), 5.87 (d, J = 14.7 Hz, 1H), 5.13 (dd, J = 9.7, 2.1 Hz, 1H), 3.34 (m, 1H) 3.33 (s, 3H), 3.17 (d, J = 17.8 Hz, 1H), 2.71 (d, J = 17.8 Hz, 1H). 1313C NMR(126MHz,CDCl3)δ176.64,168.39,143.27,133.27,131.71,130.49,129.51,129.42,128.60,128.32,126.45,125.08,123.48,123.14,122.94,109.07,77.13,48.44,42.91,37.10,26.82.HRMS(ESI)m / z(M+H) + : calculated for (C 21 H 18 NO3) + : 332.1281, found: 332.1289;[α] 20 D = -363.1 (c = 0.60, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK OD-H, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 10.61 min, t R (major) = 14.13 min.

[0039] Example 3: Preparation of chiral spirooxindole compound (S,R,R)-3aa

[0040]

[0041] Under an atmosphere of nitrogen at 25 °C, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, the chiral N-heterocyclic carbene catalyst ent-NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1a (18.7 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system and reacted at 15 °C for 10 hours. The reaction endpoint was determined by thin layer chromatography. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (S,R,R)-3aa (29.8 mg, 90% yield, 88:12 d.r., >99% e.e.), which was a white solid.

[0042] 1 H NMR (500 MHz, CDCl3) δ 7.71 (dd, J = 7.6, 1.3 Hz, 1H), 7.39 (td, J = 7.8, 1.2 Hz, 1H), 7.34 (td, J = 7.6, 1.3 Hz, 1H), 7.31–7.24 (m, 2H), 7.12 (td, J = 7.5, 1.0 Hz, 1H), 7.05 (dd, J = 7.4, 1.3 Hz, 1H), 7.01–6.96 (m, 1H), 6.35 (dd, J = 9.6, 3.0 Hz, 1H), 5.87 (d, J = 14.7 Hz, 1H), 5.13 (dd, J = 9.7, 2.1 Hz, 1H), 3.34 (m, 1H) 3.33 (s, 3H), 3.17 (d, J = 17.8 Hz, 1H), 2.71 (d, J = 17.8 Hz, 1H). 1313C NMR(126MHz,CDCl3)δ176.64,168.39,143.27,133.27,131.71,130.49,129.51,129.42,128.60,128.32,126.45,125.08,123.48,123.14,122.94,109.07,77.13,48.44,42.91,37.10,26.82.HRMS(ESI)m / z(M+H) + :calculated for(C 21 H 18 NO3) + :332.1281,found:332.1284;[α] 20 D =313.6(c=0.39,CHCl3);The product was analyzed by HPLC to determine the enantiomeric excess:>99%e.e.(CHIRALPAK OD-H,hexane / i-PrOH=70 / 30,flow rate:1.0mL / min,T=30℃,254nm),t R (major)=10.46min,t R (minor)=14.51min.

[0043] Example 4: Preparation of chiral spirooxindole compound (S,S,S)-3aa

[0044]

[0045] Under an atmosphere of nitrogen at 25 °C, bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (R)-1-[(Sp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, the chiral N-heterocyclic carbene catalyst ent-NHC (4.2 mg, 0.001 mmol, 10 mol%), an indole-derived α,β-unsaturated aldehyde 1a (18.7 mg, 0.1 mmol, 1.0 equiv), a 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The end point of the reaction was determined by thin layer chromatography. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (S,R,R)-3aa (31.8 mg, 96% yield, 95:5 d.r., >99% e.e.), which was a white solid.

[0046] 1 H NMR (400 MHz, CDCl3) δ 7.74–7.67 (m, 1H), 7.38 (td, J = 7.5, 1.7 Hz, 1H), 7.32 (td, J = 7.6, 1.4 Hz, 1H), 7.28–7.23 (m, 1H), 7.21–7.11 (m, 2H), 7.05 (dd, J = 7.4, 1.3 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.42 (dd, J = 9.6, 3.0 Hz, 1H), 6.31 (d, J = 13.9 Hz, 1H), 5.05 (dd, J = 9.6, 2.1 Hz, 1H), 3.28 (s, 3H), 3.15 (dt, J = 14.0, 2.5 Hz, 1H), 3.06 (d, J = 17.5 Hz, 1H), 2.84 (d, J = 17.5 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 177.47, 169.13, 143.67, 133.51, 131.73, 130.93, 130.09, 129.56, 128.59, 128.15, 126.50, 123.84, 123.70, 122.87, 121.81, 108.68, 75.50, 47.30, 44.08, 37.36, 26.59. HRMS (ESI) m / z (M+H) + : calculated for (C 21 H 18 NO3) + : 332.1281, found: 332.1287; [α] 20 D = 41.6 (c = 0.39, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK OD-H, hexane / i-PrOH = 80 / 20, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (major) = 20.22 min, t R (minor) = 23.09 min.

[0047] Example 5: Preparation of chiral spirooxindole compound (R,R,R)-3ba

[0048]

[0049] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%), (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 1.0 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indole-derived α,β-unsaturated aldehyde 1b (20.5 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 1.0 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. Thin layer chromatography was used to determine the end point of the reaction. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spiroindole product (R,R,R)-3ba (24.8 mg, 71% yield; 93:7 d.r., 99% e.e.), which is a colorless liquid.

[0050] 1 H NMR (400 MHz, CDCl3) δ 7.70 (dtd, J = 8.1, 1.3, 0.6 Hz, 1H), 7.33 (td, J = 7.6, 1.4 Hz, 1H), 7.29–7.23 (m, 1H), 7.12 (dd, J = 8.2, 5.1 Hz, 1H), 7.06 (dd, J = 7.4, 1.3 Hz, 1H), 6.82 (ddd, J = 9.3, 8.2, 2.3 Hz, 1H), 6.69 (dd, J = 8.6, 2.3 Hz, 1H), 6.44 (dd, J = 9.6, 3.0 Hz, 1H), 6.28 (d, J = 13.9 Hz, 1H), 5.04 (ddd, J = 9.7, 2.1, 0.6 Hz, 1H), 3.26 (s, 3H), 3.12 (ddd, J = 13.9, 3.0, 2.1 Hz, 1H), 3.06 (d, J = 17.5 Hz, 1H), 2.82 (d, J = 17.5 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 177.76, 168.86, 163.77 (d, J = 247.4 Hz), 145.25 (d, J = 11.6 Hz), 133.41, 131.65, 131.17, 128.69, 128.22, 126.57, 125.40 (d, J = 3.0 Hz), 124.14 (d, J = 9.9 Hz), 123.73, 121.43, 109.99 (d, J = 22.7 Hz), 97.66 (d, J = 27.6 Hz), 75.44, 47.05, 44.17, 37.46, 26.75. 19 19F NMR (376 MHz, CDCl3) δ -109.72. HRMS (ESI) m / z (M + H) + : calculated for (C 21 H 17 FNO3) + : 350.1187, found: 350.1186; [α] 20 D = -74.5 (c = 0.36, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: 99% e.e. (CHIRALPAK IB, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 10.51 min, t R (major) = 12.96 min.

[0051] Example 6: Preparation of chiral spirooxindole compound (R,S,S)-3ba

[0052]

[0053] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (R)-1-[(Sp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 1.0 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour; subsequently, under nitrogen protection, the chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1b (20.5 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 1.0 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction end point was determined by thin layer chromatography spotting; subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,S,S)-3ba (22.7 mg, 65% yield, 80:20 d.r., 98% e.e.), which was a colorless liquid.

[0054] 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.6 Hz, 1H), 7.34 (td, J = 7.6, 1.4 Hz, 1H), 7.31–7.19 (m, 2H), 7.06 (dd, J = 7.4, 1.4 Hz, 1H), 6.81 (ddd, J = 9.2, 8.2, 2.4 Hz, 1H), 6.73 (dd, J = 8.6, 2.4 Hz, 1H), 6.38 (dd, J = 9.7, 3.0 Hz, 1H), 5.82 (d, J = 14.7 Hz, 1H), 5.11 (dd, J = 9.6, 2.1 Hz, 1H), 3.32 (m, 1H) 3.31 (s, 3H), 3.17 (d, J = 17.7 Hz, 1H), 2.69 (d, J = 17.9 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 177.04, 168.12, 163.77 (d, J = 248.0 Hz), 144.99 (d, J = 11.1 Hz), 133.14, 131.65, 130.74, 128.74, 128.43, 126.55, 126.27 (d, J = 9.7 Hz), 124.76, 123.18, 122.64, 109.66 (d, J = 22.5 Hz), 98.09 (d, J = 27.6 Hz), 77.15, 48.22, 43.01, 37.23, 26.99. 19 19F NMR (376 MHz, CDCl3) δ -109.69. HRMS (ESI) m / z (M+H) + : calculated for (C 21 H 17 FNO3) + : 350.1187, found: 332.1287; [α] 20 D = -243.7 (c = 0.21, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: 98% e.e. (CHIRALPAK IB, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 11.64 min, t R (major) = 15.13 min.

[0055] Example 7: Preparation of chiral spirooxindole compound (S,R,R)-3ba

[0056]

[0057] Under an atmosphere of nitrogen at 25 °C, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour; then, under nitrogen protection, the chiral N-heterocyclic carbene catalyst ent-NHC (4.2 mg, 0.001 mmol, 10 mol%), an indole-derived α,β-unsaturated aldehyde 1b (20.5 mg, 0.1 mmol, 1.0 equiv), a 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The end point of the reaction was determined by thin-layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (S,R,R)-3ba (22.7 mg, 65% yield, 85:15 d.r., >99% e.e.), which was a colorless liquid.

[0058] 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.6 Hz, 1H), 7.34 (td, J = 7.6, 1.4 Hz, 1H), 7.31–7.19 (m, 2H), 7.06 (dd, J = 7.4, 1.4 Hz, 1H), 6.81 (ddd, J = 9.2, 8.2, 2.4 Hz, 1H), 6.73 (dd, J = 8.6, 2.4 Hz, 1H), 6.38 (dd, J = 9.7, 3.0 Hz, 1H), 5.82 (d, J = 14.7 Hz, 1H), 5.11 (dd, J = 9.6, 2.1 Hz, 1H), 3.32 (m, 1H) 3.31 (s, 3H), 3.17 (d, J = 17.7 Hz, 1H), 2.69 (d, J = 17.9 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 177.04, 168.12, 163.77 (d, J = 248.0 Hz), 144.99 (d, J = 11.1 Hz), 133.14, 131.65, 130.74, 128.74, 128.43, 126.55, 126.27 (d, J = 9.7 Hz), 124.76, 123.18, 122.64, 109.66 (d, J = 22.5 Hz), 98.09 (d, J = 27.6 Hz), 77.15, 48.22, 43.01, 37.23, 26.99. 19 19F NMR (376 MHz, CDCl3) δ -109.69. HRMS (ESI) m / z (M + H) + : calculated for (C 21 H 17 FNO3) + : 350.1187, found: 332.1285; [α] 20 D = 285.5 (c = 0.24, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IB, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (major) = 10.40 min, t R (minor) = 15.44 min.

[0059] Example 8: Preparation of chiral spirooxindole compound (S,S,S)-3ba

[0060]

[0061] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (R)-1-[(Sp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, the chiral N-heterocyclic carbene catalyst ent-NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1b (20.5 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction end point was determined by thin-layer chromatography spotting. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (S,S,S)-3ba (26.9 mg, 77% yield, 95:5 d.r., >99% e.e.), which was a colorless liquid.

[0062] 1 H NMR (400 MHz, CDCl3) δ 7.70 (dtd, J = 8.1, 1.3, 0.6 Hz, 1H), 7.33 (td, J = 7.6, 1.4 Hz, 1H), 7.29–7.23 (m, 1H), 7.12 (dd, J = 8.2, 5.1 Hz, 1H), 7.06 (dd, J = 7.4, 1.3 Hz, 1H), 6.82 (ddd, J = 9.3, 8.2, 2.3 Hz, 1H), 6.69 (dd, J = 8.6, 2.3 Hz, 1H), 6.44 (dd, J = 9.6, 3.0 Hz, 1H), 6.28 (d, J = 13.9 Hz, 1H), 5.04 (ddd, J = 9.7, 2.1, 0.6 Hz, 1H), 3.26 (s, 3H), 3.12 (ddd, J = 13.9, 3.0, 2.1 Hz, 1H), 3.06 (d, J = 17.5 Hz, 1H), 2.82 (d, J = 17.5 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 177.76, 168.86, 163.77 (d, J = 247.4 Hz), 145.25 (d, J = 11.6 Hz), 133.41, 131.65, 131.17, 128.69, 128.22, 126.57, 125.40 (d, J = 3.0 Hz), 124.14 (d, J = 9.9 Hz), 123.73, 121.43, 109.99 (d, J = 22.7 Hz), 97.66 (d, J = 27.6 Hz), 75.44, 47.05, 44.17, 37.46, 26.75. 19 19F NMR (376 MHz, CDCl3) δ -109.72. HRMS (ESI) m / z (M+H) + : calculated for (C 21 H 17 FNO3) + : 350.1187, found: 332.1286; [α] 20 D = 72.2 (c = 0.43, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IB, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (major) = 11.01 min, t R (minor) = 13.79 min.

[0063] Example 9: Preparation of chiral spirooxindole compound (R,R,R)-3ab

[0064]

[0065] Under an atmosphere of nitrogen at 25 °C, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, the chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1a (18.7 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2b (18.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system and reacted at 15 °C for 10 hours. The reaction end point was determined by thin layer chromatography (TLC) spotting. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,R,R)-3ab (29.8 mg, 83% yield, 94:6 d.r., >99% e.e.), which was a colorless liquid.

[0066] 1 H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.21–7.12 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.83 (s, 1H), 6.35 (dd, J = 9.7, 3.0 Hz, 1H), 6.26 (d, J = 13.9 Hz, 1H), 4.97 (d, J = 9.6 Hz, 1H), 3.27 (s, 3H), 3.09 (m, 1H), 3.07 (d, J = 17.6 Hz, 1H), 2.83 (d, J = 17.5 Hz, 1H), 2.28 (s, 3H), 2.22 (s, 3H). 1313C NMR (101 MHz, CDCl3) δ 177.57, 169.38, 143.66, 137.17, 136.21, 130.85, 130.77, 130.33, 129.47, 129.39, 127.89, 125.00, 123.80, 122.85, 120.58, 108.60, 75.66, 47.36, 44.47, 37.33, 26.54, 19.81, 19.47. HRMS (ESI) m / z (M+H) + : calculated for (C 23 H 22 NO3) + : 360.1594, found: 360.1596; [α] 20 D = -72.5 (c = 0.50, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IB-N5, hexane / i-PrOH = 80 / 20, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 16.16 min, t R (major) = 18.77 min.

[0067] Example 10: Preparation of chiral spirooxindole compound (R,S,S)-3ab

[0068]

[0069] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%), (R)-1-[(Sp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 1.0 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indole-derived α,β-unsaturated aldehyde 1a (18.7 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2b (18.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 1.0 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction end point was determined by thin layer chromatography. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,S,S)-3ab (35.6 mg, 99% yield, 87:13 d.r., >99% e.e.), which was a colorless liquid.

[0070] 1 H NMR (500 MHz, CDCl3) δ 7.48 (s, 1H), 7.38 (td, J = 7.7, 1.2 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.12 (td, J = 7.5, 0.9 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.82 (s, 1H), 6.29 (dd, J = 9.6, 3.0 Hz, 1H), 5.83 (d, J = 14.6 Hz, 1H), 5.04 (dd, J = 9.6, 2.1 Hz, 1H), 3.32 (s, 3H), 3.29 (dt, J = 14.6, 2.7 Hz, 1H), 3.16 (d, J = 17.8 Hz, 1H), 2.71 (d, J = 17.8 Hz, 1H), 2.29 (s, 3H), 2.22 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 176.77, 168.69, 143.26, 137.21, 136.40, 130.58, 130.33, 129.58, 129.43, 129.34, 127.87, 125.07, 124.43, 123.43, 121.69, 109.01, 77.27, 48.48, 43.23, 37.05, 26.78, 19.83, 19.49. HRMS (ESI) m / z (M+H) + : calculated for (C 23 H 22 NO3) + : 360.1594, found: 360.1599; [α] 20 D = -327.5 (c = 0.44, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IA, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (major) = 10.11 min, t R (minor) = 13.54 min.

[0071] Example 11: Preparation of chiral spirooxindole compound (S,R,R)-3ab

[0072]

[0073] Under nitrogen atmosphere at 25 °C, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, chiral N-heterocyclic carbene catalyst ent-NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1a (18.7 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2b (18.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction end point was determined by thin layer chromatography spotting. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (S,R,R)-3ab (35.6 mg, 99% yield, 89:11 d.r., >99% e.e.), which was a colorless liquid.

[0074] 1 H NMR (500 MHz, CDCl3) δ 7.48 (s, 1H), 7.38 (td, J = 7.7, 1.2 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.12 (td, J = 7.5, 0.9 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.82 (s, 1H), 6.29 (dd, J = 9.6, 3.0 Hz, 1H), 5.83 (d, J = 14.6 Hz, 1H), 5.04 (dd, J = 9.6, 2.1 Hz, 1H), 3.32 (s, 3H), 3.29 (dt, J = 14.6, 2.7 Hz, 1H), 3.16 (d, J = 17.8 Hz, 1H), 2.71 (d, J = 17.8 Hz, 1H), 2.29 (s, 3H), 2.22 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 176.77, 168.69, 143.26, 137.21, 136.40, 130.58, 130.33, 129.58, 129.43, 129.34, 127.87, 125.07, 124.43, 123.43, 121.69, 109.01, 77.27, 48.48, 43.23, 37.05, 26.78, 19.83, 19.49. HRMS (ESI) m / z (M+H) + : calculated for (C 23 H 22 NO3) + : 360.1594, found: 360.1597; [α] 20 D = 318.2 (c = 0.41, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IA, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 9.96 min, t R (major) = 14.33 min.

[0075] Example 12: Preparation of Chiral Spiro Oxindole Compound (S,S,S)-3ab

[0076]

[0077] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (R)-1-[(Sp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, the chiral N-heterocyclic carbene catalyst ent-NHC (4.2 mg, 0.001 mmol, 10 mol%), the indole-derived α,β-unsaturated aldehyde 1a (18.7 mg, 0.1 mmol, 1.0 equiv), the 1,4-dihydro-1,4-epoxynaphthalene compound 2b (18.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction end point was determined by thin layer chromatography. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (S,S,S)-3ab (32.3 mg, 90% yield; >95:5 d.r., >99% e.e.), which was a colorless liquid.

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.21–7.12 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.83 (s, 1H), 6.35 (dd, J = 9.7, 3.0 Hz, 1H), 6.26 (d, J = 13.9 Hz, 1H), 4.97 (d, J = 9.6 Hz, 1H), 3.27 (s, 3H), 3.09 (m, 1H), 3.07 (d, J = 17.6 Hz, 1H), 2.83 (d, J = 17.5 Hz, 1H), 2.28 (s, 3H), 2.22 (s, 3H). 1313C NMR (101 MHz, CDCl3) δ 177.57, 169.38, 143.66, 137.17, 136.21, 130.85, 130.77, 130.33, 129.47, 129.39, 127.89, 125.00, 123.80, 122.85, 120.58, 108.60, 75.66, 47.36, 44.47, 37.33, 26.54, 19.81, 19.47. HRMS (ESI) m / z (M+H) + : calculated for (C 23 H 22 NO3) + : 360.1594, found: 360.1605; [α] 20 D = 65.3 (c = 0.25, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IB-N5, hexane / i-PrOH = 80 / 20, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (major) = 16.76 min, t R (minor) = 18.73 min.

[0079] Example 13: Preparation of chiral spirooxindole compound (R,R,R)-3ca

[0080]

[0081] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%), (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1c (17.3 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system and reacted at 15 °C for 10 hours. Thin layer chromatography was used to determine the end point of the reaction. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1, V / V) to obtain the asymmetric spiroindole product (R,R,R)-3ca (27.3 mg, 86% yield; 95:5 d.r., >99% e.e.), which was a white solid.

[0082] 1 H NMR (500 MHz, CDCl3) δ 9.23 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.37–7.25 (m, 3H), 7.15 (dd, J = 7.6, 1.4 Hz, 1H), 7.11 (td, J = 7.5, 1.0 Hz, 1H), 7.07 (dd, J = 7.5, 1.3 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.45 (dd, J = 9.7, 3.0 Hz, 1H), 6.31 (d, J = 14.0 Hz, 1H), 5.20 (dd, J = 9.6, 2.1 Hz, 1H), 3.16 (dt, J = 14.1, 2.6 Hz, 1H), 3.09 (d, J = 17.6 Hz, 1H), 2.89 (d, J = 17.5 Hz, 1H). 1313C NMR (126 MHz, CDCl3) δ 180.25, 169.13, 140.92, 133.58, 131.79, 130.98, 130.41, 129.60, 128.63, 128.20, 126.55, 123.83, 123.63, 123.09, 121.99, 110.69, 75.53, 47.87, 43.90, 37.29. HRMS (ESI) m / z (M+H) + : calculated for (C 20 H 16 NO3) + : 318.1125, found: 318.1123; [α] 20 D = -84.0 (c = 0.32, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK OD-H, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 6.49 min, t R (major) = 7.57 min.

[0083] Example 14: Preparation of chiral spirooxindole compound (R,S,S)-3ca

[0084]

[0085] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (R)-1-[(Sp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour; then under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indole-derived α,β-unsaturated aldehyde 1c (17.3 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction end point was determined by thin layer chromatography spotting; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1, V / V) to obtain the asymmetric spirooxindole product (R,S,S)-3ca (28.2 mg, 89% yield; 88:12 d.r., >99% e.e.), which was a white solid.

[0086] 1 H NMR (500 MHz, CDCl3) δ 9.36 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.38–7.25 (m, 4H), 7.10 (td, J = 7.6, 1.0 Hz, 1H), 7.08–7.04 (m, 2H), 6.38 (dd, J = 9.7, 3.0 Hz, 1H), 5.89 (d, J = 14.5 Hz, 1H), 5.32 (dd, J = 9.6, 2.1 Hz, 1H), 3.35 (dt, J = 14.6, 2.5 Hz, 1H), 3.18 (d, J = 17.7 Hz, 1H), 2.79 (d, J = 17.7 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 179.33, 168.50, 140.47, 133.12, 131.73, 130.56, 129.88, 129.56, 128.66, 128.41, 126.51, 125.28, 123.53, 123.25, 122.92, 111.13, 77.12, 49.02, 42.99, 36.96. HRMS (ESI) m / z (M+H) +: calculated for (C 20 H 16 NO3) + : 318.1125, found: 318.1129; [α] 20 D = -298.1 (c = 0.45, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK OD-H, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 6.68 min, t R (major) = 7.52 min.

[0087] Example 15: Preparation of Chiral Spirooxindole Compound (R,R,R)-3da

[0088]

[0089] Under 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 1.0 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour; then under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), oxindole-derived α,β-unsaturated aldehyde 1d (21.7 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 1.0 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. Thin-layer chromatography was used to monitor the reaction endpoint; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,R,R)-3da (35.4 mg, 98% yield; 88:12 d.r., 99% e.e.), which is a colorless liquid.

[0090] 1 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.6 Hz, 1H), 7.32 (td, J = 7.6, 1.3 Hz, 1H), 7.27–7.21 (m, 1H), 7.06 (dd, J = 7.6, 2.8 Hz, 2H), 6.62 (dd, J = 8.3, 2.3 Hz, 1H), 6.51 (d, J = 2.3 Hz, 1H), 6.42 (dd, J = 9.6, 3.0 Hz, 1H), 6.28 (d, J = 14.0 Hz, 1H), 5.07 (dd, J = 9.6, 2.1 Hz, 1H), 3.85 (s, 3H), 3.25 (s, 3H), 3.09 (dt, J = 14.0, 2.8 Hz, 1H), 3.03 (d, J = 17.8 Hz, 1H), 2.81 (d, J = 17.5 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 178.03, 169.25, 161.18, 144.96, 133.60, 131.79, 130.85, 128.54, 128.09, 126.46, 123.66, 123.60, 122.02, 121.80, 107.43, 96.74, 75.53, 55.76, 46.88, 44.16, 37.68, 26.57. HRMS (ESI) m / z (M+H) + : calculated for (C 22 H 20 NO4) + : 362.1387, found: 362.1391; [α] 20 D = -82.5 (c = 0.56, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: 99% e.e. (CHIRALPAK IB, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 12.92 min, t R (major) = 20.43 min.

[0091] Example 16: Preparation of chiral spirooxindole compound (R,S,S)-3da

[0092]

[0093] Under nitrogen atmosphere at 25 °C, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (R)-1-[(Sp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 1.0 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1d (21.7 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 1.0 mL of 1,4-dioxane were added to the mixed system and reacted at 15 °C for 10 hours. The reaction end point was determined by thin layer chromatography. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,S,S)-3da (18.8 mg, 52% yield; 85:15 d.r., 95% e.e.), which was a colorless liquid.

[0094] 1 H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 7.6 Hz, 1H), 7.33 (td, J = 7.6, 1.4 Hz, 1H), 7.30–7.23 (m, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.05 (dd, J = 7.5, 1.3 Hz, 1H), 6.60 (dd, J = 8.2, 2.4 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 6.36 (dd, J = 9.6, 3.0 Hz, 1H), 5.84 (d, J = 14.6 Hz, 1H), 5.13 (dd, J = 9.7, 2.1 Hz, 1H), 3.84 (s, 3H), 3.33–3.27 (m, 1H), 3.30 (s, 3H), 3.16 (d, J = 17.8 Hz, 1H), 2.68 (d, J = 17.8 Hz, 1H). 1313C NMR(126MHz,CDCl3)δ177.22,168.58,161.10,144.63,133.32,131.77,130.44,128.59,128.31,126.44,125.81,123.19,123.12,121.21,106.98,97.25,77.22,55.74,48.08,43.01,37.47,26.84.HRMS(ESI)m / z(M+H) + : calculated for (C 22 H 20 NO4) + : 362.1387, found: 3621397;[α] 20 D = -314.2 (c = 0.30, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: 95% e.e. (CHIRALPAK IB, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 14.465 min, t R (major) = 19.87 min.

[0095] Example 17: Preparation of Chiral Spiro Oxindole Compound (R,R,R)-3ac

[0096]

[0097] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 1.0 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, the chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1a (18.7 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2c (19.8 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 1.0 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction end point was determined by thin layer chromatography spotting. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,R,R)-3ac (27.8 mg, 74% yield; 93:7 d.r., 97% e.e.), which was a white solid.

[0098] 1 H NMR (400 MHz, CDCl3) δ 7.38 (td, J = 7.6, 1.5 Hz, 1H), 7.23–7.10 (m, 3H), 6.94 (d, J = 7.8 Hz, 1H), 6.54 (s, 1H), 6.27 (dd, J = 9.7, 3.0 Hz, 1H), 6.19 (d, J = 14.3 Hz, 1H), 5.98–5.93 (m, 2H), 4.94 (dd, J = 9.6, 2.1 Hz, 1H), 3.27 (s, 3H), 3.11–3.04 (m, 1H), 3.04 (d, J = 17.5 Hz, 1H), 2.83 (d, J = 17.5 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 177.51, 169.03, 147.91, 147.26, 143.65, 130.55, 130.15, 129.53, 128.04, 125.96, 123.82, 122.88, 119.96, 108.65, 107.13, 105.27, 101.39, 75.75, 47.30, 44.23, 37.29, 26.56. HRMS (ESI) m / z (M+H)+ : calculated for (C 22 H 18 NO5) + : 376.1179, found: 376.1185; [α] 20 D = -20.7 (c = 0.41, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: 97% e.e. (CHIRALPAK IB-N5, hexane / i-PrOH = 85 / 15, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 38.61 min, t R (major) = 44.20 min.

[0099] Example 18: Preparation of chiral spirooxindole compound (R,S,S)-3ac

[0100]

[0101] Under 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (R)-1-[(Sp)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 1.0 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour; then under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), oxindole-derived α,β-unsaturated aldehyde 1a (18.7 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2c (19.8 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 1.0 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. Thin layer chromatography was used to determine the end point of the reaction; then the reaction system was diluted with ethyl acetate and extracted with water, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,S,S)-3ac (37.2 mg, 99% yield; 90:10 d.r., >99% e.e.), which was a white solid.

[0102] 1 1H NMR (500 MHz, CDCl3) δ 7.38 (td, J = 7.8, 1.2 Hz, 1H), 7.29–7.24 (m, 1H), 7.21 (d, J = 1.0 Hz, 1H), 7.12 (td, J = 7.6, 1.0 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.53 (s, 1H), 6.20 (dd, J = 9.7, 3.0 Hz, 1H), 5.95 (dd, J = 8.6, 1.4 Hz, 2H), 5.75 (d, J = 15.0 Hz, 1H), 5.02 (dd, J = 9.6, 2.2 Hz, 1H), 3.31 (s, 3H), 3.28–3.24 (m, 1H), 3.14 (d, J = 17.8 Hz, 1H), 2.69 (d, J = 17.8 Hz, 1H). 13 13C NMR (126 MHz, CDCl3) δ 176.66, 168.33, 147.90, 147.36, 143.22, 130.11, 129.47, 129.46, 127.73, 125.90, 125.10, 123.45, 121.13, 109.06, 107.16, 104.78, 101.42, 77.34, 48.38, 43.03, 37.03, 26.80. HRMS (ESI) m / z (M+H) + : calculated for (C 22 H 18 NO5) + : 376.1179, found: 376.1185; [α] 20 D = -360.0 (c = 0.58, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IA, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 12.24 min, t R (major) = 18.48 min.

[0103] Example 19: Preparation of Chiral Spirooxindole Compound (R,R,R)-3ea

[0104]

[0105] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%), (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 1.0 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1e (20.1 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 1.0 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction endpoint was determined by thin-layer chromatography spotting. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,R,R)-3ea (27.3 mg, 79% yield, 91:9 d.r., >99% e.e.), which was a colorless liquid.

[0106] 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 1H), 7.33 (td, J = 7.6, 1.3 Hz, 1H), 7.30–7.22 (m, 1H), 7.20–7.14 (m, 1H), 7.05 (dd, J = 7.6, 1.3 Hz, 1H), 6.99 (d, J = 1.7 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.42 (dd, J = 9.6, 3.1 Hz, 1H), 6.30 (d, J = 13.9 Hz, 1H), 5.06 (dd, J = 9.6, 2.1 Hz, 1H), 3.26 (s, 3H), 3.13 (dt, J = 14.0, 2.5 Hz, 1H), 3.08 (d, J = 17.4 Hz, 1H), 2.82 (d, J = 17.5 Hz, 1H), 2.33 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 177.45, 169.34, 141.26, 133.59, 133.50, 131.76, 130.84, 130.21, 129.78, 128.56, 128.14, 126.48, 123.73, 123.67, 121.97, 108.43, 75.59, 47.33, 44.23, 37.41, 26.61, 21.26. HRMS (ESI) m / z (M+H) + : calculated for (C 22 H 20 NO3) + : 346.1438, found: 346.1440; [α] 20 D = -79.0 (c = 0.30, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IC, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (major) = 45.026 min, t R (minor) = 59.48 min.

[0107] Example 20: Preparation of chiral spirooxindole compound (R,R,R)-fa

[0108]

[0109] Under nitrogen atmosphere at 25 °C, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 1.0 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1f (20.1 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 1.0 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction end point was determined by thin layer chromatography spotting. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spiroindole product (R,R,R)-3ea (31.4 mg, 91% yield, 92:8 d.r., >99% e.e.), which was a colorless liquid.

[0110] 1 H NMR (400 MHz, CDCl3) δ 7.74–7.67 (m, 1H), 7.32 (td, J = 7.6, 1.4 Hz, 1H), 7.29–7.21 (m, 1H), 7.12–7.08 (m, 1H), 7.05 (dd, J = 7.5, 1.3 Hz, 1H), 7.04–6.97 (m, 2H), 6.42 (dd, J = 9.6, 3.0 Hz, 1H), 6.30 (d, J = 13.9 Hz, 1H), 5.07 (dd, J = 9.7, 2.2 Hz, 1H), 3.55 (s, 3H), 3.09 (dt, J = 14.0, 2.6 Hz, 1H), 3.03 (d, J = 17.5 Hz, 1H), 2.80 (d, J = 17.5 Hz, 1H), 2.64 (s, 3H). 13CNMR(101MHz,CDCl3)δ178.17,169.22,141.43,133.61,133.18,131.77,130.84,130.74,128.54,128.10,126.46,123.73,123.67,121.98,120.74,120.39,75.56,46.70,44.31,37.76,29.86,19.12.HRMS(ESI)m / z(M+H) + : calculated for (C 22 H 20 NO3) + : 346.1438, found: 346.1442;[α] 20 D = -87.2 (c=0.43, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IB, hexane / i-PrOH=70 / 30, flow rate: 1.0 mL / min, T=30℃, 254 nm), t R (major)=11.59 min, t R (minor)=14.01 min.

[0111] Example 21: Preparation of chiral spirooxindole compound (R,R,R)-ga

[0112]

[0113] Under the conditions of 25 °C and nitrogen atmosphere, bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 hour. Subsequently, under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1g (20.1 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system, and the reaction was carried out at 15 °C for 10 hours. The reaction end point was determined by thin layer chromatography spotting. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,R,R)-3ga (31.8 mg, 92% yield, 95:5 d.r., >99% e.e.), which was a white solid.

[0114] 1 H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 7.6, 1.4 Hz, 1H), 7.37 (td, J = 7.7, 1.5 Hz, 1H), 7.35–7.30 (m, 1H), 7.29–7.23 (m, 1H), 7.19 (dd, J = 7.4, 1.4 Hz, 1H), 7.13 (td, J = 7.5, 1.0 Hz, 1H), 7.06 (dd, J = 7.5, 1.3 Hz, 1H), 6.96 (dd, J = 7.9, 0.9 Hz, 1H), 6.43 (dd, J = 9.7, 3.0 Hz, 1H), 6.32 (d, J = 13.9 Hz, 1H), 5.05 (dd, J = 9.6, 2.1 Hz, 1H), 3.89 (dq, J = 14.5, 7.3 Hz, 1H), 3.75 (dq, J = 14.3, 7.1 Hz, 1H), 3.17–3.11 (m, 1H), 3.07 (d, J = 17.5 Hz, 1H), 2.84 (d, J = 17.5 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H). 1313C NMR(126MHz,CDCl3)δ177.01,169.21,142.73,133.51,131.71,130.89,130.27,129.49,128.56,128.12,126.48,123.68,123.59,123.06,121.67,108.77,75.46,47.08,44.12,37.21,35.03,12.95.HRMS(ESI)m / z(M+H) + : calculated for (C 22 H 20 NO3) + : 346.1438, found: 346.1446;[α] 20 D = -95.8 (c = 0.25, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IG, hexane / i-PrOH = 70 / 30, flow rate: 1.0 mL / min, T = 30 °C, 254 nm), t R (minor) = 39.23 min, t R (major) = 46.18 min.

[0115] Example 22: Preparation of chiral spirooxindole compound (R,R,R)-ha

[0116]

[0117] Under nitrogen atmosphere at 25 °C, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (2.3 mg, 0.005 mmol, 5 mol%) and (S)-1-[(Rp)-2-(diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (3.8 mg, 0.007 mmol, 7 mol%) and 2.5 mL of 1,4-dioxane were added to a dry 10 mL Schlenk reaction tube and stirred for 1 h. Subsequently, under nitrogen protection, chiral N-heterocyclic carbene catalyst NHC (4.2 mg, 0.001 mmol, 10 mol%), indoxyl-derived α,β-unsaturated aldehyde 1h (24.9 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene compound 2a (15.1 mg, 0.105 mmol, 1.05 equiv), potassium phosphate (21.2 mg, 0.1 mmol, 1.0 equiv) and 2.5 mL of 1,4-dioxane were added to the mixed system and reacted at 15 °C for 10 h. Thin layer chromatography was used to determine the end point of the reaction. Subsequently, the reaction system was diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain the asymmetric spirooxindole product (R,R,R)-3ha (31.1 mg, 77% yield, 93:7 d.r., >99% e.e.), as a white solid.

[0118] 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 1H), 7.62–7.51 (m, 2H), 7.44 (td, J = 6.2, 5.8, 3.1 Hz, 3H), 7.36–7.23 (m, 4H), 7.18 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 6.49 (dd, J = 9.7, 3.0 Hz, 1H), 6.34 (d, J = 13.9 Hz, 1H), 5.27 (dd, J = 9.6, 2.1 Hz, 1H), 3.23 (d, J = 17.6 Hz, 1H), 3.24–3.18 (m, 1H), 2.96 (d, J = 17.5 Hz, 1H). 13CNMR(126MHz,CDCl3)δ176.98,169.07,143.58,133.79,133.40,131.66,131.26,129.90,129.47,128.67,128.64,128.20,126.57,126.51,124.33,123.77,123.20,121.35,109.96,75.40,47.37,44.77,37.35.HRMS(ESI)m / z(M+H) + : calculated for (C 26 H 20 NO3) + : 394.1438, found: 394.1437;[α] 20 D = -53.7 (c=0.46, CHCl3); The product was analyzed by HPLC to determine the enantiomeric excess: >99% e.e. (CHIRALPAK IG, hexane / i-PrOH=70 / 30, flow rate: 1.0 mL / min, T=30℃, 254 nm), t R (major)=60.09 min, t R (minor)=65.28 min.

[0119] Example 23: Activity Test of Four Isomers of Chiral Spirooxindole Compounds 3aa, 3ba and 3ab against Hela Cells

[0120] HeLa cells were cultured in DMEM dishes containing 10% fetal bovine serum and 100 units / ml penicillin + 100 μg / ml streptomycin. Four stereoisomers of compounds 3aa, 3ba and 3ab were screened at a concentration of 5 μM to test for changes associated with chromosomal misalignment during the prometaphase and anaphase onset in HeLa cells. Each compound inhibited mitosis, and among them, (R,S,S)-3aa, (R,S,S)-3ba and (R,S,S)-3ab were the most effective.

[0121] Example 24: Imaging Test of Chiral Spirooxindole Compounds (R,S,S)-3aa, (R,S,S)-3ba and (R,S,S)-3ab against Hela Cells

[0122] For time-lapse imaging, HeLa cells were cultured in glass-bottom dishes (MatTek) and transfected with mCherry-H2B and GFP-Tubulin to visualize chromosomes and microtubules. Plasmids were purified using a purification kit (QIAGEN), and cells were transfected using Lipofectamine 3000 (Invitrogen). The cells were cultured in a CO2-free medium (Gibco) supplemented with 10% fetal bovine serum and 2 mM glutamine. A dimethyl sulfoxide solution of the corresponding 5 μM compound was added 1 hour before imaging, and the control group was added with dimethyl sulfoxide. During imaging, the dishes were placed in a sealed chamber at 37 °C. Live cell images were taken every 3 minutes using a DeltaVision microscope system and deconvolved, and the resulting images are shown below. It can be concluded from the images that the mitotic process of HeLa cells in the experimental group was significantly slower than that in the control group, that is, the chiral spirooxindole compounds (R,S,S)-3aa, (R,S,S)-3ba, and (R,S,S)-3ab all had a significant inhibitory effect on the mitotic process of HeLa cells.

Claims

1. A chiral spirooxindole compound, characterized in that Selected from optically active compounds having the structure shown below: ； ； 。 2. A diastereodivergent preparation method of the chiral spirooxindole compound according to claim 1, characterized in that: Using indole-derived α,β-unsaturated aldehyde 1 and 1,4-dihydro-1,4-epoxynaphthalene compound 2 as starting materials, bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate as a metal catalyst, a chiral phosphine reagent as a ligand, and a chiral N-heterocyclic carbene as an organocatalyst, through an asymmetric [3+3] cycloaddition reaction assisted by a base, and after separation and purification, the target product I is obtained; The synthetic route is shown as follows: ； In the above formula: * represents a chiral carbon atom; Ar is phenyl; Ar' is phenyl; substituents R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 As shown in the structure of the compound according to claim 1.

3. The preparation method according to claim 2, characterized in that Comprising the following steps: Under a nitrogen atmosphere, the bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate metal catalyst and the chiral phosphine ligand are mixed in an organic solvent, and then under nitrogen protection, the chiral N-heterocyclic carbene catalyst, indole-derived α,β-unsaturated aldehyde 1, 1,4-dihydro-1,4-epoxynaphthalene compound 2, a base, and an organic solvent are added to the mixed system, and the reaction is carried out at 10-60 °C for 4-72 hours, and the reaction end point is determined by thin-layer chromatography spotting; then the reaction system is diluted with ethyl acetate and extracted with water, and then the aqueous phase is extracted with ethyl acetate, the combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure, and finally the chiral spirooxindole compound I is obtained by column chromatography separation.

4. The preparation method according to claim 2 or 3, characterized in that: The chiral phosphine ligand is selected from or ; Wherein: R 7 , R 8 , R 9 , R 10 , R 11 are each independently selected from hydrogen, halogen, or the following substituted or unsubstituted groups: C 1-10 alkyl, C 3-10 cycloalkyl, 2-furyl or C 6-20 aryl.

5. The preparation method according to claim 2 or 3, characterized in that: The chiral N-heterocyclic carbene catalyst is selected from: ； Wherein: R 12 , R 13 , R 14 are each independently selected from hydrogen, halogen, or the following substituted or unsubstituted groups: C 1-10 alkyl, C 3-10 cycloalkyl, 2-furyl or C 6-20 aryl.

6. The preparation method according to claim 2 or 3, characterized in that: The base is potassium phosphate, potassium hydrogen phosphate, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethylethylenediamine or N-methylmorpholine.

7. The preparation method according to claim 2 or 3, characterized in that: The molar ratio of bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate to indole-derived α,β-unsaturated aldehyde 1 is 0.025:1 - 1:1; the molar ratio of the chiral phosphine ligand to indole-derived α,β-unsaturated aldehyde 1 is 0.025:1 - 1:1; the molar ratio of the chiral N-heterocyclic carbene catalyst to indole-derived α,β-unsaturated aldehyde 1 is 0.025:1 - 1:1; the molar equivalent ratio of indole-derived α,β-unsaturated aldehyde 1 to 1,4-dihydro-1,4-epoxynaphthalene compound 2 is 1:1 - 1:5; the molar ratio of indole-derived α,β-unsaturated aldehyde 1 to the base is 1:0.1 - 1:

5.

8. The preparation method according to claim 7, characterized in that: The molar ratio of bis(1,5-cyclooctadiene)-rhodium(I) trifluoromethanesulfonate to the chiral phosphine ligand is 1:1 - 1:

4.

9. The preparation method according to claim 3, characterized in that: The organic solvent is 1,4-dioxane, dichloromethane, dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, toluene, ethylbenzene, fluorobenzene, chlorobenzene, bromobenzene, xylene or trimethylbenzene.

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