Chiral spirocyclic pentane oxidized indole compound, synthetic method and application

Abstract

This invention relates to a method for preparing chiral spirocyclopentane-oxidized indole compounds in the field of organic synthesis. The general reaction formula is as follows: A class of spirocyclopentane-oxidized indole compounds are synthesized from spirolylcyclopropane-oxidized indole and methyl acrylate derivatives as substrates under the combined action of a palladium catalyst and ligands. This method features mild reaction conditions and simple operation, providing a simple preparation method for chiral spirocyclopentane-oxidized indole compounds. Furthermore, the chiral spirocyclopentane-oxidized indole provided by this invention is an important synthetic intermediate that can be applied to the preparation of complex propylene oxide and tertiary amine compounds.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, specifically to a chiral spirocyclopentane-oxidized indole compound, its synthesis method, and its application. Background Technology

[0002] Chiral spirocyclopentane-oxidized indole structural units are widely found in natural products and drug molecules with significant biological activity, such as Cyclopiamine B and Notoamide A with antiparasitic activity, MI-77301 with antitumor activity, compound E with antituberculosis activity, compound F with antidiabetic activity, as well as HoRSfiline with analgesic activity, and various molecules with antibacterial and anticytotoxic properties. Therefore, the efficient and highly enantioselective synthesis of this type of structure has important medicinal and synthetic chemistry value.

[0003]

[0004] Currently, the main methods for synthesizing chiral spirocyclopentane-oxidized indole compounds include: chiral organophosphorus-catalyzed 1,3-dipolar cycloaddition reactions, typically using α,α-disubstituted allyl esters as substrates (A Voituriez, N Pinto, MNeel, et al. An Organocatalytic [3+2] Cyclisation Strategy for the Highly Enantioselective Synthesis of Spirooxindoles. [J.]). Chem. Eur. J., 2010, 16, 12541 – 12544.); Organocatalytic tandem reactions, such as Michael–Michael or Michael–Mannich tandem reactions (QWan, L Chen, SW Li, et al. Enantioselective Synthesis of Multisubstituted Spirocyclopentane Oxindoles Enabled by Pd / Chiral Rh(III) Complex SynergisticCatalysis. [J]. Org. Lett., 2020, 22, 9539-9544.); or the [3+2] cycloaddition reaction of unsaturated alkenes with helicalylcyclopropane-oxidized indole as a substrate (B Tan, NR Candeias, CF Barbas. Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst. [J.]). Nat. Chem. .,2011, 3, 473 477.

[0005] However, most of the above methods rely on intermolecular C=C double bond reactions, have limited substrate applicability, require stringent reaction conditions, or necessitate multi-step reactions to achieve structural diversity. Therefore, developing a novel method that is mild, easy to operate, widely applicable, and efficient for constructing chiral spirocyclopentane-oxidized indole skeletons is of significant research and application value. Summary of the Invention

[0006] The present invention aims to provide a method for synthesizing chiral spirocyclopentane-oxidized indole compounds with mild reaction conditions, simple operation, and wide applicability, in order to solve the problems of substrate limitations and harsh reaction conditions in the prior art.

[0007] One objective of this invention is to provide a chiral spirocyclopentane-oxidized indole compound with the following structural formula: , Where R 1 It is 4-chloro, 4-bromo, 5-fluoro, 5-chloro, 5-bromo, 5-methyl, 5-methoxy, 5-trifluoromethyl, 5-trifluoromethoxy, 5-nitro, 6-fluoro, 6-chloro, 6-bromo, 6-methyl, 6-methoxy, 6-trifluoromethoxy, 7-fluoro, 7-chloro, 7-bromo, 7-methyl, 7-methoxy, 7-trifluoromethyl, 7-trifluoromethoxy, 5-bromo-7-methyl, 5,7-dimethyl, or R. 1 The benzene ring has no other substituents; R 2 It can be methyl, benzyl, phenyl, ethyl, or tert-butyl; R 3 It is 3-fluoro, 3-nitro, 4-chloro, 4-bromo, 4-methyl, 4-nitro, 5,6-dichloro, or R. 3 The benzene ring has no other substituents; R 4 It is methyl, ethyl or tert-butyl.

[0008] A second objective of this invention is to provide a method for synthesizing the above-mentioned compound, the reaction formula of which is shown below: , Spirolene-cyclopropane-oxidized indole (S1), methyl acrylate derivative (S2), palladium catalyst, ligand, and reaction solvent were sequentially added to a 5 mL reaction flask containing a stir bar, and stirred at room temperature for 24 hours under nitrogen protection. After the reaction was completed, chiral spirocyclopentane-oxidized indole compounds were obtained by silica gel column chromatography.

[0009] Furthermore, the palladium catalyst is selected from palladium acetate, di(acetylacetone)palladium, tetra(triphenylphosphine)palladium, bis(di-tert-butylphosphine)palladium, bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium, di(cyclohexylphosphine)palladium, neopentanoate, di-bis[(1,2,3)-1-phenyl-2-propene]dipalladium or allyl(1,3-bis(trimethylyl)-1H-imidazol-2(3H)-ylidene)palladium chloride; most preferably bis(di-tert-butylphosphine)palladium.

[0010] Furthermore, the ligands are all selected from ( R )-(+)-(6,6'-dimethoxybiphenyl-2,2'-yl)bis(diphenylphosphine), 1,2-bis((2 S, 5 S )-2,5-dimethylphosphine)benzene, ( R )-4-tert-butyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline, (4 S 5 S )-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxapentane, ( R )-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl, ( R )-(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diisopropylphosphine), bis(diphenylphosphine)butane, (2 S ,2 S ,3 S ,3 S )-3,3-di-tert-butyl-4,4-dimethoxy-2,2,3,3-tetrahydro-2,2-biphenyl[d][1,3]oxaphosphatane, ( R )-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, ( R )-(+)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane, bis[2-(diphenylphosphino)phenyl] ether, ( R )-(-)-1-[( S )-2-Diphenylphosphine, ferrocene, ethyl-di-tert-butylphosphine or (2 R )-1-[(4 S[-4,5-dihydro-4-phenylmethyl-2-oxazolyl]-2-(diphenylphosphino)ferrocene; most preferably ( R )-(+)-5,5'-bis(diphenylphosphine)-4,4'-bis-1,3-benzodioxane.

[0011] Furthermore, the reaction solvent is selected from dichloromethane, tetrahydrofuran, ethyl acetate, chloroform, 1,1-dichloroethane, 1,4-dioxane, ethanol, etc. N,N -Dimethylformamide or acetonitrile. Ethyl acetate is preferred.

[0012] Furthermore, the molar ratio of the substances in the spiral-enylcyclopropane: methyl acrylate derivative: palladium catalyst: ligand is 1:1-5:0.005-0.025:0.005-0.025.

[0013] Furthermore, the molar ratio of helenecyclopropane to methyl acrylate derivative is 1:1.2.

[0014] The most preferred molar ratio of helenecyclopropane: methyl acrylate derivative: palladium catalyst: ligand is 1:1.2:0.015:0.020.

[0015] Furthermore, the reaction time is 12–36 h, preferably 24 h; the reaction temperature is 0 ℃–50 ℃, preferably 10–50 ℃, and most preferably 25 ℃; the reaction gas atmosphere is selected from argon or nitrogen, preferably argon.

[0016] This method offers a simple preparation method for chiral spirocyclopentane oxidizing indole compounds, with mild reaction conditions and simple operation.

[0017] A third objective of this invention is to provide the above-mentioned compounds as organic synthesis intermediates or pharmaceutical synthesis intermediates.

[0018] Furthermore, organic synthesis intermediates include complex tertiary amine compounds or propylene oxide precursors.

[0019] The method of this invention features mild reaction conditions and simple operation, providing a straightforward preparation method for chiral spirocyclopentane-oxidized indole compounds. Furthermore, the chiral spirocyclopentane-oxidized indole synthesized in this invention is an important synthetic intermediate that can be applied to the preparation of complex propylene oxides and tertiary amine compounds. Attached Figure Description

[0020] Figure 1 The compound P1 prepared in Example 1 1 HNMR, 13 C NMR spectrum; Figure 2 The compound P2 prepared in Example 2 1HNMR, 13 C NMR spectrum; Figure 3 The compound P5 prepared in Example 5 1 HNMR, 13 C NMR spectrum; Figure 4 The compound P10 prepared in Example 10 1 HNMR, 13 C NMR spectrum; Figure 5 The compound P12 prepared in Example 12 1 HNMR, 13 C NMR spectrum; Figure 6 For the compound P21 prepared in Example 1 1 HNMR, 13 C NMR spectrum; Figure 7 For the compound P22 prepared in Example 2 1 HNMR, 13 C NMR spectrum; Figure 8 The HPLC spectrum of compound P1 prepared in Example 1; Figure 9 The HPLC spectrum of compound P2 prepared in Example 2; Figure 10 This is a single crystal data graph of product P13. Detailed Implementation

[0021] The following detailed description illustrates the specific implementation method: Using S1-1 and S2-1 as template substrates, the optimal asymmetric reaction system was determined by screening for chiral ligands, palladium catalysts, and reaction solvents. 0.2 mmol of 1'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-1, 0.24 mmol of 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1, 0.03 mmol of palladium catalyst, and 0.04 mmol of chiral ligand L were sequentially added to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and 2.0 mL of solvent was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. The screening results are as follows: This experiment prioritizes reactions with good enantioselectivity, followed by yield. Based on comprehensive analysis, the preferred reaction solvent is ethyl acetate, and the preferred palladium catalyst is Pd(ethyl acetate). tBu3P)2, the preferred ligand is ( R When )-(+)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane is used, the following examples are all based on the above preferred embodiments.

[0022]

[0023]

[0024] Example 1

[0025] 1'-Methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-1 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.24 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol) and ( R 0.04 mmol of 5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane was added sequentially to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and then 2.0 mL of ultra-dry ethyl acetate was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was complete, a white solid was obtained by silica gel column chromatography. d.r. = 3:2:2, 39 mg, total yield = 91%).

[0026] The NMR data for the target compound P1 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.87 - 7.80 (m, 2H), 7.80 - 7.75 (m,1H), 7.75 - 7.68 (m, 2H), 7.31 - 7.26 (m, 1H), 7.14 (td, J = 7.5, 1.0 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.23 - 6.05 (m, 1H), 5.50 - 5.39 (m, 1H), 5.16 (dt, J =8.3, 1.6 Hz, 1H), 5.12 (d, J= 1.7 Hz, 1H), 3.71 (s, 3H), 3.53 (s, 1H), 3.17(s, 3H), 2.58 - 2.43 (m, 2H), 2.16 (dd, J = 12.8, 6.2 Hz, 1H). 13 C NMR(101 MHz, CDCl3) δ 181.2, 172.8, 168.6, 143.2, 136.5, 135.7,134.2, 131.7, 128.1, 123.4, 123.4, 123.1, 117.6, 108.0, 72.7, 53.1, 52.1,51.9, 43.8, 42.7, 26.6. HRMS(ESI, Q-TOF) m / z: [M+Na] + calcd for C 25 H 22 N2O5Na, 453.1426; found, 453.1429. Chiral HPLC analysis:Chiralcel AD-H (Hexane / i -PrOH = 85 / 15, flow rate1.5 mL / min, λ = 254 nm, t (1S,2R,4R) = 12.9 min (major), t (1R,2S,4S) = 19.2 min(minor)). Example 2

[0027] 1'-benzyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-2 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.24 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol) and ( R 0.04 mmol of 5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane was added sequentially to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and then 2.0 mL of ultra-dry ethyl acetate was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was complete, a white solid was obtained by silica gel column chromatography. d.r.= 2:1:1, 35 mg, total yield = 69%).

[0028] The NMR data for the target compound P2 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.98 (d, J = 6.6 Hz, 1H), 7.88 - 7.80 (m, 2H), 7.77 - 7.71 (m, 2H), 7.33 - 7.24 (m, 5H), 7.19 - 7.08 (m, 1H), 6.69 (d, J = 7.5Hz, 1H), 5.96 - 5.82 (m, 1H), 5.17 - 5.09 (m, 1H), 5.02 - 4.93 (m, 2H), 4.78(d, J = 15.8 Hz, 1H), 4.75 - 4.66 (m, 1H), 3.89 (s, 3H), 3.78 (d, J = 15.4 Hz, 1H), 2.84 (d, J = 15.4 Hz, 1H), 2.71 (t, J = 12.3 Hz, 1H), 2.31 (dd, J = 12.8, 6.8Hz, 1H). 13 C NMR (101 MHz, CDCl3) d 181.4, 171.3, 168.9, 142.7, 136.1, 135.1, 134.4, 132.7, 131.5, 128.9, 128.2, 127.7, 127.4, 124.2, 123.4, 123.2, 117.8, 108.9, 72.0, 53.2, 52.2, 48.3, 43.7, 43.3, 42.3, 31.7, 22.8, 14.3. HRMS(ESI, Q-TOF) m / z: [M+Na] + calcd for C 31 H 26 N2O5Na, 529.1739; found, 529.1741. Chiral HPLC analysis:Chiralcel AD-H (Hexane / i-PrOH = 90 / 10, flow rate2.0 mL / min, λ = 254 nm, t (1S,2R,4R) = 24.8 min (major), t (1R,2S,4S-3b = 32.7 min(minor)). Example 3

[0029] 1'-phenyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-3 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.24 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol) and ( R 0.04 mmol of 5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane was added sequentially to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and then 2.0 mL of ultra-dry ethyl acetate was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was complete, a white solid was obtained by silica gel column chromatography. d.r. = 2:2:1, 39 mg, total yield = 80%).

[0030] The NMR data for the target compound P3 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.88 - 7.63 (m, 4H), 7.63 - 7.51 (m, 1H), 7.01- 6.89 (m, 1H), 6.78 - 6.66 (m, 1H), 6.26 - 5.94 (m, 1H), 5.47 - 5.32 (m,1H), 5.13 (d, J = 4.3 Hz, 1H), 5.10 (s, 1H), 3.69 (s, 2H), 3.47 (d, J = 15.0 Hz,1H), 3.13 (s, 3H), 2.54 - 2.33 (m, 2H), 2.18 - 2.07 (m, 1H). 13 C NMR (100 MHz, CDCl3) d 181.5, 171.9, 168.4, 159.8 (d, J= 239.0 Hz)139.2, 135.8, 135.2 (d, J = 8.0 Hz), 134.2, 131.8, 123.4, 116.4, 114.3 (d, J =23.0 Hz), 112.0 (d, J = 25.0 Hz), 108.2 (d, J = 9.0 Hz), 72.4, 52.5, 51.3, 48.0,44.6, 40.4, 26.4. HRMS (ESI) m / z : calculated for C 25 H 21 N₂O₅NaF [M+Na] + : 471.1332, found:471.1335. Chiral HPLC analysis(Chiralcel AD-H (Hexane / i-PrOH = 85 / 15, flow rate1.5 mL / min, λ = 254 nm, t( 1S,2R,4R )-3d = 14.5 min (major), t( 1R,2S,4S )-3d =17.9 min (minor)), [α]D25 = - 3.40 (c = 0.50, CH2Cl2) Example 4

[0031] 5'-fluoro-1'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-4 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.24 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol) and ( R 0.04 mmol of 5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane was added sequentially to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and then 2.0 mL of ultra-dry ethyl acetate was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was complete, a white solid was obtained by silica gel column chromatography. d.r. = 4:5:2, 39 mg, total yield = 87%).

[0032] The NMR data for the target compound P4 are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.88 - 7.76 (m, 4H), 7.74 - 7.67 (m, 2H), 7.23 (dd, J = 8.2, 2.3 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.19 - 6.03 (m,1H), 5.43 - 5.33 (m, 1H), 5.17 - 5.06 (m, 2H), 3.69 (s, 2H), 3.49 (d, J =15.0 Hz, 1H), 3.13 (s, 2H), 2.49 - 2.36 (m, 2H), 2.18 - 2.09 (m, 1H). 13 C NMR(100 MHz, CDCl3) δ 181.3, 171.9, 168.4, 141.9, 135.7, 135.1,134.2, 131.8, 128.6, 128.1, 124.4, 123.4, 116.5, 108.8, 72.4, 52.6, 51.1,48.0, 44.5, 40.3, 26.4. HRMS(ESI) m / z: calculated for C25H20N2O5Cl [MH]-: 463.1061, found:463.1059. Example 5

[0033] 5'-chloro-1'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-5 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.24 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol) and ( R 0.04 mmol of 5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane was added sequentially to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and then 2.0 mL of ultra-dry ethyl acetate was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was complete, a white solid was obtained by silica gel column chromatography. d.r. = 5:5:3, 42 mg, total yield = 91%).

[0034] The NMR data for the target compound P5 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.88 - 7.76 (m, 4H), 7.74 - 7.67 (m,2H), 7.23 (dd, J = 8.2, 2.3 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.19 - 6.03 (m,1H), 5.43 - 5.33 (m, 1H), 5.17 - 5.06 (m, 2H), 3.69 (s, 2H), 3.49 (d, J = 15.0Hz, 1H), 3.13 (s, 2H), 2.49 - 2.36 (m, 2H), 2.18 - 2.09 (m, 1H). 13 C NMR(101 MHz, CDCl3) δ 181.3, 171.9, 168.4, 141.9, 135.7, 135.1,134.2, 131.8, 128.6, 128.1, 124.4, 123.4, 116.5, 108.8, 72.4, 52.6, 51.1,48.0, 44.5, 40.3, 26.4. HRMS(ESI, Q-TOF) m / z: [M+H] + calcd for C 25 H 21 N2O5Cl, 463.1061; found, 463.1059. Chiral HPLC analysis:Chiralcel AD-H (Hexane / i -PrOH = 85 / 15, flow rate1.5 mL / min, λ = 254 nm, t (1S,2R,4R) = 12.6 min (major), t (1R,2S,4S) = 19.7 min (minor)). Example 6

[0035] 5'-bromo-1'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-6 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.12 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol), and (R)-(+)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane (0.04 mmol) were sequentially added to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and ultradry ethyl acetate (2.0 mL) was added to the Schlenk tube under argon countercurrent. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was completed, silica gel column chromatography yielded a white solid (dr = 11:11:3, 47 mg, overall yield = 92%).

[0036] The NMR data for the target compound P6 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.91 (s, 1H), 7.87 - 7.78 (m, 2H), 7.75 - 7.67(m, 2H), 7.39 (d, J = 7.9 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.18 - 6.02 (m, 1H), 5.45 - 5.32 (m, 1H), 5.20 - 5.04 (m, 2H), 3.70 (s, 3H), 3.49 (d, J = 15.0 Hz,1H), 3.13 (s, 3H), 2.51 - 2.38 (m, 2H), 2.14 (dd, J = 12.9, 6.2 Hz, 1H). 13 C NMR (100 MHz, CDCl3) d 181.2, 171.9, 168.4, 142.4, 135.7, 135.5, 134.2, 131.8, 131.1, 127.1, 123.4, 116.5, 115.9, 109.3, 72.4, 52.6, 51.1, 48.0, 44.5, 40.3, 26.4. HRMS (ESI) m / z : calculated for C 25 H 21N₂O₅NaBr [M+Na] + : 531.0532, found:531.0534. HPLC (Chiralcel AD-H (Hexane / i-PrOH = 85 / 15, flow rate 1.5 mL / min, λ =254 nm, t( 1S,2R,4R )-3f = 12.9 min (major), t( 1R,2S,4S -3f = 21.3 min (minor) Example 7

[0037] 5'-methoxy-1'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-7 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.12 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol) and ( R 0.04 mmol of 5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane was added sequentially to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and ultradry ethyl acetate (2.0 mL) was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was completed, silica gel column chromatography yielded a white solid (dr = 3:5:3, 36 mg, overall yield = 78%).

[0038] The NMR data for the target compound P7 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.93 - 7.75 (m, 2H), 7.75 - 7.67 (m, 2H), 7.43(d, J = 2.8 Hz, 1H), 6.88 - 6.74 (m, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.26 - 5.95(m, 1H), 5.51 - 5.32 (m, 1H), 5.22 - 5.00 (m, 2H), 3.85 (s, 3H), 3.69 (s,3H), 3.50 (d, J= 15.0 Hz, 1H), 3.13 (s, 2H), 2.57 - 2.34 (m, 2H), 2.15 (dd, J =12.9, 6.2 Hz, 1H). 13 C NMR (100 MHz, CDCl3) d 181.5, 171.9, 168.5, 156.7, 136.8, 136.0, 134.8, 134.2, 131.9, 123.4, 116.3, 112.8, 110.9, 108.2, 72.5, 56.0, 52.5, 51.5, 48.1, 44.7, 40.6, 26.3. HRMS (ESI) m / z : calculated for C 26 H 23 N2O6[MH] - : 459.1556, found:459.1561. HPLC (Chiralcel AD-H (Hexane / i -PrOH = 85 / 15, flow rate 1.5 mL / min, λ =254 nm, t (1S,2R,4R)-3g = 13.8 min (major), t (1R,2S,4S)-3g = 20.4 min (minor)) Example 8

[0039] 6'-fluoro-1'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-8 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.12 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol), and (R)-(+)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane (0.04 mmol) were sequentially added to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and ultradry ethyl acetate (2.0 mL) was added to the Schlenk tube under argon countercurrent. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was completed, silica gel column chromatography yielded a white solid (dr = 3:2:1, 45 mg, overall yield = 86%).

[0040] The NMR data for the target compound P8 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.92 - 7.58 (m, 5H), 7.34 - 7.17 (m, 5H), 6.84- 6.68 (m, 1H), 6.44 (d, J = 8.4 Hz, 1H), 6.25 - 6.04 (m, 1H), 5.54 - 5.33 (m,1H), 5.24 - 5.02 (m, 1H), 4.93 - 4.69 (m, 2H), 3.70 (s, 3H), 3.57 (d, J = 14.9Hz, 1H), 2.66 - 2.38 (m, 2H), 2.29 - 2.09 (m, 1H). 13 C NMR (100 MHz, CDCl3) d 182.2, 172.0, 168.4, 162.9 (d, J = 243.0 Hz), 143.7 (d, J = 12.0 Hz), 135.8, 135.5, 134.2, 131.8, 128.9, 128.7 (d, J = 3.0 Hz),127.8, 127.2, 125.0 (d, J = 9.0 Hz), 123.4, 116.4, 109.3 (d, J = 22.0 Hz), 97.6(d, J = 27.0 Hz), 72.4, 52.5, 50.6, 48.2, 44.5, 43.8, 40.5.HRMS(ESI) m / z :calculated for C 25 H 22 N₂O₅Na [M+Na] + : 453.1426, found: 453.1429. HPLC (Chiralcel AD-H (Hexane / i -PrOH = 85 / 15, flow rate 1.5 mL / min, λ =254 nm, t (1S,2R,4R)-3h = 10.5 min (major), t (1R,2S,4S)-3h= 15.1 min (minor)) Example 9 6'-chloro-1'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-6 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.12 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol) and ( R 0.04 mmol of 5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane was added sequentially to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and then 2.0 mL of ultra-dry ethyl acetate was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was complete, a white solid was obtained by silica gel column chromatography. d.r. = 3:2:1, 43 mg, total yield = 93%).

[0041] The NMR data for the target compound P9 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.89 - 7.77 (m, 2H), 7.76 - 7.65 (m, 3H), 7.14- 7.02 (m, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.20 - 6.01 (m, 1H), 5.44 - 5.33 (m,1H), 5.17 - 5.05 (m, 2H), 3.68 (s, 3H), 3.48 (d, J = 15.0 Hz, 1H), 3.13 (s,3H), 2.48 - 2.35 (m, 2H), 2.18 - 2.08 (m, 1H). 13 C NMR (100 MHz, CDCl3) d 181.7, 172.0, 168.4, 144.5, 135.8, 134.2, 133.9, 131.8, 124.8, 123.4, 123.0, 116.5, 108.6, 72.4, 52.6, 50.7, 48.0, 44.5, 40.3, 26.4. HRMS (ESI) m / z: calculated for C 25 H 21 N₂O₅NaCl [M+Na] + : 487.1037, found:487.1040. HPLC(Chiralcel AD-H (Hexane / i-PrOH = 85 / 15, flow rate 1.5 mL / min, λ =254 nm, t(1S,2R,4R)-3i = 12.2 min (major), t(1R,2S,4S)-3i = 16.3 min (minor)) Example 10

[0042] The following were added: 6'-bromo-1'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-10 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.12 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol), and ( R 0.04 mmol of 5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane was added sequentially to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and then 2.0 mL of ultra-dry ethyl acetate was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was complete, a white solid was obtained by silica gel column chromatography. d.r. = 3:2:1, 45 mg, total yield = 88%).

[0043] The NMR data for the target compound P10 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.91 (S, 1H), 7.87 - 7.78 (m, 2H), 7.75 - 7.67 (m, 2H), 7.39 (d, J = 7.9 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.18 -6.02 (m, 1H), 5.45 - 5.32 (m, 1H), 5.20 - 5.04 (m, 2H), 3.70 (S, 3H), 3.49(d, J= 15.0 Hz, 1H), 3.13 (S, 3H), 2.51 - 2.38 (m, 2H), 2.14 (dd, J = 12.9, 6.2Hz, 1H). 13 C NMR(101 MHz, CDCl3) δ 181.2, 171.9, 168.4, 142.4, 135.7, 135.5,134.2, 131.8, 131.1, 127.1, 123.4, 116.5, 115.9, 109.3, 72.4, 52.6, 51.1,48.0, 44.5, 40.3, 26.4. HRMS(ESI, Q-TOF) m / z: [M+Na] + calcd for C 25 H 21 N2O5Na, 531.0532; found, 531.0534. Example 11

[0044] 7'-chloro-1'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-11 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-1 (0.12 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol), and (R)-(+)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane (0.04 mmol) were sequentially added to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and ultradry ethyl acetate (2.0 mL) was added to the Schlenk tube under argon countercurrent. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was completed, silica gel column chromatography yielded a white solid (dr = 3:2:1, 45 mg, overall yield = 97%).

[0045] The NMR data for the target compound P11 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.87 - 7.76 (m, 2H), 7.76 - 7.56 (m, 3H), 7.17(d, J = 8.2 Hz, 1H), 7.02 (t, J= 7.7 Hz, 1H), 6.19 - 6.04 (m, 1H), 5.50 - 5.36(m, 1H), 5.23 - 5.02 (m, 2H), 3.68 (s, 3H), 3.60 - 3.40 (m, 4H), 2.58 - 2.29(m, 2H), 2.20 - 2.05 (m, 1H). 13 C NMR (100 MHz, CDCl3) d 181.9, 172.1, 168.4, 139.1, 136.2, 135.7, 134.2, 131.8, 130.4, 124.0, 123.4, 122.4, 116.4, 115.1, 72.3, 52.6, 50.8, 48.5, 44.5, 40.8, 29.6. HRMS (ESI) m / z : calculated for C 25 H 21 N₂O₅NaCl [M+Na] + : 487.1037, found:487.1039. HPLC (Chiralcel AD-H (Hexane / i-PrOH = 90 / 10, flow rate 2.0 mL / min, λ =254 nm, t( 1S,2R,4R )-3k = 17.2 min (major), t(1R,2S,4S)-3k = 31.5 min (minor)) Example 12

[0046] 7'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-5 (0.2 mmol), methyl acrylate derivative S2-1 (0.24 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol) and ( R 0.04 mmol of 5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane was added sequentially to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and then 2.0 mL of ultra-dry ethyl acetate was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was complete, a pale yellow solid was obtained by silica gel column chromatography. d.r.= 4:3:3, 44 mg, total yield = 99%).

[0047] The NMR data for the target compound P12 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.87 - 7.76 (m, 2H), 7.75 - 7.67 (m,2H), 7.66 - 7.58 (m, 1H), 7.01 (d, J = 7.0 Hz, 2H), 6.23 - 6.03 (m, 1H), 5.52 -5.39 (m, 1H), 5.19 - 5.07 (m, 2H), 3.69 (s, 3H), 3.54 - 3.41 (m, 4H), 2.55(s, 3H), 2.50 - 2.39 (m, 2H), 2.18 - 2.07 (m, 1H). 13 C NMR(101 MHz, CDCl3) δ 182.5, 172.1, 168.5, 141.0, 136.0, 134.1,134.0, 131.9, 123.4, 123.2, 121.7, 119.4, 116.3, 52.5, 50.6, 48.6, 44.5,40.9, 29.6, 19.0. HRMS(ESI, Q-TOF) m / z: [MH] + calcd for C 26 H 24 N2O5Na, 467.1583; found, 467.1588. Chiral HPLC analysis:Chiralcel AD-H (Hexane / i -PrOH = 85 / 15, flow rate1.5 mL / min, λ = 254 nm, t (1S,2R,4R) = 12.5 min (major), t (1R,2S,4S) = 19.1 min(minor)). Example 13

[0048] 5'-bromo-1',7'-dimethyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-6 (0.2 mmol), methyl acrylate derivative S2-1 (0.24 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol) and ( R 0.04 mmol of 5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane was added sequentially to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and then 2.0 mL of ultra-dry ethyl acetate was added to the Schlenk tube under countercurrent argon. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was complete, a white solid was obtained by silica gel column chromatography. d.r. =9:7:4, 40 mg, total yield = 77%).

[0049] The NMR data for the target compound P13 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.82 (dd, J = 5.5, 3.0 Hz, 2H), 7.75 (d, J = 2.1Hz, 1H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.20 - 7.10 (m, 1H), 6.16 - 6.03 (m,1H), 5.47 - 5.34 (m, 1H), 5.15 - 5.12 (m, 1H), 5.12 - 5.06 (m, 1H), 3.69 (s,3H), 3.46 (d, J = 15.0 Hz, 1H), 3.41 (s, 3H), 2.52 (s, 3H), 2.47 - 2.36 (m,2H), 2.09 (dd, J = 12.9, 6.2 Hz, 1H). 13 C NMR(101 MHz, CDCl3) δ 181.9, 171.9, 168.4, 140.1, 136.0, 135.7,134.3, 134.2, 131.8, 124.8, 123.4, 121.4, 116.4, 115.6, 72.3, 52.6, 50.6,48.4, 44.4, 40.7, 29.6, 18.7. HRMS(ESI, Q-TOF) m / z: [M+ Na] + calcd for C 26 H 23 N2O5NaBr, 545.0688; found, 545.0692. Chiral HPLC analysis:Chiralcel AD-H (Hexane / i -PrOH = 85 / 15, flow rate1.5 mL / min, λ = 254 nm, t (1S,2R,4R) = 12.7 min (major), t (1R,2S,4S) = 22.5 min (minor)). Examples 14-19

[0050] 1'-Methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-1 (0.2 mmol), S(2-2)-S(2-7) (0.24 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol), and (R)-(+)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane (0.04 mmol) were sequentially added to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and ultra-dry ethyl acetate (2.0 mL) was added to the Schlenk tube under argon countercurrent. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. The target compound P14-19 was obtained.

[0051] Target compound P14 ( d.r. The NMR data for (4:2:2, 40 mg, total yield = 89%) are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.85 - 7.70 (m, 2H), 7.69 - 7.63 (m, 1H), 7.43 - 7.33 (m, 1H), 7.32 - 7.25 (m, 1H), 7.19 - 7.11 (m, 1H), 6.81 (d, J = 7.6Hz, 1H), 6.21 - 6.05 (m, 1H), 5.48 - 5.35 (m, 1H), 5.21 - 5.09 (m, 2H), 3.72(s, 3H), 3.53 (d, J= 15.1 Hz, 1H), 3.17 (s, 3H), 2.55 - 2.43 (m, 2H), 2.20 -2.12 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 181.7, 171.7, 167.0 (d, J = 3.0 Hz), 165.4,157.6 (d, J = 264.0 Hz), 143.3, 136.7 (d, J = 7.0 Hz), 135.8, 134.2, 133.2,128.2, 123.6, 123.3, 122.5 (d, J = 19.0 Hz), 119.7 (d, J = 4.0 Hz), 116.5, 107.9,72.7, 52.6, 51.1, 48.0, 44.6, 40.5, 26.3. HRMS(ESI, Q-TOF) m / z: [M+ H] + calcd for C 25 H 22 N2O5F, 449.1513; found, 449.1516. Chiral HPLC analysis:Chiralcel IF (Hexane / i -PrOH = 85 / 15, flow rate1.5 mL / min, λ = 254 nm, t (1S,2R,4R) = 15.2 min (minor), t (1R,2S,4S) = 28.6 min(major)). The NMR data for the target compound P15 (dr = 5:3:2, 37 mg, overall yield = 80%) are as follows: 1 H NMR (400 MHz, CDCl3) d 7.88 - 7.71 (m, 3H), 7.71 - 7.64 (m, 1H), 7.31- 7.24 (m, 1H), 7.20 - 7.08 (m, 1H), 6.81 (d, J= 7.6 Hz, 1H), 6.21 - 6.01 (m,1H), 5.48 - 5.33 (m, 1H), 5.25 - 5.09 (m, 2H), 3.71 (s, 3H), 3.52 (d, J = 15.0Hz, 1H), 3.16 (s, 3H), 2.58 - 2.38 (m, 2H), 2.16 (dd, J = 12.9, 6.2 Hz, 1H). 13 C NMR (100 MHz, CDCl3) d 181.7, 171.7, 167.4, 167.1, 143.3, 140.8, 135.8, 134.2, 133.5, 133.2, 129.9, 128.2, 124.7, 123.8, 123.6, 123.2, 116.5, 107.8, 72.7, 52.6, 51.1, 47.9, 44.6, 40.5, 26.2. HRMS (ESI) m / z : calculated for C 25 H 21 N₂O₅NaCl [M+Na] + : 487.1037, found:487.1037. HPLC (Chiralcel IF (Hexane / i -PrOH = 85 / 15, flow rate 1.5 mL / min, λ =254 nm, t (1S,2R,4R)-3p = 15.9 min (minor), t (1R,2S,4S)-3p = 20.7 min (major) Target compound P16 ( d.r. The NMR data for (7:2:2, 41 mg, total yield = 86%) are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.75 - 8.51 (m, 2H), 8.04 (d, J = 8.1Hz, 1H), 7.71 (d, J= 7.4 Hz, 1H), 7.35 - 7.24 (m, 1H), 7.19 - 7.11 (m, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.15 - 6.01 (m, 1H), 5.45 - 5.33 (m, 1H), 5.23 - 5.11(m, 2H), 3.73 (s, 3H), 3.53 (d, J = 15.1 Hz, 1H), 3.16 (s, 3H), 2.55 - 2.42 (m, 2H), 2.26 - 2.14 (m, 1H). 13 C NMR(101 MHz, CDCl3) δ 181.7, 171.4, 166.3, 166.2, 151.9, 143.3,136.3, 135.5, 133.1, 133.0, 129.4, 128.4, 124.7, 123.6, 123.4, 118.9, 117.0,108.0, 73.3, 52.8, 51.2, 47.8, 44.8, 40.6, 26.3. HRMS(ESI, Q-TOF) m / z: [M+ H] + calcd for C 25 H 22 N3O7, 476.1458; found, 476.1462. Chiral HPLC analysis:Chiralcel IH (Hexane / i -PrOH = 85 / 15, flow rate1.5 mL / min, λ = 254 nm, t (1S,2R,4R) = 11.0 min (minor), t (1R,2S,4S) = 13.8 min (major)). Target compound P17 ( d.r. The NMR data for (5:2:2, 43 mg, total yield = 86%) are as follows: 1 H NMR (400 MHz, CDCl3) d 7.86 (s, 2H), 7.68 (d, J = 7.3 Hz, 1H), 7.24 -7.21 (m, 1H), 7.10 (t, J= 7.5 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.13 - 5.94 (m,1H), 5.40 - 5.25 (m, 1H), 5.19 - 5.02 (m, 2H), 3.66 (s, 3H), 3.46 (d, J = 15.1Hz, 1H), 3.12 (s, 3H), 2.50 - 2.36 (m, 2H), 2.20 - 2.06 (m, 1H). 13 C NMR (100 MHz, CDCl3) d 181.6, 171.6, 166.5, 143.3, 139.1, 135.6, 133.1, 130.9, 128.3, 125.5, 123.6, 123.3, 116.7, 107.9, 72.9, 52.7, 51.1, 47.8, 44.6, 40.5, 26.3. HRMS (ESI) m / z : calculated for C 25 H 26 N₂O₅Na [MH] - : 463.1061, found:463.1059. HPLC (Chiralcel AD-H (Hexane / i -PrOH = 85 / 15, flow rate 1.5 mL / min, λ =254 nm, t (1S,2R,4R)-3r = 11.9 min (minor), t (1R,2S,4S)-3r = 13.3 min (major) The NMR data for the target compound P18 (dr = 5:2:2, 41 mg, overall yield = 94%) are as follows: 1 H NMR (400 MHz, CDCl3) d 7.72 (dd, J = 7.4, 1.2 Hz, 1H), 7.29 - 7.23 (m,2H), 7.16 - 7.06 (m, 1H), 6.80 (d, J= 7.6 Hz, 1H), 6.12 - 6.01 (m, 1H), 6.00 -5.86 (m, 2H), 5.31 - 5.18 (m, 2H), 5.11 - 4.98 (m, 3H), 3.67 (s, 3H), 3.41(d, J = 15.0 Hz, 1H), 3.17 (s, 3H), 3.15 - 3.09 (m, 1H), 3.09 - 3.00 (m, 1H), 2.65 - 2.54 (m, 2H), 2.38 (t, J = 12.8 Hz, 1H), 2.30 - 2.19 (m, 3H), 2.10 (dd, J = 12.9, 6.3 Hz, 1H). 13 C NMR (100 MHz, CDCl3) d 181.6, 180.5, 179.8, 171.3, 143.2, 136.1, 133.4, 128.1, 127.5, 127.4, 123.6, 123.1, 115.9, 107.7, 73.1, 52.2, 50.7, 47.2, 44.0, 40.2, 39.2, 38.6, 26.2, 23.6, 23.4. HRMS (ESI) m / z : calculated for C 25 H 21 N₂O₅Cl₂[M+H] + : 499.0828, found:499.0832. HPLC (Chiralcel IF (Hexane / i -PrOH = 85 / 15, flow rate 1.5 mL / min, λ =254 nm, t (1S,2R,4R)-3s = 10.4 min (minor), t (1R,2S,4S)-3s = 14.0 min (major) The NMR data for the target compound P19 (dr = 3:3:2, 42 mg, overall yield = 88%) are as follows: 1 H NMR (400 MHz, CDCl3) d8.30 (s, 2H), 8.08 - 7.97 (m, 2H), 7.81 (d, J J = 7.4 Hz, 1H), 7.74 - 7.62 (m, 2H), 7.35 - 7.23 (m, 1H), 7.20 - 7.06 (m, 1H), 6.81 (d, J J = 7.7 Hz, 1H), 6.28 - 6.10 (m, 1H), 5.59 - 5.46 (m, 1H), 5.24 - 5.06 (m, 2H), 3.71 (s, 3H), 3.60 (d, J J = 15.0 Hz, 1H), 3.17 (s, 3H), 2.61 - 2.43 (m, 2H), 2.25 - 2.13 (m, 1H). 13 C NMR(100 MHz, CDCl3) d 181.8, 172.0, 168.2, 143.3, 136.1, 135.6, 133.5, 130.3, 129.2, 128.2, 127.6, 124.8, 123.8, 123.3, 116.2, 107.8, 72.9, 52.5, 51.0, 48.1, 44.6, 40.4, 26.3. HRMS(ESI) m / z : calculated for C 26 H 23 N2O5NaBr [M+Na] + : 545.0688, found: 545.0692. HPLC(Chiralcel AD-H (Hexane / i i-PrOH = 70 / 30, flow rate 2.0 mL / min, λ = 254 nm, t (1S,2R,4R)-3t R = 10.8 min (major), t (1R,2S,4S)-3t S = 20.4 min (minor)) Example 20

[0052] 7'-bromo-1'-methyl-2-vinylspiro[cyclopropane-1,3'-indoline]-2'-one S1-1 (0.2 mmol), methyl 2-(1,3-dioxoisoindoline-2-yl)acrylate S2-3 (0.24 mmol), bis(di-tert-butylphosphine)palladium (0.03 mmol), and (R)-(+)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane (0.04 mmol) were sequentially added to a Schlenk tube equipped with a stir bar. The Schlenk tube was purged with argon three times, and ultra-dry ethyl acetate (2.0 mL) was added to the Schlenk tube under argon countercurrent. The Schlenk tube was then sealed and stirred at room temperature for 24 hours. After the reaction was completed, a white solid was obtained by silica gel column chromatography. d.r. =3:3:1, 45 mg, total yield = 87%).

[0053] The NMR data for the target compound P20 are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 5.5, 3.0 Hz, 2H), 7.75 (d, J =2.1 Hz, 1H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.20 - 7.10 (m, 1H), 6.16 - 6.03(m, 1H), 5.47 - 5.34 (m, 1H), 5.15 - 5.12 (m, 1H), 5.12 - 5.06 (m, 1H), 3.69(s, 3H), 3.46 (d, J = 15.0 Hz, 1H), 3.41 (s, 3H), 2.52 (s, 3H), 2.47 - 2.36(m, 2H), 2.09 (dd, J = 12.9, 6.2 Hz, 1H). 13 C NMR(101 MHz, CDCl3) δ 181.9, 171.9, 168.4, 140.1, 136.0, 135.7,134.3, 134.2, 131.8, 124.8, 123.4, 121.4, 116.4, 115.6, 72.3, 52.6, 50.6,48.4, 44.4, 40.7, 29.6, 18.7. HRMS(ESI, Q-TOF) m / z: [M+ Na] + calcd for C 26 H 23N2O5NaBr, 545.0688; found, 545.0692. Chiral HPLC analysis:Chiralcel AD-H (Hexane / i -PrOH = 70 / 30, flow rate2.0 mL / min, λ = 254 nm, t (1S,2R,4R) = 10.8 min (major), t (1R,2S,4S) = 20.4 min(minor)). Application Example 1

[0054] Step 1: Compound P1 (107.5 mg, 0.25 mmol, 1.0 equiv.) was added to a reaction flask equipped with a stir bar, along with 3 mL of a mixture of dichloromethane (1 mL) and methanol (1 mL). Then, ethylenediamine solution (33 μL, 0.5 mmol, 2.0 equiv.) was added dropwise. The mixture was stirred at room temperature for 6 hours. After the reaction was complete, the reaction mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain compound m.

[0055] Step 1: Benzoyl chloride (0.18 mmol, 1.2 equiv.) was added dropwise to a tetrahydrofuran (4 mL) solution containing compound m (0.15 mmol, 1 equiv.) and triethylamine (0.20 mmol, 1.3 equiv.) at 0°C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 12 hours. The resulting mixture was filtered to remove the generated NH4Cl salt. Silica gel column chromatography yielded a white solid P21 (58 mg, total yield = 58%).

[0056] The NMR data for the target compound P21 are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.87 - 7.73 (m, 3H), 7.48 - 7.43 (m, 1H), 7.43 - 7.36 (m, 2H), 7.31 - 7.23 (m, 1H), 7.22 - 7.08 (m, 2H), 6.81 (d, J = 7.7Hz, 1H), 5.81 - 5.65 (m, 1H), 5.28 (d, J= 17.0 Hz, 1H), 5.17 (d, J = 10.4 Hz,1H), 3.92 - 3.79 (m, 2H), 3.76 (s, 3H), 3.43 (d, J = 14.9 Hz, 1H), 3.18 (s,3H), 2.43 - 2.27 (m, 2H), 2.11 - 2.01 (m, 1H). 13 C NMR(101 MHz, CDCl3) δ 182.3, 173.1, 168.0, 143.1, 134.8, 133.9,133.5, 131.8, 128.5, 128.1, 127.3, 123.9, 123.4, 118.4, 107.8, 68.7, 52.6,52.4, 52.0, 47.3, 41.3, 26.4. HRMS(ESI, Q-TOF) m / z: [M+ Na] + calcd for C 24 H 24 N2O4Na, 427.1634; found, 427.1638. Application Example 2

[0057] Compound P1 (51 g, 0.5 mol) was dissolved in dichloromethane (3 ml) and stirred under ice bath cooling. A solution of m-chloroperoxybenzoic acid (90 g, 0.52 mol) in dichloromethane (5 ml) was slowly added dropwise to this solution, and the reaction was continued under ice bath cooling with stirring for 24 hours. After the reaction was complete, the reaction mixture was washed twice with saturated sodium bicarbonate solution (5 ml each time), and the organic layer was collected. The organic layer was then washed twice with water (5 ml each time), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give a white oily liquid P22 (27 mg, yield = 51%).

[0058] The NMR data for the target compound P22 are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.91 - 7.84 (m, 2H), 7.80 - 7.75 (m, 2H), 7.25 - 7.19 (m, 1H), 7.09 (d, J= 7.3 Hz, 1H), 6.98 - 6.86 (m, 1H), 6.80 (d, J =7.7 Hz, 1H), 3.93 - 3.83 (m, 4H), 3.76 - 3.71 (m, 1H), 3.51 (d, J = 15.2 Hz,1H), 3.21 (s, 3H), 3.01 (d, J = 15.2 Hz, 1H), 2.82 - 2.75 (m, 1H), 2.60 - 2.55(m, 1H), 2.48 (dd, J = 13.3, 8.7 Hz, 1H), 2.21 (dd, J = 13.3, 7.0 Hz, 1H). 13 C NMR(100 MHz, CDCl3) δ 180.2, 170.3, 168.9, 142.9, 135.9, 134.6,131.7, 128.2, 123.7, 123.1, 122.5, 108.2, 72.6, 53.3, 51.7, 51.1, 48.2, 46.0,45.7, 39.7, 26.6. HRMS (ESI, Q-TOF) m / z: [M+ Na] + calcd forC 25 H 22 N2O6Na, 469.1376; found, 469.1380. The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A chiral spirocyclopentane-oxidized indole compound, characterized in that, The structural formula is as follows: ， Where R 1 It is 4-chloro, 4-bromo, 5-fluoro, 5-chloro, 5-bromo, 5-methyl, 5-methoxy, 5-trifluoromethyl, 5-trifluoromethoxy, 5-nitro, 6-fluoro, 6-chloro, 6-bromo, 6-methyl, 6-methoxy, 6-trifluoromethoxy, 7-fluoro, 7-chloro, 7-bromo, 7-methyl, 7-methoxy, 7-trifluoromethyl, 7-trifluoromethoxy, 5-bromo-7-methyl, 5,7-dimethyl, or R. 1 It does not exist; R 2 It can be methyl, benzyl, phenyl, ethyl, or tert-butyl; R 3 It is 3-fluoro, 3-nitro, 4-chloro, 4-bromo, 4-methyl, 4-nitro, 5,6-dichloro, or R. 3 It does not exist; R 4 It is methyl, ethyl or tert-butyl.

2. The method for synthesizing the compound according to claim 1, characterized in that, The reaction formula is shown below: ， Spirolene-cyclopropane-oxidized indole S1, methyl acrylate derivative S2, palladium catalyst, ligand, and reaction solvent were sequentially added to a reaction flask and stirred at room temperature under inert gas protection. After the reaction was completed, chiral spirocyclopentane-oxidized indole compounds were isolated.

3. The synthesis method according to claim 2, characterized in that: The palladium catalyst is selected from palladium acetate, di(acetylacetone)palladium, tetra(triphenylphosphine)palladium, bis(di-tert-butylphosphine)palladium, bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium, di(cyclohexylphosphine)palladium, neopentanoate, di-bis[(1,2,3)-1-phenyl-2-propene]palladium or allyl(1,3-bis(trimethylyl)-1H-imidazol-2(3H)-ylidene)palladium chloride.

4. The synthesis method according to claim 2, characterized in that: The ligands are selected from ( R )-(+)-(6,6'-dimethoxybiphenyl-2,2'-yl)bis(diphenylphosphine), 1,2-bis((2 S, 5 S )-2,5-dimethylphosphine)benzene, ( R )-4-tert-butyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline, (4 S 5 S )-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxapentane, ( R )-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl, ( R )-(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diisopropylphosphine), bis(diphenylphosphine)butane, (2 S ,2 S ,3 S ,3 S )-3,3-di-tert-butyl-4,4-dimethoxy-2,2,3,3-tetrahydro-2,2-biphenyl[d][1,3]oxaphosphatane, ( R )-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, ( R )-(+)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane, bis[2-(diphenylphosphino)phenyl] ether, ( R )-(-)-1-[( S )-2-Diphenylphosphine, ferrocene, ethyl-di-tert-butylphosphine or (2 R )-1-[(4 S [-4,5-dihydro-4-phenylmethyl-2-oxazolyl]-2-(diphenylphosphino)ferrocene.

5. The synthesis method according to claim 2, characterized in that: The reaction solvents are selected from dichloromethane, tetrahydrofuran, ethyl acetate, chloroform, 1,1-dichloroethane, 1,4-dioxane, ethanol, etc. N,N -Dimethylformamide or acetonitrile.

6. The synthesis method according to claim 2, characterized in that: The molar ratio of the substances in the spirolene-cyclopropane, methyl acrylate derivative, palladium catalyst, and ligand is 1:1-5:0.005-0.025:0.005-0.

025.

7. The synthesis method according to claim 6, characterized in that: The molar ratio of helenecyclopropane to methyl acrylate derivative is 1:1.

2.

8. The synthesis method according to claim 7, characterized in that: The reaction time is 12–24 h; the reaction temperature is 0℃–50℃; and the reaction gas atmosphere is selected from argon or nitrogen.

9. The use of a compound according to claim 1 and / or a compound synthesized according to any one of claims 2 to 8 as an organic synthesis intermediate or a pharmaceutical synthesis intermediate.

10. The application according to claim 9, characterized in that: Organic synthesis intermediates include tertiary amine compounds or propylene oxide precursors.

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