Chiral 3-quaternary carbon propargyloxy indole compounds and asymmetric preparation method thereof

Abstract

The application discloses a chiral 3-quaternary carbon propargyl oxidized indole compound and an asymmetric preparation method thereof. 1‑10 The chiral 3-quaternary carbon propargyl oxidized indole compound is an optically active compound with the structure shown in the following formula I, and includes stereoisomers with the same chemical general formula. 1 R 2 , R 3 , R 4 , R 5 , R 6 are respectively and independently selected from hydrogen, halogen, C 1‑10 hydrocarbon group or a hydrocarbon oxy group; R 7 is independently selected from C 1‑10 alkyl or aryl. The application applies a chiral nickel complex and a chiral nitrogen heterocyclic carbine combined catalytic system, catalyzes a key step of an asymmetric propargylation reaction, and precisely and quickly synthesizes the chiral 3-quaternary carbon propargyl oxidized indole compound in a high yield and high stereoselectivity and in a gram scale. The preparation method is simple, and has biomedical practicability and industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric organic synthesis technology, specifically relating to a chiral 3-quaternary carbon propargyl oxide indole compound and its asymmetric preparation method. Background Technology

[0002] Enantiomerically enriched oxyindole skeletons are widely found in physiologically active natural products and drug intermediates, thus attracting considerable attention. Meanwhile, the "methyl effect" (the introduction of a methyl group into a drug molecule can significantly improve its efficacy and stability) has been successfully applied. Therefore, developing an efficient catalytic system to achieve the enantioselective and stereodispersive synthesis of 3-substituted oxyindole and its methylated analogs, thereby creating a richer variety of three-dimensional molecular structures, is a promising scientific research hotspot.

[0003] Asymmetric synergistic catalysis is a concise and efficient method to achieve asymmetric transformations that cannot be accomplished by a single catalytic system, and it also provides a practical synthetic approach for exploring stereodispersive synthesis. Two chiral catalysts act on two different substrates in the reaction, enabling the diastereoselective synthesis of chiral compounds with multiple chiral centers, thus providing a synthetic platform for the precise construction of bioactive molecules with multiple chiral centers.

[0004] Stereochemically controlled construction of propylitic carbon-carbon bonds is of great value in expanding the diversity of molecular skeletons, and the resulting products are easily modified, exhibiting high synthetic versatility. Meanwhile, chiral nitrogen-based carbene catalysts have been developed into a powerful tool for constructing structurally complex chiral oxidindole compounds, showing broad application prospects in the asymmetric construction of bioactive molecules.

[0005] Chiral 3-quaternary carboxypropynyl oxidindole compounds are key intermediates for constructing bioactive molecules with chiral oxidindole skeletons, possessing value in biopharmaceutical synthesis. They can facilitate the synthesis of chiral natural products (-)-debromoflustramine B and its analogues (-)-C (β-Me) Asymmetric synthesis of -debromoflustramine B. However, achieving asymmetric propargyl transformation based on endoyne at the 3-position of oxyindole compounds remains an unsolved scientific problem. Therefore, there is an urgent need to develop an efficient synthetic method for the enantioselective and stereodispersive synthesis of chiral 3-quaternary carbon propargyl oxyindole compounds. Starting from the structurally simple and readily available oxyindole skeleton, a general strategy for the precise, rapid, high-yield, and highly enantioselective diastereodispersive synthesis of structurally diverse chiral 3-quaternary carbon propargyl oxyindole compounds should be developed, and applied to the chiral natural product (-)-debromoflustramine B and its analogue (-)-C.(β-Me) The precise synthesis of -debromoflustramine B demonstrates the practicality of this preparation method and provides a novel synthetic platform for the exploration and development of bioactive molecules. Summary of the Invention

[0006] The purpose of this invention is to provide a chiral 3-quaternary carbon propargyl oxidized indole compound and its asymmetric preparation method, thereby solving the above-mentioned problems existing in the prior art.

[0007] The present invention comprises chiral 3-quaternary carboxypropynyl oxidindole compounds, which are optically active compounds having the structure shown in Formula I, including stereoisomers having the same general chemical 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; R 1 R 2 R 3 R 4 R 5 R 6 Each is independently selected from hydrogen, halogen, and C. 1-10 The hydrocarbon group or hydrocarbon oxygen group; R 7 Selected independently from C 1-10 Alkyl or aryl.

[0010] This invention discloses a stereoselective preparation method for chiral 3-quaternary carbon propargyl oxidized indole compounds. The method uses α,β-unsaturated aldehyde 1 derived from oxidized indole and propargyl alcohol derivative 2 as starting materials, alcohol 3 as a quenching agent, bis(1,5-cyclooctadiene)-nickel(0) as a metal catalyst, a chiral phosphine reagent as a ligand, and a chiral nitrogen heterocyclic carbene as an organic catalyst. The reaction proceeds via an asymmetric propargylation reaction assisted by a base, followed by separation and purification to obtain the target product I.

[0011] The synthesis route is shown below:

[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; R 1 R 2 R 3 R 4 R 5 R 6 Each is independently selected from hydrogen, halogen, and C. 1-10 The hydrocarbon group or hydrocarbon oxygen group; R 7Selected independently from C 1-10 Alkyl or aryl; substituent R 8 Selected from C 1-10 Alkyl, aryl, C 1-10 Alkyl or aryloxy groups.

[0014] Specifically, the steps include the following:

[0015] Under a nitrogen atmosphere, a bis(1,5-cyclooctadiene)-nickel(0) metal catalyst and a chiral phosphine ligand were mixed in an organic solvent. Then, under nitrogen protection, propargyl alcohol derivative 2, a chiral nitrogen heterocyclic carbene catalyst, an α,β-unsaturated aldehyde 1 derived from indole oxide, an alcohol 3, and a base were added to the mixture. The reaction was carried out at -78°C to 100°C for 4 to 240 hours, and the reaction endpoint was determined by thin-layer chromatography. The reaction system was then quenched with a saturated ammonium chloride aqueous solution, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate, and the combined organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure. Finally, the asymmetric 3-quaternary carbon propargyl indole oxide product I was obtained by column chromatography.

[0016] During the preparation process of this invention:

[0017] The chiral phosphine ligand is a commercially available ligand selected from...

[0018] In the formula: R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 The following groups, each independently selected from hydrogen, halogen, substituted or unsubstituted, are: C 1-10 Alkyl, C 3-10 cycloalkyl, 2-furanyl or C 6-20 Aryl group; Ar is an aromatic ring or a substituted aromatic ring; X is a heteroatom group.

[0019] The chiral nitrogen heterocyclic carbene catalyst is a commercially available catalyst selected from:

[0020]

[0021] In the formula: R 29 R 30 R 31 The following groups, each independently selected from hydrogen, halogen, substituted or unsubstituted, are: C 1-10 Alkyl, C 3-10 cycloalkyl, 2-furanyl or C 6-20 Aryl groups.

[0022] The base is potassium phosphate, potassium monohydrogen phosphate, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethylethylenediamine, or N-methylmorpholine.

[0023] 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.

[0024] In the preparation process of this invention, four configurations of the target product I, namely (R,R), (R,S), (S,R), and (S,S), can be selectively obtained by changing the configuration of the chiral phosphine ligand and the chiral nitrogen heterocyclic carbene.

[0025] in:

[0026] The molar ratio of bis(1,5-cyclooctadiene)-nickel (0) to α,β-unsaturated aldehyde 1 derived from indole oxycarbamate is 0.025:1-1:1; the molar ratio of chiral phosphine ligand to α,β-unsaturated aldehyde 1 derived from indole oxycarbamate is 0.025:1-1:1; the molar ratio of chiral nitrogen heterocyclic carbene catalyst to α,β-unsaturated aldehyde 1 derived from indole oxycarbamate is 0.025:1-1:1; the molar equivalent ratio of α,β-unsaturated aldehyde 1 derived from indole oxycarbamate to propargyl alcohol derivative 2 is 1:1-1:5; the molar equivalent ratio of α,β-unsaturated aldehyde 1 derived from indole oxycarbamate to alcohol 3 is 1:1-1:100; and the molar ratio of α,β-unsaturated aldehyde 1 derived from indole oxycarbamate to base is 1:0.1-1:5.

[0027] Furthermore, the molar ratio of bis(1,5-cyclooctadiene)-nickel(0) to the chiral phosphine ligand is 1:1 to 1:4.

[0028] This invention provides a method for synthesizing chiral 3-quaternary carbaryl propargyl indole compounds through a key asymmetric reaction step. Starting with an α,β-unsaturated aldehyde 1 derived from indole and a propargyl alcohol derivative 2, using alcohol 3 as a quenching agent, bis(1,5-cyclooctadiene)-nickel(0) as a metal catalyst, a chiral phosphine reagent as a ligand, and a chiral nitrogen-heterocyclic carbene as an organic catalyst, a chiral 3-quaternary carbaryl propargyl indole compound I was synthesized rapidly and precisely on a gram-scale with high yield, high stereoselectivity, and under the assistance of a base via an asymmetric reaction. This invention successfully develops a method for synthesizing chiral 3-quaternary carbaryl propargyl indole compounds, easily yielding high-yield, high-optical-purity chiral 3-quaternary carbaryl propargyl indole compounds. Furthermore, starting from this class of compounds, through multi-step transformations, the natural product (-)-debromoflustramine B and its analogue (-)-C can be synthesized. (β-Me) The asymmetric total synthesis of -debromoflustramine B demonstrates the practicality of this preparation method and provides a novel synthetic platform for the exploration and development of bioactive molecules. Detailed Implementation

[0029] Example 1: Preparation of chiral 3-quaternary carbonyl propargyl indole oxide compound 4a

[0030]

[0031] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 2a (25.5 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1a derived from indole oxide (26.3 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl indole oxidase product 4a (29.3 mg, 75% yield, 95% ee) was obtained by column chromatography as a colorless oily liquid.

[0032] 1 H NMR (400MHz, CDCl3) δ7.41-7.26(m,6H),7.21-7.14(m,1H),7.05-6.98(m,1H),6.7 2(d,J=7.8Hz,1H),5.01(d,J=15.7Hz,1H),4.90(d,J=15.7Hz,1H),3.41(s,3H),3. 18(d,J=16.4Hz,1H),3.08(d,J=16.4Hz,1H),2.75(dt,J=16.2,2.2Hz,1H),2.48(d t,J=16.2,2.1Hz,1H),2.16-1.98(m,2H),1.38-1.23(m,4H),0.84(t,J=7.2Hz,3H). 13C NMR (100MHz, CDCl3) δ178.60,170.25,143.28,136.15,130.64,128.81,128.48,127.63,127.59,123.30,122.3 9,109.16,83.97,74.35,51.77,48.57,44.22,39.56,30.92,28.75,21.94,18.46,13.73.ESIMS:calculated[C 25 H 27 NO3+Na] + :412.1883,found:412.1887.[α] 20 D =-79.5 (c=1.00, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess:95%ee (CHIRALPAK IC, hexane / i-PrOH=70 / 30, detector: 254nm, T=30℃, flow rate: 1mL / min), t1 (minor)=9.54min, t2 (major)=12.64min.

[0033] Example 2: Preparation of chiral 3-quaternary carbonylpropynyl oxidized indole compound 4b

[0034]

[0035] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 2a (25.5 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (11.6 mg, 0.02 mmol, 20 mol%), and α,β-unsaturated aldehyde 1b derived from indole oxide (28.1 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl oxidized indole product 4b (26.4 mg, 65% yield, 95% ee) was obtained by column chromatography as a colorless oily liquid.

[0036] 1 H NMR (400MHz, CDCl3) δ7.40-7.26(m,5H),7.12(dd,J=8.0,2.6Hz,1H),6.86(td,J=9.0,2. 6Hz,1H),6.62(dd,J=8.5,4.2Hz,1H),5.00(d,J=15.8Hz,1H),4.89(d,J=15.8Hz,1H),3.4 6(s,3H),3.17(d,J=16.7Hz,1H),3.08(d,J=16.7Hz,1H),2.75(dt,J=16.3,2.4Hz,1H),2 .46(dt,J=16.3,2.3Hz,1H),2.18-2.04(m,2H),1.38-1.25(m,4H),0.86(t,J=7.2Hz,3H). 19 FNMR (376MHz, CDCl3) δ -120.69. 13C NMR (101MHz, CDCl3) δ178.35, 170.11, 159.08 (d, J = 240.4Hz), 139.21, 135.8 1,132.38(d,J=8.3Hz),128.89,127.75,127.50,114.63(d,J=23.4Hz),111. 64(d,J=25.1Hz),109.61(d,J=8.1Hz),84.39,73.97,51.91,48.86(d,J=1.7Hz),44.35,39.37,30.87,28.65,21.97,18.44,13.69.ESIMS:calculated[C 25 H 26 FNO3+Na] + :430.1789,found:430.1783.[α] 20 D =-83.3(c=0.83,CH2Cl2).The product was analyzed by HPLC to determine the enantiomericexcess:95%ee(CHIRALPAK IA, hexane / i-PrOH=95 / 5, detector: 254nm, T=30℃, flowrate: 1mL / min), t1(major)=16.15min, t2(minor)=20.71min.

[0037] Example 3: Preparation of chiral 3-quaternary carbon propargyl oxidized indole compound 4c

[0038]

[0039] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 2a (25.5 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1c derived from oxidindole (20.1 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixed system. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl indole oxidase product 4c (31.5 mg, 78% yield, 92% ee) was obtained by column chromatography as a colorless oily liquid.

[0040] 1 H NMR (400MHz, CDCl3) δ7.41-7.34(m,2H),7.34-7.27(m,2H),7.25-7.21(m,1H),7.19-7.14(m,1H ),6.96(d,J=7.8Hz,1H),6.60(d,J=7.9Hz,1H),4.97(d,J=15.7Hz,1H),4.89(d,J=15.7Hz,1H),3 .42(s,3H),3.16(d,J=16.5Hz,1H),3.07(d,J=16.5Hz,1H),2.73(dt,J=16.2,2.1Hz,1H),2.45(d t,J=16.3,2.1Hz,1H),2.29(s,3H),2.17-2.00(m,2H),1.39-1.23(m,4H),0.86(t,J=7.2Hz,3H). 13C NMR (100MHz, CDCl3) δ178.53,170.30,140.85,136.26,131.78,130.67,128.77,128.74,127.56,124.19,108. 88,83.92,74.53,51.76,48.54,44.22,39.51,30.95,28.82,21.95,21.31,18.50,13.75.ESIMS:calculated[C 26 H 29 NO3+Na] + :426.2040,found:426.2045.[α] 20 D =-67.7(c=1.00,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:92%ee(CHIRALPAKIC,hexane / i-PrOH=70 / 30,detector:254nm,T=30℃,flow rate:1mL / min),t1(minor)=11.39min,t2(major)=14.76min.

[0041] Example 4: Preparation of chiral 3-quaternary carbonyl propargyl indole oxidase 4d

[0042]

[0043] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 2b (32.7 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1d derived from oxidindole (17.3 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 4:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl indole product 4d (25.6 mg, 74% yield, 92% ee) was obtained by column chromatography as a colorless oily liquid.

[0044] 1 H NMR(400MHz, CDCl3)δ8.24(brs,1H),7.34-7.27(m,2H),7.24-7.17(m,4H) ,7.14-7.10(m,1H),6.98-6.92(m,1H),6.86(d,J=7.7Hz,1H),3.47(s,3H), 3.12(d,J=16.6Hz,1H),2.99(d,J=16.6Hz,1H),2.77(t,J=7.4Hz,2H),2.6 7(dt,J=16.2,2.2Hz,1H),2.50-2.43(m,2H),2.39(dt,J=15.9,2.0Hz,1H). 13 C NMR (125MHz, CDCl3) δ180.42,170.39,141.08,140.75,131.06,128.56,128.55,128.51,126.39,123 .61,122.34,109.82,83.26,75.14,51.81,48.73,39.21,35.11,28.44,20.75.ESIMS:calculated[C 22 H 21NO3+Na] + :370.1414,found:370.1420.[α] 20 D =-97.0(c=0.39,CH2Cl2).The product wasanalyzed by HPLC to determine the enantiomeric excess:92%ee(CHIRALPAK IC,hexane / i-PrOH=70 / 30,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (major) = 7.90min, t2 (minor) = 11.66min.

[0045] Example 5: Preparation of chiral 3-quaternary carbonylpropynyl oxidized indole compound (R,R)-6a

[0046]

[0047] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1a derived from oxidindole (26.3 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, the chiral 3-quaternary carboxypropynyl indole product (R,R)-6a (35 mg, 87% yield, >20:1 d.r., 99% ee) was obtained by column chromatography using a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 as the eluent. It was a colorless oily liquid.

[0048] 1H NMR (400MHz, CDCl3) δ7.48-7.43(m,1H),7.43-7.37(m,2H),7.35-7.29(m,2H),7.28-7.26(m,1H),7 .22-7.15(m,1H),7.05-6.97(m,1H),6.74(d,J=7.8Hz,1H),5.00(d,J=15.6Hz,1H),4.88(d,J=15.6H z,1H),3.44(d,J=16.3Hz,1H),3.36(s,3H),3.11(d,J=16.3Hz,1H),3.04-2.94(m,1H),2.25(td,J= 7.0,2.2Hz,2H),1.59-1.49(m,2H),1.48-1.38(m,2H),0.94(t,J=7.2Hz,3H),0.75(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ178.47,170.39,144.19,136.24,128.81,128.63,128.53,127.77,127.66,123.97,122.32,1 08.89,84.51,80.22,52.09,51.65,44.44,41.03,34.27,31.14,22.16,18.61,16.01,13.76.ESIMS:calculated[C 26 H 29 NO3+H] + :404.2220found:404.2226.[α] 20 D =-168.2(c=1.00,CH2Cl2).The product was analyzed by HPLC to determine the enantiomericexcess:99%ee(CHIRALPAK IC, hexane / i-PrOH=70 / 30, detector: 254nm, T=30℃, flowrate: 1mL / min), t1(minor)=7.19min, t2(major)=13.76min.

[0049] Example 6: Preparation of chiral 3-quaternary carbonylpropynyl oxidized indole compound (R,R)-6b

[0050]

[0051] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1e derived from oxidindole (18.7 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl indole product (R,R)-6b (30 mg, 92% yield, 13:1 d.r., >99% ee) was obtained by column chromatography as a colorless oily liquid.

[0052] 1 H NMR (400MHz, CDCl3) δ7.45 (d, J = 7.4Hz, 1H), 7.33-7.27 (m, 1H), 7.08-7.00 (m, 1H),6.85(d,J=7.8Hz,1H),3.41(s,3H),3.40(d,J=16.5Hz,1H),3.25(s,3H), 3.05(d,J=16.5Hz,1H),2.99-2.90(m,1H),2.25(td,J=7.0,2.2Hz,2H),1.59- 1.51(m,2H),1.49-1.39(m,2H),0.95(t,J=7.3Hz,3H),0.71(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ178.41,170.49,144.91,128.63,128.60,123.82,122.29,107.83,84.36,80 .19,52.11,51.70,40.89,33.90,31.14,26.43,22.16,18.59,15.84,13.77.ESIMS:calculated[C20 H 25 NO3+Na] + :350.1727found:350.1728.[α] 20 D =-167.6(c=0.80,CH2Cl2).The product wasanalyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALPAK IC,hexane / i-PrOH=70 / 30,detector:254nm,T=30℃,flow rate:1mL / min), t1(major)=6.96min, t2(minor)=7.73min.

[0053] Example 7: Preparation of chiral 3-quaternary carbonylpropynyl oxidized indole compound (R,R)-6c

[0054]

[0055] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1d derived from oxidindole (17.3 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted again with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl oxidized indole product (R,R)-6c (20.1 mg, 64% yield, 13:1 d.r., >99% ee) was obtained by column chromatography as a colorless oily liquid.

[0056] 1H NMR (400MHz, CDCl3) δ8.42 (brs, 1H), 7.43 (d, J = 7.4Hz, 1H), 7.25-7.19 (m, 1H) ,7.04-6.99(m,1H),6.88(d,J=7.7Hz,1H),3.44(s,3H),3.42(d,J=16.7Hz,1H) ,3.06(d,J=16.4Hz,1H),2.98-2.88(m,1H),2.26(td,J=7.0,2.1Hz,2H),1.60 -1.51(m,2H),1.49-1.41(m,2H),0.95(t,J=7.3Hz,3H),0.81(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ180.42,170.58,141.98,128.99,128.58,124.23,122.22,109.64,84.51 ,80.05,52.67,51.73,40.93,34.04,31.13,22.16,18.59,15.86,13.75.ESIMS:calculated[C 19 H 23 NO3+Na] + :336.1570,found:336.1576.[α] 20 D =-158.8(c=0.60,CH2Cl2).The product wasanalyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALPAKAD-H,hexane / i-PrOH=85 / 15,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 7.04min, t2 (major) = 8.07min.

[0057] Example 8: Preparation of chiral 3-quaternary carbonyl propargyl oxidized indole compound (R,R)-6d

[0058]

[0059] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL ethanol 3b, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1e derived from oxidindole (18.7 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, the chiral 3-quaternary carboxypropynyl indole product (R,R)-6d (23 mg, 67% yield, 16:1 d.r., >99% ee) was obtained by column chromatography using a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 as the eluent. It was a colorless oily liquid.

[0060] 1 H NMR (400MHz, CDCl3) δ7.46 (d, J = 7.4Hz, 1H), 7.33-7.27 (m, 1H), 7.08-6.99 (m, 1H),6.84(d,J=7.7Hz,1H),3.91-3.73(m,2H),3.39(d,J=16.3Hz,1H),3.24(s, 3H),3.04(d,J=16.2Hz,1H),2.98-2.88(m,1H),2.25(td,J=7.0,2.2Hz,2H),1 .60-1.50(m,2H),1.49-1.40(m,2H),1.06-0.88(m,6H),0.71(d,J=6.9Hz,3H). 13C NMR (125MHz, CDCl3) δ178.44,169.94,144.93,128.65,128.58,123.98,122.27,107.73,84.35,80.24 ,60.45,52.24,41.18,33.98,31.15,26.38,22.16,18.60,15.87,13.96,13.75.ESIMS:calculated[C 21 H 27 NO3+H] + :342.2064found:342.2072.[α] 20 D =-184.1(c=0.53,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALCELOD-H,hexane / i-PrOH=90 / 10,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 4.75min, t2 (major) = 7.44min.

[0061] Example 9: Preparation of chiral 3-quaternary carbonylpropynyl oxidized indole compound (R,R)-6e

[0062]

[0063] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1f derived from indole oxide (20.1 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, the chiral 3-quaternary carboxypropynyl indole product (R,R)-6e (29.9 mg, 87% yield, 11:1 d.r., >99% ee) was obtained by column chromatography using a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 as the eluent. It was a colorless oily liquid.

[0064] 1 H NMR(400MHz, CDCl3)δ7.27(s,1H),7.09(d,J=7.8Hz,1H),6.73(d,J=7.9Hz,1H),δ3.42(s,3H),3.37(d,J=16.6Hz,1H),3.22(s,3H),3.04(d,J=16.6Hz ,1H),2.98-2.86(m,1H),2.33(s,3H),2.27(td,J=7.0,2.0Hz,2H),1.63-1. 51(m,2H),1.51-1.40(m,2H),0.95(t,J=7.2Hz,3H),0.70(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ178.35,170.51,142.55,131.62,128.85,128.59,124.76,107.49,84.24,80.37 ,52.11,51.69,40.88,33.92,31.17,26.44,22.16,21.41,18.61,15.86,13.79.ESIMS:calculated[C21 H 27 NO3+Na] + :364.1883found:364.1881.[α] 20 D =-143.7(c=0.97,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALPAKIA,hexane / i-PrOH=98 / 2,detector:254nm,T=30℃,flow rate:1mL / min), t1(major)=10.26min, t2(minor)=11.37min.

[0065] Example 10: Preparation of chiral 3-quaternary carbonylpropynyl oxidized indole compound (R,R)-6f

[0066]

[0067] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (11.6 mg, 0.02 mmol, 20 mol%), and 1 g (20.5 mg, 0.1 mmol, 1 equivalent) of oxidized indole-derived α,β-unsaturated aldehyde were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, the chiral 3-quaternary carboxypropynyl indole product (R,R)-6f (30 mg, 87% yield, 14:1 d.r., 99% ee) was obtained by column chromatography using a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 as the eluent. It was a colorless oily liquid.

[0068] 1H NMR (400MHz, CDCl3) δ7.42-7.34(m,1H),6.77-6.68(m,1H),6.64-6.55(m,1H),3.44(s,3H),3.38(d,J=16.6Hz,1H),3.23(s,3H),3.04(d,J=16 .6Hz,1H),2.97-2.86(m,1H),2.25(td,J=7.0,2.2Hz,2H),1.59-1.49(m,2H),1.49-1.38(m,2H),0.95(t,J=7.2Hz,3H),0.71(d,J=6.9Hz,3H). 19 F NMR (376MHz, CDCl3) δ -111.89. 13 C NMR (100MHz, CDCl3) δ178.75, 170.45, 163.50 (d, J = 244.9Hz), 146.47 (d, J = 11.6Hz), 124.77 (d, J = 9.7Hz), 123.90 (d, J = 2.9Hz), 108.26 ( d,J=22.1Hz),96.81(d,J=27.5Hz),84.56,79.98,51.77,40.90,33.91,31.12,26.56,22.15,18.56,15.79,13.75.ESIMS:calculated[C 20 H 24 FNO3+Na] + :368.1632found:368.1638.[α] 20 D =-156.9(c=0.77,CH2Cl2).The product wasanalyzed by HPLC to determine the enantiomeric excess:99%ee(CHIRALCEL OD-H,hexane / i-PrOH=90 / 10,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 4.86min, t2 (major) = 8.70min.

[0069] Example 11: Preparation of chiral 3-quaternary carbonylpropynyl oxidized indole compound (R,R)-6g

[0070]

[0071] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1h derived from indole oxide (20.1 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl indole product (R,R)-6 g (28 mg, 82% yield, 12:1 d.r., >99% ee) was obtained by column chromatography as a colorless oily liquid.

[0072] 1 H NMR (400MHz, CDCl3) δ7.30 (d, J = 7.3Hz, 1H), 7.02 (d, J = 7.3Hz, 1H), 6.96-6. 88(m,1H),3.52(s,3H),3.43(s,3H),3.36(d,J=16.5Hz,1H),3.04(d,J=16.6 Hz,1H),2.97-2.87(m,1H),2.58(s,3H),2.24(td,J=7.0,2.2Hz,2H),1.60-1 .48(m,2H),1.48-1.38(m,2H),0.94(t,J=7.2Hz,3H),0.70(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ179.28,170.56,142.66,132.41,129.22,122.13,121.62,119.31,84.35,80.25 ,51.68,51.32,41.11,34.15,31.15,29.86,22.15,19.31,18.60,15.84,13.76.ESIMS:calculated[C21 H 27 NO3+Na] + :364.1883 found:364.1885.[α] 20 D =-166.9 (c=0.83, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess:>99%ee (CHIRALPAKIA, hexane / i-PrOH=85 / 15, detector: 254nm, T=30℃, flow rate: 1mL / min), t1 (major)=4.60min, t2 (minor)=5.00min.

[0073] Example 12: Preparation of chiral 3-quaternary carbonyl propargyl oxidized indole compound (R,R)-6h

[0074]

[0075] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5b (30.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1e derived from indole oxide (18.7 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted again with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, the chiral 3-quaternary carboxypropynyl indole product (R,R)-6h (32 mg, 92% yield, 14:1 d.r., >99% ee) was obtained by column chromatography using a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 as the eluent. It was a colorless oily liquid.

[0076] 1H NMR (400MHz, CDCl3) δ7.48-7.37(m,1H),7.34-7.28(m,1H),7.09-7.02(m,1H),6.86(d,J=7.8Hz,1H),3.65(t,J=6.3Hz,2H),3.41(s,3H),3.35( d,J=16.4Hz,1H),3.25(s,3H),3.05(d,J=16.5Hz,1H),3.00-2.90(m,1H ),2.46(td,J=6.8,2.2Hz,2H),2.07-1.93(m,2H),0.73(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ178.22,170.34,144.90,128.74,128.53,123.70,122.38,107.92,82.19 ,81.48,51.99,51.73,43.80,40.76,33.84,31.58,26.44,16.31,15.80.ESIMS:calculated[C 19 H 22 ClNO3+H] + :348.1361found:348.1369.[α] 20 D =-173.6(c=0.77,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALPAKAD-H,hexane / i-PrOH=90 / 10,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (major) = 7.60min, t2 (minor) = 8.26min.

[0077] Example 13: Preparation of chiral 3-quaternary carbonylpropynyl oxidized indole compound (R,R)-6i

[0078]

[0079] In a glove box under a nitrogen atmosphere at 25°C, bis(1,5-cyclooctadiene)-nickel(0) (5.6 mg, 0.02 mmol, 20 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (16.4 mg, 0.024 mmol, 24 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5c (34.8 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (11.6 mg, 0.02 mmol, 20 mol%), and α,β-unsaturated aldehyde 1a derived from oxidindole (26.3 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 96 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted again with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl oxidized indole product (R,R)-6i (29.8 mg, 66% yield, 4:1 d.r., 99% ee) was obtained by column chromatography as a colorless oily liquid.

[0080] 1 H NMR (400MHz, CDCl3) δ7.50-7.45(m,1H),7.36-7.32(m,2H),7.24-7.20(m,4H),7.19-7.18(m,1H) ),7.17-7.11(m,2H),7.05-6.96(m,3H),6.71(d,J=7.8Hz,1H),5.04(d,J=15.6Hz,1H),4.79(d,J =15.6Hz,1H),3.48(d,J=16.3Hz,1H),3.35(s,3H),3.10(d,J=16.3Hz,1H),2.94-2.88(m,1H),2. 80-2.70(m,1H),2.57-2.48(m,1H),1.96(d,J=2.4Hz,3H),1.48-1.39(m,1H),1.07-0.96(m,1H). 13C NMR (125MHz, CDCl3) δ178.39,170.34,143.93,141.62,136.11,128.79,128.56,128.49,128.37,127.74,127.62,125.9 2,123.96,122.43,108.95,81.51,77.68,51.92,51.68,44.39,41.18,40.10,33.94,31.31,3.87.ESIMS:calculated[C 30 H 29 NO3+H] + :452.2220found:452.2222.[α] 20 D =-87.4(c=0.96,CH2Cl2).The product was analyzed by HPLC to determine the enantiomericexcess:99%ee(CHIRALPAK IE, hexane / i-PrOH=70 / 30, detector: 254nm, T=30℃, flowrate: 1mL / min), t1(minor)=8.92min, t2(major)=12.23min.

[0081] Example 14: Stereodivergent preparation of chiral 3-quaternary carbonylpropynyl oxidized indole compound 6b

[0082] (1) Preparation of chiral 3-quaternary carboxypropynyl oxidized indole compound (R,R)-6b

[0083]

[0084] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1e derived from oxidindole (18.7 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl indole product (R,R)-6b (30 mg, 92% yield, 13:1 d.r., >99% ee) was obtained by column chromatography as a colorless oily liquid.

[0085] 1 H NMR (400MHz, CDCl3) δ7.45 (d, J = 7.4Hz, 1H), 7.33-7.27 (m, 1H), 7.08-7.00 (m, 1H),6.85(d,J=7.8Hz,1H),3.41(s,3H),3.40(d,J=16.5Hz,1H),3.25(s,3H), 3.05(d,J=16.5Hz,1H),2.99-2.90(m,1H),2.25(td,J=7.0,2.2Hz,2H),1.59- 1.51(m,2H),1.49-1.39(m,2H),0.95(t,J=7.3Hz,3H),0.71(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ178.41,170.49,144.91,128.63,128.60,123.82,122.29,107.83,84.36,80 .19,52.11,51.70,40.89,33.90,31.14,26.43,22.16,18.59,15.84,13.77.ESIMS:calculated[C20 H 25 NO3+Na] + :350.1727found:350.1728.[α] 20 D =-167.6(c=0.80,CH2Cl2).The product wasanalyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALPAK IC,hexane / i-PrOH=70 / 30,detector:254nm,T=30℃,flow rate:1mL / min), t1(major)=6.96min, t2(minor)=7.73min.

[0086] (2) Preparation of chiral 3-quaternary carboxypropynyl oxidized indole compound (R,S)-6b

[0087]

[0088] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (S)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1e derived from oxidindole (18.7 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted again with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl indole product (R,S)-6b (28.9 mg, 88% yield, 7:1 d.r., 99% ee) was obtained by column chromatography as a colorless oily liquid.

[0089] 1H NMR (400MHz, CDCl3) δ7.33-7.27(m,1H),7.25-7.19(m,1H),7.05-7.00(m,1H ),6.83(d,J=7.7Hz,1H),3.42(s,3H),3.24(s,3H),3.19(d,J=16.5Hz,1H),3 .04(d,J=16.5Hz,1H),2.89-2.81(m,1H),2.08(td,J=6.9,2.1Hz,2H),1.40- 1.33(m,2H),1.31-1.25(m,2H),1.15(d,J=7.0Hz,3H),0.86(t,J=7.2Hz,3H). 13 C NMR (125MHz, CDCl3) δ178.10,170.60,144.90,130.11,128.53,123.24,122.04,107.85,83.52,79 .28,51.78,51.75,38.34,33.96,31.06,26.37,21.93,18.47,15.93,13.77.ESI-MS:calculated[C 20 H 25 NO3+H] + :328.1907,found:328.1911.[α] 20 D =-10.2(c=0.93, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess:99%ee(CHIRALPAK IC, hexane / i-PrOH=70 / 30, detector:254nm, T=30℃, flow rate:1mL / min), t1(major)=8.38min, t2(minor)=9.67min.

[0090] (3) Preparation of chiral 3-quaternary carboxypropynyl oxidized indole compound (S,R)-6b

[0091]

[0092] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst ent-NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1e derived from oxidindole (18.7 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl indole product (S,R)-6b (27 mg, 83% yield, 8:1 d.r., 99% ee) was obtained by column chromatography as a colorless oily liquid.

[0093] 1 H NMR (400MHz, CDCl3) δ7.33-7.27(m,1H),7.25-7.19(m,1H),7.05-7.00(m,1H ),6.83(d,J=7.7Hz,1H),3.42(s,3H),3.24(s,3H),3.19(d,J=16.5Hz,1H),3 .04(d,J=16.5Hz,1H),2.89-2.81(m,1H),2.08(td,J=6.9,2.1Hz,2H),1.40- 1.33(m,2H),1.31-1.25(m,2H),1.15(d,J=7.0Hz,3H),0.86(t,J=7.2Hz,3H). 13 C NMR (125MHz, CDCl3) δ178.10,170.60,144.90,130.11,128.53,123.24,122.04,107.85,83.52,79 .28,51.78,51.75,38.34,33.96,31.06,26.37,21.93,18.47,15.93,13.77.ESI-MS:calculated[C20 H 25 NO3+H] + :328.1907,found:328.1911.[α] 20 D =7.0 (c=0.63, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 99%ee (CHIRALPAK IC, hexane / i-PrOH=70 / 30, detector: 254nm, T=30℃, flow rate: 1mL / min), t1 (minor)=8.38min, t2 (major)=9.67min.

[0094] (4) Preparation of chiral 3-quaternary carboxypropynyl oxidized indole compound (S,S)-6b

[0095]

[0096] In a glove box at 25°C and under a nitrogen atmosphere, bis(1,5-cyclooctadiene)-nickel(0) (2.8 mg, 0.01 mmol, 10 mol%) and (S)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (8.2 mg, 0.012 mmol, 12 mol%) and 1 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube and stirred for 10 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (27.6 mg, 0.15 mmol, 1.5 equivalents), diisopropylethylamine (18 μL, 0.1 mmol, 1 equivalent), 0.3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst ent-NHC (5.8 mg, 0.01 mmol, 10 mol%), and α,β-unsaturated aldehyde 1e derived from oxidindole (18.7 mg, 0.1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted again with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 6:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl oxidized indole product (S,S)-6b (30.5 mg, 93% yield, 13:1 d.r., >99% ee) was obtained by column chromatography as a colorless oily liquid.

[0097] 1H NMR (400MHz, CDCl3) δ7.45 (d, J = 7.4Hz, 1H), 7.33-7.27 (m, 1H), 7.08-7.00 (m, 1H),6.85(d,J=7.8Hz,1H),3.41(s,3H),3.40(d,J=16.5Hz,1H),3.25(s,3H), 3.05(d,J=16.5Hz,1H),2.99-2.90(m,1H),2.25(td,J=7.0,2.2Hz,2H),1.59- 1.51(m,2H),1.49-1.39(m,2H),0.95(t,J=7.3Hz,3H),0.71(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ178.41,170.49,144.91,128.63,128.60,123.82,122.29,107.83,84.36,80 .19,52.11,51.70,40.89,33.90,31.14,26.43,22.16,18.59,15.84,13.77.ESI-MS:calculated[C 20 H 25 NO3+Na] + :350.1727,found:350.1728.[α] 20 D =153.5(c=0.97,CH2Cl2).The product wasanalyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALPAK IC,hexane / i-PrOH=70 / 30,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 6.97min, t2 (major) = 7.73min.

[0098] Example 15: Asymmetric preparation of natural product (-)-debromoflustramine B

[0099]

[0100] In a glove box under a nitrogen atmosphere at 25°C, bis(1,5-cyclooctadiene)-nickel(0) (27.5 mg, 0.1 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (82 mg, 0.12 mmol, 12 mol%) and 10 mL of anhydrous tetrahydrofuran were added to a dry 100 mL Schlenk reaction tube and stirred for 30 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 2b (327 mg, 1.5 mmol, 1.5 equivalents), diisopropylethylamine (180 μL, 1 mmol, 1 equivalent), 3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (58 mg, 0.1 mmol, 10 mol%), and α,β-unsaturated aldehyde 1d derived from indole oxide (173 mg, 1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 50 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted again with ethyl acetate (50 mL × 3). The combined organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a mixture of petroleum ether and ethyl acetate at a volume ratio of 4:1 was used as the eluent, and the chiral 3-quaternary carboxypropynyl indole product 4d (241.8 mg, 70% yield, 92% ee) was obtained by column chromatography as a colorless oily liquid.

[0101] 1 H NMR(400MHz, CDCl3)δ8.24(brs,1H),7.34-7.27(m,2H),7.24-7.17(m,4H) ,7.14-7.10(m,1H),6.98-6.92(m,1H),6.86(d,J=7.7Hz,1H),3.47(s,3H), 3.12(d,J=16.6Hz,1H),2.99(d,J=16.6Hz,1H),2.77(t,J=7.4Hz,2H),2.6 7(dt,J=16.2,2.2Hz,1H),2.50-2.43(m,2H),2.39(dt,J=15.9,2.0Hz,2H). 13 C NMR (125MHz, CDCl3) δ180.42,170.39,141.08,140.75,131.06,128.56,128.55,128.51,126.39,123 .61,122.34,109.82,83.26,75.14,51.81,48.73,39.21,35.11,28.44,20.75.ESIMS:calculated[C 22 H 21NO3+Na] + :370.1414,found:370.1420.[α] 20 D =-97.0(c=0.39,CH2Cl2).The product wasanalyzed by HPLC to determine the enantiomeric excess:92%ee(CHIRALPAK IC,hexane / i-PrOH=70 / 30,detector:254nm,T=30℃,flow rate:1mL / min), t1(major)=8.00min, t2(minor)=11.81min.

[0102]

[0103] At 25°C, starting material 4d (235.5 mg, 0.68 mmol, 1 equivalent), Lindlar catalyst (palladium / barium sulfate, 58.9 mg, 25%), quinoline (81 μL, 0.68 mmol, 1 equivalent), and 3 mL of ethyl acetate were added to a dry 10 mL reaction tube, and the mixture was stirred for 30 minutes. Subsequently, hydrogen gas was bubbled into the reaction tube, and the mixture was stirred at 25°C for 2 hours until the starting material was consumed. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and finally separated by column chromatography using a 4:1 volume ratio of petroleum ether / ethyl acetate as eluent to obtain chiral product 7 (212.5 mg, 90% yield, 92% ee), a colorless oily liquid.

[0104] 1 H NMR(400MHz, CDCl3)δ8.41(brs,1H),7.27-7.23(m,2H),7.20-7.09(m,5H),7.01-6.96(m,1H),6.87(d,J=7.7Hz,1H),5.49-5.4 0(m,1H),5.19-5.09(m,1H),3.45(s,3H),3.00(d,J=16.3Hz,1H),2.87(d,J=16.3Hz,1H),2.57-2.44(m,4H),2.29-2.18(m,2H). 13CNMR (100MHz, CDCl3) δ181.15,170.44,141.86,141.42,133.37,131.41,128.58,128.40,128.32,125 .94,123.25,122.58,122.28,109.88,51.72,50.17,40.17,35.74,35.58,29.30.ESIMS:calculated[C 22 H 23 NO3+Na] + :370.1570,found:372.1580.[α] 20 D =-15.3 (c=0.39, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess:92%ee (CHIRALPAK IC, hexane / i-PrOH=70 / 30, detector: 254nm, T=30℃, flow rate: 1mL / min), t1 (major)=7.28min, t2 (minor)=10.19min.

[0105]

[0106] In a 10 mL reaction tube, reactant 7 (35 mg, 0.1 mmol, 1 equivalent) was dissolved in 2.3 mL of a mixed solution (dichloromethane:methanol = 20:3). The reaction system was cooled to -78 °C, and ozone gas was bubbled through for about 3 minutes until the reactant was consumed. Oxygen was then bubbled through for 5 minutes, followed by the addition of dimethyl sulfide (11 μL, 0.15 mmol, 1.5 equivalent). The mixture was stirred at -78 °C for 1 hour, and then slowly restored to room temperature with stirring for 2 hours. Finally, the product was distilled under reduced pressure, using a dichloromethane / methanol mixture at a volume ratio of 80:1 as the eluent, and separated by column chromatography to obtain chiral product 8 (17.2 mg, 60% yield), a colorless oily liquid.

[0107] 1H NMR(400MHz, CDCl3)δ9.56(s,1H),8.56(brs,1H),7.32-7.26(m,1H),7.25-7.20(m,1H),7.06-6.98(m,1H),6.93(d,J=7 .8Hz,1H),3.54(s,3H),3.20(d,J=17.4Hz,1H),3.04(d,J=16.2Hz,1H),2.97(d,J=17.4Hz,1H),2.90(d,J=16.2Hz,1H). 13 C NMR (100MHz, CDCl3) δ198.36,180.22,170.11,141.20,130.48,128.95,123.93,122.78,110.36,51.95,49.33,47.07,40.32.ESIMS:calculated[C 13 H 13 NO4+Na] + :270.0737,found:270.0739.

[0108]

[0109] Under a nitrogen atmosphere and at 0 °C, triphenylphosphine isopropyl quaternary phosphine iodide (80.1 mg, 0.184 mmol, 1.5 equivalents), n-butyllithium solution (1.6 M n-hexane solution, 115 μL, 1.5 equivalents), and 0.5 mL anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube, and the mixture was stirred at 0 °C for 1 hour. Subsequently, under nitrogen protection, a solution of reactant 8 (30.5 mg, 0.123 mmol, 1 equivalent) dissolved in 1 mL anhydrous tetrahydrofuran was added dropwise to the reaction tube, and the mixture was stirred at 25 °C for 12 hours until the reactant was consumed. The reaction mixture was then quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, treated with saturated brine, and dried over anhydrous magnesium sulfate. Finally, the product was distilled under reduced pressure, using a 4:1 volume ratio of petroleum ether / ethyl acetate as eluent, and separated by column chromatography to obtain chiral product 9 (17.1 mg, 51% yield, 92% ee), a colorless oily liquid.

[0110] 1H NMR(500MHz,CDCl3)δ8.60(brs,1H),7.22-7.17(m,1H),7.14(d,J=7.3Hz,1H),7.03-6.94(m,1H),6.89(d,J=7.7Hz,1H),5.00-4.90(m,1H),3.45(s,3H),3.04(d,J=16.3Hz,1H),2.92(d,J=16.4Hz,1H),2.55-2.47(m,1H),2.46-2.36(m,1H),1.61(s,3H),1.50(s,3H). 13 C NMR(125MHz,CDCl3)δ181.68,170.61,141.38,136.49,131.66,128.16,123.28,122.10,116.98,109.85,51.72,50.44,39.86,36.51,26.02,18.10.ESIMS:calculated[C 16 H 19 NO3+Na] + :296.1257,found:296.1263.[α] 20 D =-12.4(c=0.50,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:92%e.e.(CHIRALCEL OD-H,hexane / i-PrOH=95 / 5,detector:254nm,T=30℃,flow rate:1mL / min),t1(minor)=12.56min,t2(major)=18.88min.

[0111]

[0112] In a dry 10 mL Schlenk reaction tube under nitrogen atmosphere, starting material 9 (34 mg, 0.124 mmol, 1 equivalent) and 1.2 mL N,N-dimethylformamide were added. Then, under nitrogen atmosphere, sodium hydride (6 mg, 0.149 mmol, 60% in kerosene, 1.2 equivalent) was added, and the mixture was stirred for 30 minutes at the same temperature. Subsequently, 1-bromo-3-methylbut-2-ene (17 μL, 0.149 mmol, 1.2 equivalent) was added at 0 °C, the temperature was restored to 25 °C, and the mixture was stirred for 1 hour until the starting material was consumed. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography using a 6:1 (v / v) mixture of petroleum ether and ethyl acetate as eluent to obtain chiral product 10 (38.1 mg, 90% yield, 92% ee) as a white solid.

[0113] 1 H NMR (500MHz, CDCl3) δ7.25-7.19(m,1H),7.16(d,J=7.2Hz,1H),7.02-6.96(m,1H),6.78(d,J= 7.8Hz,1H),5.17-5.10(m,1H),4.87-4.80(m,1H),4.44(dd,J=15.6,6.5Hz,1H),4.26(dd,J=15 .6,6.6Hz,1H),3.41(s,3H),3.02(d,J=16.3Hz,1H),2.90(d,J=16.3Hz,1H),2.47(dd,J=13.8, 7.5Hz,1H),2.40(dd,J=13.8,7.8Hz,1H),1.83(s,3H),1.72(s,3H),1.58(s,3H),1.47(s,3H). 13 C NMR (125MHz, CDCl3) δ178.80,170.49,143.56,136.16,136.08,131.28,128.06,122.92,121.96,118.94 ,117.13,108.55,51.59,49.83,40.01,38.18,36.61,25.94,25.77,18.23,18.07.ESIMS:calculated[C 21 H 27 NO3+Na] + :364.1883,found:364.1887.[α] 20 D=-10.5(c=0.91,CH2Cl2).The product wasanalyzed by HPLC to determine the enantiomeric excess:92%ee(CHIRALCEL OD-H,hexane / i-PrOH=85 / 15,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 4.51min, t2 (major) = 7.38min.

[0114]

[0115] Under a nitrogen atmosphere and at 25°C, starting material 10 (41.2 mg, 0.121 mmol, 1 equivalent) and 2 mL of a 30% methanol solution of methylamine were added to a dry 10 mL Schlenk reaction tube. The mixture was heated to 60°C and refluxed for 48 hours until the starting material was consumed. After cooling to 25°C, the mixture was concentrated under reduced pressure. Using a mixture of petroleum ether and ethyl acetate at a volume ratio of 1.5:1 as the eluent, the chiral product 11 (32 mg, 78% yield, 92% ee) was obtained by column chromatography as a white solid.

[0116] 1 H NMR (400MHz, CDCl3) δ7.27-7.21(m,2H),7.09-7.01(m,1H),6.78(d,J=7.7Hz,1H),6.5 7-6.39(m,1H),5.12-5.04(m,1H),4.81-4.71(m,1H),4.41(dd,J=15.5,6.3Hz,1H),4. 23(dd,J=15.4,6.7Hz,1H),2.81(d,J=14.7Hz,1H),2.70(d,J=14.9Hz,1H),2.66(d,J= 4.7Hz,3H),2.52(d,J=7.5Hz,2H),1.83(s,3H),1.72(s,3H),1.55(s,3H),1.45(s,3H). 13 C NMR (125MHz, CDCl3) δ179.67,169.85,142.68,136.48,136.07,131.58,128.11,123.45,122.53,118.60 ,117.13,108.75,50.74,42.57,38.17,36.02,26.27,25.92,25.78,18.26,18.06.ESIMS:calculated[C 21 H28 N2O2+Na] + :363.2043,found:363.2050.[α] 20 D =-13.8(c=0.75,CH2Cl2).The product was analyzed by HPLC to determine theenantiomeric excess:92%ee(CHIRALCEL OD-H,hexane / i-PrOH=85 / 15,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 6.84min, t2 (major) = 9.47min.

[0117]

[0118] Under a nitrogen atmosphere and at 25°C, reactant 11 (26.6 mg, 0.078 mmol, 1 equivalent) and 3 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube. The mixture was cooled to 0°C, and then a tetrahydrofuran solution of lithium aluminum hydride (1 M in tetrahydrofuran, 0.8 mL, 10 equivalent) was added dropwise. The mixture was stirred at 0°C for 2 hours, then restored to 25°C and stirred for 3 hours until the reactants were consumed. The reaction solution was cooled to 0°C and quenched with ethyl acetate. After filtration and vacuum distillation, the chiral product 12 (20.2 mg, 80% yield, 92% ee) was obtained by column chromatography using a 3:1 (v / v) mixture of petroleum ether and ethyl acetate as eluent. The product was a colorless liquid.

[0119] 1 H NMR (400MHz, CDCl3) δ7.15-7.09(m,1H),7.03(d,J=7.2Hz,1H),6.79-6.72( m,1H),6.52(d,J=7.9Hz,1H),5.27-5.18(m,1H),5.02-4.95(m,1H),4.71(s ,1H),3.99(dd,J=15.7,6.2Hz,1H),3.90(dd,J=15.8,7.1Hz,1H),2.88(s,3 H),2.68(s,2H),2.43-2.31(m,2H),1.74(s,6H),1.70(s,3H),1.57(s,3H). 13C NMR (125MHz, CDCl3) δ173.19,149.41,135.83,135.55,135.48,128.71,123.35,120.99,119.17,118.7 3,109.13,87.48,50.05,47.25,41.97,37.73,27.97,26.14,25.88,18.26,18.22.ESIMS:calculated[C 21 H 28 N2O+Na] + :347.2094,found:347.2092.[α] 20 D =-137.4(c=0.67,CH2Cl2).The product wasanalyzed by HPLC to determine the enantiomeric excess:92%ee(CHIRALPAKAD-H,hexane / i-PrOH=90 / 10,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 5.18min, t2 (major) = 8.33min.

[0120]

[0121] Under a nitrogen atmosphere and at 25°C, starting material 12 (19 mg, 0.057 mmol, 1 equivalent) and 2.5 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube, and the temperature was lowered to 0°C. Subsequently, a tetrahydrofuran solution of lithium aluminum hydride (1 M in tetrahydrofuran, 0.6 mL, 10 equivalent) was added dropwise. The reaction system was heated to 75°C and stirred under reflux for 12 hours until the starting material was consumed. The reaction solution was cooled to 0°C and quenched with ethyl acetate. After filtration and vacuum distillation, the chiral product (-)-debromoflustramine B(13) (15.8 mg, 87% yield) was obtained by column chromatography using a 3:1 volume ratio of petroleum ether / ethyl acetate as the eluent. The product was a colorless liquid.

[0122] 1H NMR (500MHz, CDCl3) δ7.07-7.01(m,1H),6.97(d,J=7.2Hz,1H),6.69-6.61(m,1H),6.41(d,J=7 .8Hz,1H),5.20-5.14(m,1H),5.00-4.93(m,1H),4.26(s,1H),3.93(dd,J=16.0,5.4Hz,1H),3. 80(dd,J=16.1,7.2Hz,1H),2.70-2.64(m,1H),2.59-2.54(m,1H),2.49(s,3H),2.45-2.39(m,2 H),2.09-2.02(m,1H),1.93-1.89(m,1H),1.71(s,3H),1.70(s,3H),1.65(s,3H),1.58(s,3H). 13 C NMR (125MHz, CDCl3) δ152.04,135.86,134.24,133.60,127.64,122.96,121.53,120.92,117.53,107.4 3,91.44,57.18,52.90,46.94,39.24,38.62,38.10,26.08,25.88,18.28,18.20.ESIMS:calculated[C 21 H 30 N2+H] + :311.2482,found:311.2490.[α] 20 D =-97.9 (c=0.53, CH2Cl2).

[0123] Example 16: Natural product analog (-)-C (β-Me)- Asymmetric preparation of debromoflustramine B

[0124]

[0125] In a glove box under a nitrogen atmosphere at 25°C, bis(1,5-cyclooctadiene)-nickel(0) (27.5 mg, 0.1 mmol, 10 mol%) and (R)-5,5'-bis(diphenylphosphine)-tetrafluoro-di-1,3-benzenedioxyheterocycle (82 mg, 0.12 mmol, 12 mol%) and 10 mL of anhydrous tetrahydrofuran were added to a dry 100 mL Schlenk reaction tube and stirred for 30 minutes. Subsequently, under nitrogen protection, propargyl alcohol derivative 5a (276 mg, 1.5 mmol, 1.5 equivalents), diisopropylethylamine (180 μL, 1 mmol, 1 equivalent), 3 mL methanol 3a, chiral nitrogen heterocyclic carbene catalyst NHC (58 mg, 0.1 mmol, 10 mol%), and α,β-unsaturated aldehyde 1d derived from indole oxide (173 mg, 1 mmol, 1 equivalent) were sequentially added to the mixture. The reaction was carried out at 25 °C for 48 hours, and the reaction endpoint was determined by thin-layer chromatography. Subsequently, 50 mL of saturated ammonium chloride aqueous solution was added to the reaction system, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted again with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, the chiral 3-quaternary carboxypropynyl indole product (R,R)-6c (192 mg, 61% yield, 12:1 d.r., >99% ee) was obtained by column chromatography using a mixture of petroleum ether and ethyl acetate at a volume ratio of 4:1 as the eluent. It was a colorless oily liquid.

[0126] 1 H NMR (400MHz, CDCl3) δ8.42 (brs, 1H), 7.43 (d, J = 7.4Hz, 1H), 7.25-7.19 (m, 1H) ,7.04-6.99(m,1H),6.88(d,J=7.7Hz,1H),3.44(s,3H),3.42(d,J=16.7Hz,1H) ,3.06(d,J=16.4Hz,1H),2.98-2.88(m,1H),2.26(td,J=7.0,2.1Hz,2H),1.60 -1.51(m,2H),1.49-1.41(m,2H),0.95(t,J=7.3Hz,3H),0.81(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ180.42,170.58,141.98,128.99,128.58,124.23,122.22,109.64,84.51 ,80.05,52.67,51.73,40.93,34.04,31.13,22.16,18.59,15.86,13.75.ESIMS:calculated[C 19 H23 NO3+Na] + :336.1570,found:336.1576.[α] 20 D =-158.8(c=0.60,CH2Cl2).The product wasanalyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALPAKAD-H,hexane / i-PrOH=85 / 15,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 6.83min, t2 (major) = 7.79min.

[0127]

[0128] At 25°C, the starting material (R,R)-6c (191.5 mg, 0.61 mmol, 1 equivalent), Lindlar catalyst (palladium / barium sulfate, 48.9 mg, 25%), quinoline (73 μL, 0.61 mmol, 1 equivalent), and 3 mL of ethyl acetate were added to a dry 10 mL reaction tube, and the mixture was stirred for 30 minutes. Subsequently, hydrogen gas was bubbled into the reaction tube, and the mixture was stirred at 25°C for 2 hours until the starting material was consumed. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and finally separated by column chromatography using a 4:1 volume ratio of petroleum ether / ethyl acetate as eluent to obtain chiral product 14 (180.5 mg, 94% yield, >99% ee), a white solid.

[0129] 1 H NMR (500MHz, CDCl3) δ8.51 (brs, 1H), 7.24-7.18 (m, 1H), 7.15 (d, J = 7.4Hz, 1H), 7.01 -6.96(m,1H),6.91(d,J=7.7Hz,1H),5.61-5.53(m,1H),5.38-5.30(m,1H),3.40(s,3 H),3.04(d,J=16.4Hz,1H),3.00-2.93(m,1H),2.97(d,J=16.2Hz,1H),2.23-2.13(m, 1H),2.12-2.04(m,1H),1.38-1.31(m,4H),0.95-0.89(m,3H),0.70(d,J=6.7Hz,3H). 13CNMR(125MHz, CDCl3)δ181.72,170.74,142.14,132.82,129.38,129.21,128.32,124.22,122.0 0,109.78,53.71,51.66,40.14,38.60,31.96,27.59,22.53,15.50,14.13.ESIMS:calculated[C 19 H 25 NO3+Na] + :338.1727,found:338.1727.[α] 20 D =-96.2(c=0.33,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALCEL OD-H,hexane / i-PrOH=95 / 5,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 6.51min, t2 (major) = 11.67min.

[0130]

[0131] In a 10 mL reaction tube, starting material 14 (40 mg, 0.127 mmol, 1 equivalent) was dissolved in 2.2 mL of a mixed solution (dichloromethane: methanol = 10:1). The reaction system was cooled to -78 °C, and ozone gas was bubbled through for about 3 minutes until the starting material was consumed. Oxygen was then bubbled through for 5 minutes, followed by the addition of dimethyl sulfide (14 μL, 0.19 mmol, 1.5 equivalent). The mixture was stirred at -78 °C for 1 hour, then slowly restored to room temperature and stirred for 2 hours. Finally, the product was distilled under reduced pressure, using a 3:1 volume ratio of petroleum ether / ethyl acetate as eluent, and separated by column chromatography to obtain chiral product 15 (29.7 mg, 90% yield, >99% ee), a colorless oily liquid.

[0132] 1H NMR(500MHz,CDCl3)δ9.69(d,J=1.9Hz,1H),8.60(brs,1H),7.27-7.20(m,2H),7.05-6.98(m,1H),6.91(d,J=7.7Hz,1H),3.49(s,3H),3.31(d,J=16.4Hz,1H),3.08(d,J=16.4Hz,1H),2.98(qd,J=7.2,1.8Hz,1H),1.01(d,J=7.3Hz,3H). 13 C NMR(125MHz,CDCl3)δ201.94,179.97,170.27,141.92,128.94,128.83,124.92,122.75,110.14,51.91,51.31,51.27,38.80,9.17.ESIMS:calculated[C 14 H 15 NO4+Na] + :284.0893,found:284.0895.[α] 20 D =-75.1(c=0.63,CH2Cl2).The product was analyzed by HPLC to determine theenantiomeric excess:>99%e.e.(CHIRALPAK IBN-5,hexane / i-PrOH=85 / 15,detector:254nm,T=30℃,flow rate:1mL / min),t1(minor)=12.13min,t2(major)=17.63min.

[0133]

[0134] Under a nitrogen atmosphere and at 0 °C, triphenylphosphine isopropyl quaternary phosphine iodide (74 mg, 0.171 mmol, 1.5 equivalents), n-butyllithium solution (1.6 M n-hexane solution, 107 μL, 1.5 equivalents), and 0.5 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube, and the mixture was stirred at 0 °C for 1 hour. Subsequently, under nitrogen protection, a solution of reactant 15 (29.7 mg, 0.114 mmol, 1 equivalent) dissolved in 1 mL of anhydrous tetrahydrofuran was added dropwise to the reaction tube, and the mixture was stirred at 25 °C for 12 hours until the reactant was consumed. The reaction mixture was then quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, treated with saturated brine, and dried over anhydrous magnesium sulfate. Finally, the product was distilled under reduced pressure, using a 4:1 volume ratio of petroleum ether / ethyl acetate as eluent, and separated by column chromatography to obtain chiral product 16 (18.5 mg, 57% yield, >99% ee), a colorless oily liquid.

[0135] 1 H NMR (500MHz, CDCl3) δ8.48(brs,1H),7.23-7.18(m,1H),7.14(d,J=7.3Hz,1H),7.03-6.97(m,1H),6.90(d,J=7.7Hz,1H),5.14-5. 08(m,1H),3.39(s,3H),3.04-2.94(m,2H),2.90-2.82(m,1H),1.79(d,J=1.0Hz,3H),1.72(d,J=1.1Hz,3H),0.66(d,J=6.7Hz,3H). 13 CNMR (125MHz, CDCl3) δ181.89,170.77,142.13,134.50,129.50,128.25,124.78,124.28 ,121.94,109.71,54.24,51.64,40.10,39.53,26.29,18.54,15.49.ESIMS:calculated[C 17 H 21 NO3+Na] + :310.1414,found:310.1416.[α] 20 D=-99.8(c=0.41,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALPAK IBN-5,hexane / i-PrOH=85 / 15,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 6.00min, t2 (major) = 9.46min.

[0136]

[0137] In a dry 10 mL Schlenk reaction tube under nitrogen atmosphere, starting material 16 (30 mg, 0.124 mmol, 1 equivalent) and 1.2 mL N,N-dimethylformamide were added. Then, under nitrogen atmosphere, sodium hydride (5 mg, 0.125 mmol, 60% in kerosene, 1.2 equivalent) was added, and the mixture was stirred for 30 minutes at the same temperature. Subsequently, 1-bromo-3-methylbut-2-ene (17 μL, 0.149 mmol, 1.2 equivalent) was added at 0 °C, the temperature was restored to 25 °C, and the mixture was stirred for 1 hour until the starting material was consumed. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography using a 6:1 volume ratio of petroleum ether / ethyl acetate as eluent to obtain chiral product 17 (29.7 mg, 80% yield, >99% ee) as a white solid.

[0138] 1 H NMR (500MHz, CDCl3) δ7.26-7.21(m,1H),7.15(d,J=6.8Hz,1H),7.03-6.97(m,1H),6.80(d ,J=7.7Hz,1H),5.25-5.15(m,1H),5.12-5.06(m,1H),4.47(dd,J=15.6,6.6Hz,1H),4.29( dd,J=15.6,6.5Hz,1H),3.35(s,3H),3.02-2.92(m,2H),2.90-2.83(m,1H),1.85(s,3H),1 .77(d,J=0.9Hz,3H),1.73(d,J=0.7Hz,3H),1.70(d,J=1.0Hz,3H),0.56(d,J=6.7Hz,3H). 13C NMR (125MHz, CDCl3) δ179.23,170.66,144.33,136.22,134.35,129.20,128.16,125.00,123.96,121.78,11 8.76,108.44,53.53,51.54,40.08,39.61,38.28,26.28,25.79,18.53,18.27,15.43.ESIMS:calculated[C 22 H 29 NO3+Na] + :378.2040,found:378.2039.[α] 20 D =-79.5(c=0.32,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:>99%ee(CHIRALCEL OD-H,hexane / i-PrOH=95 / 5,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 4.97min, t2 (major) = 6.83min.

[0139]

[0140] Under a nitrogen atmosphere and at 25°C, starter 17 (24 mg, 0.067 mmol, 1 equivalent) and 2 mL of a 30% methanol solution of methylamine were added to a dry 10 mL Schlenk reaction tube. The mixture was heated to 60°C and refluxed for 48 hours until the starter was consumed. After cooling to 25°C, the mixture was concentrated under reduced pressure. Using a mixture of petroleum ether and ethyl acetate at a volume ratio of 1.5:1 as eluent, the chiral product 18 (19.4 mg, 81% yield, >99% ee) was obtained by column chromatography as a white solid.

[0141] 1H NMR(500MHz,CDCl3)δ7.27-7.21(m,2H),7.07-7.01(m,1H),6.80(d,J=7.7Hz,1H),6.00-5.90(m,1H),5.16-5.09(m,2H),4.43(dd,J=15.5,6.4Hz,1H),4.29(dd,J=15.5,6.6Hz,1H),2.98-2.91(m,1H),2.79(d,J=14.5Hz,1H),2.73(d,J=14.5Hz,1H),2.55(d,J=4.8Hz,3H),1.84(s,3H),1.76(s,3H),1.72(s,3H),1.67(s,3H),0.56(d,J=6.7Hz,3H). 13 C NMR(125MHz,CDCl3)δ179.82,169.82,143.43,136.49,134.29,129.26,128.17,124.88,124.51,122.21,118.50,108.69,54.87,42.38,39.49,38.24,26.27,26.17,25.76,18.42,18.26,15.61.ESIMS:calculated[C 22 H 30 N2O2+H] + :355.2380,found:355.2383.[α] 20 D =-79.1(c=0.46,CH2Cl2).The product was analyzed by HPLC to determine theenantiomeric excess:>99%e.e.(CHIRALCEL OD-H,hexane / i-PrOH=85 / 15,detector:254nm,T=30℃,flow rate:1mL / min),t1(minor)=5.89min,t2(major)=13.67min.

[0142]

[0143] Under a nitrogen atmosphere and at 25°C, starting material 18 (35.5 mg, 0.1 mmol, 1 equivalent) and 4 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube. The mixture was cooled to 0°C, and then a tetrahydrofuran solution of lithium aluminum hydride (1 M in tetrahydrofuran, 1 mL, 10 equivalents) was added dropwise. The mixture was stirred at 0°C for 2 hours, then restored to 25°C and stirred for 3 hours until the starting material was consumed. The reaction solution was cooled to 0°C and quenched with ethyl acetate. After filtration and vacuum distillation, the chiral product 19 (29.4 mg, 87% yield, >99% ee) was obtained by column chromatography using a 3:1 volume ratio of petroleum ether / ethyl acetate as the eluent. The product was a colorless liquid.

[0144] 1 H NMR (500MHz, CDCl3) δ7.15-7.09(m,1H),7.07(d,J=7.3Hz,1H),6.76-6.69(m,1H),6.49(d ,J=7.8Hz,1H),5.31-5.25(m,1H),5.13-5.07(m,1H),4.74(s,1H),4.01(dd,J=15.7,6.2H z,1H),3.94(dd,J=15.7,6.9Hz,1H),2.85(s,3H),2.71(d,J=17.3Hz,1H),2.62(d,J=16.9 Hz,1H),2.62-2.55(m,1H),1.75(s,6H),1.71(s,3H),1.60(s,3H),0.91(d,J=6.7Hz,3H). 13 C NMR (125MHz, CDCl3) δ173.17,149.42,135.27,133.74,132.94,128.79,125.67,124.91,121.14,118.43,1 08.50,87.42,53.56,46.57,39.86,39.30,27.93,26.21,25.85,18.39,18.22,16.04.ESIMS:calculated[C 22 H 30 N2O+H] + :339.2431,found:339.2438.[α] 20 D=-122.0(c=0.44,CH2Cl2).The product was analyzed by HPLC to determine theenantiomeric excess:>99%ee(CHIRALPAK AD-H,hexane / i-PrOH=95 / 5,detector:254nm,T=30℃,flow rate: 1mL / min), t1 (minor) = 7.61min, t2 (major) = 12.38min.

[0145]

[0146] Under a nitrogen atmosphere and at 25°C, 19 mg (0.086 mmol, 1 equivalent) of reactant 19 and 4 mL of anhydrous tetrahydrofuran were added to a dry 10 mL Schlenk reaction tube. The mixture was then cooled to 0°C, followed by dropwise addition of a tetrahydrofuran solution of lithium aluminum hydride (1 M in tetrahydrofuran, 0.9 mL, 10 equivalents). The reaction mixture was refluxed at 75°C and stirred for 12 hours until the reactants were completely consumed. The reaction solution was cooled to 0°C and quenched with ethyl acetate. After filtration and vacuum distillation, the chiral product (-)-C was obtained by column chromatography using a 3:1 volume ratio of petroleum ether / ethyl acetate as the eluent. (β-Me) -debromoflustramine B(20) (21.3 mg, 76% yield) is a colorless liquid.

[0147] 1 H NMR (500MHz, CDCl3) δ7.07-7.02(m,2H),6.64-6.59(m,1H),6.40(d,J=7.7Hz, 1H),5.28-5.22(m,2H),4.24(s,1H),3.93(dd,J=15.9,5.4Hz,1H),3.85(dd,J= 15.9,7.6Hz,1H),2.64-2.57(m,2H),2.52-2.45(m,4H),2.10-2.04(m,1H),1. 86-1.81(m,1H),1.73(s,3H),1.71(s,6H),1.62(s,3H),0.82(d,J=6.7Hz,3H). 13C NMR(125MHz,CDCl3)δ152.25,134.19,133.95,131.24,127.75,127.34,124.40,121.66,116.93,106.87,91.41,61.25,53.26,46.26,40.82,38.32,36.83,26.24,25.81,18.30,18.20,17.17.ESIMS:calculated[C 22 H 32 N2+H] + :325.2638,found:325.2641.[α] 20 D =-168.9(c=0.39,CH2Cl2).

Claims

1. An asymmetric preparation method for chiral 3-quaternary carbonyl propargyl oxidized indole compounds, characterized in that: Starting with α,β-unsaturated aldehyde 1 derived from indole oxide and propargyl alcohol derivative 2, using alcohol 3 as quenching agent, bis(1,5-cyclooctadiene)-nickel(0) as metal catalyst, chiral phosphine reagent as ligand, and chiral nitrogen heterocyclic carbene as organic catalyst, the target product I was obtained after asymmetric propargylation reaction with the assistance of a base and after separation and purification. The synthesis route is shown below: ； In the above formula: * represents a chiral carbon atom; the substituent R is selected from hydrogen or C. 1-10 Alkyl; R 1 R 2 R 3 R 4 R 5 R 6 Each is independently selected from hydrogen, halogen, or C. 1-10 hydrocarbon group; R 7 Selected independently from C 1-10 Alkyl; Substituent R 8 Selected from C 1-10 alkyl; The structure of the ligand is shown below: ； The structure of the organic catalyst is shown below: 。 2. The preparation method according to claim 1, characterized in that... Includes the following steps: Under a nitrogen atmosphere, a bis(1,5-cyclooctadiene)-nickel(0) metal catalyst and a chiral phosphine ligand were mixed in an organic solvent. Then, under nitrogen protection, propargyl alcohol derivative 2, a chiral nitrogen heterocyclic carbene catalyst, an α,β-unsaturated aldehyde 1 derived from indole oxide, an alcohol 3, and a base were added to the mixture. The reaction was carried out at -78°C to 100°C for 4 to 240 hours, and the reaction endpoint was determined by thin-layer chromatography. The reaction system was then quenched with a saturated ammonium chloride aqueous solution, diluted with ethyl acetate, and extracted with water. The aqueous phase was then extracted with ethyl acetate, and the combined organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure. Finally, the asymmetric 3-quaternary carbon propargyl indole oxide product I was obtained by column chromatography.

3. The preparation method according to claim 1 or 2, characterized in that: The base is potassium phosphate, potassium monohydrogen phosphate, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethylethylenediamine, or N-methylmorpholine.

4. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of bis(1,5-cyclooctadiene)-nickel (0) to α,β-unsaturated aldehyde 1 derived from indole oxycarbamate is 0.025:1-1:1; the molar ratio of chiral phosphine ligand to α,β-unsaturated aldehyde 1 derived from indole oxycarbamate is 0.025:1-1:1; the molar ratio of chiral nitrogen heterocyclic carbene catalyst to α,β-unsaturated aldehyde 1 derived from indole oxycarbamate is 0.025:1-1:1; the molar equivalent ratio of α,β-unsaturated aldehyde 1 derived from indole oxycarbamate to propargyl alcohol derivative 2 is 1:1-1:5; the molar equivalent ratio of α,β-unsaturated aldehyde 1 derived from indole oxycarbamate to alcohol 3 is 1:1-1:100; and the molar ratio of α,β-unsaturated aldehyde 1 derived from indole oxycarbamate to base is 1:0.1-1:

5.

5. The preparation method according to claim 4, characterized in that: The molar ratio of bis(1,5-cyclooctadiene)-nickel(0) to chiral phosphine ligand is 1:1 to 1:

4.

6. The preparation method according to claim 2, 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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