A catalytic asymmetric synthesis of chiral 2-alkyl substituted pyrrolidines

Abstract

The application provides a catalytic asymmetric synthesis method of chiral 2-alkyl substituted pyrrolidine, belongs to the technical field of asymmetric organic synthesis, and relates to the reaction of acyl-protected 3-pyrroline and alkyl iodide under the catalysis of nickel and a chiral oxazoline ligand, under the action of a base and a silicon hydride reagent, in an organic solvent and at room temperature to obtain a chiral 2-alkyl substituted pyrrolidine product. The application is simple in operation, high in regioselectivity, is a cheap method with good application prospect, and can be applied to the efficient synthesis of natural products, drugs and materials.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric organic synthesis technology, and specifically relates to a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines. Background Technology

[0002] Chiral 2-substituted pyrrolidine skeletons are widely found in active natural products and pharmaceutical intermediates, and are also important skeletons for natural products, materials and pharmaceutical intermediates. The synthesis of these compounds has always attracted widespread attention from researchers and is one of the hot topics in the field of organic synthesis. At present, the synthetic methods for these chiral compounds include: asymmetric hydrogenation, enzyme catalysis and so on. However, these methods have great limitations, and the reaction conditions are generally very harsh, which greatly limits their application in drug development, natural product synthesis and other fields. Therefore, the development of efficient asymmetric synthetic methods to construct chiral 2-substituted pyrrolidine structures in one step has also received attention. For example: (1) Chiral 2-substituted pyrrolidine compounds can be synthesized by deprotonation / electrophilic coupling reaction. In 2013, Gregory C. Fu et al. obtained alkyl-substituted pyrrolidine compounds with a chiral center at the 2-position with good enantioselectivity via the Negishi coupling reaction of racemic α-zinc-N-Boc-pyrrolidine with alkyl halides (Christopher J. Cordier, Rylan J. Lundgren, and Gregory C. Fu, J. Am. Chem. Soc. 2013, 135, 10946-10949). Subsequently, Gregory C. Fu et al. synthesized bicuspid pyrrolidine compounds with a chiral center at the 2-position using nickel-catalyzed α-zinc-N-Boc-pyrrolidine and chiral alkyl halides (Xin Mu, Yu Shibata, Yusuke Makida, and Gregory C. Fu, Angew. Chem. Int. Ed. 2017, 56, 5821–5824.). (2) With the continuous development of organic synthesis methodologies, CH-bond activation, as a concise and efficient synthetic method, has been widely applied in organic synthetic chemistry. The synthesis of chiral 2-substituted pyrrolidines via asymmetric CH-bond activation is also a widely used synthetic method. For example, Takanori Shibata et al. reported the synthesis of chiral pyrrolidone structures via asymmetric sp3C-h alkylation catalyzed by a chiral iridium catalyst. (y.tahara, m.michino, m.ito, kskanyiva, t.shibata, chem.commun. 2015, 51, 16660.). Subsequently, Jin-Quan Yu et al. reported the successful construction of 2-aryl-substituted chiral pyrrolidine structures through palladium-catalyzed asymmetric CH-bond insertion. (Pankaj Jain, Pritha Verma, Guoqin Xia, Jin-Quan Yu, Nat. Chem. 2017, 9, 140-144.)

[0003] The above methods usually require the pre-preparation of metal alkyl reagents or the use of expensive transition metal catalysts. Most synthetic methods have difficulties in controlling the regioselectivity and enantioselectivity of the products, and have drawbacks such as the difficulty in preparing raw materials and the instability and mutability of enzymes. Therefore, developing a low-cost metal-catalyzed method for highly selective synthesis of chiral 2-substituted pyrrolidines has important research significance and application value. Summary of the Invention

[0004] This invention addresses the technical problems existing in the prior art by providing a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines. Using acyl-protected 3-pyrrolidines and alkyl iodides as raw materials, the method involves reacting the chiral 2-alkyl-substituted pyrrolidine products in an organic solvent at room temperature under the catalysis of nickel and chiral oxazoline ligands, and in the presence of a base and a silane reagent.

[0005] The technical solution adopted in this invention is: a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: reacting acyl-protected 3-pyrrolidines with alkyl iodides in an organic solvent under the catalysis of nickel and chiral oxazoline ligands, and in the presence of a base and a silane reagent, at room temperature to obtain chiral 2-alkyl-substituted pyrrolidine products.

[0006]

[0007] Further, nickel, chiral oxazoline ligand and organic solvent were added to the reaction flask and stirred evenly at room temperature. Then, acyl-protected 3-pyrrolidone, alkyl iodide, base and organic solvent were added. After cooling to zero degrees Celsius, silane reagent was added dropwise. Then, the mixture was restored to room temperature and reacted at room temperature for 20-30 hours.

[0008] Further, after the reaction was completed, ethyl acetate was added, the mixture was filtered, the filter cake was washed with ethyl acetate 2-3 times, the solvent was removed under reduced pressure, and the chiral 2-alkyl-substituted pyrrolidine products were separated by column chromatography.

[0009] Furthermore, the acyl protecting group of the acyl-protected 3-pyrrolidone is a benzoyl group with different substitutions, and the substituent R on the benzene ring of the benzoyl group is chlorine, alkyl, methoxy, naphthyl, phenyl or ester group;

[0010] The substituent R1 on the alkyl iodide is alkyl, ester, naphthyl, benzyl, phenyl, chlorine, carbazole, or amide.

[0011] Furthermore, the molar ratio of the acyl-protected 3-pyrrolidone to the alkyl iodide is 1:2, and the concentration is 0.05 mol / L.

[0012] Furthermore, the nickel used is at least one of NiBr2, NiCl2, NiI2, Ni(DME)Br2, Ni(OTf)2, and Ni(OAc)2, and the amount of nickel is 8-11 mol% of acyl-protected 3-pyrrolline.

[0013] Furthermore, the chiral oxazoline ligand used is at least one of L1-L8.

[0014]

[0015] The amount of chiral oxazoline ligand is 11-13 mol% of acyl-protected 3-pyrrolline.

[0016] Furthermore, the base used is at least one selected from diisopropylamine, triethylamine, tetramethylethylenediamine, N,N-dimethylethylamine, N,N-diisopropylethylamine, piperidine, 2,2,6,6-tetramethylpiperidine, 1,2,2,6,6-pentamethylpiperidine, potassium fluoride, potassium phosphate, cesium carbonate, cesium fluoride, potassium carbonate, or sodium carbonate, and the amount of base is 2-3 eq of acyl-protected 3-pyrroline.

[0017] Furthermore, the organic solvent used is at least one of tetrahydrofuran, ethylene glycol dimethyl ether, toluene, chlorobenzene, xylene, mesitylene, pentafluorobenzene, fluorobenzene, cyclopentyl methyl ether, methyl tert-butyl ether, tert-butylmethylene ether, N,N-dimethylformamide, or 1,4-dioxane.

[0018] Furthermore, the silane reagent used is at least one of dimethoxymethylsilane, methylphenyldichlorosilane, trimethoxysilane, phenyldimethylsilane, or triethoxysilane, and the amount of the silane reagent is 2-3 eq of acyl-protected 3-pyrrolline.

[0019] Compared with the prior art, the beneficial effects of this invention are as follows: This invention uses acyl-protected 3-pyrrolidine and alkyl iodide as raw materials, and obtains chiral 2-alkyl-substituted pyrrolidine products in one step under the catalysis of nickel and chiral bisoxazoline ligands and the action of base and silane reagent. The operation is simple, the regioselectivity is high, and it is an inexpensive method with good application prospects. It can be applied to the efficient synthesis of natural products, drugs and materials. Attached Figure Description

[0020] Figure 1 The hydrogen NMR spectrum of the sample obtained in Example 1 of this invention;

[0021] Figure 2 The carbon NMR spectrum of the sample obtained in Example 1 of this invention;

[0022] Figure 3 The 1H NMR spectrum of the sample obtained in Example 2 of this invention;

[0023] Figure 4 The carbon NMR spectrum of the sample obtained in Example 2 of this invention;

[0024] Figure 5 The hydrogen NMR spectrum of the sample obtained in Example 3 of this invention;

[0025] Figure 6 The carbon NMR spectrum of the sample obtained in Example 3 of this invention;

[0026] Figure 7 The 1H NMR spectrum of the sample obtained in Example 26 of this invention;

[0027] Figure 8 The carbon NMR spectrum of the sample obtained in Example 26 of this invention;

[0028] Figure 9 The hydrogen NMR spectrum of the sample obtained in Example 27 of this invention;

[0029] Figure 10 The carbon NMR spectrum of the sample obtained in Example 27 of this invention;

[0030] Figure 11 The 1H NMR spectrum of the sample obtained in Example 28 of this invention;

[0031] Figure 12 This is the carbon NMR spectrum of the sample obtained in Example 28 of the present invention. Detailed Implementation

[0032] To enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0033] Example 1

[0034] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, followed by column chromatography to obtain target product 1 (45.8 mg, yield 82%, ee value 90%). Figure 1 and Figure 2 As shown, the proton and carbon spectrum data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.43–7.36(m,5H),7.22(t,J=7.6Hz,2H),7.13(t,J=7.2Hz,3H),4.12(s ,1H),3.45–3.35(m,2H),2.64–2.50(m,2H),2.10–1.96(m,2H),1.92–1.84(m,1H),1.78–1.68(m,3H). 13 C NMR (126MHz, CDCl3) δ170.0,142.0,137.5,129.9,128.4,128.2,127.3,126.5,125.8,57.2,50.2,35.4,32.3,30.4,25.2.

[0035] Example 2

[0036] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2b (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, followed by column chromatography to obtain target product 2 (45.8 mg, yield 78%, ee value 90%). Figure 3 and Figure 4 As shown, the proton and carbon spectrum data are as follows: 1 H NMR(500MHz,DMSO-d6,100℃)δ7.45–7.36(m,5H),7.14–6.96(m,4H),4.15(s,1H),3.47–3.36(m,2H),2.6 4–2.49(m,2H),2.20(s,3H),2.10–2.02(m,1H),1.98–1.84(m,2H),1.81–1.73(m,2H),1.70–1.61(m,1H). 13 C NMR (126MHz, CDCl3) δ170.1,140.2,137.5,135.9,130.2,129.9,128.7,128.2,127.3,126.0,126.0,57.4,50.2,34.4,30.5,29.8,25.2,19.3.

[0037] Example 3

[0038] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2c (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, followed by column chromatography to obtain target product 3 (42.1 mg, yield 68%, ee value 89%). Figure 5 and Figure 6 As shown, the proton and carbon spectrum data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.44–7.34(m,5H),7.12(td,J=7.8,1.8Hz,1H),7.09–7.00(m,1H),6.89(d,J=8.1Hz,1H),6.86–6.77(m,1H),4 .10(s,1H),3.75(s,3H),3.45–3.34(m,2H),2.59–2.49(m,2H),2.07– 1.99(m,1H),1.97–1.83(m,2H),1.79–1.70(m,2H),1.69–1.59(m,1H). 13 C NMR (126MHz, CDCl3) δ169.9,157.4,137.7,130.4,129.8,129.7,128.2,127.3,127.0,120.5,110.2,57.4,55.3,50.2,33.7,30.2,26.5,25.2.

[0039] Example 4

[0040] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2d (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then brought back to room temperature and reacted for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 4 (45.2 mg, yield 73%, ee value 90%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.44–7.35(m,5H),7.13(t,J=7.5Hz,1H),6.79–6.64(m,3H),4.12(s,1H),3. 73(s,3H),3.45–3.34(m,2H),2.64–2.49(m,2H),2.10–1.94(m,2H),1.92–1.84(m,1H),1.78–1.67(m,3H). 13 C NMR (126MHz, CDCl3) δ170.0,159.7,143.6,137.5,129.9,129.3,128.2,127.3,120.8,114.0,111.4,57.2,55.2,50.2,35.3,32.4,30.4,25.2.

[0041] Example 5

[0042] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2e (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 5 (49.5 mg, yield 80%, ee value 90%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.44–7.30(m,5H),7.10–6.91(m,2H),6.83–6.71(m,2H),4.09(s,1H),3.7 1(s,3H),3.45–3.31(m,2H),2.58–2.48(m,2H),2.08–1.92(m,2H),1.91–1.82(m,1H),1.79–1.63(m,3H). 13 C NMR (126MHz, CDCl3) δ167.0,157.8,134.0,129.9,129.2,128.9,128.2,127.3,113.8,57.1,55.3,50.2,35.6,31.4,30.4,25.2.

[0043] Example 6

[0044] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2f (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 6 (50.1 mg, yield 65%, ee value 87%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.45–7.32(m,9H),7.31–7.25(m,1H),7.03(d,J=8.0Hz,2H),6.87(d,J=8.4Hz ,2H),5.05(s,2H),4.10(s,1H),3.45–3.33(m,2H),2.57–2.47(m,2H),2.04–1.83(m,3H),1.77–1.64(m,3H). 13 C NMR (126MHz, CDCl3) δ170.0,157.1,137.5,137.3,134.3,129.9,129.3,128.6 ,128.2,127.9,127.5,127.4,114.8,70.1,57.2,50.2,35.6,31.4,30.4,25.2.

[0045] Example 7

[0046] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2g (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 7 (44.6 mg, yield 75%, ee value 88%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.43–7.36(m,5H),7.24–7.08(m,2H),7.00(t,J=8.8Hz,2H) ,4.10(s,1H),3.45–3.34(m,2H),2.65–2.50(m,2H),2.06–1.84(m,3H),1.79–1.68(m,3H). 13 C NMR (126MHz, CDCl3) δ170.1, 161.3 (d, J = 243.4Hz), 137.4 (d, J = 12.4Hz), 129.9, 129.7 (d,J=7.9Hz),128.2,127.3,115.1(d,J=21.1Hz),57.1,50.2,35.5,31.5,30.4,25.2. 19 F NMR (471MHz, CDCl3) δ-117.9.

[0047] Example 8

[0048] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2h (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 8 (49.1 mg, yield 74%, ee value 90%). The 1H and 1C spectral data are as follows: 1 H NMR(500MHz,DMSO-d6,100℃)δ7.45–7.30(m,6H),7.23–7.10(m,2H),4.12(s,1H),3.47–3 .35(m,2H),2.66–2.51(m,2H),2.10–1.95(m,2H),1.93–1.87(m,1H),1.80–1.70(m,3H). 13 C NMR (126MHz, CDCl3) δ170.2,156.5(d,J=246.4Hz),138.9,137.3,130.1(d,J=36.2Hz),128.2,128.0(d,J=7.1H z), 127.3, 120.5 (d, J = 18.0Hz), 116.3 (d, J = 21.1Hz), 115.1 (d, J = 20.5Hz), 57.0, 50.2, 35.4, 31.4, 30.5, 25.2. 19 F NMR (471MHz, CDCl3) δ-120.2.

[0049] Example 9

[0050] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2i (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 9 (50.2 mg, yield 74%, ee value 91%). The 1H and 1C spectral data are as follows: 1 H NMR(500MHz,DMSO-d6,100℃)δ7.51–7.29(m,5H),6.43–6.22(m,3H),4.12(s,1H),3.7 1(s,6H),3.45–3.32(m,2H),2.62–2.47(m,2H),2.07–1.84(m,3H),1.77–1.65(m,3H). 13 C NMR (126MHz, CDCl3) δ170.0,160.8,144.4,137.5,129.9,128.2,127.3,106.3,98.1,57.1,55.3,50.2,35.2,32.7,30.4,25.2.

[0051] Example 10

[0052] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2j (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 10 (27.8 mg, yield 42%, ee value 86%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.99(s,1H),7.89(dd,J=7.4,1.9Hz,1H),7.74(d,J=8.1Hz,1H),7.60–7 .30(m,9H),4.27(s,1H),3.54–3.40(m,2H),3.12–3.03(m,2H),2.21–2.07(m,2H),1.99–1.77(m,4H). 13 C NMR (126MHz, CDCl3) δ170.2,138.1,137.5,133.9,131.9,129.9,128.8,128.2,127 .3,126.6,125.9,125.8,125.6,125.4,123.7,57.5,50.2,35.1,30.6,29.6,25.3.

[0053] Example 11

[0054] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2k (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then brought back to room temperature and reacted for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 11 (54.6 mg, yield 76%, ee value 85%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.68(t,J=9.4Hz,2H),7.55(s,1H),7.45–7.33(m,5H),7.31–7.20(m,2H),7.11(dd,J=8.9,2.5Hz ,1H),4.16(s,1H),3.86(s,3H),3.46–3.33(m,2H),2.78–2.61(m,2H),2.17–1.98(m,2H),1.93–1.85(m,1H),1.83–1.69(m,3H). 13 C NMR (126MHz, CDCl3) δ170.0,157.2,137.5,137.2,133.0,129.9,129.2,129.0,128.2 ,127.9,127.4,126.8,126.2,118.6,105.7,57.3,55.3,50.2,35.4,32.3,30.5,25.3.

[0055] Example 12

[0056] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2l (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 12 (26.8 mg, yield 58%, ee value 92%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.44–7.36(m,5H),4.13(s,1H),3.43–3.33(m,2H),2.05–1.96(m,1H ),1.91–1.81(m,1H),1.80–1.70(m,1H),1.66–1.46(m,3H),1.29–1.22(m,1H),0.90–0.71(m,6H). 13 C NMR (126MHz, CDCl3) δ169.8,137.6,129.8,128.1,127.4,55.9,49.8,43.3,30.6,25.7,25.1,23.8,21.9.

[0057] Example 13

[0058] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2m (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then brought back to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 13 (24.8 mg, yield 45%, ee value 88%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.45–7.37(m,5H),4.75(t,J=4.6Hz,1H),4.15–4.06(m,1H),3.87–3.80(m,2H),3. 77–3.69(m,2H),3.43–3.32(m,2H),2.04–1.96(m,1H),1.88–1.70(m,3H),1.67–1.60(m,1H),1.59–1.45(m,3H). 13 C NMR (126MHz, CDCl3) δ170.0,137.4,129.8,128.2,127.3,104.4,64.9,64.9,57.0,50.2,30.3,30.2,28.1,25.1.

[0059] Example 14

[0060] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2n (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 14 (45.2 mg, yield 77%, ee value 91%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.43–7.36(m,5H),7.23(t,J=7.5Hz,2H),7.18–7.09(m,3H),4.11(s,1H),3.42–3.31(m, 2H),2.60–2.50(m,2H),2.03–1.95(m,1H),1.87–1.79(m,1H),1.77–1.67(m,2H),1.66–1.53(m,3H),1.47–1.37(m,1H). 13 CNMR (126MHz, CDCl3) δ170.0,142.6,137.5,129.8,128.5,128.3,128.2,127.4,125.7,57.3,50.2,36.0,33.6,30.3,28.0,25.2.

[0061] Example 15

[0062] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2o (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then brought back to room temperature and reacted for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 15 (52.5 mg, yield 73%, ee value 92%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.81–7.72(m,3H),7.47–7.34(m,6H),7.31(t,J=7.6Hz,1H),7.27–7.20(m,1H),7.13(dd,J=8.9,2.6Hz,1 H),4.18(s,1H),4.06(t,J=6.6Hz,2H),3.46–3.32(m,2H),2.08–2.00(m,1H),1.94–1.82(m,2H),1.80–1.66(m,4H),1.64–1.55(m,1H). 13 C NMR (126MHz, CDCl3) δ170.2,157.0,137.5,134.7,129.9,129.4,129.0,128.3,127.7 ,127.4,126.8,126.3,123.5,119.0,106.7,67.9,57.1,50.2,30.5,30.4,25.9,25.1.

[0063] Example 16

[0064] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2p (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 16 (39.6 mg, yield 72%, ee value 89%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.46–7.37(m,5H),4.15(s,1H),4.04(q,J=7.1Hz,2H),3.45–3.31(m,2H),2.28(t, J=7.7Hz,2H),2.05–1.92(m,2H),1.91–1.81(m,1H),1.78–1.69(m,2H),1.68–1.60(m,1H),1.17(t,J=7.1Hz,3H). 13 C NMR (126MHz, CDCl3) δ173.5,170.3,137.2,129.9,128.2,127.3,60.4,56.6,50.1,31.2,30.2,29.2,25.0,14.2.

[0065] Example 17

[0066] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2q (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 17 (28.9 mg, yield 50%, ee value 90%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.48–7.40(m,5H),4.18–4.03(m,3H),3.46–3.34(m,2H),2.34–2.18(d,J=7.6 Hz,2H),2.08–1.99(m,1H),1.93–1.84(m,1H),1.81–1.64(m,3H),1.61–1.41(m,3H),1.20(t,J=7.1Hz,3H). 13 C NMR (126MHz, CDCl3) δ173.6,170.0,137.4,129.9,128.2,127.3,60.3,57.0,50.2,34.2,33.2,30.2,25.1,21.3,14.3.

[0067] Example 18

[0068] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2r (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 18 (61.2 mg, yield 80%, ee value 91%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ8.10 (dt, J=7.8, 1.0Hz, 2H), 7.51 (d, J=8.2Hz, 2H), 7.44–7.39 (m, 2H), 7.38–7.29 (m, 5H), 7.20–7 .15(m,2H),4.33(t,J=6.9Hz,2H),4.12(s,1H),3.33(t,J=7.0Hz,2H),2.00–1.93(m,1H),1.83–1.64(m,5H),1.59–1.46(m,2H). 13 C NMR (126MHz, CDCl3) δ170.3,140.4,137.3,130.0,128.2,127.4,125.7,122.9,120.4,118.8,108.8,57.0,50.2,43.1,31.5,30.4,25.3,25.1.

[0069] Example 19

[0070] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2s (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 19 (37.7 mg, yield 52%, ee value 92%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.88–7.76(m,4H),7.43–7.29(m,5H),4.09(s,1H),3.62–3.51(m,2H ),3.43–3.31(m,2H),2.05–1.97(m,1H),1.89–1.80(m,1H),1.77–1.58(m,5H),1.50–1.40(m,1H). 13 C NMR (126MHz, CDCl3) δ170.1,168.4,137.3,133.9,132.1,129.9,128.2,127.4,123.2,56.8,50.2,38.0,31.1,30.3,25.2,25.1.

[0071] Example 20

[0072] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2t (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then returned to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 20 (33.2 mg, yield 64%, ee value 88%). The 1H and 1C spectral data are as follows: 1 H NMR(500MHz,DMSO-d6,100℃)δ7.46–7.36(m,5H),4.05(s,1H),3.43–3.33(m,2H),2.04–1.95(m,1H) ,1.90–1.81(m,1H),1.79–1.60(m,3H),1.41–1.32(m,1H),1.29–1.17(m,8H),0.84(t,J=6.9Hz,3H). 13 C NMR (126MHz, CDCl3) δ169.8,137.6,129.8,128.2,127.3,57.4,50.2,33.8,31.9,30.3,29.4,25.9,25.2,22.6,14.1.

[0073] Example 21

[0074] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2u (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then brought back to room temperature and reacted for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 21 (38.8 mg, yield 66%, ee value 85%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.44–7.36(m,5H),4.12–4.00(m,1H),3.56(t,J=6.7Hz,2H),3.44–3.32( m,2H),2.04–1.96(m,1H),1.89–1.81(m,1H),1.78–1.61(m,5H),1.43–1.31(m,3H),1.30–1.16(m,4H). 13 C NMR (126MHz, CDCl3) δ169.9,137.6,129.8,128.2,127.3,57.3,50.2,45.2,33.7,32.6,30.3,28.9,26.9,25.8,25.1.

[0075] Example 22

[0076] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2v (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then returned to room temperature and reacted for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, followed by column chromatography to obtain the target product 22 (88.8 mg, yield 74%, dr value 95:5). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 50℃) δ7.50–7.37(m,5H),7.26(d,J=8.4Hz,1H),6.91–6.71(m,2H),4.64(t,J=8 .4Hz,1H),4.16(s,1H),3.46–3.39(m,1H),3.19(s,1H),2.84–2.75(m,2H),2.58(s,2H),2.28(td,J=7 .3,2.2Hz,3H),2.23–2.16(m,1H),2.15–2.08(m,1H),2.07–1.99(m,1H),1.97–1.79(m,3H),1.79–1.7 5(m,1H),1.74–1.62(m,4H),1.58–1.44(m,4H),1.45–1.18(m,9H),0.88(t,J=7.4Hz,3H),0.79(s,3H). 13 C NMR (126MHz, CDCl3) δ173.9,172.4,170.0,148.5,138.1,137.8,137.4,129.9,128.2,127.3,126.4,121.5,118.6,82.4,57.0 ,50.2,49.8,44.0,42.9,38.2,36.9,34.3,34.2,33.2,30.3,29.5,27.6,27.2,27.0,26.1,25.1,23.3,22.3,21.3,13.8,12.1.

[0077] Example 23

[0078] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2w (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 23 (73.9 mg, yield 72%, dr value 95:5). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 60℃) δ7.52–7.37(m,5H),7.29(d,J=8.3Hz,1H),6.95–6.75(m,2H),4.17(s,1H),3.47–3.42(m,1H),3.18(s,2H),2. 93–2.79(m,2H),2.65–2.53(m,1H),2.49–2.36(m,2H),2.26(td,J=10.8,4.2Hz,1H),2.12–1.76(m,8H),1.73–1.35(m,10H),0.86(s,3H). 13 C NMR (126MHz, CDCl3) δ220.8,172.4,170.1,148.6,138.0,137.4,137.3,129.9,128.2,127.3,126.4,121.6,118 .8,57.0,50.4,50.2,47.9,44.2,38.0,35.9,34.2,33.2,31.6,30.3,29.4,26.4,25.8,25.1,21.6,21.3,13.8.

[0079] Example 24

[0080] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2x (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 24 (54.2 mg, yield 56%, ee value 82%). The 1H and 1C spectral data are as follows: 1 H NMR(500MHz,DMSO-d6,80℃)δ7.98(d,J=2.3Hz,1H),7.79–7.77(m,1H),7.63–7.60(m,1H),7.53–7.44(m,3H),7.41–7.35(m,5H) ,7.03(d,J=8.4Hz,1H),5.24(s,2H),4.16–3.85(m,3H),3.66(s,2H),3.39–3.20(m,2H),2.00–1.92(m,1H),1.83–1.34(m,7H). 13 C NMR (126MHz, CDCl3) δ190.8,171.4,170.1,160.5,140.5,137.3,136.5,135.6,132.8,132.4,129.9,129. 5,129.3,128.2,128.0,127.8,127.3,125.1,121.1,73.6,65.0,56.9,50.2,40.3,30.3,30.3,25.2,25.1.

[0081] Example 25

[0082] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1a (0.2 mmol, 1.0 equiv.), 2y (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, followed by column chromatography to obtain the target product 25 (56.8 mg, yield 51%, dr value 98:2). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, CDCl3, 55℃) δ7.53–7.44(m,2H),7.42–7.37(m,3H),7.17(d,J=8.1Hz,1H),7.00(dd,J= 8.2,2.0Hz,1H),6.91–6.88(m,1H),5.68(s,1H),4.27(s,1H),3.45(s,2H),3.24(dd,J=13.6,6.4Hz, 1H),3.13(dd,J=13.6,6.4Hz,1H),2.96–2.79(m,3H),2.34–2.26(m,1H),2.25–2.12(m,2H),2.07–2. 02(m,1H),1.97–1.85(m,3H),1.82–1.61(m,8H),1.48–1.34(m,8H),1.26–1.22(m,9H),0.95(s,3H). 13 C NMR (126MHz, CDCl3) δ173.3,169.9,147.2,145.6,137.5,134.9,129.8,128.2,127.3,126.9,124.2,123.8,57.2,50.1, 49.8,45.4,38.4,37.5,37.3,36.8,36.2,33.4,30.3,30.3,28.9,25.7,25.5,25.3,25.1,24.0,24.0,19.0,18.7,18.6.

[0083] Example 26

[0084] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1b (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, followed by column chromatography to obtain the target product 26 (45.8 mg, yield 78%, ee value 90%). Figure 7 and Figure 8 As shown, the proton and carbon spectrum data are as follows: 1 H NMR(500MHz, CDCl3)δ7.49–6.66(m,9H),4.43–3.75(m,1H),3.64–3.08(m,2H),2.79–2.66 (m,1H),2.47–2.38(m,1H),2.28(d,J=29.6Hz,3H),2.22–1.85(m,3H),1.85–1.49(m,3H). 13 C NMR (126MHz, CDCl3) δ169.9,141.9,140.5,138.1,137.5,133.8,130.4,130.4,128.8,128.7,128.4,128.4,127.9 ,126.0,125.9,125.9,125.7,125.7,58.1,56.8,48.6,45.2,35.4,32.7,32.3,30.2,30.0,24.5,22.5,19.1,19.0.

[0085] Example 27

[0086] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1c (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then brought back to room temperature and reacted for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, followed by column chromatography to obtain the target product 27 (54.5 mg, yield 65%, ee value 87%). Figure 9 and Figure 10 As shown, the proton and carbon spectrum data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.41–6.72(m,9H),4.26–3.06(m,7H),2.66(s,1H),2.33–1.45(m,7H). 13 CNMR(126MHz, CDCl3)δ167.9,167.7,155.3,142.3,140.9,130.2,130.2,128.5,128.4,128.0,127.9,127.8, 127.3,125.7,120.8,120.7,111.3,111.1,56.8,55.6,55.4,48.0,45.4,35.2,32.3,30.1,30.0,24.3,22.5.

[0087] Example 28

[0088] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1d (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, followed by column chromatography to obtain the target product 28 (39.9 mg, yield 68%, ee value 86%). Figure 11 and Figure 12 As shown, the proton and carbon spectrum data are as follows: 1 H NMR(500MHz,DMSO-d6,100℃)δ7.30–7.07(m,9H),4.10(s,1H),3.44–3.34(m,2H),2.6 4–2.50(m,2H),2.32(s,3H),2.06–1.94(m,2H),1.92–1.84(m,1H),1.78–1.64(m,3H). 13 CNMR (126MHz, CDCl3) δ170.2,142.0,138.0,137.5,130.5,128.4,128.0,127.9,125.8,124.3,57.1,50.2,35.4,32.3,30.4,25.2,21.4.

[0089] Example 29

[0090] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1e (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 29 (32.0 mg, yield 51%, ee value 92%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.47–7.33(m,4H),7.23(t,J=7.5Hz,1H),7.13(t,J=7.2Hz,1H),4.09(s ,1H),3.46–3.33(m,2H),2.65–2.50(m,2H),2.09–1.94(m,2H),1.92–1.85(m,1H),1.80–1.69(m,3H). 13 C NMR (126MHz, CDCl3) δ168.4,141.8,139.1,134.3,130.0,129.7,128.4,128.4,127.5,125.9,125.4,57.4,50.1,35.2,32.3,30.3,25.1.

[0091] Example 30

[0092] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1f (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then brought back to room temperature and reacted for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 30 (42.2 mg, yield 72%, ee value 90%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.13–7.06(m,2H),7.06–6.82(m,7H),3.90(s,1H),3.24–3.12(m ,2H),2.45–2.28(m,2H),2.11(s,3H),1.90–1.72(m,2H),1.70–1.61(m,1H),1.57–1.42(m,3H). 13 C NMR (126MHz, CDCl3) δ170.1,142.0,140.0,134.5,128.8,128.4,128.4,127.5,125.8,57.2,50.3,35.5,32.3,30.4,25.3,21.4.

[0093] Example 31

[0094] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1 g (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then returned to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 31 (29.6 mg, yield 45%, ee value 90%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, CDCl3) δ8.03–6.32(m,12H),4.56–3.86(m,1H),3.79–3.00(m,2H),2.89–2.52(m,2H),2.31–1.39(m,6H). 13 C NMR (126MHz, CDCl3) δ169.3,141.9,140.4,136.1,133.6,129.3,129.1,129.1,128.5,128.5,128.5,128.2,127.7,127.0, 127.0,126.3,125.9,125.7,125.3,125.1,124.9,123.9,58.5,57.2,48.9,45.6,35.5,32.8,32.1,30.2,23.0,24.5,22.5.

[0095] Example 32

[0096] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1h (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 32 (44.0 mg, yield 68%, ee value 90%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.23(t,J=7.5Hz,2H),7.18–7.09(m,3H),6.95(d,J=7.7Hz,2H),6.86(d,J=7.8Hz,1H),6.01 (s,2H),4.14–4.08(m,1H),3.47–3.37(m,2H),2.64–2.50(m,2H),2.06–1.96(m,2H),1.92–1.83(m,1H),1.77–1.66(m,3H). 13 C NMR (126MHz, CDCl3) δ169.3,148.9,147.4,141.9,131.2,128.4,125.8,122.1,108.3,107.9,101.4,57.3,50.5,35.4,32.3,30.5,25.3.

[0097] Example 33

[0098] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1i (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 33 (19.9 mg, yield 43%, ee value 75%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, CDCl3) δ7.34–7.12(m,5H),4.18–3.72(m,1H),3.57–3.33(m,2H),2.7 3–2.52(m,2H),2.33–2.08(m,3H),2.02–1.51(m,6H),1.12(dt,J=16.2,7.4Hz,3H). 13 C NMR (126MHz, CDCl3) δ172.4,172.3,142.0,141.0,128.6,128.4,128.3,126.2,125.7,57. 0,57.0,46.7,45.4,36.5,34.9,32.8,32.8,30.2,29.3,28.1,27.2,24.1,22.1,9.6,9.0.

[0099] Example 34

[0100] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1j (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 34 (26.0 mg, yield 53%, ee value 84%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.32–7.11(m,5H),3.97(s,1H),3.46–3.28(m,2H),2.65–2. 51(m,2H),2.21–2.08(m,2H),1.99–1.62(m,6H),1.57–1.48(m,2H),0.87(t,J=7.6Hz,3H). 13 C NMR (126MHz, CDCl3) δ171.7,171.6,142.0,140.9,128.6,128.5,128.4,128.3,126.2,125.7,56. 9,56.8,46.9,45.3,37.0,36.6,36.2,35.0,32.8,32.7,30.1,29.3,24.1,22.1,18.9,18.3,14.0.

[0101] Example 35

[0102] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1k (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 35 (29.1 mg, yield 56%, ee value 86%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.43–6.94(m,5H),4.07–3.74(m,1H),3.48–3.27(m,2H),2.66–2.51(m,2H),2.08–1.59(m,9H),0.96–0.82(m,6H). 13 C NMR (126MHz, CDCl3) δ171.2,171.2,142.0,140.9,128.6,128.4,128.4,128.3,126.2,125.7,56.9,56. 6,47.1,45.2,44.0,43.1,36.5,35.1,32.9,32.7,30.0,29.3,25.9,25.5,24.2,22.8,22.7,22.4,22.1.

[0103] Example 36

[0104] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1 L (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then restored to room temperature and reacted at room temperature for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 36 (49.8 mg, yield 74%, ee value 83%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, DMSO-d6, 100℃) δ7.27–7.10(m,5H),4.15–4.07(m,1H),3.79–3.73(m,1H),3.52 –3.45(m,1H),2.60–2.49(m,2H),1.97–1.74(m,13H),1.70–1.64(m,6H),1.64–1.54(m,2H). 13 C NMR (126MHz, CDCl3) δ175.7,128.4,128.3,125.7,42.0,38.4,36.7,35.4,32.7,28.5.

[0105] Example 37

[0106] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1m (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then returned to room temperature and reacted for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 37 (44.7 mg, yield 78%, ee value 67%). The 1H and 1C spectral data are as follows: 1 H NMR(500MHz, CDCl3)δ7.27–7.13(m,5H),4.15–4.06(m,1H),3.37–3.27(m,2H),3.26–3.13(m,4H), 2.61(t,J=8.3Hz,2H),2.16–2.05(m,2H),1.87–1.79(m,1H),1.74–1.65(m,1H),1.62–1.45(m,8H). 13 C NMR (126MHz, CDCl3) δ163.3,142.4,128.4,128.3,125.6,57.8,50.7,47.1,36.9,32.4,31.2,25.8,25.7,24.8.

[0107] Example 38

[0108] This invention provides a catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, comprising the following steps: Under a nitrogen atmosphere, 6.2 mg NiBr2·DME, 18.2 mg L1, and 2 ml of ethylene glycol dimethyl ether are added to a reaction flask. The mixture is stirred at room temperature for 10 minutes. Then, 1n (0.2 mmol, 1.0 equiv.), 2a (0.4 mmol, 2.0 equiv.), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv.) are added. Another 2 ml of ethylene glycol dimethyl ether is then added. The reaction system is cooled to 0 degrees Celsius, and (MeO)2MeSiH (63.7 mg, 0.6 mmol, 3.0 equiv.) is added dropwise. The mixture is then brought back to room temperature and reacted for 24 hours. After the reaction is complete, 5 ml of ethyl acetate is added to the system, and the mixture is filtered. The filter cake is washed three times with ethyl acetate. Solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the target product 38 (45.2 mg, yield 61%, ee value 90%). The 1H and 1C spectral data are as follows: 1 H NMR (500MHz, CDCl3) δ7.33–7.03(m,15H),4.01(s,1H),3.42–3.33(m,1H),2.77–2.57(m,3H),2 .47–2.36(m,1H),2.12–2.03(m,1H),1.79–1.66(m,2H),1.65–1.57(m,1H),1.55–1.45(m,1H). 13 C NMR (126MHz, CDCl3) δ158.7,144.7,141.9,129.2,128.4,125.9,125.8,124.7,58.3,49.0,35.9,32.7,31.0,25.0.

[0109] Table 1. Structural Formulas of Raw Materials and Target Products in Examples 1-38

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] The present invention has been described in detail above through embodiments, but the content described is only an exemplary embodiment of the present invention and should not be considered as limiting the scope of the present invention. The scope of protection of the present invention is defined by the claims. Any technical solutions designed by those skilled in the art using the technical solutions described in the present invention, or designed by those skilled in the art under the inspiration of the technical solutions of the present invention, within the substance and protection scope of the present invention, to achieve the above-mentioned technical effects, or any equivalent changes and improvements made to the scope of the application, should still fall within the patent protection scope of the present invention.

Claims

1. A catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines, characterized in that, Includes the following steps: Acyl-protected 3-pyrrolidines react with alkyl iodides in an organic solvent at room temperature under the catalysis of nickel and chiral oxazoline ligands, and in the presence of a base and a silane reagent, to yield chiral 2-alkyl-substituted pyrrolidine products. ； The chiral oxazoline ligand used is at least one of L1-L8. ； The amount of chiral oxazoline ligand is 11-13 mol% of the acyl-protected 3-pyrrolline; Table of raw materials and target product structural formulas ； ； ； ； ； ； ； ； ； 。 2. The catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines as described in claim 1, characterized in that, Nickel, chiral oxazoline ligand and organic solvent were added to the reaction flask and stirred at room temperature until homogeneous. Then, acyl-protected 3-pyrrolidone, alkyl iodide, base and organic solvent were added. After cooling to zero degrees Celsius, silane reagent was added dropwise. The mixture was then brought back to room temperature and reacted at room temperature for 24 hours.

3. The catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines as described in claim 1 or 2, characterized in that, After the reaction was completed, ethyl acetate was added, the mixture was filtered, the filter cake was washed with ethyl acetate 2-3 times, the solvent was removed under reduced pressure, and the chiral 2-alkyl substituted pyrrolidine products were separated by column chromatography.

4. The catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines as described in claim 1, characterized in that, The molar ratio of the acyl-protected 3-pyrrolidone to the alkyl iodide is 1:2, and the concentration is 0.05 mol / L.

5. The catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines as described in claim 1, characterized in that, The nickel used is at least one of NiBr2, NiCl2, NiI2, Ni(DME)Br2, Ni(OTf)2, and Ni(OAc)2, and the amount of nickel is 10 mol of acyl-protected 3-pyrrolidine.

6. The catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines as described in claim 1, characterized in that, The base used is at least one of diisopropylamine, triethylamine, tetramethylethylenediamine, N,N-dimethylethylamine, N,N-diisopropylethylamine, piperidine, 2,2,6,6-tetramethylpiperidine, 1,2,2,6,6-pentamethylpiperidine, potassium fluoride, potassium phosphate, cesium carbonate, cesium fluoride, potassium carbonate, or sodium carbonate, and the amount of base is 2-3 eq of acyl-protected 3-pyrroline.

7. The catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines as described in claim 1, characterized in that, The organic solvent used is at least one of tetrahydrofuran, ethylene glycol dimethyl ether, toluene, chlorobenzene, xylene, mesitylene, pentafluorobenzene, fluorobenzene, cyclopentyl methyl ether, methyl tert-butyl ether, tert-butylmethylene ether, N,N-dimethylformamide, or 1,4-dioxane.

8. The catalytic asymmetric synthesis method for chiral 2-alkyl-substituted pyrrolidines as described in claim 1, characterized in that, The silane reagent used is at least one of dimethoxymethylsilane, methylphenyldichlorosilane, trimethoxysilane, phenyldimethylsilane, or triethoxysilane, and the amount of silane reagent is 2-3 eq of acyl-protected 3-pyrrolline.

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