Method for synthesizing quinary lactam containing quaternary carbon chiral center by nickel-aluminum catalysis

Abstract

The invention discloses a synthesis method of nickel-aluminum catalyzed quinary lactam containing a quaternary carbon chiral center, which comprises the following steps: in a nitrogen atmosphere, sequentially adding a secondary phosphine oxide ligand, a metal catalyst Ni (cod) 2, a formamide compound and a solvent into a reaction flask, then adding Lewis acid, stirring at a specified reaction temperature, cooling to room temperature after the reaction is completed, and filtering to obtain the quinary lactam containing the quaternary carbon chiral center. And adding 2mL of a 5wt% ethylene diamine tetraacetic acid aqueous solution for washing, separating liquid, drying an organic phase by using anhydrous sodium sulfate, and carrying out column chromatography separation to obtain the quinary lactam containing the quaternary carbon chiral center. According to the method, atom loss does not exist in the reaction process, no other waste is generated, the reaction yield is high, and the selectivity is high.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a method for synthesizing a five-membered lactam containing a quaternary carbon chiral center under nickel-aluminum catalysis. Background Art

[0002] Pentalactams containing quaternary carbon chiral centers are ubiquitous building blocks in many natural products, drugs, and agrochemicals. However, it is very difficult to construct carbonyl quaternary carbon chiral centers with high stereoselectivity, which makes the synthesis of pentalactams containing quaternary carbon chiral centers difficult.

[0003] The methods currently under development focus on the post-modification of five-membered ring lactams: first, the racemic lactam needs to be prepared; second, the chiral quaternary carbon is constructed on the racemic five-membered ring through enantioselective transformation, where the enantioselective transformation includes two major categories: free radical coupling or enol functionalization. In order to simplify the synthesis steps, a one-step cyclization strategy was developed and attracted widespread attention. One-step cyclization refers to the carbonyl precursor connected to an olefin being catalyzed by a transition metal, and a chiral carbonyl quaternary carbon is simultaneously constructed through carbonyl cyclization in one step. Although this method has the advantages of easy availability of raw materials and step economy, the generated carbonyl metal intermediate is unstable and easily decomposed before cyclization, so this method is always limited.

[0004] To solve this problem, highly active carbonyl precursors are often introduced to improve the reactivity, including C(O)-Cl / F. Based on this, although five-membered lactams containing quaternary carbon chiral centers have been successfully prepared, the pre-functionalization and instability of acyl chloride or acyl fluoride substrates and the atomic loss involved in the reaction have prompted people to try to develop a more stable C(O)-H as a one-step cyclization strategy for carbonyl precursors, but so far there has been no progress, mainly due to:

[0005] 1. Although there is no atom loss in the one-step cyclization of C(O)-H, C(O)-H is relatively inert and difficult to activate;

[0006] 2. The reaction easily produces carbon monoxide through decarbonylation, which has a strong coordination ability and often coordinates with the metal. On the one hand, it inhibits the reactivity of the metal, resulting in reduced reaction activity, and on the other hand, it weakens the coordination between the chiral ligand and the metal, resulting in reduced reaction selectivity.

[0007] In summary, although a few examples have been reported for the construction of five-membered lactams containing quaternary carbon chiral centers via one-step cyclization using C(O)-Cl / F as carbonyl precursors, the use of formyl C(O)-H as a carbonyl precursor remains an unresolved problem. Summary of the invention

[0008] The present invention aims to provide a method for synthesizing a five-membered lactam containing a quaternary carbon chiral center using nickel-aluminum catalysis, so as to solve the problems of atom uneconomical, low reaction yield and poor reaction selectivity existing in the prior art.

[0009] To this end, the present invention adopts the following technical solutions:

[0010] A method for synthesizing a nickel-aluminum-catalyzed five-membered lactam containing a quaternary carbon chiral center, the reaction formula and reaction process are as follows:

[0011]

[0012] In a nitrogen atmosphere, add the secondary phosphine oxide ligand PO, the metal catalyst Ni(cod)2, the raw material A and the solvent to the reaction bottle in sequence, then add the Lewis acid, stir at the specified reaction temperature, cool to room temperature after the reaction is completed, add 2mL 5wt% disodium ethylenediaminetetraacetic acid aqueous solution for washing, separate the liquids, dry the organic phase with anhydrous sodium sulfate, and separate by column chromatography to obtain the target product B, wherein:

[0013] PG is aryl or alkyl;

[0014] R is an aryl group;

[0015] The molar ratio of the secondary phosphine oxide ligand, the metal catalyst, the Lewis acid and the raw material A is (1-30): (1-30):

[0016] (10~80):100.

[0017] Preferably, the molar ratio of the secondary phosphine oxide ligand PO, the metal catalyst, the Lewis acid and the raw material A is (5-20):(5-20):(10-40):100.

[0018] Preferably, PG is phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2,4,6-trimethylbenzyl, cyclohexyl or isopropyl.

[0019] Preferably, R is phenyl, 4-methoxyphenyl, 3-vinylphenyl, 4-trimethylsilylphenyl, benzofuran or furan.

[0020] The secondary phosphine oxygen ligand is an achiral dinitrogen-substituted secondary phosphine oxygen or a chiral dinitrogen-substituted phosphine oxygen ligand. The structural formula of the achiral dinitrogen-substituted secondary phosphine oxygen is as follows:

[0021]

[0022] The structural formula of the chiral dinitrogen-substituted phosphine oxygen ligand is as follows:

[0023]

[0024] The Lewis acid is a metal aluminum organic compound, a metal zinc organic compound or a metal magnesium organic compound. Preferably, the metal aluminum organic compound is trimethylaluminum; the metal zinc organic compound is diethylzinc; and the metal magnesium organic compound is dibutylmagnesium.

[0025] The solvent is a non-polar solvent, a medium polar solvent or a polar solvent, and the amount of the solvent is 0.5-5 mL / mmol A. Preferably, the non-polar solvent is toluene or n-hexane; the medium polar solvent is tetrahydrofuran; and the polar solvent is dimethyl sulfoxide.

[0026] The specified reaction temperature is 20° C. to 150° C., and the stirring time is 1 to 720 minutes.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. The present invention uses C(O)-H carbonyl precursor as a raw material to improve atom economy. There is no atom loss during the reaction, no other waste is generated, and 100% atom utilization is achieved.

[0029] 2. The present invention introduces a nickel-aluminum bimetallic catalytic system to improve the reaction yield, and ultimately constructs a five-membered lactam containing a quaternary carbon chiral center with a yield as high as 99%.

[0030] 3. The present invention introduces a highly active phosphine oxide ligand to improve the reaction selectivity, and ultimately constructs a five-membered lactam containing a quaternary carbon chiral center with an enantiomeric excess (ee) of up to 98%.

[0031] 4. The raw materials of the present invention are cheap, readily available, easy to synthesize and highly stable. The product constructed by one-step cyclization, as "methosuximide" and its derivatives, has anticonvulsant biological activity. DETAILED DESCRIPTION

[0032] The synthesis method of the present invention is described in detail below with reference to the examples.

[0033] In the following examples, the purity of the product was identified by nuclear magnetic resonance, and the chirality of the product was detected by high performance liquid chromatography. The structural formula of the phosphine oxide ligand PO used in Examples 1 to 12 is as follows:

[0034]

[0035] The structural formula of the phosphine oxide ligand rac-PO used in Example 13 is as follows:

[0036]

[0037] Example 1

[0038] A method for synthesizing (S)-3-Methyl-3-phenyl-1-(2,4,6-trimethylbenzyl)pyrrolidin-2-one ((S)-3-methyl-3-phenyl-1-(2,4,6-trimethylphenyl)-2-pyrrolidone) comprises the following steps:

[0039]

[0040] In a nitrogen atmosphere, phosphine oxide ligand PO (5.0 mg, 5 mol%), Ni(cod)2 (0.6 mg, 1 mol%), A-1 (61.4 mg, 0.2 mmol), toluene (1.0 mL) and trimethylaluminum (1 M, 160 μL, 80 mol%) were added to the reaction bottle in sequence and stirred at 80 °C for 10 hours. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5 wt% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate. After concentration, it was separated by column chromatography to obtain a colorless oily liquid B-1 with a yield of 99%.

[0041] 1 H NMR (400MHz, CDCl3) δ7.43–7.21(m,5H),6.85(s,2H),4.63(d,J=14.4Hz,1H),4.53(d,J=14.5Hz,1H),3 .01(dd,J=7.6,5.8Hz,2H),2.38–2.32(m,1H),2.26(s,9H),2.02(dt,J=12.8,7.5Hz,1H),1.55(s,3H). 13 C NMR (100MHz, CDCl3) δ176.8,143.9,137.9,137.4,129.3,129.1,128.6,126.8 ,126.3,49.0,42.5,40.8,35.3,29.8,25.4,21.0,20.0.HRMS(ESI)m / z:[M+Na] + Calcd.For C 21 H 25 NNaO 330.1828; Found 330.1826. HPLCcondition: Chiracel OD-Hcolumn, n-Hex / i-PrOH=90:10, 1.0mL / min, 254nm, minorenantiomer: 8.9min, major enantiomer: 9.4min, 97%ee;

[0042] Example 2

[0043] A method for synthesizing (S)-3-(4-Methoxyphenyl)-3-methyl-1-(2,4,6-trimethylbenzyl)pyrrolidin-2-one ((S)-3-(4-methoxyphenyl)-3-methyl-1-(2,4,6-trimethylphenyl)-2-pyrrolidin-one) comprises the following steps:

[0044]

[0045] In a nitrogen atmosphere, phosphine oxide ligand PO (10.0 mg, 10 mol%), Ni(cod)2 (5.5 mg, 10 mol%), A-2 (67.4 mg, 0.2 mmol), and n-hexane (1.0 mL) were added to the reaction bottle in sequence, and then trimethylaluminum (1 M, 80 μL, 40 mol%) was added. The mixture was stirred at 80 ° C for 8 hours. After the reaction was completed, it was cooled to room temperature, and 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution was added for washing. The organic phase was separated, and the organic phase was dried over anhydrous sodium sulfate. After concentration, it was separated by column chromatography to obtain a colorless oily liquid B-2 with a yield of 91%.

[0046] 1 H NMR (400MHz, CDCl3) δ7.35–7.33(m,2H),6.87–6.84(m,4H),4.61(ABd,J=14.4Hz,1H),4.51(ABd,J=14.4Hz,1H),3.79(s ,3H),3.00(dd,J=7.6,5.8Hz,2H),2.32(dt,J=12.2,5.9Hz,1H),2.26(s,9H),2.00(dt,J=12.7,7.5Hz,1H),1.52(s,3H). 13 C NMR (100MHz, CDCl3) δ177.0,158.4,137.9,137.4,135.9,129.3,129.1,127.3 ,113.9,55.4,48.3,42.5,40.8,35.2,25.6,21.0,20.0.HRMS(ESI)m / z:[M+Na] + Calcd.For C 22 H 27NNaO2360.1934; Found 360.1932. HPLC condition: Chiracel AD-H column, n-Hex / i-PrOH=90:10, 1.0mL / min, 254nm, minor enantiomer: 10.4min, major enantiomer: 13.6min, 94%ee;

[0047] Example 3

[0048] A method for synthesizing (S)-3-Methyl-1-(2,4,6-trimethylbenzyl)-3-(3-vinylphenyl)pyrrolidin-2-one ((S)-3-methyl-1-(2,4,6-trimethylphenyl)-3-(3-vinylphenyl)-2-pyrrolidone) comprises the following steps:

[0049]

[0050] In a nitrogen atmosphere, phosphine oxide ligand PO (30.0 mg, 30 mol%), Ni(cod)2 (16.5 mg, 30 mol%), A-3 (66.6 mg, 0.2 mmol), tetrahydrofuran (1.0 mL) were added to the reaction bottle in sequence, and then trimethylaluminum (1 M, 20 μL, 10 mol%) was added. The mixture was stirred at 80 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate. After concentration, it was separated by column chromatography to obtain the target product B-3 as a colorless oily liquid with a yield of 85%.

[0051] 1 H NMR (400MHz, CDCl3) δ7.44–7.28 (m, 4H), 6.85 (s, 2H), 6.71 (dd, J = 17.6, 10.9 Hz,1H),5.73(d,J=17.6Hz,1H),5.24(d,J=10.9Hz,1H),4.62(ABd,J=14.5Hz ,1H),4.55(ABd,J=14.5Hz,1H),3.02(t,J=6.8Hz,2H),2.35(dt,J=12.2,6.0 Hz, 1H), 2.27 (s, 6H), 2.26 (s, 3H), 2.03 (dt, J = 12.8, 7.5Hz, 1H), 1.55 (s, 3H). 13C NMR (100MHz, CDCl3) δ176.7,144.2,137.9,137.9,137.4,137.1,129.4,129.1,128.8,125 .8,124.5,124.5,114.1,49.0,42.5,40.8,35.3,25.5,21.0,20.0.HRMS(ESI)m / z:[M+Na] + Calcd.ForC 23 H 27 NNaO 356.1985; Found 356.1993. HPLC condition: Chiracel AD-H column, n-Hex / i-PrOH=90:10, 1.0mL / min, 254nm, minor enantiomer: 6.2min, major enantiomer: 7.4min, 96%ee;

[0052] Example 4

[0053] A method for synthesizing (S)-3-Methyl-1-(2,4,6-trimethylbenzyl)-3-(4-(trimethylsilyl)phenyl)pyrrolidin-2-one ((S)-3-methyl-1-(2,4,6-trimethylphenyl)-3-(4-(trimethylsilyl)phenyl)-2-pyrrolidinone) comprises the following steps:

[0054]

[0055] In a nitrogen atmosphere, phosphine oxide ligand PO (10.0 mg, 10 mol%), Ni(cod)2 (16.5 mg, 30 mol%), A-4 (75.9 mg, 0.2 mmol), and dimethyl sulfoxide (1.0 mL) were added to the reaction bottle in sequence, and then diethyl zinc (1 M, 20 μL, 10 mol%) was added. The mixture was stirred at 60 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The target product B-4 was separated by column chromatography as a white solid with a yield of 81%.

[0056] 1H NMR(400MHz, CDCl3)δ7.38–7.27(m,3H),7.13(d,J=7.9Hz,1H),6.85(s,2H),4.65–4.4 6(m,2H),3.04–2.98(m,2H),2.37–2.26(m,10H),2.06–1.97(m,1H),1.56–1.52(m,3H). 13 C NMR (100MHz, CDCl3) δ176.9,176.3,142.4,140.8,137.9,137.9,137.5,137.4,136.3,132.6,129.4,129.3,129.3,129. 2,128.9,128.7,127.8,126.1,48.7,48.6,42.5,42.4,40.8,40.8,35.3,35.0,25.5,21.0,20.0.HRMS(ESI)m / z:[M+Na] + Calcd.ForC 21 H 24 ClNNaO 364.1439; Found 364.1439. HPLC condition: Chiracel AD-H column, n-Hex / i-PrOH=92:8, 1.0mL / min, 254nm, minor enantiomer: 8.9min, major enantiomer: 12.1min, 97%ee;

[0057] Example 5

[0058] A method for synthesizing (S)-3-(Dibenzo[b,d]furan-3-yl)-3-methyl-1-(2,4,6-trimethylbenzyl)pyrrolidin-2-one (S)-3-(dibenzo[b,d]-3-furan-3-yl)-3-methyl-1-(2,4,6-trimethylphenyl)-2-pyrrolidin-2-one) comprises the following steps:

[0059]

[0060] In a nitrogen atmosphere, phosphine oxide ligand PO (10.0 mg, 10 mol%), Ni(cod)2 (5.5 mg, 10 mol%), A-5 (47.4 mg, 0.2 mmol), toluene (0.5 mL) were added to the reaction bottle in sequence, and then diethyl zinc (1 M, 80 μL, 40 mol%) was added, and stirred at 80 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, and 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution was added for washing. The organic phase was separated, and the organic phase was dried over anhydrous sodium sulfate. After concentration, the target product B-5 was separated by column chromatography as a colorless oily liquid with a yield of 92%.

[0061] 1 H NMR (400MHz, CDCl3) δ8.04(s,1H),7.94(d,J=7.7Hz,1H),7.54–7.30(m,5H),6.84(s,2H),4.65(ABd,J=14.4Hz,1H),4.58(ABd,J=14.4H z,1H),3.05(dd,J=7.7,5.8Hz,2H),2.44(dt,J=12.3,5.9Hz,1H),2.28(s,6H),2.25(s,3H),2.11(dt,J=12.8,7.4Hz,1H),1.63(s,3H). 13 C NMR (100MHz, CDCl3) δ176.8,156.7,155.1,138.6,137.9,137.4,129.3,129.0,127.2,125.6,124.4,124 .3,122.7,120.8,118.4,111.7,111.6,48.9,42.5,40.9,35.6,26.1,21.0,20.0.HRMS(ESI)m / z:[M+Na] + Calcd.For C 27 H 27 NNaO2420.1934; Found 420.1938. HPLC condition: Chiracel OD-H column, n-Hex / i-PrOH=95:5, 1.0mL / min, 254nm, minor enantiomer: 14.4min, major enantiomer: 15.6min, 93%ee;

[0062] Example 6

[0063] A method for synthesizing (S)-3-(Furan-3-yl)-3-methyl-1-(2,4,6-trimethylbenzyl)pyrrolidin-2-one ((S)-3-(3-furanyl)-3-methyl-1-(2,4,6-trimethylphenyl)-2-pyrrolidone) comprises the following steps:

[0064]

[0065] In a nitrogen atmosphere, phosphine oxide ligand PO (10.0 mg, 10 mol%), Ni(cod)2 (5.5 mg, 10 mol%), A-6 (59.5 mg, 0.2 mmol), toluene (3.0 mL) were added to the reaction bottle in sequence, and then diethyl zinc (1 M, 160 μL, 80 mol%) was added. The mixture was stirred at 40 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate. After concentration, the target product B-6 was separated by column chromatography as a colorless oily liquid with a yield of 82%.

[0066] 1 H NMR (400MHz, CDCl3) δ7.37–7.35(m,2H),6.85(s,2H),6.40(s,1H),4.55(d,J=14.4Hz,1H),4.50(d,J=14.5H z,1H),3.04(t,J=7.0Hz,2H),2.26(s,3H),2.25(s,6H),2.22–2.16(m,1H),2.00–1.92(m,1H),1.46(s,3H). 13 C NMR (100MHz, CDCl3) δ176.1,143.3,138.5,137.9,137.4,129.3,129.1,128.7,109.3,43.1,42.6,40.8,33.9,25.0,21.0,20.0.HRMS(ESI)m / z:[M+Na] + Calcd.For C 19 H 23 NNaO2 320.1621; Found 320.1629. HPLCcondition: Chiracel AD-Hcolumn, n-Hex / i-PrOH=92:8, 1.0mL / min, 254nm, minorenantiomer: 8.2min, major enantiomer: 8.7min, 81%ee;

[0067] Example 7

[0068] The synthesis method of (S)-1-Cyclohexyl-3-methyl-3-phenylpyrrolidin-2-one ((S)-1-cyclohexyl-3-methyl-3-phenyl-2-pyrrolidone) comprises the following steps:

[0069]

[0070] In a nitrogen atmosphere, phosphine oxide ligand PO (10.0 mg, 10 mol%), Ni(cod)2 (5.5 mg, 10 mol%), A-7 (51.5 mg, 0.2 mmol), toluene (5.0 mL) were added to the reaction bottle in sequence, and then dibutyl magnesium (1 M, 20 μL, 10 mol%) was added. The mixture was stirred at 150 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate. After concentration, the target product B-7 was separated by column chromatography as a colorless oily liquid with a yield of 99%.

[0071] 1 H NMR (400MHz, CDCl3) δ7.38–7.19(m,5H),4.05–3.99(m,1H),3.30–3.16(m,2H),2.39 –2.33(m,1H),2.12–2.05(m,1H),1.79–1.65(m,6H),1.52(s,3H),1.46–1.33(m,4H). 13 CNMR(100MHz, CDCl3)δ176.7,144.1,128.5,126.6,126.2,50.9,49.4,39.7,35.9,30.5,30.2,25.5,25.0.HRMS(ESI)m / z:[M+H] + Calcd.For C 17 H 24 NO 258.1852; Found258.1849. HPLC condition: Chiracel AD-H column, n-Hex / i-PrOH=95:5, 1.0mL / min, 254nm, minor enantiomer: 11.8min, major enantiomer: 17.1min, 96%ee;

[0072] Example 8

[0073] The synthesis method of (S)-1-Isopropyl-3-methyl-3-phenylpyrrolidin-2-one ((S)-1-isopropyl-3-methyl-3-phenyl-2-pyrrolidone) comprises the following steps:

[0074]

[0075] In a nitrogen atmosphere, phosphine oxide ligand PO (10.0 mg, 10 mol%), Ni(cod)2 (5.5 mg, 10 mol%), A-8 (43.5 mg, 0.2 mmol), toluene (1.0 mL) were added to the reaction bottle in sequence, and then dibutyl magnesium (1 M, 80 μL, 40 mol%) was added. The mixture was stirred at 80 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate. After concentration, the target product B-8 was separated by column chromatography as a colorless oily liquid with a yield of 99%.

[0076] 1 H NMR (400MHz, CDCl3) δ7.39–7.19(m,5H),4.51–4.40(m,1H),3.29–3.15(m,2H),2.42–2. 36(m,1H),2.13–2.06(m,1H),1.52(s,3H),1.18(d,J=6.8Hz,3H),1.14(d,J=6.8Hz,3H). 13 C NMR(100MHz, CDCl3)δ176.7,144.1,128.5,126.6,126.2,49.4,42.8,38.5,35.7,25.0,20.0,19.8.HRMS(ESI)m / z:[M+H] + Calcd.For C 14 H 20 NO 218.1539; Found218.1536. HPLC condition: Chiracel OJ-H column, n-Hex / i-PrOH=90:10, 2.5mL / min, 220nm, minor enantiomer: 3.3min, major enantiomer: 4.1min, 91%ee;

[0077] Example 9

[0078] The synthesis method of (S)-3-Methyl-1,3-diphenylpyrrolidin-2-one ((S)-3-methyl-1,3-diphenyl-2-pyrrolidone) comprises the following steps:

[0079]

[0080] In a nitrogen atmosphere, phosphine oxide ligand PO (10.0 mg, 10 mol%), Ni(cod)2 (5.5 mg, 10 mol%), A-9 (50.3 mg, 0.2 mmol), tetrahydrofuran (5.0 mL) were added to the reaction bottle in sequence, and then dibutyl magnesium (1 M, 160 μL, 80 mol%) was added. The mixture was stirred at 150 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate. After concentration, the target product B-9 was separated by column chromatography as a yellow oily liquid with a yield of 97%.

[0081] 1 H NMR (400MHz, CDCl3) δ7.70–7.13(m,10H),3.81–3.69(m,2H),2.62–2.56(m,1H),2.27(dt,J=12.7,6.4Hz,1H),1.64(s,3H). 13 C NMR (100MHz, CDCl3) δ176.8,143.3,139.8,129.0,128.7,127.0,126.2,124.6,119.9,50.3,45.3,34.9,25.6.HRMS(ESI)m / z:[M+Na] + Calcd.For C 17 H 17 NNaO 274.1202; Found 274.1198. HPLC condition: Chiracel OD-Hcolumn, n-Hex / i-PrOH=90:10, 2.5mL / min, 254nm, minor enantiomer: 11.4min, majorenantiomer: 12.0min, 98%ee;

[0082] Example 10

[0083] The synthesis method of (S)-1-(Benzo[d][1,3]dioxol-5-yl)-3-methyl-3-phenylpyrrolidin-2-one ((S)-1-benzo[d][1,3]dioxol-3-methyl-3-phenyl-2-pyrrolidone) comprises the following steps:

[0084]

[0085] In a nitrogen atmosphere, phosphine oxide ligand PO (10.0 mg, 10 mol%), Ni(cod)2 (5.5 mg, 10 mol%), A-10 (59.1 mg, 0.2 mmol), tetrahydrofuran (0.5 mL) were added to the reaction bottle in sequence, and then trimethylaluminum (1 M, 80 μL, 40 mol%) was added. The mixture was stirred at 80 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate. After concentration, the target product B-10 was separated by column chromatography as a gray solid with a yield of 72%.

[0086] 1 H NMR (400MHz, CDCl3) δ8.56–7.91(m,8H),7.08(s,2H),4.87–4.76(m,2H),3.72–3.66(m,1H),3.39(dt,J=12.7,8.0Hz,1H),2.75(s,3H). 13 C NMR (100MHz, CDCl3) δ176.5,147.9,144.6,143.3,134.2,128.7,127.0,126. 2,113.1,108.0,102.9,101.4,50.2,46.0,34.9,25.5.HRMS(ESI)m / z:[M+Na] + Calcd.For C 18 H 17 NNaO3 318.1101; Found318.1100. HPLC condition: Chiracel ID column, n-Hex / i-PrOH=90:10, 1.0mL / min, 290nm, minor enantiomer: 27.8min, major enantiomer: 46.3min, 96%ee;

[0087] Embodiment 11

[0088] The synthesis method of (S)-1-(4-Methoxyphenyl)-3-methyl-3-phenylpyrrolidin-2-one ((S)-1-(4-methoxyphenyl)-3-methyl-3-phenyl-2-pyrrolidone) comprises the following steps:

[0089]

[0090] In a nitrogen atmosphere, phosphine oxide ligand PO (10.0 mg, 10 mol%), Ni(cod)2 (5.5 mg, 10 mol%), A-11 (56.3 mg, 0.2 mmol), tetrahydrofuran (3.0 mL) were added to the reaction bottle in sequence, and then trimethylaluminum (1 M, 80 μL, 40 mol%) was added. The mixture was stirred at 20 °C for 12 hours. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate. After concentration, the target product B-11 was separated by column chromatography as a gray solid with a yield of 85%.

[0091] 1 H NMR (400MHz, CDCl3) δ7.60–6.89(m,9H),3.80(s,3H),3.76–3.66(m,2H),2.59–2.54(m,1H),2.27(dt,J=12.7,8.0Hz,1H),1.63(s,3H). 13 C NMR (100MHz, CDCl3) δ176.4,156.6,143.4,133.0,128.7,126.9,126.2,121.6,114.1,55.6,50.1,45.7,35.0,25.5.HRMS(ESI)m / z:[M+Na] + Calcd.For C 18 H 19 NNaO2 304.1308; Found 304.1304. HPLC condition: Chiracel OD-H column, n-Hex / i-PrOH=90:10, 1.0mL / min, 254nm, minor enantiomer: 16.3min, major enantiomer: 20.9min, 98%ee;

[0092] Example 12

[0093] The synthesis method of (S)-3-Methyl-3-phenyl-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ((S)-3-methyl-3-phenyl-1-(4-trifluoromethyl)phenyl-2-pyrrolidone) comprises the following steps:

[0094]

[0095] In a nitrogen atmosphere, phosphine oxide ligand PO (10.0 mg, 10 mol%), Ni(cod)2 (5.5 mg, 10 mol%), A-12 (63.9 mg, 0.2 mmol), and toluene (1.0 mL) were added to the reaction bottle in sequence, and then trimethylaluminum (1 M, 80 μL, 40 mol%) was added. The mixture was stirred at 150 ° C for 10 minutes. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was separated and dried over anhydrous sodium sulfate. After concentration, the target product B-12 was separated by column chromatography as a yellow oily liquid with a yield of 90%.

[0096] 1 H NMR(400MHz, CDCl3) δ7.84(d,J=8.6Hz,2H),7.62(d,J=8.6Hz,2H),7.43–7.23(m,5H ),3.82–3.70(m,2H),2.66–2.60(m,1H),2.30(dt,J=12.8,8.1Hz,1H),1.64(s,3H). 13 CNMR(125MHz, CDCl3)δ177.4,142.70,142.66,128.9,127.3,126.1,126.2(q,J=3 .1Hz), 124.2 (q, J = 225.0Hz), 119.3, 119.2 (q, J = 16.6Hz), 50.5, 45.2, 34.6, 25.6. 19 F NMR(376MHz,CDCl3)δ-62.2.HRMS(ESI)m / z:[M+H] + Calcd.For C 18 H 17 F3NO 320.1257; Found320.1263.HPLC condition: Chiracel AD-H column, n-Hex / i-PrOH=90:10, 1.0mL / min, 254nm, minor enantiomer: 11.5min, major enantiomer: 15.9min, 92%ee;

[0097] Embodiment 13

[0098] A method for synthesizing 3-Methyl-3-phenyl-1-(2,4,6-trimethylbenzyl)pyrrolidin-2-one (-3-methyl-3-phenyl-1-(2,4,6-trimethylphenyl)-2-pyrrolidone) comprises the following steps:

[0099]

[0100] In a nitrogen atmosphere, achiral phosphine oxide ligand rac-PO (5.0 mg, 5 mol%), Ni(cod)2 (0.6 mg, 1 mol%), A-1 (61.4 mg, 0.2 mmol), toluene (1.0 mL) and trimethylaluminum (1 M, 160 μL, 80 mol%) were added to the reaction bottle in sequence and stirred at 80 °C for 10 hours. After the reaction was completed, it was cooled to room temperature and washed with 2 mL of 5 wt% disodium ethylenediaminetetraacetic acid aqueous solution. The organic phase was dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain a colorless oily liquid B-1 with a yield of 99%.

[0101] 1 H NMR (400MHz, CDCl3) δ7.43–7.21(m,5H),6.85(s,2H),4.63(d,J=14.4Hz,1H),4.53(d,J=14.5Hz,1H),3 .01(dd,J=7.6,5.8Hz,2H),2.38–2.32(m,1H),2.26(s,9H),2.02(dt,J=12.8,7.5Hz,1H),1.55(s,3H). 13 C NMR (100MHz, CDCl3) δ176.8,143.9,137.9,137.4,129.3,129.1,128.6,126.8 ,126.3,49.0,42.5,40.8,35.3,29.8,25.4,21.0,20.0.HRMS(ESI)m / z:[M+Na] + Calcd.For C 21 H 25 NNaO 330.1828; Found 330.1826.

Claims

1. A method for synthesizing a nickel-aluminum-catalyzed pentalactam containing a quaternary carbon chiral center, characterized in that The reaction formula and reaction process are as follows: In a nitrogen atmosphere, add the secondary phosphine oxide ligand PO, the metal catalyst Ni(cod)2, the raw material A and the solvent to the reaction bottle in sequence, then add the Lewis acid, stir at the specified reaction temperature, cool to room temperature after the reaction is completed, add 2mL 5wt% disodium ethylenediaminetetraacetic acid aqueous solution for washing, separate the liquids, dry the organic phase with anhydrous sodium sulfate, and separate by column chromatography to obtain the target product B, wherein: PG is aryl or alkyl; R is an aryl group; The molar ratio of the secondary phosphine oxide ligand, the metal catalyst, the Lewis acid and the raw material A is (1-30):(1-30):(10-80):

100.

2. The synthesis method according to claim 1, characterized in that: The molar ratio of the secondary phosphine oxide ligand PO, the metal catalyst, the Lewis acid and the raw material A is (5-20):(5-20):(10-40):

100.

3. The synthesis method according to claim 1, characterized in that: PG is phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2,4,6-trimethylbenzyl, cyclohexyl or isopropyl.

4. The synthesis method according to claim 1, characterized in that: R is phenyl, 4-methoxyphenyl, 3-vinylphenyl, 4-trimethylsilylphenyl, benzofuran or furan.

5. The synthesis method according to claim 1, characterized in that: The secondary phosphine oxygen ligand is an achiral dinitrogen-substituted secondary phosphine oxygen ligand or a chiral dinitrogen-substituted phosphine oxygen ligand.

6. The synthesis method according to claim 4, characterized in that The structural formula of the non-chiral dinitrogen-substituted secondary phosphine oxygen is as follows: The structural formula of the chiral dinitrogen-substituted phosphine oxygen ligand is as follows:

7. The synthesis method according to claim 1, characterized in that: The Lewis acid is a metal aluminum organic compound, a metal zinc organic compound or a metal magnesium organic compound. Preferably, the metal aluminum organic compound is trimethylaluminum; the metal zinc organic compound is diethylzinc; and the metal magnesium organic compound is dibutylmagnesium.

8. The synthesis method according to claim 1, characterized in that: The solvent is a non-polar solvent, a medium polar solvent or a polar solvent, and the amount of the solvent used is 0.5-5 mL / mmol A.

9. The synthesis method according to claim 9, characterized in that: The non-polar solvent is toluene or n-hexane; the medium-polar solvent is tetrahydrofuran; and the polar solvent is dimethyl sulfoxide.

10. The synthesis method according to claim 1, characterized in that: The specified reaction temperature is 20° C. to 150° C., and the stirring time is 1 to 720 minutes.

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