A method for the synthesis of nickel-aluminium catalysed five-membered lactams containing a quaternary carbon chiral centre

Abstract

This invention discloses a nickel-aluminum catalytic method for synthesizing a pentavalent lactam containing a quaternary carbon chiral center. Under a nitrogen atmosphere, a secondary phosphooxy ligand, a metal catalyst Ni(cod)₂, a formamide compound, and a solvent are sequentially added to a reaction flask. A Lewis acid is then added, and the mixture is stirred at a specified reaction temperature. After the reaction is complete and cooled to room temperature, the mixture is washed with 2 mL of a 5 wt% ethylenediaminetetraacetic acid disodium salt aqueous solution. The mixture is separated, and the organic phase is dried over anhydrous sodium sulfate. Column chromatography is then used to separate the pentavalent lactam containing the quaternary carbon chiral center. This method involves no atomic loss, generates no other waste, and exhibits high yield and selectivity.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a method for synthesizing a five-membered lactam containing a quaternary carbon chiral center using nickel-aluminum catalysis. Background Technology

[0002] Pentyl lactams containing a quaternary carbon chiral center are common structural units found in many natural products, pharmaceuticals, and agrochemicals. However, constructing carbonyl quaternary carbon chiral centers with high stereoselectivity is very difficult, making the synthesis of pentyl lactams containing quaternary carbon chiral centers challenging.

[0003] Current methods focus on the post-modification of five-membered ring lactams: first, the racemic lactam needs to be prepared; second, a chiral quaternary carbon is constructed on the racemic five-membered ring through enantioselective transformation, which includes two main categories: radical coupling or enol functionalization. To simplify the synthetic steps, a one-step cyclization strategy has been developed and has attracted widespread attention. One-step cyclization refers to the one-step cyclization of a carbonyl precursor attached to an olefin, catalyzed by a transition metal, to simultaneously construct a chiral carbonyl quaternary carbon. Although this method has advantages such as readily available starting materials and cost-effectiveness, the carbonyl metal intermediate generated before cyclization is unstable and easily decomposes, thus limiting its effectiveness.

[0004] To address this issue, highly reactive carbonyl precursors, including C(O)-Cl / F, are often introduced to enhance reactivity. Based on this, although penta-lactams containing quaternary carbon chiral centers have been successfully prepared, the prefunctionalization and instability of acyl chloride or acyl fluoride substrates, as well as the atom losses involved in the reaction, have prompted attempts to develop more stable one-step cyclization strategies using C(O)-H as carbonyl precursors. However, progress has been slow to date, primarily due to the following reasons:

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

[0006] 2. The reaction readily decarbonylates to produce carbon monoxide, which has a strong coordinating ability and often coordinates with metals. On the one hand, this inhibits the reactivity of the metal, leading to a decrease in reactivity; on the other hand, it weakens the coordination between the chiral ligand and the metal, resulting in a decrease in reaction selectivity.

[0007] In summary, although a few examples have been reported of constructing five-membered ring lactams with quaternary carbon chiral centers through one-step cyclization using C(O)-Cl / F as carbonyl precursors, the use of formyl C(O)-H as a carbonyl precursor remains an unsolved problem. Summary of the Invention

[0008] The purpose of this invention is to provide a nickel-aluminum catalytic method for synthesizing five-membered lactams containing a quaternary carbon chiral center, in order to solve the problems of atom uneconomy, low reaction yield, and poor reaction selectivity in the existing technology.

[0009] Therefore, the present invention adopts the following technical solution:

[0010] A nickel-aluminum catalytic method for the synthesis of a five-membered lactam containing a quaternary carbon chiral center is described below, including the reaction formula and process:

[0011]

[0012] Under a nitrogen atmosphere, secondary phosphine oxide ligand PO, metal catalyst Ni(cod)2, raw material A, and solvent were added sequentially to a reaction flask. Then, a Lewis acid was added, and the mixture was stirred at a specified reaction temperature. After the reaction was complete, the mixture was cooled to room temperature, washed with 2 mL of 5 wt% disodium ethylenediaminetetraacetate aqueous solution, separated, and the organic phase was dried over anhydrous sodium sulfate. Column chromatography was then used to separate the target product B, in which:

[0013] PG is aryl or alkyl;

[0014] R is aryl;

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

[0016] (10~80):100.

[0017] Preferably, the molar ratio of the secondary phosphooxyligand 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 phosphono ligand is either an achiral dinitrogen-substituted secondary phosphono ligand or a chiral dinitrogen-substituted phosphono ligand. The structural formula of the achiral dinitrogen-substituted secondary phosphono ligand is as follows:

[0021]

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

[0023]

[0024] The Lewis acid is an organoaluminum compound, an organozinc compound, or an organomagnesium compound. Preferably, the organoaluminum compound is trimethylaluminum; the organozinc compound is diethylzinc; and the organomagnesium compound is dibutylmagnesium.

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

[0026] The specified reaction temperature is 20℃~150℃, and the stirring time is 1~720 minutes.

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

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

[0029] 2. This invention introduces a nickel-aluminum bimetallic catalytic system to improve the reaction yield, and finally constructs a five-membered lactam containing a quaternary carbon chiral center with a yield of up to 99%.

[0030] 3. This invention introduces highly active phosphooxy ligands to improve reaction selectivity, and ultimately constructs a pentalumina containing a quaternary carbon chiral center with an enantiomeric excess rate (ee) of up to 98%.

[0031] 4. The raw materials of this invention are inexpensive, 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 Implementation

[0032] The synthesis method of the present invention will be described in detail below with reference to the embodiments.

[0033] In the following examples, product purity was determined by NMR, and product chirality was detected by high-performance liquid chromatography. The structural formulas of the phosphonooxyligand PO used in Examples 1-12 are as follows:

[0034]

[0035] The structural formula of the phosphonooxyligand 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-pyrrolidinone) includes the following steps:

[0039]

[0040] Under a nitrogen atmosphere, phosphooxyligand 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 sequentially to a reaction flask. The mixture was stirred at 80 °C for 10 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with 2 mL of 5 wt% EDTA-1 disodium ethylenediaminetetraacetate aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and 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-pyrrolidinone) includes the following steps:

[0044]

[0045] Under 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 sequentially to a reaction flask, followed by trimethylaluminum (1 M, 80 μL, 40 mol%). The mixture was stirred at 80 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and 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-pyrrolidinone) includes the following steps:

[0049]

[0050] Under a nitrogen atmosphere, phosphooxyligand PO (30.0 mg, 30 mol%), Ni(cod)₂ (16.5 mg, 30 mol%), A-3 (66.6 mg, 0.2 mmol), and tetrahydrofuran (1.0 mL) were added sequentially to a reaction flask, followed by trimethylaluminum (1 M, 20 μL, 10 mol%). The mixture was stirred at 80 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with 2 mL of 5% EDTA-disodium acetate aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product B-3, which was 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) includes the following steps:

[0054]

[0055] Under a nitrogen atmosphere, phosphooxy 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 sequentially to a reaction flask, followed by diethylzinc (1 M, 20 μL, 10 mol%). The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product B-4, 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-furanyl)-3-methyl-1-(2,4,6-trimethylphenyl)-2-pyrrolidone, comprising the following steps:

[0059]

[0060] Under a nitrogen atmosphere, phosphooxy ligand PO (10.0 mg, 10 mol%), Ni(cod)₂ (5.5 mg, 10 mol%), A-5 (47.4 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to a reaction flask. Then, diethylzinc (1 M, 80 μL, 40 mol%) was added. The mixture was stirred at 80 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. After concentration, the target product B-5 was obtained 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) includes the following steps:

[0064]

[0065] Under a nitrogen atmosphere, phosphooxyligand PO (10.0 mg, 10 mol%), Ni(cod)₂ (5.5 mg, 10 mol%), A-6 (59.5 mg, 0.2 mmol), and toluene (3.0 mL) were added sequentially to a reaction flask, followed by diethylzinc (1 M, 160 μL, 80 mol%). The mixture was stirred at 40 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. After concentration, the target product B-6 was obtained 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 method for synthesizing (S)-1-Cyclohexyl-3-methyl-3-phenylpyrrolidin-2-one ((S)-1-cyclohexyl-3-methyl-3-phenyl-2-pyrrolidinone) includes the following steps:

[0069]

[0070] Under 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), and toluene (5.0 mL) were added sequentially to a reaction flask, followed by dibutylmagnesium (1 M, 20 μL, 10 mol%). The mixture was stirred at 150 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product B-7, 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 method for synthesizing (S)-1-Isopropyl-3-methyl-3-phenylpyrrolidin-2-one ((S)-1-isopropyl-3-methyl-3-phenyl-2-pyrrolidone) includes the following steps:

[0074]

[0075] Under 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), and toluene (1.0 mL) were added sequentially to a reaction flask, followed by dibutylmagnesium (1 M, 80 μL, 40 mol%). The mixture was stirred at 80 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product B-8, 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 method for synthesizing (S)-3-Methyl-1,3-diphenylpyrrolidin-2-one includes the following steps:

[0079]

[0080] Under a nitrogen atmosphere, phosphooxyligand PO (10.0 mg, 10 mol%), Ni(cod)₂ (5.5 mg, 10 mol%), A-9 (50.3 mg, 0.2 mmol), and tetrahydrofuran (5.0 mL) were added sequentially to a reaction flask, followed by dibutylmagnesium (1 M, 160 μL, 80 mol%). The mixture was stirred at 150 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product B-9, 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 method for synthesizing (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-pyrrolidinone) includes the following steps:

[0084]

[0085] Under a nitrogen atmosphere, phosphooxyligand PO (10.0 mg, 10 mol%), Ni(cod)₂ (5.5 mg, 10 mol%), A-10 (59.1 mg, 0.2 mmol), and tetrahydrofuran (0.5 mL) were added sequentially to a reaction flask, followed by trimethylaluminum (1 M, 80 μL, 40 mol%). The mixture was stirred at 80 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product B-10, 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] Example 11

[0088] A method for synthesizing (S)-1-(4-Methoxyphenyl)-3-methyl-3-phenylpyrrolidin-2-one ((S)-1-(4-methoxyphenyl)-3-methyl-3-phenyl-2-pyrrolidone) includes the following steps:

[0089]

[0090] Under a nitrogen atmosphere, phosphooxyligand PO (10.0 mg, 10 mol%), Ni(cod)₂ (5.5 mg, 10 mol%), A-11 (56.3 mg, 0.2 mmol), and tetrahydrofuran (3.0 mL) were added sequentially to a reaction flask, followed by trimethylaluminum (1 M, 80 μL, 40 mol%). The mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product B-11, 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 method for synthesizing (S)-3-Methyl-3-phenyl-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ((S)-3-methyl-3-phenyl-1-(4-trifluoromethyl)phenyl-2-pyrrolidinone) includes the following steps:

[0094]

[0095] Under 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 sequentially to a reaction flask. 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, the mixture was cooled to room temperature and washed with 2 mL of 5% EDTA-disodium acetate aqueous solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. After concentration, the target product B-12 was obtained 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] Example 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) includes the following steps:

[0099]

[0100] In a nitrogen atmosphere, the non-chiral 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 sequentially to a reaction flask. The mixture was stirred at 80 °C for 10 hours. After the reaction was completed, the mixture was cooled to room temperature and washed with 2 mL of 5 wt% ethylenediaminetetraacetic acid disodium salt aqueous solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. After concentration, the mixture was 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 five-membered lactam containing a quaternary carbon chiral center using nickel-aluminum catalysis, characterized in that... The reaction formula and reaction process are as follows: Under a nitrogen atmosphere, secondary phosphine oxide ligand PO, metal catalyst Ni(cod)2, raw material A, and solvent were added sequentially to a reaction flask. Then, a Lewis acid was added, and the mixture was stirred at a specified reaction temperature. After the reaction was complete, the mixture was cooled to room temperature, washed with 2 mL of 5 wt% disodium ethylenediaminetetraacetate aqueous solution, separated, and the organic phase was dried over anhydrous sodium sulfate. Column chromatography was then used to separate the target product B, in which: PG is phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2,4,6-trimethylbenzyl, cyclohexyl or isopropyl; R is phenyl, 4-methoxyphenyl, 3-vinylphenyl, 4-trimethylsilylphenyl, benzofuran or furan; The structural formula of the secondary phosphooxy ligand PO is as follows: The Lewis acid is trimethylaluminum, diethylzinc, or dibutylmagnesium; The molar ratio of the secondary phosphooxyligand PO, 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 phosphooxyligand 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, The structural formula of the chiral secondary phosphooxy ligand is as follows:

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

5. The synthesis method according to claim 4, characterized in that: The non-polar solvent is toluene or n-hexane; the moderately polar solvent is tetrahydrofuran; and the polar solvent is dimethyl sulfoxide.

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

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