阅读说明：本技术 镍催化不对称烯丙基烷基化构建α-酰基内酰胺季碳手性中心化合物的方法及化合物 (Method for constructing alpha-acyllactam quaternary carbon chiral center compound by nickel-catalyzed asymmetric allyl alkylation and compound ) 是由 宋颢 秦勇 张茂杰 薛超云 于 2021-10-18 设计创作，主要内容包括：本发明涉及过渡金属不对称催化技术领域,具体涉及构建季碳手性中心化合物的方法及其通过该方法制备得到的化合物,本发明通过简易硅烷保护的烯丙醇试剂,使用低当量的镍催化剂和较为便宜的配体,制备出具有手性中心的内酰胺化合物砌块,合成效率高、操作简单、成本更低。(The invention relates to the technical field of transition metal asymmetric catalysis, in particular to a method for constructing a quaternary carbon chiral center compound and a compound prepared by the method.)

1. A method for constructing an alpha-acyl lactam quaternary carbon chiral center compound by nickel-catalyzed asymmetric allyl alkylation is characterized by comprising the following steps: the method comprises the following steps: taking a compound 2 and a compound 3, and carrying out nickel-catalyzed asymmetric allyl alkylation reaction in the presence of a ligand to obtain the compound;

wherein said compound 2 has the following general formula:

the compound 3 has the following structure:

in the formula: r₁Is methyl or ethyl;

R₂is hydrogen atom, methyl, phenyl, variously substituted phenyl or heterocyclic group;

R₃is an amide protecting group;

r is tert-butyl dimethyl silicon base, trimethyl silicon base or tert-butyl diphenyl silicon base.

2. The method of claim 1, wherein: the ligands include (S) -SunPhos, [ (2S,2' S,3S,3' S) -3,3' -di-tert-butyl-2, 2',3,3' -tetrahydro-4, 4' -dimethoxy-2, 2' -bis-1, 3-benzoxaphosphole ], (S) - (-) -5, 5-bis [ di (3, 5-xylyl) phosphino ] -4, 4-di-1, 3-benzodioxole, (R) -DTBM-SEGPHOS, (R) - (-) -1,1' -binaphthyl-2, 2' -bis (3, 5-xylyl) phosphine, (-) -1, 2-bis ((2S,5S) -2, 5-diisopropylphosphorus) benzene, one or more of (R) - (+) -2,2' -bis (diphenylphosphinyl) -5,5',6,6',7,7',8,8' -octahydro-1, 1' -binaphthyl or (S) - (-) - [ (5,6), (5',6') -bis (ethylenedioxy) biphenyl-2, 2' -yl ] diphenylphosphine.

3. The method of claim 1, wherein: in the nickel-catalyzed asymmetric allyl alkylation reaction, the nickel catalyst comprises Ni (cod)₂，NiCl₂，NiO，Ni(AcO)₂，Ni(acac)₂，Ni(pph₃)₄Or Ni (pph)₃)₂Cl₂。

4. The method of claim 1, wherein: in the asymmetric allyl alkylation reaction catalyzed by nickel, the reaction solvent is one or more of toluene, tetrahydrofuran, diethyl ether or methyl tert-butyl ether.

5. The method of claim 1, wherein: the amide protecting group is acetyl, benzoyl, benzyl, p-methoxybenzyl, methyl or p-toluenesulfonyl.

6. The method of claim 1, wherein: the reaction temperature of the nickel-catalyzed asymmetric allyl alkylation reaction is-20-50 ℃, and the reaction time is 8-72 h; preferably, the reaction temperature of the nickel-catalyzed asymmetric allyl alkylation reaction is-5 ℃ to 30 ℃, and the reaction time is 16 to 36 hours.

7. The method according to any one of claims 1-6, wherein: the dosage of the nickel catalyst in the nickel-catalyzed asymmetric allyl alkylation reaction is 2-7 mmol%;

and/or the dosage of the ligand in the nickel-catalyzed asymmetric allyl alkylation reaction is 2-8 mmol%.

8. The method of claim 7, wherein: the dosage of the nickel catalyst in the asymmetric allyl alkylation reaction catalyzed by nickel is 4-7 mmol%;

and/or the dosage of the ligand in the nickel-catalyzed asymmetric allyl alkylation reaction is 4-8 mmol%.

9. The method according to any one of claims 1-6, wherein: the general reaction formula of the compound 2 is as follows:

10. the method of claim 9, wherein: the preparation method of the compound 2 comprises the following steps: by taking a lactam ring as a five-to eight-membered azacyclic ringLactam compounds or lactam compounds of benzo-six-to eight-membered nitrogen heterocycles in an amide protecting group R₃Under the protection condition of (3), carrying out amide alpha acylation to obtain the product.

11. The method according to any one of claims 1-6, wherein: the preparation method of the compound 3 comprises the following steps: the allyl acid compound 8 is obtained by one-step silicon protection after esterification and ester group reduction; the reaction formula of the compound 3 is as follows:

in the structural formula of the compound 8, R₂The method comprises the following steps: a hydrogen atom, a differently substituted phenyl or heterocyclic group.

12. An α -acyllactam quaternary carbon chiral center compound prepared by the process of any one of claims 1 to 11, wherein: the structure of the alpha-acyl lactam quaternary carbon chiral center compound is shown as formula 1:

in the formula: r₁Is methyl or ethyl;

R₂is hydrogen atom, methyl, phenyl, variously substituted phenyl or heterocyclic group;

R₃is an amide protecting group.

Technical Field

The invention relates to the technical field of transition metal asymmetric catalysis, in particular to a method for constructing a quaternary carbon chiral center compound and a compound prepared by the method.

Background

The construction of quaternary carbon centers is one of the important scientific problems and difficulties in the field of organic synthesis, and the allyl alkylation reaction catalyzed by transition metals is an efficient and convenient method for constructing carbon chiral centers. Since the Tsuji subject group first reported the Tsuji-Trost reaction in 1965, this reaction was widely studied and applied as an important quaternary carbon construction strategy. At present, a plurality of transition metal complexes successfully catalyze asymmetric allyl alkylation reactions, wherein complexes of second and third transition metals such as palladium, rhodium, iridium and the like are studied more, and the complexes are successfully applied to the synthesis of natural products such as Zoantenol, Commuinin B and the like, while the first transition metals such as nickel, copper, iron, zinc and the like which are cheaper than the transition metals are relatively less studied in the asymmetric allyl alkylation. Therefore, the development of the first transition metal such as nickel has important significance for the research of a novel asymmetric allyl alkylation reaction catalytic system. (For reviews, see: a) Trost, B.M.; brennan, m.k. synthesis2009, 3003; b) trost, b.m.; crawley, m.l.top.organomet.chem.2012,38,321; c) trost, b.m.; van Vranken, d.l.chem.rev.1996,96,395; d) trost, b.m.; lee, C.Catalytic asymmetry Synthesis,2nd ed. (Ed.: I.Ojima), Wiley-VCH, Weinheim,2000, p.593; e) trost, b.m.; crawley, M.L.chem.Rev.2003,103, 2921; f) miyabe, h.; yamamoto, y.synlett 2005,1641; g) oliver, s.; evans, a.synthesis 2013,45, 3179; f) hong, a.y.; stoltz, b.m.eur.j.org.chem.2013, 2745).

The nitrogen heterocyclic compound is widely existed in various drug molecules and natural products, and plays a very important role in the processes of drug synthesis and discovery. How to quickly construct a nitrogen-containing heterocyclic molecular skeleton and efficiently synthesize structural diversity has been a great concern to chemists, drug research and development departments and business industries. Because different functionalized nitrogen heterocycles can be obtained by further derivatization of the alpha-acyllactam, the application of the compound in drug development will be further expanded undoubtedly if the efficient construction of the chiral quaternary carbon center of the alpha-acyllactam can be realized.

Palladium-catalyzed asymmetric allylic alkylation of α, β -unsaturated β -keto esters:

in 2010, the Trost subject group realized palladium-catalyzed asymmetric decarboxylated allyl alkylation with allyl chloroformate in-situ allyl generation strategy, and expanded the substrate applicability to aromatic and aliphatic ring β -keto esters (Trost, b.m.; Osipov, m.; Dong, g.org.lett.2010,12,1276.Trost, b.m.;B.；Osipov,M.；Wilton,D.A.A.Angew.Chem.,Int.Ed.2011,50,3548)。

in 2011, Stoltz realizes intramolecular asymmetric allyl alkylation reaction of alpha-enol carboxylate substituted caprolactam under the catalysis of palladium, obtains a series of alpha-allyl substituted lactam compounds with ideal enantioselectivity, and constructs a quaternary carbon stereocenter. However, the Pd catalyst and ligand used in this reaction are expensive, limiting their further industrial application. (Behenna, D.C.; Liu Y-Y.; Stoltz, B.M.nat. chem.2011,4,130)

In 2011, the Kitamura group achieved intramolecular or intermolecular allylic alkylation of substituted allylic alcohols with 1, 3-dicarbonyl compounds under ruthenium catalysis to give gamma-substituted products of allylic reagents with high regioselectivity and enantioselectivity (Miyata, k.; Kutsuna, h.; Kawakami, s.; Kitamura, m.angelw.chem., int.ed.2011,50,4649).

Iridium-catalyzed asymmetric allylic alkylation of α, β -unsaturated β -keto esters:

in 2016, Stoltz task group reported an iridium catalyzed asymmetric allylic alkylation of an α, β -unsaturated β -keto ester with an aryl substituted allyl carbonate. The reaction requires the addition of lithium tert-butoxide as a base to promote the reaction and is not highly diastereoselective (dr ═ 1.2: 1 to 5:1) (Liu, W-b.; Okamoto, n.; Alexy, e.j.; Hong, a.y.; Tran, k.; Stoltz, b.m.j.am.chem.soc.2016,138, 5234).

Nickel catalyzed asymmetric allylic alkylation reaction:

in 2015, the Mashima group reported that the first example was based on a nickel-catalyzed AAA reaction of a beta ketoester with allyl alcohol to construct a quaternary carbon chiral center. The reaction proceeds with high yield and high enantioselectivity, and no other activator is needed to activate allyl alcohol, but the reaction substrates are limited to cyclic ketone compounds containing different alpha acyl groups. (Kita, Y.; Kavthe, R.D.; Oda, H.; Mashima, K.Angew.chem., int.Ed.2016,55,1098)

In 2018, Stoltz topic group reported nickel catalyzed enantioselective allylic alkylation of lactone and lactam substrates. Stoltz topic group by Ni (cod)₂As a catalyst, asymmetric allylic alkylation of lactones or lactams with a range of unactivated allylic alcohols is achieved in good yield and high enantioselectivity (90% ee) in the presence of commercially available chiral bisphosphine ligands. Despite the obvious cost advantages of the more expensive palladium catalysts, the use of up to 10 mol% of catalyst and 12 mol% of ligand still greatly limits the further industrial application of the reaction (Ngamnithopporn, A.; Jette, C.I.; Bachman, S.; Virgil, S.C.; Stoltz, B.M.Chem.Sci.2018,9, 2547-.

Disclosure of Invention

The invention provides a method for constructing an alpha-acyl lactam quaternary carbon chiral center compound by nickel-catalyzed asymmetric allyl alkylation and a compound.

The purpose of the invention is realized by the following technical scheme:

a method for constructing alpha-acyl lactam quaternary carbon chiral center compounds by nickel-catalyzed asymmetric allyl alkylation comprises the following steps:

taking a compound 2 and a compound 3, and carrying out nickel-catalyzed asymmetric allyl alkylation reaction in the presence of a ligand to obtain the compound;

the compound 2 is an alpha-acylated lactam compound, the lactam ring is a five-to eight-membered nitrogen heterocycle or a six-to eight-membered benzo nitrogen heterocycle, and the compound 2 has the following general formula:

the compound 3 has the following structure:

in the formula: r₁Is methyl or ethyl;

R₂is hydrogen atom, methyl, phenyl, variously substituted phenyl or heterocyclic group;

R₃is an amide protecting group;

r is tert-butyl dimethyl silicon base, trimethyl silicon base or tert-butyl diphenyl silicon base.

Preferably, the structure of the quaternary carbon chiral center of the alpha-acyl lactam is shown as formula 1:

preferably, the nickel-catalyzed asymmetric allylic alkylation reaction comprises a nickel catalyst comprising Ni (cod)₂，NiCl₂，NiO，Ni(AcO)₂，Ni(acac)₂，Ni(pph₃)₄Or Ni (pph)₃)₂Cl₂。

Preferred ligands for use in nickel-catalyzed asymmetric allylic alkylation include (S) -SunPhos, [ (2S,2' S,3S,3' S) -3,3' -di-tert-butyl-2, 2',3,3' -tetrahydro-4, 4' -dimethoxy-2, 2' -bis-1, 3-benzoxaphosphole ], (S) - (-) -5, 5-bis [ di (3, 5-xylyl) phosphino ] -4, 4-di-1, 3-benzodioxole, (R) -DTBM-SEGPHOS, (R) - (-) -1,1' -binaphthyl-2, 2' -bis (3, 5-xylyl) phosphine, (-) -1, 2-bis ((2S,5S) -2, 5-diisopropylphosphorus) benzene, (R) - (+) -2,2' -bis (diphenylphosphino) -5,5',6,6',7,7',8,8' -octahydro-1, 1' -binaphthyl, (S) - (-) - [ (5,6), (5',6') -bis (ethylenedioxy) biphenyl-2, 2' -yl ] diphenylphosphine.

Preferably, the reaction solvent is at least one of toluene, tetrahydrofuran, diethyl ether and methyl tert-butyl ether.

Preferably, the amount of the catalyst used in the nickel-catalyzed asymmetric allylic alkylation reaction is 2-7 mmol%; the amount of catalyst used is more preferably 4 to 7 mmol%.

Preferably, the amount of ligand used in the nickel-catalyzed asymmetric allylic alkylation reaction is 2-8 mmol%; the amount of ligand used is more preferably 4 to 8 mmol%.

Preferably, the reaction temperature of the nickel-catalyzed asymmetric allyl alkylation reaction is-20 ℃ to 50 ℃, and the reaction time is 8-72 h; the reaction temperature is preferably-5-30 ℃ and the reaction time is 16-36 h.

Preferably, said R is₃The amide protecting group is one of benzoyl, acetyl, benzyl, p-methoxybenzyl, p-toluenesulfonyl and methyl.

Preferably, the preparation method of the compound 3 comprises the following steps: the allyl acid compound 8 is obtained by esterification, reduction of ester group by diisopropylaluminum hydride and one-step silicon protection:

in the structural formula of the compound 8, R₂The method comprises the following steps: a hydrogen atom, a differently substituted phenyl or heterocyclic group.

Preferably, the preparation method of the compound 2 comprises the following steps: taking a lactam compound with a lactam ring of five-to eight-membered nitrogen heterocycle or a lactam compound of benzo six-to eight-membered nitrogen heterocycle, and reacting in an amide protecting group R₃Under the protection condition of (3), carrying out amide alpha acylation to obtain the product.

Preferably, the reagents adopted in the esterification reaction are 0.05 equivalent of concentrated sulfuric acid and 1 equivalent of methanol, the solvent for the ester reduction reaction is dichloromethane, and the temperature of the ester reduction reaction is-78 ℃; TBS protection adopts 1-1.5 equivalent of TBSCl, 1.5 equivalent of imidazole as alkali and dichloromethane as solvent, and the reaction is carried out for 0.5-1.0h at normal temperature.

Preferably, the reaction formula of the compound 2 is:

preferably, said compound 2 comprises:

further, the compound 2a is obtained by benzoyl-protecting the compound 4:

the compound 2b is obtained by performing an amide alpha acylation reaction on the compound 5 under the protection of benzoyl:

the compound 2c is obtained by performing an amide alpha acylation reaction on the compound 6 under the protection of benzoyl:

the compound 2d is obtained from the compound 7 through an amide alpha acylation reaction under the protection of benzoyl:

the amide alpha acylation reaction is carried out on benzoyl-protected lactam compounds in an organic solvent system containing alkali and an acylating agent.

Preferably, in the process of preparing the compound 2a from the compound 4, the protecting reagent adopted in the benzoyl protection reaction is benzoyl chloride;

and/or, in the process of preparing the compound 2a from the compound 4, the base used in the benzoyl protection reaction is at least one of triethylamine, pyridine and potassium carbonate;

and/or, in the process of preparing the compound 2a from the compound 4, the solvent used in the benzoyl protection reaction is at least one of dichloromethane or tetrahydrofuran;

and/or, in the process of preparing the compound 2a by the compound 4, the reaction temperature of the benzoyl protection reaction is 0-10 ℃.

Preferably, in the process of preparing the compound 2a from the compound 4, the base is triethylamine, and the solvent is dichloromethane; the benzoyl chloride accounts for 1.5-2.5 equivalent, and the triethylamine accounts for 2-3 equivalent.

Preferably, the process of preparing the compound 2b from the compound 5 includes a benzoyl protection reaction and an amide alpha acylation reaction, wherein a protective reagent adopted in the benzoyl protection reaction is benzoyl chloride, a base is triethylamine, and a solvent is dichloromethane;

and/or the base used in the amide alpha acylation reaction is 1-2 equivalent of lithium bis (trimethylsilyl) amide or lithium diisopropyl amide, and the acylation agent is 1-2 equivalent of methyl cyanoformate;

and/or the solvent used in the alpha acylation reaction of the amide is tetrahydrofuran;

and/or the temperature of the acylation reaction is-78 ℃.

Preferably, in the preparation of the compound 2b from the compound 5, the benzoyl protection reaction uses 1-2 equivalents of benzoyl chloride as a protection reagent;

and/or, in the process of preparing the compound 2b from the compound 5, the base used in the benzoyl protection reaction is 1-2 equivalents of triethylamine;

and/or, in the process of preparing the compound 2b from the compound 5, the solvent used in the benzoyl protection reaction is dichloromethane;

and/or the alkali used in the amide alpha acylation reaction is 1.1 equivalent of lithium bis (trimethylsilyl) amide, the dosage of the acylating agent is 1.1 equivalent, and the reaction temperature of the amide alpha acylation reaction is-78 ℃.

Preferably, the process for preparing the compound 2c by the compound 6 comprises a benzoyl protection reaction and an amide alpha acylation reaction, wherein the benzoyl protection reaction adopts 1-2 equivalent of benzoyl chloride as a protection reagent;

and/or, in the process of preparing the compound 2c by the compound 6, the base used in the benzoyl protection reaction is 1-2 equivalents of n-butyllithium;

and/or, in the process of preparing the compound 2c by the compound 6, the solvent used in the benzoyl protection reaction is tetrahydrofuran;

and/or, in the process of preparing the compound 2c by the compound 6, the base used in the amide alpha acylation reaction is 1-2 equivalents of lithium bis (trimethylsilyl) amide or lithium diisopropylamide;

and/or, in the process of preparing the compound 2c by the compound 6, the acylating agent is 1-1.5 equivalents of methyl cyanoformate;

and/or, in the process of preparing the compound 2c from the compound 6, the solvent is tetrahydrofuran, and the temperature of acylation reaction is-78 ℃.

Preferably, in the preparation of the compound 2c from the compound 6, the amount of benzoyl chloride is 1.1 equivalent, the amount of n-butyllithium is 1.2 equivalents, the base used in the amide alpha acylation reaction is 1.5 equivalents of bistrimethylaminolithium, and the amide alpha acylation temperature is-78 ℃.

Preferably, the process for preparing the compound 2d from the compound 7 comprises a benzoyl protection reaction and an amide alpha acylation reaction, wherein the benzoyl protection reaction adopts a protective reagent with 1-1.2 equivalent of benzoyl chloride;

and/or, in the process of preparing the compound 2d from the compound 7, the base used in the benzoyl protection reaction is 1-2 equivalents of triethylamine and 0.1-0.25 equivalent of 4-diaminopyridine;

and/or, in the process of preparing the compound 2d from the compound 7, the solvent used in the benzoyl protection reaction is dichloromethane;

and/or, in the process of preparing the compound 2d from the compound 7, the base for the amide alpha acylation reaction is 1-2 equivalents of lithium bis (trimethylsilyl) amide;

and/or, in the process of preparing the compound 2d from the compound 7, the acylating agent is methyl chloroformate with 1-1.5 equivalents;

and/or in the process of preparing the compound 2d from the compound 7, the solvent used in the alpha acylation reaction of the amide is tetrahydrofuran, the temperature of the acylation reaction is-78 ℃, and the reaction time is 1-3 h.

Preferably, in the process of preparing the compound 2d from the compound 7, the dosage of benzoyl chloride is 1.1 equivalent, the dosage of triethylamine is 1.1 equivalent, and the dosage of 4-diaminopyridine is 0.2 equivalent; the amount of lithium bistrimethylsilyl amide was 1.2 equivalents and the amount of methyl chloroformate was 1.1 equivalents.

The invention also provides an alpha-acyl lactam quaternary carbon chiral center compound prepared by the method, a lactam ring connected with the quaternary carbon chiral center is a five-to eight-membered nitrogen heterocycle or a six-to eight-membered benzo nitrogen heterocycle, and the formula is shown as the formula 1:

in the formula: r₁Is methyl or ethyl;

R₂is hydrogen atom, methyl, phenyl, variously substituted phenyl or heterocyclic group;

R₃is an amide protecting group.

The invention has the beneficial effects that: the invention provides a method for constructing an alpha-acyl lactam quaternary carbon chiral center compound by nickel-catalyzed asymmetric allyl alkylation and a compound.

Detailed Description

In view of the wide variety of raw materials used in the preparation of the compounds of the present invention, the following numbers of the various compounds are independently shown and do not affect the numbers of the compounds in the specification.

Firstly, ligand, solvent and temperature screening.

Ligand, solvent and temperature screens were performed according to the following reaction:

the selected ligand has the following structure:

TABLE 1 screening of ligands

TABLE 2 solvent and temperature Screen

In combination with tables 1 and 2, it can be seen that the ligand is preferably L6, the reaction temperature is preferably 0 ℃ and 5 ℃, and the solvent is preferably toluene.

And secondly, screening the silicon protecting group allyl reagent.

The silicon protecting group allyl reagent screening was performed according to the following reaction formula, and the results are shown in table 3:

TABLE 3

Entry	PG(R)	Time(h)	Yield(％)	ee(％)
					1	H	48	62	88
2	TBS	36	90	90
					3	TMS	36	90	88
4	TBDPS	48	62	90

From Table 3, it can be seen that the silicon protecting agent is preferably isopropyldimethylsilyl (TBS).

And thirdly, preparing the compound 2.

The compound 2 of the present invention includes compounds 2a, 2b, 2c, 2d, etc., and the preparation of the compound 2a is further described as follows:

ethyl 2-oxo-3-piperidinecarboxylate (Compound 4) (2.0g,11.68mmol,1.0equiv) was dissolved in 100mL of a dry tetrahydrofuran solution, pyridine (1.85g,23.35mmol,2.0equiv) and BzCl (4.92g,35.03mmol,3.0equiv) were added at 0 ℃ and after stirring for five minutes, the mixture was allowed to stand at room temperatureThe reaction was continued. After completion of the reaction was monitored by TLC, 40mL of a saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried and concentrated, and then subjected to column chromatography (petroleum ether/ethyl acetate: 15/1) to obtain a white amorphous solid product 2a (1.96g, 61% yield).¹H NMR(400MHz,CDCl₃)δ7.70(m,,2H),7.54–7.43(m,1H),7.43-7.34(m,2H),4.25(q,J＝7.2Hz,2H),3.87–3.77(m,2H),3.55(t,J＝6.3Hz,1H),2.33(m,1H),2.21–2.01(m,2H),2.01–1.89(m,1H),1.32(t,J＝7.2Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ174.7,170.0,169.6,135.6,132.0,128.3,128.2,62.0,51.2,25.6,20.7,14.2.IR(neat):ν_max＝2959,1731,1676,1600,1448,1391,1279,1254,1145cm^–1；HRMS(ESI):m/z[M+Na]⁺calcd.for C₁₅H₁₇NNaO₄ ⁺298.1050,found298.1048.

The preparation of compound 2b is further illustrated below:

2-pyrrolidone (Compound 5) (1.3g,15.0mmol,1.0equiv) was dissolved in 50mL of dichloromethane. Triethylamine (3.1mL,22.5mmol,1.5equiv) and benzoyl chloride (2.1g,15.0mmol,1.0equiv) were added at 0 ℃ to react at room temperature for 3h, a saturated aqueous ammonium chloride solution (20 mL) was added, extraction was performed with dichloromethane (20mL × 3) after stirring, and the organic phases were combined and dried and concentrated by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give benzoyl-protected lactam as a white amorphous solid product (2.0g, 70% yield). This solid (2.0g,10.6mmol,1.0equiv) was dissolved in 100mL dry tetrahydrofuran, LiHMDS (11.7mL,11.7mmol,1M/THF,1.1equiv) was added at-78 deg.C, methyl cyanoformate (1.0g,11.7mmol,1.1equiv) was added after 2 hours, and after half an hour, the mixture was allowed to stand at room temperature overnight. After TLC monitoring, a sufficient amount of saturated ammonium chloride was added dropwise under ice bath, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried and concentrated, and then subjected to column chromatography (petroleum ether: acetone ═ 10:1) to give product 2b (1.5g, 57.4% yield) as a colorless oily liquid.¹H NMR(400MHz,CDCl₃)δ7.64–7.57(m,2H),7.57–7.47(m,1H),7.41(t,J＝8.0Hz,2H),4.14–4.02(m,1H),3.99–3.87(m,1H),3.79(s,3H),3.70–3.62(m,1H),2.59–2.46(m,1H),2.46–2.32(m,1H).¹³C NMR(100MHz,CDCl₃)δ170.9,170.1,169.7,134.3,132.8,129.5,128.5,53.5,51.0,45.4,22.4.IR(neat):ν_max＝2955,1726,1671,1600,1581,1448,1362,1285,1238,1154,1076,1045,725,695cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₁₃H₁₄NO₄ ⁺248.0917,found 248.0913.

The preparation of compound 2c is further illustrated below:

caprolactam (compound 6) (2.0g,17.7mmol,1.0equiv) was dissolved in 50mL tetrahydrofuran. N-butyllithium (12.2mL,1.6mol/hexane,19.5mmol,1.2equiv) was added at-78 ℃, stirred for thirty minutes, added with benzoyl chloride (2.3mL,19.4mmol,1.0equiv), reacted at room temperature for 2h, quenched with water 20mL in ice bath, extracted with ethyl acetate (30mL × 3) after stirring, combined organic phases and dried concentrated flash column chromatography (petroleum ether: ethyl acetate 4:1) to give benzoyl protected lactam as a white amorphous solid product (2.69g, 70% yield). The solid (2.0g,9.2mmol,1.0equiv) was dissolved in 50mL dry tetrahydrofuran, LDA (9.2mL,9.2mmol,1M/THF,1.0equiv) was added at-78 deg.C, methyl cyanoformate (0.86g,10.1mmol,1.1equiv) was added after 2 hours, and after half an hour the mixture was allowed to warm to room temperature overnight. After TLC monitoring, a sufficient amount of saturated ammonium chloride was added dropwise under ice bath, extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried, concentrated and subjected to column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give product 2c (1.6g, 63% yield) as a colorless oily liquid.¹H NMR(400MHz,CDCl₃)δ7.64–7.56(m,2H),7.48(t,J＝7.2Hz,1H),7.39(t,J＝7.6Hz,2H),4.27(dd,J＝15.6,7.6Hz,1H),3.84(dd,J＝10.4,2.4Hz,1H),3.75(s,3H),3.61(dd,J＝15.2,8.8Hz,1H),2.26–2.14(m,1H),2.11–1.91(m,3H),1.79–1.64(m,2H).¹³C NMR(100MHz,CDCl₃)δ174.0,173.9,169.9,136.0,131.9,128.3,128.1,54.0,52.6,45.0,28.6,27.5,26.4.IR(neat):ν_max＝2936,2861,1744,1676,1599,1448,1385,1360,1326,1269,1252,1209,1172,1130,1016cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₁₅H₁₈NO₄ ⁺276.1230,found 276.1231.

The preparation of compound 2d is further illustrated below:

3, 4-dihydro-2 (1H) -quinolinone (Compound 7) (2.0g,13.59mmol,1.0equiv), DMAP (0.33g,2.72mmol,0.2equiv) was dissolved in 50mL of dichloromethane. Triethylamine (1.9mL,13.59mmol,1.0equiv) and benzoyl chloride (1.9g,13.6mmol,1.0equiv) were added at 0 ℃ to react at room temperature for 3h, a saturated aqueous ammonium chloride solution (20 mL) was added, extraction was performed with dichloromethane (30mL × 3) after stirring, and the organic phases were combined and dried and concentrated by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to obtain a benzoyl-protected lactam as a white amorphous solid product (2.4g, 98% yield). The solid (2.4g,7.8mmol,1.0equiv) was dissolved in 100mL dry tetrahydrofuran, LiHMDS (3.9mL,9.31mmol,2M/THF,1.2equiv) was added at-78 deg.C, methyl chloroformate (0.8g,8.5mmol,1.1equiv) was added after half an hour, and after half an hour the mixture was allowed to warm to room temperature overnight. TLC monitoring the reaction was complete, sufficient saturated ammonium chloride was added dropwise in ice bath, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried, concentrated and subjected to column chromatography (petroleum ether: acetone ═ 10:1) to afford product 2d as a white amorphous solid (2.0g, 69.6% yield).¹H NMR(100MHz,CDCl₃)δ8.06–7.95(m,2H),7.67–7.59(m,1H),7.49(t,J＝8.0Hz,2H),7.28(d,J＝1.6Hz,1H),7.17(td,J＝8.0,2.0Hz,1H),7.09(td,J＝7.6,1.2Hz,1H),6.75(dd,J＝8.0,1.2Hz 1H),3.84–3.64(m,4H),3.47(dd,J＝16.0,7.2Hz,1H),3.30(dd,J＝16.0,5.6Hz,1H).¹³C NMR(100MHz,CDCl₃)δ173.5,169.2,166.7,137.7,134.6,133.6,130.3,129.2,128.7,128.3,125.0,123.8,117.9,53.0,48.9,29.3.IR(neat):ν_max＝3064,2954,1728,1680,1599,1493,1459,1450,1437,1314,1269,1231,1197,1173,1017cm^–1；HRMS(ESI):m/z[M+H]⁺calcd.for C₁₈H₁₆NO₄ ⁺310.1074,found 310.1071.

Fourthly, preparing the compound 1.

The compound 1 of the present invention includes compounds 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, 1n, etc., and the preparation of the compound 1a is further described as follows:

(R) -3-allyl-1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1a)

The general operation of the nickel-catalyzed asymmetric allylation reaction is: in a nitrogen-filled glove box (water content)<0.01ppm oxygen content<0.1ppm) P-Phos ligand L6(4.72mg,0.0065mmol,6 mmol%) and Ni (cod)₂(1.5mg,0.0054mmol,5 mmol%). The mixture was dissolved in 1.0mL of toluene and stirred at room temperature for half an hour. The lactam substrate 2a (0.109mmol,1.0equiv) and the silicon-protected allyl alcohol reagent 3(0.120mmol,1.1equiv) were dissolved in 1.0mL of toluene, and the above reaction system was added and the reaction was continued at 5 ℃ for 36 hours. The reaction was concentrated and column chromatographed (petroleum ether: ethyl acetate ═ 20:1) to give 1a (31mg, 90.3% yield, 90% ee) as a colorless oily liquid.¹H NMR(400MHz,CDCl₃)δ7.80–7.68(m,2H),7.54–7.45(m,1H),7.39(m,2H),5.80–5.64(m,1H),5.20–5.05(m,2H),4.30(q,J＝7.2Hz,2H),3.84-3.73(m,2H),2.78–2.66(m,1H),2.60-2.50(m,1H),2.37(dt,J＝13.2,4.4Hz,1H),2.11–1.84(m,3H),1.37(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CDCl₃)δ175.1,172.0,136.6,133.1,131.9,128.3,128.2,120.7,62.8,56.5,47.5,39.5,32.1,32.1,15.6.[α]_D ²⁵＝–39(c＝0.720,CHCl₃).IR(neat):ν_max＝2925,1729,1682,1449,1390,1277,1251,1176,1147cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₁₈H₂₂NO₄+316.1543,found 316.1544.HPLC(Column:IC,5μm,4.6×250mm；hexane/isopaopanol＝80/20；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝10.07,major＝11.62.).

The preparation of compound 1b is further illustrated below:

(R) -3-cinnamyl-1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1b)

According to the preparation method of the above 1a, the lactam substrate 2a (0.109mmol,1.0equiv) and the silicon-protected phenylallyl alcohol reagent (0.120mmol,1.1equiv) were used as raw materials, and subjected to nickel-catalyzed asymmetric allylation reaction, and column chromatography (petroleum ether: ethyl acetate: 20:1) to obtain colorless oily liquid 1b (38.8mg, 90.1% yield, 90% ee).¹H NMR(400MHz,CHCl₃)δ7.80-7.70(m,2H),7.55–7.45(m,1H),7.45–7.14(m,7H),6.45(d,J＝16.0Hz,1H),6.19-6.07(m,1H),4.31(q,J＝6.4Hz,2H),3.85-3.70(m,2H),2.90(ddd,J＝13.6,6.8,1.2Hz,1H),2.71(dd,J＝14.0,6.0Hz,1H),2.46–2.34(m,1H),2.09-1.89(m,3H),1.37(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CHCl₃)δ175.1,172.0,171.9,137.1,136.0,134.7,131.9,128.7,128.3,128.2,127.6,126.4,124.6,62.2,56.9,46.6,39.4,30.5,20.3,14.4.[α]_D ²⁵＝–55(c＝1.20,CHCl₃).IR(neat):ν_max＝2957,2926,2871,1727,1680,1599,1493,1476,1448,1389,1272,1149,1193,1171cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₄H₂₆NO₄+392.1856,found 392.1857.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝75/25；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝5.86,major＝6.80.).

The preparation of compound 1c is further illustrated below:

(R) -3- (3- (p-tolyl) allyl) -1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1c)

According to the preparation method of the above 1a, a colorless oily liquid 1c (40.0mg, 90.0% yield, 94% ee) was obtained by column chromatography (petroleum ether: ethyl acetate: 20:1) through a nickel-catalyzed asymmetric allylation reaction using the lactam substrate 2a (0.109mmol,1.0equiv) and a silicon-protected p-methylphenylallyl alcohol reagent (0.120mmol,1.1equiv) as raw materials.¹HNMR(400MHz,CHCl₃)δ7.80-7.70(m,2H),7.54–7.45(m,1H),7.39(t,J＝7.6Hz,2H),7.22(d,J＝8.0Hz,2H),7.10(d,J＝8.0Hz,2H),6.41(d,J＝16.0Hz,1H),6.06(dt,J＝15.2,7.6Hz,1H),4.31(q,J＝7.2Hz,2H),3.85-3.72(m,2H),2.89(ddd,J＝13.8,7.0,1.2Hz,1H),2.69(dd,J＝13.6,8.0Hz,1H),2.46–2.36(m,1H),2.33(s,3H),2.08-1.90(m,3H),1.36(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CDCl₃)δ175.1,172.1,172.0,137.5,136.0,134.6,134.3,131.9,129.4,128.3,128.2,126.3,123.5,62.2,57.0,46.6,39.4,30.5,21.3,20.3,14.4.[α]_D ²⁵＝–77(c＝0.720,CHCl₃).IR(neat):ν_max＝2958,2924,1727,1680,1601,1512,1449,1476,1389,1350,1193,1170,1149cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₅H₂₈NO₄+406.2013,found 406.2011.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝75/25；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝5.56,major＝6.80.).

The preparation of compound 1d is further illustrated below:

(R) -3- (3- (p-fluorophenyl) allyl) -1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1d)

According to the preparation method of the above 1a, the lactam substrate 2a (0.109mmol,1.0equiv) and the silicon-protected p-fluorophenyl allyl alcohol reagent (0.120mmol,1.1equiv) are used as raw materials, the raw materials are subjected to nickel-catalyzed asymmetric allylation reaction, the reaction is carried out at 0 ℃ for 36h, and column chromatography (petroleum ether: ethyl acetate: 25:1) is carried out to obtain colorless oily liquid 1d (20.1mg, 45.0% yield, 93%ee)。¹H NMR(400MHz,CHCl₃)δ7.84–7.70(m,2H),7.56–7.45(m,1H),7.39(t,J＝7.6Hz,2H),7.34–7.22(m,2H),6.98(t,J＝8.4Hz,2H),6.40(d,J＝16Hz,1H),6.04(dt,J＝15.2,7.6Hz,1H),4.31(q,J＝7.2Hz,2H),3.88–3.69(m,2H),2.97–2.82(m,1H),2.75–2.61(m,1H),2.49–2.33(m,1H),2.12–1.86(m,3H),1.36(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CHCl₃)δ175.1,172.0 171.9,163.2,161.6,135.9,133.4,133.3,133.2,131.9,128.3,128.2,127.9,127.9,124.4,115.6,115.5,62.3,56.9,46.6,39.3,30.6,20.3,14.4.[α]_D ²⁵＝–63(c＝0.400,CHCl₃).IR(neat):ν_max＝2925,1729,1682,1600,1508,1450,1390,1274,1229,1194,1154cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₄H₂₅FNO₄+410.1762,found 410.1765.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝80/20；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝6.57,major＝8.97.)

The preparation of compound 1e is further illustrated below:

(R) -3- (3- (p-chlorophenyl) allyl) -1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1e)

According to the preparation method of the above 1a, the lactam substrate 2a (0.109mmol,1.0equiv) and the silicon-protected p-chlorophenyl allyl alcohol reagent (0.120mmol,1.1equiv) are used as raw materials, and the raw materials are subjected to nickel-catalyzed asymmetric allylation reaction at 0 ℃ for 36 hours to obtain colorless oily liquid 1e (32.0mg, 69.0% yield, 95% ee) through column chromatography (petroleum ether: ethyl acetate: 25: 1);¹H NMR(400MHz,CHCl₃)δ7.82-7.70(m,2H),7.54–7.46(m,1H),7.43-7.35(m,2H),7.31-7.18(m,4H),6.39(d,J＝16.0Hz,1H),6.11(dt,J＝15.2,7.6Hz,1H),4.31(q,J＝7.2Hz,2H),3.88–3.70(m,2H),2.87(ddd,J＝13.8,7.0,1.2Hz,1H),2.75–2.63(m,1H),2.47–2.36(m,1H),2.09–1.87(m,3H),1.36(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CHCl₃)δ175.0,171.8,171.7,135.8,135.4,133.3,133.1,131.8,128.7,128.2,128.1,127.5,125.3,62.2,56.8,46.2,39.2,30.5,20.2,14.3.[α]_D ²⁵＝–74(c＝0.407,CHCl₃).IR(neat):ν_max＝2959,2926,1727,1680,1599,1490,1449,1366,1349,1269,1193,1171,1149,1092cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₄H₂₅ClNO₄+426.1467,found 426.1468.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝80/20；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝6.57,major＝8.97.).

the preparation of compound 1f is further illustrated below:

(R) -3- (3- (p-methoxyphenyl) allyl) -1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1f)

According to the preparation method of the above 1a, the lactam substrate 2a (0.109mmol,1.0equiv) and the silicon-protected p-methoxyphenylallyl alcohol reagent (0.120mmol,1.1equiv) are used as raw materials, and the raw materials are subjected to nickel-catalyzed asymmetric allylation reaction at 0 ℃ for 36 hours to obtain colorless oily liquid 1f (40.0mg, 89.0% yield, 89% ee) through column chromatography (petroleum ether: ethyl acetate: 25: 1);¹H NMR(400MHz,CDCl₃)δ7.78-7.67(m,2H),7.54–7.43(m,1H),7.42-7.33(m,2H),7.30-7.17(m,3H),6.83(td,J＝6.0,1.8Hz,2H),6.38(dd,J＝15.6,4.8Hz,1H),6.03–5.90(m,1H),4.35-4.25(m,2H),3.86-3.70(m,5H),2.95–2.80(m,1H),2.71-2.61(m,1H),2.39(dt,J＝10.8,4.0Hz,1H),2.08-1.88(m,3H),1.36(t,J＝7.2Hz,3H).¹³C NMR(101MHz,CDCl₃)δ175.1,172.1,172.0,159.3,136.0,134.1,131.9,129.9,128.3,128.2,127.6,122.2,114.1,62.2,57.0,55.4,46.6,39.4,30.4,20.3,14.4.[α]_D ²⁵＝–44(c＝1.120,CHCl₃).IR(neat):ν_max＝2957,2926,1727,1681,1606,1510,1449,1274,1248,1173cm^{– 1}.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₅H₂₈NO₅+426.1467,found 426.1466.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝80/20；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝7.83,major＝9.56.).

the preparation of compound 1g is further illustrated below:

(R) -3- (3- (furan-2-yl) allyl) -1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1g)

According to the preparation method of the above 1a, 1g (32.0mg, 77.0% yield, 96% ee) of a colorless oily liquid was obtained by column chromatography (petroleum ether: ethyl acetate: 25:1) through a nickel-catalyzed asymmetric allylation reaction using the lactam substrate 2a (0.109mmol,1.0equiv) and a silicon-protected furan allyl alcohol reagent (0.120mmol,1.1equiv) as raw materials at 0 ℃ for 36 hours.¹H NMR(400MHz,CDCl₃)δ7.80-7.67(m,2H),7.59–7.29(m,4H),6.42–6.13(m,3H),6.04(dt,J＝15.2,7.6Hz,1H),4.31(q,J＝6.8Hz,2H),3.90–3.70(m,2H),2.88(ddd,J＝13.6,7.2,1.2Hz,1H),2.67(ddd,J＝14.0,9.2,1.2Hz,1H),2.47–2.32(m,1H),2.12–1.91(m,3H),1.36(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CHCl₃)δ175.1,172.0,171.8,152.6,141.9,136.0,131.9,128.2,128.2,123.2,123.1,111.3,107.5,62.2,56.9,46.5,39.1,30.3,20.3,14.3.[α]_D ²⁵＝–68(c＝0.680,CHCl₃).IR(neat):ν_max＝2925,1778,1726,1679,1448,1390,1271,1148,1016cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₂H₂₄NO₅+382.1649,found 382.1502.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝80/20；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝6.77,major＝7.85.).

The preparation of compound 1h is further illustrated below:

(R) -3- (3- (thiophen-2-yl) allyl) -1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1h)

According to the preparation method of the above 1a, the lactam substrate 5(0.109mmol,1.0equiv) and the silicon-protected thiophene allyl alcohol reagent (0.120mmol,1.1equiv) are used as raw materials, and the raw materials are subjected to nickel-catalyzed asymmetric allylation reaction at 0 ℃ for 36h, and column chromatography (petroleum ether: ethyl acetate ═ 20:1) is carried out to obtain colorless oily liquid for 1h (30.1mg, 69.6% yield, 94% ee).¹H NMR(400MHz,CDCl₃)δ7.85–7.66(m,2H),7.58–7.33(m,3H),7.12(d,J＝5.2Hz,1H),6.99–6.85(m,2H),6.57(d,J＝15.6Hz,1H),5.95(dt,J＝15.2,7.6Hz,1H),4.31(q,J＝7.2Hz,2H),3.90–3.71(m,2H),2.86(ddd,J＝14.0,7.2,1.2Hz,1H),2.76–2.59(m,1H),2.50–2.32(m,1H),2.17–1.86(m,3H),1.36(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CHCl₃)δ175.0,171.9,171.8,142.1,135.9,131.9,128.3,128.2,127.8,127.4,125.4,124.2,124.2,62.3,56.9,46.5,39.2,30.4,20.3,14.3.[α]_D ²⁵＝–63(c＝0.800,CHCl₃).IR(neat):ν_max＝3020,2959,2928,1726,1680,1476,1449,1391,1367,1348,1274,1242,1214,1172,1149cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₂H₂₄NSO₄ ⁺398.1421,found 398.1418.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝80/20；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝7.63,major＝8.72.).

The preparation of compound 1i is further illustrated below:

(R) -3- (3- (p-trifluoromethylphenyl) allyl) -1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1i)

The preparation of 1a was carried out as described above with lactam substrate 2a (0.109mmol,1.0equiv) and silicon protected p-trifluoromethylphenylallyl alcohol reagent (0).120mmol,1.1equiv) as raw material, nickel-catalyzed asymmetric allylation reaction, reaction at 0 ℃ for 36h, column chromatography (petroleum ether: ethyl acetate 25: 1); this gave 1i as a colorless oily liquid (31.0mg, 62.0% yield, 92% ee)¹H NMR(400MHz,CDCl₃)δ7.82–7.71(m,2H),7.58–7.46(m,3H),7.44–7.36(m,4H),6.47(d,J＝16.0Hz,1H),6.25(dt,J＝15.2,7.2Hz,1H),4.32(q,J＝7.2Hz,2H),3.90–3.69(m,2H),2.90(dd,J＝14.0,6.8Hz,1H),2.73(dd,J＝14.0,7.6Hz,1H),2.43(dt,J＝13.2,4.0Hz,1H),2.15–1.85(m,3H),1.37(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CDCl₃)δ175.1,171.9,171.8,140.5,135.9,133.3,132.0,128.3,128.2,127.7,126.5,125.7,125.7,125.6,125.6,62.3,56.9,46.7,39.4,30.7,20.3,14.4.[α]_D ²⁵＝–43(c＝0.154,CHCl₃).IR(neat):ν_max＝2955,2923,2854,1728,1681,1614,1449,1323,1270,1161,1117,1016cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₅H₂₄F₃NaNO₄ ⁺482.1550,found 482.1545.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝80/20；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝5.93,major＝8.80.).

The preparation of compound 1j is further illustrated below:

(R) -3- (3- (naphthyl) allyl) -1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1j)

According to the preparation method of the above 1a, the lactam substrate 2a (0.109mmol,1.0equiv) and the silicon-protected naphthylallyl alcohol reagent (0.120mmol,1.1equiv) are used as raw materials, and the raw materials are subjected to nickel-catalyzed asymmetric allylation reaction at 0 ℃ for 36h, and column chromatography (petroleum ether: ethyl acetate: 20:1) is carried out to obtain colorless oily liquid 1j (29.0mg, 60.3% yield, 89% ee);¹H NMR(400MHz,CDCl₃)δ8.10–8.01(m,1H),7.88–7.81(m,1H),7.80–7.73(m,3H),7.57–7.45(m,4H),7.45–7.35(m,3H),7.20(d,J＝15.2Hz,1H),6.16(dt,J＝15.2,7.2Hz,1H),4.33(q,J＝7.2Hz,2H),3.87–3.75(m,2H),3.01(ddd,J＝13.6,6.8,1.6Hz,1H),2.85(ddd,J＝13.6,8.0,1.2Hz,1H),2.57–2.44(m,1H),2.13–1.96(m,3H),1.38(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CDCl₃)δ175.07,172.02,171.94,135.98,134.83,133.70,131.99,131.90,131.14,128.68,128.26,128.21,128.02,127.86,126.15,125.87,125.77,124.07,123.83,62.29,57.00,46.63,39.70,30.66,20.38,14.38.[α]_D ²⁵＝–61(c＝0.400,CHCl₃).IR(neat):ν_max＝2958,1727,1680,1476,1448,1391,1367,1349,1273,1214,1171,1149,748cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₈H₂₈NO₄ ⁺442.2013,found 442.2011.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝80/20；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝6.66,major＝8.60.).

the preparation of compound 1k is further illustrated below:

(R) -3- (3- (3.5 dimethoxyphenyl) allyl) -1-benzoyl-2-oxopiperidine-3-carboxylic acid ethyl ester (1k)

According to the preparation method of the previous 1a, an lactam substrate 2a (0.109mmol,1.0equiv) and a silicon-protected m-dimethoxyphenylallyl alcohol reagent (0.120mmol,1.1equiv) are used as raw materials, the raw materials are subjected to nickel-catalyzed asymmetric allylation reaction for 36 hours at the temperature of 0 ℃, and column chromatography (petroleum ether: ethyl acetate ═ 20:1) is carried out to obtain colorless oily liquid 1k (32.1mg, 65.4% yield, 94% ee);¹H NMR(400MHz,CDCl₃)δ7.86–7.65(m,2H),7.58–7.45(m,1H),7.39(t,J＝7.6Hz,2H),6.48(d,J＝2.2Hz,2H),6.43–6.32(m,2H),6.18–6.04(m,1H),4.31(q,J＝7.2Hz,2H),3.86–3.72(m,8H),2.99–2.83(m,1H),2.68(dd,J＝13.6,8.0Hz,1H),2.49–2.32(m,1H),2.10–1.89(m,3H),1.37(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CDCl₃)δ175.1,172.0,171.9,161.0,139.1,135.9,134.7,131.9,128.3,128.2,125.1,104.5,100.0,62.3,56.9,55.5,46.7,39.3,30.5,20.3,14.4.[α]_D ²⁵＝–69(c＝1.068,CHCl₃).IR(neat):ν_max＝2958,2935,1726,1679,1589,1453,1424,1347,1271,1201,1149,1061,751cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₆H₃₀NO₆+452.2068,found 452.2071.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝80/20；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝9.08,major＝11.04.).

the preparation of compound 1l is further illustrated below:

(R) -3-allyl-1-benzoyl-2-oxopyrrolidine-3-carboxylic acid ethyl ester (1l)

According to the preparation method of the above 1a, the lactam substrate 2b (0.121mmol,1.0equiv) and the silicon-protected allyl alcohol reagent (0.134mmol,1.1equiv) are used as raw materials, and the raw materials are reacted for 36 hours at 5 ℃ through asymmetric allylation reaction catalyzed by nickel. The reaction solution was concentrated and subjected to column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give 1l (32.1mg, 92.1% yield, 61% ee,) of a colorless oily liquid;¹H NMR(400MHz,CDCl₃)δ7.62–7.55(m,2H),7.52(t,J＝7.6Hz,1H),7.41(t,J＝7.6Hz,2H),5.83–5.65(m,1H),5.27–5.14(m,2H),4.01–3.89(m,2H),3.78(s,3H),2.74(dd,J＝14.0,7.6Hz,1H),2.62(dd,J＝14.0,6.8Hz,1H),2.57–2.47(m,1H),2.20(dt,J＝13.2,8.4Hz,1H).¹³C NMR(100MHz,CDCl₃)δ172.0,171.0,170.6,134.0,132.3,132.1,129.0,128.0,120.5,57.7,53.2,43.8,38.2,26.5.[α]_D ²⁵＝42(c＝0.92,CHCl₃).IR(neat):ν_max＝2955,2915,1748,1727,1675,1601,1581,1448,1362,1290,1240,1213,1100cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₁₆H₁₈NO₄+288.1230,found 288.1226.HPLC(Column:DAICEL CHIRALCE OD-H,5μm,4.6×250mm；hexane/isopaopanol＝97/3；0.8mL/min,Temperature:15℃；λ＝254nm；t_R(min):minor＝31.21,major＝33.95.).

the preparation of compound 1c is further illustrated below:

according to the preparation method of the above 1a, the lactam substrate 2c (0.109mmol,1.0equiv) and the silicon-protected allyl alcohol reagent (0.120mmol,1.1equiv) are used as raw materials, and the reaction is continued for 36h at 5 ℃ through the nickel-catalyzed asymmetric allylation reaction. The reaction solution was concentrated and subjected to column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give 1m (32.4mg, 94.1% yield, 77% ee) as a colorless oily liquid;¹H NMR(400MHz,CDCl₃)δ7.68(dt,J＝7.2,1.2Hz,2H),7.53–7.44(m,1H),7.44–7.36(m,2H),5.75–5.61(m,1H),5.15–4.95(m,2H),4.56–4.34(m,1H),3.84(s,3H),3.10(ddd,J＝15.2,10.8,1.2Hz,1H),2.70(ddt,J＝14.0,6.4,1.2Hz,1H),2.46(dd,J＝14.0,8.0Hz,1H),2.23(dt,J＝14.8,4.4Hz,1H),2.05–1.75(m,3H),1.70–1.50(m,2H).¹³C NMR(100MHz,CDCl₃)δ175.1,174.9,172.0,136.5,133.4,131.7,128.3,128.1,119.1,59.3,52.6,44.2,43.9,32.7,27.9,25.0.[α]_D ²⁵＝55(c＝0.80,CHCl₃).IR(neat):ν_max＝2949,1729,1678,1599,1449,1387,1358,1317,1279,1244,1225,1136,969cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₁₈H₂₂NO₄ ⁺316.1543,found 316.1546.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝90/10；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝6.27,major＝7.28.).

according to the preparation method of the above 1a, the lactam substrate 2d (0.100mmol,1.0equiv) and the silicon-protected allyl alcohol reagent (0.133mmol,1.1equiv) are used as raw materials, and the reaction is continued for 36h at 5 ℃ through the nickel-catalyzed asymmetric allylation reaction. Concentration reactionColumn chromatography (petroleum ether: ethyl acetate ═ 5:1) gave 1n (26.0mg, 76.8% yield, 55% ee) as a colorless oily liquid;¹H NMR(100MHz,CDCl₃)δ8.07–7.99(m,2H),7.69–7.59(m,1H),7.50(t,J＝7.6Hz,2H),7.24(d,J＝7.6Hz,1H),7.20–7.11(m,1H),7.08(td,J＝7.6,1.2Hz,1H),6.77(dd,J＝8.0,1.2Hz,1H),5.96–5.82(m,1H),5.24–5.08(m,2H),3.67(s,3H),3.33(d,J＝16.0Hz,1H),3.14(d,J＝16.0Hz,1H),2.80–2.65(m,2H).¹³C NMR(100MHz,CDCl₃)δ174.2,171.1,168.8,137.5,134.4,134.1,132.8,130.2,129.1,128.8,128.1,124.9,124.5,119.9,117.7,54.7,52.9,38.1,34.3.[α]_D ²⁵＝29(c＝0.76,CHCl₃).IR(neat):ν_max＝3022,2954,1724,1683,1600,1493,1459,1436,1354,1280,1230,1195,1174,1017cm^–1.HRMS(ESI):m/z[M+H]⁺calcd.for C₂₁H₂₀NO₄+350.1387,found 350.1387.HPLC(Column:DAICEL CHIRALCE AD-H,5μm,4.6×250mm；hexane/isopaopanol＝94/6；1.0mL/min,Temperature:25℃；λ＝254nm；t_R(min):minor＝11.35,major＝13.08.).

the foregoing is illustrative of the preferred embodiments of this invention, and it is to be understood that the invention is not limited to the precise form disclosed herein and that various other combinations, modifications, and environments may be resorted to, falling within the scope of the concept as disclosed herein, either as described above or as apparent to those skilled in the relevant art. And that modifications and variations may be effected by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.