阅读说明：本技术 手性1′H-螺[吲哚啉-3,4′-吡喃并[2,3-c]吡唑]-2-酮类化合物 (Chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone compound ) 是由 胡向平 许有伟 于 2019-11-21 设计创作，主要内容包括：本发明涉及一种由吡唑酮类化合物和3-乙炔基吲哚啉酮类化合物通过不对称[3+3]环化反应合成一系列手性1′H-螺[吲哚啉-3,4′-吡喃并[2,3-c]吡唑]-2-酮类化合物的方法。该方法采用的手性铜催化剂是由铜盐与手性P,N,N配体在各种极性和非极性溶剂中原位生成。本发明可以方便地合成各种带取代基团的手性1′H-螺[吲哚啉-3,4′-吡喃并[2,3-c]吡唑]-2-酮类化合物,其对映体过量百分数高达94％。本发明具有操作简单、原料易得、底物适用范围广、对映选择性高等特点。(The invention relates to a method for synthesizing a series of chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone compounds by asymmetric [3+3] cyclization reaction of pyrazolone compounds and 3-ethynyl indolinone compounds. The chiral copper catalyst adopted by the method is generated in situ by copper salt and chiral P, N and N ligands in various polar and nonpolar solvents. The invention can conveniently synthesize various chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone compounds with substituent groups, and the enantiomeric excess percentage of the compounds is as high as 94%. The method has the characteristics of simple operation, easily obtained raw materials, wide application range of the substrate, high enantioselectivity and the like.)

1. a chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-one compound, characterised in that: chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-ones have one of the following structures:

i and II are enantiomers of each other, wherein: r¹，R²，R³,R⁴Is one or more than two of C1-C40 alkyl, C3-C12 cycloalkyl or C3-C12 cycloalkyl with substituent, phenyl and substituted phenyl, benzyl and substituted benzyl, five-membered or six-membered heterocyclic aromatic group containing one or more than two oxygen, sulfur and nitrogen atoms and ester group; the substituents on the C3-C12 naphthenic base, the substituents on the phenyl and the substituents on the benzyl are respectively one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituents is 1-5; C1-C10 alkanoyl, C1-C10 alkoxycarbonyl, C1-C10 alkylsulfonyl, C1-C10 alkylphosphoryl, benzoyl and substituted benzoyl, phenoxycarbonyl and one or more of substituted phenoxycarbonyl, phenylsulfonyl and substituted phenylsulfonyl or phenylphosphoryl and substituted phenylphosphorylMore than two kinds.

2. A method of catalytic asymmetric synthesis of chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one compounds according to claim 1, characterized in that: in the presence of an alkali additive, a chiral copper catalyst catalyzes pyrazolone compounds and 3-ethynyl indolinone compounds to synthesize chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole-2-ketone compounds through asymmetric [3+3] cyclization reaction in a reaction medium.

3. The catalytic asymmetric synthesis method of chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one compounds according to claim 2, characterized in that:

the method comprises the following specific steps:

(1) preparation of chiral copper catalyst: under the protection of nitrogen, copper salt and chiral P, N and N ligands are stirred in a reaction medium for 1-2 hours according to a molar ratio of 1: 0.1-10 to prepare a chiral copper catalyst;

(2) preparation of 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one compounds: dissolving a 3-ethynylindolinone compound, a pyrazolone compound and an alkali additive in a reaction medium, and then adding the mixture into the solution of the chiral copper catalyst prepared in the step (1) under the protection of nitrogen; after the catalytic reaction is finished, concentrating under reduced pressure until no solvent exists basically, separating by silica gel column chromatography, concentrating under reduced pressure, and drying in vacuum to obtain a target product;

the molar ratio of the chiral copper catalyst to the 3-ethynylindolinone compound is 0.01-100% to 1;

the molar ratio of the alkali additive to the 3-ethynylindolinone compound is 0.5-10: 1;

the molar ratio of the pyrazolone compound to the 3-ethynyl indolinone compound is 1-5: 1.

The reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide.

4. The catalytic asymmetric synthesis method of chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one compounds according to claim 2, characterized in that: the pyrone compound has the following structure:

in the formula: r¹，R²Is represented by formula I, II¹，R²The same groups.

5. The catalytic asymmetric synthesis method of chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one compounds according to claim 2, characterized in that: the 3-ethynylindolinone compound has the following structure:

in the formula: r³、R⁴Is represented by formula I, II³、R⁴The same group; x is one or more than two of fluorine, chlorine, bromine, iodine, C1-C10 alkyl carboxylic ester, C1-C10 alkyl carbonate, C1-C10 alkyl sulfonate, C1-C10 alkyl phosphate, phenyl carboxylic ester and substituted phenyl carboxylic ester, phenyl carbonate and substituted phenyl carbonate, phenyl sulfonate and substituted phenyl sulfonate or phenyl phosphate and substituted phenyl phosphate; the substituent on the substituted phenyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.

6. A chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] according to claim 3]Pyrazoles]-2-ketone compound catalytic asymmetric synthesis method, characterized in that: the copper salt is Cu (OAc)₂·H₂O、CuSO₄·H₂O、Cu(OAc)₂、CuSO₄、Cu(OTf)₂、CuCl₂、CuOAc、CuCl、CuI、CuClO₄、CuOTf·0.5C₆H₆、Cu(CH₃CN)₄BF₄Or Cu (CH)₃CN)₄ClO₄One or more than two of them.

7. The catalytic asymmetric synthesis method of chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one compounds according to claim 3, characterized in that: the chiral P, N, N ligand has the following structural characteristics:

in the formula: r³，R⁴H, alkyl in C1-C10, cycloalkyl in C3-C8, phenyl and substituted phenyl, benzyl and substituted benzyl; the substituent on the substituted phenyl or the substituted benzyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;

R⁵，R⁶is H, halogen, alkyl and cycloalkyl, phenyl and substituted phenyl, alkoxy, phenoxy, acyl, nitro;

R⁷is C1-C40 alkyl, C3-C12 cycloalkyl, phenyl and substituted phenyl, naphthyl and substituted naphthyl, and contains one or more than two five-membered or six-membered heterocyclic aromatic groups of oxygen, sulfur and nitrogen atoms; the substituent on the substituted phenyl or the substituted naphthyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.

8. A chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] according to claim 2]Pyrazoles]-2-ketone compound catalytic asymmetric synthesis method, characterized in that: the alkali additive is inorganicOne or more than two of alkali or organic alkali areⁱPr₂NEt、ⁱPrNMe₂、ⁱBu₃N、CyNMe₂、Cy₂NMe、Cy₂NEt、NEt₃、^tBuOK、KOH、NaOH、Na₂CO₃、NaHCO₃、^tBuOK、K₂CO₃、Cs₂CO₃Or K₃PO₄One or more than two of them.

9. The catalytic asymmetric synthesis method of chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one compounds according to claim 2 or 3, characterized in that: the catalytic reaction conditions are as follows:

temperature: -20 to 10 ℃;

reaction medium: one or more of protic solvent and aprotic solvent

Pressure: normal pressure;

time: >0.1 hour.

10. Use of chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-ones according to claim 1, characterized in that: is used for preparing the core skeleton structure of the antibacterial active compound.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing a chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone compound from a pyrazolone compound and a 3-ethynyl indolinone compound through an asymmetric [3+3] cyclization reaction.

Background

Indolinone spiro-compound is an important structural unit in spiro-compound, and has various biological activities and pharmacological activities, such as anticancer, antibacterial, anti-inflammatory, analgesic, insecticidal effects, and the like, and besides, pyrrolidone structure also widely exists in various natural products and drug molecules with biological activity. [ (a) C.V. Gallifond, K.A.Scheidt.Angew.chem.Int.Ed.2007,46, 8748-8758. (b) T.J. Greshock, A.W.Grubbs, P.Jiano, D.T.Wicklow, J.B.Gloer, R.M.Williams.Angew.chem.Int.Ed.2008, 47, 3573-3577. ], the synthesis of these compounds has been of widespread interest to researchers and is one of the hotspots in the field of organic synthesis. As reported by Enders group, the synthesis of spiroisatin cyclopentane structures in good yields and enantioselectivity was achieved by N-heterocyclic carbene catalyzed isatin-derived unsaturated aldehydes and N-Ts alkenylimines. The group Kumar topic reports the synthesis of spiroisatin caprolactam structures by Lewis acid catalyzed hetero Diels-Alder [ L.Wang, S.Li, M.Blumel, R.Puttredy, A.peuronen, K.Rissanen, D.Enders.Angew.chem.int.Ed.2017,56, 8516-. However, the methods still have great limitations on the construction of the oxa spiro indolinone framework structure at the present stage, such as high substrate pre-functionalization degree, high catalyst price, high industrial synthesis difficulty and great limitations in the fields of drug development, natural product synthesis and the like. [ (a) m.p.castaldi, d.m.troast, j.a.porco.org.lett.2009,11, 3362. useful 3365.(b) k.damera, b.yu, b.wang.j.org.chem.2015,80, 5457. useful 5463.(c) h.mao, a.lin, y.tang, y.shi, h.hu, y.cheng, c.zhu.useful.org.lett.2013, 15, 4062. useful 4065.(d) h.wang, l.n.guo, x.dual. useful.org.useful 2013,15, 5254. useful 5257.(e) s.muthaunamy, m.prash, c.rakansan, m.170ahahanman, kehai.m.21. kawain.r, kehai.t.o, thus the synthesis of spiro-substituted ketone by the chiral spiro-v.8. chem.p.p.p.r.r.r-t.r.r.t.t.o.h.r.h.r.r.t.e.r.r.r.r.t.r.r.r.s.r.t.e.e.e.r.s.r.r.r.s.s.s.r.s.r.r.r.t.r..

Disclosure of Invention

The invention aims to provide a method for synthesizing chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone compounds through asymmetric [3+3] cyclization reaction of pyrazolone and 3-ethynylindolinone compounds catalyzed by copper. The method has the characteristics of easily obtained raw materials, simple operation, mild reaction conditions, high enantioselectivity and the like.

The invention provides a catalytic asymmetric synthesis method of a chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone compound, which is characterized in that in the presence of an alkali additive, a pyrazolone compound and a 3-ethynylindolinone compound are catalyzed by a chiral copper catalyst to carry out asymmetric [3+3] cyclization reaction to synthesize the chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone compound.

The method comprises the following specific steps:

(1) preparation of chiral copper catalyst: under the protection of nitrogen, copper salt and chiral P, N, N-ligand are stirred in a reaction medium for 1-2 hours according to the molar ratio of 1: 0.1-10 to prepare a chiral copper catalyst;

(2) preparation of chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-ones: dissolving 3-ethynylindolinone compounds, pyrazolone compounds and alkali additives in a reaction medium, and then adding the solution into the solution of the chiral copper catalyst prepared in the step (1) under the protection of nitrogen, and stirring and reacting for 24 hours at the temperature of-20 ℃; after the catalytic reaction is finished, concentrating under reduced pressure until no solvent exists basically, separating by silica gel column chromatography, concentrating under reduced pressure, and drying in vacuum to obtain a target product;

the molar ratio of the chiral copper catalyst to the 3-ethynyl oxazolidinone compound in the step (2) is 0.01-100 percent to 1,

the molar ratio of the alkali additive to the 3-ethynylindolinone compound is 0.5-10: 1;

the molar ratio of the pyrazole compound to the 3-ethynyl indolinone compound is 1-5: 1.

The reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, 1, 2-dichloroethane, diethyl ether, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide, and preferably at least one of methanol, ethanol, tetrahydrofuran and dichloromethane.

The chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone compound has one of the following structures:

i and II are enantiomers of each other, wherein: r¹，R²，R³Is one or more than two of C1-C40 alkyl, C3-C12 cycloalkyl or C3-C12 cycloalkyl with substituent, phenyl and substituted phenyl, benzyl and substituted benzyl, five-membered or six-membered heterocyclic aromatic group containing one or more than two oxygen, sulfur and nitrogen atoms and ester group; the substituents on the C3-C12 naphthenic base, the substituents on the phenyl and the substituents on the benzyl are respectively one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituents is 1-5; C1-C10 alkanoyl, C1-C10 alkoxycarbonyl, C1-C10 alkylsulfonyl, C1-C10 alkylphosphoryl, benzoyl and substituted benzoyl, phenoxycarbonyl and substituted phenoxycarbonyl, benzenesulfonyl and substituted benzenesulfonyl, or phenylphosphoryl and substituted phenylphosphoryl. .

The pyrazolone compound has the following structure:

in the formula: r¹、R²Is represented by formula I, II¹、R²The same groups.

The ethynyl oxazolidinone compound has the following structure:

in the formula: r³、R⁴Is represented by formula I, II³、R⁴The same groups.

Said copper salt is a divalent copper salt such as Cu (OAc)₂·H₂O、CuSO₄·H₂O、Cu(OAc)₂、CuSO₄、 Cu(OTf)₂、CuCl₂And a variety of monovalentCopper salts such as CuOAc, CuCl, CuI, CuClO₄、CuOTf·0.5C₆H₆、 Cu(CH₃CN)₄BF₄Or Cu (CH)₃CN)₄ClO₄Preferably Cu (OAc)₂·H₂O、Cu(CH₃CN)₄BF₄、 Cu(OTf)₂。

The chiral P, N, N ligand has the following structural characteristics:

in the formula: r³，R⁴H, alkyl in C1-C10, cycloalkyl in C3-C8, phenyl and substituted phenyl, benzyl and substituted benzyl; the substituent on the substituted phenyl or the substituted benzyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;

R⁵，R⁶is H, halogen, alkyl and cycloalkyl, phenyl and substituted phenyl, alkoxy, phenoxy, acyl, nitro;

R⁷is C1-C40 alkyl, C3-C12 cycloalkyl, phenyl and substituted phenyl, naphthyl and substituted naphthyl, and contains one or more than two five-membered or six-membered heterocyclic aromatic groups of oxygen, sulfur and nitrogen atoms; the substituent on the substituted phenyl or the substituted naphthyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.

The alkali additive is various inorganic alkalis or organic alkalis, and the alkali additive is one or more than two of inorganic alkalis or organic alkalisⁱPr₂NEt、ⁱPrNMe₂、ⁱBu₃N、CyNMe₂、Cy₂NMe、Cy₂NEt、 NEt₃、^tBuOK、KOH、NaOH、Na₂CO₃、NaHCO₃、^tBuOK、K₂CO₃、Cs₂CO₃Or K₃PO₄One or more than two of them. Preference is given toⁱPr₂NEt、Cy₂NEt or Et₃N。

The catalytic reaction conditions are preferably as follows:

temperature: -20 to 10 ℃; preferably-20 ℃;

reaction medium: one or more of a protic solvent and an aprotic solvent, preferably methanol;

pressure: normal pressure;

time: >0.1 hour, preferably 24 hours.

The molar ratio of the chiral copper catalyst to the 3-ethynylindolinone compound is preferably 1-10% to 1,

the molar ratio of the alkali additive to the 3-ethynylindolinone compound is preferably 2: 1;

the mol ratio of the pyrazolone compound to the 3-ethynyl indolinone compound is preferably 1.5: 1.

The reaction equation of the invention is as follows:

the invention has the following advantages:

1. high reaction activity, good stereoselectivity and mild reaction conditions.

2. The starting materials are cheap and easy to obtain.

3. The chiral ligand is simple and convenient to synthesize, the catalyst is cheap and easy to obtain, and the dosage is small.

4. Compared with the traditional method, the method can conveniently synthesize various chiral 1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone compounds.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of (S) -1-methyl-1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-1 prepared in example 1;

FIG. 2 is a nuclear magnetic resonance carbon spectrum of (S) -1-methyl-1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-1 prepared in example 1;

FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of (S) -3 '- (4-chlorophenyl) -1-methyl-1' -phenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-2 prepared in example 11;

FIG. 4 is a carbon nuclear magnetic resonance spectrum of (S) -3 '- (4-chlorophenyl) -1-methyl-1' -phenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-2 prepared in example 11;

FIG. 5 is a NMR spectrum of (S) -3 '- (4-bromophenyl) -1-methyl-1' -phenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-3 prepared in example 12;

FIG. 6 is a nuclear magnetic resonance carbon spectrum of (S) -3 '- (4-bromophenyl) -1-methyl-1' -phenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-3 prepared in example 12;

FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of (S) -1-benzyl-1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-4 prepared in example 13;

FIG. 8 is a nuclear magnetic resonance carbon spectrum of (S) -1-benzyl-1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-4 prepared in example 13;

FIG. 9 is a nuclear magnetic resonance hydrogen spectrum of (S) -1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-5 prepared in example 15;

FIG. 10 is a nuclear magnetic resonance carbon spectrum of (S) -1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-5 prepared in example 15;

FIG. 11 is a nuclear magnetic resonance hydrogen spectrum of (S) -5-bromo-1-methyl-1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-6 prepared in example 16;

FIG. 12 is a nuclear magnetic resonance carbon spectrum of (S) -5-bromo-1-methyl-1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazol ] -2-one I-6 prepared in example 16;

Detailed Description

The following examples further illustrate the invention but are not intended to limit the invention thereto. NMR was measured by Bruker400 NMR and High Performance Liquid Chromatography (HPLC) was measured by Agilent 1100 series HPLC.

Example 1: cu (OTf)₂The L-1-1 complex is used as a catalyst to perform catalytic reaction to generate (S) -1-methyl-1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ]]Pyrazoles]-2-keto I-1.

Adding a metal precursor Cu (OTf)₂(0.010mmol, 5 mol%) and chiral ligand L-1-1 (0.020mmol, 10 mol%), adding 1.0mL of anhydrous methanol under the protection of nitrogen, and stirring at room temperature for 1 hour. The reaction tube was then moved to an isothermal reaction freezer at-20 deg.C and 3-ethynylindolinone IV-1 (0.2 mmol, 1.0equiv), pyrazolone III-1 (0.3mmol, 1.5equiv) and NEt were added₃(0.4mmol, 2equiv) was dissolved in 2.0mL of anhydrous methanol, and the solution was added to the stirred solution of the catalyst under nitrogen protection and stirred at-20 ℃ for 24 h. After the reaction, the reaction mixture was concentrated under reduced pressure until the reaction mixture was substantially free of solvent, separated by silica gel column chromatography, concentrated under reduced pressure, and dried under vacuum to give a reddish brown oil with a yield of 95% and ee of 91.5%. The hydrogen and carbon nuclear magnetic resonance spectra of the product I-1 are shown in FIGS. 1 and 2:

¹H NMR(400MHz,CDCl₃)δ7.85(d,J＝7.7Hz,2H),7.45(t,J＝7.9Hz,2H),7.29 (t,J＝7.4Hz,1H),7.23(td,J＝7.7,0.9Hz,1H),7.15(dd,J＝12.7,7.2Hz,2H), 7.04(dt,J＝17.4,7.6Hz,3H),6.95–6.85(m,3H),6.65(d,J＝7.8Hz,1H),4.79(d, J＝6.0Hz,1H),2.95(s,3H).¹³C NMR(101MHz,CDCl₃)δ176.9,148.8,147.1, 142.4,140.9,137.9,134.5,132.5,129.0,128.9,127.9,127.8,127.6,126.5,124.9, 123.2,121.1,108.0,104.1,96.1,47.7,26.2.HPLC(Chiralpak AD-H, n-hexane/i-PrOH＝80/20,0.8ml/min,254nm,40℃):t_R(major)＝10.6min,t_R (minor)＝16.1min。

the structural formula of III-1, IV-1, I-1, L-1-1 is as follows:

example 2: l-1-2 is used as ligand to react to generate a product I-1

The ligand L-1-1 in example 1 was replaced with ligand L-1-2 in the rest of example 1. The reaction gave compound I-1 in 91% yield and 85% ee.

The structural formula of L-1-2 is as follows:

example 3:ⁱPr₂NEt as base additive to produce product I-1

The base additive of example 1 was addedⁱPrNMe₂With Et₃The same procedure as in example 1 was repeated except that N was replaced. The reaction gave compound II-1 in 45% yield and 90% ee.

Example 4:ⁱPr₂NEt as base additive to produce product I-1

The alkali additive Cy in example 1 was added₂For NMeⁱPr₂NEt was replaced, and the rest was the same as in example 1. The reaction gave compound ii-1 in 86% yield, 95.5% ee and dr 15: 1.

Example 5: CuI and L-1-1 are catalyzed to generate a product I-1

Cu (OTf) of example 1₂The remainder was the same as in example 1, except that CuI was used instead. Compound I-1 was obtained in 65% yield, 90% ee.

Example 6: CuOTf 0.5C₆H₆And L-1-1 to produce a product I-1

Cu (OTf) in example 1₂With CuOTf 0.5C₆H₆Instead, the same procedure as in example 1 gave compound II-1 in 47% yield and 90% ee.

Example 7: the alkali-free additive reacts to generate a product I-1

Et from example 1₃The temperature was-20 ℃ after N removal, as in example 1. The target product was not obtained.

Example 8: anhydrous tetrahydrofuran as solvent to produce the product I-1

The methanol solvent in example 1 was replaced with anhydrous tetrahydrofuran, and the rest was the same as in example 1. The target product was not obtained.

Example 9: dichloromethane is used as solvent to react to generate the product I-1

The anhydrous methanol solvent in example 1 was replaced with a dichloromethane solvent, and the product was not obtained as in example 1.

Example 10: reaction at-10 deg.c to produce the product I-1

The reaction temperature in example 1 was replaced with-10 ℃ as in example 1 to give compound I-1 in 90% yield and 91% ee.

Example 11: III-2 is used as a substrate to react to generate a product (S) -3 '- (4-chlorphenyl) -1-methyl-1' -phenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone I-2

The same procedure as in example 1 except for replacing pyrazolone III-1 in example 1 with III-2 gave compound II-2 in 99% yield and 92% ee. The NMR spectrum and the carbon spectrum of the product I-2 are shown in FIGS. 3 and 4:

¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝8.0Hz,2H),7.46(t,J＝7.6Hz,2H),7.29 (dd,J＝17.9,7.7Hz,2H),7.18(d,J＝7.2Hz,1H),7.06(d,J＝7.7Hz,3H),6.91(d, J＝5.9Hz,1H),6.84(d,J＝8.1Hz,2H),6.73(d,J＝7.7Hz,1H),4.80(d,J＝5.9Hz, 1H),3.02(s,3H).¹³C NMR(101MHz,CDCl₃)δ176.8,147.5,147.2,142.3,140.8, 137.8,134.5,133.9,131.2,129.2,129.1,129.0,127.8,126.7,125.0,123.4,121.2, 108.2,104.1,96.1,47.7,26.4.HPLC(Chiralpak AD-H,n-hexane/i-PrOH＝80/20,0.8 ml/min,254nm,40℃):t_R(minor)＝12.8min,t_R(major)＝17.2min.

the structural formula of III-2 and I-2 is as follows:

example 12: III-3 is used as a substrate to react to generate a product (S) -3 '- (4-bromophenyl) -1-methyl-1' -phenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-keto II-3

The compound I-3 was obtained in 91% yield and 90% ee in example 1 by substituting pyrazolone III-1 in example 1 with III-3 and following the same procedure in example 1. The NMR spectrum and the carbon spectrum of the product I-3 are shown in FIGS. 5 and 6:

¹H NMR(400MHz,CDCl₃)δ7.85(d,J＝7.7Hz,2H),7.45(t,J＝7.9Hz,2H),7.29 (t,J＝7.4Hz,1H),7.23(td,J＝7.7,0.9Hz,1H),7.15(dd,J＝12.7,7.2Hz,2H), 7.04(dt,J＝17.4,7.6Hz,3H),6.95–6.85(m,3H),6.65(d,J＝7.8Hz,1H),4.79(d, J＝6.0Hz,1H),2.95(s,3H).¹³C NMR(101MHz,CDCl₃)δ176.7,147.4,147.3, 142.3,140.8,137.7,134.5,131.7,130.8,129.5,129.1,129.0,126.7,125.0,123.4, 122.2,121.2,108.2,104.1,96.0,47.7,26.4.HPLC(Chiralcel OD-H, n-hexane/i-PrOH＝80/20,0.8ml/min,254nm,40℃):t_R(minor)＝11.4min,t_R (major)＝14.0min.

the structural formula of I-3 and III-3 is as follows:

example 13: II-2 is used as a substrate to react to generate a product (S) -1-benzyl-1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone I-4

The same procedure used in example 1 except for replacing 3-ethynylindolinone IV-1 in example 1 with IV-2 gave compound I-4 in 90% yield and 94% ee. The NMR spectrum and the carbon spectrum of the product I-4 are shown in FIGS. 7 and 8:

¹H NMR(400MHz,CDCl₃)δ7.87(d,J＝8.0Hz,2H),7.46(t,J＝7.8Hz,2H),7.32 –7.09(m,9H),7.04–6.85(m,6H),6.62(d,J＝7.7Hz,1H),4.86–4.73(m,2H), 4.55(d,J＝15.5Hz,1H).¹³C NMR(101MHz,CDCl₃)δ177.0,148.8,147.4,141.7, 140.6,137.9,135.3,134.6,132.6,129.0,128.8,128.7,128.0,127.9,127.8,127.5, 127.4,126.6,125.1,123.3,121.2,109.2,104.7,95.4,48.0,44.3.HPLC(Chiralpak OD-H,n-hexane/i-PrOH＝80/20,0.8ml/min,254nm,40℃):t_R(minor)＝13.0min, t_R(major)＝14.6min.

the structural formula of III-3 and I-4 is as follows:

example 14: IV-2 is used as a substrate to react to generate a product (S) -1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone I-5

The same procedure as in example 1 except for substituting 3-ethynylindolinone III-1 in example 1 for III-4 gave compound I-5 in 75% yield 88% ee. The NMR spectrum and the carbon spectrum of the product I-5 are shown in FIGS. 9 and 10:

¹H NMR(400MHz,CDCl₃)δ7.96(d,J＝8.1Hz,2H),7.62(d,J＝8.0Hz,2H),7.38 (d,J＝8.1Hz,2H),7.31–7.20(m,5H),7.16(d,J＝7.9Hz,2H),4.42(d,J＝10.4 Hz,1H),4.35(d,J＝10.4Hz,1H),4.14(t,J＝5.8Hz,1H),3.05(dd,J＝18.0,5.9Hz, 1H),2.66–2.59(m,2H),2.50(s,3H),2.37(s,3H).¹³C NMR(101MHz,CDCl₃)δ 179.7,148.9,147.3,140.7,139.6,137.9,135.0,132.5,129.1,128.9,128.1,127.9, 127.7,126.6,125.2,123.3,121.3,110.2,104.4,95.3,48.6.HPLC(Chiralpak IC-H, n-hexane/i-PrOH＝90/10,0.8ml/min,254nm,40℃):t_R(minor)＝21.0min,t_R (major)＝23.2min.

the structural formula of III-4 and I-5 is as follows:

example 15: III-5 is used as a substrate to react to generate a product (S) -5-bromo-1-methyl-1 ', 3' -diphenyl-1 'H-spiro [ indoline-3, 4' -pyrano [2,3-c ] pyrazole ] -2-ketone I-6

The same procedure used in example 1 except for replacing 3-ethynylindolinone IV-1 in example 1 with IV-4 gave compound I-6 in 91% yield and 83% ee. The NMR spectrum and the carbon spectrum of the product I-6 are shown in FIGS. 11 and 12:

¹H NMR(400MHz,CDCl₃)δ7.84(d,J＝7.7Hz,2H),7.46(t,J＝7.5Hz,2H),7.32 (dd,J＝17.9,7.1Hz,3H),7.21–7.05(m,3H),6.93(d,J＝7.1Hz,3H),6.51(d,J＝8.2Hz,1H),4.77(d,J＝5.8Hz,1H),2.92(s,3H).¹³C NMR(101MHz,CDCl₃)δ 176.3,148.6,146.9,141.4,141.3,137.7,136.3,132.4,131.7,129.0,128.1,128.0, 128.0,127.7,126.6,121.1,115.7,109.5,103.3,95.7,47.7,26.3.HPLC(Chiralpak AD-H,n-hexane/i-PrOH＝80/20,0.8ml/min,254nm,40℃):t_R(minor)＝10.1min, t_R(major)＝16.3min.

the structural formula of IV-4 and I-6 is as follows: