CN116178371A - Method for synthesizing spiro chiral indolinone through indole C6-position Pictet-Spengler reaction - Google Patents

Method for synthesizing spiro chiral indolinone through indole C6-position Pictet-Spengler reaction Download PDF

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CN116178371A
CN116178371A CN202111424164.3A CN202111424164A CN116178371A CN 116178371 A CN116178371 A CN 116178371A CN 202111424164 A CN202111424164 A CN 202111424164A CN 116178371 A CN116178371 A CN 116178371A
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indole
phosphoric acid
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indolinone
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周永贵
王新维
吴波
孙蕾
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Dalian Institute of Chemical Physics of CAS
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention provides a method for synthesizing spiro chiral indolinone through an indole C6-position Pictet-Spengler reaction, wherein a catalyst used by the method is chiral phosphoric acid. By the method, spiro chiral indolinone (with an enantiomeric excess of 93%) can be obtained. The method is simple and easy to operate, the catalyst is commercially available, the reaction condition is mild, the yield and the enantioselectivity are good, and the method has potential application value.

Description

Method for synthesizing spiro chiral indolinone through indole C6-position Pictet-Spengler reaction
Technical Field
The invention belongs to the field of asymmetric catalytic synthesis, and relates to a method for synthesizing spiro indolinone by taking isatin and 2- (7-indole) aniline as reaction substrates, chiral phosphoric acid as a catalyst and performing a Pictet-Spengler reaction at the C6 position of indole.
Technical Field
Indole alkaloids have various structures and important biological activities. Asymmetric catalysis of the asymmetric Pictet-Spengler reaction provides a simple and efficient method for synthesizing such chiral compounds. The asymmetric Pictet-Spengler reactions reported to date for indoles all occur on the indole electron-rich pyrrole ring. This is mainly the relatively strong nucleophilicity of the indole at the C3 and C2 positions. In contrast, the electron cloud density on the aromatic ring of indole is relatively low and the reaction is difficult. However, the asymmetric Pictet-Spengler reaction on the indole benzene ring is very valuable. For example, in 2017, the Yamada group reported a Pictet-Spengler reaction diastereoselective at position 4 of indole for the concise total synthesis of natural products (-) -Hyrtioreticulins C and (+) -Hyrtioreticulin D (Abe, t.; yamada, k.j. Nat. Prod.2017,80,241.). Catalytic asymmetric Pictet-Spengler reactions on indole benzene rings have not been reported to date.
Disclosure of Invention
The invention provides a method for synthesizing spiro chiral indolinone by using isatin and 2- (7-indole) aniline derivatives as reaction substrates and chiral phosphoric acid as a catalyst through a Pictet-Spengler reaction at the C6 position of indole.
The method has the advantages of simple and easily obtained raw materials, convenient and practical operation, high yield and enantioselectivity, environment-friendly reaction and the like.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
the invention provides a method for synthesizing spiro chiral indolinone through an indole C6-position Pictet-Spengler reaction, wherein the reaction takes isatin and a 2- (7-indole) aniline derivative as reaction substrates, chiral phosphoric acid is taken as a catalyst, and spiro indolinone containing an indole skeleton is asymmetrically synthesized, and the reaction formula is as follows:
Figure BDA0003378409670000011
wherein:
Ar 1 ,Ar 2 is phenyl or benzene ring containing substituent, the substituent is halogen, alkoxy or C 1 -C 20 At least one of the alkyl groups of (a);
R 1 ,R 2 alkyl or aryl, including methyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 3-chloromethyl, and the like;
R 3 is alkyl or arylmethyl including methyl, benzyl, naphthylmethyl, 4-methylbenzyl, 4-methoxybenzyl, benzhydryl, trityl and the like,preferably benzhydryl;
temperature: 0-100 ℃;
time: 1-120 hours;
CPA is chiral phosphoric acid.
Based on the technical scheme, preferably, the reaction steps of the method are as follows:
under the protection of nitrogen, mixing the 2- (7-indole) aniline derivative, isatin, catalyst chiral phosphoric acid and an organic solvent, stirring and reacting for 1-120h at 0-100 ℃, directly spin-drying the solvent, and performing column chromatography to obtain the corresponding chiral spiro indolinone.
Based on the technical scheme, the molar ratio of the 2- (7-indole) aniline derivative to the isatin to the catalyst is (1-2) (0.01-0.1), and is more preferably 1:1.1:0.05.
Based on the above technical scheme, preferably, the ratio of the catalyst, isatin, 2- (7-indole) aniline derivative and organic solvent is 0.01-0.1 mmol:1-2 mmol:1-50ml, preferably 0.05mmol:1.1mmol:1mmol:10ml.
Based on the above technical scheme, preferably, the organic solvent is an aromatic hydrocarbon solvent, or dichloromethane, diethyl ether, ethyl acetate, dioxane, acetonitrile, chloroform, or the like.
Further preferably, the aromatic solvent is toluene, xylene, benzene, trimethylbenzene, chlorobenzene, or the like.
Based on the above technical scheme, preferably, the chiral phosphoric acid is chiral phosphoric acid with binaphthyl skeleton, and the structural formula is as follows:
Figure BDA0003378409670000021
wherein:
Ar 3 is phenyl or benzene ring or anthryl or phenanthryl containing substituent, wherein the substituent is fluorine, methyl, trifluoromethyl or isopropyl; further preferably, the chiral phosphoric acid is pentafluorophenyl substituted chiral phosphoric acid, ar 3 Is C 6 F 5 。
The reaction is isatin and2- (7-indole) aniline derivative is used as a reaction substrate, and spiro indolinone containing indole skeleton and Ar are synthesized through indole C6-position Picet-Spengler reaction 1 ,Ar 2 Is phenyl or benzene ring containing substituent, the substituent is halogen, alkoxy or C 1 -C 20 At least one of the alkyl groups of (a); r is R 1 ,R 2 ,R 3 Is alkyl or aryl; the catalyst is pentafluorophenyl substituted chiral phosphoric acid, the solvent is toluene, the temperature is 50 ℃, and the enantiomeric excess is 93%.
The invention has the following advantages:
1. the raw materials are simple and easy to obtain, the synthetic route is mature, the operation is simple, easy and convenient, and the reaction condition is mild.
2. High yield, convenient separation, high purity product (with an enantiomeric excess of 93 percent) and potential application value.
3. The catalyst synthesis route is mature and commercially available.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited to the examples.
Examples 1 to 18
Optimization of conditions
Under the protection of nitrogen, adding a 2- (7-indole) aniline derivative (0.1 mmol), chiral phosphoric acid (0.005 mmol) and a solvent (1 ml) into a 25 ml Schelenk tube, adding isatin (0.11 mmol) into the Schelenk tube, reacting for 48 hours at 40 ℃, directly spin-drying the solvent, and adding an internal standard nuclear magnetic yield; conditions such as solvent, catalyst chiral phosphoric acid, temperature, feeding ratio and the like in the reaction are changed, and the specific conditions are shown in a table (table 1), and the structures of the reaction formula and the chiral phosphoric acid are as follows:
Figure BDA0003378409670000031
TABLE 1 Condition optimization a
Figure BDA0003378409670000032
Figure BDA0003378409670000041
a Reaction conditions 1a (0.10 mmol), 2a (0.11 mmol), solvent (1.0 ml), chiral phosphoric acid (0.005 mmol); b yield was determined using nuclear magnetism. c High performance liquid chromatography. d 50 mg of anhydrous sodium sulfate was used.
Examples 19 to 38
Expansion of spiro chiral indolinone substrate synthesized by catalyzing C6-position Pictet-Spengler reaction of indole through chiral phosphoric acid
2- (7-indole) aniline derivative (0.20 mmol), isatin (0.22 mmol), chiral phosphoric acid (R) -4h (0.01 mmol), toluene (2 ml) were added to a 25 ml Schelenk tube under nitrogen protection, stirred at 50℃for 3-72h, the solvent was directly spin-dried, and column chromatography was carried out to obtain pure product. The yield was isolated and the enantiomeric excess of the product was determined by chiral liquid chromatography. The structures of the reaction formula and the substrate scale are as follows:
Figure BDA0003378409670000051
the reaction conditions were 1 (0.20 mmol), 2 (0.22 mmol), toluene (2.0 ml), chiral phosphoric acid (R) -4h (0.01 mmol), and the reaction was carried out at 50℃for 3-72 hours.
(S)-(+)-1-Benzyl-3'-methyl-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3aa):103mg,99％yield,yellow solid,mp 156-157℃,new compound,R f ＝0.25(hexanes/ethyl acetate 5/1),89％ee,[α] 20 D ＝+84.49(c 0.60,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.68(brs,1H),7.99(d,J＝7.6Hz,1H),7.64(d,J＝7.6Hz,2H),7.51(t,J＝7.5Hz,2H),7.45–7.20(m,9H),7.16(t,J＝7.5Hz,1H),7.08–6.95(m,2H),6.86–6.71(m,2H),6.42(d,J＝8.2Hz,1H),5.07(d,J＝15.5Hz,1H),4.68(d,J＝15.5Hz,1H),4.36(brs,1H),2.43(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.9,143.2,142.6,135.9,135.3,133.2,132.9,132.6,131.7,129.7,128.9,128.9,128.4,128.0,127.8,127.6,127.6,125.4,124.5,123.5,122.1,120.1,118.7,116.9,116.8,115.8,109.4,109.2,65.0,43.8,9.6.Enantiomeric excess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 17.7min(major)and 27.5min.HRMS(ESI)m/z:[M+H] + calcd for C 36 H 28 N 3 O 518.2227,found 518.2230.
(+)-1,3'-Dimethyl-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanth ridin]-2-one(3ab):85mg,97％yield,colourless oil,new compound,R f ＝0.15(hexanes/ethyl acetate 3/1),82％ee,[α] 20 D ＝+28.33(c 0.42,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.68(brs,1H),7.96(d,J＝7.4Hz,1H),7.61(d,J＝7.3Hz,2H),7.48(t,J＝7.3Hz,2H),7.40–7.26(m,3H),7.21(d,J＝7.7Hz,1H),7.11(t,J＝7.3Hz,1H),6.98(t,J＝6.8Hz,2H),6.87(d,J＝7.7Hz,1H),6.70(d,J＝7.6Hz,1H),6.40(d,J＝8.0Hz,1H),4.25(brs,1H),3.18(s,3H),2.40(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.0,143.2,143.1,135.3,133.2,133.0,132.6,131.7,129.8,129.7,128.9,128.3,128.0,127.0,125.2,124.5,123.5,122.1,120.1,118.6,116.9,116.7,116.0,109.2,108.4,65.2,26.4,9.6.Enantiomeric excess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 18.4min(major)and 24.3min.HRMS(ESI)m/z:[M+H] + calcd for C 30 H 24 N 3 O 442.1914,found 442.1916.
(+)-3'-Methyl-1-(4-methylbenzyl)-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3ac):102mg,96％yield,colourless oil,new compound,R f ＝0.50(hexanes/ethyl acetate 5/1),89％ee,[α] 20 D ＝+89.01(c 0.51,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.67(brs,1H),7.97(d,J＝7.6Hz,1H),7.61(d,J＝7.5Hz,2H),7.47(t,J＝7.6Hz,2H),7.40–7.30(m,2H),7.29–7.16(m,4H),7.11(t,J＝8.4Hz,3H),7.02–6.91(m,2H),6.79(d,J＝7.8Hz,1H),6.72(d,J＝7.7Hz,1H),6.40(d,J＝8.2Hz,1H),5.00(d,J＝15.4Hz,1H),4.60(d,J＝15.4Hz,1H),4.32(brs,1H),2.41(s,3H),2.30(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.0,143.3,142.6,137.5,135.4,133.3,133.0,133.0,132.7,131.7,129.8,129.7,129.6,129.0,128.4,128.0,127.6,125.4,124.5,123.4,122.1,120.1,118.7,117.0,116.8,115.9,109.5,109.2,65.1,43.6,21.2,9.6.Enantiomeric excess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 17.0min(major)and 26.4min.HRMS(ESI)m/z:[M+H] + calcd for C 37 H 30 N 3 O 532.2383,found 532.2385.
(+)-1-(4-Methoxybenzyl)-3'-methyl-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3ad):108mg,98％yield,yellow oil,new compound,R f ＝0.25(hexanes/ethyl acetate 5/1),88％ee,[α] 20 D ＝+89.07(c 0.54,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.68(brs,1H),7.97(d,J＝7.5Hz,1H),7.61(d,J＝7.5Hz,2H),7.47(t,J＝7.5Hz,2H),7.39–7.28(m,2H),7.28–7.16(m,4H),7.10(d,J＝7.4Hz,1H),6.96(dd,J＝17.4,7.7Hz,2H),6.80(t,J＝7.6Hz,3H),6.71(d,J＝7.7Hz,1H),6.38(d,J＝8.2Hz,1H),4.95(d,J＝15.3Hz,1H),4.56(d,J＝15.3Hz,1H),4.35(brs,1H),3.72(s,3H),2.40(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.9,159.2,143.2,142.5,135.4,133.3,133.1,132.7,131.7,129.8,129.7,129.0,129.0,128.4,128.1,128.0,127.6,125.4,124.5,123.4,122.1,120.1,118.7,116.9,116.8,115.9,114.3,109.4,109.2,65.1,55.3,43.3,9.7.Enantiomeric excess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 21.6min(major)and 32.7min.HRMS(ESI)m/z:[M+H] + calcd for C 37 H 30 N 3 O 2 548.2333,found 548.2332.
(+)-3'-Methyl-1-(naphthalen-1-ylmethyl)-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3ae):110mg,96％yield,yellow oil,new compound,R f ＝0.35(hexanes/ethyl acetate 5/1),87％ee,[α] 20 D ＝+54.72(c 0.55,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.69(brs,1H),8.10–7.90(m,2H),7.88–7.80(m,1H),7.75(d,J＝7.6Hz,1H),7.60(d,J＝7.6Hz,2H),7.52–7.21(m,9H),7.19–7.05(m,2H),7.03–6.86(m,2H),6.72(d,J＝7.7Hz,2H),6.43(d,J＝8.2Hz,1H),5.48(d,J＝16.0Hz,1H),5.10(d,J＝16.0Hz,1H),4.36(brs,1H),2.41(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.9,143.2,143.0,135.4,134.0,133.3,133.1,132.7,131.8,131.3,130.9,129.8,129.7,129.0,128.7,128.4,128.0,127.7,126.8,126.2,125.7,125.5,125.3,124.6,123.5,123.3,122.2,120.2,118.7,117.2,117.0,115.9,110.0,109.2,65.2,42.4,9.7.Enantiomeric excess wasdetermined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 21.8min(major)and 43.2min.HRMS(ESI)m/z:[M+H] + calcd for C 40 H 30 N 3 O 568.2383,found 568.2381.
(+)-1-Benzhydryl-3'-methyl-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3af):113mg,95％yield,colourless oil,new compound,R f ＝0.25(hexanes/ethyl acetate 10/1),90％ee,[α] 20 D ＝+49.64(c 0.56,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.68(brs,1H),7.95(d,J＝7.5Hz,1H),7.60(d,J＝7.4Hz,2H),7.52–7.20(m,15H),7.18–6.84(m,5H),6.70(d,J＝7.6Hz,1H),6.54(d,J＝7.9Hz,1H),6.40(d,J＝8.1Hz,1H),4.34(brs,1H),2.40(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.2,143.2,142.1,137.8,137.8,135.4,133.3,133.3,132.7,131.8,130.0,129.3,129.0,128.8,128.5,128.4,128.0,128.0,127.9,127.6,125.4,124.6,123.2,122.0,120.1,118.8,116.9,116.8,115.9,112.4,109.2,64.8,58.3,9.7.Enantiomeric excess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 12.1min(major)and 15.6min.HRMS(ESI)m/z:[M+H] + calcd for C 42 H 32 N 3 O 594.2540,found 594.2545.
(+)-3'-Methyl-2'-phenyl-1-trityl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phena nthridin]-2-one(3ag):114mg,85％yield,yellow oil,new compound,R f ＝0.20(hexanes/ethyl acetate 10/1),90％ee,[α] 20 D ＝+90.52(c 0.57,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.64(brs,1H),7.83(d,J＝7.5Hz,1H),7.60(d,J＝7.4Hz,2H),7.46(d,J＝7.4Hz,9H),7.37–7.28(m,2H),7.23–7.05(m,9H),7.04–6.88(m,3H),6.83(t,J＝7.3Hz,1H),6.68(d,J＝8.1Hz,1H),6.56(d,J＝7.7Hz,1H),6.42(d,J＝7.9Hz,1H),4.10(brs,1H),2.45(s,3H). 13 C NMR(100MHz,CDCl 3 )δ178.5,143.8,143.8,142.4,135.4,134.1,133.2,132.7,131.7,129.6,129.0,128.4,128.3,128.0,127.9,127.7,126.8,125.0,124.6,122.9,121.1,119.5,118.6,117.2,117.1,115.8,115.2,109.2,74.2,65.1,9.7.Enantiomeric excess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 11.4min(major)and 18.0min.HRMS(ESI)m/z:[M+K] + calcd for C 48 H 35 KN 3 O 708.2412,found 708.2412.
(+)-1-Benzhydryl-3',5-dimethyl-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3ah):116mg,95％yield,colourless oil,new compound,R f ＝0.30(hexanes/ethyl acetate 10/1),80％ee,[α] 20 D ＝+58.79(c 0.58,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.68(brs,1H),7.95(d,J＝7.6Hz,1H),7.60(d,J＝7.6Hz,2H),7.45(t,J＝7.6Hz,2H),7.41–7.21(m,12H),7.14–7.05(m,2H),6.94(d,J＝9.8Hz,2H),6.85(d,J＝8.1Hz,1H),6.70(d,J＝7.8Hz,1H),6.47–6.34(m,2H),4.33(brs,1H),2.41(s,3H),2.16(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.1,143.2,139.7,137.9,135.4,133.4,133.3,132.8,132.7,131.8,130.1,129.6,129.0,128.7,128.5,128.4,128.0,127.9,127.8,127.6,126.1,124.5,121.9,120.0,118.7,117.0,116.9,115.8,112.1,109.2,64.8,58.3,21.0,9.7.Enantio-meric excess was determined by HPLC(IC column,elute:n-Hexane/i-PrOH＝60/40,the detector:254 nm,flow rate:0.6mL/min,30℃),retention time 10.7min(major)and 17.6min.HRMS(ESI)m/z:[M+H] + calcd for C 43 H 34 N 3 O 608.2696,found 608.2699.
(+)-1-Benzhydryl-5-bromo-3'-methyl-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3ai):57mg,42％yield,yellow oil,new compound,R f ＝0.20(hexanes/ethyl acetate 10/1),22％ee,[α] 20 D ＝+12.28(c 0.57,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.68(brs,1H),7.96(d,J＝7.6Hz,1H),7.61(d,J＝7.5Hz,2H),7.48(t,J＝7.6Hz,2H),7.44–7.23(m,13H),7.19–7.08(m,2H),7.03–6.87(m,2H),6.73(d,J＝7.8Hz,1H),6.39(dd,J＝8.3,4.5Hz,2H),4.34(brs,1H),2.42(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.6,142.7,141.1,137.4,135.6,135.4,133.1,132.6,132.1,131.9,129.1,129.0,128.8,128.6,128.5,128.4,128.0,128.0,127.7,124.6,121.7,120.3,118.8,116.7,116.0,115.9,113.8,109.2,64.7,58.3,9.6.Enantiomeric excess was determined by HPLC(IBcolumn,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 12.1min(major)and 14.0min.HRMS(ESI)m/z:[M+H] + calcd for C 42 H 31 BrN 3 O 672.1639( 79 Br)and 674.1617( 81 Br),found 672.1639( 79 Br)and 674.1617( 81 Br).
(+)-1-Benzhydryl-6-bromo-3'-methyl-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3aj):133mg,99％yield,colourless oil,new compound,R f ＝0.15(hexanes/ethyl acetate 10/1),84％ee,[α] 20 D ＝+21.67(c 0.66,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.67(brs,1H),7.92(d,J＝7.3Hz,1H),7.58(d,J＝7.3Hz,2H),7.50–7.19(m,14H),7.13–6.96(m,3H),6.96–6.81(m,2H),6.66(d,J＝4.1Hz,2H),6.37(d,J＝8.0Hz,1H),4.28(brs,1H),2.40(s,3H). 13 C NMR(100MHz,CDCl 3 )δ176.9,143.4,142.8,137.3,137.3,135.6,133.2,132.7,132.2,131.9,129.3,129.0,128.9,128.6,128.4,128.2,128.0,127.7,126.6,126.2,124.6,122.9,121.9,120.3,118.8,116.8,116.7,116.0,115.4,109.2,64.5,58.6,9.7.Enantiomeric excess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 9.4min(major)and 15.9min.HRMS(ESI)m/z:[M+H] + calcd for C 42 H 31 BrN 3 O 672.1645( 79 Br)and 674.1639( 81 Br),found 672.1646( 79 Br)and 674.1629( 81 Br).
(-)-1-Benzhydryl-7-bromo-3'-methyl-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3ak):129mg,96％yield,yellow oil,new compound,R f ＝0.15(hexanes/ethyl acetate 10/1),90％ee,[α] 20 D ＝-58.28(c 0.64,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.57(brs,1H),7.84(d,J＝7.2Hz,1H),7.71–7.12(m,19H),7.03(d,J＝7.2Hz,1H),6.96–6.79(m,2H),6.59(d,J＝7.4Hz,1H),6.30(d,J＝8.0Hz,1H),4.15(brs,1H),2.39(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.1,142.6,141.0,138.9,138.5,137.3,136.2,135.4,133.2,132.5,131.7,129.3,129.0,128.9,128.7,128.4,128.3,128.2,128.0,127.7,127.6,127.4,125.2,124.8,124.5,121.7,120.1,118.6,117.2,116.8,115.8,109.2,102.8,64.1,61.2,9.6.Enantiomeric excess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 14.0min(major)and 37.2min.HRMS(ESI)m/z:[M+H] + calcd for C 42 H 31 BrN 3 O 672.1645( 79 Br)and 674.1633( 81 Br),found 672.1640( 79 Br)and 674.1617( 81 Br).
(+)-1-Benzhydryl-2',3'-dimethyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3bf):105mg,99％yield,colourless oil,new compound,R f ＝0.20(hexanes/ethyl acetate 10/1),63％ee,[α] 20 D ＝+35.81(c 1.05,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.41(brs,1H),7.84(d,J＝6.6Hz,1H),7.51–7.14(m,12H),7.12–6.80(m,5H),6.67(d,J＝6.9Hz,1H),6.52(d,J＝7.6Hz,1H),6.33(d,J＝7.9Hz,1H),4.31(brs,1H),2.30(s,3H),2.15(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.4,143.1,142.0,137.9,137.8,133.5,132.1,131.9,131.2,129.1,128.7,128.6,128.5,128.1,127.9,127.9,125.4,124.6,123.1,122.2,119.8,117.7,116.2,116.1,115.7,115.6,112.3,107.6,64.8,58.3,11.7,8.5.Enantiomeric excess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 18.3min(major)and 34.3min.HRMS(ESI)m/z:[M+H] + calcd for C 37 H 30 N 3 O 532.2383,found 532.2375.
(+)-1-Benzhydryl-2'-(tert-butyl)-3'-methyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3cf):111mg,97％yield,yellow solid,new compound,R f ＝0.30(hexanes/ethyl acetate 10/1),82％ee,[α] 20 D ＝+61.81(c 0.55,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.52(brs,1H),7.87(d,J＝7.6Hz,1H),7.41–7.21(m,12H),7.11(t,J＝7.5Hz,1H),7.08–6.95(m,2H),6.96–6.85(m,2H),6.74(d,J＝7.7Hz,1H),6.52(d,J＝8.0Hz,1H),6.33(d,J＝8.2Hz,1H),4.16(brs,1H),2.35(s,3H),1.48(s,9H). 13 C NMR(100MHz,CDCl 3 )δ177.2,143.3,142.9,142.2,137.8,137.8,133.3,132.2,130.4,129.2,128.8,128.7,128.7,128.5,128.2,127.9,127.8,125.4,124.1,123.1,122.3,120.0,117.7,116.3,116.2,115.9,112.3,105.9,64.7,58.2,32.9,30.1,10.3.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝70/30,the detector:254 nm,flow rate:0.7mL/min,30℃),retention time 11.3min(major)and 22.0min.HRMS(ESI)m/z:[M+H] + calcd for C 40 H 36 N 3 O 574.2853,found 574.2850.
(+)-1-Benzhydryl-2'-(4-methoxyphenyl)-3'-methyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3ef):125mg,>99％yield,colourless oil,new compound,R f ＝0.15(hexanes/ethyl acetate 10/1),90％ee,[α] 20 D ＝+54.44(c 0.54,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.63(brs,1H),7.94(d,J＝7.6Hz,1H),7.51(d,J＝8.5Hz,2H),7.44–7.21(m,12H),7.13–6.83(m,7H),6.69(d,J＝7.8Hz,1H),6.53(d,J＝8.0Hz,1H),6.38(d,J＝8.2Hz,1H),4.31(brs,1H),3.78(s,3H),2.36(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.2,159.2,143.2,142.1,137.8,135.4,133.3,132.5,131.9,129.6,129.3,129.2,128.7,128.5,128.3,127.9,127.9,125.8,125.4,124.6,123.2,122.1,120.1,118.5,116.8,116.7,115.9,114.4,112.4,108.2,64.8,58.3,55.5,9.6.Enantiomeric excess was determined by HPLC(IC column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 16.6min(major)and 33.3min.HRMS(ESI)m/z:[M+H] + calcd for C 43 H 34 N 3 O 2 624.2646,found 624.2649.
(+)-1-Benzhydryl-3'-methyl-2'-(p-tolyl)-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3ff):120mg,98％yield,white solid,mp 170-171℃,new compound,R f ＝0.20(hexanes/ethyl acetate 10/1),93％ee,[α] 20 D ＝+56.00(c 0.30,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.66(brs,1H),7.93(d,J＝7.6Hz,1H),7.48(d,J＝7.9Hz,2H),7.29(m,14H),7.11–6.98(m,2H),6.98–6.83(m,3H),6.68(d,J＝7.8Hz,1H),6.53(d,J＝8.0Hz,1H),6.39(d,J＝8.2Hz,1H),4.32(brs,1H),2.38(s,3H),2.37(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.2,143.2,142.1,137.9,137.9,137.5,135.6,133.4,132.6,131.9,130.4,129.8,129.7,129.2,128.8,128.5,128.3,128.0,127.9,125.4,124.6,123.2,122.1,120.1,118.6,116.8,116.8,115.9,112.4,108.7,64.8,58.3,21.4,9.7.Enantio-mericexcess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 12.7min(major)and 19.2min.HRMS(ESI)m/z:[M+H] + calcd for C 43 H 34 N 3 O 608.2696,found 608.2696.
(+)-1-Benzhydryl-2'-(3-chlorophenyl)-3'-methyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3gf):118mg,94％yield,yellow oil,new compound,R f ＝0.15(hexanes/ethyl acetate 10/1),90％ee,[α] 20 D ＝+53.56(c 0.59,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.67(brs,1H),7.92(d,J＝7.5Hz,1H),7.58(s,1H),7.46(d,J＝7.6Hz,1H),7.42–7.21(m,14H),7.13–7.00(m,2H),6.99–6.88(m,3H),6.70(d,J＝7.7Hz,1H),6.54(d,J＝8.0Hz,1H),6.39(d,J＝8.2Hz,1H),4.32(brs,1H),2.39(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.1,143.1,142.0,137.8,137.7,135.0,134.8,133.9,133.2,132.8,131.6,130.4,130.1,129.2,128.7,128.5,128.4,127.9,127.9,127.8,127.5,126.1,125.3,124.5,123.2,121.8,120.1,118.8,117.0,116.9,115.9,112.4,110.1,64.7,58.3,9.7.Enantiomeric excess was determined by HPLC(IC column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 9.4min(major)and 14.1min.HRMS(ESI)m/z:[M+H] + calcd for C 42 H 31 ClN 3 O 628.2150( 35 Cl)and 630.2150( 37 Cl),found 628.2154( 35 Cl)and 630.2162( 37 Cl).
(+)-1-Benzhydryl-2',3'-diphenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3hf):123mg,94％yield,yellow oil,new compound,R f ＝0.40(hexanes/ethyl acetate 10/1),81％ee,[α] 20 D ＝+36.06(c 0.61,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.93(brs,1H),7.97(d,J＝7.3Hz,1H),7.54–7.20(m,22H),7.13–6.86(m,5H),6.70(d,J＝7.7Hz,1H),6.52(d,J＝7.8Hz,1H),6.39(d,J＝8.2Hz,1H),4.34(brs,1H). 13 C NMR(100MHz,CDCl 3 )δ177.1,143.2,142.1,137.8,137.8,135.4,134.9,133.2,132.7,132.6,130.6,130.4,130.3,129.3,128.8,128.8,128.7,128.6,128.5,128.4,128.4,128.0,127.9,126.5,125.3,124.5,123.2,121.8,120.1,119.4,117.7,117.1,115.9,115.6,112.4,64.7,58.3.Enantiomeric excess was determined by HPLC(IB column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 11.1min(major)and 13.5min.HRMS(ESI)m/z:[M+H] + calcd for C 47 H 34 N 3 O 656.2696,found 656.2695.
(+)-1-Benzhydryl-3',10'-dimethyl-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3if):114mg,93％yield,yellow oil,new compound,R f ＝0.30(hexanes/ethyl acetate 10/1),86％ee,[α] 20 D ＝+60.65(c 0.61,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.70(brs,1H),7.77(s,1H),7.62(d,J＝7.4Hz,2H),7.48(t,J＝7.5Hz,2H),7.42–7.22(m,13H),7.04(t,J＝7.6Hz,1H),6.99–6.87(m,3H),6.64(d,J＝7.9Hz,1H),6.53(d,J＝7.5Hz,1H),6.45–6.36(m,1H),4.20(brs,1H),2.41(s,3H),2.36(s,3H). 13 C NMR(100MHz,CDCl 3 )δ177.2,142.1,140.8,137.9,137.8,135.3,133.4,133.3,132.7,131.7,130.3,129.2,129.0,128.7,128.5,128.0,127.9,127.9,127.6,125.4,125.1,123.1,122.2,118.6,116.9,116.9,116.0,112.3,109.2,64.8,58.3,21.5,9.7.Enantiomeric excess was determined by HPLC(IC column,elute:n-Hexane/i-PrOH＝60/40,the detector:254nm,flow rate:0.6mL/min,30℃),retention time 15.2min(major)and 21.5min.HRMS(ESI)m/z:[M+H] + calcd for C 43 H 34 N 3 O 608.2696,found 608.2694.
(+)-1-Benzhydryl-10'-chloro-3'-methyl-2'-phenyl-1',7'-dihydrospiro[indoline-3,6'-pyrrolo[3,2-k]phenanthridin]-2-one(3jf):114mg,90％yield,yellow oil,new compound,R f ＝0.10(hexanes/ethyl acetate/dichloromethane 20/1/1),65％ee,[α] 20 D ＝+47.62(c 0.21,CH 2 Cl 2 ). 1 H NMR(400MHz,CD 2 Cl 2 )δ8.61(brs,1H),7.83(s,1H),7.55(d,J＝7.5Hz,2H),7.38(t,J＝7.6Hz,2H),7.33–7.13(m,13H),7.03–6.93(m,2H),6.87(t,J＝7.5Hz,1H),6.76(s,1H),6.57(t,J＝8.0Hz,1H),6.47(d,J＝8.0Hz,1H),6.25(d,J＝8.2Hz,1H),4.40(brs,1H),2.31(s,3H). 13 C NMR(100MHz,CD 2 Cl 2 )δ175.8,141.5,141.1,136.9,136.8,135.0,132.1,132.0,131.6,131.1,129.3,128.5,128.1,127.8,127.8,127.5,127.2,127.1,127.0,126.9,126.9,124.4,123.4,123.3,122.4,122.4,118.5,116.0,115.6,114.8,111.4,108.5,63.8,57.6,8.5.Enantiomeric excess was determined by HPLC(IC column,elute:n-Hexane/i-PrOH＝70/30,the detector:254nm,flow rate:0.7mL/min,30℃),retention time 9.5min(major)and 10.9min.HRMS(ESI)m/z:[M+H] + calcd for C 42 H 31 ClN 3 O 628.2150( 35 Cl)and 630.2145( 37 Cl),found 628.2153( 35 Cl)and 630.2134( 37 Cl).

Claims (10)

1. A method for synthesizing spiro chiral indolinone through an indole C6-position Pictet-Spengler reaction is characterized in that isatin and a 2- (7-indole) aniline derivative are taken as reaction substrates, chiral phosphoric acid is taken as a catalyst, and spiro-containing indolinone is asymmetrically synthesized, wherein the reaction formula is as follows:
Figure FDA0003378409660000011
wherein:
Ar 1 ,Ar 2 is phenyl or benzene ring containing substituent, the substituent is halogen, alkoxy or C 1 -C 20 At least one of the alkyl groups of (a);
R 1 ,R 2 ,R 3 is alkyl or aryl.
2. The method according to claim 1, characterized in that the specific reaction steps of the method are:
under the protection of nitrogen, mixing a catalyst, isatin, a 2- (7-indole) aniline derivative and an organic solvent, stirring at 0-100 ℃ for reaction for 1-120 hours, spin-drying the solvent, and separating by column chromatography to obtain the spiro-containing indolinone.
3. The method according to claim 1, wherein the molar ratio of the catalyst, isatin, 2- (7-indole) aniline derivative is 0.01-0.1:1-2:1-2.
4. A process according to claim 2 or 3, characterized in that the ratio of catalyst, isatin, 2- (7-indole) aniline and organic solvent is 0.01-0.1 mmol:1-2 mmol:1-50ml.
5. The method according to claim 2, wherein the organic solvent is an aromatic solvent.
6. The method according to claim 2, wherein the organic solvent is at least one of dichloromethane, diethyl ether, ethyl acetate, dioxane, acetonitrile, chloroform.
7. The method according to claim 1 or 2, wherein the chiral phosphoric acid is a chiral phosphoric acid of a binaphthyl skeleton.
8. The method of claim 7, wherein the chiral phosphoric acid has the structural formula:
Figure FDA0003378409660000012
wherein:
Ar 3 is phenyl or benzene ring or anthryl or phenanthryl containing substituent, wherein the substituent is fluorine, methyl, trifluoromethyl or isopropyl.
9. The method of claim 5, wherein the aromatic solvent is at least one of toluene, xylene, benzene, chlorobenzene, trimethylbenzene.
10. The method of claim 8, wherein the chiral phosphoric acid is a pentafluorophenyl substituted chiral phosphoric acid.
CN202111424164.3A 2021-11-26 2021-11-26 Method for synthesizing spiro chiral indolinone through indole C6-position Pictet-Spengler reaction Pending CN116178371A (en)

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