CN108690029A - One kind is with optical activation to adjoin double loop coil oxidized indole compounds and its application - Google Patents

One kind is with optical activation to adjoin double loop coil oxidized indole compounds and its application Download PDF

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CN108690029A
CN108690029A CN201810391499.1A CN201810391499A CN108690029A CN 108690029 A CN108690029 A CN 108690029A CN 201810391499 A CN201810391499 A CN 201810391499A CN 108690029 A CN108690029 A CN 108690029A
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loop coil
double loop
phenyl
methyl
independently selected
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CN108690029B (en
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崔宝东
陈羽
陈永正
韩文勇
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Zunyi Medical University
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

Disclosed in the present application to be that one kind in organic synthesis field is with optical activation adjoin double loop coil oxidized indole compounds, has the following structure:In formula:X is NR5, O or S substituent groups.The compound is white or faint yellow solid, has the characteristics that thermodynamic stability, optics Chun Du≤85%;The compound of the application has antitumor activity, such as has certain inhibiting effect to human hepatocellular, lung cancer and breast cancer cell.

Description

One kind is with optical activation to adjoin double loop coil oxidized indole compounds and its application
Technical field
The present invention relates to organic synthesis fields, and more specifically, the present invention, which is that one kind is with optical activation, adjoins double loop coils Oxidized indole compounds and its application.
Background technology
Loop coil Oxoindole is to constitute many pharmaceutical activity molecules and day as a kind of particularly important heterocycle structure unit The core skeleton of right product, causes the especially concern of synthesis chemists.Wherein, containing the loop coil oxygen for adjoining loop coil quaternary carbon center Change Benzazole compounds and is found to have extensive pharmaceutical activity, such as antitumor activity and antibacterial activity.Especially, containing adjoining Double loop coil Oxoindole molecules of adjacent loop coil quaternary carbon center often show special life due to its unique three-D space structure Reason activity.
In view of containing the good bioactivity of double loop coil Oxoindole molecules for adjoining loop coil quaternary carbon center and in pharmaceutical chemistry In application prospect, developed many methods for effectively building such compound at present.However, the prior art focuses primarily upon this The synthesis of class compound raceme contains asymmetric syntheses the double loop coil oxidized indoles of chirality for adjoining loop coil quaternary carbon center The report for closing object is also very limited, is primarily due to structure at least containing there are two the double spiral shells for adjoining chiral centre and space is very crowded Epoxidation indole structure unit has prodigious difficulty.In addition, the technology of the existing such compound of asymmetric syntheses is mainly concentrated In organic catalysis [3+2]It is cyclized cascade reaction, and it is mainly 3,3&apos to synthesize the such molecule obtained;Nafoxidine/dihydro The bis- loop coil Oxoindoles of furans-, for chirality 3,3'The asymmetric syntheses of the bis- loop coil oxidized indole compounds of cyclopentene-, because Lack effective Technology design, is still the work of a challenge.
Therefore, by rational asymmetric syntheses Technology design, the double spiral shells of chirality from simple raw material to structure novel are realized Epoxidation Benzazole compounds (such as chirality 3,3'The bis- loop coil Oxoindoles of cyclopentene -) conversion, for effectively abundant chiral spiral shell The type of epoxidation benzazolyl compounds is of great significance with the pharmaceutical chemistry research for carrying out related field.
Invention content
The invention is intended to provide, one kind is with optical activation to adjoin double loop coil oxidized indole compounds and its application, master Foundation is provided to carry out the pharmaceutical chemistry research of related field.
One kind of the present invention is with optical activation to adjoin double loop coil oxidized indole compounds, has the following structure:
In formula:X is NR5, O or S substituent groups.
One kind of the present invention is with optical activation to adjoin double loop coil oxidized indole compounds, generally white or yellowish Color solid is soluble in the organic solvents such as ethyl alcohol, ethyl acetate, dichloromethane, acetone, dimethyl sulfoxide (DMSO), is insoluble in water, has heat The characteristics of mechanical stability.
Further, work as X=NR5When, R5Be each independently selected from H, Me, Et,nPr,nBu,iPr, allyl, Ph or Bn;
Correspondingly, R1It is each independently selected from H, 4-F, 4-Cl, 5-Me, 5-OMe, 5-F, 5-OCF3,5-Cl,5-Br,6- Cl,6-Br,7-F,7-Cl,7-CF3Or 7-OCF3;
Correspondingly, R2Be each independently selected from H, Me, Et,nPr,nBu,iPr, allyl, Ph or Bn;
Correspondingly, R3Be each independently selected from Me, Et,nPr,iPr,nBu,iBu,tBu or Ph.
Correspondingly, R4It is each independently selected from H, 4-F, 4-Cl, 5-Me, 5-OMe, 5-F, 5-OCF3,5-Cl,5-Br,6- Cl,6-Br,7-F,7-Cl,7-CF3Or 7-OCF3;
Correspondingly, R is each independently selected from Me, OMe, OEt, OiPr,OtBu, OPh, OBn, phenyl, methyl substituted-phenyl, Methoxy substitution phenyl, fluorine substituted-phenyl, chlorine substituted-phenyl, bromine substituted-phenyl, 1- naphthalenes, 2- naphthalenes, 2- furyls or 2- thiophenes Pheno base.
Further, as X=O or S,
Correspondingly, R1It is each independently selected from H, 4-F, 4-Cl, 5-Me, 5-OMe, 5-F, 5-OCF3,5-Cl,5-Br,6- Cl,6-Br,7-F,7-Cl,7-CF3Or 7-OCF3;
Correspondingly, R2Be each independently selected from H, Me, Et,nPr,nBu,iPr, allyl, Ph or Bn;
Correspondingly, R3Be each independently selected from Me, Et,nPr,iPr,nBu,iBu,tBu or Ph;
Correspondingly, R4It is each independently selected from H, 5-Me, 4,6-Me2,4,7-Me2,5-OMe,4,6-(OMe)2Or 4,7- (OMe)2;
Correspondingly, R is each independently selected from Me, OMe, OEt, OiPr,OtBu, OPh, OBn, phenyl, methyl substituted-phenyl, Methoxy substitution phenyl, fluorine substituted-phenyl, chlorine substituted-phenyl, bromine substituted-phenyl, 1- naphthalenes, 2- naphthalenes, 2- furyls or 2- thiophenes Pheno base.
The present invention provides a kind of preparation method with optical activation for adjoining double loop coil oxidized indole compounds, packets It includes:
Step 1: MBH- carbonic esters, 3- carbonyl alkenyl benzo-heterocycle compounds derived from isatin are added in organic solvent And chiral lewis base, stir 5 under 0 DEG C~50 DEG C of reaction temperature~for 24 hours;
With optical activation adjoin double loop coil oxidized indole compounds Step 2: isolated.
MBH- structural carbonates derived from isatin are shown below:
In formula:R1It is each independently selected from H, 4-F, 4-Cl, 5-Me, 5-OMe, 5-F, 5-OCF3,5-Cl,5-Br,6-Cl, 6-Br,7-F,7-Cl,7-CF3Or 7-OCF3;
R2Be each independently selected from H, Me, Et,nPr,nBu,iPr, allyl, Ph or Bn;
R3Be each independently selected from Me, Et,nPr,iPr,nBu,iBu,tBu or Ph;
3- carbonyl alkenyl benzo-heterocycle compound structures are shown below:
In formula:Work as X=NR5When, R5Be each independently selected from H, Me, Et,nPr,nBu,iPr, allyl, Ph or Bn;
Correspondingly, R4It is each independently selected from H, 4-F, 4-Cl, 5-Me, 5-OMe, 5-F, 5-OCF3,5-Cl,5-Br,6- Cl,6-Br,7-F,7-Cl,7-CF3Or 7-OCF3;
Correspondingly, R is each independently selected from Me, OMe, OEt, OiPr,OtBu, OPh, OBn, phenyl, methyl substituted-phenyl, Methoxy substitution phenyl, fluorine substituted-phenyl, chlorine substituted-phenyl, bromine substituted-phenyl, 1- naphthalenes, 2- naphthalenes, 2- furyls or 2- thiophenes Pheno base;
As X=O or S,
Correspondingly, R4It is each independently selected from H, 5-Me, 4,6-Me2,4,7-Me2,5-OMe,4,6-(OMe)2Or 4,7- (OMe)2;Correspondingly, R is each independently selected from Me, OMe, OEt, OiPr,OtBu, OPh, OBn, phenyl, methyl substituted-phenyl, first Oxygroup substituted-phenyl, fluorine substituted-phenyl, chlorine substituted-phenyl, bromine substituted-phenyl, 1- naphthalenes, 2- naphthalenes, 2- furyls or 2- thiophene Base.
Reaction is shown below:
Such as:By MBH- carbonic esters derived from 0.2mmol 3- carbonyl alkenyls benzo-heterocycle compound, 0.3mmol isatin and 0.04mmol(12.4mg)β-6'Hydroxyl cinchonicine is dissolved in 2mL dichloromethane, under 25 DEG C of reaction temperature, stirring 5 Hour;Then, reaction solution is directly detached with column chromatography, is obtained the corresponding pair loop coils with optical activation that adjoin and is aoxidized Benzazole compounds.
Further, the described optics Chun Du with optical activation for adjoining double loop coil oxidized indole compounds≤ 85%.
Further, the described optics Chun Du with optical activation for adjoining double loop coil oxidized indole compounds≤ 95%.
Further, the described optics Chun Du with optical activation for adjoining double loop coil oxidized indole compounds≤ 98%.
The optical purity of above compound is measured by high performance liquid chromatograph, and the optical purity of a chipal compounds is The percentage of its specific rotatory power with sterling, raw material is different, and what is obtained with optical activation adjoins double loop coil oxidized indoles Compound light purity is also different, and the optical purity of generation is higher, and the pharmaceutical activity of the compound is higher, and preferably optics Chun Du≤ When 98%, which is specifically shown in embodiment Partial characterization value, what ee was represented is optical purity.
It is with optical activation to adjoin double loop coil oxidized indole compounds with antitumor activity, such as to human liver Cancer, lung cancer and breast cancer cell etc. have certain inhibiting effect, as shown in the table:
Referring to upper table, choose it is wherein several it is with optical activation adjoin double loop coil oxidized indole compounds, to people source IC50 values (i.e. the ratio between apoptosis cancer cell and whole cancer cell numbers etc. of lung cancer cell types and people source hepatoma H22 cells The concentration of corresponding compound when 50%) it is detected, numerical value is as above, wherein 5 compound of serial number is to people source lung cancer The IC50 values of cell line A549 are minimum, show that it is relatively strong to the inhibitory activity of lung carcinoma cell;The compound of serial number 6 is to people source The IC50 values of hepatoma H22 cells are minimum, show that it is relatively strong to the inhibitory activity of liver cancer cells.
Specific implementation mode
It is further described below by specific implementation mode:
The specific product of the compound of the present invention, the difference of reaction raw materials, generation is as follows:
Embodiment 1:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) indoline-of 0.2mmol (52.7mg) 2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, and reaction process is used Thin-layered chromatography monitors.After reaction carries out completely, mixture obtains (C1R, C4R, C5S) -3,3&apos through column chromatographic isolation and purification;- (1- benzoyls) cyclopentenyl adjoins double loop coil Oxoindole (yield 89%, dr values 97:3, ee value >99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl adjoins the characterize data of double loop coil Oxoindoles: [α]D 25=-101.0 (c 1.00, CHCl3);mp 230.1-231.2℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=10.5min)1H NMR(400MHz,CDCl3):δ2.98(3H,s),3.05-3.06(3H,m), 3.62-3.63 (3H, m), 4.98 (1H, d, J=2.0Hz), 6.55 (2H, dd, J=7.7Hz, 2.5Hz), 6.79 (1H, t, J= 7.6Hz), 6.94 (1H, t, J=7.6Hz), 7.09 (1H, td, J=7.7Hz, 1.3Hz), 7.15-7.18 (2H, m), 7.23- 7.24 (1H, m), 7.43-7.50 (3H, m), 7.53-7.57 (1H, m), 7.97 (2H, d, J=8.3Hz);13C NMR(100MHz, CDCl3):δ25.9,26.4,52.5,56.0,62.3,66.6,107.9,108.0,122.4,122.5,124.1,124.6, 125.1,125.2,128.7,129.3,129.4,129.9,133.2,137.2,143.0,144.4,144.7,145.0, 169.9,175.0,176.3,191.4.HRMS(ESI-TOF)calcd.for C30H25N2O5[M+H]+493.1758;found: 493.1758。
Embodiment 2:
2- (1,5- dimethyl -3- tertiary butyloxycarbonyl oxygroups-the 2- of 0.3mmol (108.4mg) are added in 2mL dichloromethane Oxoindole quinoline -3- bases) methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) Yin of 0.2mmol (52.7mg) Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'(1- benzoyls) cyclopentenyl -5- methyl adjoins double loop coil Oxoindole (yield 70%, dr values >99:1, ee value 99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -5- methyl adjoins the table of double loop coil Oxoindoles Levy data:[α]D 25=-40.7 (c 0.50, CHCl3);mp 218.7-220.3℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=7.8min, tminor=11.2min)1H NMR(400MHz,CDCl3):δ2.28(3H,s), 2.97 (3H, s), 3.08 (3H, s), 3.64 (3H, s), 4.97 (1H, s), 6.45 (1H, d, J=7.9Hz), 6.56 (1H, d, J= 7.8Hz), 6.80 (1H, t, J=7.6Hz), 6.96 (1H, d, J=7.8Hz), 7.10 (1H, t, J=7.7Hz), 7.16 (1H, d, ), J=1.2Hz 7.25 (1H, s), 7.32 (1H, s), 7.47 (2H, t, J=7.5Hz), 7.56 (1H, t, J=7.3Hz), 7.99 (2H, d, J=7.6Hz);13C NMR(100MHz,CDCl3):δ21.2,25.9,26.4,52.6,55.9,62.3,66.5, 107.6,108.0,122.5,124.6,124.8,125.1,125.2,128.7,129.2,129.6,129.9,131.9, 133.2,137.2,142.0,142.9,144.6,145.1,170.0,174.9,176.2,191.4.HRMS(ESI-TOF) calcd.for C31H27N2O5[M+H]+507.1914;found:507.1918.
Embodiment 3:
The 2-&#91 of 0.3mmol (113.2mg) is added in 2mL dichloromethane;1- methyl -3- tertiary butyloxycarbonyl oxygroup -2- (5- first Oxygroup Oxoindole quinoline) -3- Jis ]Methyl acrylate, the 1- methyl -3- (2- oxo -2- phenyl Asia second of 0.2mmol (52.7mg) Base) indole-2-ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, Reaction process is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtain through column chromatographic isolation and purification (C1R, C4R, C5S)-3,3'(1- benzoyls) cyclopentenyl -5- methoxyl groups adjoin double loop coil Oxoindole (yield 85%, dr values 97:3, Ee values 99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -5- methoxyl groups adjoin double loop coil Oxoindoles Characterize data:[α]D 25=-75.3 (c 1.00, CHCl3);mp 123.7-125.5℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=14.3min, tminor=19.8min)1H NMR(400MHz,CDCl3):δ2.96(3H,s), 3.08 (3H, s), 3.62 (3H, s), 3.72 (3H, s), 4.96 (1H, d, J=1.7Hz), 6.45 (1H, d, J=8.5Hz), 6.56 (1H, d, J=7.8Hz), 6.69 (1H, dd, J=8.4Hz, 2.3Hz), 6.78 (1H, t, J=7.6Hz), 7.09 (1H, t, J= 7.6Hz), 7.14 (2H, dd, J=5.5Hz, 2.1Hz), 7.24 (1H, d, J=2.1Hz), 7.44 (2H, t, J=7.5Hz), 7.54 (1H, t, J=7.3Hz), 7.97 (2H, d, J=7.4Hz);13C NMR(100MHz,CDCl3):δ26.0,26.4,52,5, 55.9,56.1,62.5,66.5,108.0,108.3,114.3,122.5,124.6,125.1,126.4,128.6,129.3, 129.8,133.2,137.2,137.8,143.0,144.7,144.9,155.8,169.9,174.9,175.9,191.3.HRMS (ESI-TOF)calcd.for C31H27N2O6[M+H]+523.1864;found:523.1866.
Embodiment 4:
The 2-&#91 of 0.3mmol (109.6mg) is added in 2mL dichloromethane;1- methyl -3- tertiary butyloxycarbonyl oxygroup -2- (5- fluorine Oxoindole quinoline) -3- Jis ]Methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) Yin of 0.2mmol (52.7mg) Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'(1- benzoyls) cyclopentenyl -5- fluorine adjoins double loop coil Oxoindole (yield 84%, dr values 96:4, ee value > 99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -5- fluorine adjoins the characterization of double loop coil Oxoindoles Data:[α]D 25=-144.6 (c 1.00, CHCl3);mp 197.2-199.1℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=13.3min)1H NMR(400MHz,CDCl3):δ2.99(3H,s),3.12(3H,s),3.65 (3H, s), 4.95-4.97 (1H, m), 6.50 (1H, dd, J=8.5Hz, 4.2Hz), 6.60 (1H, d, J=7.8Hz), 6.81 (1H, t, J=7.6Hz), 6.88 (1H, td, J=8.8Hz, 2.3Hz), 7.10-7.19 (2H, m), 7.25 (1H, d, J= 5.5Hz), 7.30 (1H, dd, J=8.5Hz, 2.2Hz), 7.47 (2H, t, J=7.6Hz), 7.57 (1H, t, J=7.3Hz), 7.97 (2H, d, J=7.5Hz);13C NMR(100MHz,CDCl3):δ26.1,26.5,52.6,56.2,62.3,66.5, 108.1,108.4 (1C, d, J=8.1Hz), 112.5 (1C, d, J=25.9Hz), 115.6 (1C, d, J=23.4Hz), 122.7, 124.6,124.9,127.0 (1C, d, J=8.4Hz), 128.7,129.5,129.9,133.3,137.1,140.4,143.0, (144.6,144.7,159.1 1C, d, J=239.0Hz), 169.8,174.7,176.0,191.2.HRMS (ESI-TOF) calcd.for C30H24FN2O5[M+H]+511.1664;found:511.1665.
Embodiment 5:
The 2-&#91 of 0.3mmol (127.9mg) is added in 2mL dichloromethane;1- methyl -3- tertiary butyloxycarbonyl oxygroup -2- (6- bromines Oxoindole quinoline) -3- Jis ]Methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) Yin of 0.2mmol (52.7mg) Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'(1- benzoyls) cyclopentenyl -6- bromines adjoin double loop coil Oxoindole (yield 77%, dr values 97:3, ee values 98%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -6- bromines adjoin the characterization of double loop coil Oxoindoles Data:[α]D 25=-31.2 (c 0.50, CHCl3);mp 123.3-125.1℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=13.5min, tminor=15.3min)1H NMR(400MHz,CDCl3):δ3.03(3H,s), 3.15 (3H, s), 3.70 (3H, s), 5.01 (1H, d, J=1.4Hz), 6.67 (1H, d, J=7.8Hz), 6.78 (1H, s), 6.86 (1H, t, J=7.6Hz), 7.13 (1H, d, J=8.0Hz), 7.18-7.20 (2H, m), 7.29 (1H, d, J=4.8Hz), 7.41 (1H, d, J=8.1Hz), 7.51 (2H, t, J=7.6Hz), 7.61 (1H, t, J=7.2Hz), 8.01 (2H, d, J=7.6Hz);13C NMR(100MHz,CDCl3):δ26.1,26.5,52.7,56.1,61.8,66.3,108.3,111.6,122.7,123.2, 124.3,124.5,124.9,125.3,125.5,128.7,129.5,129.8,133.3,137.1,143.0,144.6, 144.7,145.8,169.8,174.8,176.2,191.2.HRMS(ESI-TOF)calcd.for C30H24BrN2O5[M+H]+ 571.0863;found:571.0865.
Embodiment 6:
The 2-&#91 of 0.3mmol (109.6mg) is added in 2mL dichloromethane;1- methyl -3- tertiary butyloxycarbonyl oxygroup -2- (7- fluorine Oxoindole quinoline) -3- Jis ]Methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) Yin of 0.2mmol (52.7mg) Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'(1- benzoyls) cyclopentenyl -7- fluorine adjoins double loop coil Oxoindole (yield 78%, dr values 98:2, ee values 99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -7- fluorine adjoins the characterization of double loop coil Oxoindoles Data:[α]D 25=-95.1 (c 1.00, CHCl3);mp 225.3-227.1℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=8.5min, tminor=20.8min)1H NMR(400MHz,CDCl3):δ3.07(3H,s), 3.21 (3H, d, J=2.2Hz), 3.66 (3H, s), 4.97 (1H, d, J=1.5Hz), 6.60 (1H, d, J=7.8Hz), 6.83 (1H, t, J=7.6Hz), 6.87-6.93 (2H, m), 7.13-7.16 (2H, m), 7.24 (1H, d, J=6.8Hz), 7.30 (1H, D, J=7.8Hz), 7.46 (2H, t, J=7.5Hz), 7.56 (1H, t, J=7.4Hz), 7.97 (2H, d, J=7.6Hz);13C NMR(100MHz,CDCl3):δ 26.4,28.4,52.6,56.3,62.3,66.6,108.2,117.4 (1C, d, J=19.0Hz), 120.1 (1C, d, J=3.2Hz), 122.7,122.9 (1C, d, J=6.4Hz), 124.6,124.9,128.2 (1C, d, J= 3.3Hz), 128.7,129.6,129.8,131.1 (1C, d, J=8.3Hz), 133.3,137.1,142.9,144.5,144.7, 147.3 (1C, d, J=241.7Hz), 169.8,174.8,176.0,191.2.HRMS (ESI-TOF) calcd.for C30H24FN2O5[M+H]+511.1664;found:511.1672.
Embodiment 7:
The 2-&#91 of 0.3mmol (124.6mg) is added in 2mL dichloromethane;1- methyl -3- tertiary butyloxycarbonyl oxygroup -2- (7- tri- Methyl fluoride Oxoindole quinoline) -3- Jis ]Methyl acrylate, (2- oxo -2- phenyl is sub- by the 1- methyl -3- of 0.2mmol (52.7mg) Ethyl) indole-2-ketone and 12.4mg β -6'Hydroxyl cinchonicine, it is small that mixture stirs 5 under 25 DEG C of reaction temperature When, reaction process is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtain through column chromatographic isolation and purification (C1R, C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -7- trifluoromethyls adjoin double loop coil Oxoindole (yield 89%, dr values >99:1, ee value 87%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -7- trifluoromethyls adjoin double loop coil Oxoindoles Characterize data:[α]D 25=-110.0 (c 1.00, CHCl3);mp 125.8.-127.1℃.The ee was Determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ =254nm, major diastereomer:tmajor=6.6min, tminor=13.3min)1H NMR(400MHz,CDCl3):δ 3.06 (3H, s), 3.21 (3H, s), 3.67 (3H, s), 5.00 (1H, s), 6.60 (1H, d, J=7.8Hz), 6.84 (1H, t, J= 7.6Hz), 7.05 (1H, t, J=7.9Hz), 7.13-7.20 (3H, m), 7.49 (3H, t, J=7.4Hz), 7.59 (1H, t, J= 7.4Hz), 7.72 (1H, d, J=7.6Hz), 7.99 (2H, d J=7.8Hz);13C NMR(100MHz,CDCl3):δ26.4, 28.6 (1C, q, J=6.5Hz), 52.7,56.0,60.7,108.3,112.2 (1C, q, J=3.3Hz), 121.6,122.8, 124.3,124.5,124.7,127.3 (1C, q, J=6.0Hz), 127.4,127.8,128.7,129.6,129.8,133.4, 137.0,142.4,142.6,144.4,144.6,169.7,174.6,177.2,191.1.HRMS(ESI-TOF)calcd.for C31H24F3N2O5[M+H]+561.1632;found:561.1639.
Embodiment 8:
2- (1- propyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (112.6mg) are added in 2mL dichloromethane Indoline) -3- Jis ]Methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) indoles of 0.2mmol (52.7mg) Quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, reaction process It is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S) -3 through column chromatographic isolation and purification, 3'(1- benzoyls) cyclopentenyl -1- propyl adjoins double loop coil Oxoindole (yield 53%, dr values 97:3, ee values 89%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -1- propyl adjoins the table of double loop coil Oxoindoles Levy data:[α]D 25=-147.3 (c 1.00, CHCl3);mp 105.5-107.3℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=7.3min, tminor=14.0min)1H NMR(400MHz,CDCl3):δ 0.84 (3H, t, J= 7.3Hz), 1.53 (2H, q, J=7.4Hz), 3.08 (3H, s), 3.46 (2H, t, J=7.5Hz), 3.63 (3H, s), 4.99 (1H, D, J=1.8Hz), 6.59 (2H, t, J=8.9Hz), 6.80 (1H, t, J=7.6Hz), 6.95 (1H, t, J=7.6Hz), 7.11 (1H, t, J=7.8Hz), 7.16-7.19 (2H, m), 7.29 (1H, d, J=7.6Hz), 7.47 (2H, t, J=7.7Hz), 7.52- 7.60 (2H, m), 8.00 (2H, d, J=8.2Hz);13C NMR(100MHz,CDCl3):δ11.6,20.7,26.4,41.8, 52.5,56.2,62.0,66.6,108.0,108.2,122.2,122.6,124.3,124.9,125.2,125.4,128.7, 129.2,129.3,129.9,133.2,137.2,143.0,144.2,144.7,145.0,169.8,175.1,176.1, 191.4.HRMS(ESI-TOF)calcd.for C32H29N2O5[M+H]+521.2071;found:521.2080.
Embodiment 9:
2- (1- phenyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (122.8mg) are added in 2mL dichloromethane Indoline) -3- Jis ]Methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) indoles of 0.2mmol (52.7mg) Quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, reaction process It is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S) -3 through column chromatographic isolation and purification, 3'(1- benzoyls) cyclopentenyl -1- phenyl adjoins double loop coil Oxoindole (yield 85%, dr values >99:1, ee value 98%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -1- phenyl adjoins the table of double loop coil Oxoindoles Levy data:[α]D 25=-153.0 (c 1.00, CHCl3);mp 128.7-129.6℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=6.8min, tminor=11.5min)1H NMR(400MHz,CDCl3):δ3.13(3H,s), 3.72 (3H, s), 5.10 (1H, d, J=2.0Hz), 6.44 (1H, d, J=7.8Hz), 6.65 (1H, d, J=7.8Hz), 6.84 (1H, t, J=7.6Hz), 7.00 (1H, t, J=7.6Hz), 7.09-7.12 (3H, m), 7.17-7.21 (2H, m), 7.30 (1H, D, J=7.5Hz), 7.37-7.49 (5H, m), 7.54-7.60 (2H, m), 7.99 (2H, d, J=8.3Hz);13C NMR (100MHz,CDCl3):δ26.4,52.6,56.5,62.2,66.7,108.1,109.2,122.7,122.8,124.3,124.9, 125.1,125.2,127.1,128.5,128.6,129.2,129.4,129.7,129.9,133.2,134.2,137.2, 142.9,144.7,144.8,169.9,174.9,175.9,191.4.HRMS(ESI-TOF)calcd.for C35H27N2O5[M+ H]+555.1914;found:555.1911.
Embodiment 10:
2- (1- benzyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (127.0mg) are added in 2mL dichloromethane Indoline) -3- Jis ]Methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) indoles of 0.2mmol (52.7mg) Quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, reaction process It is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S) -3 through column chromatographic isolation and purification, 3'(1- benzoyls) cyclopentenyl -1- benzyls adjoin double loop coil Oxoindole (yield 62%, dr values 98:2, ee value > 99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -1- benzyls adjoin the table of double loop coil Oxoindoles Levy data:[α]D 25=-71.2 (c 1.00, CHCl3);mp 193.7-195.6℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=15.7min)1H NMR(400MHz,CDCl3):δ3.11(3H,s),3.62(3H,s),4.70 (1H, d, J=16.0Hz), 4.83 (1H, d, J=16.0Hz), 5.04 (1H, s), 6.42 (1H, d, J=7.7Hz), 6.64 (1H, D, J=7.7Hz), 6.76 (1H, t, J=7.5Hz), 6.94-6.98 (3H, m), 7.08 (1H, t, J=7.6Hz), 7.15-7.20 (5H, m), 7.30 (1H, d, J=7.4Hz), 7.49 (2H, t, J=7.3Hz), 7.56-7.60 (2H, m), 8.01 (2H, d, J= 7.6Hz);13C NMR(100MHz,CDCl3):δ26.5,43.8,52.6,56.6,62.2,66.7,108.2,109.2,110.1, 122.5,123.0,124.4,125.1,125.3,125.4,127.2,127.4,128.7,129.2,129.3,129.9, 133.2,135.3,137.2,143.0,143.9,144.8,144.9,169.8,175.1,176.4,191.3.HRMS(ESI- TOF)calcd.for C36H29N2O5[M+H]+569.2071;found:569.2075.
Embodiment 11:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- ethyls -3- (2- oxo -2- phenyl-ethylenes) indoline-of 0.2mmol (55.5mg) 2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, and reaction process is used Thin-layered chromatography monitors.After reaction carries out completely, mixture obtains (C1R, C4R, C5S) -3,3&apos through column chromatographic isolation and purification;- (1- benzoyls) cyclopentenyl -1'Ethyl adjoins double loop coil Oxoindole (yield 90%, dr values 86:14, ee values 99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -1'Ethyl adjoins the table of double loop coil Oxoindoles Levy data:[α]D 25=-130.7 (c 1.00, CHCl3);mp 79.5-81.3℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=9.8min, tminor=22.9min)1H NMR(400MHz,CDCl3):δ 1.07 (3H, t, J= 7.2Hz),3.02(3H,s),3.49-3.57(1H,m),3.65(3H,s),3.77-3.86(1H,m),5.01(1H,s),6.58- 6.61 (2H, m), 6.80 (1H, t, J=7.6Hz), 6.97 (1H, t, J=7.6Hz), 7.11 (1H, t, J=7.7Hz), 7.16- 7.21 (2H, m), 7.29 (1H, d, J=7.6Hz), 7.47 (2H, t, J=7.5Hz), 7.54-7.59 (2H, m), 8.00 (2H, d, J=8.0Hz);13C NMR(100MHz,CDCl3):δ12.49,25.93,34.94,52.54,56.12,62.21,66.29, 76.84,77.16,77.48,107.97,108.14,122.34,122.50,124.53,124.84,125.25,125.46, 128.65,129.26,129.90,133.19,137.28,143.20,143.93,144.44,144.71,169.96,174.62, 176.39,191.37.HRMS(ESI-TOF)calcd.for C31H27N2O5[M+H]+507.1914;found:507.1919.
Embodiment 12:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- propyl -3- (2- oxo -2- phenyl-ethylenes) indoline-of 0.2mmol (58.3mg) 2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, and reaction process is used Thin-layered chromatography monitors.After reaction carries out completely, mixture obtains (C1R, C4R, C5S) -3,3&apos through column chromatographic isolation and purification;- (1- benzoyls) cyclopentenyl -1'Propyl adjoins double loop coil Oxoindole (yield 76%, dr values 97:3, ee value >99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -1'Propyl adjoins the table of double loop coil Oxoindoles Levy data:[α]D 25=-116.5 (c 1.00, CHCl3);mp 105.9-107.8℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=9.4min)1H NMR(400MHz,CDCl3):δ 0.85 (3H, t, J=7.4Hz), 1.51- 1.59 (2H, m), 3.02 (3H, s), 3.43-3.51 (1H, m), 3.61-3.70 (4H, m), 5.01 (1H, d, J=2.2Hz), 6.60 (2H, dd, J=7.8Hz, 2.7Hz), 6.80 (1H, t, J=7.6Hz), 6.96 (1H, t, J=7.6Hz), 7.10 (1H, t, ), J=7.7Hz 7.15 (1H, d, J=2.2Hz), 7.19 (1H, t, J=7.8Hz), 7.29 (1H, d, J=7.6Hz), 7.48 (2H, t, J=7.7Hz), 7.53-7.58 (2H, m), 8.00 (2H, d, J=7.2Hz);13C NMR(100MHz,CDCl3):δ 11.5,20.9,25.9,42.0,52.5,56.1,62.1,66.2,107.9,108.3,122.2,122.5,124.5,124.7, 125.2,125.3,128.6,129.2,129.3,129.9,133.1,137.2,143.2,144.4,144.5,144.6, 169.9,174.9,176.4,191.3.HRMS(ESI-TOF)calcd.for C32H29N2O5[M+H]+521.2071;found: 521.2076。
Embodiment 13:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- phenyl -3- (2- oxo -2- phenyl-ethylenes) indoline-of 0.2mmol (65.1mg) 2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, and reaction process is used Thin-layered chromatography monitors.After reaction carries out completely, mixture obtains (C1R, C4R, C5S) -3,3&apos through column chromatographic isolation and purification;- (1- benzoyls) cyclopentenyl -1'Phenyl adjoins double loop coil Oxoindole (yield 72%, dr values >99:1, ee value >99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -1'Phenyl adjoins the table of double loop coil Oxoindoles Levy data:[α]D 25=-24.1 (c 1.00, CHCl3);mp 140.3-142.1℃.The ee was determined by HPLC (Chiralpak OD-H, i-PrOH/hexane=10/90, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=23.3min)1H NMR(400MHz,CDCl3):δ3.12(3H,s),3.73(3H,s),5.07 (1H, s), 5.36 (1H, s), 6.48 (1H, d, J=7.9Hz), 6.72 (1H, d, J=7.8Hz), 6.91 (1H, t, J= 7.6Hz), 7.04-7.11 (2H, m), 7.24 (1H, s), 7.31-7.35 (2H, m), 7.41 (1H, d, J=7.6Hz), 7.45- 7.48 (1H, m), 7.53-7.61 (5H, m), 7.65-7.68 (1H, m), 8.12 (2H, d, J=7.8Hz);13C NMR(100MHz, CDCl3):δ26.0,52.6,56.0,62.4,66.9,108.1,109.3,122.6,122.9,124.7,124.8,124.9, 125.3,127.4,128.5,128.7,129.2,129.5,129.7,129.9,133.3,134.4,137.2,143.2, 144.5,144.8,145.2,170.0,174.6,176.3,191.3.HRMS(ESI-TOF)calcd.for C35H27N2O5[M+ H]+555.1914;found:555.1915.
Embodiment 14:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- benzyls -3- (2- oxo -2- phenyl-ethylenes) indoline-of 0.2mmol (67.8mg) 2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, and reaction process is used Thin-layered chromatography monitors.After reaction carries out completely, mixture obtains (C1R, C4R, C5S) -3,3&apos through column chromatographic isolation and purification;- (1- benzoyls) cyclopentenyl -1'Benzyl adjoins double loop coil Oxoindole (yield 72%, dr values >99:1, ee value >99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -1'Benzyl adjoins the table of double loop coil Oxoindoles Levy data:[α]D 25=-117.1 (c 1.00, CHCl3);mp 101.7-103.0℃.The ee was determined by HPLC (Chiralpak OD-H, i-PrOH/hexane=10/90, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=30.7min)1H NMR(400MHz,CDCl3):δ3.04(3H,s),3.66(3H,s),4.74 (1H, d, J=16.2Hz), 5.02 (1H, d, J=16.9Hz), 5.04 (1H, s), 6.36 (1H, d, J=7.8Hz), 6.66 (1H, D, J=7.8Hz), 6.79 (1H, t, J=7.6Hz), 6.91-7.00 (4H, m), 7.18-7.26 (5H, m), 7.33 (1H, d, J= 7.5Hz), 7.48-7.54 (3H, m), 7.59 (1H, t, J=7.3Hz), 8.02 (2H, d, J=7.6Hz);13C NMR(100MHz, CDCl3):δ26.0,44.1,52.6,56.3,62.2,66.6,108.2,109.4,122.7,122.9,124.3,125.5, 126.9,127.3,128.6,128.7,129.3,129.3,129.9,133.3,139.3,137.3,143.4,144.2, 144.6,144.8,169.9,175.3,176.5,191.4,HRMS(ESI-TOF)calcd.for C36H29N2O5[M+H]+ 569.2071;found:569.2077.
Embodiment 15:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, the 1- tertbutyloxycarbonyls -3- (2- oxo -2- phenyl-ethylenes) of 0.2mmol (69.9mg) Indole-2-ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, reaction Process is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtain through column chromatographic isolation and purification (C1R, C4R, C5S)-3,3'(1- benzoyls) cyclopentenyl -1'Tertbutyloxycarbonyl adjoins double loop coil Oxoindole (yield 26%, dr values > 99:1, ee value 83%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -1'Tertbutyloxycarbonyl adjoins double loop coil oxidation Yin The characterize data of diindyl:[α]D 25=-100.3 (c 1.00, CHCl3);mp 163.1-165.0℃.The ee was Determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=10/90, flow rate 1.0mL/min, λ =254nm, major diastereomer:tmajor=22.0min, tminor=44.8min)1H NMR(400MHz,CDCl3): δ 1.61 (9H, s), 2.97 (3H, s), 3.66 (3H, s), 4.89 (1H, s), 6.60 (1H, d, J=7.8Hz), 6.90-6.99 (2H, m), 7.15 (1H, t, J=7.9Hz), 7.20-7.24 (2H, m), 7.29 (1H, d, J=7.6Hz), 7.45-7.51 (3H, M), 7.58-7.62 (2H, m), 7.99 (2H, d, J=8.2Hz);13C NMR(100MHz,CDCl3):δ26.0,28.2,52.7, 55.9,63.1,67.0,84.2,108.2,114.9,122.6,124.0,124.1,124.3,124.4,124.5,128.8, 129.5,129.7,129.9,133.4,136.9,140.6,142.5,144.4,145.5,148.7,169.7,173.5, 175.6,190.9.HRMS(ESI-TOF)calcd.for C34H31N2O7[M+H]+579.2126;found:579.2131.
Embodiment 16:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1,5- dimethyl -3- (2- oxo -2- phenyl-ethylenes) Yin of 0.2mmol (55.4mg) Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'(1- benzoyls) cyclopentenyl -5'Methyl adjoins double loop coil Oxoindole (yield 62%, dr values 96:4, ee values 95%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -5'Methyl adjoins the table of double loop coil Oxoindoles Levy data:[α]D 25=-98.8 (c 1.00, CHCl3);mp 167.1-168.3℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=8.6min, tminOr=18.0min)1H NMR(400MHz,CDCl3):δ2.15(3H,s), 3.01 (3H, s), 3.06 (3H, s), 3.66 (3H, s), 5.00 (1H, d, J=1.9Hz), 6.46 (1H, d, J=7.9Hz), 6.58 (1H, d, J=7.8Hz), 6.91 (1H, d, J=7.8Hz), 6.96 (1H, t, J=7.6Hz), 7.09 (1H, s), 7.17-7.20 (2H, m), 7.49 (3H, t, J=7.2Hz), 7.59 (1H, t, J=7.3Hz), 8.00 (2H, d, J=7.4Hz);13C NMR (100MHz,CDCl3):δ21.2,25.9,26.5,52.6,55.9,62.4,66.7,107.7,107.9,122.4,124.1, 125.1,125.3,128.7,129.3,129.6,129.9,132.0,133.2,137.3,142.3,143.0,144.4, 145.2,170.0,174.9,176.3,191.4.HRMS(ESI-TOF)calcd.for C31H26N2O5[M+H]+507.1914; found:507.1917。
Embodiment 17:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) -5- methoxies of 0.2mmol (58.7mg) Base indole-2-ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, instead Process is answered to be monitored with thin-layered chromatography.After reaction carries out completely, mixture obtain through column chromatographic isolation and purification (C1R, C4R, C5S)-3,3'(1- benzoyls) cyclopentenyl -5'Methoxyl group adjoins double loop coil Oxoindole (yield 55%, dr values 96:4, Ee values >99%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -5'Methoxyl group adjoins double loop coil Oxoindoles Characterize data:[α]D 25=-58.6 (c 1.00, CHCl3);mp 113.7-114.9℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=12.7min)1H NMR(400MHz,CDCl3):δ3.05(3H,s),3.06(3H,s),3.62 (3H, s), 3.65 (3H, s), 5.01 (1H, s), 6.48 (1H, d, J=8.4Hz), 6.61 (1H, d, J=7.7Hz), 6.65 (1H, Dd, J=8.4Hz, 1.9Hz), 6.95-6.99 (2H, m), 7.17-7.21 (2H, m), 7.46-7.53 (3H, m), 7.58 (1H, t, ), J=7.2Hz 8.00 (2H, d, J=7.7Hz);13C NMR(100MHz,CDCl3):δ26.0,26.5,52.5,55.8,56.2, 62.3,66.8,108.0,108.3,111.7,114.0,122.5,124.3,125.2,126.4,128.7,129.3,129.9, 133.2,137.3,138.3,143.0,144.4,145.1,155.8,169.9,174.7,176.3,191.3.HRMS(ESI- TOF)calcd.for C31H26N2O6[M+H]+523.1864;found:523.1866.
Embodiment 18:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) -5- fluorine Yin of 0.2mmol (56.2mg) Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'(1- benzoyls) cyclopentenyl -5'Fluorine adjoins double loop coil Oxoindole (yield 91%, dr values 98:2, ee values 98%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -5'Fluorine adjoins the characterization of double loop coil Oxoindoles Data:[α]D 25=-112.3 (c 1.00, CHCl3);mp 209.8-210.3℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=12.4min, tminor=20.8min)1H NMR(400MHz,CDCl3):δ3.06(3H,s), 3.08 (3H, s), 3.65 (3H, s), 5.01 (1H, d, J=1.5Hz), 6.51 (1H, dd, J=8.5Hz, 4.1Hz), 6.63 (1H, D, J=7.8Hz), 6.83 (1H, td, J=8.8Hz, J=2.3Hz), 6.98 (1H, t, J=7.6Hz), 7.08 (1H, dd, J= 8.5Hz, J=2.2Hz), 7.19-7.23 (2H, m), 7.47-7.51 (3H, m), 7.59 (1H, t, J=7.4Hz), 7.99 (2H, D, J=7.5Hz);13C NMR(100MHz,CDCl3):δ26.0,26.6,52.6,56.2,62.1,66.5,108.1,108.4 (1C, d, J=8.2Hz), 112.8 (1C, d, J=25.9Hz), 115.5 (1C, d, J=23.4Hz), 122.6,124.2, 124.9,126.9 (1C, d, J=8.4Hz), 128.7,129.5,129.8,133.4,137.0,140.7,142.7,144.3, 145.4,159.1 (1C, d, J=238.8Hz), 169.7,174.8,176.0,191.2.HRMS (ESI-TOF) calcd.for C30H24FN2O5[M+H]+511.1664;found:511.1669.
Embodiment 19:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) -5- chlorine Yin of 0.2mmol (59.5mg) Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'(1- benzoyls) cyclopentenyl -5'Chlorine adjoins double loop coil Oxoindole (yield 73%, dr values 97:3, ee values 97%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -5'Chlorine adjoins the characterization of double loop coil Oxoindoles Data:[α]D 25=-35.8 (c 1.00, CHCl3);mp 119.7-121.9℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=10/90, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=41.4min, tminor=60.0min)1H NMR(400MHz,CDCl3):δ3.06(3H,s), 3.07 (3H, s), 3.66 (3H, s), 4.99 (1H, s), 6.51 (1H, d, J=8.3Hz), 6.62 (1H, d, J=7.8Hz), 6.97 (1H, t, J=7.6Hz), 7.10 (1H, d, J=8.2Hz), 7.20-7.23 (2H, m), 7.28 (1H, s), 7.46-7.52 (3H, M), 7.60 (1H, t, J=7.2Hz), 7.98 (2H, d, J=7.7Hz);13C NMR(100MHz,CDCl3):δ26.0,26.6, 52.7,56.0,62.2,66.5,108.2,108.9,122.6,124.1,124.9,125.0,126.9,128.0,128.8, 129.3,129.5,129.9,133.4,137.1,142.6,143.4,144.4,145.7,169.7,174.6,176.0, 191.2.HRMS(ESI-TOF)calcd.for C30H24ClN2O5[M+H]+527.1368;found:527.1375.
Embodiment 20:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) -5- bromines Yin of 0.2mmol (68.4mg) Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'(1- benzoyls) cyclopentenyl -5'Bromine adjoins double loop coil Oxoindole (yield 87%, dr values >99:1, ee value 98%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -5'Bromine adjoins the characterization of double loop coil Oxoindoles Data:[α]D 25=4.5 (c 1.00, CHCl3);mp 134.6-136.5℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=12.9min, tminor=18.7min)1H NMR(400MHz,CDCl3):δ2.92(6H,s), 3.51 (3H, s), 4.83 (1H, s), 6.31 (1H, d, J=8.3Hz), 6.47 (1H, d, J=7.8Hz), 6.82 (1H, t, J= 7.6Hz), 7.04-7.11 (4H, m), 7.30-7.37 (3H, m), 7.44-7.48 (1H, m), 7.84 (2H, d, J=7.8Hz);13C NMR(100MHz,CDCl3):δ25.9,26.5,52.6,55.8,62.1,66.4,108.1,109.4,115.2,122.5, 124.0,124.8,127.2,127.6,128.7,129.5,129.8,132.2,133.4,137.0,142.5,143.8, 144.3,145.7,169.7,174.4,176.0,191.1.HRMS(ESI-TOF)calcd.for C30H24BrN2O5[M+H]+ 571.0863;found:571.0875.
Embodiment 21:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) -7- fluorine Yin of 0.2mmol (56.2mg) Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'(1- benzoyls) cyclopentenyl -7'Fluorine adjoins double loop coil Oxoindole (yield 45%, dr values 96:4, ee values 95%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) cyclopentenyl -7'Fluorine adjoins the characterization of double loop coil Oxoindoles Data:[α]D 25=-64.8 (c 1.00, CHCl3);mp 192.4-193.3℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=10.0min, tminor=15.1min)1H NMR(400MHz,CDCl3):δ3.01(3H,s), 3.30 (3H, s), 3.65 (3H, s), 4.99 (1H, s), 6.63 (1H, d, J=7.8Hz), 6.72-6.77 (1H, m), 6.82- 6.87 (1H, m), 7.00 (1H, t, J=7.6Hz), 7.08 (1H, d, J=7.5Hz), 7.18 (1H, s), 7.23 (1H, d, J= 7.8Hz), 7.48-7.51 (3H, m), 7.59 (1H, t, J=7.3Hz), 7.99 (2H, d, J=7.9Hz);13C NMR(100MHz, CDCl3):δ 26.0,29.0,52.6,56.0,62.3,66.6,108.1,117.4 (1C, d, J=19.1Hz), 120.5, 122.7,123.3 (1C, d, J=6.5Hz), 124.1,124.9,128.1 (1C, d, J=3.6Hz), 128.7,129.6, 129.9,133.4,137.1,142.8,144.4,145.3,147.3 (1C, d, J=241.7Hz), 169.8,174.7,176.1, 191.3.HRMS(ESI-TOF)calcd.for C30H24FN2O5[M+H]+511.1664;found:511.1673.
Embodiment 22:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 1- methyl -3- (2- oxo -2- phenyl-ethylenes) -7- bromines Yin of 0.2mmol (68.4mg) Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 5 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'(1- benzoyls) cyclopentenyl -7'Bromine adjoins double loop coil Oxoindole (yield 43%, dr values 98:2, ee values 95%).
(C1R,C4R,C5S)-3,3'(1- benzoyls) Huan Wuxiji ]-7'Bromine adjoins the table of double loop coil Oxoindoles Levy data:[α]D 25=-108.1 (c 1.00, CHCl3);mp 248.3-250.1℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=10.2min, tminor=18.6min)1H NMR(400MHz,CDCl3):δ2.99(3H,s), 3.45 (3H, s), 3.63 (3H, s), 4.96 (1H, d, J=2.0Hz), 6.61-6.66 (2H, m), 6.99 (1H, t, J= 7.6Hz),7.16-7.17(1H,m),7.19-7.24(3H,m),7.43-7.49(3H,m),7.56-7.60(1H,m),7.96- 7.98(2H,m);13C NMR(100MHz,CDCl3):δ26.0,30.2,52.6,56.1,62.6,66.1,102.2,108.3, 122.7,123.6,123.7,124.1,124.8,128.4,128.8,129.7,129.8,133.4,135.1,137.1, 142.0,142.7,144.3,145.4,169.8,175.6,176.0,191.2.HRMS(ESI-TOF)calcd.for C30H24BrN2O5[M+H]+571.0863;found:571.0867.
Embodiment 23:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, the 1- methyl -3-&#91 of 0.2mmol (55.5mg);The Asias 2- oxos -2- (4- aminomethyl phenyls) second Ji ]Indole-2-ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 7 hours under 25 DEG C of reaction temperature, Reaction process is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtain through column chromatographic isolation and purification (C1R, C4R, C5S)-3,3'-[1- (4- methyl benzoyls) Huan Wuxiji ]Adjoin double loop coil Oxoindole (yield 36%, dr values >99:1, Ee values 95%).
(C1R,C4R,C5S)-3,3'-[1- (4- methyl benzoyls) Huan Wuxiji ]Adjoin the table of double loop coil Oxoindoles Levy data:[α]D 25=-31.2 (c 0.50, CHCl3);mp 247.1-249.0℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=18.3min, tminor=26.0min)1H NMR(400MHz,CDCl3):δ2.40(3H,s), 2.99 (3H, s), 3.07 (3H, s), 3.63 (3H, s), 4.98 (1H, d, J=2.1Hz), 6.56 (2H, dd, J=7.7Hz, 4.2Hz), 6.79 (1H, t, J=7.6Hz), 6.95 (1H, t, J=7.6Hz), 7.10 (1H, t, J=7.8Hz), 7.12-7.13 (1H, m), 7.17 (1H, t, J=7.7Hz), 7.24-7.27 (3H, m), 7.50 (1H, d, J=7.5Hz), 7.89 (2H, d, J= 8.1Hz);13C NMR(100MHz,CDCl3):δ21.9,25.9,26.4,52.5,56.0,62.2,66.6,107.9,108.0, 122.4,122.5,124.1,124.6,125.2,125.3,129.2,129.3,129.4,130.0,134.7,143.1, 144.1,144.3,144.4,144.7,170.0,175.1,176.3,191.0.HRMS(ESI-TOF)calcd.for C31H27N2O5[M+H]+507.1914;found:507.1921.
Embodiment 24:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, the 1- methyl -3-&#91 of 0.2mmol (58.3mg);2- oxos -2- (2,4- 3,5-dimethylphenyls) is sub- Yi Ji ]Indole-2-ketone and 12.4mg β -6'Hydroxyl cinchonicine, it is small that mixture stirs 7 under 25 DEG C of reaction temperature When, reaction process is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtain through column chromatographic isolation and purification (C1R, C4R,C5S)-3,3'-[1- (2,4- dimethylbenzoyls) Huan Wuxiji ]Adjoin double loop coil Oxoindole (yield 49%, dr Value 97:3, ee value >99%).
(C1R,C4R,C5S)-3,3'-[1- (2,4- dimethylbenzoyls) Huan Wuxiji ]Adjoin double loop coil Oxoindoles Characterize data:[α]D 25=-106.8 (c 1.00, CHCl3);mp 219.1-220.5℃.The ee was determined By HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=12.6min)1H NMR(400MHz,CDCl3):δ2.36(3H,s),2.38(3H, S), 3.00 (3H, d, J=1.0Hz), 3.06 (3H, d, J=1.0Hz), 3.61 (3H, d, J=0.9Hz), 4.95 (1H, s), 6.57 (2H, d, J=7.8Hz), 6.85 (1H, t, J=7.6Hz), 6.96 (1H, t, J=7.6Hz), 7.01-7.03 (2H, m), 7.12 (2H, t, J=7.6Hz), 7.18 (1H, t, J=7.7Hz), 7.32 (1H, d, J=7.6Hz), 7.49 (1H, d, J= 7.6Hz), 7.87 (1H, d, J=7.7Hz);13C NMR(100MHz,CDCl3):δ20.6,21.6,25.9,26.4,52.5, 55.8,62.5,66.2,107.9,108.0,122.4,122.5,124.1,124.6,125.3,125.5,126.3,129.2, 129.3,131.7,132.3,134.5,138.7,142.0,144.4,144.6,144.9,145.5,169.9,175.0, 176.3,193.0.HRMS(ESI-TOF)calcd.for C32H29N2O5[M+H]+521.2071;found:521.2076.
Embodiment 25:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, the 1- methyl -3-&#91 of 0.2mmol (56.3mg);2- oxos -2- (4- fluorophenyls) Ya Yiji ]- Indole-2-ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 7 hours under 25 DEG C of reaction temperature, reaction Process is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtain through column chromatographic isolation and purification (C1R, C4R, C5S)-3,3'-[1- (4- fluoro benzoyls) Huan Wuxiji ]Adjoin double loop coil Oxoindole (yield 69%, dr values >99:1, ee Value >99%).
(C1R,C4R,C5S)-3,3'-[1- (4- fluoro benzoyls) Huan Wuxiji ]Adjoin the characterization of double loop coil Oxoindoles Data:[α]D 25=-90.5 (c 1.00, CHCl3);mp 232.3-233.9℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=11.5min)1H NMR(400MHz,CDCl3):δ 3.03 (3H, s), 3.10 (3H, d, J= 0.7Hz), 3.67 (3H, s), 5.03 (1H, d, J=1.7Hz), 6.60 (2H, dd, J=7.7Hz, J=2.6Hz), 6.84 (1H, T, J=7.6Hz), 6.99 (1H, t, J=7.6Hz), 7.12-7.23 (5H, m), 7.28 (1H, s), 7.52 (1H, d, J= 7.6Hz), 8.05 (2H, dd, J=8.1Hz, 5.7Hz);13C NMR(100MHz,CDCl3):δ25.9,26.4,52.6,56.0, 62.2,66.5,108.1 (1C, d, J=4.4Hz), 115.9 (1C, d, J=21.8Hz), 122.5,122.6,124.1,124.5, 125.0,125.1,129.3,129.4,132.4,132.5,133.6,142.8,144.4,144.7,144.8,166.0(1C,d, ), J=253.5Hz 169.9,174.9,176.3,189.9.HRMS (ESI-TOF) calcd.for C30H24FN2O5[M+H]+ 511.1664;found:511.1672.
Embodiment 26:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, the 1- methyl -3-&#91 of 0.2mmol (59.5mg);2- oxos -2- (4- chlorphenyls) Ya Yiji ]- Indole-2-ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 7 hours under 25 DEG C of reaction temperature, reaction Process is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtain through column chromatographic isolation and purification (C1R, C4R, C5S)-3,3'-[1- (4- chlorobenzene formacyls) Huan Wuxiji ]Adjoin double loop coil Oxoindole (yield 70%, dr values 97:3, ee values >99%).
(C1R,C4R,C5S)-3,3'-[1- (4- chlorobenzene formacyls) Huan Wuxiji ]Adjoin the characterization of double loop coil Oxoindoles Data:[α]D 25=-99.1 (c 1.00, CHCl3);mp 231.4-233.1℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=15.6min)1H NMR(400MHz,CDCl3):δ3.00(3H,s),3.07(3H,s),3.64 (3H, s), 4.99 (1H, d, J=2.0Hz), 6.56-6.58 (2H, m), 6.81 (1H, t, J=7.6Hz), 6.95 (1H, t, J= 7.6Hz), 7.09-7.14 (2H, m), 7.18 (1H, t, J=7.7Hz), 7.23 (1H, d, J=7.9Hz), 7.44 (2H, d, J= 8.4Hz), 7.48 (1H, d, J=7.6Hz), 7.93 (2H, d, J=8.3Hz);13C NMR(100MHz,CDCl3):δ26.0, 26.4,52.6,56.0,62.3,66.5,108.0,108.1,122.5,122.6,124.1,124.5,125.0,125.1, 129.1,129.4,131.3,135.6,139.8,142.8,144.4,144.7,145.2,169.8,174.9,176.3, 190.2.HRMS(ESI-TOF)calcd.for C30H24ClN2O5[M+H]+527.1368;found:527.1375.
Embodiment 27:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, the 1- methyl -3-&#91 of 0.2mmol (68.4mg);2- oxos -2- (4- bromophenyls) Ya Yiji ]- Indole-2-ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 7 hours under 25 DEG C of reaction temperature, reaction Process is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtain through column chromatographic isolation and purification (C1R, C4R, C5S)-3,3'-[1- (4- benzoyl bromides) Huan Wuxiji ]Adjoin double loop coil Oxoindole (yield 50%, dr values 97:3, ee values >99%).
(C1R,C4R,C5S)-3,3'-[1- (4- benzoyl bromides) Huan Wuxiji ]Adjoin the characterization of double loop coil Oxoindoles Data:[α]D 25=-31.2 (c 1.00, CHCl3);mp 233.2-234.5℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=18.0min)1H NMR(400MHz,CDCl3):δ2.99(3H,s),3.05(3H,s),3.63 (3H, s), 4.99 (1H, s), 6.56 (2H, dd, J=7.6Hz, J=2.7Hz), 6.80 (1H, t, J=7.6Hz), 6.95 (1H, T, J=7.6Hz), 7.08-7.19 (3H, m), 7.23 (1H, d, J=7.9Hz), 7.48 (1H, d, J=7.5Hz), 7.60 (2H, D, J=8.3Hz), 7.84 (2H, d, J=8.2Hz);13C NMR(100MHz,CDCl3):δ25.9,26.4,52.6,56.0, 62.2,66.5,108.0,108.1,122.4,122.5,124.0,124.5,124.9,125.0,128.4,129.4,131.3, 132.0,135.9,142.7,144.3,144.7,145.2,169.7,174.8,176.2,190.3.HRMS(ESI-TOF) calcd.for C30H24BrN2O5[M+H]+571.0870;found:571.0863.
Embodiment 28:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, the 1- methyl -3-&#91 of 0.2mmol (68.4mg);2- oxos -2- (1- naphthalenes) Ya Yiji ]- Yin Diindyl quinoline -2- ketone and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 7 hours under 25 DEG C of reaction temperature, react into Journey is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtains (C1R, C4R, C5S)-through column chromatographic isolation and purification 3,3'-[1- (1- naphthoyls) Huan Wuxiji ]Adjoin double loop coil Oxoindole (yield 47%, dr values 96:4, ee values 85%).
(C1R,C4R,C5S)-3,3'-[1- (1- naphthoyls) Huan Wuxiji ]Adjoin the characterization number of double loop coil Oxoindoles According to:[α]D 25=-4.8 (c 0.50, CHCl3);mp 232.8-234.1℃.The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane=30/70, flow rate 1.0mL/min, λ=254nm, major diastereomer:tmajor=20.3min, tminor=40.3min)1H NMR(400MHz,CDCl3):δ3.04(3H,s), 3.11 (3H, s), 3.67 (3H, s), 5.04 (1H, d, J=2.0Hz), 6.60 (2H, dd, J=7.7Hz, J=2.7Hz), 6.82 (1H, t, J=7.6Hz), 6.98 (1H, t, J=7.6Hz), 7.12 (1H, t, J=7.7Hz), 7.20 (1H, t, J=7.7Hz), 7.24-7.25 (1H, m), 7.33 (1H, d, J=7.5Hz), 7.53-7.56 (1H, m), 7.57-7.63 (2H, m), 7.85-7.90 (2H, m), 7.92-7.95 (1H, m), 8.10 (1H, d, J=7.5Hz), 8.65 (1H, s);13C NMR(100MHz,CDCl3):δ 25.8,25.9,26.3,26.4,51.9,52.6,55.4,55.6,62.9,63.0,65.9,66.1,107.8,107.9, 108.0,108.1,121.4,121.5,122.3,122.4,122.6,122.7,124.1,124.2,125.1,125.2, 125.3,125.6,125.8,126.2,129.3,129.4,129.5,134.7,135.4,144.1,144.2,144.3, 144.4,145.4,147.7,150.3,150.4,160.8,163.0,168.1,169.7,174.6,174.7,175.7, 175.8.HRMS(ESI-TOF)calcd.for C34H27N2O5[M+H]+543.1914;found:543.1923.
Embodiment 29:
2- (1- methyl -3- tertiary butyloxycarbonyl oxygroups -2- the oxidations of 0.3mmol (104.1mg) are added in 2mL dichloromethane Indoline -3- bases) methyl acrylate, 4,7- dimethyl -3- (2- oxo -2- phenyl-ethylenes) benzene of 0.2mmol (55.7mg) And (3H) -one of furans -2 and 12.4mg β -6'Hydroxyl cinchonicine, mixture stir 7 hours under 25 DEG C of reaction temperature, Reaction process is monitored with thin-layered chromatography.After reaction carries out completely, mixture obtain through column chromatographic isolation and purification (C1R, C4R, C5S)-3,3'-[1- (1- benzoyls) Huan Wuxiji ]Adjoin double loop coil Oxoindole (yield 47%, dr values >99:1, ee value > 99%).
(C1R,C4R,C5S)-3,3'-[1- (1- benzoyls) Huan Wuxiji ]Adjoin the characterization number of double loop coil Oxoindoles According to:[α]D 25=130.5 (c 1.00, CHCl3);mp 175.8-176.7℃.The ee was determined by HPLC (Chiralpak OD-H, i-PrOH/hexane=8/92, flow rate 0.8mL/min, λ=254nm, major diastereomer:tmajor=25.8min)1H NMR(400MHz,CDCl3):δ1.95(3H,s),2.08(3H,s),2.93 (3H, s), 3.62 (3H, s), 4.77 (1H, d, J=2.0Hz), 6.56 (1H, d, J=7.8Hz), 6.61 (1H, d, J= 7.9Hz), 6.79 (1H, d, J=7.9Hz), 7.04 (1H, t, J=7.6Hz), 7.21-7.25 (1H, m), 7.29-7.30 (1H, M), 7.44 (1H, d, J=7.6Hz), 7.51 (3H, t, J=7.7Hz), 7.59-7.63 (1H, m), 8.01 (1H, d, J= 8.2Hz);13C NMR(100MHz,CDCl3):δ14.5,19.3,26.1,52.6,54.7,62.2,68.9,108.0,117.6, 120.9,122.9,124.1,124.3,126.3,129.0,129.7,129.8,130.9,133.5,133.9,135.7, 140.0,144.4,145.9,152.4,169.6,174.3,176.2,190.0.HRMS(ESI-TOF)calcd.for C31H26NO6[M+H]+508.1757;found:508.1759.

Claims (7)

1. one kind is with optical activation to adjoin double loop coil oxidized indole compounds, which is characterized in that have the following structure:
In formula:X is NR5, O or S substituent groups.
With optical activation adjoin double loop coil oxidized indole compounds 2. according to claim 1, which is characterized in that
Work as X=NR5When, R5Be each independently selected from H, Me, Et,nPr,nBu,iPr, allyl, Ph or Bn;
Correspondingly, R1It is each independently selected from H, 4-F, 4-Cl, 5-Me, 5-OMe, 5-F, 5-OCF3,5-Cl,5-Br,6-Cl,6- Br,7-F,7-Cl,7-CF3Or 7-OCF3;
Correspondingly, R2Be each independently selected from H, Me, Et,nPr,nBu,iPr, allyl, Ph or Bn;
Correspondingly, R3Be each independently selected from Me, Et,nPr,iPr,nBu,iBu,tBu or Ph;
Correspondingly, R4It is each independently selected from H, 4-F, 4-Cl, 5-Me, 5-OMe, 5-F, 5-OCF3,5-Cl,5-Br,6-Cl,6- Br,7-F,7-Cl,7-CF3Or 7-OCF3;
Correspondingly, R is each independently selected from Me, OMe, OEt, OiPr,OtBu, OPh, OBn, phenyl, methyl substituted-phenyl, methoxy Base substituted-phenyl, fluorine substituted-phenyl, chlorine substituted-phenyl, bromine substituted-phenyl, 1- naphthalenes, 2- naphthalenes, 2- furyls or 2- thienyls.
With optical activation adjoin double loop coil oxidized indole compounds 3. according to claim 1, which is characterized in that
As X=O or S,
Correspondingly, R1It is each independently selected from H, 4-F, 4-Cl, 5-Me, 5-OMe, 5-F, 5-OCF3,5-Cl,5-Br,6-Cl,6- Br,7-F,7-Cl,7-CF3Or 7-OCF3;
Correspondingly, R2Be each independently selected from H, Me, Et,nPr,nBu,iPr, allyl, Ph or Bn;
Correspondingly, R3Be each independently selected from Me, Et,nPr,iPr,nBu,iBu,tBu or Ph;
Correspondingly, R4It is each independently selected from H, 5-Me, 4,6-Me2,4,7-Me2,5-OMe,4,6-(OMe)2Or 4,7- (OMe)2;
Correspondingly, R is each independently selected from Me, OMe, OEt, OiPr,OtBu, OPh, OBn, phenyl, methyl substituted-phenyl, methoxy Base substituted-phenyl, fluorine substituted-phenyl, chlorine substituted-phenyl, bromine substituted-phenyl, 1- naphthalenes, 2- naphthalenes, 2- furyls or 2- thienyls.
4. according to claims 1 to 3 it is any it is described it is with optical activation adjoin double loop coil oxidized indole compounds, it is special Sign is, optics Chun Du≤85% with optical activation for adjoining double loop coil oxidized indole compounds.
With optical activation adjoin double loop coil oxidized indole compounds 5. according to claim 4, which is characterized in that Optics Chun Du≤95% with optical activation for adjoining double loop coil oxidized indole compounds.
With optical activation adjoin double loop coil oxidized indole compounds 6. according to claim 4, which is characterized in that Optics Chun Du≤98% with optical activation for adjoining double loop coil oxidized indole compounds.
7. pair loop coil oxidized indole compounds with optical activation that adjoin according to claim 4 are in antitumor activity In application.
CN201810391499.1A 2018-04-27 2018-04-27 One kind is with optical activation to adjoin double loop coil oxidized indole compounds and its application Expired - Fee Related CN108690029B (en)

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CN111961060A (en) * 2020-08-27 2020-11-20 遵义医科大学 Preparation method of spiroheterocyclic 2, 3-dihydrobenzofuran compound with optical activity
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Publication number Priority date Publication date Assignee Title
CN111892608A (en) * 2020-08-27 2020-11-06 遵义医科大学 Spiroheterocyclic 2, 3-dihydrobenzofuran compound with optical activity and application thereof
CN111961060A (en) * 2020-08-27 2020-11-20 遵义医科大学 Preparation method of spiroheterocyclic 2, 3-dihydrobenzofuran compound with optical activity
CN111892608B (en) * 2020-08-27 2021-07-06 遵义医科大学 Spiroheterocyclic 2, 3-dihydrobenzofuran compound with optical activity and application thereof
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