CN108440542A - A kind of preparation method with optical activation for adjoining double loop coil oxidized indole compounds - Google Patents
A kind of preparation method with optical activation for adjoining double loop coil oxidized indole compounds Download PDFInfo
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- CN108440542A CN108440542A CN201810392874.4A CN201810392874A CN108440542A CN 108440542 A CN108440542 A CN 108440542A CN 201810392874 A CN201810392874 A CN 201810392874A CN 108440542 A CN108440542 A CN 108440542A
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- loop coil
- double loop
- phenyl
- indole compounds
- optical activation
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- 230000003287 optical effect Effects 0.000 title claims abstract description 32
- 150000002475 indoles Chemical class 0.000 title claims abstract description 30
- 230000004913 activation Effects 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 86
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 35
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 150000002148 esters Chemical class 0.000 claims abstract description 13
- 239000002879 Lewis base Substances 0.000 claims abstract description 10
- 150000007527 lewis bases Chemical class 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 238000000926 separation method Methods 0.000 claims abstract description 7
- PIIQLZXRLGJEKE-UHFFFAOYSA-N Cinchonicine Natural products C=CC1CNCCC1CCC(=O)C1=CC=NC2=CC=CC=C12 PIIQLZXRLGJEKE-UHFFFAOYSA-N 0.000 claims description 41
- 239000002585 base Substances 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 32
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 239000011737 fluorine Chemical group 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- -1 OBn Chemical group 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- PIIQLZXRLGJEKE-LSDHHAIUSA-N 3-[(3r,4r)-3-ethenylpiperidin-4-yl]-1-quinolin-4-ylpropan-1-one Chemical compound C=C[C@H]1CNCC[C@H]1CCC(=O)C1=CC=NC2=CC=CC=C12 PIIQLZXRLGJEKE-LSDHHAIUSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 116
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 58
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 58
- 239000000203 mixture Substances 0.000 description 58
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 56
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 36
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 30
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 238000007445 Chromatographic isolation Methods 0.000 description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 29
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 29
- 238000011097 chromatography purification Methods 0.000 description 29
- 238000004128 high performance liquid chromatography Methods 0.000 description 29
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 29
- 230000003647 oxidation Effects 0.000 description 24
- 238000007254 oxidation reaction Methods 0.000 description 24
- ZHQFLHOFPHEPSX-UHFFFAOYSA-N N1CCC2=CC=CC=C12.ClCCl Chemical compound N1CCC2=CC=CC=C12.ClCCl ZHQFLHOFPHEPSX-UHFFFAOYSA-N 0.000 description 23
- 238000012512 characterization method Methods 0.000 description 12
- 0 CN1c2ccccc2C(*)(C(C(OC)=O)=C)C1=O Chemical compound CN1c2ccccc2C(*)(C(C(OC)=O)=C)C1=O 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 238000006735 epoxidation reaction Methods 0.000 description 4
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 2
- DLJWNYDSRNGQEF-ZYQTYTJFSA-N CCC(C1CC2)(C11N2C2C1)O[C@H]2c1c(cc(cc2)O)c2ncc1 Chemical compound CCC(C1CC2)(C11N2C2C1)O[C@H]2c1c(cc(cc2)O)c2ncc1 DLJWNYDSRNGQEF-ZYQTYTJFSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 241001614291 Anoplistes Species 0.000 description 1
- LBBVXKPQDCVLGY-DVYIFPGJSA-N CN(c(c(/C1=C\C(c2ccccc2)=N)c2)ccc2Cl)C1=O Chemical compound CN(c(c(/C1=C\C(c2ccccc2)=N)c2)ccc2Cl)C1=O LBBVXKPQDCVLGY-DVYIFPGJSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
Disclosed in the present application is a kind of preparation method with optical activation for adjoining double loop coil oxidized indole compounds in organic synthesis field,By by chiral lewis base,MBH carbonic esters derived from isatin and 3 carbonyl alkenyl benzo-heterocycle compounds are dissolved in organic solvent,Under the catalysis of chiral lewis base,Asymmetric [3+2] cycloaddition reaction occurs for MBH carbonic esters derived from isatin and 3 carbonyl alkenyl benzo-heterocycle compounds,It generates and adjoins double loop coil oxidized indole compounds with optical purity high (high dr and ee),The simple column chromatography of product or chromatography separation,I.e. separable acquisition is with optical activation to adjoin double loop coil oxidized indole compounds,This method reaction condition is mild,Proper temperature,It is easy to operate,Equipment is simple,The optical purity of preparation-obtained chipal compounds is high.
Description
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
The preparation method of oxidized indole compounds.
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
It is cyclized cascade reaction in [3+2] of organic catalysis, and it is mainly 3,3'- nafoxidines/dihydro to synthesize the such molecule obtained
The bis- loop coil Oxoindoles of furans-, the asymmetric syntheses for 3,3'- of chirality cyclopentene-bis- loop coils oxidized indole compounds, 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
The conversion of epoxidation Benzazole compounds (such as 3,3'- of chirality cyclopentene-bis- loop coils Oxoindole), 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 a kind of preparation method with optical activation for adjoining double loop coil oxidized indole compounds,
The pharmaceutical chemistry research for predominantly carrying out related field provides foundation.
A kind of preparation method with optical activation for adjoining double loop coil oxidized indole compounds of the present invention, prepares
When：Including Step 1: into organic solvent be added isatin derived from MBH- carbonic esters, 3- carbonyl alkenyl benzo-heterocycle compounds with
And chiral lewis base, it stirs under 0 DEG C~40 DEG C of reaction temperature, with optical activation adjoins Step 2: isolated
Adjacent double loop coil oxidized indole compounds；Wherein, pair loop coil oxidized indole compounds with optical activation that adjoin have
It is shown below：
In formula：X is NR5, O or S substituent groups；
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,
Methoxy substitution phenyl, fluorine substituted-phenyl, chlorine substituted-phenyl, bromine substituted-phenyl, 1- naphthalenes, 2- naphthalenes, 2- furyls or 2- thiophenes
Pheno base.
Further, the lewis base of the chirality is chiral phosphine or Chiral Amine, these chiral lewis bases can be with
The MBH- carbonic esters of Isatine derivatives are completed and 3- alkenyl Oxoindoles by forming chirality 1,3- dipole intermediates
Asymmetric [3+2] cycloaddition reaction, generation is finally with optical activation to adjoin double loop coil Oxoindole products, and reaction process is such as
Shown in following formula：
Further, the Chiral Amine includes that α -6'- hydroxyl cinchonicine is fixed, α -6'- methoxyl group cinchonicine is fixed, β -6'-
Hydroxyl cinchonicine, β -6'- methoxyl groups cinchonicine or β -6'- hydroxyl cinchonicine, using these Chiral Amines as catalyst
The yield and stereoselectivity of obtained product are relatively high.
Further, the organic solvent is hydrocarbon, alcohol, ether, ester, amide, nitrile, sulfone or sulfoxide, obtained by these solvents
Product yield and stereoselectivity it is relatively high.
Further, to prevent the volatilization of low boiling point solvent, the step 1 from being carried out in closed container.
Further, the separation method of the step 2 is chromatography or chromatography method, and product is obtained using this separation method
Yield is higher.
Further, described with optical activation to adjoin double loop coil oxidized indoles under different reaction conditions
Close optics Chun Du≤85% of object.
Further, under different reaction conditions, the mixing time be 5~for 24 hours.
A kind of preparation method with optical activation for adjoining double loop coil oxidized indole compounds provided by the present invention,
It is by the way that MBH- carbonic esters and 3- carbonyl alkenyl benzo-heterocycle compounds derived from chiral lewis base, isatin to be dissolved in
In solvent, under the catalysis of chiral lewis base, MBH- carbonic esters derived from isatin and 3- carbonyl alkenyl benzo-heterocycle chemical combination
Asymmetric [3+2] cycloaddition reaction occurs for object, generates and adjoins double loop coil Oxoindoles with optical purity high (high dr and ee)
Class compound, the simple column chromatography of product or chromatography separation, you can separation acquisition is with optical activation to adjoin double spiral shells
Epoxidation Benzazole compounds, this method reaction condition is mild, and proper temperature is easy to operate, and equipment is simple, preparation-obtained
The optical purity of chipal compounds is high, to carry out the type of chiral spiro Oxoindole compound and its drug of related field
It learns research and foundation is provided.
Specific implementation mode
It is further described below by specific implementation mode：
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, it is stirred under 0 DEG C~50 DEG C of reaction temperature；
With optical activation adjoin double loop coil oxidized indole compounds Step 2: isolated.
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.
The present invention is by the way that MBH- carbonic esters derived from β -6'- hydroxyls cinchonicine, isatin and 3- carbonyl alkenyls are aoxidized Yin
Diindyl (or 3- carbonyl alkenyl benzofuran-2-ones ketone) is dissolved in organic solvent, under the catalysis of Chiral Amine, MBH- carbon derived from isatin
With 3- carbonyl alkenyls Oxoindole (or 3- carbonyl alkenyl benzofuran-2-ones ketone) asymmetric [3+2] cycloaddition reaction occurs for acid esters, generates
Adjoin double loop coil oxidized indole compounds, the simple column chromatography of product with optical purity high (high dr and ee)
Separation obtains.
In the present invention, the optical purity of product is measured by high performance liquid chromatograph.
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'- through column chromatographic isolation and purification
(1- benzoyls) cyclopentenyl adjoins double loop coil Oxoindole (yield 89%, dr values 97:3, ee values>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 adjoin 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：
2- [1- methyl -3- tertiary butyloxycarbonyl oxygroup -2- (the 5- first of 0.3mmol (113.2mg) is added in 2mL dichloromethane
Oxygroup Oxoindole quinoline) -3- bases] 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：
2- [1- methyl -3- tertiary butyloxycarbonyl oxygroup -2- (the 5- fluorine of 0.3mmol (109.6mg) is 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- fluorine adjoin double loop coil Oxoindole (yield 84%, dr values 96:4, ee values>
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：
2- [1- methyl -3- tertiary butyloxycarbonyl oxygroup -2- (the 6- bromines of 0.3mmol (127.9mg) 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 -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：
2- [1- methyl -3- tertiary butyloxycarbonyl oxygroup -2- (the 7- fluorine of 0.3mmol (109.6mg) is 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 -7- fluorine adjoin 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：
2- [1- methyl -3- tertiary butyloxycarbonyl oxygroup -2- (the 7- tri- of 0.3mmol (124.6mg) are added in 2mL dichloromethane
Methyl fluoride Oxoindole quinoline) -3- bases] 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- bases] 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- bases] 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- bases] 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 values>
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'- through column chromatographic isolation and purification
(1- benzoyls) cyclopentenyl -1'- ethyls adjoin double loop coil Oxoindole (yield 90%, dr values 86:14, ee values 99%).
(C1R, C4R, C5S) -3,3'- (1- benzoyls) cyclopentenyl -1'- ethyls adjoin 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'- through column chromatographic isolation and purification
(1- benzoyls) cyclopentenyl -1'- propyl adjoins double loop coil Oxoindole (yield 76%, dr values 97:3, ee values>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'- 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'- through column chromatographic isolation and purification
(1- benzoyls) cyclopentenyl -1'- benzyls adjoin double loop coil Oxoindole (yield 72%, dr values>99:1, 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=-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'- tertbutyloxycarbonyls adjoin double loop coil Oxoindole (yield 26%, dr values>
99:1, ee value 83%).
(C1R, C4R, C5S) -3,3'- (1- benzoyls) cyclopentenyl -1'- tertbutyloxycarbonyls adjoin 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 adjoin 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 groups adjoin double loop coil Oxoindole (yield 55%, dr values 96:4,
Ee values>99%).
(C1R, C4R, C5S) -3,3'- (1- benzoyls) cyclopentenyl -5'- methoxyl groups adjoin 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 adjoin 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 adjoin 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'- bromines adjoin double loop coil Oxoindole (yield 87%, dr values>99:1, ee value
98%).
(C1R, C4R, C5S) -3,3'- (1- benzoyls) cyclopentenyl -5'- bromines adjoin 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 adjoin 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'- bromines adjoin double loop coil Oxoindole (yield 43%, dr values 98:2, ee values
95%).
(C1R, C4R, C5S) -3,3'- (1- benzoyls) cyclopentenyl] -7'- bromines adjoin the tables 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- [Asias 2- oxos -2- (4- aminomethyl phenyls) second of 0.2mmol (55.5mg)
Base]-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) cyclopentenyl] adjoins double loop coil Oxoindole (yield 36%, dr values>99:1,
Ee values 95%).
(C1R, C4R, C5S) -3,3'- [1- (4- methyl benzoyls) cyclopentenyl] adjoins 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, [2- oxos -2- (2,4- 3,5-dimethylphenyl) is sub- by the 1- methyl -3- of 0.2mmol (58.3mg)
Ethyl]-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- dimethylbenzoyl) cyclopentenyl] adjoins double loop coil Oxoindole (yield 49%, dr
Value 97:3, ee values>99%).
(C1R, C4R, C5S) -3,3'- [1- (2,4- dimethylbenzoyls) cyclopentenyl] adjoins 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- [2- oxos -2- (4- fluorophenyls) ethylidene]-of 0.2mmol (56.3mg)
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) cyclopentenyl] adjoins double loop coil Oxoindole (yield 69%, dr values>99:1, ee
Value>99%).
(C1R, C4R, C5S) -3,3'- [1- (4- fluoro benzoyls) cyclopentenyl] adjoins 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- [2- oxos -2- (4- chlorphenyls) ethylidene]-of 0.2mmol (59.5mg)
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) cyclopentenyl] adjoins double loop coil Oxoindole (yield 70%, dr values 97:3, ee values
>99%).
(C1R, C4R, C5S) -3,3'- [1- (4- chlorobenzene formacyls) cyclopentenyl] adjoins 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- [2- oxos -2- (4- bromophenyls) ethylidene]-of 0.2mmol (68.4mg)
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) cyclopentenyl] adjoins double loop coil Oxoindole (yield 50%, dr values 97:3, ee values
>99%).
(C1R, C4R, C5S) -3,3'- [1- (4- benzoyl bromides) cyclopentenyl] adjoins 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, 1- methyl -3- [2- oxos -2- (1- naphthalenes) ethylidene]-Yin of 0.2mmol (68.4mg)
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) cyclopentenyls] adjoin double loop coil Oxoindole (yield 47%, dr values 96:4, ee values 85%).
(C1R, C4R, C5S) -3,3'- [1- (1- naphthoyls) cyclopentenyl] adjoins 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) cyclopentenyl] adjoins double loop coil Oxoindole (yield 47%, dr values>99:1, ee value>
99%).
(C1R, C4R, C5S) -3,3'- [1- (1- benzoyls) cyclopentenyl] adjoins 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. a kind of preparation method with optical activation for adjoining double loop coil oxidized indole compounds, which is characterized in that prepare
When：Including Step 1: into organic solvent be added isatin derived from MBH- carbonic esters, 3- carbonyl alkenyl benzo-heterocycle compounds with
And chiral lewis base, stir 5 under 0 DEG C~40 DEG C of reaction temperature~for 24 hours, Step 2: the polarity using compound is poor
It is different, it is isolated with optical activation to adjoin double loop coil oxidized indole compounds：
Wherein, it is described it is with optical activation adjoin double loop coil oxidized indole compounds and have be shown below：
In formula：X is NR5, O or S substituent groups；
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
Base substituted-phenyl, fluorine substituted-phenyl, chlorine substituted-phenyl, bromine substituted-phenyl, 1- naphthalenes, 2- naphthalenes, 2- furyls or 2- thienyls；
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, methoxy
Base substituted-phenyl, fluorine substituted-phenyl, chlorine substituted-phenyl, bromine substituted-phenyl, 1- naphthalenes, 2- naphthalenes, 2- furyls or 2- thienyls.
2. the preparation method with optical activation for adjoining double loop coil oxidized indole compounds according to claim 1,
It is characterized in that, the lewis base of the chirality is chiral phosphine or Chiral Amine.
3. the preparation method with optical activation for adjoining double loop coil oxidized indole compounds according to claim 2,
It is characterized in that, the Chiral Amine includes, α -6'- hydroxyl cinchonicine is fixed, α -6'- methoxyl group cinchonicine is fixed, β -6'- hydroxyls
Cinchonicine, β -6'- methoxyl groups cinchonicine or β -6'- hydroxyl cinchonicine.
4. the preparation method with optical activation for adjoining double loop coil oxidized indole compounds according to claim 1,
It is characterized in that, the organic solvent is hydrocarbon, alcohol, ether, ester, amide, nitrile, sulfone or sulfoxide.
5. the preparation method with optical activation for adjoining double loop coil oxidized indole compounds according to claim 1,
It is characterized in that, the step 1 carries out in closed container.
6. the preparation method with optical activation for adjoining double loop coil oxidized indole compounds according to claim 1,
It is characterized in that, the separation method of the step 2 is chromatography or chromatography method.
7. the preparation method with optical activation for adjoining double loop coil oxidized indole compounds according to claim 1,
It is characterized in that, optics Chun Du≤85% with optical activation for adjoining double loop coil oxidized indole compounds.
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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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| 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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