CN107383030A - Turmerone splices double loop coil Oxoindole compounds of 3,3 ' pyrroles and preparation method and application - Google Patents
Turmerone splices double loop coil Oxoindole compounds of 3,3 ' pyrroles and preparation method and application Download PDFInfo
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- CN107383030A CN107383030A CN201710229967.0A CN201710229967A CN107383030A CN 107383030 A CN107383030 A CN 107383030A CN 201710229967 A CN201710229967 A CN 201710229967A CN 107383030 A CN107383030 A CN 107383030A
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- Prior art keywords
- turmerone
- cdcl
- nmr
- pyrroles
- loop coil
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- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical class C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 title claims abstract description 29
- FZPYMZUVXJUAQA-ZDUSSCGKSA-N Turmerone Chemical compound CC(C)=CC(=O)C[C@H](C)C1=CCC(C)=CC1 FZPYMZUVXJUAQA-ZDUSSCGKSA-N 0.000 title claims abstract description 27
- FZPYMZUVXJUAQA-UHFFFAOYSA-N Turmerone Natural products CC(C)=CC(=O)CC(C)C1=CCC(C)=CC1 FZPYMZUVXJUAQA-UHFFFAOYSA-N 0.000 title claims abstract description 22
- XOCANRBEOZQNAQ-KBPBESRZSA-N alpha-turmerone Natural products O=C(/C=C(\C)/C)C[C@H](C)[C@H]1C=CC(C)=CC1 XOCANRBEOZQNAQ-KBPBESRZSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims description 10
- 150000003233 pyrroles Chemical class 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 18
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical class C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical compound OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 claims abstract description 7
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims abstract description 7
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 6
- 238000006352 cycloaddition reaction Methods 0.000 claims abstract description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims 1
- 241000234314 Zingiber Species 0.000 claims 1
- 235000006886 Zingiber officinale Nutrition 0.000 claims 1
- 229930003944 flavone Natural products 0.000 claims 1
- 150000002213 flavones Chemical class 0.000 claims 1
- 235000011949 flavones Nutrition 0.000 claims 1
- 235000008397 ginger Nutrition 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 10
- 208000032839 leukemia Diseases 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- 238000012216 screening Methods 0.000 abstract description 5
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- -1 alkenyl Oxoindole Chemical compound 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 46
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 description 45
- 239000007787 solid Substances 0.000 description 45
- 238000001819 mass spectrum Methods 0.000 description 42
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- NAAJVHHFAXWBOK-ZDUSSCGKSA-N (+)-(S)-ar-turmerone Chemical compound CC(C)=CC(=O)C[C@H](C)C1=CC=C(C)C=C1 NAAJVHHFAXWBOK-ZDUSSCGKSA-N 0.000 description 4
- 241001269238 Data Species 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- 235000003392 Curcuma domestica Nutrition 0.000 description 2
- XOCANRBEOZQNAQ-KGLIPLIRSA-N ar-turmerone Natural products C[C@H](CC(=O)C=C(C)C)[C@@H]1CC=C(C)C=C1 XOCANRBEOZQNAQ-KGLIPLIRSA-N 0.000 description 2
- 235000003373 curcuma longa Nutrition 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003034 scaffold hopping Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 235000013976 turmeric Nutrition 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- NNWGOUJBCKZULC-UHFFFAOYSA-N 5-methyl-5-(5-methylthiophen-3-yl)-4-oxofuran-2-carboxylic acid Chemical compound S1C(C)=CC(C2(C)C(C=C(O2)C(O)=O)=O)=C1 NNWGOUJBCKZULC-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 244000163122 Curcuma domestica Species 0.000 description 1
- 244000008991 Curcuma longa Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
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- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- RXHIKAIVEMAPRU-JRIGQVHBSA-N sequiterpene Natural products C1=C(C)[C@@H](OC(C)=O)[C@H](O)[C@@]2(O)[C@H](C)CC[C@@H](C(C)=C)[C@H]21 RXHIKAIVEMAPRU-JRIGQVHBSA-N 0.000 description 1
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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
- C07D487/22—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 four or more hetero rings
-
- 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
- C07D487/12—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 three hetero rings
- C07D487/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
Abstract
The invention discloses a kind of turmerone splicing 3, the double loop coil Oxoindole compounds of 3 ' pyrroles, the present invention is with various substituted isatin, the alkenyl Oxoindole of dienone 3 and proline or Thioproline or methyl amimoacetic acid, flow back in organic solvent, carry out 1,3 dipole 3+2 cycloaddition reactions, obtain turmerone splicing 3, the double loop coil Oxoindole compounds of 3' pyrroles, such skeleton includes potential bioactivity skeleton turmerone, chemical combination material resource can be provided for bioactivity screening, the screening and pharmaceutical industry to medicine have important application value.Operation is simple by the present invention, and Material synthesis is cheap and easily-available, can be carried out in various organic solvents, it may have preferable air stability, applicability is wide, has good compatibility for various substituents.And the framework compound has inhibitory activity to human leukemia cell (K562) growth.
Description
Technical field
The present invention relates to technical field of chemistry, especially a kind of turmerone splices the double loop coil Oxoindoles of 3,3'- pyrroles
Compound and preparation method and application.
Background technology
According to pharmacophore in drug design and scaffold hopping principle, active point is spliced to having bio-active group
In organic chemistry and medical chemistry it is extremely important research field in sub- skeleton.(1) polyfunctional group Oxoindole is deposited extensively
In natural products and synthetic drug molecule, wherein, the double loop coil Oxoindoles of especially 3,3'- pyrroles are because with extensive biology
Activity, the extensive concern of many chemist and medical chemistry team is attracted, for example, compound I is with antibacterium work
Property；Compound II has antifungal activity, and compound III has antitumor activity.(2) sequiterpene turmerone Turmerone
I, (S)-ar-turmerone (S)-ar-Turmerone II, turmerone derivative III-V are separated from the rhizome of turmeric, reported
Road has cell toxicant, anti-inflammatory, anticancer and Anti-snake venom activity.Turmeric also serves as one as a kind of dispensing and flavouring in food
Kind medicine uses.Therefore, according to pharmacophore in drug design and scaffold hopping principle, in view of the double loop coil oxidation Yin of 3,3'- pyrroles
Diindyl framework compound and turmerone have potential bioactivity.Therefore, turmerone skeleton is spliced to the double loop coils of 3,3'- pyrroles
Oxoindole skeleton, a series of oxoindole derivative of new potential more active function groups is synthesized, can be that bioactivity is sieved
Choosing provides chemical combination material resource, and screening and pharmaceutical industry to medicine have important application value (as shown in Figure 8).
The content of the invention
The purpose of the present invention is：A kind of double loop coil Oxoindole compounds of turmerone splicing 3,3'- pyrroles and its system are provided
Preparation Method and application, it is a kind of important medicine intermediate analog and drug molecule analog, to drug screening and pharmacy
Industry has important application value, and the very economical simplicity of its synthetic method.
It has also been found that such compound is preparing the application in preventing and treating tumor disease medicine.
What the present invention was realized in：Turmerone splices the double loop coil Oxoindole compounds of 3,3'- pyrroles, compound tool
There is the structure of below formula (I)：
In formula, R1For phenyl, ethyl, methyl or benzyl；R2For methyl, H or halogen；R3For methyl, ethyl or benzyl；R4
For methyl, H or halogen；X is C or S.
By various substituted isatin, dienone 3- alkenyls Oxoindole and proline or Thioproline or methyl amimoacetic acid, press
Mol ratio is 2:3:6 ratio flows back in organic solvent, carries out 1,3- dipole 3+2 cycloaddition reactions, obtains turmerone and spells
Connect the double loop coil Oxoindole compounds of 3,3'- pyrroles.
Synthetic route is as follows：
The structural formula of wherein various substituted isatin 1 and dienone 3- alkenyls Oxoindole 2, its substituent meet R1For
Phenyl, ethyl, methyl or benzyl；R2For methyl, H or halogen；R3For methyl, ethyl or benzyl；R4For methyl, H or halogen；X is
C or S.
Described organic solvent is acetonitrile, methanol, ethanol, propyl alcohol, isopropanol, ether, tetrahydrofuran, benzene, toluene, diformazan
Benzene, trimethylbenzene, dioxane, glycol dimethyl ether, isopropyl ether, chloroform, dichloromethane or nitrobenzene.
Various substituted isatin, dienone 3- alkenyls Oxoindole and proline or Thioproline or methyl amimoacetic acid, are having
Reaction temperature is 50-100 DEG C in solvent, and the reaction time is 5-20 hours.
The double loop coil Oxoindole compounds of turmerone splicing 3,3'- pyrroles answering in preventing and treating tumor disease medicine is prepared
With.
By using above-mentioned technical proposal, with various substituted isatin, dienone 3- alkenyls Oxoindole and proline or
Thioproline or methyl amimoacetic acid, it is in molar ratio 2:3:6 ratio flows back in organic solvent, carries out 1,3- dipole 3+2 rings
Addition reaction, obtain turmerone and splice the double loop coil Oxoindole compounds of 3,3'- pyrroles, such Oxoindole skeleton includes potential
Bioactivity turmerone skeleton, chemical combination material resource can be provided for bioactivity screening, screening to medicine and pharmaceutical industry tool
There is important application value.And the compound is to three kinds of tumor cell lines such as human prostate (PC-3), human lung carcinoma cell (A549)
And human leukemia cell (K562) has the function that inhibitory activity.Operation is simple by the present invention, and Material synthesis is cheap and easily-available,
It can be carried out in various organic solvents, it may have preferable air stability, applicability is wide, has very for various substituents
Good compatibility.
Brief description of the drawings
Accompanying drawing 1 and the compound 3aa spectral datas that accompanying drawing 2 is embodiments of the invention 1；
Accompanying drawing 3 and the compound 4aa spectral datas that accompanying drawing 4 is embodiments of the invention 2；
Accompanying drawing 5 and the compound 5aa spectral datas that accompanying drawing 6 is embodiments of the invention 3；
Accompanying drawing 7 is embodiments of the invention compound 3aa, 3ba and 5ba monocrystalline figure；
Accompanying drawing 8 is the compound test result figure of embodiments of the invention.
Embodiment
Embodiments of the invention 1：89.2mg N-methyl-isatins 1a (0.4mmol) is sequentially added in reaction tube,
144.6mg dienone 3- alkenyl Oxoindole 2a (0.6mmol), 92.0mg proline (0.8mmol) and 10mL ethanol solutions, return
Stream reaction 5h, TLC detection fundamental reaction is complete, and direct loading is through column chromatography (eluant, eluent：V (petroleum ether)：V (ethyl acetate)=
4:1) compound 3aa, yellow solid, fusing point are purified to obtain：176.5-177.8 DEG C, dr：20:1；Yield 89%.Nuclear magnetic resonance and height
The results such as Resolution Mass Spectrometry test are as follows：1H NMR(CDCl3,400MHz)δ:1.43(s,3H),1.61(s,3H), 2.05-2.10
(m,2H),2.21-2.29(m,2H),2.47-2.53(m,1H),2.66-2.71(m,1H),2.88(s,3H),3.18(s,
3H), 4.58-4.63 (m, 2H), 5.75 (s, 1H), 6.39-6.41 (m, 1H), 6.51-6.56 (m, 2H), 6.60 (d, J=
8.0Hz, 1H), 7.03-7.13 (m, 2H), 7.20-7.25 (m, 1H), 7.77 (d, J=7.6Hz, 1H)；13C NMR(CDCl3,
100MHz) δ:20.0,26.0,26.2,27.1,30.9,31.3,47.3,59.0,65.0,67.2,107.4,121.6,
122.3,123.1,125.1,125.5, 127.4,128.8,129.2,143.3,143.8,154.4,172.9,177.1,
196.9；HRMS(ESI-TOF)m/z:Calcd.for C28H29N3NaO3[M+Na]+:478.2107；Found:478.2109.
For compound 3ba to 3le preparation method with compound 3aa, rate of charge is identical with compound 3aa, can obtain chemical combination
Thing 3ba to 3le, reaction yield and cis-selectivity are shown in Tables 1 and 2, but it is emphasized that the compound of the present invention is not limited to
Content represented by table 1.
Table 1 is the chemical constitution that a kind of turmerone splices the double loop coil Oxoindole compounds of 3,3'- pyrroles
The prepare compound 3ba of the present embodiment 1：Yellow solid；Fusing point：112.2-113.6℃；Yield：83%, 12:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.40(s,3H),1.57(s,
3H), 2.02-2.08(m,2H),2.19-2.26(m,2H),2.50-2.55(m,1H),2.66-2.69(m,1H),2.87(s,
3H), 4.57-4.63 (m, 2H), 4.76 (d, J=12.4Hz, 1H), 4.94 (d, J=12.4Hz, 1H), 5.74 (s, 1H),
6.34-6.37 (m, 1H), 6.41-6.44 (m, 1H), 6.50 (d, J=6.0Hz, 1H), 6.83-6.87 (m, 1H), 7.05-
7.08 (m, 1H), 7.15-7.19 (m, 2H), 7.23-7.26 (m, 2H), 7.30-7.32 (m, 2H), 7.73 (d, J=6.0Hz,
1H)；13C NMR(CDCl3,100 MHz)δ:20.0,26.2,27.0,30.8,31.4,44.0,47.3,59.1,65.0,67.0,
107.4,108.6,122.2,123.1,127.3, 127.4,127.5,128.6,135.9,143.0,143.3,154.4,
172.9,177.0,196.9；HRMS(ESI-TOF)m/z: Calcd.for C34H33N3NaO3[M+Na]+:554.2420；
Found:554.2423.
The prepare compound 3ca of the present embodiment 1：Yellow solid；Fusing point：117.2-118.6℃；Yield：61%, 12:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.47(s,3H),1.64(s,
3H), 2.08-2.16(m,2H),2.24-2.31(m,2H),2.66-2.71(m,1H),2.82-2.85(m,1H),2.96(s,
3H), 4.66-4.68(m,2H),5.80(s,1H),6.49-6.51(m,1H),6.56-6.63(m,3H),6.99-7.03(m,
1H), 7.14-7.17(m,1H),7.24-7.28(m,1H),7.38-7.41(m,1H),7.52-7.54(m,4H),7.83(d,J
=5.6Hz, 1H)；13C NMR(CDCl3,100MHz)δ:20.0,26.2,27.0,30.8,31.2,47.4,58.9,65.1,
67.5,107.4, 108.6,121.8,123.1,125.7,126.9,127.4,128.0,128.9,129.5,143.4,
143.6,154.3,172.9,176.7, 196.9；HRMS(ESI-TOF)m/z:Calcd.for C33H31N3NaO3[M+Na]+:
540.2263；Found:540.2265.
The present embodiment prepare compound 3da：Yellow solid；Fusing point：185.4-186.8℃；Yield：72%, 13:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.45(s,3H),1.63(s,3H),
2.05-2.11(m,2H),2.23-2.33(m,2H),2.46(s,3H),2.48-2.53(m,1H),2.69-2.72(m,1H),
2.93 (s, 3H), 3.49 (s, 3H), 4.58-4.65 (m, 2H), 5.76 (s, 1H), 6.36 (d, J=5.6Hz, 1H), 6.41-
6.44 (m, 1H), 6.56 (d, J=6.4Hz, 1H), 6.80 (d, J=6.0Hz, 1H), 7.10-7.13 (m, 1H), 7.21-7.24
(m, 1H), 7.77 (d, J=6.0Hz, 1H)；13C NMR(CDCl3,100MHz)δ:19.2,20.0,26.3,27.1,29.5,
30.8,31.2,47.3,59.2, 64.9,67.4,107.4,118.7,121.3,122.2,123.1,123.6,127.5,
128.8,133.0,141.5,143.3,154.2, 173.0,177.8,197.0；HRMS(ESI-TOF)m/z:Calcd.for
C29H31N3NaO3[M+Na]+:492.2263；Found: 492.2265.
The present embodiment prepare compound 3ea：Yellow solid；Fusing point：106.8-108.5℃；Yield：92%, 20:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.42(s,3H),1.60(s,3H),
2.06-2.08(m,2H),2.22-2.25(m,2H),2.46-2.49(m,1H),2.65-2.68(m,1H),2.93(s,3H),
3.56 (s, 3H), 4.56-4.59 (m, 2H), 5.72 (s, 1H), 6.39-6.43 (m, 2H), 6.55 (d, J=8.0Hz, 1H),
6.95-6.98(m, 1H),7.07-7.11(m,1H),7.18-7.25(m,1H),7.72-7.74(m,1H)；13C NMR
(CDCl3,100MHz)δ: 20.1,26.4,27.2,29.6,30.9,31.4,47.4,59.2,65.1,67.4,107.7,
114.7,122.2,122.4,123.1,124.2, 126.2,127.5,128.1,129.1,131.6,139.7,143.4,
154.7,172.8,177.5,196.7；HRMS(ESI-TOF)m/z: Calcd.for C28H28ClN3NaO3[M+Na]+:
512.1717；Found:512.1717.
The present embodiment prepare compound 3fa：Yellow solid；Fusing point：204.3-206.5℃；Yield：82%, 10:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,500MHz)δ:1.40(s,3H),1.57(s,3H),
2.02-2.06(m,2H),2.17-2.24(m,2H),2.41-2.47(m,1H),2.63-2.67(m,1H),2.86(s,3H),
3.12(s, 3H),4.50-4.57(m,2H),5.70(s,1H),6.09-6.12(m,1H),6.46-6.49(m,1H),6.54
(d, J=7.5Hz, 1H), 6.69-6.73 (m, 1H), 7.07-7.10 (m, 1H), 7.18-7.22 (m, 1H), 7.70 (d, J=
7.0Hz,1H)；13C NMR (CDCl3,125MHz)δ:20.0,26.1,26.2,27.1,30.8,31.2,47.3,59.0,
65.1,67.1,107.6,107.7,113.7 (d,JCF=25.0Hz), 115.3 (d, JCF=23.8Hz), 122.4,123.0,
126.1,127.1,127.2,129.2,139.7,143.2, 154.6,158.3(d,JCF=238.8Hz), 172.6,176.8,
196.6；HRMS(ESI-TOF)m/z:Calcd.for C28H28FN3NaO3[M+Na]+:496.2012；Found:496.2015.
The present embodiment prepare compound 3ga：Yellow solid；Fusing point：243.3-245.5℃；Yield：85%, 19:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.48(s,3H),1.64(s,3H),
2.08-2.12(m,2H),2.23-2.29(m,2H),2.48-2.53(m,1H),2.72-2.75(m,1H),2.93(s,3H),
3.18 (s, 3H), 4.58-4.61 (m, 2H), 5.77 (s, 1H), 6.49-6.51 (m, 2H), 6.62 (d, J=6.4Hz, 1H),
7.16-7.21 (m, 2H), 7.27-7.31 (m, 1H), 7.76 (d, J=6.0Hz, 1H)；13C NMR(CDCl3,100MHz)δ:
20.0,26.1,26.2, 27.1,30.8,31.3,47.3,58.9,65.2,67.2,107.7,108.7,114.3,122.4,
122.9,127.2,128.8,129.2, 131.9,142.7,143.2,154.6,172.6,176.5,196.6；HRMS(ESI-
TOF)m/z:Calcd.for C28H28BrN3NaO3[M+Na]+:556.1212；Found:556.1214.
The present embodiment prepare compound 3ha：Yellow solid；Fusing point：204.4-205.6℃；Yield：90%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.41(s,3H),1.57(s,
3H),1.80 (s,3H),2.03-2.08(m,2H),2.18-2.29(m,2H),2.51-2.56(m,1H),2.66-2.70(m,
1H), 2.87 (s, 3H), 4.56-4.63 (m, 2H), 4.75 (d, J=12.8Hz, 1H), 4.91 (d, J=12.4Hz, 1H),
5.74 (s, 1H), 6.12 (s, 1H), 6.23 (d, J=6.4Hz, 1H), 6.49 (d, J=6.0Hz, 1H), 6.64 (d, J=
6.0Hz, 1H), 7.06-7.09 (m, 1H), 7.15-7.19 (m, 2H), 7.22-7.26 (m, 2H), 7.30 (d, J=5.6Hz,
2H), 7.73 (d, J=5.6Hz, 1H)；13C NMR (CDCl3,100MHz)δ:20.0,20.7,26.2,27.0,30.8,31.4,
44.1,47.4,59.1,65.2,67.0,107.4,108.2, 122.1,123.1,126.5,127.3,127.4,127.5,
128.5,128.7,129.2,130.9,136.1,154.3,173.0,176.8, 197.0；HRMS(ESI-TOF)m/z:
Calcd.for C35H35N3NaO3[M+Na]+:568.2576；Found:568.2575.
The present embodiment prepare compound 3ia：Yellow solid；Fusing point：161.1-162.8℃；Yield：88%, 12:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.47(s,3H),1.64(s,3H),
2.08-2.15(m,2H),2.24-2.29(m,2H),2.53-2.59(m,1H),2.73-2.77(m,1H),2.95(s,3H),
4.61-4.65 (m, 2H), 4.81 (d, J=15.6Hz, 1H), 4.97 (d, J=15.6Hz, 1H), 5.79 (s, 1H), 6.30-
6.35(m, 2H),6.59-6.62(m,1H),6.85-6.88(m,1H),7.13-7.17(m,1H),7.22-7.35(m,6H),
7.75-7.77(m, 1H)；13C NMR(CDCl3,100MHz)δ:20.2,26.3,27.2,30.9,31.5,44.3,47.4,
59.2,65.3,67.1, 107.9,109.6,123.1,126.2,127.1,127.2,127.3,127.6,127.7,128.8,
129.1,129.3,135.6,154.8, 172.8,176.7,196.7；HRMS(ESI-TOF)m/z:Calcd.for
C34H32ClN3NaO3[M+Na]+:588.2030； Found:588.2032.
The present embodiment prepare compound 3ja：Yellow solid；Fusing point：180.2-182.1℃；Yield：88%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.47(s,3H),1.63(s,
3H), 2.09-2.14(m,2H),2.25-2.29(m,2H),2.54-2.58(m,1H),2.72-2.79(m,1H),2.95(s,
3H), 4.60-4.62 (m, 2H), 4.79 (d, J=15.6Hz, 1H), 4.96 (d, J=16.0Hz, 1H), 5.78 (s, 1H),
6.26 (d, J=8.4Hz, 1H), 6.47 (d, J=2.4Hz, 1H), 6.59-6.62 (m, 1H), 6.99-7.02 (m, 1H),
7.13-7.17(m,1H), 7.23-7.34(m,6H),7.73-7.76(m,1H)；13C NMR(CDCl3,100MHz)δ:20.2,
26.3,27.2,30.9,31.5, 44.2,47.4,59.1,65.3,67.2,107.9,110.1,104.6,122.5,123.1,
127.3,127.6,127.7,128.8,129.0, 129.3,135.6,154.8,172.8,176.6,196.7；HRMS(ESI-
TOF)m/z:Calcd.for C34H32BrN3NaO3 [M+Na]+:632.1525；Found:632.1528.
The present embodiment prepare compound 3ka：Yellow solid；Fusing point：124.3-126.5℃；Yield：80%, 8:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.24-1.27(m,3H),1.47(s,
3H), 1.62(s,3H),1.92(s,3H),2.09-2.13(m,2H),2.25-2.28(m,2H),2.52-2.56(m,1H),
2.69-2.73(m, 1H),2.90(s,3H),3.63-3.67(m,1H),3.80-3.85(m,1H),4.61-4.65(m,2H),
5.78(s,1H),6.20(s, 1H),6.51-6.57(m,2H),6.84-6.87(m,1H),7.13-7.16(m,1H),7.23-
7.27 (m, 1H), 7.78 (d, J=6.0 Hz, 1H)；13C NMR(CDCl3,100MHz)δ:12.4,19.9,20.7,26.1,
27.0,30.8,31.3,34.5,47.3,58.9, 65.2,67.1,107.0,107.3,122.0,123.1,126.6,127.3,
128.7,129.2,130.6,140.3,143.3,154.1, 172.8,176.3,197.1；HRMS(ESI-TOF)m/z:
Calcd.for C30H33N3NaO3[M+Na]+:506.2420；Found: 506.2423.
The present embodiment prepare compound 3la：Yellow solid；Fusing point：206.6-207.3℃；Yield：71%, 8:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.23-1.27(m,3H),1.47(s,
3H), 1.64(s,3H),2.08-2.13(m,2H),2.22-2.28(m,2H),2.48-2.54(m,1H),2.70-2.75(m,
1H),2.93(s, 3H),3.62-3.68(m,1H),3.80-3.86(m,1H),4.58-4.62(m,2H),5.77(s,1H),
6.37 (s, 1H), 6.56 (d, J=8.0Hz, 1H), 6.61 (d, J=8.0Hz, 1H), 7.03-7.05 (m, 1H), 7.14-7.18
(m, 1H), 7.26-7.30 (m, 1H), 7.76 (d, J=8.0Hz, 1H)；13C NMR(CDCl3,100MHz)δ:12.3,20.0,
26.1,27.0,30.8,31.3,34.7, 47.2,58.9,65.1,67.0,107.6,108.2,122.3,123.0,126.2,
126.7,127.2,128.9,129.1,141.3,143.2, 154.5,172.5,176.1,196.6；HRMS(ESI-TOF)m/
z:Calcd.for C29H30ClN3NaO3[M+Na]+: 526.1873；Found:526.1876.
The present embodiment prepare compound 3ab：Yellow solid；Fusing point：188.3-190.5℃；Yield：71%, 15:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.50(s,3H),1.64(s,3H),
2.11-2.18(m,2H),2.25-2.36(m,2H),2.40(s,3H),2.54-2.61(m,1H),2.75-2.79(m,1H),
3.17 (s, 3H), 4.14 (d, J=16.0Hz, 1H), 4.63-4.71 (m, 2H), 5.20 (d, J=16.0Hz, 1H), 5.82 (s,
1H), 6.20 (d, J=7.6Hz, 1H), 6.34-6.40 (m, 3H), 6.59-6.63 (m, 1H), 6.67 (d, J=7.6Hz, 1H),
6.90 (d, J=7.6 Hz, 1H), 7.01-7.05 (m, 2H), 7.08-7.12 (m, 1H), 7.19-7.23 (m, 1H), 7.60 (s,
1H)；13C NMR(CDCl3, 100MHz)δ:20.0,21.4,26.0,27.1,30.9,31.4,43.1,47.5,58.7,65.5,
67.3,77.8,107.5,108.3, 121.7,123.1,125.7,125.8,126.9,127.9,128.5,129.1,129.3,
131.7,135.0,154.1,172.9,177.0, 197.2；HRMS(ESI-TOF)m/z:Calcd.for C35H35N3NaO3[M+
Na]+:568.2576；Found:568.2576.
The present embodiment prepare compound 3ac：Yellow solid；Fusing point：97.3-99.1℃；Yield：68%, 9:1dr；Nuclear-magnetism
The result such as resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.58(s,3H),1.67(s,3H),
2.08-2.15(m,2H),2.22-2.34(m,2H),2.45-2.52(m,1H),2.69-2.73(m,1H),2.88(s,3H),
3.17 (s, 3H), 4.43-4.49 (m, 1H), 4.65 (d, J=8.8Hz, 1H), 5.79 (s, 1H), 6.43-6.46 (m, 2H),
6.58-6.63(m, 2H),7.07-7.11(m,1H),7.36-7.38(m,1H),7.87(s,1H)；13C NMR(CDCl3,
100MHz)δ:20.4, 26.2,26.4,27.4,30.9,31.6,47.4,59.3,65.2,67.1,107.6,109.0,
115.0,121.9,122.9,124.8,125.5, 129.5,130.0,131.7,142.7,143.9,155.2,172.5,
176.9；HRMS(ESI-TOF)m/z:Calcd.for C28H28BrN3NaO3[M+Na]+:556.1212；Found:556.1215.
The present embodiment prepare compound 3dd：Yellow solid；Fusing point：165.3-166.6℃；Yield：89%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.46(s,3H),1.63(s,
3H), 2.08-2.16(m,2H),2.23-2.31(m,1H),2.33-2.38(m,1H),2.44(s,3H),2.51-2.58(m,
1H), 2.71-2.76 (m, 1H), 3.42 (s, 3H), 4.14 (d, J=16.0Hz, 1H), 4.63-4.69 (m, 2H), 5.25 (d, J
=16.4Hz, 1H), 5.81 (s, 1H), 6.28-6.31 (m, 2H), 6.36 (d, J=7.6Hz, 2H), 6.42-6.46 (m, 1H),
6.90-6.93(m, 1H),7.01-7.11(m,5H),7.74-7.76(m,1H)；13C NMR(CDCl3,100MHz)δ:19.3,
20.1,27.2,29.6, 31.0,31.5,43.2,47.6,58.8,65.5,67.5,108.5,119.1,121.6,122.3,
123.2,123.8,125.8,127.1, 127.5,128.6,128.9,135.1,154.4,173.1,177.9,197.2；HRMS
(ESI-TOF)m/z:Calcd.for C35H35N3NaO3[M+Na]+:568.2576；Found:568.2577.
The present embodiment prepare compound 3fd：Yellow solid；Fusing point：204.3-205.8℃；Yield：93%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.50(s,3H),1.64(s,
3H), 2.09-2.16(m,2H),2.23-2.35(m,2H),2.50-2.57(m,1H),2.72-2.76(m,1H),3.13(s,
3H), 4.20 (d, J=16.0Hz, 1H), 4.59-4.69 (m, 2H), 5.14 (d, J=16.0Hz, 1H), 5.82 (s, 1H),
6.07-6.10 (m, 1H), 6.36-6.38 (m, 1H), 6.46 (d, J=7.2Hz, 2H), 6.53-6.56 (m, 1H), 6.84-
6.89(m,1H),7.03-7.15(m, 5H),7.73-7.76(m,1H)；13C NMR(CDCl3,100MHz)δ:20.2,26.3,
27.2,31.0,31.5,43.3,47.6, 58.8,65.6,67.2,77.9,107.8,107.9,108.9,114.0(d,JCF=
26.0Hz),115.5(d,JCF=24.0Hz), 122.5,123.1,126.1,126.4,127.2,127.3,128.7,129.3,
135.1,140.0,142.5,155.0,158.6(d,JCF=239.0Hz), 172.8,176.8,196.8；HRMS(ESI-TOF)
m/z:Calcd.for C34H32FN3NaO3[M+Na]+: 572.2325；Found:572.2327.
The present embodiment prepare compound 3if：Yellow solid；Fusing point：177.3-178.9℃；Yield：67%, 10:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.67(s,3H),1.71(s,3H),
2.11-2.23 (m, 2H), 2.28-2.41 (m, 2H), 2.55-2.62 (m, 1H), 2.78-2.83 (m, 1H), 4.27 (d, J=
16.0Hz, 1H), 4.49-4.56 (m, 1H), 4.75-4.80 (m, 2H), 4.93 (d, J=15.6Hz, 1H), 5.17 (d, J=
16.0Hz, 1H), 5.89 (s, 1H), 6.31-6.36 (m, 3H), 6.41 (d, J=8.0Hz, 2H), 6.95-7.00 (m, 3H),
7.06-7.15(m,5H), 7.23-7.25(m,2H),7.72(s,1H)；13C NMR(CDCl3,100MHz)δ:20.6,27.5,
30.9,31.8,43.5,44.3, 47.5,59.1,65.7,67.0,109.9,110.0,122.7,126.0,127.1,127.3,
127.4,127.5,127.6,127.9,128.7, 128.8,134.5,135.1,156.0,172.4,176.5,196.3；HRMS
(ESI-TOF)m/z:Calcd.for C40H35Cl2N3NaO3[M+Na]+:698.1953；Found:698.1954.
The present embodiment prepare compound 3le：Yellow solid；Fusing point：148.3-150.5℃；Yield：84%, 14:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:0.73-0.77(m,3H),1.20-
1.24(m, 3H),1.63-1.65(m,6H),2.02-2.15(m,2H),2.21-2.32(m,2H),2.44-2.51(m,1H),
2.70-2.74(m, 1H),3.27-3.32(m,1H),3.51-3.60(m,2H),3.81-3.87(m,1H),4.46-4.52(m,
1H), 4.59 (d, J=7.6 Hz, 1H), 5.80 (s, 1H), 6.23 (s, 1H), 6.50-6.53 (m, 2H), 7.01-7.03 (m,
1H), 7.23-7.25 (m, 1H), 7.67 (d, J=1.6Hz, 1H)；13C NMR(CDCl3,100MHz)δ:12.1,12.4,
20.5,27.4,30.9,31.7,34.7,34.8, 47.4,58.4,65.6,67.1,108.3,108.6,122.8,126.1,
126.9,127.4,127.5,128.9,129.1,141.1,141.4, 155.9,171.6,175.9,196.3；HRMS(ESI-
TOF)m/z:Calcd.for C30H31Cl2N3NaO3[M+Na]+: 574.1640；Found:574.1638.
Embodiments of the invention 2：89.2mg N-methyl-isatins 1a (0.4mmol) is sequentially added in reaction tube,
144.6mg dienone 3- alkenyl Oxoindole 2a (0.6mmol), Thioproline (0.8mmol) and 10mL ethanol solutions, backflow
5h is reacted, TLC detections fundamental reaction is complete, and direct loading is through column chromatography (eluant, eluent：V (petroleum ether)：V (ethyl acetate)=3:
1) compound 4aa, yellow solid, fusing point are purified to obtain：198.2-200.1 DEG C,>20:1dr；Yield 72%.Nuclear magnetic resonance and height
The results such as Resolution Mass Spectrometry test are as follows：1H NMR(CDCl3,400MHz)δ:1.56(s,3H),1.58(s,3H),2.89(s,3H),
2.94 (s, 3H), 2.95-2.98 (m, 1H), 3.35-3.39 (m, 1H), 3.63 (d, J=6.4Hz, 1H), 3.84 (d, J=
7.2Hz, 1H), 3.91 (d, J=7.2Hz, 1H), 5.26-5.31 (m, 1H), 5.52 (s, 1H), 6.61 (d, J=6.4Hz,
1H), 6.67 (d, J=6.0Hz, 1H), 7.01-7.04 (m, 1H), 7.09-7.13 (m, 1H), 7.19-7.22 (m, 1H),
7.30-7.33(m,1H), 7.62-7.64(m,1H),7.73-7.74(m,1H)；13C NMR(CDCl3,100MHz)δ:20.3,
26.2,26.4,27.1,36.1, 50.4,62.0,65.9,67.6,76.4,107.3,107.8,121.5,122.0,122.9,
123.2,124.7,128.5,128.7,129.0, 130.0,142.4,143.5,156.1,173.8,174.2；HRMS(ESI-
TOF)m/z:Calcd.for C27H27N3NaO3S [M+Na]+:496.1671；Found:496.1673.
For compound 4da to 4nh preparation method with compound 4aa, rate of charge is identical with compound 4aa, can obtain chemical combination
Thing 4da to 4nh, reaction yield and cis-selectivity are shown in Tables 1 and 2, but it is emphasized that the compound of the present invention is not limited to
Content represented by table 2.
Table 2 is the chemical constitution that a kind of turmerone splices the double loop coil Oxoindole compounds of 3,3'- pyrroles
The present embodiment prepare compound 4da：Yellow solid；Fusing point：174.4-176.8℃；Yield：87%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.54(s,3H),1.61(s,
3H), 2.42 (s, 3H), 2.90-2.93 (m, 1H), 2.94 (s, 3H), 3.30-3.34 (m, 1H), 3.62 (d, J=6.0Hz,
1H), 3.80 (d, J=7.2Hz, 1H), 3.84 (d, J=6.0Hz, 1H), 5.26-5.30 (m, 1H), 5.48 (s, 1H), 6.61
(d, J=6.0Hz, 1H), 6.96-7.03 (m, 3H), 7.18-7.21 (m, 1H), 7.55-7.56 (m, 2H)；13C NMR
(CDCl3,100MHz)δ:19.3, 20.4,26.5,27.2,29.6,35.7,49.4,61.5,66.4,67.6,75.4,
107.2,119.1,121.4,121.9,123.0,126.3, 128.4,128.9,133.9,141.4,142.6,156.0,
174.7,195.1；HRMS(ESI-TOF)m/z:Calcd.for C28H29N3NaO3S[M+Na]+:510.1827；Found:
510.1829.
The present embodiment prepare compound 4ea：Yellow solid；Fusing point：196.8-198.7℃；Yield：71%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.55(s,3H),1.59(s,
3H), 2.90-2.94 (m, 1H), 2.96 (s, 3H), 3.23 (s, 3H), 3.32-3.35 (m, 1H), 3.57 (d, J=6.4Hz,
1H), 3.77 (d, J=7.2Hz, 1H), 3.87 (d, J=6.4Hz, 1H), 5.23-5.27 (m, 1H), 5.48 (s, 1H), 6.64
(d, J=6.4Hz, 1H), 6.99-7.04 (m, 2H), 7.20-7.24 (m, 2H), 7.55-7.57 (m, 1H), 7.62-7.64 (m,
1H)；13C NMR(CDCl3, 100MHz)δ:20.4,26.5,27.1,29.6,35.8,49.6,61.6,66.4,67.6,75.6,
107.4,115.1,122.0,122.2, 122.8,128.4,129.2,132.3,139.4,142.4,156.4,174.1,
174.2,194.6；HRMS(ESI-TOF)m/z: Calcd.for C27H26ClN3NaO3S[M+Na]+:530.1281；Found:
530.1280.
The present embodiment prepare compound 4fa：Yellow solid；Fusing point：182.3-184.5℃；Yield：74%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,500MHz)δ:1.57-1.58(m,6H),2.88
(s, 3H), 2.88-2.95 (m, 1H), 2.97 (s, 3H), 3.35-3.38 (m, 1H), 3.59 (d, J=8.5Hz, 1H), 3.77
(d, J=9.0 Hz, 1H), 3.91 (d, J=8.5Hz, 1H), 5.24-5.28 (m, 1H), 5.52 (s, 1H), 6.58-6.64 (m,
2H), 7.01-7.05 (m, 2H), 7.20-7.23 (m, 1H), 7.54-7.56 (m, 1H), 7.62 (d, J=7.5Hz, 1H)；13C
NMR(CDCl3,125 MHz)δ:20.3,26.4,26.5,27.1,36.1,50.4,62.0,65.8,67.6,76.4,107.4,
108.0,116.1(d,JCF=23.8 Hz), 117.1 (d, JCF=26.3Hz), 122.0,122.7,124.4,128.5,
129.1,139.4,142.4,156.4,158.2(d,JCF=240.0Hz), 173.6,173.9,194.5；HRMS(ESI-TOF)
m/z:Calcd.for C27H26FN3NaO3S[M+Na]+: 514.1577；Found:514.1580.
The present embodiment prepare compound 4ma：Yellow solid；Fusing point：198.3-199.7℃；Yield：79%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.55(s,3H),1.60(s,
3H), 2.40(s,3H),2.85(s,3H),2.94(s,3H),2.95-2.97(m,1H),3.33-3.37(m,1H),3.63(d,
J=6.4Hz, 1H), 3.82 (d, J=7.2Hz, 1H), 3.87 (d, J=6.4Hz, 1H), 5.27-5.31 (m, 1H), 5.52 (s,
1H), 6.55 (d, J=6.0Hz, 1H), 6.60 (d, J=6.4Hz, 1H), 6.98-7.02 (m, 1H), 7.08-7.10 (m, 1H),
7.17-7.21(m,1H), 7.58-7.60(m,1H)；13C NMR(CDCl3,100MHz)δ:20.3,21.2,26.1,26.4,
27.1,35.9,50.0,61.7, 66.0,67.6,76.3,107.2,107.4,121.9,122.9,123.1,128.4,
128.9,129.3,130.1,130.9,141.2,142.5, 156.0,173.7,174.5,195.0；HRMS(ESI-TOF)m/
z:Calcd.for C28H29N3NaO3S[M+Na]+: 510.1827；Found:510.1827.
The present embodiment prepare compound 4ag：Yellow solid；Fusing point：211.3-211.8℃；Yield：70%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.48(s,3H),1.49(s,
3H),2.27 (s,3H),2.83(s,3H),2.84(s,3H),2.87-2.91(m,1H),3.29-3.33(m,1H),3.57(d,
J=7.2Hz, 1H), 3.74 (d, J=7.2Hz, 1H), 3.86 (d, J=6.4Hz, 1H), 5.19-5.23 (m, 1H), 5.44 (s,
1H), 6.43 (d, J=6.4 Hz, 1H), 6.61 (d, J=6.4Hz, 1H), 6.92 (d, J=6.4Hz, 1H), 7.02-7.05 (m,
1H), 7.23-7.26 (m, 1H), 7.38 (s, 1H), 7.67 (d, J=6.0Hz, 1H)；13C NMR(CDCl3,100MHz)δ:
20.2,21.2,26.2,26.5,27.1, 36.2,50.7,62.1,65.8,67.6,76.5,107.0,107.8,121.4,
122.9,123.2,128.9,129.0,129.3,129.9, 131.3,140.1,143.4,155.7,173.8,174.0,
195.0；HRMS(ESI-TOF)m/z:Calcd.for C28H29N3NaO3S[M+Na]+:510.1827；Found:510.1827.
The present embodiment prepare compound 4mh：Yellow solid；Fusing point：203.8-205.4℃；Yield：93%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.52(s,3H),1.61(s,
3H), 2.33(s,3H),2.82(s,3H),2.87(s,3H),2.88-2.91(m,1H),3.27-3.30(m,1H),3.55(d,
J=6.4Hz, 1H), 3.74 (d, J=6.8Hz, 1H), 3.80 (d, J=6.4Hz, 1H), 5.14-5.19 (m, 1H), 5.47 (s,
1H),6.46-6.50 (m,2H),7.03-7.05(m,1H),7.09-7.11(m,1H),7.42(s,1H),7.53(s,1H)；13C
NMR(CDCl3,100 MHz)δ:20.5,21.2,26.2,26.5,27.2,35.9,50.0,61.7,65.8,67.5,76.0,
107.5,108.1,122.7,127.4, 128.6,128.8,129.3,130.3,131.0,141.1,141.2,156.7,
173.3,174.0,194.5；HRMS(ESI-TOF)m/z: Calcd.for C28H28ClN3NaO3S[M+Na]+:544.1438；
Found:544.1435.
The present embodiment prepare compound 4ng：Yellow solid；Fusing point：214.2-215.6℃；Yield：72%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.49(s,3H),2.27(s,
3H), 2.82 (s, 3H), 2.87 (s, 3H), 2.88-2.91 (m, 1H), 3.29-3.32 (m, 1H), 3.50 (d, J=7.2Hz,
1H), 3.68 (d, J=7.2Hz, 1H), 3.85 (d, J=7.2Hz, 1H), 5.15-5.20 (m, 1H), 5.45 (s, 1H), 6.44
(d, J=6.0Hz, 1H), 6.53 (d, J=7.2Hz, 1H), 6.93-6.94 (m, 1H), 7.20-7.23 (m, 1H), 7.36 (s,
1H),7.70(s,1H)；13C NMR(CDCl3,100MHz)δ:20.3,21.2,26.3,26.5,27.1,36.3,50.9,62.0,
65.7,67.7,76.4,107.1, 108.5,122.8,124.4,129.1,129.4,129.5,129.8,131.4,140.1,
141.9,156.0,173.5,173.7,194.7； HRMS(ESI-TOF)m/z:Calcd.for C28H28ClN3NaO3S[M+Na
]+:544.1438；Found:544.1439.
The present embodiment prepare compound 4nh:Yellow solid；Fusing point：189.7-190.8℃；Yield：90%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.54(s,3H),1.59(s,
3H), 2.85 (s, 3H), 2.88-2.91 (m, 4H), 3.29-3.32 (m, 1H), 3.49 (d, J=7.2Hz, 1H), 3.70 (d, J
=7.2Hz, 1H), 3.84 (d, J=7.2Hz, 1H), 5.10-5.15 (m, 1H), 5.49 (s, 1H), 6.49 (d, J=6.4Hz,
1H), 6.55 (d, J=6.8 Hz, 1H), 7.12-7.14 (m, 1H), 7.22-7.24 (m, 1H), 7.56 (s, 1H), 7.66 (s,
1H)；13C NMR(CDCl3,100 MHz)δ:20.5,26.4,26.6,27.2,36.3,50.7,62.0,65.5,67.5,76.1,
108.2,108.7,122.6,124.4,127.2, 128.8,129.1,129.3,130.0,141.0,141.9,157.0,
173.0,173.4,194.0；HRMS(ESI-TOF)m/z: Calcd.for C27H25Cl2N3NaO3S[M+Na]+:564.0891；
Found:564.0890.
Embodiments of the invention 3：89.2mg N-methyl-isatins 1a (0.4mmol) is sequentially added in reaction tube,
144.6mg dienone 3- alkenyl Oxoindole 2a (0.6mmol), methyl amimoacetic acid (0.8mmol) and 10mL ethanol solutions, back flow reaction
5h, TLC detection fundamental reaction are complete, and direct loading is through column chromatography (eluant, eluent：V (petroleum ether)：V (ethyl acetate)=3:1)
Purify to obtain compound 5aa, yellow solid；Fusing point：201.1-202.9℃；Yield：82%,>20:1dr.Nuclear magnetic resonance and high score
Distinguish that the results such as mass spectrometric measurement are as follows：1H NMR(CDCl3,400MHz)δ:1.49(s,3H),1.80(s,3H),2.19(s,3H),
2.84(s,3H),2.98(s,3H),3.38-3.42(m,1H),4.01-4.05(m,1H),4.51-4.54(m,1H),5.39(s,
1H), 6.55 (d, J=6.4Hz, 2H), 6.87-6.91 (m, 1H), 7.01-7.04 (m, 1H), 7.11-7.14 (m, 1H),
7.21-7.24 (m, 1H), 7.28-7.31 (m, 1H), 7.47 (d, J=6.4Hz, 1H)；13C NMR(CDCl3,100MHz)δ:
20.5,25.3,26.3, 27.1,35.3,52.9,55.8,61.8,78.6,107.1,107.5,121.7,122.1,123.9,
124.8,126.2,127.8,128.6, 129.5,143.2,144.1,155.3,173.8,176.9,195.6；HRMS(ESI-
TOF)m/z:Calcd.for C26H27N3NaO3 [M+Na]+:452.1950；Found:452.1953.
For compound 5ba to 5oc preparation method with compound 5aa, rate of charge is identical with compound 5aa, can obtain chemical combination
Thing 5ba to 5oc, reaction yield and cis-selectivity are shown in Table 3, but it is emphasized that the compound of the present invention is not limited to the institute of table 3
The content of expression.
Table 3 is the chemical constitution that a kind of turmerone splices the double loop coil Oxoindole compounds of 3,3'- pyrroles
The present embodiment prepare compound 5ba:Yellow solid；Fusing point：203.7-204.9℃；Yield：87%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.48(s,3H),1.81(s,
3H), 2.23 (s, 3H), 2.99 (s, 3H), 3.40-3.44 (m, 1H), 4.06-4.10 (m, 1H), 4.36 (d, J=12.8Hz,
1H), 4.53-4.57 (m, 1H), 4.84 (d, J=12.4Hz, 1H), 5.38 (s, 1H), 6.38 (d, J=6.0Hz, 1H), 6.61
(d, J=6.4Hz, 1H), 6.74 (d, J=5.2Hz, 2H), 6.84-6.87 (m, 1H), 6.98-7.01 (m, 1H), 7.07-
7.20(m,5H),7.33-7.35(m, 1H),7.51-7.53(m,1H)；13C NMR(CDCl3,100MHz)δ:20.5,26.3,
27.1,35.3,42.9,53.0,55.9, 61.8,78.4,107.2,108.7,122.2,123.8,126.7,127.1,
128.3,128.4,128.6,143.4,155.3,173.7, 177.1,195.7；HRMS(ESI-TOF)m/z:Calcd.for
C32H31N3NaO3[M+Na]+:528.2263；Found: 528.2265.
The present embodiment prepare compound 5ca:Yellow solid；Fusing point：191.4-193.2℃；Yield：72%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.49(s,3H),1.86(s,
3H),2.36 (s,3H),3.00(s,3H),3.46-3.50(m,1H),4.03-4.06(m,1H),4.57-4.61(m,1H),
5.41 (s, 1H), 6.41 (d, J=6.0Hz, 1H), 6.59 (d, J=6.4Hz, 1H), 6.83-6.89 (m, 3H), 7.02-7.05
(m,1H),7.09-7.13(m, 1H),7.15-7.21(m,2H),7.28-7.33(m,1H),7.36-7.39(m,2H),7.53-
7.54(m,1H)；13C NMR (CDCl3,100MHz)δ:20.6,26.3,27.2,35.3,53.4,55.4,62.3,78.8,
107.3,108.7,124.0,126.3, 126.7,128.0,128.7,129.3,129.5,143.5,144.4,155.3,
173.4,177.5,195.6；HRMS(ESI-TOF)m/z: Calcd.for C31H29N3NaO3[M+Na]+:514.2107；
Found:514.2109.
The present embodiment prepare compound 5da:Yellow solid；Fusing point：145.1-147.8℃；Yield：86%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.49(s,3H),1.82(s,
3H),2.19 (s,3H),2.34(s,3H),2.97(s,3H),3.09(s,3H),3.37-3.42(m,1H),3.98-4.03(m,
1H), 4.49-4.54 (m, 1H), 5.37 (s, 1H), 6.56 (d, J=8.0Hz, 1H), 6.86-6.94 (m, 3H), 7.12-7.15
(m,1H),7.25-7.32 (m,2H)；13C NMR(CDCl3,100MHz)δ:19.0,20.5,26.3,27.1,28.7,35.3,
52.9,55.6,62.0,77.9, 107.1,118.8,121.6,121.8,123.9,124.0,127.7,128.5,133.3,
141.8,143.2,155.2,174.5,177.0, 195.7；HRMS(ESI-TOF)m/z:Calcd.for C27H29N3NaO3[M+
Na]+:466.2107；Found:466.2105.
The present embodiment prepare compound 5ea:Yellow solid；Fusing point：181.3-183.7℃；Yield：83%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.49(s,3H),1.82(s,
3H),2.19 (s,3H),2.98(s,3H),3.19(s,3H),3.38-3.42(m,1H),3.97-4.02(m,1H),4.49-
4.53 (m, 1H), 5.35 (s, 1H), 6.59 (d, J=7.6Hz, 1H), 6.88-6.95 (m, 2H), 7.13-7.18 (m, 2H),
7.23 (d, J=7.6Hz, 1H), 7.38 (d, J=7.6Hz, 1H)；13C NMR(CDCl3,100MHz)δ:20.6,26.3,
27.2,28.7,35.2,53.0,55.6, 62.1,78.1,107.3,114.8,121.9,122.7,123.8,124.8,
128.8,131.9,139.9,143.1,155.6,174.1, 176.8,195.4；HRMS(ESI-TOF)m/z:Calcd.for
C26H26ClN3NaO3[M+Na]+:486.1560；Found: 486.1560.
The present embodiment prepare compound 5fa:Yellow solid；Fusing point：187.7-189.3℃；Yield：71%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,500MHz)δ:1.50(s,3H),1.81(s,
3H),2.20 (s,3H),2.84(s,3H),3.02(s,3H),3.36-3.40(m,1H),3.98-4.01(m,1H),4.49-
4.53 (m, 1H), 5.38 (s, 1H), 6.47-6.49 (m, 1H), 6.58 (d, J=7.5Hz, 1H), 6.88-6.95 (m, 2H),
7.13-7.16(m,1H), 7.27-7.30(m,2H)；13C NMR(CDCl3,125MHz)δ:20.6,25.5,26.4,27.2,
35.3,52.9,55.8,61.8, 78.6,107.3,107.9,108.0,114.4(d,JCF=26.3Hz), 115.8 (d, JCF=
23.8Hz),121.9,123.8,124.5, 125.9,127.9,128.9,140.1,143.2,155.6,158.8(d,JCF=
238.8Hz),173.6,176.7,195.4；HRMS (ESI-TOF)m/z:Calcd.for C26H26FN3NaO3[M+Na]+:
470.1856；Found:470.1859.
The present embodiment prepare compound 5ga:Yellow solid；Fusing point：203.3-205.8℃；Yield：81%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.48(s,3H),1.64(s,
3H), 2.07-2.11(m,2H),2.23-2.29(m,2H),2.48-2.53(m,1H),2.72-2.75(m,1H),2.93(s,
3H), 3.18 (s, 3H), 4.58-4.63 (m, 2H), 5.77 (s, 1H), 6.49-6.51 (m, 2H), 6.62 (d, J=6.4Hz,
1H), 7.16-7.21 (m, 2H), 7.27-7.31 (m, 1H), 7.76 (d, J=6.0Hz, 1H)；13C NMR(CDCl3,100MHz)
δ:20.0,26.1,26.2, 27.1,30.8,31.3,47.3,58.9,65.2,67.2,107.7,108.7,114.3,122.4,
122.9,127.2,128.8,129.2, 131.9,142.7,143.2,154.6,172.6,176.5,196.6；HRMS(ESI-
TOF)m/z:Calcd.for C26H26BrN3NaO3[M+Na]+:530.1055；Found:530.1057.
The present embodiment prepare compound 5ia:Yellow solid；Fusing point：174.7-175.9℃；Yield：71%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.50(s,3H),1.81(s,
3H), 2.24 (s, 3H), 3.04 (s, 3H), 3.39-3.44 (m, 1H), 4.04-4.08 (m, 1H), 4.36 (d, J=16.0Hz,
1H), 4.50-4.55 (m, 1H), 4.82 (d, J=16.0Hz, 1H), 5.38 (s, 1H), 6.30 (d, J=8.4Hz, 1H), 6.64
(d, J=8.0Hz, 1H), 6.71 (d, J=6.4Hz, 2H), 6.85-6.89 (m, 1H), 7.05-7.07 (m, 1H), 7.11-
7.22 (m, 4H), 7.31 (d, J=7.2 Hz, 1H), 7.53 (s, 1H)；13C NMR(CDCl3,100MHz)δ:20.6,26.4,
27.1,35.3,43.1,53.0,55.8,61.8, 78.3,107.3,109.6,122.2,123.8,126.7,126.9,
127.3,128.6,128.8,129.4,141.8,143.4,155.7, 173.2,176.8,195.4；HRMS(ESI-TOF)m/
z:Calcd.for C32H30ClN3NaO3[M+Na]+:562.1873； Found:562.1875.
The present embodiment prepare compound 5ja:Yellow solid；Fusing point：151.3-153.9℃；Yield：88%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.50(s,3H),1.82(s,
3H), 2.24 (s, 3H), 3.04 (s, 3H), 3.40-3.43 (m, 1H), 4.03-4.07 (m, 1H), 4.36 (d, J=12.8Hz,
1H), 4.50-4.54 (m, 1H), 4.81 (d, J=12.8Hz, 1H), 5.38 (s, 1H), 6.24 (d, J=6.8Hz, 1H), 6.64
(d, J=6.4Hz, 1H), 6.71 (d, J=5.6Hz, 2H), 6.85-6.88 (m, 1H), 7.12-7.22 (m, 5H), 7.28-
7.31(m,1H),7.66(s,1H)；13C NMR(CDCl3,100MHz)δ:20.6,26.4,27.2,35.4,43.1,53.1,
55.7,61.9,78.4,107.4,110.2, 115.2,122.3,123.9,124.7,126.4,126.7,127.4,128.3,
128.6,128.8,129.6,132.4,134.9,142.4, 143.4,155.7,173.1,176.9,195.4；HRMS(ESI-
TOF)m/z:Calcd.for C32H30BrN3NaO3[M+Na]+: 606.1368；Found:606.1369.
The present embodiment prepare compound 5ma:Yellow solid；Fusing point：188.2-189.6℃；Yield：89%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.50(s,3H),1.81(s,
3H), 2.19(s,3H),2.34(s,3H),2.82(s,3H),2.98(s,3H),3.37-3.41(m,1H),4.01-4.04(m,
1H), 4.49-4.53 (m, 1H), 5.40 (s, 1H), 6.43 (d, J=6.4Hz, 1H), 6.55 (d, J=6.0Hz, 1H), 6.86-
6.90(m, 1H),7.01-7.02(m,1H),7.11-7.14(m,1H),7.28-7.30(m,2H)；13C NMR(CDCl3,
100MHz)δ: 20.5,21.0,25.3,26.2,27.1,35.3,52.9,55.6,61.8,78.6,107.1,107.2,
121.7,123.9,126.8,127.8, 128.5,129.7,131.5,141.6,143.1,155.2,173.6,177.0,
195.6；HRMS(ESI-TOF)m/z:Calcd.for C27H29N3NaO3[M+Na]+:466.2107；Found:466.2108.
The present embodiment prepare compound 5na:Yellow solid；Fusing point：170.2-171.7℃；Yield：93%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:0.83-0.86(m,3H),1.49
(s, 3H),1.83(s,3H),2.19(s,3H),2.98(s,3H),3.23-3.30(m,1H),3.38-3.42(m,1H),
3.54-3.61(m, 1H),4.01-4.05(m,1H),4.52-4.55(m,1H),5.38(s,1H),6.55-6.58(m,2H),
6.86-6.89(m,1H), 6.99-7.03(m,1H),7.11-7.14(m,1H),7.19-7.23(m,1H),7.29-7.30(m,
1H),7.48-7.50(m,1H)；13C NMR(CDCl3,100MHz)δ:12.2,20.5,26.2,27.1,33.7,35.2,53.0,
55.6,61.8,78.2,107.1, 107.5,121.7,121.8,123.9,124.7,126.4,127.9,128.5,129.4,
143.1,143.2,155.2,173.3,177.2, 195.7；HRMS(ESI-TOF)m/z:Calcd.for C27H29N3NaO3[M+
Na]+:466.2107；Found:466.2107.
The present embodiment prepare compound 5oa:Yellow solid；Fusing point：181.1-182.5℃；Yield：77%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,500MHz)δ:1.49(s,3H),1.75(s,
3H),2.21 (s,3H),2.98(s,3H),3.37-3.41(m,1H),4.05-4.09(m,1H),4.49-4.53(m,1H),
4.67 (d, J=15.5 Hz, 1H), 4.80 (d, J=15.5Hz, 1H), 5.37 (s, 1H), 6.62 (d, J=8.0Hz, 1H),
6.85-6.99 (m, 5H), 7.13-7.20 (m, 4H), 7.33 (d, J=7.5Hz, 2H)；13C NMR(CDCl3,125MHz)δ:
20.5,26.4,27.1,35.3, 44.7,52.7,56.0,61.9,78.4,107.2,117.7(d,JCF=18.8Hz),
122.2,122.6,123.6,124.7,127.1, 128.3(d,JCF=16.3Hz), 128.8,136.8,143.2,146.8 (d,
JCF=242.5Hz), 155.6,173.3,176.5,195.4；HRMS(ESI-TOF)m/z:Calcd.for C32H30FN3NaO3
[M+Na]+:546.2169；Found:546.2172.
The present embodiment prepare compound 5pa:Yellow solid；Fusing point：131.3-132.8℃；Yield：77%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.48(s,3H),1.78(s,
3H),2.02 (s,3H),2.25(s,3H),3.03(s,3H),3.40-3.44(m,1H),4.06-4.10(m,1H),4.51-
4.54 (m, 1H), 4.70 (d, J=13.6Hz, 1H), 5.03 (d, J=13.6Hz, 1H), 5.38 (s, 1H), 6.62-6.66 (m,
3H), 6.79-6.82 (m, 1H), 6.88-6.95 (m, 2H), 7.11-7.19 (m, 4H), 7.27 (d, J=6.0Hz, 1H), 7.43
(d, J=6.0Hz, 1H)；13C NMR (CDCl3,100MHz)δ:18.6,20.5,26.3,27.1,35.3,44.2,52.9,
55.9,61.9,77.6,107.1,118.9,122.1, 122.2,123.8,124.5,125.3,126.6,128.4,128.5,
128.6,133.6,137.4,155.2,174.5,177.2,195.7； HRMS(ESI-TOF)m/z:Calcd.for
C33H33N3NaO3[M+Na]+:542.2420；Found:542.2423.
The present embodiment prepare compound 5ai:Yellow solid；Fusing point：138.0-139.8℃；Yield：87%, 19:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:0.81-0.83(m,3H),1.38(s,
3H), 1.74(s,3H),2.14(s,3H),2.16(s,3H),2.74(s,3H),3.27-3.34(m,2H),3.61-3.66(m,
1H), 3.91-3.95 (m, 1H), 4.45-4.49 (m, 1H), 5.27 (s, 1H), 6.37 (d, J=6.4Hz, 1H), 6.45 (d, J
=6.4Hz, 1H), 6.83 (d, J=6.4Hz, 1H), 6.91-6.95 (m, 1H), 7.04 (s, 1H), 7.11-7.14 (m, 1H),
7.41-7.43(m, 1H)；13C NMR(CDCl3,100MHz)δ:12.2,20.5,20.9,25.1,27.1,34.5,35.4,
53.2,55.9,61.7,78.7, 106.9,107.3,122.1,134.0,125.2,126.6,128.6,128.8,129.4,
130.8,140.0,144.2,154.8,174.1, 176.6,195.9；HRMS(ESI-TOF)m/z:Calcd.for
C28H31N3NaO3[M+Na]+:480.2263；Found: 480.2265.
The present embodiment prepare compound 5aj:Yellow solid；Fusing point：214.5-215.1℃；Yield：75%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.47(s,3H),1.71(s,
3H),2.11 (s,3H),2.30(s,3H),2.77(s,3H),3.18(s,3H),3.28-3.32(m,1H),3.96-3.99(m,
1H), 4.41-4.44 (m, 1H), 5.36 (s, 1H), 6.52 (d, J=6.4Hz, 1H), 6.69-6.72 (m, 1H), 6.78 (d, J
=5.6Hz, 1H), 6.96-6.99 (m, 1H), 7.11 (d, J=5.6Hz, 1H), 7.16-7.21 (m, 1H), 7.38-7.40 (m,
1H)；13C NMR (CDCl3,100MHz)δ:19.1,20.5,25.5,27.2,29.8,35.4,52.7,56.1,61.4,78.8,
107.6,118.3,121.5, 122.0,123.9,125.9,126.3,129.4,132.4,140.9,144.0,155.0,
173.7,177.4,195.7；HRMS (ESI-TOF)m/z:Calcd.for C27H29N3NaO3[M+Na]+:466.2107；
Found:466.2109.
The present embodiment prepare compound 5dh:Yellow solid；Fusing point：185.8-187.2℃；Yield：93%, 12:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.47(s,3H),1.82(s,3H),
2.11 (s,3H),2.29(s,3H),2.89(s,3H),3.07(s,3H),3.32-3.36(m,1H),3.87-3.91(m,1H),
4.40-4.43 (m, 1H), 5.35 (s, 1H), 6.41 (d, J=7.2Hz, 1H), 6.81-6.84 (m, 1H), 6.87 (d, J=
6.4Hz,1H), 7.04-7.06(m,1H),7.20-7.22(m,2H)；13C NMR(CDCl3,100MHz)δ:19.0,20.6,
26.4,27.2,28.8, 35.2,52.9,55.6,61.9,77.8,108.0,119.0,122.0,123.8,124.0,127.1,
128.0,128.5,133.5,141.8, 142.0,156.0,174.4,176.7,195.3；HRMS(ESI-TOF)m/z:
Calcd.for C27H28ClN3NaO3[M+Na]+: 500.1717；Found:500.1719.
The present embodiment prepare compound 5nb:Yellow solid；Fusing point：200.2-201.8℃；Yield：79%, 20:1dr；Core
The result such as magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.34(s,3H),1.72(s,3H),
2.12 (s, 3H), 2.16 (s, 3H), 2.75 (s, 3H), 3.32-3.35 (m, 1H), 3.95-3.99 (m, 1H), 4.41 (d, J=
12.0Hz, 1H), 4.45-4.49 (m, 1H), 4.95 (d, J=12.4Hz, 1H), 5.24 (d, J=14.0Hz, 1H), 6.24 (d,
J=6.4Hz, 1H), 6.43 (d, J=6.4Hz, 1H), 6.72 (d, J=6.4Hz, 1H), 6.80 (d, J=2.8Hz, 2H),
7.03(s,1H),7.11-7.13 (m,3H),7.15-7.17(m,1H),7.49(s,1H)；13C NMR(CDCl3,100MHz)δ:
20.5,21.0,25.4,27.1, 35.4,43.8,53.2,56.5,61.8,78.5,108.1,108.4,123.8,126.3,
126.8,127.4,128.1,128.5,128.6, 129.0,129.4,131.4,135.5,140.3,155.3,173.7,
177.0,195.5；HRMS(ESI-TOF)m/z:Calcd.for C33H32ClN3NaO3[M+Na]+:576.2030；Found:
576.2032.
The present embodiment prepare compound 5oc:Yellow solid；Fusing point：195.3-196.9℃；Yield：75%,>20:1dr；
The result such as nuclear magnetic resonance and high resolution mass spectrum test is as follows：1H NMR(CDCl3,400MHz)δ:1.47(s,3H),1.84(s,
3H), 2.15 (s, 3H), 2.95 (s, 3H), 3.34-3.37 (m, 1H), 3.91-3.94 (m, 1H), 4.29 (d, J=12.4Hz,
1H), 4.41-4.45 (m, 1H), 4.83 (d, J=12.8Hz, 1H), 5.34 (s, 1H), 6.26-6.29 (m, 1H), 6.45 (d, J
=6.4Hz, 1H), 6.72-6.76 (m, 3H), 7.11-7.13 (m, 3H), 7.20-7.22 (m, 1H), 7.26-7.28 (m, 1H),
7.41(s,1H)；13C NMR(CDCl3,100MHz)δ:20.8,26.5,27.3,35.3,43.3,53.0,55.9,61.6,
78.3,108.8,109.3,109.4, 114.5,114.7,115.1,116.0,116.2,123.6,126.8,126.9,
127.5,128.7,131.4,131.7,135.1,142.6, 156.6,158.0,159.9,173.2,176.5,195.0；HRMS
(ESI-TOF)m/z:Calcd.for C32H29BrFN3NaO3 [M+Na]+:624.1274；Found:624.1275.
Formula (1) compound of the present invention has important bioactivity, in vitro to human leukemia cell (K562) cell
Toxicity test shows：The double loop coil Oxoindole compounds of turmerone splicing 3,3'- pyrroles of structure shown in such formula (1) are to swollen
Tumor cell growth is inhibited, it is possible to develops into new preventing and treating tumour medicine.But the it is emphasized that change of the present invention
Compound is not limited to the cytotoxicity of human leukemia cell (K562) expression.
Pharmacological Examples：Compound 3le, 3fa, 3la, 3ia, 3fd, 4da, 5ia, 5ba, 5oa and 5pa are to K562 cells
Cytotoxicity
K562 (people's chronic myelogenous leukemia cell) RPMI-1640 medium cultures, 10% tire ox is contained in culture medium
Serum, 100U/mL penicillin and 100U/mL streptomysins.Cell is added in 96 holes with the concentration of every 5000 cells in hole,
37 DEG C contain 5%CO2Cultivated 24 hours in the incubator of humid air.
The measure of cell survival rate improvement mtt assay.Cell is after the incubation of 24 hours, compound that will newly match somebody with somebody respectively
3le, 3fa, 3la, 3ia, 3fd, 4da, 5ia, 5ba, 5oa and 5pa dimethyl sulphoxide solution are added to each hole with concentration gradient
In, make in hole compound ultimate density be respectively 5 μm of ol/L, 10 μm of ol/L, 20 μm of ol/L, 40 μm of ol/L and 80 μm of ol/L.48
After hour, 10 μ L MTT (5mg/mL) phosphate buffer is added per hole, is further continued for after 37 DEG C are cultivated 4 hours, centrifuges 5 points
Clock removes unconverted MTT, and 150 μ L dimethyl sulfoxide (DMSO)s are added in every hole.With the MTT crystal formazans of dissolving and reducing
(formazan) OD values, are determined in 490nm wavelength with ELIASA.Wherein compound 3le, 3fa, 3la, 3ia, 3fd, 4da, 5ia,
5ba, 5oa and 5pa are to K562 cell 503nhibiting concentrations IC50Obtained by spss softwares (19 version) analysis.3le pairs of compound
The IC of K562 tumour cells50For 43.5 μm of ol/L；ICs of the compound 3fa to K562 tumour cells50For 51.3 μm of ol/L；Chemical combination
ICs of the thing 3la to K562 tumour cells50For 33.8 μm of ol/L；ICs of the compound 3ia to K562 tumour cells50For 78.8 μ
mol/L；ICs of the compound 3fd to K562 tumour cells50For 62.3 μm of ol/L；ICs of the compound 4da to K562 tumour cells50
For 38.5 μm of ol/L；ICs of the compound 5ia to K562 tumour cells50For 49.4 μm of ol/L；Compound 5ba is thin to K562 tumours
The IC of born of the same parents50For 79.0 μm of ol/L；ICs of the compound 5oa to K562 tumour cells50For 22.3 μm of ol/L；5pa pairs of compound
The IC of K562 tumour cells50For 27.6 μm of ol/L；And positive control cis-platinum is to the IC of K562 tumour cells50For 24.7 μm of ol/
L。
Experiment conclusion：K562 cells are that test compound refers to the effective tool of the cytotoxicity of tumour cell and evaluation
Mark.This experiment shows that the turmerone shown in such formula (1) splices the double loop coil Oxoindole compounds of 3,3'- pyrroles to K562 cells
With stronger cytotoxicity, and the same order of magnitude of oncotherapy fiest-tire medication cis-platinum, it is possible to develop into it is new have it is anti-swollen
The medicine of knurl effect.
We can see that these compounds show one to human leukemia cell (K562) from above Pharmacological Examples
Fixed cytotoxicity.It can be seen that these compounds, which have, is developed into the potentiality of antineoplastic, it is worth continuing deeper into research and.
Claims (5)
1. a kind of turmerone skeleton splices the double loop coil Oxoindole compounds of 3,3'- pyrroles, it is characterised in that：The compound has
Structure as shown in formula (I)：
In formula (I), R1For phenyl, ethyl, methyl or benzyl；R2For methyl, H or halogen；R3For methyl, ethyl or benzyl；R4For
Methyl, H or halogen；X is C or S.
A kind of 2. preparation of the double loop coil Oxoindole compounds of turmerone skeleton splicing 3,3'- pyrroles as claimed in claim 1
Method, it is characterised in that：By various substituted isatin, dienone 3- alkenyls Oxoindole and proline or Thioproline or flesh
Propylhomoserin, it is in molar ratio 2:3:6 ratio flows back in organic solvent, carries out 1,3- dipole 3+2 cycloaddition reactions, obtains ginger
The double loop coil Oxoindole compounds of flavones splicing 3,3'- pyrroles；
Synthetic route is as follows：
Reaction mechanism is as follows：
3. turmerone according to claim 2 splices the preparation method of the double loop coil Oxoindole compounds of 3,3'- pyrroles, its
It is characterised by：Described organic solvent is acetonitrile, methanol, ethanol, propyl alcohol, isopropanol, ether, tetrahydrofuran, benzene, toluene, two
Toluene, trimethylbenzene, dioxane, glycol dimethyl ether, isopropyl ether, chloroform, dichloromethane or nitrobenzene.
4. turmerone according to claim 2 splices the preparation method of the double loop coil Oxoindole compounds of 3,3'- pyrroles, its
It is characterised by：Various substituted isatin, dienone 3- alkenyls Oxoindole and proline or Thioproline or methyl amimoacetic acid, are having
Reaction temperature in solvent is 50-100 DEG C, and the reaction time is 5-20 hours.
5. a kind of double loop coil Oxoindole compounds of turmerone splicing 3,3'- pyrroles as claimed in claim 1 are preparing preventing and treating
Application in tumor disease medicine.
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| CN110092793B (en) * | 2019-02-28 | 2022-04-29 | 贵州大学 | Xanthone skeleton and isoxazole spiro oxoindole splicing derivative and preparation method and application thereof |
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