CN116554185A - Chiral spiro oxindole compound and preparation method thereof - Google Patents
Chiral spiro oxindole compound and preparation method thereof Download PDFInfo
- Publication number
- CN116554185A CN116554185A CN202310001621.0A CN202310001621A CN116554185A CN 116554185 A CN116554185 A CN 116554185A CN 202310001621 A CN202310001621 A CN 202310001621A CN 116554185 A CN116554185 A CN 116554185A
- Authority
- CN
- China
- Prior art keywords
- chiral
- oxindole
- compound
- aromatic ring
- ethyl acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- -1 spiro oxindole compound Chemical class 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 125000003118 aryl group Chemical group 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000003287 optical effect Effects 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 216
- 238000006243 chemical reaction Methods 0.000 claims description 74
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 66
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 59
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 48
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 46
- 239000003054 catalyst Substances 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- JWCGDNHAPBZVHD-UHFFFAOYSA-N 1,4-epoxy-1,4-dihydronaphthalene Chemical compound C12=CC=CC=C2C2OC1C=C2 JWCGDNHAPBZVHD-UHFFFAOYSA-N 0.000 claims description 29
- GOPBTCMAUMSOBX-UHFFFAOYSA-M [Rh+].C1CC=CCCC=C1.C1CC=CCCC=C1.[O-]S(=O)(=O)C(F)(F)F Chemical compound [Rh+].C1CC=CCCC=C1.C1CC=CCCC=C1.[O-]S(=O)(=O)C(F)(F)F GOPBTCMAUMSOBX-UHFFFAOYSA-M 0.000 claims description 25
- 125000003003 spiro group Chemical group 0.000 claims description 25
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 24
- 239000008346 aqueous phase Substances 0.000 claims description 24
- 238000004440 column chromatography Methods 0.000 claims description 24
- 239000012074 organic phase Substances 0.000 claims description 24
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 24
- 235000011009 potassium phosphates Nutrition 0.000 claims description 24
- 238000004809 thin layer chromatography Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 15
- 239000003446 ligand Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound 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
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 4
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- PTXVSDKCUJCCLC-UHFFFAOYSA-N 1-hydroxyindole Chemical compound C1=CC=C2N(O)C=CC2=C1 PTXVSDKCUJCCLC-UHFFFAOYSA-N 0.000 claims description 3
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- QVMDWPVVFYBRQY-UHFFFAOYSA-K cycloocta-1,5-diene;rhodium(3+);trifluoromethanesulfonate Chemical compound [Rh+3].C1CC=CCCC=C1.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F QVMDWPVVFYBRQY-UHFFFAOYSA-K 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 7
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 238000006352 cycloaddition reaction Methods 0.000 abstract 1
- 229910052703 rhodium Inorganic materials 0.000 abstract 1
- 239000010948 rhodium Substances 0.000 abstract 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 229910052717 sulfur Inorganic materials 0.000 description 36
- 150000001299 aldehydes Chemical class 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- WHOBZBLBTZHMGY-UHFFFAOYSA-N ditert-butyl(ethyl)phosphane Chemical compound CCP(C(C)(C)C)C(C)(C)C WHOBZBLBTZHMGY-UHFFFAOYSA-N 0.000 description 22
- 239000003480 eluent Substances 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- 239000003208 petroleum Substances 0.000 description 22
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 230000011278 mitosis Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000011217 control strategy Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 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
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000378 teratogenic Toxicity 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a chiral spiro oxindole compound and a diastereoisomeric divergent preparation method thereof, wherein the chiral spiro oxindole compound is an optical active compound with a structure shown in the following formula I, and comprises stereoisomers with the same chemical general formula:wherein: * Represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1‑10 Alkyl or aryl; ar is an aromatic ring or a substituted aromatic ring; ar' is an aromatic ring or a substituted aromatic ring; r is R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Are independently selected from hydrogen, halogen, C 1‑4 A hydrocarbyl group or a hydrocarbyloxy group. The invention applies a chiral rhodium complex and a chiral aza-heterocyclic carbene combined catalytic system to catalyze a class of asymmetric [3+3]]Cycloaddition is a critical step, in high yieldsThe chiral spiro oxindole compound is synthesized with high stereoselectivity and gram scale precision and rapidly. The preparation method is simple, and has biomedical practicability and industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of asymmetric organic synthesis, and particularly relates to a chiral spiro oxindole compound and a diastereoisomeric divergent preparation method thereof.
Background
The spiro oxindole compound widely exists in natural products and drug molecules, has broad-spectrum biological activity, has great significance in drug development due to efficient construction, and is widely paid attention to chemists and pharmacists. In recent years, the highly stereoselective synthesis of chiral spiro oxindoles by asymmetric catalysis has gradually become a focus of research by organic chemists.
Chiral is one of the essential attributes of nature, and a large number of chiral molecules are stored in nature and living bodies, and many biological macromolecules such as proteins, polysaccharides, nucleic acids and the like which are important bases of life activities basically have chirality. Chiral research plays an important role in life science, pharmacy and food science. There are significant differences in pharmacology and toxicity of chiral drugs, such as thalidomide (also known as reaction arrest), which has been widely used as a sedative in europe, and many pregnant women produce abnormal fetuses after taking this drug because only the R-isomer is sedating and the S-isomer is teratogenic. The development of a novel, rapid, efficient and sensitive chiral separation analysis method has very important significance for the stereoselective synthesis of enantiomers, pharmacological research of chiral medicaments, purity analysis of enantiomers, environmental monitoring and healthy life of human beings. Thus, developing new synthetic methodologies to achieve the acquisition of all stereoisomers of fragments with multiple chiral elements is a highly challenging field with significant scientific research value.
The cooperative control strategy of the double catalytic system has proved to be a simple and effective solution. In recent years, chemists develop various types of cooperative control strategies successively, so that three-dimensional divergent synthesis with diversified structure types is realized efficiently, and under unified raw materials, synthesis routes and reaction conditions, collective asymmetric synthesis of multiple diastereomers of the multi-chiral center molecule is realized accurately and controllably, thereby providing important guarantee for synthesis of multiple chiral isomers of important physiologically active natural products and research on pharmacodynamic relations.
The wide application of chiral spiro oxindole compounds has prompted us to find a high-efficiency synthesis method for realizing different isomers of the compounds. However, no diastereoselective synthesis of chiral spiro oxindole derivative compounds has been reported. Therefore, there is an urgent need to develop a general strategy for diastereoselective synthesis of chiral spiro oxindole compounds with high yield and high enantioselectivity, which is realized in a precise and rapid manner, starting from a simple and easily available framework.
Disclosure of Invention
The invention aims to provide a chiral spiro oxindole compound and a diastereoisomeric divergent preparation method thereof, thereby solving the problems in the prior art.
The chiral spiro oxindole compound provided by the invention is an optical active compound with a structure shown in the following formula I, and comprises stereoisomers with the same chemical general formula:
wherein: * Represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1-10 Alkyl or aryl; ar is an aromatic ring or a substituted aromatic ring; ar' is an aromatic ring or a substituted aromatic ring; r is R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Are independently selected from hydrogen, halogen, C 1-4 A hydrocarbyl group or a hydrocarbyloxy group.
The invention relates to a diastereoisomeric divergent preparation method of chiral spiro oxindole compound, which takes oxindole-derived alpha, beta-unsaturated aldehyde 1 and 1, 4-dihydro-1, 4-epoxynaphthalene compound 2 as initial raw materials, rhodium (I) bis (1, 5-cyclooctadiene) -triflate as a metal catalyst, chiral phosphine reagent as a ligand, chiral aza-heterocyclic carbene as an organic catalyst, and the target product I is obtained after the separation and purification through asymmetric [3+3] cyclization reaction under the assistance of alkali.
The synthetic route is as follows:
in the above formula: * Represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1-10 Alkyl or aryl; ar is an aromatic ring or a substituted aromatic ring; ar' is an aromatic ring or a substituted aromatic ring; r is R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Are independently selected from hydrogen, halogen, C 1-4 A hydrocarbyl group or a hydrocarbyloxy group.
The method specifically comprises the following steps:
mixing and pre-stirring a bis (1, 5-cyclooctadiene) -trifluoro rhodium (I) mesylate metal catalyst and chiral phosphine ligand in an organic solvent for 1 hour under the nitrogen atmosphere, then adding the chiral azacyclo-carbene catalyst, alpha, beta-unsaturated aldehyde 1 derived from oxindole, 1, 4-dihydro-1, 4-epoxynaphthalene compound 2, alkali and the organic solvent into the mixed system under the protection of nitrogen, and reacting for 4-72 hours at the temperature of 10-60 ℃, and determining the reaction end point by using a thin-layer chromatography spot plate; the reaction system is then diluted with ethyl acetate and extracted with water, the aqueous phase is then extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and finally the asymmetric spiro oxindole product I is obtained by column chromatography separation.
The preparation process of the invention comprises the following steps:
the alkali is potassium phosphate, potassium hydrogen phosphate, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethyl ethylenediamine or N-methylmorpholine.
The organic solvent is 1, 4-dioxane, dichloromethane, dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, toluene, ethylbenzene, fluorobenzene, chlorobenzene, bromobenzene, xylene or trimethylbenzene.
The chiral phosphine ligand is selected from
Wherein: r is R 7 、R 8 、R 9 、R 10 、R 11 Each independently selected from hydrogen, halogen, or substituted or unsubstituted: c (C) 1-10 Alkyl, C 3-10 Cycloalkyl, 2-furyl or C 6-20 Aryl groups of (a).
The chiral azacyclo-carbene catalyst is selected from the group consisting of:
wherein: r is R 12 、R 13 、R 14 Each independently selected from hydrogen, halogen, or substituted or unsubstituted: c (C) 1-10 Alkyl, C 3-10 Cycloalkyl, 2-furyl or C 6-20 Aryl groups of (a).
In the preparation process of the invention, four configurations of (R, R, R), (R, S, S), (S, R, R) and (S, S, S) of the target product I can be selectively obtained by changing the configurations of the chiral phosphine ligand and the chiral N-heterocyclic carbene.
Wherein:
the molar ratio of the rhodium (1, 5-cyclooctadiene) -triflate (I) to the indole oxide-derived alpha, beta-unsaturated aldehyde 1 is 0.025:1-1:1; the molar ratio of chiral phosphine ligand to oxindole derived alpha, beta-unsaturated aldehyde 1 is 0.025:1-1:1; the molar ratio of the chiral N-heterocyclic carbene catalyst to the oxindole-derived alpha, beta-unsaturated aldehyde 1 is 0.025:1-1:1; the molar equivalent ratio of the oxindole-derived alpha, beta-unsaturated aldehyde 1 to the 1, 4-dihydro-1, 4-epoxynaphthalene compound 2 is 1:1-1:5; the molar ratio of the oxindole-derived alpha, beta-unsaturated aldehyde 1 to the alkali is 1:0.1-1:5.
Further, the molar ratio of rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate to chiral phosphine ligand is 1:1-1:4.
The invention provides a method for synthesizing chiral spiro oxindole through key steps of asymmetric reaction. The invention takes an oxindole-derived alpha, beta-unsaturated aldehyde 1 and a 1, 4-dihydro-1, 4-epoxynaphthalene compound 2 as initial raw materials, takes bis (1, 5-cyclooctadiene) -trifluoro rhodium (I) mesylate as a metal catalyst, takes a chiral phosphine reagent as a ligand and takes a chiral aza-heterocyclic carbene as an organic catalyst, and synthesizes the chiral spiro oxindole compound I accurately and rapidly in high yield, high stereoselectivity and gram scale through asymmetric reaction under the assistance of alkali. The invention successfully develops a synthesis method of chiral spiro oxindole compound, which is easy to prepare chiral spiro oxindole compound with high yield and high optical purity, and the compound also has bioactivity.
Drawings
FIG. 1 is a graph showing the results of assays for the activity of various chiral spiro oxindole compounds on HeLa cells.
FIG. 2 is a graph showing the results of imaging test of the activity of different chiral spiro oxindole compounds on HeLa cells.
Detailed Description
Example 1: preparation of chiral spirooxindole compound (R, R, R) -3aa
To a dry 10mL Schlenk reaction tube at 25deg.C under nitrogen atmosphere were added rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL 1, 4-dioxane, and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1a (18.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, R) -3aa (31.8 mg,96% yieldl, 95:5d.r., >99% e.e.) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.74–7.67(m,1H),7.38(td,J＝7.5,1.7Hz,1H),7.32(td,J＝7.6,1.4Hz,1H),7.28–7.23(m,1H),7.21–7.11(m,2H),7.05(dd,J＝7.4,1.3Hz,1H),6.95(d,J＝7.8Hz,1H),6.42(dd,J＝9.6,3.0Hz,1H),6.31(d,J＝13.9Hz,1H),5.05(dd,J＝9.6,2.1Hz,1H),3.28(s,3H),3.15(dt,J＝14.0,2.5Hz,1H),3.06(d,J＝17.5Hz,1H),2.84(d,J＝17.5Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ177.47,169.13,143.67,133.51,131.73,130.93,130.09,129.56,128.59,128.15,126.50,123.84,123.70,122.87,121.81,108.68,75.50,47.30,44.08,37.36,26.59.HRMS(ESI)m/z(M+H) + :calculated for(C 21 H 18 NO 3 ) + :332.1281,found:332.1288；[α] 20 D ＝-90.3(c＝0.59,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK OD-H,hexane/i-PrOH＝80/20,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝20.73min,t R (major)＝22.66min.
Example 2: preparation of chiral spirooxindole compound (R, S, S) -3aa
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (R) -1- [ (Sp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 1.0mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1a (18.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 1.0mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, S) -3aa (31.8 mg,96% yieldl, 86:14d.r., >99% e.e.) as a white solid.
1 H NMR(500MHz,CDCl 3 )δ7.71(dd,J＝7.6,1.3Hz,1H),7.39(td,J＝7.8,1.2Hz,1H),7.34(td,J＝7.6,1.3Hz,1H),7.31–7.24(m,2H),7.12(td,J＝7.5,1.0Hz,1H),7.05(dd,J＝7.4,1.3Hz,1H),7.01–6.96(m,1H),6.35(dd,J＝9.6,3.0Hz,1H),5.87(d,J＝14.7Hz,1H),5.13(dd,J＝9.7,2.1Hz,1H),3.34(m,1H)3.33(s,3H),3.17(d,J＝17.8Hz,1H),2.71(d,J＝17.8Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ176.64,168.39,143.27,133.27,131.71,130.49,129.51,129.42,128.60,128.32,126.45,125.08,123.48,123.14,122.94,109.07,77.13,48.44,42.91,37.10,26.82.HRMS(ESI)m/z(M+H) + :calculated for(C 21 H 18 NO 3 ) + :332.1281,found:332.1289；[α] 20 D ＝-363.1(c＝0.60,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK OD-H,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝10.61min,t R (major)＝14.13min.
Example 3: preparation of chiral spirooxindole compound (S, R, R) -3aa
To a dry 10mL Schlenk reaction tube at 25deg.C under nitrogen atmosphere were added rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL 1, 4-dioxane, and stirred for 1 hour; subsequently, a chiral azacyclo-carbene catalyst ent-NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1a (18.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system under nitrogen protection, and reacted at 15℃for 10 hours by thin layer chromatography to determine the reaction end point; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (S, R) -3aa (29.8 mg,90% yieldl, 88:12d.r., >99% e.e.) as a white solid.
1 H NMR(500MHz,CDCl 3 )δ7.71(dd,J＝7.6,1.3Hz,1H),7.39(td,J＝7.8,1.2Hz,1H),7.34(td,J＝7.6,1.3Hz,1H),7.31–7.24(m,2H),7.12(td,J＝7.5,1.0Hz,1H),7.05(dd,J＝7.4,1.3Hz,1H),7.01–6.96(m,1H),6.35(dd,J＝9.6,3.0Hz,1H),5.87(d,J＝14.7Hz,1H),5.13(dd,J＝9.7,2.1Hz,1H),3.34(m,1H)3.33(s,3H),3.17(d,J＝17.8Hz,1H),2.71(d,J＝17.8Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ176.64,168.39,143.27,133.27,131.71,130.49,129.51,129.42,128.60,128.32,126.45,125.08,123.48,123.14,122.94,109.07,77.13,48.44,42.91,37.10,26.82.HRMS(ESI)m/z(M+H) + :calculated for(C 21 H 18 NO 3 ) + :332.1281,found:332.1284；[α] 20 D ＝313.6(c＝0.39,CHCl 3 )；The product was analyzedby HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK OD-H,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (major)＝10.46min,t R (minor)＝14.51min.
Example 4: preparation of chiral spirooxindole compound (S, S, S) -3aa
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (R) -1- [ (Sp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen at 25℃and stirred for 1 hour; subsequently, a chiral azacyclo-carbene catalyst ent-NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1a (18.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system under nitrogen protection, and reacted at 15℃for 10 hours by thin layer chromatography to determine the reaction end point; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (S, R) -3aa (31.8 mg,96% yieldl, 95:5d.r., >99% e.e.) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.74–7.67(m,1H),7.38(td,J＝7.5,1.7Hz,1H),7.32(td,J＝7.6,1.4Hz,1H),7.28–7.23(m,1H),7.21–7.11(m,2H),7.05(dd,J＝7.4,1.3Hz,1H),6.95(d,J＝7.8Hz,1H),6.42(dd,J＝9.6,3.0Hz,1H),6.31(d,J＝13.9Hz,1H),5.05(dd,J＝9.6,2.1Hz,1H),3.28(s,3H),3.15(dt,J＝14.0,2.5Hz,1H),3.06(d,J＝17.5Hz,1H),2.84(d,J＝17.5Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ177.47,169.13,143.67,133.51,131.73,130.93,130.09,129.56,128.59,128.15,126.50,123.84,123.70,122.87,121.81,108.68,75.50,47.30,44.08,37.36,26.59.HRMS(ESI)m/z(M+H) + :calculated for(C 21 H 18 NO 3 ) + :332.1281,found:332.1287；[α] 20 D ＝41.6(c＝0.39,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK OD-H,hexane/i-PrOH＝80/20,flow rate:1.0mL/min,T＝30℃,254nm),t R (major)＝20.22min,t R (minor)＝23.09min.
Example 5: preparation of chiral spirooxindole compounds (R, R, R) -3ba
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 1.0mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen atmosphere at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1b (20.5 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 1.0mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, R) -3ba (24.8 mg,71% yield;93:7d.r.,99% e.e.) as a colorless liquid.
1 H NMR(400MHz,CDCl 3 )δ7.70(dtd,J＝8.1,1.3,0.6Hz,1H),7.33(td,J＝7.6,1.4Hz,1H),7.29–7.23(m,1H),7.12(dd,J＝8.2,5.1Hz,1H),7.06(dd,J＝7.4,1.3Hz,1H),6.82(ddd,J＝9.3,8.2,2.3Hz,1H),6.69(dd,J＝8.6,2.3Hz,1H),6.44(dd,J＝9.6,3.0Hz,1H),6.28(d,J＝13.9Hz,1H),5.04(ddd,J＝9.7,2.1,0.6Hz,1H),3.26(s,3H),3.12(ddd,J＝13.9,3.0,2.1Hz,1H),3.06(d,J＝17.5Hz,1H),2.82(d,J＝17.5Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ177.76,168.86,163.77(d,J＝247.4Hz),145.25(d,J＝11.6Hz),133.41,131.65,131.17,128.69,128.22,126.57,125.40(d,J＝3.0Hz),124.14(d,J＝9.9Hz),123.73,121.43,109.99(d,J＝22.7Hz),97.66(d,J＝27.6Hz),75.44,47.05,44.17,37.46,26.75. 19 F NMR(376MHz,CDCl 3 )δ-109.72.HRMS(ESI)m/z(M+H) + :calculated for(C 21 H 17 FNO 3 ) + :350.1187,found:350.1186；[α] 20 D ＝-74.5(c＝0.36,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:99％e.e.(CHIRALPAK IB,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝10.51min,t R (major)＝12.96min.
Example 6: preparation of chiral spirooxindole (R, S, S) -3ba
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (R) -1- [ (Sp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 1.0mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1b (20.5 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 1.0mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, S) -3ba (22.7 mg,65% yieldl, 80:20d.r.,98% e.e.) as a colorless liquid.
1 H NMR(400MHz,CDCl 3 )δ7.70(d,J＝7.6Hz,1H),7.34(td,J＝7.6,1.4Hz,1H),7.31–7.19(m,2H),7.06(dd,J＝7.4,1.4Hz,1H),6.81(ddd,J＝9.2,8.2,2.4Hz,1H),6.73(dd,J＝8.6,2.4Hz,1H),6.38(dd,J＝9.7,3.0Hz,1H),5.82(d,J＝14.7Hz,1H),5.11(dd,J＝9.6,2.1Hz,1H),3.32(m,1H)3.31(s,3H),3.17(d,J＝17.7Hz,1H),2.69(d,J＝17.9Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ177.04,168.12,163.77(d,J＝248.0Hz),144.99(d,J＝11.1Hz),133.14,131.65,130.74,128.74,128.43,126.55,126.27(d,J＝9.7Hz),124.76,123.18,122.64,109.66(d,J＝22.5Hz),98.09(d,J＝27.6Hz),77.15,48.22,43.01,37.23,26.99. 19 F NMR(376MHz,CDCl 3 )δ-109.69.HRMS(ESI)m/z(M+H) + :calculated for(C 21 H 17 FNO 3 ) + :350.1187,found:332.1287；[α] 20 D ＝-243.7(c＝0.21,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:98％e.e.(CHIRALPAK IB,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝11.64min,t R (major)＝15.13min.
Example 7: preparation of chiral spirooxindole (S, R, R) -3ba compounds
To a dry 10mL Schlenk reaction tube at 25deg.C under nitrogen atmosphere were added rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL 1, 4-dioxane, and stirred for 1 hour; subsequently, a chiral azacyclo-carbene catalyst ent-NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1b (20.5 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system under nitrogen protection, and reacted at 15℃for 10 hours by thin layer chromatography to determine the reaction end point; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (S, R) -3ba (22.7 mg,65% yield,85:15d.r., >99% e.e.) as a colorless liquid.
1 H NMR(400MHz,CDCl 3 )δ7.70(d,J＝7.6Hz,1H),7.34(td,J＝7.6,1.4Hz,1H),7.31–7.19(m,2H),7.06(dd,J＝7.4,1.4Hz,1H),6.81(ddd,J＝9.2,8.2,2.4Hz,1H),6.73(dd,J＝8.6,2.4Hz,1H),6.38(dd,J＝9.7,3.0Hz,1H),5.82(d,J＝14.7Hz,1H),5.11(dd,J＝9.6,2.1Hz,1H),3.32(m,1H)3.31(s,3H),3.17(d,J＝17.7Hz,1H),2.69(d,J＝17.9Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ177.04,168.12,163.77(d,J＝248.0Hz),144.99(d,J＝11.1Hz),133.14,131.65,130.74,128.74,128.43,126.55,126.27(d,J＝9.7Hz),124.76,123.18,122.64,109.66(d,J＝22.5Hz),98.09(d,J＝27.6Hz),77.15,48.22,43.01,37.23,26.99. 19 F NMR(376MHz,CDCl 3 )δ-109.69.HRMS(ESI)m/z(M+H) + :calculated for(C 21 H 17 FNO 3 ) + :350.1187,found:332.1285；[α] 20 D ＝285.5(c＝0.24,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IB,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (major)＝10.40min,t R (minor)＝15.44min.
Example 8: preparation of chiral spirooxindole (S, S, S) -3ba
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (R) -1- [ (Sp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen at 25℃and stirred for 1 hour; subsequently, a chiral azacyclo-carbene catalyst ent-NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1b (20.5 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system under nitrogen protection, and reacted at 15℃for 10 hours by thin layer chromatography to determine the reaction end point; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (S, S) -3ba (26.9 mg,77% yield,95:5d.r., >99% e.e.) as a colorless liquid.
1 H NMR(400MHz,CDCl 3 )δ7.70(dtd,J＝8.1,1.3,0.6Hz,1H),7.33(td,J＝7.6,1.4Hz,1H),7.29–7.23(m,1H),7.12(dd,J＝8.2,5.1Hz,1H),7.06(dd,J＝7.4,1.3Hz,1H),6.82(ddd,J＝9.3,8.2,2.3Hz,1H),6.69(dd,J＝8.6,2.3Hz,1H),6.44(dd,J＝9.6,3.0Hz,1H),6.28(d,J＝13.9Hz,1H),5.04(ddd,J＝9.7,2.1,0.6Hz,1H),3.26(s,3H),3.12(ddd,J＝13.9,3.0,2.1Hz,1H),3.06(d,J＝17.5Hz,1H),2.82(d,J＝17.5Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ177.76,168.86,163.77(d,J＝247.4Hz),145.25(d,J＝11.6Hz),133.41,131.65,131.17,128.69,128.22,126.57,125.40(d,J＝3.0Hz),124.14(d,J＝9.9Hz),123.73,121.43,109.99(d,J＝22.7Hz),97.66(d,J＝27.6Hz),75.44,47.05,44.17,37.46,26.75. 19 F NMR(376MHz,CDCl 3 )δ-109.72.HRMS(ESI)m/z(M+H) + :calculated for(C 21 H 17 FNO 3 ) + :350.1187,found:332.1286；[α] 20 D ＝72.2(c＝0.43,CHCl 3 )；The product was analyzedby HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IB,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (major)＝11.01min,t R (minor)＝13.79min.
Example 9: preparation of chiral spirooxindole compounds (R, R, R) -3ab
To a dry 10mL Schlenk reaction tube at 25deg.C under nitrogen atmosphere were added rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL 1, 4-dioxane, and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1a (18.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2b (18.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, R) -3ab (29.8 mg,83% yieldd, 94:6d.r., >99% e.e.) as a colorless liquid.
1 H NMR(400MHz,CDCl 3 )δ7.47(s,1H),7.38(t,J＝7.6Hz,1H),7.21–7.12(m,2H),6.94(d,J＝7.8Hz,1H),6.83(s,1H),6.35(dd,J＝9.7,3.0Hz,1H),6.26(d,J＝13.9Hz,1H),4.97(d,J＝9.6Hz,1H),3.27(s,3H),3.09(m,1H),3.07(d,J＝17.6Hz,1H),2.83(d,J＝17.5Hz,1H),2.28(s,3H),2.22(s,3H). 13 C NMR(101MHz,CDCl 3 )δ177.57,169.38,143.66,137.17,136.21,130.85,130.77,130.33,129.47,129.39,127.89,125.00,123.80,122.85,120.58,108.60,75.66,47.36,44.47,37.33,26.54,19.81,19.47.HRMS(ESI)m/z(M+H) + :calculated for(C 23 H 22 NO 3 ) + :360.1594,found:360.1596；[α] 20 D ＝-72.5(c＝0.50,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IB-N5,hexane/i-PrOH＝80/20,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝16.16min,t R (major)＝18.77min.
Example 10: preparation of chiral spirooxindole compound (R, S, S) -3ab
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (R) -1- [ (Sp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 1.0mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1a (18.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2b (18.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 1.0mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, S) -3ab (35.6 mg,99% yieldl, 87:13d.r., >99% e.e.) as a colorless liquid.
1 H NMR(500MHz,CDCl 3 )δ7.48(s,1H),7.38(td,J＝7.7,1.2Hz,1H),7.28(d,J＝7.5Hz,1H),7.12(td,J＝7.5,0.9Hz,1H),6.98(d,J＝7.8Hz,1H),6.82(s,1H),6.29(dd,J＝9.6,3.0Hz,1H),5.83(d,J＝14.6Hz,1H),5.04(dd,J＝9.6,2.1Hz,1H),3.32(s,3H),3.29(dt,J＝14.6,2.7Hz,1H),3.16(d,J＝17.8Hz,1H),2.71(d,J＝17.8Hz,1H),2.29(s,3H),2.22(s,3H). 13 C NMR(126MHz,CDCl 3 )δ176.77,168.69,143.26,137.21,136.40,130.58,130.33,129.58,129.43,129.34,127.87,125.07,124.43,123.43,121.69,109.01,77.27,48.48,43.23,37.05,26.78,19.83,19.49.HRMS(ESI)m/z(M+H) + :calculated for(C 23 H 22 NO 3 ) + :360.1594,found:360.1599；[α] 20 D ＝-327.5(c＝0.44,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IA,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (major)＝10.11min,t R (minor)＝13.54min.
Example 11: preparation of chiral spirooxindole compound (S, R, R) -3ab
To a dry 10mL Schlenk reaction tube at 25deg.C under nitrogen atmosphere were added rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL 1, 4-dioxane, and stirred for 1 hour; subsequently, a chiral azacyclo-carbene catalyst ent-NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1a (18.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2b (18.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system under nitrogen protection, and reacted at 15℃for 10 hours by thin layer chromatography to determine the reaction end point; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (S, R) -3ab (35.6 mg,99% yieldl, 89:11d.r., >99% e.e.) as a colorless liquid.
1 H NMR(500MHz,CDCl 3 )δ7.48(s,1H),7.38(td,J＝7.7,1.2Hz,1H),7.28(d,J＝7.5Hz,1H),7.12(td,J＝7.5,0.9Hz,1H),6.98(d,J＝7.8Hz,1H),6.82(s,1H),6.29(dd,J＝9.6,3.0Hz,1H),5.83(d,J＝14.6Hz,1H),5.04(dd,J＝9.6,2.1Hz,1H),3.32(s,3H),3.29(dt,J＝14.6,2.7Hz,1H),3.16(d,J＝17.8Hz,1H),2.71(d,J＝17.8Hz,1H),2.29(s,3H),2.22(s,3H). 13 C NMR(126MHz,CDCl 3 )δ176.77,168.69,143.26,137.21,136.40,130.58,130.33,129.58,129.43,129.34,127.87,125.07,124.43,123.43,121.69,109.01,77.27,48.48,43.23,37.05,26.78,19.83,19.49.HRMS(ESI)m/z(M+H) + :calculated for(C 23 H 22 NO 3 ) + :360.1594,found:360.1597；[α] 20 D ＝318.2(c＝0.41,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IA,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝9.96min,t R (major)＝14.33min.
Example 12: preparation of chiral spirooxindole compound (S, S, S) -3ab
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (R) -1- [ (Sp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen at 25℃and stirred for 1 hour; subsequently, a chiral azacyclo-carbene catalyst ent-NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1a (18.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2b (18.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system under nitrogen protection, and reacted at 15℃for 10 hours by thin layer chromatography to determine the reaction end point; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (S, S) -3ab (32.3 mg,90% yielder; >95:5d.r., >99% e.e.) as a colorless liquid.
1 H NMR(400MHz,CDCl 3 )δ7.47(s,1H),7.38(t,J＝7.6Hz,1H),7.21–7.12(m,2H),6.94(d,J＝7.8Hz,1H),6.83(s,1H),6.35(dd,J＝9.7,3.0Hz,1H),6.26(d,J＝13.9Hz,1H),4.97(d,J＝9.6Hz,1H),3.27(s,3H),3.09(m,1H),3.07(d,J＝17.6Hz,1H),2.83(d,J＝17.5Hz,1H),2.28(s,3H),2.22(s,3H). 13 C NMR(101MHz,CDCl 3 )δ177.57,169.38,143.66,137.17,136.21,130.85,130.77,130.33,129.47,129.39,127.89,125.00,123.80,122.85,120.58,108.60,75.66,47.36,44.47,37.33,26.54,19.81,19.47.HRMS(ESI)m/z(M+H) + :calculated for(C 23 H 22 NO 3 ) + :360.1594,found:360.1605；[α] 20 D ＝65.3(c＝0.25,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IB-N5,hexane/i-PrOH＝80/20,flow rate:1.0mL/min,T＝30℃,254nm),t R (major)＝16.76min,t R (minor)＝18.73min.
Example 13: preparation of chiral spirooxindole compound (R, R, R) -3ca
To a dry 10mL Schlenk reaction tube at 25deg.C under nitrogen atmosphere were added rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL 1, 4-dioxane, and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1c (17.3 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=3:1, V/V) to give the asymmetric spiro oxindole product (R, R) -3ca (27.3 mg,86% yield;95:5d.r., >99% e.e.) as a white solid.
1 H NMR(500MHz,CDCl 3 )δ9.23(s,1H),7.72(d,J＝7.6Hz,1H),7.37–7.25(m,3H),7.15(dd,J＝7.6,1.4Hz,1H),7.11(td,J＝7.5,1.0Hz,1H),7.07(dd,J＝7.5,1.3Hz,1H),7.02(d,J＝7.8Hz,1H),6.45(dd,J＝9.7,3.0Hz,1H),6.31(d,J＝14.0Hz,1H),5.20(dd,J＝9.6,2.1Hz,1H),3.16(dt,J＝14.1,2.6Hz,1H),3.09(d,J＝17.6Hz,1H),2.89(d,J＝17.5Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ180.25,169.13,140.92,133.58,131.79,130.98,130.41,129.60,128.63,128.20,126.55,123.83,123.63,123.09,121.99,110.69,75.53,47.87,43.90,37.29.HRMS(ESI)m/z(M+H) + :calculated for(C 20 H 16 NO 3 ) + :318.1125,found:318.1123；[α] 20 D ＝-84.0(c＝0.32,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK OD-H,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝6.49min,t R (major)＝7.57min.
Example 14: preparation of chiral spirooxindole compound (R, S, S) -3ca
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (R) -1- [ (Sp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1c (17.3 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=3:1, V/V) to give the asymmetric spiro oxindole product (R, S) -3ca (28.2 mg,89% yield;88:12d.r., >99% e.e.) as a white solid.
1 H NMR(500MHz,CDCl 3 )δ9.36(s,1H),7.72(d,J＝7.6Hz,1H),7.38–7.25(m,4H),7.10(td,J＝7.6,1.0Hz,1H),7.08–7.04(m,2H),6.38(dd,J＝9.7,3.0Hz,1H),5.89(d,J＝14.5Hz,1H),5.32(dd,J＝9.6,2.1Hz,1H),3.35(dt,J＝14.6,2.5Hz,1H),3.18(d,J＝17.7Hz,1H),2.79(d,J＝17.7Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ179.33,168.50,140.47,133.12,131.73,130.56,129.88,129.56,128.66,128.41,126.51,125.28,123.53,123.25,122.92,111.13,77.12,49.02,42.99,36.96.HRMS(ESI)m/z(M+H) + :calculated for(C 20 H 16 NO 3 ) + :318.1125,found:318.1129；[α] 20 D ＝-298.1(c＝0.45,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK OD-H,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝6.68min,t R (major)＝7.52min.
Example 15: preparation of chiral spirooxindole compound (R, R, R) -3da
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 1.0mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen atmosphere at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1d (21.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 1.0mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, R) -3da (35.4 mg,98% yieldl; 88:12d.r.,99% e.e.) as a colorless liquid.
1 H NMR(400MHz,CDCl 3 )δ7.70(d,J＝7.6Hz,1H),7.32(td,J＝7.6,1.3Hz,1H),7.27–7.21(m,1H),7.06(dd,J＝7.6,2.8Hz,2H),6.62(dd,J＝8.3,2.3Hz,1H),6.51(d,J＝2.3Hz,1H),6.42(dd,J＝9.6,3.0Hz,1H),6.28(d,J＝14.0Hz,1H),5.07(dd,J＝9.6,2.1Hz,1H),3.85(s,3H),3.25(s,3H),3.09(dt,J＝14.0,2.8Hz,1H),3.03(d,J＝17.8Hz,1H),2.81(d,J＝17.5Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ178.03,169.25,161.18,144.96,133.60,131.79,130.85,128.54,128.09,126.46,123.66,123.60,122.02,121.80,107.43,96.74,75.53,55.76,46.88,44.16,37.68,26.57.HRMS(ESI)m/z(M+H) + :calculated for(C 22 H 20 NO 4 ) + :362.1387,found:362.1391；[α] 20 D ＝-82.5(c＝0.56,CHCl 3 )；The product was analyzedby HPLC to determine the enantiomeric excess:99％e.e.(CHIRALPAK IB,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝12.92min,t R (major)＝20.43min.
Example 16: preparation of chiral spirooxindole compound (R, S, S) -3da
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (R) -1- [ (Sp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 1.0mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1d (21.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 1.0mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, S) -3da (18.8 mg,52% yieldl; 85:15d.r.,95% e.e.) as a colorless liquid.
1 H NMR(500MHz,CDCl 3 )δ7.70(d,J＝7.6Hz,1H),7.33(td,J＝7.6,1.4Hz,1H),7.30–7.23(m,1H),7.18(d,J＝8.3Hz,1H),7.05(dd,J＝7.5,1.3Hz,1H),6.60(dd,J＝8.2,2.4Hz,1H),6.55(d,J＝2.3Hz,1H),6.36(dd,J＝9.6,3.0Hz,1H),5.84(d,J＝14.6Hz,1H),5.13(dd,J＝9.7,2.1Hz,1H),3.84(s,3H),3.33–3.27(m,1H),3.30(s,3H),3.16(d,J＝17.8Hz,1H),2.68(d,J＝17.8Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ177.22,168.58,161.10,144.63,133.32,131.77,130.44,128.59,128.31,126.44,125.81,123.19,123.12,121.21,106.98,97.25,77.22,55.74,48.08,43.01,37.47,26.84.HRMS(ESI)m/z(M+H) + :calculated for(C 22 H 20 NO 4 ) + :362.1387,found:3621397；[α] 20 D ＝-314.2(c＝0.30,CHCl 3 )；The product was analyzedby HPLC to determine the enantiomeric excess:95％e.e.(CHIRALPAK IB,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝14.465min,t R (major)＝19.87min.
Example 17: preparation of chiral spirooxindole compound (R, R, R) -3ac
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 1.0mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen atmosphere at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1a (18.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2c (19.8 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 1.0mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, R) -3ac (27.8 mg,74% yieldl; 93:7d.r.,97% e.e.) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.38(td,J＝7.6,1.5Hz,1H),7.23–7.10(m,3H),6.94(d,J＝7.8Hz,1H),6.54(s,1H),6.27(dd,J＝9.7,3.0Hz,1H),6.19(d,J＝14.3Hz,1H),5.98–5.93(m,2H),4.94(dd,J＝9.6,2.1Hz,1H),3.27(s,3H),3.11–3.04(m,1H),3.04(d,J＝17.5Hz,1H),2.83(d,J＝17.5Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ177.51,169.03,147.91,147.26,143.65,130.55,130.15,129.53,128.04,125.96,123.82,122.88,119.96,108.65,107.13,105.27,101.39,75.75,47.30,44.23,37.29,26.56.HRMS(ESI)m/z(M+H) + :calculated for(C 22 H 18 NO 5 ) + :376.1179,found:376.1185；[α] 20 D ＝-20.7(c＝0.41,CHCl 3 )；The product was analyzedby HPLC to determine the enantiomeric excess:97％e.e.(CHIRALPAK IB-N5,hexane/i-PrOH＝85/15,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝38.61min,t R (major)＝44.20min.
Example 18: preparation of chiral spirooxindole compound (R, S, S) -3ac
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (R) -1- [ (Sp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 1.0mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1a (18.7 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2c (19.8 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 1.0mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, S) -3ac (37.2 mg,99% yieldl; 90:10d.r., >99% e.e.) as a white solid.
1 H NMR(500MHz,CDCl 3 )δ7.38(td,J＝7.8,1.2Hz,1H),7.29–7.24(m,1H),7.21(d,J＝1.0Hz,1H),7.12(td,J＝7.6,1.0Hz,1H),6.97(d,J＝7.8Hz,1H),6.53(s,1H),6.20(dd,J＝9.7,3.0Hz,1H),5.95(dd,J＝8.6,1.4Hz,2H),5.75(d,J＝15.0Hz,1H),5.02(dd,J＝9.6,2.2Hz,1H),3.31(s,3H),3.28–3.24(m,1H),3.14(d,J＝17.8Hz,1H),2.69(d,J＝17.8Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ176.66,168.33,147.90,147.36,143.22,130.11,129.47,129.46,127.73,125.90,125.10,123.45,121.13,109.06,107.16,104.78,101.42,77.34,48.38,43.03,37.03,26.80.HRMS(ESI)m/z(M+H) + :calculated for(C 22 H 18 NO 5 ) + :376.1179,found:376.1185；[α] 20 D ＝-360.0(c＝0.58,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IA,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝12.24min,t R (major)＝18.48min.
Example 19: preparation of chiral spirooxindole compound (R, R, R) -3ea
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 1.0mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen atmosphere at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1e (20.1 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 1.0mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, R) -3ea (27.3 mg,79% yieldl, 91:9d.r., >99% e.e.) as a colorless liquid.
1 H NMR(500MHz,CDCl 3 )δ7.71(d,J＝7.6Hz,1H),7.33(td,J＝7.6,1.3Hz,1H),7.30–7.22(m,1H),7.20–7.14(m,1H),7.05(dd,J＝7.6,1.3Hz,1H),6.99(d,J＝1.7Hz,1H),6.83(d,J＝7.9Hz,1H),6.42(dd,J＝9.6,3.1Hz,1H),6.30(d,J＝13.9Hz,1H),5.06(dd,J＝9.6,2.1Hz,1H),3.26(s,3H),3.13(dt,J＝14.0,2.5Hz,1H),3.08(d,J＝17.4Hz,1H),2.82(d,J＝17.5Hz,1H),2.33(s,3H). 13 C NMR(126MHz,CDCl 3 )δ177.45,169.34,141.26,133.59,133.50,131.76,130.84,130.21,129.78,128.56,128.14,126.48,123.73,123.67,121.97,108.43,75.59,47.33,44.23,37.41,26.61,21.26.HRMS(ESI)m/z(M+H) + :calculated for(C 22 H 20 NO 3 ) + :346.1438,found:346.1440；[α] 20 D ＝-79.0(c＝0.30,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IC,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (major)＝45.026min,t R (minor)＝59.48min.
Example 20: preparation of chiral spirooxindole compounds (R, R, R) -fa
Rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 1.0mL of 1, 4-dioxane were added to a dry 10mL Schlenk reaction tube under nitrogen atmosphere at 25℃and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1f (20.1 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 1.0mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, R) -3ea (31.4 mg,91% yield,92:8d.r., >99% e.e.) as a colorless liquid.
1 H NMR(400MHz,CDCl 3 )δ7.74–7.67(m,1H),7.32(td,J＝7.6,1.4Hz,1H),7.29–7.21(m,1H),7.12–7.08(m,1H),7.05(dd,J＝7.5,1.3Hz,1H),7.04–6.97(m,2H),6.42(dd,J＝9.6,3.0Hz,1H),6.30(d,J＝13.9Hz,1H),5.07(dd,J＝9.7,2.2Hz,1H),3.55(s,3H),3.09(dt,J＝14.0,2.6Hz,1H),3.03(d,J＝17.5Hz,1H),2.80(d,J＝17.5Hz,1H),2.64(s,3H). 13 C NMR(101MHz,CDCl 3 )δ178.17,169.22,141.43,133.61,133.18,131.77,130.84,130.74,128.54,128.10,126.46,123.73,123.67,121.98,120.74,120.39,75.56,46.70,44.31,37.76,29.86,19.12.HRMS(ESI)m/z(M+H) + :calculated for(C 22 H 20 NO 3 ) + :346.1438,found:346.1442；[α] 20 D ＝-87.2(c＝0.43,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IB,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (major)＝11.59min,t R (minor)＝14.01min.
Example 21: preparation of chiral spirooxindole compound (R, R, R) -ga
To a dry 10mL Schlenk reaction tube at 25deg.C under nitrogen atmosphere were added rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL 1, 4-dioxane, and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1g (20.1 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography spot plate to determine the reaction end point; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, R) -3ga (31.8 mg,92% yieldd, 95:5d.r., >99% e.e.) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.71(dd,J＝7.6,1.4Hz,1H),7.37(td,J＝7.7,1.5Hz,1H),7.35–7.30(m,1H),7.29–7.23(m,1H),7.19(dd,J＝7.4,1.4Hz,1H),7.13(td,J＝7.5,1.0Hz,1H),7.06(dd,J＝7.5,1.3Hz,1H),6.96(dd,J＝7.9,0.9Hz,1H),6.43(dd,J＝9.7,3.0Hz,1H),6.32(d,J＝13.9Hz,1H),5.05(dd,J＝9.6,2.1Hz,1H),3.89(dq,J＝14.5,7.3Hz,1H),3.75(dq,J＝14.3,7.1Hz,1H),3.17–3.11(m,1H),3.07(d,J＝17.5Hz,1H),2.84(d,J＝17.5Hz,1H),1.31(t,J＝7.2Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ177.01,169.21,142.73,133.51,131.71,130.89,130.27,129.49,128.56,128.12,126.48,123.68,123.59,123.06,121.67,108.77,75.46,47.08,44.12,37.21,35.03,12.95.HRMS(ESI)m/z(M+H) + :calculated for(C 22 H 20 NO 3 ) + :346.1438,found:346.1446；[α] 20 D ＝-95.8(c＝0.25,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IG,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (minor)＝39.23min,t R (major)＝46.18min.
Example 22: preparation of chiral spirooxindole compounds (R, R, R) -ha
To a dry 10mL Schlenk reaction tube at 25deg.C under nitrogen atmosphere were added rhodium (I) bis (1, 5-cyclooctadiene) -trifluoromethanesulfonate (2.3 mg,0.005mmol,5 mol%) and (S) -1- [ (Rp) -2- (diphenylphosphino) ferrocene ] ethyl di-tert-butylphosphine (3.8 mg,0.007mmol,7 mol%) and 2.5mL 1, 4-dioxane, and stirred for 1 hour; subsequently, under nitrogen protection, a chiral azacyclo-carbene catalyst NHC (4.2 mg,0.001mmol,10 mol%), an oxindole-derived α, β -unsaturated aldehyde 1h (24.9 mg,0.1mmol,1.0 eq.), 1, 4-dihydro-1, 4-epoxynaphthalene compound 2a (15.1 mg,0.105mmol,1.05 eq.), potassium phosphate (21.2 mg,0.1mmol,1.0 eq.) and 2.5mL of 1, 4-dioxane were added to the mixed system, and reacted at 15 ℃ for 10 hours by thin layer chromatography, and the reaction was terminated; the reaction was then diluted with ethyl acetate and extracted with water, then the aqueous phase was extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then isolated by column chromatography (eluent petroleum ether: ethyl acetate=5:1, V/V) to give the asymmetric spiro oxindole product (R, R) -3ha (31.1 mg,77% yield,93:7d.r., >99% e.e.) as a white solid.
1 H NMR(500MHz,CDCl 3 )δ7.71(d,J＝7.6Hz,1H),7.62–7.51(m,2H),7.44(td,J＝6.2,5.8,3.1Hz,3H),7.36–7.23(m,4H),7.18(t,J＝7.5Hz,1H),7.07(d,J＝7.4Hz,1H),6.93(d,J＝7.9Hz,1H),6.49(dd,J＝9.7,3.0Hz,1H),6.34(d,J＝13.9Hz,1H),5.27(dd,J＝9.6,2.1Hz,1H),3.23(d,J＝17.6Hz,1H),3.24–3.18(m,1H),2.96(d,J＝17.5Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ176.98,169.07,143.58,133.79,133.40,131.66,131.26,129.90,129.47,128.67,128.64,128.20,126.57,126.51,124.33,123.77,123.20,121.35,109.96,75.40,47.37,44.77,37.35.HRMS(ESI)m/z(M+H) + :calculated for(C 26 H 20 NO 3 ) + :394.1438,found:394.1437；[α] 20 D ＝-53.7(c＝0.46,CHCl 3 )；The product was analyzed by HPLC to determine the enantiomeric excess:>99％e.e.(CHIRALPAK IG,hexane/i-PrOH＝70/30,flow rate:1.0mL/min,T＝30℃,254nm),t R (major)＝60.09min,t R (minor)＝65.28min.
Example 23: test of Activity of four isomers of chiral spirooxindole Compounds 3aa, 3ba and 3ab on HeLa cells
HeLa cells were cultured in DMEM dishes containing 10% fetal bovine serum and 100units/ml penicillin+100. Mu.g/ml streptomycin. Four stereoisomers of compounds 3aa, 3ba and 3ab were screened at a concentration of 5 μm to test changes associated with chromosomal mismatches during mid-front and late onset of HeLa cells. Each compound inhibited mitosis, with (R, S) -3aa, (R, S) -3ba and (R, S) -3ab being most pronounced.
Example 24: imaging test of chiral spirooxindole Compounds (R, S, S) -3aa, (R, S, S) -3ba and (R, S, S) -3ab on Hela cell Activity
For time-lapse imaging, heLa cells were cultured in glass bottom dishes (MatTek) and transfected with mCherry-H2B and GFP-Tubulin to reveal chromosomes and microtubules. The plasmid was purified with a purification kit (QIAGEN) and cells were transfected with Lipofectamine 3000 (Invitrogen). Cells were added to carbon dioxide free medium (Gibco) with 10% fetal bovine serum and 2mM glutamine. Before imaging for 1 hour, 5. Mu.M of the corresponding compound in dimethyl sulfoxide was added, and the control group was added with dimethyl sulfoxide. During imaging, the dishes were placed in a sealed chamber at 37 ℃. Live cell images were taken every 3 minutes using a DeltaVision microscope system and deconvolved, and the resulting images were as follows. From the images, it can be concluded that the mitosis process of Hela cells of the experimental group is significantly slower compared with the control group, i.e. the chiral spiro oxindole compounds (R, S) -3aa, (R, S) -3ba and (R, S) -3ab all have a significant inhibitory effect on the mitosis process of Hela cells.
Claims (9)
1. A chiral spiro oxindole compound, which is characterized by being an optical active compound with a structure shown in the following formula I, and comprising stereoisomers with the same chemical general formula:
wherein: * Represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1-10 Alkyl or aryl; ar is an aromatic ring or a substituted aromatic ring; ar' is an aromatic ring or a substituted aromatic ring; r is R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Are independently selected from hydrogen, halogen, C 1-4 A hydrocarbyl group or a hydrocarbyloxy group.
2. A process for the diastereoisomeric divergent preparation of a chiral spirocyclic oxindole compound according to claim 1, wherein:
the method comprises the steps of taking indole oxide derived alpha, beta-unsaturated aldehyde 1 and 1, 4-dihydro-1, 4-epoxynaphthalene compound 2 as starting materials, taking bis (1, 5-cyclooctadiene) -trifluoro rhodium methanesulfonate (I) as a metal catalyst, taking chiral phosphine reagent as a ligand and chiral aza-heterocyclic carbene as an organic catalyst, carrying out asymmetric [3+3] cyclization reaction under the assistance of alkali, and separating and purifying to obtain a target product I;
the synthetic route is as follows:
in the above formula: * Represents a chiral carbon atom; the substituent R is selected from hydrogen, C 1-10 Alkyl or aryl; ar is an aromatic ring or a substituted aromatic ring; ar' is an aromatic ring or a substituted aromatic ring; r is R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Are independently selected from hydrogen, halogen, C 1-4 A hydrocarbyl group or a hydrocarbyloxy group.
3. The preparation method according to claim 2, characterized by comprising the steps of:
mixing a bis (1, 5-cyclooctadiene) -trifluoro rhodium (I) mesylate metal catalyst and a chiral phosphine ligand in an organic solvent under the nitrogen atmosphere, then adding a chiral azacyclo-carbene catalyst, an alpha, beta-unsaturated aldehyde 1 derived from oxindole, a 1, 4-dihydro-1, 4-epoxynaphthalene compound 2, alkali and the organic solvent into the mixed system under the protection of nitrogen, and reacting for 4-72 hours at the temperature of 10-60 ℃, wherein a thin layer chromatography point plate determines the reaction end point; the reaction system is then diluted with ethyl acetate and extracted with water, the aqueous phase is then extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and finally the asymmetric spiro oxindole product I is obtained by column chromatography separation.
4. A method of preparation according to claim 2 or 3, characterized in that:
the chiral phosphine ligand is selected from
Wherein: r is R 7 、R 8 、R 9 、R 10 、R 11 Each independently selected from hydrogen, halogen, or substituted or unsubstituted: c (C) 1-10 Alkyl, C 3-10 Cycloalkyl, 2-furyl or C 6-20 Aryl groups of (a).
5. A method of preparation according to claim 2 or 3, characterized in that:
the chiral azacyclo-carbene catalyst is selected from the group consisting of:
wherein: r is R 12 、R 13 、R 14 Each independently selected from hydrogen, halogen, or substituted or unsubstituted: c (C) 1-10 Alkyl, C 3-10 Cycloalkyl, 2-furyl or C 6-20 Aryl groups of (a).
6. A method of preparation according to claim 2 or 3, characterized in that:
the alkali is potassium phosphate, potassium hydrogen phosphate, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethyl ethylenediamine or N-methylmorpholine.
7. A method of preparation according to claim 2 or 3, characterized in that:
the molar ratio of the rhodium (1, 5-cyclooctadiene) -triflate (I) to the indole oxide-derived alpha, beta-unsaturated aldehyde 1 is 0.025:1-1:1; the molar ratio of chiral phosphine ligand to oxindole derived alpha, beta-unsaturated aldehyde 1 is 0.025:1-1:1; the molar ratio of the chiral N-heterocyclic carbene catalyst to the oxindole-derived alpha, beta-unsaturated aldehyde 1 is 0.025:1-1:1; the molar equivalent ratio of the oxindole-derived alpha, beta-unsaturated aldehyde 1 to the 1, 4-dihydro-1, 4-epoxynaphthalene compound 2 is 1:1-1:5; the molar ratio of the oxindole-derived alpha, beta-unsaturated aldehyde 1 to the alkali is 1:0.1-1:5.
8. The method of manufacturing according to claim 7, wherein:
the molar ratio of the rhodium (I) bis (1, 5-cyclooctadiene) -triflate to the chiral phosphine ligand is 1:1-1:4.
9. A method of preparation according to claim 3, characterized in that:
the organic solvent is 1, 4-dioxane, dichloromethane, dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, toluene, ethylbenzene, fluorobenzene, chlorobenzene, bromobenzene, xylene or trimethylbenzene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310001621.0A CN116554185A (en) | 2023-01-03 | 2023-01-03 | Chiral spiro oxindole compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310001621.0A CN116554185A (en) | 2023-01-03 | 2023-01-03 | Chiral spiro oxindole compound and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116554185A true CN116554185A (en) | 2023-08-08 |
Family
ID=87497152
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310001621.0A Pending CN116554185A (en) | 2023-01-03 | 2023-01-03 | Chiral spiro oxindole compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116554185A (en) |
-
2023
- 2023-01-03 CN CN202310001621.0A patent/CN116554185A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wu et al. | Secondary amines as coupling partners in direct catalytic asymmetric reductive amination | |
| Fairuz Binte Sheikh Ismail et al. | Access to 5, 6-spirocycles bearing three contiguous stereocenters via Pd-catalyzed stereoselective [4+ 2] cycloaddition of azadienes | |
| CN101679243B (en) | Atropisomer of pyrrole derivative | |
| Trost et al. | A versatile enantioselective strategy toward L-C-nucleosides: A total synthesis of L-Showdomycin | |
| US11390585B2 (en) | Quaternary heteroatom containing compounds | |
| EP3712140A1 (en) | Quaternary heteroatom containing compounds | |
| CN108409746B (en) | Chiral oxo spiro indole compound containing pyrrole or indolocarbazacycloalkane structure, racemate thereof and preparation method | |
| Shan et al. | Organocatalytic Asymmetric Mannich Reaction of 3-Hydroxyoxindoles/3-Aminooxindoles with in Situ Generated N-Boc-Protected Aldimines for the Synthesis of Vicinal Oxindole–Diamines/Amino Alcohols | |
| CN102203097B (en) | Three ring chipal compounds and the purposes in asymmetry catalysis thereof | |
| Moghaddam et al. | Diastereoselective construction of a functionalized dihydro-pyridazine-based spirooxindole scaffold via C-3 umpolung of isatin N, N′-cyclic azomethine imine | |
| Faigl et al. | Resolution of 1-[2-carboxy-6-(trifluoromethyl) phenyl]-1H-pyrrole-2-carboxylic acid with methyl (R)-2-phenylglycinate, reciprocal resolution and second order asymmetric transformation | |
| CN109776556B (en) | Pyrazolone xanthone skeleton spliced oxindole or benzofuranone compound and preparation method and application thereof | |
| CN113087714B (en) | Axial chiral aryl indole carbazole derivative and preparation method and application thereof | |
| CN109796471B (en) | Indolone spiro-propane spiro-thiazolone or spiro-tetrahydrothiazolone derivative and preparation method and application thereof | |
| CN116554185A (en) | Chiral spiro oxindole compound and preparation method thereof | |
| JP2021534102A (en) | Inhibitor of human immunodeficiency virus replication | |
| Mitasev et al. | Crystallization-Based Synthetic Route to Antimalarial Agent BRD5018: Diazocene Ring Formation via a Staudinger-aza-Wittig Reaction on an Azetidine-Ribose Template | |
| CN109134402B (en) | Chiral sulfonamide derivative and preparation method and application thereof | |
| Valachová et al. | Stereoselective synthesis of syn-γ-hydroxynorvaline and related α-amino acids | |
| US20070191614A1 (en) | Process for producing nitrogenous 5-membered cyclic compound | |
| CN107235991A (en) | Indolone spiral shell tetrahydrochysene thio-pyrylium class compound and its salt, preparation method and application | |
| Wang et al. | Substrate-Dependent Regioselectivity: Pd/PTC Cooperatively Catalyzed Domino Heck/Allylation of Allenamides with α-Carbon of Carbonyl Compounds | |
| Zhang et al. | Palladium-catalyzed asymmetric allylic alkylation of 3-aminooxindoles to access chiral homoallylic aminooxindoles | |
| CN111793017A (en) | Preparation method of lactam compound | |
| CN113461700B (en) | Application of oxygen-promoted dearomatization reaction in construction of spiro-dienone skeleton |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |