CN113004296A - General synthetic method for preparing chiral oxygen heterocyclic compound by novel [4+1] and [5+1] cyclization strategies - Google Patents
General synthetic method for preparing chiral oxygen heterocyclic compound by novel [4+1] and [5+1] cyclization strategies Download PDFInfo
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- CN113004296A CN113004296A CN202110300590.XA CN202110300590A CN113004296A CN 113004296 A CN113004296 A CN 113004296A CN 202110300590 A CN202110300590 A CN 202110300590A CN 113004296 A CN113004296 A CN 113004296A
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- oxygen
- reaction
- compound
- phenyl
- chiral
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- -1 oxygen heterocyclic compound Chemical class 0.000 title claims abstract description 61
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 24
- 239000001301 oxygen Substances 0.000 title claims abstract description 24
- 238000007363 ring formation reaction Methods 0.000 title claims abstract description 10
- 238000010189 synthetic method Methods 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- 239000000758 substrate Substances 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 60
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 37
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 36
- 239000003444 phase transfer catalyst Substances 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 238000001308 synthesis method Methods 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 229930192474 thiophene Natural products 0.000 claims description 5
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#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
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003541 2-chlorobenzoyl group Chemical group ClC1=C(C(=O)*)C=CC=C1 0.000 claims description 2
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- XVZXOLOFWKSDSR-UHFFFAOYSA-N Cc1cc(C)c([C]=O)c(C)c1 Chemical group Cc1cc(C)c([C]=O)c(C)c1 XVZXOLOFWKSDSR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 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
- 125000005843 halogen group Chemical group 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 125000001725 pyrenyl group Chemical group 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 125000004434 sulfur atom Chemical group 0.000 claims 2
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 claims 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 239000003637 basic solution Substances 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 4
- 229930014626 natural product Natural products 0.000 abstract description 3
- 238000009509 drug development Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 230000000269 nucleophilic effect Effects 0.000 abstract description 2
- 238000011160 research Methods 0.000 abstract description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000012827 research and development Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- 239000007864 aqueous solution Substances 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 229920002160 Celluloid Polymers 0.000 description 16
- 239000007832 Na2SO4 Substances 0.000 description 16
- 238000001514 detection method Methods 0.000 description 16
- 238000001035 drying Methods 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 16
- FGFUBBNNYLNVLJ-UHFFFAOYSA-N indolone Natural products C1=CC=C2C(=O)C=NC2=C1 FGFUBBNNYLNVLJ-UHFFFAOYSA-N 0.000 description 16
- 238000002156 mixing Methods 0.000 description 16
- 230000003287 optical effect Effects 0.000 description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 239000011734 sodium Substances 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 125000000864 peroxy group Chemical group O(O*)* 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000004593 Epoxy Substances 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 150000004029 oxacyclic compounds Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 229940125796 compound 3d Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
- IZGDXVLRMHXOJV-SFHVURJKSA-N (3s)-4-[2-[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]ethyl-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1CCP(O)(=O)C[C@@H](O)CC(O)=O IZGDXVLRMHXOJV-SFHVURJKSA-N 0.000 description 1
- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
- FVCDMHWSPLRYAB-UHFFFAOYSA-N 2-ethenyl-2-methyloxirane Chemical compound C=CC1(C)CO1 FVCDMHWSPLRYAB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229930192304 aspergillide Natural products 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GKPOMITUDGXOSB-UHFFFAOYSA-N but-3-yn-2-ol Chemical compound CC(O)C#C GKPOMITUDGXOSB-UHFFFAOYSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- LDCRTTXIJACKKU-ARJAWSKDSA-N dimethyl maleate Chemical compound COC(=O)\C=C/C(=O)OC LDCRTTXIJACKKU-ARJAWSKDSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000006077 hetero Diels-Alder cycloaddition reaction Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 150000005624 indolones Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 150000004395 organic heterocyclic compounds Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 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
Abstract
The oxygen heterocyclic compound containing the chiral center widely exists in natural products and active drug molecules, and has very high importance and application value in the research field of pharmaceutical chemistry. Therefore, how to efficiently and rapidly introduce the oxygen-containing heterocyclic compound into the pharmaceutically active molecule has been an important technical problem in drug development. The invention uses the peroxide compound with double-function electrophilic carbon and electrophilic oxygen as the initial raw material to perform [4+1] and [5+1] cyclization reaction with nucleophilic substrate under the alkaline condition to obtain the five-membered tetrahydrofuran ring and six-membered tetrahydro or dihydropyran oxygen-heterocyclic compound containing chiral center in one step. The method has the advantages of mild reaction conditions, simple process, no need of anhydrous and anaerobic operation to obtain the target compound, low requirement on production equipment, wide application range of the substrate and extremely high application value in the process of drug research and development.
Description
Technical Field
The invention belongs to the field of organic synthesis methodology, and particularly relates to a method for generating a five-membered tetrahydrofuran ring and a six-membered dihydropyran epoxy heterocyclic compound containing a chiral center through a cyclization reaction of a peroxy compound and a nucleophilic reagent.
Background
The oxygen heterocyclic compound containing the chiral center is an important organic heterocyclic compound, and a large number of structures of the oxygen heterocyclic compound are present in natural products and drug molecules with important physiological activity, such as a five-membered tetrahydrofuran oxygen heterocyclic compound Azaspherene with angiogenesis inhibiting effect, a five-membered tetrahydrofuran oxygen heterocyclic compound Scepan E with hepatitis C virus resistance, a six-membered dihydropyran oxygen heterocyclic compound Aspergillides C for treating lymphocytic leukemia and a six-membered dihydropyran oxygen heterocyclic compound Laulimide with anticancer effect. From these natural products and drug molecules, it can be seen that the oxacyclic compounds containing chiral centers have important applications in biomedical research. Therefore, how to efficiently and rapidly construct an oxygen heterocyclic structure containing a chiral center in a pharmaceutically active molecule is an important scientific problem in drug development.
In view of this, there is a need for the development of novel efficient asymmetric synthesis methods for such heterocyclic oxygen compounds, in particular chiral heterocyclic oxygen compounds containing five-membered tetrahydrofuran rings and six-membered dihydropyran rings.
At present, many reports are made in the literature on methods for synthesizing an oxacyclic compound containing a chiral center, but methods for efficiently obtaining the compound in one step are still few, and particularly, a method for efficiently synthesizing an oxacyclic compound in five-membered and six-membered ring systems in one step is not reported at present.
In 2002, the Jamison topic group (org. Lett.2012,4,2277-2(OAc)4Under the catalysis of the (A), the compound and dimethyl maleate generate 1, 3-dipolar cycloaddition reaction to obtain a five-membered epoxy heterocyclic compound containing a chiral center.
In 2012, the Houxulong project group (Synlett.2012,23,1035-2(dba)3·CHCl3And under the action of Ligand, 2-methyl-2-vinyl oxirane and nitryl alkene substrate are utilized to generate [3+2 ]]And (3) performing cycloaddition reaction to synthesize the chiral tetrahydrofuran compound.
In 2018, the Sharma project group (J.Org.chem.2018,83,2744-2752.) used indolone derivatives and beta-hydroxybutyne as starting substrates to perform [4+1] cycloaddition reaction under the concerted catalysis of Rh/Ag/Au, so as to synthesize a series of spiro tetrahydrofuran compounds with stereoselectivity.
In 2001, Oliver group (J.Am. chem. Soc.2001,123,3830-3831.) used cyclohexadiene and β -keto acid ester as starting substrates, and a Hetero-Diels-Alder reaction was carried out under the action of sulfadiazine and a Lewis acid to form a dihydropyran bridged ring compound containing a chiral center.
In 2011, Lambert topic group (J.org.chem.2011,76,9269-9277.) reported that [5+1] Prins cyclization reaction of silyl enol ether and propylene oxide under the action of Lewis acid selectively generates dihydropyran ring compounds with substituent groups.
Although the cyclization reaction can obtain various five-membered or six-membered oxygen heterocyclic compounds, the following defects still exist:
(1) the above reaction involves the participation of transition metals in catalysis, and these metal catalysts are expensive and have high toxicity, so that the preparation cost of the method is high;
(2) the chiral ligand involved in the above reaction is difficult to prepare and mostly can not be recycled, which is not beneficial to the requirement of industrial production;
(3) most of the above reactions are participated by Lewis acid, and the reaction conditions are harsh, so that the method is limited in practical application;
(4) the method is suitable for single synthesis of specific five-membered or six-membered oxygen ring compounds, and unified and universal synthesis of two important ring system structural compounds cannot be realized.
Disclosure of Invention
Aiming at the limitation of the synthesis method, the invention designs a bifunctional electrophilic carbon and electrophilic oxygen peroxide, and the bifunctional electrophilic carbon and electrophilic oxygen peroxide and cheap and easily-obtained carbonyl compounds are subjected to a reaction of series C-C and C-O bonds, namely a formal [4+1] cyclization reaction and a formal [5+1] cyclization reaction under a mild alkaline condition, so that the universal synthesis of five-membered ring and six-membered ring oxygen heterocyclic compounds containing chiral centers is quickly constructed in one step.
The method has mild conditions and simple operation, does not need strict anhydrous and anaerobic operation, and does not need noble metal or expensive ligand to participate, and can obtain five-membered ring and six-membered ring oxygen heterocyclic compounds with high yield and high stereoselectivity. In addition, the method has wide substrate application range and high product application value.
The invention provides a general synthetic method for preparing five-membered ring and six-membered epoxy heterocyclic compounds containing chiral centers by novel [4+1] and [5+1] cyclization reactions, which has the following reaction formula:
wherein R is1May be a substituent such as a sulfonyl group (which includes, but is not limited to, a methanesulfonyl group, an isopropylsulfonyl group, a p-toluenesulfonyl group, a benzenesulfonyl group, a p-nitrobenzenesulfonyl group and the like), a halogen atom (including chlorine, bromine, iodine and the like) and the like; a can be carbon, oxygen, sulfur, phosphorus and other atoms; b can be carbon, oxygen, sulfur, phosphorus and other atoms; r2Can be hydrogen, alkyl (such groups include but are not limited to methyl, isopropyl, t-butyl, cyclohexyl, cyclopentyl, etc.), aryl (such groups include but are not limited to phenyl, p-methoxyphenyl, p-methylphenyl, naphthalene, pyridine, furan, thiophene, pyrrole, indole, etc.), and the like; r3May be an alkyl group (such a group includes, but is not limited to, methyl, ethyl, isopropyl, cyclohexyl, etc.), an aryl group (such a group includes, but is not limited to, phenyl, p-methoxyphenyl, p-methylphenyl, naphthalene, pyridine, furan, thiophene, pyrrole, indole, etc.), a carbonyl group, a sulfonyl group, a phosphoryl group, a cyano group, and the like; r4May be an alkyl group (the group includes but is not limited to methyl, isopropylAlkyl, tert-butyl, cyclohexyl, cyclopentyl, etc.), aryl (which includes, but is not limited to, phenyl, p-methoxyphenyl, p-methylphenyl, naphthalene, pyridine, furan, thiophene, pyrrole, indole, etc.), carbonyl, sulfonyl, phosphoryl, cyano, and like substituents.
The technical scheme comprises the following operations in real time:
placing a reaction substrate and a phase transfer catalyst into a reaction tube, adding a certain amount of proper solvent, placing the reaction tube at a certain temperature, then adding alkali at the temperature for reaction, and tracking and monitoring by TLC. After the reaction is completed, adding saturated ammonium chloride solution, and extracting the aqueous solution with ethyl acetate. Combining the extracts, removing the ethyl acetate solvent, and separating and purifying the residue by silica gel column chromatography to obtain the product.
In this reaction case, the peroxy compound (1): nucleophilic substrate (2): the molar ratio of the base may be (1-2) to (1-10), and the optimum molar ratio is 1.2:1.0:2 or 1.2:1.0: 5.
In this reaction case, the reaction catalyst is a phase transfer catalyst, and the catalyst structure is shown in the following figure:
wherein R is5Hydrogen, benzyl, allyl, formyl (which groups include, but are not limited to, benzoyl, 3, 5-dimethylbenzoyl, 2,4, 6-trimethylbenzoyl, 4-tert-butylbenzoyl, 2-chlorobenzoyl, 1-naphthoyl, 2-naphthoyl, pivaloyl, adamantanoyl, and the like), trimethylsilyl, triethylsilyl, N-phosphono-alpha-amino ester, N-Boc-alpha-amino ester; wherein the N-phosphono- α -amino ester, N-Boc- α -amino ester is optionally substituted with one or more substituents independently selected from: hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, cyclohexyl; r6Is hydrogen or methoxy; ar is an aryl group (which includes but is not limited to phenyl, 3, 5-diphenyl, 2, 6-diphenyl, 3, 5-diphenyl, 4-dimethyl-t-butylsiloxyphenyl, 1-naphthyl, 2-phenyl-1-naphthyl, 2-naphthyl,9-anthracenyl, 9-phenanthryl, pyrenyl) and the like. Wherein the most preferred catalyst is R5Is N-Boc-D-valine ester, R6Is hydrogen, Ar is 1-naphthyl, and the structure of the compound is shown in the following figure:
in this reaction case, the molar percentage of the catalyst is 5 mol% to 20 mol%, with the optimum molar percentage being 10 mol%.
In the case of this reaction, the base used is an alkaline aqueous solution or a solid base, and may be sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium phosphate, dipotassium hydrogen phosphate, methylamine, ethylamine, triethylamine, diisopropylethylamine, triethylenediamine, pyridine, N-dimethylpyridine or the like, with cesium hydroxide aqueous solution being the most preferable base.
In this reaction, when the alkali used is an alkaline aqueous solution, the mass concentration of the alkali is 5% to 90%, and the most preferable mass concentration is 80%.
In this reaction case, the organic solvent used may be dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, N-dimethylformamide, acetone, acetonitrile, toluene, fluorobenzene, chlorobenzene, or the like, and may be any two mixed solvents thereof, and the most preferable solvent is a mixed solvent of toluene and dichloromethane, and toluene: dichloromethane ═ 5: 1.
In the case of this reaction, the substrate concentrations were: 0.05-2.0 mol/L, and the optimal concentration is 0.2 mol/L.
Under the reaction condition, the reaction temperature is-78-25 ℃, and the optimal temperature is-60 ℃.
In the case of this reaction, the eluents used for the separation and purification by silica gel column chromatography are a mixture of ethyl acetate and petroleum ether, petroleum ether: the ethyl acetate ratio is 20: 1-50: 1.
The method has the advantages of mild reaction conditions, simple process, no need of strict control of anhydrous, oxygen-free and the like, low requirement on production equipment, wide range of applicable substrates of a reaction route, high yield, suitability for large-scale preparation of target products and higher industrial application value.
Detailed Description
The monitoring method in any embodiment of the invention is: thin layer chromatography. The technical means for structure confirmation are all common technical means known to the technicians in the field, such as nuclear magnetic resonance technology and high-resolution mass spectrometry.
Example 1:
preparation of Compound 3a
In a 10mL reaction tube, indolone substrate 2a (0.2mmol,1.0equiv), peroxy substrate 1a (78mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved by addition of toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain chiral compound 3a 46mg with a yield of 76%.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.87(d,J＝8.5Hz,1H),7.36(dd,J＝7.0,5.0Hz,2H),7.19(t,J＝7.5Hz,1H),5.16(s,1H),5.12(s,1H),4.88(d,J＝12.5Hz,1H),4.70(d,J＝12.5Hz,1H),3.05(d,J＝16.1Hz,1H),2.83(d,J＝16.1Hz,1H),1.62(s,9H).13C NMR(100MHz,CDCl3)δ174.97,149.10,145.38,139.76,130.31,127.92,124.96,123.69,115.28,106.09,84.46,82.42,72.34,41.93,28.03.HRMS(ESI)m/z Calcd for[C17H19NNaO4,M+Na]+:324.1206,Found:324.1194.
Optical rotation value [ alpha ]]D 25＝33.5(c＝0.25,CHCl3) (ii) a ee value: 91% (HPLC condition: xylonite)IC column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 2:
preparation of Compound 3b
In a 10mL reaction tube, indolone substrate 2b (0.2mmol,1.0equiv), peroxygen substrate 1a (78mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved by addition of toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain chiral compound 3b 44mg with a yield of 70%.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.1Hz,1H),7.16(d,J＝8.5Hz,2H),5.15(s,1H),5.11(s,1H),4.87(d,J＝12.5Hz,1H),4.69(d,J＝12.5Hz,1H),3.03(d,J＝16.1Hz,1H),2.82(d,J＝16.1Hz,1H),1.62(s,9H).13C NMR(100MHz,CDCl3)δ175.16,149.15,145.49,137.38,134.70,130.75,127.81,124.24,115.08,105.98,84.28,82.55,72.28,41.85,28.04,20.96.HRMS(ESI)m/z Calcd for[C18H22NO4,M+H]+:316.1542,Found:316.1543.
Optical rotation value [ alpha ]]D 25＝-3.7(c＝0.25,CHCl3) (ii) a ee value: 91% (HPLC conditions: xylonite OJ-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 3:
preparation of Compound 3c
In a 10mL reaction tube, indolone substrate 2c (0.2mmol,1.0equiv), peroxygen substrate 1a (78mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved by addition of toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give 3c 48mg of chiral compound in a yield of 72%.
A white solid.1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.8Hz,1H),6.96–6.80(m,2H),5.16(s,1H),5.11(s,1H),4.88(d,J＝12.6Hz,1H),4.69(d,J＝12.6Hz,1H),3.80(s,3H),3.04(d,J＝16.1Hz,1H),2.80(d,J＝16.1Hz,1H),1.61(s,9H).13C NMR(100MHz,CDCl3)δ175.07,157.20,149.16,145.32,132.98,129.14,116.34,115.34,109.46,106.11,84.24,82.65,72.34,55.65,42.04,28.04.HRMS(ESI)m/z Calcd for[C18H21NNaO5,M+Na]+:354.1310,Found:354.1312.
Optical rotation value [ alpha ]]D 25＝-60.5(c＝0.25,CHCl3) (ii) a ee value: 92% (HPLC conditions: xylonite OD-H column, n-hexane/isopropanol 99:1, flow rate 1mL/min, detection wavelength 220 nm).
Example 4:
preparation of Compound 3d
In a 10mL reaction tube, indolone substrate 2d (0.2mmol,1.0equiv), peroxy substrate 1a (78mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved by addition of toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and thenThe reaction was carried out at temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give the chiral compound 3d 62mg in 82% yield.
A white solid.1H NMR(400MHz,CDCl3)δ7.95(d,J＝9.2Hz,1H),7.63–7.52(m,4H),7.44(t,J＝7.5Hz,2H),7.35(t,J＝7.3Hz,1H),5.18(s,1H),5.14(s,1H),4.91(d,J＝12.5Hz,1H),4.74(d,J＝12.5Hz,1H),3.09(d,J＝16.1Hz,1H),2.89(d,J＝16.1Hz,1H),1.65(s,9H).13C NMR(100MHz,CDCl3)δ175.01,149.08,145.29,140.11,139.01,138.26,129.01,128.80,128.52,127.39,126.85,122.41,115.60,106.19,84.55,82.56,72.37,42.02,28.04.HRMS(ESI)m/z Calcd for[C23H23NNaO4,M+Na]+:400.1517,Found:400.1519.
Optical rotation value [ alpha ]]D 25＝-40.3(c＝0.25,CHCl3) (ii) a ee value: 92% (HPLC conditions: xylonite AD-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 5:
preparation of Compound 3e
In a 10mL reaction tube, indolone substrate 2e (0.2mmol,1.0equiv), peroxygen substrate 1a (78mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved by addition of toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 3e 44mg, yield 65%.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.83(d,J＝9.3Hz,1H),7.37–7.28(m,2H),5.17(s,1H),5.12(s,1H),4.85(d,J＝12.6Hz,1H),4.68(d,J＝12.6Hz,1H),3.05(d,J＝16.1Hz,1H),2.79(d,J＝16.1Hz,1H),1.60(s,9H).13C NMR(100MHz,CDCl3)δ174.28,148.93,144.78,138.22,130.42,130.21,129.85,124.06,116.66,106.57,84.84,82.16,72.44,42.00,28.02.HRMS(ESI)m/z Calcd for[C17H18ClNNaO4,M+Na]+:358.0815,Found:358.0817.
Optical rotation value [ alpha ]]D 25＝-18.2(c＝0.25,CHCl3) (ii) a ee value: 90% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 6:
preparation of Compound 3f
In a 10mL reaction tube, indolone substrate 2f (0.2mmol,1.0equiv), peroxygen substrate 1a (78mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved with toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain 3f 59mg of the chiral compound in 85% yield.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.8Hz,1H),6.74(s,1H),6.70(d,J＝9.0Hz,1H),5.15(s,1H),5.10(s,1H),4.89(d,J＝12.6Hz,1H),4.70(d,J＝12.6Hz,1H),3.03(d,J＝16.2Hz,1H),2.93(s,6H),2.83(d,J＝16.2Hz,1H),1.61(s,9H).13C NMR(100MHz,CDCl3)δ175.44,149.23,148.63,145.74,129.96,128.60,116.01,114.05,107.93,105.74,83.88,83.03,72.31,42.10,40.95,28.07.HRMS(ESI)m/z Calcd for[C19H24N2NaO4,M+Na]+:367.1633,Found:367.1628.
Optical rotation value [ alpha ]]D 25＝-23.8(c＝0.25,CHCl3) (ii) a ee value: 87% (HPLC conditions: xylonite OD-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 7:
preparation of Compound 3g
In a 10mL reaction tube, 2g (0.2mmol,1.0equiv) of indolone substrate, 1a (78mg,0.24mmol,1.2equiv) of peroxy substrate, 4a (14mg,0.02mmol,0.1equiv) of phase transfer catalyst, followed by toluene/dichloromethane (2mL/0.4mL) were added in order to dissolve. 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain 3g of a chiral compound (52 mg) in a yield of 82%.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.2Hz,1H),7.30–7.20(m,1H),6.96(d,J＝7.7Hz,1H),5.13(s,2H),4.94(d,J＝12.5Hz,1H),4.70(d,J＝12.5Hz,1H),3.05(d,J＝16.8Hz,1H),2.97(d,J＝16.8Hz,1H),2.36(s,3H),1.62(s,9H).13C NMR(100MHz,CDCl3)δ175.99,149.14,145.60,140.02,135.85,129.86,127.09,124.83,112.65,105.95,84.36,83.57,72.59,39.46,28.05,17.52.HRMS(ESI)m/z Calcd for[C18H21NNaO4,M+Na]+:338.1361,Found:338.1363.
Optical rotation value [ alpha ]]D 25＝34.0(c＝0.25,CHCl3) (ii) a ee value: 88% (HPLC condition: xylonite IC-H columnN-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 8:
preparation of Compound 3h
In a 10mL reaction tube, indolone substrate 2h (0.2mmol,1.0equiv), peroxygen substrate 1a (78mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved with toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4Drying, filtering, concentrating, separating the residue by silica gel column chromatography, and purifying to obtain chiral compound 3h 47mg with yield 71%.
A white solid.1H NMR(400MHz,CDCl3)δ7.50(d,J＝8.2Hz,1H),7.30(t,J＝8.3Hz,1H),6.70(d,J＝8.4Hz,1H),5.08(s,1H),5.05(s,1H),4.81(d,J＝12.3Hz,1H),4.70(d,J＝12.3Hz,1H),3.85(s,3H),3.30(d,J＝16.0Hz,1H),2.83(d,J＝16.0Hz,1H),1.60(s,9H).13C NMR(100MHz,CDCl3)δ175.21,156.74,149.11,146.64,141.25,131.48,113.94,108.04,107.57,104.75,84.36,82.89,72.48,55.58,38.09,28.04.HRMS(ESI)m/z Calcd for[C18H21NNaO5,M+Na]+:354.1312,Found:354.1312.
Optical rotation value [ alpha ]]D 25＝-10.4(c＝0.3,CHCl3) (ii) a ee value: 88% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 70:30, flow rate 1mL/min, detection wavelength 220 nm).
Example 9:
preparation of Compound 3i
In a 10mL reaction tube, indolone substrate 2i (0.2mmol,1.0equiv), peroxygen substrate 1a (78mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved by addition of toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain 3i 42mg of chiral compound in 67% yield.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.24(d,J＝7.6Hz,1H),7.00(d,J＝7.6Hz,1H),5.15(s,1H),5.10(s,1H),4.86(d,J＝12.6Hz,1H),4.68(d,J＝12.6Hz,1H),3.02(d,J＝16.1Hz,1H),2.80(d,J＝16.1Hz,1H),2.39(s,3H),1.62(s,10H).13C NMR(100MHz,CDCl3)δ175.21,149.31,145.60,140.68,139.85,125.53,124.98,123.48,115.97,105.91,84.36,82.42,72.17,41.86,28.05,22.07.HRMS(ESI)m/z Calcd for[C18H21NNaO4,M+Na]+:338.1363,Found:338.1363.
Optical rotation value [ alpha ]]D 25＝-27.9(c＝0.25,CHCl3) (ii) a ee value: 88% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 10:
preparation of Compound 3j
In a 10mL reaction tube, indolone substrate 2a (0.2mmol,1.0equiv), peroxygen substrate 1b (85mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved by addition of toluene/dichloromethane (2mL/0.4 mL). At-60 deg.C, 80% aq. CsOH (26. mu.L, 0.4mmol, 2).0equiv) was added to the reaction tube, and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain 3j 52mg of the chiral compound with a yield of 79%.
A white solid.1H NMR(400MHz,CDCl3)δ7.87(d,J＝8.4Hz,1H),7.40–7.31(m,2H),7.18(t,J＝7.5Hz,1H),4.87(d,J＝12.0Hz,1H),4.70(d,J＝12.1Hz,1H),2.96(d,J＝16.1Hz,1H),2.72(d,J＝16.1Hz,1H),1.69(s,3H),1.66(s,3H),1.62(s,9H).13C NMR(100MHz,CDCl3)δ175.27,149.18,139.76,130.08,129.37,128.33,124.87,123.73,123.15,115.19,84.30,82.86,71.36,39.69,28.04,21.62,20.97.IR(KBr)3414,2924,2858,1776,1731,1466,1352,1290,1254,1152,1099,1009,749,467(cm-1).HRMS(ESI)m/z Calcd for[C19H23NNaO4,M+Na]+:352.15164,Found:352.15193.
Optical rotation value [ alpha ]]D 25＝1.7(c＝0.3,CHCl3) (ii) a ee value: 88% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 11:
preparation of Compound 3k
In a 10mL reaction tube, indolone substrate 2a (0.2mmol,1.0equiv), peroxygen substrate 1c (115mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved by addition of toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (26. mu.L, 0.4mmol,2.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4Drying, filtering, concentrating, and collecting the residueThe residue was separated and purified by silica gel column chromatography to give 3k 75mg of chiral compound in 83% yield.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.2Hz,1H),7.42(d,J＝7.3Hz,1H),7.34(t,J＝7.7Hz,3H),7.31–7.15(m,9H),5.12(d,J＝13.4Hz,1H),4.74(d,J＝13.4Hz,1H),3.13(d,J＝16.7Hz,1H),3.03(d,J＝16.7Hz,1H),1.63(s,9H).13C NMR(100MHz,CDCl3)δ174.88,148.97,141.61,141.22,139.77,135.81,134.64,130.24,128.75,128.64,128.35,128.21,127.78,127.12,126.91,124.89,123.73,115.25,84.42,82.35,72.00,41.70,28.02.HRMS(ESI)m/z Calcd for[C29H27NNaO4,M+Na]+:476.18271,Found:476.18323.
Optical rotation value [ alpha ]]D 25＝-62.9(c＝0.25,CHCl3) (ii) a ee value: 92% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 12:
preparation of Compound 3l
In a 10mL reaction tube, indolone substrate 2a (0.2mmol,1.0equiv), peroxygen substrate 1d (122mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved by addition of toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (26. mu.L, 0.4mmol,2.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give 3l of chiral compound 75mg in 78% yield.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.87(d,J＝8.2Hz,1H),7.47–7.08(m,13H),5.13(d,J＝12.5Hz,1H),4.94(d,J＝12.5Hz,1H),3.32(s,1H),3.27(s,1H),3.18(d,J＝16.2Hz,1H),2.94(d,J＝16.2Hz,1H),1.67(s,9H).13C NMR(100MHz,CDCl3)δ175.04,149.04,139.87,138.91,138.80,134.07,130.32,129.45,128.74,128.61,128.53,128.49,127.76,126.25,126.18,124.93,123.87,115.30,84.50,82.70,77.20,71.36,39.95,38.76,38.43,28.07.HRMS(ESI)m/z Calcd for[C31H31NNaO4,M+Na]+:504.21406,Found:504.21453.
Optical rotation value [ alpha ]]D 25＝30.1(c＝0.3,CHCl3) (ii) a ee value: 90% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 13:
preparation of Compound 3m
In a 10mL reaction tube, indolone substrate 2a (0.2mmol,1.0equiv), peroxygen substrate 1e (91mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved with toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain 3m 37mg of the chiral compound with a yield of 52%.
Brown solid.1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.2Hz,1H),7.43–7.21(m,3H),7.19–7.11(m,2H),7.04(t,J＝7.5Hz,1H),6.87(d,J＝7.5Hz,1H),5.21(d,J＝14.8Hz,1H),4.95(d,J＝14.8Hz,1H),3.36(d,J＝16.1Hz,1H),2.98(d,J＝16.1Hz,1H),1.64(s,9H).13C NMR(100MHz,CDCl3)δ173.26,149.14,139.39,134.37,130.28,130.02,128.77,128.56,127.14,126.73,124.60,124.16,124.02,115.32,84.55,74.75,64.91,34.37,28.04.HRMS(ESI)m/z Calcd for[C21H21NNaO4,M+Na]+:374.1351,Found:374.1363.
Optical rotation value [ alpha ]]D 25＝24.5(c＝0.25,CHCl3) (ii) a ee value: 90% (HPLC conditions: xylonite AD-H column, n-hexane/isopropanol 95:5, flow rate 1mL/min, detection wavelength 220 nm).
Example 14:
preparation of Compound 3n
In a 10mL reaction tube, indolone substrate 2b (0.2mmol,1.0equiv), peroxygen substrate 1e (91mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved with toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain 3n 37mg of the chiral compound in 51% yield.
A white solid.1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.4Hz,1H),7.36–7.21(m,2H),7.19–7.10(m,3H),6.72(s,1H),5.21(d,J＝14.8Hz,1H),4.93(d,J＝14.8Hz,1H),3.29(d,J＝16.3Hz,1H),3.00(d,J＝16.3Hz,1H),2.22(s,3H),1.62(s,9H).13C NMR(100MHz,CDCl3)δ173.38,149.18,136.96,134.36,130.50,130.25,128.68,127.07,126.64,124.46,124.14,115.11,84.37,74.76,64.92,34.31,28.04,20.98.HRMS(ESI)m/z Calcd for[C22H23NNaO4,M+Na]+:388.1506,Found:388.1519.
Optical rotation value [ alpha ]]D 25＝-19.36(c＝0.25,CHCl3) (ii) a ee value: 94% (HPLC conditions: xylonite AD-H column, n-hexane/isopropanol 95:5, flow rate 1mL/min, detection wavelength 220 nm).
Example 15:
preparation of Compound 3o
In a 10mL reaction tube, indolone substrate 2c (0.2mmol,1.0equiv), peroxygen substrate 1e (91mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved with toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give the chiral compound 3o 39mg, yield 51%.
A white solid.1H NMR(400MHz,CDCl3)δ7.83(dd,J＝9.0,1.8Hz,1H),7.33–7.21(m,2H),7.15(d,J＝6.2Hz,2H),6.86(dt,J＝9.0,2.4Hz,1H),6.41(t,J＝2.3Hz,1H),5.22(d,J＝14.8Hz,1H),4.95(d,J＝14.8Hz,1H),3.66(s,3H),3.34(d,J＝16.1Hz,1H),2.97(d,J＝16.1Hz,1H),1.63(s,9H).13C NMR(100MHz,CDCl3)δ173.45,156.81,149.22,134.48,132.60,130.25,129.90,128.77,127.20,126.81,124.22,116.30,114.61,110.27,110.18,84.37,74.98,65.04,55.51,55.43,34.54,28.08.HRMS(ESI)m/z Calcd for[C22H23NNaO5,M+Na]+:404.1453,Found:404.1468.
Optical rotation value [ alpha ]]D 25＝-17.28(c＝0.25,CHCl3) (ii) a ee value: 89% (HPLC conditions: xylonite AD-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 16:
preparation of Compound 3p
In a 10mL reaction tube, indolone substrate 2e (0.2mmol,1.0equiv), peroxy substrate 1e (91mg,0.24mmol,1.2equiv), phase transfer catalyst 4a (14mg,0.02mmol,0.1equiv) were added sequentially and then dissolved by addition of toluene/dichloromethane (2mL/0.4 mL). 80% aq. CsOH (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give 3p 45mg of chiral compound in 58% yield.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.88(d,J＝8.8Hz,1H),7.37–7.23(m,3H),7.16(d,J＝7.1Hz,2H),6.81(d,J＝2.3Hz,1H),5.20(d,J＝14.8Hz,1H),4.93(d,J＝14.8Hz,1H),3.33(d,J＝16.2Hz,1H),2.97(d,J＝16.2Hz,1H),1.63(s,9H).13C NMR(100MHz,CDCl3)δ172.70,148.97,137.85,134.21,130.42,130.10,129.97,129.72,128.71,127.37,126.98,124.29,124.24,116.65,84.92,74.66,65.06,34.34,28.01.HRMS(ESI)m/z Calcd for[C21H20ClNNaO4,M+Na]+:408.0959,Found:408.0973.
Optical rotation value [ alpha ]]D 25＝-15.6(c＝0.25,CHCl3) (ii) a ee value: 89% (HPLC conditions: xylonite AD-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
It is noted herein that the above-mentioned embodiments illustrate rather than limit the technical solution of the present invention, and although the present invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention.
Claims (8)
1. A general synthetic method for preparing chiral oxygen heterocyclic compound by novel [4+1] and [5+1] cyclization strategies is disclosed, and the reaction formula is shown as follows:
wherein R is1May be a substituent such as a sulfonyl group (e.g., methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, benzenesulfonyl, etc.), a halogen atom (e.g., chlorine, bromine, iodine, etc.); a can be carbon, oxygen, sulfur atom; b can be carbon, oxygen, sulfur atom; r2Can be hydrogen, alkyl (such as methyl, isopropyl, tert-butyl, cyclohexyl, cyclopentyl, etc.), aryl (such as phenyl, p-methoxyphenyl, p-methylphenyl, etc.), etc.; r3May be an alkyl group (e.g., methyl, ethyl, isopropyl, allyl, etc.), an aryl group (e.g., phenyl, thiophene, furan, naphthalene, etc.), a carbonyl group, a sulfonyl group, a phosphoryl group, a cyano substituent, etc.; r4There may be mentioned alkyl groups (e.g., methyl, ethyl, isopropyl, etc.), aryl groups (phenyl, thiophene, furan, naphthalene, etc.), carbonyl groups, acyl groups (benzoyl, acetyl, furoyl, sulfonyl, phosphoryl, etc.), cyano substituents, etc.
2. The synthesis method of claim 1, wherein the chiral oxygen-containing compound is synthesized by using a phase transfer catalyst, and the catalyst structure is shown in the following figure:
wherein R is5Hydrogen, benzyl, allyl, pivaloyl, adamantanoyl, benzoyl, 3, 5-dimethylbenzoyl, 2,4, 6-trimethylbenzoyl, 4-tert-butylbenzoyl, 2-chlorobenzoyl, 1-naphthoyl, 2-naphthoyl, trimethylsilenyl, triethylsilyl, N-phosphono-alpha-amino ester, N-Boc-alpha-amino ester; wherein the N-phosphono- α -amino ester, N-Boc- α -amino ester is optionally substituted with one or more substituents independently selected from: hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, cyclohexyl; r6Is hydrogen or methoxy; ar is phenyl, 3, 5-diphenyl2, 6-diphenyl, 3, 5-diphenyl-4-dimethyl-t-butylsiloxyphenyl, 1-naphthyl, 2-phenyl-1-naphthyl, 2-naphthyl, 9-anthryl, 9-phenanthryl, pyrenyl and the like.
3. The synthesis process according to claim 1, wherein the chiral oxygen-containing compound is synthesized by using 5 mol% to 20 mol% of the catalyst.
4. The synthesis method according to claim 1, wherein the base used is an aqueous basic solution or a solid base, and may be sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, etc., wherein the aqueous cesium hydroxide solution is the optimum base.
5. The synthesis method of claim 1, wherein the chiral oxygen-containing compound is synthesized by using an aqueous alkali solution, wherein the mass concentration of the alkali is 5-90%.
6. The process as claimed in claim 1, wherein the chiral oxygen-containing compound is synthesized at a reaction temperature of-78 ℃ to 25 ℃.
7. The synthesis method according to claim 1, wherein the organic solvent used is 1, 2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, t-butyl methyl ether, N-dimethylformamide, N-dimethylacetamide, acetone, acetonitrile, toluene, fluorobenzene, chlorobenzene, or the like, and any two of them are mixed solvents.
8. The synthetic method of claim 1 wherein the substrate concentrations are: 0.05 to 2.0 mol/L.
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| CN102093370A (en) * | 2011-01-14 | 2011-06-15 | 华南理工大学 | Spirosthydroxyindole heterocyclic compounds and preparation method and use thereof |
| CN102675339A (en) * | 2012-04-27 | 2012-09-19 | 华南理工大学 | Screw epoxidation indole heterocyclic compound as well as synthetic method and purpose thereof |
| CN106188078A (en) * | 2016-07-15 | 2016-12-07 | 苏州大学 | A kind of chiral spiro hydroxyindole benzopyrone the synthetic method of 3,4 dihydropyrane compounds |
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2021
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093370A (en) * | 2011-01-14 | 2011-06-15 | 华南理工大学 | Spirosthydroxyindole heterocyclic compounds and preparation method and use thereof |
| CN102675339A (en) * | 2012-04-27 | 2012-09-19 | 华南理工大学 | Screw epoxidation indole heterocyclic compound as well as synthetic method and purpose thereof |
| CN106188078A (en) * | 2016-07-15 | 2016-12-07 | 苏州大学 | A kind of chiral spiro hydroxyindole benzopyrone the synthetic method of 3,4 dihydropyrane compounds |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114105860A (en) * | 2021-11-12 | 2022-03-01 | 重庆大学 | Catalytic asymmetric synthesis method and application of chiral oxindole spiro-analogue |
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