CN112920221A - 具有螺双二氢苯并噻咯骨架的手性磷酸及其制备方法与用途 - Google Patents
具有螺双二氢苯并噻咯骨架的手性磷酸及其制备方法与用途 Download PDFInfo
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- CN112920221A CN112920221A CN202110103676.3A CN202110103676A CN112920221A CN 112920221 A CN112920221 A CN 112920221A CN 202110103676 A CN202110103676 A CN 202110103676A CN 112920221 A CN112920221 A CN 112920221A
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- Prior art keywords
- phosphoric acid
- chiral
- compound
- chiral phosphoric
- reaction
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 229910000147 aluminium phosphate Inorganic materials 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 10
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 239000010703 silicon Substances 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 30
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 230000026731 phosphorylation Effects 0.000 claims description 2
- 238000006366 phosphorylation reaction Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 30
- 239000003054 catalyst Substances 0.000 abstract description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 30
- 235000011007 phosphoric acid Nutrition 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- -1 amino compound Chemical class 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 102100030621 Carboxypeptidase A4 Human genes 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 101100112225 Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139) cpa-1 gene Proteins 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FLEHQRTTWKDNGI-XTJILODYSA-N (1s,3r)-5-[(2e)-2-[(7ar)-1-[(2s)-5-(cyclopropylamino)pentan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-2-methylidenecyclohexane-1,3-diol Chemical compound C([C@H](C)C1[C@]2(CCCC(/C2CC1)=C\C=C1C[C@@H](O)C(=C)[C@@H](O)C1)C)CCNC1CC1 FLEHQRTTWKDNGI-XTJILODYSA-N 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000004679 31P NMR spectroscopy Methods 0.000 description 5
- 102100030613 Carboxypeptidase A1 Human genes 0.000 description 5
- 101000772551 Homo sapiens Carboxypeptidase A1 Proteins 0.000 description 5
- 101000772572 Homo sapiens Carboxypeptidase A4 Proteins 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 description 4
- 102100030614 Carboxypeptidase A2 Human genes 0.000 description 4
- 108091006675 Monovalent cation:proton antiporter-2 Proteins 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 4
- HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 125000003003 spiro group Chemical group 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 108091006676 Monovalent cation:proton antiporter-3 Proteins 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000006086 Paal-Knorr synthesis reaction Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000003016 phosphoric acids Chemical class 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 102100026794 Carboxypeptidase A5 Human genes 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 101000910789 Homo sapiens Carboxypeptidase A5 Proteins 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000002642 lithium compounds Chemical class 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FLEHQRTTWKDNGI-WSGFCWAJSA-N (1r,3r)-5-[(2e)-2-[(1r,3as,7ar)-1-[(2r)-5-(cyclopropylamino)pentan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-2-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C1C[C@@H](O)C(=C)[C@H](O)C1)C)CCNC1CC1 FLEHQRTTWKDNGI-WSGFCWAJSA-N 0.000 description 1
- DJGHSJBYKIQHIK-UHFFFAOYSA-N (3,5-dimethylphenyl)boronic acid Chemical compound CC1=CC(C)=CC(B(O)O)=C1 DJGHSJBYKIQHIK-UHFFFAOYSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HFZZPWGYPHTLQU-UHFFFAOYSA-N 1-phenyl-3H-benzo[e]indole Chemical class C=1NC2=CC=C3C=CC=CC3=C2C=1C1=CC=CC=C1 HFZZPWGYPHTLQU-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- AEIOZWYBDBVCGW-UHFFFAOYSA-N 2-tert-butylaniline Chemical compound CC(C)(C)C1=CC=CC=C1N AEIOZWYBDBVCGW-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 238000006783 Fischer indole synthesis reaction Methods 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000007059 Strecker synthesis reaction Methods 0.000 description 1
- 102100030302 TBC1 domain family member 8 Human genes 0.000 description 1
- BPTABBGLHGBJQR-UHFFFAOYSA-N [3,5-bis(trifluoromethyl)phenyl]boronic acid Chemical compound OB(O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 BPTABBGLHGBJQR-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- VHHDLIWHHXBLBK-UHFFFAOYSA-N anthracen-9-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=C(C=CC=C3)C3=CC2=C1 VHHDLIWHHXBLBK-UHFFFAOYSA-N 0.000 description 1
- 125000005577 anthracene group Chemical group 0.000 description 1
- 238000006208 aza-Diels-Alder reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- CVDGHGWEHQIJTE-UHFFFAOYSA-N bromo(bromomethoxy)methane Chemical compound BrCOCBr CVDGHGWEHQIJTE-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- YNXURHRFIMQACJ-UHFFFAOYSA-N lithium;methanidylbenzene Chemical compound [Li+].[CH2-]C1=CC=CC=C1 YNXURHRFIMQACJ-UHFFFAOYSA-N 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical group [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- JCDAUYWOHOLVMH-UHFFFAOYSA-N phenanthren-9-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC3=CC=CC=C3C2=C1 JCDAUYWOHOLVMH-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000005954 phosphonylation reaction Methods 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- AAAQKTZKLRYKHR-UHFFFAOYSA-N triphenylmethane Chemical compound C1=CC=CC=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 AAAQKTZKLRYKHR-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明属于有机合成领域，公开了一种具有螺双二氢苯并噻咯骨架的手性磷酸，具有通式Ⅰ的结构：
其中，Ar选自
中的一种，R选自烷基、环烷基、烷氧基、三氟甲基、卤素、硝基、芳基中的一种，m表示1～5的整数，当取代基为多个时，R相同或不同，*表示手性硅中心，其为S构型手性硅或R手性硅。本发明还公开了手性磷酸的制备方法。本发明构建了一类结构新颖的手性磷酸，丰富了手性磷酸催化剂的种类，与现有手性磷酸相比，本发明的手性磷酸在催化不对称反应方面具有更优异的对映选择性。
Description
技术领域
本发明属于有机合成领域，具体是一种具有螺双二氢苯并噻咯骨架的手性磷酸及其制备方法与用途。
背景技术
有机小分子催化剂促进的不对称催化反应是有机合成化学研究的前沿和热点。其中，以手性磷酸为催化剂的不对称催化反应是合成手性化合物的重要方法之一，并已在手性医药、农药、香料以及功能材料等的合成中得到广泛的应用。但迄今为止，已报道的能够被广泛使用的优势手性磷酸催化剂骨架并不多，主要以轴手性联萘、螺二氢茚为主。其中，螺二氢茚为手性全碳螺环结构，以其作为手性骨架的配体和催化剂在有机不对称催化氢化、不对称碳-碳键、碳-杂键的形成等多种类型的反应中均表现出优异的催化活性和对映选择性，但其全碳螺环结构导致其可改造空间较少，因此，设计开发具有新型骨架的手性磷酸具有重要的科研意义和社会价值。
发明内容
本发明的目的是提供一种结构新颖的、具有螺双二氢苯并噻咯骨架的手性磷酸。
本发明的另一目的是提供该手性磷酸的制备方法。
本发明的另一目的是提供该手性磷酸的用途。
为达到上述目的之一，本发明采用以下技术方案：
一种具有螺双二氢苯并噻咯骨架的手性磷酸，其具有通式Ⅰ的结构：
其中，Ar选自
中的一种，R选自烷基、环烷基、烷氧基、三氟甲基、卤素、硝基、芳基中的一种，m表示1～5的整数，当取代基为多个时，R相同或不同，*表示手性硅中心，其为S构型手性硅或R手性硅。
进一步地，所述Ar选自
中的一种。
进一步地，所述R选自烷基、环烷基、烷氧基、三氟甲基、卤素中的一种。
进一步地，所述R选自烷基或三氟甲基。
进一步地，所述R选自(C1-C4)烷基或三氟甲基。
进一步地，所述R选自甲基或三氟甲基。
进一步地，所述m表示1或2。
进一步地，所述手性硅中心为S构型手性硅。
进一步地，手性磷酸选自以下化合物中的一种：
一种手性磷酸的制备方法，包括以下步骤：
化合物1和MOMBr反应，得到化合物2；
化合物2和单质碘反应，得到化合物3；
化合物3和Rm-Ar-B(OH)2反应，得到化合物4；
化合物4脱保护得到化合物5；
化合物5磷酸化得到产物。
进一步地，包括以下步骤：
化合物1和无机强碱、MOMBr反应，得到化合物2；无机强碱为碱金属氢化物或氨基化合物，碱金属氢化物具体如氢化钠、氢化钾，氨基化合物具体如氨基钾、氨基钠，最优的无机强碱为钠氢。
化合物2和有机强碱、单质碘反应，得到化合物3；有机强碱为有机金属锂化合物、醇钠、醇钾，有机金属锂化合物具体如正丁基锂、叔丁基锂、仲丁基锂、二异丙基氨锂、苄基锂等，醇钠具体如甲醇钠、乙醇钠、叔丁醇钠，醇钾具体如甲醇钾、乙醇钾、叔丁醇钾，最优选的有机强碱为正丁基锂。
化合物3和Rm-Ar-硼酸、钯催化剂、无机钾盐反应，得到化合物4；钯催化剂如钯碳、醋酸钯、PdCl2(dppf)、Pd(PPh3)4、(PPh3)2PdCl2，无机钾盐如磷酸钾、碳酸钾。
化合物4和酸反应得到化合物5；典型的酸如盐酸。
化合物5和三氯氧磷、吡啶反应后水解得到手性磷酸。
本发明的手性磷酸可以用于各种不对称反应，包括亚胺的加成和还原反应、Mannich反应、亚胺的氢转移、亚胺的膦酰化、Strecker反应、aza-Diels-Alder反应、α-重氮酯的烷基化反应、烯丙基化反应、Friedel-Crafts烷基化反应、费歇尔吲哚合成反应、去芳化反应、环加成反应、插入反应、去对称性反应、皮克特-施彭格勒反应、Paal-Knorr反应、多组分反应、共轭加成反应等，尤其是用于2-甲基吲哚与2-萘偶氮酯类化合物不对称反应构建1-苯基-3H-苯并[e]吲哚类化合物。
本发明所用的“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。烷基基团的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基、3-甲基戊基。
本发明所用的“环烷基”指非芳族碳环，其通常具有3至8个环碳原子。所述环可以是饱和的或具有一个或更多个碳-碳双键。环烷基基团的实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基或环庚基。
本发明所用的“烷氧基”是指-O-烷基基团，其中烷基如上所定义。本文所用烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基。烷氧基还包括取代烷氧基。烷氧基可任选被卤素取代一次或多次。
本发明所用的“芳基”是指5-12个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳基的非限制性实例有：苯环、萘环、蒽环。
本发明具有以下有益效果：
1、本发明构建了一类结构新颖的手性磷酸，丰富了手性磷酸催化剂的种类，为应对有机小分子催化在立体选择调控中面临的挑战提供了新的选择。
2、本发明提供了一条全新的路线合成具有螺双二氢苯并噻咯骨架的手性磷酸。
3、本发明的手性磷酸与目前商业可得的螺二氢茚骨架磷酸相比，在催化不对称反应方面具有更优异的对映选择性，具有良好的应用前景。
附图说明
图1为化合物CPA1的X射线单晶衍射图。
具体实施方式
除非另有说明，化学品均购自商业化产品并且不经进一步纯化。实验中使用的四氢呋喃、二氯甲烷、甲苯均为分析纯溶剂。薄层色谱分析(TLC)使用GF254硅胶板。硅胶柱层析使用青岛海洋硅胶(粒径0.040-0.063mm)。TLC显色采用UV光(254nm)或碘。NMR图谱使用Bruker DPX 400或DPX 500核磁共振仪表征，1H NMR为400MHz，13C NMR为100MHz，溶剂为氘代氯仿或氘代二氯甲烷，以四甲基硅烷(TMS)为内标。化学位移的单位是ppm，耦合常数的单位是Hz。在1HNMR中，δ表示化学位移，s表示单峰，d表示双峰，t表示三重峰，q表示四重峰，p表示五重峰，m表示多重峰，br表示宽峰。
实施例1
化合物(S)-3的合成
氩气氛围下，将NaH(2.0g,50mmol)和20mL THF置于双颈瓶中，0℃下滴加原料(S)-1(2.68g,10mmol,合成参考：Angew.Chem.Int.Ed.2020,59,8937–8940)的THF(15mL)溶液，滴加完毕继续搅拌2h，随后滴加MOMBr(溴甲基甲醚，2mL)的THF(10mL)溶液。缓慢升至室温搅拌至原料消失。反应完毕向体系中加入饱和氯化铵溶液，二氯甲烷萃取，合并有机层，经饱和食盐水洗涤、无水Na2SO4干燥后，旋干溶剂，并向浓缩物加入10mL甲醇中，搅拌2h，抽滤得白色固体(S)-2。收率89％。
氩气氛围下，将(S)-2(2.0g,5.6mmol)、1.69mL TMEDA(四甲基乙二胺)和25mL无水乙醚置于100mL封管中，降至-78℃，缓慢滴加n-BuLi(1.6M in n-hexane,10.5mL)，滴加完毕缓慢升至室温，搅拌5h后复降至-78℃，滴加碘的乙醚溶液(4.3g in 25mL)，滴加完毕缓慢升至室温，继续搅拌过夜。原料消失后加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，合并有机层，经饱和食盐水洗涤，无水Na2SO4干燥后，旋干溶剂。浓缩物经快速柱层析(PE/EA＝50:1)得黄色固体(S)-3。收率73％。1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.0Hz,2H),6.86(d,J＝8.0Hz,2H),4.83(d,J＝5.2Hz,2H),4.65(d,J＝5.6Hz,2H),3.29(s,6H),3.28–3.13(m,4H),1.52–1.46(m,2H),1.28–1.14(m,2H)。
实施例2
CPA1的合成
第一步：化合物(S)-4-A的合成
氩气氛围下，将中间体(S)-3(1.2g,2.0mmol)、1-萘硼酸(8.0mmol)、Pd/C(200mg)和1.1g K2CO3，置于100mL封管中，加入20mL二氧六环和20mL水，排气15min，塞上盖子加热至100℃反应24h。反应完毕用硅藻土过滤，滤液用乙酸乙酯萃取，合并有机层，经饱和食盐水洗涤，无水Na2SO4干燥后旋干经快速柱层析(PE/EA＝50:1)得白色固体(S)-4-A。收率89％。1H NMR(400MHz,CDCl3)δ7.87–7.81(m,4H),7.71(d,J＝8.0Hz,1H),7.61(d,J＝8.4Hz,1H),7.51–7.38(m,7H),7.35–7.26(m,3H),7.18(d,J＝7.5Hz,2H),4.43–4.23(m,4H),3.43–3.28(m,4H),2.39(d,J＝3.0Hz,3H),2.33(d,J＝3.0Hz,3H),1.69–1.62(m,2H),1.38–1.34(m,4H)。
第二步：化合物(S)-5-A的合成
将中间体(S)-4-A(608mg,1.0mmol)溶于10mL二氯甲烷中，加入2mL 6N HCl，搅拌24h。反应完毕有机层经快速柱层析(PE/DCM＝5:1)得白色固体(S)-5-A。收率53％；1H NMR(400MHz,CDCl3)δ7.90–7.84(m,4H),7.75(t,J＝7.6Hz,1H),7.66–7.59(m,1H),7.54–7.39(m,7H),7.35–7.31(m,1H),7.23–7.20(m,2H),6.98(dd,J＝6.8,4.4Hz,2H),4.93(s,1H),4.90(s，1H),3.38–3.21(m,4H),1.62–1.56(m,2H),1.35–1.28(m,2H)。
第三步：手性磷酸CPA1的合成
氩气氛围下，将中间体(S)-5-A(300mg,0.6mmol)加入干燥的反应管中，加入干燥的吡啶(3毫升)，然后在室温下滴加三氯氧磷(154μL，1.2mmol)，滴加完成后升温至90℃，反应16小时。停止加热，降至室温后滴加入0.5毫升去离子水，然后升温至90℃，继续反应12小时。停止加热，加入浓盐酸将溶液的pH值调至1～2，二氯甲烷萃取两次，合并有机相，经饱和食盐水洗涤，无水硫酸钠干燥，减压旋蒸除去溶剂。所得的粗产物经快速柱层析(DCM/MeOH＝200:1)纯化，得到淡黄色油状物。将所得产物溶解于二氯甲烷(10毫升)，并加入4摩尔/升的盐酸(10毫升)酸化过夜，萃取分离出二氯甲烷溶液，减压旋蒸除去溶剂，得到磷酸CPA1，收率63％。1H NMR(600MHz,DMSO)δ7.81(s,6H),7.43–7.34(m,12H),3.38(s,1H),3.32(d,J＝8.4Hz,4H),1.54(d,J＝13.2Hz,2H),1.42–1.36(m,2H).13C NMR(101MHz,CDCl3)δ160.7(d,J＝53.2Hz),156.8,140.8(d,J＝35.7Hz),138.9,137.8,136.9,136.2(d,J＝32.2Hz),133.9,133.2,132.7(d,J＝17.7Hz),1325(d,J＝16.6Hz),131.8,131.3–130.4(m),130.0,128.3,127.3,36.1,19.6.31P NMR(162MHz,CDCl3)δ-13.5.ESI-MS:m/z＝581[M-H]-。
实施例3
CPA2的合成
第一步：化合物(S)-4-B的合成
(S)-4-B的合成参考化合物(S)-4-A的合成路线，将1-萘硼酸替换成3,5-二甲基苯硼酸。收率88％；1H NMR(400MHz,CDCl3)δ7.33(d,J＝7.6Hz,2H),7.15(d,J＝10.8Hz,6H),6.93(s,2H),4.50(d,J＝5.6Hz,2H),4.38(d,J＝5.6Hz,2H),3.43–3.35(m,2H),3.30–3.22(m,2H),2.75(s,6H),2.34(s,12H),1.66–1.59(m,2H),1.32–1.24(m,2H)。
第二步：化合物(S)-5-B的合成
(S)-5-B的合成参考化合物(S)-5-A的合成路线。收率70％；1H NMR(400MHz,CDCl3)δ7.25(s,1H),7.23(s,1H),7.06(s,4H),7.01(s,2H),7.00(d,J＝7.6Hz,2H),5.43(s,2H),3.40–3.32(m,2H),3.27–3.19(m,2H),2.35(s,12H),1.61–1.54(m,2H),1.31–1.25(m,2H)。
第三步：手性磷酸CPA2的合成
CPA2的合成参考化合物CPA1的合成路线。收率74％；1H NMR(400MHz,CDCl3)δ7.42(d,J＝7.6Hz,2H),7.23(d,J＝7.6Hz,2H),7.00(s,4H),6.79(s,2H),3.31(s,1H),3.26–3.14(m,4H),2.12(s,12H),1.41(t,J＝7.6Hz,4H).13C NMR(100MHz,CDCl3)δ155.4(d,J＝2.2Hz),150.7(d,J＝8.2Hz),137.8,134.3(d,J＝1.8Hz),133.4(d,J＝3.4Hz),129.7(d,J＝3.0Hz),128.2,127.3,123.4(d,J＝1.9Hz),31.4,21.1,14.5.31P NMR(162MHz,CDCl3)δ-12.4.ESI-MS:m/z＝537[M-H]-。
实施例4
CPA3的合成
第一步：化合物(S)-5-C的合成
氩气氛围下，将中间体(S)-3(1.2g,2.0mmol)、9-蒽硼酸(2.64g,12.0mmol)、Pd(PPh3)4(708mg)和5.0g磷酸钾置于100mL封管中，加入70mL乙二醇二甲醚，排气15min，塞上盖子加热至120℃反应48h。反应完用乙酸乙酯萃取，合并有机层，经饱和食盐水洗涤，无水Na2SO4干燥，减压旋蒸除去溶剂，浓缩物经快速柱层析(PE/EA＝50:1)得黄色固体(S)-4-C，收率70％。
(S)-5-C的合成参考化合物(S)-5-A的合成路线。收率60％；1H NMR(400MHz,CDCl3)δ8.57(s,2H),8.11(t,J＝7.6Hz,4H),7.83(d,J＝8.4Hz,2H),7.64(d,J＝8.8Hz,2H),7.55–7.45(m,6H),7.28–7.18(m,4H),7.08(d,J＝7.6Hz,2H),4.63(s,1H),3.45–3.30(m,4H),1.72–1.65(m,2H),1.47–1.39(m,2H)。
第二步：手性磷酸CPA3的合成
CPA3的合成参考化合物CPA1的合成路线。收率40％；1H NMR(400MHz,CDCl3)δ8.13(s,2H),7.82–7.76(m,4H),7.69–7.61(m,4H),7.38–7.30(m,8H),7.19–7.17(m,4H),3.44–3.32(m,4H),1.92(s,1H),1.67–1.55(m,4H).13C NMR(100MHz,CDCl3)δ156.5,152.3(d,J＝8.9Hz),137.4,132.2,131.3,130.8,130.8,129.6,129.4,128.9,128.9,128.4,128.1,127.9,127.1,126.5,125.9,124.9,124.8,123.3,31.5,14.8.31P NMR(162MHz,CDCl3)δ-11.83.ESI-MS:m/z＝681[M-H]-。
实施例5
CPA4的合成
第一步：化合物(S)-4-D的合成
(S)-4-D的合成参考化合物(S)-4-A的合成路线，将1-萘硼酸替换成3,5-双三氟甲基苯硼酸。收率87％；1H NMR(400MHz,CDCl3)δ8.02(s,4H),7.83(s,2H),7.40(d,J＝8.0Hz,2H),7.29(d,J＝7.6Hz,2H),4.51(d,J＝6.0Hz,2H),4.40(d,J＝6.0Hz,2H),3.46–3.29(m,4H),2.73(s,6H),1.70–1.60(m,2H),1.39–1.29(m,2H)。
第二步：化合物(S)-5-D的合成
(S)-5-D的合成参考化合物(S)-5-A的合成路线。收率47％；1H NMR(400MHz,CDCl3)δ7.96(s,4H),7.83(s,2H),7.34(d,J＝7.6Hz,2H),7.08(d,J＝7.6Hz,2H),4.81(s,2H),3.40–3.24(m,4H),1.63–1.55(m,2H),1.44–1.37(m,2H)。
第三步：手性磷酸CPA4的合成
CPA4的合成参考化合物CPA1的合成路线。收率62％；1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.53(s,4H),7.32(s,2H),3.35(s,4H),3.31–3.18(m,4H),1.50–1.43(m,4H).13CNMR(101MHz,CDCl3)δ157.3(d,J＝2.0Hz),149.9(d,J＝8.3Hz),139.8,134.7,131.3(q,J＝33.1Hz),130.7(d,J＝3.5Hz),129.9(d,J＝3.0Hz),129.3,126.0(q,J＝272.7Hz),124.1(d,J＝1.8Hz),120.6,31.6,14.3.19F NMR(376MHz,CDCl3)δ62.65.31P NMR(162MHz,CDCl3)δ-8.52.ESI-MS:m/z＝753[M-H]-。
实施例6
CPA5的合成
第一步：化合物(S)-4-E的合成
(S)-4-E的合成参考化合物(S)-4-A的合成路线，将1-萘硼酸替换成9-菲硼酸。收率93％；1H NMR(400MHz,CDCl3)δ8.80–8.76(m,4H),7.96(dd,J＝16.0,7.6Hz,2H),7.81(s,2H),7.75–7.61(m,9H),7.49–7.93(m,3H),7.24(d,J＝7.2Hz,2H),4.60–4.41(m,4H),3.44–3.38(m,4H),2.47(dd,J＝17.6,7.6Hz,6H),1.74(s,2H),1.60–1.43(m,2H)。
第二步：化合物(S)-5-D的合成
(S)-5-E的合成参考化合物(S)-5-A的合成路线。收率60％；1H NMR(400MHz,CDCl3)δ8.82–8.73(m,4H),7.96–7.86(m,3H),7.80–7.57(m,10H),7.44–7.35(m,3H)7.11(t,J＝6.8Hz,2H),5.13–5.10(m,2H),3.49–3.33(m,4H),1.78–1.73(m,2H),1.48–1.40(m,2H)。
第三步：手性磷酸CPA4的合成
CPA5的合成参考化合物CPA1的合成路线。收率72％；1H NMR(600MHz,DMSO)δ8.73(s,4H),7.79–7.38(m,17H),3.77(s,1H),3.34(s,4H),1.58–1.56(m,2H),1.44(s,2H).13CNMR(101MHz,CDCl3)δ161.2,157.1,140.9,140.5,139.5,138.6,136.3,136.1(d,J＝9.1Hz),135.5(d,J＝9.2Hz),134.6(t,J＝9.8Hz),133.9,133.7,132.7,131.8(d,J＝8.2Hz),131.4,131.2(d,J＝11.9Hz),128.4,128.2,127.7,127.3,36.2,19.6.31P NMR(162MHz,CDCl3)δ-11.94.ESI-MS:m/z＝681[M-H]-。
实施例7
CPA1的单晶培养：将5mg CPA1溶于1mL DCM中，逐滴滴加0.5mL甲醇，超声待完全溶解，过滤至2mL小瓶中，加具孔瓶塞，静至1-3天，析出晶体。收集并对其进行单晶衍射实验。结果如图1所示，为S构型。
实施例8
手性磷酸的应用
空气氛围中，于10mL封管中依次加入2-萘偶氮酯衍生物(21.4mg，0.1mmol)、2-甲基吲哚(15.7mg，0.12mmol)、1mol％的CPA和4mL二氯甲烷，将反应于室温下搅拌反应6h，待反应原料消失，减压蒸馏除去溶剂，以三苯基甲烷为内标，利用粗反应的1H NMR来测定产物的收率，快速柱层析得产物，用来测定对映体过量比(ee)。
以上数据可以看出，本发明的以螺双二氢苯并噻咯为骨架的手性磷酸CPA1、CPA2和CPA4能够以较高收率和优秀的立体选择性催化该反应的进行，说明该发明的催化剂具有较好的应用价值。
1H NMR(400MHz,CDCl3)δ7.84(d,J＝7.8Hz,1H),7.74(d,J＝8.1Hz,1H),7.60(d,J＝8.7Hz,1H),7.52–7.37(m,2H),7.37–7.09(m,4H),6.98–6.74(m,2H),4.27(s,2H),3.63(s,2H),2.21(s,3H),1.32(s,3H).HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝254nm,tR(minor)＝6.6min,tR(major)＝22.6min。
实施例9
手性磷酸的对比
空气氛围中，于2mL小瓶中依次加入吲哚(18mg，0.15mmol)、硝基烯烃衍生物(17.9mg，0.1mmol)、1mol％的CPA和0.5mL二氯甲烷，将反应于室温下搅拌反应6天，快速柱层析得产物，用来测定对映体过量比(ee)。
以上数据可以看出，以螺双二氢苯并噻咯为骨架的手性磷酸CPA-4和CPA-5在控制该反应的立体选择性方面较以螺二氢茚为骨架的手性磷酸C-CPA-4和C-CPA-5更优；特别是CPA-4，是C-CPA-4的3-4倍。
1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.45(d,J＝8.0Hz,1H),7.37(d,J＝8.4Hz,1H),7.27–7.23(m,2H),7.21–7.18(m,1H),7.08(t,J＝7.2Hz,1H),7.02(d,J＝2.4Hz,1H),6.91–6.78(m,2H),5.14(t,J＝8.0Hz,1H),5.07(dd,J＝12.3,7.5Hz,1H),4.90(dd,J＝12.3,8.4Hz,1H),3.77(s,3H)；HPLC:Daicel Chiralcel OD-H column,正己烷/i-PrOH＝70/30,流速＝1.0mL/min,UV＝254nm,tR＝23.8min(major)and tR＝29.5min。
实施例10
手性磷酸的对比：Paal-Knorr反应
空气氛围中，于2mL小瓶中依次加入2-叔丁基苯胺(8mg，0.05mmol)、二酮衍生物(18mg，0.075mmol)、10mol％的CPA和0.5mL四氯化碳，将反应于室温下搅拌反应2天，快速柱层析得产物，用来测定对映体过量比(ee)。
以上数据可以看出，在经典的Paal-Knorr反应中，螺双二氢苯并噻咯为骨架的手性磷酸CPA-1、CPA-2和CPA-5均表现出较以螺二氢茚为骨架的手性磷酸更优的立体选择性。说明在某些反应的立体选择性控制方面，该发明的催化剂较已知催化剂具有明显的优势。
1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.1Hz,1H),7.43-7.39(m,1H),7.31-7.27(m,1H),7.13-7.03(m,6H),6.85(s,1H),3.85(s,3H),2.31(s,3H),0.93(s,9H).HPLC:HPLCDAICEL CHIRALCEL OD-3,正己烷/异丙醇＝98/2,1.0mL/min,λ＝270nm,tR(major)＝5.7min,tR(minor)＝7.6min。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何属于本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求的保护范围为准。
Claims (10)
1.一种具有螺双二氢苯并噻咯骨架的手性磷酸，其具有通式Ⅰ的结构：
其中，Ar选自
中的一种，R选自烷基、环烷基、烷氧基、三氟甲基、卤素、硝基、芳基中的一种，m表示1～5的整数，当取代基为多个时，R相同或不同，*表示手性硅中心，其为S构型手性硅或R手性硅。
2.根据权利要求1所述的手性磷酸，其特征在于，所述Ar选自
中的一种。
3.根据权利要求1所述的手性磷酸，其特征在于，所述R选自烷基或三氟甲基。
4.根据权利要求3所述的手性磷酸，其特征在于，所述R选自(C1-C4)烷基或三氟甲基。
5.根据权利要求4所述的手性磷酸，其特征在于，所述R选自甲基或三氟甲基。
6.根据权利要求1～5任意一项所述的手性磷酸，其特征在于，所述m表示1或2。
7.根据权利要求1～5任意一项所述的手性磷酸，其特征在于，所述手性硅中心为S构型手性硅。
8.根据权利要求1所述的手性磷酸，其特征在于，其选自以下化合物中的一种：
9.一种权利要求1～8任意一项所述的手性磷酸的制备方法，其特征在于，包括以下步骤：
化合物1和MOMBr反应，得到化合物2；
化合物2和单质碘反应，得到化合物3；
化合物3和Rm-Ar-B(OH)2反应，得到化合物4；
化合物4脱保护得到化合物5；
化合物5磷酸化得到产物。
10.权利要求1～8任意一项所述的手性磷酸在不对称反应中的应用。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113735908A (zh) * | 2021-08-05 | 2021-12-03 | 中国科学院上海有机化学研究所 | 一种螺双二氢苯并噻咯磷酸类化合物、合成方法及其应用 |
| CN114292300A (zh) * | 2021-12-30 | 2022-04-08 | 中国科学院上海有机化学研究所 | 螺双二氢苯并噻咯亚膦酸单酯类化合物、其制备及应用 |
| CN114315906A (zh) * | 2022-01-05 | 2022-04-12 | 中国科学院上海有机化学研究所 | 螺双二氢苯并噻咯亚磷酸酯类化合物、其制备方法及应用 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030780A (zh) * | 2010-10-26 | 2011-04-27 | 浙江大学 | 一种手性螺环磷酸和制备方法及其应用 |
| CN107501163A (zh) * | 2017-09-07 | 2017-12-22 | 南方科技大学 | 一种手性磷酸催化合成轴手性苯胺吲哚的方法 |
| CN111217848A (zh) * | 2020-02-25 | 2020-06-02 | 中国科学院上海有机化学研究所 | 螺双二氢苯并噻咯二酚类化合物、合成方法及其应用 |
| CN111253439A (zh) * | 2020-02-25 | 2020-06-09 | 中国科学院上海有机化学研究所 | 螺双二氢苯并噻咯亚磷酰胺类化合物、其制备方法及应用 |
-
2021
- 2021-01-26 CN CN202110103676.3A patent/CN112920221B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030780A (zh) * | 2010-10-26 | 2011-04-27 | 浙江大学 | 一种手性螺环磷酸和制备方法及其应用 |
| CN107501163A (zh) * | 2017-09-07 | 2017-12-22 | 南方科技大学 | 一种手性磷酸催化合成轴手性苯胺吲哚的方法 |
| CN111217848A (zh) * | 2020-02-25 | 2020-06-02 | 中国科学院上海有机化学研究所 | 螺双二氢苯并噻咯二酚类化合物、合成方法及其应用 |
| CN111253439A (zh) * | 2020-02-25 | 2020-06-09 | 中国科学院上海有机化学研究所 | 螺双二氢苯并噻咯亚磷酰胺类化合物、其制备方法及应用 |
Non-Patent Citations (1)
| Title |
|---|
| XIN CHANG等: ""Asymmetric Synthesis and Application of Chiral Spirosilabiindanes"", 《ANGEW.CHEM.INT.ED.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113735908A (zh) * | 2021-08-05 | 2021-12-03 | 中国科学院上海有机化学研究所 | 一种螺双二氢苯并噻咯磷酸类化合物、合成方法及其应用 |
| CN114292300A (zh) * | 2021-12-30 | 2022-04-08 | 中国科学院上海有机化学研究所 | 螺双二氢苯并噻咯亚膦酸单酯类化合物、其制备及应用 |
| CN114292300B (zh) * | 2021-12-30 | 2023-09-15 | 中国科学院上海有机化学研究所 | 螺双二氢苯并噻咯亚膦酸单酯类化合物、其制备及应用 |
| CN114315906A (zh) * | 2022-01-05 | 2022-04-12 | 中国科学院上海有机化学研究所 | 螺双二氢苯并噻咯亚磷酸酯类化合物、其制备方法及应用 |
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