CN109503670A - 一类二茂铁骨架的手性单膦配体WJ-Phos及制备方法和应用 - Google Patents
一类二茂铁骨架的手性单膦配体WJ-Phos及制备方法和应用 Download PDFInfo
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- CN109503670A CN109503670A CN201811587236.4A CN201811587236A CN109503670A CN 109503670 A CN109503670 A CN 109503670A CN 201811587236 A CN201811587236 A CN 201811587236A CN 109503670 A CN109503670 A CN 109503670A
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- alkyl
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- 239000003446 ligand Substances 0.000 title claims abstract description 52
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title claims abstract description 46
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 44
- 229910052751 metal Inorganic materials 0.000 claims abstract description 29
- 239000002184 metal Substances 0.000 claims abstract description 29
- 229910052796 boron Inorganic materials 0.000 claims abstract description 28
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000001336 alkenes Chemical class 0.000 claims abstract description 20
- 238000007259 addition reaction Methods 0.000 claims abstract description 17
- 239000010949 copper Substances 0.000 claims abstract description 17
- 229940125904 compound 1 Drugs 0.000 claims abstract description 15
- 238000006482 condensation reaction Methods 0.000 claims abstract description 15
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052802 copper Inorganic materials 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 66
- -1 titanate ester Chemical class 0.000 claims description 39
- 230000015572 biosynthetic process Effects 0.000 claims description 36
- 238000003786 synthesis reaction Methods 0.000 claims description 36
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 20
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 20
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- 238000006555 catalytic reaction Methods 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical group [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 10
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 10
- 229910052723 transition metal Inorganic materials 0.000 claims description 10
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 9
- 150000001265 acyl fluorides Chemical class 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 4
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 claims description 2
- 229910018030 Cu2Te Inorganic materials 0.000 claims description 2
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 2
- SFJMFSWCBVEHBA-UHFFFAOYSA-M copper(i)-thiophene-2-carboxylate Chemical compound [Cu+].[O-]C(=O)C1=CC=CS1 SFJMFSWCBVEHBA-UHFFFAOYSA-M 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 claims description 2
- ZKXWKVVCCTZOLD-FDGPNNRMSA-N copper;(z)-4-hydroxypent-3-en-2-one Chemical compound [Cu].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O ZKXWKVVCCTZOLD-FDGPNNRMSA-N 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 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
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 229910009112 xH2O Inorganic materials 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 12
- 241000790917 Dioxys <bee> Species 0.000 claims 4
- 150000002431 hydrogen Chemical class 0.000 claims 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- 229910052786 argon Inorganic materials 0.000 claims 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 13
- 230000003287 optical effect Effects 0.000 abstract description 4
- 150000002466 imines Chemical class 0.000 abstract description 2
- 230000009257 reactivity Effects 0.000 abstract description 2
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 214
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 38
- 238000005160 1H NMR spectroscopy Methods 0.000 description 38
- 238000004679 31P NMR spectroscopy Methods 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 238000000926 separation method Methods 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 239000002024 ethyl acetate extract Substances 0.000 description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000000758 substrate Substances 0.000 description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 3
- PZIIGUMPOSVMSD-UHFFFAOYSA-M [Br-].C1=CC=C2C([Mg+])=CC=CC2=C1 Chemical compound [Br-].C1=CC=C2C([Mg+])=CC=CC2=C1 PZIIGUMPOSVMSD-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- SXERGJJQSKIUIC-UHFFFAOYSA-N 2-Phenoxypropionic acid Chemical compound OC(=O)C(C)OC1=CC=CC=C1 SXERGJJQSKIUIC-UHFFFAOYSA-N 0.000 description 1
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 241000282373 Panthera pardus Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- NTWZYMJGDYYGNL-UHFFFAOYSA-N [Na].C[Si] Chemical compound [Na].C[Si] NTWZYMJGDYYGNL-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- WWYCCHFWPNKQPM-UHFFFAOYSA-N boric acid;2-methylpentane-2,4-diol Chemical compound OB(O)O.CC(O)CC(C)(C)O WWYCCHFWPNKQPM-UHFFFAOYSA-N 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- GVLUZLIABKNMAY-UHFFFAOYSA-N lithium;methoxybenzene Chemical compound [Li+].COC1=CC=[C-]C=C1 GVLUZLIABKNMAY-UHFFFAOYSA-N 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000006250 specific catalysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
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Abstract
本发明公开了一类二茂铁骨架的手性单膦配体WJ‑Phos及制备方法和应用,所述手性单膦配体为化合物1或化合物1对映异构体、非对映异构体或消旋体;本发明还公开了所述手性单膦配体的制备方法,以二茂铁甲醛为原料两种方式制备WJ‑Phos:a)以化合物 和R3[M]为原料,进行缩合反应、加成反应制备所述手性单膦配体;b)以化合物和和R3[M]为原料,进行缩合反应、加成反应制备所述手性单膦配体。本发明通过使用四种构型的二茂铁骨架的亚胺和不同类型的金属试剂进行加成反应,可得到所述手性单膦配体的八种全构型的光学纯。本发明还公开了所述手性单膦配体在铜催化联烯的硼酰化不对称反应中的应用,具有很高的反应活性和立体选择性,具有广泛的应用价值。
Description
技术领域
本发明属于有机化学技术领域,涉及新骨架手性单膦配体及其制备方法和应用,具体涉及一类基于二茂铁骨架改造的新型手性单膦配体WJ-Phos及制备方法和应用。
背景技术
手性广泛的存在于自然界中,手性化合物就如同人们的左右手一样不能相互重叠,两个对映异构体互为镜像却不能完全重合。看似相近的两个对映体却往往具有不同的光学性质、物理化学性质以及不同甚至截然相反的生物活性,如著名的“反应停”药物,欧洲曾给孕妇服用消旋体药物有效地阻止女性怀孕早期的呕吐,很多孕妇服用后,导致大量“海豹畸形婴儿”出生,后经研究发现(R)构型可用作镇定剂减轻人类妊娠反应,而其(S)构型则导致畸形;在农业化学品中,如芳氧基丙酸类除草剂fluazifop-buty,只有(R)-异构体是有效的;可见,合成光学纯的手性分子不仅是化学界的挑战,而且对于人类医药健康、农业和材料等方面也有极其重要的意义。手性化合物的获得方法主要有以下几种:天然产物的分离、底物或手性试剂的诱导、外消旋化合物的拆分以和不对称催化。由于不对称催化具有独特的优点:通过使用少量的催化剂可获得大量光学纯的产物,数十年来一直是研究的热点和前沿。在2001年,诺贝尔化学奖被授予Knowles、Noyori和Sharpless三位从事不对称催化氢化和不对称催化氧化的研究。
含有二茂铁骨架的手性配体如Josiphos,在不对称催化中广泛的被使用(J.Am.Chem.Soc.2017,139,8337-8345),这类手性的双膦配体,与过渡金属的络合物可用作C-C/C-N/C-O/C-S偶合反应等有机合成催化剂。而本课题组一直致力于C-中心手性新型单膦配体(催化剂)的开发,先后开发了Ming-Phos(Angew.Chem.Int.Ed.2014,53,4350;Angew.Chem.,Int.Ed.2016,55,6324;ACS Catal.2015,5,7488;ACS Catal.2017,7,210)、Xiao-Phos(Angew.Chem.Int.Ed.2015,54,6874)、Wei-Phos(Angew.Chem.Int.Ed.2015,54,14853)、Peng-Phos(Angew.Chem.Int.Ed.2016,55,13316)、PC-Phos(Angew.Chem.,Int.Ed.2017,56,15905;J.Am.Chem.Soc.2018,140,3467)和N-Me-XuPhos(Angew.Chem.,Int.Ed.2018,57,10373)等多种C-中心手性新型单膦配体(催化剂)。本发明基于二茂铁骨架改造合成手性单膦配体WJ-Phos,并应用于四级碳手性中心的构建。
发明内容
本发明的目的是提供一类手性单膦配体WJ-Phos及制备方法和应用。
本发明提供的一类手性单膦配体WJ-Phos是基于二茂铁面手性、C-中心手性和S-中心手性的单膦配体,如下式所示的化合物1或化合物1的对映体、消旋体或非对映异构体,共计((SFC,SC,RS)-1、化合物(SFC,RC,RS)-1、化合物(SFC,SC,SS)-1、化合物(SFC,RC,SS)-1、(RFC,SC,RS)-1、化合物(RFC,RC,RS)-1、化合物(RFC,SC,SS)-1、化合物(RFC,RC,SS)-1)八种全构型的光学纯的WJ-Phos∶
其中,R1、R2、R4分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、 R3选自C2~C12的烷烃基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基、ORw或SRw;其中,Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基或C1~C10的磺酸酯基;Ry、Ry′、Ry″、Rz、Rz′和Rw分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基或C1~C10的磺酸酯基;“*”表示手性中心。
作为一种优选方案,上述化合物1中的R1、R2同时选自C1~C12的烷烃基、 R3选自C2~C12的烷烃基、C1~C10的硅氧基、C1~C10的酯基或R4选自C1~C12的烷烃基、其中Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基或C1~C10的磺酸酯基;“*”表示手性中心。
作为一种优选方案,化合物1中的R1、R2同时选自C1~C12的烷烃基、R3选自C2~C12的烷烃基或R4选自叔丁基。其中Rx和Rx′分别独立选自氢、C1~C12的烷烃基、C1~C10的烷氧基或C1~C10的硅氧基。
作为进一步优选方案,化合物1中的R1、R2同时选自C1~C12的烷烃基、
作为更进一步优选方案,所述手性单膦配体WJ-Phos选自如下化合物或所述化合物的对映体、消旋体或非对映异构体,如下所示:
本发明还提供了化合物1的制备方法,包括以下两种方案:
方案一:
第一步:参照文献(J.Org.Chem.1997,62,6733)报道方法,制备S构型的醛SFC-2或RFC-2。在溶剂中,化合物SFC-2或RFC-2分别与化合物3(Rs)或化合物3(Ss)在缩合剂作用下进行缩合反应,得到化合物(SFC,Rs)-4或(SFC,Ss)-4或(RFC,Rs)-4或(RFC,Ss)-4,具体操作参见文献(Angew.Chem.Int.Ed.2014,53,4350),反应过程如下反应式(I)所示:
式(I)中各基团的定义与化合物1中各基团定义相同。
所述溶剂选自干燥的二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯、苯、氯苯、氟苯、氯仿、正己烷;优选地,为干燥的四氢呋喃。
所述缩合反应的温度为-50~100℃;优选地,为50~70℃。
所述缩合反应的时间为10分钟~48小时;优选地,为8小时。
所述化合物SFC-2或化合物RFC-2、化合物3(Rs)或化合物3(Ss)与缩合剂的摩尔比为1∶(1~10)∶(1~100);优选地,为1∶(1~3)∶(1~4)。
所述缩合剂的作用为促进缩合反应的进行,选自钛酸四乙酯(Ti(OEt)4)、钛酸四异丙酯、钛酸四甲酯;优选地,为Ti(OEt)4。
第二步:化合物(SFC,Rs)-4或(SFC,Ss)-4或(RFC,Rs)-4或(RFC,Ss)-4在干燥的溶剂中,分别与金属试剂R3MgX或R3Li化合物进行加成反应,得到手性单膦配体WJ-Phos即化合物(SFC,SC,RS)-1、化合物(SFC,RC,RS)-1、化合物(SFC,SC,SS)-1、化合物(SFC,RC,SS)-1、(RFC,SC,RS)-1、化合物(RFC,RC,RS)-1、化合物(RFC,SC,SS)-1或化合物(RFC,RC,SS)-1,反应过程如下反应式(II)所示:
式(II)中各基团的定义与化合物1中各基团定义相同;M为锂或卤化镁。
所述溶剂选自干燥的二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯、苯、氯苯、氟苯、氯仿、正己烷;优选地,为干燥的四氢呋喃。
所述加成反应的温度为-78~30℃;优选地,为-78~-40℃。
所述加成反应的时间为10分钟~48小时;优选地,为10分钟~12小时。
所述化合物(SFC,Rs)-4或化合物(SFC,Ss)-4或(RFC,Rs)-4或化合物(RFC,Ss)-4与R3[M]的摩尔比为1∶(1~50);优选地,为1∶(1~4)。
所述R3[M]为R3MgX或R3Li,其作用为和(SFC,Rs)-4或化合物(SFC,Ss)-4或(RFC,Rs)-4或化合物(RFC,Ss)-4进行加成反应。
方案二:
第一步:参照文献(Eur.J.Org.Chem.2014,6676)报道方法,制备醛SFC-2和RFC-2。在溶剂中,化合物SFC-2和化合物RFC-2与化合物3(Rs)或化合物3(Ss)在缩合剂作用下进行缩合反应,得到化合物(SFC,Rs)-4和化合物(RFC,Rs)-4或化合物(SFC,Rs)-4和化合物(RFC,Rs)-4,具体操作参见文献(Angew.Chem.Iht.Ed.2014,53,4350),反应过程如下反应式(III)所示:
式(III)中各基团的定义与化合物1中各基团定义相同。
所述溶剂选自干燥的二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯、苯、氯苯、氟苯、氯仿、正己烷;优选地,为干燥的四氢呋喃。
所述缩合反应的温度为-50~100℃;优选地,为50~70℃。
所述缩合反应的时间为10分钟~48小时;优选地,为8小时。
所述化合物SFC-2和化合物RFC-2、化合物3(Rs)或化合物3(Ss)与缩合剂的摩尔比为1∶(1~10)∶(1~100);优选地,为1∶(1~3)∶(1~4)。
所述缩合剂的作用为促进缩合反应的进行,选自钛酸四乙酯(Ti(OEt)4)、钛酸四异丙酯、钛酸四甲酯;优选地,为Ti(OEt)4。
第二步:化合物(SFC,Rs)-4和化合物(RFC,Rs)-4或化合物(SFC,Rs)-4和化合物(RFC,Rs)-4在干燥的溶剂中,分别与金属试剂R3MgX或者R3Li化合物进行加成反应,得到手性单膦配体WJ-Phos,即化合物(SFC,SC,RS)-1、化合物(SFC,RC,RS)-1、化合物(RFC,SC,RS)-1、化合物(RFC,RC,RS)-1、化合物(SFC,SC,SS)-1、化合物(SFC,RC,SS)-1、化合物(RFC,SC,SS)-1或化合物(RFC,RC,SS)-1,反应过程如下反应式(IV)所示:
式(IV)中各基团的定义与化合物1中各基团定义相同;M为锂或卤化镁。
所述溶剂选自干燥的二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯、苯、氯苯、氟苯、氯仿、正己烷;优选地,为干燥的四氢呋喃。
所述加成反应的温度为-78~30℃;优选地,为-78~-40℃。
所述加成反应的时间为10分钟~48小时;优选地,为10分钟~12小时。
所述化合物(SFC,Rs)-4和(RFC,Rs)-4或(SFC,Rs)-4和(RFC,Rs)-4与R3[M]的摩尔比为1∶(1~50);优选地为1∶(1~4)。
所述R3[M]为R3MgX或R3Li,其作用为和(SFC,Rs)-4和(RFC,Rs)-4或(SFC,Rs)-4和(RFC,Rs)-4进行加成反应。
本发明通过使用四种构型的二茂铁骨架的亚胺和不同类型的金属试剂加成,可方便地得到手性单膦配体WJ-Phos八种全构型((SFC,SC,RS)-1、化合物(SFC,RC,RS)-1、化合物(SFC,SC,SS)-1、化合物(SFC,RC,SS)-1、(RFC,SC,RS)-1、化合物(RFC,RC,RS)-1、化合物(RFC,SC,Ss)-1、化合物(RFC,RC,SS)-1)的光学纯化合物。
本发明还提供了所述手性单膦配体WJ-Phos用于铜催化联烯的硼酰化不对称反应,所述手性单膦配体WJ-Phos是具有化合物1或所述化合物1的对映体、消旋体或非对映异构体。
本发明提供了所述手性单膦配体WJ-Phos用于铜催化联烯、酰氟和硼酯的三组分不对称反应合成具有四级碳手性中心的硼取代的不饱和酮类化合物;将如上所述的手性单膦配体与过渡金属盐形成金属配合物溶液,然后催化联烯的硼酰化不对称反应,合成所述硼取代的不饱和酮类化合物。
如上所述的手性单膦配体用于联烯的硼酰化不对称反应的应用中构建硼取代的不饱和酮类化合物的方法中:
作为一种优选方案,首先使所述手性单膦配体WJ-Phos与过渡金属盐形成配合物,然后用于催化联烯的硼酰化不对称反应。
作为进一步优选方案,所述配合物的制备包括如下步骤:在惰性气氛下,将所述手性单膦配体WJ-Phos与过渡金属盐加入到有机溶剂中,在-10~50℃搅拌,反应0.1~20小时,形成配合物溶液。
作为更进一步优选方案,所述手性单膦配体和过渡金属盐的摩尔比为(1~50)∶1,以(1~5)∶1最佳。
作为更进一步优选方案,所述过渡金属盐为铜盐。
作为更进一步优选方案,所述铜盐包括CuCl、Cu(OTf)2、Cu2(OTf)2·Tol、Cu(OAc)2、CuOAc、CuCl2、CuCl2、CuBr、CuF2、CuI、CuSO4、Cu(NO3)2·3H2O、Cu(TFA)2·xH2O、Cu2Te、Cu(acac)2、CuTC、Cu(CH3CN)4ClO4、Cu(CH3CN)4PF6、Cu(CH3CN)4BF4或CuBr·SMe2。
作为更进一步优选方案,所述惰性气氛为氩气气氛或者氮气气氛;所述有机溶剂选自二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯、苯、氯苯、氟苯、氯仿。
作为进一步优选方案,所述催化联烯的硼酰化不对称反应包括如下步骤:向所述配合物溶液中加入碱,加入硼酯,再加入联烯及酰氟底物,在-90~90℃条件下进行硼酰化反应,合成所述硼取代的不饱和酮类化合物。
不对称反应中,所述碱、硼酯、联烯和酰氟与所述所述配体和铜的配合物的摩尔比为(1~100000)∶(1~100000)∶(1~10000)∶(1~100000)∶1;优选地,所述碱、硼酯、联烯和酰氟与所述所述配合物的摩尔比为(20~120)∶(20~120)∶(20~100)∶(20~200)∶1。
作为更进一步优选方案,所述碱Et3N、DBU、DABCO、Bn2NH、Bu3N、Pr2NH、K2CO3、TMSONa、Na2CO3、KOH、NaOH、Cs2CO3、Li2CO3、CsOH、LiOH、NaOtBu、KOtBu或LiOtBu。
所述联烯可以是结构如式(V)所示的化合物:
上述式(V)中:R5、R6、R7、R8分别独立选自氢、卤素、硝基、氰基、炔基、C1~C10的烷烃基、C1~C10的烷氧基、C1~C10的烷酰基或C1~C10的酯基;优选地,R5、R6、R7、R8分别独立选自氢、卤素、硝基、氰基、炔基、C1~C5的烷烃基、C1~C5的烷氧基、C1~C5的烷酰基或C1~C5的酯基;
进一步优选地,R5选自氢、C1~C10的烷烃基、C1~C10的烷氧基;R6、R7、R8分别独立选自氢、卤素、硝基、C1~C5的烷烃基或C1~C5的烷氧基。
所述硼酯选自联硼酸新戊二醇酯、双联(2-甲基-2,4-戊二醇)硼酸酯、联硼酸频那醇酯或4-吡唑硼酸频哪醇酯。
所述酰氟可以是结构如式(VI)所示的化合物:
上述式(VI)中:R9、R10、R11分别独立选自氢、卤素、硝基、氰基、炔基、C1~C10的烷烃基、C1~C10的烷氧基、C1~C10的烷酰基或C1~C10的酯基;优选地,R9、R10、R11分别独立选自氢、卤素、硝基、氰基、炔基、C1~C5的烷烃基、C1~C5的烷氧基、C1~C5的烷酰基或C1~C5的酯基;
进一步优选地,R9、R10、R11分别独立选自氢、卤素、硝基、C1~C5的烷烃基、C1~C5的烷氧基。
与现有技术相比,本发明具有如下有益效果:
(1)本发明提供了一类新骨架手性单膦配体,催化联烯的硼酰化不对称反应,获得硼取代的不饱和酮类化合物的产率为47%-87%,对映体过量(ee)为87%-94%。
(2)本发明提供的手性单膦配体的制备方法,克服了现有技术中合成含膦手性配体时,原料昂贵、合成路线冗长、反应试剂毒性大、对映异构体的合成难度大、产率低等缺陷,本发明的制备方法多样且路线短、操作简单,收率为50%-90%,适合规模化生产,具有实用价值。
本发明中:
n-BuLi为正丁基锂;ClPPh2为二苯基氯化膦;Ti(OEt)4为钛酸四乙酯;TMSONa为三甲基硅醇钠。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
下述实施例提供了上述手性单膦配体即化合物1的全部两种合成方案,具体为:
实施例1(SFC,SC,Ss)-1a的合成(参考方案一)
参照文献(J.Org.Chem.1997,62,6733)报道方法,制备S构型的醛SFC-2
第一步:将制备的(2g,5.0mmol)和(0.9g,1.5equiv)加入100mL的三颈瓶中,在N2的氛围下加入50mL THF,加Ti(OEt)2(3.1mL,3.0equiv),在60℃下搅拌24小时,分液,水层用乙酸乙酯萃取三次,合并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化,得产率为88%。1H NMR(500MHz,CDCl3)δ(ppm)8.63(d,J=1.1Hz,1H),7.51(ddd,J=9.6,4.8,2.4Hz,2H),7.37(dd,J=9.4,4.8Hz,3H),7.20(dd,J=4.3,2.1Hz,3H),7.14-7.07(m,2H),4.96-4.93(m,1H),4.56(t,J=2.5Hz,1H),4.20(s,5H),3.92-3.88(m,1H),0.90(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-20.12;13C NMR(126MHz,CDCl3)δ(ppm)163.5(d,J=2.5Hz),139.4(d,J=11.3Hz),137.7(d,J=12.1Hz),135.3(d,J=21.3Hz),132.2(d,J=18.4Hz),129.4,128.4(d,J=7.5Hz),128.3(d,J=6.2Hz),128.0,83.0(d,J=15.8Hz),78.0(d,J=15.5Hz),77.4,75.8(d,J=4.7Hz),74.3(d,J=2.4Hz),72.6,70.8(d,J=0.7Hz),56.7,22.1。
其中,THF为四氢呋喃;N2为氮气;Ti(OEt)4为钛酸四乙酯。
第二步:将第一步制备的(1g,2mmol)加入到干燥的50mL的单支口反应管中,氮气保护,加入10mL THF。在-78℃下,加入苯基锂(3equiv,6mL,1M in THF),搅拌30分钟后,加饱和氯化铵淬灭,分液,水层用乙酸乙酯萃取三次,合并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化。产率为73%。1H NMR(500MHz,CDCl3)δ(ppm)7.57-7.49(m,2H),7.36(dd,J=9.7,4.9Hz,3H),7.10(d,J=7.1Hz,2H),6.99(t,J=7.4Hz,1H),6.92(t,J=7.2Hz,1H),6.87(dd,J=14.1,7.2Hz,4H),6.60(t,J=7.3Hz,2H),5.71(d,J=3.0Hz,1H),4.70(s,1H),4.54(s,1H),4.30(t,J=2.2Hz,1H),4.15(s,5H),3.80(s,1H),1.27(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-24.46;13C NMR(126MHz,CDCl3)δ(ppm)140.5,138.7(d,J=8.7Hz),137.1(d,J=9.3Hz),135.4(d,J=21.5Hz),131.9(d,J=18.0Hz),129.4,128.4,128.2(d,J=7.9Hz),127.9,127.6(d,J=6.1Hz,),127.3(d,J=2.5Hz),98.1(d,J=24.0Hz),76.1(d,J=11.3Hz),71.7(d,J=4.7Hz),70.0,69.4,67.1(d,J=3.8Hz),55.9(d,J=10.1Hz),55.4,22.7。
实施例2(SFC,RC,Ss)-1a的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为苯基溴化镁(3equiv,6mL,1M inTHF),住-78℃下搅拌1小时后,自然升温,搅拌过夜,加饱和氯化铵淬灭,分液,水层用乙酸乙酯萃取三次,个并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化。产率为67%。1H NMR(500MHz,CDCl3)δ(ppm)7.63-7.57(m,2H),7.55(d,J=7.3Hz,2H),7.39(dt,J=9.3,4.9Hz,5H),7.30(t,J=7.3Hz,1H),7.25-7.20(m,3H),7.20-7.14(m,2H),5.57(dd,J=6.6,3.7Hz,1H),4.37(s,1H),4.34(t,J=2.4Hz,1H),3.97(s,1H),3.70(d,J=6.7Hz,1H),3.68(s,5H),0.85(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-25.59;13C NMR δ(ppm)(126MHz,CDCl3)δ142.1,140.2(d,J=7.6Hz),137.8(d,J=7.6Hz),135.5(d,J=22.0Hz),132.5(d,J=17.5Hz),129.5,128.6,128.3,128.2(d,J=17.0Hz),127.9(d,J=14.5Hz),96.1(d,J=26.3Hz),74.9(d,J=10.0Hz),71.9(d,J=4.5Hz),70.8(d,J=4.2Hz),70.5,69.9,59.9(d,J=9.7Hz),56.0,22.1。
实施例3(SFC,SC,Rs)-1a的合成(参考方案一)
具体操作与实施例1相同,所用原料为产率为73%。1H NMR(500MHz,CDCl3)δ(ppm)7.61-7.50(m,2H),7.40(dd,J=3.8,2.4Hz,3H),7.31-7.26(m,2H),7.26-7.19(m,3H),7.18-7.11(m,5H),5.66(s,1H),4.43(s,1H),4.35(d,J=3.1Hz,1H),4.32(t,J=2.4Hz,1H),4.06(s,5H),3.78(s,1H),1.16(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-24.17;13C NMR(126MHz,CDCl3)δ(ppm)141.2,139.2(d,J=9.9Hz),137.2(d,J=9.8Hz),135.3(d,J=21.6Hz),133.0(d,J=18.8Hz),129.3,128.4,128.3,128.2(d,J=2.5Hz),128.1,128.0,127.4,96.1(d,J=22.4Hz),73.9(d,J=13.0Hz),72.4(d,J=3.9Hz),72.1(d,J=4.1Hz),70.2,70.1,57.9(d,J=3.7Hz),55.8,22.7。
实施例4(SFC,RC,Rs)-1a的合成(参考方案一)
具体操作与实施例1相同,所用原料为所用金属试剂为苯基溴化镁(3equiv,6mL,1M in THF),在-78℃下搅拌1小时后,自然升温,搅拌过夜,加饱和氯化铵淬灭,分液,水层用乙酸乙酯萃取三次,合并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化。产率为75%。1H NMR(500MHz,CDCl3)δ(ppm)7.54-7.48(m,2H),7.35(d,J=5.3Hz,3H),7.08(d,J=7.6Hz,2H),6.98(t,J=7.3Hz,1H),6.89(dd,J=13.2,7.2Hz,5H),6.66(t,J=7.4Hz,2H),5.71(t,J=3.0Hz,1H),4.80(s,1H),4.37(t,J=2.1Hz,1H),4.11(s,5H),3.95(d,J=3.2Hz,1H),3.88(s,1H),1.29(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-24.57;13C NMR(126MHz,CDCl3)δ(ppm)141.2,138.4(d,J=8.1Hz),137.4(d,J=8.4Hz),135.3(d,J=21.5Hz),132.0(d,J=18.5Hz),129.3,128.4,128.3,128.2,128.1,127.6(d,J=2.0Hz),127.5,127.3,97.9(d,J=23.9Hz),74.2(d,J=11.0Hz),72.2(d,J=4.6Hz),70.0,69.7(d,J=3.9Hz),69.4,59.1(d,J=10.5Hz),56.2,23.0。
实施例5(SFC,SC,Ss)-1b的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为1-萘基锂试剂,产率为81%。1H NMR(300MHz,CDCl3)δ(ppm)8.73(d,J=8.9Hz,1H),7.937.82(m,3H),7.77-7.69(m,1H),7.68-7.59(m,2H),7.57-7.50(m,2H),7.45-7.36(m,3H),7.29-7.23(m,5H),6.53(t,J=4.9Hz,1H),4.51(s,1H),4.36(t,J=2.4Hz,1H),4.00(s,1H),3.84(d,J=5.1Hz,1H),3.29(s,5H),0.84(s,9H);31P NMR(122MHz,CDCl3)δ(ppm)-26.08;13C NMR(126MHz,CDCl3)δ(ppm)140.1(d,J=7.1Hz),138.6,137.9(d,J=7.2Hz),135.5(d,J=22.1Hz),134.0,132.6(d,J=17.5Hz),131.60,129.5,129.2,128.4(d,J=14.8Hz),128.3,128.0,126.2,126.1,125.6(d,J=44.8Hz),124.0,96.6(d,J=26.4Hz),75.2(d,J=9.6Hz),71.6(d,J=4.7Hz),70.7,70.2(d,J=1.8Hz),69.8,56.0,22.0。
实施例6(SFC,RC,Ss)-1b的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为1-萘基溴化镁(3equiv),在-78℃下搅拌1小时后,自然升温,搅拌过夜,加饱和氯化铵淬灭,分液,水层用乙酸乙酯萃取三次,合并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化。产率为74%。1H NMR(500MHz,CDCl3)δ(ppm)8.75(d,J=8.5Hz,1H),7.94(d,J=8.1Hz,1H),7.90(d,J=7.1Hz,1H),7.85(d,J=8.1Hz,1H),7.75(s,1H),7.70-7.63(m,2H),7.56(dt,J=10.6,7.6Hz,2H),7.45-7.39(m,3H),7.30-7.27(m,5H),6.55(s,1H),4.53(s,1H),4.38(t,J=2.3Hz,1H),4.02(s,1H),3.86(d,J=5.3Hz,1H),3.31(s,5H),0.86(s,9H);31P NMR(122MHz,CDCl3)δ(ppm)-26.12;13C NMR(126MHz,CDCl3)δ(ppm)140.0(d,J=7.1Hz),138.4,137.8(d,J=7.2Hz),135.4(d,J=22.1Hz),133.8,132.5(d,J=17.5Hz),131.5,129.4,129.1,128.2(t,J=7.4Hz,),127.9,126.1,125.6,125.3,124.0,96.5(d,J=25.6Hz),75.1(d,J=9.5Hz),71.5(d,J=4.7Hz),70.8,70.0,56.0,22.0。
实施例7(SFC,RC,Rs)-1b的合成(参考方案一)
具体操作与实施例1相同,所用原料为所用金属试剂为1-萘基溴化镁(3equiv),在-78℃下搅拌1小时后,自然升温,搅拌过夜,加饱和氯化铵淬灭,分液,水层用乙酸乙酯萃取三次,合开有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化。产率为77%。1H NMR(500MHz,CDCl3)δ(ppm)8.23(d,J=8.5Hz,1H),7.62(d,J=8.0Hz,1H),7.53-7.41(m,4H),7.37(t,J=7.4Hz,1H),7.32(s,3H),7.13(d,J=7.0Hz,1H),7.03(t,J=7.7Hz,1H),6.80(t,J=7.1Hz,1H),6.68(t,J=7.2Hz,2H),6.60(t,J=7.5Hz,2H),6.53(d,J=2.6Hz,1H),5.21(s,1H),4.45(s,1H),4.36(s,1H),4.22(s,5H),3.95(s,1H),1.21(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-24.84;13C NMR(126MHz,CDCl3)δ(ppm)137.1(t,J=8.3Hz),135.0,134.7(d,J=19.6Hz),133.5,132.5(d,J=20.0Hz),131.0,129.0,128.5(d,J=16.7Hz),128.2(d,J=7.6Hz),127.7(d,J=28.7Hz),127.2(d,J=7.1Hz),126.1,125.1(d,J=56.5Hz),123.7,98.1(d,J=22.4Hz),76.1(d,J=9.9Hz),72.2(d,J=3.8Hz),71.7(d,J=2.8Hz),70.5,69.9,69.6,55.6,54.2(d,J=13.8Hz),23.1。
实施例8(SFC,SC,SS)-1c的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为试剂。产率为80%。1H NMR(500MHz,CDCl3)δ(ppm)8.98(d,J=9.1Hz,1H),8.85(d,J=9.2Hz,1H),8.52(s,1H),8.12-8.04(m,2H),7.837.76(m,1H),7.75-7.69(m,2H),7.57-7.46(m,4H),7.41(dd,J=12.5,5.8Hz,5H),7.35(dd,J=7.8,6.8Hz,2H),7.30(t,J=7.2Hz,1H),4.39(s,1H),4.26(t,J=2.4Hz,1H),4.07(s,1H),4.05(d,J=4.3Hz,1H),3.24(s,5H),0.76(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-25.94;13C NMR(126MHz,CDCl3)δ(ppm)140.8(d,J=7.6Hz),138.3(d,J=7.5Hz),135.7(d,J=22.4Hz),133.0,132.6(d,J=17.1Hz),132.3,131.7,130.5,130.0,129.8,129.5(d,J=12.3Hz),128.9,128.5(d,J=5.8Hz),128.3(d,J=8.3Hz),128.0,126.7,125.0(d,J=6.9Hz),124.7,124.3(d,J=2.6Hz),95.8(d,J=26.8Hz),77.4,76.4(d,J=10.4Hz),72.0(t,J=4.4Hz),70.4,69.8,55.9,53.1(d,J=12.0Hz),22.04。
实施例9(SFC,SC,RS)-1c的合成(参考方案一)
具体操作与实施例1相同,所用原料为所用金属试剂为试剂。产率为70%。
1H NMR(500 MHz,CDCl3)δ(ppm)8.78(d,J=9.1Hz,1H),8.52-8.46(m,1H),7.78(s,1H),7.74-7.68(m,2H),7.62-7.57(m,1H),7.55(d,J=3.3Hz,1H),7.48-7.40(m,1H),7.27-7.14(m,7H),6.76(s,1H),6.43-6.34(m,2H),5.84(t,J=7.3Hz,2H),5.21(d,J=1.7Hz,1H),4.34(t,J=2.4Hz,1H),4.26(s,5H),4.04(d,J=3.6Hz,1H),3.69(s,1H),1.36(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-24.72;13C NMR(126MHz,CDCl3)δ(ppm)137.7(d,J=11.0Hz),136.5(d,J=9.8Hz),135.1(d,J=21.5Hz),132.5,131.5(d,J=28.6Hz),130.9(d,J=19.7Hz),129.7(d,J=8.1Hz),129.4,129.2(d,J=2.8Hz),128.8(d,J=19.7Hz),127.8(d,J=7.6Hz),126.8(d,J=6.8Hz),126.7(d,J=12.9Hz),125.3,124.8(d,J=19.9Hz),124.5(d,J=4.9Hz),123.8,98.3(d,J=24.1Hz),74.2(d,J=13.7Hz),72.7(d,J=4.5Hz),72.0(d,J=4.2Hz),70.7,67.7,56.3,53.6(d,J=5.3Hz),23.1。
实施例10(SFC,SC,SS)-1d的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为试剂。产率为78%。1H NMR(500MHz,CDCl3)δ(ppm)8.80(d,J=8.3Hz,1H),8.75(d,J=6.0Hz,1H),8.68(d,J=8.3Hz,1H),8.16(s,1H),7.85(d,J=7.3Hz,2H),7.73(t,J=7.5Hz,1H),7.67-7.61(m,3H),7.57(t,J=7.3Hz,1H),7.46-7.36(m,3H),7.20(s,5H),6.53(s,1H),4.57(s,1H),4.36(s,1H),4.12(s,1H),4.00(s,1H),3.42(s,5H),0.88(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-25.96;13C NMR(126MHz,CDCl3)δ(ppm)139.8,137.9(d,J=7.1Hz),136.4,135.4(d,J=22.0Hz),132.5(d,J=17.5Hz),131.3,130.9,130.8,130.1,129.5,129.1,128.3(d,J=5.9Hz),128.2,128.0,126.8,126.7,126.5,123.6,122.5,96.5(d,J=28.5Hz),77.4,74.6,71.8(d,J=4.6Hz),70.6,70.0,56.2,52.0,22.2。
实施例11(SFC,SC,SS)-1e的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为试剂。产率为80%。1H NMR(300MHz,DMSO)δ(ppm)9.15(d,J=9.6Hz,1H),8.70(d,J=8.2Hz,1H),8.59(d,J=9.3Hz,1H),8.43(dd,J=7.9,4.3Hz,2H),8.36(s,2H),8.30-8.21(m,2H),8.15(t,J=7.6Hz,1H),7.83-7.72(m,2H),7.58-7.46(m,3H),7.40-7.26(m,4H),6.80(t,J=6.3Hz,1H),5.84(d,J=8.4Hz,1H),4.74(s,1H),4.53(s,1H),4.12(s,1H),2.95(s,5H),0.81(s,9H);31P NMR(122MHz,DMSO)δ(ppm)-26.10;13C NMR(101MHz,DMSO)δ(ppm)140.2(d,J=7.0Hz),138.6,138.5,138.06(d,J=6.6Hz),135.2(d,J=22.6Hz),131.9(d,J=16.9Hz),131.02,130.3,129.7,129.5,128.3(d,J=8.5Hz),128.0(d,J=5.5Hz),127.6,127.5,127.3,127.1,126.4,126.2,125.4,124.9(d,J=15.5Hz),124.3,123.8,123.4(d,J=9.1Hz),97.4(d,J=20.7Hz),79.274.6(d,J=9.5Hz),70.7,70.5(d,J=4.7Hz),70.1(d,J=2.5Hz),69.1,55.2,22.1。
实施例12(SFC,SC,RS)-1e的合成(参考方案一)
具体操作与实施例1相同,所用原料为所用金属试剂为试剂。产率为85%。1H NMR(300MHz,DMSO)δ(ppm)8.95(d,J=8.0Hz,1H),8.70(d,J=8.1Hz,1H),8.66(d,J=9.2Hz,1H),8.43(dd,J=7.9,4.3Hz,2H),8.39(s,2H),8.30-8.21(m,2H),8.05(t,J=6.6Hz,1H),7.83-7.72(m,2H),7.54-7.45(m,3H),7.40-7.29(m,4H),6.50(t,J=6.3Hz,1H),5.44(d,J=8.4Hz,1H),4.34(s,1H),4.53(s,1H),3.075(s,1H),2.95(s,5H),1.21(s,9H);31P NMR(122MHz,DMSO)δ(ppm)-24.85;13C NMR(126MHz,DMSO)δ(ppm)139.7(d,J=10.8Hz),137.4(d,J=10.1Hz),135.4(d,J=21.9Hz),132.7(d,J=18.2Hz),131.3,130.6,130.0,128.8,128.7,128.6,127.9,127.8,127.7,126.7,125.9,125.6,125.1,124.5,124.4,96.5(d,J=26.0Hz),79.6,74.3(d,J=13.0Hz),72.0,71.9,70.9,70.1,55.4,51.8,22.4。
实施例13(SFC,SC,SS)-1f的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为4-甲氧基苯基锂试剂。产率为65%。1HNMR(300MHz,CDCl3)δ(ppm)7.57-7.44(m,2H),7.40-7.31(m,3H),7.04-6.94(m,3H),6.88(t,J=6.9Hz,2H),6.60(t,J=7.2Hz,2H),6.38(d,J=8.7Hz,2H),5.67(d,J=3.0Hz,1H),4.68(s,1H),4.49(s,1H),4.28(t,J=2.2Hz,1H),4.15(s,5H),3.76(s,1H),3.61(s,3H),1.27(s,9H);31P NMR(122MHz,CDCl3)δ(ppm)-24.37;13C NMR(126MHz,CDCl3)δ(ppm)158.7,138.7(d,J=8.8Hz),137.1(d,J=9.2Hz),135.4(d,J=21.4Hz),132.5,132.0(d,J=18.2Hz,7H),129.6,129.3,128.2(d,J=7.9Hz),127.6(d,J=6.2Hz),127.2,113.3,98.1(d,J=23.4Hz),75.9(d,J=10.9Hz),71.7(d,J=4.6Hz),70.0,69.3,67.0(d,J=3.7Hz),55.5,55.3(d,J=32.5Hz),22.8。
实施例14(SFC,SC,SS)-1g的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为试剂。产率为86%。1HNMR(400MHz,CDCl3)δ(ppm)7.61(d,J=4.4Hz,2H),7.47(d,J=6.5Hz,2H),7.40(s,4H),7.29-7.17(m,7H),7.17-7.07(m,2H),6.12(s,1H),4.50(s,1H),4.30(s,1H),4.25-4.08(m,1H),3.94(s,1H),3.62(s,5H),1.71(s,3H),1.64(s,3H),0.83(s,9H);31P NMR(122MHz,CDCl3)δ(ppm)-25.24;13C NMR(101MHz,CDCl3)δ(ppm)150.2,148.0(d,J=0.8Hz),140.7(d,J=8.3Hz),138.3(d,J=8.4Hz),135.6(d,J=22.0Hz),132.5(d,J=17.2Hz),130.5(d,J=9.8Hz),129.9,129.4,128.2(d,J=14.2Hz),128.1,127.7,127.5,126.3,125.5,123.5,122.9,116.6,96.0(d,J=26.6Hz),75.4(d,J=10.5Hz),71.5(d,J=5.1Hz),70.8(d,J=3.5Hz),70.3,69.9,55.9,34.4,32.9,32.0,22.1。
实施例15(SFC,SC,RS)-1g的合成(参考方案一)
具体操作与实施例1相同,所用原料为所用金属试剂为试剂。产率为66%。1H NMR(500MHz,CDCl3)δ(ppm)7.56-7.48(m,2H),7.42(dd,J=7.8,0.7Hz,1H),7.38(d,J=5.0Hz,3H),7.33-7.27(m,2H),7.17(t,J=7.3Hz,1H),7.09(ddd,J=12.4,9.8,4.8Hz,5H),6.97(t,J=7.2Hz,2H),6.49(t,J=7.7Hz,1H),6.21(s,1H),4.80(s,1H),4.77(d,J=2.4Hz,1H),4.28(t,J=2.3Hz,1H),4.10(s,5H),3.68(s,1H),1.58(t,J=13.7Hz,6H),1.30(m,9H);31P NMR(122MHz,CDCl3)δ(ppm)-22.33;13C NMR(126MHz,CDCl3)δ150.2,147.7,139.3(d,J=9.5Hz),137.7(d,J=10.0Hz),135.4(d,J=21.9Hz),132.7(d,J=18.3Hz),130.2,129.7,129.3,128.6,128.1(d,J=7.8Hz),128.0(d,J=6.2Hz),127.9,127.5,126.9(d,J=2.8Hz),126.1,124.8,123.3,122.1,116.8,96.1(d,J=21.9Hz),73.5(d,J=13.8Hz),73.1(d,J=4.3Hz),72.1(d,J=4.0Hz),70.2,69.9,56.1,34.1,32.6,32.5,23.0。
实施例16(SFC,SC,SS)-1h的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为试剂。得到两个产物点,产物1产率为26%,产物2产率为51%。产物1,1H NMR(400MHz,CDCl3)δ(ppm)7.69-7.51(m,7H),7.45-7.38(m,9H),7.31-7.22(m,4H),7.07(d,J=7.9Hz,5H),6.89(s,2H),5.95(s,1H),4.83(s,1H),4.66(s,1H),4.40(s,1H),4.18(s,5H),3.98(s,1H),1.35(s,9H);31P NMR(122MHz,CDCl3)δ(ppm)-25.28;13C NMR(101MHz,CDCl3)δ(ppm)140.1,139.5(d,J=8.7Hz),139.2,137.9,137.3(d,J=9.2Hz),137.1,135.6(d,J=21.9Hz),132.3(d,J=17.8Hz),131.4,131.0,129.9(d,J=11.2Hz),129.5,128.5,128.4,128.3(d,J=8.1Hz),127.8,127.7(d,J=4.0Hz),127.6,127.3,127.0,125.0(d,J=17.5Hz),98.2(d,J=24.8Hz),76.6(d,J=11.8Hz),71.7(d,J=4.9Hz),70.1,69.8,67.3(d,J=3.8Hz),56.0(d,J=11.2Hz),55.6,22.9。
产物2,1H NMR(300MHz,CDCl3)δ(ppm)7.85-7.54(m,12H),7.54-7.47(m,4H),7.43(d,J=1.4Hz,3H),7.33(dd,J=5.9,4.0Hz,4H),7.25(d,J=4.4Hz,4H),5.75(dd,J=6.4,3.8Hz,1H),4.61(s,1H),4.47(s,1H),4.05(dd,J=7.2,1.0Hz,2H),3.86(s,5H),1.01(s,9H);31P NMR(122MHz,CDCl3)δ(ppm)-25.55;13C NMR(101MHz,CDCl3)δ(ppm)141.8,140.1(d,J=7.5Hz),139.3,138.5,137.8(d,J=7.6Hz),137.3,136.9,135.5(d,J=22.0Hz),132.6(d,J=17.6Hz),131.4(d,J=16.9Hz),130.0(d,J=1.5Hz),129.5,128.5,128.4,128.3,128.2,128.1,127.6,127.1(d,J=9.5Hz),125.2(d,J=9.6Hz),96.6(d,J=26.0Hz),75.1(d,J=10.3Hz),72.0(d,J=4.2Hz),70.8(d,J=4.1Hz),70.7,70.1,59.8(d,J=9.4Hz),56.3,22.4。
实施例17(SFC,SC,RS)-1h的合成(参考方案一)
具体操作与实施例1相同,所用原料为所用金属试剂为试剂。产率为70%。1H NMR(400MHz,CDCl3)δ(ppm)7.74-7.54(m,9H),7.52-7.40(m,7H),7.39-7.31(m,4H),7.25-7.11(m,7H),5.78(s,1H),4.66(s,2H),4.42(s,1H),4.18(s,5H),3.83(s,1H),1.33(s,9H);31P NMR(122MHz,CDCl3)δ(ppm)-23.70;13C NMR(101 MHz,CDCl3)δ(ppm)140.6,139.2(d,J=12.4Hz),137.9,137.3(d,J=10.1Hz),137.1(d,J=7.0Hz),135.2(d,J=21.6Hz),133.2(d,J=18.9Hz),131.5,131.0,1230.0(d,J=4.1Hz),129.4,128.5,128.4(d,J=5.1Hz),128.3(d,J=3.7Hz),128.2,128.1,127.6,127.1(d,J=13.5Hz),125.1(d,J=10.0Hz),96.3(d,J=21.8Hz),74.1(d,J=13.5Hz),72.6(d,J=3.5Hz),72.4(d,J=3.7Hz),70.3,70.2,57.9(d,J=2.0Hz),56.1,22.9。
实施例18(SFC,SC,SS)-1i的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为试剂。产率为65%。1H NMR(500MHz,CDCl3)δ(ppm)7.46-7.43(m,2H),7.37-7.28(m,3H),6.95(d,J=7.4Hz,1H),6.84(td,J=7.6,1.2Hz,2H),6.76(t,J=8.3Hz,1H),6.61-6.58(m,2H),6.37(dd,J=6.3,2.3Hz,1H),6.13(d,J=8.3Hz,1H),5.91(d,J=8.3Hz,1H),4.90-4.86(m,1H),4.55(d,J=6.3Hz,1H),4.21(d,J=2.4Hz,1H),4.20(d,J=6.3Hz,5H),3.61(s,3H),3.60(d,J=1.0Hz,1H),3.56(s,3H),1.13(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-22.07;13C NMR(126MHz,CDCl3)δ(ppm)158.4,156.9,139.7(d,J=11.3Hz),138.4(d,J=10.7Hz),135.6(d,J=21.7Hz),131.6(d,J=18.0Hz),128.9(d,J=16.2Hz),127.9(d,J=7.7Hz),127.2(d,J=5.8Hz),126.8,117.5,103.7(d,J=11.2Hz),97.2(d,J=24.6Hz),74.4(d,J=12.1Hz),71.2(d,J=4.0Hz),71.0(d,J=4.6Hz),70.1,68.2,55.5(d,J=30.3Hz),55.1,49.3(d,J=7.9Hz),22.4。
实施例19(SFC,SC,RS)-1i的合成(参考方案一)
具体操作与实施例1相同,所用原料为所用金属试剂为试剂。产率为65%。1H NMR(500MHz,CDCl3)δ(ppm)7.68-7.65(m,2H),7.43-7.36(m,3H),7.24-7.16(m,6H),6.62(d,J=8.3Hz,1H),6.47(d,J=8.3Hz,1H),6.42(dd,J=8.3,2.5Hz,1H),5.14(dd,J=8.2,5.0Hz,1H),4.52(d,J=1.3Hz,1H),4.23(t,J=2.3Hz,1H),3.99(s,3H),3.93-3.88(m,1H),3.75(s,5H),3.50(s,3H),0.91(d,J=13.5Hz,9H);31P NMR(202MHz,CDCl3)δ(ppm)-22.46;13C NMR(126MHz,CDCl3)δ158.4,157.1,141.3(d,J=8.1Hz),139.2(d,J=9.2Hz),135.8(d,J=22.4Hz),132.5(d,J=16.5Hz),129.2,128.7,128.1(d,J=8.2Hz),127.8(d,J=5.4Hz),127.2,119.2,104.2(d,J=32.0Hz),96.5(d,J=24.9Hz),74.83(d,J=13.4Hz),71.29(d,J=4.6Hz),70.9(d,J=4.5Hz),70.0,69.9,56.2,55.4,54.7,50.6(d,J=5.7Hz),22.3。
实施例20(SFC,SC,SS)-1j的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为试剂。产率为75%。1H NMR(400MHz,CDCl3)δ(ppm)7.66-7.63(m,3H),7.44-7.34(m,13H),7.26-7.12(m,7H),7.05(s,1H),6.56(s,1H),4.42(s,1H),4.29(s,1H),3.99(s,1H),3.93(s,1H),3.80(s,5H),0.72(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-17.00(d,J=13.0Hz),-24.88(d,J=13.0Hz);13C NMR(126MHz,CDCl3)δ(ppm)147.1(d,J=25.0Hz),140.3(d,J=10.7Hz),138.1(d,J=9.7Hz),136.9(d,J=7.4Hz),136.7(d,J=6.9Hz),135.7(d,J=18.6Hz),135.5,135.3,134.8(d,J=20.0Hz),134.4(d,J=19.4Hz),134.0,132.5(d,J=17.5Hz),129.3(d,J=8.1Hz),129.3,128.8,128.7,128.5(d,J=6.9Hz),128.2,127.8,96.3(d,J=26.3Hz),77.51(s,13H),75.1(d,J=12.1Hz),71.9(d,J=3.8Hz),70.8,70.2,56.7(dd,J=28.8,8.7Hz),55.8,22.0。
实施例21(SFC,SC,SS)-1k的合成(参考方案一)
具体操作与实施例1相同,所用金属试剂为试剂。产率为88%。1H NMR(500MHz,CDCl3)δ(ppm)8.22-8.13(m,1H),7.87(dd,J=8.1,1.0Hz,1H),7.76(dd,J=16.9,7.7Hz,2H),7.59(tt,J=5.0,2.8Hz,4H),7.52-7.43(m,4H),7.40(dd,J=7.9,2.8Hz,3H),7.33-7.27(m,7H),7.25-7.18(m,5H),4.87(d,J=0.9Hz,1H),4.41(s,1H),4.25(t,J=2.4Hz,1H),3.93(d,J=0.9Hz,1H),3.64(s,5H),0.99(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-8.23(d,J=12.4Hz),-23.70(d,J=12.4Hz);13C NMR(126MHz,CDCl3)δ(ppm)140.7(d,J=3.9Hz),140.0(d,J=7.7Hz),138.5,138.4,138.3(d,J=4.4Hz),138.2(d,J=8.4Hz),138.1,135.4(d,J=5.7Hz),135.3(d,J=21.8Hz),135.1(d,J=19.4Hz),134.5(d,J=20.1Hz),133.8(d,J=19.2Hz),132.8(d,J=17.6Hz),132.5(d,J=26.4Hz),132.0,131.5(d,J=3.2Hz),130.0,129.3,128.9,128.8,128.6(d,J=6.4Hz),128.5,128.3(d,J=6.0Hz),128.1(d,J=8.1Hz),128.0,125.0,124.6,97.4(d,J=24.9Hz),74.3(dd,J=12.9,1.0Hz),72.3(d,J=4.0Hz),71.4(dd,J=6.3,5.0Hz),70.7,69.9,58.0(d,J=2.6Hz),57.7(d,J=2.6Hz),56.3,22.7。
实施例22(RFC,SC,Rs)-1a的合成(参考方案二)
参照文献(Eur.J.Org.Chem.2014,6676)报道方法,制备醛SFC-2和RFC-2
第一步:将制备的(2g,5.0mmol)和(0.9g,1.5equiv)加入100mL的三颈瓶中,在N2的氛围下加入50mL THF,加Ti(OEt)2(3.1mL,3.0equiv),在60℃下搅拌24小时,分液,水层用乙酸乙酯萃取三次,合并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化,得产率为85%。1HNMR(500MHz,CDCl3)δ(ppm)8.63(s,2H),7.51(dt,J=9.6,3.5Hz,4H),7.38(d,J=5.0Hz,6H),7.20(d,J=2.4Hz,6H),7.14-7.05(m,4H),4.94(d,J=0.7Hz,2H),4.56(t,J=2.4Hz,1H),4.54(t,J=2.4Hz,1H),4.20(s,5H),4.18(s,5H),1.21(s,9H),0.90(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-19.69,-20.12;13C NMR(126MHz,CDCl3)δ(ppm)163.5(d,J=2.5Hz),162.9(d,J=3.1Hz),139.4(d,J=7.8Hz),139.3(d,J=8.1Hz),137.8(d,J=12.6Hz),137.7(d,J=12.1Hz),135.4(d,J=15.7Hz),135.2(d,J=15.8Hz),132.2(d,J=18.4Hz),129.3(d,J=15.5Hz),128.4(d,J=5.4Hz),128.3(d,J=5.3Hz),128.2(d,J=6.3Hz),128.1,128.0,127.9,83.1(t,J=15.9Hz),78.7(d,J=16.5Hz),78.0(d,J=15.5Hz),75.8(d,J=4.6Hz),75.6(d,J=4.8Hz),74.3(d,J=2.3Hz),73.7(d,J=2.3Hz),72.6(d,J=9.8Hz),70.8,56.7(d,J=7.8Hz),27.0,22.4(d,J=2.0Hz),22.1.
其中,THF为四氢呋喃;N2为氮气;Ti(OEt)4为钛酸四乙酯。
第二步:将第一步制备的(1g,2mmol)加入到干燥的50mL的单支口反应管中,氮气保护,加入10mL THF。在-78℃下,苯基溴化镁(3equiv,6mL,1Min THF),在-78℃下搅拌1小时后,自然升温,搅拌过夜,加饱和氯化铵淬灭,分液,水层用乙酸乙酯萃取三次,合并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化得(SFC,RC,Rs)-1a和(RFC,SC,Rs)-1a,产率分别为35%和40%。(RFC,SC,Rs)-1a,1H NMR(500MHz,CDCl3)δ(ppm)7.66-7.56(m,2H),7.54(d,J=7.0Hz,2H),7.38(dt,J=9.2,4.5Hz,5H),7.32(t,J=7.4Hz,1H),7.24-7.21(m,3H),7.23-7.14(m,2H),5.57(dd,J=6.6,3.7Hz,1H),4.36(s,1H),4.35(t,J=2.4Hz,1H),3.97(s,1H),3.71(d,J=6.8Hz,1H),3.68(s,5H),0.87(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-25.57;13C NMR δ(ppm)(126MHz,CDCl3)δ142.2,140.4(d,J=7.6Hz),137.9(d,J=7.1Hz),135.7(d,J=22.4Hz),132.7(d,J=17.6Hz),129.5,128.7,128.3,128.0(d,J=17.0Hz),127.9(d,J=14.7Hz),96.3(d,J=26.3Hz),74.9(d,J=10.5Hz),71.9(d,J=4.7Hz),70.5(d,J=4.4Hz),70.4,69.9,59.9(d,J=9.7Hz),56.6,22.4。
实施例23(RFC,RC,Rs)-1a的合成(参考方案二)
具体操作与实施例22相同。在-78℃下,加入苯基锂(3equiv,6mL,1M inTHF),搅拌30分钟后,加饱和氯化铵淬灭,分液,水层用乙酸乙酯萃取三次,合并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化,得(SFC,SC,Rs)-1a和(RFC,RC,Rs)-1a,产率分别为39%和41%。(RFC,RC,Rs)-1a,1H NMR(500MHz,CDCl3)δ(ppm)7.58-7.50(m,2H),7.38(dd,J=9.0,4.9Hz,3H),7.11(d,J=7.2Hz,2H),6.97(t,J=7.6Hz,1H),6.90(t,J=7.0Hz,1H),6.86(dd,J=14.0,7.3Hz,4H),6.61(t,J=7.2Hz,2H),5.70(d,J=3.0Hz,1H),4.70(s,1H),4.53(s,1H),4.30(t,J=2.2Hz,1H),4.10(s,5H),3.80(s,1H),1.28(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-24.44;13C NMR(126MHz,CDCl3)δ(ppm)140.6,138.8(d,J=8.7Hz),137.2(d,J=9.2Hz),135.5(d,J=21.6Hz),131.9(d,J=18.1Hz),129.0,128.3,128.2(d,J=7.9Hz),127.8,127.7(d,J=6.5Hz,),127.3(d,J=2.5Hz),98.1(d,J=24.2Hz),76.4(d,J=11.6Hz),71.7(d,J=4.9Hz),70.1,69.4,67.2(d,J=3.9Hz),55.8(d,J=10.5Hz),55.6,22.6。
实施例24(RFC,SC,Ss)-1a的合成(参考方案二)
具体操作与实施例22相同,所用原料为金属试剂为苯基溴化镁。得(SFC,RC,Ss)-1a和(RFC,SC,Ss)-1a,产率分别为40%和42%。(RFC,SC,Ss)-1a,1H NMR(500MHz,CDCl3)δ(ppm)7.55-7.49(m,2H),7.37(d,J=4.3Hz,3H),7.09(d,J=7.9Hz,2H),6.98(t,J=7.3Hz,1H),6.88-6.75(m,5H),6.67(t,J=7.5Hz,2H),5.70(t,J=3.0Hz,1H),4.82(s,1H),4.36(t,J=2.0Hz,1H),4.10(s,5H),3.95(d,J=3.1Hz,1H),3.89(s,1H),1.30(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-24.58;13C NMR(126MHz,CDCl3)δ(ppm)141.3,138.5(d,J=8.2Hz),137.5(d,J=8.3Hz),135.2(d,J=20.5Hz),132.1(d,J=18.5Hz),129.3,128.4,128.2(d,J=7.5Hz),128.1,127.6(d,J=2.1Hz),127.6,127.3,97.7(d,J=22.9Hz),74.0(d,J=11.0Hz),72.2(d,J=4.6Hz),70.0,69.7(d,J=3.9Hz),69.4,59.2(d,J=10.5Hz),56.0,23.1。
实施例25(RFC,RC,Ss)-1a的合成(参考方案二)
具体操作与实施例22相同,所用原料为在-78℃下,加入苯基锂(3equiv,6mL,1M in THF),搅拌30分钟后,加饱和氯化铵淬灭,分液,水层用乙酸乙酯萃取三次,合并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化,得(SFC,SC,Ss)-1a和(RFC,RC,Ss)-1a,产率分别为39%和41%。(RFC,RC,Ss)-1a,1H NMR(500MHz,CDCl3)δ(ppm)7.65-7.59(m,2H),7.45(dd,J=4.2,2.5Hz,3H),7.37-7.29(m,2H),7.24-7.17(m,3H),7.14-7.05(m,5H),5.45(s,1H),4.33(s,1H),4.23(d,J=4.1Hz,1H),4.32(t,J=2.4Hz,1H),4.06(s,5H),3.77(s,1H),1.14(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-24.16;13C NMR(126MHz,CDCl3)δ(ppm)141.3,139.0(d,J=10.0Hz),137.4(d,J=9.9Hz),136.3(d,J=20.6Hz),133.5(d,J=17.2Hz),129.5,128.4(d,J=5.2Hz),128.2(d,J=2.5Hz),128.1,128.0,127.3,96.0(d,J=20.4Hz),73.7(d,J=12.0Hz),72.4(d,J=3.9Hz),72.1(d,J=4.1Hz),70.3,70.2,57.8(d,J=3.6Hz),55.9,22.5。
实施例26(SFC,SC,Rs)-1b和(RFC,RC,Rs)-1b的合成(参考方案二)
具体操作与实施例22相同。在-78℃下,加入1-萘基锂(3equiv,6mL,1M in THF),搅拌30分钟后,加饱和氯化铵淬灭,分液,水层用乙酸乙酯萃取三次,合并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化,得(SFC,SC,Rs)-1b和(RFC,RC,Rs)-1b,产率分别为35%和39%。(RFC,RC,Rs)-1b,1H NMR(500MHz,CDCl3)δ(ppm)8.77(d,J=7.9Hz,1H),7.93(dd,J=12.7,7.8Hz,2H),7.86(d,J=8.0Hz,1H),7.76(d,J=7.1Hz,1H),7.67(s,2H),7.57(dd,J=14.8,7.4Hz,2H),7.43(s,3H),7.29(d,J=3.1Hz,5H),6.57(s,1H),4.55(s,1H),4.39(s,1H),4.02(d,J=12.7Hz,1H),3.88(d,J=2.9Hz,1H),3.32(s,5H),0.88(s,9H);31P NMR(202MHz,CDCl3)δ(ppm)-26.11;13C NMR(126MHz,CDCl3)δ(ppm)140.1(d,J=7.1Hz),138.52,137.9(d,J=7.2Hz),135.4(d,J=22.1Hz),133.9,132.5(d,J=17.5Hz),131.6,129.5,129.2,128.3(t,J=7.2Hz),128.0,126.2,125.7,125.4,96.6(d,J=27.6Hz),75.1(d,J=9.5Hz),71.5(d,J=4.6Hz),70.8(d,J=18.8Hz),69.8,56.0,22.0。
实施例27(SFC,RC,Rs)-1l和(RFC,SC,Rs)-1l的合成(参考方案二)
具体操作与实施例22相同。金属试剂为得(SFC,RC,Rs)-1l和(RFC,SC,Rs)-1l,产率分别为37%和39%。(SFC,RC,Rs)-11,1H NMR(400MHz,CDCl3)δ(ppm)7.53(d,J=7.7Hz,1H),7.50-7.39(m,4H),7.39-7.20(m,7H),6.53(d,J=27.1Hz,5H),5.90(s,1H),4.85(s,1H),4.38(s,1H),4.16(s,5H),3.98(d,J=2.4Hz,1H),3.84(s,1H),1.28(s,9H);31P NMR(162MHz,CDCl3)δ(ppm)-24.90(s,1H);13C NMR(101MHz,CDCl3)δ(ppm)138.5,137.2(dd,J=22.1,8.0Hz),135.1(d,J=21.2Hz),132.8(d,J=15.6Hz),131.7(d,J=19.1Hz),129.1,128.2(d,J=12.1Hz),128.1(d,J=7.9Hz),127.9,127.2(d,J=22.7Hz),126.9(d,J=9.7Hz),125.7(d,J=2.5Hz),1255,97.3(d,J=23.3Hz),74.3(d,J=10.4Hz),72.2(d,J=4.4Hz),70.0,69.7(d,J=3.8Hz),69.2,59.2(d,J=10.2Hz),56.1,23.0。(RFC,SC,Rs)-1l,1H NMR(400MHz,CDCl3)δ(ppm)8.01(s,1H),7.92-7.81(m,3H),7.71(d,J=8.5Hz,1H),7.67-7.59(m,2H),7.53-7.45(m,2H),7.44-7.39(m,3H),7.21(dd,J=10.4,7.6Hz,5H),5.78(dd,J=6.4,3.0Hz,1H),4.43(s,1H),4.35(t,J=2.3Hz,1H),4.01(s,1H),3.93(d,J=6.7Hz,1H),3.72(s,5H),0.90(s,9H);31P NMR(162MHz,CDCl3)δ(ppm)-25.44;13C NMR(101 MHz,CDCl3)δ(ppm)140.1(d,J=7.5Hz),139.4,137.6(d,J=7.5Hz),135.4(d,J=22.0Hz),133.1(d,J=13.0Hz),132.4(d,J=17.5Hz),129.4,128.3,128.2,128.1,127.9(d,J=7.7Hz),127.6(d,J=22.7Hz),126.5,126.1(d,J=12.1Hz),96.1(d,J=26.2Hz),74.6(d,J=10.1Hz),71.9(d,J=4.4Hz),71.0(d,J=4.2Hz),70.4,69.9,60.1(d,J=8.8Hz),56.1,22.1。
实施例28(SFC,SC,Rs)-1m和(RFC,RC,Rs)-1m的合成(参考方案二)
具体操作与实施例22相同。在-78℃下,加入叔丁基基锂(3equiv,6mL,1M inTHF),搅拌30分钟后,加饱和氯化铵淬灭,分液,水层用乙酸乙酯萃取三次,合并有机相,分别用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干,柱层析纯化,得(SFC,SC,Rs)-1m和(RFC,RC,Rs)-1m,产率分别为35%和39%。(SFC,SC,Rs)-1m,1H NMR(400MHz,CDCl3)δ(ppm)7.60-7.49(m,2H),7.37-7.30(m,6H),7.26-7.23(m,2H),5.94(dd,J=13.0,4.1Hz,1H),4.39-4.34(m,2H),4.11(s,1H),4.06(d,J=4.1Hz,1H),4.02(s,5H),1.55(s,9H),0.66(s,9H);31P NMR(162MHz,CDCl3)δ(ppm)-23.31;13C NMR(101MHz,CDCl3)δ(ppm)139.2(d,J=5.6Hz),138.3(d,J=5.0Hz),135.2(d,J=22.4Hz),132.7(d,J=18.4Hz),129.3,128.1(d,J=8.6Hz),128.0,127.9(d,J=2.5Hz),94.3(d,J=24.2Hz),74.3(d,J=6.1Hz),72.8(d,J=3.1Hz),70.6,69.6,65.4(d,J=1.6Hz),57.3(d,J=0.9Hz),37.6,27.9(d,J=1.2Hz),23.9(d,J=2.8Hz)。
(RFC,RC,Rs)-1m,1H NMR(400MHz,CDCl3)δ(ppm)7.58-7.50(m,2H),7.40-7.33(m,3H),7.31-7.21(m,5H),4.81(s,1H),4.40-4.32(m,2H),4.13(s,1H),3.98(d,J=1.0Hz,1H),3.89(s,5H),1.55(s,9H),0.76(s,9H);31P NMR(162MHz,CDCl3)δ(ppm)-23.50;13C NMR(101MHz,CDCl3)δ(ppm)139.6(d,J=6.6Hz),138.6(d,J=7.0Hz),136.2(d,J=25.4Hz),134.7(d,J=15.4Hz),129.3,128.0(d,J=8.6Hz),128.0,127.9(d,J=2.5Hz),94.6(d,J=24.2Hz),74.3(d,J=6.1Hz),72.8(d,J=3.1Hz),70.6,68.6,65.6,56.3,37.6,27.8(d,J=1.8Hz),23.6。
实施例29(SFC,RC,Rs)-1n和(RFC,SC,Rs)-1n的合成(参考方案二)
具体操作与实施例22相同。金属试剂为得(SFC,RC,Rs)-1n和(RFC,SC,Rs)-1n,产率分别为34%和35%。(SFC,RC,Rs)-1n,1H NMR(500MHz,CDCl3)δ(ppm)7.52(s,2H),7.38(s,3H),7.22-7.15(m,5H),4.83(s,1H),4.35(s,1H),4.03(s,6H),3.88(s,1H),3.54(s,1H),1.32(s,9H),1.07(s,1H),0.60(s,1H),0.37(s,1H),0.21(s,1H),0.11(s,1H);31P NMR(202MHz,CDCl3)δ(ppm)-23.59;13C NMR(126MHz,CDCl3)δ(ppm)140.2(d,J=9.0Hz),137.9(d,J=9.1Hz),135.4(d,J=21.9Hz),132.5(d,J=17.8Hz),131.6(d,J=8.2Hz),129.3,128.2(d,J=8.0Hz),128.1(d,J=6.0Hz),127.9,99.1(d,J=24.5Hz),74.2(d,J=11.5Hz),72.0(d,J=4.1Hz),70.7(d,J=3.9Hz),70.2,69.8,69.5,59.8(d,J=6.0Hz),55.9,23.0,18.3,7.0(d,J=4.9Hz),6.57。
(RFC,SC,Rs)-1n,1H NMR(500MHz,CDCl3)δ(ppm)7.58-7.50(m,2H),7.41-7.35(m,3H),7.25-7.16(m,5H),4.49(d,J=1.4Hz,1H),4.36(t,J=2.4Hz,1H),3.98(s,5H),3.93-3.90(m,1H),3.88(dd,J=7.2,4.7Hz,1H),3.52(ddd,J=9.4,7.5,1.8Hz,1H),1.17-1.11(m,1H),1.08(s,9H),0.74(ddd,J=10.1,7.4,5.0Hz,1H),0.70-0.63(m,1H),0.62-0.57(m,1H),0.53(td,J=9.3,4.9Hz,1H);31P NMR(202MHz,CDCl3)δ(ppm)-23.93;13C NMR(126MHz,CDCl3)δ(ppm)139.8(d,J=7.7Hz),137.8(d,J=8.1Hz),135.3(d,J=21.7Hz),132.7(d,J=17.7Hz),129.4,128.3,128.2,128.1,128.0,97.3(d,J=24.9Hz),73.4(d,J=10.1Hz),71.7(d,J=4.1Hz),70.4(d,J=4.9Hz),69.8(d,J=4.9Hz),61.7(d,J=4.9Hz),56.0,22.8,19.3,7.1,6.9。
实施例30(SFC,RC,Rs)-1g和(RFC,SC,Rs)-1g的合成(参考方案二)
具体操作与实施例22相同。金属试剂为得(SFC,RC,Rs)-1g和(RFC,SC,Rs)-1g,产率分别为35%和41%。(SFC,RC,Rs)-1g,1H NMR(400MHz,CDCl3)δ(ppm)7.49(dd,J=9.3,5.4Hz,2H),7.34(s,3H),6.99(dd,J=16.7,7.9Hz,3H),6.90(t,J=7.2Hz,2H),6.69(t,J=7.4Hz,2H),6.39(d,J=8.5Hz,2H),5.70(s,1H),4.80(s,1H),4.35(s,1H),4.12(s,5H),3.89(d,J=2.7Hz,1H),3.85(s,1H),3.58(s,3H),1.29(s,9H);31PNMR(162MHz,CDCl3)δ(ppm)-24.52;13C NMR(101MHz,CDCl3)δ(ppm)158.7,138.3(d,J=8.3Hz),137.3(d,J=8.5Hz),135.2(d,J=21.4Hz),133.6,132.8(d,J=18.8Hz),129.5,129.1,128.1(d,J=7.9Hz),127.5(d,J=6.5Hz),127.2,113.5,98.1(d,J=23.5Hz),74.0(d,J=10.7Hz),72.1(d,J=3.5Hz),69.9,69.6(d,J=3.9Hz),69.1,58.5(d,J=10.4Hz),56.0,55.0,23.0。
(RFC,SC,Rs)-1g,1H NMR(400MHz,CDCl3)δ(ppm)7.63-7.54(m,2H),7.46(d,J=8.6Hz,2H),7.38(d,J=4.7Hz,3H),7.25-7.20(m,3H),7.18-7.12(m,2H),6.91(d,J=8.6Hz,2H),5.52(dd,J=6.6,3.6Hz,1H),4.38-4.30(m,2H),3.96(s,1H),3.82(s,3H),3.71(s,5H),3.62(d,J=6.7Hz,1H),0.83(s,9H);31P NMR(162MHz,CDCl3)δ(ppm)-25.49;13C NMR(101MHz,CDCl3)δ(ppm)159.1,140.3(d,J=7.8Hz),137.8(d,J=7.8Hz),135.5(d,J=22.0Hz),134.3,132.5(d,J=17.5Hz),129.8,129.5,128.3(dd,J=10.5,7.1Hz),128.0,113.6,96.6(d,J=26.3Hz),74.8(d,J=10.0Hz),71.9(d,J=4.7Hz),70.9(d,J=4.2Hz),70.4,69.9,59.5(d,J=9.6Hz),56.0,55.4(d,J=1.7Hz),22.1。.
实施例31联烯的硼酰化不对称反应
将实施例5所得的手性单膦配体(SFC,SC,Ss)-1d与铜盐形成的配合物用于反应的催化,具体操作为:在氮气气气氛中,室温下将手性单膦配体(SFC,SC,Ss)-1d(0.05mmo1)和Cu(OAc)2(0.06mmol)加入经无水无氧处理过的反应管中,然后加入无水四氢呋喃溶液(1mL),室温搅拌1h后,加入三甲基硅醇钠(0.6mmol)。然后,在0℃下,加入溶于1mL四氢呋喃的联硼酸频那醇酯(0.6mmol),同时加入溶于1mL四氢呋喃的联烯(0.5mmol)及酰氟(0.75mmol),维持在0℃,通过TLC检测,底物全部转化后,反应液浓缩至1mL,柱层析分析其产率,HPLC分析其对映体过量值(ee)。
具体催化反应如下反应式(VII)所示:
柱层析分析得知:目标产物产率63%:HPLC分析得知:ee=90%
目标产物的1H NMR(400MHz,CDCl3)δ(ppm)7.40(m,4H),7.33(m,3H),7.27-7.18(m,3H),5.84(s,1H),5.07(s,1H),2.44(dq,J=14.4,7.2Hz,1H),2.31(dq,J=14.6,7.4Hz,1H),1.31(s,6H),1.31(s,6H),0.88(t,J=7.3Hz,3H);13C NMR(101MHz,CDCl3),δ(ppm)203.8,141.7,137.4,131.6,129.5,128.7,128.0,127.6,127.0,83.2,65.6,28.3,25.0,24.8,10.5。高分辨率质谱理论数据C24H29BO3[M+Na]+=399.2106,实验数据:399.2104。手性通过HPLC测定,使用IE手性柱(hexanes,0.5mL/min,220nm);小的对映异构体保留时间10.46min,大的对映异构体保留时间13.53min。[α]D 22=-186.7(c=0.33,CHCl3)。
实施例32-79
考察本发明所述的手性单膦配体WJ-Phos即化合物1与铜盐形成的配合物,配体R3取代基、铜盐类型、反应温度及溶剂反应的影响,具体操作及其余条件均参照实施例31所述。各实施例的反应条件及实验结果详见表1所示。
表1 实施例32-49的反应条件和反应结果
通过实施例31-36,说明(SFC,SC,Ss)-1b为最合适的配体,以70%产率,90%ee得到目标产物;通过实施例33、实施例37-41,说明醋酸铜为最合适的铜盐,以70%产率,90%ee得到目标产物;通过实施例33、实施例42-45,说明四氢呋喃为最合适的溶剂,以70%产率,90%ee得到目标产物;实施例33、实施例46-49说明0℃为最合适的温度,以70%产率,90%ee得到目标产物。
实施例50-79
考察本发明所述的底物的普适性,具体操作及其余条件均参照实施例33所述。各实施例的反应条件及实验结果详见表2所示。
催化反应如下式式(VIII)所示:
表2 实施例50-79的反应条件和反应结果
通过实施例50-79,在联烯的硼酰化不对称反应中的应用中,所述手性单膦配体WJ-Phos有很好的底物普适性,且具有很高的反应活性和对映选择性。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (9)
1.一类二茂铁骨架的手性单膦配体WJ-Phos,其特征在于,所述手性单膦配体为如下式所示的化合物1或化合物1对映体、消旋体或非对映异构体:
化合物1中,R1、R2、R4分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、 R3选自C2~C12的烷烃基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基、ORw或SRw;其中,Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基或C1~C10的磺酸酯基;Ry、Ry′、Ry〃、Rz、Rz′和Rw分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基或C1~C10的磺酸酯基;“*”表示手性中心。
2.如权利要求1所述的手性单膦配体WJ-Phos,其特征在于,所述化合物1中的R1、R2同时选自C1~C12的烷烃基、R3选自C2~C12的烷烃基、C1~C10的硅氧基、C1~C10的酯基或R4选自C1~C12的烷烃基、其中Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基或C1~C10的磺酸酯基。
3.一种权利要求1所述手性单膦配体WJ-Phos的制备方法,其特征在于,该方法包括以下具体步骤:
第一步:在溶剂中,化合物SFC-2或化合物RFC-2分别与化合物3(Rs)或化合物3(Ss)在缩合剂作用下进行缩合反应,得到化合物(SFC,Rs)-4或化合物(SFC,Ss)-4或化合物(RFC,Rs)-4或化合物(RFC,Ss)-4,反应过程如下反应式(I)所示:
所述溶剂选自干燥的二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺、甲苯、二甲苯、苯、氯苯、氟苯、氯仿或正己烷;
所述缩合剂为钛酸四乙酯、钛酸四异丙酯或钛酸四甲酯;
所述缩合反应的温度为-50~100℃;
所述缩合反应的时间为10分钟~48小时;
所述化合物SFC-2或化合物RFC-2、化合物3(Rs)或化合物3(Ss)与缩合剂的摩尔比为1∶(1~10)∶(1~100);
第二步:化合物(SFC,Rs)-4或化合物(SFC,Ss)-4或化合物(RFC,Rs)-4或化合物(RFC,Ss)-4在干燥的溶剂中,分别与金属试剂R3MgX或R3Li化合物进行加成反应,得到手性单膦配体WJ-Phos即化合物(SFC,SC,RS)-1、化合物(SFC,RC,RS)-1、化合物(SFC,SC,SS)-1、化合物(SFC,RC,SS)-1、(RFC,SC,RS)-1、化合物(RFC,RC,RS)-1、化合物(RFC,SC,SS)-1或化合物(RFC,RC,SS)-1,反应过程如下反应式(II)所示:
所述溶剂选自干燥的二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺、甲苯、二甲苯、苯、氯苯、氟苯、氯仿或正己烷;
所述加成反应的温度为-78~30℃;
所述加成反应的时间为10分钟~48小时;
所述化合物(SFC,Rs)-4或化合物(SFC,Ss)-4或(RFC,Rs)-4或化合物(RFC,Ss)-4与R3[M]的摩尔比为1∶(1~50);
化合物1中,R1、R2、R4分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、 R3选自C2~C12的烷烃基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基、ORw或SRw;其中,Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基或C1~C10的磺酸酯基;Ry、Ry′、Ry〃、Rz、Rz′和Rw分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基或C1~C10的磺酸酯基;X为卤素,M为锂或卤化镁,(SFC,SC,SS)中FC表示面手性、C表示碳中心手性、S表示硫中心手性。
4.一种权利要求1所述手性单膦配体WJ-Phos的制备方法,其特征在于,该方法包括以下具体步骤:
第一步:在溶剂中,化合物SFC-2和化合物RFC-2与化合物3(Rs)或化合物3(Ss)在缩合剂作用下进行缩合反应,得到化合物(SFC,Rs)-4和化合物(RFC,Rs)-4或化合物(SFC,Rs)-4和化合物(RFC,Rs)-4,反应过程如下反应式(III)所示:
所述溶剂选自干燥的二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺、甲苯、二甲苯、苯、氯苯、氟苯、氯仿或正己烷;
所述缩合剂为钛酸四乙酯、钛酸四异丙酯或钛酸四甲酯;
所述缩合反应的温度为-50~100℃;
所述缩合反应的时间为10分钟~48小时;
所述化合物SFC-2和化合物RFC-2、化合物3(Rs)或化合物3(Ss)与缩合剂的摩尔比为1∶(1~10)∶(1~100);
第二步:化合物(SFC,Rs)-4和化合物(RFC,Rs)-4或化合物(SFC,Rs)-4和化合物(RFC,Rs)-4在干燥的溶剂中,分别与金属试剂R3MgX或者R3Li化合物进行加成反应,得到手性单膦配体WJ-Phos,即化合物(SFC,SC,RS)-1、化合物(SFC,RC,RS)-1、化合物(RFC,SC,RS)-1、化合物(RFC,RC,RS)-1、化合物(SFC,SC,SS)-1、化合物(SFC,RC,SS)-1、化合物(RFC,SC,SS)-1、化合物(RFC,RC,SS)-1,反应过程如下反应式(IV)所示:
所述溶剂选自干燥的二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺、甲苯、二甲苯、苯、氯苯、氟苯、氯仿或正己烷;
所述加成反应的温度为-78~30℃;
所述加成反应的时间为10分钟~48小时;
所述化合物(SFC,Rs)-4和(RFC,Rs)-4或(SFC,Rs)-4和(RFC,Rs)-4与R3[M]的摩尔比为1∶(1~50);
化合物1中,R1、R2、R4分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、 R3选自C2~C12的烷烃基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基、ORw或SRw;其中,Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基或C1~C10的磺酸酯基;Ry、Ry′、Ry〃、Rz、Rz′和Rw分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基或C1~C10的磺酸酯基;X为卤素,M为锂或卤化镁,(SFC,SC,SS)中FC表示面手性、C表示碳中心手性、S表示硫中心手性。
5.一种如权利要求1所述的手性单膦配体WJ-Phos在铜催化联烯的硼酰化不对称反应构建含有四级碳手性中心的硼取代的不饱和酮类化合物中的应用。
6.根据权利要求5所述的应用,其特征在于,将手性单膦配体WJ-Phos与过渡金属盐形成配合物,然后催化联烯的硼酰化不对称反应,合成硼取代的不饱和酮类化合物,具体包括:
惰性气氛下,将所述手性单膦配体WJ-Phos与过渡金属盐加入到有机溶剂中,在-10~150℃搅拌,反应0.1~20小时,形成配合物溶液,向配合物溶液中加入碱、硼酯、联烯、酰氟,在-90~190℃条件下进行联烯的硼酰化反应,合成所述硼取代的不饱和酮类化合物;其中:
所述手性单膦配体和过渡金属盐的摩尔比为(1~50):1;
所述碱、硼酯、联烯、酰氟与所述所述配合物的摩尔比为(1~100000)∶(1~10000)∶(1~100000)∶(1~100000)∶1。
7.根据权利要求6所述的方法,其特征在于,所述惰性气氛为氩气或氮气气氛;所述有机溶剂选自二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯、苯、氯苯、氟苯或氯仿。
8.根据权利要求6所述的方法,其特征在于,所述过渡金属盐为铜盐,所述铜盐选自CuCl、Cu(OTf)2、Cu2(OTf)2·Tol、Cu(OAc)2、CuOAc、CuCl2、CuCl2、CuBr、CuF2、CuI、CuSO4、Cu(NO3)2·3H2O、Cu(TFA)2·xH2O、Cu2Te、Cu(acac)2、CuTC、Cu(CH3CN)4ClO4、Cu(CH3CN)4PF6、Cu(CH3CN)4BF4或CuBr·SMe2。
9.根据权利要求6所述的应用,其特征在于,所述碱为Et3N、DBU、DABCO、Bn2NH、Bu3N、Pr2NH、K2CO3、TMSONa、Na2CO3、KOH、NaOH、Cs2CO3、Li2CO3、CsOH、LiOH、NaOtBu、KOtBu或LiOtBu。
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