CN114716466A - 一种镍催化的不对称氢酰胺化制备手性α-氨基硼酸/硼酸酯的方法 - Google Patents
一种镍催化的不对称氢酰胺化制备手性α-氨基硼酸/硼酸酯的方法 Download PDFInfo
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- CN114716466A CN114716466A CN202210526440.5A CN202210526440A CN114716466A CN 114716466 A CN114716466 A CN 114716466A CN 202210526440 A CN202210526440 A CN 202210526440A CN 114716466 A CN114716466 A CN 114716466A
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- Prior art keywords
- nickel
- boric acid
- amino
- hydroamidation
- chiral
- Prior art date
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Links
- 239000004327 boric acid Substances 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 34
- -1 boric acid ester Chemical class 0.000 title claims abstract description 33
- 239000003446 ligand Substances 0.000 claims abstract description 33
- 150000001336 alkenes Chemical class 0.000 claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000654 additive Substances 0.000 claims abstract description 13
- 230000000996 additive effect Effects 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 230000009435 amidation Effects 0.000 claims abstract description 5
- 238000007112 amidation reaction Methods 0.000 claims abstract description 5
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 5
- 229910052751 metal Inorganic materials 0.000 claims abstract description 3
- 239000002184 metal Substances 0.000 claims abstract description 3
- 150000002815 nickel Chemical class 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 72
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 44
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 25
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 claims description 24
- 238000000746 purification Methods 0.000 claims description 21
- 238000000926 separation method Methods 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 5
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000001347 alkyl bromides Chemical class 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001642 boronic acid derivatives Chemical class 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- JRTIUDXYIUKIIE-KZUMESAESA-N (1z,5z)-cycloocta-1,5-diene;nickel Chemical compound [Ni].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 JRTIUDXYIUKIIE-KZUMESAESA-N 0.000 claims description 2
- 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 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- VHSVJTYBTJCDFL-UHFFFAOYSA-L 1,2-dimethoxyethane;nickel(2+);dibromide Chemical compound Br[Ni]Br.COCCOC VHSVJTYBTJCDFL-UHFFFAOYSA-L 0.000 claims description 2
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- RRSIMIHTHWYRRA-UHFFFAOYSA-L dibromonickel;1-methoxy-2-(2-methoxyethoxy)ethane Chemical compound Br[Ni]Br.COCCOCCOC RRSIMIHTHWYRRA-UHFFFAOYSA-L 0.000 claims description 2
- OCMNCWNTDDVHFK-UHFFFAOYSA-L dichloronickel;1,2-dimethoxyethane Chemical compound Cl[Ni]Cl.COCCOC OCMNCWNTDDVHFK-UHFFFAOYSA-L 0.000 claims description 2
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 claims description 2
- HHPKUIWWHLVHQQ-UHFFFAOYSA-L difluoronickel;tetrahydrate Chemical compound O.O.O.O.F[Ni]F HHPKUIWWHLVHQQ-UHFFFAOYSA-L 0.000 claims description 2
- IBSOYFJDSVROOT-UHFFFAOYSA-L diiodonickel;hexahydrate Chemical compound O.O.O.O.O.O.I[Ni]I IBSOYFJDSVROOT-UHFFFAOYSA-L 0.000 claims description 2
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 claims description 2
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001641 magnesium iodide Inorganic materials 0.000 claims description 2
- VWQUXHVMSWBXML-UHFFFAOYSA-L magnesium;dibromide;hydrate Chemical compound O.Br[Mg]Br VWQUXHVMSWBXML-UHFFFAOYSA-L 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 claims description 2
- HIIGGQNLPWIVAG-UHFFFAOYSA-L nickel(2+);diacetate;hydrate Chemical compound O.[Ni+2].CC([O-])=O.CC([O-])=O HIIGGQNLPWIVAG-UHFFFAOYSA-L 0.000 claims description 2
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 claims description 2
- AOPCKOPZYFFEDA-UHFFFAOYSA-N nickel(2+);dinitrate;hexahydrate Chemical compound O.O.O.O.O.O.[Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O AOPCKOPZYFFEDA-UHFFFAOYSA-N 0.000 claims description 2
- WHGYCGOFTBFDLW-UHFFFAOYSA-L nickel(2+);diperchlorate;hexahydrate Chemical compound O.O.O.O.O.O.[Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O WHGYCGOFTBFDLW-UHFFFAOYSA-L 0.000 claims description 2
- KVRSDIJOUNNFMZ-UHFFFAOYSA-L nickel(2+);trifluoromethanesulfonate Chemical compound [Ni+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F KVRSDIJOUNNFMZ-UHFFFAOYSA-L 0.000 claims description 2
- QEKXARSPUFVXIX-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dibromide Chemical compound [Ni+2].[Br-].[Br-].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 QEKXARSPUFVXIX-UHFFFAOYSA-L 0.000 claims description 2
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].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 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 claims description 2
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 claims description 2
- 230000001699 photocatalysis Effects 0.000 claims description 2
- 229920001843 polymethylhydrosiloxane Polymers 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 150000003346 selenoethers Chemical class 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- 150000003568 thioethers Chemical class 0.000 claims description 2
- BZLZKLMROPIZSR-UHFFFAOYSA-N triphenylsilicon Chemical compound C1=CC=CC=C1[Si](C=1C=CC=CC=1)C1=CC=CC=C1 BZLZKLMROPIZSR-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims 4
- RKDAZQALARYTFL-UHFFFAOYSA-L dichloronickel triphenylphosphane Chemical compound Cl[Ni]Cl.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 RKDAZQALARYTFL-UHFFFAOYSA-L 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000000975 bioactive effect Effects 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000006772 olefination reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 136
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000047 product Substances 0.000 description 39
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- 238000004607 11B NMR spectroscopy Methods 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 21
- 239000007810 chemical reaction solvent Substances 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 20
- 230000006837 decompression Effects 0.000 description 20
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 18
- 239000007788 liquid Substances 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 150000002923 oximes Chemical class 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 2
- 238000006219 Matteson homologation reaction Methods 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- LTYZGLKKXZXSEC-UHFFFAOYSA-N copper dihydride Chemical compound [CuH2] LTYZGLKKXZXSEC-UHFFFAOYSA-N 0.000 description 2
- 229910000050 copper hydride Inorganic materials 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 238000010813 internal standard method Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- KCOPAESEGCGTKM-UHFFFAOYSA-N 1,3-oxazol-4-one Chemical compound O=C1COC=N1 KCOPAESEGCGTKM-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- DFCAFRGABIXSDS-UHFFFAOYSA-N Cycloate Chemical compound CCSC(=O)N(CC)C1CCCCC1 DFCAFRGABIXSDS-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
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Abstract
本发明公开了一种镍催化的不对称氢酰胺化制备手性α‑氨基硼酸/硼酸酯的方法。在金属镍盐、手性配体、氢源、添加剂等作用下,使烯烃和酰胺化试剂溶于有机溶剂中进行反应,得到区域选择性和对映选择性优秀的手性α‑氨基硼酸/硼酸酯。本方法原料易得,催化剂简单,操作简便,利用本方法可以合成一系列含有手性α‑氨基硼酸/硼酸酯的药物(生物活性)分子,如Vaborbactam。
Description
技术领域
本发明方法属于合成化学和药物化学领域,涉及烯基硼酸/烯基硼酸酯和酰 胺化试剂发生不对称氢酰胺化制备具有光学活性的含有手性α-氨基硼酸/硼酸酯 结构产物以及相关结构的药物(生物活性)分子的方法
背景技术
手性α-氨基硼酸/硼酸酯及其衍生物是氨基酸的生物电子等排体,广泛地应 用于合成化学、材料科学和药物科学的研究中。以药物科学为例,下式代表性地 列举了近年来含有手性α-氨基硼酸/硼酸酯的活性药物分子,其中部分已经作为 商业化的药物分子上市销售。
发展廉价高效高选择性地制备手性α-氨基硼酸/硼酸酯类化合物的方法是重 要的研究领域。[(a)W.Ming,H.S.Soor,X.Liu,A.Trofimova,A.K.Yudin,T.B. Marder,Chem.Soc.Rev.2021,50,12151;(b)A.I.S.Gobec,Z.Org.Chem.Front.2019,6,2991;(c)D.B.Diaz,A.K.Yudin,Nat.Chem.2017,9, 731;(d)R.Smoum,A.Rubinstein,V.M.Dembitsky,M.Srebnik,Chem.Rev.2012, 112,4156;(e)T.Ohmura,T.Awano,M.Suginome,J.Am.Chem.Soc.2010,132, 13191;(f)T.Awano,T.Ohmura,M.Suginome,J.Am.Chem.Soc.2011,133,20738.]
目前,除了传统的依靠手性辅基的合成方法,过渡金属不对称催化的方法也 有一系列报道,但其缺点在于催化剂昂贵且难以合成、反应条件苛刻等。此外, 铜氢催化的烯基硼酸酯的不对称氢氨化已有两例报道,但反应得到的手性α-二烷 基胺Bdan分子仍需要额外的多个步骤才能转化为手性α-氨基硼酸/硼酸酯化合 物,限制了该方法的使用。[(a)D.S.Matteson,K.M.Sadhu,G.E.Lienhard,J.Am. Chem.Soc.1981,103,5241;(b)M.A.Beenen,C.An,J.A.Ellman,J.Am.Chem.Soc. 2008,130,6910;(c)Q.Qi,X.Yang,X.Fu,S.Xu,E.Negishi,Angew.Chem.,Int.Ed. 2018,57,15138;(d)K.Hong,J.P.Morken,J.Am.Chem.Soc.2013,135,9252;(e) C.B.Schwamb,K.P.Fitzpatrick,A.C.Brueckner,H.C.Richardson,P.H.Y.Cheong, K.A.Scheidt,J.Am.Chem.Soc.2018,140,10644;(f)N.Hu,G.Zhao,Y.Zhang,X. Liu,G.Li,W.Tang,J.Am.Chem.Soc.2015,137,6746;(g)X.-Y.Bai,W.Zhao,X. Sun,B.-J.Li,J.Am.Chem.Soc.2019,141,19870;(h)I.E. Casas-Arcé,S.J.Roseblade,U.Nettekoven,A.Zanotti-Gerosa,M.Z.Angew.Chem.,Int.Ed.2012,51,1014;(i)Y.Lou,J.Wang,G.Gong,F.Guan, J.Lu,J.Wen,X.Zhang,Chem.Sci.2020,11,851;(j)D.Fan,J.Zhang,Y.Hu,Z. Zhang,I.D.Gridnev,W.Zhang,ACS Catal.2020,10,3232;(k)R.L.Reyes,M.Sato, T.Iwai,M.Sawamura,J.Am.Chem.Soc.2020,142,589.(l)D.Nishikawa,K. Hirano,M.Miura,J.Am.Chem.Soc.2015,137,15620;(m)D.-W.Gao,Y.Gao,H. Shao,T.-Z.Qiao,X.Wang,B.B.Sanchez,J.S.Chen,P.Liu,K.M.Engle,Nat.Catal. 2019,3,23.]
近几年,镍氢催化的烯烃不对称氢官能团化方法得到了较大的发展,高活性 的镍氢物种对烯烃迁移插入后,在手性配体的控制下可以与多种亲电试剂偶联得 到高对映选择性的产物。[(a)Z.Wang,H.Yin,G.C.Fu,Nature 2018,563,379;(b)F. Zhou,Y.Zhang,X.Xu,S.Zhu,Angew.Chem.,Int.Ed.2019,58,1754;(c)S.-J.He, J.-W.Wang,Y.Li,Z.-Y.Xu,X.-X.Wang,X.Lu,Y.Fu,J.Am.Chem.Soc.2020,142, 214;(d)Z.-P.Yang,G.C.Fu,J.Am.Chem.Soc.2020,142,5870;(e)Y.He,C.Liu,L. Yu,S.Zhu,Angew.Chem.,Int.Ed.2020,59,21530;(f)S.Bera,R.Mao,X.Hu,Nat. Chem.2021,13,270;(g)L.Shi,L.-L.Xing,W.-B.Hu,W.Shu,Angew.Chem.,Int. Ed.2021,60,1599;(h)S.Cuesta-Galisteo,J.X.Wei,E.Merino,C. Nevado,Angew.Chem.,Int.Ed.2021,60,1605;(i)J.Liu,H.Gong,S.Zhu,Angew. Chem.,Int.Ed.2021,60,4060;(j)Y.He,H.Song,S.Zhu,Nat.Commun.2021,12, 638;(k)D.Qian,S.Bera,X.Hu,J.Am.Chem.Soc.2021,143,1959;(l)J.-W.Wang, Y.Li,W.Nie,Z.Chang,Z.-A.Yu,Y.-F.Zhao,X.Lu,Y.Fu,Nat.Commun.2021,12,1313;(m)X.-X.Wang,L.Yu,X.Lu,Z.-L.Zhang,D.-G.Liu,C.Tian,Y.Fu,CCS Chem.2021,3,727;(n)S.Wang,J.-X.Zhang,T.-Y.Zhang,H.Meng,B.-H.Chen,W. Shu,Nat.Commun.2021,12,2771;(o)X.Jiang,B.Han,Y.Xue,M.Duan,Z.Gui,Y. Wang,S.Zhu,Nat.Commun.2021,12,3792;(p)F.Zhou,S.Zhu,ACS Catal.2021, 11,8766;(q)J.Chen,S.Zhu,J.Am.Chem.Soc.2021,143,14089;(r)Y.Zhang,J. Ma,J.Chen,L.Meng,Y.Liang,S.Zhu,Chem 2021,7,3171.]
在此,我们以烯基硼酸/烯基硼酸酯为原料,二恶唑酮为酰胺化试剂,多取 代氨基醇为手性配体,一步合成手性α-氨基硼酸/硼酸酯化合物。该方法原料简 单廉价、容易合成,反应条件简单温和,产物区域选择性单一、对映选择性优秀 (一般ee值大于90%)。该方法可以用于含有手性α-氨基硼酸/硼酸酯结构的药 物(生物活性)分子合成。
发明内容
本发明的目的是提供一种含多种官能团的手性类化合物的合成方法,该方法原料便宜易得,操作简便,底物范围广且官能团兼容性好,具有优秀的区域选择性 和对映选择性。具体为一种镍催化的不对称氢酰胺化制备手性α-氨基硼酸/硼酸 酯的方法及其在手性α-氨基硼酸药物分子合成中的应用。
本发明实现上述目的之一采用以下技术方案:
一种镍氢催化烯基硼酸/硼酸酯的不对称氢酰胺化的方法,包括以下步骤: 在惰性气体中,将金属镍类催化剂、手性配体L*、氢源、添加剂溶于干燥的有 机溶剂中,然后加入烯基硼酸/硼酸酯和酰胺化试剂得到反 应混合物,随后将上述反应混合物密封并从惰性气体中取出,反应完全后,减压 浓缩除去有机溶剂,再经分离纯化得到目标的手性化合物
其中,1)R1为原烯烃的取代基,为氢原子、烷基、酯基、酰胺基、磺酰基、 烷氧基、硅醚、芳基、卤素中的任一种;2)R2为氨化试剂的取代基,为烷基、 烯基、芳基、炔基中的一种;3)BR2为硼酸或硼酸酯。
优选地,所述方法反应路线如下:
优选地,金属镍类催化剂:手性配体:氢源:离子添加剂:质子添加剂:烯 烃:亲电试剂:有机溶剂的用量比为摩尔:摩尔:摩尔:摩尔:摩尔:摩尔:摩 尔:体积mL=0.01-0.50:0.01-1.0:1.5-4.0:0.1-5.0:0.1-10.0:1.0-3.0:1.0-3.0: 0.2-5.0。
优选地,所述的金属镍盐是碘化镍、碘化镍水合物、氯化镍、氯化镍六水合 物、氯化镍乙二醇二甲醚复合物、溴化镍、溴化镍三水合物、溴化镍二乙二醇二 甲醚复合物、溴化镍乙二醇二甲醚复合物、双-(1,5-环辛二烯)镍复合物、硝酸 镍六水合物、高氯酸镍六水合物、四氟硼酸镍六水合物、乙酰丙酮镍、氟化镍、 氟化镍四水合物、三氟甲磺酸镍、乙酸镍水合物、双三苯基膦二氯化镍、双(三 苯基膦)二溴化镍、1,3-双(二苯基膦)丙烷二氯化镍、(1,1'-双(二苯基膦)二茂铁)二 氯化镍、四(三苯基膦)镍中的任一种;
优选地,所述的手性配体L*为具有以下结构的任一种(包括其对映异构体):
其中,R6-R17为手性配体上的取代基,为氢原子、烷基、酯基、氨基、取代胺基、 膦酰基、膦酰胺基、酰胺基、磺酰基、烷氧基、硅醚、硫醚、硒醚、芳基、烯基、 炔基、氰基、异氰基、卤素中的任一种。
优选地,所述的氢源为聚甲基氢硅氧烷、三甲氧基氢硅烷、三乙氧基氢硅烷、 二乙氧基甲基氢硅烷、二甲氧基甲基氢硅烷、苯基氢硅烷、二苯基氢硅烷、三苯 基氢硅烷、硼烷及其复合物、频那醇硼烷、烷基溴和锰粉的组合、烷基溴和锌粉 的组合、电化学还原、光催化还原剂(如二异丙基胺和光催化剂的组合)中的任一 种。
优选地,所述的离子添加剂为氯化锂、氯化钠、溴化锂、溴化钾、溴化镁、 溴化镁水合物、碘化锂、碘化钠、碘化钾、碘化锌、碘化镁、四丁基氟化铵、四 丁基氯化铵、四丁基溴化铵、四丁基碘化铵、乙酸钠、乙酸钾中的一种或多种。
优选地,所述的质子添加剂为水、醇、酚、胺类化合物、硫醇、硫酚中的一 种或多种。
优选地,所述的溶剂为四氢呋喃、甲苯、二氯甲烷、1,2-二氯乙烷、氯仿、 乙腈、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、N,N-二甲基丙酰胺、N,N-二甲基 丙烯基脲、N-甲基吡咯烷酮、甲醇、乙醇、水、乙二醇二甲醚、二乙二醇二乙醚 和二甲基亚砜中的一种或多种。
优选地,所述的反应温度为0~50℃。
本发明的目的是提供一种全新的合成手性α-氨基硼酸/硼酸酯化合物的方 法。
本发明的有益效果是:
目前,合成手性α-氨基硼酸/硼酸酯化合物主要通过手性辅基辅助合成(如 反应式(1-2)),该类方法中手性辅基的引入和脱除增加了反应步骤,造成当量 的手性辅基浪费,降低了反应的原子利用效率[(a)Matteson,D.S.;Majumdar,D.J. Am.Chem.Soc.1980,102,7588;(b)Matteson,D.S.;Sadhu,K.M.J.Am.Chem.Soc. 1981,103,5241;(c)Beenen,M.A.;An,C.-H.;Ellman,J.A.J.Am.Chem.Soc.2008, 130,6910.];已有报道的过渡金属催化的方法,催化剂价格昂贵且难以合成,反 应条件苛刻(如反应式(3-5))[(a)Hong,K.;Morken,J.P.J.Am.Chem.Soc.2013, 135,9252;(b)Schwamb,C.B.;Fitzpatrick,K.P.;Brueckner,A.C.;Camille Richardson,H.;Cheong,P.H.-Y.;ScheidtK.A.J.Am.Chem.Soc.2018,140,10644; (c)Bai,X.-Y.;Zhao,W.;Sun,X.;Li,B.-J.J.Am.Chem.Soc.2019,141,19870.];铜 氢催化的不对称氢氨化反应制备所得的分子需要额外的多个步骤才能转化为所 需的手性α-氨基硼酸/硼酸酯,限制了该反应的使用价值(如反应式(6-8))。本 发明通过镍氢催化烯基硼酸/硼酸酯的不对称氢酰胺化,以恶唑啉酮为氨化试剂, 一步即可高效(反应化学选择性单一,酰胺基只在硼的α位生成)、高对映选择性(一般ee值能达到90%)地制备手性α-氨基硼酸/硼酸酯(反应式9),并可以 顺利应用于含有手性α-氨基硼酸/硼酸酯的药物(生物活性)分子,如Vaborbactam 的合成中(反应式10),利用本方法,可以从5步简单反应制备得到的端炔出发, 经过3步反应得到Vaborbactam。对比以前报道的方法(反应式11)[S.J.Hecker, K.R.Reddy,M.Totrov,G.C.Hirst,O.Lomovskaya,D.C.Griffith,P.King,R. Tsivkovski,D.Sun,M.Sabet,Z.Tarazi,M.C.Clifton,K.Atkins,A.Raymond,K.T. Potts,J.Abendroth,S.H.Boyer,J.S.Loutit,E.E.Morgan,S.Durso,M.N.Dudley,J. Med.Chem.2015,58,3682.],本方法优势在于步骤较短,不需要手性辅基参与, 不需要贵金属催化、酶催化、-40℃以下的低温反应条件。因此,相较于以前制 备手性α-氨基硼酸/硼酸酯的方法而言,本发明具有明显的实用性和竞争力。
(10)制备Vaborbactam(详见实施例19)
(11)已报道的Vaborbactam制备路线
附图说明
下面结合附图对本发明的作进一步说明。
图1是实施例1产物的H谱;
图2是实施例1产物的C谱;
图3是实施例2产物的H谱;
图4是实施例2产物的C谱;
图5是实施例10产物的H谱;
图6是实施例10产物的C谱;
图7是实施例16产物的H谱;
图8是实施例16产物的C谱;
图9是实施例19中产物3a的H谱;
图10是实施例19中产物3a的C谱;
图11是实施例19中产物Vaborbactam的H谱;
图12是实施例19中产物Vaborbactam的C谱。
具体实施方式
通过以下详细说明可以进一步理解本发明的特点和优点。所提供的实施例仅 是对本发明方法的说明,而不以任何方式限制本发明揭示的其余内容。
实施例1
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2a(48.9mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反 应20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产 物(白色固体,产率71%),1H NMR(500MHz,CDCl3)δ8.47(s,1H),7.80(d,J= 7.4Hz,2H),7.45(t,J=7.4Hz,1H),7.32(t,J=7.7Hz,2H),2.79(t,J=6.3Hz,1H),1.75–1.65(m,1H),1.61–1.52(m,1H),1.49–1.37(m,2H),1.34–1.28(m,4H), 1.26(s,12H),0.88(t,J=7.0Hz,3H);13C NMR(126MHz,CDCl3)δ170.8,133.1, 128.6,128.2,128.1,81.2,32.1,31.3,27.7,25.4,25.2,22.7,14.2;11B NMR(160 MHz,CDCl3)δ17.8;HRMS(ESI)calcd.for C19H30BNNaO3[M+Na]+m/z 354.2211, found 354.2202;IR(neat,cm-1)3079,2925,1608,1530,1127,1099,709;m.p.130– 132℃;[α]D 25=–35.8(c=1.06,CHCl3);HPLCanalysis:the ee(95%)was determined using aIE-3column,5%EtOH inhexane,1.0mL/min, 240nm UV detector,tR(major)=6.8min,tR(minor)=7.4min.
实施例2
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2a(48.9mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1b(39.2mg,0.2mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反 应20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产 物(白色固体,产率68%),1H NMR(500MHz,CDCl3)δ7.77(d,J=7.4Hz,2H), 7.64(s,1H),7.50(t,J=7.4Hz,1H),7.38(t,J=7.7Hz,2H),2.95(t,J=6.8Hz,1H),1.79–1.67(m,1H),1.53–1.47(m,2H),1.27(s,12H),0.96(d,J=6.5Hz,6H);13C NMR(126MHz,CDCl3)δ170.9,133.1,128.7,128.4,128.0,81.2,40.6,26.3,25.3, 25.3,23.6,22.2;11B NMR(160MHz,CDCl3)δ18.6;HRMS(ESI)calcd.for C18H29BNO3[M+H]+m/z 318.2235,found 318.2231;IR(neat,cm-1)2958,1609, 1528,1113,1098,707;[α]D 25=–37.3(c=0.96,CHCl3);HPLC analysis:the ee (92%)was determined using aAD-Hcolumn,5%iPrOH in hexane, 1.0mL/min,240nm UV detector,tR(minor)=4.8min,tR(major)=5.5min.
实施例3
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2a(48.9mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1c(46.1mg,0.2mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反 应20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产 物(无色液体,产率55%),1H NMR(500MHz,CDCl3)δ8.52(s,1H),7.80(d,J= 7.3Hz,2H),7.47(t,J=7.5Hz,1H),7.34(t,J=7.8Hz,2H),3.59–3.48(m,2H), 2.83–2.75(m,1H),1.83–1.74(m,2H),1.74–1.66(s,1H),1.64–1.51(m,3H), 1.26(s,12H);13CNMR(126MHz,CDCl3)δ171.1,133.3,128.7,128.3,127.7,81.2, 45.2,32.8,30.7,25.5,25.3,25.1;11B NMR(160MHz,CDCl3)δ17.6;HRMS(ESI) calcd.for C18H27BClNNaO3[M+Na]+m/z 374.1665,found 374.1656;IR(neat,cm-1) 3193,2971,2929,1610,1576,1111,734;[α]D 25=–40.0(c=1.08,CHCl3);HPLC analysis:the ee(96%)was determined using aAD-H column,5% iPrOH in hexane,1.0mL/min,240nm UV detector,tR(minor)=6.9min,tR(major)= 8.2min.
实施例4
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2a(48.9mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1g(65.3mg,0.2mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无 色液体,产率76%),1H NMR(500MHz,CDCl3)δ7.82–7.77(m,2H),7.68(s,1H), 7.53(t,J=7.5Hz,1H),7.41(t,J=7.8Hz,2H),3.64(t,J=6.2Hz,2H),2.92–2.83 (m,1H),1.78–1.67(m,1H),1.68–1.44(m,5H),1.27(s,6H),1.26(s,6H),0.88(s,9H),0.04(s,6H);13C NMR(126MHz,CDCl3)δ170.9,133.2,128.8,128.5,128.0, 81.3,63.3,32.9,31.0,26.2,25.4,25.2,24.2,18.5,-5.1;11B NMR(160MHz,CDCl3) δ18.9;HRMS(ESI)calcd.for C24H42BNNaO4Si[M+Na]+m/z 470.2868,found 470.2858;IR(neat,cm-1)3070,2928,2857,1611,1096,706;[α]D 25=–41.6(c=0.98, CHCl3);HPLC analysis:the ee(95%)was determined using aIG-3 column,5%EtOH in hexane,0.8mL/min,240nm UV detector,tR(major)=4.9min, tR(minor)=5.7min.
实施例5
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2a(48.9mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1e(66.0mg,0.2mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无 色液体,产率66%),1H NMR(500MHz,CDCl3)δ8.06–7.92(m,3H),7.87(d,J= 7.3Hz,2H),7.57–7.48(m,2H),7.44–7.37(m,4H),4.48–4.39(m,1H),4.32–4.22(m,1H),2.83(t,J=5.9Hz,1H),1.87–1.78(m,1H),1.78–1.67(m,2H),1.66 –1.57(m,1H),1.56–1.39(m,4H),1.26(s,6H),1.25(s,6H);13C NMR(126MHz, CDCl3)δ171.0,167.2,133.3,133.1,130.5,129.7,128.8,128.5,128.2,81.1,64.7, 31.2,29.0,27.1,25.7,25.5,25.2;11B NMR(160MHz,CDCl3)δ18.2;HRMS(ESI) calcd.for C26H34BNNaO5[M+Na]+m/z474.2422,found 474.2413;IR(neat,cm-1) 3050,2970,2930,1716,1610,1265,1117,734;[α]D 25=–58.1(c=0.98,CHCl3); HPLC analysis:the ee(95%)was determined using aIF-3column, 10%EtOH in hexane,1.0mL/min,254nm UV detector,tR(major)=6.3min,tR (minor)=7.2min.
实施例6
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2a(48.9mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1f(78.7mg,0.2mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(白 色固体,产率57%),1H NMR(500MHz,CDCl3)δ8.10(s,1H),7.92(d,J=7.5Hz, 2H),7.63(d,J=8.2Hz,2H),7.51(t,J=7.4Hz,1H),7.39(t,J=7.7Hz,2H),7.30 (d,J=8.1Hz,2H),3.21–3.11(m,1H),2.93–2.85(m,1H),2.82–2.73(m,1H), 2.68(s,3H),2.42(s,3H),1.72–1.43(m,7H),1.38–1.31(m,1H),1.27(s,6H),1.26 (s,6H);13C NMR(126MHz,CDCl3)δ171.3,143.5,134.4,133.2,129.8,128.7, 128.4,127.9,127.4,80.8,49.0,34.5,30.9,26.4,26.0,25.5,25.2,24.8,21.6;11B NMR(160MHz,CDCl3)δ17.3;m.p.123–125℃;HRMS(ESI)calcd.for C27H39BN2NaO5S[M+Na]+m/z 537.2565,found537.2556;IR(neat,cm-1)3050, 2929,1610,1156,732;[α]D 25=–25.5(c=1.05,CHCl3);HPLC analysis:the ee (97%)was determined using aIG-3column,20%EtOH in hexane, 1.0mL/min,254nm UV detector,tR(major)=9.5min,tR(minor)=12.0min.
实施例7
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2a(48.9mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1g(60.4mg,0.2mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无 色液体,产率66%),1H NMR(500MHz,CDCl3)δ7.93(s,1H),7.77(d,J=7.5Hz, 2H),7.50(t,J=7.5Hz,1H),7.36(t,J=7.8Hz,2H),7.33–7.29(m,4H),7.28–7.24(m,1H),4.50(s,2H),3.51(t,J=6.3Hz,2H),2.90–2.80(m,1H),1.76–1.57 (m,4H),1.57–1.51(m,2H),1.26(s,12H);13C NMR(126MHz,CDCl3)δ171.0, 138.6,133.2,128.7,128.5,128.1,127.8,127.7,81.1,73.1,70.6,30.9,29.6,25.4,25.2, 24.6;11B NMR(160MHz,CDCl3)δ18.3;HRMS(ESI)calcd.for C25H34BNNaO4 [M+Na]+m/z 446.2473,found446.2462;IR(neat,cm-1)3195,2927,2856,1610, 1098,707;[α]D 25=–41.6(c=1.06,CHCl3);HPLC analysis:the ee(96%)was determined using aIG-3column,5%EtOH in hexane,1.0mL/min, 254nm UV detector,tR(major)=8.3min,tR(minor)=11.6min.
实施例8
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2b(57.9mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(白 色固体,产率72%),1H NMR(500MHz,CDCl3)δ8.52(s,1H),7.78(d,J=8.9Hz, 2H),6.79(d,J=8.9Hz,2H),3.80(s,3H),2.69(t,J=6.6Hz,1H),1.72–1.63(m, 1H),1.58–1.48(m,1H),1.47–1.36(m,2H),1.35–1.27(m,4H),1.26(s,6H),1.25 (s,6H),0.88(t,J=7.0Hz,3H);13C NMR(126MHz,CDCl3)δ170.7,163.6,130.5, 119.4,113.8,80.7,55.5,32.2,31.4,27.7,25.5,25.3,22.7,14.3;11B NMR(160MHz, CDCl3)δ15.8;m.p.166–168℃;HRMS(ESI)calcd.for C20H33BNO4[M+H]+m/z 362.2497,found 362.2489;IR(neat,cm-1)3064,2925,2854,1609,1497,1260,1108; [α]D 25=–59.2(c=0.98,CHCl3);HPLC analysis:the ee(95%)was determined using aIG-3column,5%EtOH in hexane,1.0mL/min,254nm UV detector,tR(major)=7.2min,tR(minor)=8.1min.
实施例9
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2c(62.8mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(白 色固体,产率61%),1H NMR(500MHz,CDCl3)δ8.68(s,1H),7.70(d,J=8.5Hz, 2H),7.10(d,J=8.5Hz,2H),2.73(t,J=6.5Hz,1H),2.47(s,3H),1.74–1.63(m, 1H),1.59–1.49(m,1H),1.48–1.37(m,2H),1.35–1.27(m,4H),1.27(s,12H), 0.88(t,J=7.0Hz,3H);13C NMR(126MHz,CDCl3)δ170.5,146.2,128.7,124.9, 123.2,81.0,32.2,31.4,27.6,25.4,25.3,22.7,14.8,14.2;11B NMR(160MHz,CDCl3) δ16.6;m.p.166–167℃;HRMS(ESI)calcd.for C20H33BNO3S[M+H]+m/z 378.2269,found 378.2260;IR(neat,cm-1)3205,2969,2929,1602,1547,1115,733; [α]D 25=–59.5(c=1.16,CHCl3);HPLC analysis:the ee(93%)was determined using aIE-3column,5%EtOH in hexane,1.0mL/min,220nm UV detector,tR(major)=9.3min,tR(minor)=10.4min.
实施例10
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2d(66.4mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol),甲醇(3.2mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(白 色固体,产率62%),1H NMR(500MHz,CDCl3)δ8.18(s,1H),7.98(d,J=8.4Hz, 2H),7.85(d,J=8.5Hz,2H),3.93(s,3H),3.00–2.91(m,1H),1.77–1.68(m,1H), 1.65–1.53(m,1H),1.48–1.37(m,2H),1.35–1.24(m,16H),0.88(t,J=7.0Hz,3H);13C NMR(126MHz,CDCl3)δ169.2,166.1,133.8,133.3,129.8,128.1,82.1, 52.6,32.1,31.2,27.4,25.3,25.2,22.7,14.2;11B NMR(160MHz,CDCl3)δ21.8;m.p.116–118℃;HRMS(ESI)calcd.for C21H33BNO5[M+H]+m/z 390.2446, found 390.2436;IR(neat,cm-1)2925,2856,1730,1603,1278,1107,725;[α]D 25= –27.8(c=1.01,CHCl3);HPLC analysis:theee(93%)was determined using two connectedOD-H columns,3%iPrOHin hexane,0.8mL/min,254nm UV detector,tR(major)=15.7min,tR(minor)=18.7min.
实施例11
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2e(50.7mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无 色液体,产率74%),1H NMR(500MHz,CDCl3)δ8.65(s,1H),8.09(dd,J=2.9, 1.0Hz,1H),7.44(dd,J=5.1,1.1Hz,1H),7.21(dd,J=5.1,3.0Hz,1H),2.76(t,J= 5.9Hz,1H),1.74–1.63(m,1H),1.60–1.48(m,1H),1.48–1.36(m,2H),1.35– 1.27(m,4H),1.26(s,12H),0.88(t,J=7.0Hz,3H);13C NMR(126MHz,CDCl3)δ 166.4,132.3,130.5,126.6,126.6,81.3,32.1,31.3,27.5,25.3,25.2,22.7,14.2;11B NMR(160MHz,CDCl3)δ17.3;HRMS(ESI)calcd.for C17H28BNNaO3S[M+Na]+ m/z 360.1775,found360.1765;IR(neat,cm-1)3119,2965,2925,1594,1098;[α]D 25=–51.0(c=1.01,CHCl3);HPLC analysis:the ee(98%)was determined using a OD-H column,2%iPrOH in hexane,1.0mL/min,254nm UV detector,tR(minor)=6.1min,tR(major)=8.4min.
实施例12
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2f(42.6mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无 色液体,产率63%),1H NMR(500MHz,CDCl3)δ8.65(s,1H),5.74(s,1H),2.40– 2.33(m,1H),2.18(s,3H),1.87(s,3H),1.60–1.51(m,1H),1.47–1.39(m,1H), 1.36–1.24(m,6H),1.21(s,6H),1.19(s,6H),0.87(t,J=6.9Hz,3H);13C NMR(126MHz,CDCl3)δ170.8,158.2,112.1,80.2,32.2,31.5,28.3,28.0,25.5,25.1,22.8,21.0,14.3;11B NMR(160MHz,CDCl3)δ14.1;HRMS(ESI)calcd.for C17H33BNO3 [M+H]+m/z310.2548,found 310.2543;IR(neat,cm-1)3176,2965,2927,1665,1573, 1156,1107;[α]D 25=–79.0(c=1.00,CHCl3);HPLC analysis:the ee(97%)was determined using aAD-H column,5%iPrOH in hexane,1.0mL/min, 240nm UV detector,tR(major)=5.2min,tR(minor)=7.2min.
将羧酸2f’(1.00g,10mmol,1.0equiv)溶于干燥的四氢呋喃(1.0M)中,加入 N,N'-羰基二咪唑(CDI,1.5equiv),室温搅拌2小时后,加入盐酸羟胺 (NH2OH·HCl,2.0equiv)搅拌过夜。反应用5%KHSO4水溶液稀释,乙酸乙酯 萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,蒸去溶剂得到肟酸。将肟酸 溶于干燥的二氯甲烷,加入N,N'-羰基二咪唑(CDI,1.0equiv),室温搅拌2小时 后,用1N HCl水溶液淬灭,乙酸乙酯萃取,有机相用饱和食盐水洗涤,无水硫 酸钠干燥,蒸去溶剂,粗产品快速过短硅胶柱纯化(石油醚/乙酸乙酯=10:1~ 5:1)得2f(黄色液体,产率55%)。1H NMR(500MHz,CDCl3)δ5.83–5.74(m,1H), 2.13(d,J=0.9Hz,3H),2.04(d,J=1.3Hz,3H);13C NMR(126MHz,CDCl3)δ 163.0,156.6,154.0,104.8,27.8,21.8;HRMS(ESI)calcd.for C5H8NO[M–CO2+H]+ m/z 98.0601,found 98.0602.
实施例13
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2g(57.4mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无 色液体,产率61%),1H NMR(500MHz,CDCl3)δ7.43(s,1H),7.30–7.24(m,2H), 7.20(t,J=7.3Hz,1H),7.15(d,J=7.4Hz,2H),2.91(t,J=7.8Hz,2H),2.64–2.51 (m,3H),1.61–1.51(m,1H),1.39–1.32(m,1H),1.31–1.22(m,6H),1.21(s,12H), 0.87(t,J=6.8Hz,3H);13C NMR(126MHz,CDCl3)δ176.3,139.8,128.8,128.4, 126.7,81.1,34.1,32.0,31.2,31.2,27.8,25.4,25.2,22.7,14.2;11B NMR(160MHz, CDCl3)δ19.2;HRMS(ESI)calcd.for C21H35BNO3[M+H]+m/z 360.2705,found 360.2696;IR(neat,cm-1)3168,2961,2926,1604,1550,1155,1109;[α]D 25=–43.0 (c=0.91,CHCl3);HPLC analysis:theee(97%)was determined using a OD-H column,5%iPrOH in hexane,1.0mL/min,220nm UV detector,tR(minor)=5.4min,tR(major)=6.2min.
实施例14
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2h(54.3mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(黄 色液体,产率58%),1H NMR(500MHz,CDCl3)δ7.34–7.26(m,2H),6.26(dd,J =3.1,1.9Hz,1H),6.04(d,J=2.7Hz,1H),2.95(t,J=7.6Hz,2H),2.69–2.55(m, 3H),1.62–1.52(m,1H),1.43–1.35(m,1H),1.33–1.23(m,6H),1.21(s,12H), 0.87(t,J=6.8Hz,3H);13C NMR(126MHz,CDCl3)δ175.6,153.3,141.6,110.5, 106.2,81.3,32.0,31.3,31.2,27.7,25.3,25.1,23.7,22.7,14.2;11B NMR(160MHz, CDCl3)δ19.9;HRMS(ESI)calcd.for C19H33BNO4[M+H]+m/z 350.2497,found 350.2491;IR(neat,cm-1)3168,2964,2926,1605,1552,1154,1109,729;[α]D 25= –37.7(c=1.04,CHCl3);HPLC analysis:theee(96%)was determined using a AD-H column,5%iPrOH in hexane,0.8mL/min,220nm UV detector,tR(major)=5.6min,tR(minor)=7.5min.
将羧酸2h’(1.40g,10mmol,1.0equiv)溶于干燥的四氢呋喃(1.0M)中, 加入N,N'-羰基二咪唑(CDI,1.5equiv),室温搅拌2小时后,加入盐酸羟胺 (NH2OH·HCl,2.0equiv)搅拌过夜。反应用5%KHSO4水溶液稀释,乙酸乙酯 萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,蒸去溶剂得到肟酸中间体。 将肟酸溶于干燥的二氯甲烷,加入N,N'-羰基二咪唑(CDI,1.0equiv),室温搅拌 2小时后,用1N HCl水溶液淬灭,乙酸乙酯萃取,有机相用饱和食盐水洗涤,无 水硫酸钠干燥,蒸去溶剂,粗产品快速过短硅胶柱纯化(石油醚/乙酸乙酯=10:1 ~5:1)得2h(白色固体,产率72%)。1H NMR(500MHz,CDCl3)δ7.34(dd,J=1.8,0.6Hz,1H),6.30(dd,J=3.2,1.9Hz,1H),6.15–6.06(m,1H),3.08(t,J=7.3Hz, 2H),3.03–2.94(m,2H);13C NMR(126MHz,CDCl3)δ165.7,154.1,151.4,142.2, 110.6,106.8,24.1,23.3;m.p.50–51℃;HRMS(ESI)calcd.for C7H7NNaO2 [M–CO2+Na]+m/z 160.0369,found160.0365。
实施例15
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2i(38.1mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1j(54.4mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无 色液体,产率55%),1H NMR(500MHz,CDCl3)δ8.32(s,1H),7.28–7.22(m,2H), 7.19–7.12(m,3H),2.67–2.53(m,2H),2.52–2.45(m,1H),1.70–1.52(m,4H),1.52–1.32(m,3H),1.31–1.21(m,1H),1.16(s,6H),1.15(s,6H),1.12–1.06(m, 1H),0.95–0.85(m,2H);13C NMR(126MHz,CDCl3)δ178.6,142.8,128.5,128.4, 125.8,80.5,36.0,31.7,31.3,27.9,25.5,25.1,10.9,8.6;11B NMR(160MHz,CDCl3) δ16.2;HRMS(ESI)calcd.for C21H33BNO3[M+H]+m/z 358.2548,found 358.2538; IR(neat,cm-1)3206,3062,2929,1603,1548,1154,1115,734;[α]D 25=–61.3(c= 0.97,CHCl3);HPLC analysis:theee(98%)was determined using a AD-H column,5%iPrOH in hexane,1.0mL/min,220nm UV detector,tR(major)= 4.3min,tR(minor)=6.4min.
实施例16
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2j(82.9mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(黄 色液体,产率47%),1H NMR(500MHz,CDCl3)δ7.36–7.29(m,5H),6.14(s,1H), 5.08(s,2H),4.24–4.14(m,2H),4.11(t,J=8.5Hz,2H),3.29–3.20(m,1H),3.06– 2.96(m,1H),1.67–1.56(m,1H),1.54–1.42(m,1H),1.33–1.26(m,6H),1.24(s, 6H),1.24(s,6H),0.87(t,J=6.6Hz,3H);13C NMR(126MHz,CDCl3)δ172.9, 156.4,136.6,128.6,128.2,128.1,83.2,66.9,52.0,32.5,31.9,31.0,27.1,25.1,25.1, 22.6,14.1;11B NMR(160MHz,CDCl3)δ27.9;HRMS(ESI)calcd.for C24H37BN2NaO5[M+Na]+m/z 467.2688,found467.2678;IR(neat,cm-1)3210,2959, 2829,1711,1605,1352,1132;[α]D 25=–13.4(c=0.95,CHCl3);HPLC analysis:the ee(96%)was determined using aOD-Hcolumn,5%iPrOH in hexane, 1.0mL/min,210nm UV detector,tR(minor)=9.9min,tR(major)=11.7min.
将羧酸2j’(2.35g,10mmol,1.0equiv)溶于干燥的四氢呋喃(1.0M)中, 加入N,N'-羰基二咪唑(CDI,1.5equiv),室温搅拌2小时后,加入盐酸羟胺 (NH2OH·HCl,2.0equiv)搅拌过夜。反应用5%KHSO4水溶液稀释,乙酸乙酯 萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,蒸去溶剂得到肟酸中间体。 将肟酸溶于干燥的二氯甲烷,加入N,N'-羰基二咪唑(CDI,1.0equiv),室温搅拌 2小时后,用1N HCl水溶液淬灭,乙酸乙酯萃取,有机相用饱和食盐水洗涤,无 水硫酸钠干燥,蒸去溶剂,粗产品快速过短硅胶柱纯化(石油醚/乙酸乙酯=10:1 ~5:1)得2j(白色固体,产率63%)。1H NMR(500MHz,CDCl3)δ7.42–7.29(m, 5H),5.12(s,2H),4.37(t,J=9.0Hz,2H),4.26(dd,J=9.1,6.0Hz,2H),3.84–3.73 (m,1H);13CNMR(126MHz,CDCl3)δ165.6,156.0,153.6,136.1,128.7,128.5, 128.3,67.4,51.3,24.7;m.p.110–111℃;HRMS(ESI)calcd.for C12H12N2NaO3 [M–CO2+Na]+m/z 255.0740,found255.0733.
实施例17
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2j(42.9mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1k(60.4mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无 色液体,产率53%),1H NMR(500MHz,CDCl3)δ7.35–7.30(m,4H),7.29–7.25 (m,1H),6.85(s,1H),4.49(s,2H),3.49(t,J=6.3Hz,2H),2.59–2.51(m,1H),1.72 –1.56(m,3H),1.51–1.38(m,3H),1.21–1.16(m,21H);13C NMR(126MHz, CDCl3)δ183.9,138.6,128.5,127.8,127.7,80.4,73.1,70.5,35.7,30.9,29.6,26.9, 25.4,25.2,24.8;11B NMR(160MHz,CDCl3)δ15.8;HRMS(ESI)calcd.for C23H39BNO4[M+H]+m/z 404.2967,found 404.2956;IR(neat,cm-1)3204,2970, 2931,1581,1097,732;[α]D 25=–49.9(c=0.99,CHCl3);HPLC analysis:the ee(83%) was determined using aOD-Hcolumn,5%iPrOH in hexane,1.0 mL/min,220nm UV detector,tR(major)=5.3min,tR(minor)=8.2min.
实施例18
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体 L*(8.0mg,12mol%),碘化锂(13.4mg,0.1mmol),2l(92.8mg,0.3mmol), 无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol),水(1.8mg,0.1mmol) 和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃下反应 20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无 色液体,产率50%),1H NMR(500MHz,CDCl3)δ8.05(d,J=2.2Hz,1H),7.92– 7.82(m,1H),7.59–7.53(m,1H),7.51–7.44(m,1H),7.40(dd,J=8.4,2.3Hz,1H), 7.38–7.34(m,1H),7.03(d,J=8.4Hz,1H),6.47(s,1H),5.18(s,2H),3.64(s,2H),2.76–2.68(m,1H),1.61–1.51(m,1H),1.44–1.34(m,1H),1.29–1.17(m,18H), 0.82(t,J=6.7Hz,3H);13C NMR(126MHz,CDCl3)δ190.7,174.2,160.9,140.4, 136.4,135.6,133.1,132.7,129.6,129.5,128.0,127.1,125.5,121.8,81.8,73.8,39.3, 31.9,31.1,27.4,25.3,25.1,22.6,14.1;11B NMR(160MHz,CDCl3)δ22.4;HRMS (ESI)calcd.for C28H36BNNaO5[M+Na]+m/z 500.2579,found 500.2569;IR(neat, cm-1)3055,2927,1660,1613,1265,735;[α]D 25=–20.5(c=1.01,CHCl3);HPLC analysis:the ee(97%)was determined using aAD-H column,10% iPrOH in hexane,1.0mL/min,240nm UV detector,tR(major)=6.3min,tR(minor)= 7.7min.
实施例19:制备Vaborbactam
氮气氛围下,烧瓶中加入氢氯二茂锆(HZrCp2Cl,0.351g,10mol%),CH2Cl2 (13mL)和端炔(2l’,4.060g,13.6mmol,1.0equiv),室温搅拌5分钟后置于冰 水浴,滴加频哪醇硼烷(HBpin,2.089g,16.3mmol,1.2equiv),室温下搅拌反 应。反应完成后,小心滴加水淬灭反应,乙醚萃取,减压浓缩除去反应溶剂,柱 层析分离纯化得到烯基硼酸酯2l(无色液体,产率53%),1H NMR(500MHz, CDCl3)δ6.57(dt,J=17.9,7.0Hz,1H),5.47(d,J=17.9Hz,1H),4.22–4.13(m, 1H),2.40–2.32(m,4H),1.43(s,9H),1.25(s,12H),0.86(s,9H),0.06(s,3H),0.05 (s,3H);13C NMR(126MHz,CDCl3)δ171.0,150.1,83.2,80.4,68.9,44.4,43.7,28.3,26.0,24.9,24.9,18.2,-4.3,-4.6;11B NMR(160MHz,CDCl3)δ29.9;HRMS (ESI)calcd.for C22H43BNaO5Si[M+Na]+m/z 449.2865,found 449.2853;IR(neat, cm-1)2978,2930,1730,1640,1361,1142,832;[α]D 25=+13.8(c=1.09,CHCl3); HPLC analysis:theee(>99%)was determined using aIF-3column, 0.5%iPrOH in hexane,1.0mL/min,220nm UV detector,tR(minor)=6.9min,tR (major)=8.8min.
在充满氮气的手套箱中,将氯化镍六水合物(5.9mg,12.5mol%),手性配 体L*(12.0mg,15mol%),四丁基碘化铵(18.5mg,0.05mmol),2m(44.0mg,0.24 mmol),无水DMA(1mL,0.2M),烯烃1l(85.3mg,0.20mmol),水(5.4mg,0.3 mmol)和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取出,在25℃ 下反应20小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标 产物(黄色液体,产率50%),1H NMR(500MHz,CDCl3)δ7.25(dd,J=5.1,0.9Hz, 1H),6.98(dd,J=5.1,3.5Hz,1H),6.93(d,J=3.1Hz,1H),6.58(s,1H),4.08–3.97 (m,1H),3.87(s,2H),2.76–2.66(m,1H),2.39–2.26(m,2H),1.65–1.55(m,1H), 1.55–1.44(m,3H),1.41(s,9H),1.22(s,12H),0.84(s,9H),0.02(s,3H),0.02(s,3H);13C NMR(126MHz,CDCl3)δ173.9,171.3,133.9,128.2,127.7,126.2,81.7, 80.5,68.9,43.6,35.0,34.1,28.3,26.4,26.0,25.3,25.1,18.1,-4.4,-4.6;11B NMR (160MHz,CDCl3)δ21.8;HRMS(ESI)calcd.for C28H50BNNaO6SSi[M+Na]+m/z 590.3113,found 590.3103;IR(neat,cm-1)2968,2929,1729,1607,1149,834;[α]D 25=–20.2(c=1.00,CHCl3);HPLCanalysis:the dr(97:3)was determined using a AD-H column,5%iPrOHin hexane,1.0mL/min,240nm UV detector,tR(major)=4.3min,tR(minor)=6.5min.
50mL烧瓶中加入3a(398mg,0.7mmol),二氧六环(2mL)、3N HCl(2mL), 体系回流2h。冷却后,加入2mL水,用乙醚洗涤3次,水相旋干后用乙腈共沸旋 干,再溶于20%的二氧六环-水溶液,冷冻干燥24h得白色粉末。取该白色粉末(150 mg)加入乙酸乙酯(3mL)和水(0.5mL),超声30min,静置后产生白色固体 沉淀,过滤沉淀,用石油醚或乙醚洗涤,得白色固体,再溶于20%的二氧六环- 水溶液,充分冷冻干燥得白色粉末即为产物。1H NMR(500MHz,CD3OD)δ7.34 (dd,J=5.2,1.2Hz,1H),7.09–7.02(m,1H),7.00(dd,J=5.2,3.5Hz,1H),4.14– 4.04(m,1H),3.97(s,2H),2.66–2.57(m,1H),2.37(dd,J=15.0,7.3Hz,1H),2.25 (dd,J=15.0,5.8Hz,1H),1.78–1.68(m,1H),1.68–1.52(m,2H),1.11–0.97(m,1H);13C NMR(126MHz,CD3OD)δ177.8,175.6,135.2,128.8,128.2,126.7,70.5, 44.4,32.6,28.5,27.6;11B NMR(160MHz,CD3OD)δ11.7;HRMS(ESI)calcd.for C12H15BNO4S[M–H2O+H]+m/z280.0809,found 280.0802;IR(neat,cm-1)3511, 2941,1718,1607,1225,1183,701;[α]D 25=–6.1(c=0.85,CH3OH).
将羧酸2m’(1.42g,10mmol,1.0equiv)溶于干燥的四氢呋喃(1.0M)中, 加入N,N'-羰基二咪唑(CDI,1.5equiv),室温搅拌2小时后,加入盐酸羟胺 (NH2OH·HCl,2.0equiv)搅拌过夜。反应用5%KHSO4水溶液稀释,乙酸乙酯 萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,蒸去溶剂得到肟酸中间体。 将肟酸溶于干燥的二氯甲烷,加入N,N'-羰基二咪唑(CDI,1.0equiv),室温搅拌 2小时后,用1N HCl水溶液淬灭,乙酸乙酯萃取,有机相用饱和食盐水洗涤,无 水硫酸钠干燥,蒸去溶剂,粗产品快速过短硅胶柱纯化(石油醚/乙酸乙酯=10:1 ~5:1)得2m(橙色固体,产率62%)。1H NMR(500MHz,CDCl3)δ7.30(dd,J=5.1,1.2Hz,1H),7.08–6.97(m,2H),4.17(s,2H);13C NMR(126MHz,CDCl3)δ164.5, 153.8,131.0,128.4,127.7,126.6,25.7;m.p.51–52℃;HRMS(ESI)calcd.for C6H6NOS[M–CO2+H]+m/z140.0165,found 140.0161.
对比例1(与实施例1对比)
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体L*(8.0mg,12mol%),2a(48.9mg,0.3mmol),无水DMA(1mL,0.2M),烯 烃1a(42.0mg,0.20mmol),水(1.8mg,0.1mmol)和EtO3SiH(92μL,0.5mmol), 将反应管密封并从手套箱中取出,在25℃下反应20小时。反应结束后,通过气 相色谱法(内标法)测得该反应的目标产物收率为46%,产物分离后用高效液相 测得ee值为97%。不加离子添加剂的情况下,反应收率较低但对映选择性较好。
对比例2(与实施例1对比)
在充满氮气的手套箱中,将氯化镍六水合物(4.8mg,10mol%),手性配体L*(8.0mg, 12mol%),2a(48.9mg,0.3mmol),无水DMA(1mL,0.2M),烯烃1a(42.0mg,0.20mmol), 碘化锂(13.4mg,0.1mmol)和EtO3SiH(92μL,0.5mmol),将反应管密封并从手套箱中取 出,在25℃下反应20小时。反应结束后,通过气相色谱法(内标法)测得该反应的目标产 物收率为58%,产物分离后用高效液相测得ee值为81%。不加质子添加剂的情况下,反应收 率和对映选择性均降低。
Claims (10)
2.根据权利要求1所述的镍催化的不对称氢酰胺化制备手性α-氨基硼酸/硼酸酯的方法,其特征在于:BR2为硼酸(-B(OH)2)、硼酸酯(-B(OR3)2、-B(NR4R5)2中的任一种,其中R3-R5为氢原子、烷基、芳基、酰基中的一种或多种)。
4.根据权利要求1所述的镍催化的不对称氢酰胺化制备手性α-氨基硼酸/硼酸酯的方法,其特征在于:金属镍类催化剂:手性配体:氢源:离子添加剂:质子添加剂:烯烃:亲电试剂:有机溶剂的用量比为摩尔:摩尔:摩尔:摩尔:摩尔:摩尔:摩尔:体积mL=0.01-0.50:0.01-1.0:1.5-4.0:0.1-5.0:0.1-10.0:1.0-3.0:1.0-3.0:0.2-5.0。
5.根据权利要求1所述的镍催化的不对称氢酰胺化制备手性α-氨基硼酸/硼酸酯的方法,其特征在于:所述的金属镍盐是碘化镍、碘化镍水合物、氯化镍、氯化镍六水合物、氯化镍乙二醇二甲醚复合物、溴化镍、溴化镍三水合物、溴化镍二乙二醇二甲醚复合物、溴化镍乙二醇二甲醚复合物、双-(1,5-环辛二烯)镍复合物、硝酸镍六水合物、高氯酸镍六水合物、四氟硼酸镍六水合物、乙酰丙酮镍、氟化镍、氟化镍四水合物、三氟甲磺酸镍、乙酸镍水合物、双三苯基膦二氯化镍、双(三苯基膦)二溴化镍、1,3-双(二苯基膦)丙烷二氯化镍、(1,1'-双(二苯基膦)二茂铁)二氯化镍、四(三苯基膦)镍中的任一种。
7.根据权利要求1所述的镍氢催化烯基硼酸/硼酸酯的不对称氢酰胺化的方法,其特征在于:所述的氢源为聚甲基氢硅氧烷、三甲氧基氢硅烷、三乙氧基氢硅烷、二乙氧基甲基氢硅烷、二甲氧基甲基氢硅烷、苯基氢硅烷、二苯基氢硅烷、三苯基氢硅烷、硼烷及其复合物、频那醇硼烷、烷基溴和锰粉的组合、烷基溴和锌粉的组合、电化学还原、光催化还原剂中的任一种。
8.根据权利要求1所述的镍氢催化烯基硼酸/硼酸酯的不对称氢酰胺化的方法,其特征在于:所述的离子添加剂为氯化锂、氯化钠、溴化锂、溴化钾、溴化镁、溴化镁水合物、碘化锂、碘化钠、碘化钾、碘化锌、碘化镁、四丁基氟化铵、四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、乙酸钠、乙酸钾中的一种或多种。
9.根据权利要求1所述的镍氢催化烯基硼酸/硼酸酯的不对称氢酰胺化的方法,其特征在于:所述的质子添加剂为水、醇、酚、胺类化合物、硫醇、硫酚中的一种或多种。
10.根据权利要求1所述的镍氢催化烯基硼酸/硼酸酯的不对称氢酰胺化的方法,其特征在于:所述的溶剂为四氢呋喃、甲苯、二氯甲烷、1,2-二氯乙烷、氯仿、乙腈、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、N,N-二甲基丙酰胺、N,N-二甲基丙烯基脲、N-甲基吡咯烷酮、甲醇、乙醇、水、乙二醇二甲醚、二乙二醇二乙醚和二甲基亚砜中的一种或多种,反应温度为0~50℃。
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