CN115340446B - 一种手性苯并环丁烯醇、其合成方法及用途 - Google Patents
一种手性苯并环丁烯醇、其合成方法及用途 Download PDFInfo
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- CN115340446B CN115340446B CN202110518853.4A CN202110518853A CN115340446B CN 115340446 B CN115340446 B CN 115340446B CN 202110518853 A CN202110518853 A CN 202110518853A CN 115340446 B CN115340446 B CN 115340446B
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- benzocyclobutene
- chiral
- alcohol
- electron
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- UMIVXZPTRXBADB-UHFFFAOYSA-N benzocyclobutene Chemical compound C1=CC=C2CCC2=C1 UMIVXZPTRXBADB-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- -1 benzocyclobutene ketone Chemical class 0.000 claims abstract description 65
- 125000001424 substituent group Chemical group 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 29
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- 125000003118 aryl group Chemical group 0.000 claims abstract description 19
- 125000002252 acyl group Chemical group 0.000 claims abstract description 14
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 14
- 125000003368 amide group Chemical group 0.000 claims abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 11
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 10
- 125000004185 ester group Chemical group 0.000 claims abstract description 8
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 7
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 7
- 239000000852 hydrogen donor Substances 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 230000009467 reduction Effects 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 28
- MWHUSIKAKGHWCP-UHFFFAOYSA-N bicyclo[4.2.0]octa-1,3,5,7-tetraen-7-ol Chemical class C1=CC=C2C(O)=CC2=C1 MWHUSIKAKGHWCP-UHFFFAOYSA-N 0.000 claims description 20
- 229910052741 iridium Inorganic materials 0.000 claims description 19
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- UCXUKTLCVSGCNR-UHFFFAOYSA-N diethylsilane Chemical group CC[SiH2]CC UCXUKTLCVSGCNR-UHFFFAOYSA-N 0.000 claims description 15
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 14
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 14
- 229910052751 metal Inorganic materials 0.000 claims description 13
- 239000002184 metal Substances 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical group OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 238000006459 hydrosilylation reaction Methods 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- ZJZVENPDGLOUHW-UHFFFAOYSA-M [Ir]Cl.C1CCCC=CCC1.C1CCCC=CCC1 Chemical group [Ir]Cl.C1CCCC=CCC1.C1CCCC=CCC1 ZJZVENPDGLOUHW-UHFFFAOYSA-M 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 150000002430 hydrocarbons Chemical group 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 4
- 125000006659 (C1-C20) hydrocarbyl group Chemical group 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 100
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 80
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 40
- 239000000543 intermediate Substances 0.000 description 39
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 38
- 239000012300 argon atmosphere Substances 0.000 description 30
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
- 238000001514 detection method Methods 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 229910052786 argon Inorganic materials 0.000 description 19
- XOGFXHMYHKGOGP-UHFFFAOYSA-N bicyclo[4.2.0]octa-1,3,5-trien-7-one Chemical compound C1=CC=C2C(=O)CC2=C1 XOGFXHMYHKGOGP-UHFFFAOYSA-N 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 229920001971 elastomer Polymers 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000000375 direct analysis in real time Methods 0.000 description 12
- 238000012063 dual-affinity re-targeting Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- DBYQHFPBWKKZAT-UHFFFAOYSA-N lithium;benzene Chemical compound [Li+].C1=CC=[C-]C=C1 DBYQHFPBWKKZAT-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- YNJJJJLQPVLIEW-UHFFFAOYSA-M [Ir]Cl Chemical class [Ir]Cl YNJJJJLQPVLIEW-UHFFFAOYSA-M 0.000 description 10
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 239000000203 mixture Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 1
- 125000006657 (C1-C10) hydrocarbyl group Chemical group 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- RRRQFPCYRFHXBX-UHFFFAOYSA-M [Ir]Cl.C1=CCCCCCC1 Chemical class [Ir]Cl.C1=CCCCCCC1 RRRQFPCYRFHXBX-UHFFFAOYSA-M 0.000 description 1
- TVRHDFJMHSSQCP-UHFFFAOYSA-M [Ir]Cl.C1CC=CCCC=C1 Chemical class [Ir]Cl.C1CC=CCCC=C1 TVRHDFJMHSSQCP-UHFFFAOYSA-M 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 1
- FOTDHUVOUZZTTB-UHFFFAOYSA-N cyclobuten-1-ol Chemical compound OC1=CCC1 FOTDHUVOUZZTTB-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- MRBYWQHXPYOYEW-UHFFFAOYSA-N cyclopropyl-(4-methylphenyl)methanol Chemical compound C1=CC(C)=CC=C1C(O)C1CC1 MRBYWQHXPYOYEW-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZXPDYFSTVHQQOI-UHFFFAOYSA-N diethoxysilane Chemical compound CCO[SiH2]OCC ZXPDYFSTVHQQOI-UHFFFAOYSA-N 0.000 description 1
- YQGOWXYZDLJBFL-UHFFFAOYSA-N dimethoxysilane Chemical compound CO[SiH2]OC YQGOWXYZDLJBFL-UHFFFAOYSA-N 0.000 description 1
- UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 description 1
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229960000504 ivabradine hydrochloride Drugs 0.000 description 1
- HLUKNZUABFFNQS-ZMBIFBSDSA-N ivabradine hydrochloride Chemical compound Cl.C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 HLUKNZUABFFNQS-ZMBIFBSDSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930003658 monoterpene Natural products 0.000 description 1
- 150000002773 monoterpene derivatives Chemical class 0.000 description 1
- 235000002577 monoterpenes Nutrition 0.000 description 1
- UOPFIWYXBIHPIP-NHCUHLMSSA-N n-[(1r,2r)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C=1C=CC=CC=1)[C@H](N)C1=CC=CC=C1 UOPFIWYXBIHPIP-NHCUHLMSSA-N 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 238000005475 siliconizing Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BZBMBZJUNPMEBD-UHFFFAOYSA-N tert-butyl bicyclo[2.2.1]hept-2-ene-5-carboxylate Chemical compound C1C2C(C(=O)OC(C)(C)C)CC1C=C2 BZBMBZJUNPMEBD-UHFFFAOYSA-N 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
- C07C35/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings
- C07C35/27—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system containing six carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
- C07C35/37—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with a hydroxy group on a condensed system having three rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/48—Halogenated derivatives
- C07C35/52—Alcohols with a condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/36—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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Abstract
本发明公开了一种手性苯并环丁烯醇、其合成方法及用途,该方法是以带有取代基的苯并环丁烯酮1为原料,在钌催化剂、氢供体的共同作用下,进行不对称还原,制备具有手性中心的苯并环丁烯醇化合物,反应方程式如下:其中,R1为取代或未取代的C1‑C20的烃基、苯基、芳基或杂环基,取代基选自碳‑碳双键、碳‑碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基;所述芳基包含邻、间、对位带有吸电子或给电子取代的苯基,所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基,所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基。本发明反应条件温和,操作简单;底物普适性广;产物具有高对映选择性,且易分离纯化。
Description
技术领域
本发明属于化学合成领域,涉及一种手性苯并环丁烯醇、其合成方法及用途。
背景技术
具有手性中心的苯并环丁烯醇是一类重要的手性化合物。Toshio Honda在1993年首次利用不对称还原策略将环丁烯酮还原成手性环丁烯醇中间体并应用在具有手性环丁烷骨架的单萜grandisol的合成(Tetrahedron:Asymmetry 1993,4,1537.)。E.Peter Kündig在1996年首次实现苯并环丁烯酮的不对称还原并用于扩环反应上(Tetrahedron,1996,52.)。但是,基于苯并环丁酮底物的不对称还原反应未有报道。
手性环丁烯骨架结构是一类重要的合成砌块,可以转化为多种多样的分子结构。而且,手性环丁烯骨架结构广泛存在于天然产物与药物分子中,如用于治疗心脏疾病的市售药物盐酸伊伐布雷定以及具有潜在药物活性的麻醉药物(J.Med.Chem.2017,60,3618)。
因此,进一步发展高效的方法合成手性苯并环丁烯酮中间体具有重要的理论与现实意义。
发明内容
本发明的目的在于提供一类手性苯并环丁烯醇及其合成方法,首先通过转移氢化方法将苯并环丁烯酮还原成手性苯并环丁烯醇,然后在铱催化下利用醇导向策略实现醇γ位碳氢键选择性硅化反应,直接构建含有季碳手性中心的环丁烯醇化合物。
为了达到上述目的,本发明提供了一种手性苯并环丁烯醇的合成方法,该方法是以带有取代基的苯并环丁烯酮1为原料,在钌催化剂、氢供体的共同作用下,进行不对称还原,制备具有手性中心的苯并环丁烯醇化合物,反应方程式如下:
其中,R1选自取代或未取代的C1-C20的烃基、取代或未取代的苯基、取代或未取代的芳基、取代或未取代的杂环基中的任意一种或两种以上,取代基选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基中的任意一种或任意两种以上;所述芳基包含邻、间、对位带有吸电子或给电子取代的苯基,所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基中的任意一种或任意两种以上,所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基中的任意一种或任意两种以上。
可选地,R1为取代或未取代的C1-C10的烃基,优选地,R1选自甲基,乙基,正丙基,异丙基,正丁基,正戊基,正己基,正庚基,正辛基,苯乙基,4-氯丁基,3-甲基丁基,3-氰基丙基,烯丙基中的任意一种或任意两种以上。
可选地,所述的氢供体包含甲酸三乙胺共沸物,其用量为以带有取代基的苯并环丁烯酮1的摩尔数为基准计(1~10):1。
可选地,所述的钌催化剂为(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基苯)氯化钌(II),(R,R)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基苯)氯化钌(II),N-[(1R,2R)-1,2-二苯基-2-(2-(4-甲基苄氧基)乙基氨基)乙基]-4-甲基苯磺酰胺(氯)钌(II)中的任意一种或多种;所述钌催化剂的用量为以带有取代基的苯并环丁烯酮(1)的摩尔数为基准计0.01-20%,优选0.1~10%。
本发明还提供了一种手性苯并环丁烯醇,其结构通式如下:
其中,R1选自取代或未取代的C1-C20的烃基、取代或未取代的苯基、取代或未取代的芳基、取代或未取代的杂环基中的任意一种或两种以上,取代基选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基中的任意一种或任意两种以上;所述芳基包含邻、间、对位带有吸电子或给电子取代的苯基,所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基中的任意一种或任意两种以上,所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基中的任意一种或任意两种以上。
本发明还提供了一种根据上述的手性苯并环丁烯醇的用途,该手性苯并环丁烯醇用于制备具有季碳手性中心的苯并环丁烯醇衍生物3,反应方程式如下:
R1选自取代或未取代的C1-C20的烃基、取代或未取代的苯基、取代或未取代的芳基、取代或未取代的杂环基中的任意一种或两种以上,取代基选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基中的任意一种或任意两种以上;所述芳基包含邻、间、对位带有吸电子或给电子取代的苯基,所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基中的任意一种或任意两种以上,所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基中的任意一种或任意两种以上;R2选自C1-C10直链烷基,C1-C10环烷基,末端带有官能团的C1-C10烷基,苯基,芳基,杂环基中的任意一种或任意两种以上;优选地,R2选自甲基,乙基,正丙基,叔丁基,苯基,邻甲基苯基,间甲基苯基,对甲基苯基,间甲氧基苯基,对氯苯基,对溴苯基,对酯基苯基,2-萘基,3-噻吩基中的任意一种或任意两种以上。
可选地,制备具有季碳手性中心的苯并环丁烯醇衍生物3的方法包含:
步骤1,惰性气氛下,手性苯并环丁烯醇、第一铱催化剂、与硅氢试剂室温反应,得到硅醚中间体;
步骤2,惰性气氛下,所述的硅醚中间体、菲啰啉配体、氢受体、第二铱催化剂在20-100℃反应2-24h;
步骤3,加入有机金属试剂,-78℃继续反应,直至反应完成,得到具有季碳手性中心的苯并环丁烯醇衍生物3;
其中,所述的第一铱催化剂、第二铱催化剂分别独立选择二(1,5-环辛二烯)二-Μ-甲氧基二铱(I),(1,5-环辛二烯)氯化铱(I)二聚体,二(环辛烯)氯化铱(I)二聚体中的任意一种或多种;所述的第一铱催化剂、第二铱催化剂的用量为以手性苯并环丁烯醇的摩尔数比例计为0.01-10%,优选为0.05-1%;所述的有机金属试剂包含有机金属锂试剂、有机金属镁试剂中的任意一种或多种;所述的有机金属试剂的用量以手性苯并环丁烯醇的摩尔数为基准为(1~5):1。
可选地,所述的菲啰啉配体包含L1,L2,L3,L4中的任意一种或多种,
所述的氢受体为降冰片烯,环辛二烯,双环[2.2.1]-5-庚烯-2-甲酸叔丁酯(包括甲酯、乙酯、苄酯、叔丁基酯等等)中的任意一种或多种。所述的硅氢试剂包含二乙基硅烷、二甲基硅氢、二苯基硅氢、二乙氧基硅氢、二甲氧基硅氢中的任意一种或任意两种以上。
可选地,所述的有机金属锂试剂的结构通式为R2-Li,所述的有机金属镁试剂的结构通式为R2-MgX,X代表卤素,R2为C1~C6的烃基、苯基或芳基,所述芳基是邻、间、对位有C1~C6烃基取代的苯基。
本发明还提供了一种手性苯并环丁烯醇产物3,其结构通式为:
其中,R1为取代或未取代的C1-C20的烃基、苯基、芳基或杂环基,取代基选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基;所述芳基包含邻、间、对位带有吸电子或给电子取代的苯基,所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基,所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基;R2选自C1-C10直链烷基,C1-C10环烷基,末端带有官能团的C1-C10烷基,苯基,芳基或者杂环基。
本发明的创新点在于,以简单易得的官能化苯并环丁烯酮为起始原料,在钌催化剂,氢供体的作用下,首次实现了一步合成具有高光学活性的苯并环丁烯醇化合物(手性醇)。并且,还可通过手性醇在铱催化下实现碳氢键活化,进而合成季碳手性苯并环丁烯醇。
本发明的有益效果还包括:原料和试剂简单易得,制备方便;反应条件温和,操作简单;底物普适性广;官能团兼容性好;产物具有高对映选择性(85%ee~>99%ee);产物易分离纯化等。
具体实施方式
下面将结合以下具体实施例,对本发明作进一步的详细说明。显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明的具体步骤主要包含:
1)向干燥的反应管中加入钌催化剂,将反应管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气,依次加入一定体积的甲酸/三乙胺共沸物5:2,和反应底物苯并环丁烯酮,将反应管置于25℃或者60℃油浴中反应12-72小时;
其中,所述有机溶剂(甲酸/三乙胺共沸物5:2)的用量为1.0-5.0mL/mmol。优选地,为1.0mL/mmol。以式(1)所示的官能化苯并环丁烯醇的用量为基准。
2)待步骤1)反应完全后,所得混合液用硅胶短柱过滤,并用一定量体积比1:1的石油醚和乙酸乙酯洗涤后,浓缩,快速柱层析得具有手性的苯并环丁烯醇化合物;
其中,所述一定体积的乙酸乙酯是指以式(1)所示的官能化苯并环丁烯酮的用量为基准,所述乙酸乙酯的用量为1.0-100mL/mmol。优选地,为30mL/mmol。
3)待步骤2)得到手性苯并环丁烯醇后,向一个干燥的反应管中加入铱催化剂,连接真空泵,在氩气氛围下置换氩气,依次加入一定体积的手性苯并环丁烯醇的四氢呋喃溶液,和硅氢试剂,然后室温反应12小时,真空1小时抽干多余的四氢呋喃和硅氢试剂得到苯并环丁烯醇硅醚衍生物。
4)待步骤3)真空除去低沸点物质后,在另一个干燥的反应管中加入铱催化剂,菲啰啉配体,连接真空泵,在氩气氛围下置换氩气,依次加入苯并环丁烯醇硅醚衍生物,四氢呋喃,氢受体。将反应管置于室温下搅拌2小时,再放入100℃油浴下反应24小时。
5)待步骤4)反应完成后,将反应管置于-78℃下冷却并加入一定量有机金属试剂,在-78℃下反应3小时。其中,所述一定量的有机溶剂是指以步骤3)中手性苯并环丁烯醇的用量为基准,所述一定量有机金属试剂用量为1.0-5.0mmol/mmol;
其中,所述一定量有机金属试剂用量为1.0-5.0mmol/mmol;优选地,为3mmol/mmol。
6)待步骤5)反应完全后,向反应管中加入一定量的饱和氯化铵溶液,恢复室温,所得混合液用二氯甲烷萃取,干燥,浓缩,快速柱层析得到具有季碳手性中心的苯并环丁烯醇衍生物。
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。所有实施例中所涉及的钌金属催化剂,氢受体,菲啰啉配体的具体结构式和对应编号如下所示:
实施例1
其中,mol表示摩尔,HOOH表示甲酸,Et3N表示三乙胺,ee表示对映异构体过量百分数。
向一个干燥的封管中依次加入(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基苯)氯化钌(II)(6.2mg,10.0μmol)。将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,加入苯并环丁烯醇1a(0.146g,1.00mmol),甲酸三乙胺共沸物5:2(1mL)。联通氩气,搅拌24小时。将反应液通过硅胶短柱,用30mL体积比1:1石油醚乙酸乙酯冲洗,浓缩,快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(S)-2a(0.139g,94%)固体;Ee:97%(OJ-H;3%i-PrOHin hexanes;flow rate=1.0mL/min;detection at 210nm;t1=8.2min(major);t2=20.9min(minor)/>23.34(c 1.3,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.31–7.19(m,3H),7.13–7.06(m,1H),4.81(d,J=9.0Hz,1H),2.18(d,J=9.1Hz,1H),1.39(s,3H),1.33(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):152.55,144.21,129.43,127.66,123.32,120.91,79.40,51.07,25.13,22.17.HRMS-DART(m/z):[M+NH4]+calcd.for C10H16ON,166.1225;found,166.1226。
向一个干燥的封管中依次加入手性苯并环丁烯醇(S)-2a(81.0mg,0.500mmol)。将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,加入新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于室温反应12小时。将封管连接真空系统,真空下将多余的四氢呋喃与二乙基硅烷抽去得到硅醚中间体(苯并环丁烯醇硅醚衍生物)。在另一个封管中加入二(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)。将封管密闭好置于室温反应2小时,再放入100℃油浴下反应24小时。恢复室温,置于-78℃下并加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol),在-78℃下反应3小时,加入饱和氯化铵溶液(1.0mL)淬灭反应,恢复室温加入水(5.0mL),分别用二氯甲烷(10mL),二氯甲烷(10mL),二氯甲烷(5.0mL)萃取,干燥,浓缩,快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=50/1)得到手性苯并环丁烯醇产物3a(86.4mg,56%)无色液体;Ee:95%(AD-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at210nm;t1=8.1min(minor);t2=8.7min(major)./>(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.55–7.45(m,2H),7.42–7.33(m,3H),7.21–7.09(m,3H),6.56(dt,J=7.0,1.2Hz,1H),4.62(d,J=7.2Hz,1H),2.04(d,J=8.6Hz,1H),1.35(d,J=14.7Hz,1H),1.37(s,3H),1.23(d,J=14.7Hz,1H),1.05–0.91(m,10H).13C NMR(101MHz,CDCl3)δ(ppm):152.64,143.98,137.29,134.45,129.13,129.03,127.89,127.43,123.32,122.12,80.36,53.60,26.26,19.82,7.47,4.69,4.56.HRMS-EI(m/z):[M]+calcd.for C20H26OSi,310.1744;found,310.1747。
实施例2
操作同实施例1。(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基苯)氯化钌(II)(6.2mg,10.0μmol),甲酸三乙胺共沸物5:2(1mL),1b(0.160g,1.0mmol),在室温下,反应48小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(S)-2b(0.136g,84%)白色固体;Ee:95%(IC;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=6.3min(minor);t2=7.2min(major).(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.10(d,J=7.0Hz,2H),7.04–6.97(m,1H),4.79(d,J=9.4Hz,1H),2.35(s,3H),2.01(d,J=9.4Hz,1H),1.38(s,3H),1.31(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):149.44,144.24,137.41,130.24,123.77,120.68,79.19,50.44,25.27,22.28,21.97.HRMS-EI(m/z):[M]+calcd.for C10H14O,162.1034;found,162.1039。
操作同实施例1。硅醚中间体的制备使用(S)-2b(81.1mg,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。向封管中分别加入(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL);与硅醚中间体100℃油浴下反应24小时。再加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得3b(0.110g,68%)无色液体;Ee:95%(IC;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=11.2min(major);t2=11.9min(minor).(c 1.2,CHCl3).1HNMR(400MHz,CDCl3)δ(ppm):7.56–7.47(m,2H),7.44–7.32(m,3H),7.02(s,1H),6.97(d,J=7.6Hz,1H),6.45(dd,J=7.6,0.9Hz,1H),4.59(d,J=8.9Hz,1H),2.32(s,3H),2.04(d,J=9.2Hz,1H),1.35(s,3H),1.34(d,J=14.7Hz,1H),1.21(d,J=14.7Hz,1H),1.07–0.91(m,10H).13C NMR(101MHz,CDCl3)δ(ppm):149.58,144.01,137.36,137.14,134.46,129.96,128.97,127.85,123.74,121.91,80.14,52.93,26.34,21.88,19.90,7.48,4.68,4.60.HRMS-EI(m/z):[M]+calcd.for C21H28OSi,324.1910;found,324.1904。
实施例3
操作同实施例1。(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基苯)氯化钌(II)(6.2mg,10.0μmol),甲酸三乙胺共沸物5:2(1mL),1c(0.181g,1.0mmol),在室温下,反应48小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(S)-2c(0.170g,93%)白色固体;Ee:88%(AD-H;2%i-PrOH inhexanes;flow rate=1.0mL/min;detection at210nm;t1=14.5min(major);t2=15.4min(minor)./>33.03(c 1.2,CHCl3).1HNMR(400MHz,CDCl3)δ(ppm):7.26–7.17(m,2H),7.05–6.97(m,1H),4.73(d,J=6.7Hz,1H),3.03(d,J=7.2Hz,1H),1.35(s,3H),1.29(s,3H).13CNMR(101MHz,CDCl3)δ(ppm):150.46,145.31,133.06,129.79,123.83,122.46,78.66,50.55,25.01,21.94.HRMS-EI(m/z):[M]+calcd.for C10H11OCl,182.0490;found,182.0493。
操作同实施例1。硅醚中间体的制备使用(S)-2c(91.3mg,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,再加入硅醚中间体、A(92.1mg,0.500mmol),四氢呋喃(2.0mL);与硅醚中间体100℃油浴下反应24小时。加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得3c(0.106g,62%)无色液体;Ee:88%(AD-H;2%i-PrOH in hexanes;flow rate=1.0mL/min;detectionat 210nm;t1=14.5min(major);t2=15.4min(minor)./>33.03(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.26–7.17(m,2H),7.05–6.97(m,1H),4.73(d,J=6.7Hz,1H),3.03(d,J=7.2Hz,1H),1.35(s,3H),1.29(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):150.46,145.31,133.06,129.79,123.83,122.46,78.66,50.55,25.01,21.94.HRMS-EI(m/z):[M]+calcd.for C10H11OCl,182.0490;found,182.0493。
实施例4
操作同实施例1。(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基苯)氯化钌(II)(6.2mg,10.0μmol),甲酸三乙胺共沸物5:2(1mL),1d(0.164g,1.0mmol),在室温下,反应48小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(S)-2d(0.133g,93%)白色固体;Ee:89%(OJ-H;3%i-PrOH inhexanes;flow rate=1.0mL/min;detection at 210nm;t1=7.9min(major);t2=18.5min(minor)/>12.13(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.09–7.01(m,1H),7.01–6.91(m,2H),4.77(s,1H),2.15(brs,1H),1.37(s,3H),1.31(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):162.66(d,J=244.7Hz),147.52(d,J=2.8Hz),145.19(d,J=6.6Hz),122.62(d,J=8.7Hz),116.89(d,J=23.6Hz),110.86(d,J=21.9Hz),78.49(d,J=2.8Hz),50.19,25.18,22.16.19F NMR(376MHz,CDCl3)δ(ppm):–112.70.HRMS-EI(m/z):[M]+calcd.for C10H11OF,166.0792;found,166.0788。
操作同实施例1。硅醚中间体的制备使用(S)-2d(83.1mg,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。将(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol)加入到封管中,用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,加入硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL);与硅醚中间体100℃油浴下反应24小时。加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得3d(65.0mg,40%)无色液体;Ee:85%(ODH;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=14.7min(minor);t2=16.2min(major)./>(c 2.0,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):δ7.52–7.45(m,2H),7.44–7.31(m,3H),6.88(dd,J=7.6,2.3Hz,1H),6.79(ddd,J=10.6,8.1,2.3Hz,1H),6.38(dd,J=8.1,4.5Hz,1H),4.55(d,J=8.7Hz,1H),2.00(d,J=9.0Hz,1H),1.34(s,3H),1.31(d,J=14.7Hz,1H),1.18(d,J=14.7Hz,1H),1.05–0.88(m,10H).13C NMR(101MHz,CDCl3)δ(ppm):162.52(d,J=244.8Hz),147.61(d,J=2.8Hz),145.07(d,J=6.5Hz),137.09,134.45,129.16,127.98,123.97(d,J=8.7Hz),116.59(d,J=23.5Hz),110.70(d,J=21.6Hz),79.46(d,J=2.6Hz),52.74,26.36,19.85,7.43,4.68,4.48.19FNMR(376MHz,CDCl3)δ(ppm):–112.98.HRMS-DART(m/z):[M+NH4]+calcd.for C20H29ONFSi,346.1994;found,346.1997。
实施例5
操作同实施例1。(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基苯)氯化钌(II)(6.2mg,10.0μmol),甲酸三乙胺共沸物5:2(1mL),1e(88.1mg,0.5mmol),在室温下,反应100小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(S)-2e(49.7mg,56%)白色固体;Ee:94%OJ-H;3%i-PrOH inhexanes;flow rate=1.0mL/min;detection at 210nm;t1=14.1min(major);t2=23.8min(minor)./>15.85(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.17(d,J=8.0Hz,1H),6.77(dd,J=8.1,2.2Hz,1H),6.66(d,J=2.2Hz,1H),4.73(s,1H),3.78(s,3H),2.02(brs,1H),1.37(s,3H),1.31(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):161.06,153.74,135.83,124.76,114.59,105.93,78.58,55.38,50.37,24.99,22.09.HRMS-EI(m/z):[M]+calcd.forC11H14O2,178.0984;found,178.0988。
操作同实施例1。硅醚中间体的制备使用(S)-2e(89.1mg,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。将(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol)加入封管,用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL),与硅醚中间体100℃油浴下反应24小时。再加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得3e(87.7mg,52%)无色液体;Ee:93%(AD-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=10.7min(minor);t2=16.1min(major)./>(c1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.57–7.50(m,2H),7.41–7.33(m,3H),7.09(d,J=8.1Hz,1H),6.71(dd,J=8.1,2.2Hz,1H),6.01(d,J=2.1Hz,1H),4.53(d,J=9.0Hz,1H),3.62(s,3H),1.96(d,J=9.2Hz,1H),1.35(s,3H),1.34(d,J=14.5Hz,1H),1.20(d,J=14.7Hz,1H),1.10–0.83(m,10H).13C NMR(101MHz,CDCl3)δ(ppm):160.77,153.92,137.36,135.54,134.56,129.07,127.90,124.73,114.97,106.80,79.55,55.37,52.86,26.08,19.75,7.48,7.46,4.76,4.60.HRMS-DART(m/z):[M+H]+calcd.for C21H29O2Si,341.1928;found,341.1931。
实施例6
操作同实施例1。N-[(1R,2R)-1,2-二苯基-2-(2-(4-甲基苄氧基)乙基氨基)乙基]-4-甲基苯磺酰胺(氯)钌(II)(6.5mg,10.0μmol),甲酸三乙胺共沸物5:2(1mL),1f(0.160g,0.5mmol),在室温下,反应48小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(R)-2f(0.125g,77%)白色固体;Ee:98%(OD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=17.0min(minor);t2=19.4min(major)./>(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.16(d,J=7.5Hz,1H),7.06(d,J=7.5Hz,1H),6.93(s,1H),4.77(d,J=9.4Hz,1H),2.35(s,3H),1.99(d,J=9.5Hz,1H),1.38(s,3H),1.31(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):152.62,141.12,139.41,128.52,123.13,121.39,79.02,50.67,25.14,22.19.HRMS-EI(m/z):[M]+calcd.for C11H14O,162.1039;found,162.1037。
操作同实施例1。硅醚中间体的制备使用(R)-2f(80.1mg,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。将(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol)加入封管,用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL);与硅醚中间体100℃油浴下反应24小时。再加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得3f(95.1mg,59%)无色液体;Ee:98%(OJ-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=8.8min(major);t2=16.9min(minor)./>13.97(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.56–7.47(m,2H),7.44–7.31(m,3H),7.06(d,J=7.5Hz,1H),6.97(d,J=7.5Hz,1H),4.56(d,J=8.0Hz,1H),2.19(s,3H),1.92(d,J=9.1Hz,1H),1.35(s,3H),1.33(d,J=14.6Hz,1H),1.17(d,J=14.6Hz,1H),1.06–0.90(m,10H).13CNMR(101MHz,CDCl3)δ(ppm):152.65,140.81,138.93,137.32,134.59,129.02,128.22,127.87,123.03,122.76,80.04,53.15,26.09,22.02,19.89,7.48,7.45,4.75,4.50.HRMS-DART(m/z):[M+NH4]+calcd.for C21H32ONSi,342.2244;found,342.2248。
实施例7
操作同实施例1。N-[(1R,2R)-1,2-二苯基-2-(2-(4-甲基苄氧基)乙基氨基)乙基]-4-甲基苯磺酰胺(氯)钌(II)(6.5mg,10.0μmol),甲酸三乙胺共沸物5:2(1mL),1g(0.252g,1.0mmol),在60℃下,反应48小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(R)-2g(0.236g,99%)白色固体;Ee:99%(OD-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=11.7min(major);t2=14.3min(minor)./>(c 1.3,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.48–7.41(m,2H),7.43–7.34(m,2H),7.36–7.28(m,1H),7.23(t,J=7.8Hz,1H),6.81(d,J=8.4Hz,1H),6.70(d,J=7.1Hz,1H),5.37(d,J=12.0Hz,1H),5.26(d,J=12.0Hz,1H),4.79(d,J=9.8Hz,1H),2.21(d,J=9.9Hz,1H),1.36(s,3H),1.34(s,3H).13CNMR(101MHz,CDCl3)δ(ppm):154.71,154.59,137.45,131.41,128.50,127.84,127.34,127.31,115.21,112.96,78.97,71.19,50.41,25.07,22.13.HRMS-EI(m/z):[M]+calcd.forC17H18O2,254.1301;found,254.1302。
操作同实施例1。硅醚中间体的制备使用(R)-2g(0.127g,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。将(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol)加入封管,用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL);与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得3g(0.162g,78%)无色液体;Ee:99%(OD-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=9.5min(minor);t2=11.8min(major)./>(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.50–7.42(m,2H),7.45–7.27(m,8H),7.11(dd,J=8.3,7.2Hz,1H),6.75(d,J=8.3Hz,1H),6.28(d,J=7.2Hz,1H),5.20(d,J=11.9Hz,1H),5.14(d,J=11.9Hz,1H),4.57(d,J=9.9Hz,1H),2.03(d,J=9.9Hz,1H),1.34(d,J=14.7Hz,1H),1.34(s,3H),1.26(d,J=14.7Hz,1H),1.05–0.88(m,10H).13CNMR(101MHz,CDCl3)δ(ppm):154.74,154.63,137.45,137.16,134.48,131.08,129.12,128.42,127.99,127.77,127.40,127.22,114.98,114.08,79.74,71.14,52.87,26.47,20.02,7.47,7.45,4.64,4.43.HRMS-DART(m/z):[M+H]+calcd.for C27H33O2Si,417.2246;found,417.2244。
实施例8
操作同实施例1。N-[(1R,2R)-1,2-二苯基-2-(2-(4-甲基苄氧基)乙基氨基)乙基]-4-甲基苯磺酰胺(氯)钌(II)(6.5mg,10.0μmol),甲酸三乙胺共沸物5:2(1mL),1h(0.190g,1.0mmol),在60℃下,反应48小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(R)-2h(0.175g,91%)白色固体;Ee:99%(OD-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=7.2min(minor);t2=7.9min(major)./>(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):6.52(s,2H),4.84(d,J=10.1Hz,1H),3.96(s,3H),2.30(d,J=0.7Hz,3H),2.08(d,J=10.1Hz,1H),1.36(s,3H),1.32(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):155.12,154.58,141.70,124.03,114.79,113.40,78.35,56.75,50.19,25.02,21.95,21.91.HRMS-EI(m/z):[M]+calcd.for C12H16O2,192.1145;found,192.1139。
操作同实施例1。硅醚中间体的制备使用(R)-2h(96.1mg,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。将(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol)加入封管,用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL);与硅醚中间体100℃油浴下反应24小时。再加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得3h(0.136g,77%)无色液体;(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.55–7.42(m,2H),7.44–7.31(m,3H),6.45(s,1H),5.84(s,1H),4.62(d,J=10.0Hz,1H),3.86(s,3H),2.17(s,3H),2.00(d,J=10.0Hz,1H),1.34(s,3H),1.33(d,J=14.7Hz,1H),1.19(d,J=14.7Hz,1H),1.13–0.82(m,10H).13C NMR(101MHz,CDCl3)δ(ppm):155.27,154.63,141.43,137.21,134.57,129.07,127.92,123.97,114.75,114.44,79.35,56.84,52.72,26.19,21.91,20.01,7.46,4.70,4.42.HRMS-DART(m/z):[M+H]+calcd.for C22H31O2Si,355.2088;found,355.2088。
实施例9
操作同实施例1。N-[(1R,2R)-1,2-二苯基-2-(2-(4-甲基苄氧基)乙基氨基)乙基]-4-甲基苯磺酰胺(氯)钌(II)(6.5mg,10.0μmol),甲酸三乙胺共沸物5:2(1mL),1i(0.206g,1.0mmol),在60℃下,反应48小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(R)-2i(0.175g,91%)白色固体;Ee:99%(AD-H;5%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=12.7min(major);t2=17.6min(minor)./>(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):6.27(d,J=1.8Hz,1H),6.23(d,J=1.9Hz,1H),4.78(d,J=9.8Hz,1H),3.94(s,3H),3.75(s,3H),2.33(d,J=9.9Hz,1H),1.34(s,3H),1.30(s,3H).13CNMR(101MHz,CDCl3)δ(ppm):162.84,156.76,155.30,119.23,100.46,98.73,78.16,57.00,55.41,50.13,24.91,21.97.HRMS-EI(m/z):[M]+calcd.for C12H16O3,208.1094;found,208.1088。
操作同实施例1。硅醚中间体的制备使用(R)-2i(0.104g,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。将(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol)加入封管,用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,加入硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL);与硅醚中间体100℃油浴下反应24小时。再加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol),在-78℃下反应3小时。柱层析得3i(0.153g,82%):无色液体;Ee:99%(OD-H;3%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=15.1min(major);t2=16.4min(minor)./>(c 1.25,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.53–7.48(m,2H),7.41–7.33(m,3H),6.19(d,J=1.8Hz,1H),5.74(d,J=1.9Hz,1H),4.58(d,J=9.7Hz,1H),3.85(s,3H),3.62(s,3H),2.02(d,J=9.9Hz,1H),1.33(d,J=14.7Hz,1H)1.33(s,3H),1.22(d,J=14.7Hz,1H),1.06–0.89(m,10H).13C NMR(101MHz,CDCl3)δ(ppm):162.59,156.76,155.46,137.25,134.54,129.11,127.93,119.24,100.60,99.53,78.96,56.92,55.45,52.61,26.15,19.86,7.46,4.71,4.50.HRMS-DART(m/z):[M+H]+calcd.for C22H31O3Si,371.2037;found,371.2037。
实施例10
操作同实施例1。N-[(1R,2R)-1,2-二苯基-2-(2-(4-甲基苄氧基)乙基氨基)乙基]-4-甲基苯磺酰胺(氯)钌(II)(26.0mg,40.0μmol),甲酸三乙胺共沸物5:2(3mL),1j(0.380g,2.0mmol),在60℃下,反应48小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(R)-2j(0.379g,99%)白色固体;Ee:99%(AD-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=7.3min(major);t2=9.0min(minor)./>(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.07(d,J=7.1Hz,2H),6.58(d,J=7.1Hz,2H),4.88(d,J=10.5Hz,1H),4.07(s,3H),2.19(d,J=10.5Hz,1H),2.17(s,3H),1.37(s,3H),1.32(s,3H).13CNMR(101MHz,CDCl3)δ(ppm):153.84,151.95,132.48,126.03,124.79,112.23,79.18,57.57,49.89,25.29,22.23,16.75.HRMS-DART(m/z):[M+H]+calcd.for C12H17O2,193.1226;found,193.1223。
操作同实施例1。硅醚中间体的制备使用(R)-2j(96.2mg,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。将(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol)加入封管,用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL);与硅醚中间体100℃油浴下反应24小时。再加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol),在-78℃下反应3小时。柱层析得3j(0.138g,78%)无色液体;Ee:99%(AD-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=6.4min(major);t2=7.1min(minor)./>(c 1.30,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.49–7.42(m,2H),7.41–7.30(m,3H),6.96(d,J=7.2Hz,1H),6.14(d,J=7.2Hz,1H),4.66(d,J=10.5Hz,1H),3.94(s,3H),2.15(s,3H),1.99(d,J=10.5Hz,1H),1.34(s,3H),1.32(d,J=14.6Hz,1H),1.21(d,J=14.6Hz,1H),1.08–0.84(m,10H).13C NMR(101MHz,CDCl3)δ(ppm):153.81,152.08,137.19,134.49,132.21,129.09,127.94,125.93,124.53,113.37,79.94,57.53,52.30,26.66,20.19,16.74,7.50,7.48,4.63,4.49.HRMS-DART(m/z):[M+NH4]+calcd.for C22H34O2NSi,372.2350;found,372.2353。
实施例11
操作同实施例1。N-[(1R,2R)-1,2-二苯基-2-(2-(4-甲基苄氧基)乙基氨基)乙基]-4-甲基苯磺酰胺(氯)钌(II)(6.5mg,10.0μmol),甲酸三乙胺共沸物5:2(1mL),1k(0.206g,1.0mmol),在60℃下,反应48小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=5/1)得到手性苯并环丁烯醇产物(R)-2k(0.201g,97%)白色固体;Ee:99%(OD-H;5%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=12.6min(major);t2=14.3min(minor)/>(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):6.83(d,J=7.6Hz,1H),6.61(d,J=7.6Hz,1H),4.88(d,J=10.3Hz,1H),4.11(s,3H),3.82(s,3H),2.20(d,J=10.5Hz,1H),1.37(s,3H),1.31(s,3H).13CNMR(101MHz,CDCl3)δ(ppm):147.81,145.61,145.54,126.94,114.20,112.48,78.75,58.12,56.48,49.50,25.43,22.28.HRMS-EI(m/z):[M]+calcd.for C12H16O3,208.1094;found,208.1095。
操作同实施例1。硅醚中间体的制备使用(R)-2k(0.104g,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。将(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol)加入封管,用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL);与硅醚中间体100℃油浴下反应24小时。再加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol),在-78℃下反应3小时。柱层析得3k(0.154g,83%)无色液体;Ee:99%(AD-H;5%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=10.3min(major);t2=7.9min(minor)./>(c1.3,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.50–7.42(m,2H),7.43–7.30(m,3H),6.71(d,J=7.8Hz,1H),6.13(d,J=7.8Hz,1H),4.64(d,J=10.4Hz,1H),3.98(s,3H),3.80(s,3H),2.10(d,J=10.5Hz,1H),1.33(s,3H),1.31(d,J=14.6Hz,1H),1.21(d,J=14.6Hz,1H),1.06–0.88(m,10H).13C NMR(101MHz,CDCl3)δ(ppm):147.60,145.62,145.48,137.10,134.45,129.10,127.94,126.89,113.90,113.67,79.44,58.03,56.39,51.90,26.83,20.16,7.44,4.60,4.41.HRMS-DART(m/z):[M+H]+calcd.for C22H31O3Si,371.2037;found,371.2037。/>
实施例12
操作同实施例1。(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基苯)氯化钌(II)(6.2mg,10.0μmol),甲酸三乙胺共沸物5:2(1mL),1l(0.196g,1.0mmol),在室温下,反应48小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性苯并环丁烯醇产物(S)-2l(0.182g,92%)白色固体;Ee:99%(AD-H;3%i-PrOH inhexanes;flow rate=1.0mL/min;detection at 210nm;t1=15.5min(major);t2=19.0min(minor)./>111.08(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.90(d,J=8.7Hz,1H),7.85(d,J=8.2Hz,1H),7.80(d,J=8.1Hz,1H),7.51(ddd,J=8.2,6.9,1.3Hz,1H),7.43(ddd,J=8.2,6.8,1.3Hz,1H),5.07(d,J=5.3Hz,1H),2.22(d,J=6.4Hz,1H),1.44(s,3H),1.40(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):150.41,139.36,133.52,130.48,129.60,129.55,126.80,125.12,122.54,119.38,78.91,51.01,24.95,22.39.HRMS-DART(m/z):[M+NH4]+calcd.for C14H18ON,216.1382;found,216.1383。
操作同实施例1。硅醚中间体的制备使用(S)-2l(99.2mg,0.500mmol),新鲜制备的二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(0.166mg,0.250μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(52.9mg,0.500mmol),四氢呋喃溶液(0.4mL),室温反应12小时后抽干。将(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol)加入封管,用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL);与硅醚中间体100℃油浴下反应24小时。再加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol),在-78℃下反应3小时。柱层析得3l(87.6mg,49%)无色液体;Ee:93%(AD-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=13.1min(major);t2=16.2min(minor)./>99.88(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.83(ddd,J=7.7,4.2,1.2Hz,2H),7.66(d,J=8.2Hz,1H),7.51–7.35(m,5H),7.36–7.27(m,2H),6.69(d,J=8.2Hz,1H),4.87(d,J=9.7Hz,1H),2.14(d,J=9.8Hz,1H),1.44(d,J=14.7Hz,1H),1.42(s,3H),1.29(d,J=14.7Hz,1H),1.08–0.90(m,10H).13C NMR(101MHz,CDCl3)δ(ppm):150.45,139.29,137.24,134.46,133.29,129.97,129.67,129.33,129.05,127.92,126.59,125.10,122.64,120.59,79.77,53.58,26.09,20.26,7.49,4.70,4.54.HRMS-DART(m/z):[M+NH4]+calcd.forC24H32ONSi,378.2242;found,378.2248。
尽管本发明的内容已经通过上述优选实施例作了详细介绍,但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后,对于本发明的多种修改和替代都将是显而易见的。因此,本发明的保护范围应由所附的权利要求来限定。
Claims (14)
1.一种手性苯并环丁烯醇,其特征在于,其结构通式如下:
其中,R1选自取代或未取代的C1-C20的烃基、取代或未取代的杂环基中的任意一种或两种以上,取代基选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基中的任意一种或两种以上。
2.如权利要求1所述的手性苯并环丁烯醇,其特征在于,R1为取代或未取代的苯基。
3.如权利要求1所述的手性苯并环丁烯醇,其特征在于,R1为取代或未取代的芳基,所述芳基包含邻、间、对位带有吸电子或给电子取代的苯基,所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基中的任意一种或两种以上,所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基中的任意一种或两种以上。
4.如权利要求1所述的手性苯并环丁烯醇,其特征在于,R1为取代或未取代的C1-C10的烃基。
5.如权利要求1所述的手性苯并环丁烯醇,其特征在于,R1选自甲基,乙基,正丙基,异丙基,正丁基,正戊基,正己基,正庚基,正辛基,苯乙基,4-氯丁基,3-甲基丁基,3-氰基丙基,烯丙基中的任意一种或任意两种以上。
6.一种根据权利要求1所述的手性苯并环丁烯醇的合成方法,其特征在于,该方法是以带有取代基的苯并环丁烯酮(1)为原料,在钌催化剂、氢供体的共同作用下,进行不对称还原,制备具有手性中心的苯并环丁烯醇化合物,反应方程式如下:
所述的钌催化剂为(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基苯)氯化钌(II),N-[(1R,2R)-1,2-二苯基-2-(2-(4-甲基苄氧基)乙基氨基)乙基]-4-甲基苯磺酰胺(氯)钌(II)中的任意一种或两种;所述的氢供体为甲酸三乙胺共沸物。
7.如权利要求6所述的手性苯并环丁烯醇的合成方法,其特征在于,所述钌催化剂的用量为以带有取代基的苯并环丁烯酮(1)的摩尔数为基准计0.01-20%。
8.如权利要求6所述的手性苯并环丁烯醇的合成方法,其特征在于,所述的氢供体的用量为以带有取代基的苯并环丁烯酮(1)的摩尔数为基准计(1~10):1。
9.一种根据权利要求1所述的手性苯并环丁烯醇的用途,其特征在于,该手性苯并环丁烯醇用于制备具有季碳手性中心的苯并环丁烯醇衍生物(3),反应方程式如下:
所述手性苯并环丁烯醇在第一铱催化剂、硅氢试剂、菲啰啉配体、氢受体、第二铱催化剂及有机金属试剂作用下反应生成苯并环丁烯醇衍生物(3),R2选自苯基,芳基,杂环基,C1-C10直链烷基,
C1-C10环烷基,末端带有官能团的C1-C10烷基中的任意一种或两种以上;所述的第一铱催化剂为二(1,5-环辛二烯)二-Μ-甲氧基二铱(I);所述的硅氢试剂为二乙基硅烷;所述的菲啰啉配体为化合物L1:
所述氢受体为化合物A:/>
所述第二铱催化剂为二(环辛烯)氯化铱(I)二聚体;所述的有机金属试剂为PHLi。
10.如权利要求9所述的用途,其特征在于,R2选自甲基,乙基,正丙基,叔丁基,苯基,邻甲基苯基,间甲基苯基,对甲基苯基,间甲氧基苯基,对氯苯基,对溴苯基,对酯基苯基,2-萘基,3-噻吩基中的任意一种或两种以上。
11.如权利要求9所述的用途,其特征在于,制备具有季碳手性中心的苯并环丁烯醇衍生物(3)的方法包含:
步骤1,惰性气氛下,手性苯并环丁烯醇、第一铱催化剂、与硅氢试剂室温反应,得到硅醚中间体;
步骤2,惰性气氛下,所述的硅醚中间体、菲啰啉配体、氢受体、第二铱催化剂在20-100℃反应2-24h;
步骤3,加入有机金属试剂,-78℃继续反应,直至反应完成,得到具有季碳手性中心的苯并环丁烯醇衍生物(3);
其中,所述的第一铱催化剂、第二铱催化剂的用量为以手性苯并环丁烯醇的摩尔数比例计为0.01-10%;所述的有机金属试剂的用量以手性苯并环丁烯醇的摩尔数为基准为(1~5):1。
12.一种手性苯并环丁烯醇产物(3),其特征在于,其结构通式为:
其中,R1选自取代或未取代的杂环基、取代或未取代的C1-C20的烃基中的任意一种或任意两种以上,取代基选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基中的任意一种或两种以上;R2选自苯基,芳基,杂环基,C1-C10直链烷基,C1-C10环烷基,末端带有官能团的C1-C10烷基中的任意一种或两种以上。
13.如权利要求12所述的手性苯并环丁烯醇产物(3),其特征在于,R1选自取代或未取代的苯基。
14.如权利要求12所述的手性苯并环丁烯醇产物(3),其特征在于,R1选自取代或未取代的芳基;所述芳基包含邻、间、对位带有吸电子或给电子取代的苯基,所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基中的任意一种或两种以上,所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基中的任意一种或两种以上。
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