CN115448949A - 一种手性烯丙基膦化合物的合成方法 - Google Patents
一种手性烯丙基膦化合物的合成方法 Download PDFInfo
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- -1 allyl phosphine compound Chemical class 0.000 title claims abstract description 50
- 238000001308 synthesis method Methods 0.000 title description 5
- 238000000034 method Methods 0.000 claims abstract description 31
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 239000003446 ligand Substances 0.000 claims abstract description 20
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 15
- 150000008300 phosphoramidites Chemical class 0.000 claims abstract description 14
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000007848 Bronsted acid Substances 0.000 claims abstract description 6
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 150000004808 allyl alcohols Chemical class 0.000 claims abstract description 6
- XXROGKLTLUQVRX-UHFFFAOYSA-N hydroxymethylethylene Natural products OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- QHJWOSHIGFDANE-UHFFFAOYSA-N prop-2-enylphosphane Chemical class PCC=C QHJWOSHIGFDANE-UHFFFAOYSA-N 0.000 claims abstract description 5
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 claims abstract 4
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- HLHNOIAOWQFNGW-UHFFFAOYSA-N 3-bromo-4-hydroxybenzonitrile Chemical compound OC1=CC=C(C#N)C=C1Br HLHNOIAOWQFNGW-UHFFFAOYSA-N 0.000 claims description 12
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 239000000654 additive Substances 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- SPXOTSHWBDUUMT-UHFFFAOYSA-N 138-42-1 Chemical compound OS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical group [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=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
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 239000004305 biphenyl Chemical group 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 150000002148 esters Chemical group 0.000 claims description 2
- 125000005059 halophenyl group Chemical class 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
- DANYXEHCMQHDNX-UHFFFAOYSA-K trichloroiridium Chemical compound Cl[Ir](Cl)Cl DANYXEHCMQHDNX-UHFFFAOYSA-K 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 2
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 4
- 239000012038 nucleophile Substances 0.000 abstract description 4
- 150000003003 phosphines Chemical class 0.000 abstract description 4
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 4
- 239000011574 phosphorus Substances 0.000 abstract description 4
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract description 3
- 150000004696 coordination complex Chemical class 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 229910052723 transition metal Inorganic materials 0.000 abstract 1
- 150000003624 transition metals Chemical class 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 62
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 60
- 238000004128 high performance liquid chromatography Methods 0.000 description 60
- 238000012512 characterization method Methods 0.000 description 32
- 238000003756 stirring Methods 0.000 description 26
- 239000003480 eluent Substances 0.000 description 24
- 239000011734 sodium Substances 0.000 description 24
- 238000010568 chiral column chromatography Methods 0.000 description 23
- 239000012265 solid product Substances 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 16
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- FFDLFWMUMGTWIB-UHFFFAOYSA-N boron;phosphane Chemical compound [B].P.P FFDLFWMUMGTWIB-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000000080 chela (arthropods) Anatomy 0.000 description 2
- 101150038575 clpS gene Proteins 0.000 description 2
- 238000006477 desulfuration reaction Methods 0.000 description 2
- 230000023556 desulfurization Effects 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 150000003018 phosphorus compounds Chemical class 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5333—Arylalkane phosphine oxides or thioxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5329—Polyphosphine oxides or thioxides
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种手性烯丙基膦化合物的合成方法，在有机溶剂体系中，以二取代硫膦及氧膦化合物和取代烯丙基醇为基本原料，在铱催化剂和手性亚磷酰胺配体及路易斯酸或布朗斯特酸的作用下合成手性烯丙基硫膦和氧膦类化合物。本发明所用二取代硫膦及氧膦化合物来源简单易得，底物的官能团容忍性高，反应条件温和，实验操作简便；所使用的手性配体简单易得，在反应中配体与过渡金属结合，实现了磷亲核试剂参与的不对称烯丙基取代反应，以中等以上收率和优异的对映选择性合成具有支链选择性的烯丙基膦化合物。产物进一步还原后得到的三价膦衍生物也作为配体合成钳形金属络合物作为催化剂应用于手性化学品的合成。
Description
技术领域
本发明属于手性膦化合物合成技术领域，具体涉及一种手性烯丙基膦化合物的合成方法。
背景技术
手性膦化合物被广泛应用于有机合成、催化、材料等多个领域，尤其是手性膦可以作为高效配体控制有机反应的催化效率及立体选择性。自从上世纪70年代化学家使用手性膦配体在不对称氢化反应中取得高立体选择性的结果后，各种结构的膦配体被合成。此后研究催化合成手性膦化合物的方法也受到研究者的关注，早期经过拆分方法以及使用手性辅助试剂的途径可以获得纯的对映异构手性膦化合物。近期，由于过程具有更高的原子经济性，通过不对称催化合成的方法合成手性膦化合物的途径备受关注，多种例子也被先后报道。
不对称烯丙基取代反应有着长久的研究历史，各种含碳及杂原子亲核试剂都已被实现。然而含磷亲核试剂的使用却很少，原因为磷亲核试剂容易毒化金属催化剂，导致反应不能顺利进行。因此，探索合成烯丙基膦化合物的合成具有重要意义，所得产物可以转化为手性膦配体应用于有机合成中制备手性物质。
发明内容
针对现有技术中的不足之处，本发明提供一种以亚磷酰胺作为配体，与铱催化剂、添加剂共同作用实现不对称烯丙基取代反应合成手性烯丙基膦化合物，其过程具有反应步骤短、原子经济效益好等特点。
为实现上述目的，本发明提供的技术方案为：在氮气气氛下，将式1所示取代烯丙醇与式2所示二取代硫膦或氧膦化合物在金属铱催化剂、手性亚磷酰胺配体及添加剂的作用下，在有机溶剂中-20～50℃反应6～24小时，生成式3所示手性烯丙基膦化合物；
其中，R1选自苯基、C1～C8烷基取代苯基、C1～C5烷氧基取代苯基、硝基取代苯基、氰基取代苯基、三氟甲基取代苯基、卤代苯基、酯基取代苯基、烯基取代苯基、酰基取代苯基、联苯基、萘基、噻吩基、烷基、卤代烷基、苯基取代烷基中任意一种，具体如：苯基、3-甲基苯基、4-甲基苯基、4-苯基苯基、3-甲氧基亚甲氧基苯基、4-甲酸甲酯苯基、4-甲氧基苯基、4-硝基苯基、4-氰基苯基、3-硝基苯基、3-氰基苯基、4-三氟甲基苯基、4-乙烯苯基、4-氯苯基、3-氯苯基、4-乙酰基苯基、1-萘基、2-萘基、2-甲氧基苯基、3-羟基苯基、2-溴苯基、3-噻吩基、2-苯基乙基、正壬基、正己基、4-氯丁基等；X代表O或S；R2、R3各自独立的选自苯基、C1～C8烷基取代苯基、C1～C5烷氧基取代苯基、三氟甲基取代苯基、卤代苯基、萘基、噻吩基、C1～C8烷基中任意一种，具体如：4-甲基苯基、4-氯苯基、3,5-二甲基苯基、3,5-二叔丁基苯基、2-甲氧基苯基、环己基、甲基等。
上述手性亚磷酰胺配体的结构式为下述任意一种：
上述添加剂为路易斯酸或布朗斯特酸，其中所述路易斯酸优选三氟甲磺酸钪、三氟甲磺酸铜、三氟甲磺酸锌中任意一种，所述布朗斯特酸优选三氟乙酸、三氯乙酸、三溴乙酸、乙酸、苯甲酸、对甲苯磺酸、对硝基苯磺酸、二(苯磺酰)胺、二苯酚基磷酸中任意一种。
上述有机溶剂优选二氯乙烷、二氯甲烷、四氢呋喃、甲苯、甲醇中任意一种。
上述金属铱催化剂优选1,5-环辛二烯氯化铱或双环辛烯氯化铱。
上述合成方法中，优选所述取代烯丙醇、二取代硫膦或氧膦化合物的摩尔比是1:2.5～2:1，所述金属铱催化剂的加入量为二取代硫膦或氧膦化合物摩尔量的2.5％～5％，手性亚磷酰胺配体的加入量为金属铱催化剂摩尔量的3～5倍，添加剂的加入量为二取代硫膦或氧膦化合物摩尔量的10％～100％。
上述合成方法中，进一步优选在有机溶剂中0℃反应6～12小时。
本发明的有益效果如下：
本发明由二取代硫膦或氧膦化合物出发，在铱催化剂以及手性亚磷酰胺化合物作为配体的存在下，实现了磷亲核试剂参与的烯丙基取代反应，以中等以上收率和优异的对映选择性合成具有碳手性的化合物。反应中使用的二取代硫膦或氧膦化合物简单易合成，底物的普适性较好，反应操作简便效率高。配体的合成也比较方便，在反应中配体与金属结合，在路易斯酸/布朗斯特酸的帮助下，离去羟基以形成烯丙基铱中间体，最后，二取代硫膦或氧膦化合物进攻烯丙基铱中间体得到具有手性的化合物。所得的产物可以作为医药中间体或者手性配体，产物进一步还原后得到的三价膦也可以充当手性膦配体。其中1,3-二取代芳基烯丙醇所得的产物通过铱催化剂进行氢化还原，脱硫后生成一种有价值的手性钳形金属配合物的合成前体：双膦硼烷络合物，双膦硼烷络合物可用于钳型钯催化剂的合成。此钳型钯催化剂可用于催化不对称氢磷化反应合成手性磷化合物(Org.Lett.,2011，Vol(13)，5824–5826)。
具体实施方式
下面将结合实施例对本发明的技术方案进行清楚、完整地描述，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。
以下是本发明实施例中所用取代烯丙醇1a～1r的具体结构式，根据文献方法使用乙烯基溴化镁与相应的醛反应得到。
以下是本发明实施例中二取代硫膦化合物2a～2h以及二取代氧膦化合物2i～2l的具体结构式：
其中，二取代硫膦化合物通过如下方法合成：
在氮气氛围下，将相应的二取代氧膦化合物(8.8mmol，2.2equiv.)和Lawesson试剂(1.6g，4mmol，1.0equiv.)溶解在20mL无水THF中，所得黄色溶液在70℃下回流5小时。然后将其冷却至室温，真空浓缩，通过快速柱层析(PE/DCM＝5/1至1/1)纯化后，再用二氯甲烷/正己烷重结晶，获得二取代硫膦化合物。
实施例1
在手套箱中，向配备磁子的10mL Schlenk管中加入1,5-环辛二烯氯化铱(3.4mg,0.005mmol)、手性亚磷酰胺(S)-L1(10.4mg,0.02mmol)、二氯乙烷(1mL)，在室温下搅拌15分钟，然后依次加入1a(53.7mg,0.4mmol)、三氟甲磺酸钪(19.7mg,0.04mmol)、二氯乙烷(0.5mL)，将Schlenk管从手套箱中取出放置于0℃并搅拌5min，在氮气氛围下，将2a(43.6mg,0.2mmol)、二氯乙烷(1.5mL)加入混合物中并在0℃搅拌12小时。升温至室温后，将反应混合物通过硅藻土过滤，真空浓缩，柱层析分离(PE/DCM＝5/1～1/1)，得到白色固体产物(S)-3aa，产率92％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC：IC,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝19.4min,tr(主)＝17.6min，99％ee，[α]D 20-84(c 0.200,CH2Cl2)。(S)-3aa的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.07(dd,J＝12.2,7.1Hz,2H),7.56(dd,J＝12.6,7.7Hz,2H),7.51-7.46(m,3H),7.32(t,J＝7.4Hz,1H),7.26-7.20(m,4H),7.14-7.11(m,3H),6.40-6.29(m,1H),5.16(dd,J＝10.5,3.1Hz,1H),5.06(dd,J＝17.0,4.4Hz,1H),4.60(t,J＝9.9Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm)135.2(d,J＝5.3Hz),133.4(d,J＝4.0Hz),132.4(d,J＝9.0Hz),131.7(d,J＝9.5Hz),131.6(d,J＝2.9Hz),131.4(d,J＝78.9Hz),131.3(d,J＝3.0Hz),130.8(d,J＝77.9Hz),129.6(d,J＝5.7Hz),128.5(d,J＝11.7Hz),128.1(d,J＝7.7Hz),128.0(d,J＝1.1Hz),127.4(d,J＝3.1Hz),119.7(d,J＝12.6Hz),52.9(d,J＝48.9Hz).31PNMR(162MHz,CDCl3)δ(ppm)49.0.HRMS(ESI)C21H19PS(M+Na)+:理论值357.0837,实测值:357.0837。
实施例2
本实施例中，用等摩尔手性亚磷酰胺(R)-L1替换实施例1中的手性亚磷酰胺(S)-L1，其他步骤与实施例1相同，得到白色固体产物(R)-3aa，产率92％，99％ee。
实施例3
本实施例中，用等摩尔手性亚磷酰胺(S)-L2替换实施例1中的手性亚磷酰胺(S)-L1，其他步骤与实施例1相同，得到白色固体产物(S)-3aa，产率92％，96％ee。
实施例4
本实施例中，用三氟乙酸(5.7mg,0.05mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中在0℃搅拌12小时，其他步骤与实施例1相同，得到白色固体产物(S)-3aa，产率85％，98％ee。
实施例5
本实施例中，用三溴乙酸(14.8mg,0.05mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中在0℃搅拌12小时，其他步骤与实施例1相同，得到白色固体产物(S)-3aa，产率79％，99％ee。
实施例6
本实施例中，用等摩尔1b替换实施例1中的1a，用PE/Acetone＝40/1～8/1作为洗脱剂替换实施例1中柱层析分离的洗脱剂PE/DCM＝5/1～1/1，其他步骤与实施例1相同，得到白色固体产物(S)-3ba，产率94％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC：IC,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝19.9min,tr(主)＝17.9min)，98％ee，[α]D 20-78(c 0.200,CH2Cl2)。(S)-3ba的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.05(ddd,J＝12.1,7.7,1.8Hz,2H),7.58-7.48(m,5H),7.35(td,J＝7.3,1.7Hz,1H),7.26(td,J＝7.8,3.0Hz,2H),7.08-7.05(m,2H),6.99-6.96(m,2H),6.40-6-29(m,1H),5.18(dd,J＝10.3,3.0Hz,1H),5.06(dd,J＝17.1,4.4Hz,1H),4.53(dd,J＝10.9,9.0Hz,1H),2.19(s,3H).13C NMR(100MHz,CDCl3)δ(ppm)137.7(d,J＝2.4Hz),135.1(d,J＝5.2Hz),133.5(d,J＝4.3Hz),132.6(d,J＝8.9Hz),131.9(d,J＝9.4Hz),131.71(d,J＝79.8Hz),131.70(d,J＝2.9Hz),131.3(d,J＝2.9Hz),130.9(d,J＝77.5Hz),130.5(d,J＝5.8Hz),128.5(d,J＝11.7Hz),128.2(d,J＝2.9Hz),128.1(d,J＝12.6Hz),128.0(d,J＝3.0Hz),126.7(d,J＝5.7Hz),119.7(d,J＝12.7Hz),53.1(d,J＝48.8Hz),21.4.31P NMR(162MHz,CDCl3)δ(ppm)48.8.HRMS(ESI)C22H18PS(M+Na)+:理论值371.0994,实测值:371.0998.
实施例7
本实施例中，用等摩尔1c替换实施例1中的1a，其他步骤与实施例1相同，得到白色固体产物(S)-3ca，产率89％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝16.9min,tr(主)＝14.3min，99.8％ee，[α]D 20-84(c 0.200,CH2Cl2)。(S)-3ca的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.05(dd,J＝12.3,7.1Hz,2H),7.60-7.49(m,5H),7.37(t,J＝7.5Hz,1H),7.30-7.24(m,2H),7.17-7.06(m,4H),6.35-6.24(m,1H),5.20(d,J＝10.1Hz,1H),5.07(dd,J＝16.9,4.3Hz,1H),4.55(t,J＝9.9Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm)137.3(d,J＝4.9Hz),133.7(d,J＝2.5Hz),132.9(d,J＝4.3Hz),132.5(d,J＝8.9Hz),131.9(d,J＝2.7Hz),131.8(d,J＝9.6Hz),131.6(d,J＝3.1Hz),131.2(d,J＝80.1Hz),130.5(d,J＝78.8Hz),129.7(d,J＝5.7Hz),129.2(d,J＝1.8Hz),128.6(d,J＝11.7Hz),128.3(d,J＝12.1Hz),127.8(d,J＝5.2Hz),127.5(d,J＝2.9Hz),120.3(d,J＝12.5Hz),52.6(d,J＝49.0Hz).31PNMR(162MHz,CDCl3)δ(ppm)48.9.HRMS(ESI)C21H18ClPS(M+Na)+:理论值391.0448,实测值:391.0450。
实施例8
本实施例中，用等摩尔1d替换实施例1中的1a，用三氟甲磺酸钪(49.2mg,0.1mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，其他步骤与实施例1相同，得到白色固体产物(S)-3da，产率96％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇90:10,流速1mL/min,25℃,tr(次)＝15.5min,tr(主)＝11.5min，99.6％ee，[α]D 20-110(c 0.200,CH2Cl2)。(S)-3da的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.10-8.00(m,3H),7.87(q,J＝2.2Hz,1H),7.70(dd,J＝7.6,2.5Hz,1H),7.62-7.51(m,5H),7.40-7.33(m,2H),7.31-7.26(m,2H),6.40-6.29(m,1H),5.27(dd,J＝10.2,2.8Hz,1H),5.15(dd,J＝17.0,4.1Hz,1H),4.73(dd,J＝10.9,8.9Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm)147.6(d,J＝1.6Hz),137.5(d,J＝4.8Hz),135.6(d,J＝4.9Hz),132.5(d,J＝8.9Hz),132.3(d,J＝4.1Hz),132.1(d,J＝3.4Hz),131.9(d,J＝3.4Hz),131.7(d,J＝9.5Hz),130.7(d,J＝79.5Hz),130.1(d,J＝79.3Hz),128.81,128.75(d,J＝12.0Hz),128.5(d,J＝12.0Hz),124.6(d,J＝5.7Hz),122.4(d,J＝2.3Hz),121.0(d,J＝12.4Hz),52.6(d,J＝48.2Hz).31P NMR(162MHz,CDCl3)δ(ppm)49.2.HRMS(ESI)C21H18NO2PS(M+Na)+:理论值402.0688,实测值:402.0692。
实施例9
本实施例中，用等摩尔1e替换实施例1中的1a，用三氟甲磺酸钪(49.2mg,0.1mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，其他步骤与实施例1相同，得到白色固体产物(S)-3ea，产率99％，使用Daicel ADH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ADH,254nm,正己烷/异丙醇90:10,流速1mL/min,25℃,tr(次)＝13.8min,tr(主)＝15.6min，99.5％ee，[α]D 20-123(c 0.200,CH2Cl2)。(S)-3ea的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.06(dd,J＝12.3,7.1Hz,2H),7.59-7.51(m,6H),7.46-7.39(m,2H),7.35(s,1H),7.32-7.25(m,3H),6.36-6.24(m,1H),5.25(dd,J＝10.1,2.8Hz,1H),5.12(dd,J＝17.2,4.1Hz,1H),4.63(t,J＝10.0Hz,1H).13CNMR(100MHz,CDCl3)δ(ppm)137.0(d,J＝4.8Hz),134.0(d,J＝5.0Hz),133.1(d,J＝5.1Hz),132.4(d,J＝9.6Hz),132.3(d,J＝5.2Hz),132.1(d,J＝2.6Hz),131.8(d,J＝3.3Hz),131.7(d,J＝9.5Hz),131.0(d,J＝3.4Hz),130.8(d,J＝79.1Hz),130.1(d,J＝79.1Hz),128.71(d,J＝1.9Hz),128.70(d,J＝11.8Hz),128.4(d,J＝12.2Hz),120.9(d,J＝12.5Hz),118.6,111.9(d,J＝2.2Hz),52.4(d,J＝48.7Hz).31P NMR(162MHz,CDCl3)δ(ppm)49.1.HRMS(ESI)C22H18NPS(M+Na)+:理论值382.0790,实测值:382.0790。
实施例10
本实施例中，用等摩尔1f替换实施例1中的1a，用PE/DCM＝10/1～2/1作为洗脱剂替换实施例1中柱层析分离的洗脱剂PE/DCM＝5/1～1/1，其他步骤与实施例1相同，得到黄色固体产物(S)-3fa，产率89％，使用Daicel ADH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ADH,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝14.7min,tr(主)＝21.8min，98％ee，[α]D 20-76(c 0.200,CH2Cl2)。(S)-3fa的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.10-8.05(m,2H),7.61-7.49(m,5H),7.40-7.34(m,5H),7.29-7.24(m,2H),6.39-6.28(m,1H),5.21(dd,J＝10.1,3.0Hz,1H),5.09(dd,J＝17.0,4.1Hz,1H),4.70-4.65(m,1H).13C NMR(100MHz,CDCl3)δ(ppm)139.5(d,J＝5.1Hz),132.8(d,J＝4.6Hz),132.4(d,J＝9.1Hz),131.9(d,J＝3.0Hz),131.7(d,J＝9.6Hz),131.6(d,J＝3.2Hz),131.2(d,J＝85.7Hz),131.0(d,J＝79.0Hz),129.9(d,J＝5.7Hz),129.5(dd,J＝32.6,3.2Hz),128.6(d,J＝11.8Hz),128.3(d,J＝12.1Hz),124.9(quint,J＝3.6Hz),124.2(q,J＝271.8Hz),120.5(d,J＝12.4Hz),52.7(d,J＝48.6Hz).31P NMR(162MHz,CDCl3)δ(ppm)49.0.HRMS(ESI)C22H18F3PS(M+Na)+:理论值425.0711,实测值:425.0709。
实施例11
本实施例中，用等摩尔1g替换实施例1中的1a，用PE/EA＝25/1～5/1作为洗脱剂替换实施例1中柱层析分离的洗脱剂PE/DCM＝5/1～1/1，其他步骤与实施例1相同，得到白色固体产物(S)-3ga，产率99％，使用Daicel ADH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ADH,254nm,正己烷/异丙醇95:5,流速1mL/min,25℃,tr(次)＝16.3min,tr(主)＝23.6min，99％ee，[α]D 20-78(c 0.200,CH2Cl2)。(S)-3ga的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.10-8.04(m,2H),7.82(d,J＝8.2Hz,2H),7.62-7.56(m,2H),7.55-7.48(m,3H),7.37-7.30(m,3H),7.28-7.23(m,2H),6.40-6.28(m,1H),5.20(dd,J＝10.2,3.0Hz,1H),5.08(dd,J＝17.0,4.2Hz,1H),4.67(dd,J＝11.0,8.9Hz,1H),3.86(s,3H).13CNMR(100MHz,CDCl3)δ(ppm)166.9,140.6(d,J＝5.1Hz),132.8(d,J＝4.5Hz),132.4(d,J＝9.1Hz),131.8(d,J＝2.9Hz),131.7(d,J＝9.5Hz),131.5(d,J＝3.0Hz),131.0(d,J＝78.9Hz),130.5(d,J＝78.6Hz),129.6(d,J＝5.5Hz),129.2(d,J＝2.5Hz),129.0(d,J＝3.0Hz),128.6(d,J＝11.8Hz),128.2(d,J＝12.1Hz),120.3(d,J＝12.5Hz),53.0(d,J＝48.2Hz),52.1.31P NMR(162MHz,CDCl3)δ(ppm)48.9.HRMS(ESI)C23H21O2PS(M+Na)+:理论值415.0892,实测值:415.0893。
实施例12
本实施例中，用等摩尔1h替换实施例1中的1a，用PE/DCM＝1/1至DCM作为洗脱剂替换实施例1中柱层析分离的洗脱剂PE/DCM＝5/1～1/1，其他步骤与实施例1相同，得到白色固体产物(S)-3ha，产率95％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇95:5,流速1mL/min,25℃,tr(次)＝17.3min,tr(主)＝12.3min，99.3％ee，[α]D 20-72(c 0.200,CH2Cl2)。(S)-3ha的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.09-8.03(m,2H),7.62-7.56(m,2H),7.55-7.47(m,3H),7.37-7.32(m,1H),7.28-7.23(m,2H),7.09(t,J＝7.9Hz,1H),6.99-6.95(m,1H),6.88(q,J＝2.1Hz,1H),6.85-6.81(m,1H),6.39-6.28(m,1H),5.17(dd,J＝10.2,3.2Hz,1H),5.09-5.03(m,1H),5.02(d,J＝6.7Hz,1H),4.96(d,J＝6.7Hz,1H),4.58-4.53(m,1H),3.39(s,3H).13C NMR(100MHz,CDCl3)δ(ppm)156.9(d,J＝2.4Hz),136.7(d,J＝5.2Hz),133.3(d,J＝4.3Hz),132.5(d,J＝9.0Hz),131.8(d,J＝9.3Hz),131.7(d,J＝3.0Hz),131.6(d,J＝78.7Hz),131.3(d,J＝3.3Hz),130.8(d,J＝79.6Hz),129.0(d,J＝2.6Hz),128.5(d,J＝11.8Hz),128.1(d,J＝12.0Hz),123.2(d,J＝5.7Hz),119.8(d,J＝12.6Hz),117.6(d,J＝5.7Hz),115.4(d,J＝3.0Hz),94.5,56.0,53.0(d,J＝49.0Hz).31P NMR(162MHz,CDCl3)δ(ppm)49.0.HRMS(ESI)C23H23O2PS(M+Na)+:理论值417.1049,实测值:417.1048。
实施例13
在手套箱中，向配备磁子的10mL Schlenk管中加入1,5-环辛二烯氯化铱(6.7mg,0.01mmol)、手性亚磷酰胺(S)-L1(20.8mg,0.04mmol)、二氯乙烷(1mL)，在室温下搅拌15分钟，然后依次加入1i(19.0mg,0.1mmol)、三氟甲磺酸钪(98.4mg,0.2mmol)、二氯乙烷(0.5mL)，将Schlenk管从手套箱中取出放置于0℃并搅拌5min。在氮气氛围下，将2a(48.0mg,0.22mmol)、二氯乙烷(1.5mL)加入混合物中并在0℃搅拌12小时。升温至室温后，将反应混合物通过硅藻土过滤，真空浓缩，柱层析分离(PE/DCM＝10/1～1/1)，得到白色固体产物(S,S)-3ia，产率68％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇90:10,流速0.5mL/min,25℃,tr(次)＝22.2min,tr(主)＝20.8min，98％ee，dr＝10:1，[α]D 20-34(c 0.200,CH2Cl2)。(S,S)-3ia的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.03(dd,J＝12.3,7.1Hz,4H),7.57-7.48(m,10H),7.39(s,1H),7.30(t,J＝7.5Hz,2H),7.26-7.19(m,6H),6.91(t,J＝7.7Hz,1H),6.27-6.16(m,2H),5.13(dd,J＝10.2,3.3Hz,2H),4.91(dd,J＝17.1,4.6Hz,2H),4.48(t,J＝9.8Hz,2H).13CNMR(100MHz,CDCl3)δ(ppm)135.5(d,J＝5.8Hz),133.5(d,J＝3.3Hz),132.4(d,J＝9.2Hz),131.9(d,J＝9.6Hz),131.7,131.6(d,J＝75.1Hz),131.5(d,J＝78.7Hz),131.3,131.1(d,J＝78.0Hz),128.5(d,J＝12.4Hz),128.48(d,J＝7.2Hz),128.4(d,J＝12.7Hz),128.1(d,J＝10.5Hz),119.6(d,J＝12.6Hz),52.8(d,J＝49.4Hz).31P NMR(162MHz,CDCl3)δ(ppm)48.7(minor diast.),48.6(major diast.).HRMS(ESI)C36H32P2S2(M+Na)+:理论值613.1313,实测值:613.1313。
实施例14
本实施例中，用1j(64.9mg,0.4mmol)替换实施例13中的1i(19.0mg,0.1mmol)，2a(43.6mg,0.2mmol)替换实施例13中的2a(48.0mg,0.22mmol)，柱层析分离(PE/Acetone＝50/1to 10/1)，其他步骤与实施例13相同，得到黄色粘性固体产物(S)-3ja，产率37％，使用Daicel ADH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ADH,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝12.8min,tr(主)＝16.1min，87％ee，[α]D 20+6(c0.200,CH2Cl2)。(S)-3ja的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)7.78-7.70(m,4H),7.50-7.45(m,1H),7.43-7.33(m,5H),7.30-7.25(m,2H),7.24-7.20(m,1H),7.05-7.03(m,2H),5.85-5.75(m,1H),5.21(ddd,J＝10.2,3.9,1.4Hz,1H),4.96(ddd,J＝17.2,5.1,1.4Hz,1H),3.27-3.19(m,1H),2.84-2.78(m,1H),2.56-2.48(m,1H),2.16-2.05(m,1H),1.91-1.80(m,1H).13C NMR(100MHz,CDCl3)δ(ppm)140.9,132.8(d,J＝5.8Hz),131.9(d,J＝79.2Hz),131.8(d,J＝9.3Hz),131.6(d,J＝9.3Hz),131.3(d,J＝2.9Hz),131.2(d,J＝76.9Hz),128.9,128.7(d,J＝11.8Hz),128.6,128.3(d,J＝11.9Hz),126.3,44.1(d,J＝54.0Hz),32.9(d,J＝14.7Hz),29.3.31P NMR(162MHz,CDCl3)δ(ppm)48.8.HRMS(ESI)C23H23PS(M+Na)+:理论值385.1150,实测值:385.1148。
实施例15
本实施例中，用等摩尔1k替换实施例1中的1a，用三溴乙酸(14.8mg,0.05mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中的在0℃搅拌12小时，用PE/Acetone＝40/1～8/1作为洗脱剂替换实施例1中柱层析分离的洗脱剂PE/DCM＝5/1～1/1，其他步骤与实施例1相同，得到白色固体产物(S)-3ka，产率75％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝21.2min,tr(主)＝19.4min，99.4％ee，[α]D 20+143(c0.200,CH2Cl2)。(S)-3ka的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.29(dd,J＝7.3,2.5Hz,1H),8.16-8.11(m,2H),7.83-7.71(m,3H),7.59-7.52(m,3H),7.45-7.32(m,5H),7.14-7.10(m,1H),6.99(td,J＝7.7,3.0Hz,2H),6.45-6.34(m,1H),5.50(dd,J＝11.8,8.4Hz,1H),5.20(dd,J＝10.1,3.5Hz,1H),5.03(dd,J＝17.0,4.6Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm)133.76,133.74(d,J＝4.4Hz),132.6(d,J＝9.1Hz),131.8(d,J＝3.6Hz),131.59(d,J＝80.0Hz),131.55(d,J＝9.9Hz),131.53(d,J＝5.8Hz),131.4(d,J＝77.0Hz),131.39(d,J＝4.7Hz),131.2(d,J＝3.9Hz),129.2,128.6(d,J＝12.1Hz),128.1(d,J＝2.4Hz),127.9(d,J＝11.7Hz),127.6(d,J＝6.8Hz),126.1,125.4(d,J＝1.8Hz),125.3,122.0,119.8(d,J＝12.5Hz),46.2(d,J＝50.8Hz).31P NMR(162MHz,CDCl3)δ(ppm)49.5.HRMS(ESI)C25H21PS(M+Na)+:理论值407.0994,实测值:407.0997。
实施例16
本实施例中，用等摩尔1l替换实施例1中的1a，用三溴乙酸(14.8mg,0.05mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中的在0℃搅拌12小时，其他步骤与实施例1相同，得到白色固体产物(S)-3la，产率85％，使用DaicelADH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ADH,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝18.0min,tr(主)＝20.3min，99.7％ee，[α]D 20-7(c0.200,CH2Cl2)。(S)-3la的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.15-8.10(m,2H),7.88(dt,J＝7.8,2.2Hz,1H),7.54-7.45(m,5H),7.29-7.25(m,1H),7.18-7.12(m,3H),6.95(t,J＝7.5Hz,1H),6.55(d,J＝8.2Hz,1H),6.38-6.27(m,1H),5.38(dd,J＝11.3,8.9Hz,1H),5.14(dd,J＝10.3,3.3Hz,1H),5.03(dd,J＝17.0,4.5Hz,1H),3.41(s,3H).13C NMR(100MHz,CDCl3)δ(ppm)155.8(d,J＝6.1Hz),133.4(d,J＝4.3Hz),132.6(d,J＝9.0Hz),132.2(d,J＝80.0Hz),131.7(d,J＝10.2Hz),131.6(d,J＝4.4Hz),131.1(d,J＝77.2Hz),130.9(d,J＝3.1Hz),130.1(d,J＝4.9Hz),128.5(d,J＝12.1Hz),128.4(d,J＝4.3Hz),127.5(d,J＝12.1Hz),123.7(d,J＝4.8Hz),120.5(d,J＝3.1Hz),119.5(d,J＝12.8Hz),109.9(d,J＝2.3Hz),55.1,42.7(d,J＝50.3Hz).31P NMR(162MHz,CDCl3)δ(ppm)50.3.HRMS(ESI)C22H21OPS(M+Na)+:理论值387.0943,实测值:387.0940。
实施例17
本实施例中，用等摩尔1m替换实施例1中的1a，用三溴乙酸(14.8mg,0.05mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中的在0℃搅拌12小时，其他步骤与实施例1相同，得到白色固体产物(S)-3ma，产率78％，使用DaicelIC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝13.9min,tr(主)＝12.9min，99.9％ee，[α]D 20+26(c0.200,CH2Cl2)。(S)-3ma的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.23-8.20(m,1H),8.17-8.12(m,2H),7.58-7.49(m,5H),7.37(d,J＝7.9Hz,1H),7.34-7.27(m,2H),7.20(td,J＝7.7,3.1Hz,2H),7.07-7.02(m,1H),6.27-6.16(m,1H),5.38(dd,J＝11.3,8.3Hz,1H),5.17(dd,J＝10.2,3.5Hz,1H),4.98(dd,J＝17.2,4.5Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm)135.1(d,J＝3.6Hz),132.8(d,J＝4.2Hz),132.6(d,J＝6.0Hz),132.5(d,J＝9.3Hz),131.9(d,J＝3.0Hz),131.8(d,J＝9.7Hz),131.4(d,J＝3.0Hz),131.36(d,J＝76.6Hz),130.7(d,J＝4.9Hz),130.5(d,J＝79.1Hz),129.0(d,J＝2.5Hz),128.7(d,J＝11.9Hz),128.0(d,J＝12.1Hz),127.6(d,J＝2.4Hz),125.6(d,J＝8.2Hz),120.1(d,J＝12.4Hz),50.0(d,J＝50.5Hz).31P NMR(162MHz,CDCl3)δ(ppm)50.0.HRMS(ESI)C21H18BrPS(M+Na)+:理论值434.9942,实测值:434.9944。
实施例18
本实施例中，用等摩尔1n替换实施例1中的1a，用三溴乙酸(14.8mg,0.05mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中的在0℃搅拌12小时，其他步骤与实施例1相同，得到白色固体产物(S)-3na，产率77％，使用DaicelIC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇95:5,流速1mL/min,25℃,tr(次)＝18.2min,tr(主)＝11.5min，99.9％ee，[α]D 20-97(c0.200,CH2Cl2)。(S)-3na的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.08(ddd,J＝12.2,7.6,2.0Hz,2H),7.60(dd,J＝12.4,7.5Hz,2H),7.53-7.48(m,5H),7.42-7.23(m,10H),6.44-6.33(m,1H),5.20(dd,J＝10.2,3.0Hz,1H),5.09(dd,J＝17.0,4.4Hz,1H),4.64(dd,J＝10.9,9.0Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm)140.7,140.2(d,J＝3.2Hz),134.3(d,J＝5.3Hz),133.4(d,J＝4.1Hz),132.5(d,J＝9.0Hz),131.9(d,J＝9.5Hz),131.7(d,J＝3.0Hz),131.5(d,J＝77.2Hz),131.4(d,J＝2.9Hz),130.9(d,J＝77.7Hz),130.0(d,J＝5.6Hz),128.8,128.6(d,J＝11.8Hz),128.2(d,J＝12.0Hz),127.4,127.1,126.8(d,J＝2.6Hz),119.9(d,J＝12.6Hz),52.8(d,J＝48.9Hz).31P NMR(162MHz,CDCl3)δ(ppm)48.9.HRMS(ESI)C27H23PS(M+Na)+:理论值433.1150,实测值:433.1146。
实施例19
本实施例中，用等摩尔1o替换实施例1中的1a，用三溴乙酸(14.8mg,0.05mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中的在0℃搅拌12小时，其他步骤与实施例1相同，得到白色固体产物(S)-3oa，产率80％，使用DaicelIC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝21.2min,tr(主)＝19.1min，99％ee，[α]D 20-31(c 0.200,CH2Cl2)。(S)-3oa的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.06-8.01(m,2H),7.66-7.61(m,2H),7.55-7.47(m,3H),7.41-7.37(m,1H),7.33-7.28(m,2H),7.14-7.11(m,2H),6.99-6.98(m,1H),6.30-6.19(m,1H),5.17(dd,J＝10.1,3.3Hz,1H),5.04(dd,J＝17.0,4.5Hz,1H),4.80(dd,J＝11.1,8.6Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm)134.7(d,J＝4.9Hz),133.0(d,J＝4.1Hz),132.4(d,J＝9.0Hz),131.71(d,J＝3.8Hz),131.70(d,J＝9.1Hz),131.68(d,J＝79.0Hz),131.4(d,J＝3.1Hz),130.8(d,J＝77.9Hz),128.5(d,J＝11.8Hz),128.4(d,J＝3.9Hz),128.2(d,J＝12.0Hz),124.8,123.6(d,J＝7.7Hz),119.6(d,J＝12.3Hz),49.0(d,J＝50.7Hz).31P NMR(162MHz,CDCl3)δ(ppm)48.2.HRMS(ESI)C19H17PS2(M+Na)+:理论值363.0401,实测值:363.0405。
实施例20
本实施例中，用等摩尔1p替换实施例1中的1a，用三氟甲磺酸钪(48.5mg,0.1mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中的在0℃搅拌12小时，其他步骤与实施例1相同，得到白色固体产物(S)-3pa，产率97％，使用Daicel AD-H手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇90:10,流速1.0mL/min,25℃,tr(次)＝16.3min,tr(主)＝21.7min，99％ee，[α]D 20-83(c0.200,CH2Cl2)。(S)-3pa的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.07(dd,J＝12.6,7.2Hz,2H),7.74(d,J＝8.0Hz,2H),7.64-7.49(m,5H),7.38-7.33(m,3H),7.29-7.25(m,2H),6.40-6.28(m,1H),5.21(dd,J＝10.1,3.2Hz,1H),5.09(dd,J＝16.9,4.4Hz,1H),4.70(t,J＝9.9Hz,1H),2.53(s,3H).13C NMR(100MHz,CDCl3)δ(ppm)197.9,140.9(d,J＝4.9Hz),135.9(d,J＝2.7Hz),132.8(d,J＝4.4Hz),132.4(d,J＝8.9Hz),131.9(d,J＝2.4Hz),131.7(d,J＝9.6Hz),131.6(d,J＝3.1Hz),131.0(d,J＝79.0Hz),130.5(d,J＝78.8Hz),129.8(d,J＝5.6Hz),128.6(d,J＝11.7Hz),128.3(d,J＝12.1Hz),128.0(d,J＝1.7Hz),120.4(d,J＝12.6Hz),52.9(d,J＝48.4Hz),26.7.31P NMR(162MHz,CDCl3)δ(ppm)48.8.HRMS(ESI)C23H21OPS(M+Na)+:理论值399.0943,实测值:399.0944。
实施例21
本实施例中，用等摩尔1q替换实施例1中的1a，用三氟甲磺酸钪(97.0mg,0.2mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，其他步骤与实施例1相同，得到白色固体产物(R)-3qa，产率32％，使用Daicel AD-H手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:AD-H,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝9.0min,tr(主)＝10.6min，81％ee，[α]D 20+34(c 0.200,CH2Cl2)。(R)-3qa的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)7.98-7.93(m,2H),7.89-7.84(m,2H),7.51-7.39(m,6H),5.79-5.68(m,1H),5.12(dd,J＝10.4,3.9Hz,1H),4.93(dd,J＝17.1,5.2Hz,1H),3.30-3.22(m,1H),1.77-1.68(m,1H),1.54-1.38(m,2H),1.27-1.25(m,2H),1.21-1.16(m,11H),0.86(t,J＝6.9Hz,3H).13C NMR(100MHz,CDCl3)δ(ppm)133.2(d,J＝6.0Hz),131.9(d,J＝9.3Hz),131.8(d,J＝78.9Hz),131.65(d,J＝76.0Hz),131.6(d,J＝9.4Hz),131.56(d,J＝3.1Hz),131.3(d,J＝3.0Hz),128.7(d,J＝11.7Hz),128.3(d,J＝11.9Hz),120.4(d,J＝13.0Hz),45.7(d,J＝53.3Hz),32.0,29.6,29.5,29.4,29.2,27.6,27.5(d,J＝14.0Hz),22.8,14.3.31P NMR(162MHz,CDCl3)δ(ppm)48.9.HRMS(ESI)C24H33PS(M+H)+:理论值385.2113,实测值:385.2106。
实施例22
本实施例中，用等摩尔1r替换实施例1中的1a，用三氟甲磺酸钪(97.0mg,0.2mmol)替换实施例1中的三氟甲磺酸钪(19.7mg,0.04mmol)，其他步骤与实施例1相同，得到白色固体产物(R)-3ra，产率35％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇90:10,流速0.5mL/min,25℃,tr(次)＝15.4min,tr(主)＝14.3min，65％ee，[α]D 20+23(c 0.200,CH2Cl2)。(R)-3ra的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)7.98-7.92(m,2H),7.89-7.84(m,2H),7.54-7.40(m,6H),5.80-5.69(m,1H),5.14(dd,J＝10.3,3.8Hz,1H),4.96(dd,J＝17.1,5.1Hz,1H),3.45(t,J＝6.6Hz,2H),3.27(q,J＝10.0,9.6Hz,1H),1.81-1.65(m,3H),1.63-1.51(m,2H),1.42-1.33(m,1H).13C NMR(100MHz,CDCl3)δ(ppm)132.9(d,J＝6.0Hz),131.9(d,J＝9.0Hz),131.7(d,J＝2.5Hz),131.6(d,J＝9.5Hz),131.5(d,J＝78.7Hz),131.47(d,J＝2.6Hz),128.8(d,J＝11.6Hz),128.4(d,J＝11.8Hz),120.8(d,J＝12.9Hz),45.8(d,J＝53.7Hz),44.8,32.1,27.0,24.9(d,J＝14.5Hz).31P NMR(162MHz,CDCl3)δ(ppm)48.8.HRMS(ESI)C19H22ClPS(M+H)+:理论值371.0761,实测值371.0759。
实施例23
本实施例中，用等摩尔2b替换实施例1中的2a，用PE/DCM＝10/1～2/1作为洗脱剂替换实施例1中柱层析分离的洗脱剂PE/DCM＝5/1～1/1，其他步骤与实施例1相同，得到白色固体产物(S)-3ab，产率88％，使用Daicel ADH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ADH,254nm,正己烷/异丙醇99.5:0.5,流速0.5mL/min,25℃,tr(次)＝15.2min,tr(主)＝16.0min，99％ee，[α]D 20-57(c 0.200,CH2Cl2)。(S)-3ab的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)7.89(dd,J＝12.9,1.9Hz,2H),7.59(q,J＝1.8Hz,1H),7.40-7.39(m,2H),7.36(d,J＝1.8Hz,1H),7.20-7.17(m,2H),7.15-7.13(m,3H),6.47-6.36(m,1H),5.19(dd,J＝10.8,2.9Hz,1H),5.05(dd,J＝17.0,4.2Hz,1H),4.46(dd,J＝11.1,9.1Hz,1H),1.36(s,18H),1.20(s,18H).13C NMR(100MHz,CDCl3)δ(ppm)150.7(d,J＝11.4Hz),150.4(d,J＝11.6Hz),136.1(d,J＝4.9Hz),134.3(d,J＝4.0Hz),130.6(d,J＝78.1Hz),129.9(d,J＝77.2Hz),129.6(d,J＝5.5Hz),128.0(d,J＝1.4Hz),127.2(d,J＝2.9Hz),127.0(d,J＝9.6Hz),126.3(d,J＝10.1Hz),125.7(d,J＝3.1Hz),125.4(d,J＝3.2Hz),118.9(d,J＝12.4Hz),54.2(d,J＝47.8Hz),35.2(d,J＝21.2Hz),31.5(d,J＝17.0Hz).31PNMR(162MHz,CDCl3)δ(ppm)51.0.HRMS(ESI)C37H51PS(M+H)+:理论值559.3522,实测值:559.3519.
实施例24
本实施例中，用等摩尔2c替换实施例1中的2a，用PE/DCM＝10/1～2/1作为洗脱剂替换实施例1中柱层析分离的洗脱剂PE/DCM＝5/1～1/1，其他步骤与实施例1相同，得到白色固体产物(S)-3ac，产率92％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇95:5,流速0.5mL/min,25℃,tr(次)＝8.9min,tr(主)＝9.8min，99.3％ee，[α]D 20-84(c 0.200,CH2Cl2)。(S)-3ac的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)7.64(d,J＝12.4Hz,2H),7.27-7.24(m,2H),7.17-7.15(m,4H),7.08(d,J＝12.7Hz,2H),6.95(s,1H),6.38-6.27(m,1H),5.18(dd,J＝10.3,2.9Hz,1H),5.04(dd,J＝17.0,4.2Hz,1H),4.55(dd,J＝11.1,8.7Hz,1H),2.38(s,6H),2.17(s,6H).13C NMR(100MHz,CDCl3)δ(ppm)138.1(d,J＝12.5Hz),137.6(d,J＝12.5Hz),135.6(d,J＝5.2Hz),133.7(d,J＝4.2Hz),133.4(d,J＝3.0Hz),133.0(d,J＝3.0Hz),131.4(d,J＝78.0Hz),130.4(d,J＝77.1Hz),130.2(d,J＝9.0Hz),129.8(d,J＝5.5Hz),129.5(d,J＝9.4Hz),127.9(d,J＝2.4Hz),127.3(d,J＝3.1Hz),119.4(d,J＝12.5Hz),52.9(d,J＝48.6Hz),21.4(d,J＝25.0Hz).31P NMR(162MHz,CDCl3)δ(ppm)49.0.HRMS(ESI)C25H27PS(M+Na)+:理论值413.1463,实测值:413.1463。
实施例25
本实施例中，用等摩尔2d替换实施例1中的2a，用PE/DCM＝10/1～2/1作为洗脱剂替换实施例1中柱层析分离的洗脱剂PE/DCM＝5/1～1/1，其他步骤与实施例1相同，得到白色固体产物(S)-3ad，产率98％，使用Daicel ODH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ODH,254nm,正己烷/异丙醇90:10,流速1mL/min,25℃,tr(次)＝11.1min,tr(主)＝12.0min，99.7％ee，[α]D 20-103(c 0.200,CH2Cl2)。(S)-3ad的结构表征数据为：1HNMR(400MHz,CDCl3)δ(ppm)7.99-7.93(m,2H),7.47-7.42(m,2H),7.26-7.23(m,2H),7.18-7.15(m,3H),6.99(dd,J＝8.8,2.3Hz,2H),6.74(dd,J＝8.7,2.3Hz,2H),6.38-6.27(m,1H),5.16(dd,J＝10.4,3.1Hz,1H),5.03(dd,J＝17.1,4.4Hz,1H),4.49(dd,J＝11.2,8.9Hz,1H),3.83(s,3H),3.73(s,3H).13C NMR(100MHz,CDCl3)δ(ppm)162.2(d,J＝2.9Hz),161.9(d,J＝2.9Hz),135.6(d,J＝5.1Hz),134.3(d,J＝10.5Hz),133.8(d,J＝4.3Hz),133.6(d,J＝10.8Hz),129.6(d,J＝5.7Hz),128.0(d,J＝2.5Hz),127.3(d,J＝3.2Hz),123.1(d,J＝85.4Hz),122.0(d,J＝84.5Hz),119.4(d,J＝12.5Hz),114.0(d,J＝12.9Hz),113.6(d,J＝13.1Hz),55.4(d,J＝12.5Hz),53.6(d,J＝49.6Hz).31P NMR(162MHz,CDCl3)δ(ppm)47.6.HRMS(ESI)C23H23O2PS(M+Na)+:理论值417.1049,实测值:417.1051。
实施例26
本实施例中，用等摩尔2e替换实施例1中的2a，三氟甲磺酸钪(49.2mg,0.1mmol)替换实施例1中三氟甲磺酸钪(19.7mg,0.04mmol)，其他步骤与实施例1相同，得到白色固体产物(S)-3ae，产率87％，使用Daicel ODH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ODH,254nm,正己烷/异丙醇99:1,流速0.5mL/min,25℃,tr(次)＝10.2min,tr(主)＝11.7min，98％ee，[α]D 20+18(c 0.200,CH2Cl2)。(S)-3ae的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)7.49-7.47(m,2H),7.34-7.25(m,3H),6.57-6.46(m,1H),5.24(d,J＝10.1Hz,1H),5.17(dd,J＝17.3,3.3Hz,1H),4.03(t,J＝9.6Hz,1H),2.24-2.18(m,1H),2.13-2.07(m,1H),2.01-1.91(m,1H),1.88-1.82(m,3H),1.78-1.58(m,6H),1.49-0.97(m,10H).13CNMR(100MHz,CDCl3)δ(ppm)137.1(d,J＝5.1Hz),135.8(d,J＝3.9Hz),129.1(d,J＝4.9Hz),128.7,127.6(d,J＝1.3Hz),117.8(d,J＝11.5Hz),49.3(d,J＝40.6Hz),40.0(d,J＝43.4Hz),38.6(d,J＝44.2Hz),27.6(d,J＝3.8Hz),27.4(d,J＝3.0Hz),27.3,27.25(d,J＝3.0Hz),27.1(d,J＝10.6Hz),26.9(d,J＝3.8Hz),26.82,26.80(d,J＝4.2Hz),26.1(d,J＝16.2Hz).31P NMR(162MHz,CDCl3)δ(ppm)62.1.HRMS(ESI)C21H31PS(M+Na)+:理论值369.1776,实测值:369.1779。
实施例27
本实施例中，用等摩尔2f替换实施例1中的2a，三溴乙酸(14.8mg,0.05mmol)替换实施例1中三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中在0℃搅拌12小时，PE/Acetone＝50/1～10/1为洗脱剂替换实施例1中PE/DCM＝5/1～1/1为洗脱剂柱层析分离，其他步骤与实施例1相同，得到白色固体产物(S)-3af，产率75％，使用Daicel ADH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ADH,254nm,正己烷/异丙醇90:10,流速0.5mL/min,25℃,tr(次)＝18.5min,tr(主)＝20.6min)，99.9％ee，[α]D 20-108(c0.200,CH2Cl2)。(S)-3af的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.07(ddd,J＝12.3,7.7,2.0Hz,2H),7.59-7.47(m,5H),7.35-7.31(m,1H),7.26-7.21(m,2H),7.16-7.13(m,3H),6.40-6.29(m,1H),5.17(dd,J＝10.3,3.1Hz,1H),5.06(dd,J＝17.0,4.4Hz,1H),4.59(t,J＝9.9Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm)138.7(d,J＝3.7Hz),138.2(d,J＝3.6Hz),134.8(d,J＝5.1Hz),133.8(d,J＝9.8Hz),133.1(d,J＝10.5Hz),133.0(d,J＝4.1Hz),129.9(d,J＝80.0Hz),129.2(d,J＝79.2Hz),128.9(d,J＝12.4Hz),128.5(d,J＝12.6Hz),128.4(d,J＝1.7Hz),127.8(d,J＝2.7Hz),120.2(d,J＝12.9Hz),53.1(d,J＝49.4Hz).31P NMR(162MHz,CDCl3)δ(ppm)47.7.HRMS(ESI)C21H17Cl2OP(M+Na)+:理论值425.0058,实测值:425.0057。
实施例28
本实施例中，用等摩尔2g替换实施例1中的2a，三溴乙酸(14.8mg,0.05mmol)替换实施例1中三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中在0℃搅拌12小时，其他步骤与实施例1相同，得到白色固体产物(S)-3ag，产率84％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇80:20,流速1mL/min,25℃,tr(次)＝12.9min,tr(主)＝15.4min，99.9％ee，[α]D 20-117(c 0.200,CH2Cl2)。(S)-3ag的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)7.92(ddd,J＝14.6,7.8,1.7Hz,1H),7.82(ddd,J＝15.8,7.8,1.8Hz,1H),7.40(t,J＝7.7Hz,1H),7.33-7.25(m,3H),7.08-6.97(m,4H),6.88-6.81(m,2H),6.77-6.63(m,2H),5.27(d,J＝10.2Hz,1H),5.21-5.14(m,2H),3.61(s,3H),3.52(s,3H).13C NMR(100MHz,CDCl3)δ(ppm)160.0(d,J＝1.8Hz),159.3(d,J＝1.7Hz),137.6(d,J＝4.7Hz),136.8(d,J＝3.5Hz),135.2(d,J＝8.8Hz),133.6(d,J＝8.0Hz),132.9(d,J＝1.5Hz),132.7(d,J＝1.6Hz),129.3(d,J＝6.4Hz),127.7(d,J＝1.5Hz),126.9(d,J＝3.5Hz),123.3(d,J＝80.6Hz),120.8(d,J＝82.6Hz),120.78(d,J＝12.3Hz),120.6(d,J＝12.9Hz),117.7(d,J＝13.8Hz),111.8(d,J＝6.1Hz),110.6(d,J＝6.2Hz),55.4(d,J＝21.1Hz),51.0(d,J＝52.2Hz).31PNMR(162MHz,CDCl3)δ(ppm)46.4.HRMS(ESI)C23H23O2PS(M+Na)+:理论值417.1049,实测值:417.1051。
实施例29
本实施例中，用等摩尔2h替换实施例1中的2a，三溴乙酸(14.8mg,0.05mmol)替换实施例1中三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中在0℃搅拌12小时，PE/EA＝50/1～10/1为洗脱剂替换实施例1中PE/DCM＝5/1～1/1为洗脱剂柱层析分离，其他步骤与实施例1相同，得到白色固体产物3ah，产率70％，dr＝1.3:1。
白色固体产物3ah的异构体1使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇90:10,流速0.5mL/min,25℃,tr(次)＝24.2min,tr(主)＝26.6min，99％ee，[α]D 20-15(c 0.200,CH2Cl2)。结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)7.87-7.81(m,2H),7.55-7.45(m,3H),7.37-7.28(m,5H),6.21-6.10(m,1H),5.11(dd,J＝10.1,4.0Hz,1H),4.85(dd,J＝16.9,4.7Hz,1H),3.96(dd,J＝12.3,9.1Hz,1H),1.78(d,J＝12.7Hz,3H).13C NMR(100MHz,CDCl3)δ(ppm)135.5(d,J＝5.6Hz),132.8(d,J＝5.2Hz),131.7(d,J＝1.6Hz),131.5(d,J＝9.5Hz),131.4(d,J＝76.1Hz),129.1(d,J＝5.5Hz),128.6(d,J＝1.7Hz),128.4(d,J＝11.6Hz),127.9(d,J＝2.7Hz),119.3(d,J＝12.2Hz),56.1(d,J＝46.4Hz),18.9(d,J＝57.4Hz).31P NMR(162MHz,CDCl3)δ(ppm)45.9.HRMS(ESI)C16H17PS(M+Na)+:理论值295.0681,实测值:295.0683。
白色固体产物3ah的异构体2使用Daicel ADH手性柱色谱柱，采用高效液相色谱法测定其ee值。(HPLC:IC,254nm,正己烷/异丙醇90:10,流速0.5mL/min,25℃,tr(次)＝13.8min,tr(主)＝12.6min，99.6％ee，[α]D 20-58(c0.200,CH2Cl2)。结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)7.63-7.57(m,2H),7.47-7.42(m,1H),7.38-7.33(m,2H),7.17-7.10(m,3H),7.00-6.96(m,2H),6.41-6.30(m,1H),5.36(dd,J＝10.1,3.8Hz,1H),5.30(dd,J＝16.9,4.6Hz,1H),3.95(dd,J＝11.9,9.6Hz,1H),2.02(d,J＝12.5Hz,3H).13C NMR(100MHz,CDCl3)δ(ppm)135.2(d,J＝6.0Hz),133.1(d,J＝5.3Hz),131.7(d,J＝2.7Hz),131.4(d,J＝9.6Hz),130.9(d,J＝79.4Hz),128.9(d,J＝5.1Hz),128.3(d,J＝11.9Hz),128.1(d,J＝2.5Hz),127.4(d,J＝3.5Hz),119.8(d,J＝12.7Hz),56.7(d,J＝46.3Hz),18.7(d,J＝57.8Hz).31P NMR(162MHz,CDCl3)δ(ppm)45.0.HRMS(ESI)C16H17PS(M+Na)+:理论值295.0681,实测值:295.0685。
实施例30
本实施例中，用等摩尔2i替换实施例1中的2a，4-硝基苯磺酸(10.2mg,0.02mmol)替换实施例1中三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中在0℃搅拌12小时，PE/EA＝3/1～1/1为洗脱剂替换实施例1中PE/DCM＝5/1～1/1为洗脱剂柱层析分离，其他步骤与实施例1相同，得到白色固体产物(S)-3ai，产率88％，使用Daicel ID手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ID,254nm,正己烷/异丙醇80:20,流速0.5mL/min,25℃,tr(次)＝41.2min,tr(主)＝45.0min，99％ee。(S)-3ai的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)7.97–7.79(m,2H),7.52(dd,J＝17.1,9.0Hz,5H),7.40–7.07(m,8H),6.24(td,J＝16.8,9.1Hz,1H),5.15(dd,J＝10.0,2.0Hz,1H),5.04(dd,J＝17.0,3.4Hz,1H),4.26(t,J＝9.2Hz,1H).31P NMR(162MHz,CDCl3)δ(ppm)31.66。
实施例31
本实施例中，用等摩尔2j替换实施例1中的2a，4-硝基苯磺酸(10.2mg,0.02mmol)替换实施例1中三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中在0℃搅拌12小时，PE/EA＝3/1～1/1为洗脱剂替换实施例1中PE/DCM＝5/1～1/1为洗脱剂柱层析分离，其他步骤与实施例1相同，得到白色固体产物(S)-3aj，产率90％，使用Daicel ADH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ADH,254nm,正己烷/异丙醇90:10,流速1mL/min,25℃,tr(次)＝10.2min,tr(主)＝11.6min，99％ee。(S)-3aj的结构表征数据为：1HNMR(400MHz,CDCl3)δ(ppm)δ7.46(d,J＝11.1Hz,2H),7.30(d,J＝7.9Hz,2H),7.25–7.12(m,4H),7.09(d,J＝11.3Hz,2H),6.96(s,1H),6.30–6.14(m,1H),5.15(dd,J＝10.2,2.8Hz,1H),5.03(dd,J＝17.0,3.9Hz,1H),4.21(t,J＝9.2Hz,1H),2.36(s,6H),2.19(s,6H).31PNMR(162MHz,CDCl3)δ(ppm)32.25。
实施例32
本实施例中，用等摩尔2k替换实施例1中的2a，4-硝基苯磺酸(10.2mg,0.02mmol)替换实施例1中三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中在0℃搅拌12小时，PE/EA＝2/1～1/1为洗脱剂替换实施例1中PE/DCM＝5/1～1/1为洗脱剂柱层析分离，其他步骤与实施例1相同，得到白色固体产物(S)-3ak，产率91％，使用Daicel ADH手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:ADH,254nm,正己烷/异丙醇70:30,流速1mL/min,25℃,tr(次)＝23.3min,tr(主)＝36.1min，99％ee。(S)-3ak的结构表征数据为：1HNMR(400MHz,CDCl3)δ(ppm)δ7.81–7.69(m,2H),7.48–7.36(m,2H),7.32–7.13(m,5H),6.99(d,J＝6.9Hz,2H),6.77(d,J＝6.9Hz,2H),6.23(td,J＝16.8,9.1Hz,1H),5.15(dd,J＝10.0,2.0Hz,1H),5.03(dd,J＝17.0,3.5Hz,1H),4.17(t,J＝9.6Hz,1H),3.83(s,3H),3.73(s,3H).31P NMR(162MHz,CDCl3)δ(ppm)31.76。
实施例33
本实施例中，用等摩尔2l替换实施例1中的2a，4-硝基苯磺酸(10.2mg,0.02mmol)替换实施例1中三氟甲磺酸钪(19.7mg,0.04mmol)，在0℃搅拌6小时替换实施例1中在0℃搅拌12小时，PE/EA＝4/1～2/1为洗脱剂替换实施例1中PE/DCM＝5/1～1/1为洗脱剂柱层析分离，其他步骤与实施例1相同，得到白色固体产物(S)-3al，产率98％，使用Daicel IC手性柱色谱柱，采用高效液相色谱法测定其ee值。HPLC:IC,254nm,正己烷/异丙醇90:10,流速1mL/min,25℃,tr(主)＝19.8min,tr(次)＝25.2min，99％ee。(S)-3al的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)δ7.90–7.72(m,2H),7.58–7.39(m,4H),7.36–7.17(m,7H),6.20(td,J＝16.8,9.2Hz,1H),5.19(dd,J＝10.1Hz,1H),5.06(dd,J＝16.9,3.7Hz,1H),4.19(t,J＝9.1Hz,1H).31P NMR(162MHz,CDCl3)δ(ppm)30.62。
本发明方法合成的手性烯丙基硫膦化合物通过铱催化剂进行氢化还原，脱硫后生成一种有价值的手性钳形金属配合物的合成前体：双膦硼烷络合物，双膦硼烷络合物可用于钳型钯催化剂的合成。下面以(S,S)-3ia为例进行说明：
将(S,S)-3ia(59.1,0.1mmol)和([Ir(cod)(PCy3)(Py)]PF6(16.1mg,0.02mmol)的DCE(2mL)溶液在70℃下用20atm H2氢化28小时，冷却至室温后，混合物通过硅藻土过滤，真空浓缩，残余物通过柱层析纯化(PE/DCM＝5/1～1/1)，得到白色固体(S,S)-4，产率95％，dr＝10:1，[α]D 29-186(c 0.100,CH2Cl2)。(S,S)-4的结构表征数据为：1H NMR(400MHz,CDCl3)δ(ppm)8.10-8.05(m,4H),7.56-7.50(m,6H),7.49-7.43(m,4H),7.27-7.15(m,9H),6.93(t,J＝7.7Hz,1H),3.58(ddd,J＝12.4,9.7,3.1Hz,2H),2.20-2.10(m,2H),1.86-1.76(m,2H),0.67(t,J＝7.3Hz,6H).13C NMR(100MHz,CDCl3)δ(ppm)135.0(d,J＝6.0Hz),132.1(d,J＝82.3Hz),132.0(d,J＝75.5Hz),131.9(d,J＝9.3Hz),131.8(d,J＝75.4Hz),131.7(d,J＝9.9Hz),131.0(d,J＝2.7Hz),128.8(d,J＝4.7Hz),128.75(d,J＝11.5Hz),128.2(d,J＝12.1Hz),127.9(d,J＝2.7Hz),48.7(d,J＝51.2Hz),23.7,12.5(d,J＝15.7Hz).31P NMR(162MHz,CDCl3)δ(ppm)50.5(minor diast.),50.3(major diast.).HRMS(ESI)C36H36P2S2(M+Na)+:理论值617.1626,实测值:617.1624。
向配备有磁子的10mL Schlenk管中加入(S,S)-4(29.7mg,0.05mmol)，在氮气氛围下，将DME(2mL)、MeOTf(19.7mg,0.12mmol)加入管中并在室温下搅拌4小时，然后在0℃将上述反应混合物加入到硼氢化钠(11.3mg，0.3mmol)的DME(0.5mL)溶液中，升温至室温并搅拌3小时。反应结束后用水(1mL)淬灭，混合物用乙酸乙酯萃取，合并的有机相用无水硫酸镁干燥，真空浓缩，残余物通过柱层析纯化(PE/DCM＝5:1)，得到白色固体产物(S,S)-5(CAS:1224869-06-0)，产率83％，dr＝10:1。(S,S)-5可用于钳型钯催化剂的合成，此钳型钯催化剂可用于催化不对称氢磷化反应合成手性磷化合物(Org.Lett.,2011，Vol(13)，5824–5826)。(S,S)-5的结构表征数据为：1HNMR(400MHz,CDCl3)δ(ppm)7.89-7.83(m,4H),7.54-7.47(m,6H),7.34-7.26(m,6H),7.20-7.16(m,4H),6.97-6.96(m,4H),3.38(ddd,J＝15.3,12.1,3.0Hz,2H),2.05-1.95(m,2H),1.89-1.77(m,2H),1.31-0.69(m,6H),0.67(t,J＝7.3Hz,6H)。
Claims (8)
1.一种手性烯丙基膦化合物的合成方法，其特征在于，在氮气气氛下，将式1所示取代烯丙醇与式2所示二取代硫膦或氧膦化合物在金属铱催化剂、手性亚磷酰胺配体及添加剂的作用下，在有机溶剂中-20～50℃反应6～24小时，生成式3所示手性烯丙基膦化合物；
其中，R1选自苯基、C1～C8烷基取代苯基、C1～C5烷氧基取代苯基、硝基取代苯基、氰基取代苯基、三氟甲基取代苯基、卤代苯基、酯基取代苯基、烯基取代苯基、酰基取代苯基、联苯基、萘基、噻吩基、烷基、卤代烷基、苯基取代烷基中任意一种；X代表O或S；R2、R3各自独立的选自苯基、C1～C8烷基取代苯基、C1～C5烷氧基取代苯基、三氟甲基取代苯基、卤代苯基、萘基、噻吩基、C1～C8烷基中任意一种；
所述手性亚磷酰胺配体的结构式为下述任意一种：
所述添加剂为路易斯酸或布朗斯特酸。
2.根据权利要求1所述的手性烯丙基膦化合物的合成方法，其特征在于，所述R1选自苯基，3-甲基苯基、4-甲基苯基、4-苯基苯基、3-甲氧基亚甲氧基苯基、4-甲酸甲酯苯基、4-甲氧基苯基、4-硝基苯基、4-氰基苯基、3-硝基苯基、3-氰基苯基、4-三氟甲基苯基、4-乙烯苯基、4-氯苯基、3-氯苯基、4-乙酰基苯基、1-萘基、2-萘基、2-甲氧基苯基、3-羟基苯基、2-溴苯基、3-噻吩基、2-苯基乙基、正壬基、正己基、4-氯丁基中任意一种；R2、R3各自独立的选自4-甲基苯基、4-氯苯基、3,5-二甲基苯基、3,5-二叔丁基苯基、2-甲氧基苯基、环己基、甲基中任意一种。
3.根据权利要求1所述的手性烯丙基膦化合物的合成方法，其特征在于，所述有机溶剂为二氯乙烷、二氯甲烷、四氢呋喃、甲苯、甲醇中任意一种。
4.根据权利要求1所述的手性烯丙基膦化合物的合成方法，其特征在于，所述金属铱催化剂为1,5-环辛二烯氯化铱或双环辛烯氯化铱。
5.根据权利要求1所述的手性烯丙基膦化合物的合成方法，其特征在于，所述路易斯酸为三氟甲磺酸钪、三氟甲磺酸铜、三氟甲磺酸锌中任意一种。
6.根据权利要求1所述的手性烯丙基膦化合物的合成方法，其特征在于，所述布朗斯特酸为三氟乙酸、三氯乙酸、三溴乙酸、乙酸、苯甲酸、对甲苯磺酸、对硝基苯磺酸、二(苯磺酰)胺、二苯酚基磷酸中任意一种。
7.根据权利要求1所述的手性烯丙基膦化合物的合成方法，其特征在于，所述取代烯丙醇、二取代硫膦或氧膦化合物的摩尔比是1:2.5～2:1，所述金属铱催化剂的加入量为二取代硫膦或氧膦化合物摩尔量的2.5％～5％，手性亚磷酰胺配体的加入量为金属铱催化剂摩尔量的3～5倍，添加剂的加入量为二取代硫膦或氧膦化合物摩尔量的10％～100％。
8.根据权利要求1所述的手性烯丙基膦化合物的合成方法，其特征在于，所述在有机溶剂中0℃反应6～12小时。
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