CN114380863A - 金鸡纳碱衍生的nnp配体及其制备方法与用途 - Google Patents
金鸡纳碱衍生的nnp配体及其制备方法与用途 Download PDFInfo
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- CN114380863A CN114380863A CN202111546885.1A CN202111546885A CN114380863A CN 114380863 A CN114380863 A CN 114380863A CN 202111546885 A CN202111546885 A CN 202111546885A CN 114380863 A CN114380863 A CN 114380863A
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- ligand
- nnp
- phenyl
- reaction
- inositol
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- 239000003446 ligand Substances 0.000 title claims abstract description 56
- 241000157855 Cinchona Species 0.000 title claims abstract description 11
- 235000021513 Cinchona Nutrition 0.000 title claims abstract description 9
- 229930013930 alkaloid Natural products 0.000 title abstract description 6
- 150000003797 alkaloid derivatives Chemical class 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- CDAISMWEOUEBRE-UHFFFAOYSA-N inositol Chemical compound OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 11
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 7
- 229960000367 inositol Drugs 0.000 claims description 22
- -1 4-tert-butylphenyl Chemical group 0.000 claims description 21
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 21
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 12
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 12
- 239000002808 molecular sieve Substances 0.000 claims description 9
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical class C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 5
- BESNXTPHHWCFPI-UHFFFAOYSA-N copper;triphenylphosphane Chemical compound [Cu].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 BESNXTPHHWCFPI-UHFFFAOYSA-N 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 229940126062 Compound A Drugs 0.000 claims description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910052710 silicon Inorganic materials 0.000 claims description 3
- 239000010703 silicon Substances 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
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 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
- 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
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 238000006392 deoxygenation reaction Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])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 1
- 239000000126 substance Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 238000012512 characterization method Methods 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 238000004679 31P NMR spectroscopy Methods 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- MJWVCJUSRGLHFO-UHFFFAOYSA-N cyclohexanesulfonyl chloride Chemical compound ClS(=O)(=O)C1CCCCC1 MJWVCJUSRGLHFO-UHFFFAOYSA-N 0.000 description 4
- 238000010596 desymmetrization reaction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- INAPMGSXUVUWAF-GCVPSNMTSA-N [(2r,3s,5r,6r)-2,3,4,5,6-pentahydroxycyclohexyl] dihydrogen phosphate Chemical compound OC1[C@H](O)[C@@H](O)C(OP(O)(O)=O)[C@H](O)[C@@H]1O INAPMGSXUVUWAF-GCVPSNMTSA-N 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 229960000948 quinine Drugs 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KWEKXPWNFQBJAY-UHFFFAOYSA-N (dimethyl-$l^{3}-silanyl)oxy-dimethylsilicon Chemical compound C[Si](C)O[Si](C)C KWEKXPWNFQBJAY-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- LRLQQERNMXHASR-UHFFFAOYSA-N 2-diphenylphosphanylpropan-2-yl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)(C)P(C=1C=CC=CC=1)C1=CC=CC=C1 LRLQQERNMXHASR-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- GJWAPAVRQYYSTK-UHFFFAOYSA-N [(dimethyl-$l^{3}-silanyl)amino]-dimethylsilicon Chemical compound C[Si](C)N[Si](C)C GJWAPAVRQYYSTK-UHFFFAOYSA-N 0.000 description 1
- YUWBVKYVJWNVLE-UHFFFAOYSA-N [N].[P] Chemical compound [N].[P] YUWBVKYVJWNVLE-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 125000005577 anthracene group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
-
- 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 Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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Abstract
本发明属于有机化学配体领域，具体是一种金鸡纳碱衍生的NNP配体，具有通式Ⅰ的结构或其互变异构体、对映异构体、非对映异构体：
Description
技术领域
本发明属于有机化学配体领域，具体是一种金鸡纳碱衍生的NNP配体及其制备方法与用途。
背景技术
金鸡纳碱(奎宁)及其类似物是一类在自然界中广泛存在的天然手性产物，基于其空间结构复杂以及多配位点等特点，之前一直被用于有机小分子催化的不对称反应中。近年来，随着过渡金属不对称催化领域快速发展，各类新手性配体骨架的需求日益增加。奎宁及其类似物衍生的氮氮磷配体含有一个三级胺、一个三价磷以及一个酰胺结构(在碱的作用下可以被去质子化生成酰胺负离子)，这类配体不仅可以提供氢键等作用，还可以与过渡金属配位，产生手性金属络合物用以催化反应。
肌醇磷酸酯广泛纯在于动植物及微生物体内，在细胞信号传导中起到至关重要的作用。手性肌醇磷酸酯的合成在生物化学中非常重要，目前手性肌醇磷酸酯的合成主要是通过经典的拆分方法，其催化不对称合成的报道非常少，并且主要集中于1,3-去对称化，而4,6-去对称化仅有一例报道，Miller等人报道了多肽催化的1,3,5-位保护的肌醇底物的4,6-去对称化不对称磷酰基化反应，但是得到的6位羟基磷酰基化的产物ee值并不是十分理想(71％ee)，此外，由于使用的是多肽类催化剂，其催化剂的对映异构体难以获得，因此难以得到4位羟基磷酰基化为主的产物，如下式所示：
由于上述生物催化存在的一些问题，因此发展新的化学催化体系来实现肌醇的4,6-去对称化反应，以高对映选择性得到4位/6位羟基保护的产物是非常有必要的。
发明内容
本发明的目的是提供一种结构新颖的金鸡纳碱衍生的NNP配体。
本发明的另一目的是提供该NNP配体的制备方法。
本发明的另一目的是将该NNP配体用于肌醇4,6-去对称化不对称磺酰基化反应。
为达到上述目的之一，本发明采用以下技术方案；
本发明的第一方面，一种金鸡纳碱衍生的NNP配体，具有通式Ⅰ的结构或其互变异构体、对映异构体、非对映异构体：
其中，R选自苯基、萘基，或者烷基、烷氧基、三氟甲基取代的苯基。
进一步地，所述R选自苯基、萘基，或者(C1～C4)烷基、(C1～C4)烷氧基、三氟甲基取代的苯基。
进一步地，所述R选自苯基、萘基，或者甲基、异丙基、叔丁基、甲氧基、三氟甲基取代的苯基。
进一步地，所述R选自苯基、2-萘基、4-甲基苯基、4-叔丁基苯基、4-甲氧基苯基、3,5-二三氟甲基苯基、3,5-二叔丁基苯基、2,4,6-三甲基苯基、2,4,6-三异丙基苯基。
本发明的第二方面，一种NNP配体的制备方法，包括以下步骤：
化合物S1和亚磷酸二乙酯反应，得到中间体S2；
中间体S2脱氧得到中间体S3；
中间体S3和邻溴苯甲醛反应，得到中间体S4；
中间体S4和奎宁衍生物S5进行缩合反应，得到产物；
R如权利要求1～4所定义。
本发明的第三方面，NNP配体在肌醇不对称磺酰基化反应的应用。
进一步地，所述肌醇不对称磺酰基化反应包括：
使用NNP配体，使化合物A与R3SO2Cl反应制备化合物B的步骤，
其中，R1为氢、烷基或芳基；R2为硅基、苄基、酰基或磺酰基；R3为烷基、环烷基或芳基。
进一步地，R1为氢、(C1～C4)烷基或苯基；R2为硅基或酰基；R3为(C4～C7)环烷基或苯基。
进一步地，R1为甲基或苯基；R2为乙酰基或TBS；R3为环己基或苯基。
进一步地，所述肌醇不对称磺酰基化反应加入双三苯基膦硼氢化亚铜、碳酸银和分子筛。
进一步地，所述化合物A与R3SO2Cl的摩尔比为1:(1～3)。
进一步地，相对于化合物A，所述双三苯基膦硼氢化亚铜的用量为1～30mol％；所述L配体的用量为2～30mol％；所述碳酸银的用量为30～100mol％，即当化合物A的用量为1mol时，双三苯基膦硼氢化亚铜的用量为0.01～0.3mol，L配体的用量为0.02～0.3mol，碳酸银的用量为0.3～1mol。
进一步地，所述肌醇不对称磺酰基化反应的温度为-10℃～室温，溶剂为二氯甲烷、二氯乙烷、氯仿或四氯化碳。
本发明所用的“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。烷基基团的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基、3-甲基戊基。
本发明所用的“烷氧基”是指-O-烷基基团，其中烷基如上所定义。本文所用烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基。烷氧基还包括取代烷氧基。烷氧基可任选被卤素取代一次或多次。
本发明所用的“环烷基”指非芳族碳环，其通常具有3至8个环碳原子。所述环可以是饱和的或具有一个或更多个碳-碳双键。环烷基基团的实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基或环庚基。
本发明所用的“芳基”是指5～12个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳基的非限制性实例有：苯环、萘环、蒽环。
本文所用的“苄基”指C6H5CH2-。
本文所用的“磺酰基”指-S(＝O)2-，磺酰基的非限制性实例有：对甲苯磺酰基、对溴苯磺酰基、硝基苯磺酰基、甲磺酰基、三氟甲磺酰基、5-(二甲氨基)萘-1-磺酰基。
本文所用的“酰基”指R-C(＝O)-，R指烷基、芳基，烷基、芳基的定义如本文所述，酰基的非限制性实例有：邻苯二甲酰基、特戊酰基、乙酰基、苯甲酰基。
本文所用的“硅基”指R1R2R3Si-O-，R1、R2、R3指烷基或苯基，烷基的定义如本文所述，硅基的非限制性实例有：三甲基硅基(TMS)、叔丁基二苯基硅基(TBDPS)、叔丁基二甲基硅基(TBS/TBDMS)和三异丙基硅基(TIPS)。
本文所述“取代的苯基”的“取代”可以是单取代，也可以是多取代，“取代的苯基”包括：(1)苯环有一个取代基；(2)苯环有两个及两个以上相同或不同取代基。取代的位置可以是苯环2、3、4、5、6的任意位置。
本发明具有以下有益效果：
本发明合成了一类结构新颖的金鸡纳碱衍生的NNP配体，具有烷基胺结构，可以将之用于催化肌醇不对称磺酰基化反应，在立体选择性与反应效率方面都具有优势，反应的收率和对映选择性高(收率60％以上，对映体过量ee值可达91％)，能获得很高对映体过量的产物，同时改变手性配体的绝对构型，则可以得到产物的另一个对映异构体，反应条件比较温和，可重复性较好，易于进行工业化扩大合成，具有很好的应用前景。
具体实施方式
除非另有说明，化学品均购自商业化产品并且不经进一步纯化。实验中使用的二氯甲烷等溶剂均为无水溶剂。薄层色谱分析(TLC)使用60F254硅胶板。硅胶柱层析使用青岛海洋硅胶(粒径0.040-0.063mm)。TLC显色采用UV光(254nm)或碘。NMR图谱使用BrukerDPX400或DPX 500核磁共振仪表征，1HNMR为400或500MHz，31PNMR为162MHz，溶剂为氘代氯仿，以四甲基硅烷(TMS)为内标。化学位移的单位是ppm，耦合常数的单位是Hz。在1HNMR中，δ表示化学位移，s表示单峰，d表示双峰，t表示三重峰，q表示四重峰，p表示五重峰，m表示多重峰，br表示宽峰。
实施例1
配体的合成
上述配体可以按照以下路线合成：
步骤1：在0℃下向格式试剂S1(3.0mmol)的四氢呋喃溶液中缓慢滴加亚磷酸二乙酯(1.0mmol)。然后将反应液恢复至室温并继续搅拌12小时。反应完全后，反应液通过硅胶柱色谱(石油醚与乙酸乙酯比例为50:1)直接进行纯化，得到S2(40～80％产率)。
步骤2：在室温下，向S2(1.0mmol)的甲苯溶液中加入三氟甲磺酸铜(0.1mmol)和1,1,3,3-四甲基二硅氧烷TMDS(2.0mmol)。将反应混合物搅拌并加热回流12小时。冷却至室温后，减压条件下除去甲苯溶剂，得到粗产物S3，直接进行下一步反应。
步骤3：将上一步得到的粗产物S3溶解到二甲基亚砜中，随后加入醋酸钯(0.1mmol)、双二苯基膦丙烷(0.1mmol)、二异丙基乙基胺(1.0mmol)和邻溴苯甲醛(1.0mmol)。将反应混合物脱气并加热(100℃)搅拌24小时。冷却至室温并加入乙酸乙酯(100mL)和水(50mL)，有机层用水洗4次后用无水硫酸钠干燥。过滤并真空浓缩。由此获得的残余物通过硅胶柱色谱法(石油醚与乙酸乙酯比例为5:1)纯化，得到S4(50～80％收率)。
步骤4：将S4溶解在乙醇中，加入S5并加热回流10小时，随后冷却至室温并加入硼氢化钠，在室温下反应6小时后加入丙酮(50mL)淬灭反应，真空浓缩后加入二氯甲烷(100mL)和饱和氯化铵(100mL)，有机层用无水硫酸钠干燥，过滤并真空浓缩。由此获得的残余物通过硅胶柱色谱法(石油醚与乙酸乙酯比例为1:1)纯化，得到配体I(40～70％收率)。
配体L1的表征数据：
1H NMR(400MHz,CDCl3)δ9.33(s,1H×0.3),9.00–8.84(m,1H),8.76(s,1H×0.3),8.17–8.15(m,2H+1H×0.3),7.91–7.78(m,1H),7.73–7.69(m,1H+1H×0.3),7.58–7.49(m,1H+1H×0.3),7.35–7.05(m,13H+14H×0.3),6.89–6.80(m,1H+1H×0.3),5.77–5.54(m,1H+1H×0.3),4.98–4.76(m,2H+2H×0.3),4.60(d,J＝9.5Hz,1H),3.98–3.84(m,2H×0.3),3.79(d,J＝12.8Hz,1H),3.51(d,J＝13.1Hz,1H+1H×0.3),3.40(s,1H×0.3),3.23–3.04(m,1H+2H×0.3),3.04–2.76(m,4H),2.76–2.41(m,3H),2.19(s,1H+1H×0.3),1.51(s,4H+2H×0.3),1.20–1.02(m,1H+2H×0.3),0.91–0.63(m,2H)。
13C NMR(100MHz,CDCl3)δ150.6,148.6,148.2,144.7,144.4,141.8,136.9,136.8,136.6,135.7,135.5,133.8,133.7,133.6,133.5,130.4,129.44,129.38,129.0,128.8,128.7,128.5,128.44,128.41,128.34,128.28,127.2,126.2,122.7,120.1,114.1,69.2,62.4,58.3,57.0,56.0,50.0,49.8,40.9,39.9,29.2,28.1,27.5,26.8,25.2。
31P NMR(162MHz,CDCl3)δ-16.3。
配体L2的表征数据：
1H NMR(400MHz,CDCl3)δ9.43(s,1H×0.3),9.10–8.95(m,1H),8.85(s,1H×0.3),8.22–8.11(m,2H+1H×0.3),7.98–7.86(m,1H),7.83–7.69(m,1H+1H×0.3),7.68–7.59(m,1H+1H×0.3),7.54–7.23(m,12H+13H×0.3),7.01–6.86(m,1H+1H×0.3),5.77–5.54(m,1H+1H×0.3),4.98–4.73(m,2H+2H×0.3),4.20(d,J＝9.5Hz,1H),4.08–3.89(m,2H×0.3),3.85(d,J＝12.8Hz,1H),3.61(d,J＝13.1Hz,1H+1H×0.3),3.48(s,1H×0.3),3.34–3.24(m,1H+2H×0.3),3.25–2.95(m,4H),2.89–2.78(m,3H),2.69(s,3H+3H×0.3),2.09(s,1H+1H×0.3),1.70(s,4H+2H×0.3),1.32–1.12(m,1H+2H×0.3),0.95–0.68(m,2H)。
13C NMR(100MHz,CDCl3)δ152.6,148.9,149.2,145.1,145.0,141.9,137.1,137.0,136.9,135.9,135.8,134.0,133.8,133.7,133.6,130.6,129.8,129.5,129.3,128.9,128.9,128.7,128.6,128.5,128.4,128.3,127.6,126.7,122.9,120.4,114.6,69.8,62.7,58.6,57.4,56.5,50.7,49.9,40.9,39.9,29.8,28.5,27.8,27.0,25.8,21.8。
31P NMR(162MHz,CDCl3)δ-16.6。
配体L3的表征数据：
1H NMR(400MHz,CDCl3)δ9.41(s,1H×0.3),9.11–8.98(m,1H),8.87(s,1H×0.3),8.35–8.21(m,2H+1H×0.3),8.14–7.99(m,1H),7.93–7.81(m,1H+1H×0.3),7.74–7.61(m,1H+1H×0.3),7.54–7.33(m,12H+13H×0.3),7.21–6.97(m,1H+1H×0.3),5.86–5.64(m,1H+1H×0.3),4.98–4.81(m,2H+2H×0.3),4.34(d,J＝9.5Hz,1H),4.43–3.98(m,2H×0.3),3.91(d,J＝12.8Hz,1H),3.71(d,J＝13.1Hz,1H+1H×0.3),3.53(s,1H×0.3),3.43–3.24(m,1H+2H×0.3),3.34–2.99(m,4H),2.96–2.86(m,3H),2.72(s,3H+3H×0.3),2.29(s,1H+1H×0.3),1.80(s,4H+2H×0.3),1.42(s,9H+9H×0.3),1.39–1.21(m,1H+2H×0.3),0.96–0.69(m,2H)。
13C NMR(100MHz,CDCl3)δ152.8,148.9,149.2,145.3,145.1,141.9,137.3,137.2,136.9,136.0,135.8,134.4,133.9,133.8,133.7,130.9,129.8,129.8,129.3,129.0,128.9,128.7,128.6,128.5,128.4,128.3,127.8,126.8,123.2,120.1,114.7,69.9,62.9,58.6,57.7,56.9,50.5,49.9,40.9,39.9,35.8,31.4,29.9,28.2,27.9,27.3,25.8。
31P NMR(162MHz,CDCl3)δ-16.2。
配体L4的表征数据：
1H NMR(400MHz,CDCl3)δ9.40(s,1H×0.3),9.00–8.83(m,1H),8.79(s,1H×0.3),8.27–8.18(m,2H+1H×0.3),7.96–7.83(m,1H),7.80–7.72(m,1H+1H×0.3),7.68–7.59(m,1H+1H×0.3),7.38–7.25(m,13H+14H×0.3),6.93–6.84(m,1H+1H×0.3),5.87–5.64(m,1H+1H×0.3),5.01–4.87(m,2H+2H×0.3),4.70(d,J＝9.5Hz,1H),4.26(s,3H),4.12(s,3H×0.3),3.98–3.86(m,2H×0.3),3.82(d,J＝12.8Hz,1H),3.62(d,J＝13.1Hz,1H+1H×0.3),3.51(s,1H×0.3),3.43–3.21(m,1H+2H×0.3),3.12–2.87(m,4H),2.76–2.46(m,3H),2.19(s,1H+1H×0.3),1.51(s,4H+2H×0.3),1.21–1.12(m,1H+2H×0.3),0.91–0.73(m,2H)。
13C NMR(100MHz,CDCl3)δ160.0,152.6,149.6,148.8,145.6,144.9,142.8,137.2,136.8,136.6,135.7,135.6,134.0,133.9,133.7,133.5,131.4,129.8,129.6,129.4,129.2,128.9,128.6,128.5,128.4,128.3,127.2,126.2,123.2,120.5,1144,69.7,62.6,58.7,57.3,56.6,55.9,50.8,49.9,41.3,39.9,29.6,28.3,27.7,26.9,25.5。
31P NMR(162MHz,CDCl3)δ-13.6。
配体L5的表征数据：
1H NMR(400MHz,CDCl3)δ9.66(s,1H×0.3),9.43–8.98(m,1H),8.96(s,1H×0.3),8.57–8.35(m,2H+1H×0.3),7.99–7.86(m,1H),7.55–7.21(m,13H+14H×0.3),6.96–6.87(m,1H+1H×0.3),5.98–5.64(m,1H+1H×0.3),4.98–4.76(m,2H+2H×0.3),4.80(d,J＝9.5Hz,1H),4.01–3.94(m,2H×0.3),3.89(d,J＝12.8Hz,1H),3.71(d,J＝13.1Hz,1H+1H×0.3),3.45(s,1H×0.3),3.27–3.09(m,1H+2H×0.3),3.24–2.79(m,4H),2.76–2.52(m,3H),2.25(s,1H+1H×0.3),1.71(s,4H+2H×0.3),1.43–1.22(m,1H+2H×0.3),0.95–0.73(m,2H)。
13C NMR(100MHz,CDCl3)δ152.6,149.6,148.2,144.7,144.9,142.8,136.9,136.8,136.6,135.9,135.8,133.9,133.8,133.6,133.5,132.4,129.42,129.39,129.1,128.8,128.7,128.6,128.5,128.4,128.3,128.2,127.2,126.5,123.7,120.5,114.6,69.7,62.5,58.2,57.0,56.4,50.7,49.8,40.9,39.9,29.4,28.8,27.5,26.9,25.5。
31P NMR(162MHz,CDCl3)δ-7.3.19F NMR(376MHz,CDCl3)δ-62.97,-63.00。
配体L6的表征数据：
1H NMR(400MHz,CDCl3)δ9.32(s,1H×0.3),9.09–8.98(m,1H),8.83(s,1H×0.3),8.31–8.21(m,2H+1H×0.3),8.11–7.99(m,1H),7.91–7.71(m,1H+1H×0.3),7.69–7.61(m,1H+1H×0.3),7.51–7.31(m,12H+13H×0.3),7.14–6.96(m,1H+1H×0.3),5.66–5.54(m,1H+1H×0.3),4.85–4.71(m,2H+2H×0.3),4.30(d,J＝9.5Hz,1H),4.25–3.98(m,2H×0.3),3.87(d,J＝12.8Hz,1H),3.63(d,J＝13.1Hz,1H+1H×0.3),3.43(s,1H×0.3),3.33–3.24(m,1H+2H×0.3),3.22–2.99(m,4H),2.96–2.88(m,3H),2.71(s,3H+3H×0.3),2.25(s,1H+1H×0.3),1.80(s,4H+2H×0.3),1.40(s,19H+19H×0.3),1.35–1.23(m,1H+2H×0.3),0.96–0.69(m,2H)。
13C NMR(100MHz,CDCl3)δ152.1,148.5,149.2,145.3,145.1,141.4,137.3,137.1,136.5,136.0,135.5,134.1,133.1,133.6,133.5,130.5,129.6,129.5,129.3,129.0,128.7,128.6,128.5,128.4,128.3,127.1,126.2,123.0,120.0,114.1,69.6,62.6,58.3,57.2,56.7,50.1,49.1,40.4,39.5,35.5,31.1,29.1,28.0,27.6,27.0,25.1。
31P NMR(162MHz,CDCl3)δ-16.1。
配体L7的表征数据：
1H NMR(400MHz,CDCl3)δ9.33(s,1H×0.3),9.05–8.95(m,1H),8.81(s,1H×0.3),8.20–8.10(m,2H+1H×0.3),7.91–7.82(m,1H),7.80–7.65(m,1H+1H×0.3),7.64–7.55(m,1H+1H×0.3),7.52–7.33(m,12H+13H×0.3),7.00–6.83(m,1H+1H×0.3),5.74–5.51(m,1H+1H×0.3),4.91–4.70(m,2H+2H×0.3),4.14(d,J＝9.5Hz,1H),4.02–3.81(m,2H×0.3),3.82(d,J＝12.8Hz,1H),3.51(d,J＝13.1Hz,1H+1H×0.3),3.42(s,1H×0.3),3.30–3.20(m,1H+2H×0.3),3.15–2.95(m,4H),2.85–2.75(m,3H),2.70(s,6H+6H×0.3),2.63(s,3H+3H×0.3),2.01(s,1H+1H×0.3),1.70(s,4H+2H×0.3),1.31–1.10(m,1H+2H×0.3),0.91–0.62(m,2H)。
13C NMR(100MHz,CDCl3)δ152.0,148.2,149.0,145.0,144.7,141.5,137.0,136.9,136.6,135.5,135.4,134.5,133.9,133.8,133.1,130.0,129.4,129.3,129.2,128.8,128.5,128.3,128.2,128.0,127.8,127.4,126.4,122.5,120.1,114.0,69.1,62.3,58.5,57.4,56.5,50.7,49.5,40.3,39.7,29.1,28.4,27.7,27.0,25.1,22.3,21.8。
31P NMR(162MHz,CDCl3)δ-16.5。
配体L8的表征数据：
1H NMR(400MHz,CDCl3)δ9.30(s,1H×0.3),9.01–8.83(m,1H),8.74(s,1H×0.3),8.17–8.12(m,2H+1H×0.3),7.94–7.78(m,1H),7.79–7.64(m,1H+1H×0.3),7.59–7.44(m,1H+1H×0.3),7.33–7.08(m,13H+14H×0.3),6.91–6.85(m,1H+1H×0.3),5.79–5.56(m,1H+1H×0.3),4.99–4.78(m,2H+2H×0.3),4.62(d,J＝9.5Hz,1H),3.98–3.82(m,2H×0.3),3.79(d,J＝12.8Hz,1H),3.52(d,J＝13.1Hz,1H+1H×0.3),3.40(s,1H×0.3),3.23–3.04(m,1H+2H×0.3),3.08–2.79(m,4H),2.72–2.46(m,3H),2.52(m,4H+2H×0.3),2.41(m,2H+2H×0.3),2.19(s,1H+1H×0.3),1.68(d,J＝9.1Hz,24H+24H×0.3),1.51(s,12H+12H×0.3),1.21–1.02(m,1H+2H×0.3),0.93–0.61(m,2H)。
13C NMR(100MHz,CDCl3)δ150.3,148.6,148.2,144.6,144.2,141.8,136.6,136.5,136.4,135.4,135.3,133.8,133.7,133.6,133.5,130.2,129.41,129.39,129.0,128.8,128.7,128.5,128.43,128.41,128.32,128.29,127.1,126.0,122.3,120.5,114.0,69.1,62.5,58.3,57.3,56.1,50.1,49.9,40.4,39.6,33.1,29.0,28.2,27.6,26.8,25.2,23.2。31PNMR(162MHz,CDCl3)δ-16.3。
配体L9的表征数据：
1H NMR(400MHz,CDCl3)δ9.35(s,1H×0.3),9.01–8.85(m,1H),8.66(s,1H×0.3),8.27–8.14(m,2H+1H×0.3),7.92–7.77(m,1H),7.72–7.67(m,1H+1H×0.3),7.51–7.41(m,1H+1H×0.3),7.35–7.05(m,17H+17H×0.3),6.85–6.80(m,1H+1H×0.3),5.76–5.52(m,1H+1H×0.3),4.94–4.73(m,2H+2H×0.3),4.61(d,J＝9.5Hz,1H),3.98–3.81(m,2H×0.3),3.75(d,J＝12.8Hz,1H),3.50(d,J＝13.1Hz,1H+1H×0.3),3.41(s,1H×0.3),3.21–3.04(m,1H+2H×0.3),3.02–2.78(m,4H),2.76–2.42(m,3H),2.22(s,1H+1H×0.3),1.55(s,4H+2H×0.3),1.21–1.01(m,1H+2H×0.3),0.96–0.68(m,2H)。
13C NMR(100MHz,CDCl3)δ151.6,147.5,148.4,144.5,144.1,141.3,137.2,136.6,136.5,135.8,135.4,133.4,133.3,133.2,133.1,132.9,132.5,130.1,129.9,129.7,129.1,128.9,128.7,128.5,128.42,128.40,128.38,128.36,127.1,126.7,122.5,120.2,114.5,69.0,62.2,58.6,57.1,56.1,50.4,49.4,40.8,39.5,29.2,28.1,27.5,26.8,25.2。
31P NMR(162MHz,CDCl3)δ-16.9。
实施例2
将实施例1的配体用于肌醇4,6-去对称化不对称磺酰基化反应
向装有搅拌棒、经烘箱干燥的250mL圆底烧瓶装入保护的肌醇底物(1.0g,2.63mmol,1.0eq.)、双三苯基膦硼氢化亚铜(157.8mg,0.26mmol,10mol％)、手性配体L1(179.3mg,0.32mmol,12mol％)、碳酸银(435.5mg,1.58mmol,0.6eq.)、
分子筛(0.4g)，然后加入干燥氯仿(50mL)。室温条件下搅拌5分钟后加入苯磺酰氯(0.4mL,3.16mmol,1.2eq.)。室温条件下反应2天，用铺有硅藻土的过滤装置过滤，滤液浓缩并通过硅胶柱色谱纯化(石油醚/乙酸乙酯＝4/1)。得到白色固体(1.07g,产率：78％，ee：91％)。
产物表征数据：
HPLC条件:Chiralcel OD(正己烷/异丙醇＝95/5,流速0.5mL/min,λ＝214nm),tR(major)＝20.81min,tR(minor)＝14.33min。
1H NMR(400MHz,CDCl3)δ8.03–7.92(m,2H),7.77–7.69(m,1H),7.66–7.56(m,4H),7.37–7.30(m,3H),5.25(td,J＝4.0,1.7Hz,1H),4.68–4.64(m,1H),4.44–4.39(m,1H),4.30–4.27(m,1H),4.25(t,J＝1.8Hz,1H),4.19–4.16(m,1H),2.43(d,J＝6.6Hz,1H),0.92(s,9H),0.13(s,3H),0.10(s,3H)。
13C NMR(100MHz,CDCl3)δ136.5,135.3,134.7,129.7,129.6,128.03,127.95,125.3,107.4,75.4,74.6,73.4,69.5,67.5,59.3,25.8,18.2,-4.65,-4.71。
HRMS(ESI)m/z精确质量计算C25H33O8SSi[M+H]+521.1660,实测值521.1660。
将配体L1替换为配体L2～L9，反应结果如下：
可见，本发明的配体用于肌醇4,6-去对称化不对称磺酰基化反应，ee值在80％以上，显著提升了此类反应的对映选择性，是一类良好配体。
实施例3
向装有搅拌棒、经烘箱干燥的250mL圆底烧瓶装入保护的肌醇底物(0.84g,2.63mmol,1.0eq.)、双三苯基膦硼氢化亚铜(157.8mg,0.26mmol,10mol％)、手性配体L1(179.3mg,0.32mmol,12mol％)、碳酸银(435.5mg,1.58mmol,0.6eq.)、
分子筛(0.4g)，然后加入干燥氯仿(50mL)。室温条件下搅拌5分钟后加入苯磺酰氯(0.4mL,3.16mmol,1.2eq.)。室温条件下反应2天，用铺有硅藻土的过滤装置过滤，滤液浓缩并通过硅胶柱色谱纯化(石油醚/乙酸乙酯＝4/1)。得到白色固体(0.96g,产率：80％，ee：88％)。
表征数据：
HPLC条件:Chiralcel OD(正己烷/异丙醇＝95/5,流速0.5mL/min,λ＝214nm),tR(major)＝25.55min,tR(minor)＝15.35min。
1H NMR(400MHz,CDCl3)δ7.76–7.66(m,4H),7.31–7.25(m,1H),5.35(td,J＝4.0,1.7Hz,1H),4.78–4.74(m,1H),4.49–4.39(m,1H),4.36–4.37(m,1H),4.25(t,J＝1.8Hz,1H),4.19–4.16(m,1H),2.80(s,3H),2.43(d,J＝6.6Hz,1H),0.92(s,9H),0.13(s,3H),0.10(s,3H)。
13C NMR(100MHz,CDCl3)δ135.0,134.8,129.9,125.0,108.4,76.4,74.6,74.4,69.8,68.5,59.9,30.1,25.7,18.0,-4.6,-4.7。
HRMS(ESI)m/z精确质量计算C20H31O8SSi[M+H]+459.1503,实测值459.1505。
实施例4
向装有搅拌棒、经烘箱干燥的250mL圆底烧瓶装入保护的肌醇底物(0.81g,2.63mmol,1.0eq.)、双三苯基膦硼氢化亚铜(157.8mg,0.26mmol,10mol％)、手性配体L1(179.3mg,0.32mmol,12mol％)、碳酸银(435.5mg,1.58mmol,0.6eq.)、
分子筛(0.4g)，然后加入干燥氯仿(50mL)。室温条件下搅拌5分钟后加入苯磺酰氯(0.4mL,3.16mmol,1.2eq.)。室温条件下反应2天，用铺有硅藻土的过滤装置过滤，滤液浓缩并通过硅胶柱色谱纯化(石油醚/乙酸乙酯＝4/1)。得到白色固体(0.92g,产率：78％，ee：86％)。
表征数据：
HPLC条件:Chiralcel OD(正己烷/异丙醇＝95/5,流速0.5mL/min,λ＝214nm),tR(major)＝31.82min,tR(minor)＝24.73min。
1H NMR(400MHz,CDCl3)δ8.43–8.12(m,2H),7.97–7.73(m,1H),7.88–7.66(m,4H),7.33–7.38(m,3H),5.35(td,J＝4.0,1.7Hz,1H),4.86–4.76(m,1H),4.56–4.50(m,1H),4.44–4.37(m,1H),4.31(t,J＝1.8Hz,1H),4.29–4.26(m,1H),2.80(s,3H)2.55(d,J＝6.6Hz,1H)。
13C NMR(100MHz,CDCl3)δ165.5,136.2,135.7,134.0,129.9,129.7,128.4,127.9,126.0,107.8,76.0,75.6,74.7,69.9,67.7,59.6,38.8,25.9。
HRMS(ESI)m/z精确质量计算C21H21O9S[M+H]+449.0901,实测值449.0900。
实施例5
向装有搅拌棒、经烘箱干燥的250mL圆底烧瓶装入保护的肌醇底物(1.0g,2.63mmol,1.0eq.)、双三苯基膦硼氢化亚铜(157.8mg,0.26mmol,10mol％)、手性配体L1(179.3mg,0.32mmol,12mol％)、碳酸银(435.5mg,1.58mmol,0.6eq.)、
分子筛(0.4g)，然后加入干燥氯仿(50mL)。室温条件下搅拌5分钟后加入环己基磺酰氯(0.46mL,3.16mmol,1.2eq.)。室温条件下反应2天，用铺有硅藻土的过滤装置过滤，滤液浓缩并通过硅胶柱色谱纯化(石油醚/乙酸乙酯＝4/1)。得到白色固体(1.14g,产率：82％，ee：90％)。
表征数据：
HPLC条件:Chiralcel OD(正己烷/异丙醇＝95/5,流速0.5mL/min,λ＝214nm),tR(major)＝21.75min,tR(minor)＝13.33min。
1H NMR(400MHz,CDCl3)δ8.01–7.91(m,2H),7.73–7.64(m,1H),7.33–7.30(m,2H),5.35(td,J＝4.0,1.7Hz,1H),4.63–4.60(m,1H),4.54–4.32(m,1H),4.33–4.25(m,1H),4.45(t,J＝1.8Hz,1H),4.16–4.13(m,1H),2.43(d,J＝6.6Hz,1H),2.33–2.23(m,1H),1.53–1.49(m,4H),1.46–1.43(m,4H),1.33–1.25(m,2H),0.92(s,9H),0.13(s,3H),0.10(s,3H)。
13C NMR(100MHz,CDCl3)δ135.1,129.1,129.0,125.3,107.1,75.0,74.0,73.2,69.3,67.2,59.0,31.9,25.6,22.1,21.5,20.3,18.1,-4.66,-4.70。
HRMS(ESI)m/z精确质量计算C25H39O8SSi[M+H]+527.2129,实测值527.2125。
实施例6
向装有搅拌棒、经烘箱干燥的250mL圆底烧瓶装入保护的肌醇底物(1mmol)、双三苯基膦硼氢化亚铜(0.01mmol)、手性配体L3(0.02mmol)、碳酸银(0.35mmol)、
分子筛(0.2g)，然后加入干燥四氯化碳(50mL)。室温条件下搅拌5分钟后加入环己基磺酰氯(3mmol)。室温条件下反应2天，用铺有硅藻土的过滤装置过滤，滤液浓缩并通过硅胶柱色谱纯化(石油醚/乙酸乙酯＝4/1)。得到白色固体(产率：70％，ee：86％)。
实施例7
向装有搅拌棒、经烘箱干燥的250mL圆底烧瓶装入保护的肌醇底物(1mmol)、双三苯基膦硼氢化亚铜(0.3mmol)、手性配体L6(0.28mmol)、碳酸银(1mmol)、
分子筛(0.2g)，然后加入干燥二氯乙烷(50mL)。-10℃条件下搅拌5分钟后加入环己基磺酰氯(1mmol)。-10℃条件下反应2天，用铺有硅藻土的过滤装置过滤，滤液浓缩并通过硅胶柱色谱纯化(石油醚/乙酸乙酯＝4/1)。得到白色固体(产率：87％，ee：88％)。
实施例8
向装有搅拌棒、经烘箱干燥的250mL圆底烧瓶装入保护的肌醇底物(1mmol)、双三苯基膦硼氢化亚铜(0.05mmol)、手性配体L9(0.08mmol)、碳酸银(0.5mmol)、
分子筛(0.2g)，然后加入干燥二氯甲烷(50mL)。0℃条件下搅拌5分钟后加入环己基磺酰氯(2mmol)。0℃条件下反应2天，用铺有硅藻土的过滤装置过滤，滤液浓缩并通过硅胶柱色谱纯化(石油醚/乙酸乙酯＝4/1)。得到白色固体(产率：76％，ee：90％)。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何属于本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求的保护范围为准。
Claims (10)
1.一种金鸡纳碱衍生的NNP配体，具有通式Ⅰ的结构或其互变异构体、对映异构体、非对映异构体：
其中，R选自苯基、萘基，或者烷基、烷氧基、三氟甲基取代的苯基。
2.根据权利要求1所述的NNP配体，其特征在于，所述R选自苯基、萘基，或者(C1～C4)烷基、(C1～C4)烷氧基、三氟甲基取代的苯基。
3.根据权利要求2所述的NNP配体，其特征在于，所述R选自苯基、萘基，或者甲基、异丙基、叔丁基、甲氧基、三氟甲基取代的苯基。
4.根据权利要求3所述的NNP配体，其特征在于，所述R选自苯基、2-萘基、4-甲基苯基、4-叔丁基苯基、4-甲氧基苯基、3,5-二三氟甲基苯基、3,5-二叔丁基苯基、2,4,6-三甲基苯基、2,4,6-三异丙基苯基。
5.一种权利要求1～4任意一项所述的NNP配体的制备方法，包括以下步骤：
化合物S1和亚磷酸二乙酯反应，得到中间体S2；
中间体S2脱氧得到中间体S3；
中间体S3和邻溴苯甲醛反应，得到中间体S4；
中间体S4和奎宁衍生物S5进行缩合反应，得到产物；
R如权利要求1～4所定义。
6.权利要求1～4任意一项所述的NNP配体在肌醇不对称磺酰基化反应的应用。
7.根据权利要求6所述的应用，其特征在于，所述肌醇不对称磺酰基化反应包括：
使用NNP配体，使化合物A与R3SO2Cl反应制备化合物B的步骤，
其中，R1为氢、烷基或芳基；R2为硅基、苄基、酰基或磺酰基；R3为烷基、环烷基或芳基。
8.根据权利要求7所述的应用，其特征在于，所述肌醇不对称磺酰基化反应加入双三苯基膦硼氢化亚铜、碳酸银和分子筛。
9.根据权利要求8所述的应用，其特征在于，所述化合物A与R3SO2Cl的摩尔比为1:(1～3)；相对于化合物A，所述双三苯基膦硼氢化亚铜的用量为1～30mol％；所述L配体的用量为2～30mol％；所述碳酸银的用量为30～100mol％。
10.根据权利要求7～9任意一项所述的应用，其特征在于，所述肌醇不对称磺酰基化反应的温度为-10℃～室温，溶剂为二氯甲烷、二氯乙烷、氯仿或四氯化碳。
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| CN110627610A (zh) * | 2019-08-29 | 2019-12-31 | 南方科技大学 | 一种催化不对称交叉偶联合成炔的方法 |
| CN114213460A (zh) * | 2021-11-01 | 2022-03-22 | 贵州医科大学 | 一种用于酮不对称氢化反应或转移加氢反应的手性氮氮膦化合物、制备方法及应用 |
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