CN115611797A - Asymmetric synthesis method of chiral gamma-indole-alpha-keto acid ester compound - Google Patents
Asymmetric synthesis method of chiral gamma-indole-alpha-keto acid ester compound Download PDFInfo
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- CN115611797A CN115611797A CN202211344626.5A CN202211344626A CN115611797A CN 115611797 A CN115611797 A CN 115611797A CN 202211344626 A CN202211344626 A CN 202211344626A CN 115611797 A CN115611797 A CN 115611797A
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- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000011914 asymmetric synthesis Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 44
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 22
- 239000002841 Lewis acid Substances 0.000 claims abstract description 21
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000000654 additive Substances 0.000 claims abstract description 13
- 230000000996 additive effect Effects 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- FJOLTQXXWSRAIX-UHFFFAOYSA-K silver phosphate Chemical compound [Ag+].[Ag+].[Ag+].[O-]P([O-])([O-])=O FJOLTQXXWSRAIX-UHFFFAOYSA-K 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 73
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 48
- 239000002808 molecular sieve Substances 0.000 claims description 22
- 238000004440 column chromatography Methods 0.000 claims description 20
- 239000011259 mixed solution Substances 0.000 claims description 18
- 239000003208 petroleum Substances 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000012295 chemical reaction liquid Substances 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 10
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- -1 silver tetrafluoroborate Chemical compound 0.000 claims description 8
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 8
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 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 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000001311 chemical methods and process Methods 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 4
- 229940071536 silver acetate Drugs 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 3
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 3
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 claims description 3
- KZJPVUDYAMEDRM-UHFFFAOYSA-M silver;2,2,2-trifluoroacetate Chemical compound [Ag+].[O-]C(=O)C(F)(F)F KZJPVUDYAMEDRM-UHFFFAOYSA-M 0.000 claims description 3
- XAYJXAUUXJTOSI-UHFFFAOYSA-M silver;2,2,3,3,3-pentafluoropropanoate Chemical compound [Ag+].[O-]C(=O)C(F)(F)C(F)(F)F XAYJXAUUXJTOSI-UHFFFAOYSA-M 0.000 claims description 3
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 3
- OMQSJNWFFJOIMO-UHFFFAOYSA-J zirconium tetrafluoride Chemical compound F[Zr](F)(F)F OMQSJNWFFJOIMO-UHFFFAOYSA-J 0.000 claims description 3
- LSWWNKUULMMMIL-UHFFFAOYSA-J zirconium(iv) bromide Chemical compound Br[Zr](Br)(Br)Br LSWWNKUULMMMIL-UHFFFAOYSA-J 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 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
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 20
- 239000000203 mixture Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 2
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 2
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 229930194542 Keto Natural products 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- OSHOQERNFGVVRH-UHFFFAOYSA-K iron(3+);trifluoromethanesulfonate Chemical compound [Fe+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 OSHOQERNFGVVRH-UHFFFAOYSA-K 0.000 description 1
- GYCHYNMREWYSKH-UHFFFAOYSA-L iron(ii) bromide Chemical compound [Fe+2].[Br-].[Br-] GYCHYNMREWYSKH-UHFFFAOYSA-L 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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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Abstract
The invention discloses an asymmetric synthesis method of chiral gamma-indole-alpha-keto acid ester compounds, belonging to the field of organic synthesis. The method comprises the following steps: adding gamma-indole-beta, gamma-unsaturated-alpha-keto ester, hanster, lewis acid 1, lewis acid 2, chiral phosphoric acid, silver salt, additive and solvent into a reactor, and stirring at a certain temperature until the reaction is finished to selectively obtain one of two enantiomers of the chiral gamma-indole-alpha-keto ester compound. Wherein, gamma-indole-beta, gamma-unsaturated-alpha-keto ester, hans ester, lewis acid 1, chiral phosphoric acid, silver salt, additive and solvent are added to selectively obtain the compound with S configurationThe chiral gamma-indole-alpha-keto acid ester compound has the following reaction formula:
adding gamma-indole-beta, gamma-unsaturated-alpha-keto ester, hans ester, lewis acid 2, chiral phosphoric acid, additive and solvent to selectively obtain chiral gamma-indole-alpha-keto ester compounds with R configuration, wherein the reaction equation is as follows:
Description
Technical Field
The invention discloses an asymmetric synthesis method of chiral gamma-indole-alpha-keto acid ester compounds, belonging to the technical field of organic synthesis.
Background
The chiral gamma-indole-alpha-keto acid ester compounds are important organic molecules, and both indole skeletons and keto ester skeletons in the molecules of the chiral gamma-indole-alpha-keto acid ester compounds are widely existed in natural products and bioactive molecules, so that the chiral gamma-indole-alpha-keto acid ester compounds have important research significance. The synthesis of the compounds can be realized by asymmetric reduction of carbon-carbon double bonds of gamma-indole-beta, gamma-unsaturated-alpha-keto ester.
Asymmetric reduction reaction of carbon-carbon double bond of unsaturated carbonyl compound is a very important reaction. This type of reaction utilizes the sp of the prochiral pair of negative hydrogens 2 And (3) performing addition on hybridized carbon atoms to realize the construction of a chiral center. This type of reaction can be achieved using amine-based catalysis (org.lett., 2009,11, 2756-2759), chiral ion-pair catalysis (j.am.chem.soc.2006, 128,13368-13369, angelw.chem.int.ed.2006, 45, 4193-4195) and like strategies. Chemists have successfully achieved the asymmetric reduction reaction of the carbon-carbon double bond of compounds such as gamma-substituted unsaturated aldehydes and ketones by using these strategies, but the above strategies are not applicable to gamma-indole-beta, gamma-unsaturated-alpha-keto esters with large steric hindrance at the gamma-position. Therefore, the realization of a novel selective synthesis method of the gamma-indole-alpha-keto acid ester compound has great significance for the research of the applicability range of the reaction.
Disclosure of Invention
The invention aims to overcome the problems of method limitation and enantioselectivity in the existing synthesis process of gamma-indole-alpha-keto ester compounds, and provides a method for selectively synthesizing two enantiomers of chiral gamma-indole-alpha-keto ester compounds by using different catalytic systems.
In order to achieve the above objects, the present invention provides an asymmetric synthesis method of a chiral γ -indole- α -keto acid ester compound, wherein the structural formulas of two enantiomers of the chiral γ -indole- α -keto acid ester compound have the structures shown in formula I and formula II, respectively:
the method comprises the following steps: adding gamma-indole-beta, gamma-unsaturated-alpha-keto ester, hanster, lewis acid 1, lewis acid 2, chiral phosphoric acid, silver salt, additive and solvent into a reactor, stirring at a certain temperature until the reaction is finished, concentrating the reaction liquid by a rotary evaporator to obtain a crude product, and performing column chromatography separation to obtain the product. Wherein, gamma-indole-beta, gamma-unsaturated-alpha-keto ester, hans ester, lewis acid 1, chiral phosphoric acid, silver salt, additive and solvent are added to selectively obtain the chiral gamma-indole-alpha-keto ester compound with S configuration, and the chemical process is shown in a reaction formula III:
adding gamma-indole-beta, gamma-unsaturated-alpha-keto ester, hans ester, lewis acid 2, chiral phosphoric acid, additive and solvent to selectively obtain a chiral gamma-indole-alpha-keto ester compound with R configuration, wherein the chemical process is shown in a reaction formula IV:
wherein R is selected from any one of phenyl, substituted phenyl and thienyl, and the substituent of the substituted phenyl is any one of halogen atom, saturated alkyl, alkoxy, phenyl and trifluoromethyl.
R 1 Selected from any one of hydrogen atom, halogen atom, saturated alkyl and alkoxy.
R 2 Is selected from any one of hydrogen atom, methyl and benzyl.
R 3 Is selected from any one of methyl, ethyl, isopropyl and benzyl.
R 4 Is selected from any one of methyl, ethyl, tertiary butyl and benzyl.
The Lewis acid 1 is any one selected from zirconium fluoride, zirconium chloride and zirconium bromide.
The Lewis acid 2 is selected from any one of ferric chloride, ferric bromide and ferric trifluoromethanesulfonate.
The silver salt is selected from any one of silver carbonate, silver acetate, silver trifluoroacetate, silver pentafluoropropionate, silver trifluoromethanesulfonate, silver tetrafluoroborate and silver hexafluorophosphate.
The additive is selected from
A molecular sieve,
Molecular sieve,
Any one of molecular sieves.
The chiral phosphoric acid has a structure shown in formula V and formula VI:
wherein Ar is 1 The compound is selected from substituted phenyl, and the substituent of the substituted phenyl is any one of phenyl, pentafluorophenyl and 1-naphthyl; ar (Ar) 2 Selected from biphenyl.
The solvent is any one of dichloromethane, 1, 2-dichloroethane, diethyl ether, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, toluene and p-xylene.
The molar ratio of the gamma-indole-beta, gamma-unsaturated-alpha-keto ester, hans ester, lewis acid 1, lewis acid 2, chiral phosphoric acid and silver salt is 1.0 (1.0-2.0): 0-0.2): 0.05-0.2): 0-0.2; the dosage of the additive is 100-300mg/mmol.
The reaction time is 6-18h.
The reaction temperature is 0-60 ℃.
After the reaction, column chromatography separation is carried out by using a mixed solution of dichloromethane and petroleum ether.
The beneficial effects of the invention are as follows: the asymmetric synthesis method of the chiral gamma-indole-alpha-ketonic acid ester compound provided by the invention is scientific and reasonable, and can selectively synthesize two enantiomers of the chiral gamma-indole-alpha-ketonic acid ester compound; but also has the advantages of high yield, good enantioselectivity, wide substrate application range, simple operation, mild reaction, convenient post-treatment and the like.
Drawings
FIG. 1 is an NMR and high performance liquid chromatography spectrum of a compound (S-3 cc) prepared in example 5;
FIG. 2 is an NMR and high performance liquid chromatography spectrum of a compound (R-3 cc) prepared in example 6;
FIG. 3 is an NMR and high performance liquid chromatography spectrum of the compound (S-3 dd) prepared in example 7;
FIG. 4 is an NMR and HPLC spectrum of the compound (R-3 dd) prepared in example 8;
FIG. 5 is an NMR and high performance liquid chromatography spectrum of the compound (S-3 fa) produced in example 11;
FIG. 6 is an NMR and high performance liquid chromatography spectrum of the compound (R-3 fa) produced in example 12;
FIG. 7 is an NMR and high performance liquid chromatography spectrum of the compound (S-3 ha) prepared in example 15;
FIG. 8 is an NMR and high performance liquid chromatography spectrum of the compound (R-3 ha) prepared in example 16.
Detailed Description
The method of the present invention is described herein by way of examples, but the present invention is not limited thereto, and any modifications, equivalents, improvements, etc. within the technical spirit of the present invention should be included in the scope of the present invention.
Example 1:
the reaction equation is as follows:
compound 1a (5 mmol), 2a (7.5 mmol), zirconium chloride (0.5 mmol), chiral phosphoric acid (0.5 mmol), silver acetate (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, and 100mL of methylene chloride was added thereto, followed by stirring at room temperature until the reaction was completed. After the reaction is finished, a crude product obtained by concentrating the reaction liquid by a rotary evaporator is separated by column chromatography by using a mixed solution of dichloromethane and petroleum ether with the volume ratio of 4.
Nuclear magnetic data for S-3aa are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.53(d,J＝8.0Hz,2H),7.48(t,J＝8.0Hz,3H),7.40-7.37(m,4H),7.31-7.24(m,2H),7.18(t,J＝7.0Hz,1H),7.03(t,J＝7.5Hz,1H),6.89(s,1H),4.95(t,J＝7.5Hz,1H),3.75(s,3H),3.71(s,3H),3.69-3.61(m,2H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.6,161.3,142.5,140.9,139.4,137.3,128.7,128.2,127.3,127.1,127.0,126.4,121.9,119.5,119.1,116.7,109.3,52.9,45.8,37.3,32.8ppm.
example 2
The reaction equation is as follows:
a mixture of compound 1a (5 mmol), 2a (7.5 mmol), ferric bromide (0.5 mmol), chiral phosphoric acid (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, and 100mL of methylene chloride was added and the mixture was stirred at room temperature until the reaction was complete. After the reaction is finished, a crude product obtained by concentrating the reaction liquid by a rotary evaporator is separated by column chromatography by using a mixed solution of dichloromethane and petroleum ether with the volume ratio of 4.
Nuclear magnetic data for R-3aa are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.53(d,J＝8.0Hz,2H),7.48(t,J＝8.0Hz,3H),7.40-7.37(m,4H),7.31-7.24(m,2H),7.18(t,J＝7.0Hz,1H),7.03(t,J＝7.5Hz,1H),6.89(s,1H),4.95(t,J＝7.5Hz,1H),3.75(s,3H),3.71(s,3H),3.69-3.61(m,2H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.6,161.3,142.5,140.9,139.4,137.3,128.7,128.2,127.3,127.1,127.0,126.4,121.9,119.5,119.1,116.7,109.3,52.9,45.8,37.3,32.8ppm.
example 3
The reaction equation is as follows:
compound 1b (5 mmol), 2b (7.5 mmol), zirconium fluoride (0.5 mmol), chiral phosphoric acid (0.5 mmol), silver trifluoroacetate (0.5 mmol) and
molecular sieves (1 g) were charged into the reactor, and 100mL of 1, 2-dichloroethane was added and stirred at room temperature until the reaction was complete. After the reaction is finished, a crude product obtained by concentrating the reaction liquid by a rotary evaporator is subjected to column chromatography by using a mixed solution of dichloromethane and petroleum ether with the volume ratio of 4.
The nuclear magnetic data for S-3bb are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.52(d,J＝8.5Hz,2H),7.45(d,J＝8.5Hz,2H),7.38(d,J＝8.0Hz,1H),7.28(d,J＝8.0Hz,1H),7.20(t,J＝7.5Hz,1H),7.03(t,J＝7.0Hz,1H),6.90(s,1H),4.97(t,J＝7.5Hz,1H),3.79(s,3H),3.75(s,3H),3.69(dd,J＝7.0,17.5Hz,1H),3.62(dd,J＝8.0,17.5Hz,1H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.0,161.1,147.5,137.3,128.1,126.5,126.3,125.5,122.1,119.2,115.9,109.4,53.0,45.4,37.4,32.8ppm.
example 4
The reaction equation is as follows:
a mixture of compound 1b (5 mmol), 2b (7.5 mmol), ferric chloride (0.5 mmol), chiral phosphoric acid (0.5 mmol) and
molecular sieves (1 g) were charged into the reactor, and 100mL of 1, 2-dichloromethane was added thereto, followed by stirring at room temperature until the reaction was completed. After the reaction is finished, a crude product obtained by concentrating the reaction liquid by a rotary evaporator is subjected to column chromatography by using a mixed solution of dichloromethane and petroleum ether with the volume ratio of 4.
The nuclear magnetic data for R-3bb are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.52(d,J＝8.5Hz,2H),7.45(d,J＝8.5Hz,2H),7.38(d,J＝8.0Hz,1H),7.28(d,J＝8.0Hz,1H),7.20(t,J＝7.5Hz,1H),7.03(t,J＝7.0Hz,1H),6.90(s,1H),4.97(t,J＝7.5Hz,1H),3.79(s,3H),3.75(s,3H),3.69(dd,J＝7.0,17.5Hz,1H),3.62(dd,J＝8.0,17.5Hz,1H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.0,161.1,147.5,137.3,128.1,126.5,126.3,125.5,122.1,119.2,115.9,109.4,53.0,45.4,37.4,32.8ppm.
example 5
The reaction equation is as follows:
a mixture of compound 1c (5 mmol), 2c (7.5 mmol), zirconium bromide (0.5 mmol), chiral phosphoric acid (0.5 mmol), silver carbonate (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, and 100mL of diethyl ether was added and stirred at room temperature until the reaction was complete. After the reaction is finished, concentrating the reaction solution by a rotary evaporator to obtain crude productThe product was separated by column chromatography using a mixed solution of dichloromethane and petroleum ether in a volume ratio of 4.
The nuclear magnetic data of S-3cc is as follows:
1 H NMR(500MHz,CDCl 3 )δ7.50(d,J＝7.5Hz,1H),7.26(d,J＝8.0Hz,1H),7.20(t,J＝7.0Hz,1H),7.10(d,J＝5.0Hz,1H),7.05(t,J＝7.5Hz,1H),6.93-6.91(m,2H),6.88-6.87(m,1H),5.18(t,J＝7.5Hz,1H),3.75(s,3H),3.71(s,3H),3.70-3.65(m,2H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.0,161.1,147.9,137.3,126.6,126.6,126.4,124.3,123.8,121.9,119.4,119.2,116.4,109.4,53.0,46.7,33.0,32.8ppm.
example 6
The reaction equation is as follows:
compound 1c (5 mmol), 2c (7.5 mmol), ferric triflate (0.5 mmol), chiral phosphoric acid (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, and 100mL of diethyl ether was added thereto, followed by stirring at room temperature until the reaction was completed. After the reaction was completed, the crude product obtained by concentrating the reaction solution by a rotary evaporator was separated by column chromatography using a mixed solution of dichloromethane and petroleum ether in a volume ratio of 4.
The nuclear magnetic data for R-3cc is as follows:
1 H NMR(500MHz,CDCl 3 )δ7.50(d,J＝7.5Hz,1H),7.26(d,J＝8.0Hz,1H),7.20(t,J＝7.0Hz,1H),7.10(d,J＝5.0Hz,1H),7.05(t,J＝7.5Hz,1H),6.93-6.91(m,2H),6.88-6.87(m,1H),5.18(t,J＝7.5Hz,1H),3.75(s,3H),3.71(s,3H),3.70-3.65(m,2H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.0,161.1,147.9,137.3,126.6,126.6,126.4,124.3,123.8,121.9,119.4,119.2,116.4,109.4,53.0,46.7,33.0,32.8ppm.
example 7
The reaction equation is as follows:
a mixture of compound 1d (5 mmol), 2d (7.5 mmol), zirconium chloride (0.5 mmol), chiral phosphoric acid (0.5 mmol), silver pentafluoropropionate (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, and 100mL of tetrahydrofuran was added thereto, followed by stirring at room temperature until the reaction was completed. After the reaction is finished, a crude product obtained by concentrating the reaction solution by a rotary evaporator is subjected to column chromatography separation by using a mixed solution of dichloromethane and petroleum ether with the volume ratio of 4.
The nuclear magnetic data for S-3dd are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.33(d,J＝7.5Hz,2H),7.26(t,J＝7.0Hz,2H),7.21(s,1H),7.18-7.12(m,2H),7.02(t,J＝7.5Hz,1H),7.00(d,J＝8.5Hz,1H),6.80(s,1H),4.88(t,J＝7.5Hz,1H),3.75(s,3H),3.68(s,3H),3.63-3.56(m,2H),2.38(s,3H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.7,161.4,143.4,135.8,128.5,128.2,127.8,127.0,126.5,126.5,123.5,119.0,116.2,109.0,52.9,45.9,37.7,32.8,21.5ppm.
example 8
The reaction equation is as follows:
a mixture of compound 1d (5 mmol), 2d (7.5 mmol), ferric bromide (0.5 mmol), chiral phosphoric acid (0.5 mmol) and
molecular sieve (1 g) was added to the reactor, and tetrahydrofuran (100 mL) was added thereto, followed by stirring at room temperature to reactAnd (6) ending. After the reaction is finished, a crude product obtained by concentrating the reaction liquid by a rotary evaporator is subjected to column chromatography separation by using a mixed solution of dichloromethane and petroleum ether with the volume ratio of 4.
Nuclear magnetic data for R-3dd are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.33(d,J＝7.5Hz,2H),7.26(t,J＝7.0Hz,2H),7.21(s,1H),7.18-7.12(m,2H),7.02(t,J＝7.5Hz,1H),7.00(d,J＝8.5Hz,1H),6.80(s,1H),4.88(t,J＝7.5Hz,1H),3.75(s,3H),3.68(s,3H),3.63-3.56(m,2H),2.38(s,3H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.7,161.4,143.4,135.8,128.5,128.2,127.8,127.0,126.5,126.5,123.5,119.0,116.2,109.0,52.9,45.9,37.7,32.8,21.5ppm.
example 9:
the reaction equation is as follows:
compound 1e (5 mmol), 2a (7.5 mmol), zirconium chloride (0.5 mmol), chiral phosphoric acid (0.5 mmol), silver triflate (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, and 100mL of ethyl acetate was added thereto, followed by stirring at room temperature until the reaction was completed. After the reaction is finished, concentrating the reaction liquid by a rotary evaporator to obtain a crude product, and performing column chromatography separation by using a mixed solution of dichloromethane and petroleum ether in a volume ratio of 4.
The nuclear magnetic data for S-3ea are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.44(s,1H),7.32(s,1H),7.28-7.25(m,4H),7.21-7.17(m,1H),6.90(s,1H),4.80(t,J＝7.5Hz,1H),3.79(s,3H),3.66(s,3H),3.62(dd,J＝7.5,17.0Hz,1H),3.55(dd,J＝7.0,17.0Hz,1H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.2,161.2,142.7,136.2,128.7,128.1,127.6,126.9,126.5,125.9,123.2,120.4,116.6,110.9,53.0,45.6,37.3,33.0ppm.
example 10
The reaction equation is as follows:
a mixture of compound 1e (5 mmol), 2a (7.5 mmol), ferric bromide (0.5 mmol), chiral phosphoric acid (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, and 100mL of ethyl acetate was added and the mixture was stirred at room temperature until the reaction was complete. After the reaction is finished, a crude product obtained by concentrating the reaction liquid by a rotary evaporator is subjected to column chromatography separation by using a mixed solution of dichloromethane and petroleum ether in a volume ratio of 4.
The nuclear magnetic data for R-3ea is as follows:
1 H NMR(500MHz,CDCl 3 )δ7.44(s,1H),7.32(s,1H),7.28-7.25(m,4H),7.21-7.17(m,1H),6.90(s,1H),4.80(t,J＝7.5Hz,1H),3.79(s,3H),3.66(s,3H),3.62(dd,J＝7.5,17.0Hz,1H),3.55(dd,J＝7.0,17.0Hz,1H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.2,161.2,142.7,136.2,128.7,128.1,127.6,126.9,126.5,125.9,123.2,120.4,116.6,110.9,53.0,45.6,37.3,33.0ppm.
example 11
The reaction equation is as follows:
compound 1f (5 mmol), 2a (7.5 mmol), zirconium chloride (0.5 mmol), chiral phosphoric acid (0.5 mmol), silver tetrafluoroborate (0.5 mmol) and
molecular sieves (1 g) were charged to a reactor and toluene 1 was added00mL, stirring at room temperature until the reaction was complete. After the reaction is finished, a crude product obtained by concentrating the reaction liquid by a rotary evaporator is subjected to column chromatography separation by using a mixed solution of dichloromethane and petroleum ether in a volume ratio of 4.
The nuclear magnetic data for S-3fa are as follows:
1 H NMR(500MHz,CDCl 3 )δ8.06(s,1H),7.46(s,1H),7.40(d,J＝8.0Hz,1H),7.34-7.30(m,2H),7.27(d,J＝8.0Hz,1H),7.17(t,J＝7.5Hz,1H),7.13(t,J＝8.0Hz,1H),7.06-7.03(m,2H),4.88(t,J＝7.5Hz,1H),3.79(s,3H),3.67(dd,J＝7.5,17.5Hz,1H),3.56(dd,J＝7.5,17.0Hz,1H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.1,161.2,145.7,136.6,130.8,130.1,129.8,126.6,122.7,122.5,121.5,119.7,119.2,117.6,111.2,53.0,45.5,37.3ppm.
example 12
The reaction equation is as follows:
the compound 1f (5 mmol), 2a (7.5 mmol), ferric bromide (0.5 mmol), chiral phosphoric acid (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, and 100mL of toluene was added and stirred at room temperature until the reaction was complete. After the reaction is finished, a crude product obtained by concentrating the reaction liquid by a rotary evaporator is subjected to column chromatography by using a mixed solution of dichloromethane and petroleum ether with the volume ratio of 4.
The nuclear magnetic data for R-3fa is as follows:
1 H NMR(500MHz,CDCl 3 )δ8.06(s,1H),7.46(s,1H),7.40(d,J＝8.0Hz,1H),7.34-7.30(m,2H),7.27(d,J＝8.0Hz,1H),7.17(t,J＝7.5Hz,1H),7.13(t,J＝8.0Hz,1H),7.06-7.03(m,2H),4.88(t,J＝7.5Hz,1H),3.79(s,3H),3.67(dd,J＝7.5,17.5Hz,1H),3.56(dd,J＝7.5,17.0Hz,1H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.1,161.2,145.7,136.6,130.8,130.1,129.8,126.6,122.7,122.5,121.5,119.7,119.2,117.6,111.2,53.0,45.5,37.3ppm.
example 13
The reaction equation is as follows:
1g (5 mmol) of the compound, 2a (7.5 mmol), zirconium chloride (0.5 mmol), chiral phosphoric acid (0.5 mmol), silver hexafluorophosphate (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, p-xylene was added to the reactor in an amount of 100mL, and the mixture was stirred at 60 ℃ until the reaction was completed. After the reaction is finished, a crude product obtained by concentrating the reaction solution by a rotary evaporator is subjected to column chromatography by using a mixed solution of dichloromethane and petroleum ether in a volume ratio of 4.
Nuclear magnetic data for S-3ga are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.42(d,J＝8.0Hz,1H),7.32(d,J＝7.5Hz,2H),7.29-7.24(m,5H),7.21-7.14(m,2H),7.11(t,J＝7.5Hz,1H),7.06(d,J＝7.5Hz,2H),7.00(t,J＝7.5Hz,1H),6.97(s,1H),4.92(t,J＝7.5Hz,1H),3.71(s,3H),3.73(s,3H),3.66(dd,J＝7.5,17.5Hz,1H),3.59(dd,J＝8.0,17.0Hz,1H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.6,161.4,143.3,137.6,137.0,128.8,128.6,127.8,127.2,126.7,126.6,125.7,122.1,119.7,119.3,117.5,109.8,52.9,50.0,45.8,37.8ppm.
example 14
The reaction equation is as follows:
1g (5 mmol) of the compound, 2a (7.5 mmol), iron bromide (0.5 mmol), chiral phosphoric acid (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, p-xylene was added to the reactor in an amount of 100mL, and the mixture was stirred at 60 ℃ until the reaction was completed. After the reaction is finished, a crude product obtained by concentrating the reaction liquid by a rotary evaporator is subjected to column chromatography by using a mixed solution of dichloromethane and petroleum ether in a volume ratio of 4.
Nuclear magnetic data for R-3ga are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.42(d,J＝8.0Hz,1H),7.32(d,J＝7.5Hz,2H),7.29-7.24(m,5H),7.21-7.14(m,2H),7.11(t,J＝7.5Hz,1H),7.06(d,J＝7.5Hz,2H),7.00(t,J＝7.5Hz,1H),6.97(s,1H),4.92(t,J＝7.5Hz,1H),3.71(s,3H),3.73(s,3H),3.66(dd,J＝7.5,17.5Hz,1H),3.59(dd,J＝8.0,17.0Hz,1H)ppm.
13 C NMR(125MHz,CDCl 3 )δ192.6,161.4,143.3,137.6,137.0,128.8,128.6,127.8,127.2,126.7,126.6,125.7,122.1,119.7,119.3,117.5,109.8,52.9,50.0,45.8,37.8ppm.
example 15
The reaction equation is as follows:
compound 1h (5 mmol), 2a (7.5 mmol), zirconium chloride (0.5 mmol), chiral phosphoric acid (0.5 mmol), silver acetate (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, followed by addition of 100mL of methylene chloride and stirring at 0 ℃ until the reaction was complete. After the reaction is finished, a crude product obtained by concentrating the reaction solution by a rotary evaporator is subjected to column chromatography separation by using a mixed solution of dichloromethane and petroleum ether with the volume ratio of 4.
The nuclear magnetic data for S-3ha are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.42(d,J＝8.0Hz,1H),7.33(d,J＝7.5Hz,2H),7.27-7.23(m,3H),7.19-7.15(m,2H),7.01(t,J＝7.5Hz,1H),6.86(s,1H),5.07-4.99(m,1H),4.90(t,J＝7.5Hz,1H),3.71(s,3H),3.64(dd,J＝7.5,17.0Hz,1H),3.57(dd,J＝8.0,17.0Hz,1H),1.26(d,J＝6.5Hz,3H),1.23(d,J＝6.5Hz,3H)ppm.
13 C NMR(125MHz,CDCl 3 )δ193.5,160.6,143.5,137.3,128.5,127.8,126.9,126.5,126.4,121.8,119.5,119.0,116.9,109.2,70.7,45.7,37.8,32.7,21.5,21.5ppm.
example 16
The reaction equation is as follows:
the compound was reacted with 1h (5 mmol), 2a (7.5 mmol), ferric bromide (0.5 mmol), chiral phosphoric acid (0.5 mmol) and
molecular sieves (1 g) were added to the reactor, followed by addition of 100mL of methylene chloride and stirring at 0 ℃ until the reaction was complete. After the reaction is finished, a crude product obtained by concentrating the reaction solution by a rotary evaporator is subjected to column chromatography separation by using a mixed solution of dichloromethane and petroleum ether with the volume ratio of 4.
The nuclear magnetic data for R-3ha are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.42(d,J＝8.0Hz,1H),7.33(d,J＝7.5Hz,2H),7.27-7.23(m,3H),7.19-7.15(m,2H),7.01(t,J＝7.5Hz,1H),6.86(s,1H),5.07-4.99(m,1H),4.90(t,J＝7.5Hz,1H),3.71(s,3H),3.64(dd,J＝7.5,17.0Hz,1H),3.57(dd,J＝8.0,17.0Hz,1H),1.26(d,J＝6.5Hz,3H),1.23(d,J＝6.5Hz,3H)ppm.
13 C NMR(125MHz,CDCl 3 )δ193.5,160.6,143.5,137.3,128.5,127.8,126.9,126.5,126.4,121.8,119.5,119.0,116.9,109.2,70.7,45.7,37.8,32.7,21.5,21.5ppm.
as can be seen from the above examples, two enantiomers of chiral γ -indole- α -keto acid ester compounds can be selectively synthesized according to the present invention using different combinations of Lewis acids, chiral phosphoric acids, and silver salts.
Claims (6)
1. The asymmetric synthesis method of the chiral gamma-indole-alpha-keto acid ester compound is characterized in that two enantiomer structural formulas of the chiral gamma-indole-alpha-keto acid ester compound respectively have structures shown in a formula I and a formula II:
the method comprises the following steps: adding gamma-indole-beta, gamma-unsaturated-alpha-keto ester, hanster, lewis acid 1, lewis acid 2, chiral phosphoric acid, silver salt, additive and solvent into a reactor, stirring at a certain temperature until the reaction is finished, concentrating the reaction liquid by a rotary evaporator to obtain a crude product, and performing column chromatography separation to obtain the product. Wherein, gamma-indole-beta, gamma-unsaturated-alpha-keto ester, hans ester, lewis acid 1, chiral phosphoric acid, silver salt, additive and solvent are added to selectively obtain the chiral gamma-indole-alpha-keto ester compound with S configuration, and the chemical process is shown in a reaction formula III:
adding gamma-indole-beta, gamma-unsaturated-alpha-keto ester, hans ester, lewis acid 2, chiral phosphoric acid, additive and solvent to selectively obtain chiral gamma-indole-alpha-keto ester compounds with R configuration, wherein the chemical process is shown in a reaction formula IV:
wherein R is selected from any one of phenyl, substituted phenyl and thienyl, and the substituent of the substituted phenyl is any one of halogen atom, saturated alkyl, alkoxy, phenyl and trifluoromethyl;
R 1 any one selected from hydrogen atom, halogen atom, saturated alkyl group and alkoxy group;
R 2 any one selected from hydrogen atom, methyl and benzyl;
R 3 any one of methyl, ethyl, isopropyl and benzyl;
R 4 any one of methyl, ethyl, tertiary butyl and benzyl;
the Lewis acid 1 is selected from any one of zirconium fluoride, zirconium chloride and zirconium bromide;
the Lewis acid 2 is selected from any one of ferric chloride, ferric bromide and ferric trifluoromethanesulfonate;
the silver salt is selected from any one of silver carbonate, silver acetate, silver trifluoroacetate, silver pentafluoropropionate, silver trifluoromethanesulfonate, silver tetrafluoroborate and silver hexafluorophosphate;
the additive is selected from
Molecular sieve,
A molecular sieve,
Any one of molecular sieves;
the chiral phosphoric acid has a structure shown in formula V and formula VI:
wherein Ar is 1 The compound is selected from substituted phenyl, and the substituent of the substituted phenyl is any one of phenyl, pentafluorophenyl and 1-naphthyl; ar (Ar) 2 Selected from biphenyl.
2. The method according to claim 1, wherein the solvent is selected from the group consisting of dichloromethane, 1, 2-dichloroethane, diethyl ether, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, toluene, and p-xylene.
3. The method of claim 1, wherein the molar ratio of the γ -indole- β, γ -unsaturated- α -keto ester, hans-ester, lewis acid 1, lewis acid 2, chiral phosphoric acid, silver salt is 1.0 (1.0-2.0): 0-0.2): 0.05-0.2): 0-0.2; the dosage of the additive is 100-300mg/mmol.
4. The process according to claim 1, wherein the reaction time is 6 to 18 hours.
5. The method according to claim 1, wherein the reaction temperature is 0 to 60 ℃.
6. The preparation method according to claim 1, wherein the column chromatography is performed using a mixed solution of dichloromethane and petroleum ether.
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| CN112778191A (en) * | 2021-01-06 | 2021-05-11 | 青岛科技大学 | Visible light mediated method for synthesizing allyl alcohol compound containing indole skeleton |
| CN112812122A (en) * | 2020-12-31 | 2021-05-18 | 青岛科技大学 | Method for selectively synthesizing beta-indole-alpha, beta-unsaturated carbonyl compound and pyrano [2,3-b ] indole |
| CN113788756A (en) * | 2021-10-12 | 2021-12-14 | 青岛科技大学 | Method for green synthesis of optically pure allyl alcohol compound by using diacid as catalyst |
| CN114478245A (en) * | 2022-01-21 | 2022-05-13 | 青岛科技大学 | Asymmetric synthesis method of chiral gamma-alkynyl-alpha-keto acid ester compound |
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| CN112812122A (en) * | 2020-12-31 | 2021-05-18 | 青岛科技大学 | Method for selectively synthesizing beta-indole-alpha, beta-unsaturated carbonyl compound and pyrano [2,3-b ] indole |
| CN112778191A (en) * | 2021-01-06 | 2021-05-11 | 青岛科技大学 | Visible light mediated method for synthesizing allyl alcohol compound containing indole skeleton |
| CN113788756A (en) * | 2021-10-12 | 2021-12-14 | 青岛科技大学 | Method for green synthesis of optically pure allyl alcohol compound by using diacid as catalyst |
| CN114478245A (en) * | 2022-01-21 | 2022-05-13 | 青岛科技大学 | Asymmetric synthesis method of chiral gamma-alkynyl-alpha-keto acid ester compound |
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