CN109317195A - 一种含有酸基的金鸡纳碱伯胺催化剂及其合成方法和在不对称反应中的应用 - Google Patents
一种含有酸基的金鸡纳碱伯胺催化剂及其合成方法和在不对称反应中的应用 Download PDFInfo
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- CN109317195A CN109317195A CN201811317969.6A CN201811317969A CN109317195A CN 109317195 A CN109317195 A CN 109317195A CN 201811317969 A CN201811317969 A CN 201811317969A CN 109317195 A CN109317195 A CN 109317195A
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- primary amine
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- quinine
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- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Natural products 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 title claims abstract description 50
- -1 quinine primary amine Chemical class 0.000 title claims abstract description 45
- 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 title claims abstract description 40
- 239000003054 catalyst Substances 0.000 title claims abstract description 39
- 235000001258 Cinchona calisaya Nutrition 0.000 title claims abstract description 38
- 229960000948 quinine Drugs 0.000 title claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 36
- 230000002378 acidificating effect Effects 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 238000004440 column chromatography Methods 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 150000003141 primary amines Chemical class 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003480 eluent Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 239000013067 intermediate product Substances 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000000269 nucleophilic effect Effects 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 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 6
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 5
- JMQGGPRJQOQKRT-UHFFFAOYSA-N diphenyl hydrogen phosphate;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 JMQGGPRJQOQKRT-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 238000006751 Mitsunobu reaction Methods 0.000 claims description 4
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000006073 displacement reaction Methods 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- BZCGWAXQDLXLQM-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O.ClP(Cl)(Cl)=O BZCGWAXQDLXLQM-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000007806 chemical reaction intermediate Substances 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 abstract description 8
- 150000001450 anions Chemical class 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 150000002500 ions Chemical class 0.000 abstract description 3
- 150000002192 fatty aldehydes Chemical class 0.000 abstract description 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 abstract 1
- 241000157855 Cinchona Species 0.000 description 31
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 230000029936 alkylation Effects 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 2
- 241000288027 Chrysolophus pictus Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 2
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 description 2
- 125000003410 quininyl group Chemical group 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VLUMOWNVWOXZAU-VQHVLOKHSA-N (e)-2-methyl-3-phenylprop-2-enal Chemical compound O=CC(/C)=C/C1=CC=CC=C1 VLUMOWNVWOXZAU-VQHVLOKHSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 235000021513 Cinchona Nutrition 0.000 description 1
- 235000006768 Cinchona succirubra Nutrition 0.000 description 1
- 244000182633 Cinchona succirubra Species 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000039 congener Substances 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FXHGMKSSBGDXIY-UHFFFAOYSA-N heptanal Chemical compound CCCCCCC=O FXHGMKSSBGDXIY-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical group FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
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- 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
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
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- B01J31/0257—Phosphorus acids or phosphorus acid esters
- B01J31/0258—Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
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- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
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Abstract
本发明公开了一种含有酸基的金鸡纳碱伯胺催化剂及其合成方法和在不对称反应中的应用,其中含有酸基的金鸡纳碱伯胺催化剂的结构为如下结构式中的一种:
Description
技术领域
本发明属于有机化学领域,具体涉及一种含有酸基的金鸡纳碱伯胺催化剂及其合成方法和在不对称反应中的应用。
背景技术
手性是自然界的基本特征之一,手性科学的研究有助于人类进一步认识自然界中的基本问题,如生命过程中手性的起源、传递和放大等。手性活性物质已被广泛应用于新药的创制,以手性为特征的新型材料的研究也得到迅速的发展。不对称催化是获得手性分子最直接和最有效的方法之一,开发高选择性、高效的手性催化剂并扩展其在多种有机反应中的应用,已经成为发展不对称催化的核心问题。
金鸡纳碱(Cinchona alkaloids)是一类发现于金鸡纳树及其同属植物的树皮中的主要生物碱,主要包括奎宁、奎尼丁、辛可宁和辛可宁定等。金鸡纳碱具有重要的生物活性,如抗热、抗疟等,曾得到广泛应用。同时,金鸡纳碱在化学合成上作为一种重要的催化剂和配体被应用于各种催化反应特别是不对称催化中。
自1995年,金鸡纳碱衍生的具有高光学活性的伯胺催化剂被Brunner小组首次合成以来(Tetrahedron:Asymmetry1995,6,1699-1702),其在不对称催化反应尤其是具有挑战性的空间位阻较大的羰基活化反应中,表现出极其优异的催化性能(Synlett2008,1759-1772;Synlett2008,1919-1930;Synthesis2010,1229-1279;Catal.Sci.Technol.2014,4,311-320;Angew.Chem.Int.Ed.2012,51,9748-9770)。
金鸡纳碱伯胺催化剂可以活化α,β-不饱和脂肪醛γ位的C(sp3)-H键,生成的二烯胺中间体可进一步进行直接不对称官能团化。亲核进攻时,γ位的碳与胺催化剂的手性中心相距较远,不能很好地进行立体控制。而当反应体系中引入手性阴离子如磷酸负离子、羧酸负离子等,可以与亲电试剂E+形成手性离子对,从而提高不对称官能团化的对映选择性。
Melchiorre小组发现,α,β-不饱和脂肪醛的γ位进行对映选择性烷基化时,当反应中加入联萘酚骨架的手性磷酸后,反应的对映选择性(93%ee)远高于三氟乙酸所参与的反应(60%ee)。该反应经历SN1历程,手性磷酸负离子与苄基正离子形成离子对。同时,金鸡纳碱骨架6’-位的羟基也对该反应起到至关重要的作用,即当其6’-位是甲氧基时,无论是转化率还是对映选择性均很低;而当其6’-位是羟基时,作为氢键的给体与磷氧双键的氧原子键合,从过渡态TS中可以看到,亲电位点与亲核位点的距离最终被拉近,同时反应位点的空间环境被固定,从而提高了反应活性和对映选择性(Angew.Chem.,Int.Ed.2010,49,9685)。
根据上述6’-位形成的氢键中间体的关键作用,我们认为将氢键键合的方式改为共价键,直接连接磷酸基团或羧酸基团,从而合成新型的含有酸基的伯胺催化剂。
发明内容
本发明旨在提供一种含有酸基的金鸡纳碱伯胺催化剂及其合成方法和在不对称反应中的应用。该催化剂的伯胺可活化α,β-不饱和脂肪醛的γ位,而6’-位连接的负离子将与亲电试剂形成离子对,从而提高脂肪醛远端的不对称控制。该催化剂合成步骤简单,反应条件温和,在不对称催化领域应用广泛。
本发明含有酸基的金鸡纳碱伯胺催化剂,其结构为如下结构式中的一种:
式中R1为氢、苯基、取代苯基、C1~C6的直链或支链的烷基或C1~C4的烷氧基;
R2为氢、苯基、取代苯基或C1~C6的直链或支链的烷基。
所述取代苯基为烷基、烷氧基、硝基、氰基、酯基或卤素等取代的苯基。
本发明含有酸基的金鸡纳碱伯胺催化剂的典型化合物的结构式如下:
本发明含有酸基的金鸡纳碱伯胺催化剂的合成方法,是以金鸡纳碱(奎宁或奎尼丁)为手性源,经亲核取代、Mitsunobu取代/还原、水解等三步反应合成目标产物,其制备过程可用以下反应式表示:
其中,由金鸡纳碱(奎宁或奎尼丁)脱去6’-位甲氧基上的甲基,生成酚羟基化合物1的合成步骤可参见文献(J.Am.Chem.Soc.,2009,131,418–419)。
本发明含有酸基的金鸡纳碱伯胺催化剂的合成方法,具体包括如下步骤:
步骤1:亲核取代
碱性条件下,酚羟基化合物1与α-氯代酯或磷酰氯在溶剂中发生取代反应,反应结束后通过柱层析分离得到中间产物2或中间产物3;
所述α-氯代酯的结构式如下:
其中,R1为氢、苯基、取代苯基、C1~C6的直链或支链的烷基或C1~C4的烷氧基;
R3为苯基、取代苯基、C1~C6的直链或支链的烷基
所述磷酰氯的结构式如下:
其中,R2为氢、苯基、取代苯基或C1~C6的直链或支链的烷基。
所述柱层析分离是使用薄层层析硅胶H柱在空气加压下进行柱层析,洗脱液为体积比100~10:1的二氯甲烷和甲醇混合物。
所述碱性条件是指反应体系中加入NaOH、KOH、Na2CO3、Cs2CO3、三乙胺或吡啶等碱。
步骤2:Mitsunobu取代/还原
在溶剂中,偶氮二甲酸二乙酯、叠氮磷酸二苯酯和三苯基磷的存在下,中间产物2上9-位的羟基经Mitsunobu反应转化为叠氮,进一步被还原成伯胺4;
在溶剂中,偶氮二甲酸二乙酯、叠氮磷酸二苯酯和三苯基磷的存在下,中间产物3上9-位的羟基经Mitsunobu反应转化为叠氮,进一步被还原成伯胺5;
步骤3:水解
碱性条件下,在溶剂中,伯胺4或伯胺5上的酯基发生水解,pH值调至酸性,通过柱层析分离得到目标产物——催化剂I、II、III或IV。
所述碱性条件是指反应体系中加入NaOH、KOH、Na2CO3、Cs2CO3、三乙胺或吡啶等碱。
步骤1中,所述溶剂为二氯甲烷、氯仿或1,2-二氯乙烷等。
步骤2中,所述溶剂为乙醚、乙二醇二乙醚或四氢呋喃等。
步骤3中,所述溶剂为甲醇、乙醇、异丙醇、二甲亚砜或N,N-二甲基甲酰胺等。
所述柱层析分离是使用薄层层析硅胶H柱在空气加压下进行柱层析,洗脱液为体积比10~5:5~2:1的二氯甲烷、甲醇和水的混合物。
本发明含有酸基的金鸡纳碱伯胺催化剂的应用,是在不对称反应中作为催化剂使用,所述不对称反应为α-碳上带有支链的烯醛在γ位上的烷基化反应等。
本发明与现有技术相比,其有益效果在于:
本发明提供了一类结构新颖的含有酸基的金鸡纳碱伯胺催化剂,该类催化剂由易得手性源经简单反应制备得到,并且在不对称烷基化反应中避免了手性添加剂的加入并表现出了高效的手性催化能力,是一类颇具研究潜力和工业价值的有机分子催化剂。
具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不限于此。
实施例1:金鸡纳碱取代乙酸乙酯的制备
在50mL干燥的三颈瓶中加入168mg(3.0mmol)氢氧化钾,加入DMSO,搅拌10分钟后加入465mg(1.5mmol)6’-脱甲基奎宁(保持N2保护)。室温下搅拌4小时后溶液变色,逐滴加入366mg(3.0mmol)氯代乙酸乙酯,室温搅拌24h。反应结束后向反应液中加入50mL乙酸乙酯和25mL水,萃取分液。有机相浓缩后,向其中加入1克硅胶,旋干溶剂后,通过干法上样进行柱层析纯化。在层析柱中加入薄层层析硅胶H,将上述样品用空气加压,进行柱层析(柱长33厘米,流速5滴/秒),洗脱剂为二氯甲烷:甲醇=60:1(体积比),得到目标产物363mg,产率61%。
1H NMR(600MHz,CDCl3)δ8.48(d,J=4.5Hz,1H),7.78(d,J=9.2Hz,1H),7.46(d,J=4.5Hz,1H),7.17(dd,J=9.2,2.5Hz,1H),7.07(d,J=2.4Hz,1H),5.66(s,1H),5.62–5.54(m,1H),4.89(d,J=17.1Hz,1H),4.84(d,J=10.4Hz,1H),4.19–4.12(m,2H),3.72–3.63(m,1H),3.36(s,1H),3.06–2.96(m,2H),2.70–2.60(m,2H),2.28(brs,1H),1.84–1.74(m,3H),1.49(brs,1H),1.34–1.26(m,1H),1.21(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ168.8,155.7,148.0,147.6,144.0,140.9,131.2,126.0,121.5,118.6,114.8,102.6,70.3,65.5,61.3,59.8,56.2,43.1,39.3,27.6,26.8,20.6,14.2.HRMS(ESI)exact mass calcd for:C23H29N2O4(M+H)+397.2122,found397.2123.
实施例2:金鸡纳碱取代乙酸乙酯伯胺的制备
在氮气氛围、0℃下,偶氮二甲酸二乙酯(1.49g,7.35mmol)滴加到金鸡纳碱取代乙酸乙酯(2.00g,6.13mmol)和三苯基磷(1.93g,7.35mmol)的四氢呋喃(35mL)溶液中。5分钟后,滴加叠氮磷酸二苯酯(2.02g,7.35mmol)到反应液中。室温下搅拌4小时后,反应液升温至50℃并搅拌2小时。三苯基磷(1.93g,7.35mmol)加入到反应体系中,并持续搅拌2小时。2mL水加入到反应液中,室温下继续搅拌4小时。反应液浓缩后,加入15mL二氯甲烷和10%的盐酸溶液,水相用二氯甲烷萃取2遍并用饱和氨水调至PH=9,再用二氯甲烷萃取3遍,有机相旋干后,通过干法上样进行柱层析纯化。在层析柱中加入薄层层析硅胶H,将上述样品用空气加压,进行柱层析(柱长33厘米,流速5滴/秒),洗脱剂为二氯甲烷:甲醇=50:1(体积比),得到目标产物1.31g,产率54%。
1H NMR(600MHz,CDCl3)δ8.65(d,J=4.2Hz,1H),7.94(d,J=9.2Hz,1H),7.73–7.46(m,1H),7.38(brs,1H),7.33(dd,J=9.2,2.5Hz,1H),5.72–5.64(m,1H),5.18(s,1H),4.90(d,J=17.2Hz,1H),4.87(d,J=10.4Hz,1H),4.46(brs,1H),4.17(q,J=7.0Hz,1H),3.70(s,1H),3.22–3.10(m,2H),3.06(d,J=7.9Hz,1H),2.78–2.68(m,2H),2.20(brs,1H),1.53(brs,1H),1.48(t,J=7.3Hz,2H),1.32(brs,1H),1.19(t,J=7.1Hz,2H),0.79–0.71(m,1H),0.68–0.61(m,1H).13C NMR(150MHz,CDCl3)δ169.7,167.7,155.9,148.4,147.5,144.0,131.5,128.8,122.1,118.6,116.7,101.7,68.1,65.8,61.2,60.1,52.1,43.8,38.7,30.3,28.9,23.0,14.0.HRMS(ESI)exact mass calcd for:C23H30N3O3(M+H)+396.2282,found396.2280.
实施例3:含有酸基的金鸡纳碱伯胺催化剂的制备
将金鸡钠碱衍生物(0.59g,1.5mmol)溶解在含10%氢氧化钾(19.4mmol,1.1g)的1.3ml乙醇溶液中,室温下搅拌12小时,反应结束后反应液加入2ml水,用1mol/L的盐酸调节PH=6,旋干后,在层析柱中加入薄层层析硅胶H,将上述样品用空气加压,进行柱层析(柱长33厘米,流速5滴/秒),洗脱剂为二氯甲烷:甲醇:水=7:3:1(体积比),得到目标产物280mg,产率51%。1H NMR(600MHz,CD3OD)δ8.69(d,J=4.6Hz,1H),7.98(d,J=9.2Hz,1H),7.56(d,J=4.6Hz,1H),7.54–7.48(m,2H),5.98–5.86(m,1H),5.20(d,J=17.1Hz,1H),5.14(d,J=10.4Hz,1H),4.81(d,J=10.6Hz,1H),4.64(brs,2H),3.88–3.69(m,2H),3.67–3.57(m,1H),3.35(s,1H),2.76(brs,1H),2.15–2.03(m,1H),1.99–1.88(m,2H),1.77–1.71(m,1H),1.15–1.06(m,1H),0.91–0.85(m,1H).13C NMR(100MHz,CD3OD)δ174.6,157.8,147.1,145.6,143.9,138.6,130.2,127.7,123.0,115.5,102.0,67.6,61.2,53.6,52.8,40.6,37.5,26.9,24.4,23.8.HRMS(ESI)exact mass calcd for:C21H26N3O3(M+H)+368.1969,found368.1972.
实施例4:含有酸基的金鸡纳碱伯胺催化剂在不对称烷基化反应中的应用
在密封管中加入含有酸基的金鸡纳碱伯胺催化剂(5.5mg,0.015mmol),邻氟苯甲酸(4.2mg,0.03mmol),(E)-2-甲基-5-苯基-2-烯戊醛(35mg,0.2mmol)和1mL氯仿,室温下搅拌10分钟后,加入米氏醇(27mg,0.1mmol),在50℃下搅拌16小时,旋干后,在层析柱中加入薄层层析硅胶,将上述样品用空气加压,进行柱层析(柱长33厘米,流速5滴/秒),洗脱剂为石油醚:乙酸乙酯=30:1(体积比),得到目标产物30mg,产率68%,ee值96%。1H NMR(400MHz,CDCl3):δ9.18(s,1H),7.25-7.10(m,5H),7.05-6.96(m,4H),6.73(d,2H,J=8.47Hz),6.54(d,2H,J=8.51Hz),6.20(d,1H,J=10.51Hz),3.78(d,1H,J=10.34Hz),3.61(dq,J=3.29,10.10Hz,1H),3.00(dd,J=3.00,13.61Hz,1H),2.92(s,6H),2.84(s,6H),2.40(dd,J=9.97,13.35Hz,1H),1.17(s,3H).13C NMR(100MHz,CDCl3):195.4,157.4,139.8,139.6,129.1,128.6,128.3,128.1,126.0,113.1,112.6,54.9,46.4,40.7,40.6,39.8,9.14.HPLC analysis on a Daicel Chiralpak IC column:90/10hexane/i-PrOH,flow rate 1.00mL/min,λ=254nm:Tmajor=20.79min,Tminor=22.63min;HRMS(ESI)exactmass calcd for:C29H35N2O(M+H)+427.2749,found427.2746;[α]25 D=+6.1(1.00,CHCl3,96%ee).
实施例5:含有酸基的金鸡纳碱伯胺催化剂在不对称烷基化反应中的应用
密封管中加入含有酸基的金鸡纳碱伯胺催化剂(5.5mg,0.015mmol),邻氟苯甲酸(4.2mg,0.03mmol),(E)-2-甲基-3-苯基-丙烯醛(29mg,0.2mmol)和1mL氯仿,室温下搅拌10分钟后,加入米氏醇(27mg,0.1mmol),在50℃下搅拌16小时,旋干后,在层析柱中加入薄层层析硅胶,将上述样品用空气加压,进行柱层析(柱长33厘米,流速5滴/秒),洗脱剂为石油醚:乙酸乙酯=30:1(体积比),得到目标产物29mg,产率70%,ee值93%。1H NMR(400MHz,CDCl3):δ9.24(s,1H),7.22-7.16(m,2H);7.16-7.07(m,6H);6.93(d,2H,J=8.58Hz);6.65-6.59(m,3H);6.50(d,2H,J=8.56Hz);4.49(t,1H,J=10.44Hz),4.25(d,1H,J=11.03Hz);2.88(s,6H);2.81(s,6H),1.69(s,3H).13C NMR(100MHz,CDCl3):δ195.4,157.0,149.1,141.8,138.0,128.8,128.7,128.5,128.3,126.5,112.7,112.6,55.5,50.3,40.7,40.6,9.5.HPLC analysis on a Daicel Chiralpak IC column:90/10hexane/i-PrOH,flowrate 1.00mL/min,λ=254nm:Tmajor=24.31min,Tminor=27.35min;HRMS(ESI)exact masscalcd for:C28H33N2O(M+H)+413.2593,found 413.2593;[α]25 D=+7.0(1.00,CHCl3,93%ee).
实施例6:含有酸基的金鸡纳碱伯胺催化剂在不对称烷基化反应中的应用
密封管中加入含有酸基的金鸡纳碱伯胺催化剂(5.5mg,0.015mmol),邻氟苯甲酸(4.2mg,0.03mmol),(E)-2-甲基-2,6-二烯庚醛(25mg,0.2mmol)和1mL氯仿,室温下搅拌10分钟后,加入米氏醇(27mg,0.1mmol),在50℃下搅拌16小时,旋干后,在层析柱中加入薄层层析硅胶,将上述样品用空气加压,进行柱层析(柱长33厘米,流速5滴/秒),洗脱剂为石油醚:乙酸乙酯=30:1(体积比),得到目标产物28mg,产率75%,ee值95%。1H NMR(400MHz,CDCl3):δ9.25(s,1H),7.15(d,2H,J=8.79Hz);7.02(d,2H,J=8.79Hz);6.68(d,2H,J=8.78Hz);6.56(d,2H,J=8.78Hz);6.24(dd,1H,J1=10.47Hz,J2=0.99Hz);5.72-5.59(m,1H),5.00-4.87(m,2H);3.73(d,1H,J=10.46Hz);3.45(dq,1H,Jq=10.30Hz,Jd=3.61Hz);2.90(s,6H);2.85(s,6H),2.41-2.30(m,1H);2.07-1.96(m,1H);1.69(d,3H,J=0.86Hz).13CNMR(100MHz,CDCl3):δ195.5,158.1,139.2,135.4,128.6,128.4,116.9,113.0,112.7,54.4,43.6,40.7,40.6,37.8,9.93.HPLC analysis on a Daicel Chiralpak IC column:90/10hexane/i-PrOH,flow rate 1.00mL/min,λ=254nm:Tmajor=18.56min,Tminor=19.96min;HRMS(ESI)exact mass calcd for:C25H33N2O(M+H)+377.2593,found 377.2599;[α]25 D=-15.1(1.00,CHCl3,95%ee).
Claims (9)
1.一种含有酸基的金鸡纳碱伯胺催化剂,其特征在于其结构为如下结构式中的一种:
式中R1为氢、苯基、取代苯基、C1~C6的直链或支链的烷基或C1~C4的烷氧基;
R2为氢、苯基、取代苯基或C1~C6的直链或支链的烷基;
所述取代苯基为烷基、烷氧基、硝基、氰基、酯基或卤素等取代的苯基。
2.根据权利要求1所述的含有酸基的金鸡纳碱伯胺催化剂,其特征在于其结构为如下结构式中的一种:
3.一种权利要求1所述的含有酸基的金鸡纳碱伯胺催化剂的合成方法,其特征在于:
以金鸡纳碱为手性源,经亲核取代、Mitsunobu取代/还原、水解等三步反应合成目标产物,其制备过程可用以下反应式表示:
4.根据权利要求3所述的合成方法,其特征在于包括如下步骤:
步骤1:亲核取代
碱性条件下,酚羟基化合物1与α-氯代酯或磷酰氯在溶剂中发生取代反应,反应结束后通过柱层析分离得到中间产物2或中间产物3;
所述α-氯代酯的结构式如下:
其中,R1为氢、苯基、取代苯基、C1~C6的直链或支链的烷基或C1~C4的烷氧基;
R3为苯基、取代苯基、C1~C6的直链或支链的烷基;
所述磷酰氯的结构式如下:
其中,R2为氢、苯基、取代苯基或C1~C6的直链或支链的烷基;
步骤2:Mitsunobu取代/还原
在溶剂中,偶氮二甲酸二乙酯、叠氮磷酸二苯酯和三苯基磷的存在下,中间产物2上9-位的羟基经Mitsunobu反应转化为叠氮,进一步被还原成伯胺4;
在溶剂中,偶氮二甲酸二乙酯、叠氮磷酸二苯酯和三苯基磷的存在下,中间产物3上9-位的羟基经Mitsunobu反应转化为叠氮,进一步被还原成伯胺5;
步骤3:水解
碱性条件下,在溶剂中,伯胺4或伯胺5上的酯基发生水解,pH值调至酸性,通过柱层析分离得到目标产物——催化剂I、II、III或IV。
5.根据权利要求4所述的合成方法,其特征在于:
步骤1中,所述柱层析分离是使用薄层层析硅胶H柱在空气加压下进行柱层析,洗脱液为体积比100~10:1的二氯甲烷和甲醇混合物。
6.根据权利要求4所述的合成方法,其特征在于:
步骤3中,所述柱层析分离是使用薄层层析硅胶H柱在空气加压下进行柱层析,洗脱液为体积比10~5:5~2:1的二氯甲烷、甲醇和水的混合物。
7.根据权利要求4所述的合成方法,其特征在于:
步骤1、步骤3中,所述碱性条件是指反应体系中加入NaOH、KOH、Na2CO3、Cs2CO3、三乙胺或吡啶等碱。
8.一种权利要求1所述的含有酸基的金鸡纳碱伯胺催化剂的应用,其特征在于:是在不对称反应中作为催化剂使用。
9.根据权利要求8所述的应用,其特征在于:
所述不对称反应为α-碳上带有支链的烯醛在γ位上的烷基化反应。
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