CN117603088A - 一种基于氨基酸乙酯的芳香醛席夫碱及其在不对称烷基化中的应用 - Google Patents
一种基于氨基酸乙酯的芳香醛席夫碱及其在不对称烷基化中的应用 Download PDFInfo
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- CN117603088A CN117603088A CN202311410954.5A CN202311410954A CN117603088A CN 117603088 A CN117603088 A CN 117603088A CN 202311410954 A CN202311410954 A CN 202311410954A CN 117603088 A CN117603088 A CN 117603088A
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- Prior art keywords
- phenyl
- amino acid
- ethyl ester
- mmol
- catalyst
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- -1 Aromatic aldehyde Schiff base Chemical class 0.000 title claims abstract description 104
- 239000002262 Schiff base Substances 0.000 title claims abstract description 31
- 238000005804 alkylation reaction Methods 0.000 title claims abstract description 13
- 230000029936 alkylation Effects 0.000 title claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 17
- 150000003862 amino acid derivatives Chemical class 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 239000000758 substrate Substances 0.000 claims description 15
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 238000011911 α-alkylation Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 54
- 125000000958 aryl methylene group Chemical group 0.000 abstract description 18
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 abstract description 12
- 150000001413 amino acids Chemical class 0.000 abstract description 8
- 238000003442 catalytic alkylation reaction Methods 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 4
- 125000004494 ethyl ester group Chemical group 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 4
- 239000003444 phase transfer catalyst Substances 0.000 abstract description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000007788 liquid Substances 0.000 description 39
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- JCXLZWMDXJFOOI-UHFFFAOYSA-N ethyl 2-aminopropanoate;hydron;chloride Chemical compound [Cl-].CCOC(=O)C(C)[NH3+] JCXLZWMDXJFOOI-UHFFFAOYSA-N 0.000 description 27
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 229940024606 amino acid Drugs 0.000 description 19
- 235000001014 amino acid Nutrition 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- QIGLJVBIRIXQRN-ZETCQYMHSA-N ethyl (2s)-2-amino-4-methylpentanoate Chemical compound CCOC(=O)[C@@H](N)CC(C)C QIGLJVBIRIXQRN-ZETCQYMHSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- QIGLJVBIRIXQRN-UHFFFAOYSA-N DL-leucine ethyl ester Natural products CCOC(=O)C(N)CC(C)C QIGLJVBIRIXQRN-UHFFFAOYSA-N 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
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- OTXINXDGSUFPNU-UHFFFAOYSA-N 4-tert-butylbenzaldehyde Chemical compound CC(C)(C)C1=CC=C(C=O)C=C1 OTXINXDGSUFPNU-UHFFFAOYSA-N 0.000 description 6
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- NOUDPBCEONUCOV-UHFFFAOYSA-N ethyl 2-amino-4-methylpentanoate;hydron;chloride Chemical compound Cl.CCOC(=O)C(N)CC(C)C NOUDPBCEONUCOV-UHFFFAOYSA-N 0.000 description 5
- 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 5
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- 239000004471 Glycine Substances 0.000 description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- WTWBUQJHJGUZCY-UHFFFAOYSA-N cuminaldehyde Chemical compound CC(C)C1=CC=C(C=O)C=C1 WTWBUQJHJGUZCY-UHFFFAOYSA-N 0.000 description 4
- BQIVJVAZDJHDJF-LURJTMIESA-N ethyl (2s)-2-amino-3-methylbutanoate Chemical compound CCOC(=O)[C@@H](N)C(C)C BQIVJVAZDJHDJF-LURJTMIESA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 3
- KRNAJRBXIMJEFF-UHFFFAOYSA-N 4-hexylbenzaldehyde Chemical compound CCCCCCC1=CC=C(C=O)C=C1 KRNAJRBXIMJEFF-UHFFFAOYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- 229960003767 alanine Drugs 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 150000003934 aromatic aldehydes Chemical class 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 3
- 238000003408 phase transfer catalysis Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- GHMOHPITLLRUAC-UHFFFAOYSA-N 3,4,5-trichlorobenzaldehyde Chemical compound ClC1=CC(C=O)=CC(Cl)=C1Cl GHMOHPITLLRUAC-UHFFFAOYSA-N 0.000 description 2
- MAUCRURSQMOFGV-UHFFFAOYSA-N 4-propylbenzaldehyde Chemical compound CCCC1=CC=C(C=O)C=C1 MAUCRURSQMOFGV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000006717 asymmetric allylation reaction Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000006278 bromobenzyl group Chemical group 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- WARHPMHWMSXJRA-UHFFFAOYSA-N ethyl 2-amino-3-(3-methoxy-2-phenylmethoxyphenyl)propanoate Chemical compound CCOC(=O)C(N)CC1=CC=CC(OC)=C1OCC1=CC=CC=C1 WARHPMHWMSXJRA-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- XFFTWZZGUGZURK-UHFFFAOYSA-N 2,3,4,5,6-pentachlorobenzaldehyde Chemical compound ClC1=C(Cl)C(Cl)=C(C=O)C(Cl)=C1Cl XFFTWZZGUGZURK-UHFFFAOYSA-N 0.000 description 1
- DMIYKWPEFRFTPY-UHFFFAOYSA-N 2,6-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(Cl)=C1C=O DMIYKWPEFRFTPY-UHFFFAOYSA-N 0.000 description 1
- SOWRUJSGHKNOKN-UHFFFAOYSA-N 2,6-difluorobenzaldehyde Chemical compound FC1=CC=CC(F)=C1C=O SOWRUJSGHKNOKN-UHFFFAOYSA-N 0.000 description 1
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- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
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- HKEQMVXZDQLSDY-UHFFFAOYSA-N 3-tert-butylbenzaldehyde Chemical compound CC(C)(C)C1=CC=CC(C=O)=C1 HKEQMVXZDQLSDY-UHFFFAOYSA-N 0.000 description 1
- LXPWGAZYJHUWPM-UHFFFAOYSA-N 4-(2-methylpropyl)benzaldehyde Chemical compound CC(C)CC1=CC=C(C=O)C=C1 LXPWGAZYJHUWPM-UHFFFAOYSA-N 0.000 description 1
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 description 1
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- 125000002884 4-methylphenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910014455 Ca-Cb Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
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- 238000010306 acid treatment Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
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- 125000004429 atom Chemical group 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 description 1
- 229960004114 olopatadine Drugs 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 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
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
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Abstract
本发明属于合成化学和催化化学技术领域,具体涉及基于氨基酸乙酯的芳香醛西弗碱(结构式如下所示),及其在相转移催化剂:Maruoka催化剂、简化的Maruoka催化剂、和氘代Maruoka催化剂、氘代简化的Maruoka催化剂的催化下进行不对称催化烷基化反应制备复杂手性氨基酸衍生物及其应用。本发明采用Maruoka催化剂、简化的Maruoka催化剂、氘代Maruoka催化剂、氘代简化的Maruoka催化剂,催化N‑(芳基亚甲基)‑α‑烷基氨基酸乙酯或N‑(芳基亚甲基)甘氨酸乙酯的不对称催化烷基化反应制备复杂手性氨基酸衍生物,效率高,对映选择性好。通过该方法进行不对称烷基化制备手性氨基酸衍生物易于产业化,为复杂手性氨基酸砌块的制备提供了可行方案。该方法成功应用于Olodanrigan和LX9211的关键手性氨基酸中间体的制备。
Description
技术领域
本发明属于合成化学和催化化学技术领域,更具体地,涉及一种基于氨基酸乙酯的芳香醛席夫碱及其通过不对称催化烷基化反应制备复杂手性氨基酸衍生物的方法及其应用。
背景技术
不对称相转移催化是一种绿色、可持续的化学转化方法,是公认的应用于构建手性功能分子并以高对映选择性获得光学纯异构体的最重要且非常实用的策略之一。因此,不对称相转移催化方法引起学术界和工业界越来越广泛的注意和青睐,并因此开发了许多具有高对映选择性的新型不对称转化。
但合成具有实用的、手性的非蛋白质原性和光学活性的氨基酸仍然是一个非常重要且极具挑战性的课题,因为它们在有机化学、药物化学和生物化学(包括生物学)中具有重要意义。不对称相转移催化是一种最可靠、绿色和可持续的转化方法,该催化方法已被公认为实现各种手性氨基酸衍生物的对映选择性合成的最有价值和实用的策略之一。长期以来,N-(芳基亚甲基)甘氨酸叔丁基酯、N-(芳基亚甲基)-α-烷基氨基酸叔丁酯,在手性Maruoka催化剂和碱存在的条件下与卤代烷进行不对称烷基化反应,可以分别得到高对映选择性的α-烷基化氨基酸衍生物、α,α-二烷基化氨基酸衍生物,而叔丁基酯的存在是实现高对映选择性不可缺少的基团。
然而N-(芳基亚甲基)甘氨酸叔丁基酯、N-(芳基亚甲基)-α-烷基氨基酸叔丁酯的实用性受到一定限制,该类物质市场售价高于容易获得的氨基酸甲酯或氨基酸乙酯衍生物。因而使得在工业合成上应用受限。
发明内容
为解决现有技术中N-(芳基亚甲基)甘氨酸叔丁基酯、N-(芳基亚甲基)-α-烷基氨基酸叔丁酯等作为相转移催化剂实用性低的缺陷,本发明提供一种易于成本低廉、选择性高、易于产业化的,基于氨基酸乙酯的芳香醛席夫碱不对称催化烷基化反应制备复杂手性氨基酸衍生物的方法及应用,以替代氨基酸叔丁酯衍生物及其使用上的不足。
为实现上述目的,本发明提供如下技术方案:
一种氨基酸乙酯的芳香醛西弗碱(席夫碱),该席夫碱作为反应模板底物,所述氨基酸乙酯的芳香醛西弗碱的结构式如下所示:
其中,Ar代表苯基或取代苯基、萘基或取代萘基;取代苯基代表苯基上的氢原子被1个或多个取代基取代,取代基选自卤素、三氟甲基、硝基、C1~C22烷基、C1~C22烯基、C1~C22炔基、C1~C22烷氧基、苯基、巯基;
R1代表氢、C1~C22烷基、C1~C22烯基、C1~C22炔基、苯基、取代苯基、萘基或取代萘基;R1代表C1~C22烷基时,烷基上的氢可被卤基、三氟甲基、硝基、苯基、巯基取代;取代基选自卤素、三氟甲基、硝基、C1~C22烷基、C1~C22烯基、C1~C22炔基、C1~C22烷氧基、苯基、巯基。
优选地,Ar代表苯基或取代苯基、萘基。
优选地,R1代表C1~C22烷基、C1~C22烯基、C1~C22炔基时,氢可被苯基取代。
优选地,R1代表氢、C1~C22烷基;具体地,R1代表C1~C22烷基时,Ar代表卤基、硝基、C1~C22烷基、C1~C22烯基、C1~C22炔基、C1~C22烷氧基、苯基或萘基。进一步地,所述卤素为溴、氯、碘或氟。
作为一种优选,本申请中C1~C22烷基以C1~C8烷基内最佳。
本申请同时研究了所述氨基酸乙酯的芳香醛西弗碱在不对称催化反应中的应用。进一步地,所述氨基酸乙酯的芳香醛西弗碱是在不对称烷基化催化反应中的应用。更进一步地,所述氨基酸乙酯的芳香醛西弗碱是在不对称α-烷基化催化反应中的应用。
如前所述,不对称相转移催化是一种最可靠、绿色和可持续的转化方法,该催化方法已被公认为实现各种手性氨基酸衍生物的对映选择性合成的最有价值和实用的策略之一,利用本申请提供的一种新的模板底物化合物,采用常规的催化合成路线,可以通过不对称α-烷基化催化反应用于制备手性氨基酸衍生物。
更进一步地,本申请验证了利用本申请的模板底物化合物进行合成,得到AT2R型拮抗剂Olodanrigan或LX9211的关键中间体。
以上不对称催化反应参考现有路线进行,例如,上述不对称烷基化催化反应为采用所述氨基酸乙酯的芳香醛西弗碱作为模板底物A,将卤代烃作为模板底物B,在Maruoka催化剂、碱和溶剂参与下,得到相应目标物。即解决了现有技术中采用的模板底物A中叔丁基酯带来的应用限制,同时更加简便的实现各种手性氨基酸衍生物的对映选择性合成。
将本申请中提供的新的模板底物化合物应用于不对称催化反应时,所使用的Maruoka催化剂结构式如下中任一或多种:
其中,Ar选自氢,苯基,3,4,5-三氟苯基,3,5-双(三氟甲基)苯基,3,5-双(苯基)苯基,β萘基,3,5-双[3,5-双(苯基)苯基]苯基,3,5-双[3,5-双(三氟甲基)苯基]苯基,3,5-双(3,4,5-三氟苯基)苯基。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~Cb烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,C1~C4烷基是指包含1~4个碳原子的烷基。
所述C1~C6烷基是指C1、C2、C3、C4、C5、C6的烷基,即具有1~6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等等。C1-C6的烷氧基也具有与其基团相应的含义。
与现有技术相比,本发明的有益效果是:
本发明采用Maruoka催化剂、简化的Maruoka催化剂、氘代Maruoka催化剂或氘代简化的Maruoka催化剂,催化N-(芳基亚甲基)-α-烷基氨基酸乙酯或N-(芳基亚甲基)甘氨酸乙酯的不对称烷基化反应,效率高,对映选择性好。通过该方法进行不对称α-烷基化制备手性氨基酸衍生物易于产业化,为复杂手性氨基酸砌块的制备提供了可行方案。该方法成功应用于Olodanrigan和LX9211的关键手性氨基酸中间体的制备。
具体实施方式
下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行制备。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
实施例1化合物的制备和表征
底物亚胺的合成
方法一:
在5mL甲苯中加入芳香醛和1.5当量的氨基酸乙酯盐酸盐溶液,室温下加入1.5等量的三乙胺。在75℃下搅拌18h后,将所得混合物倒入水中,用甲苯提取。有机层用盐水洗涤,用无水硫酸钠干燥,减压浓缩得到相应的氨基乙酯希夫碱,无需进一步纯化即可用于反应。
方法二:
在氨基酸乙酯盐酸盐(1.1当量)溶液中,在二氯甲烷(10mL)中加入无水硫酸镁(1.0当量)和三乙胺(1.0等量),在室温下加入芳香醛。室温搅拌18h后,将所得混合物倒入水中,用二氯甲烷萃取。有机层用盐水洗涤,用无水硫酸钠干燥,减压浓缩得到相应的氨基酸乙酯希夫碱,无需进一步纯化即可用于反应。
2-((4-氯苄基)氨基)丙酸乙酯(11a)
以对氯苯甲醛(500mg,3.6mmol)和DL-丙氨酸乙酯盐酸盐(820mg,5.4mmol)为原料通过方法一得到产物,无色油状液体,770mg,90%收率。1HNMR(400MHz,CDCl3):δ8.28(s,1H),7.77–7.68(m,2H),7.43–7.35(m,2H),4.22–4.13(m,3H),1.53(d,J=6.8Hz,3H),1.28(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.4,161.5,137.1,134.2,129.7,128.9,67.9,61.1,19.4,14.2.
2-((3-氯苄基)氨基)丙酸乙酯(11b)
以间氯苯甲醛(500mg,3.6mmol)和DL-丙氨酸乙酯盐酸盐(600mg,3.9mmol)为原料通过方法二得到产物,无色油状液体,760mg,89%收率。
1H NMR(400MHz,CDCl3):δ8.22(s,1H),7.77–7.66(m,1H),7.55–7.45(m,1H),7.33–7.17(m,2H),4.23–4.14(m,3H),1.47(d,J=6.9Hz,3H),1.23(t,J=7.1Hz,3H);13CNMR(100MHz,CDCl3):δ172.3,161.4,137.5,134.8,131.0,129.8,128.0,126.9,67.8,61.1,19.3,14.2;IR(neat):2983,2937,2873,1739,1647,1597,1571,1474,1191,1128,1097,1076,860,788,707cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C12H15ClNO2 +240.0786;Found240.0794.
2-((3-氟苄基)氨基)丙酸乙酯(11c)
以间氟苯甲醛(500mg,4.0mmol)和DL-丙氨酸乙酯盐酸盐(680mg,4.4mmol)为原料通过方法二得到产物,无色油状液体,810mg,91%收率。1HNMR(400MHz,CDCl3):δ8.29(s,1H),7.59–7.47(m,2H),7.41–7.33(m,1H),7.13–7.11(m,1H),4.27–4.11(m,3H),1.52(d,J=6.8Hz,3H),1.28(t,J=7.2Hz,3H)13C NMR(100MHz,CDCl3):δ172.3,163.1(d,JC-F=246.5Hz),161.7(d,JC-F=2.9Hz),138.3(d,JC-F=7.3Hz),130.3(d,JC-F=8.0Hz),124.8(d,JC-F=2.9Hz),118.2(d,JC-F=21.5Hz),114.7(d,JC-F=21.9Hz),68.0,61.3,19.5,14.3;19FNMR(376MHz,CDCl3)δ-112.9;IR(neat):2984,2938,2872,1736,1647,1588,1488,1451,1194,1128,1050,1022,884,788cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C12H15FNO2 +224.1081;Found 224.1086.
2-((4-氟苄基)氨基)丙酸乙酯(11d)
以对氟苯甲醛(500mg,4.0mmol)和DL-丙氨酸乙酯盐酸盐(680mg,4.4mmol)为原料通过方法二得到产物,无色油状液体,710mg,79%收率。1HNMR(400MHz,CDCl3):δ8.26(s,1H),7.78–7.73(m,2H),7.10–7.04(m,2H),4.21–4.10(m,3H),1.51(d,J=6.8Hz,3H),1.28(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.4,164.5(d,JC-F=251.3Hz),161.3,132.1(d,JC-F=3.0Hz),130.4(d,JC-F=8.8Hz),115.6(d,JC-F=21.9Hz),67.8,61.0,19.3,14.1;19F NMR(376MHz,CDCl3)δ-109.3.
2-((3,5-二氟苄基)氨基)丙酸乙酯(11e)
以3,5-二氟苯甲醛(500mg,3.5mmol)和DL-丙氨酸乙酯盐酸盐(600mg,3.9mmol)为原料通过方法二得到产物,无色油状液体,750mg,89%收率。1HNMR(400MHz,CDCl3):δ8.28(s,1H),7.80–7.75(m,2H),7.13–7.07(m,1H),4.23–4.12(m,3H),1.51(d,J=6.9Hz,3H),1.28(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.4,164.5(d,JC-F=251.3Hz),161.3,132.0(d,JC-F=3.1Hz),130.4(d,JC-F=8.7Hz),115.6(d,JC-F=22.0Hz),67.8,61.0,19.3,14.1;19F NMR(376MHz,CDCl3)δ-108.8,-108.9;IR(neat):2985,2939,2876,1736,1624,1597,1445,1192,1120,1050,1021,858,780cm-1;HRMS(ESI)m/z:[M+H]+Calcd forC12H14F2NO2+242.0987;Found 242.0991.
2-((4-三氟甲基苄基)氨基)丙酸乙酯(11f)
以对三氟甲基苯甲醛(500mg,2.8mmol)和DL-丙氨酸乙酯盐酸盐(486mg,3.2mmol)为原料通过方法二得到产物,无色油状液体,680mg,87%收率。1HNMR(400MHz,CDCl3):δ8.37(s,1H),7.91–7.88(m,2H),7.69–7.66(m,2H),4.23–4.17(m,3H),1.55(d,J=6.8Hz,3H),1.28(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.1,161.3,138.8,132.5(q,JC-F=33.8Hz),128.6,125.4(q,JC-F=4.4Hz),123.8(q,JC-F=272.5Hz),67.9,61.0,19.2,14.0;19FNMR(376MHz,CDCl3)δ-62.9;IR(neat):2986,2939,2877,1739,1647,1620,1582,1449,1166,1125,1066,1018,840,763cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C13H15F3NO2+274.1049;Found 274.1053.
2-((4-甲氧基苄基)氨基)丙酸乙酯(11g)
以对甲氧基苯甲醛(500mg,3.7mmol)和DL-丙氨酸乙酯盐酸盐(620mg,4mmol)为原料通过方法二得到产物,无色油状液体,750mg,87%收率。1HNMR(400MHz,CDCl3):δ8.24(s,1H),7.74–7.71(m,2H),6.94–6.91(m,2H),4.23–4.16(m,2H),4.13–4.06(q,J=6.8Hz,1H),3.84(s,3H),1.52(d,J=6.8Hz,3H),1.29(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.7,162.1,161.9,130.1,128.7,113.9,67.9,60.9,55.3,19.4,14.1.
2-((4-甲基苄基)氨基)丙酸乙酯(11h)
以对甲基苯甲醛(500mg,4.2mmol)和DL-丙氨酸乙酯盐酸盐(700mg,4.6mmol)为原料通过方法二得到产物,无色油状液体,720mg,79%收率。1H NMR(400MHz,CDCl3):δ8.27(s,1H),7.67(dd,J=8.1,2.1Hz,2H),7.22(dd,J=8.3,3.4Hz,2H),4.22–4.16(m,2H),4.15–4.08(q,J=6.9Hz,1H),2.38(s,3H),1.53(d,J=6.8Hz,3H),1.28(t,J=7.1Hz,3H);13CNMR(100MHz,CDCl3):δ172.7,162.7,141.4,133.2,129.3,128.4,68.0,61.0,21.5,19.4,14.1.
2-((4-正丙基苄基)氨基)丙酸乙酯(11i)
以对正丙基苯甲醛(500mg,3.4mmol)和DL-丙氨酸乙酯盐酸盐(570mg,3.7mmol)为原料通过方法二得到产物,无色油状液体,790mg,94%收率。1HNMR(400MHz,CDCl3):δ8.28(s,1H),7.72–7.66(m,2H),7.24–7.19(m,2H),4.25–4.07(m,3H),2.63–2.57(m,2H),1.71–1.57(m,2H),1.52(d,J=6.8Hz,3H),1.27(t,J=7.1Hz,3H),0.93(t,J=7.3Hz,3H);13CNMR(100MHz,CDCl3):δ172.6,162.7,146.1,133.4,128.7,128.4,68.0,60.9,37.9,24.3,19.4,14.1,13.7;IR(neat):2961,2934,2872,1739,1643,1609,1572,1511,1449,1419,1190,1126,1049,1020,862,799cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C15H22NO2+248.1645;Found 248.1647.
2-((4-正己基苄基)氨基)丙酸乙酯(11j)
以对正己基苯甲醛(350mg,1.9mmol)和DL-丙氨酸乙酯盐酸盐(430mg,2.8mmol)为原料通过方法一得到产物,无色油状液体,410mg,76%收率。1H NMR(400MHz,CDCl3):δ8.28(s,1H),7.70–7.66(m,2H),7.23–7.20(m,2H),4.22–4.10(m,3H),2.65–2.60(m,2H),1.63–1.60(m,2H),1.52(d,J=6.8Hz,3H),1.34–1.25(m,9H),0.90–0.85(m,3H);13C NMR(100MHz,CDCl3):δ172.6,162.7,146.4,133.3,128.6,128.4,68.0,60.9,35.9,31.6,31.2,28.8,22.5,19.4,14.1,14.0;IR(neat):2930,2856,1736,1642,1609,1572,1510,1419,1187,1126,1050,1020,829,777cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C18H28NO2 +290.2115;Found290.2115.
2-((4-异丁基苄基)氨基)丙酸乙酯(11k)
以对异丁基苯甲醛(500mg,3.1mmol)和DL-丙氨酸乙酯盐酸盐(520mg,3.4mmol)为原料通过方法二得到产物,无色油状液体,787mg,98%收率。1HNMR(400MHz,CDCl3):δ8.29(s,1H),7.69(d,J=8.0Hz,2H),7.19(d,J=7.9Hz,2H),4.23–4.10(m,3H),2.50(d,J=7.2Hz,2H),1.96–1.80(m,1H),1.52(d,J=6.8Hz,3H),1.28(t,J=7.1Hz,3H),0.90(d,J=6.6Hz,6H);13C NMR(100MHz,CDCl3):δ172.6,162.8,145.2,133.4,129.3,128.3,68.0,61.0,45.3,30.1,22.3,19.4,14.1;IR(neat):2957,2933,2870,1739,1643,1572,1466,1189,1126,1049,1020,847,788cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C16H24NO2+262.1802;Found 262.1806.
2-((4-异丙基苄基)氨基)丙酸乙酯(11l)
以对异丙基苯甲醛(500mg,3.4mmol)和DL-丙氨酸乙酯盐酸盐(570mg,3.7mmol)为原料通过方法二得到产物,无色油状液体,770mg,92%收率。1HNMR(400MHz,CDCl3):δ8.28(s,1H),7.72–7.68(m,2H),7.28–7.25(m,2H),4.22–4.10(m,3H),2.95–2.91(m,2H),1.51(d,J=6.8Hz,3H),1.27–1.24(m,9H);13C NMR(100MHz,CDCl3):δ172.5,162.6,152.2,133.5,128.5,126.6,68.0,60.8,34.0,23.7,19.3,14.1;IR(neat):2962,2872,1736,1681,1643,1572,1459,1177,1127,1054,1019,832,776cm-1;HRMS(ESI)m/z:[M+H]+Calcd forC15H22NO2+248.1645;Found 248.1653.
2-((4-叔丁基苄基)氨基)丙酸乙酯(11m)
以对叔丁基苯甲醛(500mg,3.1mmol)和DL-丙氨酸乙酯盐酸盐(520mg,3.4mmol)为原料通过方法二得到产物,无色油状液体,760mg,94%收率。1H NMR(400MHz,CDCl3):δ8.29(s,1H),7.73–7.70(m,2H),7.45–7.42(m,2H),4.22–4.10(m,3H),1.52(d,J=6.8Hz,3H),1.33(s,9H),1.27(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.6,162.6,154.5,133.1,128.3,125.5,68.1,60.9,34.9,31.1,19.4,14.1;IR(neat):2966,2905,2871,1736,1643,1609,1569,1463,1189,1050,1021,834,777cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C16H24NO2 +262.1802;Found 262.1813.
2-((4-苯基苄基)氨基)丙酸乙酯(11n)
以联苯甲醛(500mg,2.7mmol)和DL-丙氨酸乙酯盐酸盐(520mg,3.4mmol)为原料通过方法二得到产物,无色油状液体,722mg,94%收率。1HNMR(400MHz,CDCl3):δ8.35(s,1H),7.88–7.81(m,2H),7.66–7.59(m,4H),7.47–7.41(m,2H),7.39–7.32(m,1H),4.30–4.15(m,3H),1.54(d,J=6.8Hz,3H),1.28(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.9,162.8,144.1,140.6,135.0,129.2,129.1,128.1,127.6,127.4,68.4,61.3,19.7,14.5;IR(neat):2982,2936,2873,1736,1640,1607,1487,1449,1188,1128,1049,840,764cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C18H20NO2 +282.1489;Found 282.1505.
2-((2-萘基)氨基)丙酸乙酯(11o)
以2-萘甲醛(500mg,3.2mmol)和DL-丙氨酸乙酯盐酸盐(540mg,3.5mmol)为原料通过方法二得到产物,白色固体,776mg,95%收率。1HNMR(400MHz,CDCl3):δ8.49(s,1H),8.11–8.04(m,2H),7.90–7.85(m,3H),7.56–7.52(m,2H),4.28–4.22(m,3H),1.61(d,J=6.8Hz,3H),1.28(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.6,162.9,134.8,133.4,132.9,130.4,128.6,128.4,127.8,127.3,126.4,124.0,68.0,61.0,19.4,14.1;IR(neat):2982,2938,2871,1741,1640,1596,1450,1189,1129,1023,864,833,754cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C16H18NO2 +256.1332;Found 256.1342.
2-((2,6-二氯苄基)氨基)丙酸乙酯(11p)
以2,6-二氯苯甲醛(500mg,2.9mmol)和DL-丙氨酸乙酯盐酸盐(480mg,3.1mmol)为原料通过方法二得到产物,白色固体,730mg,93%收率。1HNMR(400MHz,CDCl3):δ8.46(s,1H),7.34–7.19(m,3H),4.25–4.19(m,3H),1.56(d,J=6.8Hz,3H),1.27(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ171.7,158.7,134.6,132.9,130.5,128.5,128.4,68.6,61.1,19.1,14.1;IR(neat):2983,2918,2874,1736,1638,1580,1562,1433,1185,1150,1090,1019,823,715cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C12H14Cl2NO2 +274.0396;Found274.0399.
2-((3,5-二氯苄基)氨基)丙酸乙酯(11q)
以3,5-二氯苯甲醛(500mg,2.9mmol)和DL-丙氨酸乙酯盐酸盐(480mg,3.1mmol)为原料通过方法二得到产物,无色油状液体,730mg,93%收率。1HNMR(400MHz,CDCl3):δ8.21(s,1H),7.67–7.65(m,2H),7.64–7.40(m,1H),4.23–4.14(m,3H),1.54–1.49(m,3H),1.27(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.0,160.0,138.5,135.4,130.8,126.7,126.6,67.7,61.2,19.2,14.1;IR(neat):2983,2937,2873,1736,1649,1588,1566,1423,1129,1113,1050,1021,860,739cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C12H14Cl2NO2 +274.0396;Found 274.0398.
2-((3,4,5-三氯苄基)氨基)丙酸乙酯(11r)
以3,4,5-三氯苯甲醛(500mg,2.4mmol)和DL-丙氨酸乙酯盐酸盐(410mg,2.6mmol)为原料通过方法二得到产物,无色油状液体,710mg,91%收率。1H NMR(400MHz,CDCl3):δ8.19(s,1H),7.81–7.78(m,2H),4.23–4.15(m,3H),1.53(d,J=6.8Hz,3H),1.28(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ171.9,159.2,135.5,134.7,128.1,128.0,67.7,61.2,19.2,14.1;IR(neat):2982,2937,2873,1735,1685,1648,1551,1430,1191,1128,1046,1021,868,805,728cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C12H13Cl3NO2 +308.0006;Found308.0008.
2-((2,6-二氟苄基)氨基)丙酸乙酯(11s)
以2,6-二氟苯甲醛(500mg,3.5mmol)和DL-丙氨酸乙酯盐酸盐(600mg,3.9mmol)为原料通过方法二得到产物,无色油状液体,760mg,90%收率。1H NMR(400MHz,CDCl3):δ8.50(s,1H),7.35–7.31(m,1H),6.95–6.87(m,2H),4.22–4.11(m,3H),1.57–1.52(m,3H),1.22–1.14(m,3H);13C NMR(100MHz,CDCl3):δ172.0,161.7(d,JC-F=259Hz),161.6(d,JC-F=259Hz),153.7,131.9(t,JC-F=10.8Hz),112.0(t,JC-F=1.9Hz),111.8(m),69.3,61.1,19.2,14.1.
2-((3,4,5-三氟苄基)氨基)丙酸乙酯(11t)
以3,4,5-三氯苯甲醛(500mg,3.1mmol)和DL-丙氨酸乙酯盐酸盐(530mg,3.4mmol)为原料通过方法二得到产物,无色油状液体,750mg,93%收率。1H NMR(400MHz,CDCl3):δ8.17(s,1H),7.44–7.39(m,2H),4.23–4.13(m,3H),1.50(d,J=6.9Hz,3H),1.25(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3):δ172.0,159.3,159.3,131.8(m),112.3(dd,JC-F=16.2,6.0Hz),67.4,61.2,19.2,14.1;IR(neat):2986,2940,2876,1732,1652,1621,1594,1531,1446,1044,1201,860,784cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C12H13F3O2 +260.0893;Found260.0896.
2-((2,3,4,5,6-五氟苄基)氨基)丙酸乙酯(11u)
以五氯苯甲醛(500mg,2.6mmol)和DL-丙氨酸乙酯盐酸盐(430mg,2.8mmol)为原料通过方法二得到产物,无色油状液体,591mg,79%收率。1HNMR(400MHz,CDCl3):δ8.41(s,1H),4.31–4.05(m,3H),1.54(d,J=6.8Hz,3H),1.27(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ171.4,151.2,145.9(dt,JC-F=257.5,JC-F=15.6Hz),142.3(dt,JC-F=258.4,JC-F=13.7Hz),138.9,110.9(t,JC-F=23.9Hz),69.1,61.3,19.0,14.0;IR(neat):2988.7,2940.6,2885.0,1735.6,1655.2,1523.9,1422.8,1125.6,1004.5,861.1,796.4cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C12H11F3O2 +296.0710;Found 296.0706.
2-((4-硝基苄基)氨基)丙酸乙酯(11v)
以4-硝基苯甲醛(500mg,3.3mmol)和DL-丙氨酸乙酯盐酸盐(560mg,3.6mmol)为原料通过方法二得到产物,无色油状液体,800mg,96%收率。1HNMR(400MHz,CDCl3):δ8.39(s,1H),8.28–8.23(m,2H),7.97–7.91(m,2H),4.25–4.15(m,3H),1.54(d,J=6.8Hz,3H),1.27(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3):δ171.9,160.5,149.3,141.2,129.2,123.9,123.8,77.4,77.1,76.8,67.9,61.3,19.3,14.2;IR(neat):2982,2951,2893,1735,1693,1560,1522,1448,1108,1016,857,750cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C12H15N2O2 +251.1026;Found 251.1029.
2-((2,6-二甲基苄基)氨基)丙酸乙酯(11w)
以2,6-二甲基苯甲醛(300mg,2.2mmol)和DL-丙氨酸乙酯盐酸盐(380mg,2.5mmol)为原料通过方法二得到产物,无色油状液体,490mg,94%收率。1H NMR(400MHz,CDCl3):δ8.62(s,1H),7.14–7.12(m,1H),7.04–7.01(m,2H),4.19–4.07(m,3H),2.40(s,6H),1.54(d,J=6.8Hz,3H),1.28(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3):δ172.3,163.4,137.1,133.8,128.9,128.2,68.8,60.9,20.2,19.3,14.1;IR(neat):2981,2935,2871,1739,1690,1643,1595,1465,1191,1127,1053,861,773cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C14H20NO2 +234.1489;Found 234.1494.
2-((3,5-二甲基苄基)氨基)丙酸乙酯(11x)
以3,5-二甲基苯甲醛(500mg,3.7mmol)和DL-丙氨酸乙酯盐酸盐(630mg,4.1mmol)为原料通过方法二得到产物,无色油状液体,720mg,83%收率。1H NMR(400MHz,CDCl3):δ8.25(s,1H),7.40–7.38(m,2H),7.08–7.05(m,1H),4.28–4.09(m,3H),2.34(s,3H),2.32(s,3H),1.52(d,J=6.8Hz,3H),1.27(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.6,163.3,138.1,135.7132.8,126.2,68.1,61.0,21.0,19.4,14.1;IR(neat):2982,2935,2869,1736,1638,1605,1506,1449,1187,1126,1050,854,778cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C14H20NO2 +234.1489;Found 234.1493.
2-((2,6-异丙基苄基)氨基)丙酸乙酯(11y)
以2,6-异丙基苯甲醛(300mg,1.6mmol)和DL-丙氨酸乙酯盐酸盐(270mg,1.7mmol)为原料通过方法二得到产物,无色油状液体,260mg,56%收率。1H NMR(400MHz,CDCl3):δ8.73(s,1H),7.32–7.25(m,1H),7.15(d,J=7.8Hz,2H),4.24–4.16(m,3H),3.30–3.10(m,2H),1.57–1.55(m,3H),1.33–1.24(m,3H),1.22(d,J=8.8Hz,6H),1.19(d,J=6.8Hz,6H);13C NMR(100MHz,CDCl3):δ172.1,164.1,146.6,133.4,129.1,122.6,68.9,61.0,29.5,23.6,23.4,18.9,14.1;IR(neat):2963,2910,2870,1740,1650,1592,1459,1191,1124,1054,802,749cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C18H28NO2 +290.2115;Found290.2118.
2-((3,5-叔丁基苄基)氨基)丙酸乙酯(11z)
以3,5-叔丁基苯甲醛(500mg,2.3mmol)和DL-丙氨酸乙酯盐酸盐(380mg,2.5mmol)为原料通过方法二得到产物,无色油状液体,620mg,86%收率。1H NMR(400MHz,CDCl3):δ8.33(s,1H),7.61(d,J=1.9Hz,2H),7.52(d,J=1.9Hz,1H),4.25–4.09(m,3H),1.53(d,J=6.8Hz,3H),1.35(s,18H),1.28(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.6,163.8,151.0,135.2,125.3,122.8,68.0,60.8,34.8,31.3,31.2,19.3,14.1;IR(neat):2962,2916,2889,1736,1698,1596,1477,1189,1125,1050,878,707cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C18H28NO2 +318.2433;Found 318.2428.
2-((3,5-苯基苄基)氨基)丙酸乙酯(11A)
以3,5-苯基苯甲醛(350mg,1.4mmol)和DL-丙氨酸乙酯盐酸盐(230mg,1.5mmol)为原料通过方法二得到产物,无色油状液体,390mg,81%收率。1H NMR(400MHz,CDCl3):δ8.43(s,1H),7.98(d,J=1.7Hz,2H),7.87(s,1H),7.72–7.62(m,4H),7.51–7.41(m,4H),7.38(d,J=7.3Hz,2H),4.29–4.10(m,3H),1.56(d,J=6.8Hz,3H),1.28(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ172.5,162.7,142.2,140.4,136.8,128.8,128.7,127.7,127.3,126.1,68.1,61.1,19.4,14.2;IR(neat):2980,2951,2883,1736,1647,1595,1499,1188,1126,1068,881,758cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C18H28NO2 +358.1807;Found358.1802.
2-((4-苯基苄基)氨基)亮氨酸乙酯(13a)
以联苯甲醛(500mg,2.7mmol)和DL-亮氨酸乙酯盐酸盐(806mg,4.1mmol)为原料通过方法一得到产物,无色油状液体,800mg,90%收率。1HNMR(400MHz,CDCl3):δ8.34(s,1H),7.89–7.81(m,2H),7.67–7.43(m,4H),7.48–7.37(m,3H),4.21–4.09(m,3H),1.88–1.85(m,2H),1.63–1.54(m,1H),1.35–1.25(m,3H),0.98–0.90(m,6H);13C NMR(100MHz,CDCl3):δ172.5,162.6,143.8,140.3,134.7,129.0,128.9,127.8,127.3,127.2,71.7,61.0,42.1,24.4,23.1,21.5,14.2;IR(neat):2968,2955,2869,1747,1643,1558,1448,1182,1142,1066,866,767cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C21H26NO2 +324.1958;Found324.1959.
2-((4-异丙基苄基)氨基)亮氨酸乙酯(13b)
以对异丙基苯甲醛(500mg,3.4mmol)和DL-亮氨酸乙酯盐酸盐(990mg,5.1mmol)为原料通过方法一得到产物,无色油状液体,850mg,87%收率。1H NMR(400MHz,CDCl3):δ8.26(s,1H),7.73–7.70(m,2H),7.28(d,J=8.2Hz,2H),4.23–4.02(m,3H),2.94(m,1H),1.90–1.79(m,2H),1.60–1.24(m,9H),0.99–0.88(m,6H);13C NMR(100MHz,CDCl3):δ172.6,162.8,152.3,133.5,128.6,126.6,71.7,60.9,60.8,42.0,34.1,24.4,23.8,23.1,21.4,14.2;IR(neat):2959,2871,1739,1644,1609,1572,1466,1179,1142,1097,1054,832,778cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C18H28NO2 +290.2115;Found 290.2116.
2-((4-叔丁基苄基)氨基)亮氨酸乙酯(13c)
以对叔丁基苯甲醛(500mg,3.1mmol)和DL-亮氨酸乙酯盐酸盐(910mg,4.7mmol)为原料通过方法一得到产物,无色油状液体,730mg,78%收率。1H NMR(400MHz,CDCl3):δ8.27(s,1H),7.77–7.71(m,2H),7.46–7.43(m,2H),4.21–4.04(m,3H),1.88–1.79(m,2H),1.33(s,9H),1.28(t,J=7.1Hz,3H),0.97–0.91(m,6H);13C NMR(100MHz,CDCl3):δ172.6,162.8,154.6,133.1,128.3,125.5,71.8,60.9,42.0,34.9,31.2,31.1,24.4,23.2,21.4,14.2;IR(neat):2956,2906,2871,1736,1681,1609,1509,1466,1182,1108,1030,832,739cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C19H29NO2 +304.2271;Found 304.2272.
2-((4-正丁基苄基)氨基)亮氨酸乙酯(13d)
以对正丁基苯甲醛(500mg,3.1mmol)和DL-亮氨酸乙酯盐酸盐(910mg,4.7mmol)为原料通过方法一得到产物,无色油状液体,820mg,88%收率。1H NMR(400MHz,CDCl3):δ8.26(s,1H),7.71–7.68(m,2H),7.24–7.21(m,2H),4.21–4.02(m,3H),2.61(t,J=7.7Hz,2H),1.91–1.79(m,2H),1.68–1.57(m,4H),1.27(t,J=7.1Hz,3H),0.95–0.89(m,9H);13CNMR(100MHz,CDCl3):δ172.6,162.9,146.2,133.4,128.7,128.5,71.7,60.9,42.1,38.0,24.4,24.3,23.1,21.4,14.2,13.7;IR(neat):2957,2871,1736,1685,1610,1572,1511,1419,1181,1031,832,799cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C19H30NO2 +304.2271;Found304.2272.
2-((4-正己基苄基)氨基)亮氨酸乙酯(13e)
以对正己基苯甲醛(390mg,2.1mmol)和DL-亮氨酸乙酯盐酸盐(605mg,3.1mmol)为原料通过方法一得到产物,无色油状液体,610mg,90%收率。1H NMR(400MHz,CDCl3):δ8.26(s,1H),7.71–7.68(m,2H),7.22(d,J=7.9Hz,2H),4.25–4.13(m,2H),4.04(q,J=8.8Hz,1H),2.66–2.60(m,2H),1.87–1.80(m,2H),1.64–1.53(m,3H),1.35–1.25(m,9H),
0.96–0.86(m,9H);13C NMR(100MHz,CDCl3):δ172.6,162.9,146.4,133.3,128.6,128.5,71.7,60.9,42.1,35.9,31.7,31.2,28.9,24.4,23.1,22.6,21.4,14.2,14.1;IR(neat):2955,2935,2868,1743,1647,1578,1570,1466,1174,1031,825,776cm-1;HRMS(ESI)m/z:[M+H]+
Calcd for C21H34NO2 +332.2584;Found 332.2586.
2-((4-苯基苄基)氨基)苯丙氨酸乙酯(15)
以联苯甲醛(500mg,2.7mmol)和DL-苯丙氨酸乙酯盐酸盐(950mg,4.1mmol)为原料通过方法一得到产物,白色固体,940mg,96%收率。1HNMR(400MHz,CDCl3):δ8.00(s,1H),7.77–7.74(m,2H),7.63–7.58(m,4H),7.46–7.42(m,2H),7.38–7.26(m,1H),7.25–7.17(m,4H),4.22–4.15(m,3H),3.42(dd,J=13.6,5.3Hz,1H),3.20(dd,J=13.6,8.7Hz,1H),1.29(t,J=7.0Hz,3H);13C NMR(100MHz,CDCl3):δ171.6,163.2,143.7,140.3,137.4,134.5,129.7,129.3,128.9,128.8,128.5,128.3,127.8,127.2,127.1,126.5,75.1,61.1,39.8,14.1;IR(neat):2980,2966,2872,1736,1647,1601,1585,1562,1488,1454,1175,1083,1032,841,764.4cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C24H24NO2 +358.1802;Found358.1802.
2-((4-苯基苄基)氨基)缬氨酸乙酯(17)
以联苯甲醛(500mg,2.7mmol)和DL-缬氨酸乙酯盐酸盐(750mg,4.1mmol)为原料通过方法一得到产物,白色固体,770mg,90%收率。1HNMR(400MHz,CDCl3):δ8.21(s,1H),7.81–7.78(m,2H),7.59–7.55(m,4H),7.54–7.52(m,2H),7.40–7.29(m,1H),4.15(q,J=7.1Hz,2H),3.66(d,J=7.5Hz,1H),2.41–2.25(m,1H),1.29(t,J=7.2,3H),0.93–0.86(m,6H);13CNMR(100MHz,CDCl3):δ172.0,162.7,143.8,140.4,134.7,129.0,128.8,127.8,127.2,127.1,80.6,60.8,31.7,19.5,18.7,14.2;IR(neat):2959.8,2870.2,2849.2,1737.5,1639.1,1604.6,1581.5,1468.7,1180.4,1136.6,1028.8,841.0,760.4cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C20H24NO2 +310.1802;Found 310.1803.
2-((4-正丙基苄基)氨基)甘氨酸乙酯(19a)
以对正丙基苯甲醛(500mg,3.4mmol)和DL-甘氨酸乙酯盐酸盐(520mg,3.7mmol)为原料通过方法二得到产物,无色油状液体,510mg,67%收率。1H NMR(400MHz,CDCl3):δ8.24(s,1H),7.69(d,J=8.1Hz,2H),7.22(d,J=7.9Hz,2H),4.37(s,2H),4.22(q,J=7.2Hz,2H),2.62(t,J=7.6Hz,2H),1.65(q,J=7.5Hz,3H),1.30(t,J=7.1Hz,3H),0.93(t,J=7.3Hz,3H);13C NMR(100MHz,CDCl3):δ170.1,165.1,146.1,133.1,128.6,128.3,61.9,60.8,37.8,24.1,14.0,13.6;IR(neat):2960,2931,2871,1737,1645,1608,1572,1513,1464,1186,1096,1030,831,798.3cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C14H20NO2 +234.1489;
Found 234.1489.
2-((4-正己基苄基)氨基)甘氨酸乙酯(19b)
以对正己基苯甲醛(1400mg,7.4mmol)和DL-甘氨酸乙酯盐酸盐(1540mg,11.0mmol)为原料通过方法一得到产物,无色油状液体,1940mg,96%收率。1H NMR(400MHz,CDCl3):δ8.26(s,1H),7.67(d,J=7.9Hz,2H),7.23(d,J=7.9Hz,2H),4.37(s,2H),4.27–4.17(q,J=7.2Hz,2H),,2.63(t,J=7.7Hz,2H),,1.62–1.53(m,2H),1.34–1.29(m,9H),0.90–0.85(m,3H);13C NMR(100MHz,CDCl3):δ170.2,165.3,151.1,133.1,128.6,128.4,62.1,60.9,35.9,31.6,31.1,28.8,22.5,14.1,14.0;IR(neat):2929,2856,1740,1609,1571,1514,1458,1197,1097,1025,827,725cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C15H26NO2 +276.1958;Found276.1960.
2-((4-异丙基苄基)氨基)甘氨酸乙酯(19c)
以对异丙基苯甲醛(500mg,3.4mmol)和DL-甘氨酸乙酯盐酸盐(520mg,3.7mmol)为原料通过方法二得到产物,无色油状液体,590mg,75%收率。1HNMR(400MHz,CDCl3):δ8.25(s,1H),7.72–7.69(m,2H),7.28(d,J=8.1Hz,2H),4.25(s,2H),4.20(q,J=7.1Hz,2H),2.95–2.91(m,1H),1.32–1.24(m,9H);13C NMR(100MHz,CDCl3):δ170.1,165.2,152.3,133.3,128.5,126.6,62.1,60.1,34.0,23.7,14.1;IR(neat):2960,2912,2872,1738,1647,1610,1572,1512,1463,1421,1186,1097,1054,830,732cm-1;HRMS(ESI)m/z:[M+H]+Calcdfor C14H19NO2 +234.1489;Found 234.1489.
2-((4-叔丁基苄基)氨基)甘氨酸乙酯(19d)
以对叔丁基苯甲醛(500mg,3.4mmol)和DL-甘氨酸乙酯盐酸盐(710mg,5.1mmol)为原料通过方法一得到产物,无色油状液体,730mg,78%收率。1HNMR(400MHz,CDCl3):δ8.26(s,1H),7.74–7.69(m,2H),7.48–7.33(m,2H),4.38(s,2H),4.23(q,J=7.2Hz,2H),1.33(s,9H),1.29(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3):δ170.2,165.2,154.7,133.0,128.3,125.5,62.2,61.0,60.8,34.9,31.2,31.0,29.7,14.2.
2-((4-苯基苄基)氨基)甘氨酸乙酯(19e)
以联苯甲醛(2000mg,11.0mmol)和DL-甘氨酸乙酯盐酸盐(1840mg,13.2mmol)为原料通过方法二得到产物,白色固体,2690mg,86%收率。1HNMR(400MHz,CDCl3):δ8.33(s,1H),7.85(d,J=7.9Hz,2H),7.69–7.58(m,4H),7.45(t,J=7.5Hz,2H),7.37(t,J=7.3Hz,1H),4.42(s,2H),4.25(q,J=7.2Hz,2H),1.31(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3):δ170.2,165.0,143.9,140.2,134.5,128.9,128.8,127.8,127.3,127.1,62.1,61.1,14.2.
实施例2化合物的应用一:丙氨酸乙酯希夫碱11的不对称苄基化
在简化的Maruoka催化剂(S)-10(1mol%)和50%KOH水溶液(2mL)存在下,在氩气气氛下,0℃条件下,丙氨酸乙酯席夫碱10(1.25mmol)进行了不对称苄基化反应。同时硅胶柱层析后进行分离,并计算分离收率,结果如表1所示,使用氘代简化的Maruoka催化剂,得到一样的结果。催化反应如下:
表1
从表1中,可以看到,在不对称相转移条件下,芳醛(ArCHO)中芳基(Ar)部分对N-(芳基亚甲基)丙氨酸乙酯11不对称烷基化反应的影响。因此,我们在(S)-简化Maruoka (S)-10的存在下(也可采用其他催化剂,本申请对此不做严格限制),在0℃下,用50%KOH水溶液与苄溴(1.2当量)在甲苯中进行了各种N-(芳基亚甲基)丙氨酸乙酯11与苄溴(1.2当量)的不对称苄基化反应,反应时间为6小时,选择性的结果总结在表1中。首先,对常用的N-(对氯苯基亚甲基)丙氨酸乙酯11a进行不对称苄基化,然后进行酸处理,得到(R)-2-氨基-2-甲基-3-苯基丙酸乙酯(12),收率为74%,ee为92%(第一行)。
将底物转换为N-(3-氯苯基亚甲基)丙氨酸乙酯11b,得到(R)-氨基乙酯12,产率为76%,ee为86%(第二行)。N-(聚氯苯亚甲基)丙氨酸乙酯的使用降低了对映体选择性(55~70%ee);在氟化苯基底物的情况下,N-(3-氟苯基亚甲基)丙氨酸乙酯11c在12中比N-(4-氟苯基亚甲基)丙氨酸乙酯11d具有更好的对映选择性(第三行对比第四行)。N-(3,5-二氟苯基亚甲基)丙氨酸乙酯11e产率82%,ee为90%(第五行)。其他N-(多氟苯基亚甲基)丙氨酸乙酯的使用降低了对映体选择性(81~85%ee)。N-(4-(三氟甲基)苯基亚甲基)丙氨酸乙酯11f含有95%ee(第六行)。含有供电子甲氧基和甲基取代基的底物,如N-(4-甲氧基苯基亚甲基)丙氨酸乙酯11g和N-(4-甲基苯基亚甲基)丙氨酸乙酯11h,在12(第七行和第八行)中也表现出很高的对映选择性。在具有N-(4-烷基苯基亚甲基)丙氨酸乙酯等烷基取代基的底物中,11i~11m(烷基=丙基、己基、异丁基、异丙基和叔丁基),11i、11j、11l和11m对12具有优异的对映选择性(ee为95~98%;第九行到第十三行)。
此外,N-(4-苯基苯基亚甲基)丙氨酸乙酯11n的使用对12(第十四行)也有很高的对映选择性(96%ee),尽管N-(2-萘基亚甲基)丙氨酸乙酯11o对映选择性略低(第十五行)。
化合物的应用二:a-烷基氨基酸衍生物的不对称相转移烷基化反应,具体反应和收率如下:
具体制备和表征如下:亮氨酸乙酯席夫碱不对称苄基化
将溴苄(210mg,1.20mmol)在0℃氩气气氛下缓慢加入到N-(芳基亚甲基)亮氨酸乙酯13(1.00mmol)和(S)-10(7.8mg,1mol%)和碱(CsOH.H2O(840mg,5.00mmol)或50%KOH水溶液(2mL))的甲苯(6mL)溶液中。将反应混合物在相同温度下剧烈搅拌6-48h,将反应混合物倒入冰水(20mL)中,然后用二氯甲烷(60mL)提取。减压浓缩有机层,将残留物溶解于四氢呋喃(12mL)中,加入0.5M柠檬酸溶液(12mL),室温搅拌1h。减压除去四氢呋喃后,用固体碳酸氢钠碱化,用二氯甲烷(60mL)萃取。有机层用无水硫酸钠干燥,过滤,减压浓缩。用石油醚/乙酸乙酯=1:1-1:2梯度洗脱,得到氨基乙酯14。
2-氨基-2-异丁基-3-苄基乙酯(14)
无色油状液体,50%分离产率(95mg,0.38mmol),96%ee.[α]D=+45.4(c=0.1,CHCl3).1H NMR(400MHz,CDCl3):δ7.31–7.23(m,3H),7.19–7.12(m,2H),4.15(q,J=7.2Hz,2H),3.18(d,J=13.1Hz,1H),2.74(d,J=13.1Hz,1H),1.94(dd,J=13.8,7.9Hz,1H),1.81–1.73(m,3H),1.63(dd,J=13.8,4.8Hz,1H),1.29(t,J=7.1Hz,3H),0.99(d,J=6.6Hz,3H),0.87(d,J=6.6Hz,3H);13C NMR(100MHz,CDCl3):δ179.1,135.7,130.0,128.4,127.0,61.6,60.9,50.4,47.0,27.2,24.7,21.2,12.3;IR(neat):3320,3031,2960,2871,1732,1616,1652,1599,1496,1188,1079,1033,862,768cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C15H24NO2 +250.1802;Found 250.1804.
苯丙氨酸乙酯席夫碱的不对称烯丙基化
以N-(4-苯基苯基亚甲基)苯丙氨酸乙酯15(400mg,1.12mmol),(S)-10(8.4mg,1mol%)和CsOH-H2O(940mg,5.6mmol)的甲苯(6mL)溶液为溶液,在0℃氩气气氛下缓慢加入烯丙基溴(202mg,1.68mmol)。将反应混合物在相同温度下剧烈搅拌12h,将反应混合物倒入冰水(20mL)中,然后用二氯甲烷(60mL)提取。减压浓缩有机层,将残留物溶解于四氢呋喃(12mL)中。加入0.5M柠檬酸溶液(12mL),室温搅拌1h。减压除去四氢呋喃后,用固体碳酸氢钠碱化,用二氯甲烷(60mL)萃取。有机层用无水硫酸钠干燥,过滤,减压浓缩。用柱层析纯化(石油醚/乙酸乙酯=1:1-1:2,梯度洗脱)得到氨基乙酯15。
2-氨基-2-烯丙基-3-苄基乙酯(16)
无色油状液体,57%分离产率(149mg,0.64mmol),93%ee.1H NMR(400MHz,CDCl3):δ7.31–7.26(m,1H),7.26–7.20(m,2H),7.19–7.12(m,2H),5.78–5.63(m,1H),5.24–5.10(m,2H),4.19–4.12(m,2H),3.18(d,J=13.2Hz,1H),2.78(d,J=13.3Hz,1H),2.75–2.68(m,1H),2.36–2.25(m,1H),1.26(t,J=7.2,3H);13C NMR(100MHz,CDCl3):δ176.1,136.3,132.6,130.0,128.4,127.0,119.7,61.6,61.1,45.8,44.6,14.3。
缬氨酸乙酯席夫碱的不对称苄基化
以N-(4-苯基苯基亚甲基)缬氨酸乙酯17(300mg,0.97mmol)和(S)-10(7.3mg,1mol%)和CsOH-H2O(490mg,2.91mmol)为溶液,在甲苯(6mL)中缓慢加入溴化苄(199mg,1.16mmol),温度为0℃,氩气气氛。将反应混合物在相同温度下剧烈搅拌20h,将反应混合物倒入冰水(20mL)中,然后用二氯甲烷(60mL)提取。减压浓缩有机层,将残留物溶解于四氢呋喃(12mL)中。加入0.5M柠檬酸溶液(12mL),室温搅拌1h。减压除去四氢呋喃后,用固体碳酸氢钠碱化,用二氯甲烷(60mL)萃取。有机层用无水硫酸钠干燥,过滤,减压浓缩。用石油醚/乙酸乙酯=1:1-1:2梯度洗脱,得到氨基乙酯18。
同样,在(S)-10存在下,在不对称相转移条件下,N-(芳基亚甲基)亮氨酸乙酯13也进行了不对称苄基化反应。在含有苯基和烷基取代基的N-(4-烷基苯基亚甲基)亮氨酸乙酯13(烷基=苯基、异丙基、叔丁基、正丁基和己基)的底物中,13(烷基=苯基和异丙基)和13(烷基=叔丁基和己基)经硅胶处理后的氨基乙酯14分别具有优异的对映选择性(96%ee和94%ee)。其他例子包括N-(4-苯基苯基亚甲基)苯丙氨酸乙酯15的不对称烯丙基化和N-(4-苯基苯基亚甲基)缬氨酸乙酯17的不对称苄基化,从而分别得到相应的氨基酯16和18,具有优异的对映选择性。
2-氨基-2-异丙基-3-苄基乙酯(18)
白色固体,39%分离产率(89mg,0.38mmol),98%ee.1H NMR(400MHz,CDCl3):δ7.29–7.19(m,3H),7.18–7.11(m,2H),4.19–4.06(m,2H),3.15(d,J=13.1Hz,1H),2.81(d,J=13.1Hz,1H),2.21–2.12(m,1H),1.26(t,J=7.1Hz,3H),1.05(d,J=6.8Hz,3H),0.91(d,J=6.9Hz,3H);13C NMR(100MHz,CDCl3):δ171.2,134.3,130.0,128.0,118.3,64.1,55.3,41.3,35.2,19.3,16.4,12.1。
化合物的应用三:甘氨酸乙酯希夫碱19的不对称苄基化,催化反应如下:
在简化版Maruoka催化剂(1mol%)和50%KOH水溶液(2mL)的存在下,在氩气气氛下,0℃下,3-22h,进行了甘氨酸乙酯席夫碱19(1.25mmol)的不对称苄基化反应。硅胶柱层析后进行分离,并计算收率。结果如表2所示:
表2
具体过程和表征如下:甘氨酸乙酯席夫碱不对称苄基化
在-20℃或0℃氩气条件下,将溴苄(250mg,1.44mmol)缓慢加入到N-(芳基亚甲基)甘氨酸乙酯19(1.10mmol)和(S)-10(8.1mg,1mol%)和碱(CsOH.H2O(3.30mmol)或50%KOH水溶液(2mL))在甲苯(6mL)中的溶液中。将反应混合物在相同温度下剧烈搅拌3-6h,将反应混合物倒入冰水(20mL)中,然后用二氯甲烷(60mL)提取。减压浓缩有机层,将残留物溶解于四氢呋喃(12mL)中。加入0.5M柠檬酸溶液(12mL),室温搅拌1h。减压除去四氢呋喃后,用固体碳酸氢钠碱化,用二氯甲烷(60mL)萃取。有机层在无水硫酸钠上干燥,过滤,减压浓缩。用硅胶柱层析纯化(石油醚/乙酸乙酯=1:1-1:2,梯度洗脱)得到氨基乙酯20。
2-氨基-3-苄基乙酯(20)
无色油状液体,87%分离产率(202mg,1.04mmol),95%ee.1H NMR(400MHz,CDCl3):δ7.25–7.09(m,5H),4.08(q,J=7.1Hz,2H),3.63(dd,J=7.8,5.4Hz,1H),3.00(dd,J=13.5,5.4Hz,1H),2.79(dd,J=13.5,7.8Hz,1H),1.19–1.13(m,3H);13C NMR(100MHz,CDCl3):δ174.9,137.3,129.3,128.5,126.8,61.0,55.8,41.1,14.2。
化合物的应用四:以甘氨酸和丙氨酸乙酯席夫碱为原料合成奥罗丹根和LX9211前体的方法,反应过程和收率如下:
(a)化合物24的合成过程
以甲苯(6ml)/50%KOH水溶液(2ml)为溶剂,在-20℃氩气气氛下缓慢加入N-(芳基亚甲基)甘氨酸乙酯19(1.1mmol)和(R)-10(8.2mg,1mol%)。将反应混合物在相同温度下剧烈搅拌3h,将反应混合物倒入冰水(20mL)中,然后用二氯甲烷(60mL)提取。减压浓缩有机层,将残留物溶解于四氢呋喃(12mL)中。加入0.5M柠檬酸溶液(12mL),室温搅拌1h。减压除去四氢呋喃后,用固体碳酸氢钠碱化,用二氯甲烷(60mL)萃取。有机层用无水硫酸钠干燥,过滤,减压浓缩。经硅胶柱层析纯化(石油醚/乙酸乙酯=1:1-1:2,梯度洗脱)得到产物24。
2-氨基-3-(2-(苄氧基)-3-甲氧基苯基)丙酸乙酯(24)
无色油状液体,92%分离产率,95%ee.1H NMR(400MHz,CDCl3):δ7.51–7.42(m,2H),7.41–7.28(m,3H),7.01(t,J=7.9Hz,1H),6.86(dd,J=8.3,1.5Hz,1H),6.77(dd,J=7.7,1.5Hz,1H),5.14–4.93(m,2H),4.13–4.09(m,2H),3.88(s,3H),3.75(dd,J=8.7,5.2Hz,1H),3.07(dd,J=13.3,5.2Hz,1H),2.74(dd,J=13.3,8.7Hz,1H),1.19(t,J=7.1Hz,3H);13CNMR(100MHz,CDCl3):δ175.2,152.8,146.4,137.8,131.7,128.4,128.2,127.9,124.0,122.8,111.374.6,60.8,55.7,55.0,36.3,14.1。
(b)化合物26的合成过程
将3-溴-2-甲基丙烯25(214mg,1.60mmol)在0℃氩气气氛下缓慢加入到甲苯(6ml)/
50%KOH水溶液(2ml)中的N-(4-苯基苯基亚甲基)丙烯乙酯10n(300mg,1.1mmol)和(R)-10(8.0mg,1mol%)溶液中。将反应混合物在相同温度下剧烈搅拌5h,将反应混合物倒入冰水(20mL)中,然后用二氯甲烷(60mL)提取。减压浓缩有机层,将残留物溶解于四氢呋喃(12mL)中。加入0.5M柠檬酸溶液(12mL),室温搅拌1h。减压除去四氢呋喃后,用固体碳酸氢钠碱化,用二氯甲烷(60mL)萃取。有机层用无水硫酸钠干燥,过滤,减压浓缩。经硅胶柱层析纯化(石油醚/乙酸乙酯=10:1-5:1,梯度洗脱)得到产物26。
2-氨基-3-(2-甲基丙烯基)丙氨酸乙酯(26)
无色油状液体,70%分离产率,94%ee,1H NMR(400MHz,CDCl3):δ4.86(t,J=1.8Hz,1H),4.77(dt,J=2.2,1.1Hz,1H),4.17(m,2H),3.60(dd,J=8.8,5.2Hz,1H),2.48(dd,J=13.7,5.1Hz,1H),2.27–2.19(m,1H)2.23(ddd,J=13.9,8.9,1.1Hz,1H),1.83–1.72(m,3H),1.26(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3):δ177.7,141.2,115.2,61.0,56.9,48.5,27.6,23.5,14.1.;IR:3335,2981,1731,1645,1597,1455,1375,1198,1109,1024,897,770cm-1;HRMS(ESI)m/z:[M+H]+Calcd for C9H18NO2+172.1259;Found 172.1329.
综上,本申请在(S)-或(R)-10催化下建立了N-(芳基亚甲基)-a-烷基胺酸乙酯和N-(芳基亚甲基)甘氨酸乙酯的对映选择性相转移烷基化反应,具有高效率和良好的对映选择性。这个实用的过程允许生成的烷基化产物容易衍生为其他合成有用的手性构建砌块,如Olodanrigan和LX9211的关键中间体。
本发明的上述实施例仅仅是为了清楚地说明本发明技术方案的所作的举例,而并非是对本发明的具体实施方式的限定。凡在本发明权利要求书的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明权利要求的保护范围之内。
Claims (10)
1.一种氨基酸乙酯的芳香醛西弗碱,其特征在于,所述氨基酸乙酯的芳香醛西弗碱的结构式如下所示:
其中,Ar代表苯基或取代苯基、萘基或取代萘基;取代苯基代表苯基上的氢原子被1个或多个取代基取代,取代基选自卤素、三氟甲基、硝基、C1~C22烷基、C1~C22烯基、C1~C22炔基、C1~C22烷氧基、苯基、巯基;
R1代表氢、C1~C22烷基、C1~C22烯基、C1~C22炔基、苯基、取代苯基、萘基或取代萘基;R1代表C1~C22烷基时,烷基上的氢可被卤基、三氟甲基、硝基、苯基、巯基取代;取代基选自卤素、三氟甲基、硝基、C1~C22烷基、C1~C22烯基、C1~C22炔基、C1~C22烷氧基、苯基、巯基。
2.根据权利要求1所述氨基酸乙酯的芳香醛西弗碱,其特征在于,Ar代表苯基或取代苯基、萘基。
3.根据权利要求1所述氨基酸乙酯的芳香醛西弗碱,其特征在于,R1代表C1~C22烷基、C1~C22烯基、C1~C22炔基时,氢可被苯基取代。
4.根据权利要求1所述氨基酸乙酯的芳香醛西弗碱,其特征在于,R1代表氢、C1~C22烷基;具体地,R1代表C1~C22烷基时,Ar代表卤基、硝基、C1~C22烷基、C1~C22烯基、C1~C22炔基、C1~C22烷氧基、苯基或萘基,进一步地,所述卤素为溴、氯、碘或氟。
5.权利要求1所述氨基酸乙酯的芳香醛西弗碱在不对称催化反应中的应用。
6.根据权利要求4所述的应用,其特征在于,所述氨基酸乙酯的芳香醛西弗碱是在不对称烷基化催化反应中的应用;所述不对称烷基化催化反应为采用所述氨基酸乙酯的芳香醛西弗碱作为模板底物A,将卤代烃作为模板底物B,在Maruoka催化剂、碱和溶剂参与下,得到相应目标物。
7.根据权利要求5所述的应用,其特征在于,所述氨基酸乙酯的芳香醛西弗碱是在不对称α-烷基化催化反应中的应用。
8.根据权利要求6或7所述的应用,其特征在于,所述不对称α-烷基化催化反应用于制备手性氨基酸衍生物。
9.根据权利要求8所述的应用,其特征在于,所述手性氨基酸衍生物是作为关键中间体,用于合成AT2R型拮抗剂Olodanrigan或LX9211。
10.根据权利要求6所述的应用,其特征在于,当所述氨基酸乙酯的芳香醛西弗碱应用在不对称烷基化催化反应时,所使用的Maruoka催化剂结构式如下中任一或多种:
其中,Ar选自氢,苯基,3,4,5-三氟苯基,3,5-双(三氟甲基)苯基,3,5-双(苯基)苯基,β萘基,3,5-双[3,5-双(苯基)苯基]苯基,3,5-双[3,5-双(三氟甲基)苯基]苯基,3,5-双(3,4,5-三氟苯基)苯基。
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