CN114195793B - Preparation method of chiral amino acid containing C-N-axis nitrogen aryl indole axis - Google Patents
Preparation method of chiral amino acid containing C-N-axis nitrogen aryl indole axis Download PDFInfo
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- CN114195793B CN114195793B CN202111502845.7A CN202111502845A CN114195793B CN 114195793 B CN114195793 B CN 114195793B CN 202111502845 A CN202111502845 A CN 202111502845A CN 114195793 B CN114195793 B CN 114195793B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 25
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 23
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 21
- 125000003118 aryl group Chemical group 0.000 title claims description 3
- 150000001413 amino acids Chemical class 0.000 title abstract description 14
- -1 nitrogen aryl indole lactam Chemical class 0.000 claims abstract description 73
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000000758 substrate Substances 0.000 abstract description 36
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 235000021513 Cinchona Nutrition 0.000 abstract description 2
- 241000157855 Cinchona Species 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 abstract 1
- 125000001041 indolyl group Chemical group 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
- 238000004896 high resolution mass spectrometry Methods 0.000 description 40
- 239000011734 sodium Substances 0.000 description 39
- 239000000047 product Substances 0.000 description 31
- 239000002904 solvent Substances 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 239000000741 silica gel Substances 0.000 description 27
- 229910002027 silica gel Inorganic materials 0.000 description 27
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 26
- 238000004809 thin layer chromatography Methods 0.000 description 25
- 239000012230 colorless oil Substances 0.000 description 24
- 239000003480 eluent Substances 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
- 239000003208 petroleum Substances 0.000 description 23
- 238000012360 testing method Methods 0.000 description 23
- 238000012544 monitoring process Methods 0.000 description 22
- 150000003951 lactams Chemical class 0.000 description 19
- 238000001228 spectrum Methods 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 229940125904 compound 1 Drugs 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 8
- 230000002194 synthesizing effect Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000007142 ring opening reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 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
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N Minaline Natural products OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalene Chemical group C1=CC=C2C(C=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000006481 2-iodobenzyl group Chemical group [H]C1=C([H])C(I)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- BOWZZLREAAXNBT-UHFFFAOYSA-N 5h-quinoxalin-6-one Chemical compound C1=CN=C2C=CC(=O)CC2=N1 BOWZZLREAAXNBT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- 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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07B53/00—Asymmetric syntheses
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07B2200/07—Optical isomers
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Abstract
The invention discloses a preparation method of an indole axial chiral amino acid containing C-N axial nitrogen and belongs to the field of chemical synthesis. According to the invention, a cinchona alkaloid derivative organic micromolecular catalyst is used for catalyzing alcohol and prochiral nitrogen aryl indole lactam substrate to carry out dynamic kinetic resolution reaction under mild conditions, so that an axially chiral C-N-axis amino acid ester compound with optical purity can be constructed. The invention has good substrate universality, and the target product can be obtained with excellent yield and stereoselectivity on the 3,4,5,6 positions of indole and the benzene ring connected with the indole.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and in particular relates to a method for synthesizing an axial chiral compound of C-N axial chiral amino acid ester by taking nitrogen aryl indole lactam as a substrate.
Background
Chiral amino acids are one of the most important basic substances in nature, and are the basic units constituting proteins. In addition, chiral amino acids are widely used in the fields of medicine, chemical synthesis, food industry and the like. In view of the importance of chiral amino acids, the synthesis and use of chiral amino acids has been a focus of research in organic chemistry and biochemistry. As a novel chiral amino acid, the axial chiral amino acid has potential application value in the chemical and biological fields, and deserves deep research. However, synthesis and use of axial chiral amino acids have been recently reported, particularly in the construction of C-N axial chiral amino acids, as compared to central chiral amino acids which have been widely studied. The development of a simple and efficient synthesis method is a new opportunity for the discovery and development of drugs and materials containing amino acids.
Disclosure of Invention
The invention provides a method for synthesizing an axial chiral compound of C-N axial chiral amino acid ester by taking nitrogen aryl indole lactam as a substrate and carrying out dynamic kinetic resolution.
In order to solve the technical problems of the invention, the technical proposal provided by the invention is as follows: a nitrogen aryl indolyl lactam compound having the structural formula I:
in order to solve the technical problems of the invention, the technical proposal provided by the invention is as follows:
preferably, the nitrogen aryl indole lactam is used as a substrate to synthesize a chiral amino acid ester compound with a C-N axis, nitrogen aryl indole lactam with a structural formula 3 and alcohol with a structural formula 2 are used as raw materials, chiral base is used as a catalyst, 1,2 dichloroethane is used as a solvent to react for 24 hours at room temperature until the reaction is completed, and a target product compound 3ar-abq with the structural formula 3 is obtained by purifying a reaction liquid through a silica gel column;
wherein: r is R 1 Is halogen atom F, cl, br, phenyl or ethyl group; r is R 2 Is halogen atom I, cl, br, R 3 Is halogen atom F, cl, br, methyl or methoxy; r is R F Is fluorine atom, trifluoromethyl, difluoromethyl or monofluoromethyl; ar is phenyl, thiophene
Thiophene->
Naphthyl->
Thienothiophene->
Furan->
Benzofuran->
Pyridine->
R is benzyl, cyclopentyl, methyl, and ethyl.
Preferably, the nitrogen aryl indole lactam compound is used as a substrate to synthesize an axial chiral compound with C-N axial chiral amino acid ester, and the nitrogen aryl indole lactam compound can be subjected to ring opening reaction with alcohol under the condition that chiral base is used as a catalyst. Preferably, the process for synthesizing an axichiral compound with a C-N axichiral amino acid ester using the azaarylindololactam compound of formula 1 (when R 1 Is methyl, R 2 Is hydrogen, R 3 Hydrogen, ar is phenyl) and different alcohols with a structural formula of 2 are used as raw materials, stirring is carried out at room temperature under the condition that chiral base is used as a catalyst and 1,2 dichloroethane is used as a solvent until the reaction is completed, and the reaction liquid is purified by a silica gel column to obtain target product compounds 3a-3aq with the structural formula of 3;
wherein: alcohols in which R is a different substituent
Preferably, the chiral base is present in an amount of 10 mole% based on the amount of the compound of formula I; the molar ratio of the compound of formula I to the compound of formula 2 is 1:1.2; the amount of solvent 1,2 dichloroethane was 0.1M.
Preferably, the alcohol moiety of compound 3 has the structural formula:
in order to solve the technical problem of the invention, the invention provides another technical scheme as follows: a compound having the structural formula 3ar-3 bq:
the beneficial effects are that:
the present invention relates to a method for synthesizing an axichiral compound with a C-N axichiral amino acid ester using an azaarylindole lactam as a substrate and applications thereof. The invention uses a chiral cinchona derivative organic micromolecular catalyst to catalyze alcohol and nitrogen aryl indole lactam substrates to generate dynamic ring-opening reaction under mild condition, and can efficiently construct an axial chiral compound with C-N axial chiral amino acid ester. The invention has good substrate universality, and when different alcohols are adopted to remove the ring-opened lactam and substituents are placed on different positions of the nitrogen aryl indole lactam substrate, the target product can be obtained with excellent yield and stereoselectivity.
The invention discloses a novel method for synthesizing an axial chiral compound of C-N axial chiral amino acid ester by taking nitrogen aryl indole lactam as a substrate.
Under mild reaction conditions, the invention uses chiral base catalyst to catalyze and activate alcohol and nitrogen aryl indole lactam as substrates to generate dynamic ring-opening reaction, thus constructing the chiral amino acid ester compound containing the C-N axis in one step. The method has mild condition and high reaction efficiency, has good substrate universality, and the reported dynamic kinetic ring-opening reaction of the organic catalytic nitrogen aryl indole lactam provides an important method for synthesizing various axial chiral amino acids, and has potential for industrial production.
Drawings
FIG. 1 is a hydrogen spectrum of Compound 1 a; the carbon spectrum of compound 1a of fig. 2; FIG. 3 is a hydrogen spectrum of Compound 1 c; FIG. 4 is a carbon spectrum of Compound 1 c; FIG. 5 is a hydrogen spectrum of Compound 1 d; FIG. 6 is a carbon spectrum of Compound 1 d; FIG. 7 is a hydrogen spectrum of Compound 1e; FIG. 8 is a carbon spectrum of Compound 1e; fig. 9. 19 F NMR Spectrum of 1e; FIG. 10 is a hydrogen spectrum of Compound 1 f; FIG. 11 is a carbon spectrum of Compound 1 f; FIG. 12 is a hydrogen spectrum of Compound 1g; FIG. 13 carbon spectrum of Compound 1g; fig. 14. 19 F NMR Spectrum of compound 1g; FIG. 15 hydrogen spectrum of Compound 1 h; FIG. 16 carbon spectrum of Compound 1 h; FIG. 17 shows the hydrogen spectrum of Compound 1 i; FIG. 18 carbon spectrum of Compound 1 i; FIG. 19 is a hydrogen spectrum of Compound 1 s; FIG. 20 carbon spectrum of Compound 1s
Detailed Description
The following chemicals were all purchased from commercial products. The solvent is a super dry solvent commercially available. Thin Layer Chromatography (TLC) was performed using 60F254 silica gel plates and developed under UV light at 254 nm. 1 H NMR 13 C NMR was characterized using a Bruker 400M NMR instrument with deuterated chloroform as the solvent. The unit of coupling constant is Hz.. Optical rotation was measured using a Jasco P-1030 polarimeter. Enantiomeric excess was determined using Shimadzu LC-20AD HPLC High Resolution Mass Spectrometry (HRMS) using Waters Q-TOF Permier Spectrometer.
The following is the hand basicity used in the examples as follows
Example 1
1. Preparation of raw materials (1 a is taken as an example, other similar)
In the first step, cesium carbonate (12 mmol,1.2 equiv) was added to a solution of 2-carboxyethyl-substituted indole-2-carboxylic acid ester (10 mmol,1.0 equiv) in 50 mL of N, N-dimethylformamide. The mixture was stirred at room temperature for 10 minutes, then 1-fluoro-2-nitrobenzene (15 mmol,1.5 equiv) was added and the mixture was stirred at 150 degrees for 2 hours. The reaction was quenched with water and diluted with ethyl acetate. The combined organic layers were washed with brine and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography using 10% ethyl acetate/hexane as eluent to give the desired product (0.82 g,7.5mmol,75% yield) as a yellow oil.
In a second step, a solution of the product obtained above (7.5 mmol,1.0 equiv) and iron powder (45 mmol,6.0 equiv) in 75mL of acetic acid was heated at reflux for 4 hours. The reaction mixture was cooled, concentrated in vacuo and poured into 100mL of 1M aqueous HCl, stirred, then filtered, washed sequentially with 1M (30 mL) HCl, water, ethyl acetate, diethyl ether, and then dried. 1-methylindole [1,2-a ] quinoxalin-6 (5H) -one as a white solid (1.71 g,6.9mmol,92% yield).
In a third step, a 100mL two-necked round bottom flask was taken, equipped with a magnetic stirrer, and the product after the second purification step (5.0 mmol,1.0 equiv) was added, DMAP (4-dimethylaminopyridine: 61.0mg,0.5 mmol) dissolved in THF (40 mL) and Boc was then added 2 O (5.7 mL,25 mmol), N' N-dimethylformamide (8.0 mL), and Et 3 N (0.7 mL,5.0 mmol). After the addition was completed, the resulting mixture was stirred at room temperature for 3 hours, and after completion of the reaction was checked by a glass thin layer silica gel analysis plate, the reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Purifying the crude product by silica gel column chromatography (n-hexane/ethyl acetate, 10:1) to obtain 1-methyl-6-oxo-indolo [1,2-a ]]Quinoxaline-5 (6H) -carboxylic acid tert-butyl ester is a white solid. (1.74 g,4.5mmol,91% yield)
1, 3-dimethyl-6-oxo-benzo [ k ] phenanthridine-5 (6H) -carboxylic acid tert-butyl ester (1 a)
1 H NMR(400MHz，CDCl 3 )δ7.84(d，J＝8.0Hz，1H)，7.64(s，1H)，7.50(d，J＝8.4Hz，1H)，7.42-7.46(m，1H)，7.29-7.33(m，1H)，7.24(d，J＝8.0Hz，1H)，7.19(d，J＝7.6Hz，1H)，7.12(d，J＝8.0Hz，1H)，2.46(s，3H)，1.67(s，9H). 13 C NMR(100MHz,CDCl 3 )δ155.5，150.6，136.5，129.5，128.8，128.8，128.0，128.0，125.1，124.7，123.6，123.0，122.3，115.3，113.3，109.5，86.4，27.8，22.1.HRMS(ESI)Calcd for C 21 H 20 N 2 NaO 3 + [M+Na] + 371.1366；Found：371.1360.
1-chloro-6-oxoindolo [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 c)
1 H NMR(400MHz，CDCl 3 )δ7.81(d，J＝8.0Hz，1H)，7.74-7.76(m，1H)，7.68(s，1H)，7.42-7.47(m，1H)，7.31-7.38(m，2H)，7.25-7.26(m，2H)，1.67(s，9H). 13 C NMR(100MHz，CDCl 3 )δ155.3，150.2，136.0，130.1，129.2，129.0，127.2，125.7，124.6，123.6，122.7，122.7，117.8，114.8，111.0，86.8，27.8.HRMS(ESI)Calcd for C 20 H 17 N 2 ClNaO 3 + [M+Na] + 391.0820；Found：391.0816.
1-bromo-6-oxoindolo [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 d)
1 H NMR(400MHz，CDCl 3 )δ7.82(d，J＝7.2Hz，1H)，7.68(s，1H)，7.56(d，J＝8.0Hz，1H)，7.45(d，J＝8.0Hz，1H)，7.30-7.36(m，2H)，7.19(t，J＝8.0Hz，1H)，1.67(s，9H). 13 C NMR(100MHz，CDCl 3 )δ155.3，150.2，135.4，130.7，130.2，129.3，128.9，126.1，124.3，124.0，122.7，118.3，115.4，111.5，110.9，86.8，27.8.HRMS(ESI)Calcd for C 20 H 17 N 2 BrNaO 3 + [M+Na] + 435.0315；Found：435.0310.
1, 2-difluoro-6-oxoindolo [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 e)
1H NMR(400MHz，CDCl 3 )δ7.94(t，J＝8.4Hz，1H)，7.82(d，J＝8.0Hz，1H)，7.72(s，1H)，7.49(t，J＝7.6Hz，1H)，7.36(t，J＝8.0Hz，1H)，7.10-7.16(m，1H)，7.03-7.07(m，1H)，1.68(s，9H). 13 C NMR(100MHz，CDCl 3 )δ154.7，150.0，148.2(dd，J＝12.9，244.3Hz)，141.1(dd，J＝12.9，244.3Hz)，136.0，129.1，127.7，126.2，126.2，124.8，123.2，122.9，116.0，115.7，112.3，112.2，111.3，111.0，87.2，27.7. 19 F NMR(376MHz，CDCl 3 )δ-136.52(d，J＝25.94Hz，1F)，-140.63(d，J＝28.20Hz，1F).HRMS(ESI)Calcd for C 20 H 16 N 2 F 2 NaO 3 + [M+Na] + 393.1021；Found：393.1018.
1-Ethyl-6-oxoindolo [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 f)
1 H NMR(400MHz，CDCl 3 )δ7.83(d，J＝8.0Hz，1H)，7.74-7.76(m，1H)，7.62-7.64(m，2H)，7.39-7.43(m，2H)，7.30-7.36(m，2H)，3.95(q，J＝7.2Hz，2H)，1.69(s，9H)，0.68(t，J＝7.2Hz，3H). 13 C NMR(100MHz，CDCl 3 )δ167.4，155.1，150.3，137.2，128.6，128.5，128.2，126.8，125.6，124.4，123.3，123.2，123.0，118.8，112.8，109.7，87.0，62.0，27.7，13.3.HRMS(ESI)Calcd for C 23 H 22 N 2 NaO 5 + [M+Na] + 429.1421；Found：429.1417.
8-fluoro-1-methyl-6-oxoindolo [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 g)
1 H NMR(400MHz，CDCl 3 )δ7.73(s，1H)，7.33-7.39(m，1H)，7.25-7.29(m，2H)，7.19(d，J＝7.2Hz，1H)，7.12(d，J＝8.0Hz，1H)，6.97(t，J＝8.8Hz，1H)，2.44(s，3H)，1.68(s，9H). 13 C NMR(100MHz，CDCl 3 )δ158.3，155.5(d，J＝62.4Hz)，150.4，138.3(d，J＝9.6Hz)，129.6，128.9，128.1，128.1，125.6，125.3(d，J＝7.7Hz)，123.3，118.7(d，J＝23Hz)，113.4，111.4(d，J＝3.9Hz)，106.7(d，J＝18.1Hz)，105.4，86.6，27.7，22.0. 19 F NMR(376MHz，CDCl 3 )δ-119.12.HRMS(ESI)Calcd for C 21 H 19 FN 2 NaO 3 + [M+Na] + 389.1272；Found：389.1266.
8-chloro-1-methyl-6-oxoindolo [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1H)
1 H NMR(400MHz，CDCl 3 )δ7.6(s，1H)，7.25-7.38(m，4H)，7.18(d，J＝7.2Hz，1H)，7.13(d，J＝8.0Hz，1H)，2.41(s，3H)，1.68(s，9H). 13 C NMR(100MHz，CDCl 3 )δ155.2，150.4，136.9，129.9，128.9，128.1，128.1，128.0，127.8，125.7，125.1，123.2，121.9，113.9，113.4，107.9，86.7，27.8，22.0.HRMS(ESI)Calcd for C 21 H 19 N 2 ClNaO 3 + [M+Na] + 405.0976；Found：405.0967.
8-bromo-1-methyl-6-oxoindolo [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 i)
1 H NMR(400MHz，CDCl 3 )δ7.71(s，1H)，7.48(d，J＝7.6Hz，1H)，7.43(d，J＝8.4Hz，1H)，7.25-7.29(m，2H)，7.19(d，J＝7.2Hz，1H)，7.13(d，J＝8.0Hz，1H)，2.42(s，3H)，1.67(s，9H). 13 C NMR(100MHz，CDCl 3 )δ155.2，150.4，136.5，129.9，129.6，128.9，128.2，128.0，125.7，125.3，125.2，123.3，116.7，114.4，113.5，109.6，86.7，27.8，22.1.HRMS(ESI)Calcd for C 21 H 19 BrN 2 NaO 3 + [M+Na] + 449.0471；Found：449.0468.
1-methyl-6-oxo-benzo [4,5] indolo [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 s)
1 H NMR(400MHz，CDCl 3 )δ8.36(d，J＝7.6Hz，1H)，8.17(s，1H)，7.95(d，J＝8.0Hz，1H)，7.67(t，J＝8.0Hz，1H)，7.53-7.59(m，2H)，7.30(t，J＝8.0Hz，1H)，7.16-7.22(m，2H)，2.50(s，3H)，1.69(s，9H). 13 C NMR(100MHz，CDCl 3 )δ155.2，150.7，134.0，129.7，129.2，128.6，128.4，128.2，127.9，127.2，126.0，125.6，125.5，125.2，123.5，123.3，115.7，113.4，108.5，86.5，27.8，22.0.HRMS(ESI)calcd for C 25 H 22 N 2 NaO 3 + (M+Na) + ：421.1523，Found：421.1530.
1-methyl-6-thieno [2',3':4,5] pyrrole [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 t)
1 H NMR(400MHz，CDCl 3 )δ7.60(s，1H)，7.44(d，J＝5.6Hz，1H)，7.23(t，J＝8.0Hz，1H)，7.14-7.19(m，2H)，7.40(d，J＝8.0Hz，1H)，2.63(s，3H)，1.68(s，9H). 13 C NMR(100MHz，CDCl 3 )δ154.4，150.7，141.1，128.9，128.7，128.3，128.2，127.7，127.2，125.2，123.6，115.2，112.9，107.7，86.5，27.7，21.6.HRMS(ESI)calcd for C 19 H 18 N 2 O 3 NaS + [M+Na] + ：377.0930，Found：377.0929.
1-methyl-6-thieno [3',2':4,5] pyrrole [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 u)
1 H NMR(400MHz，CDCl 3 )δ7.60(s，1H)，7.44(d，J＝5.6Hz，1H)，7.23(t，J＝8.0Hz，1H)，7.14-7.19(m，2H)，7.40(d，J＝8.0Hz，1H)，2.63(s，3H)，1.68(s，9H). 13 C NMR(100MHz，CDCl 3 )δ154.0，150.6，137.6，134.1，130.6，128.1，127.8，127.0，125.5，123.4，123.4，117.4，113.0，107.7，86.6，27.7，22.8.HRMS(ESI)calcd for C1 9 H 18 N 2 O 3 NaS + (M+Na) + ：377.0930，Found：377.0930.
1-methyl-6-oxothieno [2 ", 3": 4',5' ] thieno [2',3':4,5] pyrrolo [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 v)
1 H NMR(400MHz，CDCl 3 )δ7.59(s，1H)，7.37(d，J＝5.2Hz，1H)，7.24-7.29(m，2H)，7.13-7.19(m，2H)，7.40(d，J＝8.0Hz，1H)，2.67(s，3H)，1.67(s，9H). 13 C NMR(100MHz，CDCl 3 )δ154.4，150.6，143.5，134.8，131.1，128.9，128.8，127.9，127.4，126.7，126.0，125.3，123.7，120.8，113.5，109.5，86.3，27.8，20.3.HRMS(ESI)calcd for C 21 H 18 N 2 O 3 NaS 2 + (M+Na) + ：433.0651，Found：433.0655.
1-methyl-6-furo [2',3':4,5] pyrrole [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 w)
1 H NMR(400MHz，CDCl 3 )δ7.59(d，J＝2.4Hz，1H)7.30(s，1H)，7.17-7.21(m，1H)，7.10(d，J＝7.6Hz，1H)，6.81-6.83(m，1H)，2.81(s，3H)，1.69(s，9H). 13 C NMR(100MHz，CDCl 3 )δ154.2，150.7，149.6，147.5，127.8，127.6，126.5，126.4，125.0，123.6，113.3，104.1，96.6，86.6，81.2，28.0，27.7，22.5.HRMS(ESI)calcd for C 19 H 18 N 2 O 4 Na + [M+Na] + ：361.1159，Found：361.1168.
1-methyl-6-benzofuro [2',3':4,5] pyrrole [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 x)
1 H NMR(400MHz，CDCl 3 )δ7.66(d，J＝8.0Hz，1H)，7.58(d，J＝8.0Hz，1H)，7.27-7.38(m，4H)，7.21(d，J＝7.2Hz，1H)，7.12(d，J＝8.0Hz，1H)，2.71(s，3H)，1.68(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.5，154.4，151.5，150.6，128.8，128.3，127.5，127.3，126.0，125.8，125.4，123.4，122.8，120.6，120.0，113.1，112.9，96.8，86.5，77.5，77.1，76.8，27.7，19.5.HRMS(ESIcalcd for C 23 H 20 N 2 NaO 4 + [M+Na] + ：411.1315，Found：411.1320.
1-methyl-6-oxopyrido [3',2':4,5] pyrrolo [1,2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1 y)
1 H NMR(400MHz，CDCl 3 )δ8.52-8.53(m，1H)，8.08(dd，J＝1.6，8.0Hz，1H)，7.52(s，1H)，7.13-7.22(m，3H)，6.96(dd，J＝1.6，7.6Hz，1H)，2.60(s，3H)，1.60(s，9H). 13 C NMR(100MHz，CDCl 3 )δ155.2，150.4，147.4，145.8，131.1，131.0，129.1，128.5，128.4，125.6，122.5，121.2，118.3，112.6，106.9，86.7，27.7，24.2.HRMS(ESI)calcd for C 20 H 19 N 3 NaO 3 + (M+Na) + ：372.1319，Found：372.1315.
2. Reaction procedure
The following preparation method is adopted for preparing 3a:
to a dry test tube was added the substrate azaarylindole lactam 1a (0.1 mmol), alcohol 2a (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
(S) -1- (2- ((tert-Butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylic acid benzyl ester, 94% yield,97% ee, [ alpha ]] D 23 (c1.0，CHCl 3 )＝-39.74.HPLC condition：Chiralpak AZ-H(Hex/iPrOH＝80/20，1.0mL/min，t R (major)＝6.0min，t R (minor)＝7.7min).
1 H NMR(400MHz，CDCl 3 )δ8.09(d，J＝8.0Hz，1H)，7.78(d，J＝8.0Hz，1H)，7.61(d，J＝0.8Hz，1H)，7.29-7.36(m，5H)，7.22-7.26(m，3H)，6.96(d，J＝7.2Hz，1H)，6.89(d，J＝9.2Hz，1H)，6.05(s，1H)，5.20(dd，J＝12.4，23.2Hz，2H)，1.62(m，3H)，1.38(s，9H)； 13 C NMR(100MHz，CDCl 3 )δ159.6，151.5，138.5，136.1，135.4，134.4，128.1，127.8，127.5，127.2，127.1，125.6，125.3，125.2，123.6，121.6，120.8，116.4，111.9，110.4，79.7，65.5，27.1，15.9.；HRMS(ESI)Calcd for C 28 H 28 N 2 NaO 4 + [M+Na] + 479.1941；Found：479.1937.
Preparation 3b was carried out using the following preparation method
To a dry test tube was added the substrate azaarylindole lactam 1a (0.1 mmol), alcohol 2b (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil. The product was a colorless oil:
4-methoxybenzyl (S) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylic acid ester (3 b): 95% yield,97% ee, [ alpha ]] D 23 (c 1.0，CHCl 3 )＝-34.57.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝80/20，1.0mL/min，t R (major)＝7.2min，t R (minor)＝10.5min).
1 H NMR(400MHz，CDCl 3 )δ8.10(d，J＝8.0Hz，1H)，7.77(d，J＝8.0Hz，1H)，7.58(s，1H)，7.35(t，J＝8.0Hz，1H)，7.30(t，J＝7.2Hz，1H)，7.23(t，J＝9.2Hz，1H)，7.19(d，J＝8.8Hz，2H)，6.96(d，J＝7.6Hz，1H)，6.85-6.90(m，3H)，6.05(s，1H)，5.13(dd，J＝12.0，25.6Hz，2H)，3.81(s，3H)，1.62(s，3H)，1.38(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.8，159.7，152.7，139.6，137.3，136.6，130.2，129.3，129.1，127.7，126.7，126.4，124.7，122.7，121.9，117.6，114.0，112.9，111.6，80.8，66.5，55.4，28.3，17.1.HRMS(ESI)Calcd for C 29 H 30 N 2 NaO 5 + [M+Na] + 509.2047；Found：509.2049.
The following preparation method was used to prepare 3c
To a dry test tube was added the substrate azaarylindole lactam 1a (0.1 mmol), alcohol 2c (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
3-methoxybenzyl(s) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylic acid ester (3 c): 96% yield,96% ee, [ alpha ]] D 23 (c1.0，CHCl 3 )＝-35.21.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝80/20，1.0mL/min，t R (major)＝9.8min，t R (minor)＝13.1min).
1 H NMR(400MHz，CDCl 3 )δ8.06(d，J＝8.0Hz，1H)，7.76(d，J＝8.0Hz，1H)，7.59(s，1H)，7.21-7.34(m，5H)，6.81-6.95(m，5H)，6.03(s，1H)，5.16(dd，J＝12.0，24.8Hz，2H)，3.80(s，3H)，1.61(s，3H)，1.36(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.7，159.7，152.7，139.6，137.2，137.1，136.5，129.7，129.3，128.8，126.7，126.4，126.4，124.8，122.8，122.0，120.5，117.6，113.9，113.8，113.0，111.6，80.8，66.5，55.4，28.3，17.1.HRMS(ESI)Calcd for C 29 H 30 N 2 NaO 5 + [M+Na] + 509.2047；Found：509.2044.
The following preparation method is adopted to prepare 3d
To a dry test tube was added the substrate azaarylindole lactam 1a (0.1 mmol), alcohol 2d (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
2-methoxybenzyl(s) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylic acid ester (3 d): 98% yield,96% ee, [ alpha ]] D 23 (c1.0，CHCl 3 )＝-30.87.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝8.9min，t R (minor)＝11.8min).
1 H NMR(400MHz，CDCl 3 )δ8.05(d，J＝10.0Hz，1H)，7.78(d，J＝8.0Hz，1H)，7.61(s，1H)，7.27-7.32(m，3H)，7.22-7.26(m，1H)，7.14-7.17(m，1H)，6.85-6.93(m，4H)，6.07(s，1H)，5.27(dd，J＝12.8，19.2Hz2H)，3.80(s，3H)，1.64(s，3H)，1.38(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.9，157.5，152.7，139.6，137.2，136.5，129.6，129.6，129.2，126.7，126.3，124.7，123.9，122.7，121.9，120.5，117.5，112.8，111.6，110.4，80.8，62.2，55.4，28.3，17.1.HRMS(ESI)Calcd for C 29 H 30 N 2 NaO 5 + [M+Na] + 495.1890；Found：495.1890.
The following preparation method was used to prepare 3e
To a dry test tube was added the substrate azaarylindole lactam 1a (0.1 mmol), alcohol 2e (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
4-nitrobenzyl (S) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylic acid ester (3 e): 94% yield,97% ee, [ alpha ]] D 23 (c 1.0，CHCl 3 )＝-33.33.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝80/20，1.0mL/min，t R (major)＝14.8min，t R (minor)＝16.7min).
1 H NMR(400MHz，CDCl 3 )δ8.18(d，J＝8.0Hz，2H)，8.08(d，J＝8.0Hz，1H)，7.80(d，J＝8.4Hz，1H)，7.67(s，1H)，7.31-7.38(m，4H)，7.24-7.28(m，1H)，6.98(d，J＝7.2Hz，1H)，6.90(d，J＝8.4Hz，1H)，6.02(s，1H)，5.28(dd，J＝9.6，23.2Hz，2H)，1.64(s，3H)，1.37(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.4，152.6，147.7，142.8，139.7，137.3，136.6，129.4，128.4，128.3，126.8，126.7，126.4，124.9，123.9，122.9，122.2，117.8，113.7，111.6，81.0，65.1，28.3，17.1.HRMS(ESI)Calcd for C 28 H 27 N 3 NaO 6 + [M+Na] + 524.1492；Found：524.1497.
The following preparation method was used to prepare 3f
To a dry test tube was added the substrate azaarylindole lactam 1a (0.1 mmol), alcohol 2f (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
4-chlorobenzyl (S) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylic acid ester (3 f): 90% yield,98% ee,[α] D 23 (c 1.0，CHCl 3 )＝-41.30.
HPLC condition：Chiralpak AS-H(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝8.7min，t R (minor)＝10.3min).
1 H NMR(400MHz，CDCl 3 )δ8.08(d，J＝8.0Hz，1H)，7.77(d，J＝8.0Hz，1H)，7.60(s，1H)，7.34(t，J＝8.0Hz，1H)，7.22-7.30(m，4H)，7.13(d，J＝8.4Hz，2H)，6.95(d，J＝7.8Hz，1H)，6.88(d，J＝8.0Hz，1H)，6.02(s，1H)，5.14(dd，J＝12.4，22.8Hz 2H)，1.61(s，3H)，1.37(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.6，152.6，139.6，137.2，136.6，134.2，134.0，129.7，129.3，128.8，128.7，126.7，126.6，126.3，124.8，122.8，122.0，117.6，113.2，111.6，80.9，65.8，28.3，17.1.HRMS(ESI)Calcd for C 28 H 27 ClN 2 NaO 4 + [M+Na] + 513.1552；Found：513.1557.
3g of the extract was prepared by the following method
To a dry test tube was added the substrate azaarylindole lactam 1a (0.1 mmol), alcohol 2g (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1mL 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after which the reaction mixture was purified by TLC monitoring the reaction completion using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
3-methylbenzyl (S) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylic acid ester (3 g): 94% yield,94% ee, [ alpha ]] D 23 (c 1.0，CHCl 3 )＝-37.30.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝5.4min，t R (minor)＝5.8min).
1 H NMR(400MHz，CDCl 3 )δ8.07(d，J＝8.4Hz，1H)，7.77(d，J＝7.6Hz，1H)，7.60(s，1H)，7.28-7.35(m，2H)，7.20-7.26(m，2H)，7.13(d，J＝7.6Hz，1H)，7.04(d，J＝6.4Hz，2H)，6.95(d，J＝7.2Hz，1H)，6.89(dd，J＝0.8，8.4Hz，1H)，6.04(s，1H)，5.16(dd，J＝12.4，28.0Hz，2H)，2.35(s，3H)，1.62(s，3H)，1.37(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.8，152.7，139.6，138.3，137.2，136.6，135.4，129.2，129.1，129.0，128.5，126.7，126.4，125.4，124.7，122.7，121.9，117.6，113.0，111.6，80.8，66.7028.3，21.5，17.1.HRMS(ESI)Calcd for C 29 H 30 N 2 NaO 4 + [M+Na] + 493.2098；Found：493.2092.
The preparation is carried out for 3 hours by adopting the following preparation method
To a dry test tube was added the substrate azaarylindole lactam 1a (0.1 mmol), alcohol 2h (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
2-iodobenzyl (S) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylic acid ester (3H): 93% yield,96% ee, [ alpha ]] D 23 (c 1.0，CHCl 3 )＝-29.9.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝8.3min，t R (minor)＝11.3min).
1 H NMR(400MHz，CDCl 3 )δ8.06(d，J＝8.0Hz，1H)，7.79-7.85(m，2H)，7.67(s，1H)，7.28-7.34(m，3H)，7.23-7.27(m，1H)，7.20-7.22(m，1H)，6.95(d，J＝12.4Hz，1H)，6.91(d，J＝8.4Hz，1H)，6.07(s，1H)，5.23(q，J＝13.2，20.8Hz2H)，1.67(s，3H)，1.39(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.5，152.6，139.7，139.5，138.0，137.2，136.6，130.0，129.5，129.3，128.6，128.5，126.7，126.6，126.2，124.8，122.8，122.0，117.5，113.3，111.6，98.4，80.9，70.4，28.3，17.2，1.2.HRMS(ESI)Calcd for C 28 H 27 IN 2 NaO 4 + [M+Na] + 605.0908；Found：605.0910.
The preparation of 3an was carried out by the following preparation method
To a dry test tube was added the substrate azaarylindololactam 1a (0.1 mmol), alcohol 2an (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml of 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
2- (4- (3- (8- (trifluoromethyl) -4a,10 a-dihydro-10H-phenothiazin-10-yl) propyl) piperazin-1-yl) ethyl 1- (2- ((tert-butoxycarbonyl) amino)) -6-methylphenyl) -1H-indole-2-carboxylate (3 an): 92% yield,87% ee, [ alpha ]] D 23 (c 1，CHCl 3 )＝-24.23.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝9.0min，t R (minor)＝12.5min).
1 H NMR(400MHz，CDCl 3 )δ 8.00(d，J＝7.2Hz，1H)，7.76(d，J＝8Hz，1H)，7.53(s，1H)，7.27-7.32(m，2H)，7.19-7.25(m，3H)，7.12-7.17(m，2H)，7.03(s，1H)，6.86-6.98(m，4H)，6.15(s，1H)，4.25(t，J＝5.2Hz，2H)，3.99(t，J＝6.4Hz，2H)，2.53-2.72(m，11H)，2.09-2.12(m，2H)，1.90(s，1H)，1.63(s，3H)，1.33(s，9H). 13 C NMR(100MHz，CDCl 3 )δ175.1，160.8，152.8，145.7，144.0，139.5，137.3，136.6，130.5，130.0，129.7，129.2，128.8，128.0，127.9，127.8，127.0，126.7，126.5，125.5，124.9，124.6，123.6，122.8，122.0，119.5，118.1，116.3，112.9，112.2，111.6，80.9，61.3，56.1，55.0，52.2，51.4，45.1，28.3，22.7，21.8，17.2. 19 F NMR(376MHz，CDCl 3 )δ-119.67.HRMS(ESI)calcd for C 43 H 48 F 3 N 5 NaO 4 S + (M+Na) + ：810.3271，Found：810.3720.
The preparation of 3ao was carried out using the following preparation method
To a dry test tube was added the substrate azaarylindole lactam 1a (0.1 mmol), alcohol 2ao (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was isolated and purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
(S) -2- ((2 '- (benzyloxy) - [1,1' -binaphthyl)]-2-yl) oxy) ethyl 1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-2-carboxylic acid indole (3 ao): 95% yield,96% ee, [ alpha ]] D 23 (c 1，CHCl 3 )＝-35.50.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝11.1min，t R (minor)＝13.1min).
1 H NMR(400MHz,CDCl 3 )δ 8.11(d，J＝7.6Hz，1H)，8.01(d，J＝8.8Hz，1H)，7.83-7.93(m，3H)，7.74(d，J＝7.6Hz，1H)，7.44(dd，J＝8.8，12.4Hz，2H)，7.20-7.39(m，9H)，7.14-7.16(m，3H)，7.02(s，1H)，6.98-7.00(m，2H)，6.89-6.93(m，2H)，6.06(s，1H)，5.07(dd，J＝12.4，7.6Hz，2H)，4.06-4.19(m，4H))，1.51(s，3H)，1.39(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.5，154.1，152.7，139.5，137.6，137.3，136.4，134.2，129.9，129.6，129.4，129.2，128.3，128.1，128.0，127.5，126.9，126.6，126.5，126.5，126.3，125.8，125.5，124.8，124.1，123.9，122.9，121.9，121.4，120.5，117.6，116.5，115.9，112.9，111.5，80.9，71.2，67.8，63.4，28.3，17.0.HRMS(ESI)calcd for C 50 H 44 N 2 NaO 6 + [M+Na] + ：791.3092，Found：791.3099.
The preparation of 3ap was carried out by the following preparation method
To a dry test tube was added the substrate azaarylindole lactam 1a (0.1 mmol), alcohol 2ap (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after which the reaction mixture was purified by TLC monitoring the reaction completion using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
(R) - (1- (tert-Butoxycarbonyl) pyrrolidin-2-yl) methyl 1- (2- ((tert-Butoxyca) -carbonyl (amino) -6-methylphenyl) -1H-indole-2-carboxylate (3 ap): 90% yield 94% ee, [ alpha ]] D 23 (c 1，CHCl 3 )＝+33.8.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝7.7min，t R (minor)＝7.2min).
1 H NMR(400MHz，CDCl 3 )δ 8.10(d，J＝8.0Hz，1H)，7.77(d，J＝7.2Hz，1H)，7.56(d，J＝6.4Hz，1H)，7.28-7.36(m，2H)，7.16-7.24(m，1H)，6.97(d，J＝8.0Hz，1H)，6.88(d，J＝8.0Hz，1H)，6.02-6.12(m，1H)，3.75-4.30(m，3H)，3.29-3.35(m，2H)，1.78-1.83(m，3H)，1.64(s，3H)，1.58-1.61(m，1H)，1.43(s，9H)，1.36(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.7，154.5，152.6，139.6，137.2，136.6，129.3，128.8，126.7，126.3，124.8，122.8，122.0，118.0，117.7，113.1，112.8，111.6，80.8，79.9，79.5，65.0，55.6，46.8，46.5，28.6，28.3，23.8，23.0，17.1.HRMS(ESI)calcd for C 31 H 39 N 3 NaO 6 + [M+Na] + ：572.2731，Found：572.2733.
The following preparation method was used to prepare 3as
To a dry test tube was added the substrate azaarylindololactam 1f (0.1 mmol), alcohol 2ad (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
1- (2- ((tert-butoxycarbonyl) amino) -6- (ethoxycarbonyl) phenyl) -1H-indole-2-carboxylic acid cyclopentyl ester (3 av): 96% yield,99% ee, [ alpha ]] D 23 (c 1.0，CHCl 3 )＝-18.80.
HPLC condition：Chiralpak IA(Hex/iPrOH＝95/5，1.0mL/min，t R (major)＝6.1min，t R (minor)＝6.8min).
1 H NMR(400MHz，CDCl 3 )δ8.51(d，J＝8.4Hz，1H)，7.75(d，J＝7.6Hz，1H)，7.68-7.70(n，1H)，7.57(s，1H)，7.54(t，，J＝8.4Hz，1H)，7.19-7.28(m，2H)，6.81(d，J＝8.4Hz，1H)，6.18(s，1H)，5.22-5.26(m，1H)，3.76-3.86(m，2H)，1.69-1.80(m，2H)，1.43-1.57(m，6H)，1.38(s，9H)，0.76(t，，J＝7.2Hz，3H)； 13 C NMR(100MHz，CDCl 3 )δ165.5，160.8，152.5，140.2，137.7，131.1，130.9，129.3，126.9，126.7，126.1，125.0，123.3，122.6，121.8，112.6，111.2，81.4，78.0，61.3，32.7，32.6，28.2，23.7，13.5；HRMS(ESI)Calcd for C 28 H 32 N 2 NaO 6 + [M+Na]+515.2153；Found：515.2150.
The preparation of 3at was carried out using the following preparation method
To a dry test tube was added the substrate azaarylindololactam 1c (0.1 mmol), alcohol 2ad (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
1- (2- ((tert-butoxycarbonyl) amino) -6-chlorophenyl) -1H-indole-2-carboxylic acid cyclopentyl ester (3 as): 94% yield, > 99% ee, [ alpha ]] D 23 (c 1.0，CHCl 3 )＝-40.4.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝4,5min，t R (minor)＝5.2min).
1 H NMR(400MHz，CDCl 3 )δ8.27(d，J＝8.4Hz，1H)，7.90(d，J＝8.0Hz，1H)，7.60(s，1H)，7.40(t，J＝8.4Hz，1H)，7.30-7.35(m，1H)，7.24-7.28(m，1H)，7.16-7.19(m，1H)，6.89(d，J＝7.6Hz，1H)，6.24(s，1H)，5.25-5.30(m，1H)，1.48-1.59(m，1H)，1.40(s，9H)； 13 C NMR(100MHz，CDCl 3 )δ160.6，152.3，139.4，138.4，134.1，130.3，130.0，127.0，126.4，125.4，123.5，122.8，122.2，117.8，113.3，111.3，81.5，78.1，77.5，77.1，76.8，32.7，32.7，28.2，23.7，23.7；HRMS(ESI)Calcd for C 25 H 27 ClNNaO 4 + [M+Na] + 447.1552；Found：447.1550.
The preparation of 3au was carried out using the following preparation method
To a dry test tube was added the substrate azaarylindololactam 1d (0.1 mmol), alcohol 2ad (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
1- (2-bromo-6- ((tert-butoxycarbonyl) amino) phenyl) -1H-indole-2-carboxylic acid cyclopentester (3 au): 90% yield,99% ee, [ alpha ]] D 23 (c1.0，CHCl 3 )＝-42.70.
HPLC condition：Chiralpak IA(Hex/iPrOH＝95/5，1.0mL/min，t R (major)＝5.6min，t R (minor)＝7.6min).
1 H NMR(400MHz，CDCl 3 )δ8.31(d，J＝9.6Hz，1H)，7.79(d，J＝8.4Hz，1H)，7.60(s，1H)，7.31-7.36(m，3H)，7.24-7.28(m，1H)，6.88(d，J＝8.0Hz，1H)，6.22(s，1H)，5.26-5.29(m，1H)，1.70-1.81(m，2H)，1.48-1.59(m，6H)，1.40(s，9H)； 13 C NMR(100MHz，CDCl 3 )δ160.6，152.3，139.2138.6，130.5，130.1，127.0，126.8，126.7，126.4，124.0，122.8，122.2，118.4，113.3，111.3，81.5，78.1，32.7，32.7，28.2，23.7；HRMS(ESI)Calcd for C 25 H 27 BrN 2 NaO 4 + [M+Na] + 521.1046；Found：521.1040.
The preparation of 3av was carried out by the following preparation method
To a dry test tube was added the substrate azaarylindololactam 1d (0.1 mmol), alcohol 2ad (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
1- (6- ((tert-Butoxycarbonyl) amino) -2, 3-difluorophenyl) -1H-indole-2-carboxylic acid benzyl ester (3 av): 86% yield,94% ee, [ alpha ]]D 23 (c 1.0，CHCl 3 )＝-16.7.
HPLC condition：Chiralpak IA(Hex/iPrOH＝95/5，1.0mL/min，t R (major)＝7.2min，t R (minor)＝9.2min).
1 H NMR(400MHz，CDCl 3 )δ7.96(s，1H)，7.78(d，J＝7.6Hz，1H)，7.64(s，1H)，7.34-7.38(m，4H)，7.28-7.32(m，3H)，7.20-7.24(m，3H)，6.97(d，，J＝8.4Hz，1H)，6.11(s，1H)，5.24(dd，J＝12.4，25.2Hz，2H)，1.39(s，9H). 13 C NMR(100MHz，CDCl 3 )δ160.6，152.5，148.0(dd，d，J＝13.4，106.5Hz)，145.5(dd，d，J＝13.8，102.5Hz)，139.9，135.3，133.4，129.2，128.7，128.5，128.4，127.0，126.9，123.0，122.5，117.5，117.3，114.9，114.1，111.1，81.5，77.5，77.2，76.8，66.9，28.2. 19 F NMR(376MHz，CDCl 3 )δ-142.9，-144.0.HRMS(ESI)Calcd for C 27 H 24 F 2 N 2 NaO 4 + [M+Na] + 501.1596；Found：501.1590.
The preparation was carried out for 3ax using the following preparation method
To a dry test tube was added the substrate azaarylindole lactam 1i (0.1 mmol), alcohol 2ad (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent, the reaction system was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -4-bromo-1H-indole-2-carboxylic acid cyclopent-ester (3 ax): 94% yield,99% ee, [ alpha ]] D 23 (c 1.0，CHCl 3 )＝-20.4.
HPLC condition：Chiralpak IA(Hex/iPrOH＝95/5，0.5mL/min，t R (major)＝9.3min，t R (minor)＝9.7min).
1 H NMR(400MHz，CDCl 3 )δ8.11(d，J＝8.4Hz，1H)，7.59(S，1H)，7.34-7.42(m，2H)，7.26(m，1H)，7.14(d，J＝8.0Hz，1H)，6.98(d，J＝7.2Hz，1H)，6.82(d，J＝8.4Hz，1H)，6.01(s，1H)，5.23-5.29(m，1H)，1.69-1.81(m，2H)，1.65(s，3H)，1.44-1.61(m，6H)，1.39(s，9H)； 13 C NMR(100MHz，CDCl 3 )δ160.4，152.6，139.4，137.1，136.4，130.5，129.5，127.7，127.0，126.5，124.8，124.7，117.6，116.5，112.5，110.7，81.1，78.3，32.7，32.6，28.3，23.7，23.6，17.1.HRMS(ESI)Calcd for C 34 H 31 NNaO 5 S + [M+Na] + 535.1203；Found：535.1200.
The preparation of 3bi is carried out by the following preparation method
To a dry test tube was added the substrate azaaryllactam 1s (0.1 mmol), benzyl alcohol 2a (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1mL 1,2 dichloroethane as solvent was added to the mixture and the reaction system was stirred at room temperature for 24 hours, after which the reaction was monitored by TLC and the reaction mixture was purified using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
Benzyl 1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-benzofuran [3,2-b]Pyrrole-2-carboxylic acid ester (3 bi): 85, 95% ee, [ alpha ]] D 23 (c1，CHCl 3 )＝+12.15.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝5.6min，t R (minor)＝6.4min).
1 H NMR(400MHz，CDCl 3 )δ8.08(d，J＝7.6Hz，1H)，7.54(d，J＝8.4Hz，1H)，7.28-7.40(m，6H)，7.23-7.24(m，2H)，7.11(t，J＝7.6Hz，1H)，7.01(d，J＝7.6Hz，1H)，6.92(d，J＝8Hz，1H)，6.13(s，1H)，5.15-5.23(dd，J＝12.4，22Hz，2H)，1.83(s，3H)，1.34(s，9H)； 13 C NMR(100MHz，CDCl 3 )δ160.8，160.4，152.6，148.1，136.3，135.7，135.6，129.4，128.6，128.3，128.3，128.1，125.6，125.2，124.9，123.2，118.2，117.9，112.7，101.1，81.0，66.3，28.2，17.4；HRMS(ESI)calcd for C 30 H 28 N 2 NaO 5 + (M+Na) + ：519.1890，Found：519.1887.
The following preparation method was used to prepare 3ay
To a dry test tube was added substrate azaaryl lactam 1t (0.1 mmol), alcohol 2a (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1mL 1,2 dichloroethane as solvent was added to the mixture and the reaction system was stirred at room temperature for 24 hours, after which the reaction mixture was purified by TLC monitoring the reaction completion using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
Benzyl 4- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -4H-thieno [3,2-b]Pyrrole-5-carboxylic acid ester (3 bl): 91, 99% ee, [ alpha ]] D 23 (c 1，CHCl 3 )＝-2.60.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝6.2min，t R (minor)＝6.9min).
1 H NMR(400MHz，CDCl 3 )δ8.02(d，J＝8Hz，1H)，7.51(s，1H)，7.29-7.35(m，5H)，7.20-7.23(m，2H)，6.94(d，J＝7.2Hz，1H)，6.56(d，J＝5.6Hz，1H)，6.08(s，1H)，5.17(dd,J＝12.4，22.4Hz，2H)，1.73(s，3H)，1.40(s，9H)； 13 C NMR(100MHz，CDCl 3 )δ160.4，152.7，145.3，136.7，135.8，135.8，130.6，129.2，128.6，128.3，128.2，127.7，124.7，123.8，117.8，111.7，111.2，80.9，66.3，28.3，17.2；HRMS(ESI)calcd for C 26 H2 6 N 2 NaO 4 S + (M+Na) + ：377.0930，Found：377.0929.
The preparation of 3bm was carried out by the following preparation method
To a dry test tube was added substrate azaaryl lactam 1u (0.1 mmol), alcohol 2a (0.12 mmol), chiral base (6.3 mg,10 mol%), then 1ml 1,2 dichloroethane as solvent was added to the mixture, the reaction system was stirred at room temperature for 24 hours, and after TLC monitoring the reaction was complete, the reaction mixture was purified using a silica gel column, eluent petroleum ether/dichloromethane=2: 1, the product was a colorless oil.
Benzyl 6- (2- ((tert-Butoxycarbonyl) amino) -6-methylphenyl) -6H-thieno [2,3-b]Pyrrole-5-carboxylic acid ester (3 bm): 82, 96% ee, [ alpha ]] D 23 (c 1，CHCl 3 )＝+10.17.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝9.3min，t R (minor)＝11.8min).
1 H NMR(400MHz，CDCl 3 )δ 8.04(d，J＝7.6Hz，1H)，7.48(s，1H)，7.30-7.34(m，4H)，7.20-7.23(m，2H)，7.09(d，J＝5.6Hz，1H)，6.94-6.98(m，2H)，6.09(s，1H)，5.16(dd,J＝12.4，23.2Hz，2H)，1.78(s，3H)，1.41(s，9H)； 13 C NMR(100MHz，CDCl 3 )δ160.1，152.6，143.6，136.4，135.8，135.6，130.0，129.6，128.8，128.6，128.3，128.2，127.9，124.9，121.8，118.4，117.8，111.7，81.0，66.2，28.3，17.2；HRMS(ESI)calcd for C 26 H 26 N 2 NaO 4 S + (M+Na) + ：377.0930，Found：377.0938.
The preparation of 3bm was carried out by the following preparation method
To a dry test tube was added substrate azaaryl lactam 1v (0.1 mmol), alcohol 2a (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent was added to the mixture and the reaction system was stirred at room temperature for 24 hours, after which the reaction mixture was purified by TLC monitoring completion using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
Benzyl 7- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -7H-thieno [2',3':4,5]Thieno [3,2-b]Pyrrole-6-carboxylic acid ester (3 bm): 95, 99% ee, [ alpha ]] D 23 (c0.278，CHCl 3 )＝-36.77.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝10.3min，t R (minor)＝12.5min).
1 H NMR(400MHz，CDCl 3 )δ8.10(d，J＝7.6Hz，1H)，7.54(s，1H)，7.38(t，J＝8Hz，1H)，7.30-7.35(m，3H)，7.20-7.26(m，4H)，6.99(d，J＝7.6Hz，1H)，6.10(s，1H)，5.18(t，J＝12.4Hz，2H)，1.76(s，3H)，1.36(s，9H)； 13 C NMR(100MHz，CDCl 3 )δ160.1，152.5，143.5，136.7，136.7，136.0，135.8，129.7，128.6，128.3，128.2，127.4，126.9，126.1，125.9，124.8，122.7，121.0，117.9，113.3，81.0，77.5，77.2，76.9，66.3，28.3，17.4；HRMS(ESI)calcd for C 28 H 26 N 2 NaO 4 S 2 + (M+Na) + ：541.1226，Found：541.1229.
The preparation of 3bo was carried out using the following preparation method
To a dry test tube was added substrate azaaryl lactam 1w (0.1 mmol), alcohol 2a (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent was added to the mixture and the reaction system was stirred at room temperature for 24 hours, after which the reaction mixture was purified by TLC monitoring completion using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
Benzyl 4- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -4H-furan [3,2-b]Pyrrole-5-carboxylic acid ester (3 bo): 78, 95% ee, [ alpha ]] D 23 (c 1，CHCl 3 )＝+8.43.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝5.5min，t R (minor)＝6.4min).
1 H NMR(400MHz，CDCl 3 )δ 7.99(d，J＝8.0Hz，1H)7.55(d，J＝2.0Hz，1H)，7.27-7.34(m，4H)，7.19-7.22(m，2H)，7.16(s，1H)，6.93(d，J＝7.6Hz，1H)，6.21(d，J＝2.0Hz，1H)，6.09(s，1H)，5.14(dd,J＝12.4，21.6Hz，2H)，1.78(s，3H)，1.42(s，9H)； 13 C NMR(100MHz，CDCl3)δ160.7，152.7，149.5，146.7，136.6，135.9，135.8，133.3，129.1，128.6，128.2，128.2，127.6，125.0，124.7，117.7，101.1，99.0，80.9，77.5，77.2，76.8，66.1，28.3，17.2；
HRMS(ESI)calcd for C 26 H2 6 N 2 NaO 5 + [M+Na] + ：469.1734，Found：469.1735.
The preparation of 3bp was carried out by the following preparation method
To a dry test tube was added substrate azaaryl lactam 1x (0.1 mmol), alcohol 2a (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent was added to the mixture and the reaction system was stirred at room temperature for 24 hours, after which the reaction mixture was purified by TLC monitoring the reaction completion using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
Benzyl 1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl)-1H-benzofuran [3,2-b ]]Pyrrole-2-carboxylic acid ester (3 bp): 85, 95% ee, [ alpha ]] D 23 (c 1，CHCl 3 )＝+12.15.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝5.6min，t R (minor)＝6.4min).
1 H NMR(400MHz，CDCl 3 )δ8.08(d，J＝7.6Hz，1H)，7.54(d，J＝8.4Hz，1H)，7.28-7.40(m，6H)，7.23-7.24(m，2H)，7.11(t，J＝7.6Hz，1H)，7.01(d，J＝7.6Hz，1H)，6.92(d，J＝8Hz，1H)，6.13(s，1H)，5.15-5.23(dd，J＝12.4，22Hz，2H)，1.83(s，3H)，1.34(s，9H)； 13 C NMR(100MHz，CDCl 3 )δ160.8，160.4，152.6，148.1，136.3，135.7，135.6，129.4，128.6，128.3，128.3，128.1，125.6，125.2，124.9，123.2，118.2，117.9，112.7，101.1，81.0，66.3，28.2，17.4；HRMS(ESI)calcd for C 30 H 28 N 2 NaO 5 + (M+Na) + ：519.1890，Found：519.1887.
The preparation of 3bq was carried out using the following preparation method
To a dry test tube was added the substrate azaaryl lactam 1y (0.1 mmol), alcohol 2a (0.12 mmol), chiral base (6.3 mg,10 mol%) and then 1ml 1,2 dichloroethane as solvent was added to the mixture and the reaction system stirred at room temperature for 24 hours after which the reaction mixture was purified by TLC monitoring completion using a silica gel column with petroleum ether/dichloromethane=2:1 as eluent and the product was a colorless oil.
Benzyl 1- (2- ((tert-Butoxycarbonyl) amino) -6-methylphenyl) -1H-pyrrolo [2,3-b]Pyridine-2-carboxylate (3 bq): 90%,93% ee, [ alpha ]] D 23 (c 1，CHCl 3 )＝-0.53.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，t R (major)＝7.3min，t R (minor)＝7.8min).
1 H NMR(400MHz，CDCl 3 )δ＝8.45-8.48(m，1H)，8.04-8.12(m，2H)，7.55-7.56(m，1H)，7.31-7.36(m，4H)，7.19-7.24(m，3H)，6.95-6.98(m，1H)，6.98-6.60(m，1H)，5.12-5.28(m，2H)，1.64(d，J＝6.4Hz，3H)，1.36(d，J＝6.4Hz，9H)； 13 C NMR(100MHz，CDCl 3 )δ160.4，152.6，149.8，148.4，137.0，136.5，135.3，131.4，129.5，129.2，128.6，128.4，128.4，125.8，124.9，119.1，118.3，111.0，80.7，80.7，66.9，28.3，17.5；HRMS(ESI)calcd for C 27 H 27 N 3 NaO 4 + (M+Na) + ：480.1894，Found：480.1897.
Claims (3)
1. A preparation method of an axial chiral compound containing C-N axial nitrogen aryl indole axial chiral amino acid ester is characterized by comprising the following steps: the nitrogen aryl indole lactam shown in the formula 1 and the alcohol shown in the formula 2 are used as raw materials, and chiral base is used as a catalyst to complete the reaction to obtain a target product compound shown in the formula 3;
wherein: r is R 1 Methyl, halogen atom, ethyl group; r is R 2 Is a hydrogen, halogen atom; r is R 3 Is hydrogen, halogen atom, methyl or methoxy; ar is phenyl;
the compound shown in the formula 2 is as follows:
the chiral base is shown as follows
2. The method of manufacturing according to claim 1, characterized in that: the nitrogen aryl indole lactam shown in the formula 1a and the alcohol shown in the formula 2 are used as raw materials, chiral base is used as a catalyst, and the reaction is completed to obtain a target product compound shown in the formula 3;
3. the method of manufacturing according to claim 1, characterized in that: the chiral base catalyst is used in an amount of 10mol% based on the amount of the nitrogen aryl indole lactam shown in the formula 1; the molar ratio of the nitrogen aryl indole lactam shown in formula 1 to the alcohol shown in formula 2 is 1:1.2.
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