CN114195793A - Nitrogen-aryl indole lactam compound, application thereof and preparation method of C-N axis-containing nitrogen-aryl indole axial chiral amino acid - Google Patents

Nitrogen-aryl indole lactam compound, application thereof and preparation method of C-N axis-containing nitrogen-aryl indole axial chiral amino acid Download PDF

Info

Publication number
CN114195793A
CN114195793A CN202111502845.7A CN202111502845A CN114195793A CN 114195793 A CN114195793 A CN 114195793A CN 202111502845 A CN202111502845 A CN 202111502845A CN 114195793 A CN114195793 A CN 114195793A
Authority
CN
China
Prior art keywords
compound
nmr
cdcl
reaction
indole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202111502845.7A
Other languages
Chinese (zh)
Other versions
CN114195793B (en
Inventor
黄杰
付振乾
洪先芳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Tech University
Original Assignee
Nanjing Tech University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Tech University filed Critical Nanjing Tech University
Priority to CN202111502845.7A priority Critical patent/CN114195793B/en
Publication of CN114195793A publication Critical patent/CN114195793A/en
Application granted granted Critical
Publication of CN114195793B publication Critical patent/CN114195793B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/12—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
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • 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
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • 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
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—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 three hetero rings
    • C07D495/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

The invention discloses a nitrogen aryl indole lactam compound, application thereof and a preparation method of C-N axis nitrogen aryl indole axial chiral amino acid, belonging to the field of chemical synthesis. The invention uses cinchona alkaloid derivative organic micromolecule catalyst to catalyze alcohol and prochiral nitrogen aryl indole lactam substrate to carry out dynamic kinetic resolution reaction under mild condition, and can construct optically pure axial chirality C-N axial amino acid ester compound. The invention has good substrate universality, and the target product can be obtained with excellent yield and stereoselectivity on 3, 4, 5 and 6 positions of indole and the benzene ring connected with the indole.

Description

Nitrogen-aryl indole lactam compound, application thereof and preparation method of C-N axis-containing nitrogen-aryl indole axial chiral amino acid
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing an axial chiral compound of C-N axial chiral amino acid ester by using 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 application of chiral amino acids have been the 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 is worthy of deep research. However, the synthesis and application of axial chiral amino acids are rarely reported, especially the construction of C-N axial chiral amino acids, compared to the central chiral amino acids which have been extensively studied. The development of a simple and efficient synthetic method becomes a new opportunity for the discovery and development of amino acid-containing drugs and materials.
Disclosure of Invention
The invention provides a method for constructing and synthesizing an axial chiral compound of C-N axial chiral amino acid ester by taking nitrogen aryl indole lactam as a substrate to perform dynamic kinetic resolution.
In order to solve the technical problem, the technical scheme provided by the invention is as follows: a nitrogen aryl indole lactam compound, the structural formula of which is formula I:
Figure BDA0003401645620000011
in order to solve the technical problem, the technical scheme provided by the invention is as follows:
preferably, the method for synthesizing the chiral amino acid ester compound with the C-N axis by using the nitrogen aryl indole lactam as the substrate uses the nitrogen aryl indole lactam with the structural formula 3 and the alcohol with the structural formula 2 as raw materials, and reacts for 24 hours at room temperature under the conditions that chiral alkali is used as a catalyst and 1, 2 dichloroethane is used as a solvent until the reaction is completed, and the reaction solution is purified by a silica gel column to obtain a target product compound 3ar-abq with the structural formula 3;
Figure BDA0003401645620000012
wherein: r1Is halogen atom F, Cl, Br, phenyl or carbethoxy; r2Is a halogen atom I, Cl, Br, R3Is halogen atom F, Cl, Br, methyl or methoxy; RF is fluorine atom, trifluoromethyl, difluoromethyl or monofluoromethyl; ar is phenyl, thiophene
Figure BDA0003401645620000013
Is thiophene
Figure BDA0003401645620000014
Naphthyl radical
Figure BDA0003401645620000015
Thienothiophenes
Figure BDA0003401645620000016
Furan compounds
Figure BDA0003401645620000017
Benzofuran derivatives
Figure BDA0003401645620000018
Pyridine compound
Figure BDA0003401645620000019
R is benzyl, cyclopentyl, methyl or 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 of using a chiral base as a catalyst. Preferably, the method for synthesizing the axial chiral compound with C-N axial chiral amino acid ester by using the nitrogen aryl indole lactam as a substrate uses the nitrogen aryl indole lactam compound (when R is R) of the structural formula 11Is methyl, R2Is hydrogen, R3Hydrogen, Ar is phenyl) and different alcohols with the structural formula of 2 are used as raw materials, the raw materials are stirred at room temperature under the conditions that chiral base is used as a catalyst and 1, 2 dichloroethane is used as a solvent until the reaction is finished, and the reaction liquid is purified by a silica gel column to obtain a target product compound 3a-3aq with the structural formula of 3;
Figure BDA0003401645620000021
wherein: alcohols with R as different substituents
Preferably, the amount of the chiral base is 10 mol% of the amount of the compound of the formula I; the molar ratio of the compound of formula I to the compound of formula 2 is 1: 1.2; the amount of 1, 2-dichloroethane solvent used was 0.1M.
Preferably, the alcohol moiety of compound 3 has the following structural formula:
Figure BDA0003401645620000022
in order to solve the technical problem of the invention, the invention provides another technical scheme that: a compound, said compound 3ar-3bq having the formula:
Figure BDA0003401645620000031
has the advantages that:
the invention relates to a method for synthesizing an axial chiral compound with C-N axial chiral amino acid ester by using nitrogen aryl indole lactam as a substrate and application thereof. The invention discloses a method for efficiently constructing an axial chiral compound with C-N axial chiral amino acid ester by using a chiral cinchona derivative organic micromolecule catalyst to catalyze alcohol and an N-aryl indole lactam substrate to perform dynamic kinetic ring-opening reaction under mild conditions. The invention has good substrate universality, and when different alcohols are adopted to open the ring lactam and substituent groups 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 using nitrogen aryl indole lactam as a substrate.
Under mild reaction conditions, the invention uses a chiral base catalyst to catalyze and activate alcohol and nitrogen aryl indole lactam as substrates to carry out dynamic kinetic ring-opening reaction, and a C-N axis chiral amino acid ester compound with a novel structure is constructed in one step. The method has the advantages of mild condition, high reaction efficiency and good substrate universality, and the reported dynamic kinetic ring-opening reaction of the organic-catalyzed nitrogen aryl indole lactam provides an important method for synthesizing various axial chiral amino acids and has the potential of being applied to industrial production.
Drawings
FIG. 1 is a hydrogen spectrum of Compound 1 a; FIG. 2 carbon spectrum of Compound 1 a; 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. Hydrogen spectrum of Compound 1 e; FIG. 8. carbon spectra of Compound 1 e; fig. 9.19F NMR Spectrum of 1 e; FIG. 10 shows the hydrogen spectrum of Compound 1 f; FIG. 11 carbon spectra of Compound 1 f; FIG. 12 hydrogen spectrum of Compound 1 g; FIG. 13 carbon spectrum of Compound 1 g; fig. 14.19F NMRSpectrum of compound 1 g; FIG. 15 hydrogen spectrum of Compound 1 h; FIG. 16. carbon spectrum of Compound 1 h; FIG. 17. Hydrogen spectra of Compound 1 i; FIG. 18 carbon spectra of Compound 1 i; FIG. 19. Hydrogen spectrum of Compound 1 s; FIG. 20 carbon spectra of Compound 1s
Detailed Description
The chemicals used below were all purchased from commercial products. The solvent is a commercial ultra-dry solvent. Thin Layer Chromatography (TLC) Using a 60F254 silica gel plate, color was developed under UV light at 254 nm.1H NMR and13c NMR was characterized using a Bruker400M NMR spectrometer with deuterated chloroform as solvent. The unit of the coupling constant is Hz.. Optical rotation was measured using a Jasco P-1030 polarimeter. Enantiomeric excess was measured by Shimadzu LC-20AD HPLC High Resolution Mass Spectrometry (HRMS) was performed using a Waters Q-TOF Permier Spectrometer.
The following are the hand alkalines used in the examples as shown below
Figure BDA0003401645620000041
Example 1
1. Preparation of the starting materials (taking 1a as an example, otherwise analogously)
Figure BDA0003401645620000042
In the first step, cesium carbonate (12mmol, 1.2equiv) was added to a solution of 2-carboxylic acid ethyl-substituted indole-2-carboxylic acid ester (10mmol, 1.0equiv) in 50 ml of N, N-dimethylformamide. The mixture was stirred at room temperature for 10 minutes, then 1-fluoro-2-nitrobenzene (15mmol, 1.5equiv) 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/hexanes as the eluent to give the desired product as a yellow oil (0.82g, 7.5mmol, 75% yield).
In the second step, a solution of the product obtained above (7.5mmol, 1.0equiv) and iron powder (45mmol, 6.0equiv) in 75mL of acetic acid was heated under 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 (30mL) HCl, water, ethyl acetate, diethyl ether, then dried. 1-methylindolo [1, 2-a ] quinoxalin-6 (5H) -one as a white solid (1.71g, 6.9mmol, 92% yield).
Third step, a 100mL two-necked round-bottomed flask was taken, charged with a magnetic stirrer, charged with the product after the second purification (5.0mmol, 1.0equiv), DMAP (4-dimethylaminopyridine: 61.0mg, 0.5mmol) and THF (40mL), and then Boc was added2O (5.7mL, 25mmol), N-dimethylformamide (8.0mL) and Et3N (0.7mL, 5.0 mmol). After the addition was completed, the resulting mixture was stirred at room temperature for 3 hours, and the reaction was quenched with water (20mL) after completion of the reaction was checked by a glass thin-layer silica gel analysis plate. 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-oxoindolo [1, 2-a ]]Quinoxaline-5 (6H) -carboxylic acid tert-butyl ester is a white solid. (1.74g, 4.5mmol, 91% yield)
Figure BDA0003401645620000051
1, 3-dimethyl-6-oxobenzo [ k ] phenanthridine-5 (6H) -carboxylic acid tert-butyl ester (1a)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C21H20N2NaO3 +[M+Na]+371.1366；Found：371.1360.
1-chloro-6-oxoindolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1c)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C20H17N2ClNaO3 +[M+Na]+391.0820；Found：391.0816.
1-bromo-6-oxoindolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1d)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C20H17N2BrNaO3 +[M+Na]+435.0315；Found：435.0310.
1, 2-difluoro-6-oxoindolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1e)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)δ154.7，150.0，148.2(dd，J＝12.9，244.3Hz)，141.1(dd，J＝12.9，244.3Hz)，136.0，129.1，127.7，126.2，126.2，124.8，123.2，122.9，116.0，115.7，112.3，112.2，111.3，111.0，87.2，27.7.19F NMR(376MHz，CDCl3)δ-136.52(d，J＝25.94Hz，1F)，-140.63(d，J＝28.20Hz，1F).HRMS(ESI)Calcd for C20H16N2F2NaO3 +[M+Na]+393.1021；Found：393.1018.
1-Ethyl-6-oxoindolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1f)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C23H22N2NaO5 +[M+Na]+429.1421；Found：429.1417.
8-fluoro-1-methyl-6-oxoindolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1g)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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)，105.4，86.6，27.7，22.0.19F NMR(376MHz，CDCl3)δ-119.12.HRMS(ESI)Calcd for C21H19FN2NaO3 +[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)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C21H19N2ClNaO3 +[M+Na]+405.0976；Found：405.0967.
8-bromo-1-methyl-6-oxoindolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1i)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C21H19BrN2NaO3 +[M+Na]+449.0471；Found：449.0468.
1-methyl-6-oxobenzo [4, 5] indolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (ls)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C25H22N2NaO3 +(M+Na)+：421.1523，Found：421.1530.
1-methyl-6-thieno [2 ', 3': 4, 5] pyrrolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1t)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C19H18N2O3NaS+[M+Na]+：377.0930，Found：377.0929.
1-methyl-6-thieno [3 ', 2': 4, 5] pyrrolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1u)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C19H18N2O3NaS+(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 (1v)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C21H18N2O3NaS2 +(M+Na)+：433.0651，Found：433.0655.
1-methyl-6-furo [2 ', 3': 4, 5] pyrrolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1w)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C19H18N2O4Na+[M+Na]+：361.1159，Found：361.1168.
1-methyl-6-benzofuro [2 ', 3': 4, 5] pyrrolo [1, 2-a ] quinoxaline-5 (6H) -carboxylic acid tert-butyl ester (1x)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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(ESI)calcd for C23H20N2NaO4 +[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 (1y)
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C20H19N3NaO3 +(M+Na)+：372.1319，Found：372.1315.
2. Reaction process
Figure BDA0003401645620000071
Preparation 3a was carried out using the following preparation method:
the substrate azaarylindolinamide 1a (0.1mmol), alcohol 2a (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
Benzyl (S) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylate, 94% yield, 97% ee, [ alpha ]]D 23(c1.0，CHCl3)＝-39.74.HPLC condition：Chiralpak AZ-H(Hex/iPrOH＝80/20，1.0mL/min，tR(major)＝6.0min，tR(minor)＝7.7min).
1H NMR(400MHz，CDCl3)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)；13C NMR(100MHz，CDCl3)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 C28H28N2NaO4 +[M+Na]+479.1941；Found：479.1937.
Figure BDA0003401645620000081
Preparation 3b by the following preparation method
The substrate azaarylindolinamide 1a (0.1mmol), alcohol 2b (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, 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-carboxylate (3 b): 95% yield, 97% ee, [ alpha ]]D 23(c1.0，CHCl3)＝-34.57.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝80/20，1.0mL/min，tR(major)＝7.2min，tR(minor)＝10.5min).
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C29H30N2NaO5 +[M+Na]+ 509.2047；Found：509.2049.
Figure BDA0003401645620000082
Preparation 3c by the following preparation method
The substrate azaarylindolinamide 1a (0.1mmol), alcohol 2c (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
3-methoxybenzyl(s) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylate (3 c): 96% yield, 96% ee, [ alpha ]]D 23(c1.0，CHCl3)＝-35.21.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝80/20，1.0mL/min，tR(major)＝9.8min，tR(minor)＝13.1min).
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C29H30N2NaO5 +[M+Na]+509.2047；Found：509.2044.
Figure BDA0003401645620000091
Preparation 3d by the following preparation method
The substrate azaarylindolelactam 1a (0.1mmol), alcohol 2d (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
2-methoxybenzyl(s) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylate (3 d): 98% yield, 96% ee, [ alpha ]]D 23(c1.0，CHCl3)＝-30.87.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝8.9min，tR(minor)＝11.8min).
1H NMR(400MHz，CDCl3)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＝12.8，19.2Hz 2H)，3.80(s，3H)，1.64(s，3H)，1.38(s，9H).13C NMR(100MHz，CDCl3)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 C29H30N2NaO5 +[M+Na]+ 495.1890；Found：495.1890.
Figure BDA0003401645620000092
Preparation 3e by the following preparation method
The substrate azaarylindolelactam 1a (0.1mmol), alcohol 2e (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
4-nitrobenzyl (S) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylate (3 e): 94% yield, 97% ee, [ alpha ]]D 23(c1.0，CHCl3)＝-33.33.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝80/20，1.0mL/min，tR(major)＝14.8min，tR(minor)＝16.7min).
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C28H27N3NaO6 +[M+Na]+524.1492；Found：524.1497.
Figure BDA0003401645620000101
Preparation 3f by the following preparation method
The substrate azaarylindolelactam 1a (0.1mmol), alcohol 2f (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
4-chlorobenzyl (S) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylate (3 f): 90% yield, 98% ee, [ alpha ]]D 23(c 1.0，CHCl3)＝-41.30.
HPLC condition：Chiralpak AS-H(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝8.7min，tR(minor)＝10.3min).
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C28H27ClN2NaO4 +[M+Na]+513.1552；Found：513.1557.
Figure BDA0003401645620000102
Preparation of 3g was carried out by the following preparation method
The substrate azaarylindolelactam 1a (0.1mmol), alcohol 2g (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
3-methylbenzyl (S) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylate (3 g): 94% yield, 94% ee, [ alpha ]]D 23(c 1.0，CHCl3)＝-37.30.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝5.4min，tR(minor)＝5.8min).
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C29H30N2NaO4 +[M+Na]+493.2098；Found：493.2092.
Figure BDA0003401645620000111
The following preparation method is adopted for preparation for 3h
The substrate azaarylindolelactam 1a (0.1mmol), alcohol 2h (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
2-iodobenzyl (S) -1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-indole-2-carboxylate (3H): 93% yield, 96% ee, [ alpha ]]D 23(c 1.0，CHCl3)＝-29.9.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝8.3min，tR(minor)＝11.3min).
1H NMR(400MHz，CDCl3)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＝13.2，20.8Hz 2H)，1.67(s，3H)，1.39(s，9H).13C NMR(100MHz，CDCl3)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 C28H27IN2NaO4 +[M+Na]+605.0908；Found：605.0910.
Figure BDA0003401645620000112
Preparation of 3an by the following preparation method
The substrate azaarylindolelactam 1a (0.1mmol), alcohol 2an (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, 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，CHCl3)＝-24.23.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝9.0min，tR(minor)＝12.5min).
1H NMR(400MHz，CDCl3)δ8.00(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).13C NMR(100MHz，CDCl3)δ175.1，160.8，152.8，145.7，144.0，139.5，137.3，136.6，130.5，130.0，129.7，129.2，128.8，128.0，127.9，127.8，127.0，126.7，126.5，125.5，124.9，124.6，123.6，122.8，122.0，119.5，118.1，116.3，112.9，112.2，111.6，80.9，61.3，56.1，55.0，52.2，51.4，45.1，28.3，22.7，21.8，17.2.19F NMR(376MHz，CDCl3)δ-119.67.HRMS(ESI)calcd for C43H48F3N5NaO4S+(M+Na)+：810.3271，Found：810.3720.
Figure BDA0003401645620000121
Preparation of 3ao Using the following preparation method
The substrate azaarylindolinamide 1a (0.1mmol), alcohol 2ao (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after completion of the reaction monitored by TLC, the reaction mixture was purified by silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, and the product was 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，CHCl3)＝-35.50.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝11.1min，tR(minor)＝13.1min).
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)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 C50H44N2NaO6 +[M+Na]+：791.3092，Found：791.3099.
Figure BDA0003401645620000131
Preparation of 3ap Using the following preparation method
The substrate azaarylindolelactam 1a (0.1mmol), alcohol 2ap (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after completion of the reaction monitored by TLC, the reaction mixture was purified by silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was colorless oil.
(R) - (1- (tert-Butoxycarbonyl) pyrrolidin-2-yl) methyl 1- (2- ((tert-butoxy) carbanion
Carbonyl (amino) -6-methylphenyl) -1H-indole-2-carboxylate (3 ap): 90% yield, 94% ee, [ alpha ]]D 23(c 1，CHCl3)＝+33.8.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝7.7min，tR(minor)＝7.2min).
1H NMR(400MHz，CDCl3)δ8.10(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).13C NMR(100MHz，CDCl3)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 C31H39N3NaO6 +[M+Na]+：572.2731，Found：572.2733.
Figure BDA0003401645620000132
Preparation of 3as by the following preparation method
The substrate azaarylindolelactam 1f (0.1mmol), alcohol 2ad (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
Cyclopentyl 1- (2- ((tert-butoxycarbonyl) amino) -6- (ethoxycarbonyl) phenyl) -1H-indole-2-carboxylate (3 av): 96% yield, 99% ee, [ alpha ]]D 23(c1.0，CHCl3)＝-18.80.
HPLC condition：Chiralpak IA(Hex/iPrOH＝95/5，1.0mL/min，tR(major)＝6.1min，tR(minor)＝6.8min).
1H NMR(400MHz，CDCl3)δ8.51(d，J＝8.4Hz，1H)，7.75(d，J＝7.6Hz，1H)，7.68-7.70(m，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)；13C NMR(100MHz，CDCl3)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 C28H32N2NaO6 +[M+Na]+515.2153；Found：515.2150.
Figure BDA0003401645620000141
Preparation of 3at was carried out by the following preparation method
The substrate azaarylindolelactam 1c (0.1mmol), alcohol 2ad (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
1- (2- ((tert-butyl)Butoxycarbonyl) amino) -6-chlorophenyl) -1H-indole-2-carboxylic acid cyclopentyl ester (3 as): 94% yield, > 99% ee, [ alpha ]]D 23(c 1.0，CHCl3)＝-40.4.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝4，5min，tR(minor)＝5.2min).
1H NMR(400MHz，CDCl3)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)；13C NMR(100MHz，CDCl3)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 C25H27ClNNaO4 +[M+Na]+447.1552；Found：447.1550.
Figure BDA0003401645620000142
Preparation of 3au Using the following preparation method
The substrate azaarylindolelactam 1d (0.1mmol), alcohol 2ad (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
1- (2-bromo-6- ((tert-butoxycarbonyl) amino) phenyl) -1H-indole-2-carboxylic acid cyclopentyl ester (3 au): 90% yield, 99% ee, [ alpha ]]D 23(c1.0，CHCl3)＝-42.70.
HPLC condition：Chiralpak IA(Hex/iPrOH＝95/5，1.0mL/min，tR(major)＝5.6min，tR(minor)＝7.6min).
1H NMR(400MHz，CDCl3)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)；13C NMR(100MHz，CDCl3)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 C25H27BrN2NaO4 +[M+Na]+521.1046；Found：521.1040.
Figure BDA0003401645620000151
Preparation of 3av by the following preparation method
The substrate azaarylindolelactam 1d (0.1mmol), alcohol 2ad (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
Benzyl 1- (6- ((tert-butoxycarbonyl) amino) -2, 3-difluorophenyl) -1H-indole-2-carboxylate (3 av): 86% yield, 94% ee, [ alpha ]]D 23(c 1.0，CHCl3)＝-16.7.
HPLC condition：Chiralpak IA(Hex/iPrOH＝95/5，1.0mL/min，tR(major)＝7.2min，tR(minor)＝9.2min).
1H NMR(400MHz，CDCl3)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).13C NMR(100MHz，CDCl3)δ160.6，152.5，148.0(dd，d，J＝13.4，106.5Hz)，145.5(dd，d，J＝13.8，102.5Hz)，139.9，135.3，133.4，129.2，128.7，128.5，128.4，127.0，126.9，123.0，122.5，117.5，117.3，114.9，114.1，111.1，81.5，77.5，77.2，76.8，66.9，28.2.19F NMR(376MHz，CDCl3)δ-142.9，-144.0.HRMS(ESI)Calcd for C27H24F2N2NaO4 +[M+Na]+501.1596；Found：501.1590.
Figure BDA0003401645620000152
Preparation of 3ax Using the following preparation method
The substrate azaarylindolinamide 1i (0.1mmol), alcohol 2ad (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
Cyclopentyl 1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -4-bromo-1H-indole-2-carboxylate (3 ax): 94% yield, 99% ee, [ alpha ]]D 23(c 1.0，CHCl3)＝-20.4.
HPLC condition：Chiralpak IA(Hex/iPrOH＝95/5，0.5mL/min，tR(major)＝9.3min，tR(minor)＝9.7min).
1H NMR(400MHz，CDCl3)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)；13C NMR(100MHz，CDCl3)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 C34H31NNaO5S+[M+Na]+535.1203；Found：535.1200.
Figure BDA0003401645620000161
Preparation of 3bi by the following preparation method
The substrate azaaryllactam 1s (0.1mmol), benzyl alcohol 2a (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
Benzyl 1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-benzofuran [3, 2-b]Pyrrole-2-carboxylate (3 bi): 85%, 95% ee, [ alpha ]]D 23(c 1，CHCl3)＝+12.15.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝5.6min，tR(minor)＝6.4min).
1H NMR(400MHz，CDCl3)δ 8.08(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)；13C NMR(100MHz，CDCl3)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 C30H28N2NaO5 +(M+Na)+：519.1890，Found：519.1887.
Figure BDA0003401645620000162
Preparation of 3ay by the following preparation method
To a dry tube was added the substrate azaaryllactam 1t (0.1mmol), alcohol 2a (0.12mmol), chiral base (6.3mg, 10 mol%), then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
Benzyl 4- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -4H-thieno [3, 2-b]Pyrrole-5-carboxylate (3 bl): 91%, 99% ee, [ alpha ]]D 23(c 1，CHCl3)＝-2.60.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝6.2min，tR(minor)＝6.9min).
1H NMR(400MHz，CDCl3)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)；13C NMR(100MHz，CDCl3)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 C26H26N2NaO4S+(M+Na)+：377.0930，Found：377.0929.
Figure BDA0003401645620000171
Preparation of 3bm by the following preparation method
The substrate azaaryllactam 1u (0.1mmol), alcohol 2a (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, 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-carboxylate (3 bm): 82%, 96% ee, [ alpha ]]D 23(c 1，CHCl3)＝+10.17.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝9.3min，tR(minor)＝11.8min).
1H NMR(400MHz，CDCl3)δ8.04(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)；13CNMR(100MHz，CDCl3)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 C26H26N2NaO4S+(M+Na)+：377.0930，Found：377.0938.
Figure BDA0003401645620000172
Preparation of 3bm by the following preparation method
The substrate azaaryllactam 1v (0.1mmol), alcohol 2a (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, 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-carboxylate (3 bm): 95%, 99% ee, [ alpha ]]D 23(c 0.278，CHCl3)＝-36.77.
HPLC condition：Chiralpak AZH(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝10.3min，tR(minor)＝12.5min).
1H NMR(400MHz，CDCl3)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)；13C NMR(100MHz，CDCl3)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 C28H26N2NaO4S2 +(M+Na)+：541.1226，Found：541.1229.
Figure BDA0003401645620000181
Preparation of 3bo by the following preparation method
To a dry tube was added the substrate azaaryllactam 1w (0.1mmol), alcohol 2a (0.12mmol), chiral base (6.3mg, 10 mol%), then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
Benzyl 4- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -4H-furan [3, 2-b]Pyrrole-5-carboxylate (3 bo): 78%, 95% ee, [ alpha ]]D 23(c 1，CHCl3)＝+8.43.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝5.5min，tR(minor)＝6.4min).
1H NMR(400MHz，CDCl3)δ7.99(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)；13C 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 C26H26N2NaO5 +[M+Na]+：469.1734，Found：469.1735.
Figure BDA0003401645620000182
Preparation of 3bp was carried out by the following preparation method
The substrate azaaryllactam 1x (0.1mmol), alcohol 2a (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, the product was a colorless oil.
Benzyl 1- (2- ((tert-butoxycarbonyl) amino) -6-methylphenyl) -1H-benzofuran [3, 2-b]Pyrrole-2-carboxylate (3 bp): 85%, 95% ee, [ alpha ]]D 23(c 1，CHCl3)＝+12.15.
HPLC conditioin：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，tR(major)＝5.6min，tR(minor)＝6.4min).
1H NMR(400MHz，CDCl3)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)；13C NMR(100MHz，CDCl3)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 C30H28N2NaO5 +(M+Na)+：519.1890，Found：519.1887.
Figure BDA0003401645620000191
Preparation of 3bq by the following preparation method
The substrate azaaryllactam 1y (0.1mmol), alcohol 2a (0.12mmol), chiral base (6.3mg, 10 mol%) were added to the dried tube, then 1mL 1, 2 dichloroethane was added as solvent to the mixture, the reaction was stirred at room temperature for 24 hours, after TLC monitoring the reaction was complete, the reaction mixture was purified using silica gel column separation, eluent petroleum ether/dichloromethane 2: 1, 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，CHCl3)＝-0.53.
HPLC condition：Chiralpak IA(Hex/iPrOH＝90/10，1.0mL/min，tR(mnajor)＝7.3min，tR(minor)＝7.8min).
1H NMR(400MHz，CDCl3)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)；13C NMR(100MHz，CDCl3)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 C27H27N3NaO4 +(M+Na)+：480.1894，Found：480.1897.

Claims (9)

1. A nitrogen aryl indole lactam compound, characterized in that: the structural formula of the compound is formula 1:
Figure FDA0003401645610000011
wherein: r1Is methyl, halogen atom, phenyl, carbethoxy or
Figure FDA0003401645610000012
R2Hydrogen and halogen atoms; r3Is hydrogen, a halogen atom, methyl or methoxy; ar is phenyl,
Figure FDA0003401645610000013
Figure FDA0003401645610000014
2. The nitrogen aryl indolium lactam compound of claim 1, wherein:
when R is1Is methyl, halogen atom, phenyl, carbethoxy,
Figure FDA0003401645610000015
When R is2And R3Are both hydrogen, Ar is phenyl;
when R is2Is a halogen atom, R1Is methyl, R3Is hydrogen, Ar is phenyl;
when R is3Is a halogen atom, a methyl or methoxy group, R1Is methyl, R2Is hydrogen, Ar is phenyl;
when Ar is
Figure FDA0003401645610000016
R1Is methyl, R2And R3Are both hydrogen and Ar is phenyl.
3. The nitrogen aryl indolium lactam compound of claim 1, wherein: the nitrogen aryl indole lactam compound has the following structure:
Figure FDA0003401645610000017
Figure FDA0003401645610000021
4. the application of an axial chiral compound containing C-N axial chiral amino acid ester is characterized in that: use of a nitrogen aryl indole lactam compound according to any one of claims 1 to 3as a substrate.
5. A preparation method of an axial chiral compound containing C-N axial chiral amino acid ester is characterized in that: a method for synthesizing an axial chiral compound having a C-N axial chiral amino acid ester using the nitrogen aryl indole lactam compound according to any one of claims 1 to 3as a substrate.
6. The method of claim 5, wherein: taking nitrogen aryl indole lactam shown in a formula 1 and alcohol shown in a formula 2 as raw materials, and taking chiral base as a catalyst to complete the reaction to obtain a target product compound shown in a formula 3;
Figure FDA0003401645610000022
wherein: the compound represented by the formula 2 is as follows:
Figure FDA0003401645610000031
7. the method of claim 5, wherein: taking nitrogen aryl indole lactam shown in a formula 1a and alcohol shown in a formula 2 as raw materials, and taking chiral base as a catalyst, and completing the reaction to obtain a target product compound shown in a formula 3;
Figure FDA0003401645610000032
8. the production method according to any one of claims 5 to 7, characterized in that: the chiral base is shown as follows
Figure FDA0003401645610000033
9. The method of claim 8, wherein: the dosage of the chiral base catalyst is 10 mol% of the dosage of the compound shown in the formula I; the molar ratio of the compound of formula I to the compound of formula 2 is 1: 1.2.
CN202111502845.7A 2021-12-09 2021-12-09 Preparation method of chiral amino acid containing C-N-axis nitrogen aryl indole axis Active CN114195793B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202111502845.7A CN114195793B (en) 2021-12-09 2021-12-09 Preparation method of chiral amino acid containing C-N-axis nitrogen aryl indole axis

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111502845.7A CN114195793B (en) 2021-12-09 2021-12-09 Preparation method of chiral amino acid containing C-N-axis nitrogen aryl indole axis

Publications (2)

Publication Number Publication Date
CN114195793A true CN114195793A (en) 2022-03-18
CN114195793B CN114195793B (en) 2023-05-23

Family

ID=80651841

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111502845.7A Active CN114195793B (en) 2021-12-09 2021-12-09 Preparation method of chiral amino acid containing C-N-axis nitrogen aryl indole axis

Country Status (1)

Country Link
CN (1) CN114195793B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114671816A (en) * 2022-04-08 2022-06-28 浙江大学 Preparation method of axial chiral aryl triazole compound
CN115536662A (en) * 2022-06-29 2022-12-30 广州大学 Guanyl structure-containing tetracyclic indole compound, and synthesis method and application thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1063379A (en) * 1963-07-13 1967-03-30 Basf Ag Production of dyes of the anthraquinone series
GB1081134A (en) * 1963-09-05 1967-08-31 Merck & Co Inc 1,3,4,5-tetrahydrobenz-[c,d]-indole-3-carboxylic acids and derivatives thereof
US5183820A (en) * 1988-08-02 1993-02-02 Glaxo Group Limited Lactam derivatives
CN101203495A (en) * 2005-06-23 2008-06-18 默克公司 Benzocycloheptapyridines as inhibitors of the receptor tyrosine kinase met
CN101333230A (en) * 2008-07-02 2008-12-31 武汉大学 Phosphoramidite type diphosphine ligand, preparation method and application thereof
CN109912511A (en) * 2019-04-28 2019-06-21 南京工业大学 A kind of preparation method of chiral amino acid esters or its hydrochloride synthesis azepine Cabbeen
CN110551136A (en) * 2019-09-16 2019-12-10 贵州大学 preparation method and application of chiral spiro compound containing indole skeleton and catalyzed by N-heterocyclic carbene
CN110885301A (en) * 2019-10-30 2020-03-17 南京工业大学 Biaryl axial chiral compound and preparation method thereof
CN112321593A (en) * 2020-11-24 2021-02-05 浙江理工大学 Preparation method of indolo [1,2-a ] quinazoline-6 (5H) -ketone compound

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1063379A (en) * 1963-07-13 1967-03-30 Basf Ag Production of dyes of the anthraquinone series
GB1081134A (en) * 1963-09-05 1967-08-31 Merck & Co Inc 1,3,4,5-tetrahydrobenz-[c,d]-indole-3-carboxylic acids and derivatives thereof
US5183820A (en) * 1988-08-02 1993-02-02 Glaxo Group Limited Lactam derivatives
CN101203495A (en) * 2005-06-23 2008-06-18 默克公司 Benzocycloheptapyridines as inhibitors of the receptor tyrosine kinase met
CN101333230A (en) * 2008-07-02 2008-12-31 武汉大学 Phosphoramidite type diphosphine ligand, preparation method and application thereof
CN109912511A (en) * 2019-04-28 2019-06-21 南京工业大学 A kind of preparation method of chiral amino acid esters or its hydrochloride synthesis azepine Cabbeen
CN110551136A (en) * 2019-09-16 2019-12-10 贵州大学 preparation method and application of chiral spiro compound containing indole skeleton and catalyzed by N-heterocyclic carbene
CN110885301A (en) * 2019-10-30 2020-03-17 南京工业大学 Biaryl axial chiral compound and preparation method thereof
CN112321593A (en) * 2020-11-24 2021-02-05 浙江理工大学 Preparation method of indolo [1,2-a ] quinazoline-6 (5H) -ketone compound

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
QIAN GAO等: ""Cobalt-Catalyzed Direct C−H Carbonylative Synthesis of Free (NH)‑Indolo[1,2‑a]quinoxalin-6(5H)‑ones"", 《ORG. LETT.》 *
廖益均等: "手性膦酸催化3-取代吲哚不对称F-C烷基化反应构建手性双吲哚基烷烃类化合物", 《中国抗生素杂志》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114671816A (en) * 2022-04-08 2022-06-28 浙江大学 Preparation method of axial chiral aryl triazole compound
CN114671816B (en) * 2022-04-08 2023-11-17 浙江大学 Preparation method of axial chiral aryl triazole compound
CN115536662A (en) * 2022-06-29 2022-12-30 广州大学 Guanyl structure-containing tetracyclic indole compound, and synthesis method and application thereof

Also Published As

Publication number Publication date
CN114195793B (en) 2023-05-23

Similar Documents

Publication Publication Date Title
CN114195793B (en) Preparation method of chiral amino acid containing C-N-axis nitrogen aryl indole axis
CN112778328B (en) N-heterocyclic carbene catalytic functionalized imine as novel 1, 4-dipole synthesizer and synthesis application thereof
JP2008069170A (en) Novel intermediate and method for preparing camptothecine derivative (cpt-11) and correlated compound
FI74002C (en) Process for the preparation of beta-carboline derivatives
KR20220157999A (en) monoacylglycerol lipase modulator
ZA200604134B (en) Tricyclic imidazopyridines for use as gastric secretion inhibitors
Chiassai et al. Approaches for the introduction of fluorinated substituents into [1, 2, 3] Triazolo [1, 5-a] pyridines
JPH08319290A (en) Imidazole derivative
CA2730071A1 (en) Antineoplastic derivatives of 4-oxo-l, 4-dihydro-quinolin?, preparation thereof, and therapeutic use thereof
ES2692656T3 (en) Diastereoselective preparation of the bicyclo [2.2.2] octan-2-one compounds
Boynton et al. Synthesis of the necine base (−)-supinidine from (S)-glutamic acid
TWI511949B (en) Diastereoselective preparation of bicyclo(2.2.2)octan-2-one compounds
Pandey et al. Organocatalytic dynamic kinetic resolution via conjugate addition: synthesis of chiral trans-2, 5-dialkylcyclohexanones
WO2007064861A2 (en) Asymmetric friedel-crafts alkylations catalyzed by byfunctional cinchona alkaloids
CN110590774B (en) Trifluoromethyl imidazole condensed ring compound and preparation method thereof
Yoshida et al. Enantioselective synthesis of a chiral pyridazinone derivative by lipase-catalyzed hydrolysis
FI73680C (en) Process for the preparation of therapeutically active 5,11-dihydro-11- [(4-methyl-1-piperazinyl) -acetyl] -6H-pyrido / 2,3-b // 1,4 / benzodiazepin-6-one.
CN113045566B (en) Pi-conjugated polycyclic amino isoquinoline compound and synthesis method and application thereof
CN114380735B (en) Method for synthesizing fluorene and indeno [2,1-b ] indolyl spiro indole
CN115010715B (en) Synthesis method and anticancer activity of 3- (indole-2-yl) succinimide and indolobenzodiazepine compounds
JP2006176531A (en) Optical isomer of optically active benzimidazole derivative
Ruxer et al. Synthesis of 1, 4‐dihydro‐4‐oxopyridazino [1, 6‐a] indole‐3‐carboxylic acids and 1, 4‐dihydro‐4‐oxopyrido [3′, 2′: 4, 5] pyrrolo [1, 2‐b]‐pyridazine‐3‐carboxylic acids as potential antibacterial agents
Zhao et al. Cp* Rh (III)-Catalyzed C—H 3, 3-Difluoroallylation of Indoles and N-Iodosuccinimide-Mediated Cyclization for the Synthesis of Fluorinated 3, 4-Dihydropyrimido-[1, 6-a]-indol-1 (2H)-one Derivatives
US6872830B1 (en) Synthesized γ-carbolines
JPH07278141A (en) Production of optically active benzimidazole derivative and its intermediate

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant