Synthesis and application of chiral oxazoline ligand containing indole skeleton

Abstract

The invention discloses a chiral oxazoline ligand containing an indole skeleton as well as a synthesis method and application of the chiral oxazoline ligand. The chiral ligand has a structure as shown in a formula 1, and R1 is selected from one of alkyl, substituted alkyl, aryl and substituted aryl. The chiral oxazoline ligand of the indole skeleton can realize high-enantioselectivity Friedel-Crafts reaction of an indole skeleton compound, the reaction is one of important carbon-carbon bond forming methods in organic synthesis, and a chiral indole derivative can be efficiently generated; the chiral indole derivative has important application in synthesis of natural products and bioactive compounds. In addition, raw materials used for preparing the compound are cheap and easy to obtain, the synthesis route is short, the related reaction is a basic organic chemical reaction, the process is simple and convenient, the product is easy to separate and purify, and the method is suitable for large-scale synthesis.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a chiral oxazoline ligand containing an indole skeleton, and a synthesis method and application thereof. BACKGROUND

[0002] The strategy of asymmetric catalysis by metal complexes has been an effective method for preparing chiral compounds. The development of new and efficient chiral ligands is the core of asymmetric catalysis. Because of their unique stereo and electronic properties, ligands containing chiral oxazoline structures have been increasingly widely used, and ligands with different chiral ligating groups and ligand skeletons have also been designed.

[0003] Pyridine monooxazoline ligand Pyox and pyridine bisoxazoline ligand Pybox containing pyridine and oxazoline skeletons are widely used because of their stable catalytic conditions and relatively simple synthesis; through calculation and a series of studies, it is found that the nitrogen atom of the pyridine part of the pyridine-oxazoline ligand is relatively electron-poor, and thus can promote the reductive elimination. The nitrogen atom on the oxazoline ring is relatively electron-rich due to the conjugation of the oxygen atom, and thus can promote the oxidative addition of organometallic reactions. The Pyox ligand is a bidentate ligand, and the Pybox ligand is a tridentate ligand, both of which can form stable complexes with a variety of transition metals, which helps to form a stable chiral environment and a rigid catalytically active site to improve catalytic efficiency, and has a wide application in the field of asymmetric catalysis. However, the existing oxazoline skeleton ligand library still needs to be expanded to meet the needs of different types of asymmetric catalytic reactions. SUMMARY

[0004] To solve the above problems, the purpose of the present application is to provide a chiral oxazoline ligand containing an indole skeleton, and a synthesis method and application thereof. The present application uses inexpensive and readily available simple raw materials to synthesize a class of chiral oxazoline ligands containing an indole skeleton through a simple and efficient synthesis route, and successfully realizes the application thereof in asymmetric catalytic reactions.

[0005] In one aspect of the present application, a chiral oxazoline ligand containing an indole skeleton is provided. The chiral oxazoline ligand containing an indole skeleton has the structure shown in Formula 1:

[0006]

[0007] wherein R 1 is selected from one of alkyl, substituted alkyl, aryl, and substituted aryl.

[0008] The chiral oxazoline ligand with the indole skeleton can realize high enantioselective Friedel-Crafts reaction of indole skeleton compounds, which is one of important carbon-carbon bond formation methods in organic synthesis, and can efficiently generate chiral indole derivatives, and the chiral indole derivatives have important application in synthesis of natural products and bioactive compounds.

[0009] In one embodiment of the present application, the alkyl is C1-C6 alkyl, the aryl is C4-C18 aryl; the substituted alkyl is C1-C6 alkyl substituted by one or more substituents, and the substituted aryl is C4-C18 aryl substituted by one or more substituents, and the substituents are one of methyl, methoxy, tert-butyl, trifluoromethyl and halogen atom.

[0010] In one embodiment of the present application, the alkyl is one of methyl, tert-butyl and trifluoromethyl, and the aryl is one of phenyl, benzyl, naphthyl and anthracenyl.

[0011] In one embodiment of the present application, the substituted alkyl is one of methyl, tert-butyl and trifluoromethyl substituted by one or more substituents, and the substituted aryl is one of phenyl, benzyl, naphthyl and anthracenyl substituted by one or more substituents, and the substituents are one of methyl, methoxy, tert-butyl, trifluoromethyl and halogen atom.

[0012] In one embodiment of the present application, the chiral oxazoline ligand with the indole skeleton has one of the following structures:

[0013]

[0014]

[0015] In another aspect of the present application, the present application provides a method for synthesizing the chiral oxazoline ligand with the indole skeleton, which comprises: coupling an indole carboxylate reagent and a halogenated pyridine reagent under the action of a copper metal catalyst and a first base to obtain a coupling product; performing hydrolysis reaction on the coupling product under the action of a hydrolysis agent, and then performing acidification reaction to obtain a carboxylic acid product; performing condensation reaction on the carboxylic acid product with a condensation agent under the action of a chiral amino alcohol and a second base to obtain an amide product; and performing cyclization reaction on the amide product under the action of a third base and acyl chloride to obtain the chiral oxazoline ligand with the indole skeleton; wherein the chiral amino alcohol is a compound shown in formula 2:

[0016]

[0017] R 1 is as described previously.

[0018] In one embodiment of the present application, the metal copper catalyst is selected from at least one of copper oxide, copper chloride, copper triflate, cuprous iodide, cuprous tetrafluoroborate.

[0019] In some embodiments of the present application, the indole carboxylate reagent is selected from at least one of indole-2-carboxylic acid methyl ester, indole-2-carboxylic acid ethyl ester, indole-2-carboxylic acid tert-butyl ester, indole-2-carboxylic acid allyl ester, indole-2-carboxylic acid benzyl ester.

[0020] In some embodiments of the present application, the halogenated pyridine reagent is selected from at least one of 2-bromopyridine, 2-iodopyridine, 2-chloropyridine.

[0021] In some embodiments of the present application, the hydrolysis reagent is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate.

[0022] In one embodiment of the present application, the first base is selected from at least one of N,N'-dimethylethylenediamine, potassium carbonate.

[0023] In one embodiment of the present application, the coupling reaction is carried out in a first solvent selected from at least one of toluene, ethanol, N,N-dimethylformamide, dichloromethane.

[0024] In some embodiments of the present application, a proton acid such as hydrochloric acid is used as a proton source in the acidification reaction.

[0025] In one embodiment of the present application, the condensing agent is selected from at least one of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate, benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-propylphosphonic anhydride.

[0026] In one embodiment of the present application, the second base is selected from at least one of triethylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylpropanediamine, N,N,N',N'-tetramethylbutanediamine, N,N,N',N'-tetraethylethylenediamine.

[0027] In one embodiment of the present application, the condensation reaction is carried out in a second solvent selected from at least one of toluene, methanol, ethanol, water, N,N-dimethylformamide, dichloromethane.

[0028] In one embodiment of the present application, the third base is selected from at least one of triethylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylpropylenediamine, N,N,N',N'-tetramethylbutylenediamine, N,N,N',N'-tetraethylethylenediamine.

[0029] In one embodiment of the present application, the acyl chloride is selected from at least one of p-toluenesulfonyl chloride, methylsulfonyl chloride.

[0030] In one embodiment of the present application, the second solvent is selected from at least one of toluene, methanol, ethanol, water, N,N-dimethylformamide, dichloromethane.

[0031] In one embodiment of the present application, the molar ratio of the indole carboxylate reagent, the halopyridine reagent, the copper metal catalyst, the first base, the hydrolysis agent is 2:(2.5-3.5):(5.5-7.5):12:8, preferably 2:3:6:12:8.

[0032] In one embodiment of the present application, the first base is N,N'-dimethylethylenediamine and potassium carbonate, and the molar ratio of the N,N'-dimethylethylenediamine and the potassium carbonate is (0.5-1.5):(0.5-1.5), preferably 1:1.

[0033] In one embodiment of the present application, the molar ratio of the carboxylic acid product, the condensing agent, the acyl chloride is 1.7:5.1:(2.19-4.28).

[0034] In another aspect of the present application, the present application provides the use of the chiral oxazoline ligand with indole skeleton of the above-mentioned embodiments, or the chiral oxazoline ligand with indole skeleton prepared by the method of the above-mentioned embodiments in catalyzing asymmetric synthesis reaction. As mentioned above, the use of the chiral oxazoline ligand with indole skeleton can realize high enantioselective Friedel-Crafts reaction of indole skeleton compounds, which is one of important carbon-carbon bond formation methods in organic synthesis, and can efficiently generate chiral indole derivatives, and the chiral indole derivatives have important application in synthesis of natural products and bioactive compounds. BRIEF DESCRIPTION OF DRAWINGS

[0035] The above and / or additional aspects and advantages of the present application will become apparent and be readily understood from the following description, taken in conjunction with the following drawings, in which:

[0036] Figure 1 The synthesis of (S)-4-phenyl-2-[1-(2-pyridyl)-1H-indol-2-yl]-4,5-dihydro-1,3- oxazolium (structure L1) for Example 1 1H NMR spectra;

[0037] Figure 2 (S)-4-(tert-Butyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3-oxazolium (Structure L2) synthesized for Example 2 1 H NMR spectra;

[0038] Figure 3 (S)-4-Benzyl-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3-oxazolium (Structure L3) synthesized for Example 3 1 H NMR spectra;

[0039] Figure 4 (S)-4-(4-Bromophenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3-oxazolium (Structure L4) synthesized for Example 4 1 H NMR spectra;

[0040] Figure 5 (S)-4-(3-Bromophenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3-oxazolium (Structure L5) synthesized for Example 5 1 H NMR spectra;

[0041] Figure 6 (S)-4-(4-Methoxyphenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3-oxazolium (Structure L6) synthesized for Example 6 1 H NMR spectra;

[0042] Figure 7 (S)-2-[l-(2-Pyridinyl)-lH-indol-2-yl]-4-(3-methylphenyl)-4,5-dihydro-l,3-oxazolium (Structure L7) synthesized for Example 7 1 H NMR spectra;

[0043] Figure 8 (S)-4-(4-Chlorophenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3-oxazolium (Structure L8) synthesized for Example 8 1 H NMR spectra;

[0044] Figure 9(S)-4-(4-Fluorophenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3- oxazol e (Formula L9) synthesized for Example 9 1 H NMR spectra;

[0045] Figure 10 (S)-2-[l-(2-Pyridinyl)-lH-indol-2-yl]-4-(4-methylphenyl)-4,5-dihydro-l,3- oxazol e (Formula L10) synthesized for Example 10 1 H NMR spectra;

[0046] Figure 11 (S)-2-[l-(2-Pyridinyl)-lH-indol-2-yl]-4-(4-trifluoromethylphenyl)-4,5-dihydro- l,3-oxazol e (Formula L11) synthesized for Example 11 1 H NMR spectra;

[0047] Figure 12 (S)-4-(3,5-Di-tert-butylphenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro- l,3-oxazol e (Formula L12) synthesized for Example 12 1 H NMR spectra;

[0048] Figure 13 (S)-4-(l-Naphthyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3-oxazol e (Formula L13) synthesized for Example 13 1 H NMR spectra;

[0049] Figure 14 (S)-4-(2-Bromophenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3- oxazol e (Formula L14) synthesized for Example 14 1 H NMR spectra;

[0050] Figure 15 (S)-4-(4-tert-Butylphenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3- oxazol e (Formula L15) synthesized for Example 15 1 H NMR spectra;

[0051] Figure 16 (S)-2-[l-(2-Pyridinyl)-lH-indol-2-yl]-4-(3-trifluoromethylphenyl)-4,5-dihydro- l,3-oxazol e (Formula L16) synthesized for Example 161 H NMR spectrum;

[0052] Figure 17 This is the (S)-2-[1-(2-pyridyl)-1H-indol-2-yl]-4-(2-trifluoromethylphenyl)-4,5-dihydro-1,3-oxazolium (structural formula L17) synthesized in Example 17. 1 H NMR spectrum;

[0053] Figure 18 This refers to (S)-2-[1-(2-pyridyl)-1H-indol-2-yl]-4-(2-methylphenyl)-4,5-dihydro-1,3-oxazolium (structural formula L18) synthesized in Example 18. 1 H NMR spectrum;

[0054] Figure 19 The HPLC spectrum of the synthesized 4-phenyl-2-[1-(2-pyridyl)-1H-indol-2-yl]-4,5-dihydro-oxazole (racemic product);

[0055] Figure 20 The HPLC spectrum of (S)-4-phenyl-2-[1-(2-pyridyl)-1H-indol-2-yl]-4,5-dihydro-1,3-oxazolium (structural formula L1) synthesized in Example 1 is shown.

[0056] Figure 21 The HPLC spectrum of (R)-4-phenyl-2-[1-(2-pyridyl)-1H-indol-2-yl]-4,5-dihydro-1,3-oxazolium (structural formula L21) synthesized in Example 21 is shown.

[0057] Figure 22 The chiral product ethyl 4-(1H-indol-3-yl)-2-oxo-4-phenylbutyrate obtained by the asymmetric catalytic application of ligand compound L1. 1 H NMR spectrum. Detailed Implementation

[0058] In the following description, only certain exemplary embodiments are briefly described. As those skilled in the art will recognize, the described embodiments can be modified in various ways without departing from the spirit or scope of this application, and different embodiments can be combined arbitrarily without conflict. Therefore, the following description is to be considered exemplary in nature and not restrictive.

[0059] In one aspect of the invention, a chiral oxazoline ligand containing an indole skeleton is provided. This chiral oxazoline ligand containing an indole skeleton has the structure shown in Formula 1:

[0060]

[0061] wherein R 1 is selected from one of alkyl, substituted alkyl, aryl, substituted aryl.

[0062] The chiral oxazoline ligand with indole skeleton can realize high enantioselective Friedel-Crafts reaction of indole skeleton compounds, which is one of important carbon-carbon bond formation methods in organic synthesis, and can efficiently generate chiral indole derivatives, and the chiral indole derivatives have important application in synthesis of natural products and bioactive compounds.

[0063] In addition, the raw materials used for preparing the compounds are cheap and easy to obtain, the synthesis route is short, the involved reactions are basic organic chemical reactions, the process is simple, the product is easy to separate and purify, and the synthesis is suitable for scale-up.

[0064] In an embodiment of the present application, the alkyl is C1-C6 alkyl, and the aryl is C4-C18 aryl; the substituted alkyl is C1-C6 alkyl substituted by one or more substituents, and the substituted aryl is C4-C18 aryl substituted by one or more substituents, and the substituents are one of methyl, methoxy, tert-butyl, trifluoromethyl and halogen atom.

[0065] In some embodiments of the present application, the substituted alkyl is one of methyl, tert-butyl and trifluoromethyl substituted by one or more substituents, and the substituted aryl is one of phenyl, benzyl, naphthyl and anthracenyl substituted by one or more substituents, and the substituents are one of methyl, methoxy, tert-butyl, trifluoromethyl and halogen atom.

[0066] In some embodiments of the present application, the one or more substituents can refer to one substituent, two substituents, three substituents, etc.

[0067] In an embodiment of the present application, the alkyl is selected from one of methyl, tert-butyl and trifluoromethyl, and the aryl is selected from one of phenyl, benzyl, naphthyl and anthracenyl.

[0068] In an embodiment of the present application, the chiral oxazoline ligand with indole skeleton has one of the following structures:

[0069]

[0070] In another aspect of the present application, the present application provides a method for synthesizing the chiral oxazoline ligand containing the above-mentioned indole skeleton. The method uses inexpensive and readily available starting materials such as indole carboxylate reagent and halogenated pyridine reagent, uses inexpensive copper metal catalyst for catalysis, uses common bases such as N,N'-dimethylethylenediamine and potassium carbonate, uses common organic solvents such as toluene, and performs coupling reaction under heating or normal temperature conditions to obtain a coupling product. The coupling product is hydrolyzed and re-acidified to obtain a carboxylic acid product. The carboxylic acid product is mixed with a condensing agent such as N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate and a solvent, and reacted in the presence of a common organic base such as triethylamine, and then a chiral amino alcohol is added, and reacted at normal temperature to obtain an amide product. The amide product is mixed with an acyl chloride reagent such as p-toluenesulfonyl chloride and a solvent, and reacted at normal temperature or under heating in the presence of a common organic base such as triethylamine to obtain the chiral oxazoline ligand containing the indole skeleton. The obtained ligand is a polydentate chiral ligand, which can form stable complexes with various metals and is suitable for asymmetric catalytic reactions. The method has the advantages of inexpensive and readily available starting materials, short synthesis route, simple process involving basic organic chemical reactions, easy separation and purification of products, and suitability for scale-up synthesis.

[0071] wherein the chiral amino alcohol is a compound shown in formula 2:

[0072]

[0073] R 1 is as described above.

[0074] According to a specific example of the present application, in the above-mentioned method, commercially available indole carboxylate reagent and halogenated pyridine reagent are used as starting materials, and coupling reaction is performed at 120°C in the presence of copper metal catalyst, N,N'-dimethylethylenediamine and potassium carbonate to obtain a coupling product. The coupling product is mixed with sodium hydroxide and a solvent, and reacted at 95°C, and then acidified in an ice bath to obtain a carboxylic acid product. The carboxylic acid product is mixed with condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate and a solvent, and reacted in the presence of triethylamine for 1 h, and then a chiral amino alcohol is added and reacted at normal temperature to obtain an amide product. The amide product is mixed with p-toluenesulfonyl chloride and a solvent, and reacted at 40°C in the presence of triethylamine to obtain the chiral oxazoline ligand containing the indole skeleton. The entire synthesis process is simple and easy to operate, and the starting materials are simple and readily available. Further, the chiral ligand prepared by the method of the present application can be used in the research of asymmetric catalytic reactions, and also provides a reference for the synthesis of similar ligands.

[0075] More specifically, the reaction in the method can be carried out in the following procedure: using copper oxide as catalyst, methyl indole-2-carboxylate and 2-bromopyridine as raw materials, coupling reaction is carried out at 120℃ in the presence of N,N'-dimethylethylenediamine and potassium carbonate to obtain a coupling product. The coupling product is mixed with sodium hydroxide and a solvent, and reacted at 95℃, and then acidified in an ice bath to obtain a carboxylic acid product. The carboxylic acid product is mixed with a condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate and a solvent, reacted in the presence of triethylamine for 1h, then a chiral amino alcohol is added, and reacted at room temperature for 36h to obtain an amide product. The amide product is mixed with p-toluenesulfonyl chloride and a solvent, reacted at 40℃ in the presence of triethylamine to obtain a chiral oxazoline ligand containing an indole skeleton.

[0076] The chiral oxazoline ligand containing an indole skeleton prepared by the method of the present application can be in R configuration or S configuration. In some embodiments of the present application, the chiral amino alcohol (compound shown in formula 2) as raw material can control the chiral structure part of the chiral oxazoline ligand containing an indole skeleton. Specifically, the chiral part of the chiral ligand is introduced by the chiral amino alcohol as raw material, and the configuration is consistent with that of the chiral amino alcohol as raw material.

[0077] In embodiments of the present application, stirring at room temperature and continuing to stir at room temperature refer to carrying out the reaction under the condition that the reaction system is not additionally cooled or heated, and the room temperature is the ambient temperature of the reaction system. The specific temperature range of the room temperature is not particularly limited, for example, it can be 10-30℃.

[0078] In embodiments of the present application, the reactants can be separated and treated by using conventional separation methods such as column chromatography.

[0079] In an embodiment of the present application, the above-mentioned copper metal catalyst is selected from at least one of copper oxide, copper chloride, copper triflate, cuprous iodide, and cuprous tetrafluoroborate.

[0080] In some embodiments of the present application, the above-mentioned indole carboxylate reagent is selected from at least one of methyl indole-2-carboxylate, ethyl indole-2-carboxylate, tert-butyl indole-2-carboxylate, allyl indole-2-carboxylate, and benzyl indole-2-carboxylate.

[0081] In some embodiments of the present application, the above-mentioned halogenated pyridine reagent is selected from at least one of 2-bromopyridine, 2-iodopyridine, and 2-chloropyridine.

[0082] In some embodiments of the present application, the above-mentioned hydrolysis agent is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, and sodium carbonate.

[0083] In one embodiment of the present application, the first base is selected from at least one of N,N'-dimethylethylenediamine, potassium carbonate, sodium carbonate, cesium carbonate.

[0084] In one embodiment of the present application, the coupling reaction is carried out in a first solvent selected from at least one of toluene, ethanol, N,N-dimethylformamide, dichloromethane.

[0085] In some embodiments of the present application, a proton acid such as hydrochloric acid is used as a proton source in the acidification reaction.

[0086] In one embodiment of the present application, the condensing agent is selected from at least one of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate, benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-propylphosphonic anhydride.

[0087] In one embodiment of the present application, the second base is selected from at least one of triethylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylpropanediamine, N,N,N',N'-tetramethylbutanediamine, N,N,N',N'-tetraethylethylenediamine.

[0088] In one embodiment of the present application, the condensation reaction is carried out in a second solvent selected from at least one of toluene, methanol, ethanol, water, N,N-dimethylformamide, dichloromethane.

[0089] In one embodiment of the present application, the third base is selected from at least one of triethylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylpropanediamine, N,N,N',N'-tetramethylbutanediamine, N,N,N',N'-tetraethylethylenediamine.

[0090] In one embodiment of the present application, the acyl chloride is selected from at least one of p-toluenesulfonyl chloride, methylsulfonyl chloride.

[0091] In one embodiment of the present application, the second solvent is selected from at least one of toluene, methanol, ethanol, water, N,N-dimethylformamide, dichloromethane.

[0092] In one embodiment of the present application, the molar ratio of the indole carboxylate reagent, the halopyridine reagent, the copper metal catalyst, the first base, the hydrolysis agent is 2:(2.5-3.5):(5.5-7.5):12:8, preferably 2:3:6:12:8.

[0093] In one embodiment of the present application, the above first base is N,N'-dimethylethylenediamine and potassium carbonate, and the molar ratio of the above N,N'-dimethylethylenediamine and the above potassium carbonate is (0.5-1.5):(0.5-1.5), preferably 1:1.

[0094] In one embodiment of the present application, the molar ratio of the above carboxylic acid product, the above condensing agent, and the above acyl chloride is 1.7:5.1:(2.19-4.28).

[0095] In another aspect of the present application, the present application provides the chiral oxazoline ligand containing indole skeleton of the above embodiments, or the chiral oxazoline ligand containing indole skeleton prepared by the method of the above embodiments. The use in catalytic asymmetric synthesis reaction. As described above, the use of the chiral oxazoline ligand containing indole skeleton can achieve high enantioselective Friedel-Crafts reaction of indole skeleton compounds, which is one of the important carbon-carbon bond formation methods in organic synthesis, and can efficiently generate chiral indole derivatives, and the chiral indole derivatives have important applications in the synthesis of natural products and biologically active compounds.

[0096] The embodiments of the present application are described in detail below. The embodiments described below are exemplary and are only used to explain the present application, and cannot be understood as a limitation of the present application. If the specific techniques or conditions are not described in the embodiments, the techniques or conditions described in the literature in the art or according to the product instructions are used. If the reagents or instruments are not described by the manufacturer, they are all conventional products that can be obtained by market purchase.

[0097] Example 1

[0098] (1) Synthesis of carboxylic acid 1-(pyridin-2-yl)-1H-indole-2-carboxylic acid (d):

[0099] In a reactor was added methyl indole-2-carboxylate (0.35 g, 2 mmol) of formula la, copper oxide (0.48 g, 6 mmol), potassium carbonate (0.83 g, 6 mmol), 10 mL of toluene, 2-bromopyridine (0.29 mL, 3 mmol) of formula lb, N,N'-dimethylethylenediamine (0.65 mL, 6 mmol), fitted with a reflux condenser, and the heating plate temperature was adjusted to 120 °C. The reaction was stopped after 24 h. It was cooled to room temperature, 10 mL of water was added, and then extracted three times with ethyl acetate (10 mL). The organic phase after extraction was dried, concentrated, and column chromatography was performed with petroleum ether, and the eluent was petroleum ether: ethyl acetate 5: 1, to obtain a white solid. (0.45 g, 90% yield). In a reactor was added the coupled product of formula lc (0.45 g, 1.8 mmol), sodium hydroxide (0.29 g, 7.2 mmol), 40 mL of a 1: 1 mixture of methanol (MeOH): water (H2O). It was fitted with a reflux condenser, and the heating plate temperature was adjusted to 95 °C. The reaction was stopped after 4 h. It was cooled to room temperature, and 7.2 mL of a 1 mol / L solution of hydrochloric acid was added dropwise in an ice bath. Then it was extracted three times with dichloromethane (10 mL). The organic phase after extraction was dried, concentrated, and a white solid d was obtained. (0.40 g, 94% yield).

[0100] (2) Synthesis of (S)-4-phenyl-2-[l-(2-pyridyl)-lH-indol-2-yl]-4,5-dihydro-l,3- oxazol (formula Ll):

[0101] To the reactor was added the carboxylic acid product of structure 1d (0.40 g, 1.7 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU) (1.94 g, 5.1 mmol), N,N-dimethylformamide (DMF) 15 mL, and triethylamine (TEA) (1.89 mL, 13.6 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h, then L-phenylglycinol of structure 1e (0.35 g, 2.55 mmol) was added and the reaction was allowed to proceed at room temperature for 36 h. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase was then washed three times with water (10 mL) to remove the DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1:5 to give a brown viscous liquid. (0.36 g, 62% yield). To the reactor was added the amide product of structure 1f (0.36 g, 1.05 mmol), p-toluenesulfonyl chloride (TsCl) (0.60 g, 3.15 mmol), dichloromethane 10 mL, and triethylamine (TEA) (0.40 mL, 2.91 mmol) was added. The reaction was allowed to proceed at room temperature for 30 min, then triethylamine (TEA) (1.78 mL, 12.84 mmol) was added dropwise, the condenser was attached and the heating plate was set to 40 °C. The reaction was allowed to proceed for 4 h, then the heating was stopped. The reaction was allowed to cool to room temperature, 10 mL of water was added, followed by three extractions with dichloromethane (10 mL). The organic phase was then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3:1 to give a yellow viscous liquid. (0.26 g, 74% yield).

[0102] Reference is made to Figure 1 and Figure 20 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 8.67 (d, J = 4.9 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.48 - 7.38 (m, 2H), 7.38 - 7.20 (m, 5H), 7.13 (dd, J = 13.8, 7.8 Hz, 3H), 5.27 (t, J = 9.2 Hz, 1H), 4.62 (t, J = 9.1 Hz, 1H), 4.08 (t, J = 8.3 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 158.31, 149.48, 148.89, 142.15, 140.33, 135.80, 135.36, 128.63, 127.44, 127.29, 127.04, 126.34, 125.11, 123.45, 122.12, 121.54, 110.76, 110.14, 73.94, 70.17. HRMS (ESI) m / z. calcd for [M+H]+C22H17N3OH: 340.1444; found: 340.1449. [Chiral column CHIRALCEL OD-H (4.6 mm x 250 mm), n-hexane: isopropyl alcohol = 80:20, v = 1 mL / min, detection wavelength = 254 nm, t(major) = 15.805 min, t(major) = 34.662 min, >99% ee.

[0103] Example 2

[0104] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0105] (2) Synthesis of (S)-4-(tert-butyl)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4,5-dihydro-l,3- oxazol (Formula L2):

[0106] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.92 g, 5.06 mmol), N,N-dimethylformamide (DMF) 15 mL, and triethylamine (TEA) (1.87 mL, 13.48 mmol) was added dropwise. After 1 h at room temperature, (S)-tert-leucinol of structure 2e (0.35 g, 2.53 mmol) was added and the reaction was allowed to proceed for 36 h at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 :5 to give a brown viscous liquid. (0.40 g, 71% yield). To the reactor was added the amide product of structure 2f (0.40 g, 1.04 mmol), p-toluenesulfonyl chloride (TsCl) (0.60 g, 3.13 mmol), dichloromethane 15 mL, and triethylamine (TEA) (0.40 mL, 2.89 mmol) was added. The reaction was allowed to proceed for 30 min at room temperature, then triethylamine (TEA) (1.77 mL, 12.74 mmol) was added dropwise. The reaction was fitted with a reflux condenser and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 h, then the heat was removed. The reaction was allowed to cool to room temperature, 15 mL of water was added, followed by three extractions with dichloromethane (15 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a light brown solid. (0.18 g, 48% yield).

[0107] Reference Figure 2 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.63 - 8.51 (m, 1H), 7.86 (td, J = 7.7, 1.9 Hz, 1H), 7.69 (dt, J = 7.8, 1.0 Hz, 1H), 7.42 (dt, J = 7.9, 1.0 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.26 - 7.23 (m, 2H), 7.18 - 7.11 (m, 1H), 4.18 (dd, J = 10.0, 8.5 Hz, 1H), 4.11 - 4.03 (m, 1H), 3.90 (dd, J = 10.0, 7.6 Hz, 1H), 0.79 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 157.21, 151.87, 149.15, 139.47, 137.66, 127.25, 127.06, 124.79, 122.55, 122.46, 121.87, 121.35, 111.20, 109.89, 76.56, 68.13, 34.05, 25.75. HRMS (ESI) m / z calcd for [M+H]+C20H21N3OH: 320.1757; found: 320.1760.

[0108] Example 3

[0109] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0110] (2) Synthesis of (S)-4-benzyl-2-[l-(2-pyridyl)-lH-indol-2-yl]-4,5-dihydro-l,3- oxazol (structure L3):

[0111] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.90 g, 4.99 mmol), N,N-dimethylformamide (DMF) 10 mL, and triethylamine (TEA) (1.85 mL, 13.32 mmol) was added dropwise. After 1 hour at room temperature, the L-phenylalaninol of structure 3e (0.39 g, 2.51 mmol) was added and the reaction was allowed to proceed for 36 hours at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove the DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1:3 to yield a white, viscous liquid. (0.28 g, 46% yield). To the reactor was added the amide product of structure 3f (0.28 g, 0.74 mmol), p-toluenesulfonyl chloride (TsCl) (0.43 g, 2.23 mmol), dichloromethane 10 mL, and triethylamine (TEA) (0.29 mL, 2.06 mmol) was added. The reaction was allowed to proceed for 30 minutes at room temperature, then triethylamine (TEA) (1.26 mL, 9.10 mmol) was added dropwise. The reaction was fitted with a reflux condenser and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 hours, then the heat was removed. The reaction was allowed to cool to room temperature, 10 mL of water was added, followed by three extractions with dichloromethane (10 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to yield a white, viscous liquid. (0.23 g, 89% yield).

[0112] Reference Figure 3 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (d, J = 4.8 Hz, 1H), 7.81 (td, J = 7.7, 2.0 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.36 - 7.25 (m, 6H), 7.22 (dd, J = 8.9, 6.1 Hz, 2H), 7.15 (d, J = 7.3 Hz, 2H), 4.46 (p, J = 7.5 Hz, 1H), 4.21 (t, J = 8.8 Hz, 1H), 3.99 (t, J = 7.8 Hz, 1H), 2.99 (dd, J = 13.9, 5.8 Hz, 1H), 2.69 (dd, J = 13.8, 7.9 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 158.04, 151.72, 149.06, 139.36, 138.04, 137.81, 129.41, 128.43, 127.34, 127.09, 126.44, 125.00, 122.52, 122.04, 121.97, 121.57, 111.43, 110.43, 71.30, 68.08, 41.39. HRMS (ESI) m / z calcd for [M+H]+C23H19N3OH: 354.1601; found: 354.1605.

[0113] Example 4

[0114] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0115] (2) Synthesis of (S)-4-(4-bromophenyl)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4,5- dihydro-l,3-oxazol (Formula L4):

[0116] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.94 g, 5.07 mmol), N,N-dimethylformamide (DMF) 10 mL, and triethylamine (TEA) (1.88 mL, 13.54 mmol) was added dropwise. After 1 h at room temperature, (S)-2-amino-2-(4-bromophenyl)ethanol of structure 4e (0.55 g, 2.53 mmol) was added and the reaction was allowed to proceed for 36 h at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1:2 to give a yellow viscous liquid. (0.53 g, 72% yield). To the reactor was added the amide product of structure 4f (0.53 g, 1.22 mmol), p-toluenesulfonyl chloride (TsCl) (0.70 g, 3.66 mmol), dichloromethane 10 mL, and triethylamine (TEA) (0.48 mL, 3.37 mmol) was added. The reaction was allowed to proceed for 30 min at room temperature, then triethylamine (TEA) (2.05 mL, 14.92 mmol) was added dropwise, the condenser was attached and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 h, then the heating was stopped. The reaction was allowed to cool to room temperature, 10 mL of water was added, followed by three extractions with dichloromethane (10 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a yellow viscous liquid. (0.44 g, 88% yield).

[0117] Reference Figure 4 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.61 - 8.32 (m, 1H), 7.85 (td, J = 7.7, 1.9 Hz, 1H), 7.72 (dt, J = 7.9, 1.1 Hz, 1H), 7.48 - 7.42 (m, 3H), 7.40 - 7.35 (m, 2H), 7.34 - 7.27 (m, 2H), 7.21 - 7.15 (m, 1H), 7.11 - 7.04 (m, 2H), 5.23 (dd, J = 10.0, 7.9 Hz, 1H), 4.62 (dd, J = 10.0, 8.3 Hz, 1H), 4.03 (t, J = 8.1 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 159.22, 151.60, 149.23, 141.40, 139.47, 137.95, 131.61, 128.38, 127.27, 126.71, 125.19, 122.68, 122.09, 121.86, 121.63, 121.30, 111.18, 110.93, 74.02, 69.63. HRMS (ESI) m / z. calcd for [M+H]+C22H16BrN3OH: 418.0550; found: 418.0554.

[0118] Example 5

[0119] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0120] (2) Synthesis of (S)-4-(3-bromophenyl)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4,5- dihydro-l,3-oxazol (structure L5):

[0121] In a reactor was added sequentially the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.94 g, 5.07 mmol), N,N-dimethylformamide (DMF) 20 mL, and triethylamine (TEA) (1.88 mL, 13.54 mmol) dropwise. After 1 h at room temperature, (S)-2-amino-2-(3-bromophenyl)ethanol of structure 5e (0.54 g, 2.50 mmol) was added and the reaction was allowed to proceed for 36 h at room temperature. 20 mL of water was added and the reaction mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed three times with water (20 mL) to remove DMF, dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 :7 to give a brown viscous liquid. (0.44 g, 60% yield). In a reactor was added sequentially the amide product of structure 5f (0.44 g, 1.01 mmol), p-toluenesulfonyl chloride (TsCl) (0.58 g, 3.03 mmol), dichloromethane 20 mL, and triethylamine (TEA) (0.39 mL, 2.79 mmol). The reaction was allowed to proceed for 30 min at room temperature, then triethylamine (TEA) (1.70 mL, 12.35 mmol) was added dropwise, a reflux condenser was attached, and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 h, then the heating was stopped. The reaction mixture was allowed to cool to room temperature, 20 mL of water was added, and the reaction mixture was extracted three times with dichloromethane (20 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a purple viscous liquid. (0.22 g, 51% yield).

[0122] Reference Figure 5 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.72 (dd, J = 5.0, 1.9 Hz, 1H), 7.90 (td, J = 7.7, 2.0 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.47 - 7.38 (m, 4H), 7.38-

[0123] 7.31 (m, 2H), 7.30 - 7.24 (m, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.12 (dt, J = 7.7, 1.4 Hz, 1H), 5.28 (dd, J = 10.1, 8.0 Hz, 1H), 4.66 (dd, J = 10.1, 8.3 Hz, 1H), 4.09 (t, J = 8.1 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 159.29, 151.59, 149.42, 144.77, 139.56, 138.08, 130.50, 130.09, 129.74, 127.28, 126.75, 125.28, 125.22, 122.82, 122.77, 122.13, 121.89, 121.65, 111.23, 110.93, 73.95, 69.69. HRMS (ESI) m / z. calcd for [M+H]+

[0124] C22H16BrN3OH: 418.0550; found: 418.0554.

[0125] Example 6

[0126] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0127] (2) Synthesis of (S)-4-(4-methoxyphenyl)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4,5- dihydro-l,3-oxazol (Formula L6):

[0128] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.92 g, 5.03 mmol), N,N-dimethylformamide (DMF) 10 mL, and triethylamine (TEA) (1.87 mL, 13.45 mmol) was added dropwise. After 1 hour at room temperature, (S)-2-amino-2-(4-methoxyphenyl)ethanol of structure 6e (0.42 g, 2.53 mmol) was added and the reaction was allowed to proceed for 36 hours at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove the DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1:4 to give a brown, viscous liquid. (0.32 g, 50% yield). To the reactor was added the amide product of structure 6f (0.32 g, 0.83 mmol), p-toluenesulfonyl chloride (TsCl) (0.48 g, 2.50 mmol), dichloromethane 10 mL, and triethylamine (TEA) (0.33 mL, 2.30 mmol) was added. The reaction was allowed to proceed for 30 minutes at room temperature, then triethylamine (TEA) (1.40 mL, 10.18 mmol) was added dropwise. The condenser was attached and the heating plate was set to 40 °C. The reaction was allowed to proceed for 4 hours, then the heat was removed. The reaction was allowed to cool to room temperature, 10 mL of water was added, followed by three extractions with dichloromethane (10 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a white solid. (0.22 g, 72% yield).

[0129] Reference Figure 6 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.63 (d, J = 5.1 Hz, 1H), 7.93 - 7.81 (m, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.45 (dd, J = 14.7, 8.1 Hz, 2H), 7.38 (d, J = 2.8 Hz, 1H), 7.34 - 7.22 (m, 3H), 7.19 - 7.09 (m, 2H), 6.94 - 6.82 (m, 2H), 5.26 (t, J = 8.9 Hz, 1H), 4.68 - 4.54 (dd, 1H), 4.08 (dd, J = 5.1 Hz, 1H), 3.82 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 158.96, 158.67, 151.66, 149.16, 139.35, 137.84, 134.55, 127.78, 127.35, 127.03, 125.02, 122.53, 122.00, 121.82, 121.56, 113.90, 111.25, 110.71, 74.41, 69.71, 55.31.

[0130] HRMS (ESI) m / z calcd for [M+H]+C23H19N3O2H: 370.1550; found: 370.1556.

[0131] Example 7

[0132] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0133] (2) Synthesis of (S)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4-(3-methylphenyl)-4,5- dihydro-l,3-oxazol (Formula L7):

[0134] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.92 g, 5.04 mmol), N,N-dimethylformamide (DMF) 20 mL, and triethylamine (TEA) (1.87 mL, 13.48 mmol) was added dropwise. After 1 h at room temperature, (S)-2-amino-2-(3-methylphenyl)ethanol of structure 7e (0.39 g, 2.53 mmol) was added and the reaction was allowed to proceed for 36 h at room temperature. 20 mL of water was added, followed by three extractions with ethyl acetate (20 mL). The organic phase after extraction was rinsed three times with water (20 mL) to remove the DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 :7 to give a brown, viscous liquid. (0.35 g, 56% yield). To the reactor was added the amide product of structure 7f (0.35 g, 0.94 mmol), p-toluenesulfonyl chloride (TsCl) (0.54 g, 2.81 mmol), dichloromethane 20 mL, and triethylamine (TEA) (0.38 mL, 2.58 mmol) was added. The reaction was allowed to proceed for 30 min at room temperature, then triethylamine (TEA) (1.57 mL, 11.43 mmol) was added dropwise. The condenser was fitted and the heating plate temperature was adjusted to 40 °C. The reaction was allowed to proceed for 4 h, then the heat was removed. The reaction was allowed to cool to room temperature, 20 mL of water was added, followed by three extractions with dichloromethane (20 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give an orange-red, viscous liquid. (0.18 g, 57% yield).

[0135] Reference Figure 7 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.67 (dd, J = 4.9, 2.0 Hz, 1H), 7.85 (td, J = 7.7, 1.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.53 - 7.41 (m, 3H), 7.35 - 7.30 (m, 2H), 7.27 (td, J = 7.6, 2.7 Hz, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.09 - 7.01 (m, 2H), 5.38 - 5.23 (m, 1H), 4.66 (dd, J = 10.0, 8.2 Hz, 1H), 4.12 (t, J = 8.2 Hz, 1H), 2.40 (s, 3H). 13CNMR (101 MHz, Chloroform-d) δ 158.85, 151.73, 149.18, 142.36, 139.49, 138.19, 137.91, 128.49, 128.18, 127.42, 127.35, 127.13, 125.11, 123.74, 122.62, 122.07, 121.97, 121.65, 111.37, 110.76, 74.32, 70.26, 21.52. HRMS (ESI) m / z. calcd for [M+H]+C23H19N3OH: 354.1601; found: 354.1606.

[0136] Example 8

[0137] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0138] (2) Synthesis of (S)-4-(4-chlorophenyl)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4,5- dihydro-l,3-oxazol (Formula L8):

[0139] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.94 g, 5.08 mmol), N,N-dimethylformamide (DMF) 20 mL, and triethylamine (TEA) (1.89 mL, 13.59 mmol) was added dropwise. After 1 h at room temperature, (S)-2-amino-2-(4-chlorophenyl)ethanol of structure 8e (0.43 g, 2.52 mmol) was added and the reaction was allowed to proceed for 36 h at room temperature. Water 20 mL was added and the reaction was extracted three times with ethyl acetate (20 mL). The organic phase was washed three times with water (20 mL) to remove DMF, dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 :4 to give a brown viscous liquid. (0.28 g, 43% yield). To the reactor was added the amide product of structure 8f (0.28 g, 0.73 mmol), p-toluenesulfonyl chloride (TsCl) (0.42 g, 2.18 mmol), dichloromethane 20 mL, and triethylamine (TEA) (0.29 mL, 2.00 mmol) was added. The reaction was allowed to proceed for 30 min at room temperature, then triethylamine (TEA) (1.22 mL, 8.87 mmol) was added dropwise. The reaction was fitted with a reflux condenser and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 h, then heating was stopped. The reaction was allowed to cool to room temperature, water 20 mL was added, and the reaction was extracted three times with dichloromethane (20 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a pink viscous liquid. (0.14 g, 53% yield).

[0140] Reference Figure 8 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.63 (d, J = 2.9 Hz, 1H), 7.86 (td, J = 7.8, 2.0 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.32 - 7.27 (m, 4H), 7.25 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 5.33 - 5.22 (m, 1H), 4.64 (dd, J = 10.1, 8.2 Hz, 1H), 4.06 (t, J = 8.1 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 159.19, 151.60, 149.22, 140.91, 139.48, 137.97, 133.19, 128.67, 128.05, 127.30, 126.78, 125.20, 122.69, 122.11, 121.87, 121.66, 111.22, 110.92, 74.10, 69.59. HRMS (ESI) m / z. calcd for [M+H]+C22H16CIN3OH: 374.1055; found: 374.1059.

[0141] Example 9

[0142] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0143] (2) Synthesis of (S)-4-(4-fluorophenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5- dihydro-l,3-oxazol (Formula L9):

[0144] To the reactor was added the carboxylic acid product of structure 9d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.93 g, 5.06 mmol), N,N-dimethylformamide (DMF) 20 mL, and triethylamine (TEA) (1.88 mL, 13.54 mmol) was added dropwise. After 1 h at room temperature, (S)-2-amino-2-(4-fluorophenyl)ethanol of structure 9e (0.39 g, 2.51 mmol) was added and the reaction was allowed to proceed for 36 h at room temperature. 20 mL of water was added, followed by three extractions with ethyl acetate (20 mL). The organic phase after extraction was washed three times with water (20 mL) to remove DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 :4 to give a brown viscous liquid. (0.32 g, 51% yield). To the reactor was added the amide product of structure 9f (0.32 g, 0.87 mmol), p-toluenesulfonyl chloride (TsCl) (0.50 g, 2.60 mmol), dichloromethane 20 mL, and triethylamine (TEA) (0.35 mL, 2.39 mmol) was added. The reaction was allowed to proceed for 30 min at room temperature, then triethylamine (TEA) (1.45 mL, 10.60 mmol) was added dropwise. The condenser was replaced with a reflux condenser and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 h, then heating was stopped. The reaction was allowed to cool to room temperature, 20 mL of water was added, followed by three extractions with dichloromethane (20 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a yellow viscous liquid. (0.14 g, 45% yield).

[0145] Reference Figure 9 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.63 - 8.54 (m, 1H), 7.86 (td, J = 7.7, 1.9 Hz, 1H), 7.76 (dt, J = 7.8, 1.0 Hz, 1H), 7.49 (dd, J = 7.9, 1.0 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.37 - 7.30 (m, 2H), 7.29 - 7.24 (m, 1H), 7.23 - 7.16 (m, 2H), 7.08 - 6.99 (m, 2H), 5.28 (dd, J = 9.9, 7.9 Hz, 1H), 4.63 (dd, J = 10.0, 8.2 Hz, 1H), 4.07 (t, J = 8.1 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 163.38, 160.94, 159.03, 151.61, 149.22, 139.43, 138.17 (d, J = 3.1 Hz), 137.96, 128.28 (d, J = 8.1 Hz), 127.32, 126.85, 125.17, 122.66, 121.96 (d, J = 26.5 Hz), 121.66, 115.36 (d, J = 21.3 Hz), 111.23, 110.88, 74.27, 69.57. .19 FNMR (376 MHz, Chloroform-d) δ -115.19. HRMS (ESI) m / z. calcd for [M+H]+C22H16FN3OH: 358.1350; found: 358.1358.

[0146] Example 10

[0147] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0148] (2) Synthesis of (S)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4-(4-methylphenyl)-4,5- dihydro-l,3-oxazol (Formula L10):

[0149] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.95 g, 5.12 mmol), 10 mL of N,N-dimethylformamide (DMF), and then triethylamine (TEA) (1.90 mL, 13.68 mmol) was added dropwise. After 1 h at room temperature, (S)-2-amino-2-(4-methylphenyl)ethanol of structure 10e (0.38 g, 2.54 mmol) was added and the reaction was allowed to proceed for 36 h at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove the DMF, and then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 :3 to give a brown, viscous liquid. (0.36 g, 57% yield). To the reactor was added the amide product of structure 10f (0.36 g, 0.96 mmol), p-toluenesulfonyl chloride (TsCl) (0.55 g, 2.88 mmol), 10 mL of dichloromethane, and then triethylamine (TEA) (0.38 mL, 2.65 mmol) was added. After 30 min at room temperature, triethylamine (TEA) (1.62 mL, 11.75 mmol) was added dropwise, the condenser was attached, and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 h, after which the heating was stopped. The reaction was allowed to cool to room temperature, 10 mL of water was added, followed by three extractions with dichloromethane (10 mL). The organic phase was then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a white, powdery, viscous liquid. (0.12 g, 36% yield).

[0150] Reference Figure 10 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (dd, J = 4.8, 1.9 Hz, 1H), 7.85 (td, J = 7.7, 1.9 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.46 (dd, J = 12.6, 8.1 Hz, 2H), 7.39 (s, 1H), 7.37 - 7.28 (m, 2H), 7.27 - 7.19 (m, 1H), 7.13 (t, J = 9.1 Hz, 4H), 5.28 (dd, J = 9.9, 8.0 Hz, 1H), 4.63 (dd, J = 10.0, 8.2 Hz, 1H), 4.09 (t, J = 8.1 Hz, 1H), 2.36 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 158.78, 151.66, 149.17, 139.39, 137.86, 137.03, 129.69, 129.20, 127.36, 127.03, 126.55, 125.04, 122.56, 122.02, 121.88, 121.58, 111.29, 110.74, 74.39, 69.99, 21.12. HRMS (ESI) m / z. calcd for [M+H]+C23H19N3OH: 354.1601; found: 354.1605.

[0151] Example 11

[0152] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0153] (2) Synthesis of (S)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4-(4-trifluoromethylphenyl)-4,5- dihydro-l,3-oxazol (Formula Ll l):

[0154] In a reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.98 g, 5.18 mmol), 10 mL of N,N-dimethylformamide (DMF), and then triethylamine (TEA) (1.92 mL, 13.81 mmol) was added dropwise. After 1 hour of reaction at room temperature, (S)-2-amino-2-(4- trifluoromethylphenyl)ethanol of structure 11e (0.53 g, 2.57 mmol) was added and the reaction was left to proceed for 36 hours at room temperature. 10 mL of water was added and then the product was extracted three times with ethyl acetate (10 mL). The organic phase after extraction was washed three times with water (10 mL) to remove the DMF, and then dried, concentrated and column chromatographed. The column was packed with petroleum ether and the eluent was petroleum ether: ethyl acetate 1 : 1 to obtain a brown viscous liquid. (0.48 g, 65% yield). In a reactor was added the amide product of structure 11f (0.48 g, 1.12 mmol), p-toluenesulfonyl chloride (TsCl) (0.65 g, 3.35 mmol), 10 mL of dichloromethane, and then triethylamine (TEA) (0.44 mL, 3.07 mmol) was added. After 30 minutes of reaction at room temperature, triethylamine (TEA) (1.87 mL, 13.64 mmol) was added dropwise, a reflux condenser was attached and the heating plate was adjusted to 40 °C. The reaction was left to proceed for 4 hours and then the heating was stopped. The reaction was cooled to room temperature, 10 mL of water was added and then the product was extracted three times with dichloromethane (10 mL). The organic phase was dried, concentrated and column chromatographed. The column was packed with petroleum ether and the eluent was petroleum ether: ethyl acetate 4: 1 to obtain an orange-red viscous liquid. (0.25 g, 57% yield).

[0155] Reference is made to Figure 11 , the product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (dd, J = 5.3, 1.9 Hz, 1H), 7.88 (td, J = 7.7, 1.9 Hz, 1H), 7.76 (dd, J = 7.8, 1.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.50 (dd, J = 7.9, 1.1 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.34 - 7.30 (m, 4H), 7.29 - 7.22 (m, 1H), 5.36 (dd, J = 10.1, 8.0 Hz, 1H), 4.69 (dd, J = 10.1, 8.3 Hz, 1H), 4.09 (t, J = 8.2 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 159.46, 151.60, 149.26, 146.35, 139.53, 138.00, 129.86, 129.54, 127.26, 126.99, 126.63, 125.54 (d, J = 3.9 Hz), 125.38 (d, J = 21.2 Hz), 122.75, 122.14, 121.91, 121.69, 111.20, 111.03, 73.88, 69.78. 19 F NMR (376 MHz, Chloroform-d) δ -62.43. HRMS (ESI) m / z. calcd for [M+H]+C23H16F3N3OH: 408.1318; found: 408.1322.

[0156] Example 12

[0157] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0158] (2) Synthesis of (S)-4-(3,5-di-tert-butylphenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5- dihydro-l,3-oxazol (Formula L12):

[0159] In a reactor, a carboxylic acid product with structural formula d (0.40 g, 1.70 mmol), the condensing agent N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (HATU) (1.93 g, 5.04 mmol), and N,N-dimethylformamide (DMF) (10 mL) were added sequentially, followed by the dropwise addition of triethylamine (TEA) (1.87 mL, 13.44 mmol). After reacting at room temperature for 1 hour, (S)-2-amino-2-(3,5-bis(tert-butyl)phenyl)ethanol with structural formula 12e (0.63 g, 2.50 mmol) was added, and the reaction was carried out at room temperature for 36 hours. 10 mL of water was added, followed by extraction three times with ethyl acetate (10 mL). The extracted organic phase was then washed three times with water (10 mL) to remove DMF, dried, concentrated, and subjected to column chromatography. The specific conditions were as follows: A column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 1:2, yielding a brown viscous liquid (0.43 g, 55% yield). In a reactor, the amide product with structural formula 12f (0.43 g, 0.92 mmol), p-toluenesulfonyl chloride (TsCl) (0.53 g, 2.75 mmol), 10 mL of dichloromethane, and triethylamine (TEA) (0.37 mL, 2.53 mmol) were added sequentially. The reaction was carried out at room temperature for 30 minutes, followed by dropwise addition of triethylamine (TEA) (1.54 mL, 11.21 mmol). A reflux condenser was attached, and the heating plate temperature was adjusted to 40°C. Heating was stopped after 4 hours. The mixture was cooled to room temperature, 10 mL of water was added, and the mixture was extracted three times with dichloromethane (10 mL). The extract was then dried, concentrated, and subjected to column chromatography. The specific conditions were as follows: A column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 3:1, yielding an orange-red viscous liquid. (0.24g, 58% yield).

[0160] refer to Figure 12 The results of the product structure confirmation are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.68(dd,J=5.0,1.9Hz,1H),7.89-7.75(m,2H),7.48(dd,J=15.6,7.1Hz,3H),7.41(t,J=1.8Hz,1H),7.39-7. 31(m,2H),7.30-7.23(m,1H),7.12(d,J=1.9Hz,2H),5.39-5.29(m,1H),4.68(dd,J=10.0,8.2Hz,1H),4.17(t,J=8.4Hz,1H),1.39(s,18H). 13C NMR (101 MHz, Chloroform-d) δ 158.65, 151.78, 151.04, 149.13, 141.34, 139.49, 137.78, 127.38, 127.10, 125.06, 122.60, 122.09, 122.02, 121.60, 121.53, 120.89, 111.47, 110.72, 74.36, 70.95, 34.96, 31.59. HRMS (ESI) m / z. calcd for [M+H]+C30H33N3OH: 452.2696; found: 452.2703.

[0161] Example 13

[0162] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0163] (2) Synthesis of (S)-4-(l-naphthalenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5- dihydro-l,3-oxazol (Formula L13):

[0164] In a reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.94 g, 5.16 mmol), 10 mL of N,N-dimethylformamide (DMF), and then triethylamine (TEA) (1.94 mL, 13.81 mmol) was added dropwise. After 1 hour of reaction at room temperature, (S)-2-amino-2-(naphthalen-l-yl)ethanol of structure 13e (0.48 g, 2.55 mmol) was added and the reaction was allowed to proceed for 36 hours at room temperature. 10 mL of water was added and then the reaction was extracted three times with ethyl acetate (10 mL). The organic phase after extraction was washed three times with water (10 mL) to remove the DMF, and then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 : 1 to give a brown viscous liquid. (0.59 g, 84% yield). In a reactor was added the amide product of structure 13f (0.59 g, 1.43 mmol), p-toluenesulfonyl chloride (TsCl) (0.84 g, 4.29 mmol), 5 mL of dichloromethane, and then triethylamine (TEA) (0.57 mL, 3.94 mmol) was added. The reaction was allowed to proceed for 30 minutes at room temperature, and then triethylamine (TEA) (2.40 mL, 17.47 mmol) was added dropwise. The reaction was fitted with a reflux condenser and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 hours and then the heating was stopped. The reaction was allowed to cool to room temperature, 5 mL of water was added, and then the reaction was extracted three times with dichloromethane (5 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 4: 1 to give a white powdery viscous liquid. (0.25 g, 44% yield).

[0165] Reference Figure 13 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.71 (dd, J = 5.0, 1.9 Hz, 1H), 7.94 - 7.85 (m, 2H), 7.83 - 7.76 (m, 3H), 7.60 - 7.51 (m, 3H), 7.50 - 7.41 (m, 4H), 7.39 - 7.32 (m, 2H), 7.31 - 7.23 (m, 1H), 6.02 (dd, J = 10.2, 8.3 Hz, 1H), 4.93 (dd, J = 10.2, 8.1 Hz, 1H), 4.09 (t, J = 8.2 Hz, 1H). 13CNMR (101 MHz, Chloroform-d) δ 159.02, 151.78, 149.30, 139.62, 138.45, 138.03, 133.81, 130.57, 130.06, 129.02, 127.80, 127.33, 127.11, 126.30, 125.64, 125.17, 123.59, 122.88, 122.80, 122.18, 122.13, 121.65, 111.30, 110.77, 73.85, 67.24. HRMS (ESI) m / z. calcd for [M+H]+C26H19N3OH: 390.1601; found: 390.1605.

[0166] Example 14

[0167] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0168] (2) Synthesis of (S)-4-(2-bromophenyl)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4,5- dihydro-l,3-oxazol (Formula L14):

[0169] To the reactor was added the carboxylic acid product of structural formula 14d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.96 g, 5.18 mmol), N,N-dimethylformamide (DMF) 10 mL, and triethylamine (TEA) (1.96 mL, 13.82 mmol) was added dropwise. After 1 hour at room temperature, (S)-2-amino-2-(2-bromophenyl)ethanol of structural formula 14e (0.56 g, 2.58 mmol) was added and the reaction was allowed to proceed for 36 hours at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove the DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1:1 to yield a brown, viscous liquid. (0.36 g, 48% yield). To the reactor was added the amide product of structural formula 14f (0.36 g, 0.82 mmol), p-toluenesulfonyl chloride (TsCl) (0.49 g, 2.47 mmol), dichloromethane 5 mL, and triethylamine (TEA) (0.33 mL, 2.27 mmol) was added. The reaction was allowed to proceed for 30 minutes at room temperature, then triethylamine (TEA) (1.38 mL, 10.04 mmol) was added dropwise. The condenser was attached and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 hours, then the heat was removed. The reaction was allowed to cool to room temperature, 5 mL of water was added, followed by three extractions with dichloromethane (5 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 4:1 to yield a white, viscous liquid. (0.33 g, 96% yield).

[0170] Reference Figure 14 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.67 (d, J = 4.8 Hz, 1H), 7.90 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.4 Hz, 2H), 7.35 (dd, J = 31.6, 10.9 Hz, 4H), 7.29 - 7.20 (m, 3H), 7.14 (t, J = 7.6 Hz, 1H), 5.59 (t, J = 9.2 Hz, 1H), 4.84 (t, J = 9.3 Hz, 1H), 3.98 (t, J = 8.2 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 159.65, 151.74, 149.30, 142.34, 139.64, 138.08, 132.35, 128.88, 128.26, 127.52, 127.27, 126.93, 126.20, 125.22, 122.85, 122.29, 122.15, 121.65, 111.22, 110.85, 73.59, 69.71. HRMS (ESI) m / z. calcd for [M+H]+C22H16BrN3OH: 418.0550; found: 418.0555.

[0171] Example 15

[0172] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0173] (2) Synthesis of (S)-4-(4-tert-butylphenyl)-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5- dihydro-l,3-oxazol (Formula L15):

[0174] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.62 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.89 g, 4.97 mmol), N,N-dimethylformamide (DMF) 10 mL, and triethylamine (TEA) (1.89 mL, 13.28 mmol) was added dropwise. After 1 hour at room temperature, (S)-2-amino-2-(4-tert-butylphenyl)ethanol of structure 15e (0.48 g, 2.46 mmol) was added and the reaction was allowed to proceed for 36 hours at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove the DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1:2 to give a brown, viscous liquid. (0.44 g, 65% yield). To the reactor was added the amide product of structure 15f (0.44 g, 1.05 mmol), p-toluenesulfonyl chloride (TsCl) (0.63 g, 3.14 mmol), dichloromethane 5 mL, and triethylamine (TEA) (0.42 mL, 2.90 mmol) was added. The reaction was allowed to proceed for 30 minutes at room temperature, then triethylamine (TEA) (1.75 mL, 12.80 mmol) was added dropwise. The condenser was replaced with a reflux condenser and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 hours, then the heat was removed. The reaction was allowed to cool to room temperature, 5 mL of water was added, followed by three extractions with dichloromethane (5 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a white, viscous liquid. (0.34 g, 83% yield).

[0175] Reference Figure 15 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (dd, J = 5.0, 2.0 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.46 (dd, J = 8.2, 4.5 Hz, 2H), 7.41 - 7.34 (m, 3H), 7.31 (td, J = 7.5, 7.0, 1.8 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.20 - 7.12 (m, 2H), 5.28 (dd, J = 9.9, 8.0 Hz, 1H), 4.62 (dd, J = 10.0, 8.1 Hz, 1H), 4.12 (t, J = 8.1 Hz, 1H), 1.34 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 158.72, 151.69, 150.36, 149.16, 139.39, 139.33, 137.87, 127.38, 127.08, 126.37, 125.47, 125.06, 122.57, 122.04, 121.91, 121.60, 111.36, 110.75, 74.24, 69.92, 34.55, 31.43. HRMS (ESI) m / z. calcd for [M+H]+C26H25N3OH: 396.2070; found: 396.2074.

[0176] Example 16

[0177] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0178] (2) Synthesis of (S)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4-(3-trifluoromethylphenyl)-4,5- dihydro-l,3-oxazol (Formula L16):

[0179] In a reactor was added sequentially the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.88 g, 4.96 mmol), 10 mL of N,N-dimethylformamide (DMF), and then triethylamine (TEA) (1.88 mL, 13.26 mmol) dropwise. After 1 hour of reaction at room temperature, (S)-2-amino-2-(3- trifluoromethylphenyl)ethanol of structure 16e (0.50 g, 2.44 mmol) was added and the reaction was allowed to proceed for 36 hours at room temperature. 10 mL of water was added and then the reaction was extracted three times with ethyl acetate (10 mL). The organic phase after extraction was washed three times with water (10 mL) to remove the DMF, and then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1:3 to give a brown viscous liquid. (0.38 g, 55% yield). In a reactor was added sequentially the amide product of structure 16f (0.38 g, 0.90 mmol), p-toluenesulfonyl chloride (TsCl) (0.54 g, 2.70 mmol), 5 mL of dichloromethane, and then triethylamine (TEA) (0.36 mL, 2.48 mmol). The reaction was allowed to proceed for 30 minutes at room temperature, and then triethylamine (TEA) (1.50 mL, 11.00 mmol) was added dropwise. The reaction was heated at 40 °C with a reflux condenser for 4 hours. The heating was stopped and the reaction was allowed to cool to room temperature. 5 mL of water was added and then the reaction was extracted three times with dichloromethane (5 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a red viscous liquid. (0.34 g, 93% yield).

[0180] Reference Figure 16 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (dd, J = 5.0, 2.0 Hz, 1H), 7.87 (td, J = 7.8, 2.0 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.50 - 7.40 (m, 3H), 7.40 - 7.27 (m, 5H), 7.23 (td, J = 8.1, 7.6, 6.3 Hz, 1H), 5.35 (dd, J = 10.1, 8.2 Hz, 1H), 4.70 (dd, J = 10.2, 8.4 Hz, 1H), 4.08 (t, J = 8.3 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 159.44, 151.59, 149.32, 143.42, 139.64, 138.06, 131.01, 130.69, 130.09, 129.03, 127.25, 126.65, 125.29, 124.27 (q, J = 3.9 Hz), 123.47 (q, J = 3.8 Hz), 122.87, 122.15, 121.99, 121.68, 111.25, 110.99, 73.87, 69.81. 19 F NMR (376 MHz, Chloroform-d) δ -62.36. HRMS (ESI) m / z. calcd for [M+H]+C23H16F3N3OH: 408.1318; found: 408.1321.

[0181] Example 17

[0182] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0183] (2) Synthesis of (S)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4-(2-trifluoromethylphenyl)-4,5- dihydro-l,3-oxazol (Formula L17):

[0184] In a reactor was added sequentially the carboxylic acid product of formula d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.87 g, 4.93 mmol), N,N-dimethylformamide (DMF) 5 mL, and triethylamine (TEA) (1.87 mL, 3.96 mmol) dropwise. After 1 h of reaction at room temperature, (S)-2-amino-2-(2- trifluoromethylphenyl)ethanol of formula 17e (0.5 g, 2.47 mmol) was added and the reaction was allowed to proceed for 36 h at room temperature. 10 mL of water was added and then the reaction was extracted three times with ethyl acetate (10 mL). The organic phase after extraction was washed three times with water (5 mL) to remove DMF and then dried, concentrated and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 : 1 to give a brown viscous liquid. (0.40 g, 67% yield). In a reactor was added sequentially the amide product of formula 17f (0.40 g, 1.10 mmol), p-toluenesulfonyl chloride (TsCl) (0.67 g, 3.30 mmol), dichloromethane 5 mL, triethylamine (TEA) (0.43 mL, 3.03 mmol), and the reaction was allowed to proceed for 30 min at room temperature. Then triethylamine (TEA) (1.83 mL, 13.43 mmol) was added dropwise and the reaction was heated at 40 °C with a reflux condenser for 4 h. The heating was then stopped and the reaction was allowed to cool to room temperature. 5 mL of water was added and then the reaction was extracted three times with dichloromethane (5 mL). The organic phase was then dried, concentrated and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a yellow viscous liquid. (0.20 g, 47% yield).

[0185] Reference is made to Figure 17 , the product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.67 (dd, J = 4.9, 1.9 Hz, 1H), 7.90 (td, J = 7.7, 2.0 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 8.2 Hz, 2H), 7.50 (d, J = 7.8 Hz, 1H), 7.46 - 7.31 (m, 5H), 7.26 (t, J = 7.4 Hz, 1H), 5.73 (t, J = 9.2 Hz, 1H), 4.70 (t, J = 9.4 Hz, 1H), 3.96 (t, J = 8.3 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 160.05, 151.62, 149.27, 140.99, 139.50, 138.12, 132.34, 128.23, 127.37, 127.32, 126.98, 126.81, 125.71, 125.62 (d, J = 5.8 Hz), 125.24, 122.79, 122.17, 121.81, 121.69, 111.14, 111.00, 74.56 (d, J = 2.4 Hz), 66.44. 19 F NMR (376 MHz, Chloroform-d) δ -59.10. HRMS (ESI) m / z. calcd for [M+H]+C23H16F3N3OH: 408.1318; found: 408.1323.

[0186] Example 18

[0187] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0188] (2) Synthesis of (S)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4-(2-methylphenyl)-4,5- dihydro-l,3-oxazol (Formula L18):

[0189] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.92 g, 5.10 mmol), N,N-dimethylformamide (DMF) 10 mL, and triethylamine (TEA) (1.92 mL, 13.66 mmol) was added dropwise. After 1 h at room temperature, (S)-2-amino-2-(2-methylphenyl)ethanol of structure 18e (0.48 g, 2.53 mmol) was added and the reaction was allowed to proceed for 36 h at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 :6 to give a brown viscous liquid. (0.46 g, 74% yield). To the reactor was added the amide product of structure 18f (0.46 g, 1.26 mmol), p-toluenesulfonyl chloride (TsCl) (0.76 g, 3.77 mmol), dichloromethane 10 mL, and triethylamine (TEA) (0.50 mL, 3.47 mmol) was added. The reaction was allowed to proceed for 30 min at room temperature, then triethylamine (TEA) (2.10 mL, 15.35 mmol) was added dropwise. The reaction was fitted with a reflux condenser and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 h, then the heat was removed. The reaction was allowed to cool to room temperature, 10 mL of water was added, followed by three extractions with dichloromethane (10 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a yellow viscous liquid. (0.25 g, 57% yield).

[0190] Reference Figure 18 The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.66 (dd, J = 4.9, 2.0 Hz, 1H), 7.85 - 7.81 (m, 1H), 7.80 - 7.72 (m, 1H), 7.50 (dd, J = 8.1, 2.9 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.33 - 7.25 (m, 2H), 7.21 - 7.16 (m, 5H), 5.49 (dd, J = 10.1, 8.3 Hz, 1H), 4.70 (dd, J = 10.0, 8.0 Hz, 1H), 3.98 (t, J = 8.2 Hz, 1H), 2.27 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 158.88, 151.74, 149.26, 140.83, 139.54, 137.98, 134.50, 130.14, 127.35, 127.23, 127.13, 126.25, 126.20, 125.11, 124.46, 122.73, 122.08, 121.62, 111.31, 110.64, 73.49, 67.50, 19.54. HRMS (ESI) m / z. calcd for [M+H]+C23H19N3OH: 354.1601; found: 354.1605.

[0191] Example 19

[0192] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0193] (2) Synthesis of (S)-4-m- Tolyl-2-[l-(2-pyridinyl)-lH-indol-2-yl]-4,5-dihydro-l,3- oxazol (Formula L19):

[0194] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.85 g, 4.95 mmol), N,N-dimethylformamide (DMF) 10 mL, and triethylamine (TEA) (1.85 mL, 13.22 mmol) was added dropwise. After 1 hour at room temperature, (S)-2-amino-2-mesityl ethanol of structure 19e (0.53 g, 2.44 mmol) was added and the reaction was allowed to proceed for 36 hours at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove DMF, then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1:5 to give a brown viscous liquid. (0.34 g, 52% yield). To the reactor was added the amide product of structure 19f (0.34 g, 0.86 mmol), p-toluenesulfonyl chloride (TsCl) (0.53 g, 2.59 mmol), dichloromethane 10 mL, and triethylamine (TEA) (0.34 mL, 2.38 mmol) was added. The reaction was allowed to proceed for 30 minutes at room temperature, then triethylamine (TEA) (1.43 mL, 10.53 mmol) was added dropwise. The condenser was attached and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 hours, then the heat was removed. The reaction was allowed to cool to room temperature, 10 mL of water was added, followed by three extractions with dichloromethane (10 mL). The organic phase was dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 4: 1 to give a white viscous liquid. (0.21 g, 64% yield).

[0195] The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.63 (d, J = 4.9 Hz, 1H), 7.87 (td, J = 7.8, 2.1 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.41 (t, J = 4.3 Hz, 2H), 7.36 - 7.27 (m, 2H), 7.24 (t, J = 7.4 Hz, 1H), 6.84 (s, 2H), 5.72 (t, J = 10.8 Hz, 1H), 4.58 (dd, J = 11.8, 8.9 Hz, 1H), 4.06 (t, J = 8.7 Hz, 1H), 2.32 (s, 6H), 2.27 (s, 3H). 13CNMR (101 MHz, Chloroform-d) δ 158.24, 151.63, 149.13, 139.32, 137.91, 137.01, 136.91, 133.35, 130.18, 127.41, 127.36, 124.94, 122.65, 121.96, 121.79, 121.56, 111.24, 110.52, 71.61, 66.80, 20.76, 20.54. HRMS (ESI) m / z. calcd for [M+H]+C25H23N3OH: 382.1914; found: 382.1920.

[0196] Example 20

[0197] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0198] (2) Synthesis of (S)-4-(2-anthryl)-2-[l-(2-pyridyl)-lH-indol-2-yl]-4,5-dihydro- 1,3-oxazol (Formula L20):

[0199] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.70 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (HATU) (1.90 g, 5.07 mmol), 10 mL of N,N-dimethylformamide (DMF), and then triethylamine (TEA) (1.90 mL, 13.54 mmol) was added dropwise. After 1 hour of reaction at room temperature, (2S)-2-amino-2-(2-anthryl)ethan-l-ol of structure 20e (0.59 g, 2.53 mmol) was added and the reaction was allowed to proceed for 36 hours at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove the DMF, and then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 :7 to give a brown viscous liquid. (0.46 g, 60% yield). To the reactor was added the amide product of structure 20f (0.46 g, 1.00 mmol), p-toluenesulfonyl chloride (TsCl) (0.61 g, 3.02 mmol), 10 mL of dichloromethane, and then triethylamine (TEA) (0.40 mL, 2.78 mmol) was added. The reaction was allowed to proceed for 30 minutes at room temperature, followed by the dropwise addition of triethylamine (TEA) (1.66 mL, 12.24 mmol). The condenser was attached and the heating plate temperature was adjusted to 40 °C. The reaction was allowed to proceed for 4 hours, after which the heating was stopped. The reaction was allowed to cool to room temperature, 10 mL of water was added, followed by three extractions with dichloromethane (10 mL). The organic phase was then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 2: 1 to give a yellow solid. (0.21 g, 48% yield).

[0200] The product structure confirmation results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.65 (dd, J = 5.0, 2.0 Hz, 1H), 8.39 (d, J = 9.8 Hz, 2H), 8.00 (td, J = 8.2, 5.2 Hz, 3H), 7.92 - 7.73 (m, 3H), 7.59 - 7.42 (m, 5H), 7.34 - 7.21 (m, 4H), 5.48 (dd, J = 10.0, 7.7 Hz, 1H), 4.71 (t, J = 9.1 Hz, 1H), 4.23 (t, J = 7.9 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 159.10, 151.64, 149.24, 139.46, 138.82, 137.94, 131.93, 131.71, 131.45, 131.10, 128.88, 128.22, 128.16, 127.36, 126.97, 126.24, 126.20, 126.10, 125.47, 125.35, 125.15, 124.49, 122.64, 122.09, 121.89, 121.63, 111.27, 110.91, 73.86, 70.52. HRMS (ESI) m / z. calcd for [M+H]+C30H21N3OH: 440.1757; found: 440.1765.

[0201] Example 21

[0202] (1) Synthesis of carboxylic acid l-(pyridin-2-yl)-lH-indole-2-carboxylic acid (d) Reference Example 1.

[0203] (2) Synthesis of (R)-4-phenyl-2-[l-(2-pyridyl)-lH-indol-2-yl]-4,5-dihydro-l,3- oxazol (Formula L21):

[0204] To the reactor was added the carboxylic acid product of structure d (0.40 g, 1.7 mmol), the condensing agent N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) urea hexafluorophosphate (HATU) (1.94 g, 5.1 mmol), N,N-dimethylformamide (DMF) 15 mL, and triethylamine (TEA) (1.89 mL, 13.6 mmol) was added dropwise. After 1 h at room temperature, L-phenylglycinol of structure le (0.35 g, 2.55 mmol) was added and the reaction was allowed to proceed for 36 h at room temperature. 10 mL of water was added, followed by three extractions with ethyl acetate (10 mL). The organic phase after extraction was rinsed three times with water (10 mL) to remove DMF, and then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 1 :5 to give a brown viscous liquid. (0.36 g, 62% yield). To the reactor was added the amide product of structure If (0.36 g, 1.05 mmol), p-toluenesulfonyl chloride (TsCl) (0.60 g, 3.15 mmol), dichloromethane 10 mL, and triethylamine (TEA) (0.40 mL, 2.91 mmol) was added. The reaction was allowed to proceed for 30 min at room temperature, followed by the dropwise addition of triethylamine (TEA) (1.78 mL, 12.84 mmol). The condenser was attached and the heating plate was adjusted to 40 °C. The reaction was allowed to proceed for 4 h, after which the heating was stopped. The reaction was allowed to cool to room temperature, 10 mL of water was added, followed by three extractions with dichloromethane (10 mL). The organic phase was then dried, concentrated, and column chromatographed. The column was packed with petroleum ether and eluted with petroleum ether: ethyl acetate 3: 1 to give a yellow viscous liquid. (0.25 g, 70% yield).

[0205] Reference is made to Figure 21 in conjunction with Figure 19 and Figure 20 The product structure confirmation results are as follows: 1 HNMR (400 MHz, Chloroform-d) δ 8.62 (dd, J = 4.9, 1.8 Hz, 1H), 7.83 (td, J = 7.7, 2.0 Hz, 1H), 7.72 (dd, J = 7.9, 1.1 Hz, 1H), 7.48 - 7.27 (m, 8H), 7.25 - 7.18 (m, 3H), 5.29 (dd, J = 10.0, 8.0 Hz, 1H), 4.63 (dd, J = 10.0, 8.2 Hz, 1H), 4.09 (t, J = 8.1 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 158.91, 151.65, 149.19, 142.38, 139.42, 137.91, 128.56, 127.44, 127.36, 126.99, 126.67, 125.10, 122.61, 122.06, 121.89, 121.61, 111.31, 110.79, 74.30, 70.24. HRMS (ESI) m / z. calcd for [M+H]+C22H17N3OH: 340.1444; found: 340.1447. [Chiral column CHIRALCEL OD-H (4.6 mm x 250 mm), n-hexane: isopropyl alcohol = 80:20, v = 1 mL / min, detection wavelength = 254 nm, t(major) = 14.888 min, > -99% ee.

[0206] Example 22

[0207] In a dry 25 mL Schlenk tube A, NiPy2Br2(2.30 mg, 0.6% mmol) was added, and ligand compound L1 (compound shown in structure L1) was dissolved in dichloromethane to form a solution with a concentration of 1 mol / L. 20 μL of the solution was added to the Schlenk tube A, and argon was replaced. 1 mL of dichloromethane solution was added, and the mixture was stirred at room temperature for 1 hour and then cooled to -50°C. In a dry 25 mL Schlenk tube B, the reactant (E)-2-oxo-4-phenyl-3-butenoic acid ethyl ester (40.80 mg, 0.20 mmol) was added, and the reactant indole (35.10 mg, 0.30 mmol) was added. Argon was replaced, 1 mL of dichloromethane solution was added, and the mixture was cooled to -50°C. Finally, the mixed solution of reactants in the Schlenk tube B was added to the Schlenk tube A, and the reaction was carried out at -50°C for 24 hours. After the reaction was completed, the temperature was returned to room temperature, 5 mL of water was added, and then dichloromethane (5 mL) was extracted three times, and then dried, concentrated, and column chromatography was performed. The column was filled with petroleum ether, and the eluent was petroleum ether: ethyl acetate = 4:1, and a yellow solid was obtained. (44.30 mg, 69% yield, 92% ee).

[0208] Reference Figure 22 The product structure confirmation results are as follows 1H NMR (400 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40-7.27 (m, 5H), 7.25-7.15 (m, 2H), 7.10-7.02 (m, 2H), 4.96 (t, J = 7.6 Hz, 1H), 4.32-4.18 (m, 2H), 3.68 (qd, J = 16.9, 7.6 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0209] The above application provides many different embodiments or examples for implementing different structures of the application. In the interest of simplifying the present application, the embodiments of the various examples described above are not intended to limit the application. Of course, they are merely examples and are not intended to limit the application. In addition, the present application can repeat reference numerals and / or reference letters in different examples. Such repetition is for the purpose of simplification and clarity and does not in itself indicate a relationship between the various embodiments and / or arrangements discussed.

[0210] The above merely provides specific implementation manners of the present application, but the protection scope of the present application is not limited to this. Any person skilled in the art can easily think of various changes or replacements within the technical scope disclosed by the present application, and these should be covered in the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A chiral oxazoline ligand containing an indole backbone, characterized in that, having a structure represented by Formula 1: wherein R 1 is selected from one of alkyl, substituted alkyl, aryl, substituted aryl.

2. The chiral oxazoline ligand containing an indole backbone according to claim 1, characterized in that, the alkyl group is C1-C6 alkyl, and the aryl group is C4-C18 aryl; the substituted alkyl group is C1-C6 alkyl substituted by one or more substituents, and the substituted aryl group is C4-C18 aryl substituted by one or more substituents, the substituents being one of a methyl group, a methoxy group, a tert-butyl group, a trifluoromethyl group, and a halogen atom.

3. The chiral oxazoline ligand containing an indole backbone according to claim 1, characterized in that, the alkyl group is one of a methyl group, a tert-butyl group, and a trifluoromethyl group, and the aryl group is one of a phenyl group, a benzyl group, a naphthyl group, and an anthryl group; the substituted alkyl group is one of a methyl group, a tert-butyl group, and a trifluoromethyl group substituted by one or more substituents, and the substituted aryl group is one of a phenyl group, a benzyl group, a naphthyl group, and an anthryl group substituted by one or more substituents, the substituents being one of a methyl group, a methoxy group, a tert-butyl group, a trifluoromethyl group, and a halogen atom.

4. The chiral oxazoline ligand containing an indole backbone according to claim 1, characterized in that, the chiral oxazoline ligand having an indole-containing skeleton has a structure represented by one of:

5. A method of synthesizing a chiral oxazoline ligand containing an indole skeleton according to any one of claims 1 to 4, characterized in that, comprising: under the action of a copper metal catalyst and a first base, coupling an indole carboxylate reagent and a halogenated pyridine reagent to obtain a coupling product; under the action of a hydrolysis agent, hydrolyzing the coupling product to obtain a carboxylic acid product; under the action of a chiral amino alcohol and a second base, condensing the carboxylic acid product with a condensing agent to obtain an amide product; under the action of a third base and an acid chloride, cyclizing the amide product to obtain the chiral oxazoline ligand having an indole-containing skeleton; the chiral amino alcohol is a compound represented by Formula 2: R 1 is as defined in any of claims 1 to 3.

6. The method of claim 5, wherein, the copper metal catalyst is selected from at least one of copper oxide, copper chloride, copper triflate, cuprous iodide, and cuprous tetrafluoroborate; the indole carboxylate reagent is selected from at least one of indole-2-carboxylic acid methyl ester, indole-2-carboxylic acid ethyl ester, indole-2-carboxylic acid tert-butyl ester, indole-2-carboxylic acid allyl ester, and indole-2-carboxylic acid benzyl ester; the halogenated pyridine reagent is selected from at least one of 2-bromopyridine, 2-iodopyridine, and 2-chloropyridine; the hydrolysis agent is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, and sodium carbonate; the first base is selected from at least one of N,N'-dimethylethylenediamine, potassium carbonate, sodium carbonate, and cesium carbonate; the coupling reaction is performed in a first solvent selected from at least one of toluene, ethanol, N,N-dimethylformamide, and dichloromethane.

7. The method of claim 5, wherein, the condensing agent is selected from at least one of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and 1-propylphosphonic anhydride; the second base is selected from at least one of triethylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylpropylenediamine, N,N,N',N'-tetramethylbutylenediamine, and N,N,N',N'-tetraethylethylenediamine; the condensing reaction is performed in a second solvent selected from at least one of toluene, methanol, ethanol, water, N,N-dimethylformamide, and dichloromethane.

8. The method of claim 5, wherein, the third base is selected from at least one of triethylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylpropylenediamine, N,N,N',N'-tetramethylbutylenediamine, N,N,N',N'-tetraethylethylenediamine; the acyl chloride is selected from at least one of p-toluenesulfonyl chloride, methylsulfonyl chloride; the cyclization reaction is carried out in a second solvent selected from at least one of toluene, methanol, ethanol, water, N,N-dimethylformamide, dichloromethane.

9. The method of claim 5, wherein, the molar ratio of the indole carboxylate reagent, the halopyridine reagent, the copper metal catalyst, the first base, the hydrolysis agent is 2:(2.5-3.5):(5.5-7.5):12:8; the first base is N,N'-dimethylethylenediamine and potassium carbonate, and the molar ratio of the N,N'-dimethylethylenediamine and the potassium carbonate is (0.5-1.5):(0.5-1.5); the molar ratio of the carboxylic acid product, the condensing agent, the acyl chloride is 1.7:5.1:(2.19-4.28).

10. Use of a chiral oxazoline ligand comprising an indole skeleton according to any one of claims 1 to 4 or prepared according to the process of any one of claims 5 to 9 in a catalytic asymmetric synthesis reaction.

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