A method for the c2 alkylation modification of tryptophan and tryptophan containing polypeptides

Abstract

The application belongs to the field of organic synthesis and relates to a preparation method of a tryptophan compound. The method is to modify an alkyl functional group on the basis of tryptophan and tryptophan-containing polypeptides, that is, to use tryptophan and tryptophan-containing polypeptides and 1,3-dithiane derivatives as raw materials to react in a system of a promoter and silane to obtain a kind of C2 alkylated modified tryptophan and tryptophan-containing polypeptide compound. The method does not need noble metal catalysis, does not need anhydrous and anaerobic operation, has mild conditions, wide substrate applicability, high selectivity, is suitable for free carboxyl or amino groups, and has strong practicability. Moreover, the application provides a metal-free and more environmentally-friendly method for selective alkyl modification of peptides, which has great potential in pharmaceutical chemistry and industrial application.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a method for C2 alkylation modification of tryptophan and tryptophan-containing polypeptides. BACKGROUND

[0002] Tryptophan skeleton is commonly found in various alkaloid natural products and drug molecules. Although the relative abundance of tryptophan (Trp) in peptide and protein sequences is low, the presence of tryptophan is essential for the activity of biological molecules due to its unique properties. In recent years, with the continuous development and maturation of modern biotechnology, the synthesis of polypeptide drugs has become one of the hotspots in drug research and development, because the chemical modification of peptides can usually improve their biological activity and pharmacokinetics (Angew. Chem., Int. Ed. 2018, 57, 14414-14438). Non-natural amino acids and peptides are essential for various application fields, such as medical diagnosis, treatment, drug delivery, antibacterial materials and medical dressings, etc. (J. Med. Chem. 2016, 59, 10807-10836). Therefore, many strategies for preparing non-natural amino acids through post-alkylation have been developed. For example, in 2019, the Lutz Ackermann group established a ruthenium (II) catalyzed C-H alkylation reaction of structurally complex peptides with acrylate as the alkylation agent, and proved that it is feasible to perform C-H alkylation in a bio-orthogonal manner on a support through solid-phase peptide synthesis (Nat. Commun. 2019, 10, 3553). In 2020, the Wang group developed a method for post-peptide ligation and macrocyclization through rhodium-catalyzed selective alkylation of tryptophan residues at C7. (Angew. Chem., Int. Ed. 2022, 61, e202206177). However, this C-H activation method is largely limited to highly reactive, noble and toxic metals such as Pd, Ru, Mo, Rh and Co, etc. This essentially limits the diversification of active peptides, because the active pharmaceutical ingredients need to be strictly controlled at low levels of residual transition metals. Therefore, developing a metal-free, more environmentally friendly method for selective C2 alkylation modification of peptides has great potential in pharmaceutical chemistry and industry. SUMMARY

[0003] The purpose of the present application is to provide a method for C2 alkylation modification of tryptophan and tryptophan-containing polypeptides. The method is to modify the alkyl functional group on the basis of tryptophan and tryptophan-containing polypeptides, that is, to add tryptophan derivatives, 1,3-dithiane derivatives, suitable solvents, promoters and silanes in sequence in a reactor, and to react at a suitable temperature to obtain a kind of C2 alkylation modified tryptophan and tryptophan-containing peptide compounds. This method does not require noble metal catalysis, does not require anhydrous and anaerobic operation, has mild conditions, wide substrate applicability, high selectivity, and is suitable for free carboxyl or amino groups.

[0004] The present application adopts the following technical scheme: adding tryptophan or tryptophan-containing polypeptide and 1,3-dithiane derivative into a reactor, and reacting under the action of a suitable promoter and silane for a certain time, then separating and purifying after the reaction is completed to obtain tryptophan or tryptophan-containing polypeptide C2 alkylation product, and the reaction equation is as follows:

[0005]

[0006] In the above technical scheme, the promoter is one of iodine, trifluoroacetic acid, N-iodosuccinimide, and [bis(trifluoroacetyloxy)iodo]benzene.

[0007] In the above technical scheme, the silane is one of dimethylmonochlorosilane, triethylsilane, triphenylsilane, triethoxysilane, diphenylsilane, and phenylsilane.

[0008] In the above technical scheme, the solvent is one of 1,2-dichloroethane, chloroform, dichloromethane, nitromethane, toluene, and acetonitrile.

[0009] In the above technical scheme, the molar ratio of the promoter, silane, tryptophan or tryptophan-containing polypeptide, and 1,3-dithiane derivative is (0.5-2.0):(1.5-3.0):(0.1-2.0):(0.1-2.0).

[0010] In the above technical scheme, the reaction specific steps include: sequentially adding 1,3-dithiane derivative, tryptophan or tryptophan polypeptide, a suitable solvent, a promoter, and silane into a reaction bottle, stirring at 0-60°C for 8-24 hours, monitoring the reaction by TLC, adding saturated sodium sulfite aqueous solution into the reaction system after the reaction is completed, extracting three times with dichloromethane (15 mL), washing the combined organic phase three times with saturated brine (15 mL), drying with anhydrous sodium sulfate, filtering, removing volatile matter under vacuum, and column chromatography to obtain the product. DETAILED DESCRIPTION

[0011] The following detailed description is an elaboration of the present application, which can be more fully understood, but does not limit the present application in any way. The raw materials used in the present application are known compounds, which can be purchased from the market or synthesized by known methods in the art.

[0012] Implementation 1: Reaction steps for preparing Methyl (S)-2-acetamido-3-(2-(4-methoxybenzyl)-1H-indol-3-yl) propanoate:

[0013] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylamino-chlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered and the volatiles were removed in vacuo and the product was obtained by column chromatography.

[0014] Product of Example 1

[0015] The structure and NMR data of Methyl (S)-2-acetamido-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate are as follows:

[0016]

[0017] 1 H NMR (600 MHz, Chloroform-d) δ 8.13 (s, 1H), 7.48 - 7.45 (m, 1H), 7.19 - 7.15 (m, 1H), 7.10 - 7.05 (m, 4H), 6.81 (d, J = 8.7 Hz, 2H), 6.06 (d, J = 7.9 Hz, 1H), 4.92 - 4.85 (m, 1H), 3.97 (s, 2H), 3.74 (s, 3H), 3.61 (s, 3H), 3.34 - 3.26 (m, 2H), 1.77 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.73, 169.99, 158.57, 135.69, 135.64, 130.52, 129.70, 128.85, 121.66, 119.63, 118.20, 114.37, 110.85, 106.41, 55.39, 53.23, 52.50, 31.28, 26.96, 23.06.

[0018] Example 2: Reaction steps for the preparation of Methyl (S)-2-acetamido-3-(2-(4-methylbenzyl)-1H-indol-3-yl)propanoate:

[0019] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2-(4-methphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of 1,2-dichloroethane, trifluoroacetic acid and triethylsilane were added, the reaction was stirred at room temperature until the reaction was complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were combined and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum, and the product was obtained by column chromatography.

[0020] The structure and NMR data of the product obtained in Example 2, Methyl (S)-2-acetamido-3-(2-(4-methylbenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0021] The structure and NMR data of the product obtained in Example 2, Methyl (S)-2-acetamido-3-(2-(4-methylbenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0022]

[0023] 1 H NMR (600 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.50 - 7.44 (m, 1H), 7.21 - 7.16 (m, 1H), 7.13 - 7.04 (m, 6H), 5.99 (d, J = 7.9 Hz, 1H), 4.91 (d, J = 7.9 Hz, 1H), 4.01 (s, 2H), 3.63 (s, 3H), 3.33 (dd, J = 5.5, 4.7 Hz, 2H), 2.32 (s, 3H), 1.79 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.68, 169.87, 136.59, 135.62, 135.38, 135.32, 129.68, 128.87, 128.62, 121.72, 119.69, 118.25, 110.77, 106.57, 100.01, 53.15, 52.51, 31.76, 26.97, 23.10, 21.10.

[0024] Example 3: Reaction steps for preparing Methyl (S)-2-acetamido-3-(2-(4-hydroxybenzyl)-1H-indol-3-yl)propanoate:

[0025] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2-(4-hydroxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of chloroform, N-iodosuccinimide and triphenylsilane were added, the reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite solution (10 mL), and extracted with dichloromethane (15 mL), the organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were combined and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum, and column chromatography was used to obtain the product.

[0026] The structure and NMR data of the product obtained in Example 3, Methyl (S)-2-acetamido-3-(2-(4-hydroxybenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0027]

[0028] 1 H NMR (400 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.49 - 7.43 (m, 1H), 7.19 (dd, J = 7.9, 1.5 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.99 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 6.03 (d, J = 7.9 Hz, 1H), 5.85 (s, 1H), 4.91 (d, J = 7.9 Hz, 1H), 3.99 (s, 2H), 3.64 (s, 3H), 3.35 - 3.28 (m, 2H), 1.83 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.77, 170.90, 155.39, 135.80, 135.57, 129.72, 129.62, 128.69, 121.69, 119.67, 118.01, 115.92, 110.89, 106.11, 53.38, 52.70, 31.25, 26.95, 22.90.

[0029] Example 4: Reaction steps for preparing Methyl (S)-2-acetamido-3-(2-benzyl-1H-indol-3-yl)propanoate:

[0030] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2-phenyl-1,3-dithiane (0.2 mmol) were added successively, dissolved in 15 mL of nitromethane, then [bis(trifluoroacetoxy)iodo]benzene and triethoxysilane were added, the reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite solution (10 mL), and extracted with dichloromethane (15 mL), the organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were mixed and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum, and column chromatography was used to obtain the product.

[0031] The structure and NMR data of the product obtained in Example 4, methyl (S)-2-acetamido-3-(2-benzyl-1H-indol-3-yl)propanoate, are as follows:

[0032]

[0033] 1 H NMR (600 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.47 (dd, J = 7.5, 1.5 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.22 (d, J = 7.3 Hz, 1H), 7.20 - 7.14 (m, 3H), 7.11 - 7.05 (m, 2H), 6.02 (d, J = 7.9 Hz,

[0034] 1H), 4.92 - 4.85 (m, 1H), 4.05 (s, 2H), 3.61 (s, 3H), 3.32 (dd, J = 5.6, 4.1 Hz, 2H), 1.76 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.69, 169.94, 138.55, 135.70, 135.09, 129.19, 128.89, 128.81, 128.49, 127.14, 126.75, 121.99, 121.56, 119.90, 119.50, 118.39, 118.16, 111.03, 110.63, 106.74, 53.38, 52.98, 52.60, 32.14, 26.98, 23.18, 22.96.

[0035] Example 5: Reaction steps to prepare Methyl (S)-2-acetamido-3-(2-(4- chlorobenzyl)-1H-indol-3-yl)propanoate:

[0036] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2-

[0037] (4-chlorophenyl-1,3-dithiane (0.2 mmol) was dissolved in 15 mL of toluene, and then iodine and diphenylsilane were added. The reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0038] The structure and NMR data of the product Methyl (S)-2-acetamido-3-(2-(4- chlorobenzyl)-1H-indol-3-yl)propanoate obtained in Example 5 are as follows:

[0039]

[0040]

[0041] 1 H NMR (400 MHz, Chloroform-d) δ 7.97 (s, 1H), 7.46 (t, J = 6.6 Hz, 1H), 7.27 (s, 1H), 7.23 (dd, J = 7.2, 2.8 Hz, 2H), 7.17 - 6.99 (m, 4H), 6.16 - 5.92 (m, 1H), 4.99 - 4.82 (m, 1H), 4.03 (s, 2H), 3.77 - 3.56 (m, 3H), 3.41 - 3.18 (m, 2H), 1.93 - 1.76 (m, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.63, 169.84, 136.96, 135.70, 134.43, 132.79, 130.04, 129.06, 128.77, 121.96, 119.84, 118.32, 110.85, 107.09, 53.22, 52.54, 31.53, 27.02, 23.17.​

[0042] Example 6: Reaction steps for the preparation of Methyl (S)-2-acetamido-3-(2-(4- bromobenzyl)-1H-indol-3-yl)propanoate:

[0043] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2- (4-bromophenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of acetonitrile, and then iodine and phenylsilane were added. The reaction was stirred at room temperature until completion as detected by TLC, at which point the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined, washed with saturated brine (15 mL x 3), dried over anhydrous Na2S04, filtered, and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0044] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2- (4-bromophenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of acetonitrile, and then iodine and phenylsilane were added. The reaction was stirred at room temperature until completion as detected by TLC, at which point the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined, washed with saturated brine (15 mL x 3), dried over anhydrous Na2S04, filtered, and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0045] The structure and NMR data for the product obtained in Example 6, Methyl (S)-2-acetamido-3-(2-(4-bromobenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0046]

[0047] 1 H NMR (600 MHz, Chloroform-d) δ 7.73 (s, 1H), 7.46 (dd, J = 23.3, 8.1 Hz, 3H), 7.24 - 7.21 (m, 1H), 7.15 - 7.08 (m, 2H), 7.05 (d, J = 8.3 Hz, 2H), 5.99 (d, J = 7.9 Hz, 1H), 4.95 - 4.88 (m, 1H), 4.04 (s, 2H), 3.63 (s, 3H), 3.34 (dd, J = 5.6, 3.7 Hz, 2H), 1.86 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.62, 169.84, 137.47, 135.69, 134.31, 132.10, 131.96, 130.49, 128.76, 120.82, 119.77, 118.38, 110.92, 107.14, 53.31, 52.50, 31.60, 27.02, 23.22.

[0048] Example 7: Reaction steps for the preparation of Methyl (S)-4-((3-(2-acetamido-3- methoxy-3-oxopropyl)-1H-indol-2-yl)methyl)benzoate:

[0049] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and methyl 4-(1,3-dithian-2-yl)benzoate (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2S04, filtered and the volatiles were removed under vacuum, the product was obtained by column chromatography.

[0050] The structure and NMR data of the product obtained in Example 7, Methyl (S)-4-((3-(2- acetamido-3-methoxy-3-oxopropyl)-1H-indol-2-yl)methyl)benzoate, are as follows:

[0051]

[0052] 1 H NMR (600 MHz, Chloroform-d) δ 7.97 (d, J = 8.3 Hz, 2H), 7.86 (s, 1H), 7.51 - 7.47 (m, 1H), 7.25 - 7.22 (m, 3H), 7.12 (m, J = 19.6, 7.0, 1.2 Hz, 2H), 6.02 (d, J = 7.9 Hz, 1H), 4.91 (d, J = 7.9 Hz, 1H), 4.14 (s, 2H), 3.90 (s, 3H), 3.62 (s, 3H), 3.34 (dd, J = 5.6, 1.7 Hz, 2H), 1.84 (s, 3H).

[0053] 13C NMR (101 MHz, Chloroform-d) δ 172.59, 169.76, 166.88, 143.80, 135.72, 133.95, 130.25, 128.95, 128.71, 122.05, 119.89, 118.39, 110.82, 107.41, 53.20, 52.53, 52.22, 32.20, 27.05, 23.20.

[0054] Example 8: Reaction steps for the preparation of Methyl (S)-2-acetamido-3-(2-(2- methoxybenzyl)-1 H-indol-3-yl)propanoate:

[0055] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2- methoxyphenylboronic acid (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and then added with iodine and dimethylchlorosilane, the reaction was stirred at room temperature until the reaction was complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were mixed and washed with saturated brine (15 mL x 3) and then dried with anhydrous Na2S04, filtered and the volatile removed under vacuum, column chromatography gave the product.

[0056] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2- methoxyphenylboronic acid (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and then added with iodine and dimethylchlorosilane, the reaction was stirred at room temperature until the reaction was complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were mixed and washed with saturated brine (15 mL x 3) and then dried with anhydrous Na2S04, filtered and the volatile removed under vacuum, column chromatography gave the product.

[0057] The structure and NMR data of the product obtained in Example 8, Methyl (S)-2-acetamido-3-(2-(2-methoxybenzyl)-1 H-indol-3-yl)propanoate, are as follows:

[0058]

[0059] 1H NMR(600MHz,Chloroform-d)δ8.32(s,1H),7.44(dd,J=7.6,1.3Hz,1H),7.22–7.17(m,2H),7.10–7.00(m,3H),6.92–6.84(m,2H) ,6.10(d,J=7.8Hz,1H),4.90(d,J=7.9Hz,1H),4.01(s,2H),3.87(s,3H),3.62(s,3H),3.33(dd,J=5.7,1.5Hz,2H),1.77(s,3H). 13 C NMR(101MHz,Chloroform-d)δ172.79,169.96,157.20,135.72,135.53,130.15,128.73,128.35,12 7.36,121.51,121.23,119.48,118.18,110.94,110.75,105.92,55.72,53.18,52.44,26.97,23.03.

[0060] Implementation 9: Reaction steps for preparing Methyl(S)-2-acetamido-3-(2-(3-methoxybenzyl)-1H-indol-3-yl)propanoate:

[0061] In a 25 mL round-bottom flask, add methyl acetyl-L-tryptophanate (0.2 mmol) and 2-

[0062] (3-methoxyphenyl)-1,3-dithiane (0.2 mmol) was dissolved in 15 mL of dichloromethane, and then iodine and dimethylchlorosilane were added. The mixture was stirred at room temperature until the reaction was complete as detected by TLC. The reaction was then stopped. The mixture was quenched with saturated sodium sulfite aqueous solution (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL × 3). The resulting organic extracts were mixed and washed with saturated brine (15 mL × 3), then dried with anhydrous Na2SO4, filtered, and volatiles were removed under vacuum. The product was obtained by column chromatography.

[0063] The structure and NMR data of the product Methyl(S)-2-acetamido-3-(2-(3-methoxybenzyl)-1H-indol-3-yl)propanoate obtained in Example 9 are as follows:

[0064]

[0065] 1 H NMR (600 MHz, Chloroform-d) δ 7.76 (s, 1H), 7.50 - 7.46 (m, 1H), 7.25 - 7.21 (m, 2H), 7.14 - 7.07 (m, 2H), 6.82 - 6.76 (m, 2H), 6.73 (s, 1H), 5.99 (d, J = 7.9 Hz, 1H), 4.95 - 4.91 (m, 1H), 4.05 (s, 2H), 3.78 (s, 3H), 3.65 (s, 3H), 3.36 (dd, J = 5.6, 2.5 Hz, 2H), 1.84 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.63, 169.79, 160.20, 139.94, 135.61, 134.84, 130.04, 128.85, 121.82, 121.05, 119.75, 118.31, 114.63, 112.21, 110.75, 106.80, 55.31, 53.14, 52.51, 32.22, 26.97, 23.15.

[0066] Implementation 10: Reaction steps for preparing Methyl (S)-2-acetamido-3-(2-(3,4-dimethoxybenzyl)-1H-indol-3-yl)propanoate:

[0067] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2- (3,4-dimethoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane, and then iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete as detected by TLC, at which point the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined, washed with saturated brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0068] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2- (3,4-dimethoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane, and then iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete as detected by TLC, at which point the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined, washed with saturated brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0069] The structure and NMR data of the product obtained in Example 10, Methyl (S)-2-acetamido-3-(2-(3,4-dimethoxybenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0070]

[0071] 1 H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.24 - 7.19 (m, 1H), 7.14 - 7.05 (m, 2H), 6.80 (d, J = 7.4 Hz, 1H), 6.71 (d, J = 8.9 Hz, 2H), 6.04 (d, J = 8.0 Hz, 1H), 4.92 (td, J = 5.5, 4.9, 3.2 Hz, 1H), 4.01 (s, 2H), 3.84 (d, J = 1.8 Hz, 3H), 3.80 (d, J = 1.6 Hz, 3H), 3.63 (d, J = 1.6 Hz, 3H), 3.39 - 3.30 (m, 2H), 1.82 (d, J = 1.7 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.66, 169.84, 149.43, 148.07, 135.59, 135.37, 130.82, 128.92, 121.71, 120.72, 119.69, 118.21, 112.00, 111.53, 110.81, 106.49, 56.01, 53.21, 52.51, 31.82, 26.97, 23.15.

[0072] Example 11: Reaction steps to prepare Methyl (S)-2-acetamido-3-(2-(3-hydroxy-4- methoxybenzyl)-1H-indol-3-yl)propanoate:

[0073] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2-(3-hydroxy-4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered and the volatiles were removed in vacuo and the product was obtained by column chromatography.

[0074] The structure and NMR data of the product obtained in Example 11, Methyl (S)-2-acetamido-3-(2-(3-hydroxy-4-methoxybenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0075]

[0076] 1 H NMR (600 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.47 - 7.42 (m, 1H), 7.18 - 7.13 (m, 1H), 7.06 (ddd, J = 8.9, 7.4, 1.3 Hz, 2H), 6.75 - 6.70 (m, 2H), 6.61 (dd, J = 8.2, 2.2 Hz, 1H), 6.12 (d, J = 1.8 Hz, 1H), 6.08 (d, J = 7.8 Hz, 1H), 4.87 (d, J = 7.8 Hz, 1H), 3.92 (s, 2H), 3.80 (s, 3H), 3.60 (s, 3H), 3.28 (dd, J = 7.6, 5.7 Hz, 2H), 1.76 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.77, 170.23, 146.14, 145.80, 135.67, 135.54, 131.65, 128.79, 121.64, 120.01, 119.59, 118.17, 115.15, 111.27, 110.86, 106.29, 56.11, 53.23, 52.52, 31.50, 26.92, 22.98.

[0077] Example 12: Reaction steps to prepare Methyl (S)-2-acetamido-3-(2-(3-chloro-4- methoxybenzyl)-1H-indol-3-yl)propanoate:

[0078] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2-(3-chloro-4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, and after dissolution with 15 mL of dichloromethane, iodine and dimethylchlorosilane were added, and the reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite solution (10 mL), and extracted with dichloromethane (15 mL), the organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were mixed and washed with saturated brine (15 mL x 3), then dried with anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum, and column chromatography was used to obtain the product.

[0079] The structure and NMR data of the product obtained in Example 12, Methyl (S)-2-acetamido-3-(2-(3-chloro-4-methoxybenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0080]

[0081] 1 H NMR (600 MHz, Chloroform-d) δ 8.10 (d, J = 13.5 Hz, 1H), 7.47 (dd, J = 7.7, 1.3 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.99 (dd, J = 8.4, 2.2 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.10 - 6.04 (m, 1H), 4.91 - 4.83 (m, 1H), 3.97 (s, 2H), 3.84 (s, 3H), 3.62 (s, 3H), 3.31 (t, J = 5.7 Hz, 2H), 1.83 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 172.67, 169.91, 153.98, 135.72, 134.76, 131.60, 130.35, 128.78, 127.90, 122.80, 121.87, 119.76, 118.28, 112.46, 110.88, 106.84, 56.29, 53.24, 52.53, 31.02, 27.02, 23.15.

[0082] Example 13: Reaction steps for the preparation of Methyl (S)-2-acetamido-3-(2-(thiophen-2-ylmethyl)-1H-indol-3-yl)propanoate:

[0083] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2- thiophen-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and then iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered and the volatiles were removed under vacuum, the product was obtained by column chromatography.

[0084] The structure and NMR data of the product obtained in Example 13, Methyl (S)-2-acetamido-3-(2-(thiophen-2-ylmethyl)-1H-indol-3-yl)propanoate, are as follows:

[0085]

[0086] 1H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.48 (dd, J = 8.0, 1.1 Hz, 1H), 7.23 (s, 1H), 7.20 - 7.18 (m, 1H), 7.16 - 7.06 (m, 2H), 6.95 (dd, J = 5.2, 3.4 Hz, 1H), 6.85 - 6.83 (m, 1H), 6.02 (d, J = 7.9 Hz, 1H), 4.92 (m, J = 7.9, 5.5 Hz, 1H), 4.25 (d, J = 1.0 Hz, 2H), 3.63 (d, J = 0.6 Hz, 3H), 3.33 (d, J = 5.5 Hz, 2H), 1.82 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.60, 169.90, 141.06, 135.61, 134.21, 128.70, 127.26, 125.93, 124.86, 122.04, 119.82, 118.47, 110.90, 106.56, 53.14, 52.58, 26.92, 26.71, 23.12.

[0087] Implementation 14: Reaction steps for preparing Methyl (S,E)-4-(3-(3-(2-acetamido-3-methoxy-3-oxopropyl)-1H-indol-2-yl)-1-chloroprop-1-en-1-yl)benzoate:

[0088] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and methyl (E)-4-(1-chloro-2-(1,3-dithian-2-yl)vinyl)benzoate (0.2 mmol) were added sequentially, which was dissolved in 15 mL of dichloromethane, and then iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were mixed and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum. Column chromatography gave the product.

[0089] The structure and NMR data of the product obtained in Example 14, Methyl (S,E)-4-(3-(3-(2-acetamido-3-methoxy-3-oxopropyl)-1H-indol-2-yl)-1-chloroprop-1-en-1-yl)benzoate, are as follows:

[0090]

[0091] 1 H NMR (600 MHz, Chloroform-d) δ 8.18 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.48 - 7.45 (m, 1H), 7.30 - 7.27 (m, 1H), 7.16 - 7.12 (m, 1H), 7.11 - 7.07 (m, 1H), 6.39 (t, J = 7.1 Hz, 1H), 6.05 (d, J = 8.0 Hz, 1H), 4.96 - 4.91 (m, 1H), 3.92 (s, 3H), 3.83 (dd, J = 20.9, 7.1 Hz, 2H), 3.67 (s, 3H), 3.33 (dd, J = 15.3, 5.5 Hz, 2H), 1.92 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.59, 169.86, 166.59, 141.34, 135.67, 133.78, 133.36, 130.38, 129.82, 128.80, 126.40, 126.02, 125.93, 122.02, 119.88, 118.31, 118.24, 110.87, 106.48, 53.28, 53.14, 52.57, 52.49, 52.41, 52.29, 26.96, 26.84, 23.27.

[0092] Example 15: Reaction steps to prepare Methyl (S,E)-2-acetamido-3-(2-(3-(4- methoxyphenyl)allyl)-1H-indol-3-yl)propanoate:

[0093] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and (E)-2-(4-methoxystyryl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2S04, filtered and the volatiles were removed under vacuum, column chromatography gave the product.

[0094] The structure and NMR data of the product obtained in Example 15, Methyl (S,E)-2-acetamido-3-(2-(3-(4-methoxyphenyl)allyl)-1H-indol-3-yl)propanoate, are as follows:

[0095]

[0096] 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.29 (dd, J = 8.0, 1.0 Hz, 1H), 7.22 (d, J = 8.7 Hz, 2H), 7.18 - 7.07 (m, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.73 (d, J = 7.4 Hz, 1H), 4.84 (dd, J = 7.5, 5.6 Hz, 1H), 4.65 (t, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.75 - 3.70 (m, 1H), 3.60 (s, 3H), 3.37 - 3.24 (m, 2H), 2.79 - 2.75 (m, 2H), 1.70 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.90, 170.00, 158.72, 137.19, 135.72, 133.67, 128.67, 122.03, 119.88, 118.61, 114.54, 111.08, 107.63, 55.44, 55.36, 53.30, 53.22, 52.53, 52.47, 44.43, 44.36, 41.15, 37.93, 29.98, 29.76, 26.88, 25.94, 23.03.

[0097] Example 16: Reaction steps to prepare Methyl (S)-2-acetamido-3-(2-benzhydryl-1H- indol-3-yl)propanoate:

[0098] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 2,2-diphenyl-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered and the volatiles were removed under vacuum, the product was obtained by column chromatography.

[0099] The structure and NMR data of the product obtained in Example 16, Methyl (S)-2-acetamido-3-(2-benzhydryl-1H-indol-3-yl)propanoate, are as follows:

[0100]

[0101] 1 H NMR (600 MHz, Chloroform-d) δ 7.69 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 4H), 7.27 (dd, J = 8.2, 2.0 Hz, 2H), 7.23 (d, J = 7.7 Hz, 1H), 7.16 - 7.12 (m, 5H), 7.11 - 7.08 (m, 1H), 5.76 (s, 1H), 5.74 (d, J = 7.7 Hz, 1H), 4.85 (m, J = 7.8, 5.9 Hz, 1H), 3.60 (s, 3H), 3.29 (t, J = 5.6 Hz, 2H), 1.61 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.75, 169.87, 142.15, 141.99, 137.29, 135.60, 128.98, 128.91, 127.22, 122.01, 119.91, 118.64, 111.01, 107.12, 52.94, 52.42, 47.98, 27.12, 22.87.

[0102] Example 17: Reaction steps to prepare Methyl (S)-2-acetamido-3-(2-((S)-(4- hydroxyphenyl)(phenyl)methyl)-1H-indol-3-yl)propanoate:

[0103] In a 25 mL round bottom flask, methyl acetyl-L-tryptophanate (0.2 mmol) and 4-(2-phenyl-1,3-dithian-2-yl)phenol (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added, the reaction was stirred at room temperature until the reaction was complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were combined and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum, and the product was obtained by column chromatography.

[0104] The structure and NMR data of the product obtained in Example 17, Methyl (S)-2-acetamido-3-(2-((S)-(4-hydroxyphenyl)(phenyl)methyl)-1H-indol-3-yl)propanoate, are as follows:

[0105]

[0106] 1 H NMR (600 MHz, Chloroform-d) δ 7.73 (d, J = 6.6 Hz, 1H), 7.47 (t, J = 6.9 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 3.6 Hz, 1H), 7.17 (t, J = 7.0 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 7.08 (t, J = 7.8 Hz, 3H), 6.93 (dd, J = 15.2, 8.4 Hz, 2H), 6.72 (dd, J = 8.4, 4.9 Hz, 2H), 5.82 (d, J = 7.6 Hz, 1H), 5.66 (d, J = 3.6 Hz, 1H), 4.85 - 4.79 (m, 1H), 3.60 (d, J = 2.2 Hz, 3H), 3.26 (dd, J = 6.1, 3.7 Hz, 2H), 1.60 (d, J = 1.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 172.94, 172.87, 171.27, 171.21, 155.88, 142.67, 142.40, 138.15, 138.09, 135.67, 133.18, 132.97, 130.08, 130.02, 128.96, 128.92, 128.62, 127.13, 121.94, 119.86, 118.36, 116.00, 115.94, 111.21, 106.43, 53.31, 53.22, 52.67, 47.30, 47.25, 27.11, 22.61.

[0107] Example 18: Reaction steps for the preparation of Ethyl (S)-2-acetamido-3-(2-(4- methoxybenzyl)-1 H-indol-3-yl)propanoate:

[0108] In a 25 mL round bottom flask, ethyl acetyl-L-tryptophanate (0.2 mmol) and 2-(4- methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2S04, filtered and the volatiles were removed under vacuum, the product was obtained by column chromatography.

[0109] The structure and NMR data of the product obtained in Example 18, Ethyl (S)-2-acetamido-3-(2-(4- methoxybenzyl)-1 H-indol-3-yl)propanoate, are as follows:

[0110]

[0111] 1H NMR (600 MHz, Chloroform-d) δ 7.76 (s, 1H), 7.50 - 7.47 (m, 1H), 7.22 - 7.19 (m, 1H), 7.09 (t, J = 7.2 Hz, 4H), 6.86 (d, J = 8.6 Hz, 2H), 6.02 - 5.98 (m, 1H), 4.93 - 4.88 (m, 1H), 4.17 - 4.11 (m, 1H), 4.02 (s, 2H), 3.99 (dd, J = 10.8, 7.1 Hz, 1H), 3.79 (s, 3H), 3.34 (d, J = 5.7 Hz, 2H), 1.84 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 172.22, 169.76, 158.47, 135.51, 135.42, 130.35, 129.61, 128.83, 121.53, 119.48, 118.14, 114.25, 110.65, 106.49, 61.57, 55.29, 53.19, 31.24, 26.94, 23.04, 13.92.

[0112] Implementation 19: Reaction steps for preparing Ethyl (S)-2-acetamido-3-(2-((3-chloro-1H-indol-2-yl)methyl)-1H-indol-3-yl)propanoate:

[0113] In a 25 mL round bottom flask, ethyl acetyl-L-tryptophanate (0.2 mmol) and 3-chloro-2-(1,3-dithian-2-yl)-1H-indole (0.2 mmol) were added sequentially, dissolved with 15 mL of dichloromethane, and then iodine monomer and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were mixed and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum. Column chromatography gave the product.

[0114] The structure and NMR data of the product obtained in Example 19, Ethyl (S)-2-acetamido-3-(2-((3-chloro-1H-indol-2-yl)methyl)-1H-indol-3-yl)propanoate, are as follows:

[0115]

[0116] 1 H NMR (600 MHz, Chloroform-d) δ 8.99 (s, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.49 - 7.45 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.14 - 7.08 (m, 2H), 7.04 (d, J = 9.2 Hz, 2H), 6.99 (t, J = 7.8 Hz, 1H), 6.11 (d, J = 7.9 Hz, 1H), 5.00 - 4.95 (m, 1H), 4.18 - 4.13 (m, 1H), 4.13 (s, 2H), 4.05 (dd, J = 10.8, 7.1 Hz, 1H), 3.43 (dd, J = 5.9, 2.0 Hz, 2H), 1.83 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.47, 170.29, 135.29, 134.84, 134.78, 129.03, 127.15, 122.72, 122.02, 121.49, 120.64, 119.63, 118.28, 118.03, 110.94, 110.89, 107.71, 105.63, 61.85, 53.34, 27.13, 23.18, 21.09, 14.05.

[0117] Run 20: Reaction steps for preparing Ethyl (S)-3-(2-((9H-carbazol-3-yl)methyl)-1H-indol-3-yl)-2-acetamidopropanoate:

[0118] In a 25 mL round bottom flask, ethyl acetyl-L-tryptophanate (0.2 mmol) and 3-(1,3-dithian-2-yl)-9H-carbazole (0.2 mmol) were added successively, dissolved with 15 mL of dichloromethane, and then iodine monomer and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were mixed and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum. Column chromatography gave the product.

[0119] The structure and NMR data of the product obtained in Example 20, Ethyl (S)-3-(2-((9H-carbazol-3-yl)methyl)-1H-indol-3-yl)-2-acetamidopropanoate, are as follows:

[0120]

[0121] 1 H NMR (600 MHz, Chloroform-d) δ 8.18 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.88 (t, J = 1.1 Hz, 1H), 7.79 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.42 - 7.40 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 7.23 - 7.18 (m, 2H), 7.16 (d, J = 9.1 Hz, 1H), 7.10 - 7.08 (m, 2H), 6.03 (d, J = 7.9 Hz, 1H), 4.95 (d, J = 7.9 Hz, 1H), 4.23 (s, 2H), 4.16 (dd, J = 10.8, 7.1 Hz, 1H), 4.02 (dd, J = 10.7, 7.2 Hz, 1H), 3.40 (d, J = 5.8 Hz, 2H), 1.80 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.29, 169.83, 139.91, 138.51, 136.00, 135.49, 129.02, 128.99, 126.65, 126.13, 123.75, 122.88, 121.55, 120.41, 120.23, 119.57, 119.55, 118.18, 111.07, 110.77, 110.68, 106.40, 61.65, 53.25, 32.26, 27.01, 23.11, 13.98.

[0122] Example 21: Reaction steps for preparing Ethyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate:

[0123] In a 25 mL round bottom flask, ethyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate was prepared by sequentially adding

[0124] (((9H-fluoren-9-yl)methoxy)carbonyl)-L-tryptophanate (0.2 mmol) and 2-(4- methoxyphenyl)-l,3-dithiane (0.2 mmol) were dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete by TLC. The reaction was then quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined and washed with saturated brine (15 mL x 3), dried over anhydrous Na2S04, filtered, and the volatiles were removed in vacuo. The product was obtained by column chromatography.

[0125] The structure and NMR data for the product from Example 21, Ethyl (S)-2-((((9H- fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxybenzyl)-lH-indol-3-yl)propanoate, are as follows:

[0126]

[0127] 1 H NMR (600 MHz, Chloroform-d) δ 7.75 (dd, J = 7.7, 5.3 Hz, 2H), 7.67 (s, 1H), 7.56 - 7.51 (m, 3H), 7.39 (d, J = 7.4 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 8.6 Hz, 4H), 6.84 (d, J = 8.6 Hz, 2H), 5.41 (d, J = 8.4 Hz, 1H), 4.73 - 4.68 (m, 1H), 4.33 (d, J = 7.3 Hz, 2H), 4.19 - 4.10 (m, 2H), 4.03 (s, 2H), 3.76 (s, 3H), 3.36 (dd, J = 6.0, 2.5 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 158.58, 143.94, 141.28, 135.56, 135.46, 129.80, 127.68, 127.06, 125.17, 121.63, 119.95, 119.68, 118.23, 114.32, 110.56, 61.59, 55.29, 47.15, 31.41, 27.39, 13.94.

[0128] Example 22: Reaction steps to prepare N-(2-(2-(4-methoxybenzyl)-1H-indol-3- yl)ethyl)acetamide:

[0129] In a 25 mL round bottom flask, N-(2-(1H-indol-3-yl)ethyl)acetamide (0.2 mmol) and 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x), and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed in vacuo, and the product was obtained by column chromatography.

[0130] The structure and NMR data of the product obtained in Example 22, N-(2-(2-(4- methoxybenzyl)-1H-indol-3-yl)ethyl)acetamide, are as follows:

[0131]

[0132] 1 H NMR (600 MHz, Chloroform-d) δ 8.08 (d, J = 7.9 Hz, 1H), 7.52 (dd, J = 7.9, 1.2 Hz, 1H), 7.22 - 7.20 (m, 1H), 7.12 - 7.06 (m, 4H), 6.81 (d, J = 8.7 Hz, 2H), 5.61 (s, 1H), 4.01 (s, 2H), 3.75 (s, 3H), 3.48 (d, J = 6.3 Hz, 2H), 2.95 (t, J = 6.7 Hz, 2H), 1.77 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ 170.43, 158.36, 135.60, 134.83, 130.74, 129.50, 128.43, 121.48, 119.41, 118.16, 114.21, 110.74, 108.91, 55.30, 40.23, 31.27, 24.15, 23.18.

[0133] Example 23: Reaction steps to prepare N-(2-(2-((9H-carbazol-3-yl)methyl)-1H- indol-3-yl)ethyl)acetamide:

[0134] In a 25 mL round bottom flask, N-(2-(1H-indol-3-yl)ethyl)acetamide (0.2 mmol) and 3-(1,3-dithian-2-yl)-9H-carbazole (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added, the reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were mixed and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2S04, filtered, and the volatiles were removed under vacuum, and column chromatography gave the product.

[0135] The structure and NMR data of the product N-(2-(2-((9H-carbazol-3-yl)methyl)-1H- indol-3-yl)ethyl)acetamide obtained in Example 23 are as follows:

[0136]

[0137] 1 H NMR (600 MHz, Chloroform-d) δ 8.27 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.91 (s, 1H), 7.83 - 7.81 (m, 1H), 7.55 - 7.52 (m, 1H), 7.39 - 7.34 (m, 2H), 7.23 - 7.16 (m, 3H), 7.12 - 7.06 (m, 3H), 5.46 (s, 1H), 4.17 (s, 2H), 3.50 (d, J = 6.3 Hz, 2H), 2.98 (t, J = 6.7 Hz, 2H), 1.68 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 170.39, 140.05, 138.57, 135.67, 135.47, 129.42, 128.65, 126.57, 126.14, 123.71, 122.91, 121.56, 120.41, 120.04, 119.52, 118.26, 111.13, 110.86, 108.95, 100.01, 40.31, 32.30, 24.28, 23.23.

[0138] Example 24: Reaction steps to prepare N-(2-(2-(thiophen-2-ylmethyl)-1H-indol-3- yl)ethyl)acetamide:

[0139] In a 25 mL round bottom flask, N-(2-(1H-indol-3-yl)ethyl)acetamide (0.2 mmol) and 2-thiophen-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added, the reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were mixed and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum, and the product was obtained by column chromatography.

[0140] The structure and NMR data of the product obtained in Example 24, N-(2-(2-(thiophen-2- ylmethyl)-1H-indol-3-yl)ethyl)acetamide, are as follows:

[0141]

[0142] 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.16 - 7.06 (m, 3H), 6.92 (t, J = 4.3 Hz, 1H), 6.85 - 6.82 (m, 1H), 5.55 (s, 1H), 4.25 (d, J = 1.4 Hz, 2H), 3.51 (d, J = 6.3 Hz, 2H), 3.00 - 2.93 (m, 2H), 1.76 (d, J = 1.3 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 170.34, 141.71, 135.77, 133.66, 128.38, 127.23, 125.61, 124.65, 121.93, 119.65, 118.51, 110.97, 109.22, 40.14, 26.74, 24.29, 23.30.

[0143] Example 25: Reaction steps for the preparation of N-(2-(5-methoxy-2-(4- methoxybenzyl)-1 H-indol-3-yl)ethyl)acetamide:

[0144] In a 25 mL round bottom flask, N-(2-(5-methoxy-1 H-indol-3-yl)ethyl)acetamide (0.2 mmol) and 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until completion was detected by TLC, at which point the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined, washed with saturated brine (15 mL x 3), dried over anhydrous Na2S04, filtered, and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0145] The structure and NMR data for the product obtained in Example 25, N-(2-(5- methoxy-2-(4-methoxybenzyl)-1 H-indol-3-yl)ethyl)acetamide, are as follows:

[0146] 1 H NMR (600 MHz, Chloroform-d) δ 7.64 (s, 1H), 7.12 (dd, J = 20.2, 8.2 Hz, 3H), 7.01 (s, 1H), 6.87 - 6.84 (m, 2H), 6.79 (d, J = 8.8 Hz, 1H), 5.47 (s, 1H), 4.04 (s, 2H), 3.86 (d, J = 2.2 Hz, 3H), 3.80 - 3.78 (m, 3H), 3.52 (d, J = 6.7 Hz, 2H), 2.96 (t, J = 6.5 Hz, 2H), 1.83 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ 170.11, 158.47, 154.14, 135.60, 130.63, 130.57, 129.53, 128.94, 114.28, 111.38, 108.95, 100.41, 56.01, 55.33, 40.06, 31.45, 29.72, 24.25, 23.32.

[0147] Example 26: Reaction steps to prepare Methyl (S)-2-((3S,5S,7S)-adamantane-1- carboxamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate:

[0148] In a 25 mL round bottom flask, methyl

[0149] ((3S,5S,7S)-adamantane-1-carbonyl)-L-tryptophanate (0.2 mmol) and 2-(4- methoxyphenyl)-1,3-dithiane (0.2 mmol) were dissolved in 15 mL of dichloromethane and then iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete by TLC analysis. The reaction was then quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The organic extracts were combined and washed with saturated brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0150] The structure and NMR data of the product obtained in Example 26, Methyl (S)-2- ((3S,5S,7S)-adamantane-1-carboxamido)-3-(2-(4-methoxybenzyl)-1H-indol-3- yl)propanoate, are as follows:

[0151]

[0152] 1H NMR (400 MHz, Chloroform-d) δ 7.72 (s, 1H), 7.51 (d, J = 6.5 Hz, 1H), 7.18 (s, 1H), 7.13 - 7.05 (m, 4H), 6.85 (dd, J = 8.7, 1.6 Hz, 2H), 6.18 (d, J = 7.8 Hz, 1H), 4.95 - 4.86 (m, 1H), 4.03 (s, 2H), 3.79 (d, J = 1.5 Hz, 3H), 3.62 (d, J = 1.5 Hz, 3H), 3.39 - 3.25 (m, 2H), 1.95 (t, J = 3.3 Hz, 3H), 1.72 (d, J = 2.9 Hz, 6H), 1.63 (t, J = 14.9 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 177.77, 173.04, 158.64, 135.50, 130.16, 129.89, 128.99, 121.68, 119.61, 118.51, 114.36, 110.63, 106.68, 55.36, 52.94, 40.62, 38.94, 36.51, 31.47, 28.11, 27.05.

[0153] Implementation 27: Reaction steps for preparing Methyl (S)-2-(benzo[d][l,3]dioxole-5-carboxamido)-3-(2-(4-methoxybenzyl)-lH-indol-3-yl)propanoate:

[0154] In a 25 mL round bottom flask, methyl

[0155] (benzo[d][l,3]dioxole-5-carbonyl)-L-tryptophanate (0.2 mmol) and

[0156] 2-(4-methoxyphenyl)-l,3-dithiane (0.2 mmol) were dissolved in 15 mL of dichloromethane and then iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete by TLC detection. The reaction was then quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined, washed with saturated brine (15 mL x 3), dried over anhydrous Na2S04, filtered, and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0157] The structure and NMR data of the product obtained in Example 27, Methyl (S)-2- (benzo[d][l,3]dioxole-5-carboxamido)-3-(2-(4-methoxybenzyl)-lH-indol-3- yl)propanoate, are as follows:

[0158]

[0159] 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.67 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.43 (dd, J = 8.2, 1.8 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.3 Hz, 3H), 6.80 (d, J = 8.6 Hz, 2H), 6.09 (s, 2H), 4.67 (d, J = 6.0 Hz, 1H), 4.12 - 3.94 (m, 2H), 3.68 (s, 3H), 3.59 (s, 3H), 3.29 (dd, J = 12.8, 7.2 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 173.16, 166.05, 158.19, 150.40, 147.79, 136.50, 136.10, 132.03, 129.84, 128.54, 128.16, 123.12, 120.97, 118.87, 118.23, 114.29, 111.32, 108.31, 107.99, 107.05, 102.22, 55.50, 54.64, 52.42, 31.00, 26.55.

[0160] Example 28: Reaction steps to prepare (S)-2-acetamido-N-benzyl-3-(2-(4- methoxybenzyl)-lH-indol-3-yl)propenamide:

[0161] In a 25 mL round bottom flask, (S)-2-acetamido-N-benzyl-3-(lH-indol-3- yl)propanamide (0.2 mmol) and 2-(4-methoxyphenyl)-l,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered and the volatiles were removed in vacuo and the product was obtained by column chromatography.

[0162] The structure and NMR data of the product obtained in Example 28, (S)-2- acetamido-N-benzyl-3-(2-(4-methoxybenzyl)-lH-indol-3-yl)propenamide, are as follows:

[0163]

[0164] 1 H NMR (400 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.21 - 7.12 (m, 4H), 7.09 - 6.95 (m, 4H), 6.81 (q, J = 3.9, 2.9 Hz, 2H), 6.74 - 6.65 (m, 3H), 6.27 (s, 1H), 4.79 - 4.67 (m, 1H), 4.18 - 4.08 (m, 2H), 4.01 - 3.80 (m, 2H), 3.69 (d, J = 1.5 Hz, 3H), 3.21 (dd, J = 18.0, 7.1 Hz, 2H), 1.80 (d, J = 1.4 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 171.73, 170.38, 158.39, 137.62, 135.79, 135.64, 130.73, 129.76, 128.66, 128.58, 127.58, 127.36, 121.64, 119.75, 118.55, 114.25, 110.78, 106.99, 55.44, 55.37, 55.30, 54.28, 54.20, 43.62, 31.23, 28.09, 23.04.

[0165] Example 29: Reaction steps to prepare Methyl (S)-3-(2-(4-methoxybenzyl)-1H- indol-3-yl)-2-(3-methylbut-2-enamido)propanoate:

[0166] In a 25 mL round bottom flask, methyl (3-methylbut-2-enoyl)-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed in vacuo, and the product was obtained by column chromatography.

[0167] The structure and NMR data of the product obtained in Example 29, Methyl (S)-3-(2-(4- methoxybenzyl)-1H-indol-3-yl)-2-(3-methylbut-2-enamido)propanoate, are as follows:

[0168]

[0169] 1 H NMR (400 MHz, Chloroform-d) δ 7.76 (s, 1H), 7.53 - 7.45 (m, 1H), 7.22 - 7.17 (m, 1H), 7.14 - 7.03 (m, 4H), 6.88 - 6.82 (m, 2H), 5.85 (d, J = 7.8 Hz, 1H), 5.33 - 5.25 (m, 1H), 4.94 (dt, J = 7.8, 5.5 Hz, 1H), 4.01 (s, 2H), 3.79 (s, 3H), 3.63 (s, 3H), 3.35 (d, J = 5.5 Hz, 2H), 2.10 (s, 3H), 1.76 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 172.85, 166.43, 158.60, 152.22, 135.57, 135.51, 130.39, 129.76, 128.84, 121.68, 119.66, 118.43, 118.01, 114.37, 110.64, 106.73, 55.37, 52.78, 52.43, 31.33, 27.20, 27.06, 19.87.

[0170] Example 30: Reaction steps for the preparation of Methyl (S)-3-(2-(4- methoxybenzyl)-1 H-indol-3-yl)-2-propionamidopropanoate:

[0171] In a 25 mL round bottom flask, methyl palmitoyl-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and then iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2S04, filtered and the volatiles were removed under vacuum, the product was obtained by column chromatography.

[0172] The structure and NMR data of the product obtained in Example 30, Methyl (S)-3-(2-(4- methoxybenzyl)-1 H-indol-3-yl)-2-propionamidopropanoate, are as follows:

[0173] 1H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 7.3 Hz, 4H), 6.82 (d, J = 7.9 Hz, 2H), 5.97 (d, J = 7.7 Hz, 1H), 4.90 (d, J = 6.3 Hz, 1H), 3.99 (s, 2H), 3.76 (s, 3H), 3.61 (s, 3H), 3.31 (d, J = 5.7 Hz, 2H), 1.97 (t, J = 7.6 Hz, 2H), 1.48 (t, J = 7.3 Hz, 2H), 1.25 (s, 24H), 0.88 (t, J = 6.4 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.97, 172.80, 158.60, 135.63, 135.54, 130.40, 129.72, 128.90, 121.67, 119.64, 118.27, 114.36, 110.77, 106.53, 55.35, 53.03, 52.44, 36.53, 32.03, 31.34, 29.80, 29.76, 29.72, 29.57, 29.46, 29.42, 29.32, 27.04, 25.43, 22.79, 14.22.

[0174] Implementation 31: Reaction steps to make Methyl (S)-2-(2-(l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl)acetamido)-3-(2-(4-methoxybenzyl)-lH-indol-3-yl)propanoate:

[0175] Into a 25 mL round bottom flask, was added methyl

[0176] (2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete by TLC. The reaction was then quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined and washed with saturated brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and the volatiles were removed in vacuo. The product was purified by column chromatography.

[0177] The structure and NMR data for the product from Example 31, Methyl (S)-2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0178]

[0179] 1 H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 3.5 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.29 (dd, J = 15.3, 8.1 Hz, 3H), 7.15 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.94 - 6.87 (m, 3H), 6.84 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.8, 6.4 Hz, 3H), 6.11 (d, J = 7.4 Hz, 1H), 4.85 - 4.76 (m, 1H), 3.70 (d, J = 5.7 Hz, 6H), 3.62 (s, 4H), 3.46 (d, J = 16.1 Hz, 3H), 3.21 (d, J = 6.1 Hz, 2H), 1.95 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 172.47, 170.11, 168.44, 158.49, 156.53, 139.37, 135.96, 135.82, 135.61, 133.80, 131.20, 131.13, 130.40, 130.28, 129.56, 129.24, 128.34, 121.69, 119.67, 117.89, 115.28, 114.25, 112.77, 112.68, 110.96, 105.75, 100.90, 55.77, 55.33, 53.00, 52.51, 32.05, 30.72, 26.35, 13.33.

[0180] Example 32: Reaction steps for the preparation of Methyl (S)-2-(2-acetoxybenzamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate:

[0181] In a 25 mL round bottom flask, methyl (2-acetoxybenzoyl)-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered and the volatiles were removed under vacuum, the product was obtained by column chromatography.

[0182] The structure and NMR data of the product obtained in Example 32, Methyl (S)-2-(2-acetoxybenzamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0183]

[0184] 1H NMR (400 MHz, Chloroform-d) δ 7.91 - 7.87 (m, 1H), 7.75 (s, 1H), 7.48 - 7.41 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 7.3 Hz, 2H), 6.99 (d, J = 8.2 Hz, 3H), 6.79 - 6.71 (m, 2H), 5.15 - 5.06 (m, 1H), 4.02 - 3.84 (m, 2H), 3.75 (s, 3H), 3.68 (s, 3H), 3.55 - 3.44 (m, 2H), 1.93 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.64, 168.77, 164.45, 158.52, 148.27, 136.09, 135.54, 132.26, 130.87, 130.13, 129.77, 128.72, 126.45, 126.28, 123.39, 121.72, 119.73, 118.34, 114.26, 110.62, 106.32, 55.34, 53.67, 52.63, 31.28, 26.94, 20.54.

[0185] Implementation 33: Reaction steps for preparing Methyl (S)-2-((S)-2-acetamido-3- phenylpropanamido)-3-(2-(4-hydroxybenzyl)-lH-indol-3-yl)propanoate:

[0186] In a 25 mL round bottom flask, methyl acetyl-L-phenylalanyl-L-tryptophanate (0.2 mmol) and 4-(l,3-dithian-2-yl)phenol (0.2 mmol) were added successively, dissolved with 15 mL of dichloromethane, and then iodine monomer and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were mixed and washed with saturated brine (15 mL x 3), then dried with anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum. Column chromatography gave the product.

[0187] The structure and NMR data of the product obtained in Example 33, Methyl (S)-2-((S)-2-acetamido-3-phenylpropanamido)-3-(2-(4-hydroxybenzyl)-1H-indol-3- yl)propanoate, are as follows:

[0188]

[0189] 1 H NMR (600 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.20 - 7.16 (m, 5H), 7.07 (d, J = 6.5 Hz, 3H), 7.01 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.9 Hz, 2H), 6.71 (d, J = 8.0 Hz, 2H), 6.11 (d, J = 7.9 Hz, 1H), 5.95 (d, J = 7.6 Hz, 1H), 4.79 (d, J = 6.7 Hz, 1H), 4.41 (d, J = 7.3 Hz, 1H), 3.86 (q, J = 16.4 Hz, 2H), 3.63 (s, 3H), 3.28 (dd, J = 14.9, 5.7 Hz, 1H), 3.19 (dd, J = 14.9, 5.8 Hz, 1H), 2.89 (d, J = 6.6 Hz, 2H), 1.82 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.12, 172.42, 169.94, 156.59, 138.82, 137.42, 136.42, 130.59, 130.09, 129.97, 129.18, 128.92, 127.13, 121.28, 119.27, 118.50, 116.10, 111.73, 106.41, 54.51, 54.33, 52.79, 38.55, 31.50, 27.52, 23.41.

[0190] Example 34: Reaction steps to make Methyl (S)-2-((S)-2-acetamido-3-phenylpropanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate:

[0191] In a 25 mL round bottom flask, methyl acetyl-L-phenylalanyl-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-l,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2S04, filtered and the volatiles were removed in vacuo and the product was obtained by column chromatography.

[0192] The structure and NMR data of the product obtained in Example 34, Methyl (S)-2-((S)-2-acetamido-3-phenylpropanamido)-3-(2-(4-methoxybenzyl)-lH-indol-3-yl)propanoate, are as follows:

[0193]

[0194] 1 H NMR (600 MHz, Chloroform-d) δ 7.74 (s, 1H), 7.25 - 7.21 (m, 3H), 7.19 - 7.13 (m, 4H), 7.10 - 7.07 (m, 1H), 7.06 - 7.04 (m, 2H), 6.99 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 6.14 (d, J = 7.8 Hz, 1H), 5.88 (d, J = 8.1 Hz, 1H), 4.83 (d, J = 7.8 Hz, 1H), 4.57 (d, J = 6.1 Hz, 1H), 3.92 (d, J = 3.8 Hz, 2H), 3.79 (s, 3H), 3.62 (s, 3H), 3.28 - 3.25 (m, 2H), 3.00 (dd, J = 13.8, 6.0 Hz, 1H), 2.93 (dd, J = 13.8, 7.3 Hz, 1H), 1.77 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 171.84, 170.46, 169.75, 158.65, 136.53, 135.71, 135.50, 130.04, 129.82, 129.50, 128.68, 127.10, 121.75, 119.70, 118.08, 114.39, 110.84, 106.13, 55.40, 54.25, 53.16, 52.55, 38.38, 31.25, 26.89, 23.08.

[0195] Example 35: Reaction steps to prepare Methyl (S)-2-((S)-2-acetamido-3- phenylpropanamido)-3-(2-(thiophen-2-ylmethyl)-1 H-indol-3-yl)propanoate:

[0196] In a 25 mL round bottom flask, methyl acetyl-L-phenylalanyl-L-tryptophanate (0.2 mmol) and 2-thiophen-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and then iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2S04, filtered and the volatiles were removed under vacuum, the product was obtained by column chromatography.

[0197] The structure and NMR data of the product obtained in Example 35, Methyl (S)-2-((S)-2-acetamido-3-phenylpropanamido)-3-(2-(thiophen-2-ylmethyl)-1 H-indol-3- yl)propanoate, are as follows:

[0198]

[0199] 1H NMR (600 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.51 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.34 - 7.30 (m, 1H), 7.28 - 7.21 (m, 6H), 7.18 (d, J = 6.8 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.99 - 6.93 (m, 2H), 6.90 (s, 1H), 4.61 - 4.56 (m, 1H), 4.54 (q, J = 7.3 Hz, 1H), 4.34 - 4.19 (m, 2H), 3.51 (s, 3H), 3.21 - 3.06 (m, 2H), 2.97 (dd, J = 13.8, 4.6 Hz, 1H), 2.70 (dd, J = 13.8, 9.8 Hz, 1H), 1.73 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 172.68, 172.00, 169.61, 142.83, 138.35, 136.02, 135.74, 129.67, 128.52, 128.30, 127.46, 126.75, 125.67, 124.84, 121.26, 119.05, 118.31, 111.49, 106.30, 54.05, 53.77, 52.39, 38.15, 27.01, 26.40, 22.95.

[0200] Implementation 36: Reaction steps to make Methyl (S)-3-(2-((9H-carbazol-3-yl)methyl)-1H-indol-3-yl)-2-((S)-2-acetamido-3-phenylpropanamido)propanoate:

[0201] In a 25 mL round bottom flask, methyl acetyl-L-phenylalanyl-L-tryptophanate (0.2 mmol) and 3-(l,3-dithian-2-yl)-9H-carbazole (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2S04, filtered and the volatiles were removed under vacuum to give the product.

[0202] The structure and NMR data of the product obtained in example 36, Methyl (S)-3-(2-((9H-carbazol-3-yl)methyl)-lH-indol-3-yl)-2-((S)-2-acetamido-3-phenylpropanamido)propanoate, are as follows:

[0203]

[0204] 1 H NMR (400 MHz, Chloroform-d) δ 8.18 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.91 - 7.83 (m, 2H), 7.40 (d, J = 3.8 Hz, 2H), 7.31 - 7.27 (m, 2H), 7.22 - 7.16 (m, 4H), 7.14 (s, 2H), 7.10 - 7.03 (m, 3H), 7.03 - 6.97 (m, 1H), 6.09 (d, J = 7.8 Hz, 1H), 5.83 (d, J = 7.9 Hz, 1H), 4.86 (d, J = 7.7 Hz, 1H), 4.54 - 4.44 (m, 1H), 4.14 (d, J = 1.7 Hz, 2H), 3.62 (s, 3H), 3.32 (s, 2H), 2.92 - 2.83 (m, 2H), 1.73 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 171.95, 170.55, 169.87, 140.04, 138.61, 136.44, 135.60, 129.40, 128.95, 128.75, 128.59, 127.01, 126.64, 126.19, 123.75, 122.92, 121.65, 120.47, 120.35, 119.63, 119.56, 118.11, 111.17, 111.00, 110.90, 105.94, 54.27, 53.25, 52.60, 38.34, 32.23, 26.95, 23.02.

[0205] Example 37: Reaction steps to prepare Methyl (S)-2-((S)-2-acetamido-4-methylpentanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate:

[0206] In a 25 mL round bottom flask, methyl acetyl-L-leucyl-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, at which point the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined, washed with saturated brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and the volatiles were removed in vacuo. The product was obtained by column chromatography.

[0207] The structure and NMR data for the product from Example 37, Methyl (S)-2-((S)-2-acetamido-4-methylpentanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0208]

[0209] 1H NMR (600 MHz, Chloroform-d) δ 7.74 (s, 1H), 7.50 - 7.47 (m, 1H), 7.21 - 7.19 (m, 1H), 7.13 - 7.08 (m, 4H), 6.86 (d, J = 8.7 Hz, 2H), 6.46 (d, J = 7.6 Hz, 1H), 5.66 (d, J = 8.5 Hz, 1H), 4.90 - 4.84 (m, 1H), 4.41 (td, J = 9.0, 5.2 Hz, 1H), 4.02 (s, 2H), 3.79 (s, 3H), 3.65 (s, 3H), 3.35 (dd, J = 8.2, 5.9 Hz, 2H), 1.86 (s, 3H), 1.61 - 1.52 (m, 2H), 1.41 - 1.35 (m, 1H), 0.87 (dd, J = 6.4, 5.4 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 172.22, 171.84, 169.83, 158.63, 135.77, 130.17, 129.87, 128.78, 121.75, 119.71, 118.25, 114.38, 110.78, 106.31, 55.39, 53.18, 52.58, 51.55, 41.55, 31.31, 26.97, 24.79, 23.17, 22.96, 22.08.

[0210] Implementation 38: Reaction steps to prepare Methyl (S)-2-((S)-2-acetamido-3-methylbutanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate:

[0211] In a 25 mL round bottom flask, methyl acetyl-L-valyl-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane, and then iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete as detected by TLC, at which point the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined, washed with saturated brine (15 mL x 3), dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0212] The structure and NMR data of the product obtained in Example 38, Methyl (S)-2-((S)-2-acetamido-3-methylbutanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3- yl)propanoate, are as follows:

[0213]

[0214] 1 H NMR (600 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.49 - 7.46 (m, 1H), 7.20 (dd, J = 7.7, 1.3 Hz, 1H), 7.12 - 7.07 (m, 4H), 6.86 (d, J = 8.7 Hz, 2H), 6.32 (d, J = 7.7 Hz, 1H), 6.09 (d, J = 8.9 Hz, 1H), 4.89 (d, J = 7.6 Hz, 1H), 4.20 (dd, J = 8.9, 6.2 Hz, 1H), 4.01 (s, 2H), 3.79 (s, 3H), 3.65 (s, 3H), 3.33 (dd, J = 6.0, 2.2 Hz, 2H), 2.00 - 1.95 (m, 1H), 1.92 (s, 3H), 0.86 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 172.21, 171.01, 169.97, 158.58, 135.80, 135.56, 130.19, 129.77, 128.58, 121.80, 119.79, 118.12, 114.40, 110.82, 106.07, 58.12, 55.43, 53.14, 52.63, 31.57, 26.97, 23.31, 19.49, 18.97, 18.01.

[0215] Example 39: Reaction steps to prepare Methyl (S)-2-((2S,3S)-2-acetamido-3- methylpentanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate:

[0216] In a 25 mL round bottom flask, methyl acetyl-L-isoleucyl-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-l,3-dithiane (0.2 mmol) were added sequentially, dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, at which point the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed in vacuo, and the product was obtained by column chromatography.

[0217] The structure and NMR data for the product from Example 39, Methyl (S)-2-((2S,3S)-2-acetamido-3-methylpentanamido)-3-(2-(4-methoxybenzyl)-lH-indol-3-yl)propanoate, are as follows:

[0218]

[0219] 1 H NMR (600 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.49 - 7.46 (m, 1H), 7.20 (d, J = 6.8 Hz, 1H), 7.13 - 7.07 (m, 4H), 6.86 (d, J = 8.6 Hz, 2H), 6.27 (d, J = 7.6 Hz, 1H), 6.04 (d, J = 8.8 Hz, 1H), 4.89 (d, J = 7.7 Hz, 1H), 4.22 (dd, J = 8.8, 6.5 Hz, 1H), 4.01 (s, 2H), 3.79 (s, 3H), 3.65 (s, 3H), 3.34 (d, J = 5.9 Hz, 2H), 2.09 - 2.06 (m, 1H), 1.92 (s, 3H), 1.06 - 0.90 (m, 2H), 0.85 - 0.82 (m, 6H). 13C NMR (101 MHz, Chloroform-d) δ 172.14, 170.88, 169.73, 158.65, 135.79, 135.56, 130.11, 129.81, 128.64, 121.83, 119.85, 118.12, 114.43, 110.80, 106.10, 57.54, 55.38, 53.05, 52.55, 37.88, 31.30, 26.97, 24.93, 23.31, 15.12, 11.51.

[0220] Example 40: Reaction steps to prepare Methyl (2S)-2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate:

[0221] In a 25 mL round bottom flask, methyl(((9H-fluoren-9-yl)methoxy)carbonyl)

[0222] In a 25 mL round bottom flask, methyl(((9H-fluoren-9-yl)methoxy)carbonyl)

[0223] The structure and NMR data of the product Methyl (2S)-2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate obtained in Example 40 is as follows:

[0224]

[0225] 1 H NMR (600 MHz, Chloroform-d) δ 7.77 (d, J = 7.7 Hz, 2H), 7.64 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.40 (s, 3H), 7.30 (s, 4H), 7.15 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.8 Hz, 5H), 6.82 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 6.20 (d, J = 7.9 Hz, 1H), 5.12 (d, J = 8.4 Hz, 1H), 4.85 (d, J = 6.9 Hz, 1H), 4.36 (d, J = 8.4 Hz, 1H), 4.27 (dd, J = 15.4, 8.0 Hz, 2H), 4.13 (d, J = 3.3 Hz, 1H), 3.91 (d, J = 2.6 Hz, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.62 (s, 2H), 3.27 (d, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 171.81, 170.39, 158.63, 158.58, 143.78, 141.31, 135.51, 135.40, 130.40, 129.97, 129.74, 128.66, 128.25, 127.72, 127.08, 125.08, 121.69, 119.97, 119.67, 117.96, 114.32, 114.07, 110.74, 106.17, 66.99, 55.28, 55.18, 53.17, 52.41, 47.14, 37.78, 31.22, 26.97.

[0226] Implementation 41: Reaction steps to prepare Methyl (S)-2-((S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-4-(methylthio)butanamido)-3-(2-(4-methoxybenzyl)- 1H-indol-3-yl)propanoate:

[0227] Into a 25 mL round bottom flask, methyl

[0228] (((9H-fluoren-9-yl)methoxy)carbonyl)-L-methionyl-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-l,3-dithiane (0.2 mmol) were dissolved in 15 mL of dichloromethane and iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until complete by TLC, then the reaction was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3) and the resulting organic extracts were combined, washed with saturated brine (15 mL x 3), dried over anhydrous Na2S04, filtered, and the volatiles were removed in vacuo. The product was purified by column chromatography.

[0229] The structure and NMR data for the product from Example 41, Methyl (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylthio)butanamido)-3-(2-(4- methoxybenzyl)-lH-indol-3-yl)propanoate, are as follows:

[0230]

[0231] 1 H NMR (600 MHz, Chloroform-d) δ 7.77 - 7.75 (m, 2H), 7.75 (s, 1H), 7.57 - 7.52 (m, 2H), 7.46 - 7.43 (m, 1H), 7.38 (t, J = 7.4 Hz, 3H), 7.31 - 7.26 (m, 3H), 7.15 (d, J = 7.8 Hz, 1H), 7.06 - 7.02 (m, 4H), 6.80 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 8.1 Hz, 1H), 5.35 (d, J = 8.5 Hz, 1H), 4.91 - 4.84 (m, 1H), 4.40 - 4.29 (m, 2H), 4.25 (d, J = 7.3 Hz, 1H), 4.17 (d, J = 7.0 Hz, 1H), 3.99 (s, 2H), 3.73 (s, 3H), 3.64 (s, 3H), 3.38 - 3.27 (m, 2H), 2.41 (d, J = 7.2 Hz, 2H), 1.96 (s, 5H). 13C NMR (151 MHz, Chloroform-d) δ 172.09, 170.76, 158.48, 155.78, 143.89, 141.30, 135.62, 135.44, 130.04, 129.68, 128.55, 127.74, 127.10, 125.09, 121.72, 120.00, 119.70, 118.01, 114.27, 110.76, 106.03, 66.92, 55.26, 53.51, 53.11, 52.54, 47.10, 31.97, 31.22, 29.69, 26.81, 14.96.

[0232] Example 42: Reaction steps for the preparation of Methyl (S)-2-(2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)acetamido)-3-(2-(4-methoxybenzyl)-1H-indol-3- yl)propanoate:

[0233] In a 25 mL round bottom flask, methyl

[0234] (((9H-fluoren-9-yl)methoxy)carbonyl)glycyl-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol) were dissolved in 15 mL of dichloromethane and then iodine and dimethylchlorosilane were added. The reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped. The mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The resulting organic extracts were combined and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0235] The structure and NMR data of the product Methyl (S)-2-(2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)acetamido)-3-(2-(4-methoxybenzyl)-1H-indol-3- yl)propanoate obtained in Example 42 are as follows:

[0236]

[0237] 1H NMR (600 MHz, Chloroform-d) δ 7.73 (d, J = 7.7 Hz, 2H), 7.52 (d, J = 7.3 Hz, 2H), 7.42 (s, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.4 Hz, 2H), 7.13 - 7.09 (m, 1H), 7.05 - 7.02 (m, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 6.59 (s, 1H), 5.29 (d, J = 8.1 Hz, 1H), 4.89 (d, J = 7.4 Hz, 1H), 4.29 (d, J = 7.2 Hz, 2H), 4.14 (s, 1H), 3.92 (d, J = 3.5 Hz, 2H), 3.70 (d, J = 1.7 Hz, 3H), 3.65 (d, J = 5.6 Hz, 2H), 3.60 (s, 3H), 3.30 (dd, J = 13.5, 5.8 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 172.34, 168.80, 158.59, 156.46, 143.92, 141.39, 135.71, 135.58, 130.32, 129.73, 128.72, 127.85, 127.21, 125.22, 121.76, 120.10, 119.74, 118.06, 114.36, 110.89, 106.24, 67.25, 55.38, 53.24, 52.64, 47.13, 44.29, 31.22, 26.91.

[0238] Implementation 43: Reaction steps to make (2S)-2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxybutanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate:

[0239] In a 25 mL round bottom flask, methyl(((9H-fluoren-9-yl)methoxy)carbonyl)azetidine-3-carboxylate (0.100 g, 0.25 mmol) was added followed by 2-(4-methoxybenzyl)-1H-indole-3-carboxylic acid (0.100 g, 0.33 mmol) and DMF (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC to give (2S)-2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxybutanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate (0.100 g, 0.17 mmol, 68% yield).

[0240] threonyl-L-tryptophanate (0.2 mmol) and 2-(4-methoxyphenyl)-l,3-dithiane (0.2 mmol), dissolved in 15 mL of dichloromethane, followed by addition of iodine and dimethylchlorosilane, the reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were combined and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum, and the product was obtained by column chromatography.

[0241] The structure and NMR data of the product obtained in Example 43, Methyl (2S)-2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxybutanamido)-3-(2-(4-methoxybenzyl)-lH-indol-3-yl)propanoate, are as follows:

[0242]

[0243] 1 H NMR (600 MHz, Chloroform-d) δ 7.77 - 7.74 (m, 2H), 7.69 (s, 1H), 7.54 (t, J = 8.0 Hz, 2H), 7.47 - 7.45 (m, 1H), 7.38 (s, 2H), 7.30 - 7.27 (m, 2H), 7.13 - 7.10 (m, 1H), 7.04 (d, J = 8.6 Hz, 4H), 6.93 (d, J = 7.8 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 5.63 (d, J = 7.9 Hz, 1H), 4.86 (d, J = 7.1 Hz, 1H), 4.38 (dd, J = 10.6, 7.1 Hz, 1H), 4.25 (s, 1H), 4.16 (d, J = 7.2 Hz, 2H), 4.06 (dd, J = 8.0, 2.7 Hz, 1H), 3.98 (d, J = 5.7 Hz, 2H), 3.75 (s, 3H), 3.65 (s, 3H), 3.30 (dd, J = 33.9, 6.3 Hz, 2H), 2.84 (d, J = 4.0 Hz, 1H), 1.08 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 172.40, 170.51, 158.62, 156.61, 143.88, 141.40, 135.63, 135.49, 130.08, 129.79, 128.60, 127.86, 127.20, 125.17, 121.84, 120.11, 119.77, 118.07, 114.37, 110.84, 106.22, 67.28, 58.59, 55.37, 53.36, 52.67, 47.17, 32.29, 31.32, 26.83, 17.86.

[0244] Example 44: Reaction steps to prepare Methyl (S)-2-((2S,3S)-2-((S)-2-acetamido-3- phenylpropanamido)-3-methylpentanamido)-3-(2-(4-methoxybenzyl)-1H-indol-3- yl)propanoate:

[0245] In a 25 mL round bottom flask, methyl

[0246] acetyl-L-phenylalanyl-L-isoleucyl-L-tryptophanate (0.2 mmol) and 2-(4- methoxyphenyl)-1,3-dithiane (0.2 mmol) were added sequentially and dissolved in 15 mL of dichloromethane followed by addition of iodine and dimethylchlorosilane. The reaction was stirred at room temperature until completion as monitored by TLC. The reaction was then quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane (15 mL). The organic layer was separated and the aqueous phase was re-extracted with dichloromethane (15 mL x 3). The organic extracts were combined and washed with saturated brine (15 mL x 3) and dried over anhydrous Na2S04, filtered and the volatiles were removed under vacuum. The product was obtained by column chromatography.

[0247] The structure and NMR data of the product obtained in Example 44, Methyl (S)-2- ((2S,3S)-2-((S)-2-acetamido-3-phenylpropanamido)-3-methylpentanamido)-3-(2-(4- methoxybenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0248]

[0249] 1 H NMR (600 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.48 (d, J = 7.3 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.6 Hz, 3H), 7.21 (t, J = 7.5 Hz, 2H), 7.16 (d, J = 8.6 Hz, 3H), 7.00 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 6.8 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 4.61 - 4.56 (m, 1H), 4.52 (d, J = 7.3 Hz, 1H), 4.30 (dd, J = 9.0, 7.3 Hz, 1H), 4.06 - 3.94 (m, 2H), 3.69 (s, 3H), 3.47 (s, 3H), 3.39 (s, 3H), 3.14 (dd, J = 51.5, 6.6 Hz, 2H), 2.95 (d, J = 4.0 Hz, 1H), 2.78 - 2.72 (m, 1H), 1.76 (s, 3H), 0.85 - 0.81 (m, 5H). 13 C NMR (101 MHz, DMSO-d6) δ 172.69, 171.69, 171.49, 169.74, 158.22, 138.59, 136.63, 136.05, 132.00, 129.86, 129.75, 129.66, 128.47, 126.66, 120.96, 118.91, 118.13, 114.36, 111.32, 106.19, 57.07, 55.52, 54.31, 53.89, 52.23, 37.79, 37.65, 31.09, 27.16, 24.63, 22.93, 15.64, 11.64.

[0250] Implementation 45: Reaction steps to make Methyl (S)-2-amino-3-(2-(4- methoxybenzyl)-1H-indol-3-yl)propanoate:

[0251] In a 25 mL round bottom flask, methyl L-tryptophanate (0.2 mmol) and

[0252] 2-(4-methoxyphenyl)-1,3-dithiane (0.2 mmol), dissolved in 15 mL of dichloromethane, was added with iodine and dimethylchlorosilane, the reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were mixed and washed with saturated brine (15 mL x 3), then dried with anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum, and the product was obtained by column chromatography.

[0253] The structure and NMR data of the product obtained in Example 45, Methyl (S)-2-amino-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoate, are as follows:

[0254]

[0255] 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (s, 1H), 7.61 - 7.53 (m, 1H), 7.22 - 7.17 (m, 1H), 7.14 - 7.07 (m, 4H), 6.84 (d, J = 8.7 Hz, 2H), 4.08 (s, 2H), 3.84 (dd, J = 8.1, 5.1 Hz, 1H), 3.79 (d, J = 0.8 Hz, 3H), 3.69 (d, J = 0.8 Hz, 3H), 3.35 - 3.01 (m, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 174.71, 157.46, 134.48, 129.28, 128.71, 127.54, 120.53, 118.48, 117.34, 113.22, 109.55, 106.50, 54.28, 51.06, 30.43, 29.01, 28.68.

[0256] Example 46: Reaction steps for preparing (S)-2-acetamido-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid:

[0257] In a 25 mL round-bottom flask, methyl L-tryptophanate (0.2 mmol) and

[0258] 2,2-diphenyl-1,3-dithiane (0.2 mmol), dissolved in 15 mL of dichloromethane, was added iodine and dimethylchlorosilane, the reaction was stirred at room temperature until the reaction was complete by TLC detection, then the reaction was stopped, the mixture was quenched with saturated aqueous sodium sulfite solution (10 mL) and extracted with dichloromethane (15 mL), the organic layer was separated, and the aqueous phase was re-extracted with dichloromethane (15 mL x 3), and the resulting organic extracts were combined and washed with saturated brine (15 mL x 3), then dried over anhydrous Na2SO4, filtered, and the volatiles were removed under vacuum, column chromatography to obtain the product.

[0259] The structure and NMR data of the product obtained in Example 46, (S)-2-acetamido-3-(2-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid, are as follows:

[0260]

[0261] 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.32 (dt, J = 11.5, 8.2 Hz, 5H), 7.22 (dd, J = 22.2, 7.4 Hz, 6H), 7.05 - 6.94 (m, 2H), 5.93 (s, 1H), 4.56 - 4.44 (m, 1H), 3.20 (dd, J = 14.4, 5.2 Hz, 1H), 3.04 (dd, J = 14.4, 8.5 Hz, 1H), 1.66 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 174.19, 169.80, 143.12, 143.06, 137.92, 136.60, 129.33, 129.28, 128.96, 128.82, 128.11, 126.95, 126.89, 121.22, 119.01, 118.45, 111.78, 108.32, 53.90, 47.44, 27.07, 22.93.

Claims

1. A method for preparing tryptophan compound III, characterized in that: In the reactor, formula I and formula II are added to react under the action of a promoter and silane to realize the synthesis of tryptophan compound III, and the reaction equation is as follows: The promoter used is one of iodine, trifluoroacetic acid, N-iodosuccinimide, and [bis(trifluoroacetyloxy)iodo]benzene; the silane used is one of dimethylchlorosilane, triethylsilane, triphenylsilane, triethoxysilane, diphenylsilane, and phenylsilane; the solvent used is one of 1,2-dichloroethane, chloroform, dichloromethane, nitromethane, toluene, and acetonitrile; and the temperature used is 0-60℃. R in the above reaction formulae 1 is selected from hydrogen, acetyl (Ac), 9-fluorenylmethyloxycarbonyl (Fmoc), 1-adamantylcarbonyl, benzo[d][l,3]dioxol-5-ylcarbonyl, 3,3-dimethylacryloyl, palmitoyl, 2-(l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl)acetyl, 2-acetoxybenzoyl; R 2 is selected from hydrogen, methyl, ethyl, benzylamino; R 3 and R 4 are selected from phenyl, substituted phenyl, alkenyl, indolyl, thienyl or carbazolyl, the substituted phenyl being meta- or para- or ortho-substituted and poly-substituted with different substituents being methyl, methoxy, chloro, bromo, ester, hydroxy.

2. The method of claim 1, wherein the preparation of a tryptophan analogue compound III is characterized by: The molar ratio of the promoter, the silane, formula I, and formula II is (0.5-2.0):(1.5-3.0):(0.1-2.0):(0.1-2.0).

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