Electrocatalytic oxidation modification method of indole skeleton-containing compound

Abstract

The application discloses an electrocatalytic oxidation modification method of a compound containing an indole skeleton, and specifically comprises the following steps: adding a polypeptide containing tryptophan shown in formula I or a derivative containing indole shown in formula III into a reaction bottle, adding a metal catalyst, a ligand, an electrolyte and a reaction solvent, introducing oxygen, and performing an electrooxidation reduction reaction at room temperature under the condition that an electrode is electrified; after the reaction is completed, a rotary evaporator is used to remove the solvent to obtain a crude product; and the crude product is further separated through column chromatography to obtain a pure product, i.e., a polypeptide compound containing a 3-hydroxy-2-indole ketone skeleton shown in formula II or a small molecule compound containing a 3-hydroxy-2-indole ketone skeleton shown in formula IV; and a reaction formula is as follows: The method is green and cheap oxygen as an oxygen source, and uses an electrochemical technology which is green to the environment and has high atomic economy, so that the use of an oxidant and an expensive catalyst is avoided, and the catalytic efficiency is high.

Description

Technical Field

[0001] The invention belongs to the field of late-stage modification of polypeptides or small molecules, and particularly relates to an electrocatalytic oxidation modification method for an indole skeleton-containing compound. Background Art

[0002] Among the 20 common amino acids, tryptophan has the lowest abundance, but is present in 90% of natural proteins. Tryptophan is a precursor of the human neurotransmitter serotonin and a chemical precursor of serotonin. It participates in the synthesis of melatonin and serotonin in animals and has the functions of regulating mood, sleep and behavior (Enzyme Microb.Tech.2023,165,110198-110204). With the development of peptide drugs, tryptophan has become a key part of modification in peptide drugs and biological activities (Nature.2019,576,459-464). Based on the special skeleton of the relatively complex indole ring in the tryptophan side chain and its low abundance, tryptophan is a very promising target for peptide modification.

[0003] The functional groups contained in the drug will affect the physicochemical properties of the whole drug molecule, affect the drug's liposolubility, solubility, and other physicochemical properties, and also affect the drug's charge density. When the functional groups change, the binding effect between the drug and the receptor will change, and in turn the drug's absorption and transport in the body will change. Natural drugs are limited by their original chemical structure, showing poor selectivity, unstable structure, poor solubility, strong side effects, low bioavailability, poor membrane permeability, short half-life, and other drawbacks (Nat. Chem. 2018, 10, 383-394). Therefore, in order to improve the adverse factors of these drugs, scientists will modify the structure of natural drugs (Front. Cell Dev. Biol. 2021, 9, 694363-694378). The 3-hydroxy-2-indolone skeleton is a key structural feature of many alkaloid natural products and important compounds with pharmacological and biological activity, with strong antioxidant, anticancer, anti-HIV, neuroprotective and other biological activities (Synthesis. 2009, 18, 3003-3025). For example, in 1995, Kamano's group first isolated the natural alkaloid containing 3-hydroxy-indolone skeleton small molecule Convolutamydine A from the Florida marine bryozoan. Studies have found that this alkaloid has strong inhibitory activity on the differentiation of HL-60 human promyelocytic leukemia cells in the concentration range of 0.1-25 mg / mL, and shows high anticancer activity (Org. Let. 2022, 24, 791-796). In addition, TMC-95A, which was first isolated from the fermentation broth of Montagnellia sp. Sacc. TC 109, is a cyclic tripeptide compound containing a 3-hydroxy-2-indolone skeleton, which is coupled by a tyrosine side chain and a highly oxidized tryptophan side chain. Studies have found that this compound is a highly selective and competitive proteasome inhibitor, which can bind to the enzyme in a non-covalent manner, and its IC 50 value is in the low nanomolar level (Org. Let, 2003, 5, 3435-3437).

[0004] Electrochemistry is a powerful and sustainable tool with advantages such as mild and green conditions, low energy consumption, high efficiency, convenience, high selectivity, and the absence of the need for additional oxidants. Currently, the use of electrochemical methods for tryptophan modification is still under development, and the modification sites are mostly concentrated at the C-2 position of the indole backbone of the tryptophan side chain. Combining electrochemistry with peptide modification overcomes the limitations of existing peptide synthesis and modification methods, creating a milder, highly selective, inexpensive, and sustainable method, undoubtedly paving a more gentle path for tryptophan modification and peptide modification. In summary, this greatly encouraged us to use tandem electrochemical hydroxylation reactions to modify the C-2 and C-3 positions of the indole backbone of the tryptophan side chain, introduce hydroxyl functional groups, and construct peptide compounds and small molecules containing a 3-hydroxy-2-indolone backbone. Summary of the Invention

[0005] In response to the above-mentioned technical problems existing in the prior art, the present invention aims to provide a method for electrocatalytic oxidation modification of compounds containing an indole skeleton. The present invention employs a one-pot tandem electrochemical hydroxylation reaction using a tryptophan-containing polypeptide compound or a small molecule compound containing an indole skeleton as a substrate to modify the C-2 and C-3 positions of the tryptophan chain residues at multiple sites, introducing hydroxyl functional groups. This method successfully constructs polypeptide compounds and small molecule compounds containing a 3-hydroxy-2-indolone skeleton. The present invention utilizes green and inexpensive oxygen as an oxygen source and utilizes environmentally friendly, atom-economical electrochemical technology, avoiding the use of oxidants and expensive catalysts, resulting in high catalytic efficiency.

[0006] The technical solution adopted in the present invention is as follows:

[0007] The electrocatalytic oxidation modification method for an indole-containing compound comprises the following steps: adding a tryptophan-containing polypeptide of Formula I or an indole-containing derivative of Formula III to a reaction flask, along with a metal catalyst, a ligand, an electrolyte, and a reaction solvent; introducing oxygen; and conducting an electrooxidation-reduction reaction at room temperature with the electrodes energized. After the reaction, the solvent is removed by vacuum distillation on a rotary evaporator to obtain a crude product. The crude product is further separated by column chromatography to obtain a pure product, a polypeptide compound containing a 3-hydroxy-2-indole skeleton of Formula II or a small molecule compound containing a 3-hydroxy-2-indole skeleton of Formula IV; the reaction formula is as follows:

[0008]

[0009] In formulas I and II, (AA) nrepresents a plurality of identical or different amino acids, n represents the number of amino acids, and n is an integer from 0 to 30; AA is glycine, alanine, serine, cysteine, threonine, valine, leucine, isoleucine, proline, methionine, phenylalanine, tyrosine, aspartic acid, asparagine, glutamic acid, pyroglutamic acid, pyroglutamine, glutamine, lysine, arginine or histidine; R 1 An amino terminal protecting group selected from hydrogen, phthaloyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methyl (or ethyl)oxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, tert-butyloxycarbonyl, acetyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl; R 2 is selected from hydrogen, methoxy, ethoxy, benzyl or tert-butyl ester and other carboxyl terminal protecting groups; in formula III and IV, R 3 is selected from C1-15 alkyl, wherein any -CH2- is substituted by -O-, -S-, -NH-, -CO-, -CN-, -CO-O- or -O-CO-, or is substituted by an alkyl group having 1-15 carbon atoms, an amide carboxyl group, an alcohol hydroxyl group, an ester group, a cyano group, an amino group, an aryl group or a halogen group; R 4 Selected from halogen, carboxyl, amide, C1-C4 alkyl, phenolic hydroxyl, ester, cyano or amino.

[0010] In the present invention, the tryptophan-containing polypeptide in the compound of formula I comprises a short peptide composed of amino acids and a dipeptide R protected at the N-terminus and the C-terminus. 1 -Trp-AA-R 2 、R 1 -AA-Trp-R 2 , tripeptide R 1 -Trp-AA-AA-R 2 、R 1 -AA-Trp-AA-R 2 、R 1 -AA-AA-Trp-R 2 , tetrapeptide R 1 -Trp-AA-AA-AA-R 2 、R 1 -AA-Trp-AA-AA-R 2 、R 1 -AA-AA-Trp-AA-R 2 、R 1 -AA-AA-AA-Trp-R 2 and pentapeptide R 1 -Trp-AA-AA-AA-AA-R 2 、R 1 -AA-Trp-AA-AA-AA-R 2 、R1 -AA-AA-Trp-AA-AA-R 2 、R 1 -AA-AA-AA-Trp-AA-R 2 、R 1 -AA-AA-AA-AA-Trp-R 2 As substrate. 1 An amino terminal protecting group selected from hydrogen, phthaloyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methyl (or ethyl)oxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, tert-butyloxycarbonyl, acetyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl; R 2 is selected from hydrogen, methoxy, ethoxy, benzyl or tert-butyl ester and other carboxyl terminal protecting groups; in formula III and IV, R 3 is selected from C1-15 alkyl, wherein any -CH2- is substituted by -O-, -S-, -NH-, -CO-, -CN-, -CO-O- or -O-CO-, or is substituted by an alkyl group having 1-15 carbon atoms, an amide carboxyl group, an alcohol hydroxyl group, an ester group, a cyano group, an amino group, an aryl group or a halogen group; R 4 Selected from halogen, carboxyl, amide, C1-C4 alkyl, phenolic hydroxyl, ester, cyano or amino.

[0011] In the present invention, the active peptide in the compound of formula I can be the following compounds:

[0012]

[0013] The electrocatalytic oxidation modification method for an indole skeleton-containing compound is characterized in that the metal catalyst is selected from the following: palladium, manganese, iron, copper, cobalt, titanium, aluminum, lithium, cobalt, or nickel compounds. The molar amount of the metal catalyst is 1-50%, preferably 5-8%, of the molar amount of the tryptophan-containing polypeptide of Formula I or the indole-containing derivative of Formula III.

[0014] Furthermore, the manganese compound is preferably a monovalent manganese catalyst Mn(CO)5Br, a divalent manganese catalyst MnF2, MnCl2, MnBr2, MnBr2·4H2O, MnI2, Mn(OAc)2, Mn(OAc)2·4H2O, MnSO4, MnO, Mn(OH)2, Mn(o-phen)2I2 (structure and high-resolution data characterization as shown in FIG. Figure 1 As shown), trivalent manganese catalyst Mn(acac)3, Mn(OAc)3·2H2O, Mn III (salen)(Cl), [Mn III (TPP)Cl]、[Mn IIIT4(-OMe)PPCl] or at least one of the tetravalent manganese catalyst MnO2.

[0015] Mn(o-phen)2I2(structure and high resolution data characterization Figure 1 Synthesis steps (shown): Dissolve the ligand 1,10-phenanthroline and MnI2 in CH3CN, reflux with stirring at 75°C under nitrogen, and monitor the reaction system by TLC. After the raw materials react completely, filter and collect the precipitate to obtain the corresponding metal catalyst.

[0016] The electrocatalytic oxidation modification method of an indole skeleton-containing compound is characterized in that the metal complex is any one of the substituted or unsubstituted phthalocyanine, porphyrin, oxazole, pyridine, salen, and other ligands shown in the following structural formula:

[0017]

[0018] wherein R represents a single or multiple substitution; when multiple Rs are present in any structure, the Rs may be the same or different; each R is independently selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted alkyl having 1-20 carbon atoms, substituted or unsubstituted cycloalkyl having 3-20 ring carbon atoms, substituted or unsubstituted heteroalkyl having 1-20 carbon atoms, substituted or unsubstituted aralkyl having 7-30 carbon atoms, substituted or unsubstituted alkoxy having 1-20 carbon atoms, acyl, carbonyl, carboxylic acid, nitro, ester, cyano, isocyano, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof; two adjacent substituents can optionally be linked to form a ring; the molar amount of the ligand is 2 to 100% of the molar amount of the tryptophan-containing polypeptide shown in Formula I or the indole-containing derivative shown in Formula III, preferably 10%.

[0019] The electrocatalytic oxidation modification method of the indole skeleton-containing compound is characterized in that the electrolyte is selected from one of the following: NH4I, NH4PF6, Me4NI, Et4NI, LiNO3, LiClO4, nMe4NBF4, Et4NBF4, nBu4NBF4, Me4NBF6, Et4NBF6, nBu4NPF6, nBu4NClO4, Me4NClO4, nBu4NI, nBu4NBr, nBu4NCl, nBu4NOAc, nBu4NHSO4, Et4NClO4, Me4NI, Et4NBF4, Et4NPF6; the molar amount of the electrolyte is 100-300% of the molar amount of the tryptophan-containing polypeptide shown in formula I or the indole-containing derivative shown in formula III, preferably 100%.

[0020] The electro-catalytic oxidation modification method of the indole skeleton-containing compound is characterized in that the reaction solvent comprises an organic solvent and a buffer-acid system; the buffer is a buffer composed of tris(hydroxymethyl) aminomethyl) ethane sulfonic acid and (tris(hydroxymethyl) aminomethane) (Tricine) with pH = 6-8, a mannitol buffer (MB) with pH = 6-8, a sulfonic acid buffer (HEPES) with pH = 6-8, a phosphate buffer (PB) with pH = 6-8, a phosphate buffer (PBS) with pH = 6-8, tris(hydroxymethyl) aminomethane (Tris) with pH = 6-8, and tris(hydroxymethyl) aminomethane hydrochloride (Tris-HCl) with pH = 6-8; the buffer-acid system is a mixed liquid system formed by adjusting the pH of the buffer to 5-8 with an acid, and the acid is at least one selected from formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, iso-octanoic acid, 2-dimethylbutyric acid, n-hexanoic acid, n-butyric acid, n-valeric acid, n-octanoic acid, 3-cyclohexylpropionic acid, 3-cyclopentylpropionic acid, 3-cyclooctylpropionic acid, 4-methylvaleric acid, 3-methylvaleric acid, 2-methylvaleric acid, cyclohexanoic acid, cyclooctanoic acid, cyclopentanoic acid, 1-phenylcyclopentane carboxylic acid, 1-methylcyclohexane carboxylic acid, and 1-phenyl-1-cyclohexane carboxylic acid;

[0021] The organic solvent is at least one selected from methanol, ethanol, isopropanol, hexafluoroisopropanol, propylene glycol, glycerol, tert-butyl alcohol, tert-amyl alcohol, benzene, toluene, xylene, methyl acetate, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, and 1,4-dioxane, and is preferably acetonitrile;

[0022] The volume ratio of the organic solvent to the buffer-acid system is 1:0.5-2, preferably 0.8-1.5:1, and more preferably 0.8-1:1;

[0023] The electro-catalytic oxidation modification method of the indole skeleton-containing compound is characterized in that the reaction temperature is 15-45°C, and the reaction time is 1-10 hours; the reaction temperature is preferably 25-30°C, and the reaction time is preferably 2-8 hours.

[0024] The electro-catalytic oxidation modification method of the indole skeleton-containing compound is characterized in that the electrode used in the reaction is at least one selected from GF, Ni, Sn, Al, Zn, Carbon rod, Pt, RVC, Carbon cloth, and GC as the anode, and at least one selected from GF, Ni, Sn, Al, Zn, Carbon rod, Pt, RVC, Carbon cloth, and GC as the cathode, and the electrode combination of the anode and the cathode is preferably GF-Pt.

[0025] The electrocatalytic oxidation modification method of the indole skeleton-containing compound is characterized in that the reaction voltage is 1-6V; the preferred reaction voltage is 1.5-4.5V.

[0026] The present invention has the following advantages:

[0027] (1) For the first time, green and inexpensive oxygen was used as an oxygen source for the direct hydroxylation of tryptophan under metal catalysis. The reaction system has high catalytic efficiency and mild reaction conditions.

[0028] (2) This method has excellent functional group compatibility and chemical and site selectivity;

[0029] (3) It uses environmentally friendly and atom-economical electrochemical technology, using only catalytic amounts of locally abundant manganese metal, thus avoiding the use of oxidants and expensive catalysts.

[0030] (4) The reaction conditions are mild and can be carried out at room temperature and buffer conditions;

[0031] (5) Gram-scale reactions can be carried out, which makes industrial production possible.

[0032] In summary, this invention utilizes environmentally friendly, atom-economical electrochemical technology to replace traditional reaction methods, avoiding the use of oxidants and expensive catalysts while achieving high catalytic efficiency. This one-pot method achieves hydroxylation modification of indole-containing compounds with excellent atom economy, high reaction efficiency, and good site selectivity. It also exhibits excellent functional group compatibility and a wide range of applications, making it a highly promising method for peptide modification. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is the structural formula and high-resolution data characterization results of Mn(o-phen)2I2;

[0034] Figure 2 The full liquid phase diagram and the enlarged liquid phase diagram of the modified leuprorelin (i.e., product 7) in Example 18 are shown;

[0035] Figure 3 This is the high-resolution mass spectrum of leuprorelin after modification in Example 18. DETAILED DESCRIPTION

[0036] The technical solutions of the present invention are described below with reference to specific embodiments (Examples 1-19), but the protection scope of the present invention is not limited thereto.

[0037] In the embodiment of the present invention, the tryptophan-containing polypeptide represented by Formula I is reacted under electrochemical conditions to prepare a polypeptide compound containing a 3-hydroxy-2-indolone skeleton represented by Formula II, and the reaction formula is as follows:

[0038]

[0039] The substituent R in formula II 1 、R 2 The substituents at the corresponding positions are the same as those in formula I.

[0040] Similarly, the indole-containing derivative shown in Formula III is reacted under electrochemical conditions to prepare a small molecule compound containing a 3-hydroxy-2-indolone skeleton shown in Formula IV, and the reaction formula is as follows:

[0041]

[0042] The substituent R in formula IV 3 、R 4 The substituents at the corresponding positions are the same as those in formula III.

[0043] Example 1: Compound I, a tryptophan-containing polypeptide, was prepared using the dipeptide substrate Ac-Trp-Val-OMe. Compound I (Ac-Trp-Val-OMe) (90 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), and a buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH 6-8 and mixed to form a buffer-acid system at pH 5-6). Conductive electrodes were installed in the reaction flask, using GF as the anode and Pt as the cathode. Electrolysis was carried out at 30°C under an oxygen atmosphere at a constant voltage of 2 V with stirring for 4 hours. After completion, the reaction system was removed from the solvent under reduced pressure and purified and separated by silica gel column chromatography (dichloromethane / methanol volume ratio = 25:1) to obtain a pair of diastereoisomers 1a and 1b. The total yield of the reaction was 82%.

[0044] Example 1 Compound II data characterization:

[0045]

[0046] 1a, 1H NMR(600 MHz,DMSO-d6)(600 MHz,DMSO-d6)δ10.25(s,1H),7.88(d,J=8.4Hz,1H),7.50(d,J=8.4 Hz,1H),7.22–7.17(m,2H),6.95(td,J=7.8,1.2 Hz,1H),6.76(d,J=7.8 Hz,1H),6.07(s,1H),4.23–4.19(m,1H),4.13(dd,J=8.4,6.0 Hz,1H),3.61(s,3H),2.30(dd,J=13.8,3.0 Hz,1H),2.06–1.98(m,2H),1.75(s,3H),0.83(d,J=7.2Hz,6H).

[0047] 13 C NMR(100 MHz,DMSO-d6)δ179.1,171.7,171.6,169.2,141.8,130.9,129.1,124.2,121.4,109.7,74.2,57.1,51.8,48.9,38.8,30.2,22.4,18.9,17.9.

[0048] HR-MS(ESI)m / z calcd.for C 19 H 26 N3O6[M+H] + :392.1822;found:392.1816.

[0049]

[0050] 1b, 1 H NMR(600 MHz,DMSO-d6)7.70(d,J=8.4 Hz,1H),7.66(d,J=8.4 Hz,1H),7.27(dd,J=7.2,1.2 Hz,1H),7.18(td,J=7.2,1.2Hz,1H),6.96(t,J=7.8 Hz,1H),6.77(d,J=7.8 Hz,1H),6.04(s,1H),4.31–4.27(m,1H),4.13(dd,J=8.4,6.0 Hz,1H),3.62(s,3H),2.19(dd,J=14.4,3.6 Hz,1H),2.09(dd,J=14.4,10.2 Hz,1H),2.05–1.97(m,1H),1.52(s,3H),0.82(d,J=6.6 Hz,6H).

[0051] 13 C NMR(100MHz,DMSO-d6)δ178.7,171.8,171.7,169.1,141.6,131.5,129.0, 124.7,121.6,109.8,74.7,57.2,51.9,49.2,38.1,30.2,22.3,19.0,18.0.

[0052] HR-MS(ESI)m / z calcd.for C 19 H 26 N3O6[M+H] + :392.1822; found:392.1816.

[0053] Example 2: The steps and materials of Example 2 are exactly the same as those of Example 1, except that the metal catalyst MnF2 is replaced by the same molar amount of Mn(o-phen)2I2 (structure and high-resolution data characterization are as follows Figure 1 49 mg of product was obtained, with an overall reaction yield of 50%.

[0054] Mn(o-phen)2I2(structure and high resolution data characterization Figure 1 Synthesis steps (shown): Dissolve the ligand 1,10-phenanthroline (2.00 mmol) and MnI2 (1.00 mmol) in 5 mL of CH3CN. Stir and reflux at 75°C under nitrogen. Monitor the reaction system by TLC. After the raw materials react completely, the precipitate is filtered to obtain the corresponding metal catalyst, totaling 602.00 mg, for a yield of 90%.

[0055] Example 3: The steps and materials added in Example 3 are exactly the same as those in Example 1, except that the ligand 1,10-phenanthroline is replaced by the same molar amount of 4,4'-di-tert-butyl-2,2'-bipyridine to obtain 39 mg of product with a total reaction yield of 40%.

[0056] Example 4: The steps and materials added in Example 4 are exactly the same as those in Example 1, except that the ligand 1,10-phenanthroline is replaced by the same molar amount of 4,4'-diamino-2,2'-bipyridine to obtain 20 mg of product with a total reaction yield of 21%.

[0057] Example 5: The steps and materials added in Example 5 are exactly the same as those in Example 1, except that the ligand 1,10-phenanthroline is replaced by the same molar amount of 5-nitro-1,10-phenanthroline to obtain 12 mg of product with a total reaction yield of 13%.

[0058] Example 6: The steps and added materials of Example 6 are exactly the same as those of Example 1, except that the reaction electrolyte is adjusted to the same molar amount of lithium perchlorate, to obtain 76 mg of product, with a total reaction yield of 78%.

[0059] Example 7: The steps and added materials of Example 7 are exactly the same as those of Example 1, except that the reaction electrolyte is adjusted to the same molar amount of tetrabutylammonium tetrafluoroborate, to obtain 54 mg of product, and the total reaction yield is 56%.

[0060] Example 8: The steps and added materials of Example 8 are exactly the same as those of Example 1, except that the reaction electrolyte is adjusted to the same molar amount of tetrabutylammonium hexafluorophosphate, to obtain 41 mg of product, with a total reaction yield of 43%.

[0061] Example 9: The steps and added materials of Example 9 are exactly the same as those of Example 1, except that the reaction solvent MeCN (1.5 mL) is replaced by DMF (1.5 mL). 27 mg of product is obtained, and the total yield of the reaction is 28%.

[0062] Example 10: The steps and added materials of Example 10 are exactly the same as those of Example 1, except that the constant voltage of 2V is adjusted to 3V. 62 mg of product is obtained, and the total yield of the reaction is 64%.

[0063] Example 11: The steps and added materials of Example 11 are exactly the same as those of Example 1, except that the reaction constant voltage of 2V is adjusted to a constant current of 4mA, and 56mg of product is obtained, with a total reaction yield of 58%.

[0064] Example 12: The steps and added materials of Example 12 are exactly the same as those of Example 1, except that the reaction constant voltage of 2V is adjusted to a constant current of 6mA, and 69mg of product is obtained, with a total reaction yield of 71%.

[0065] Example 13: Compound I (Ac-Trp-Tyr-OMe) (106 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), and a buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH 6-8 and mixed to form a buffer-acid system at pH 5-6) were added to a clean, dry 10 mL reaction flask. Conductive electrodes were installed in the reaction flask, using GF as the anode and Pt as the cathode. Electrolysis was carried out at 30°C under an oxygen atmosphere at a constant voltage of 2 V with stirring for 4.0 hours. After completion, the reaction system was removed from the solvent under reduced pressure and purified and separated by silica gel column chromatography (dichloromethane / methanol volume ratio = 25:1) to obtain a pair of diastereoisomers 2a and 2b. The total yield of the reaction was 60%.

[0066] Example 13 Compound II data characterization:

[0067]

[0068] 2a, 1 H NMR (400MHz, DMSO-d6): δ10.20(s,1H),9.25(s,1H),7.74(d,J=8.8Hz,1H),7.57(d,J=7.2Hz,1H),7.21–7.16(m,2H),6.95–6.90(m, 3H),6.75(d,J=7.6Hz,1H),6.66–6.62(m,2H),6.01(s,1H),4.35–4.30(m,1H),4.19–4.13(m,1H),3.57(s,3H),2.87(dd,J=13.6,5.6 Hz,1H),2.79(dd,J=14.0,7.6 Hz, 1H), 2.30 (dd, J=14.0, 3.2Hz, 1H), 1,98 (dd, J=14.0, 9.6 Hz, 1H), 1.73 (s, 3H).

[0069] 13 C NMR(100 MHz, DMSO-d6)δ179.0,171.6,171.3,169.0,156.0,141.9,130.9,130.0,129.1 ,126.6,124.2,121.4,115.1,109.6,74.2,53.7,51.8,48.6,35.9,31.0,22.4.

[0070] HR-MS (ESI) m / z calcd for C 23 H 26 N3O7[M+H] + :456.1771;found:456.1758.

[0071]

[0072] 2b, 1 H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.26 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.96 - 6.90 (m, 3H), 6.76 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 8.0 Hz, 2H), 5.97 (s, 1H), 4.36 - 4.31 (m, 1H), 4.28 - 4.22 (m, 1H), 3.58 (s, 3H), 2.89 - 2.76 (m, 2H), 2.18 (dd, J = 14.4, 3.2 Hz, 1H), 2.05 (dd, J = 14.0, 10.0 Hz, 1H), 1.49 (s, 3H).

[0073] 13 C NMR (100 MHz, DMSO-d6) δ 178.6, 171.6, 171.3, 168.7, 156.0, 141.6, 131.4, 130.0, 128.8, 126.7, 124.6, 121.4, 115.0, 109.6, 74.6, 53.7, 51.8, 48.8, 37.9, 35.8, 22.2.

[0074] HR-MS (ESI) m / z calcd for C 23 H 26 N3O7[M+H] + :456.1771;found:456.1758.

[0075] Example 14: To a clean, dry 10 mL reaction flask were added Compound I (Ac-Trp-Val-Thr-OMe) (115.1 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), and a buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH 6-8 and mixed to form a buffer-acid system at pH 5-6). Conductive electrodes were installed in the reaction flask, using GF as the anode and Pt as the cathode. Electrolysis was carried out at 30°C under an oxygen atmosphere at a constant voltage of 2 V with stirring for 4.0 hours. After completion, the reaction system was removed from the solvent under reduced pressure and purified and separated by silica gel column chromatography (dichloromethane / methanol volume ratio = 20:1) to obtain a pair of diastereoisomers 3a and 3b. The total yield of the reaction was 61%.

[0076] Example 14 Compound II data characterization:

[0077]

[0078] 3a, 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.15(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.33(d,J=8.8Hz,1H),7.27( d,J=7.2Hz,1H),7.17(t,J=7.6Hz,1H),6.95(t,J=7.2Hz,1H),6.76(d,J=7.6Hz,1H),6.01(s,1H),4.32(dd,J=9. 2,6.4Hz,1H),4.27-4.22(m,2H),4.11–4.06(m,1H),3.60(s,3H),2.23(dd,J=14.4,3.2Hz,1H),2.11(dd,J=14.0 ,10.0,1H),2.03–1.94(m,1H),1.49(s,3H),1.05(d,J=6.0Hz,3H),0.83(d,J=6.8Hz,3H),0.78(d,J=6.8Hz,3H).

[0079] 13C NMR(100MHz,DMSO-d6)δ178.7,171.3,171.1,171.0,168.8,141.6,131.5,128.9,124.7,121.5,109.7,74.7,66.2,58.1,56.8,51.8,49.4,38.2,31.1,22.2,20.1,19.1,17.5.

[0080] HR-MS(ESI)m / z calcd for C 23 H 31 N4O8[M-H] - :491.2142;found:491.2142.

[0081]

[0082] . 3b, 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.12(d,J=8.0Hz,1H),7.95(d,J=8.4Hz,1H),7.24–7.16(m,3H),6.94(t,J=7.6Hz,1H),6.76(d,J=7.6Hz,1H),4.32(dd,J=9.2,6.4Hz,1H),4.21(dd,J=8.0,3.6Hz,1H),4.17–4.11(m,1H),4.09–4.05(m,1H),3.60(s,3H),2.33(d,J=14.4,2.8Hz,1H),2.05(d,J=14.0,9.6Hz,1H),2.00–1.94(m,1H),1.74(s,3H),1.04(d,J=6.0Hz,3H),0.83(d,J=6.8Hz,3H),0.81(d,J=6.8Hz,3H).

[0083] 13 C NMR(100MHz,DMSO-d6)δ179.1,171.2,171.1,170.9,169.2,141.9,131.0,129.1,124.2,121.4,109.7,74.3,66.1,58.1,56.7,51.8,49.1,39.0,31.1,22.4,20.1,19.1,17.5.

[0084] HR-MS(ESI)m / z calcd for C 23 H 31 N4O8[M-H] -:491.2142;found:491.2141.

[0085] Example 15: Compound I (Ac-Trp-Ala-Val-Phe-OMe) (144.3 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), and a buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH 6-8 and mixed to form a buffer-acid system at pH 5-6). Conductive electrodes were installed in the reaction flask, using GF as the anode and Pt as the cathode. Electrolysis was carried out at 30°C under an oxygen atmosphere at a constant voltage of 2 V and stirred for 4.0 hours. After completion, the reaction system was separated and the solvent removed under reduced pressure. The diastereoisomers 4a and 4b were purified by silica gel column chromatography to obtain a pair of products in a total yield of 50%.

[0086] Example 15 Compound II data characterization:

[0087]

[0088] 4a, 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.38(d,J=7.2Hz,1H),7.73(d,J=8.8Hz,1H),7.70–7.65(m,2H),7.28–7.23(m,3 H),7.21–7.15(m,4H),6.94(t,J=7.2Hz,1H),6.76(d,J=7.6Hz,1H),6.01(s,1H),4.48–4.43(m,1H),4.29–4.21(m,2H) ,4.12(dd,J=8.8,6.8Hz,1H),3.55(s,3H),3.01(dd,J=13.6,5.6Hz,1H),2.91(dd,J=14.0,8.8Hz,1H),2.21(dd,J=14. 0,3.2Hz,1H),2.06(dd,J=14.0,10.0Hz,1H),1.94–1.86(m,1H),1.52(s,3H),1.10(d,J=7.2Hz,3H),0.79–0.76(m,6H).

[0089] 13C NMR(100MHz,DMSO-d6)δ178.7,171.8,171.7,171.0,168.8,141.6,137.1,131.5,129.0,128.9,128.2,126.5,124.6,121.4,109.6,74.7,57.4,53.5,51.7,49.2,48.0,38.3,36.5,30.7,22.3,19.0,18.1,18.0.

[0090] HR-MS(ESI)m / z calcd for C 31 H 38 N5O8[M-H] - :608.2720;found:608.2715.

[0091]

[0092] 4b,(400MHz,DMSO-d6)δ10.23(s,1H),8.39(d,J=7.2Hz,1H),7.81(d,J=8.4Hz,1H),7.74(d,J=9.2Hz,1H),7.60(d,J=7.2Hz,1H),7.27–7.15(m,7H),6.93(t,J=7.2Hz,1H),6.75(d,J=7.6Hz,1H),4.49–4.43(m,1H),4.26–4.21(m,1H),4.19–4.09(m,2H),3.55(s,3H),3.01(dd,J=13.6,5.6Hz,1H),2.92(dd,J=13.6,8.8Hz,1H),2.32(dd,J=14.0,3.2Hz,1H),2.00(dd,J=14.4,10.0Hz,1H),1.94–1.85(m,1H),1.74(s,3H),1.11(d,J=6.8Hz,3H),0.79–0.75(m,6H).

[0093] 13 C NMR(100MHz,DMSO-d6)δ179.1171.8,171.6,171.0,171.0,169.0,141.9,137.1,131.0,129.1,129.0,128.2,126.5,124.3,121.4,109.6,74.3,57.4,53.5,51.7,48.9,48.0,39.0,36.5,30.6,22.5,19.1,18.1,18.0.

[0094] HR-MS(ESI)m / z calcd for C 31 H 38 N5O8[MH] - :608.2720; found:608.2716.

[0095] Example 16: Compound I (Ac-Gly-Phe-Ala-Val-Trp-OH) (173.1 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), and a buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH 6-8 and mixed to form a buffer-acid system at pH 5-6) were added to a clean, dry 10 mL reaction tube. Conductive electrodes were installed in the reaction tube, using GF as the anode and Pt as the cathode. Electrolysis was carried out at 30°C under an oxygen atmosphere at a constant voltage of 2 V with stirring for 4.0 hours. After completion, the reaction system was decompressed to remove the solvent, and the mixture was purified and separated by silica gel column chromatography to obtain a pair of diastereoisomers 5a and 5b. The total yield of the reaction was 45%.

[0096] Example 16 Compound II data characterization:

[0097]

[0098] 5a, 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.30(d,J=7.2Hz,1H),8.06–8.01(m,3H),7.62(d,J=9.2Hz,1H),7.26–7.21(m,5H),7.2 0–7.15(m,2H),6.92(t,J=7.6Hz,1H),6.77(d,J=8.0Hz,1H),4.57–4.51(m,1H),4.42–4.34(m,2H),4.10(dd,J=8.8,6.0Hz,1H ),3.68(dd,J=16.4,5.6Hz,1H),3.52(dd,J=16.8,5.6Hz,1H),3.01(dd,J=13.6,3.6Hz,1H),2.75(dd,J=13.6,9.6Hz,1H),2.2 9(dd,J=14.0,4.8Hz,1H),2.01–1.90(m,2H),1.81(s,3H),1.26(d,J=7.2Hz,3H),0.82(d,J=6.8Hz,3H),0.78(d,J=6.4Hz,3H).

[0099] 13 C NMR(100MHz,DMSO-d6)δ179.1,173.2,171.8,170.8,170.3,169.6,168.8,141.5,137.8,129.3,129.01,128.96,128.0,126.3,124.7,121.5,109.6,74.1,57.1,53.6,48.3,47.9,41.9,38.7,37.6,31.0,22.4,19.2,17.9,17.7.

[0100] HR-MS(ESI)m / z calcd for C 32 H 41 N6O9[M+H] + :653.2935;found:653.2933.

[0101]

[0102] 5b,1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.25(d,J=7.6Hz,1H),8.06–8.01(m,2H),7.75–7.67(m,J=9.2Hz,1H),7.24–

[0103] 7.12(m,8H),6.89(t,J=7.2Hz,1H),6.75(d,J=8.0Hz,1H),4.55–

[0104] 4.50(m,1H),4.40–4.32(m,2H),4.02(dd,J=9.2,5.6Hz,1H),3.67(dd,J=16.4,5.6Hz,1H),3.52(dd,J=16.8,5.6Hz,1H),2.99(dd,J=13.6,4.0Hz,1H),2.74(dd,J=13.6,9.6Hz,1H),2.07–1.92(m,3H),1.81(s,3H),1.26–1.23(m,3H),0.80(d,J=6.8Hz,3H),0.76(d,J=6.8Hz,3H).

[0105] 13C NMR (100MHz, DMSO-d6) δ179.0,173.2,171.8,170.8,170.2,169.5,168.8,141.5,137.8,129.2,128.9,128. 0,126.2,124.6,121.5,109.6,74.0,57.0,53.6,48.3,41.9,40.1,38.7,37.6,30.9,22.4,19.1,17.9,17.6.

[0106] HR-MS(ESI)m / z calcd for C 32 H 41 N6O9[M+H] + :653.2935; found:653.2933.

[0107] Example 17: To a clean, dry 10 mL reaction tube, Compound I (endorphin) (30.1 mg, 0.05 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), a buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH 6-8 and mixed to form a buffer-acid system at pH 5-6), and acetonitrile (1.5 mL) were added. Conductive electrodes were installed in the reaction flask, using GF as the anode and Pt as the cathode. Electrolysis was carried out at a constant voltage of 2 V and stirred at 30°C under an oxygen atmosphere for 15 minutes. After completion, product 6 was obtained by preparative liquid phase separation and purification, with a reaction yield of 30%.

[0108]

[0109] High-resolution data characterization of product 6:

[0110] HR-MS(ESI)m / z calcd.for C 34 H 39 N6O7[M+H] + :643.2802; found:643.2800.

[0111] Example 18: Compound I (leuprorelin) (24.8 mg, 0.02 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), and a buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH 6-8 and mixed to form a buffer-acid system at pH 5-6). Conductive electrodes were installed in the reaction flask, using GF as the anode and Pt as the cathode. Electrolysis was carried out at a constant voltage of 2 V and stirred at 30°C under an oxygen atmosphere for 20 minutes. After completion, the reaction system was separated, the solvent was removed under reduced pressure, and product 7 was purified by preparative liquid phase chromatography to obtain product 7 in a reaction yield of 24%.

[0112] High-resolution data characterization of product 7:

[0113] HR-MS(ESI)m / z calcd.for C 59 H 84 N 16 O 14 [M+H] + :1241.6426; found:1241.6392.

[0114] The full liquid phase diagram and enlarged liquid phase diagram of modified leuprorelin (i.e., product 7) in Example 18 are as follows: Figure 2 As shown, it can be seen that after modification, a hydroxyl group was introduced at the indole C3 position of leuprorelin, and the retention time was 10.326 min.

[0115] The high-resolution mass spectrum of leuprorelin after modification in Example 18 is as follows Figure 3 As shown in the figure, it can be seen that a hydroxyl group is introduced into the indole C3 position of leuprorelin after modification, with a retention time of 10.326 min. The product obtained after modification has a mass of [M+H] + :1241.6426.

[0116] Example 19: Compound III (3-indoleacetone) (43 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), and a buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH 6-8 and mixed to form a buffer-acid system at pH 5-6). Conductive electrodes were installed in the reaction flask, using GF as the anode and Pt as the cathode. Electrolysis was carried out at a constant voltage of 2 V and stirred at 30°C under an oxygen atmosphere for 4 hours. After completion, the reaction system was separated, the solvent was removed under reduced pressure, and product 8 was isolated by column chromatography with a reaction yield of 67%.

[0117] Example 19 Compound IV Product Data Characterization:

[0118]

[0119] 1 H NMR (400 MHz, DMSO-d6) δ10.21 (s, 1H), 7.24 (dd, J=7.2Hz, 1.2 Hz, 1H), 7.17 (td, J=7.6 Hz, 1.6 Hz, 1H), 6.90 (td, J=7.2, 0.8Hz, 1H), 6.77 (d, J=7.6 Hz,1H),5.97(s,1H),3.27(d,J=16.8 Hz,1H),3.00(d,J=16.4 Hz,1H),2.00(s,3H).

[0120] 13 C NMR (100 MHz, DMSO-d6) δ205.2,178.2,142.5,131.5,129.0,123.7,121.2,109.4,72.7,50.3,30.6.

[0121] HR-MS(ESI): m / z calcd.for C 11 H 11 NNaO3[M+Na] + :228.0637;found:228.0633.

Claims

1. A method for electrocatalytic oxidation modification of an indole skeleton compound, characterized in that The method comprises the following steps: adding a tryptophan-containing polypeptide represented by Formula I or an indole-containing derivative represented by Formula III into a reaction flask, and adding a metal catalyst, a ligand, an electrolyte and a reaction solvent, introducing oxygen, and performing an electric redox reaction at room temperature with the electrodes energized; after the reaction, removing the solvent by reduced pressure distillation on a rotary evaporator to obtain a crude product; and further separating the crude product by column chromatography to obtain a pure product, a 3-hydroxy-2-indole-containing skeleton polypeptide compound represented by Formula II or a small molecule compound represented by Formula IV containing a 3-hydroxy-2-indole-containing skeleton; the reaction formula is as follows: ； In formulas I and II, (AA) n represents a plurality of identical or different amino acids, n represents the number of amino acids, and n is an integer from 0 to 30; AA is glycine, alanine, serine, cysteine, threonine, valine, leucine, isoleucine, proline, methionine, phenylalanine, tyrosine, aspartic acid, asparagine, glutamic acid, pyroglutamic acid, pyroglutamine, glutamine, lysine, arginine or histidine; R 1 an amino terminal protecting group selected from hydrogen, phthaloyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, tert-butyloxycarbonyl, acetyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl; R 2 is selected from hydrogen, methoxy, ethoxy, benzyl or tert-butyl ester carboxyl terminal protecting group; wherein, R 1 、R 2 When H is selected, it means no protecting group is used; In formula III and IV, R 3 is selected from C1-15 alkyl groups, wherein any -CH2- is substituted by -O-, -S-, -NH-, -CO-, -CN-, -CO-O-, or -O-CO-, or is substituted by an alkyl group having 1 to 15 carbon atoms, an amide carboxyl group, an alcohol hydroxyl group, an ester group, a cyano group, an amino group, an aryl group, or a halogen group; R 4 Selected from halogen, carboxyl, amide, C1-C4 alkyl, phenolic hydroxyl, ester, cyano or amino.

2. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The metal catalyst is selected from one of the following: palladium, manganese, iron, copper, titanium, aluminum, lithium, cobalt or nickel compounds; the molar amount of the metal catalyst is 1-50% of the molar amount of the tryptophan-containing polypeptide represented by formula I or the indole-containing derivative represented by formula III.

3. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 2, characterized in that The molar amount of the metal catalyst is 5-8% of the molar amount of the tryptophan-containing polypeptide represented by Formula I or the indole-containing derivative represented by Formula III; The metal catalyst is a manganese compound selected from monovalent manganese catalyst Mn(CO)5Br, divalent manganese catalyst MnF2, MnCl2, MnBr2, MnBr2·4H2O, MnI2, Mn(OAc)2, Mn(OAc)2·4H2O, MnSO4, MnO, Mn(OH)2, Mn( o -phen)2I2, trivalent manganese catalyst Mn(acac)3, Mn(OAc)3·2H2O, Mn III (salen)(Cl), [Mn III (TPP)Cl]、[Mn III T4(-OMe)PPCl] or at least one of the tetravalent manganese catalyst MnO2.

4. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The ligand is any one of substituted or unsubstituted phthalocyanine, porphyrin, oxazole, pyridine, and salen ligands: ； wherein R represents a single or multiple substitution; when multiple Rs are present in any structure, the Rs may be the same or different; each R is independently selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted alkyl having 1-20 carbon atoms, substituted or unsubstituted cycloalkyl having 3-20 ring carbon atoms, substituted or unsubstituted heteroalkyl having 1-20 carbon atoms, substituted or unsubstituted aralkyl having 7-30 carbon atoms, substituted or unsubstituted alkoxy having 1-20 carbon atoms, acyl, carbonyl, carboxylic acid, ester, nitro, cyano, isocyano, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof; two adjacent substituents can optionally be linked to form a ring; and the molar amount of the ligand is 2 to 100% of the molar amount of the tryptophan-containing polypeptide shown in Formula I or the indole-containing derivative shown in Formula III.

5. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 4, characterized in that The molar amount of the ligand is 10% of the molar amount of the tryptophan-containing polypeptide shown in Formula I or the indole-containing derivative shown in Formula III.

6. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The electrolyte is selected from one of the following: NH4I, NH4PF6, Me4NI, Et4NI, LiNO3, LiClO4, nMe4NBF4, Et4NBF4, nBu4NBF4, Me4NBF6, Et4NBF6, nBu4NPF6, nBu4NClO4, Me4NClO4, nBu4NI, nBu4NBr, nBu4NCl, nBu4NOAc, nBu4NHSO4, Et4NClO4, Me4NI, Et4NBF4, Et4NPF6; the molar amount of the electrolyte is 100-300% of the molar amount of the tryptophan-containing polypeptide shown in Formula I or the indole-containing derivative shown in Formula III.

7. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 6, characterized in that The molar amount of the electrolyte is 100% of the molar amount of the tryptophan-containing polypeptide shown in Formula I or the indole-containing derivative shown in Formula III.

8. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The reaction solvent includes an organic solvent and a buffer-acid system; the buffer is a buffer composed of tris(hydroxymethyl)aminomethyl)ethanesulfonic acid and (tris(hydroxymethyl)aminomethane) at pH = 6~8 (Tricine), mannitol buffer (MB) at pH = 6~8, sulfonic acid buffer (HEPES) at pH = 6~8, phosphate buffer (PB) at pH = 6~8, phosphate buffer (PBS) at pH = 6~8, tris(hydroxymethyl)aminomethane (Tris) at pH = 6~8, 6-8 tris(hydroxymethylaminomethane) hydrochloric acid (Tris-HCl); the buffer-acid system is a mixed liquid system formed by adjusting the buffer solution pH to 5-8 with an acid, and the acid is selected from at least one of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, isooctanoic acid, 2,2-dimethylbutyric acid, n-hexanoic acid, n-butyric acid, n-pentanoic acid, n-octanoic acid, 3-cyclohexylpropionic acid, 3-cyclopentylpropionic acid, 3-cyclooctylpropionic acid, 4-methylpentanoic acid, 3-methylpentanoic acid, 2-methylpentanoic acid, cyclohexanoic acid, cyclooctanoic acid, cyclopentanoic acid, 1-phenylcyclopentanecarboxylic acid, 1-methylcyclohexanecarboxylic acid, and 1-phenyl-1-cyclohexanecarboxylic acid; The organic solvent is selected from methanol, ethanol, isopropanol, hexafluoroisopropanol, propylene glycol, glycerol, tert-butyl alcohol, tert-amyl alcohol, benzene, toluene, xylene, methyl acetate, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, N,N - at least one of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, and 1,4-dioxane; The volume ratio of organic solvent to buffer-acid system is 1:0.5~2.

9. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 8, characterized in that The organic solvent is selected from acetonitrile, and the volume ratio of the organic solvent to the buffer-acid system is 0.8-1.5:

1.

10. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 9, characterized in that The organic solvent is selected from acetonitrile, and the volume ratio of the organic solvent to the buffer-acid system is 0.8-1:

1.

11. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The reaction temperature is 15-45° C., and the reaction time is 1-10 hours.

12. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 11, characterized in that The reaction temperature is 25-30°C, and the reaction time is 2-8 hours.

13. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The electrodes used in the reaction are one of the following: the anode is at least one of GF, Ni, Sn, Al, Zn, Carbon rod, Pt, RVC, Carbon cloth, and GC; the cathode is at least one of GF, Ni, Sn, Al, Zn, Carbon rod, Pt, RVC, Carbon cloth, and GC.

14. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 13, characterized in that The electrode combination of the anode and cathode is GF-Pt.

15. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The voltage of the reaction is 1~6 V.

16. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 15, characterized in that The voltage of the reaction is 1.5-4.5 V.

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