Electrocatalytic phosphorylation modification method of indole skeleton-containing compound

Abstract

The invention discloses an electrocatalytic phosphorylation modification method of an indole skeleton-containing compound, which specifically comprises the following steps: adding tryptophan-containing polypeptide as shown in a formula I or an indole-containing derivative as shown in a formula III into a reaction bottle, adding a phosphorus source, a manganese metal catalyst, an alkaline substance, an electrolyte and a reaction solvent, introducing nitrogen, reacting for 2-4 hours at the temperature of 60-80 DEG C, and filtering, thereby obtaining the indole skeleton-containing compound. Carrying out electrooxidation reduction reaction under the condition that the electrodes are electrified; after the reaction is finished, carrying out reduced pressure distillation through a rotary evaporator to remove the solvent to obtain a crude product; further performing column chromatography separation on the crude product to obtain a pure product which is a tryptophan side chain indole C-2 phosphorylated polypeptide compound as shown in a formula II or a small molecule compound as shown in a formula IV, wherein the tryptophan side chain indole C-2 phosphorylated polypeptide compound is shown in a formula II; according to the method disclosed by the invention, green and cheap nitrogen is used as a protective gas, an electrochemical technology which is green and friendly to the environment and high in atom economy is applied, the use of an expensive catalyst is avoided, and the catalytic efficiency is high.

Description

Technical Field

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

[0002] Phosphorylation, the most common peptide post-translational modification (PTM) in living organisms, plays a central role in regulating protein function, particularly influencing cell signaling and cell cycle progression. Existing research has confirmed that phosphorylation of peptide chains can significantly alter their transmembrane transport capacity, physicochemical properties, and biological activity, providing important insights into innovative drug development.

[0003] In the field of chemical synthesis, a variety of mature methods have been developed for the phosphorylation modification of peptides. The reaction mechanism mainly relies on the nucleophilic attack of nucleophilic amino acid residues such as serine (Ser), tyrosine (Tyr), and threonine (Thr) on electrophilic phosphorus reagents. It is worth noting that although the abundance of tryptophan (Trp) in proteins is only 1.3%, it is widely present in the primary structure of more than 90% of natural proteins. The unique indole ring structure of this amino acid and its low abundance in proteins make it a high-value target in chemical modification research, especially showing great potential in late-stage functional modification.

[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 the addition of oxidants. Currently, electrochemical methods for tryptophan modification are 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. This undoubtedly paves a more gentle path for tryptophan modification and peptide modification. 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 phosphorylation modification of compounds containing an indole skeleton. This method employs a one-pot cascade electrochemical phosphorylation reaction using a tryptophan-containing polypeptide compound or an indole-containing small molecule compound as a substrate to phosphorylate the C-2 residue of the tryptophan chain. By introducing diphenylphosphine oxide and its derivatives, the method successfully constructs polypeptide compounds and small molecule compounds containing a diphenylphosphine oxide skeleton. This method utilizes inexpensive manganese metal as a catalyst and employs environmentally friendly, atom-economical electrochemical technology, avoiding the use of catalytic agents and expensive catalysts, resulting in high catalytic efficiency.

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

[0007] A method for electrocatalytic phosphorylation modification of an indole skeleton-containing compound is characterized by comprising the following steps: adding a tryptophan-containing polypeptide of Formula I or an indole-containing derivative of Formula III to a reaction flask, and adding a phosphorus source, a metal manganese catalyst, an alkaline substance, an electrolyte, and a reaction solvent, mixing to form an electrolytic reaction solution; inserting an anode and a cathode into the electrolytic reaction solution, introducing nitrogen gas, and conducting an electro-oxidation-reduction reaction under the condition that the cathode and cathode are 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 of a tryptophan side chain indole C-2 phosphorylated polypeptide compound of Formula II or a small molecule compound of Formula IV; the reaction formula is as follows:

[0008]

[0009] 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, 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 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.

[0010] The phosphorus source is diarylphosphine oxide Ar2P(O)H, Ar represents different substituents containing a benzene ring, and Ar represents different substituents on the phosphorus source, selected from phenyl, naphthyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl or 2,4-dimethylphenyl.

[0011] 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 、R1 -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 、R 1 -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.

[0012] The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound is characterized in that the molar amount of the metal manganese catalyst is 1-50% of the molar amount of the tryptophan-containing polypeptide shown in formula I or the indole-containing derivative shown in formula III, preferably 5-8%.

[0013] Furthermore, the metal manganese catalyst is 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, a 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.

[0014] The electrocatalytic phosphorylation modification method of an 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% to 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% to 200%.

[0015] The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound is characterized in that the reaction solvent includes an organic solvent and a buffer-acid system; the buffer is a buffer (Tricine) composed of tris (hydroxymethyl) aminomethyl) ethanesulfonic acid and (tris hydroxymethylaminomethane) with a pH of 6 to 8, mannitol buffer (MB) with a pH of 6 to 8, sulfonic acid buffer (HEPES) with a pH of 6 to 8, phosphate buffer (PB) with a pH of 6 to 8, phosphate buffer (PBS) with a pH of 6 to 8, tris hydroxymethylaminomethane (Tris) with a pH of 6 to 8, tris(hydroxymethylaminomethane) hydrochloric acid (Tris-HCl); 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 selected from at least one of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, isooctanoic acid, 2-dimethylbutanoic 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;

[0016] The organic solvent is selected from at least one of methanol, ethanol, isopropanol, hexafluoroisopropanol, propylene glycol, glycerol, tert-butanol, 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, preferably acetonitrile or tetrahydrofuran;

[0017] 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.

[0018] Furthermore, the dispersion concentration of the tryptophan-containing polypeptide represented by Formula I or the indole-containing derivative represented by Formula III in the reaction solvent is 0.02-0.2 mol / L, preferably 0.05-0.1 mol / L.

[0019] Furthermore, the alkaline substance is sodium acetate, potassium acetate or potassium carbonate, preferably sodium acetate, and the molar amount of the alkaline substance is 100% to 300% of the molar amount of the tryptophan-containing polypeptide represented by Formula I or the indole-containing derivative represented by Formula III, preferably 100% to 200%.

[0020] Furthermore, the molar amount of the phosphorus source is 100-300%, preferably 100-200%, of the molar amount of the tryptophan-containing polypeptide represented by Formula I or the indole-containing derivative represented by Formula III.

[0021] The electrocatalytic phosphorylation modification method of an 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.

[0022] The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound is 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, GC, etc.; the cathode is at least one of GF, Ni, Sn, Al, Zn, Carbon rod, Pt, RVC, Carbon cloth, GC, etc., and the electrode combination of the anode and cathode is preferably GF-Pt.

[0023] The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound is characterized in that the reaction voltage is 1 to 6V; the preferred reaction voltage is 1.5 to 4.5V.

[0024] The present invention has the following advantages:

[0025] (1) For the first time, indole C-2 position was phosphorylated using a cheap metal in a buffered system, with high catalytic efficiency and mild reaction conditions;

[0026] (2) This method has excellent functional group compatibility and chemical and site selectivity;

[0027] (3) It uses environmentally friendly and atom-economical electrochemical technology, using only catalytic amounts of locally abundant manganese metal, thus avoiding the use of expensive catalysts.

[0028] (4) The reaction conditions are mild and can be carried out at room temperature and buffer conditions;

[0029] In summary, this invention utilizes environmentally friendly, atom-economical electrochemical technology to replace traditional reaction methods, avoiding the use of expensive catalysts and achieving high catalytic efficiency. This one-pot method achieves phosphorylation 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. DETAILED DESCRIPTION

[0030] 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.

[0031] In the embodiment of the present invention, the tryptophan-containing polypeptide represented by Formula I is reacted under electrochemical conditions to prepare the indole C-2 phosphorylated polypeptide compound represented by Formula II, and the reaction formula is as follows:

[0032]

[0033] The substituent R in formula II 1 、R 2 The substituents at the corresponding positions are the same as those in formula I.

[0034] Similarly, the indole-containing derivative shown in Formula III is reacted under electrochemical conditions to prepare the small molecule compound with indole C-2 phosphorylated shown in Formula IV, and the reaction formula is as follows:

[0035]

[0036] The substituent R in formula IV 3 、R 4 The substituents at the corresponding positions are the same as those in formula III.

[0037] Example 1: Synthesis of Compound 1: Using the tryptophan-containing peptide starting material, the dipeptide substrate Ac-Trp-Val-OMe, a clean, dry 10 mL reaction flask was charged with Ac-Trp-Val-OMe (90.0 mg, 0.25 mmol), diphenylphosphine oxide (101.0 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate nBu4NBF4 (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 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 40°C under a nitrogen atmosphere at a constant voltage of 2.3 V with stirring for 3.5 hours. After completion, the reaction system was separated by removing the solvent under reduced pressure and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate, volume ratio = 1:1) to obtain the target product with a reaction yield of 84%.

[0038] Example 1 Compound 1 Data Characterization:

[0039]

[0040] 1, 1 H NMR(400MHz, CDCl3)δ9.27(d,J=5.6Hz,1H),7.86–7.80(m,1H),7.71–7.53(m,11H),7.48–7.42(m,2H),7.27–7.26(m,1H),7.20–7.14(m,1H), 4.63–4.57(m,1H),4.46–4.42(m,1H),3.70(s,3H),3.48–3.43(m,1H), 3.33–3.27(m,1H),2.16–2.08(m,1H),2.00(s,3H),0.88–0.86(m,6H).

[0041] 13C NMR (100MHz, CDCl3) δ172.3, 172.0, 137.8 (d, J = 8.9Hz), 133.2 (d, J = 3.0Hz), 132.9 (d, J = 3.0Hz),131.8(d,J=23.1Hz),131.8(d,J=2.1.0Hz),131.7,130.6(d,J=13.0Hz),129.4( d,J=12.4Hz),129.1(d,J=29.0Hz),128.1(d,J=11.0Hz),125.5,124.8(d,J=122.0Hz),1 24.4(d,J=11.8Hz),121.1,120.2,112.0,57.5,54.4,52.1,31.1,25.4,22.8,19.1,17.8.

[0042] 31 P NMR (162 MHz, CDCl3) δ 23.06.

[0043] HR-MS(ESI):m / z calcd.for C 31 H 35 N3O5P[M+H] + :560.2314,found:560.2317.

[0044] Example 2: The steps and added 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(OAc)2 to obtain 43 mg of product with a reaction yield of 31%.

[0045] Example 3: The steps and added materials of Example 3 are exactly the same as those of Example 1, except that sodium acetate is replaced by potassium acetate of the same molar amount, to obtain 61 mg of product with a reaction yield of 44%.

[0046] Example 4: The steps and added materials of Example 4 are exactly the same as those of Example 1, except that sodium acetate is replaced by the same molar amount of potassium carbonate to obtain 53 mg of product with a reaction yield of 38%.

[0047] Example 5: The steps and added materials of Example 5 are exactly the same as those of Example 1, except that sodium acetate is replaced by ammonium acetate of the same molar amount, to obtain 58 mg of product with a reaction yield of 42%.

[0048] 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 tetrabutylammonium acetate nBu4NOAc, to obtain 74 mg of product with a reaction yield of 53%.

[0049] 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 lithium perchlorate LiClO4, to obtain 77 mg of product, with a reaction yield of 55%.

[0050] 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 nBu4NPF6, and 68 mg of product is obtained with a reaction yield of 49%.

[0051] Example 9: The steps and added materials of Example 9 are exactly the same as those of Example 1, except that the reaction solvent tetrahydrofuran (THF) (2.0 mL) is replaced by MeCN (2.0 mL), and 109 mg of product is obtained with a reaction yield of 78%.

[0052] 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. 91 mg of product is obtained, and the reaction yield is 65%.

[0053] 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 81mg of product is obtained with a reaction yield of 58%.

[0054] 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 99mg of product is obtained with a reaction yield of 71%.

[0055] Example 13: Synthesis of Compound 2: Using the tryptophan peptide starting material, dipeptide substrate Ac-Trp-Ala-OMe, a clean, dry 10 mL reaction flask was charged with Ac-Trp-Ala-OMe (82.5 mg, 0.25 mmol), diphenylphosphine oxide (101.0 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 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 40°C under a nitrogen atmosphere with stirring at a constant voltage of 2.3 V for 3.5 hours. After completion, the reaction system was decompressed to remove the solvent, and the residue was purified and separated by silica gel column chromatography (eluent: n-hexane: ethyl acetate, volume ratio = 1:1) to obtain the target product with a reaction yield of 68%.

[0056] Example 13 Compound 2 Data Characterization:

[0057]

[0058] 2, 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.71–8.68(m,2H),7.94(d,J=8.0Hz,1H),7.74–7.57(m,10H),7.42(d,J=8.0Hz,1H),7.25(t,J=7.6Hz,1H), 7.12(t,J=7.6Hz,1H)4.50–4.45(m,1H),4.34–4.27(m,1H),3.60(s,3H), 3.32–3.28(m,1H),3.25–3.19(m,1H),1.68(s,3H),1.35(d,J=7.2Hz,3H).

[0059] 13 C NMR(100MHz,DMSO-d6)δ173.1,172.0,169.1,138.3(d,J=9.8Hz),132.7(d,J=1.6Hz),1 32.6(d,J=29.4Hz),132.6,131.5(d,J=32.0Hz),131.5(d,J=16.1Hz),131.4(d,J=16.1H z),129.1(d,J=12.0Hz),129.0(d,J=13.0Hz),127.3(d,J=11.0Hz),125.0(d,J=121.2Hz ),124.3,124.0(d,J=12.7Hz),120.0,119.7,112.5,54.5,51.9,47.7,27.0,22.6,17.3.

[0060] 31 P NMR (162 MHz, CDCl3) δ 22.23.

[0061] HR-MS(ESI):m / z calcd.for C 29 H 30 N3NaO5P[M+Na] + :554.1821,found:554.1851.

[0062] Example 14: Synthesis of Compound 3: Using the tryptophan-containing peptide starting material, the dipeptide substrate Ac-Trp-Phe-OMe, a clean, dry 10 mL reaction flask was charged with Ac-Trp-Phe-OMe (101.5 mg, 0.25 mmol), diphenylphosphine oxide (101.0 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 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 40°C under a nitrogen atmosphere with stirring at a constant voltage of 2.3 V for 3.5 hours. After completion, the reaction system was decompressed to remove the solvent, and the residue was purified and separated by silica gel column chromatography (eluent: n-hexane: ethyl acetate, volume ratio = 1:1) to obtain the target product with a reaction yield of 60%.

[0063] Example 14 Compound 3 Data Characterization:

[0064]

[0065] 3, 1 H NMR(400MHz, CDCl3)δ9.18(d,J=5.6Hz,1H),7.94–7.90(m,1H),7.72–7.44(m,13H),7.27–7.26(m,1H),7.19–7.15(m,4H),7.07–7.05(m,2H), 4.82–4.77(m,1H),4.56–4.51(m,1H),3.68(s,3H),3.46–3.41(m,1H), 3.25–3.19(m,1H),3.10–3.05(m,1H),3.00–2.95(m,1H),1.94(s,3H).

[0066] 13C NMR (100MHz, CDCl3) δ172.1, 171.8, 171.5, 137.8 (d, J = 9.0Hz), 136.1, 133.2 (d, J = 2.6Hz ),133.0(d,J=2.7Hz),131.8(d,J=10.4Hz),131.7(d,J=10.4Hz),130.6(d,J=2.4Hz),129 .5,129.4,129.1(d,J=12.8.0Hz),128.4,128.1(d,J=10.9Hz),127.0,125.5,124.8(d,J= 121.0Hz), 124.3 (d, J = 12.0Hz), 121.0, 120.2, 112.0, 54.5, 53.5, 52.3, 38.1, 25.6, 22.7.

[0067] 31 P NMR (162 MHz, CDCl3) δ 22.95.

[0068] HR-MS(ESI):m / z calcd.for C 35 H 34 N3NaO5P[M+Na] + :630.2134,found:630.2170.

[0069] Example 15: Synthesis of Compound 4: Using the tryptophan-containing peptide starting material, dipeptide substrate Ac-Trp-Val-OMe, a clean, dry 10 mL reaction flask was charged with Ac-Trp-Val-OMe (90.0 mg, 0.25 mmol), bis(p-methylphenyl)phosphine oxide (115 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 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 40°C under a nitrogen atmosphere at a constant voltage of 2 V with stirring for 3.5 hours. After completion, the reaction system was separated by removing the solvent under reduced pressure and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate, volume ratio = 1:1) to obtain the target product with a reaction yield of 79%.

[0070] Example 15 Compound 4 Data Characterization:

[0071]

[0072] 4, 1 H NMR(400MHz,CDCl3)δ9.33(d,J=5.6Hz,1H),7.72(d,J=8.0Hz,1H),7.63–7.47(m,6H),7.38–7.36(m,2H),7.30–7.27(m,4H),7.20–7.16(m,1H),4.62–4.57(m,1H),4.47–4.44(m,1H),3.72(s,3H),3.48–3.44(m,1H),3.33–3.26(m,1H),2.47(s,3H),2.41(s,3H),2.16–2.09(m,1H),2.03(s,3H),0.88(d,J=1.2Hz,3H),0.86(d,J=1.2Hz,3H).

[0073] 13 C NMR(100MHz,CDCl3)δ172.4,172.3,172.0,144.0(d,J=2.9Hz),143.6(d,J=3.0Hz),137.6(d,J=9.0Hz),131.9(d,J=10.9Hz),131.7(d,J=11.2Hz),130.1(d,J=35.4Hz),129.9(d,J=36.1Hz),128.5(d,J=8.7Hz),128.2(d,J=10.9Hz),127.4(d,J=15.6Hz),125.5(d,J=120.9Hz),125.3,124.0(d,J=11.8Hz),121.0,120.3,111.9,57.5,54.4,52.1,31.2,25.4,22.8,21.9,21.8,19.0,17.9.

[0074] 31 PNMR(162MHz,CDCl3)δ23.10.

[0075] HRMS(ESI):m / z calcd.for C 33 H 39 N3O5P[M+H] + :588.2627,found:588.2628.

[0076] Example 16: Synthesis of Compound 5: Using the tryptophan-containing peptide starting material, dipeptide substrate Ac-Trp-Val-OMe, a clean, dry 10 mL reaction flask was charged with Ac-Trp-Val-OMe (90.0 mg, 0.25 mmol), bis(3,5-dimethylphenyl)phosphine oxide (129 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 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 40°C under a nitrogen atmosphere at a constant voltage of 2 V with stirring for 3.5 hours. After completion, the reaction system was removed from the solvent under reduced pressure, and the residue was purified and separated by silica gel column chromatography (eluent: n-hexane:ethyl acetate, volume ratio = 1:1) to obtain the target product with a reaction yield of 68%.

[0077] Example 16 Compound 5 Data Characterization:

[0078]

[0079] 5, 1 H NMR (400MHz, CDCl3) δ9.36(d,J=5.6Hz,1H),7.73(d,J=8.0Hz,1H),7.63(d,J=8.8Hz ,1H),7.56(s,1H),7.30–7.27(m,4H),7.24–7.16(m,5H),4.62–4.57(m,1H),4.47–4 .44(m,1H),3.72(s,3H),3.49–3.45(m,1H),3.34–3.27(m,1H),2.36(s,6H),2.31(s ,6H),2.17–2.10(m,1H),2.05(s,3H),0.89(d,J=2.0Hz,3H),0.87(d,J=2.0Hz,3H).

[0080] 13C NMR (100MHz, CDCl3) δ172.4, 172.3172.1, 139.3 (d, J = 13.0Hz), 138.9 (d, J = 13.6Hz), 137.6 (d, J =9.0Hz),135.0(d,J=2.8Hz),134.8(s,J=2.9Hz),131.5(d,J=21.6Hz),130.4(d,J=29.0Hz),129 .3(d,J=14.1Hz),129.2(d,J=14.1Hz),128.3(d,J=10.8Hz),125.6(d,J=119.9Hz),125.2,124.0 (d,J=11.6Hz),120.9,120.4,111.9,57.5,54.4,52.1,31.2,25.3,22.8,21.5,21.4,19.1,17.9.

[0081] 31 P NMR (162 MHz, CDCl3) δ 23.38.

[0082] HRMS(ESI):m / z calcd.for C 35 H 43 N3O5P[M+H] + :616.2940,found:616.2943.

[0083] Example 17: Synthesis of Compound 6: Using the tryptophan-containing peptide starting material, dipeptide substrate Ac-Trp-Val-OMe, a clean, dry 10 mL reaction flask was charged with Ac-Trp-Val-OMe (90.0 mg, 0.25 mmol), bis(4-chlorophenyl)phosphine oxide (135 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 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 40°C under a nitrogen atmosphere at a constant voltage of 2 V with stirring for 3.5 hours. After completion, the reaction system was removed from the solvent under reduced pressure, and the residue was purified and separated by silica gel column chromatography (eluent: n-hexane:ethyl acetate, volume ratio = 1:1) to obtain the target product with a reaction yield of 52%.

[0084]

[0085] Example 17 Compound 6 Data Characterization:

[0086] 1 H NMR (400MHz, CDCl3) δ11.07(s,1H),8.57(d,J=8.0Hz,1H),8.46(d,J=8.0Hz,1H),7.94(d, J=8.0Hz,1H),7.73–7.65(m,8H),7.40(d,J=8.4Hz,1H),7.25(t,J=7.2Hz,1H),7.11(t,J= 7.6Hz,1H),4.66–4.60(m,1H),4.21–4.18(m,1H),3.61(s,3H),3.34–3.30(m,1H),3.16–3 .10(m,1H),2.14–2.06(m,1H),1.68(s,3H),0.95(d,J=6.8Hz,3H),0.92(d,J=6.8Hz,3H).

[0087] 13 C NMR (100MHz, CDCl3) δ172.2,171.9,169.1,138.3(d,J=10.1Hz),138.0(d,J=3.3Hz),138.0( d,J=3.3Hz),133.4(d,J=6.5Hz),133.3(d,J=6.5Hz),131.1(d,J=5.4Hz),130.0(d,J=4.0Hz ),129.4(d,J=5.0Hz),129.2(d,J=5.0Hz),127.5(d,J=11.4Hz),124.8(d,J=13.0Hz),124.5 ,122.9(d,J=124.1Hz),120.2,119.7,112.4,57.6,54.7,51.6,29.8,27.2,22.5,19.0,18.2.

[0088] 31 P NMR (162 MHz, CDCl3) δ 20.77.

[0089] HR-MS(ESI):m / z calcd.for C 31 H 32 Cl2N3NaO5P[M+Na] + :650.1354,found:650.1343.

[0090] Example 18: Synthesis of Compound 7: Using the tryptophan-containing peptide starting material, dipeptide substrate Ac-Trp-Val-OMe, a clean, dry 10 mL reaction flask was charged with Ac-Trp-Val-OMe (90.0 mg, 0.25 mmol), bis(4-methoxyphenyl)phosphine oxide (131 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 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 40°C under a nitrogen atmosphere at a constant voltage of 2 V with stirring for 3.5 hours. After completion, the reaction system was removed from the solvent under reduced pressure, and the residue was purified and separated by silica gel column chromatography (eluent: n-hexane:ethyl acetate, volume ratio = 1:1) to obtain the target product with a reaction yield of 45%.

[0091]

[0092] Example 18 Product 7 Compound Data Characterization:

[0093] 1 H NMR (400MHz, CDCl3) δ10.88(s,1H),8.77(d,J=7.6Hz,1H),8.55(d,J=8.0Hz,1H),7.90(d ,J=8.4Hz,1H),7.61–7.54(m,4H),7.39(d,J=8.0Hz,1H),7.23–7.06(m,6H),4.62–4.56( m,1H),4.20–4.17(m,1H),3.83(d,J=4.8Hz,6H),3.61(s,3H),3.32–3.28(m,1H),3.17–3 .10(m,1H),2.14–2.06(m,1H),1.69(s,3H),0.96(d,J=6.4Hz,3H),0.92(d,J=6.8Hz,3H).

[0094] 13C NMR (100MHz, CDCl3) δ172.4, 172.0, 169.2, 162.5 (d, J = 2.7Hz), 162.4 (d, J = 2.7Hz), 138.1 (d, J = 9.8Hz), 133.4(d,J=11.6Hz), 133.4(d,J=11.3Hz), 127.5(d,J=11.0Hz), 125.0(d,J=121.4Hz), 124.0(d,J=5.5Hz),124.0,123.5(d,J=13.4Hz),122.9(d,J=7.3Hz),120.0,119.5,114.6(d,J= 5.0Hz), 114.5 (d, J = 5.0Hz), 112.4, 57.6, 55.5, 55.5, 54.8, 51.7, 29.9, 27.1, 22.5, 19.0, 18.2.

[0095] 31 P NMR (162 MHz, CDCl3) δ 21.47.

[0096] HR-MS(ESI):m / z calcd.for C 33 H 38 N3NaO7P[M+Na] + :642.2345,found:642.2331.

[0097] Example 19: Synthesis of Compound 8: Using the tryptophan-containing peptide starting material, the dipeptide substrate Ac-Trp-Val-OMe, a clean, dry 10 mL reaction flask was charged with Ac-Trp-Val-OMe (90.0 mg, 0.25 mmol), dinaphthylphosphine oxide (151 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 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 40°C under a nitrogen atmosphere at a constant voltage of 2 V with stirring for 3.5 hours. After completion, the reaction system was separated by removing the solvent under reduced pressure and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate, volume ratio = 1:1) to obtain the target product with a reaction yield of 48%.

[0098]

[0099] Example 19 Product 8 Compound Data Characterization:

[0100] 1 H NMR(400MHz,CDCl3)δ11.09(s,1H),8.73(d,J=7.6Hz,1H),8.55(d,J=8.0Hz,1H),8.44(d,J=14.4Hz,1H),8.39(d,J=14.4Hz,1H),8.16–78.04(m,6H),7.94(d,J=8.0Hz,1H),7.78–7.62(m,6H),7.38(d,J=8.4Hz,1H),7.23(t,J=7.6Hz,1H),7.11(t,J=6.8Hz,1H),4.72–4.67(m,1H),4.22–4.20(m,1H),3.56(s,3H),3.37–3.36(m,1H),3.22–3.20(m,1H),2.16–2.08(m,1H),1.71(s,3H),0.97(d,J=6.8Hz,3H),0.93(d,J=6.8Hz,3H).

[0101] 13 C NMR(100MHz,CDCl3)δ172.3,171.5,169.2,138.3(d,J=10.0Hz),134.6(d,J=1.9Hz),134.6(d,J=2.3Hz),133.4(d,J=15.2Hz),133.3(d,J=10.1Hz),132.1(d,J=13.5Hz),129.8(d,J=2.9Hz),129.1,128.8(d,J=7.6Hz),128.7(d,J=3.7Hz),127.9,127.6(d,J=11.2Hz),127.3(d,J=1.5Hz),126.3(d,J=11.3Hz),124.4(d,J=12.05Hz),124.2,124.1(d,J=121.5Hz),120.1,119.6,112.4,57.5,54.8,51.6,29.5,27.7,22.5,19.0,18.2.

[0102] 31 PNMR(162MHz,CDCl3)δ26.87.

[0103] HR-MS(ESI):m / z calcd.for C 39 H 39 N3O5P[M+H] + :660.2627,found:660.2630.

[0104] Example 20: Synthesis of Compound 9: Using the tryptophan-containing peptide starting material, the tripeptide substrate Boc-Gln-Trp-Val-OMe, a clean, dry 10 mL reaction flask was charged with Boc-Gln-Trp-Val-OMe (133 mg, 0.25 mmol), bisphenylphosphine oxide (101 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 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 40°C under a nitrogen atmosphere at a constant voltage of 2 V with stirring for 3.5 hours. After completion, the reaction system was removed from the solvent under reduced pressure, and the residue was purified and separated by silica gel column chromatography (eluent: dichloromethane:methanol, volume ratio = 20:1) to obtain the target product with a reaction yield of 65%.

[0105] Example 20 Compound 9 Product Data Characterization:

[0106]

[0107] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.30(d,J=5.6Hz,1H),8.60(d,J=8.0Hz,1H),7.74–7.65( m,6H),7.62–7.55(m,5H),7.50(d,J=8.4Hz,1H),7.42(d,J=8.0Hz,1H),7.24(t,J=6.8Hz,1H),7 .13–7.05(m,2H),6.75(s,1H),4.32–4.21(m,2H),3.94–3.89(m,1H),3.49(s,3H),2.16–2.04(m ,2H),2.00–1.93(m,1H),1.87–1.79(m,1H),1.69–1.60(m,1H),1.32(s,9H),0.80–0.78(m,6H).

[0108] 13C NMR(100MHz,DMSO-d6)δ173.9,171.9,171.7,170.8,155.4,138.4(d,J=10.0Hz),132.7 ,132.4,132.2,131.6(d,J=30.0Hz),131.5(d,J=28.0Hz),131.1,129.1(d,J=12.0Hz), 129.0(d,J=12.0Hz),127.1(d,J=11.0Hz),124.7(d,J=121.0Hz),124.4,121.8(d,J=13 .0Hz),120.0,118.9,112.8,78.2,56.8,54.2,54.0,51.8,31.2,28.1,27.6,18.9,17.5.

[0109] 31 P NMR (162 MHz, DMSO-d6) δ 22.08.

[0110] HRMS(ESI):m / z calcd.for C 38 H 47 N5O8P[M+H] + :732.3162,found:732.3168.

[0111] Example 21: Synthesis of Compound 10: Using the tryptophan-containing peptide starting material, the tetrapeptide substrate Ac-Trp-Ala-Phe-Val-OMe, a clean, dry 10 mL reaction flask was charged with Ac-Trp-Ala-Phe-Val-OMe (147 mg, 0.25 mmol), bis(4-methoxyphenyl)phosphine oxide (131 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 mL) at pH 6-8 and mixed to form a buffer-acid system at pH 5-6). A conductive electrode was installed in the reaction flask, using GF as the anode and Pt as the cathode. Electrolysis was carried out at 40°C under a nitrogen atmosphere at a constant voltage of 2V for 3.5 hours with stirring. After completion, the reaction system was freed from the solvent under reduced pressure and purified by silica gel column chromatography (eluent: dichloromethane:methanol, volume ratio = 20:1) to obtain the desired product in a reaction yield of 31%.

[0112] Example 21 Compound 10 Product Data Characterization:

[0113]

[0114] 1 H NMR(400MHz,CDCl3)δ10.84(s,1H),9.13(d,J=6.0Hz,1H),8.35(d,J=7.2Hz,1H),7.91(d,J=8.4Hz,1H),7.81(dd,J=15.2,8.4Hz,2H),7.64-7.59(m,2H),7.56-7.50(m,2H),7.40(d,J=8.4Hz,1H),7.24–7.07(m,11H),4.55-4.49(m,1H),4.31-4.26(m,1H),4.20–4.11(m,2H),3.83(d,J=7.20Hz,6H),3.62(s,3H),3.20(d,J=7.2Hz,2H),3.07-3.02(m,1H),2.84-2.78(m,1H),2.08-2.00(m,1H),1.78(s,3H),1.09(d,J=7.2Hz,3H),0.87-0.83(m,6H).

[0115] 13 C NMR(100MHz,CDCl3)δ171.9,171.8,171.7,170.1,170.14,164.0(d,J=2.8Hz),162.4(d,J=2.6Hz),138.1(d,J=9.9Hz),137.7,133.5(d,J=11.9Hz),133.2(d,J=11.9Hz),133.2(d,J=11.9Hz),129.2,128.0,127.3(d,J=10.6Hz),126.2,124.9,124.1(d,J=9.1Hz),123.0,122.9(d,J=115.8Hz),122.6(d,J=12.5Hz),119.6,119.5,114.6(d,J=13.4Hz),114.5(d,J=13.3Hz),112.5,57.5,55.5,55.4,55.3,53.6,51.7,48.7,37.2,29.4,26.4,22.7,18.9,18.3,17.5.

[0116] 31 PNMR(162MHz,CDCl3)δ26.54.

[0117] HR-MS(ESI):m / z calcd for C 45 H 53 N5O9P[M+H]+ 838.3581,found:838.3590.

[0118] Example 22: Synthesis of Compound 11: 3-methylindole, a small indole-containing substrate, was used. To a clean, dry 10 mL reaction flask were added 3-methylindole (32 mg, 0.25 mmol), diphenylphosphine oxide (131 mg, 0.5 mmol), sodium acetate (41.0 mg, 0.5 mmol), catalyst manganese difluoride (1.16 mg, 5 mol%), electrolyte tetrabutylammonium tetrafluoroborate (165.0 mg, 0.50 mmol), tetrahydrofuran (2.0 mL), and a buffer-acid system (acetic acid (1.0 mL) was added to Tris (1.0 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 40°C under a nitrogen atmosphere at a constant voltage of 2 V with stirring for 3.5 hours. After completion, the reaction system was removed from the solvent under reduced pressure, and the residue was purified and separated by silica gel column chromatography (eluent: dichloromethane:methanol, volume ratio = 20:1) to obtain the target product with a reaction yield of 70%.

[0119] Example 22 Compound 11 Product Data Characterization

[0120]

[0121] 1H NMR(400MHz, CDCl3)δ9.54(s,1H),7.77–7.72(m,4H),7.64–7.57(m,3H),7.51–7.47(m,4H) ,7.42(d,J=8.4Hz,1H),7.28(t,J=7.6Hz,1H),7.16(t,J=7.6Hz,1H),2.11(d,J=1.6Hz,3H).

[0122] 13C NMR (100MHz, CDCl3) δ37.7(d,J=9.0Hz),132.8,132.4,132.4,132.0,131.9,131.7,129.1(d,J=9.0H z),128.8,127.7,124.5,123.1(d,J=123.0Hz),120.8(d,J=14.0Hz),119.8,119.7,112.1,10.1.31P NMR (162MHz, CDCl3) δ22.26.

[0123] HRMS(ESI): m / z calcd for C21H19NOP[M+H]+332.1204, found332.1204.

Claims

1. A method for electrocatalytic phosphorylation 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 phosphorus source, a metal manganese catalyst, an alkaline substance, an electrolyte and a reaction solvent, mixing to form an electrolytic reaction solution, inserting an anode and a cathode into the electrolytic reaction solution, introducing nitrogen gas, and performing an electric redox reaction under the condition that the cathode and cathode are energized; after completion of the reaction, performing reduced pressure distillation on a rotary evaporator to remove the solvent to obtain a crude product; the crude product is further separated by column chromatography to obtain a pure product of a tryptophan side chain indole C-2 phosphorylated polypeptide compound represented by formula II or a small molecule compound represented by formula IV; 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; The phosphorus source is a diarylphosphine oxide Ar2P(O)H, Ar represents a different substituent containing a benzene ring, and Ar represents a different substituent on the phosphorus source, selected from phenyl, naphthyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl or 2,4-dimethylphenyl; In formula III and IV, R 3 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.

2. The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The molar amount of the metal manganese catalyst is 1 to 50% of the molar amount of the tryptophan-containing polypeptide represented by formula I or the indole-containing derivative represented by formula III, preferably 5 to 8%; The metal manganese catalysts are monovalent manganese catalyst Mn(CO)5Br, divalent manganese catalysts MnF2, MnCl2, MnBr2, MnBr2·4H2O, MnI2, Mn(OAc)2, Mn(OAc)2·4H2O, MnSO4, MnO, Mn(OH)2, Mn(o-phen)2I2, trivalent manganese catalysts Mn(acac)3, Mn(OAc3·2H2O, Mn III (salen)(Cl), [Mn III (TPP)Cl]、[Mn III T4(-OMe)PPCl] or at least one of a tetravalent manganese catalyst MnO2.

3. The electrocatalytic phosphorylation 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% to 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% to 200%.

4. The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The reaction solvent comprises an organic solvent and a buffer-acid system; the buffer is one of a Tricine buffer with a pH of 6 to 8, an MB buffer with a pH of 6 to 8, a HEPES buffer with a pH of 6 to 8, a PB buffer with a pH of 6 to 8, a PBS buffer with a pH of 6 to 8, a Tris buffer with a pH of 6 to 8, and a Tris-HCl buffer with a pH of 6 to 8; the buffer-acid system is a mixed liquid system formed by adjusting the pH of the buffer to 5 to 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-dimethylbutanoic 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 at least one of methanol, ethanol, isopropanol, hexafluoroisopropanol, propylene glycol, glycerol, tert-butanol, 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, preferably acetonitrile or tetrahydrofuran; 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.

5. The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound according to claim 4, characterized in that The tryptophan-containing polypeptide represented by formula I or the indole-containing derivative represented by formula III is dispersed in the reaction solvent at a concentration of 0.02-0.2 mol / L, preferably 0.05-0.1 mol / L.

6. The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The alkaline substance is sodium acetate, potassium acetate or potassium carbonate, preferably sodium acetate. The molar amount of the alkaline substance 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%-200%.

7. The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The molar amount of the phosphorus source is 100-300%, preferably 100-200%, 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 phosphorylation 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; the reaction temperature is preferably 25-30° C., and the reaction time is preferably 2-8 hours.

9. The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound according to claim 1, characterized in that 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, and the electrode combination of the anode and cathode is preferably GF-Pt.

10. The electrocatalytic phosphorylation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The voltage of the reaction is 1-6V; the voltage of the reaction is preferably 1.5-4.5V.

Images