CN117105805A - Tyrosine alkene etherification reaction and directional modification of polypeptide or protein tyrosine - Google Patents

Tyrosine alkene etherification reaction and directional modification of polypeptide or protein tyrosine Download PDF

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CN117105805A
CN117105805A CN202311074251.XA CN202311074251A CN117105805A CN 117105805 A CN117105805 A CN 117105805A CN 202311074251 A CN202311074251 A CN 202311074251A CN 117105805 A CN117105805 A CN 117105805A
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tyrosine
reaction
etherification
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compound
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朱勍
苑玉晴
刘霞
强雨杰
曾伟
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Zhejiang University of Technology ZJUT
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Abstract

The invention relates to the technical field of organic synthesis, and discloses a tyrosine alkene etherification reaction and directional modification of polypeptide or protein tyrosine. In the etherification reaction, the tyrosine-containing compound and the olefin compound are reacted under a certain condition, the olefin compound can position the phenolic hydroxyl group of the tyrosine-containing compound, the site-specific reaction is carried out, and the hydrogen on the phenolic hydroxyl group is replaced, so that the etherification tyrosine-containing compound is obtained. The method for the etherification reaction of the tyrosine-containing compound does not need to introduce a guide group, and has the advantages of simple operation, mild reaction conditions and high site selectivity.

Description

Tyrosine alkene etherification reaction and directional modification of polypeptide or protein tyrosine
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a tyrosine alkene etherification reaction and directional modification of polypeptide or protein tyrosine.
Background
Chemical modification refers to the attachment of a specific functional group to a target molecule by means of a chemical reaction. Polypeptides or proteins are the main targets of chemical modification. The nature realizes the diversification of protein functions through a series of post-translational modifications, which in turn mediate the activity of the protein, and the complex modifications in the living body lead to the limited use of purely natural modified proteins, and the chemical modification of the proteins has emerged. The chemical modification can improve the functions of the polypeptide and the protein, can endow the polypeptide with new functions, can realize the functional diversification of the protein by introducing various functional groups through a chemical method, and plays an important role in life science, medicine and biological materials. In pharmaceutical chemistry, the chemical modification of the drug can improve the biological activity and the bioavailability.
The polypeptide is a compound formed by connecting 10-100 amino acids together through peptide bonds by dehydration condensation. In pharmaceutical research, native sequence polypeptides are ideal choices, which are generally potent and selective agonists or antagonists of the different receptors involved in the pathology study. Meanwhile, polypeptide drugs have higher receptor affinity and specificity and generally exhibit lower toxicity than small molecule drugs. However, polypeptide drugs also have several adverse properties of absorption, delivery, metabolism and excretion (ADME), which can be effectively ameliorated by chemical modification of the polypeptide-containing drug.
In the prior art, for example, chinese patent application publication No. CN115108953a discloses the hydrosulfide reaction of alkynylamides and their selective modification of polypeptide cysteines. In the polypeptide selective modification method provided by the patent, the selective modification of the cysteine in the polypeptide and the protein is realized by utilizing the reaction selectivity of the carbon-carbon triple bond in the alkynylamide to the sulfhydryl in the cysteine. However, the modified product obtained by the method is a specific cis-form single configuration product.
Tyrosine is a non-essential amino acid, the chemical name of which is 2-amino-3-p-hydroxyphenyl propionic acid, which occurs at low to medium frequency in natural proteins and is an important amino acid involved in cell signaling. Many polypeptide drugs also contain tyrosine. Tyrosine has electron-rich, hydrophobic phenol side chains, which are good sites for highly diverse biological modifications. In pharmaceutical chemistry, the modification of the tyrosine phenol side chain is generally carried out by: firstly, the tyrosine phenolic hydroxyl group is protected, then other sites of the tyrosine phenolic hydroxyl group are modified, and finally deprotection is carried out to realize modification. The method has the advantages of more severe conditions, more steps and low reaction yield. In tyrosine-containing polypeptide modifications, the methods aimed at modifying tyrosine are generally: the ortho position of the tyrosine phenolic hydroxyl is esterified and modified, but the ester bond is unstable and is easy to be hydrolyzed by esterase, etc.
Therefore, a tyrosine chemical modification method which is easy to operate is developed, and the method has important significance in the field of protein modification.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for the etherification reaction of the alkene containing tyrosine compound and a method for the directional modification of polypeptide or protein. The invention creatively discovers that under certain reaction conditions, the olefin compound can locate the phenolic hydroxyl group of the tyrosine-containing compound, react at fixed points, replace hydrogen on the phenolic hydroxyl group to obtain the olefin-etherified tyrosine compound, and the site selectivity is high. Meanwhile, the invention adjusts the reaction condition, so that the reaction has the characteristic of high efficiency under mild reaction condition.
The specific technical scheme of the invention is as follows:
in one aspect, the present invention provides a method for the etherification of a tyrosine-containing compound comprising the steps of:
the preparation method comprises the steps of reacting a tyrosine-containing compound with a structural general formula (II) with an olefin compound with a structural general formula (III) in a solvent under the action of a catalyst, an oxidant, an additive and alkali to obtain an olefin etherified tyrosine compound with a structural general formula (I):
wherein R is 1 A linear or branched alkoxy group selected from C1 to C7, a linear or branched alkoxycarbonyl group selected from C1 to C7; r is R 2 A linear or branched alkyl group selected from C1 to C7; r is R 3 Selected from methoxycarbonyl, ethoxycarbonyl, phenyl, phenoxycarbonyl, chlorobenzene, t-butyl ether.
The invention creatively discovers that under certain reaction conditions, the olefin compound can locate the phenolic hydroxyl group of the tyrosine-containing compound, react at fixed points, replace hydrogen on the phenolic hydroxyl group to obtain the olefin-etherified tyrosine compound, and the site selectivity is high. The invention can obtain the alkene etherified tyrosine compound with the structural general formula (I) by reacting the tyrosine-containing compound with the structural general formula (II) with the alkene compound with the structural general formula (III) under certain conditions. Meanwhile, the reaction condition is adjusted, so that the reaction has the characteristic of high efficiency under mild reaction condition. The method for the etherification reaction of the tyrosine-containing compound does not need to introduce a guide group, and has the advantages of simple operation, mild reaction conditions and high site selectivity.
As a preferable mode of the above technical scheme of the invention, the R is 1 Is acetyl or t-butoxycarbonyl, R 2 Methyl or ethyl; r is R 3 Selected from methoxycarbonyl, ethoxycarbonyl, phenyl, phenoxycarbonyl, p-methylphenoxycarbonyl, chlorobenzene or t-butyl ether.
As a preferable mode of the technical scheme, the ratio of the tyrosine-containing compound, the olefin compound, the catalyst, the oxidant, the additive and the alkali is 1:1-3:0.1-0.3:1-3:1-2:0.5-1.2.
The dosage proportion of the reaction substrate of the chemical reaction plays an important role in the chemical reaction. In the method, the reasonable substrate dosage proportion of the etherification reaction can control the selectivity of the product, lead the phenolic hydroxyl of the alkene compound and the tyrosine-containing compound to react at a fixed point, lead the target product to be preferentially generated, and lead the reaction to have higher reaction rate due to the proper substrate dosage proportion. In the process of the present invention, the substrate amount for the etherification reaction is preferably 1:1 to 3:0.1 to 0.3:1 to 3:1 to 2:0.5 to 1.2, and an amount exceeding this range may result in a lower reaction yield or the reaction may not proceed.
Preferably, the catalyst is palladium acetate and/or palladium trifluoroacetate.
In the etherification reaction of the present invention, the catalyst is preferably selected from palladium acetate and palladium trifluoroacetate. The catalyst is the guarantee of the occurrence of the etherification reaction of the alkene of the present invention. Under the catalysis of palladium acetate or palladium trifluoroacetate, the etherification reaction of the alkene has better reaction effect and high reaction rate and yield. The reaction is carried out under the catalysis of other catalysts, such as tetraphenylphosphine palladium, dichlorophenyl phosphine palladium and DPPF palladium dichloride, and the reaction yield is low.
Preferably, the oxidant is selected from one or more of potassium persulfate, silver acetate and tert-butyl peroxybenzoate.
In the etherification reaction of the present invention, the oxidizing agent is preferably selected from one or more of potassium persulfate, silver acetate and t-butyl peroxybenzoate. The role of the oxidizing agent in the etherification reaction of the present invention is that the oxidation catalyst ensures cyclic catalysis of the catalyst. Under the participation of oxidizing agents such as potassium persulfate, silver acetate or tert-butyl peroxybenzoate, the etherification reaction of the alkene has good reaction effect and high reaction rate and yield. When other oxidants such as oxygen, hydrogen peroxide, tert-butyl hydroperoxide, copper acetate and silver acetate are added, the reaction yield is low, wherein when copper acetate or silver acetate is added as the oxidant, the reaction yield is extremely low.
Preferably, the additive is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium iodide and tetrabutylammonium chloride.
In the etherification reaction of the present invention, the additive is preferably selected from one or more of tetrabutylammonium bromide, tetrabutylammonium iodide and tetrabutylammonium chloride. The above-mentioned additive functions to temporarily coordinate with the substrate in the etherification reaction of the present invention, thereby preventing deactivation of the catalyst coordination.
As a preferable aspect of the above-described technical scheme of the present invention, the base is selected from one or more of potassium carbonate, cesium carbonate, potassium fluoride and cesium fluoride.
In the etherification reaction of the present invention, the base is preferably one or more selected from potassium carbonate, cesium carbonate, potassium fluoride and cesium fluoride. The alkali substance has the function of ionizing phenolic hydroxyl groups on the tyrosine-containing compound in the etherification reaction of the invention, thereby improving the reaction rate.
The invention provides a method for the etherification reaction of tyrosine-containing compounds, which comprises the following steps: under the conditions of an additive and alkali, tyrosine-containing compound is converted into negative ions through tyrosine side chain phenolic hydroxyl groups in the tyrosine-containing compound to obtain an intermediate compound A, palladium is subjected to oxidative intercalation, the intermediate compound A is coordinated with the phenolic hydroxyl groups to form an intermediate B, then an olefin compound is subjected to addition intercalation with palladium to form a palladium olefin compound, then addition migration is carried out to form a new compound intermediate C, and finally reduction and elimination are carried out to obtain the product olefin-etherified tyrosine compound.
Preferably, the solvent is methylene chloride.
As the preferable mode of the invention, the reaction temperature is 20-55 ℃ and the reaction time is 6-24 h.
In the etherification reaction of the present invention, the reaction temperature is preferably 20 to 55℃and the reaction temperature has a good reaction effect. The reaction time is preferably 6-24 hours, and under the reaction time, the reaction has better reaction degree and higher yield.
As a preferable mode of the technical scheme, the method for purifying the catalyst comprises the following steps of:
(1) Filtering the reaction product by diatomite, washing by DCM, collecting an organic phase, concentrating, extracting by ethyl acetate and water, taking an organic layer, drying, filtering, and concentrating to obtain a crude product;
(2) And (3) performing silica gel column chromatography on the crude product, taking a mixed solution of ethyl acetate and petroleum ether as a mobile phase, tracking and collecting eluent with the Rf value of 0.3-0.5 by TLC, and removing the solvent from the eluent to obtain the etherified tyrosine compound.
Further, the volume ratio of the ethyl acetate to the petroleum ether is preferably 1:8-10.
In another aspect, the invention also provides a method for targeted modification of a polypeptide or protein, comprising the steps of: based on the method of the etherification reaction, the polypeptide or the protein is chemically modified; wherein the polypeptide or protein contains tyrosine.
In the method for the etherification reaction of the alkene disclosed in the prior art, the alkyne addition reaction is usually adopted, the reaction condition is harsh, the operation is complex, the control difficulty of reaction sites is high, and the yield is low; meanwhile, the existing reported alkene etherification reaction methods based on alkyne addition reaction are all carried out on small molecular compounds, the reaction is difficult to be carried out on macromolecular substances or the yield of alkene etherification products is extremely low.
The invention provides a directional modification method of polypeptide or protein based on the etherification reaction of tyrosine-containing compound and olefin compound, which is used for carrying out positioning olefin etherification on the polypeptide or protein containing tyrosine, carrying out directional chemical modification on the polypeptide or protein medicine containing tyrosine, improving the biological activity of the medicine and improving the bioavailability of the medicine; the method can also be applied to labeling of the polypeptide or the protein, and the polypeptide or the protein is tracked.
Compared with the prior art, the invention has the following technical effects:
the invention provides an etherification reaction, which is characterized in that a tyrosine-containing compound and an olefin compound react under a certain condition, the olefin compound can position a phenolic hydroxyl group of the tyrosine-containing compound, the reaction is performed at a fixed point, and hydrogen on the phenolic hydroxyl group is replaced, so that the etherification tyrosine compound is obtained. The method for the etherification reaction of the tyrosine-containing compound does not need to introduce a guide group, and has the advantages of simple operation, mild reaction conditions and high site selectivity.
The invention provides a directional modification method of polypeptide or protein based on the etherification reaction of tyrosine-containing compound and olefin compound, which is used for carrying out positioning olefin etherification on the polypeptide or protein containing tyrosine, carrying out directional chemical modification on the polypeptide or protein medicine containing tyrosine, improving the biological activity of the medicine and improving the bioavailability of the medicine; the method can also be applied to labeling of the polypeptide or the protein, and the polypeptide or the protein is tracked.
Drawings
FIG. 1 is a reaction schematic diagram of an etherification reaction of a tyrosine-containing compound according to the present invention;
FIG. 2 is a fluorescence imaging of a tyrosine site-selective modification BSA protein marker of example 9 of the present invention;
FIG. 3 is a fluorescent bake-staining chart of a tyrosine-site-selective modified BSA protein marker according to example 9 of the present invention.
Detailed Description
The invention is further described below with reference to examples. Those of ordinary skill in the art will be able to implement the invention based on these descriptions. In addition, the embodiments of the present invention referred to in the following description are typically only some, but not all, embodiments of the present invention. Therefore, all other embodiments, which can be made by one of ordinary skill in the art without undue burden, are intended to be within the scope of the present invention, based on the embodiments of the present invention.
The invention provides a method for the etherification reaction of tyrosine-containing compounds, which comprises the following steps: the preparation method comprises the steps of reacting a tyrosine-containing compound with an olefin compound in a solvent under the action of a catalyst, an oxidant, an additive and alkali to obtain an olefin etherified tyrosine compound.
For example, when the tyrosine-containing compound isThe alkene compound is->When in use, palladium acetate, potassium persulfate as oxidant, TBAB as additive and KHCO as alkali are used as catalysts 3 Under the action of the above reaction, the reaction principle is shown in fig. 1, which is a reaction principle diagram of an etherification reaction of an alkene containing tyrosine compound, and the reaction principle is as follows: tyrosine-containing compounds in TBAB and KHCO 3 Under the action, tyr side chain phenolic hydroxyl is converted into negative ions to form an intermediate compound I, palladium is oxidized and intercalated, the intermediate compound I is coordinated with phenolic hydroxyl to form an intermediate II, then an olefin compound is added and intercalated with palladium to form a palladium olefin compound III, then addition migration is carried out to form a new compound IV, and finally reduction and elimination are carried out to obtain the product of the etherified tyrosine compound.
Example 1
The structural formula of the olefination tyrosine compound is as follows:the preparation method comprises the following steps: 0.2mmol of acetyl-L-tyrosine ethyl ester was weighed into 1.5mL of methylene chloride solvent, 0.01mmol of palladium trifluoroacetate, 0.3mmol of tetrabutylammonium bromide, 0.1mmol of potassium carbonate, 0.3mmol of tert-butyl peroxybenzoate, 0.6mmol of ethyl acrylate was added thereto, and the mixture was reacted at 20℃for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, washed 3 times with dichloromethane, and the organic phase was collected and concentrated in vacuo. Adding 10mL of ethyl acetate and 5mL of water into a separating funnel, vibrating, shaking, standing, separating, taking an organic phase, and using anhydrous Na 2 SO 4 Drying, vacuum concentrating to obtain crude product, and purifying by column chromatography to obtain 29.5mg of olefine etherified tyrosine compound.
The product alkene etherified tyrosine compound is taken for nuclear magnetic detection, and NMR data are as follows: 1 H NMR(400MHz,CDCl3)δ7.78(d,J＝12.2Hz,1H),7.17–7.09(m,2H),7.06–6.96(m,2H),6.03(d,J＝7.8Hz,1H),5.56(d,J＝12.2Hz,1H),4.86(dt,J＝7.8,5.8Hz,1H),4.19(pd,J＝6.5,5.9,3.8Hz,4H),3.13(qd,J＝14.0,5.8Hz,2H),2.02(s,3H),1.28(dt,J＝11.6,7.1Hz,6H). 13 C NMR(101MHz,CDCl3)δ171.54,169.65,167.23,158.86,154.98,132.74,130.84,118.05,102.29,61.67,60.14,53.18,37.23,23.17,14.32,14.15.
as can be confirmed from NMR data analysis of the product, the method of this example gave an etherified tyrosine compound (I-1).
Example 2
The structural formula of the olefination tyrosine compound is as follows:the preparation method comprises the following steps:
0.2mmol of t-butoxycarbonyl-L-tyrosine methyl ester was weighed and added to 1.5mL of methylene chloride solvent, to which 0.01mmol of palladium trifluoroacetate, 0.3mmol of tetrabutylammonium bromide, 0.1mmol of potassium carbonate, 0.3mmol of t-butyl peroxybenzoate, 0.6mmol of ethylene glycol diacrylate was added and reacted at 30℃for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, washed 3 times with dichloromethane, and the organic phase was collected and concentrated in vacuo. Adding 10mL of ethyl acetate and 5mL of water into a separating funnel, vibrating, shaking, standing, separating, taking an organic phase, and using anhydrous Na 2 SO 4 Drying, vacuum concentrating to obtain crude product, and purifying by column chromatography to obtain 16.7mg of olefine etherified tyrosine compound.
The product alkene etherified tyrosine compound is taken for nuclear magnetic detection, and NMR data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.81(d,J＝12.2Hz,1H),7.17–7.11(m,2H),7.02–6.98(m,2H),6.98–6.94(m,5H),6.75(d,J＝8.1Hz,5H),6.55(s,2H),6.44(dd,J＝17.3,1.4Hz,1H),6.15(dd,J＝17.3,10.5Hz,1H),5.87(dd,J＝10.5,1.4Hz,1H),5.57(d,J＝12.2Hz,1H),5.06(t,J＝9.0Hz,3H),4.58–4.51(m,3H),4.40(s,4H),3.72(d,J＝5.3Hz,11H),3.00(qd,J＝13.7,5.7Hz,6H),1.42(s,28H).
13 C NMR(126MHz,CDCl3)δ172.64,172.20,167.05,166.04,159.70,155.30,154.83,132.99,131.46,130.84,130.33,127.97,127.36,118.07,115.52,101.46,80.15,62.39,61.88,54.63,54.42,52.33,52.23,50.72,37.69,37.52,28.29.
as can be confirmed from NMR data analysis of the product, the method of this example gave an etherified tyrosine compound (I-11).
Example 3
The structural formula of the olefination tyrosine compound is as follows:the preparation method comprises the following steps:
the two substrate structures used for the synthesis of (I-13) are shown in the following formula:
0.1mmol (I-13 a) was weighed into 1.5mL of methylene chloride solvent, 0.01mmol of palladium trifluoroacetate, 0.3mmol of tetrabutylammonium bromide, 0.1mmol of potassium carbonate, 0.3mmol of tert-butyl peroxybenzoate, 0.6mmol (I-13 b) was added thereto, and the mixture was reacted at 37℃for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, washed 3 times with dichloromethane, and the organic phase was collected and concentrated in vacuo. Adding 10mL of ethyl acetate and 5mL of water into a separating funnel, vibrating, shaking, standing, separating, taking an organic phase, and using anhydrous Na 2 SO 4 Drying, vacuum concentrating to obtain crude product, and purifying by column chromatography to obtain the final product, namely, alkene etherified tyrosine compound 43.7mg.
The product alkene etherified tyrosine compound is taken for nuclear magnetic detection, and NMR data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.78(d,J＝12.2Hz,1H),7.13(d,J＝8.6Hz,2H),6.99(d,J＝8.6Hz,2H),6.03(d,J＝7.7Hz,1H),5.51(d,J＝12.2Hz,1H),5.35(d,J＝8.4Hz,1H),4.89–4.80(m,1H),4.63–4.48(m,2H),4.40(dd,J＝11.2,3.5Hz,1H),4.18(td,J＝7.1,3.1Hz,2H),3.77(s,3H),3.17–3.07(m,2H),2.01(s,3H),1.45(s,9H),1.25(d,J＝7.1Hz,3H).
13 C NMR(126MHz,CDCl3)δ171.50,169.62,166.65,159.86,154.75,133.03,130.88,130.27,121.60,118.07,101.11,80.34,64.02,61.65,53.16,52.72,37.25,28.27,23.15,21.10,14.14.
as can be confirmed from NMR data analysis of the product, the method of this example gave an etherified tyrosine compound (I-13).
Example 4
The structural formula of the olefination tyrosine compound is as follows:the preparation method comprises the following steps:
the two substrate structures used for the synthesis of (I-16) are shown in the following formula:
0.1mmol (I-16 a) was weighed into 1.5mL of methylene chloride solvent, 0.01mmol of palladium trifluoroacetate, 0.3mmol of tetrabutylammonium bromide, 0.1mmol of potassium carbonate, 0.3mmol of tert-butyl peroxybenzoate, 0.6mmol (I-16 b) was added thereto, and the mixture was reacted at 37℃for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, washed 3 times with dichloromethane, and the organic phase was collected and concentrated in vacuo. Adding 10mL of ethyl acetate and 5mL of water into a separating funnel, vibrating, shaking, standing, separating, taking an organic phase, and using anhydrous Na 2 SO 4 Drying, vacuum concentrating to obtain crude product, and purifying by column chromatography to obtain the final product, namely, alkene etherified tyrosine compound 43.9mg.
The product alkene etherified tyrosine compound is taken for nuclear magnetic detection, and NMR data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.79(d,J＝12.2Hz,1H),7.15(d,J＝8.1Hz,2H),7.03–6.99(m,2H),6.97(d,J＝7.9Hz,1H),5.51(d,J＝12.2Hz,1H),5.04(dd,J＝7.8,5.3Hz,2H),4.86(dt,J＝7.9,3.8Hz,1H),4.58(q,J＝6.6Hz,1H),4.48(ddd,J＝42.7,11.4,3.9Hz,2H),4.23(s,1H),3.78(s,3H),3.73(s,3H),3.08(ddd,J＝47.8,13.9,6.0Hz,2H),1.44(s,9H),1.43(s,9H),1.38(d,J＝7.1Hz,3H).
13 C NMR(126MHz,CDCl3)δ172.60,172.14,169.71,166.73,160.00,155.02,154.75,133.26,133.12,130.88,130.06,128.37,118.02,100.98,80.07,63.46,54.39,52.84,52.30,51.85,38.62,37.70,28.28,18.08.
as can be confirmed from NMR data analysis of the product, the method of this example gave an etherified tyrosine compound (I-16).
Example 5
The structural formula of the olefination tyrosine compound is as follows:the preparation method comprises the following steps:
the structure of the substrate used for the synthesis of (I-18) is shown in the following formula:
0.1mmol (I-18 a) was weighed into 1.5mL of methylene chloride solvent, 0.01mmol of palladium trifluoroacetate, 0.3mmol of tetrabutylammonium bromide, 0.1mmol of potassium carbonate, 0.3mmol of tert-butyl peroxybenzoate, 0.6mmol (I-13 b) was added thereto, and the mixture was reacted at 55℃for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, washed 3 times with dichloromethane, and the organic phase was collected and concentrated in vacuo. Adding 10mL of ethyl acetate and 5mL of water into a separating funnel, vibrating, shaking, standing, separating, taking an organic phase, and using anhydrous Na 2 SO 4 Drying, vacuum concentrating to obtain crude product, and purifying by column chromatography to obtain the final product, namely, alkene etherified tyrosine compound 43.7mg.
The product alkene etherified tyrosine compound is taken for nuclear magnetic detection, and NMR data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.78(d,J＝12.2Hz,1H),7.23–7.21(m,2H),7.00–6.96(m,2H),6.61–6.49(m,2H),6.42(dd,J＝8.1,3.2Hz,1H),5.52(d,J＝12.2Hz,1H),5.38(d,J＝8.6Hz,1H),4.75–4.72(m,1H),4.61–4.51(m,1H),4.42(dd,J＝8.7,5.0Hz,2H),3.77(s,3H),3.71(s,3H),3.06(dd,J＝6.9,3.7Hz,2H),2.14–2.10(m,1H),1.99(s,3H),1.45(s,9H),0.89–0.86(m,6H).
13 C NMR(126MHz,CDCl3)δ171.68,170.79,170.22,166.70,159.97,154.71,133.40,130.89,130.33,121.68,118.18,115.58,101.04,80.34,57.50,54.45,52.72,52.17,37.62,31.11,28.28,23.07,21.09,18.83,17.71.
as can be confirmed from NMR data analysis of the product, the method of this example gave an etherified tyrosine compound (I-18).
Example 6
The structural formula of the olefination tyrosine compound is as follows:the preparation method comprises the following steps:
the structure of the substrate used for the synthesis of (I-28) is shown in the following formula:
0.1mmol (I-28 a) was weighed into 1.5mL of methylene chloride solvent, 0.01mmol of palladium trifluoroacetate, 0.3mmol of tetrabutylammonium bromide, 0.1mmol of potassium carbonate, 0.3mmol of tert-butyl peroxybenzoate, 0.6mmol (I-28 b) was added thereto, and the mixture was reacted at 40℃for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, washed 3 times with dichloromethane, and the organic phase was collected and concentrated in vacuo. Adding 10mL of ethyl acetate and 5mL of water into a separating funnel, vibrating, shaking, standing, separating, taking an organic phase, and using anhydrous Na 2 SO 4 Drying, vacuum concentrating to obtain crude product, and purifying by column chromatography to obtain 46.9mg of olefine etherified tyrosine compound.
The product alkene etherified tyrosine compound is taken for nuclear magnetic detection, and NMR data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.92(d,J＝12.2Hz,1H),7.24–7.21(m,2H),7.15(d,J＝8.1Hz,1H),7.06–7.03(m,2H),6.94(d,J＝8.0Hz,2H),6.75(d,J＝7.9Hz,2H),6.55–6.51(m,1H),5.70(d,J＝12.1Hz,1H),5.08(s,1H),4.83(s,1H),4.47(dd,J＝8.6,5.1Hz,1H),4.39–4.31(m,1H),4.30–4.21(m,1H),3.73(s,3H),3.71(s,3H),3.33(tt,J＝7.2,3.7Hz,2H),3.20(dd,J＝14.0,5.7Hz,1H),3.14–3.09(m,1H),3.02(dd,J＝13.9,6.8Hz,1H),2.95–2.88(m,1H),2.15–2.09(m,1H),1.81(d,J＝23.6Hz,4H),1.43(s,18H),0.87(dd,J＝14.5,6.9Hz,6H). 13 C NMR(126MHz,CDCl 3 )δ171.77,171.50,171.13,165.53,160.57,155.49,154.76,149.59,134.02,130.84,130.29,130.20,121.82,118.12,118.09,115.52,115.44,101.31,80.95,80.43,57.31,55.77,53.41,52.38,52.26,52.10,46.96,37.36,37.12,31.22,29.67,28.25,18.82,17.74.
as can be confirmed from NMR data analysis of the product, the method of this example gave an etherified tyrosine compound (I-28).
Example 7
The structural formula of the olefination tyrosine compound is as follows:the preparation method comprises the following steps:
the structure of the substrate used for the synthesis of (I-30) is shown in the following formula:
0.1mmol (I-30 a) was weighed into 1.5mL of methylene chloride solvent, 0.01mmol of palladium trifluoroacetate, 0.3mmol of tetrabutylammonium bromide, 0.1mmol of potassium carbonate, 0.3mmol of tert-butyl peroxybenzoate, 0.6mmol (I-30 b) was added thereto, and the mixture was reacted at 37℃for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, washed 3 times with dichloromethane, and the organic phase was collected and concentrated in vacuo. Adding 10mL of ethyl acetate and 5mL of water into a separating funnel, vibrating, shaking, standing, separating, taking an organic phase, and using anhydrous Na 2 SO 4 Drying, vacuum concentrating to obtain crude product, and purifying by column chromatography to obtain 45.1mg of olefine etherified tyrosine compound.
The product alkene etherified tyrosine compound is taken for nuclear magnetic detection, and NMR data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.94(d,J＝12.2Hz,1H),7.14(s,2H),7.06–7.04(m,2H),7.03–7.00(m,2H),6.91(d,J＝8.1Hz,2H),6.72(d,J＝8.4Hz,2H),6.36(d,J＝7.8Hz,2H),5.69(d,J＝12.1Hz,1H),4.84(ddt,J＝19.3,7.9,5.8Hz,2H),3.86(dd,J＝9.7,4.2Hz,2H),3.73(s,3H),3.71(s,3H),3.19–3.05(m,4H),1.45(d,J＝1.3Hz,18H),0.95(d,J＝2.8Hz,18H). 13 C NMR(126MHz,CDCl 3 )δ172.29,171.71,171.48,170.67,165.58,160.64,155.58,154.80,149.66,130.94,130.31,130.21,121.76,118.22,115.62,101.30,80.06,79.95,62.44,62.25,54.40,53.29,53.09,52.42,52.24,37.68,37.21,36.90,34.50,34.36,28.33,26.44,26.39.
as can be confirmed from NMR data analysis of the product, the method of this example gave an etherified tyrosine compound (I-30).
Example 8
The structural formula of the olefination tyrosine compound is as follows:the preparation method comprises the following steps: 0.1mmol Boc-Tyr-OMe was weighed into 1.5mL dichloromethane solvent, 0.01mmol palladium trifluoroacetate, 0.3mmol tetrabutylammonium bromide, 0.1mmol potassium carbonate, 0.3mmol tert-butyl peroxybenzoate, 0.6mmol menthol was added thereto and reacted at 37℃for 24h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, washed 3 times with dichloromethane, and the organic phase was collected and concentrated in vacuo. Adding 10mL of ethyl acetate and 5mL of water into a separating funnel, vibrating, shaking, standing, separating, taking an organic phase, and using anhydrous Na 2 SO 4 Drying, vacuum concentrating to obtain crude product, and purifying by column chromatography to obtain 38.2mg of olefine etherified tyrosine compound.
The product alkene etherified tyrosine compound is taken for nuclear magnetic detection, and NMR data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.76(d,J＝12.2Hz,1H),7.14(d,J＝8.4Hz,2H),7.01(d,J＝8.6Hz,2H),5.54(d,J＝12.2Hz,1H),5.01(d,J＝8.3Hz,1H),4.77(td,J＝10.9,4.4Hz,1H),4.59(q,J＝6.6Hz,1H),3.73(s,3H),3.08(ddd,J＝50.3,13.9,6.0Hz,2H),2.03(dtd,J＝12.0,3.7,1.8Hz,1H),1.89(pd,J＝7.0,2.8Hz,1H),1.72–1.67(m,2H),1.52(tt,J＝6.7,3.3Hz,1H),1.43(s,9H),1.41–1.37(m,2H),1.10–0.98(m,2H),0.91(dd,J＝6.8,5.6Hz,6H),0.79(d,J＝6.9Hz,3H).
13 C NMR(126MHz,CDCl3)δ172.17,166.81,158.76,154.95,132.80,130.80,118.14,102.57,80.06,73.80,54.39,52.30,47.15,41.07,37.72,34.29,31.40,29.69,28.29,26.36,23.57,22.03,20.74,16.47.
as can be confirmed from NMR data analysis of the product, the method of this example gave an etherified tyrosine compound (I-31).
EXAMPLE 9 tyrosine C (sp 2)Application of-O-olefine etherification in protein modification uses Bovine Serum Albumin (BSA) as modified protein, acrylated BODIPY as labeled substrate, palladium trifluoroacetate as catalyst, meCN solution (volume ratio: meCN: H) 2 O=1:3) as solvent, BSA fluorescent labeling was performed. The reaction equation is as follows:
the method comprises the following steps:
1mg BSA (1 eq) and 500. Mu.g acrylated BODIPY are weighed and dissolved in 4.5ml PBS with pH of 8.4, and evenly mixed to obtain PBS mixed solution; weighing palladium trifluoroacetate (0.1 eq) and TBAB (2 eq) TBPB (1.5 eq) and dissolving in MeCN, and uniformly mixing to obtain a MeCN mixture; 900. Mu.L of PBS mixture and 300. Mu.L of LMeCN mixture were mixed uniformly in 2.5mL ep tube, and the mixed reaction tube was placed in a metal bath reactor and shaken overnight at 37 ℃. The reaction solution obtained was put into a dialysis bag (MW: 35000), and dialyzed 3 times in 10X neutral PBS for 2 hours each. Adding 20 mu L of dialyzed protein into an ep tube, adding 2.5 mu L of loading buffer, boiling for 10min at 95 ℃, adding 10 mu L of dialyzed protein into a sample adding hole, switching in a power supply 90V for 1h, adjusting the voltage to 120V, keeping for 0.5h, and taking off the gel plate after the completion of the dialysis. And placing the glue plate in a fluorescent channel to observe the marking condition, and finally, baking and dyeing. The fluorescence imaging diagram and the baking and dyeing diagram of the tyrosine site selective modification BSA protein marker are respectively shown in fig. 2 and 3.
The results of the example show that the reaction can successfully label BSA, meanwhile, only weak fluorescent labels exist in the control group without the catalyst, and three groups of 15:1, 10:1 and 5:1 are respectively set in the mass ratio of protein to fluorescent dye, so that the results show that the labeling effect is similar and no large difference exists. The number of tyrosine residues contained in the protein is limited, namely the labeling results are similar or identical.
Comparative example 1
The main difference from example 1 is that: the catalyst is tetraphenylphosphine palladium. Other operation steps were the same as in example 1.
The reaction results are: the product obtained after purification by column chromatography was 11.8mg.
Comparative example 2
The main difference from example 1 is that: the catalyst is dichlorophenyl phosphine palladium. Otherwise, the same as in example 1 was used.
The reaction results are: the product obtained after purification by column chromatography was 8.68mg.
Comparative example 3
The main difference from example 1 is that: the catalyst is DPPF palladium dichloride. Otherwise, the same as in example 1 was used.
The reaction results are: the product obtained after purification by column chromatography was 6.6mg.
By combining the reaction results of example 1 and comparative examples 1 to 3, it is demonstrated that the reaction takes place under the catalysis of other catalysts, such as tetrakis triphenylphosphine palladium, dichlorophenyl phosphine palladium, DPPF palladium dichloride, and the reaction yield is low. In the etherification reaction of the alkene, the catalyst is only palladium acetate and palladium trifluoroacetate, and the etherification reaction of the alkene has good effect.
Comparative example 4
The main difference from example 1 is that: the oxidant is oxygen. Otherwise, the same as in example 1 was used.
The reaction results are: the product obtained after purification by column chromatography was 6.35mg.
Comparative example 5
The main difference from example 1 is that: the oxidant is hydrogen peroxide. Otherwise, the same as in example 1 was used.
The reaction results are: the product obtained after purification by column chromatography was 6.78mg.
Comparative example 6
The main difference from example 1 is that: the oxidant is tert-butyl hydroperoxide. Otherwise, the same as in example 1 was used.
The reaction results are: the product obtained after purification by column chromatography was 18.73mg.
Comparative example 7
The main difference from example 1 is that: the oxidant is copper acetate. Otherwise, the same as in example 1 was used.
The reaction results are: is substantially nonreactive.
Comparative example 8
The main difference from example 1 is that: the oxidant is silver acetate. Otherwise, the same as in example 1 was used.
The reaction results are: is substantially nonreactive.
The reaction results of example 1 and comparative examples 4 to 8 are combined, thereby demonstrating that the reaction yield is low when other oxidizing agents such as oxygen, hydrogen peroxide, t-butyl hydroperoxide, copper acetate, silver acetate are added to promote the reaction, wherein copper acetate or silver acetate is not substantially reacted when the oxidizing agents are added. In the etherification reaction of the alkene, the oxidant is selected from potassium persulfate, silver acetate and tert-butyl peroxybenzoate, and the etherification reaction of the alkene has good effect.
Comparative example 9
The main difference from example 1 is that: the reaction temperature was 15 ℃. Otherwise, the same as in example 1 was used.
The reaction results are: the product obtained after purification by column chromatography was 19.91mg.
Comparative example 9
The main difference from example 1 is that: the reaction temperature was 60 ℃. Otherwise, the same as in example 1 was used.
The reaction results are: the product obtained after purification by column chromatography was 20.01mg.
As is clear from comparison of the reaction results of example 1 and comparative examples 8 to 9, the reaction yields were lower when the reaction temperature of the etherification reaction was 15℃or 60 ℃. As can be seen from the other examples, in the etherification reaction of the present invention, the reaction temperature is preferably 20 to 55℃and the reaction temperature is preferably a reaction temperature.
The method for purifying the sample by the column chromatography of the embodiment of the invention, namely the comparative example, comprises the following steps: and (3) taking a mixed solution of ethyl acetate and petroleum ether with the volume ratio of 1:10 as a mobile phase, tracking and collecting eluent with the Rf value of 0.3-0.5 by TLC, removing the solvent from the collected eluent under reduced pressure, and drying to obtain the product. Meanwhile, through verification, the invention has better elution effect when the volume ratio of the mobile phase to the ethyl acetate to the petroleum ether is 1:8-10.
In the embodiment of the invention, the reaction is realized in the pressure-resistant pipe under the closed condition, so that when the reaction temperature is higher than the boiling point of the solvent, the reaction can be realized at the temperature.
The raw materials and equipment used in the invention are common raw materials and equipment in the field unless specified otherwise; the methods used in the present invention are conventional in the art unless otherwise specified.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and any simple modification, variation and equivalent transformation of the above embodiment according to the technical substance of the present invention still fall within the scope of the technical solution of the present invention.

Claims (10)

1. A method for the etherification of a tyrosine-containing compound by an alkene, characterized by: the method comprises the following steps:
the preparation method comprises the steps of reacting a tyrosine-containing compound with a structural general formula (II) with an olefin compound with a structural general formula (III) in a solvent under the action of a catalyst, an oxidant, an additive and alkali to obtain an olefin etherified tyrosine compound with a structural general formula (I):
；
wherein R is 1 A linear or branched alkoxy group selected from C1 to C7, a linear or branched alkoxycarbonyl group selected from C1 to C7; r is R 2 A linear or branched alkyl group selected from C1 to C7; r is R 3 Selected from methoxycarbonyl, ethoxycarbonyl, phenyl, phenoxycarbonyl, chlorobenzene, t-butyl ether.
2. A method for the etherification of a tyrosine-containing compound according to claim 1, wherein: the R is 1 Is acetyl or t-butoxycarbonyl, R 2 Methyl or ethyl; r is R 3 Selected from methoxycarbonyl, ethoxycarbonyl, phenyl, phenoxycarbonyl, p-methylphenoxycarbonyl, chlorobenzene or t-butyl ether.
3. A method for the etherification of a tyrosine-containing compound according to claim 1, wherein: the ratio of the amounts of the tyrosine-containing compound, the olefin compound, the catalyst, the oxidant, the additive and the alkali is 1:1-3:0.1-0.3:1-3:1-2:0.5-1.2.
4. A method for the etherification of a tyrosine-containing compound according to claim 1, wherein: the catalyst is palladium acetate and/or palladium trifluoroacetate.
5. A method for the etherification of a tyrosine-containing compound according to claim 1, wherein: the oxidant is selected from one or more of potassium persulfate, silver acetate and tert-butyl peroxybenzoate.
6. A method for the etherification of a tyrosine-containing compound according to claim 1, wherein: the additive is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium iodide and tetrabutylammonium chloride.
7. A method for the etherification of a tyrosine-containing compound according to claim 1, wherein: the base is selected from one or more of potassium carbonate, cesium carbonate, potassium fluoride and cesium fluoride.
8. A method for the etherification of a tyrosine-containing compound according to claim 1, wherein: the solvent is dichloromethane.
9. A method for the etherification of a tyrosine-containing compound according to claim 1, wherein: the reaction is followed by purification, the purification method comprises the following steps:
(1) Filtering the reaction product by diatomite, washing by DCM, collecting an organic phase, concentrating, extracting by ethyl acetate and water, taking an organic layer, drying, filtering, and concentrating to obtain a crude product;
(2) And (3) performing silica gel column chromatography on the crude product, taking a mixed solution of ethyl acetate and petroleum ether as a mobile phase, collecting eluent with the Rf value of 0.3-0.5, and removing the solvent from the eluent to obtain the etherification tyrosine compound.
10. A method for targeted modification of a polypeptide or protein, characterized by: the method comprises the following steps:
chemically modifying a polypeptide or protein based on the method of the etherification reaction according to any one of claims 1 to 9;
wherein the polypeptide or protein contains tyrosine.
CN202311074251.XA 2023-08-24 2023-08-24 Tyrosine alkene etherification reaction and directional modification of polypeptide or protein tyrosine Pending CN117105805A (en)

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