CN108484461B - Preparation method of alkynylamide-mediated thioamide and application of thioamide in thiopolypeptide synthesis - Google Patents

Preparation method of alkynylamide-mediated thioamide and application of thioamide in thiopolypeptide synthesis Download PDF

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CN108484461B
CN108484461B CN201810280726.3A CN201810280726A CN108484461B CN 108484461 B CN108484461 B CN 108484461B CN 201810280726 A CN201810280726 A CN 201810280726A CN 108484461 B CN108484461 B CN 108484461B
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thioester
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赵军锋
王辉
杨进华
王长流
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Guangzhou Xinpeptide Biopharmaceutical Technology Co ltd
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Abstract

The invention discloses a method for selectively synthesizing thiocarbonyl ester and common thioester mediated by alkynylamide, and further uses the common thioester for preparing amide and polypeptide, and uses the thiocarbonyl ester for preparing thioamide and thiopolypeptide. Under the condition of 40 ℃ below zero, the alkyne amide and the thiocarboxylic acid in the m-xylene are subjected to addition reaction to selectively obtain thiocarbonyl ester and common thioester (3: 1); ordinary thioester can react with amine to produce amide, polypeptide; the thiocarbonyl ester can be chemically reacted with amines to form thioamides or thiopolypeptides. The method has the advantages of mild reaction conditions, no need of metal catalysts, high reaction speed, high yield, simple operation and wide application range. In the thiocarboxylic acid with chirality at the alpha position of carboxyl, racemization does not occur when thiocarbonyl ester forms thioamide bond or thiopeptide bond, or common thioester forms amide bond or peptide bond.

Description

Preparation method of alkynylamide-mediated thioamide and application of thioamide in thiopolypeptide synthesis
Technical Field
The invention relates to a method for selectively synthesizing thiocarbonyl ester and common thioester, and application of thiocarbonyl ester in preparing thioamide, thiopolypeptide and common thioester in preparing amide and polypeptide, in particular to a method for selectively and efficiently preparing thiocarbonyl ester and common thioester compounds at room temperature under the condition of no metal catalysis, and a method for preparing thioamide, thiopolypeptide and common thioester by using thiocarbonyl ester to prepare amide and polypeptide.
Background
In recent years, with the gradual and slow development of new organic micromolecule medicines, polypeptide, protein medicines, diagnostic reagents and the like are more and more emphasized due to the characteristics of small toxic and side effects and the like, and the polypeptide also becomes an important source for research and development of new medicines. However, the polypeptide drug has large relative molecular mass and poor lipid solubility, and is difficult to permeate a biological membrane; and the polypeptide drug is inevitably identified by in vivo proteolytic enzyme, is degraded quickly after entering the organism, and has poor stability. Therefore, the polypeptide drugs cannot be taken orally generally, and can be only administered by injection, inhalation and the like. Its market potential is severely limited due to its route of administration limitations. The improvement of polypeptide drugs is to develop new dosage forms on one hand, and the comprehensive modification of the chemical structure of polypeptide drugs on the other important hand.
The currently used methods for polypeptide modification mainly include substitution of unnatural amino acids, N-methyl substitution of amide bonds, and substitution of thioamine bonds (tetrahedron.1985,41(23), 5595-5606). One of the most synthetically accessible functional groups for amide bond replacement is the thioamide bond, and merely replacing the amide carbonyl oxygen with sulfur is a modification with minimal change in the amide bond structure. Experiments have shown that thioamide bonds are isosteres of oxoamide bonds (Phosphorus, sulfurr, and Silicon and the Related elements.1996,108(1-4), 257-. Despite similar structures, the two functional groups exhibit different chemical and physical properties. Such as: the bond energy of C ═ S is weaker than that of C ═ O (130kcal mol)-1vs 170kcal mol-1) (Angew chem. 1960,72(16),602-,2052 ═ S) bond is more susceptible to nucleophilic substitution than C ═ O bond; thioamides N-H bonds are more acidic (pKa 18.5vs 25.5) than amide N-H bonds (J Am Chem Soc.1988,110(17),5903-5904), and therefore thioamides have a stronger hydrogen donor than oxoamides, while sulfur is a weaker electron acceptor due to delocalization of part of the electrons on the nitrogen atom; thioamides exhibit unique absorption peaks (π - π maximum absorption peak 270nm vs 200nm) (Canadian Journal of chemistry 1987,65(9),2100-2105) and redox properties (Eox 1.21V vs 3.29V) (J Am Chem Soc.1988,110(17), 5903-5904). Because of their unique properties, thiopolypeptides are used in many fields, such as to increase the stability of polypeptide peptide chains to enzymatic degradation; analyzing the importance of specific hydrogen bonds to secondary structure folding; as fluorescent extract and kill agent, etc.
Recently, we have developed a new class of efficient condensation reagents, acetylenic amides, for the condensation of carboxylic acids with amines under mild conditions. If the addition reaction of thiocarboxylic acids with alkynylamides can be carried out under mild and simple conditions to selectively form thiocarbonyl esters or common thioesters, we will be able to successfully develop a new process for the formation of thioamides and common amides using alkynylamides as condensation reagents.
Disclosure of Invention
The invention aims to solve the problem that thiocarbonyl ester and common thioester are selectively obtained by adding thiocarboxylic acid and alkynylamide in the prior art, and then the thiocarbonyl ester is used for preparing thioamide and thiopolypeptide, and the common thioester is used for preparing amide and polypeptide. Provides a simple, high-efficiency and practical method for preparing thioamide and thiopolypeptide compounds.
We first conducted a systematic and intensive study of the addition reaction of thiocarboxylic acids with alkynylamides, which was found to be very solvent sensitive. Under the condition of room temperature and no metal catalysis, in solvents such as N, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, dimethyl sulfoxide and the like, basically, a product cannot be obtained; in large polar solvents such as acetone, acetonitrile, methanol and the like, the reaction can occur, but ordinary thioester is obtained in a higher proportion; in halogenated hydrocarbon solvent, such as dichloromethane, 1, 2-dichloromethane, chloroform and the like, thiocarbonyl ester and common thioester are obtained basically in the ratio of 1: 1; in benzene solvents, such as m-xylene, benzene, etc., thiocarbonyl ester and common thioester were obtained in a yield of 2: 1. When the reaction selectivity of different alkynylamides is examined, the common thioester compound is obtained with single selectivity when the alkynylamide end group is protected by silicon-containing groups such as TMS, TIPS and the like, and the thiocarbonyl ester and the common thioester are obtained with higher selectivity of 1:3.4 when the alkynylamide end group is methyl. Referring to the previous work of our group of subjects, we found further research that thiocarbonyl esters can be used as simple and readily available thiocarbonylation reagents, which can be smoothly reacted with primary or secondary amines at room temperature to prepare thioamides and thiopeptides; a common thioester is an activated ester that reacts readily with primary or secondary amines at room temperature to produce amides and polypeptides. We therefore conclude the present invention, which is achieved in the following manner.
The first part of the invention provides a mild and efficient method for selectively synthesizing thiocarbonyl ester and common thioester compounds, which comprises the following steps:
(1) adding 0.2-2.0 mmol of alkynylamide and a proper amount of benzene solvent into a clean reaction tube, adding 0.2-2.0 mmol of thiocarboxylic acid, and reacting under the condition of continuously stirring at-40-45 ℃;
(2) detecting the previous step of reaction by TLC point plate, after the previous step of reaction is finished, concentrating the solvent and carrying out column chromatography to obtain pure thiocarbonyl ester and common thioester (the ratio of the thiocarbonyl ester to the common thioester is about 2: 1).
The chemical reaction formula in the step (1) is as follows:
Figure BDA0001614567900000031
in the formula, 1 represents alkynylamide, 2 represents thiocarboxylic acid, 3 represents thiocarbonyl ester compound, and 4 represents thioester compound; r1Selected from hydrogen, alkyl, aryl, alkoxy, alkylthio, etc., and EWG (electron withdrawing group) selected from alkylsulfonyl, arylsulfonyl, aroyl, alkanoyl, nitro, nitrilePhosphono, etc., R2Is alkyl or aryl, R3Selected from alkyl, aryl, alkenyl, alkynyl.
In this production method, the carboxylic acid may be a thiocarboxylic acid such as an aliphatic thioacid, an aromatic thioacid, a heterocyclic thioacid, an alkynylthio acid, an alkenylthio acid, an α -aminothio acid, or a β -aminothio acid.
In the preparation method, the molar ratio of the alkynylamide to the thiocarboxylic acid is 0.1-10.
In the preparation method, the benzene solvent is m-xylene or benzene; the benzene solvent may be replaced by methylene chloride, chloroform, 1, 2-dichloroethane or the like, and the ratio of the thiocarbonyl ester thus obtained to the ordinary thioester is approximately 1: 1.
In this preparation method, the optimum temperature for the reaction is-40 ℃.
In a second aspect of the invention, there is provided the use of a thiocarbonyl ester compound in the synthesis of a thioamide and a thiopolypeptide, which comprises the steps of:
(1) adding 0.2-2.0 mmol of thiocarbonyl ester compound and a proper amount of dichloromethane solvent into a clean reaction tube, adding 0.2-2.0 mmol of amine compound, and continuously stirring for reaction at-78-45 ℃;
(2) detecting the reaction of the previous step by TLC spot plate, and after the reaction of the previous step is finished, separating and purifying by column chromatography to directly obtain the thioamide compound.
Wherein, the chemical reaction formula of the step (1) is as follows:
Figure BDA0001614567900000032
in the formula, 3 represents a thiocarbonyl ester compound, 5 represents an amine compound, 6 represents a thioamide compound, and 7 represents an amide by-product; r1Selected from hydrogen, alkyl, aryl, alk (ar) oxy, alk (ar) thio and the like, EWG (electron withdrawing group) selected from alkylsulfonyl, arylsulfonyl, aroyl, alkanoyl, nitro, nitrile, phosphonyl, sulfonimide and the like, R2Selected from alkyl or aryl, R3Selected from alkyl, aryl, alkenyl, alkynylEtc. R4Selected from hydrogen, aliphatic substituent groups, aromatic substituent groups, R5Selected from hydrogen, aliphatic substituent groups, aromatic substituent groups.
In this application method, the amine compound may be a primary amine or a secondary amine, including aliphatic amines and aromatic amines.
In the application method, the ratio of the thiocarbonyl ester compound to the amine compound is 0.1-10.
In this application, methylene chloride is used as a solvent, and it may be replaced with water, or an organic solvent such as N, N-dimethylformamide, chloroform, 1, 2-dichloroethane, etc.
In this application, the optimum temperature for the reaction is-40 ℃.
In a third aspect of the present invention, the use of a general thioester compound for amide and polypeptide synthesis, comprising the steps of:
(1) adding 0.2-2.0 mmol of thioester compound and a proper amount of dichloromethane solvent into a clean reaction tube, adding 0.2-2.0 mmol of amine compound, and continuously stirring for reaction at-78-45 ℃;
(2) detecting the reaction of the previous step by TLC spot plate, and after the reaction of the previous step is finished, separating and purifying by column chromatography to directly obtain the thioamide compound.
Wherein, the chemical reaction formula of the step (1) is as follows:
Figure BDA0001614567900000041
in the formula, 4 represents a common thioester compound, 5 represents an amine compound, 8 represents an amide compound, and 9 represents a thioamide by-product; r1Selected from hydrogen, alkyl, aryl, alk (ar) oxy, alk (ar) thio and the like, EWG (electron withdrawing group) selected from alkylsulfonyl, arylsulfonyl, aroyl, alkanoyl, nitro, nitrile, phosphonyl, sulfonimide and the like, R2Selected from alkyl or aryl, R3Selected from alkyl, aryl, alkenyl, alkynyl, etc., R4Selected from hydrogen, aliphatic substituent groups, aromatic substituent groups, R5Selected from hydrogen, aliphatic substituent groups, aromatic substituent groups.
In this application method, the amine compound may be a primary amine or a secondary amine, including aliphatic amines and aromatic amines.
In the application method, the ratio of the thiocarbonyl ester compound to the amine compound is 0.1-10.
In this application, methylene chloride is used as a solvent, and it may be replaced with water, or an organic solvent such as chloroform or 1, 2-dichloroethane.
In this application, the optimum temperature for the reaction is 25 ℃.
The invention has the beneficial effects that: (1) the method realizes the selective synthesis of the thiocarbonyl ester and the common thioester compound by the simple alkynylamide and the thiocarboxylic acid under the conditions of room temperature and no metal catalysis, so that the synthesis of the thiocarbonyl ester and the common thioester compound is milder, more direct and simpler, and the potential application value can be better realized; (2) the synthesis of the thioamide bond by the thiocarbonyl ester compound and the primary and secondary amine compounds is realized, and the reaction can effectively control the racemization of amino acid in the synthesis process, so that the synthesis of the thioamide bond and the thiopeptide bond is simpler and more efficient; (3) the synthesis of the amido bond by the thioester compound and the primary and secondary amine compounds, especially the thioester compound formed by natural alpha-amino acid and other chiral acid and alkynylamide, can effectively control the racemization of amino acid in the synthesis process, thereby leading the synthesis of the amido bond and the peptide bond to be simpler and more efficient, leading the thioester compound obtained by single selectivity to be applied to the natural connection of polypeptide and having wide scientific research and industrial application prospects.
Detailed Description
The following detailed description will explain the advantageous effects of the present invention with reference to examples 1 to 19, and is intended to help the reader to better understand the spirit of the present invention, but not to limit the scope of the present invention.
The first part is a specific example of a mild and efficient preparation method for selectively synthesizing thiocarbonyl ester and common thioester, examples 1-5.
Example 1
N-methylacetylene p-toluenesulfonamide (0.24mmol), thioacetic acid (0.20mmol), appropriate amount of dichloromethane as solvent were added to a clean 25mL reaction tube, reacted at room temperature for 5min, checked by TLC dot plate, after the reaction was finished, the solvent was concentrated and column chromatographed to give pure product, yellow liquid a1 (yield 53%) and white solid a2 (yield 46%). The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000051
1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.0Hz,2H),7.26(d,J＝8.0Hz,2H),4.72 (d,J＝2.8Hz,1H),4.54(d,J＝2.8Hz,1H),2.99(s,3H),2.50(s,3H),2.37(s,3H)；13C NMR(100 MHz,CDCl3)δ217.5,150.2,144.3,133.5,129.6,128.0,100.4,38.2,34.0,21.6ppm.
Figure BDA0001614567900000052
1H NMR(400MHz,CDCl3)δ7.58(d,J＝8.0Hz,2H),7.25(d,J＝8.0Hz,2H),5.84(s,1H), 5.55(s,1H),2.90(s,3H),2.38(s,3H),2.22(s,3H)；13C NMR(100MHz,CDCl3)δ192.9,144.1, 135.4,134.3,130.1,129.6,127.9,36.4,30.2,21.6ppm.
example 2
N-methylacetylene p-toluenesulfonamide (0.24mmol), thiobenzoic acid (0.20mmol), appropriate amount of dichloromethane as solvent were added to a clean 25mL reaction tube, reacted at room temperature for 5min, checked by TLC dot plate, after the reaction was completed, the solvent was concentrated and column chromatographed to give pure product, yellow liquid b1 (55% yield) and colorless liquid b2 (43% yield). The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000061
1H NMR(400MHz,CDCl3)δ8.10(dd,J＝8.5,1.2Hz,2H),7.72(d,J＝8.3Hz,2H), 7.56(ddt,J＝8.7,7.6,1.2Hz,1H),7.36(t,J＝7.9Hz,2H),7.25(d,J＝7.9Hz,2H),4.93(d,J＝ 2.9Hz,1H),4.81(d,J＝2.8Hz,1H),3.12(s,3H),2.39(s,3H)；13C NMR(100MHz,CDCl3)δ 208.6,150.1,144.2,137.4,133.8,133.4,129.5,129.4,128.2,128.1,101.5,38.1,21.6ppm.
Figure BDA0001614567900000062
1H NMR(400MHz,CDCl3)δ7.83(dd,J＝8.3,1.3Hz,2H),7.70(d,J＝8.3Hz,2H),7.59(t, J＝7.1Hz,1H),7.44(t,J＝7.9Hz,2H),7.33–7.25(m,2H),6.00(d,J＝0.8Hz,1H),5.75(d,J＝ 0.8Hz,1H),3.07(s,3H),2.42(s,3H)；13C NMR(100MHz,CDCl3)δ189.2,143.9,136.0,135.2, 134.7,134.0,130.5,129.6,128.8,127.9,127.6,36.7,21.6ppm.
example 3
N-Methylalkyne p-toluenesulfonamide (0.24mmol), p-chlorothiobenzoic acid (0.20mmol) were added to a clean 25mL reaction tube, appropriate amount of dichloromethane was added as solvent, reacted at room temperature for 5min, checked by TLC dot plate, after the reaction was finished, the solvent was concentrated and column chromatographed to give pure product, yellow solid c1 (57% yield) and yellow solid c2 (41% yield). The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000063
1H NMR(400MHz,CDCl3)δ8.06(d,J＝8.7Hz,2H),7.71(d,J＝8.3Hz,2H),7.34 (d,J＝8.7Hz,2H),7.27(d,J＝8.2Hz,2H),4.92(d,J＝2.9Hz,1H),4.75(d,J＝2.8Hz,1H),3.11 (s,3H),2.41(s,3H)；13C NMR(100MHz,CDCl3)δ206.9,150.2,144.2,140.1,135.9,133.6, 130.7,129.5,128.4,128.1,101.3,38.3,21.6ppm.
Figure BDA0001614567900000071
1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.6Hz,2H),7.69(d,J＝8.2Hz,2H),7.41(d,J＝ 8.6Hz,2H),7.29(d,J＝8.0Hz,2H),5.96(s,1H),5.74(s,1H),3.07(s,3H),2.41(s,3H)；13C NMR(100MHz,CDCl3)δ188.1,144.0,140.4,135.1,134.6,134.4,130.3,129.6,129.1,128.9, 127.9,36.9,21.6ppm.
example 4
N-methylyne p-toluenesulfonamide (0.24mmol), N-benzyloxycarbonyl-L-glycine (0.20mmol) and the appropriate amount of m-xylene as solvent were added to a clean 25mL reaction tube, reacted at room temperature for 5min, checked by TLC dot plate, and after the reaction was complete, the solvent was concentrated and column chromatographed to give the pure product as yellow liquid d1 (68% yield) and colorless liquid d2 (30% yield). The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000072
1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.0Hz,2H),7.34–7.16(m,7H),5.46(t,J＝ 5.8Hz,1H),5.07(s,2H),4.74(d,J＝3.0Hz,1H),4.53(d,J＝3.0Hz,1H),4.07(d,J＝5.9Hz, 2H),2.95(s,3H),2.35(s,3H)；13C NMR(100MHz,CDCl3)δ215.0,156.1,149.7,144.5,136.3, 133.2,129.7,128.5,128.2,128.1,128.0,100.3,67.1,51.8,38.0,21.6ppm.
Figure BDA0001614567900000073
1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.0Hz,2H),7.43–7.07(m,7H),5.74(s,1H),5.54 (s,1H),5.49–5.36(m,1H),5.03(s,2H),3.97(d,J＝6.1Hz,2H),2.88(s,3H),2.34(s,3H)；13C NMR(100MHz,CDCl3)δ195.2,156.2,144.2,136.0,134.7,134.1,130.2,129.7,128.6,128.3, 128.1,127.9,67.4,50.5,36.7,21.6ppm.
example 5
N-methylyne p-toluenesulfonamide (0.24mmol), N-benzyloxycarbonyl-L-phenylalanine (0.20mmol), appropriate amount of m-xylene as solvent were added to a clean 25mL reaction tube, reacted at room temperature for 5min, checked by TLC dot plate, after the reaction was completed, the solvent was concentrated and column chromatographed to give the pure product as yellow liquid e1 (65% yield) and colorless liquid e2 (34% yield). The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000081
1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.0Hz,2H),7.38–7.28(m,7H),7.28– 7.22(m,3H),7.20–7.11(m,2H),5.41(d,J＝9.0Hz,1H),5.07(d,J＝1.9Hz,2H),4.91–4.83(m, 1H),4.81(d,J＝3.0Hz,1H),4.67(d,J＝3.0Hz,1H),3.24(dd,J＝13.9,5.7Hz,1H),3.04(dd,J＝ 13.9,7.1Hz,1H),2.98(s,3H),2.42(s,3H)；13C NMR(100MHz,CDCl3)δ217.8,155.4,149.7, 144.5,136.3,135.6,133.0,129.6,129.6,128.5,128.4,128.2,128.1,128.0,127.0,102.0,66.9,62.6, 40.5,37.9,21.6ppm.
Figure BDA0001614567900000082
1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.0Hz,2H),7.39–7.32(m,3H),7.31–7.23(m, 7H),7.10(dd,J＝7.4,2.0Hz,2H),5.84(s,1H),5.58(s,1H),5.12(d,J＝8.5Hz,1H),5.06(s,2H), 4.75–4.57(m,1H),3.19–2.97(m,2H),2.92(s,3H),2.41(s,3H)；13C NMR(100MHz,CDCl3)δ 198.0,155.5,144.1,135.9,135.1,135.0,134.3,130.0,129.6,129.3,128.8,128.6,128.3,128.0, 127.9,127.4,67.3,61.5,38.2,36.6,21.6ppm.
second, specific embodiments of the use of thionyl compounds in the synthesis of amides and polypeptides, examples 6-14.
Example 6
Adding alpha-thioacetoxyalkenylamide (0.20mmol) and 2-phenylethylamine (0.24mmol) into a clean 25mL reaction tube, adding a proper amount of dichloromethane as a solvent, reacting for 5 minutes at 25 ℃, detecting by a TLC point plate, and after the reaction is finished, concentrating and carrying out column chromatography on an organic layer to obtain a pure product, namely a yellow liquid with the yield of 98%. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000091
1H NMR(400MHz,CDCl3)δ7.33(t,J＝7.3Hz,2H),7.28–7.19(m,3H),3.92(q,J ＝6.9Hz,2H),2.98(t,J＝7.1Hz,2H),2.50(s,3H)；13C NMR(100MHz,CDCl3)δ201.0,138.1, 128.8,128.7,126.8,47.1,34.3,33.8ppm.
example 7
Adding alpha-thiobenzoyloxyalkenylamide (0.20mmol) and 2-phenylethylamine (0.24mmol) into a clean 25mL reaction tube, adding a proper amount of dichloromethane as a solvent, reacting for 20 minutes at 25 ℃, detecting by a TLC point plate, and after the reaction is finished, concentrating and carrying out column chromatography on an organic layer to obtain a pure product, namely a yellow liquid with the yield of 98%. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000092
1H NMR(400MHz,CDCl3)δ7.74–7.52(m,3H),7.40(t,J＝7.4Hz,1H),7.37–7.28 (m,4H),7.28–7.20(m,3H),4.05(td,J＝7.0,5.5Hz,2H),3.05(t,J＝7.0Hz,2H)；13C NMR(100 MHz,CDCl3)δ199.2,141.8,138.3,131.1,128.9,128.8,128.5,126.9,126.6,47.5,33.8ppm.
example 8
Alpha-p-chlorobenzothioyloxyalkenylamide (0.20mmol) and 2-morpholinoethylamine (0.24mmol) were added to a clean 25mL reaction tube, and appropriate amount of dichloromethane was added as solvent, followed by 5 minutes at room temperature, TLC dot plate detection, after the reaction was completed, the organic layer was concentrated and column chromatographed to give pure product as yellow solid with 95% yield. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000093
1H NMR(400MHz,CDCl3)δ8.31(s,1H),7.71(d,J＝8.5Hz,2H),7.37(d,J＝8.5 Hz,2H),3.85(q,J＝5.8Hz,2H),3.72(t,J＝4.6Hz,4H),2.73(t,J＝6.0Hz,2H),2.53(t,J＝4.5 Hz,4H)；13C NMR(100MHz,CDCl3)δ196.9,139.8,137.3,128.7,128.0,66.9,55.4,53.2,42.7 ppm.
example 9
Adding alpha-2-furancarbothioformyloxyalkenylamide (0.20mmol) and 2-phenylethylamine (0.24mmol) into a clean 25mL reaction tube, adding a proper amount of dichloromethane as a solvent, reacting for 20 minutes at room temperature, detecting by a TLC (thin layer chromatography) spot plate, and after the reaction is finished, concentrating and carrying out column chromatography on an organic layer to obtain a pure product, namely a light yellow liquid with the yield of 94%. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000101
1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.38(d,J＝1.6Hz,1H),7.37–7.30(m, 3H),7.29–7.20(m,3H),6.45(dd,J＝3.6,1.8Hz,1H),4.13–4.01(m,2H),3.04(t,J＝7.1Hz, 2H)；13C NMR(100MHz,CDCl3)δ182.5,152.3,143.7,138.2,128.8,128.7,126.8,117.7,113.1, 45.9,34.2ppm.
example 10
Adding alpha-sulfo-amiloride oxyalkenylamide (0.20mmol) and N-ethyl-2-aminomethyl pyrrolidine (0.24mmol) into a clean 25mL reaction tube, adding a proper amount of dichloromethane as a solvent, reacting at room temperature for 20 minutes, detecting by a TLC point plate, and after the reaction is finished, concentrating and carrying out column chromatography on an organic layer to obtain a pure product, namely a light yellow solid with the yield of 94%. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000102
1H NMR(400MHz,CDCl3)δ9.91(s,1H),8.99(s,1H),6.31(s,1H),5.72(s,2H),4.15 (d,J＝14.8Hz,1H),3.93(s,3H),3.60(dd,J＝14.8,4.6Hz,1H),3.23(t,J＝8.1Hz,1H),3.12(q, J＝7.4Hz,2H),2.91–2.80(m,1H),2.80–2.71(m,1H),2.31–2.16(m,2H),2.02–1.89(m,1H), 1.74(q,J＝7.8,7.0Hz,2H),1.68–1.58(m,1H),1.27(t,J＝7.4Hz,3H),1.11(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ192.4,161.0,150.6,139.6,117.7,112.1,98.4,61.4,56.2,53.3,49.7, 48.1,47.5,28.6,22.6,13.9,7.2ppm.
example 11
1- (N-methyl-p-toluenesulfonamido) ethylene-N-benzyloxycarbonyl-phenylalanine thiocarbonyl ester (0.20mmol) and leucine tert-butyl ester (0.24mmol) were added to a clean 25mL reaction tube, and an appropriate amount of methylene chloride was added as a solvent to react at-40 ℃ for 8 hours, followed by detection on a TLC dot plate, after the reaction was completed, the organic layer was concentrated and subjected to column chromatography to give a pure product as a colorless liquid in a yield of 97%. The following are the structural formula of the product, nuclear magnetic resonance experimental data and mass spectrum experimental data:
Figure BDA0001614567900000111
1H NMR(400MHz,CDCl3)δ8.15(s,1H),7.38–7.26(m,5H),7.27–7.14(m,5H), 5.86–5.62(m,1H),5.06(s,2H),4.87(q,J＝6.9Hz,1H),4.80–4.61(m,1H),3.12(d,J＝7.0Hz, 2H),1.73–1.52(m,3H),1.43(s,9H),0.91(d,J＝5.8Hz,3H),0.87(d,J＝5.8Hz,3H)；13CNMR (100MHz,CDCl3)δ202.5,170.4,155.7,136.3,136.2,129.3,128.6,128.5,128.1,128.0,127.0, 82.5,67.1,62.4,57.0,41.9,40.5,28.0,25.0,22.8,22.3ppm.
example 12
1- (N-methyl-p-toluenesulfonamido) ethylene-N-benzyloxycarbonyl-alanine thiocarbonyl ester (0.20mmol) and tert-butyl phenylalanine (0.24mmol) were added to a clean 25mL reaction tube, and an appropriate amount of methylene chloride was added as a solvent to react at-40 ℃ for 8 hours, followed by detection on TLC dot plates, after the reaction was completed, the organic layer was concentrated and subjected to column chromatography to give a pure product as a colorless liquid in a yield of 94%. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000112
1H NMR(400MHz,CDCl3)δ8.40(s,1H),7.40–7.27(m,5H),7.26–7.19(m,3H), 7.17–7.09(m,2H),5.67(s,1H),5.20(d,J＝6.2Hz,1H),5.15–4.95(m,2H),4.58(s,1H),3.50– 2.94(m,2H),1.44(d,J＝6.8Hz,3H),1.39(s,9H)；13C NMR(100MHz,CDCl3)δ204.5,169.5, 155.6,136.2,135.7,129.6,128.5,128.4,128.2,128.0,127.1,83.1,67.1,58.8,56.6,36.2,28.0,22.1 ppm.
example 13
1- (N-methyl-p-toluenesulfonamido) ethylene-N-benzyloxycarbonyl-serine ester (0.20mmol) and leucine tert-butyl ester (0.24mmol) were added to a clean 25mL reaction tube, and an appropriate amount of methylene chloride was added as a solvent to react at-40 ℃ for 6 hours, followed by detection on a TLC dot plate, after the reaction was completed, the organic layer was concentrated and subjected to column chromatography to give a pure product as a colorless liquid in 83% yield. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000121
1H NMR(400MHz,CDCl3)δ8.60(s,1H),7.35(d,J＝3.5Hz,5H),6.12(d,J＝8.0 Hz,1H),5.12(s,2H),5.02–4.88(m,1H),4.56(dt,J＝11.5,5.2Hz,1H),4.03(dd,J＝10.3,5.9 Hz,1H),3.82(s,1H),3.61(dt,J＝12.4,6.7Hz,1H),1.76–1.66(m,3H),1.46(s,9H),0.96(d,J＝ 5.9Hz,3H),0.92(d,J＝6.0Hz,3H)；13C NMR(100MHz,CDCl3)δ202.4,171.0,156.2,136.0, 128.6,128.2,128.1,83.1,67.3,65.2,60.6,57.5,40.0,28.0,25.1,22.7,22.0ppm.
example 14
1- (N-methyl-p-toluenesulfonamido) ethylene-N-benzyloxycarbonyl-complex amino acid thiocarbonyl ester (0.20mmol) and leucine tert-butyl ester (0.24mmol) are added into a clean 25mL reaction tube, a proper amount of dichloromethane is added as a solvent, the mixture reacts for 10 hours at the temperature of minus 40 ℃, TLC point plate detection is carried out, and after the reaction is finished, an organic layer is concentrated and subjected to column chromatography to obtain a pure product, a colorless liquid and the yield is 85%. The following are the structural formula of the product, nuclear magnetic resonance experimental data and mass spectrum experimental data:
Figure BDA0001614567900000122
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.42–7.19(m,5H),7.02(d,J＝8.4Hz, 2H),6.69(d,J＝8.5Hz,2H),5.72(s,1H),5.07(s,2H),4.88(q,J＝6.6Hz,1H),4.61(q,J＝7.4 Hz,1H),3.05(d,J＝6.9Hz,2H),1.70–1.55(m,3H),1.44(s,9H),0.92(d,J＝5.8Hz,3H),0.88 (d,J＝6.1Hz,3H)；13C NMR(100MHz,CDCl3)δ202.5,170.5,170.5,155.8,154.9,136.1,130.4, 128.5,128.2,127.9,115.6,82.7,67.2,57.0,41.1,40.5,29.7,28.0,25.0,22.8,22.3ppm.
and the third part, the specific implementation mode of the application of the thioester compounds in amide and polypeptide synthesis, and examples 15-19.
Example 15
Adding alpha-acetylthioalkenylamide (0.20mmol) and 2-phenylethylamine (0.24mmol) into a clean 25mL reaction tube, adding a proper amount of dichloromethane as a solvent, reacting at 30 ℃ for 1.5 hours, detecting by a TLC point plate, and after the reaction is finished, concentrating and carrying out column chromatography on an organic layer to obtain a pure product, namely a white solid, wherein the yield is 98%. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000131
1H NMR(400MHz,CDCl3)δ7.27(t,J＝7.3Hz,2H),7.21–7.16(m,3H),6.50(s, 1H),3.45(dd,J＝13.3,7.0Hz,2H),2.79(t,J＝7.2Hz,2H),1.90(s,3H).13C NMR(100MHz, CDCl3)δ170.2,138.7,128.4,128.3,126.1,40.5,35.3,22.8ppm.
example 16
1- (N-methyl-p-toluenesulfonamido) -benzoic acid thioester (0.30mmol) is added into a clean 25mL reaction tube, then 2-phenethylamine (0.36mmol) is added, the mixture is stirred for 0.5 hour at room temperature, TLC point plate detection reaction is carried out, and after the reaction is finished, the pure product is directly obtained through column chromatography and separation purification, and the white solid is obtained, and the yield is 95%. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000132
1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.5Hz,2H),7.46(t,J＝7.3Hz,1H),7.38(t, J＝7.3Hz,2H),7.31(t,J＝7.2Hz,2H),7.23(t,J＝8.0Hz,3H),6.36(s,1H),3.70(q,J＝6.3Hz, 2H),2.92(t,J＝6.8Hz,2H)；13C NMR(100MHz,CDCl3)δ167.5,138.9,134.6,131.3,128.7, 128.6,128.5,126.8,126.5,41.1,35.6ppm.
example 17
1- (N-methyl-p-toluenesulfonamido) ethylene p-chlorobenzoic acid thioester (0.20mmol) and 2-morpholine ethylamine (0.24mmol) are added into a clean 25mL reaction tube, a proper amount of dichloromethane is added as a solvent, the mixture reacts for 3 hours at room temperature, TLC point plate detection is carried out, and after the reaction is finished, an organic layer is concentrated and subjected to column chromatography to obtain a pure product which is a white solid and has the yield of 98%. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000133
1H NMR(400MHz,CDCl3)δ7.76–7.65(m,2H),7.44–7.35(m,2H),3.76–3.66(m, 4H),3.52(dd,J＝11.2,5.8Hz,2H),2.58(t,J＝6.0Hz,2H),2.54–2.43(m,4H)；13C NMR(100 MHz,CDCl3)δ166.3,137.6,132.9,128.8,128.3,66.9,56.8,53.3,36.1ppm.
example 18
1- (N-methyl-p-toluenesulfonamido) ethylene-N-9-fluorenylmethoxycarbonyl-leucine thioester (0.20mmol) and leucine tert-butyl ester (0.24mmol) are added into a clean 25mL reaction tube, a proper amount of dichloromethane is added as a solvent, the reaction is carried out at room temperature for 10 hours, TLC point plate detection is carried out, and after the reaction is finished, an organic layer is concentrated and subjected to column chromatography to obtain a pure product, namely a white solid, wherein the yield is 95%. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000141
1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.5Hz,2H),7.58(d,J＝7.3Hz,2H),7.38(t, J＝7.2Hz,2H),7.29(td,J＝7.4,1.2Hz,2H),6.54(d,J＝7.6Hz,1H),5.49(d,J＝8.3Hz,1H), 4.53–4.46(m,1H),4.43–4.33(m,2H),4.27(d,J＝4.6Hz,1H),4.20(t,J＝6.9Hz,1H),1.70– 1.57(m,5H),1.46(s,9H),0.96–0.89(m,12H).13C NMR(100MHz,CDCl3)δ171.8,171.7, 156.1,143.8,141.2,127.6,127.0,125.0,119.9,81.8,67.0,53.3,51.4,47.1,41.6,27.9,26.8,24.8, 24.6,22.9,22.6,22.0,22.0ppm.
example 19
1- (N-methyl-p-toluenesulfonamido) ethylene-N-9-fluorenylmethoxycarbonyl-serine thioester (0.20mmol) and O-tert-butyl-leucine tert-butyl ester (0.24mmol) are added into a clean 25mL reaction tube, a proper amount of dichloromethane is added as a solvent, the reaction is carried out for 10 hours at room temperature, TLC point plate detection is carried out, and after the reaction is finished, an organic layer is concentrated and subjected to column chromatography to obtain a pure product, namely a white solid, wherein the yield is 95%. The following are the structural formula of the product and the data of the nuclear magnetic resonance experiment:
Figure BDA0001614567900000142
1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.5Hz,2H),7.60(d,J＝7.3Hz,2H),7.39(t, J＝7.4Hz,2H),7.34–7.28(m,2H),7.04(d,J＝8.4Hz,2H),6.95(s,1H),6.88(d,J＝8.4Hz, 2H),5.84(s,1H),4.70(dd,J＝14.1,6.4Hz,1H),4.47–4.33(m,2H),4.22(t,J＝7.0Hz,2H), 4.01(d,J＝10.1Hz,1H),3.64(d,J＝5.0Hz,1H),3.29(s,1H),3.03(qd,J＝14.1,6.4Hz,2H), 1.39(s,9H),1.29(s,9H)；13C NMR(100MHz,CDCl3)δ170.6,170.4,156.4,154.4,143.7,143.6, 141.3,130.7,129.8,127.7,127.1,125.1,124.1,120.0,82.7,78.4,67.3,62.9,55.3,54.0,47.0,37.1, 28.8,27.9ppm.
the above-mentioned embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solution of the present invention by those skilled in the art should fall within the protection scope defined by the claims of the present invention without departing from the spirit of the present invention.

Claims (14)

1. A method for synthesizing thiocarbonyl ester compounds is characterized by comprising the following steps: the method comprises the following steps: dissolving alkynylamide in a benzene solvent, adding thiocarboxylic acid, reacting at the temperature of-40-45 ℃ under continuous stirring, and purifying after reaction to obtain a thiocarbonyl ester compound; the chemical reaction formula can be represented as follows:
Figure DEST_PATH_IMAGE002
wherein 1 represents an alkynylamide, 2 represents a thiocarboxylic acid, and 3 represents a thiocarbonyl ester compound;
R1selected from hydrogen, alkyl, aryl, alkoxy and alkylthio, and EWG is selected from alkylsulfonyl, arylsulfonyl, aroyl, alkanoyl, nitro, nitrile and phosphonyl, R2Is alkyl or aryl, R3Selected from alkyl, aryl, alkenyl, alkynyl.
2. The method of claim 1, wherein: the thiocarboxylic acid is selected from aliphatic thioacid, aromatic thioacid, heterocyclic thioacid, alkynyl thioacid, alkenyl thioacid, alpha-amino thioacid and beta-amino thioacid.
3. The method of claim 1, wherein: the benzene solvent is m-xylene or benzene.
4. The method of claim 1, wherein: the benzene solvent is replaced by dichloromethane, chloroform or 1, 2-dichloroethane solvent.
5. A method of synthesizing thioesters, comprising: the method comprises the following steps: dissolving alkynylamide in a halogenated hydrocarbon solvent, adding thiocarboxylic acid, reacting at the temperature of-40-45 ℃ under continuous stirring, and purifying to obtain a thioester compound after reaction; the chemical reaction formula can be represented as follows:
Figure DEST_PATH_IMAGE004
wherein 1 represents an alkynylamide, 2 represents a thiocarboxylic acid, and 4 represents a thioester compound;
R1selected from hydrogen, alkyl, aryl, alkoxy and alkylthio, and EWG is selected from alkylsulfonyl, arylsulfonyl, aroyl, alkanoyl, nitro, nitrile and phosphonyl, R2Is alkyl or aryl, R3Selected from alkyl, aryl, alkenyl, alkynyl.
6. The method of claim 5, wherein: the thiocarboxylic acid is selected from aliphatic thioacid, aromatic thioacid, heterocyclic thioacid, alkynyl thioacid, alkenyl thioacid, alpha-amino thioacid and beta-amino thioacid.
7. The method of claim 5, wherein: the halogenated hydrocarbon solvent is dichloromethane, chloroform or 1, 2-dichloroethane.
8. The method of claim 5, wherein: the halogenated hydrocarbon solvent is replaced by benzene solvent.
9. The use of the thiocarbonyl ester compounds prepared by the method according to any one of claims 1 to 4 in the synthesis of thioamides and thiopolypeptides, wherein: the method comprises the following steps: dissolving a thiocarbonyl compound in a proper amount of organic solvent or water, adding an amine compound, reacting at the temperature of-78-45 ℃ under the condition of continuous stirring, and separating and purifying after the reaction to obtain a thioamide compound; the chemical reaction formula can be represented as follows:
Figure DEST_PATH_IMAGE006
in the formula, 3 represents a thiocarbonyl ester compound, 5 represents an amine compound, 6 represents a thioamide compound, and 7 represents an amide by-product; r1Selected from the group consisting of hydrogen, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, EWG selected from the group consisting of alkylsulfonyl, arylsulfonyl, arylacyl, alkanoyl, nitro, nitrile, phosphonyl, sulfonimide, R2Selected from alkyl or aryl, R3Selected from alkyl, aryl, alkenyl, alkynyl, R4Selected from hydrogen, aliphatic substituent groups, aromatic substituent groups, R5Selected from hydrogen, aliphatic substituent groups, aromatic substituent groups.
10. Use according to claim 9, characterized in that: the amine compound is primary amine or secondary amine.
11. Use according to claim 9, characterized in that: the organic solvent is dichloromethane, N-dimethylformamide, chloroform or 1, 2-dichloroethane.
12. Use of thioesters prepared according to the process of any one of claims 5-8 in amide and polypeptide synthesis, characterized by: dissolving a common thioester compound in a proper amount of organic solvent or water, adding an amine compound, reacting at the temperature of-78-45 ℃ under the condition of continuous stirring, and separating and purifying after the reaction to obtain a thioamide compound; the chemical reaction formula can be represented as follows:
Figure DEST_PATH_IMAGE008
in the formula, 4 represents a common thioester compound, 5 represents an amine compound, 8 represents an amide compound, and 9 represents a thioamide by-product; r1Selected from the group consisting of hydrogen, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, EWG selected from the group consisting of alkylsulfonyl, arylsulfonyl, arylacyl, alkanoyl, nitro, nitrile, phosphonyl, sulfonimide, R2Selected from alkyl or aryl, R3Selected from alkyl, aryl, alkenyl, alkynyl, R4Selected from hydrogen, aliphatic substituent groups, aromatic substituent groups, R5Selected from hydrogen, aliphatic substituent groups, aromatic substituent groups.
13. Use according to claim 12, characterized in that: the amine compound is primary amine or secondary amine.
14. Use according to claim 12, characterized in that: the organic solvent is dichloromethane, chloroform, N-dimethylformamide or 1, 2-dichloroethane.
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