CN110183366B

CN110183366B - Method for synthesizing thioester compound through alkene carbonylation thioesterification

Info

Publication number: CN110183366B
Application number: CN201910561163.XA
Authority: CN
Inventors: 廖建; 王夕虹; 喻望知; 王敏
Original assignee: Chengdu Institute of Biology of CAS
Current assignee: Chengdu Institute of Biology of CAS
Priority date: 2019-06-26
Filing date: 2019-06-26
Publication date: 2021-02-26
Anticipated expiration: 2039-06-26
Also published as: CN110183366A

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing chiral or achiral thioester compounds through palladium-catalyzed alkene carbonylation thioesterification. The specific technical scheme is as follows: a synthesis method of thioester compounds is carried out in a ventilated environment, and comprises the steps of mixing a palladium source, a ligand and a solvent uniformly, and stirring for 30min to obtain a reaction solution; adding an additive, an acid and an inhibitor into the reaction solution, uniformly mixing, and stirring at-20-25 ℃; sequentially adding mercaptan and olefin, and reacting at-20-25 ℃ for 12-24 h; after the reaction is finished, the thioester compound is obtained by separation and purification. The invention provides a method for thioesterification by alkene carbonylation under mild conditions, which can be used for post-modification of drugs, amino acids, polypeptides and the like.

Description

Method for synthesizing thioester compound through alkene carbonylation thioesterification

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing chiral or achiral thioester compounds through palladium-catalyzed alkene carbonylation thioesterification.

Background

Olefins are a large class of industrial feedstocks and are important basic feedstocks in organic synthesis. The carbonylation of olefins is an important class of industrial catalytic reaction in the industrial production of olefins and has become a mature technology in industry. For example, where the two most important conversions, the conversion of olefins directly to aldehydes and esters, are carried out with annual yields on the scale of 1 million tons and millions of tons, respectively. However, because of the harsh reaction conditions of such processes, high temperatures and pressures are generally required, and in addition, asymmetric catalyzed carbonylation reactions are limited, with only a few successful cases to date, such as Godard, c;

B.K.；Ruiz,A.；Claver,C.Dalton Trans.2008,853.。

thioesters are a class of compounds of great biological interest that participate in biochemical activities, such as the transacylation of coenzyme A. Thioesters are important intermediates in synthesis, and are used in many synthetic reactions, such as the synthesis of amides, esters, aldehydes, ketones, acids, etc. Furthermore, thioesters are widely present in natural products such as Lactacystin (lactysin) and in drug molecules, for example, Fluticasone (Fluticasone) and Fluticasone propionate (Fluticasone).

Methods for synthesizing thioesters are numerous, but the most interesting isThe method is also a method for alkene carbonylation thioesterification with easy raw material acquisition and high atom economy. Since thiol compounds which strongly coordinate to transition metals and easily poison metals are required, the thioesterification by interposing carbonyi is more challenging than the esterification and thus has been rarely reported. Currently, only some special olefins (allyl alcohol, allene, 1, 3-conjugated diene, conjugated eneyne, alkenyl cyclopropane, terminal alkyl olefin, ethylene) are subjected to carbonylation and thioesterification, and the methods generally require high temperature, high pressure and harsh reaction conditions, so that the industrial application of the method is limited, and the research and application of asymmetric catalytic carbonylation and thioesterification are rare. Therefore, the method for preparing the thioester compound, in particular the chiral thioester compound by carrying out the insertion carbonytation thioesterification on the olefin under the mild condition is developed, and has very good industrial application prospect. In addition, the method can realize the post-modification of active molecules such as drugs, amino acids, polypeptides and the like, and also can provide important technical support for the research and development of new drugs.

Disclosure of Invention

The invention aims to provide a method for synthesizing thioester compounds through alkene carbonylation thioesterification under mild conditions, namely a novel palladium-catalyzed alkene carbonylation thioesterification method.

In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows: a method for synthesizing thioester compounds, the method corresponding to the reaction formula:

r1, R2, R3 and R4 are any one or combination of any several of hydrogen, alkyl or aryl; and R is any one of alkyl, aryl, amino acid containing sulfhydryl, polypeptide or other sulfhydryl-containing compounds.

Accordingly, a method of synthesizing thioesters, the method comprising the steps of:

(1) uniformly mixing a palladium source, a ligand and a solvent to obtain a reaction solution;

(2) adding an additive, an acid and an inhibitor into the reaction solution, and uniformly mixing;

(3) sequentially adding mercaptan and olefin into the reaction solution, and reacting at-20-25 ℃;

(4) after the reaction is finished, separating and purifying to obtain the thioester compound.

Preferably, the ligand is a sulphoxide phosphine ligand, and the structural formula of the ligand is as follows:

wherein, R is^aThe radical and the R' radical are both any one of aryl or alkyl (alkyl with 1-18 carbon atoms); ar refers to conventional aromatic groups such as phenyl, naphthyl, phenanthrene and anthracene and aromatic groups with one to more substituted hydrogen atoms on aromatic rings.

Preferably, the ligand is a sulphoxide phosphine ligand, and the R in the structural formula^aThe radical is tert-butyl.

Preferably, the palladium source is any one of tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, allylcyclopentadienyl palladium, palladium acetate, palladium chloride, palladium bromide, palladium trifluoroacetate, bis (triphenylphosphine) palladium chloride, bis (benzonitrile) palladium chloride and bis (acetonitrile) palladium p-toluenesulfonate.

Preferably, the acid is any one of benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, trifluoromethylbenzenesulfonic acid, trifluoroacetic acid, diphenyl phosphate and hydrochloric acid.

Preferably, the inhibitor is any one of 4-tert-butyl catechol, 3, 5-di-tert-butyl catechol, hydroquinone and tetramethylpiperidine oxynitride; and/or; the additive is any one of phosphorus pentoxide and a 4A molecular sieve.

Preferably, the solvent is any one or a mixture of any two of chloroform, dichloromethane, 1, 2-dichloroethane, 1,2, 2-tetrachloroethane, nitrobenzene, fluorobenzene, chlorobenzene, trifluorotoluene, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether and ethylene glycol diethyl ether pure solvents; and/or; the olefin is any one of alkyl olefin, aryl olefin and polysubstituted olefin; and/or; the mercaptan is any one of alkyl mercaptan, aryl mercaptan, amino acid and polypeptide containing sulfhydryl or other sulfhydryl compounds.

Preferably, the molar ratio of the olefin to the mercaptan to the palladium source to the ligand to the acid to the inhibitor to the additive is 1: 1-2: 0.02-0.2: 0.024-0.24: 0.04-0.4: 0.02-0.2: 0-0.1.

Preferably, the temperature range is-20 to 25 ℃, and the pressure range is 1 to 50 atm.

The invention has the following beneficial effects:

1. the method uses bulk industrial raw material olefin as raw material, and generates the carbonylation thioesterification reaction under the catalysis system of palladium source/phosphine ligand (including chiral sulfoxide phosphine ligand).

2. The synthetic method has mild reaction conditions, avoids the reaction conditions of high-temperature and high-pressure dangerous energy consumption, and has potential application prospect.

3. Chiral or racemic thioesters can be synthesized specifically using the methods provided by the present invention; provides a brand new technical platform for the development and design of drug molecules (such as modification of drugs, amino acids, polypeptides and the like). The thioester prepared by the invention can be used as a precursor of some medicines, for example, the precursor of ibuprofen is synthesized in a gram-scale manner in example twenty-three, and the optically pure ibuprofen can be obtained through one-step subsequent conversion.

Drawings

FIG. 1 is a schematic diagram of the structural formula of each ligand used in the present invention;

FIG. 2 is a schematic diagram of the structure of the product produced by the various embodiments of the present invention.

Detailed Description

The synthesis reaction formula of the invention is as follows:

in the reaction formula, R₁、R₂、R₃、R₄All are any one or combination of any several of hydrogen, alkyl or aryl; r is any one of alkyl, aryl, amino acid containing sulfhydryl, polypeptide or other sulfhydryl-containing compounds.

The reaction needs to be carried out in a ventilated environment, carbon monoxide gas is needed as a reactant in the reaction process, and part of reaction reagents are sensitive to water and oxygen, so that the preparation of the catalyst is carried out in a glove box for convenient operation.

The specific synthesis mode is as follows:

1. adding a palladium source, a ligand and a solvent into a dry reaction tube in a glove box to obtain a mixed solution; the mixed solution was rapidly stirred at room temperature for 30 minutes, and then the additive, acid and inhibitor were added. The reaction tube was then removed from the glove box and replaced with carbon monoxide at 1 atmosphere. Then the reaction system is placed at the temperature of minus 20 ℃ to 25 ℃ and stirred, and then mercaptan and olefin are sequentially added to react for 24 hours at the temperature of minus 20 ℃ to 25 ℃. Wherein the molar ratio of the olefin to the mercaptan to the palladium salt or palladium complex (palladium source) to the ligand to the acid to the inhibitor to the additive is 1: 1-2: 0.02-0.2: 0.024-0.24: 0.04-0.4: 0.02-0.2: 0-0.1. After the reaction, the product was obtained by filtration through celite, washing with dichloromethane, collecting the filtrate, and separation and purification through silica gel column. The whole reaction is carried out under the pressure range of 1-50 atm.

Wherein the palladium source is any one of tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, allyl cyclopentadienyl palladium, palladium acetate, palladium chloride, palladium bromide, palladium trifluoroacetate, bis (triphenylphosphine) palladium chloride, bis (benzonitrile) palladium chloride and bis (acetonitrile) palladium p-toluenesulfonate.

The ligand is a sulphoxide phosphine ligand, and the preferable ligand structure is as follows:

hereinafter referred to as L-A ligand. Wherein, R is^aThe group and the R' group are both any one of aryl or alkyl (alkyl with 1-18 carbon atoms). Ar refers to phenyl, naphthyl, phenanthrene, anthracene and the likeAromatic groups and aromatic groups in which one to more hydrogen atoms in the aromatic ring are substituted. The absolute configuration of the S atom is R or S configuration, or the ligand is racemate.

More preferred ligand structures are: the R in the L-A ligand^aThe radical is defined as tert-butyl.

The more preferable ligand structure is any one of L1-L16, and the specific structural formula of the L1-L16 ligand is shown in figure 1. Wherein, the L1-L8 are racemic ligands, and the L9-L16 are R-configuration chiral ligands.

The acid is any one of benzene sulfonic acid, p-methyl benzene sulfonic acid, benzoic acid, trifluoromethyl benzene sulfonic acid, trifluoroacetic acid, diphenyl phosphate and hydrochloric acid; the inhibitor is any one of 4-tert-butyl catechol, 3, 5-di-tert-butyl catechol, hydroquinone and tetramethyl piperidine oxynitride. The additive is any one of phosphorus pentoxide and a 4A molecular sieve. The solvent is any one or the mixture of any two of chloroform, dichloromethane, 1, 2-dichloroethane, 1,2, 2-tetrachloroethane, nitrobenzene, fluorobenzene, chlorobenzene, trifluorotoluene, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether and ethylene glycol diethyl ether pure solvents. The olefin is any one of alkyl olefin, aryl olefin and polysubstituted olefin; the mercaptan is any one of alkyl mercaptan, aryl mercaptan, amino acid and polypeptide containing sulfhydryl or other sulfhydryl compounds.

The present invention will be further explained with reference to specific embodiments.

The first embodiment is as follows: synthesis of S-benzyl-2-phenylpropylthio ester

The synthesis reaction involved in this example is:

wherein 1a is styrene, 2a is benzyl mercaptan, and 3aa is S-benzyl-2-phenylpropylthioether.

In a glove box, tris (dibenzylideneacetone) dipalladium (11.5mg, 0.0125mmol), ligand L3(12.3mg, 0.03mmol) and 500 μ L of 2-methyltetrahydrofuran/chloroform (v/v ═ 1:1) were added to a dried reaction tube to obtain a reaction solution. Stirring was carried out rapidly for 30 minutes, then phosphorus pentoxide (1.4mg, 0.01mmol), p-toluenesulfonic acid monohydrate (9.5mg, 0.05mmol) and 4-tert-butylcatechol (6.6mg, 0.04mmol) were added in this order. The reaction tube was taken out of the glove box and replaced with carbon monoxide at 1 atmosphere. The reaction was left to stir at 0 ℃ and then 2a (88. mu.L, 0.75mmol) and 1a (58. mu.L, 0.5mmol) were added and the mixture stirred at 0 ℃ for 24 h. After the reaction is finished, the product is obtained by filtering and concentrating by using kieselguhr and separating and purifying by using a silica gel column.

The product was a colorless oil, 115.4mg, yield 90%. Nuclear magnetic resonance (¹H NMR、¹³C NMR), measurement conditions and results of High Resolution Mass Spectrometry (HRMS) were as follows:

¹H NMR(400MHz,CDCl3)δ7.36-7.25(m,10H),4.17(ABq,ΔδAB＝0.09,J_AB＝13.7Hz,2H),3.96(q,J＝7.1Hz,1H),1.59(d,J＝7.1Hz,3H)。¹³C NMR(100MHz,CDCl3)δ200.6,139.7,137.4,128.8,128.7,128.6,128.0,127.5,127.2,54.1,33.5,18.4。HRMS(m/z,ESI):Calcd.for C₁₆H₁₆OS[M+H]+:257.1000,found:257.1033。[α]D20＝-100.5(c＝0.38,EtOH)。

example two: synthesis of S-benzyl-2-phenylpropylthio ester

The synthesis reaction involved in this example is:

the specific operation, raw material and reactant molar ratios in this example were the same as in example one. Except that the ligand used in this example was ligand L1. The product was a colorless oil, 114mg, 89% yield.

Example three: synthesis of S-benzyl-2-phenylpropylthio ester

The synthesis reaction involved in this example is:

the specific operation, raw material and reactant molar ratios in this example were the same as in example one. Except that the ligand used in this example was ligand L2. The product was a colorless oil, 64mg, yield 50%.

Example four: synthesis of S-benzyl-2-phenylpropylthio ester

The synthesis reaction involved in this example is:

the specific operation, raw material and reactant molar ratios in this example were the same as in example one. Except that the ligand used in this example was ligand L4. The product was a colorless oil, 84mg, 65% yield.

Example five: synthesis of S-benzyl-2-phenylpropylthio ester

The synthesis reaction involved in this example is:

the specific operation, raw material and reactant molar ratios in this example were the same as in example one. Except that the ligand used in this example was ligand L5. The product was a colorless oil, 115mg, yield 90%.

Example six: synthesis of S-benzyl-2-phenylpropylthio ester

The synthesis reaction involved in this example is:

the specific operation, raw material and reactant molar ratios in this example were the same as in example one. Except that the ligand used in this example was ligand L6. The product was a colorless oil, 66.7mg, 52% yield.

Example seven: synthesis of S-propyl-2-phenylpropylthio ester

The synthesis reaction involved in this example is:

wherein 1a is styrene, 2b is n-propanethiol, and 3ab is S-propyl-2-phenylpropylthioester. The specific operation, raw material and reactant molar ratios in this example were the same as in example one. The product was a colorless oil, 88.5mg, 85% yield. Nuclear magnetic resonance (¹H NMR、¹³C NMR), measurement conditions and results of High Resolution Mass Spectrometry (HRMS) were as follows:

¹H NMR(400MHz,CDCl₃)δ7.39-7.28(m,5H),3.95(q,J＝7.1Hz,1H),2.90-2.78(m,2H),1.63-1.54(m,5H),0.97(t,J＝7.4Hz,3H)。¹³C NMR(100MHz,CDCl₃)δ201.3,140.0,128.6,127.9,127.4,54.3,31.0,22.9,18.5,13.3。HRMS(m/z,ESI):Calcd.forC₁₂H₁₆OS[M+Na]⁺:231.0820,found:231.0813。

example eight: synthesis of S-isopropyl-2-phenylpropylthio ester

The synthesis reaction involved in this example is:

wherein 1a is styrene, 2c is isopropylmercaptan, and 3ac is S-isopropyl-2-phenylpropylthioether. The specific operation, raw material and reactant molar ratios in this example were the same as in example one. The product was a colorless oil, 86.4mg, 83% yield. Nuclear magnetic resonance (¹H NMR、¹³C NMR), measurement conditions and results of High Resolution Mass Spectrometry (HRMS) were as follows:

¹H NMR(400MHz,CDCl₃)δ7.38-7.29(m,5H),3.90(q,J＝7.1Hz,1H),3.65-3.58(m,1H),1.56(d,J＝7.1Hz,3H),1.32(dd,J＝22.1Hz,6.9Hz,6H)。¹³C NMR(100MHz,CDCl₃)δ201.3,140.1,128.6,127.9,127.3,54.2,34.8,23.0,22.8,18.5。HRMS(m/z,ESI):Calcd.for C₁₂H₁₆OS[M+Na]⁺:231.0820,found:231.0814。

example nine: synthesis of S-cyclohexyl-2-phenylpropylthio ester

The synthesis reaction involved in this example is:

wherein 1a is styrene, 2d is cyclohexyl mercaptan, and 3ad is S-cyclohexyl-2-phenylpropylthioether. The specific operation, raw material and reactant molar ratios in this example were the same as in example one. The product was a colorless oil, 111.8mg, yield 90%. High performance liquid chromatography, nuclear magnetic resonance (¹H NMR、¹³C NMR), measurement conditions and results of High Resolution Mass Spectrometry (HRMS) were as follows:

¹H NMR(400MHz,CDCl₃)δ7.38-7.28(m,5H),3.90(q,J＝7.1Hz,1H),3.51-3.46(m,1H),1.95-1.91(m,1H),1.87-1.84(m,1H),1.71-1.66(m,2H),1.61-1.54(m,4H),1.43-1.23(m,6H)。¹³C NMR(100MHz,CDCl₃)δ201.0,140.1,128.6,127.9,127.3,54.3,42.5,33.0,32.9,26.0,25.9,25.5,18.5。HRMS(m/z,ESI):Calcd.forC₁₂H₁₆OS[M+Na]⁺:271.1133,found:271.1128。

example ten: synthesis of S-phenyl-2-phenylpropylthio ester

The synthesis reaction involved in this example is:

wherein 1a is styrene, 2e is thiophenol, and 3ae is S-phenyl-2-phenylpropylthioester. The specific operation, raw material and reactant molar ratios in this example were the same as in example one. The product was a colorless oilSubstance (112.7 mg), yield 93%. Nuclear magnetic resonance (¹H NMR、¹³CNMR), measurement conditions and results of High Resolution Mass Spectrometry (HRMS) are as follows:

¹H NMR(400MHz,CDCl₃)δ7.43-7.29(m,10H),4.08(q,J＝7.1Hz,1H),1.64(d,J＝7.1Hz,3H)。¹³C NMR(100MHz,CDCl₃)δ199.1,139.6,134.5,129.3,129.1,128.8,128.1,127.9,127.6,54.1,18.7。HRMS(m/z,ESI):Calcd.for C₁₅H₁₄OS[M+Na]⁺:265.0663,found:265.0655。

example eleven: synthesis of S-benzyl 2-phenylbutanoate

The synthesis reaction involved in this example is:

wherein 1b is trans beta-methylstyrene, 2a is benzylthiol, and 3ba is S-benzyl 2-phenylbutanoate. The specific operation, molar ratios of the starting materials and reactants in this example were all performed in the same manner. The product was a colorless oil, 51.4mg, 38% yield. Nuclear magnetic resonance (¹H NMR、¹³C NMR), measurement conditions and results of High Resolution Mass Spectrometry (HRMS) were as follows:

¹H NMR(400MHz,CDCl3)δ7.37-7.25(m,10H),4.20(ABq,ΔδAB＝0.12,J_AB＝13.8Hz,2H),3.71(t,J＝7.6Hz,1H),2.26-2.19(m,1H),1.94-1.87(m,1H),0.95(t,J＝7.4Hz,3H)。¹³C NMR(100MHz,CDCl3)δ200.0,138.3,137.4,128.8,128.7,128.6,128.3,127.5,127.2,62.0,33.5,26.6,12.1。HRMS(m/z,ESI):Calcd.For C₁₇H₁₈OS[M+Na]⁺:293.0976,found:293.0968.

example twelve: s-benzylnonyl thioesters

Wherein 1c is trans-1-octene, 2a is benzyl mercaptan, and 3ca is S-benzylnonanethiol. The specific operation, raw material and reactant molar ratios in this example were the same as in example one. The product was a colorless oil, 52.9mg, 40% yield. Nuclear magnetic resonance (¹H NMR、¹³C NMR), measurement conditions and results of High Resolution Mass Spectrometry (HRMS) were as follows:

¹H NMR(400MHz,CDCl3)δ7.35-7.25(m，5H),4.15(s,2H),2.60(t,J＝7.4Hz,2H),1.73-1.66(m,2H),1.28(brs,10H),0.92(t,J＝6.7Hz,3H).¹³C NMR(100MHz,CDCl3)δ199.0，137.8，128.8，128.6，127.2，43.9，33.1，31.8，29.2,29.07，29.0，25.6，22.6，14.09。HRMS(m/z,ESI):Calcd.For C₁₇H₁₈OS[M+Na]⁺:287.1446,found:287.1439。

example thirteen: synthesis of S-benzyl (R) -2-phenylpropylthio ester

The synthesis reaction involved in this example is:

wherein, the 1a is styrene, the 2a is benzyl mercaptan, and the 4aa is S-benzyl (R) -2-phenylpropylthioether.

In a glove box, tris (dibenzylideneacetone) dipalladium (11.5mg, 0.0125mmol), ligand L11(12.3mg, 0.03mmol) and 500 μ L of 2-methyltetrahydrofuran/chloroform (v/v ═ 1:1) were added to a dried reaction tube to obtain a reaction solution. Stirring was carried out rapidly for 30 minutes, and then phosphorus pentoxide (1.4mg, 0.01mmol), p-toluenesulfonic acid monohydrate (9.5mg, 0.05mmol) and 4-tert-butylcatechol (6.6mg, 0.04mmol) were added successively. The reaction tube was taken out of the glove box and replaced with carbon monoxide at 1 atmosphere. The reaction was left to stir at 0 ℃ and then 2a, i.e. benzylthiol (88. mu.L, 0.75mmol) and 1a, i.e. styrene (58. mu.L, 0.5mmol) were added and the mixture was stirred at 0 ℃ for 24 h. After the reaction is finished, the product is obtained by filtering and concentrating by using kieselguhr and separating and purifying by using a silica gel column.

The product was a colorless oil, 119.2mg, 93% yield, 94% enantiomeric excess. High performance liquid chromatography and specific optical rotation ([ alpha ]]_D ²⁰) The measurement conditions and results of (1) were as follows:

daicel Chiralpak OJ-H, n-hexane/isopropanol 90:10,1.0mL/min, λ 254nm, retention time 14.50 min (main peak), 17.85 min. [ alpha ] to]_D ²⁰＝-100.5(c＝0.38,EtOH)。

Example fourteen: synthesis of S-benzyl (R) -2-phenylpropylthio ester

The synthesis reaction involved in this example is:

the specific operation, raw material and reactant molar ratios in this example were the same as in example thirteen. Except that the ligand used in this example was ligand L9. The product was a colorless oil, 115mg, yield 90%, and enantiomeric excess of 93%.

Example fifteen: synthesis of S-benzyl (R) -2-phenylpropylthio ester

The synthesis reaction involved in this example is:

the specific operation, raw material and reactant molar ratios in this example were the same as in example thirteen. Except that the ligand used in this example was ligand L10. The product was a colorless oil, 66mg, 51% yield, 94% enantiomeric excess.

Example sixteen: synthesis of S-benzyl (R) -2- (3-methoxyphenyl) propylthioester

The synthesis reaction involved in this example is:

wherein 1d is m-methoxystyrene and 4da is S-benzyl (R) -2- (3-methoxyphenyl) propylthioester. This exampleThe specific operation method, raw materials and molar ratio of the reactants are the same as those in example thirteen. The product was a colorless oil, 130.2mg, 91% yield, 96% enantiomeric excess. High performance liquid chromatography, nuclear magnetic resonance (¹H NMR、¹³C NMR), High Resolution Mass Spectrometry (HRMS), specific optical rotation ([ α [ ])]_D ²⁰) The measurement conditions and results of (1) were as follows:

daicel Chiralpak OJ-H, n-hexane/isopropanol 90:10,1.0mL/min, λ 254nm, retention time 19.21 min, (main peak), 28.12 min.¹H NMR(400MHz,CDCl₃)δ7.30-7.25(m,6H),6.93-6.84(m,3H),4.17(q,J＝13.7Hz,2H),3.93(q,J＝7.1Hz,1H),3.82(s,3H),1.58(d,J＝7.1Hz,3H)。¹³C NMR(100MHz,CDCl₃)δ200.4,159.8,141.2,137.4,129.7,128.8,128.6,127.2,120.4,113.7,112.9,55.2,54.0,33.5,18.4。HRMS(m/z,ESI):Calcd.for C₁₇H₁₈O₂S[M+Na]⁺:309.0925,found:309.0921.[α]_D ²⁰＝-106.9(c＝0.52,EtOH)。

Example seventeen: synthesis of S-benzyl (R) -2- (4- (phenyl) propylthioester

The synthesis reaction involved in this example is:

wherein, the 1e is p-styrene, and the 4ea is S-benzyl (R) -2- (4- (acetoxy) phenyl) propyl thioester. The specific operation and the molar ratio of the reactants in this example are the same as those in the thirteenth example. 1e was first predissolved in 0.5ml of a mixed solvent (2-methyltetrahydrofuran/chloroform, v/v ═ 1:1) and the subsequent operation was carried out as in example thirteen. The product was a white solid, 147mg, 89% yield, 95% enantiomeric excess. High performance liquid chromatography, nuclear magnetic resonance (¹H NMR、¹³C NMR), High Resolution Mass Spectrometry (HRMS), specific optical rotation ([ α [ ])]_D ²⁰) The measurement conditions and results of (1) were as follows:

daicel Chiralpak OD-H, n-hexane/isopropanol 90:10,1.0mL/min, λ 254nm, retention time 6.13 min(main peak), 7.09 minutes.¹H NMR(400MHz,CDCl₃)δ7.63-7.59(m,4H),7.49-7.38(m,5H),7.31-7.26(m,5H),4.20(q,J＝13.7Hz,2H),4.00(q,J＝7.1Hz,1H),1.64(d,J＝7.1Hz,3H)。¹³C NMR(100MHz,CDCl₃)δ200.5,140.7,140.5,138.7,137.3,128.9,128.8,128.6,128.4,127.5,127.4,127.3,127.1,53.8,33.6,18.5。HRMS(m/z,ESI):Calcd.for C₂₂H₂₀OS[M+Na]⁺:355.1133,found:355.1123。[α]_D ²⁰＝-73.2(c＝0.27,EtOH)。

Example eighteen: synthesis of S-benzyl (1R, 2R, 4R) -bicyclo [2.2.1] hept-5-ene-2-thiocarbamate

The synthesis reaction involved in this example is:

wherein, the 1f is norbornadiene, and the 4fa is S-benzyl (1R, 2R, 4R) -bicyclo [2.2.1]Hept-5-ene-2-thiocarbamate. The specific operation, raw material and reactant molar ratios in this example were the same as in example thirteen. The product was a colorless oil, 61.9mg, 51% yield, and 38% enantiomeric excess. High performance liquid chromatography, nuclear magnetic resonance (¹H NMR、¹³CNMR), High Resolution Mass Spectrometry (HRMS), specific optical rotation ([ α ])]_D ²⁰) The measurement conditions and results of (1) were as follows:

daicel Chiralpak OJ-H, n-hexane/isopropanol 85:15,1.0mL/min, λ 254nm, retention time 6.08 min, (main peak), 6.48 min.¹H NMR(400MHz,CDCl₃)δ7.33-7.27(m,5H),6.20(d,J＝8Hz,1H),4.16(s,2H),3.10(brs,1H),2.97(brs,1H),2.52-2.48(m,1H),2.02-1.97(m,1H),1.64(d,J＝8.3Hz,3H),1.42-1.40(m,2H)。¹³C NMR(100MHz,CDCl3)δ201.7,138.6,137.8,135.7,128.8,128.6,127.2,52.3,47.8,46.3,41.8,33.4,30.9。HRMS(m/z,ESI):Calcd.ForC15H16OS[M+Na]+:267.0820,found:267.0809.[α]^D ₂₀＝-43.0(c＝0.38,EtOH)。

Example nineteenth: synthesis of (R) -2- ((8R, 9S, 13S, 14S) -13-methyl-17-oxo 7,8,9,11,12,13,14,15,16,17 decahydro-6H-cyclopenta [ a ] phenanthren-3-yl) propylthio ester

The synthesis reaction involved in this example is:

wherein 1A is (8R, 9S, 13S, 14S) -13-methyl-3-vinyl-6, 7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] a]Phenanthrene-17-one, wherein 2a is benzyl mercaptan, and 3A is (R) -2- ((8R, 9S, 13S, 14S) -13-methyl-17-oxo 7,8,9,11,12,13,14,15,16,17 decahydro-6H-cyclopentadiene [ a ] or (I) or (II)]Phenanthren-3-yl) propylthioester. The specific operation and the molar ratio of the reactants in this example are the same as those in the thirteenth example. 1A was first predissolved in 1ml of a mixed solvent (2-methyltetrahydrofuran/chloroform, v/v. RTM. 1:1) and the subsequent operation was carried out as in example thirteen. The product was a white solid, 183.3mg, 85% yield, with a diastereomeric excess ratio of 98: 2. High performance liquid chromatography, nuclear magnetic resonance (¹H NMR、¹³C NMR), High Resolution Mass Spectrometry (HRMS), specific optical rotation ([ α [ ])]_D ²⁰) The measurement conditions and results of (1) were as follows:

daicel Chiralpak OJ-H, n-hexane/isopropanol 80:20,1.0mL/min, λ 254nm, retention time 24.32 min (main peak), 46.15 min.¹H NMR(400MHz,CDCl₃)δ7.32-7.24(m,5H),7.12-7.10(m,1H),7.05(brs,1H),4.17-4.03(q,J＝13.7Hz,2H),3.89-3.84(q,J＝7.1Hz,1H),2.94-2.92(m,2H),2.57-2.50(m,1H),2.45-2.42(m,1H),2.34-2.29(m,1H),2.21-1.98(m,4H),1.70-1.43(m,10H),0.93(s,3H)。¹³C NMR(100MHz,CDCl₃)δ200.66,139.05,137.40,137.17,136.85,128.86,128.59,128.53,127.22,125.70,125.26,53.62,50.55,47.99,44.35,38.08,35.86,33.52,31.61,29.40,26.49,25.64,21.59,18.49,13.86。HRMS(m/z,ESI):Calcd.forC₂₈H₃₂O₂S[M+Na]⁺:455.2021,found:455.2014。[α]_D ²⁰＝+43.2(c＝0.43,THF)。

Example twenty: synthesis of methyl (S) -3- (4- ((R) -1- (benzylsulfanyl) -1-oxopropan-2-yl) phenyl) -2- ((tert-butoxycarbonyl) amino) propionate

The synthesis reaction involved in this example is:

wherein 1B is methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-vinylphenyl) propanoate, 2a is benzylthiol, and 3B is methyl (S) -3- (4- ((R) -1- (benzylthio) -1-oxopropan-2-yl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoate. The specific operation and the molar ratio of the reactants in this example are the same as those in the thirteenth example. 1B was pre-dissolved in 500. mu.L of a mixed solvent (2-methyltetrahydrofuran/chloroform, v/v ═ 1:1) and the next procedure was carried out as in example thirteen. The product was a colorless oil, 144.5mg, 63% yield, with a diastereomeric excess ratio of 97.5: 2.5. High performance liquid chromatography, nuclear magnetic resonance (¹H NMR、¹³C NMR), High Resolution Mass Spectrometry (HRMS), specific optical rotation ([ α [ ])]_D ²⁰) The measurement conditions and results of (1) were as follows:

daicel Chiralpak OJ-H, n-hexane/isopropanol 90:10,1.0mL/min, λ 254nm, retention time 24.69 min (main peak), 33.64 min.¹H NMR(400MHz,CDCl₃)δ7.30-7.23(m,7H),7.12-7.11(d,J＝7.9Hz,2H),5.05-5.03(d,J＝8.0Hz,1H),4.62-4.60(q,J＝7.2Hz,1H),4.15-4.03(q,J＝13.7Hz,2H),3.92-3.87(q,J＝7.1Hz,1H),3.71(s,3H),3.14-3.03(m,2H),1.56-1.54(d,J＝7.1Hz,3H),1.44(s,9H)。¹³C NMR(100MHz,CDCl₃)δ200.5,172.3,155.1,138.4,137.3,135.4,129.6,128.8,128.6,128.1,127.2,79.9,54.4,53.7,52.2,38.0,33.5,28.3,18.4。HRMS(m/z,ESI):Calcd.forC₂₈H₃₂O2S[M+Na]⁺:480.1821,found:480.1810。[α]_D ²⁰＝-34.6(c＝0.27,EtOH)。

Example twenty one: synthesis of N- (tert-butoxycarbonyl) -S- ((R) -2-phenylpropionyl) -L-cysteinylglycine methyl ester

The synthesis reaction involved in this example is:

wherein 1a is styrene, 2C is (tert-butoxycarbonyl) -L-cysteinylglycine methyl ester, and 3C is N- (tert-butoxycarbonyl) -S- ((R) -2-phenylpropionyl) -L-cysteinylglycine methyl ester. In this example, 2C (1.0equiv.) and styrene (1.5equiv.) were used as starting materials, and the catalyst/ligand ratio was not changed, and it was necessary to dissolve 2C in 1mL of a mixed solvent (2-methyltetrahydrofuran/chloroform, v/v 1:1) in advance, and the specific operation method was otherwise the same as in example thirteen. The product was a colorless oil, 120.9mg, 57% yield, with a diastereomeric excess ratio of 97: 3. High performance liquid chromatography, nuclear magnetic resonance (¹H NMR、¹³C NMR), High Resolution Mass Spectrometry (HRMS), specific optical rotation ([ α [ ])]_D ²⁰) The measurement conditions and results of (1) were as follows:

daicel Chiralpak OJ-H, n-hexane/isopropanol 90:10,1.0mL/min, λ 254nm, retention time 16.38 min (main peak), 24.73 min.¹H NMR(400MHz,CDCl₃)δ7.35-7.29(m,4H),6.87(brs,1H),5.31(brs,1H),4.32(brs,1H),4.08-3.91(m,3H),3.76(s,3H),3.35-3.16(m,2H),1.57(d,J＝7.1Hz,3H),1.44(s,9H)。¹³C NMR(100MHz,CDCl₃)δ201.8,170.5,169.9,155.7,139.4,128.7,127.9,127.6,80.4,54.4,54.2,52.4,41.2,31.0,28.2,18.4。HRMS(m/z,ESI):Calcd.for C₂₀H₂₈N₂O₆S[M+Na]⁺:447.1566,found:447.1559.[α]_D ²⁰＝-69.2(c＝0.26,EtOH)。

Example twenty two: synthesis of N- (tert-butoxycarbonyl) -S- ((R) -2- ((8R, 9S, 13S, 14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14 methyl), 15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-2-yl) propanoyl) -L-cysteinyl glycinate

The synthesis reaction involved in this example is:

wherein the 1A is (8R,9S, 13S, 14S) -13-methyl-3-vinyl-6, 7,8,9,11,12,13,14,15, 16-decahydro-17H cyclopenta [ a]Phenanthren-17-one, 2C (tert-butoxycarbonyl) -L-cysteinylglycine methyl ester, and 3D (N- (tert-butoxycarbonyl) -S- ((R) -2- ((8R, 9S, 13S, 14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14 methyl), 15,16, 17-decahydro-6H-cyclopenta [ a)]Phenanthren-2-yl) propionyl) -L-cysteinyl glycine ester. In this example, the specific procedure was the same as in example thirteen except that 2C (1.0 equivalent), 1A (1.5 equivalents) and the remaining catalyst/ligand ratios were unchanged as raw materials, and 2C and 1A were previously dissolved in 1mL of a mixed solvent (2-methyltetrahydrofuran/chloroform, v/v ═ 1: 1). The product was a colorless oil, 197.1mg, 66% yield, with a diastereomeric excess ratio of 98: 2. High performance liquid chromatography, nuclear magnetic resonance (¹H NMR、¹³C NMR), High Resolution Mass Spectrometry (HRMS), specific optical rotation ([ α [ ])]_D ²⁰) The measurement conditions and results of (1) were as follows:

daicel Chiralpak AD-H, n-hexane/isopropanol 90:10,1.0mL/min, λ 254nm, retention time 67.82 min (main peak), 80.31 min.¹H NMR(400MHz,CDCl₃)δ7.25(d,J＝8.1Hz,1H),7.08(d,J＝8.1Hz,1H),7.02(s,1H),6.98(brs,1H),5.41(d,J＝7.5Hz,1H),4.34(brs,1H),4.06-3.91(m,2H),3.88(q,J＝7Hz,1H),3.74(s,3H),3.35-3.31(m,1H),3.16-3.11(m,1H),2.92-2.90(m,2H),2.54-2.47(m,1H),2.42-2.38(m,1H),2.30-2.26(m,1H),2.19-1.94(m,4H),1.68-1.42(m,18H),0.90(s,3H)。¹³C NMR(100MHz,CDCl₃)δ201.8,170.5,169.9,155.7,139.1,136.9,136.8,128.6,125.7,125.2,80.3,54.3,53.8,52.3,50.5,47.9,44.3,41.2,38.0,35.8,31.6,31.1,29.4,28.3,26.5,25.6,21.6,18.4,13.8。HRMS(m/z,ESI):Calcd.forC₃₂H₄₄N₂O₇S[M+Na]⁺:623.2767,found:623.2772。[α]_D ²⁰＝+5.9(c＝1.36,EtOH)。

Example twenty three: gram-order synthesis of (R) -ibuprofen

Wherein, the 1g is 4-isobutyl styrene, the 2a is benzyl mercaptan, and the 4ga is S-benzyl (R) -2- (4-isobutyl phenyl) propyl thioester.

In a glove box, to a dry 25mL Schlenk bottle were added tris (dibenzylideneacetone) dipalladium (230mg, 0.25mmol), ligand L11(246mg, 0.60mmol) and 10mL of a mixed solvent of 2-methyltetrahydrofuran and chloroform (v/v ═ 1: 1). The reaction solution was rapidly stirred at room temperature for 30 minutes, and then phosphorus pentoxide (28mg, 0.2mmol), p-toluenesulfonic acid monohydrate (190mg, 1mmol) and 4-tert-butylcatechol (132mg, 0.8mmol) were added. The Schlenk bottle was removed from the glove box and replaced with 1 atmosphere of carbon monoxide. The reaction was stirred at 0 ℃ for 5 minutes after which 2a, i.e. benzylthiol (1.86g, 15mmol) was added followed by 1g, i.e. 4-isobutylstyrene (1.60g, 10mmol) and the mixture was stirred at 0 ℃ for 24 hours. After the reaction is finished, the product S-benzyl (R) -2- (4-isobutylphenyl) propylthioester 4ga is obtained by filtering through kieselguhr, washing through dichloromethane, spin-drying, sample mixing and purifying through column chromatography, and colorless oily matter, 2.87g, the yield is 92 percent and the enantiomeric excess percentage is 95 percent. High performance liquid chromatography, nuclear magnetic resonance (¹H NMR、¹³C NMR), High Resolution Mass Spectrometry (HRMS), specific optical rotation ([ α [ ])]_D ²⁰) The measurement conditions and results of (1) were as follows:

daicel Chiralpak OJ-H, n-hexane/isopropanol 1000:1,1.0mL/min, λ 254nm, retention time 26.30 min (main peak), 35.36 min.¹H NMR(400MHz,CDCl₃)δ7.30-7.25(m,7H),7.16(d,J＝7.8Hz,2H),4.19(q,J＝13.7Hz,2H),3.94(q,J＝7.1Hz,1H),2.51(d,J＝18.0Hz,2H),1.94(m,1H),1.60(d,J＝7.1Hz,3H),0.96(d,J＝6.6Hz,6H)。¹³C NMR(100MHz,CDCl₃)δ200.8,141.0,137.5,136.9,129.4,128.9,128.6,127.7,127.2,53.8,45.1,33.5,30.2,22.4,18.4。HRMS(m/z,ESI):Calcd.for C₂₀H₂₄OS[M+Na]⁺:335.1446,found:335.1437。[α]_D ²⁰＝-85.6(c＝0.50,EtOH)。

S-benzyl (R) -2- (4-isobutylphenyl) propylthio ester 4ga (2.87g, 9.2mmol) was dissolved in EtOH (30mL) and then the previously prepared LiOH/H was added₂O₂Solutions of(LiOH0.92g，38.4mmol；30％H₂O₂ 6.2mL；H₂O11.5 mL). The mixture was stirred at room temperature for 3 minutes, quenched with dilute hydrochloric acid, then extracted with dichloromethane and worked up conventionally. The residue was purified by column chromatography using petroleum ether/ethyl acetate (100: 1 to 10: 1) as eluent to give (R) -ibuprofen (white solid, 1.75g, 92% yield, 96% ee). High performance liquid chromatography, nuclear magnetic resonance (¹H NMR、¹³C NMR), specific optical rotation (. alpha.) ([ alpha. ]]_D ²⁰) The measurement conditions and results of (1) were as follows:

the percent enantiomeric excess of (R) -ibuprofen was measured by converting (R) -ibuprofen to (R) ibuprofen methyl ester in one step. Daicel Chiralpak OD-H, n-hexane/isopropanol 1000:1,1.0mL/min, λ 254nm, retention time 6.40 min (main peak), 7.92 min.¹H NMR(400MHz,CDCl₃)δ7.26(d,J＝8.0Hz,2H),7.14(d,J＝7.9Hz,2H),3.75(q,J＝7.1Hz,1H),2.49(d,J＝7.2Hz,2H),1.93-1.83(m,1H),1.53(d,J＝7.2Hz,3H),0.94(d,J＝6.6 Hz,6H)。¹³C NMR(100 MHz,CDCl₃)δ181.0,140.8,137.1,129.4,127.3,45.1,30.2,22.4,18.2。[α]_D ²⁰＝-48.0(c＝0.47,EtOH)。

Claims

1. A method of synthesizing thioesters, comprising: the reaction formula corresponding to the method is as follows:

the R is₁、R₂、R₃、R₄All are any one or combination of any several of hydrogen, alkyl or aryl; r is any one of alkyl, aryl, amino acid containing sulfhydryl, polypeptide or other sulfhydryl-containing compound residue without sulfhydryl;

the ligand is a sulphoxide phosphine ligand, and the structural formula of the ligand is as follows:

wherein, R is^aBoth the radical and the radical R' are alkyl radicals; ar refers to an aromatic group and an aromatic group in which one to more hydrogen atoms in the aromatic ring are substituted.

2. The method of synthesizing thioesters according to claim 1, wherein: the ligand is a sulphoxide phosphine ligand, and R in the structural formula of the ligand^aThe radical is tert-butyl.

3. The method of synthesizing thioesters according to claim 1, wherein: the palladium source is any one of tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, allyl cyclopentadienyl palladium, palladium acetate, palladium chloride, palladium bromide, palladium trifluoroacetate, bis (triphenylphosphine) palladium chloride, bis (benzonitrile) palladium chloride and bis (acetonitrile) p-toluene sulfonic acid palladium.

4. The method of synthesizing thioesters according to claim 1, wherein: the acid is any one of benzene sulfonic acid, p-methyl benzene sulfonic acid, benzoic acid, trifluoromethyl benzene sulfonic acid, trifluoroacetic acid, diphenyl phosphate and hydrochloric acid.

5. The method of synthesizing thioesters according to claim 1, wherein: the inhibitor is any one of 4-tert-butyl catechol, 3, 5-di-tert-butyl catechol, hydroquinone and tetramethylpiperidine oxynitride; and/or; the additive is any one of phosphorus pentoxide and a 4A molecular sieve.

6. The method of synthesizing thioesters according to claim 1, wherein: the solvent is any one or a mixture of any two of chloroform, dichloromethane, 1, 2-dichloroethane, 1,2, 2-tetrachloroethane, nitrobenzene, fluorobenzene, chlorobenzene, trifluorotoluene, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether and ethylene glycol diethyl ether pure solvents; and/or; the olefin is any one of alkyl olefin, aryl olefin and polysubstituted olefin; and/or; the mercaptan is any one of alkyl mercaptan, aryl mercaptan, amino acid and polypeptide containing sulfhydryl or other sulfhydryl compounds.

7. The method of synthesizing thioesters according to claim 1, wherein: the molar ratio of the olefin to the mercaptan to the palladium source to the ligand to the acid to the inhibitor to the additive is 0.9-1: 1-2: 0.02-0.2: 0.024-0.24: 0.04-0.4: 0.02-0.2: 0-0.1.

8. The method of synthesizing thioesters according to claim 1, wherein: the temperature range is-20 to 25 ℃, and the pressure range is 1 to 50 atm.