CN110963980B - Method for synthesizing beta-S amino acid - Google Patents

Method for synthesizing beta-S amino acid Download PDF

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CN110963980B
CN110963980B CN201911100880.9A CN201911100880A CN110963980B CN 110963980 B CN110963980 B CN 110963980B CN 201911100880 A CN201911100880 A CN 201911100880A CN 110963980 B CN110963980 B CN 110963980B
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maj
rot
active ester
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CN110963980A (en
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王平
尹红礼
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Shanghai Jiaotong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
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Abstract

The invention discloses the application of methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-methyl formate (I) in preparing beta-S amino acid (II), wherein the raw materials are simple and easy to obtain, and the synthesis of a general intermediate is simple; the invention has the advantages of short route, high yield and capability of large-scale synthesis.

Description

Method for synthesizing beta-S amino acid
Technical Field
The invention belongs to the field of organic synthesis, and relates to a method for synthesizing beta-S amino acid.
Background
The acquisition of polypeptides, proteins and glycoproteins with defined structures and homogeneity is crucial to elucidating the relationship between protein structure and function. Chemical synthesis is the most efficient and direct method for obtaining high-purity and post-translational modified proteins and glycoproteins. Synthetic chemistry therefore helps complement and extend the role of biological expression techniques.
At present, the native chemical ligation technique is one of the most widely used methods for synthesizing proteins and glycoproteins. The method is developed by Kent group in 1994, and more than 200 proteins and glycoproteins synthesized by natural connection are available at present. However, this approach has major limitations. Firstly, the C-terminus of the polypeptide must contain a thioester, and secondly the N-terminus of the polypeptide must also contain a cysteine (cys). However, the abundance of cysteine in nature is only about 1.2%, thus greatly limiting the application of this method.
For this reason, scientists imagine that S/Se is introduced into the beta position of other amino acids, so that the beta position has cysteine skeleton, and the S/Se is removed by a free radical method after the linkage of the polypeptide is completed, so that the linkage site is not limited to cysteine, and the application range of natural chemical linkage is further expanded. This requires that the β -S amino acid must be chemically synthesized as a building block. However, through literature research, we can find that the existing methods for synthesizing the beta-S amino acid are complex, long in route and low in total yield, and almost all the beta-S amino acids can be synthesized by one substrate, so that the application range of the strategy is greatly limited. If a universal substrate can be used to synthesize a plurality of beta-S amino acids, the application range of natural chemical connection can be greatly expanded.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing beta-S amino acid by using a universal substrate.
In order to solve the technical problems, the invention adopts the technical scheme that:
use of methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate (I) for the preparation of a β -S amino acid (II).
Figure BDA0002269835880000021
Wherein R is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C12 cycloalkyl, substituted or unsubstituted C1-C12 heterocyclic compounds and substituted or unsubstituted C6-C12 aryl;
the substituted substituent is C1-C6 alkyl, aldehyde group, COOR1、OR2、(CH2)n NH2，(CH2)n NHR3；
n is any integer between 0 and 6;
R1and R2Each independently is H or methyl, ethyl, n-propyl or isopropyl;
R3are commonly used amino protecting groups in the art.
Preferably, R is selected from phenyl, p-methoxyphenyl, p-tert-butylphenyl, methyl or any of the following structures:
Figure BDA0002269835880000022
in some embodiments of the present invention, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate is used in the following manner:
in a first organic solvent, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-methyl formate and a metal organic reagent are subjected to 1, 4-addition reaction and then quenched.
The first organic solvent is selected from one or more of tetrahydrofuran, dichloromethane or diethyl ether; the reaction temperature is-78 ℃ to-42 ℃, and the reaction time is 30-60 minutes; the molar ratio of the methyl- (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate to the metal organic reagent is 1: 2-3; the concentration of the methyl- (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate in the first organic solvent is 0.1-0.2M, and the metal organic reagent is an aryl copper reagent or an alkyl copper lithium reagent. The metal organic reagent is an aryl copper reagent or an alkyl copper lithium reagent.
The preparation method of the aryl copper reagent comprises the following steps: reacting CuBr & Me2Dissolving S in THF or ether solvent, adding aryl magnesium bromide at-78-75 ℃, heating to 0-5 ℃ and reacting for 30-50 minutes. CuBr. Me2The concentration of S in the solvent is 0.2-0.3M.
The preparation method of the alkyl copper lithium reagent comprises the following steps: reacting CuBr & Me2Dissolving S in THF or ether solvent, adding alkyl lithium at-78 deg.C to-75 deg.C, heating to 0-5 deg.C, and reacting for 30-50 min.
CuBr·Me2The concentration of S in the solvent is 0.2-0.3M.
In another embodiment of the present invention, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate is used in the following manner:
in a second organic solvent, under the action of DIPEA, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-methyl formate (I) and active ester (III) react under the catalysis of a catalyst and under the condition of illumination to obtain a compound (II),
Figure BDA0002269835880000031
wherein R is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C12 cycloalkyl, substituted or unsubstituted C1-C12 heterocyclic compounds and substituted or unsubstituted C6-C12 aryl;
the substituted substituent is C1-C6 alkyl, aldehyde group, COOR1、OR2、(CH2)n NH2，(CH2)n NHR3；
n is any integer between 0 and 6;
R1and R2Each independently is H or methyl, ethyl, n-propyl or isopropyl;
R3are commonly used amino protecting groups in the art.
The second organic solvent is selected from one or two of dichloromethane or acetonitrile; the concentration of methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate in the second organic solvent is 0.1-0.3M.
When the active ester (III) is a secondary or tertiary active ester, the illumination condition is blue light illumination, and the catalyst is a ruthenium catalyst and diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate; the ruthenium catalyst is selected from Ru (bpy)3(PF6)2Or Ru (bpy)3Cl2(ii) a Methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate (I), active ester (III), a ruthenium catalyst, diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate and DIPEA in a molar ratio of 1:1:0.01:1.3:1.2 to 1:3:0.3:2: 2; when the active ester (III) is a primary active ester or pyridine active ester, the lighting conditions are visible light, and the catalyst is eosin Y; the molar ratio of methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate (I), active ester (III), eosin Y and DIPEA is 1:1:0.1:2 to 1:2:0.3: 2.
Preferably, R of the secondary or tertiary active ester is selected from
Figure BDA0002269835880000041
Or
Figure BDA0002269835880000042
Any one of the groups in (1); the R group of the primary active ester is selected from
Figure BDA0002269835880000043
Figure BDA0002269835880000044
Or
Figure BDA0002269835880000045
The R group of the pyridine active ester is selected from
Figure BDA0002269835880000046
Or
Figure BDA0002269835880000047
In another embodiment of the present invention, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate is used in the following manner:
in a third organic solvent, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate (I) and acid (IV) are added in Ir [ dF (CF)3)ppy]2(dtbbpy)PF6Under the catalysis of cesium carbonate and under the illumination of blue light, a compound (II) is generated,
Figure BDA0002269835880000048
wherein R is selected from any of the following structures:
Figure BDA0002269835880000049
the third organic solvent is one or two selected from DMSO or acetone, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-formic acid methyl ester (I), acid (IV) and Ir [ dF (CF)3)ppy]2(dtbbpy)PF6And cesium carbonate in a molar ratio of 1:2.0:0.01:2.5 to 1:3.0:0.03:5, wherein the concentration of methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate in the fourth organic solvent is 0.03 to 0.05M.
In some embodiments of the present invention, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate is used in the following manner:
reacting methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-methyl formate (I) with aldehyde (V) in a fourth organic solvent under the catalysis of TBADT and the illumination of ultraviolet light,
Figure BDA0002269835880000051
wherein R is NH2。
The fourth organic solvent is acetonitrile, the molar ratio of methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate (I) to aldehyde (V) to TBADT is 1:2: 0.1-1: 5:0.3, and the concentration of methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate in the fourth organic solvent is 0.1-0.5M.
In some embodiments of the present invention, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate is used in the following manner:
in a fifth organic solvent, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-methyl formate (I) and iodide (VI) react under the catalysis of a photocatalyst and the action of DIPEA and the irradiation of blue light,
Figure BDA0002269835880000052
wherein R is NH2Or OH.
The fifth organic solvent is selected from acetonitrile, the photocatalyst is Ru (bpy)3(PF6)2(ii) a Methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate (I), iodide (VI), photocatalyst and, DIPEA in a molar ratio of 1:2: 0.01: 2-1: 3:0.03:4, methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate in a seventh organic solvent at a concentration of 0.2-0.5M.
Has the advantages that:
the raw materials are simple and easy to obtain, and the synthesis of the general intermediate is simple; the invention has the advantages of short route, high yield and capability of large-scale synthesis.
The reaction in the invention is carried out under anhydrous and oxygen-free conditions.
In the invention, C1-C6 means that the total number of C on the main chain and the branched chain is 1-6.
Commonly used amino protecting groups in the art include CBz, Boc, Fmoc, Alloc, Teoc, Bn, Phth or PMB, among others.
The blue light has a wavelength of 450nm and the visible light has a full wavelength.
Detailed Description
The abbreviations used in the present invention have the following meanings:
HE: 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylic acid diethyl ester
TBADT: tetrabutylammonium decatungstate salt
CBz: benzyloxycarbonyl group
Boc: tert-butyloxycarbonyl radical
Fmoc: fluorenyl methoxy carbonyl
And (3) Alloc: allyloxycarbonyl radical
Teoc: trimethylsilylethoxycarbonyl radical
Bn: benzyl radical
Phth: phthaloyl radical
PMB: p-methoxybenzyl
DIPEA: n, N-diisopropylethylamine
DIC: n, N-diisopropylcarbodiimide
DMAP: 4-dimethylaminopyridine
Eosin Y: eosin Y or 2 ', 4', 5 ', 7' -tetrabromo fluorescein
Maj denotes the isomer that accounts for the majority of rotamers
And rot.min indicates the isomer that makes up a small proportion of the rotamers.
The starting materials or reagents not specifically mentioned in the present invention are all commercially available products.
Synthesis of starting materials
1. Synthesis of methyl (R) -2- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate (I).
Figure BDA0002269835880000061
Compound 1, i.e., native L-cysteine hydrochloride (30.0388g, 175mmol, 1.0equiv) was added to a 500mL round-bottomed flask, dissolved in 200mL n-hexane (bp 69 ℃ C.), followed by pivalaldehyde (45mL, 85%, 350mmol, 2.0equiv), triethylamine (27mL, 192.5mmol, 1.1equiv) in that order, and heated under reflux using a water separator for 24 hours. After the reaction is finished, carrying out suction filtration, washing filter residues by using anhydrous ether, directly carrying out rotary evaporation on the filtrate, and directly carrying out the next reaction.
In a 100mL round bottom flask, the product 2(234.65g, 171mmol, 1.0equiv.) of the previous step was added, formic acid 400mL was added and dissolved, then sodium formate (13.93g, 204mmol, 1.2equiv) was added, stirring was performed at 0 ℃, then acetic anhydride (48.4mL, 512mmol, 3.0equiv) was slowly added dropwise to the reaction system, and after 1 hour of reaction, the reaction was returned to room temperature, and stirring was performed for 24 hours. And then determining that most of the reactant 2 has been reacted through a point plate, and carrying out post-treatment on the reaction system. Firstly, carrying out rotary evaporation on part of formic acid, then adding an excessive saturated sodium bicarbonate solution into a reaction system at 0 ℃, adding 120mL of diethyl ether after the reaction is finished, then extracting with diethyl ether for 3 times, drying with anhydrous sodium sulfate, and then carrying out rotary evaporation on an organic phase. Product 3(35.6g) was obtained in 90% yield.
A500 mL round bottom flask was charged with starting material (35.6g, 154mmol, 1.0equiv), dissolved in anhydrous DCM300mL, after which DBU (42mL, 98%, 277.2mmol, 1.8equiv), CBrCl, was added sequentially at 0 deg.C3(20mL, 200mmol, 1.3equiv), at 0 ℃ for 24 hours. After that, the reaction was quenched by adding an equal volume of saturated sodium bicarbonate solution of DCM at 0 ℃ to determine that most of the reaction had been completed, the product was extracted with DCM, the organic phase was dried over anhydrous sodium sulphate, rotary evaporated and the mixture was separated by column chromatography to give 25.74g of product (I) with a total yield of 74%.
1H NMR(400MHz,Chloroform-d)δ8.81(s,1H),7.05(s,1H),5.79(s,1H),3.79(s,3H),0.92(s,9H).
13C NMR(101MHz,Chloroform-d)δ164.0,159.3,128.7,127.6,74.4,52.5,39.3,24.6.
2. Synthesis of starting active esters
Figure BDA0002269835880000071
The starting active ester (III) was synthesized by the following general procedure:
the acid (VII) (1.0equiv) and phthalimide (1.2equiv) were added to a round-bottomed flask, and DCM was added to dissolve the compound with stirring at room temperature, followed by the addition of DIC (1.5equiv) and a catalytic amount of DMAP, and the reaction was stirred at room temperature for 24 hours. After the reaction of most raw materials is determined by a dot plate, the raw materials are steamed in a rotary mode, and the active ester (III) is obtained through column chromatography separation.
The active ester (III) prepared by the steps is as follows:
Figure BDA0002269835880000081
Figure BDA0002269835880000082
Figure BDA0002269835880000091
Figure BDA0002269835880000101
EXAMPLE 1 preparation of methyl (2R, 4R, 5R) -2- (tert-butyl) -3-formyl-5-phenylthiazolidine-4-carboxylate (4).
Figure BDA0002269835880000102
A50 mL long-neck flask is roasted by a heating gun, and an argon filling balloon and gas replacement gas in the round-bottom flask are charged to achieve the anhydrous and oxygen-free conditions. After the reaction system is treated, quickly weighing CuBr. Me2S (0.6167g, 3.0mmol, 2.0equiv), adding into the reaction system, adding into super-dry tetrahydrofuran 8mL for dissolving, stirring at-78 deg.C for 10minAfter that, phenylmagnesium bromide (1.93mL, 6.0mmol, 4.0equiv) was added to the reaction system at this temperature, and after the addition was completed, the reaction system was placed in an ice-water bath and reacted at 0 ℃ for 30 minutes to produce a phenylcopper reagent. At this time, the low temperature reactor was adjusted from-78 ℃ to-42 ℃, the reaction system was left at this temperature and stirred for 10 minutes to ensure that the reaction system was reduced to-42 ℃, after which intermediate (I) (0.3435g, 1.5mmol, 1.0equiv) was dissolved in 4mL of ultra-dry Tetrahydrofuran (THF) and slowly added dropwise to the reaction system, and after completion of the dropwise addition, the reaction system was stirred for 30-60 minutes at-42 ℃. After confirming that most of the intermediate 1 had reacted by TLC, a saturated ammonium chloride solution was added to the reaction system to quench the reaction, and extraction was performed with DCM, and then a saturated sodium chloride solution was added to back-extract the organic phase, and the organic phase was dried with anhydrous sodium sulfate, rotary evaporated, and separated by column chromatography to give product 4, which was 0.3016g, yield 71%.
1H NMR (500MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj and rot.min. (1/0.18)]δ8.42(s,1H,rot.maj.),8.23(s,1H,rot.min.),7.43–7.30(m,5H,rot.maj.),5.54(s,1H,rot.min.)5.12(d,J＝4Hz,1H,rot.min.),4.93(s,1H,rot.maj.),4.88(s,2H,rot.maj.),4.62(d,J＝8Hz,1H,rot.min.),3.78(s,3H,rot.min.)3.67(s,3H,rot.maj.),1.11(s,9H,rot.maj.),1.02(s,9H,rot.min.).
13C NMR(126MHz,CDCl3)δ170.1(rot.min.),169.9,(rot.maj.)164.0(rot.min.),162.6(rot.maj.),139.2(rot.min.),136.7(rot.maj.)129.0(rot.min.),128.9(rot.maj.),128.6(rot.maj.),128.3,(rot.min.),127.9(rot.maj.),127.7(rot.min.),75.7(rot.maj.),72.7(rot.min.),71.8(rot.min.),68.4(rot.maj.),53.1(rot.maj.),53.0(rot.min.),52.5(rot.maj.),51.5(rot.min.),38.7(rot.min.),38.7(rot.maj.),26.8(rot.min.),26.4(rot.maj.).
Example 2: preparation of methyl (2R, 4R, 5R) -2- (tert-butyl) -3-formyl-5- (4-methoxyphenyl) thiazolidine-4-carboxylate (5).
Figure BDA0002269835880000111
A50 mL long-neck flask is roasted by a heating gun, and an argon filling balloon and gas replacement gas in the round-bottom flask are charged to achieve the anhydrous and oxygen-free conditions. After the reaction system is treated, quickly weighing CuBr. Me2S (0.6167g, 3.0mmol, 2.0equiv), adding into the reaction system, adding 8mL of ultra-dry tetrahydrofuran for dissolving, stirring at-78 ℃ for 10 minutes, adding aryl magnesium bromide (1.93mL, 4.0mmol, 4.0equiv) into the reaction system at the temperature, placing the reaction system in an ice-water bath after the addition is finished, and reacting at 0 ℃ for 30 minutes to generate the aryl copper reagent. At this time, the low temperature reactor was adjusted from-78 ℃ to-42 ℃, the reaction system was left at this temperature and stirred for 10 minutes to ensure that the reaction system was reduced to-42 ℃, after which intermediate (I) (0.3435g, 1.5mmol, 1.0equiv) was dissolved in 4mL of ultra-dry Tetrahydrofuran (THF) and slowly added dropwise to the reaction system, and after completion of the dropwise addition, the reaction system was stirred for 30-60 minutes at-42 ℃. After confirming that the intermediate 1 had mostly reacted by TLC, the reaction was quenched by adding saturated ammonium chloride solution to the reaction system, extracted with DCM, and then back extracted with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, rotary evaporated, and isolated by column chromatography to give product 5 (65%).
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.16)]δ8.40(s,1H,rot.maj.),8.25(s,1H,rot.min.),7.37–7.30(m,2H,rot.maj.),7.37–7.30(m,2H,rot.min.),6.90–6.84(m,2H,rot.maj.),,6.90–6.84(m,2H,rot.min.),5.52(s,1H,rot.min.),5.10(d,J＝8Hz,1H,rot.min.),4.91(s,1H,rot.maj.),4.87–4.76(m,2H,rot.maj.),4.60(d,J＝4Hz,1H,rot.min.),3.81(s,3H,rot.maj.),3.80(s,3H,rot.min.),3.79(s,3H,rot.min.),3.69(s,3H,rot.maj.),1.13(s,9H,rot.maj.),1.03(s,9H,rot.min.).
13C NMR(101MHz,Chloroform-d)δ170.00(maj.),162.61(maj.),159.73(min.),129.13(maj.),128.89(min.),128.25(maj.),114.33(min.),114.25(maj.),75.59(maj.),74.13(min.),72.05(min.),68.56(maj.),56.26(min.),55.30(maj.),53.01(min.),52.74(maj.),52.51(maj.),51.12(min.),38.74(maj.),26.85(min.),26.45(maj.).
Example 3 preparation of methyl (2R, 4R, 5R) -5- (4- (tert-butoxy) phenyl) -2- (tert-butyl) -3-formylthiazolidine-4-carboxylate (6).
Figure BDA0002269835880000121
A50 mL long-neck flask is roasted by a heating gun, and an argon filling balloon and gas replacement gas in the round-bottom flask are charged to achieve the anhydrous and oxygen-free conditions. After the reaction system is treated, quickly weighing CuBr. Me2S (0.6167g, 3.0mmol, 2.0equiv), adding into the reaction system, adding 8mL of ultra-dry tetrahydrofuran for dissolving, stirring at-78 ℃ for 10 minutes, adding aryl magnesium bromide (1.93mL, 4.0mmol, 4.0equiv) into the reaction system at the temperature, placing the reaction system in an ice-water bath after the addition is finished, and reacting at 0 ℃ for 30 minutes to generate the aryl copper reagent. At this time, the low temperature reactor was adjusted from-78 ℃ to-42 ℃, the reaction system was left at this temperature and stirred for 10 minutes to ensure that the reaction system was reduced to-42 ℃, after which intermediate (I) (0.3435g, 1.5mmol, 1.0equiv) was dissolved in 4mL of ultra-dry Tetrahydrofuran (THF) and slowly added dropwise to the reaction system, and after completion of the dropwise addition, the reaction system was stirred for 30-60 minutes at-42 ℃. After confirming that the intermediate 1 had mostly reacted by TLC, the reaction was quenched by adding saturated ammonium chloride solution to the reaction system, extracted with DCM, and then back extracted with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, rotary evaporated, and isolated by column chromatography to give product 6 (57%).
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.16)]δ8.39(s,1H,rot.maj.),8.27(s,1H,rot.min.),7.30–7.27(m,2H,rot.maj.),7.30–7.27(m,2H,rot.min.),6.95(d,J＝8Hz 2H,rot.maj.),6.95(d,J＝8Hz 2H,rot.min.),5.53(s,1H,rot.min.),5.10(d,J＝4Hz,1H,rot.min.),4.91(s,1H,rot.maj.),4.86–4.80(m,2H,rot.maj.),4.60(d,J＝8Hz,1H,rot.min.),3.78(s,3H,rot.min.),3.67(s,3H,rot.maj.),1.35(s,9H,rot.maj.),1.34(s,9H,rot.min.),1.11(s,9H,rot.maj.),1.02(s,9H,rot.min.)。
13C NMR(101MHz,CDCl3)δ170.1(rot.maj.),164.1(rot.min.),162.7(rot.maj.),155.8(rot.min.),131.2(rot.maj.),128.6(rot.maj.),128.4(rot.min.),124.4(rot.min.),124.3(rot.maj.),78.9(rot.maj.),77.4(rot.min.),75.8(rot.maj.),72.8(rot.min.),72.0(rot.min.),68.7(rot.maj.),53.2(rot.min.),52.8(rot.maj.),52.6(rot.maj.),51.2(rot.min.),38.8(rot.min.),38.8(rot.maj.),29.0(rot.maj.),27.0(rot.min.),26.6(rot.maj.)。
Example 4: preparation and application of (R) -2- (tert-butyl) -3-formyl-5-methyl-2, 3-dihydrothiazole-4-carboxylic acid methyl ester (7).
Figure BDA0002269835880000131
A50 mL long-neck flask is roasted by a heating gun, and an argon filling balloon and gas replacement gas in the round-bottom flask are charged to achieve the anhydrous and oxygen-free conditions. After the reaction system is treated, CuBr. Me2S (616.7mg, 3.0mmol, 2.0equiv) is weighed rapidly and added into the reaction system, 8mL of ultra-dry tetrahydrofuran is added for dissolution, the mixture is stirred at-78 ℃ for 10 minutes, then methyllithium (1.93mL, 6.0mmol, 4.0equiv) is added into the reaction system at the temperature, and after the addition is finished, the reaction system is placed in an ice-water bath and reacts at 0 ℃ for 30 minutes to generate the methyl copper lithium reagent. At this time, the low temperature reactor was adjusted from-78 ℃ to-42 ℃, the reaction system was left at this temperature and stirred for 10 minutes to ensure that the reaction system was reduced to-42 ℃, after which intermediate (I) (343.5mg, 1.5mmol, 1.0equiv) was dissolved in 4mL of ultra-dry Tetrahydrofuran (THF) and slowly added dropwise to the reaction system, and after completion of the dropwise addition, the reaction system was stirred for 30-60 minutes at-42 ℃. After confirming that the intermediate (I) had mostly reacted by TLC, the reaction was quenched by adding saturated ammonium chloride solution to the reaction system, extracted with DCM, and then back extracted with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography to give compound 7 (65%).
1H NMR (400MHz, Chloroform-d) delta [ containing rotamers, where the molar ratio between rot.maj and rot.min. (1/0.05)]8.37(s,1H,maj.),8.34(s,1H,min.),4.79(s,1H,maj.),4.76(s,1H,min.),4.42(d,J＝8.2Hz,1H,maj.),4.35(d,J＝8.3Hz,1H,min.),3.87–3.74(m,1H,maj.),2.33(s,3H,maj.),1.50(d,J＝6.5Hz,3H,min.),1.46(d,J＝6.5Hz,3H,maj.),1.07(s,9H,min.),1.04(s,9H,maj.).
13C NMR(101MHz,Chloroform-d)δ169.58(min.),169.01(maj.),164.75(min.),163.70(maj.),73.99(maj.),71.05(min.),68.09(min.),65.16(maj.),56.13(maj.),53.98(min.),52.37(min.),51.09(maj.),39.08(min.),38.93(maj.),32.17(min.),31.52(maj.),26.78(min.),26.34(maj.).
A50 mL round bottom flask was charged with Compound 7, dissolved in anhydrous DCM, followed by the sequential addition of DBU, CBrCl at 0 deg.C3The reaction was carried out at 0 ℃ for 24 hours. TLC monitored the reaction was complete and the reaction was quenched by addition of an equal volume of saturated sodium bicarbonate solution of DCM at 0 ℃ before the product was extracted with DCM, the organic phase was dried over anhydrous sodium sulphate, rotary evaporated and the mixture was separated by column chromatography to give product 8 (76%).
1H NMR(400MHz,Chloroform-d)δ8.79(s,1H),7.13(s,1H),5.86(s,1H),3.69(s,3H),2.35(s,3H),0.90(s,9H).
13C NMR(101MHz,Chloroform-d)δ163.9,159.1,129.1,128.5,75.8,53.3,38.9,25.3,17.1
A50 mL long-neck flask is roasted by a heating gun, and an argon filling balloon and gas replacement gas in the round-bottom flask are charged to achieve the anhydrous and oxygen-free conditions. After the reaction system is treated, quickly weighing CuBr. Me2S (616.7mg, 3.0mmol, 2.0equiv), adding into the reaction system, adding 8mL of ultra-dry tetrahydrofuran for dissolving, stirring at-78 ℃ for 10 minutes, adding methyllithium (1.93mL, 4.0mmol, 4.0equiv) into the reaction system at the temperature, placing the reaction system in an ice-water bath after the addition is finished, and reacting at 0 ℃ for 30 minutes to generate the methyllithium copper reagent. At this time, the low temperature reactor was adjusted from-78 ℃ to-42 ℃, the reaction system was left at this temperature and stirred for 10 minutes to ensure that the reaction system was reduced to-42 ℃, after which compound 8(366mg, 1.5mmol, 1.0equiv) was dissolved in 4mL of ultra-dry Tetrahydrofuran (THF) and slowly added dropwise to the reaction system, and after completion of the dropwise addition, the reaction system was stirred for 30-60 minutes at-42 ℃. Confirmation by TLC that Compound 8 has been mostly invertedAfter completion, the reaction was quenched by adding saturated ammonium chloride solution to the reaction system, extracted with DCM, and then back extracted with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography to give product 9 (60%).
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.15)]δ8.25(s,1H,maj.),5.20(s,1H,min.),4.68(d,J＝6.4Hz,1H,maj.),4.53(s,1H,maj.),4.33(d,J＝4.7Hz,1H,min.),3.67(s,3H,min.),3.56(s,3H,maj.),2.10(s,3H,maj.),2.05(s,3H,min.),1.98(s,3H,maj.),1.85(s,3H,min.),1.01–0.85(m,9H,maj.),1.01–0.85(m,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.51(min.),170.45(maj.),163.73(min.),162.54(maj.),74.88(maj.),71.13(min.),66.05(min.),62.36(maj.),55.69(maj.),54.10(min.),52.88(min.),52.39(maj.),38.10(min.),37.03(maj.),32.17(min.),31.00(maj.),25.36(min.),23.46(maj.),21.30(maj.),20.57(min.),18.01(min.),17.88(maj.).
Example 5: preparation of methyl (2R, 4R, 5R) -2- (tert-butyl) -3-formyl-5-isopropylthiazolidine-4-carboxylate (10)
Figure BDA0002269835880000151
A50 mL round-bottom flask was charged with Compound (I) (0.2290g, 1.0mmol, 1.0equiv), active ester (III) -1(0.2563g, 1.1mmol, 1.1equiv), Ru (bpy)3(PF6)2(4mg, 0.01mmol, 0.01equiv), HE (0.3289g, 1.3mmol, 1.3equiv), dissolved in 15mL of extra dry DCM, after which DIPEA (0.258mL, 1.5mmol, 1.5equiv) was added using a microsyringe. Note that oxygen-free conditions were required for this reaction, and therefore, an argon balloon was filled, and the reaction system was bubbled for 10 minutes to remove oxygen in the reaction system, and then the reaction system was placed under blue light for reaction, that is, under an LED of 450nm for reaction for 8 hours at room temperature. TLC monitoring reaction is completed, the reaction system is taken out under the condition of LED illumination, silica gel is added for sample mixing, and then the product 10(90 percent) is obtained by column chromatography separation).
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.15)]δ8.28(s,1H,maj.),5.24(s,1H,min.),4.78(d,J＝6.4Hz,1H,maj.),4.74(s,1H,maj.),4.43(d,J＝4.7Hz,1H,min.),3.91(dd,J＝6.3,4.6Hz,1H,min.),3.87–3.81(m,1H,maj.),3.77(s,3H,min.),3.74(s,3H,maj.),2.10–1.96(m,1H,maj.),1.93–1.82(m,1H,min.),1.04–0.87(m,15H,maj.),1.04–0.87(m,15H,min.).
13C NMR(101MHz,Chloroform-d)δ170.71(min.),170.54(maj.),163.95(min.),162.65(maj.),74.89(maj.),71.17(min.),67.07(min.),63.46(maj.),55.80(maj.),54.39(min.),52.97(min.),52.59(maj.),38.37(min.),38.03(maj.),32.57(min.),31.25(maj.),26.66(min.),26.25(maj.),21.60(maj.),21.37(min.),19.11(min.),17.97(maj.).
Example 6: preparation and application of (2R, 4R, 5R) -2- (tert-butyl) -3-formyl-5-isopropylthiazolidine-4-carboxylic acid methyl ester (11)
Figure BDA0002269835880000161
Compound (I) (130mg, 0.58mmol, 1.0equiv), active ester (III) -2(190mg, 0.68mmol, 1.2equiv) and Eosin Y (146mg, 0.225mmol, 0.3equiv) were dissolved in ultra-dry DCM2mL and DIPEA (210mL, 2.0equiv) was added using a pipette gun. Because the reaction system needs anaerobic condition, after adding the reagent, filling argon balloon, bubbling for 10 minutes to remove the oxygen in the reaction system, then placing the reaction system under the illumination of a household lighting lamp for reaction, and reacting for 72 hours at room temperature. Taking out the reaction system under the LED illumination condition, and directly separating by column chromatography to obtain the compound 11.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.18)]δ8.35(s,1H,maj.),8.31(s,1H,min.),5.31(s,1H,min.),4.76(s,1H,maj.),4.56(d,J＝5.5Hz,1H,min.),4.52(dd,J＝8.6,0.9Hz,1H,maj.),4.49–4.43(m,1H,min.),4.43(dd,J＝6.7,4.4Hz,1H,maj.),3.83(s,3H,min.),3.80(s,3H,maj.),3.37(s,6H,maj.),3.35(s,1H,min.),2.42(ddd,J＝14.1,6.7,3.9Hz,1H,maj.),2.28–2.10(m,2H,min.),1.85(ddd,J＝14.3,10.2,4.4Hz,1H,maj.),1.06(s,9H,maj.),0.97(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.31(min.),169.84(maj.),164.26(min.),162.56(maj.),103.25(min.),103.08(maj.),74.92(maj.),71.23(min.),68.79(min.),66.52(maj.),53.83(min.),53.55(maj.),53.49(maj.),53.41(min.),52.96(min.),52.68(maj.),44.99(maj.),43.62(min.),38.41(maj.),38.26(min.),37.41(maj.),26.77(min.),26.35(maj.).
Figure BDA0002269835880000171
Adding the compound 11 into a reaction system containing DCM/TFA, adding phenylhydrazine (4equiv.), stirring for 2h at rt, blowing dry Ar, and carrying out column chromatography to obtain a product 22 (100%).
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.18)]δ8.45(s,1H,maj.),8.25(s,1H,min.),7.69(d,J＝7.9Hz,1H,maj.),7.39(d,J＝8.1Hz,1H,maj.),7.30–7.21(m,2H,maj.),7.19–7.14(m,1H,maj.),5.59(s,1H,min.),5.49(d,J＝5.3Hz,1H,min.),5.30(d,J＝8.9Hz,1H,maj.),5.13(d,J＝8.8Hz,1H,maj.),4.94(s,1H,maj.),4.87(d,J＝5.3Hz,1H,min.),3.81(s,1H,min.),3.67(s,3H,maj.),1.18(s,9H,maj.),1.08(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.36(maj.),164.46(min.),163.00(maj.),136.85(min.),136.60(maj.),125.94(maj.),125.26(min.),123.53(min.),122.69(maj.),122.67(maj.),120.00(min.),119.93(maj.),119.13(maj.),118.84(min.),113.47(min.),111.79(min.),111.65(maj.),110.99(maj.),75.21(maj.),72.27(min.),70.27(min.),66.75(maj.),53.01(min.),52.60(maj.),45.53(maj.),44.08(min.)38.66(maj.),38.58(min.),26.90(min.),26.55(maj.).
Example 7: preparation of methyl (2R, 4R, 5R) -2- (tert-butyl) -3-formyl-5-isopropylthiazolidine-4-carboxylate (12)
Figure BDA0002269835880000181
Prepared by the method of reference example 6. Yield 65%, with 96% recovery yield.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.11)]δ8.31(s,1H,maj.),8.25(s,1H,min.),5.26(s,1H,min.),4.74(s,1H,maj.),4.64(bs,1H,maj.),4.46(d,J＝8.2Hz,1H,maj.),4.32(d,J＝6.0Hz,1H,min.),3.80(s,3H,min.),3.76(s,3H,maj.),3.73(dt,J＝8.5,4.3Hz,1H,min.),3.13(q,J＝7.1,6.6Hz,2H,maj.),2.12–2.04(m,1H,maj.),1.92(s,9H,min.),1.63–1.52(m,2H,maj.),1.43(s,9H,maj.),1.02(s,9H,maj.),0.94(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.41(min.),169.93(maj.),163.94(min.),162.56(maj.),155.90(maj.),74.80(maj.),71.23(min.),69.16(min.),66.55(maj.),53.00(min.),52.62(maj.),49.21(maj.),48.04(min.),38.63(min.)38.40(maj.),32.84(min.),31.62(maj.),29.08(min.),28.39(maj.),26.73(min.),26.32(maj.).
Example 8: preparation of methyl (2R, 4R, 5R) -2- (tert-butyl) -5-cyclobutyl-3-formylthiazolidine-4-carboxylate (13).
Figure BDA0002269835880000182
Prepared by the method of reference example 5. The yield thereof was found to be 85%.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.15)]δ8.29(s,1H,maj.),8.24(s,1H,min.),5.26(s,1H,min.),4.73(s,1H,maj.),4.52(d,J＝6.7Hz,1H,maj.),4.23(d,J＝4.1Hz,1H,min.),3.99–3.91(m,1H,min.),3.86(dd,J＝8.1,6.8Hz,1H,maj.),3.78(s,3H,min.),3.74(s,3H,maj.),2.64–2.50(m,1H,maj.),2.44(dq,J＝8.8,6.9,6.0Hz,1H,min.),2.15–1.94(m,2H,maj.),1.93–1.70(m,4H,maj.),1.01(s,9H,maj.),0.93(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.49(min.),170.46(maj.),164.26(min.),162.90(maj.),74.88(maj.),71.37(min.),67.66(min.),64.67(maj.),54.23(maj.),53.02(min.),52.65(maj.),39.53(min.),38.87(maj.),38.39(min.),38.24(maj.),27.52(maj.),26.86(min.),26.46(maj.),25.63(maj.),17.69(maj.),17.44(min.).
Example 9: preparation of methyl (2R, 4R, 5R) -2- (tert-butyl) -5-cyclohexyl-3-formylthiazolidine-4-carboxylate (14).
Figure BDA0002269835880000191
Prepared by the method of reference example 5. The yield thereof was found to be 87%.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.18)]δ8.27(s,1H,min.),8.25(s,1H,maj.),5.58(s,1H,min.),5.10(d,J＝6.0Hz,1H,maj.),5.02(s,1H,maj.),4.62(d,J＝4.4Hz,1H,min.),4.17–4.12(m,1H,min.),4.10(t,J＝5.9Hz,1H,maj.),3.77(s,3H,min.),3.74(s,3H,maj.),1.92–1.52(m,7H,maj.),1.29–1.18(m,2H,maj.),1.18–1.04(m,2H,maj.),0.99(s,9H,maj.),0.93(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.80(min.),170.75(maj.),164.04(min.),162.65(maj.),70.36(maj.),68.35(min.),66.17(min.),63.95(maj.),52.96(min.),52.60(maj.),51.17(maj.),49.47(min.),42.68(min.),41.54(maj.),38.09(min.),37.75(maj.),33.24(maj.),32.89(min.),31.40(min.),29.97(maj.),27.10(min.),26.69(maj.),26.18(maj.),26.06(maj.),25.99(min.),25.95(min.),25.92(maj.).
Example 10: preparation and application of (2R, 4R, 5R) -5- (2- (((tert-butyloxycarbonyl) amino) ethyl) -2- (tert-butyl) -3-formylthiazolidine-4-carboxylic acid methyl ester (15).
Figure BDA0002269835880000192
Prepared by the method of reference example 6. Yield 60%, with recovery yield 95%.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.15)]δ8.31(s,1H,maj.),8.28(s,1H,min.),5.27(s,1H,min.),4.75(s,1H,maj.),4.50(d,J＝8.1Hz,1H,maj.),4.44–4.39(m,1H,min.),3.79(s,3H,min.),3.76(s,3H,maj.),3.77–3.69(m,1H,maj.),3.41(q,J＝6.1,5.7Hz,1H,min.),3.27–3.16(m,2H,maj.),2.50(td,J＝5.8,2.9Hz,1H,min.),2.24(dtd,J＝14.0,7.0,4.0Hz,1H,maj.),2.13–2.00(m,1H,min.),1.72(ddt,J＝13.6,9.9,6.6Hz,1H,maj.),1.43(s,9H,maj.),1.41(s,9H,min.),1.01(s,9H,maj.),0.93(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.27(min.),169.85(maj.),164.08(min.),162.55(maj.),155.86(min.),155.74(maj.),74.97(maj.),71.25(min.),68.99(min.),66.47(maj.),52.99(min.),52.66(maj.),46.83(maj.),45.28(min.),39.32(min.),38.47(min.),38.36(maj.),34.90(maj.),28.40(maj.),28.37(min.),26.73(min.),26.30(maj.).
Figure BDA0002269835880000201
In a 20mL sample bottle, compound 15(0.1364g) obtained in the previous step is put into reaction, 6N HCl 3mL is added, the mixture is stirred for 8 hours at 90 ℃, the protection is removed to obtain compound 23, the product is dried in a spinning mode, 5mL of methanol is added, the reaction system is placed in an ice water bath at 0 ℃, N' -di-Boc-1H-1-guanidinopyrazole (0.0134mg, 0.043mmol and 1.0equiv) is added, a liquid transfer gun is used for adding DIPEA (37uL, 0.0216mmol and 5.0equiv) to react for 4 hours at 0 ℃, finally, the completion of the reaction is preliminarily determined by TLC, the methanol in the reaction system is removed by rotary evaporation, and the compound is purified by 25 two-step 78% yield.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.18)]δ11.48(s,1H,maj.),11.43(s,1H,min.),8.43(q,J＝5.7,4.9Hz,1H,maj.),8.35(s,1H,min.),8.31(s,1H,maj.),5.30(s,1H,min.),4.75(s,1H,maj.),4.73(s,1H,min.),4.48(d,J＝8.4Hz,1H,maj.),3.95–3.86(m,1H,min.),3.79(s,3H,min.),3.78(s,3H,maj.),3.78–3.69(m,1H,maj.),3.50(q,J＝7.1Hz,2H,maj.),3.44(d,J＝7.0Hz,2H,min.),2.39(dtd,J＝14.3,7.4,3.7Hz,1H,maj.),2.21–2.10(m,1H,min.),1.81(tdt,J＝13.8,10.2,6.8Hz,1H,maj.),1.49(d,J＝2.1Hz,18H,maj.),1.02(s,9H,maj.),0.93(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.44(min.),169.65(maj.),164.45(min.)163.48(maj.),163.30(min.),162.53(maj.),156.22(maj.),156.12(min.),153.25(maj.),148.77(min.),83.29(min.),83.26(maj.),79.34(maj.),74.97(maj.),71.31(min.),68.62(min.),66.61(maj.),52.92(min.),52.67(maj.),46.84(maj.),45.19(min.),39.50(maj.),38.96(min.),38.46(maj.),38.42(min.),34.95(min.),33.74(maj.),28.27(maj.),28.24(min.),28.02(maj.),27.96(min.),26.72(min.),26.31(maj.).
Example 11: preparation and application of (2R, 4R, 5S) -2- (tert-butyl) -3-formylthiazolidine-4, 5-dicarboxylic acid dimethyl ester (16).
Figure BDA0002269835880000211
Prepared by the method of reference example 6. The yield thereof was found to be 53%.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.15)]δ8.35(s,1H,min.),8.26(s,1H,maj.),5.99(s,1H,maj.),5.59(s,1H,min.),5.32(s,1H,maj.),5.29(s,1H,min.),5.25(s,1H,min.),4.79(s,1H,maj.),3.77(s,3H,min.),3.73(s,3H,min.),3.70(s,3H,maj.),3.66(s,3H,maj.),0.93(s,9H,maj.),0.91(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ172.31(maj.),171.52(min.),170.03(min.),169.53(maj.),166.12(min.),163.17(maj.),77.13(maj.),73.57(min.),65.19(maj.),62.07(min.),54.25(min.),53.90(maj.),52.6(min.),51.90(maj.),50.61(maj.),49.52(min.),39.17(min.),38.53(maj.),27.31(min.),27.06(maj.).
Example 12: preparation of methyl (2R, 4R, 5S) -2- (tert-butyl) -3-formyl-5- (pyridin-2-yl) thiazolidine-4-carboxylate (17).
Figure BDA0002269835880000212
Prepared by the method of reference example 6. The yield was 63% and the recovery yield was 96%.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.4)]δ8.61–8.56(m,1H,maj.),8.61–8.56(m,1H,min.),8.39(s,1H,maj.),8.36(s,1H,min.),7.69–7.63(m,1H,maj.),7.69–7.63(m,1H,min.),7.39–7.37(m,1H,min.),7.35–7.33(m,1H,maj.),7.23–7.20(m,1H,maj.),7.19–7.17(m,1H,min.),5.61(d,J＝3.6Hz,1H,min.),5.47(d,J＝6.7Hz,1H,maj.),5.41(s,1H,min.),5.19(d,J＝3.6Hz,1H,min.)),5.04(d,J＝6.7Hz,1H,maj.),5.00(s,1H,maj.),3.79(s,3H,min.),3.70(s,3H,maj.),1.09(s,9H,maj.),0.99(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.63(min.),170.08(maj.),165.40(min.),163.15(maj.),158.22(min.),157.15(maj.),150.18(maj.),149.47(min.),137.24(min.),137.05(maj.),123.29(maj.),123.19(min.),122.96(min.),122.64(maj.),76.54(maj.),72.71(min.),68.37(min.),66.44(maj.),53.60(maj.),53.08(min.),52.76(maj.),51.39(min.),38.37(maj.),38.36(min.),26.99(min.),26.56.(maj.)
Example 13: preparation of methyl (2R, 4R, 5R) -2- (tert-butyl) -5- (2-cyclopentylethyl) -3-formylthiazolidine-4-carboxylate (18).
Figure BDA0002269835880000221
Prepared by the method of reference example 6. The yield was 58% and the recovery yield was 96%.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.12)]δ8.30(s,1H,maj.),8.25(s,1H,min.),5.25(s,1H,min.),4.72(s,1H,maj.),4.45(d,J＝8.3Hz,1H,maj.),4.30(d,J＝6.0Hz,1H,min.),3.86(dt,J＝10.3,5.2Hz,1H,min.),3.80(s,3H,min.),3.76(s,3H,maj.),3.70(ddd,J＝9.7,8.4,4.0Hz,1H,maj.),2.40–2.23(m,1H,min.),2.13–1.97(m,1H,maj.),1.74(qt,J＝7.1,5.4,4.2Hz,4H,maj.),1.64–1.45(m,6H,maj.),1.37(tt,J＝11.7,5.1Hz,2H,maj.),1.02(s,9H,maj.),0.94(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.60(min.),170.19(maj.),163.97(min.),162.58(maj.),74.76(maj),71.18(min.),69.21(min.),66.61(maj.),52.93(min.),52.55(maj.),49.84(maj.),48.59(min.),39.76(maj.),39.73(min.),38.64(min.),38.43(maj.),34.99(maj.),34.89(min.),33.59(maj.),32.72(min.),32.71(maj.),32.56(min.),32.44(min.),32.41(maj.),26.76(min.),26.35(maj.),25.12(maj.).
Example 14: preparation of methyl (2R, 4R, 5R) -5- ((3R, 5R, 7R) -adamantan-1-yl) -2- (tert-butyl) -3-formylthiazolidine-4-carboxylate (19).
Figure BDA0002269835880000231
Prepared by the method of reference example 5. The yield thereof was found to be 90%.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.23)]δ8.30(s,1H,min.),8.23(s,1H,maj.),5.24(d,J＝2.9Hz,1H,maj.),5.22(s,1H,min.),4.75(s,1H,maj.),4.58(d,J＝3.3Hz,1H,min.),3.84(d,J＝3.2Hz,1H,min.),3.78(d,J＝2.9Hz,1H,maj.),3.76(s,3H,min.),3.71(s,3H,maj.),1.96(s,3H,maj.),1.71–1.37(m,12H,maj.),1.71–1.37(m,12H,min.),0.93(s,9H,maj.),0.89(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.92(maj.),164.08(min.),162.58(maj.),75.73(maj.),71.10(min.),63.67(min.),59.84(maj.),59.29(maj.),58.23(min.),53.01(min.),52.72(maj.),39.74(min.),39.21(maj.),38.16(min.),37.35(maj.),36.65(min.),36.61(maj.),36.29(maj.),36.06(min.),28.17(maj.),26.60(min.),26.13(maj.).
Example 15: preparation of methyl (2R, 4R, 5R) -5-benzyl-2- (tert-butyl) -3-formylthiazolidine-4-carboxylate (20).
Figure BDA0002269835880000241
Prepared by the method of reference example 6. 67%, recovery yield 94%.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.14)]δ8.34(s,1H,maj.),8.28(s,1H,min.),7.37–7.29(m,3H,maj.),7.37–7.19(m,5H,min.),7.26c 7.19(m,2H,maj.),5.32(s,1H,min.),4.76(s,1H,maj.),4.67(d,J＝7.7Hz,1H,maj.),4.44(d,J＝4.8Hz,1H,min.),4.24–4.17(m,1H,min.),4.12–4.02(m,1H,maj.),3.78(s,3H,maj.),3.78(s,3H,min.),3.32(dd,J＝14.1,5.1Hz,1H,maj.),3.10(dd,J＝14.0,6.8Hz,1H,min.),2.98–2.92(m,1H,min.),2.89(dd,J＝14.0,8.9Hz,1H,maj.),1.02(s,9H,maj.),0.95(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.13(min.),169.86(maj.),164.54(min.),163.07(maj.),137.73(min.),137.69(maj.),128.92(maj.),128.86(min.),128.83(min.),128.65(maj.),127.24(min.),127.13(maj.),74.96(maj.),71.39(min.),68.11(min.),65.74(maj.),53.00(min.)52.71(maj.),50.48(maj.),48.73(min.),41.66(min.),40.47(maj.),38.49(min.),38.29(maj.),26.78(min.),26.31(maj.).
Example 16: preparation of methyl (2R, 4R, 5S) -5- (1- (tert-butoxycarbonyl) -1H-imidazol-4-yl) -2- (tert-butyl) -3-formylthiazolidine-4-carboxylate (21).
Figure BDA0002269835880000242
Prepared by the method of reference example 6. 45% and recovery yield 90%.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj and rot.min. (1/0.3)]8.39(s,1H,maj.),8.36(s,1H,min.),8.13(s,1H,maj.),8.07(s,1H,min.)7.33(s,1H,maj.),7.19(s,1H,min.),5.61(d,J＝3.6Hz,1H,min.),5.47(d,J＝6.7Hz,1H,maj.),5.41(s,1H,min.),5.19(d,J＝3.6Hz,1H,min.)),5.04(d,J＝6.7Hz,1H,maj.),5.00(s,1H,maj.),3.79(s,3H,min.),3.70(s,3H,maj.),1.09(s,15H,maj.),0.99(s,15H,min.).
13C NMR(101MHz,Chloroform-d)δ171.53(min.),170.08(maj.),166.50(min.),164.35(maj.),158.22(min.),157.15(maj.),146.52(min.),145.15(maj.),138.18(maj.),137.89(min.),137.14(min.),136.05(maj.),76.34(maj.),74.91(min.),73.5(min.),73.18(maj.),68.17(min.),66.54(maj.),53.60(maj.),53.08(min.),52.76(maj.),51.39(min.),38.37(maj.),38.36(min.),26.79(min.),26.66.(maj.),21.98(min.),21.05(maj.)
Example 16 preparation of methyl (2R, 4R, 5S) -2- (tert-butyl) -3-formyl-5- ((methylthio) methyl) thiazolidine-4-carboxylate (26).
Figure BDA0002269835880000251
A50 mL round-bottom flask was charged with starting material (I) (229mg, 1mmol), acid (220uL,2.5mmol) followed by photocatalyst Ir [ dF (CF)3)ppy]2(dtbbpy)PF6Cesium carbonate (650mg,2mmol) and DMSO (30mL) are dissolved by ultrasonic, Ar is bubbled to remove oxygen for 10min, the reaction is performed for 8H under Ar atmosphere and rt blue light of 450nm, TLC is used for monitoring the completion of the reaction, and 300mL of H is added2O, ethyl acetate 100mL, liquid separation, water phase back extraction twice, organic phase combination, Na2SO4Drying, spin-drying under reduced pressure, and column chromatography to give 26(253mg, 77%).
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj and rot.min. (1/0.2)]δ8.27(s,1H,maj.),8.26(s,1H,min.),5.28(s,1H,min.),4.80(d,J＝6.7Hz,1H,maj.),4.75(s,1H,maj.),4.08(ddd,J＝9.3,5.8,3.5Hz,1H,min.),4.00(dt,J＝8.3,6.2Hz,1H,maj.),3.75(s,3H,min.),3.72(s,3H,maj.),2.95(dd,J＝13.6,5.8Hz,1H,maj.),2.72(dd,J＝13.8,5.8Hz,1H,min.),2.64(dd,J＝13.6,8.2Hz,1H,maj.),2.58(dd,J＝13.8,9.2Hz,1H,min.),2.11(s,3H,maj.),2.10(s,3H,min.),0.96(s,9H,maj.),0.88(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.09(min.),169.71(maj.),164.35(min.),162.69(maj.),74.94(maj.),71.32(min.),67.35(min.),64.87(maj.),52.99(min.),52.71(maj.),48.94(maj.),45.90(min.),39.03(min.),38.62(maj.),38.15(min.),38.12(maj.),26.67(min.),26.22(maj.),16.09(maj.),15.51(min.).
Example 17 preparation of methyl (2R, 4R, 5R) -5- ((S) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl) -2- (tert-butyl) -3-formylthiazolidine-4-carboxylate (27).
Figure BDA0002269835880000261
Prepared by the method of reference example 17. The yield thereof was found to be 86%.
1H NMR (400MHz, Chloroform-d) delta [ containing rotamers, where the molar ratio between rot.maj and rot.min. (1/0.21)]8.31(s,1H,maj.),8.27(s,1H,min.),5.34(s,1H,min.),4.79(d,J＝5.4Hz,1H,maj.),4.73(s,1H,maj.),4.56(d,J＝3.3Hz,1H,min.),4.10–4.05(m,2H,min.),4.05–3.90(m,1H,maj.),3.87(t,J＝5.3Hz,1H,maj.),3.80(q,J＝7.0Hz,1H,maj.),3.74(s,3H,min.),3.08(s,4H,maj.),1.95(dddd,J＝12.3,8.1,6.5,4.4Hz,1H,maj.),1.95(dddd,J＝12.3,8.1,6.5,4.4Hz,1H,min.),1.83(dtt,J＝12.3,7.6,2.9Hz,1H,maj.),1.83(dtt,J＝12.3,7.6,2.9Hz,1H,min.),1.81–1.60(m,1H,maj.),1.81–1.60(m,1H,min.),1.59(dq,J＝12.1,8.1Hz,1H,maj.),1.59(dq,J＝12.1,8.1Hz,1H,min.),0.97(s,18H,maj.),0.90(s,18H,min.).
13C NMR(101MHz,Chloroform-d)δ171.47(min.),170.79(maj.),165.13(min.),163.99(maj.),158.82(min.),157.95(maj.),80.21(maj.),80.10(min.),75.56(maj.),74.92(min.),73.58(min.),72.98(maj.),69.14(min.),68.90(maj.),67.25(min.),63.35(maj.),53.09(maj.),52.94(min.),52.62(maj.),51.61(min.),38.10(min.),37.76(maj.),30.58(maj.),30.45(min.),26.64(min.),26.20(maj.),26.04(maj.),25.97(min.),23.15(min.),22.80(maj.).
Example 18: preparation of methyl (2R, 4R, 5S) -2- (tert-butyl) -3-formyl-5- ((S) -tetrahydrofuran-2-yl) thiazolidine-4-carboxylate (28).
Figure BDA0002269835880000271
Prepared by the method of reference example 17. The yield thereof was found to be 83%.
1H NMR (400MHz, Chloroform-d) delta [ containing rotamers, where the molar ratio between rot.maj and rot.min. (1/0.21)]8.26(s,1H,maj.),8.23(s,1H,min.),5.24(s,1H,min.),4.97(d,J＝5.4Hz,1H,maj.),4.78(s,1H,maj.),4.67(d,J＝3.3Hz,1H,min.),4.13–4.05(m,2H,min.),4.06–3.96(m,1H,maj.),3.95(t,J＝5.3Hz,1H,maj.),3.85(q,J＝7.0Hz,1H,maj.),3.77(s,3H,min.),3.74(s,4H,maj.),2.05(dddd,J＝12.3,8.1,6.5,4.4Hz,1H,maj.),2.05(dddd,J＝12.3,8.1,6.5,4.4Hz,1H,min.),1.95(dtt,J＝12.3,7.6,2.9Hz,1H,maj.),1.95(dtt,J＝12.3,7.6,2.9Hz,1H,min.),1.91–1.80(m,1H,maj.),1.91–1.80(m,1H,min.),1.62(dq,J＝12.1,8.1Hz,1H,maj.),1.62(dq,J＝12.1,8.1Hz,1H,min.),0.97(s,9H,maj.),0.90(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ170.47(min.),170.19(maj.),164.83(min.),163.09(maj.),80.20(maj.),80.11(min.),75.26(maj.),71.62(min.),69.14(min.),68.90(maj.),67.25(min.),63.35(maj.),53.09(maj.),52.94(min.),52.62(maj.),51.61(min.),38.10(min.),37.76(maj.),30.58(maj.),30.45(min.),26.64(min.),26.20(maj.),26.04(maj.),25.97(min.).
Example 19:
Figure BDA0002269835880000272
raw material 1(68.7mg, 0.3mmol), formamide (100uL,1.2mmol), TBADT (40mg,0.006mmol), acetonitrile (8mL),310nm ultraviolet radiation for 72h, spin-drying, and direct column chromatography to obtain 29 (63%).
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/1)]δ8.13(s,1H,maj.),8.13(s,1H,min.),6.78(s,1H,maj.),6.18(s,1H,min.),5.63(s,1H,min.),4.91(s,1H,maj.),4.85(d,J＝3.6Hz,1H,min.),4.65(d,J＝7.5Hz,1H,maj.),4.39–4.31(m,1H,min.),4.30–4.16(m,1H,min.)3.78(s,3H,min.),3.75(s,3H,maj.),1.12(s,9H,maj.),0.95(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ175.08(min.),174.84(maj.),168.97(min.),167.56(maj.),165.58(min.),163.91(maj.),75.32(maj.),71.98(min.),68.92(min.),66.74(maj.),54.17(min.),53.10(maj.),45.24(maj.),44.06(min.),41.88(min.),40.56(maj.),26.98(min.),26.52(maj.).
Example 20: preparation of methyl (2R, 4R, 5R) -5- (2-amino-2-oxoethyl) -2- (tert-butyl) -3-formylthiazolidine-4-carboxylate (31).
Figure BDA0002269835880000281
Adding raw material (I) (229mg, 1mmol) and 30(555mg,3mmol) into a 20mL sample bottle, then adding photocatalyst RuLn, DIPEA (688uL,4mmol) and MeCN (5mL), ultrasonically dissolving, bubbling Ar for deoxygenation for 10min, performing light reaction for 8h under Ar atmosphere and rt blue light of 450nm, drying, and performing direct column chromatography to obtain product 31 (40%).
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.18)]δ8.33(s,1H,maj.),8.33(s,1H,min.),6.80(s,1H,maj.),6.38(s,1H,min.),5.33(s,1H,min.),4.81(s,1H,maj.),4.75(d,J＝3.6Hz,1H,min.),4.65(d,J＝7.5Hz,1H,maj.),4.33–4.29(m,1H,min.),4.33–4.16(m,1H,min.)3.80(s,3H,min.),3.76(s,3H,maj.),2.96(dd,J＝5.2,15.6Hz,1H,maj.),2.73-2.64(m,1H,min.),2.56(dd,J＝15.5,8.6Hz,1H,maj.),1.02(s,9H,maj.),0.93(s,9H,min.).
13C NMR(101MHz,Chloroform-d)δ174.08(min.),173.84(maj.),169.57(min.),169.16(maj.),165.18(min.),163.41(maj.),75.31(maj.),71.51(min.),68.32(min.),65.74(maj.),53.17(min.),52.90(maj.),44.24(maj.),43.06(min.),40.88(min.),40.26(maj.),38.29(min.),38.24(maj.),26.68(min.),26.22(maj.).
Example 21: preparation of 2- ((2R, 4R, 5R) -2- (tert-butyl) -3-formyl-4- (methoxycarbonyl) thiazolidin-5-yl) acetic acid (33).
Figure BDA0002269835880000291
A20 mL sample vial was charged with starting material (I) (229mg, 1mmol), 32(555mg,3mmol) followed by the addition of photocatalyst Ru (bpy)3(PF6)2DIPEA (688uL,4mmol) and MeCN (5mL) are dissolved by ultrasonic wave, Ar is bubbled to remove oxygen for 10min, the reaction is carried out for 8h under Ar atmosphere and rt blue light of 450nm, and the product is dried by spinning and is subjected to column chromatography directly to obtain 33 (20%).
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.18)]δ8.30(s,1H,maj.),8.27(s,1H,min.),6.81(s,1H,maj.),6.35(s,1H),5.30(s,1H,min.),4.78(s,1H,maj.),4.70(d,J＝3.6Hz,1H,min.),4.65(d,J＝7.5Hz,1H,maj.),4.30–4.27(m,1H,min.),4.32–4.16(m,1H,min.)3.76(s,3H,min.),3.70(s,3H,maj.),2.80(dd,J＝5.2,15.6Hz,1H,maj.),2.75-2.50(m,1H,min.),2.20(dd,J＝15.5,8.6Hz,1H,maj.),1.00(s,9H,maj.),0.90(s,3H,min.).
13C NMR(101MHz,Chloroform-d)δ171.08(min.),170.84(maj.),168.50(min.),167.16(maj.),164.78(min.),162.41(maj.),73.30(maj.),71.50(min.),68.12(min.),64.74(maj.),53.10(min.),52.80(maj.),44.21(maj.),43.00(min.),38.53(min.),38.05(maj.),34.03(min.),33.78(maj.),26.06(min.),25.03(maj.)
Example 22: preparation of methyl (2R, 4R, 5R) -2- (tert-butyl) -5-butyl-3-formylthiazolidine-4-carboxylate.
Figure BDA0002269835880000292
A50 mL long-neck flask is roasted by a heating gun, and an argon filling balloon and gas replacement gas in the round-bottom flask are charged to achieve the anhydrous and oxygen-free conditions. After the reaction system is treated, CuCN (268.7mg, 3.0mmol, 2.0equiv) is quickly weighed and added into the reaction system, 8mL of ultra-dry tetrahydrofuran is added for dissolving, stirring is carried out for 10 minutes at-78 ℃, then n-butyl lithium (2.4mL, 6.0mmol, 4.0equiv) is added into the reaction system at the temperature, the temperature of the low-temperature reactor is adjusted to-42 ℃ from-78 ℃ after the addition is finished, and stirring is carried out continuously for 15 minutes to generate the n-butyl copper reagent in situ. Then (I) (343mg, 1.5mmol, 1.0equiv) was dissolved in 4mL of ultra-dry Tetrahydrofuran (THF), and slowly added dropwise to the reaction system, and after completion of the dropwise addition, the reaction system was stirred at-42 ℃ for 30 to 60 minutes. After the completion of the reaction of (I) was confirmed by TLC, a saturated ammonium chloride solution was added to the reaction system to quench the reaction, and extraction was performed with DCM, and then a saturated sodium chloride solution was added to back-extract the organic phase, and the organic phase was dried with anhydrous sodium sulfate, rotary evaporated, and separated by column chromatography to give product 34, which was 220mg in 51% yield.
1H NMR (400MHz, Chloroform-d) [ containing rotamers, with a molar ratio of rot.maj to rot.min. (1/0.11)]δ8.30(s,1H,maj.),8.27(s,1H,min.),5.64(s,1H,min.),5.05(s,1H,maj.),4.65(d,J＝8.5Hz,1H,maj.),4.46(d,J＝5.3Hz,0H),4.13(dt,J＝10.2,5.2Hz,0H),4.03–3.91(m,1H),3.82(s,1H,min.),3.79(s,1H,maj.),2.22–2.10(m,1H,maj.),1.74–1.65(m,1H,maj.),1.47–1.30(m,4H,maj.),1.07(s,9H,maj.),0.99(s,9H,min.),0.93(ddd,J＝7.4,4.9,2.5Hz,3H,maj.).
13C NMR(101MHz,Chloroform-d)δ170.46(maj.),164.08(min.),162.65(maj.),71.12(min.),70.30(maj.),68.10(maj.),66.46(min.),52.95(min.),52.58(maj.),44.59(maj.),43.22(min.),38.37(min.),38.25(maj.),36.28(min.),34.97(maj.),32.34(maj.),31.89(min.),27.13(min.),26.69(maj.),22.35(maj.),22.28(min.),13.87(min.).
Comparative example 1:
Figure BDA0002269835880000301
a50 mL long-neck flask is roasted by a heating gun, and an argon filling balloon and gas replacement gas in the round-bottom flask are charged to achieve the anhydrous and oxygen-free conditions. After the reaction system is treated, CuCN (268.7mg, 3.0mmol, 2.0equiv) is quickly weighed and added into the reaction system, 8mL of ultra-dry tetrahydrofuran is added for dissolving, stirring is carried out for 10 minutes at-78 ℃, then n-butyl lithium (2.4mL, 6.0mmol, 4.0equiv) is added into the reaction system at the temperature, the temperature of the low-temperature reactor is adjusted to-42 ℃ from-78 ℃ after the addition is finished, and stirring is carried out continuously for 15 minutes to generate the n-butyl copper reagent in situ. Then 35(502mg, 1.5mmol, 1.0equiv) was dissolved in 4mL of ultra-dry Tetrahydrofuran (THF) and slowly added dropwise to the reaction system, and after completion of the addition, the reaction system was stirred at-42 ℃ for 30-60 minutes. After the completion of the reaction was confirmed by TLC 35, a saturated ammonium chloride solution was added to the reaction system to quench the reaction, and extraction was performed with DCM, and then a saturated sodium chloride solution was added to back-extract the organic phase, and the organic phase was dried with anhydrous sodium sulfate, rotary evaporated, and separated by column chromatography to give 36 mg of the product, which was obtained in 21% yield.
1H NMR(400MHz,DMSO-d6,80℃)δ7.43-7.23(m,5H)，5.21-5.00(m,3H)，4.36(d,J＝8.6,1H)，3.63(s,3H),3.75-3.60(m,1H)，2.04-1.90(m,1H)，1.50-1.45(m,1H),1.40-1.15(m,4H),1.05-0.72(m,3H),0.96(s,9H).
13C NMR(101MHz,DMSO-d6,80℃)δ170.03,154.28,138.5,127.9,127.3,126.9,83.1,76.5,67.9,52.3,44.9,34.1,31.6,27.8,27.2,22.5,13.9.

Claims (4)

  1. Use of methyl 2R- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate (I) for the preparation of a beta-S amino acid (II),
    reacting 2R- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-methyl formate (I) and active ester (III) in a second organic solvent under the action of DIPEA under the catalysis of a catalyst under the illumination condition to obtain a compound (II);
    Figure FDA0003487097580000011
    r is selected from phenyl, p-methoxyphenyl, p-tert-butylphenyl, methyl or any of the following structures:
    Figure FDA0003487097580000012
    when the active ester (III) is a secondary or tertiary active ester, the illumination condition is blue illumination;
    the catalyst is ruthenium catalyst and 2, 6-dimethyl-1, 4-dihydro-3, 5-diethyl pyridinedicarboxylate;
    when the active ester (III) is a primary active ester or pyridine active ester, the lighting conditions are household lamp lighting, and the catalyst is eosin Y.
  2. 2. Use according to claim 1, wherein the second organic solvent is selected from one or both of dichloromethane or acetonitrile; the concentration of methyl 2R- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate (I) in the second organic solvent is 0.1-0.3M.
  3. 3. Use according to claim 1,
    when the active ester (III) is a secondary or tertiary active ester, the ruthenium catalyst is selected from the group consisting of Ru (bpy)3(PF6)2Or Ru (bpy)3Cl2；
    The molar ratio of 2R- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylic acid methyl ester (I), active ester (III), ruthenium catalyst, diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate to DIPEA is 1:1:0.01:1.3: 1.5-1: 2:0.05:2: 2.5;
    when the active ester (III) is a primary active ester or pyridine active ester, the catalyst is eosin Y;
    the molar ratio of methyl 2R- (tert-butyl) -3-formyl-2, 3-dihydrothiazole-4-carboxylate (I), active ester (III), eosin Y and DIPEA is 1:1:0.1: 2-1: 2:0.3: 2.
  4. 4. Use according to claim 3,
    r of the secondary or tertiary active ester is selected from
    Figure FDA0003487097580000021
    Any one of the groups in (1);
    the R group of the primary active ester is selected from
    Figure FDA0003487097580000022
    Any one of the groups in (1);
    the R group of the pyridine active ester is selected from
    Figure FDA0003487097580000023
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