CN103272638B - Chiral guanidine catalyst based on tartaric acid skeleton and its preparation method and application - Google Patents

Abstract

The invention relates toA series of chiral guanidine catalysts based on tartaric acid skeleton, a preparation method and asymmetric catalytic application thereof belong to the field of catalyst technology and preparation method thereof. The chiral guanidine catalyst has a structure shown in a general formula I or II, and a basic skeleton seven-membered ring and five-membered ring respectively contain guanidyl and ketal structural units; the alpha, alpha' -position of guanidino on the seven-membered ring is respectively connected with two aryl groups.Ⅰ

Description

Chiral guanidine catalyst based on tartaric acid skeleton and its preparation method and application

technical field

The invention relates to a chiral guanidine catalyst based on a tartaric acid skeleton, a preparation method thereof, and an application thereof in catalyzing the asymmetric α-hydroxylation reaction of β-dicarbonyl compounds. The invention belongs to the field of catalyst technology and its preparation method.

Background technique

Chirality is one of the essential properties of nature. Biomacromolecules, such as proteins, polysaccharides, nucleic acids and enzymes, which are the important basis of life activities, are almost all chiral, and these molecules often have important physiological functions in the body. In recent years, with the development of synthetic methods, more and more chiral compounds can be obtained by chemical synthesis. Asymmetric catalytic synthesis has become an important means of obtaining chiral substances, and is one of the key technologies that must be broken through in the industrial production of chiral drugs. The use of enzymes as catalysts is well known, and its high reactivity and high stereoselectivity have been long-awaited goals. Organosmall molecule catalysts have been considered as the third class of widely used chiral catalysts after enzymes and chiral metal complex catalysts, and are a relatively new and interesting field in the synthesis of chiral molecules. The guanidine functional group exists widely in various natural molecules. Due to the strong basicity of the guanidine group, it can be Alkali activates a variety of reaction substrates. Therefore, chiral guanidine catalysts with high activity and high selectivity are used as one of the important members of organic catalysts (other organic small molecule catalysts include L-proline and its derivatives, Jinji Sodium base and its derivatives, chiral phosphonic acid, chiral thiourea, azacyclic carbene, etc.) have been widely used in asymmetric synthesis. Therefore, the development of new chiral guanidine catalysts and their application in asymmetric catalysis have attracted much attention in recent years.

The reported chiral guanidine catalysts mainly include: amino acid-derived five-membered bicyclic chiral guanidine catalysts (E.J.Corey Org. Monocyclic chiral guanidine catalyst (T.Ishikawa Chem.Commun.2001,245-246), amino acid derived dithiourea chain guanidine salt (K.Nagasawa Adv.Synth.Catal.2005,347,1643-1648), BINOL Derived monocyclic chiral guanidine catalyst (M.Terada J.Am.Chem.Soc.2006,128,16044-16045), chiral cyclohexanediamine derived chain guanidine salt (E.N.Jacobsen J.Am.Chem.Soc. 2008,130,9228-9229), proline-derived bifunctional chiral guanidine catalyst (X.M.Feng Angew.Chem.Int.Ed.2009,48,5195-5198), serine-derived bicyclic bifunctional chiral guanidine catalyst (T .Misaki and T.Sugimura J.Am.Chem.Soc.2010,132,6286-6287).

Overall, although many chiral guanidine catalysts have been developed, the types of chiral guanidines are still limited, and their catalytic properties have yet to be fully explored. Therefore, the development of chiral guanidine catalysts with novel structures, high activity and high stereoselectivity and their application in chiral synthesis is still one of the important goals in the field of asymmetric organic synthesis.

Contents of the invention

The invention focuses on the design and synthesis of novel chiral guanidine and its application in asymmetric catalysis. A series of new chiral guanidine catalysts based on tartaric acid skeleton were synthesized by seven-step reaction using cheap and easy-to-obtain tartrate esters as raw materials; and it was different from the synthesis of isothiourea from thiourea and then the synthesis of chiral guanidine catalysts reported in the literature According to the traditional route, the present invention reacts thiourea derived from tartaric acid with amine under the action of cuprous chloride and potassium carbonate to synthesize a chiral guanidine catalyst in one step, and the reaction conditions are mild (40°C), which is suitable for various amines (primary amines : Alkylamine, benzylamine, substituted benzylamine, aniline, substituted phenylamine, aminoalcohol; secondary amine: cyclohexylamine).

The object of the present invention is to provide a kind of chiral guanidine catalyst based on tartaric acid skeleton, it is the compound with general formula I or II:

I

II

in,

R ₁ is C ₁ -C ₄ alkyl or phenyl;

R ₂ is selected from one of hydrogen, C _1-6 alkyl, aromatic group, halogen, C _1-6 alkoxy and C _1-6 haloalkyl;

R ₃ is C _1-6 alkyl, aromatic group or aminoalcohol residual chain;

In the general formula II, n=0, 1 or 2.

The basic skeleton of the chiral guanidine catalyst of the present invention contains a seven-membered ring and a five-membered ring respectively containing guanidine and ketal structural units; the α and α'-positions of the guanidine group on the seven-membered ring are respectively connected with two aryl groups group.

In the general formula I and II of the chiral guanidine catalyst of the present invention, R ₁ is C ₁ -C ₄ alkyl or phenyl, preferably methyl.

In the general formula I and II of the chiral guanidine catalyst of the present invention, R _is selected from hydrogen, C _1-6 alkyl, aromatic group, halogen, C _1-6 alkoxy and C _1-6 haloalkane One of the radicals, preferably methyl, isopropyl, tert-butyl, phenyl, 4- or 3,5-substituted phenyl, methoxy or trifluoromethyl, more preferably hydrogen or benzene base.

In the general formula I and general formula II of the chiral guanidine catalyst of the present invention, R ₂ is an optionally substituted substituent. R ₂ group substitution includes single substitution and multiple substitution, and the substitution position includes phenyl ortho, meta, para substitution.

In the chiral guanidine catalyst general formula I and general formula II of the present invention, _R is C _1-6 alkyl, aromatic group or aminoalcohol residual chain, preferably methyl, cyclohexyl, phenyl, 4- or 3,5-position substituted phenyl, benzyl, 4-position or 3,4,5-position substituted benzyl, more preferably p-methylbenzyl, 3,4,5-trimethoxybenzyl, 2,6-diisopropylphenyl, 3,5-di-tert-butylphenyl, L-tert-leucinol or (1S,2S)-cyclohexylamino alcohol.

In the general formula II of the chiral guanidine catalyst of the present invention, n=0, 1 or 2, preferably n=1.

In the general formula I and general formula II of the chiral guanidine catalyst described in the present invention, the 4-position or 3,5-position substituted phenyl or 4-position, 3,4,5-position of _R2 or _R3 group In the substituted benzyl group, the substituents on the phenyl group or benzyl group are preferably methyl group, isopropyl group, t-butyl group, methoxy group, trifluoromethyl group, fluorine, chlorine and the like.

The aminoalcohol residual chain in the present invention refers to the part other than the amino group in the aminoalcohol obtained by reducing the amino acid. For example, L-tert-leucinol obtained by reduction of L-tert-leucine, the amino acid residue is L-tert-leucinol residue or 1-tert-butyl-2-hydroxyl-ethyl.

Typical compounds of the chiral guanidine catalyst of the present invention are listed in Table 1. In Table 1, the R ₂ group includes two kinds of substitution means two compounds, such as 4-Me, 3,5-(Me) ₂ means that R ₂ is 4-Me or R ₂ is 3,5-(Me) ₂ of the two compounds.

The structure of the compound shown in the general structural formula (I, II) of Table 1

Table 2 Compound structure, physical properties and characterization data

The chiral guanidine catalyst of the present invention is preferably selected from one of the following numbered 1-12 compounds:

Chiral guanidine catalyst 1: R ₁ =CH ₃ , R ₂ =H, R ₃ =(1S)-1-tert-butyl-2-hydroxyethyl;

Chiral guanidine catalyst 2: R ₁ =CH ₃ , R ₂ =H, R ₃ =(1S,2S)-2-hydroxycyclohexyl;

Chiral guanidine catalyst 3: R ₁ =CH ₃ , R ₂ =H, R ₃ =2,6-diisopropylphenyl;

Chiral guanidine catalyst 4: R ₁ =CH ₃ , R ₂ =H, R ₃ =3,5-di-tert-butylphenyl;

Chiral guanidine catalyst 5: R ₁ =CH ₃ , R ₂ =H, R ₃ =3,4,5-trimethoxybenzyl;

Chiral guanidine catalyst 6: R ₁ =CH ₃ , R ₂ =Ph, R ₃ =p-methylbenzyl;

Chiral guanidine catalyst 7: R ₁ =CH ₃ , R ₂ =Ph, R ₃ =(1S)-1-tert-butyl-2-hydroxyethyl;

Chiral guanidine catalyst 8: R ₁ =CH ₃ , R ₂ =Ph, R ₃ =2,6-diisopropylphenyl;

Chiral guanidine catalyst 9: n=1, R ₂ =H, R ₃ =(1S)-1-tert-butyl-2-hydroxyethyl;

Chiral guanidine catalyst 10: n=1, R ₂ =H, R ₃ =3,5-di-tert-butylphenyl;

Chiral guanidine catalyst 11: n=1, R ₂ =Ph, R ₃ =(1S)-1-tert-butyl-2-hydroxyethyl;

Chiral guanidine catalyst 12: n=1, R ₂ =Ph, R ₃ =3,5-di-tert-butylphenyl;

Another object of the present invention is to provide a method for preparing the above-mentioned chiral guanidine catalyst based on tartaric acid skeleton.

Wherein, the preparation method of the compound of general formula I is carried out according to the following operational route:

The preparation method of the compound of general formula II is the same as the process route of the preparation method of the compound of general formula I.

In the method of the present invention, the compound of general formula II is prepared by the same process route as the compound of general formula I, and is carried out according to the following route:

Include the following steps:

①Condensation reaction: The tartrate ester and ketone or ketal molar ratio 1:1~1:1.5 are catalyzed by Lewis acid, and reflux reaction in benzene or toluene for 12~24h; the obtained reaction solution is treated with sodium bicarbonate and water , extraction, washing, drying, and finally concentrating to obtain a concentrated product;

②Grignard reaction: react the condensation product obtained in step ① with the Grignard reagent in tetrahydrofuran at a molar ratio of 1:4.5 to 1:5 under reflux for 30 to 90 minutes; cool down, quench, extract, wash, dry, Concentrate and recrystallize from ethyl acetate/petroleum ether to obtain the product;

③ Chlorination reaction: Dissolve the Grignard reaction product obtained in step ② in dichloromethane, and thionyl chloride and triethylamine in a molar ratio of 1:3:4.2～1:3.5:7, at room temperature to reflux temperature , reacted for 3 to 12 hours; after the reaction was completed, the solvent was distilled off to obtain the chlorinated product;

④Azidation reaction: Dissolve the chlorination reaction product obtained in step ③ in N,N-dimethylformamide, and react with sodium azide at a molar ratio of 1:4 at 80°C for 72 hours; cool down and pour the reaction solution Pour into water, extract with ether, wash the organic layer with water, dry, filter, concentrate, and obtain a solid by flash column chromatography, and recrystallize with ether/ethanol to obtain the product;

⑤ Reduction reaction: Dissolve the azide product obtained in step ④ in tetrahydrofuran, and react with lithium tetrahydrogen at a molar ratio of 1:6 at 0°C for 1.5 to 6 hours; quench, extract, wash, dry, concentrate, diethyl ether/ The product was obtained by recrystallization from n-hexane;

⑥Preparation of chiral thiourea with tartaric acid skeleton: dissolve the reduction product obtained in step ⑤ in pyridine, and react with carbon disulfide at a molar ratio of 1:2 at 60°C for 12 to 24 hours; cool down, pour the reaction solution into water, and use two Chloromethane extraction; the organic layer was washed with water, dried, filtered, concentrated, and recrystallized from dichloromethane/n-hexane to obtain the product;

⑦ preparation of chiral guanidine catalyst with tartaric acid skeleton: thiourea obtained in step ⑥ and amine, cuprous chloride, potassium carbonate are added in tetrahydrofuran in a molar ratio of 1:1.2:2:4～1:10:2.1:15, React at 40°C for 4-72 hours; cool down, quench, extract, filter, wash, dry, concentrate, and column chromatography to obtain a solid product.

Another object of the present invention is to provide the application of the above-mentioned chiral guanidine catalyst in catalyzing the asymmetric α-hydroxylation reaction of β-dicarbonyl compounds.

Asymmetric α-hydroxylation reaction of a β-dicarbonyl compound, comprising the steps of:

Under a nitrogen atmosphere, the β-dicarbonyl compound and the above-mentioned chiral guanidine catalyst are dissolved in toluene at a molar ratio of 1:0.1 to 1:0.01. Cool to -78°C. Add the oxidizing agent (the molar ratio of oxidizing agent to β-dicarbonyl compound is 1.2:1). Reaction at -78°C. Petroleum ether and ethyl acetate were used as eluents, and the asymmetric α-hydroxylation reaction product was obtained by column chromatography.

β-dicarbonyl compounds include: β-ketoesters and β-diketones derived from indanone, β-ketoesters and β-diketones derived from tetralone, etc.

Unless otherwise specified, the terms used herein have the following meanings.

The term "alkyl" as used herein includes straight chain alkyl groups and branched chain alkyl groups. If a single alkyl group such as "propyl" is mentioned, it only refers to a straight chain alkyl group, and if a single branched chain alkyl group such as "isopropyl" is mentioned, it only refers to a branched chain alkyl group. For example, "C _1-6 alkyl" includes C _1-4 alkyl, C _1-3 alkyl, methyl, ethyl, n-propyl, isopropyl and tert-butyl. Similar rules apply to other groups used in this specification.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

The beneficial effects of the present invention are: 1) synthesis of a series of new chiral guanidine catalysts based on tartaric acid skeleton; 2) development of a new method for the preparation of chiral guanidine catalysts; 3) new chiral guanidine based on tartaric acid skeleton to be prepared The catalyst is applied to the asymmetric α-hydroxylation reaction of β-dicarbonyl compounds to obtain almost quantitative yield and very good enantioselectivity, which provides an important basis for the synthesis of optically active α-hydroxy-β-dicarbonyl compounds. Asymmetric organocatalytic approaches.

Detailed ways

The following examples can enable those skilled in the art to understand the present invention more fully, but do not limit the present invention in any way.

Example 1:

Reagents and conditions: a) 2,2-dimethoxypropane, p-toluenesulfonic acid, benzene, reflux, 12h; b) bromobenzene, magnesium powder, tetrahydrofuran, reflux, 1.5h, yield 91% (two steps reaction); c) thionyl chloride, triethylamine, dichloromethane, reflux, 3h, yield 65%; d) sodium azide, N,N-dimethylformamide, 80°C, 72h, yield 77%; e) lithium aluminum tetrahydrogen, tetrahydrofuran, 0 ℃, 4h, yield 93%; f) carbon disulfide, pyridine, 60 ℃, yield 98%; g) substituted amine, cuprous chloride, potassium carbonate, tetrahydrofuran , 40°C, 4-30h, yield 87-95%.

1. Synthesis of G1-1:

Under nitrogen atmosphere, add anhydrous benzene (148mL), L-diethyl tartrate (12.4g, 60mmol), 2,2-dimethoxypropane (9.4g, 11mL, 90mmol, 1.5 eq.), p-toluenesulfonic acid (0.12g). Warm up to reflux and react for 12h. After cooling to room temperature, NaHCO ₃ (1.5 g) was added and stirring was continued for 30 min. Add water (100mL), separate the organic phase, extract the aqueous phase twice with ethyl acetate (60mL×2), combine the organic phases, wash with water (50mL×1), and wash with saturated sodium chloride aqueous solution (50mL×1). Dry over sodium sulfate, and distill off the solvent to obtain 14.8 g of the ketal as a yellow oil, with a yield of 100%.

Under a nitrogen atmosphere, place a 250mL three-neck flask containing a newly prepared Grignard reagent {made from 47.1g (300mmol, 5.0eq.) of bromobenzene, 8.0g (330mmol, 5.5eq.) of magnesium powder and tetrahydrofuran (180mL)} into In an ice-water bath, a solution of tetrahydrofuran (15 mL) dissolved with the above obtained ketal (14.8 g, 60 mmol, 1.0 eq.) was slowly added dropwise. After the addition, the temperature was raised to reflux, and the reaction was carried out for 1.5h. After cooling to room temperature, saturated aqueous ammonium chloride solution (400 mL) was added to quench the reaction. Separate the organic phase, extract the aqueous phase with ethyl acetate (300mL×1, 100mL×2), combine the organic phases, wash with water (100mL×1), wash with saturated sodium chloride aqueous solution (100mL×1), and dry over anhydrous sodium sulfate , evaporated the solvent, and recrystallized from ethyl acetate/petroleum ether to obtain a white solid G1-125.6g, yield 91%. ¹ H NMR (400MHz, CDCl ₃ /TMS): δ7.52(dd,J=7.8,1.3Hz,4H),7.33-7.22(m,16H),4.59(s,2H),3.92(s,2H) ,1.03(s,6H).

2. Synthesis of G1-2:

Under a nitrogen atmosphere, add thionyl chloride (1.8g, 30mmol, 3.0eq.) dropwise to a 250mL three-necked flask containing a solution of G1-1 (4.7g, 10mmol, 1.0eq.) in dichloromethane (60mL) . The temperature of the reaction solution was raised to reflux, and a solution of triethylamine (4.2g, 42mmol, 4.2eq.) in dichloromethane (60mL) was slowly added dropwise, and the reaction was detected by TLC. After the reaction was complete, it was cooled to room temperature, and the reaction solution was poured into cold saturated sodium bicarbonate (200 mL) solution, and stirred for 2 h. Separate the organic phase, take the aqueous phase as dichloromethane (100mL×1), combine the organic phases, wash with saturated sodium chloride aqueous solution (100mL×1), dry over anhydrous sodium sulfate, evaporate the solvent and flash column chromatography (petroleum ether/ Diethyl ether = 10/1) to obtain a brown solid. The crude product was recrystallized from dichloromethane/petroleum ether to obtain a white solid G1-23.3g with a yield of 65%. ¹ H NMR (400MHz, CDCl ₃ /TMS): δ7.48-7.41 (m, 8H), 7.33-7.16 (m, 12H), 5.45 (s, 2H), 0.97 (s, 6H).

3. Synthesis of G1-3:

Under nitrogen atmosphere, add sodium azide (1.3g, 20mmol ,4.0eq.). The temperature of the reaction solution was raised to 80°C, and the reaction was carried out for 72h. After the reaction was complete, cool to room temperature, pour the reaction solution into cold water (100 mL), separate the organic phase, and take the aqueous phase ether three times (50 mL×3). The organic phases were combined, washed three times with water (35mL×3), dried over anhydrous sodium sulfate, and the solvent was distilled off. The crude product was recrystallized in ether/ethanol to obtain a white solid G1-32.0g, with a yield of 77%. ¹ H NMR (400 MHz, CDCl ₃ /TMS): δ 7.34-7.24 (m, 10H), 4.92 (s, 2H), 1.11 (s, 6H).

4. Synthesis of G1-4:

Under nitrogen atmosphere, LiAlH4 (1.6g, 42mmol, 6.0eq.) was suspended in tetrahydrofuran (40mL) and cooled to 0°C. A solution of G1-3 (3.6g, 7mmol, 1.0eq.) in tetrahydrofuran (40mL) was slowly added dropwise. 0 ℃ reaction 4h. After the reaction was complete, the reaction was quenched with 1M NaOH (5 mL). After diluting the reaction solution with diethyl ether (20 mL), anhydrous sodium sulfate (20 g) was added and stirred at room temperature for 2 h. The solid was filtered off, dried with anhydrous potassium carbonate, and the solvent was distilled off. The crude product was recrystallized in ether/n-hexane to obtain a white solid G1-43.0 g, with a yield of 93%. ¹ H NMR (400MHz, CDCl ₃ /TMS): δ7.55-7.53 (m, 4H), 7.36-7.29 (m, 6H), 7.20-7.13 (m, 10H), 4.92 (s, 2H), 2.30 ( brs,4H), 1.11(s,6H).

5. Synthesis of G1-5:

Under a nitrogen atmosphere, carbon disulfide (361 μL, 6 mmol, 2.0 eq.) was added to a solution of G1-4 (1.393 g, 3 mmol, 1.0 eq.) in pyridine (5 mL). The temperature of the reaction solution was raised to 60° C., and the reaction was carried out for 18 hours. After the reaction is complete, cool to room temperature, add dichloromethane (20mL) and water (10mL) to the reaction solution, adjust the pH to 2 with 1M HCl, separate the organic phase, and take three times (50mL×3) of the aqueous phase dichloromethane, and combine Organic phase, washed with 1M NaOH solution (50mL×1), washed with saturated sodium chloride solution (60mL×1), dried over anhydrous sodium sulfate, evaporated the solvent, and recrystallized the crude product from dichloromethane/n-hexane to obtain a white solid G1- 51.489g, yield 98%. Mp277.4-278.6℃;[α] _D ²⁴ =-191.3(c0.31,CH ₂ Cl ₂ ); ¹ H NMR(400MHz,CDCl ₃ /TMS):δ7.63-7.61(m,4H),7.44 -7.39(m,6H),7.28(m,6H),7.15(m,4H),6.85(s,2H),4.59(s,2H),1.20(s,6H); ¹³ C NMR(101MHz,CDCl ₃ /TMS): δ185.9, 143.4, 139.6, 129.3, 128.8, 128.5, 128.1, 128.0, 127.7, 110.8, 78.0, 70.5, 26.9; IR(KBr): 3386, 3062, 2983, 2904, 1515, 1495, 1457, 1444, 1164, 1105, 755, 698, 681; HRMS (ESI) Calcd. for C ₃₂ H ₃₀ N ₂ O ₂ NaS ⁺ ([M+Na] ⁺ ) 529.1926, Found 529.1921.

5. Synthesis of chiral guanidine:

1) Synthesis of chiral guanidine 2:

Under nitrogen atmosphere, add anhydrous potassium carbonate (165.9mg, 1.2mmol, 6.0eq.), cuprous chloride (41.6mg, 0.42mmol, 2.1eq.), tetrahydrofuran (2mL), G1- 5 (101.3 mg, 0.2 mmol, 1.0 eq.). After stirring at room temperature for 10 min, 1S,2S,-cyclohexylaminoalcohol hydrochloride (60.7mg, 0.4mmol, 2.0eq.) was added, the temperature was raised to 40°C, and the reaction was carried out for 30h. After the reaction is complete, cool to room temperature, add saturated ammonium chloride solution (30mL) to the reaction solution, adjust the pH to 4 with 1M HCl, take three times of dichloromethane (30mL×3), combine the organic phases and filter, and the filtrate is saturated with sodium chloride solution Wash (20mL×1), dry over anhydrous sodium sulfate, evaporate the solvent, and column chromatography (dichloromethane/methanol=50/1) of the crude product gives a white solid. The obtained solid was dissolved in dichloromethane (25 mL), added with 2M NaOH solution (5 mL), and stirred at room temperature for 2 h. The aqueous phase dichloromethane was taken (5 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (10 mL×1), dried with anhydrous potassium carbonate, and the solvent was distilled off to obtain 2102.3 mg of a white solid, with a yield of 87%.

2) Synthesis of chiral guanidine 13:

Under nitrogen atmosphere, add anhydrous potassium carbonate (276.4mg, 2.0mmol, 4.0eq.), cuprous chloride (104.0mg, 1.05mmol, 2.1eq.), tetrahydrofuran (5mL), G1- 5 (235.3mg, 0.5mmol, 1.0eq.), after stirring at room temperature for 10min, (S)-phenylethylamine (72.7mg, 76.5μL, 0.6mmol, 1.2eq.) was added. Raise the temperature to 40°C and react for 4h. After the reaction is complete, cool to room temperature, add saturated ammonium chloride solution (30mL) to the reaction solution, adjust the pH to 4 with 1M HCl, take three times of dichloromethane (30mL×3), combine the organic phases and filter, and the filtrate is saturated with sodium chloride solution Wash (20mL×1), dry over anhydrous sodium sulfate, evaporate the solvent, and column chromatography (dichloromethane/methanol=50/1) of the crude product gives a white solid. Dissolve the obtained solid in dichloromethane (30mL), add 2M NaOH solution (5mL), stir at room temperature for 2h, take the aqueous phase in dichloromethane (5mL×2), combine the organic phases, and wash with saturated sodium chloride solution (10mL×2) 1), dried with anhydrous potassium carbonate, and distilled off the solvent to obtain 13282.3 mg of white solid, with a yield of 95%.

Example 2:

Reagents and conditions: a) 2,2-dimethoxypropane, p-toluenesulfonic acid, benzene, reflux, 12h; b) 4-phenylbromobenzene, magnesium powder, tetrahydrofuran, reflux, 1.5h, yield 95 % (two-step reaction); c) thionyl chloride, triethylamine, dichloromethane, reflux, 3h; d) sodium azide, N,N-dimethylformamide, 80 ° C, 72h, yield 79 % (two-step reaction); e) lithium aluminum tetrahydrogen, tetrahydrofuran, 0 ℃, 4h, yield 84%; f) carbon disulfide, pyridine, 60 ℃, yield 99%; g) substituted amine, cuprous chloride, Potassium carbonate, tetrahydrofuran, 40°C, 15-48h, yield 71-85%.

1. Synthesis of G2-1:

Under nitrogen atmosphere, add anhydrous benzene (148mL), L-diethyl tartrate (4.1g, 20mmol), 2,2-dimethoxypropane (3.1g, 3.7mL, 30mmol, 1.5 eq.), p-toluenesulfonic acid (0.03g). Warm up to reflux and react for 12h. After cooling to room temperature, NaHCO ₃ (0.5 g) was added and stirring was continued for 30 min. Add water (40mL), separate the organic phase, extract the aqueous phase with ethyl acetate twice (30mL×2), combine the organic phases, wash with water (30mL×1), wash with saturated sodium chloride aqueous solution (30mL×1), anhydrous Dry over sodium sulfate, and distill off the solvent to obtain 4.9 g of the ketal as a yellow oil, with a yield of 100%.

Under nitrogen atmosphere, put the newly prepared Grignard reagent {from p-bromobiphenyl (22.4g, 96mmol, 4.8eq.); The flask was placed in an ice water bath. A solution of tetrahydrofuran (10 mL) dissolved in the above obtained ketal (4.9 g, 20 mmol, 1.0 eq.) was slowly added dropwise. After the addition, the temperature was raised to reflux, and the reaction was carried out for 1.5h. After cooling to room temperature, saturated aqueous ammonium chloride solution (100 mL) was added to quench the reaction. Separate the organic phase, extract the aqueous phase with ethyl acetate three times (150mL extraction once, 100mL extraction twice, expressed as 150mL×1, 100mL×2, the same below), combine the organic phases, wash with water (80mL×1), saturated chlorine Wash with sodium chloride aqueous solution (100mL×1), dry over anhydrous sodium sulfate, distill off the solvent ethyl acetate/petroleum ether and recrystallize to obtain white solid G2-114.6g, yield 95%. ¹ H NMR (400MHz, CDCl ₃ /TMS): δ7.67-7.56(m,12H),7.53-7.29(m,24H),4.72(s,2H),4.23(brs,1H),1.16(s, 3H).

2. Synthesis of G2-2:

Under a nitrogen atmosphere, add thionyl chloride (0.71g, 3mmol, 3.0eq.) dropwise to a 100mL three-necked flask containing a solution of G2-1 (1.54g, 2mmol, 1.0eq.) in dichloromethane (15mL) . The temperature of the reaction solution was raised to reflux, and a solution of triethylamine (0.85g, 8.4mmol, 4.2eq.) in dichloromethane (20mL) was slowly added dropwise, and the reaction was detected by TLC. After the reaction was complete, it was cooled to room temperature, and the solvent was distilled off to obtain a dark brown solid. N,N-Dimethylformamide (15 mL), and sodium azide (0.52 g, 8 mmol, 4.0 eq.) were added. After adding, the temperature of the reaction solution was raised to 80°C, and the reaction was carried out for 72h. After the reaction was complete, cool to room temperature, pour the reaction solution into cold water (100 mL), separate the organic phase, and extract the aqueous phase with ether three times (50 mL×3). The organic phases were combined, washed with water (35mL×3), dried over anhydrous sodium sulfate, and the solvent was distilled off. The crude product was recrystallized in ether/ethanol to obtain a white solid G2-21.29g, with a yield of 79%. Mp142.1-143.9℃;[α] _D ²⁴ =-38.162(c0.36,CH ₂ Cl ₂ ); ¹ H NMR(400MHz,CDCl ₃ /TMS):δ7.65-7.54(m,16H),7.47 -7.31(m,20H),5.08(s,2H),1.25(s,6H); ¹³ C NMR(101MHz,CDCl ₃ /TMS)δ140.7,140.5,140.5,140.4,139.2,130.0,128.9,128.8,128.7 ,127.6,127.4,127.1,127.1,126.8,126.4,110.8,80.8,73.0,27.6; 1070,978,764,745,703; Calcd. for C ₅₅ H ₄₄ N ₆ O ₂ Na ⁺ ([M+Na] ⁺ ) 843.3423, Found 843.3452.

3. Synthesis of G2-3:

Under nitrogen atmosphere, LiAlH ₄ (173.1mg, 4.6mmol, 6.0eq.) was suspended in tetrahydrofuran (8mL) and cooled to 0°C. A solution of G2-2 (626.7mg, 0.76mmol, 1.0eq.) in tetrahydrofuran (8mL) was slowly added dropwise. 0 ℃ reaction 4h. After the reaction was complete, quench the reaction with 1M NaOH (2 mL), dilute the reaction solution with ether (10 mL), add anhydrous sodium sulfate (4 g), and stir at room temperature for 2 h. The solid was filtered off, dried with anhydrous potassium carbonate, the solvent was distilled off, and the crude product was recrystallized from ether/n-hexane to obtain 3493.1 mg of white solid G2-349, with a yield of 84%. Mp276.1-277.7℃;[α] _D ²⁴ =-28.4(c0.34,CH ₂ Cl ₂ ); ¹ H NMR(400MHz,CDCl ₃ /TMS):δ7.71-7.25(m,36H),4.39 (s,2H),2.46(brs,4H),1.20(s,6H); ¹³ C NMR(101MHz,CDCl ₃ /TMS):δ148.9,142.9,140.7,140.7,139.6,139.3,129.7,128.9,128.7, 127.9, 127.4, 127.2, 127.0, 126.8, 126.0, 107.7, 81.9, 62.4, 27.3; , 1072, 1007, 844, 833, 766, 745, 698; HRMS (ESI) Calcd. for C ₅₅ H ₄₉ N ₂ O ₂ ⁺ ([M+H] ⁺ ) 769.3794, Found 769.3782.

4. Synthesis of G2-4:

Under a nitrogen atmosphere, carbon disulfide (120 μL, 2 mmol, 2.0 eq.) was added to a solution of G2-3 (768.9 mg, 1 mmol, 1.0 eq.) in pyridine (2 mL). The temperature of the reaction solution was raised to 60° C., and the reaction was carried out for 18 hours. After the reaction is complete, cool to room temperature, add dichloromethane (20mL) and water (20mL) to the reaction solution, adjust the pH to 2 with 1M HCl, separate the organic phase, and take three times (50mL×3) of the aqueous phase dichloromethane, and combine Organic phase, washed with 1M NaOH solution (50mL×1), washed with saturated sodium chloride solution (60mL×1), dried over anhydrous sodium sulfate, evaporated the solvent, and recrystallized the crude product from dichloromethane/n-hexane to obtain white solid G2-4810mg , Yield 99%. Mp322.9-324.3℃;[α] _D ²⁴ =-131.1(c0.339,CH ₂ Cl ₂ ); ¹ H NMR(400MHz,CDCl ₃ /TMS):δ7.79-7.71(m,12H),7.55 -7.28(m,24H),6.96(s,2H),4.74(s,2H),1.32(s,6H); ¹³ C NMR(101MHz,CDCl ₃ /TMS):δ186.1,142.110,141.510,140.7,140.2 ,140.1,138.6,129.8,129.0,128.9,128.2,127.7,127.6,127.1,127.1,126.6,111.1,78.3,70.3,27.1;IR(KBr):3383,3055,3028,2989,2985,148189, 1421, 1166, 1099, 837, 765, 696; HRMS (ESI) Calcd. for C ₅₆ H ₄₇ N ₃ O ₂ S ⁺ ([M+H] ⁺ ) 811.3358, Found 811.3355.

4. Chiral guanidine synthesis:

1) Synthesis of chiral guanidine 6:

Under nitrogen atmosphere, add anhydrous potassium carbonate (276.4mg, 2.0mmol, 4.0eq.), cuprous chloride (104.0mg, 1.05mmol, 2.1eq.), tetrahydrofuran (5mL), G2- 4 (405.5mg, 0.5mmol, 1.0eq.), stirred at room temperature for 10min, added p-methylbenzylamine (84.8mg, 0.7mmol, 1.4eq.), heated to 40°C, and reacted for 15h. After the reaction is complete, cool to room temperature, add saturated ammonium chloride solution (30mL) to the reaction solution, adjust the pH to 4 with 1M HCl, extract three times with dichloromethane (40mL×3), combine the organic phases and filter, and the filtrate is saturated with sodium chloride solution Wash (20mL×1), dry over anhydrous sodium sulfate, evaporate the solvent, and column chromatography (dichloromethane/methanol=20/1) of the crude product gives a white solid. Dissolve the obtained solid in dichloromethane (40mL), add 2M NaOH solution (8mL), stir at room temperature for 2h, extract the aqueous phase with dichloromethane (5mL×2), combine the organic phases, wash with saturated sodium chloride solution (10mL ×1), dried with anhydrous potassium carbonate, and distilled off the solvent to obtain 6332.9 mg of white solid, with a yield of 85%.

2) Synthesis of chiral guanidine 7:

Under nitrogen atmosphere, add anhydrous potassium carbonate (55.3mg, 10.4mmol, 4.0eq.), cuprous chloride (20.8mg, 0.21mmol, 2.1eq.), tetrahydrofuran (1mL), G2- 4 (81.1 mg, 0.1 mmol, 1.0 eq.). After stirring at room temperature for 10 min, L-tert-leucinol (23.4 mg, 0.2 mmol, 2.0 eq.) was added, and the temperature was raised to 40°C for 48 h. After the reaction is complete, cool to room temperature, add saturated ammonium chloride solution (15mL) to the reaction solution, adjust the pH to 4 with 1M HCl, take dichloromethane three times (20mL×3), combine the organic phases and filter, and the filtrate is saturated with sodium chloride solution Wash (10mL×1), dry over anhydrous sodium sulfate, evaporate the solvent, the crude product is column chromatographed (dichloromethane/methanol=50/1) as a white solid. Dissolve the obtained solid in dichloromethane (25mL), add 2M NaOH solution (5mL), stir at room temperature for 2h, extract the aqueous phase with dichloromethane (5mL×2), combine the organic phases, wash with saturated sodium chloride solution (5mL× 1), dried with anhydrous potassium carbonate, and distilled off the solvent to obtain 763.5 mg of white solid, with a yield of 71%.

Example 3:

Reagents and conditions: a) cyclohexanone, p-toluenesulfonic acid, zinc chloride, benzene, reflux, 18h; b) bromobenzene, magnesium powder, tetrahydrofuran, reflux, 1.5h, yield 75% (two-step reaction) ; c) thionyl chloride, triethylamine, dichloromethane, reflux, 3h; d) sodium azide, N,N-dimethylformamide, 80℃, 72h, yield 71% (two-step reaction) ; e) lithium aluminum tetrahydride, tetrahydrofuran, 0 ℃, 4h, yield 84%; f) carbon disulfide, pyridine, 60 ℃, yield 83%; g) p-methylbenzylamine, cuprous chloride, potassium carbonate, Tetrahydrofuran, 40°C, 12h, yield 62%.

1. Synthesis of G3-1:

Under nitrogen atmosphere, add anhydrous benzene (200mL), L-diethyl tartrate (11.5g, 56mmol), cyclohexanone (8.2g, 8.7mL, 84mmol, 1.5eq.), p-toluene Sulfonic acid (0.35g), zinc dichloride (0.35g). The temperature was raised to reflux, and the reaction was carried out for 18h. After cooling to room temperature, NaHCO ₃ (1.4 g) was added and stirring was continued for 30 min. Add water (100mL), separate the organic phase, extract the aqueous phase with ethyl acetate twice (100mL×2), combine the organic phases, wash with water (100mL×1), wash with saturated sodium chloride aqueous solution (100mL×1), no Dry over sodium sulfate and distill off the solvent to obtain 16 g of the ketal as a yellow oil, with a yield of 100%.

Under nitrogen atmosphere, put a 250mL three-necked flask containing newly prepared Grignard reagent {made from bromobenzene (12.6g, 80mmol, 5.0eq.), magnesium powder (2.1g, 88mmol, 5.5eq.) and tetrahydrofuran (60mL)} into in an ice water bath. A solution of tetrahydrofuran (4 mL) in which the above obtained ketal (4.6 g, 216 mmol, 1.0 eq.) was dissolved was slowly added dropwise. The reaction was completed overnight at room temperature. The reaction was quenched by adding saturated aqueous ammonium chloride (100 mL). Separate the organic phase, extract the aqueous phase with ethyl acetate three times (100mL×3), combine the organic phases, wash with water (80mL×1), wash with saturated sodium chloride aqueous solution (100mL×1), dry over anhydrous sodium sulfate, and evaporate the solvent Ethyl acetate/petroleum ether was recrystallized to obtain white solid G3-16.1g with a yield of 75%. ¹ H NMR (400MHz, CDCl ₃ /TMS): δ7.57-7.47 (m, 4H), 7.39-7.21 (m, 16H), 4.55 (s, 2H), 3.73 (brs, 2H), 1.50-1.31 ( m, 4H), 1.31-1.07 (m, 6H).

2. Synthesis of G3-2:

Under a nitrogen atmosphere, add thionyl chloride (1.07g, 9mmol, 3.0eq.) dropwise to a 100mL three-necked flask containing a solution of G2-1 (1.52g, 3mmol, 1.0eq.) in dichloromethane (20mL) . The temperature of the reaction solution was raised to reflux, and a solution of triethylamine (1.21g, 18mmol, 6eq.) in dichloromethane (20mL) was slowly added dropwise, and the reaction was detected by TLC. After the reaction was complete, it was cooled to room temperature, and the solvent was distilled off to obtain a dark brown solid. Add N,N-dimethylformamide (12 mL), sodium azide (0.78 g, 12 mmol, 4.0 eq.). After adding, the temperature of the reaction solution was raised to 80°C, and the reaction was carried out for 72h. After the reaction is complete, cool to room temperature, pour the reaction solution into cold water (100m), separate the organic phase, extract the aqueous phase with ether three times (100mL×1, 60mL×2), combine the organic phases, wash with water (50mL×3) , dried over anhydrous sodium sulfate, the solvent was distilled off, and the crude product was subjected to column chromatography (petroleum ether/ethyl acetate=50/1) to obtain a white solid G3-21.19g with a yield of 71%. Mp162.1-163.7℃; ¹ H NMR (400MHz, CDCl ₃ ) δ7.40-7.18(m,20H),4.90(s,2H),1.49-1.39(m,4H),1.30-1.22(m,6H ); ¹³ C NMR (101MHz, CDCl ₃ ) δ142.0, 140.2, 129.6, 128.3, 128.1, 127.8, 127.7, 127.6, 110.7, 80.0, 73.2, 36.7, 25.0, 24.1; IR(KBr): 3446, 3060, 2929, 2853, 2120, 1376, 1366, 1267, 1107, 756, 737, 698; HRMS (ESI) Calcd. for C ₃₄ H ₃₂ N ₆ O ₂ Na ⁺ ([M+Na] ⁺ ) 579.2484, Found 579.2473.

3. Synthesis of G3-3:

Under nitrogen atmosphere, LiAlH ₄ (455.4mg, 12mmol, 6.0eq.) was suspended in tetrahydrofuran (15mL) and cooled to 0°C. A solution of G3-2 (1113.7mg, 2mmol, 1.0eq.) in tetrahydrofuran (15mL) was slowly added dropwise. 0 ℃ reaction 4h. After the reaction was complete, the reaction was quenched with 1M NaOH (8 mL), and the reaction solution was diluted with ether (15 mL), then anhydrous sodium sulfate (8 g) was added, and stirred at room temperature for 2 h. The solid was filtered off, dried with anhydrous potassium carbonate, and the solvent was distilled off. The crude product was subjected to column chromatography (dichloromethane/methanol=20/1) to obtain 1.1 mg of white solid G3-3851, with a yield of 84%. Mp228.4-231.7℃; ¹ H NMR (400MHz, CDCl ₃ )δ 7.55-7.50(m,4H),7.35-7.29(m,6H),7.24-7.10(m,10H),4.20(s,2H) ,2.21(brs,4H),1.51-1.36(m,4H),1.28-1.22(m,6H);IR(KBr):3359,2942,2858,1493,1367,1352,1122,767,740,704;HRMS(ESI ) Calcd. for C ₃₄ H ₃₇ N ₂ O ₂ ⁺ ([M+H] ⁺ ) 505.2855, Found 505.2863.

4. Synthesis of G3-4:

Under a nitrogen atmosphere, carbon disulfide (204 μL, 3.37 mmol, 2.0 eq.) was added to a solution of G3-3 (850 mg, 1.68 mmol, 1.0 eq.) in pyridine (2 mL). The temperature of the reaction solution was raised to 60° C., and the reaction was carried out for 20 h. After the reaction is complete, cool to room temperature, add dichloromethane (50mL) and water (20mL) to the reaction solution, adjust the pH to 2 with 1M HCl, separate the organic phase, extract the aqueous phase with dichloromethane three times (20mL×3), and combine Organic phase, washed with 1M NaOH solution (20mL×1), washed with saturated sodium chloride solution (30mL×1), dried over anhydrous sodium sulfate, evaporated the solvent, crude product column chromatography (petroleum ether/ethyl acetate=10/ 1) The white solid G3-4762mg was obtained, and the yield was 83%. Mp258.3-261.2℃; [α] _D ²⁴ =-197.5(c0.11, CH ₂ Cl ₂ ); ¹ H NMR (400MHz, CDCl ₃ ) δ7.60-7.57(m, 4H), 7.44-7.34( m,6H),7.29-7.26(m,6H),7.20-7.11(m,4H),6.87(s,2H),4.58(s,2H),1.55-1.22(m,10H); ¹³ C NMR( 101MHz,CDCl ₃ )δ185.7,143.6,139.8,129.3,128.8,128.4,128.0,127.9,127.7,111.3,77.3,70.7,36.3,24.9,23.7;IR(KBr):3378,3058,2935,4735,14 1366, 1119, 755, 699; HRMS (ESI) Calcd. for C ₃₅ H ₃₄ N ₂ O ₂ SNa ⁺ ([M+Na] ⁺ ) 569.2239, Found 569.2216.

4. Synthesis of chiral guanidine 20:

Under nitrogen atmosphere, add anhydrous potassium carbonate (55.3mg, 20.4mmol, 4.0eq.), cuprous chloride (20.8mg, 0.21mmol, 2.1eq.), tetrahydrofuran (1mL), G3- 4 (54.7mg, 0.1mmol, 1.0eq.), stirred at room temperature for 10min, added p-methylbenzylamine (18.2mg, 0.15mmol, 1.5eq.), heated to 40°C, and reacted for 12h. After the reaction is complete, cool to room temperature, add saturated ammonium chloride solution (25mL) to the reaction solution, adjust the pH to 4 with 1M HCl, extract three times with dichloromethane (25mL×3), combine the organic phases and filter, and the filtrate is saturated with sodium chloride solution Wash (15mL×1), dry over anhydrous sodium sulfate, evaporate the solvent, and column chromatography (dichloromethane/methanol=20/1) of the crude product gives a white solid. Dissolve the obtained solid in dichloromethane (20mL), add 2M NaOH solution (4mL), stir at room temperature for 2h, take the aqueous phase in dichloromethane (5mL×2), combine the organic phases, and wash with saturated sodium chloride solution (5mL×2) 1), dried with anhydrous potassium carbonate, and distilled off the solvent to obtain 2039.4 mg of white solid, with a yield of 62%.

Catalytic application examples

The optically active α-hydroxy-β-dicarbonyl structure widely exists in natural products, pharmaceutical and agrochemical chemical molecules, and is also a key intermediate for the synthesis of some chiral compounds. Asymmetric catalytic oxidation of β-dicarbonyl compounds is one of the most effective methods to obtain such building blocks. In organic catalysis, only cinchona alkaloids catalyze the asymmetric α-hydroxylation of β-keto esters to achieve industrialization, which can obtain better yield and moderate enantioselectivity. Therefore, it is of great theoretical significance and application value to continue to develop cheap and effective chiral organic small molecule catalysts with novel framework structures. This patent prepared a series of new chiral guanidine catalysts based on tartaric acid skeleton, and applied them to the asymmetric α-hydroxylation reaction of β-dicarbonyl compounds, achieving almost quantitative yield and very good enantioselectivity (Table 3 ), providing an important catalytic method for the synthesis of optically active α-hydroxy-β-dicarbonyl structures.

Table 3: Under nitrogen atmosphere, 21 (1.0eq.), 6 (0.1eq.) and 22 (1.2eq.) were reacted in toluene at -78°C for 0.5~13h, petroleum ether and ethyl acetate were used as eluents, The product 23 was isolated by column chromatography.

When examining the asymmetric α-hydroxylation of β-ketoesters, the size of the ester group has a strong influence on the enantioselectivity of the reaction (entries 1-5). β-Keto acid methyl ester gave a very good result 93% ee (entry 1). Both the reactivity and enantioselectivity decreased with the enlargement of the β-ketoester ester group. The reaction of tert-butyl β-ketoacid was completed after 13 hours, and the product (entry4) was obtained with a yield of 96% and an ee value of 86%. The electron cloud density and substituent position of the benzene ring of the β-ketoester substrate affect the enantioselectivity of the α-hydroxylation reaction (entries 6–11). Electron-withdrawing substituents (F, Cl, Br) or electron-donating substituents (OMe) attached to the 5-position of the benzene ring can give good yields and enantioselectivities (entries6-11). However, the enantioselectivity of the reaction is reduced when there is a substituent at the 4 or 6 position (entries10,11). When the reaction substrate was 6-membered ring β-ketoester, the reactivity decreased (12h to complete the reaction), and the enantioselectivity decreased significantly (55% ee). When investigating the asymmetric α-hydroxylation of indanone-derived β-diketones, the size of the exocyclic acyl group has little effect on the enantioselectivity of the reaction. Acetyl, propionyl and butyryl groups were all obtained in similar yields and ee values (entries 13-15). However, when a substituent is attached to the 5-position of the benzene ring, whether it is an electron-withdrawing substituent (F, Cl, Br) or an electron-donating substituent (OMe), although the enantioselectivity of the reaction is reduced, the obtained Enantioselective products with synthetic utility were obtained (entries16-19).

Catalytic Reaction Product Data

min,t _minor =27.2min).

mL/min, t _major =15.8min, t _minor =18.9min).

λ=254nm, 30°C, 0.8mL/min, t _major =12.6min, t _minor =14.3min).

(determined by HPLC using chiral OD-H column, hexane/2-propanol=95/5, λ=254nm, 30°C, 0.8mL/min, t _major =9.9min, t _minor =11.0min).

hexane/2-propanol=95/5, λ=254nm, 30°C, 0.8mL/min, t _major =27.5min, t _minor =33.6min).

80.5,53.6,39.1(d,J=2.0Hz);IR(KBr):3398,1752,1719,1205,1182,798,656cm ^-1 ;HRMS(ESI)Calcd.for C ₁₁ H ₈ O ₄ F([ MH] ^- )223.0407,Found223.0411; Enantiomeric excess was determined to be91%(determined by HPLC using chiral OD-H column, hexane/2-propanol=95/5,λ=254nm,30°C,0.8mL/min ,t _major =23.3min,t _minor =29.7min).

24.3min, t _minor =30.9min).

31.3min).

856,657cm ^-1 ;HRMS(ESI)Calcd.for C ₁₂ H ₁₂ O ₅ Na([M+Na] ⁺ )259.0582,Found259.0572;Enantiomeric excess was determined to be91%(determined by HPLC using chiral OD-H column , hexane/2-propanol=9/1, λ=254nm, 30°C, 0.8mL/min, t _major =20.5min, t _minor =24.6min).

53.4,38.2,17.8.IR(KBr):3423,1749,1714,1260,1200,1179,769,677cm ^-1 ; HRMS(ESI) Calcd.for C ₁₂ H ₁₂ O ₄ Na([M+Na] ⁺ ) 243.0633, Found243.0640; Enantiomeric excess was determined to be80%(determined by HPLC using chiral OD-H column, hexane/2-propanol=95/5, λ=254nm, 30°C, 0.8mL/min, t _major = 19.1min, t _minor =22.2min).

t _major =19.9min,t _minor =23.9min).

mL/min, t _major =16.1min, t _minor =18.2min).

27.3min).

39.0,29.8,7.5;IR(KBr):3407,1724,1703,1130,1109,781,735,667cm ^-1 ;HRMS(ESI) Calcd.for C ₁₂ H ₁₂ O ₃ Na([M+Na] ⁺ )227.0684, Found227.0689;Enantiomeric excess was determined to be88%(determined by HPLC using chiral AS-H column, hexane/2-propanol=8/2,λ=254nm,30°C,0.7mL/min,t _minor =11.0min ,t _major =19.8min).

16.9,13.4;IR(Neat):3427,1727,1704,1124,1064,733cm ^-1 ;HRMS(ESI)Calcd.for C ₁₃ H ₁₄ O ₃ Na([M+Na] ⁺ )241.0841,Found241.0838 ;Enantiomeric excess was determined to be86%(determined by HPLC using chiral AS-H column, hexane/2-propanol=8/2,λ=254nm,30°C,0.7mL/min,t _minor =11.7min,t _major =20.3min).

1699,1255,1128,624cm ^-1 ;HRMS(ESI)Calcd.for C ₁₁ H ₉ O ₃ FNa([M+Na] ⁺ )231.0433,Found231.0437;Enantiomeric excess was determined to be79%(determined by HPLC using chiral AS-H column, hexane/2-propanol=8/2, λ=254nm, 30°C, 0.7mL/min, t _minor =13.0min, t _major =29.0min).

min).

Excess was determined to be81%(determined by HPLC using chiral AS-H column, hexane/2-propanol=8/2, λ=254nm, 30°C, 0.7mL/min, t _minor =13.3min, t _major =28.3 min).

243.0633, Found243.0629; Enantiomeric excess was determined to be80% (determined by HPLC using chiral AS-H column, hexane/2-propanol=7/3, λ=254nm, 30°C, 0.4mL/min, t _minor = 14.7min, t _major =31.1min).

Claims (10)

1. A chiral guanidine catalyst based on tartaric acid skeleton is a compound with general formula I or II: in: R ₁ is C ₁ -C ₄ alkyl or phenyl; R ₂ is selected from one of hydrogen, C _1-6 alkyl, aromatic group, halogen, C _1-6 alkoxy and C _1-6 haloalkyl; R ₃ is C _1-6 alkyl, aromatic group or aminoalcohol residual chain; In the general formula II, n=0, 1 or 2. 2. The chiral guanidine catalyst according to claim 1, characterized in that: n=1. 3. chiral guanidine catalyst according to claim 1, is characterized in that: _R is methyl. 4. According to the chiral guanidine catalyst according to any one of claims 1 to 3, it is characterized in that: _R is a hydrogen atom, methyl, isopropyl, tert-butyl, phenyl, 4-position or 3,5 - Substituted phenyl, methoxy or trifluoromethyl. _5. The chiral guanidine catalyst according to any one of claims 1 to 3, characterized in that: R is methyl, cyclohexyl, phenyl, 4-, 3,5-substituted phenyl, benzyl , 4- or 3,4,5-substituted benzyl, aminoalcohol residues. 6. according to the described chiral guanidine catalyst of claim 4, it is characterized in that: R ₂ is a hydrogen atom or a phenyl group. 7. according to the described chiral guanidine catalyst of claim 1, it is characterized in that: _R3 is p-methylbenzyl, 3,4,5-trimethoxybenzyl, 2,6-diisopropylphenyl, 3 , 5-di-tert-butylphenyl, (1S)-1-tert-butyl-2-hydroxyethyl or (1S,2S)-2-hydroxycyclohexyl. 8. The chiral guanidine catalyst according to claim 1, characterized in that: the catalyst is selected from one of the following numbered 1-12 compounds: 9. a kind of preparation method based on the chiral guanidine catalyst of tartaric acid skeleton is characterized in that: the preparation method of general formula I compound is carried out by following operational route: The preparation method of general formula II compound is carried out according to following operational route: 10. The preparation method according to claim 9, characterized in that: comprising the following steps: (1) Condensation reaction: under the catalysis of Lewis acid, tartrate ester and ketone or ketal molar ratio 1:1~1:1.5 are refluxed in benzene or toluene for 12~24h; the obtained reaction solution is added with sodium bicarbonate, Water treatment, extraction, washing, drying, and finally concentration to obtain the concentrated product; (2) Grignard reaction: react the condensation product obtained in step (1) with the Grignard reagent in a molar ratio of 1:4.5 to 1:5 in tetrahydrofuran for 30 to 90 minutes under reflux; cooling, quenching, extraction, Wash, dry, concentrate, and recrystallize from ethyl acetate/petroleum ether to obtain the product; (3) Chlorination reaction: Dissolve the Grignard reaction product obtained in step (2) in dichloromethane, with thionyl chloride and triethylamine in a molar ratio of 1:3:4.2～1:3.5:7, at room temperature At the reflux temperature, react for 3 to 12 hours; after the reaction, distill off the solvent to obtain the chlorinated product; (4) Azidation reaction: dissolve the chlorination reaction product obtained in step (3) in N,N-dimethylformamide, and react with sodium azide at a molar ratio of 1:4 at 80°C for 72h; cool down , the reaction solution was poured into water, extracted with ether, the organic layer was washed with water, dried, filtered, concentrated, and flash column chromatography was used to obtain a solid, which was recrystallized with ether/ethanol to obtain the product; (5) Reduction reaction: Dissolve the azidation product obtained in step (4) in tetrahydrofuran, and react with tetrahydroaluminum lithium at a molar ratio of 1:6 at 0°C for 1.5 to 6 hours; quenching, extraction, washing, drying, Concentrate and recrystallize from ether/n-hexane to obtain the product; (6) Thiourea reaction: dissolve the reduction product obtained in step (5) in pyridine, and react with carbon disulfide at a molar ratio of 1:2 at 60°C for 12 to 24 hours; cool down, pour the reaction solution into water, and dichloromethane Extraction; the organic layer was washed with water, dried, filtered, concentrated, and recrystallized from dichloromethane/n-hexane to obtain the product; (7) Guanidation reaction: add thiourea obtained in step (6) to tetrahydrofuran with amine, cuprous chloride, and potassium carbonate in a molar ratio of 1:1.2:2:4～1:10:2.1:15, and heat at 40°C React for 4-72 hours; cool down, quench, extract, filter, wash, dry, concentrate, and column chromatography to obtain a solid product.