CN105148988B - A kind of chiral pyridoxal class catalyst and its synthetic method and application - Google Patents

Abstract

The present invention relates to a kind of chiral pyridoxal catalyst and its synthetic method and application, and this catalyst has the structure shown in general formula S-1, R-1, S-2 and R-2: During preparation, with pyridoxine hydrochloride 5 and chiral prolinol compound 9 as starting raw materials, it is prepared through a multi-step reaction. Catalyst S-2 and R-2 are obtained by adding Catalysts S-1, R-1, S-2 and R-2 obtained by the selective protection of prolinol hydroxyl group can be used to biosimulate the asymmetric transamination of α-keto acids to synthesize a series of chiral α- amino acid. Compared with the prior art, the invention has mild reaction conditions, easy operation and good repeatability, and the prepared catalyst has higher ee value and higher yield when used for synthesizing α-amino acids.

Description

A kind of chiral pyridoxal catalyst and its synthesis method and application

technical field

The invention belongs to the technical field of organic synthesis, and relates to a chiral pyridoxal catalyst, a synthesis method and application thereof.

Background technique

Amino acids in organisms are mainly realized through the transamination of ketoacids under the action of transaminases, which is a very important biological process. Transaminase transfers the α-amino group of one amino acid to the carbonyl group of another α-keto acid to generate a new amino acid [D.Zhu and L.Hua, Biotechnol.J., 2009, 4, 420]; at the same time, the original amino acid It is transformed into α-keto acid, and its reaction center is vitamin B ₆ , that is, pyridoxal and its derivatives.

Pyridoxal (PL) participates in many metabolic activities. It can be used as a coenzyme in the synthesis of amino acids [D.Zhu and L.Hua, Biotechnol.J., 2009, 4, 1420.], and it can also be used as a vitamin in vitro. B ₆ itself can catalyze the transamination of α-ketoacids to generate corresponding α-amino acids [J. Ward and R. Wohlgemuth, Curr. Org. Chem., 2010, 14, 1914.]. The key to the transamination reaction is to design and develop highly active pyridoxal catalysts. The continuous research on the transamination reaction has promoted the continuous development of catalysts. In 1952, the Snell research group discovered that pyridoxal could undergo transamination with a series of amino acids to generate corresponding pyridoxamine and ketoacids [David.E.Metzler.and Esmond E, Snell.J.Am.Chem .Soc.1952,74(4),979-983.]; In 1957, Matsuo used pyridoxal as a catalyst to realize the transamination reaction of amino acid and ketoacid in ethanol [Yoshihiko.MJAm.Chem.Soc. 1957,79,2016-2019.]; In 1978, Kuzuhara's subject combined chiral pyridoxal derivatives for transamination reactions and obtained better ee values [Malkov, AV; Mariani, A. ; MacDougall, KN; Kocovsky, P.Org.Lett.2004,6,2253.]; Breslow's research group has done a lot of work in biosimulating transamination, and obtained an ee value greater than 92 under certain synthetic conditions % of α-amino acids [SC Zimmerman, AWCzarnik and R. Breslow, J.Am.Chem.Soc., 1983, 105, 1694.], [SCZimmerman and R.Breslow, J.Am.Chem.Soc., 1984, 106 ,1490],[R.Breslow,AWCzarnik,M.Lauer,R.Leppkes,J.Winklerand S.Zimmerman,J.Am.Chem.Soc.,1986,108,1969.],[W.Zhou,N. Yerkes, JJ Chruma, L. Liu and R. Breslow, Bioorg. Med. Chem. Lett., 2005, 15, 1351.]. At the same time, the use of chiral small molecule pyridoxal and its derivatives as catalysts to catalyze the synthesis of chiral α-amino acids has not been paid attention to by chemists. , the structure is easy to modify, and it is used in mild transamination conditions with good yield and high ee value.

Contents of the invention

The object of the present invention is to provide a kind of chiral pyridoxal catalyst and its synthetic method and application in order to overcome the defective that above-mentioned prior art exists, wherein, described chiral pyridoxal catalyst can be used for biological simulation α- Asymmetric transamination of keto acids to synthesize a series of chiral amino acids with high ee value.

The purpose of the present invention can be achieved through the following technical solutions:

A kind of chiral pyridoxal catalyst, this catalyst has the structure shown in general formula S-1, R-1, S-2 and R-2:

Wherein, R ¹ and R ² are hydrogen or one of C _1-24 hydrocarbon groups, and the hydrocarbon groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl One of base, cyclohexyl, cycloheptyl, phenyl, benzyl, (1-phenyl) ethyl, 1-naphthyl, 2-naphthyl or halogen;

R ³ and R ⁴ are C _1-24 hydrocarbon groups or One of, the hydrocarbon group includes one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl or cycloheptyl, wherein, R ^x , R ^x' are hydrogen, methyl, methoxy, ethyl, ethoxy, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, benzene One of base, benzyl, (1-phenyl) ethyl, 1-naphthyl, 2-naphthyl or halogen;

R ⁵ is C _1-12 hydrocarbon group, One of, the hydrocarbon group includes one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl or cycloheptyl, wherein R ^x , R ^x' is hydrogen, methyl, methoxy, ethyl, ethoxy, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl , benzyl, (1-phenyl) ethyl, 1-naphthyl, 2-naphthyl or halogen, R ^y , R ^y' and R ^y" are hydrogen, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, (1-phenyl)ethyl, 1-naphthyl or 2-naphthyl kind of.

A kind of synthetic method of chiral pyridoxal catalyst, this synthetic method specifically comprises the following steps:

(1) In an organic solvent, add pyridoxine hydrochloride 5 and alkali, then drop tert-butyldiphenylchlorosilane (TBDPSCl), wherein, pyridoxine hydrochloride 5 and alkali, tert-butyldiphenylchlorosilane The molar ratio of (TBDPSCl) is 1:(3~6):(1~5), stirred and reacted, the reaction temperature is controlled at -20~-50°C, and the reaction time is 1~24h, and the intermediate 6 is obtained;

(2) In the organic solvent, according to the molar ratio of intermediate 6 and oxidizing agent as 1: (1~5), add intermediate 6 and oxidizing agent, stir and react, control the reaction temperature to be 0~100°C, and the reaction time is 1~5 24h, Intermediate 6 was oxidized to obtain Intermediate 7;

(3) In the organic solvent, according to the molar ratio of the intermediate 7 and the oxidizing agent as 1: (1-5), add the intermediate 7 and the oxidizing agent, stir and react, control the reaction temperature to be 0-100°C, and the reaction time to be 1-5 24h, Intermediate 7 was further oxidized to obtain Intermediate 8;

(4) In the organic solvent, according to the molar ratio of intermediate 8 and chiral prolinol compound 9, condensing agent is 1: (1 ~ 5): (1 ~ 5), add intermediate 8, chiral proline The alcohol compound 9 and the condensing agent are stirred and reacted, the reaction temperature is controlled to be 0-100° C., and the reaction time is 1-24 hours to prepare the intermediate 10;

(5) In an organic solvent, according to the molar ratio of intermediate 10 and tetrabutylammonium fluoride as 1: (1-5), add intermediate 10 and tetrabutylammonium fluoride, stir and react, and control the reaction temperature to 0～100°C, the reaction time is 1～48h, and the intermediate 10 is removed from tert-butyldiphenylsilane to obtain the intermediate 11;

(6) In the organic solvent, according to the molar ratio of the intermediate 11 and the oxidizing agent is 1: (1-20), add the intermediate 11 and the oxidizing agent, stir and react, control the reaction temperature to be 0-100°C, and the reaction time to be 1-20 48h, intermediate 11 was oxidized to obtain chiral catalyst S-1 or R-1;

(7) In an organic solvent, according to the chiral catalyst S-1 or R-1 and R ⁵ X, the molar ratio of the base is 1: (1-5): (3-6), add the chiral catalyst S-1 Or R-1, R ⁵ X and alkali, react with stirring, control the reaction temperature at 0-100°C, and the reaction time is 1-24h, then the chiral catalyst S-2 or R-2 can be obtained.

Described pyridoxine hydrochloride 5, intermediate 6, intermediate 7 and intermediate 8 have structures as shown in general formulas 5, 6, 7 and 8:

Wherein, R ¹ and R ² are hydrogen or one of C _1-24 hydrocarbon groups, and the hydrocarbon groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl One of radical, cyclohexyl, cycloheptyl, phenyl, benzyl, (1-phenyl)ethyl, 1-naphthyl, 2-naphthyl or halogen.

The chiral prolinol compound 9 has the structure shown in general formula S-9, R-9:

When the chiral prolinol compound 9 is S-9, the intermediates 10 and 11 have the structures shown in the general formulas S-10 and S-11 respectively:

When the chiral prolinol compound 9 is R-9, the intermediates 10 and 11 have the structures shown in the general formulas R-10 and R-11 respectively:

Wherein, R ¹ and R ² are hydrogen or one of C _1-24 hydrocarbon groups, and the hydrocarbon groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl One of base, cyclohexyl, cycloheptyl, phenyl, benzyl, (1-phenyl) ethyl, 1-naphthyl, 2-naphthyl or halogen;

R ³ and R ⁴ are C _1-24 hydrocarbon groups or One of, the hydrocarbon group includes one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl or cycloheptyl, wherein, R ^x , R ^x' are hydrogen, methyl, methoxy, ethyl, ethoxy, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, benzene One of radical, benzyl, (1-phenyl)ethyl, 1-naphthyl, 2-naphthyl or halogen.

In said R ⁵ X, R ⁵ is a C _1-12 hydrocarbon group, One of, the hydrocarbon group includes one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl or cycloheptyl, wherein R ^x , R ^x' is hydrogen, methyl, methoxy, ethyl, ethoxy, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl , benzyl, (1-phenyl) ethyl, 1-naphthyl, 2-naphthyl or halogen, R ^y , R ^y' and R ^y" are hydrogen, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, (1-phenyl)ethyl, 1-naphthyl or 2-naphthyl X is one of F, Cl, Br, I, sulfonyl, phenylmethylsulfonyl or p-toluenesulfonyl.

Described organic solvent comprises benzene, toluene, xylene, mesitylene, acetonitrile, ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, methanol, ethanol, isopropanol, N,N-dimethyl One or more of formamide, N,N-dimethylacetamide, dimethylsulfoxide or N-methylpyrrolidone;

Described alkali comprises sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, calcium hydride, triethylamine, diisopropylethylamine , Tetramethylethylenediamine, N, N-dimethylaniline, N, N-diethylaniline, 1,4-diazabicyclooctane, diazabicyclododecane, 1,4 -one or more of dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, quinoline or pyridine;

Described oxidant comprises chromium trioxide, sodium dichromate, potassium dichromate, sodium hypochlorite, sodium chlorate, sodium perchlorate, sodium dihydrogen phosphate, potassium permanganate, manganese dioxide, periodic acid, lead tetraacetate , Swern oxidant, DMSO, selenium dioxide, Dess-Martin oxidant or DCC;

Described condensing agent comprises a kind of in TBTU, DIC, EDCI, EDDQ or Mukaiyama's reagent.

The preparation process of the catalyst of the present invention, taking S-configuration compounds S-1 and S-2 as examples, can be simply represented by the following reaction process:

A kind of application of chiral pyridoxal catalyst, the catalyst is used to catalyze the synthesis of chiral α-amino acid, chiral α-amino acid has the structure shown in general formula S-4, R-4:

^Wherein , R is hydrogen, substituted or unsubstituted following groups:

C ₁ -C ₂₄ hydrocarbon group, C ₃ -C ₃₀ cycloalkyl or aryl group, C ₁ -C ₂₄ carbonyl group, C ₁ -C ₂₄ sulfonyl or phosphoryl group;

Described substitution refers to being substituted by the following substituents:

Halogen, C ₁ -C ₈ hydrocarbon group, C ₃ -C ₁₂ cycloalkyl or aryl group, C ₁ -C ₈ carbonyl group, C ₁ -C ₈ sulfonyl group, C ₁ -C ₈ phosphoryl group, C ₁ -C ₈ alkoxy group or C ₁ -C ₈ amine group;

The carbonyl group is one of aldehyde group, ketone carbonyl group, ester carbonyl group, carboxyl group or amide group.

The synthesis method of the chiral α-amino acid is as follows: in an organic solvent, the molar ratio of the ketoacid to the amine source is (0.5-5): 1, adding the ketoacid and the amine source, then adding a catalyst, stirring the reaction, The reaction temperature is controlled to be -10-100° C., and the reaction time is 1-72 hours to obtain the chiral α-amino acid.

The ketoacid and the amine source have the structures shown in the general formulas 3 and 12 respectively:

Wherein, R ⁹ is one of hydrogen or carboxyl;

R ⁶ , R ⁷ , R ⁸ are hydrogen, substituted or unsubstituted following groups:

C ₁ -C ₂₄ hydrocarbon group, C ₃ -C ₃₀ cycloalkyl or aryl group, C ₁ -C ₂₄ carbonyl group, C ₁ -C ₂₄ sulfonyl or phosphoryl group;

Described substitution refers to being substituted by the following substituents:

Halogen, C ₁ -C ₈ hydrocarbon group, C ₃ -C ₁₂ cycloalkyl or aryl group, C ₁ -C ₈ carbonyl group, C ₁ -C ₈ sulfonyl group, C ₁ -C ₈ phosphoryl group, C ₁ -C ₈ alkoxy group or C ₁ -C ₈ amine group;

The carbonyl group is one of aldehyde group, ketone carbonyl group, ester carbonyl group, carboxyl group or amide group.

Described organic solvent comprises benzene, toluene, xylene, mesitylene, acetonitrile, ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, methanol, ethanol, isopropanol, N,N-dimethyl One or more of formamide, N,N-dimethylacetamide, dimethylsulfoxide or N-methylpyrrolidone.

The present invention prepares chiral α-amino acid and can simply represent with following reaction scheme:

The present invention takes pyridoxine hydrochloride 5 and chiral prolinol 9 as starting raw materials, and the catalyst S-1 or R-1 prepared through multi-step reaction, catalyst S-2 or R-2 is catalyst S- 1 or the selective protection of the prolinol hydroxyl group in R-1, the chiral pyridoxal catalyst of the present invention can be used for the asymmetric transamination of biosimulating α-keto acids, and the conditions of the transamination reaction are mild, The method is easy to operate, has good repeatability, has high ee value and good yield, and provides a new method for the synthesis of chiral α-amino acid.

Compared with the prior art, the present invention has the following characteristics:

(1) Pyridoxal is a very important compound with good biological activity. In biological systems, it is the coenzyme of many transaminases, which can catalyze the transamination of ketoacids to synthesize various biologically active amino acids. The present invention designs and synthesizes a class of chiral pyridoxal catalysts, which can be used to simulate the process of biological transamination reactions to realize the rapid and effective synthesis of chiral amino acids;

(2) The chiral pyridoxal catalysts 1 and 2 developed in the present invention can be prepared by multi-step reaction of cheap and easy-to-obtain raw materials, the reaction conditions are mild, easy to scale up, and can be prepared on a large scale;

(3) The enantioselectivity of pyridoxal catalyst 1 and 2 developed in the present invention is realized by the induction of the chiral prolinol segment in the catalyst, and the chiral prolinol S-9 of two configurations and R-9 are easy to obtain, which is conducive to the large-scale preparation of chiral catalysts with different configurations, and no chiral resolution is required in the catalyst synthesis;

(4) The keto acid transamination reaction catalyzed by pyridoxal catalyst 1 and 2 in the present invention is a new method for preparing chiral amino acid compounds, which simulates the biological transamination process: pyridoxal catalyst 1 or 2 React with the amine source 12 in the system to generate pyridoxamine, which condenses with α-ketoacid 3 to form ketimine, which undergoes 1,3-hydrogen migration to form aldimine, which is released by hydrolysis The α-amino acid 4, simultaneously regenerates pyridoxal catalyst 1 or 2, completes a catalytic cycle;

(5) The ketoacid transamination reaction conditions catalyzed by pyridoxal catalysts 1 and 2 in the present invention are very mild, and are not very sensitive to water and air. They can be carried out at room temperature and in water. The reaction is stable and easy to operate. The product ee The value is higher, the yield is better, and it is an effective method for preparing chiral α-amino acid compounds.

Due to the above outstanding features and advantages, the present invention has better application value.

Detailed ways

The present invention will be described in detail below in conjunction with specific embodiments.

Example 1: Synthesis of Intermediate 6.

Take a 2L dry reaction flask, add pyridoxine hydrochloride 5 (50g, 243mmol), dichloromethane (600mL) and anhydrous triethylamine (85.9g, 850.5mmol) into the reaction flask respectively, and agglomeration occurs at this time , place the reaction bottle in an ice bath, add tert-butyldiphenylchlorosilane (36.7g, 267mmol) dropwise to the reaction bottle under mechanical stirring, continue stirring for 1.5h after the addition is complete, and then add tert-butyldiphenylchlorosilane (36.7g, 267mmol) was added dropwise in , and stirred overnight. Add dichloromethane (500mL) and water (500mL) to the reaction flask, there are solid insoluble matter, suction filter to obtain filter cake, wash with petroleum ether (200mL) to obtain pure product, the mother liquor is separated to obtain an organic layer, and the organic layer is spin-dried , washed with ethyl acetate (200mL) to remove impurities, suction filtered, and the filter cake was washed with petroleum ether (200mL) to obtain a white solid, the combined products were dried under reduced pressure to obtain intermediate 6 (105g, 67%).

White solid; mp196-198℃; IR(KBr)3301,3071,1471,1444,1385,1115cm ^-1 ; ¹ HNMR(400MHz, CDCl ₃ )δ8.14(s,1H),7.54(d,J＝6.8 Hz, 4H), 7.45(t, J=7.2Hz, 2H), 7.41-7.27(m, 10H), 7.16(t, J=7.6Hz, 4H), 4.75-4.65(m, 2H), 4.61(s ,2H),2.09(s,3H),0.97(s,9H),0.76(s,9H); ¹³ C NMR(100MHz,CDCl ₃ )δ149.5,147.5,142.5,136.5,135.6,135.3,134.3,132.3, 132.1, 130.0, 129.9, 127.9, 127.6, 61.3, 59.5, 26.6, 26.5, 21.9, 19.9, 19.0.

Example 2: Intermediate 6 is oxidized to the corresponding Intermediate 7.

Take a 1L reaction flask, add intermediate 6 (131.5g, 203.9mmol) and anhydrous dichloromethane (300mL) to the reaction flask respectively, stir at room temperature for 10min to completely dissolve the solid, add Dess-Martin oxidant (112.36g, 265mmol) , the reaction solution quickly turned into a yellow-green turbid solution, and the reaction was completed in 1h. The reaction solution was washed with NaHCO ₃ (200mL×2), saturated NaCl solution (150mL×3), and the organic layer was dried with anhydrous sodium sulfate, filtered, and spin-dried A white solid was obtained. Add ethyl acetate (200mL) to this white solid, stir, suction filtration, this operation is repeated three times, the filter cake obtained at last is washed with ethyl acetate (150mL) and sherwood oil (150mL) respectively in the filter funnel again, reduce Drying under pressure gave white solid intermediate 7 (97 g, 74%).

White solid; mp176-182℃; IR(KBr)3070,1695; 1588,1572cm ^-1 ; ¹ H NMR(600MHz, CDCl ₃ )δ10.37(s,1H),8.57(s,1H),7.46-7.40 (m,6H),7.36-7.29(m,10H),7.20-7.14(m,4H),4.57(s,2H),2.23(s,3H),0.91(s,9H),0.89(s,9H ); ¹³ C NMR (100MHz, CDCl ₃ ) δ191.5, 155.4, 147.4, 142.2, 139.8, 135.5, 135.4, 132.5, 131.7, 130.3, 129.9, 129.5, 127.8, 57.9, 26.6, 22.4, 20.0, 19.1.

Example 3: Synthesis of Intermediate 8.

Take a 1L reaction bottle, add intermediate 7 (97g, 150.9mmol), dichloromethane (700mL) and tert-butanol (40mL) into the bottle respectively, and stir in an ice-water bath. Another 250mL reaction bottle was taken, and NaH ₂ PO ₄ 2H ₂ O (58.83g, 377mmol), NaClO ₂ (27.3g, 301.7mmol) and water (100mL) were added to the bottle respectively, placed in an ice bath and stirred for 2min. The solid was dissolved, and the newly prepared inorganic oxidant solution was dropped into the first reaction flask within 10 minutes; after 1 hour, the same amount of oxidant solution was added, and after 2 hours, the same amount of oxidant solution was added again. After the reaction was complete, direct suction filtration, Drying in vacuo afforded intermediate 8 (85 g, 85%).

White solid; mp222-224℃; IR(KBr)3072,1712,1589,1293cm ^-1 ; ¹ H NMR(400MHz,CD ₃ OD with 1equiv.of KOH)δ8.22(s,1H),7.72(d, J＝7.6Hz, 4H), 7.48(d, J＝7.2Hz, 4H), 7.45-7.34(m, 8H), 7.26(t, J＝7.6Hz, 4H), 5.18(s, 2H), 1.83( s,3H),1.04(s,9H),0.79(s,9H); ¹³ C NMR(100MHz,CD ₃ OD with 1equiv.of KOH)δ174.8,149.6,149.0,141.9,139.1,137.6,136.9,136.4, 134.8, 133.6, 131.2, 130.6, 128.7, 128.6, 59.8, 27.3, 27.1, 21.6, 20.7, 20.1.

Example 4: Intermediate 8 and compound 9a Synthesis of intermediate S-10a (taking the S configuration as an example).

Take a 25mL eggplant-shaped bottle, weigh Intermediate 8 (2g, 3.03mmol) and compound 9a, i.e., diphenylprolinol (0.922g, 3.64mmol) into the reaction bottle, and then add diisopropylethylamine to the system (1.167g, 9.09mmol), add anhydrous dichloromethane (5mL) into the reaction system, stir at room temperature for two minutes and the system is completely dissolved, then O-benzotriazole-N,N,N',N'- Add tetramethylurea tetrafluoroboric acid (1.95g, 6.06mmol) into the reaction flask, stir overnight at room temperature, spin off most of the solvent, put it on the column by wet method, and obtain white foamy solid intermediate S-10a (0.9 g, 33%).

White solid; [α] ²⁵ _D ＝-11.5(c 0.26, CH ₂ Cl ₂ ); IR (KBr) 3261, 2858, 1762, 1614, 1112 cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ7.71- 7.62(m, 6H), 7.57-7.21(m, 23H), 7.14(t, J=7.2Hz, 2H), 5.18-5.02(m, 2H), 4.78(d, J=12.4Hz, 1H); 3.30 -3.15(m,1H),3.05-2.90(m,1H),2.00(s,3H),1.95-1.80(m,2H),1.35-1.17(m,2H),1.04(s,9H),0.78 (s,9H); ¹³ C NMR (100MHz, CDCl ₃ )δ170.7, 151.0, 147.4, 145.6, 143.0, 140.6, 136.4, 135.6, 135.5, 135.3, 135.1, 133.4, 132.9, 132.6, 132.1, 130.19, 130. ,129.94,129.90,128.7,128.43,128.42,,128.0,127.9,127.89,127.88,127.81,127.6,127.4,126.1,125.6,82.1,69.4,69.1,58.9,52.0,127.2,39.1 25.0, 23.6, 22.3, 19.9, 19.4.

Example 5: Deprotection of intermediate S-10a to obtain intermediate S-11a.

Take a 25mL eggplant-shaped bottle, add intermediate S-10a (0.9g, 1.01mmol), THF (10mL) and tetrabutylammonium fluoride trihydrate (0.945g, 3.03mmol) into the reaction bottle, and stir at room temperature for 4h After the reaction is complete, spin off the tetrahydrofuran in the system under reduced pressure, then add dichloromethane (20mL) and water (10mL) to the system, separate the layers, continue to wash the organic layer with water (10mL×2), wash the organic layer with anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and wet-loaded to the column to obtain intermediate S-11a (0.2g, 48%).

White solid; [α] ²⁵ _D ＝-58.1(c 0.33, CH ₂ Cl ₂ ); IR(KBr) 3231, 2980, 1609.1446, 1032cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ7.55(dd, J=7.6,1.2Hz,2H),7.47-7.24(m,9H),5.25(t,J=8.0Hz,1H),4.68(d,J=14.0,1H),4.52(d,J=14.0Hz ,1H),3.25-3.10(m,1H),2.95-2.78(m,1H).2.46(s,3H),2.20-2.09(m,1H),2.05-1.94(m,1H),1.65-1.35 (m,2H); ¹³ C NMR (100MHz, CDCl ₃ )δ169.8, 151.5, 149.4, 144.9, 142.6, 136.4, 128.6, 128.5, 128.2, 128.0, 127.9, 127.74, 127.71, 127.7, 82.2, 68.2, 60.4, , 30.2, 24.1, 18.9.

Example 6: Synthesis of Catalyst S-1a.

Take a 25mL eggplant-shaped bottle, add intermediate S-11a (0.20g, 0.5mmol), anhydrous dichloromethane (10mL) and active manganese dioxide (0.26g, 3.0mmol) into the reaction bottle, stir at room temperature for 2h, After the reaction of the raw materials was complete, the system was filtered through a diatomaceous earth layer and spin-dried to obtain catalyst S-1a (0.12 g, 60%).

Yellow solid; [α] ²⁵ _D ＝-78.0(c 0.28,CH ₂ Cl ₂ )IR(KBr)3420,1667,1613,1494,1385,1242,1033cm ^-1 ; ¹ H NMR(400MHz,CDCl ₃ )δ11 .31(brs,1H),9.59(s,1H),7.72(s,1H),7.61(d,J=6.0Hz,2H),7.50-7.26(m,8H),6.31(s,1H), 5.32(dd,J＝8.8,8.0Hz,1H),3.35-3.25(m,1H),3.10-2.98(m,1H),2.53(s,3H),2.25-2.00(m,2H),1.75- 1.54(m,2H); ¹³ C NMR(100MHz,CDCl ₃ )δ196.7,167.2,153.6,153.4,144.9,142.9,136.9,130.0,128.2,128.1,127.9,127.7,127.6,127.5,118.69.9,81.9, 52.0, 30.4, 24.4, 19.0.

Example 7: Synthesis of Catalyst S-2a.

Take a 10mL eggplant-shaped bottle, add catalyst S-1a (0.060g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) into the reaction bottle, triethylchlorosilane ( 0.063g, 0.576mmol), stirred at room temperature for 2h to complete the reaction, added silica gel, spin off the solvent, put it on the column by dry method, and obtained catalyst S-2a (0.036g, 53%) by silica gel column chromatography.

Yellow solid; [α] ²⁵ _D ＝-35.6(c 0.73, CH ₂ Cl ₂ ) IR (KBr) 3432, 2957, 1664, 1640, 1385, 1247, 1070 cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11 .33(s,1H),9.83(s,1H),7.89(s,1H),7.48-7.38(m,4H),7.36-7.25(m,6H),5.80(dd,J＝6.0,5.6Hz ,1H),3.18-3.10(m,1H),3.00-2.90(m,1H),2.53(s,3H),2.38-2.28(m,2H),1.76-1.64(m,2H),-0.12( s, 9H); ¹³ C NMR (100MHz, CDCl ₃ ) δ197.4, 165.3, 153.5, 152.8, 144.6, 144.2, 137.9, 130.8, 129.2, 128.5, 128.04, 127.95, 127.7, 127.5, 119.3, 85.3, 0.4, 63. 27.4, 24.5, 19.0, 2.0.

Example 8: Intermediate 8 and Compound S-9b Synthesis of Intermediate S-10b.

Take a 25mL eggplant-shaped bottle, weigh Intermediate 8 (2g, 3.03mmol) and compound S-9b (1.476g, 3.64mmol) into the reaction flask, and then add diisopropylethylamine (1.167g, 9.09mmol) to the system mmol), add anhydrous dichloromethane (5mL) into the reaction system, stir at room temperature for two minutes and the system is completely dissolved, then add O-benzotriazole-N,N,N',N'-tetramethylurea tetra Fluoroboric acid (1.95g, 6.06mmol) was added into the reaction flask and stirred overnight at room temperature. Most of the solvent was spun off, applied to the column by wet method, and silica gel column chromatography gave white foamy solid intermediate S-10b (1.1 g, 35%).

Example 9: Deprotection of intermediate S-10b to obtain intermediate S-11b.

Take a 25mL eggplant-shaped bottle, add intermediate S-10b (1.1g, 1.01mmol), THF (10mL) and tetrabutylammonium fluoride trihydrate (0.945g, 3.03mmol) into the reaction bottle, and stir at room temperature for 4h After the reaction is complete, spin off the tetrahydrofuran in the system under reduced pressure, then add dichloromethane (20mL) and water (10mL) to the system, separate the layers, continue to wash the organic layer with water (10mL×2), wash the organic layer with anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and wet applied to the column to obtain intermediate S-11b (0.33g, 58%).

Example 10: Synthesis of Catalyst S-1b.

Take a 25mL eggplant-shaped bottle, add intermediate S-11b (0.28g, 0.5mmol), anhydrous dichloromethane (10mL) and active manganese dioxide (0.26g, 3.0mmol) into the reaction bottle, stir at room temperature for 2h, After the reaction of the raw materials was complete, the system was filtered through a layer of diatomaceous earth and spin-dried to obtain catalyst S-1b (0.15 g, 54%).

Yellow solid; [α] ²⁵ _D ＝-47.6(c 0.41,CH ₂ Cl ₂ )IR(KBr)3285,3058,1666,1613,1413,1242,1034cm ^-1 ; ¹ H NMR(400MHz,CDCl ₃ )δ11 .31(s,1H),9.47(s,1H),7.92(s,1H),7.81(s,1H),7.76(s,1H),7.73-7.35(m,16H),6.59(s,1H ),5.42(t,J＝8.0Hz,1H),3.34-3.25(m,1H),3.00-3.20(m,1H),2.53(s,3H),2.10-2.35(m,2H),1.55- 1.80(m,2H); ¹³ C NMR(100MHz,CDCl ₃ )δ196.5,167.3,153.5,153.4,145.3,143.4,141.2.141.1,140.0,136.7,137.0,128.9,128.8,128.6,128.4,127.4,127.6, 127.3, 127.3, 126.8, 126.6, 126.4, 126.3, 118.6, 82.0, 69.4, 52.1, 30.7, 24.4, 19.0.

Example 11: Synthesis of Catalyst S-2b.

Take a 10mL eggplant-shaped bottle, and add catalyst S-1b (0.082g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) to the reaction bottle, and triethylchlorosilane ( 0.063g, 0.576mmol), stirred at room temperature for 2h to complete the reaction, added silica gel, spin off the solvent, put it on the column by dry method, and obtained catalyst S-2b (0.062g, 67%) by silica gel column chromatography.

Yellow solid; IR(KBr)3440,2954,1664,1639,1478,1246,1069cm ^-1 ; ¹ H NMR(400MHz, CDCl ₃ )δ11.30(s,1H),9.68(s,1H),7.85( s,1H),7.71(s,1H),7.68-7.30(m,17H),5.97(dd,J＝8.0,3.6Hz,1H),3.24-3.14(m,1H),3.06-2.95(m, 1H),2.51(s,3H),2.50-2.35(m,2H),1.82-1.68(m,2H),-0.05(s,9H); ¹³ C NMR(100MHz,CDCl ₃ )δ197.3,165.4,153.5 ,152.8,145.1,144.8,141.4,141.0,140.9,140.6,137.7,130.9,129.0,128.9,128.6,128.4,128.0,127.8,127.6,127.5,127.4,127.2,127.0,3139.5,127.5,127.0,3139.5,127.3 ,27.6,24.5,19.0,2.2.

Example 12: Intermediate 8 and Compound S-9c Synthesis of Intermediate S-10c.

Take a 25mL eggplant-shaped bottle, weigh Intermediate 8 (2g, 3.03mmol) and compound S-9c (1.328g, 3.64mmol) into the reaction flask, and then add diisopropylethylamine (1.167g, 9.09mmol) to the system mmol), add anhydrous dichloromethane (5mL) into the reaction system, stir at room temperature for two minutes and the system is completely dissolved, then add O-benzotriazole-N,N,N',N'-tetramethylurea tetra Fluoroboric acid (1.95g, 6.06mmol) was added into the reaction flask and stirred overnight at room temperature. Most of the solvent was spun off, applied to the column by wet method, and silica gel column chromatography gave white foamy solid intermediate S-10c (1.49 g, 49%).

Example 13: Deprotection of intermediate S-10c to obtain intermediate S-11c.

Take a 25mL eggplant-shaped bottle, add intermediate S-10c (1.02g, 1.01mmol), THF (10mL) and tetrabutylammonium fluoride trihydrate (0.945g, 3.03mmol) into the reaction bottle, and stir at room temperature for 4h After the reaction is complete, spin off the tetrahydrofuran in the system under reduced pressure, then add dichloromethane (20mL) and water (10mL) to the system, separate the layers, continue to wash the organic layer with water (10mL×2), wash the organic layer with anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and wet-loaded to the column to obtain intermediate S-11c (0.28g, 53%).

Example 14: Synthesis of Catalyst 1c.

Take a 25mL eggplant-shaped bottle, add intermediate S-11c (0.27g, 0.5mmol), anhydrous dichloromethane (10mL) and active manganese dioxide (0.26g, 3.0mmol) into the reaction bottle, stir at room temperature for 2h, After the reaction of the raw materials was complete, the system was filtered through a layer of diatomaceous earth and spin-dried to obtain catalyst S-1c (0.17 g, 60%).

Yellow solid; .[α] ²⁵ _D = -94.3 (c 0.38, CH ₂ Cl ₂ ); IR (KBr) 3313, 2962, 1666, 1616, 1508, 1424, 1207, 1006cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ )δ11.30(s,1H),9.41(s,1H),7.79(s,1H),7.52(d,J=8.0Hz,2H),7.41(d,J=8.0Hz,2H), 7.37(d, J=8.4Hz, 2H), 7.33(d, J=8.4Hz, 2H), 6.35(s, 1H), 5.28(dd, J=8.8, 8.0Hz, 1H), 3.32-3.22(m ,1H),3.06-2.96(m,1H),2.52(s,3H),2.22-2.02(m,2H),1.74-1.46(m,2H),1.36(s,9H),1.29(s,9H ); ¹³ C NMR (100MHz, CDCl ₃ ) δ196.7, 167.2, 153.4, 153.3, 150.9, 150.4, 142.1, 139.8, 136.9, 130.2, 127.3, 127.2, 125.0, 124.8, 118.6, 81.5, 69.5, 56.0, 3 ,31.5,31.4,30.6,24.3,19.0.

Example 15: Synthesis of Catalyst S-2c.

Take a 10mL eggplant-shaped bottle, add catalyst S-1c (0.076g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) to the reaction bottle, triethylchlorosilane ( 0.063g, 0.576mmol), and stirred at room temperature for 2h to complete the reaction. Add silica gel, spin off the solvent, apply to the column by dry method, and obtain catalyst S-2c (0.066g, 76%) by silica gel column chromatography.

Yellow liquid; [α] ²⁵ _D = -64.6 (c 0.71, CH ₂ Cl ₂ ); IR (KBr) 3427, 2982, 1741, 1640, 1387, 1191, 1093 cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11.32(s,1H),9.70(s,1H),7.88(s,1H),7.37(d,J＝8.8Hz,2H),7.33(d,J＝8.8Hz,2H),7.33-7.30 (m,4H),5.82(dd,J＝7.6,3.6Hz,1H),3.10-3.02(m,1H),2.84-2.74(m,1H),2.52(s,3H),2.34-2.20(m ,2H),1.72-1.52(m,2H),1.32(s,9H),1.29(s,9H),-0.17(s,9H); ¹³ C NMR(100MHz,CDCl ₃ )δ197.6,165.4,153.4, 152.7, 151.1, 150.7, 141.4, 141.2, 137.8, 131.2, 128.9, 128.3, 124.6, 124.4, 119.2, 84.8, 63.2, 50.2, 34.62, 34.61, 31.5, 27.3, 24.4, 19.0, 2.0.

Example 16: Intermediate 8 and Compound S-9d Synthesis of Intermediate S-10d.

Take a 25mL eggplant-shaped bottle, weigh Intermediate 8 (2g, 3.03mmol) and compound S-9d (1.12g, 3.64mmol) into the reaction flask, and then add diisopropylethylamine (1.167g, 9.09mmol) to the system mmol), add anhydrous dichloromethane (5mL) into the reaction system, stir at room temperature for two minutes and the system is completely dissolved, then add O-benzotriazole-N,N,N',N'-tetramethylurea tetra Fluoroboric acid (1.95g, 6.06mmol) was added into the reaction flask and stirred overnight at room temperature. Most of the solvent was spun off, applied to the column by wet method, and silica gel column chromatography gave white foamy solid intermediate S-10d (1.84 g, 54%).

Example 17: Deprotection of intermediate S-10d to obtain intermediate S-11d.

Take a 25mL eggplant-shaped bottle, add intermediate S-10d (0.96g, 1.01mmol), THF (10mL) and tetrabutylammonium fluoride trihydrate (0.945g, 3.03mmol) into the reaction bottle, and stir at room temperature for 4h After the reaction is complete, spin off the tetrahydrofuran in the system under reduced pressure, then add dichloromethane (20mL) and water (10mL) to the system, separate the layers, continue to wash the organic layer with water (10mL×2), wash the organic layer with anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and applied to the column by wet method to obtain intermediate S-11d (0.42g, 87%).

Example 18: Synthesis of Catalyst S-1d.

Take a 25mL eggplant-shaped bottle, add intermediate S-11d (0.24g, 0.5mmol), anhydrous dichloromethane (10mL) and active manganese dioxide (0.26g, 3.0mmol) into the reaction bottle, stir at room temperature for 2h, After the reaction of the raw materials was complete, the system was filtered through a diatomaceous earth layer, and the catalyst S-1d (0.14 g, 60%) was obtained by spinning to dryness.

Yellow solid; [α] ²⁵ _D = -67.0 (c 0.5, CH ₂ Cl ₂ ); IR (KBr) 3408, 2917, 1666, 1497, 1292, 1207, 1037cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11.31(s,1H),9.55(s,1H),7.85(s,1H),7.19(s,2H),7.06(s,2H),7.02(s,1H),6.91(s,1H) ,6.03(s,1H),5.32(dd,J＝8.0,6.8Hz,1H),3.32-3.18(m,1H),3.16-2.90(m,1H),2.53(s,3H),2.34(s ,6H),2.29(s,6H),2.22-1.98(m,2H),1.72-1.50(m,2H); ¹³ C NMR(100MHz,CDCl ₃ )δ197.8,167.1,153.5,153.2,145.0,143.0, 137.4, 136.8, 130.3, 129.3, 129.2, 125.4, 125.3, 118.7, 81.9, 68.6, 51.9, 30.1, 24.3, 21.6, 21.6, 18.9.

Example 19: Synthesis of Catalyst S-2d.

Take a 10mL eggplant-shaped bottle, add catalyst S-1d (0.068g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) to the reaction bottle, triethylchlorosilane ( 0.063g, 0.576mmol), stirred at room temperature for 2h to complete the reaction, added silica gel, spin off the solvent, put it on the column by dry method, and obtained the catalyst S-2d (0.038g, 49%) by silica gel column chromatography.

Yellow solid; [α] ²⁵ _D = -8.6 (c 0.74, CH ₂ Cl ₂ ); IR (KBr) 3421, 2956, 1664, 1642, 1385, 1247, 1111 cm ^-1 ; ¹ H NMR (600MHz, CDCl ₃ ) δ9.76(s,1H),7.95(s,1H),7.02(s,2H),7.01(s,2H),6.94(s,1H),6.90(s,1H),5.73(dd,J= 5.6,5.2Hz,1H),3.15-3.04(m,1H),2.90-2.80(m,1H),2.52(s,3H),2.30(s,6H),2.29(s,6H),2.34-2.20 (m,2H),1.72-1.52(m,2H),-0.13(s,9H); ¹³ C NMR(100MHz,CDCl ₃ )δ197.6,165.3,153.4,152.6,144.5,144.2,137.7,137.1,136.8, 131.1, 129.3, 129.0, 126.9, 126.5, 119.2, 85.1, 63.3, 50.3, 27.4, 24.3, 21.6, 18.9, 2.1.

Example 20: Intermediate 8 and Compound S-9e Synthesis of Intermediate S-10e.

Take a 25mL eggplant-shaped bottle, weigh Intermediate 8 (2g, 3.03mmol) and Compound S-9e (1.736g, 3.64mmol) into the reaction flask, and then add diisopropylethylamine (1.167g, 9.09mmol) to the system mmol), add anhydrous dichloromethane (5mL) into the reaction system, stir at room temperature for two minutes and the system is completely dissolved, then add O-benzotriazole-N,N,N',N'-tetramethylurea tetra Fluoroboric acid (1.95g, 6.06mmol) was added into the reaction flask and stirred overnight at room temperature. Most of the solvent was spun off, applied to the column by wet method, and silica gel column chromatography gave white foamy solid intermediate S-10e (2.07g, 61%).

Example 21: Deprotection of Intermediate S-10e to obtain Intermediate S-11e.

Take a 25mL eggplant-shaped bottle, add intermediate S-10e (1.13g, 1.01mmol), THF (10mL) and tetrabutylammonium fluoride trihydrate (0.945g, 3.03mmol) into the reaction bottle, and stir at room temperature for 4h After the reaction is complete, spin off the tetrahydrofuran in the system under reduced pressure, then add dichloromethane (20mL) and water (10mL) to the system, separate the layers, continue to wash the organic layer with water (10mL×2), wash the organic layer with anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and wet-loaded to the column to obtain intermediate S-11e (0.41g, 68%).

Example 22: Synthesis of Catalyst S-1e.

Take a 25mL eggplant-shaped bottle, add intermediate S-11e (0.32g, 0.5mmol), anhydrous dichloromethane (10mL) and active manganese dioxide (0.26g, 3.0mmol) into the reaction bottle, stir at room temperature for 2h, After the reaction of the raw materials was complete, the system was filtered through a diatomaceous earth layer, and the catalyst S-1e (0.22 g, 70%) was obtained by spinning to dryness.

Yellow solid; [α] ²⁵ _D = -48.5 (c 0.31, CH ₂ Cl ₂ ); IR (KBr) 3312, 2963, 1667, 1618, 1597, 1386, 1204, 1042 cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11.32(s,1H),8.93(s,1H),7.67(s,1H),7.50-7.44(m,3H),7.32(t,J＝1.6Hz,1H),7.28(d, J＝1.6Hz, 2H), 6.89(s, 1H), 5.28(t, J＝8.8Hz, 1H), 3.28-3.18(m, 1H), 3.05-2.94(m, 1H), 2.52(s, 3H ),2.20-1.96(m,2H),1.72-1.52(m,2H),1.30(s,18H),1.28(s,18H); ¹³ C NMR(100MHz,CDCl ₃ )δ196.8,167.0,153.3,153.2 ,150.1,150.0,144.0,141.2,136.7,130.2,122.4,121.8,121.5,121.4,118.4,82.4,71.5,52.2,35.1,35.0,31.7,31.6,24.3,19.0.

Example 23: Synthesis of Catalyst S-2e.

Take a 10mL eggplant-shaped bottle, add catalyst S-1e (0.092g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) into the reaction bottle, triethylchlorosilane ( 0.063g, 0.576mmol), and stirred at room temperature for 2h to complete the reaction. Add silica gel, spin off the solvent, apply to the column by dry method, and obtain catalyst S-2e (0.060g, 59%) by silica gel column chromatography.

Yellow solid; [α] ²⁵ _D = -43.1 (c 0.25, CH ₂ Cl ₂ ); IR (KBr) 3431, 2963, 1665, 1642, 1597, 1249, 1106, 1065 cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11.30(s,1H),9.42(s,1H),7.77(s,1H),7.36(t,J=1.6Hz,1H),7.33(t,J=1.6Hz,1H),7.29 (d,J=1.6Hz,1H),7.21(d,J=1.6Hz,2H),5.89(dd,J=8.4,2.0Hz,1H),3.14-3.04(m,1H),2.75-2.65( m,1H),2.51(s,3H),2.45-2.20(m,2H),1.75-1.55(m,2H),1.29(s,18H),1.28(s,18H),-0.19(s,9H ); ¹³ CNMR (100MHz, _CDCl3 ) 31.6, 27.6, 24.3, 19.0, 1.9.

Example 24: Intermediate 8 and Compound S-9f Synthesis of Intermediate S-10f.

Take a 25mL eggplant-shaped bottle, weigh Intermediate 8 (2g, 3.03mmol) and compound S-9f (2.03g, 3.64mmol) into the reaction flask, add Mukaiyama's reagent (1.5g, 6.06mmol) to the system, and then Triethylamine (0.918 g, 9.09 mmol) was added to the system, anhydrous dichloromethane (5 mL) was added to the reaction system, and stirred overnight at room temperature. Most of the solvent was spun off, applied to the column by wet method, and silica gel column chromatography gave white foamy solid intermediate S-10f (1.67 g, 46%).

Example 25: Deprotection of Intermediate S-10f to obtain Intermediate S-11f.

Take a 25mL eggplant-shaped bottle, add intermediate S-10f (1.21g, 1.01mmol), THF (10mL) and tetrabutylammonium fluoride trihydrate (0.945g, 3.03mmol) into the reaction bottle, and stir at room temperature for 4h After the reaction is complete, spin off the tetrahydrofuran in the system under reduced pressure, then add dichloromethane (20mL) and water (10mL) to the system, separate the layers, continue to wash the organic layer with water (10mL×2), wash the organic layer with anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and applied to the column by wet method to obtain intermediate S-11f (0.4g, 55%).

Example 26: Synthesis of Catalyst S-If.

Take a 25mL eggplant-shaped bottle, add intermediate S-11f (0.36g, 0.5mmol), anhydrous dichloromethane (10mL) and active manganese dioxide (0.26g, 3.0mmol) into the reaction bottle, stir at room temperature for 2h, After the reaction of the raw materials was complete, the system was filtered through a diatomaceous earth layer, and the catalyst S-1f (0.43 g, 60%) was obtained by spinning to dryness.

Yellow solid; [α] ²⁵ _D = -9.6 (c 0.56, CH ₂ Cl ₂ ); IR (KBr) 3277, 3034, 1734, 1665, 1595, 1497, 1242, 1230cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11.27(s,1H),9.33(s,1H),7.91(s,2H),7.86(s,1H),7.82-7.70(m,2H),7.70-7.55(m,9H), 7.49-7.32(m,13H),6.72(s,1H),5.49(t,J＝8.0Hz,1H),3.41-3.21(m,1H),3.15-2.97(m,1H),2.50(s, 3H),2.41-2.19(m,2H),1.81-1.52(m,2H); ¹³ C NMR(100MHz,CDCl ₃ )δ196.3,167.3,153.2,145.7,144.0,141.6,141.1,140.8,136.5,129.9, 128.9, 128.8, 127.7, 127.5, 127.3, 127.2, 126.0, 125.6, 125.1, 118.5, 82.1, 69.4, 52.0, 30.8, 24.3, 18.9.

Example 27: Synthesis of Catalyst S-2f.

Take a 10mL eggplant-shaped bottle, add catalyst S-1f (0.103g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) into the reaction bottle, triethylchlorosilane ( 0.063g, 0.576mmol), and stirred at room temperature for 2h to complete the reaction. Add silica gel, spin off the solvent, apply to the column by dry method, and obtain catalyst S-2f (0.049g, 43%) by silica gel column chromatography.

Yellow solid; [α] ²⁵ _D ＝54.0(c 0.53, CH ₂ Cl ₂ ); IR (KBr) 3058, 2954, 1664, 1640, 1595, 1452, 1068 cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11 .22(s,1H),9.40(s,1H),7.80-7.73(m,5H),7.72-7.64(m,6H),7.62-7.56(m,4H),7.50-7.41(m,8H) ,7.40-7.32(m,4H),6.11(dd,J＝8.4,2.0Hz,1H),3.30-3.10(m,2H),2.65-2.45(m,2H),2.47(s,3H),1.90 -1.75(m,2H),0.02(s,9H); ¹³ C NMR(100MHz,CDCl ₃ )δ197.1,165.3,153.3,152.6,145.7,145.3,141.7,141.3,141.0,140.9,137.2,130.7,129.0, 128.9, 127.8, 127.5, 127.3, 127.0, 126.2, 126.1, 125.7, 119.1, 85.9, 63.3, 50.1, 27.8, 24.5, 18.9, 2.3.

Example 28: Compound S-10g was synthesized from Intermediate 8 and Compound S-9g.

Take a 25mL eggplant-shaped bottle, weigh Intermediate 8 (2g, 3.03mmol) and Compound S-9g (1.892g, 3.64mmol) into the reaction flask, add Mukaiyama's reagent (1.5g, 6.06mmol) to the system, and then Triethylamine (0.918 g, 9.09 mmol) was added to the system, anhydrous dichloromethane (5 mL) was added to the reaction system, and stirred overnight at room temperature. Most of the solvent was spun off, applied to the column by wet method, and silica gel column chromatography gave white foamy solid intermediate S-10g (1.8g, 51%).

Example 29: Deprotection of Intermediate S-10g to obtain Intermediate S-11g.

Take a 25mL eggplant-shaped bottle, add intermediate S-10g (1.173g, 1.01mmol), THF (10mL) and tetrabutylammonium fluoride trihydrate (0.945g, 3.03mmol) into the reaction bottle, and stir at room temperature for 4h After the reaction is complete, spin off the tetrahydrofuran in the system under reduced pressure, then add dichloromethane (20mL) and water (10mL) to the system, separate the layers, continue to wash the organic layer with water (10mL×2), wash the organic layer with anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and applied to the column by wet method to obtain intermediate S-11g (0.33g, 48%).

Example 30: Synthesis of Catalyst S-1g.

Take a 25mL eggplant-shaped bottle, add intermediate S-11g (0.34g, 0.5mmol), anhydrous dichloromethane (10mL) and active manganese dioxide (0.26g, 3.0mmol) to the reaction bottle, stir at room temperature for 2h, After the reaction of the raw materials was complete, the system was filtered through a layer of diatomaceous earth and spin-dried to obtain catalyst S-1g (0.22g, 61%).

Yellow solid; [α] ²⁵ _D = +4.3 (c 0.63, CH ₂ Cl ₂ ); IR (KBr) 3300, 3023, 2917, 1735, 1666, 1593, 1241, 1037cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) 11.30(s,1H),9.33(s,1H),7.85(s,2H),7.82(s,1H),7.80(s,1H),7.76(s,2H),7.71(s,1H) ,7.32-7.18(m,8H),7.00(s,4H),6.73(s,1H),5.48(t,J＝8.0Hz,1H),3.40-3.25(m,1H),3.15-2.98(m ,1H),2.51(s,3H),2.45-2.15(m,26H),1.80-1.52(m,2H);δ ¹³ C NMR(100MHz,CDCl ₃ )δ196.4,167.4,153.4,153.2,145.5,143.5 ,141.8,141.8,141.3,141.1,138.4,138.3,136.6,130.1,129.3,129.2,126.1,125.6,125.3,125.1,118.6,82.2,69.8,52.1,31.0,24.4,21.5,29.4,

Example 31: Intermediate 8 and Compound S-9h Synthesis of Intermediate S-10h.

Take a 25mL eggplant-shaped bottle, weigh intermediate 8 (2g, 3.03mmol) and compound S-9h (1.284g, 3.64mmol) into the reaction flask, and then add diisopropylethylamine (1.167g, 9.09mmol) to the system mmol), add anhydrous dichloromethane (5mL) into the reaction system, stir at room temperature for two minutes and the system is completely dissolved, then add O-benzotriazole-N,N,N',N'-tetramethylurea tetra Fluoroboric acid (1.95g, 6.06mmol) was added into the reaction flask and stirred overnight at room temperature. Most of the solvent was spun off, applied to the column by wet method, and silica gel column chromatography gave white foamy solid intermediate S-10h (1.3 g, 43%).

Example 32: Deprotection of intermediate S-10h yields intermediate S-11h.

Take a 25mL eggplant-shaped bottle, add intermediate S-10h (1.0g, 1.01mmol), THF (10mL) and tetrabutylammonium fluoride trihydrate (0.945g, 3.03mmol) into the reaction bottle, and stir at room temperature for 4h After the reaction is complete, spin off the tetrahydrofuran in the system under reduced pressure, then add dichloromethane (20mL) and water (10mL) to the system, separate the layers, continue to wash the organic layer with water (10mL×2), wash the organic layer with anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and applied to the column by wet method to obtain intermediate S-11h (0.29g, 56%).

Example 33: Synthesis of Catalyst S-1h.

Take a 25mL eggplant-shaped bottle, add intermediate S-11h (0.26g, 0.5mmol), anhydrous dichloromethane (10mL) and active manganese dioxide (0.26g, 3.0mmol) into the reaction bottle, stir at room temperature for 2h, After the reaction of the raw materials was complete, the system was filtered through a diatomaceous earth layer, and the catalyst S-1h (0.18g, 70%) was obtained by spinning to dryness.

Yellow solid; [α] ²⁵ _D = -85.3 (c 0.38, CH ₂ Cl ₂ ); IR(KBr) 3285, 3055, 1733, 1666, 1612, 1242, 1037cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11.24(s,1H),9.63(s,1H),8.19(s,1H),7.95-7.7.73(m,8H),7.72-7.60(m,2H),7.60-7.7.42(m ,4H),6.35(s,1H),5.59(t,J=7.8Hz,1H),3.35-3.20(m,1H),3.12-2.93(m,1H),2.50(s,3H),2.40- 2.32(m,2H),1.75-1.45(m,2H).

Example 34: Catalyst S-1f Catalyst S-2g was synthesized.

Take a 10mL eggplant-shaped bottle, add catalyst S-1f (0.104g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) into the reaction bottle, triethylsilyltri Fluoromethanesulfonate (0.152g, 0.576mmol) was stirred at room temperature for 2h to complete the reaction. Silica gel was added, the solvent was spun off, the column was dry-loaded, and catalyst S-2g (0.082g, 81%) was obtained by silica gel column chromatography.

Yellow solid; [α] ²⁵ _D ＝+13.0(c 0.50, CH ₂ Cl ₂ ); IR(KBr) 3059, 2953, 1664, 1640, 1594, 1383, 1010cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11.25(s,1H),9.68(s,1H),7.83-7.72(m,7H),7.67(d,J=7.6Hz,4H),7.61(d,J=7.6Hz,4H),7.50 -7.41(m,8H),7.40-7.33(m,4H),6.08(dd,J＝8.4,2.0Hz,1H),3.25-3.15(m,1H),3.04-2.93(m,1H),2.64 -2.50(m,1H),2.47(s,3H),2.48-2.36(m,1H),1.80-1.65(m,2H),0.88(t,J＝8.0Hz,9H),0.55-0.35(m ,6H); ¹³ CNMR (100MHz, CDCl ₃ ) δ197.1, 165.8, 153.4, 152.7, 145.35, 145.33, 141.4, 141.2, 141.0, 140.9, 137.5, 130.8, 129.03, 128.96, 127.7, 1271.4, 127.6, 12 126.5, 126.0, 125.8, 119.1, 85.1, 63.7, 50.4, 27.6, 24.5, 18.9, 7.5, 6.7.

Example 35: Catalyst S-1f Catalyst S-2h was synthesized.

Take a 10mL eggplant-shaped bottle, and add catalyst S-1f (0.104g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) to the reaction bottle, and tri-n-butylsilyl Trifluoromethanesulfonate (0.20g, 0.576mmol) was stirred at room temperature for 2h to complete the reaction. Silica gel was added, the solvent was spun off, the column was dry-loaded, and catalyst S-2h (0.070g, 63%) was obtained by silica gel column chromatography.

Yellow solid; [α] ²⁵ _D = -74.4 (c 0.25, CH ₂ Cl ₂ ); IR (KBr) 3292, 3055, 1665, 1612, 1505, 1385, 1242, 1036 cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11.25(s,1H),9.58(s,1H),7.83-7.71(m,7H),7.68(d,J＝7.6Hz,4H),7.60(d,J＝7.6Hz,4H) ,7.50-7.41(m,8H),7.40-7.32(m,4H),6.07(dd,J＝8.8,2.4Hz,1H),3.27-3.17(m,1H),3.09-3.00(m,1H) ,2.64-2.54(m,1H),2.47(s,3H),2.48-2.36(m,1H),1.84-1.72(m,2H),1.26-1.06(m,12H),0.71(t,J= 7.2Hz,9H),0.55-0.35(m,6H); ¹³ C NMR(100MHz,CDCl ₃ )δ197.1,165.6,153.4,152.7,145.6,145.5,141.6,141.3,141.0,137.5,130.7,129.0,128.9, 127.7, 127.6, 127.5, 127.3, 126.5, 126.0, 125.6, 119.2, 85.1, 63.6, 50.3, 27.7, 26.8, 26.1, 24.6, 18.9, 15.8, 13.7.

Example 36: Catalyst S-1g Catalyst S-2i was synthesized.

Take a 10mL eggplant-shaped bottle, add catalyst S-1g (0.098g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) to the reaction bottle, triethylchlorosilane ( 0.063g, 0.576mmol), stirred at room temperature for 2h to complete the reaction, added silica gel, spin off the solvent, put it on the column by dry method, and obtained the catalyst S-2i (0.060g, 55%) by silica gel column chromatography.

White solid; IR(KBr)3424,2952,2919,1665,1640,1593,1383,1250,1070cm ^-1 ; ¹ HNMR(400MHz, CDCl ₃ )11.27(s,1H),9.55(s,1H),7.88 (s,1H),7.75-7.65(m,3H),7.67(s,1H),7.63(s,2H),7.26(s,4H),7.20(s,4H),7.00(s,2H), 6.99(s,2H),6.08(dd,J＝8.0,3.2Hz,1H),3.29-3.17(m,1H),3.15-3.05(m,1H),2.48(s,3H),2.45-2.25( m,26H),1.85-1.67(m,2H),0.01(s,9H); ¹³ C NMR(100MHz,CDCl ₃ )δ197.2,165.6,153.4,152.6,145.1,145.0,141.7,141.6,141.3,141.2, 138.5, 138.4, 137.5, 130.9, 129.3, 129.1, 126.9, 126.5, 126.2, 125.9, 125.5, 125.4, 125.3, 119.2, 85.8, 63.5, 50.3, 27.8, 24.5, 21.5, 18.9, 2.3.

Example 37: Catalyst S-1g Catalyst S-2j was synthesized.

Take a 10mL eggplant-shaped bottle, add catalyst S-1g (0.098g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) into the reaction bottle, triethylsilyltri Fluoromethanesulfonate (0.152g, 0.576mmol) was stirred at room temperature for 2h to complete the reaction. Silica gel was added, the solvent was spun off, the column was dry-loaded, and catalyst S-2j (0.083g, 87%) was obtained by silica gel column chromatography.

Yellow solid; [α] ²⁵ _D = +4.6 (c 0.60, CH ₂ Cl ₂ ); IR (KBr) 3024, 2953, 1665, 1641, 1593, 1410, 1382, 1240cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ11.29(s,1H),9.77(s,1H),7.89(s,1H),7.78-7.65(m,6H),7.26(s,4H),7.22(s,4H),7.00( s,2H),6.99(s,2H),6.06(d,J＝6.8Hz,1H),3.24-3.15(m,1H),2.96-2.85(m,1H),2.48(s,3H),2.54 -2.25(m,26H),1.75-1.55(m,2H),0.90(t,J＝7.6Hz,9H),0.58-0.30(m,6H); ¹³ C NMR(100MHz,CDCl ₃ )δ197.2,166.0 ,153.4,152.7,144.9,144.8,141.5,141.4,141.3,141.2,138.5,138.4,137.7,130.9,129.3,129.2,127.0,126.7,126.1,125.9,125.6,120.3,38.5,119.2,119.3 ,24.5,21.5,19.0,7.6,6.8.

Example 38: Catalyst S-1h Catalyst S-2k was synthesized.

Take a 10mL eggplant-shaped bottle, add catalyst S-1h (0.074g, 0.144mmol), anhydrous dichloromethane (2mL) and triethylamine (0.087g, 0.864mmol) to the reaction bottle, triethylchlorosilane ( 0.063g, 0.576mmol), and stirred at room temperature for 2h to complete the reaction. Add silica gel, spin off the solvent, apply to the column by dry method, and obtain catalyst S-2k (0.061g, 72%) by silica gel column chromatography.

Yellow solid; IR(KBr)3425,2955,1664,1640,1385,1247,1072cm ^-1 ; ¹ H NMR(400MHz,CDCl ₃ )δ11.26(s,1H),9.87(s,1H),8.10( s,1H),8.04(s,1H),7.95(s,1H),7.93-7.70(m,6H),7.60-7.35(m,6H),6.05(t,J＝6.0Hz,1H),3.20 -3.09(m,1H),3.00-2.85(m,1H),2.55-2.41(m,5H),1.77-1.60(m,2H); ¹³ C NMR(100MHz,CDCl ₃ )δ197.3,165.7,153.5, 152.9, 142.0, 141.5, 137.8, 132.9, 132.8, 132.7, 132.6, 130.8, 128.6, 128.4, 127.9, 127.8, 127.7, 127.6, 127.1, 126.9, 126.7, 126.5, 126.4, 113, 525, 0.6, 3 24.5, 19.0, 2.3.

Example 39: Catalytic synthesis of α-amino acid 4a by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3a (0.046g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4a (0.039g, 86%) was obtained. The ee value of α-amino acid 4a was obtained by analyzing its carboxymethyl ester by HPLC, and the ee value was 80%.

White solid; IR(KBr) 3405, 1593, 1510, 1396cm ^-1 ; ¹ H NMR (400MHz, D ₂ O) δ7.88(d, J=8.4Hz, 1H), 7.71(d, J=7.6Hz, 1H), 7.57(d, J=7.6Hz, 1H), 7.44-7.28(m, 2H), 7.27-7.16(m, 2H), 3.11(dd, J=7.6, 6.0Hz, 1H), 2.85(t ,J＝8.4Hz,2H),1.82-1.61(m,2H).

Example 40: Catalytic synthesis of α-amino acid 4b by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh ketoacid 3b (0.036g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4b (0.024g, 67%) was obtained. The ee value of α-amino acid 4b was obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value was 70%.

White solid; [α] ²⁵ _D ＝+33.2(c 0.26,1N HCl)IR(KBr)3431,3026,1582,1521,1409,cm ^-1 ; ¹ H NMR(400MHz,D ₂ O)δ7.27( dd,J=7.6,7.2Hz,2H),7.21(d,J=7.6Hz,2H),7.16(t,J=7.2Hz,1H),3.16(dd,J=6.4,6.0Hz,1H), 2.60-2.50(m,2H),1.88-1.66(m,2H); ¹³ CNMR(100MHz,D ₂ O)δ183.6,142.7,129.0,128.8,126.3,56.1,37.1,31.8.

Example 41: Catalytic synthesis of α-amino acid 4c by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3c (0.051g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4c (0.021 g, 42%) was obtained. The ee value of α-amino acid 4c was obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value was 70%.

White solid; IR(KBr)3432,3057,1668,1566,1009cm ^-1 ; ¹ H NMR(400MHz,D ₂ O)δ7.45-7.16(m,8H),7.14(d,J＝7.2Hz,1H ), 2.95 (dd, J＝6.4, 6.0Hz, 1H), 2.58-2.42 (m, 2H), 1.68-1.45 (m, 2H); ¹³ C NMR (100MHz, D ₂ O) δ183.1, 141.9, 141.6, 139.9, 130.3, 130.0, 129.5, 128.7, 128.2, 127.5, 126.5, 56.1, 37.0, 29.1.

Example 42: Catalytic synthesis of α-amino acid 4d by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh ketoacid 3d (0.044g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4d (0.031g, 70%) was obtained. The ee value of α-amino acid 4d was obtained by analyzing its carboxymethyl ester and amino 2-naphthoylated derivatives by HPLC, and the ee value was 74%.

White solid; IR(KBr)3428,3117,1613,1574,1403cm ^-1 ; ¹ H NMR(600MHz,D ₂ O)δ6.80(s,2H),3.20(dd,J＝6.6,6.0Hz,1H ),2.54-2.42(m,2H),2.13(s,6H),2.08(s,3H),1.58-1.46(m,2H); ¹³ C NMR(100MHz,D ₂ O)δ183.3,136.9,136.2, 136.1, 129.0, 56.7, 34.4, 25.1, 20.1, 18.9.

Example 43: Catalytic synthesis of α-amino acid 4e by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3e (0.037g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4e (0.012g, 29%) was obtained. The ee value of α-amino acid 4e was obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value was 66%.

White solid; IR(KBr)2918,1582,1514,1411,1353cm ^-1 ; ¹ H NMR(600MHz,D ₂ O)δ3.08(dd,J＝6.6,6.0Hz,1H),1.50-1.35(m ,2H),1.24-1.08(m,12H),0.73(t,J=6.6Hz,3H); ¹³ C NMR(150MHz,D ₂ O)δ183.9,56.0,34.7,31.1,28.7,28.5,28.4 , 24.9, 22.0, 13.4.

Example 44: Catalytic synthesis of α-amino acid 4f by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3f (0.046g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4f (0.035g, 76%) was obtained. The ee value of α-amino acid 4f was obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value was 73%.

White solid; IR(KBr)3432,2143,1582,1507,1320cm ^-1 ; ¹ H NMR(400MHz,D ₂ O)δ7.85-7.75(m,3H),7.68(s,1H),7.48-7.35 (m,3H),3.19(dd,J＝6.8,6.0Hz,1H),2.78-2.66(m,2H),1.96-1.75(m,2H); ¹³ C NMR(100MHz,D ₂ O)δ183. 6,140.4,133.6,131.9,128.3,127.89,127.86,127.7,126.6,126.5,125.8,56.1,36.9,31.9.

Example 45: Catalytic synthesis of α-amino acid 4g by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3g (0.026g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4g (0.010g, 38%) was obtained. The ee value of α-amino acid 4g is obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value is 66%.

White solid; [α] ²⁵ _D ＝+16.0(c 0.095,1N HCl)IR(KBr)3423,2954,1586,1411cm ^-1 ; ¹ H NMR(400MHz,D ₂ O)δ3.10(dd,J＝ 8.4,6.0Hz,1H),1.56-1.44(m,1H),1.35-1.16(m,2H),0.76(d,J=6.4Hz,3H),0.74(d,J=6.8Hz,3H); ¹³ C NMR (150MHz, D ₂ O) δ184.4, 54.5, 44.2, 24.3, 22.4, 21.3.

Example 46: Catalytic synthesis of α-amino acid 4h by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3h (0.034g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4h (0.023g, 67%) was obtained. The ee value of α-amino acid 4h is obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value is 66%.

White solid; [α] ²⁵ _D ＝+5.8(c 0.37,1N HCl)IR(KBr)3104,2594,1586,1340cm ^-1 ; ¹ H NMR(400MHz,D ₂ O)δ3.20(dd,J＝ 8.0,6.0Hz,1H),1.70-1.49(m,5H),1.45-1.35(m,1H),1.35-1.24(m,2H),1.24-1.00(m,3H),0.94-0.75(m, 2H); ¹³ C NMR (150MHz, D ₂ O) δ 184.5, 53.8, 42.7, 33.8, 33.4, 32.2, 26.1, 25.8, 25.7.

Example 47: Catalytic synthesis of α-amino acid 4i by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3i (0.032g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4i (0.017g, 52%) was obtained. The ee value of α-amino acid 4i was obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value was 78%.

White solid; [α] ²⁵ _D ＝-2.9(c 0.27,1N HCl)IR(KBr)3423,2964,1583,1407,1324cm ^-1 ; ¹ H NMR(400MHz,D ₂ O)δ3.17(dd, J＝7.6, 6.4Hz, 1H), 1.50-1.40(m, 1H), 1.35-1.15(m, 6H), 0.80-0.65(t, J＝7.2Hz, 6H); ¹³ C NMR (150MHz, D ₂ O) δ184.4, 54.5, 38.8, 36.4, 25.0, 24.3, 9.9, 9.7.

Example 48: Catalytic synthesis of α-amino acid 4j by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3j (0.037g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4j (0.019g, 51%) was obtained. The ee value of α-amino acid 4j was obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value was 76%.

White solid; [α] ²⁵ _D ＝+3.9(c 0.33,1N HCl)IR(KBr)3393,2955,1667,1608,1400,1125cm ^-1 ; ¹ H NMR(400MHz,D ₂ O)δ3.22( dd, J＝7.6, 6.4Hz, 1H), 1.55-1.45(m, 1H), 1.45-1.15(m, 10H), 0.90-0.75(t, J＝6.8Hz, 6H); ¹³ C NMR (100MHz, D ₂ O) δ184.7, 54.9, 40.1, 35.9, 35.2, 33.4, 21.5, 19.2, 19.0, 14.01, 14.00.

Example 49: Catalytic synthesis of α-amino acid 4k by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3k (0.051g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4k (0.037g, 73%) was obtained. The ee value of α-amino acid 4k is obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value is 78%.

White solid; [α] ²⁵ _D ＝+12.6(c 0.19,1N HCl)IR(KBr)3474,2637,1602,1351,1157cm ^-1 ; ¹ H NMR(400MHz,D ₂ O)δ7.37-7.22( m,8H),7.20-7.12(m,2H),4.04(dd,J＝8.0,7.6Hz,1H),2.95(dd,J＝8.0,5.6Hz,1H),2.45-2.32(m,1H) ,2.15-2.00(m,1H); ¹³ C NMR (100MHz, D ₂ O) δ183.4, 145.4, 144.7, 129.19, 129.15.

Example 50: Catalytic synthesis of α-amino acid 4l by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3l (0.029g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4l (0.011g, 37%) was obtained. The ee value of α-amino acid 4l was obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value was 67%.

White solid; [α] ²⁵ _D ＝+6.0(c 0.22,1N HCl)IR(KBr)3393,2957,1505,1582,1277cm ^-1 ; ¹ H NMR(400MHz,D ₂ O)δ3.18(dd, J=6.4,6.0Hz,1H),1.56-1.44(m,1H),1.35-1.16(m,2H),0.76(d,J=6.4Hz,3H),0.74(d,J=6.8Hz,3H ); ¹³ C NMR (150MHz, D ₂ O) δ 184.4, 54.5, 44.2, 24.3, 22.4, 21.3.

Example 51: Catalytic synthesis of α-amino acid 4n by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3n (0.037g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4n (0.023g, 61%) was obtained. The ee value of α-amino acid 4n was obtained by analyzing its carboxymethyl ester and aminobenzoylated derivatives by HPLC, and the ee value was 79%.

White solid; [α] ²⁵ _D ＝+1.0(c 0.27,1N HCl)IR(KBr)3424,2929,1605,1405cm ^-1 ; ¹ H NMR(400MHz,D ₂ O)δ3.17(dd,J＝ 6.8,6.4Hz,1H),1.52-1.38(m,1H),1.35-1.14(m,10H),0.85-0.71(m,6H); ¹³ C NMR(150MHz,D ₂ O)δ184.7,184.6,54.91 ,54.88,39.7,39.6,35.3,35.2,32.6,32.0,28.3,28.1,25.9,25.1,22.7,13.74,13.73,10.2,10.0.

Example 52: Catalytic synthesis of α-amino acid 4m by chiral pyridoxal catalyst S-2g.

Take a 5mL reaction bottle, weigh keto acid 3m (0.054g, 0.20mmol), chiral pyridoxal catalyst S-2g (0.017g, 0.020mmol), 2,2-diphenylglycine 12a ( 0.050g, 0.22mmol), then add THF (1.4mL) and water (0.6mL) into the bottle, add a magnet, stopper the bottle, and place it in a constant temperature oil bath at 20°C for 3 days. Stop the reaction, transfer the reactant in the bottle to a 25mL eggplant-shaped bottle, add 10mL of methanol to dissolve all the solids in the bottle, then add silica gel (0.2g), spin off the solvent at room temperature, put it on the column by dry method, and perform silica gel column chromatography The product α-amino acid 4m (0.042g, 77%) was obtained. The ee value of the α-amino acid 4m was determined by 1H NMR analysis, and the ee value was 92%.

White solid; IR (KBr) 3405, 1606, 1584, 1028cm ^-1 ; ¹ H NMR (400MHz, D ₂ O) δ7.78 (dd, J = 9.0, 4.2Hz, 2H), 7.70 (s, 1H), 7.44(d,J=8.4Hz,1H),7.29(s,1H),7.16(dd,J=9.0,1.8Hz,1H),3.89(s,3H),3.15-2.90(m,2H),2.80 -1.98(m,1H),1.80-1.71(m,1H),1.35-1.24(d,J＝7.2Hz,3H); ¹³ C NMR(150MHz,D ₂ O)δ182.0,155.2,141.1,131.7,127.9 ,127.7,126.0,125.1,123.8,116.9,140.8,53.9,53.4,42.2,35.0,21.1.

Example 53:

The catalyst of this embodiment has the structure shown in general formula S-1, R-1, S-2 and R-2:

Wherein, R ¹ and R ² are methyl and ethyl;

R ³ and R ⁴ are n-propyl, Wherein, R ^x and R ^x' are methoxy and n-propyl;

R ⁵ is Wherein R ^x and R ^x' are tert-butyl or phenyl.

During synthesis, specifically include the following steps:

(1) In the organic solvent, add pyridoxine hydrochloride 5 and alkali, then drop tert-butyldiphenylchlorosilane, wherein, the molar ratio of pyridoxine hydrochloride 5 to alkali, tert-butyldiphenylchlorosilane 1:3:1, stirring the reaction, controlling the reaction temperature to -20°C, and the reaction time is 1h, the intermediate 6 is obtained;

(2) In an organic solvent, according to the molar ratio of intermediate 6 and oxidizing agent as 1:5, add intermediate 6 and oxidizing agent, stir and react, control the reaction temperature at 0°C, and the reaction time is 24h. Intermediate 6 is oxidized to produce Intermediate 7 was obtained;

(3) In an organic solvent, according to the molar ratio of intermediate 7 and oxidant as 1:5, add intermediate 7 and oxidant, stir and react, control the reaction temperature to 0°C, and the reaction time is 24h. Intermediate 7 is further Oxidation produced intermediate 8;

(4) In an organic solvent, according to the molar ratio of intermediate 8, compound 9, and condensing agent as 1:5:5, add intermediate 8, compound 9, and condensing agent, stir and react, control the reaction temperature to 0°C, and react The time is 24h, and intermediate 10 is obtained;

(5) In an organic solvent, according to the molar ratio of intermediate 10 and tetrabutylammonium fluoride as 1:5, add intermediate 10 and tetrabutylammonium fluoride, stir and react, control the reaction temperature to 0°C, and react The time is 48h, the intermediate 10 removes tert-butyldiphenylsilane, and the intermediate 11 is obtained;

(6) In an organic solvent, according to the molar ratio of intermediate 11 and oxidant as 1:20, add intermediate 11 and oxidant, stir and react, control the reaction temperature at 0°C, and the reaction time is 48h, intermediate 11 is oxidized to produce Obtained chiral catalyst S-1 or R-1;

(7) In an organic solvent, according to the molar ratio of chiral catalyst S-1 or R-1 to R ⁵ X and base is 1:5:3, add chiral catalyst S-1 or R-1, R ⁵ X And alkali, stirring and reacting, controlling the reaction temperature to 0°C, and the reaction time to 24h, the chiral catalyst S-2 or R-2 is obtained.

Wherein, pyridoxine hydrochloride 5, intermediate 6, intermediate 7 and intermediate 8 have the structures shown in general formulas 5, 6, 7 and 8:

Wherein, R ¹ and R ² are methyl or ethyl.

Compound 9 has the structure shown in general formula S-9, R-9:

When compound 9 is S-9, intermediates 10 and 11 have the structures shown in general formulas S-10 and S-11 respectively:

When compound 9 is R-9, intermediates 10 and 11 have the structures shown in general formulas R-10 and R-11 respectively:

Among them, R ¹ and R ² are methyl and ethyl, R ³ and R ⁴ are n-propyl, Among them, R ^x and R ^x' are methoxy and n-propyl.

And in R ⁵ X, R ⁵ is Wherein R ^x and R ^x' are tert-butyl or phenyl, and X is Cl.

The organic solvent is a mixed solvent of dimethyl sulfoxide and N-methylpyrrolidone with a mass ratio of 1:1, the alkali is sodium hydroxide, sodium carbonate and sodium hydride, the oxidizing agent is DCC, and the condensing agent is EDDQ.

Example 54:

The catalyst of this embodiment has the structure shown in general formula S-1, R-1, S-2 and R-2:

Wherein, R ¹ and R ² are isopropyl and cyclopentyl;

R ³ and R ⁴ are cyclohexyl, Wherein, R ^x and R ^x' are tert-butyl and benzyl;

R ⁵ is Wherein R ^y , R ^y' and R ^y" are n-butyl, cycloheptyl, (1-phenyl)ethyl.

During synthesis, specifically include the following steps:

(1) In the organic solvent, add pyridoxine hydrochloride 5 and alkali, then drop tert-butyldiphenylchlorosilane, wherein, the molar ratio of pyridoxine hydrochloride 5 to alkali, tert-butyldiphenylchlorosilane 1:6:5, stirring the reaction, controlling the reaction temperature to -50°C, and the reaction time is 24h, the intermediate 6 is obtained;

(2) In an organic solvent, according to the molar ratio of intermediate 6 and oxidizing agent as 1:3, add intermediate 6 and oxidizing agent, stir and react, control the reaction temperature at 100°C, and the reaction time is 1h, intermediate 6 is oxidized to produce Intermediate 7 was obtained;

(3) In an organic solvent, according to the molar ratio of intermediate 7 and oxidant as 1:3, add intermediate 7 and oxidant, stir and react, control the reaction temperature to 100°C, and the reaction time is 1h. Intermediate 7 is further Oxidation produced intermediate 8;

(4) In an organic solvent, according to the molar ratio of intermediate 8, compound 9, and condensing agent as 1:3:3, add intermediate 8, compound 9, and condensing agent, stir and react, control the reaction temperature to 100°C, and react The time is 1h, and intermediate 10 is obtained;

(5) In an organic solvent, according to the molar ratio of intermediate 10 and tetrabutylammonium fluoride as 1:3, add intermediate 10 and tetrabutylammonium fluoride, stir and react, control the reaction temperature to 100°C, and react The time is 1 h, and the intermediate 10 is desorbed from tert-butyldiphenylsilane to obtain the intermediate 11;

(6) In an organic solvent, according to the molar ratio of intermediate 11 and oxidizing agent as 1:20, add intermediate 11 and oxidizing agent, stir and react, control the reaction temperature to 100°C, and the reaction time is 1h. Intermediate 11 is oxidized to produce Obtained chiral catalyst S-1 or R-1;

(7) In an organic solvent, according to the molar ratio of chiral catalyst S-1 or R-1 to R ⁵ X and base is 1:1:6, add chiral catalyst S-1 or R-1, R ⁵ X and alkali, stirring and reacting, controlling the reaction temperature to 100°C, and the reaction time to 1h, that is, the chiral catalyst S-2 or R-2 is obtained.

Wherein, pyridoxine hydrochloride 5, intermediate 6, intermediate 7 and intermediate 8 have the structures shown in general formulas 5, 6, 7 and 8:

Wherein, R ¹ and R ² are isopropyl and cyclopentyl.

Compound 9 has the structure shown in general formula S-9, R-9:

When compound 9 is S-9, intermediates 10 and 11 have the structures shown in general formulas S-10 and S-11 respectively:

When compound 9 is R-9, intermediates 10 and 11 have the structures shown in general formulas R-10 and R-11 respectively:

Wherein, R ¹ and R ² are isopropyl and cyclopentyl;

R ³ and R ⁴ are cyclohexyl, Among them, R ^x and R ^x' are tert-butyl or benzyl.

And in R ⁵ X, R ⁵ is Wherein R ^y , R ^y' and R ^y" are n-butyl, cycloheptyl, (1-phenyl) ethyl, and X is F.

The organic solvent is a mixed solvent of dichloromethane, xylene, N,N-dimethylformamide and isopropanol, and the base is N,N-diethylaniline, 1,4-diazabicyclooctane and 1-methylpiperidine, the oxidizing agent is sodium perchlorate, and the condensing agent is EDCI.

Example 55:

The catalyst of this embodiment has the structure shown in general formula S-1, R-1, S-2 and R-2:

Wherein, R ¹ and R ² are benzyl, (1-phenyl) ethyl;

R ³ and R ⁴ are tert-butyl, Wherein, R ^x and R ^x' are ethoxy and 2-naphthyl;

R ⁵ is Wherein R ^y , R ^y' and R ^y" are tert-butyl, isopropyl and 1-naphthyl.

During synthesis, specifically include the following steps:

(1) In the organic solvent, add pyridoxine hydrochloride 5 and alkali, then drop tert-butyldiphenylchlorosilane, wherein, the molar ratio of pyridoxine hydrochloride 5 to alkali, tert-butyldiphenylchlorosilane 1:4:3, stirring the reaction, controlling the reaction temperature to -30°C, and the reaction time is 12h, the intermediate 6 is obtained;

(2) In an organic solvent, according to the molar ratio of intermediate 6 and oxidizing agent as 1:1, add intermediate 6 and oxidizing agent, stir and react, control the reaction temperature at 60°C, and the reaction time is 12h. Intermediate 6 is oxidized to produce Intermediate 7 was obtained;

(3) In an organic solvent, according to the molar ratio of intermediate 7 and oxidizing agent as 1:1, add intermediate 7 and oxidizing agent, stir and react, control the reaction temperature at 60°C, and the reaction time is 12h. Intermediate 7 is further processed Oxidation produced intermediate 8;

(4) In an organic solvent, according to the molar ratio of intermediate 8, compound 9, and condensing agent as 1:2:4, add intermediate 8, compound 9, and condensing agent, stir and react, control the reaction temperature to 60°C, and react The time is 12h, and intermediate 10 is obtained;

(5) In an organic solvent, according to the molar ratio of intermediate 10 and tetrabutylammonium fluoride as 1:1, add intermediate 10 and tetrabutylammonium fluoride, stir and react, control the reaction temperature to 60°C, and react The time is 12 hours, and the intermediate 10 is desorbed from tert-butyldiphenylsilane to obtain the intermediate 11;

(6) In an organic solvent, according to the molar ratio of intermediate 11 and oxidizing agent as 1:1, add intermediate 11 and oxidizing agent, stir and react, control the reaction temperature at 60°C, and the reaction time is 12h, intermediate 11 is oxidized to produce Obtained chiral catalyst S-1 or R-1;

(7) In an organic solvent, according to the molar ratio of chiral catalyst S-1 or R-1 to R ⁵ X and base is 1:5:3, add chiral catalyst S-1 or R-1, R ⁵ X And alkali, stirring and reacting, controlling the reaction temperature to 60°C, and the reaction time to 12h, the chiral catalyst S-2 or R-2 is obtained.

Wherein, pyridoxine hydrochloride 5, intermediate 6, intermediate 7 and intermediate 8 have the structures shown in general formulas 5, 6, 7 and 8:

Wherein, R ¹ and R ² are benzyl or (1-phenyl)ethyl.

Compound 9 has the structure shown in general formula S-9, R-9:

When compound 9 is S-9, intermediates 10 and 11 have the structures shown in general formulas S-10 and S-11 respectively:

When compound 9 is R-9, intermediates 10 and 11 have the structures shown in general formulas R-10 and R-11 respectively:

Wherein, R ¹ and R ² are benzyl, (1-phenyl) ethyl;

R ³ and R ⁴ are tert-butyl, Wherein, R ^x and R ^x' are ethoxy and 2-naphthyl;

R ⁵ is Wherein R ^y , R ^y' and R ^y" are tert-butyl, isopropyl, 1-naphthyl, and X is Br.

The organic solvent is a mixed solvent of toluene, acetonitrile, ethylene glycol dimethyl ether, chloroform, N,N-dimethylformamide, and the base is diazabicyclododecane, tetramethylethylenediamine, 1,4 -Dimethylpiperazine, 1-methylpyrrole and quinoline, the oxidizing agent is sodium dichromate and sodium hypochlorite, and the condensing agent is TBTU.

Claims (9)

1. A kind of 1. synthetic method of chiral pyridoxal class catalyst, it is characterised in that described catalyst have as formula S-1, Structure shown in R-1, S-2 and R-2：

   Wherein, R¹、R²For hydrogen or C_1-24Alkyl in one kind, described alkyl be selected from methyl, ethyl, n-propyl, isopropyl, Normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl, (1- phenyl) ethyl, 1- naphthyls, 2- naphthyls or halogen In one kind；

   R³、R⁴For C_1-24Alkyl orIn one kind, described alkyl is selected from methyl, ethyl, n-propyl, isopropyl, just One kind in butyl, the tert-butyl group, cyclopenta, cyclohexyl or suberyl, wherein, R^x、R^x′For hydrogen, methyl, methoxyl group, ethyl, second Epoxide, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl, (1- phenyl) ethyl, One kind in 1- naphthyls, 2- naphthyls or halogen；

   R⁵For C_1-12Alkyl,In one kind, described alkyl be selected from methyl, ethyl, n-propyl, isopropyl One kind in base, normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl or suberyl, wherein R^x、R^x′For hydrogen, methyl, methoxyl group, second Base, ethyoxyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl, (1- phenyl) One kind in ethyl, 1- naphthyls, 2- naphthyls or halogen, R^y、R^{Y ＇}And R^y″For hydrogen, methyl, ethyl, n-propyl, isopropyl, positive fourth One kind in base, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl, (1- phenyl) ethyl, 1- naphthyls or 2- naphthyls；

   Described synthetic method specifically includes following steps：

   (1) in organic solvent, puridoxine hydrochloride 5 and alkali are added, then tert-butyl diphenyl chlorosilane is added dropwise, wherein, hydrochloric acid The mol ratio of pyridoxol 5 and alkali, tert-butyl diphenyl chlorosilane is 1：(3~6)：(1~5), stirring reaction, controlling reaction temperature For -20~-50 DEG C, the reaction time is 1~24h, that is, intermediate 6 is made；

   (2) in organic solvent, it is 1 by the mol ratio of intermediate 6 and oxidant：(1~5), intermediate 6 and oxidant are added, Stirring reaction, controlling reaction temperature are 0~100 DEG C, and the reaction time is 1~24h, the oxidized obtained intermediate 7 of intermediate 6；

   (3) in organic solvent, it is 1 by the mol ratio of intermediate 7 and oxidant：(1~5), intermediate 7 and oxidant are added, Stirring reaction, controlling reaction temperature are 0~100 DEG C, and the reaction time be 1~24h, intermediate 7 through further aoxidize it is obtained in Mesosome 8；

   (4) in organic solvent, it is 1 by intermediate 8 and chiral dried meat ammonia alcoholic compound 9, the mol ratio of condensing agent：(1~5)：(1 ~5) intermediate 8, chiral dried meat ammonia alcoholic compound 9 and condensing agent, stirring reaction, are added, controlling reaction temperature is 0~100 DEG C, instead It is 1~24h between seasonable, intermediate 10 is made；

   (5) in organic solvent, it is 1 by the mol ratio of intermediate 10 and tetrabutyl amine fluoride：(1~5), add intermediate 10 with Tetrabutyl amine fluoride, stirring reaction, controlling reaction temperature are 0~100 DEG C, and the reaction time is 1~48h, and intermediate 10 sloughs uncle Butyl diphenyl silicon, that is, intermediate 11 is made；

   (6) in organic solvent, it is 1 by the mol ratio of intermediate 11 and oxidant：(1~20), add intermediate 11 and oxidation Agent, stirring reaction, controlling reaction temperature are 0~100 DEG C, and the reaction time is 1~48h, and the oxidized obtained chirality of intermediate 11 is urged Agent S-1 or R-1；

   (7) in organic solvent, by chiral catalyst S-1 or R-1 and R⁵X, the mol ratio of alkali is 1：(1-5)：(3-6), add hand Property catalyst S-1 or R-1, R⁵X and alkali, stirring reaction, controlling reaction temperature are 0~100 DEG C, and the reaction time is 1~24h, i.e., Chiral catalyst S-2 or R-2 is made.
2. A kind of 2. synthetic method of chiral pyridoxal class catalyst according to claim 1, it is characterised in that described salt Sour pyridoxol 5, intermediate 6, intermediate 7 and intermediate 8 have the structure as shown in formula 5,6,7 and 8：

   Wherein, R¹、R²For hydrogen or C_1-24Alkyl in one kind, described alkyl be selected from methyl, ethyl, n-propyl, isopropyl, Normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl, (1- phenyl) ethyl, 1- naphthyls, 2- naphthyls or halogen In one kind.
3. A kind of 3. synthetic method of chiral pyridoxal class catalyst according to claim 1, it is characterised in that described hand Property dried meat ammonia alcoholic compound 9 there is structure as shown in formula S-9, R-9：

   When described chiral dried meat ammonia alcoholic compound 9 is S-9, intermediate 10, intermediate 11 have such as formula S-10, S-11 institute respectively The structure shown：

   When described chiral dried meat ammonia alcoholic compound 9 is R-9, intermediate 10, intermediate 11 have such as general formula R -10, R-11 institutes respectively The structure shown：

   Wherein, R¹、R²For hydrogen or C_1-24Alkyl in one kind, described alkyl be selected from methyl, ethyl, n-propyl, isopropyl, Normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl, (1- phenyl) ethyl, 1- naphthyls, 2- naphthyls or halogen In one kind；

   R³、R⁴For C_1-24Alkyl orIn one kind, described alkyl is selected from methyl, ethyl, n-propyl, isopropyl, just One kind in butyl, the tert-butyl group, cyclopenta, cyclohexyl or suberyl, wherein, R^x、R^x′For hydrogen, methyl, methoxyl group, ethyl, second Epoxide, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl, (1- phenyl) ethyl, One kind in 1- naphthyls, 2- naphthyls or halogen.
4. A kind of 4. synthetic method of chiral pyridoxal class catalyst according to claim 1, it is characterised in that described R⁵X In, R⁵For C_1-12Alkyl,In one kind, described alkyl be selected from methyl, ethyl, n-propyl, isopropyl One kind in base, normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl or suberyl, wherein R^x、R^x′For hydrogen, methyl, methoxyl group, second Base, ethyoxyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl, (1- phenyl) One kind in ethyl, 1- naphthyls, 2- naphthyls or halogen, R^y、R^{Y ＇}And R^y″For hydrogen, methyl, ethyl, n-propyl, isopropyl, positive fourth One kind in base, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl, (1- phenyl) ethyl, 1- naphthyls or 2- naphthyls, X is one kind in F, Cl, Br, I, sulfonyl, benzene mesyl or p-toluenesulfonyl.
5. 5. the synthetic method of a kind of chiral pyridoxal class catalyst according to claim 1, it is characterised in that described has Solvent includes benzene,toluene,xylene, trimethylbenzene, acetonitrile, ether, tetrahydrofuran, glycol dimethyl ether, chloroform, dichloromethane Alkane, methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N- methylpyrroles One or more in alkanone；

   Described alkali includes sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acid carbonate, saleratus, hydrogenation Sodium, hydrofining, calcium hydride, triethylamine, diisopropyl ethyl amine, tetramethylethylenediamine, DMA, N, N- diethyl Aniline, Isosorbide-5-Nitrae-diazabicyclooctane, diazabicylo dodecane, Isosorbide-5-Nitrae-lupetazin, 1- methyl piperidines, 1- methyl pyrroles Cough up, the one or more in quinoline or pyridine；

   Described oxidant includes chromium trioxide, sodium dichromate, potassium bichromate, sodium hypochlorite, sodium chlorate, sodium perchlorate, phosphoric acid Sodium dihydrogen, potassium permanganate, manganese dioxide, periodic acid, lead tetra-acetate, Swern oxidants, selenium dioxide, Dai Si-Martin's oxidant Or one kind in DCC；

   Described condensing agent includes TBTU, DIC, EDCI, EDDQ or Mukaiyama ' one kind in s reagents.
6. 6. the application of the chiral pyridoxal class catalyst using method as claimed in claim 1 synthesis, it is characterised in that described Catalyst is used for catalytically synthesizing chiral a-amino acid, and chiralα-aminoacid has the structure as shown in formula S-4, R-4：

   Wherein, R⁶For hydrogen, substituted or unsubstituted following group：

   C₁~C₂₄Alkyl, C₃~C₃₀Cycloalkyl or aryl, C₁~C₂₄Carbonyl, C₁~C₂₄Sulfonyl or phosphoryl；

   Described substitution refers to be substituted by following substituent：

   Halogen, C₁~C₈Alkyl, C₃~C₁₂Cycloalkyl or aryl, C₁~C₈Carbonyl, C₁~C₈Sulfonyl, C₁~C₈'s Phosphoryl, C₁~C₈Alkoxy or C₁~C₈Amido；

   Described carbonyl is one kind in aldehyde radical, ketone carbonyl, ester carbonyl group, carboxyl or amide groups.
7. 7. the application of chiral pyridoxal class catalyst according to claim 6, it is characterised in that described chiral alpha-amido Acid synthetic method be：In organic solvent, it is (0.5~5) by the mol ratio in ketone acid and amine source：1, ketone acid and amine source are added, Add catalyst, stirring reaction, controlling reaction temperature is -10~100 DEG C, and the reaction time be 1~72h, that is, be made described in Chiralα-aminoacid.
8. 8. the application of chiral pyridoxal class catalyst according to claim 7, it is characterised in that described ketone acid, amine source There is the structure as shown in formula 3,12 respectively：

   Wherein, R⁹For one kind in hydrogen or carboxyl；

   R⁶、R⁷、R⁸For hydrogen, substituted or unsubstituted following group：

   C₁~C₂₄Alkyl, C₃~C₃₀Cycloalkyl or aryl, C₁~C₂₄Carbonyl, C₁~C₂₄Sulfonyl or phosphoryl；

   Described substitution refers to be substituted by following substituent：

   Halogen, C₁~C₈Alkyl, C₃~C₁₂Cycloalkyl or aryl, C₁~C₈Carbonyl, C₁~C₈Sulfonyl, C₁~C₈'s Phosphoryl, C₁~C₈Alkoxy or C₁~C₈Amido；

   Described carbonyl is one kind in aldehyde radical, ketone carbonyl, ester carbonyl group, carboxyl or amide groups.
9. 9. the application of a kind of chiral pyridoxal class catalyst according to claim 7, it is characterised in that described is organic molten Agent includes benzene,toluene,xylene, trimethylbenzene, acetonitrile, ether, tetrahydrofuran, glycol dimethyl ether, chloroform, dichloromethane, first Alcohol, ethanol, isopropanol, N, N-dimethylformamide, N, in N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or 1-METHYLPYRROLIDONE One or more.