Chiral pyridinium salt carbonyl catalyst as well as preparation method and application thereof

Abstract

The invention relates to a chiral pyridinium salt carbonyl catalyst as well as a preparation method and application thereof, the structural general formula of the catalyst is # imgabs0 #, in the formula, R1 is # imgabs1 #, X1-6 comprises N or C-R6-11; r2, R4 and R6-11 comprise hydrogen, alkyl of C1-24, alkyloxy, # imgabs2 # CO2Rd, halogen, nitryl, cyano or trifluoromethyl; r3 comprises substituted or unsubstituted C1-24 alkyl groups, substituent groups comprise halogen, C1-10 alkyl groups, C3-10 cycloalkyl or aryl groups, C1-8 carbonyl groups, C1-8 sulfonyl or phosphoryl groups, and C1-10 alkoxy or amido groups, and carbonyl groups comprise aldehyde groups, ketone carbonyl groups, ester carbonyl groups, carboxyl groups or amido groups; and R5 has the structural formula of # imgabs3 # X <-> which is an anion. Compared with the prior art, the catalyst disclosed by the invention is used for a bionic aldol reaction of amino acid derivatives to synthesize a series of beta-hydroxyl-alpha-amino acid compounds with extremely high enantioselectivity.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims partial priority to a Chinese patent application with an application date of 2023 / 6 / 30, application number 202310794646.0, and invention name “A chiral pyridinium salt carbonyl catalyst, preparation method and application thereof”, and the relevant contents of which are incorporated into this application by reference. Technical Field

[0003] The invention belongs to the technical field of chemical synthesis and relates to a chiral pyridinium salt carbonyl catalyst and a preparation method and application thereof. Background Art

[0004] Threonine aldolase in the body catalyzes the direct addition of glycine to acetaldehyde to generate β-hydroxy α-aminobutyric acid, namely threonine. In this reaction, the active center of the enzyme is vitamin B6, which is the general name for pyridoxal, pyridoxine, pyridoxamine and their phosphate derivatives. It is a water-soluble vitamin that mainly acts as a coenzyme factor in a variety of enzyme-catalyzed reactions. Since the 1980s, chemists have begun to simulate the chemical structure of vitamin B6 to develop bionic catalysts / artificial enzymes. For example, the Kuzuhara and Breslow groups used an equivalent amount of chiral carbonyl catalysts to participate in the asymmetric aldol reaction of glycine with aldehydes, laying a solid foundation for the bionic simulation research of threonine aldolase (H. Kuzuhara, N. Watanabe, M. Ando, ​​J. Chem. Soc., Chem. Commun. 1987, 95-96; M. Ando, ​​H. Kuzuhara, Bull. Chem. Soc. Jpn. 1990, 63, 1925-1928; JT Koh, L. Delaude, R. Breslow, J. Am. Chem. Soc. 1994, 116, 11234-11240). These studies generally require the use of an equivalent amount of chiral pyridoxal, the reaction activity and stereoselectivity are at a moderate level, and the applicable range of aldehyde substrates is also narrow. Therefore, the early chiral pyridoxal carbonyl catalysts have poor applicability in organic synthesis. In recent years, Zhao's research group has synthesized and developed a series of chiral pyridoxal carbonyl catalysts, which have been successfully applied to the asymmetric Mannich reaction of glycine esters, the asymmetric aldol reaction, asymmetric Michael addition reaction and asymmetric α-allylation reaction of trifluoromethyl ketones, and the asymmetric aldol reaction of inert aromatic and alkynyl methylamines, and achieved quite good results (Chen, J. et al, Science 2018, 360, 1438-1442; Ma, J. et al, Angew. Chem. Int. Ed. 2021, 60, 10588-10592; Cheng, A. et al, Angew. Chem. Int. Ed. 2021, 60, 20166-20172; Ma, J. et al, Angew. Chem. Int. Ed. 2022, 61, e202200850; Hou, K ...2, 61, e202200850; Hou, K. et al, Science 2018, 360 al, Nat. Catal. 2022, 5, 1061-1068; Ji, P. et al, Angew. Chem. Int. Ed. 2022, 61, e202206111).However, chiral carbonyl catalysts that can efficiently catalyze the aldol reaction of glycine compounds with aldehydes have not yet been successfully developed. The main reason is that this reaction faces many challenges: (1) Aldehydes easily form imines with glycine compounds, resulting in the inability to carry out the aldol reaction; (2) The product is prone to reverse aldol reaction under carbonyl catalysis, resulting in decomposition and racemization of the product; (3) Due to the strong acidity of the amino α-H of the product, it is easy to undergo phase isomerization under alkaline conditions, resulting in difficulty in controlling the enantioselectivity and diastereoselectivity of the product. It is precisely because of these challenges that catalysts that can efficiently catalyze this transformation have not yet been developed.

[0005] Many β-hydroxy-α-amino acid compounds are important drug intermediates, and their synthesis has received widespread attention. Studies have reported on the aldol reaction of glycine and aldehydes catalyzed by bioenzymes, but the moderate conversion rate and low diastereoselectivity limit the application of the synthesis of β-hydroxy-α-amino acids prepared by bioprocesses (Dückers, N. et al, Appl. Microbiol. Biotechnol. 2010, 88, 409-424; Fesko, K. et al, Appl. Microbiol. Biotechnol. 2016, 100, 2579-2590; Wang, S. et al, Appl. Microbiol. Biotechnol. 2021, 105, 3507-3520). Chemical catalysis of the asymmetric aldol reaction of glycine and its derivatives with aldehydes is also difficult to achieve because there is currently a lack of chiral catalysts that can efficiently catalyze the reaction, making it difficult to achieve rapid chemical synthesis of chiral β-hydroxy-α-amino acid compounds. Summary of the invention

[0006] The purpose of the present invention is to provide a chiral pyridinium salt carbonyl catalyst and its preparation method and application in order to overcome at least one defect of the above-mentioned prior art. The chiral pyridinium salt carbonyl catalyst of the present invention is used for the biomimetic aldol reaction of amino acid derivatives to synthesize a series of β-hydroxy-α-amino acid compounds with extremely high enantioselectivity.

[0007] The purpose of the present invention can be achieved by the following technical solutions:

[0008] One of the technical solutions of the present invention is to provide a chiral pyridinium salt carbonyl catalyst, the pyridinium salt carbonyl catalyst 1 has a general structural formula:

[0009]

[0010] Among them, R 1 The structural formula is:

[0011]

[0012] X1 includes N or CR 6 , X2 includes N or CR 7 , X3 includes N or CR 8 , X4 includes N or CR 9 , X5 includes N or CR 10 , X6 includes N or CR 11 ;

[0013] R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Including hydrogen, C 1～24 Alkyl, alkyloxy, CO2R d , halogen, nitro, cyano or trifluoromethyl;

[0014] R a Including hydrogen, C 1～10 alkyl, aryl, halogen, nitro, cyano or trifluoromethyl, R b , R 2b , R 3b , R c , R 2c and R d Including hydrogen, C 1～10 alkyl or aryl, m is 1, 2 or 3, and n is 0, 1, 2, 3, 4 or 5;

[0015] R 3 Including substituted or unsubstituted C 1～24 Alkyl, substituents include halogen, C 1～10 Alkyl, C 3～10 Cycloalkyl or aryl, C 1～8 The carbonyl group, C 1～8 Sulfonyl or phosphoryl, C 1～10 The carbonyl group includes an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group;

[0016] R 5 The structural formula is:

[0017]

[0018] R 12 and R 13 Including hydrogen, C 1～24 Alkyl or R 14 Including hydrogen, C1～24 The alkyl group Arylmethyl, diarylmethyl, triarylmethyl, halogen or trifluoromethyl;

[0019] R e Including hydrogen, C 1～10 alkyl, alkyloxy, aryl, halogen, nitro, cyano or trifluoromethyl, x and y are 0, 1, 2 or 3;

[0020] The alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, cyclopentyl, isobutyl, n-hexyl, cyclohexyl, n-heptyl, cycloheptyl, n-octyl, cyclooctyl, n-nonyl, cyclononyl, n-decyl or cyclodecyl, and the aryl group includes benzene, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2,6-biphenyl, 3,5-biphenyl, 1-naphthyl, 2-naphthyl, 3,5-di-tert-butylbenzene, 4-tert-butylbenzene, 3,5-difluorobenzene, 4-fluorobenzene, 3,5-dichlorobenzene, 4-chlorobenzene, 3,5-ditrifluoromethylbenzene, 4-trifluoromethylbenzene, 3,5-dimethylbenzene, 4-methylbenzene or 4-methoxybenzene;

[0021] X - is an anion, and the anion includes fluoride ion, chloride ion, bromide ion, iodide ion, trifluoromethanesulfonate ion, hexafluorophosphate ion, tetrafluoroborate ion, sulfate ion, sulfite ion, hydroxide ion, nitrate ion, phosphate ion, carbonate ion, silicate ion, bicarbonate ion, hydrogenphosphate ion, dihydrogenphosphate ion, iodate ion, cyanide ion or thiocyanate ion.

[0022] Furthermore, the R 1 It forms axial chirality with the pyridine ring, and the axial chirality configuration is R or S configuration.

[0023] Furthermore, the catalyst has a formula a , Formula I b , Formula II a Or Formula II b The structure shown in Formula I a With formula I b are enantiomers of each other, formula II a With formula II b Enantiomers:

[0024]

[0025] One of the technical schemes of the present invention is to provide a method for preparing a chiral pyridinium salt carbonyl catalyst. The method uses the split single configuration compound 5 as a starting material. In a solvent, the chiral amine compound 5 is condensed with dimethyl squarate to generate compound 6. Compound 6 is then condensed with a primary amine to obtain an amide intermediate, which is then reacted with a halogenated hydrocarbon to obtain a quaternary ammonium salt intermediate, and finally hydrolyzed under the action of an acid to obtain a final pyridinium salt carbonyl catalyst 1a. The reaction process is as follows:

[0026]

[0027] Furthermore, the molar ratio of the compound 5 to dimethyl squarate is 1:(1-10), the reaction temperature is -20-120°C, and the reaction time is 1-72h;

[0028] The molar ratio of the compound 6 to the primary amine and the halogenated hydrocarbon is 1:(1-50):(1-50), the reaction temperature is 0-100° C., and the reaction time is 1-48 hours.

[0029] One of the technical solutions of the present invention is to provide a method for preparing a chiral pyridinium salt carbonyl catalyst. The method uses the split single-configuration compound 5 as a starting material, condenses the chiral amine compound 5 with a unilateral square amide to obtain an amide intermediate, then reacts with a halogenated hydrocarbon to obtain a quaternary ammonium salt intermediate, and finally hydrolyzes to obtain the final pyridinium salt carbonyl catalyst 1a. The reaction process is as follows:

[0030]

[0031] The difference between the above methods is that in method 2, the condensed unilateral squarylamide is used to replace the two-step reaction of dimethyl squarate and primary amine in method 1.

[0032] Furthermore, the molar ratio of the compound 5 to the unilateral square amide and the halogenated hydrocarbon is 1:(1-50):(1-50), the reaction temperature is -20-120°C, and the reaction time is 1-72h.

[0033] One of the technical solutions of the present invention is to provide a method for preparing a chiral pyridinium salt carbonyl catalyst. The method uses the resolved single-configuration compound 5 as a starting material. In a solvent, the chiral amine compound 5 is condensed with a thioisocyanate or an isocyanate to generate a compound 7 or 8. The compound 7 or 8 is then reacted with a halogenated hydrocarbon to obtain a quaternary ammonium salt intermediate, and finally hydrolyzed under the action of an acid to obtain a final pyridinium salt carbonyl catalyst 1b or 1c. The reaction process is as follows:

[0034]

[0035] Furthermore, the molar ratio of the compound 5 to the thioisocyanate or isocyanate is 1:(1-10), the reaction temperature is -20-120°C, and the reaction time is 1-72h;

[0036] The molar ratio of the compound 7 or 8 to the halogenated hydrocarbon is 1:(1-50), the reaction temperature is 0-100° C., and the reaction time is 1-48 hours.

[0037] One of the technical schemes of the present invention is to provide a method for preparing a chiral pyridinium salt carbonyl catalyst. The method uses a split single-configuration compound 5 as a starting material. In a solvent, a chiral amine compound 5 is condensed with a thioisocyanate to generate a compound 9. Compound 9 is coupled with a primary amine under the action of carbodiimide hydrochloride (EDCl) to generate a compound 10. Compound 10 is deprotected from an ethyl carbonate protecting group under the action of trimethylsilyl bromide to generate a compound 11. Compound 11 is then reacted with a halogenated hydrocarbon to obtain a quaternary ammonium salt intermediate. Finally, the compound is hydrolyzed under the action of an acid to obtain a final pyridinium salt carbonyl catalyst 1d. The reaction process is as follows:

[0038]

[0039] Furthermore, the molar ratio of the compound 5 to the thioisocyanate is 1:(1-10), the reaction temperature is -20-120°C, and the reaction time is 1-72h;

[0040] The molar ratio of the compound 9 to carbodiimide hydrochloride and primary amine is 1:(1-10):(1-10), the reaction temperature is 0-100° C., and the reaction time is 1-72 h;

[0041] The molar ratio of the compound 10 to trimethylsilyl bromide is 1:(1-10), the reaction temperature is 0-100° C., and the reaction time is 1-72 h;

[0042] The molar ratio of the compound 11 to the halogenated hydrocarbon is 1:(1-50), the reaction temperature is 0-100° C., and the reaction time is 1-48 hours.

[0043] Further, the solvent used in the method is selected from one or more of water, benzene, toluene, xylene, trimethylbenzene, acetonitrile, ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone;

[0044] The acid used is selected from one or more of sulfuric acid, hydrochloric acid, dichloromethane solution of hydrochloric acid, methanol solution of hydrochloric acid, tetrahydrofuran solution of hydrochloric acid, dioxane solution of hydrochloric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid.

[0045] Furthermore, the method adds silver salt to the iodide ion pyridinium salt carbonyl catalyst to replace it to obtain the pyridinium salt carbonyl catalyst with the corresponding anion of the silver salt;

[0046] The silver salt includes silver fluoride, silver chloride, silver bromide, silver trifluoromethanesulfonate, silver hexafluorophosphate, silver tetrafluoroborate, silver sulfate, silver sulfite, silver hydroxide, silver nitrate, silver phosphate, silver carbonate, silver silicate, silver bicarbonate, silver hydrogen phosphate, silver dihydrogen phosphate, silver iodate, silver cyanide or silver thiocyanate.

[0047] As a preferred technical solution, the silver salt can also be selected from one of silver bisulfate, silver bisulfite, silver arsenate, silver arsenite, silver borate, silver bromate, silver hypobromite, silver chlorate, silver perchlorate, silver hypochlorite, silver chromate, silver aluminosilicate, silver acetate, silver formate, silver hydrogen oxalate, and silver hydrogen sulfide. The catalyst X - You can also choose one of the following: bisulfate ion, bisulfite ion, arsenate ion, arsenite ion, borate ion, bromate ion, hypobromite ion, chlorate ion, perchlorate ion, hypochlorite ion, chromate ion, aluminosilicate ion, acetate ion, formate ion, hydrogen oxalate ion, and hydrogen sulfide ion.

[0048] As a preferred technical solution, the molar ratio of the iodide ion pyridinium salt carbonyl catalyst to the silver salt is 1:1, the reaction temperature is room temperature, and the reaction time is 2 hours.

[0049] One of the technical solutions of the present invention is to provide an application of a chiral pyridinium salt carbonyl catalyst, wherein the pyridinium salt carbonyl catalyst 1 is used for an asymmetric biomimetic aldol reaction of an amino acid derivative with a carbonyl compound to synthesize a chiral β-hydroxy-α-amino acid compound (chiral β-hydroxy-α-amino acid and its derivatives), and the reaction comprises the following steps:

[0050] In a solvent, amino acid derivative 2 and carbonyl compound 3 undergo aldol reaction under the catalysis of pyridinium salt carbonyl catalyst 1, the action of base and additives to generate chiral β-hydroxy-α-amino acid compound 4, including syn-4A, anti-4A and syn-4B, anti-4B different configurations. The absolute configuration of pyridinium salt carbonyl catalyst 1 determines the absolute configuration of chiral β-hydroxy-α-amino acid compound 4. The reaction equation is:

[0051]

[0052] Among them, R 15 including hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C3-C 18 Aryl, substituted or unsubstituted C 2～18 Alkenyl, substituted or unsubstituted C 2～24 Alkynyl, or C 1～18 The carbonyl group, the substituents include halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 The aromatic group, C 1-18 The carbonyl group, C 1～18 Sulfonyl or phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 The carbonyl group includes an aldehyde group, a ketone carbonyl group, an ester carbonyl group, a carboxyl group or an amide group;

[0053] R 16 OR 19 or NR 20 R 21 , where R 19 including hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, C 1～18 The carbonyl group, R 20 and R 21 including hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, C 1～18 The carbonyl group, or R 20 and R 21 Together they form ring B, or NR 20 R 21 It includes amino acid amine, amino acid ester amine, amino acid amide amine or polypeptide amine, and the substituent includes halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 The aromatic group, C 1-18 The carbonyl group, C 1～18 Sulfonyl or phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 The carbonyl group includes an aldehyde group, a ketone carbonyl group, an ester carbonyl group, a carboxyl group or an amide group, and the ring B is a C containing 1 to 4 heteroatoms. 1～18 The heteroatom is an O, N or S atom;

[0054] R 17 and R 18including hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, substituted or unsubstituted C 2～18 Alkenyl, substituted or unsubstituted C 2～24 Alkynyl, substituents include halogen, cyano, hydroxy, nitro, trifluoromethyl, C 1～18 Alkyl, C 3～18 The aromatic group, C 1-18 The carbonyl group, C 1～18 Sulfonyl or phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 The amino group, The carbonyl group includes an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group;

[0055] R b , R 2b and R 3b Including hydrogen, C 1～10 wherein m is 1, 2 or 3, and n is 0, 1, 2, 3, 4 or 5.

[0056] Furthermore, the molar ratio of the amino acid derivative 2 to the carbonyl compound 3 is (0.5-5):1, the molar ratio of the pyridinium salt carbonyl catalyst 1 to the carbonyl compound 3 is (0.00001-0.5):1, the reaction temperature is -60-100°C, and the reaction time is 1-72h;

[0057] The solvent used in the reaction is selected from one or more of water, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, 1,4-dioxane, trifluoroethanol, benzene, toluene, xylene, trimethylbenzene, acetonitrile, ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone;

[0058] The base used is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydride, potassium hydride, calcium hydride, trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, N,N-diethylmethylamine, N,N-dimethylethylamine, N,N-dimethylpropylamine, N,N-dimethylbutylamine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane (DABCO), diazabicyclododecane (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), n-butyllithium, 1,4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, n-butylamine, tert-butylamine, diethylamine, ethylenediamine, quinoline and pyridine;

[0059] The additives used are selected from one or more of ammonium phosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, lithium phosphate, lithium dihydrogen phosphate, dilithium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium acetate, potassium acetate, potassium fluoride and sodium fluoride.

[0060] In any of the above technical solutions, C 1～24 The alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, 3-pentyl, cyclopentyl, n-hexyl, 2-hexyl, 3-hexyl, cyclohexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, cycloheptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, cyclooctyl, n-nonyl, 2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl, cyclononyl, n-decyl, 2-decyl, 3-decyl, 4-decyl, 5-decyl, cyclodecyl, n-undecyl, One or more of alkyl, cycloundecyl, n-dodecyl, cyclododecyl, n-tridecyl, cyclotridecyl, n-tetradecyl, cyclotetradecyl, n-pentadecyl, cyclopentadecyl, n-hexadecyl, cyclohexadecyl, n-heptadecyl, cycloheptadecyl, n-octadecyl, cyclooctadecyl, n-nonadecyl, cyclononadecyl, n-eicosyl, cycloeicosyl, n-heneicosyl, cycloheneicosyl, n-docosanyl, cyclodocosanyl, n-tricosanyl, cyclotricosanyl, n-tetracosanyl, and cyclotetracosanyl.

[0061] In any of the above technical solutions, C 1～18The alkyl group is selected from one or more of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, 3-pentyl, cyclopentyl, n-hexyl, 2-hexyl, 3-hexyl, cyclohexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, cycloheptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, cyclooctyl, n-nonyl, 2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl, cyclononyl, n-decyl, 2-decyl, 3-decyl, 4-decyl, 5-decyl, cyclodecyl, n-undecyl, cycloundecyl, n-dodecyl, cyclododecyl, n-tridecyl, cyclotridecyl, n-tetradecyl, cyclotetradecyl, n-pentadecyl, cyclopentadecyl, n-hexadecyl, cyclohexadecyl, n-heptadecyl, cycloheptadecyl, n-octadecyl, and cyclooctadecyl.

[0062] In any of the above technical solutions, C 1～10 The alkyl group is selected from one or more of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, 3-pentyl, cyclopentyl, n-hexyl, 2-hexyl, 3-hexyl, cyclohexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, cycloheptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, cyclooctyl, n-nonyl, 2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl, cyclononyl, n-decyl, 2-decyl, 3-decyl, 4-decyl, 5-decyl and cyclodecyl.

[0063] In any of the above technical solutions, C 3～18 The aryl group is selected from 1-naphthyl, 2-naphthyl, 9-anthryl, 10-anthryl, 9-phenanthrenyl, 10-phenanthrenyl, 1-pyrenyl, 2-pyrenyl, 5-naphthyl, 2-peryl, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-imidazolyl, 2-oxazolyl, 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 2-indolyl, 3-indolyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, and benzoheteroaromatic ring groups of the above heteroaromatic ring groups, wherein R a , R b , R c Independently selected from one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, trifluoromethyl, phenyl, halogen, methoxy, ethoxy, dimethylamino, diethylamino, and nitro.

[0064] In any of the above technical solutions, C 2～18The alkenyl group is selected from the group consisting of vinyl, prop-1-en-1-yl, prop-2-en-1-yl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, hex-1-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl, hept-1-en-1-yl, hept-2-en-1-yl, hept-3-en-1-yl, hept-4-en-1-yl, hept-5-en-1-yl, hept-6-en-1-yl, oct-1-en-1-yl, oct-2-en-1-yl, oct-3-en-1-yl, 1-en-1-yl, oct-4-en-1-yl, oct-5-en-1-yl, oct-6-en-1-yl, oct-7-en-1-yl, non-1-en-1-yl, non-2-en-1-yl, non-3-en-1-yl, non-4-en-1-yl, non-5-en-1-yl, dec-1-en-1-yl, dec-2-en-1-yl, dec-3-en-1-yl, dec-4-en-1-yl, dec-5-en-1-yl, undec-1-en-1-yl, dodec-1-en-1-yl, tridec-1-en-1-yl, tetradec-1-en-1-yl, pentadec-1-en-1-yl, hexadec-1-en-1-yl, heptadeca-1-en-1-yl, and octadec-1-en-1-yl.

[0065] In any of the above technical solutions, C 2～24 The alkynyl group is selected from the group consisting of ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-2-yn-1-yl, but-3-yn-1-yl, pent-1-yn-1-yl, pent-2-yn-1-yl, pent-3-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl, hex-2-yn-1-yl, hex-3-yn-1-yl, hex-4-yn-1-yl, hex-5-yn-1-yl, hept-1-yn-1-yl, hept-2-yn-1-yl, hept-3-yn-1-yl, hept-4-yn-1-yl, hept-5-yn-1-yl, hept-6-yn-1-yl, oct-1-yn-1-yl, oct-2-yn-1-yl, oct-3-yn-1-yl. The invention relates to one or more of 1-yl, oct-4-yn-1-yl, oct-5-yn-1-yl, oct-6-yn-1-yl, oct-7-yn-1-yl, non-1-yn-1-yl, non-2-yn-1-yl, non-3-yn-1-yl, non-4-yn-1-yl, non-5-yn-1-yl, dec-1-yn-1-yl, dec-2-yn-1-yl, dec-3-yn-1-yl, dec-4-yn-1-yl, dec-5-yn-1-yl, undec-1-yn-1-yl, dodeca-1-yn-1-yl, trideca-1-yn-1-yl, tetradeca-1-yn-1-yl, pentadec-1-yn-1-yl, hexadec-1-yn-1-yl, heptadeca-1-yn-1-yl and octadec-1-yn-1-yl.

[0066] In any of the above technical solutions, C 1～18 Alkoxy is selected from methoxy, methylene 1,1-dioxy Ethyl 1,2-dioxy One or more of ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, tert-butoxy, isobutoxy, cyclobutyloxy, cyclopentyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy, cyclohexyloxy, n-heptyloxy, cycloheptyloxy, n-octyloxy, cyclooctyloxy, n-nonyloxy, cyclononyloxy, n-decyloxy, cyclodecyloxy, n-undecyloxy, cycloundecyloxy, n-dodecyloxy, and cyclododecyloxy.

[0067] In any of the above technical solutions, the halogen is selected from one or more of fluorine, chlorine, bromine and iodine.

[0068] The invention relates to a novel biaryl chiral pyridinium salt carbonyl catalyst, and a synthesis method and use of the catalyst. The catalyst can be used for biomimetic aldol reaction, and a series of chiral β-hydroxy-α-amino acid compounds are synthesized, providing a new method for asymmetric synthesis of β-hydroxy-α-amino acid compounds. The biomimetic aldol reaction has mild conditions, is easy to operate, has good repeatability, and has extremely high DR value and EE value, as well as relatively high to extremely high yield.

[0069] Compared with the prior art, the present invention has the following beneficial effects:

[0070] (1) Pyridoxal belongs to the vitamin B6 family. In organisms, it is a coenzyme of many biological enzymes and acts as a reaction center to catalyze numerous biological transformations. Among them, the reaction of preparing β-hydroxy-α-amino acid compounds by the addition of amino acid derivatives to carbonyl compounds catalyzed by pyridoxal has important synthetic significance. However, the bionic simulation of this reaction has not been successfully realized for a long time. The present invention designs and synthesizes a new type of chiral pyridinium salt carbonyl catalyst, which catalyzes the bionic aldol reaction process of amino acid derivatives and carbonyl compounds with high activity and high stereoselectivity, thereby realizing the efficient synthesis of chiral β-hydroxy-α-amino acid compounds.

[0071] (2) The chiral pyridinium salt carbonyl catalyst of the present invention can be prepared by multi-step reaction of cheap and readily available raw materials, the reaction conditions are mild, most of them are easy to scale up, and can be prepared on a large scale;

[0072] (3) The pyridinium salt carbonyl catalyst of the present invention has very mild reaction conditions for catalyzing the biomimetic aldol reaction, stable reaction, easy operation, excellent product stereoselectivity and yield, and is one of the most efficient methods for preparing optically active β-hydroxy-α-amino acid compounds;

[0073] (4) The chiral β-hydroxy-α-amino acid compounds prepared by the biomimetic aldol reaction catalyzed by a pyridinium salt carbonyl catalyst can be used as important intermediates in the synthesis of drugs such as florfenicol, droxidopa and eliglus, providing a new green synthesis process for the synthesis of these drug molecules. DETAILED DESCRIPTION

[0074] The present invention is described in detail below in conjunction with specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and a specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0075] Unless otherwise specified, the equipment used in the following examples are all conventional equipment in the art; the reagents used are all commercially available products or prepared by conventional methods in the art unless otherwise specified. Anything not described in detail in the following examples can be achieved by conventional experimental means in the art.

[0076] The structural formula of the chiral pyridinium salt carbonyl catalyst 1 of this embodiment and the reaction equation for preparing the β-hydroxy-α-amino acid compound 4 using the same are:

[0077]

[0078] The preparation method of this embodiment can be further embodied by the preparation process of representative compounds as follows:

[0079] Embodiments 1 to 9:

[0080] A catalyst (S,S)-1a and a preparation method thereof, wherein the reaction equation is:

[0081]

[0082] The general steps are as follows:

[0083] Compound (S,S)-5a (1.0 g, 2.06 mmol) and dimethyl squarate (1.46 g, 10.3 mmol) were dissolved in anhydrous methanol (10 mL), reacted at 50°C overnight, concentrated the system, and column chromatography was performed to obtain compound (S,S)-6a (colorless oil, 0.75 g, yield 61%);

[0084] Compound (S,S)-6a (0.15 g, 0.25 mmol) and primary amine compound (1.38 mmol) were dissolved in anhydrous ethanol (1.5 mL), reacted at 42 ° C for 48 h, concentrated the system, and obtained an amide intermediate by column chromatography; the amide intermediate was dissolved in CH3CN (1.5 mL), CH3I (20 equivalents of the amide intermediate) was added, and the reaction was carried out at 30 ° C for 8 h. The system was concentrated and the quaternary ammonium salt intermediate was obtained by column chromatography. After being spin-dried, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added, and the reaction was carried out at 55 ° C for 6 h. After the reaction, the tetrahydrofuran was spin-dried, and the water was removed in vacuo with phosphorus pentoxide. After grinding into powder with a small spoon, 4 mL of Et2O was added first and then 7 drops of tetrahydrofuran were added. The solid was cleaned by ultrasonication and rolling, and the supernatant was sucked out. This was repeated 3 times. The supernatant and the solid were filtered together, and the filter cake was dried to obtain the catalyst (S,S)-1a.

[0085] Embodiment 1:

[0086]

[0087] The basic parameters of the compound are as follows: (S,S)-6a: colorless oil; [α] D 25 =4.1 (c = 0.10, CHCl3); 1 HNMR (400MHz, CDCl3) δ8.54 (s, 1H), 7.86-7.82 (m, 2H), 7.56 (s, 1H), 7.46 (t, J = 7.6 Hz,1H),7.36-7.31(m,3H),7.29-7.28(m,2H),7.20(d,J=8.0Hz,1H),7.14(d,J=6.4 Hz,2H),5.75(s,1H),5.43(s,1H),5.29(s,2H),4.10(s,3H),3.59(s,3H),3.45-3.2 9(m,3H),3.12-3.04(m,1H),1.86(s,3H),0.91(t,J=6.8Hz,3H),0.65-0.48(m,3H); 13 C NMR (100MHz, CDCl3) δ189.0,183.8,177.8,171.7,151.7,150.0,140.2,138.1,135.8,135.3,134.1,132.8,132.4,131.0 ,128.9,128.7,128.05,128.98,127.6,126.7,126.5,126.4,124.5,99.4,96.2,64.7,64.2,60.3,56.6,22.5,15.1,14.5.

[0088] Embodiment 2:

[0089]

[0090] The basic parameters of the catalyst are as follows: (S,S)-1a-1: brownish yellow solid, yield 71%; [α] D 25 = -16.3 (c = 0.050, MeOH); 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.89(s,1H),9.33(d,J=10.0Hz,1H),8.92(s,1H) ,8.21(d,J=8.8Hz,1H),8.07(d,J=8.4Hz,1H),7.65(d,J=8.4Hz,1H),7.61(t,J=8.0Hz, 1H),7.49(t,J=8.4Hz,1H),7.45-7.38(m,2H),7.38-7.31(m,4H),7.20(d,J=6.8Hz,2H) ,7.06(t,J=1.6Hz,1H),6.23(d,J=9.6Hz,1H),4.28(s,3H),1.81(s,3H),1.26(s,18H); 13 C NMR (100MHz, DMSO-d6) δ188.9,182.9,179.9,167.0,164.5,155.2,151.6,145.6,140.0,138.2,137.6,136.9,136.1,133.4 ,132.3,131.3,130.4,129.1,128.4,128.1,127.8,127.1,127.0,125.2,124.3,116.7,112.6,58.2,47.4,34.7,31.2,15.9.

[0091] Embodiment 3:

[0092]

[0093] The basic parameters of the catalyst are as follows: (S,R)-1a-1, brown-yellow solid, yield 50%; [α] D 25 =61.5 (c=0.050, MeOH); 1H NMR(400MHz,DMSO-d6)δ10.64(s,0.54H for 1a-1-aldehyde),9.78(brs,0.46Hfor 1a-1-hemiacetal),9.58(d,J=9.2Hz,0.54H for 1a-1-aldehyde),9.48(s,0.54H for1a-1-aldehyde),8.97(s,0.54H for 1a-1-aldehyde),8.31(s,0.46H for 1a-1-hemiacetal),8.25(d,J=8.4Hz,0.46H for 1a-1-hemiacetal),8.21(d,J=8.8Hz,0.54H for 1a-1-aldehyde),8.14(d,J=8.0Hz,0.46H for 1a-1-hemiacetal),8.08(d,J=8.4Hz,0.54H for 1a-1-aldehyde),7.70(d,J=8.8Hz,0.54H for 1a-1-aldehyde),7.68-7.58(m,1H),7.58-7.52(m,0.92H for1a-1-hemiacetal),7.52-7.46(m,,0.54H for1a-1-aldehyde),7.46-7.27(m,4H),7.21-7.12(m,2H),7.12-7.02(m,3H),6.81(d,J=6.4Hz,0.92H for 1a-1-hemiacetal),6.14(d,J=9.4Hz,0.54H for 1a-1-aldehyde),4.31(s,1.62H for 1a-1-aldehyde),3.95(s,1.38H for1a-1-hemiacetal),2.11(s,1.62Hfor 1a-1-aldehyde),1.83(s,1.38H for 1a-1-hemiacetal),1.27(s,8.28H for 1a-1-hemiacetal),1.26(s,9.72H for 1a-1-aldehyde); 13C NMR(100MHz,DMSO-d6)δ188.7,183.8,182.9,182.0,179.8,166.9,164.7,155.2,151.6,150.5,14 6.0,145.5,140.4,139.9,138.3,137.5,137.1,136.8,136.0,133.7,132.9,132.5,132.2,131.2, 130.9,130.3,129.0,128.8,128.7,128.4,127.9,127.7,127.5,127.0,126.7,126.5,125.4,125.3,124.5,124.2,116.6,116.2,112.6,72.6,58.3,54.9,47.5,46.3,34.7,34.6,31.2,17.7,16.7.

[0094] Embodiment 4:

[0095]

[0096] The basic parameters of the catalyst are as follows: (S,S)-1a-2: brownish yellow solid, yield 64%; [α] D 25 =17.3 (c=0.050, MeOH); 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.87(s,1H),9.73(d,J=9.6Hz,1H),8.92(s,1H),8.20(d, J=8.4Hz,1H),8.06(d,J=8.0Hz,1H),7.73(d,J=8.8Hz,1H),7.60(t,J=7.6Hz,1H),7.48(dd,J=8 .4,6.8Hz,1H),7.43-7.38(m,2H),7.35(d,J=7.2Hz,1H),7.31(d,J=8.4Hz,1H),7.20(d,J=7.2H z,2H),7.12(s,2H),6.66(s,1H),6.25(d,J=9.6Hz,1H),4.27(s,3H),2.22(s,6H),1.76(s,3H); 13C NMR(100MHz,DMSO-d6)δ188.9,183.0,179.7,167.0,164.3,155.0,145.6,139.9,138.8,138.4,137.5,136.8,136.1,133.4, 132.2,131.3,130.4,129.0,128.8,128.4,128.0,127.8,127.2,127.0,125.1,124.5,124.4,115.8,58.4,47.4,21.1,15.9.

[0097] Embodiment 5:

[0098]

[0099] The basic parameters of the catalyst are as follows: (S,S)-1a-3, brown-yellow solid, yield 58%; [α] D 25 =21.8 (c=0.050, MeOH); 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.88(s,1H),9.33(d,J=9.6Hz,1H),8.90(s,1H),8.20(d,J=8.8Hz,1H),8.06(d,J=8.0Hz,1H),7.65-7.58(m, 2H),7.52-7.45(m,1H),7.45-7.39(m,3H),7.38-7.32(m,5H),7.20(d,J= 7.2Hz,2H),6.24(d,J=9.6Hz,1H),4.28(s,3H),1.81(s,3H),1.25(s,9H); 13 C NMR (100MHz, DMSO-d6) δ188.9,182.9,179.8,166.8,164.2,155.1,145.5,145.4,139.8,137.6,136.8,136.3,136.0,133.4,13 2.3,131.3,130.4,129.1,129.0,128.4,128.0,127.8,127.1,127.0,126.0,125.2,124.3,117.9,58.2,47.4,34.0,31.2,15.9.

[0100] Embodiment 6:

[0101]

[0102] The basic parameters of the catalyst are as follows: (S,S)-1a-4, brown-yellow solid, yield 60%; [α] D 25 =31.5 (c=0.050, MeOH); 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),9.88(s,1H),9.54(d,J=9.6Hz,1H),8.91(s, 1H),8.21(d,J=8.8Hz,1H),8.06(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.61(t,J =7.6Hz,1H),7.52-7.45(m,3H),7.45-7.38(m,2H),7.38-7.30(m,4H),7.20(d,J=7 .2Hz,2H),7.02(t,J=7.2Hz,1H),6.24(d,J=9.6Hz,1H),4.27(s,3H),1.79(s,3H); 13 CNMR(100MHz,DMSO-d6)δ188.9,183.1,179.7,167.1,164.2,155.1,145.6,139.8,138.9,137.6,136.8,136.0,133.4,132 .3,131.3,130.4,129.3,129.0,128.9,128.4,128.0,127.8,127.1,127.0,125.2,124.3,122.9,118.0,58.3,47.4,15.9.

[0103] Embodiment 7:

[0104]

[0105] The basic parameters of the catalyst are as follows: (S,S)-1a-5, brown-yellow solid, yield 54%; [α] D 25 = -28.0 (c = 0.050, MeOH); 1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.21(d,J=9.6Hz,1H),9.07(d,J=9.6Hz ,1H),8.87(s,1H),8.17(d,J=8.8Hz,1H),8.05(d,J=8.0Hz,1H),7.64-7.57(m ,2H),7.47(ddd,J=8.4,6.8,1.2Hz,1H),7.41-7.26(m,14H),7.14(d,J=7.6Hz ,2H),6.36(d,J=9.6Hz,1H),6.17(d,J=9.6Hz,1H),4.25(s,3H),1.76(s,3H); 13 C NMR(100MHz,DMSO-d6)δ188.9,183.0,179.7,167.0,164.3,155.0,145.6,139.9,138.8,138.4,137.5,136.8,136.1,133.4, 132.2,131.3,130.4,129.0,128.8,128.4,128.0,127.8,127.2,127.0,125.1,124.5,124.4,115.8,58.4,47.4,21.1,15.9.

[0106] Embodiment 8:

[0107]

[0108] The basic parameters of the catalyst are as follows: (S,S)-1a-6, brown-yellow solid, yield 51%; [α] D 25 =105.8 (c=0.050, MeOH); 1 H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.86(s,1H),9.38(d,J=9.6Hz,1H), 8.92(s,1H),8.20(d,J=8.8Hz,1H),8.07(d,J=8.0Hz,1H),7.65-7.57(m,2H ),7.52-7.47(m,3H),7.37-7.31(m,3H),7.26(d,J=8.4Hz,2H),7.06(t,J= 1.6Hz,1H),6.23(d,J=9.6Hz,1H),4.33(s,3H),1.96(s,3H),1.26(s,18H); 13C NMR(100MHz,DMSO-d6)δ189.2,183.3,180.4,167.3,165.0,155.7,152.1,145.8,139.5,138.7,138.3,136.9,136.4,133.8 ,133.1,132.8,131.7,131.0,129.8,129.4,128.9,128.3,127.6,125.8,124.9,117.1,113.1,58.0,48.0,35.2,31.6,16.6.

[0109] Embodiment 9:

[0110]

[0111] The basic parameters of the catalyst are as follows: (S,S)-1a-7, brown-yellow solid, yield 13%; 1 H NMR(400MHz,DMSO-d6)δ12.65(s,1H),δ11.17(s,1H),9.88(s,1H),9.83(d,J =9.6Hz,1H),8.92(s,1H),8.22(d,J=8.6Hz,1H),8.07(d,J=8.0Hz,1H),7.76( d,J=8.6Hz,1H),7.61(t,J=7.6Hz,1H),7.48(t,J=7.6Hz,1H),7.45-7.15(m, 10H),6.85(t,J=9.4Hz,1H),6.22(d,J=9.6Hz,1H),4.26(s,3H),1.72(s,3H); 13 C NMR(100MHz,DMSO-d6)δ189.5,184.1,180.1,168.0,164.7,164.6,164.0,162 .3,162.2,155.5,146.1,142.3,142.1,140.1,138.1,137.2,136.4,133.9,13 2.7,131.7,130.9,129.5,129.5,129.2,128.9,128.6,128.3,127.9,127.6,127.5,125.6,124.7,101.7,101.6,101.4,98.3,98.1,97.8,59.0,47.9,16.3; 19 FNMR(376MHz,DMSO-d6)δ-108.53.

[0112] Examples 10 to 14:

[0113] A catalyst (S,S)-1a and a preparation method thereof, wherein the reaction equation is:

[0114]

[0115] The general steps are as follows:

[0116] Compound (S,S)-5a (0.195 g, 0.40 mmol) and a squaramide compound (2.21 mmol) were dissolved in anhydrous ethanol (2.0 mL), reacted at 42 °C for 72 h, concentrated the system, and obtained an amide intermediate by column chromatography; the amide intermediate was dissolved in CH3CN (1.5 mL), CH3I (20 equivalents of the amide intermediate) was added, reacted at 30 °C for 8 h, concentrated the system, and obtained a quaternary ammonium salt intermediate by column chromatography. After being spin-dried, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added, and reacted at 55 °C for 6 h. After the reaction, tetrahydrofuran was spin-dried, and water was removed in vacuo with phosphorus pentoxide. After grinding into powder with a small spoon, 4 mL of Et2O was added first and then 7 drops of tetrahydrofuran were added. The solid was cleaned by ultrasonication and rolling, and the supernatant was sucked out. This was repeated 3 times. The supernatant and the solid were filtered together, and the filter cake was dried to obtain the catalyst (S,S)-1a.

[0117] Embodiment 10:

[0118]

[0119] The basic parameters of the catalyst are as follows: (S,S)-1a-8, brown-yellow solid, yield 29%; [α] D 25 = -6.8 (c = 0.050, MeOH); 1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H),9.87(s,1H),9.26(d,J=9.6Hz,1H),8.93(s,1H),8 .20(d,J=8.8Hz,1H),8.07(d,J=8.4Hz,1H),7.67(d,J=8.8Hz,1H),7.61(t,J=7.2Hz,1H) ,7.51-7.45(m,1H),7.38-7.33(m,2H),7.32(d,J=8.8Hz,1H),7.06(s,1H),6.98(s,1H), 6.79(s,2H),6.16(d,J=9.2Hz,1H),4.28(s,3H),2.25(s,6H),1.83(s,3H),1.27(s,18H); 13C NMR (100MHz, DMSO-d6) δ188.9,182.9,179.9,166.9,164.4,155.1,151.6,145.6,139.9,138.24,138.19,137.5,137.1,136.2,133. 4,132.2,131.3,130.4,129.4,128.8,128.4,127.8,127.0,125.1,124.7,124.3,116.6,112.6,58.2,47.3,34.7,31.1,20.9,16.1.

[0120] Embodiment 11:

[0121]

[0122] The basic parameters of the catalyst are as follows: (S,S)-1a-9, brownish yellow solid, yield 53%; [α] D 25 =30.8 (c=0.050, MeOH); 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),9.89(s,1H),9.71(d,J=9.6Hz,1H),8.91(s,1H),8.22(d ,J=8.4Hz,1H),8.12(s,2H),8.07(d,J=8.0Hz,1H),7.74(d,J=8.8Hz,1H),7.67(s,1H),7.62(t ,J=7.2Hz,1H),7.49(ddd,J=8.4,6.8,1.2Hz,1H),7.41(t,J=7.2Hz,2H),7.36(d,J=7.2Hz,1H) ,7.33(d,J=8.4Hz,1H),7.19(d,J=7.2Hz,2H),6.23(d,J=9.6Hz,1H),4.27(s,3H),1.74(s,3H); 13 C NMR (100MHz, DMSO-d6) δ189.6,184.4,180.4,168.2,163.8,155.6,146.0,141.6,140.1,138.2,137.1,136.4,133.9,132.8,131.9(q,J C-F =32.8Hz),131.7,130.9,129.5,129.3,128.9,128.6,128.3,127.6,127.5,125.7,124.7,123.6(q,J C-F=271.2Hz),118.3,115.5,59.0,47.9,16.4; 19 F NMR (376 MHz, DMSO-d6) δ-61.7.

[0123] Embodiment 12:

[0124]

[0125] The basic parameters of the catalyst are as follows: (S,S)-1a-10, brown-yellow solid, yield 41%; [α] D 25 =3.0 (c = 0.050, MeOH); 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.77(s,1H),8.90(s,1H),8.81(d,J=9.6Hz,1H),8 .24(d,J=8.8Hz,1H),8.07(d,J=8.0Hz,1H),7.96(d,J=8.8Hz,1H),7.59(t,J=7.6Hz,1H) ,7.46(d,J=8.4Hz,1H),7.38-7.29(m,2H),7.25(d,J=8.4Hz,1H),7.06-7.01(m,1H),5.1 0(dq,J=9.6,6.8Hz,1H),4.41(s,3H),2.18(s,3H),1.56(d,J=6.8Hz,3H),1.26(s,18H); 13 C NMR (100MHz, DMSO-d6) δ188.6,182.9,179.5,167.0,164.0,155.1,151.5,145.7,138.3,137.9,137.2,135.9,133.6 ,132.3,131.0,130.5,128.3,128.1,127.6,126.7,125.2,123.3,116.5,112.5,50.6,47.5,34.7,31.1,22.8,16.3.

[0126] Embodiment 13:

[0127]

[0128] The basic parameters of the catalyst are as follows: (S,S)-1a-11, brown-yellow solid, yield 32%; [α] D 25 =16.5 (c=0.050, MeOH); 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.89(s,1H),9.30(d,J=9.6Hz,1H),8.91(s,1H),8.21 (d,J=8.8Hz,1H),8.07(d,J=8.4Hz,1H),7.71(d,J=8.4Hz,1H),7.61(t,J=7.6Hz,1H),7.48(t ,J=8.0Hz,1H),7.34(s,2H),7.31(d,J=8.4Hz,1H),7.10(d,J=8.8Hz,2H),7.06(s,1H),6.96( d,J=8.8Hz,2H),6.17(d,J=9.6Hz,1H),4.27(s,3H),3.75(s,3H),1.76(s,3H),1.26(s,18H); 13 C NMR(100MHz,DMSO-d6)δ189.0,183.0,180.0,167.0,164.4,158.9,155.1,151.6,145.6,138.3,137.5,137.2,136.1,133.4,132.2 ,131.9,131.3,130.3,128.7,128.4,128.4,127.7,126.9,125.1,124.2,116.6,114.3,112.6,57.8,55.3,47.4,34.7,31.1,15.9.

[0129] Embodiment 14:

[0130]

[0131] The basic parameters of the catalyst are as follows: (S)-1a-12, brownish yellow solid, yield 58%; [α] D 25 = -71.3 (c = 0.050, MeOH); 1H NMR(400MHz,DMSO-d6)δ10.44(s,0.30H for 1a-12-aldehyde),9.88(s,0.30Hfor 1a-12-aldehyde),9.80(s,0.70H for 1a-12-hemiacetal),8.89(s,0.30H for1a-12-aldehyde),8.77-8.65(m,1H),8.17(d,J=8.4Hz,0.30H for 1a-12-aldehyde),8.11(d,J=8.4Hz,0.70Hfor 1a-12-hemiacetal),8.07(d,J=7.6Hz,1H),7.80(d,J=8.8Hz,0.30H for 1a-12-aldehyde),7.69-7.53(m,0.60H for 1a-12-aldehyde and3.50H for 1a-12-hemiacetal),7.51-7.44(m,0.30Hfor 1a-12-aldehyde),7.35(s,0.70Hfor 1a-12-hemiacetal),7.29(d,J=8.8Hz,0.30H for1a-12-aldehyde),7.23-7.10(m,2H),7.05(s,0.30H for 1a-12-aldehyde),δ4.67(m,0.60H for1a-12-aldehyde),4.52-4.13(m,1.40H for 1a-12-hemiacetal),4.33(s,3H),3.64(brs,0.7H for1a-12-hemiacetal),2.25(s,2.10H for 1a-12-hemiacetal),2.14(s,0.90H for 1a-12-aldehyde),1.28(s,12.60H for 1a-12-hemiacetal),1.26(s,5.40H for 1a-12-aldehyde); 13C NMR(100MHz,DMSO-d6)δ189.5,183.1,181.9,179.8,168.0,167.6,165.0,164.2,154.7,151.5, 150.6,150.1,146.1,145.9,139.8,138.4,137.4,137.1,136.3,136.1,134.3,133.9,133.6,132 .9,132.4,132.3,131.2,130.3,130.1,128.9,128.7,128.4,127.5,127.3,126.8,126.7,126.4,125.7,125.0,117.5,116.5,115.7,112.6,73.1,47.5,46.9,45.6,34.7,34.6,31.2,18.3,16.4.

[0132] Embodiment 15:

[0133] A catalyst (S,S)-1a-13 and a preparation method thereof, the reaction equation is:

[0134]

[0135] The steps are as follows: dissolve compound (S,S)-6a (0.15 g, 0.25 mmol) and 3,5-di-tert-butylaniline (0.28 g, 1.38 mmol) in anhydrous ethanol (1.5 mL), react at 42° C. for 48 h, concentrate the system, and perform column chromatography to obtain an amide intermediate; dissolve the amide intermediate in CH3CN (1.5 mL), add iodide (20 equivalents of the amide intermediate), react at 30° C. for 8 h, concentrate the system, and perform column chromatography to obtain a quaternary ammonium salt intermediate. After drying, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added, and the mixture was reacted at 55 ° C for 6 h. After the reaction, the tetrahydrofuran was dried by spinning, and the water was removed in vacuo with phosphorus pentoxide. After grinding into powder with a small spoon, 4 mL of Et2O was added first and then 7 drops of tetrahydrofuran were added. The solid was cleaned by ultrasonic and rolling, and the supernatant was sucked out. This was repeated 3 times, and the supernatant and the solid were filtered together. The filter cake was drained to obtain the catalyst (S, S)-1a-13 (brown solid, 0.1501 g, yield 69%);

[0136] The basic parameters of the compound are as follows: 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.90(s,1H),9.32(d,J=10.0Hz,1H),8.93(s,1H) ,8.22(d,J=8.8Hz,1H),8.09(d,J=8.4Hz,1H),7.63(d,J=8.4Hz,1H),7.60(t,J=8.0Hz, 1H),7.50(t,J=8.4Hz,1H),7.46-7.39(m,2H),7.36-7.26(m,9H),7.21(d,J=6.8Hz,2H) ,7.05(t,J=1.6Hz,1H),6.22(d,J=9.6Hz,1H),5.88(s,2H),1.82(s,3H),1.25(s,18H).

[0137] Embodiment 16:

[0138] A catalyst (R,R)-1a-14 and a preparation method thereof, wherein the reaction equation is:

[0139]

[0140] The specific steps are as follows: Compound (R,R)-5b (0.247 g, 0.55 mmol) and dimethyl squarate (0.560 g, 3.3 mmol) were dissolved in anhydrous methanol (2.5 mL), reacted at 50°C overnight, concentrated the system, and column chromatography obtained compound (R,R)-6b (colorless oil, 0.1417 g, yield 53%);

[0141] The basic parameters of this compound are as follows: 1 H NMR (400MHz, CDCl3) δ8.54(s,1H),7.86-7.82(m,1H),7.56(s,1H),7.46(t,J=7.6Hz,1 H),7.36-7.31(m,1H),7.29-7.28(m,2H),7.20(d,J=8.0Hz,1H),7.14(d,J=6.4Hz,2H) ,5.75(s,1H),5.43(s,1H),5.29(s,2H),4.10(s,3H),3.59(s,3H),3.45-3.29(m,3H), 3.12-3.04(m,1H),2.0(s,3H),1.86(s,3H),0.91(t,J=6.8Hz,3H),0.65-0.48(m,3H).

[0142] Compound (R,R)-6b (0.1417 g, 0.25 mmol), 3,5-di-tert-butylaniline (0.4152 g, 2.02 mmol) and zinc trifluoromethanesulfonate (0.014 g, 0.038 mmol) were dissolved in anhydrous ethanol (1.4 mL), reacted at 42 ° C for 48 h, concentrated the system, and obtained an amide intermediate by column chromatography; the amide intermediate (0.148 g, 0.21 mmol) was dissolved in CH3CN (1.5 mL), CH3I (20 equivalents of the amide intermediate) was added, and reacted at 30 ° C for 8 h, concentrated the system, and obtained a quaternary ammonium salt intermediate by column chromatography. After being spin-dried, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added, and reacted at 55 ° C for 6 h, and the tetrahydrofuran was spin-dried, and the water was removed in vacuo with phosphorus pentoxide. After grinding into powder with a small spoon, 4 mL of Et2O was then added with 7 drops of tetrahydrofuran, the solid was cleaned by ultrasonication and rolling, the supernatant was sucked out, and the reaction was repeated 3 times. The supernatant and the solid were filtered together, and the filter cake was dried to obtain the catalyst (R,R)-1a-14 (brown solid, 0.1235 g, yield 65%);

[0143] The basic parameters of this compound are as follows: 1 H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 10.02 (s, 1H), 9.05 (d, J = 9.6Hz, 1H), 8.79(s,1H),7.49(t,J=7.6Hz,1H),7.44-7.33(m,4H),7.32(d,J=1.6Hz,2H) ,7.22(d,J=7.6Hz,1H),7.14(dd,J=7.0,1.6Hz,2H),7.06(t,J=1.6Hz,1H), 5.97(d,J=9.6Hz,1H),4.23(s,3H),1.94(s,3H),1.90(s,3H),1.27(s,18H).

[0144] Embodiment 17:

[0145] A catalyst (S,S)-1a-15 and a preparation method thereof, the reaction equation is:

[0146]

[0147] The specific steps are as follows: compound (S,S)-1a-1 (0.0476 g, 0.06 mmol) was dissolved in tetrahydrofuran (0.5 mL), silver tetrafluoroborate (0.0117 g, 0.06 mmol) was dissolved in 0.5 mL of water and added to the system, reacted at room temperature for 2 h under nitrogen protection, filtered, the tetrahydrofuran was spin-dried, and water was removed in vacuo with phosphorus pentoxide, ground into powder with a small spoon, 4 mL of Et2O was added first and then 7 drops of tetrahydrofuran were added, the solid was cleaned by ultrasonic and rolling, the supernatant was sucked out, and the process was repeated 3 times, the supernatant and the solid were filtered together, and the filter cake was dried to obtain the catalyst (S,S)-1a-15 (brown solid, 0.0407 g, yield 90%);

[0148] The basic parameters of the compound are as follows: 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.89(s,1H),9.33(d,J=10.0Hz,1H),8.92(s,1H) ,8.21(d,J=8.8Hz,1H),8.07(d,J=8.4Hz,1H),7.65(d,J=8.4Hz,1H),7.61(t,J=8.0Hz, 1H),7.49(t,J=8.4Hz,1H),7.45-7.38(m,2H),7.38-7.31(m,4H),7.20(d,J=6.8Hz,2H) ,7.06(t,J=1.6Hz,1H),6.23(d,J=9.6Hz,1H),4.28(s,3H),1.81(s,3H),1.26(s,18H).

[0149] Embodiment 18:

[0150] A catalyst (S,S)-1c and a preparation method thereof, wherein the reaction equation is:

[0151]

[0152] The specific steps are as follows: Compound (S,S)-5a (0.1463 g, 0.3 mmol) and 1,3-di-tert-butyl-5-isocyanobenzene (0.0722 g, 0.315 mmol) were dissolved in DMF (1.5 mL), nitrogen was replaced, and the mixture was reacted at room temperature for 24 h. After the reaction, 3 mL of ethyl acetate was added, the mixture was washed with water three times and saturated brine once, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain a urea intermediate. The urea intermediate was dissolved in CH3CN (1.5 mL), CH3I (20 equivalents of thiourea) was added, the mixture was reacted at 30°C for 8 h, the mixture was concentrated, and the mixture was subjected to column chromatography to obtain a quaternary ammonium salt intermediate. After being spin-dried, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added, and the mixture was reacted at 55°C for 6 h. After the reaction, the tetrahydrofuran was spin-dried, and water was removed in vacuo with phosphorus pentoxide. After the mixture was ground into powder with a small spoon, 4 mL of the mixture was first added. Then 7 drops of tetrahydrofuran were added to Et2O, and the solid was cleaned by ultrasonication and rolling, and the supernatant was sucked out. This was repeated 3 times, and the supernatant and the solid were filtered together. The filter cake was drained to obtain the catalyst (S,S)-1c (brown solid, 0.0905 g, yield 49%);

[0153] The basic parameters of the compound are as follows: 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),9.90(s,1H),9.32(d,J=10.0Hz,1H),8.91(s,1H) ,8.22(d,J=8.8Hz,1H),8.07(d,J=8.4Hz,1H),7.66(d,J=8.4Hz,1H),7.62(t,J=8.0Hz, 1H),7.49(t,J=8.4Hz,1H),7.46-7.38(m,2H),7.38-7.30(m,4H),7.20(d,J=6.8Hz,2H) ,7.07(t,J=1.6Hz,1H),6.24(d,J=9.6Hz,1H),4.29(s,3H),1.82(s,3H),1.25(s,18H); 13 C NMR (100MHz, DMSO-d6) δ188.8,182.8,179.8,167.1,164.6,155.3,151.6,145.5,140.1,138.3,137.7,136.8,136.3,133.4 ,132.2,131.4,130.3,129.2,128.4,128.2,127.7,127.1,127.0,125.1,124.3,116.6,112.7,58.2,47.3,34.6,31.1,15.9.

[0154] Examples 19 to 68:

[0155] This example screens the reaction conditions for the preparation of (2R, 3S) or (2S, 3R)-β-hydroxy-β-(p-methylsulfonylphenyl)-α-alanine tert-butyl ester. The general steps of this series of examples are as follows:

[0156] According to the specific requirements in Table 1, in a glove box, p-methylsulfonylbenzaldehyde 3a (0.2321 g, 1.26 mmol), additives (1.512 mmol) and chiral pyridinium salt carbonyl catalyst (0.00126 mmol) were weighed into a 50 mL Shrek tube, and then the solvent (7.0 mL) was added to the Shrek tube in sequence using a syringe at room temperature, and glycine tert-butyl ester 2a (0.4127 g, 3.15 mmol) was added at low temperature, and the reaction was carried out for the required time at this temperature; after the reaction was completed, anhydrous methanol (1.0 mL) and hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at the reaction temperature for 1 h, and then the reaction was continued at room temperature for 30 min, and then the diatomaceous earth was filtered, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude product of compound 4a; the NMR yield and dr value of compound 4a were obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative after the reaction with 1,1'-thiocarbonyldiimidazole;

[0157] The reaction equation is:

[0158]

[0159] The basic parameters of the compound are as follows:

[0160] 4a: white solid; 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 4.87 (d, J = 5.0 Hz, 1H), 3.53 (d, J = 5.0 Hz, 1H), 3.05 (s, 3H), 1.40 (s, 9H); 13 C NMR (100MHz, CDCl3) δ171.9,147.8,139.9,127.5,127.4,82.4,73.6,60.6,44.6,27.9.

[0161] Table 1 Reaction conditions, yields, dr values ​​and ee values ​​of Examples 19 to 68

[0162]

[0163]

[0164] The reaction conditions were screened in Table 1. First, the catalysts were screened. From Examples 19 to 35, it can be seen that the chiral pyridinium salt carbonyl catalysts (S,S)-1a-1~15 and (S,S)-1c can catalyze this reaction. Comparison found that the yield, dr value and ee value of the reactions using (S,S)-1a-1~3, 8, 13 and 15 as catalysts were relatively good and not much different, and they can all be used as preferred catalysts to catalyze the reaction (Examples 19, 21, 22, 27, 32 and 34). Among them, the best yields were (S,S)-1a-3 and (S,S)-1a-8 (86%), the best dr values ​​were (S,S)-1a-1~3 and 13 (12:1), and the best ee values ​​were (S,S)-1a-1 and 15 (98%). In comparison, at least one of the three results of (S,S)-1a-4~7, 9~12, 14 and (S,S)-1c was slightly worse, but they could all catalyze the reaction to obtain a better reaction result. Considering the catalytic reaction results and the difficulty of catalyst preparation, (S,S)-1a-1 was finally selected as the main catalyst for subsequent screening (Example 19).

[0165] Subsequently, the solvent, additive, catalyst equivalent and temperature of the reaction were screened. Five different solvents were screened for solvent, namely dichloromethane, tetrahydrofuran, toluene, methanol and ether (Examples 36 to 40). Except for methanol, which reacts with the catalyst to form acetal and causes the reaction to fail, the others can achieve the reaction, among which tetrahydrofuran has the highest yield. After shortening the reaction time to 6 hours, the dr value can also continue to increase (Example 40); different solvents were screened for additives, namely Na2HPO4·12H2O, Na2HPO4 (equivalent was screened at the same time), no additive (temperature was screened at the same time), MgSO4, NaH2PO4, KH2PO4, LiH2PO4 and NH4H2PO4 (Examples 40 to 5 0), these additive conditions can all achieve the reaction, among which NH4H2PO4 has the best reaction result, and the yield, dr value and ee value are improved at the same time (Example 50); in terms of temperature screening, the temperature was further lowered (-40 to -20°C, Examples 50 to 52), and it can be seen that the dr value of the reaction continued to increase with the decrease in temperature, but at -40°C, the reaction time needs to be extended (6 to 48h) and the ee value is slightly reduced, and although the dr value at -30°C is slightly lower, it is already greater than 20:1; then the catalysts were re-screened at this temperature (Examples 52 to 63), and it was found that catalyst (S,S)-1a-1 still had the best effect, with a slightly lower dr value but the best ee value, so we finally determined Example 52 as the reaction condition for substrate expansion. In addition, we also tried to reduce the catalyst equivalent (0.01~0.1mol%) and screened the temperature (-30~-10℃, Examples 64 to 68). The lowest temperature can be reduced to one ten-thousandth. At -20℃ and extending the reaction time (24~72h) to 72h, 1mg of catalyst can produce 3.22g of product. The dr and ee values ​​of these products maintain good results (15:1 / 98%).

[0166] Examples 69 to 87:

[0167] This example screens the reaction conditions for the preparation of (2R, 3S) or (2S, 3R)-β-hydroxy-β-(p-phenylphenyl)-α-alanine tert-butyl ester. The general steps of this example are as follows:

[0168] According to the specific requirements in Table 2, in a glove box, p-phenylbenzaldehyde 3af (0.2293 g, 1.26 mmol), additives (1.512 mmol), solid base (1.89 mmol) and chiral pyridinium salt carbonyl catalyst (0.00126 mmol) were weighed into a 50 mL Shrek tube, and then a solvent (6.0 mL) and a liquid base (1.89 mmol) were added to the Shrek tube in sequence using a syringe at room temperature, and glycine tert-butyl ester 2a (0.4127 g, 3.15 mmol) was added at low temperature, and the reaction was carried out for the required time at this temperature; after the reaction was completed, anhydrous methanol (1.0 mL) and a hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at the reaction temperature for 1 h, and then the reaction was continued at room temperature for 30 min, and then filtered with diatomaceous earth, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude compound 4af; the NMR yield and dr value of compound 4af were obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0169] The reaction equation is:

[0170]

[0171] The basic parameters of the compound are as follows:

[0172] 4af: white solid; 1 H NMR (400MHz, CDCl3) δ7.65-7.57(m,4H), δ7.51-7.42(m,4H), 7.37(t,J=7.2Hz,1H), 4.82(d,J=5.4Hz,1H), 3.59(d,J=5.4Hz,1H), 1.39(s,9H). 13 CNMR (100MHz, CDCl3) δ172.5,140.9,140.8,140.1,128.8,127.3,127.1,127.1,127.0,81.9,74.4,61.0,27.9.

[0173] Table 2 Bases, yields, dr values ​​and ee values ​​for reaction screening of Examples 69 to 87

[0174] Example catalyst additive Solvent Alkali Temperature / ℃ Reaction time / h Yield (%) dr value / ee value (%) 69 (S,S)-1a-1 / 0.5mol% none Dichloromethane <![CDATA[Na3PO4]]> -5 48 35 1.6:1 / 52 70 (S,S)-1a-1 / 0.5mol% none Dichloromethane <![CDATA[K3PO4]]> -5 48 25 1.6:1 / 58 71 (S,S)-1a-1 / 0.5mol% none Dichloromethane <![CDATA[Cs2CO3]]> -5 48 32 1:0.8 / 55 72 (S,S)-1a-1 / 0.5mol% none Dichloromethane DIPEA -5 48 60 1.6:1 / 90 73 (S,S)-1a-1 / 0.5mol% none Dichloromethane <![CDATA[Et3N]]> -5 48 70 1.9:1 / 49 74 (S,S)-1a-1 / 0.5mol% none Dichloromethane <![CDATA[Et3N]]> -5 20 71 3:1 / 68 75 (S,S)-1a-5 / 0.5mol% none Dichloromethane <![CDATA[Et3N]]> -5 20 67 1.9:1 / 69 76 (S,S)-1a-1 / 0.5mol% none Dichloromethane <![CDATA[Et3N]]> -20 24 86 5:1 / 93 77 (S,S)-1a-1 / 0.5mol% none Chloroform <![CDATA[Et3N]]> -20 24 52 5:1 / 90 78 (S,S)-1a-1 / 0.5mol% none Toluene <![CDATA[Et3N]]> -20 24 87 6:1 / 79 79 (S,S)-1a-1 / 0.5mol% none Methanol <![CDATA[Et3N]]> -20 24 5 1:1 / 9 80 (S,S)-1a-1 / 0.5mol% none Acetonitrile <![CDATA[Et3N]]> -20 24 55 5:1 / 87 81 (S,S)-1a-1 / 0.5mol% none Tetrahydrofuran <![CDATA[Et3N]]> -20 24 92 10:1 / 91 82 (S,S)-1a-1 / 0.25mol% none Tetrahydrofuran <![CDATA[Et3N]]> -20 24 91 9:1 / 93 83 (S,S)-1a-1 / 0.1mol% none Tetrahydrofuran <![CDATA[Et3N]]> -20 24 85 15:1 / 94 84 (S,S)-1a-1 / 0.1mol% none Tetrahydrofuran <![CDATA[Et3N]]> -30 24 94 ＞20:1 / 97 85 (S,S)-1a-1 / 0.1mol% none Tetrahydrofuran <![CDATA[Et3N]]> -30 48 94 15:1 / 98 86 (S,S)-1a-1 / 0.1mol% none Tetrahydrofuran <![CDATA[Et3N]]> -40 48 94 ＞20:1 / 98 87 (S,S)-1a-1 / 0.1mol% <![CDATA[NaH2PO4]]> Tetrahydrofuran <![CDATA[Et3N]]> -40 48 94 ＞20:1 / 99

[0175] The reaction conditions were screened in Table 2. In Examples 69 to 75, five bases, Na3PO4, K3PO4, Cs2CO3, DIPEA and Et3N were compared (Examples 69 to 73), and it was found that the base with the best result was Et3N. The reaction time and catalyst type were screened (Examples 73 to 75), and it was found that shortening the time (20 to 48 h) could improve the selectivity of the reaction and that the catalytic effect of (S,S)-1a-1 was still the best compared with (S,S)-1a-5. The temperature was then lowered to -20°C (-20 to -5°C) and the solvents were screened. Dichloromethane, chloroform, toluene, methanol, acetonitrile and tetrahydrofuran were screened respectively (Examples 76 to 81), and it was found that the reaction time and catalyst type were still the best except for (S,S)-1a-5. Except for methanol, which had a very poor reaction effect, other solvents had very good effects, among which tetrahydrofuran had the best effect (Example 81); then the equivalent of the catalyst was screened (0.1-0.5 mol%, Examples 81 to 83), and it was found that a good yield could be maintained when the equivalent was reduced to one thousandth, and the dr value continued to increase as the temperature decreased; finally, the temperature was screened (-40--20°C, Examples 83 to 86), and as the temperature decreased, the dr value and ee value increased. Comparison of Examples 84 and 85 once again proved that the dr value would decrease with prolonged time (24-48h); after adding NaH2PO4 in Example 87, the ee value of the reaction was increased to 99%, and the reaction conditions for substrate expansion were finally determined.

[0176] Examples 88 to 113:

[0177] This example screens the reaction conditions for the preparation method of (2R, 3S) or (2S, 3R)-β-hydroxy-β-(n-nonyl)-α-alanine tert-butyl ester. The general steps of this example are as follows:

[0178] According to the specific requirements in Table 3, in a glove box, NH4H2PO4 and a chiral pyridinium salt carbonyl catalyst were weighed into a 50 mL Shrek tube, and then tetrahydrofuran, decanal 3bb (0.1969 g, 1.26 mmol) and triethylamine were added to the Shrek tube in sequence using a syringe at -30°C. After stirring at -30°C for 20 min, glycine tert-butyl ester 2a was added dropwise at low temperature, and the reaction was carried out for the required time at this temperature; after the reaction was completed, anhydrous methanol (1.0 mL) and hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at the reaction temperature for 1 h, and then the reaction was continued at room temperature for 30 min, and then filtered with diatomaceous earth, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude product of compound 4bb; the NMR yield and dr value of compound 4bb were obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0179] The reaction equation is:

[0180]

[0181] The basic parameters of this compound are as follows:

[0182] 4bb: yellow oil; 1 H NMR(400MHz, CDCl3) δ3.70-3.62(m,1H),3.22(d,J=5.2Hz,1H),2.06(brs,3H),1.52-1 .49(m,1H),1.48(s,9H),1.46-1.44(m,1H),1.34-1.22(m,14H),0.87(t,J=6.8Hz,3H). 13 C NMR (100MHz, CDCl3) δ173.7,81.8,72.3,59.0,34.2,32.0,29.8,29.7,29.7,29.4,28.2,25.8,22.8,14.2.

[0183] Table 3 Bases, yields, dr values ​​and ee values ​​for reaction screening of Examples 88 to 113

[0184]

[0185] In Table 3, the reaction conditions were screened. In Examples 88 to 91, the temperature was screened, and it was found that as the temperature decreased (-40 to -10°C), the reaction results gradually improved, and the effect was best at -30°C; in Examples 92 to 94, the equivalents of glycine tert-butyl ester (1.2 to 4.0) were screened, and it was found that 2.0 equivalents still had the best effect; in Examples 95 to 98, the equivalents of the base (1.5 to 3.0) were screened by shortening the reaction time (24 to 48h), and it was found that 2.0 equivalents still had the best effect, and the results could still be maintained by shortening the time by half; in Examples 99 to 103, the equivalents of NH4H2PO4 (0.6 to 2.0) were screened, and it was found that 0.8-1.2 equivalents had similar effects, and finally 1.0 equivalents were selected for subsequent screening; in Examples 104 to 106, the equivalents of the catalyst (0.1 to 1.0mol%) was screened, and it was found that with the increase of catalyst equivalent, the yield gradually increased while keeping the selectivity unchanged, but the result from 0.5 to 1000 did not change significantly, and the screening was continued at 0.5%; in Examples 107 to 110, the concentration (solvent volume 6-20mL) was screened, and it was found that with the decrease of concentration, the yield gradually increased and the dr value gradually decreased, and the reaction result was best when the solvent volume was 12-15mL, and the screening was continued at 12mL; in Examples 111 and 112, the catalyst equivalent (0.1-0.5mol%) was screened again at this concentration, and it was found that the reaction result could still be maintained when it was reduced to 0.2%, and the yield decreased at 0.1%; finally, in Example 113, the addition method of glycine tert-butyl ester and solvent was changed under the condition of 0.2% catalyst, and the reaction conditions for substrate expansion were determined.

[0186] Examples 114 to 1905:

[0187] This example expands the aromatic aldehyde and alkyl aldehyde substrates adapted to the preparation method of chiral β-hydroxy-α amino acid derivatives catalyzed by pyridoxal quaternary ammonium salt. The general steps of this example are as follows (Examples 114 to 116, 130, 136 and 143 use general method one, Examples 150 to 175 use general method two, Examples 117 to 129, 131 to 135, 137 to 142, 144 to 149, 176 to 182 use general method three, and Examples 183 to 1905 use general method four):

[0188] General method 1 (aromatic aldehyde with strong electron-withdrawing substituent): In a glove box, aromatic aldehyde (1.26 mmol), NH4H2PO4 (0.1739 g, 1.512 mmol) and chiral pyridinium salt carbonyl catalyst (R,R)-1a-1 (0.001 g, 0.00126 mmol) were weighed into a 50 mL Shrek tube. Then, tetrahydrofuran (7.0 mL) was added to the Shrek tube in sequence using a syringe at room temperature. Glycine was added at -30 °C. Derivative 2 (3.15 mmol) was reacted at this temperature for 10 h; after the reaction, anhydrous methanol (1.0 mL) and hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at -30 ° C for 10 min, at -20 ° C for 50 min, and after returning to room temperature for 30 min, diatomaceous earth was filtered, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude chiral β-hydroxy-α amino acid derivative; the NMR yield and dr value of the product were obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0189] General method 2 (aromatic aldehydes with strong electron donating, weak electron withdrawing and weak electron donating substituents): In a glove box, aromatic aldehyde (1.26 mmol), chiral pyridinium salt carbonyl catalyst (R,R)-1a-1 (0.001 g, 0.00126 mmol) and NaH2PO4 (0.1814 g, 1.512 mmol) were weighed into a 50 mL Shrek tube, and then tetrahydrofuran (6.0 mL) and triethylamine (0.263 mL, 1.89 mmol) were added to the Shrek tube in sequence using a syringe at room temperature. In a Leick tube, glycine derivative 2 (3.15 mmol) was added at -40°C and reacted at this temperature for 48 h; after the reaction, anhydrous methanol (1.0 mL) and hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at -40°C for 10 min, at -20°C for 50 min, and after returning to room temperature for 30 min, diatomaceous earth was filtered, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude chiral β-hydroxy-α amino acid derivative; the NMR yield and dr value of the product were obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0190] General method three (alkyl aldehyde): In a glove box, alkyl aldehyde (1.26 mmol), NH4H2PO4 (0.145 g, 1.26 mmol) and chiral pyridinium salt carbonyl catalyst (R,R)-1a-1 (0.00252 mmol) were weighed into a 50 mL Shrek tube. Then, at -30 ° C, the solvent (11.5 mL) and triethylamine (350 μL, 2.52 mmol) were added to the Shrek tube in sequence using a syringe. After stirring at -30 ° C for 20 min, the glycine derivative 2 (3.15 mmol) was added. , dissolved in 0.5 mL of tetrahydrofuran and then frozen at -30°C for 30 min) was quickly added with a syringe and reacted at this temperature for 20 min; after the reaction, anhydrous methanol (1.0 mL) and hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction continued at -30°C for 10 min, at -20°C for 50 min, and after returning to room temperature for 30 min, diatomaceous earth was filtered, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude chiral β-hydroxy-α amino acid derivative; the NMR yield and dr value of the product were obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0191] General method 4 (high-throughput synthesis): A module capable of accommodating 20 threaded test tubes for simultaneous reaction was customized and placed in a low-temperature reactor for reaction; in a glove box, aromatic aldehyde (0.315 mmol), NH4H2PO4 (43.5 mg, 0.378 mmol) or NaH2PO4 (45.3 mg, 0.378 mmol), and chiral pyridinium salt carbonyl catalyst (S,S)-1a-1 or (R,R)-1a-1 (0.5 mg in 1.0 mL THF, 0.00063mmol), take the sealed vial out of the glove box, place it at -40°C, then add glycine tert-butyl ester (82.5mg, 0.63mmol) or a mixture of glycine tert-butyl ester and triethylamine (66μL, 0.4725mmol) through a syringe, and react at -40°C for 48h; after the reaction, add anhydrous methanol (0.2mL) and hydroxylamine aqueous solution (0.2mL, 50wt.% aqueous solution), and continue to react at -40°C for 10min , react at -20°C for 40 min, return to room temperature for 30 min, dilute with dichloromethane / anhydrous methanol (3 mL / 2 mL), filter through a syringe filter, concentrate under reduced pressure, and dry in vacuo for 20 h in the presence of phosphorus pentoxide; dissolve the dried crude product with deuterated chloroform (2 mL) and water (0.1 mL) to remove excess hydroxylamine in the crude product; transfer the organic layer directly to a syringe containing sodium sulfate with a pipette and filter through a syringe filter; the NMR yield and dr value of the product are obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0192] The reaction equation is:

[0193]

[0194] The basic parameters of the compounds are shown in Table 4.

[0195] Table 4 Product structures, yields, dr values, ee values ​​and NMR characterization of Examples 114 to 1905

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A chiral pyridinium salt carbonyl catalyst, characterized in that: The general structural formula of the pyridinium salt carbonyl catalyst 1 is: Among them, R 1 The structural formula is: X1 includes N or CR 6 , X2 includes N or CR 7 , X3 includes N or CR 8 , X4 includes N or CR 9 , X5 includes N or CR 10 , X6 includes N or CR 11 ; R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Including hydrogen, C 1～24 Alkyl, alkyloxy, CO2R d , halogen, nitro, cyano or trifluoromethyl; R a Including hydrogen, C 1～10 alkyl, aryl, halogen, nitro, cyano or trifluoromethyl, R b , R 2b , R 3b , R c , R 2c and R d Including hydrogen, C 1～10 alkyl or aryl, m is 1, 2 or 3, and n is 0, 1, 2, 3, 4 or 5; R 3 Including substituted or unsubstituted C 1～24 Alkyl, substituents include halogen, C 1～10 Alkyl, C 3～10 Cycloalkyl or aryl, C 1～8 The carbonyl group, C 1～8 Sulfonyl or phosphoryl, C 1～10 The carbonyl group includes an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group; R 5 The structural formula is: R 12 and R 13 Including hydrogen, C 1～24 Alkyl or R 14 Including hydrogen, C 1～24 The alkyl group Arylmethyl, diarylmethyl, triarylmethyl, halogen or trifluoromethyl; R e Including hydrogen, C 1～10 alkyl, alkyloxy, aryl, halogen, nitro, cyano or trifluoromethyl, x and y are 0, 1, 2 or 3; The alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, cyclopentyl, isobutyl, n-hexyl, cyclohexyl, n-heptyl, cycloheptyl, n-octyl, cyclooctyl, n-nonyl, cyclononyl, n-decyl or cyclodecyl, and the aryl group includes benzene, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2,6-biphenyl, 3,5-biphenyl, 1-naphthyl, 2-naphthyl, 3,5-di-tert-butylbenzene, 4-tert-butylbenzene, 3,5-difluorobenzene, 4-fluorobenzene, 3,5-dichlorobenzene, 4-chlorobenzene, 3,5-ditrifluoromethylbenzene, 4-trifluoromethylbenzene, 3,5-dimethylbenzene, 4-methylbenzene or 4-methoxybenzene; X - is an anion, and the anion includes fluoride ion, chloride ion, bromide ion, iodide ion, trifluoromethanesulfonate ion, hexafluorophosphate ion, tetrafluoroborate ion, sulfate ion, sulfite ion, hydroxide ion, nitrate ion, phosphate ion, carbonate ion, silicate ion, bicarbonate ion, hydrogenphosphate ion, dihydrogenphosphate ion, iodate ion, cyanide ion or thiocyanate ion.

2. A chiral pyridinium salt carbonyl catalyst according to claim 1, characterized in that: The R 1 It forms axial chirality with the pyridine ring, and the axial chirality configuration is R or S configuration.

3. A chiral pyridinium salt carbonyl catalyst according to claim 2, characterized in that: The catalyst has a formula I a , Formula I b , Formula II a Or Formula II b The structure shown in Formula I a With formula I b are enantiomers of each other, formula II a With formula II b Enantiomers:

4. A method for preparing a chiral pyridinium salt carbonyl catalyst as claimed in any one of claims 1 to 3, characterized in that: The method uses the split single-configuration compound 5 as the starting material, and the chiral amine compound 5 is condensed with dimethyl squarate to generate compound 6, which is then condensed with a primary amine to obtain an amide intermediate, which is then reacted with a halogenated hydrocarbon to obtain a quaternary ammonium salt intermediate, and finally hydrolyzed to obtain the final pyridinium salt carbonyl catalyst 1a. The reaction process is as follows:

5. The method for preparing a chiral pyridinium salt carbonyl catalyst according to claim 4, characterized in that: The molar ratio of the compound 5 to dimethyl squarate is 1:(1-10), the reaction temperature is -20-120°C, and the reaction time is 1-72h; The molar ratio of the compound 6 to the primary amine and the halogenated hydrocarbon is 1:(1-50):(1-50), the reaction temperature is 0-100° C., and the reaction time is 1-48 hours.

6. A method for preparing a chiral pyridinium salt carbonyl catalyst as claimed in any one of claims 1 to 3, characterized in that: The method uses the split single-configuration compound 5 as the starting material, and the chiral amine compound 5 is condensed with a unilateral square amide to obtain an amide intermediate, which is then reacted with a halogenated hydrocarbon to obtain a quaternary ammonium salt intermediate, and finally hydrolyzed to obtain the final pyridinium salt carbonyl catalyst 1a. The reaction process is as follows:

7. The method for preparing a chiral pyridinium salt carbonyl catalyst according to claim 6, characterized in that: The molar ratio of the compound 5 to the unilateral square amide and the halogenated hydrocarbon is 1:(1-50):(1-50), the reaction temperature is -20-120°C, and the reaction time is 1-72h.

8. A method for preparing a chiral pyridinium salt carbonyl catalyst as claimed in any one of claims 1 to 3, characterized in that: The method uses the resolved single-configuration compound 5 as the starting material, and the chiral amine compound 5 is condensed with thioisocyanate or isocyanate to generate compound 7 or 8. Compound 7 or 8 is then reacted with a halogenated hydrocarbon to obtain a quaternary ammonium salt intermediate, and finally hydrolyzed to obtain the final pyridinium salt carbonyl catalyst 1b or 1c. The reaction process is as follows:

9. The method for preparing a chiral pyridinium salt carbonyl catalyst according to claim 8, characterized in that: The molar ratio of the compound 5 to the thioisocyanate or isocyanate is 1:(1-10), the reaction temperature is -20-120°C, and the reaction time is 1-72h; The molar ratio of the compound 7 or 8 to the halogenated hydrocarbon is 1:(1-50), the reaction temperature is 0-100° C., and the reaction time is 1-48 hours.

10. A method for preparing a chiral pyridinium salt carbonyl catalyst as claimed in any one of claims 1 to 3, characterized in that: The method uses the resolved single-configuration compound 5 as a starting material, the chiral amine compound 5 is condensed with thioisocyanate to generate compound 9, compound 9 is coupled with primary amine under the action of carbodiimide hydrochloride to generate compound 10, compound 10 is deprotected from ethyl carbonate protecting group under the action of trimethylsilyl bromide to generate compound 11, compound 11 is then reacted with a halogenated hydrocarbon to obtain a quaternary ammonium salt intermediate, and finally hydrolyzed to obtain the final pyridinium salt carbonyl catalyst 1d. The reaction process is as follows:

11. The method for preparing a chiral pyridinium salt carbonyl catalyst according to claim 10, characterized in that: The molar ratio of the compound 5 to the thioisocyanate is 1:(1-10), the reaction temperature is -20-120°C, and the reaction time is 1-72h; The molar ratio of the compound 9 to carbodiimide hydrochloride and primary amine is 1:(1-10):(1-10), the reaction temperature is 0-100° C., and the reaction time is 1-72 h; The molar ratio of the compound 10 to trimethylsilyl bromide is 1:(1-10), the reaction temperature is 0-100° C., and the reaction time is 1-72 h; The molar ratio of the compound 11 to the halogenated hydrocarbon is 1:(1-50), the reaction temperature is 0-100° C., and the reaction time is 1-48 hours.

12. A method for preparing a chiral pyridinium salt carbonyl catalyst according to claim 4, 6, 8 or 10, characterized in that: The solvent used in the method is selected from one or more of water, benzene, toluene, xylene, trimethylbenzene, acetonitrile, ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, methanol, ethanol, isopropanol, tert-butyl alcohol, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone; The acid used is selected from one or more of sulfuric acid, hydrochloric acid, dichloromethane solution of hydrochloric acid, methanol solution of hydrochloric acid, tetrahydrofuran solution of hydrochloric acid, dioxane solution of hydrochloric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid.

13. A method for preparing a chiral pyridinium salt carbonyl catalyst as claimed in any one of claims 1 to 3, characterized in that: The method comprises adding silver salt to a pyridinium salt carbonyl catalyst of iodide ion to perform substitution to obtain a pyridinium salt carbonyl catalyst with the corresponding anion of the silver salt; The silver salt includes silver fluoride, silver chloride, silver bromide, silver trifluoromethanesulfonate, silver hexafluorophosphate, silver tetrafluoroborate, silver sulfate, silver sulfite, silver hydroxide, silver nitrate, silver phosphate, silver carbonate, silver silicate, silver bicarbonate, silver hydrogen phosphate, silver dihydrogen phosphate, silver iodate, silver cyanide or silver thiocyanate.

14. Use of a chiral pyridinium salt carbonyl catalyst as claimed in any one of claims 1 to 3, characterized in that: The pyridinium salt carbonyl catalyst 1 is used for the asymmetric biomimetic aldol reaction of amino acid derivatives and carbonyl compounds to synthesize chiral β-hydroxy-α-amino acid compounds. The reaction comprises the following steps: Amino acid derivative 2 and carbonyl compound 3 undergo aldol reaction under the catalysis of pyridinium salt carbonyl catalyst 1 to generate chiral β-hydroxy-α-amino acid compound 4, including syn-4A, anti-4A and syn-4B, anti-4B different configurations. The absolute configuration of pyridinium salt carbonyl catalyst 1 determines the absolute configuration of chiral β-hydroxy-α-amino acid compound 4. The reaction equation is: Among them, R 15 including hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C3-C 18 Aryl, substituted or unsubstituted C 2～18 Alkenyl, substituted or unsubstituted C 2～24 Alkynyl, or C 1～18 The carbonyl group, the substituents include halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 The aromatic group, C 1-18 The carbonyl group, C 1～18 Sulfonyl or phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 The carbonyl group includes an aldehyde group, a ketone carbonyl group, an ester carbonyl group, a carboxyl group or an amide group; R 16 OR 19 or NR 20 R 21 , where R 19 including hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, C 1～18 The carbonyl group, R 20 and R 21 including hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, C 1～18 The carbonyl group, or R 20 and R 21 Together they form ring B, or NR 20 R 21 It includes amino acid amine, amino acid ester amine, amino acid amide amine or polypeptide amine, and the substituent includes halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 The aromatic group, C 1-18 The carbonyl group, C 1～18 Sulfonyl or phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 The carbonyl group includes an aldehyde group, a ketone carbonyl group, an ester carbonyl group, a carboxyl group or an amide group, and the ring B is a C containing 1 to 4 heteroatoms. 1～18 The heteroatom is an O, N or S atom; R 17 and R 18 including hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, substituted or unsubstituted C 2～18 Alkenyl, substituted or unsubstituted C 2～24 Alkynyl, substituents include halogen, cyano, hydroxy, nitro, trifluoromethyl, C 1～18 Alkyl, C 3～18 The aromatic group, C 1-18 The carbonyl group, C 1～18 Sulfonyl or phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 The amino group, The carbonyl group includes an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group; R b , R 2b and R 3b Including hydrogen, C 1～10 wherein m is 1, 2 or 3, and n is 0, 1, 2, 3, 4 or 5.

15. The use of a chiral pyridinium salt carbonyl catalyst according to claim 14, characterized in that: The molar ratio of the amino acid derivative 2 to the carbonyl compound 3 is (0.5-5):1, the molar ratio of the pyridinium salt carbonyl catalyst 1 to the carbonyl compound 3 is (0.00001-0.5):1, the reaction temperature is -60-100°C, and the reaction time is 1-72h; The solvent used in the reaction is selected from one or more of water, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, 1,4-dioxane, trifluoroethanol, benzene, toluene, xylene, trimethylbenzene, acetonitrile, ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone; The base used is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydride, potassium hydride, calcium hydride, trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, N,N-diethylmethylamine, N,N-dimethylethylamine, N,N-dimethylpropylamine, N,N-dimethylbutylamine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane, diazabicyclododecane, 1,5-diazabicyclo[4.3.0]-5-nonene, n-butyllithium, 1,4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, n-butylamine, tert-butylamine, diethylamine, ethylenediamine, quinoline and pyridine; The additives used are selected from one or more of ammonium phosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, lithium phosphate, lithium dihydrogen phosphate, dilithium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium acetate, potassium acetate, potassium fluoride and sodium fluoride.

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