Chiral pyridinium salt carbonyl catalysts and methods for their preparation and use

Abstract

The present invention provides chiral pyridinium salt carbonyl catalysts and methods for their preparation and use. The general structural formula of the catalyst is [Formula 1] TIFF2026501952000195.tif36170[where, R 1 Structural formula of [chemical 2] TIFF2026501952000196.tif25170X 1-6 is N or CR 6-11 Including, R 2 , R 4 , R 6-11 is hydrogen, C 1~24 alkyl groups, alkoxy groups, [C3] TIFF2026501952000197.tif7170 groups, [C4] TIFF2026501952000198.tif14170, [C5] TIFF2026501952000199.tif14170 [6] TIFF2026501952000200.tif14170, CO2R d , halogen, nitro group, cyano group or trifluoromethyl group, R 3 is a substituted or unsubstituted C 1~24 The alkyl group may be substituted with halogen or C 1~10 Alkyl groups of C 3~10 cycloalkyl or aryl group, C 1~8 carbonyl group, C 1~8 a sulfonyl group or a phosphoryl group of C 1~10 The carbonyl group includes an aldehyde group, a ketocarbonyl group, an estercarbonyl group, a carboxyl group, or an amide group; R 5 Structural formula of [C7] TIFF2026501952000201.tif18170X - is an anion] Compared with the prior art, the catalyst of the present invention can be used in the biomimetic aldol reaction of amino acid derivatives to synthesize a series of β-hydroxy-α-amino acid compounds with extremely high enantioselectivity.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims partial priority from Chinese Patent Application No. 202310794646.0, entitled "Chiral Pyridinium Salt Carbonyl Catalysts and Preparation Methods and Uses Thereof," filed on June 30, 2023, and Chinese Patent Application No. 202410863976.5, entitled "Chiral Pyridinium Salt Carbonyl Catalysts and Preparation Methods and Uses Thereof," filed on June 30, 2024, the relevant contents of which are incorporated herein by reference.

[0002] The present invention belongs to the technical field of chemical synthesis, and relates to chiral pyridinium salt carbonyl catalysts and their preparation methods and uses. [Background technology]

[0003] In vivo, threonine aldolase catalyzes the direct addition of glycine to acetaldehyde to produce threonine (β-hydroxyα-aminobutyric acid). The active center of this enzyme is vitamin B6, a water-soluble vitamin that includes pyridoxal, pyridoxine, pyridoxamine, and their phosphate ester derivatives. Its main function is as a coenzyme factor, participating in various enzyme-catalyzed reactions. Since the 1980s, chemists have been mimicking the chemical structure of vitamin B6 to develop biomimetic catalysts / artificial enzymes. For example, the asymmetric aldol reaction of glycine with aldehydes involving an equivalent amount of chiral carbonyl catalyst, conducted by Kuzuhara and Breslow, laid the foundation for biomimetic studies 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; J. T. Koh, L. Delaude, R. Breslow, J. Am. Chem. Soc. 1994, 116, 11234-11240). These studies usually required the use of an equivalent amount of chiral pyridoxal, and the early chiral pyridoxal carbonyl catalysts were not widely applicable to organic synthesis due to their moderate reactivity and stereoselectivity and limited applicability to aldehyde substrates.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 of trifluoromethyl ketones, the asymmetric Michael addition reaction and asymmetric α-allylation reaction, and the asymmetric aldol reaction of unactivated aromatic and alkynylmethylamines, achieving very 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. et al. al, Nat. Catal. 2022, 5, 1061-1068; Ji, P. et al, Angew. Chem. Int. Ed. 2022, 61, e202206111). However, a chiral carbonyl catalyst capable of efficiently catalyzing the aldol reaction of glycine compounds with aldehydes has not yet been successfully developed. The main reasons for this are that the reaction faces many challenges, including: (1) aldehydes readily form imines with glycine compounds, preventing the aldol reaction from proceeding; (2) under carbonyl catalysis, the product is prone to undergo a retroaldol reaction, resulting in decomposition and racemization; and (3) the product amino α-H is highly acidic, prone to epimerization under basic conditions, making it difficult to control the enantioselectivity and diastereoselectivity of the product. Due to these challenges, no catalyst capable of efficiently catalyzing this transformation has yet been developed.

[0004] Many β-hydroxy-α-amino acids are important pharmaceutical intermediates, and their synthesis has attracted widespread attention. Although there have been reports on the aldol reaction of glycine with aldehydes catalyzed by biological enzymes, the moderate conversion and low diastereoselectivity have limited the synthetic application of biological methods for preparing β-hydroxy-α-amino acids (Duckers, 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). The asymmetric aldol reaction of glycine and its derivatives with aldehydes using chemical catalysts is also difficult to achieve. This is because there is currently a lack of chiral catalysts that can efficiently catalyze this reaction, making it difficult to achieve rapid chemical synthesis of chiral β-hydroxy-α-amino acid compounds. Summary of the Invention [Problem to be solved by the invention]

[0005] The object of the present invention is to overcome at least one of the deficiencies of the above-mentioned prior art by providing a chiral pyridinium salt carbonyl catalyst, which can be used in the biomimetic aldol reaction of amino acid derivatives to synthesize a series of β-hydroxy-α-amino acid compounds with extremely high enantioselectivity, as well as a preparation method and use thereof. [Means for solving the problem]

[0006] The object of the present invention can be achieved through the following technical means.

[0007] One of the technical solutions of the present invention is to provide a chiral pyridinium salt carbonyl catalyst, the general structural formula of which is as follows:

[0008] [ka]

[0009] In the formula, R 1 The structural formula is as follows:

[0010] [ka] [X1 is N or CR 6 and X2 is N or CR 7 X3 is N or CR 8 X4 is N or CR 9 Includes, X5 is N or CR 10 X6 is N or CR 11 Including, R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is hydrogen, C 1~24 Alkyl groups, alkoxy groups, [ka] base, [ka] , [ka] [ka] , CO2R d , halogen, nitro group, cyano group or trifluoromethyl group, R a is hydrogen, C 1~10 R b , R 2b , R 3b , R c , R 2cand R d is hydrogen, C 1~10 wherein m is 1, 2, or 3, and n is 0, 1, 2, 3, 4, or 5; R 3 is a substituted or unsubstituted C 1~24 The alkyl group may be substituted with halogen or C 1~10 Alkyl groups of C 3~10 cycloalkyl or aryl group, C 1~8 carbonyl group, C 1~8 a sulfonyl group or a phosphoryl group of C 1~10 The carbonyl group includes an aldehyde group, a ketocarbonyl group, an estercarbonyl group, a carboxyl group, or an amide group. R 5 The structural formula is as follows:

[0011] [ka] [R 12 and R 13 is hydrogen, C 1~24 or an alkyl group of [ka] Contains R 14 is hydrogen, C 1~24 an alkyl group of [ka] , arylmethyl, diarylmethyl, triarylmethyl, halogen or trifluoromethyl; R e is hydrogen, C 1~10 wherein x and y are 0, 1, 2, or 3; Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, an isobutyl group, a cyclopentyl group, a cyclobutyl group, an n-hexyl group, a cyclohexyl group, an n-heptyl group, a cycloheptyl group, an n-octyl group, a cyclooctyl group, an n-nonyl group, a cyclononyl group, an n-decyl group, and a cyclodecyl group. Examples of the aryl group include a benzene group, a 2-biphenyl group, a 3-biphenyl group, a 4-biphenyl group, Examples include a 2,6-diphenyl group, a 3,5-diphenyl group, a 1-naphthyl group, a 2-naphthyl group, a 3,5-di-tert-butylbenzene group, a 4-tert-butylbenzene group, a 3,5-difluorobenzene group, a 4-fluorobenzene group, a 3,5-dichlorobenzene group, a 4-chlorobenzene group, a 3,5-ditrifluoromethylbenzene group, a 4-trifluoromethylbenzene group, a 3,5-dimethylbenzene group, a 4-methylbenzene group, and a 4-methoxybenzene group; X - is an anion, and examples of the anion include a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a trifluoromethanesulfonate ion, a hexafluorophosphate ion, a tetrafluoroborate ion, a sulfate ion, a sulfite ion, a hydroxide ion, a nitrate ion, a phosphate ion, a carbonate ion, a silicate ion, a bicarbonate ion, a hydrogen phosphate ion, a dihydrogen phosphate ion, an iodate ion, a cyanide ion, and a thiocyanate ion.]

[0012] In addition, the R 1 and the pyridine ring, axial asymmetry is formed, and the axial asymmetry has an R or S configuration.

[0013] The catalyst may also be a compound represented by formula I a , Formula I b , formula II a or Formula II b and having the structure shown in Formula I a and Formula I b are enantiomers of each other and have formula II a and Equation II b are enantiomers of each other.

[0014] [ka]

[0015] One technical solution of the present invention is to provide a method for preparing chiral pyridinium salt carbonyl catalysts, which involves using the single-configuration compound 5 after resolution as the starting material, condensing the chiral amine compound 5 with dimethyl squarate in a solvent to produce compound 6, which is then condensed with a primary amine to produce an amide intermediate, which is then reacted with a halogenated hydrocarbon to produce a quaternary ammonium salt intermediate, and finally hydrolyzing the intermediate under acid to produce the final product, pyridinium salt carbonyl catalyst 1a. The reaction process is as follows:

[0016] [ka]

[0017] The molar ratio of the compound 5 to dimethyl squarate is 1:(1 to 10), the reaction temperature is −20 to 120° C., and the reaction time is 1 to 72 hours. The molar ratio of the compound 6 to the primary amine and halogenated hydrocarbon is 1:(1-50):(1-50), the reaction temperature is 0-100° C., and the reaction time is 1-48 hours.

[0018] One technical solution of the present invention is to provide a method for preparing chiral pyridinium salt carbonyl catalysts, which involves using the single-configuration compound 5 after resolution as the starting material, condensing the chiral amine compound 5 with one side of squaramide to obtain an amide intermediate, which is then reacted with a halogenated hydrocarbon to obtain a quaternary ammonium salt intermediate, and finally hydrolyzing it to obtain the final product, pyridinium salt carbonyl catalyst 1a. The reaction process is as follows:

[0019] [ka]

[0020] The difference between the above methods is that in Method 2, instead of the two-step reaction of dimethyl squaramide and a primary amine in Method 1, one of the squaramides is used after condensation.

[0021] The molar ratio of the compound 5 to one of the squaramide and halogenated hydrocarbon is 1:(1 to 50):(1 to 50), the reaction temperature is −20 to 120° C., and the reaction time is 1 to 72 hours.

[0022] One technical solution of the present invention is to provide a method for preparing chiral pyridinium salt carbonyl catalysts, which involves using the single-configuration compound 5 after resolution as the starting material, condensing the chiral amine compound 5 with an isothiocyanate or isocyanate in a solvent to produce compound 7 or 8, which is then reacted with a halogenated hydrocarbon to obtain a quaternary ammonium salt intermediate, which is finally hydrolyzed under acid to obtain the final product, pyridinium salt carbonyl catalyst 1b or 1c. The reaction process is as follows:

[0023] [ka]

[0024] The molar ratio of the compound 5 to the isothiocyanate or isocyanate is 1:(1 to 10), the reaction temperature is −20 to 120° C., and the reaction time is 1 to 72 hours. The molar ratio of the compound 7 or 8 to the halogenated hydrocarbon is 1:(1 to 50), the reaction temperature is 0 to 100° C., and the reaction time is 1 to 48 hours.

[0025] One technical solution of the present invention is to provide a method for preparing chiral pyridinium salt carbonyl catalysts, starting from the single-configuration resolved compound 5. The chiral amine compound 5 is condensed with an isothiocyanate in a solvent to produce compound 9. Compound 9 is then coupled with a primary amine under the action of carbodiimide hydrochloride (EDCl) to produce compound 10. The ethyl carbonate protecting group of compound 10 is then removed under the action of trimethylsilyl bromide to produce compound 11. Compound 11 is then reacted with a halogenated hydrocarbon to produce a quaternary ammonium salt intermediate, which is finally hydrolyzed under the action of acid to produce the final product, pyridinium salt carbonyl catalyst 1d. The reaction process is as follows:

[0026] [ka]

[0027] The molar ratio of the compound 5 to the isothiocyanate is 1:(1 to 10), the reaction temperature is −20 to 120° C., and the reaction time is 1 to 72 hours. the molar ratio of the compound 9 to the carbodiimide hydrochloride and the primary amine is 1:(1-10):(1-10), the reaction temperature is 0-100°C, and the reaction time is 1-72 hours; The molar ratio of the compound 10 to trimethylsilyl bromide is 1:(1 to 10), the reaction temperature is 0 to 100°C, and the reaction time is 1 to 72 hours. The molar ratio of the compound 11 to the halogenated hydrocarbon is 1:(1 to 50), the reaction temperature is 0 to 100° C., and the reaction time is 1 to 48 hours.

[0028] In addition, 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; The acid used is selected from one or more of sulfuric acid, hydrochloric acid, a solution of hydrochloric acid in dichloromethane, a solution of hydrochloric acid in methanol, a solution of hydrochloric acid in tetrahydrofuran, a solution of hydrochloric acid in dioxane, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

[0029] The method also includes adding a silver salt to a pyridinium salt carbonyl catalyst having an iodide ion, and carrying out a substitution reaction to obtain a pyridinium salt carbonyl catalyst having a corresponding anion of the silver salt; Examples of the silver salt include 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 hydrogen carbonate, silver hydrogen phosphate, silver dihydrogen phosphate, silver iodate, silver cyanide, and silver thiocyanate.

[0030] As a preferred technical means, the silver salt may be selected from 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. - may be selected from a bisulfite ion, a bisulfite ion, an arsenate ion, an arsenite ion, a borate ion, a bromate ion, a hypobromite ion, a chlorate ion, a perchlorate ion, a hypochlorite ion, a chromate ion, an aluminosilicate ion, an acetate ion, a formate ion, a hydrogen oxalate ion, and a hydrogen sulfide ion.

[0031] In the preferred technical means, the molar ratio of the pyridinium salt carbonyl catalyst of iodide ion to silver salt is 1:1, the reaction temperature is room temperature, and the reaction time is 2 hours.

[0032] One technical solution of the present invention is to provide a chiral pyridinium salt carbonyl catalyst. The pyridinium salt carbonyl catalyst 1 is used in the asymmetric biomimetic aldol reaction of an amino acid derivative with a carbonyl compound to synthesize chiral β-hydroxy-α-amino acids (chiral β-hydroxy-α-amino acids and their derivatives). In a solvent, amino acid derivative 2 and carbonyl compound 3 undergo aldol reaction under the catalytic action of pyridinium salt carbonyl catalyst 1, in the presence of a base and an additive, to produce chiral β-hydroxy-α-amino acids 4, which have different configurations, syn-4A, anti-4A, and syn-4B, anti-4B. The absolute configuration of chiral β-hydroxy-α-amino acids 4 is determined by the absolute configuration of pyridinium salt carbonyl catalyst 1. The reaction scheme is as follows:

[0033] [ka] [In the formula, R 15 is hydrogen, substituted or unsubstituted C 1~24 Alkyl groups, substituted or unsubstituted C3-C 18 Aryl group, substituted or unsubstituted C 2~18 Alkenyl group, substituted or unsubstituted C 2~24 Alkynyl group or C 1~18 The carbonyl group is substituted with halogen, cyano, hydroxy, nitro, or C 1~18 Alkyl groups of C 3~18 aryl groups, C 1-18 carbonyl group, C 1~18 a sulfonyl or phosphoryl group of C 1~18 Alkoxy groups, C 3~18 or an aryloxy group of C 1~18 and the carbonyl group comprises an aldehyde group, a ketocarbonyl group, an estercarbonyl group, a carboxyl group, or an amide group; R 16 is OR 19 or NR 20 R 21 and R19 is hydrogen, substituted or unsubstituted C 1~24 Alkyl groups, substituted or unsubstituted C3-C 18 Aryl group, C 1~18 containing a carbonyl group of R 20 and R 21 is hydrogen, substituted or unsubstituted C 1~24 Alkyl groups, substituted or unsubstituted C3-C 18 Aryl group, C 1~18 or R 20 and R 21 are bonded to form ring B, or NR 20 R 21 contains an amino acid amine group, an amino acid ester amine group, an amino acid amide amine group, or a polypeptide amine group, and the substituents are halogen, cyano group, hydroxy group, nitro group, C 1~18 Alkyl groups of C 3~18 aryl groups, C 1-18 carbonyl group, C 1~18 a sulfonyl or phosphoryl group of C 1~18 Alkoxy groups, C 3~18 or an aryloxy group of C 1~18 wherein the carbonyl group comprises an aldehyde group, a ketocarbonyl group, an estercarbonyl group, a carboxyl group, or an amide group; and ring B comprises a C 1~18 wherein the heteroatom is an O, N or S atom; R 17 and R 18 is hydrogen, substituted or unsubstituted C 1~24 Alkyl groups, substituted or unsubstituted C3-C 18 Aryl group, substituted or unsubstituted C 2~18 Alkenyl group, substituted or unsubstituted C 2~24 Contains alkynyl groups, and the substituents are halogen, cyano, hydroxy, nitro, trifluoromethyl, C 1~18 Alkyl groups of C 3~18 aryl groups, C 1-18 carbonyl group, C 1~18 a sulfonyl or phosphoryl group of C 1~18 Alkoxy groups, C 3~18 or an aryloxy group of C 1~18amine groups, [ka] wherein the carbonyl group comprises an aldehyde group, a ketocarbonyl group, an estercarbonyl group, a carboxyl group, or an amide group; R b , R 2b and R 3b is hydrogen, C 1~10 wherein m is 1, 2, or 3, and n is 0, 1, 2, 3, 4, or 5.

[0034] the molar ratio of the amino acid derivative 2 to the carbonyl compound 3 is (0.5 to 5):1, the molar ratio of the pyridinium salt carbonyl catalyst 1 to the carbonyl compound 3 is (0.00001 to 0.5):1, the reaction temperature is −60 to 100° C., and the reaction time is 1 to 72 hours; 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 bases used are 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-diisopropyl ... selected from one or more of methylpropylamine, N,N-dimethylbutylamine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane (DABCO), diazabicycloundecene (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; The additive used is 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.

[0035] In any of the above technical measures, C 1~24The alkyl groups are 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 group, cyclodecyl group, n-undecyl group, cycloundecyl group, n-dodecyl group, cyclododecyl group, n-tridecyl group, cyclotridecyl group, n-tetradecyl group, cyclotetradecyl group, n-pentadecyl group, cyclopentadecyl group, n-hexadecyl group, cyclohexadecyl group, n-heptadecyl group, cycloheptadecyl group, n-octadecyl group, cyclooctadecyl group, n-nonadecyl group, cyclononadecyl group, n-eicosyl group, cycloeicosyl group, n-heneicosyl group, cycloheneicosyl group, n-docosyl group, cyclodocosyl group, n-tricosyl group, cyclotricosyl group, n-tetracosyl group, and cyclotetracosyl group.

[0036] In any of the above technical measures, C 1~18The alkyl group includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, a tert-butyl group, an isobutyl group, a cyclobutyl group, an n-pentyl group, an isopentyl group, a 3-pentyl group, a cyclopentyl group, an n-hexyl group, a 2-hexyl group, a 3-hexyl group, a cyclohexyl group, an n-heptyl group, a 2-heptyl group, a 3-heptyl group, a 4-heptyl group, a cycloheptyl group, an n-octyl group, a 2-octyl group, a 3-octyl group, a 4-octyl group, a cyclooctyl group, an n-nonyl group, a 2-nonyl group, a 3-nonyl group, The alkyl group may be selected from one or more of a 4-nonyl group, a 5-nonyl group, a cyclononyl group, an n-decyl group, a 2-decyl group, a 3-decyl group, a 4-decyl group, a 5-decyl group, a cyclodecyl group, an n-undecyl group, a cycloundecyl group, an n-dodecyl group, a cyclododecyl group, an n-tridecyl group, a cyclotridecyl group, an n-tetradecyl group, a cyclotetradecyl group, an n-pentadecyl group, a cyclopentadecyl group, an n-hexadecyl group, a cyclohexadecyl group, an n-heptadecyl group, a cycloheptadecyl group, an n-octadecyl group, and a cyclooctadecyl group.

[0037] In any of the above technical measures, C 1~10 The alkyl group is selected from one or more of a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, a tert-butyl group, an isobutyl group, a cyclobutyl group, an n-pentyl group, an isopentyl group, a 3-pentyl group, a cyclopentyl group, an n-hexyl group, a 2-hexyl group, a 3-hexyl group, a cyclohexyl group, an n-heptyl group, a 2-heptyl group, a 3-heptyl group, a 4-heptyl group, a cycloheptyl group, an n-octyl group, a 2-octyl group, a 3-octyl group, a 4-octyl group, a cyclooctyl group, an n-nonyl group, a 2-nonyl group, a 3-nonyl group, a 4-nonyl group, a 5-nonyl group, a cyclononyl group, an n-decyl group, a 2-decyl group, a 3-decyl group, a 4-decyl group, a 5-decyl group, and a cyclodecyl group.

[0038] In any of the above technical measures, C 3~18 The aryl group is [ka] , 1-naphthyl group, 2-naphthyl group, 9-anthryl group, 10-anthryl group, 9-phenanthrenyl group, 10-phenanthrenyl group, 1-pyrenyl group, 2-pyrenyl group, 5-tetraphenyl, 2-peryl group, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-furanyl group, 3-furanyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-thienyl group, 3-thienyl group, 2-imidazolyl group, R is selected from the group consisting of 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; a , R b , R c are 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, dimethylamino, diethylamino, and nitro.

[0039] In any of the above technical measures, C 2~18The alkenyl group includes 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, hex-6-en-1-yl, hex-7-en-1-yl, hex-8-en-1-yl, hex-9-en-1-yl, hex-10-en-1-yl, hex-11-en-1-yl, hex-12-en-1-yl, hex-13-en-1-yl, hex-14-en-1-yl, hex-15-en-1-yl, hex-16-en-1-yl, hex-17-en-1-yl, hex-18-en-1-yl, hex-19-en-1-yl, hex-20-en-1-yl, hex-21-en-1-yl, hex-22-en-1-yl, hex-23-en-1-yl, hex-24-en-1-yl, hex-25-en-1-yl, hex-26-en-1-yl, hex-27-en-1-yl, hex-28-en-1-yl, hex-29 ... Hex-3-en-1-yl group, hex-4-en-1-yl group, hex-5-en-1-yl group, hept-1-en-1-yl group, hept-2-en-1-yl group, hept-3-en-1-yl group, hept-4-en-1-yl group, hept-5-en-1-yl group, hept-6-en-1-yl group, oct-1-en-1-yl group, oct-2-en-1-yl group, oct-3-en-1-yl group group, oct-4-en-1-yl group, oct-5-en-1-yl group, oct-6-en-1-yl group, oct-7-en-1-yl group, non-1-en-1-yl group, non-2-en-1-yl group, non-3-en-1-yl group, non-4-en-1-yl group, non-5-en-1-yl group, dec-1-en-1-yl group, dec-2-en-1-yl group, dec-3-en-1-yl group, dec- 1-en-1-yl, 2-en-1-yl, 3-en-1-yl, 4-en-1-yl, 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, heptadec-1-en-1-yl, and octadec-1-en-1-yl groups.

[0040] In any of the above technical measures, C 2~24The alkynyl group includes an ethynyl group, a prop-1-yn-1-yl group, a prop-2-yn-1-yl group, a but-1-yn-1-yl group, a but-2-yn-1-yl group, a but-3-yn-1-yl group, a penta-1-yn-1-yl group, a penta-2-yn-1-yl group, a penta-3-yn-1-yl group, a penta-4-yn-1-yl group, a hex-1-yn-1-yl group, a hex-2-yn-1-yl group, Hex-3-yn-1-yl group, hex-4-yn-1-yl group, hex-5-yn-1-yl group, hept-1-yn-1-yl group, hept-2-yn-1-yl group, hept-3-yn-1-yl group, hept-4-yn-1-yl group, hept-5-yn-1-yl group, hept-6-yn-1-yl group, oct-1-yn-1-yl group, oct-2-yn-1-yl group, oct-3-yn-1-yl group oct-4-yn-1-yl group, oct-5-yn-1-yl group, oct-6-yn-1-yl group, oct-7-yn-1-yl group, non-1-yn-1-yl group, non-2-yn-1-yl group, non-3-yn-1-yl group, non-4-yn-1-yl group, non-5-yn-1-yl group, dec-1-yn-1-yl group, dec-2-yn-1-yl group, dec-3-yn-1-yl group, dec- 1-yn-1-yl, 4-yn-1-yl, dec-5-yn-1-yl, undec-1-yn-1-yl, dodec-1-yn-1-yl, tridec-1-yn-1-yl, tetradec-1-yn-1-yl, pentadec-1-yn-1-yl, hexadec-1-yn-1-yl, heptadec-1-yn-1-yl, and octadec-1-yn-1-yl groups.

[0041] In any of the above technical measures, C 1~18The alkoxy group is selected from one or more of a methoxy group, a methylenedioxybenzene group, a 1,2-diethoxyethane group, an ethoxy group, an n-propoxy group, an isopropoxy group, a cyclopropyloxy group, an n-butoxy group, a tert-butoxy group, an isobutoxy group, a cyclobutyloxy group, a cyclopentyloxy group, an n-pentyloxy group, an isopentyloxy group, an n-hexyloxy group, a cyclohexyloxy group, an n-heptyloxy group, a cycloheptyloxy group, an n-octyloxy group, a cyclooctyloxy group, an n-nonyloxy group, a cyclononyloxy group, an n-decyloxy group, a cyclodecyloxy group, an n-undecyloxy group, a cycloundecyloxy group, an n-dodecyloxy group, and a cyclododecyloxy group.

[0042] In any of the above technical means, the halogen is selected from one or more of fluorine, chlorine, bromine, and iodine.

[0043] The present invention relates to novel biaryl chiral pyridinium salt carbonyl catalysts, as well as methods for synthesizing and using such catalysts. These catalysts can be used in biomimetic aldol reactions to synthesize a series of chiral β-hydroxy-α-amino acids, providing a new method for the asymmetric synthesis of β-hydroxy-α-amino acids. The biomimetic aldol reactions are carried out under mild conditions, are simple to operate, highly reproducible, and have extremely high dr and ee values ​​and high to very high yields. [Effects of the Invention]

[0044] The present invention has the following advantageous effects compared to the prior art: (1) Pyridoxal belongs to the vitamin B6 family and functions as a coenzyme for many enzymes in the body, catalyzing numerous biotransformations as a reaction center. The pyridoxal-catalyzed addition reaction of amino acid derivatives with carbonyl compounds to prepare β-hydroxy-α-amino acid compounds is of great synthetic significance, but biomimetic simulation of this reaction has not been successful for many years. The novel chiral pyridinium salt carbonyl catalyst designed and synthesized in this invention catalyzes the biomimetic aldol reaction process of amino acid derivatives and carbonyl compounds with high activity and high stereoselectivity, enabling the efficient synthesis of chiral β-hydroxy-α-amino acid compounds. (2) The chiral pyridinium salt carbonyl catalyst of the present invention can be prepared by a multi-step reaction from inexpensive and readily available raw materials, and the reaction occurs under mild conditions, so that it is generally easy to scale up and large-scale preparation is possible. (3) The pyridinium salt carbonyl catalyst of the present invention catalyzes the biomimetic aldol reaction under very mild conditions, and the reaction is stable, the operation is easy, and the stereoselectivity and yield of the product are excellent. This makes it one of the most efficient methods for preparing optically active β-hydroxy-α-amino acid compounds. (4) The chiral β-hydroxy-α-amino acid compounds prepared by the biomimetic aldol reaction catalyzed by pyridinium salt carbonyl catalysts in this invention can be used as important intermediates in the synthesis of pharmaceuticals such as florfenicol, droxidopa, and eliglustat, providing a new green synthetic method for the synthesis of these drug molecules. DETAILED DESCRIPTION OF THE INVENTION

[0045] The present invention will be described in detail below with reference to specific embodiments, which are implemented based on the technical solutions of the present invention and provide detailed implementation methods and specific operation procedures, but the scope of protection of the present invention is not limited to the following embodiments.

[0046] Unless otherwise specified, all the equipment used in the following embodiments is conventional equipment in the art. All the reagents used are commercially available or prepared by conventional methods in the art, unless otherwise specified. Anything not described in detail in the following examples can be achieved by ordinary experimentation in the art.

[0047] The structural formula of the chiral pyridinium salt carbonyl catalyst 1 of this embodiment and the reaction scheme for preparing the β-hydroxy-α-amino acid compound 4 using the same are as follows:

[0048] [ka]

[0049] The preparation method of this embodiment can be further embodied as follows using a preparation process for a representative compound. [Example]

[0050] Examples 1 to 9 Catalyst (S,S)-1a and its preparation method, the reaction formula is as follows:

[0051] [ka]

[0052] The general steps are as follows: Compound (S,S)-5a (1.0 g, 2.06 mmol) and dimethyl squartate (1.46 g, 10.3 mmol) were dissolved in anhydrous methanol (10 mL) and reacted overnight at 50°C. The mixture was then concentrated and subjected to column chromatography to obtain compound (S,S)-6a (colorless oil, (0.75 g, yield 61%)). Compound (S,S)-6a (0.15 g, 0.25 mmol) and a primary amine compound (1.38 mmol) were dissolved in absolute ethanol (1.5 mL) and reacted at 42°C for 48 hours. The mixture was then concentrated and subjected to column chromatography to obtain an amide intermediate. The amide intermediate was dissolved in CH3CN (1.5 mL), and CH3I (20 equivalents of the amide intermediate) was added. After reacting at 30 °C for 8 hours, the system was concentrated and subjected to column chromatography to obtain a quaternary ammonium salt intermediate. After spin drying, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added and reacted at 55 °C for 6 hours. After the reaction was completed, the tetrahydrofuran was spin dried, and the water was removed under vacuum with phosphorus pentoxide. The mixture was ground into powder with a teaspoon. The solid was washed with a mixture of 4 mL of Et2O and then 7 drops of tetrahydrofuran. The supernatant was removed by suction. This process was repeated three times, and the supernatant and solid were suction filtered together. The filter cake was dried to obtain catalyst (S,S)-1a.

[0053] Example 1 [ka] Basic parameters of the compound: (S,S)-6a, colorless oil; [α] D 25 = 4.1 (c = 0.10, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 8.54 (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 = 8.0 Hz, 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), 3.45-3.29 (m, 3H), 3.12-3.04 (m, 1H), 1.86 (s, 3H), 0.91 (t, J = 6.8 Hz, 3H), 0.65-0.48 (m, 3H);13 C NMR (100 MHz, CDCl3) δ 189.0, 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.

[0054] (Example 2)

change

[0055] Example 3 [ka] Basic parameters of the catalyst: (S,R)-1a-1, yellow-brown solid, 50% yield; [α] D 25 = 61.5 (c = 0.050, MeOH); 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 0.54H for 1a-1-aldehyde), 9.78 (brs, 0.46H for 1a-1-hemiacetal), 9.58 (d, J = 9.2 Hz, 0.54H for 1a-1-aldehyde), 9.48 (s, 0.54H for 1a-1-aldehyde), 8.97 (s, 0.54H for 1a-1-aldehyde), 8.31 (s, 0.46H for 1a-1-hemiacetal), 8.25 (d, J = 8.4 Hz, 0.46H for 1a-1-hemiacetal), 8.21 (d, J = 8.8 Hz, 0.54H for 1a-1-aldehyde), 8.14 (d, J = 8.0 Hz, 0.46H for 1a-1-hemiacetal), 8.08 (d, J= 8.4 Hz, 0.54H for 1a-1-aldehyde), 7.70 (d, J = 8.8 Hz, 0.54H for 1a-1-aldehyde), 7.68-7.58 (m, 1H), 7.58-7.52 (m, 0.92H for 1a-1-hemiacetal), 7.52-7.46 (m, , 0.54H for 1a-1-aldehyde), 7.46-7.27 (m, 4H), 7.21-7.12 (m, 2H), 7.12-7.02 (m, 3H), 6.81 (d, J = 6.4 Hz, 0.92H for 1a-1-hemiacetal), 6.14 (d, J = 9.4 Hz, 0.54H for 1a-1-aldehyde), 4.31 (s, 1.62H for 1a-1-aldehyde), 3.95 (s, 1.38H for 1a-1-hemiacetal), 2.11 (s, 1.62H for 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 (100 MHz, DMSO-d6) δ 188.7, 183.8, 182.9, 182.0, 179.8, 166.9, 164.7, 155.2, 151.6, 150.5, 146.0, 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.

[0056] Example 4 [ka] Basic parameters of the catalyst: (S,S)-1a-2, yellow-brown solid, yield 64%; [α] D 25 = 17.3 (c = 0.050, MeOH); 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.87 (s, 1H), 9.73 (d, J = 9.6 Hz, 1H), 8.92 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.48 (dd, J= 8.4, 6.8 Hz, 1H), 7.43-7.38 (m, 2H), 7.35 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 7.2 Hz, 2H), 7.12 (s, 2H), 6.66 (s, 1H), 6.25 (d, J = 9.6 Hz, 1H), 4.27 (s, 3H), 2.22 (s, 6H), 1.76 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 188.9, 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.

[0057] (Example 5)

change

[0058] (Example 6)

change

[0059] (Example 7)

change

[0060] (Example 8)

change

[0061] (Example 9)

change

[0062] (Examples 10 to 14) Catalyst (S,S)-1a and its preparation method, the reaction formula is as follows: [ka]

[0063] The general steps are as follows: Compound (S,S)-5a (0.195 g, 0.40 mmol) and a squaramide compound (2.21 mmol) were dissolved in absolute ethanol (2.0 mL) and reacted at 42°C for 72 hours. The mixture was then concentrated and subjected to column chromatography to obtain an amide intermediate. The amide intermediate was dissolved in CH3CN (1.5 mL), and CH3I (20 equivalents of the amide intermediate) was added. After reacting at 30 °C for 8 hours, the system was concentrated and subjected to column chromatography to obtain a quaternary ammonium salt intermediate. After spin drying, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added and reacted at 55 °C for 6 hours. After the reaction was completed, the tetrahydrofuran was spin dried, and the water was removed under vacuum with phosphorus pentoxide. The mixture was ground into powder with a teaspoon. The solid was washed with a mixture of 4 mL of Et2O and then 7 drops of tetrahydrofuran. The supernatant was removed by suction. This process was repeated three times, and the supernatant and solid were suction filtered together. The filter cake was dried to obtain catalyst (S,S)-1a.

[0064] Example 10 [ka] Basic parameters of the catalyst: (S,S)-1a-8, yellow-brown solid, yield 29%; [α] D 25 = -6.8 (c = 0.050, MeOH); 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.87 (s, 1H), 9.26 (d, J = 9.6 Hz, 1H), 8.93 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.51-7.45 (m, 1H), 7.38-7.33 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.06 (s, 1H), 6.98 (s, 1H), 6.79 (s, 2H), 6.16 (d, J = 9.2 Hz, 1H), 4.28 (s, 3H), 2.25 (s, 6H), 1.83 (s, 3H), 1.27 (s, 18H); 13 C NMR (100 MHz, DMSO-d6) δ 188.9, 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.

[0065] (Example 11)

change

[0066] (Example 12)

change

[0067] (Example 13)

change

[0068] (Example 14)

change

[0069] Example 15 Catalyst (S,S)-1a-13 and its preparation method, the reaction formula is as follows: [ka]

[0070] Procedure: Compound (S,S)-6a (0.15 g, 0.25 mmol) and 3,5-di-tert-butylaniline (0.28 g, 1.38 mmol) were dissolved in absolute ethanol (1.5 mL) and reacted at 42 °C for 48 h. The mixture was then concentrated and subjected to column chromatography to obtain the amide intermediate. The amide intermediate was dissolved in CH3CN (1.5 mL), and iodide (20 equivalents of the amide intermediate) was added. The mixture was allowed to react at 30°C for 8 hours. The mixture was then concentrated and subjected to column chromatography to obtain a quaternary ammonium salt intermediate. After spin drying, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added, and the mixture was allowed to react at 55°C for 6 hours. After the reaction was completed, the tetrahydrofuran was spin dried, and the water was removed under vacuum using phosphorus pentoxide. The mixture was ground into powder using a teaspoon. The solid was washed with a mixture of 4 mL of Et2O and then 7 drops of tetrahydrofuran. The supernatant was removed by suction. This process was repeated three times, and the supernatant and solid were filtered by suction together. The filter cake was dried to obtain catalyst (S,S)-1a-13 (a yellowish-brown solid (0.1501 g, yield 69%)). Basic parameters of said compound: 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.90 (s, 1H), 9.32 (d, J = 10.0 Hz, 1H), 8.93 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.50 (t, J = 8.4 Hz, 1H), 7.46-7.39 (m, 2H), 7.36-7.26 (m, 9H), 7.21 (d, J= 6.8 Hz, 2H), 7.05 (t, J = 1.6 Hz, 1H), 6.22 (d, J = 9.6 Hz, 1H), 5.88 (s, 2H), 1.82 (s, 3H), 1.25 (s, 18H).

[0071] Example 16 Catalyst (R,R)-1a-14 and its preparation method, the reaction formula is as follows:

[0072] [ka]

[0073] Specific procedure: 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) and reacted at 50°C overnight. The mixture was concentrated and subjected to column chromatography to obtain compound (R,R)-6b (colorless oil (0.1417 g, yield 53%)). Basic parameters of said compound: 1 H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.86-7.82 (m, 1H), 7.56 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.36-7.31 (m, 1H), 7.29-7.28 (m, 2H), 7.20 (d, J = 8.0 Hz, 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), 3.45-3.29 (m, 3H), 3.12-3.04 (m, 1H), 2.0 (s, 3H),1.86 (s, 3H), 0.91 (t, J = 6.8 Hz, 3H), 0.65-0.48 (m, 3H).

[0074] 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 absolute ethanol (1.4 mL) and reacted at 42°C for 48 hours. The mixture was then concentrated and subjected to column chromatography to obtain the amide intermediate. The amide intermediate (0.148 g, 0.21 mmol) was dissolved in CH3CN (1.5 mL), and CH3I (20 equivalents of the amide intermediate) was added. After reacting at 30 °C for 8 hours, the system was concentrated and subjected to column chromatography to obtain a quaternary ammonium salt intermediate. After spin drying, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added, and the reaction was continued at 55 °C for 6 hours. After the reaction was completed, the tetrahydrofuran was spin dried, and water was removed under vacuum using phosphorus pentoxide. The mixture was ground into powder with a teaspoon. The solid was washed with a mixture of 4 mL of Et2O and then 7 drops of tetrahydrofuran. The supernatant was removed by suction. This process was repeated three times, and the supernatant and solid were suction filtered together. The filter cake was dried to obtain catalyst (R,R)-1a-14 (yellow-brown solid (0.1235 g, yield 65%)). Basic parameters of said compound: 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 10.02 (s, 1H), 9.05 (d, J = 9.6 Hz, 1H), 8.79 (s, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.44-7.33 (m, 4H), 7.32 (d, J = 1.6 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.14 (dd, J= 7.0, 1.6 Hz, 2H), 7.06 (t, J = 1.6 Hz, 1H), 5.97 (d, J = 9.6 Hz, 1H), 4.23 (s, 3H), 1.94 (s, 3H), 1.90 (s, 3H), 1.27 (s, 18H).

[0075] Example 17 Catalyst (S,S)-1a-15 and its preparation method, the reaction formula is as follows:

[0076] [ka]

[0077] Specific procedure: Compound (S,S)-1a-1 (0.0476 g, 0.06 mmol) was dissolved in tetrahydrofuran (0.5 mL), and silver tetrafluoroborate (0.0117 g, 0.06 mmol) was dissolved in 0.5 mL of water and added to the system. Under the protection of nitrogen gas, the mixture was reacted at room temperature for 2 hours, then suction filtered, the tetrahydrofuran was spin-dried, and the water was removed under vacuum with phosphorus pentoxide. The mixture was ground into powder with a teaspoon, and the solid was washed with a mixture of 4 mL of EtO and 7 drops of tetrahydrofuran. The supernatant was removed by suction, and this process was repeated three times. The supernatant and the solid were suction filtered together, and the filter cake was dried to obtain catalyst (R,R)-1a-15 (yellow-brown solid (0.0407 g, yield 90%)). Basic parameters of said compound: 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.89 (s, 1H), 9.33 (d, J = 10.0 Hz, 1H), 8.92 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.45-7.38 (m, 2H), 7.38-7.31 (m, 4H), 7.20 (d, J= 6.8 Hz, 2H), 7.06 (t, J = 1.6 Hz, 1H), 6.23 (d, J = 9.6 Hz, 1H), 4.28 (s, 3H), 1.81 (s, 3H), 1.26 (s, 18H).

[0078] Example 18 Catalyst (S,S)-1c and its preparation method, the reaction scheme is as follows:

[0079] [ka]

[0080] Specific procedure: 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), purged with nitrogen gas, and reacted at room temperature for 24 hours. After the reaction was completed, 3 mL of ethyl acetate was added, and the mixture was washed three times with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated, and subjected to column chromatography to obtain the urea intermediate. The urea intermediate was dissolved in CH3CN (1.5 mL), and CH3I (20 equivalents of thiourea) was added. After reacting at 30 °C for 8 hours, the system was concentrated and subjected to column chromatography to obtain a quaternary ammonium salt intermediate. After spin drying, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added and reacted at 55 °C for 6 hours. After the reaction was completed, the tetrahydrofuran was spin dried, water was removed under vacuum using phosphorus pentoxide, and the solid was ground into powder using a teaspoon. The solid was washed with a mixture of 4 mL of Et2O and then 7 drops of tetrahydrofuran, and the supernatant was removed by suction. This process was repeated three times, and the supernatant and solid were suction filtered together. The filter cake was dried to obtain catalyst (S,S)-1c (a yellow-brown solid (0.0905 g, yield 49%)). Basic parameters of said compound: 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.90 (s, 1H), 9.32 (d, J = 10.0 Hz, 1H), 8.91 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.46-7.38 (m, 2H), 7.38-7.30 (m, 4H), 7.20 (d, J= 6.8 Hz, 2H), 7.07 (t, J = 1.6 Hz, 1H), 6.24 (d, J = 9.6 Hz, 1H), 4.29 (s, 3H), 1.82 (s, 3H), 1.25 (s, 18H); 13 C NMR (100 MHz, DMSO-d6) δ 188.8, 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.

[0081] (Examples 19 to 68) In this example, reaction conditions are screened for the preparation of (2R,3S) or (2S,3R)-β-hydroxy-β-(p-methylsulfonylphenyl)-α-alanine tert-butyl ester, and the general procedure for this series of examples is as follows: According to the specific requirements in Table 1, p-methylsulfonylbenzaldehyde 3a (0.2321 g, 1.26 mmol), additive (1.512 mmol), and chiral pyridinium salt carbonyl catalyst (0.00126 mmol) were weighed into a 50 mL Schlenk tube in a glovebox. Solvent (7.0 mL) was added sequentially to the Schlenk tube using a syringe at room temperature. Glycine tert-butyl ester 2a (0.4127 g, 3.15 mmol) was then added at low temperature and the reaction was continued for the required time at this temperature. After completion of the reaction, anhydrous methanol (1.0 mL) and aqueous hydroxylamine solution (1.0 mL, 50 wt% aqueous solution) were added. The reaction was continued at the reaction temperature for 1 hour, then returned to room temperature and continued for 30 minutes. The diatomaceous earth was then filtered off with suction, the organic solvent was removed, and the water was removed under vacuum using phosphorus pentoxide to obtain crude compound 4a. The NMR yield and dr values ​​of compound 4a were the same as those of the crude reaction product. 1 The ee values ​​were obtained by HPLC analysis of the oxazolidine-2-thione derivatives after reaction with 1,1'-thiocarbonyldiimidazole. The reaction equation is as follows:

[0082] [ka] Basic parameters of said compound: 4a: white solid; 1 H NMR (400 MHz, CDCl3) δ 7.93 (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 (100 MHz, CDCl3) δ 171.9, 147.8, 139.9, 127.5, 127.4, 82.4, 73.6, 60.6, 44.6, 27.9.

[0083] Table 1. Reaction conditions, yields, dr values, and ee values ​​for Examples 19 to 68 [Table 1] [Table 2] [Table 3]

[0084] Table 1 shows the reaction conditions screened. First, catalysts were screened. Examples 19-35 show that the chiral pyridinium salt carbonyl catalysts (S,S)-1a-1-15 and (S,S)-1c can all catalyze this reaction. Comparisons of the yields, dr, and ee values ​​of the reactions using (S,S)-1a-1-3, 8, 13, and 15 as catalysts were relatively good, with no significant differences, indicating that all catalysts can catalyze the reaction as preferred catalysts (Examples 19, 21, 22, 27, 32, and 34). Among these, the highest yields were (S,S)-1a-3 and (S,S)-1a-8 (86%), the highest dr values ​​were (S,S)-1a-1-3 and 13 (12:1), and the highest ee values ​​were (S,S)-1a-1 and 15 (98%). Although at least one of the three catalysts (S,S)-1a-4 to 7, 9 to 12, 14, and (S,S)-1c) performed slightly worse than the others, they all catalyzed the reaction and achieved better results. Considering the catalytic reaction results and the difficulty of catalyst preparation, (S,S)-1a-1 was ultimately selected as the lead catalyst for subsequent screening (Example 19).

[0085] Next, in screening the solvent, additive, catalyst equivalent, and reaction temperature, five solvents were screened: dichloromethane, tetrahydrofuran, toluene, methanol, and ether (Examples 36-40). Except for methanol, which failed due to the formation of acetal upon reaction with the catalyst, the others were able to achieve the reaction. Among them, tetrahydrofuran produced the highest yield, and the dr value continued to increase even after shortening the reaction time to 6 hours (Example 40). Various additives were screened: NaHPO-12H0, NaHPO (equivalents were also screened), no additive (temperature was also screened), MgSO, NaHPO, KHPO, LiHPO, and NHHPO (Examples 40-50). All of these additive conditions were able to achieve the reaction, and NHHPO produced the best results, with the yield, dr, and ee values ​​increasing simultaneously (Example 50). Regarding temperature screening, the temperature was further lowered (-40 to -20 °C, Examples 50 to 52). The reaction dr value continued to improve with decreasing temperature, but at -40 °C, the reaction time (6 to 48 hours) had to be extended, and the ee value slightly decreased. At -30 °C, the dr value was slightly lower, but it exceeded 20:1. Subsequently, catalysts were screened again at this temperature (Examples 52 to 63). It was again found that catalyst (S,S)-1a-1 was most effective, with a slightly lower dr value but the highest ee value. Therefore, Example 52 was finally selected as the reaction condition for substrate expansion. We also attempted to reduce the catalyst equivalent (0.01 to 0.1 mol%) and screen the temperature (-30 to -10 °C, Examples 64 to 68). The reduction was at least 1 / 10,000, and when the reaction time (24-72 hours) was extended to 72 hours at -20°C, 3.22 g of product was obtained from 1 mg of catalyst, and the dr and ee values ​​of these products maintained good results (15:1 / 98%).

[0086] (Examples 69 to 87) In this example, the reaction conditions for the preparation of (2R,3S) or (2S,3R)-β-hydroxy-β-(4-biphenylyl)-α-alanine tert-butyl ester are screened, and the general procedure of this example is as follows: According to the specific requirements in Table 2, p-phenylbenzaldehyde 3af (0.2293 g, 1.26 mmol), additive (1.512 mmol), solid base (1.89 mmol), and chiral pyridinium salt carbonyl catalyst (0.00126 mmol) were weighed into a 50 mL Schlenk tube in a glovebox. Solvent (6.0 mL) and liquid base (1.89 mmol) were sequentially added to the Schlenk tube using a syringe at room temperature. Glycine tert-butyl ester 2a (0.4127 g, 3.15 mmol) was then added at low temperature and allowed to react for the required time. After completion of the reaction, anhydrous methanol (1.0 mL) and aqueous hydroxylamine solution (1.0 mL, 50 wt% aqueous solution) were added. The reaction was continued at room temperature for 1 hour, then cooled to room temperature and continued for 30 minutes. The diatomaceous earth was then filtered off with suction, the organic solvent was removed, and the water was removed under vacuum with phosphorus pentoxide to give crude compound 4af. The NMR yield and dr values ​​of compound 4af were the same as those of the crude reaction product. 1 The ee values ​​were obtained by HPLC analysis of the oxazolidine-2-thione derivatives after reaction with 1,1'-thiocarbonyldiimidazole. The reaction equation is as follows:

[0087] [ka] Basic parameters of said compound: 4af: white solid; 1 H NMR (400 MHz, CDCl3) δ 7.65-7.57 (m, 4H), δ 7.51-7.42 (m, 4H), 7.37 (t, J = 7.2 Hz, 1H), 4.82 (d, J = 5.4 Hz, 1H), 3.59 (d, J= 5.4 Hz, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 172.5, 140.9, 140.8, 140.1, 128.8, 127.3, 127.1, 127.1, 127.0, 81.9, 74.4, 61.0, 27.9.

[0088] Table 2: Bases, yields, dr values ​​and ee values ​​in reaction screening of Examples 69 to 87 [Table 4]

[0089] Table 2 shows the reaction conditions screened. In Examples 69-75, five bases, Na3PO4, K3PO4, Cs2CO3, DIPEA, and Et3N, were compared (Examples 69-73), and Et3N was found to be the base that produced the best results. The reaction time and catalyst type were also screened (Examples 73-75). Reducing the reaction time (20-48 hours) improved the reaction selectivity, and the catalytic effect of (S,S)-1a-1 was found to be the best compared to (S,S)-1a-5. The temperature was then lowered to -20°C (-20 to -5°C) to screen solvents. Dichloromethane, chloroform, toluene, methanol, acetonitrile, and tetrahydrofuran were screened (Examples 76-81). Except for methanol, which showed very poor reaction efficiency, the other solvents showed good effects, with tetrahydrofuran showing the best effect (Example 81). We then screened the catalyst equivalent (0.1-0.5 mol%, Examples 81-83). We found that good yields could be maintained even when the equivalent was reduced by a factor of 1,000. Furthermore, the dr value improved as the equivalent decreased. Finally, we screened the temperature (-40 to -20°C, Examples 83-86). The dr and ee values ​​increased as the temperature decreased. A comparison of Examples 84 and 85 again demonstrated that the dr value decreased over time (24-48 hours). In Example 87, after adding NaH2PO4, the ee value of the reaction increased to 99%, ultimately determining the reaction conditions for substrate expansion.

[0090] (Examples 88 to 113) In this example, the reaction conditions for the preparation of (2R,3S) or (2S,3R)-β-hydroxy-β-(n-nonyl)-α-alanine tert-butyl ester are screened, and the general procedure of this example is as follows: According to the specific requirements in Table 3, NH4H2PO4 and chiral pyridinium salt carbonyl catalyst were weighed into a 50 mL Schlenk tube in a glove box. Tetrahydrofuran, decanal 3bb (0.1969 g, 1.26 mmol), and triethylamine were added sequentially to the Schlenk tube using a syringe at -30°C. After stirring for 20 minutes at -30°C, glycine tert-butyl ester 2a was added dropwise at low temperature and the reaction was continued for the required time at this temperature. After the reaction was complete, anhydrous methanol (1.0 mL) and aqueous hydroxylamine solution (1.0 mL, 50 wt% aqueous solution) were added and the reaction was continued for 1 hour at the reaction temperature. After returning to room temperature, the reaction was continued for 30 minutes. The diatomaceous earth was then filtered off with suction, the organic solvent was removed, and the water was removed under vacuum using phosphorus pentoxide to obtain the crude product of compound 4bb. The NMR yield and dr values ​​of compound 4bb were the same as those of the crude reaction product. 1 The ee values ​​were obtained by HPLC analysis of the oxazolidine-2-thione derivatives after reaction with 1,1'-thiocarbonyldiimidazole. The reaction scheme is as follows:

[0091] [ka] Basic parameters of said compound: 4bb: Yellow oil; 1 H NMR (400 MHz, CDCl3) δ 3.70-3.62 (m, 1H), 3.22 (d, J = 5.2 Hz, 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 = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.7, 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.

[0092] Table 3: Bases, yields, dr values ​​and ee values ​​in reaction screening of Examples 88 to 113 [Table 5] [Table 6]

[0093] Table 3 shows the reaction conditions screened. In Examples 88-91, the temperature was screened, and the reaction results gradually improved as the temperature decreased (-40 to -10°C), with -30°C being the most effective. In Examples 92-94, the equivalents of glycine tert-butyl ester (1.2 to 4.0) were screened, and 2.0 equivalents was again found to be the most effective. In Examples 95-98, the reaction time was shortened (24 to 48 hours) and the base equivalents (1.5 to 3.0) were screened. 2.0 equivalents was found to be the most effective, and results could be maintained even if the time was halved. In Examples 99-103, the equivalents of NH4H2PO4 (0.6 to 2.0) were screened, and it was found that there was no significant difference in effectiveness between 0.8 and 1.2 equivalents. Ultimately, 1.0 equivalent was selected for subsequent screening. In Examples 104-106, catalyst equivalents (0.1-1.0 mol%) were screened. As the catalyst equivalent increased, selectivity remained unchanged and yield gradually increased. However, there was no significant difference between the results for 5 / 1000 and 20 / 1000, so screening continued at 5 / 1000. In Examples 107-110, concentrations (solvent volume 6-20 mL) were screened. As the concentration decreased, yield gradually increased and DR gradually decreased. It was found that the reaction results were best when the solvent volume was 12-15 mL, so screening continued at 12 mL. In Examples 111 and 112, catalyst equivalents (0.1-0.5 mol%) were screened again at this concentration. It was found that the reaction results were maintained even when reduced to 2 / 1000, while the yield decreased at 1 / 1000. Finally, in Example 113, the method of adding glycine tert-butyl ester and solvent was changed under the 2 / 1000 catalyst condition, and the reaction conditions for substrate expansion were finally determined.

[0094] (Examples 114 to 1905) In this example, the arylaldehyde and alkylaldehyde substrates applicable to the preparation of chiral β-hydroxy-α-amino acid derivatives catalyzed by pyridoxal quaternary ammonium salts were expanded. The general procedures for this example are as follows (General Method 1 was used in Examples 114-116, 130, 136, and 143; General Method 2 was used in Examples 150-175; General Method 3 was used in Examples 117-129, 131-135, 137-142, 144-149, and 176-182; and General Method 4 was used in Examples 183-1905). General method 1 (aromatic aldehydes with strong electron-withdrawing substituents): In a glovebox, the 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 Schlenk tube. Tetrahydrofuran (7.0 mL) was then added to the Schlenk tube via syringe at room temperature, and the glycine derivative 2 (3.15 mmol) was added at -30 °C. The reaction was carried out at this temperature for 10 h. After the reaction was completed, anhydrous methanol (1.0 mL) and aqueous hydroxylamine solution (1.0 mL, 50 wt% aqueous solution) were added, and the reaction was continued at -30°C for 10 minutes, then at -20°C for 50 minutes. After returning to room temperature and reaction for 30 minutes, the diatomaceous earth was filtered off with suction, the organic solvent was removed, and water was removed under vacuum with phosphorus pentoxide to obtain a crude chiral β-hydroxy-α-amino acid derivative. The NMR yield and dr value of the product were 1 The ee values ​​were obtained by HPLC analysis of the oxazolidine-2-thione derivatives after reaction with 1,1'-thiocarbonyldiimidazole. General method 2 (aromatic aldehydes with strong electron-donating, weak electron-withdrawing, and weak electron-donating substituents): In a glovebox, the aromatic aldehyde (1.26 mmol), the 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 Schlenk tube. Tetrahydrofuran (6.0 mL) and triethylamine (0.263 mL, 1.89 mmol) were then added sequentially to the Schlenk tube using a syringe at room temperature. Glycine derivative 2 (3.15 mmol) was then added at -40 °C, and the reaction was carried out at this temperature for 48 h. After the reaction was completed, anhydrous methanol (1.0 mL) and aqueous hydroxylamine solution (1.0 mL, 50 wt% aqueous solution) were added, and the reaction was continued at -40°C for 10 minutes, then at -20°C for 50 minutes. After returning to room temperature and reaction for 30 minutes, the diatomaceous earth was filtered off with suction, the organic solvent was removed, and water was removed under vacuum with phosphorus pentoxide to obtain a crude chiral β-hydroxy-α-amino acid derivative. The NMR yield and dr value of the product were 1 The ee values ​​were obtained by HPLC analysis of the oxazolidine-2-thione derivatives after reaction with 1,1'-thiocarbonyldiimidazole. General Method 3 (Alkyl Aldehyde): In a glovebox, 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 Schlenk tube. Tetrahydrofuran (7.0 mL) was then added sequentially to the Schlenk tube using a syringe at room temperature. The mixture was stirred at -30 °C for 20 min, and then glycine derivative 2 (3.15 mmol, dissolved in 0.5 mL of tetrahydrofuran and frozen at -30 °C for 30 min) was quickly added using a syringe. The reaction was continued at this temperature for 20 min. After the reaction was completed, anhydrous methanol (1.0 mL) and aqueous hydroxylamine solution (1.0 mL, 50 wt% aqueous solution) were added, and the reaction was continued at -30°C for 10 minutes, then at -20°C for 50 minutes. After returning to room temperature and reaction for 30 minutes, the diatomaceous earth was filtered off with suction, the organic solvent was removed, and water was removed under vacuum with phosphorus pentoxide to obtain a crude chiral β-hydroxy-α-amino acid derivative. The NMR yield and dr value of the product were 1 The ee values ​​were obtained by HPLC analysis of the oxazolidine-2-thione derivatives after reaction with 1,1'-thiocarbonyldiimidazole. General method 4 (high-throughput synthesis): A module capable of accommodating 20 threaded test tubes for simultaneous reactions was customized, and the module was placed in a low-temperature reactor to perform the reactions. 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, 0.00063 mmol) were weighed into a vial. The sealed vial was removed from the glove box and placed at −40 °C. Glycine tert-butyl ester (82.5 mg, 0.63 mmol) or a mixture of glycine tert-butyl ester and triethylamine (66 μL, 0.4725 mmol) was then added via syringe and the reaction was continued at −40 °C for 48 h. After the reaction was completed, anhydrous methanol (0.2 mL) and an aqueous hydroxylamine solution (0.2 mL, 50 wt% aqueous solution) were added, and the reaction was continued at -40°C for 10 minutes, then at -20°C for 40 minutes. After returning to room temperature and reaction for 30 minutes, the mixture was diluted with dichloromethane / anhydrous methanol (3 mL / 2 mL), filtered through a syringe filter, concentrated under reduced pressure, and vacuum dried in the presence of phosphorus pentoxide for 20 hours. The dried crude product was dissolved in deuterated chloroform (2 mL) and water (0.1 mL) to remove excess hydroxylamine from the crude product. The organic layer was transferred directly to a syringe containing sodium sulfate using a pipette and filtered through a syringe filter. The NMR yield and dr value of the product were determined based on the crude reaction product. 1 The ee values ​​were obtained by HPLC analysis of the oxazolidine-2-thione derivatives after reaction with 1,1'-thiocarbonyldiimidazole. The reaction equation is as follows:

[0095] [ka] The basic parameters of the compounds are shown in Table 4.

[0096] Table 4. Structures, yields, dr values, ee values ​​and NMR properties of the products of Examples 114 to 1905 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 Table 65 Table 66 Table 67 Table 68 Table 69 Table 70 Table 71 Table 72 Table 73 Table 74 Table 75 Table 76 Table 77 Table 78 Table 79 Table 80 Table 81 Table 82 Table 83 Table 84 Table 85 Table 86 Table 87 Table 88 Table 89 Table 90 Table 91 Table 92 Table 93 Table 94 Table 95 Table 96 Table 97 Table 98 Table 99 Table 100 Table 101 Table 102 Table 103 Table 104 Table 105 Table 106 Table 107 Table 108 Table 109 Table 110 Table 111 Table 112 Table 113 Table 114 Table 115 Table 116 Table 117 Table 118 Table 119 Table 120 Table 121 Table 122

Table 123

[0097] The above-described embodiments are described to facilitate understanding and use of the present invention by those skilled in the art. It will be apparent to those skilled in the art that various modifications can be easily made to these embodiments without any creative effort, and that the general principles described herein can be applied to other embodiments. Therefore, the present invention is not limited to the above-described 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 also be included in the scope of protection of the present invention.

Claims

1. 1. Chiral pyridinium salt carbonyl catalyst 1, characterized in that it has a structure represented by the following formula: 【Chemistry 1】 In the formula, R １ Structural formula of 【Chemistry 2】 [X １ is N or C-R ６ Including X ２ is N or C-R ７ Including X ３ is N or C-R ８ Including X ４ is N or C-R ９ Including X ５ is N or C-R １０ Including X ６ is N or C-R １１ Including, R ２ , R ４ , R ６ , R ７ , R ８ , R ９ , R １０ and R １１ is hydrogen, C １～２４ alkyl groups, alkoxy groups, 【Transformation 3】 base 、 【Chemistry 4】 、 【Transformation 5】 、 【Transformation 6】 , CO ２ R ｄ , halogen, nitro group, cyano group or trifluoromethyl group, R ａ is hydrogen, C １～１０ R ｂ , R ２ｂ , R ３ｂ , R ｃ , R ２ｃ and R ｄ is hydrogen, C １～１０ wherein m is 1, 2, or 3, and n is 0, 1, 2, 3, 4, or 5; R ３ is a substituted or unsubstituted C １～２４ The alkyl group may be substituted with halogen, C １～１０ alkyl group of C ３～１０ a cycloalkyl group or an aryl group represented by C １～８ a carbonyl group of C １～８ a sulfonyl group or a phosphoryl group of C １～１０ and the carbonyl group includes an aldehyde group, a ketocarbonyl group, an estercarbonyl group, a carboxyl group, or an amide group. R ５ Structural formula of 【Transformation 7】 [R １２ and R １３ is hydrogen, C １～２４ or an alkyl group of 【Transformation 8】 and R １４ is hydrogen, C １～２４ an alkyl group of 【Chemistry 9】 , arylmethyl, diarylmethyl, triarylmethyl, halogen or trifluoromethyl; R ｅ is hydrogen, C １～１０ wherein x and y are 0, 1, 2, or 3; Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, an isobutyl group, a cyclopentyl group, a cyclobutyl group, an n-hexyl group, a cyclohexyl group, an n-heptyl group, a cycloheptyl group, an n-octyl group, a cyclooctyl group, an n-nonyl group, a cyclononyl group, an n-decyl group, and a cyclodecyl group. Examples of the aryl group include a benzene group, a 2-biphenyl group, a 3-biphenyl group, a 4-biphenyl group, Examples of the alkyl group include a 2,6-diphenyl group, a 3,5-diphenyl group, a 1-naphthyl group, a 2-naphthyl group, a 3,5-di-tert-butylbenzene group, a 4-tert-butylbenzene group, a 3,5-difluorobenzene group, a 4-fluorobenzene group, a 3,5-dichlorobenzene group, a 4-chlorobenzene group, a 3,5-ditrifluoromethylbenzene group, a 4-trifluoromethylbenzene group, a 3,5-dimethylbenzene group, a 4-methylbenzene group, and a 4-methoxybenzene group. X － is an anion, and examples of the anion include a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a trifluoromethanesulfonate ion, a hexafluorophosphate ion, a tetrafluoroborate ion, a sulfate ion, a sulfite ion, a hydroxide ion, a nitrate ion, a phosphate ion, a carbonate ion, a silicate ion, a bicarbonate ion, a hydrogen phosphate ion, a dihydrogen phosphate ion, an iodate ion, a cyanide ion, and a thiocyanate ion.]

2. The R １ The chiral pyridinium salt carbonyl catalyst according to claim 1, wherein axial asymmetry is formed between the pyridine ring and the pyridine ring, and the axial asymmetry has an R or S configuration.

3. The catalyst has the formula I ａ , Formula I ｂ , formula II ａ or Formula II ｂ and having the structure shown in Formula I ａ and Formula I ｂ are enantiomers of each other, and have formula II ａ and Formula II ｂ 3. The chiral pyridinium salt carbonyl catalyst of claim 2, wherein: 【Chemistry 10】

4. 4. A method for preparing the chiral pyridinium salt carbonyl catalyst according to claim 1, comprising using the single-configuration compound 5 after resolution as a starting material, condensing the chiral amine compound 5 with dimethyl squarate to produce compound 6, further condensing compound 6 with a primary amine to produce an amide intermediate, which is then reacted with a halogenated hydrocarbon to produce a quaternary ammonium salt intermediate, and finally hydrolyzing the resulting product, pyridinium salt carbonyl catalyst 1a. Reaction Process 【Chemistry 11】

5. The molar ratio of the compound 5 to dimethyl squarate is 1:(1-10), the reaction temperature is -20 to 120°C, and the reaction time is 1 to 72 hours; The molar ratio of compound 6 to the primary amine and halogenated hydrocarbon is 1:(1-50):(1-50), the reaction temperature is 0-100°C, and the reaction time is 1-48 hours.

5. The method for preparing the chiral pyridinium salt carbonyl catalyst according to claim 4,

6. 4. A method for preparing the chiral pyridinium salt carbonyl catalyst according to claim 1, wherein the single-configuration compound 5 after resolution is used as a starting material, and the chiral amine compound 5 is condensed with one of the squaramides 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 product, pyridinium salt carbonyl catalyst 1a. Reaction Process 【Chemistry 12】

7. 7. The method for preparing chiral pyridinium salt carbonyl catalyst according to claim 6, wherein the molar ratio of compound 5 to one of squaramide and halogenated hydrocarbon is 1:(1-50):(1-50), the reaction temperature is -20 to 120°C, and the reaction time is 1 to 72 hours.

8. 4. A method for preparing the chiral pyridinium salt carbonyl catalyst according to claim 1, comprising using the single-configuration compound 5 after resolution as a starting material, condensing the chiral amine compound 5 with an isothiocyanate or an isocyanate to produce compound 7 or 8, which is then reacted with a halogenated hydrocarbon to give a quaternary ammonium salt intermediate, which is finally hydrolyzed to give the final product pyridinium salt carbonyl catalyst 1b or 1c. Reaction Process 【Chemistry 13】

9. The molar ratio of the compound 5 to the isothiocyanate or isocyanate is 1:(1 to 10), the reaction temperature is −20 to 120° C., and the reaction time is 1 to 72 hours; 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.

9. The method for preparing the chiral pyridinium salt carbonyl catalyst according to claim 8,

10. 4. A method for preparing the chiral pyridinium salt carbonyl catalyst according to claim 1, wherein the single-configuration compound 5 after resolution is used as a starting material, the chiral amine compound 5 is condensed with an isothiocyanate to produce compound 9, which is coupled with a primary amine under the action of carbodiimide hydrochloride (EDCl) to produce compound 10, which is then subjected to removal of the ethyl carbonate protecting group under the action of trimethylsilyl bromide to produce compound 11, which is then reacted with a halogenated hydrocarbon to produce a quaternary ammonium salt intermediate, which is finally hydrolyzed to produce the final product pyridinium salt carbonyl catalyst 1d. Reaction Process 【Chemistry 14】

11. The molar ratio of the compound 5 to the isothiocyanate is 1:(1 to 10), the reaction temperature is −20 to 120° C., and the reaction time is 1 to 72 hours. The molar ratio of 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 hours. 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 hours. 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.

11. The method for preparing the chiral pyridinium salt carbonyl catalyst according to claim 10,

12. the solvent used 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; 11. The method for preparing a chiral pyridinium salt carbonyl catalyst according to claim 4, 6, 8 or 10, characterized in that the acid used is selected from one or more of sulfuric acid, hydrochloric acid, a solution of hydrochloric acid in dichloromethane, a solution of hydrochloric acid in methanol, a solution of hydrochloric acid in tetrahydrofuran, a solution of hydrochloric acid in dioxane, 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 the chiral pyridinium salt carbonyl catalyst according to any one of claims 1 to 3, comprising adding a silver salt to a pyridinium salt carbonyl catalyst having an iodide ion and carrying out a substitution reaction to obtain a pyridinium salt carbonyl catalyst having a corresponding anion of the silver salt; Examples of the silver salt include 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 hydrogen carbonate, silver hydrogen phosphate, silver dihydrogen phosphate, silver iodate, silver cyanide, and silver thiocyanate.

1. A method for preparing a chiral pyridinium salt carbonyl catalyst, comprising:

14. 4. Use of the chiral pyridinium salt carbonyl catalyst according to any one of claims 1 to 3, wherein the pyridinium salt carbonyl catalyst 1 is used in an asymmetric biomimetic aldol reaction of an amino acid derivative with a carbonyl compound to synthesize a chiral β-hydroxy-α-amino acid compound, the reaction comprising: an aldol reaction between an amino acid derivative 2 and a carbonyl compound 3 under the catalytic action of the pyridinium salt carbonyl catalyst 1 to produce a chiral β-hydroxy-α-amino acid compound 4 having different stereoconfigurations, syn-4A, anti-4A, and syn-4B, anti-4B; and a step of determining the absolute stereoconfiguration of the chiral β-hydroxy-α-amino acid compound 4 based on the absolute stereoconfiguration of the pyridinium salt carbonyl catalyst 1. Reaction equation 【Chemistry 15】 [In the formula, R １５ is hydrogen, substituted or unsubstituted C １～２４ alkyl group, substituted or unsubstituted C ３ -C １８ aryl group, substituted or unsubstituted C ２～１８ Alkenyl group, substituted or unsubstituted C ２～２４ Alkynyl group, or C １～１８ The substituents include halogen, cyano, hydroxy, nitro, and C １～１８ alkyl group of C ３～１８ an aryl group of C １－１８ a carbonyl group of C １～１８ a sulfonyl group or a phosphoryl group of C １～１８ an alkoxy group of C ３～１８ or an aryloxy group of C １～１８ and the carbonyl group comprises an aldehyde group, a ketocarbonyl group, an estercarbonyl group, a carboxyl group, or an amide group; R １６ is OR １９ or NR ２０ R ２１ and R １９ is hydrogen, substituted or unsubstituted C １～２４ alkyl group, substituted or unsubstituted C ３ -C １８ Aryl group, C １～１８ and R ２０ and R ２１ is hydrogen, substituted or unsubstituted C １～２４ alkyl group, substituted or unsubstituted C ３ -C １８ Aryl group, C １～１８ or R ２０ and R ２１ are bonded to form ring B, or NR ２０ R ２１ contains an amino acid amine group, an amino acid ester amine group, an amino acid amide amine group, or a polypeptide amine group, and the substituents are halogen, cyano group, hydroxy group, nitro group, C １～１８ alkyl group of C ３～１８ an aryl group of C １－１８ a carbonyl group of C １～１８ a sulfonyl group or a phosphoryl group of C １～１８ an alkoxy group of C ３～１８ or an aryloxy group of C １～１８ wherein the carbonyl group comprises an aldehyde group, a ketocarbonyl group, an estercarbonyl group, a carboxyl group or an amide group, and ring B comprises a C １～１８ wherein the heteroatom is an O, N or S atom; R １７ and R １８ is hydrogen, substituted or unsubstituted C １～２４ alkyl group, substituted or unsubstituted C ３ -C １８ aryl group, substituted or unsubstituted C ２～１８ Alkenyl group, substituted or unsubstituted C ２～２４ It contains an alkynyl group, and the substituents are halogen, cyano, hydroxy, nitro, trifluoromethyl, C １～１８ alkyl group of C ３～１８ an aryl group of C １－１８ a carbonyl group of C １～１８ a sulfonyl group or a phosphoryl group of C １～１８ an alkoxy group of C ３～１８ or an aryloxy group of C １～１８ amine groups, 【Chemistry 16】 wherein the carbonyl group comprises an aldehyde group, a ketocarbonyl group, an estercarbonyl group, a carboxyl group, or an amide group; R ｂ , R ２ｂ and R ３ｂ is hydrogen, C １～１０ wherein m is 1, 2, or 3, and n is 0, 1, 2, 3, 4, or 5.

15. the molar ratio of the amino acid derivative 2 to the carbonyl compound 3 is (0.5 to 5):1, the molar ratio of the pyridinium salt carbonyl catalyst 1 to the carbonyl compound 3 is (0.00001 to 0.5):1, the reaction temperature is −60 to 100° C., and the reaction time is 1 to 72 hours; 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 hydrogen carbonate, potassium hydrogen carbonate, 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, diazabicycloundecene, 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.

15. Use of a chiral pyridinium salt carbonyl catalyst according to claim 14.

Images