General chiral catalysts containing a quinacrine arylcarboxamide skeleton, and preparation method and application thereof

Abstract

This invention provides a class of general-purpose chiral catalysts containing a cinchona primary amine arylformamide skeleton, along with their preparation methods and applications, belonging to the field of catalytic materials technology. The chiral catalysts provided by this invention link cinchona primary amine with oxazole / thiazole / imidazolium formamide structural units capable of coordination. Through the coordination of the oxazole / thiazole / imidazolium and amide coordinating groups with the central metal, they act as chiral ligands to catalyze a wider range of asymmetric reactions. They can also be used alone as chiral small-molecule catalysts for cinchona-like tertiary amine (thiourea) and square amides to catalyze asymmetric organic reactions. Furthermore, they can achieve synergistic (co-catalytic) catalysis of small molecules and metals in the same reaction system through different combinations. These chiral catalysts can be widely used as Lewis bases, Lewis acids, or small-molecule chiral catalysts and chiral ligands, possessing potential scientific and applied value in chiral sciences such as asymmetric catalysis, chiral synthesis, and chiral resolution.

Description

Technical Field

[0001] This invention relates to the field of catalytic materials technology, and in particular to a class of general chiral catalysts containing a cinchona primary amine arylcaramide skeleton, their preparation methods, and applications. Background Technology

[0002] Asymmetric catalysis is a cutting-edge topic in organic and pharmaceutical synthesis, and it is the most important and challenging synthetic method for obtaining optically pure chiral compounds. Asymmetric catalysis includes enzymatic catalysis, metal catalysis, and small molecule organic catalysis, each with its own complementary advantages. While enzymatic catalysis is highly efficient and specific, it has stringent requirements for the reaction environment; metal catalysis has a broad activation range for chemical bonds, including inert bonds, but it has poor tolerance for functional groups and is highly sensitive to the structure of ligands and reaction substrates; small molecule organic catalysis has better tolerance for functional groups, but its activation and catalytic modes are relatively limited.

[0003] Chiral small molecule catalysis can be traced back to the early 20th century, but it did not receive much attention or importance for a long time. It was not until 2000 that List and Barbas reported the asymmetric Aldol reaction catalyzed by L-proline, and the MacMillan group reported the asymmetric Diels-Alder reaction catalyzed by chiral imidazolinones. After that, asymmetric reactions catalyzed by small organic molecules attracted widespread attention and quickly became a research hotspot in the field of asymmetric synthesis. Due to its low cost, high efficiency and environmental friendliness, small organic molecule catalysis has attracted widespread attention and research from chemists, thus developing small molecule catalysis modes such as enamine mechanism, imine ion mechanism, chiral bifunctional catalysis and Bronsted acid and base catalysis, which has strongly promoted the development of asymmetric catalysis of small organic molecules (Santanu Mukherjee, et al. Chem. Rev. 2007, 107, 5471−5569; Albert Moyano, et al. Chem. Rev. 2011, 111, 4703–4832).

[0004] Cinchona alkaloids are natural alkaloids derived from the bark of the cinchona tree and related species, belonging to the Rubiaceae family. Their main chemical components include quinine, quinidine, cinchonine, and cinchonidine, and may also contain small amounts of their dihydrogen compounds. Due to their natural chiral centers and active reactivity, cinchona alkaloids are readily derivatized to synthesize compounds with diverse structures, and are widely used by chemists in the field of asymmetric organic synthesis. As early as 2003, Jacobson et al. proposed the broad application prospects of these alkaloids in asymmetric catalytic synthesis (Yoon T. P, et al. Science, 2003, 299(5613): 1691-1693.). In the past two decades, base catalysis mediated by cinchona alkaloid derivatives has become a widely used strategy in asymmetric organic catalysis.

[0005] The discovery and development of cinchona base catalysts have secured a significant place for bronsted base catalysts in the field of organic catalysis; it represents a major advancement in asymmetric organic catalysis, exemplified by chiral bronsted base catalysis. Besides providing asymmetric organic base catalysis based on nucleophilic activation, this new development also points to the possibility of developing powerful bifunctional asymmetric catalysis. Subsequently, scientists have successively developed bifunctional catalysts substituted with cinchona-derived (thio)urea and squamamide groups (as shown in the structural formula below). This catalytic approach, combining chiral tertiary amines and hydrogen bonding activation strategies, has become a widely used strategy in the field of asymmetric organic catalysis. Connon et al. have provided a detailed summary of the applications of such bifunctional catalysts in asymmetric catalysis. (Connon S J. Chemicalcommunications, 2008 (22): 2499-2510.)

[0006]

[0007] Cinchona-derived (thio)urea- and squamamide-substituted bifunctional catalysts

[0008] However, despite the excellent results achieved by the aforementioned asymmetric reactions catalyzed by small organic molecule catalysts, these catalytic modes all require functionalized substrates. Therefore, small organic molecule catalysis struggles to activate inert chemical bonds or molecular systems. Transition metals, on the other hand, can activate a variety of chemical bonds, and with the assistance of chiral ligands, hold promise for achieving a wide range of asymmetric catalytic reactions. Chiral ligands can influence the activation ability of the metal center on the substrate through activation or deactivation, and also dissolve the complex in organic solvents. Furthermore, their chiral environment controls or influences the stereoselectivity of the reaction. Due to the wide variety of metals and their diverse activities, they are easily modulated by ligands, enabling the catalysis of various chemical transformations with different requirements. For over half a century since the 1960s, asymmetric metal catalysis has developed rapidly, with transition metal catalysis long holding a dominant position and becoming a cutting-edge research direction in organic synthesis methodology and an important branch of homogeneous catalysis. Moreover, in metal-catalyzed asymmetric reactions, chiral ligands play a crucial role in the enantioselectivity and efficiency of the reaction. Summary of the Invention

[0009] The purpose of this invention is to provide a class of universal chiral catalysts containing a cinchona primary amine aryl carboxamide skeleton, their preparation methods, and applications. The universal chiral catalysts containing a cinchona primary amine aryl carboxamide skeleton provided by this invention, as a novel multifunctional universal chiral catalyst, can participate in catalytic organic reactions and asymmetric organic reactions. They can be used as Lewis bases, Lewis acids, or small molecule chiral catalysts and chiral ligands, and have potential scientific and applied value in chiral sciences such as asymmetric catalysis, chiral synthesis, and chiral resolution.

[0010] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0011] This invention provides a class of general chiral catalysts containing a cinchona primary amine arylcaramide skeleton, having the structure shown in Formula 1 below:

[0012] Formula 1;

[0013] In Formula 1, Ar is independently selected from substituted or unsubstituted C5~C6 groups. 50 One of cyclopentadienyl, aryl, benzoaryl, and fused aryl;

[0014] In Equation 1, R' in X is independently selected from C1 to C2. 30 Alkyl, C1~C 30 Silyl groups, C1~C 30 Haloalkyl, C2~C 30 alkenyl, C2~C 30 Alkyne, acyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylamine carbonyl, arylamine carbonyl, chain length C1~C 30One of the electron-withdrawing or electron-donating substituents;

[0015] In Equation 1, Ar' in X is independently selected from substituted or unsubstituted C6~C6. 50 aryl, benzo[a]aryl, fused[a]aryl, substituted or unsubstituted C7~C 50 Aryl groups, substituted or unsubstituted C7~C 50 arylalkoxy, substituted or unsubstituted C7~C 50 Aryl thiol group, substituted or unsubstituted C7~C 50 One of the aromatic heterocyclic groups;

[0016] In Equation 1, R in Z is independently selected from hydrogen atoms, C1~C1 atoms. 30 Alkyl, C1~C 30 Silyl groups, C1~C 30 Haloalkyl, C2~C 30 alkenyl, C2~C 30 Alkyne, acyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylamine carbonyl, arylamine carbonyl, chain length C1~C 30 Electron-withdrawing or electron-donating substituents, substituted or unsubstituted C6~C 50 aryl, benzo[a]aryl, fused[a]aryl, substituted or unsubstituted C7~C 50 Aryl groups, substituted or unsubstituted C7~C 50 arylalkoxy, substituted or unsubstituted C7~C 50 Aryl thiol group, substituted or unsubstituted C7~C 50 Aromatic heterocyclic groups, substituted or unsubstituted C7~C 30 One of the aromatic amine group, aromatic heterocycle, fused heterocycle, or fused heterocycle;

[0017] The condensed aryl group is independently one of naphthalene, anthracene, phenanthrene, and carbazole;

[0018] The aromatic heterocycle is independently one of thiophene, furan, pyrrole, pyridine, and pyrimidine;

[0019] The fused heterocycle is independently one of benzothiophene, benzofuran, indole, quinoline, isoquinoline, and benzoquinoline.

[0020] Preferably, it has the structure shown in formula 1a, 1b or 1c;

[0021] ;

[0022] In formulas 1a, 1b, or 1c, Ar is independently selected from substituted or unsubstituted C5-C. 50 One of cyclopentadienyl, aryl, benzoaryl, and fused aryl;

[0023] In formulas 1a, 1b, or 1c, X is independently selected from one of hydrogen atom, phenolic hydroxyl group, methoxy group, alkoxy group, and aryloxy group;

[0024] In formula 1c, R is independently selected from hydrogen atoms, C1~C1 atoms. 30 Alkyl, C1~C 30 Silyl groups, C1~C 30 Haloalkyl, C2~C 30 alkenyl, C2~C 30 Alkyne, acyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylamine carbonyl, arylamine carbonyl, and chains with chain lengths of C1~C 30 Electron-withdrawing or electron-donating substituents or any substituents, etc.; can also be selected from substituted or unsubstituted C6~C6 substituents. 50 aryl, benzoyl, fused aryl, substituted or unsubstituted C7~C 50 Aryl groups, substituted or unsubstituted C7~C 50 arylalkoxy, substituted or unsubstituted C7~C 50 Aryl thiol group, substituted or unsubstituted C7~C 50 Aromatic heterocyclic groups, substituted or unsubstituted C7~C 30 One of the aromatic amine group, aromatic heterocyclic group, fused heterocyclic group, or fused heterocyclic group;

[0025] The condensed aryl group is independently one of naphthalene, anthracene, phenanthrene, and carbazole;

[0026] The aromatic heterocycle is independently one of thiophene, furan, pyrrole, pyridine, and pyrimidine;

[0027] The fused heterocycle is independently one of benzothiophene, benzofuran, indole, quinoline, isoquinoline, and benzoquinoline.

[0028] In this invention, the compounds having the structure shown in formula 1a, 1b, or 1c are more preferably (dihydro)quinine primary amine aryl-oxazole formamide, (dihydro)quinidine primary amine aryl-oxazole formamide, (dihydro)cinconidine primary amine aryl-oxazole formamide, (dihydro)cinconidine primary amine aryl-oxazole formamide, 6'-hydroxy(dihydro)quinine primary amine aryl-oxazole formamide, 6'-hydroxy(dihydro)quinidine primary amine aryl-oxazole formamide; (dihydro)quinine primary amine aryl-thiazolidinyl formamide, (dihydro)quinidine primary amine aryl-thiazolidinyl formamide, (dihydro)cinconidine primary amine One of the following: aryl-2-thiazole carboxamide, (dihydro)cinconine primary amine aryl-2-thiazole carboxamide, 6'-hydroxy(dihydro)quinine primary amine aryl-2-thiazole carboxamide, 6'-hydroxy(dihydro)quinidine primary amine aryl-2-thiazole carboxamide; (dihydro)quinine primary amine aryl-2-imidazolium carboxamide, (dihydro)cinconine primary amine aryl-2-imidazolium carboxamide, (dihydro)cinconine primary amine aryl-2-imidazolium carboxamide, 6'-hydroxy(dihydro)quinine primary amine aryl-2-imidazolium carboxamide, 6'-hydroxy(dihydro)quinidine primary amine aryl-2-imidazolium carboxamide.

[0029] Preferably, it has the structure shown in formulas 1a'-1 to 1a'-12, 1b'-1 to 1b'-12, or 1c'-1 to 1c'-12:

[0030]

[0031] .

[0032] Preferably, it has the structure shown in formulas 1a-1 to 1a-28, 1b-1 to 1b-28, or 1c-1 to 1c-64:

[0033]

[0034] .

[0035] This invention also provides a method for preparing a universal chiral catalyst containing a cinchona primary amine arylformamide skeleton as described in the above-mentioned technical solution, comprising the following steps:

[0036]

[0037] Using cinchona amine as shown in Formula 2 and arylbenzoxazole / thiazole / imidazol-2-carboxylic acid as shown in Formula 3 as raw materials, a condensation reaction is carried out in the presence of condensing agent C1 and solvent S1 at a temperature of T1 to obtain the universal chiral catalyst containing the cinchona amine arylcarboxamide skeleton as described in Formula 1.

[0038] In Equation 2, R' in X is independently selected from C1 to C2. 30 Alkyl, C1~C 30 Silyl groups, C1~C 30 Haloalkyl, C2~C 30 alkenyl, C2~C 30 Alkyne, acyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylamine carbonyl, arylamine carbonyl, chain length C1~C 30 One of the electron-withdrawing or electron-donating substituents;

[0039] In Equation 2, Ar' in X is independently selected from substituted or unsubstituted C6~C6. 50 aryl, benzo[a]aryl, fused[a]aryl, substituted or unsubstituted C7~C 50 Aryl groups, substituted or unsubstituted C7~C 50 arylalkoxy, substituted or unsubstituted C7~C 50 Aryl thiol group, substituted or unsubstituted C7~C 50 One of the aromatic heterocyclic groups;

[0040] In Formula 3, Ar is independently selected from substituted or unsubstituted C5~C6 groups. 50 One of cyclopentadienyl, aryl, benzoaryl, and fused aryl;

[0041] In Equation 3, R in Z is independently selected from hydrogen atoms, C1~C1 atoms. 30 Alkyl, C1~C 30 Silyl groups, C1~C 30 Haloalkyl, C2~C 30 alkenyl, C2~C 30 Alkyne, acyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylamine carbonyl, arylamine carbonyl, chain length C1~C 30 Electron-withdrawing or electron-donating substituents, substituted or unsubstituted C6~C 50 aryl, benzo[a]aryl, fused[a]aryl, substituted or unsubstituted C7~C 50 Aryl groups, substituted or unsubstituted C7~C 50 arylalkoxy, substituted or unsubstituted C7~C 50 Aryl thiol group, substituted or unsubstituted C7~C 50 Aromatic heterocyclic groups, substituted or unsubstituted C7~C 30 One of the aromatic amine group, aromatic heterocycle, fused heterocycle, or fused heterocycle;

[0042] The condensed aryl group is independently one of naphthalene, anthracene, phenanthrene, and carbazole;

[0043] The aromatic heterocycle is independently one of thiophene, furan, pyrrole, pyridine, and pyrimidine;

[0044] The fused heterocycle is independently one of benzothiophene, benzofuran, indole, quinoline, isoquinoline, and benzoquinoline.

[0045] The preparation method provided by the present invention has advantages such as inexpensive and readily available raw materials, simple synthesis process, mild reaction conditions, short synthesis route, and low cost.

[0046] Preferably, the cinchona amine shown in Formula 2 is 1.2 equivalents; the aryloxazole / thiazole / imidazol-2-carboxylic acid shown in Formula 3 is 1.0 equivalents; and the condensing agent C1 is 2.0 equivalents.

[0047] Preferably, the condensing agent C1 is one or more of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), and diisopropylcarbodiimide (DIC).

[0048] Preferably, the volume ratio of the solvent S1 to the total mass of cinchona amine (Formula 2), aryloxazole / thiazole / imidazol-2-carboxylic acid (Formula 3), and condensing agent C1 is (1~20) mL: 1 g.

[0049] In this invention, the solvent S1 is preferably one or more of halogenated hydrocarbons, ethers, and aromatic hydrocarbons, and more preferably one or more of dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, toluene, o-xylene, and m-xylene.

[0050] Preferably, the temperature T1 of the condensation reaction is from 0°C to the solvent reflux temperature; the time of the condensation reaction is 5~10h.

[0051] In this invention, the condensation reaction is preferably monitored by TLC to ensure complete reaction of the starting materials. After the condensation reaction is completed, the process preferably further includes subjecting the product of the condensation reaction to vacuum distillation and column chromatography sequentially to obtain a universal chiral catalyst containing a cinchona primamine arylcaramide skeleton. In this invention, all eluents used in the column chromatography are preferably a mixed solvent composed of DCM and MeOH in a volume ratio of 20:1.

[0052] The present invention also provides the application of the universal chiral catalyst containing the cinchona primamine arylformamide skeleton described in the above technical solution in catalytic organic synthesis and / or preparation of antimalarial drugs.

[0053] In this invention, the catalytic organic synthesis preferably includes: the universal chiral catalyst containing the cinchona primary amine arylcaramide skeleton can be used as a Lewis base, Lewis acid, or small molecule chiral catalyst and chiral ligand, and its application in asymmetric catalysis, chiral synthesis, and chiral resolution reactions. In this invention, the preparation of antimalarial drugs is preferably the preparation of cinchona alkaloid antimalarial drugs.

[0054] This invention provides a class of universal chiral catalysts containing a cinchona primary amine aryl carboxamide skeleton, with the following beneficial effects:

[0055] (1) Based on the concept of “universal chiral catalysis”, a class of multifunctional universal chiral catalysts containing formamide skeletons such as cinchona alkaloid primary amine oxazole were designed and synthesized, namely the universal chiral catalyst containing cinchona alkaloid primary amine aryl formamide skeleton shown in Formula 1. Compared with traditional cinchona alkaloid (thiourea) and square amide catalysts, this chiral catalyst has different structures and more and richer catalytic functions. It can be used as a new type of universal chiral catalyst to participate in catalytic organic reactions and asymmetric organic reactions. Its significant feature lies in linking cinchona primary amine with formamide structures such as oxazole, introducing oxazole / thiazole / imidazolium formamide structural units that can participate in coordination. These units can coordinate with the central metal through oxazole / thiazole / imidazolium and amide coordinating groups, acting as chiral ligands to catalyze a wider range of asymmetric reactions. Furthermore, this type of chiral catalyst can also act alone as a chiral small molecule catalyst for asymmetric organic reactions, similar to cinchona alkaloids such as tertiary amine (thiourea) and squaramides. It can also achieve synergistic (co-catalytic) catalysis of small molecules and metals in the same reaction system through different combinations—a molecular structure and catalytic function not possessed by traditional cinchona alkaloid-based chiral small molecule catalysts. The target chiral catalyst containing the cinchona primary amine aromatic formamide skeleton can be widely used as a Lewis base, Lewis acid, or small molecule chiral catalyst and chiral ligand, possessing potential scientific and applied value in chiral sciences such as asymmetric catalysis, chiral synthesis, and chiral resolution.

[0056] (2) Due to the coordination effect of the oxazole / thiazole / imidazolium carboxamide structural unit and cinchona alkaloid tertiary amine in the chiral catalyst, this type of compound containing cinchona primary amine aryl carboxamide skeleton can act as a chiral ligand to form a chiral metal complex with the central metal and participate in various metal-catalyzed asymmetric reactions.

[0057] (3) Since the cinchona alkaloid skeleton has a natural chiral tertiary amine, it can act as a chiral Lewis base, and the Lewis acidity and strong hydrogen bond donor of the amide active H of the oxazole / thiazole / imidazolium formamide structural unit makes the chiral catalyst a chiral bifunctional organic small molecule catalyst that catalyzes organic reactions or asymmetric organic reactions.

[0058] (4) The chiral catalyst described herein can achieve synergistic catalysis between chiral small molecules and metals through different combination modes;

[0059] (5) Because the chiral catalyst contains amide-active H, it can act as a Lewis acid and strong hydrogen bond donor to catalyze organic reactions or asymmetric organic reactions.

[0060] (6) Due to the presence of chiral tertiary amines in the chiral catalyst, it can be used as a chiral Lewis base and a small organic molecule catalyst to catalyze organic reactions or asymmetric organic reactions;

[0061] (7) New chiral catalysts can be synthesized by derivatizing the chiral tertiary amine structure in the chiral catalyst;

[0062] (8) New catalysts can be synthesized by derivatizing the pyridine structure in the chiral catalyst;

[0063] (9) By N-quaternization derivatization of the chiral tertiary amine structure in the chiral catalyst, a chiral quaternary amine salt phase transfer catalyst is synthesized;

[0064] (10) Synthesize pyridine-based phase transfer catalysts by derivatizing the pyridine structure in the chiral catalyst;

[0065] (11) Due to the antimalarial drug activity of cinchonasal, the chiral catalyst can be used in pharmaceuticals and their intermediates;

[0066] (12) The preparation method of the chiral catalyst and its chiral isomer described in this invention has the advantages of cheap and readily available raw materials, simple synthesis process, mild reaction conditions, short synthesis route and low cost. Attached Figure Description

[0067] Figure 1 This is a structural diagram of a general chiral catalyst containing a cinchona primary amine aryl formamide skeleton in this invention. The cinchona primary amine oxazole and other formamide skeletons are composed of cinchona base skeletons and oxazole and other formamide structural units. The tertiary amine structure of cinchona base can be used as a Lewis base, and the amide H of oxazole and other formamides can be used as a Lewis acid.

[0068] Figure 2 The diagram shows the structure of a general chiral catalyst containing a cinchona primary amine aryl carboxamide skeleton as shown in Formulas 1a, 1b and 1c in this invention, wherein Formulas 1a, 1b and 1c respectively contain an oxazole carboxamide skeleton, a thiazole carboxamide skeleton and an imidazole carboxamide skeleton.

[0069] Figure 3This diagram illustrates a structural comparison between the universal chiral catalyst containing the cinchona primary amine arylformamide skeleton of this invention and the representative cinchona alkaloid dominant skeleton small molecule chiral catalyst in the prior art. The left-hand diagram represents the universal chiral catalyst containing the cinchona primary amine arylformamide skeleton, possessing a chiral tertiary amine (which can act as a chiral Lewis base catalyst), an amide active H (a strong Lewis acid and strong hydrogen bond donor), and formamide structural units such as oxazole (which can act as chiral ligands). The upper right-hand diagram represents a representative cinchona alkaloid (thiourea) small molecule chiral catalyst with a (thio)urea structural unit, possessing a chiral tertiary amine (which can act as a chiral Lewis base catalyst) and a (thio)urea active H (a strong Lewis acid and strong hydrogen bond donor). The lower right-hand diagram represents a representative cinchona alkaloid (squamous amide) small molecule chiral catalyst with a square amide structural unit, possessing a chiral tertiary amine (which can act as a chiral Lewis base catalyst) and a square amide active H (a strong Lewis acid and strong hydrogen bond donor). Detailed Implementation

[0070] The universal chiral catalyst containing a cinchona primary amine arylformamide skeleton provided by this invention contains a cinchona alkaloid skeleton that can not only participate in asymmetric reactions as a small organic molecule catalyst, but also as a ligand in transition metal-catalyzed asymmetric reactions. The N atom on the quinine bridge ring has unpaired lone pairs of electrons, which can coordinate with metals with empty orbitals. Furthermore, the cinchona alkaloid skeleton has multiple modifiable sites, allowing for the regulation of the spatial and electronic effects of the metal catalytic center through reasonable structural modifications. The coordinating atoms in the ligand can bond with the metal as anions or provide lone pairs of electrons to form Lewis acid-base adducts with the metal. In other words, the cinchona alkaloid skeleton in the chiral catalyst of this invention, due to the tertiary amine group on its quinine ring, is not only a nucleophilic catalytic active center but also a Lewis and Bronsted base, and can also bond with transition metals, thus participating in metal-catalyzed asymmetric reactions as a chiral ligand. Therefore, through derivatization, the coordination ability and coordination mode of cinchona derivatives can be further enhanced, enabling them to be used as ligands in the field of asymmetric metal catalysis.

[0071] Furthermore, taking advantage of the good coordination and derivatization abilities of oxazole, thiazole, and imidazole units, and their ability to be linked with other catalytic functional units through linking units, this invention synthesizes a new compound containing cinchona amine oxazole and other formamide structures by linking cinchona amine primary amine and oxazole, thiazole, and imidazole units through an amide structure. That is, the universal chiral catalyst containing the cinchona amine primary amine arylformamide skeleton shown in Formula 1. This new compound also retains all the characteristics of cinchona alkaloid (thio)urea and square amide chiral small molecule catalysts. It can be used alone as a chiral small molecule catalyst, or as a chiral ligand to achieve asymmetric metal catalysis through metal coordination, or in combination (synergistic) catalysis to achieve more and richer asymmetric catalytic reactions. It is expected to become a cross-border "universal" chiral catalyst.

[0072] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0073] Unless otherwise specified, all experiments were repeated three times, and the results are expressed as averages.

[0074] Example 1

[0075] A general chiral catalyst containing a cinchona primary amine aryl carboxamide skeleton, as shown in Formula 1a-1, also known as quinine primary amine benzoxazole carboxamide, is prepared by the following steps:

[0076] The synthetic route is as follows:

[0077] ;

[0078] In a round-bottom flask, benzoxazole-2-carboxylic acid (0.91 g, 5.58 mmol) as shown in Formula 3a, quinine primary amine (2.17 g, 6.70 mmol) as shown in Formula 2a, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (4.24 g, 11.16 mmol) were added, followed by 20 mL of dichloromethane. The mixture was placed at room temperature and reacted. After approximately 6 h, the reaction was monitored by TLC until the reactants were completely reacted, at which point the reaction was terminated. The organic solvent was removed by vacuum distillation, and the crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain the white solid product, the compound shown in Formula 1a-1 (2.00 g, 76% yield).

[0079] The characterization data of the compound shown in Formula 1a-1 are as follows: 1H NMR (400 MHz, Chloroform-d) δ 8.79(d, J = 4.6 Hz, 1H), 8.41 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.84 – 7.73 (m,2H), 7.62 (d, J = 8.0 Hz, 1H), 7.53 – 7.37 (m, 4H), 5.83 (ddd, J = 17.4,10.4, 7.2 Hz, 1H), 5.18 – 4.99 (m, 2H), 4.04 (s, 3H), 3.52 (s, 1H), 3.38 (dd,J = 14.2, 10.3 Hz, 2H), 2.90 (dd, J = 21.6, 9.9 Hz, 2H), 2.42 (d, J = 8.8 Hz, 1H), 1.81 – 1.65 (m, 4H), 1.29 (s, 1H), 1.02 (dd, J = 14.2, 6.5 Hz, 1H). 13 CNMR (101 MHz, Chloroform-d) δ 158.21, 155.62, 155.22, 151.10, 147.59, 144.99,140.98, 140.29, 131.96, 127.39, 125.52, 122.09, 121.34, 114.97, 111.81,101.69, 55.98, 55.83, 41.23, 39.29, 29.75, 29.36, 27.67, 27.42, 26.54. HRMS(ESI) m / z calcd for C 28 H 28 N4O3H + (M+H) + 469.22342, found 469.22349.

[0080] Example 2

[0081] A general chiral catalyst containing a cinchona primary amine aryl carboxamide skeleton, as shown in Formula 1b-1, also known as quinine primary amine benzothiazole carboxamide, is prepared by the following steps:

[0082] The synthetic route is as follows:

[0083] ;

[0084] In a round-bottom flask, benzothiazol-2-carboxylic acid (1.00 g, 5.58 mmol) as shown in Formula 3b, quinine primary amine (2.17 g, 6.70 mmol) as shown in Formula 2a, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (4.24 g, 11.16 mmol) were added, followed by 20 mL of dichloromethane. The mixture was placed at room temperature and reacted. After approximately 6 h, the reaction was monitored by TLC until the reactants were completely reacted, at which point the reaction was terminated. The organic solvent was removed by vacuum distillation, and the crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain a white solid product, the compound shown in Formula 1b-1 (1.92 g, 71% yield).

[0085] The characterization data of the compound shown in Formula 1b-1 are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 8.74(d, J=4.6 Hz, 1H), 8.46 (s, 1H), 8.03 (dd, J=21.6, 8.7 Hz, 2H), 7.91-7.85 (m,1H), 7.71 (d, J=2.7 Hz, 1H), 7.49 (ddd, J=8.4, 7.2, 1.3 Hz, 1H), 7.46-7.40(m, 2H), 7.36 (dd, J=9.2, 2.7 Hz, 1H), 5.77 (ddd, J=17.4, 10.4, 7.3 Hz, 1H),5.05-4.93 (m, 2H), 3.97 (s, 3H), 3.47-3.18 (m, 3H), 2.85-2.76 (m, 2H), 2.31(dt, J=10.6, 6.4 Hz, 1H), 1.71-1.50 (m, 4H), 1.27-1.21 (m, 1H), 0.95 (dd, J=14.2, 6.6 Hz, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 163.62, 159.94, 158.18,153.06, 147.67, 144.95, 141.34, 137.16, 131.98, 126.86, 126.82, HRMS (ESI) m / z calcd for C28 H 28 N4O2SH + (M+H) + 485.20057, found 485.20172.

[0086] Example 3

[0087] A method for preparing a universal chiral catalyst containing a cinchona primary amine aryl carboxamide skeleton, as shown in Formula 1c-1, also known as quinine primary amine benzimidazole carboxamide, comprises the following steps:

[0088] The synthetic route is as follows:

[0089]

[0090] In a round-bottom flask, benzimidazole-2-carboxylic acid (1.00 g, 6.17 mmol) as shown in Formula 3c, quinine primary amine (2.39 g, 7.40 mmol) as shown in Formula 2a, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (4.69 g, 12.33 mmol) were added, followed by 20 mL of dichloromethane. The mixture was placed at room temperature and reacted. After approximately 6 h, the reaction was monitored by TLC until the reactants were completely reacted, at which point the reaction was terminated. The organic solvent was removed by vacuum distillation, and the crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain the white solid product, the compound shown in Formula 1c-1 (1.82 g, 63% yield).

[0091] The characterization data of the compound shown in Formula 1c-1 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 13.18 (s,1H), 9.23-9.12 (m, 1H), 8.71 (d, J=4.6 Hz, 1H), 7.92 (d, J=9.1 Hz, 1H), 7.84-7.81 (m, 1H), 7.65 (d, J=4.6 Hz, 2H), 7.51-7.44 (m, 1H), 7.39 (dd, J=9.1, 2.7Hz, 1H), 7.23 (s, 2H), 5.87 (dt, J=17.5, 8.7 Hz, 1H), 5.03 (d, J=17.2 Hz, 1H), 4.96 (d, J=10.7 Hz, 1H), 3.91 (s, 3H), 3.14 (q, J=15.8, 13.7 Hz, 2H),2.79-2.73 (m, 1H), 2.66 (s, 2H), 2.25 (s, 1H), 1.57 (s, 2H), 1.47 (s, 2H),1.17 (d, J=4.3 Hz, 1H), 0.77 (ddd, J=26.7, 13.3, 6.9 Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ161.31, 158.77, 157.92, 148.33, 148.22, 145.79, 144.59,142.53, 131.86, 130.18, 124.76, 123.20, 121.79,114.94,103.06,102.98,56.53,56.15,55.49,41.27,40.51,29.53,29.21,27.83,27.58,27.41,26.59.HRMS (ESI) m / z calcd for C 28 H 29 N5O2H + (M+H) + 468.23940, found 468.24089.

[0092] Application Example 1 (as a chiral ligand)

[0093] The universal chiral catalyst containing the cinchona primary amine arylcarboxamide skeleton prepared in Example 1, namely the compound shown in Formula 1a-1, was used as the ligand Ligand and applied to the asymmetric addition reaction of the N-Boc indorubin imine compound shown in Formula 4-1 with methanol catalyzed by copper trifluoromethanesulfonate CuOTf, to synthesize a compound with the structure shown in Formula 6-1. The steps were as follows: Quinine primary amine benzoxazole carboxamide 1a-1 (2.4 mg, 10 mol%), CuOTf (1.1 mg, 10 mol%), and dichloromethane (1.0 mL) were added to a test tube equipped with a magnetic stir bar and stirred at room temperature for 4 h. Then, the N-Boc indorubin imine compound shown in Formula 4-1 (12.3 mg, 0.05 mmol) and methanol (10 μL) were added sequentially, and the reaction was carried out at room temperature. After the reaction was completed (monitored by TLC), the compound with the target product structure shown in Formula 6-1 was obtained by silica gel column chromatography after concentration under reduced pressure.

[0094] The characterization data of the compound with the structure shown in Formula 6-1 are: white solid; 1 H NMR (600 MHz, DMSO-d6)δ10.36 (s, 1H), 7.88 (s, 1H), 7.29–7.17 (m, 2H), 6.94 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 3.14 (s, 3H), 1.17 (s, 9H). 13 C NMR (151 MHz, DMSO-d6) δ173.62, 153.80, 143.06, 130.56, 128.02, 124.60, 122.17, 110.38, 85.23,79.35, 51.41, 28.34. HRMS (ESI) m / z calcd for C 14 H 18 N2O4K + (M+K) + 317.08981, found 317.09104. HPLC separation conditions: CHIRALP AK AD-H (n-hexane / isopropanol = 50 / 50, flow rate 0.6 mL / min, λ = 254 nm), t R (minor) = 5.86 min, t R (major) = 8.07min

[0095] The reaction formula is as follows:

[0096]

[0097] Application Examples 2-6

[0098] Following the method of Application Example 1, a compound with the structure shown in Formula 6-1 was prepared, the difference being that the ligand Ligand shown in Formula 1a-1 was replaced with the compounds shown in Formula 1b-1, Formula 1c-1, Formula 1a-4, Formula 1b-4, and Formula 1c-4, respectively.

[0099]

[0100] The yields and enantiomeric excesses of the compounds with the structures shown in Formula 6-1 prepared in Examples 1-6 were determined by silica gel column chromatography and chiral liquid chromatography, respectively, and the results are shown in Table 1.

[0101] Table 1. Yields and enantiomeric excesses of compounds with the structures shown in Formula 6-1

[0102]

[0103] As shown in Table 1, the novel chiral catalyst containing the cinchona primamine arylformamide skeleton shown in Formula 1 can participate as a chiral ligand in the CuOTf-catalyzed asymmetric addition reaction of N-Boc indorubin imine with methanol, making it a potential advantageous chiral ligand for participating in more types of asymmetric catalytic reactions.

[0104] Application Examples 7-11

[0105] Following the method of Application Example 1, the asymmetric addition reaction of N-Boc indorubin imine with methanol was catalyzed by CuOTf trifluoromethanesulfonate. The difference from Application Example 1 was that the substrate N-Boc indorubin imine was replaced with compounds with the structures shown in Formulas 4-2 to 4-6, respectively, to prepare compounds with the structures shown in Formulas 6-2 to 6-6.

[0106] The yields and enantiomeric excesses (ee) of the compounds with structures of formulas 6-2 to 6-6 prepared in Examples 7 to 11 were determined by silica gel column chromatography and chiral liquid chromatography, respectively, and the results are shown in the following formulas:

[0107] .

[0108] Application Example 12 (as a chiral small molecule catalyst)

[0109] The universal chiral catalyst containing the quinine primary amine arylcarboxamide skeleton prepared in Example 1, namely the compound shown in Formula 1a-1, was used as a chiral small molecule catalyst to catalyze the asymmetric Mannich reaction of the N-Boc indorubin imine compound shown in Formula 4-6 with the edaravone shown in Formula 7, to synthesize a compound with the structure shown in Formula 8. The steps were as follows: Quinine primary amine benzoxazole carboxamide 1a-1 (2.4 mg, 10 mol%), N-Boc indorubin imine 4-6 (16.8 mg, 0.05 mmol), and edaravone 7 (8.7 mg, 0.05 mmol) were added to a test tube equipped with a magnetic stir bar, and then toluene (1.0 mL) was added. The reaction was carried out at room temperature. After the reactants had reacted completely (as monitored by TLC), Ac2O (0.05 mmol) and TEA (0.015 mmol) were added. After the reaction was complete (as monitored by TLC), the product was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the compound with the structure shown in Formula 8.

[0110] The characterization data for the compound with the structure shown in Formula 8 are: white solid; 1 H NMR (600 MHz, Chloroform-d) δ 7.45 (d, J=7.4 Hz, 1H), 7.38-7.34 (m, 6H), 7.30 (t, J=7.5 Hz, 3H), 7.23(d, J=7.3 Hz, 1H), 7.18 (td, J=7.7, 1.2 Hz, 1H), 7.04 (td, J=7.5, 1.0 Hz,1H), 6.66 (d, J=7.8 Hz, 1H), 5.63 (s, 1H), 4.94 (s, 2H), 2.43 (s, 3H), 1.65(s, 3H), 1.31 (s, 9H). 13 C NMR (151 MHz, Chloroform-d) δ 175.23, 167.03,153.84, 148.00, 143.30, 141.48, 137.47, 135.63, 129.33, 129.28, 128.77,127.95, HRMS (ESI) m / z calcd for C 32 H 32 N4O5Na + (M+Na) +575.22649, found 575.22726. HPLC separation conditions: CHIRALP AK AD-H (n-hexane / isopropanol = 80 / 20, flow rate 1.0 mL / min, λ = 254 nm), t R (minor) = 8.2min, t R (major) = 16.5 min.

[0111] The reaction formula is as follows:

[0112]

[0113] Application Example 13

[0114] Following the method of Application Example 12, a compound with the structure shown in Formula 8 was prepared, except that the chiral small molecule catalyst shown in Formula 1a-1 used in Application Example 12 was replaced with the compound shown in Formula 1c-1.

[0115] The yields and enantiomeric excesses of the compounds with the structures shown in Formula 8 prepared in Examples 12 and 13 were determined by silica gel column chromatography and chiral liquid chromatography, respectively, and the results are shown in Table 2 below.

[0116] Table 2 shows the yields and enantiomeric excesses of compounds with the structures shown in Formula 8.

[0117]

[0118] As shown in Table 2, the novel chiral catalyst containing the cinchona primamine arylformamide skeleton shown in Formula 1 can be used as a chiral small molecule catalyst to catalyze the asymmetric Mannich reaction of N-Boc indorubin imine with edaravone, making it a potential superior chiral small molecule catalyst for catalyzing more types of asymmetric reactions.

[0119] In summary, the significant difference between the chiral catalyst provided by this invention and existing cinchona alkaloid-based small molecule catalysts lies in the introduction of oxazole / thiazole / imidazolium formamide structural units that can participate in coordination. These units can coordinate with the central metal through oxazole / thiazole / imidazolium and amide coordinating groups, acting as chiral ligands to catalyze a wider range of asymmetric reactions. Furthermore, this type of chiral catalyst can also be used alone as a cinchona alkaloid, a cinchona alkaloid tertiary amine (thiourea), or a square amide chiral small molecule catalyst to catalyze asymmetric organic reactions. It can also achieve synergistic (co-)catalysis of small molecules and metals in the same reaction system through different combinations. The general-purpose chiral catalyst containing the cinchona primary amine arylformamide skeleton can be widely used as a Lewis base, Lewis acid, or small molecule chiral catalyst and chiral ligand, possessing potential scientific and applied value in chiral sciences such as asymmetric catalysis, chiral synthesis, and chiral resolution. Furthermore, the universal chiral catalyst containing the cinchona primary amine arylformamide skeleton prepared by this invention has the advantages of short synthetic route, simple operation and easy availability of raw materials, and has been successfully used as a chiral ligand for asymmetric metal catalysis and as an organic small molecule catalyst for catalyzing asymmetric reactions, showing great application prospects.

[0120] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A class of general chiral catalysts containing a cinchona primary amine arylcaramide skeleton, characterized in that, It has the structure shown in Equation 1: Formula 1; Ar in the formula 1 is independently selected from one of substituted or unsubstituted C5-C20 cyclopentadienyl, aryl, heteroaryl, and fused aryl groups; 50 Ar in the formula 1 is independently selected from one of substituted or unsubstituted C5-C20 cyclopentadienyl, aryl, heteroaryl, and fused aryl groups; In Equation 1, R' in X is independently selected from C1 to C2. 30 Alkyl, C1~C 30 Silyl groups, C1~C 30 Haloalkyl, C2~C 30 alkenyl, C2~C 30 Alkyne, acyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylamine carbonyl, arylamine carbonyl, chain length C1~C 30 One of the electron-withdrawing or electron-donating substituents; In Equation 1, Ar' in X is independently selected from substituted or unsubstituted C6~C6. 50 aryl, benzo[a]aryl, fused[a]aryl, substituted or unsubstituted C7~C 50 Aryl groups, substituted or unsubstituted C7~C 50 arylalkoxy, substituted or unsubstituted C7~C 50 Aryl thiol group, substituted or unsubstituted C7~C 50 One of the aromatic heterocyclic groups; In Equation 1, R in Z is independently selected from hydrogen atoms, C1~C1 atoms. 30 Alkyl, C1~C 30 Silyl groups, C1~C 30 Haloalkyl, C2~C 30 alkenyl, C2~C 30 Alkyne, acyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylamine carbonyl, arylamine carbonyl, chain length C1~C 30 Electron-withdrawing or electron-donating substituents, substituted or unsubstituted C6~C 50 aryl, benzo[a]aryl, fused[a]aryl, substituted or unsubstituted C7~C 50 Aryl groups, substituted or unsubstituted C7~C 50 arylalkoxy, substituted or unsubstituted C7~C 50 Aryl thiol group, substituted or unsubstituted C7~C 50 Aromatic heterocyclic groups, substituted or unsubstituted C7~C 30 One of the aromatic amine group, aromatic heterocycle, fused heterocycle, or fused heterocycle; The condensed aryl group is independently one of naphthalene, anthracene, phenanthrene, and carbazole; The aromatic heterocycle is independently one of thiophene, furan, pyrrole, pyridine, and pyrimidine; The fused heterocycle is independently one of benzothiophene, benzofuran, indole, quinoline, isoquinoline, and benzoquinoline.

2. The universal chiral catalyst containing a cinchona primary amine aromatic formamide skeleton according to claim 1, characterized in that, It has the structure shown in formula 1a, 1b or 1c; ； In formulas 1a, 1b, or 1c, Ar is independently selected from substituted or unsubstituted C5-C. 50 One of cyclopentadienyl, aryl, benzoaryl, and fused aryl; In formulas 1a, 1b, or 1c, X is independently selected from one of hydrogen atom, phenolic hydroxyl group, methoxy group, alkoxy group, and aryloxy group; In formula 1c, R is independently selected from hydrogen atoms, C1~C1 atoms. 30 Alkyl, C1~C 30 Silyl groups, C1~C 30 Haloalkyl, C2~C 30 alkenyl, C2~C 30 Alkyne, acyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylamine carbonyl, arylamine carbonyl, and chains with chain lengths of C1~C 30 Electron-withdrawing or electron-donating substituents or any substituents, etc.; can also be selected from substituted or unsubstituted C6~C6 substituents. 50 aryl, benzoaryl, fused aryl, substituted or unsubstituted C7~C 50 Aryl groups, substituted or unsubstituted C7~C 50 arylalkoxy, substituted or unsubstituted C7~C 50 Aryl thiol group, substituted or unsubstituted C7~C 50 Aromatic heterocyclic groups, substituted or unsubstituted C7~C 30 One of the aromatic amine group, aromatic heterocyclic group, fused heterocyclic group, or fused heterocyclic group; The condensed aryl group is independently one of naphthalene, anthracene, phenanthrene, and carbazole; The aromatic heterocycle is independently one of thiophene, furan, pyrrole, pyridine, and pyrimidine; The fused heterocycle is independently one of benzothiophene, benzofuran, indole, quinoline, isoquinoline, and benzoquinoline.

3. The universal chiral catalyst containing a cinchona primary amine aromatic formamide skeleton according to claim 2, characterized in that, It has the structure shown in formulas 1a'-1 to 1a'-12, 1b'-1 to 1b'-12, or 1c'-1 to 1c'-12: 。 4. The universal chiral catalyst containing a cinchona primary amine aromatic formamide skeleton according to any one of claims 1 to 3, characterized in that, It has the structure shown in formulas 1a-1~1a-28, 1b-1~1b-28 or 1c-1~1c-64: 。 5. A method for preparing a universal chiral catalyst containing a cinchona primary amine arylcaramide skeleton as described in any one of claims 1 to 4, characterized in that, Includes the following steps: Using cinchona primary amine as shown in Formula 2 and arylbenzoxazole / thiazole / imidazol-2-carboxylic acid as shown in Formula 3 as raw materials, a condensation reaction was carried out in the presence of condensing agent C1 and solvent S1 at a temperature of T1 to obtain a general chiral catalyst containing the cinchona primary amine arylcarboxamide skeleton as shown in Formula 1. In Equation 2, R' in X is independently selected from C1 to C2. 30 Alkyl, C1~C 30 Silyl groups, C1~C 30 Haloalkyl, C2~C 30 alkenyl, C2~C 30 Alkyne, acyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylamine carbonyl, arylamine carbonyl, chain length C1~C 30 One of the electron-withdrawing or electron-donating substituents; In Equation 2, Ar' in X is independently selected from substituted or unsubstituted C6~C6. 50 aryl, benzo[a]aryl, fused[a]aryl, substituted or unsubstituted C7~C 50 Aryl groups, substituted or unsubstituted C7~C 50 arylalkoxy, substituted or unsubstituted C7~C 50 Aryl thiol group, substituted or unsubstituted C7~C 50 One of the aromatic heterocyclic groups; In Formula 3, Ar is independently selected from substituted or unsubstituted C5~C6 groups. 50 One of cyclopentadienyl, aryl, benzoaryl, and fused aryl; In Equation 3, R in Z is independently selected from hydrogen atoms, C1~C1 atoms. 30 Alkyl, C1~C 30 Silyl groups, C1~C 30 Haloalkyl, C2~C 30 alkenyl, C2~C 30 Alkyne, acyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylamine carbonyl, arylamine carbonyl, chain length C1~C 30 Electron-withdrawing or electron-donating substituents, substituted or unsubstituted C6~C 50 aryl, benzo[a]aryl, fused[a]aryl, substituted or unsubstituted C7~C 50 Aryl groups, substituted or unsubstituted C7~C 50 arylalkoxy, substituted or unsubstituted C7~C 50 Aryl thiol group, substituted or unsubstituted C7~C 50 Aromatic heterocyclic groups, substituted or unsubstituted C7~C 30 One of the aromatic amine group, aromatic heterocycle, fused heterocycle, or fused heterocycle; The condensed aryl group is independently one of naphthalene, anthracene, phenanthrene, and carbazole; The aromatic heterocycle is independently one of thiophene, furan, pyrrole, pyridine, and pyrimidine; The fused heterocycle is independently one of benzothiophene, benzofuran, indole, quinoline, isoquinoline, and benzoquinoline.

6. The preparation method according to claim 5, characterized in that, The cinchona amine shown in Formula 2 is 1.2 equivalents; the aryloxazole / thiazole / imidazol-2-carboxylic acid shown in Formula 3 is 1.0 equivalents; and the condensing agent C1 is 2.0 equivalents.

7. The preparation method according to claim 5 or 6, characterized in that, The condensing agent C1 is one or more of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), and diisopropylcarbodiimide (DIC).

8. The preparation method according to claim 5, characterized in that, The volume ratio of solvent S1 to the total mass of cinchona amine (Formula 2), aryloxazole / thiazole / imidazol-2-carboxylic acid (Formula 3), and condensing agent C1 is (1~20) mL: 1 g.

9. The preparation method according to claim 5, characterized in that, The temperature T1 of the condensation reaction is from 0°C to the solvent reflux temperature; the time of the condensation reaction is 5~10h.

10. The use of a universal chiral catalyst containing the cinchona primamine arylcarbamate skeleton as described in any one of claims 1 to 4 in catalytic organic synthesis and / or preparation of antimalarial drugs.

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