General method for generating axial chirality by means of chiral companion strategy and preparing axially chiral aromatic tertiary amine n-oxide ligand compound

Abstract

The present invention relates to the field of asymmetric catalysis and organic synthesis, and specifically provides a general method for generating axial chirality by means of a chiral companion strategy. The features and concept of the method are: a chiral aromatic tertiary amine compound without a nitrogen chiral center is subjected to intramolecular chiral oxidation to induce the formation of a new aromatic tertiary amine N-oxide (NO) chiral center. Due to the structural rigidity of the chiral aromatic tertiary amine N-oxide compound, when the steric hindrance of different substituents Rb and Rs connected to ortho positions of an aromatic ring is relatively large, the rotation of the aromatic ring is hindered, and new rotation-hindered axial chirality is generated while an aromatic tertiary amine chiral N-oxide center is formed. By means of the method and by regulating the structural and functional characteristics of the different substituents Rb and Rs, various axial chiral ligands, chiral small-molecule catalysts, pharmaceutical and agrochemical intermediates, and chiral synthons can be prepared. The present invention has important scientific and application values for the design, synthesis, and application of chiral ligands, chiral catalysts, especially ligands and catalysts containing axial chirality, and chiral compounds having special functions.

Description

A general method for generating axial chirality and preparing axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds via a chiral consortium strategy. Technical Field

[0001] This invention belongs to the field of asymmetric catalysis and organic synthesis, specifically relating to a general method for generating axial chirality and preparing axial chiral aromatic tertiary amine nitrogen-oxygen ligand compounds through a chiral concomitant strategy. Background Technology

[0002] According to IUPAC rules, axial chirality refers to stereoisomerism formed by four groups arranged non-planarly around a chiral axis. Axially chiral compounds include transisomers, whose chirality originates from the steric hindrance, dipole-dipole interactions, or other electrostatic interactions of the substituents at both ends of the chemical bond, thus hindering the free rotation of the chemical bond and producing two isomers that cannot be completely superimposed and are mirror images of each other. Based on the energy required for interconversion between the two forms or the racemic half-life at 37°C, transisomers are divided into three categories: Category I transisomers include those with a fast equilibrium rate (t... 1 / 2 Type II transisomers are those with a rotational energy barrier of <~20 kcal / mol and a unit time of less than minutes; their solutions at room temperature exhibit moderate equilibrium rates (t0.05). 1 / 2 Units range from hours to days. This applies to compounds with a trans-restriction energy barrier between ΔErot≈20-30 kcal / mol; the equilibrium rate of Class III trans-restricted isomers is very slow (t). 1 / 2 (In years, ΔErot >> 20-30 kcal / mol), meaning there is practically no interconversion. These compounds are very similar to traditional compounds with chiral stereocenters.

[0003] Axially chiral compounds are found in a wide variety of natural products, such as vancomycin, nefran, malinopyridine, gossypol, and polyphages. Furthermore, they exhibit numerous examples of rotational inhibition in pharmaceutical active ingredients (APIs), agricultural products, chiral ligands and organic catalysts, as well as functional materials such as liquid crystals, chiral switches, coolants and lubricants, and even molecular rotors. In the field of chemistry, particularly in asymmetric synthesis, the discovery of axially chiral ligands, such as BINAP, BINOL, and BINAM, as well as axially chiral phosphoric acid catalysts, has been significant.

[0004] In recent years, the structures of blocked transisomers have evolved from classic structures composed solely of identical di(hetero)aryl skeletons, such as C2 symmetric binaphthyl catalysts, to axially chiral skeletons connecting two different rings, and even to skeletons containing only one ring. Axially chiral compounds, with their rigid and precise structures and stability, have become one of the most attractive ligands and fundamentally advantageous skeleton catalysts in asymmetric synthesis and catalysis. Therefore, the catalytic enantioselective synthesis of axially chiral skeletons has attracted increasing attention and achieved significant progress. Currently established catalytic asymmetric synthetic methods mainly include center-axial chiral transformation, racemic or pre-chiral binaaryl functionalization (desymmetry, kinetic decomposition), aryl-aryl coupling, direct arylization, and cycloaddition synthesis methods.

[0005] Over the past few decades, the chemical applications and development of tertiary amine nitroxide (NO) compounds have garnered increasing attention. Functional molecules with tertiary amine nitroxide (NO) structures are ubiquitous in nature. For example, trimethylamine nitroxide (TMAO) is a compound potentially linked to human cancer and cardiovascular disease, and is also a protein stabilizer in fish. Furthermore, many nitroxides are non-toxic derivatives of their corresponding amines and are common metabolites of pharmaceuticals and natural products. Artificially synthesized nitroxides are increasingly used in various medical and health fields; recent examples include magnetic resonance imaging reagents, prodrugs, targeted cytotoxic agents, and antibacterial drugs. In addition, oligomeric nitroxides have the potential to replace other hydrophilic oligomers and polymers, such as polyethylene glycol (PEG). Studies have shown that oligomeric nitroxides possess good blood compatibility and can be used as stealth agents for drug or material surface bonding. The application of nitroxides in the biomedical field has advanced rapidly due to their unique chemical properties. For example, the bioactivity of botulinum toxin depends on the unique N+-O- bond and the resulting zwitterionic properties of the nitroxide. In addition, they are key components in the preparation of various functionalized nitrogen-heterocyclic compounds, drugs and pharmaceutical intermediates, as well as detergents, soaps, toothpastes, shampoos and cosmetics, and are also crucial for the design and development of drugs with unknown biological activities.

[0006] Nitrogen oxides exhibit significant nucleophilicity and basicity, enabling them to react with various molecules or metals to form complexes. The Lewis basic oxygen atom of nitrogen oxides acts as an electron pair donor, forming molecular adducts or complexes with Lewis acidic compounds. Similarly, chiral nitrogen oxides have significant applications as ligands or catalysts in asymmetric synthesis. However, the application of chiral nitrogen oxides in asymmetric catalytic reactions has only been developed in recent decades. In 1993, Ian O'Neil et al. synthesized a series of chiral tertiary amine nitrogen oxides (as shown in Scheme 5a) by selectively oxidizing N-alkylated L-proline derivatives (O'Neil, IA; Miller, ND; Kalindjian, SBSynlett. 1993, 515-518). Chiral tertiary amine nitrogen oxides have been shown to generate a stable chiral center on nitrogen through hydrogen bonding with the hydrogen atoms of adjacent amides within the molecule and through a stable conformation. In 1997, they further developed similar tertiary amine nitrides derived from α,α-diphenylpyrrolidine methanol (as shown in Scheme 5b) and used them as organic catalysts for the asymmetric reaction of α-chloroethyl ketone.

[0007] Borane reduction reactions (O'Neil, IA; Turner, CD; Kalindjian, SBSynlett. 1997, 777-780.). In 1998, Nakajima et al. reported a class of C2-symmetric axially chiral bipyridine N,N'-dioxides derived from BINOL (as shown in Scheme 5c(S)-1) and bisquinoline N,N'-dioxides (as shown in Scheme 5c(S)-2). Bisquinoline N,N'-dioxides have been shown to be good catalysts for the asymmetric addition of allyltrichlorosilanes to aldehydes (Nakajima, M.; Saito, M.; Hashimoto, SJAm. Chem. Soc. 1998, 120, 6419-6420.).

[0008] Feng Xiaoming's research group initially conducted studies on chiral nitrogen oxides through asymmetric silylation reactions. In 2001, they investigated the asymmetric Strecker reaction promoted by C2 symmetric bisquinoline N,N'-dioxide, with mediocre results. Inspired by the bifunctional catalysis concept of Shibasaki's group, they developed prolylamino-based nitrogen oxide (S)-1-titanium(IV) catalysts for the asymmetric silylation of ketones, exhibiting moderate enantioselectivity (Shen, Y.-C.; Feng, X.-M.; Zhang, G.-L.; Jiang, Y.-Z. Synlett. 2002, 1353-1355.). Based on these studies, they proposed combining the key characteristics of multidentate, bifunctional catalysts, and ultimately synthesized a novel C2 symmetric prolylamino-based N,N'-dioxide, as shown below, by connecting two nitrogen oxide units with a variable linker.

[0009] In 2006, Feng Xiaoming's research group first applied their designed C2-symmetric N,N'-dioxide to the asymmetric silanization reaction of ketones catalyzed by titanium, achieving an ee value as high as 92% (Li,Q.-H.; Liu,X.-H.; Wang,J.; Shen,K.; Feng,X.-M. Tetrahedron Lett. 2006,47,4011–4014.). In 2007, Feng Xiaoming's research group achieved a major breakthrough in the study of N,N'-dioxide ligands in the enantioselective allylation reaction catalyzed by tunable N,N'-dioxide and its In(III) complexes (Zhang,X.; Chen,D.-H.; Liu,X.-H.; Feng,X.-M. J Org. Chem. 2007,72,5227-5233.). To date, Professor Feng Xiaoming's research group has established a structurally diverse library of N,N'-dioxide ligands, including N,N'-dioxane (D) with both N-terminal linkers (AC) and carboxyl-terminal linkers. The linking units can be conformationally flexible alkyl chains (A and D) or rigid aryl chains (B and C).

[0010] In recent years, Liu Xiongli's team at Guizhou University has developed a series of rigid, C2-symmetric chiral "Qianying" catalysts based on the multidentate ligand chelation catalysis mechanism of the "eagle catching chicks" biomimetic model and using inexpensive and readily available amino acids as raw materials.

[0011] Furthermore, it has been successfully applied in the asymmetric catalytic Friedel-Crafts alkylation of indole, achieving yields up to 90% and enantioselectivity up to 99% for a variety of substrates under mild conditions ((a) Chen, Z.-Y.; Liu, X.-L. New J. Chem., 2024, 48, 1688-1695. (b) Wang, Y.-H.; Liu, X.-L. Org. Chem. Front., 2024, 11, 1314-1321.). These results further demonstrate the promising application of nitrogen-oxygen ligands in asymmetric catalysis.

[0012] In summary, numerous reports have been published on bi / pyridine chiral nitrides and von Willebrand aliphatic tertiary amine chiral nitride ligands, demonstrating promising applications in asymmetric catalysis. However, no reports have yet been published on chiral aromatic tertiary amine nitride compounds. Structurally, aromatic tertiary amine nitrides differ from both pyridine nitrides and aliphatic tertiary amine nitrides. Generally, for aromatic tertiary amines, due to the conjugated delocalization of the N lone pair electrons, aromatic tertiary amine nitrides are easier to prepare than aliphatic tertiary amine nitrides, and the size of the nitride-oxygen (NO) dipole is more easily controlled. Furthermore, due to the structural and steric diversity of aromatic tertiary amines, the control of electrons and steric hindrance is more flexible and diverse. Therefore, the preparation, NO dipole control, and coordination ability of aromatic tertiary amine nitrides are more tunable and yield more diverse results compared to pyridine nitrides and aliphatic tertiary amine nitrides, potentially allowing coordination with more types of central metals, lowering the catalytic energy barrier, and improving catalytic activity and selectivity. Summary of the Invention

[0013] The primary objective of this invention is to propose a novel concept of "chiral co-occurrence": chiral aromatic tertiary amine compounds without nitrogen chiral centers generate new aromatic tertiary amine nitrogen-oxygen (NO) chiral centers through intramolecular chiral oxidation. Due to the structural rigidity of chiral aromatic tertiary amine nitrogen-oxygen compounds, when the steric hindrance of different substituents Rb and Rs connected to the ortho position of the aromatic ring is large, their rotation is hindered, and a new rotationally hindered axial chirality is generated simultaneously with the formation of the aromatic tertiary amine chiral nitrogen-oxygen center.

[0014] The above concepts and principles are illustrated in Figure 6.

[0015] By controlling the structural and functional properties of different substituents Rb and Rs, various types of axial chiral ligands and chiral small molecule catalysts can be prepared. Rb and Rs are functional groups that can participate in coordination bonds, hydrogen bonds, and other functions with specific functions. The substituents shown in Figure 1 are preferred, and Rb and Rs are different commonly used coordination substituents.

[0016] Steric hindered groups BG and chiral sources include, but are not limited to, the groups shown in Figure 2;

[0017] In Figures 1-2 and 6, R* is a chiral source, Ar is one of the following: substituted or unsubstituted C6-C50 aryl, terylaryl, fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 arylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amine, aromatic heterocyclic, etc. a R c R d R f R p R q R u R v R 2a R 2b R 2c R 2u R 3a R 3b R 1 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R49 R 50 Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens, hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing or... The group may be an electron-donating protecting group or any substituent; it may also be selected from substituted or unsubstituted C6-C50 aryl, benzoaryl, fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 aralkoxy, substituted or unsubstituted C7-C50 aralkyl mercapto, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amino, aromatic heterocyclic, benzoheterocyclic, fused heterocyclic.

[0018] The second objective of this invention is to synthesize a series of novel axially chiral aromatic tertiary amine nitrogen oxide ligand compounds based on the new concept of "chiral concomitant". The aryl substituents (Rb, Rs) attached to nitrogen and oxygen are simultaneously generated (concomitantly) with new axial chirality due to steric hindrance and rotational obstruction. Through the structural and functional regulation of the aryl substituents (Rb, Rs) and their interaction with chiral nitrogen oxide (NO) compounds, aromatic tertiary amine nitrogen oxide (NO) axially chiral compounds with diverse structures and functions can be obtained.

[0019] Specifically, the aforementioned axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds include the compounds shown in Figure 3. The structural formulas are for illustrative purposes only and include, but are not limited to, all racemic compounds with relative or absolute configurations represented by them, and all possible chiral isomers such as (R)- or (S)- isomers.

[0020] In the formula shown in Figure 3, Y is selected from H and O; X is selected from O and S; and R2 is selected from H, OH, and OR. 2a NR g R h ;R c R d R f R g R h R 2a R 3a R 3b R 1 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R11 R 12 R 13 R 14 Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens, hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing groups with chain lengths of C1-C30. Electron-donating protecting group or any substituent; it may also be selected from substituted or unsubstituted C6-C50 aryl, benzoaryl, fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 arylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amino, any aromatic heterocyclic, benzoheterocyclic, fused heterocyclic.

[0021] Representative examples of the aforementioned axially chiral aromatic tertiary amine nitroxide ligands include: (hydroxy)proline nitroxides, (hydroxy)proline ester nitroxides, (hydroxy)proline amide nitroxides, (hydroxy)proline aldehyde nitroxides, 2-pyrrolidineamine nitroxides, 2-pyrrolidine oxalamide nitroxides, 2-pyrrolidine urea nitroxides, 2-pyrrolidine thiourea nitroxides, 2-pyrrolidine oxazoline nitroxides, 2-pyrrolidine imidazole nitroxides, 2-pyrrolidine triazole nitroxides, 2-pyrrolidine benzothiazole nitroxides, 2-pyrrolidine benzoxazole nitroxides, and 2-pyrrolidine benzimidazole nitroxides. These chiral compounds can be widely used as small-molecule chiral catalysts, chiral ligands, and pharmaceutical actives.

[0022] To increase the variety and applications of the target chiral compounds, the substituents Rb or Rs can be widely selected from different types of (chiral) ligands or their structural combinations, which can form bidentate or multidentate chiral ligands together with chiral nitroxide compounds; the ligands include, but are not limited to, the following commonly used ligand types: oxygen ligands, nitrogen ligands, sulfur ligands, double bond ligands, sulfoxide ligands, nitrile ligands, sulfonamides, phosphonamides, amide ligands, urea, thiourea, oxazoline ligands, imidazoline ligands, thiazoline ligands, pyrazoles, triazoles, tetrazolium, pyrazoline, pyrrole, indole, and other heterocyclic ligands (Figure 7).

[0023] In Figure 7, R*, R a R c R d R f R21 R 23 R 24 R 25 R 26a R 27a R 30 R 31 R 35 R 36 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 50 R 51 R 52 Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens (F, Cl, Br, I), hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing or electron-donating protecting groups or arbitrary substituents with chain lengths of C1-C30; they can also be selected from substituted or unsubstituted C6-C50 aromatic groups. The group consisting of alkyl, benzo[a]aryl, fused aryl (such as naphthalene, anthracene, phenanthrene, carbazole, etc.), substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 aryl thiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amine, any aromatic heterocyclic (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrroleyl, pyridyl, quinolinyl, benzoquinolinyl, etc.), fused heterocyclic, and fused heterocyclic (such as tetrahydroquinolinyl, dihydroindolyl, dihydropyranyl, etc.).

[0024] Different chiral nitrogen oxide (NO) sources can be combined with different ligands (represented by Rb and Rs) to obtain more types and different functions of chiral functional compounds. Representative axial chiral aromatic tertiary amine NO ligand compounds include, but are not limited to: o-(p-methylbenzenesulfonamide)diphenyl(hydroxy)proline nitrogen oxides, o-(methylsulfonamide)diphenyl(hydroxy)proline nitrogen oxides, o-(p-nitrobenzenesulfonamide)diphenyl(hydroxy)proline nitrogen oxides, o-(formonitrile)diphenyl(hydroxy)proline nitrogen oxides, o-(benzaldehyde)diphenyl(hydroxy)proline nitrogen oxides, o-(alkene)diphenyl(hydroxy)proline nitrogen oxides, o-(ester)diphenyl(hydroxy)proline nitrogen oxides, o-(amide)diphenyl(hydroxy)proline nitrogen oxides, o-(urea)diphenyl(hydroxy)proline nitrogen oxides, o-(thiourea)diphenyl(hydroxy)proline nitrogen oxides, and o-(thiourea)diphenyl(hydroxy)proline nitrogen oxides. Diphenyl(hydroxy)proline nitrogen oxides, o-(oxazoline) diphenyl(hydroxy)proline nitrogen oxides, o-(imidazolium) diphenyl(hydroxy)proline nitrogen oxides, o-(benzimidazole) diphenyl(hydroxy)proline nitrogen oxides, o-(thiazole) diphenyl(hydroxy)proline nitrogen oxides, o-(benzothiazole) diphenyl(hydroxy)proline nitrogen oxides, o-(triazole) diphenyl(hydroxy)proline nitrogen oxides, o-(tetraazole) diphenyl(hydroxy)proline nitrogen oxides, o-(p-methylbenzenesulfonamide)(hydroxy)proline nitrogen oxides, o-(methylsulfonamide)(hydroxy)proline nitrogen oxides, o-(p-nitrobenzenesulfonamide)(hydroxy)proline nitrogen oxides Hydroxy)proline nitrile compounds, o-(formonitrile)(hydroxy)proline nitrile compounds, o-(benzaldehyde)(hydroxy)proline nitrile compounds, o-(alkenes)(hydroxy)proline nitrile compounds, o-(esters)(hydroxy)proline nitrile compounds, o-(amides)(hydroxy)proline nitrile compounds, o-(ureas)(hydroxy)proline nitrile compounds, o-(thioureas)(hydroxy)proline nitrile compounds, o-(oxazoline)(hydroxy)proline nitrile compounds, o-(imidazolium)(hydroxy)proline nitrile compounds, o-(benzimidazole)(hydroxy)proline nitrile compounds, o-(thiazole)(hydroxy)proline nitrile compounds, o-(benzimid ... β-thiazoles (hydroxy)prolyl nitroxides, o-(triazoles) (hydroxy)prolyl nitroxides, o-(tetraazoles) (hydroxy)prolyl nitroxides, o-(p-methylbenzenesulfonamides) (hydroxy)prolyl nitroxides, o-(methylsulfonamides) (hydroxy)prolyl nitroxides, o-(p-nitrobenzenesulfonamides) (hydroxy)prolyl nitroxides, o-(formonitrile) (hydroxy)prolyl nitroxides, o-(benzaldehyde) (hydroxy)prolyl nitroxides, o-(alkenes) (hydroxy)prolyl nitroxides, o-(esters) (hydroxy)prolyl nitroxides, o-(amides) (hydroxy)prolyl nitroxideso-(urea) (hydroxy)prolyl oxazoline nitrogen oxides, o-(thiourea) (hydroxy)prolyl oxazoline nitrogen oxides, o-(oxazoline) (hydroxy)prolyl oxazoline nitrogen oxides, o-(imidazolium) (hydroxy)prolyl oxazoline nitrogen oxides, o-(benzimidazole) (hydroxy)prolyl oxazoline nitrogen oxides, o-(thiazole) (hydroxy)prolyl oxazoline nitrogen oxides, o-(benzothiazole) (hydroxy)prolyl oxazoline nitrogen oxides, o-(triazole) (hydroxy)prolyl oxazoline nitrogen oxides, o-(tetraazole) (hydroxy)prolyl oxazoline nitrogen oxides.

[0025] Specifically, the aforementioned axially chiral aromatic tertiary amine nitroxide ligand compounds include the compounds shown in Figures 4a-4d, where R... c R d R f R 1 R 2 R 4 R 5 R 6 R 7a R 8a R 11 R 12 R 13 R 14 R 21 R 22 R 23 R 24 R 25 R 28a R 29a R 33 R 34 R 35 R 36 R 37 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens, hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing groups with chain lengths of C1-C30. Electron-donating protecting group or any substituent; it may also be selected from substituted or unsubstituted C6-C50 aryl, benzoaryl, fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 arylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amino, any aromatic heterocyclic, benzoheterocyclic, fused heterocyclic.

[0026] Specifically, the aforementioned axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds, including those shown in Figures 5a-5f, possess the potential to serve as small-molecule chiral catalysts and chiral ligands, catalyzing different types of asymmetric reactions either alone or after coordination with a metal. Where: R 2u R 2c R 3c R 5 R 6 R 7a R 8a R 14 R 36 R 37 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens, hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing groups with chain lengths of C1-C30. Electron-donating protecting group or any substituent; it may also be selected from substituted or unsubstituted C6-C50 aryl, benzoaryl, fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 arylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amino, any aromatic heterocyclic, benzoheterocyclic, fused heterocyclic.

[0027] A third objective of this invention is to provide applications of these novel axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds in various fields such as small molecule catalysis, asymmetric metal catalysis, chiral pharmaceuticals, pesticides, and chiral optoelectronic materials.

[0028] Specifically, axially chiral aromatic tertiary amine nitrogen-oxygen ligands can act as novel Lewis bases or chiral small organic molecule catalysts to catalyze organic or asymmetric organic reactions; as metal ligands, they can form chiral catalysts to participate in asymmetric reactions catalyzed by various metal catalysts or chiral metal catalysts; as organic synthons or chiral organic synthons, they can synthesize new catalysts or chiral catalysts; and as synthons, they can synthesize novel phase transfer catalysts or chiral phase transfer catalysts.

[0029] The axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds provided by this invention can be used to prepare electroluminescent, photoluminescent, magnetoluminescent, acid-luminescent, and alkali-luminescent optoelectronic materials.

[0030] The axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds provided by this invention can also be used to synthesize fluorescent materials, such as fluorescent probes, and can also be used to prepare trace metal detection reagents, dyes, fine chemical raw materials or pharmaceuticals, pesticides and their intermediates or bioactive compounds.

[0031] The fourth objective of this invention is to provide a method for synthesizing a representative o-aryl chiral diamine compound, the synthetic route of which is shown in Figure 8.

[0032] The specific reaction steps are as follows:

[0033] (1) Using o-fluoronitrobenzene as the starting material, under the conditions of temperature T1, solvent S1, and base B1, it reacts with a chiral proline compound C1. N Ar2 reaction, followed by nitro reduction, forms the o-aryl chiral diamine compound shown in Formula II;

[0034] The solvent S1 includes one or more of alcohols, halogenated hydrocarbons, and ether solvents; the base B1 includes one or more of inorganic bases and organic bases; the reaction temperature T1 is 25℃~100℃;

[0035] (2) Under the action of temperature T4, solvent S4 and oxidant O1, the target axial chiral aromatic tertiary amine nitrogen oxide ligand compound shown in Formula I was obtained by selective nitrogen oxidation of chiral tertiary amine.

[0036] The oxidant O1 includes m-chloroperoxybenzoic acid, peracetic acid, carboxylic acid, hydrogen peroxide, and ruthenium trichloride; the solvent S4 includes one or more of halogenated hydrocarbons, ethers, and nitrile solvents; the reaction temperature T4 is -78℃ to 20℃.

[0037] The raw materials used in this method, o-fluoronitrobenzene and various chiral secondary amine compounds, have advantages such as easy commercial availability, low cost, and thermal stability. Since the synthetic steps and reaction process do not involve chiral centers, by controlling the configuration and purity of the chiral raw materials, it is easy to obtain target chiral o-aryl diamine compounds (II) with defined structures, controllable chiral purity, and diverse structures and functions. These compounds can be widely applied in fields such as organocatalysis and optoelectronic materials.

[0038] After derivatization by amino substitution, alkylation, acylation, sulfonation, and phosphonylation, o-aryl chiral diamine compounds (II) are further derivatized by selective nitrogen oxidation of chiral tertiary amines using suitable oxidants to obtain the target chiral nitrogen oxide (NO) compound (I), which also exhibits axial chirality. These novel chiral aromatic nitrogen oxide compounds with axial chirality possess stable structures, simple preparation steps, high optical purity, and excellent coordination ability. They can form complexes with various metal ions, becoming chiral catalysts participating in asymmetric catalytic reactions catalyzed by various (chiral) metal catalysts. They also act as chiral Lewis bases and small organic molecule catalysts for various asymmetric reactions, exhibiting unique photoelectric properties and possessing excellent application potential.

[0039] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0040] 1. A new concept of "chiral concomitant" is proposed, which has important scientific and applied value for the design, synthesis and application of chiral ligands, chiral catalysts, especially ligands and catalysts containing axial chirality, as well as chiral compounds with special functions.

[0041] 2. The method provided by this invention for constructing oxy-oxidized chiral centers and simultaneously generating hindered axial chiral centers through the oxy-oxidation of chiral aromatic tertiary amines, as well as a representative preparation method for o-aryl chiral diamine compounds, is particularly suitable for preparing o-aryl chiral diamine compounds with highly hindered secondary amines. When the steric hindrance of the ortho-group on the benzene ring is relatively large, the target compound will exhibit axial chirality. Furthermore, the target product is also an intermediate and chiral synthon for preparing multidentate (chiral) ligand compounds and electron transfer materials. It has significant scientific and applied value for the design, synthesis, and application of chiral ligands, chiral catalysts, especially axially chiral ligands, catalysts, and chiral compounds with special functions.

[0042] 3. The axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds synthesized based on this novel concept of "chiral co-occurrence" provided by this invention can be widely used as novel Lewis bases or small molecule chiral catalysts and chiral ligands through the structural and functional regulation of aryl substituents (Rb, Rs) adjacent to the chiral nitrogen-oxygen center and their synergistic effect with chiral nitrogen-oxygen (NO) compounds. They have potential scientific and applied value in chiral sciences such as asymmetric catalysis, chiral synthesis, chiral resolution, and chiral substances.

[0043] 4. The axially chiral aromatic tertiary amine nitrogen-oxygen ligand compound provided by this invention has an o-phenylenediamine structural unit, high optical purity and good coordination ability, can form complexes with a variety of metal ions, is a good (chiral) metal ligand and catalyst, has special photoelectric properties, and has good application potential.

[0044] 5. The axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds provided by this invention, due to their structural diversity and variety of functional groups and types, can be widely used in the fields of chiral medicine, pesticides and chiral materials. They can also be used as (chiral) metal ligands to form chiral catalysts to participate in various (chiral) metal catalyst-catalyzed asymmetric organic reactions, as well as as chiral Lewis bases and chiral small organic molecule catalysts to catalyze various asymmetric organic reactions.

[0045] 6. The method for preparing axially chiral aromatic tertiary amine nitric oxide ligands provided by this invention has a short synthetic route, simple operation steps, and is easy to separate and purify. By controlling the configuration and purity of readily available, low-cost, and thermally stable o-fluoronitrobenzene and various chiral secondary amine compounds, structurally diverse o-aryl chiral diamine compounds with defined structures and controllable chiral purity can be easily obtained. After derivatization and transformation, they can be further selectively oxidized with tertiary amines to obtain the target axially chiral aromatic nitric oxide (NO) compound.

[0046] The present invention will now be described in further detail with reference to the accompanying drawings. Attached Figure Description

[0047] Figure 1 is a schematic diagram of the Rb and Rs substituent groups in one embodiment of the present invention.

[0048] Figure 2 is a schematic diagram of the steric hindrance group BG in one embodiment of the present invention.

[0049] Figure 3 is a schematic diagram of a representative axially chiral aromatic tertiary amine nitrogen-oxygen ligand compound in one embodiment of the present invention.

[0050] Figures 4a-4d are schematic diagrams of representative axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds in another embodiment provided by the present invention.

[0051] Figures 5a-5f are schematic diagrams of representative axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds in another embodiment of the present invention.

[0052] Figure 6 is a schematic diagram of the principle of the general method for generating axial chirality through a chiral companion strategy provided by the present invention.

[0053] Figure 7 is a schematic diagram of a representative ligand structure provided by the present invention.

[0054] Figure 8 is a synthetic route diagram of the axial chiral aromatic tertiary amine nitrooxy ligand compound (I) and the intermediate o-aryl chiral diamine compound (II) provided by the present invention.

[0055] Figure 9 is a schematic diagram of the preparation of o-aryl chiral diamine compound (II) by nitro reduction provided by the present invention.

[0056] Figure 10 is a schematic diagram of the oxidation preparation method of the axially chiral aromatic tertiary amine nitrogen-oxygen ligand compound (I) provided by the present invention.

[0057] Figure 11 shows a representative structural compound in one embodiment of the present invention.

[0058] Figure 12 is a schematic diagram of the compound structure in a specific embodiment of the present invention.

[0059] Figure 13 is a synthesis route diagram in Embodiment 1 of the present invention. Detailed Implementation

[0060] The technical solutions of the present invention will be clearly and completely described below with reference to embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Although representative embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and changes can be made to the present invention without departing from the scope of the present invention. Therefore, the scope of the present invention should not be limited to the embodiments, but should be defined by the appended claims and their equivalents.

[0061] This invention provides a general method for generating axial chirality through a chiral co-occurrence strategy, comprising: a chiral aromatic tertiary amine compound without a nitrogen chiral center generates a new aromatic tertiary amine nitrogen oxide (NO) chiral center through intramolecular chiral oxidation. Due to the structural rigidity of the chiral aromatic tertiary amine nitrogen oxide compound, when the steric hindrance of different substituents Rb, Rs connected to the ortho position of the aromatic ring is large, its rotation is hindered, and a new rotationally hindered axial chirality is generated simultaneously with the formation of the aromatic tertiary amine chiral nitrogen oxide center.

[0062] The features and concept are shown in Figure 6, where Rb and Rs are different commonly used coordination substituents, including but not limited to the substituents shown in Figure 1;

[0063] Steric hindered groups BG and chiral sources include, but are not limited to, the groups shown in Figure 2;

[0064] In Figures 1-2 and 6, R* is a chiral source, Ar is one of the following: substituted or unsubstituted C6-C50 aryl, terylaryl, fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 arylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amine, aromatic heterocyclic, etc. a R c R d R f R p R q R u R v R 2a R 2b R 2c R 2u R 3a R 3b R 1 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens (F, Cl, Br, I), hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing or electron-donating protecting groups or arbitrary substituents with chain lengths of C1-C30; they can also be selected from substituted or unsubstituted C6-C50 aromatic groups. The group consisting of alkyl, benzo[a]aryl, fused aryl (such as naphthalene, anthracene, phenanthrene, carbazole, etc.), substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 aryl thiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amine, any aromatic heterocyclic (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrroleyl, pyridyl, quinolinyl, benzoquinolinyl, etc.), fused heterocyclic, and fused heterocyclic (such as tetrahydroquinolinyl, dihydroindolyl, dihydropyranyl, etc.).

[0065] Referring to Figure 6, chiral aromatic tertiary amine compounds without a tertiary amine nitrogen chiral center generate a new nitric oxide (NO) chiral center through intramolecular chiral oxidation. Along with the generation of the NO chiral center, different aryl substituents (Rb, Rs) attached to the nitrogen and oxygen groups simultaneously generate (as a concomitant) new axial chirality due to steric hindrance and hindered rotation. A single chiral oxidation can construct a NO chiral center and simultaneously generate a monocyclic axial chirality. This provides a new approach, strategy, and method for the precise and efficient synthesis of novel aromatic axial chiral NO compounds with diverse structures and functions. Through the structural and functional regulation of the aryl substituents (Rb, Rs) adjacent to the NO chiral center and their synergistic effect with the chiral NO compound, these novel axial chiral compounds can be widely applied in various fields such as small molecule catalysis, asymmetric metal catalysis, chiral pharmaceuticals, pesticides, and chiral optoelectronic materials.

[0066] Based on the above method, the present invention provides a class of novel chiral aromatic nitrogen oxide compounds with axial chirality as shown in Figure 3. The structural formula is for illustration only and includes, but is not limited to, all racemic compounds with relative or absolute configurations represented by it, and all possible chiral isomers such as (R)- or (S)- isomers.

[0067] In the formula of Figure 3, Y is selected from H and O; X is selected from O and S; R 2 Selected from H, OH, OR 2a NR g R h ;R c R d R f R g R h R 2a R 3a R 3b R 1 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens (F, Cl, Br, I), hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing or electron-donating protecting groups or arbitrary substituents with chain lengths of C1-C30; they can also be selected from substituted or unsubstituted C6-C50 aromatic groups. The group consisting of alkyl, benzo[a]aryl, fused aryl (such as naphthalene, anthracene, phenanthrene, carbazole, etc.), substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 aryl thiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amine, any aromatic heterocyclic (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrroleyl, pyridyl, quinolinyl, benzoquinolinyl, etc.), fused heterocyclic, and fused heterocyclic (such as tetrahydroquinolinyl, dihydroindolyl, dihydropyranyl, etc.).

[0068] Representatively, axially chiral aromatic tertiary amine nitroxide ligands include, but are not limited to: (hydroxy)proline nitroxides, (hydroxy)proline ester nitroxides, (hydroxy)proline amide nitroxides, (hydroxy)proline aldehyde nitroxides, 2-pyrrolidineamine nitroxides, 2-pyrrolidine oxalamide nitroxides, 2-pyrrolidine urea nitroxides, 2-pyrrolidine thiourea nitroxides, 2-pyrrolidine oxazoline nitroxides, 2-pyrrolidine imidazole nitroxides, 2-pyrrolidine triazole nitroxides, 2-pyrrolidine benzothiazole nitroxides, 2-pyrrolidine benzoxazole nitroxides, and 2-pyrrolidine benzimidazole nitroxides. These chiral compounds can be widely used as small molecule chiral catalysts, chiral ligands, and pharmaceutical actives.

[0069] To increase the variety and applications of target chiral compounds, substituent R b Or R s A wide range of (chiral) ligands or their structural combinations can be selected, which can co-form bidentate or multidentate chiral ligands with chiral nitrogen oxides. These ligands can be selected from, but are not limited to, the commonly used ligand types listed below, such as: oxygen ligands, nitrogen ligands, sulfur ligands, double bond ligands, sulfoxide ligands, nitrile ligands, sulfonamides, phosphonamides, amide ligands, urea, thiourea, oxazoline ligands, imidazoline ligands, thiazoline ligands, pyrazoles, triazoles, tetrazolium, pyrazoline, pyrrole, indole, and other heterocyclic ligands (Figure 7).

[0070] In Figure 7, R*, Ra R c R d R f R 21 R 23 R 24 R 25 R 26a R 27a R 30 R 31 R 35 R 36 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 50 R 51 R 52 Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens (F, Cl, Br, I), hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing or electron-donating protecting groups or arbitrary substituents with chain lengths of C1-C30; they can also be selected from substituted or unsubstituted C6-C50 aromatic groups. The group consisting of alkyl, benzo[a]aryl, fused aryl (such as naphthalene, anthracene, phenanthrene, carbazole, etc.), substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 aryl thiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amine, any aromatic heterocyclic (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrroleyl, pyridyl, quinolinyl, benzoquinolinyl, etc.), fused heterocyclic, and fused heterocyclic (such as tetrahydroquinolinyl, dihydroindolyl, dihydropyranyl, etc.).

[0071] Different chiral nitrogen oxide (NO) sources can be combined with different ligands (represented by Rb and Rs) to obtain more types and functions of chiral functional compounds. Representative examples of these chiral NO compounds include, but are not limited to: o-(p-methylbenzenesulfonamide)diphenyl(hydroxy)proline nitrogen oxides, o-(methylsulfonamide)diphenyl(hydroxy)proline nitrogen oxides, o-(p-nitrobenzenesulfonamide)diphenyl(hydroxy)proline nitrogen oxides, o-(formonitrile)diphenyl(hydroxy)proline nitrogen oxides, o-(benzaldehyde)diphenyl(hydroxy)proline nitrogen oxides, o-(alkene)diphenyl(hydroxy)proline nitrogen oxides, o-(ester)diphenyl(hydroxy)proline nitrogen oxides, o-(amide)diphenyl(hydroxy)proline nitrogen oxides, o-(urea)diphenyl(hydroxy)proline nitrogen oxides, and o-(thiourea) compounds. Diphenyl(hydroxy)proline nitrogen oxides, o-(oxazoline) diphenyl(hydroxy)proline nitrogen oxides, o-(imidazolium) diphenyl(hydroxy)proline nitrogen oxides, o-(benzimidazole) diphenyl(hydroxy)proline nitrogen oxides, o-(thiazole) diphenyl(hydroxy)proline nitrogen oxides, o-(benzothiazole) diphenyl(hydroxy)proline nitrogen oxides, o-(triazole) diphenyl(hydroxy)proline nitrogen oxides, o-(tetraazole) diphenyl(hydroxy)proline nitrogen oxides, o-(p-methylbenzenesulfonamide)(hydroxy)proline nitrogen oxides, o-(methylsulfonamide)(hydroxy)proline nitrogen oxides, o-(p-nitrobenzenesulfonamide)(hydroxy)proline nitrogen oxides Proline nitrile compounds, o-(formonitrile)-(hydroxy)proline nitrile compounds, o-(benzaldehyde)-(hydroxy)proline nitrile compounds, o-(alkenes)-(hydroxy)proline nitrile compounds, o-(esters)-(hydroxy)proline nitrile compounds, o-(amides)-(hydroxy)proline nitrile compounds, o-(ureas)-(hydroxy)proline nitrile compounds, o-(thioureas)-(hydroxy)proline nitrile compounds, o-(oxazoline)-(hydroxy)proline nitrile compounds, o-(imidazolium)-(hydroxy)proline nitrile compounds, o-(benzimidazole)-(hydroxy)proline nitrile compounds, o-(thiazole)-(hydroxy)proline nitrile compounds, o-(benzimid ... Thiazole (hydroxy)prolyl nitroxides, o-(triazole)prolyl nitroxides, o-(tetraazole)prolyl nitroxides, o-(p-methylbenzenesulfonamide) (hydroxy)prolyl oxazoline nitroxides, o-(methylsulfonamide) (hydroxy)prolyl oxazoline nitroxides, o-(p-nitrobenzenesulfonamide) (hydroxy)prolyl oxazoline nitroxides, o-(formonitrile) (hydroxy)prolyl oxazoline nitroxides, o-(benzaldehyde) (hydroxy)prolyl oxazoline nitroxides, o-(alkenes) (hydroxy)prolyl oxazoline nitroxides, o-(esters) (hydroxy)prolyl oxazoline nitroxides, o-(amides) (hydroxy)prolyl oxazoline nitroxidesNitrogen oxides include o-(urea)-(hydroxy)prolyl oxazoline compounds, o-(thiourea)-(hydroxy)prolyl oxazoline compounds, o-(oxazoline)-(hydroxy)prolyl oxazoline compounds, o-(imidazolium)-(hydroxy)prolyl oxazoline compounds, o-(benzimidazole)-(hydroxy)prolyl oxazoline compounds, o-(thiazole)-(hydroxy)prolyl oxazoline compounds, o-(benzothiazole)-(hydroxy)prolyl oxazoline compounds, o-(triazole)-(hydroxy)prolyl oxazoline compounds, and o-(tetraazole)-(hydroxy)prolyl oxazoline compounds, as shown in Figures 4a-4d.

[0072] In the formulas shown in Figures 4a-4d, R c R d R f R 1 R 2 R 4 R 5 R 6 R 7a R 8a R 11 R 12 R 13 R 14 R 21 R 22 R 23 R 24 R 25 R 28a R 29a R 33 R 34 R 35 R 36 R 37 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens (F, Cl, Br, I), hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing or electron-donating protecting groups or arbitrary substituents with chain lengths of C1-C30; they can also be selected from substituted or unsubstituted C6-C50 aromatic groups. The group consisting of alkyl, benzo[a]aryl, fused aryl (such as naphthalene, anthracene, phenanthrene, carbazole, etc.), substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 aryl thiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amine, any aromatic heterocyclic (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrroleyl, pyridyl, quinolinyl, benzoquinolinyl, etc.), fused heterocyclic, and fused heterocyclic (such as tetrahydroquinolinyl, dihydroindolyl, dihydropyranyl, etc.).

[0073] Furthermore, the representative structural compounds illustrated in Figures 5a-5f possess the potential to serve as small-molecule chiral catalysts and chiral ligands, catalyzing different types of asymmetric reactions either alone or in coordination with a metal. In the compounds shown in Figures 5a-5f: R 2u R 2c R 3c R 5 R 6 R 7a R 8a R 14 R 36 R 37 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens (F, Cl, Br, I), hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing or electron-donating protecting groups or arbitrary substituents with chain lengths of C1-C30; they can also be selected from substituted or unsubstituted C6-C50 aromatic groups. The group consisting of alkyl, benzo[a]aryl, fused aryl (such as naphthalene, anthracene, phenanthrene, carbazole, etc.), substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 aryl thiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amine, any aromatic heterocyclic (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrroleyl, pyridyl, quinolinyl, benzoquinolinyl, etc.), fused heterocyclic, and fused heterocyclic (such as tetrahydroquinolinyl, dihydroindolyl, dihydropyranyl, etc.).

[0074] In a detailed embodiment, the present invention uses chiral secondary amines such as chiral (hydroxy)diphenylprolyl as an example. These secondary amines are reacted with o-fluoronitrobenzene via nucleophilic substitution and nitro reduction to obtain o-aryl chiral diamine compound (II). O-aryl chiral diamine compound (II) can be prepared into an amino monosubstituted compound (II-2) by conventional methods (such as direct alkylation or reductive amination). Compound (II-2) is then acylated, sulfonated, or phosphonylated using known or disclosed methods to obtain an acylated compound (II-1). Further, using a suitable oxidant O1, the target chiral nitric oxide (NO) compound is obtained through selective nitrogen oxidation of the chiral tertiary amine. The synthetic route, including but not limited to that described in Figure 8, includes the following independent, combined, or one-pot steps:

[0075] (1) Using o-fluoronitrobenzene as the starting material, under the action of temperature T1, solvent S1 and base B1, it reacts with chiral proline compound C1 in an SNAr2 reaction, and then through nitro reduction, an o-aryl chiral diamine compound (II) is formed.

[0076] Solvent S1 is an inert solvent that can dissolve the substrate without reacting with it, including but not limited to alcohol solvents such as anhydrous methanol, anhydrous ethanol, tert-butanol, and n-butanol; halogenated hydrocarbon solvents such as dichloromethane, chloroform, and carbon tetrachloride; and ether solvents such as methyl tert-ethyl ether, tetrahydrofuran, and dioxane (1,6-dioxane). Tert-butanol is usually chosen as the reaction solvent.

[0077] Bases B1 include, but are not limited to, inorganic bases such as sodium carbonate and potassium carbonate, and one or more organic bases such as triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), and 4-dimethylaminopyridine (DMAP).

[0078] The molar ratio of o-fluoronitrobenzene to secondary amine substrate is generally between 1:1.2 and 1:1.5, with 1:1.2 usually being sufficient; the amount of base is between 2.5 and 3 molar equivalents, with 3 molar equivalents usually being sufficient.

[0079] The reaction temperature is the reflux temperature of the solvent, which is usually between 25°C and 120°C, with 85°C to 100°C being more suitable. The reaction time is determined by whether the main raw material, o-fluoronitrobenzene, has been completely reacted. Usually, a reaction of more than 18 hours is required to obtain the intermediate o-nitro chiral aromatic amine compound.

[0080] (2) Nitro reduction reactions can usually be carried out by hydrogen reduction catalyzed by noble metals (palladium, nickel, ruthenium, rhodium, etc.), MLiH4, MBH4, and chemical reduction methods such as metals and (zinc, iron, etc.) acids, including but not limited to the representative methods shown in Figure 9.

[0081] The intermediate o-nitro chiral aromatic amines were catalytically reduced to the target o-aryl chiral diamine (II) under the action of reducing agents such as palladium on carbon (Pd / C), zinc powder, iron powder, and sodium hydrosulfite, in a suitable solvent (S2) and at a suitable temperature (T2).

[0082] The reducing agent R1 can be palladium on carbon (Pd / C), zinc powder, iron powder, sodium hydrosulfite, or metal chloride, etc. The amount of palladium on carbon (Pd / C) is 5% to 10% of the amount of o-fluoronitrobenzene substrate, and the amount of zinc powder, iron powder, etc. is the same as the amount of substrate. The reaction solvent S2 is an inert solvent that can dissolve the substrate but does not react with it, including but not limited to: alcohol solvents such as anhydrous methanol and anhydrous ethanol; ether solvents such as methyl ether, tetrahydrofuran, and dioxane (1,6-dioxane), etc. Anhydrous methanol or tetrahydrofuran is usually chosen as the reaction solvent. The reaction temperature is suitable between 25℃ and 60℃. It can usually be reacted at room temperature. If the reaction proceeds slowly, the temperature can be gradually increased. Usually, 60℃ to 70℃ is more suitable. The reaction time is determined by whether the main raw material, o-nitrochiral aromatic amine, has reacted completely. The reaction time is usually between 3 hours and 12 hours.

[0083] In addition, the reduction of intermediate o-nitro chiral aromatic amines requires the addition of different proton-based solvents (S3) depending on the reducing agent. The amount of acidic solvent S3 used is generally 2 to 5 times that of the o-fluoronitrobenzene substrate, and its types include, but are not limited to, acetic acid and dilute hydrochloric acid. After the reaction is complete, a saturated sodium bicarbonate aqueous solution is added to quench the reaction, and the pH is adjusted to neutral to weakly alkaline (pH 7-9). Filtration yields the crude o-aryl chiral diamine compound. High-quality target products can be obtained using conventional purification methods such as water washing (desalting), crystallization, or column chromatography. However, the pure o-phenylenediamine product is unstable and needs to be further processed into a hydrochloride salt for storage at room temperature.

[0084] (3) The method for preparing the target axial chiral nitrogen oxide (NO) compound by selective nitrogen oxidation of chiral tertiary amine under the conditions of solvent S4 and temperature T4 is shown in Figure 10.

[0085] Oxidizing agent O1 includes m-chloroperoxybenzoic acid, peracetic acid, carboxylic acid (persulfuric acid), hydrogen peroxide, ruthenium trichloride, etc., with m-chloroperoxybenzoic acid being preferred as the oxidizing agent. The amount used is usually between 2.5 and 4 molar equivalents of the substrate, and usually 3 molar equivalents are sufficient.

[0086] Solvent S4 is an inert solvent that can dissolve the substrate without reacting with it, including but not limited to one or more of halogenated hydrocarbons, ethers and nitrile solvents, with dichloromethane usually chosen as the solvent.

[0087] The reaction temperature T4 is usually suitable between -78℃ and 20℃, generally between -10℃ and 0℃. The reaction time is determined by whether the main raw materials have reacted completely, and the reaction time is usually between 8 hours and 24 hours.

[0088] The above-mentioned synthetic route provided by the present invention uses inexpensive o-fluoronitrobenzene as the starting material. In a suitable solvent S1, under the action of base B1, it reacts with a sterically hindered chiral secondary amine compound at a suitable temperature T1 to form an o-nitro chiral aromatic amine intermediate.

[0089] This invention also provides a series of representative structural compounds with the potential to serve as small-molecule chiral catalysts and chiral ligands, capable of catalyzing different types of asymmetric reactions alone or in coordination with metals. These include, but are not limited to, the compounds shown in Figure 11.

[0090] The following specific embodiments illustrate the effects of the axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds of the present invention, their preparation methods, and their applications. Representative compounds in the embodiments are shown in Figure 12.

[0091] Example 1:

[0092] This embodiment provides a method for synthesizing an axially chiral aromatic nitrogen oxide (NO) compound (Ⅰa-1). The synthetic route is shown in Figure 13.

[0093] The preparation process is as follows:

[0094] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolyl (1,2 eq.) in a 25 mL round-bottom flask, add an appropriate amount of tert-butanol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90 °C to allow it to reflux fully. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was confirmed by TLC to be complete, and the reaction was terminated. The product was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the o-nitroaniline intermediate. 3 molar equivalents of glacial acetic acid and zinc powder (added slowly) were then added, along with an appropriate amount of tetrahydrofuran. The temperature was lowered to 0°C, and the mixture was magnetically stirred. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was confirmed by TLC to be complete, and the reaction was terminated. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to alkaline. The tetrahydrofuran was removed by rotary evaporation under reduced pressure. Extraction was performed with an appropriate amount of water and dichloromethane, and the aqueous phase was discarded. The product was washed with anhydrous sodium sulfate, filtered, and the dichloromethane was removed by rotary evaporation under reduced pressure. The product (II) was then purified by column chromatography. Subsequently, the o-phenylenediamine intermediate was sterically hindered by a substitution reaction. Specifically, the o-phenylenediamine intermediate (1 eq.) and methanesulfonic anhydride (1.5 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. Using pyridine (1.5 eq.) as a solvent and as a base, the mixture was magnetically stirred overnight at room temperature. The reaction was stopped after TLC detection showed complete reaction of the reactants. A dilute hydrochloric acid aqueous solution was added and stirred for half an hour. Water and dichloromethane were added for extraction, the aqueous phase was discarded, and the mixture was washed with anhydrous sodium sulfate. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The purified compound was then separated by column chromatography for further selective nitrogen oxidation. A suitable amount of dichloromethane was added as a solvent to dissolve the reactants. The reaction solution was cooled to 0°C, and the oxidant m-chloroperoxybenzoic acid (2.5 eq.) was added. The mixture was magnetically stirred for 8–10 hours. The reaction was stopped after TLC detection showed complete reaction of the reactants. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to neutral. Water and dichloromethane were added for extraction, the aqueous phase was discarded, and anhydrous sodium sulfate was added for washing. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-1) was obtained by column chromatography.

[0095] Characterization data for (Ⅰa-1) are as follows: mp: 165–167 °C; ¹H NMR (400 MHz, Chloroform-d) δ 14.68 (s, ¹H), 9.18 (s, ¹H), 7.56–7.49 (m, 2H), 7.36–7.31 (m, 2H), 7.31–7.26 (m, 3H), 7.19–7.05 (m, 3H), 6.95–6.79 (m, 4H), 5.36 (dd, J = 9.5, 7.6 Hz, ¹H), 3.96–3.80 (m, 2H), 2.85 (s, 3H), 2.77–2.53 (m, 2H), 2.22 (m, 1H), 2.06 (m, 1H). ¹³C NMR(101MHz,Chloroform-d)δ145.89,143.83,129.79,128.43,127.53,127.01,126.25,124 .92,121.70(d,J=20.2Hz),120.49,83.31,79.31,78.33,40.09,25.43,22.1.HRMS(ESI)m / z calcd for C24H26N2O4SNa+(M+Na)+461.1505, found 461.1507.

[0096] Example 2

[0097] In Example 1, the solvent tert-butanol in the first step was replaced with n-butanol, while all other conditions remained the same. Product (Ⅰa-1) was obtained in the same yield.

[0098] Example 3

[0099] In Example 1, the solvent tert-butanol in the first step was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and all other conditions remained the same. Product (Ⅰa-1) was obtained in the same yield.

[0100] Example 4:

[0101] In Example 1, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous sodium carbonate, while all other conditions remained the same. Product (Ⅰa-1) was obtained in the same yield.

[0102] Example 5:

[0103] In Example 1, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous cesium carbonate, while all other conditions remained the same. Product (Ⅰa-1) was obtained in the same yield.

[0104] Example 6:

[0105] In Example 1, the anhydrous potassium carbonate alkali used in the first step was replaced with triethylamine, while all other conditions remained the same. Product (Ⅰa-1) was obtained in the same yield.

[0106] Example 7:

[0107] In Example 1, the solvent tetrahydrofuran in step 2 was replaced with dichloromethane, while all other conditions remained the same. Product (Ⅰa-1) was obtained in a slightly higher yield.

[0108] Example 8:

[0109] In Example 1, the solvent tetrahydrofuran in step 2 was replaced with dioxane, while all other conditions remained the same. Product (Ⅰa-1) was obtained in the same yield.

[0110] Example 9:

[0111] In Example 1, the solvent tetrahydrofuran in step 2 was replaced with 1,2-dichloroethane, while all other conditions remained the same. Product (Ⅰa-1) was obtained in the same yield.

[0112] Example 10:

[0113] In Example 1, the solvent tetrahydrofuran in step 2 was replaced with acetonitrile, while all other conditions remained the same. Product (Ⅰa-1) was obtained in a slightly lower yield.

[0114] Example 11:

[0115] In Example 1, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Raney nickel, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-1) was obtained in a slightly higher yield.

[0116] Example 12:

[0117] In Example 1, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Pd / C, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-1) was obtained in a slightly lower yield.

[0118] Example 13:

[0119] In Example 1, the zinc powder in step 2 was replaced with iron powder, the glacial acetic acid was replaced with dilute hydrochloric acid, and the solvent was replaced with an aqueous system, while other conditions remained the same. Product (Ⅰa-1) was obtained in a slightly lower yield.

[0120] Example 14:

[0121] In Example 1, the zinc powder in step 2 was replaced with tin dichloride, the glacial acetic acid was replaced with dilute hydrochloric acid, the solvent was replaced with water, the temperature was increased to 50°C, and other conditions remained unchanged, to obtain product (Ⅰa-1) in a slightly lower yield.

[0122] Example 15:

[0123] By replacing the solvent dichloromethane in step 3 of Example 1 with acetonitrile, while keeping other conditions unchanged, product (Ⅰa-1) was obtained in a slightly lower yield.

[0124] Example 16:

[0125] In Example 1, the solvent dichloromethane in step 3 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰa-1) in the same yield.

[0126] Example 17:

[0127] In Example 1, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and other conditions remained unchanged, yielding product (Ⅰa-1) in the same yield.

[0128] Example 18:

[0129] In Example 1, the solvent dichloromethane in step 3 was replaced with ethyl acetate, and other conditions remained unchanged, yielding product (Ⅰa-1) in the same yield.

[0130] Example 19:

[0131] In Example 1, the solvent dichloromethane in step 3 was replaced with toluene, and other conditions remained unchanged, yielding product (Ⅰa-1) in the same yield.

[0132] Example 20:

[0133] In Example 1, the solvent dichloromethane in step 3 was replaced with N,N-dimethylformamide, and other conditions remained unchanged, yielding product (Ⅰa-1) in the same yield.

[0134] Example 21:

[0135] In Example 1, the base pyridine in step 3 was replaced with triethylamine, and other conditions remained unchanged, yielding product (Ⅰa-1) in the same yield.

[0136] Example 22:

[0137] In Example 1, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with a methanol and water system. Under the same conditions, the product (Ⅰa-1) was obtained in the same yield.

[0138] Example 23:

[0139] In Example 1, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetone and water system. Under the same conditions, the product (Ⅰa-1) was obtained in the same yield.

[0140] Example 24:

[0141] In Example 1, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetonitrile and water system. With other conditions unchanged, the product (Ⅰa-1) was obtained in the same yield.

[0142] Example 25:

[0143] In Example 1, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and other conditions remained unchanged, yielding product (Ⅰa-1) in the same yield.

[0144] Example 26:

[0145] In Example 1, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and the solvent was replaced with 1,2-dichloroethane. Under the same conditions, the product (Ⅰa-1) was obtained in the same yield.

[0146] Example 27:

[0147] In Example 1, the solvent dichloromethane in step 4 was replaced with chloroform, and other conditions remained unchanged, yielding product (Ⅰa-1) in the same yield.

[0148] Example 28:

[0149] In Example 1, the solvent dichloromethane in step 4 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰa-1) in the same yield.

[0150] Example 29:

[0151] In Example 1, the solvent dichloromethane in step 4 was replaced with acetonitrile, and other conditions remained unchanged, yielding product (Ⅰa-1) in the same yield.

[0152] Example 30:

[0153] By replacing the solvent dichloromethane in step four of Example 1 with tetrahydrofuran, while keeping other conditions unchanged, product (Ⅰa-1) was obtained in a slightly lower yield.

[0154] Example 31:

[0155] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolyl (1,2 eq.) in a 25 mL round-bottom flask, add an appropriate amount of tert-butanol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90 °C to allow it to reflux fully. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was confirmed by TLC to be complete, and the reaction was terminated. The product was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the o-nitroaniline intermediate. 3 molar equivalents of glacial acetic acid and zinc powder (added slowly) were then added, along with an appropriate amount of tetrahydrofuran. The temperature was lowered to 0°C, and the mixture was magnetically stirred. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was confirmed by TLC to be complete, and the reaction was terminated. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to alkaline. The tetrahydrofuran was removed by rotary evaporation under reduced pressure. Extraction was performed with an appropriate amount of water and dichloromethane, and the aqueous phase was discarded. The product was washed with anhydrous sodium sulfate, filtered, and the dichloromethane was removed by rotary evaporation under reduced pressure. The product (II) was then purified by column chromatography. Subsequently, the o-phenylenediamine intermediate was sterically hindered by a substitution reaction. Specifically, the o-phenylenediamine intermediate (1 eq.) and p-toluenesulfonyl chloride (1.5 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. Using alkylene as a solvent, pyridine (1.5 eq.) was weighed as a base and magnetically stirred overnight at room temperature. The reaction was stopped after TLC detection showed complete reaction of the starting material. Dilute hydrochloric acid aqueous solution was added and stirred for half an hour. Water and dichloromethane were added for extraction, the aqueous phase was discarded, and anhydrous sodium sulfate was added for washing. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The purified compound obtained by column chromatography was used for the next step of selective nitrogen oxidation reaction. Dichloromethane was added as a solvent to dissolve the starting material, and the reaction solution was cooled to 0°C. The oxidant m-chloroperoxybenzoic acid (2.5 eq.) was added, and the mixture was magnetically stirred for 8–10 hours. The reaction was stopped after TLC detection showed complete reaction of the starting material. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to neutral. Water and dichloromethane were added for extraction, the aqueous phase was discarded, and anhydrous sodium sulfate was added for washing. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-2) was obtained by column chromatography.

[0156] Characterization data for (Ⅰa-2) are as follows: mp: 157–160℃; ¹H NMR (600MHz, Chloroform-d) δ 14.75 (s, ¹H), 9.32 (s, ¹H), δ 7.73–7.68 (m, 2H), 7.52–7.46 (m, 2H), 7.30–7.26 (m, 3H), 7.25–7.21 (m, 4H), 7.20–7.15 (m, ¹H), 6.95 (ddd, J = 8.4, 7.2, 1.3Hz, ¹H), 6.86 (dd, J =8.6,1.3Hz,1H),6.77–6.69(m,4H),5.20(t,J=8.9Hz,1H),3.55(td,J=11.4,7.2Hz,1H),3.32(dd,J =11.1,7.3Hz,1H),2.69(m,1H),2.56–2.42(m,1H),2.37(s,3H),2.21(m,1H),2.00–1.91(m,1H).13C NMR(151MHz,Chloroform-d)δ145.87,143.27,143.16,137.73,135.35,134.96,129.32,129.15,128.31,127.47,127. 28,126.96,126.36,126.24,125.02,122.07,120.85,82.42,78.41,78.07,72.74,25.02,21.61,21.51.HRMS(ESI)m / z calcd for C30H31N2O4S+(M+H)+515.1999,found 515.2002.

[0157] Example 32:

[0158] In Example 31, the solvent tert-butanol in the first step was replaced with n-butanol, while all other conditions remained the same. Product (Ⅰa-2) was obtained in the same yield.

[0159] Example 33:

[0160] In Example 31, the solvent tert-butanol in the first step was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and all other conditions remained the same. Product (Ⅰa-2) was obtained in the same yield.

[0161] Example 34:

[0162] In Example 31, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous sodium carbonate, while other conditions remained the same. Product (Ⅰa-2) was obtained in the same yield.

[0163] Example 35:

[0164] In Example 31, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous cesium carbonate, while other conditions remained the same. Product (Ⅰa-2) was obtained in the same yield.

[0165] Example 36:

[0166] In Example 31, the anhydrous potassium carbonate alkali in the first step was replaced with triethylamine, while all other conditions remained the same. Product (Ⅰa-2) was obtained in the same yield.

[0167] Example 37:

[0168] In Example 31, the solvent tetrahydrofuran in step 2 was replaced with dichloromethane, while all other conditions remained the same. Product (Ⅰa-2) was obtained in a slightly higher yield.

[0169] Example 38:

[0170] In Example 31, the solvent tetrahydrofuran in step 2 was replaced with dioxane, while all other conditions remained the same. Product (Ⅰa-2) was obtained in the same yield.

[0171] Example 39:

[0172] In Example 31, the solvent tetrahydrofuran in step 2 was replaced with 1,2-dichloroethane, while all other conditions remained the same. Product (Ⅰa-2) was obtained in the same yield.

[0173] Example 40:

[0174] In Example 31, the solvent tetrahydrofuran in step 2 was replaced with acetonitrile, while all other conditions remained the same. Product (Ⅰa-2) was obtained in a slightly lower yield.

[0175] Example 41:

[0176] In Example 31, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Raney nickel, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-2) was obtained in a slightly higher yield.

[0177] Example 42:

[0178] In Example 31, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Pd / C, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-2) was obtained in a slightly lower yield.

[0179] Example 43:

[0180] In Example 31, the zinc powder in step 2 was replaced with iron powder, the glacial acetic acid was replaced with dilute hydrochloric acid, and the solvent was replaced with an aqueous system, while other conditions remained the same. Product (Ⅰa-2) was obtained in a slightly lower yield.

[0181] Example 44:

[0182] In Example 31, the zinc powder in step 2 was replaced with tin dichloride, the glacial acetic acid was replaced with dilute hydrochloric acid, the solvent was replaced with water, the temperature was increased to 50°C, and other conditions remained unchanged, to obtain product (Ⅰa-2) in a slightly lower yield.

[0183] Example 45:

[0184] By replacing the solvent dichloromethane in step 3 of Example 31 with acetonitrile, while keeping other conditions unchanged, product (Ⅰa-2) was obtained in a slightly lower yield.

[0185] Example 46:

[0186] In Example 31, the solvent dichloromethane in step 3 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰa-2) in the same yield.

[0187] Example 47:

[0188] In Example 31, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and other conditions remained unchanged, yielding product (Ⅰa-2) in the same yield.

[0189] Example 48:

[0190] In Example 31, the solvent dichloromethane in step 3 was replaced with ethyl acetate, and other conditions remained unchanged, yielding product (Ⅰa-2) in the same yield.

[0191] Example 49:

[0192] In Example 31, the solvent dichloromethane in step 3 was replaced with toluene, and other conditions remained unchanged, yielding product (Ⅰa-2) in the same yield.

[0193] Example 50:

[0194] In Example 31, the solvent dichloromethane in step 3 was replaced with N,N-dimethylformamide, and other conditions remained unchanged, yielding product (Ⅰa-2) in the same yield.

[0195] Example 51:

[0196] In Example 31, the base pyridine in step 3 was replaced with triethylamine, and other conditions remained unchanged, yielding product (Ⅰa-2) in the same yield.

[0197] Example 52:

[0198] In Example 31, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with a methanol and water system. Under the same conditions, the product (Ⅰa-2) was obtained in the same yield.

[0199] Example 53:

[0200] In Example 31, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetone and water system. With other conditions unchanged, the product (Ⅰa-2) was obtained in the same yield.

[0201] Example 54:

[0202] In Example 31, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetonitrile and water system. With other conditions unchanged, the product (Ⅰa-2) was obtained in the same yield.

[0203] Example 55:

[0204] In Example 31, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and other conditions remained unchanged, yielding product (Ⅰa-2) in the same yield.

[0205] Example 56:

[0206] In Example 31, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and the solvent was replaced with 1,2-dichloroethane. Under the same conditions, the product (Ⅰa-2) was obtained in the same yield.

[0207] Example 57:

[0208] In Example 31, the solvent dichloromethane in step 4 was replaced with chloroform, and other conditions remained unchanged, yielding product (Ⅰa-2) in the same yield.

[0209] Example 58:

[0210] In Example 31, the solvent dichloromethane in step 4 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰa-2) in the same yield.

[0211] Example 59:

[0212] In Example 31, the solvent dichloromethane in step 4 was replaced with acetonitrile, and other conditions remained unchanged, yielding product (Ⅰa-2) in the same yield.

[0213] Example 60:

[0214] In Example 31, the solvent dichloromethane in step 4 was replaced with tetrahydrofuran, while other conditions remained unchanged, to obtain product (Ⅰa-2) in a slightly lower yield.

[0215] Example 61:

[0216] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolyl (1,2 eq.) in a 25 mL round-bottom flask, add an appropriate amount of tert-butanol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90 °C to allow it to reflux fully. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was confirmed by TLC to be complete, and the reaction was terminated. The mixture was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the o-nitroaniline intermediate. 3 molar equivalents of glacial acetic acid and zinc powder (added slowly) were then added, along with an appropriate amount of tetrahydrofuran. The temperature was lowered to 0°C, and the mixture was magnetically stirred. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was confirmed by TLC to be complete, and the reaction was terminated. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to alkaline. The tetrahydrofuran was removed by rotary evaporation under reduced pressure. An appropriate amount of water and dichloromethane were added for extraction, and the aqueous phase was discarded. Anhydrous sodium sulfate was added for washing, and the mixture was filtered. The dichloromethane was removed by rotary evaporation under reduced pressure, and the product (II) was purified by column chromatography. Subsequently, the o-phenylenediamine intermediate was sterically hindered by a substitution reaction. Specifically, the o-phenylenediamine intermediate (1 eq.) and 4-nitrobenzenesulfonyl chloride (1.5 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. Using alkylene as a solvent, pyridine (1.5 eq.) was weighed as a base and magnetically stirred overnight at room temperature. The reaction was stopped after TLC detection showed complete reaction of the starting material. Dilute hydrochloric acid aqueous solution was added and stirred for half an hour. Water and dichloromethane were added for extraction, the aqueous phase was discarded, and anhydrous sodium sulfate was added for washing. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The purified compound was then separated by column chromatography for the next step of selective nitrogen oxidation reaction. A suitable amount of dichloromethane was added as a solvent to dissolve the starting material. The reaction solution was cooled to 0°C, and m-chloroperoxybenzoic acid (2.5 eq.) was added as an oxidant. The mixture was magnetically stirred for 8–10 hours. The reaction was stopped after TLC detection showed complete reaction of the starting material. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to neutral. Water and dichloromethane were added for extraction, the aqueous phase was discarded, and anhydrous sodium sulfate was added for washing. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-3) was obtained by column chromatography.

[0217] Characterization data for (Ⅰa-3) are as follows: mp: 158–162℃; ¹H NMR (600MHz, Chloroform-d) δ 8.29–8.24 (m, 2H), 8.00–7.96 (m, 2H), 7.51–7.46 (m, 2H), 7.28 (t, J = 7.8Hz, 2H), 7.26–7.24 (m, 2H), 7.22 (dd, J = 8.3, 1.5Hz, 1H), 7.20–7.15 (m, 1H), 7.04–6.96 (m, 2H), 6.87 (ddd, J = 8.6, 7.2,1.5Hz,1H),6.83–6.79(m,3H),5.25(dd,J=9.5,8.1Hz,1H),4.12(q,J=7.2Hz,1H),3.68(td,J=11.3,7. 0Hz,1H),3.36(dd,J=11.0,7.2Hz,1H),2.70(m,1H),2.60–2.48(m,1H),2.29–2.15(m,1H),2.04(m,1H).13C NMR(151MHz,Chloroform-d)δ149.85,146.50,145.55,143.11,135.04,134.95,129.62,128.42(d,J=2.3Hz),127.58 ,127.08,126.44,126.04,124.84,123.97,122.77,121.82,121.19,83.89,79.31,78.15,25.21,22.00.HRMS(ESI)m / z calcd for C29H27N3O6SNa+(M+Na)+568.1513, found 568.1516.

[0218] Example 62:

[0219] In Example 61, the solvent tert-butanol in the first step was replaced with n-butanol, while all other conditions remained the same. Product (Ⅰa-3) was obtained in the same yield.

[0220] Example 63:

[0221] In Example 61, the solvent tert-butanol in the first step was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and all other conditions remained the same. Product (Ⅰa-3) was obtained in the same yield.

[0222] Example 64:

[0223] In Example 61, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous sodium carbonate, while all other conditions remained the same. Product (Ⅰa-3) was obtained in the same yield.

[0224] Example 65:

[0225] In Example 61, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous cesium carbonate, while all other conditions remained the same. Product (Ⅰa-3) was obtained in the same yield.

[0226] Example 66:

[0227] In Example 61, the anhydrous potassium carbonate alkali in the first step was replaced with triethylamine, while all other conditions remained the same. Product (Ⅰa-3) was obtained in the same yield.

[0228] Example 67:

[0229] In Example 61, the solvent tetrahydrofuran in step 2 was replaced with dichloromethane, while all other conditions remained the same. Product (Ⅰa-3) was obtained in a slightly higher yield.

[0230] Example 68:

[0231] In Example 61, the solvent tetrahydrofuran in step 2 was replaced with dioxane, while all other conditions remained the same. Product (Ⅰa-3) was obtained in the same yield.

[0232] Example 69:

[0233] In Example 61, the solvent tetrahydrofuran in step 2 was replaced with 1,2-dichloroethane, while all other conditions remained the same. Product (Ⅰa-3) was obtained in the same yield.

[0234] Example 70:

[0235] In Example 61, the solvent tetrahydrofuran in step 2 was replaced with acetonitrile, while all other conditions remained the same. Product (Ⅰa-3) was obtained in a slightly lower yield.

[0236] Example 71:

[0237] In Example 61, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Raney nickel, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-3) was obtained in a slightly higher yield.

[0238] Example 72:

[0239] In Example 61, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Pd / C, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-3) was obtained in a slightly lower yield.

[0240] Example 73:

[0241] In Example 61, the zinc powder in step 2 was replaced with iron powder, the glacial acetic acid was replaced with dilute hydrochloric acid, and the solvent was replaced with an aqueous system, while other conditions remained the same. Product (Ⅰa-3) was obtained in a slightly lower yield.

[0242] Example 74:

[0243] In Example 61, the zinc powder in step 2 was replaced with tin dichloride, the glacial acetic acid was replaced with dilute hydrochloric acid, the solvent was replaced with water, the temperature was increased to 50°C, and other conditions remained unchanged, to obtain product (Ⅰa-3) in a slightly lower yield.

[0244] Example 75:

[0245] By replacing the solvent dichloromethane in step 3 of Example 61 with acetonitrile, while keeping other conditions unchanged, product (Ⅰa-3) was obtained in a slightly lower yield.

[0246] Example 76:

[0247] In Example 61, the solvent dichloromethane in step 3 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰa-3) in the same yield.

[0248] Example 77:

[0249] In Example 61, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰa-3) in the same yield.

[0250] Example 78:

[0251] In Example 61, the solvent dichloromethane in step 3 was replaced with ethyl acetate, and other conditions remained unchanged, yielding product (Ⅰa-3) in the same yield.

[0252] Example 79:

[0253] In Example 61, the solvent dichloromethane in step 3 was replaced with toluene, and other conditions remained unchanged, yielding product (Ⅰa-3) in the same yield.

[0254] Example 80:

[0255] In Example 61, the solvent dichloromethane in step 3 was replaced with N,N-dimethylformamide, and other conditions remained unchanged, yielding product (Ⅰa-3) in the same yield.

[0256] Example 81:

[0257] In Example 61, the base pyridine in step 3 was replaced with triethylamine, and the other conditions remained unchanged, yielding product (Ⅰa-3) in the same yield.

[0258] Example 82:

[0259] In Example 61, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with a methanol and water system. Under the same conditions, the product (Ⅰa-3) was obtained in the same yield.

[0260] Example 83:

[0261] In Example 61, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetone and water system. With other conditions unchanged, the product (Ⅰa-3) was obtained in the same yield.

[0262] Example 84:

[0263] In Example 61, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetonitrile and water system. With other conditions unchanged, the product (Ⅰa-3) was obtained in the same yield.

[0264] Example 85:

[0265] In Example 61, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and other conditions remained unchanged, yielding product (Ⅰa-3) in the same yield.

[0266] Example 86:

[0267] In Example 61, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and the solvent was replaced with 1,2-dichloroethane. Under the same conditions, the product (Ⅰa-3) was obtained in the same yield.

[0268] Example 87:

[0269] In Example 61, the solvent dichloromethane in step 4 was replaced with chloroform, and other conditions remained unchanged, yielding product (Ⅰa-3) in the same yield.

[0270] Example 88:

[0271] In Example 61, the solvent dichloromethane in step 4 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰa-3) in the same yield.

[0272] Example 89:

[0273] In Example 61, the solvent dichloromethane in step 4 was replaced with acetonitrile, and other conditions remained unchanged, yielding product (Ⅰa-3) in the same yield.

[0274] Example 90:

[0275] By replacing the solvent dichloromethane in step 4 of Example 61 with tetrahydrofuran, while keeping other conditions unchanged, product (Ⅰa-3) was obtained in a slightly lower yield.

[0276] Example 91:

[0277] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolyl (1,2 eq.) in a 25 mL round-bottom flask, add an appropriate amount of tert-butanol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90 °C to allow it to reflux fully. After 18 hours, the reaction of the o-fluoronitrobenzene raw material was confirmed by TLC to be complete, and the reaction was terminated. The product was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the o-nitroaniline intermediate. 3 molar equivalents of glacial acetic acid and zinc powder (added slowly) were then added, along with an appropriate amount of tetrahydrofuran. The temperature was lowered to 0°C, and the mixture was magnetically stirred. After 12 hours, the reaction of the o-nitroaniline intermediate was confirmed by TLC to be complete, and the reaction was terminated. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to alkaline. The tetrahydrofuran was removed by rotary evaporation under reduced pressure. Extraction was performed with an appropriate amount of water and dichloromethane, and the aqueous phase was discarded. The product was washed with anhydrous sodium sulfate, filtered, and the dichloromethane was removed by rotary evaporation under reduced pressure. The product (II) was purified by column chromatography. Subsequently, the o-phenylenediamine intermediate was further reacted to attach a sterically hindered group. Specifically, the o-phenylenediamine intermediate (1 eq.) and triethylamine (1.5 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added as a solvent. The reaction mixture was cooled to 0°C. At ℃, a diluted dichloromethane solution of oxaloyl chloride (0.5 eq.) was slowly added dropwise. The mixture was magnetically stirred for 2 h at room temperature. The reaction was stopped after TLC detection showed that the reactants were completely reacted. Saturated ammonium chloride aqueous solution was added and stirred for half an hour. Water and dichloromethane were added for extraction. The aqueous phase was discarded. Anhydrous sodium sulfate was added for washing. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The purified compound was then separated by column chromatography for the next step of selective nitrogen oxidation reaction. A suitable amount of dichloromethane was added as a solvent to dissolve the reactants. The reaction solution was cooled to 0℃, and m-chloroperoxybenzoic acid (2.5 eq.) was added as an oxidant. The mixture was magnetically stirred for 8–10 h. The reaction was stopped after TLC detection showed that the reactants were completely reacted. Saturated sodium bicarbonate solution was added for quenching. The pH was adjusted to neutral. Water and dichloromethane were added for extraction. The aqueous phase was discarded. Anhydrous sodium sulfate was added for washing. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-4) was obtained by column chromatography for purification.

[0278] Characterization data for (Ⅰa-4) are as follows: mp: 141–152 °C; ¹H NMR (400 MHz, Chloroform-d) δ 15.06 (s, ¹H), 8.40 (d, J = 8.5 Hz, ¹H), 7.63–7.59 (m, ¹H), 7.58–7.54 (m, 3H), 7.37–7.30 (m, ¹²H), 7.22–7.07 (m, 5H), 7.03–6.94 (m, 3H), 6.90–6.77 (m, 4H), 5.36–5.26 (m, 2H), 4.09–3.98 (m, 4H), 3.75 (m, 2H), 3.53 (m, 3H), 2.84–2.68 (m, 3H), 2.42–2.02 (m, 2H). ¹³C NMR(151MHz,Chloroform-d)δ128.32,127.96,127.62,127.06,126.79(d,J=6.8Hz),126.21,1 24.85,121.08,117.26,84.67,78.08,30.82,29.71,29.34,25.54,22.71,22.27.HRMS(ESI)m / z calcd for C48H46N4O6Na+(M+Na)+797.3309, found 797.3309.

[0279] Example 92:

[0280] In Example 91, the solvent tert-butanol in the first step was replaced with n-butanol, while all other conditions remained the same. Product (Ⅰa-4) was obtained in the same yield.

[0281] Example 93:

[0282] In Example 91, the solvent tert-butanol in the first step was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and all other conditions remained the same. Product (Ⅰa-4) was obtained in the same yield.

[0283] Example 94:

[0284] In Example 91, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous sodium carbonate, while other conditions remained the same. Product (Ⅰa-4) was obtained in the same yield.

[0285] Example 95:

[0286] In Example 91, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous cesium carbonate, while all other conditions remained the same. Product (Ⅰa-4) was obtained in the same yield.

[0287] Example 96:

[0288] In Example 91, the anhydrous potassium carbonate alkali in the first step was replaced with triethylamine, while all other conditions remained the same. Product (Ⅰa-4) was obtained in the same yield.

[0289] Example 97:

[0290] In Example 91, the solvent tetrahydrofuran in step 2 was replaced with dichloromethane, while all other conditions remained the same. Product (Ⅰa-4) was obtained in a slightly higher yield.

[0291] Example 98:

[0292] In Example 91, the solvent tetrahydrofuran in step 2 was replaced with dioxane, while all other conditions remained the same. Product (Ⅰa-4) was obtained in the same yield.

[0293] Example 99:

[0294] In Example 91, the solvent tetrahydrofuran in step 2 was replaced with 1,2-dichloroethane, while all other conditions remained the same. Product (Ⅰa-4) was obtained in the same yield.

[0295] Example 100:

[0296] In Example 91, the solvent tetrahydrofuran in step 2 was replaced with acetonitrile, while all other conditions remained the same. Product (Ⅰa-4) was obtained in a slightly lower yield.

[0297] Example 101:

[0298] In Example 91, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Raney nickel, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-4) was obtained in a slightly higher yield.

[0299] Example 102:

[0300] In Example 91, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Pd / C, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-4) was obtained in a slightly lower yield.

[0301] Example 103:

[0302] In Example 91, the zinc powder in step 2 was replaced with iron powder, the glacial acetic acid was replaced with dilute hydrochloric acid, and the solvent was replaced with an aqueous system, while other conditions remained the same. Product (Ⅰa-4) was obtained in a slightly lower yield.

[0303] Example 104:

[0304] In Example 91, the zinc powder in step 2 was replaced with tin dichloride, the glacial acetic acid was replaced with dilute hydrochloric acid, the solvent was replaced with water, the temperature was increased to 50°C, and other conditions remained unchanged, to obtain product (Ⅰa-4) in a slightly lower yield.

[0305] Example 105:

[0306] By replacing the solvent dichloromethane in step 3 of Example 91 with acetonitrile, while keeping other conditions unchanged, product (Ⅰa-4) was obtained in a slightly lower yield.

[0307] Example 106:

[0308] In Example 91, the solvent dichloromethane in step 3 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰa-4) in the same yield.

[0309] Example 107:

[0310] In Example 91, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰa-4) in the same yield.

[0311] Example 108:

[0312] In Example 91, the solvent dichloromethane in step 3 was replaced with 1,2-dioxane, and other conditions remained unchanged, yielding product (Ⅰa-4) in the same yield.

[0313] Example 109:

[0314] In Example 91, the solvent dichloromethane in step 3 was replaced with chloroform, and other conditions remained unchanged, yielding product (Ⅰa-4) in the same yield.

[0315] Example 110:

[0316] In Example 91, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with a methanol and water system. Under the same conditions, the product (Ⅰa-4) was obtained in the same yield.

[0317] Example 111:

[0318] In Example 91, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetone and water system. Under the same conditions, the product (Ⅰa-4) was obtained in the same yield.

[0319] Example 112:

[0320] In Example 91, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetonitrile and water system. With other conditions unchanged, the product (Ⅰa-4) was obtained in the same yield.

[0321] Example 113:

[0322] In Example 91, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and other conditions remained unchanged, yielding product (Ⅰa-4) in the same yield.

[0323] Example 114:

[0324] In Example 91, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and the solvent was replaced with 1,2-dichloroethane. Under the same conditions, the product (Ⅰa-4) was obtained in the same yield.

[0325] Example 115:

[0326] In Example 91, the solvent dichloromethane in step 4 was replaced with chloroform, and other conditions remained unchanged, yielding product (Ⅰa-4) in the same yield.

[0327] Example 116:

[0328] In Example 91, the solvent dichloromethane in step 4 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰa-4) in the same yield.

[0329] Example 117:

[0330] In Example 91, the solvent dichloromethane in step 4 was replaced with acetonitrile, and other conditions remained unchanged, yielding product (Ⅰa-4) in the same yield.

[0331] Example 118:

[0332] By replacing the solvent dichloromethane in step 4 of Example 91 with tetrahydrofuran, while keeping other conditions unchanged, product (Ⅰa-4) was obtained in a slightly lower yield.

[0333] Example 119:

[0334] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolyl (1,2 eq.) in a 25 mL round-bottom flask, add an appropriate amount of tert-butanol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90 °C to allow it to reflux fully. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was confirmed by TLC to be complete, and the reaction was stopped. The mixture was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the o-nitroaniline intermediate. 3 molar equivalents of glacial acetic acid and zinc powder (added slowly) were then added, along with an appropriate amount of tetrahydrofuran. The temperature was lowered to 0°C, and the mixture was magnetically stirred. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was confirmed by TLC to be complete, and the reaction was stopped. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to alkaline. Tetrahydrofuran was removed by rotary evaporation under reduced pressure. Extraction was performed with an appropriate amount of water and dichloromethane, and the aqueous phase was discarded. The mixture was washed with anhydrous sodium sulfate, filtered, and the dichloromethane was removed by rotary evaporation under reduced pressure. The product (II) was then purified by column chromatography. Subsequently, the o-phenylenediamine intermediate was sterically hindered by a condensation reaction. Specifically, the o-phenylenediamine intermediate (1 eq.) and 2-cyanobenzenesulfonyl chloride (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. Using methane as a solvent and pyridine (1.5 eq.) as a base, the mixture was magnetically stirred overnight at room temperature. The reaction was stopped after TLC detection showed complete reaction of the reactants. A dilute hydrochloric acid aqueous solution was added and stirred for half an hour. Water and dichloromethane were added for extraction, the aqueous phase was discarded, and the mixture was washed with anhydrous sodium sulfate. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The purified compound was then separated by column chromatography for the next step of selective nitrogen oxidation. A suitable amount of dichloromethane was added as a solvent to dissolve the reactants. The reaction solution was cooled to 0°C, and the oxidant m-chloroperoxybenzoic acid (2.5 eq.) was added. The mixture was magnetically stirred for 8–10 hours. The reaction was stopped after TLC detection showed complete reaction of the reactants. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to neutral. Water and dichloromethane were added for extraction, the aqueous phase was discarded, and anhydrous sodium sulfate was added for washing. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-5) was obtained by column chromatography.

[0335] Characterization data for (Ⅰa-5) are: mp: 133~136℃; 1H NMR(400MHz,Chloroform-d)δ8.19(d,J=7.9Hz,1H),7.89(dd,J=7.6,1.4Hz,1H ),7.79(td,J=7.8,1.4Hz,1H),7.70(td,J=7.6,1.3Hz,1H),7.61–7.54(m,2H), 7.38–7.32(m,4H),7.28–7.20(m,1H),7.16(dd,J=8.3,1.5Hz,1H),7.08–6.96( m,2H),6.87–6.75(m,4H),5.35(t,J=8.9Hz,1H),3.90–3.71(m,2H),2.87–2.75( m,1H),2.65(d,J=9.8Hz,1H),2.39–2.24(m,1H),2.10(m,2H).13CNMR(101MHz, Chloroform-d)δ145.73,143.60,143.22,135.23,134.12,132.73,132.29,129. 75,129.53,128.37,127.49,127.04,126.36(d,J=6.0Hz),125.11,121.96,121 .20,120.54,115.97,110.90,83.27,78.53,78.12,24.99,21.77.HRMS(ESI)m / z calcd for C30H27N3O4SNa+(M+Na)+548.1615, found 548.1617.

[0336] Example 120:

[0337] In Example 119, the solvent tert-butanol in the first step was replaced with n-butanol, while all other conditions remained the same. Product (Ⅰa-5) was obtained in the same yield.

[0338] Example 121:

[0339] In Example 119, the solvent tert-butanol in the first step was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and all other conditions remained the same. Product (Ⅰa-5) was obtained in the same yield.

[0340] Example 122:

[0341] In Example 119, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous sodium carbonate, while other conditions remained the same. Product (Ⅰa-5) was obtained in the same yield.

[0342] Example 123:

[0343] In Example 119, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous cesium carbonate, while other conditions remained the same. Product (Ⅰa-5) was obtained in the same yield.

[0344] Example 124:

[0345] In Example 119, the anhydrous potassium carbonate alkali in the first step was replaced with triethylamine, while all other conditions remained the same. Product (Ⅰa-5) was obtained in the same yield.

[0346] Example 125:

[0347] In Example 119, the solvent tetrahydrofuran in step 2 was replaced with dichloromethane, while all other conditions remained the same. Product (Ⅰa-5) was obtained in a slightly higher yield.

[0348] Example 126:

[0349] In Example 119, the solvent tetrahydrofuran in step 2 was replaced with dioxane, while all other conditions remained the same. Product (Ⅰa-5) was obtained in the same yield.

[0350] Example 127:

[0351] In Example 119, the solvent tetrahydrofuran in step 2 was replaced with 1,2-dichloroethane, while all other conditions remained the same. Products (Ⅰa-5) were obtained in equal yields.

[0352] Example 128:

[0353] In Example 119, the solvent tetrahydrofuran in step 2 was replaced with acetonitrile, while all other conditions remained the same. Product (Ⅰa-5) was obtained in a slightly lower yield.

[0354] Example 129:

[0355] In Example 119, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Raney nickel, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-5) was obtained in a slightly higher yield.

[0356] Example 130:

[0357] In Example 119, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Pd / C, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-5) was obtained in a slightly lower yield.

[0358] Example 131:

[0359] In Example 119, the zinc powder in step 2 was replaced with iron powder, the glacial acetic acid with dilute hydrochloric acid, and the solvent with an aqueous system, while other conditions remained the same. Product (Ⅰa-5) was obtained in a slightly lower yield.

[0360] Example 132:

[0361] In Example 119, the zinc powder in step 2 was replaced with tin dichloride, the glacial acetic acid was replaced with dilute hydrochloric acid, the solvent was replaced with water, the temperature was increased to 50°C, and other conditions remained unchanged, to obtain product (Ⅰa-5) in a slightly lower yield.

[0362] Example 133:

[0363] By replacing the solvent dichloromethane in step 3 of Example 119 with acetonitrile, while keeping other conditions unchanged, product (Ⅰa-5) was obtained in a slightly lower yield.

[0364] Example 134:

[0365] In Example 119, the solvent dichloromethane in step 3 was replaced with 1,2-dichloroethane, and all other conditions remained unchanged, yielding product (Ⅰa-5) in the same yield.

[0366] Example 135:

[0367] In Example 119, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰa-5) in the same yield.

[0368] Example 136:

[0369] In Example 119, the solvent dichloromethane in step 3 was replaced with ethyl acetate, and other conditions remained unchanged, yielding product (Ⅰa-5) in the same yield.

[0370] Example 137:

[0371] In Example 119, the solvent dichloromethane in step 3 was replaced with toluene, while other conditions remained unchanged, and product (Ⅰa-5) was obtained in the same yield.

[0372] Example 138:

[0373] In Example 119, the solvent dichloromethane in step 3 was replaced with N,N-dimethylformamide, and other conditions remained unchanged, yielding product (Ⅰa-5) in the same yield.

[0374] Example 139:

[0375] In Example 119, the base pyridine in step 3 was replaced with triethylamine, and the other conditions remained unchanged, yielding product (Ⅰa-5) in the same yield.

[0376] Example 140:

[0377] In Example 119, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with a methanol and water system. Under the same conditions, the product (Ⅰa-5) was obtained in the same yield.

[0378] Example 141:

[0379] In Example 119, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetone and water system. With other conditions unchanged, the product (Ⅰa-5) was obtained in the same yield.

[0380] Example 142:

[0381] In Example 119, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetonitrile and water system. With other conditions unchanged, the product (Ⅰa-5) was obtained in the same yield.

[0382] Example 143:

[0383] In Example 119, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and other conditions remained unchanged, yielding product (Ⅰa-5) in the same yield.

[0384] Example 144:

[0385] In Example 119, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and the solvent was replaced with 1,2-dichloroethane. Under the same conditions, the product (Ⅰa-5) was obtained in the same yield.

[0386] Example 145:

[0387] In Example 119, the solvent dichloromethane in step 4 was replaced with chloroform, and other conditions remained unchanged, yielding product (Ⅰa-5) in the same yield.

[0388] Example 146:

[0389] In Example 119, the solvent dichloromethane in step 4 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰa-5) in the same yield.

[0390] Example 147:

[0391] In Example 119, the solvent dichloromethane in step 4 was replaced with acetonitrile, and other conditions remained unchanged, yielding product (Ⅰa-5) in the same yield.

[0392] Example 148:

[0393] In Example 119, the solvent dichloromethane in step 4 was replaced with tetrahydrofuran, while other conditions remained unchanged, to obtain product (Ⅰa-5) in a slightly lower yield.

[0394] Example 149:

[0395] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolyl (1,2 eq.) in a 25 mL round-bottom flask, add an appropriate amount of tert-butanol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90 °C to allow it to reflux fully. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was confirmed by TLC to be complete, and the reaction was terminated. The mixture was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the o-nitroaniline intermediate. 3 molar equivalents of glacial acetic acid and zinc powder (added slowly) were then added, along with an appropriate amount of tetrahydrofuran. The temperature was lowered to 0°C, and the mixture was magnetically stirred. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was confirmed by TLC to be complete, and the reaction was terminated. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to alkaline. The tetrahydrofuran was removed by rotary evaporation under reduced pressure. An appropriate amount of water and dichloromethane were added for extraction, and the aqueous phase was discarded. Anhydrous sodium sulfate was added for washing, and the mixture was filtered. The dichloromethane was removed by rotary evaporation under reduced pressure, and the product (II) was purified by column chromatography. Subsequently, the o-phenylenediamine intermediate was sterically hindered by a condensation reaction. Specifically, the o-phenylenediamine intermediate (1 eq.) and 3,5-bis(trifluoromethyl)benzoic acid (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of... Using dichloromethane as a solvent, HATU (1.5 eq.) was weighed as a condensing agent and magnetically stirred overnight at room temperature. The reaction was stopped after TLC detection showed complete reaction of the starting material. An aqueous solution was added and stirred for half an hour. A suitable amount of water and dichloromethane were added for extraction, the aqueous phase was discarded, and the mixture was washed with anhydrous sodium sulfate. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The purified compound obtained by column chromatography was used for the next step of selective nitrogen oxidation reaction. A suitable amount of dichloromethane was added as a solvent to dissolve the starting material. The reaction solution was cooled to 0°C, and the oxidant m-chloroperoxybenzoic acid (2.5 eq.) was added. The mixture was magnetically stirred for 8–10 hours. The reaction was stopped after TLC detection showed complete reaction of the starting material. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to neutral. A suitable amount of water and dichloromethane were added for extraction, the aqueous phase was discarded, and anhydrous sodium sulfate was added for washing. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-6) was obtained by column chromatography purification.

[0396] Characterization data for (Ⅰa-6) are as follows: mp: 165–171 °C; ¹H NMR (400 MHz, Chloroform-d) δ 15.38 (s, 1H), 8.93 (s, 1H), 8.52 (dd, J = 8.3, 1.5 Hz, 1H), 8.23 ​​(d, J = 1.7 Hz, 2H), 7.95 (s, 1H), 7.48–7.38 (m, 2H), 7.28–7.11 (m, 6H), 7.12–6.93 (m, 2H). H),6.74(t,J=7.3Hz,1H),6.62(t,J=7.6Hz,2H),5.32(dd,J=9.7,6.1Hz,1H),4.00(td, J=10.9,6.3Hz,1H),3.91(m,1H),2.68–2.54(m,2H),2.14(m,1H),2.08–1.91(m,1H).13C NMR(101MHz,Chloroform-d)δ160.11,144.37,142.98,136.73,135.35,134.93,131.35(d,J=33.7Hz),130.68(d,J=33.7Hz),128.63,127.4 3,126.61(d,J=4.1Hz),126.33,125.97,125.46,124.54,123.71,121.83,121.65,120.09,85.36,79.80,77.57,25.20,22.20.HRMS(ESI)m / z calcd for C32H26F6N2O3Na+(M+Na)+623.1740,found 623.1740.

[0397] The crystal data for (Ⅰa-6) are shown in Table 1-9.

[0398] Table 1. Crystal data and structural refinement for Ia-6

[0399] Table 4 Bond lengths of Ia-6

[0400] Table 5 Bond angles of Ⅰa-6

[0401] Table 7 Torsional angles of Ⅰa-6

[0402] Example 150:

[0403] In Example 149, the solvent tert-butanol in the first step was replaced with n-butanol, while all other conditions remained the same. Product (Ⅰa-6) was obtained in the same yield.

[0404] Example 151:

[0405] In Example 149, the solvent tert-butanol in the first step was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and all other conditions remained the same. Product (Ⅰa-6) was obtained in the same yield.

[0406] Example 152:

[0407] In Example 149, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous sodium carbonate, while all other conditions remained the same. Product (Ⅰa-6) was obtained in the same yield.

[0408] Example 153:

[0409] In Example 149, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous cesium carbonate, while all other conditions remained the same. Product (Ⅰa-6) was obtained in the same yield.

[0410] Example 154:

[0411] In Example 149, the anhydrous potassium carbonate alkali in the first step was replaced with triethylamine, while all other conditions remained the same. Product (Ⅰa-6) was obtained in the same yield.

[0412] Example 155:

[0413] In Example 149, the solvent tetrahydrofuran in step 2 was replaced with dichloromethane, while all other conditions remained the same. Product (Ⅰa-6) was obtained in a slightly higher yield.

[0414] Example 156:

[0415] In Example 149, the solvent tetrahydrofuran in step 2 was replaced with dioxane, while all other conditions remained the same. Product (Ⅰa-6) was obtained in the same yield.

[0416] Example 157:

[0417] In Example 149, the solvent tetrahydrofuran in step 2 was replaced with 1,2-dichloroethane, while all other conditions remained the same. Product (Ⅰa-6) was obtained in the same yield.

[0418] Example 158:

[0419] In Example 149, the solvent tetrahydrofuran in step 2 was replaced with acetonitrile, while all other conditions remained the same. Product (Ⅰa-6) was obtained in a slightly lower yield.

[0420] Example 159:

[0421] In Example 149, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Raney nickel, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-6) was obtained in a slightly higher yield.

[0422] Example 160:

[0423] In Example 149, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Pd / C, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-6) was obtained in a slightly lower yield.

[0424] Example 161:

[0425] In Example 149, the zinc powder in step 2 was replaced with iron powder, the glacial acetic acid was replaced with dilute hydrochloric acid, and the solvent was replaced with an aqueous system, while other conditions remained the same. Product (Ⅰa-6) was obtained in a slightly lower yield.

[0426] Example 162:

[0427] In Example 149, the zinc powder in step 2 was replaced with tin dichloride, the glacial acetic acid was replaced with dilute hydrochloric acid, the solvent was replaced with water, the temperature was increased to 50°C, and other conditions remained unchanged, to obtain product (Ⅰa-6) in a slightly lower yield.

[0428] Example 163:

[0429] By replacing the solvent dichloromethane in step 3 of Example 149 with acetonitrile, while keeping other conditions unchanged, product (Ⅰa-6) was obtained in a slightly lower yield.

[0430] Example 164:

[0431] In Example 149, the solvent dichloromethane in step 3 was replaced with 1,2-dichloroethane, and all other conditions remained unchanged, yielding product (Ⅰa-6) in the same yield.

[0432] Example 165:

[0433] In Example 149, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰa-6) in the same yield.

[0434] Example 166:

[0435] In Example 149, the solvent dichloromethane in step 3 was replaced with 1,2-dioxane, and the other conditions remained unchanged, yielding product (Ⅰa-6) in the same yield.

[0436] Example 167:

[0437] In Example 149, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰa-6) in the same yield.

[0438] Example 168:

[0439] In Example 149, the solvent dichloromethane in step 3 was replaced with N,N-dimethylformamide, and other conditions remained unchanged, yielding product (Ⅰa-6) in the same yield.

[0440] Example 169:

[0441] In Example 149, the condensing agent HATU in step 3 was replaced with CDI, and under nitrogen protection, with other conditions unchanged, the product (Ⅰa-6) was obtained in the same yield.

[0442] Example 170:

[0443] In Example 149, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with a methanol and water system. Under the same conditions, the product (Ⅰa-6) was obtained in the same yield.

[0444] Example 171:

[0445] In Example 149, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetone and water system. Under the same conditions, the product (Ⅰa-6) was obtained in the same yield.

[0446] Example 172:

[0447] In Example 149, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetonitrile and water system. With other conditions unchanged, the product (Ⅰa-6) was obtained in the same yield.

[0448] Example 173:

[0449] In Example 149, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and other conditions remained unchanged, yielding product (Ⅰa-6) in the same yield.

[0450] Example 174:

[0451] In Example 149, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and the solvent was replaced with 1,2-dichloroethane. Under the same conditions, the product (Ⅰa-6) was obtained in the same yield.

[0452] Example 175:

[0453] In Example 149, the solvent dichloromethane in step 4 was replaced with chloroform, and other conditions remained unchanged, yielding product (Ⅰa-6) in the same yield.

[0454] Example 176:

[0455] In Example 149, the solvent dichloromethane in step 4 was replaced with 1,2-dichloroethane, and all other conditions remained unchanged, yielding product (Ⅰa-6) in the same yield.

[0456] Example 177:

[0457] In Example 149, the solvent dichloromethane in step 4 was replaced with acetonitrile, and other conditions remained unchanged, yielding product (Ⅰa-6) in the same yield.

[0458] Example 178:

[0459] By replacing the solvent dichloromethane in step four of Example 149 with tetrahydrofuran, while keeping other conditions unchanged, product (Ⅰa-6) was obtained in a slightly lower yield.

[0460] Example 179:

[0461] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolyl (1,2 eq.) in a 25 mL round-bottom flask, add an appropriate amount of tert-butanol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90 °C to allow it to reflux fully. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was confirmed by TLC to be complete, and the reaction was stopped. The mixture was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the o-nitroaniline intermediate. 3 molar equivalents of glacial acetic acid and zinc powder (added slowly) were then added, along with an appropriate amount of tetrahydrofuran. The temperature was lowered to 0°C, and the mixture was magnetically stirred. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was confirmed by TLC to be complete, and the reaction was stopped. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to alkaline. The tetrahydrofuran was removed by rotary evaporation under reduced pressure. An appropriate amount of water and dichloromethane were added for extraction, and the aqueous phase was discarded. Anhydrous sodium sulfate was added for washing, and the mixture was filtered. The dichloromethane was removed by rotary evaporation under reduced pressure, and the product (II) was purified by column chromatography. Subsequently, the o-phenylenediamine intermediate was sterically hindered by a condensation reaction. Specifically, the o-phenylenediamine intermediate (1 eq.) and 2-cyanobenzoic acid (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. Using alkylene as a solvent, HATU (1.5 eq.) was weighed as a condensing agent and magnetically stirred overnight at room temperature. The reaction was stopped after TLC detection showed complete reaction of the starting material. An aqueous solution was added and stirred for half an hour. Extraction was performed using water and dichloromethane, and the aqueous phase was discarded. The mixture was washed with anhydrous sodium sulfate, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The purified compound was then separated by column chromatography for the next step of selective nitrogen oxidation. The starting material was dissolved in dichloromethane as a solvent, and the reaction solution was cooled to 0°C. The oxidant m-chloroperoxybenzoic acid (2.5 eq.) was added, and the mixture was magnetically stirred for 8–10 hours. The reaction was stopped after TLC detection showed complete reaction of the starting material. The reaction was quenched with saturated sodium bicarbonate solution, and the pH was adjusted to neutral. Extraction was performed using water and dichloromethane, and the aqueous phase was discarded. Washing was performed with anhydrous sodium sulfate, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-7) was obtained by column chromatography.

[0462] Characterization data for (Ⅰa-7) are as follows: mp: 115–130℃; ¹H NMR (400MHz, Chloroform-d) δ 15.11 (s, ¹H), 8.18–8.12 (m, ¹H), 8.02 (dd, J = 17.2, 7.4Hz, 2H), 7.89 (td, J = 6.7, 6.1, 3.4Hz, 2H), 7.56–7.49 (m, ¹H), 7.32 (td, J = 5.0, 2.5Hz, 2H), 7.28 (d, J = 1.9Hz, ¹H), 7.25–7. 18(m,2H),7.17–7.10(m,1H),7.08–6.98(m,2H),6.93–6.88(m,3H),6.82(t,J=7.6Hz,1H),5.55(dd,J= 9.0,6.7Hz,1H),4.18–3.94(m,1H),3.24(s,1H),2.81–2.65(m,1H),2.56(m,2H),1.87–1.72(m,2H).13C NMR(151MHz,Chloroform-d)δ161.14,148.52,134.10,132.26,128.43,128.38,127.39,125.58,124.69,1 23.40,122.97,121.86,121.78,119.46,109.55,85.42,78.40,42.79,29.71,26.06,23.47.HRMS(ESI)m / z calcd for C31H27N3O3Na+(M+Na)+512.1945, found 512.1946.

[0463] Example 180:

[0464] In Example 179, the solvent tert-butanol in the first step was replaced with n-butanol, while all other conditions remained the same. Product (Ⅰa-7) was obtained in the same yield.

[0465] Example 181:

[0466] In Example 179, the solvent tert-butanol in the first step was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and all other conditions remained the same. Product (Ⅰa-7) was obtained in the same yield.

[0467] Example 182:

[0468] In Example 179, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous sodium carbonate, while all other conditions remained the same. Product (Ⅰa-7) was obtained in the same yield.

[0469] Example 183:

[0470] In Example 179, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous cesium carbonate, while all other conditions remained the same. Product (Ⅰa-7) was obtained in the same yield.

[0471] Example 184:

[0472] In Example 179, the anhydrous potassium carbonate alkali in the first step was replaced with triethylamine, while all other conditions remained the same. Product (Ⅰa-7) was obtained in the same yield.

[0473] Example 185:

[0474] In Example 179, the solvent tetrahydrofuran in step 2 was replaced with dichloromethane, while all other conditions remained the same. Product (Ⅰa-7) was obtained in a slightly higher yield.

[0475] Example 186:

[0476] In Example 179, the solvent tetrahydrofuran in step 2 was replaced with dioxane, while all other conditions remained the same. The product (Ⅰa-7) was obtained in the same yield.

[0477] Example 187:

[0478] In Example 179, the solvent tetrahydrofuran in step 2 was replaced with 1,2-dichloroethane, while all other conditions remained the same. Products (Ⅰa-7) were obtained in equal yields.

[0479] Example 188:

[0480] In Example 179, the solvent tetrahydrofuran in step 2 was replaced with acetonitrile, while all other conditions remained the same. Product (Ⅰa-7) was obtained in a slightly lower yield.

[0481] Example 189:

[0482] In Example 179, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Raney nickel, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-7) was obtained in a slightly higher yield.

[0483] Example 190:

[0484] In Example 179, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Pd / C, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-7) was obtained in a slightly lower yield.

[0485] Example 191:

[0486] In Example 179, the zinc powder in step 2 was replaced with iron powder, the glacial acetic acid was replaced with dilute hydrochloric acid, and the solvent was replaced with an aqueous system, while other conditions remained the same. Product (Ⅰa-7) was obtained in a slightly lower yield.

[0487] Example 192:

[0488] In Example 179, the zinc powder in step 2 was replaced with tin dichloride, the glacial acetic acid was replaced with dilute hydrochloric acid, the solvent was replaced with water, the temperature was increased to 50°C, and other conditions remained unchanged, to obtain product (Ⅰa-7) in a slightly lower yield.

[0489] Example 193:

[0490] By replacing the solvent dichloromethane in step 3 of Example 179 with acetonitrile, while keeping other conditions unchanged, product (Ⅰa-7) was obtained in a slightly lower yield.

[0491] Example 194:

[0492] In Example 179, the solvent dichloromethane in step 3 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰa-7) in the same yield.

[0493] Example 195:

[0494] In Example 179, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰa-7) in the same yield.

[0495] Example 196:

[0496] In Example 179, the solvent dichloromethane in step 3 was replaced with 1,2-dioxane, and other conditions remained unchanged, yielding product (Ⅰa-7) in the same yield.

[0497] Example 197:

[0498] In Example 179, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰa-7) in the same yield.

[0499] Example 198:

[0500] In Example 179, the solvent dichloromethane in step 3 was replaced with N,N-dimethylformamide, and the other conditions remained unchanged, yielding the product (Ⅰa-7) in the same yield.

[0501] Example 199:

[0502] In Example 179, the condensing agent HATU in step 3 was replaced with CDI, and under nitrogen protection, with other conditions unchanged, the product (Ⅰa-7) was obtained in the same yield.

[0503] Example 200:

[0504] In Example 179, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with a methanol and water system. Under the same conditions, the product (Ⅰa-7) was obtained in the same yield.

[0505] Example 201:

[0506] In Example 179, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetone and water system. With other conditions unchanged, the product (Ⅰa-7) was obtained in the same yield.

[0507] Example 202:

[0508] In Example 179, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetonitrile and water system. With other conditions unchanged, the product (Ⅰa-7) was obtained in the same yield.

[0509] Example 203:

[0510] In Example 179, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and other conditions remained unchanged, yielding product (Ⅰa-7) in the same yield.

[0511] Example 204:

[0512] In Example 179, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and the solvent was replaced with 1,2-dichloroethane. Under the same conditions, the product (Ⅰa-7) was obtained in the same yield.

[0513] Example 205:

[0514] In Example 179, the solvent dichloromethane in step 4 was replaced with chloroform, and other conditions remained unchanged, yielding product (Ⅰa-7) in the same yield.

[0515] Example 206:

[0516] In Example 179, the solvent dichloromethane in step 4 was replaced with 1,2-dichloroethane, and all other conditions remained unchanged, yielding product (Ⅰa-7) in the same yield.

[0517] Example 207:

[0518] In Example 179, the solvent dichloromethane in step 4 was replaced with acetonitrile, and other conditions remained unchanged, yielding product (Ⅰa-7) in the same yield.

[0519] Example 208:

[0520] By replacing the solvent dichloromethane in step 4 of Example 179 with tetrahydrofuran, while keeping other conditions unchanged, product (Ⅰa-7) was obtained in a slightly lower yield.

[0521] Example 209:

[0522] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolyl (1,2 eq.) in a 25 mL round-bottom flask, add an appropriate amount of tert-butanol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90 °C to allow it to reflux fully. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was confirmed by TLC to be complete, and the reaction was stopped. The mixture was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the o-nitroaniline intermediate. 3 molar equivalents of glacial acetic acid and zinc powder (added slowly) were then added, along with an appropriate amount of tetrahydrofuran. The temperature was lowered to 0°C, and the mixture was magnetically stirred. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was confirmed by TLC to be complete, and the reaction was stopped. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to alkaline. The tetrahydrofuran was removed by rotary evaporation under reduced pressure. An appropriate amount of water and dichloromethane were added for extraction, and the aqueous phase was discarded. Anhydrous sodium sulfate was added for washing, and the mixture was filtered. The dichloromethane was removed by rotary evaporation under reduced pressure, and the product (II) was purified by column chromatography. Subsequently, the o-phenylenediamine intermediate was sterically hindered by a condensation reaction. Specifically, the o-phenylenediamine intermediate (1 eq.) and 2-isopropylbenzoic acid (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. Using alkylene as a solvent, HATU (1.5 eq.) was weighed as a condensing agent and magnetically stirred overnight at room temperature. The reaction was stopped after TLC detection showed complete reaction of the starting material. An aqueous solution was added and stirred for half an hour. Extraction was performed with appropriate amounts of water and dichloromethane. The aqueous phase was discarded, and the mixture was washed with anhydrous sodium sulfate. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The purified compound obtained by column chromatography was used for the next step of selective nitrogen oxidation reaction. An appropriate amount of dichloromethane was added as a solvent to dissolve the starting material. The reaction solution was cooled to 0°C, and the oxidant m-chloroperoxybenzoic acid (2.5 eq.) was added. The mixture was magnetically stirred for 8–10 hours. The reaction was stopped after TLC detection showed complete reaction of the starting material. The mixture was quenched with saturated sodium bicarbonate solution, and the pH was adjusted to neutral. Extraction was performed with appropriate amounts of water and dichloromethane. The aqueous phase was discarded, and the mixture was washed with anhydrous sodium sulfate. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-8) was obtained by column chromatography purification.

[0523] Characterization data for (Ⅰa-8) are as follows: mp: 110–125 °C; ¹H NMR (600 MHz, Chloroform-d) δ 14.28 (s, ¹H), 9.66 (s, ¹H), 8.61 (dd, J = 8.8, 1.6 Hz, ¹H), 7.54–7.50 (m, 3H), 7.44–7.37 (m, 2H), 7.33–7.26 (m, 5H), 7.19–7.14 (m, 1H), 7.14–7.08 (m, 2H), 6. 93(ddd,J=8.5,7.2,1.5Hz,1H),6.90–6.83(m,3H),5.30(t,J=8.8Hz,1H),4.00(td,J=11.3, 7.2Hz,1H),3.89(dd,J=11.2,7.4Hz,1H),3.54(hept,J=6.9Hz,1H),2.70(m,1H),2.63–2.52 (m,1H),2.20(m,1H),2.08–2.03(m,1H),1.36(d,J=6.8Hz,3H),1.26(d,J=6.9Hz,3H).13CNM R(151MHz,Chloroform-d)δ167.60,147.40,146.08,143.41,136.88,136.57,134.53,130.0 7,129.34,128.37,127.28,126.92,126.53(d,J=9.2Hz),126.30,125.89(d,J=3.4Hz),124. 77,122.77,121.87,121.04,84.05,79.31,78.14,29.64,25.21,24.28,21.97.HRMS(ESI)m / z calcd for C33H35N2O3+(M+H)+507.2642, found 507.2649.

[0524] Example 210:

[0525] In Example 209, the solvent tert-butanol in the first step was replaced with n-butanol, while all other conditions remained the same. Product (Ⅰa-8) was obtained in the same yield.

[0526] Example 211:

[0527] In Example 209, the solvent tert-butanol in the first step was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and all other conditions remained the same. Product (Ⅰa-8) was obtained in the same yield.

[0528] Example 212:

[0529] In Example 209, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous sodium carbonate, while all other conditions remained the same. Product (Ⅰa-8) was obtained in the same yield.

[0530] Example 213:

[0531] In Example 209, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous cesium carbonate, while all other conditions remained the same. Product (Ⅰa-8) was obtained in the same yield.

[0532] Example 214:

[0533] In Example 209, the anhydrous potassium carbonate alkali in the first step was replaced with triethylamine, while all other conditions remained the same. Product (Ⅰa-8) was obtained in the same yield.

[0534] Example 215:

[0535] In Example 209, the solvent tetrahydrofuran in step 2 was replaced with dichloromethane, while all other conditions remained the same. Product (Ⅰa-8) was obtained in a slightly higher yield.

[0536] Example 216:

[0537] In Example 209, the solvent tetrahydrofuran in step 2 was replaced with dioxane, while all other conditions remained the same. Product (Ⅰa-8) was obtained in the same yield.

[0538] Example 217:

[0539] In Example 209, the solvent tetrahydrofuran in step 2 was replaced with 1,2-dichloroethane, while all other conditions remained the same. Product (Ⅰa-8) was obtained in the same yield.

[0540] Example 218:

[0541] In Example 209, the solvent tetrahydrofuran in step 2 was replaced with acetonitrile, while all other conditions remained the same. Product (Ⅰa-8) was obtained in a slightly lower yield.

[0542] Example 219:

[0543] In Example 209, the solvent tetrahydrofuran was replaced with anhydrous methanol, zinc powder with Raney nickel, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-8) was obtained in a slightly higher yield.

[0544] Example 220:

[0545] In Example 209, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Pd / C, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰa-8) was obtained in a slightly lower yield.

[0546] Example 221:

[0547] In Example 209, the zinc powder in step 2 was replaced with iron powder, the glacial acetic acid was replaced with dilute hydrochloric acid, and the solvent was replaced with an aqueous system, while other conditions remained the same. Product (Ⅰa-8) was obtained in a slightly lower yield.

[0548] Example 222:

[0549] In Example 209, the zinc powder in step 2 was replaced with tin dichloride, the glacial acetic acid was replaced with dilute hydrochloric acid, the solvent was replaced with water, the temperature was increased to 50°C, and other conditions remained unchanged, to obtain product (Ⅰa-8) in a slightly lower yield.

[0550] Example 223:

[0551] By replacing the solvent dichloromethane in step 3 of Example 209 with acetonitrile, while keeping other conditions unchanged, product (Ⅰa-8) was obtained in a slightly lower yield.

[0552] Example 224:

[0553] In Example 209, the solvent dichloromethane in step 3 was replaced with 1,2-dichloroethane, and other conditions remained unchanged, yielding product (Ⅰa-8) in the same yield.

[0554] Example 225:

[0555] In Example 209, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰa-8) in the same yield.

[0556] Example 226:

[0557] In Example 209, the solvent dichloromethane in step 3 was replaced with 1,2-dioxane, and other conditions remained unchanged, yielding product (Ⅰa-8) in the same yield.

[0558] Example 227:

[0559] In Example 209, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰa-8) in the same yield.

[0560] Example 228:

[0561] In Example 209, the solvent dichloromethane in step 3 was replaced with N,N-dimethylformamide, and other conditions remained unchanged, yielding product (Ⅰa-8) in the same yield.

[0562] Example 229:

[0563] In Example 209, the condensing agent HATU in step 3 was replaced with CDI, and under nitrogen protection, with other conditions unchanged, the product (Ⅰa-8) was obtained in the same yield.

[0564] Example 230:

[0565] In Example 209, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with a methanol and water system. Under the same conditions, the product (Ⅰa-8) was obtained in the same yield.

[0566] Example 231:

[0567] In Example 209, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetone and water system. With other conditions unchanged, the product (Ⅰa-8) was obtained in the same yield.

[0568] Example 232:

[0569] In Example 209, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetonitrile and water system. With other conditions unchanged, the product (Ⅰa-8) was obtained in the same yield.

[0570] Example 233:

[0571] In Example 209, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and other conditions remained unchanged, yielding product (Ⅰa-8) in the same yield.

[0572] Example 234:

[0573] In Example 209, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and the solvent was replaced with 1,2-dichloroethane. Under the same conditions, the product (Ⅰa-8) was obtained in the same yield.

[0574] Example 235:

[0575] In Example 209, the solvent dichloromethane in step 4 was replaced with chloroform, and other conditions remained unchanged, yielding product (Ⅰa-8) in the same yield.

[0576] Example 236:

[0577] In Example 209, the solvent dichloromethane in step 4 was replaced with 1,2-dichloroethane, and other conditions remained unchanged, yielding product (Ⅰa-8) in the same yield.

[0578] Example 237:

[0579] In Example 209, the solvent dichloromethane in step 4 was replaced with acetonitrile, and other conditions remained unchanged, yielding product (Ⅰa-8) in the same yield.

[0580] Example 238:

[0581] In Example 209, the solvent dichloromethane in step 4 was replaced with tetrahydrofuran, while other conditions remained unchanged, to obtain product (Ⅰa-8) in a slightly lower yield.

[0582] Example 239:

[0583] Place o-fluoronitrobenzene (1 eq.) and (S)-2-diphenylmethylpyrrolidine (1,2 eq.) in a 25 mL round-bottom flask, add an appropriate amount of tert-butanol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90 °C to allow it to reflux fully. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was confirmed by TLC to be complete, and the reaction was terminated. The mixture was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the o-nitroaniline intermediate. 3 molar equivalents of glacial acetic acid and zinc powder (added slowly) were then added, along with an appropriate amount of tetrahydrofuran. The temperature was lowered to 0°C, and the mixture was magnetically stirred. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was confirmed by TLC to be complete, and the reaction was terminated. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to alkaline. The tetrahydrofuran was removed by rotary evaporation under reduced pressure. An appropriate amount of water and dichloromethane were added for extraction, and the aqueous phase was discarded. Anhydrous sodium sulfate was added for washing, and the mixture was filtered. The dichloromethane was removed by rotary evaporation under reduced pressure, and the product (II) was purified by column chromatography. Subsequently, the o-phenylenediamine intermediate was sterically hindered by a condensation reaction. Specifically, the o-phenylenediamine intermediate (1 eq.) and 3,5-bis(trifluoromethyl)benzoic acid (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of... Using dichloromethane as a solvent, HATU (1.5 eq.) was weighed as a condensing agent and magnetically stirred overnight at room temperature. The reaction was stopped after TLC detection showed complete reaction of the reactants. An aqueous solution was added and stirred for half an hour. A suitable amount of water and dichloromethane were added for extraction, the aqueous phase was discarded, and the mixture was washed with anhydrous sodium sulfate. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The purified compound obtained by column chromatography was used for the next step of selective nitrogen oxidation reaction. A suitable amount of dichloromethane was added as a solvent to dissolve the reactants. The reaction solution was cooled to 0°C, and the oxidant m-chloroperoxybenzoic acid (2.5 eq.) was added. The mixture was magnetically stirred for 8–10 hours. The reaction was stopped after TLC detection showed complete reaction of the reactants. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to neutral. A suitable amount of water and dichloromethane were added for extraction, the aqueous phase was discarded, and anhydrous sodium sulfate was added for washing. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰb-1) was obtained by column chromatography purification.

[0584] Characterization data for (Ⅰb-1) are as follows: ¹H NMR (600 MHz, Chloroform-d) δ 16.00 (s, ¹H), 8.47–8.42 (m, ¹H), 8.34 (d, J = 1.7 Hz, 2H), 7.96 (s, ¹H), 7.23 (m, ¹H), 7.17–7.11 (m, 3H), 7.09–7.06 (m, 2H), 7.01 (m, ¹H), 6.98–6.94 (m, 2H) ,6.87–6.83(m,3H),6.81–6.76(m,1H),5.24(dt,J=9.0,6.9Hz,1H),4.30(td,J=10.3,7.3H z,1H),3.95(m,1H),3.64(d,J=9.1Hz,1H),2.57(m,1H),2.39(m,1H),1.98–1.85(m,2H).13C NMR(151MHz,Chloroform-d)δ161.31,141.30,140.01,137.66,137.06,134.39,132.11(d,J=11.0Hz),131.92,130.44,129.00,128.51,12 7.85(d,J=3.9Hz),127.30,127.14,126.45,125.22–124.80(m),122.83,122.52,120.56,87.48,71.25,54.38,28.72,20.86.HRMS(ESI)m / z calcd for C32H27F6N2O2+(M+H)+585.1971,found 585.1973.

[0585] Example 240:

[0586] In Example 239, the solvent tert-butanol in the first step was replaced with n-butanol, while all other conditions remained the same. Product (Ⅰb-1) was obtained in the same yield.

[0587] Example 241:

[0588] In Example 239, the solvent tert-butanol in the first step was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and all other conditions remained the same. Product (Ⅰb-1) was obtained in the same yield.

[0589] Example 242:

[0590] In Example 239, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous sodium carbonate, while all other conditions remained the same. Product (Ⅰb-1) was obtained in the same yield.

[0591] Example 243:

[0592] In Example 239, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous cesium carbonate, while all other conditions remained the same. Product (Ⅰb-1) was obtained in the same yield.

[0593] Example 244:

[0594] In Example 239, the anhydrous potassium carbonate alkali in the first step was replaced with triethylamine, while all other conditions remained the same. Product (Ⅰb-1) was obtained in the same yield.

[0595] Example 245:

[0596] In Example 239, the solvent tetrahydrofuran in step 2 was replaced with dichloromethane, while all other conditions remained the same. Product (Ⅰb-1) was obtained in a slightly higher yield.

[0597] Example 246:

[0598] In Example 239, the solvent tetrahydrofuran in step 2 was replaced with dioxane, while all other conditions remained the same. Product (Ⅰb-1) was obtained in the same yield.

[0599] Example 247:

[0600] In Example 239, the solvent tetrahydrofuran in step 2 was replaced with 1,2-dichloroethane, while all other conditions remained the same. Product (Ⅰb-1) was obtained in the same yield.

[0601] Example 248:

[0602] In Example 239, the solvent tetrahydrofuran in step 2 was replaced with acetonitrile, while all other conditions remained the same. Product (Ⅰb-1) was obtained in a slightly lower yield.

[0603] Example 249:

[0604] In Example 239, the solvent tetrahydrofuran was replaced with anhydrous methanol, zinc powder with Raney nickel, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰb-1) was obtained in a slightly higher yield.

[0605] Example 250:

[0606] In Example 239, the solvent tetrahydrofuran in step 2 was replaced with anhydrous methanol, zinc powder with Pd / C, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰb-1) was obtained in a slightly lower yield.

[0607] Example 251:

[0608] In Example 239, the zinc powder in step 2 was replaced with iron powder, the glacial acetic acid was replaced with dilute hydrochloric acid, and the solvent was replaced with an aqueous system, while other conditions remained the same. Product (Ⅰb-1) was obtained in a slightly lower yield.

[0609] Example 252:

[0610] In Example 239, the zinc powder in the second step was replaced with tin dichloride, the glacial acetic acid was replaced with dilute hydrochloric acid, the solvent was replaced with water, the temperature was increased to 50°C, and other conditions remained unchanged, to obtain product (Ⅰb-1) in a slightly lower yield.

[0611] Example 253:

[0612] By replacing the solvent dichloromethane in step 3 of Example 239 with acetonitrile, while keeping other conditions unchanged, product (Ⅰb-1) was obtained in a slightly lower yield.

[0613] Example 254:

[0614] In Example 239, the solvent dichloromethane in step 3 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰb-1) in the same yield.

[0615] Example 255:

[0616] In Example 239, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰb-1) in the same yield.

[0617] Example 256:

[0618] In Example 239, the solvent dichloromethane in step 3 was replaced with 1,2-dioxane, and the other conditions remained unchanged, yielding product (Ⅰb-1) in the same yield.

[0619] Example 257:

[0620] In Example 239, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰb-1) in the same yield.

[0621] Example 258:

[0622] In Example 239, the solvent dichloromethane in step 3 was replaced with N,N-dimethylformamide, and the other conditions remained unchanged, yielding product (Ⅰb-1) in the same yield.

[0623] Example 259:

[0624] In Example 239, the condensing agent HATU in step 3 was replaced with CDI, and under nitrogen protection, with other conditions unchanged, the product (Ⅰb-1) was obtained in the same yield.

[0625] Example 260:

[0626] In Example 239, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with a methanol and water system. With other conditions unchanged, the product (Ⅰb-1) was obtained in the same yield.

[0627] Example 261:

[0628] In Example 239, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetone and water system. With other conditions unchanged, the product (Ⅰb-1) was obtained in the same yield.

[0629] Example 262:

[0630] In Example 239, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetonitrile and water system. With other conditions unchanged, the product (Ⅰb-1) was obtained in the same yield.

[0631] Example 263:

[0632] In Example 239, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and other conditions remained unchanged, yielding product (Ⅰb-1) in the same yield.

[0633] Example 264:

[0634] In Example 239, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, the solvent was replaced with 1,2-dichloroethane, and other conditions remained unchanged, yielding product (Ⅰb-1) in the same yield.

[0635] Example 265:

[0636] In Example 239, the solvent dichloromethane in step 4 was replaced with chloroform, and other conditions remained unchanged, yielding product (Ⅰb-1) in the same yield.

[0637] Example 266:

[0638] In Example 239, the solvent dichloromethane in step 4 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰb-1) in the same yield.

[0639] Example 267:

[0640] In Example 239, the solvent dichloromethane in step 4 was replaced with acetonitrile, and other conditions remained unchanged, yielding product (Ⅰb-1) in the same yield.

[0641] Example 268:

[0642] By replacing the solvent dichloromethane in step four of Example 239 with tetrahydrofuran, while keeping other conditions unchanged, product (Ⅰb-1) was obtained in a slightly lower yield.

[0643] Example 269:

[0644] Place o-fluoronitrobenzene (1 eq.) and (S)-2-diphenylmethylpyrrolidine (1,2 eq.) in a 25 mL round-bottom flask, add an appropriate amount of tert-butanol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90 °C to allow it to reflux fully. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was confirmed by TLC to be complete, and the reaction was stopped. The mixture was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the o-nitroaniline intermediate. 3 molar equivalents of glacial acetic acid and zinc powder (added slowly) were then added, along with an appropriate amount of tetrahydrofuran. The temperature was lowered to 0°C, and the mixture was magnetically stirred. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was confirmed by TLC to be complete, and the reaction was stopped. Saturated sodium bicarbonate solution was added to quench the reaction, and the pH was adjusted to alkaline. Tetrahydrofuran was removed by rotary evaporation under reduced pressure. Extraction was performed with an appropriate amount of water and dichloromethane, and the aqueous phase was discarded. The mixture was washed with anhydrous sodium sulfate, filtered, and the dichloromethane was removed by rotary evaporation under reduced pressure. The product (II) was purified by column chromatography. Subsequently, the o-phenylenediamine intermediate was sterically hindered by a condensation reaction. Specifically, the o-phenylenediamine intermediate (1 eq.) and benzofuran-2-carboxylic acid (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. Using methane as a solvent, HATU (1.5 eq.) was weighed as a condensing agent and magnetically stirred overnight at room temperature. The reaction was stopped after TLC detection showed complete reaction of the reactants. An aqueous solution was added and stirred for half an hour. Extraction was performed using water and dichloromethane, and the aqueous phase was discarded. The mixture was washed with anhydrous sodium sulfate, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The purified compound was then separated by column chromatography for further selective nitrogen oxidation. The reactants were dissolved in dichloromethane and the reaction solution was cooled to 0°C. The oxidant m-chloroperoxybenzoic acid (2.5 eq.) was added, and the mixture was magnetically stirred for 8–10 hours. The reaction was stopped after TLC detection showed complete reaction of the reactants. The mixture was quenched with saturated sodium bicarbonate solution, and the pH was adjusted to neutral. Extraction was performed using water and dichloromethane, and the aqueous phase was discarded. Washing was performed with anhydrous sodium sulfate, and the mixture was filtered. Dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰb-2) was obtained by column chromatography.

[0645] Characterization data for (Ⅰb-2) are: mp: 122–135 °C; 1H NMR(400MHz,Chloroform-d)δ15.38(s,1H),8.47(dd,J=8.7,1.5Hz,1H),7.73(t, J=8.1Hz,2H),7.54(s,1H),7.47(ddd,J=8.4,7.2,1.4Hz,1H),7.35(t,J=7.5Hz,1H ),7.32–7.12(m,5H),7.12–7.06(m,2H),7.03(td,J=7.8,1.6Hz,1H),7.00–6.89(m ,5H),5.44(td,J=7.6,4.3Hz,1H),4.37(q,J=9.6Hz,1H),3.93(m,1H),3.74(d,J=8 .9Hz,1H),2.79–2.64(m,2H),2.14–2.00(m,2H).13CNMR(101MHz,Chloroform-d)δ 156.41,155.37,150.03,141.26,139.85,136.62,134.78,130.19,128.95,128.51 (d,J=8.7Hz),127.78,127.22,127.04,126.70,126.43,123.55,122.95,122.54,1 22.07,120.08,112.56,110.07,86.36,68.87,54.86,28.04,20.66.HRMS(ESI)m / z calcd for C32H29N2O3+(M+H)+489.2173, found 489.2174.

[0646] Example 270:

[0647] In Example 269, the solvent tert-butanol in the first step was replaced with n-butanol, while all other conditions remained the same. Product (Ⅰb-2) was obtained in the same yield.

[0648] Example 271:

[0649] In Example 269, the solvent tert-butanol in the first step was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and all other conditions remained the same. Product (Ⅰb-2) was obtained in the same yield.

[0650] Example 272:

[0651] In Example 269, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous sodium carbonate, while all other conditions remained the same. Product (Ⅰb-2) was obtained in the same yield.

[0652] Example 273:

[0653] In Example 269, the anhydrous potassium carbonate alkali in the first step was replaced with anhydrous cesium carbonate, while all other conditions remained the same. Product (Ⅰb-2) was obtained in the same yield.

[0654] Example 274:

[0655] In Example 269, the anhydrous potassium carbonate alkali in the first step was replaced with triethylamine, while all other conditions remained the same. Product (Ⅰb-2) was obtained in the same yield.

[0656] Example 275:

[0657] In Example 269, the solvent tetrahydrofuran in step 2 was replaced with dichloromethane, while all other conditions remained the same. Product (Ⅰb-2) was obtained in a slightly higher yield.

[0658] Example 276:

[0659] In Example 269, the solvent tetrahydrofuran was replaced with dioxane in step 2, while all other conditions remained the same. Product (Ⅰb-2) was obtained in the same yield.

[0660] Example 277:

[0661] In Example 269, the solvent tetrahydrofuran in step 2 was replaced with 1,2-dichloroethane, while all other conditions remained the same. Product (Ⅰb-2) was obtained in the same yield.

[0662] Example 278:

[0663] In Example 269, the solvent tetrahydrofuran in step 2 was replaced with acetonitrile, while all other conditions remained the same. Product (Ⅰb-2) was obtained in a slightly lower yield.

[0664] Example 279:

[0665] In Example 269, the solvent tetrahydrofuran was replaced with anhydrous methanol, zinc powder with Raney nickel, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰb-2) was obtained in a slightly higher yield.

[0666] Example 280:

[0667] In Example 269, the solvent tetrahydrofuran was replaced with anhydrous methanol, zinc powder with Pd / C, and glacial acetic acid with H2. The mixture was then subjected to pressure, with all other conditions remaining the same. Product (Ⅰb-2) was obtained in a slightly lower yield.

[0668] Example 281:

[0669] In Example 269, the zinc powder in step 2 was replaced with iron powder, the glacial acetic acid was replaced with dilute hydrochloric acid, and the solvent was replaced with an aqueous system, while other conditions remained the same. Product (Ⅰb-2) was obtained in a slightly lower yield.

[0670] Example 282:

[0671] In Example 269, the zinc powder in step 2 was replaced with tin dichloride, the glacial acetic acid was replaced with dilute hydrochloric acid, the solvent was replaced with water, the temperature was increased to 50°C, and other conditions remained unchanged, to obtain product (Ⅰb-2) in a slightly lower yield.

[0672] Example 283:

[0673] By replacing the solvent dichloromethane in step 3 of Example 269 with acetonitrile, while keeping other conditions unchanged, product (Ⅰb-2) was obtained in a slightly lower yield.

[0674] Example 284:

[0675] In Example 269, the solvent dichloromethane in step 3 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰb-2) in the same yield.

[0676] Example 285:

[0677] In Example 269, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰb-2) in the same yield.

[0678] Example 286:

[0679] In Example 269, the solvent dichloromethane in step 3 was replaced with 1,2-dioxane, and the other conditions remained unchanged, yielding product (Ⅰb-2) in the same yield.

[0680] Example 287:

[0681] In Example 269, the solvent dichloromethane in step 3 was replaced with tetrahydrofuran, and the other conditions remained unchanged, yielding product (Ⅰb-2) in the same yield.

[0682] Example 288:

[0683] In Example 269, the solvent dichloromethane in step 3 was replaced with N,N-dimethylformamide, and other conditions remained unchanged, yielding product (Ⅰb-2) in the same yield.

[0684] Example 289:

[0685] In Example 269, the condensing agent HATU in step 3 was replaced with CDI, and under nitrogen protection, with other conditions unchanged, the product (Ⅰb-2) was obtained in the same yield.

[0686] Example 290:

[0687] In Example 269, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with a methanol and water system. Under the same conditions, the product (Ⅰb-2) was obtained in the same yield.

[0688] Example 291:

[0689] In Example 269, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetone and water system. With other conditions unchanged, the product (Ⅰb-2) was obtained in the same yield.

[0690] Example 292:

[0691] In Example 269, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with hydrogen peroxide, and the solvent was replaced with an acetonitrile and water system. With other conditions unchanged, the product (Ⅰb-2) was obtained in the same yield.

[0692] Example 293:

[0693] In Example 269, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and other conditions remained unchanged, yielding product (Ⅰb-2) in the same yield.

[0694] Example 294:

[0695] In Example 269, the oxidant m-chloroperoxybenzoic acid in step 4 was replaced with ruthenium trichloride, and the solvent was replaced with 1,2-dichloroethane. Under the same conditions, the product (Ⅰb-2) was obtained in the same yield.

[0696] Example 295:

[0697] In Example 269, the solvent dichloromethane in step 4 was replaced with chloroform, and the other conditions remained unchanged, yielding product (Ⅰb-2) in the same yield.

[0698] Example 296:

[0699] In Example 269, the solvent dichloromethane in step 4 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged, yielding product (Ⅰb-2) in the same yield.

[0700] Example 297:

[0701] In Example 269, the solvent dichloromethane in step 4 was replaced with acetonitrile, and other conditions remained unchanged, yielding product (Ⅰb-2) in the same yield.

[0702] Example 298:

[0703] By replacing the solvent dichloromethane in step four of Example 269 with tetrahydrofuran, while keeping other conditions unchanged, product (Ⅰb-2) was obtained in a slightly lower yield.

[0704] The above examples are merely illustrative of the present invention and do not constitute a limitation on the scope of protection of the present invention. All designs that are the same as or similar to the present invention are within the scope of protection of the present invention.

Claims

1. A general method for generating axial chirality through a chiral consortium strategy, the features and concept of which are as follows: The substituents Rb and Rs are different. Rb and Rs substituents: functional groups that can participate in the formation of coordination bonds, hydrogen bonds, and other functional groups with specific functions. Chiral aromatic tertiary amines without nitrogen chiral centers can generate new aromatic tertiary amine nitrogen-oxygen (NO) chiral centers through intramolecular chiral oxidation. Due to the structural rigidity of chiral aromatic tertiary amine nitrogen-oxygen compounds, when the steric hindrance of different substituents Rb and Rs connected to the ortho position of the aromatic ring is large, their rotation is hindered, and new rotationally hindered axial chirality is generated simultaneously with the formation of the aromatic tertiary amine chiral nitrogen-oxygen center.

2. The general method for generating axial chirality through a chiral co-occurrence strategy as described in claim 1, by controlling the structural and functional properties of different substituent groups Rb and Rs, and through different combinations of groups Rb, Rs, and BG, can prepare various types of axial chiral ligands and chiral small molecule catalysts. Representatively, R... b and R s Different commonly used coordinating substituents or coordinating atoms, including but not limited to Steric hindered groups BG and chiral sources, including but not limited to In the formula, R* is a chiral source, Ar is one of the following: substituted or unsubstituted C6-C50 aryl, benzoaryl, fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 arylalkoxy, substituted or unsubstituted C7-C50 arylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amine, aromatic heterocyclic, etc., R, R a R c R d R f R p R q R u R v R 2a R 2b R 2c R 2u R 3a R 3b R 1 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens, hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing or... The group may be an electron-donating protecting group or any substituent; it may also be selected from substituted or unsubstituted C6-C50 aryl, benzoaryl, fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 aralkoxy, substituted or unsubstituted C7-C50 aralkyl mercapto, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amino, aromatic heterocyclic, benzoheterocyclic, fused heterocyclic.

3. A chiral aromatic tertiary amine nitrogen-oxygen ligand compound, characterized in that, Based on the method of claim 2, the substituent Rb or Rs can be widely selected from different types of ligands or combinations thereof, and can co-form bidentate or multidentate chiral ligands with chiral nitrogen oxides; the ligands include, but are not limited to: oxygen ligands, nitrogen ligands, sulfur ligands, double bond ligands, sulfoxide ligands, nitrile ligands, sulfonamides, phosphonamides, amide ligands, urea, thiourea, oxazoline ligands, imidazoline ligands, thiazoline ligands, pyrazoles, triazoles, tetrazolium, pyrazoline, pyrrole, indole, and other heterocyclic ligands.

4. The axially chiral aromatic tertiary amine nitroxide ligand compound as described in claims 2 and 3, characterized in that, Different types and functions of chiral compounds are obtained by combining different chiral nitrogen-oxygen sources with different ligands; the axial chiral aromatic tertiary amine nitrogen-oxygen ligand compounds include, but are not limited to: o-(p-methylbenzenesulfonamide)diphenyl(hydroxy)proline nitrogen-oxygen compounds, o-(methylsulfonamide)diphenyl(hydroxy)proline nitrogen-oxygen compounds, o-(p-nitrobenzenesulfonamide)diphenyl(hydroxy)proline nitrogen-oxygen compounds, o-(formonitrile)diphenyl(hydroxy)proline nitrogen-oxygen compounds, o-(benzaldehyde)diphenyl(hydroxy)proline nitrogen-oxygen compounds, o-(alkene)diphenyl(hydroxy)proline nitrogen-oxygen compounds, o-(ester)diphenyl(hydroxy)proline nitrogen-oxygen compounds, o-(amide)diphenyl(hydroxy)proline nitrogen-oxygen compounds, and o-(urea) compounds. Diphenyl(hydroxy)proline nitrogen oxides, o-(thiourea) diphenyl(hydroxy)proline nitrogen oxides, o-(oxazoline) diphenyl(hydroxy)proline nitrogen oxides, o-(imidazolium) diphenyl(hydroxy)proline nitrogen oxides, o-(benzimidazole) diphenyl(hydroxy)proline nitrogen oxides, o-(thiazole) diphenyl(hydroxy)proline nitrogen oxides, o-(benzothiazole) diphenyl(hydroxy)proline nitrogen oxides, o-(triazole) diphenyl(hydroxy)proline nitrogen oxides, o-(tetraazole) diphenyl(hydroxy)proline nitrogen oxides, o-(p-methylbenzenesulfonamide)(hydroxy)proline nitrogen oxides, o-(methylsulfonamide)(hydroxy)proline nitrogen oxides, o-(p-nitro) Benzenesulfonamide (hydroxy)proline nitrile compounds, o-(formonitrile)proline nitrile compounds, o-(benzaldehyde)proline nitrile compounds, o-(alkenes)proline nitrile compounds, o-(esters)proline nitrile compounds, o-(amides)proline nitrile compounds, o-(ureas)proline nitrile compounds, o-(thioureas)proline nitrile compounds, o-(oxazoline)proline nitrile compounds, o-(imidazolium)proline nitrile compounds, o-(benzimidazole)proline nitrile compounds, o-(thiazole)proline nitrile compounds, o-(benzothiazole)proline nitrile compounds, o-(benzothiazole)proline nitrile compounds Proline nitrile oxides, o-(triazole) proline nitrile oxides, o-(tetraazole) proline nitrile oxides, o-(p-methylbenzenesulfonamide) hydroxyproline nitrile oxides, o-(methylsulfonamide) hydroxyproline nitrile oxides, o-(p-nitrobenzenesulfonamide) hydroxyproline nitrile oxides, o-(formonitrile) hydroxyproline nitrile oxides, o-(benzaldehyde) hydroxyproline nitrile oxides, o-(alkenes) hydroxyproline nitrile oxides, o-(esters) hydroxyproline nitrile oxides, o-(amides) hydroxyproline nitrile oxides, o-(ureas) hydroxyproline nitrile oxides,o-(thiourea) (hydroxy)prolyl oxazoline nitrogen oxides, o-(oxazoline) (hydroxy)prolyl oxazoline nitrogen oxides, o-(imidazolium) (hydroxy)prolyl oxazoline nitrogen oxides, o-(benzimidazole) (hydroxy)prolyl oxazoline nitrogen oxides, o-(thiazole) (hydroxy)prolyl oxazoline nitrogen oxides, o-(benzothiazole) (hydroxy)prolyl oxazoline nitrogen oxides, o-(triazole) (hydroxy)prolyl oxazoline nitrogen oxides, o-(tetraazole) (hydroxy)prolyl oxazoline nitrogen oxides; The structure of the axially chiral aromatic tertiary amine nitrogen-oxygen ligand compound is shown below: In the formula, Y is selected from H and O; Z is selected from O and N; X 1 Selected from O, S; X 2 X 4 Selected from O, S; X 3 Selected from C, P; X 5 Selected from H, O, N; R c R d R f R 1 R 2 R 4 R 5 R 6 R 7a R 8a R 11 R 12 R 13 R 14 R 21 R 22 R 23 R 24 R 25 R 28a R 29a R 33 R 34 R 35 R 36 R 37 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens, hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing or... The group may be an electron-donating protecting group or any substituent; or selected from substituted or unsubstituted C6-C50 aryl, benzoaryl, fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 aralkoxy, substituted or unsubstituted C7-C50 aralkyl mercapto, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amino, any aromatic heterocyclic, benzoheterocyclic, fused heterocyclic.

5. The axially chiral aromatic tertiary amine nitroxide ligand compound as described in claim 4, characterized in that, It possesses the potential to serve as a small-molecule chiral catalyst and chiral ligand, capable of catalyzing various types of asymmetric reactions; the axially chiral aromatic tertiary amine nitrogen-oxygen ligand compounds include, but are not limited to: In the formula: Y 1 Selected from C, N; X 6 Selected from O, S, NR 14 ;R 2u R 2c R 3c R 5 R 6 R 7a R 8a R 14 R 36 R 37 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 Each group is independently selected from hydrogen atoms, C1-C30 alkyl groups, C1-C30 silyl groups, C1-C30 haloalkyl groups, C2-C30 alkenyl groups, C2-C30 alkynyl groups, halogens, hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, thioether groups, nitro groups, carbonyl groups, carboxyl groups, ester groups, amino and substituted amino groups, imino groups, cyano groups, amide groups, phosphonamide groups, sulfonamide groups, alkoxycarbonyl groups, aryloxycarbonyl groups, alkylamine carbonyl groups, arylamine carbonyl groups, and electron-withdrawing or... The group may be an electron-donating protecting group or any substituent; or selected from substituted or unsubstituted C6-C50 aryl, benzoaryl, fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 aralkoxy, substituted or unsubstituted C7-C50 aralkyl mercapto, substituted or unsubstituted C7-C50 aromatic heterocyclic, substituted or unsubstituted C7-C30 aromatic amino, any aromatic heterocyclic, benzoheterocyclic, fused heterocyclic.

6. A method for preparing an aromatic tertiary amine nitric oxide axis chiral ligand compound, which can be obtained through the following representative synthetic route:

7. The method for preparing the aromatic tertiary amine nitric oxide axial chiral ligand compound as described in claim 6, characterized in that, The specific reaction steps are as follows: (1) Using o-fluoronitrobenzene as the starting material, under the conditions of temperature T1, solvent S1, and base B1, it reacts with a chiral proline compound C1. N Ar2 reaction, followed by nitro reduction, forms the o-aryl chiral diamine compound shown in Formula II; The solvent S1 includes one or more of alcohols, halogenated hydrocarbons, and ether solvents; the base B1 includes one or more of inorganic bases and organic bases; the reaction temperature T1 is 25℃~100℃; (2) Under the action of temperature T4, solvent S4 and oxidant O1, the target aromatic tertiary amine nitric oxide axis chiral ligand compound shown in Formula I was obtained by selective nitrogen oxidation of the chiral tertiary amine. The oxidant O1 includes m-chloroperoxybenzoic acid, peracetic acid, carboxylic acid, hydrogen peroxide, and ruthenium trichloride; the solvent S4 includes one or more of halogenated hydrocarbons, ethers, and nitrile solvents; the reaction temperature T4 is -78℃ to 20℃.

8. The method for preparing the aromatic tertiary amine nitric oxide axial chiral ligand compound according to any one of claims 6 or 7, characterized in that, The synthetic route, since the key intermediate chiral tertiary amine can further form a chiral quaternary ammonium salt, can be used as a chiral phase transfer catalyst to catalyze different types of asymmetric reactions, and can also be used as a precursor or synthon for pharmaceuticals, pesticides or bioactive compounds.

9. The application of the axially chiral aromatic tertiary amine nitroxide ligand compound according to any one of claims 3-5, characterized in that, By regulating the structure and function of the aryl substituents adjacent to the nitrogen-oxygen chiral center, the nitrogen-oxygen (NO) coordinating atom of the axially chiral aromatic tertiary amine, together with the coordinating group Rs or Rb, acts as a bidentate or polydentate chiral ligand, catalyzing different types of asymmetric reactions with various central metals.

10. The application as described in claim 9, characterized in that, Due to the dipole properties of chiral nitrogen oxides, they exhibit significant nucleophilicity and Lewis basicity. Oxygen atoms can act as electron pair donors, forming molecular adducts or complexes with Lewis acidic compounds. They can be widely used as novel Lewis bases or small molecule chiral catalysts, chiral reverse phase transfer catalysts, etc., in the fields of asymmetric catalysis, chiral synthesis, chiral resolution, and chiral materials.

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