Diaryl n-oxide atropisomers and uses thereof

Abstract

The application provides a diaryl N-oxide atropisomer and use thereof, and belongs to the technical field of chemical medicines.The diaryl N-oxide atropisomer is a compound shown in formula I, a salt or a stereoisomer thereof.A new strategy for synthesizing a diaryl heteroaromatic N-oxide is developed by constructing a novel heteroaromatic N-oxide ring.The copper-catalyzed novel heteroaromatic N-oxide ring synthesis can efficiently construct various novel N-oxide skeletons, and high yield and excellent enantioselectivity are achieved.The compound synthesized by the application can be used as an efficient and recyclable Lewis base organic catalyst for asymmetric allylation of aldehydes;meanwhile, the compound synthesized by the application also has excellent antitumor effect.The application promotes the synthesis of novel structure heteroaromatic N-oxide, and lays a foundation for developing excellent heteroaromatic N-oxide.

Description

Technical Field

[0001] This invention belongs to the field of chemical and pharmaceutical technology, specifically relating to a diaryl N-oxide blocked spin isomer and its uses. Background Technology

[0002] Since its discovery in the early 1960s, the importance of heterocyclic N-oxides in pharmaceutical research has increased significantly. Initially recognized for its antihypertensive properties, minoxidil later saw breakthrough progress in the treatment of alopecia, a condition characterized by androgen miniaturization. This serendipitous discovery not only expanded the therapeutic scope of minoxidil but also revealed the immense potential of heterocyclic N-oxides in drug innovation.

[0003] The chemical structure of heterocyclic N-oxides plays a crucial role in enhancing the efficacy of drug molecules. They can act as mimics of nitric oxide (NO), NO donors, carbonyl biostabilizers, and hypoxia-selective cytotoxins. Each of these functions provides a unique pathway for contact with biological systems, exhibiting a variety of activities including anticancer, antibacterial, and neuroprotective effects. Furthermore, incorporating N-oxide properties into drug molecules may enhance their water solubility, reduce membrane permeability, and mitigate immunogenic responses. These properties are essential for effective drug design and delivery, highlighting the key role of heterocyclic aromatic N-oxides in shaping future drug therapies.

[0004] On the other hand, axially chiral heteroaromatic N-oxides, especially those with axially chiral diaryl frameworks, have become indispensable in organic synthesis. Their stable molecular structures and unique Lewis basicity enable them to effectively act as chiral organic catalysts and ligands. Quinoxa, bispyridine-N,N′-dioxide, Me2PINDOX, and bisquinoline-N,N′-dioxide are notable examples, used in various synthetic processes such as asymmetric allylation, aldehyde-ketone reactions, meso-epoxide ring-opening reactions, and cyanosilylation of aldehyde imines. These developments underscore the growing importance and role of chiral heteroaromatic N-oxides in contemporary chemistry.

[0005] The synthesis of axially chiral heteroaromatic N-oxides is an important research area that has attracted great attention from the scientific community. Despite its undeniable importance, this field still faces challenges, primarily because existing synthetic methods rely on chiral starting materials or complex resolution methods. This highlights the need for innovative strategies to simplify the synthesis of these compounds and potentially open new avenues for their practical applications. Currently, reported axially selective catalytic synthesis methods for heteroaromatic N-oxides are limited. In their earlier studies, You (DOI:10.1021 / cs500813z), Lin (DOI:10.1002 / chem.202203051), Tan (DOI:10.1038 / s41467-021-22621-2), and Miller (DOI:10.1021 / jacs.9b10414) explored kinetic resolution (KR) methods, including Pd(II)-catalyzed CH bond iodization, NHC-catalyzed acylation, and peptide-catalyzed N-oxidation. Notably, Matsubara (DOI:10.1021 / jacs.5b04151) developed a highly organocatalytic electrophilic bromination reaction in 2015 for the enantioselective synthesis of axially chiral isoquinoline N-oxides.

[0006]

[0007] Subsequently, Clayden (DOI:10.1002 / anie.201605486) reported a biocatalytic dynamic kinetic resolution (DKR) method for biarylisoquinoline-N-oxide treatment utilizing the bonding between N-oxides and aldehyde groups on adjacent aromatic rings. Building upon this, Wang's team (DOI:10.1007 / s11426-022-1402-9) developed an efficient DKR process via a chiral phosphoric acid-catalyzed cascade reaction.

[0008]

[0009] Unlike these KR and DKR strategies based on existing biaryl N-oxide skeletons, the Li (DOI:10.1002 / anie.202312923) and Niu (DOI:10.1021 / acscatal.3c04853) teams recently successfully and efficiently synthesized axially chiral N-oxides and constructed associated structures through asymmetric CH activation and cyclization reactions of heteroaromatic N-oxides.

[0010]

[0011] Despite these advances, the synthesis of racked isomers via de novo construction of heteroaromatic N-oxide rings remains challenging. While this promising approach could significantly expand the N-oxide skeleton, it is still largely unexplored. Summary of the Invention

[0012] The purpose of this invention is to provide a diaryl N-oxide blocked spin isomer and its uses.

[0013] This invention provides compounds of Formula I, their salts, or stereoisomers thereof:

[0014]

[0015] in,

[0016] The A ring is a substituted or unsubstituted 6-10 aryl group or a substituted or unsubstituted 5-10 heteroaryl group;

[0017] R 1 R 2 Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, halogens, and -NR. 4 R 5 -O(CH2) n OR 6 -OC(O)R 6 Or, R 1 and R 2 The linkage forms substituted or unsubstituted 4- to 10-membered cycloalkyl, substituted or unsubstituted 4- to 10-membered heterocycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl;

[0018] n is an integer from 1 to 6;

[0019] R 4 R 5 R 6 Each alkyl group is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0020] R 3 Selected from

[0021] R 7 R 8 R 9 Each is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted.

[0022] Substituted C1-C6 alkoxy groups, substituted or unsubstituted 4-10 membered cycloalkyl groups, substituted or unsubstituted 4-10 membered heterocycloalkyl groups, substituted or unsubstituted 6-10 membered aryl groups, and substituted or unsubstituted 5-10 membered heteroaryl groups;

[0023] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are independently selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted 6-10 aryl groups, halogens, and -NR groups. 10 R 11 ;

[0024] R 10 R 11 Each alkyl group is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0025] The alkyl and alkoxy substituents are independently selected from C1-C6 alkyl, C1-C6 alkoxy, and halogen, respectively.

[0026] Furthermore,

[0027] Ring A may be substituted or unsubstituted. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced

[0028] The The substituents are independently selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, halogens, and -NR groups. 10 R 11 ;

[0029] R 10 R 11 Each alkyl group is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0030] The alkyl and alkoxy substituents are independently selected from C1-C6 alkyl, C1-C6 alkoxy, and halogen, respectively.

[0031] Furthermore,

[0032] R 1 R 2 Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, halogens, and -O(CH2). n OR 6 -OC(O)R 6 Or, R 1 and R 2 Connect to form substituted or unsubstituted 4- to 6-membered cycloalkyl groups, or substituted or unsubstituted phenyl groups;

[0033] n is 1, 2, 3, 4, or 5;

[0034] R 6 Selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups;

[0035] The substituents of the cycloalkyl and phenyl groups are independently selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, phenyl groups, and halogens, respectively.

[0036] The alkyl and alkoxy substituents are independently selected from C1-C6 alkyl, C1-C6 alkoxy, and halogen, respectively;

[0037] And / or,

[0038] R 3 Selected from

[0039] R 7 R 8 R 9 Each is independently selected from substituted or unsubstituted C1-C4 alkyl or phenyl groups;

[0040] The substituents of the alkyl group are each independently selected from halogens.

[0041] Furthermore, the compound is as shown in Formula II:

[0042]

[0043] in,

[0044] R 1’ R 2’ R 3’ R 4’ Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, halogens, and -NR. 10 R 11 ;

[0045] R 10 R 11 Each alkyl group is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0046] R 1 R 2 Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, halogens, and -O(CH2). n OR 6 -OC(O)R 6 Or, R 1 and R 2 Connect to form substituted or unsubstituted 4- to 6-membered cycloalkyl groups, or substituted or unsubstituted phenyl groups;

[0047] n is 1, 2, 3, 4, or 5;

[0048] R 6 Selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups;

[0049] R 3 Selected from

[0050] R 7 R 8 R 9 Each is independently selected from substituted or unsubstituted C1-C4 alkyl or phenyl groups;

[0051] The substituents of the cycloalkyl and phenyl groups are independently selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, phenyl groups, and halogens, respectively.

[0052] The alkyl and alkoxy substituents are independently selected from C1-C6 alkyl, C1-C6 alkoxy, and halogen, respectively;

[0053] Alternatively, the compound may be of formula III:

[0054]

[0055] in,

[0056] Ring A may be substituted or unsubstituted. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced

[0057] The The substituents are independently selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, halogens, and -NR groups. 10 R 11 ;

[0058] R 10 R 11 Each alkyl group is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0059] R 5’ R 6’ R 7’ R 8’ Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, phenyl, and halogen;

[0060] R 3 Selected from

[0061] R 7 R 8 R 9 Each is independently selected from substituted or unsubstituted C1-C4 alkyl or phenyl groups;

[0062] The alkyl and alkoxy substituents are independently selected from C1-C6 alkyl, C1-C6 alkoxy, and halogen, respectively.

[0063] Furthermore, the compound is as shown in Formula IV:

[0064]

[0065] in,

[0066] R 1’ R 2’ R 3’ R 4’ Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, halogens, and -NR. 10 R 11 ;

[0067] R 10 R 11 Each alkyl group is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0068] R 3 Selected from

[0069] R 7 R 8 R 9 Each is independently selected from substituted or unsubstituted C1-C4 alkyl or phenyl groups;

[0070] The alkyl and alkoxy substituents are independently selected from C1-C6 alkyl, C1-C6 alkoxy, and halogen, respectively.

[0071] Furthermore, the compound is as shown in formula V:

[0072]

[0073] in,

[0074] R 3’ Selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, -NR 10 R 11 ;

[0075] R 10 R 11 Each alkyl group is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0076] The alkyl and alkoxy substituents are independently selected from C1-C6 alkyl, C1-C6 alkoxy, and halogen, respectively.

[0077] Furthermore, the compound is one of the following compounds:

[0078]

[0079]

[0080] The present invention also provides the use of the aforementioned compounds, their salts, or their stereoisomers in the preparation of Lewis base catalysts;

[0081] Preferably, the Lewis base catalyst is used for the asymmetric allylation reaction of aldehydes.

[0082] The present invention also provides the use of the aforementioned compounds, their salts or stereoisomers thereof in the preparation of antitumor drugs;

[0083] Preferably, the tumor is colon cancer, liver cancer, or breast cancer.

[0084] The present invention also provides an antitumor drug, which is prepared by using the aforementioned compound, its salt or its stereoisomer as the active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients.

[0085] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0086] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0087] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0088] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a ~C bAlkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C1 to C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, and C6 alkyl; "C1 to C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, and C6 alkoxy.

[0089] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group with 1 to 6 carbon atoms, that is, alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, etc.

[0090] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0091] "Cycloalkyl" refers to saturated or unsaturated all-carbon monocyclic or polycyclic (including fused, spiro, or bridged rings) that do not possess a conjugated π-electron system, such as, but not limited to:

[0092] wait.

[0093] "Heterocyclic alkyl" refers to a cycloalkyl group in which at least one carbon atom on the ring is replaced by a heteroatom, which is O, N, or S, and is a saturated or unsaturated monocyclic or polycyclic (including fused, spiro, or bridged rings) that does not have a conjugated π-electron system, such as including but not limited to:

[0094]

[0095] wait.

[0096] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused rings, spiro rings, or bridged rings) with a conjugated π-electron system, such as, but not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indene. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N, or S. Furthermore, the point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system, such as, but not limited to:

[0097] wait.

[0098] "Heteroaryl" refers to an aryl group in which at least one carbon atom on the ring of a conjugated π-electron system is replaced by a heteroatom, which is O, N, or S, such as including but not limited to thienyl, furanyl, isothiazolyl, etc.

[0099] This invention develops a novel strategy for the transisomerization synthesis of diaryl heteroaromatic N-oxides through the construction of novel heteroaromatic N-oxide rings. Copper-catalyzed synthesis of novel heteroaromatic N-oxide rings can efficiently construct a variety of novel N-oxide skeletons, achieving high yields and excellent enantioselectivity. The compounds synthesized in this invention can serve as efficient and recyclable Lewis base organocatalysts for the asymmetric allylation of aldehydes, with compound 3f showing the best performance. Furthermore, the compounds synthesized in this invention also exhibit excellent antitumor effects, with compound 3e showing the best performance. This invention advances the synthesis of novel heteroaromatic N-oxide structures and lays the foundation for the development of highly effective heteroaromatic N-oxides.

[0100] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0101] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0102] Figure 1 This study describes the application of compound 3f as a Lewis base catalyst in the asymmetric allylation reaction of aldehydes.

[0103] Figure 2 The results of the antitumor activity evaluation of the diaryl N-oxide of the present invention are as follows: a) IC50 value of the antitumor effect of diaryl N-oxide on tumor cells determined by MTT assay; b) Western blot experiment in MDA-MB-231 cells to evaluate the effect of the compound of the present invention on apoptosis-related proteins and tumor metastasis-related proteins, with GAPDH used as a load control, showing quantitative and representative images of the expression levels of related proteins; c) Colony formation assay to evaluate the effect of 3e on the proliferation of MDA-MB-231 and MDA-MB-468 cells; d) Cell scratch assay to evaluate the effect of 3e on M... Effects of DA-MB-231 and MDA-MB-468 cell migration, scale bar 400 μm; e is the quantitative result of Figure c; f is the quantitative result of Figure d; g is the result of 3e-induced apoptosis in MDA-MB-231 cells, scale bar 20 μm; data are expressed as mean ± SEM; these results are consistent with the results of at least three different experiments; compared with the control group (Con), ns, not significant, *, P<0.05, **, P<0.01, ***, P<0.001, ****, P<0.0001, statistical significance was determined relative to the appropriate control group. Detailed Implementation

[0104] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0105] Synthesis Route 1:

[0106]

[0107] Reaction conditions: 1 (0.1 mmol), Cu(CH3CN)4PF6 (5 mol%), and chiral ligand L12 (6 mol%) were dissolved in 1 mL of dry dichloromethane and reacted at room temperature under argon atmosphere for 24 hours. Product 3 was obtained after purification by silica gel column chromatography. The separation yield of the product was calculated. The enantiomer ratio (er) was determined by chiral high-performance liquid chromatography (HPLC). The molar amounts of Cu(CH3CN)4PF6 and chiral ligand L12 were 5 mol% and 6 mol%, respectively, based on a 1 mol amount.

[0108] Compounds 3a to 3s of this invention were synthesized using synthetic route 1:

[0109]

[0110]

[0111] Example 1: Preparation of compound 3a

[0112] Under argon atmosphere, Cu(CH3CN)4PF6 (1.9 mg, 5 mol%), L12 (3.2 mg, 6 mol%), and dry dichloromethane (0.4 mL) were added to a 10 mL Schlenk tube. The mixture was stirred at room temperature for 30 minutes. Subsequently, starting material 1a was added. (52.6 mg, 0.1 mmol) dissolved in dry dichloromethane (0.6 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 24 hours under TLC monitoring, and then purified directly by silica gel column chromatography (200-300 mesh) to give compound 3a.

[0113] Compound 3a was obtained in 52.2 mg, 99% yield, as a pale yellow solid with a melting point of 116.4–117.5 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.35min (major),t R =13.34min (minor); enantiomer ratio er = 95.5:4.5, specific curl [α] D 20= +306.667 (c = 0.12, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.95(s,1H),7.74–7.71(m,2H),7.69(d,J=7.8Hz,1H),7.68–7.65(m,3H),7.60– 7.55(m,3H),7.51(t,J=7.8Hz,2H),7.35–7.27(m,4H),7.26–7.22(m,5H),6.77(d,J=9.0Hz,1H),0.66(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.8,144.5,136.8,135.7,135.4,133.6,132.8,132.3,130.7,130.11,130.08,129.6,129.1,129.0, 128.8,128.6,128.3,128.01,127.97,127.3,127.2,126.7,124.5,124.2,124.0,120.4,118.2,26.1,19.2.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 35 H 32 NO2Si + 526.2197; Found 526.2193.

[0114] Example 2, Preparation of compound 3b

[0115] Synthesize 3b according to the method for compound 3a, using only starting material 1a. Replace with 1b

[0116] Compound 3b was obtained in 54 mg, 99% yield, as a pale yellow solid with a melting point of 107.8–109.7 °C; HPLC (Daicel chiral column IA, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.34min(major),t R =11.30 min (minor); enantiomer ratio er = 96.5:3.5, specific curl [α] D 20 = -87.333 (c = 0.15, ethyl acetate). 1H NMR(600MHz,DMSO-d6)δ8.71(s,1H),7.91–7.86(m,2H),7.70–7.65(m,3H),7.62(dd,J=8.4Hz,1.2Hz,2H),7.54–7.50(m,2H),7 .41(d,J=8.4Hz,1H),7.34–7.30(m,2H),7.30–7.26(m,2H),7.27-7.22(m,6H),6.82(d,J=9.0Hz,1H),3.82(s,3H),0.68(s,9H). 13 CNMR(150MHz,DMSO-d6)δ161.62(d,J CF =246.0Hz), 151.0,142.69,142.67,135.23(d,J CF =6.0Hz), 135.1,134.8,133.1,131.8,131.5,130.69(d,J CF =10.5Hz),130.30,130.27,130.1,129.98(d,J CF =9.0Hz),128.3,128.1,128.0,127.9,127.00(d,J CF =24.0Hz),125.2,124.0,119.4,118.3,118.3,118.2,107.79(d,J CF =22.5Hz), 25.5, 18.5. 19 F NMR(659MHz,DMSO-d6)δ-110.0.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 35 H 30 FNNaO2Si + 556.1923; Found 556.1930.

[0117] Example 3: Preparation of compound 3c

[0118] Synthesize 3c according to the method for compound 3a, using only starting material 1a. Replace with 1c

[0119] Compound 3c was given in 55.8 mg, 99% yield, as a pale yellow solid with a melting point of 118.5–119.9 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R=5.25min (major),t R =12.83min (minor); enantiomer ratio er = 95:5, specific curl [α] D 20 = +90.625 (c = 0.16, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.91(s,1H),7.68–7.65(m,5H),7.63(s,1H),7.58(d,J=1.2Hz,1H),7.57(d,J=1.8Hz, 1H),7.53–7.49(m,2H),7.35–7.30(m,2H),7.30–7.28(m,2H),7.27–7.23(m,5H),6.77(d,J=9.0Hz,1H),0.68(s,9H). 13 CNMR(150MHz,Chloroform-d)δ151.8,145.8,136.6,135.7,135.4,134.5,133.4,132.7,132.1,131.0,130.3,130.2,128. 4,128.04,128.01,127.9,127.3,126.3,126.0,125.6,124.1,123.9,120.4,117.7,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 35 H 30 ClNNaO2Si + 582.1627; Found 582.1632.

[0120] Example 4: Preparation of compound 3d

[0121] Synthesize 3d according to the method of compound 3a, using only starting material 1a. Replace with 1d

[0122] Compound 3d was obtained in 53.8 mg, 99% yield, as a pale yellow solid with a melting point of 120.6–122.1 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.96min(major),t R = 9.92 min (minor); enantiomer ratio er = 96:4, specific curl [α] D 20= +460.286 (c = 0.14, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.91(s,1H),7.69–7.61(m,5H),7.59(d,J=7.8Hz,2H),7.51–7.46(m,2H),7.41(d,J=8.4 Hz,1H),7.35–7.30(m,3H),7.28(t,J=6.6Hz,1H),7.26–7.21(m,5H),6.76(d,J=9.0Hz,1H),2.48(s,3H),0.67(s,9H). 13 CNMR(150MHz,Chloroform-d)δ151.8,144.3,139.1,136.7,135.7,135.4,133.6,132.9,132.3,131.5,130.7,130.09,130.06,129 .0,128.3,128.00,127.96,127.2,126.7,125.7,124.5,124.2,124.0,120.4,118.3,26.1,22.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd forC 36 H 33 NNaO2Si + 562.2173; Found 562.2165.

[0123] Example 5: Preparation of compound 3e

[0124] Synthesize 3e according to the method for compound 3a, using only starting material 1a. Replace with 1e

[0125] Compound 3e was obtained in 53.1 mg, 95% yield, as a pale yellow solid with a melting point of 193.6–194.5 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.00min(major),t R =12.10min (minor); enantiomer ratio er = 96.5:3.5, specific curl [α] D 20 = +76.714 (c = 0.14, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ8.87(s,1H),7.69–7.64(m,3H),7.63(d,J=9.0Hz,1H),7.61– 7.57(m,3H),7.50(d,J=9.0Hz,1H),7.35–7.30(m,3H),7.28(d,J=7.8Hz,1H),7.26–7.21(m 6H), 6.96 (d, J = 2.4Hz, 1H), 6.77 (d, J = 9.0Hz, 1H), 3.87 (s, 3H), 0.68 (s, 9H). 13 C NMR(150MHz,Chloroform-d)δ160.0,151.7,144.5,136.7,135.7,135.4,133.6,132.9,132.3,130.7,130.1,130.0,129.0,128.3,1 28.01,127.95,127.2,126.4,126.2,125.0,124.3,124.0,122.2,120.4,118.4,104.8,55.7,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 36 H 33 NNaO3Si + 578.2122; Found 578.2122.

[0126] Example 6: Preparation of compound 3f

[0127] Synthesize 3f according to the method for compound 3a, using only starting material 1a. Replace with 1f

[0128] Compound 3f was obtained in 32 mg, 56% yield, as a pale yellow solid with a melting point of 134.3–136.4 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.03min(major),t R =10.80 min (minor); enantiomer ratio er = 97:3, specific curl [α] D 20 = +136.000 (c = 0.13, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ8.79(s,1H),7.69(dd,J=7.8,1.2Hz,2H),7.65(d,J=8.4Hz,1H),7.62–7.58(m,3H),7.50–7.45(m,2H), 7.38(d,J=8.4Hz,1H),7.35–7.27(m,3H),7.28–7.19(m,6H),6.77(d,J=9.0Hz,1H),6.65(d,J=2.4Hz,1H),3.05(s,6H),0.70(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.6,150.2,143.8,136.7,135.8,135.5,133.7,133.1,132.4,131.4,130.4,130.03,139.99,129.0,12 8.2,128.0,127.9,127.0,126.0,125.3,124.5,123.9,122.1,120.5,118.9,118.4,103.8,40.5,26.1,19.3.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 37 H 36 N2NaO2Si + 591.2439; Found 491.2449.

[0129] Example 7: Preparation of 3g of compound

[0130] 3g was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1g

[0131] The compound was obtained as a pale yellow solid (3 g 54.1 mg, 99% yield) with a melting point of 207.8–209.7 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.26min(major),t R =24.98min (minor); enantiomer ratio er = 95.5:4.5, specific curl [α] D 20 = +137.067 (c = 0.14, ethyl acetate). 1H NMR(600MHz, DMSO-d6)δ9.20(s,1H),8.26(s,1H),8.09(dd,J=9.0,6.0Hz,1H),7.83(d,J=7.2Hz,1H),7.80(dd,J=9.6,2.4Hz,1H),7.74–7.6 9(m,3H),7.65(dd,J=7.8,1.8Hz,2H),7.57(td,J=9.0,3.0Hz,1H),7.50–7.43(m,2H),7.42–7.32(m,7H),6.69(d,J=9.0Hz,1H),0.66(s,9H). 13 C NMR(150MHz,DMSO-d6)δ161.62(d,J CF =246.0Hz),150.9,142.69,142.67,135.23(d,J CF =6.0Hz),134.8,133.1,131.8,131.5,130.69(d,J CF =10.5Hz),130.29,130.26,130.1,129.97(d,J CF =10.5Hz),128.3,128.1,128.0,127.9,127.00(d,J CF =24.0Hz),125.2,124.0,119.4,118.3,118.3,118.1,107.79(d,JCF=22.5Hz),25.5,18.5. 19 F NMR(659MHz,DMSO-d6)δ-109.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcdfor C 35 H 30 FNNaO2Si + 556.1923; Found 556.1931.

[0132] Example 8: Preparation of compound 3h

[0133] Synthesize compound 3a according to method 3h, using only starting material 1a. Replace with 1h

[0134] The compound was obtained as a pale yellow solid (56 mg, 99% yield) with a melting point of 198.9–201.9 °C. HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R=6.69min(major),t R =25.96 min (minor); enantiomer ratio er = 95:5, specific curl [α] D 20 = +117.077 (c = 0.13, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.85(s,1H),7.71–7.68(m,2H),7.68–7.65(m,3H),7.63(d,J=9Hz,1H),7.60–7.57(m,2H),7 .51(d,J=9.0Hz,1H),7.44(dd,J=9,1.8Hz,1H),7.40–7.29(m,4H),7.28-7.23(m,5H),6.77(d,J=9.0Hz,1H),0.67(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.8,145.0,135.8,135.7,135.4,135.2,133.4,132.7,132.1,130.9,130.3,130.15,130.12,129.4,1 29.0,128.4,128.3,128.27,128.03,127.3,127.1,126.8,124.1,124.0,123.0,120.4,117.7,26.0,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd forC 35 H 30 ClNNaO2Si + 582.1627; Found 582.1633.

[0135] Example 9: Preparation of compound 3i

[0136] Synthesize 3i according to the method for compound 3a, using only starting material 1a. Replace with 1i

[0137] Compound 3i was obtained in 52 mg, 96% yield, as a pale yellow solid with a melting point of 122.8–124.9 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.61min(major),t R =15.73 min (minor); enantiomer ratio er = 95:5, specific curl [α] D20 = -97.455 (c = 0.11, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.95(s,1H),7.74(td,J=8.4,1.8Hz,4H),7.68–7.64(m,3H),7.57(d,J=9.0Hz,2H ),7.44–7.37(m,4H),7.36(d,J=7.8Hz,1H),7.34–7.29(m,5H),6.84(d,J=9.0Hz,1H),2.58(s,3H),0.73(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.8,143.5,139.4,136.4,135.7,135.4,133.6,132.9,132.3,131.0,130.7,130.09,130.07,129.9,1 29.0,128.3,128.01,127.97,127.15,127.07,126.5,124.3,124.0,123.4,120.4,118.3,26.1,22.0,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 36 H 33 NNaO2Si + 562.2173; Found 562.2176.

[0138] Example 10: Preparation of Compound 3j

[0139] Synthesize 3j according to the method of compound 3a, using only starting material 1a. Replace with 1j

[0140] Compound 3j was obtained in 55.3 mg, 99% yield, as a pale yellow solid with a melting point of 133.5–135.9 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.19min(major),t R =35.40 min (minor); enantiomer ratio er = 95:5, specific curl is [α] D 20 = -37.500 (c = 0.12, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ8.87(s,1H),7.67(dd,J=8.4,1.8Hz,2H),7.65(d,J=9.0Hz,1H),7.62(s,1H),7.60–7.56(m,3H),7.49(d,J=9.0Hz,1H),7.3 5–7.30(m,3H),7.30–7.27(m,1H),7.27–7.22(m,5H),7.15(dd,J=8.4,2.4Hz ,1H),6.95(d,J=2.4Hz,1H),6.76(d,J=9.0Hz,1H),3.91(s,3H),0.67(s,9H). 13 C NMR (150MHz, Chloroform-d) δ160.0,151.8,142.0,135.9,135.7,135.4,133.7,132.9,132.3,131.2,130.6,130.09,130.06,129.0,128. 30,128.26,128.00,127.96,127.1,127.0,124.5,124.3,124.0,121.7,120.4,118.3,102.1,55.8,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 36 H 33 NNaO3Si + 578.2122; Found 578.2121.

[0141] Example 11, Preparation of compound 3k

[0142] Synthesize 3K according to the method for compound 3a, using only starting material 1a. Replace with 1k

[0143] Compound 3k was obtained in 43 mg, 76% yield, as a pale yellow solid with a melting point of 122.1–123.2 °C; HPLC (Daicel chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.42min(major),t R =11.87min (minor); enantiomer ratio er = 97.5:2.5, specific curl [α] D 20 = +61.267 (c = 0.3, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ8.78(s,1H),7.68(dd,J=8.4,1.8Hz,2H),7.64(d,J =7.8Hz,1H),7.60(dd,J=7.8,1.2Hz,2H),7.55–7.51(m,2H),7.47(d,J=9.0Hz,1H ),7.37(d,J=7.8Hz,1H),7.34–7.29(m,2H),7.28–7.21(m,6H),7.13(dd,J=9.0,2 .4Hz,1H),6.76(d,J=9.0Hz,1H),6.66(d,J=2.4Hz,1H),3.07(s,6H),0.69(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.8,150.2,139.7,135.8,135.5,135.4,133.9,133.0,132.4,131.5,130.3,130.03,130.00,129.0,12 8.2,128.0,127.9,127.5,127.0,126.8,124.5,123.9,122.0,120.5,118.8,118.2,101.4,40.6,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcdfor C 37 H 36 N2NaO2Si + 591.2439; Found 591.2438.

[0144] Example 12, Preparation of Compound 3l

[0145] 3l was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1l

[0146] Compound 31 (50.3 mg) was obtained in 92% yield as a pale yellow solid with a melting point of 114.3–115.8 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.80min(major),t R =7.72min (minor); enantiomer ratio er = 95.5:4.5, specific curl [α] D 20 = +61.267 (c = 0.3, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ9.12(s,1H),7.72(s,1H),7.68–7.64(m,3H),7.58(dd,J=7.8,1.2Hz,2H),7.51( d,J=9.0Hz,1H),7.48–7.40(m,2H),7.34–7.28(m,4H),7.27–7.19(m,6H),6.78(d,J=9.0Hz,1H),0.68(s,9H). 13 C NMR(150MHz,Chloroform-d)δ155.96(d,J CF =253.5Hz),151.8,145.8,135.7,135.4,133.4,132.7,132.1,131.2,131.2,130.9,130.2,130.1,129.7,129.7,129.0,128.59(d,J CF =7.5Hz),128.4,128.0,128.0,127.3,127.10(d,J CF =3.0Hz),124.1,124.0,122.48(d,J CF =3.0Hz), 120.51(d,J CF =16.5Hz),120.4,117.8,112.87(d,J CF =18.0Hz), 26.0, 19.2. 19 F NMR(565MHz,Chloroform-d)δ-121.8.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 35 H 30 FNNaO2Si + 566.1923; Found 566.1923.

[0147] Example 13, Preparation of compound 3m

[0148] Synthesize 3m according to the method for compound 3a, using only starting material 1a. Replace with 1m

[0149] The compound was obtained in 3m 46 mg, 78% yield, as a pale yellow solid with a melting point of 171.1–173.5 °C; HPLC (Daicel chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.34min(major),tR =17.80 min (minor); enantiomer ratio er = 96:4, specific curl [α] D 20 = +170.615 (c = 0.13, ethyl acetate). 1 H NMR(700MHz,Chloroform-d)δ8.83(s,1H),7.68(dd,J=7.7,1.4Hz,2H),7.66(d,J=8.4Hz,1H),7.59(dd,J=8.4,1.4Hz,2H),7.54(s,1H),7.49(d,J=8.4 Hz,1H),7.35–7.30(m,3H),7.30–7.27(m,1H),7.27–7.22(m,5H),6.95(d,J =20.3Hz,2H),6.77(d,J=9.1Hz,1H),4.00(s,3H),3.94(s,3H),0.69(s,9H). 13 C NMR(175MHz,Chloroform-d)δ152.1,151.9,151.7,142.3,135.7,135.6,135.4,133.6,133.0,132.3,130.6,130.1,130.0,129.0,128.3,1 28.0,127.9,127.1,125.83,125.78,125.5,124.4,124.0,120.4,118.5,105.1,102.8,56.4,56.3,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 37 H 35 NNaO4Si + 608.2228; Found 608.2225.

[0150] Example 14: Preparation of compound 3n

[0151] Synthesize 3n according to the method for compound 3a, using only starting material 1a. Replace with 1n

[0152] Compound 3n was obtained in 52 mg, 91% yield, as a pale yellow solid with a melting point of 180.2–182.9 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.68min(major),t R=16.72 min (minor); enantiomer ratio er = 95.5:4.5, specific curl [α] D 20 = +188.286 (c = 0.14, ethyl acetate). 1 H NMR (600MHz, Chloroform-d) δ8.78 (s, 1H), 7.70–7.64 (m, 3H), 7.60 (d, J = 6.6Hz, 2H), 7.52–7.47 (m, 2H), 7.35–7. 28(m,4H),7.28–7.23(m,5H),6.97(d,J=22.2Hz,2H),6.76(d,J=9.0Hz,1H),6.07(d,J=6.6Hz,2H),0.69(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.7,150.2,150.1,142.6,136.2,135.7,135.4,133.6,132.9,130.6,130.11,130.08,129.1,128.3,12 8.02,127.98,127.14,127.12,126.9,126.3,124.3,124.0,120.4,118.3,103.0,102.1,100.6,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 36 H 31 NNaO4Si + 592.1915; Found 592.1912.

[0153] Example 15, Preparation of Compound 3o

[0154] Synthesize 3o according to the method for compound 3a, using only starting material 1a. Replace with 1o

[0155] Compound 3o 26 mg was obtained in 40% yield as a pale yellow solid with a melting point of 235.7–237.2 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.37min(major),t R = 8.99 min (minor); enantiomer ratio er = 96.5:3.5, specific curl [α] D 20 = +215.333 (c = 0.12, ethyl acetate).1 H NMR (600MHz, Chloroform-d) δ8.97 (s, 1H), 8.49 (s, 1H), 8.29 (dd, J = 7.2, 2.4Hz, 1H), 7. 87(dd,J=6.6,1.8Hz,1H),7.83(d,J=9.0Hz,1H),7.69(d,J=7.8Hz,1H),7.66(dd,J=8.4, 1.8Hz,2H),7.62–7.58(m,4H),7.55(d,J=9.0Hz,1H),7.35(d,J=7.8Hz,1H),7.33–7.29( m,3H),7.28(dd,J=6,1.8Hz,1H),7.26–7.20(m,5H),6.83(d,J=9.0Hz,1H),0.64(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.9,144.7,137.5,135.7,135.4,133.4,132.9,132.7,132.3,130.9,130.8,130.11,130.08,129.2,129.1,128. 8,128.5,128.4,128.3,128.1,128.02,128.00,127.3,124.2,124.1,12 3.2,123.0,122.3,120.5,118.4,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 39 H 33 NNaO2Si + 598.2173; Found 598.2173.

[0156] Example 16: Preparation of compound 3p

[0157] 3p was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1p

[0158] Compound 3p was given in 22.6 mg, 42% yield, as a pale yellow solid with a melting point of 130.1–132.5 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.67min(major),t R =27.6 min (minor); enantiomer ratio er = 93:7, specific curl [α] D 20= +125.667 (c = 0.18, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.94(s,1H),7.68–7.64(m,4H),7.60–7.56(m,3H),7.50(d ,J=9.0Hz,1H),7.35–7.28(m,4H),7.27–7.22(m,6H),6.77(d,J=9.0Hz,1H),0.70(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.7,143.6,137.2,136.6,135.7,135.4,133.7,133.4,132.9,132.2,130.8,130.7,130.13,1 30.09,129.1,128.4,128.01,127.97,127.2,124.2,124.1,123.0,122.7,120.4,118.4,26.1,19.2.HRMS(ESI-TOF)m / z:[M+H] + Calcdfor C 33 H 30 NO2SSi + 532.1762; Found 532.1766.

[0159] Example 17, Preparation of compound 3q

[0160] 3q was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1q

[0161] Compound 3q was given in 24.8 mg, 48% yield, as a pale yellow solid with a melting point of 160.3–162.8 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.57min(major),t R =13.06 min (minor); enantiomer ratio er = 87:13, specific curl [α] D 20 = +149.667 (c = 0.12, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ8.79(s,1H),7.74(d,J=1.8Hz,1H),7.68(dd,J=7.8,1.2Hz,2H),7.65(d,J=7.8Hz,1H), 7.59(dd,J=7.8,1.2Hz,2H),7.50–7.47(m,2H),7.35–7.30(m,2H),7.30–7.23(m,7H),6.76–6.73(m,2H),0.71(s,9H). 13 CNMR(150MHz,Chloroform-d)δ152.3,151.6,149.0,143.0,135.7,135.4,133.4,132.9,132.1,130.6,130.13,130.10,129.1, 128.3,128.03,127.98,127.2,125.9,125.7,124.1,124.0,120.4,120.2,118.5,106.5,26.0,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 29 NNaO3Si + 538.1809; Found 538.1818.

[0162] Example 18, Preparation of compound 3r

[0163] 3r was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1r

[0164] Compound 3r was obtained in 36 mg, 68% yield, as a pale yellow solid with a melting point of 107.9–109.8 °C; HPLC (Daicel chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.52min(major),t R =23.37min (minor); enantiomer ratio er = 95:5, specific curl [α] D 20 = +203.167 (c = 0.12, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ9.10(s,1H),8.86(s,1H),8.60(d,J=5.4Hz,1H),7.80(s,1H),7.68(dd,J=8.4,1.8Hz,1H),7.56(dd,J=7.8,1.2Hz,2H ),7.65(dd,J=7.8,1.2Hz,2H),7.54(d,J=9.0Hz,1H),7.50(d,J=6Hz,1H), 7.40–7.27(m,4H),7.27–7.22(m,5H),6.79(d,J=9.0Hz,1H),0.67(s,9H). 13 C NMR(150MHz,Chloroform-d)δ152.0,150.9,147.0,146.2,135.6,135.43,135.36,135.3,133.3,132.5,132.2,132.0,131 .2,130.2,129.0,128.5,128.0,127.4,124.2,123.7,122.9,120.4,117.2,116.2,26.0,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 34 H 30 N2NaO2Si + 527.2150; Found 527.2151.

[0165] Example 19, Preparation of compound 3s

[0166] Synthesize 3S according to the method for compound 3a, using only starting material 1a. Replace with 1s

[0167] Compound 3s was given in 35.1 mg, 60% yield, as a yellow oil with a melting point of 209.1–212.0 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.10min(major),t R = 6.34 min (minor); enantiomer ratio er = 90.5:9.5, specific curl [α] D 20 = +169.222 (c = 0.18, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ8.71(s,1H),7.91–7.86(m,2H),7.70–7.65(m,3H),7.62(dd,J=8.4Hz,1.2Hz,2H),7.54–7.50(m,2H) ,7.41(d,J=8.4Hz,1H),7.34–7.30(m,2H),7.30–7.26(m,2H),7.27-7.22(m,6H),6.82(d,J=9.0Hz,1H),3.82(s,3H),0.68(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.8,143.1,138.4,138.3,135.8,135.5,133.7,133.0,132.5,130.5,130.04,130.01,129.2,128.3, 128.0,127.98,127.94,127.0,124.5,124.0,122.9,121.3,120.7,120.6,119.8,109.4,29.8,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 38 H 34 N2NaO2Si + 601.2282; Found 601.2287.

[0168] Synthesis Route 2:

[0169]

[0170] Reaction conditions: 1 (0.1 mmol), Cu(CH3CN)4PF6 (5 mol%), and chiral ligand L12 (6 mol%) were dissolved in 1 mL of dry dichloromethane and reacted at room temperature under argon atmosphere for 24 hours. The product 3t-3ae was obtained after purification by silica gel column chromatography, and the separation yield was calculated. The enantiomer ratio (er) was determined by chiral high-performance liquid chromatography (HPLC). The molar amounts of Cu(CH3CN)4PF6 and chiral ligand L12 were 5 mol% and 6 mol%, respectively, based on a 1 mol mole.

[0171] The compounds 3t~3z and 3aa~3ae of this invention were synthesized using synthetic route 2:

[0172]

[0173]

[0174] Example 20: Preparation of compound 3t

[0175] 3t was synthesized according to the method for compound 3a, using only the starting material 1a. Replace with 1t

[0176] Compound 3t 39 mg was obtained in 97% yield as a pale yellow solid with a melting point of 150.3–153.1 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =8.15min(major),t R =9.31 min (minor); enantiomer ratio er = 93:7, specific curl [α] D 20 = +74.500 (c = 0.2, ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ8.92(s,1H),7.81(d,J=9.0Hz,1H),7.78–7.72(m,2H),7.70(t,J=7.2Hz,2H),7.55(t,J =7.8Hz,1H),7.51(t,J=7.8Hz,1H),7.36–7.25(m,3H),7.13(d,J=9.0Hz,1H),0.62(s,9H),0.09(s,3H),-0.03(s,3H). 13 C NMR(150MHz,Chloroform-d)δ151.9,144.2,136.7,133.5,131.3,129.5,129.24,129.16,128.8,128.7,128.3,1 27.7,127.2,126.6,124.6,124.5,124.1,120.9,119.0,25.5,17.9,1.2,-4.1,-4.5.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 25 H 27 NNaO2Si + 424.1704; Found 424.1700.

[0177] Example 21: Preparation of compound 3u

[0178] 3u was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1u

[0179] Compound 3u was obtained in 40.2 mg, 90% yield, as a pale yellow solid with a melting point of 140.2–143.3 °C; HPLC (Daicel chiral column OD-H, n-hexane / isopropanol = 90:10, 1.0 mL / min, at 254 nm): t R =7.53min(major),t R =10.31min (minor); enantiomer ratio er = 92:8, specific curl [α] D 20 = +105.700 (c = 0.2, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.92(s,1H),7.79(dd,J=9.0,3.6Hz,1H),7.76–7.72(m,2H),7.70(t,J=7.8Hz,2H),7.54(t,J =7.2Hz,1H),7.50(t,J=7.2Hz,1H),7.30–7.23(m,3H),7.14(dd,J=9.0,3.6Hz,1H),1.14–1.07(m,3H),0.88–0.82(m,18H). 13 C NMR(150MHz,Chloroform-d)δ152.2,144.5,136.7,133.7,131.1,129.5,129.1,128.91,128.86,128.6,128 .3,127.4,127.2,126.5,124.5,124.3,123.9,120.2,118.0,17.95,17.91,13.0.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 28 H 34 NO2Si + 444.2354; Found444.2351.

[0180] Example 22, Preparation of compound 3v

[0181] 3V was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1v

[0182] Compound 3v was given in 31.4 mg, 52% yield, as a pale yellow solid with a melting point of 183.4–185.1 °C; HPLC (Daicel chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =7.62min(major),tR =14.09min (minor); enantiomer ratio er = 90:10, specific curl [α] D 20 = +302.00 (c = 0.12, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.97(s,1H),7.86(d,J=1.8Hz,1H),7.75(s,1H), 7.73(d,J=8.4Hz,1H),7.71(d,J=9.0Hz,1H),7.68–7.66(m,2H),7.61–7.59(m, 2H),7.58–7.54(m,5H),7.54–7.50(m,1H),7.41(d,J=8.4Hz,1H),7.38–7.32(m ,3H),7.32–7.30(m,1H),7.27–7.22(m,5H),6.80(d,J=9.0Hz,1H),0.67(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.9,144.3,141.2,136.9,136.8,135.7,135.4,132.82,132.76,132.2,131.0,130.13,130.11,129.6,129.3,129.2, 128.9,128.8,128.6,128.1,128.05,128.03,127.4,127.3,126.9,126.7, 126.3,124.8,124.6,120.9,118.1,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 41 H 35 NNaO2Si + 624.2330; Found 624.2336.

[0183] Example 23, Preparation of compound 3w

[0184] 3w was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1w

[0185] The compound was obtained in 3 w 46 mg, 76% yield, as a pale yellow solid with a melting point of 169.3–171.8 °C; HPLC (Daicel chiral column IA, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =7.21min(major),tR =21.49min (minor); enantiomer ratio er = 95:5, specific curl [α] D 20 = +200.133 (c = 0.15, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.94(s,1H),7.82(d,J=1.8Hz,1H),7.73(d,J=8.4Hz,1H),7.70(t,J=4.2Hz,2H),7.64(dd,J=8.4,1.8Hz,2H),7.60–7.56(m,3 H),7.54(td,J=8.4,1.2Hz,1H),7.41(d,J=9.0Hz,1H),7.36–7.30(m,3H),7.2 4(t,J=7.8Hz,4H),7.20(d,J=9.0Hz,1H),6.79(d,J=9.0Hz,1H),0.66(s,9H). 13 C NMR(150MHz,Chloroform-d)δ152.1,143.8,136.8,135.7,135.4,132.6,132.1,132.0,130.4,130.21,130.19,130.1,129.8, 129.7,129.3,128.8,128.1,128.0,127.4,126.7,126.1,124.6,121.5,118.5,117.8,26.0,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 35 H 30 BrNNaO2Si + 626.1122; Found 628.1113.

[0186] Example 24, Preparation of compound 3x

[0187] Synthesize 3x according to the method for compound 3a, using only starting material 1a. Replace with 1x

[0188] The compound was obtained in 3 x 48 mg fractions, 84% yield, as a pale yellow solid with a melting point of 238.0–241.9 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.96min(major),t R=21.26min (minor); enantiomer ratio er = 68:32, specific curl [α] D 20 = +77.920 (c = 0.25, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.96(s,1H),7.74–7.69(m,3H),7.66(dd,J=7.8,1.2Hz,2H),7.59–7.55(m,4H),7.52(t,J=8.4Hz,1H),7 .42(d,J=8.4Hz,1H),7.34–7.29(m,2H),7.26–7.21(m,4H),6.91(dd,J=9.0,2.4Hz,1H),6.63–6.59(m,2H),3.62(s,3H),0.65(s,9H). 13 C NMR(150MHz,Chloroform-d)δ158.8,152.5,144.8,136.8,135.7,135.4,135.0,132.9,132.3,130.4,130.1,130.06,130.05,129.6,12 9.1,128.9,128.6,128.0,127.9,127.2,126.7,124.6,124.6,117.9,117.4,116.3,103.1,55.4,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 36 H 33 NNaO3Si + 578.2122; Found 578.2116.

[0189] Example 25: Preparation of compound 3y

[0190] Synthesize 3y according to the method for compound 3a, using only starting material 1a. Replace with 1y

[0191] Compound 3y was given in 24.1 mg, 45% yield, as a pale yellow solid with a melting point of 115.3–117.5 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.23min(major),t R =7.54min (minor); enantiomer ratio er = 97.5:2.5, specific curl [α] D20 = +199.167 (c = 0.12, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ8.90(s,1H),7.67(d,J=8.4Hz,2H),7.62–7.58(m,3H) ,7.55(dd,J=7.8,1.8Hz,2H),7.52(dd,J=8.4,1.8Hz,1H),7.49(td,J=8.4,1.8Hz,1 H),7.33–7.28(m,2H),7.23(td,J=7.8,3.6Hz,4H),6.70(d,J=8.4Hz,1H),6.26(d,J =8.4Hz,1H),2.68–2.52(m,3H),2.42–2.34(m,1H),1.76–1.60(m,4H),0.59(s,9H). 13 C NMR(150MHz,Chloroform-d)δ151.2,145.6,137.8,136.6,135.7,135.4,133.1,132.4,130.8,129.91,129.90,129.8,129.4,129. 0,128.9,128.5,127.9,127.8,126.5,126.2,124.5,123.8,116.4,29.2,27.2,26.1,23.0,22.9,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd forC 35 H 35 NNaO2Si + 552.2330; Found 552.2332.

[0192] Example 26: Preparation of compound 3z

[0193] 3z was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1z

[0194] Compound 3z was obtained in 50 mg, 98% yield, as a pale yellow solid with a melting point of 122.1–124.8 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.55min(major),t R = 5.35 min (minor); enantiomer ratio er = 98.5:1.5, specific curl [α] D 20= +207.167 (c = 0.12, ethyl acetate). 1 H NMR(700MHz,Chloroform-d)δ8.87(s,1H),7.71(d,J=8.4Hz,1H),7.68(d,J=8.4Hz,1H),7.66(s,1H),7.62(dd,J=7.7,1.4Hz,2H),7.56–7.53(m,3H),7.52 –7.49(m,1H),7.36–7.30(m,2H),7.25(td,J=7.7,2.8Hz,4H),6.99(dd,J=8.4 ,1.4Hz,1H),6.90(t,J=8.4Hz,1H),6.39(dd,J=8.4,1.4Hz,1H),0.61(s,9H). 13 CNMR(175MHz,Chloroform-d)δ155.0,143.5,136.4,135.7,135.4,135.1,132.3,131.5,130.6,130.2,129 .6,129.3,128.6,128.0,126.8,126.6,124.6,124.4,122.1,117.6,25.9,19.1.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 31 H 28 ClNNaO2Si + 532.1471; Found 532.1472.

[0195] Example 27, Preparation of compound 3aa

[0196] 3aa was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1aa

[0197] Compound 3aa was obtained in 51 mg, 92% yield, as a pale yellow solid with a melting point of 136.1–139.0 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.59min(major),t R =5.56 min (minor); enantiomer ratio er = 99:1, specific curl [α] D 20 = +209.538 (c = 0.13, ethyl acetate). 1H NMR(700MHz,Chloroform-d)δ8.87(s,1H),7.72(d,J=8.4Hz,1H),7.69(d,J=7.7H z,1H),7.65(s,1H),7.62(dd,J=6.3,1.4Hz,2H),7.57–7.53(m,3H),7.51(td,J=7 .0,1.4Hz,1H),7.36–7.30(m,2H),7.25(td,J=7.7,2.1Hz,4H),7.16(dt,J=8.4,1 .4Hz,1H),6.84(td,J=8.4,1.4Hz,1H),6.42(dt,J=7.2,0.7Hz,1H),0.60(s,9H). 13 C NMR(175MHz,Chloroform-d)δ154.9,145.0,136.4,135.7,135.4,132.2,131.5,131.0,130.20,130.18,129.6,129.3, 128.7,128.6,128.03,128.01,126.8,126.4,126.4,125.2,124.8,124.6,118.2,25.9,19.1.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 31 H 29 BrNO2Si + 554.1146; Found 554.1138.

[0198] Example 28: Preparation of compound 3ab

[0199] Synthesize 3ab according to the method for compound 3a, using only starting material 1a. Replace with 1ab

[0200] Compound 3ab was obtained in 48 mg, 98% yield, as a pale yellow solid with a melting point of 212.9–215.3 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.01min(major),t R =5.10min (minor); enantiomer ratio er = 98:2, specific curl [α] D 20 = +91.625 (c = 0.16, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ8.89(s,1H),7.79–7.67(m,2H),7.63(s,1H),7.60(dd,J=8.4,1.2Hz,2H),7.57–7.52(m,3H),7.50(t,J=7.8Hz,1 H),7.34–7.28(m,2H),7.24(td,J=7.8,2.4,4H),6.88(t,J=7.8Hz,1H), 6.80(d,J=7.8Hz,1H),6.33(d,J=8.4Hz,1H),2.13(s,3H),0.60(s,9H). 13 C NMR(150MHz,Chloroform-d)δ153.6,145.4,139.3,136.5,135.7,135.4,132.9,132.1,130.0,129.8,129.4,129. 0,128.9,128.6,127.91,127.89,126.6,126.2,124.5,122.7,116.6,26.0,19.9,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcdfor C 32 H 31 NNaO2Si + 512.2017; Found 512.2016

[0201] Example 29: Preparation of compound 3ac

[0202] 3ac was synthesized according to the method for compound 3a, using only starting material 1a. Replace with 1ac

[0203] Compound 3ac was obtained in 48 mg, 95% yield, as a pale yellow solid with a melting point of 170.3–173.1 °C; HPLC (Daicel chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.39min(major),t R = 6.56 min (minor); enantiomer ratio er = 97:3, specific curl [α] D 20 = +238.500 (c = 0.12, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ8.88(s,1H),7.69–7.65(m,2H),7.65–7.61(m,3H),7.56(dd,J=7.8,1.2Hz,2H),7.51(t,J=7.2Hz,1H),7.48(t,J=7. 2Hz,1H),7.34–7.29(m,2H),7.24(t,J=7.2Hz,4H),6.94(t,J=7.8Hz,1H) ,6.51(d,J=8.4Hz,1H),6.13(d,J=8.4Hz,1H),3.69(s,3H),0.62(s,9H). 13 C NMR(150MHz,Chloroform-d)δ158.9,154.7,143.1,136.5,135.7,135.44,135.39,132.9,132.1,130.5,130.0,129.4,128 .9,128.8,128.4,127.90,127.88,126.9,126.6,124.6,113.7,112.2,104.0,56.1,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 31 NNaO3Si + 528.1966; Found 528.1969.

[0204] Example 30: Preparation of compound 3ad

[0205] 3ad was synthesized according to the method for compound 3a, with only 1a being used. Replace with 1ad

[0206] Compound 3ad was obtained in 53.2 mg, 99% yield, as a pale yellow solid with a melting point of 232.3–233.8 °C; HPLC (Daicel chiral column IA, n-hexane / isopropanol = 90:10, 1.0 mL / min, at 254 nm): t R =16.06min(major),t R =17.54 min (minor); enantiomer ratio er = 97:3, specific curl [α] D 20 = +91.857 (c = 0.14, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ8.84(s,1H),7.68–7.63(m,3H),7.63–7.60(m,2H),7 .57–7.54(m,2H),7.53–7.49(m,1H),7.48–7.45(m,1H),7.34–7.28(m,2H),7.24(t, J=7.8Hz, 4H), 6.91 (t, J=8.4Hz, 1H), 6.72 (dd, J=8.4, 0.6Hz, 1H), 6.18 (dd, J=8.4, 0.6Hz,1H),5.14(d,J=6.6Hz,1H),4.94(d,J=6.6Hz,1H),3.29(s,3H),0.63(s,9H). 13 C NMR(150MHz,Chloroform-d)δ156.7,154.6,143.1,136.2,135.7,135.4,132.8,132.1,130.5,130.0,129.5,128.8,1 28.7,128.3,127.89,127.88,126.7,126.6,124.4,113.2,107.7,95.0,56.3,26.1,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 33 NNaO4Si + 558.2072; Found 558.2080.

[0207] Example 31: Preparation of compound 3ae

[0208] Synthesize 3ae according to the method for compound 3a, using only 1a Replace with 1ae

[0209] Compound 3ae was obtained in 32.3 mg, 60% yield, as a pale yellow solid with a melting point of 115.3–118.6 °C; HPLC (Daicel chiral column AD-H, hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.45min (major),t R =11.33min (minor); enantiomer ratio er = 90.5:9.5, specific curl [α] D 20 = -388.769 (c = 0.13, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ8.88(s,1H),7.69(dd,J=7.8,3.0Hz,2H),7.65–7.60(m,3H),7.58–7.54(m,3H),7.51(t,J=8.4Hz,1H),7.32(dd,J=1 6.8,7.2Hz,2H),7.25(q,J=7.8Hz,4H),7.00(t,J=8.4Hz,1H),6.72(dd,J=8.4,1.2Hz,1H),6.38(dd,J=8.4,0.6Hz,1H),1.94(s,3H),0.62(s,9H). 13 C NMR(150MHz,Chloroform-d)δ169.7,154.8,150.1,141.8,136.5,135.7,135.4,132.3,131.7,130.4,130.2,130.1,129.5,1 29.3,128.8,128.6,128.01,127.98,126.8,126.5,124.6,118.4,116.9,115.3,26.0,20.9,19.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 31 NNaO4Si + 556.1915; Found 556.1923

[0210] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0211] Experimental Example 1: Study on the use of the compound of the present invention as a Lewis base catalyst

[0212] Applications of compound 3f as a Lewis base catalyst in the asymmetric allylation reaction of aldehydes, such as... Figure 1 As shown, the synthesis route 3 is as follows:

[0213]

[0214] Compounds 7a to 7c were synthesized using synthetic route 3:

[0215] (1) Preparation of compound 7a

[0216] In an argon atmosphere, 6a 0.2 mmol), 3f (22.8 mg, 20 mol%), N-ethyldiisopropylamine (73.9 mg, 0.2 mmol), tetrabutylammonium iodide (31.1 mg, 0.24 mmol), allyltrichlorosilane (42.3 mg, 0.24 mmol), and acetonitrile (2.0 mL) were sequentially added to a 25 mL Schlenk tube. The reaction mixture was stirred at -40 °C for 48 h, followed by warming to room temperature. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (2.0 mL), and the aqueous layer was extracted with dichloromethane (3 × 3.0 mL). The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was purified directly by silica gel column chromatography (petroleum ether:ethyl acetate = 40:1 to 20:1) to obtain product 7a.

[0217] The product 7a was obtained as 29.4 mg, 74% yield, a pale yellow oil; HPLC (Daicel chiral column OD-H, n-hexane / isopropanol = 95:5, 0.5 mL / min, at 254 nm): t R =30.50min (major), t R =33.94min (minor); enantiomer ratio er = 91:9, specific curl [α] D 20 = +92.375 (c = 0.16, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ7.78–7.71(m,4H),7.43–7.36(m,3H),5.79–5.70(m,1H),5.10(dd,J=17.4, 1.8Hz,1H),5.07(dd,J=10.2,1.8Hz,1H),4.82(t,J=6.6Hz,1H),2.57–2.46(m,2H),2.12(d,J=2.4Hz,1H). 13 C NMR(150MHz,Chloroform-d)δ141.4,134.5,133.4,133.1,128.3,128.1,127.8,126.3,126.0,124.6,124.1,118.7,73.5,43.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 14 H 14 NaO + 221.0937.;Found 221.0946.

[0218] (2) Preparation of compound 7b

[0219] Synthesize 7b according to the method for compound 7a, using only starting material 6a. Replace with 6b

[0220] The product 7b was obtained as 17.8 mg, 60% yield, a pale yellow oil; HPLC (Daicel chiral column OD-H, n-hexane / isopropanol = 99:1, 0.8 mL / min, at 254 nm): t R =15.86min (major), t R =17.85min (minor); enantiomer ratio er = 85.5:14.5, specific curl [α] D 20 = +101.200 (c = 0.18, ethyl acetate). 1 H NMR (600MHz, Chloroform-d) δ7.28–7.16(m,5H),5.78–5.68(m,1H),5.12–5.04(m,2H),4.70–4.60(m,1H),2.49–2.38(m,2H),2.02(s,1H). 13 C NMR(150MHz,Chloroform-d)δ144.0,134.6,128.5,127.7,125.9,118.6,73.4,44.0.HRMS(ESI-TOF)m / z:[M+H] + Calcd forC 10 H 13 O + 149.0961.;Found 149.0963.

[0221] (3) Preparation of compound 7c

[0222] 7c was synthesized according to the method for compound 7a, using only the starting material 6a. Replace with 6c

[0223] The product obtained was 7c 20.8 mg, 58% yield, a pale yellow oil; HPLC (Daicel chiral column OD-H, n-hexane / isopropanol = 95:5, 0.8 mL / min, at 254 nm): t R =12.66min(major),t R =14.49 min (minor); enantiomer ratio er = 88.5:11.5, specific curl [α] D 20 = +53.108 (c = 0.14, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ7.23–7.19(m,2H),6.83–6.79(m,2H),5.77–5.68(m,1H), 5.11–5.03(m,2H),4.61(t,J=6.6Hz,1H),3.73(s,3H),2.45–2.40(m,2H),1.93(s,1H). 13 C NMR(150MHz,Chloroform-d)δ159.2,136.2,134.8,127.2,118.4,113.9,73.1,55.4,43.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 11 H 14 NaO2 201.0886. Found 201.0888.

[0224] Methods for recovering and reusing compound 3f as a catalyst:

[0225] In an argon atmosphere, 6a 0.2 mmol), 3f (22.8 mg, 20 mol%), N-ethyldiisopropylamine (73.9 mg, 0.2 mmol), tetrabutylammonium iodide (31.1 mg, 0.24 mmol), allyltrichlorosilane (42.3 mg, 0.24 mmol), and acetonitrile (2.0 mL) were sequentially added to a 25 mL Schlenk tube. The reaction mixture was stirred at -40 °C for 48 h, followed by warming to room temperature. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (2.0 mL), and the aqueous layer was extracted with dichloromethane (3 × 3.0 mL). The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was purified directly by silica gel column chromatography (petroleum ether:ethyl acetate = 40:1 to 20:1) to obtain product 7a, and catalyst 3f was purified by silica gel column chromatography and recovered for use in a second cycle, which was repeated three times.

[0226] The above experiments show that isoquinoline N-oxide 3f with a 6-dimethylamino group has been proven to be a highly efficient Lewis base organic catalyst for the asymmetric allylation reaction of aldehydes. Figure 1 In acetonitrile, using 3f as a catalyst, the reaction of different aldehydes (6a-6c) with propenyltrichlorosilane immediately yielded good yields and enantiomeric ratios of up to 91:9.

[0227] Due to the excellent structural and configurational stability of the catalyst, this invention attempts to recover and reuse it in the allylation reaction. It was found that catalyst 3f, after two rounds of recovery and reuse, could continue to catalyze the reaction efficiently, generating compound 7a in 63% yield with an er value of 90.5:9.5. The recovered catalyst consistently maintained a high enantiomeric ratio (er value). This result highlights the potential of the novel framework as a recoverable and highly stereoselective Lewis base catalyst.

[0228] Experimental Example 2: Biological Evaluation of the Compounds of the Invention

[0229] Cell culture: The HCT116, HepG2, RKO, MDA-MB-231, MCF-7 and MDA-MB-468 cells used in this invention were obtained from the American Type Culture Collection (ATCC, Manassas, Virginia, USA) and cultured in Gibco™ Duchenne Modified Culture Medium (DMEM) with 10% fetal bovine serum (FBS) in an incubator maintained at 37°C and 95% air and 5% CO2.

[0230] Antibodies: MTT assay kits were purchased from Solarbio (M8180). Mitochondrial membrane potential and apoptosis assay kits (C1071S, Beyotime) and crystal violet staining solution (C0121, Beyotime) were purchased from Beyotime (Shanghai, China). The following antibodies were used in this study: GAPDH (ab8245, Abcam), Bcl-2 (ER0602, HuaBio), LC3 (ab192890, Abcam), MMP2 (ab92536, Abcam), N-cadherin (22018-1-AP, Proreintech), P62 (ab109012, Abcam), and Caspase-3 (TA6311, Abmart).

[0231] Cytotoxicity test

[0232] Cells were loaded at 5 × 10 3Cells were seeded at density in 96-well plates and cultured in a cell culture incubator for 24 hours before drug treatment. The compound concentrations used were 100, 50, 25, 12.5, 6.25, 3.12, and 1.56 μM. After 24 hours of compound treatment, 0.5 mg / mL MTT was added to each well, and the cells were incubated at 37°C for 4 hours. The culture medium was then removed, and dimethyl sulfoxide (DMSO) was added to dissolve the toluidine salt crystals in each well, followed by incubation at 37°C for 10 minutes. Finally, the absorbance of the dye-forming cells was measured at 490 nm using a microplate reader (BioTek, USA). The inhibition rate was calculated as 1 - (average absorbance of the treated group / average absorbance of the control group) × 100%, and the IC50 value of the compound against each tumor cell type was calculated.

[0233] WB test

[0234] (1) Sample preparation: MDA-MB-231 cells were seeded in 6 wells and cultured overnight. When the cell density reached about 70%, the cells were treated. The groups were: control group (no drug treatment, Con) and experimental group (compound treatment). After 24 hours of compound treatment, the culture medium was discarded and the cells were gently rinsed 3 times with PBS. All subsequent experimental operations were performed on ice. First, 100-200 μL of RIPA lysis buffer containing a mixture of protease inhibitors was added to each well. After lysis on ice for 5 minutes, the cells were scraped off with a cell scraper and collected in a 1.5 mL centrifuge tube. After lysis on ice for another 15 minutes, the cells were centrifuged at 12,000 rpm for 15 minutes at 4 °C. The supernatant was collected and the concentration was detected by BCA protein concentration assay kit. Protein samples were prepared with 30-50 μg of total protein and denatured by loading buffer and metal bath (95 °C, 5 minutes) to obtain protein samples suitable for WB experiments.

[0235] (2) Polyacrylamide gel electrophoresis (SDS-PAGE): Prepare sufficient electrophoresis buffer in advance, assemble the pre-cast gel in the electrophoresis tank, and electrophoresis for 60 minutes at 140V. Carefully cut the gel, measure the size of the cut gel piece, cut a PVDF membrane of appropriate size, and activate it with methanol for about 2 minutes. Flatten the PVDF membrane and gel with a sponge pad and filter paper, and place them in the transfer tank according to the electrode order. Add transfer buffer, set the voltage to 106V, and set the corresponding transfer time according to the molecular weight of the target protein. Prepare blocking buffer in advance, completely immerse the PVDF membrane in the blocking buffer, and block at room temperature for 2-4 hours. Wash the PVDF membrane 2-3 times with 1×TBST at room temperature, 10-15 minutes each time. Incubate with primary antibody overnight at 4℃. After incubating the PVDF membrane with primary antibody, wash it 3 times with 1×TBST at room temperature, 10-15 minutes each time. Incubate the secondary antibody at room temperature for 1-2 hours, then wash the membrane 2-3 times with 1×TBST, 10-15 minutes each time. Prepare the developing working solution by mixing luminescent reagent A and luminescent reagent B at a 1:1 volume ratio. After washing the PVDF membrane, place it in a clean cell culture dish, add the developing working solution, place the dish in an ECL gel imaging system, and expose and develop the PVDF membrane using chemiluminescence software.

[0236] Clonal Formation and Cell Migration Experiments

[0237] (1) For the clonogenic assay, 1000 cells (MDA-MB-231 or MDA-MB-468 cells) were seeded in 6-well plates and cultured in an incubator for 24 hours. Then, the cells were treated with different concentrations of compound 3e for two consecutive weeks. After treatment, the culture medium was removed, and the wells were washed three times with PBS. Then, 1 mL of methanol was added to each well for fixation for 15 minutes, after which the methanol was discarded, and the cells were washed three more times with PBS. Finally, the cells were stained with crystal violet solution.

[0238] (2) Cell scratch assay: When the cell density (MDA-MB-231 cells or MDA-MB-468 cells) in the 96-well plate is 90-100%, scratches are made using a Woundmaker Tool (Sartorius, 4563). Each well is then gently washed 1-2 times with PBS to remove detached cells. Next, drug treatment is performed, with groups set as follows: control group (no drug treatment, Con) and experimental group (compound treatment). Finally, the 96-well plate is placed in... In the Live-Cell Analysis instrument, images were taken to record cell migration in each well, with the image taking time set to 0 or 12 hours.

[0239] Perform scratch healing assays to determine cell migration ability; use Live cell analysis was performed. In short, once the cells in the 96-well plate reached 90-100% filling, scratches were generated using a 96-well Woundmaker Tool (Sartorius, 4563), the cells were then processed, and images were taken every 4 hours. Figure 2 d, the first row represents the cell migration status at 0 hours, that is, before migration has started; the second row represents the cell migration status at 12 hours.

[0240] Mitochondrial membrane potential and apoptosis detection: This experiment used the Mitochondrial Membrane Potential and Apoptosis Detection Kit (Catalog No.: C1071) manufactured by Shanghai Beyotime Biotechnology Co., Ltd. MDA-MB-231 cells were seeded in laser confocal microscopy dishes and cultured overnight. When the cell density reached 60-70%, the cells were treated with the drug. Groups were set as follows: control group (no drug treatment, Con) and experimental group (compound treatment). Cells were collected after 12 hours. First, the cell culture medium was aspirated, and the cells were washed once with PBS. Then, 188 μL of Annexin V-FITC binding solution and 5 μL of Annexin V-FITC were added and gently mixed. 2 μL of Mito-Tracker Red CMXRos staining solution and 5 μL of Hoechst 33342 staining solution were added and gently mixed. The cells were incubated at room temperature (20-25℃) in the dark for 20-30 minutes, and then placed in an ice bath. Aluminum foil can be used for light protection. Subsequently, under a fluorescence microscope, Mito-Tracker Red CMXRos showed red fluorescence, Annexin V-FITC showed green fluorescence, and Hoechst33342 showed blue fluorescence.

[0241] result

[0242] First, the antitumor efficacy of the compounds of this invention was evaluated using the MTT (methylthiazoline diphenyltetrazol bromide) assay. Figure 2 a) The compounds of the present invention exhibit significant antitumor activity against various tumor types, with the methoxy-substituted isoquinoline N-oxide 3e showing the best effect, with IC50 values ​​of 4.8 μM and 5.2 μM in triple-negative breast cancer cells MDA-MB-231 and MDA-MB-468, respectively.

[0243] Programmed cell death in tumor cells is a common mechanism employed by antitumor drugs. To gain a deeper understanding of the potential mechanisms underlying the antitumor effects of these heteroaromatic N-oxides, this invention performed Western blot (WB) experiments to detect the expression of key proteins involved in apoptosis (Caspase-3, BCL-2), autophagy (LC3, P62), and tumor metastasis (N-cadherin, MMP2) in MDA-MB-231 and MDA-MB-468 cells. The results showed ( Figure 2 (b) Among these compounds, 3e in particular significantly enhanced apoptosis and autophagy while inhibiting tumor metastasis. Therefore, 3e was chosen to further verify its antitumor activity.

[0244] Subsequently, this invention evaluated the anti-proliferative capacity of compound 3e against tumors through cloning experiments. Figure 2 (c and 2e), which significantly inhibited tumor proliferation in both cell lines in a dose-dependent manner. Furthermore, cell scratch assays showed that N-oxide 3e possessed significant anti-metastatic properties. Figure 2 d and 2f).

[0245] Mitochondrial membrane potential and phosphatidylserine eversion are key indicators of apoptosis. Therefore, this invention used a mitochondrial membrane potential kit to assess the ability of 3e to induce apoptosis in tumor cells. Live cells were labeled with Mito-Tracker RedCMXRos, a red fluorescent probe dependent on mitochondrial membrane potential, resulting in red fluorescently positive cells. Apoptotic cells were stained with Annexin V-FITC green fluorescent probe, showing green fluorescent positivity and a significant reduction or disappearance of red fluorescence signal. This invention found that 3e effectively promoted apoptosis, consistent with Western blot analysis results. Figure 2 g). These findings indicate that this series of heteroaromatic N-oxides possesses significant antitumor activity, with 3e showing particular promise for development as a therapeutic agent for breast cancer.

[0246] In summary, this invention develops a novel strategy for the transisomerization synthesis of diaryl heteroaromatic N-oxides through the construction of novel heteroaromatic N-oxide rings. Copper-catalyzed synthesis of novel heteroaromatic N-oxide rings can efficiently construct a variety of novel N-oxide skeletons, achieving high yields and excellent enantioselectivity. The compounds synthesized in this invention can serve as efficient and recyclable Lewis base organocatalysts for the asymmetric allylation of aldehydes, with compound 3f being the most effective. Furthermore, the compounds synthesized in this invention also exhibit excellent antitumor effects, with compound 3e being the most effective. This invention advances the synthesis of novel heteroaromatic N-oxide structures and lays the foundation for the development of highly effective heteroaromatic N-oxides.

Claims

1. The compound shown in Formula I or its salt: Formula I in, Ring A may be substituted or unsubstituted. Replaced or not replaced ; The , The substituents are independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and -NR groups. 10 R 11 ; R 10 R 11 Each is independently selected from hydrogen and C1-C6 alkyl groups; R 1 R 2 Each of the following is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, and -O(CH2). n OR 6 -OC(O)R 6 Or, R 1 and R 2 The linkage forms substituted or unsubstituted phenyl groups; n is 1, 2, 3, 4, or 5; R 6 Selected from hydrogen and C1-C6 alkyl groups; The substituents of the phenyl group are selected from C1-C6 alkyl, C1-C6 alkoxy, phenyl, and halogen. R 3 Selected from ; R 7 R 9 Selected from phenyl; R 8 Selected from C1~C4 alkyl groups.

2. The compound or its salt according to claim 1, characterized in that: The compound is shown in Formula II: Formula II in, R 1’ R 2’ R 3’ R 4’ Each of the following is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, and -NR. 10 R 11 ; R 10 R 11 Each is independently selected from hydrogen and C1-C6 alkyl groups; R 1 R 2 Each of the following is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, and -O(CH2). n OR 6 -OC(O)R 6 Or, R 1 and R 2 The linkage forms substituted or unsubstituted phenyl groups; n is 1, 2, 3, 4, or 5; R 6 Selected from hydrogen and C1-C6 alkyl groups; The substituents of the phenyl group are selected from C1-C6 alkyl, C1-C6 alkoxy, phenyl, and halogen. R 3 Selected from ; R 7 R 9 Selected from phenyl; R 8 Selected from C1~C4 alkyl groups; Alternatively, the compound may be of formula III: Formula III in, Ring A may be substituted or unsubstituted. Replaced or not replaced ; The , The substituents are independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and -NR groups. 10 R 11 ; R 10 R 11 Each is independently selected from hydrogen and C1-C6 alkyl groups; R 5’ R 6’ R 7’ R 8’ Each of the following is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, phenyl, and halogen; R 3 Selected from ; R 7 R 9 Selected from phenyl; R 8 Selected from C1~C4 alkyl groups.

3. The compound or its salt according to claim 1, characterized in that: The compound is shown in Formula IV: Formula IV in, R 1’ R 2’ R 3’ R 4’ Each of the following is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, and -NR. 10 R 11 ; R 10 R 11 Each is independently selected from hydrogen and C1-C6 alkyl groups; R 3 Selected from ; R 7 R 9 Each is independently selected from phenyl; R 8 Selected from C1~C4 alkyl groups.

4. The compound or its salt according to claim 3, characterized in that: The compound is shown in formula V: Formula V in, R 3’ Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -NR 10 R 11 ; R 10 R 11 Each is independently selected from hydrogen and C1~C6 alkyl groups.

5. A compound or a salt thereof, characterized in that: The compound is one of the following compounds: 。 6. The use of a compound or a salt thereof in the preparation of Lewis base catalysts; characterized in that: The compound is .

7. The use according to claim 6, characterized in that: The Lewis base catalyst is used for the asymmetric allylation reaction of aldehydes.

8. Use of the compound or salt thereof according to any one of claims 1 to 5 in the preparation of an antitumor drug; The tumors mentioned are colon cancer, liver cancer, and breast cancer.

9. An antitumor drug, characterized in that: It is prepared using the compound or its salt as the active ingredient as described in any one of claims 1 to 5, plus pharmaceutically acceptable excipients.

Images