A method for synthesizing chiral eight-membered ring ether compounds

Abstract

This invention provides a method for synthesizing chiral eight-membered ring ether compounds. The method comprises the following steps: in dichloromethane, under the catalysis of a gold catalyst system, an alkynylcyclopropanone compound I and an o-methylenebenzoquinone compound II react to obtain a chiral eight-membered ring ether compound III; the gold catalyst system consists of a gold catalyst AuCl (SMe2), a chiral ligand, and lithium tetrafluoroborate (LiBF4), wherein the chiral ligand has the structure shown in Formula IV. This invention synthesizes chiral eight-membered ring ether compounds via a gold-catalyzed asymmetric cycloaddition reaction, offering advantages such as convenient and simple operation, high yield, readily available and inexpensive reactants, low catalyst cost, wide substrate applicability, good diastereoselectivity, and high trigonometric selectivity.

Description

Technical Field

[0001] This invention relates to a method for synthesizing chiral eight-membered ring ether compounds, belonging to the field of organic synthesis technology. Background Technology

[0002] Chiral eight-membered ring ethers are widely found in bioactive natural products and drug molecules. For example, the sesquiterpene compound Heliannuol A exhibits significant antiviral activity, the carbazole alkaloid Cyclomahanimbine demonstrates good anti-hyperlipidemic activity, and Protosappanin A possesses anti-inflammatory activity. The synthesis of these compounds is challenging due to unfavorable enthalpy, entropy, and transcyclic interactions. Furthermore, these molecules often contain multiple chiral centers, posing significant challenges to their stereoselective construction. Common strategies for constructing eight-membered ring ethers include Michael addition, Claisen rearrangement, ring expansion reactions, and transition metal-catalyzed intramolecular cyclization reactions; however, most methods only produce racemic products. Therefore, developing a concise, efficient, and highly stereoselective method for synthesizing eight-membered ring ethers is of great importance. In recent decades, transition metal-catalyzed dipolar ion cycloaddition methods have emerged, enabling the generation of multiple carbon-carbon or carbon-heteroatom bonds in a single step. These methods offer high atom economy and step economy, and have become a common approach for constructing various cyclic compounds. In the process of chiral control, multiple chiral centers can be controlled in one step by binding chiral ligands with transition metals.

[0003] Kinetic resolution, which can convert racemic compounds into highly optically active chiral molecules, is an efficient and widely used asymmetric synthetic strategy. However, the low resolution efficiency or narrow substrate applicability of kinetic resolution processes has significantly hampered its development and application. In the past few decades, with the rapid development of chiral catalysts and ligands, kinetic resolution strategies have been widely applied in asymmetric catalysis, leading to the acquisition of chiral compounds with excellent optical purity. Combining the advantages of kinetic resolution and dipolar cycloaddition, dipolar cycloaddition reactions under kinetic resolution have seen some development (Chin. J. Org. Chem. 2022, 42, 3322-3334). In 2012, Zhang Junliang's research group reported a gold-catalyzed asymmetric [4+3] cycloaddition reaction of 2-(1-ynyl)-2-alkyl-1-one with nitrone, synthesizing a seven-membered heterocycle with moderate enantioselectivity, and simultaneously achieving the kinetic resolution of racemic 1-(1-ynyl)cyclopropylone (Chem. Commun., 2012, 48, 4710-4712). However, there have been no reports on obtaining chiral eight-membered oxygen heterocyclic compounds via gold-catalyzed [4+4] cycloaddition reactions.

[0004] The core structure of ortho-quinone methides is based on cyclohexadiene, with a carbonyl group and an exocyclic olefin unit at the ortho position. The carbonyl group highly polarizes this structure, and their resonance structure can be represented as an aromatic zwitterion, where oxygen is negatively charged and benzyl carbon is positively charged. Due to the special nature of the structure, it has a strong tendency to aromatize, which leads to its excellent electrophilicity and easy nucleophilic addition reaction. Over the past century, ortho-quinone methides have demonstrated rich chemical properties in the field of asymmetric catalysis and have been widely used in the construction of natural product skeletons and the synthesis of drug molecules. In previous work, our group has completed the palladium-catalyzed asymmetric [4+4] cycloaddition reaction of ortho-quinone methides with γ-methylene-δ-valerolactone (Org. Chem. Front., 2022, 9, 3493-3498). Building on this work, we envision using 1-(1-alkynyl)cyclopropyl ketone in Au (Ⅰ) Under the action of [a process], a 1,4-dipolar ion is generated as a quaternary synthon, which then undergoes a [4+4] cycloaddition reaction with ortho-quinone methides under kinetic resolution. This achieves the asymmetric and efficient construction of a furan-fused benzoxoxane eight-membered skeleton, providing a scientific basis for the development of new drug candidates for the treatment of multiple myeloma and is of great significance for the treatment of multiple myeloma patients. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for synthesizing chiral eight-membered ring ether compounds. This invention utilizes a simple gold catalyst and chiral ligands as the catalyst system, and uses alkynylcyclopropionates and o-methylenebenzoquinones as raw materials to carry out gold-catalyzed asymmetric cycloaddition reactions and kinetic resolution, achieving efficient asymmetric synthesis of chiral eight-membered ring ethers.

[0006] Terminology Explanation:

[0007] Room temperature: as is known in the art, refers to 25±5℃.

[0008] The technical solution adopted in this invention is as follows:

[0009] A method for synthesizing chiral eight-membered ring ether compounds includes the following steps:

[0010] In dichloromethane, under the catalysis of a gold catalytic system, alkynylcyclopropionate compound I and o-methylenebenzoquinone compound II react to obtain chiral eight-membered ring ether compound III; the gold catalytic system consists of gold catalyst AuCl (SMe2), chiral ligands and lithium tetrafluoroborate (LiBF4), wherein the chiral ligands have the structure shown in Formula IV.

[0011]

[0012] In the compound of formula I, R1 is a phenyl or a substituted phenyl, wherein the substituent of the substituted phenyl is selected from halogens; R2 is selected from substituted or unsubstituted aryl groups, wherein the substituent of the substituted aryl group is selected from halogens or C1-C3 alkyl groups; and R3 is a methyl, phenyl, or halogen-substituted phenyl.

[0013] In the structural formula of compound II, R4 is a substituted phenyl or a substituted styrene group, wherein the substituent of the substituted phenyl group is methoxy, ethoxy, or 2,4-dimethoxy, and the substituent of the substituted styrene group is methoxy or ethoxy, and the substituent is attached to the benzene ring of the substituted styrene group;

[0014] In the structural formula of compound III, substituents R1, R2, and R3 are the same as those in the structural formula of compound I; substituent R4 is the same as those in the structural formula of compound II.

[0015] According to a preferred embodiment of the present invention, in the compound of formula I, R1 is phenyl or 4-chlorophenyl, R2 is phenyl, 4-fluorophenyl, 4-methylphenyl or 3-bromophenyl, and R3 is p-fluorophenyl.

[0016] According to a preferred embodiment of the present invention, the volume ratio of the dichloromethane to the molar ratio of the alkynylcyclopropionate compound I is 3–10 mL: 1 mmol; the dichloromethane is anhydrous.

[0017] According to a preferred embodiment of the present invention, the molar ratio of the gold catalyst AuCl(SMe2) to the alkynylcyclopropanone compound I is 0.01 to 0.03:1; the molar ratio of the gold catalyst AuCl(SMe2) to the chiral ligand is 1:2 to 2.2; and the molar ratio of the gold catalyst AuCl(SMe2) to lithium tetrafluoroborate (LiBF4) is 1:3 to 3.3.

[0018] According to the present invention, the preparation method of the chiral ligand is prior art and can be prepared with reference to Chinese patent document CN103570600A.

[0019] According to a preferred embodiment of the present invention, the molar ratio of the alkynylcycloacetone compound I and the o-methylenebenzoquinone compound II is 1:0.5 to 0.8.

[0020] According to a preferred embodiment of the present invention, the reaction system of the alkynylcycloacetone compound I and the o-methylbenzoquinone compound II further includes... Molecular sieve; the The ratio of the mass of the molecular sieve to the molar number of alkynylcyclopropionate compound I is 1–3 g: 1 mmol.

[0021] According to a preferred embodiment of the present invention, the reaction is carried out under the protection of a protective gas, wherein the protective gas is nitrogen or argon.

[0022] According to a preferred embodiment of the present invention, the reaction temperature is 10–30°C, more preferably 25°C; the reaction time is 2–48 h, more preferably 12–24 h; the reaction process is monitored by HPLC, and the reaction ends when the ee value of the chiral raw material alkynylcycloacetone compound obtained in the system is >80%.

[0023] According to the present invention, after the reaction of alkynylcycloacetone compound I and o-methylenebenzoquinone compound II, the products can be separated and characterized by conventional separation and purification methods; preferably, the specific post-reaction processing steps are as follows: the solvent is removed from the reaction solution, and the crude product is separated by silica gel column chromatography to obtain chiral eight-membered ring ether compound III, the eluent being a mixed solvent of ethyl acetate and petroleum ether, wherein the volume ratio of ethyl acetate to petroleum ether in the mixed solvent is 0.02 to 0.2:1.

[0024] According to a preferred embodiment of the present invention, the steps include the following:

[0025] Under a protective gas atmosphere, AuCl(SMe2), chiral ligands, lithium tetrafluoroborate (LiBF4), and dichloromethane were added to a dry reaction flask. After stirring for 15–20 min, the mixture was filtered. The resulting filtrate was then added to a container containing alkynylcycloacetone compound I, o-methylenebenzoquinone compound II, and... The reaction was carried out in a molecular sieve reaction flask; after the reaction was completed, the solvent was removed, and the crude product was separated by silica gel column chromatography to obtain chiral eight-membered ring ether compound III.

[0026] A chiral eight-membered ring ether compound was prepared by the above method, and its structural formula is shown in Formula III below:

[0027]

[0028] According to the present invention, the above-mentioned chiral eight-membered ring ether compounds are used in the preparation of drugs for treating multiple myeloma.

[0029] According to the present invention, the alkynylcycloacetone compound I is obtained from α,β-unsaturated ketones as starting materials by a known method (see: Chem. Eur. J. 2009, 15, 8975-8978.), and the reaction route is as follows:

[0030]

[0031] In the above formula, the substituents R1, R2, and R3 are as described above.

[0032] According to the present invention, the o-methylenebenzoquinone compounds II are all synthesized from the corresponding aryl formaldehydes by known methods (see references: An, XT; Du, JY; Jia, ZL; Zhang, Q.; Yu, KY; Zhang, YZ; Zhao, XH; Fang, R.; Fan, CAChem. Eur. J. 2020, 26, 3803-3809.), and the reaction route is shown in the following formula:

[0033]

[0034] In the above formula, the substituent R 4 As stated above.

[0035] The technical features and beneficial effects of this invention are as follows:

[0036] This invention provides a method for synthesizing chiral eight-membered ring ether compounds. The method of this invention has the following advantages: (1) It uses a simple gold catalyst and a chiral ligand as the catalytic system, which has the advantages of low catalyst cost, high efficiency and low catalyst dosage; (2) It has high reaction yield, good diastereoselectivity (all dr>20:1) and high enantioselectivity (up to 99% ee); (3) The reaction raw materials are inexpensive and readily available, have good atom economy and a wide range of substrate applications; (4) The reaction conditions are mild and the operation is convenient and simple; (5) The chiral eight-membered ring ether compounds obtained by this invention have excellent inhibitory effects on peripheral blood B lymphocytes of multiple myeloma, providing a scientific basis for the development of new candidate drugs for the treatment of multiple myeloma, and are of great significance for the treatment of multiple myeloma patients. Attached Figure Description

[0037] Figure 1 The graph shows the inhibitory effect of the compounds synthesized in Examples 1-8 of Application Example 1 on peripheral blood B lymphocytes (RPMI8226) cells of multiple myeloma.

[0038] Figure 2 To illustrate the inhibition rate and concentration-inhibition rate curves of different concentrations of compound IIIba against peripheral blood B lymphocytes (RPMI8226) in multiple myeloma, as described in Example 2.

[0039] Figure 3 To illustrate the inhibition rate and concentration-inhibition rate curves of different concentrations of compound IIIca against peripheral blood B lymphocytes (RPMI8226) in multiple myeloma, as described in Example 3.

[0040] Figure 4 To illustrate the inhibition rate and concentration-inhibition rate curves of different concentrations of compound IIIcb in Example 4 against peripheral blood B lymphocytes (RPMI8226) from multiple myeloma. Detailed Implementation

[0041] The present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited thereto.

[0042] Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods; unless otherwise specified, the reagents and raw materials can be obtained commercially or prepared according to known methods.

[0043] The solvent used in the examples was treated with anhydrous solvents, and the treatment method is existing technology.

[0044] The yield described in the examples is molar yield.

[0045] Example 1

[0046] Synthesis of (5S,12S)-12-(4-methoxyphenyl)-3-methyl-1,5-diphenyl-4,5-dihydro-12H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]furan[3,4-e]oxooctane (Ⅲaa)

[0047] The reaction route is as follows:

[0048]

[0049] The operation steps are as follows:

[0050] Under nitrogen protection, AuCl(SMe2) (4.0 μmol, 1.2 mg), chiral ligand IV (8.0 μmol, 5.3 mg), LiBF4 (12 μmol, 1.1 mg), and 1.0 mL of dichloromethane were added to a dry 5 mL reaction flask. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a container containing substrate Ia (0.2 mmol, 52.0 mg), substrate IIa (0.13 mmol, 33.3 mg), and 300 mg of [unspecified substance]. The reaction was carried out in a molecular sieve reaction flask and stirred at 25°C. HPLC analysis was performed, and the reaction was stopped when the enantioselectivity of the chiral raw material Ia′ in the system was greater than 80%. The reaction lasted for 24 hours. The solvent was then removed by vacuum concentration, and the crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIaa (39 mg, 38% yield).

[0051] The characterization data of the obtained product (Ⅲaa) are as follows:

[0052] White solid, mp = 186-187℃; 39mg, 38% yield; 90% ee; [Daicel Chiralpak IC-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=254nm, t(major)=7.3min, t(minor)=6.3min];

[0053] 1 H NMR (400MHz, CDCl3) δ2.18 (s, 3H), 2.66 (dd, J=4.2, 15.7Hz, 1H), 2.77 (dd, J=1 0.4,15.7Hz,1H),3.77(s,3H),5.13(dd,J=4.1,10.3Hz,1H),5.44(s,1H),5.91 (d,J=1.4Hz,1H),5.92(d,J=1.4Hz,1H),6.30(s,1H),6.72-6.83(m,3H),7.05 (d,J=8.4Hz,2H),7.16-7.26(m,3H),7.27-7.36(m,5H),7.45(d,J=7.4Hz,2H);

[0054] 13 C NMR (100MHz, CDCl3) δ11.9,30.3,45.7,55.3,82.8,101.4,105.8,111.3,113.6,117.4,121.2,126.5,126.8 ,127.1,127.3,127.8,128.3,128.4,128.5,131.5,137.3,142.2,143.8,146.8,147.8,148.6,150.8,157.8;

[0055] HRMS(ESI)m / z calcd for C 34 H 28 O5[M+H]+ :517.2010,found:517.1996.

[0056] The characterization data of the obtained chiral starting material alkynylcyclopropanone (Ⅰa′) are as follows:

[0057] 1-((1S,2R)-2-phenyl-1-(phenylethynyl)cyclopropyl)ethane-1-one (Ⅰa′)

[0058] Yellow oil, 21 mg, 39% yield; 97% ee; [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min-1, λ=254nm, t(major)=6.6min, t(minor)=6.3min];

[0059] 1 H NMR (400MHz, CDCl3) δ1.87 (dd, J=8.0, 4.2Hz, 1H), 2.22 (dd, J=9.1, 4.3Hz, 1H), 2.60 (s ,3H),3.07(t,J=8.5Hz,1H),6.90-6.97(m,2H),7.10-7.15(m,2H),7.27-7.43(m,5H);

[0060] 13 C NMR (100MHz, CDCl3) δ26.5,29.7,33.4,39.2,84.4,87.4,123.0,127.3,128.0,128.1,128.3,128.7,131.4,135.9,205.0;

[0061] HRMS(ESI)m / z calcd for C 19 H 16 O[M+H] + :261.1279,found:261.1281.

[0062] Example 2

[0063] Synthesis of (5S,12S)-1-(4-fluorophenyl)-12-(4-methoxyphenyl)-3-methyl-5-phenyl-4,5-dihydro-12H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]furan[3,4-e]oxooctane (Ⅲba)

[0064] The reaction route is as follows:

[0065]

[0066] The operation steps are as follows:

[0067] Under nitrogen protection, AuCl(SMe2) (4.0 μmol, 1.2 mg), chiral ligand IV (8.0 μmol, 5.3 mg), LiBF4 (12 μmol, 1 mg), and 1.0 mL of dichloromethane were added to a dry 5 mL reaction flask. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a container containing substrate Ib (0.2 mmol, 55.6 mg), substrate IIa (0.13 mmol, 33.3 mg), and 300 mg of [unspecified substance]. The reaction was carried out in a molecular sieve reaction flask and stirred at 25°C. HPLC analysis was performed, and the reaction was stopped when the enantioselectivity of the chiral raw material Ib′ in the system was greater than 80%. The reaction lasted for 24 hours. The solvent was then removed by vacuum concentration, and the crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIba (33 mg, 31% yield).

[0068] The characterization data of the obtained product (Ⅲba) are as follows:

[0069] White solid, mp = 90-91℃; 33mg, 31% yield; 86% ee; [Daicel Chiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=254nm, t(major)=8.2min, t(minor)=7.8min];

[0070] 1 H NMR (400MHz, CDCl3) δ2.16 (s, 3H), 2.67 (dd, J = 4.2, 15.7Hz, 1H), 2.76 (dd, J = 10.0 ,15.7Hz,1H),3.77(s,3H),5.12(dd,J=4.2,10.0Hz,1H),5.35(s,1H),5.92(d,J= 1.4Hz,1H),5.93(d,J=1.5Hz,1H),6.29(s,1H),6.72(s,1H),6.78(d,J=8.7Hz,2H ),6.97-7.09(m,4H),7.21(d,J=7.1Hz,2H),7.26-7.35(m,3H),7.37-7.44(m,2H);

[0071] 13C NMR (100MHz, CDCl3) δ11.9,30.1,45.8,55.3,82.9,101.5,105.8,111.1,113.6,115.5(d,J=21.6Hz),117.3,121.1,126.5,127.3,127.7 (d,J=3.2Hz),127.8,128.4,128.5,128.6(d,J=8.0Hz),137.1,142.0,143.9,146.8,147.6,147.7,150.7,157.8,162.0(d,J=247.0Hz);

[0072] HRMS(ESI)m / z calcd for C 34 H 27 FO5[M+H] + :535.1915,found:535.1915.

[0073] The characterization data of the obtained chiral starting material alkynylcyclopropanone (Ⅰb′) are as follows:

[0074] ((1S,2R)-1-((4-fluorophenyl)ethynyl)-2-phenylcyclopropyl)methyl ketone (Ⅰb′)

[0075] Yellow oil, 27.7 mg, 37% yield; 97% ee; [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=254nm, t(major)=7.5min, t(minor)=6.9min];

[0076] 1 H NMR (400MHz, CDCl3) δ1.96 (dd, J=7.9, 4.8Hz, 1H), 2.50 (dd, J=9.1, 4.7Hz, 1H), 3.02 (t, J=8.5Hz, 1H),6.86(t,J=8.7Hz,2H),6.95(dd,J=8.6,5.6Hz,2H),7.31-7.45(m,7H),8.01(d,J=8.6Hz,2H);

[0077] 13C NMR (100MHz, CDCl3) δ23.7, 32.0, 38.3, 84.1, 87.5, 115.5 (d, J = 22.1Hz), 118.9 (d, J = 3.5Hz), 127.6, 128.2, 128.4, 128.7, 130.7, 133.1 (d, J = 8.4Hz), 135.1, 135.6, 139.1, 162.3 (d, J = 249.3Hz), 195.5;

[0078] HRMS(ESI)m / z calcd.for C 19 H 15 FO[M+H] + :279.1185,found:279.1189.

[0079] Example 3

[0080] Synthesis of (5S,12S)-3-(4-fluorophenyl)-12-(4-methoxyphenyl)-1,5-diphenyl-4,5-dihydro-12H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]furan[3,4-e]oxooctane (Ⅲca)

[0081] The reaction route is as follows:

[0082]

[0083] The operation steps are as follows:

[0084] Under nitrogen protection, AuCl(SMe2) (4.0 μmol, 1.2 mg), chiral ligand IV (8.0 μmol, 5.3 mg), LiBF4 (12 μmol, 1.1 mg), and 1.0 mL of dichloromethane were added to a dry 5 mL reaction flask. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a container containing substrate Ic (0.2 mmol, 68 mg), substrate IIa (0.13 mmol, 33.3 mg), and 300 mg of [unspecified substance]. The reaction was carried out in a molecular sieve reaction flask and stirred at 25°C. The reaction was stopped when the enantioselectivity of the chiral raw material Ic′ in the system was greater than 80% by HPLC detection, and the reaction lasted for 12 hours. The solvent was then removed by vacuum concentration, and the crude product was purified by silica gel column chromatography (eluent EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIca (43 mg, 36% yield).

[0085] The characterization data of the obtained product (Ⅲca) are as follows:

[0086] White solid, mp = 198-199℃; 43mg, 36% yield; 97% ee; [Daicel Chiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=254nm, t(major)=8.9min, t(minor)=8.0min];

[0087] 1 H NMR (400MHz, CDCl3) δ2.83 (dd, J=15.9, 4.3Hz, 1H), 3.08 (dd, J=16.0, 11.3Hz, 1H) ,3.79(s,3H),5.25(dd,J=11.2,4.2Hz,1H),5.56(s,1H),5.95(s,1H),5.97(s,1H) ,6.41(s,1H),6.81-6.84(m,3H),7.02-7.08(m,2H),7.09-7.13(m,4H),7.25-7.35 (m,4H),7.41(t,J=7.6Hz,2H),7.51(dd,J=8.6,5.5Hz,2H),7.55(d,J=7.4Hz,2H);

[0088] 13 C NMR (100MHz, CDCl3) δ33.1,45.6,55.4,82.8,101.6,105.3,111.7,113.8, 115.6(d,J=21.6Hz),119.2,122.0,125.2,126.1,127.4,127.5(d,J=3.0H z),127.8(d,J=13.0Hz),128.1,128.3,128.4,128.5,128.6,131.0,137.0 ,142.2,143.8,146.9,148.6,150.7,152.4,158.0,162.0(d,J=247.5Hz);

[0089] HRMS(ESI)m / z calcd for C 39 H 29 FO5[M+H] + :597.2072found:597.2075.

[0090] The characterization data of the obtained chiral starting material alkynylcyclopropanone (Ⅰc′) are as follows:

[0091] (4-Fluorophenyl)((1R,2S))-2-phenyl-1-(phenylethynyl)cyclopropyl)methyl ketone (Ⅰc′):

[0092] Yellow oily liquid, 24 mg, 35% yield; 95% ee. [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=254nm, t(major)=7.5min, t(minor)=7.0min];

[0093] 1 H NMR(400MHz, CDCl3)1.96(dd,J=7.9,4.7Hz,1H),2.51(dd,J=9.1,4.7Hz,1H),3.01(t,J=8.5Hz,1H),6.99( d,J=5.8Hz,2H),7.10(t,J=8.7Hz,2H),7.15-7.22(m,3H),7.30-7.45(m,5H),8.12(dd,J=8.7,5.6Hz,2H);

[0094] 13 C NMR (100MHz, CDCl3) δ23.6,32.0,38.1,85.2,88.0,115.1(d,J=21.9Hz),122.9,127.5,128.0,128.0 ,128.2,128.7,131.2,132.0(d,J=9.2Hz),133.0(d,J=3.0Hz),135.7,165.5(d,J=254.2Hz),195.1;

[0095] HRMS(ESI)m / z calcd for C 24 H 17 FO[M+H] + :341.1336,found:341.1339.

[0096] Example 4

[0097] Synthesis of (5S,12S)-3-(4-fluorophenyl)-12-(4-methoxyphenyl)-5-phenyl-1-(p-tolyl)-4,5-dihydro-12H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]furan[3,4-e]oxooctane (Ⅲda)

[0098] The reaction route is as follows:

[0099]

[0100] The operation steps are as follows:

[0101] Under nitrogen protection, AuCl(SMe2) (4.0 μmol, 1.2 mg), chiral ligand IV (8.0 μmol, 5.3 mg), LiBF4 (12 μmol, 1.1 mg), and 1.0 mL of dichloromethane were added to a dry 5 mL reaction flask. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a container containing substrate Id (0.2 mmol, 71 mg), substrate IIa (0.13 mmol, 33.3 mg), and 300 mg of [unspecified substance]. The reaction was carried out in a molecular sieve reaction flask and stirred at 25°C. The reaction was stopped when the enantioselectivity of the chiral raw material Id′ in the system was greater than 80% by HPLC detection, and the reaction was carried out for a total of 12 h. The solvent was then removed by vacuum concentration, and the crude product was purified by silica gel column chromatography (eluent EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIda (38 mg, 31% yield).

[0102] The characterization data of the obtained product (Ⅲda) are as follows:

[0103] White solid, mp = 94-96℃; 38mg, 31% yield; 91% ee; [Daicel Chiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=254nm, t(major)=7.8min, t(minor)=7.1min];

[0104] 1 H NMR (400MHz, CDCl3) δ2.37(s,3H),2.83(dd,J=4.2,15.9Hz,1H),3.07(dd,J=11.2,15 .9Hz,1H),3.79(s,3H),5.25(dd,J=4.1,11.2Hz,1H),5.54(s,1H),5.93(s,1H),5.96( s,1H),6.39(s,1H),6.81(d,J=3.6Hz,2H),6.83(s,1H),7.04(t,J=8.5Hz,2H),7.10(t ,J=7.2Hz,4H),7.19-7.30(m,5H),7.44(d,J=7.9Hz,2H),7.49(dd,J=5.6,8.3Hz,2H);

[0105] 13 C NMR (100MHz, CDCl3) δ21.4,33.1,45.7,55.4,82.8,101.5,105.3,111.7,11 3.9,115.5(d,J=21.7Hz),119.2,121.5,125.4,126.1,127.5,127.6(d,J=3 .3Hz),127.7,128.2,128.3,128.4(d,J=8.2Hz),128.5,129.4,137.1,137. 8,142.3,143.8,146.9,148.3,150.9,152.4,158.1,162.0(d,J=247.7Hz);

[0106] HRMS(ESI)m / z calcd.for C 40 H 31 FO5[M+H] + :611.2228,found:611.2232.

[0107] The characterization data of the obtained chiral starting material alkynylcyclopropanone (Ⅰd′) are as follows:

[0108] (4-Fluorophenyl)-((1R,2S))-2-phenyl-1-(p-Tolyethynyl)cyclopropyl)methyl ketone (Id′)

[0109] Yellow oily liquid, 27.6 mg, 39% yield; 94% ee; [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=254nm, t(major)=7.0min, t(minor)=6.5min];

[0110] 1 H NMR (400MHz, CDCl3) δ1.93(dd,J=4.7,7.8Hz,1H),2.27(s,3H),2.49(dd,J=4.7,9.1Hz,1H),2.99(t,J=8.5Hz,1H), 6.89(d,J=7.9Hz,2H),6.97(d,J=7.9Hz,2H),7.08(t,J=8.6Hz,2H),7.28-7.41(m,5H),8.12(dd,J=8.6,5.7Hz,2H);

[0111] 3C NMR (100MHz, CDCl3) δ21.5, 23.6, 32.1, 38.1, 85.2, 87.2, 115.1 (d, J = 21.9Hz), 119.8, 127.4, 128.2, 12 8.7,129.0,131.1,132.0(d,J=9.2Hz),133.1(d,J=3.1Hz),135.8,138.2,165.5(d,J=254.1Hz),195.3;

[0112] HRMS(ESI)m / z calcd.for C 25 H 19 FO[M+H] + :355.1493,found:355.1493.

[0113] Example 5

[0114] Synthesis of (5S,12S)-1-(3-bromophenyl)-3-(4-chlorophenyl)-12-(4-methoxyphenyl)-5-phenyl-4,5-dihydro-12H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]furan[3,4-e]oxooctane (Ⅲea)

[0115] The reaction route is as follows:

[0116]

[0117] The operation steps are as follows:

[0118] Under nitrogen protection, AuCl(SMe2) (4.0 μmol, 1.2 mg), chiral ligand IV (8.0 μmol, 5.3 mg), LiBF4 (12 μmol, 1.1 mg), and 1.0 mL of dichloromethane were added to a dry 5 mL reaction flask. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a container containing substrate Ie (0.2 mmol, 86.8 mg), substrate IIa (0.13 mmol, 33.3 mg), and 300 mg of [unspecified substance]. The reaction was carried out in a molecular sieve reaction flask and stirred at 25°C. HPLC analysis was performed, and the reaction was stopped when the enantioselectivity of the chiral raw material Ie′ in the system was greater than 80%, with a total reaction time of 12 h. The solvent was then removed by vacuum concentration, and the crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIea (40 mg, 29% yield).

[0119] The characterization data of the obtained product (Ⅲea) are as follows:

[0120] White solid, mp = 110-111℃; 40mg, 29% yield; 96% ee; [Daicel Chiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=254nm, t(major)=12.5min, t(minor)=9.3min];

[0121] NMR (400MHz, CDCl3) δ2.92 (dd, J=15.7, 4.7Hz, 1H), 3.05 (dd, J=15.7, 8.8Hz, 1H),

[0122] 3.77(s,3H),5.27(dd,J=8.9,4.5Hz,1H),5.32(s,1H),5.91(s,1H),5.94(s,1H),6.50(s,2H),6.77(d,J=8.5Hz,2H),7.0 7(d,J=8.3Hz,2H),7.13(d,J=7.2Hz,2H),7.16-7.22(m,2H),7.22-7.26(m,4H),7.26-7.32(m,4H),7.62(d,J=7.8Hz,1H);

[0123] 13 C NMR (100MHz, CDCl3) δ32.6,45.2,55.4,83.2,101.5,104.6,111.4,113.8,118.1,124.7,125.0,125.3,126.1,127.0,127.8,12 7.9,128.4,128.6,128.8,129.7,130.4,132.4,132.7,133.0,133.1,136.4,141.5,143.7,146.9,148.9,150.0,152.0,158.1;

[0124] HRMS(ESI)m / z calcd for C 39 H 28 BrClO5[M+H] + :691.0881,found:691.0879.

[0125] The characterization data of the obtained chiral starting material alkynylcyclopropanone (Ⅰe′) are as follows:

[0126] ((1R,2S)-1-((3-bromophenyl)ethynyl)-2-phenylcyclopropyl)(4-chlorophenyl)(Ie′)

[0127] Yellow oily liquid, 31 mg, 36% yield; 98% ee. [Daicel Chiralpak IJ-3 (0.45cm×25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=254nm, t(major)=14.9min, t(minor)=22.2min];

[0128] 1 H NMR (400MHz, CDCl3) δ2.03(dd,J=7.9,4.8Hz,1H),2.52(dd,J=9.1,4.7Hz,1H),3.08(t,J=8.5Hz,1H),6.90(dd,J =7.5,1.9Hz,1H),7.00-7.11(m,2H),7.31(d,J=5.5Hz,1H),7.40(dt,J=13.7,4.0Hz,7H),8.07(d,J=8.5Hz,2H);

[0129] 13 C NMR (100MHz, CDCl3) δ24.0,32.2,38.4,83.9,92.4,125.0,125.1,126.8,127.6 ,128.3,128.4,128.9,129.2,130.9,132.3,133.3,135.0,135.4,139.1,195.3;

[0130] HRMS(ESI)m / z calcd.for C 24 H 16 BrClO[M+H] + :435.0146,found:435.0144.

[0131] Example 6

[0132] Synthesis of (5S,12S)-3-(4-fluorophenyl)-12-(4-methoxybenzyl)-1,5-diphenyl-4,5-dihydro-12H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]furan[3,4-e]oxooctane (Ⅲfa)

[0133] The reaction route is as follows:

[0134]

[0135] The operation steps are as follows:

[0136] Under nitrogen protection, AuCl(SMe2) (4.0 μmol, 1.2 mg), chiral ligand IV (8.0 μmol, 5.3 mg), LiBF4 (12 μmol, 1.1 mg), and 1.0 mL of dichloromethane were added to a dry 5 mL reaction flask. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a container containing substrate If (0.2 mmol, 71 mg), substrate IIa (0.13 mmol, 33.3 mg), and 300 mg of [unspecified substance]. The reaction was carried out in a molecular sieve reaction flask and stirred at 25°C. The reaction was stopped when the enantioselectivity of the chiral raw material If′ in the system was greater than 80% by HPLC detection, and the reaction was carried out for a total of 12 h. The solvent was then removed by vacuum concentration, and the crude product was purified by silica gel column chromatography (eluent EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIfa (48 mg, 39% yield).

[0137] The characterization data of the obtained product (Ⅲfa) are as follows:

[0138] White solid, mp = 138-139℃; 48mg, 39% yield; 90% ee; [Daicel Chiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=90 / 10, v=1.0mL·min -1 ,λ=254nm, t(major)=6.5min, t(minor)=5.7min];

[0139] 1 H NMR(400MHz,)δ2.86(dd,J=16.0,4.2Hz,1H),3.08(dd,J=16.0,11.2Hz,1H),3.79 (s,3H),5.22(dd,J=11.1,4.1Hz,1H),5.56(s,1H),5.94(d,J=1.4Hz,1H),5.97(d, J=1.4Hz,1H),6.36(s,1H),6.80-6.86(m,3H),7.03-7.07(m,2H),7.10(d,J=8.4Hz ,2H),7.22-7.25(m,2H),7.27-7.30(m,1H),7.31-7.43(m,5H),7.51-7.58(m,4H);

[0140] 13C NMR (100MHz, CDCl3) δ32.8,45.6,55.4,82.2,101.6,105.2,111.7,113.8,119.1,122.0,125.5,126.7,127.4,127.5,12 7.6,127.8,128.1,128.5,128.6,128.7,131.1,131.2,133.5,137.0,140.7,143.9,147.0,149.5,150.6,152.0,158.0;

[0141] HRMS(ESI)m / z calcd for C 39 H 29 ClO5[M+H] + :613.1776,found:613.1781.

[0142] The characterization data of the obtained chiral starting material alkynylcyclopropanone (Ⅰf′) are as follows:

[0143] (1R,2S)-2-(4-chlorophenyl)-1-(phenylethynyl)cyclopropyl-(phenyl)-methyl ketone (Ⅰf′)

[0144] Yellow oily liquid; 29 mg, 41% yield; 98% ee. [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=254nm, t(major)=7.3min, t(minor)=8.2min];

[0145] H NMR (400MHz, CDCl3) δ1.90 (dd, J=7.8, 4.8Hz, 1H), 2.50 (dd, J=9.1, 4.8Hz, 1H),

[0146] 3.00(t,J=8.4Hz,1H),7.01(dd,J=7.9,1.7Hz,2H),7.14-7.24(m,3H),7.30(d,J=8.5Hz,2H ),7.37(d,J=8.5Hz,2H),7.44(dd,J=8.4,7.0Hz,2H),7.51-7.58(m,1H),8.02-8.09(m,2H);

[0147] 13C NMR (100MHz) δ23.8,32.1,37.0,85.3,87.8,122.9,128.0,128.1,128.2,128.3,129.3,130.0,131.2,132.8,133.2,134.5,136.7,196.5;

[0148] HRMS(ESI)m / z calcd for C 24 H 17 ClO[M+H] + :357.1041,found:357.1039.

[0149] Example 7

[0150] Synthesis of (5S,12S)-12-(benzo[d][1,3]dihydroxy-5-yl)-3-(4-fluorophenyl)-1,5-diphenyl-4,5-dihydro-12H-[1,3]dihydroxy[4',5':4,5]benzo[1,2-b]furano[3,4-e]oxooctane (Ⅲcb)

[0151] The reaction route is as follows:

[0152]

[0153] The operation steps are as follows:

[0154] Under nitrogen protection, AuCl(SMe2) (4.0 μmol, 1.2 mg), chiral ligand IV (8.0 μmol, 5.3 mg), LiBF4 (12 μmol, 1.1 mg), and 1.0 mL of dichloromethane were added to a dry 5 mL reaction flask. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a container containing substrate Ic (0.2 mmol, 68 mg), substrate IIb (0.13 mmol, 35.1 mg), and 300 mg of [unspecified substance]. The reaction was carried out in a molecular sieve reaction flask and stirred at 25°C. The reaction was stopped when the enantioselectivity of the chiral raw material Ic′ in the system was greater than 80% by HPLC detection, and the reaction lasted for 12 hours. The solvent was then removed by vacuum concentration, and the crude product was purified by silica gel column chromatography (eluent EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIcb (51 mg, 42% yield).

[0155] The characterization data of the obtained product (Ⅲcb) are as follows:

[0156] White solid, mp = 84-86℃; 51mg, 42% yield; 95% ee; [Daicel Chiralpak IB-3(0.45cm×25cm),n-hexane / 2-propanol=90 / 10,v=1.0mL·min -1 ,λ=254nm,t(major)=6.9min,t(minor)=6.4min];

[0157] 1 H NMR(400MHz,CDCl3)δ2.91(dd,J=15.9,4.1Hz,1H),3.09(dd,J=15.9,11.1Hz,1H),5.30(dd,J=11.1,4.0Hz,1H),5.50(s,1H),5.92(d,J=1.4Hz,1H),5.94(d,J=1.3Hz,1H),5.95(d,J=1.4Hz,1H),5.97(d,J=1.4Hz,1H),6.37(s,1H),6.66(s,1H),6.69(s,1H),6.73(d,J=8.1Hz,1H),6.79(s,1H),7.05(t,J=8.7Hz,2H),7.14-7.19(m,2H),7.25(d,J=3.4Hz,1H),7.25-7.30(m,1H),7.20-7.35(m,2H),7.41(t,J=7.6Hz,2H),7.47-7.52(m,2H),7.52-7.57(m,2H);

[0158] 13 C NMR(100MHz,CDCl3)δ32.5,46.1,82.8,101.1,101.6,105.4,108.0(d,J=10.5Hz),111.6,115.6(d,J=21.7Hz),119.1,120.3,121.9,125.4,126.2,127.3,127.4,127.5,127.9(d,J=5.2Hz),128.5,128.6,128.7,128.8,130.9,139.1,142.0,143.9,145.9,147.0,147.9,148.7,150.6,151.9,162.1(d,J=247.6Hz);

[0159] HRMS(ESI)m / z calcd for C 39 H 27 FO6[M+H] + :611.1864,found:611.1859。

[0160] The characterization data of the obtained chiral starting material alkynylcyclopropanone (Ⅰc′) are as follows:

[0161] (4-Fluorophenyl)((1R,2S))-2-phenyl-1-(phenylethynyl)cyclopropyl)methyl ketone (Ⅰc′)

[0162] Yellow oily liquid, 27.2 mg, 40% yield; 99% ee. [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=254nm, t(major)=7.5min, t(minor)=7.0min];

[0163] 1 H NMR(400MHz, CDCl3)1.96(dd,J=7.9,4.7Hz,1H),2.51(dd,J=9.1,4.7Hz,1H),3.01(t,J=8.5Hz,1H),6.99( d,J=5.8Hz,2H),7.10(t,J=8.7Hz,2H),7.15-7.22(m,3H),7.30-7.45(m,5H),8.12(dd,J=8.7,5.6Hz,2H);

[0164] 13 C NMR (100MHz, CDCl3) δ23.6,32.0,38.1,85.2,88.0,115.1(d,J=21.9Hz),122.9,127.5,128.0,128.0 ,128.2,128.7,131.2,132.0(d,J=9.2Hz),133.0(d,J=3.0Hz),135.7,165.5(d,J=254.2Hz),195.1;

[0165] HRMS(ESI)m / z calcd for C 24 H 17 FO[M+H] + :341.1336,found:341.1339.

[0166] Example 8

[0167] Synthesis of (5R,12R)-3-(4-fluorophenyl)-12-((E)-2-methoxystyryl)-1,5-diphenyl-4,5-dihydro-12H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]furan[3,4-E]oxooctane (Ⅲcc)

[0168] The reaction route is as follows:

[0169]

[0170] The operation steps are as follows:

[0171] Under nitrogen protection, AuCl(SMe2) (4.0 μmol, 1.2 mg), chiral ligand IV (8.0 μmol, 5.3 mg), LiBF4 (12 μmol, 1.1 mg), and 1.0 mL of dichloromethane were added to a dry 5 mL reaction flask. The mixture was stirred at room temperature for 15 minutes, and the precipitate was removed by filtration. The filtrate was transferred to a container containing substrate Ic (0.2 mmol, 68 mg), substrate IIc (0.13 mmol, 36.7 mg), and 300 mg of [unspecified substance]. The reaction was carried out in a molecular sieve reaction flask and stirred at 25°C. The reaction was stopped when the enantioselectivity of the chiral raw material Ic′ in the system was greater than 80% by HPLC detection, and the reaction lasted for 12 hours. The solvent was then removed by vacuum concentration, and the crude product was purified by silica gel column chromatography (eluent EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIIcc (50 mg, 40% yield).

[0172] The characterization data of the obtained product (Ⅲcc) are as follows:

[0173] White solid, mp = 89-90℃; 50mg, 40% yield; 90% ee; [Daicel Chiralpak IA-3 (0.45cm×25cm), n-hexane / 2-propanol=90 / 10, v=1.0mL·min -1 ,λ=254nm, t(major)=6.2min, t(minor)=6.5min];

[0174] 1 H NMR (400MHz, CDCl3) δ3.10-3.32(m,2H),3.77(s,3H),5.14(br,1H),5.61(br,1H),5.92(s,1H),5.95(s,1H),6.45(s,1H),6.52-6.61(m,1H),6 .66-6.77(m,1H),6.82-6.90(m,3H),7.05(t,J=8.7Hz,2H),7.21(d,J=7 .5Hz,1H),7.27-7.39(m,7H),7.41-7.49(m,4H),7.62(d,J=3.2Hz,2H);

[0175] 13 C NMR (100MHz, CDCl3) δ29.8,33.0,55.4,83.8,100.0,101.5,105.0,110.7,115.5( d,J=21.8Hz),119.2,120.7,125.1,125.9,126.0(d,J=2.7Hz),126.6,127.0,127 .4,127.5,127.8,127.9,128.0,128.1,128.4,128.5,128.6,128.7,128.9(d,J=1 1.2Hz),131.0,142.6,144.1,146.7,148.5,152.3,156.6,162.0(d,J=247.4Hz);

[0176] HRMS(ESI)m / z calcd for C 41 H 31 FO5[M+H] + :623.2228,found:623.2225.

[0177] The characterization data of the obtained chiral starting material alkynylcyclopropanone (Ⅰc′) are as follows:

[0178] Synthesis of (4-fluorophenyl)((1R,2S))-2-phenyl-1-(phenylethynyl)cyclopropyl)methyl ketone (Ⅰc′):

[0179] Yellow oily liquid, 28 mg, 41% yield; 98% ee. [DaicelChiralpak IB-3 (0.45cm×25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=254nm, t(major)=7.5min, t(minor)=7.0min];

[0180] 1 H NMR(400MHz, CDCl3)1.96(dd,J=7.9,4.7Hz,1H),2.51(dd,J=9.1,4.7Hz,1H),3.01(t,J=8.5Hz,1H),6.99( d,J=5.8Hz,2H),7.10(t,J=8.7Hz,2H),7.15-7.22(m,3H),7.30-7.45(m,5H),8.12(dd,J=8.7,5.6Hz,2H);

[0181] 13C NMR (100MHz, CDCl3) δ23.6,32.0,38.1,85.2,88.0,115.1(d,J=21.9Hz),122.9,127.5,128.0,128.0 ,128.2,128.7,131.2,132.0(d,J=9.2Hz),133.0(d,J=3.0Hz),135.7,165.5(d,J=254.2Hz),195.1;

[0182] HRMS(ESI)m / z calcd for C 24 H 17 FO[M+H] + :341.1336,found:341.1339.

[0183] Comparative Example 1

[0184] The synthesis of (5S,12S)-12-(4-methoxyphenyl)-3-methyl-1,5-diphenyl-4,5-dihydro-12H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]furan[3,4-e]oxooctane (Ⅲaa) was as described in Example 1, except that no gold catalyst was added.

[0185] No gold catalyst was added in this comparative example, and no reaction occurred.

[0186] Comparative Example 2

[0187] The synthesis of (5S,12S)-12-(4-methoxyphenyl)-3-methyl-1,5-diphenyl-4,5-dihydro-12H-[1,3]dioxane[4',5':4,5]benzo[1,2-b]furan[3,4-e]oxooctane (Ⅲaa) was as shown in Example 1, except that LiBF4 was not added.

[0188] No LiBF4 was added in this comparative example, so no reaction occurred.

[0189] Application Example 1

[0190] The inhibitory effects of the compounds synthesized in Examples 1-8 on peripheral blood B lymphocytes (RPMI8226) in multiple myeloma were tested.

[0191] Peripheral blood B lymphocytes (RPMI8226) from multiple myeloma were purchased from Shanghai Saibaikang Biotechnology Co., Ltd. The culture medium used was a complete cell culture medium prepared according to the ratio of (culture medium: fetal bovine serum = 9:1), and the culture medium type was RPMI1640.

[0192] The specific steps are as follows:

[0193] (1) Preparation of sample solution: The compound to be tested was dissolved with DMSO, filtered through a 0.22 μm filter to remove bacteria, and a 100 μM sample stock solution was obtained. Then, it was diluted with complete culture medium to a concentration of 5 μM to obtain the sample solution. At the same time, a culture medium with an equal volume of DMSO was used as a control solution.

[0194] (2) Cell thawing and passage: Turn on the water bath and adjust the temperature to 37℃. Take out the cells frozen in liquid nitrogen, quickly place them in the 37℃ water bath and shake them rapidly. After the cells are completely thawed, remove the cryovial from the water bath. Take a 10mL sterile centrifuge tube, add 4mL of culture medium, and then transfer the cells from the cryovial to the centrifuge tube. Centrifuge at 1000rpm for 5min at room temperature. Take a new 25T cell culture flask and add 5mL of culture medium. Discard the supernatant from the centrifuge tube, leaving the precipitate, and add it all to the culture flask. Incubate at 37℃ with 5% CO2 for 8h, then aspirate all the culture medium, add 5mL of fresh culture medium, and continue culturing. Once the cells have confluently grown in the culture flask, discard the old culture medium, add 2 mL of PBS to wash the cells, discard the PBS, add 1 mL of trypsin, and digest at room temperature for about 30 seconds. Gently tap around the culture flask to detach the digested cells. For cells that are difficult to detach, gently pipette them off. Add 2 mL of culture medium. Transfer the digested cells to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes at room temperature. Discard the supernatant, add 1 mL of culture medium, mix well, and transfer to a new culture flask. Incubate until confluent, then proceed with experiments.

[0195] (3) Sample to cell viability detection: RPMI8226 cells in logarithmic growth phase were collected, cell counts were performed, and cell concentration was adjusted to 6 × 10⁻⁶ cells / cells. 3 Cells were seeded at a rate of 100 μL / well into 96-well plates and cultured at 37°C in a 5% CO2 incubator. After 24 h of cell adhesion and growth, the cell culture medium was discarded, and 100 μL of sample solution and control solution were added to each well. The cells were then incubated at 37°C in a 5% CO2 incubator for 72 h. The culture medium was then removed, and each well was washed three times with PBS. 100 μL of medium containing 10% CCK-8 was added to each well, and the cells were then incubated at 37°C in a 5% CO2 incubator for 2 h. The absorbance at 450 nm was measured using a microplate reader, and cell viability was calculated. The experiment was repeated three times, and the average value was taken. The results are shown below. Figure 1 .

[0196] from Figure 1 It can be seen that different compounds have varying degrees of inhibitory effects on peripheral blood B lymphocytes (RPMI8226) in multiple myeloma. We further determined the IC50 values ​​of IIIba, IIIca and IIIcb on peripheral blood B lymphocytes (RPMI8226) in multiple myeloma.

[0197] Application Example 2: Inhibitory activity of synthetic compound IIIba against peripheral blood B lymphocytes (RPMI 8226) in multiple myeloma.

[0198] The specific steps are as follows:

[0199] Peripheral blood B lymphocytes (RPMI8226) from multiple myeloma were purchased from Shanghai Saibaikang Biotechnology Co., Ltd. The culture medium used was a complete cell culture medium prepared according to the ratio of (culture medium: fetal bovine serum = 9:1), and the culture medium type was RPMI1640.

[0200] (1) Preparation of sample solution: The test compound Ⅲba was dissolved with DMSO and sterilized by 0.22 μm filtration to obtain a 100 μM stock solution. Then, it was diluted with complete culture medium to working concentrations of 0.1, 0.2, 0.5, 1, 5 and 20 μM to obtain sample solutions.

[0201] (2) Cell thawing and passage: Turn on the water bath and adjust the temperature to 37℃. Take out the cells frozen in liquid nitrogen, quickly place them in the 37℃ water bath and shake them rapidly. After the cells are completely thawed, remove the cryovial from the water bath. Take a 10mL sterile centrifuge tube, add 4mL of culture medium, and then transfer the cells from the cryovial to the centrifuge tube. Centrifuge at 1000rpm for 5min at room temperature. Take a new 25T cell culture flask and add 5mL of culture medium. Discard the supernatant from the centrifuge tube, leaving the precipitate, and add it all to the culture flask. Incubate at 37℃ with 5% CO2 for 8h, then aspirate all the culture medium, add 5mL of fresh culture medium, and continue culturing. Once the cells have confluently grown in the culture flask, discard the old culture medium, add 2 mL of PBS to wash the cells, discard the PBS, add 1 mL of trypsin, and digest at room temperature for about 30 seconds. Gently tap around the culture flask to detach the digested cells. For cells that are difficult to detach, gently pipette them off. Add 2 mL of culture medium. Transfer the digested cells to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes at room temperature. Discard the supernatant, add 1 mL of culture medium, mix well, and transfer to a new culture flask. Incubate until confluent, then proceed with experiments.

[0202] (3) Sample to cell viability detection: RPMI8226 cells in logarithmic growth phase were collected, cell counts were performed, and cell concentration was adjusted to 6 × 10⁻⁶ cells / cells. 3Cells were seeded at a rate of 100 μL / well into 96-well plates and cultured at 37°C in a 5% CO2 incubator. After 24 h of cell adhesion and growth, the cell culture medium was discarded, and 100 μL of sample solution and control solution were added to each well. The plates were then incubated at 37°C in a 5% CO2 incubator for 72 h. The culture medium was then removed, and each well was washed three times with PBS. 100 μL of medium containing 10% CCK-8 was added to each well, and the plates were then incubated at 37°C in a 5% CO2 incubator for 2 h. The absorbance at 450 nm was measured using a microplate reader. The absorbance values ​​for each group were entered into Excel, and the relative activity was calculated (relative activity % = (experimental group OD value - background OD value) / (control group OD value - background OD value) × 100), where the background OD value was the absorbance with only CCK8 reagent and culture medium added. The relative activity values ​​were then plotted in GraphPad Prism. The test results were displayed in [image / image / link]. Figure 2 As shown in the figure, Figure 2 As shown, the synthetic compound IIIba of the present invention exhibited excellent inhibitory activity against peripheral blood B lymphocytes (RPMI8226) of multiple myeloma, with an IC50 value of 1.74 μM.

[0203] Application Example 3: The specific test method for the inhibitory activity of the synthetic compound IIIca against peripheral blood B lymphocytes (RPMI8226) in multiple myeloma is as shown in Application Example 2, except that the concentrations of the sample solutions are 1, 2, 3, 5, 20, and 50 μM.

[0204] Test results in Figure 3 As shown in the figure, Figure 3 As shown, the synthetic compound IIIca of the present invention exhibited good inhibitory activity against peripheral blood B lymphocytes (RPMI8226) of multiple myeloma, with an IC50 value of 9.5 μM.

[0205] Application Example 4: The specific test method for the inhibitory activity of the synthetic compound IIIcb on peripheral blood B lymphocytes (RPMI8226) of multiple myeloma is as shown in Application Example 3.

[0206] Test results in Figure 4 As shown in the figure, Figure 4 As shown, the synthetic compound Ⅲfc of the present invention exhibited good inhibitory activity against peripheral blood B lymphocytes (RPMI8226) of multiple myeloma, with an IC50 value of 20.2 μM.

[0207] The above are only some embodiments of the present invention and are not intended to limit the present invention in any way. Any simple modifications, equivalent changes or alterations made to the above embodiments based on the present invention shall fall within the scope of the present invention.

Claims

1. A method for synthesizing chiral eight-membered ring ether compounds, comprising the following steps: In dichloromethane, under the catalysis of a gold catalytic system, alkynylcyclopropionate compound I and o-methylenebenzoquinone compound II react to obtain chiral eight-membered ring ether compound III; the gold catalytic system consists of gold catalyst AuCl(SMe2), chiral ligands and lithium tetrafluoroborate salt, wherein the chiral ligands have the structure shown in Formula IV. ； in, In the structural formula of compound I, R1 is a phenyl or a substituted phenyl, wherein the substituent of the substituted phenyl is selected from halogens; R2 is a phenyl, 4-fluorophenyl, 4-methylphenyl or 3-bromophenyl; R3 is a methyl, phenyl or halogen-substituted phenyl. In the structural formula of compound II, R4 is a substituted phenyl or a substituted styrene group, wherein the substituent of the substituted phenyl group is methoxy, ethoxy, or 2,4-dimethoxy, and the substituent of the substituted styrene group is methoxy or ethoxy, and the substituent is attached to the benzene ring of the substituted styrene group; In the structural formula of compound III, substituents R1, R2, and R3 are the same as those in the structural formula of compound I; substituent R4 is the same as those in the structural formula of compound II.

2. The method for synthesizing chiral eight-membered ring ether compounds according to claim 1, characterized in that, In the structural formula of compound I, R1 is phenyl or 4-chlorophenyl, and R3 is p-fluorophenyl.

3. The method for synthesizing chiral eight-membered ring ether compounds according to claim 1, characterized in that, The volume ratio of the dichloromethane to the molar ratio of the alkynylcyclopropionate compound I is 3~10 mL:1 mmol; the dichloromethane is anhydrous.

4. The method for synthesizing chiral eight-membered ring ether compounds according to claim 1, characterized in that, The molar ratio of the gold catalyst AuCl(SMe2) to alkynylcyclopropanone compound I is 0.01~0.03:1; the molar ratio of the gold catalyst AuCl(SMe2) to the chiral ligand is 1:2~2.2; and the molar ratio of the gold catalyst AuCl(SMe2) to lithium tetrafluoroborate is 1:3~3.

3.

5. The method for synthesizing chiral eight-membered ring ether compounds according to claim 1, characterized in that, The molar ratio of the alkynylcycloacetone compound I and the o-methylenebenzoquinone compound II is 1:0.5~0.

8.

6. The method for synthesizing chiral eight-membered ring ether compounds according to claim 1, characterized in that, The reaction system of alkynylcyclopropanone compound I and o-methylenebenzoquinone compound II also includes a 4Å molecular sieve; the mass ratio of the 4Å molecular sieve to the molar number of alkynylcyclopropanone compound I is 1~3g:1mmol.

7. The method for synthesizing chiral eight-membered ring ether compounds according to claim 1, characterized in that, The reaction is carried out under the protection of a protective gas, namely nitrogen or argon. The reaction temperature is 10~30℃; the reaction time is 2~48h.

8. The method for synthesizing chiral eight-membered ring ether compounds according to claim 1, characterized in that, The reaction temperature is 25°C; the reaction time is 12~24h.

9. The method for synthesizing chiral eight-membered ring ether compounds according to claim 1, characterized in that, After the reaction of alkynylcyclopropionate compound I and o-methylenebenzoquinone compound II, the specific post-reaction processing steps are as follows: the solvent is removed from the reaction solution, and the crude product is separated by silica gel column chromatography to obtain chiral eight-membered ring ether compound III. The eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the mixed solvent is 0.02~0.2:

1.

10. A chiral eight-membered ring ether compound, characterized in that, The material is prepared by the method described in claim 1, and its structural formula is shown in Formula III below: ； In Formula III, the substituents R1, R2, R3, and R4 are as described in claim 1.

11. The use of the chiral eight-membered ring ether compound of claim 10 in the preparation of an anti-multiple myeloma drug.

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