Chiral eight-membered ring ether compound and synthesis method and application thereof

Abstract

The application discloses a kind of chiral eight-membered ring ether compound and its synthesis method and application, and the chiral eight-membered ring ether compound has antitumor activity.The synthesis method is: with (E) 2-oxo-4-phenylbut-3-enoate compound and alkyne ketone compound as raw material, under the continuous action of chiral catalyst and DBU catalyst, asymmetric addition / cyclization reaction is carried out in organic solvent until reaction is complete, and chiral eight-membered ring ether compound is obtained.The chiral eight-membered ring ether disclosed in the application is an important structural unit, widely exists in pesticide and pharmaceutical field, and has wide application prospect.The synthesis method of the application has mild conditions, high yield, good enantioselectivity, wide reaction substrate range, cheap and easy-to-obtain reaction reagent, and strong operability.

Description

Technical Field

[0001] This invention relates to a chiral eight-membered ring ether compound, its synthesis method and application, and particularly to a method for synthesizing a chiral eight-membered ring ether compound by a continuous asymmetric addition / cyclization reaction of a (E)-2-oxo-4-phenylbut-3-enoate compound and an acetylacetonate compound under the co-catalysis of a chiral tertiary amine-nitrogenic acid and DBU (1,8-diazabicycloundec-7-ene). Background Technology

[0002] Chiral eight-membered ring ethers are an important core structure widely found in many natural molecules with different biological activities. Compared to five- and six-membered rings, the construction of eight-membered rings is hampered by unfavorable enthalpy and entropy effects, as well as the influence of transring interactions, making the construction of such skeletons difficult. Traditional methods for constructing eight-membered ring ethers often suffer from harsh temperature conditions, long reaction steps, and the involvement of transition metals. Therefore, developing an efficient and mild asymmetric catalytic strategy for constructing chiral eight-membered ring ether compounds is essential. Among these methods, asymmetric synthesis using small organic molecule catalysis has attracted much attention as it is another highly efficient asymmetric catalytic method developed after organometallic catalysis and enzyme catalysis. Compared to organometallic catalysis, small organic molecule catalysts are generally stable to water and air, have simple reaction operations, are easy to scale up industrially, and, importantly, do not contain toxic metals, which is particularly important in drug synthesis. Compared to enzyme catalysis, small molecule catalysis does not have the strong substrate and reaction specificity of enzyme catalysis; one catalyst can catalyze several types of reactions, and the substrate adaptability is relatively good. The 2021 Nobel Prize in Chemistry was awarded to Benjamin List and David MacMillan for their outstanding contributions to asymmetric reactions catalyzed by small organic molecules, demonstrating the significant importance of asymmetric catalytic synthesis. Due to its unique advantages over other catalytic methods, small organic molecule catalysis based on different catalytic mechanisms has made considerable progress over the past decade. As an important branch of small organic molecule catalysis, hydrogen bond-based asymmetric reactions have also seen significant development. Catalysts containing hydrogen bond donors in various structures (such as urea, thiourea, azirconic acid, guanidine, phosphonic acid, etc.) have been designed and have shown excellent chiral induction effects in many asymmetric catalytic reactions, becoming an important synthetic strategy for constructing carbon-carbon and carbon-heteroatom bonds. (AB Erkessel and H. Asymmetric Organocatalysis, Wiley VCH, Weinheim, 2005. PIDalko, Enantioselective Organocatalysis, Wiley-VCH, Weinheim, 2007).

[0003] With the deepening development of organic synthesis, traditional, single-catalytic systems are gradually facing bottlenecks and challenges in terms of substrate reactivity and reaction selectivity, such as substrate activation efficiency, regulation of reaction sites, and precise control of reactivity and selectivity. To address this issue, chemists have combined different types of catalysts for co-catalytic reactions within the same reaction system. Co-catalytic systems can leverage the advantages of each catalytic system, continuously activating multiple chemical bonds and causing them to recombine in an orderly manner, effectively reducing the reaction energy barrier between reactants, and enabling many reactions that cannot be completed by a single catalytic system, thus compensating for the shortcomings of each. This not only reduces waste emissions and solvent consumption but also improves reaction efficiency, providing convenience for chemical research. Therefore, designing and developing more novel, efficient, and versatile co-catalytic systems not only has significant theoretical importance but also has important practical value in the synthesis of natural products and drug molecules. Summary of the Invention

[0004] The purpose of this invention is to provide a chiral eight-membered ring ether compound and a method for synthesizing a chiral eight-membered ring ether compound by using a chiral tertiary amine-nitrosuccinic acid and DBU in combination to catalyze (E)-2-oxo-4-phenylbut-3-enoate esters and acetylacetones via asymmetric addition / cyclization reactions.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] In a first aspect, the present invention provides a chiral eight-membered ring ether compound of formula (3).

[0007]

[0008] Among them, R 1 It is styryl, thiophene, naphthyl, phenyl, or phenyl substituted with C1-C4 alkyl, C1-C4 alkoxy, or halogen;

[0009] R 2 C1-C4 alkyl, benzyl,

[0010]

[0011] R 3 It is a phenyl group or a phenyl group substituted with methyl, methoxy, or halogen.

[0012] R 4 It is a C1 to C10 alkyl or phenyl group, or a phenyl group substituted with a C1-C4 alkyl, C1-C4 alkoxy, or halogen.

[0013] Preferably, R 1It is β-styryl, 2-thienyl, 2-naphthyl, phenyl, or phenyl substituted with methyl, methoxy, or halogen;

[0014] R 2 Methyl, ethyl, isopropyl, benzyl,

[0015] R 3 It is a phenyl group or a phenyl group substituted with methyl, methoxy, or halogen.

[0016] R 4 It is a C1 to C10 alkyl or phenyl group, or a phenyl group substituted with methyl, methoxy or halogen.

[0017] Furthermore, the chiral eight-membered ring ether compound is one of the following:

[0018]

[0019] Secondly, the present invention provides the application of the chiral eight-membered ring ether compound shown in formula (3) above in the preparation of antitumor drugs.

[0020] Furthermore, the tumor in question is human breast cancer.

[0021] The preferred chiral eight-membered ring ether compound is compound 3-6.

[0022] Thirdly, the present invention provides a method for synthesizing the chiral eight-membered ring ether compound shown in formula (3) above, wherein the synthesis method is as follows:

[0023] Using the compounds shown in formula (1) and formula (2) as raw materials, an asymmetric addition reaction was carried out in organic solvent A at room temperature under the action of a chiral catalyst until the reaction was complete (the complete consumption of compound 1 by TLC detection was considered as the complete reaction). The resulting reaction solution A was separated and purified to obtain an addition product containing the compound shown in formula (10).

[0024]

[0025] The addition product containing the compound shown in formula (10) was dissolved in organic solvent B, and 1,8-diazabicycloundec-7-ene (DBU catalyst) was added. The cyclization reaction was carried out at room temperature for 1-2 h (preferably 2 h). The resulting reaction solution B was post-treated to obtain the chiral eight-membered ring ether compound shown in formula (3).

[0026]

[0027] The molar ratio of the compound shown in formula (1), the compound shown in formula (2) to the chiral catalyst is 1:1.0 to 2.0:0.01 to 0.1 (preferably 1:1.2:0.1); the molar ratio of the 1,8-diazabicycloundec-7-ene to the compound shown in formula (1) is 0.1 to 1:1 (preferably 0.2:1);

[0028] The reaction formula is as follows:

[0029]

[0030] In equations (1), (2), (3), and (10), R 1 R 2 R 3 R 4 The scope is the same as above;

[0031] The chiral catalyst is one of the following compounds:

[0032]

[0033] In formula (4) or (5), the carbon atom marked with * is a chiral carbon atom;

[0034] In equations (4), (5), (6) or (7), R 5 R 8 R 11 Or R 14 Each is independently a phenyl, a phenyl C1-C4 alkyl group, or a phenyl group substituted with a trifluoromethyl group; R 6 R 7 R 9 Or R 10 Each is independent and can be categorized as C1 to C2. 10 Alkyl group; R 12 Or R 15 Each is independently a C2-C4 alkenyl group; R 13 Or R 16 Each can be an H or C1-C4 alkoxy group.

[0035] Furthermore, in equations (4), (5), (6), or (7), R 5 R 8 R 11 Or R 14 Each can be independently phenyl, (S)-1-phenylethyl, (R)-1-phenylethyl, or phenyl or benzyl substituted with trifluoromethyl;

[0036] R 6 R 7 R 9 Or R 10 Each is independent and can be C1 to C2. 10 Alkyl groups;

[0037] R 12 Or R 15 Each is a vinyl group;

[0038] R 13 Or R 16 Each can be either H or methoxy.

[0039] Furthermore, and more preferably, the chiral catalyst is selected from one of the following:

[0040]

[0041] Furthermore, the organic solvent A is one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, and 1,4-dioxane, preferably diethyl ether.

[0042] Furthermore, the organic solvent B is one or more of dichloromethane, diethyl ether, chloroform, tetrahydrofuran, and 1,4-dioxane, preferably dichloromethane.

[0043] Furthermore, the volume of the organic solvent A, in terms of the amount of substance of the compound shown in formula (1), is 5 to 20 mL / mmol, and in one embodiment of the present invention, it is 15 mL / mmol. Furthermore, the volume of the organic solvent B, in terms of the amount of substance of the compound shown in formula (1), is 5 to 20 mL / mmol, and in one embodiment of the present invention, it is 10 mL / mmol.

[0044] Further, the separation and purification are as follows: the reaction solution A is concentrated under reduced pressure, and a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 30:1 is used as the eluent for silica gel column chromatography separation. The eluent containing the addition product is collected, and the solvent is evaporated to obtain the addition product containing the compound shown in formula (10).

[0045] Further, the post-processing is as follows: the reaction solution B is concentrated under reduced pressure, and silica gel column chromatography is performed using a mixture of petroleum ether and ethyl acetate with a volume ratio of 1 to 30:1 as the eluent. The eluent containing the target compound is collected, and the solvent is evaporated to obtain the chiral eight-membered ring ether compound shown in product formula (3).

[0046] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0047] The synthetic method of this invention uses a chiral catalyst containing at least one tertiary amine and a zosquamous acid functional group, along with a DBU catalyst, as the catalytic system. The reaction is carried out in an organic solvent, followed by post-treatment separation to obtain chiral eight-membered ring ether compounds. These chiral eight-membered ring ethers are an important structural unit widely found in the pesticide and pharmaceutical fields, and have broad application prospects. The synthetic method of this invention features mild conditions, high yield, high purity (all compounds have a purity of over 97%), good enantioselectivity, a broad substrate range, inexpensive and readily available reagents, and strong operability. Attached Figure Description

[0048] Figure 1 The following are images of the tumor inhibition effect in Example 36: the control group is a photograph of human breast cancer cell culture medium without added drugs, and the other images are photographs of human breast cancer cell culture medium after treatment with the compound prepared in the corresponding example (concentration of 62.5 μg / mL). Detailed Implementation

[0049] In the following examples, the compound of formula (1) was synthesized according to the literature Tang, X.; Tong, L.; Liang, H., et al. Facile synthesis of substituted diaryl sulfones via a [3+3]benzannulation strategy[J]. Organic & Biomolecular Chemistry, 2018, 16, 3560-3563. DOI:10.1039 / C8OB00662H.

[0050] Reference literature for compounds of formula (2) Campano, TE; Iriarte, I.; Olaizola, O.; et al. Enantioselective Addition of Alkynyl Ketones to Nitroolefins Assisted by Base / H-Bonding Catalysis[J]. Chemistry-A European Journal, 2019, 25, 4390-4397. DOI: 10.1002 / chem.201805542. Synthesis.

[0051] Example 1:

[0052]

[0053] In a dry reaction tube, catalyst (7)-b (0.01 mmol, 6 mg), methyl (E)-2-oxo-4-phenylbut-3-enoate (0.1 mmol, 19.0 mg), acetylene (0.12 mmol, 26.4 mg), and diethyl ether (1.5 ml) were added sequentially. After the addition was complete, the mixture was stirred at room temperature for 48 h with a magnetic stirrer. TLC showed that methyl (E)-2-oxo-4-phenylbut-3-enoate was completely consumed. The reaction solution was concentrated under reduced pressure and subjected to rapid column chromatography on silica gel (petroleum ether / ethyl acetate = 3:1). The eluent containing the target compound was collected, and the solvent was evaporated to obtain the addition product. The addition product was dissolved in CH2Cl2 (1 mL), and then DBU catalyst (0.02 mmol, 3.0 mg) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel chromatography. Elution was performed using a petroleum ether and ethyl acetate in a volume ratio of 5:1. The eluent containing the target compound was collected, and the solvent was evaporated to give a white solid product (39.3 mg, purity: 98.3%, yield: 94%, >99:1dr, 96:4er). 1 H NMR (500MHz, CDCl3) δ8.07-8.05(m,2H),7.53-7.49(m,3H),7.40-7.38(m,2H),7.27-7.21(m,7H),7.18(dd,J=9.0, 4.8Hz,1H),7.14(d,J=9.0Hz,1H),6.03(s,1H),4.75(d,J=12.3Hz,1H),4.55(dd,J=12.2,9.2Hz,1H),3.79(s,3H). 13 C NMR (125MHz, CDCl3) δ200.7,162.5,144.3,138.1,136.7,133.9,130.8,128.7, 128.6,128.4,128.3,128.0,127.4,127.3,127.3,107.5,64.5,52.4,45.4.[α] D 25 = -12.3 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 80 / 20), 1.0 mL / min, Major enantiomer:t R =7.6min,minor enantiom er:t R =9.2min.HRMS(ESI)m / z:[M+Na] + Calcd for C27 H 22 O4Na 433.1410; Found 433.1414.

[0054] Using the same reactants and the same operating procedures, catalyst (7)-b was replaced with a catalyst of less than 0.01 mmol. The results are shown in Table 1 below:

[0055] Table 1

[0056]

[0057]

[0058] In Table 1, the superscript a Indicates the separation yield. b This indicates that the corresponding selectivity was obtained through chiral high-performance liquid chromatography analysis.

[0059] Using the same reactants and following the same operating procedures, the reactions were carried out by replacing diethyl ether with less than 1.5 ml of organic solvent (solvent A). The results are shown in Table 2 below:

[0060] Table 2

[0061]

[0062] In Table 2, the superscript a Indicates the separation yield. b This indicates that the corresponding selectivity was obtained through chiral high-performance liquid chromatography analysis.

[0063] Using the same reactants and following the same operating procedures, the reactions were carried out by replacing CH2Cl2 with less than 1 ml of organic solvent (solvent B). The results are shown in Table 3 below:

[0064] Table 3

[0065]

[0066] In Table 3, the superscript a Indicates the separation yield. b This indicates that the corresponding selectivity was obtained through chiral high-performance liquid chromatography analysis.

[0067] Example 2:

[0068]

[0069] The difference from Example 1 is that the substrate ketone used was (E)-4-(2-fluorophenyl)-2-oxobut-3-enoic acid methyl ester (0.1 mmol, 20.8 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (39.3 mg, purity: 99%, yield: 91%, >99:1dr, 93:7er). 1 H NMR (400MHz, CDCl3) δ8.02-8.00(m,2H),7.53-7.48(m,3H),7.39-7.37(m,2H),7.32(td,J=7.5,1.7Hz,1H),7.26-7.12(m,4H),7.09(d,J=9.1Hz,1H ),7.05(td,J=7.5,1.2Hz,1H),6.93(ddd,J=10.3,8.2,1.2Hz,1H),5.96( s,1H),4.93(dd,J=12.6,9.2Hz,1H),4.76(d,J=12.6Hz,1H),3.81(s,3H). 13 C NMR (100MHz, CDCl3) δ200.4,162.5,161.6,160.8(d, 1 J C-F =245.2Hz),144.7,136.5,134.1,132.6,130.9,129.4(d, 3 J C-F =3.9Hz), 129.1(d, 3 J C-F =8.4Hz),128.6,128.7,128.5,127.7,127.5,125.1(d, 3 J C-F =13.9Hz), 124.5(d, 4 J C-F =3.5Hz), 115.8(d, 2 J C-F =22.3Hz),106.8,63.5,52.5,38.4,29.7.[α] D 25 = -7.2 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =9.2min,minor enantiom er:t R=11.2min.HRMS(ESI)m / z:[M+Na] + Calcd for C 27 H 21 FO4Na451.1316;Found 451.1318.

[0070] Example 3:

[0071]

[0072] The difference from Example 1 is that the substrate ketone used was (E)-4-(2-chlorophenyl)-2-oxobut-3-enoic acid ethyl ester (0.1 mmol, 23.8 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (41.4 mg, purity: 98.5%, yield: 92%, >99:1dr, 92:8er). 1 H NMR (400MHz, CDCl3) δ8.05-8.02(m,2H),7.53-7.48(m,4H),7.43(d,J=7.7Hz,2H),7.28-7.20(m,5H),7.10(td,J=7.7,1.4Hz,1H) ,6.98(d,J=9.0Hz,1H),6.00(s,1H),5.26(d,J=9.1Hz,1H),4.94(d,J=12.6Hz,1H),4.25(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ200.5,162.4,162.1,145.1,136.2,136.0,134.5,134.2,132.2,130.9 ,129.9,128.8,128.6,128.6,128.5,128.5,127.7,127.5,107.4,62.8,61.9,40.5,14.0.[α] D 25 = -3.9 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =7.7min,minor enantiom er:t R =8.4min.HRMS(ESI)m / z:[M+Na] + Calcd for C 27 H 21ClO4Na 467.1021; Found 467.1027.

[0073] Example 4:

[0074]

[0075] The difference from Example 1 is that the substrate ketone used was (E)-4-(3-bromophenyl)-2-oxobut-3-enoic acid methyl ester (0.1 mmol, 26.9 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (46.8 mg, purity: 98.1%, yield: 94%, >99:1dr, 95:5er). 1 H NMR(500MHz, CDCl3)δ8.02-8.00(m,2H),7.54-7.48(m,3H),7.36-7.34(m,3H),7.31-7.21(m,4H), 7.09-7.03(m,3H),6.01(s,1H),4.68(d,J=12.4Hz,1H),4.45(dd,J=12.3,9.0Hz,1H),3.79(s,3H). 13 C NMR (125MHz, CDCl3) δ200.3,162.5,162.4,144.9,140.6,136.3,133.7,132.9,131.1,130.9, 130.6,130.2,128.8,128.5,128.5,127.7,127.4,126.8,122.7,107.8,64.1,52.6,45.3.[α] D 25 = -6.9 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =11.6min,minor enantiomer:t R =14.5min.HRMS(ESI)m / z:[M+Na] + Calcd for C 27 H 21 BrO4Na 511.0515; Found511.0517.

[0076] Example 5:

[0077]

[0078] The difference from Example 1 is that the substrate ketone used was (E)-4-(4-chlorophenyl)-2-oxobut-3-enoic acid methyl ester (0.1 mmol, 22.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (41.8 mg, purity: 97.5%, yield: 92%, >99:1dr, 94:6er). 1 H NMR (500MHz, CDCl3) δ8.03-8.01(m,2H),7.53-7.48(m,3H),7.35-7.34(m,2H),7.28-7.21(m,3H),7.20-7.17(m,2H),7. 13-7.10(m,2H),7.06(d,J=8.9Hz,1H),6.03(s,1H),4.68(d,J=12.3Hz,1H),4.46(dd,J=12.2,9.0Hz,1H),3.79(s,3H). 13 C NMR (125MHz, CDCl3) δ200.4,162.5,144.8,136.8,136.4,133.7,133.1,133.1, 130.9,129.4,128.8,128.7,128.5,127.6,127.4,107.9,64.2,52.5,45.1.[α] D 25 =-6 (c=10mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254nm (n-hexane / i-PrOH = 90 / 10), 1.0mL / min, Major enantiomer:t R =11.1min,minor enantiomer:t R =13.4min.HRMS(ESI)m / z:[M+Na] + Calcd forC 27 H 21 ClO4Na467.1021; Found 467.1016.

[0079] Example 6:

[0080]

[0081] The difference from Example 1 is that the substrate ketone used was (E)-4-(4-bromophenyl)-2-oxobut-3-enoic acid methyl ester (0.1 mmol, 26.9 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (45.7 mg, purity: 97.3%, yield: 91%, >99:1dr, 94:6er). 1 H NMR (500MHz, CDCl3) δ8.03-8.00(m,2H),7.52-7.48(m,3H),7.33(d,J=8.4Hz,4H),7.27-7.19(m,3H) ,7.07-7.03(m,3H),6.01(s,1H),4.67(d,J=12.3Hz,1H),4.44(dd,J=12.2,9.0Hz,1H),3.79(s,3H). 13 C NMR (125MHz, CDCl3) δ200.5,162.5,144.8,137.3,136.4,133.7,133.1,131.8, 130.9,129.8,128.8,128.5,127.7,127.4,121.3,107.9,64.2,52.5,45.2.[α] D 25 = -5.7 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =11.1min,minor enantiomer:t R =13.4min.HRMS(ESI)m / z:[M+Na] + Calcd for C 27 H 21 BrO4Na 511.0515; Found 511.0517.

[0082] Example 7:

[0083]

[0084] The difference from Example 1 is that the substrate ketone used was (E)-4-(2-methoxyphenyl)-2-oxobut-3-enoic acid ethyl ester (0.1 mmol, 23.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (33.9 mg, purity: 98.4%, yield: 76%, >99:1dr, 94:6er). 1H NMR (400MHz, CDCl3) δ8.04 (dd, J=6.7, 1.3Hz, 2H), 7.52-7.48 (m, 3H), 7.39 ( d,J=7.7Hz,2H),7.29(d,J=7.1Hz,1H),7.24-7.13(m,5H),6.87(t,J=7.5Hz, 1H),6.77(d,J=8.2Hz,1H),5.97(s,1H),5.08(dd,J=12.2,9.5Hz,1H),4.90( d,J=12.5Hz,1H),4.25(q,J=7.1Hz,2H),3.76(s,3H),1.28(t,J=7.1Hz,3H). 13 CNMR(100MHz, CDCl3)δ201.4,162.4,161.9,157.4,144.6,137.2,134.5,133.6,130.7,129.0,128. 8,128.5,128.5,128.2,127.5,127.3,126.2,120.9,111.0,107.2,63.2,61.7,55.4,38.8,14.1.[α] D 25 = -6.5 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 95 / 5), 1.0 mL / min, Major enantiomer:t R =11.3min,minor enantiomer:t R =12.6min.HRMS(ESI)m / z:[M+Na] + Calcd forC 28 H 24 O5Na 463.1516; Found 463.1515.

[0085] Example 8:

[0086]

[0087] The difference from Example 1 is that the substrate ketone used was (E)-2-oxo-4-(p-tolyl)but-3-enoate methyl ester (0.1 mmol, 20.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (34.7 mg, purity: 97.6%, yield: 80%, >99:1dr, 94.5:5.5er). 1H NMR (500MHz, CDCl3) δ8.02-8.00(m,2H),7.52-7.48(m,2H),7.37-7.35(m,2H),7.26-7.20(m,3H),7.08(dd,J=8.6,3.5Hz ,3H),7.02(d,J=8.0Hz,2H),5.97(s,1H),4.68(d,J=12.3Hz,1H),4.49(dd,J=12.1,9.2Hz,1H),3.78(s,3H),2.25(s,3H). 13 C NMR (125MHz, CDCl3) δ205.7,167.5,166.8,149.0,141.8,141.6,139.9,139.0,138.8,13 5.6,134.2,133.6,133.3,133.2,132.7,132.3,132.2,112.2,69.4,57.3,49.7,25.8.[α] D 25 =-11 (c=10mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254nm (n-hexane / i-PrOH=90 / 10), 1.0mL / min, Majoranantiomer:t R =9.2min,minor enantiom er:t R =12.1min.HRMS(ESI)m / z:[M+Na] + Calcdfor C 28 H 24 O4Na 447.1567; Found 447.1579.

[0088] Example 9:

[0089]

[0090] The difference from Example 1 is that the substrate ketone used was (E)-4-(4-methoxyphenyl)-2-oxobut-3-enoic acid methyl ester (0.1 mmol, 22.0 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (32.5 mg, purity: 98.8%, yield: 73%, >99:1dr, 92:8er). 1H NMR (500MHz, CDCl3) δ8.02-8.00(m,2H),7.53-7.47(m,3H),7.36-7.34(m,2H),7.26-7.18(m,3H),7.10(d,J=8.7Hz,2H),7.06(d ,J=9.0Hz,1H),6.76-6.73(m,2H),5.98(s,1H),4.66(d,J=12.3Hz,1H),4.44(dd,J=12.1,9.2Hz,1H),3.78(s,3H),3.73(s,3H). 13 C NMR (125MHz, CDCl3) δ201.0,162.7,162.2,158.7,144.3,136.9,134.2,133.9,130.8,13 0.1,129.1,128.8,128.5,128.4,127.5,127.4,114.1,107.6,64.6,55.1,52.5,44.7.[α] D 25 = -6.6 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =12.7min,minor enantiomer:t R =16.2min.HRMS(ESI)m / z:[M+Na] + Calcd for C 28 H 24 O5Na 463.1516; Found 463.1517.

[0091] Example 10:

[0092]

[0093] The difference from Example 1 is that the substrate ketone used was (E)-2-oxo-4-(thiophen-2-yl)but-3-enoate methyl ester (0.1 mmol, 19.6 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (32.1 mg, purity: 97.1%, yield: 75%, >99:1dr, 92:8er). 1H NMR (500MHz, CDCl3) δ8.00-7.97(m,2H),7.52-7.47(m,3H),7.44-7.41(m,2H),7.33-7.25(m,3H),7.11-7.09(m,2H),6.83(dd,J=5 .1,3.5Hz,1H),6.78(ddd,J=3.5,1.1,0.6Hz,1H),5.90(s,1H),4.92(dd,J=12.1,9.3Hz,1H),4.56(d,J=12.2Hz,1H),3.82(s,3H). 13 CNMR (125MHz, CDCl3) δ199.6,162.3,160.9,144.0,141.1,136.6,133.9,133.4,130.8 ,128.7,128.6,128.5,127.8,127.4,126.7,125.7,124.6,106.3,66.1,52.6,39.8.[α] D 25 = -5.8 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =10.0min,minor enantiomer:t R =13.4min.HRMS(ESI)m / z:[M+Na]+Calcd for C 25 H 20 O4SNa 439.0975;Found 439.0981.

[0094] Example 11:

[0095]

[0096] The difference from Example 1 is that the substrate ketone used was (E)-4-(naphth-1-yl)-2-oxobut-3-enoate methyl ester (0.1 mmol, 25.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (32.7 mg, purity: 98.3%, yield: 70%, >99:1dr, 94:6er). 1H NMR (400MHz, CDCl3) δ8.11(d,J=8.3Hz,1H),8.06(dt,J=7.2,1.6Hz,2H),7.83(d,J=7.9Hz,1H) ,7.73(d,J=8.2Hz,1H),7.58-7.53(m,5H),7.50(d,J=7.9Hz,1H),7.46(d,J=8.3Hz,2H),7.41(t ,J=7.7Hz,1H),7.20(t,J=7.6Hz,2H),7.14(t,J=7.2Hz,1H),6.99(d,J=9.5Hz,1H),5.91(s,1H ),5.64(t,J=10.7Hz,1H),5.04(d,J=12.4Hz,1H),4.25(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ200.4,161.9,160.7,144.0,136.5,134.6,134.5,133.9,132.2,130.8,129.0,128.6 ,128.6,128.5,128.1,127.6,127.6,126.6,125.8,125.5,124.6,122.7,105.9,63.4,61.9,29.7,14.0.[α] D 25 = -5.3 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =7.9min,minor enantiom er:t R =9.9min.HRMS(ESI)m / z:[M+Na] + Calcd for C 31 H 24 O4Na483.1567;Found 483.1550.

[0097] Example 12:

[0098]

[0099] The difference from Example 1 is that the substrate ketone used was (3E,5E)-2-oxo-6-phenylhexa-3,5-dienoic acid methyl ester (0.1 mmol, 21.6 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (32.2 mg, purity: 98.7%, yield: 73%, >99:1dr, 85:15er). 1 H NMR (500MHz, CDCl3) δ7.96-7.95(m,2H),7.51-7.46(m,5H),7.36(t,J=7.5Hz,2H),7.30(d,J=7.3Hz,1H),7.26-7.19(m,5H) ,6.99(d,J=8.6Hz,1H),6.39(d,J=15.9Hz,1H),5.97(dd,J=15.9,6.8Hz,1H),5.87(s,1H),4.30-4.22(m,2H),3.83(s,3H). 13 C NMR (125MHz, CDCl3) δ200.3,162.5,160.9,144.5,136.8,136.5,134.1,133.2,132.7,130 .8,128.8,128.5,128.5,127.8,127.7,127.4,126.3,126.2,106.4,64.1,52.6,41.7.[α] D 25 = -8.6 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Majoranantiomer:t R =11.2min,minor enantiomer:t R =20.0min.HRMS(ESI)m / z:[M+Na] + Calcd for C 29 H 24 O4Na 475.1306; Found 475.1305.

[0100] Example 13:

[0101]

[0102] The difference from Example 1 is that the substrate ketone used was ethyl (E)-2-oxo-4-phenylbut-3-enoate (0.1 mmol, 20.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (37.6 mg, purity: 99.0%, yield: 88%, >99:1dr, 94.5:5.5er). 1 H NMR (500MHz, CDCl3) δ8.07-8.05(m,2H),7.53-7.50(m,3H),7.41-7.39(m,2H),7.27-7.21(m,7H),7.18(dd,J=8.4,4.0Hz,1H),7.1 5(d,J=8.9Hz,1H),6.05(s,1H),4.78(d,J=12.3Hz,1H),4.54(dd,J=12.2,9.1Hz,1H),4.26(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H). 13 CNMR(125MHz, CDCl3)δ200.8,162.3,162.1,144.8,138.2,136.7,133.9,133.5,130.7,12 8.7,128.6,128.4,128.3,128.0,127.4,127.3,127.2,107.8,64.3,61.7,45.6,13.9.[α] D 25 = -9.1 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IF column at 254 nm (n-hexane / i-PrOH = 80 / 20), 1.0 mL / min, Majoranantiomer:t R =9.9min,minor enantiom er:t R =10.7min.HRMS(ESI)m / z:[M+Na] + Calcdfor C 28 H 24 O4Na 447.1567; Found 447.1571.

[0103] Example 14:

[0104]

[0105] The difference from Example 1 is that the substrate ketone used was (E)-2-oxo-4-phenylbut-3-enoic acid isopropyl ester (0.1 mmol, 21.8 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (41.8 mg, purity: 97.3%, yield: 93%, >99:1dr, 95:5er). 1 H NMR (500MHz, CDCl3) δ8.06-8.05(m,2H),7.53-7.49(m,3H),7.39-7.38(m,2H),7.27-7.22(m,7H),7.20-7.17(m,1H),7.11(d,J=8.9 Hz,1H),6.05(s,1H),5.11(hept,J=6.2Hz,1H),4.80(d,J=12.3Hz,1H),4.51(dd,J=12.1,9.1Hz,1H),1.25(dd,J=20.5,6.2Hz,6H). 13 CNMR(125MHz, CDCl3)δ200.9,162.6,161.6,145.2,138.3,136.8,134.0,133.1,130.7,128. 8,128.6,128.4,128.3,128.1,127.4,127.3,127.2,108.1,69.7,64.2,53.3,45.7,21.6.[α] D 25 =-7 (c=10mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: ID column at 254nm (n-hexane / i-PrOH=90 / 10), 1.0mL / min, Major enantiomer:t R =13.2min,minor enantiomer:t R =15.4min.HRMS(ESI)m / z:[M+Na] + Calcd for C 29 H 26 O4Na 461.1723; Found 461.1727.

[0106] Example 15:

[0107]

[0108] The difference from Example 1 is that the substrate ketone used was benzyl(E)-2-oxo-4-phenylbut-3-enoic acid (0.1 mmol, 26.6 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (46.0 mg, purity: 97.1%, yield: 92%, >99:1dr, 96:4er). 1 H NMR (500MHz, CDCl3) δ7.98-7.96(m,2H),7.50-7.47(m,1H),7.42(t,J=7.5Hz,2H),7.37-7.31(m,7H),7.24-7.1 6(m,8H),7.13(d,J=9.0Hz,1H),6.00(s,1H),5.20(s,2H),4.71(d,J=12.3Hz,1H),4.49(dd,J=12.2,9.1Hz,1H). 13 C NMR (125MHz, CDCl3) δ200.9,162.3,162.0,144.6,138.2,136.8,134.9,134.1,133.9,130.8,128 .8,128.7,128.6,128.5,128.5,128.4,128.1,127.5,127.4,127.4,107.8,67.7,64.5,45.7.[α] D 25 = -7.4 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =11.8min,minor enantiomer:t R =12.9min.HRMS(ESI)m / z:[M+Na] + Calcd forC 33 H 26 O4Na509.1723;Found 509.1729.

[0109] Example 16:

[0110]

[0111] The difference from Example 1 is that the substrate ketone used was (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl(E)-2-oxo-4-phenylbut-3-enoic acid (0.1 mmol, 31.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (51.0 mg, purity: 97.3%, yield: 93%, >99:1dr, 96:4er). 1 HNMR(400MHz, CDCl3)δ8.02(d,J=6.1Hz,2H),7.52(s,3H),7.36(d,J=7.1Hz,2H),7.24-7.18(m,7H ),7.10(d,J=8.7Hz,1H),6.06(d,J=13.3Hz,1H).,4.78(t,J=10.8Hz,2H),4.48(q,J=13.1Hz,1H),2 .04(t,J=12.8Hz,1H),1.84-1.67(m,4H),1.48(s,1H),1.31(d,J=11.2Hz,1H),1.11(dt,J=68.8,1 1.6Hz,2H),0.92(t,J=6.9Hz,3H),0.86(d,J=5.9Hz,2H),0.80(d,J=6.5Hz,2H),0.75-0.74(m,3H). 13 C NMR (100MHz, CDCl3) δ201.2,161.9,145.4,138.5,137.0,134.2,134.0,133.3,130.9,128.9,128.9,128.7,128.7,128. 5,128.4,128.3,128.2,127.5,127.4,76.2,76.1,46.8,40.8,40.6,34.1,31.4,26.1,23.3,23.2,22.0,20.8,16.11.[α] D 25 = -5.3 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 96 / 4), 1.0 mL / min, Major enantiomer:t R =13.3min,minor enantiomer:t R =12.2min.HRMS(ESI)m / z:[M+Na] + Calcd for C 36 H 38 O4Na557.2662;Found 557.2673.

[0112] Example 17:

[0113]

[0114] The difference from Example 1 is that the substrate ketone used was (S)-3,7-dimethyloct-6-en-1-yl(E)-2-oxo-4-phenylbut-3-enoic acid (0.1 mmol, 31.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (48.7 mg, purity: 98.6%, yield: 90%, >99:1dr, 96:4er). 1 H NMR (400MHz, CDCl3) δ8.02(d,J=6.9Hz,2H),7.50(d,J=6.3Hz,3H),7.35(d,J=7.3Hz,2H),7.29(s, 1H),7.24-7.20(m,8H),7.08(d,J=8.9Hz,1H),6.01(s,1H),5.08(s,1H),4.72(d,J=12.2Hz,1H),4 .49(t,J=10.5Hz,1H),4.22(d,J=4.0Hz,2H),2.03-1.90(m,2H),1.69(s,3H),1.61(s,4H),1.47(d dd,J=20.4,13.9,6.5Hz,2H),1.30(d,J=10.6Hz,2H),1.18(p,J=7.4Hz,1H),0.90(d,J=6.3Hz,3H). 13 C NMR (100MHz, CDCl3) δ201.1,162.4,144.9,138.4,136.4,134.0,133.1,131.4,130.9,128.9,128.7,128.5 ,128.5,128.2,127.6,127.4,127.4,124.5,77.2,62.7,45.7,36.6,34.3,29.4,25.7,24.9,19.3,17.3.[α] D 25 = -4.4 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =8.7min,minor enantiom er:t R =10.5min.HRMS(ESI)m / z:[M+Na]+ Calcd for C 36 H 38 O4Na 557.2662; Found 557.2681.

[0115] Example 18:

[0116]

[0117] The difference from Example 1 is that the substrate ketone used was (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptane-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-3-yl(E)-2-oxo-4-phenylbut-3-enoic acid (0.1 mmol, 54.5 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (69.2 mg, purity: 97.2%, yield: 88%, >99:1dr, 95:5er). 1 H NMR(400MHz, CDCl3)δ8.03(d,J=7.7Hz,2H),7.52(s,3H),7.36(d,J=7.3Hz,2H),7.29-7.18(m,9H), 7.08(d,J=8.8Hz,1H),6.05(s,1H),5.38(s,1H),4.80(d,J=12.2Hz,1H),4.72(d,J=11.8Hz,1H),4. 45(t,J=10.5Hz,1H),2.31(d,J=8.6Hz,1H),2.20(d,J=12.2Hz,1H),2.01(t,J=17.4Hz,2H),1.87(d ,J=12.2Hz,3H),1.62-1.30(m,13H),1.15-1.09(d,J=8.9Hz,5H),1.00-0.89(m,14H),0.71(s,3H). 13C NMR (100MHz, CDCl3) δ203.6,161.3,145.4,139.2,138.5,136.9,134.1,133.3,1 30.9,128.9,128.7,128.5,128.4,128.3,127.5,127.4,127.4,123.0,77.3,75. 8,64.1,57.6,56.1,50.0,46.1,43.3,39.7,39.5,37.8,36.9,36.6,36.2,35.4, 31.9,31.8,28.3,28.0,27.1,24.3,23.9,22.9,22.6,21.0,19.3,18.7,11.3.[α] D 25 = -6.8 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IF column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =13.1min,minor enantiomer:t R =19.0min.HRMS(ESI)m / z:[M+Na] + Calcd forC 53 H 64 O4Na 787.4697; Found 787.2672.

[0118] Example 19:

[0119]

[0120] The difference from Example 1 is that the substrate acetylacetonate used was 1-(2-fluorophenyl)-4-phenylbut-3-yn-2-one (0.12 mmol, 28.6 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (39.0 mg, purity: 98.7%, yield: 90%, >99:1dr, 93:7er). 1H NMR(500MHz, CDCl3)δ8.08-8.07(m,2H),7.73(td,J=7.3,2.1Hz,1H),7.54-7.49(m,3H),7.28-7.22(m,4H),7.20-7.12(m,3H),7.10 (d,J=8.5Hz,1H),6.87(ddd,J=9.7,7.7,1.5Hz,1H),6.16(s,1H),5.39(d,J=12.5Hz,1H),4.44(dd,J=12.5,8.6Hz,1H),3.76(s,3H). 13 C NMR (125MHz, CDCl3) δ200.1,164.2,162.7,161.5(d, 1 J C-F =245.1Hz),145.0,137.9,133.6,133.2,131.0,129.8(d, 4 J C-F =3.3Hz), 128.8(d, 3 J C-F =8.4Hz),128.7,128.4,128.0,127.5,124.2(d, 2 J C-F =13.8Hz), 123.9(d, 4 J C-F =3.2Hz), 115.2(d, 2 J C-F =22.9Hz),109.1,54.0,52.4,45.4.[α] D 25 = -4.7 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =10.3min,minor enantiomer:t R =14.3min.HRMS(ESI)m / z:[M+Na] + Calcd for C 27 H 21 FO4Na 451.1316;Found 451.1317.

[0121] Example 20:

[0122]

[0123] The difference from Example 1 is that the substrate acetylene used was 1-(2-chlorophenyl)-4-phenylbut-3-yn-2-one (0.12 mmol, 30.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (38.2 mg, purity: 97.6%, yield: 84%, >99:1dr, 92:8er). 1 H NMR(500MHz, CDCl3)δ8.08-8.07(m,2H),7.80(dd,J=7.9,1.4Hz,1H),7.54-7.49(m,3H),7.30-7.26(m,3H),7.24 -7.16(m,4H),7.12-7.08(m,2H),6.18(s,1H),5.85(d,J=12.5Hz,1H),4.35(dd,J=12.5,8.3Hz,1H),3.75(s,3H). 13 C NMR (125MHz, CDCl3) δ200.2,165.0,162.9,145.3,137.8,134.6,134.5,133.5,133.0,131.1, 129.7,129.4,128.7,128.5,128.3,128.2,127.6,127.5,126.6,110.0,56.1,52.4,46.0.[α] D 25 = -4.8 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =11.1min,minor enantiomer:t R =13.9min.HRMS(ESI)m / z:[M+Na] + Calcd forC 27 H 21 ClO4Na467.1021; Found 467.1025.

[0124] Example 21:

[0125]

[0126] The difference from Example 1 is that the substrate acetylene used was 1-(3-chlorophenyl)-4-phenylbut-3-yn-2-one (0.12 mmol, 30.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (40.1 mg, purity: 97.4%, yield: 88%, >99:1dr, 88:12er). 1 H NMR (500MHz, CDCl3) δ8.04-8.02(m,2H),7.53-7.49(m,3H),7.39(d,J=1.8Hz,1H),7.25-7.22(m,2H),7.20-7.18(m,4H), 7.17-7.12(m,2H),7.07(d,J=8.7Hz,1H),6.06(s,1H),4.78(d,J=12.3Hz,1H),4.36(dd,J=12.2,8.8Hz,1H),3.77(s,3H). 13 C NMR (125MHz, CDCl3) δ205.0,168.5,167.5,149.8,143.6,142.7,138.9,138.4,138.1,135.9, 134.3,133.8,133.6,133.3,132.9,132.5,132.4,132.3,131.9,113.2,68.0,57.3,50.9.[α] D 25 = -3.3 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =11.2min,minor enantiomer:t R =12.4min.HRMS(ESI)m / z:[M+Na] + Calcd forC 27 H 21 ClO4Na 467.1021; Found 467.1024.

[0127] Example 22:

[0128]

[0129] The difference from Example 1 is that the substrate acetylene used was 1-(4-chlorophenyl)-4-phenylbut-3-yn-2-one (0.12 mmol, 30.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (36.2 mg, purity: 98.0%, yield: 80%, >99:1dr, 90:10er). 1 H NMR (400MHz, CDCl3) δ8.05-8.03(m,2H),7.54-7.49(m,3H),7.30(d,J=8.9Hz,2H),7.24-7.18(m,6H), 7.09(d,J=8.7Hz,1H),6.06(s,1H),4.80(d,J=12.3Hz,1H),4.37(dd,J=12.2,8.8Hz,1H),3.78(s,3H). 13 C NMR (100MHz, CDCl3) δ200.5,163.6,162.7,145.0,138.1,135.5,133.7,133.5,133 .4,131.1,130.2,128.9,128.6,128.2,127.6,127.5,108.4,63.2,52.5,46.2.[α] D 25 = -4.4 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =10.3min,minor enantiomer:t R =12.6min.HRMS(ESI)m / z:[M+Na] + Calcd for C 27 H 21 ClO4Na 467.1021; Found 467.1023.

[0130] Example 23:

[0131]

[0132] The difference from Example 1 is that the substrate acetylene used was 4-phenyl-1-(o-tolyl)but-3-yn-2-one (0.12 mmol, 28.0 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (36.8 mg, purity: 97.7%, yield: 85%, >99:1dr, 97:3er). 1H NMR(500MHz, CDCl3)δ8.00(dd,J=7.7,1.9Hz,2H),7.75(d,J=7.7Hz,1H),7.53-7.48(m,3H),7.24-7.19(m,5H),7.18-7.14(m,2H),7.08(t d,J=7.4,1.0Hz,1H),7.00(d,J=7.4Hz,1H),5.91(s,1H),5.01(d,J=12.3Hz,1H),4.62(dd,J=12.2,9.4Hz,1H),3.81(s,3H),2.19(s,3H). 13 C NMR (125MHz, CDCl3) δ200.5,162.6,160.8,144.1,138.2,137.1,135.1,134.2,134.0,130.8,13 0.5,128.6,128.6,127.9,127.5,127.5,127.4,127.2,126.1,106.9,59.5,52.5,44.9,20.1.[α] D 25 = -8.9 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =9.2min,minor enantiom er:t R =10.7min.HRMS(ESI)m / z:[M+Na] + Calcd for C 28 H 24 O4Na 447.1567; Found 447.1568.

[0133] Example 24:

[0134]

[0135] The difference from Example 1 is that the substrate acetylene used was 1-(2-methoxyphenyl)-4-phenylbut-3-yn-2-one (0.12 mmol, 30.0 mg), and the other reaction conditions and operating steps were the same as in Example 1 (36.7 mg, purity: 99.3%, yield: 83%, >99:1dr, 95.5:4.5er). 1H NMR (500MHz, CDCl3) δ8.06-8.04 (m, 2H), 7.63 (dd, J = 7.7, 1.5Hz, 1H), 7.52-7. 50(m,3H),7.28-7.27(m,2H),7.21(t,J=7.5Hz,2H),7.17-7.13(m,2H),7.09(d ,J=9.1Hz,1H),6.93(td,J=7.6,0.9Hz,1H),6.72-6.70(m,1H),6.06(s,1H),5 .44(d,J=12.6Hz,1H),4.53(dd,J=12.5,9.1Hz,1H),3.77(s,3H),3.64(s,3H). 13 CNMR(125MHz, CDCl3)δ201.4,162.8,161.7,157.1,144.2,138.5,134.2,134.1,130.7,128.7,12 8.5,128.5,128.3,128.1,127.4,127.2,125.8,120.5,110.9,108.3,55.6,54.5,52.4,44.8.[α] D 25 = -6.2 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =11.9min,minor enantiomer:t R =13.8min.HRMS(ESI)m / z:[M+Na] + Calcd forC 28 H 24 O5Na 463.1516; Found 463.1514.

[0136] Example 25:

[0137]

[0138] The difference from Example 1 is that the substrate acetylene used was 4-phenyl-1-(p-tolyl)but-3-yn-2-one (0.12 mmol, 28.0 mg), and the other reaction conditions and operating steps were the same as in Example 1 (37.5 mg, purity: 97.1%, yield: 86%, >99:1dr, 95:5er). 1H NMR (500MHz, CDCl3) δ8.01-7.99(m,2H),7.52-7.48(m,3H),7.25-7.16(m,7H),7.09(d,J=8.9Hz,1H),7.05(d ,J=7.9Hz,2H),5.94(s,1H),4.63(d,J=12.4Hz,1H),4.53(dd,J=12.2,9.2Hz,1H),3.79(s,3H),2.27(s,3H). 13 C NMR (125MHz, CDCl3) δ200.9,162.6,161.5,144.2,138.3,137.2,134.2,134.1,133.6,13 0.8,129.2,128.7,128.5,128.5,128.1,127.4,127.3,107.1,64.5,52.5,45.1,21.0.[α] D 25 = -11.7 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 85 / 15), 1.0 mL / min, Major enantiomer:t R =7.8min,minor enantiomer:t R =10.6min.HRMS(ESI)m / z:[M+Na] + Calcd for C 28 H 24 O4Na 447.1567; Found447.1565.

[0139] Example 26:

[0140]

[0141] The difference from Example 1 is that the substrate acetylacetonate used was 1-(2-methoxyphenyl)-4-phenylbut-3-yn-2-one (0.12 mmol, 30.0 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (35.9 mg, purity: 98.0%, yield: 80%, >99:1dr, 94:6er). 1H NMR (500MHz, CDCl3) δ8.02-8.00(m,2H),7.52-7.48(m,3H),7.28(d,J=2.1Hz,1H),7.27-7.26(m,1H),7.23-7.16(m,5H),7.10(d ,J=9.0Hz,1H),6.80-6.75(m,2H),5.97(s,1H),4.62(d,J=12.3Hz,1H),4.48(dd,J=12.0,9.3Hz,1H),3.79(s,3H),3.74(s,3H). 13 C NMR (125MHz, CDCl3) δ201.1,162.6,161.6,158.9,144.3,138.4,134.1,134.0,130.8,12 9.7,128.8,128.7,128.5,128.1,127.4,127.3,113.9,107.3,63.9,55.1,52.5,45.4.[α] D 25 = -10.9 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer: t R =13.5min,minor enantiomer:t R =18.2min.HRMS(ESI)m / z:[M+Na] + Calcd for C 28 H 24 O5Na 463.1516; Found 463.1518.

[0142] Example 27:

[0143]

[0144] The difference from Example 1 is that the substrate acetylene used was 4-(2-chlorophenyl)-1-phenylbut-3-yn-2-one (0.12 mmol, 30.4 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (34.3 mg, purity: 97.9%, yield: 76%, >99:1dr, 95.5:4.5er). 1H NMR (500MHz, CDCl3) δ8.00-7.98(m,1H),7.52-7.50(m,1H),7.45-7.43(m,2H),7.41-7.39(m,2H),7.25-7.22(m,6H),7.2 0-7.18(m,2H),7.02(d,J=10.0Hz,1H),5.63(s,1H),4.87(dd,J=12.4,10.0Hz,1H),4.43(d,J=12.4Hz,1H),3.80(s,3H). 13 C NMR (125MHz, CDCl3) δ200.2,162.3,155.8,142.6,137.9,135.9,134.4,134.0,132.5,131.2, 130.8,130.2,128.8,128.8,128.6,128.0,127.7,127.4,127.0,109.7,65.3,52.6,43.6.[α] D 25 = -8.8 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =7.6min,minor enantiom er:t R =8.2min.HRMS(ESI)m / z:[M+Na] + Calcd forC 27 H 21 ClO4Na 467.1021; Found 467.1020.

[0145] Example 28:

[0146]

[0147] The difference from Example 1 is that the substrate acetylacetonate used was 4-(4-fluorophenyl)-1-phenylbut-3-yn-2-one (0.12 mmol, 28.6 mg), and the other reaction conditions and operating steps were the same as in Example 1 (38.7 mg, purity: 97.2%, yield: 88%, >99:1dr, 95.5:4.5er). 1H NMR (500MHz, CDCl3) δ8.05-8.02(m,2H),7.37-7.35(m,2H),7.28-7.17(m,10H),7.12(d,J= 8.9Hz,1H),5.95(s,1H),4.74(d,J=12.3Hz,1H),4.50(dd,J=12.2,9.1Hz,1H),3.79(s,3H). 13 C NMR(125MHz,CDCl3)δ200.6,165.4(d, 1 J C-F =250.5Hz),162.6,161.6,144.4,138.1,136.6,134.0,130.0(d, 4 J C-F =2.8Hz), 129.6(d, 3 J C-F =8.6Hz),128.8,128.7,128.4,128.1,127.5,127.4,115.6(d, 2 J C-F =21.8Hz),107.7,64.3,52.5,45.6.[α] D 25 = -8.5 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer: t R =8.5min,minor enantiom er:t R =10.6min.HRMS(ESI)m / z:[M+Na] + Calcd forC 27 H 21 FO4Na 451.1316;Found 451.1317.

[0148] Example 29:

[0149]

[0150] The difference from Example 1 is that the substrate acetylacetonate used was 1-phenyl-4-(m-tolyl)but-3-yn-2-one (0.12 mmol, 30.0 mg), and the other reaction conditions and operating steps were the same as in Example 1 (40.8 mg, purity: 98.1%, yield: 91%, >99:1dr, 95.5:4.5er). 1H NMR (500MHz, CDCl3) δ7.65-7.64(m,1H),7.55-7.53(m,1H),7.39(t,J=8.0Hz,1H),7.35-7.34(m,2H),7.25-7.16(m,8H),7.09(d,J=9.0 Hz,1H),7.06(ddd,J=8.2,2.6,0.7Hz,1H),5.98(s,1H),4.68(d,J=12.4Hz,1H),4.50(dd,J=12.3,9.1Hz,1H),3.91(s,3H),3.79(s,3H). 13 C NMR (125MHz, CDCl3) δ200.8,162.6,159.7,144.4,138.2,136.7,135.4,133.9,129.5,128.8 ,128.7,128.4,128.1,127.5,127.4,119.8,116.8,112.8,107.7,64.6,55.4,52.5,45.5.[α] D 25 = -9.2 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =13.3min,minor enantiomer:t R =15.0min.HRMS(ESI)m / z:[M+Na] + Calcd for C 28 H 24 O5Na 463.1516; Found 463.1518.

[0151] Example 30:

[0152]

[0153] The difference from Example 1 is that the substrate acetylacetonate used was 1-phenyl-4-(p-toluene)but-3-yn-2-one (0.12 mmol, 28.0 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (40.1 mg, purity: 97.4%, yield: 92%, >99:1dr, 94:6er). 1H NMR (500MHz, CDCl3) δ7.94(d,J=8.3Hz,2H),7.37-7.35(m,2H),7.32(d,J=8.0Hz,2H),7.25-7.16(m,8H),7.11 (d,J=8.9Hz,1H),6.00(s,1H),4.76(d,J=12.3Hz,1H),4.48(dd,J=12.2,9.0Hz,1H),3.78(s,3H),2.46(s,3H). 13 C NMR (125MHz, CDCl3) δ200.9,162.8,162.7,144.6,141.3,138.3,136.9,133.8,131.0 ,129.2,128.8,128.6,128.3,128.1,127.4,127.3,107.2,64.3,52.4,45.8,21.4.[α] D 25 =-10 (c=10mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254nm (n-hexane / i-PrOH=90 / 10), 1.0mL / min, Major enantiomer:t R =9.0min,minor enantiomer:t R =11.0min.HRMS(ESI)m / z:[M+Na] + Calcd for C 28 H 24 O4Na 447.1567; Found447.1568.

[0154] Example 31:

[0155]

[0156] The difference from Example 1 is that the substrate acetylene used was 1-phenylhept-3-yn-2-one (0.12 mmol, 22.3 mg), and the other reaction conditions and operating procedures were the same as in Example 1 (34.1 mg, purity: 98.0%, yield: 89%, >99:1dr, 96:4er). 1H NMR (500MHz, CDCl3) δ7.30-7.28(m,2H),7.22-7.13(m,8H),6.92(d,J=9.0Hz,1H),5.29(s,1H),4.57(d,J=12.3Hz,1H),4.39(dd,J=1 2.3,9.1Hz,1H),3.78(s,3H),2.55(dddd,J=49.7,15.3,8.5,6.5Hz,2H),1.79(ddh,J=20.2,12.9,6.2Hz,2H),1.09(t,J=7.4Hz,3H). 13 C NMR (125MHz, CDCl3) δ201.3,166.2,162.7,143.9,138.3,136.7,132.7,128.7,1 28.6,128.3,128.1,127.4,127.2,108.2,63.9,52.4,45.2,37.5,20.0,13.6.[α] D 25 = -8.2 (c = 10 mg / mL in CH2Cl2). Stereoselectivity was determined by chiral HPLC under the following conditions: IB column at 254 nm (n-hexane / i-PrOH = 90 / 10), 1.0 mL / min, Major enantiomer:t R =15.4min,minor enantiomer:t R =22.2min.HRMS(ESI)m / z:[M+Na] + Calcd forC 24 H 24 O4Na399.1567; Found 399.1571.

[0157] Example 32:

[0158]

[0159] The difference from Example 1 is that no chiral catalyst was added to the reaction system, and the other reaction conditions and operating steps were the same as in Example 1 (36.9 mg, purity: 99.0%, yield: 90%, >99:1dr, 50:50er).

[0160] Example 33:

[0161]

[0162] The difference from Example 1 is that different equivalence ratios of acetylacetonates were used in the reaction, and the results are shown in Table 4 below:

[0163] Table 4

[0164] 1 0.1mmol 87 94:6 2 0.14mmol 94 95:5 3 0.16mmol 95 94:6 4 0.18mmol 96 94:6 5 0.2mmol 96 94:6

[0165] In Table 4, the superscript a indicates the separation yield, and b indicates the corresponding selectivity obtained by chiral high performance liquid chromatography analysis.

[0166] Example 34:

[0167]

[0168] The difference from Example 1 is that different percentages of (7)-b were used in the reaction, and the results are shown in Table 5 below:

[0169] Table 5

[0170] 1 0.001mol 46 95:5 2 0.004mol 76 96:4 3 0.007mol 86 96:4

[0171] In Table 5, the superscript a indicates the separation yield, and b indicates the corresponding selectivity obtained by chiral high performance liquid chromatography analysis.

[0172] Example 35:

[0173]

[0174] The difference from Example 1 is that different percentages of DBU were used in the reaction, and the results are shown in Table 6 below:

[0175] Table 6

[0176] 1 0.01mol 86 96:4 2 0.05mol 94 96:4 3 0.07mol 95 96:4 4 0.1mol 95 96:4

[0177] In Table 6, the superscript a indicates the separation yield, and b indicates the corresponding selectivity obtained by chiral high performance liquid chromatography analysis.

[0178] Example 36

[0179] Selected compounds from the synthesized compounds were subjected to biological testing.

[0180]

[0181] Experimental procedure: MCF-7 cells in logarithmic growth phase were collected, cell counts were performed, and cell concentration was adjusted to 6 × 10⁻⁶ cells / cells. 3 / wells were seeded into 96-well plates. Following the grouping and treatment described above, the plates were incubated at 37°C with 5% CO2 for 72 hours. The culture medium was removed, and each well was washed three times with PBS. 10% CCK-8 medium was added to each well at 100 μL / well, and the plates were incubated at 37°C with 5% CO2 for 2 hours. 75 μL of the medium was transferred to a new 96-well plate, and the absorbance at 450 nm was measured using a microplate reader.

[0182] Table 7

[0183]

[0184]

[0185] Note: MCF-7 cells are human breast cancer cells.

[0186] The background group refers to the culture medium that does not contain MCF-7 cells or samples.

[0187] The control group refers to the culture medium containing MCF-7 cells but without the sample.

[0188] The OD value represents the absorbance of the culture medium.

[0189] IC50 refers to the drug concentration required to reduce the number of surviving cells by half after drug administration.

[0190] To investigate the potential bioactivity of the prepared compounds, the anticancer activity of some chiral eight-membered ring ethers against human breast cancer cells was tested, as shown in Table 7. The chiral products exhibited strong anticancer activity against human breast cancer cells, with IC50 values ​​all below 62.5 μg / mL. At a concentration of 62.5 μg / mL, the tested compounds all showed inhibition rates of over 70% against human breast cancer cells. Among them, compounds 3-6 exhibited the strongest anticancer activity against human breast cancer cells, with an inhibition rate of 96.65%.

[0191] Figure 1 The control group is a photograph of human breast cancer cell culture medium without the added sample. All other images were taken after the human breast cancer cell culture medium was treated with the sample (concentration of 62.5 μg / mL).

Claims

1. A chiral eight-membered ring ether compound as shown in formula (3), in, R 1 A phenyl group that is substituted with a phenyl or halogen; R 2 It is a C1-C4 alkyl group; R 3 It is a phenyl group or a phenyl group substituted with methyl, methoxy, or halogen. R 4 It is a phenyl or a phenyl substituted with a C1-C4 alkyl group or a halogen.

2. The chiral eight-membered ring ether compound as described in claim 1, characterized in that... The chiral eight-membered ring ether compound is one of the following: 。 3. The use of the chiral eight-membered ring ether compound as described in claim 1 in the preparation of an antitumor drug, wherein the tumor is human breast cancer.

4. The method for synthesizing chiral eight-membered ring ether compounds as described in claim 1, characterized in that... The method is as follows: Using the compounds shown in formula (1) and formula (2) as raw materials, an asymmetric addition reaction was carried out in organic solvent A at room temperature under the action of a chiral catalyst until the reaction was complete. The resulting reaction solution A was separated and purified to obtain an addition product containing the compound shown in formula (10). （10） The addition product containing the compound shown in formula (10) was dissolved in organic solvent B, and 1,8-diazabicycloundec-7-ene was added. The cyclization reaction was carried out at room temperature for 1-4 hours. The resulting reaction solution B was post-treated to obtain the chiral eight-membered ring ether compound shown in formula (3). The molar ratio of the compound shown in formula (1), the compound shown in formula (2) to the chiral catalyst is 1:1.0~2.0:0.01~0.1; the molar ratio of 1,8-diazabicycloundec-7-ene to the compound shown in formula (1) is 0.1~1:1; In equations (1), (2), (3), and (10), R 1 It is a phenyl group or a phenyl group substituted with a halogen; R 2 It is a C1-C4 alkyl group; R 3 It is a phenyl group or a phenyl group substituted with methyl, methoxy, or halogen. R 4 It is a phenyl group or a phenyl group substituted with a C1-C4 alkyl group or a halogen; The chiral catalyst is one of the following compounds: In formula (4) or (5), the carbon atom marked with * is a chiral carbon atom; In equations (4), (5), or (7), R 5 R 8 、or R 14 Each is independently a phenyl, a phenyl C1-C4 alkyl group, or a phenyl group substituted with a trifluoromethyl group; R 6 R 7 R 9 Or R 10 Each is independent and can be C1 to C2. 10 Alkyl groups; R 15 Each is independently a C2-C4 alkenyl group; R 16 Each can be an H or C1-C4 alkoxy group.

5. The method for synthesizing chiral eight-membered ring ether compounds as described in claim 4, characterized in that: The chiral catalyst is selected from (4)-a or (5)-a, or may be replaced by (6)-a, (6)-b, (7)-a, (7)-b, (7)-c, (7)-e, (7)-f, or (7)-g: 　 。 6. The method for synthesizing chiral eight-membered ring ether compounds as described in claim 4, characterized in that: The organic solvent A is one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, and 1,4-dioxane; The organic solvent B is one or more of dichloromethane, diethyl ether, chloroform, tetrahydrofuran, and 1,4-dioxane.

7. The method for synthesizing chiral eight-membered ring ether compounds as described in claim 4, characterized in that: The volume of organic solvent A is 5 to 20 mL / mmol, calculated as the amount of the compound shown in formula (1); the volume of organic solvent B is 5 to 20 mL / mmol, calculated as the amount of the compound shown in formula (1).

8. The method for synthesizing chiral eight-membered ring ether compounds as described in claim 4, characterized in that: The separation and purification process is as follows: the reaction solution A is concentrated under reduced pressure, and a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 30:1 is used as the eluent for silica gel column chromatography. The eluent containing the addition product is collected, and the solvent is removed by evaporation to obtain the addition product containing the compound shown in formula (10).

9. The method for synthesizing chiral eight-membered ring ether compounds as described in claim 4, characterized in that: The post-processing is as follows: the reaction solution B is concentrated under reduced pressure, and silica gel column chromatography is performed using a mixture of petroleum ether and ethyl acetate with a volume ratio of 1 to 30:1 as the eluent. The eluent containing the target compound is collected, and the solvent is evaporated to obtain the chiral eight-membered ring ether compound shown in product formula (3).

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