Chiral furan naphthoacenaphthene derivative, preparation method thereof and application of chiral furan naphthoacenaphthene derivative in antitumor activity

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a chiral furan naphthoacenaphthene derivative, a preparation method thereof and application of the chiral furan naphthoacenaphthene derivative in antitumor activity. Compared with the prior art, the chiral furan naphtho-acenaphthene derivative is obtained through asymmetric domino-aza-Friedel-Crafts / hemiketal reaction of acenaphthequinone imine and naphthol which are different in substitution, the reaction enantioselectivity is high, the yield is good, the reaction is complete, no by-product is detected in a nuclear magnetic hydrogen spectrum and a carbon spectrum, a high-enantiomer optical pure compound can be obtained, and the chiral furan naphtho-acenaphthene derivative can be used for preparing the chiral furan naphtho-acenaphthene derivative. And the method has the advantages of wide substrate universality, potential antitumor activity of the furan naphtho acenaphthene derivative generated by the reaction, simple operation, mild reaction conditions, and environmental protection.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and particularly relates to a chiral furan naphthalene derivative, its preparation method, and its application in antitumor activity. Background Technology

[0002] Acenathoquinone is an important skeleton in many bioactive natural products and synthetic compounds, and can be used in antibacterial, antifungal, anticancer, and antitumor drugs, playing a vital role in photochemistry, electrochemistry, and organic synthesis. Furthermore, acenathoquinone has been widely used as a starting material for the synthesis of heterocyclic compounds in multicomponent reactions. Most nucleophilic additions occur at one carbonyl group of acenathoquinone to construct spirocyclic orthoquinone analogs, while only a limited number of biadditions involving two carbonyl groups lead to the formation of bridged polycyclic compounds. Notably, the C8 and C9 dicarbonyl groups of acenathoquinone are prochiral nucleophilic addition sites, which can undergo asymmetric addition reactions with many nucleophiles to yield chiral adducts. However, enantioselective transformations using acenathoquinone as a substrate are rarely reported.

[0003] Dihydronaphthofuran scaffolds are the core structure of many natural and synthetic bioactive molecules and have wide applications. Currently, only a few asymmetric methods are available for constructing optically pure dihydronaphthofurans. In 2017, Enders' group reported an asymmetric domino aza-Friedel-Crafts / N,O-acetalization reaction of pyrazolone imines and 2-naphthol, providing a series of novel furanonaphthopyrazolone derivatives. However, in the presence of 1-naphthol and other electron-rich phenols, only the corresponding aza-Friedel-Crafts adducts are obtained due to their different reactivity. Summary of the Invention

[0004] In view of this, the technical problem to be solved by the present invention is to provide a chiral furanonaphthene derivative, its preparation method and its application in antitumor activity, wherein the preparation method has high enantioselectivity and good yield.

[0005] This invention provides a chiral furanonaphthene derivative, characterized in that it is a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt, deuterated derivative, optical isomer, solvate, hydrate, complex, or chelate thereof:

[0006]

[0007] In formulas (I), (II) and (III), R1 is independently selected from H, halogen, C1-C10 alkyl or C1-C10 alkoxy.

[0008] R2, R3 and R5 are each independently selected from halogens, C1-C10 alkyl groups, C1-C10 alkoxy groups or cyano groups;

[0009] n, m, and p are the number of substituents, each independently selected from integers from 0 to 4;

[0010] In formulas (I), (II) and (III), R4 is independently selected from the protected amino group or amino group.

[0011] More specifically, R1 in formulas (I), (II) and (III) is independently selected from H, halogen, C1-C5 alkyl or C1-C5 alkoxy.

[0012] More specifically, R1 in formulas (I), (II) and (III) is independently selected from H, halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0013] More specifically, the halogen is selected from Br or Cl.

[0014] In one specific embodiment of the present invention, R1 in formulas (I), (II) and (III) is independently selected from H, Br, methyl or methoxy.

[0015] More specifically, R2, R3 and R5 are each independently selected from halogens, C1-C5 alkyl groups, C1-C5 alkoxy groups or cyano groups.

[0016] More specifically, R2, R3 and R5 are each independently selected from halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups or cyano groups.

[0017] In one specific embodiment of the present invention, R2, R3 and R5 are each independently selected from Br, Cl, methyl, ethyl, methoxy, ethoxy or cyano.

[0018] n, m, and p are the number of substituents on the aromatic ring, each independently selected from an integer from 0 to 4; more specifically, n, m, and p are each independently selected from an integer from 0 to 3; even more specifically, n, m, and p are each independently selected from 0, 1, or 2.

[0019] In a specific embodiment of the present invention, R4 in formulas (I), (II) and (III) is independently selected from the protected amino group or amino group; the protected amino group can be any protected amino group known to those skilled in the art, and there are no special limitations, including but not limited to Cbz-NH-, Boc-NH-, Fmoc-NH-, Alloc-NH-, Teoc-NH-, etc.

[0020] In a specific embodiment of the present invention, the chiral furanonaphthene derivatives, such as compounds of formulas 5aa-5af, 5ba-5bf, 6aa-6ah, 6ba-6bh, 7, or 8, or their pharmaceutically acceptable salts, deuterated derivatives, optical isomers, solvates, hydrates, complexes, chelates, or derivatives, are described below.

[0021]

[0022]

[0023] The chiral furanonaphthene derivatives provided by this invention can be obtained through an organocatalytic asymmetric domino reaction. Cell experiments have shown that the synthesized compounds have good antitumor activity.

[0024] The present invention also provides a method for preparing the above-mentioned chiral furanonaphthene derivative, comprising the following steps: reacting a acenaphthene compound of formula (A) with a phenolic compound in an organic solvent in the presence of a catalyst to obtain a chiral furanonaphthene derivative; wherein the phenolic compound has a structure shown in formula (B), formula (C) or formula (D); and wherein the catalyst is selected from catalysts containing a chiral cinchonasal base structure and / or Takemoto-type catalysts.

[0025]

[0026] This invention combines two moieties into a single molecule by biaddition of a acenaphthene-derived ketimine to a naphthol containing two nucleophilic centers. This asymmetric dominoaza-Friedel-Crafts / hemacol reaction provides a valuable pathway for the synthesis of novel chiral polycyclic compounds containing dihydronaphthofuran and an acenaphthene skeleton. Furthermore, both 2-naphthol and 1-naphthol, along with other electron-rich phenols, exhibit the same reactivity for the dominoaza-Friedel-Crafts / hemacol reaction.

[0027] In a specific embodiment of the present invention, the compound represented by formula (A) is prepared by the following method: the compound represented by formula (E) is reacted with N-Bocamidine triphenylphosphine in an organic solvent under reflux, cooled and solidified, then dissolved under reflux in ethyl acetate, and recrystallized to obtain the compound represented by formula (A); the organic solvent is preferably toluene; the molar ratio of the compound represented by formula (E) to N-Bocamidine triphenylphosphine is preferably 1:1 to 1.2, more preferably 1:1.05 to 1.1; the temperature of the reflux reaction is preferably 100℃ to 120℃, more preferably 110℃; the time of the reflux reaction is preferably 2 to 6 h, more preferably 3 to 5 h, and even more preferably 4 h.

[0028]

[0029] In a specific embodiment of the present invention, the compound represented by formula (E) is preferably obtained by oxidizing the compound represented by formula (F); the oxidant used for oxidation can be any oxidant well known to those skilled in the art, and there are no special limitations. In the present invention, a chromium trioxide and acetic anhydride system is preferred; more specifically, the compound represented by formula (E) is mixed with an acetic anhydride solution, heated to the reaction temperature, and then a chromium trioxide acetic anhydride solution is added under stirring to react and obtain the compound represented by formula (E); the molar ratio of the compound represented by formula (F) to chromium trioxide is preferably 0.1 to 0.5:1, more preferably 0.2 to 0.4:1, and even more preferably 0.3:1; the concentration of chromium trioxide in the chromium trioxide acetic anhydride solution is preferably 1 to 2 ppm. The concentration of the hydrochloric acid is preferably 1.5–1.7 mol / L, more preferably 1.5–1.7 mol / L; the reaction temperature is preferably 60–80 °C, more preferably 70 °C; the reaction time is preferably 1–2 h, more preferably 1.5 h; after the reaction is completed, it is preferably cooled to room temperature, the reaction solution is mixed with ice water, then concentrated hydrochloric acid is added, filtered, dried, and recrystallized in toluene to obtain the compound shown in formula (E); the volume ratio of the reaction solution to ice water is preferably (10–20):20, more preferably (10–15):20, and even more preferably (12–15):20; the mass concentration of the concentrated hydrochloric acid is preferably 36%–38%; the volume ratio of the reaction solution to concentrated hydrochloric acid is preferably (10–20):4, more preferably (10–15):4, and even more preferably (12–15):4.

[0030]

[0031] In one specific embodiment of the present invention, the catalyst is preferably one or more of chiral cinchona alkaloid, cinchona alkaloid-squamamide, and Takemoto-type catalyst.

[0032] In one specific embodiment of the present invention, the catalyst is preferably one or more selected from 1a to 1h:

[0033]

[0034] In one specific embodiment of the present invention, the molar amount of the catalyst is preferably 1% to 10% of the molar amount of the acenaphthoquinone compound shown in formula (A); optionally, the molar amount of the catalyst is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% of the molar amount of the acenaphthoquinone compound shown in formula (A) or a range between any two of the above values.

[0035] In one specific embodiment of the present invention, the organic solvent is preferably one or more selected from dichloromethane, trichloromethane, 1,2-dichloroethane, toluene, and diethyl ether.

[0036] In a specific embodiment of the present invention, the ratio of the acenaphthoquinone compound shown in formula (A) to the organic solvent is preferably (0.01-0.5) mmol:1 ml; optionally, the ratio of the acenaphthoquinone compound shown in formula (A) to the organic solvent is 0.01 mmol:1 ml, 0.05 mmol:1 ml, 0.1 mmol:1 ml, 0.2 mmol:1 ml, 0.5 mmol:1 ml, or any two of the above values.

[0037] In one specific embodiment of the present invention, the reaction is carried out under closed conditions; the reaction temperature is preferably 0°C to room temperature, more preferably 5°C to room temperature, even more preferably 10°C to room temperature, and most preferably 15°C to room temperature; the reaction time is preferably 12 to 48 hours; optionally, the reaction time is 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 ​​hours or any two of the above values.

[0038] In a specific embodiment of the present invention, taking R4 as the Boc-protected amino group as an example, the chiral furanonaphthene derivative is prepared according to the following synthetic route:

[0039]

[0040] In a specific embodiment of the present invention, the chiral furanonaphthene derivative is preferably obtained by column chromatography after the reaction; the eluent for the column chromatography purification is n-hexane and ethyl acetate; the volume ratio of n-hexane to ethyl acetate is preferably (3-5):1; optionally, the volume ratio of n-hexane to ethyl acetate is 3:1, 4:1, 5:1 or any two of the above values.

[0041] The present invention also provides the application of the above-mentioned chiral furanonaphthene derivative in the preparation of tumor drugs.

[0042] Compared with existing technologies, this invention obtains chiral furanonaphthene derivatives through an asymmetric domino-aza-Friedel-Crafts / hemietal reaction of acenaphthene imines with different substitutions and naphthol. The reaction exhibits high enantioselectivity, good yield, and complete reaction. No byproducts were detected in 1H and 1C NMR spectra, and highly enantiomeric optically pure compounds can be obtained. Furthermore, this method not only has broad substrate applicability, but the furanonaphthene derivatives generated in the reaction have potential antitumor activity. Moreover, the operation is simple, the reaction conditions are mild, and it is environmentally friendly.

[0043] Experimental results show that this invention, for the first time, yields a series of previously unreported optically pure furanonaphthene derivatives via an organocatalytic asymmetric domino reaction. Single-crystal X-ray diffraction experiments confirmed the absolute configuration of the main product to be (6S, 13R). Cell experiments revealed that the synthesized compounds exhibit good antitumor activity. This invention utilizes mild reaction conditions, inexpensive and readily available raw materials, and a catalyst system free of heavy metals, making it safe and environmentally friendly, suitable for industrial production. The reaction yield is high (93%–98%), with an enantioselectivity of 90%–>99%, providing a basis for the research of chiral drugs. Attached Figure Description

[0044] Figure 1 The 1H NMR spectrum of acenaphthene imine 2b obtained in Example 1 of this invention;

[0045] Figure 2 The carbon NMR spectrum of acenaphthene imine 2b obtained in Example 1 of this invention;

[0046] Figure 3 This is the mass spectrum of acenaphthene imine 2b obtained in Example 1 of the present invention;

[0047] Figure 4 The 1H NMR spectrum of compound 5aa obtained in Example 17 of this invention;

[0048] Figure 5 The image shows the carbon NMR spectrum of compound 5aa obtained in Example 17 of this invention.

[0049] Figure 6 This is the mass spectrum of compound 5aa obtained in Example 17 of the present invention;

[0050] Figure 7 The HPLC chromatogram of the racemic compound with the same structure as compound 5aa obtained in Example 17 of this invention;

[0051] Figure 8 This is the HPLC chromatogram of compound 5aa obtained in Example 17 of the present invention;

[0052] Figure 9 The 1H NMR spectrum of compound 6aa obtained in Example 27 of this invention;

[0053] Figure 10 The image shows the carbon NMR spectrum of compound 6aa obtained in Example 27 of this invention.

[0054] Figure 11 The mass spectrum of compound 6aa obtained in Example 27 of this invention;

[0055] Figure 12The HPLC chromatogram of the racemic compound with the same structure as compound 6aa obtained in Example 27 of this invention;

[0056] Figure 13 This is the HPLC chromatogram of compound 6aa obtained in Example 27 of the present invention;

[0057] Figure 14 This is a single-crystal X-ray diffraction pattern of compound 6ad obtained in Example 30 of the present invention;

[0058] Figure 15 This is a synthetic route diagram of compound 7 in Example 39 and compound 8 in Example 40 of the present invention;

[0059] Figure 16 This is a graph showing the inhibitory effect of compound 6af on the proliferation of tumor cells A549 in an application example of the present invention;

[0060] Figure 17 This is a diagram showing the inhibitory effect of compound 6af on the proliferation of tumor cells HUVEC in an application example of the present invention. Detailed Implementation

[0061] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0062] To further illustrate the present invention, the following describes in detail, with reference to embodiments, a chiral furanonaphthene derivative provided by the present invention, its preparation method, and its application in antitumor activity.

[0063] All reagents used in the following examples are commercially available.

[0064] Example 1

[0065] Example 1: Preparation of 5,6-dibromoacenaphthoquinone and acenaphthoquinone imine

[0066]

[0067] 5,6-Dibromoacenaphthoquinone was prepared according to synthetic route I:

[0068] Step 1: Add 15.42 g (0.10 mol) acenaphthene and 100 mL N,N-dimethylformamide to a 250 mL reaction flask, and add 44.50 g (0.25 mol) N-bromosuccinimide (NBS) under ice bath conditions. Stir the reaction overnight at room temperature. Monitor the reaction by TLC until complete. Filter to obtain 10.50 g of a pale yellow solid, yield 34%.

[0069] Step 2: Add 9.36 g (0.03 mol) of the product from the previous step and 60 mL of acetic anhydride solution to a 500 mL reaction flask. While stirring at 70 °C, add 60 mL of acetic anhydride solution containing 10.00 g (0.10 mol) of chromium trioxide dropwise. Stop the reaction after 1.5 h. After cooling to room temperature, pour the solution into 200 mL of ice water, then slowly add 40 mL of concentrated hydrochloric acid (36.0–38.0%). After cooling, filter, dry, recrystallize in toluene, and dry to obtain 6.53 g of reddish-brown powder, yield 64%.

[0070]

[0071] Different substituted acenaphthoquinone imines were prepared according to synthetic route II, taking the synthesis of unsubstituted acenaphthoquinone imine 2a (R=H) as an example:

[0072] In a 100 mL reaction flask, 2 g (10.98 mmol) of acenaphthene and 4.5 g (11.92 mmol) of N-Bocamidine triphenylphosphine were added, followed by 10 mL of toluene solvent. The reaction was placed in an oil bath, and the temperature was slowly raised to 110 °C and refluxed for 4 h. The reaction was monitored by TLC until complete. After cooling to room temperature, the solidified product was dissolved in ethyl acetate under reflux, recrystallized, filtered, and washed with n-hexane (3 × 30 mL) to give 2.37 g of a yellow solid, with a yield of 80%.

[0073] The synthesis method of 5,6-dibromoacenaphthoquinone imine compound 2b (R=Br) is the same as that of 2a.

[0074] The results of NMR and mass spectrometry analysis of compound 2b (R = Br) prepared in Example 1 are as follows:

[0075] tert-butyl(E)-(5,6-dibromo-2-oxoacenaphthylen-1(2H)-ylidene)carbamate(2b):

[0076] 1 H NMR (500MHz, CDCl3) δ8.33 (d, J = 7.5 Hz, 2H), 7.96 (d, J = 7.5 Hz, 2H), 1.58 (s, 9H); such as Figure 1 As shown;

[0077] 13 C NMR (100MHz, CDCl3) δ 182.4, 160.5, 156.8, 145.6, 136.9, 130.2, 129.7, 127.7, 127.4, 124.4, 123.3, 122.4, 83.9, 28.0; (e.g.) Figure 2As shown;

[0078] HRMS(ESI)m / z:[M+H] + calcd for C 17 H 14 Br2NO3 + :437.9335; found:437.9330; such as Figure 3 As shown.

[0079] Examples 2-16: Catalyst screening and optimization of reaction conditions

[0080] 0.10 mmol of acenaphthene imine, 0.10 mmol of 6-OMe-1-naphthol, and a chiral catalyst (types and amounts relative to acenaphthene imine are shown in Table 1) were placed in a dry, sealed reaction tube. A magnetic stir bar was added, and 1 mL of solvent (types shown in Table 1) was added using a syringe. The tube was then placed in a magnetic stirrer and reacted at room temperature for 24 h. The reaction progress was monitored by TLC. After the reaction was complete, the pure product was separated by silica gel column chromatography, with hexane and ethyl acetate as the eluent in a volume ratio of 4:1.

[0081] The reaction formula and the structures of the chiral cinchona base and Takemoto catalyst are as follows:

[0082]

[0083]

[0084] The yields were the separation yields, and the enantiomeric excess (ee) of the product was determined by HPLC chiral OD-H column. See Table 1 for details.

[0085] Table 1. Results of catalyst screening and optimized reaction conditions in Examples 2-16

[0086] Example catalyst solvent Catalyst dosage (mol%) Yield (%) %ee 2 1a <![CDATA[CH2Cl2]]> 10 90 9 3 1b <![CDATA[CH2Cl2]]> 10 91 0 4 1c <![CDATA[CH2Cl2]]> 10 93 97 5 1d <![CDATA[CH2Cl2]]> 10 98 99 6 1e <![CDATA[CH2Cl2]]> 10 95 98 7 1f <![CDATA[CH2Cl2]]> 10 90 20 8 1g <![CDATA[CH2Cl2]]> 10 92 85 9 1h <![CDATA[CH2Cl2]]> 10 95 92 10 1d <![CDATA[CHCl3]]> 10 95 97 11 1d <![CDATA[C2H4Cl2]]> 10 95 96 12 1d <![CDATA[Et2O]]> 10 85 77 13 1d Toulene 10 90 91 14 1d <![CDATA[CH2Cl2]]> 5 98 99 15 1d <![CDATA[CH2Cl2]]> 2 87 92 16 1d <![CDATA[CH2Cl2]]> 1 89 84

[0087] Catalysts 1a to 1h were applied to the asymmetric domino reaction of acenaphthene imine and naphthol in an aza-Friedel-Crafts / hemiketal reaction, using dichloromethane as solvent, and reacted at room temperature for 24 hours to screen for the optimal catalyst. The results, as shown in Table 1, indicate that all catalysts successfully catalyzed the reaction, yielding the target product in 90%–98% yields with enantioselectivity ranging from 0% to 99%. The catalyst 1d yielded the best ee value and yield (Example 5). Since a stereoselectivity as high as 99% has already been achieved under current conditions, there is limited room for further improvement. However, this invention aims to investigate the effect of the solvent on the stereoselectivity of the reaction and whether reducing the catalyst loading can maintain excellent enantioselectivity. The results show that the solvent has a significant impact on the catalytic performance of the catalyst. Of the five solvents selected, dichloromethane was screened as the optimal solvent for yield and enantioselectivity (Example 5), and haloalkanes were found to be suitable solvents for the reaction, yielding 97% and 96% ee, respectively (Examples 10, 11), while diethyl ether yielded low enantioselectivity (Example 12). Furthermore, reducing the catalyst loading to 5 mol% still achieved excellent enantioselectivity of 99% (Example 14). Further reducing the catalyst loading to 2 mol% and 1 mol% resulted in a 7% and 15% decrease in enantioselectivity, respectively, and a significant decrease in yield (Examples 15, 16 vs 5). Therefore, the optimal catalyst system was determined to be: dichloromethane as the solvent at room temperature, with a catalyst loading of 5 mol% for 1 day.

[0088] Example 17

[0089] 0.10 mmol of substituted acenaphthene imine, 0.10 mmol of 1-naphthol (compound 3) or 2-naphthol (compound 4) (specific structures shown in Table 2), and 5 mol% catalyst 1d were placed in a dry and sealed reaction tube. A magnetic stir bar was added, and 1 mL of dichloromethane was added using a syringe. The tube was placed in a magnetic stirrer and reacted at room temperature for 24 h. The reaction progress was monitored by TLC. After the reaction was completed, the pure product was obtained by silica gel column chromatography, with hexane:ethyl acetate as the eluent in a volume ratio of 4:1. The reaction formula and the structure of catalyst 1d are as follows:

[0090]

[0091] The compound 5aa prepared in Example 17 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0092] tert-butyl((6bS,13bR)-6b-hydroxyacenaphtho[1,2-b]naphtho[2,1-d]furan-13b(6bH)-yl)carba mate (compound 5aa):

[0093] 1 H NMR (400MHz, DMSO-d6) δ8.26 (s, 1H), 7.83 (t, J = 5.4Hz, 4H), 7.74 (dd, J = 17.3, 8.3Hz, 3H), 7.65(t,J=7.6Hz,1H),7.56(t,J=7.7Hz,1H),7.50–7.39(m,3H),0.94(d,J=239.0Hz,9H); such as Figure 4 As shown;

[0094] 13 C NMR (100MHz, DMSO-d6) δ 154.8, 152.1, 141.2, 135.2, 134.2, 130.6, 128.4, 128.1, 127.9, 126.4, 125.6, 125.3, 123.4, 122.5, 121.7, 121.2, 120.6, 119.8, 119.5, 117.4, 77.8, 73.5, 27.7; e.g. Figure 5 As shown;

[0095] HRMS(ESI)m / z:[M+H]+calcd for C27H24NO4+:426.1700; found:426.1693; such as Figure 6 As shown;

[0096] HPLC (Chiralcel OD-H, hexane: i PrOH = 80:20, 1.0 mL / min, 254 nm), tR = 4.8 min (major), 8.7 min (minor), such as Figure 8 As shown; Figure 7 High-performance liquid chromatography (HPLC) spectra of racemic compounds with the same structure as compound 5aa under the same conditions; by Figure 7 and Figure 8 It is known that the product prepared by the method provided by this invention is a single-rotator.

[0097] Example 18

[0098] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R2 was different from that in Example 17, as detailed in Table 2.

[0099] The compound 5ab prepared in Example 18 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0100] tert-butyl((6bS,13bR)-12-chloro-6b-hydroxyacenaphtho[1,2-b]naphtho[2,1-d]furan-13b(6bH)-yl)carbamate (compound 5ab):

[0101] 1 H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.04(d,J=8.6Hz,1H),7.97(d,J=2.3Hz,1H),7.90(d,J=8.3Hz,1H),7.82(dd,J= 17.4,7.2Hz,3H),7.73(d,J=8.2Hz,1H),7.66(t,J=7.9Hz,1H),7.56(dq,J=16.2,7.9Hz,3H),0.93(d,J=223.7Hz,9H);

[0102] 13 C NMR(100MHz,DMSO-d6)δ154.7,151.6,140.9,135.1,130.6,130.4,128.5,128.1,128.0,126 .6,125.5,124.1,123.6,122.9,122.1,122.0,121.6,120.7,119.6,117.9,77.9,73.4,27.5;

[0103] HRMS(ESI)m / z:[M+H] + calcd for C 27 H 23 ClNO4 + :460.1310; found:460.1316;

[0104] HPLC (Chiralpak AD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.0min(major),5.8min(minor).

[0105] Example 19

[0106] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R2 was different from that in Example 17, as detailed in Table 2.

[0107] The compound 5ac prepared in Example 19 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0108] tert-butyl((6bS,13bR)-6b-hydroxy-12-methoxyacenaphtho[1,2-b]naphtho[2,1-d]furan-13b(6bH)-yl)carbamate (compound 5ac):

[0109] 1 H NMR(400MHz, DMSO-d6))δ8.14(s,1H),8.07–8.02(m,1H),7.86–7.75(m,4H),7.72(d,J=8.2Hz,1H),7.65(t ,J=7.6Hz,1H),7.57(t,J=7.6Hz,1H),7.45(td,J=5.7,3.1Hz,2H),7.26(s,1H),3.98(s,3H),0.62(s,9H);

[0110] 13 C NMR(100MHz,DMSO-d6))δ154.8,149.6,145.6,135.3,130.6,128.4,128.1,126.3,125.9, 125.6,125.2,123.3,122.1,121.2,120.5,120.3,119.3,117.1,100.9,77.8,74.1,56.1;

[0111] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 26 NO5 + :456.1805; found:456.1800;

[0112] HPLC (Chiralpak AS-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.7min(minor),8.0min(major).

[0113] Example 20

[0114] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R2 was different from that in Example 17, as detailed in Table 2.

[0115] The compound 5ad prepared in Example 20 was subjected to NMR, mass spectrometry and HPLC analysis, and the results are as follows:

[0116] tert-butyl((6bS,13bR)-6b-hydroxy-12-methoxyacenaphtho[1,2-b]naphtho[2,1-d]furan-13b(6bH)-yl)carbamate (compound 5ad):

[0117] 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),7.90–7.61(m,6H),7.56(t,J=7.6Hz,1H),7.35(d,J=8.5Hz ,1H),7.24(d,J=2.2Hz,1H),7.07(dd,J=9.1,2.5Hz,1H),3.81(s,3H),0.93(d,J=247.6Hz,9H);

[0118] 13 C NMR(100MHz,DMSO-d6)δ157.6,154.8,152.4,135.9,135.2,130.6,128.4,128.1,125.4, 123.3,123.1,122.9,119.7,119.6,118.0,117.6,115.0,106.4,77.8,73.4,55.1,27.6;

[0119] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 26 NO5 + :456.1805; found:456.1801;

[0120] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.9min(minor),7.7min(major).

[0121] Example 21

[0122] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R2 was different from that in Example 17, as detailed in Table 2.

[0123] The compound 5ae prepared in Example 21 was subjected to NMR, mass spectrometry and HPLC analysis, and the results are as follows:

[0124] tert-butyl((6bS,13bR)-9-chloro-6b-hydroxyacenaphtho[1,2-b]naphtho[2,1-d]furan-13b(6bH)-yl)carbamate (compound 5ae):

[0125] 1 H NMR (400MHz, DMSO-d6) δ8.35(s,1H),7.82(dt,J=25.4,7.6Hz,5H),7.69(dt,J=20.0,7. 1Hz, 3H), 7.57 (t, J = 7.6Hz, 1H), 7.47 (dd, J = 17.2, 9.1Hz, 2H), 0.93 (d, J = 229.3Hz, 9H);

[0126] 13 C NMR(100MHz,DMSO-d6)δ154.8,151.4,141.0,135.2,132.4,130.6,130.2,128.5,128 .2,126.9,125.5,123.5,123.2,120.5,120.3,119.9,119.6,117.7,77.9,73.4,27.6;

[0127] HRMS(ESI)m / z:[M+H] + calcd for C 27 H 23 ClNO4 + :460.1310; found:460.1305;

[0128] HPLC (Chiralpak AD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =6.6min(minor),8.4min(major).

[0129] Example 22

[0130] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R2 was different from that in Example 17, as detailed in Table 2.

[0131] The compound 5af prepared in Example 22 was subjected to NMR, mass spectrometry and HPLC analysis, and the results are as follows:

[0132] tert-butyl((6bS,13bR)-6b-hydroxy-9-methoxyacenaphtho[1,2-b]naphtho[2,1-d]furan-13b(6bH)-yl)carbamate (compound 5af):

[0133] 1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.94–7.79(m,2H),7.79–7.52(m,5H),7. 40(d,J=8.4Hz,1H),7.17–7.02(m,2H),3.83(s,3H),0.93(d,J=245.3Hz,10H);

[0134] 13 C NMR(100MHz,DMSO-d6)δ157.3,155.1,151.5,141.4,135.4,130.8,130.0,129.8,128.7,128 .4,125.6,123.7,122.4,120.9,120.8,120.0,119.7,119.3,117.5,99.5,78.3,55.4,27.7;

[0135] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 26 NO5 + :456.1805; found:456.1801;

[0136] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.1min(minor),7.8min(major).

[0137] Example 23

[0138] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituents R1 and R2 were different from those in Example 17, as detailed in Table 2.

[0139] The compound 5ba prepared in Example 23 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0140] tert-butyl((6bS,13bR)-3,4-dibromo-6b-hydroxyacenaphtho[1,2-b]naphtho[2,1-d]furan-13b(6bH)-yl)carbamate(5ba):

[0141] 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.12(d,J=7.6Hz,1H),8.02(d,J=7.5Hz,1H),7 .88–7.71(m,4H),7.67(d,J=7.6Hz,1H),7.51–7.43(m,3H),0.97(d,J=250.8Hz,9H);

[0142] 13 C NMR(100MHz,DMSO-d6)δ154.5,152.0,137.8,136.8,136.6,134.4,128.0,126.7,126.2, 125.8,122.3,121.7,121.2,120.8,120.6,119.8,116.9,115.7,114.7,78.1,73.8,28.0;

[0143] HRMS(ESI)m / z:[M+H] + calcd for C 27 H 22 Br2NO4 + :581.9910; found:581.9906;

[0144] HPLC (Chiralpak AD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =6.2min(minor),8.1min(major).

[0145] Example 24

[0146] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituents R1 and R2 were different from those in Example 17, as detailed in Table 2.

[0147] The compound 5bc prepared in Example 24 was subjected to NMR, mass spectrometry and HPLC analysis, and the results are as follows:

[0148] tert-butyl((6bS,13bR)-3,4-dibromo-6b-hydroxy-12-methoxyacenaphtho[1,2-b]naphtho[2,1-d]furan-13b(6bH)-yl)carbamate (compound 5bc):

[0149] 1 H NMR(400MHz, DMSO-d6)δ8.54–8.32(m,1H),8.11(d,J=7.6Hz,1H),8.08–7.97(m,2H),7. 81–7.68(m,3H),7.51–7.43(m,2H),7.25(s,1H),3.98(s,3H),0.97(d,J=251.2Hz,9H);

[0150] 13 C NMR(100MHz,DMSO-d6)δ154.5,149.8,145.4,137.8,136.8,136.5,126.4,126.2,126.1,125.8,12 2.2,121.5,121.2,120.7,120.2,119.6,116.7,115.3,114.6,100.7,78.0,73.1,56.1,28.2,26.9;

[0151] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 24 Br2NO5 + :612.0016; found:612.0006;

[0152] HPLC (Chiralpak AS-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.1min(minor),6.9min(major).

[0153] Example 25

[0154] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituents R1 and R2 were different from those in Example 17, as detailed in Table 2.

[0155] The compound 5bd prepared in Example 25 was subjected to NMR, mass spectrometry and HPLC analysis, and the results are as follows:

[0156] tert-butyl((6bS,13bR)-3,4-dibromo-6b-hydroxy-10-methoxyacenaphtho[1,2-b]naphtho[2,1-d]furan-13b(6bH)-yl)carbamate (compound 5bd):

[0157] 1 H NMR(500MHz,DMSO-d6)δ8.50(s,1H),8.11(d,J=7.5Hz,1H),8.00(d,J=7.5Hz,1H),7.80–7.70(m,2H),7.63(d,J=7.5Hz ,2H),7.36(d,J=8.5Hz,1H),7.25(d,J=2.5Hz,1H),7.08(dd,J=9.0,2.5Hz,1H),3.82(s,3H),0.96(d,J=304.4Hz,9H);

[0158] 13 C NMR(125MHz,DMSO-d6)δ157.8,154.5,152.2,137.8,136.8,136.6,136.1,126.3,122.9,121 .7,120.5,119.9,118.7,118.1,116.9,115.8,114.9,114.6,106.5,78.0,72.4,55.2,28.0;

[0159] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 24 Br2NO5 + :612.0016; found:612.0022;

[0160] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.6min(minor),7.7min(major).

[0161] Example 26

[0162] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituents R1 and R2 were different from those in Example 17, as detailed in Table 2.

[0163] The compound 5bf prepared in Example 26 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0164] tert-butyl((6bS,13bR)-3,4-dibromo-6b-hydroxy-9-methoxyacenaphtho[1,2-b]naphtho[2,1-d]furan-13b(6bH)-yl)carbamate (compound 5bf):

[0165] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.12(d,J=7.6Hz,1H),8.01(d,J=7.6Hz,1H),7.77(t,J=9.1Hz,2H),7.65(d,J=7.6Hz,1H),7.5 9(d,J=8.4Hz,1H),7.41(d,J=8.4Hz,1H),7.10(dd,J=9.0,2.6Hz,1H),7.05(d,J=2.6Hz,1H),3.83(s,3H),0.96(d,J=250.5Hz,9H);

[0166] 13 C NMR(100MHz,DMSO-d6)δ157.2,154.6,151.2,137.8,136.8,136.6,129.8,129.7,126.3,121.7 ,121.4,120.9,120.6,119.6,119.3,116.9,115.6,114.7,99.2,78.1,72.7,55.2,28.2,26.9;

[0167] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 24 Br2NO5 + :612.0016; found:612.0011;

[0168] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.2min(minor),7.2min(major).

[0169] Example 27

[0170] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R3 was different when 2-naphthol was used as the substrate, as detailed in Table 3.

[0171] The compound 6aa prepared in Example 27 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0172] tert-butyl((6bS,13cR)-6b-hydroxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carba matee (compound 6aa):

[0173] 1 H NMR(400MHz, DMSO-d6)δ8.59(d,J=8.5Hz,1H),8.00(s,1H),7.93–7.80(m,3H),7.80–7.71(m,3H),7.67(q,J= 7.0Hz,2H),7.57–7.49(m,1H),7.37(t,J=7.7Hz,1H),7.04(dd,J=8.7,2.0Hz,1H),1.04(d,J=149.5Hz,9H), such as Figure 9 As shown;

[0174] 13 C NMR (100MHz, DMSO-d6) δ 155.1, 154.5, 141.1, 135.4, 130.8, 130.7, 129.8, 129.3, 129.0, 128.2, 128.0, 127.0, 125.2, 123.8, 122.9, 119.3, 118.3, 116.4, 112.5, 77.8, 74.6, 27.4, as shown Figure 10 As shown;

[0175] HRMS(ESI)m / z:[M+H] + calcd for C 27 H 24 NO4 + :426.1700; found:426.1691, such as Figure 11 As shown;

[0176] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =4.8min(major),8.7min(minor), such as Figure 13 As shown; Figure 12 High-performance liquid chromatography (HPLC) spectra of racemic compounds with the same structure as compound 6aa under the same conditions; by Figure 12 and Figure 13 It is known that the product prepared by the method provided by this invention is a single-rotator.

[0177] Example 28

[0178] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R3 was different when 2-naphthol was used as the substrate, as detailed in Table 3.

[0179] The compound 6ab prepared in Example 28 was subjected to NMR, mass spectrometry and HPLC analysis, and the results are as follows:

[0180] tert-butyl((6bS,13cR)-8-bromo-6b-hydroxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6ab):

[0181] 1 H NMR(400MHz,DMSO-d6)δ8.51(d,J=8.5Hz,1H),8.31(s,1H),8.00(s,1H),7.91–7.70(m,4H) ,7.70–7.54(m,3H),7.43(t,J=7.7Hz,1H),7.30(t,J=7.6Hz,1H),0.87(d,J=197.6Hz,9H);

[0182] 13 C NMR(100MHz,DMSO-d6)δ155.0,151.2,140.7,135.3,132.2,130.7,130.2,128.9,128 .3,128.2,127.4,125.5,124.1,123.9,123.0,119.7,116.6,104.9,77.9,75.7,27.4;

[0183] HRMS(ESI)m / z:[M+H] + calcd for C 27 H 23 BrNO4 + :504.0805; found:504.0797;

[0184] HPLC (Chiralcel OD-H, hexane:i PrOH=80:20,1.0mL / min,254nm),t R =4.9min(major),7.8min(minor).

[0185] Example 29

[0186] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R2 was different when 2-naphthol was used as the substrate, as detailed in Table 3.

[0187] The compound 6ac prepared in Example 29 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0188] tert-butyl((6bS,13cR)-6b-hydroxy-8-methylacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6ac):

[0189] 1 H NMR (400MHz, DMSO-d6) δ8.56(d,J=8.4Hz,1H),8.00(s,1H),7.88(d,J=7.1Hz,1H),7.83(t,J=9.1Hz,2H),7.79–7.70(m,2H),7.70 –7.64(m,1H),7.61(t,J=7.8Hz,1H),7.56(s,1H),7.54–7.48(m,1H),7.33(t,J=7.7Hz,1H),2.22(s,3H),1.04(d,J=150.3Hz,9H);

[0190] 13 C NMR(100MHz,DMSO-d6)δ155.1,153.9,141.3,135.4,130.7,129.8,129.5,128.5,128.2, 128.1,126.0,125.2,123.7,122.9,122.6,121.9,119.3,117.6,116.2,77.8,75.0,15.7;

[0191] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 26 NO4 + :440.1856; found:440.1851;

[0192] HPLC (Chiralpak AD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.4min(major),6.0min(minor).

[0193] Example 30

[0194] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R3 was different when 2-naphthol was used as the substrate, as detailed in Table 3.

[0195] The compound 6ad prepared in Example 30 was subjected to single-crystal X-ray diffraction, and its single-crystal diffraction pattern is shown below. Figure 14 As shown, its absolute configuration is determined to be (6S, 13R).

[0196] The compound 6ad prepared in Example 30 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0197] tert-butyl((6bS,13cR)-6b-hydroxy-8-methoxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6ad):

[0198] 1 H NMR (400MHz, DMSO-d6) δ8.50(d,J=8.4Hz,1H),8.07(s,1H),7.85(dd,J=7.6,5.7Hz,2H),7.81–7.75(m,2H),7.74(d,J=8.2Hz,1H),7.66(dd, J=8.2,7.0Hz,1H),7.52(ddd,J=9.3,7.6,6.4Hz,2H),7.34(ddd,J=8.1,6.9,1.2Hz,1H),7.24(s,1H),3.81(s,3H),0.95(d,J=221.1Hz,9H);

[0199] 13C NMR(100MHz,DMSO-d6)δ155.1,145.9,145.2,141.0,135.4,130.7,130.3,128.2,128.1,127 .7,125.3,124.81,124.4,123.8,123.4,122.7,119.4,116.8,107.9,77.9,75.0,55.4,27.6;

[0200] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 26 NO5 + :456.1805; found:456.1803;

[0201] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.9min(minor),8.1min(major).

[0202] Example 31

[0203] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R3 was different when 2-naphthol was used as the substrate, as detailed in Table 3.

[0204] The compound 6ae prepared in Example 31 was subjected to NMR, mass spectrometry and HPLC analysis, and the results are as follows:

[0205] tert-butyl((6bS,13cR)-11-bromo-6b-hydroxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6ae):

[0206] 1 H NMR(400MHz,DMSO-d6)δ8.55(d,J=9.0Hz,1H),8.14(s,2H),7.92–7.78(m,4H),7.74(t,J=8.5Hz,2H) ,7.66(t,J=7.5Hz,1H),7.51(t,J=7.6Hz,1H),7.10(dd,J=8.9,2.2Hz,1H),1.03(d,J=152.5Hz,9H);

[0207] 13C NMR(100MHz,DMSO-d6)δ155.0,154.9,141.0,135.4,130.7,130.6,130.6,130.1,129.8, 128.4,128.2,128.1,125.3,123.8,119.4,118.8,116.5,115.7,113.8,77.8,74.5,27.4;

[0208] HRMS(ESI)m / z:[M+H] + calcd for C 27 H 23 BrNO4 + :504.0805; found:504.0797;

[0209] HPLC (Chiralpak AD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =7.1min(major),12.3min(minor).

[0210] Example 32

[0211] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R3 was different when 2-naphthol was used as the substrate, as detailed in Table 3.

[0212] The compound 6af prepared in Example 32 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0213] tert-butyl((6bS,13cR)-6b-hydroxy-11-methoxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6af):

[0214] 1H NMR(400MHz,DMSO-d6)δ8.50(d,J=9.1Hz,1H),7.88–7.79(m,2H),7.74(dd,J=11.7,7.6Hz,2H),7.65(dd,J=8.3,7.0Hz,2H),7.50 (t,J=7.7Hz,1H),7.36(dd,J=9.1,2.6Hz,1H),7.31(d,J=2.6Hz,1H),6.99(d,J=8.8Hz,1H),3.84(s,3H),1.04(d,J=106.0Hz,9H);

[0215] 13 C NMR(100MHz,DMSO-d6)δ155.1,152.9,141.3,135.4,130.7,130.5,129.5,128.2,128.0,125 .2,125.0,124.4,123.7,119.3,119.2,118.6,116.1,112.7,107.6,77.8,74.8,55.1,27.4;

[0216] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 26 NO5 + :456.1805; found:456.1797;

[0217] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.5min(minor),9.1min(major).

[0218] Example 33

[0219] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R3 was different when 2-naphthol was used as the substrate, as detailed in Table 3.

[0220] The compound 6ag prepared in Example 33 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0221] tert-butyl((6bS,13cR)-11-cyano-6b-hydroxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6ag):

[0222] 1 H NMR (400MHz, DMSO-d6) δ8.71(d,J=8.7Hz,1H),8.49(s,1H),8.30(s,1H),7.97–7.83(m,4H),7.80(d,J=7.1Hz,1H),7.75( dd,J=8.3,2.2Hz,1H),7.67(t,J=7.7Hz,1H),7.52(t,J=7.5Hz,1H),7.21(dd,J=9.0,2.2Hz,1H),1.04(d,J=151.5Hz,9H);

[0223] 13 C NMR(100MHz,DMSO-d6)δ157.0,155.0,140.7,135.3,135.2,131.9,131.6,130.7,128.3,128.2, 128.1,127.5,125.4,124.3,124.0,119.5,119.4,119.2,117.0,114.5,105.0,77.8,74.2,27.4;

[0224] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 23 N2O4 + :451.1652; found:451.1648;

[0225] HPLC (Chiralpak AD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =10.5min(major),18.4min(minor).

[0226] Example 34

[0227] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituent R3 was different when 2-naphthol was used as the substrate, as detailed in Table 3.

[0228] The compound 6ah prepared in Example 34 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0229] tert-butyl((6bS,13cR)-6b-hydroxy-12-methoxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6ah):

[0230] 1 H NMR (400MHz, DMSO-d6) δ7.98–7.83(m,4H),7.80–7.73(m,3H),7.70–7.63(m,2H),7.55(dd,J= 8.3,7.1Hz,1H),7.04(dd,J=8.9,2.5Hz,1H),6.86(d,J=8.7Hz,1H),4.04(s,3H),0.99(s,9H);

[0231] 13 C NMR(100MHz,DMSO-d6)δ158.0,155.3,155.1,141.1,135.3,131.2,130.7,130.7,130.6,128.3, 128.1,125.3,124.7,123.9,119.3,117.4,116.4,114.7,109.9,102.2,78.0,74.6,55.3,27.5;

[0232] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 26 NO5 + :456.1805; found:456.1799;

[0233] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =4.6min(minor),12.8min(major).

[0234] Example 35

[0235] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17. The difference is that the substituents R1 and R3 are different when 2-naphthol is used as the substrate, as detailed in Table 3.

[0236] The compound 6ba prepared in Example 35 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0237] tert-butyl((6bS,13cR)-3,4-dibromo-6b-hydroxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6ba):

[0238] 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=8.4Hz,1H),8.33(s,1H),8.13(d,J=7.6Hz,1H),7.96(d,J=7.6Hz,1H),7 .90–7.77(m,3H),7.75–7.64(m,2H),7.38(t,J=7.5Hz,1H),7.05(d,J=8.8Hz,1H),0.96(d,J=203.0Hz,9H);

[0239] 13 C NMR(100MHz,DMSO-d6)δ154.8,154.4,142.6,138.0,136.6,131.4,129.7,129.5,129.1, 127.3,126.3,123.2,122.9,121.5,121.2,116.8,115.2,114.6,112.5,78.0,73.7,27.5;

[0240] HRMS(ESI)m / z:[M+H] + calcd for C 27 H 22 Br2NO4 + :581.9910; found:581.9905;

[0241] HPLC (Chiralpak AD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =7.1min(minor),7.9min(major).

[0242] Example 36

[0243] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17. The difference is that the substituents R1 and R3 are different when 2-naphthol is used as the substrate, as detailed in Table 3.

[0244] The compound 6bd prepared in Example 36 was subjected to NMR, mass spectrometry and HPLC analysis, and the results are as follows:

[0245] tert-butyl((6bS,13cR)-3,4-dibromo-6b-hydroxy-8-methoxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6bd):

[0246] 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=8.5Hz,2H),8.13(d,J=7.5Hz,1H),7.96(d,J=7.7Hz,1H),7.77(dt,J=16.8 ,8.1Hz,3H),7.53(t,J=7.8Hz,1H),7.35(t,J=7.5Hz,1H),7.27(s,1H),3.82(s,3H),0.94(d,J=218.9Hz,9H);

[0247] 13 C NMR(100MHz,DMSO-d6)δ154.8,145.9,145.0,142.5,138.0,136.6,130.4,127.8,126.3, 124.6,123.6,122.6,121.6,118.6,116.8,115.2,115.0,108.4,78.1,74.0,55.5,27.6;

[0248] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 24 Br2NO5 + :612.0016; found:612.0012;

[0249] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.6min(minor),7.5min(major).

[0250] Example 37

[0251] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17. The difference is that the substituents R1 and R3 are different when 2-naphthol is used as the substrate, as detailed in Table 3.

[0252] The compound 6bf prepared in Example 37 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0253] tert-butyl((6bS,13cR)-3,4-dibromo-6b-hydroxy-11-methoxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6bf):

[0254] 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=9.1Hz,1H),8.27(s,1H),8.13(d,J=7.6Hz,1H),7.96(d,J=7.7Hz,1H),7.79(d,J =7.7Hz,1H),7.71(t,J=7.7Hz,2H),7.41–7.31(m,2H),7.01(d,J=8.8Hz,1H),3.85(s,3H),0.96(d,J=219.4Hz,9H);

[0255] 13 C NMR(100MHz,DMSO-d6)δ155.2,154.8,152.8,142.8,138.0,136.6,130.7,130.0,126.3, 124.8,124.3,121.4,119.5,116.7,115.1,114.4,112.7,107.7,78.0,73.8,55.2,27.6;

[0256] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 24 Br2NO5 + :612.0016; found:612.0008;

[0257] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =4.7min(minor),8.4min(major).

[0258] Example 38

[0259] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17. The difference is that the substituents R1 and R3 are different when 2-naphthol is used as the substrate, as detailed in Table 3.

[0260] The compound 6bh prepared in Example 38 was subjected to NMR, mass spectrometry and HPLC detection, and the results are as follows:

[0261] tert-butyl((6bS,13cR)-3,4-dibromo-6b-hydroxy-12-methoxyacenaphtho[1,2-b]naphtho[1,2-d]furan-13c(6bH)-yl)carbamate (compound 6bh):

[0262] 1 H NMR(400MHz, DMSO-d6)δ8.28(s,1H),8.13(d,J=7.6Hz,1H),8.02(d,J=7.7Hz,1H),7.87–7.75(m,3H),7.71 (t,J=8.7Hz,2H),7.06(dd,J=9.0,2.4Hz,1H),6.87(d,J=8.7Hz,1H),4.03(s,3H),1.02(d,J=157.2Hz,9H);

[0263] 13 C NMR(100MHz,DMSO-d6)δ158.1,155.1,154.9,142.6,137.9,136.8,136.6,131.0,130.8,126 .3,124.8,121.5,116.8,116.5,115.2,114.8,114.6,109.8,102.2,78.1,73.6,55.3,27.5;

[0264] HRMS(ESI)m / z:[M+H] + calcd for C 28 H 24 Br2NO5 + :612.0016; found:612.0007;

[0265] HPLC (Chiralcel OD-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R=4.6min(major),11.9min(minor).

[0266] Example 39

[0267] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituents R1 and R5 were different when substituted phenol was used as the substrate, as detailed in Example 17. Figure 15 .

[0268] Compound 7, prepared in Example 39, was subjected to NMR, mass spectrometry, and HPLC analysis. The results are as follows:

[0269] tert-butyl((6bS,11bR)-6b-hydroxy-9,11-dimethoxyacenaphtho[1,2-b]benzofuran-11b(6bH)-yl)carbamate (compound 7):

[0270] 1 H NMR(400MHz,DMSO-d6)δ7.98–7.57(m,6H),7.53(dd,J=8.2,7.0Hz,1H),6.05( d,J=2.1Hz,1H),5.93(d,J=2.1Hz,1H),3.87(s,3H),3.63(s,3H),0.58(s,9H);

[0271] 13 C NMR (100MHz, DMSO-d6) δ162.2,158.6,157.3,154.5,130.4,128.2,127.7,125.2,123.1,117.2,107.0,91.5,88.2,55.6,55.4,27.4;

[0272] HRMS(ESI)m / z:[M+H] + calcd for C 25 H 26 NO6 + :436.1755; found:436.1748;

[0273] HPLC (Chiralpak AS-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =7.9min(major),15.5min(minor).

[0274] Example 40

[0275] Chiral furanonaphthene derivatives were prepared according to the preparation method of Example 17, except that the substituents R1 and R5 were different when phenol was used as the substrate, as described in Example 17. See details below. Figure 15 .

[0276] Compound 8, prepared in Example 40, was subjected to NMR, mass spectrometry, and HPLC analysis. The results are as follows:

[0277] tert-butyl((6bS,11bR)-6b-hydroxy-9,10,11-trimethoxyacenaphtho[1,2-b]benzofuran-11b(6bH)-yl)carbamate (compound 8):

[0278] 1 H NMR(400MHz, DMSO-d6)δ7.83(d,J=8.0Hz,1H),7.76–7.70(m,2H),7.68(d,J=7.0Hz,1H),7.60(dt,J=15 .6,7.6Hz,2H),6.21(d,J=1.4Hz,1H),4.03(s,3H),3.67(s,3H),3.60(s,3H),1.01(d,J=242.2Hz,9H);

[0279] 13 C NMR(100MHz,DMSO-d6)δ155.1,155.0,153.1,150.1,141.1,135.4,135.0,130.5,128. 4,127.9,125.3,123.4,119.3,116.8,111.6,90.4,77.8,73.5,60.6,60.5,56.0,27.6;

[0280] HRMS(ESI)m / z:[M+H] + calcd for C 26 H 28 NO7 + :446.1860; found:446.1863;

[0281] HPLC (Chiralpak AS-H, hexane: i PrOH=80:20,1.0mL / min,254nm),t R =5.6min(major),10.4min(minor).

[0282] The products of Examples 17–41 were measured, and the yields were the separation yields. The ee values ​​of the products were determined by HPLC chiral OD-H, AD-H, and AS-H columns. For details, please refer to Tables 2 and 3.

[0283] Table 2. Yields and enantiomeric excess values ​​(ee) of the reactions in Examples 17–26.

[0284]

[0285]

[0286] Table 3. Yields and enantiomeric excess values ​​(ee) of the reactions in Examples 27–41.

[0287] Example <![CDATA[R1]]> <![CDATA[R3]]> product Yield (%) %ee 27 H 2a H 4a 6aa 97 98 28 H 2a 3-Br 4b 6ab 98 96 29 H 2a 3-Me 4c 6ac 98 >99 30 H 2a 3-OMe 4d 6ad 95 97 31 H 2a 6-Br 4e 6ae 98 >99 32 H 2a 6-OMe 4f 6af 95 97 33 H 2a 6-CN 4g 6ag 93 91 34 H 2a 7-OMe 4h 6ah 94 95 35 Br 2b H 4a 6ba 95 90 36 Br 2b 3-OMe 4d 6bd 96 >99 37 Br 2b 6-OMe 4f 6bf 95 96 38 Br 2b 7-OMe 4h 6bh 97 99

[0288] As shown in Tables 2 and 3, all asymmetric domino aza-Friedel-Crafts / hemietal reactions involving 1-naphthol or 2-naphthol proceeded smoothly, yielding almost completely diastereoselective products with high yields (93%–98%) and excellent enantioselectivity (90–99%). Therefore, the selected catalytic conditions are highly versatile, and the electronic properties (electron-donating or electron-withdrawing groups) and positions (C3, C4, C6, C7) of the substituents in naphthol have almost no effect on the reaction performance.

[0289] To broaden the scope of this method, electron-rich phenols, such as 3,5-dimethoxyphenol and 3,4,5-trimethoxyphenol, were tested with N-Boc acenaphthene imine 2a under optimized reaction conditions. The desired benzofuran-acenaphthene derivatives 7 and 8 could be obtained in high yields and with high enantioselectivity, such as... Figure 15 As shown.

[0290] Application example: Study on the antitumor activity of compounds

[0291] The corresponding products were prepared using Examples 17, 20, 27, 30, and 32, respectively, and their structures are shown below:

[0292]

[0293] Using the CCK-8 assay, the above compounds were applied to four types of human cancer cells and one type of normal human cell line, with doxorubicin as a positive control, to investigate their antiproliferative activity. The cancer cells included human hepatocellular carcinoma cells (HepG-2), human non-small cell lung cancer cells (A549), human breast cancer cells (MCF-7), human gastric adenocarcinoma cells (MKN-45), and one type of normal human cell line, human umbilical vein endothelial cells (HUVEC).

[0294] The results showed that all tested compounds exhibited better inhibitory activity against A549 cells. Furthermore, products with methoxy substitution generally showed better cytotoxic activity than unsubstituted products. Among them, 6af demonstrated excellent cytotoxic activity against A549 cells, with an IC50 value of [missing value]. 50 The concentration was 0.98 ± 0.05 μM, significantly lower than the positive control drug (doxorubicin, IC50). 50 (2.06±0.14μM), such as Figure 16 As shown. 6af cytotoxicity (IC50) to HUVECs. 50 The concentration of 20.72 ± 1.80 μM was significantly lower than that of doxorubicin (IC50). 50 (0.44±0.02μM), such as Figure 17 As shown.

[0295] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A chiral furanonaphthene derivative, characterized in that, Compounds of formula (I), (II), or (III) or their pharmaceutically acceptable salts, deuterated derivatives, optical isomers, solvates, hydrates, complexes, chelates, or derivatives thereof: In formulas (I), (II) and (III), R1 is independently selected from H, halogen, C1-C10 alkyl or C1-C10 alkoxy. R2, R3 and R5 are each independently selected from halogens, C1-C10 alkyl groups, C1-C10 alkoxy groups or cyano groups; n, m, and p are the number of substituents, each independently selected from integers from 0 to 4; In formulas (I), (II) and (III), R4 is independently selected from the protected amino group or amino group.

2. The chiral furanonaphthene derivative according to claim 1, characterized in that, In formulas (I), (II) and (III), R1 is independently selected from H, halogen, C1-C3 alkyl, and C1-C3 alkoxy. R2, R3 and R5 are each independently selected from halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups or cyano groups; n, m, and p are the number of substituents, each independently selected from integers from 0 to 3.

3. The chiral furanonaphthene derivative according to claim 1, characterized in that, Compounds of formulas 5aa–5af, 5ba–5bf, 6aa–6ah, 6ba–6bh, 7, or 8, or their pharmaceutically acceptable salts, deuterated derivatives, optical isomers, solvates, hydrates, complexes, chelates, etc.

4. A method for preparing the chiral furanonaphthene derivative according to claim 1, characterized in that, Includes the following steps: In the presence of a catalyst, the acenaphthene compound of formula (A) is reacted with a phenolic compound in an organic solvent to obtain a chiral furanonaphthene derivative; the phenolic compound has the structure shown in formula (B), formula (C) or formula (D); the catalyst is selected from catalysts containing a chiral cinchonasal base structure and / or Takemoto type catalysts.

5. The preparation method according to claim 4, characterized in that, The molar amount of the catalyst is 1% to 10% of the molar amount of the acenaphthoquinone compound shown in formula (A).

6. The preparation method according to claim 4, characterized in that, The catalyst is selected from one or more of 1a to 1h:

7. The preparation method according to claim 4, characterized in that, The organic solvent is selected from one or more of dichloromethane, trichloromethane, 1,2-dichloroethane, toluene, and diethyl ether.

8. The preparation method according to claim 4, characterized in that, The reaction temperature is 0℃ to room temperature; the reaction time is 12 to 48 hours.

9. The preparation method according to claim 4, characterized in that, After the reaction, the chiral furan-naphthene derivative was obtained by column chromatography separation and purification; the eluent for column chromatography purification was n-hexane and ethyl acetate; the volume ratio of n-hexane to ethyl acetate was (3-5):

1.

10. The use of the chiral furanonaphthene derivative according to any one of claims 1 to 3 or the chiral furanonaphthene derivative prepared by any one of claims 4 to 9 in the preparation of antitumor drugs.

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