A method for the total synthesis of cephinold H and fortalpinoid C

Abstract

The application discloses a full synthesis method of cephinold H and fortalpinoid C, comprising the following steps: taking natural product cephanolide B as a raw material, carrying out oxidative de-arrangement and acetylation to obtain a dienone compound, then carrying out ring expansion rearrangement to obtain natural product cephinold H as a secondary product, then introducing an occupying group (Br or Cl atom) to improve the regioselectivity of the ring expansion rearrangement, so that a ring expansion product substituted with a halogen atom (Br or Cl atom) is obtained in a high proportion, then removing the halogen atom (Br or Cl atom) under a palladium catalytic reduction condition to obtain natural product cephinold H, then oxidizing cephinold H by selenium dioxide and reducing by sodium borohydride to obtain natural product fortalpinoid C with opposite configuration, and finally inverting the configuration of the hydroxyl group through a Mitsunobu reaction, so that the chemical synthesis of fortalpinoid C is realized, and the synthesis route has the advantages of simplicity, high efficiency, simple operation, low cost and the like, and is suitable for the mass synthesis of cephinold H and fortalpinoid C, and provides an important material basis for the bioactivity evaluation of the two products.

Description

Technical Field

[0001] This invention belongs to the field of natural product synthesis technology, specifically relating to a total synthesis method of cephinold H and fortalpinoid C. Background Technology

[0002] Cephalotaxus (also known as the Torreya genus) is an important medicinal plant in my country, with its biological activities mainly manifested in anti-inflammatory, lung-moistening, anti-cancer, and anthelmintic properties, and it has wide applications in traditional Chinese medicine. Since 1969, extensive research has been conducted on Cephalotaxus plants both domestically and internationally, and more than 70 natural products have been isolated. Preliminary biological activity studies have shown that these natural products possess a wide range of important biological activities, including antiviral, antitumor, and inhibition of transcription factor signaling pathways.

[0003] In 2018, Cai Xianghai's research group isolated a class of structurally complex troponoid-type carbon-decyl diterpenoid natural products from Cephalotaxus fortunei. Cephinold H, as a representative molecule, has a unique and rigid 7-5-6-6-6 pentacyclic basic skeleton, a cycloheptatrienone and a lactone bridging ring unit, and five consecutive chiral centers, including one all-carbon and quaternary carbon chiral center. Fortalpinoid C was isolated from the seeds of Cephalotaxus fortunei by Yue Jianmin's research group in 2019. It has a similar molecular skeleton to cephinold H. The complex and unique structure of this type of molecule has attracted the attention of many organic synthetic chemists. Summary of the Invention

[0004] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0005] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0006] Therefore, the purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing cephinold H.

[0007] To solve the above technical problems, the present invention provides the following technical solution: the compound cephanolide B shown in formula (1) is brominated under N-bromosuccinimide conditions to obtain the compound shown in formula (5), and then oxidatively dearomatized and acetylated to obtain the diene compound shown in formula (6).

[0008]

[0009] The diene compound shown in formula (6) undergoes a regioselective ring expansion rearrangement reaction with TMSCHN2 as a diazotizing reagent and under the conditions of solvent and Lewis acid in a 1:1 ratio to give the cycloheptatrienone product shown in formula (8).

[0010]

[0011] The cycloheptatrienone product shown in formula (8) under palladium-catalyzed reduction conditions was subjected to halogen removal to obtain the natural product cephinold H shown in formula (4);

[0012]

[0013] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing cephinold H.

[0014] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0015] The compound cephanolide B shown in formula (1) was chlorinated under the condition of SO2Cl2 as chlorine source to obtain the compound shown in formula (9), and then oxidative dearomatization and acetylation were carried out to obtain the diene compound shown in formula (10).

[0016]

[0017] The diene compound shown in formula (10) underwent a regioselective ring expansion rearrangement reaction with TMSCHN2 as a one-carbon unit and AlCl3 as a Lewis acid in a ratio of 3:1 to obtain the cycloheptatrienone product shown in formula (12), successfully reversing the ratio of the ring-expanded products.

[0018]

[0019] The cycloheptatrienone product shown in formula (12) undergoes chlorine atom removal under palladium-catalyzed reduction to yield the natural product cephinold H shown in formula (4).

[0020] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing cephinold H.

[0021] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0022] The compound cephanolide B shown in formula (1) was oxidized and dearomatized while undergoing acetyl protection to obtain the diene compound shown in formula (2). The diene compound shown in formula (2) underwent ring expansion and rearrangement reaction under the conditions of diazotizing reagent and Lewis acid to obtain the natural product cephinold H.

[0023]

[0024]

[0025] Another objective of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing fortalpinoid C.

[0026] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0027] The natural product cephinold H shown in formula (4) was oxidized under the conditions of SeO2 and additives to obtain the compound shown in formula (13);

[0028]

[0029] The compound shown in formula (13) was reduced with NaBH4 to give the secondary alcohol compound shown in formula (14), and then the hydroxyl configuration was inverted by photo-extending reaction to give the natural product fortalpinoid C shown in formula (15).

[0030]

[0031] In a preferred embodiment of the preparation method described in this invention, the diazotizing agent is any one of trimethylsilazomethane or diazomethane.

[0032] In a preferred embodiment of the preparation method described in this invention, the Lewis acid is any one of boron trifluoride ether, aluminum trichloride, or ethyl aluminum dichloride.

[0033] In a preferred embodiment of the preparation method described in this invention, the solvent is either dichloromethane or dichloromethane / diethyl ether.

[0034] In a preferred embodiment of the preparation method described in this invention, the volume ratio of dichloromethane to diethyl ether is 1:1.

[0035] As a preferred embodiment of the preparation method described in this invention, the compound cephanolide B(1) of formula (1) is chlorinated under the condition of adding a base in the presence of SO2Cl2 as a chlorine source, wherein the base is any one of triethylamine, N,N-diisopropylethylamine, or 1,8-diazacyclo[5,4,0]undecene-7.

[0036] In a preferred embodiment of the preparation method described in this invention, the chlorination condition is that no alkali is added.

[0037] As a preferred embodiment of the preparation method described in this invention, the additive Molecular sieves or any type of water.

[0038] In a preferred embodiment of the preparation method described in this invention, the Lewis acid is either aluminum trichloride or ethyl aluminum dichloride.

[0039] Beneficial effects of this invention:

[0040] This invention uses the natural product cephanolide B as a synthetic raw material. After oxidative dearomatization and acetylation, a dienone compound is obtained. Following a ring-expansion rearrangement reaction, the natural product cephinold H is obtained as a minor product. Subsequently, a Br atom is introduced as a site group, and after oxidative dearomatization and acetylation, a brominated dienone compound is obtained. A ring-expansion rearrangement reaction yields a ring-expansion product with an increased proportion of Br atom substitution. Then, under palladium-catalyzed reduction, the Br atom is removed to obtain the natural product cephinold H. To further improve the regioselectivity of the ring-expansion rearrangement reaction, a Cl atom is introduced as a site group. After oxidative dearomatization and acetylation, a Cl-substituted dienone compound is obtained. Following a ring-expansion rearrangement reaction, a chlorine-substituted ring-expansion product is obtained as the major product. Then, under palladium-catalyzed reduction, the Cl atom is removed to obtain the natural product cephinold H. Cephinold H is then oxidized with selenium dioxide and reduced with sodium borohydride to obtain the natural product fortalpinoid C with the opposite hydroxyl configuration. Finally, the configuration of the hydroxyl group is reversed through a photo-extending reaction, thus achieving fortalpinoid. The chemical synthesis of C, the synthetic route of this invention has the advantages of being simple, efficient, easy to operate, and low in cost, and is suitable for the large-scale synthesis of cephinold H and fortalpinoid C, providing an important material basis for their bioactivity evaluation. Attached Figure Description

[0041] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0042] Figure 1 This is a synthesis route diagram for Embodiment 1 of the present invention.

[0043] Figure 2 The hydrogen spectrum of formula (4) in Example 1 of this invention.

[0044] Figure 3 The carbon spectrum of formula (4) in Example 1 of this invention.

[0045] Figure 4 The hydrogen spectrum of formula (15) in Example 1 of this invention.

[0046] Figure 5 The carbon spectrum of formula (15) in Example 1 of the present invention. Detailed Implementation

[0047] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0048] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0049] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0050] Unless otherwise specified, all the reagents used in this invention are commercially available in the field, as shown in Table 1. The synthesis of formula (1) can be referred to the synthesis route of Scheme 3 in document 10.1021 / jacs.8b03015.

[0051] Table 1

[0052]

[0053]

[0054] Example 1

[0055] This embodiment provides a method for the total synthesis of cephinold H and fortalpinoid C:

[0056] (1) Cephanolide B(1) (114 mg, 0.40 mmol, 1.0 equiv) as shown in formula (1) was dissolved in HFIP (5 mL), and HOAc (0.69 mL, 12.04 mmol, 30.0 equiv) and PIDA (155 mg, 0.48 mmol, 1.2 equiv) were added sequentially at 0 °C, and the reaction was maintained at this temperature for 10 min. After the reaction was completed, the mixture was quenched with saturated sodium thiosulfate aqueous solution (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL), extracted with EtOAc (5 x 30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate / CH2Cl2). Oxidation and dearomatization were carried out under PIDA conditions, and acetyl protection was performed to obtain diene compound 2 (96 mg, 0.28 mmol, 70%) as shown in formula (2) in 70% yield.

[0057] The diene compound 2 (72 mg, 0.21 mmol, 1.0 equiv) shown in formula (2) was dissolved in CH2Cl2 (5 mL), stirred at -78 °C for 5 min, and then BF3·Et2O (52 μL, 0.42 mmol, 2.0 equiv) was added. The reaction was allowed to proceed for 10 min, and then TMSCHN2 (0.21 mL, 0.42 mmol, 2.0 equiv, 2.0 M in hexane) was added. The reaction was continued at this temperature for another 10 min. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL), extracted with EtOAc (3 x 30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate / hexane).

[0058] Under the conditions of TMSCHN2 as a one-carbon unit and BF3·Et2O as a Lewis acid, a ring expansion and rearrangement reaction was carried out to obtain the natural product cephinold H(4) as shown in formula (4) in a 1:3.5 ratio with an overall yield of 68%, as a white foam (9 mg, 0.03 mmol, 15%) and the byproduct 3 as shown in formula (3), as a white solid (32 mg, 0.11 mmol, 53%). Since the natural product cephinold H(4) as shown in formula (4) is not the major product in this ring expansion reaction, we adjusted the synthetic route.

[0059]

[0060] The structural characterization data of the compound shown in formula (2) are as follows:

[0061] 1 H NMR(600MHz, CDCl3)δ6.09(d,J=2.4Hz,1H),4.64(dd,J=4.0and4.0Hz,1H),3.19–3.13(m,1H),3.04–2.97(m,1H), 2.94–2.87(m,1H),2.82(d,J=10.2Hz,1H),2.49–2.43(m,1H),2.42(d,J=17.8Hz,1H),2.31(ddd,J=17.2,11.8and 5.0Hz,1H),2.12(ddd,J=14.4,9.8and 4.4Hz,1H),2.02–1.97(m,1H),1.95(s,3H),1.89(d,J=1.9Hz,3H),1.91–1.86(m,1H),1.39(dddd,J=14.4,4.8,4.8and 1.7Hz,1H),0.84(d,J=6.9Hz,3H);

[0062] 13 C NMR (151MHz, CDCl3) δ187.3,174.7,169.7,155.8,155.2,132.7,128.1,81 .8,77.7,48.3,43.8,38.4,30.4,30.1,26.3,25.4,23.1,22.1,19.9,12.2;

[0063] IR(KBr,cm -1 )3214,1675,1576,1397,869;

[0064] HRMS(ESI)calcd.for[C 20 H 22 O5Na] + (M+Na) + :m / z 365.1359,found 365.1370.

[0065] The structural characterization data of the compound shown in formula (3) are as follows:

[0066] 1H NMR of3(600MHz, CDCl3)δ6.96(d,J=12.2Hz,1H),6.92(d,J=12.2Hz,1H),4.69(dd,J=4.4and 4.4Hz,1H),3.30(dd,J=18.8and 10.4Hz,1H),3.18(d,J=11.4Hz,1H),3.09–3.03(m,1H),2.88–2.81(m,1H),2.73(dd,J=19.0and 3.4Hz,1H),2.70–2.64(m,1H),2.23(ddd,J=14.6,10.0and 5.6Hz,1H),2.20(s,3H),2.01–1.92(m,2H),1.75–1.70(m,1H),1.48(dddd,J=14.6,4.6,4.6and 1.8Hz,1H),0.91(d,J=7.0Hz,3H);

[0067] 13 C NMR of 3(151MHz, CDCl3)δ185.5,175.8,150.5,145.0,144.7,138.7,137.8,137.7,78.0,49.9,45.4,37.2,36.3,29.4,28.7,27.6,22.0,19.3,18.2;

[0068] IR of 3(KBr,cm -1 )3095,1745,1561,1075,901,849;

[0069] HRMS of3(ESI)calcd.for[C 19 H 21 O3] + (M+H) + :m / z 297.1485, found 297.1490;

[0070] Melting point of 3 230-232℃.

[0071] The structural characterization data of the compound shown in equation (4) are as follows:

[0072] 1H NMR of 4(600MHz, DMSO-d6)δ6.81(s,1H),6.75(s,1H),4.65(dd,J=4.4and4.4Hz,1H),3.44(d,J=10.6Hz,1H),3.19(dd,J=18.8and 10.0Hz,1H),2.91–2.85(m,1H),2.84–2.79(m,1H),2.78–2.72(m,1H),2.59(ddd,J=16.0,7.8and 2.6Hz,1H),2.28–2.23(m,1H),2.22(s,3H),2.11(dd,J=14.8and 10.2Hz,1H),1.69(ddd,J=14.2,8.0and8.0Hz,1H),1.47–1.41(m,1H),1.30–1.25(m,1H),0.76(d,J=7.0Hz,3H);

[0073] 13 C NMR of 4(151MHz, DMSO-d6)δ184.6,175.2,146.0,145.5,144.7,143.1,139.6,137.1,77.6,50.2,44.3,37.4,34.4,29.7,29.0,28.6,24.3,21.5,19.1;

[0074] IR of 4(KBr,cm -1 )2956,1737,1617,1174,908,804;

[0075] HRMS of 4(ESI)calcd.for[C 19 H 20 O3Na] + (M+Na) + :m / z 319.1305,found319.1303.

[0076] (2) At room temperature, cephanolide B(1) (2.00 g, 7.04 mmol, 1.0 equiv) as shown in formula (1) was dissolved in CHCl3 (50 mL), and then N-bromosuccinimide solution in CHCl3 (1.25 g, 7.04 mmol, 1.0 equiv, 0.2 M in CHCl3) was slowly added to the system, and the reaction was carried out at room temperature for 5 min. After the reaction was completed, the system was directly separated by column chromatography (ethylacetate / CH2Cl2).

[0077] The bromination reaction was carried out under N-bromosuccinimide conditions to give compound 5, as shown in formula (5), in 90% yield as a pale yellow foam (2.29 g, 6.33 mmol, 90%). Compound 5 (240 mg, 0.66 mmol, 1.0 equiv) was then dissolved in HFIP (12 mL), and HOAc (1.1 mL, 19.8 mmol, 30.0 equiv) and PIDA (255 mg, 0.79 mmol, 1.2 equiv) were added sequentially at 0 °C, maintaining this temperature for 10 min. After the reaction was complete, the solution was quenched with saturated sodium thiosulfate aqueous solution (5 mL) and saturated sodium bicarbonate aqueous solution (5 mL), extracted with EtOAc (5 x 30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate / CH2Cl2).

[0078] Oxidative dearomatization with acetyl protection under PIDA conditions yielded diene compound 6 as shown in formula (6) in 71% yield, which was a yellow foam (197 mg, 0.47 mmol, 71%).

[0079]

[0080] The structural characterization data of the compound shown in formula (5) are as follows:

[0081] 1 H NMR (600MHz, CDCl3) δ5.56(s,1H),4.66(dd,J=4.6and 4.6Hz,1H),3.26(d,J=10.4Hz,1H),3.21(dd,J=17.4and 9.6Hz,1H),3.17–3.10(m,1H),2.89(dd,J=18.2and9.6Hz,1H),2.58(dd,J=17.4and 8.6Hz,1H),2.54(d,J=16.2Hz,1H),2.24–2.20(m,1H),2.19(s,3H),2.11–2.03(m,1H),1.70(dd,J=14.2and 10.4Hz,1H),1.34–1.28(m,1H),1.28–1.21(m,1H),0.84(d,J=7.2Hz,3H);

[0082] 13C NMR (151MHz, CDCl3) δ176.5,150.1,140.7,132.5,131.1,119.5,110.2,79.0,47.7,45.3,39.3,32.6,28.6,26.1,25.9,23.6,19.4,13.3;

[0083] IR(KBr,cm -1 )3303,1733,1552,1067,733;

[0084] HRMS(ESI)calcd.for[C 18 H 19 BrO3Na] + (M+Na) + :m / z 385.0410,found385.0416.

[0085] The structural characterization data of the compound shown in formula (6) are as follows:

[0086] 1 H NMR (600MHz, CDCl3) δ4.64 (dd, J=4.1and 3.8Hz, 1H), 3.20–3.12 (m, 1H), 3.02 (dd, J=18.6and 10.8Hz,1H),2.87–2.74(m,1H),2.82(d,J=10.8Hz,2H),2.44(d,J=18.6Hz,1H),2.35–2.27(m,1H),2.22–2.17(m ,1H),1.95(s,6H),1.91(dd,J=14.5and10.6Hz,1H),1.84–1.76(m,1H),1.45–1.38(m,1H),0.86(d,J=6.8Hz,3H);

[0087] 13 C NMR (151MHz, CDCl3) δ180.0,174.3,169.6,156.0,154.3,132.0,126.7,83 .0,77.5,48.7,43.9,38.4,30.2,30.0,28.2,26.1,23.0,21.8,19.8,13.1;

[0088] IR(KBr,cm -1 )3352,1661,1534,1099,882;

[0089] HRMS(ESI)calcd.for[C 20 H 21BrO5Na] + (M+Na) + :m / z 443.0465,found443.0466.

[0090] (3) Under a nitrogen atmosphere, the diene compound 6 (77 mg, 0.18 mmol, 1.0 equiv) as shown in formula (6) was dissolved in CH2Cl2 (4 mL), cooled to -78 °C, and EtAlCl2 (0.55 mL, 0.55 mmol, 3.0 equiv, 1.0 M inhexane) was added. After stirring for 10 min, TMSCHN2 (0.27 mL, 0.55 mmol, 3.0 equiv, 2.0 M inhexane) was added, and the reaction was maintained at this temperature for 10 min. After the reaction was completed, the product was quenched with saturated sodium bicarbonate aqueous solution (5 mL), extracted with EtOAc (3 x 30 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate / CH2Cl2) to obtain pale yellow foamy product 7 (20 mg, 0.053 mmol, 29%) and pale yellow foamy product 8 (20 mg, 0.053 mmol, 29%).

[0091] The diene compound 6, as shown in formula (6), underwent a ring expansion rearrangement reaction with TMSCHN2 as a one-carbon unit and EtAlCl2 as a Lewis acid, yielding the cycloheptatrienone product 8, as shown in formula (8), and the byproduct 7, as shown in formula (7), in a 1:1 ratio with an overall yield of 58%.

[0092]

[0093] The structural characterization data of the compound shown in formula (7) are as follows:

[0094] 1H NMR of 7(600MHz, CDCl3)δ7.70(s,1H),4.69(dd,J=4.0and 4.0Hz,1H),3.29(dd,J=19.2and 10.6Hz,1H),3.24(d,J=11.4Hz,1H),3.08–3.02(m,2H),2.83–2.76(m,1H),2.73(dd,J=19.0and 3.0Hz,1H),2.26(ddd,J=14.9,9.4and 6.5Hz,1H),2.19(s,3H),2.00(dd,J=14.7and 10.4Hz,1H),1.99–1.94(m,1H),1.78–1.72(m,1H),1.54–1.48(m,1H),0.93(d,J=6.9Hz,3H);

[0095] 13 C NMR of 7(151MHz, CDCl3)δ182.6,175.4,149.5,145.1,144.3,141.4,138.4,138.2,77.8,51.2,45.0,37.2,35.7,32.4,28.8,27.7,23.0,19.2,18.2;

[0096] IR of 7(KBr,cm -1 )3209,1654,1538,1293,730;

[0097] HRMS of 7(ESI)calcd.for[C 19 H 19 BrO3Na] + (M+Na) + :m / z 397.0410,found397.0418.

[0098] The structural characterization data of the compound shown in formula (8) are as follows:

[0099] 1H NMR of 8(600MHz, CDCl3)δ6.99(s,1H),4.68–4.62(m,1H),3.42(d,J=10.6Hz,1H),3.18(dd,J=18.6and 10.6Hz,1H),3.08(d,J=7.0Hz,1H),3.06(d,J=7.0Hz,1H),3.03–2.96(m,1H),2.70(d,J=18.6Hz,1H),2.35 –2.29(m,1H),2.25(s,3H),2.11–2.03(m,2H),1.81–1.74(m,1H),1.55–1.49(m,1H),0.94(d,J=7.0Hz,3H);

[0100] 13 C NMR of 8(151MHz, CDCl3)δ180.2,175.3,144.6,144.1,142.9,140.4,140.1,135.6,77.8,52.9,44.6,37.7,35.0,33.7,29.0,28.0,24.3,23.5,19.2;

[0101] IR of 8(KBr,cm -1 )3194,1629,1551,1222,950,731;

[0102] HRMS of 8(ESI)calcd.for[C 19 H 19 BrO3Na] + (M+Na) + :m / z 397.0410,found397.0409.

[0103] (4) Under a nitrogen atmosphere, add the cycloheptatrienone product 8 (8.0 mg, 0.021 mmol, 1.0 equiv), Pd(OAc)2 (2.0 mg, 0.008 mmol, 0.4 equiv), dppp (5.2 mg, 0.012 mmol, 0.6 equiv), and DMF (0.5 mL, degassed) as shown in formula (8) to a 10 mL reaction tube. After heating to 60 °C, add Et3SiH (20 μL, 0.13 mmol, 6.0 equiv) and continue stirring for 2-3 h. After the reaction is complete, filter the mixture through a short silica gel column, elute with ethyl acetate / CH2Cl2 (1:1, 100 mL), concentrate, and separate by column chromatography (ethyl acetate / hexane).

[0104] The cycloheptatrienone product 8 shown in formula (8) was subjected to halogen removal under palladium-catalyzed reduction to give the natural product cephinold H (4) shown in formula (4) in 75% yield. It was a white foamy product (4.7 mg, 0.016 mmol, 75%).

[0105]

[0106] (5) Under a nitrogen atmosphere, cephanolide B(1) (100 mg, 0.35 mmol, 1.0 equiv) as shown in formula (1) was dissolved in CH2Cl2 (8 mL), cooled to 0 °C, and then freshly distilled SO2Cl2 (29 μL, 0.35 mmol, 1.0 equiv) was added, and the reaction was allowed to proceed for 20 min. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL), extracted with EtOAc (3 x 30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product.

[0107] The crude product was dissolved in THF (20 mL), and TBACl (175 mg, 0.63 mmol, 1.8 equiv) was added at room temperature. The reaction was allowed to proceed for 2 h. After the reaction was completed, the product was quenched with distilled water (10 mL), extracted with EtOAc (3 x 20 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate / CH2Cl2).

[0108] Cephanolide B(1) as shown in formula (1) was chlorinated under SO2Cl2 conditions to give compound 5' as shown in formula (9) in 72% yield, which was a pale yellow foam (80 mg, 0.25 mmol, 72%).

[0109] Compound 5' (60 mg, 0.19 mmol, 1.0 equiv) as shown in formula (9) was dissolved in HFIP (2.5 mL). HOAc (0.32 mL, 5.66 mmol, 30.0 equiv) and PIDA (73 mg, 0.23 mmol, 1.2 equiv) were added sequentially at 0 °C, and the reaction was maintained at this temperature for 10 min. After the reaction was completed, the solution was quenched with saturated sodium thiosulfate aqueous solution (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL), extracted with EtOAc (5 x 20 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate / CH2Cl2).

[0110] Oxidative dearomatization and acetylation were performed to give the diene compound 6' as shown in formula (10) in 72% yield, which was yellow foam (52 ​​mg, 0.14 mmol, 72%).

[0111]

[0112] The structural characterization data of the compound shown in formula (9) are as follows:

[0113] 1 H NMR (600MHz, CDCl3) δ5.56 (s, 1H), 4.68–4.63 (m, 1H), 3.25 (d, J = 10.4Hz, 1H), 3.22 (d, J = 1 4.8Hz,1H),3.18–3.09(m,1H),2.92(dd,J=18.2and9.6Hz,1H),2.64(ddd,J=17.4,8.4and 8.4Hz,1H),2.55(d,J=17.4Hz,1H),2.24–2.13(m,1H),2.17(s,3H),2.11–2.04(m,1H),1.70(dd,J=12.4and 12.4Hz,1H),1.30(d,J=14.0Hz,1H),1.26–1.21(m,1H),0.84(d,J=6.8Hz,3H);

[0114] 13 C NMR (151MHz, CDCl3) δ176.5,149.4,139.9,132.1,129.2,119.5,117.8,79.0,47.6,45.3,39.3,32.7,28.6,26.2,23.3,23.3,19.4,13.1;

[0115] IR(KBr,cm-1)3519,3371,1650,1071,831;

[0116] HRMS(ESI)calcd.for[C 18 H 19 ClO3Na] + (M+Na) + :m / z 341.0915,found341.0914.

[0117] The structural characterization data of the compound shown in formula (10) are as follows:

[0118] 1H NMR (600MHz, CDCl3) δ4.63 (dd, J=4.0and 4.0Hz,1H),3.19–3.12(m,1H),3.05–2.97(m,1H),2.85–2.79(m,3H),2.44(d,J=18.7Hz,1H),2.3 2–2.25(m,1H),2.21–2.16(m,1H),1.95(s,3H),1.93(d,J=1.8Hz,3H),1.90(ddd,J=14.5,10.4and 0.6Hz,1H),1.83–1.77(m,1H),1.43–1.38(m,1H),0.85(d,J=6.8Hz,3H);

[0119] 13 C NMR (151MHz, CDCl3) δ179.9,174.3,169.6,156.3,150.6,132.4,132.1,82 .6,77.5,48.5,43.9,38.4,30.2,30.0,26.0,24.9,22.8,21.8,19.8,12.9;

[0120] IR(KBr,cm -1 )3297,1747,1547,1224,962,757;

[0121] HRMS(ESI)calcd.for[C 20 H 21 ClO5Na] + (M+Na) + :m / z 399.0970,found399.0973.

[0122] (6) Under a nitrogen atmosphere, the diene compound 6' (30 mg, 0.08 mmol, 1.0 equiv) as shown in formula (10) was dissolved in CH2Cl2 (3 mL), cooled to -78 °C, and AlCl3 (21 mg, 0.16 mmol, 2.0 equiv) was added. After stirring for 10 min, TMSCHN2 (60 μL, 0.12 mmol, 1.5 equiv, 2.0 M in hexane) was added, and the reaction was maintained at this temperature for 10 min. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL), extracted with EtOAc (5 x 10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate / CH2Cl2).

[0123] The diene compound 6', as shown in formula (10), under conditions of TMSCHN2 as a one-carbon unit and AlCl3 as a Lewis acid, under regioselectivity with an overall yield of 58% and a 3:1 ratio, underwent a ring-expansion rearrangement reaction to give the compound as shown in formula (10).

[0124] (12) The cycloheptatrienone product 8' shown is a white solid (11 mg, 0.03 mmol, 43.5%) and as shown in formula

[0125] (11) The byproduct 7' shown is a white foam (3.8 mg, 0.01 mmol, 14.5%), which successfully reversed the proportion of the ring-expanding product.

[0126]

[0127] The structural characterization data of the compound shown in formula (11) are as follows:

[0128] 1 H NMR of 7'(600MHz, CDCl3)δ7.38(s,1H),4.70(dd,J=4.3and 4.3Hz,1H),3.31(dd,J=18.8and 10.6Hz,1H),3.24(d,J=11.2Hz,1H),3.09–3.01(m,2H),2.83–2.77(m,1H),2.74(dd,J=19.2and 3.6Hz,1H),2.26(ddd,J=14.8,9.2and 6.4Hz,1H),2.20(s,3H),2.05–1.98(m,2H),1.80–1.75(m,1H),1.52(ddd,J=14.8,4.6and 1.6Hz,1H),0.93(d,J=7.0Hz,3H);

[0129] 13 C NMR of 7'(151MHz, CDCl3)δ182.6,175.4,149.4,145.6,145.5,144.7,137.7,137.1,77.8,51.0,45.0,37.2,35.7,28.9,28.8,27.6,22.6,19.3,18.2;

[0130] IR of 7'(KBr,cm -1 )3337,1651,1604,1065,705;

[0131] HRMS of 7'(ESI)calcd.for[C 19 H 19 ClO3Na] +(M+Na) + :m / z 353.0915,found353.0927.

[0132] The structural characterization data of the compound shown in formula (12) are as follows:

[0133] 1 H NMR of 8'(600MHz, CDCl3)δ7.05(s,1H),4.65(dd,J=4.4and 4.4Hz,1H),3.41(d,J=10.8Hz,1H),3.24(dd,J=18.6and 10.2Hz,1H),3.12(ddd,J=18.2,7.6and 7.4Hz,1H),3.04–2.96(m,2H),2.73(ddd,J=18.6,2.6and 2.6Hz,1H),2.32(ddd,J=14.6,9.0and6.8Hz,1H),2.25(s,3H),2.10–2.02(m,2H),1.76–1.71(m,1H),1.54–1.48(m,1H),0.92(d,J=6.8Hz,3H);

[0134] 13 C NMR of 8'(151MHz, CDCl3)δ179.3,175.3,144.5,144.1,143.4,142.4,140.8,137.0,77.8,52.7,44.5,37.7,35.1,29.6,28.9,28.1,24.6,23.0,19.2;

[0135] IR of 8'(KBr,cm -1 )3432,1693,1556,1107,905;

[0136] HRMS of 8'(ESI)calcd.for[C 19 H 19 ClO3Na] + (M+Na) + :m / z 353.0915,found353.0918;

[0137] Melting point of 8'249-251℃.

[0138] (7) Under a nitrogen atmosphere, add the cycloheptatrienone product 8' (10.0 mg, 0.030 mmol, 1.0 equiv), Pd(OAc)2 (2.7 mg, 0.012 mmol, 0.4 equiv), dppp (7.5 mg, 0.018 mmol, 0.6 equiv), and DMF (0.6 mL, degassed) as shown in formula (12) to a 10 mL reaction tube. After heating to 60 °C, add Et3SiH (29 μL, 0.18 mmol, 6.0 equiv) and continue stirring for 2-3 h. After the reaction is complete, filter the mixture with a short silica gel column, elute with ethylacetate / CH2Cl2 (1:1, 100 mL), concentrate and separate by column chromatography (ethyl acetate / hexane) to a white foamy natural product cephinold H(4) (6.3 mg, 0.021 mmol, 70%) as shown in formula (4);

[0139] Under a nitrogen atmosphere, the natural product cephinoid H(4) (10.0 mg, 0.034 mmol, 1.0 equiv) as shown in formula (4) was added to a 10 mL reaction tube. Molecular sieve (38 mg) and 1,4-dioxane (2 mL) were added, followed by SeO2 (38 mg, 0.34 mmol, 10.0 equiv.), and the mixture was heated to 60 °C and stirred for 5 h. After the reaction was completed, the mixture was filtered through a short silica gel column, eluted with ethyl acetate (50 mL), concentrated, and separated by column chromatography (ethyl acetate / hexane) to obtain compound 9 as shown in formula (13), which was a pale yellow solid (7.3 mg, 0.024 mmol, 70%).

[0140] The cycloheptatrienone product 8' shown in formula (12) was subjected to palladium-catalyzed reduction to remove chlorine atoms, yielding the natural product cephinold H (4) shown in formula (4) in 70% yield. Subsequently, it was oxidized by SeO2 to yield the product 9, which was oxidized at the C7 position, shown in formula (13) in 70% yield.

[0141]

[0142] The structural characterization data of the compound shown in formula (13) are as follows:

[0143] 1H NMR (600MHz, CDCl3) δ7.55(s,1H),6.99(s,1H),4.74–4.69(m,1H),3.65(d,J=9.6Hz,1H),3.34(dd,J=17.6and 9.2Hz,1H),3.12–3.07(m,1H),3.04(d,J=19.4Hz,1H),2.98(d,J=19.4Hz,1H),2.80(d,J=18.8Hz, 1H),2.29(s,3H),2.14–2.08(m,1H),1.97–1.92(m,1H),1.60–1.56(m,1H),0.97(d,J=5.2Hz,3H);

[0144] 13 C NMR (151MHz, CDCl3) δ196.0,186.3,173.6,146.4,145.4,141.6,140.3,139.7,135.7,78.0,51.8,44.9,40.9,38.1,35.1,28.8(double C),25.3,19.4;

[0145] IR(KBr,cm -1 )3316,1694,1337,1110,882,636;

[0146] HRMS(ESI)calcd.for[C 19 H 18 O4Na] + (M+Na) + :m / z 333.1097, found 333.1090;

[0147] Meltingpoint: 173-175℃.

[0148] (8) Compound 9 (5.0 mg, 0.016 mmol, 1.0 equiv) as shown in formula (13) was dissolved in MeOH / THF (0.25 / 0.25 mL), and NaBH4 (1.8 mg, 0.048 mmol, 3.0 equiv) was added at 0 °C. The reaction was maintained at this temperature for 10 min. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate aqueous solution (0.5 mL), extracted with EtOAc (10 x 5 mL), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate / hexane) to obtain a white foamy product 10 (3.5 mg, 0.011 mmol, 70%).

[0149] The secondary alcohol compound 10 (4.0 mg, 0.013 mmol, 1.0 equiv) as shown in formula (14) was dissolved in THF (0.3 mL). Ph3P (13 mg, 0.052 mmol, 4.0 equiv) and PNBA (8.6 mg, 0.052 mmol, 4.0 equiv) were added at 20 °C. The reaction mixture was placed at 0 °C and DEAD (0.1 mL, 0.052 mmol, 4.0 equiv, 0.5 M in THF) was added. The mixture was then heated to 20 °C and reacted for 1 h. After the reaction was complete, the reaction mixture was filtered through a silica short column and eluted with ethyl acetate / n-hexane (3:1100 mL). The eluent was concentrated under vacuum, and the crude product was used in the next step without purification. The crude product was dissolved in CH2Cl2 / MeOH (0.1 mL / 0.2 mL) at 0 °C (ice bath), and K2CO3 (4.4 mg, 0.032 mmol, 2.5 equiv) was added. After stirring at this temperature for 30 minutes, the reaction mixture was diluted with CH2Cl2 (0.3 mL) and then purified by rapid column chromatography (SiO2, ethyl acetate / hexane) to give white powder 11 (3.2 mg, 0.010 mmol, 81% yield over two-step).

[0150] The structural characterization data of the compound shown in formula (14) are as follows:

[0151] 1 H NMR (600MHz, Pyridine-d5) δ8.01(s,1H),7.85(d,J=5.2Hz,1H),4.58(dd,J=4.6and 4.6Hz,1H),3.52(d,J=10.6Hz,1H),3.45(dd,J=14.4and 9.4Hz,1H),2.93–2.86(m,1H),2.84–2.78(m,1H),2.60–2.55(m,1H),2.07(s,3H) ,1.89–1.82(m,2H),1.50–1.44(m,1H),1.30–1.22(m,3H),0.74(d,J=7.0Hz,3H);

[0152] 13 C NMR (151MHz, Pyridine-d5) δ186.1,175.4,145.2,144.1,142.0,141.3,134.9,78.3,67.9,49.4,45.0,38.2,35.2,33.4,31.0,29.2,24.6,19.3;

[0153] IR(KBr,cm -1 )3209,2962,1652,1538,1258,918,673;

[0154] HRMS(ESI)calcd.for[C 19 H 20 O4Na] + (M+Na) + :m / z 335.1254,found 335.1242.

[0155] Natural product compound 9, as shown in formula (13), was reduced with NaBH4 to give secondary alcohol compound 10, as shown in formula (14), in 70% yield. Subsequently, the C7 hydroxyl configuration was reversed by photoelectrophoresis to give natural product fortalpinoid C (11), as shown in formula (15), in 81% yield.

[0156]

[0157] The structural characterization data of the compound shown in formula (15) are as follows:

[0158] 1 H NMR (600MHz, Pyridine-d5) δ7.31(d,J=2.0Hz,1H),7.18–7.14(m,1H),4.92(d,J=4.8Hz,1H),4.61(dd,J=4.2and 4.2Hz,1H),4.35–4.30(m,1H),3.01(dd,J=15.1and1.9Hz,1H),2.89–2.80(m,2H),2.58–2.52(m,1H),2.35(dd,J=15.0and 6.3Hz,1H),2.07(s,3H),1.91(dd,J=14.9and 10.2Hz,1H),1.58–1.51(m,1H),1.32(dtd,J=14.8,4.3and1.6Hz,1H),0.86(d,J=7.0Hz,3H);

[0159] 13 C NMR(151MHz,Pyridine-d5)δ187.1,176.2,147.2,146.7,145.4,143.8,141 .2,139.2,78.4,72.5,49.8,46.3,38.4,35.8,33.8,30.3,29.7,25.1,20.3;

[0160] IR(KBr,cm -1)3110,2919,2313,1740,1519,1360,941

[0161] HRMS(ESI)calcd.for[C 19 H 20 O4Na] + (M+Na) + :m / z 335.1254,found 335.1251.

[0162] Example 2

[0163] The difference from Example 1 is that boron trifluoride ether was replaced with ethyl aluminum dichloride in step (1), resulting in a final yield of 10% for compound 4 and 30% for compound 3.

[0164] Example 3

[0165] The difference from Example 1 is that in step (3), ethyl aluminum dichloride was replaced with aluminum trichloride, resulting in a final yield of 17.5% for compound 7 and 17.5% for compound 8.

[0166] Example 4

[0167] The difference from Example 1 is that in step (7)... Replacing the molecular sieve with water yielded a final yield of 62%.

[0168] Figure 1 This is a synthetic route diagram of Embodiment 1 of the present invention. Figures 2-5 The images show the proton and carbon spectra of cephinold H and fortalpinoid C.

[0169] This invention uses the natural product cephanolide B as a synthetic raw material. After oxidative dearomatization and acetylation, a dienone compound is obtained. This is followed by a ring-expansion rearrangement reaction to obtain the natural product cephinold H as a minor product. Subsequently, a Br atom is introduced, followed by oxidative dearomatization and acetylation to obtain a brominated dienone compound. A ring-expansion rearrangement reaction yields a ring-expansion product with an increased proportion of Br atom substitution. The removal of the Br atom under palladium-catalyzed reduction gives the natural product cephinold H. To further improve the regioselectivity of the ring-expansion rearrangement reaction, a Cl atom is introduced as a site group. After oxidative dearomatization and acetylation, a Cl-substituted dienone compound is obtained. This is followed by a ring-expansion rearrangement reaction to obtain a chlorine-substituted ring-expansion product as the major product. The removal of the Cl atom under palladium-catalyzed reduction gives the natural product cephinold H. Cephinold H is then oxidized with selenium dioxide and reduced with sodium borohydride to obtain the natural product fortalpinoid C with the opposite configuration at the C7 position. Finally, the configuration of the hydroxyl group is reversed through a photoelectroporation reaction, thus achieving fortalpinoid. The chemical synthesis of C, the synthetic route of this invention has the advantages of being simple, efficient, easy to operate, and low in cost, and is suitable for the large-scale synthesis of cephinold H and fortalpinoid C, providing an important material basis for their bioactivity evaluation.

[0170] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the present invention.

Claims

1. A method for synthesizing cephinold H, characterized in that: include, The compound cephanolide B shown in formula (1) was brominated under N-bromosuccinimide conditions to obtain the compound shown in formula (5), and then subjected to oxidative dearomatization and acetylation to obtain the diene compound shown in formula (6). Equation (1); Equation (5); Equation (6); The diene compound shown in formula (6) undergoes a regioselective ring expansion and rearrangement reaction with a ratio of 1:1 under the conditions of solvent and Lewis acid, with the diazotizing reagent TMSCHN2 as a one-carbon unit, to obtain the cycloheptatrienone product shown in formula (8). Equation (8); The cycloheptatrienone product shown in formula (8) under palladium-catalyzed reduction conditions was subjected to halogen removal to obtain the natural product cephinold H shown in formula (4); Equation (4); The Lewis acid is either aluminum trichloride or ethyl aluminum dichloride.

2. A method for synthesizing cephinold H, characterized in that: include, The compound cephanolide B shown in formula (1) was chlorinated under the condition of SO2Cl2 as chlorine source to obtain the compound shown in formula (9), and then oxidative dearomatization and acetylation were carried out to obtain the diene compound shown in formula (10). Equation (9); Equation (10); The diene compound shown in formula (10) underwent a regioselective ring expansion rearrangement reaction with TMSCHN2 as a one-carbon unit and AlCl3 as a Lewis acid in a ratio of 3:1 to give the cycloheptanetrienone product shown in formula (12). Equation (12); The cycloheptatrienone product shown in formula (12) was subjected to palladium-catalyzed reduction to remove chlorine atoms, yielding the natural product cephinold H.

3. A method for synthesizing cephinold H, characterized in that: include, The compound cephanolide B shown in formula (1) undergoes oxidative dearomatization and acetyl protection to yield the diene compound shown in formula (2). The diene compound shown in formula (2) then undergoes ring expansion and rearrangement under the conditions of a diazotizing agent and a Lewis acid to yield the natural product cephinold H as shown in formula (4). Equation (1); Equation (2); Equation (4); The diazotizing agent is trimethylsilyldiazomethane; the Lewis acid is any one of boron trifluoride ether, aluminum trichloride, or ethyl aluminum dichloride.

4. A method for synthesizing fortalpinoid C, characterized in that: include, The natural product cephinold H shown in formula (4) in SeO 2， And under additive conditions, oxidation yields the compound shown in formula (13); Equation (13); The compound shown in formula (13) was reduced with NaBH4 to give the secondary alcohol compound 10 shown in formula (14), and then the hydroxyl configuration was inverted by photo-extending reaction to give the natural product fortalpinoid C shown in formula (15). Equation (14); Equation (15).

5. The method for synthesizing cephinold H as described in claim 1, characterized in that: The solvent is either dichloromethane or dichloromethane / diethyl ether, wherein the volume ratio of dichloromethane / diethyl ether is 1:

1.

6. The method for synthesizing cephinold H as described in claim 2, characterized in that: The compound cephanolide B (1) shown in formula (1) is chlorinated under the condition of adding or not adding a base in the presence of SO2Cl2 as the chlorine source, wherein the base is any one of triethylamine, N,N-diisopropylethylamine, or 1,8-diazacyclic[5,4,0]undecene-7.

7. The method for synthesizing fortalpinoid C as described in claim 4, characterized in that: The additive is either a 4Å molecular sieve or water.

Images