A method for the asymmetric synthesis of (-)-fish oxalic acid

Abstract

A method for the asymmetric synthesis of (-)-Anisomelic Acid. Starting with the commercially available chiral compound (-)-Costunolide, a key intermediate is obtained via a regioselective ozone decomposition reaction. The carbon chain is then extended via a Horner-Wadsworth-Emmons (HWE) reaction and a Peterson olefination reaction. A fourteen-membered carbon ring skeleton of (-)-Anisomelic Acid is constructed via a ring-closing metathesis (RCM) reaction. This method lays an important foundation for subsequent research on the bioactivity of (-)-Anisomelic Acid. In this synthetic route, various (-)-Anisomelic Acid analogues can also be obtained from the key intermediate. The reaction operation in this synthetic route is simple and can be widely applied.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis and relates to a method for the asymmetric synthesis of (–)-Anisomelic Acid by a synthetic strategy of expanding a ten-membered ring into a fourteen-membered macrocycle through ozonolysis, Horner–Wadsworth–Emmons (HWE) reaction, Peterson olefination reaction, and ring-closing metathesis (RCM) reaction. Background Technology

[0002] The fully synthesized racemic mixture of anisomelic acid (±) was first described in 1987. In the last decade, a research team at Abo Akademi University, the only university in Finland where instruction is in Swedish, has used this as a basis for a series of studies on the anti-human papillomavirus-induced cervical cancer using anisomelic acid and its derivatives.

[0003] For over two decades, the inventors' team has been breeding *Anisomelesindica* O. Kuntze (GenBank: GU726292), also known as "guest grass," and has been conducting a series of studies on the whole herb extracts of *Anisomelesindica* grown at Zixiu Farm in Yuli Township, Hualien County, Taiwan. Specifically, they have carried out extraction, separation, purification, analysis, and identification of a series of natural substances from *Anisomelesindica*, as well as research on its pharmacological effects, including anti-inflammatory, anti-fatigue, anti-allergic, anti-asthmatic, anti-influenza virus, anti-Helicobacter pylori, anti-cancer, and anti-cancer stem cell effects. In particular, they have confirmed the stereochemical structure of the natural substance (–)-Anisomelic Acid ((–)-Anisomelic Acid) crystalline pure substance contained in *Anisomelesindica*, such as... Figure 1 The chemical formula of the invention is shown as (–)-fish oxalic acid.

[0004] In summary, (–)-fish oxalic acid is a valuable molecular probe that can be used to study the mechanisms of anticancer biological activity.

[0005] (–)-Anisomelic acid is a natural diterpenoid compound extracted from *Anisomelesindica* O. Kuntze. The content of (–)-Anisomelic acid in the whole plant is generally about 70 to 100 ppm dry weight. Clearly, (–)-Anisomelic acid has a low abundance in nature, is difficult to extract, and has limited sources. The lack of (–)-Anisomelic acid and its derivatives hinders comprehensive biological research on anticancer properties. Currently, there are no reports on the total synthesis of (–)-Anisomelic acid. Summary of the Invention

[0006] To advance comprehensive biological research on the anticancer effects of (–)-anisomelic acid, this invention provides an asymmetric synthesis method for (–)-anisomelic acid via a synthetic strategy involving ozonolysis, HWE reaction, Peterson olefination, and RCM reaction to expand a ten-membered ring into a fourteen-membered macrocycle. The synthetic reactions are simple to perform, widely applicable, provide ample samples for activity testing, and lay the foundation for further structural optimization of complex macrocyclic skeletons and the development of highly active and selective anticancer drugs.

[0007] The chemical formula of the oxalic acid mentioned above is shown below:

[0008]

[0009] In order to achieve the above object, the present invention adopts the following technical solutions:

[0010] A method for the asymmetric synthesis of (–)-fish oxalic acid, comprising the following steps:

[0011] 1) Aldehyde compound 1 was prepared by using chiral compound (–)-costunolide as the starting material under ozonolysis conditions;

[0012] 2) Using the aldehyde-ketone compound 1 and compound 6, unsaturated lactone compound (Z)-3 and unsaturated lactone compound (E)-3 were prepared under alkaline conditions;

[0013] 3) Using this unsaturated lactone compound (Z)-3, under cerium trichloride-promoted 1,2-addition conditions, a tetraene compound 4 was subsequently prepared by elimination.

[0014] 4) Using this tetraene compound 4, a fourteen-membered macrocyclic compound (Z)-5 and a one-fourteen-membered macrocyclic compound (E)-5 were prepared under olefin metathesis conditions;

[0015] 5) Using the fourteen-membered macrocyclic compound (E)-5, the natural product (–)-Anisomelic Acid was prepared under conditions of desiliconization and hydrolysis.

[0016] The chemical formulas of each compound are as follows Figure 2 As shown, in compounds 6, (Z)-3, (E)-3, 4, (E)-5 and (Z)-5, the R group can be alkoxy, aromatic oxy, alkylamine, aromatic amine, alkyl mercapto, aromatic mercapto, or silyl.

[0017] Further, step 1) involves preparing aldehyde / ketone compound 1 using the chiral compound (–)-Costunolide as a starting material under ozonochemical decomposition conditions, comprising:

[0018] The solution of compound (–)-ausnezyl lactone was purged with ozone at -78°C, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, the reducing agent dimethyl sulfide was added to quench the reaction. After the reaction system was heated to room temperature, the solvent was removed, and the residue was purified by silica gel column chromatography to obtain compound 1.

[0019] Compound 1 can be obtained from mixed solvents, dichloromethane-methanol, dichloromethane-acetone, and dichloromethane-acetic acid. Dimethyl sulfide or triphenylphosphine can be used as the reducing quencher. If acetic acid is used as a co-solvent, in addition to adding the reducing quencher, the acetic acid in the reaction system needs to be neutralized with a saturated sodium bicarbonate solution. Sudan III can also be used as an indicator to monitor the completion of the reaction.

[0020] Further, step 2) involves the preparation of unsaturated lactone compound (Z)-3 and unsaturated lactone compound (E)-3 under alkaline conditions using aldehyde / ketone compound 1 and phosphate ester compound 6, comprising:

[0021] At -78°C, an alkaline substance was added dropwise to a tetrahydrofuran solution of compound 6, and the mixture was stirred at this temperature for 30 minutes. Then, a tetrahydrofuran solution of compound 1 was added. After the reaction was completed, a quencher was added, and the residue was purified by silica gel column chromatography to obtain compounds (Z)-3 and (E)-3.

[0022] The unsaturated lactone is an α,β-unsaturated lactone. The basic substance can be sodium hexamethylsilylamino, potassium hexamethylsilylamino, lithium hexamethylsilylamino, or a sterically hindered basic substance that does not readily undergo Michael reaction on the exocyclic double bond. The choice of solvent, reagent, and basic substance will affect the ratio of compound (Z)-3 to compound (E)-3.

[0023] Further, step 3) involves the preparation of tetraene compound 4 using unsaturated lactone compound (Z)-3 under cerium trichloride-promoted 1,2-addition conditions, followed by elimination.

[0024] Cerium trichloride was added to a round-bottom flask and heated to 135–150 °C under vacuum, with stirring for a certain time (e.g., 3 hours). An inert gas was introduced, and the reaction system was transferred to an ice-water bath. Tetrahydrofuran was added, and the mixture was then heated to room temperature and stirred for a certain time (e.g., 12 hours). The reaction system was then cooled to -78–-80 °C, and a solution of trimethylsilylmethyllithium reagent in n-pentane was added dropwise, maintaining the same temperature and stirring for a certain time (e.g., 1.5 hours). Compound (Z)-3 was then added to the reaction system, and the mixture was stirred at -78–-80 °C for a certain time (e.g., 1.5 hours). The reaction was quenched by adding an aqueous acetic acid solution. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, and the solvent was removed. The residue was evaporated to dryness and then redissolved in dichloromethane. Silica gel was added to promote elimination, and the mixture was stirred for 24 hours. The solvent was evaporated to dryness, and the residue was separated by silica gel column chromatography to obtain compound 4.

[0025] The mass of cerium trichloride has a crucial impact on the reaction. Elimination-promoting agents can be acidic or basic, such as concentrated sulfuric acid or potassium tert-butoxide.

[0026] Furthermore, step 4) involves preparing the fourteen-membered macrocyclic compound (Z)-5 and the fourteen-membered macrocyclic compound (E)-5 using tetraene compound 4 under olefin metathesis conditions:

[0027] After adding an olefin metathesis catalyst to a solution of tetraene compound 4, the residual oxygen in the reaction system was removed under an inert gas atmosphere for a period of time. Then, the reaction system was heated to 60°C until tetraene compound 4 was completely converted. The solvent was removed, and the residue was purified by silica gel column chromatography to obtain fourteen-membered macrocyclic compounds (Z)-5 and (E)-5.

[0028] The reaction solvent, reaction concentration, reaction temperature, and choice of catalyst all have a significant impact on the compounds produced by the reaction and the reaction time.

[0029] Further, step 5) involves the preparation of the natural product (–)-fish oxalic acid using the fourteen-membered macrocyclic compound (E)-5 under conditions of desilylation and hydrolysis, including:

[0030] A tetrahydrofuran solution of the fourteen-membered macrocyclic compound (E)-5 was cooled to 0°C, and a tetrabutylammonium fluoride solution was added dropwise as a desilication reagent. The reaction was carried out at this temperature for 1 hour. The reaction system was quenched with saturated ammonium chloride solution, and after being heated to room temperature, it was extracted with ethyl acetate. The organic phases were combined, dried, and the solvent was removed. The residue was purified by silica gel column chromatography to give the natural product (–)-fish needle oxalic acid.

[0031] Among them, the desilication reagent can be tetrabutylammonium fluoride, aqueous solution of hydrogen fluoride, etc.

[0032] Further, step 2) prepares the key intermediate compound 6 via a nucleophilic substitution reaction, including the following steps:

[0033] 2-1) Using compounds 2 and 3, phosphate ester compound 6 was prepared under alkaline conditions;

[0034] The chemical formulas of compounds 2 and 3 are as follows: Figure 3 As shown, in compound 2, the R1 group can be alkoxy, aromatic oxy, alkylamine, aromatic amine, alkyl mercapto, aromatic mercapto, or silyl, and the R3 group can be phenyl or trifluoroethyl.

[0035] In compound 3, the R2 group can be chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy.

[0036] Further, step 2-1) involves the preparation of phosphate ester compound 6 under alkaline conditions using compounds 2 and 3, comprising:

[0037] The tetrahydrofuran solution of compound 2 was cooled to 0°C, and sodium hydride, an alkaline substance, was slowly added under an inert gas atmosphere. After stirring at this temperature for a period of time, the tetrahydrofuran solution of compound 3 was slowly added dropwise. The temperature was then raised until the reaction was complete. The reaction system was quenched with saturated ammonium chloride solution, and after being brought to room temperature, it was extracted with ethyl acetate. The organic phases were combined, dried, and the solvent was removed. The residue was purified by silica gel column chromatography to obtain compound 6.

[0038] Among them, the R2 group of compound 3 has a greater impact on the reaction time.

[0039] Preferably, the above reactions require an inert gas atmosphere, and are all carried out under an argon atmosphere.

[0040] Preferably, the extraction in the above reactions is carried out using ethyl acetate.

[0041] Preferably, in the above steps, the organic phase is dried with anhydrous sodium sulfate, and the solvent is removed using a rotary evaporator.

[0042] Preferably, in step 1), dichloromethane-acetic acid is used as a mixed solvent. Acetic acid can react with secondary ozonides, and the resulting peroxide intermediate is more easily reduced to compound 1. Dimethyl sulfide is preferred as the reducing quenching agent, and the product is easier to separate and purify after the reaction.

[0043] Preferably, in step 2), the alkaline reagent is sodium hexamethylsilylamino, the solvent is tetrahydrofuran, and the proportion of compound (Z)-3 is the highest.

[0044] Preferably, in step 3), the cerium trichloride is anhydrous cerium trichloride. Cerium trichloride containing water of crystallization needs to be ground into powder, which is also possible, but requires a better drying process and a longer drying time. Choosing weakly acidic silica gel as an elimination promoter can maximize the yield of compound 4.

[0045] Preferably, in step 4), the Hoveyda-Grubbs II catalyst has better thermal stability, allowing for a reduction in the amount of catalyst used. Controlling the reaction concentration at approximately 0.005 M effectively prevents the formation of intermolecular olefin metathesis products.

[0046] Preferably, in step 5), an anhydrous tetrabutylammonium fluoride tetrahydrofuran solution provides the highest yield.

[0047] Preferably, in step 2-1), the R2 group of compound 3 is iodine, which can shorten the reaction time and eliminate the need to add iodide as a promoter.

[0048] In this invention, compounds 2 and 3 are known compounds, meaning that compounds 2 and 3 can be prepared without using the method of this invention, but using existing compound products. Other compounds must be prepared using the method of this invention.

[0049] The technical effects of this invention are as follows:

[0050] The asymmetric total synthesis of (–)-acrylic acid was achieved through a synthetic strategy of ozonolysis of the chiral compound (–)-ausnezole lactone, followed by carbon chain extension and RCM reaction to construct a fourteen-membered macrocyclic skeleton. In other words, the basis of this invention is the preparation of (–)-acrylic acid from (–)-ausnezole lactone, such as... Figure 4 As shown.

[0051] This invention starts with the chiral compound (–)-ausnelide, a ten-membered carbon ring, and develops a regioselective ozonolysis process to cleave the double bond. Following HWE reaction and Peteson olefination, the carbon chain is extended, and the key fourteen-membered carbon ring skeleton structure of (–)-stigmocarboxylic acid is obtained via RCM reaction. Finally, total synthesis of (–)-stigmocarboxylic acid is achieved by desilylation. In the synthesis of (–)-stigmocarboxylic acid, the regioselective ozonolysis reaction significantly improves the preparation efficiency of the key intermediate compound 1, providing sufficient raw materials for subsequent synthesis. Furthermore, the intermediate constructed via RCM reaction can also yield various derivatized products. The reaction operation in this synthesis is simple and widely applicable, providing sufficient samples for bioactivity testing. Attached Figure Description

[0052] Figure 1 The chemical formula of (–)-fish needle oxalic acid of the present invention is shown.

[0053] Figure 2 The diagram shows the compounds used or produced in the asymmetric synthesis method of the present invention.

[0054] Figure 3 Here are the chemical formulas for compounds 2 and 3.

[0055] Figure 4 This invention provides a retrosynthetic analytical procedure for preparing (–)-stigmacolic acid from (–)-ausnezole lactone.

[0056] Figure 5 This is for the synthesis of compound 1.

[0057] Figure 6 For the synthesis of compound 6.

[0058] Figure 7 Synthesis of compounds (Z)-3 and (E)-3.

[0059] Figure 8 For the synthesis of compound 4.

[0060] Figure 9 Synthesis of compounds (Z)-5 and (E)-5.

[0061] Figure 10 Synthesis of the natural product (–)-fish needle oxalic acid. Detailed Implementation

[0062] The following specific embodiments further illustrate the technical solution of the present invention. These specific embodiments do not represent a limitation on the scope of protection of the present invention. Non-essential modifications and adjustments made by others based on the concept of the present invention still fall within the scope of protection of the present invention.

[0063] Example 1: Synthesis of Compound 1

[0064] like Figure 5 As shown.

[0065] (–)-Saussurea lactone (800 mg, 3.54 mmol) was dissolved in 250 mL of dichloromethane containing acetic acid (25 mL, 10% v / v), and the resulting mixture was cooled to -78 °C. Ozone was carefully introduced into the reaction system, and the reaction was monitored by thin-layer chromatography until (–)-Saussurea lactone was completely consumed. Dimethyl sulfide (1.0 mL) was added, and the mixture was slowly heated to room temperature. A saturated sodium bicarbonate solution (200 mL) was slowly added to the reaction system, and the mixture was then extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (300 mL) and dried over sodium sulfate. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1 to 4:1) to give a colorless oily compound 1 (773 mg, 85% yield).

[0066] The detection data for compound 1 are as follows:

[0067] R f =0.25 (ethyl acetate / petroleum ether = 1 / 1).

[0068]

[0069] 1 H NMR (400MHz, CDCl3) δ9.75(s,1H),6.24(d,J=2.8Hz,1H),5.57(d,J=2.5Hz,1H),5.17(d,J=8.3Hz,1H),4.75(dd,J=8.9,6.1 Hz,1H),2.72(dt,J=8.3,5.8Hz,1H),2.57-2.37(m,5H),2.19-2.06(m,4H),1.95(dt,J=13.7,7.4Hz,1H),1.85-1.75(m,4H).

[0070] 13 C NMR (101MHz, CDCl3) δ207.29,201.26,170.00,142.50,138.76,123.25,122.02,79.36,45.06,41.53,39.69,31.39,30.07,25.66,17.17.

[0071] IR ν max (film):2949,2730,1726,1684,1450,1389,1250,1189,737cm -1 .

[0072] HRMS(ESI)m / z:C 15 H20 NaO4[M+Na] + Calculated value: 287.1254; Measured value: 287.1248.

[0073] Example 2 Synthesis of Compound 6

[0074] like Figure 6 As shown.

[0075] Compound 2 (5.0 g, 12.7 mmol) was dissolved in tetrahydrofuran (350 mL). Sodium hydride (60% dispersion in mineral oil, 720 mg) was added dropwise to the stirred solution at 0 °C, producing bubbles. The mixture was stirred at room temperature for another hour. A tetrahydrofuran solution of compound 3 (3.9 g, 21.6 mmol) (10 mL) was slowly added dropwise to the reaction system, and the mixture was then heated to 60 °C for 48 hours. After completion as monitored by thin-layer chromatography, a saturated ammonium chloride solution (200 mL) was slowly added to quench the reaction. The mixture was then extracted with ethyl acetate (3 × 150 mL). The combined organic extracts were washed with saturated brine (500 mL) and dried over sodium sulfate. The solvent was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give a colorless oily compound 6 (4.7 g, 83% yield).

[0076] The detection data for compound 6 are as follows:

[0077] R f =0.5 (ethyl acetate / petroleum ether = 1 / 10).

[0078] 1 H NMR (500MHz, CDCl3) δ7.31(dd,J=14.9,7.4Hz,4H),7.18(dd,J=13.6,6.4Hz,6H),5.77(ddt,J=12.6,10.2,6.2Hz,1H),5.06(dd,J=13 .7,7.1Hz,2H),4.31-4.21(m,2H),3.31(ddd,J=23.1,10.5,2.8Hz,1H),2.39-2.08(m,4H),1.06-0.95(m,2H),0.04(d,J=0.6Hz,9H).

[0079] 13C NMR (126MHz, CDCl3) δ168.34,136.49,129.85,125.46,120.66,116.68,115.50,64.38,45.88,44.82,32.34,32.21,26.27,26.23,17.50,-1.45.

[0080] IR ν max (film):3442,2920,1696,1415,1257,1230,861cm -1 .

[0081] HRMS(ESI)m / z:C 23 H 31 NaO5PSi[M+Na] + Calculated value: 496.1571; Measured value: 496.1571.

[0082] Example 3 Synthesis of compounds (Z)-3 and (E)-3

[0083] like Figure 7 As shown.

[0084] Compound 6 (1.0 g, 2.27 mmol) was dissolved in tetrahydrofuran (100 mL). A sodium hexamethylsilylamino sodium solution (1.0 mL, 2.0 M THF solution) was slowly added dropwise to the reaction system at -78 °C. After the addition was complete, the mixture was stirred at -78 °C for 1 hour. Then, compound 1 (500 mg, 1.89 mmol) dissolved in THF (20 mL) was added dropwise. After reacting for 30 minutes, the reaction was monitored by thin-layer chromatography. The reaction was quenched by adding saturated ammonium chloride solution (100 mL). The mixture was then extracted with ethyl acetate (3 × 150 mL). The combined organic phases were washed with saturated brine (500 mL) and dried over sodium sulfate. The solvent was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give colorless oily compound (Z)-3 (514 mg, 59% yield) and colorless oily compound (E)-3 (201 mg, 23% yield).

[0085] The detection data for compound (Z)-3 are as follows:

[0086] R f =0.4 (ethyl acetate / petroleum ether = 1 / 1).

[0087]

[0088] 1H NMR(500MHz, CDCl3) δ6.28(d,J=2.9Hz,1H),5.82-5.72(m,2H),5.58(d,J=2.5Hz,1H),5.20(dd,J=9.1, 1.2Hz,1H),5.03-4.93(m,2H),4.80(dd,J=9.1,5.9Hz,1H),4.25-4.19(m,2H),2.78-2.71(m,1H),2.58 (dd,J=15.2,7.4Hz,2H),2.50(t,J=7.6Hz,2H),2.35-2.30(m,2H),2.20-2.13(m,7H),1.98(ddd,J=14. 0,7.4,6.0Hz,1H),1.84(td,J=14.4,7.7Hz,1H),1.78(d,J=1.3Hz,3H),1.06-1.01(m,2H),0.05(s,9H).

[0089] 13 C NMR (126MHz, CDCl3) δ207.06,167.97,143.67,140.51,138.92,137.80,132.35,122.89,121.85,115 .09,79.54,62.46,45.14,39.66,39.06,34.00,33.36,30.08,27.43,25.76,17.53,16.99,-1.47ppm.

[0090] IR ν max (film):3310.2926,2375,1507,1262,1019,1011,851,837,799cm -1 .

[0091] HRMS(ESI)m / z:C 26 H 40 NaO5Si[M+Na] + Calculated value: 483.2537; Measured value: 483.2537.

[0092] The detection data for compound (E)-3 are as follows:

[0093] R f =0.35 (ethyl acetate / petroleum ether = 1 / 1).

[0094]

[0095] 1H NMR (500MHz, CDCl3) δ6.70(t,J=7.3Hz,1H),6.29(d,J=2.9Hz,1H),5.80(ddt,J=17.0,10.1,6.8Hz,1H),5.59(d,J=2.5Hz,1 H),5.22(dd,J=9.0,1.2Hz,1H),5.05-4.93(m,2H),4.80(dd,J=9.0,5.9Hz,1H),4.26-4.18(m,2H),2.83-2.69(m,1H),2.57- 2.43(m,2H),2.42-2.35(m,2H),2.31(dd,J=15.2,7.5Hz,2H),2.21-2.12(m,7H),2.03-1.92(m,1H), 1.86(tt,J=14.4,7.2Hz,1H), 1.80(d,J=1.2Hz,3H), 1.02(ddd,J=10.5,7.2,3.8Hz,2H), 0.05(s,9H).

[0096] 13 C NMR (126MHz, CDCl3) δ207.06,169.98,167.78,143.20,141.06,138.82,137.91,132.59,123.21,121.9 7,115.12,79.41,62.76,45.13,39.67,38.47,33.37,30.06,26.66,26.46,25.77,17.42,17.06,-1.44.

[0097] IR ν max (film):3440,3310,2926,2375,1262,1250,1019,1011,861,837,799cm -1 .

[0098] HRMS(ESI)m / z:C 26 H 40 NaO5Si[M+Na] + Calculated value: 483.2537; Measured value: 483.2539.

[0099] Example 4: Synthesis of Compound 4

[0100] like Figure 8 As shown.

[0101] Anhydrous cerium trichloride (493 mg, 2.0 mmol) was added to a round-bottom flask, heated to 150 °C under vacuum, and stirred for 3 hours. Argon gas was introduced, and the system was transferred to an ice bath at 0 °C. Tetrahydrofuran (5 mL) was added, and the mixture was then heated to room temperature and stirred for at least 24 hours. The system was then cooled to -78 °C, and trimethylsilylmethyllithium (1.5 mL, 1.5 mmol, 1.0 M n-pentane solution) was added dropwise. The mixture was stirred at the same temperature for 1 hour. Then, compound (Z)-3 (460 mg, 1.0 mmol, in 2.0 mL tetrahydrofuran) was added to the system, and the mixture was stirred at -78 °C for 1 hour. Thin-layer chromatography was used to confirm the reaction was complete. The reaction was quenched with 10% acetic acid aqueous solution (10 mL), and the mixture was separated. The aqueous phase was extracted with dichloromethane, and the organic phases were combined, dried, and the solvent was removed under reduced pressure. The residue was redissolved in dichloromethane (5.0 mL), silica gel (2.4 g, 500% w / w) was added, and the mixture was stirred for 24 hours. The solvent was removed under reduced pressure, and the remaining silica gel was separated by column chromatography (petroleum ether / ethyl acetate = 20:1) to give colorless oily compound 4 (341 mg, 75% yield).

[0102] The detection data for compound 4 are as follows:

[0103] R f =0.5 (ethyl acetate / petroleum ether = 1 / 10).

[0104]

[0105] 1 H NMR(500MHz, CDCl3) δ6.26(d,J=2.8Hz,1H),5.82-5.70(m,2H),5.57(d,J=2.5Hz,1H),5.22(dd,J =9.1,0.8Hz,1H),5.04-4.92(m,2H),4.84(dd,J=9.1,5.7Hz,1H),4.76(s,1H),4.68(s,1H),4.25 -4.19(m,2H),2.74-2.67(m,1H),2.57(dd,J=15.1,7.4Hz,2H),2.34-2.27(m,2H),2.19-2.12(m, 4H), 2.05 (t, J = 7.9Hz, 2H), 1.86-1.75 (m, 4H), 1.75-1.62 (m, 4H), 1.10-0.96 (m, 2H), 0.05 (s, 9H).

[0106] 13C NMR (126MHz, CDCl3) δ170.31,167.99,144.37,142.94,140.58,139.42,137.81,132.27,123.19,121.50,11 5.06,110.96,79.85,62.44,45.48,39.05,34.37,34.02,33.38,30.77,27.36,22.41,17.52,16.92,-1.47.

[0107] IR ν max (film):2845,2410,1825,1260,1176,1132,1114,1012,934,857,835,797cm -1 .

[0108] HRMS(ESI)m / z:C 27 H 42 NaO4Si[M+Na] + Calculated value: 481.2745; Measured value: 481.2743.

[0109] Example 5: Synthesis of compounds (Z)-5 and (E)-5

[0110] like Figure 9 As shown.

[0111] Compound 4 (100 mg, 0.22 mmol) was dissolved in dichloromethane (1.0 L), and Hoveyda-Grubbs second-generation catalyst (6.8 mg, 0.01 mmol) was added at room temperature. Argon gas was then introduced into the reaction system for 30 minutes. After purging the reaction system, the temperature was raised to 60 °C and stirred for 48 hours. Thin-layer chromatography confirmed the completion of the reaction, and the solvent was removed directly under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give colorless oily compound (E)-5 (65 mg, 69% yield) and colorless oily compound (Z)-5 (13 mg, 14% yield).

[0112] The detection data for compound (E)-5 are as follows:

[0113] R f =0.35 (ethyl acetate / petroleum ether = 1 / 10).

[0114]

[0115] 1H NMR (400MHz, CDCl3) δ6.24(d,J=2.6Hz,1H),5.64(t,J=6.6Hz,1H),5.57(d,J=2.3Hz,1H),5 .21-5.15(m,1H),5.05-4.96(m,1H),4.88(dd,J=9.7,4.0Hz,1H),4.23(ddd,J=8.0,5.0,1.3 Hz,2H),2.86-2.73(m,1H),2.71-2.56(m,2H),2.47(dd,J=13.1,6.6Hz,1H),2.32-2.02(m, 7H), 1.78 (d, J = 1.0Hz, 3H), 1.76-1.67 (m, 2H), 1.59 (s, 3H), 1.07-0.99 (m, 2H), 0.05 (s, 9H).

[0116] 13 C NMR (101MHz, CDCl3) δ170.58,168.13,142.21,141.22,140.76,132.19,131.00,125.61,124.18,12 1.66,79.17,62.52,43.04,38.49,36.18,34.71,32.30,25.71,25.13,17.67,16.59,15.76,-1.40.

[0117] HRMS(ESI)m / z:C 25 H 38 NaO4Si[M+Na] + Calculated value: 453.2432; Measured value: 453.2430.

[0118] The detection data for compound (Z)-5 are as follows:

[0119] R f =0.25 (ethyl acetate / petroleum ether = 1 / 10).

[0120]

[0121] 1H NMR(400MHz, CDCl3) δ6.23(d,J=3.2Hz,1H),5.75(dd,J=10.1,4.2Hz,1H),5.55(d,J=2.9Hz,1 H),5.30(d,J=8.9Hz,1H),5.21(t,J=7.9Hz,1H),4.73(t,J=8.6Hz,1H),4.22-4.15(m,2H),3.1 4-2.99(m,1H),2.69(dd,J=8.1,3.3Hz,1H),2.59-2.50(m,1H),2.38-2.19(m,5H),2.13-2.03( m,3H),1.98-1.92(m,1H),1.81(s,4H),1.68(s,3H),1.03(dd,J=9.9,7.6Hz,2H),0.06(s,9H).

[0122] 13 C NMR (101MHz, CDCl3) δ170.50,168.19,145.53,141.93,140.27,135.90,134.14,125.10,123.71,12 0.34,80.01,62.49,47.17,39.17,35.26,30.28,29.93,29.71,25.84,23.00,17.73,16.43,-1.38.

[0123] HRMS(ESI)m / z:C 25 H 38 NaO4Si[M+Na] + Calculated value: 453.2432; Measured value: 453.2430.

[0124] Example 6 Synthesis of the natural product (–)-Anisomelic Acid

[0125] like Figure 10 As shown.

[0126] Compound (E)-5 (50 mg, 0.12 mmol) was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride solution (0.17 mL, 0.17 mmol, 1.0 M tetrahydrofuran solution) was added at 0 °C. After stirring for 1 hour, the reaction was detected by thin-layer chromatography. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), and then the mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with saturated brine (10 mL) and dried over sodium sulfate. The solvent was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1).

[0127] The detection data for the natural product (–)-fish oxalic acid are as follows:

[0128] R f =0.3 (ethyl acetate / petroleum ether = 1 / 2).

[0129]

[0130] 1 H NMR (500MHz, CDCl3) δ6.25(d,J=2.6Hz,1H),5.88(t,J=6.5Hz,1H),5.59(d,J=2.3Hz ,1H),5.18(d,J=9.6Hz,1H),4.99(d,J=5.3Hz,1H),4.88(dd,J=9.6,4.2Hz,1H),2.88 (ddd,J=21.6,14.2,7.1Hz,1H),2.77-2.64(m,2H),2.50(t,J=13.4Hz,1H),2.36-2. 16(m,6H),2.11-2.02(m,1H),1.78(d,J=0.8Hz,1H),1.76-1.63(m,2H),1.60(s,3H).

[0131] 13 C NMR (126MHz, CDCl3) δ173.11,170.62,146.93,141.15,140.66,132.52,129.68,125.36, 124.36,121.77,79.16,43.07,38.46,36.18,34.44,32.21,26.16,25.08,16.64,15.83.

[0132] HRMS(ESI)m / z:C 20 H 26 NaO4[M+Na] + Calculated value: 353.1723; Measured value: 353.1723.

[0133] The technical features of the above embodiments can be combined in any suitable manner. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0134] The above-described embodiments are merely examples of several implementations of the present invention, intended to facilitate a detailed understanding of the technical solutions of the present invention, but should not be construed as limiting the scope of protection of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. It should be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided by the present invention through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the claims of the present invention.

Claims

1. A method for the asymmetric synthesis of (-)-anisomelic acid, characterized in that, include: 1) Aldehyde compound 1 was prepared by using the chiral compound (-)-ausne lactone as the starting material under ozonolysis conditions; 2) Using the aldehyde-ketone compound 1 and the phosphate ester compound 6, unsaturated lactone compound (Z)-3 and unsaturated lactone compound (E)-3 were prepared under alkaline conditions; 3) Using the unsaturated lactone compound (Z)-3 and trimethylsilylmethyllithium, under cerium trichloride-promoted 1,2-addition conditions, a tetraene compound 4 was prepared by elimination. 4) Using the tetraene compound 4, fourteen-membered macrocyclic compound (Z)-5 and fourteen-membered macrocyclic compound (E)-5 were prepared under olefin metathesis conditions; as well as 5) Using the fourteen-membered macrocyclic compound (E)-5, the natural product (-)-fish needle oxalic acid was prepared under conditions of desiliconization and hydrolysis. The chemical formulas of each compound are shown below: Furthermore, in compounds 6, (Z)-3, (E)-3, 4, (E)-5, and (Z)-5, the R group is OTMSE.

2. The method as described in claim 1, characterized in that, The method of ozonolysis in step 1) includes: passing ozone through a solution of the compound (-)-ausmentin lactone at low temperature, adding a reducing reagent to quench the reaction after the reaction is completed, removing the solvent after the reaction system is heated to room temperature, and purifying the residue by silica gel column chromatography to obtain the compound 1.

3. The method as described in claim 1, characterized in that, The method of step 2) includes: adding an alkaline substance to the solution of compound 6 at low temperature, then adding the solution of compound 1, adding a quenching agent after the reaction is completed, and purifying the residue by silica gel column chromatography to obtain compound (Z)-3 and compound (E)-3.

4. The method as described in claim 1, characterized in that, The method in step 3) includes: adding cerium trichloride to a round-bottom flask, heating under vacuum and stirring for a certain time, purging with an inert gas, transferring the reaction system to an ice-water bath, adding tetrahydrofuran, and then raising it to room temperature and stirring for a certain time; adding trimethylsilylmethyllithium reagent at low temperature and maintaining the same temperature while stirring for a certain time, then adding the compound (Z)-3 to the reaction system and continuing to stir at the same temperature for a certain time; quenching the reaction system by adding an aqueous acetic acid solution, separating the phases, and extracting the aqueous phase with ethyl acetate; combining the organic phases, drying, removing the solvent, then adding a reagent to promote elimination to the residue, and finally purifying it by silica gel column chromatography to obtain the tetraene compound 4.

5. The method as described in claim 1, characterized in that, The method of step 4) includes: after adding the solution of the tetraene compound 4 to the olefin metathesis catalyst, removing the residual oxygen in the reaction system under an inert gas atmosphere for a period of time, then heating the reaction system until the tetraene compound 4 is completely converted, removing the solvent, and purifying the residue by silica gel column chromatography to obtain the fourteen-membered macrocyclic compound (Z)-5 and the fourteen-membered macrocyclic compound (E)-5.

6. The method as described in claim 1, characterized in that, The method of step 5) includes: cooling the solution of the fourteen-membered macrocyclic compound (E)-5 to 0°C, adding a desilication reagent dropwise, reacting at the temperature for 1 hour, quenching the reaction system with saturated ammonium chloride solution, raising it to room temperature, extracting with ethyl acetate, combining the organic phases, drying, removing the solvent, and purifying the residue by silica gel column chromatography to obtain the natural product (-)-fish needle oxalic acid.

7. The method as described in claim 1, characterized in that, Step 2) further includes the following steps: 2-1) Using compound 2 and compound 3, the phosphate ester compound 6 is prepared under alkaline conditions; The chemical formulas of compound 2 and compound 3 are shown below: In compound 2, R1 group is OTMSE; R3 group is phenyl; and In compound 3, the R2 group is selected from chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy.

8. The method as described in claim 7, characterized in that, The method in step 2-1) includes: cooling the solution of compound 2 to 0°C, slowly adding an alkaline substance under an inert gas atmosphere, stirring for a period of time at the temperature, slowly adding the solution of compound 3 dropwise, then heating until the reaction is complete, quenching the reaction system with a saturated ammonium chloride solution, raising it to room temperature, extracting with ethyl acetate, combining the organic phases, drying, removing the solvent, and purifying the residue by silica gel column chromatography to obtain the phosphate ester compound 6.

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