(2S,3R)-2,3-epoxy-8-methyl-1-nonanol and synthesis method of gypsy moth sex pheromone

Abstract

The present invention belongs to the field of drug synthesis and discloses a method for synthesizing a gypsy moth sex pheromone. Propargyl alcohol is reacted with 5-methylhexyl bromide to obtain 8-methyl-2-alkyne-1-nonanol, catalytic hydrogenation is performed to obtain 8-methyl-2-alkene-1-nonanol, and (2S,3R)-2,3-epoxy-8-methyl-2-alkene-1-nonanol is obtained by Sharpless asymmetric epoxidation. Under an alkaline environment, an activated hydroxyl group is coupled with 1-nonyne to obtain (7R,8S)-7,8-epoxy-2-methyl-10-octadecane, and finally the main component of the gypsy moth pheromone is obtained by catalytic hydrogenation. The hydroxyl group of (2S,3R)-2,3-epoxy-8-methyl-2-alkene-1-nonanol is iodinated and subjected to a Grignard reaction with nonene magnesium bromide to obtain a secondary component of the gypsy moth pheromone. The synthetic method of the gypsy moth sex pheromone of the present invention simplifies the experimental steps, the raw materials are cheap and easily available, and the operation is simple.

Description

Technical Field

[0001] The invention relates to a new method for synthesizing a natural product gypsy moth sex pheromone component which is insect-attracting and harmless to five toxic substances, and belongs to the field of drug synthesis. Background Art

[0002] The gypsy moth, belonging to the order Lepidoptera and family Lysimachia, harms over 500 plant species, including apple, pear, peach, apricot, cherry, oak, poplar, willow, mulberry, elm, and larch. It is primarily distributed in northern my country and parts of North America. Due to the large, extensive forests of tall trees, effective control measures are difficult to implement, leading to widespread infestations of gypsy moths, which can affect tree growth, cause tree death, and severely damage the environment. Traditional control methods involve spraying pesticides, but these pesticides not only cause significant environmental damage but also encourage pest resistance. Since the 1970s, the use of synthetic pheromones for pest control has been pursued. By capturing gypsy moths and extracting pheromones, their structure has been determined and synthesized, allowing them to be captured and effectively harvested, achieving significant economic benefits.

[0003] Using gypsy moth pheromones is not only highly effective in trapping and killing adult gypsy moths, thereby reducing their damage, but also requires very small amounts compared to traditional pesticide spraying, posing no environmental risk and reducing the likelihood of pest resistance. In 1972, B.A. Bierl et al. extracted 7,8-epoxy-2-methyloctadecane from female gypsy moths as a pheromone component. In 1984, K. Hansen et al. found through EAD monitoring that (7R,8S)-7,8-epoxy-2-methyloctadecane caused a reaction when tested against gypsy moth, but the reaction was inhibited when (7S,8R)-7,8-epoxy-2-methyloctadecane was added. They concluded that (7R,8S)-7,8-epoxy-2-methyloctadecane was an effective component of gypsy moth (K. Hansen, et al. Discrimination and production of disparlure enantiomers by the gypsy moth and the nun moth. Physiological Entomology 1984, 9, 9-18). In 2005, G. Gries et al. used GC-EAD to detect that among all possible monounsaturated 7,8-epoxy-2-methyloctadecene, only 7,8-epoxy-2-methyloctadecene elicited antennal reactions similar to those produced by insects (G. Gries, et al. (7R,8S)-cis-7,8-epoxy-2-methyloctadec-17-ene: a novel trance component from the pheromone gland of gypsy moth, Lymantria dispar. Journal of Chemical Ecology, 2005, 31, 1).

[0004]

[0005] In recent years, some research groups have synthesized components of gypsy moth pheromones, but the raw materials used in these synthesis processes are difficult to obtain or the steps involved are cumbersome. Therefore, synthesizing high-purity, well-defined gypsy moth pheromone components is crucial and holds great promise for gypsy moth control.

[0006] In 1978, G.A. Toletiko et al. synthesized the main component of the racemic gypsy moth sex pheromone from cyclohexadiene through ozone oxidation, bromination, Grignard reaction, and MPP oxidation. However, the disadvantage was that the final epoxidation step had poor regioselectivity, resulting in a mixture that was difficult to separate and purify and had low biological activity. (Ge.A.Toletiko, et al. A new stereoselective synthesis of racemic disparlure, the sex pheromone of gypsymoth, Tetrahedron Letters, 1978, 21, 1857-1858.)

[0007]

[0008] In 2005, Zhang Chaoxin et al. completed the asymmetric total synthesis of (7R,8S)-7,8-epoxy-2-methyloctadecane using n-undecanal and cyclopentanone as starting materials via an L-profine-catalyzed asymmetric aldol reaction, a Baeyer-Villiger oxidation, followed by hydrogenation reduction and a Wittig reaction. Finally, catalytic hydrogenation and epoxidation were performed to complete the asymmetric total synthesis. The reaction scheme is shown below. However, the Baeyer-Villiger oxidation reaction yields a low yield, making it unsuitable for large-scale production. (Zhang Chaoxin et al., Asymmetric Total Synthesis of (+)-(7R,8S)-7,8-epoxy-2-methyl-octadecane: A Gypsy Moth Attractant, Acta Chimica Sinica, 2007, 65, 2433-2436.)

[0009]

[0010] In 2012, Huang Peiqiang et al. synthesized (7R,8S)-7,8-epoxy-2-methyloctadecane through a series of steps: coupling, reduction, Sharpless epoxy, activation of the hydroxyl group, and further coupling. The reaction scheme is shown below (Huang, Peiqiang. Asymmetric Synthesis of Both Enantiomers of Disparlure. Chin. J. Chem. 2012, 30, 23-28). A limitation of this route is that the intermediate 4-methyl-1-pentyne is difficult to purchase and is expensive.

[0011]

[0012] (2S,3R)-2,3-epoxy-8-methyl-1-nonanol is a common component in the synthesis of gypsy moth sex pheromones. Current methods for synthesizing (2S,3R)-2,3-epoxy-8-methyl-1-nonanol all yield low yields. Therefore, the present invention provides a method for synthesizing (2S,3R)-2,3-epoxy-8-methyl-1-nonanol that improves its yield. This would further facilitate its use in the synthesis of gypsy moth sex pheromones. Summary of the Invention

[0013] In response to the problems existing in the prior art, the present invention provides a method for synthesizing (2S,3R)-2,3-epoxy-8-methyl-1-nonanol, which is simple to operate, low in cost, and uses cheap and readily available raw materials. The obtained (2S,3R)-2,3-epoxy-8-methyl-1-nonanol can be used to prepare (7R,8S)-7,8-epoxy-2-methyloctadecane, the main component of gypsy moth pheromone, and (7R,8S)-7,8-epoxy-2-methyl-17-octadecene, the secondary component of gypsy moth pheromone.

[0014] The synthesis method of (2S,3R)-2,3-epoxy-8-methyl-1-nonanol is as follows:

[0015] (1) Using propargyl alcohol as the starting material, a coupling reaction was carried out with 5-methylbromohexane under alkaline conditions and the reaction was carried out overnight to obtain 8-methyl-2-yn-1-nonanol.

[0016] (2) 8-methyl-2-alkyn-1-nonanol is subjected to catalytic hydrogenation in the presence of a catalyst to obtain cis-8-methyl-2-alkene-1-nonanol.

[0017] (3) 8-Methyl-2-ene-1-nonanol was subjected to Sharpless asymmetric epoxidation in the presence of L-(+)-diisopropyl tartarate, tetraisopropyl titanate, tert-butyl hydroperoxide, a catalyst, and a desiccant to obtain the product (2S,3R)-2,3-epoxy-8-methyl-1-nonanol.

[0018] Specifically, the above step (1) is specifically as follows: at -78 ° C, under nitrogen protection, dissolving propargyl alcohol and hexamethylphosphoramide (HMPA) in tetrahydrofuran, adding a base, and then adding 5-methylbromide, stirring and reacting for 12 hours, and after quenching, extraction, drying and post-treatment steps and column chromatography purification, obtaining 8-methyl-2-alkyn-1-nonanol. The base described in step (1) is n-butyl lithium or sodium hydride, and the molar ratio of propargyl alcohol to 5-methylbromide is 1:2 to 3. The molar ratio of propargyl alcohol to the base is 1:2 to 2.5; the volume ratio of tetrahydrofuran to hexamethylphosphoramide is 1:3 to 5;

[0019] Specifically, the above step (2) is specifically as follows: at 0°C, the catalyst is added to an organic solvent, and then 8-methyl-2-alkyn-1-nonanol is added, and the reaction is stirred for 2 hours under a hydrogen environment, and 8-methyl-2-alkene-1-nonanol is obtained after filtration, extraction, drying and column chromatography purification.

[0020] Wherein, the catalyst in step (2) is a Lindlar catalyst or a P2-Ni catalyst.

[0021] Wherein, the organic solvent in step (2) is methanol, ethanol or propanol.

[0022] Specifically, the above step (3) is specifically as follows: at -35°C, a desiccant, a catalyst and tetraisopropyl titanate are added to dichloromethane, followed by addition of L-(+)-diisopropyl tartarate, 8-methyl-2-ene-1-nonanol, and tert-butyl hydroperoxide. The reaction is stirred at -25°C for 2 days, and after quenching, extraction, drying, post-treatment and column chromatography purification, (2S,3R)-2,3-epoxy-8-methyl-1-nonanol is obtained.

[0023] Wherein, the desiccant and catalyst in step (3) are silicon dioxide and calcium hydride respectively.

[0024] The molar ratio of 8-methyl-2-ene-1-nonanol, L-(+)-diisopropyl tartarate and tetraisopropyl titanate is 1:1.2-1.5:1.2-1.5;

[0025] The main component of the gypsy moth sex pheromone synthesized from (2S,3R)-2,3-epoxy-8-methyl-1-nonanol is (7R,8S)-7,8-epoxy-2-methyloctadecane, and the process is as follows:

[0026] (A) (2S,3R)-2,3-epoxy-8-methyl-1-nonanol is reacted with trifluoromethanesulfonic anhydride under alkaline conditions to obtain (2S,3R)-2,3-epoxy-8-methyl-1-nonyl trifluoromethanesulfonate.

[0027] (B) (2S,3R)-2,3-epoxy-8-methyl-2-en-1-nonyl trifluoromethanesulfonate reacts with 1-nonyne under alkaline conditions to obtain (7R,8S)-7,8-epoxy-2-methyl-10-octadecyne.

[0028] (C) (7R,8S)-7,8-epoxy-2-methyl-10-octadecane is reacted with a catalyst in a hydrogen environment to obtain (7R,8S)-7,8-epoxy-2-methyloctadecane.

[0029] Specifically, the above step (A) is specifically as follows: at -78°C, (2S, 3R)-2,3-epoxy-8-methyl-1-nonanol is added to dichloromethane, triethylamine and trifluoromethanesulfonic anhydride are added, and the mixture is stirred for 1 hour. After quenching, extraction, and drying, (2S, 3R)-2,3-epoxy-8-methyl-1-nonyl trifluoromethanesulfonate is obtained.

[0030] Wherein, in step (A), the molar ratio of (2S,3R)-2,3-epoxy-8-methyl-1-nonanol to trifluoromethanesulfonic anhydride is 1:2-4. The molar ratio of (2S,3R)-2,3-epoxy-8-methyl-1-nonanol to triethylamine is 1:3-4;

[0031] Specifically, the above step (B) is specifically as follows: at -78 ° C, nonyne is added to an organic solvent, a base is added, and then (2S, 3R)-2,3-epoxy-8-methyl-1-nonyl trifluoromethanesulfonate is added, a co-solvent is added, and the reaction is stirred for 1 hour. After quenching, extraction, drying and other post-treatments and column chromatography purification, (7R, 8S)-7,8-epoxy-2-methyl-10-octadecane is obtained.

[0032] Wherein, in step (B), the molar ratio of (2S,3R)-2,3-epoxy-8-methyl-1-nonyl trifluoromethanesulfonate to nonyne is 1:2-3.

[0033] Wherein, the organic solvent in step (B) is diethyl ether or tetrahydrofuran.

[0034] Wherein, the base in step (B) is n-butyllithium.

[0035] Wherein, the cosolvent in step (B) is HMPA or DMPU.

[0036] Specifically, the above step (C) is specifically as follows: (7R,8S)-7,8-epoxy-2-methyl-10-octadecane is added to n-hexane, and then a catalyst is added to carry out catalytic reduction to (7R,8S)-7,8-epoxy-2-methyloctadecane under a hydrogen environment.

[0037] Wherein, the catalyst in step (C) is 10% palladium carbon.

[0038] Its synthetic route is as follows:

[0039]

[0040] When synthesizing gypsy moth pheromones, the key intermediate (2S,3R)-2,3-epoxy-8-methyl-2-ene-1-nonanol can be obtained, on which basis the main component (7R,8S)-7,8-epoxy-2-methyloctadecane and the secondary component (7R,8S)-7,8-epoxy-2-methyloctadecene of gypsy moth can be synthesized more conveniently.

[0041] A method for synthesizing gypsy moth sex pheromones (7R,8S)-7,8-epoxy-2-methyloctadecane and (7R,8S)-7,8-epoxy-2-methyl-17-octadecene is carried out according to the following steps.

[0042] (a) (2S,3R)-2,3-Epoxy-8-methyl-1-nonanol is reacted with iodine in the presence of imidazole and triphenylphosphine to produce (2S,3R)-2,3-epoxy-8-methyl-1-iodonane.

[0043] (b) (2S,3R)-2,3-epoxy-8-methyl-1-iodonane is reacted with a Grignard reagent to produce (7R,8S)-7,8-epoxy-2-methyl-17-octadecene or (7R,8S)-7,8-epoxy-2-methyloctadecane.

[0044] Specifically, the above step (a) is specifically as follows: (2S, 3R)-2,3-epoxy-8-methyl-1-nonanol is added to dichloromethane at 0°C, and then a base, iodine, and triphenylphosphine are added in sequence, and the reaction is stirred for 1 hour. After filtration, washing, drying and column chromatography purification, (2S, 3R)-2,3-epoxy-8-methyl-1-iodonane is obtained.

[0045] Wherein, the base in step (a) is imidazole.

[0046] Specifically, the above step (b) is specifically as follows: (2S, 3R)-2,3-epoxy-8-methyl-1-iodonane is added to dry tetrahydrofuran, cuprous iodide is added, and under nitrogen, Grignard reagent is slowly added, stirred and reacted for 40 minutes, quenched, extracted, dried, and purified by column chromatography to obtain (7R, 8S)-7,8-epoxy-2-methyl-17-octadecene or (7R, 8S)-7,8-epoxy-2-methyloctadecane.

[0047] Wherein, the Grignard reagents in step (b) are 1-nonenylmagnesium bromide and nonanemagnesium bromide respectively.

[0048] Its synthetic route is as follows:

[0049] DETAILED DESCRIPTION

[0050] The present invention is described in detail with reference to examples.

[0051] Example 1

[0052] Step 1: Preparation of 8-methyl-2-yn-1-nonanol

[0053] Dissolve propargyl alcohol (9.4 mL, 159 mmol) in THF (100 mL), add HMPA (20 mL), evacuate the mixture, and replace with nitrogen. Add n-butyl lithium (51 mL, 2.5 M, 127 mmol) dropwise at -78°C. After half an hour, add 5-methylhexyl bromide (10 mL, 64 mmol). Allow to react overnight at room temperature. Monitor by TLC. After completion of the reaction, add saturated ammonium chloride solution (40 mL) at 0°C. Extract with 2M hydrochloric acid (150 mL) and methyl tert-butyl ether (200 mL), spin dry, and filter through a column (PE:EA = 10:1) to obtain 8-methyl-2-yn-1-nonanol (8.3 g, 85% yield). 1 H NMR (400MHz, CDCl3): δ4.25 (s, 2H), 2.22-2.19 (m, 2H), 1.57-1.43 (m, 3H), 1.41-1.32 (m, 2H), 1.16 (q, J = 7.0Hz, 2H), 0.87 (d, J = 6.6Hz, 6H); 13 C NMR (101MHz, CDCl3): δ78.4,77.5,77.2,76.8,51.6,38.6,29.0,28.00,26.8,22.7,18.9.HRMS(ESI)calcd forC 10 H 18 NaO + [M+Na + ]177.1250,found 177.1265.

[0054] The yield was 64% when n-butyl lithium was replaced with sodium hydride in step 1 and other conditions remained unchanged.

[0055] Step 2: Preparation of 8-methyl-2-ene-1-nonanol

[0056] Nickel acetate tetrahydrate (12.5 g, 50 mmol) was added to anhydrous methanol (120 mL), followed by sodium borohydride (1.9 g, 50 mmol) at 0°C. After 15 minutes, ethylenediamine (3.4 mL, 60 mmol) was added, and finally 8-methyl-2-yn-1-nonanol (7.8 g, 50 mmol) was added. The mixture was allowed to react at room temperature under hydrogen for 2 hours. After completion of the reaction, the mixture was filtered, the methanol was dried, and the mixture was extracted with ethyl acetate (200 mL) and water (150 mL). The mixture was dried over anhydrous sodium sulfate, and the organic phase was collected and filtered through a column chromatography column (PE:EA = 10:1) to obtain 8-methyl-2-ene-1-nonanol (7.5 g, 95% yield). 1 H NMR (500MHz, CDCl3) δ5.64-5.54(m,2H),4.21(d,J=6.3Hz,2H),2.12-2.06(m,2H) ,1.50-1.57(m,1H),1.38-1.28(m,4H),1.20-1.16(m,2H),0.88(d,J=6.6Hz,6H); 13 C NMR(126MHz, CDCl3)δ133.3,128.5,77.4,77.2,76.9,58.7,38.9,30.0,28.0,27.6,27.1,22.8.HRMS(ESI)calcd for C 10 H 20 ONH4 + [M+NH4 + ]174.1852,found 174.1866.

[0057] The nickel acetate tetrahydrate and sodium borohydride in step 2 were replaced with Lindlar catalyst, and the other conditions remained unchanged, and the yield was 94%.

[0058] Step 3: Preparation of (2S,3R)-2,3-epoxy-8-methyl-1-nonanol

[0059] Calcium hydride (800 mg, 19 mmol) and silica (400 mg, 7 mmol) were added to DCM (200 mL) and tetraisopropyl titanate (17.2 mL, 58 mmol). Under nitrogen protection, diisopropyl L-(+)-tartrate (17.7 g, 62 mmol) was added at -35 ° C. After 30 minutes, 8-methyl-2-ene-1-nonanol (7.5 g, 48 mmol) was added. After 30 minutes, tert-butyl hydroperoxide (19 mL, 5.5 M, 105 mmol) was added. The temperature was raised to -25 ° C. and the reaction was carried out for 2 days. After the reaction was completed, 10% tartaric acid (50 mL) was added, the mixture was filtered, extracted with dichloromethane (200 mL), dried over anhydrous sodium sulfate, and the organic phase was collected and passed through a column (PE:EA=5:1) to obtain (2S,3R)-2,3-epoxy-8-methyl-2-ene-1-nonanol (7.2 g, yield 88%). 1 H NMR (400MHz, CDCl3) δ3.88-3.80(m,1H),3.67-3.62(m,1H),3.16-3.13(m,1H), 3.04-3.00(m,1H),1.55-1.30(m,7H),1.19-1.13(m,2H),0.85(d,J=6.6Hz,6H); 13 C NMR(101MHz, CDCl3)δ77.5,77.2,76.9,61.0,57.5,57.1,38.9,28.1,27.3,27.0,22.7,22.7.HRMS(ESI)calcd for C 10 H 20 O2NH4 + [M+NH4 + ]190.1801,found 190.1792.

[0060] The calcium hydride in step 3 was removed, and other conditions remained unchanged, and the yield was 60%.

[0061] The silica in step 3 was removed and other conditions remained unchanged, and the yield was 62%.

[0062] Neither silicon dioxide nor calcium hydride was added in step 3, and other conditions remained unchanged, resulting in a yield of 45%.

[0063] Example 2: Preparation of (7R,8S)-7,8-epoxy-2-methyloctadecane

[0064] Step 1: Add (2S,3R)-2,3-epoxy-8-methyl-2-ene-1-nonanol (400 mg, 2.3 mmol) to DCM (50 mL), add triethylamine (1.4 mL, 8.3 mmol) and trifluoromethanesulfonic anhydride (1.4 mL, 7 mmol) at -78 ° C, raise the temperature to -60 ° C, react for 30 minutes, cool to -78 ° C, react for 30 minutes. After the reaction is complete, quench with saturated ammonium chloride (10 mL), extract with dichloromethane (50 mL), dry over anhydrous sodium sulfate, and collect the organic phase to obtain a crude product (700 mg). This is the preparation of (2S,3R)-2,3-epoxy-8-methyl-1-nonyl trifluoromethanesulfonate.

[0065] Step 2: Preparation of (7R,8S)-7,8-epoxy-2-methyl-10-octadecyne

[0066] Nonyne (1.1 mL, 6.7 mmol) was added to tetrahydrofuran (40 mL), and n-butyllithium (2 mL, 2.5 M, 4.1 mmol) was added dropwise at -78 ° C under nitrogen protection. After 30 min, the crude product obtained in the previous step (700 mg, 2.3 mmol) was added, and DMPU (8 mL) was added. The reaction was allowed to react for 1 h. After the reaction was completed, saturated ammonium chloride (15 mL) was quenched, the mixture was spin-dried, extracted with dichloromethane, and passed through a column (PE:EA=100:1) to give (7R,8S)-7,8-epoxy-2-methyl-10-octadecyne (466 mg, total yield of step 1 and step 2 was 72%). 1 H NMR (400MHz, CDCl3) δ3.13-3.08(m,1H),2.97-2.91(m,1H),2.59-2.54(m,1H),2.26-2.20(m,1H),2 .17-2.12(m,2H),1.58-1.41(m,7H),1.38-1.24(m,10H),1.22-1.15(m,2H),0.88(t,J=6.9Hz,9H); 13 C NMR (126MHz, CDCl3) δ82.6,77.4,77.2,76.9,75.0,57.3,55.6,39.0,31.9,29.0, 28.9,28.0,27.7,27.4,26.9,22.8,22.8,18.91,18.9,14.23.HRMS(ESI)calcdfor C 19 H 34 ONH4 + [M+NH4 + ]296.2948,found 296.2942.

[0067] Step 3: Preparation of (7R,8S)-7,8-epoxy-2-methyloctadecane

[0068] (7R,8S)-7,8-epoxy-2-methyl-10-octadecane (390 mg, 1.7 mmol) was added to n-hexane (60 mL), and 10% palladium on carbon was added under an ice bath. The mixture was allowed to react under hydrogen for 2 h. After completion, the reaction was filtered, extracted with ethyl acetate (50 mL), and filtered through a column chromatography (PE:EA = 100:1) to obtain (7R,8S)-7,8-epoxy-2-methyloctadecane (316 mg, 80% yield). 1 H NMR (400MHz, CDCl3) δ2.92-2.88(m,2H),1.57-1.40(m,8H),1.38-1.22(m,17H),1.21-1.14(m,2H),0.87(t,J=6.6Hz,9H); 13 C NMR(101MHz, CDCl3)δ77.5,77.2,76.8,57.4,39.1,32.1,29.7,29.7,28.0,28.0,28.0,27.0,22.9,22.8,22.8,14.26.HRMS(ESI)calcd for C 19 H 38 ONH4 + [M+NH4 + ]300.3261,found 300.3261.

[0069] Example 3: Preparation of 7R,8S)-7,8-epoxy-2-methyl-17-octadecene

[0070] Step a: Preparation of (2S,3R)-2,3-epoxy-8-methyl-1-iodonane

[0071] Epoxy (2S, 3R)-2,3-epoxy-8-methyl-1-nonanol (1 g, 5.8 mmol) was added to dry dichloromethane (40 mL). Imidazole (1 g, 16.2 mmol) and iodine (2.6 g, 10.4 mmol) were added dropwise at 0°C under nitrogen. Triphenylphosphine (2.7 g, 10.4 mmol) was added dropwise for 15 minutes. After the addition, stirring was continued at 0°C for one hour. After the reaction was completed, petroleum ether (50 mL) was added and stirred to precipitate a solid. The solid was filtered and passed through a column (PE:EA=100:1) to obtain pure (2S, 3R)-2,3-epoxy-8-methyl-1-iodonane (1.4 g, yield 91%). 1H NMR (400MHz, CDCl3) δ3.36-3.26(m,2H),3.09-3.00(m,2H),1.59-1.43(m,5H),1.40-1.31(m,2H),1.21-1.16(m,2H),0.87(d,J=6.6Hz,6H); 13 C NMR (101MHz, CDCl3) δ77.5,77.2,76.8,60.1,56.9,38.9,28.0,27.4,27.2,27.0,22.7.

[0072] Step b: Preparation of (7R,8S)-7,8-epoxy-2-methyl-17-octadecene

[0073] The iodide from the previous step (240 mg, 0.9 mmol) and cuprous iodide (64 mg, 0.36 mmol) were evacuated and replaced with argon three times, cooled to -23°C, and THF (10 mL) and HMPA (1.5 mL) were syringe-injected. 1-Nonenylmagnesium bromide (1 g, 4.5 mmol) was added and stirred for 40 minutes. After completion of the reaction, ammonium chloride solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL). The mixture was dried over anhydrous sodium sulfate and passed through a column (PE:EA = 100:1) to obtain (7R,8S)-7,8-epoxy-2-methyl-17-octadecene (150 mg, 63% yield). 1 H NMR (400MHz, CDCl3) δ5.85-5.75(m,1H),5.00-4.91(m,2H),2.89(d,J=4.0Hz,2H) ,2.06-2.01(m,2H),1.56-1.25(m,21H),1.21-1.75(m,2H),0.86(d,J=6.6Hz,6H); 13 CNMR (101MHz, CDCl3) δ139.3,114.3,77.5,77.2,76.8,57.3,39.0,33.9,29.7,2 9.7,29.5,29.2,29.0,28.0,28.0,27.9,27.5,27.0,26.7,22.7.HRMS(ESI)calcd for C 19 H 36 NaO + [M+Na + ]303.2658,found 303.2661.

[0074] Example 4: Another method for preparing (7R,8S)-7,8-epoxy-2-methyloctadecane

[0075] The iodide compound (240 mg, 0.9 mmol) from step a of Example 3 and cuprous iodide (64 mg, 0.36 mmol) were evacuated and replaced with argon three times, cooled to -23°C, and THF (10 mL) and HMPA (1.5 mL) were syringe-injected. 1-Nonenylmagnesium bromide (1 g, 4.5 mmol) was added and stirred for 40 minutes. After completion of the reaction, ammonium chloride solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL). The mixture was dried over anhydrous sodium sulfate and passed through a column (PE:EA = 100:1) to obtain (7R,8S)-7,8-epoxy-2-methyloctadecane (160 mg, 63% yield). 1H NMR (400MHz, CDCl3) δ2.92-2.88(m,2H),1.57-1.40(m,8H),1.38-1.22(m,17H),1.21-1.14(m,2H),0.87(t,J=6.6Hz,9H); 13 C NMR(101MHz, CDCl3)δ77.5,77.2,76.8,57.2,39.1,32.1,29.7,29.7,28.04,28.0,28.0,27.0,22.9,22.8,22.8,14.26.HRMS(ESI)calcd for C 19 H 38 ONH4 + [M+NH4 + ]300.3261,found 300.3261.

Claims

1. A method for synthesizing (2S,3R)-2,3-epoxy-8-methyl-1-nonanol, characterized in that: The synthesis method is as follows: Dissolve 159 mmol of propargyl alcohol in 100 mL of THF, add 20 mL of HMPA, evacuate the atmosphere for nitrogen replacement, and add 127 mmol of n-butyl lithium dropwise at -78°C. After half an hour, add 64 mmol of 5-methylhexyl bromide. Allow to react overnight at room temperature. Monitor by TLC. After completion of the reaction, add 40 mL of saturated ammonium chloride solution at 0°C. Extract with 150 mL of 2 M hydrochloric acid and 200 mL of methyl tert-butyl ether, spin dry, and pass through a column with PE:EA (10:1) to obtain 8-methyl-2-yn-1-nonanol in an 85% yield. To 120 mL of anhydrous methanol, add 50 mmol of nickel acetate tetrahydrate and 50 mmol of sodium borohydride at 0°C. After 15 minutes, add 60 mmol of ethylenediamine and finally 50 mmol of 8-methyl-2-yn-1-nonanol. The reaction is allowed to proceed at room temperature under hydrogen for 2 hours. After completion of the reaction, the product is filtered, the methanol is dried, and the product is extracted with 200 mL of ethyl acetate and 150 mL of water. The product is dried over anhydrous sodium sulfate, and the organic phase is collected and passed through a column with a PE:EA ratio of 10:1 to obtain 8-methyl-2-ene-1-nonanol in a yield of 95%. Calcium hydride (19 mmol) and silicon dioxide (7 mmol) were added to 200 mL of DCM and 58 mmol of tetraisopropyl titanate. Under nitrogen, 62 mmol of diisopropyl L-(+)-tartrate was added at -35°C. After 30 minutes, 48 ​​mmol of 8-methyl-2-ene-1-nonanol was added. After 30 minutes, 105 mmol of tert-butyl hydroperoxide was added. The temperature was raised to -25°C and the reaction was allowed to proceed for 2 days. After completion of the reaction, 50 mL of 10% tartaric acid was added. The mixture was filtered, extracted with 200 mL of dichloromethane, and dried over anhydrous sodium sulfate. The organic phase was collected and passed through a column with PE:EA=5:1 to obtain (2S,3R)-2,3-epoxy-8-methyl-1-nonanol in a yield of 88%.

2. The use of (2S,3R)-2,3-epoxy-8-methyl-1-nonanol synthesized by the method according to claim 1 in the gypsy moth sex pheromone, characterized in that: 8-Methyl-2-ene-1-nonanol is subjected to Sharpless asymmetric epoxidation to give (2S,3R)-2,3-epoxy-8-methyl-1-nonanol. Under alkaline conditions, the hydroxyl group is activated and coupled with 1-nonyne to give (7R,8S)-7,8-epoxy-2-methyl-10-octadecyne. Finally, catalytic hydrogenation is performed to obtain the main component of the gypsy moth pheromone. The hydroxyl group of (2S,3R)-2,3-epoxy-8-methyl-2-ene-1-nonanol was iodinated and reacted with nonenyl magnesium bromide to obtain the minor component of the gypsy moth pheromone.

3. The use according to claim 2, characterized in that: The synthesis steps of (7R,8S)-7,8-epoxy-2-methyloctadecane, the main component of the gypsy moth sex pheromone, are as follows: (1) At -78°C, (2S,3R)-2,3-epoxy-8-methyl-1-nonanol prepared in claim 1 was added to dichloromethane, and triethylamine and trifluoromethanesulfonic anhydride were added. The mixture was stirred for 1 hour, and then quenched, extracted, and dried to obtain (2S,3R)-2,3-epoxy-8-methyl-1-nonyl trifluoromethanesulfonate. The molar ratio of (2S,3R)-2,3-epoxy-8-methyl-1-nonanol to trifluoromethanesulfonic anhydride was 1:2-4. (2) (2S,3R)-2,3-epoxy-8-methyl-1-nonyl trifluoromethanesulfonate reacts with 1-nonyne under alkaline conditions to obtain (7R,8S)-7,8-epoxy-2-methyl-10-octadecyne; (3) (7R,8S)-7,8-epoxy-2-methyl-10-octadecane is reacted with a catalyst in a hydrogen environment to obtain (7R,8S)-7,8-epoxy-2-methyloctadecane.

4. The use according to claim 2, characterized in that: The synthesis steps of the minor component (7R,8S)-7,8-epoxy-2-methyl-17-octadecene of the gypsy moth pheromone are as follows: (1) At 0°C, (2S,3R)-2,3-epoxy-8-methyl-1-nonanol prepared in claim 1 was added to dichloromethane, and then imidazole, iodine, and triphenylphosphine were added in sequence. The mixture was stirred for 1 hour, and after filtration, washing, drying, and column chromatography purification, (2S,3R)-2,3-epoxy-8-methyl-1-iodonane was obtained. (2) Add (2S,3R)-2,3-epoxy-8-methyl-1-iodonane to dry tetrahydrofuran. Add cuprous iodide, slowly add 1-nonenylmagnesium bromide or nonanemagnesium bromide under nitrogen, stir and react for 40 minutes, quench, extract, dry, and purify by column chromatography to obtain (7R,8S)-7,8-epoxy-2-methyl-17-octadecene or (7R,8S)-7,8-epoxy-2-methyloctadecane.

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