Method for asymmetrically synthesizing pyrethroid aggregation pheromone ferruginactone II

Abstract

The invention discloses a method for asymmetrically synthesizing a ferruginactone II (ferruginactone II) of a cryptolepsis rusteri gather pheromone. The method comprises the following steps: by taking octyl-1-alkyne as a starting raw material, firstly, carrying out amide reaction on octyl-1-alkyne and Weinreb to prepare deca-3-alkyne-2-ketone; then, carrying out Corey-Bakshii-Shibata reduction and alkyne zipper reaction to synthesize (S)-decane-9-alkyne-2-alcohol, and carrying out a reaction on the (S)-decane-9-alkyne-2-alcohol and an alkyne zipper; then carrying out catalytic hydrogenation with NiAc2 / NaBH4 by utilizing a coupling reaction, so as to prepare (S, Z)-11-hydroxydodecane-3-olefine acid ethyl ester; and finally, carrying out catalytic hydrolysis by using lithium hydroxide, and carrying out an esterification reaction with Yamaguchi, so as to prepare the pyrethroid aggregation pheromone ferrulactone II (1). The method has the advantages of high total yield, simple synthetic route and the like.

Description

Technical Field

[0001] This invention belongs to the field of biopesticide technology, specifically relating to a method for the asymmetric synthesis of the ferrulactone II aggregation pheromone from the rusty red beetle. Background Technology

[0002] The rusty red flour beetle (Cryptolestes ferrugineus) is a significant storage pest. It bores into grains, flour, and processed grains (such as flour and cornmeal), accelerating grain breakage and pulverization, leading to grain loss and quality degradation. Furthermore, it easily spreads mold spores, accelerating grain spoilage and thus endangering human health (Jin Yuyang, Wang Dianxuan, Sang Haoshan, Wang Chen, Jin Zhenhui, Yao Junji, Shen Ruotong, Sun Haoran, China Cereals and Oils Association, 2025, 1. Javer, A.; Borden, JH; Pierce, HD, Jr.; Pierce, AM J Econ. Entomol. 1990, 83, 268.). Oehlschlager et al. identified the active components of the aggregated pheromone of the rusty red beetle as (3Z,11S)-dodec-3-ene-11-lactone (ferrulactone II) (Formula 1) and (E,E)-4,8-dimethyldec-4,8-diene-10-lactone (ferrulactone I) (Wong, JW; Verigin, V.; Oehlschlager, AC; Borden, JH; Pierce, HD; Pierce, AM; Chong, LJ Econ. Entomol. 1983, 9, 451. Oehlschlager, AC; Borden, JH J Agric. Food Chem. 1985, 33, 848. Oehlschlager, AC; King, GGS; Pierce, HD; Pierce, AM; Slessor, KN; Millar, JG; Borden, JHJEcon. Entomol. 1987, 13, 1543.). Chambers' research showed that the aggregation pheromones ferrulactone I and ferrulactone II can attract the rusty grain beetle (Chambers, J.; Morgan, CP; White, PR; Mori, K.; Finnegan, DE; Pinniger, DBJChem. Ecol. 1990, 16, 3353.).Therefore, this pheromone can be used for population monitoring (Javer, A.; Borden, JH; Pierce, HD, Jr.; Pierce, AM J Econ. Entomol. 1990, 83, 268.) and trapping (Loschiavo, SR; Wong, J.; White, NDG; Pierce, HD; Borden, JH; Oehlschlager, ACCA, Academia Entomologist 1986, 118, 1. Stevens, MM; Wood, RM; Mo, JH J Stored Prod. Res. 2019, 83, 227.

[0003]

[0004] Integrated pest management using insect sex pheromones offers advantages such as high efficiency, extremely low toxicity to the environment and natural enemies, and low resistance in pests. However, the aggregation pheromone ferrulactone II of the rusty red flour beetle is present in extremely low concentrations within the insect and is difficult to extract and separate, failing to meet the needs of the grain storage industry. Therefore, research on the asymmetric synthesis of the rusty red flour beetle aggregation pheromone ferrulactone II (Formula 1) has significant theoretical and practical value. Currently, no literature reports on the synthesis of the rusty red flour beetle aggregation pheromone ferrulactone II using CBS reduction. This patent is the first to utilize CBS reduction to construct a chiral center, completing the asymmetric synthesis research of this pheromone. Summary of the Invention

[0005] This invention aims to provide a method for synthesizing the pheromone ferrulactone II (1) of the rusty red beetle. The invention uses oct-1-yne (2) as the starting material, first preparing a lithium salt, which reacts with Weinreb amide 3 to obtain dec-3-yne-2-one (4); then reducing it with Corey-Bakshi-Shibata (CBS) to obtain (S)-dec-3-yne-2-ol (6); then synthesizing (S)-dec-9-yne-2-ol (7) via an alkyne zipper reaction; subsequently coupling it with ethyl diazonium acetate (8) to generate ethyl (S)-11-hydroxydodec-3-yne acid (9). The triple bond of alkynyl ester 9 was hydrogenated to a cis double bond via NiAc2 / NaBH4 catalysis to obtain ethyl (S,Z)-11-hydroxydodecano-3-enoate (10); then hydrolyzed under lithium hydroxide catalysis to obtain (S,Z)-11-hydroxydodecano-3-enoic acid (11); finally, esterification by Yamaguchi reaction yielded the target compound, ferrulactone II (1), an aggregation pheromone from *Hemiberlesia lataniae*. This invention utilizes the CBS asymmetric reduction reaction to construct a chiral center and extends the carbon chain through the reaction of alkynyl lithium salt with Weinreb amide and the coupling reaction of ethyl diazonium acetate, offering advantages such as high overall yield and a simple synthetic route. The synthetic route for ferrulactone II is shown in Formula 2.

[0006]

[0007] The method for synthesizing the ferrulactone II aggregation pheromone of the rust-red flatbread beetle according to the present invention includes the following steps.

[0008] (1) Synthesis of dec-3-yn-2-one (4)

[0009] Under argon protection and at -78°C, n-butyllithium was added to a tetrahydrofuran solution of oct-1-yne (2), and the mixture was stirred for 1 h. Weinreb amide 3 was then added. The mixture was heated to room temperature and stirred for 7 h before the reaction was stopped. The mixture was then quenched, separated, extracted, washed, dried, and concentrated. Finally, it was purified by silica gel column chromatography to obtain dec-3-yne-2-one (4).

[0010] (2) Synthesis of (S)-dec-3-yne-2-ol (6)

[0011] Argon protection at -40°C A borane dimethyl sulfide complex was added to a THF mixture of molecular sieve and (S)-2-methyl-CBS-oxazolborane (5), and the mixture was stirred for 2 h. A THF solution of dec-3-yn-2-one (4) was added dropwise, and the mixture was stirred for another 7 h before the reaction was stopped. The mixture was then quenched, filtered, concentrated, and finally purified by silica gel column chromatography to obtain (S)-dec-3-yn-2-ol (6).

[0012] Synthesis of (3)(S)-dec-9-yne-2-ol(7)

[0013] At room temperature, In a mixture of molecular sieve and sodium hydride, propan-1,3-diamine was added and stirred until homogeneous. The mixture was heated to 60°C and stirred under reflux for 5 hours. The mixture was cooled to 0°C and (S)-dec-3-yyn-2-ol was added dropwise (6). The mixture was stirred for another 4 hours and the reaction was stopped. The mixture was then quenched, extracted, dried and concentrated. Finally, (S)-dec-9-yyn-2-ol (7) was purified by silica gel column chromatography.

[0014] Synthesis of (4) (S)-11-hydroxydodec-3-acetylic acid ethyl ester (9)

[0015] Under argon protection and at room temperature, ethyl diazonium acetate (8) was added to an anhydrous acetonitrile mixture of cuprous iodide and (S)-dec-9-yn-2-ol (7), and the mixture was stirred for 17 h before the reaction was stopped. The mixture was then filtered, concentrated, and finally purified by silica gel column chromatography to obtain ethyl (S)-11-hydroxydodec-3-ynyl ester (9).

[0016] (5) Synthesis of (S,Z)-11-hydroxydodec-3-enoic acid ethyl ester (10)

[0017] Nickel acetate tetrahydrate, sodium borohydride, and ethanol were mixed and stirred for 1 h under H2 atmosphere and room temperature. After cooling to 0 °C, ethylenediamine and ethyl (S)-11-hydroxydodec-3-acetylacetic acid (9) were added and reacted for 1 h. The reaction was then stopped. The mixture was then filtered, concentrated, and finally purified by silica gel column chromatography to obtain ethyl (S,Z)-11-hydroxydodec-3-acetylacetic acid (10).

[0018] Synthesis of (6) (S,Z)-11-hydroxydodec-3-enoic acid (11)

[0019] Under argon protection and at room temperature, an aqueous solution of lithium hydroxide was added to a mixture of ethyl (S,Z)-11-hydroxydodecano-3-enoic acid (10), THF, and water. The mixture was stirred for 24 hours and then the reaction was stopped. The pH was then adjusted to 2 with dilute hydrochloric acid, and the mixture was washed, extracted, dried, concentrated under reduced pressure, and finally purified by silica gel column chromatography to obtain (S,Z)-11-hydroxydodecano-3-enoic acid (11).

[0020] Synthesis of (7) (3Z,11S)-dodec-3-ene-11-lactone ferrulactone II (1)

[0021] Under argon protection and at room temperature, triethylamine was added to a THF solution of (S,Z)-11-hydroxydodecano-3-enoic acid (11), and the mixture was stirred for 5 min. Then, 2,4,6-trichlorobenzoyl chloride was added, and the mixture was stirred for 1 h before the reaction was stopped. The mixture was then filtered and concentrated under reduced pressure to obtain the crude product of (S,Z)-11-hydroxydodecano-3-enoic acid trichlorobenzoic anhydride.

[0022] Under argon protection and at room temperature, a toluene solution of crude (S,Z)-11-hydroxydodecano-3-ene trichlorobenzoic anhydride was slowly added dropwise to a toluene solution of 4-dimethylaminopyridine. The mixture was stirred for 16 h, and then the reaction was stopped. The mixture was then filtered, concentrated under reduced pressure, and finally purified by silica gel column chromatography to obtain (3Z,11S)-dodecano-3-ene-11-lactone ferrulactone II (1).

[0023] Beneficial effects: The synthetic route of this invention is simple and does not involve the protection and deprotection reactions of hydroxyl groups, thus possessing the advantages of atom economy and low synthesis cost. The ferrulactone II aggregation pheromone synthesized in this invention has the biological activity of attracting rusty red flour beetles and can be used for population monitoring and trapping of rusty red flour beetles, which can promote the research and practice of green protection against stored-store pests in my country. Detailed Implementation

[0024] This invention provides a method for the asymmetric synthesis of the pheromone ferrulactone II, commonly known as the pheromone beetle aggregation pheromone. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired result. It is particularly important to note that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art can clearly modify or appropriately alter and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to implement and apply the technology of this invention.

[0025] The test materials used in this invention are all commercially available products. The invention will be further illustrated below with reference to specific embodiments.

[0026] Example 1

[0027] Dec-3-yn-2-one (4)

[0028] Under argon protection, octyl-1-yne (2) (5.51 g, 50.00 mmol) and THF (100 mL) were added to a 250 mL Shrek flask and stirred until homogeneous at room temperature. The mixture was then cooled to -78 °C, and n-BuLi (21 mL, 2.5 M n-hexane solution, 52.50 mmol) was slowly added dropwise under argon protection. The mixture was stirred for 2 h, and then Weinreb amide (3) (5.67 g, 55.00 mmol) was slowly added. The reaction mixture was then heated to room temperature and stirred for 7 h, followed by quenching with saturated NH4Cl aqueous solution (30 mL). The organic phase was separated, and the aqueous phase was extracted with Et2O (3 × 30 mL). The combined organic phases were washed with saturated NaCl aqueous solution (90 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100:1) to give a pale yellow oily compound dec-3-yn-2-one (4) (7.60 g, yield 99%). 1 HNMR (500MHz, CDCl3) δ2.35(t,J=7.1Hz,2H),2.32(s,3H),1.60–1.54(m,2H),1.43–1.37(m,2H),1.34–1.26(m,4H),0.89(t,J=6.8Hz,3H). 13 C NMR (126MHz, CDCl3) δ185.11,94.35,81.56,32.91,31.35,28.67,27.79,22.61,19.07,14.15.

[0029] Example 2

[0030] Synthesis of (S)-dec-3-yne-2-ol (6)

[0031] Add to a 250mL Shrek bottle Molecular sieves were used, and the process was repeated three times under vacuum and argon purging. Under argon protection and at -40°C, (S)-2-methyl-CBS-oxazolborane (5) (12 mL, 1M toluene solution, 12.00 mmol) and THF (10 mL) were added and stirred until homogeneous. Then, BH3·BMS (12 mL, 2M THF solution, 24.00 mmol) was slowly added. After stirring the mixture for 2 h, dec-3-yn-2-one (4) (3.04 g, 20.00 mmol) in THF solution (50 mL) was slowly added dropwise using a syringe pump, completing the addition over 48 h. The mixture was stirred for another 7 h, and the reaction was stopped. Methanol (20 mL) was slowly added, and the mixture was stirred for another 3 h, then heated to room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20:1) to give a colorless oil (Z)-undec-2-en-1-ol (6) (2.43 g, yield 79%). 1 H NMR(500MHz, CDCl3)δ4.54–4.49(m 1H),2.19(td,J=7.2,2.0Hz,2H),1.74(d,J=4.8Hz,1H),1.51–1.47(m,2H),1.4 3(d,J=6.4Hz,3H),1.40–1.36(m,2H),1.32–1.25(m,4H),0.89(t,J=6.9Hz,3H). 13 CNMR (126MHz, CDCl3) δ84.93,82.34,58.78,31.47,28.75,28.66,24.92,22.68,18.79,14.18.

[0032] Example 3

[0033] Synthesis of (S)-dec-9-yne-2-ol (7)

[0034] At room temperature, Molecular sieve (2.00 g) and NaH (3.46 g, 144.00 mmol) were added sequentially to a 100 mL three-necked flask, followed by propan-1,3-diamine (25 mL), and stirred until homogeneous. The mixture was heated to 60 °C and stirred under reflux for 5 h. The mixture was cooled to 0 °C, and (S)-decyl-3-yn-2-ol (6) (2.22 g, 14.40 mmol) was added. The reaction mixture was heated to room temperature and stirred for another 4 h, after which the reaction was stopped. The reaction was quenched with ice water (10 mL) at 0 °C. Extraction was performed with Et₂O (3 × 30 mL). The combined organic phases were washed with a saturated NaCl aqueous solution (90 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20:1) to give a pale yellow oil (S)-decyl-9-yn-2-ol (7) (2.05 g, yield 92%). 1 H NMR(500MHz, CDCl3)δ3.81–3.76(m,1H),2.19(td,J=7.1,2.6Hz,2H),1.94(t ,J=2.7Hz,1H),1.56–1.50(m,2H),1.45–1.31(m,8H),1.19(d,J=6.2Hz,3H). 13 C NMR (126MHz, CDCl3) δ84.82,68.26,68.25,39.40,29.22,28.81,28.52,25.75,23.65,18.50.

[0035] Example 4

[0036] (S)-11-hydroxydodec-3-acetylacetic acid ethyl ester (9)

[0037] Under argon protection and at room temperature, CuI (57 mg, 0.30 mmol) and anhydrous acetonitrile (10 mL) were added to a 50 mL Shrek tube and stirred until homogeneous. (S)-decyl-9-yn-2-ol (7) (0.93 g, 6.00 mmol) and ethyl diazonate (8) (0.82 g, 7.20 mmol) were added. The reaction was stirred for 17 h, then stopped. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 50:1) to give a colorless oily substance (S)-11-hydroxydodec-3-yn-ethyl ester (9) (1.08 g, 75% yield). 1H NMR (500MHz, CDCl3) δ4.19(q,J=7.1Hz,2H),3.81–3.76(m,1H),3.24(t,J=2.5Hz,2H),2.21–2.18(m,2H),1.60(br s,1H),1.52–1.48(m,2H),1.45–1.36(m,6H),1.33–1.31(m,2H),1.28(t,J=5.3Hz,3H),1.19(d,J=6.1Hz,3H). 13 CNMR (126MHz, CDCl3) δ169.18,83.93,71.67,68.27,61.56,39.41,29.22,28.86,28.70,26.25,25.74,23.63,18.88,14.27.

[0038] Example 5

[0039] (S,Z)-11-hydroxydodec-3-enoic acid ethyl ester (10)

[0040] At room temperature, Ni(OAc)₂·4H₂O (120 mg, 0.48 mmol) was added to a 50 mL Shrek tube, and the tube was evacuated and purged with hydrogen. NaBH₄ (18 mg, 0.48 mmol) and anhydrous ethanol (10 mL) were slowly added, and the mixture was stirred for 1 h. The mixture was cooled to 0 °C, and ethylenediamine (115 mg, 1.91 mmol) and anhydrous ethanol (1 mL) solution of (S)-11-hydroxydodec-3-acetylic acid ethyl ester (9) (460 mg, 1.91 mmol) were added. The reaction mixture was stirred under H₂ atmosphere for 1 h, and the reaction was stopped. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 50:1) to give a colorless oily substance (S,Z)-11-hydroxydodec-3-acetylic acid ethyl ester (10) (392 mg, yield 84%). 1 H NMR (500MHz, CDCl3) δ5.60–5.53(m,2H),4.14(q,J=7.0Hz,2H),3.81–3.76(m,1H),3.07(d,J=6.0Hz,2H),2.06–2.02(m,2H),1.66(br s,1H),1.45–1.29(m,10H),1.26(t,J=7.0Hz,3H),1.19(d,J=6.2Hz,3H). 13C NMR (126MHz, CDCl3) δ172.23,133.54,121.02,68.27,60.74,39.45,33.20,29.59,29.35,29.29,27.49,25.82,23.64,14.34.

[0041] Example 6

[0042] (S,Z)-11-hydroxydodec-3-enoic acid (11)

[0043] Under argon protection and at room temperature, ethyl (S,Z)-11-hydroxydodec-3-enoate (10) (390 mg, 1.61 mmol), THF (9 mL), and water (3 mL) were added to a 50 mL Shrek tube and stirred until homogeneous. Lithium hydroxide (1.2 mL, 2 M aqueous solution, 2.40 mmol) was added. The reaction mixture was stirred for 24 h, and then the reaction was stopped. The pH was adjusted to 2 with 1 M dilute hydrochloric acid. The mixture was washed with water (30 mL), extracted with ethyl acetate (3 × 30 mL), and the organic phases were combined. The mixture was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 2:1) to give a colorless oily substance (S,Z)-11-hydroxydodec-3-enoic acid (11) (344 mg, 99% yield). 1 H NMR (500MHz, CDCl3) δ5.64–5.52(m,2H),3.84–3.78(m,1H),3.13(d,J=6.4Hz,2H) ,2.07–2.03(m,2H),1.44–1.36(m,4H),1.32–1.25(m,6H),1.19(d,J=6.2Hz,3H). 13 C NMR (126MHz, CDCl3) δ176.85,134.20,120.36,68.41,39.28,32.67,29.40,29.14,29.11,27.38,25.70,23.56.

[0044] Example 7

[0045] (3Z,11S)-dodec-3-ene-11-lactone (ferrulactone II) (1)

[0046] Under argon protection and at room temperature, (S,Z)-11-hydroxydodecano-3-enoic acid (11) (37 mg, 0.17 mmol) and THF (3 mL) were added to a 10 mL Shrek tube, followed by triethylamine (86 mg, 0.85 mmol). The mixture was stirred and dissolved for 5 min, then 2,4,6-trichlorobenzoyl chloride (63 mg, 0.26 mmol) was added. The reaction mixture was stirred for 1 h, and the reaction was stopped. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of (S,Z)-11-hydroxydodecano-3-enoic acid trichlorobenzoic anhydride.

[0047] At room temperature, DMAP (415 mg, 3.40 mmol) was added to a 500 mL three-necked flask, and the mixture was evacuated and purged with argon three times. Toluene (250 mL) was added and stirred until completely dissolved. A toluene (40 mL) solution of the crude (S,Z)-11-hydroxydodecano-3-ene trichlorobenzoic anhydride was slowly added dropwise over 2 hours using a syringe pump. The reaction was continued to be stirred at room temperature for 16 hours, and then the reaction was stopped. The mixture was then filtered, concentrated under reduced pressure, and finally purified by silica gel column chromatography to obtain (3Z,11S)-dodecano-3-ene-11-lactone ferrulactone II (1) (23 mg, yield 69%). 1 H NMR(500MHz, CDCl3)δ5.59–5.52(m,2H),4.94–4.88(m,1H),3.09–2.98(m,2H), 2.07–2.02(m,2H),1.55–1.48(m,2H),1.31–1.25(m,8H),1.20(d,J=6.3Hz,3H). 13 C NMR (126MHz, CDCl3) δ171.74,133.82,121.29,71.23,36.13,33.75,29.48,29.22,29.17,27.39,25.36,20.27.

[0048] The above are merely preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for asymmetric synthesis of the pheromone ferrulactone II, characterized in that, Includes the following steps: Starting with oct-1-yne (2), a lithium salt was first prepared and reacted with Weinreb amide 3 to obtain dec-3-yne-2-one (4); then reduced by Corey-Bakshi-Shibata (CBS) to obtain (S)-dec-3-yne-2-ol (6); then (S)-dec-9-yne-2-ol (7) was synthesized by alkyne chain reaction; then coupled with ethyl diazonoacetate (8) to generate ethyl (S)-11-hydroxydodec-3-yne acid (9); Hydrogenation catalyzed by NiAc2 / NaBH4 yielded ethyl (S,Z)-11-hydroxydodecano-3-enoate (10); followed by lithium hydroxide-catalyzed hydrolysis to yield (S,Z)-11-hydroxydodecano-3-enoic acid (11); finally, esterification by Yamaguchi reaction yielded the target compound, ferrulactone II (1), an aggregation pheromone from *Ichthyophthirius multifiliis*. The synthetic route for ferrulactone II (1) is as follows:

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