阅读说明：本技术 一种合成地衣蛾性信息素及其非对映体的方法 (Method for synthesizing lichen moth sex pheromone and diastereomer thereof ) 是由 王敏 袁谷城 刘嘉威 于士航 王雪扬 杨宇雄 钟江春 边庆花 于 2021-09-14 设计创作，主要内容包括：本发明属于绿色农药技术领域,公开了一种新的合成地衣蛾性信息素及其非对映体的方法。该方法以(R)-3-甲基庚醛(2)为起始原料,先与原位生成的1-癸炔锂发生加成反应,得到炔丙醇3a和3b,然后利用色谱法分离,最后将3a与3b分别用钯碳催化氢化,得到(5R,7R)-5-甲基-7-十七醇(1a)与(5R,7S)-5-甲基-7-十七醇(1b)。本发明首次利用醛的炔化反应构建地衣蛾性信息素及其非对映体的仲羟基,具有合成路线简捷,仅包括2步反应,总产率高(77％)等优势。(The invention belongs to the technical field of green pesticides, and discloses a novel method for synthesizing lichen moth sex pheromone and diastereomers thereof. The method comprises the steps of taking (R) -3-methylheptanal (2) as a starting material, firstly carrying out addition reaction with in-situ generated 1-decyne lithium to obtain propargyl alcohol 3a and 3b, then separating by using chromatography, and finally carrying out catalytic hydrogenation on the 3a and 3b by using palladium carbon respectively to obtain (5R,7R) -5-methyl-7-heptadecanol (1a) and (5R,7S) -5-methyl-7-heptadecanol (1 b). The invention firstly utilizes the ethynylation reaction of aldehyde to construct the secondary hydroxyl of the sex pheromone and diastereomer of the sex pheromone of the chlamydomone, and has the advantages of simple synthetic route, only comprising 2 steps of reaction, high total yield (77 percent) and the like.)

1. A novel method for synthesizing lichen moth sex pheromone and diastereomer thereof by utilizing a strategy of constructing secondary hydroxyl group by utilizing ethynylation reaction of aldehyde is characterized by comprising the following steps: taking (R) -3-methyl heptanal (2) as a starting material, firstly carrying out addition reaction with in-situ generated 1-decyne lithium to obtain propargyl alcohol 3a and 3b, then separating by using chromatography, and finally respectively carrying out catalytic hydrogenation on the 3a and 3b by using palladium carbon to obtain (5R,7R) -5-methyl-7-heptadecanol (1a) and (5R,7S) -5-methyl-7-heptadecanol (1 b); the synthesis route of the lichen ruber sex pheromone (1a) and the diastereomer thereof (1b) is as follows:

Technical Field

The invention relates to the field of natural product chemistry, in particular to a novel method for synthesizing lichen moth sex pheromone and diastereomer thereof.

Background

Chlamydomonas armyworms (Miltochrista calamina) belongs to the family Lepidoptera (Lepidotera) Arctidae, the adults of which feed on lichen and are therefore called Chlamydomonas armyworms (Do Nguyen, D.; Kinjo, M.; Taguri, T.; Adachi, Y.; Yamakawa, R.; Ando, T.Biosci Biotechnol Biochem 2009,73, 1618-. In 2011, Ando et al extracted Chlamydomonas ni from female Chlamydomonas ni for the first time and determined that its main active ingredient was (5R,7R) -5-methyl-7-heptadecanol (1a, formula 1) (Yamakawa, R.; Kiyota, R.; Taguri, T.; Ando, T.tetrahedron Lett.2011,52, 5808-. In 2014, the group showed by field trial studies that the lichen moth sex pheromone has physiological activity of attracting males (Muraki, Y.; Taguri, T.; Yamakawa, R.; Ando, T.J.chem.Ecol.2014,40,250-. Although the sex pheromone of the lichen moth has important physiological activity, the content of the sex pheromone in the lichen moth is very low, and the sex pheromone is difficult to extract, so that the sex pheromone cannot meet the requirements of application research. The method is particularly important for further carrying out biological activity of the lichen moth sex pheromone and physiological and ecological research of the lichen moth and realizing artificial synthesis of the lichen moth sex pheromone and diastereomer (1b, formula 1).

The key for synthesizing the lichen moth sex pheromone and the diastereomer thereof is to construct chiral methyl and chiral hydroxyl, and the synthesis methods reported in the literature at present have the following two.

(1) In 2011, Ando and the like take 1-dodecene as a starting material, synthesize racemic 1, 2-epoxydodecane under the action of m-chloroperoxybenzoic acid, obtain (R) -1, 2-epoxydodecane through Jacobsen kinetic resolution, finally perform addition reaction with 2-methylhexyl magnesium bromide, and finally obtain (5R,7R) -5-methyl-7-heptadecanol (1a) through high performance liquid chromatography purification; the group also completed the synthesis of the lichen moth pheromone diastereomer (1b) in a manner similar to that for the synthesis of 1a (Yamakawa, R.; Kiyota, R.; Taguri, T.; Ando, T.tetrahedron Lett.2011,52,5808-

(2) In 2014, Ando et al used (S) -propylene oxide as a chiral source, added with n-propyl Grignard reagent to construct a chiral methyl group, then subjected to tosylation, nucleophilic substitution with dimethyl malonate, hydrolysis, decarboxylation, lithium aluminum hydride reduction, Swern oxidation to form an epoxide, and finally subjected to the Jacobsen kinetic resolution and n-nonylmagnesium bromide addition reaction to construct a chiral hydroxyl group, thereby obtaining (5R,7R) -5-methyl-7-heptadecanol (1a) (Muraki, Y.; Taguri, T.; Yamakawa, R.; Ando, T.J.Chem.ecol.2014,40, 250-258.).

Although the synthesis of sex pheromone of lichen moth and diastereomer thereof has been reported in literature, the existing method has the problems of difficult amplification, long synthetic route and the like. Therefore, there is a need for the chemist to develop new, efficient, simple, and easily-scalable methods for synthesizing lichen moth sex pheromones and their diastereomers.

Disclosure of Invention

The invention aims to provide a novel method for synthesizing lichen moth sex pheromone and diastereomer thereof. The method comprises the steps of taking (R) -3-methylheptanal (2) as a starting material, firstly carrying out addition reaction with in-situ generated 1-decyne lithium to obtain propargyl alcohol 3a and 3b, then separating by using chromatography, and finally carrying out catalytic hydrogenation on the 3a and 3b by using palladium carbon respectively to obtain (5R,7R) -5-methyl-7-heptadecanol (1a) and (5R,7S) -5-methyl-7-heptadecanol (1 b). The invention firstly utilizes the ethynylation reaction of aldehyde to construct the secondary hydroxyl of the sex pheromone and diastereomer of the sex pheromone of the chlamydomone, and has the advantages of simple synthetic route, only comprising 2 steps of reaction, high total yield (77 percent) and the like. The synthetic route of the sex pheromone and the diastereomer thereof of the lichen sanguinea is shown in a formula 2.

The method for synthesizing the lichen moth sex pheromone and the diastereomer thereof comprises the following steps.

(1) Synthesis of propargyl alcohols 3a and 3b

1-decyne and anhydrous THF were added to a 50mL Schlenk tube at room temperature under an argon blanket. After cooling to-78 ℃, n-butyllithium was added dropwise. Stirring for 0.5h, adding aldehyde 2, continuing to react for 0.5h, and reacting with saturated NH₄The reaction was quenched with Cl solution. The organic phase was separated, the aqueous phase was extracted with EtOAc, and the organic phases were combined. The organic phase is washed, dried, concentrated under reduced pressure and chromatographed to provide propargyl alcohols 3a and 3 b.

(2) Synthesis of (5R,7R) -5-methyl-7-heptadecanol (1a)

At room temperature, palladium carbon is added into a 100mL three-necked bottle, a hydrogen balloon is arranged on the three-necked bottle, an ethanol solution of propargyl alcohol 3a and 3 drops of glacial acetic acid are added, and the three-necked bottle is stirred and reacted for 8 hours. After completion of the reaction monitored by TLC, the reaction was stopped. The solid was removed by means of a short column of silica gel and the filter cake was washed with petroleum ether. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give (5R,7R) -5-methyl-7-heptadecanol (1 a).

(3) Synthesis of (5R,7S) -5-methyl-7-heptadecanol (1b)

At room temperature, palladium carbon is added into a 100mL three-necked bottle, a hydrogen balloon is arranged on the three-necked bottle, an ethanol solution of propargyl alcohol 3b and 3 drops of glacial acetic acid are added, and the three-necked bottle is stirred and reacted for 8 hours. After completion of the reaction monitored by TLC, the reaction was stopped. The solid was removed by means of a short column of silica gel and the filter cake was washed with petroleum ether. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give (5R,7S) -5-methyl-7-heptadecanol (1 b).

Detailed Description

Example 1

Synthesis of propargyl alcohols 3a and 3b

1-decyne (0.59g, 4.28mmol) and anhydrous THF (20mL) were added to a 50mL Schlenk tube at room temperature under argon. After cooling to-78 deg.C, n-butyllithium (1.34mL, 2.4M THF solution, 3.21mmol) was added dropwise over 15 minutes via a syringe pump. Stirring at-78 deg.C for 0.5h, then adding (R) -3-methylheptanal (2) (0.27g, 2.14mmol), continuing the reaction for 0.5h, adding saturated NH₄The reaction was quenched with Cl solution (10 mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (3X 10mL), and the organic phases were combined. The organic phase was washed with saturated NaCl solution (100mL) and driedNa₂SO₄Drying and concentrating under reduced pressure to obtain a crude product. The crude product was isolated by preparative thin layer chromatography (n-hexane/EtOAc 9:1) to give propargyl alcohols 3a (0.28g) and 3b (0.20g) as colorless oils (0.48 g total, 84% yield). 3a: [ alpha ]]_D ²⁶＝-5.64(c 0.78,CHCl₃)；¹H NMR(500MHz,CDCl₃)δ4.42(t,J＝7.2Hz,1H),2.20(td,J＝7.1,1.8Hz,2H),1.75–1.66(m,3H),1.55–1.46(m,3H),1.44–1.10(m,16H),0.93–0.87(m,9H).¹³C NMR(126MHz,CDCl₃)δ85.49,81.88,61.10,45.87,36.78,31.98,29.84,29.39,29.33,29.23,29.16,28.99,28.81,23.06,22.80,19.63,18.82,14.25.HRMS(ESI)calcd for C₁₈H₃₅O[M+H]⁺267.26824,found 267.26822.3b:[α]_D ²⁶＝+1.67(c 0.96,CHCl₃)；¹H NMR(500MHz,CDCl₃)δ4.41(t,J＝6.6Hz,1H),2.20(td,J＝7.1,1.9Hz,2H),1.70–1.62(m,3H),1.54–1.46(m,3H),1.37–1.13(m,16H),0.93–0.87(m,9H).¹³C NMR(126MHz,CDCl₃)δ85.81,81.54,61.64,45.71,36.88,31.98,29.83,29.35,29.24,29.18,28.98,28.81,23.06,22.80,19.85,18.83,14.27,14.24.HRMS(ESI)calcd for C₁₈H₃₅O[M+H]⁺267.26824,found 267.26840.

Example 2

Synthesis of (5R,7R) -5-methyl-7-heptadecanol (1a)

Palladium on carbon (0.10g, 10%) was charged into a 100mL three-necked flask at room temperature, and the reaction system was filled with H by filling a hydrogen balloon₂. Then, a solution of 3a (82.3mg, 0.31mmol) in ethanol (15mL) and 3 drops of glacial acetic acid were added and the reaction was stirred for 8 h. After completion of the reaction monitored by TLC, the reaction was stopped. The solid was removed using a short column of silica gel, the filter cake was washed with petroleum ether (50mL), and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (n-hexane) to give colorless oily liquid 1a (77.7mg, yield 93%). [ alpha ] to]_D ²⁶＝-2.61(c 1.38,CHCl₃)；¹H NMR(500MHz,CDCl₃)δ3.68(ddt,J＝12.2,5.4,3.4Hz,1H),1.62(ddt,J＝12.2,6.5,2.5Hz,1H),1.44–1.40(m,4H),1.30–1.25(m,22H),1.17–1.15(m,1H),0.90–0.86(m,9H).¹³C NMR(126MHz,CDCl₃)δ69.84,45.18,38.54,37.76,32.06,29.86,29.79,29.77(×2),29.48,29.43,29.36,25.84,23.12,22.84,19.45,14.28,14.26.HRMS(ESI)calcd for C₁₈H₃₈ONa[M+Na]⁺293.28149,found 293.28293.

Example 3

Synthesis of (5R,7S) -5-methyl-7-heptadecanol (1b)

Palladium on carbon (0.10g, 10%) was charged into a 100mL three-necked flask at room temperature, and the reaction system was filled with H by filling a hydrogen balloon₂. Then 3b (92.8mg, 0.35mmol) in ethanol (15mL) and 3 drops of glacial acetic acid were added and the reaction was stirred for 8 h. After completion of the reaction monitored by TLC, the reaction was stopped. The solid was removed using a short column of silica gel, the filter cake was washed with petroleum ether (50mL), and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (n-hexane) to give colorless oily liquid 1b (85.7mg, yield 91%). [ alpha ] to]_D ²⁶＝+0.73(c 1.65,CHCl₃)；¹H NMR(500MHz,CDCl₃)δ3.69(tdd,J＝8.5,4.9,3.4Hz,1H),1.60–1.56(m,1H),1.43–1.38(m,4H),1.37–1.26(m,22H),1.12–1.05(m,1H),0.91–0.87(m,9H).¹³C NMR(126MHz,CDCl₃)δ70.20,45.45,37.95,36.45,32.06,29.87,29.84,29.80,29.77,29.74,29.49,29.24,25.71,23.18,22.84,20.56,14.29,14.26.HRMS(ESI)calcd for C₁₈H₃₈ONa[M+Na]⁺293.28149,found 293.28244.