Method for synthesizing sex pheromones of beeswax borers

Abstract

The invention belongs to the technical field of biopesticides, and discloses a method for asymmetrically synthesizing sex pheromone of beeswax borers. The method comprises the following steps: by taking (R)-epoxypropane (2) as a raw material, firstly, reacting the (R)-epoxypropane (2) with pent-4-alkenyl magnesium bromide (3) to prepare (R)-octyl-7-ene-2-alcohol (4); then carrying out THP protection and NaIO4 oxidation synthesis to obtain (R)-6-[(tetrahydro-2H-pyran-2-yl) oxy] heptanoic acid (6); then introducing a chiral methyl group by utilizing a chiral induction strategy to prepare oxazolidinone imide 9; then, carrying out NaBH4 reductive cracking, Dess-Martin oxidation and Wittig reaction, so as to obtain THP protected dienol 12; and finally, carrying out deprotection and Pd / C catalytic hydrogenation to prepare the sex pheromone (2R, 6R, 10R)-6, 10, 14-trimethylpentadecan-2-ol (1) of the beewax borers. The method has the advantages of high total yield, simple synthetic route and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological pesticides, and particularly relates to a method for synthesizing aphomia sociella sex pheromone. BACKGROUND

[0002] Aphomia sociella belongs to Lepidoptera and Pyralidae, and is a specific parasitic pest of bumblebee nests (Goulson, D.; Hughes, W. O. H.; Derwent, L. C.; Stout, J. C. Oecologia 2002, 130, 267.). Aphomia sociella larvae invade the inside of the beehive, eat beeswax, pollen and larvae, cause damage to the beehive, cause the beehive to shrink, and further pose a significant threat to the pollination ecological chain (Crowther, L. I.; Reader, T.; Gilbert, F. Ecol. Entomol. 2022, 47, 911. Sharma, H. K.; Kalia, L.; Sharma, R.; Thakur, M.; Prasad, H.; Devi, M.; Thakur, P.; Sharma, D.; Rana, K. Int. J. Trop. Insect Sci. 2021, 41, 2555.). Valterova and Komonen et al. identified the active components of the sex pheromone secreted by female adults of aphomia sociella as hexan-1-ol, 6,10,14-trimethylpentadecan-2-ol (formula 1) and 6,10,14-trimethylpentadecan-2-one (Kindl, J.; Jiros, P.; Kalinova, B.; Zácek, P.; Valterova, I. J. Chem. Ecol. 2012, 38, 400. Komonen, A. J. Hymenopt. Res. 2023, 96, 45.). Valterova et al. determined the absolute configuration of 6,10,14-trimethylpentadecan-2-ol as (2R,6R,10R) by using the combination of electroantennographic detection technology (EAG) and gas chromatography mass spectrometry (GC-MS) (Wallin, E. A.; Kalinova, B.; Kindl, J.; Hedenström, E.; Valterova, I. Sci Rep 2020, 10, 2094.).

[0003]

[0004] Formula 1

[0005] Insect pheromones can be used for pest population monitoring, mass trapping and mating interference, etc., with the advantages of high efficiency, extremely low toxicity to the environment and natural enemies, and pests not easy to develop resistance (Wu F; Liu Shenyun; Zhang Li; Zhang Xufeng; Li Hongliang; Plant Protection, 2023, 50, 287. Li Chenhao; Liang Chizhou; Lu Yu; Zhu Xuhui; Du Yongjun; Yan Tie; Lu Jianfei; China Plant Protection, 2025, 45, 23.). However, the content of female sex pheromone of Cephalonomia stephanoderis is very low in pests, and it is difficult to extract and separate, which cannot meet the needs of bee industry. Therefore, the asymmetric synthesis of Cephalonomia stephanoderis female sex pheromone (Formula 1) has important theoretical significance and application value. SUMMARY

[0006] The present application aims to provide a method for synthesizing Cephalonomia stephanoderis sex pheromone (1). In the present application, (R)-propylene oxide (2) is used as the starting material, first reacts with pent-4-enyl magnesium bromide (3) to prepare (R)-oct-7-en-2-ol (4); then THP protection is carried out to obtain 2-[(R)-oct-7-en-2-yloxy]tetrahydro-2H-pyran (5); then NaIO4 oxidation is carried out to synthesize (R)-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanoic acid (6); then reacts with pivaloyl chloride to generate mixed anhydride, and then acylates with (S)-4-benzyl oxazolidine-2-ketone (7) to generate (4S)-4-benzyl-3-[(6R)-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidine-2-ketone (8); then diastereoselective methylation is carried out to synthesize (4S)-4-benzyl-3-[(2S,6R)-2-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidine-2-ketone (9). The oxazolidinone imide 9 is reduced and cleaved by NaBH4 to prepare (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptan-1-ol (10); then Dess-Martin oxidation is carried out to obtain (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanal, and then Wittig reaction is carried out with phosphonium salt 11 to prepare (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanal; finally, deprotection and Pd / C catalytic hydrogenation are carried out to prepare Cephalonomia stephanoderis sex pheromone (2R,6R,10R)-6,10,14-trimethylpentadecan-2-ol (1). The present application has the advantages of high total yield and simple synthesis route. The synthesis route of the present application for synthesizing Cephalonomia stephanoderis sex pheromone (2R,6R,10R)-6,10,14-trimethylpentadecan-2-ol (1) is shown in Formula 2.

[0007]

[0008] Formula 2

[0009] The method for synthesizing the sex pheromone of the Megachile grandis includes the following steps.

[0010] (1) Synthesis of (R)-oct-7-en-2-ol (4)

[0011] Under argon protection and at -40 o C, (R)-epoxypropane (2) was added into the mixture of CuI and pent-4-enyl magnesium bromide (3) in tetrahydrofuran solution, and the reaction was carried out for 12 h, and then the reaction was stopped. Then, quenching, separation, extraction, washing, drying and concentration were carried out, and finally, (R)-oct-7-en-2-ol (4) was obtained by silica gel column chromatography.

[0012] (2) Synthesis of 2-[(R)-oct-7-en-2-yloxy]tetrahydro-2H-pyran (5)

[0013] At 0 o C, 3,4-dihydro-2H-pyran and p-toluenesulfonic acid were added into the DCM solution of (R)-oct-7-en-2-ol (4), and the reaction was carried out for 2 h, and then the reaction was stopped. Then, quenching, separation, extraction, washing, drying and concentration were carried out, and finally, 2-[(R)-oct-7-en-2-yloxy]tetrahydro-2H-pyran (5) was obtained by silica gel column chromatography.

[0014] (3) Synthesis of (R)-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanoic acid (6)

[0015] At 0 o C, 2-[(R)-oct-7-en-2-yloxy]tetrahydro-2H-pyran (5) and ruthenium trichloride were added into the mixture of NaIO4, MeCN, H2O and EtOAc, and the reaction was carried out for 0.5 h, and then the reaction was stopped. Then, quenching, extraction, drying and concentration were carried out, and finally, (R)-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanoic acid (6) was obtained by silica gel column chromatography.

[0016] (4) Synthesis of (4S)-4-benzyl-3-[(6R)-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (8)

[0017] At -78 o C, triethylamine and pivaloyl chloride were added into the THF solution of (R)-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanoic acid (6), and the reaction was carried out for 0.5 h; the temperature was increased to room temperature, and the reaction was carried out for 1 h; the temperature was decreased to -78 oC, lithium chloride and a THF solution of (S)-4-benzyl oxazolidin-2-one (7) were added, and the reaction was allowed to proceed for 1 h; the temperature was raised to room temperature, and the reaction was allowed to proceed for 8 h, and then the reaction was stopped. Subsequently, the reaction mixture was quenched, extracted, dried, and concentrated, and finally purified by silica gel column chromatography to obtain (4S)-4-benzyl-3-[(6R)-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (8).

[0018] (5) Synthesis of (4S)-4-benzyl-3-[(2S,6R)-2-methyl-6-((tetrahydro-2H-pyran-2- yl)oxy)heptanoyl]oxazolidin-2-one (9)

[0019] At -78 o C, NaHMDS was added to a THF solution of (4S)-4-benzyl-3-[(6R)-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (8), and the mixture was stirred for 1 h; MeI was then added, and the mixture was stirred for 2 h; the temperature was raised to -60 o C, and the reaction was allowed to proceed for 3 h, and then the reaction was stopped; subsequently, the reaction mixture was quenched, extracted, dried, and concentrated, and finally purified by silica gel column chromatography to obtain (4S)-4-benzyl-3-[(2S,6R)-2-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (9).

[0020] (6) Synthesis of (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptan-1-ol (10)

[0021] At 0 o C, a THF solution of (4S)-4-benzyl-3-[(2S,6R)-2-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (9) was added, and the temperature was raised to room temperature, and the reaction was allowed to proceed for 2 h, and then the reaction was stopped; subsequently, the reaction mixture was quenched, extracted, dried, and concentrated, and finally purified by silica gel column chromatography to obtain (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptan-1-ol (10).

[0022] (7) Synthesis of 2-[(2R,6S,10R)-6,10,14-trimethylpentadec-7,13-dien-2-yloxy]tetrahydro-2H-pyran (12)

[0023] At 0 oC, to a solution of (2S, 6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptan-1-ol (10) in DCM was added DMP reagent, and the mixture was warmed to room temperature and stirred for 2 h. The reaction was then quenched, filtered, washed, and concentrated under reduced pressure to give (2S, 6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanal crude product.

[0024] At -15 o C, to a mixture of (R)-bromo(3,7-dimethyloct-6-en-1-yl)triphenylphosphonium (11), n-BuLi, and THF was added a THF solution of (2S, 6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanal crude product; the mixture was warmed to room temperature and stirred for 8 h. The reaction was then quenched, extracted, dried, and concentrated, and finally purified by silica gel column chromatography to give 2-[(2R, 6S, 10R)-6, 10, 14-trimethylpentadec-7, 13-dien-2-yloxy]tetrahydro-2H-pyran (12).

[0025] (8) Synthesis of (2R, 6R, 10R)-6, 10, 14-trimethylpentadecan-2-ol (1)

[0026] At room temperature, to a solution of 2-[(2R, 6R, 10R)-6, 10, 14-trimethylpentadecan-2-yloxy]tetrahydro-2H-pyran (12) in MeOH was added p-toluenesulfonic acid, and the mixture was stirred for 8 h. The reaction was then quenched and concentrated under reduced pressure to give (2R, 6R, 10R)-6, 10, 14-trimethylpentadec-7, 13-dien-2-ol crude product.

[0027] At room temperature, under a hydrogen atmosphere, to a mixture of (2R, 6R, 10R)-6, 10, 14-trimethylpentadec-7, 13-dien-2-ol crude product was added Pd / C and MeOH, and the mixture was stirred for 8 h. The reaction was then filtered and concentrated, and finally purified by silica gel column chromatography to give (2R, 6R, 10R)-6, 10, 14-trimethylpentadecan-2-ol (1). DETAILED DESCRIPTION

[0028] The present application provides a method for synthesizing the sex pheromone of Megachile pluto. Those skilled in the art can make appropriate improvements to the process parameters based on the content herein. In particular, it should be noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are considered to be included in the present application. The method and application of the present application have been described by preferred embodiments, and relevant personnel can obviously make modifications or appropriate changes and combinations to the method and application herein without departing from the content, spirit and scope of the present application, to realize and apply the present application technology.

[0029] The test materials used in the present application are all ordinary commercially available products, which can be purchased in the market.

[0030] The present application is further described below in conjunction with examples:

[0031] Example 1

[0032] (R)-oct-7-en-2-ol (4)

[0033] Under argon protection and at -40 o C, CuI (328 mg, 1.72 mmol) and THF (50 mL) were added into a 250 mL three-necked flask, and stirred thoroughly, then pent-4-enyl magnesium bromide (3) (52 mL, 0.5 M tetrahydrofuran solution, 26.00 mmol) was slowly added. The reaction was stirred for 0.5 hours under the condition of -40 o C, then a solution of (R)-oxirane (2) (1.00 g, 17.22 mmol) in THF (5 mL) was added dropwise, and the dropwise time was 1 hour. The reaction was continuously stirred for 12 hours under the condition of -40 o C, then saturated NH4Cl aqueous solution (20 mL) was added to quench the reaction. The aqueous phase and the organic phase were separated, and the aqueous phase was extracted with Et2O (3×50 mL), and the extract and the organic phase were combined. The combined solution was washed with saturated NaCl aqueous solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. Finally, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 8:1) to obtain colorless oil (R)-oct-7-en-2-ol (4) (2.10 g, 95% yield). 1 H NMR (500 MHz, CDCl3) δ 5.81 (ddt, J = 16.9, 10.1, 6.7Hz, 1H), 5.02 – 4.92 (m, 2H), 3.79 (dq, J = 12.6, 6.3, 5.6 Hz, 1H), 2.06 (q,J = 6.8 Hz, 2H), 1.50 – 1.38 (m, 6H), 1.19 (d, J = 6.2 Hz, 3H). 13 C NMR (126MHz, CDCl3) δ 139.01, 114.51, 68.20, 39.29, 33.85, 29.02, 25.36, 23.62.

[0034] Example 2

[0035] Synthesis of 2-[(R)-oct-7-en-2-yloxy]tetrahydro-2H-pyran (5)

[0036] In 0 o At C, (R)-oct-7-en-2-ol (4) (1.50 g, 11.70 mmol) and DCM (30 mL) were added to a 250 mL Shrek flask and stirred thoroughly. 3,4-dihydro-2H-pyran (1.48 g, 17.55 mmol) and p-toluenesulfonic acid (102 mg, 0.59 mmol) were then added. The mixture was stirred for 2 hours, and the reaction was quenched with water (20 mL). The aqueous and organic phases were separated. The aqueous phase was extracted with DCM (3 × 30 mL), and the extracts were combined with the organic phase. The mixture was washed with saturated NaCl aqueous solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. Finally, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20:1) to give a pale yellow oily substance 2-[(R)-oct-7-en-2-yloxy]tetrahydro-2H-pyran (5) (2.31 g, 93% yield). 1 H NMR (500MHz, CDCl3) δ 5.77 – 5.71 (m, 1H), 4.95 – 4.90 (m, 1H), 4.88 – 4.85 (m, 1H), 4.64 – 4.55 (m, 1H), 3.88 – 3.80 (m, 1H), 3.73 – 3.63 (m, 1H), 3.44 – 3.40 (m, 1H), 2.01 – 1.96 (m, 2H), 1.79 – 1.74 (m, 1H), 1.67 – 1.61 (m, 1H), 1.52– 1.43 (m, 5H), 1.39 – 1.29(m, 5H), 1.15 (d, J = 6.3 Hz, 2H), 1.03 (d, J =6.1 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 139.20, 139.07, 114.44, 114.33, 98.73,95.74, 73.95, 71.20, 62.97, 62.57, 37.50, 36.44, 33.88, 33.86, 31.36, 31.34,29.13, 25.71, 25.65, 25.49, 25.05, 21.70, 20.23, 19.88, 19.21.

[0037] Example 3

[0038] Synthesis of (R)-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanic acid (6)

[0039] In 0o C. Into a 250 mL three-necked flask was added NaIO4(4.13 g, 19.31 mmol), followed by MeCN (10 mL), H2O (15 mL) and EtOAc (10 mL) and stirred thoroughly. To this was added 2-[(R)-oct-7-en-2-yloxy]tetrahydro-2H-pyran (5) (1.00 g, 4.71 mmol) and ruthenium trichloride (20.7 mg, 0.10 mmol). The reaction was stirred for 0.5 h, warmed to room temperature and stirred for 8 h. The reaction was quenched with water (20 mL). The aqueous and organic phases were separated and the aqueous phase was extracted with EtOAc (3 x 30 mL) and the combined extracts were combined with the organic phase. The combined organic phase was washed with saturated aqueous NaCl (50 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 5:1) to give (R)-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanoic acid (6) as a pale yellow oil (1.07 g, 99% yield). 1 H NMR (500 MHz, CDCl3)δ 4.70 – 4.63 (m, 1H), 3.95 – 3.85 (m, 1H), 3.82 – 3.69 (m, 1H), 3.52 – 3.47(m, 1H), 2.38 – 2.34 (m, 2H), 1.86 – 1.79 (m, 1H), 1.73 – 1.51 (m, 8H), 1.49– 1.33 (m, 3H), 1.22 (d, J = 6.3 Hz, 1.5H), 1.11 (d, J = 6.3 Hz, 1.5H). 13 CNMR (126 MHz, CDCl3) δ 179.70, 179.61, 98.88, 95.90, 73.89, 71.07, 62.98,62.72, 37.19, 36.25, 34.13, 34.11, 31.35, 31.31, 25.66, 25.62, 25.41, 25.05,24.90, 24.88, 21.71, 20.18, 19.93, 19.26.

[0040] Example 4

[0041] (4S)-4-benzyl-3-[(6R)-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (8)

[0042] At room temperature, add (R)-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanic acid (6) (0.89 g, 3.90 mmol) and THF (25 mL) to a 100 mL Shrek flask and stir thoroughly. Cool to -78°C. o At C, triethylamine (1.12 mL, 8.00 mmol) and pentanoyl chloride (0.74 mL, 6.00 mmol) were slowly added dropwise, and the mixture was stirred for 0.5 hours. The mixture was allowed to warm naturally to room temperature, and the reaction was continued with stirring for 1 hour. The mixture was then cooled to -78°C. o C, add lithium chloride (0.53 g, 12.40 mmol), and slowly add (S)-4-benzyloxazolidine-2-one (7) (0.85 g, 4.80 mmol) in THF solution (7 mL) at -78°C. o The reaction was stirred at C for 1 hour. The mixture was then allowed to cool naturally to room temperature and stirred for another 8 hours. The reaction was quenched with a saturated NH4Cl aqueous solution (25 mL). The aqueous and organic phases were separated, and the aqueous phase was extracted with EtOAc (3 × 30 mL). The extracts and organic phases were combined. The mixture was washed with a saturated NaCl aqueous solution (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. Finally, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 5:1) to give a pale yellow oily substance (4S)-4-benzyl-3-[(6R)-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (8) (1.26 g, 83% yield). 1 H NMR (500 MHz, CDCl3) δ 7.35 – 7.20 (m, 5H), 4.71 – 4.63 (m, 2H), 4.22 – 4.15 (m, 2H), 3.95 – 3.87 (m, 1H), 3.84 – 3.71 (m,1H), 3.51 – 3.47 (m, 1H), 3.29 (dd, J = 13.4, 3.3 Hz, 1H), 3.02 – 2.87 (m,2H), 2.77 (dd, J = 13.4, 9.6 Hz, 1H), 1.86 – 1.79 (m, 1H), 1.74 – 1.67 (m,3H), 1.60 – 1.37 (m, 8H), 1.23 (d, J = 6.2 Hz, 1.5H), 1.11 (d, J = 6.2 Hz, 1.5H). 13C NMR (126 MHz, CDCl3) δ 173.42, 173.33, 153.57, 135.45, 135.42,129.54, 129.07, 127.47, 127.45, 98.95, 95.77, 77.36, 73.95, 70.99, 66.29,66.27, 63.02, 62.67, 55.27, 38.05, 37.39, 36.44, 35.65, 31.35, 25.67, 25.63,25.51, 25.18, 24.46, 21.77, 20.24, 19.92, 19.25.

[0043] Example 5

[0044] (4S)-4-benzyl-3-[(2S,6R)-2-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (9)

[0045] At -78 o At C, (4S)-4-benzyl-3-[(6R)-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (8) (1.10 g, 2.80 mmol) and THF (14 mL) were added to a 200 mL Shrek flask and stirred to dissolve. Sodium bis(trimethylsilyl)amino (NaHMDS, 2.1 mL, 2.0 M tetrahydrofuran solution, 4.2 mmol) was slowly added and stirred for 1 hour. Then, MeI (0.88 mL, 14.00 mmol) at 2.28 g / cm³ was slowly added dropwise. The reaction mixture was stirred for another 2 hours, and the temperature was raised to -60°C. o C. The reaction was stirred for 3 hours, and the reaction was quenched with saturated NH4Cl aqueous solution (15 mL). The aqueous phase and organic phase were separated, and the aqueous phase was extracted with EtOAc (3 × 20 mL). The extracts and organic phases were combined. The mixture was washed with saturated NaCl aqueous solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. Finally, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 5:1) to give a pale yellow oil (4S)-4-benzyl-3-[(2S,6R)-2-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (9) (0.84 g, 69% yield). 1H NMR (500 MHz, CDCl3) δ 7.35 – 7.20(m, 5H), 4.70 – 4.62 (m, 2H), 4.21 – 4.16 (m, 2H), 3.94 – 3.85 (m, 1H), 3.73– 3.68 (m, 1H), 3.50 – 3.47 (m, 1H), 3.26 (dd, J = 13.4, 3.3 Hz, 1H), 2.77 (dd, J = 13.4, 9.6 Hz, 1H), 1.86 – 1.67 (m, 3H), 1.59 – 1.29 (m, 9H), 1.23 –1.21 (m, 4.5H), 1.10 (d, J = 6.1 Hz, 1.5H). 13 C NMR (126 MHz, CDCl3) δ 177.38,177.29, 153.20, 135.49, 135.45, 129.58, 129.07, 127.48, 127.46, 98.93, 95.80,73.90, 71.14, 66.17, 66.15, 63.04, 62.69, 55.50, 55.48, 38.05, 37.85, 37.79,37.61, 36.58, 33.61, 33.52, 31.37, 31.35, 25.69, 25.64, 23.67, 23.27, 21.76, 20.25, 19.93, 19.25, 17.49, 17.47.

[0046] Example 6

[0047] (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]hepta-1-ol (10)

[0048] At room temperature, add (4S)-4-benzyl-3-[(2S,6R)-2-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (9) (0.40 g, 1.00 mmol) and THF (7 mL) to a 50 mL Shrek flask. Cool to 0 °C. o C. Slowly add 2 mL of H₂O solution containing sodium borohydride (0.20 g, 5.00 mmol). Heat to room temperature and react for 2 hours, then stop the reaction. Cool to 0°C. oC. Adjust the pH to 6-7 with 2M HCl, separate the aqueous and organic phases, extract the aqueous phase with EtOAc (3 × 20 mL), and combine the extracts with the organic phases. Wash with saturated NaCl aqueous solution (20 mL), dry with anhydrous Na2SO4, and concentrate under reduced pressure to obtain the crude product. Finally, purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate 5:1) to obtain the colorless oily substance (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]hepta-1-ol (10) (202 mg, 88% yield). 1 H NMR(500 MHz, CDCl3) δ 4.67 – 4.63 (m, 1H), 3.95 – 3.88 (m, 1H), 3.84 – 3.70 (m,1H), 3.52 – 3.40 (m, 3H), 1.87 – 1.80 (m, 1H), 1.70 – 1.38 (m, 12H), 1.22 (d,J = 6.3 Hz, 1.5H), 1.11 (d, J = 6.2 Hz, 1.5H), 0.92 (d, J = 6.8, 1.5H), 0.91(d, J = 6.8, 1.5H). 13 C NMR (126 MHz, CDCl3) δ 98.73, 96.36, 73.92, 71.18,68.44, 68.11, 63.14, 63.00, 37.65, 36.80, 35.85, 35.78, 33.31, 32.92, 31.50,31.35, 25.65, 23.16, 22.94, 21.69, 20.26, 20.22, 19.45, 16.95, 16.67. HRMS(ESI, m / z): calculated for C 13 H 27 O3 + [M + H] + : 231.1890, found: 231.1894.

[0049] Example 7

[0050] 2-[(2R,6S,10R)-6,10,14-trimethylpentadecano-7,13-diene-2-yloxy]tetrahydro-2H-pyran(12)

[0051] In 0 oC, to a 50 mL Schlenk flask was added (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2- yl)oxy]heptan-1-ol (10) (184 mg, 0.80 mmol) and DCM (3 mL) and stirred thoroughly. DMP reagent (509 mg, 1.20 mmol) was added portionwise. The reaction was allowed to warm to room temperature and stirred for 2 hours before being quenched. EtOAc was added and filtered through celite, the filter cake was washed with EtOAc (3 x 10 mL) and the washings combined with the filtrate. The solution was washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to give crude (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanal.

[0052] at -15 o C, to a 20 mL Schlenk flask was added (R)-bromo(3,7-dimethyloct-6-en-1-yl)triphenylphosphonium (11) (578 mg, 1.20 mmol), n-BuLi (0.5 mL, 2.4 M in n-hexane, 1.2 mmol) and THF (10 mL) and allowed to warm to room temperature and stirred for 0.5 hours. The solution was then cooled to -15 o C and the crude aldehyde solution in THF (3 mL) was added. The reaction was allowed to warm to room temperature and stirred for 8 hours before being quenched with saturated aqueous NH4Cl (10 mL). The aqueous and organic phases were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL) and the extracts combined with the organic phase. The solution was washed with saturated aqueous NaCl (10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to give a crude product. The crude product was finally purified by silica gel column chromatography (petroleum ether / ethyl acetate 20:1) to give 2-[(2R,6S,10R)-6,10,14-trimethylpentadeca-7,13-dien-2-yloxy]tetrahydro-2H-pyran (12) as a colourless oil (252 mg, 90% yield). 1H NMR (500 MHz, CDC13) δ 5.31 - 5.26 (m, 1H), 5.18 - 5.08 (m, 2H), 4.72 - 4.61 (m, 1H), 3.94 - 3.69 (m, 1H), 3.50 - 3.46 (m, 1H), 2.43 - 2.39 (m, 1H), 2.04 - 1.80 (m, 6H), 1.68 (s, 3H), 1.60 (s, 3H), 1.58 - 1.26 (m, 15H), 1.20 (d, J = Hz, 1.5H), 1.09 (d, J = Hz, 1.5H), 0.92 (d, J = Hz, 3H), 0.87 (d, J = Hz, 3H). 13 C NMR (126 MHz, CDC13) δ 137.25, 137.12, 131.22, 131.19, 127.10, 126.97, 125.07, 125.05, 98.83, 95.57, 74.05, 71.20, 63.00, 62.40, 37.90, 37.76, 37.07, 36.87, 34.83, 33.23, 31.87, 31.39, 31.36, 25.87, 25.78, 25.70, 23.98, 23.57, 21.76, 21.37, 21.34, 20.29, 19.79, 19.64, 19.20, 17.80.

[0053] Example 8

[0054] (2R,6R,10R)-6,10,14-Trimethylpentadecan-2-ol (1)

[0055] To a 20 mL Schlenk tube was added 2-[(2R,6R,10R)-6,10,14-trimethylpentadecan-2- yloxy]tetrahydro-2H-pyran (12) (140 mg, 0.40 mmol) and MeOH (5 mL) at room temperature, and stirred to dissolve. p-Toluenesulfonic acid (72.3 mg, 0.42 mmol) was added, and the reaction was stirred at room temperature for 8 hours, and then stopped. The crude (2R,6R,10R)-6,10,14-trimethylpentadec-7,13-dien-2-ol was obtained by concentration under reduced pressure.

[0056] To a 50 mL Schlenk tube was added Pd / C (21.0 mg, 10%) at room temperature, then vacuumed, replaced with hydrogen gas using a hydrogen balloon, then added MeOH (5 mL) and stirred thoroughly. The above dienol crude product was added slowly, stirred under hydrogen atmosphere for 8 hours, then the reaction was stopped. Filtered using celite, the filtrate was concentrated under reduced pressure to give the crude product. Finally, the crude product was purified using silica gel column chromatography (petroleum ether) to give (2R,6R,10R)-6,10,14-trimethylpentadecan-2-ol (1) as colorless oil (92 mg, 85% yield). 1 H NMR (500 MHz, CDCl3) δ 3.82 – 3.78 (m, 1H), 1.55 –1.49 (m, 1H), 1.40 – 1.09 (m, 24H), 0.87 – 0.74 (m, 12H). 13 C NMR (126 MHz,CDCl3) δ 68.40, 39.89, 39.53, 37.54, 37.49, 37.45, 37.28, 32.93, 32.91,28.13, 24.96, 24.62, 23.65, 23.41, 22.87, 22.77, 19.84, 19.77.

[0057] The above merely is the preferred embodiment of the present application, it should be pointed out that, for the ordinary skilled in the technical field, without departing from the principles of the present application, can also make several improvements and refinements, these improvements and refinements also should be considered as the protection scope of the present application.

Claims

1. A method for the asymmetric synthesis of the bumblebee wax borer sex pheromone (2R,6R,10R)-6,10,14-trimethylpentadecano-2-ol (1), characterized in that... Includes the following steps: Using (R)-propylene oxide (2) as a raw material, it is first reacted with pent-4-enylmagnesium bromide (3) to prepare (R)-oct-7-en-2-ol (4); then protected by THP to obtain 2-[(R)-oct-7-en-2-yloxy]tetrahydro-2H-pyran (5); then oxidized with NaIO4 to synthesize (R)-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanoic acid (6); then reacted with pivaloyl chloride to generate The mixed anhydride is then acylated with (S)-4-benzyloxazolidin-2-one (7) to generate (4S)-4-benzyl-3-[(6R)-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one (8); then, (4S)-4-benzyl-3-[(2S,6R)-2-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)heptanoyl]oxazolidin-2-one is synthesized by diastereoselective methylation. [Oxazolidinone-2-one (9); Oxazolidinone imide 9 was reduced and cleaved by NaBH4 to obtain (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptan-1-ol (10); then oxidized by Dess-Martin to (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanal, and then reacted with quaternary phosphonium salt 11 in a Wittig reaction. (2S,6R)-2-methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]heptanal was prepared; finally, after deprotection and Pd / C catalytic hydrogenation, the bumblebee wax borer sex pheromone (2R,6R,10R)-6,10,14-trimethylpentadecano-2-ol (1) was prepared; the synthetic route of bumblebee wax borer sex pheromone (2R,6R,10R)-6,10,14-trimethylpentadecano-2-ol (1) is as follows: 。

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