Synthesis of a sex pheromone of the cucumber beetle

Abstract

The application belongs to the technical field of pesticide chemistry, and specifically discloses a synthesis method of cucumber beetle sex pheromone, wherein compound (R)-3 and n-valeryl chloride are used as raw materials, chiral methyl is introduced through Evans template chiral induction of oxazolinone, compared with general methods, the reaction yield is greatly improved, and no by-product is generated; compound 4 and compound 10 are used as raw materials respectively, chiral asymmetric synthesis reaction is carried out through iodomethane and NaHMDS to prepare compound (R)-5 and compound (R)-11, the reaction by-product is less, and the reaction yield is greatly improved, compared with general synthesis routes, the total reaction yield is 15%, and the reaction yield of most reactions is more than 85%, and the synthesis method is relatively simple.

Description

Technical Field

[0001] This invention belongs to the field of pesticide chemistry technology, specifically a method for synthesizing the sex pheromone of the cucumber beetle. Background Technology

[0002] The cucumber beetle (Diabrotica balteata LeConte), belonging to the family Chrysomelidae in the order Coleoptera, is a major pest of cucurbit crops. Its host plant range is very wide, including vine-like cucurbits such as cucumbers, sweet potatoes, beans, and zucchini. Control is particularly challenging in organic farming due to its increased resistance to pesticides and restrictions on chemical pesticide use. The cucumber beetle primarily feeds on cucurbit plants, with both adults and larvae causing damage. Adults feed on leaves, flowers, and fruits, while larvae mainly feed on roots and near-surface stems, leading to stunted growth and even plant death. This pest has a high reproductive rate, and when population density is too high, it can rapidly and devastate crops. It also spreads bacterial wilt disease, causing severe economic losses. Using the cucumber beetle's sex pheromones to control this pest offers high precision and environmental friendliness while effectively reducing economic costs. This technology provides a sustainable and efficient solution for agricultural pest management and has broad application prospects.

[0003] Currently, the structure of the cucumber beetle sex pheromone has been determined by spectral analysis to be 6,12-dimethylpentadecane-2-one. Field trapping experiments have confirmed that the female cucumber beetle's sex pheromone is (6R,12R)-6,12-dimethylpentadecane-2-one (as shown in formula (1)). The absolute configuration of this compound is R-configuration at the C-6 and C-12 positions, which is crucial to its biological activity. The other three stereoisomers have no attraction effect on males.

[0004] In existing technologies, various strategies have been employed for the synthesis of (6R,12R)-6,12-dimethylpentadecan-2-one. In 1987, Chuman et al. used methylcycloacetone as a starting material and constructed a carbon-carbon skeleton via Grignard reagent coupling, hydrogenation, and Wittig coupling, synthesizing the racemic form of the cucumber beetle sex pheromone in an overall yield of 3.9%. This route determined the molecular structure of the cucumber beetle sex pheromone, providing a foundation for further determination of the absolute configuration of the molecule. In 1988, Mori et al. used (R)- and (S)-citronellol as chiral sources, obtaining four chiral modules, respectively. These were then used to construct a carbon-carbon skeleton via alkylation coupling with phenyl sulfone, preparing four isomers of the cucumber beetle sex pheromone in an overall yield of 38%. In 1995, Enders et al. used (4S,2E)-4-benzyloxyphenyl 2-butenyl sulfone as a starting material, obtained a tetracarbonyl iron complex via metallization, and then synthesized two chiral methyl modules from the tetracarbonyl iron complex. Following alkylation coupling, a C-C bond skeleton was constructed. This method achieved high enantiomeric purity (ee > 99%) and a good overall yield (13 steps, 39%). In 2002, Chow et al. reported the preparation of (R)-configuration cucumber beetle sex pheromones from 1,8-nonadiene as a starting material, via m-CPBA oxidation, hydrolysis kinetic resolution (HKR), Grignard coupling, and Me2CuLi reagent methylation to construct chiral centers, with an overall yield of only 0.43%. In 2024, Wu et al. used n-valeryl chloride as a starting material, and through Evans asymmetric alkylation and S-methylation of sec-toluenesulfonate... N 2. Alkylation to construct the chiral center. Another intermediate was obtained by ring-opening, decarboxylation, and toluenesulfonation of the chiral source (R)-2-methylethylene oxide. Finally, the two chiral intermediates were coupled and oxidized with Grignard reagent under LiCuCl4 catalysis to yield the (R)-configuration cucumber beetle sex pheromone.

[0005] Equation (1). Summary of the Invention

[0006] To address the shortcomings of existing technologies, such as cumbersome procedures and low yield, this invention provides a novel, efficient, and simple method for synthesizing the cucumber beetle sex pheromone (6R,12R)-6,12-dimethylpentadecan-2-one.

[0007] The purpose of this invention is to provide a method for synthesizing the sex pheromone of the cucumber beetle, comprising the following steps:

[0008] S1: Compound (R)-3, n-BuLi, and compound 2 were reacted in an inert gas at low temperature, then naturally heated and stirred overnight to obtain compound 4;

[0009] S2: Compound 4, THF, NaHMDS and MeI were added sequentially, and the reaction was carried out under inert gas protection at low temperature to obtain compound (R)-5;

[0010] S3: Add LiAlH4, diethyl ether, and a diethyl ether solution of compound (R)-5, stir the reaction to obtain compound (R)-6;

[0011] S4: Compound (R)-6, Ph3P, BT-SH and THF were added sequentially under inert gas protection, and DIAD was added dropwise under an ice-water bath to give compound (R)-7.

[0012] S5: Compound (R)-7, CH2Cl2 and m-CPBA were added sequentially under inert gas protection to obtain compound (R)-8;

[0013] S6: Compound 9, THF, TEA, PivCl, compound (R)-3 and LiCl were added sequentially under inert gas protection and reacted at low temperature to obtain compound 10;

[0014] S7: Compound 10, THF, NaHMDS and MeI were added sequentially, and the reaction was carried out under inert gas protection at low temperature to obtain compound (R)-11;

[0015] S8: Add LiAlH4, diethyl ether, and a diethyl ether solution of compound (R)-11, stir the reaction to obtain compound (R)-12;

[0016] S9: Add compound (R)-12, CH2Cl2, imidazole, and TBSCl, and under inert gas protection, to obtain compound (R)-13; S10: Add compound (R)-13, anhydrous MeOH, and 20% Pt(OH)2 / C sequentially to obtain compound (R)-14.

[0017] S11: Compound (R)-14, CH2Cl2, 4A molecular sieve and PCC were added sequentially to obtain compound (R)-15;

[0018] S12: Compound (R)-8, THF, NaHMDS, and compound (R)-15 were added sequentially under inert gas protection to obtain compound 16;

[0019] S13: Compound 16, anhydrous ethanol and 10% Pt / C were added sequentially to obtain compound 17;

[0020] S14: Compound 17, Ph3P, BT-SH and THF were added sequentially under inert gas protection to obtain compound 18;

[0021] S15: Compound 18, dry CH2Cl2 and m-CPBA were added sequentially under inert gas protection to obtain compound 19;

[0022] S16: Compound 19, THF, NaHMDS, and Compound 20 were added sequentially under inert gas protection to obtain Compound 21;

[0023] S17: Compound 21, anhydrous ethanol and 10% Pt / C were added sequentially to obtain compound 22;

[0024] S18: Compound 22, TBAF and THF were added sequentially under inert gas protection to obtain compound 23;

[0025] S19: Compound 23, CH2Cl2, silica gel and PCC were added sequentially under inert gas protection and reacted at room temperature to give compound 24;

[0026] S20: Compound 24, THF, and MeMgCl were added sequentially under inert gas protection to obtain compound 25;

[0027] S21: Compound 25, CH2Cl2, silica gel and PCC were added sequentially under inert gas protection to obtain compound (6R,12R)-1;

[0028] The structural formula of the compound is as follows:

[0029] , , , , , , , , , , , , , , , , , , , , , , , , .

[0030] Preferably, the molar ratio of compound (R)-3, n-BuLi, and compound 2 in step S1 is 1:1.2:1.5; the molar ratio of compound 4 to NaHMDS and MeI in step S2 is 1:2:5; the molar ratio of compound (R)-5 to LiAlH4 in step S3 is 1:1.5; the molar ratio of compound (R)-6, Ph3P, BT-SH, and DIAD in step S4 is 1:1.2:1.2:1.2; the molar ratio of compound (R)-7 and m-CPBA in step S5 is 1:5; the molar ratio of compound 9, TEA, PivCl, compound (R)-3, and LiCl in step S6 is 1:2:1.2:1:3; and the molar ratio of compound 10 to NaHMDS and MeI in step S7 is 1:2:1:3. 5. In step S8, the molar ratio of compound (R)-11 to LiAlH4 is 1:1.5; in step S9, the molar ratio of compound (R)-12, imidazole, and TBSCl is 1:2:1.5; in step S10, the molar ratio of compound (R)-13 to 20% Pt(OH)2 / C is 1:0.08; in step S11, the molar ratio of compound (R)-14, 4A molecular sieve, and PCC is 1:1.5:1.5; in step S12, the molar ratio of compound (R)-8 to NaHMDS and compound (R)-15 is 1:1:0.7; in step S13, the molar ratio of compound 16 to 10% Pt(OH)2 / C is... The molar ratio of Pt / C is 1:0.08. The molar ratio of compound 17, Ph3P and BT-SH in step S14 is 1:1.2:1.2:1.2. The molar ratio of compound 18 and m-CPBA in step S15 is 1:5. The molar ratio of compound 19, NaHMDS and compound 20 in step S16 is 1:1:0.7. The molar ratio of compound 21 and 10% Pt / C in step S17 is 1:0.08. The molar ratio of compound 22 and TBAF in step S18 is 1:2. The molar ratio of compound 23 and PCC in step S19 is 1:1.5. The molar ratio of compound 24 and MeMgCl in step S20 is 1:2. The molar ratio of compound 25 and PCC in step S21 is 1:1.5.

[0031] Preferably, the inert gas is argon.

[0032] The preferred synthetic route is as follows:

[0033]

[0034]

[0035]

[0036] .

[0037] Preferably, the synthesis method is as follows:

[0038] S1: Take a single-necked round-bottom flask, add compound (R)-3, Ar protection, then add dry THF, and slowly add n-BuLi dropwise with a syringe at -78 ℃. After stirring for 30 min, add compound 2 dropwise. After the addition is complete, react at -78 ℃ for about 30 min, then turn off the refrigeration, allow the temperature to rise naturally, and stir overnight to obtain compound 4.

[0039] S2: Take a single-necked round-bottom flask, add compound 4 and dry THF in sequence, and protect with Ar; after cooling at -78 ℃ for 15 min, slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min and then add MeI dropwise; after reacting for 2.0 h, adjust the temperature to -50 ℃ and stir overnight to obtain compound (R)-5.

[0040] S3: Take a single-necked round-bottom flask, add LiAlH4 and dry diethyl ether, place it in an ice-water bath at 0 ℃ and stir, with Ar protection; then inject the diethyl ether solution of compound (R)-5 with a syringe, heat naturally, and stir at room temperature for 12 h to obtain compound (R)-6.

[0041] S4: Take a single-necked round-bottom flask, add compound (R)-6, Ph3P, BT-SH and dry THF in sequence, and protect with Ar; add DIAD dropwise under an ice-water bath, heat naturally, and react for 12 h to obtain compound (R)-7.

[0042] S5: Take a single-necked round-bottom flask, add compound (R)-7, dry CH2Cl2 and m-CPBA in sequence, and protect with Ar; stir at room temperature for 12 h to obtain compound (R)-8;

[0043] S6: Take a single-necked round-bottom flask, add compound 9 and dry THF, Ar protection, and cool at -78 ℃ for 15 min; then add TEA and PivCl, stir at -78 ℃ for 20 min, then move to room temperature and react for 1 h; after cooling at -78 ℃ for 15 min, add (R)-3 and LiCl, react at -78 ℃ for 1 h, then turn off the refrigeration, let it heat up naturally, stir overnight to obtain compound 10;

[0044] S7: Take a single-necked round-bottom flask, add compound 10 and dry THF in sequence, and protect with Ar; after cooling at -78 ℃ for 15 min, slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min and then add MeI dropwise; after reacting for 2.0 h, adjust the temperature to -50 ℃ and stir overnight to obtain compound (R)-11;

[0045] S8: Take a single-necked round-bottom flask, add LiAlH4 and dry diethyl ether, place it in a 0 ℃ ice-water bath and stir, with Ar protection; then inject the diethyl ether solution of compound (R)-11 with a syringe, heat naturally, and stir at room temperature for 12 h to obtain compound (R)-12.

[0046] S9: Take a single-necked round-bottom flask, add compound (R)-12, protect with Ar, and inject CH2Cl2 with a syringe; add imidazole at 0 ℃, stir for 15 min, then add TBSCl, and naturally raise the temperature from 0 ℃ and react for 12 h to obtain compound (R)-13.

[0047] S10: Take a single-necked round-bottom flask, add compound (R)-13, anhydrous MeOH, and 20% Pt(OH)2 / C in sequence, evacuate the H2 bag with a vacuum pump, then fill it with H2, connect it to the round-bottom flask, change the air 5 times with a vacuum pump to remove all the air, stir in an oil bath at 55 ℃ for 24 h to obtain compound (R)-14;

[0048] S11: Take a single-necked round-bottom flask, add compound (R)-14, dry CH2Cl2, 4A molecular sieve and PCC in sequence, and react at room temperature for 12 h to obtain compound (R)-15;

[0049] S12: Take a single-necked round-bottom flask, add compound (R)-8 and dry THF in sequence, and protect with Ar; cool at -78 ℃ for 15 min and slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min and then add a THF solution of compound (R)-15 dropwise; after reacting for 3.0 h, turn off the refrigeration, let it heat up naturally, and stir overnight to obtain compound 16;

[0050] S13: Take a single-necked round-bottom flask, add compound 16, anhydrous ethanol and 10% Pt / C in sequence, then connect a hydrogen bag, replace the air-hydrogen gas five times with a water pump, stir in an oil bath at 55 ℃ for 24 h to obtain compound 17.

[0051] S14: Take a single-necked round-bottom flask, add compound 17, Ph3P, BT-SH and dry THF in sequence, and protect with Ar; add DIAD dropwise under an ice-water bath, heat naturally, and react for 12 h to obtain compound 18;

[0052] S15: Take a single-necked round-bottom flask, add compound 18, dry CH2Cl2 and m-CPBA in sequence, under argon protection; stir at room temperature for 12.0 h to obtain compound 19;

[0053] S16: Take a single-necked round-bottom flask, add compound 19 and dry THF in sequence, and protect with Ar; after cooling at -78 ℃ for 15 min, slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min and then add a THF solution of compound 20 dropwise; after reacting for 3.0 h, turn off the refrigeration, allow the temperature to rise naturally, and stir overnight to obtain compound 21;

[0054] S17: Take a single-necked round-bottom flask, add compound 21, anhydrous ethanol and 10% Pt / C in sequence, then connect a hydrogen bag, replace the air-hydrogen gas five times with a water pump, stir in an oil bath at 55 ℃ for 24 h to obtain compound 22.

[0055] S18: Take a single-necked round-bottom flask, add compound 22, TBAF and THF in sequence, protect with Ar, stir at room temperature for 3 h to obtain compound 23;

[0056] S19: Take a single-necked round-bottom flask, add compound 23, CH2Cl2, silica gel and PCC in sequence, protect with Ar, and react at room temperature for 12 h to obtain compound 24;

[0057] S20: Take a single-necked round-bottom flask, add compound 24, protect with Ar, inject dry THF with a syringe, and add MeMgCl dropwise at 0 °C; after naturally raising the temperature from 0 °C, react at room temperature for 30 min to obtain compound 25;

[0058] S21: Take a single-necked round-bottom flask, add compound 25, CH2Cl2, silica gel and PCC in sequence, Ar protection, react at room temperature for 12 h to obtain compound (6R,12R)-1.

[0059] The beneficial effects of this invention are:

[0060] (1) This invention uses compound (R)-3 and n-valeryl chloride as raw materials, and introduces chiral methyl groups by Evans template chiral induction through oxazolinone. Compared with the general method, the reaction yield is greatly improved and no by-products are generated. The yield is as high as 100%.

[0061] (2) In this invention, compounds (R)-5 and (R)-11 were prepared by chiral asymmetric synthesis reaction of compound 4 and compound 10 respectively via iodomethane and NaHMDS. The reaction conditions were optimized, the reaction byproducts were reduced, and the reaction yield was greatly improved from 58% to 91%.

[0062] (3) In this invention, (R)-2-methylpentan-1-ol (R)-6 and BT-SH are used as raw materials to prepare sulfide compound (R)-7 by Mitsunobu reaction with a reaction yield of 97%. Then, compound (R)-7 undergoes oxidation reaction with m-CPBA to prepare sulfone compound (R)-8 with a reaction yield of 95%. The total yield of the two-step reaction is 92%.

[0063] (4) In this invention, compound 16 was prepared by Julia-Kocienski olefin coupling reaction using compound (R)-8 and compound (R)-15 as raw materials. The reaction conditions were optimized and the reaction yield was greatly improved from 60% to 86%.

[0064] (5) Compound 16 of the present invention can be directly converted into compound 17 in one step by catalytic hydrogenation with 10% Pt / C, avoiding the step of first catalytic hydrogenation and then removing the TBS protecting group with TBAF, simplifying the experimental route, and the yield is 91%.

[0065] (6) Compared with the general synthesis route, the raw materials of this invention are inexpensive and readily available, reducing the cost of synthesis, and the overall reaction yield is 15%. Moreover, the yield of most reactions is above 85%, and the synthesis method is relatively simple. Detailed Implementation

[0066] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below in conjunction with specific embodiments.

[0067] The technical solution of the present invention is as follows:

[0068] A method for synthesizing a cucumber beetle sex pheromone, the synthetic route is as follows:

[0069]

[0070]

[0071]

[0072] .

[0073] S1: Take a single-necked round-bottom flask, add compound (R)-3 [(R)-4-benzyl-2-oxazolidinone], Ar protection, then add dry THF, and slowly add n-BuLi dropwise with a syringe at -78 ℃. After stirring for 30 min, add compound 2 [n-valeryl chloride] dropwise. After the addition is complete, react at -78 ℃ for about 30 min, then turn off the refrigeration, let it rise naturally, and stir overnight to obtain compound 4 [(R)-4-benzyl-3-valeryloxyazolidinone-2-one];

[0074] S2: Take a single-necked round-bottom flask, add compound 4 [(R)-4-benzyl-3-pentanoyloxyazolidin-2-one] and dry THF in sequence, and protect with Ar; after cooling at -78 ℃ for 15 min, slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min and then add MeI dropwise; after reacting for 2.0 h, adjust the temperature to -50 ℃ and stir overnight to obtain compound (R)-5 [(R)-4-benzyl-3-((R)-2-methylpentanoyl)oxazolidin-2-one];

[0075] S3: Take a single-necked round-bottom flask, add LiAlH4 and dry diethyl ether, place it in an ice-water bath at 0 ℃ and stir, with Ar protection; then inject the diethyl ether solution of compound (R)-5 [(R)-4-benzyl-3-((R)-2-methylpentanoyl)oxazolidine-2-one] with a syringe, heat naturally, and stir at room temperature for 12 h to obtain compound (R)-6 [(R)-2-methylpentan-1-ol];

[0076] S4: Take a single-necked round-bottom flask and add compound (R)-6 [(R)-2-methylpentan-1-ol], Ph3P, BT-SH and dry THF in sequence, and protect with Ar; add DIAD dropwise under ice-water bath, heat naturally, and react for 12 h to obtain compound (R)-7 [(R)-2-((2-methylpentyl)thio)benzo[d]thiazole];

[0077] S5: Take a single-necked round-bottom flask and add compound (R)-7 [(R)-2-((2-methylpentyl)thio)benzo[d]thiazole], dry CH2Cl2 and m-CPBA in sequence, and protect with Ar; stir at room temperature for 12.0 h to obtain compound (R)-8 [(R)-2-((2-methylpentyl)sulfonyl)benzo[d]thiazole];

[0078] S6: Take a single-necked round-bottom flask, add compound 9 [6-benzyloxyhexanoic acid] and dry THF, Ar protection, and cool at -78℃ for 15 min; then add TEA and PivCl, stir at -78℃ for 20 min, and then move to room temperature to react for 1 h; after cooling at -78℃ for 15 min, add (R)-3 [(R)-4-benzyl-2-oxazolidinone] and LiCl, react at -78℃ for 1 h, then turn off the refrigeration, naturally heat up, and stir overnight to obtain compound 10 [(R)-4-benzyl-3-(6-(benzyloxy)hexanoyl)oxazolidinone-2-one];

[0079] S7: Take a single-necked round-bottom flask, add compound 10 [(R)-4-benzyl-3-(6-(benzyloxy)hexanoyl)oxazolidin-2-one] and dry THF in sequence, and protect with Ar; after cooling at -78 ℃ for 15 min, slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min and then add MeI dropwise; after reacting for 2.0 h, adjust the temperature to -50 ℃ and stir overnight to obtain compound (R)-11 [(R)-4-benzyl-3-((R)-2-methyl-6-benzyloxyhexanoyl)oxazolidin-2-one];

[0080] S8: Take a single-necked round-bottom flask, add LiAlH4 and dry diethyl ether, place it in an ice-water bath at 0 ℃ and stir, with Ar protection; then inject the diethyl ether solution of compound (R)-11 with a syringe, heat naturally, and stir at room temperature for 12 h to obtain compound (R)-12 [(R)-2-methyl-6-benzyloxy-hex-1-ol];

[0081] S9: Take a single-necked round-bottom flask, add compound (R)-12, protect with Ar, and inject CH2Cl2 with a syringe; add imidazole at 0 ℃, stir for 15 min, then add TBSCl, and naturally raise the temperature from 0 ℃ and react for 12 h to obtain compound (R)-13 [(R)-((6-(benzyloxy)-2-methylhexyl)oxy)(tert-butyl)dimethylsilane];

[0082] S10: Take a single-necked round-bottom flask and add compound (R)-13 [(R)-((6-(benzyloxy)-2-methylhexyl)oxy)(tert-butyl)dimethylsilane], anhydrous MeOH, and 20% Pt(OH)2 / C in sequence. Evacuate the H2 bag with a vacuum pump, then fill it with H2, connect it to the round-bottom flask, and purge the air 5 times with a vacuum pump to remove all the air. Stir in an oil bath at 55 °C for 24.0 h to obtain compound (R)-14 [(R)-6-((tert-butyldimethylsilyl)oxy)-5-methylhex-1-ol];

[0083] S11: Take a single-necked round-bottom flask and add compound (R)-14 [(R)-6-((tert-butyldimethylsilyl)oxy)-5-methylhexan-1-ol], dry CH2Cl2, 4A molecular sieve and PCC in sequence. React at room temperature for 12 h to obtain compound (R)-15 [(R)-6-((tert-butyldimethylsilyl)oxy)-5-methylhexanal];

[0084] S12: Take a single-necked round-bottom flask and add compound (R)-8 [(R)-2-((2-methylpentyl)sulfonyl)benzo[d]thiazole] and dry THF in sequence, with Ar protection; after cooling at -78 ℃ for 15 min, slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min and then add a THF solution of compound (R)-15 [(R)-6-((tert-butyldimethylsilyl)oxy)-5-methylhexanal] dropwise; after reacting for 3.0 h, turn off the refrigeration, allow the temperature to rise naturally, and stir overnight to obtain compound 16 [tert-butyl((2R,8R)-2,8-dimethylundec-6-en-1-yl)oxy)dimethylsilane].

[0085] S13: Take a single-necked round-bottom flask, add compound 16 [tert-butyl((2R,8R)-2,8-dimethylundec-6-en-1-yl)oxy)dimethylsilane], anhydrous ethanol and 10% Pt / C in sequence, then connect a hydrogen bag, replace the air-hydrogen gas five times with a water pump, stir in an oil bath at 55 ℃ for 24 h to obtain compound 17 [(2R,8R)-2,8-dimethylundec-1-ol];

[0086] S14: Take a single-necked round-bottom flask and add compound 17 [(2R,8R)-2,8-dimethylundecyl-1-ol], Ph3P, BT-SH and dry THF in sequence, and protect with Ar; add DIAD dropwise under an ice-water bath, raise the temperature naturally, and react for 12 h to obtain compound 18 [2-(((2R,8R)-2,8-dimethylundecyl)thio)benzo[d]thiazole].

[0087] S15: Take a single-necked round-bottom flask, add compound 18, dry CH2Cl2 and m-CPBA in sequence, and protect with argon gas; stir at room temperature for 12.0 h to obtain compound 19 [2-(((2R,8R)-2,8-dimethylundecyl)sulfonyl)benzothiazole];

[0088] S16: Take a single-necked round-bottom flask, add compound 19 and dry THF in sequence, and protect with Ar; cool at -78 ℃ for 15 min and slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min and then add a THF solution of compound 20 dropwise; after reacting for 3.0 h, turn off the refrigeration, let it heat up naturally, and stir overnight to obtain compound 21 [((5R,11R)-5,11-dimethyl-3-en-tetradecyloxy)dimethyltert-butylsilane];

[0089] S17: Take a single-necked round-bottom flask, add compound 21, anhydrous ethanol and 10% Pt / C in sequence, then connect a hydrogen bag, replace the air-hydrogen gas five times with a water pump, stir in an oil bath at 55 ℃ for 24 h to obtain compound 22 [((5R,11R)-5,11-dimethyl-tetradecyloxy)dimethyltert-butylsilane;

[0090] S18: Take a single-necked round-bottom flask, add compound 22, TBAF and THF in sequence, protect with Ar, stir at room temperature for 3 h to obtain compound 23 [(5R,11R)-5,11-dimethyltetradecane-1-ol];

[0091] S19: Take a single-necked round-bottom flask and add compound 23 [(5R,11R)-5,11-dimethyltetradecane-1-ol], CH2Cl2, silica gel and PCC in sequence. Protect with Ar and react at room temperature for 12 h to obtain compound 24 [(5R,11R)-5,11-dimethyltetradecanealdehyde].

[0092] S20: Take a single-necked round-bottom flask, add compound 24 [(5R,11R)-5,11-dimethyltetradecanoal], Ar protection, inject dry THF with a syringe, and add MeMgCl dropwise at 0 ℃; after naturally raising the temperature from 0 ℃, react at room temperature for 30 min to obtain compound 25 [(6R,12R)-6,12-dimethylpentadecan-2-ol];

[0093] S21: Take a single-necked round-bottom flask and add compound 25 [(6R,12R)-6,12-dimethylpentadecan-2-ol], CH2Cl2, silica gel and PCC in sequence. Protect with Ar and react at room temperature for 12 h to obtain compound (6R,12R)-1.

[0094] Example 1: Synthesis of Compound 4

[0095]

[0096] Take a 500 mL single-necked round-bottom flask, add compound (R)-3 (10.00 g, 56.43 mmol, 1.0 eq) and ultra-dry THF (200 mL) solution, Ar protection, and stir and cool at -78 °C for 15 min. Add n-BuLi (27.09 mL, 67.72 mmol, 1.2 eq) dropwise, and react at -78 °C for 30 min after the addition is complete. Then add compound 2 (9.95 mL, 84.65 mmol, 1.5 eq) dropwise, and react at -78 °C for 30 min after the addition is complete. Turn off the refrigeration and allow the temperature to rise naturally, stirring overnight until the reaction is complete. Post-reaction treatment: Quench the reaction with saturated NH4Cl solution, extract three times with EA, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and column chromatography to obtain 14.747 g of a pale yellow oil, 100% yield. 1 H NMR (600 MHz, CDCl3) δ 7.33 (t, J =7.4 Hz, 2H), δ 7.28 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.4 Hz, 2H), 4.69-4.66(m, 1H), 4.20-4.15 (m, 2H), 3.30 (dd, J = 3.1, 13.4 Hz, 1H), 3.01-2.87 (m,2H), 2.78 (dd, J = 9.6, 13.4 Hz, 1H), 1.73-1.66 (m, 2H), 1.45-1.39 (m, 2H),0.96 (t, J = 7.4 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 173.38, 153.46, 135.36,129.42, 128.91, 127.29, 66.14, 55.10, 37.87, 35.23, 26.34, 22.25, 13.86.

[0097] Example 2 Synthesis of compound (R)-5

[0098]

[0099] Take a 500 mL single-necked round-bottom flask, add compound 4 (14.75 g, 56.43 mmol, 1.0 eq) and dry THF (190 mL), protect with Ar, and cool at -78 °C for 15 min. Slowly add NaHMDS (56.43 mL, 112.87 mmol, 2.0 eq). After the addition is complete, stir at -78 °C for 30 min, then add MeI (17.57 mL, 282.17 mmol, 5.0 eq), and react at -78 °C for 2.0 h. Adjust the temperature to -50 °C and stir overnight. Post-reaction treatment: Quench the reaction with saturated NH4Cl solution, extract three times with EA, dry and concentrate with anhydrous sodium sulfate, and column chromatography to obtain 14.01 g of yellow oil, yield 90%. [α] 20 D = -50.43 (c = 0.84, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 7.33 (t, J = 7.3 Hz, 2H),7.27 (dd, J = 7.3, 10.6 Hz, 1H), 7.22 (d, J = 7.4 Hz, 2H), 4.69-4.65 (m, 1H),4.21-4.15 (m, 2H), 3.75-3.70 (m, 1H), 3.28-3.25 (m, 1H), 2.77 (dd, J = 9.6,13.3 Hz, 1H), 1.76-1.70 (m, 1H), 1.43-1.36 (m, 2H), 1.34-1.24 (m, 2H), 1.23(d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ177.45, 153.17, 135.47, 129.56, 129.02, 127.42, 66.10, 55.46, 38.01, 37.55,35.67, 20.51, 17.40, 14.18.

[0100] Example 3 Synthesis of compound (R)-6

[0101]

[0102] A 500 mL single-necked round-bottom flask was filled with LiAlH4 (2.44 g, 64.31 mmol, 1.5 eq) and anhydrous diethyl ether (100 mL) under Ar protection. After cooling at 0 °C for 10 min, a solution of compound (R)-5 (11.81 g, 42.87 mmol, 1.0 eq) in anhydrous diethyl ether (50 mL) was added dropwise. The reaction was monitored by TLC after 2.0 h, and the reaction was complete. Post-reaction treatment: The reaction was quenched with 1 mol / L HCl solution, followed by the addition of saturated sodium bicarbonate solution and washing with sodium chloride solution. The mixture was extracted three times with Et2O, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 20 °C, and column chromatography yielded 4.3 g of a pale yellow liquid, with a yield of 97%. [α] 20 D =+2.49 (c = 1.32, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 3.48 (dd, J = 5.9, 10.4 Hz,1H), 3.38 (t, J = 6.8, 1H), 1.76 (s, 1H), 1.62-1.59 (m, 1H), 1.38-1.35 (m,2H), 1.30-1.23 (m, 1H), 1.09-1.04 (m, 1H), 0.88 (t, J = 7.0 Hz, 6H); 13 C NMR (150 MHz, CDCl3) δ 68.45, 35.58, 35.51, 20.17, 16.64, 14.44.

[0103] Example 4 Synthesis of compound (R)-7

[0104]

[0105] A 250 mL single-necked round-bottom flask was filled with compound (R)-6 (5.20 g, 50.89 mmol, 1.0 eq), BT-SH (10.42 g, 61.06 mmol, 1.2 eq), PPh3 (16.34 g, 61.06 mmol, 1.2 eq), and dry THF (170 mL) under Ar protection. DIAD (12.11 mL, 61.06 mmol, 1.2 eq) was added dropwise under an ice-water bath, and the mixture was allowed to rise naturally from 0 °C for 12 h. Post-reaction treatment: The solvent was removed by direct vacuum distillation, and column chromatography yielded 12.40 g of a pale yellow oily compound, 97% yield. [α] 25 D= +0.58 (c = 0.10, CHCl3). 1 H NMR (600 MHz, CDCl3) δ7.85 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 8.3 Hz, 1H), 7.29-7.25 (m, 1H), 3.42-3.39 (m, 1H), 3.20-3.17 (m, 1H), 1.95-1.93 (m, 1H), 1.52-1.40 (m, 2H), 1.37-1.26 (m, 2H), 1.07 (d, J = 6.7 Hz, 3H), 0.92 (t, J =7.3 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 167.87, 153.48, 135.27, 126.09,124.18, 121.54, 121.00, 40.86, 38.49, 33.12, 20.18, 19.46, 14.32.

[0106] Example 5 Synthesis of compound (R)-8

[0107]

[0108] A 100 mL single-necked round-bottom flask was used to add compound (R)-7 (0.38 g, 1.51 mmol, 1.0 eq) and 10 mL of dry CH₂Cl₂, along with m-CPBA (1.54 g, 7.56 mmol, 5.0 eq). The mixture was stirred at room temperature for 12 h. Post-reaction treatment: Sodium thiosulfate was added to remove m-CPBA, and saturated NaHCO₃ solution was used to remove acid. The mixture was extracted three times with CH₂Cl₂, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 0.41 g of a pale yellow oil, with a yield of 95%. [α] 25 D = +1.71 (c = 0.38, CHCl3). 1H NMR (600 MHz, CDCl3) δ 8.20 (d, J =9.5 Hz, 1H), 8.00 (d, J = 9.4 Hz, 1H), 7.62-7.57 (m, 2H), 3.56-3.52 (m, 1H), 3.36-3.32 (m, 1H), 2.31-2.27 (m, 1H), 1.47-1.45 (m, 1H), 1.32-1.29 (m, 3H), 1.13 (d, J = 8.0 Hz, 3H), 0.84 (t, J = 8.3 Hz, 3H); 13 C HRMS (ESI) m / z calculated for C 13 H 17 NNaO2S2 + (M+Na) + 306.0593, found 306.0600.

[0109] Example 6 Synthesis of Compound 10

[0110]

[0111] Take a 100 mL single-necked round-bottom flask, add compound 9 (0.79 g, 3.53 mmol, 1.0 eq), Ar protection, add dry THF (15 mL) using a syringe, and cool at -78 °C for 15 min. Then add TEA (0.98 mL, 7.06 mmol, 2.0 eq) and PivCl (0.52 mL, 4.24 mmol, 1.2 eq), and stir at -78 °C for 20 min after the addition is complete. After reacting at room temperature for 1 h, place in a low-temperature reaction bath and cool at -78 °C for 15 min. Add (R)-4-benzyl-2-oxazolinone (R)-3 (0.63 g, 3.53 mmol, 1.0 eq) and LiCl (0.45 g, 10.59 mmol, 3.0 eq), react at -78 °C for 1 h, then turn off the refrigeration, allow to rise naturally overnight. Post-reaction treatment: The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain 1.27 g of a pale yellow oil, with a yield of 94%. 1H NMR (600 MHz, CDCl3) δ 7.33(s, 6H), 7.26 (d, J = 6.2 Hz, 2H), 7.20 (s, 2H), 4.66 (s, 1H), 4.50 (s, 2H), 4.18 (d, J = 8.8 Hz, 2H), 3.48 (d, J = 4.9 Hz, 2H), 2.95 (dt, J = 5.8, 30.2Hz, 2H), 2.75 (t, J = 6.4 Hz, 1H), 1.71 (s, 2H), 1.68 (d, J = 5.5 Hz, 2H), 1.57 (s, 1H), 1.48 (d, J = 5.7 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 173.40,153.59, 138.79, 135.47, 129.56, 129.10, 128.50, 127.76, 127.63, 127.49,73.06, 70.31, 66.32, 55.30, 38.10, 35.62, 29.68, 25.91, 24.24.

[0112] Example 7 Synthesis of compound (R)-11

[0113]

[0114] Take a 500 mL single-necked round-bottom flask, add compound 10 (10.42 g, 27.30 mmol, 1.0 eq), Ar protection, add dry THF (100 mL), cool at -78 °C for 15 min, add NaHMDS (27.30 mL, 54.60 mmol, 2.0 M in THF, 2.0 eq) dropwise, stir at -78 °C for 30 min after the addition is complete. Add MeI (8.50 mL, 136.51 mmol, 5.0 eq) dropwise, react at -78 °C for 2 h, then adjust the temperature to -50 °C overnight. Post-reaction treatment: Quench the reaction by adding saturated NH4Cl solution to the reaction system at -50 °C, extract three times with EA, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and column chromatography to obtain 9.77 g of a pale yellow oil, yield 91%. [α] 25 D = -3.31 (c = 0.24, CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.32 (t, J = 4.4 Hz, 6H), 7.27-7.24 (m, 2H), 7.20 (d, J = 7.3 Hz, 2H), 4.66-4.61 (m, 1H), 4.48 (s, 2H), 4.16-4.12 (m, 2H), 3.73-3.69 (m, 1H), 3.47-3.44 (m, 2H), 3.26 (dd, J = 3.1, 13.4 Hz, 1H), 2.75(dd, J = 9.5, 13.3 Hz, 1H), 1.79-1.73 (m, 1H), 1.65-1.59 (m, 2H), 1.47-1.35(m, 3H), 1.22-1.21 (d, J = 6.8 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 177.27,153.15, 138.74, 135.44, 129.55, 129.02, 128.44, 127.72, 127.58, 127.43,72.96, 70.24, 66.10, 55.44, 38.00, 37.77, 33.29, 29.82, 24.02, 17.49. HRMS(ESI) m / z calculated for C 24 H 29 NNaO4 + (M+Na) + : 418.1989, found 418.1997.

[0115] Example 8 Synthesis of compound (R)-12

[0116]

[0117] Take a 100 mL two-necked round-bottom flask and add LiAlH4 (0.42 g, 11.02 mmol, 4.0 eq). Protect with Ar and inject dry THF (15 mL) under an ice-water bath. Take another single-necked round-bottom flask and add (R)-11 (1.10 g, 2.76 mmol, 1.0 eq). Protect with Ar and inject dry THF (5 mL). Slowly add this mixture dropwise to the reaction system, then allow it to heat naturally from 0 °C and stir overnight. Post-reaction processing: Under an ice-water bath, add water (1:2:3 ratio), 10% NaOH solution, and quench the reaction with water sequentially. Filter the solid using a sintered glass funnel, wash with EA, dry with anhydrous sodium sulfate, filter, concentrate, and column chromatography to obtain 0.58 g of a colorless oily substance, yield 95%. [α] 20 D = +5.00 (c = 0.96, CHCl3). 1 HNMR (500 MHz, CDCl3) δ 7.32 (s, 4H), 7.27-7.24 (m, 1H), 3.46 (t, J = 6.5 Hz,3H), 3.39-3.36 (m, 1H), 1.66 (s, 1H), 1.61-1.57 (m, 3H), 1.45-1.32 (m, 3H),1.12-1.07 (m, 1H), 0.90 (d, J = 5.6 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ138.69, 128.45, 127.76, 127.61, 72.98, 70.42, 68.28, 35.81, 33.01, 30.09,23.67, 16.65.

[0118] Example 9 Synthesis of compound (R)-13

[0119]

[0120] A 250 mL single-necked round-bottom flask was filled with compound (R)-12 (9.19 g, 41.33 mmol, 1.0 eq). Under Ar protection, 150 mL of CH2Cl2 was injected using a syringe. Imidazole (5.63 g, 82.66 mmol, 2.0 eq) was added at 0 °C, and the mixture was stirred for 15 min. Then, TBSCl (9.35 g, 62.00 mmol, 1.5 eq) was added, and the mixture was allowed to rise naturally from 0 °C for 12 h. Post-reaction processing: The solvent CH2Cl2 was removed by direct concentration, and column chromatography yielded 13.23 g of a colorless oil, with a yield of 95%. [α] 25 D =+5.64 (c = 0.24, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 7.35 (d, J = 4.4 Hz, 4H),7.29-7.27 (m, 1H), 4.51 (s, 2H), 3.48-3.43 (m, 3H), 3.37-3.34 (m, 1H), 1.64-1.55 (m, 4H), 1.44-1.38 (m, 2H), 1.09-1.02 (m, 1H), 0.90 (s, 9H), 0.87 (d, J= 6.7 Hz, 3H), 0.04 (s, 6H); 13 C NMR (150 MHz, CDCl3) δ 138.85, 128.48,127.77, 127.61, 73.01, 70.60, 68.52, 35.89, 33.16, 30.23, 26.11, 23.77,16.83, -5.20.

[0121] Example 10 Synthesis of compound (R)-14

[0122]

[0123] A 250 mL single-necked round-bottom flask was filled with compound (R)-13 (5.80 g, 17.26 mmol, 1.0 eq), anhydrous methanol (60 mL), and 20% Pd(OH)₂ / C (0.97 g, 1.38 mmol, 0.08 eq). A hydrogen gas bag was connected, and the air-hydrogen mixture was purged five times with a water pump. The mixture was stirred in an oil bath at 55 °C for 24 h until the reaction was complete. Post-reaction treatment: Palladium hydroxide on carbon was removed by filtration, the organic phase was concentrated, and column chromatography yielded 4.25 g of a colorless oil, with a yield of 100%. [α] 25 D= +5.85 (c = 0.20, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 3.64 (t, J = 6.2 Hz, 2H), 3.44-3.35 (m, 2H), 1.57-1.54 (m, 3H), 1.42 (d, J = 7.6 Hz, 3H), 1.34-1.26 (m, 1H), 1.10-1.05 (m,1H), 0.88 (s, 9H), 0.87 (d, J = 6.7 Hz, 3H), 0.03 (s, 6H); 13 C NMR (150 MHz, CDCl3) δ 68.46, 63.13, 35.85, 33.22, 33.05, 26.09, 23.27, 18.49, 16.79, -5.22.

[0124] Example 11 Synthesis of compound (R)-15

[0125]

[0126] A 250 mL single-necked round-bottom flask was used to sequentially add compound (R)-14 (8.94 g, 36.27 mmol, 1.0 eq), CH2Cl2 (150 mL), 4A molecular sieve (11.73 g, 54.40 mmol, 1.5 eq), and PCC (11.73 g, 54.40 mmol, 1.5 eq). The reaction was allowed to proceed for 12 h at room temperature. Post-reaction treatment: Petroleum ether was added to the reaction system to precipitate chromium ions. The mixture was then filtered through a sintered glass funnel lined with diatomaceous earth and silica gel, washed with dichloromethane, and concentrated to obtain 7.56 g of a colorless oil, yielding 85%. [α] 20 D = +4.21 (c = 0.72, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 9.75(t, J = 1.7 Hz, 1H), 3.43-3.37 (m, 2H), 1.73-1.66 (m, 1H), 1.63-1.56 (m, 2H),1.46-1.40 (m, 1H), 1.13-1.07 (m, 1H), 0.88 (s, 10H), 0.86 (s, 2H), 0.02(s,6H); 13C NMR (150 MHz, CDCl3) δ 202.92, 68.19, 44.33, 35.72, 32.85, 26.06,19.76, 18.46, 16.67, -5.25.

[0127] Example 12 Synthesis of Compound 16

[0128]

[0129] Take a 250 mL single-necked round-bottom flask, add compound (R)-8 (5.09 g, 17.95 mmol, 1.0 eq), Ar protection, add dry THF (50 mL), cool at -78 °C for 15 min, add NaHMDS (8.97 mL, 17.95 mmol, 2.0 M in THF, 1.0 eq) dropwise, stir for 30 min, then add a mixture of (R)-15 (3.07 g, 12.56 mmol, 0.7 eq) and dry THF (10 mL), stir at -78 °C for 3 h, then turn off the refrigeration, allow to warm naturally, and stir overnight. Post-reaction treatment: Quench the reaction with saturated NH4Cl solution, extract three times with EA, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 3.39 g of colorless oil, yield 86%. [α] 25 D = +5.00 (c = 0.24, CHCl3). 1 HNMR (600 MHz, CDCl3) δ 5.35-5.23 (m, 1H), 5.11 (t, J = 10.6 Hz, 1H), 3.46-3.43 (m, 1H), 3.36-3.33 (m, 1H), 2.07-1.94 (m, 3H), 1.43-1.35 (m, 2H), 1.31-1.21 (m, 5H), 1.17-1.14 (m, 1H), 1.08-1.02 (m, 1H), 0.93 (dd, J = 6.7, 14.8Hz, 3H), 0.89 (s, 9H), 0.88-0.86 (m, 6H), 0.03 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 136.62, 128.39, 68.51, 40.02, 39.64, 35.84, 33.07, 31.54, 27.95, 27.53, 26.12, 21.54, 20.74, 16.91, 14.40, -5.20.

[0130] Example 13 Synthesis of Compound 17

[0131]

[0132] A 250 mL single-necked round-bottom flask was used to sequentially add compound 16 (0.7 g, 2.24 mmol, 1.0 eq), anhydrous ethanol (10 mL), and 10% Pt / C (0.35 g, 0.18 mmol, 0.08 eq). A hydrogen gas bag was then connected, and the air-hydrogen gas was replaced five times with a water pump. The reaction was stirred at 55 °C in an oil bath for 66 h until complete. Post-reaction processing: The anhydrous ethanol was removed by concentration, and direct column chromatography yielded 0.41 g of a colorless oil, with a yield of 91%. [α] 25 D = +5.30 (c = 0.50, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 3.51-3.49 (m, 1H), 3.42-3.39 (m, 1H), 1.63-1.57 (m, 1H), 1.43 (s,1H), 1.43-1.34 (m, 3H), 1.28-1.22 (m, 9H), 1.12-1.04 (m, 3H), 0.91 (d, J =6.7 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H); 13 C NMR (125MHz, CDCl3) δ 68.56, 39.55, 37.21, 35.92, 33.32, 32.62, 30.45, 27.18, 20.28,19.80, 16.73, 14.54.

[0133] Example 14 Synthesis of Compound 18

[0134]

[0135] Take a 100 mL single-necked round-bottom flask and add compound 17 (2.55 g, 12.74 mmol, 1.0 eq), BT-SH (6.39 g, 38.21 mmol, 3.0 eq), PPh3 (10.02 g, 38.21 mmol, 3.0 eq), and dry THF (25 mL) sequentially. Start stirring in an ice-water bath. After cooling to 0 °C, add DEAD (5.55 mL, 38.21 mol, 3.0 eq) dropwise. Allow the mixture to rise naturally to room temperature and stir overnight. Post-reaction treatment: Directly remove the solvent by rotary evaporation, and column chromatography yields 3.5 g of a pale yellow oil, 79% yield. [α] 20 D = -4.17 (c = 0.44, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.28-7.25 (m, 1H), 3.42-3.38 (m, 1H), 3.20-3.17 (m, 1H), 1.94-1.89 (m, 1H), 1.53-1.48 (m, 1H), 1.37-1.22 (m, 13H), 1.07 (d, J = 6.6 Hz, 5H), 0.87 (t, J =7.1, 7.0 Hz, 3H), 0.83 (t, J = 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 167.91,153.48, 135.27, 126.10, 124.19, 121.54, 121.02, 40.85, 39.54, 37.17, 36.24,33.37, 32.61, 30.24, 27.14, 27.07, 20.28, 19.81, 19.53, 14.57. HRMS (ESI) m / zcalculated for C 20 H 32 NS2 + (M+H) + : 350.1971, found 350.1978.

[0136] Example 15 Synthesis of Compound 19

[0137]

[0138] Take a 100 mL single-necked round-bottom flask and add compound 18 (2.13 g, 6.09 mmol, 1.0 eq) and dry CH2Cl2 (20 mL) sequentially. After the starting materials dissolve, add m-CPBA (5.26 g, 30.45 mmol, 5.0 eq) and stir the reaction at room temperature for 12 h. Post-reaction treatment: Add sodium thiosulfate to the reaction system to remove excess m-CPBA, remove acid with saturated NaHCO3 solution, extract three times with CH2Cl2, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and column chromatography to obtain 2.16 g of colorless oil, yield 93%. [α] 25 D = +4.71 (c = 0.16, CHCl3). 1 H NMR (600 MHz, CDCl3) δ8.22 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 3.57 (d, J = 14.3 Hz,1H), 3.36-3.32 (m, 1H), 1.47-1.42 (m, 1H), 1.33-1.17 (m, 13H), 1.14 (d, J =6.5 Hz, 1H), 1.32-1.19 (m, 10H), 1.14 (d, J = 6.65 Hz, 3H), 1.06-0.99 (m,2H), 0.87 (d, J = 6.95 Hz, 4H), 1.07-0.98 (m, 2H), 0.86 (t, J = 6.7 Hz, 3H), 0.81 (d, J = 6.4 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 166.89, 152.84, 136.87,128.11, 127.77, 125.55, 122.49, 60.88, 39.49, 37.07, 36.79, 32.55, 29.93,28.65, 27.04, 26.47, 20.25, 20.03, 19.76, 14.55.

[0139] Example 16 Synthesis of Compound 21

[0140]

[0141] Take a 50 mL single-necked round-bottom flask, add compound 19 (0.54 g, 1.42 mmol, 1.0 eq), Ar protection, add dry THF (5 mL), cool at -78 °C for 15 min, add NaHMDS (0.85 mL, 1.70 mmol, 2.0 min THF, 1.2 eq), stir for 30 min, then add a mixed solution of compound 20 (0.32 g, 1.70 mmol, 1.2 eq) and dry THF (5 mL), react at -78 °C for 3 h, then adjust the temperature to -50 °C and stir overnight. Post-reaction treatment: quench the reaction with saturated NH4Cl solution, extract three times with EA, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain a pale yellow oil of 379 mg, yield 75%. [α] 25 D = +5.64 (c = 0.28, CHCl3). 1 H NMR (600MHz, CDCl3) δ 5.34-5.18 (m, 2H), 3.61-3.60 (m, 2H), 2.41-2.04 (m, 3H), 1.37-1.07 (m, 15H), 0.95-0.92 (m, 3H), 0.90 (s, 9H), 0.87-0.83 (m, 6H), 0.06 (s,6H); 13 C NMR (150 MHz, CDCl3) δ 138.56, 124.04, 63.42, 39.58, 37.69, 37.30,37.25, 36.49, 32.65, 32.02, 31.58, 30.35, 27.74, 27.23, 26.15, 26.13, 21.53,20.30, 19.82, 14.57, -5.08.

[0142] Example 17 Synthesis of compounds 22 and 23

[0143]

[0144] Take a 250 mL single-necked round-bottom flask, add compound 21 (0.38 g, 1.07 mmol, 1.0 eq), EA (10 mL), and 10% Pt / C (0.17 g, 0.09 mmol, 0.08 eq), then connect a hydrogen bag, and purge the air-hydrogen mixture five times with a water pump. Stir at 35 °C for 24 h. Post-reaction treatment: Remove EA using a rotary evaporator, and proceed directly to the next reaction step.

[0145]

[0146] Take a 25 mL single-necked round-bottom flask, add compound 22 (0.38 g, 1.07 mmol, 1.0 eq), Ar protection, add THF (10 mL) and TBAF (0.67 g, 2.14 mmol, 2.0 eq), and stir at rt for 3 h. Post-reaction treatment: Quench the reaction with water, extract three times with EA, wash with saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, concentrate, and column chromatography to obtain 0.23 g of a colorless oil. The overall yield of the two steps is 88%. [α] 25 D = +5.32 (c = 0.24, CHCl3). 1 H NMR(600 MHz, CDCl3) δ 3.64 (d, J = 5.8 Hz, 2H), 1.55 (s, 2H), 1.38-1.23 (m,18H), 1.12-1.08 (m, 4H), 0.88-0.83 (m, 9H); 13 C NMR (150 MHz, CDCl3) δ 63.28,39.57, 37.25, 37.18, 36.99, 33.32, 32.91, 32.63, 30.51, 27.26, 23.37, 20.29,19.83, 19.80, 14.56.

[0147] Example 18 Synthesis of Compound 24

[0148]

[0149] A 50 mL single-necked round-bottom flask was used to sequentially add compound 23 (0.20 g, 0.84 mmol, 1.0 eq), CH₂Cl₂ (10 mL), silica gel (0.27 g), and PCC (0.27 g, 1.26 mmol, 1.5 eq). The mixture was reacted at room temperature for 12 h. Post-reaction treatment: Petroleum ether was added to the reaction system to precipitate chromium ions. The mixture was then filtered through a sintered glass funnel lined with diatomaceous earth and silica gel, washed with CH₂Cl₂, concentrated, and subjected to column chromatography to obtain 178 mg of a colorless oil, with a yield of 88%. [α] 25 D = +5.20 (c = 0.42, CHCl3). 1H NMR (600 MHz, CDCl3) δ 9.76 (s, 1H), 2.40 (s, 2H), 1.66 (s,1H), 1.59 (s, 1H), 1.27-1.08 (m, 18H), 0.87 (s, 6H), 0.84 (d, J = 4.6 Hz,3H); 13 C NMR (150 MHz, CDCl3) δ 203.07, 44.37, 39.56, 37.23, 37.01, 36.65,32.78, 32.63, 30.47, 27.23, 27.19, 20.28, 19.82, 19.66, 14.55.

[0150] Example 19 Synthesis of Compound 25

[0151]

[0152] A 50 mL single-necked round-bottom flask was used to add compound 24 (0.18 g, 0.74 mmol, 1.0 eq). Ar protection was applied, followed by the addition of 10 mL of dry THF. MeMgCl (0.50 mL, 1.48 mmol, 3.0 M in THF, 2.0 eq) was added dropwise at 0 °C. The mixture was allowed to rise naturally from 0 °C, and the reaction was monitored by TLC after 30 min at room temperature. The reaction was complete. Post-reaction treatment: The reaction was quenched with saturated NH4Cl solution, extracted three times with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain 157 mg of a colorless liquid, yielding 83%. [α] 25 D = +5.26 (c = 0.34, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 3.80 (s, 1H), 1.37 (d, J = 14.3 Hz, 4H), 1.32 (s, 2H), 1.27-1.08 (m,19H), 0.87-0.83 (m, 9H); 13 C NMR (150 MHz, CDCl3) δ 68.35, 39.88, 39.57,37.24, 37.20, 37.18, 32.89, 32.63, 30.51, 27.26, 23.67, 23.63, 23.40, 23.38,20.29, 19.82, 14.56.

[0153] Example 20 Synthesis of compound (6R,12R)-1

[0154]

[0155] A 50 mL single-necked round-bottom flask was used to sequentially add compound 25 (0.16 g, 0.61 mmol, 1.0 eq), CH₂Cl₂ (10 mL), silica gel (0.20 g), and PCC (0.20 g, 0.92 mmol, 1.5 eq). The mixture was reacted at room temperature for 12 h. Post-reaction treatment: Petroleum ether was added to the reaction system to precipitate chromium ions. The mixture was then filtered through a sintered glass funnel lined with diatomaceous earth and silica gel, washed with CH₂Cl₂, concentrated, and column chromatography was performed to obtain 0.13 g of a colorless oily substance, with a yield of 85%. [α] 25 D = +5.24 (c = 0.26, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 3.80 (s, 1H), 1.37 (d, J = 14.3 Hz, 4H), 1.32 (s, 2H), 1.27-1.08 (m, 19H), 0.87-0.83 (m, 9H); 13 C NMR (150 MHz, CDCl3) δ 209.52, 44.29, 39.57, 37.24, 37.05, 36.66, 32.80, 32.63, 30.48, 30.00, 27.25, 27.21, 21.59, 20.29, 19.82, 19.70, 14.56.

[0156] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or basic characteristics. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

[0157] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for synthesizing a sex pheromone from the cucumber beetle, characterized in that, Includes the following steps: S1: Compound (R)-3, n-BuLi, and compound 2 were reacted in an inert gas at low temperature, then naturally heated and stirred overnight to obtain compound 4; S2: Compound 4, THF, NaHMDS and MeI were added sequentially, and the reaction was carried out under inert gas protection at low temperature to obtain compound (R)-5; S3: Add LiAlH4, diethyl ether, and a diethyl ether solution of compound (R)-5, stir the reaction to obtain compound (R)-6; S4: Compound (R)-6, Ph3P, BT-SH and THF were added sequentially under inert gas protection, and DIAD was added dropwise under an ice-water bath to give compound (R)-7. S5: Compound (R)-7, CH2Cl2 and m-CPBA were added sequentially under inert gas protection to obtain compound (R)-8; S6: Compound 9, THF, TEA, PivCl, compound (R)-3 and LiCl were added sequentially under inert gas protection and reacted at low temperature to obtain compound 10; S7: Compound 10, THF, NaHMDS and MeI were added sequentially, and the reaction was carried out under inert gas protection at low temperature to obtain compound (R)-11; S8: Add LiAlH4, diethyl ether, and a diethyl ether solution of compound (R)-11, stir the reaction to obtain compound (R)-12; S9: Add compound (R)-12, CH2Cl2, imidazole, and TBSCl, and under inert gas protection, to obtain compound (R)-13; S10: Add compound (R)-13, anhydrous MeOH, and 20% Pt(OH)2 / C sequentially to obtain compound (R)-14. S11: Compound (R)-14, CH2Cl2, 4A molecular sieve and PCC were added sequentially to obtain compound (R)-15; S12: Compound (R)-8, THF, NaHMDS, and compound (R)-15 were added sequentially under inert gas protection to obtain compound 16; S13: Compound 16, anhydrous ethanol and 10% Pt / C were added sequentially to obtain compound 17; S14: Compound 17, Ph3P, BT-SH and THF were added sequentially under inert gas protection to obtain compound 18; S15: Compound 18, dry CH2Cl2 and m-CPBA were added sequentially under inert gas protection to obtain compound 19; S16: Compound 19, THF, NaHMDS, and Compound 20 were added sequentially under inert gas protection to obtain Compound 21; S17: Compound 21, anhydrous ethanol and 10% Pt / C were added sequentially to obtain compound 22; S18: Compound 22, TBAF and THF were added sequentially under inert gas protection to obtain compound 23; S19: Compound 23, CH2Cl2, silica gel and PCC were added sequentially under inert gas protection and reacted at room temperature to give compound 24; S20: Compound 24, THF, and MeMgCl were added, and under inert gas protection, compound 25 was obtained; S21: Compound 25, CH2Cl2, silica gel and PCC were added sequentially under inert gas protection to obtain compound (6R,12R)-1; The structural formula of the compound is as follows: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The method for synthesizing the sex pheromone of the cucumber beetle as described in claim 1, characterized in that, In step S1, the molar ratio of compound (R)-3, n-BuLi, and compound 2 is 1:1.2:1.5; in step S2, the molar ratio of compound 4 with NaHMDS and MeI is 1:2:5; in step S3, the molar ratio of compound (R)-5 with LiAlH4 is 1:1.5; in step S4, the molar ratio of compound (R)-6, Ph3P, BT-SH, and DIAD is 1:1.2:1.2:1.2; in step S5, the molar ratio of compound (R)-7 and m-CPBA is 1:5; in step S6, the molar ratio of compound 9, TEA, PivCl, compound (R)-3, and LiCl is 1:2:1.2:1:3; and in step S7, the molar ratio of compound 10 with NaHMDS and MeI is 1:2:1:

3.

5. In step S8, the molar ratio of compound (R)-11 to LiAlH4 is 1:1.5; in step S9, the molar ratio of compound (R)-12, imidazole, and TBSCl is 1:2:1.5; in step S10, the molar ratio of compound (R)-13 to 20% Pt(OH)2 / C is 1:0.08; in step S11, the molar ratio of compound (R)-14, 4A molecular sieve, and PCC is 1:1.5:1.5; in step S12, the molar ratio of compound (R)-8 to NaHMDS and compound (R)-15 is 1:1:0.7; in step S13, the molar ratio of compound 16 to 10% Pt(OH)2 / C is... The molar ratio of Pt / C is 1:0.

08. The molar ratio of compound 17, Ph3P and BT-SH in step S14 is 1:1.2:1.2:1.

2. The molar ratio of compound 18 and m-CPBA in step S15 is 1:

5. The molar ratio of compound 19, NaHMDS and compound 20 in step S16 is 1:1:0.

7. The molar ratio of compound 21 and 10% Pt / C in step S17 is 1:0.

08. The molar ratio of compound 22 and TBAF in step S18 is 1:

2. The molar ratio of compound 23 and PCC in step S19 is 1:1.

5. The molar ratio of compound 24 and MeMgCl in step S20 is 1:

2. The molar ratio of compound 25 and PCC in step S21 is 1:1.

5.

3. The method for synthesizing the sex pheromone of the cucumber beetle as described in claim 2, characterized in that, The inert gas is argon.

4. The method for synthesizing the sex pheromone of the cucumber beetle as described in claim 1, characterized in that, The synthesis route is as follows: 。 5. The method for synthesizing the sex pheromone of the cucumber beetle as described in claim 4, characterized in that, The specific synthesis method is as follows: S1: Take a single-necked round-bottom flask, add compound (R)-3, Ar protection, then add dry THF, and slowly add n-BuLi dropwise with a syringe at -78 ℃. After stirring for 30 min, add compound 2 dropwise. After the addition is complete, react at -78 ℃ for about 30 min, then turn off the refrigeration, allow the temperature to rise naturally, and stir overnight to obtain compound 4. S2: Take a single-necked round-bottom flask, add compound 4 and dry THF in sequence, and protect with Ar; after cooling at -78 ℃ for 15 min, slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min and then add MeI dropwise; after reacting for 2.0 h, adjust the temperature to -50 ℃ and stir overnight to obtain compound (R)-5. S3: Take a single-necked round-bottom flask, add LiAlH4 and dry diethyl ether, place it in an ice-water bath at 0 ℃ and stir, with Ar protection; then inject the diethyl ether solution of compound (R)-5 with a syringe, heat naturally, and stir at room temperature for 12 h to obtain compound (R)-6. S4: Take a single-necked round-bottom flask, add compound (R)-6, Ph3P, BT-SH and dry THF in sequence, and protect with Ar; add DIAD dropwise under an ice-water bath, heat naturally, and react for 12 h to obtain compound (R)-7. S5: Take a single-necked round-bottom flask, add compound (R)-7, dry CH2Cl2 and m-CPBA in sequence, and protect with Ar; stir at room temperature for 12.0 h to obtain compound (R)-8; S6: Take a single-necked round-bottom flask, add compound 9 and dry THF, Ar protection, and cool at -78 ℃ for 15 min; then add TEA and PivCl, stir at -78 ℃ for 20 min, then move to room temperature and react for 1 h; after cooling at -78 ℃ for 15 min, add (R)-3 and LiCl, react at -78 ℃ for 1 h, then turn off the refrigeration, let it heat up naturally, stir overnight to obtain compound 10; S7: Take a single-necked round-bottom flask, add compound 10 and dry THF in sequence, and protect with Ar; after cooling at -78 ℃ for 15 min, slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min, and then add MeI dropwise; after reacting for 2.0 h, adjust the bath temperature to -50 ℃ and stir overnight to obtain compound (R)-11; S8: Take a single-necked round-bottom flask, add LiAlH4 and dry diethyl ether, place it in a 0 ℃ ice-water bath and stir, with Ar protection; then inject the diethyl ether solution of compound (R)-11 with a syringe, heat naturally, and stir at room temperature for 12 h to obtain compound (R)-12. S9: Take a single-necked round-bottom flask, add compound (R)-12, protect with Ar, and inject CH2Cl2 with a syringe; add imidazole at 0 ℃, stir for 15 min, then add TBSCl, and naturally raise the temperature from 0 ℃ and react for 12 h to obtain compound (R)-13. S10: Take a single-necked round-bottom flask, add compound (R)-13, anhydrous MeOH, and 20% Pt(OH)2 / C in sequence, evacuate the H2 bag with a vacuum pump, then fill it with H2, connect it to the round-bottom flask, change the air 5 times with a vacuum pump to remove all the air, stir in an oil bath at 55 ℃ for 24 h to obtain compound (R)-14; S11: Take a single-necked round-bottom flask, add compound (R)-14, dry CH2Cl2, 4A molecular sieve and PCC in sequence, and react at room temperature for 12 h to obtain compound (R)-15; S12: Take a single-necked round-bottom flask, add compound (R)-8 and dry THF in sequence, and protect with Ar; after cooling at -78 ℃ for 15 min, slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min, and then add a THF solution of compound (R)-15 dropwise; after reacting for 3.0 h, turn off the refrigeration, let it heat up naturally, and stir overnight to obtain compound 16; S13: Take a single-necked round-bottom flask, add compound 16, anhydrous ethanol and 10% Pt / C in sequence, then connect a hydrogen bag, replace the air-hydrogen gas five times with a water pump, stir in an oil bath at 55 ℃ for 24 h to obtain compound 17. S14: Take a single-necked round-bottom flask, add compound 17, Ph3P, BT-SH and dry THF in sequence, and protect with Ar; add DIAD dropwise under an ice-water bath, heat naturally, and react for 12 h to obtain compound 18; S15: Take a single-necked round-bottom flask, add compound 18, dry CH2Cl2 and m-CPBA in sequence, under argon protection; stir at room temperature for 12.0 h to obtain compound 19; S16: Take a single-necked round-bottom flask, add compound 19 and dry THF in sequence, and protect with Ar; cool at -78 ℃ for 15 min and slowly add NaHMDS dropwise. After the addition is complete, stir at -78 ℃ for 30 min and then add a THF solution of compound 20 dropwise; after reacting for 3.0 h, turn off the refrigeration, let it heat up naturally, and stir overnight to obtain compound 21; S17: Take a single-necked round-bottom flask, add compound 21, anhydrous ethanol and 10% Pt / C in sequence, then connect a hydrogen bag, replace the air-hydrogen gas five times with a water pump, stir in an oil bath at 55 ℃ for 24 h to obtain compound 22. S18: Take a single-necked round-bottom flask, add compound 22, TBAF and THF in sequence, protect with Ar, stir at room temperature for 3 h to obtain compound 23; S19: Take a single-necked round-bottom flask, add compound 23, CH2Cl2, silica gel and PCC in sequence, protect with Ar, and react at room temperature for 12 h to obtain compound 24; S20: Take a single-necked round-bottom flask, add compound 24, protect with Ar, inject dry THF with a syringe, and add MeMgCl dropwise at 0 °C; after naturally raising the temperature from 0 °C, react at room temperature for 30 min to obtain compound 25; S21: Take a single-necked round-bottom flask, add compound 25, CH2Cl2, silica gel and PCC in sequence, Ar protection, react at room temperature for 12 h to obtain compound (6R,12R)-1.

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