CN114751814B - Preparation method of sesquiterpenoids - Google Patents
Preparation method of sesquiterpenoids Download PDFInfo
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Abstract
The invention provides a preparation method of sesquiterpenoids, and relates to the technical field of organic synthesis. According to the preparation method of the sesquiterpenoids, sclareolide is used as an initial raw material, 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butane-2-ketone and/or (+) -drim-9 (11) -en-8 alpha-ol are prepared through four steps of reaction of reduction, iodination, hydrolysis and elimination, and the yield of the product is high. The invention has the advantages of cheap and easily obtained raw materials, low production cost and suitability for industrial production. In addition, the invention avoids the use of expensive noble metals, and further reduces the production cost.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of sesquiterpenoids.
Background
Sesquiterpenoids contain 15 carbon atoms and consist of 3 isoprene units, and are a huge and important class of natural products. Among them, terpenes and mixed source terpenes natural products containing a Drimane (Drimane) skeleton are widely present in plants, microorganisms, marine organisms and some insects, and exhibit a wide variety of biological activities. For example, the Drimane-like sesquiterpene component isolated from Canlol tree, which was found to have a higher non-competitive inhibition of the α4β2 nicotinic acetylcholine receptor than the human α3β4 and α7 subtypes, may be used to develop new anti-addiction antidepressant ligands; 14 rimane sesquiterpenes extracted from the leaves of white cinnamon (Canella winterana), 8 of which were phytotoxic in duckweed test; the obtained product has good inhibiting effect on secondary coleoptile and rice husk germination when the content of pinolenic acid is concentrated to 200 ppm. In recent years, more and more sesquiterpenes and complex natural products containing a Drimane backbone have been discovered and exhibit a diversity of structural and biological activities. 4- ((1 s,6 r) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one was isolated from tobacco (Nicotiana tabacum l.), possibly contributing to aroma. In 1983, (+) -drim-9 (11) -en-8α -ol was isolated from Aspergillus (Aspergillus oryzae) by Shangho Marumo et al, which was used to roast and manufacture some Japanese beverages such as sake, sesame paste and distilled liquor. More importantly, the two Drimane sesquiterpenes can be used as key intermediates for synthesizing other complex terpene molecules and mixed source terpene molecules, such as (+) -drim-9 (11) -en-8 alpha-ol which is used as key synthons for synthesizing mixed source terpene natural products such as auststrodoral, auststrodoric acid, silicondictyal B and liphagal.
However, the currently reported method for extracting and preparing Drimane sesquiterpenes from plants generally has the defects of multiple reaction steps, low reaction efficiency, product isomerization, and wide application range of noble metals, so that the research on the biological activity of the Drimane sesquiterpenes is greatly limited, and a chemical synthesis method is needed to obtain a large amount of the Drimane sesquiterpenes. For example, in 1974, enzell, C.R et al, 6 steps were performed to synthesize 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one using the sesquiterpene Drimenol as the starting material (Hlubucek, J.R.; aasen, A.J.; almqvist, S.O., et al acta Chem.Scand., ser.B 1974,28 (1), 18). In 1990, kametani, T et al synthesized 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one (K.Shishido, Y.Tokunaga, N.Omachi, K.Hiroya, et al chem. Soc., perkin Trans.1,1990, 2481-2486.) from (+) -Wieland-Miescher ketone as the starting material by 9 steps, both of which were long and the starting materials used were prepared. Subsequently, 4- ((1 s,6 r) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one (Barrero, a.f.; alvarez-Manzaneda, e.j.; chahbou, r.; tetrahedron lett.1998,39 (51), 9543.(+) -drim-9 (11) -en-8α -ol [ Barrero, a.f.; manzaneda, e.a.; altarejos, j.; et al Tetrahedron 1995,51 (27), 7435.) was synthesized from sclareol as an initial starting material by a 6-step reaction, and the reaction route was as shown in formula 1. However, the total yield of the Drimane sesquiterpenes prepared by the chemical synthesis method is 65% for 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one, 40% for (+) -drim-9 (11) -en-8α -ol, and very low for 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one and (+) -drim-9 (11) -en-8α -ol.
Disclosure of Invention
In view of the above, the present invention aims to provide a preparation method of sesquiterpenoids, which provides a preparation method with high total yield of products.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of sesquiterpenoids, which is characterized by comprising the following steps:
carrying out a reduction reaction on sclareolide by using a reducing agent to obtain a compound 1;
mixing the compound 1, iodobenzene diacetic acid and iodine for iodination reaction to obtain a compound 2;
carrying out hydrolysis reaction on the compound 2 in the presence of a first alkaline reagent to obtain a compound 3;
subjecting said compound 3 to a hydrogen iodide elimination reaction in the presence of a second basic reagent to yield 4- ((1 s,6 r) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one and/or (+) -drim-9 (11) -en-8α -ol;
preferably, the reducing agent comprises lithium diisopropylamide and/or diisobutylaluminum hydride;
the molar ratio of sclareolide to reducing agent is 1:1 to 3.
Preferably, the temperature of the reduction reaction is-78-0 ℃ and the time is 1-3 h.
Preferably, the molar ratio of the compound 1, the iodobenzene diacetic acid and the iodine is 1: 1-2: 1 to 2.
Preferably, the temperature of the iodination reaction is 70-90 ℃ and the time is 1-3 h.
Preferably, the first and second alkaline reagents independently comprise hydroxides, carbonates, alkali metal alkoxides, and nitrogen-containing organic compounds;
the molar ratio of the compound 2 to the first alkaline reagent is 1:1 to 10.
Preferably, the hydrolysis reaction time is 2 to 5 hours.
Preferably, the molar ratio of compound 3 to the second basic agent is 1: 1-10, wherein the temperature of the hydrogen iodide elimination reaction is 60 ℃ and the time is 6-10 h, and the hydrogen iodide elimination reaction is carried out to obtain 4- ((1S, 6R) -2, 6-trimethyl-6-vinyl cyclohexyl) butane-2-ketone and/or (+) -drim-9 (11) -en-8 alpha-ol.
Preferably, the molar ratio of compound 3 to the second basic agent is 1: 1-50, wherein the temperature of the hydrogen iodide elimination reaction is 25-60 ℃ and the time is 0.1-3 h, and the hydrogen iodide elimination reaction is carried out to obtain 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butane-2-ketone.
Preferably, the molar ratio of compound 3 to the second basic agent is 1: 1-50, wherein the temperature of the hydrogen iodide elimination reaction is 25-80 ℃ and the time is 3-6 h, and the hydrogen iodide elimination reaction is carried out to obtain (+) -drim-9 (11) -en-8 alpha-ol.
The invention provides a preparation method of sesquiterpenoids, which comprises the following steps: carrying out a reduction reaction on sclareolide by using a reducing agent to obtain a compound 1; mixing the compound 1, iodobenzene diacetic acid and iodine for iodination reaction to obtain a compound 2; carrying out hydrolysis reaction on the compound 2 in the presence of a first alkaline reagent to obtain a compound 3; the compound 3 is subjected to a hydrogen iodide elimination reaction in the presence of a second alkaline reagent to obtain 4- ((1S, 6R) -2, 6-trimethyl-6-vinyl cyclohexyl) butane-2-ketone and/or (+) -drim-9 (11) -en-8 alpha-ol. The invention takes sclareolide as an initial raw material, and 4- ((1S, 6R) -2, 6-trimethyl-6-vinyl cyclohexyl) butane-2-ketone and/or (+) -drim-9 (11) -en-8 alpha-ol are prepared by four steps of reactions of reduction, iodination, hydrolysis and elimination, and the total yield of the product is high; the invention has the advantages of cheap and easily obtained raw materials, low production cost and suitability for industrial production. In addition, the invention avoids the use of expensive noble metals, and further reduces the production cost. As shown in the test results of the examples, the preparation method provided by the invention has the total yield of 36.5% and 27.6% when the product is 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butane-2-ketone and/or (+) -drim-9 (11) -en-8α -ol; when the product was 4- ((1 s,6 r) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one, the overall yield of product was 62.5%; when the product was (+) -drim-9 (11) -en-8α -ol, the overall yield of the product was 74.6%.
Detailed Description
The invention provides a preparation method of sesquiterpenoids, which comprises the following steps:
carrying out a reduction reaction on sclareolide by using a reducing agent to obtain a compound 1;
mixing the compound 1, iodobenzene diacetic acid and iodine for iodination reaction to obtain a compound 2;
carrying out hydrolysis reaction on the compound 2 in the presence of a first alkaline reagent to obtain a compound 3;
subjecting said compound 3 to a hydrogen iodide elimination reaction in the presence of a second basic reagent to yield 4- ((1 s,6 r) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one and/or (+) -drim-9 (11) -en-8α -ol;
in the present invention, all raw material components are commercially available products well known to those skilled in the art unless specified otherwise.
In the present invention, the reaction scheme for the 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one and/or (+) -drim-9 (11) -en-8α -ol is as follows:
the invention utilizes a reducing agent to carry out a reduction reaction on sclareolide to obtain the compound 1.
In a specific embodiment of the present invention, sclareolide, a reducing agent, and an organic solvent are preferably mixed to perform a reduction reaction to obtain compound 1. In the present invention, the reducing agent preferably includes lithium diisopropylamide and/or diisobutylaluminum hydride. In the invention, the molar ratio of sclareolide to reducing agent is preferably 1:1 to 3, more preferably 1:1.5 to 2.5, more preferably 1:2. In the present invention, the organic solvent preferably includes one or more of dichloromethane, tetrahydrofuran and methanol; the amount of the organic solvent used in the present invention is not particularly limited, and the reduction reaction may be performed in a proper order. The mode of the mixing is not particularly limited in the present invention, and the raw materials may be uniformly mixed, and in particular, the raw materials may be mixed by stirring. In the present invention, the temperature of the reduction reaction is preferably-78 to 0 ℃, more preferably-78 to-20 ℃, and even more preferably-78 to-50 ℃; the time of the reduction reaction is preferably 1 to 3 hours, more preferably 1.5 to 2.5 hours, and still more preferably 2 hours.
After completion of the reduction reaction, the present invention preferably further includes a post-treatment, which preferably includes: water is added into the obtained reduction reaction liquid to terminate the reaction, the organic solvent is extracted, and the obtained organic phase is washed by saturated sodium chloride aqueous solution, dried by anhydrous sodium sulfate and concentrated in sequence, thus obtaining the compound 1. In the present invention, the temperature of the termination reaction is preferably room temperature, the termination reaction is preferably performed under stirring, the speed of the stirring is not particularly limited, and the termination reaction can be performed; the stirring time is preferably 30 to 60 minutes, more preferably 30 to 50 minutes. In the present invention, the organic solvent for extraction preferably includes methylene chloride or ethyl acetate; the number of times of the organic solvent extraction is preferably 2 to 4 times, more preferably 3 times. The concentration is not particularly limited, and the concentration may be carried out by a concentration method well known to those skilled in the art to a constant weight, specifically, concentration under reduced pressure.
After the compound 1 is obtained, the compound 1, the iodobenzene diacetic acid and iodine are mixed for iodination reaction to obtain the compound 2.
In a specific embodiment of the present invention, the compound 1, iodobenzene diacetic acid, iodine and an organic solvent are preferably mixed to perform an iodination reaction to obtain a compound 2. In the present invention, the molar ratio of the compound 1, iodobenzene diacetic acid to iodine is preferably 1: 1-2: 1 to 2, more preferably 1:1.2 to 1.8 to: 1.2 to 1.8, more preferably 1:1.4 to 1.6:1.2 to 1.5, most preferably 1:1.4:1.2. In the present invention, the iodination reaction is preferably performed in the presence of an organic solvent, which preferably includes one or more of benzene, toluene and xylene; the amount of the organic solvent used in the present invention is not particularly limited, and the iodination reaction may be performed in a certain order. The mode of the mixing is not particularly limited in the present invention, and the raw materials may be uniformly mixed, and in particular, the raw materials may be mixed by stirring. In the present invention, the temperature of the iodination reaction is preferably 70 to 90 ℃, more preferably 75 to 85 ℃, still more preferably 80 ℃; the time of the iodination reaction is preferably 1 to 3 hours, more preferably 1.5 to 2.5 hours, and still more preferably 2 hours; in a specific embodiment of the invention, the temperature of the iodination reaction is preferably provided by a metal bath, preferably comprising an aluminum sand bath and/or an aluminum wire bath. In the present invention, the iodination reaction is preferably performed under an illumination condition, the illumination is preferably a metal halide lamp illumination, and the power of the metal halide lamp illumination is preferably 100 to 250W, more preferably 150 to 200W.
After completion of the iodination reaction, the present invention preferably further comprises a post-treatment, preferably comprising: and (3) sequentially cooling the obtained iodized reaction liquid to room temperature, pre-concentrating, diluting with saturated sodium chloride aqueous solution and extracting with an organic solvent, and washing the obtained organic phase with saturated sodium thiosulfate aqueous solution, drying with anhydrous sodium sulfate and concentrating to obtain the compound 2. The cooling method is not particularly limited, and a cooling method well known to those skilled in the art, such as natural cooling, may be used. The method of the present invention is not particularly limited, and the method of concentration known to those skilled in the art may be used, for example, concentration under reduced pressure. In the present invention, the dilution factor of the saturated sodium chloride is preferably 1 to 5 times, more preferably 2 to 3 times. In the present invention, the organic solvent for extraction preferably includes ethyl acetate or methylene chloride; the number of times of the organic solvent extraction is preferably 2 to 4 times, more preferably 3 times. The concentration method is not particularly limited, and the concentration method known to those skilled in the art may be used to concentrate the mixture to a constant weight, such as vacuum concentration.
After the compound 2 is obtained, the compound 2 is subjected to hydrolysis reaction in the presence of a first alkaline reagent to obtain a compound 3.
In a specific embodiment of the present invention, compound 2, the first alkaline reagent and the organic solvent are preferably mixed to perform a hydrolysis reaction to obtain compound 3. In the present invention, the first alkaline reagent preferably includes hydroxide, carbonate, alkali metal alkoxide and nitrogen-containing organic compound, and more preferably includes one or more of sodium hydroxide, potassium hydroxide, sodium hydride, cesium carbonate, potassium t-butoxide, sodium methoxide, tripotassium phosphate, triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo undec-7-ene, diethylenetriamine and triethylenediamine. In the present invention, the molar ratio of the compound 2 to the first basic agent is preferably 1:1 to 10, more preferably 1:1.1 to 5, more preferably 1:1.2 to 3. In the present invention, the organic solvent preferably includes one or more of methanol, tetrahydrofuran, acetonitrile and methylene chloride; the amount of the organic solvent used in the present invention is not particularly limited, and the iodination reaction may be performed in a certain order. The mixing mode is not particularly limited, and the raw materials can be uniformly mixed, such as stirring and mixing; the mixing is preferably carried out under ice bath (0 ℃) conditions. In the present invention, the temperature of the hydrolysis reaction is preferably room temperature, and the time of the hydrolysis reaction is preferably 2 to 5 hours, more preferably 2.5 to 4.5 hours, and still more preferably 3 to 4 hours.
After completion of the hydrolysis reaction, the present invention preferably further comprises a post-treatment, preferably comprising: the obtained hydrolysis reaction liquid is subjected to pre-concentration, organic solvent aqueous solution dilution and organic solvent extraction in sequence, and the obtained organic phase is sequentially washed by saturated sodium chloride aqueous solution, dried by anhydrous sodium sulfate and concentrated to obtain the compound 3. The method of the present invention is not particularly limited, and the method of concentration known to those skilled in the art may be used, for example, concentration under reduced pressure. In the present invention, the organic solvent in the aqueous organic solvent solution preferably includes ethyl acetate or methylene chloride; the volume ratio of the organic solvent to the water in the organic solvent aqueous solution is preferably 1:1 to 1:3, more preferably 1:1, a step of; the dilution factor is preferably 1 to 5 times, more preferably 2 to 3 times. In the present invention, the organic solvent for extraction preferably includes ethyl acetate or methylene chloride; the number of times of the organic solvent extraction is preferably 2 to 4 times, more preferably 3 times. The concentration method is not particularly limited, and the concentration method known to those skilled in the art may be used to concentrate the mixture to a constant weight, such as vacuum concentration.
After compound 3 is obtained, the invention carries out the hydrogen iodide elimination reaction of the compound 3 in the presence of a second alkaline reagent to obtain 4- ((1S, 6R) -2, 6-trimethyl-6-vinyl cyclohexyl) butane-2-ketone and/or (+) -drim-9 (11) -en-8 alpha-ol.
In a specific embodiment of the invention, compound 3, a second basic reagent and an organic solvent are preferably mixed and subjected to a hydrogen iodide elimination reaction to give 4- ((1 s,6 r) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one and/or (+) -drim-9 (11) -en-8α -ol. In the present invention, the optional species of the second alkaline agent is preferably the same as the optional species of the first alkaline agent, and will not be described herein. In the present invention, the organic solvent preferably includes one or more of dichloroethane, methanol, ethanol, toluene, tetrahydrofuran, t-butanol, acetonitrile, toluene, dioxane and N, N-dimethylformamide; the invention is not particularly limited to the amount of the organic solvent, and the reaction sequence of eliminating hydrogen iodide can be ensured. The mode of the mixing is not particularly limited in the present invention, and the raw materials may be uniformly mixed, and in particular, the raw materials may be mixed by stirring. In a specific embodiment of the invention, the hydrogen iodide elimination reaction is preferably carried out in a metal bath, preferably comprising an aluminum sand bath and/or an aluminum wire bath.
In the present invention, the molar ratio of the compound 3 to the second basic agent is preferably 1:1 to 10, more preferably 1:1.1 to 5, more preferably 1:1.2 to 3; the temperature of the hydrogen iodide elimination reaction is preferably 25-60 ℃, more preferably 50-60 ℃; the hydrogen iodide elimination reaction is preferably carried out for a period of 6 to 10 hours, more preferably 7 to 9 hours, still more preferably 8 hours, and gives 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one and/or (+) -drim-9 (11) -en-8α -ol.
In the present invention, the molar ratio of the compound 3 to the second basic agent is preferably 1:1 to 50, more preferably 1:1.5 to 10, more preferably 1:2; the temperature of the hydrogen iodide elimination reaction is preferably 25-60 ℃, more preferably 40-55 ℃, further preferably 50 ℃, the time of the hydrogen iodide elimination reaction is preferably 0.1-3 h, more preferably 0.1-2 h, further preferably 10min, and the hydrogen iodide elimination reaction is carried out to obtain 4- ((1S, 6R) -2, 6-trimethyl-6-vinyl cyclohexyl) butane-2-ketone.
In the present invention, the molar ratio of the compound 3 to the second basic agent is preferably 1:1 to 50, more preferably 1:20 to 50, more preferably 1:50; the temperature of the hydrogen iodide elimination reaction is preferably 25-80 ℃, more preferably 50-70 ℃, further preferably 60 ℃, the time of the hydrogen iodide elimination reaction is preferably 3-6 h, more preferably 3.5-5 h, further preferably 4h, and the hydrogen iodide elimination reaction is carried out to obtain (+) -drim-9 (11) -en-8 alpha-ol.
After completion of the hydrogen iodide elimination reaction, the present invention preferably further comprises a post-treatment, which preferably comprises: the obtained reaction solution for eliminating hydrogen iodide is cooled to room temperature, pre-concentrated, diluted by saturated ammonium chloride aqueous solution and extracted by organic solvent, the obtained organic phase is washed by saturated sodium chloride aqueous solution sequentially, dried by anhydrous sodium sulfate, concentrated and separated by column chromatography, and 4- ((1S, 6R) -2, 6-trimethyl-6-vinyl cyclohexyl) butane-2-ketone and/or (+) -drim-9 (11) -en-8 alpha-ol are obtained. The cooling method is not particularly limited, and a cooling method well known to those skilled in the art, such as natural cooling, may be used. The method of the present invention is not particularly limited, and the method of concentration known to those skilled in the art may be used, for example, vacuum concentration. In the present invention, the dilution factor is preferably 1 to 5 times, more preferably 2 to 3 times. In the present invention, the organic solvent for extraction preferably includes ethyl acetate or methylene chloride; the number of times of the organic solvent extraction is preferably 2 to 4 times, more preferably 3 times. In the present invention, the concentration method is not particularly limited, and the concentration method known to those skilled in the art may be used to concentrate the mixture to a constant weight, such as vacuum concentration. In the present invention, the packing for column chromatography separation is preferably silica gel, the eluent for column chromatography separation is preferably a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the eluent is preferably 1:1 to 50, more preferably 1:10 to 40, further and preferably 1: 20-30 parts.
The preparation method provided by the invention has the advantages of simple and easily obtained preparation raw materials, mild preparation conditions and lower requirements on equipment; the obtained product has wide application in the field of natural product synthesis, has high added value of the process flow, and is suitable for large-scale industrial production. In addition, the preparation method provided by the invention adopts the alkaline reagent with low price as the catalyst, so that the efficient preparation of the target compound is realized; has the advantages of high conversion efficiency, low substrate cost, simple operation, low equipment requirement, excellent yield and the like.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
(1) Diisobutylaluminum hydride (60.0 mmol) was added dropwise to a solution of sclareolide (12.0 g,50.0mmol,1.0 eq.) in 250mL of methylene chloride at-78 ℃ under stirring, and the mixture was uniformly mixed, the reduction was carried out for 1 hour under heat preservation, water was added to the obtained reduction reaction solution, and the mixture was heated to room temperature, stirred for 30 minutes, extracted 3 times with 100mL of methylene chloride each, and the organic phases were combined, washed with 150mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to constant weight to give compound 1 (white solid, 12.1g, yield 96%).
(2) Compound 1 (12.1 g,48.0mmol,1.0 eq.) was dissolved in 200mL benzene, iodobenzene diacetic acid (21.6 g,67.2 mmol) and iodine (14.6 g,57.6mmol,1.2 eq.) were added and mixed well, iodination was carried out in 70 ℃ (aluminum sand bath) under the condition of 800r/min, 150W of metal halide lamp irradiation for 1h, the obtained iodination reaction solution was cooled to room temperature, concentrated in vacuo, diluted 2 times with saturated sodium chloride aqueous solution, extracted 3 times with 100mL ethyl acetate respectively, the organic layers were combined, then washed with saturated sodium thiosulfate aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give Compound 2 (white solid, 16.0g, yield 88%).
(3) Compound 2 (7.56 g,20mmol,1.0 eq.) was dissolved in 100mL of methanol under ice-bath conditions, potassium carbonate (3.3 g,24mmol,1.2 eq.) was added, mixed well, the ice-bath was removed, warmed to room temperature, the hydrolysis reaction was carried out for 2h under 500r/min conditions, the resulting hydrolysis reaction was concentrated to constant weight, diluted with 100mL of water and 100mL of ethyl acetate, each of which was extracted 3 times with 100mL of ethyl acetate, the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 3 (white solid, 6.7g, yield 96%).
(4) Compound 3 (70 mg,0.2mmol,1.0 eq.) was dissolved in 2mL methanol, potassium carbonate (83 mg,0.6mmol,3 eq.) was added and mixed well, then the reaction mixture was quenched at 60 ℃ (aluminum sand bath), 800r/min for 6h, the resulting quenched reaction solution was cooled to room temperature, concentrated in vacuo, diluted 5-fold with saturated ammonium chloride, extracted 3 times with 20mL ethyl acetate, the organic layers combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to give 4- ((1 s,6 r) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one (pale yellow oil, 20mg, yield 45%, purity > 95%) and (+) -drim-9 (11) -en-8α -ol (white solid, 15mg, yield 34%, purity > 95%); wherein, the packing for column chromatography separation is silica gel, and the volume ratio of the eluent is 1:10 ethyl acetate-petroleum ether mixed solvent.
Example 2
Compound 3 (70 mg,0.2mmol,1.0 eq.) prepared in example 1 was dissolved in 10mL tetrahydrofuran, potassium tert-butoxide (43.5 mg,0.4mmol,2 eq.) was added and mixed well, then the reaction mixture was reacted at 50deg.C (aluminum sand bath) for 10min with elimination of hydrogen iodide, the resulting reaction solution was cooled to room temperature, concentrated in vacuo, diluted 3 times with saturated ammonium chloride, extracted 3 times with 10mL ethyl acetate each, the organic layers were combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to give 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one (pale yellow oil, 34mg, yield 77%, purity > 95%); wherein, the packing for column chromatography separation is silica gel, and the volume ratio of the eluent is 1:10 ethyl acetate-petroleum ether mixed solvent.
Structural characterization data for 4- ((1 s,6 r) -2, 6-trimethyl-6-vinylcyclohexyl) butan-2-one prepared in example 1 and example 2:
1 H NMR(500MHz,CDCl 3 )δ5.61(dd,J＝17.8,10.4Hz,1H),4.90(d,J＝1.1Hz,1H),4.87(dd,J＝5.0,1.2Hz,1H),2.45(ddd,J＝16.9,11.4,5.5Hz,1H),2.37(ddd,J＝16.8,11.4,5.4Hz,1H),2.07(s,3H),1.63-1.46(m,2H),1.44-1.36(m,3H),1.34-1.09(m,4H),1.00(s,3H),0.89(s,3H),0.86(s,3H).
13 C NMR(126MHz,CDCl 3 )δ209.61,151.50,110.66,52.91,47.34,42.18,41.56,40.32,34.64,33.71,29.90,21.99,21.07,18.76,17.21.
HRMS(m/z)calcd for C 15 H 26 O[M+H] + 222.1984,found 222.1975.
example 3
Dissolving compound 3 (70 mg,0.2mmol,1.0 eq.) prepared in example 1 in 10mL tetrahydrofuran, adding diethylenetriamine (1 mL,10mmol,50 eq.) and mixing well, then reacting the reaction mixture at 60 ℃ (aluminium sand bath) under 800r/min to eliminate hydrogen iodide for 4h, cooling the obtained reaction solution to room temperature, concentrating in vacuo, adding saturated ammonium chloride to dilute 3 times, extracting with 10mL ethyl acetate respectively for 3 times, combining organic layers, washing with saturated sodium chloride aqueous solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure and separating by column chromatography to obtain (+) -drim-9 (11) -en-8 alpha-ol (white solid, 41mg, yield 92%, purity > 95%); wherein, the packing for column chromatography separation is silica gel, and the volume ratio of the eluent is 1:10 ethyl acetate-petroleum ether mixed solvent.
Structural characterization data for (+) -drim-9 (11) -en-8α -ol prepared in example 1 and example 3:
1 HNMR(500MHz,CDCl 3 )δ5.22(s,1H),4.84(s,1H),2.04-1.98(m,1H),1.83-1.76(m,1H),1.73-1.62(m,2H),1.58-1.50(m,1H),1.48-1.42(m,2H),1.41(s,3H),1.40-1.31(m,3H),1.17-1.10(m,1H),1.08(s,3H),0.97(dd,J＝11.5,2.5Hz,1H),0.87(s,3H),0.84(s,3H).
13 C NMR(126MHz,CDCl 3 )δ166.77,103.78,73.52,53.63,44.35,41.90,40.16,39.15,33.94,33.40,30.65,22.53,21.77,20.34,19.20.
HRMS(m/z)calcd for C 15 H 26 O[M+H] + 222.1984,found 222.1976.
the foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (8)
1. The preparation method of the sesquiterpenoids is characterized by comprising the following steps:
carrying out a reduction reaction on sclareolide by using a reducing agent to obtain a compound 1;
mixing the compound 1, iodobenzene diacetic acid and iodine for iodination reaction to obtain a compound 2;
carrying out hydrolysis reaction on the compound 2 in the presence of a first alkaline reagent to obtain a compound 3; the first alkaline reagent is selected from one or two of potassium carbonate and cesium carbonate;
carrying out hydrogen iodide elimination reaction on the compound 3 in the presence of a second alkaline reagent to obtain 4- ((1S, 6R) -2, 6-trimethyl-6-vinyl cyclohexyl) butane-2-ketone; the second alkaline reagent is selected from one or more of potassium carbonate, cesium carbonate and alkali metal alcoholates;
the wavy line in the compound 1 indicates an R-form or an S-form.
2. The process according to claim 1, wherein the reducing agent is selected from lithium diisopropylamide and/or diisobutylaluminum hydride;
the molar ratio of sclareolide to reducing agent is 1:1 to 3.
3. The preparation method according to claim 1 or 2, wherein the temperature of the reduction reaction is-78 to 0 ℃ for 1 to 3 hours.
4. The preparation method according to claim 1, wherein the molar ratio of the compound 1, iodobenzene diacetic acid and iodine is 1: 1-2: 1 to 2.
5. The method according to claim 1 or 4, wherein the iodination reaction is carried out at a temperature of 70 to 90 ℃ for a time of 1 to 3 hours.
6. The method of claim 1, wherein the molar ratio of compound 2 to the first basic reagent is 1:1 to 10.
7. The method according to claim 1 or 6, wherein the hydrolysis reaction time is 2 to 5 hours.
8. The method of claim 1 or 6, wherein the molar ratio of compound 3 to the second basic agent is 1: 1-50, wherein the temperature of the hydrogen iodide elimination reaction is 25-60 ℃ and the time is 0.1-3 h, and the hydrogen iodide elimination reaction is carried out to obtain 4- ((1S, 6R) -2, 6-trimethyl-6-vinylcyclohexyl) butane-2-ketone.
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