CN109096114B

CN109096114B - Method for synthesizing marine natural product smenodiol

Info

Publication number: CN109096114B
Application number: CN201811170441.0A
Authority: CN
Inventors: 吴彦超; 程云飞; 李惠静; 谭效帅
Original assignee: Weihai Marine Biological Medicine Industry Technology Research Institute Co Ltd
Current assignee: Weihai marine biological medicine industry technology Research Institute Co., Ltd
Priority date: 2018-10-09
Filing date: 2018-10-09
Publication date: 2021-02-26
Anticipated expiration: 2038-10-09
Also published as: CN109096114A

Abstract

The patent relates to a method for synthesizing a marine natural product smenodiol, and belongs to the field of chemical synthesis. According to the method, the mussaendaol skeleton is constructed by taking sclareol hydrazone and 3-iodine-4, 5-dimethoxymethyl benzoate as raw materials through palladium-catalyzed coupling reaction of the mussaendosulfan hydrazone and the 3-iodine-4, 5-dimethoxymethyl benzoate, and a natural product, namely the musiodool, is finally synthesized through reduction, dehydration and demethylation. The method has the characteristics of good economical efficiency of steps, simple and convenient operation, suitability for industrial production and the like.

Description

Method for synthesizing marine natural product smenodiol

Technical Field

The invention relates to a method for synthesizing a marine natural product smenodiol.

Background

The marine natural product smenodiol was first isolated in 1991 from Seychelles sponge of the species Smenospongia sp (Journal of Organic Chemistry,1991,56(22): 6271-. Smenodiol belongs to bicyclic sesquiterpenoids, and the compounds have excellent antitumor activity, can selectively kill tumor cells without damaging normal cells in the antitumor process, have small adverse reaction, and have the advantages of regulating immunity, reversing the drug resistance of tumor cells and the like (Tetrahedron, 1992,48(32): 6667-6680).

In view of the above discussion, it is particularly necessary to develop a chemical synthesis method of the marine natural product smenodiol. However, no report is made on the synthesis of the marine natural product smenodiol so far, and the invention reports the synthesis method of the natural product for the first time and has the advantages of few reaction steps, simple and convenient operation, suitability for industrial production and the like.

Disclosure of Invention

The invention aims to provide a method for synthesizing a marine natural product smenodiol, which has the advantages of few reaction steps and good product selectivity and is suitable for industrial production.

1. In order to achieve the above object, the present invention comprises the steps of:

a) and (3) coupling and synthesizing a skeleton compound 4 by carrying out palladium-catalyzed carbene migration insertion reaction on methyl 3-iodo-4, 5-dimethoxybenzoate 2 and sclareolide 3.

b) The framework structure 4 is reduced by hydrogen catalyzed by palladium carbon to obtain a reduction product 5.

c) And (3) catalyzing and dehydrating the compound 5 by using trifluoromethanesulfonate to obtain a compound 6.

d) The compound 6 and boron tribromide react for demethylation protection to finally obtain the natural product smenodiol 1.

2. The step a optimization scheme is as follows: coupling reaction of 3-iodine-4, 5-dimethoxybenzoic acid methyl ester and sclareol hydrazone, preferably selecting palladium hydroxide, tetratriphenylphosphine palladium and the like as catalysts, and toluene and xylene as solvents, wherein the reaction temperature is 90-110 DEG^oC, the reaction time is 6-9 hours.

3. The step b is an optimization scheme: the skeleton structure 4 is subjected to hydrogen reduction reaction, Pd/C is preferably selected as a catalyst, methanol, ethyl acetate and the like are taken as solvents, and the reaction temperature is 20-45 DEG^oAnd C, the reaction time is 2-4 hours.

4. The step c comprises the following optimization scheme: the reduction product 5 is subjected to the reaction of catalyzing and dehydrating by trifluoromethanesulfonate, tin trifluoromethanesulfonate is preferably selected as a catalyst, and the reaction temperature is 20-50 DEG^oAnd C, the reaction time is 4-6 hours.

5. The step d optimization scheme is as follows: the demethylation protection reaction of the compound 6, preferably boron tribromide and boron triiodide as additives, at-78 deg.C^oAnd C, the reaction time is 1-2 hours.

The invention has the following characteristics:

1. the invention discloses a method for synthesizing a reported marine natural product smenodiol for the first time;

2. the method takes the known sclareolide and 3-iodo-4, 5-dimethoxymethyl benzoate as starting materials, and has the advantages of few reaction steps, suitability for industrial production and the like;

3. high total yield and good product selectivity.

Drawings

FIG. 1: the structural formula of a marine natural product smenodiol is shown in the figure; FIG. 2 is a drawing: the invention specifically synthesizes a route map.

Detailed Description

Example 1: synthesis of the coupling product (4, see FIG. 2)

Dissolving sclareolide (1.6 g, 4 mmol) in a high-temperature high-pressure reaction tube containing 40mL of dry tetrahydrofuran, introducing argon for protection, adding catalytic equivalent of tetrakis (triphenylphosphine) palladium (231 mg, 0.2 mmol), adding potassium carbonate (2.5 g, 18 mmol), finally adding methyl 3-iodo-4, 5-dimethoxybenzoate (1.2 g, 4 mmol) to the reaction, heating the reaction to 90%^oAnd C, performing treatment. When the reaction time is 5h, the TLC detection shows that the reaction is complete. The reaction was quenched with water, the reaction mixture was extracted three times with ethyl acetate (3 × 20 mL), and the organic phase was washed with saturated brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give a total of 502mg of yellow solid 3 with a yield of 32% and 842mg of yellow foam 3 with a yield of 54%. Both are cis-trans isomers identified by NMR structure.

Example 2: synthesis of the reduction product (5, see FIG. 2)

To a solution of compound 4 (0.19 g, 0.5 mmol) in anhydrous MeOH (15 mL) was added 10% Pd/C (50 mg) and the mixture was stirred at 40 deg.C under hydrogen atmosphere for 4 h. The resulting mixture was then filtered and concentrated. The residue was purified by flash column chromatography over silica gel (100-200 mesh) with EtOAc/petroleum ether (1: 20 to 1: 10) to give 5 as a white solid (121 mg, 62%)

Example 3: synthesis of dehydration product (6, see FIG. 2)

To a solution of Compound 5 (0.80 g, 2 mmol) in dichloromethane (5 mL) at room temperature was added tin trifluoromethanesulfonate Sn (OTf)₂(83 mg, 0.2 mmol) and the resulting mixture was stirred at room temperature for 6h and the starting material was detected by TLC to be completely reacted. Diluted with dichloromethane and the mixture thus obtained was successively saturated with Na₂CO₃The aqueous solution (2X 20 mL) and brine (2X 20 mL) were each washed twice and the organic phases combined. The organic layer was passed over anhydrous Na₂SO₄Dried and filtered. The solvent was evaporated under vacuum using a rotary evaporator.The residue was purified by flash column chromatography over silica gel (100-200 mesh) with EtOAc/petroleum ether (1: 10 → 1: 5) to give 745mg of a white solid in 93% yield.

Example 4: synthesis of smenodiol (1, see FIG. 2)

Dissolve compound 6 (400.5 mg, 1 mmol) in a round bottom flask with 2mL dry dichloromethane, put under argon, and put the system at-78^oC in a low-temperature reaction bath, 1M BBr is slowly dropped into the reaction bath₃10mL of dichloromethane solution was added and the reaction was continued at this temperature. The reaction progress is detected by TLC, and when the reaction time is 5h, the reaction is completely detected by TLC. The reaction was quenched by addition of water, the reaction was extracted three times with dichloromethane (3X 10 mL), and the organic phase was washed with saturated brine (2X 20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated by column chromatography to give a yellow solid, smenodiol, 302mg in total, 81.2% yield. Hydrogen spectrum of nuclear magnetic resonance¹H NMR (400 MHz, CDCl₃/CD₃OD) delta 7.49 (br s, 1H), 7.26 (br s, 1H), 5.35 (br 8, 1H), 3.85 (s, 3H), 2.65 (m, 2H), 2.40 (m, 1H), 1.89 (m, 2H), 1.40 (s, 3H), 1.18-1.34 (m, 6H), 0.88 (s, 6H), 0.86(s, 3H), NMR spectrum¹³C NMR (100MHz,CDCl₃/CD₃OD)δ167.9,147.6,143.0,135.4,129.6,122.9,122.0,120.3,112.6,53.6,51.8,50.6,42.0,39.2,36.7,33.1,32.9,25.6,23.6,22.1, 21.8, 18.8 ,13.7 ppm.

The invention relates to palladium-catalyzed coupling reaction, hydrogen reduction reaction, trifluoromethanesulfonate-catalyzed dehydration reaction and demethylation 4-step reaction, and the marine natural product smenodiol is synthesized.

Claims

1. A method for synthesizing a natural product smenodiol, which is characterized by comprising the following steps:

a) taking 4mmol of clary sage hydrazone 2

Dissolved in waterIntroducing argon into a high-temperature high-pressure reaction tube of 40mL dry tetrahydrofuran for protection, adding 0.2mmol tetratriphenylphosphine palladium into the reaction tube, adding 18mmol potassium carbonate, and finally adding 4mmol 3-iodine-4, 5-dimethoxybenzoic acid methyl ester 3 into the reaction

Heating the reaction to 90 ℃, when the reaction time is 5 hours, detecting the complete reaction by TLC, adding water to quench the reaction, extracting the reaction solution by 20mL ethyl acetate for three times, washing the organic phase by 50mL saturated salt solution twice, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and extracting by column chromatography to obtain a coupling product 4

502mg total yellow solid, yield 32% and 842mg total yellow foam, yield 54%;

b) to 0.5mmol of Compound 4

50mg of 10% Pd/C in anhydrous MeOH, and the mixture was stirred at 40 ℃ under an atmosphere of hydrogen for 4h, then the resulting mixture was filtered and concentrated, and the residue was purified by flash column chromatography over 100-200 mesh silica gel with EtOAc/petroleum ether at 1:20 to 1:10 to give 121mg of the reduced product 5

The yield is 62 percent;

c) to 2mmol of Compound 5 at room temperature

0.2mmol of tin trifluoromethanesulfonate was added to 5mL of dichloromethane solution, the resulting mixture was stirred at room temperature for 6 hours, the starting material was completely reacted by TLC, diluted with dichloromethane, and the mixture thus obtained was successively diluted with 20mL of saturated Na₂CO₃The aqueous solution and 20mL of brine were washed twice each, the organic phases were combined, and the organic layer was washed with anhydrous Na₂SO₄Drying and passing throughFiltration, evaporation of the solvent under vacuum using a rotary evaporator, purification of the residue by flash column chromatography through 100-200 mesh silica gel with EtOAc/petroleum ether at 1:10 to 1:5 gave 745mg of a white solid, 6

The yield is 93 percent;

d) 1mmol of compound 6 is taken

Dissolving in a round-bottom flask containing 2mL of dried dichloromethane, introducing argon for protection, placing the system in a low-temperature reaction bath at-78 ℃, and slowly dropwise adding 1M BBr₃10mL of dichloromethane solution, continuously reacting at the temperature, detecting the reaction process by TLC (thin layer chromatography), when the reaction time is 5 hours, completely detecting the reaction by TLC, adding water to quench the reaction, extracting the reaction solution by 10mL of dichloromethane for three times, washing an organic phase by 20mL of saturated saline solution twice, drying the organic phase by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and extracting by column chromatography to obtain 302mg of yellow solid smenodiol 1

The yield thereof was found to be 81.2%.