CN109336899B - Method for synthesizing natural product gamma-lycorane - Google Patents
Method for synthesizing natural product gamma-lycorane Download PDFInfo
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- CN109336899B CN109336899B CN201811427964.9A CN201811427964A CN109336899B CN 109336899 B CN109336899 B CN 109336899B CN 201811427964 A CN201811427964 A CN 201811427964A CN 109336899 B CN109336899 B CN 109336899B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract
The invention discloses a method for synthesizing natural product gamma-lycorane. By the classical Johnson-claisen rearrangement reaction, I 2 The catalytic construction reaction of N heterocycle and the palladium-catalyzed coupling ring-closing reaction are used as key reaction steps in the synthesis process, and the final realizationThe natural product gamma-lycorane is formalized and synthesized. The whole route of the invention has unique and novel design, mild reaction conditions in the reaction process, high speed, relatively few side reactions and simple and convenient operation, and the route utilizes conventional chemical reagents, has cheap and easily obtained raw materials and can greatly reduce the synthesis cost.
Description
Technical Field
The invention relates to a synthesis method of a key intermediate of a compound with anticancer activity, in particular to a synthesis method of a natural product gamma-lycorane.
Background
The gamma-lycorane group belongs to the class of lycorine alkaloids. The lycorine alkaloid is an alkaloid found in amarillidic species of the monophyllaceae of angiospermae, and the lycorine-type alkaloid has been shown to have antiviral, antitumor or antitumor activity and other pharmacological effects. Morisima first isolated this alkaloid from lycoris radiata Herb. Leo et al report that these alkaloids inhibit the growth of higher plants and yeasts, and that the ascorbic acid/dehydroascorbic acid ratio is reduced in plants treated with the lycorine alkaloid. Gamma-lycorane is a typical lycoris alkaloid, both enantiomers of which were obtained by Kotera group in lycoris alkaloid lycorine degradation studies. The chemical structure of gamma-lycorane is as follows:
unlike other types of lycoris radiata alkaloids, it does not show significant pharmacological activity, but is a popular target compound because its unique five-membered ring structure can be used to validate new synthetic methods and strategies, leading to extensive synthetic studies where the literature reports of chemical methods for synthesizing the natural product are mainly: hideo Iido et al published in 1978 on JACS as a research paper titled An Intramolecular cycling of amines inviting Benzyne Intermediates and Application to the Synthesis of gamma-lysine and Related Compounds; a research paper entitled Palladium-media asymmetry Synthesis of Cis-3, 6-disubstitated Cyclohexenes.A Short Total Synthesis of OpticalActive (+) - γ -lysine published by Hiroki Yoshizaki et al in J.org.chem.1995; (a research paper of Total Synthesis of (+ -) -Lycorane and (+ -) -Crinane, published 2005 on J.org.chem, entitled A General and Efficient Strategy for 7-Aryloctahydro-indole and cis-3 a-Aryloctahydro-alkane; wai L.Yu et al, a research paper of the subject Short, Gram-Scale Syntheses of beta-and gamma-Lycorane Using Two diagnostic photo synthetic applications published in 2018 on org.Lett; ronan Rocaboy et al published a research paper on org.Lett in 2018 titled A Four-Step Synthesis of (+ -) - γ -lysine via Pd0-Catalyzed Double C (sp2) -H/C (sp3) -H Arylation.
Through the known synthetic routes, the inventor finds that many researchers at home and abroad use various methods to synthesize target molecules, and carefully analyzes the existing fully-synthetic route design and method, and has the defects of long synthetic steps, single synthetic strategy, difficult operation of individual reaction, expensive reagent and high toxicity. Therefore, the need for a general, efficient, and low-cost synthetic route is urgent.
Disclosure of Invention
The invention aims to solve the problems of long route, high synthesis cost and the like of the existing synthesis method and provides a brand new synthesis method of a natural product gamma-lycorane.
The invention aims to provide a brand new synthetic route: starting from the known compound of the formula 1, by means of a Johnson-claisen rearrangement reaction, I 2 The target molecule is synthesized through the catalytic construction reaction of N heterocycle, the palladium-catalyzed coupling ring closing reaction and the like. The whole route is unique and novel in design, the reaction conditions in the reaction process are mild, the speed is high, and side reactions are relatively fewThe method is simple and convenient to operate, conventional chemical reagents are utilized in the route, raw materials are cheap and easy to obtain, and the synthesis cost can be greatly reduced.
The method for synthesizing the natural product gamma-lycorane is characterized by comprising the following steps of:
1) taking 2-cyclohexene-1-alcohol as an initial raw material, carrying out Johnson-claisen rearrangement reaction on the compound of the formula 2, taking xylene as a solvent, and heating and refluxing at 150 ℃ to obtain a compound 3 which is efficiently controlled;
2) then dissolving the compound 3 in dichloromethane, and then carrying out DIBAL-H reduction to obtain an aldehyde compound 4;
3) aldehyde compound 4 and amine compound 5 undergo an aldehyde-amine condensation reaction, and sodium borohydride reduction reaction to obtain compound 6.
4) The compound 6 of formula is subjected to N heterocyclic ring construction under alkaline conditions and iodine catalysis, and finally a compound 7 is synthesized.
5) The compound 7 is prepared by taking cesium carbonate as an alkali source and coupling and closing a ring under the catalysis of a palladium reagent to complete the formalized synthesis of the natural product gamma-lycorane.
The reaction formula is as follows
In the step 1), 2-cyclohexene-1-alcohol is used as an initial raw material, and the conditions for Johnson-claisen rearrangement reaction by using the compound shown in the formula 2 are as follows: dissolving the compound 1 in dimethylbenzene under the protection of nitrogen at normal temperature, then adding the compound 2 and o-nitrophenol, changing the solution into light yellow, heating and refluxing for 7-9 hours at 150 ℃, concentrating under reduced pressure, and separating and purifying to obtain a compound 3.
In the step 2) of the invention, under the condition of room temperature nitrogen protection, the compound of the formula 3 is dissolved in dry dichloromethane, the temperature is shifted to-78 ℃, diisobutylaluminum hydride solution is slowly added into the reaction system for reaction for 0.5 hour, methanol and potassium sodium tartrate are added for quenching, after being stirred for 1-2 hours at room temperature for layering, the mixture is extracted by dichloromethane, decompressed and concentrated, separated and purified to obtain the compound 4.
In step 3), the reaction conditions for the aldehyde-amine condensation reduction reaction of the compound of formula 4 are as follows: at room temperature, under the protection of nitrogen, the compound 4 is dissolved in methanol, and the compound 5 is slowly added into the reaction system and stirred for 4 hours at the temperature. Cooling to 0 ℃, adding sodium borohydride, continuing stirring for 4 hours under the ice bath condition, then adding 2.5M sodium hydroxide solution for alkalization, raising the mixed system to room temperature, adding dichloromethane for extraction, concentrating under reduced pressure, separating and purifying to obtain the compound 6.
In step 4) of the present invention, formula 6 is performed 2 The catalytic N-heterocyclic reaction conditions are as follows: under the condition of room temperature and nitrogen protection, firstly dissolving anhydrous potassium carbonate in dry dichloromethane, adding the iodine simple substance until the liquid becomes purple, then adding a dichloromethane solution of a compound 6, continuing stirring for 30 minutes, adding a saturated ammonium chloride aqueous solution for quenching, extracting dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound shown in the formula 7.
In step 5) of the present invention, the reaction conditions for palladium-catalyzed coupling and ring closure of the compound of formula 7 are: under the protection of nitrogen at room temperature, dissolving the compound 7 in 1.4-dioxane, ultrasonically degassing at room temperature, adding palladium tetrakis (triphenylphosphine) and cesium carbonate, heating and refluxing at 100 ℃, and reacting for one hour to obtain the compound shown in the formula 8.
The invention has the beneficial effects that:
1. the design of the whole synthesis route is unique and novel, the single selective synthesis of the gamma-lycorane obtained by theory is realized, the speed is high, the side reaction is relatively less, and the product yield is high;
2. the conventional chemical reagents are utilized in the route, and raw materials and the reagents are cheap and easy to obtain, so that the production cost can be greatly reduced;
3. the synthesis route has simple and reasonable design, simple and convenient operation process, mild reaction conditions in the reaction process, less linear steps and suitability for industrial preparation.
Detailed Description
In order to better explain the present invention, the present invention is further described in detail with reference to the following specific examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
1. Synthesis of Compound 3: under the protection of nitrogen at normal temperature, compound 1(1.50g, 15.2842mmol, 1.0eq) was dissolved in xylene (100.22mL), and triethyl orthoacetate (22.97mL, 8.2eq) and o-nitrophenol (0.106g, 0.05eq) were added. Heating and refluxing at 150 deg.C for 7-9h, cooling to room temperature after TLC detection reaction, washing with dichloromethane DCM (1 × 30mL), and adding anhydrous NaSO 4 Drying, filtering to remove solid impurities, distilling under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether 1:150), and finally concentrating the eluent to obtain yellow oily liquid 3(2.1493 g). Yield: 83.5 percent.
2. Synthesis of Compound 4: under the protection of nitrogen at room temperature, dissolving a compound 3(1.1139g, 6.621mmol, 1.0eq) in 40mL of dry dichloromethane, cooling the solution to-78 ℃, after the temperature is stabilized, dropwise adding diisobutylaluminum hydride DIBAL-H (6.6mmol, 1.5eq), after dropwise adding, allowing the reaction system to continue to react at-78 ℃ for 30 minutes, monitoring by TLC, adding 10mL of methanol to quench, adding 30mL of saturated potassium sodium potassium tartrate solution, heating the mixed system to room temperature, stirring for 1-2 hours, filtering by using kieselguhr when the system is obviously layered, extracting the filtrate by using dichloromethane (3X 15mL), combining the obtained organic phases, washing by using saturated NaCl solution once, adding anhydrous NaSO 4 Drying, filtering to remove solid impurities, distilling under reduced pressure, purifying by column chromatography (ethyl acetate: petroleum ether 1:100), and concentrating the eluate to obtain compound 4(0.7017 g). Yield: 85 percent.
3. Synthesis of Compound 6: compound 4(0.6477g, 5.2156mmol, 1eq) was dissolved in 5.2mL of methanol at room temperature under nitrogen, then compound 5(0.65mL, 1eq) was added dropwise slowly to the reaction and stirred at this temperature for 4 hours. Then the system is put in ice water bath to be cooled to 0 ℃, and sodium borohydride NaBH is added 4 (0.6g, 3eq) at this temperature for 4 hours, then 2.6mL of 2.5M sodium hydroxide solution are added, the temperature is raised to room temperature, dichloromethane is added(3X 15mL), combine all the organic phases, remove some of the solvent by concentration under reduced pressure, combine the organic phases, add anhydrous MgSO 4 Drying, filtering to remove solid impurities, vacuum distilling, separating by column chromatography (ethyl acetate: petroleum ether: 1:5) and purifying to obtain compound 6(1.0125 g). Yield: 75 percent.
4. Synthesis of compound 7: anhydrous potassium carbonate (2.25g, 16.273mmol, 5eq) was dissolved in 163mL of dry methylene chloride under nitrogen at room temperature, followed by addition of iodine I 2 (0.83g, 3.2546mmol, 1eq) into the reaction until the solution becomes purple, which requires protection from light. Then, compound 6(0.8441g, 3.2546mmol, 1eq) was dissolved in 65mL of dry dichloromethane, slowly added dropwise to the iodine-containing reaction solution, stirred at room temperature for 30 minutes, quenched by adding 32mL of saturated ammonium chloride solution after TLC monitoring of the reaction, extracted by adding dichloromethane (3X 15mL) to the mixture, the resulting organic phases were combined, and anhydrous NaSO was added 4 Drying, filtering to remove solid impurities, distilling under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether 1:50), and finally concentrating the eluent to obtain the yield of a dark yellow thick liquid 7(1.0305 g): 82 percent.
5. Synthesis of compound 8: dissolving compound 7(0.15g, 0.3893mmol, 1eq) in 0.8mL of 1.4-dioxane under the protection of nitrogen at room temperature, then carrying out ultrasonic degassing, then adding tetrakis (triphenylphosphine) palladium (0.04g, 0.1eq) and cesium carbonate (0.25g, 2eq), heating and refluxing at 100 ℃ for one hour, reducing to room temperature after TLC monitoring of the reaction is finished, quenching with 1N hydrochloric acid solution, adding dichloromethane (3X 15mL) into the mixed system for extraction, combining the obtained organic phases, adding MgSO (MgSO) into the mixed system, and carrying out extraction by using anhydrous hydrochloric acid solution 4 Drying, filtering to remove solid impurities, distilling under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether 1:5), and finally concentrating the eluate to obtain the compound of formula 8 (0.059g) in yield: 50 percent.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, so that any modifications, equivalents and improvements made within the spirit and principle of the present invention are included in the scope of the present invention.
Claims (6)
1. A formalization synthesis method of a natural product gamma-lycorane is characterized by comprising the following steps:
1) taking 2-cyclohexene-1-alcohol as an initial raw material, carrying out Johnson-claisen rearrangement reaction on the compound of the formula 2, taking xylene as a solvent, and heating and refluxing at 150 ℃ to obtain a compound of the formula 3 which is efficiently controlled;
2) then dissolving the compound shown in the formula 3 in dichloromethane at normal temperature, and carrying out ester reduction reaction with diisobutyl aluminum hydride at-78 ℃ to obtain a compound shown in the formula 4;
3) dissolving the compound shown in the formula 4 in methanol, slowly dropping the compound 5, reacting at normal temperature for 4 hours, adding sodium borohydride in ice bath, reacting at the temperature for 4 hours, and performing an aldehyde-amine condensation reduction reaction to obtain a compound shown in the formula 6;
4) the compound of formula 6 is prepared at room temperature using dichloromethane as solvent, K 2 CO 3 As alkali source, use I 2 Catalyzing and constructing an N heterocycle to obtain a compound shown in a formula 7;
5) dissolving the compound shown in the formula 7 in 1, 4-dioxane, carrying out ultrasonic deoxygenation, then refluxing for 1.5 hours at 100 ℃ by taking tetrakis (triphenylphosphine) palladium as a catalyst and cesium carbonate as an alkali source to obtain a compound shown in the formula 8;
the reaction formula is as follows:
2. the process for the formal synthesis of the natural product γ -lycorane according to claim 1, characterized in that: in the step 1), in Johnson-claisen rearrangement, under the normal temperature and the protection of nitrogen, the compound of formula 2 and o-nitrophenol are added into a xylene solution of the compound of formula 1, the solution turns to light yellow, and then the solution is heated and refluxed for 7 to 9 hours at 150 ℃, and the compound of formula 3 is obtained through separation and purification.
3. The process for the formal synthesis of the natural product γ -lycorane according to claim 1, characterized in that: in the step 2), under the protection of nitrogen, the compound shown in the formula 3 is dissolved in dichloromethane at normal temperature and is subjected to ester reduction reaction with diisobutyl aluminum hydride at-78 ℃ to obtain the compound shown in the formula 4.
4. The process for the formal synthesis of natural product γ -lycorane according to claim 1, characterized in that: in the step 3), the reaction conditions for the aldehyde-amine condensation reduction reaction of the compound of formula 4 are as follows: dissolving the compound 4 in methanol at room temperature under the protection of nitrogen, slowly adding the compound shown in the formula 5 into a reaction system, reacting for 4 hours at room temperature, then adding sodium borohydride at ice bath, reacting for 4 hours at the temperature, and carrying out aldehyde-amine condensation reduction reaction to obtain the compound shown in the formula 6.
5. The process for the formal synthesis of natural product γ -lycorane according to claim 1, characterized in that: in step 4), the compounds of the formula 6 are subjected to I 2 The reaction conditions for the catalyzed N-heterocycle building reaction are: under the condition of room temperature, dissolving anhydrous potassium carbonate in dichloromethane, adding iodine simple substance until the solution becomes purple, dissolving the compound 6 in dichloromethane, and then dropwise adding the solution into iodine solution to obtain the compound shown in the formula 7.
6. The process for the formal synthesis of the natural product γ -lycorane according to claim 1, characterized in that: in step 5), the reaction conditions for palladium-catalyzed ring closure coupling of the compound of formula 7 are: under the protection of nitrogen at room temperature, dissolving the compound 7 in 1, 4-dioxane, carrying out ultrasonic degassing, adding tetrakis (triphenylphosphine) palladium and cesium carbonate, and heating and refluxing at 100 ℃ to obtain the compound shown in the formula 8.
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