KR100979633B1 - Synthesis of Biologically Interesting Pyranochromenes and its Natural Product Analoges - Google Patents

Abstract

The present invention relates to a method for synthesizing a pyranochrome and a natural product having a skeleton thereof. The present invention relates to a double condensation reaction with α, β-unsaturated aldehyde under an ethylenediamine diacetate catalyst using a substituted trihydroxybenzene as a starting material. Through the synthesis of biologically important pyranochrome, and using the synthesis method to synthesize a variety of natural products and derivatives including the pyranochrome skeleton, this synthesis method is very simple and efficient It also provides a method of synthesizing various natural products, particularly physiologically useful.

Pyranochromen, double condensation, trihydroxybenzene, electron ring reaction

Description

Synthesis of Biologically Interesting Pyranochromenes and its Natural Product Analoges

The present invention relates to a method for synthesizing pyranochromen and related natural products.

Pyranochromenes or pyranobenzopyrans, one of the heterocycles, have received considerable attention in the field of organic and natural product synthesis. Compounds with these pyranochromens show a range of biological and pharmacological properties, including antioxidant, anticancer, anti-inflammatory, antiviral, antibacterial and anti-HIV activity ((a) Ellis, GP Chromenes, Chromanones , and Chromones in The Chemistry of Heterocyclic Compounds; Wiley: New York, 1977; Vol. 31, p 11. (b) Hepworth, J. Comprehensive Heterocyclic Chemistry; Katrizky, AR, Rees, CW, Eds .; Pergamon: Oxford, UK, 1984; Vol. 3, p 737. (c) McKee, T .; Fuller, RW; Covington, CD; Cardellina II, JH; Gulakowski, RJ; Krepps, BL; McMahon, JB; Boyd, MRJ Nat. Prod 1996, 59, 754. (d) Galinis, DL; Fuller, RW; McKee, TC; Cardellina II, JH; Gulakowski, RJ; McMahon, JB; Boyd, MRJ Med. Chem. 1996, 39, 4507. (e Cardellina, JH; Bokesch, HR; McKee, TC; Boyd, MR Bioorg.Med. Chem. Lett. 1995, 5, 1011.).

Examples of the molecules having pyranocromene found in nature include molecules represented by the chemical structural formula of FIG. 1, and molecules having such pyranocromene are widely found in nature.

Clusiaphenone A of Formula 1 is a natural product extracted from Clusia elipticifolia (Olivares, E, M .; Gonzalez, JG; Monache, FD Phytochemistry 1994, 36, 473.).

Formula 2 octane drain nolron, frans of formula (3) of the O- methyl octane drain nolron, formula (4) ^... , 4 ^... -Dihydro-3 ^... , 4 ^... - dihydroxy -O- methyl octane drain nolron, trans -3 ^‥, 4 ^‥ of formula (5), and 6-dihydro -3 ^‥, 4 ^{‥-dihydroxy} -O- methyl octane drain nolron is mellitic Corp. Thermal carbonate ( Melicope ternate ) and M. erromangensis ((a) Davis, M .; Pettett, M. Aust. J. Chem. 1979, 32, 369. (b) Rustaiyan, A Nazarians, L. Bohlmann, F. Phytochemistry 1980, 19, 1254. (c) Kamperdick, C .; Van, NH; Sung, TV; Adam, G. Phytochemistry 1997, 45, 1049. (d) Cambie, RC; Pan, YJ; Bowden, BF Biochem.System.Ecol. 1996, 24, 461. (e) Muyard, F .; Bissoue, AN; Bevalot, F .; Tillequin, F .; Cabalion, P .; Vaquette, J. Phytochemistry 1996, 42, 1175.).

Flemiculosin of formula (8) having a chalcone structure is represented by Flemengia fruticulosa ), and its derivative, Lacchacon , of Formula 9 was extracted from the roots of Derris laxichalcone . (-)-3-deoxy-MS-II of Chemical Formula 10 is extracted from the extracts of the bark and leaves of Mundulea chapelieri , which has been reported to have potential activity against human ovarian cancer cell lines. It is becoming.

Benzopyran  Preceding Study on Synthesis Method

We have developed a method for preparing various benzopyrans using catalyzed reactions of ethylenediaminediacetate with α, β-unsaturated aldehydes from substituted resorcinols (Lee, YR; Choi, JH; Yoon, SH Tetrahedron Lett. 2005, 46,7539.).

The following chemical scheme shows the process for the reaction of substituted resorcinol with α, β-unsaturated aldehyde to reflux in xylene solvent in the presence of 10 mol% using ethylenediaminediacetate as catalyst to produce benzopyran .

At this time, R, R ₁ , R ₂ , R ₃ , R ₄ is selected from H, methyl, alkyl, OH, OMe, OEt.

In addition, the present inventors have developed a method for synthesizing various physiologically significant natural products having a benzopyran skeleton using the above synthesis method ((a) Lee, YR; Kim, DH Synthesis 2006, 603. (b Lee, YR; Lee, WK; Noh, SK; Lyoo, WS Synthesis 2006, 853. (c) Lee, YR; Wang, X. Bull.Korean Chem. Soc. 2005, 26, 1933. (d) Wang, X .; Lee, YR Synthesis 2007, 3044. (e) Lee, YR; Xia, L. Synthesis 2007, 3244. (f) Wang, X .; Lee, YR Tetrahedron Lett. 2007, 48,6275. (G) Lee , YR; Kim, JH Synlett 2007, 2232.).

The present invention confirms that the benzopyran synthesis methodologies lead to efficient and ideal results, and to provide a method for simply and effectively synthesizing pyranochromen (or pyranobenzopyran) on an extension thereof.

Another objective is to use this synthetic method to produce physiologically important natural products with this pyranochrome skeleton, clusiaphenone A, octandrenolone, and O-methyloctanedrenolone. O-methyloctandrenolone), trans-3 ^... , 4 ^... -Dihydro-3 ^... , 4 ^... -Dihydroxy-O-methyloctanedrenolone (trans-3 ^… , 4 ^… -dihydro-3 ^… , 4 ^… -dihydroxy-O-methyloctandrenolone), trans-3 ^‥ , 4 ^‥ -dihydro-3 ^‥ , 4 ^‥ -dihydroxy-O-methyloctanedrenolone (trans-3 ^‥ , 4 ^‥ -dihydro-3 ^‥ , 4 ^‥ -dihydroxy-O-methyloctandrenolone), flemiculosin, laxichalcone And 3-dioxy-Ms-II (racemic 3-deoxy-Ms-II) synthesis method.

The present invention synthesizes a biologically meaningful pyranochromen by using a substituted trihydroxybenzene as a starting material through a double condensation reaction with α, β-unsaturated aldehyde under the catalyst of ethylenediamine diacetate.

In addition, the synthesis method is applied to synthesize a variety of natural products containing pyranochromen.

Pyranocromene has been the subject of research for a long time due to its diverse biological activity and wide application potential, but the results of the methodology capable of synthesizing molecules having pyranocromene have been negligible.

The present invention provides a very simple and efficient method for synthesizing pyranochromen for a wider range of applications in the industry, and in particular, provides a method for synthesizing a variety of physiologically useful natural products with a simple route.

Hereinafter, the present invention will be described in detail with reference to FIGS. 2 to 7.

2 shows the results of reaction with 3-methyl-2-butenal under the use of several catalysts.

In synthesizing the pyranocromene skeleton according to the present invention, the selection range of the reaction process, the catalyst and the reaction conditions will be described in detail.

As a starting material, 2.5 equivalent of 3-methyl-2-butenal as an unsaturated aldehyde was added to 2,4,6-trihydroxybenzoic acid of Chemical Formula 11, and the reaction results according to the catalyst and reaction conditions were investigated.

First, indium (III) chloride (20 mol%), ytterbium (III) triflate (20 mol%) as Lewis acid catalysts, pyridine, Ca (OH) ₂ and weak acid PPTS as base catalysts were used as catalysts. No products were obtained when the reaction proceeded under.

 On the other hand, when ethylenediamine diacetate is used as a catalyst, it can be seen that benzopyrans and pyranocromenes represented by Chemical Formulas 12 and 13 are produced as products.

Using 20 mol% of ethylenediamine diacetate as a catalyst, 2.5 equivalent of 3-methyl-2-butenal was added to 2,4,6-trihydroxybenzoic acid of Chemical Formula 11, and refluxed under a benzene solvent for 10 hours. In other words, benzopyran represented by the formula (12) was obtained in 34% yield, pyranocromene represented by the formula (13) was obtained in 10% yield.

On the other hand, when refluxed for 10 hours in a toluene solvent, only the compound of Formula 13 was produced in a yield of 40%.

Different solvents were investigated to give higher yields of product.

That is, upon heating for 10 hours in a chloroform solvent, only the compound of formula 13 was obtained in a yield of 56%. In contrast, the highest yield (91%) of the compound of Formula 13 was obtained when the reaction was carried out for 10 hours at room temperature in a methylene chloride solvent.

In the above experimental study, the reaction with α, β-unsaturated aldehydes using various forms of substituted trihydroxybenzenes in order to generate various forms of pyranochromen derivatives was examined.

Figure 3 shows derivatives of pyranochromen produced through the reaction between various forms of substituted trihydroxybenzenes and α, β-unsaturated aldehydes.

Entry 1 is a 20 mol% catalyst as a starting material for the reaction of 3-methyl-2-butenal with 2,4,6-trihydroxybenzaldehyde, represented by chemical formula 14. Ethylenediamine diacetate was added and the compound of Chemical Formula 17 was obtained in a yield of 69% when reacted in methylene chloride for 12 hours at room temperature.

Entry 2 is a starting material, 20 mol% of ethylenediamine diacetate is added as a catalyst in the reaction of 2,4,6-trihydroxyacetophenone and crotonaldehyde represented by Chemical Formula 15, and 12 at room temperature. When reacted in methylene chloride for a time, the compound of Chemical Formula 18 was obtained in a yield of 60%.

Noteworthy results indicate that compounds with longer substituents on α, β-unsaturated aldehydes yield higher yields, for example entry 3 is the starting material 2,4,6- In the reaction of trihydroxyacetophenone with citral, 20 mol% of ethylenediamine diacetate was added as a catalyst, and when reacted in methylene chloride for 12 hours at room temperature, the compound of Chemical Formula 19 was obtained in a yield of 93%.

On the other hand, under the same conditions, entry 4 is 20 mol as a catalyst in the reaction of 2,4,6-trihydroxyacetophenone represented by chemical formula 15 as a starting material with trans, trans-farnesal. % Ethylenediamine diacetate was added, and the reaction mixture was reacted in methylene chloride at room temperature for 12 hours to provide a compound of Chemical Formula 20 in a yield of 84%.

Entry 5 is a catalyst in the reaction of 3-methyl-2-butenal with methyl-2,4,6-trihydroxybenzoate represented by chemical formula 16 as starting material. Ethylenediamine diacetate in mol% was added and the compound of Chemical Formula 21 was obtained in a yield of 80% when reacted in methylene chloride for 12 hours at room temperature.

The above findings provide a rapid route for the synthesis of pyranochromen derivatives having various substituents on the pyranyl ring.

As another object of the present invention, a method for producing biologically important natural products, including a pyranochrome skeleton, by applying the above synthesis method, will be described below with reference to FIGS.

Figure 4 is a chemical scheme showing the synthetic route of the natural product clusciaphenone A.

As a starting material, 20 mol% of ethylenediamine diacetate was added as a catalyst in the reaction of 2,4,6-trihydroxybenzophenone represented by Chemical Structural Formula 28 with 3-methyl-2-butenal, followed by 10 hours at room temperature. When the reaction was carried out in methylene chloride for a compound of formula 1 was obtained in 92% yield

FIG. 5 is a chemical scheme showing a synthetic route of octane drenolone as natural products.

When reacting a compound represented by the formula (15) with 3-methyl-2-butenal as a starting material, 20 mol% of ethylenediamine diacetate was used as a catalyst, and when reacted in methylene chloride for 10 hours at room temperature, octane of the formula (2) Drenolone was obtained with a yield of 91%. The spectral data of Synthesis 2 was consistent with the reported data (Cambie, R. C .; Pan, Y. J .; Bowden, B. F. Biochem. System. Ecol. 1996, 24, 461.).

Under K ₂ CO ₃ in an acetone solvent, O-methyloctanedrenolone, a compound represented by the formula (3), was obtained in a yield of 94% through the reaction of the compound represented by the formula (2) with methyl iodide. .

At room temperature in acetone solvent, including water, if dimethyl Oaks Lane (dimethyldioxrane) the reaction of a compound of formula (3) 1.1 equivalent of trans 32 ^... , 4 ^... -Dihydro-3 ^... , 4 ^... - dihydroxy -O- methyl octane nolron drain (4) and trans -3 ^{‥, ‥} 4-dihydro -3 ^‥, 4 ^‥ - that were 52% dihydroxy -O- methyl octane drain nolron 6 and Obtained with a yield of 27%. No epoxide compound was produced which was the expected product.

The structure of the compounds of Formulas 4 and 6 can be clearly confirmed by comparing the chemical change of the methoxy group on the pyranyl ring and the two methine protons with those reported in the literature (Muyard, F ;; Bissoue, AN; Bevalot, F .; Tillequuin, F .; cabalion, P .; vaquette, J. Phytochemistry 1996, 42, 1175)

Formation of the trans-product proceeds through the epoxidation of olefins in the pyranyl ring, followed by direct ring opening by attack of water in an acetone solvent containing water.

FIG. 6 is a chemical scheme showing a synthetic route of plemiculosin (Formula 8), lacchaconone (Formula 9), and racemate 3-dioxy-Ms-II (Formula 10) as natural products.

In the presence of KOH in an ethanol solution for 48 hours at room temperature, the condensation reaction of the compound represented by the formula (2) with benzaldehyde (benzaldehyde) was obtained in 90% yield of the plemiculosin represented by the formula (8).

When reacting the compound represented by the formula (8) and sodium acetate in reflux ethanol, 3-dioxy-Ms-II (Chemical Formula 10) as a racemate was obtained in a yield of 47%. The spectral data of compounds (8) and (10) were the same as reported in the literature (Khattri, PS; Sahai, M .; Dasgupta, B .; Ray, AB Heterocycles 1984, 22, 249.) (Cao, S Schilling, JK; Miller, JS; Andriantsiferana, R .; Rasamison, VE; Kingston, DGIJ Nat. Prod. 2004, 67, 454.).

On the other hand, using KOH in ethanol for 48 hours at room temperature, condensation reaction of the compound represented by the formula (2) and 4-methoxybenzaldehyde obtained a compound represented by the formula (29) in a yield of 85% (Basaif, SA; Sobahi , TR; Khalil, AK; Hassan, MA Bull.Korean Chem. Soc. 2005, 26, 1677.).

Removal of methyl ether using Compound 29 with concentrated hydrochloric acid (c-HCL) in methanol solvent, a known method, was unsuccessful (Deodhar, M .; Black, DS; Kumar, N.). Org.Prep.Proc.Int. 2006, 38, 94.).

Fortunately, in the methylene chloride solvent, the reaction of the compound represented by the formula (29) and BBr ₃ to obtain the compound laxichalcone (laxichalcone) represented by the formula (9) in a yield of 86%. The spectral data of this compound (9) were the same as reported in the literature (Lin, YL; Chen, YL; Kuo, YH Chem. Pharm. Bull. 1992, 40, 2295.).

Example

Hereinafter, the present invention will be described in detail through specific examples.

All experiments according to the invention were carried out under a nitrogen atmosphere. Merck silica gel plates (Art. 5554) pre-coated with fluorescent indicators were used for thin film chromatography (TLC) for analysis. Flash column chromatography was performed using silica gel 9385 (manufactured by Merck). Proton nuclear magnetic resonance spectroscopy ( ¹ H NMR) spectra and carbon 13 nuclear magnetic resonance spectroscopy ( ¹³ C NMR) spectra were identified as solvent chemical shifts with a Bruker model ARX (300 MHz and 75 MHz, respectively) spectrometer. Recordings were made in CDCl ₃ using 7.24 and δ = 77.0 ppm. Infrared spectroscopic analysis spectra were recorded on a Jasco FTIR 5300 spectrophotometer. High resolution mass spectroscopy (HRMS) and mass spectrometry (MS) spectra were performed by the Korea Basic Science Institute.

Pyranochrome  Common Process for Synthesis

Common reaction procedures and procedures for the synthesis of Formula 13, Formula 17, Formula 18, Formula 19, Formula 20, and Formula 21 will be described.

Ethylenediamine diacetate (36 mg, 0.2 mmol) was added to 1.0 mmol of substituted trihydroxybenzene and 2.5-3.0 mmol of α, β-unsaturated aldehyde solution in the presence of 10 ml of methylene chloride, and at room temperature Stir for 10-12 hours. Removal of the solvent left an oily residue which was then purified by column chromatography on silica gel to give the products of the above formula.

5-hydroxy-2,2,8,8- Tetramethyl -2H, 8H- Pyrano [2,3-f] chromen -6- Carboxylic acid (13).

In the presence of 10 ml of methylene chloride, the compound of formula 11 (170 mg, 1.0 mmol) and 3-methyl-2-butenal (252 mg, 3.0 mmol) were reacted to give a compound of formula 13 (275 mg, 91%) were obtained: melting point 98-99 ° C .; Proton Nuclear Magnetic Resonance Spectroscopy (300MHz, CDCl ₃ ) δ 12.37 (1H, s), 11.50 (1H, s), 6.63 (1H, d, J = 10.0㎐), 6.58 (1H, d, J = 10.0㎐ ), 5.49 (1H, d, J = 10.0 ms), 5.47 (1H, d, J = 10.0 ms), 1.53 (6H, s), 1.43 (6H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75 MHz, CDCl ₃ ) δ 170.8, 160.0, 154.4, 152.8, 126.3, 124.9, 116.3, 115.9, 103.8, 102.3, 94.9, 81.2, 78.4, 28.3, 27.7; Infrared spectroscopy (KBr) 3229, 2976, 2928, 1691, 1647, 1591, 1439, 1368, 1292, 1248, 1171, 1128, 997, 818, 714 cm ⁻¹ ; High resolution mass spectrometry m / z (M ⁺ ) Calcd for C ₁₇ H ₁₈ O ₅ : 302.1154. Found: 302.1152.

5-hydroxy-2,2,8,8- Tetramethyl -2H, 8H- Pyrano [2,3-f] chromen -6- Carboaldehyde (17).

In the presence of 10 ml of methylene chloride, the reaction of the compound of formula 14 (154 mg, 1.0 mmol) with 3-methyl-2-butenal (252 mg, 3.0 mmol) in the oil state represented by the formula (17) 198 mg, 69%): proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 12.34 (1H, s), 10.05 (1H, s), 6.57 (1H, d, J = 10.0 μs), 6.51 (1H, d, J = 10.0 kPa), 5.45 (1H, d, J = 10.0 kPa), 5.43 (1H, d, J = 10.0 kPa), 1.42 (12H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75 MHz, CDCl ₃ ) δ 192.1, 159.4, 157.9, 156.9, 126.1, 125.9, 116.2, 115.8, 105.9, 102.4, 102.0, 78.9, 78.6, 28.3, 28.3; Infrared spectroscopic analysis (original) 2976, 1647, 1439, 1368, 1302, 1142, 1113, 999, 872, 796, 721 cm ^-1 ; High resolution mass spectrometry m / z (M ⁺ ) Calcd for C ₁₇ H ₁₈ O ₄ : 286.1205. Found: 286.1207.

1- (5-hydroxy-2,8-dimethyl-2H, 8H- Pyrano [2,3-f] chromen -6- days) Ethanone (18).

In the presence of 10 ml of methylene chloride, the compound of Formula 15 (154 mg, 1.0 mmol) and crotonaldehyde (210 mg, 3.0 mmol) were reacted to obtain a compound represented by Formula 18 (163 mg, 60%) as an oil. Proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 13.95 (1H, s), 6.67 (1H, dd, J = 10.0, 1.7 Hz), 6.59 (1H, dd, J = 10.0, 1.7 Hz) , 5.49 (1H, d, J = 10.0 μs), 5.47 (1H, d, J = 10.0 μs), 5.06-4.99 (2H, m), 2.61 (3H, s), 1.47 (3H, d, J = 6.6 Viii), 1.42 (3H, d, J = 6.6 kPa); Carbon 13 nuclear magnetic resonance spectroscopy (75 MHz, CDCl ₃ ) δ 203.8, 160.8, 157.7, 155.8, 121.8, 121.3, 118.5, 118.0, 105.8, 103.4, 103.1, 73.2, 72.9, 33.5, 22.1, 21.5; Infrared spectroscopy (original) 2978, 2932, 1601, 1433, 1366, 1319, 1292, 1262, 1200, 1148, 1117, 1028, 880, 733 cm ^-1 ; High resolution mass spectrometry m / z (M ⁺ ) Calcd for C ₁₆ H ₁₆ O ₄ : 272.1049. Found: 272.1052.

1- (5-hydroxy-2,8-dimethyl-2,8- Vis -(4- methyl -3- Pentenyl ) -2H, 8H- Pyrano [2,3-f] chromen -6- days) Ethanone (19).

In the presence of 10 ml of methylene chloride, the compound of formula 15 (154 mg, 1.0 mmol) and citral (456 mg, 3.0 mmol) were reacted to give the compound represented by formula 19 (406 mg, 93%) as an oil. Obtained: proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 14.00 (1H, s), 6.66 (1H, d, J = 10.0 μs), 6.60 (1H, d, J = 10.0 μs), 5.38 ( 1H, d, J = 10.0 Hz), 5.35 (1H, d, J = 10.0 Hz), 5.10-5.03 (2H, m), 2.62 (3H, s), 2.14-2.01 (4H, m), 1.87-1.67 (4H, m), 1.63 (6H, s), 1.54 (6H, s), 1.40 (3H, s), 1.39 (3H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75MHz, CDCl ₃ ) δ 203.5, 160.9, 157.4, 155.6, 132.4, 132.1, 124.5, 124.3, 124.1, 123.7, 117.3, 117.0, 105.6, 102.3, 102.0, 81.3, 80.9, 42.0 , 41.9, 33.7, 27.4, 27.3, 26.1, 23.5, 23.0, 18.0; Infrared spectroscopy (original) 2971, 2926, 1599, 1429, 1364, 1298, 1192, 1105, 1074, 1001, 897, 837, 729 cm ^-1 ; High resolution mass spectrometry m / z (M ⁺ ) Calcd for C ₂₈ H ₃₆ O ₄ : 436.2614. Found: 436.2612.

1- [2,8- Vis -(4,8- Dimethylnona -3,7- Dini ) -5-hydroxy-2,8-dimethyl-2H, 8H- Pyrano [2,3-f] chromen -6- days) Ethanone (20).

In the presence of 10 ml of methylene chloride, the compound represented by Formula 15 (154 mg, 1.0 mmol) and trans, trans-parnesal (661 mg, 3.0 mmol) were reacted to react the compound of Formula 20 (481 mg, 84%). Was obtained as an oil: proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 14.03 (1H, s), 6.67 (1H, d, J = 10.0 μs), 6.62 (1H, d, J = 10.0 μs) , 5.38 (1H, d, J = 10.0 kPa), 5.37 (1H, d, J = 10.0 kPa), 5.10-5.05 (2H, m), 2.64 (3H, s), 2.10-1.85 (14H, m), 1.81-1.70 (2H, m), 1.65 (9H, s), 1.57 (9H, s), 1.40 (3H, s), 1.40 (3H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75MHz, CDCl ₃ ) δ 203.9, 161.6, 157.9, 156.2, 136.6, 136.3, 132.1, 125.4, 125.3, 125.1, 124.8, 124.7, 124.6, 118.0, 117.7, 106.2, 103.0, 102.7 , 102.6, 81.9, 81.5, 42.7, 42.6, 40.7, 34.2, 32.6, 28.0, 27.9, 27.7, 27.6, 26.7, 24.0, 23.7, 23.5, 18.7, 16.9; Infrared spectroscopic analysis (original) 2926, 1601, 1429, 1366, 1296, 1153, 1105, 1001, 895, 729 cm ^-1 ; Mass spectrometry (EI) 572 (M ⁺ ), 423, 422, 421, 285, 231, 69; High resolution mass spectrometry m / z (M ⁺ ) calcd for C ₃₈ H ₅₂ O ₄ : 572.3866. Found: 572.3863.

5-hydroxy-2,2,8,8- Tetramethyl -2H, 8H- Pyrano [2,3-f] chromen -6- Carboxylic acid methyl ester (21).

Compound represented by formula 21 (253 mg, 80) by reacting compound of formula 16 (184 mg, 1.0 mmol) with 3-methyl-2-butenal (252 mg, 3.0 mmol) in 10 ml of methylene chloride. %) As an oil: proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 11.96 (1H, s), 6.60 (1H, d, J = 10.0 μs), 6.52 (1H, d, J = 10.0 Iii), 5.40 (1H, d, J = 10.0 Hz), 5.39 (1H, d, J = 10.0 Hz), 3.84 (3H, s), 1.38 (12H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75 MHz, CDCl ₃ ) δ 172.3, 159.2, 156.3, 154.3, 125.9, 125.8, 116.8, 116.7, 78.2, 77.9, 52.4, 28.7, 28.1; Infrared spectroscopy (KBr) 2924, 1732, 1651, 1443, 1366, 1290, 1246, 1211, 1142, 999, 883, 740 cm ⁻¹ ; High resolution mass spectrometry m / z (M ⁺ ) calcd for C ₁₈ H ₂₀ O ₅ : 316.1311. Found: 316.1310.

Clasiaphenone  A (1).

Ethylenediaminediacetate by reaction with 2,4,6-trihydroxybenzophenone (230 mg, 1.0 mmol) and 3-methyl-2-butenal (252 mg, 3.0 mmol) in the presence of 10 ml of methylene chloride. (36 mg, 0.2 mmol) was added and stirred at room temperature for 10 hours. Removal of the solvent left a residue, which was then purified by column chromatography on silica gel to give the compound of formula 1 (333 mg, 92%) as a solid: melting point 146-147 ° C .; Proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 12.72 (1H, s), 7.47-7.35 (5H, m), 6.68 (1H, d, J = 10.0 μs), 6.49 (1H, d, J = 10.0 μs), 5.47 (1H, d, J = 10.0 μs), 5.26 (1H, d, J = 10.0 μs), 1.45 (6H, s), 0.96 (6H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75 MHz, CDCl ₃ ) δ 200.4, 159.7, 156.1, 155.4, 142.7, 129.8, 127.4, 127.1, 125.3, 125.0, 116.0, 115.8, 105.0, 102.2, 102.0, 78.2, 77.7, 28.4 , 27.4; Infrared spectroscopic analysis (KBr) 2980, 1645, 1589, 1447, 1429, 1312, 1286, 1138, 1113, 875, 713 cm ⁻¹ ; High resolution mass spectrometry m / z (M ⁺ ) calcd for C ₂₃ H ₂₂ O ₄ : 362.1518. Found: 362.1520.

Octanedrenolone (2).

Ethylenediamine diacetate (36 mg, 0.2 mmol) was added in the presence of 10 ml of methylene chloride, and 2,4,6-trihydroxyacetophenone (168 mg, 1.0 mmol) and 3-methyl-2-butenal ( 252 mg, 3.0 mmol) was stirred at room temperature for 10 hours. Solvent removal left a residue, which was then purified by column chromatography on silica gel to give the compound represented by formula (273 mg, 91%) as a solid: melting point 88-90 ° C .; Proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 13.98 (1H, s), 6.63 (1H, d, J = 10.0 μs), 6.56 (1H, d, J = 10.0 μs), 5.44 (1H, d , J = 10.0 μs), 5.41 (1H, d, J = 10.0 μs), 2.63 (3H, s), 1.58 (6H, s), 1.42 (6H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75 MHz, CDCl ₃ ) δ 203.6, 160.9, 157.1, 155.4, 125.7, 125.1, 116.8, 116.6, 105.9, 102.7, 102.6, 78.6, 78.5, 33.6, 28.7, 28.4; Infrared spectroscopic analysis (KBr) 3401, 1642, 1599, 1464, 1427, 1362, 1302, 1283, 1196, 1140, 1119, 882, 729 cm ^-1 ; High resolution mass spectrometry m / z (M ⁺ ) Calcd for C ₁₈ H ₂₀ O ₄ : 300.1362. Found: 300.1363.

O- Methyloctanedrenolone (3).

1 ml of methyl iodide (85 mg, 0.6 mmol) in a solution of the compound of Formula 2 (150 mg, 0.5 mmol) and 5 ml of acetone solution in which potassium carbonate (345 mg, 2.5 mmol) was mixed Acetone solution was added. The mixture was stirred at rt for 10 h and evaporated under reduced pressure. The residue was treated with water, acidified with 1N hydrochloric acid and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to give compound (148 mg, 94%) as a liquid: proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 6.60 ( 1H, d, J = 10.0 Hz), 6.48 (1H, d, J = 10.0 Hz), 5.55 (1H, d, J = 10.0 Hz), 5.52 (1H, d, J = 10.0 Hz), 3.77 (3H, s), 2.52 (3H, s), 1.56 (6H, s), 1.43 (6H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75 MHz, CDCl ₃ ) δ 200.6, 153.4, 151.2, 150.3, 127.7, 127.6, 117.4, 116.5, 116.0, 108.1, 106.3, 77.1, 76.6, 63.4, 32.5, 27.8, 27.7; Infrared spectroscopy (original) 2972, 1700, 1593, 1134, 999, 883, 741 cm ^-1 ; High resolution mass spectrometry m / z (M ⁺ ) calcd for C ₁₉ H ₂₂ O ₄ : 314.1518. Found: 314.1516.

Trans-3 ^… ,4 ^… - Dihydro -3 ^… ,4 ^… Dihydroxy-O- Methyloctanedrenolone 4 and trans-3 ^‥ ,4 ^‥ - Dihydro -3 ^‥ ,4 ^‥ Dihydroxy-O- Methyloctanedrenolone (6).

To a compound of formula 3 (126 mg, 0.4 mmol) was added dimethyldioxirane (15.4 mL, 0.052 M in acetone, 0.8 mmol) in acetone solvent (10 mL) with water at room temperature. The mixture was stirred at rt for 5 h and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to obtain the compound represented by formula 4 (73 mg, 52%) and the compound represented by formula 6 (38 mg, 17%). Compound (4): melting point 138-139 ° C .; Proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 6.55 (1H, d, J = 10.0 μs), 5.49 (1H, d, J = 10.0 μs), 4.70 (1H, d, J = 7.0 μs), 3.83 (3H, s), 3.72 (1H, d, J = 7.0 kPa), 2.51 (3H, s), 1.47 (3H, s), 1.43 (3H, s), 1.39 (3H, s), 1.23 (3H , s); Carbon 13 nuclear magnetic resonance spectroscopy (75 MHz, CDCl ₃ ) δ 200.7, 156.5, 151.6, 149.6, 127.4, 117.3, 116.1, 109.6, 106.4, 78.5, 77.1, 75.1, 67.6, 62.4, 28.1, 27.3, 25.7, 19.2 ; Infrared spectroscopy (KBr) 3445, 2976, 1693, 1586, 1468, 1181, 1132, 802, 736 cm ⁻¹ ; High resolution mass spectrometry m / z (M ⁺ ) calcd for C ₁₉ H ₂₄ O ₆ : 348.1573. Found: 348.1575. Compound (6): melting point 129-130 ° C .; Proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 6.47 (1H, d, J = 10.0 μs), 5.52 (1H, d, J = 10.0 μs), 4.71 (1H, d, J = 7.0 μs), 3.75 (3H, s), 3.75 (1H, d, J = 7.0 kPa), 2.45 (3H, s), 1.60 (3H, s), 1.44 (6H, s), 1.24 (3H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75 MHz, CDCl ₃ ) δ 200.6, 153.7, 153.3, 150.2, 127.0, 118.1, 116.4, 108.1, 108.0, 79.1, 78.0, 75.0, 67.8, 63.1, 32.3, 28.1, 28.0, 25.6 , 19.4; Infrared spectroscopy (KBr) 3454, 2976, 1695, 1635, 1591, 1466, 1181, 1130, 887, 742 cm ^-1 ; High resolution mass spectrometry m / z (M ⁺ ) calcd for C ₁₉ H ₂₄ O ₆ : 348.1573. Found: 348.1574.

Flemiculosin (8).

Potassium hydroxide (112 mg, 2.0 mmol) and benzaldehyde (64 mg, 0.6 mmol) in a solution containing the compound of Formula 2 (150 mg, 0.5 mmol) in 10 ml of ethanol and 2 ml of water at room temperature. Was added. The mixture was stirred at room temperature for 48 hours, acidified with 2N hydrochloric acid (20 mL), the mixture was extracted with ethyl acetate (3 * 30 mL), washed with water and dried over anhydrous sodium sulfate. Solvent removal left a residue, which was then purified by column chromatography on silica gel to give the compound of formula 8 (175 mg, 90%) as a solid: melting point 98-99 ° C .; Proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 8.08 (1H, d, J = 15.6 μs), 7.75 (1H, d, J = 15.6 μs), 7.60-7.57 (2H, m), 7.43-7.34 (3H, m), 6.67 (1H, d, J = 10.0 kPa), 6.56 (1H, d, J = 10.0 kPa), 4.88 (2H, d, J = 10.0 kPa), 1.53 (6H, s), 1.44 (6H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75MHz, CDCl ₃ ) δ 193.3, 161.9, 156.6, 155.7, 142.5, 136.0, 130.5, 129.4, 128.7, 128.0, 125.8, 125.2, 117.0, 116.7, 106.4, 103.0, 102.9, 78.7 , 77.6, 28.8, 28.5; Infrared spectroscopy (KBr) 2975, 2928, 1640, 1588, 1551, 1450, 1424, 1343, 1186, 1157, 1115, 1001, 878, 768, 723 cm ⁻¹ ; High resolution mass spectrometry m / z (M ⁺ ) Calcd for C ₂₅ H ₂₄ O ₄ : 388.1675. Found: 388.1673.

3- Deoxy - Ms -II (10).

To a solution of 10 ml of ethanol and sodium acetate (246 mg, 3.0 mmol) at room temperature was added the compound of Formula 8 (117 mg, 0.3 mmol). The reaction mixture was refluxed for 48 hours. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in 20 ml of water. After acidification with 2N hydrochloric acid (20 mL), the mixture was extracted with ethyl acetate (3 * 30 mL), washed with water and dried over anhydrous sodium sulfate. The solvent was removed to leave an oily residue which was then purified by column chromatography on silica gel to give compound 10 (55 mg, 47%) as a solid: melting point 145-146 ° C .; Proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 7.46-7.34 (5H, m), 6.59 (1H, d, J = 10.0 μs), 6.55 (1H, d, J = 10.0 μs), 5.48 (1H , d, J = 10.0 μs), 5.43 (1H, d, J = 10.0 μs), 5.38 (1H, dd, J = 13.1, 3.0 μs), 2.95 (1H, dd, J = 16.5, 13.1 μs), 2.76 (1H, doublet of doublets , J = 16.5, 3.0 Hz), 1.53 (3H, s), 1.47 (3H, s), 1.44 (3H, s), 1.42 (3H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75MHz, CDCl ₃ ) δ 188.8, 157.6, 156.0, 154.3, 139.2, 128.9, 128.6, 126.5, 126.3, 126.0, 116.4, 115.9, 105.6, 104.7, 102.3, 79.0, 77.8, 77.7 , 45.9, 28.6, 28.2, 28.0, 26.9; Infrared spectroscopy (KBr) 2976, 2926, 1682, 1642, 1574, 1453, 1366, 1196, 1140, 1119, 1011, 764, 731 cm ^-1 ; High resolution mass spectrometry m / z (M ⁺ ) Calcd for C ₂₅ H ₂₄ O ₄ : 388.1675. Found: 388.1676.

1- (5-hydroxy-2,2,8,8- Tetramethyl -2H, 8H- Pyrano [2,3-f] chromen -6-yl) -3- (4- Methoxyphenyl ) Propenone (29).

Potassium hydroxide (112 mg, 2.0 mmol) and 4-methoxybenzaldehyde (95 mg, 0.7) in a solution mixed with a compound of formula (150 mg, 0.5 mmol), 10 ml ethanol and 2 ml water at room temperature mmol) was added and the mixture was stirred for 48 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in 20 ml of water. After acidification with 2N hydrochloric acid (20 mL), the mixture was extracted with ethyl acetate (3 * 30 mL), washed with water and dried over anhydrous sodium sulfate. After removal of the solvent, purification by flash column chromatography on silica gel afforded the compound of formula 29 (178 mg, 85%) as a solid: melting point 125-126 ° C .; Proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 14.49 (1H, s), 7.98 (1H, d, J = 15.6 μs), 7.64 (1H, d, J = 15.6 μs), 7.54 (2H, d , J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 6.67 (1H, d, J = 10.0 Hz), 6.60 (1H, d, J = 10.0 Hz), 5.46 (2H, d, J = 10.0 Hz), 3.83 (3H, s), 1.53 (6H, s), 1.43 (6H, s); Infrared spectroscopic analysis (KBr) 2975, 2932, 1634, 1607, 1543, 1510, 1460, 1422, 1344, 1292, 1155, 1115, 1032, 879, 827, 704 cm ^-1 ; High resolution mass spectrometry m / z (M ⁺ ) calcd for C ₂₆ H ₂₆ O ₅ : 418.1780. Found: 418.1778.

Lock inspection cone (9).

To a solution of methylene chloride (10 ml) of boron tribromide (0.3 ml, 1.0 M in CH ₂ Cl ₂ , 0.3 mmol) was added the compound of formula 29 (100 mg, 0.2 mmol) and the reaction. The mixture was stirred at rt for 10 h. 20 mL of ice water was added and the mixture was extracted with methylene chloride (3 * 30 mL), washed with water and dried over anhydrous sodium sulfate. After removal of the solvent, purification by flash column chromatography on silica gel yielded the compound of formula 9 (83 mg, 86%) as a solid: melting point 174-175 ° C .; Proton nuclear magnetic resonance spectroscopy (300 MHz, CDCl ₃ ) δ 14.45 (1H, s), 7.97 (1H, d, J = 15.6 μs), 7.72 (1H, d, J = 15.6 μs), 7.48 (2H, d , J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 6.59 (1H, d, J = 10.0 Hz), 6.54 (1H, d, J = 10.0 Hz), 5.44 (2H, d, J = 10.0 Hz), 1.52 (6H, s), 1.43 (6H, s); Carbon 13 nuclear magnetic resonance spectroscopy (75 MHz, CDCl ₃ ) δ 188.9, 157.6, 156.0, 154.2, 139.3, 128.8, 128.5, 126.7, 126.3, 126.1, 116.4, 115.9, 105.5, 104.7, 102.4, 79.0, 78.0, 77.8 , 46.0, 28.6, 28.3, 28.0, 27.9; Infrared spectroscopic analysis (KBr) 3333, 2976, 1604, 1443, 1346, 1281, 1157, 1076, 880, 831, 739 cm ⁻¹ ; High resolution mass spectrometry m / z (M ⁺ ) calcd for C ₂₅ H ₂₄ O ₅ : 404.1624. Found: 404.1626.

It can be applied to a wide range of medical uses by using properties such as antioxidant, anticancer, anti-inflammatory, antiviral, antibacterial and anti-HIV activity.

Figure 1 shows the chemical structural formula of molecules with pyranochromen found in nature.

Figure 2 shows the result of the reaction with 3-methyl-2-butenal under the use of several catalysts to produce pyranochromen derivatives according to the present invention.

Figure 3 shows the result of the reaction between various forms of substituted trihydroxybenzenes and α, β-unsaturated aldehydes to produce pyranocromene derivatives according to the present invention.

4 to 6 are chemical reaction schemes showing the synthetic route of various pyranochromen natural products according to the present invention.

Claims (14)

delete delete delete delete delete delete delete delete delete As a starting material, 20 mol% of ethylenediamine diacetate is used as a catalyst in the reaction of the compound represented by Formula 15 with 3-methyl-2-butenal, and reacted in methylene chloride at room temperature for 10 hours to give octane of Formula 2 Producing drenolone; And Reacting the compound represented by Chemical Formula 2 with methyl iodide under K ₂ CO ₃ in an acetone solvent to produce O-methyloctanedrenolone, which is a compound represented by Chemical Formula 3; Method of synthesizing pyranochromen natural synthetic analogues. Formula 15

Formula 2

Formula 3

As a starting material, 20 mol% of ethylenediamine diacetate is used as a catalyst in the reaction of the compound represented by Formula 15 with 3-methyl-2-butenal, and reacted in methylene chloride at room temperature for 10 hours to give octane of Formula 2 Producing drenolone; Reacting the compound represented by Chemical Formula 2 with methyl iodide (methyl iodide) under K ₂ CO ₃ in an acetone solvent to produce O-methyloctanedrenolone, a compound represented by Chemical Formula 3; And At room temperature under an acetone solvent containing water, the compound of formula 3 is reacted with 1.1 equivalents of dimethyldioxrane to give trans-3 ^.. , 4 ^... -Dihydro-3 ^... , 4 ^... - dihydroxy -O- methyl octane drain nolron and trans -3 ^‥ of formula 6, 4 ^‥-dihydro -3 ^‥, 4 ^‥ - dihydroxy -O- methyl octane drain comprises a step of generating a nolron A method of synthesizing a pyranochromen natural composite analogue characterized by the above. Formula 15

Formula 2

Formula 3

Formula 4

6

As a starting material, 20 mol% of ethylenediamine diacetate is used as a catalyst in the reaction of the compound represented by Formula 15 with 3-methyl-2-butenal, and reacted in methylene chloride at room temperature for 10 hours to give octane of Formula 2 Producing drenolone; And Pyranoke, characterized in that the condensation reaction of the compound represented by the formula (2) and benzaldehyde (benzaldehyde) in the presence of KOH in an ethanol solution for 48 hours at room temperature to produce a plemiculosin represented by the formula (8) Method for the synthesis of Lomen natural synthetic analogues. Formula 15

Formula 2

Formula 8

As a starting material, 20 mol% of ethylenediamine diacetate is used as a catalyst in the reaction of the compound represented by Formula 15 with 3-methyl-2-butenal, and reacted in methylene chloride at room temperature for 10 hours to give octane of Formula 2 Producing drenolone; Condensation of the compound represented by Formula 2 with benzaldehyde in the presence of KOH in an ethanol solution for 48 hours at room temperature to produce a plemiculosin represented by Formula 8; And Reaction of the compound represented by the formula (8) and sodium acetate in refluxing ethanol to produce the compound 3-dioxy-Ms-II represented by the formula (10) Synthesis method. Formula 15

Formula 2

Formula 8

Formula 10

As a starting material, 20 mol% of ethylenediamine diacetate is used as a catalyst in the reaction of the compound represented by Formula 15 with 3-methyl-2-butenal, and reacted in methylene chloride at room temperature for 10 hours to give octane of Formula 2 Producing drenolone; Using KOH in ethanol for 48 hours at room temperature to condense the compound represented by Chemical Formula 2 with 4-methoxybenzaldehyde to produce a compound represented by Chemical Formula 29; And In methylene chloride (methylene chloride) for 10 hours at room temperature, when reacting the compound represented by the formula (B29) and BBr _{3 The} pyra characterized in that it comprises the step of producing a compound lacsychalcone (laxichalcone) represented by the formula (9) Method for the synthesis of nochromen natural synthetic analogues. Formula 15

Formula 2

Formula 29

Formula 9

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