KR20160080799A - METHOD FOR TOTAL SYNTHESIZING α-PYRONE DERIVATIVES USING BY GOLD CATALYST AND α-PYRONE DERIVATIVES HAVING CYTOTOXICITY AGAINST HUMAN CANCER CELL SYNTHESIZED THEREBY - Google Patents

Abstract

The present invention relates to a method for total synthesis of an α-pyrone derivative comprises preparing a β-ketoester compound starting from butanol through the Witting olefin reaction, Swern oxidation reaction, Corey-Fuchs reaction and Claisen condensation, and subjecting the β-ketoester compound to 6-endo-dig intramolecular cyclization using a gold catalyst to form an α-pyrone ring and to carry out total synthesis of an α-pyrone derivative. The α-pyrone derivative obtained by the total synthesis method is (+)-violapyrone C having the same shape as the naturally occurring α-pyrone derivative and has cytotoxicity against at least 10 human cancer cell lines, and thus can be useful as an anti-cancer agent.

Description

Pyrone derivative having a cytotoxic activity in a human cancer cell, and a method for synthesizing an? -Pyrone derivative having a cytotoxicity against human cancer cell synthesized thereby}

The present invention relates to a pre-synthesis method of an? -Pyrone derivative for producing an? -Pyrone derivative by using a gold (Au) catalyst, and an? -Pyrone derivative synthesized by the method and cytotoxic to a human cancer cell.

With the increase in the elderly population and the deterioration of the environment, the incidence of cancer has increased by 5% every year in the world. In 1997, 6 million people died from cancer, accounting for 12% of the global death toll. Therefore, cancer is recognized as a top priority to be overcome in order to extend human life in the 21st century.

Recent advances in the diagnosis and treatment of diseases have led to limited improvements in cure rates and improved functional outcomes, but the survival rates for many advanced cancers have remained high for the past five years Is estimated to be about 5 to 50 percent annually, with about 100,000 new cancer cases annually and about 50,000 deaths each year. These cancers are characterized by aggressive invasion, lymph node metastasis, distant metastasis, and the development of secondary cancers. Despite a variety of studies and treatments for some cancers, survival rates have not increased significantly over the past 20 years.

Recently, there have been a lot of attempts to increase the treatment rate through a molecular biological approach to cancer, and studies on target treatment related to cancer proliferation, metastasis and apoptosis have been actively conducted, and at the same time, Researches on anticancer drugs using natural extracts derived from plants, oceans and the like or antioxidants have been actively carried out.

For example, in the prior art of Non-Patent Document 1, Streptomyces ( Streptomyces ) isolated from Hylobates hoolock feces violascens , YIM100525) to produce Violapyrones , a kind of α-pyrone derivative having cytotoxicity in human cancer cell lines. The present invention relates to a method for producing Violapyrones, which comprises fermenting natural microorganisms, J. Zhang, Y. Jiang, Y. Cao, J. Liu, D. Zheng, X. Chen, L. Han, C. Jiang, X. Huang, J. Nat. Prod. 2013 , 76, 2126-130.).

However, in the above-mentioned prior art, the method of producing the α-pyrone derivative as a natural substance by fermenting the microorganism after culturing has stability and superiority of the natural substance, but since the amount of the obtained α-pyrone derivative is small, There is a limit to use in mass production methods.

Therefore, there is a need for a study on a total synthesis method capable of mass production of an? -Pyrone derivative having anticancer activity.

Korean Patent No. 10-1151993 (published on January 15, 2010) Korean Patent Publication No. 10-2013-0077458 (published on; Korean Patent Laid-Open No. 10-2010-0017766 (published on February 16, 2010) Korean Patent Laid-Open No. 10-2002-0063293 (published on August, 2002)

 J. Zhang, Y. Jiang, Y. Cao, J. Liu, D. Zheng, X. Chen, L. Han, C. Jiang, X. Huang, J. Nat. Prod. 2013, 76, 2126-130.

SUMMARY OF THE INVENTION The present invention has been conceived to solve the problems of the prior art as described above, and it is an object of the present invention to provide a method for total synthesis of an? -Pyrone derivative having anticancer activity to mass produce a compound having the same structure as a natural substance It is intended to provide a way to be able to.

(A) reacting butanol with iodide and then reacting with triphenyl phosphine (PPh ₃ ) to produce phosphonium iodide (B) preparing butane aldehyde by using a silver (Ag) catalyst, introducing aldehyde through a swern oxidation reaction to prepare butane aldehyde, (c) reacting the phosphonium iodide salt prepared in step (a) with an ylide compound under an n-butyllithium catalyst, and reacting the butane aldehyde prepared in step (b) (D) a hydrogenation reaction in the presence of palladium (Pd) catalyst to remove carbon-carbon double bonds in the olefin compound to form a monohydric alcohol compound (E) introducing an aldehyde group into the monohydric alcohol compound prepared in the step (d) through a swhen oxidation reaction, and carrying out a Corey-Fuchs reaction to add carbon to the aldehyde group, (F) reacting a monohydric alcohol compound containing an alkyne at the terminal residue formed in the step (e) with methyl chloroformate under an n-butyllithium catalyst to form an alkyne at the terminal residue of the alcohol compound; (G) reacting the zeinioate compound with Claisen condensation to obtain a tautomeric form of β-keto (h) preparing β-keto ester compounds of the above-mentioned isomeric forms in the presence of a gold (Au) catalyst to form 6-endo-dig molecular intermolecular cyclizati pyrone derivatives by reacting an α-pyrone derivative with an α-pyrone ring to form an α-pyrone ring.

Also, the gold (Au) catalyst can be prepared by reacting [bis (trifluoromethanesulfonyl) -imidate] - (triphenylphosphine) -imidate] - (PPh ₃ ) gold I)).

The present invention also provides an? -Pyrone derivative prepared by the above-described all-synthetic method for the? -Pyrone derivative.

The α-pyrone derivative may be used in the cervix cancer cell line, the renal cancer cell line, the colon cancer cell line, the breast cancer cell line, the lung cancer cell line, the stomach cell line, and has cytotoxicity to human cancer cell lines including liver cancer cell lines and prostate cancer cell lines.

The α-pyrone derivative according to the present invention can be synthesized in a wide variety of α-pyrone derivatives using a gold (Au) catalyst at a yield of 20% or more, and thus can be applied to mass production of α-pyrone derivatives .

The α-pyrone derivative according to the present invention has anticancer activity on 10 or more kinds of human cancer cell lines and can be used for the preparation of a cancer treatment agent containing an α-pyrone derivative as an active ingredient.

1 is a graph showing the results of the synthesis of (S) - (((6-methyloct-4-en-1-yl) oxy) methyl) benzene, which is an intermediate for the preparation of? -Pyrone derivatives, And the first reactant for the preparation and the second reactant for the third reaction.
FIG. 2 is a schematic diagram showing a step of preparing an olefin compound through a Wittling reaction in the method of synthesizing an? -Pyrone derivative according to the present invention.
FIG. 3 is a reaction formula showing the step of preparing (S) -6-methyloctan-1-ol, which is a monohydric alcohol compound, in the method of synthesizing an? -Pyrone derivative according to the present invention.
FIG. 4 is a reaction formula showing the step of preparing (S) -6-methyloctanal in the whole synthesis method of an? -Pyrone derivative according to the present invention.
FIG. 5 is a reaction formula showing the step of preparing (S) -methyl 8-methyldeck-2-aminoate as a zincate compound in the method for synthesizing an? -Pyrone derivative according to the present invention.
6 is a diagram illustrating a step of preparing (10S) -tert-butyl 2,10-dimethyl-3-oxododec-4-aminoate, which is a? -Ketoester compound, in the entire synthesis method of an? -Pyrone derivative according to the present invention This is the reaction scheme shown.
FIG. 7 is a reaction formula showing the step of preparing an? -Pyrone derivative in the method for synthesizing an? -Pyrone derivative according to the present invention.

Hereinafter, the present invention will be described in detail.

The method for preparing α-pyrone derivatives using a gold catalyst according to the present invention can be broadly classified into a Witting olefin reaction, a Swern oxidation reaction and a Cori-Fuchs reaction with butanol as a starting material Pyrone derivatives can be synthesized through the formation of an α-pyrone ring using a gold catalyst via the Corey-Fuchs reaction and Claisen condensation. have.

The total synthesis method of the present invention will be described in more detail. The method for synthesizing an α-pyrone derivative using a gold catalyst according to the present invention comprises: (a) iodination of butanol with iodide, (B) reacting butanediol with monohydric alcohol using a silver (Ag) catalyst, followed by subjecting to swern oxidation reaction to produce a phosphonium iodide salt by reacting with triphenyl phosphine (PPh ₃ ) (C) reacting the phosphonium iodide salt prepared in the step (a) with an ylide compound under an n-butyllithium catalyst to produce butane aldehyde by introducing an aldehyde (B) adding the butane aldehyde prepared in step (b) to the olefin compound to form an olefin compound; and (d) hydrogenating the olefin compound under palladium (Pd) (E) introducing an aldehyde group into the monohydric alcohol compound prepared in the step (d) through a swhen oxidation reaction, removing the aldehyde group from the corey-Fuchs (F) reacting a monohydric alcohol compound containing an alkyne at the terminal moiety formed in the step (e) with an aldehyde group, - reacting with methyl chloroformate under butyl lithium catalyst to introduce an ester group to produce a ynoate compound; (g) reacting the zeinioate compound with Claisen condensation Keto ester compound in the form of a tautomer; and (h) reacting the? -Ketoester compound in the form of a racemic isomer with a gold (Au) Under 6-endo-dig cyclization in the molecule to form (intermolecular cyclization) α- Piron ring (α-pyrone ring) through the reaction and a step of producing the α- Piron derivative.

For reference, each of the above-mentioned steps can be configured to facilitate the purification, separation and recovery of the product produced in each step through column chromatography in order to produce an alpha -pyrone derivative.

The step (a) is a step of reacting butanol with iodide and then reacting with triphenyl phosphine (PPh ₃ ) to produce a phosphonium salt.

In this step, in order to prepare an intermediate (S) - ((6-methyloct-4-en-1-yl) oxy) methyl) benzene as an intermediate for the preparation of? -Pyrone derivative, a first reaction product, When the steps of manufacturing, to FIG. 1 (a), a starting material in (S) - (-) - 2- a triphenylphosphine (triphenylphosphine dissolved in the methyl-1-butanol, dichloromethane (CH ₂ Cl _{2) (- -, Ph 3 P)} , imidazole (imidazole), iodine _{(iodine, I 2) (S} ) with a) - 2-methyl-1 to a hydroxyl group iodination reaction of butanol, (S) -1- (S) -1-iodo-2-methylbutane), and a step of adding triphenylphosphine and toluene to (S) -1- (S) - (2-methylbutyl) triphenyl-phosphonium iodide, which is a phosphonium iodide salt, is reacted for a sufficient time and heated to 100 ° C or higher. iodide can be produced.

In the step (b), butanediol is prepared from a monohydric alcohol using a silver (Ag) catalyst and an aldehyde is introduced through a swern oxidation reaction to produce butane aldehyde.

The above-mentioned swan oxidation reaction is a general method used for oxidizing a primary alcohol to an aldehyde or a secondary alcohol to a ketone. In this step, an intermediate (S) - (((6-methylocte -4-en-1-yl) oxy) methyl) benzene, 4- (benzyloxy) butanal, the butanaldehyde of the second reactant, is prepared.

1 (b), a benzylation reaction in which a benzyl group is introduced into the butanediol using benzyl bromide (BnBr), dichloromethane, and silver (I) oxide, Ag ₂ O To obtain 4- (benzyloxy) butan-1-ol. To a solution of 4- (benzyloxy) butan-1-ol in trifluoroacetic acid 4- (benzyloxy) butanal), a second reactant, can be prepared through swain oxidation using trifluoroacetic anhydride (TFAA) and dimethyl sulfoxide (DMSO).

The step (c) may be performed by preparing the phosphonium iodide salt prepared in the step (a) as an ylide compound under an n-butyllithium catalyst and reacting the phosphonium iodide salt prepared in the step Butane aldehyde is added and the mixture is subjected to a wetting reaction to produce an olefin compound.

Referring to FIG. 2, in this step, the olefin compound is prepared by feeding a strong base to produce an olefin compound through the above-described polymerization reaction, thereby synthesizing an olefin. To this end, the first reaction product, (2-methylbutyl) triphenylphosphonium iodide is treated with a strong base n-butyl lithium catalyst to prepare a phosphorus ylide.

In this case, an ilid is a molecule having a positive charge and a negative charge. In general, a proline is removed from a nearby carbon of a heteroatom having a positive charge to form an ilid. In this step, a phosphonium Salts can be formed and treated with strong bases such as n-butyllithium and tetrahydropyran (THP) to remove protons from the phosphonium ions to form phosphoryl iodides.

Then, the prepared second phosphorus compound (4-benzyloxy) butanal is mixed with the prepared phosphorus ylide and the resulting mixture is subjected to a wittig reaction in an environment of moisture-shielding feed of nitrogen gas to form an olefin Compound (S) - (((6-methyloct-4-en-1-yl) oxy) methyl) benzene is formed.

In the step (d), a hydrogenation reaction is performed under a palladium-carbon catalyst (Pd / C catalyst) to remove carbon-carbon double bonds in the olefin compound to prepare a monohydric alcohol compound.

3, in this step, a hydrogenation reaction is induced with a palladium-carbon catalyst under an atmosphere saturated with hydrogen gas (H ₂ ) to produce the olefin compound (S) - (((6-methyloct- (S) -6-methyloctan-2-yl) oxy) methyl) benzene and converting the carbon-carbon double bond into a single bond to obtain a monohydric alcohol compound, 1-ol. ≪ / RTI >

The step (e) comprises introducing an aldehyde group into the monohydric alcohol compound prepared in the step (d) through a swhen oxidation reaction, reacting with a Corey-Fuchs reaction, adding carbon to the aldehyde group, To form an alkyne at the terminal residue of the compound.

Referring to FIG. 4, in this step, the reaction of (S) -6-methyloctan-1-ol with trifluoroacetoxydimethylsulfonium trifluoroacetic acid prepared by mixing TFAA and DMSO in dichloromethane To prepare an alkoxysulfonium salt. The alkoxysulfonyl salt is reacted with N, N-diisopropylethylamine (DIPEA) to prepare an alkoxysulfonium ylide. (S) -6-methyloctanal) is prepared by rearranging the sulfonyl chloride of (S) -6-methyloctanal.

For reference, the Cori-Fuchs reaction is a reaction for converting an aldehyde group into an alkyne. In this step, alkyne can be added to the terminal residue of the reactive ylid compound. In this step, the (S) -6- (S) -1,1-dibromo-7-methylnon-1-ene (S) -1,1'-dibromoquinoline is reacted with phosphorous ylide prepared by reaction with carbon tetrabromide and triphenylphosphine (S) -1,1-dibromo-7-methylnon-1-ene is reacted with the n-butyllithium and the (S) -7-methylnon-1-yne) was synthesized by hydrolysis of lithium acetylide by the above Corynebacterium glutamic acid, To form an alkyne at the terminal residue of the monohydric alcohol compound.

In the step (f), an ester group is introduced by reacting a monohydric alcohol compound containing an alkyne at a terminal residue formed in the step (e) with methyl chloroformate under an n-butyl lithium catalyst Is a step for preparing a ynoate compound.

Referring to FIG. 5, in this step, (S) -7-methylnon-1-phosphorus which is a monohydric alcohol compound containing an alkyne at the terminal residue is reacted with methyl chloroformate under n-butyl lithium catalyst (S) -methyl 8-methyldeck-2-aminoacetate ((S) -methyl 8-methyldec-2-yneate) prepared in the step (f) S) -methyl 8-methyldec-2-ynoate.

The step (g) is a step of producing a β-keto ester compound in the form of a tautomer by Claisen condensation reaction of the zeinite compound.

For reference, the Clagen condensation reaction is a reaction occurring between carbon-carbon bonds of an ester group, which is a reaction for forming an alcohol with a? -Keto (? -Keto) ester in the presence of a strong base. Referring to FIG. 6, (S) -methyl 8-methyldeck-2-aminoacetate is reacted with a strong base such as lithium diisopropylamide (LDA) and tert-butylpropionic acid (tert -butyl propionate) used a mixture of Cloud now to condensation reaction β- keto ester compound present in tautomeric forms (10S) - tert-butyl-2,10- dimethyl-3-oxo-4-deck chair also Ino benzoate ((10S) -tert-butyl 2,10-dimethyl-3-oxododec-4-ynoate).

In step (h), the β-keto ester compound in the form of an awx isomer is reacted with an α-pyrone ring through a 6-endo-dig molecular intermolecular cyclization reaction under a gold (Au) Pyrone derivative to produce an? -Pyrone derivative.

Referring to FIG. 7, in this step, the intramolecular cyclization reaction can convert the .beta.-keto ester compound turbutyl-zinioate into an .alpha.-pyrone ring in the interior of the viola pyrone in the presence of an acidic metal catalyst, Thus, an? -Pyrone derivative can be synthesized.

In this case, the acidic metal catalyst that can be used may be a platinum or gold catalyst. In this step, bis (trifluoromethanesulfonyl) imidate- (triphenylphosphine) gold (I) trifluoromethanesulfonyl) -imidate] - (PPh ₃ ) gold (I).

(+) -, (-) - violapyrone C can be selectively synthesized, respectively. Compared with (+) - violapyrone C,

The α-pyrone derivative prepared as described above is (+) - viola pyrone C ((+) - violapyrone C), which has the same form as the compound isolated and purified from natural products, and is a cervix cancer cell line, kidney human cancer cells, including renal cancer cell lines, colon cancer cell lines, breast cancer cell lines, lung cancer cell lines, stomach cell lines, liver cancer cell lines and prostate cancer cell lines, Can be used for the preparation of an anticancer therapeutic agent having cytotoxicity in the human cancer cell line and containing the above-mentioned? -Pyrone derivative as an active ingredient.

The α-pyrone derivatives according to the present invention can synthesize α-pyrone derivatives starting from the starting materials, and various α-pyrone derivatives can be prepared using gold (Au) catalysts.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments.

The embodiments presented are only a concrete example of the present invention and are not intended to limit the scope of the present invention.

<Examples>

In order to prepare the? -Pyrone derivative according to this example, all reactions were carried out under atmospheric pressure in a nitrogen atmosphere, except under a separate instruction.

(CH ₂ Cl ₂ ), toluene, acetonitrile (MeCN), dimethyl sulfoxide (DMSO), nitromethane (MeNO ₂ ) and tetrahydrofuran (THF) The concentration of n-butyllithium was determined by titration using menthol (-) - menthol and 1,10-phenanthroline. Respectively. All reagents were used without further purification.

All workup, washing and chromatography solvents used in the examples were used by sterilization. Anhydrous sodium sulfate (Na ₂ SO ₄ ) was used and thin-layer chromatography was configured to monitor the reaction situation by spotting with the starting material. The p-anisaldehyde used was a composition containing 1350 mL of anhydrous ethanol, 50 mL of concentrated sulfuric acid and 37 mL of p-anisaldehyde, which was the composition of a commonly used TLC emotion solution.

The flash chromatography purification was carried out using 230 to 400 mesh of silica gel, and ¹ H NMR and ¹³ C NMR analysis data contained chloroform as solvent and residual chloroform ( 隆 = 7.24 (for ¹ H ) And 77.23 ppm ( ¹³ C)) were stored in a diversity 500 NMR analyzer capable of expressing up to ppm units. Mass spectra analysis was performed using Surveyor MSQ Benchtop (Thermo Finnigan) and 6128 Quadrupole LC-MS (Agilent Technologies).

1. (S) - (((6- methyloct -4- en -One- yl ) oxy ) methyl ) benzene Manufacturing

(S) - ((6-methyloct-4-en-1-yl) oxy) methyl) benzene, which is an intermediate for the preparation of? -pyrone derivatives, (S) - (2-methylbutyl) triphenyl phosphonium iodide), which is a first reagent, was used to prepare .

The synthesis of the above-mentioned (S) - ((6-methyloct-4-en-1-yl) oxy) methyl) benzene was carried out by using imidazole, iodine, triphenylphosphine and dichloromethane (CH ₂ Cl ₂ ) (I) - (-) - (-) - 2-methyl-1-butanol by inducing an iodination reaction to the hydroxyl group of (s) - -2-methylbutane ((S) -1-iodo-2-methylbutane) was prepared in a yield of 83%. Then, the produced (S) -1-iodo-2-methylbutane was heated to 105 DEG C for 63 hours using triphenylphosphine and toluene to filter the reaction product, and then the filter cake was dried at room temperature for 16 hours (S) -2- (methylbutyl) triphenylphosphonium iodide in a yield of 82%.

The second reactant, 4- (benzyloxy) butanal, for preparing (S) - ((6-methyloct-4- en-1-yl) oxy) Benzylation to selectively introduce a benzyl group using 1,4-butanediol using silver (I) (Ag ₂ O), benzyl bromide and dichloromethane (CH ₂ Cl ₂ ) (S) - (-) - 2-methyl-1-butanol, which is an intermediate having an introduced benzyl group, was prepared in a yield of 83%.

The prepared intermediate (S) - (-) - 2-methyl-1-butanol was subjected to Swen oxidation reaction (Swern) in trifluoroacetic anhydride (TFAA) and dimethyl sulfoxide (DMSO) Oxidation was induced to give 4- (benzyloxy) butanal in a yield of 83%.

(S) - (2-methylbutyl) triphenylphosphine (S) - ((6-methyloct-4- 2.3 g of phosphonium iodide was added to the flask and dissolved in THF, followed by cooling to 0 ° C. Then, 2.7 mL of n-butyllithium dissolved in 5.0 mmol of hexane at a concentration of 1.85 M was added slowly, and the mixture was stirred at room temperature for 30 minutes. After the reaction vessel was cooled to 0 ° C, 6.50 mmol of the second reactant dissolved in THF and 1.3 g of 4- (benzyloxy) butanal were added thereto, and the mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride Aqueous solution was added thereto. The organic layer was extracted with pentane, dried over sodium sulfate, filtered, and concentrated under reduced pressure.

After concentration under reduced pressure, the reaction product was separated and purified by flash column chromatography using a developing solvent of CH ₂ Cl ₂ / Pentane = 5:95 to 15:85 to obtain 3.84 mmol of (S) - ((6- (2-methylbut-3-yl) oxy) methyl) benzene was obtained in the same manner as in Example 1, except that (S) - (2-methylbutyl) triphenylphosphonium iodide and n-butyllithium Wet olefination produced the desired olefin ( E / Z = isomer mixture in a ratio of 2.3: 1) in a yield of 77%.

The results of ¹ H NMR and ¹³ C NMR analysis of (S) - (((6-methyloct-4-en-1-yl) oxy) methyl) benzene produced are as follows.

^{1 H NMR (500 MHz, CDCl3} ): δ = 7.33-7.34 (d, J = 4.1 Hz, 4 H), 7.26-7.29 (m, 1 H), 5.29-5.34 (m, 1 H), 5.11-5.16 (t, J = 10.3 Hz, 1 H), 4.50 (s, 2 H), 3.47-3.49 (t, J = 6.5 Hz, 2 H), 2.33-2.36 (m, 1 H), 2.07-2.16 (m J = 6.6 Hz, 3 H), 0.82-0.85 ppm (t, J = 7.4 Hz, 2H), 1.65-1.71 (m, 2H), 1.17-1.35 Hz, 3 H).

^{13 C NMR (125 MHz, CDCl} 3): δ = 138.9, 137.0, 136.97, 128.5, 127.92, 127.88, 127.82, 127.81, 127.7, 73.10, 73.07, 70.1, 70.0, 38.6, 33.5, 30.4, 30.2, 30.1, 29.9 , 29.3, 24.3, 21.2, 20.6, 12.2, 12.0 ppm.

HRMS (ESI): calculated for C ₁₆ H ₂₃ O [M + H] &lt; ⁺ &gt;231.1749; C ₁₆ H ₂₃ O [M + H] &lt; ⁺ &gt; 231.1768.

2. (S) -6- 메틸로탄 -One- be  And (S) -6- 메틸코타탄 Manufacturing

(S) -6- methyloctan-1-ol, 652.0 mg of 2.82 mmol of (S) - ((6-methyloct-4- en- 1 -yl) oxy) methyl) benzene was dissolved in ethanol , And 2.54 mmol of 10% palladium (Palladium), 270.4 mg of the catalyst, was added to the mixture. The mixture was heated while supplying hydrogen gas and stirred at 50 ° C for 45 hours to induce a hydrogenation reaction. Filtered through Celite and washed three times with CH ₂ Cl ₂ . The catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated under reduced pressure. The concentrate was purified by flash column chromatography using an eluent of acetylacetonate / n-hexane = 1: 20-1: 5 as the developing solvent. After separation and purification, 2.74 mmol of (S) -6-methyloctan- 395.9 mg of ((S) -6-methyloctan-1-ol) was prepared in 97% yield.

The results of ¹ H NMR and ¹³ C NMR analyzes of the produced (S) -6-methyloctan- ¹ -ol are as follows.

^{1 H NMR (500 MHz, CDCl3} ): δ = 3.60-3.62 (t, J = 6.6 Hz, 2 H), 1.52-1.57 (m, 2 H), 1.22-1.32 (m, 7 H), 1.06-1.12 (m, 2H), 0.81-0.84 (t, J = 7.5 Hz, 3 H), 0.81-0.83 ppm (d, J = 7.8 Hz, 3 H).

^{13 C NMR (125 MHz, CDCl} 3): δ = 63.3, 36.8, 34.5, 33.0, 29.7, 27.1, 26.3, 19.4, 11.6 ppm.

HRMS (ESI): calculated for C ₉ H ₂₀ O [M + H] &lt; ⁺ &gt;144.1514; _{C 9 H 20 O [M +} H] ⁺ measurement value of 144.0677.

3. (S) -1,1- dibromo -7- 메틸 니론 -One- ene Manufacturing

The flask was charged with 3.07 mmol, 3.0 equivalents of TFAA 427.3 μL and CH ₂ Cl ₂ and cooled to -78 ° C. to give trifluoro-acetoxy-dimethyl-sulfonium trifluoro-acetic acid acetate. In another flask, 6.15 mmol dissolved in CH ₂ Cl ₂ and 436.6 μL of 6.0 equivalents of DMSO were added. The mixture was stirred at -78 ° C for 10 minutes, and then 147.7 mg of 1.02 mmol of (S) -6-methyloctan-1-ol was added thereto, followed by stirring at -78 ° C for 1 hour.

To the stirred mixture was added 5.12 mmol of 5.04 eq. Of N, N-diisopropylhexylamine (DI-PEA) and ethyl acetic acid (EtOAc) was added at room temperature to dilute the reaction product.

The organic layer was washed with brine, and the resulting solution was concentrated under reduced pressure, followed by separation by flash column chromatography using an eluent of ethyl acetate / hexane = 1: 40 to obtain 0.87 mmol of (S) -6-methyl octanal &Lt; / RTI &gt;

To the flask was added 1.74 mmol, 2.0 equivalents of carbon tetrabromide (575.9 mg) and dissolved in CH ₂ Cl ₂ at room temperature.

After cooling the flask to 0 캜, 3.47 mmol of 4.0 equivalent of triphenylphosphine (911.0 mg) was added, and the mixture was stirred at 0 캜 for 1 hour. After stirring, 0.87 mmol of (S) -6-methyl octanal was added, and the temperature was raised to room temperature, followed by stirring for 18 hours. After stirring, the reaction mixture was diluted with CH ₂ Cl ₂ and the reaction was terminated using distilled water. The organic layer was washed with brine, and the resulting solution was evaporated under reduced pressure. The residue was purified by column chromatography using 100% pentane as eluent to obtain 0.67 mmol of (S) - (S) -1,1-dibromo-7- Methyl-1-ene was obtained, which was prepared in a yield of 65%

The results of ¹ H NMR and ¹³ C NMR analyzes of (S) -1,1-dibromo-7-methyln- ¹ -ene produced were as follows.

^{1 H NMR (500 MHz, CDCl} 3): δ = 6.35-6.38 (t, J = 7.0 Hz, 1 H), 2.05-2.10 (q, 2 H), 1.38-1.39 (m, 2 H), 1.25- 1.30 (m, 5H), 1.07-1.13 (m, 2H), 0.83-0.85 (t, J = 7.2 Hz, 3 H), 0.83-0.84 ppm (d, J = 6.8 Hz, 3 H).

^{13 C NMR (125 MHz, CDCl} 3): δ = 139.1, 88.7, 36.5, 34.5, 33.3, 29.7, 28.4, 26.8, 19.4, 11.6 ppm.

HRMS (ESI): calculated for C ₁₀ H ₁₉ Br ₂ [M + H] &lt; ⁺ &gt;296.9853; C ₁₀ H ₁₉ Br ₂ [M + H] &lt; ⁺ &gt; 296.9890.

4. (S) -7- 메틸 니론 -One- yne Manufacturing

2.53 mmol of (S) -1,1-dibromo-7-methyl-1-ene was added to the flask and dissolved in THF and cooled to -78 ° C. After cooling, 5.9 mL of 1.85 M n-butyllithium was added to the flask, stirred at -78 ° C for 1 hour, stirred at room temperature for 3 hours, and then distilled water and pentane were added sequentially , Filtered and dried over sodium sulfate. The filtrate was concentrated under reduced pressure and then purified by flash column chromatography using 100% pentane as eluent to obtain 2.44 mmol of (S) -7-methylnon-1- ((S) -7-methylnon-1-yne) was prepared in a yield of 96%.

The results of ¹ H NMR and ¹³ C NMR analyzes of (S) -7-methylnon-1 -ine produced are as follows.

^{1 H NMR (500 MHz, CDCl} 3): δ = 2.15-2.18 (dt, J = 7.2 Hz, 2 H), 1.91-1.92 (t, J = 2.7 Hz, 1 H), 1.46-1.53 (m, 2 H), 1.25-1.44 (m, 5 H), 1.06-1.14 (m, 2 H), 0.820.85 (t, J = 6.8 Hz, 3 H), 0.82-0.84 ppm (d, J = 6.4 Hz, 3 H).

^{13 C NMR (125 MHz, CDCl} 3): δ = 85.0, 68.3, 36.2, 34.5, 29.7, 29.0, 26.5, 19.4, 18.6, 11.6 ppm.

HRMS (ESI): calculated for C ₁₀ H ₁₇ [M + H] &lt; ⁺ &gt;137.1330; C ₁₀ H ₁₇ [M + H] &lt; ⁺ &gt; 137.1341.

5. (10S) - tert - butyl  2,10- dimethyl -3- oxododec -4- ynoate Manufacturing

226 mg of (S) -7-methylnon-1-one and 142.6 占 퐉 of 0.2638 mmol of n-butyllithium dissolved in 1.85 M of hexane were mixed in THF in a nitrogen gas atmosphere, Lt; / RTI &gt; After stirring, methyl chloroformate was added, and the mixture was stirred at room temperature. The temperature was raised to room temperature, diethyl ether was added thereto, diluted, and distilled water was added to terminate the reaction.

After the reaction was completed, the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to prepare a concentrate, which was purified by flash column chromatography using a developing solvent of ethyl acetate / n-hexane = 1: 0.13 mmol of (S) -methyl 8-methyldec-2-xenoate was obtained.

Then, to the flask, 59.7 쨉 L of tert-butyl propionate (0.39 mmol) and tert-butyl propionate (0.39 mmol) were added to a mixed solution of 1.31 mmol of lithium diisopropylamide (LDA) and 2.0 M of THF Then, the mixture was stirred at -78 ° C for 30 minutes. After stirring, 0.13 mmol of (S) -methyl 8-methyldeck-2-aminoate (25.8 mg) was added and the mixture was stirred at -78 ° C for 2 hours. The mixture was diluted with diethyl ether and then saturated aqueous ammonium chloride solution And the reaction was terminated.

The organic layer extracted with diethyl ether was concentrated under reduced pressure and purified by flash column chromatography using a developing solvent of ethyl acetate / n-hexane = 1: 35 to obtain 0.12 mmol of (10S) -tet- 34.3 mg of 10-dimethyl-3-oxododec-4-zinoate ((10S) -tert-butyl 2,10-dimethyl-3-oxododec-4-ynoate) was obtained and showed a yield of 86%.

The results of ¹ H NMR and ¹³ C NMR analyzes of the produced 2,10-dimethyl-3-oxododec-4-ynamoate were as follows.

^{1 H NMR (500 MHz, CDCl} 3): δ = 12.27 (s, 1 H), 3.40-3.44 (q, 1 H), 2.39-2.41 (t, J = 7.0 Hz, 2 H), 2.34-2.37 ( (m, t, J = 7.1 Hz, 2H), 1.81 (s, 3H), 1.55 (m), 1.48 (s, 9H) (m), 0.82-0.85 (t, J = 7.0 Hz, 6 H), 0.82-0.84 ppm (d, J = 6.6 Hz, 6 H).

^{13 C NMR (125 MHz, CDCl} 3): δ = 183.8, 173.2, 169.0, 152.1, 104.5, 100.1, 96.8, 82.0, 81.9, 79.7, 75.3, 56.1, 49.9, 36.2, 36.1, 34.5, 34.4, 29.624, 29.617 , 28.6 28.4, 28.32, 28.27, 28.22, 28.19, 28.17, 28.09, 28.0, 26.6, 26.6, 19.7, 19.4, 19.34, 19.26, 14.0, 13.6, 13.0, 11.6 ppm.

_{HRMS (ESI): C 18 H} 29 O 3 [M + H] ⁺ calculated value of 293.2117; C ₁₈ H ₂₉ O ₃ [M + H] &lt; ⁺ &gt; 293.2127.

6. Preparation of? -Pyrone derivatives

(PPh3) -imidate] - (PPh3) gold (I) catalyst at a concentration of 10.0 mol% in a mixed solution containing 0.01 mmol of [bis (trifluoromethanesulfonyl) imidate] - (PPh3) 34.3 mg of 0.12 mmol of (10S) -tert-butyl 2,10-dimethyl-3-oxododec-4-ynamoate was dissolved in a solvent mixture of nitromethane (MeNO ₂ ) and acetic acid (AcOH) And stirred at room temperature for 20 hours. After stirring, ethyl acetic acid was added to dilute, and saturated sodium bicarbonate (NaHCO ₃ ) aqueous solution was added to terminate the reaction. The organic layer extracted with ethyl acetate was concentrated under reduced pressure and purified by flush column chromatography using ethyl acetate / n-hexane = 1: 4 to 1: 2 as a developing solvent to obtain violapyrone C as an? -Pyrone derivative. 0.09 mmol 22.5 mg of violapyrone C was obtained and the yield obtained was 81%.

In the whole reaction, violapyrone C was produced in a yield of 22%. The measured rotation value of the produced bollulapyrone C showed the same structure as that of the ballolapyrone C separated and purified from the natural product (+) - violapyrone C was found.

Claims (11)

(a) preparing a phosphonium iodide salt by reacting butanol with iodide and then reacting with triphenyl phosphine (PPh ₃ );
(b) preparing butane aldehyde by introducing an aldehyde through a swern oxidation reaction after preparing butanediol from a monohydric alcohol using a silver (Ag) catalyst;
(c) reacting the phosphonium iodide salt prepared in step (a) with an ylide compound under an n-butyllithium catalyst, and reacting the butane aldehyde prepared in step (b) And then subjecting the mixture to a wetting reaction to prepare an olefin compound;
(d) hydrogenating the catalyst under palladium (Pd) catalyst to remove carbon-carbon double bonds in the olefin compound to produce a monohydric alcohol compound;
(e) introducing an aldehyde group into the monohydric alcohol compound prepared in the step (d) through a swhen oxidation reaction, and carrying out a Corey-Fuchs reaction to add carbon to the aldehyde group to form a terminal residue of the monohydric alcohol compound To form an alkyne on the substrate;
(f) reacting a monohydric alcohol compound containing an alkyne at the terminal residue formed in the step (e) with methyl chloroformate under an n-butyllithium catalyst to introduce an ester group to form a cyanoate ynoate) compound;
(g) subjecting the zeinioate compound to a Claisen condensation reaction to prepare a tautomeric β-keto ester compound; And
(h) Formation of the? -ketoester compound of the above-mentioned isomeric form by an intermolecular cyclization reaction of 6-endo-dig in an Au catalyst to form an? -pyrone ring, - &lt; / RTI &gt; pyrone derivative of formula (I). The method according to claim 1,
The step (a)
(S) - (-) - 2-methyl-1-butanol dissolved in dichloromethane (CH ₂ Cl ₂ ) using triphenylphosphine (PPh ₃ ), imidazole and iodine Iodination of the hydroxyl group to produce (S) -1-iodo-2-methylbutane ((S) -1-iodo-2-methylbutane); And
To the above (S) -1-iodo-2-methylbutane, triphenylphosphine and toluene were mixed and heated to 100 ° C or higher to obtain (S) - (2-methylbutyl) tri To prepare phenylphosphonium iodide ((S) - (2-methylbutyl) triphenylphosphonium iodide)
The step (b)
Benzylation reaction of the butanediol using the silver catalyst including benzyl bromide, dichloromethane and silver (I) oxide to produce 4- (benzyloxy) butane-1- Ol (4- (benzyloxy) butan-1-ol); And
4- (benzyloxy) butanal (4- (benzyloxy) butanal) was prepared by mixing TFAA (trifluoroacetic anhydride) and dimethyl sulfoxide (DMSO) Wherein the method comprises the steps of: 3. The method of claim 2,
Treating the (S) - (2-methylbutyl) triphenylphosphonium iodide with the n-butyllithium catalyst to prepare a phosphorus ylide; And
(4-ene-1-yl) oxy) methyl) benzene ((S) - ) - (((6-methyloct-4-en-1-yl) oxy) methyl) benzene)
Wherein the olefin compound of step (c) is prepared. The method of claim 3,
The present invention relates to a process for the production of an olefin compound by hydrogenating the (S) - ((6-methyloct-4- en-1-yl) oxy) methyl) benzene under palladium (Pd) Comprising:
(S) -6-methyloctan-1-ol, which is a monohydric alcohol compound prepared in the step (d) Synthesis method. 5. The method of claim 4,
Reacting the above (S) -6-methyloctan-1-ol with trifluoroacetoxydimethylsulfonium trifluoroacetic acid prepared by mixing TFAA and DMSO dissolved in the dichloromethane to prepare an alkoxysulfonium salt ;
Reacting the alkoxysulfonyl salt with N, N-diisopropylethylamine (DIPEA) to prepare an alkoxysulfonyl ylide;
Rearranging said alkoxysulfonylidide to produce (S) -6-methyloctanal ((S) -6-methyloctanal);
Reacting the (S) -6-methyl octanal with a phosphorous ylide prepared by reacting the (S) -6-methyl octanal with carbon tetrabromide and triphenylphosphine to obtain (S) -1,1- 7-methylnon-1-ene ((S) -1,1-dibromo-7-methylnon-1-ene);
Mixing the (S) -1,1-dibromo-7-methylnon-1-ene with n-butyl lithium to prepare lithium acetylide; And
(S) -7-methylnon-1-yne by hydrolyzing the lithium acetylide and subjecting it to the Cori-Fuchs reaction to prepare (S) -7-
Wherein the alkyne is formed in the terminal residue of the monohydric alcohol compound in the step (e). 6. The method of claim 5,
The step of reacting the above (S) -7-methylnon-1-yn with methyl chloroformate under n-butyllithium catalyst to introduce an ester group to prepare a ynoate compound including,
(S) -methyl 8-methyldec-2-ynoate (S) -methyl 8-methyldec-2-ynoate, which is the zeinioate compound produced in the step (f) all-synthetic method for? -pyrone derivative. The method according to claim 6,
The (S) - methyl 8-methyl-2-deck chair Ino Eight lithium diisopropylamide (lithium diisopropylamide, LDA) and tert-butyl propionate using (tert -butyl propionate) Now step of the condensation reaction mixture Cloud Including,
(10S) -tert-butyl 2,10-dimethyl-3-oxododec-4-yninoate ((10S) -tert-butyl 2,10-dimethyl-3-oxododec-4-ynoate). The method according to claim 1,
The gold (Au) catalyst may be selected from the group consisting of bis (trifluoromethanesulfonyl) -imidate- (triphenylphosphine) -imidate- (PPh ₃ ) gold (I) ). &Lt; / RTI &gt; 9. An? -Pyrone derivative produced by the all-synthetic method for producing an? -Pyrone derivative according to any one of claims 1 to 8. 10. The method of claim 9,
(+) - viola pyrone C ((+) - violapyrone C). 10. The method of claim 9,
Colon cancer cell line, lung cancer cell line, lung cancer cell line, stomach cell line, liver cancer cell line, and prostate (including, but not limited to, cervix cancer cell line, renal cancer cell line, colon cancer cell line, prostate cancer cell line, which has cytotoxicity in a human cancer cell line including a prostate cancer cell line.

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