JP2006206541A - Method for stereoselective chemical synthesis of 1'-(s)-acetoxychavicol acetate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for stereoselective chemical synthesis of an anti-HIV compound 1'-(S)-acetoxychavicol acetate. <P>SOLUTION: The 1'-(S)-acetoxychavicol acetate is obtained as follows. A ketone compound represented by formula (I) äwherein, R represents a TBS (tert-butyldimethylsilyl) group} is reduced in the presence of an optically active oxazaborolidine with a borane compound to afford an optically active alcohol. The TBS group of the optically active alcohol is eliminated to afford a hydroxy group. The two hydroxy groups are then acetylated. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a practical stereoselective chemical synthesis method of an anti-HIV compound 1 '-(S) -acetoxychavicol acetate (1'-(S) -acetoxychavicol acetate).

  The number of AIDS patients, that is, those infected with HIV (Human Immunodeficiency Virus), has been increasing worldwide since the discovery, and the establishment of an immediate treatment is essential. As chemotherapy at the present stage, a method using a reverse transcriptase inhibitor and a protease inhibitor in combination is generally employed.

  A reverse transcriptase is an enzyme possessed by HIV that is necessary for translating viral RNA into DNA, and examples of inhibitors include AZT.

  Protease is an enzyme required after viral protein translation, and saquinavir or the like is used as its inhibitor.

  By the way, HIV gene codes Rev protein which is RNA binding protein. This Rev protein has a nuclear export signal (NES), is necessary for the export of viral mRNA, and can thus be said to be an essential protein for HIV replication / proliferation. As a substance that inhibits or suppresses the function of the Rev protein, leptomycin B, valtrate, and the like have been reported so far (see Non-Patent Documents 1 and 2 below).

Wolff, B. et al., Chem. Biol., 1997, 4, 139-147 Murakami, N. et al., Bioorg. Med. Chem. Lett., 2002, 12, 2807-2810

  As described above, reverse transcriptase inhibitors and protease inhibitors are generally used in conventional AIDS treatment.

  However, it is known that HIV has a high frequency of mutation, and drug-resistant viruses easily appear. Therefore, there is an increasing need for development of anti-HIV agents based on a novel mechanism of action different from the conventional drugs.

Under such circumstances, the present inventors have used 1 '-(S) -acetoxychavicol acetate (1'-(S) -acetoxychavicol acetate) having the following chemical structure as an anti-HIV active substance from natural products. Isolated (Japanese Patent Application No. 2003-418796).

  1 '-(S) -acetoxyshavicol acetate has low cytotoxicity and exhibits anti-HIV activity with a novel mechanism of action that inhibits and suppresses the nuclear export of Rev protein essential for HIV replication. Anti-HIV agents and their use as lead compounds for their development are expected. Therefore, in synthesizing each type of rim with an eye on structure-activity relationship studies, etc., establishment of a stereoselective chemical synthesis method of 1 ′-(S) -acetoxyshabicol acetate that is not solely based on supply from natural resources It is an important issue.

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a stereoselective chemical synthesis method of the anti-HIV compound 1 '-(S) -acetoxyshabicol acetate.

  As a result of diligent research in view of the above problems, the inventors of the present invention stereoselectively chemically synthesize 1 ′-(S) -acetoxychabicol acetate in a practical yield using an organic synthetic method. A method has been established, and it has been found that this method can be applied to the stereoselective chemical synthesis of each type of isomer, and the present invention has been completed.

（式中、Ｒは、水素原子、炭素数２〜８のアシル基、またはトリ（炭素数１〜６の炭化水素基）置換シリル基を表す）で表されるケトン化合物を、光学活性オキサザボロリジンの存在下、ボラン化合物等により還元することを特徴とする下記一般式（ＩＩ）

（式中、Ｒは、一般式（Ｉ）と同じ意味を表す）で表される光学活性アルコールの製造方法。 That is, the present invention includes the following inventions (A) and (B) as medically and industrially useful inventions.
(A) The following general formula (I)

(In the formula, R represents a hydrogen atom, an acyl group having 2 to 8 carbon atoms, or a tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group). Reduction with a borane compound or the like in the presence of borolidine, represented by the following general formula (II)

(Wherein R represents the same meaning as in general formula (I)).

（式中、Ｒは水素原子を表す）で表される光学活性アルコールにおいて、二個の水酸基をアセチル化することを特徴とする下記式（ＩＩＩ）

で表される１’−（Ｓ）−アセトキシシャビコールアセテートの製造方法。 (B) The following formula (II)

(Wherein R represents a hydrogen atom), two hydroxyl groups are acetylated in the optically active alcohol represented by the following formula (III)

The manufacturing method of 1 '-(S) -acetoxy shabicol acetate represented by these.

  According to the present invention, for example, the presence of optically active oxazaborolidine ((R) -oxazaborolidine) is obtained from the ketone compound (I) obtained using 4-hydroxybenzaldehyde as a starting material by using the method (A). Then, 1 ′-(S) -acetoxychabicol acetate (III) can be stereoselectively produced in a practical yield by a key reaction for asymmetric reduction.

  In addition, the compound represented by the general formula (II) can be effectively used as an intermediate for producing a 1 '-(S) -acetoxychabicol acetate analog. That is, from this optically active alcohol (II), an analog can be stereoselectively chemically synthesized, which is an effective means for lead optimization including structure-activity relationship studies.

  Hereinafter, preferred embodiments of the present invention will be described. However, the present invention is not limited to the following embodiments, and various modifications can be made without changing the gist thereof. is there.

  As described above, in the general formula (I), R represents a hydrogen atom, an acyl group having 2 to 8 carbon atoms, or a tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group. Examples of the acyl group having 2 to 8 carbon atoms (including carbonyl carbon) of R include, for example, acetyl group, pivaloyl group, hexanoyl group, cyclohexanoyl group, benzoyl group, ethoxycarbonyl group, methoxymethyl group, A methoxyethoxymethyl group, p-methoxyphenylmethyl group, etc. are mentioned. Examples of the tri (C 1-6 hydrocarbon group) substituted silyl group of R include, for example, trimethylsilyl group, triisopropylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, and the like. And preferably a t-butyldimethylsilyl group.

  Optically active oxazaborolidine is a known one (for example, those described in JP-A No. 2000-256368, JP-A No. 8-1334076, JP-A No. 7-109231, JP-A No. 6-340673, etc.) ) Can be used.

  Examples of the borane compound include diborane, tetrahydrofuran borane complex, dioxane borane complex, thioxane borane complex, dimethylaniline borane complex, diethylaniline borane complex, phenylmorpholine borane complex, catechol borane, in addition to dimethyl sulfide borane complex. Etc.

  In order to perform asymmetric reduction of ketone compound (I) in the presence of optically active oxazaborolidine, the amount of optically active oxazaborolidine is used in terms of optically active alcohol (II) relative to ketone compound (I). Usually, about 0.01 to 3 mole times, preferably about 0.05 to 2 mole times is used. The borane compound is usually used in an amount of about 1 to 20 moles, preferably about 1 to 10 moles in terms of boron with respect to the optically active alcohol (II).

  Examples of the solvent used in the above reaction include tetrahydrofuran (THF), 1,3-dioxane, 1,4-dioxane, 1,3-dioxolane, thioxan, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl t-butyl ether, and the like. Ethers, aromatics such as benzene, toluene, xylene, chlorobenzene, hydrocarbons such as 1,2-methoxyethane, n-hexane, n-heptane, cyclohexane, methylene chloride, ethylene chloride, carbon tetrachloride, etc. Examples thereof include halogenated hydrocarbons and mixtures thereof. In addition, a solvent is normally used about 0.5-30 mass times with respect to ketone compound (I). The temperature of the asymmetric reduction reaction is usually about -20 to 100 ° C, preferably about 0 to 80 ° C. In addition, the asymmetric reduction reaction of the present invention is generally performed in the presence of an inert gas such as argon or nitrogen.

  Thus, the synthesized optically active alcohol (II) can be used as an intermediate for synthesizing an analog of 1 '-(S) -acetoxychabicol acetate.

  In the general formula (II), 1 '-(S) -acetoxychabicol acetate can be obtained by acetylating two hydroxyl groups in which R is a hydrogen compound. In synthesizing the optically active alcohol described in the general formula (II), when an appropriate protecting group other than a hydrogen compound is added to R, the protecting group is removed, and then an acetylation reaction is performed. I do.

  Next, a method for producing 1 '-(S) -acetoxychabicol acetate according to an embodiment of the present invention will be described with reference to FIG.

  50 mg of compound 2 (4-hydroxybenzaldehyde) was allowed to act on tert-butyldimethylsilyl chloride (TBDMS, TBDMS, 75 mg) in 4 mL of dichloromethane in the presence of 40 mg of imidazole in the presence of 40 mg of tert-butyldimethylsilyl chloride at room temperature for 1 hour. Or protected with TBS) groups. The reaction solution was poured into saturated brine, extracted with ethyl acetate, the resulting ethyl acetate layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 3. This compound 3 was dissolved in 3 mL of tetrahydrofuran (THF) and reacted with 0.82 mL of 1.0 M vinylmagnesium bromide THF solution under ice cooling for 1 hour. The reaction was stopped with a saturated aqueous solution of ammonium chloride, and the post-treatment was carried out in the same manner as in the synthesis of Compound 3. The obtained crude product was subjected to silica gel column chromatography (silica gel 5 g, elution solvent; n-hexane: ethyl acetate = 3). 1) to obtain 105 mg of allyl alcohol form 4.

Allyl alcohol 4: [α] _D ²⁴ = 0 ° (EtOH, c = 1.00). ¹ H-NMR (CDCl ₃ ) δ: 7.22 (2H, d, J = 8.5 Hz), 6.68 (2H, d, J = 8.5 Hz), 6.04 (1H, ddd, J = 6.1, 10.4, 17.0 Hz), 5.32 (1H, d, 17.0 Hz), 5.18 (1H, d, 10.4 Hz), 5.14 (1H, d, J = 6.1 Hz ), 0.99 (3H x 3, s), 0.20 (3H x 2, s). FABMS m / z: 265 ([M + H] ⁺ ). HRFABMS: found 265.1596, calcd. C ₁₅ H ₂₅ O ₂ Si; 265.1624.

  Subsequently, 105 mg of allyl alcohol body 4 was added with 500 mg of Dess-Martin periodinane in 4 mL of dichloromethane, and the mixture was stirred at room temperature for 2 hours to convert the hydroxyl group into a ketocarbonyl group. A saturated aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was stirred at room temperature until it became transparent. The mixture was extracted with ethyl acetate, and after the same post treatment as in the synthesis of Compound 3, the mixture was purified by silica gel column chromatography (silica gel 5 g, elution solvent; n-hexane: ethyl acetate = 6: 1) 98 mg of ketone body 5 was obtained. The ketone body 5 corresponds to the “ketone compound” in the present invention.

Furthermore, the ketone body 5 was obtained at −40 ° C. in the presence of 52 mg of (R) -oxazaborolidine (compound (IV) below. Corresponding to “optically active oxazaborolidine” in the present invention) in 5 mL of THF. A stereoselective reduction reaction was carried out by reducing with 0.23 mL of a 2.0 M THF solution of dimethyl sulfide borane complex (BH ₃ .S (CH ₃ ) ₂ ), which is a borane compound.

  After 2 hours, MeOH was added dropwise to the reaction solution to stop the reaction. Distilled water was added and the mixture was extracted with ethyl acetate. The resulting ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. As a result, 82 mg of optically active alcohol 6 was obtained. This alcohol 6 uses an optically active HPLC column DAICEL chiral OD and has an optical purity of 90% e.e. e. It was confirmed that.

Optically active alcohol 6: [α] _D ²⁴ = −1.2 ° (EtOH, c = 1.00). ¹ H-NMR (CDCl ₃ ) δ: 7.21 (2H, d, J = 8.5 Hz), 6.68 (2H, d, J = 8.5 Hz), 6.03 (1H, ddd, J = 6.1, 10.4, 17.1 Hz), 5.31 (1H, d, 17.1 Hz), 5.17 (1H, d, 10.4 Hz), 5.13 (1H, d, J = 6.1 Hz), 0.99 (3H x 3, s), 0.20 (3H x 2, s). FABMS m / z: 265 ([M + H] ⁺ ). HRFABMS: found 265.1599, calcd. C ₁₅ H ₂₅ O ₂ Si; 265.1624.
HPLC condition; DAICEL chiral OD 4.6 idx 250 mm, mobile phase; Hex: iPrOH = 99: 1, flow rate; 1.0 mL / min, detection; UV (λ = 254 nm), Rt: S body 13.2 min, R body: 12.4 min.

Furthermore, 82 mg of optically active alcohol 6 was added with 0.62 mL of 1.0 M THF solution of tetrabutylammonium fluoride (n-Bu ₄ NF) in 3 mL of THF, and the mixture was stirred at room temperature for 2 hours to give a tert-butyldimethylsilyl group. And the diol compound 7 was obtained by post-treatment similar to the synthesis of Compound 3. This diol 7 is dissolved in 2 mL of pyridine, 0.2 mL of acetyl chloride (AcCl) is added under ice cooling, and both hydroxyl groups are acetylated by stirring at room temperature for 3 hours. It was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (silica gel 4 g, elution solvent: n-hexane: ethyl acetate = 5: 1), and 1 mg of 1 ′-(S) -acetoxychabicol acetate of the following formula (III) was synthesized.

1 '-(S) -acetoxychavicol acetate: [α] _D ²⁴ = -49.5 ° (EtOH, c = 1.00). ¹ H-NMR (CDCl ₃ ) δ: 7.37 (2H, d, J = 8,5 Hz) , 7.07 (2H, d, J = 8.5 Hz), 6.26 (1H, d, J = 6.1 Hz), 5.98 (1H, ddd, J = 6.1, 11.0, 17.1 Hz), 5.30 (1H, dd, J = 1.2 , 17.1 Hz), 5.25 (1H, dd, J = 1.2, 11.0 Hz), 2.30 (3H, s), 2.11 (3H, s). FABMS m / z: 235 ([M + H] ⁺ ). HRFABMS: found 235.0966, calcd.C ₁₃ H ₁₅ O ₄ ; 235.0970.

  As described above, according to the present invention, the anti-HIV compound 1 '-(S) -acetoxychabicol acetate can be produced stereoselectively in a practical yield. In addition, since it can be applied to stereoselective chemical synthesis of each type of rim, it is an effective means for lead optimization including structure-activity relationship studies.

It is a figure which shows the manufacturing process of 1 '-(S) -acetoxy shabicol acetate based on the Example of this invention.

Claims (2)

The following general formula (I)

(In the formula, R represents a hydrogen atom, an acyl group having 2 to 8 carbon atoms, or a tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group). Reduction with a borane compound or the like in the presence of borolidine, represented by the following general formula (II)

(Wherein R represents the same meaning as in general formula (I)). The following formula (II)

(Wherein R represents a hydrogen atom), two hydroxyl groups are acetylated in the optically active alcohol represented by the following formula (III)

The manufacturing method of 1 '-(S) -acetoxy shabicol acetate represented by these.

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