JP3726332B2 - Process for producing optically active dicyclopentadiene derivatives - Google Patents
Process for producing optically active dicyclopentadiene derivatives Download PDFInfo
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- dihydrodicyclopentadiene
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- dihydroxy
- optically active
- lipase
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Description
【0001】
【発明の属する技術分野】
本発明は、種々の生理活性物質の合成中間体として有用な光学活性3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン誘導体の新規製造法に関する。
【0002】
【従来の技術】
本発明に係る光学活性3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン誘導体は、種々の生理活性物質の合成中間体として広範囲に利用できる有用な化合物である。例えば、本化合物から短工程で得られる(−)−3−オキソジシクロペンタジエンを出発物質とすれば、経口避妊薬として有望なエストロゲンステロイドホルモンの一種である(+)−エキレニン(J.Chem.Soc.,Chem.Commun.,1990,1544)や(+)−エストロン(Tetrahedron Lett.,1992,33,1909)を容易に合成できる。
また、麻酔・鎮痛作用を示すモルフィン系アルカロイドである(−)−アファノルフィン(J.Chem.Soc.,Chem.Commun.,1990,290)や、中枢神経興奮作用を有する(−)−フィソベニン(J.Org.Chem.,1991,56,5982)も(−)−3−オキソジシクロペンタジエンから効率よく合成することができる。
【0003】
【発明が解決しようとする課題】
本発明に係る化合物の有用性に鑑み、本発明者らは、光学活性3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン誘導体を効率的に製造する方法を見出すべく鋭意検討した結果、(±)−3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエンを、塩基の存在下、リパーゼを用いた脂肪酸ビニルとのエステル交換反応に付すことにより、光学活性3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン導体を効率的に得る製造法を見出し本発明に至った。
【0004】
【課題を解決するための手段】
本発明は、下記(1)ないし(4)の構成を有する。
(1)式(I)
【化3】
で表される(±)−3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエンを、塩基の存在下、リパーゼを用いた脂肪酸ビニルとのエステル交換反応に付すことを特徴とする、式(II)
【化4】
(式中、Rは水素、または炭素数1〜20のアシル基を表す。)
で表される光学活性3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン誘導体を得る製造法。
(2)リパーゼがシュウドモナス属由来のものである前記(1)に記載の製造法。
(3)リパーゼがトヨチーム・LIP(東洋紡製)である前記(1)に記載の製造法。
(4)塩基がトリエチルアミンである前記(1)に記載の製造法。
【0005】
次に、本発明について詳細に述べる。本発明の光学活性3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン誘導体は、以下の工程に従って製造することができる。
【0006】
【化5】
【0007】
本発明に用いられる式(I)で表される化合物は、以下のスキームに従って容易に合成することができる。
【0008】
【化6】
【0009】
式(IIa)で表される化合物は、式(I)で表される化合物を、塩基の存在下、リパーゼを用いて脂肪酸ビニルとエステル交換反応することにより合成することができる。リパーゼとしては、次の表1に示した市販のリパーゼを用いることができる。
【0010】
【表1】
【0011】
これらの他にエステル交換能を有するリパーゼを産生する微生物であれば、その種類を問わずにそのリパーゼを使用することができる。かかる微生物の例として、
シュウドモナス(Pseudomonus)属、
クロモバクテリウム(Chromobacterium)属、
アルスロバクター(Arthrobacter)属、
アクロモバクター(Acromobacter)属、
アルカリゲネス(Alcaligenes)属、
アスペルギルス(Aspergilius)属、
カンジタ(Candida)属、
ムコール(Mucor)属、
リゾプス(Rhizopus)属、
等に属するものが挙げられる。これらの中で特に好ましいのは、シュウドモナス属由来のものであるが、最も好ましいのはトヨチーム・LIP(東洋紡製)である。
【0012】
脂肪酸ビニルとしては、酢酸ビニル、プロピオン酸ビニル、カプロン酸ビニル、ラウリン酸ビニル等が挙げられる。脂肪酸ビニルは基質に対して0.1〜50当量用いることができるが、最も好ましくは1〜20当量である。
【0013】
本反応を円滑に進行させるためには、塩基の添加が不可欠である。反応に用いられる塩基として最も好ましいのはトリエチルアミンであるが、これ以外にもピリジン等の有機塩基や炭酸水素ナトリウム、炭酸ナトリウム等の無機塩基等、リパーゼ活性を阻害しない塩基であれば広く用いることができる。塩基は基質に対して0.1〜50当量用いることができるが、特に好ましくは1〜20当量である。
【0014】
反応溶媒としては、ヘプタン、ヘキサン等の炭化水素系溶媒、トルエン、ベンゼン等の芳香族炭化水素系溶媒、ジエチルエーテル、t−ブチルメチルエーテル、テトラヒドロフラン等のエーテル系溶媒が代表的なものであるが、リパーゼ活性を阻害しない有機溶媒であれば広く用いることができる。
反応温度は10〜100℃が適当であり、特に好ましくは20〜50℃である。
反応時間は0.5〜100時間であり、好ましくは1〜50時間である。
【0015】
また、式(IIa)で表される化合物は、既知の方法による塩基性条件下の加水分解もしくは加アルコール分解により、式(IIb)で表される化合物に容易に導くことができる。加水分解に用いられる塩基としては、水酸化ナトリウム、水酸化カリウム等が挙げられる。加アルコール分解の代表的な方法としては、例えば、炭酸カリウム−メタノール等の方法が挙げられる。
以上の操作により、光学純度の高い光学活性3,5−ジヒドロキシ−4,5 −ジヒドロジシクロペンタジエン誘導体を効率的に製造することができる。
式(IIb)で表される化合物は、ピリジニウムクロロクロメート等の酸化剤を用いて酸化した後、塩基処理することにより、光学活性3−オキソジシクロペンタジエン(III)に容易に導かれる。
【0016】
【発明の効果】
本発明の製造法を用いることにより、光学活性3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン誘導体が効率的に製造できる。光学活性3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン誘導体は、種々の生理活性物質等の合成中間体として有用な化合物である。
【0017】
【実施例】
以下、実施例、比較例及び参考例により本発明を更に詳しく説明するが、本発明はこれらの例によって制限されるものではない。
参考例1:(±)−エンド−3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエンの合成
工程1
(±)−3−オキソ−5−tert−ブトキシ−4,5−ジヒドロジシクロペンタジエンの合成
(±)−4−tert−ブトキシシクロペンテン−2−エノン(536mg,3.5mmol)を無水ベンゼン(30ml)に溶解し、塩化亜鉛(570mg,4.2mmol)を加えて、アルゴン気流下室温で30分間撹拌した。次いでシクロペンタジエン(0.84ml,10.4mmol)を滴下し、同温度で3時間撹拌した。
反応液に氷冷下、飽和重曹水を加えてアルカリ性とし、混合物をセライトで濾過した。セライト層を酢酸エチルで洗浄し、有機相を分取した。水相を酢酸エチルで抽出し、有機相を合わせて飽和食塩水で洗浄した。硫酸マグネシウム上で乾燥後、濾過、減圧濃縮した。残さをシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=2/98(v/v))を用いて精製し、無色固形の(±)−エンド−3−オキソ−5−tert−ブトキシ−4,5−ジヒドロジシクロペンタジエン(703mg,92%)と無色油状の(±)−エキソ−3−オキソ−5−tert−ブトキシ−4,5−ジヒドロジシクロペンタジエン(48mg,6%)を得た。
【0018】
工程2
(±)−3−オキソ−5−ヒドロキシ−4,5−ジヒドロジシクロペンタジエンの合成
(±)−エンド−3−オキソ−5−tert−ブトキシ−4,5−ジヒドロジシクロペンタジエン(375mg,1.7mmol)を無水塩化メチレン(7ml)に溶解し、四塩化チタン(0.23ml,2.0mmol)を加えて、アルゴン気流下0℃にて5分間撹拌した。反応液に飽和重曹水を加えてアルカリ性とし、混合物をセライトで濾過した。セライト層を塩化メチレンで洗浄し、有機相を分取した。
水相を塩化メチレンで抽出し、有機相を合わせて飽和食塩水で洗浄した。硫酸マグネシウム上で乾燥後、濾過、減圧濃縮した。残さをシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/9→1/4(v/v))を用いて精製し、無色固形の(±)−3−オキソジシクロペンタジエン(46mg,19%)と(±)−エンド−3−オキソ−5−ヒドロキシ−4,5−ジヒドロジシクロペンタジエン(225mg,80%)を得た。
【0019】
工程3
(±)−エンド−3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエンの合成
(±)−エンド−3−オキソ−5−ヒドロキシ−4,5−ジヒドロジシクロペンタジエン(376mg,2.3mmol)をメタノール(12ml)に溶解し、撹拌下0℃にて水素化ホウ素ナトリウム(58mg,1.5mmol)を少量ずつ加えた。同温度で15分間撹拌した後、メタノールを減圧濃縮した。残さに水を加え、10%メタノール−酢酸エチルで抽出した。
抽出液を硫酸マグネシウム上で乾燥し、濾過、減圧濃縮した。残さをシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/9(v/v))を用いて精製し、無色固形の(±)−3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン(314mg,83%)を得た。
mp:152−155℃
IR(Nujol):3316cm-1
1H−NMR(CDCl3 ):δ 1.31(d,J=8.1Hz),1.44(dt,J=8.1,1.5Hz),1.79(dt,J=12.0,10.0Hz),2.02(dt,J=12.0,7.3Hz),2.20(brs),2.85(m),2.97(brs),4.22(m),6.23(t,J=1.5Hz)
MS(m/z):166(M+ ),148,130,83,66
【0020】
実施例1
(+)−エンド−3,5−ヒドロキシ−5−アセトキシ−4,5−ジヒドロジシクロペンタジエンの合成
(±)−エンド−3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン(65mg,0.4mmol)をテトラヒドロフラン(2ml)に溶解し、トリエチルアミン(0.2ml)、酢酸ビニル(0.22ml,2.4mmol)、トヨチーム・LIP(東洋紡、65mg)を順次加えて、室温下で2.5時間撹拌した。反応混合物をセライトで濾過し、セライト層をエーテルで洗浄した。有機相を減圧濃縮し、残さをシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/3(v/v))を用いて精製し、(+)−エンド−3−ヒドロキシ−5−アセトキシ−4,5−ジヒドロジシクロペンタジエン(82mg,100%)を得た。
[α]p +90.8゜(c0.99,CHCl3 )
IR(neat):3500,1731cm-1
1H−NMR(CDCl3 ):δ 1.28(d,J=8.0Hz),1.41(dt,J=8.0,2.0Hz),1.83(dt,J=12.0,10.6Hz),2.07(s),2.13(dt,J=12.0,8.0Hz),2.83(brs),2.88(m),2.99(brs),3.04(m),4.27(m),4.97(dt,J=10.6,8.4Hz),6.14(dd,J=5.5,2.9Hz),6.23(dd,J=5.5,2.9Hz)
MS(m/z):208(M+ ),148,125,83,66
(+)−エンド−3−ヒドロキシ−5−アセトキシ−4,5−ジヒドロジシクロペンタジエンを参考例2に示すように(−)−3−オキソジシクロペンタジエンに誘導した後、光学純度を光学異性体分離カラム(CHIRALCEL OB、イソプロパノール/ヘキサン=1/9)を用いたHPLCにより測定したところ、99%ee以上であることが判明した。
【0021】
比較例1:(+)−3−エンド−3−ヒドロキシ−5−アセトキシ−4,5−ジヒドロジシクロペンタジエンの合成
(±)−エンド−3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン(65mg,0.4mmol)をテトラヒドロフラン(2ml)に溶解し、酢酸ビニル(0.22ml,2.4mmol)、トヨチーム・LIP(東洋紡、65mg)を順次加えて室温下で10日間撹拌した。実施例1と同様に後処理し、(+)−エンド−3−ヒドロキシ−5−アセトキシ−4,5−ジヒドロジシクロペンタジエン(75mg,92%)を得た。また、原料である(±)−エンド−3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジエン(5mg,8%)が回収された。
比較例1に示されるように、エステル交換反応の際に塩基が存在しないと、反応の進行は非常に緩慢である。これに対して、実施例1に示されるように、塩基を添加した場合には反応は迅速に進行するようになる。これらの結果から、本発明のエステル交換反応を円滑に進行させるためには、塩基の存在が不可欠であることは明らかである。
【0022】
参考例2:(−)−3−オキソジシクロペンタジエンの合成
実施例1で得た(+)−エンド−3−ヒドロキシ−5−アセトキシ−4,5−ジヒドロジシクロペンタジエン(82mg,0.4mmol)を無水塩化メチレン(2ml)に溶解し、アルゴン気流下、室温にてピリジニウムクロロクロメート(125mg,0.57mmol)を少量ずつ加えた。同温度で1.5時間撹拌した後、無水塩化メチレン(5ml)を加えて希釈した。
反応混合物をシリカゲルで濾過し、シリカゲル層をエーテルで洗浄した。有機相を減圧濃縮し、粗製のアセテート(60mg)を得た。このものを無水塩化メチレン(0.2ml)に溶解し、トリエチルアミン(45m1,0.32mmol)を加えてアルゴン気流下、室温にて1時間撹拌した。反応混合物を減圧濃縮し、残さをシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/9(v/v))を用いて精製し、無色固形の(−)−3−オキソジシクロペンタジエン(38mg,67%)を得た。
[α]p 27 −135.7゜(c 0.734,MeOH)
IR(Nujol):1713cm-1
1H−NMR(CDCl3 ):δ 1.62(d,J=8.4Hz),1.72,dt,J=8.4,1.6Hz),2.80(t,J=5.1Hz),2.97(brs),3.22(brs),3.42(m),5.78(dd,J=5.6,3.0Hz),5.94(dd,J=5.6,2.7Hz),5.96(dd,J=5.8,1.6Hz),7.39(dd,J=5.8,2.5Hz)このものの光学純度を光学異性体分離カラム(CHIRALCEL OB、イソプロパノール/ヘキサン=1/9)を用いたHPLCにより測定したところ、99%ee以上であった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for producing optically active 3,5-dihydroxy-4,5-dihydrodicyclopentadiene derivatives useful as synthetic intermediates for various physiologically active substances.
[0002]
[Prior art]
The optically active 3,5-dihydroxy-4,5-dihydrodicyclopentadiene derivative according to the present invention is a useful compound that can be widely used as a synthetic intermediate for various physiologically active substances. For example, if (-)-3-oxodicyclopentadiene obtained in a short step from this compound is used as a starting material, (+)-echlenine (J. Chem. Soc., Chem. Commun., 1990, 1544) and (+)-estrone (Tetrahedron Lett., 1992, 33, 1909) can be easily synthesized.
Further, (−)-aphanorphine (J. Chem. Soc., Chem. Commun., 1990, 290), which is a morphine alkaloid exhibiting anesthesia and analgesia, and (−)-physobenin having central nervous excitability. (J. Org. Chem., 1991, 56, 5982) can also be efficiently synthesized from (−)-3-oxodicyclopentadiene.
[0003]
[Problems to be solved by the invention]
In view of the usefulness of the compound according to the present invention, the present inventors have conducted extensive studies to find a method for efficiently producing an optically active 3,5-dihydroxy-4,5-dihydrodicyclopentadiene derivative. ±) -3,5-dihydroxy-4,5-dihydrodicyclopentadiene is subjected to a transesterification reaction with a fatty acid vinyl using lipase in the presence of a base to give optically active 3,5-dihydroxy-4, The inventors have found a production method for efficiently obtaining a 5-dihydrodicyclopentadiene conductor and have reached the present invention.
[0004]
[Means for Solving the Problems]
The present invention has the following configurations (1) to (4).
(1) Formula (I)
[Chemical 3]
(±) -3,5-dihydroxy-4,5-dihydrodicyclopentadiene represented by the formula (1) is subjected to a transesterification reaction with a fatty acid vinyl using a lipase in the presence of a base. II)
[Formula 4]
(In the formula, R represents hydrogen or an acyl group having 1 to 20 carbon atoms.)
A process for obtaining an optically active 3,5-dihydroxy-4,5-dihydrodicyclopentadiene derivative represented by the formula:
(2) The production method according to (1), wherein the lipase is derived from the genus Pseudomonas.
(3) The manufacturing method as described in said (1) whose lipase is Toyoteam * LIP (made by Toyobo).
(4) The production method according to (1), wherein the base is triethylamine.
[0005]
Next, the present invention will be described in detail. The optically active 3,5-dihydroxy-4,5-dihydrodicyclopentadiene derivative of the present invention can be produced according to the following steps.
[0006]
[Chemical formula 5]
[0007]
The compound represented by the formula (I) used in the present invention can be easily synthesized according to the following scheme.
[0008]
[Chemical 6]
[0009]
The compound represented by the formula (IIa) can be synthesized by transesterifying the compound represented by the formula (I) with a fatty acid vinyl using lipase in the presence of a base. As the lipase, commercially available lipases shown in the following Table 1 can be used.
[0010]
[Table 1]
[0011]
In addition to these, any lipase capable of producing a lipase having transesterification ability can be used regardless of its type. Examples of such microorganisms include
Genus Pseudomonus,
The genus Chromobacterium,
Arthrobacter genus,
Achromobacter genus,
Genus Alcaligenes,
Aspergillus genus,
Candida genus,
Genus Mucor,
Rhizopus genus,
And the like. Of these, those derived from the genus Pseudomonas are particularly preferred, but most preferred is Toyoteam LIP (manufactured by Toyobo).
[0012]
Examples of the fatty acid vinyl include vinyl acetate, vinyl propionate, vinyl caproate, and vinyl laurate. The fatty acid vinyl can be used in an amount of 0.1 to 50 equivalents relative to the substrate, but most preferably 1 to 20 equivalents.
[0013]
Addition of a base is indispensable for allowing this reaction to proceed smoothly. Triethylamine is most preferred as the base used in the reaction, but other bases that do not inhibit lipase activity such as organic bases such as pyridine and inorganic bases such as sodium bicarbonate and sodium carbonate can be used widely. it can. The base can be used in an amount of 0.1 to 50 equivalents, particularly preferably 1 to 20 equivalents, relative to the substrate.
[0014]
Typical reaction solvents include hydrocarbon solvents such as heptane and hexane, aromatic hydrocarbon solvents such as toluene and benzene, and ether solvents such as diethyl ether, t-butyl methyl ether and tetrahydrofuran. Any organic solvent that does not inhibit lipase activity can be used widely.
The reaction temperature is suitably 10 to 100 ° C., particularly preferably 20 to 50 ° C.
The reaction time is 0.5 to 100 hours, preferably 1 to 50 hours.
[0015]
In addition, the compound represented by the formula (IIa) can be easily led to the compound represented by the formula (IIb) by hydrolysis or alcoholysis under basic conditions by a known method. Examples of the base used for the hydrolysis include sodium hydroxide and potassium hydroxide. As a typical method of alcoholysis, a method such as potassium carbonate-methanol is exemplified.
By the above operation, an optically active 3,5-dihydroxy-4,5-dihydrodicyclopentadiene derivative having high optical purity can be efficiently produced.
The compound represented by the formula (IIb) is easily led to optically active 3-oxodicyclopentadiene (III) by oxidizing with an oxidizing agent such as pyridinium chlorochromate and then treating with a base.
[0016]
【The invention's effect】
By using the production method of the present invention, an optically active 3,5-dihydroxy-4,5-dihydrodicyclopentadiene derivative can be produced efficiently. Optically active 3,5-dihydroxy-4,5-dihydrodicyclopentadiene derivatives are useful compounds as synthetic intermediates for various physiologically active substances.
[0017]
【Example】
EXAMPLES Hereinafter, although an Example, a comparative example, and a reference example demonstrate this invention further in detail, this invention is not restrict | limited by these examples.
Reference Example 1: Synthesis step 1 of (±) -endo-3,5-dihydroxy-4,5-dihydrodicyclopentadiene
Synthesis of (±) -3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (±) -4-tert-butoxycyclopenten-2-enone (536 mg, 3.5 mmol) was added to anhydrous benzene (30 ml) ), Zinc chloride (570 mg, 4.2 mmol) was added, and the mixture was stirred at room temperature for 30 minutes under an argon stream. Next, cyclopentadiene (0.84 ml, 10.4 mmol) was added dropwise, and the mixture was stirred at the same temperature for 3 hours.
Under ice-cooling, the reaction mixture was made alkaline by adding saturated aqueous sodium hydrogen carbonate, and the mixture was filtered through celite. The celite layer was washed with ethyl acetate, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine. After drying over magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate / hexane = 2/98 (v / v)) to give colorless solid (±) -endo-3-oxo-5-tert-butoxy-4,5- Dihydrodicyclopentadiene (703 mg, 92%) and colorless oily (±) -exo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (48 mg, 6%) were obtained.
[0018]
Process 2
Synthesis of (±) -3-oxo-5-hydroxy-4,5-dihydrodicyclopentadiene (±) -endo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (375 mg, 1 0.7 mmol) was dissolved in anhydrous methylene chloride (7 ml), titanium tetrachloride (0.23 ml, 2.0 mmol) was added, and the mixture was stirred at 0 ° C. for 5 minutes under an argon stream. Saturated aqueous sodium bicarbonate was added to the reaction solution to make it alkaline, and the mixture was filtered through celite. The celite layer was washed with methylene chloride, and the organic phase was separated.
The aqueous phase was extracted with methylene chloride, and the organic phases were combined and washed with saturated brine. After drying over magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate / hexane = 1/9 → 1/4 (v / v)) to give colorless solid (±) -3-oxodicyclopentadiene (46 mg, 19%). And (±) -endo-3-oxo-5-hydroxy-4,5-dihydrodicyclopentadiene (225 mg, 80%).
[0019]
Process 3
Synthesis of (±) -endo-3,5-dihydroxy-4,5-dihydrodicyclopentadiene (±) -endo-3-oxo-5-hydroxy-4,5-dihydrodicyclopentadiene (376 mg, 2.3 mmol) ) Was dissolved in methanol (12 ml), and sodium borohydride (58 mg, 1.5 mmol) was added little by little at 0 ° C. with stirring. After stirring at the same temperature for 15 minutes, methanol was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with 10% methanol-ethyl acetate.
The extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate / hexane = 1/9 (v / v)) to give colorless solid (±) -3,5-dihydroxy-4,5-dihydrodicyclopentadiene (314 mg). 83%).
mp: 152-155 ° C
IR (Nujol): 3316 cm −1
1 H-NMR (CDCl 3 ): δ 1.31 (d, J = 8.1 Hz), 1.44 (dt, J = 8.1, 1.5 Hz), 1.79 (dt, J = 12. 0, 10.0 Hz), 2.02 (dt, J = 12.0, 7.3 Hz), 2.20 (brs), 2.85 (m), 2.97 (brs), 4.22 (m ), 6.23 (t, J = 1.5 Hz)
MS (m / z): 166 (M + ), 148, 130, 83, 66
[0020]
Example 1
Synthesis of (+)-endo-3,5-hydroxy-5-acetoxy-4,5-dihydrodicyclopentadiene (±) -endo-3,5-dihydroxy-4,5-dihydrodicyclopentadiene (65 mg, 0 .4 mmol) was dissolved in tetrahydrofuran (2 ml), triethylamine (0.2 ml), vinyl acetate (0.22 ml, 2.4 mmol) and Toyoteam · LIP (Toyobo, 65 mg) were sequentially added, and 2.5 ml at room temperature. Stir for hours. The reaction mixture was filtered through celite, and the celite layer was washed with ether. The organic phase was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (ethyl acetate / hexane = 1/3 (v / v)) to obtain (+)-endo-3-hydroxy-5-acetoxy-4, 5-Dihydrodicyclopentadiene (82 mg, 100%) was obtained.
[Α] p + 90.8 ° (c0.99, CHCl 3 )
IR (neat): 3500, 1731 cm −1
1 H-NMR (CDCl 3 ): δ 1.28 (d, J = 8.0 Hz), 1.41 (dt, J = 8.0, 2.0 Hz), 1.83 (dt, J = 12. 0, 10.6 Hz), 2.07 (s), 2.13 (dt, J = 12.0, 8.0 Hz), 2.83 (brs), 2.88 (m), 2.99 (brs) ), 3.04 (m), 4.27 (m), 4.97 (dt, J = 10.6, 8.4 Hz), 6.14 (dd, J = 5.5, 2.9 Hz), 6.23 (dd, J = 5.5, 2.9 Hz)
MS (m / z): 208 (M + ), 148, 125, 83, 66
(+)-Endo-3-hydroxy-5-acetoxy-4,5-dihydrodicyclopentadiene was converted to (−)-3-oxodicyclopentadiene as shown in Reference Example 2, and the optical purity was changed to optical isomerism. It was found to be 99% ee or more when measured by HPLC using a body separation column (CHIRALCEL OB, isopropanol / hexane = 1/9).
[0021]
Comparative Example 1: Synthesis of (+)-3-endo-3-hydroxy-5-acetoxy-4,5-dihydrodicyclopentadiene (±) -endo-3,5-dihydroxy-4,5-dihydrodicyclopentadiene (65 mg, 0.4 mmol) was dissolved in tetrahydrofuran (2 ml), vinyl acetate (0.22 ml, 2.4 mmol) and Toyoteam · LIP (Toyobo, 65 mg) were sequentially added, and the mixture was stirred at room temperature for 10 days. Post-treatment was conducted in the same manner as in Example 1 to obtain (+)-endo-3-hydroxy-5-acetoxy-4,5-dihydrodicyclopentadiene (75 mg, 92%). In addition, (±) -endo-3,5-dihydroxy-4,5-dihydrodicyclopentadiene (5 mg, 8%) as a raw material was recovered.
As shown in Comparative Example 1, the reaction proceeds very slowly if no base is present during the transesterification reaction. On the other hand, as shown in Example 1, when a base is added, the reaction proceeds rapidly. From these results, it is clear that the presence of a base is indispensable for smoothly proceeding the transesterification reaction of the present invention.
[0022]
Reference Example 2: Synthesis of (-)-3-oxodicyclopentadiene (+)-endo-3-hydroxy-5-acetoxy-4,5-dihydrodicyclopentadiene (82 mg, 0.4 mmol) obtained in Example 1 ) Was dissolved in anhydrous methylene chloride (2 ml), and pyridinium chlorochromate (125 mg, 0.57 mmol) was added in small portions at room temperature under a stream of argon. After stirring at the same temperature for 1.5 hours, anhydrous methylene chloride (5 ml) was added for dilution.
The reaction mixture was filtered through silica gel and the silica gel layer was washed with ether. The organic phase was concentrated under reduced pressure to give crude acetate (60 mg). This was dissolved in anhydrous methylene chloride (0.2 ml), triethylamine (45 ml, 0.32 mmol) was added, and the mixture was stirred at room temperature for 1 hour under an argon stream. The reaction mixture was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (ethyl acetate / hexane = 1/9 (v / v)) to give colorless solid (−)-3-oxodicyclopentadiene (38 mg, 67%).
[Α] p 27 -135.7 ° (c 0.734, MeOH)
IR (Nujol): 1713 cm -1
1 H-NMR (CDCl 3 ): δ 1.62 (d, J = 8.4 Hz), 1.72, dt, J = 8.4, 1.6 Hz), 2.80 (t, J = 5. 1 Hz), 2.97 (brs), 3.22 (brs), 3.42 (m), 5.78 (dd, J = 5.6, 3.0 Hz), 5.94 (dd, J = 5 .6, 2.7 Hz), 5.96 (dd, J = 5.8, 1.6 Hz), 7.39 (dd, J = 5.8, 2.5 Hz). It was 99% ee or more when measured by HPLC using a column (CHIRALCEL OB, isopropanol / hexane = 1/9).
Claims (4)
で表される光学活性3,5−ジヒドロキシ−4,5−ジヒドロジシクロペンタジェン誘導体を得る製造法。Formula (I)
A process for obtaining an optically active 3,5-dihydroxy-4,5-dihydrodicyclopentagen derivative represented by the formula:
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