JP3541417B2 - Phenyl-substituted hydroxycyclopentenones, pentanones and phenyl-substituted prostaglandin I2 intermediates, and their production and optical resolution - Google Patents

Description

【０００６】
しかしながら、スキ−ム１は、全１１工程、スキ−ム２では、全２０工程であり、収率はどちらも１％以下であり、実用的な製造法としては満足のいく方法ではない。
【０００７】
【課題を解決するための手段】
本発明者らは鋭意検討を行なった結果、以下に示すような新規な中間体及びそれらを用いたフェニル置換ＰＧＩ_２類の有効な製造法を見いだし、本発明を完成するに至った。
【０００８】
すなわち、本発明は、スキ−ム３に示すごとく、式［ＩＩ］のフラン誘導体を酸触媒存在下転位反応させて式［ＩＩＩ］の化合物とし、さらに酸性条件または塩基性条件下で異性化反応させ、必要に応じて水酸基を保護することにより、式［Ｉ］の新規フェニル置換ヒドロキシシクロペンテノン類を製造することができ、このフェニル置換ヒドロキシシクロペンテノン類［Ｉ］に式［ＶＩＩＩ］の Ｍ−Ｘ^３で示される求核試薬を反応させることにより、式［ＩＶ］の新規フェニル置換ヒドロキシシクロペンタノン類を製造することができ、このフェニル置換ヒドロキシシクロペンタノン類［ＩＶ］を還元剤と反応させることにより、式［Ｖ］の新規フェニル置換ジヒドロキシシクロペンタン類を製造することができ、さらにこのフェニル置換ジヒドロキシシクロペンタン類［Ｖ］を環化させることで式［ＶＩ］のフェニル置換ＰＧＩ_２類を製造し得ると共に、この式［ＶＩ］のフェニル置換ＰＧＩ_２類の内、式［ＶＩＩ］で表わされる化合物は、フェニル置換プロスタグランジンＩ_２類へと誘導するのに有用である新規な中間体であることを見い出した。
【０００９】
さらに、フェニル置換ヒドロキシシクロペンテノン類［Ｉ］の両対掌体の混合物を酵素分割することにより、光学活性な式［Ｉ］のフェニル置換ヒドロキシシクロペンテノン類を得ることができ、これを用いることにより、対応する光学活性なフェニル置換ヒドロキシシクロペンタノン類［ＩＶ］、光学活性なフェニル置換ジヒドロキシシクロペンタン類［Ｖ］、さらには光学活性なフェニル置換ＰＧＩ_２類を効率的に製造することができることを知見し、本発明をなすに至ったものである。
【００１０】
【化１６】

【００１１】
式中、Ｘ¹はハロゲン原子、水酸基、保護された水酸基、チオ−ル基、保護されたチオ−ル基、アミノ基、保護されたアミノ基、あるいは「炭素数１〜６のアルキル基、または炭素数１〜８のアラルキル基」で置換されたアミノ基を示す。Ｘ²はハロゲン原子、
−Ｙ¹ _h（ＣＲ¹Ｒ²）_mＡ_n（ＣＨ₂）_pＹ² _q（ＣＲ³Ｒ⁴）_rＱ_s
（式中、Ｙ¹及びＹ²はそれぞれ酸素原子または硫黄原子を示し、Ａはビニレン基、エチニレン基、またはアレンの両端の炭素原子から１個ずつ水素原子を除いてできる２価の基を示し、Ｒ¹、Ｒ²、Ｒ³及びＲ⁴は水素原子、炭素数１〜４のアルキル基、または炭素数１〜４のアルコキシ基を示し、Ｑは水素原子、
−ＣＯＯＲ⁵
（式中、Ｒ⁵は水素原子、炭素数１〜６のアルキル基または炭素数２〜６のアルケニル基を示す。）で表わされる基、シアノ基、水酸基、
−ＯＣＯＲ⁶
（式中、Ｒ⁶は水素原子、炭素数１〜６のアルキル基または炭素数２〜６のアルケニル基を示す。）で表わされる基、
−ＣＯＮＲ⁷Ｒ⁸
（式中、Ｒ⁷及びＲ⁸は水素原子、炭素数１〜６のアルキル基またはフェニル基を示す。）で表わされる基またはフェニル基を示し、ｈ、ｎ、ｑ、ｓは０または１を示し、ｍ、ｐ、ｒは０〜５の整数を示す。）を示す。
【００１２】
Ｘ³は
−Ｔ−（ＣＨ₂）_j−Ｃ（Ｒ⁹）_(2-k)（ＯＺ²）_k−Ｒ¹⁰
（式中、ＴはＣＨ₂ＣＨ₂、ＣＨ＝ＣＨ、またはＣ≡Ｃより選ばれる基を示し、ｊ及びｋはそれぞれ独立に０、１または２の整数を示し、Ｒ⁹は（２−ｋ）個の水素原子、炭素数１〜４のアルキル基または炭素数１〜４のアルコキシ基を示し、Ｒ¹⁰は炭素数１〜１０のアルキル基、炭素数３〜８のシクロアルキル基、炭素数２〜１０のアルケニル基、炭素数２〜１０のアルキニル基、フェニル基、フェノキシ基、（該フェニル基及びフェノキシ基は、ハロゲン原子、トリフルオロメチル基、炭素数１〜６のアルキル基または炭素数１〜６のアルコキシ基で任意に置換されていてもよい。）または−Ｂ−Ｄ（Ｂは炭素数１〜４のアルキレン基を、Ｄはフェニル基、フェノキシ基、（該フェニル基及びフェノキシ基は、ハロゲン原子、トリフルオロメチル基、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシ基、フェニル基またはフェノキシ基で任意に置換されていてもよい。）または炭素数５〜７のシクロアルキル基を示す。）で表わされる基を示し、Ｚ²は水素原子または水酸基の保護基を示し、ただしＴがＣ≡Ｃなる基の場合水酸基の保護基を示す。ＭはＬｉ、Ｎａ、Ｋ、Ｍｇ、Ｃａ、Ｔｉ、Ｚｒ、Ｎｉ、Ｃｕ、Ｚｎ、Ａｌ、Ｓｎより選ばれる金属または該金属を含む基を示す。）を示す。
【００１３】
Ｙ^３は酸素原子、硫黄原子、−ＮＨ−または−ＮＲ^１１−（式中、Ｒ^１１は炭素数１〜６のアルキル基を示す。）を示す。
【００１４】
Ｘ^４はハロゲン原子、水酸基、チオ−ル基、アリル基、ビニル基、エチニル基、エステル基またはシアノ基を示す。
【００１５】
以下、本発明につき更に詳しく説明する。
本発明の第１発明は、下記式［Ｉ］で表されるフェニル置換ヒドロキシシクロペンテノン類に係わる。
【００１６】
【化１７】

［式中、Ｚ¹は水素原子または水酸基の保護基を示し、Ｘ¹はハロゲン原子、水酸基、保護された水酸基、チオ−ル基、保護されたチオ−ル基、アミノ基、保護されたアミノ基、あるいは「炭素数１〜６のアルキル基、または炭素数１〜８のアラルキル基」で置換されたアミノ基を示す。Ｘ²はハロゲン原子、
−Ｙ¹ _h（ＣＲ¹Ｒ²）_mＡ_n（ＣＨ₂）_pＹ² _q（ＣＲ³Ｒ⁴）_rＱ_s
（式中、Ｙ¹及びＹ²はそれぞれ酸素原子または硫黄原子を示し、Ａはビニレン基、エチニレン基、またはアレンの両端の炭素原子から１個ずつ水素原子を除いてできる２価の基を示し、Ｒ¹、Ｒ²、Ｒ³及びＲ⁴は水素原子、炭素数１〜４のアルキル基、または炭素数１〜４のアルコキシ基を示し、Ｑは水素原子、
−ＣＯＯＲ⁵
（式中、Ｒ⁵は水素原子、炭素数１〜６のアルキル基または炭素数２〜６のアルケニル基を示す。）で表わされる基、シアノ基、水酸基、
−ＯＣＯＲ⁶
（式中、Ｒ⁶は水素原子、炭素数１〜６のアルキル基または炭素数２〜６のアルケニル基を示す。）で表わされる基、
−ＣＯＮＲ⁷Ｒ⁸
（式中、Ｒ⁷及びＲ⁸は水素原子、炭素数１〜６のアルキル基またはフェニル基を示す。）で表わされる基またはフェニル基を示し、ｈ、ｎ、ｑ、ｓは０または１を示し、ｍ、ｐ、ｒは０〜５の整数を示す。）
を示す。］
【００１７】
本発明において、Ｚ^１の水酸基の保護基としてはＰＧの分野で通常用いられるものでよく、例えば置換シリル基（トリメチルシリル基、トリエチルシリル基、ｔ−ブチルジメチルシリル基、ｔ−ブチルジフェニルシリル基、フェニルジメチルシリル基など）、テトラヒドロピラニル（ＴＨＰ）基、テトラヒドロフラニル基、アルコキシアルキル基（メトキシメチル基、エトキシエチル基など）、ベンジルオキシメチル基、ベンジル基、トリチル基、アリル基、アシル基（ホルミル基、アセチル基、ベンゾイル基など）を挙げることができる。
【００１８】
Ｘ^１はハロゲン原子、水酸基、保護された水酸基、チオ−ル基、保護されたチオ−ル基、アミノ基、保護されたアミノ基、あるいは「炭素数１〜６のアルキル基、または炭素数７〜１０のアラルキル基」で置換されたアミノ基を示す。ハロゲン原子としては、フッ素原子、塩素原子、臭素原子またはヨウ素原子が用いられる。保護された水酸基、保護されたチオ−ル基、または保護されたアミノ基の保護基としては、上記の水酸基の保護基と同様のものを挙げることができる。炭素数１〜６のアルキル基としては、メチル基、エチル基、プロピル基、ｉ−プロピル基、ブチル基、ｉ−ブチル基、ｔ−ブチル基、ペンチル基、ヘキシル基、シクロプロピル基、シクロペンチル基、またはシクロヘキシル基などが挙げられる。炭素数７〜１０のアラルキル基としては、ベンジル基、ｐ−クロロベンジル基、ｐ−ニトロベンジル基、ｐ−メトキシベンジル基、ｐ−メチルベンジル基などが挙げられる。
【００１９】
Ｘ²は、α鎖としての官能基を有するフェニル基上の側鎖、またはα鎖の導入・変換が可能なフェニル基上の置換基を表し、ハロゲン原子、
−Ｙ¹ _h（ＣＲ¹Ｒ²）_mＡ_n（ＣＨ₂）_pＹ² _q（ＣＲ³Ｒ⁴）_rＱ_s
（式中、Ｙ¹及びＹ²はそれぞれ酸素原子または硫黄原子を示し、Ａはビニレン基、エチニレン基、またはアレンの両端の炭素原子から１個ずつ水素原子を除いてできる２価の基を示し、Ｒ¹、Ｒ²、Ｒ³及びＲ⁴は水素原子、炭素数１〜４のアルキル基、または炭素数１〜４のアルコキシ基を示し、Ｑは水素原子、
−ＣＯＯＲ⁵
（式中、Ｒ⁵は水素原子、炭素数１〜６のアルキル基、または炭素数２〜６のアルケニル基を示す。）で表わされる基、シアノ基、水酸基、
−ＯＣＯＲ⁶
（式中、Ｒ⁶は水素原子、炭素数１〜６のアルキル基、炭素数２〜６のアルケニル基を示す。）で表わされる基、
−ＣＯＮＲ⁷Ｒ⁸
（式中、Ｒ⁷及びＲ⁸は水素原子、炭素数１〜６のアルキル基またはフェニル基を示す。）で表わされる基またはフェニル基を表す。）を表す。
【００２０】
炭素数１〜４のアルキル基としては、具体的にはメチル基、エチル基、プロピル基、ｉ−プロピル基、ｎ−ブチル基、ｉ−ブチル基、ｔ−ブチル基またはシクロプロピル基を挙げることができる。炭素数１〜４のアルコキシ基としては、具体的にはメトキシ基、エトキシ基、プロポキシ基、ｉ−プロポキシ基、ブトキシ基、ｉ−ブトキシ基、ｔ−ブトキシ基またはシクロプロポキシ基を挙げることができる。炭素数１〜６のアルキル基としては、具体的には前記と同じものを挙げることができる。炭素数２〜６のアルケニル基としては、具体的にはビニル基、アリル基、２−ブテニル基、３−メチル−２−ブテニル基または３−メチル−２−ペンテニル基などを挙げることができる。
【００２１】
上記Ｘ^２の具体的な例としては、塩素原子、臭素原子、ヨウ素原子、水酸基、メトキシ基、アリルオキシ基、ベンジルオキシ基、チオ−ル基、メチルチオ基、ベンジルチオ基、及び下記式で示されるものなどが挙げられる。
【００２２】
【化１８】

【００２３】
【化１９】

【００２４】
本発明の第２発明は、式［ＩＩ］で表わされるフラン誘導体を酸触媒存在下転位反応させて式［ＩＩＩ］の化合物とし、続いて酸性条件または塩基性条件下で異性化反応させ、必要に応じて水酸基を保護することからなる上記式［Ｉ］のフェニル置換ヒドロキシシクロペンテノン類の製造方法に係わる。
【００２５】
ここで、原料であるフラン誘導体［ＩＩ］は、フランの２−リチオ体（１）と、置換フェニルアルデヒド（２）を反応させる方法（反応式１）、フルフラ−ル（３）に、置換フェニルの求核試薬（４）を反応させる方法（反応式２）等で合成することができる。
【００２６】
【化２０】

【００２７】
フラン誘導体［ＩＩ］は、酸触媒存在下加熱すると転位反応が起こり、式［ＩＩＩ］の化合物となり、続いて酸性条件または塩基性条件下で異性化させ必要に応じて水酸基を保護することにより、フェニル置換ヒドロキシシクロペンテノン類［Ｉ］が製造できる（反応式３）。
【００２８】
【化２１】

【００２９】
転位反応は、そのままあるいは適当な溶媒中で行なうことができる。溶媒としては、水あるいは、エ−テル系（ジエチルエ−テル、ジオキサン、テトラヒドロフランなど）、ハロゲン系（ジクロロメタン、ジクロロエタンなど）、ケトン系（アセトン、メチルイソブチルケトンなど）、エステル系（酢酸エチルなど）、脂肪族炭化水素系（ヘキサン、ヘプタン、シクロヘキサンなど）または芳香族炭化水素系（ベンゼン、トルエン、ジクロロベンゼンなど）の有機溶媒を単独または混合して用いることができる。好ましくは水とテトラヒドロフランの混合溶媒である。酸触媒としては、無機酸（塩酸、硫酸など）あるいは有機酸（酢酸、トリフルオロ酢酸、ｐ−トルエンスルホン酸、メタンスルホン酸など）を、式［ＩＩ］の化合物に対して０．００１〜１００当量、好ましくは０．０１〜１当量用いる。反応温度は、０℃〜溶媒の還流温度、好ましくは５０〜１００℃である。反応時間は、基質や反応温度により異なるが、通常０．５〜２４時間である。反応溶液を中和後、適当な有機溶媒で抽出すれば式［ＩＩＩ］の化合物が得られる。式［ＩＩＩ］の化合物は精製してあるいは粗製物のまま次の反応に用いることができる。
【００３０】
異性化反応は、そのままあるいは適当な溶媒中で行なうことができる。溶媒としては、水あるいは、エ−テル系（ジエチルエ−テル、ジオキサン、テトラヒドロフランなど）、ハロゲン系（ジクロロメタン、ジクロロエタンなど）、ケトン系（アセトン、メチルイソブチルケトンなど）、エステル系（酢酸エチルなど）、脂肪族炭化水素系（ヘキサン、ヘプタン、シクロヘキサンなど）または芳香族炭化水素系（ベンゼン、トルエン、ジクロロベンゼンなど）の有機溶媒を単独または混合して用いることができる。酸性または塩基性条件下どちらでも反応は進行するが、好ましくは塩基性条件下で反応することが望ましい。酸触媒としては、無機酸（塩酸、硫酸など）あるいは有機酸（酢酸、トリフルオロ酢酸、ｐ−トルエンスルホン酸、メタンスルホン酸など）を、式［ＩＩ］の化合物に対して０．００１〜１００当量、好ましくは０．０１〜１当量用いる。塩基性触媒としては、有機アミン（トリエチルアミン、ピリジン、Ｎ−メチルモルホリン、ジアザビシクロウンデセンなど）、金属酸化物（アルミナ、シリカゲルなど）、無機塩基（水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、リン酸水素カリウムなど）を単独または混合して用いることができる。使用量は、塩基によって異なり０．００１〜１００当量または溶媒として用いることもでき、好ましくは式［ＩＩＩ］の化合物に対して０．０１〜５０当量用いる。反応温度は−４０〜１００℃、好ましくは−２０〜５０℃である。反応時間は、基質、溶媒や反応温度により異なるが、通常５分〜２０時間である。なお本反応において、クロラ−ル（Ｃｌ_３ＣＣＨＯ）などの電子吸引性基を持つアルデヒドを式［ＩＩ］の化合物に対して０．１〜３当量程度共存させておくと、反応がスム−ズに進行し生成物の純度も高くなる。反応溶液を中和後、適当な有機溶媒で抽出、再結晶あるいはカラムクロマトグラフィ−等で精製すればフェニル置換ヒドロキシシクロペンテノン類［Ｉ］（Ｚ^１が水素原子）が得られる。水酸基の保護は通常の方法で行なうことができフェニル置換ヒドロキシシクロペンテノン類［Ｉ］（Ｚ^１が水酸基の保護基）に容易に誘導できる。
【００３１】
本発明の第３発明は、式［ＩＶ］で表わされるフェニル置換ヒドロキシシクロペンタノン類に係わる。
【００３２】
【化２２】

［式中、Ｚ¹、Ｘ¹、Ｘ²は前記に同じ。Ｘ³は
−Ｔ−（ＣＨ₂）_j−Ｃ（Ｒ⁹）_(2-k)（ＯＺ²）_k−Ｒ¹⁰
（式中、ＴはＣＨ₂ＣＨ₂、ＣＨ＝ＣＨ、またはＣ≡Ｃより選ばれる基を示し、ｊ及びｋはそれぞれ独立に０、１または２の整数を示し、Ｒ⁹は（２−ｋ）個の水素原子、炭素数１〜４のアルキル基または炭素数１〜４のアルコキシ基を示し、Ｒ¹⁰は炭素数１〜１０のアルキル基、炭素数３〜８のシクロアルキル基、炭素数２〜１０のアルケニル基、炭素数２〜１０のアルキニル基、フェニル基、フェノキシ基、（該フェニル基及びフェノキシ基は、ハロゲン原子、トリフルオロメチル基、炭素数１〜６のアルキル基または炭素数１〜６のアルコキシ基で任意に置換されていてもよい。）または−Ｂ−Ｄ（Ｂは炭素数１〜４のアルキレン基を、Ｄはフェニル基、フェノキシ基、（該フェニル基及びフェノキシ基は、ハロゲン原子、トリフルオロメチル基、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシ基、フェニル基またはフェノキシ基で任意に置換されていてもよい。）または炭素数５〜７のシクロアルキル基を示す。）で表わされる基を示す。Ｚ²は水素原子または水酸基の保護基を示し、ただしＴがＣ≡Ｃなる基の場合水酸基の保護基を示す。）
を示す。］
ここで、Ｘ³はω鎖であり、上述したように、
−Ｔ−（ＣＨ₂）_j−Ｃ（Ｒ⁹）_(2-k)（ＯＺ²）_k−Ｒ¹⁰
（式中、ＴはＣＨ₂ＣＨ₂、ＣＨ＝ＣＨ、またはＣ≡Ｃより選ばれる基を示し、ｊ及びｋはそれぞれ独立に０、１または２の整数を示し、Ｒ⁹は（２−ｋ）個の水素原子、炭素数１〜４のアルキル基または炭素数１〜４のアルコキシ基を示し、Ｒ¹⁰は炭素数１〜１０のアルキル基、炭素数２〜１０のアルケニル基、炭素数２〜１０のアルキニル基、フェニル基、フェノキシ基、（該フェニル基及びフェノキシ基は、ハロゲン原子、トリフルオロメチル基、炭素数１〜６のアルキル基または炭素数１〜６のアルコキシ基で任意に置換されていてもよい。）または−Ｂ−Ｄ（Ｂは炭素数１〜４のアルキレン基を、Ｄはフェニル基、フェノキシ基、（該フェニル基及びフェノキシ基は、ハロゲン原子、トリフルオロメチル基、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシ基、フェニル基またはフェノキシ基で任意に置換されていてもよい。）または炭素数５〜７のシクロアルキル基を示す。）で表わされる基を示す。）を示す。Ｚ²は水素原子または水酸基の保護基を示し、ただしＴがＣ≡Ｃなる基の場合水酸基の保護基を示す。
【００３３】
Ｚ^２の水酸基の保護基としてはＺ¹と同様のものを挙げることができる。
【００３４】
炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシ基は前記と同様のものを挙げることができる。炭素数１〜１０のアルキル基としては、メチル基、エチル基、プロピル基、ｉ−プロピル基、ブチル基、ｉ−ブチル基、ｔ−ブチル基、ペンチル基、ヘキシル基ヘプチル基、オクチル基、１−メチルペンチル基、２−メチルペンチル基、１−メチルヘキシル基、２−メチルヘキシル基、２，４−ジメチルペンチル基、２−エチルペンチル基、２−メチルペプチル基、２−エチルヘキシル基、２−プロピルペンチル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、４−メチルシクロペンチル基、２，５−ジメチルシクロヘキシル基、シクロペンチルメチル基、シクロヘキシルメチル基、シクロペンチルエチル基、またはシクロヘキシルエチル基などを挙げることができる。炭素数２〜１０のアルケニル基としては、ビニル基、アリル基、１−ブテニル基、２−ブテニル基、１−ペンテニル基、２−ヘキセニル基、３−メチル−２−ブテニル基または３−メチル−２−ペンテニル基、２，６−ジメチル−５−ヘプテニル基などを挙げることができる。炭素数２〜１０のアルキニル基としては、エチニル基、１−プロピニル基、１−ブチニル基、１−メチル−３−ペンチニル基、１−メチル−３−ヘキシニル基、２−メチル−３−ヘキシニル基などを挙げることができる。炭素数５〜７のシクロアルキル基としては、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、または４−メチルシクロヘキシル基などを挙げることができる。
【００３５】
本発明の第４発明は、上記式［ＩＶ］のフェニル置換ヒドロキシシクロペンタノン類の製造法に係わり、これは上記第２発明により得られたフェニル置換ヒドロキシシクロペンテノン類［Ｉ］に求核試薬Ｍ−Ｘ^３［ＶＩＩＩ］を反応させてω鎖Ｘ^３を導入することにより、フェニル置換ヒドロキシシクロペンタノン類［ＩＶ］を製造するものである（反応式４）。
【００３６】
【化２３】

【００３７】
式中、Ｚ^１、Ｘ^１、Ｘ^２、Ｘ^３は上記と同様の意味を示し、ＭはＬｉ、Ｎａ、Ｋ、Ｍｇ、Ｃａ、Ｔｉ、Ｚｒ、Ｎｉ、Ｃｕ、Ｚｎ、Ａｌ、Ｓｎより選ばれる金属または該金属を含む基を示す。具体的には、Ｌｉ、ＭｇＢｒ、ＭｇＩ、ＺｎＢｒ、ＺｎＩ、ＣｕＬｉ、Ｃｕ（ＣＮ）Ｌｉ、ＣｕＭｅ（ＣＮ）Ｌｉ_２、Ｅｔ_２ Ａｌ、Ｅｔ_３ ＡｌＬｉ、Ｃｕ（ＳＰｈ）Ｌｉ、（２−チエニル）Ｃｕ（ＣＮ）Ｌｉ_２などを挙げることができる。
【００３８】
この式［ＶＩＩＩ］の求核試薬としては、通常ＰＧ類のω鎖導入反応に用いられるもので、Ｘ^３の種類によりリチウム試薬、銅−リチウム試薬、グリニヤ−ル（マグネシウム）試薬、亜鉛試薬、アルミニウム試薬などが用いられる。特にＸ^３中のＴがＣＨ_２ＣＨ_２の場合、ＺｎＩＸ^３、Ｃｕ（ＣＮ）ＬｉＸ^３が好ましく、ＴがＣＨ＝ＣＨの場合、（２−チエニル）Ｃｕ（ＣＮ）Ｌｉ_２Ｘ^３が好ましく、ＴがＣ≡Ｃの場合、Ｅｔ_２ ＡｌＸ^３が好ましく用いられる。求核試薬は式［Ｉ］の化合物に対して、０．５〜４当量、好ましくは０．８〜２当量用いる。反応溶媒としては、反応を阻害しないものであればよく、例えばテトラヒドロフラン、ジエチルエ−テル、ヘキサン、ペンタン、ベンゼン、トルエン等が挙げられる。反応温度は、求核試薬により異なり、−１００℃〜溶媒の還流温度、通常−７０〜４０℃である。反応時間は、基質、溶媒や反応温度により異なるが、通常５分〜５０時間である。
【００３９】
次に、本発明の第５発明は式［Ｖ］のフェニル置換ジヒドロキシシクロペンタン類に係わり、第６発明は、このフェニル置換ジヒドロキシシクロペンタン類［Ｖ］を上記フェニル置換ヒドロキシペンタノン類［ＩＶ］を還元することにより製造する方法に係わる（反応式５）。
【００４０】
【化２４】

【００４１】
ここで、還元剤としては、ボラン、水素化ホウ素ナトリウム、トリ−ｓ−ブチル水素化ホウ素カリウム、トリ−ｓ−ブチル水素化ホウ素リチウム、トリサイアミル水素化ホウ素カリウムなどの水素化ホウ素化合物、または水素化アルミニウムリチウム、ジイソブチル水素化アルミニウム、ビス（２−メトキシエトキシ）アルミニウムナトリウムなどの水素化アルミニウム化合物が用いられる。還元剤は式［ＩＶ］の化合物に対して、１〜５当量用いる。反応溶媒としては、還元剤によって適宜選択すればよく、例えば水あるいは、アルコ−ル系（メタノ−ル、エタノ−ルなど）、エ−テル系（ジエチルエ−テル、ジオキサン、テトラヒドロフランなど）、脂肪族炭化水素系（ヘキサン、ヘプタン、シクロヘキサンなど）または芳香族炭化水素系（ベンゼン、トルエン、ジクロロベンゼンなど）の有機溶媒を単独または混合して用いることができる。反応温度は、還元剤によって異なり、−８０℃〜５０℃、通常−１０〜３０℃である。反応時間も制限されないが、通常３０分〜２０時間である。
【００４２】
本発明の第７発明は、フェニル置換ジヒドロキシシクロペンタン類［Ｖ］を、必要に応じてＸ^１の保護基をはずして環化することにより、式［ＶＩ］のフェニル置換ＰＧＩ_２類を製造する方法に係わる（反応式６）。
【００４３】
【化２５】

【００４４】
式中、Ｚ^１、Ｘ^１、Ｘ^２、Ｘ^３は上記と同様の意味を示し、Ｙ^３は酸素原子、硫黄原子、−ＮＨ−または−ＮＲ^１１−（式中、Ｒ^１１は炭素数１〜６のアルキル基を示す。）を示す。炭素数１〜６のアルキル基は前記と同じものを表す。
【００４５】
ここで、環化反応は、Ｘ^１の種類により異なるが、例えばＸ^１が水酸基、チオ−ル基、アミノ基の場合、５員環上の水酸基との脱水反応であり、リン酸、塩酸、硫酸などの無機酸、またはｐ−トルエンスルホン酸、カンファ−スルホン酸などの有機酸存在下、ベンゼン、トルエン、ジクロロメタン、クロロホルム、テトラヒドロフラン、ジオキサン、メタノ−ル、エタノ−ル、水などの溶媒中、０〜１５０℃、好ましくは室温〜溶媒の還流温度で進行する。より好ましくは、トリフェニルホスフィンなどのトリアリ−ルホスフィン、またはトリエチルホスフィンなどのトリアルキルホスフィンと、ジエチルアゾジカルボキシレ−ト、ジメチルアゾジカルボキシレ−ト、ジシクロヘキシルジカルボキシレ−トなどのアゾジカルボキシレ−ト類の存在下、エ−テル系（ジエチルエ−テル、ジオキサン、テトラヒドロフランなど）、脂肪族炭化水素系（ヘキサン、ヘプタン、シクロヘキサンなど）、ハロゲン系（ジクロロメタン、ジクロロエタンなど）または芳香族炭化水素系（ベンゼン、トルエン、ジクロロベンゼンなど）の有機溶媒中、−４０〜１５０℃、好ましくは−１０〜７０℃で脱水させることで環化させることができる。
【００４６】
あるいは、５員環上の水酸基を常法により臭素原子、塩素原子などのハロゲン原子に置換するか、またはトシル基、メシル基などに変換後、有機アミン（トリエチルアミン、ピリジン、Ｎ−メチルモルホリン、ジアザビシクロウンデセンなど）、金属酸化物（アルミナ、シリカゲルなど）、無機塩基（水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、リン酸水素カリウムなど）の塩基触媒存在下、エ−テル系（ジエチルエ−テル、ジオキサン、テトラヒドロフランなど）、脂肪族炭化水素系（ヘキサン、ヘプタン、シクロヘキサンなど）、ハロゲン系（ジクロロメタン、ジクロロエタンなど）または芳香族炭化水素系（ベンゼン、トルエン、ジクロロベンゼンなど）の有機溶媒中、−７０〜１５０℃、好ましくは−３０〜５０℃で反応させることにより環化させることができる。
【００４７】
Ｘ^１が保護された水酸基、保護されたチオ−ル基、保護されたアミノ基の場合、保護基をはずして上記と同様に反応させることができる。Ｘ^１がハロゲン原子の場合、ヨウ化銅などの銅触媒存在下、３０℃〜溶媒の還流温度に加熱反応することにより環化させることができる。
【００４８】
本発明の第７発明は、式［ＶＩＩ］で示されるフェニル置換ＰＧＩ_２類中間体に係わる。
【００４９】
【化２６】

【００５０】
式中、Ｚ^１、Ｘ^３、Ｙ³は上記と同様の意味を示し、Ｘ^４はハロゲン原子、水酸基、チオ−ル基、アリル基、ビニル基、エチニル基、エステル基またはシアノ基を示す。
【００５１】
すなわち、フェニル置換ＰＧＩ_２類［ＶＩ］のうち、Ｘ^２がＸ^４であるフェニル置換ＰＧＩ_２類中間体［ＶＩＩ］は新規化合物であり、Ｘ^２やＸ^４部分を必要なα鎖に変換することにより、種々のフェニル置換ＰＧＩ_２類を合成することができる有用中間体である。（反応式７）
【００５２】
【化２７】

【００５３】
なお、フェニル置換ヒドロキシシクロペンテノン類［Ｉ］を両対掌体の混合物として用いた場合、得られるフェニル置換ヒドロキシシクロペンタノン類［ＩＶ］、さらにはフェニル置換ＰＧＩ₂類は５員環部の水酸基について両対掌体の混合物となる。しかしながら、ω鎖であるＸ³部分に光学活性な水酸基等がある場合、式［ＩＶ］の化合物はジアステレオマ−混合物となるため再結晶あるいはカラムクロマトグラフィ−等で分離することができ、光学活性なフェニル置換ヒドロキシシクロペンタノン類［ＩＶ］、さらには光学活性なフェニル置換ＰＧＩ₂類を得ることができる（反応式８）（＊は光学活性を示す。）。
【００５４】
【化２８】

【００５５】
本発明の第９発明は、上記式［Ｉ］のフェニル置換ヒドロキシシクロペンテノン類の両対掌体の混合物を酵素で処理して、下記式［Ｉ^R］，［Ｉ^S］のフェニル置換ヒドロキシシクロペンテノン類の光学活性体を得る光学分割法に係わる。
【００５６】
すなわち、フェニル置換ヒドロキシシクロペンテノン類［Ｉ］のエステル体［Ｚ^１がアシル基（ホルミル基、アセチル基、ベンゾイル基など）の場合］を酵素により不斉水解するか、フェニル置換ヒドロキシシクロペンテノン類［Ｉ］の水酸基体（Ｚ^１が水素原子の場合）を酵素により不斉エステル化することで、両対掌体を分割することができる。酵素としては、微生物または動植物由来のエステラ−ゼあるいはリパ−ゼを用いる。具体的には、シュ−ドモナス属、アスペルギルス属、ムコ−ル属、カンジダ属、リゾプス属、サッカロマイセス属等の微生物由来のリパ−ゼ、あるいはステアプシン、パンクレアチン、ブタ肝臓エステラ−ゼ、ブタ膵臓リパ−ゼ、小麦胚芽リパ−ゼ等の動植物由来の酵素が挙げられる。反応は水溶液中または有機溶媒中あるいはそれらの混合液中で行なうことができる。水溶液としては、通常、リン酸ナトリウム、リン酸カリウムのような無機酸塩の緩衝液、クエン酸ナトリウム、酢酸ナトリウムのような有機酸塩の緩衝液を用いることが望ましい。有機溶媒としては、ヘプタン、トルエン、メチルイソブチルケトン、ジクロロメタン、ジエチルエ−テルなどを挙げることができる。
【００５７】
なお、不斉エステル化を行なう場合には、酢酸ビニル、酢酸トリクロロエチル等のエステル源を共存させて行なう。反応液のｐＨ、反応温度、反応時間は、基質や酵素により異なるが、通常ｐＨは５〜１０、温度は１０〜５０℃に保つことが望ましい。反応終了後、生成物を有機溶媒で抽出し、再結晶あるいはカラムクロマトグラフィ−で両異性体を分離することにより、光学活性なフェニル置換ヒドロキシシクロペンテノン類［Ｉ］が得られる。
【００５８】
このようにして得られた光学活性なフェニル置換ヒドロキシシクロペンテノン類［Ｉ］を用いることにより、異性体を分離することなく、光学活性なフェニル置換ヒドロキシシクロペンタノン類［ＩＶ］、さらには光学活性なフェニル置換ＰＧＩ₂類を得ることができる（反応式９）（＊は光学活性を示す。）。
【００５９】
【化２９】

【００６０】
【発明の効果】
本発明のフェニル置換ヒドロキシシクロペンテノン類［Ｉ］、フェニル置換ヒドロキシシクロペンタノン類［ＩＶ］、フェニル置換ジヒドロキシシクロペンタン類［Ｖ］、及びフェニル置換ＰＧＩ_２類中間体［ＶＩＩ］は医薬品としての用途が期待されるフェニル置換ＰＧＩ_２類の合成中間体として有用である。さらに、本発明の方法によれば、フェニル置換ＰＧＩ_２類を効率的に製造することができる。加えて本発明の方法によれば、光学活性なフェニル置換ヒドロキシシクロペンテノン類［Ｉ］及び光学活性なフェニル置換ＰＧＩ_２類を効率的に製造することができる。
【００６１】
【実施例】
以下、実施例及び参考例を挙げて本発明をさらに詳しく説明する。
【００６２】
【化３０】

【００６３】
２，６−ジブロモフェノール（２０ｇ，７９ｍｍｏｌ）のアセトン（２００ｍｌ）溶液にアリルブロミド（１１．５ｇ，９５ｍｍｏｌ，Ｋ₂ＣＯ₃（４ｇ）を加え、５時間撹拌した。反応液を水にあけ、エーテル（４００ｍｌ）まで抽出した。有機層をＭｇＳＯ₄で乾燥後、減圧濃縮すると、アリル−２，６−ジブロモフェニルエーテル（２２．０ｇ，収率９５％）が得られた。その分析値を下記に示す。
【００６４】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δ：７．５１（ｄ，８．１Ｈｚ，２Ｈ），６．８６（ｔ，８０Ｈｚ，１Ｈ），６．１９（ｄｄｔ，１７．０，１０．４，５．９Ｈｚ，１Ｈ），５．５２〜５．２６（ｍ，２Ｈ），４．５５（ｄ，５．８２Ｈｚ，２Ｈ）
¹³Ｃ−ＮＭＲ（ＣＤＣｌ₃）δ（ｐｐｍ）：１５３．１，１３２．９，１３２．６，１２６．２，１１８．６，１１８．５，７３．９
ＩＲ（ｎｅａｔ）：１４２０，１２４５，９８０，９２５，７６５，７２０
【００６５】
【化３１】

【００６６】
アリル−２，６−ジブロモフェニルエーテル（１１．６８ｇ，４０ｍｍｏｌ）のＴＨＦ（２００ｍｌ）溶液を−７８℃に冷却し、撹拌しながら、ｎ−ＢｕＬｉ（２０．１ｍｌ，２．１９Ｍのヘキサン溶液、４４ｍｍｏｌ）を３０分かけてゆっくり滴下した。−７８℃で３０分間撹拌した後、フルフラール（３．６５ｍｌ，４４ｍｍｏｌ）を滴下した。１０分間撹拌した後、飽和塩化アンモニウム水溶液（２００ｍｌ）を加え、室温まで昇温した。有機層を分離し、水層をエーテル（１００ｍｌ）で抽出した。得られた有機層をＭｇＳＯ₄を用いて乾燥した後、濾過した。濾液を減圧下濃縮した後、３ｃｍのシリカゲル層を通して濾過した。シリカゲル層をヘキサンとエーテルの混合液（１００ｍｌ，１：１）で洗浄した。濾液を減圧下濃縮して得られた粗化合物をそのまま次の反応に用いた。
【００６７】
【化３２】

【００６８】
前の反応で得られた粗化合物１をＴＨＦ（８０ｍｌ）および水（１０ｍｌ）の溶液とした後、ｐ−ＴｓＯＨ・Ｈ₂Ｏ（３５０ｍｇ，２ｍｍｏｌ）を加え、２時間加熱還流した。室温に冷却した後、飽和ＮａＨＣＯ₃水溶液（９０ｍｌ）を加えて中和した。反応液をＡｃＯＥＴ（２×７０ｍｌ）で抽出した後、得られた有機層をＭｇＳＯ₄を用いて乾燥した。濾過後、濾液を減圧下濃縮して得られた粗化合物２をそのまま次の反応に用いた。
【００６９】
【化３３】

【００７０】
前の反応で得られた粗化合物２のＴＨＦ（２５ｍｌ）溶液にクロラール（０．３９ｍｌ，４ｍｍｏｌ），トリエチルアミン（６．７ｍｌ，４８ｍｍｏｌ）を加え、室温で２時間撹はんした。反応液に飽和ＮＨ₄Ｃｌ水溶液（３０ｍｌ）を加えた後、ＡｃＯＥｔ（２×３０ｍｌ）で抽出した。得られた有機層をＭｇＳＯ₄で乾燥した後、濾過した。濾液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、化合物３（３．８５ｇ）をアリル−２，６−ジブロモフェニルエーテルより収率３１％で得た。その分析値を下記に示す。
【００７１】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δ：７．８８（ｄ，２．５Ｈｚ，１Ｈ），７．５５（ｄｄ，８．０，１．６Ｈｚ，１Ｈ），７．４８（ｄｄ，７．８，１．６Ｈｚ，１Ｈ），７．０３（ｔ，７．９Ｈｚ，１Ｈ），６．００（ｄｄｔ，１７．２，１０．４，５．７Ｈｚ，１Ｈ），５．３９〜５．１９（ｍ，１Ｈ），５．１２〜５．０４（ｍ，１Ｈ），４．３９〜４．２５（ｍ，１Ｈ），２．９５（ｄｄ，１８．６，６．２Ｈｚ，１Ｈ），２．４７（ｄｄ，１８．５，２．２Ｈｚ）
¹³Ｃ−ＮＭＲ（ＣＤＣｌ₃）δ（ｐｐｍ）：２０４．１，１６０．９，１５３．９，１４０．７，１３３．９，１３３．２，１２９．６，１２５．３，１１８．０，１１７．９，７４．０，６８．１，４４．８
ＩＲ（ｎｅａｔ）：３４２５，２９２０，２８６０，１７００，１４３８，１３００，１２２５，１１１５，９７８，７４８
【００７２】
【化３４】

【００７３】
化合物３（１０．０ｇ，３７ｍｍｏｌ）の塩化メチレン（３７ｍｌ）溶液に、０℃でトリエチルアミン（７．６８ｍｌ，５５．５ｍｍｏｌ），Ｎ，Ｎ−ジメチルアミノピリジン（９０．５ｍｇ，０．７４ｍｍｏｌ），ｔ−ブチルジメチルシリルクロリド（７．７９ｇ，４８．１ｍｍｏｌ）を加え、室温に昇温した後、１２時間撹はんした。ヘキサン（１００ｍｌ）および飽和ＮａＨＣＯ₃水溶液（１００ｍｌ）を加え、よく撹拌した後、有機層を分離、水層をヘキサン（１００ｍｌ）で抽出した。得られた有機層をＭｇＳＯ₄を用いて乾燥した後、濾過した。濾液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して化合物４（１３．８ｇ）を収率８８％で得た。その分析値を下記に示す。
【００７４】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δ：７．８４（ｄ，２．５Ｈｚ，１Ｈ），７．５４（ｄ，７．９Ｈｚ，２Ｈ），７．０３（ｔ，７．９Ｈｚ，１Ｈ），６．０２（ｄｄｔ，１７．１，１０．３，５．８Ｈｚ，１Ｈ），５．１９〜５．４０（ｍ，２Ｈ），５．０１（ｄｄｄ，６．１，２．４Ｈｚ，１Ｈ），４．２１〜４．４０（ｍ，２Ｈ），２．９０（ｄｄ，１８．２，６．１Ｈｚ，１Ｈ），２．４４（ｄｄ，１８．３，２．３Ｈｚ，１Ｈ），０．９２（ｓ，９Ｈ），０．１５（ｓ，６Ｈ）
¹³Ｃ−ＮＭＲ（ＣＤＣｌ₃）δ（ｐｐｍ）：２０４．０，１６１．９，１５３．９，１３９．６，１３３．７，１３３．２，１２９，１２６．６，１２５．２，１１８．１，１１８．０，７４．０，６８．６，４５．６，２５．７，１８．１，−４．８
ＩＲ（ｎｅａｔ）：２９４０，２８６０，１７２０，１４４０，１２５５，１０８５，８３５
【００７５】
【化３５】

【００７６】
（１Ｅ，３Ｓ）−１−ヨード−３−［（ｔ−ブチルジメチルシリル）オキシ］−１−オクテン（１．１０ｇ，３．０ｍｍｏｌ）のヘキサン（１２ｍｌ）溶液に−７８℃でｎ−ＢｕＬｉ（１．３７ｍｌ，３．０ｍｍｏｌ，２．１９Ｍのヘキサン溶液）を加え、撹はんしながら１．５時間かけて０℃までゆっくり昇温した。−７８℃に冷却し、（２−チエニル）シアノ銅（ＩＩ）リチウム（１４．４ｍｌ，３．６ｍｍｏｌ，０．２５ＭのＴＨＦ溶液）を加えた。２０分間撹はんした後、化合物４（１．０６ｇ，２．５ｍｍｏｌ）のエーテル（１０ｍｌ）溶液を滴下した。撹拌しながら２時間かけて−２０℃まで昇温した。反応液を飽和塩化アンモニウム水溶液（１００ｍｌ）とヘキサン（３０ｍｌ）の混合液に撹拌しながら注いだ。有機層を分離し、水層をヘキサン（３０ｍｌ）で抽出した。得られた有機層をＭｇＳＯ₄を用いて乾燥した後、濾過した。濾液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーにより精製して化合物５及び化合物５’（１．５１ｇ）を収率９１％で得た。その分析値を下記に示す。
【００７７】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δ：７．４０〜７．４６（ｍ，１Ｈ），７．０４〜６．９７（ｍ，１Ｈ），６．９６〜６．８８（ｍ，１Ｈ），６．１５〜６．００（ｍ，１Ｈ），５．５６〜５．２２（ｍ，４Ｈ），４．５１〜４．４４（ｍ，２Ｈ），４．１０〜４．２３（ｍ，１Ｈ），４．０３〜３．９２（ｍ，１Ｈ），３．５５（ｔ，１２．９Ｈｚ，１Ｈ），２．８９〜３．０２（ｍ，１Ｈ），２．７９（ｄｄ，１８．４，７．３Ｈｚ，１Ｈ），２．４７ ａｎｄ ２．４４（２ｄｄ，１８．４，５３Ｈｚ，１Ｈ），１．４５〜１．００（ｍ，８Ｈ），０．９３〜０．８０（ｍ，３Ｈ），０．９０，０．８９，０．８４ ａｎｄ ０．７９（４ｓ，１８Ｈ），０．０９，０．０８，−０．０５，−０．０９，−０．１１ ａｎｄ −０．２３（６ｓ，９Ｈ）
¹³Ｃ−ＮＭＲ（ＣＤＣｌ₃）δ（ｐｐｍ）：２１２．７，２１２．５，１５４．７，１３７．７，１３７．１，１３３．４，１３２．９，１３２．８，１２９．２，１２９．０，１２７．５，１２７．１，１２５．３，１２５．２，１１７．３，７４．１，７３．１，７２．９，７２．７，７２．６，５６．６，５５．８，５５．５，４７．６，３８．４，３８．３，３１．８，３１．６，２５．８，２５．７，２４．８，２４．５，２２．６，２２．５，１８．１，１８．０，１４．１，１４．０，−４．４，−４．５，−４．７，−４．８，−４．９
ＩＲ（ｎｅａｔ）：２９４０，２８６０，１７４０，１４４５，１２５０，１１１５，８４０，７７５
【００７８】
【化３６】

【００７９】
化合物５（６４６ｍｇ，０．９７ｍｍｏｌ）のＴＨＦ（３２ｍｌ）溶液に−７８℃でＤｉｂａｌ−Ｈ（１．１ｍｌ，１．１ｍｍｏｌ，１．０Ｍのトルエン溶液）を滴下し、２０分間撹拌した。反応液中にＮａ₂ＳＯ₄・１０Ｈ₂Ｏ（３５０ｍｇ）を加え、室温まで昇温した後、ＮａＦセライト（２００ｍｇ）を加え、セライトパッドのフィルターで濾過した。濾液を減圧下濃縮して得られた粗化合物６（６８９ｍｇ）をそのまま次の反応に用いた。その分析値を下記に示す。
【００８０】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δ：７．４６〜７．３６（ｍ，１Ｈ），７．３４〜７．１７（ｍ，１Ｈ），７．０２〜６．９２（ｍ，１Ｈ），６．２２〜６．０２（ｍ，１Ｈ），５．５４〜５．２３（ｍ，４Ｈ），４．６３〜３．８８（ｍ，５Ｈ），３．３０〜３．１２（ｍ，１Ｈ），３．００〜１．６０（ｍ，４Ｈ），１．４８〜１．０３（ｍ，８Ｈ），０．９０，０．８１ ａｎｄ ０．７８（３ｓ，１８Ｈ），０．９０〜０．８０（ｍ，３Ｈ），０．０８，０．０６，−０．０５，−０．１１，−０．１３ ａｎｄ −０．２１（６ｓ，９Ｈ）
¹³Ｃ−ＮＭＲ（ＣＤＣｌ₃）δ（ｐｐｍ）：１５４．６，１５４．５，１３６．５，１３６．３，１３５．８，１３５．７，１３３．９，１３３．８，１３３．５，１３３．２，１３１．９，１３１．８，１３１．６，１２９．６，１２９．４，１２９．１，１２９．０，１２８．８，１２７．０，１２６．９，１２５．８，１２５．７，１２５．１，１２５．０，１１８．２，１１８．１，１１７．５，１１７．４，７８．０，７７．９，７７．７，７６．１，７５．８，７４．４，７４．３，７３．６，７３．３，７３．１，５６．１，５５．９，５３．３，５１．８，４９．１，４８．９，４３．６，４３．３，４３．２，３８．５，３８．４，３１．８，２５．９，２５．８，２４．８，２４．６，２２．６，１８．１，１８．０，１４．０，−４．４，−４．５，−４．６，−４．７，−４．９
ＩＲ（ｎｅａｔ）：３４２０，２９４０，２８６０，１４６０，１４４０，１２５０，１１１５，１０７０，８３５，７７５
【００８１】
【化３７】

【００８２】
Ｐｄ₂（ｄｂａ）₃ＣＨＣｌ₃（２２ｍｇ）のＴＨＦ（０．８２ｍｌ）溶液にトリブチルホスフィン（２１μｌ）を加え、室温で１０分間撹拌した後に、前の反応で得られた粗化合物６（５７５ｍｇ）のＴＨＦ（２．９ｍｌ）溶液を滴下した。２０分間撹拌した後にモルホリン（０．３７ｍｌ）を加え、さらに２０分間撹拌し、反応液に飽和ＮａＣｌ水溶液（５ｍｌ）を加え、エーテル（２×１０ｍｌ）で抽出した。得られた有機層をＭｇＳＯ₄を用いて乾燥した後、濾過し、濾液を減圧下濃縮して得られた粗化合物７（５８２ｍｇ）をそのまま次の反応に用いた。
【００８３】
【化３８】

【００８４】
前の反応で得られた粗化合物７（５８２ｍｇ）のＴＨＦ（５ｍｌ）溶液中にトリフェニルホスフィン（３１６ｍｇ）を加え、０℃でアゾジカルボン酸ジエチル（０．１９ｍｌ）を滴下し、１時間かけて室温まで昇温した。よう化メチル（０．２８９ｍｌ）を滴下し、室温で２時間撹拌した後、飽和ＮａＣｌ水溶液（５ｍｌ）を加え、エーテル（２×１０ｍｌ）で抽出した。得られた有機層をＭｇＳＯ₄を用いて乾燥した後、濾過し、濾液を減圧下濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーにより精製して化合物８（１７５ｍｇ，０．２８７ｍｍｏｌ）を収率３５％で得た。その分析値を下記に示す。
【００８５】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δ：７．２３（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．０９〜７．０１（ｍ，１Ｈ），６．７１〜６．６４（ｍ，１Ｈ），５．６１〜５．４４（ｍ，２Ｈ），５．３０〜５．２０（ｍ，１Ｈ），４．１５〜４．０６（ｍ，１Ｈ），４．００〜３．８７（ｍ，１Ｈ），３．６４〜３．５５（ｍ，１Ｈ），２．６５〜２．５２（ｍ，１Ｈ），２．５０〜２．３５（ｍ，１Ｈ），２．１５〜２．０１（ｍ，１Ｈ），１．６５〜１．０５（ｍ，８Ｈ），０．９３，０．７６ ａｎｄ ０．７５（３ｓ，１８Ｈ），０．９５〜０．８５（ｍ，３Ｈ），０．０８，０．０７，０．０６，０．０１ ａｎｄ −０．０５（５ｓ，１２Ｈ）
¹³Ｃ−ＮＭＲ（ＣＤＣｌ₃）δ（ｐｐｍ）：１５６．６，１３５．９，１３５．６，１３２．５，１３２．４，１３１．１，１２９．３，１２９．２，１２３．１，１２３．０，１２１．５，１０２．４，８６．４，８６．１，７７．３，７３．３，７３．０，５８．５，５８．４，５１．２，５０．９，４２．１，４２．０，３８．５，３８．４，３１．８，２５．９，２５．６，２５．１，２４．８，２２．６，１８．３，１７．８，１４．０，−４．２，−４．６，−４．７，−４．８，−４．９，−５．０
ＩＲ（ｎｅａｔ）：２９２０，２８５０，１４４５，１２４３，１０８０，８２８，７６５
【００８６】
【化３９】

【００８７】
ｎ−ＢｕＬｉ（０．９ｍｌ，１．９７ｍｍｏｌ，２．１９Ｍのヘキサン溶液）に０℃で化合物８（３２９ｍｇ，０．５４ｍｍｏｌ）のＴＨＦ（５ｍｌ）を滴下し、５分間撹拌した後に化合物９（３０６ｍｇ，１．０８ｍｍｏｌ）を滴下した。室温まで昇温した後、飽和塩化アンモニウム水溶液（５ｍｌ）を加え、エーテル（２×１０ｍｌ）で抽出した。得られた有機層をＭｇＳＯ₄を用いて乾燥した後、濾過した。濾液を減圧下濃縮した後、２０ｍｌのシリカゲル層を通し、濾液を再び減圧下濃縮して得られた粗化合物１０をそのまま次の反応に用いた。
【００８８】
【化４０】

【００８９】
前の反応で得られた粗化合物１０のイソプロピルアルコールエーテル混合溶液（５：１，５．８ｍｌ）中にピリジニウムｐ−トルエンスルホネートを触媒量加え、３５℃の恒温槽中で撹拌した。２４時間後、飽和炭酸水素ナトリウム水溶液（５ｍｌ）を加え、エーテル（２×１０ｍｌ）で抽出した。得られた有機層をＭｇＳＯ₄を用いて乾燥し、濾過した後、濾液を減圧下濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーにより精製して化合物１１（１０４ｍｇ，０．１７２ｍｍｏｌ）を化合物８より３２％で得た。その分析値を下記に示す。
【００９０】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δ：７．０２〜６．９０（ｍ，２Ｈ），６．７３（ｔ，Ｊ＝７．４Ｈｚ，１Ｈ），５．６４〜５．４７（ｍ，２Ｈ），５．１４〜５．０４（ｍ，１Ｈ），４．１６〜４．０７（ｍ，１Ｈ），３．９６〜３．８１（ｍ，１Ｈ），３．６８（ｔ，Ｊ＝６．３Ｈｚ，２Ｈ），３．５０〜３．３８（ｍ，１Ｈ），２．６２〜２．４３（ｍ，４Ｈ），２．００〜１．８５（ｍ，１Ｈ），１．７５〜１．２０（ｍ，１２Ｈ），０．９２，０．７９ ａｎｄ ０．７８（３ｓ，１８Ｈ），０．９１〜０．８５（ｍ，３Ｈ），０．０９，０．０８，０．０７，０．０２ ａｎｄ −０．０３（５ｓ，１２Ｈ）
¹³Ｃ−ＮＭＲ（ＣＤＣｌ₃）δ（ｐｐｍ）：１５７．２，１５７．１，１３５．８，１３５．５，１３０．２，１２９．７，１２９．４，１２８．３，１２４．０，１２１．８，１２１．７，１２０．２，１２０．１，８４．５，８４．３，７６．８，７３．５，７３．０，６２．８，５８．２，５８．１，５０．０，４９．７，４２．５，３８．６，３８．５，３２．４，３１．９，３１．８，２９．５，２５．９，２５．８，２５．７，２５．１，２４．８，２２．６，１８．３，１７．９，１４．０，−４．２，−４．６，−４．７，−４．８
ＩＲ（ｎｅａｔ）：３４００，２９３５，２８６０，１４５２，１２５０，１１２０，１０８０，８３５
【００９１】
【化４１】

【００９２】
Ｊｏｎｅｓ試薬（０．３３ｍｌ，３．０Ｍ）のアセトン−エーテル（１：１，５．０ｍｌ）混合液中に０℃で化合物１１（１０４ｍｇ，０．１７２ｍｍｏｌ）のアセトン−エーテル（１：１，３．０ｍｌ）をゆっくりと滴下した。２０分撹拌した後、Ｈ₂Ｏ（３ｍｌ）で希釈し、エーテル（２×１０ｍｌ）で抽出した。得られた有機層をＭｇＳＯ₄を用いて乾燥し、濾過した。濾液を減圧下濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにより精製して化合物１２（８０ｍｇ，０．１３ｍｍｏｌ）を７６％で得た。その分析値を下記に示す。
【００９３】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δ：７．０４〜６．８７（ｍ，２Ｈ），６．７３（ｔ，Ｊ＝７．４Ｈｚ，１Ｈ），５．６３〜５．４８（ｍ，２Ｈ），５．１５〜５．０３（ｍ，１Ｈ），４．１９〜４．０６（ｍ，１Ｈ），３．９６〜３．８１（ｍ，１Ｈ），３．５１〜３．３６（ｍ，１Ｈ），２．７０〜２．２６（ｍ，６Ｈ），２．０６〜１．８０（ｍ，３Ｈ），１．８０，１．１５（ｍ，８Ｈ），０．９１，０．７７ ａｎｄ ０．７６（３ｓ，１８Ｈ），０．９０〜０．８０（ｍ，３Ｈ），０．０８，０．０７，０．０１ ａｎｄ −０．０３（４ｓ，１２Ｈ）
¹³Ｃ−ＮＭＲ（ＣＤＣｌ₃）δ（ｐｐｍ）：１７９．４，１５７．３，１３５．８，１３５．５，１３０．３，１２９．８，１２９．５，１２８．４，１２２．８，１２２．１，１２２．０，１２０．２，８４．７，８４．５，７７．１，７６．９，７３．５，７３．１，５８．２，５８．１，５０．０，４９．７，４２．５，４２．４，３８．６，３８．５，３４．７，３３．４，２５．９，２５．７，２５．３，２５．１，２４．８，２４．５，２２．６，１８．３，１７．９，１４．１，１４．０，−４．２，−４．６，−４．７，−４．８
ＩＲ（ｎｅａｔ）：２９４０，２８６０，１７０５，１４５５，１２５０，１１２０，１０８５，８３８，７７５
【００９４】
【化４２】

【００９５】
化合物１２（７９．６ｍｇ，０．１２９ｍｍｏｌ）のＴＨＦ（３．９ｍｌ）溶液に０℃で５５％のＨＦ水溶液（１．３ｍｌ）とＴＨＦ（１．２ｍｌ）の混合溶液をゆっくりと滴下した。室温まで昇温した後、２時間撹拌し、反応液をＮａＨＣＯ₃（３２ｇ）Ｈ₂Ｏ（１４ｍｌ）、酢酸エチル（８．４ｍｌ）の混合液に撹拌しながら注いだ。有機層を分離し、水層を酢酸エチル（２×１０ｍｌ）で抽出した。得られた有機層をＭｇＳＯ₄を用いて乾燥した後、濾過した。濾液は減圧下濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィーにより精製して化合物１３（２０．５ｍｇ，０．０５３ｍｍｏｌ）及び化合物１３’（１８．０ｍｇ，０．０４６ｍｍｏｌ）を４１％，３６％でそれぞれ得た。その分析値を下記に示す。
化合物１３
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δ：６．９８〜６．８７（ｍ，２Ｈ），６．７４（ｔ，７．４Ｈｚ，１Ｈ），５．６５〜５．４７（ｍ，２Ｈ），５．１１〜５．００（ｍ，１Ｈ），４．１４〜４．０３（ｍ，１Ｈ），３．９３〜３．８０（ｍ，１Ｈ），３．３７（ｔ，８．９Ｈｚ，１Ｈ），２．７３〜２．５０（ｍ，３Ｈ），２．４２〜２．２５（ｍ，３Ｈ），２．０６〜１．８０（ｍ，３Ｈ），１．７０，１．０５（ｍ，８Ｈ），１．００〜０．８０（ｍ，３Ｈ）
¹³Ｃ−ＮＭＲ（ＣＤＣｌ₃）δ（ｐｐｍ）：１７８．０，１５７．２，１３６．１，１３１．７，１２９．７，１２９．０，１２３．２，１２１．９，１２０．５，８４．４，７６．３，７３．２，５８．７，５０．３，４１．２，３７．１，３３．１，３１．７，２９．１，２５．２，２４．６，２２．６，１４．０ＩＲ（ｎｅａｔ）：３４１２，２９２８，２８５９，１７１９，１４５３，１２６７，１２０４，１０８０，１０１９，９６８，８６２，７６８，７４７ｃｍ^-1
［α］²² _D＋１０１°（ｃ ０．４４５，ＭｅＯＨ），ｍ．ｐ．９５〜９６℃
化合物１３’
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δ：７．０３〜６．９１（ｍ，２Ｈ），６．７６（ｔ，７．４Ｈｚ，１Ｈ），５．７５〜５．５８（ｍ，２Ｈ），５．１８〜５．０７（ｍ，１Ｈ），４．１９〜４．１０（ｍ，１Ｈ），４．０１〜３．９０（ｍ，１Ｈ），３．４９（ｔ，８２Ｈｚ，１Ｈ），２．７３〜２．４０（ｍ，４Ｈ），２．３４（ｔ，７．４Ｈｚ，２Ｈ），２．０８〜１．８２（ｍ，３Ｈ），１．７０〜１．１５（ｍ，８Ｈ），１．００〜０．８０（ｍ，３Ｈ）
¹³Ｃ−ＮＭＲ（ＣＤＣｌ₃）δ（ｐｐｍ）：１７８．０，１５７．２，１３５．７，１３０．３，１２９．９，１２８．９，１２３．１，１２２．０，１２０．６，８４．９，７６．８，７２．４，５８．５，５０．６，４１．４，３７．４，３３．１，３１．７，２９．０，２５．１，２４．６，２２．６，１４．０ＩＲ（ｎｅａｔ）：３３５０，２９３０，１７０５，１４５０，１２４０，１１９０，１０４０，９６５，８６０，７４０ｃｍ^-1
［α］²² _D−６６°（ｃ ０．２３２，ＭｅＯＨ）
【００９６】
【化４３】

【００９７】
化合物３（２２０ｍｇ，０．７１ｍｍｏｌ）に酢酸ビニル（３．０ｍｌ）及びＰＰＬ（Ｐｏｒｃ ｎｅ Ｐａｒｃｒｅａｓ Ｌｉｐａｓｅ，２３４ｍｇ）を加え、室温で８日間激しく撹拌した。反応液にセライト（３００ｍｇ）を加え、セライトパッドのフィルターで濾過した。濾液を減圧下濃縮した。得られた粗生成物をそのままシリカゲルカラムクロマトグラフィーにより精製して化合物１４（８４ｍｇ，０．２４ｍｍｏｌ）^*と化合物３’（１２８ｍｇ，０．４１ｍｍｏｌ）^**を収率３４％，５８％でそれぞれ得た。
＊９７．５％ｅｅ，＊＊６３．２％ｅｅ
【００９８】
【化４４】

【００９９】
金属Ｎａ（２６．８ｍｇ，１．１７ｍｍｏｌ）のＭｅＯＨ（２．３４ｍｌ）溶液中に炭酸グアニジン（２．１１ｍｇ，１．１７ｍｍｏｌ）を加え室温で２５分間撹拌した。調整したグアニジン溶液（０．１５２ｍｌ）を化合物１４（２６．８ｍｇ，０．０７６ｍｍｏｌ）のＭｅＯＨ（０．３ｍｌ）溶液中に０℃で滴下した。５分間撹拌した後、氷酢酸（４．３μｌ）を加え、反応液をそのまま濃縮し、ＭｅＯＨを留去した。これにＨ₂Ｏ（１ｍｌ）を加え、酢酸エチル（２×５ｍｌ）で抽出し、有機層をＭｇＳＯ₄で乾燥した後、濾過した。濾液は減圧下濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィーにより精製して化合物３”（１６．８ｍｇ，０．０５４ｍｍｏｌ）を収率７２％で得た。[0001]
[Industrial applications]
The present invention relates to phenyl-substituted prostaglandins I useful as various pharmaceuticals.₂(Hereinafter phenyl-substituted PGI₂) And novel intermediates useful therefor.
[0002]
[Prior art]
Since prostaglandin (hereinafter abbreviated as PG) shows various important physiological actions in a small amount, studies for its application to medicines are being actively conducted. Prostaglandin I₂(Hereinafter PGI₂) Are natural PGIs₂Not only prostacyclin, but also many analogs have been synthesized and their biological activities have been studied, and some compounds have been put into practical use as pharmaceuticals.
[0003]
In particular, a phenyl-substituted PGI having a benzofuran ring in the furan ring portion₂The derivative, beraprost (Toray, Kaken Pharmaceutical) is commercially available as an orally administrable prostacyclin derivative.
[0004]
[Problems to be solved by the invention]
Previously reported phenyl-substituted PGI₂As a method for synthesizing a derivative, a method for synthesizing a racemic beraprost [Tetrahedron Lett. , 1990, p. 4489] (scheme 1), and a method for synthesizing an optically active substance [Tetrahedron Lett. , 1990, p. 4493] (Scheme 2) is known.
[0005]
Embedded image

[0006]
However, the scheme 1 has a total of 11 steps, and the scheme 2 has a total of 20 steps, and the yields are both 1% or less, which is not a satisfactory production method.
[0007]
[Means for Solving the Problems]
The present inventors have conducted intensive studies and as a result, have found the following novel intermediates and phenyl-substituted PGIs using them₂The present inventors have found a class of effective manufacturing methods and have completed the present invention.
[0008]
That is, as shown in Scheme 3, the present invention provides a compound of the formula [III] by subjecting a furan derivative of the formula [II] to a rearrangement reaction in the presence of an acid catalyst, followed by an isomerization reaction under acidic or basic conditions. And optionally protecting the hydroxyl group to produce novel phenyl-substituted hydroxycyclopentenones of formula [I], wherein the phenyl-substituted hydroxycyclopentenones [I] have the formula [VIII] MX³A novel phenyl-substituted hydroxycyclopentanone of the formula [IV] can be produced by reacting a nucleophile represented by the formula: and reacting the phenyl-substituted hydroxycyclopentanone [IV] with a reducing agent. Can produce the novel phenyl-substituted dihydroxycyclopentanes of the formula [V], and the phenyl-substituted dihydroxycyclopentanes [V] can be cyclized to obtain the phenyl-substituted PGI of the formula [VI]₂And the phenyl-substituted PGI of the formula [VI]₂Among the compounds, the compound represented by the formula [VII] is a phenyl-substituted prostaglandin I₂Have been found to be novel intermediates that are useful for directing
[0009]
Further, by enzymatically resolving a mixture of both enantiomers of the phenyl-substituted hydroxycyclopentenones [I], optically active phenyl-substituted hydroxycyclopentenones of the formula [I] can be obtained and used. Thus, corresponding optically active phenyl-substituted hydroxycyclopentanones [IV], optically active phenyl-substituted dihydroxycyclopentanes [V], and optically active phenyl-substituted PGI₂The present inventors have found that such compounds can be efficiently produced, and have accomplished the present invention.
[0010]
Embedded image

[0011]
Where X¹Is a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group, or an "alkyl group having 1 to 6 carbon atoms, or 1 to 8 carbon atoms" An amino group substituted with an “aralkyl group”. X^TwoIs a halogen atom,
-Y¹ _h(CR¹R^Two)_mA_n(CH_Two)_pY^Two _q(CR^ThreeR^Four)_rQ_s
(Where Y¹And Y^TwoEach represents an oxygen atom or a sulfur atom; A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of an allene;¹, R^Two, R^ThreeAnd R^FourRepresents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
-COOR^Five
(Where R^FiveRepresents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms. ), Cyano group, hydroxyl group,
-OCOR⁶
(Where R⁶Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms. ) Group,
-CONR⁷R⁸
(Where R⁷And R⁸Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group. ) Or a phenyl group, h, n, q, and s represent 0 or 1, and m, p, and r represent an integer of 0-5. ).
[0012]
X^ThreeIs
-T- (CH_Two)_j-C (R⁹)_(2-k)(OZ^Two)_k-R^Ten
(Where T is CH_TwoCH_Two, CH = CH or a group selected from C≡C, j and k each independently represent an integer of 0, 1 or 2;⁹Represents (2-k) hydrogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms;^TenRepresents an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, a phenyl group, a phenoxy group, (the phenyl group and the phenoxy group The group may be arbitrarily substituted with a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms) or -BD (where B is 1 carbon atom). A phenyl group, a phenoxy group, (the phenyl group and the phenoxy group are a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, A phenyl group or a phenoxy group.) Or a cycloalkyl group having 5 to 7 carbon atoms.)^TwoRepresents a protecting group for a hydrogen atom or a hydroxyl group, provided that when T is a group of C≡C, it represents a protecting group for a hydroxyl group. M represents a metal selected from Li, Na, K, Mg, Ca, Ti, Zr, Ni, Cu, Zn, Al and Sn or a group containing the metal. ).
[0013]
Y³Is an oxygen atom, a sulfur atom, -NH- or -NR¹¹-(Wherein, R¹¹Represents an alkyl group having 1 to 6 carbon atoms. ).
[0014]
X⁴Represents a halogen atom, a hydroxyl group, a thiol group, an allyl group, a vinyl group, an ethynyl group, an ester group or a cyano group.
[0015]
Hereinafter, the present invention will be described in more detail.
The first invention of the present invention relates to a phenyl-substituted hydroxycyclopentenone represented by the following formula [I].
[0016]
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[Where Z¹Represents a hydrogen atom or a protecting group for a hydroxyl group;¹Is a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group, or an "alkyl group having 1 to 6 carbon atoms, or 1 to 8 carbon atoms" An amino group substituted with an “aralkyl group”. X^TwoIs a halogen atom,
-Y¹ _h(CR¹R^Two)_mA_n(CH_Two)_pY^Two _q(CR^ThreeR^Four)_rQ_s
(Where Y¹And Y^TwoA represents an oxygen atom or a sulfur atom, A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of an allene;¹, R^Two, R^ThreeAnd R^FourRepresents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
-COOR^Five
(Where R^FiveRepresents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms. ), Cyano group, hydroxyl group,
-OCOR⁶
(Where R⁶Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms. ) Group,
-CONR⁷R⁸
(Where R⁷And R⁸Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group. ) Or a phenyl group, h, n, q, and s represent 0 or 1, and m, p, and r represent an integer of 0-5. )
Is shown. ]
[0017]
In the present invention, Z¹Examples of the hydroxyl-protecting group include those commonly used in the field of PG, for example, substituted silyl groups (trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, phenyldimethylsilyl group, etc.). , Tetrahydropyranyl (THP) group, tetrahydrofuranyl group, alkoxyalkyl group (methoxymethyl group, ethoxyethyl group, etc.), benzyloxymethyl group, benzyl group, trityl group, allyl group, acyl group (formyl group, acetyl group, Benzoyl group).
[0018]
X¹Is a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group, or an "alkyl group having 1 to 6 carbon atoms or 7 to 10 carbon atoms". An amino group substituted with an “aralkyl group”. As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom is used. Examples of the protected hydroxyl group, protected thiol group, and protected amino group include the same as the above-mentioned hydroxyl group. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, an i-propyl group, a butyl group, an i-butyl group, a t-butyl group, a pentyl group, a hexyl group, a cyclopropyl group, and a cyclopentyl group. Or a cyclohexyl group. Examples of the aralkyl group having 7 to 10 carbon atoms include a benzyl group, a p-chlorobenzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, and a p-methylbenzyl group.
[0019]
X^TwoRepresents a side chain on a phenyl group having a functional group as an α chain, or a substituent on a phenyl group capable of introducing and converting an α chain, and represents a halogen atom,
-Y¹ _h(CR¹R^Two)_mA_n(CH_Two)_pY^Two _q(CR^ThreeR^Four)_rQ_s
(Where Y¹And Y^TwoEach represents an oxygen atom or a sulfur atom; A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of an allene;¹, R^Two, R^ThreeAnd R^FourRepresents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
-COOR^Five
(Where R^FiveRepresents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms. ), Cyano group, hydroxyl group,
-OCOR⁶
(Where R⁶Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms. ) Group,
-CONR⁷R⁸
(Where R⁷And R⁸Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group. ) Or a phenyl group. ).
[0020]
Specific examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group and a cyclopropyl group. Can be. Specific examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, an i-propoxy group, a butoxy group, an i-butoxy group, a t-butoxy group and a cyclopropoxy group. . Specific examples of the alkyl group having 1 to 6 carbon atoms include the same as described above. Specific examples of the alkenyl group having 2 to 6 carbon atoms include a vinyl group, an allyl group, a 2-butenyl group, a 3-methyl-2-butenyl group, and a 3-methyl-2-pentenyl group.
[0021]
X above²Specific examples include a chlorine atom, a bromine atom, an iodine atom, a hydroxyl group, a methoxy group, an allyloxy group, a benzyloxy group, a thiol group, a methylthio group, a benzylthio group, and those represented by the following formulas. Can be
[0022]
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[0023]
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[0024]
According to a second aspect of the present invention, a furan derivative represented by the formula [II] is subjected to a rearrangement reaction in the presence of an acid catalyst to give a compound of the formula [III], followed by an isomerization reaction under acidic or basic conditions, And a method for producing a phenyl-substituted hydroxycyclopentenone of the above formula [I] comprising protecting a hydroxyl group in accordance with the formula (I).
[0025]
Here, a furan derivative [II] as a raw material is obtained by reacting a 2-lithio-form of furan (1) with a substituted phenyl aldehyde (2) (reaction formula 1). (Reaction formula 2) and the like.
[0026]
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[0027]
The furan derivative [II] undergoes a rearrangement reaction when heated in the presence of an acid catalyst to give a compound of the formula [III], which is then isomerized under acidic or basic conditions to protect a hydroxyl group as required, Phenyl-substituted hydroxycyclopentenones [I] can be produced (Scheme 3).
[0028]
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[0029]
The rearrangement reaction can be carried out as it is or in a suitable solvent. Examples of the solvent include water or ethers (diethyl ether, dioxane, tetrahydrofuran, etc.), halogens (dichloromethane, dichloroethane, etc.), ketones (acetone, methyl isobutyl ketone, etc.), esters (ethyl acetate, etc.), Organic solvents based on aliphatic hydrocarbons (hexane, heptane, cyclohexane, etc.) or aromatic hydrocarbons (benzene, toluene, dichlorobenzene, etc.) can be used alone or as a mixture. Preferred is a mixed solvent of water and tetrahydrofuran. As the acid catalyst, an inorganic acid (such as hydrochloric acid or sulfuric acid) or an organic acid (such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, or methanesulfonic acid) is used in an amount of 0.001 to 100 based on the compound of the formula [II]. The equivalent is used, preferably 0.01 to 1 equivalent. The reaction temperature is from 0 ° C to the reflux temperature of the solvent, preferably from 50 to 100 ° C. The reaction time varies depending on the substrate and the reaction temperature, but is usually 0.5 to 24 hours. After neutralizing the reaction solution, extraction with a suitable organic solvent gives the compound of the formula [III]. The compound of the formula [III] can be purified or used as a crude product in the next reaction.
[0030]
The isomerization reaction can be performed as it is or in an appropriate solvent. Examples of the solvent include water or ethers (diethyl ether, dioxane, tetrahydrofuran, etc.), halogens (dichloromethane, dichloroethane, etc.), ketones (acetone, methyl isobutyl ketone, etc.), esters (ethyl acetate, etc.), Organic solvents based on aliphatic hydrocarbons (hexane, heptane, cyclohexane, etc.) or aromatic hydrocarbons (benzene, toluene, dichlorobenzene, etc.) can be used alone or as a mixture. The reaction proceeds under either acidic or basic conditions, but preferably under basic conditions. As the acid catalyst, an inorganic acid (such as hydrochloric acid or sulfuric acid) or an organic acid (such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, or methanesulfonic acid) is used in an amount of 0.001 to 100 based on the compound of the formula [II]. The equivalent is used, preferably 0.01 to 1 equivalent. Examples of the basic catalyst include organic amines (triethylamine, pyridine, N-methylmorpholine, diazabicycloundecene, etc.), metal oxides (alumina, silica gel, etc.), inorganic bases (sodium hydroxide, potassium hydroxide, sodium carbonate, Potassium carbonate, sodium hydrogen carbonate, potassium hydrogen phosphate, etc.) can be used alone or in combination. The amount used varies depending on the base, and can be used as 0.001 to 100 equivalents or as a solvent, preferably 0.01 to 50 equivalents to the compound of the formula [III]. The reaction temperature is from -40 to 100C, preferably from -20 to 50C. The reaction time varies depending on the substrate, solvent and reaction temperature, but is usually 5 minutes to 20 hours. In this reaction, chloral (Cl₃If an aldehyde having an electron-withdrawing group such as (CCHO) is coexisted with about 0.1 to 3 equivalents of the compound of the formula [II], the reaction proceeds smoothly and the purity of the product increases. After neutralization of the reaction solution, extraction with an appropriate organic solvent, recrystallization, or purification by column chromatography or the like, the phenyl-substituted hydroxycyclopentenones [I] (Z¹Is a hydrogen atom). The protection of the hydroxyl group can be carried out by a usual method, and the phenyl-substituted hydroxycyclopentenones [I] (Z¹Can be easily derived into a hydroxyl-protecting group).
[0031]
The third invention of the present invention relates to phenyl-substituted hydroxycyclopentanones represented by the formula [IV].
[0032]
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[Where Z¹, X¹, X^TwoIs the same as above. X^ThreeIs
-T- (CH_Two)_j-C (R⁹)_(2-k)(OZ^Two)_k-R^Ten
(Where T is CH_TwoCH_Two, CH = CH or a group selected from C≡C, j and k each independently represent an integer of 0, 1 or 2;⁹Represents (2-k) hydrogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms;^TenRepresents an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, a phenyl group, a phenoxy group, (the phenyl group and the phenoxy group The group may be arbitrarily substituted with a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms) or -BD (where B is 1 carbon atom). A phenyl group, a phenoxy group, (the phenyl group and the phenoxy group are a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, Which may be optionally substituted with a phenyl group or a phenoxy group) or a cycloalkyl group having 5 to 7 carbon atoms). Z^TwoRepresents a protecting group for a hydrogen atom or a hydroxyl group, provided that when T is a group of C≡C, it represents a protecting group for a hydroxyl group. )
Is shown. ]
Where X^ThreeIs the ω chain, and as described above,
-T- (CH_Two)_j-C (R⁹)_(2-k)(OZ^Two)_k-R^Ten
(Where T is CH_TwoCH_Two, CH = CH or a group selected from C≡C, j and k each independently represent an integer of 0, 1 or 2;⁹Represents (2-k) hydrogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms;^TenIs an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, a phenyl group, a phenoxy group, (the phenyl group and the phenoxy group are a halogen atom, a trifluoromethyl group , Optionally substituted by an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms) or -BD (B is an alkylene group having 1 to 4 carbon atoms, D is phenyl Group, phenoxy group, (the phenyl group and the phenoxy group are optionally substituted with a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenoxy group. Or a cycloalkyl group having 5 to 7 carbon atoms.). ). Z^TwoRepresents a protecting group for a hydrogen atom or a hydroxyl group, provided that when T is a group of C≡C, it represents a protecting group for a hydroxyl group.
[0033]
Z²As a protecting group for a hydroxyl group of¹The same can be mentioned.
[0034]
Examples of the alkyl group having 1 to 4 carbon atoms, the alkoxy group having 1 to 4 carbon atoms, the alkyl group having 1 to 6 carbon atoms, and the alkoxy group having 1 to 6 carbon atoms are the same as those described above. Examples of the alkyl group having 1 to 10 carbon atoms include methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, -Methylpentyl group, 2-methylpentyl group, 1-methylhexyl group, 2-methylhexyl group, 2,4-dimethylpentyl group, 2-ethylpentyl group, 2-methylpentyl group, 2-ethylhexyl group, 2-propyl Examples include a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a 4-methylcyclopentyl group, a 2,5-dimethylcyclohexyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cyclopentylethyl group, and a cyclohexylethyl group. Examples of the alkenyl group having 2 to 10 carbon atoms include vinyl, allyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-hexenyl, 3-methyl-2-butenyl and 3-methyl-. Examples thereof include a 2-pentenyl group and a 2,6-dimethyl-5-heptenyl group. Examples of the alkynyl group having 2 to 10 carbon atoms include an ethynyl group, a 1-propynyl group, a 1-butynyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group, and a 2-methyl-3-hexynyl group. And the like. Examples of the cycloalkyl group having 5 to 7 carbon atoms include a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a 4-methylcyclohexyl group.
[0035]
The fourth invention of the present invention relates to a process for producing the phenyl-substituted hydroxycyclopentanones of the formula [IV], which is nucleophilic to the phenyl-substituted hydroxycyclopentenones [I] obtained by the second invention. Reagent MX³[VIII] to react with ω chain X³To produce phenyl-substituted hydroxycyclopentanones [IV] (reaction formula 4).
[0036]
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[0037]
Where Z¹, X¹, X², X³Represents the same meaning as described above, and M represents a metal selected from Li, Na, K, Mg, Ca, Ti, Zr, Ni, Cu, Zn, Al, and Sn or a group containing the metal. Specifically, Li, MgBr, MgI, ZnBr, ZnI, CuLi, Cu (CN) Li, CuMe (CN) Li₂, Et₂Al, Et₃AlLi, Cu (SPh) Li, (2-thienyl) Cu (CN) Li₂And the like.
[0038]
As the nucleophile of the formula [VIII], those which are usually used for the ω chain introduction reaction of PGs,³Depending on the type, a lithium reagent, a copper-lithium reagent, a Grignard (magnesium) reagent, a zinc reagent, an aluminum reagent and the like are used. Especially X³T inside is CH₂CH₂In the case of ZnIX³, Cu (CN) LiX³Is preferable, and when T is CH = CH, (2-thienyl) Cu (CN) Li₂X³Is preferable, and when T is C≡C, Et₂AlX³Is preferably used. The nucleophile is used in 0.5 to 4 equivalents, preferably 0.8 to 2 equivalents, relative to the compound of the formula [I]. The reaction solvent may be any solvent that does not hinder the reaction, and examples thereof include tetrahydrofuran, diethyl ether, hexane, pentane, benzene, and toluene. The reaction temperature varies depending on the nucleophile, and is from -100 ° C to the reflux temperature of the solvent, usually -70 to 40 ° C. The reaction time varies depending on the substrate, solvent and reaction temperature, but is usually 5 minutes to 50 hours.
[0039]
Next, the fifth invention of the present invention relates to phenyl-substituted dihydroxycyclopentanes of the formula [V], and the sixth invention relates to the above-mentioned phenyl-substituted hydroxypentanones [IV] (Reaction formula 5).
[0040]
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[0041]
Here, as the reducing agent, borohydride compounds such as borane, sodium borohydride, potassium tri-s-butyl borohydride, lithium tri-s-butyl borohydride, potassium trithiamyl borohydride, or hydride Aluminum hydride compounds such as lithium aluminum, diisobutyl aluminum hydride, and sodium bis (2-methoxyethoxy) aluminum are used. The reducing agent is used in an amount of 1 to 5 equivalents based on the compound of the formula [IV]. The reaction solvent may be appropriately selected depending on the reducing agent, for example, water or an alcohol (e.g., methanol, ethanol), an ether (e.g., diethyl ether, dioxane, tetrahydrofuran), or an aliphatic solvent. A hydrocarbon-based (hexane, heptane, cyclohexane, etc.) or aromatic hydrocarbon-based (benzene, toluene, dichlorobenzene, etc.) organic solvent can be used alone or as a mixture. The reaction temperature varies depending on the reducing agent, and is -80C to 50C, usually -10C to 30C. The reaction time is not limited, but is usually 30 minutes to 20 hours.
[0042]
The seventh invention of the present invention relates to a method for converting a phenyl-substituted dihydroxycyclopentane [V] into X¹By cyclizing by removing the protecting group of phenyl-substituted PGI of the formula [VI]₂The method relates to a method for producing a compound (Reaction Scheme 6).
[0043]
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[0044]
Where Z¹, X¹, X², X³Has the same meaning as above, and Y³Is an oxygen atom, a sulfur atom, -NH- or -NR¹¹-(Wherein, R¹¹Represents an alkyl group having 1 to 6 carbon atoms. ). The alkyl group having 1 to 6 carbon atoms is the same as described above.
[0045]
Here, the cyclization reaction is represented by X¹, For example, X¹Is a hydroxyl group, a thiol group, or an amino group, a dehydration reaction with a hydroxyl group on a 5-membered ring, and an inorganic acid such as phosphoric acid, hydrochloric acid, and sulfuric acid, or p-toluenesulfonic acid, camphor-sulfonic acid, and the like. It proceeds in a solvent such as benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, methanol, ethanol and water in the presence of an organic acid at 0 to 150 ° C, preferably at room temperature to the reflux temperature of the solvent. More preferably, triaryl phosphine such as triphenyl phosphine or trialkyl phosphine such as triethyl phosphine and azo dicarboxylic acid such as diethyl azodicarboxylate, dimethyl azodicarboxylate and dicyclohexyl dicarboxylate. In the presence of carboxylates, ether-based (diethyl ether, dioxane, tetrahydrofuran, etc.), aliphatic hydrocarbon-based (hexane, heptane, cyclohexane, etc.), halogen-based (dichloromethane, dichloroethane, etc.) or aromatic hydrocarbons The cyclization can be achieved by dehydration in a hydrogen-based (benzene, toluene, dichlorobenzene, etc.) organic solvent at -40 to 150C, preferably -10 to 70C.
[0046]
Alternatively, the hydroxyl group on the 5-membered ring is replaced with a halogen atom such as a bromine atom or a chlorine atom by a conventional method, or is converted into a tosyl group, a mesyl group, or the like, and then the organic amine (triethylamine, pyridine, N-methylmorpholine, Zabicycloundecene), metal oxides (alumina, silica gel, etc.), inorganic bases (sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen phosphate, etc.) in the presence of a base catalyst, Ether type (diethyl ether, dioxane, tetrahydrofuran, etc.), aliphatic hydrocarbon type (hexane, heptane, cyclohexane, etc.), halogen type (dichloromethane, dichloroethane, etc.) or aromatic hydrocarbon type (benzene, toluene, dichlorobenzene) ) In an organic solvent of -70 to 150 Preferably it can be cyclized by reaction at -30 to 50 ° C..
[0047]
X¹Is a protected hydroxyl group, a protected thiol group, or a protected amino group, the protecting group can be removed and the reaction can be carried out in the same manner as described above. X¹Is a halogen atom, cyclization can be carried out by heating and reacting at 30 ° C. to the reflux temperature of the solvent in the presence of a copper catalyst such as copper iodide.
[0048]
The seventh invention of the present invention provides a phenyl-substituted PGI represented by the formula [VII]₂Related to intermediates.
[0049]
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[0050]
Where Z¹, X³, Y^ThreeHas the same meaning as above, and X⁴Represents a halogen atom, a hydroxyl group, a thiol group, an allyl group, a vinyl group, an ethynyl group, an ester group or a cyano group.
[0051]
That is, the phenyl-substituted PGI₂X of the class [VI]²Is X⁴Phenyl-substituted PGI₂A class intermediate [VII] is a novel compound,²And X⁴By converting the moiety to the required α-chain, a variety of phenyl-substituted PGI₂Are useful intermediates from which compounds can be synthesized. (Reaction formula 7)
[0052]
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[0053]
When the phenyl-substituted hydroxycyclopentenones [I] are used as a mixture of both enantiomers, the resulting phenyl-substituted hydroxycyclopentanones [IV], and further, phenyl-substituted PGI_TwoThe compounds are mixtures of both enantiomers for the hydroxyl group of the 5-membered ring. However, the ω chain X^ThreeWhen the moiety has an optically active hydroxyl group or the like, the compound of the formula [IV] becomes a diastereomer mixture and can be separated by recrystallization or column chromatography, etc., and the optically active phenyl-substituted hydroxycyclopentanone [IV] And optically active phenyl-substituted PGI_Two(Reaction formula 8) (* indicates optical activity).
[0054]
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[0055]
A ninth invention of the present invention is a method for treating a mixture of both enantiomers of the phenyl-substituted hydroxycyclopentenone of the above formula [I] with an enzyme to obtain a compound of the following formula [I]^R], [I^SThe present invention relates to an optical resolution method for obtaining an optically active isomer of a phenyl-substituted hydroxycyclopentenone.
[0056]
That is, an ester [Z] of a phenyl-substituted hydroxycyclopentenone [I]¹Is an acyl group (formyl group, acetyl group, benzoyl group, etc.)] by enzymatic hydrolysis with an enzyme or a phenyl-substituted hydroxycyclopentenone [I] hydroxyl substrate (Z¹Is enzymatically esterified with an enzyme, whereby both enantiomers can be separated. Esterase or lipase derived from microorganisms or animals and plants is used as the enzyme. Specifically, lipases derived from microorganisms such as Pseudomonas, Aspergillus, Mucor, Candida, Rhizopus, Saccharomyces, or stearpsin, pancreatin, pig liver esterase, pig pancreatic lipase And animal and plant-derived enzymes such as wheat germ lipase. The reaction can be performed in an aqueous solution, an organic solvent, or a mixture thereof. As the aqueous solution, it is usually desirable to use a buffer solution of an inorganic acid salt such as sodium phosphate or potassium phosphate, or a buffer solution of an organic acid salt such as sodium citrate or sodium acetate. Examples of the organic solvent include heptane, toluene, methyl isobutyl ketone, dichloromethane, diethyl ether and the like.
[0057]
When performing asymmetric esterification, the esterification is performed in the presence of an ester source such as vinyl acetate or trichloroethyl acetate. The pH, reaction temperature, and reaction time of the reaction solution vary depending on the substrate and the enzyme, but it is usually desirable to maintain the pH at 5 to 10 and the temperature at 10 to 50 ° C. After completion of the reaction, the product is extracted with an organic solvent, and both isomers are separated by recrystallization or column chromatography to obtain an optically active phenyl-substituted hydroxycyclopentenone [I].
[0058]
By using the optically active phenyl-substituted hydroxycyclopentenones [I] thus obtained, the optically active phenyl-substituted hydroxycyclopentanones [IV] and the optically active phenyl-substituted hydroxycyclopentanones [IV] can be obtained without separating the isomers. Active phenyl substituted PGI_Two(Reaction formula 9) (* indicates optical activity).
[0059]
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[0060]
【The invention's effect】
Phenyl-substituted hydroxycyclopentenones [I], phenyl-substituted hydroxycyclopentanones [IV], phenyl-substituted dihydroxycyclopentanes [V], and phenyl-substituted PGI of the present invention₂Intermediate [VII] is a phenyl-substituted PGI expected to be used as a pharmaceutical₂Useful as a class of synthetic intermediates. Further, according to the method of the present invention, the phenyl-substituted PGI₂Can be produced efficiently. In addition, according to the method of the present invention, the optically active phenyl-substituted hydroxycyclopentenones [I] and the optically active phenyl-substituted PGI₂Can be produced efficiently.
[0061]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples.
[0062]
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[0063]
Allyl bromide (11.5 g, 95 mmol, K) was added to a solution of 2,6-dibromophenol (20 g, 79 mmol) in acetone (200 ml)._TwoCO_Three(4 g) was added and stirred for 5 hours. The reaction solution was poured into water and extracted to ether (400 ml). Organic layer MgSO_FourAfter concentrating under reduced pressure, allyl-2,6-dibromophenyl ether (22.0 g, yield 95%) was obtained. The analytical values are shown below.
[0064]
¹H-NMR (CDCl_Three) Δ: 7.51 (d, 8.1 Hz, 2H), 6.86 (t, 80 Hz, 1H), 6.19 (ddt, 17.0, 10.4, 5.9 Hz, 1H), 5. 52 to 5.26 (m, 2H), 4.55 (d, 5.82 Hz, 2H)
¹³C-NMR (CDCl_Three) Δ (ppm): 153.1, 132.9, 132.6, 126.2, 118.6, 118.5, 73.9
IR (neat): 1420, 1245, 980, 925, 765, 720
[0065]
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[0066]
A solution of allyl-2,6-dibromophenyl ether (11.68 g, 40 mmol) in THF (200 ml) was cooled to −78 ° C., and n-BuLi (20.1 ml, 2.19 M in hexane, 44 mmol) was stirred. ) Was slowly added dropwise over 30 minutes. After stirring at −78 ° C. for 30 minutes, furfural (3.65 ml, 44 mmol) was added dropwise. After stirring for 10 minutes, a saturated aqueous ammonium chloride solution (200 ml) was added, and the temperature was raised to room temperature. The organic layer was separated and the aqueous layer was extracted with ether (100ml). The obtained organic layer was washed with MgSO_FourAfter drying using, it was filtered. The filtrate was concentrated under reduced pressure, and then filtered through a 3 cm layer of silica gel. The silica gel layer was washed with a mixed solution of hexane and ether (100 ml, 1: 1). The filtrate was concentrated under reduced pressure, and the obtained crude compound was directly used in the next reaction.
[0067]
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[0068]
The crude compound 1 obtained in the previous reaction was converted into a solution of THF (80 ml) and water (10 ml), and then p-TsOH.H_TwoO (350 mg, 2 mmol) was added, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, saturated NaHCO_ThreeAn aqueous solution (90 ml) was added for neutralization. After the reaction solution was extracted with AcOET (2 × 70 ml), the obtained organic layer was extracted with MgSO 4._FourAnd dried. After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude compound 2 was directly used in the next reaction.
[0069]
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[0070]
Chloral (0.39 ml, 4 mmol) and triethylamine (6.7 ml, 48 mmol) were added to a THF (25 ml) solution of the crude compound 2 obtained in the previous reaction, and the mixture was stirred at room temperature for 2 hours. Saturated NH_FourAfter adding a Cl aqueous solution (30 ml), the mixture was extracted with AcOEt (2 × 30 ml). The obtained organic layer was washed with MgSO_FourAnd then filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain Compound 3 (3.85 g) from allyl-2,6-dibromophenyl ether in a yield of 31%. The analytical values are shown below.
[0071]
¹H-NMR (CDCl_Three) Δ: 7.88 (d, 2.5 Hz, 1H), 7.55 (dd, 8.0, 1.6 Hz, 1H), 7.48 (dd, 7.8, 1.6 Hz, 1H), 7.03 (t, 7.9 Hz, 1H), 6.00 (ddt, 17.2, 10.4, 5.7 Hz, 1H), 5.39 to 5.19 (m, 1H), 5.12 -5.04 (m, 1H), 4.39-4.25 (m, 1H), 2.95 (dd, 18.6, 6.2 Hz, 1H), 2.47 (dd, 18.5, 2.2Hz)
¹³C-NMR (CDCl_Three) Δ (ppm): 204.1, 160.9, 153.9, 140.7, 133.9, 133.2, 129.6, 125.3, 118.0, 117.9, 74.0, 68.1, 44.8
IR (neat): 3425, 2920, 2860, 1700, 1438, 1300, 1225, 1115, 978, 748
[0072]
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[0073]
To a solution of compound 3 (10.0 g, 37 mmol) in methylene chloride (37 ml) at 0 ° C. was added triethylamine (7.68 ml, 55.5 mmol), N, N-dimethylaminopyridine (90.5 mg, 0.74 mmol), t -Butyldimethylsilyl chloride (7.79 g, 48.1 mmol) was added, and the mixture was heated to room temperature and stirred for 12 hours. Hexane (100 ml) and saturated NaHCO_ThreeAfter adding an aqueous solution (100 ml) and stirring well, the organic layer was separated and the aqueous layer was extracted with hexane (100 ml). The obtained organic layer was washed with MgSO_FourAfter drying using, it was filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain Compound 4 (13.8 g) at a yield of 88%. The analytical values are shown below.
[0074]
¹H-NMR (CDCl_Three) Δ: 7.84 (d, 2.5 Hz, 1H), 7.54 (d, 7.9 Hz, 2H), 7.03 (t, 7.9 Hz, 1H), 6.02 (ddt, 17. 1, 10.3, 5.8 Hz, 1H), 5.19 to 5.40 (m, 2H), 5.01 (ddd, 6.1, 2.4 Hz, 1H), 4.21 to 4.40. (M, 2H), 2.90 (dd, 18.2, 6.1 Hz, 1H), 2.44 (dd, 18.3, 2.3 Hz, 1H), 0.92 (s, 9H), 0 .15 (s, 6H)
¹³C-NMR (CDCl_Three) Δ (ppm): 204.0, 161.9, 153.9, 139.6, 133.7, 133.2, 129, 126.6, 125.2, 118.1, 118.0, 74. 0,68.6,45.6,25.7,18.1, -4.8
IR (neat): 2940, 2860, 1720, 1440, 1255, 1085, 835
[0075]
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[0076]
N-BuLi (1E, 3S) -1-iodo-3-[(t-butyldimethylsilyl) oxy] -1-octene (1.10 g, 3.0 mmol) in hexane (12 ml) at −78 ° C. 1.37 ml, 3.0 mmol, 2.19 M hexane solution) was added thereto, and the temperature was slowly raised to 0 ° C. over 1.5 hours with stirring. After cooling to −78 ° C., lithium (2-thienyl) cyanocopper (II) (14.4 ml, 3.6 mmol, 0.25 M in THF) was added. After stirring for 20 minutes, a solution of compound 4 (1.06 g, 2.5 mmol) in ether (10 ml) was added dropwise. The temperature was raised to −20 ° C. over 2 hours with stirring. The reaction mixture was poured into a mixture of a saturated aqueous ammonium chloride solution (100 ml) and hexane (30 ml) with stirring. The organic layer was separated, and the aqueous layer was extracted with hexane (30 ml). The obtained organic layer was washed with MgSO_FourAfter drying using, it was filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain Compound 5 and Compound 5 '(1.51 g) in a yield of 91%. The analytical values are shown below.
[0077]
¹H-NMR (CDCl_Three) Δ: 7.40 to 7.46 (m, 1H), 7.04 to 6.97 (m, 1H), 6.96 to 6.88 (m, 1H), 6.15 to 6.00 ( m, 1H), 5.56 to 5.22 (m, 4H), 4.51 to 4.44 (m, 2H), 4.10 to 4.23 (m, 1H), 4.03 to 3.0. 92 (m, 1H), 3.55 (t, 12.9 Hz, 1H), 2.89 to 3.02 (m, 1H), 2.79 (dd, 18.4, 7.3 Hz, 1H), 2.47 and 2.44 (2dd, 18.4, 53 Hz, 1H), 1.45 to 1.00 (m, 8H), 0.93 to 0.80 (m, 3H), 0.90, 0 .89, 0.84 and 0.79 (4s, 18H), 0.09, 0.08, -0.05, -0.09, -0.11 and -0.23 (6s, 9H)
¹³C-NMR (CDCl_Three) Δ (ppm): 212.7, 212.5, 154.7, 137.7, 137.1, 133.4, 132.9, 132.8, 129.2, 129.0, 127.5. 127.1, 125.3, 125.2, 117.3, 74.1, 73.1, 72.9, 72.7, 72.6, 56.6, 55.8, 55.5, 47. 6, 38.4, 38.3, 31.8, 31.6, 25.8, 25.7, 24.8, 24.5, 22.6, 22.5, 18.1, 18.0, 14.1, 14.0, -4.4, -4.5, -4.7, -4.8, -4.9
IR (neat): 2940, 2860, 1740, 1445, 1250, 1115, 840, 775
[0078]
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[0079]
To a solution of compound 5 (646 mg, 0.97 mmol) in THF (32 ml) was added dropwise Dropal-H (1.1 ml, 1.1 mmol, 1.0 M toluene solution) at -78 ° C, and the mixture was stirred for 20 minutes. Na in the reaction solution_TwoSO_Four・ 10H_TwoAfter O (350 mg) was added and the temperature was raised to room temperature, NaF celite (200 mg) was added, and the mixture was filtered through a filter of a celite pad. The filtrate was concentrated under reduced pressure, and the obtained crude compound 6 (689 mg) was directly used in the next reaction. The analytical values are shown below.
[0080]
¹H-NMR (CDCl_Three) Δ: 7.46 to 7.36 (m, 1H), 7.34 to 7.17 (m, 1H), 7.02 to 6.92 (m, 1H), 6.22 to 6.02 ( m, 1H), 5.54 to 5.23 (m, 4H), 4.63 to 3.88 (m, 5H), 3.30 to 3.12 (m, 1H), 3.00 to 1. 60 (m, 4H), 1.48 to 1.03 (m, 8H), 0.90, 0.81 and 0.78 (3s, 18H), 0.90 to 0.80 (m, 3H), 0.08, 0.06, -0.05, -0.11, -0.13 and -0.21 (6s, 9H)
¹³C-NMR (CDCl_Three) Δ (ppm): 154.6, 154.5, 136.5, 136.3, 135.8, 135.7, 133.9, 133.8, 133.5, 133.2, 131.9, 131.8, 131.6, 129.6, 129.4, 129.1, 129.0, 128.8, 127.0, 126.9, 125.8, 125.7, 125.1, 125. 0, 118.2, 118.1, 117.5, 117.4, 78.0, 77.9, 77.7, 76.1, 75.8, 74.4, 74.3, 73.6, 73.3, 73.1, 56.1, 55.9, 53.3, 51.8, 49.1, 48.9, 43.6, 43.3, 43.2, 38.5, 38. 4,31.8,25.9,25.8,24.8,24.6,22.6,18.1,18.0,14.0, -4.4, -4 5, -4.6, -4.7, -4.9
IR (neat): 3420, 2940, 2860, 1460, 1440, 1250, 1115, 1070, 835, 775
[0081]
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[0082]
Pd_Two(Dba)_ThreeCHCl_ThreeTo a solution of (22 mg) in THF (0.82 ml) was added tributylphosphine (21 μl), and the mixture was stirred at room temperature for 10 minutes. A solution of the crude compound 6 (575 mg) obtained in the previous reaction in THF (2.9 ml) was added. It was dropped. After stirring for 20 minutes, morpholine (0.37 ml) was added, and the mixture was further stirred for 20 minutes. To the reaction solution was added a saturated aqueous NaCl solution (5 ml), and the mixture was extracted with ether (2 × 10 ml). The obtained organic layer was washed with MgSO_FourAfter drying using, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude compound 7 (582 mg) was directly used in the next reaction.
[0083]
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[0084]
Triphenylphosphine (316 mg) was added to a solution of the crude compound 7 (582 mg) obtained in the previous reaction in THF (5 ml), and diethyl azodicarboxylate (0.19 ml) was added dropwise at 0 ° C., and the reaction was carried out for 1 hour. The temperature was raised to room temperature. Methyl iodide (0.289 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours, then a saturated aqueous NaCl solution (5 ml) was added, and the mixture was extracted with ether (2 × 10 ml). The obtained organic layer was washed with MgSO_FourAfter drying using, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain Compound 8 (175 mg, 0.287 mmol) in a yield of 35%. The analytical values are shown below.
[0085]
¹H-NMR (CDCl_Three) Δ: 7.23 (d, J = 8.0 Hz, 1H), 7.09 to 7.01 (m, 1H), 6.71 to 6.64 (m, 1H), 5.61 to 5. 44 (m, 2H), 5.30 to 5.20 (m, 1H), 4.15 to 4.06 (m, 1H), 4.00 to 3.87 (m, 1H), 3.64 to 3.55 (m, 1H), 2.65 to 2.52 (m, 1H), 2.50 to 2.35 (m, 1H), 2.15 to 2.01 (m, 1H), 1. 65 to 1.05 (m, 8H), 0.93, 0.76 and 0.75 (3s, 18H), 0.95 to 0.85 (m, 3H), 0.08, 0.07, 0 .06,0.01 and -0.05 (5s, 12H)
¹³C-NMR (CDCl_Three) (Ppm): 156.6, 135.9, 135.6, 132.5, 132.4, 131.1, 129.3, 129.2, 123.1, 123.0, 121.5, 102.4, 86.4, 86.1, 77.3, 73.3, 73.0, 58.5, 58.4, 51.2, 50.9, 42.1, 42.0, 38. 5,38.4,31.8,25.9,25.6,25.1,24.8,22.6,18.3,17.8,14.0, -4.2, -4. 6, -4.7, -4.8, -4.9, -5.0
IR (neat): 2920, 2850, 1445, 1243, 1080, 828, 765
[0086]
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[0087]
Compound 8 (329 mg, 0.54 mmol) in THF (5 ml) was added dropwise to n-BuLi (0.9 ml, 1.97 mmol, 2.19 M hexane solution) at 0 ° C., and after stirring for 5 minutes, compound 9 (306 mg) was added. , 1.08 mmol) was added dropwise. After warming to room temperature, a saturated aqueous ammonium chloride solution (5 ml) was added, and the mixture was extracted with ether (2 × 10 ml). The obtained organic layer was washed with MgSO_FourAfter drying using, it was filtered. The filtrate was concentrated under reduced pressure, passed through a 20 ml silica gel layer, and the filtrate was again concentrated under reduced pressure, and the obtained crude compound 10 was directly used in the next reaction.
[0088]
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[0089]
A catalytic amount of pyridinium p-toluenesulfonate was added to a mixed solution (5: 1, 5.8 ml) of the crude compound 10 obtained in the previous reaction in isopropyl alcohol ether, and the mixture was stirred in a thermostat at 35 ° C. After 24 hours, a saturated aqueous sodium hydrogen carbonate solution (5 ml) was added, and the mixture was extracted with ether (2 × 10 ml). The obtained organic layer was washed with MgSO_FourAfter drying using and filtering, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain Compound 11 (104 mg, 0.172 mmol) at 32% from Compound 8. The analytical values are shown below.
[0090]
¹H-NMR (CDCl_Three) Δ: 7.02 to 6.90 (m, 2H), 6.73 (t, J = 7.4 Hz, 1H), 5.64 to 5.47 (m, 2H), 5.14 to 5. 04 (m, 1H), 4.16 to 4.07 (m, 1H), 3.96 to 3.81 (m, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3. 50 to 3.38 (m, 1H), 2.62 to 2.43 (m, 4H), 2.00 to 1.85 (m, 1H), 1.75 to 1.20 (m, 12H), 0.92, 0.79 and 0.78 (3s, 18H), 0.91 to 0.85 (m, 3H), 0.09, 0.08, 0.07, 0.02 and -0.03 (5s, 12H)
¹³C-NMR (CDCl_Three) Δ (ppm): 157.2, 157.1, 135.8, 135.5, 130.2, 129.7, 129.4, 128.3, 124.0, 121.8, 121.7, 120.2, 120.1, 84.5, 84.3, 76.8, 73.5, 73.0, 62.8, 58.2, 58.1, 50.0, 49.7, 42. 5,38.6,38.5,32.4,31.9,31.8,29.5,25.9,25.8,25.7,25.1,24.8,22.6, 18.3, 17.9, 14.0, -4.2, -4.6, -4.7, -4.8
IR (neat): 3400, 2935, 2860, 1452, 1250, 1120, 1080, 835
[0091]
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[0092]
A mixture of Jones reagent (0.33 ml, 3.0 M) in acetone-ether (1: 1, 5.0 ml) at 0 ° C. in acetone-ether (1: 1,3) of compound 11 (104 mg, 0.172 mmol) .0 ml) was slowly added dropwise. After stirring for 20 minutes, H_TwoDilute with O (3 ml) and extract with ether (2 × 10 ml). The obtained organic layer was washed with MgSO_FourDry using and filter. After the filtrate was concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain Compound 12 (80 mg, 0.13 mmol) at 76%. The analytical values are shown below.
[0093]
¹H-NMR (CDCl_Three) Δ: 7.04 to 6.87 (m, 2H), 6.73 (t, J = 7.4 Hz, 1H), 5.63 to 5.48 (m, 2H), 5.15 to 5. 03 (m, 1H), 4.19 to 4.06 (m, 1H), 3.96 to 3.81 (m, 1H), 3.51 to 3.36 (m, 1H), 2.70 to 2.26 (m, 6H), 2.06-1.80 (m, 3H), 1.80, 1.15 (m, 8H), 0.91, 0.77 and 0.76 (3s, 18H) ), 0.90 to 0.80 (m, 3H), 0.08, 0.07, 0.01 and -0.03 (4s, 12H).
¹³C-NMR (CDCl_Three) Δ (ppm): 179.4, 157.3, 135.8, 135.5, 130.3, 129.8, 129.5, 128.4, 122.8, 122.1, 122.0, 120.2, 84.7, 84.5, 77.1, 76.9, 73.5, 73.1, 58.2, 58.1, 50.0, 49.7, 42.5, 42. 4,38.6,38.5,34.7,33.4,25.9,25.7,25.3,25.1,24.8,24.5,22.6,18.3 17.9, 14.1, 14.0, -4.2, -4.6, -4.7, -4.8
IR (neat): 2940, 2860, 1705, 1455, 1250, 1120, 1085, 838, 775
[0094]
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[0095]
A mixed solution of 55% aqueous HF (1.3 ml) and THF (1.2 ml) was slowly added dropwise to a solution of compound 12 (79.6 mg, 0.129 mmol) in THF (3.9 ml) at 0 ° C. After heating to room temperature, the mixture was stirred for 2 hours,_Three(32g) H_TwoThe mixture was poured into a mixture of O (14 ml) and ethyl acetate (8.4 ml) with stirring. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 ml). The obtained organic layer was washed with MgSO_FourAfter drying using, it was filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain a compound 13 (20.5 mg, 0.053 mmol) and a compound 13 ′ (18.0 mg, 0.046 mmol) of 41%. 36% each was obtained. The analytical values are shown below.
Compound 13
¹H-NMR (CDCl_Three) Δ: 6.98 to 6.87 (m, 2H), 6.74 (t, 7.4 Hz, 1H), 5.65 to 5.47 (m, 2H), 5.11 to 5.00 ( m, 1H), 4.14 to 4.03 (m, 1H), 3.93 to 3.80 (m, 1H), 3.37 (t, 8.9 Hz, 1H), 2.73 to 2. 50 (m, 3H), 2.42 to 2.25 (m, 3H), 2.06 to 1.80 (m, 3H), 1.70, 1.05 (m, 8H), 1.00 0.80 (m, 3H)
¹³C-NMR (CDCl_Three) Δ (ppm): 178.0, 157.2, 136.1, 131.7, 129.7, 129.0, 123.2, 121.9, 120.5, 84.4, 76.3. 73.2, 58.7, 50.3, 41.2, 37.1, 33.1, 31.7, 29.1, 25.2, 24.6, 22.6, 14.0 IR (neat) : 3412, 2928, 2859, 1719, 1453, 1267, 1204, 1080, 1019, 968, 862, 768, 747 cm^-1
[Α]^{twenty two} _D+ 101 ° (c 0.445, MeOH), m.p. p. 95-96 ° C
Compound 13 '
¹H-NMR (CDCl_Three) Δ: 7.03 to 6.91 (m, 2H), 6.76 (t, 7.4 Hz, 1H), 5.75 to 5.58 (m, 2H), 5.18 to 5.07 ( m, 1H), 4.19 to 4.10 (m, 1H), 4.01 to 3.90 (m, 1H), 3.49 (t, 82 Hz, 1H), 2.73 to 2.40 (m, 1H). m, 4H), 2.34 (t, 7.4 Hz, 2H), 2.08-1.82 (m, 3H), 1.70-1.15 (m, 8H), 1.00-0. 80 (m, 3H)
¹³C-NMR (CDCl_Three) (Ppm): 178.0, 157.2, 135.7, 130.3, 129.9, 128.9, 123.1, 122.0, 120.6, 84.9, 76.8, 72.4, 58.5, 50.6, 41.4, 37.4, 33.1, 31.7, 29.0, 25.1, 24.6, 22.6, 14.0 IR (neat) ： 3350,2930,1705,1450,1240,1190,1040,965,860,740cm^-1
[Α]^{twenty two} _D-66 ° (c 0.232, MeOH)
[0096]
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[0097]
To compound 3 (220 mg, 0.71 mmol) were added vinyl acetate (3.0 ml) and PPL (Porcne Parkreas Lipase, 234 mg), and the mixture was vigorously stirred at room temperature for 8 days. Celite (300 mg) was added to the reaction solution, and the mixture was filtered with a filter of a Celite pad. The filtrate was concentrated under reduced pressure. The obtained crude product was directly purified by silica gel column chromatography to obtain Compound 14 (84 mg, 0.24 mmol).^*And compound 3 '(128 mg, 0.41 mmol)^**Was obtained with a yield of 34% and a yield of 58%, respectively.
* 97.5% ee, ** 63.2% ee
[0098]
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[0099]
Guanidine carbonate (2.11 mg, 1.17 mmol) was added to a solution of metal Na (26.8 mg, 1.17 mmol) in MeOH (2.34 ml), and the mixture was stirred at room temperature for 25 minutes. The prepared guanidine solution (0.152 ml) was added dropwise at 0 ° C. to a solution of compound 14 (26.8 mg, 0.076 mmol) in MeOH (0.3 ml). After stirring for 5 minutes, glacial acetic acid (4.3 μl) was added, the reaction solution was concentrated as it was, and MeOH was distilled off. This is H_TwoO (1 ml) was added, extracted with ethyl acetate (2 × 5 ml) and the organic layer was dried over MgSO 4._FourAnd then filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain compound 3 ″ (16.8 mg, 0.054 mmol) with a yield of 72%.

Claims (9)

Phenyl-substituted hydroxycyclopentenone represented by the formula [I].

[In the formula, Z ¹ represents a hydrogen atom or a hydroxyl-protecting group, and X ¹ represents a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group. A group or an amino group substituted by an "alkyl group having 1 to 6 carbon atoms or an aralkyl group having 1 to 8 carbon atoms". X ² is a halogen atom,
−Y ¹ _h (CR ¹ R ² ) _{m An} (CH ₂ ) _p Y ² _q (CR ³ R ⁴ ) _r Q _s
(Wherein, Y ¹ and Y ² each represent an oxygen atom or a sulfur atom, and A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of allene. , R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
−COOR ⁵
(Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms), a cyano group, a hydroxyl group,
-OCOR ⁶
(In the formula, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms.)
-CONR ⁷ R ⁸
(Wherein, R ⁷ and R ⁸ represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group) or a phenyl group, and h, n, q, and s represent 0 or 1. And m, p, and r represent integers of 0 to 5. )
Is shown. ] Formula [II]

[In the formula, X ¹ is a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group, or an “alkyl group having 1 to 6 carbon atoms, Or an amino group substituted with an "aralkyl group having 1 to 8 carbon atoms". X ² is a halogen atom,
−Y ¹ _h (CR ¹ R ² ) _{m An} (CH ₂ ) _p Y ² _q (CR ³ R ⁴ ) _r Q _s
(Wherein, Y ¹ and Y ² each represent an oxygen atom or a sulfur atom, and A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of allene. , R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
−COOR ⁵
(Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms), a cyano group, a hydroxyl group,
-OCOR ⁶
(In the formula, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms.)
-CONR ⁷ R ⁸
(Wherein, R ⁷ and R ⁸ represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group) or a phenyl group, and h, n, q, and s represent 0 or 1. And m, p, and r represent integers of 0 to 5. )
Is shown. ]
Is subjected to a rearrangement reaction in the presence of an acid catalyst to give a compound of the formula [III]

Wherein X ¹ and X ² are the same as above. A compound of the formula [I], which is then subjected to isomerization under acidic or basic conditions to protect a hydroxyl group if necessary.

Wherein X ¹ and X ² are the same as above. Z ¹ represents a hydrogen atom or a hydroxyl-protecting group. ] A method for producing a phenyl-substituted hydroxycyclopentenone represented by the formula: Phenyl-substituted hydroxycyclopentanones represented by the formula [IV].

[In the formula, Z ¹ represents a hydrogen atom or a hydroxyl-protecting group, and X ¹ represents a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group. A group or an amino group substituted by an "alkyl group having 1 to 6 carbon atoms or an aralkyl group having 1 to 8 carbon atoms". X ² is a halogen atom,
−Y ¹ _h (CR ¹ R ² ) _{m An} (CH ₂ ) _p Y ² _q (CR ³ R ⁴ ) _r Q _s
(Wherein, Y ¹ and Y ² each represent an oxygen atom or a sulfur atom, and A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of allene. , R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
−COOR ⁵
(Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms), a cyano group, a hydroxyl group,
-OCOR ⁶
(In the formula, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms.)
-CONR ⁷ R ⁸
(Wherein, R ⁷ and R ⁸ represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group) or a phenyl group, and h, n, q, and s represent 0 or 1. And m, p, and r represent integers of 0 to 5. ) Indicates, X ³ is _{-T- (CH 2) j -C (} R 9) (2-k) (OZ 2) k -R 10
(Wherein T represents a group selected from CH ₂ CH ₂ , CHＣＨCH, or C≡C, j and k each independently represent an integer of 0, 1, or 2, and R ⁹ represents (2-k ) Hydrogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, wherein R ¹⁰ is an alkyl group having 1 to ¹⁰ carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, An alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, a phenyl group, a phenoxy group, wherein the phenyl group and the phenoxy group are Or an optionally substituted alkoxy group of 1 to 6) or -BD (B is an alkylene group having 1 to 4 carbon atoms, D is a phenyl group, a phenoxy group, (the phenyl group and the phenoxy group Is a halogen atom, trif Or an optionally substituted alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenoxy group) or a cycloalkyl group having 5 to 7 carbon atoms. Z ² represents a hydrogen atom or a hydroxyl-protecting group, provided that when T is a group of C≡C, it represents a hydroxyl-protecting group.)
Is shown. ] Formula [I]

[In the formula, Z ¹ represents a hydrogen atom or a hydroxyl-protecting group, and X ¹ represents a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group. A group or an amino group substituted by an "alkyl group having 1 to 6 carbon atoms or an aralkyl group having 1 to 8 carbon atoms". X ² is a halogen atom,
−Y ¹ _h (CR ¹ R ² ) _{m An} (CH ₂ ) _p Y ² _q (CR ³ R ⁴ ) _r Q _s
(Wherein, Y ¹ and Y ² each represent an oxygen atom or a sulfur atom, and A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of an arene. , R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
−COOR ⁵
(Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms), a cyano group, a hydroxyl group,
-OCOR ⁶
(In the formula, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms.)
-CONR ⁷ R ⁸
(Wherein, R ⁷ and R ⁸ represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group) or a phenyl group, and h, n, q, and s represent 0 or 1. And m, p, and r represent integers of 0 to 5. )
Is shown. ]
A phenyl-substituted hydroxycyclopentenone represented by
MX ³
[Wherein X ³ is -T- (CH ₂ ) _j -C (R ⁹ ) _(2-k) (OZ ² ) _k -R ¹⁰
(Wherein T represents a group selected from CH ₂ CH ₂ , CHＣＨCH, or C≡C, j and k each independently represent an integer of 0, 1, or 2, and R ⁹ represents (2-k ) Hydrogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, wherein R ¹⁰ is an alkyl group having 1 to ¹⁰ carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, An alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, a phenyl group, a phenoxy group, wherein the phenyl group and the phenoxy group are a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 6 carbon atoms or a carbon atom Or an optionally substituted alkoxy group of 1 to 6) or -BD (B is an alkylene group having 1 to 4 carbon atoms, D is a phenyl group, a phenoxy group, (the phenyl group and the phenoxy group Is a halogen atom, trifle A methyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenoxy group, or a cycloalkyl group having 5 to 7 carbon atoms. Z ² represents a hydrogen atom or a hydroxyl-protecting group, provided that T is a group represented by C≡C, and a hydroxyl-protecting group, and M represents Li, Na, K, Mg, Ca, A metal selected from Ti, Zr, Ni, Cu, Zn, Al and Sn or a group containing the metal is shown.)
Is shown. ]
Characterized by reacting a nucleophile represented by the formula [IV]:

Wherein Z ¹ , X ¹ , X ² and X ³ are the same as above. ] A method for producing a phenyl-substituted hydroxycyclopentanone represented by the formula: Phenyl-substituted dihydroxycyclopentanes represented by the formula [V]

[In the formula, Z ¹ represents a hydrogen atom or a hydroxyl-protecting group, and X ¹ represents a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group. A group or an amino group substituted by an "alkyl group having 1 to 6 carbon atoms or an aralkyl group having 1 to 8 carbon atoms". X ² is a halogen atom,
−Y ¹ _h (CR ¹ R ² ) _{m An} (CH ₂ ) _p Y ² _q (CR ³ R ⁴ ) _r Q _s
(Wherein, Y ¹ and Y ² each represent an oxygen atom or a sulfur atom, and A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of allene. , R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
−COOR ⁵
(Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms), a cyano group, a hydroxyl group,
-OCOR ⁶
(In the formula, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms.)
-CONR ⁷ R ⁸
(Wherein, R ⁷ and R ⁸ represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group) or a phenyl group, and h, n, q, and s represent 0 or 1. And m, p, and r represent integers of 0 to 5. ) Indicates, X ³ is _{-T- (CH 2) j -C (} R 9) (2-k) (OZ 2) k -R 10
(Wherein T represents a group selected from CH ₂ CH ₂ , CHＣＨCH, or C≡C, j and k each independently represent an integer of 0, 1, or 2, and R ⁹ represents (2-k ) Hydrogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, wherein R ¹⁰ is an alkyl group having 1 to ¹⁰ carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, An alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, a phenyl group, a phenoxy group, wherein the phenyl group and the phenoxy group are a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 6 carbon atoms or a carbon atom May be arbitrarily substituted with 1 to 6 alkoxy groups) or -BD (B is an alkylene group having 1 to 4 carbon atoms, D is a phenyl group, a phenoxy group, (the phenyl group and the phenoxy group Is a halogen atom, trifluoro A methyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenoxy group, or a cycloalkyl group having 5 to 7 carbon atoms. Z ² represents a hydrogen atom or a hydroxyl-protecting group, provided that when T is a group of C≡C, it represents a hydroxyl-protecting group.)
Is shown. ] Formula [IV]

[In the formula, Z ¹ represents a hydrogen atom or a hydroxyl-protecting group, and X ¹ represents a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group. A group or an amino group substituted by an "alkyl group having 1 to 6 carbon atoms or an aralkyl group having 1 to 8 carbon atoms". X ² is a halogen atom,
−Y ¹ _h (CR ¹ R ² ) _{m An} (CH ₂ ) _p Y ² _q (CR ³ R ⁴ ) _r Q _s
(Wherein, Y ¹ and Y ² each represent an oxygen atom or a sulfur atom, and A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of allene. , R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
−COOR ⁵
(Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms), a cyano group, a hydroxyl group,
-OCOR ⁶
(In the formula, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms.)
-CONR ⁷ R ⁸
(Wherein, R ⁷ and R ⁸ represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group) or a phenyl group, and h, n, q, and s represent 0 or 1. And m, p, and r represent integers of 0 to 5. ) Indicates, X ³ is _{-T- (CH 2) j -C (} R 9) (2-k) (OZ 2) k -R 10
(Wherein T represents a group selected from CH ₂ CH ₂ , CHＣＨCH, or C≡C, j and k each independently represent an integer of 0, 1, or 2, and R ⁹ represents (2-k ) Hydrogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, wherein R ¹⁰ is an alkyl group having 1 to ¹⁰ carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, An alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, a phenyl group, a phenoxy group, wherein the phenyl group and the phenoxy group are May be arbitrarily substituted with 1 to 6 alkoxy groups) or -BD (B is an alkylene group having 1 to 4 carbon atoms, D is a phenyl group, a phenoxy group, (the phenyl group and the phenoxy group Represents a halogen atom, A cycloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenoxy group, or a cycloalkyl group having 5 to 7 carbon atoms. Z ² represents a hydrogen atom or a hydroxyl-protecting group, provided that when T is a group of C≡C, it represents a hydroxyl-protecting group.)
Is shown. ]
Wherein the phenyl-substituted hydroxycyclopentanone represented by the formula is reacted with a reducing agent.

Wherein Z ¹ , X ¹ , X ² and X ³ are the same as above. ] A method for producing a phenyl-substituted dihydroxycyclopentane represented by the formula: Equation [V]

[In the formula, Z ¹ represents a hydrogen atom or a hydroxyl-protecting group, and X ¹ represents a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group. A group or an amino group substituted by an "alkyl group having 1 to 6 carbon atoms or an aralkyl group having 1 to 8 carbon atoms". X ² is a halogen atom,
−Y ¹ _h (CR ¹ R ² ) _{m An} (CH ₂ ) _p Y ² _q (CR ³ R ⁴ ) _r Q _s
(Wherein, Y ¹ and Y ² each represent an oxygen atom or a sulfur atom, and A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of allene. , R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
−COOR ⁵
(Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms), a cyano group, a hydroxyl group,
-OCOR ⁶
(In the formula, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms.)
-CONR ⁷ R ⁸
(Wherein, R ⁷ and R ⁸ represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group) or a phenyl group, and h, n, q, and s represent 0 or 1. And m, p, and r represent integers of 0 to 5. ) Indicates, X ³ is _{-T- (CH 2) j -C (} R 9) (2-k) (OZ 2) k -R 10
(Wherein T represents a group selected from CH ₂ CH ₂ , CHＣＨCH, or C≡C, j and k each independently represent an integer of 0, 1, or 2, and R ⁹ represents (2-k ) Hydrogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, wherein R ¹⁰ is an alkyl group having 1 to ¹⁰ carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, An alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, a phenyl group, a phenoxy group, wherein the phenyl group and the phenoxy group are a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 6 carbon atoms or a carbon atom May be arbitrarily substituted with 1 to 6 alkoxy groups) or -BD (B is an alkylene group having 1 to 4 carbon atoms, D is a phenyl group, a phenoxy group, (the phenyl group and the phenoxy group Is a halogen atom, trifluoro A methyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenoxy group, or a cycloalkyl group having 5 to 7 carbon atoms. Z ² represents a hydrogen atom or a hydroxyl-protecting group, provided that when T is a group of C≡C, it represents a hydroxyl-protecting group.)
Is shown. ]
Cyclizing a phenyl-substituted dihydroxycyclopentane represented by the formula [VI]:

Wherein Z ¹ , X ² and X ³ are the same as above. Y ³ represents an oxygen atom, a sulfur atom, —NH— or —NR ¹¹ — (wherein, R ¹¹ represents an alkyl group having 1 to 6 carbon atoms). Method for producing a phenyl-substituted prostaglandin I ₂ class represented by. Phenyl substituted prostaglandin I ₂ such intermediates of the formula [VII].

[In the formula, Z ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, and X ³ represents -T- (CH ₂ ) _j -C (R ⁹ ) _(2-k) (OZ ² ) _k -R ¹⁰
(Wherein T represents a group selected from CH ₂ CH ₂ , CHＣＨCH, or C≡C, j and k each independently represent an integer of 0, 1, or 2, and R ⁹ represents (2-k ) Hydrogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, wherein R ¹⁰ is an alkyl group having 1 to ¹⁰ carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, An alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, a phenyl group, a phenoxy group, wherein the phenyl group and the phenoxy group are a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 6 carbon atoms or a carbon atom May be arbitrarily substituted with 1 to 6 alkoxy groups) or -BD (B is an alkylene group having 1 to 4 carbon atoms, D is a phenyl group, a phenoxy group, (the phenyl group and the phenoxy group Is a halogen atom, trifluoro A methyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenoxy group, or a cycloalkyl group having 5 to 7 carbon atoms. And Z ² represents a hydrogen atom or a hydroxyl-protecting group, provided that T is a group represented by C≡C, and a hydroxyl-protecting group, and X ⁴ represents a halogen atom, a hydroxyl group or a thiol group. , An allyl group, a vinyl group, an ethynyl group, an ester group or a cyano group, wherein Y ³ is an oxygen atom, a sulfur atom, —NH— or —NR ¹¹ — (wherein, R ¹¹ is an alkyl group having 1 to 6 carbon atoms) Is shown.) Is shown.] Formula [I]

[In the formula, Z ¹ represents a hydrogen atom or a hydroxyl-protecting group, and X ¹ represents a halogen atom, a hydroxyl group, a protected hydroxyl group, a thiol group, a protected thiol group, an amino group, a protected amino group. A group or an amino group substituted by an "alkyl group having 1 to 6 carbon atoms or an aralkyl group having 1 to 8 carbon atoms". X ² is a halogen atom,
−Y ¹ _h (CR ¹ R ² ) _{m An} (CH ₂ ) _p Y ² _q (CR ³ R ⁴ ) _r Q _s
(Wherein, Y ¹ and Y ² each represent an oxygen atom or a sulfur atom, and A represents a vinylene group, an ethynylene group, or a divalent group formed by removing one hydrogen atom from each of carbon atoms at both ends of allene. , R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom,
−COOR ⁵
(Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms), a cyano group, a hydroxyl group,
-OCOR ⁶
(In the formula, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms.)
-CONR ⁷ R ⁸
(Wherein, R ⁷ and R ⁸ represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group) or a phenyl group, and h, n, q, and s represent 0 or 1. And m, p, and r represent integers of 0 to 5. )
Is shown. ]
A method for optically resolving phenyl-substituted hydroxycyclopentenones of formula [I], comprising treating a mixture of both enantiomers of phenyl-substituted hydroxycyclopentenones represented by the formula with an enzyme.