JP4970682B2

JP4970682B2 - Vitamin D precursors, methods and intermediates

Info

Publication number: JP4970682B2
Application number: JP2001543549A
Authority: JP
Inventors: パスカルジャン−クロード; ヴァンドワルモリッツ; メロスフィリップ; ドクレルクピエール
Original assignee: ラボラトワールテラメックス
Priority date: 1999-12-08
Filing date: 2000-12-04
Publication date: 2012-07-11
Anticipated expiration: 2020-12-04
Also published as: AR034113A1; KR20020061632A; IL150089A; JP2003535816A; KR100732271B1

Description

【０００１】
本発明は１９−ノール−ビタミンＤ類似化合物の合成に有効に用いられる前駆物質、更にそれを調製するための方法及び中間体に関する。より具体的には、本発明は上記ビタミンＤ類似化合物のＡ−環の前駆物質に関する。このＡ環は下記の構造で表される（例えば、Ｍａｚｕｒｅｔａｌ．，ＴｅｔｒａｈｅｄｒｏｎＬｅｔｔｅｒｓ１９９５，２９８７参照）。
【０００２】
【化８】

【０００３】
（−）−キナ酸又はシクロヘキサン−トリオールから、１９−ノール−Ａ−環前駆物質としてのビシクロ［３．１．０］ヘキサン誘導体を合成する技術は、Ｍ．Ｖａｎｄｅｗａｌｌｅらによって（ＴｅｔｒａｈｅｄｒｏｎＬｅｔｔｅｒｓ，１９９５，３６（４５），８２９９−８３０２）発展してきた、また、それはシクロプロピリックアルコ−ルからホモアリリックアルコールへの公知のシグマトロピー再配列に基づいている。天然ビタミンＤにおけるこの再配列の可能性は、Ｍａｚｕｒら（ｏｐ．ｃｉｔ．）によって初めて立証された。他に２，４−ペンタン−ジオンからの合成技術も報告された（Ｓ．Ｚ．Ｚｈｏｕ，Ｓ．Ａｎｎｅ，Ｍ．Ｖａｎｄｅｗａｌｌｅ，ＴｅｔｒａｈｅｄｒｏｎＬｅｔｔｅｒｓ，１９９６，３７（４２），７６３７−７６４０）。３−シクロペンテノールもまた、上記調製のための前駆物質として使用された（Ｗ．Ｙｏｎｇ，Ｍ．Ｖａｎｄｅｗａｌｌｅ；Ｓｙｎｌｅｔｔ，１９９６，９，９１１−９１２）。
【０００４】
これらの方法は、しかしながら、以下の不都合がある：
−（−）−キナ酸からの調製には、大量生産での制御が難しいラジカル脱酸素反応が含まれ、さらに有毒なトリブチルスズ水素化物を使用している；
−シクロヘキサントリオールからの工程は多くのステップ（１２）を通して行なわれ、２つの酵素反応を必要とする；
−開始物質である３−シクロペンテノールは市販されていない。シクロペンタジエンから収率の低いヒドロホウ素化ステップを用いて調製しなければいけない。さらに、ホルミル基のシクロプロパネーション及び導入は扱いにくい；
−２，４−ペンタンジオンから開始する合成（１０ステップ）は中間体ビスエポキシドを調製する第一ステップにおいて低収率になる。さらに、それらが低分子量であるために、中間体の中には揮発しやすくて、大量スケール工程では精製しにくいものもある。
【０００５】
広範囲の１９−ノール−Ａ−環前駆物質は３，５−ジヒドロキシ安息香酸誘導体又はその４−アルキル置換同族体から開始することで調製されることが分かっている。これらの前駆物質はこれまでに開示された方法より効果的な方法によって大量スケールで得ることができる。
【０００６】
従って第一の特徴において、本発明は式（Ｉ）：
【０００７】
【化９】

【０００８】
式中、
−Ａは−ＣＨ_２ＯＨ基， −ＣＨ_２−ＯＣＯＲ’基， −ＣＯＲ’’基， −ＣＳＲ’’基又はエチニル基であり；
−Ｒは水素又は（Ｃ_１−Ｃ_６）アルキルであり；
−Ｒ_１は水素、（Ｃ_１−Ｃ_６）アルキル又は−（ＣＨ_２）_ｎ−ＯＰ基であり；
−Ｒ_２は水素又は−ＯＰ基であり；
−Ｒ’は（Ｃ_１−Ｃ_６）アルキル又はフェニルであり；
−Ｒ’’は水素、ヒドロキシル、（Ｃ_１−Ｃ_６）アルキル、（Ｃ_１−Ｃ_６）アルコキシ、（Ｃ_１−Ｃ_６）アルキルチオ、又は、ジ（Ｃ_１−Ｃ_３）アルキルアミノであり；
−Ｐは水素；（Ｃ_１−Ｃ_６）アルカノイル；（Ｃ_１−Ｃ_４）アルキル、ハロゲン若しくはニトロによってフェニルが任意に置換されたベンゾイル；（Ｃ_１−Ｃ_６）アルコキシカルボニル；各Ｒ_３が独立に（Ｃ_１−Ｃ_６）アルキル若しくはフェニルを表す−Ｓｉ（Ｒ_３）_３基；モノ若しくはジ（Ｃ_１−Ｃ_６）アルコキシ（Ｃ_１−Ｃ_６）アルキル；テトラヒドロフラニル；又は、テトラヒドロピラニルであり；
−ｎは０、１、２、３、又は、４である：
の化合物の調製方法であって、
（ｉ）式１

【０００９】
【化１０】

【００１０】
式中、Ａは（Ｃ_１−Ｃ_６）アルコキシカルボニル、好ましくはメトキシカルボニル、又は、ジ（Ｃ_１−Ｃ_３）アルキルアミノカルボニルであり、Ｒは上記に定義したものと同様である；
の化合物とリパーゼを、ビニル脂肪酸又は酸無水物中で反応させるステップ、
（ｉｉ）得られた式２又は２’
【００１１】
【化１１】

【００１２】
式中、Ｚは（Ｃ_１−Ｃ_６）アルキルなどのアルキル、好ましくは（Ｃ_１−Ｃ_３）アルキルである；
の化合物を対応する式（Ｉ）の化合物に変換させるステップ、
からなる調製方法に関する。
【００１３】
一般スキーム１に示したように、Ａ−環前駆物質の調製に用いられる開始物質はメチル３，５−ジヒドロキシ−安息香酸又はそのエステル、若しくは、その４−アルキル置換同族体のエステルに水素添加し、Ｐ．ＷａｎｇとＪ．ＡｄａｍｓによってＪＡｍＣｈｅｍＳｏｃ１９９４，１１６，３２９６−３３０５に記載された方法から少し変更した方法を行なって得られる。
【００１４】
最初のステップは、１−アルコキシ（又はジアルキルアミノ）カルボニル−３，５−ジヒドロキシ−シクロヘキサン又はその４−アルキル置換同族体を、例えば、ビニルアセテート、ビニルプロピオネート若しくはビニルブチレート等のビニルアルカノエート、又は、無水酢酸、無水プロピオン酸若しくは無水酪酸などの酸無水物の溶媒中で、ＳＡＭＩＩ（Ｐｓｅｕｄｏｍｏｎａｓｆｌｕｏｒｅｓｃｅｎｓ由来のリパーゼ），ＣＣＬ（Ｃａｎｄｉｄａｃｙｌｉｎｄｒａｃｅａ由来のリパーゼ），ＰＰＬ（ｐｏｒｃｉｎｅｐａｎｃｒｅａｓ由来のリパーゼ），ＰＳＬ（Ｐｓｅｕｄｏｍｏｎａｓｃｅｐａｃｉａ由来のリパーゼ），ＧＣＬ（Ｇｏｔｒｉｃｈｕｍｃａｎｄｉｄｕｍ由来のリパーゼ）などのリパーゼを用いて、１０℃〜４０℃で好ましくは２０℃で６〜７２時間かけて、酵素により触媒作用を持たせて不斉化することからなる。このステップによって対応するアルキル（又はジアルキル）（１Ｓ，３Ｓ，５Ｒ）−３−アルキルカルボニルオキシ−５−ヒドロキシ若しくは（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−４−アルキル−３−アルキルカルボニルオキシ−５−ヒドロキシ−シクロヘキサンカルボキシレート（又はカルボキシアミド）２、又は、対応するアルキル（又はジアルキル）（１Ｓ，３Ｓ，５Ｒ）−５−アルキルカルボニルオキシ−３−ヒドロキシ若しくは（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−４−アルキル−５−アルキルカルボニルオキシ−３−ヒドロキシ−シクロヘキサンカルボキシレート（又はカルボキシアミド）２’が得られる。
【００１５】
また、ジエステル３を、適当な酵素を用いて、ｅｎａｎｔｉｏｔｏｐｏｓｅｌｅｃｔｉｖｅ酵素により触媒作用を持たせて加水分解することによる不斉化は、同一ファミリーの化合物につながるために起こりうる。
【００１６】
スキーム２及び３にはスキーム１に記載した化合物２又は２’から、Ｒ＝Ｈ、Ｒ_２＝ＯＰの一般式（Ｉ）のすべてのジアステレオ異性体を合成する方法について記載されている。
【００１７】
これらのスキームに示された通り、化合物（Ｉ）への化合物２又は２’の変換は、結果として得られるジアステレオ異性体に依存して様々な順序で部分的に又は全体的に行なわれ得る以下のステップの１つ又は複数を用いて行なわれる：（１）ヒドロキシ基の保護（例えば、Ｐ＝ＴＢＤＭＳ、ＴＢＤＰＳ）、（２）エステル加水分解、（３）３又は５−ヒドロキシ基の反転、（４）脱離基の形成（例えば、Ｌ＝ＯＴｏｓ、ＯＢｒｏｓ、ＯＭｓ）、（５）所望のビシクロ［３．１．０］ヘキサンへの塩基含有閉環反応、（６）カルボアルコキシ又はカルバモイル官能基（Ａ）から所望の置換基Ａへの変換。
【００１８】
ステップ（２）及び（４）は従来から当業者によく知られた公知の反応である。ステップ（１）はＪ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．（１９７２，９４，６１９０）又はＰｒｏｔｅｃｔｉｖｅｇｒｏｕｐｓｉｎＯｒｇａｎｉｃＳｙｎｔｈｅｓｉｓ，Ｔ．Ｗ．Ｇｒｅｅｎｅ，ＪｏｈｎＷｉｌｅｙＳｏｎｓ（ＮｅｗＹｏｒｋ）に従って行なわれ得る。ステップ（３）はＳｙｎｔｈｅｓｉｓ（１９８１，１）に従って、又は、２段階の工程によって行なわ得る（脱離反応、ヒドロホウ素化反応）。ステップ（５）はＴｅｔｒａｈｅｄｒｏｎＬｅｔｔｅｒｓ，１９９５，３６（４５），８２９９−８３０２に従って行なわれ得る。ステップ（６）はＪ．Ｇｅｎ．Ｃｈｅｍ．ＵＳＳＲ１９６４，３４，１０２１に従って行なわれ得る。
【００１９】
スキーム２は、具体的には、３ａＳコンフィグレーション（α配向シクロプロピル環）を持ったすべてのジアステレオ異性体の合成法について記載されている。
【００２０】
スキーム３は、具体的には、３ａＲコンフィグレーション（β配向シクロプロピル環）を持ったすべてのジアステレオ異性体の合成法について記載されている。
【００２１】
一般的なスキーム４に示されているように、Ｒ＝Ｈ及びＡ＝ＣＨ_２ＯＨの３ａヒドロキシメチル置換ビシクロ［３．１．０］ヘキサン化合物（Ｉ）はＣ−１で変成するビタミンＤ類似化合物に対するＡ−環前駆物質の合成に役に立つことができる。その可能性は、重要な中間体としてケトン４．２を用いるＩ．ａ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）から例示される。グリニャール反応（例えばＲ_１＝Ｍｅ又はＥｔ）によってジアステレオ選択的に三級アルコールＩ．ｉが得られ、同時に保護エステル官能基の除去が起こる。一方、４．２のメチレン化によって４．３が得られる。最も良い結果（収率６８％）はＬｏｍｂａｒｄｏ法（ＴｅｔｒａｈｅｄｒｏｎＬｅｔｔ．，１９８２，２３，４２９３）により得られる。また、Ｗｉｔｔｉｇ又はＴｅｂｂｅ反応（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９８５，５０，１２１２）によってそれぞれ３９％、５４％の収率が得られる。
【００２２】
４．３の二ヒドロキシル化によって、エピマー４．４の次に主要な生成物として所望のジオールＩ．ｍ．が得られる（比率８５：１５：ここには示さない）。一方、４．３のヒドロホウ素化によって２Ｒ及び２Ｓヒドロキシメチル化合物が７５：２５の比率で得られる（７３％）。これらのエピマーアルコールが分けられて、ＴＢＤＰＳエーテル形成後Ｉ．ｊが得られ（８１％）、次にエステル加水分解後Ｉ．ｋが得られる（８１％）。４．３において酢酸水銀が介在する水の添加によって、三級アルコールＩ．ｌ、次にＩ．ｉが７５：２５の比率で得られる。
【００２３】
３，５−ジヒドロキシ安息香酸誘導体から１９−ノールＡ環前駆物質を調製する新規の方法は、これまでに述べられた方法よりも短い。上記経路の実際的な重要性は、主に、中間体の大部分は結晶性で、シリカゲルクロマトグラフィーによる昔からの精製法より大量スケールにおいてより簡易である結晶化によって精製出来るという事実にあり、異性体の純度を高いレベルで保証する。
【００２４】
【化１２】

【００２５】
【化１３】

【００２６】
【化１４】

【００２７】
【化１５】

【００２８】
このように調製されたすべての化合物（Ｉ）はコンフィグレーション２Ｓ、３ａＳ、４ａＳ（Ａはホルミル基、ヒドロキシメチル基、エチニル基又はメトキシカルボニル基であり、Ｒ及びＲ_２は共に水素であり、Ｒ_１は−ＯＳｉ（Ｒ_３）_３基である）の化合物を除いて新規である。
【００２９】
従って、これらの新規の化合物は本発明の他の特徴を表す。
好ましい化合物（Ｉ）としては
−Ａは−ＣＨ_２ＯＨ基， −ＣＨ_２−ＯＣＯＲ’基， −ＣＯＲ’’基又はエチニル基であり；
−Ｒ_１は（Ｃ_１−Ｃ_６）アルキル又は−（ＣＨ_２）_ｎ−ＯＰ基であり；
−Ｒ’はフェニルであり；
−Ｒ’’は水素であり；
−Ｐは水素又は−Ｓｉ（Ｒ_３）_３基であり；
−ｎは０、又は、１である
化合物が挙げられる。
【００３０】
化合物（Ｉ）は、例えば、ＴｅｔｒａｈｅｄｒｏｎＬｅｔｔｅｒｓ，１９９６；３７（４２）：７６３７−７６４０に記載されている以下のスキームに従ってビタミンＤ（１９−ノール、１α、２５（ＯＨ）_２−Ｄ_３）の合成に使用することが出来る。
【００３１】
【化１６】

【００３２】
本発明は更に、化合物（Ｉ）を調製するための中間体に関する。特に、本発明は式（ＩＩ）：
【００３３】
【化１７】

【００３４】
式中：
−Ａ及びＲは上記に定義したものと同様であり、
−Ｒ_４及びＲ_５はそれぞれ独立に上記に定義したＰ基、メシル基、トシル基、ブロシル基、又は、トリフルオロメシル基を表す、
ただし、Ａがメトキシカルボニルで、Ｒが水素である時、化合物（ＩＩ）のコンフィグレーションは１Ｒ、３Ｒ、５Ｒではない：
のジアステレオ異性体化合物に関する。
【００３５】
また、式２又は２’：
【００３６】
【化１８】

式中、
−Ａ及びＲは上記に定義したものと同様であり、
−Ｚはアルキルである：
の化合物、さらに式１：
【００３７】
【化１９】

【００３８】
式中、Ａは上記に定義したものと同様であり、Ｒは（Ｃ_１−Ｃ_６）アルキルである：
の化合物も本発明の範囲である。
【００３９】
本明細書、及び、添付した請求項において、「（Ｃ_１−Ｃ_３）アルキル」、「（Ｃ_１−Ｃ_４）アルキル」又は「（Ｃ_１−Ｃ_６）アルキル」という用語は、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔ−ブチル基、ペンチル基、イソペンチル基又はヘキシル基などの１〜３個（それぞれ４個又は６個）の炭素原子を含有する直鎖又は分枝の炭化水素鎖を意図していると理解されたい。
【００４０】
「（Ｃ_１−Ｃ_６）アルコキシ」又は「（Ｃ_１−Ｃ_６）アルキルチオ」という用語は、上記に定義したようにＲが（Ｃ_１−Ｃ_６）アルキルであるＯＲ基、ＳＲ基をそれぞれ意図していると理解されたい。
次に本発明を以下の調製法及び実施例によって説明する。
【００４１】
式Ｉの中間体の調製
ａ）シス，シス−３，５−ジヒドロキシ−１−（メトキシカルボニル）シクロヘキサン：１．Ａ（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３）
ＰｅｎｇＷａｎｇ及びＪｕｌｉａｎＡｄａｍｓが３，５−ジヒドロキシ安息香酸の水素化に関してＪ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．（１９９４，１１６，３２９６−３３０５）で記載したものと同様の条件で、メチル３，５−ジヒドロキシベンゾエートをＭｅＯＨ中で水素化した。
メチル３，５−ジヒドロキシベンゾエート（５７．６ｇ，０．６２９ｍｏｌ，９７％）、０．１％のＡｃＯＨを含有する５％のＲｈ／Ａｌ_２Ｏ_３（５．７６ｇ）のＭｅＯＨ（４００ｍｌ）溶液をオートクレーブ（１Ｌ）に加えた。オートクレーブに水素を用いてスチームを２回あてた（１３０ａｔｍから４０ａｔｍ）。水素圧は１３０ａｔｍに達し、温度は８０〜８５℃まで上昇した。温度が上がる過程で水素圧は低下する。圧が９０ａｔｍまで低下したとき、水素圧は再び１３０ａｔｍまで上昇した。水素化は８０〜８５℃、１３０ａｔｍで１２時間かけて行なわれ、次に、１５０℃まで加熱して、対応して圧は約１５５ａｔｍに達した。反応は３６時間継続した。触媒をろ過して、ろ液を濃縮し、残留物をＥｔＯＡＣ／イソオクタンから結晶化して１．Ａを得た（３１．１ｇ、収率５０％）。
mp : 135.9 °C ;
UV (EtOH) : 211.4 nm (ε= 90.9) ;
IR (KBr) : 3284, 1734, 1259, 1015 cm^-1 ;
¹H-NMR (DMSO-d₆) : δ1.13 (3H,m) ; 2.06 (3H,m) ; 2.30 (1H,m) ; 3.47 (2H,m) ; 3.61 (3H,s) ; 4.70 (2H,d) ppm.
【００４２】
メチル３，５−ジヒドロキシベンゾエートを以下の化合物に置き換えた以外は、上述と同様の反応を行い：
−メチル３，５−ジヒドロキシ−４−メチルベンゾエート、又は、
−メチル３，５−ジヒドロキシ−４−エチルベンゾエート：
以下の化合物を得た：
−メチルオール−シス−３，５−ジヒドロキシ−４−メチル−シクロヘキサンカルボキシレート：１．Ｂ（Ｒ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）
mp : 123 °C ;
¹H-NMR (500 MHz, CD₃OD) : δ3.698 (2H,dt,J=4.0,12.0 Hz) ; 3.666 (3H,s) ; 2.40 (2H,tt,J=4.0,13.0 Hz) ; 2.23 (1H,m) ; (2H,dt,J=4.0,13.0 Hz) ; 1.54 (2H,q,J=13.0 Hz) ; 0.88 (3H,d,J=7.08 Hz) ppm.
−メチルオール−シス−４−エチル−３，５−ジヒドロキシ−シクロヘキサンカルボキシレート：１．Ｃ（Ｒ＝Ｅｔ，Ａ＝ＣＯＯＣＨ_３）
mp : 94-96 °C;
¹H-NMR (500 MHz, MeOD) : δ3.72 (2H, dt, J=10.9, 4.1 Hz), 3.66 (3H, s), 2.42 (1H, m), 1.86 (1H, bs), 1.79 (2H, dt, J=12.8, 4.1 Hz), 1.59 (2H, d, J=9.0 Hz), 1.46 (2H, m), 1.02 (3H, t, J=7.5 Hz) ppm.
【００４３】
式２及び２’の中間体の調製（スキーム１）
Ｉ）一般式（Ｉ）とジオールの酵素エステル化
Ｉａ）メチル（１Ｓ，３Ｓ，５Ｒ）−３−アセトキシ−５−ヒドロキシ−シクロヘキサンカルボキシレート：２．Ａ（Ｒ＝Ｈ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）
メチルシス，シス−３，５−ジヒドロキシ−シクロヘキサンカルボキシレート１．Ａ（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３）（１５．２ｇ，８７ｍｍｏｌ）と豚膵臓由来のリパーゼ（ＰＰＬ −１６．８Ｕ／ｍｇ，９．１２ｇ）を円底フラスコに取り、続いてビニルアセテート（４５０ｍｌ）を室温で加えた。フラスコを窒素で置換し、懸濁液を２２時間、暗い中で攪拌した。次にセライトのパッドを通してろ過し、リパーゼを除去した。ろ液を蒸発させて濃縮した。残留物をシリカゲルのパッド（７０〜２００メッシュ、４５ｇ）を通してろ過することにより分離した。トルエン（２１０ｍＬ）で溶出し、次にトルエン／エチルアセテート＝７５／２５（Ｖ／Ｖ，２１０ｍＬ）の混合液、続いてトルエン／エチルアセテート＝５０／５０（Ｖ／Ｖ，２１０ｍＬ）の混合液で溶出し、最後に酢酸エチル（２４０ｍＬ）で溶出して濃縮後に２．Ａ（Ｒ＝Ｈ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）（２２．３ｇ，収量）を黄色油状物として得た。
IR (film) : 3447, 1734, 1243 cm^-1 ;
¹H-NMR (CDCl₃) : δ1.4 (3H,m), 2.1 (3H,s), 2.3 (5H,m), 3.7 (3H,s), 3.75 (1H,m), 4.7 (1H,m) ppm ;
[α]_D ²⁵ : +22.4 (c=1.25, CHCl₃).
【００４４】
Ｉｂ）メチル（１Ｒ，３Ｓ，４Ｓ，５Ｒ）−５−アセトキシ−３−ヒドロキシ−４−メチルシクロヘキサンカルボキシレート：２’．Ｂ（Ｒ＝Ｍｅ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）及びメチル（１Ｒ，３Ｓ，４Ｓ，５Ｒ）−５−アセトキシ−３−ヒドロキシ−４−エチルシクロヘキサンカルボキシレート：２’．Ｃ（Ｒ＝Ｅｔ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）
ＰＰＬをＳＡＭＩＩ、ＰＳＬ又はＣＣＬに置き換える以外はＩａに記載と同様の手順によって以下の化合物それぞれから：
−メチルオールシス−３，５−ジヒドロキシ−４−メチル−シクロヘキサンカルボキシレート：１．Ｂ（Ｒ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）
−メチルオールシスジヒドロキシ−４−エチル−３，５−シクロヘキサンカルボキシレート：１．Ｃ（Ｒ＝Ｅｔ，Ａ＝ＣＯＯＣＨ_３）
以下の化合物を得た：
−メチル（１Ｒ，３Ｓ，４Ｓ，５Ｒ）−５−アセトキシ−３−ヒドロキシ−４−メチル−シクロヘキサンカルボキシレート：２’．Ｂ（Ｒ＝Ｍｅ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）：
IR (film) : 3434, 1731, 1439, 1243, 1027 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ4.84(1H, dt, J=4.3, 4.3 Hz) ; 3.82 (1H,m) ; 3.69 (3H,s) ; 2.45 (1H,m) ; 2.32 (1H,d, J=6.4 Hz) ; 2.05 (3H,s) ; 1.92 (2H,dt, J=4.0,
4.0 Hz) ; 1.77 (3H,m) ; 0.96 (3H,d, J=7.0 Hz) ppm ;
MS (m/z) : 231 (M+, 1) ; 213 ; 199 ; 186 ; 170 ; 152 ; 127 ; 111 ; 83 ; 87 ; 67 ; 43 (base peak) ;
[α]_D ²⁵ : -22.7 (c=0.38, CHCl₃).
メチル（１Ｒ，３Ｓ，４Ｓ，５Ｒ）−５−アセトキシ−４−エチル−３−ヒドロキシ−シクロヘキサンカルボキシレート：２’．Ｃ（Ｒ＝Ｅｔ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）：
IR (film) : 3421, 2958, 2360, 1733, 1437, 1239, 1027, 739 cm^-1
¹H-NMR (500 MHz, CDCl₃) : δ4.98 (1H, t, J=4.1 Hz), 3.87 (1H, m), 3.69 (3H, s), 2.60 (1H, bs), 2.16 (2H, m), 2.02 (3H, s), 1.84 (2H, m), 1.72 (1H, bs), 1.59 (2H, m), 1.47 (1H, m), 0.97 (3H, t, J=7.5 Hz) ppm ;
MS (m/z) : 245 (M⁺+1), 233, 206, 184, 166, 141, 125, 111, 95, 87, 57, 43 (base peak).
[α]_D ²⁵: -50.2 (c=1.08, CHCl₃)．
【００４５】
ＩＩ）式３のジエステル類の酵素的加水分解
ＩＩａ）メチル（１Ｓ，３Ｓ，５Ｒ）−３−アセトキシ−５−ヒドロキシ−シクロヘキサン−カルボキシレート：２．Ａ（Ｒ＝Ｈ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）
メソ−ジアセテート３．Ａ（Ｒ＝Ｈ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）（９２．１ｍｇ，０．３６ｍｍｏｌ）の３．０ｍｌＣＨ_３ＣＮ溶液に２７．０ｍｌの緩衝液（ｐＨ＝７．０）を加え、次にＳＡＭＩＩ（１３．８ｍｇ，４６．８Ｕ／ｍｇ）を加えた。得られた混合液を室温で攪拌し、正確に計った１．０ＭＮａＯＨ溶液を加えてｐＨを７．０に保った。反応物は薄層クロトグラフィー分析によって測定した。ＮａＣｌを加えて反応を終了させ、反応溶液を飽和させた。反応混合液をＡｃＯＥｔ（３ × ５０ｍｌ）で抽出した。ひとまとめの有機抽出物を飽和食塩水（３ × １０ｍｌ）で洗浄し、ＭｇＳＯ_４で乾燥し、濃縮した。残留物をイソオクタン／ＥｔＯＡｃ（６：４）を溶離液としたＨＰＬＣで精製し、モノアセテート２．Ａ（Ｒ＝Ｈ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）（３０．１ｍｇ，３８．９％）を無色油状物として得た。
【００４６】
ＩＩｂ）メチル（１Ｓ，３Ｒ，４Ｒ，５Ｓ）−３−ブタノイルオキシ−５−ヒドロキシ−４−メチル−シクロヘキサン−カルボキシレート：２Ｂ（Ｒ＝Ｍｅ，Ｚ＝ｎ−Ｃ_３Ｈ_７，Ａ＝ＣＯＯＣＨ_３）
１．Ｂ（Ｒ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）（０．２ｇ，１．１０ｍｍｏｌ）のＣＨ_２Ｃｌ_２（２ｍｌ）溶液に、室温で無水酪酸（５３８ μｌ，３．２９ｍｍｏｌ）を加え、次にＴＭＳｏＴｆ（トリメチルシリルトリフレート）（２５μｌ，１Ｍ）の溶液を加えた。この混合液を室温で３０分間攪拌し、２．５ｍｌのＭｅＯＨを加え、さらに２時間攪拌し、５％ＮａＨＣＯ_３で反応を終了させた。反応溶液を飽和食塩水（３ × ２０ｍｌ）で洗浄し、で洗浄し、ＭｇＳＯ_４で乾燥し、濃縮して残留物を得た。この残留物をイソオクタン：ＡｃＯＥｔ（９：１）を溶離液としたシリカゲルクロマトグラフィーで精製し、ジブチレート３．Ｂ（Ｒ＝Ｍｅ，Ｚ＝ｎ−Ｃ_３Ｈ_７，Ａ＝ＣＯＯＣＨ_３）（３．９ｇ，９８．８％）を無色油状物として得た。このメソ−ジエステル（１１０ｍｇ，０．３４ｍｍｏｌ）のＣＨ_３ＣＮ（２．０ｍｌ）溶液に２２．０ｍｌの緩衝液（ｐＨ＝７．０）を加え、次にＳＡＭＩＩ（３７ｍｇ，４６．８Ｕ／ｍｇ）を加えた。得られた混合液を室温で攪拌し、正確に計った１．０ＭＮａＯＨ溶液を加えてｐＨを７．０に保った。反応物は薄層クロトグラフィー分析によって測定した。ＮａＣｌを反応溶液に加えて反応を終了させた。反応混合液をＥｔＯＡｃ（３ × ５０ｍｌ）で抽出し、ＭｇＳＯ_４で乾燥し、濃縮して残留物を得た。残留物をイソオクタン／ＥｔＯＡｃ（７：３）を溶離液としたＨＰＬＣで精製し、モノブチレート２．Ｂ（Ｒ＝Ｍｅ，Ｚ＝ｎ−Ｃ_３Ｈ_７，Ａ＝ＣＯＯＣＨ_３）（７８ｍｇ，９０％）を無色油状物として得た。
IR (film) : 3495, 2964, 2878, 1731, 1438, 1281, 1183, 990 cm^-1,
¹H-NMR (CDCl₃) : 4.83 (1H, dt), 3.83 (1H, m), 3.68 (3H, s), 2.45 (1H, m), 2.32 (1H, m), 2.28 (2H, t, J=7.9 Hz), 1.91 (2H, m), 1.82-1.62 (5H, m), 0.95 (6H, m).
[α]_D ²⁵ : +16.2 (c=2.09, CHCl₃)
MS : 259 (M⁺+1), 227, 214, 187, 170, 152, 127, 111, 93, 71, 43
【００４７】
ＩＩｃ）メチル（１Ｓ，３Ｒ，４Ｒ，５Ｓ）−３−アセトキシ−５−ヒドロキシ−４−メチル−シクロヘキサンカルボキシレート：２．Ｃ（Ｒ＝Ｍｅ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）
メソ−ジアセテート３．Ｃ（Ｒ＝Ｍｅ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）からＩＩａ）記載と同様に反応を行なう。
[α]_D ²⁵ : +20 (c=2.9, CHCl₃)
【００４８】
ＩＩｄ）メチル（１Ｒ，３Ｓ，４Ｓ，５Ｒ）−５−アセトキシ−３−ヒドロキシ−４−メチル−シクロヘキサンカルボキシレート：２’．Ｂ（Ｒ＝Ｍｅ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）
リパーゼとしてＰＰＬを用いた以外は、メソ−ジアセテート３．Ｃ（Ｒ＝Ｍｅ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）からＩＩａ）記載と同様に反応を行なう。
[α]_D ²⁵ : -19.5 (c=2.88, CHCl₃)
【００４９】
実施例１：（２Ｓ，３ａＳ，４ａＳ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｂ．１（Ａ＝ＣＯＯＣＨ_３，Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ）
ａ）メチル（１Ｒ，３Ｓ，５Ｒ）−３−アセトキシ−５−トシルオキシ−シクロヘキサンカルボキシレート：２．４．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）
トリエチルアミン（５０ｍｌ）とメチレンクロライド（１０ｍｌ）混合液中のメチル（１Ｓ，３Ｓ，５Ｒ）−３−アセトキシ−５−ヒドロキシ−シクロヘキサンカルボキシレート２．Ａ（Ｒ＝Ｈ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）（１０．１ｇ，４３．７ｍｍｏｌ）及びジメチルアミノ−ピリジン（０．１ｇ）溶液に、ｐ−トルエンスルホニルクロライド（１３．３ｇ，７０ｍｍｏｌ）を０°Ｃで加えた。得られた溶液を０℃で１時間攪拌した後、室温で２２時間攪拌した。反応を水（３００ｍｌ）で終了させ、メチレンクロライドで抽出した。有機層を水で洗浄し、ＭｇＳＯ_４で乾燥させ、ろ過した後濃縮した。粗生成物をＥｔＯＨから結晶化し、２．４．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（１３．２ｇ，８１．６％）を得た。
mp : 83.1 °C ;
IR (KBr) : 1734, 1175 cm^-1 ;
¹H-NMR (CDCl₃) : δ 1.5 (3H,m), 2.0 (3H,s), 2.28 (4H,m), 2.47 (3H,s), 3.68 (3H,s), 4.4 (1H,m), 4.68 (1H,m), 7.35 (1H,d, J=8.5Hz), 7.8 (2H,d, J=8.5 Hz) ppm.
【００５０】
ｂ）メチル（１Ｒ，３Ｓ，５Ｒ）−３−ヒドロキシ−５−トシルオキシ−シクロヘキサンカルボキシレート：２．５．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）
２．４．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（２３．３５ｇ，６３ｍｍｏｌ）のＭｅＯＨ懸濁液中に炭酸カリウム（４．３６ｇ，３１ｍｍｏｌ）を加えた。得られた懸濁液を３０分間攪拌し、水（１．５Ｌ）に注いだ。析出物をろ過し、乾燥して２．５．ａを得た（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（１８．５ｇ，８９％）。
mp : 98.4 °C ;
UV (EtOH) : 225 nm (ε= 11935) ;
IR (KBr) : 3447, 1719, 1176 cm^-1 ;
¹H-NMR (CDCl₃) : δ1.52 (4H,m), 2.25 (4H,m), 2.45 (3H,s), 3.6 (1H,m), 3.68 (3H,s), 4.42 (1H,m), 7.35 (2H,d, J=8.5Hz), 7.8 (2H,d, J=8.5 Hz) ppm ;[α]_D ²⁵ : -19 (c=1.00, EtOH)
【００５１】
ｃ）メチル（１Ｒ，３Ｒ，５Ｒ）−３−ベンゾイルオキシ−５−トシルオキシ−シクロヘキサンカルボキシレート：２．６．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）
０℃の、２．５．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（１８．３５ｇ，５６ｍｍｏｌ）、トリフェニルホスフィン（１８．４ｇ，７０ｍｍｏｌ）、及び、安息香酸（８．５３ｇ，７０ｍｍｏｌ）のトルエン（１８０ｍｌ）とＴＨＦ（７０ｍｌ）溶液に、ジエチルアゾジカルボキシレート（１１ｍｌ，７０ｍｍｏｌ）を加えた。得られた混合液を室温で３０分間攪拌し、ヘプタン（７３５ｍｌ）を加えた後、ろ過してろ液を濃縮した。トルエンを粗生成物に加えて、得られた溶液をシリカゲルパッド（３０〜７０メッシュ）を用いてろ過した。トルエンで溶出し、次にトルエン／メチレンクロライドの混合液で溶出し、濃縮した後残留物を得た。この残留物をＥｔＯＨから結晶化して２．６．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（１９．７７ｇ，８２％）を得た。
mp : 76.2 °C ;
UV (EtOH) : 227 nm (ε= 20840) ;
IR (KBr) : 1709, 1177 cm^-1 ;
¹H-NMR (CDCl₃) : δ1.7 (3H,m), 2.14 (2H,m), 2.35 (3H,s), 2.48 (1H,m), 2.83 (1H,m), 3.18 (3H,s), 4.75 (1H,m), 5.43 (1H,m), 7.2 (2H,d, J=11.4Hz), 7.5 (2H,d, J=8.5Hz), 7.6 (1H,m), 7.75 (2H,d, J=11.4 Hz), 7.94 (2H,d, J=8.5Hz) ppm ;
[α]_D ²⁵ : -65.8 (c=0.98, EtOH).
【００５２】
ｄ）メチル（１Ｒ，３Ｒ，５Ｒ）−３−ヒドロキシ−５−トシルオキシ−シクロヘキサンカルボキシレート：２．７．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）
２．６．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（１９．７７ｇ，４６ｍｍｏｌ）のＭｅＯＨ懸濁液中に炭酸カリウム（３．１６ｇ，２２．９ｍｍｏｌ）を加えた。得られた混合液を室温で６時間攪拌し、水（１Ｌ）に注いだ。水層をジイソプロピルオキサイドで抽出し、ＭｇＳＯ_４で乾燥し、ろ過した後濃縮して２．７．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（１７．４５ｇ，定量分析）を油状物として得た。
UV (EtOH) : 224 nm (ε= 12262) ;
IR (KBr) : 3525, 1731, 1174 cm^-1 ;
¹H-NMR (CDCl₃) : δ1.67 (3H,m), 2.1 (3H,m), 2.45 (3H,s), 2.85 (1H,m), 3.7 (3H,s), 4.3 (1H,s), 4.82 (1H,m), 7.35 (2H,d, J=8.5Hz), 7.8 (2H,d, J=8.5Hz) ppm ;
[α]_D ²⁵ : -36.7 (c=1.06, CHCl₃)
【００５３】
ｅ）メチル（１Ｒ，３Ｒ，５Ｒ）−３−ｔ−ブチルジメチルシリルオキシ−５−トシルオキシ−シクロヘキサンカルボキシレート：２．８．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）
２．７．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（１７．４５ｇ，４６ｍｍｏｌ）及びイミダゾール（３．９ｇ，５７ｍｍｏｌ）の無水ジメチルホルムアミド（８０ｍｌ）溶液中に、ｔ−ブチルジメチルシリルクロライド（８．６ｇ，５７ｍｍｏｌ）を加えた。得られた混合液を室温で１．５時間攪拌し、水上に注いで、トルエンで抽出した。有機層を水で洗浄した後濃縮した。粗生成物をヘプタンから結晶化し、２．８．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（１３．９４ｇ，６９％）を得た。
mp : 68.2 °C ;
UV (EtOH) : 225 nm (ε= 12390) ;
IR (KBr) : 2853, 1726, 1436, 1359, 1173, 831 cm^-1 ;
¹H-NMR (CDCl₃) : δ0.02 (3H,s), 0.05 (3H,s), 0.82 (9H,s), 1.55 (4H,m), 1.85 (2H,m), 2.45 (3H,s), 2.8 (1H,m), 3.67 (3H,s), 4.2 (1H,bs), 4.7 (1H,m), 7.33 (2H,d, J=8.5Hz), 7.8 (2H,d, J=8.5Hz) ppm ;
[α]_D ²⁵ : -41.6 (c=1.00, EtOH).
【００５４】
ｆ）（２Ｓ，３ａＳ，４ａＳ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｂ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）
攪拌した、６４°Ｃの２．８．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（３７８．５ｇ，８５６ｍｍｏｌ）のｔ−ブタノール溶液に、ゆっくり１時間かけてｔ−ブチル酸カリウムのｔ−ブタノール溶液（１．０２Ｌ）を加えた。添加終了５分後に、得られた懸濁液を３０℃まで冷却し、アンモニウムクロライドの飽和溶液（３Ｌ）を加えた。１０分後、水層をジイソプロピルオキサイドで抽出した。有機層を水で洗浄し、ＭｇＳＯ_４で乾燥し、ろ過した後濃縮した。残留物を、ヘプタン／酢酸エチルの混合溶液を溶離液としてシリカゲル上でフラッシュクロマトグラフィーにより精製し、Ｉ．ｂ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（２１１．３ｇ，９１．３％）を黄色油状物として得た。
Eb₇₆₀ : 135 °C ;
UV (EtOH) : 201 nm (ε= 742) ;
IR (film) 1726 cm^-1, 1458 cm^-1, 1437 cm^-1, 1254 cm^-1, 837 cm^-1 ;
¹H-NMR (CDCl₃) : δ0.01 (6H,s), 0.83 (9H,s), 1.28 (2H,m), 1.8 (2H,m), 2.11 (3H,m), 3.65 (3H,s), 3.9 (1H,m) ppm ;
[α]_D ²⁵ : -43 (c=1.04, EtOH).
【００５５】
実施例２：（２Ｓ，３ａＳ，４ａＳ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−（ヒドロキシメチル）−ビシクロ［３．１．０］ヘキサン：Ｉ．ｂ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）
（２Ｓ，３ａＳ，４ａＳ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサンＩ．ｂ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（２０７．５ｇ，７６８ｍｍｏｌ）のトルエン（２．１Ｌ）溶液（−７０℃）に、１．５Ｍのジイソブチルアンモニウムヒドライドのトルエン溶液（１．２５Ｌ）を１．５時間かけて添加した。添加終了後、酒石酸カリウムナトリウムの飽和溶液をゆっくり加え、０℃まで加熱した。２時間攪拌した後、反応混合液をトルエンで抽出し、有機層をＭｇＳＯ_４で乾燥し、濃縮して標題化合物Ｉ．ｂ．２を黄色油状物として１４２．９ｇ（８８％）得た。
IR (KBr) : 3355, 1471, 1255, 835, 774 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.32 (1H,m), 0.5 (1H,m), 0.83 (9H,s), 1.16 (1H,m), 1.87 (5H,m), 3.54 (2H,m), 4.0 (1H,m) ppm
【００５６】
実施例３：（２Ｓ，３ａＳ，４ａＳ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサン：Ｉ．ｂ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）
Ｉ．ｂ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）（６９．６ｇ，２８７ｍｍｏｌ）のメチレンクロライド（７００ｍｌ）溶液にピリジニウムクロロクロメート（６８ｇ，３１５ｍｍｏｌ）を室温で添加した。得られた混合液を１時間力強く攪拌した。３５℃まで加熱し、次に２５℃まで冷却した。懸濁液をセライトのパッドを用いてろ過し、メチレンクロライド及びジイソプロピルオキサイドで洗浄した。有機層を順に、水、炭酸水素ナトリウムの飽和溶液、ｐＨ６〜７の水で洗浄した。結合した有機層をＭｇＳＯ_４で乾燥し、ろ過した後濃縮した。残留物（６６．８ｇ）をヘプタン／酢酸エチル＝９５／５（Ｖ／Ｖ）を溶離液としてフロリジル上でフラッシュクロマトグラフィーにより精製し、Ｉ．ｂ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）を黄色油状物（５０．３３ｇ，７３％）として得た。
UV (EtOH) : 204 nm (ε= 6292) ;
IR (KBr) : 1726, 1253, 1119, 838 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.87 (9H,s), 1.3 (2H,m), 1.85 (2H,m), 2.1 (3H,m), 4 (1H,m), 8.9 (1H,s) ppm ;
[α]_D ²⁵ : -49.4 (c=1.06, EtOH).
【００５７】
実施例４：（２Ｒ，３ａＲ，４ａＲ）２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｈ．１（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３，Ｐ＝ＴＢＤＭＳ）
ａ）メチル（１Ｒ，３Ｓ，５Ｓ）−３−アセトキシ−５−ベンゾイルオキシ−シクロヘキサンカルボキシレート：３．９．ａ（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３）２．６．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）で述べたように、メチル（１Ｓ，３Ｓ，５Ｒ）−３−アセトキシ−５−ヒドロキシ−シクロヘキサンカルボキシレート２．Ａ（Ｒ＝Ｈ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）（２５ｇ，１１１．３ｍｍｏｌ）をメチル（１Ｒ，３Ｓ，５Ｓ）３−アセトキシ−５−ベンゾイルオキシ−シクロヘキサンカルボキシレート３．９．ａ（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３）（３２．４ｇ，９１％）に変換した。
¹H-NMR (CDCl₃) : δ1.68 (3H,m), 2.05 (3H,s), 2.34 (3H,m), 2.92 (1H,m), 3.70 (3H,s), 5.18 (1H,m), 5.55 (1H,m), 7.50 (3H,m), 8.05 (2H,m) ppm ;
[α]_D ²⁵: +42.3 (c=0.82, CHCl₃)
【００５８】
ｂ）メチル（１Ｒ，３Ｓ，５Ｓ）−５−ベンゾイルオキシ−３−ヒドロキシ−シクロヘキサンカルボキシレート：３．１０．ａ（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３）メチル（１Ｒ，３Ｓ，５Ｓ）−３−アセトキシ−５−ベンゾイルオキシ−シクロヘキサンカルボキシレート：３．９．ａ（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３）（３２．４ｇ，１５１，９ｍｍｏｌ）を２．５．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様に加水分解した。粗精製物をシリカゲル上でフラッシュクロマトグラフィーにより精製し、３．１０．ａ（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３）（２２．３８ｇ，７９．５％）を得た。
¹H-NMR (CDCl₃) : δ 1.63 (4H,m), 1.92 (1H,s), 2.3 (2H,m), 2.86 (1H,m), 3.7 (3H,s), 4.1 (1H,m), 5.53 (1H,m), 7.5 (3H,m), 8.0 (2H,m) ppm ;
[α]_D ²⁵ : -13.5 (c=1.43, CHCl₃)
【００５９】
ｃ）メチル（１Ｓ，３Ｓ，５Ｓ）− ５−ベンゾイルオキシ−３−トシルオキシ−シクロヘキサンカルボキシレート：３．１１．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）
アルコール３．１０．ａ（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３）（２５．２ｇ，９０．８８ｍｍｏｌ）を２．４．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様にトシラート化した。フラッシュクロマトグラフィー（ヘプタン／酢酸エチル＝７／３）により精製し、及びヘプタン／ＥｔＯＨから結晶化することにより標題化合物３．１１．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（３９．７５ｇ）を計量可能な収量で得た。
mp : 128.4 °C ;
IR (KBr) : 2950, 1715, 1175, 939 cm^-1 ;
¹H-NMR (CDCl₃) : δ1.7 (3H,m), 2.18 (2H,m), 2.38 (3H,s), 2.5 (1H,m), 2.85 (1H,m), 3.68 (3H,s), 4.76 (1H,m), 5.43 (1H,m), 7.19 (2H,d), 7.5 (2H,d), 7.58 (1H,m), 7.77 (2H,d), 7.96 (2H,d) ppm ;
[α]_D ²⁵ : +69 (c=1.014, CHCl₃).
【００６０】
ｄ）メチル（１Ｓ，３Ｓ，５Ｓ）−５−ヒドロキシ−３−トシルオキシ−シクロヘキサンカルボキシレート：３．１２．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）
３．１１．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（３８．２５ｇ，８８．４ｍｍｏｌ）から２．７．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様にして、メチル（１Ｓ，３Ｓ，５Ｓ）−５−ヒドロキシ−３−トシルオキシ−シクロヘキサンカルボキシレート３．１２．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（２９．２５ｇ）を黄色油状物として計量可能な収量で得た。
¹H-NMR (CDCl₃) : δ1.6 (4H,m), 2.08 (3H,m), 2.47 (3H,s), 2.83 (1H,m), 3.68 (3H,s), 4.3 (1H,m), 4.82 (1H,m), 7.36 (2H,d), 7.8 (2H,d) ppm.
【００６１】
ｅ）メチル（１Ｓ，３Ｓ，５Ｓ）−５−ｔ−ブチルジメチルシリルオキシ−３−トシルオキシ−シクロヘキサンカルボキシレート：３．１３．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）
３．１２．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（２９．２ｇ，８９．０７ｍｍｏｌ）から２．８．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。シリカゲル上のフラッシュクロマトグラフィー（ヘプタン／酢酸エチル＝８／２）により精製し、３．１３．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（３４．８ｇ，８８％）を黄色油状物として得た。
IR (film) : 2953, 2855, 1725, 1278, 1177, 949 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,d), 0.85 (9H,s), 1.55 (3H,m), 1.88 (2H,m), 2.38 (1H,s), 2.48 (3H,s), 2.82 (1H,m), 3.7 (3H, s), 4.2 (1H, m), 4.7 (1H,m), 7.8 (2H, d), 8.09 (2H,d) ppm ;
[α]_D ²⁵ : +29.5 (c=1.06, EtOH)
【００６２】
ｆ）（２Ｒ，３ａＲ，４ａＲ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｈ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）
３．１３．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（３３．２ｇ，７５ｍｍｏｌ）からＩ．ｂ．１（Ａ＝ＣＯＯＣＨ_３，Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ）と同様に反応を行なった。シリカゲル上のフラッシュクロマトグラフィー（ヘプタン／酢酸エチル＝９５／５）により精製し、（２Ｒ，３ａＲ，４ａＲ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサンＩ．ｈ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（１５．５ｇ，７８％）を黄色油状物として得た。
IR (film) : 2952, 2856, 1724, 1113, 837 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.85 (9H,s), 1.11 (1H,d), 1.27 (2H,m), 1.6 (3H,s), 1.8 (1H,m), 2.11 (3H,m), 3.65 (3H, s), 3.9 (1H, m) ppm ;
[α]_D ²⁵ : +38.3 (c=1.122, EtOH)
【００６３】
実施例５：（２Ｒ，３ａＲ，４ａＲ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−（ヒドロキシメチル）−ビシクロ［３．１．０］ヘキサン：Ｉ．ｈ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）
（２Ｒ，３ａＲ，４ａＲ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサンＩ．ｈ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（１５．１５ｇ，５６ｍｍｏｌ）をＩ．ｂ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）と同様の条件を用いてＩ．ｈ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）（１１．８５ｇ，８７％）に変換した。
IR (film) : 3354, 2928, 2856, 1255, 835 cm^-1 ;
¹H-NMR (CDCl₃) : δ 0.1 (6H,s), 0.35 (1H,t), 0.5 (1H,t), 0.86 (9H,s), 1.17 (1H,s), 1.85 (5H,m), 3.52 (2H,m), 4.0 (1H, m) ppm ;
[α]_D ²⁵ : +17.4 (c=1.15, EtOH)
【００６４】
実施例６：（２Ｒ，３ａＲ，４ａＲ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサン：Ｉ．ｈ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）
Ｉ．ｈ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）（１１．３ｇ，４６．６ｍｍｏｌ）からＩ．ｂ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）の方法に従って、Ｉ．ｈ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）（６．２ｇ，５５％）を黄色油状物として得た。
UV (EtOH) : 204.5 mm (ε= 6600) ;
IR (film) : 2930, 2880, 2856, 1705, 1119, 1097, 836 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.83 (9H,s), 0.95 (1H,t), 1.22 (2H,m), 1.85 (2H,m), 2.1 (3H,m), 4.0 (1H,quintuplet), 8.87 (1H, s) ppm ;
[α]_D ²⁵ : +53.6 (c=1.008, EtOH)
【００６５】
実施例７：（２Ｒ，３ａＲ，４ａＲ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ａ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）
ａ．メチル（１Ｒ，３Ｓ，５Ｒ）−３−ｔ−ブチルジメチルシリルオキシ−５−トシルオキシ−シクロヘキサンカルボキシレート：２．３．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）
メチル（１Ｒ，３Ｓ，５Ｒ）−３−ヒドロキシ−５−トシルオキシ−シクロヘキサンカルボキシレート：２．５．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（２９．３ｇ，８９．２ｍｍｏｌ）のヒドロキシ官能基は２．８．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）と同様に保護され、２．３．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（３６，７５ｇ，９３％）を得た。
mp : 70.9 °C ;
IR (KBr) : 2957, 2855, 1734, 1174, 923 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.82 (9H,s), 1.41 (3H,m), 2.16 (4H,m), 2.46 (3H,s), 3.54 (1H,m), 3.69 (3H,s), 4.41 (1H,m), 7.34 (2H,d), 7.8 (2H,d) ppm ;
[α]_D ²⁵ : -8.2 (c=1.2, EtOH)
【００６６】
ｂ）（２Ｒ，３ａＳ，４ａＳ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ａ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）
２．３．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（３４．８１ｇ，７８．６ｍｍｏｌ）から、Ｉ．ｂ．１（Ａ＝ＣＯＯＣＨ_３，Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ）と同様に反応を行なった。シリカゲル上のフラッシュクロマトグラフィー（ヘプタン／酢酸エチル＝５／５）により精製し、Ｉ．ａ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（１６．６ｇ，７８％）を黄色油状物として得た。
IR (film) : 2953, 2855, 1726, 1148, 836 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.86 (9H,s), 1.5 (5H,m), 2.1 (1H,m), 2.48 (1H,m), 3.68 (3H,s), 4.33 (1H,t) ppm ;
[α]_D ²⁵ : -60.1 (c=0.998, EtOH)
【００６７】
実施例８：（２Ｒ，３ａＳ，４ａＳ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−（ヒドロキシメチル）−ビシクロ［３．１．０］ヘキサン：Ｉ．ａ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）．
Ｉ．ａ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）（１５．６ｇ，５７．７ｍｍｏｌ）からＩ．ｂ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）と同様に反応を行なった。Ｉ．ａ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）（１１．７ｇ，８３．７％）を黄色油状物として得た。
IR (film) : 3331, 2927, 2855, 1254, 1094, 1006, 835 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.5 (1H,m), 0.88 (9H,s), 1.19 (3H,m), 1.72 (2H,m), 2.1 (2H,m), 3.6 (2H,s), 4.34 (1H,t) ppm ;
[α]_D ²⁵ : -23.5 (c=1.062, EtOH)
【００６８】
実施例９：（２Ｒ，３ａＳ，４ａＳ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサン：Ｉ．ａ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，ＣＨＯ）．
Ｉ．ａ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）（１１．１ｇ，４５．５ｍｍｏｌ）から、Ｉ．ｂ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）と同様にして、Ｉ．ａ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）（８．８ｇ，８０％）を黄色油状物として得た。
UV (EtOH) : 204.7 nm (ε= 6991) ;
IR (film) : 2928, 2855, 1702, 1255, 1072, 837 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.85 (9H,s), 1.45 (1H,m), 1.78 (3H,m), 2.02 (2H,m), 2.5 (1H,m), 4.35 (1H,m), 8.81 (1H,s) ppm ;
[α]_D ²⁵ : -71.8 (c=1.406, EtOH)
【００６９】
実施例１０：（２Ｓ，３ａＲ，４ａＲ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｆ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）．
ａ）メチル（１Ｒ，３Ｓ，５Ｒ）−３−アセトキシ−５−ｔ−ブチルジメチルシリルオキシ−シクロヘキサンカルボキシレート：３．７．ａ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）
メチル（１Ｓ，３Ｓ，５Ｒ）−３−アセトキシ−５−ヒドロキシ−シクロヘキサンカルボキシレート２．Ａ（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３）（４５．５ｇ，０．２１０ｍｍｏｌ）のヒドロキシ官能基を２．８．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）と同様にシリレート化した。ヘプタン／酢酸エチル（９／１）混合液を溶離液としてシリカゲル上のフラッシュクロマトグラフィーにより精製し、３．７．ａ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（６９．９７ｇ，９２％）を黄色油状物として得た。
IR (film) : 2953, 2856, 1736, 1240 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.8 (9H,s), 1.33 (4H,m), 2 (3H,s), 2.1 (2H,m), 2.32 (1H,m), 3.55 (1H,m), 3.62 (3H,s), 4.66 (1H,m) ppm
【００７０】
ｂ）メチル（１Ｒ，３Ｓ，５Ｒ）−５−ｔ−ブチルジメチルシリルオキシ−３−ヒドロキシ−シクロヘキサンカルボキシレート：３．８．ａ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）
３．７．ａ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（６３．６７ｇ，０．１９２６ｍｍｏｌ）から２．５．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。ヘプタン／酢酸エチル（７／３）を溶離液としてシリカゲル上のフラッシュクロマトグラフィーにより精製し、３．８．ａ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（４６，２４ｇ，８３％）を黄色油状物として得た。
IR (film) : 3404, 2952, 2856, 1736, 837 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.81 (9H,s), 1.3 (3H,m), 1.67 (1H,m), 2.13 (4H,m), 3.56 (2H,m), 3.63 (3H,s) ppm ;
[α]_D ²⁵ : +6.8 (c=1.036, CHCl₃).
【００７１】
ｃ）メチル（１Ｓ，３Ｓ，５Ｒ）−５−ｔ−ブチルジメチルシリルオキシ−３−トシルオキシ−シクロヘキサンカルボキシレート：３．６．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）
３．８．ａ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（４５．９９ｇ，０．１５９ｍｍｏｌ）から２．４．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。ヘプタン／酢酸エチル（８／２）を溶離液としてシリカゲル上のフラッシュクロマトグラフィーにより精製し、次にＥｔＯＨから結晶化し３．６．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（５３．７ｇ，７６％）を得た。
mp : 71 °C ;
IR (KBr) : 2957, 2855, 1734, 1174, 923 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.82 (9H,s), 1.41 (3H,m), 2.16 (4H,m), 2.46 (3H,s), 3.54 (1H,m), 3.69 (3H,s), 4.41 (1H,m), 7.34 (2H,d), 7.8 (2H,d) ppm ;
[α]_D ²⁵ : +6.8 (c=1.032, EtOH).
【００７２】
ｄ）（２Ｓ，３ａＲ，４ａＲ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｆ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）．
３．６．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（５３．７ｇ，０．１２１ｍｍｏｌ）からＩ．ｂ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。Ｉ．ｆ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（２４．４８ｇ，７４．６％）を淡黄色油状物として得た。
IR (film) : 2953, 2856, 1726, 1148, 836 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.86 (9H,s), 1.5 (5H,m), 2.1 (1H,m), 2.48 (1H,m), 3.68 (3H,s), 4.33 (1H,t) ppm ;
[α]_D ²⁵ : +62.9 (c 1.066, EtOH).
【００７３】
実施例１１：（２Ｓ，３ａＲ，４ａＲ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−（ヒドロキシメチル）−ビシクロ［３．１．０］ヘキサン：Ｉ．ｆ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）
Ｉ．ｆ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（１０ｇ，０．０３７ｍｍｏｌ）からＩ．ｂ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）と同様にして反応を行なった。Ｉ．ｆ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）を油状物として計量可能な収量（１０ｇ）で得た。
IR (film) : 3331, 2927, 2855, 1254, 1094, 1006, 835 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.5 (1H,m), 0.88 (9H,s), 1.19 (3H,m), 1.72 (2H,m), 2.1 (2H,m), 3.6 (2H,s), 4.34 (1H,t) ppm ;
[α]_D ²⁵ : +23.2 (c=0.99, EtOH)
【００７４】
実施例１２：（２Ｓ，３ａＲ，４ａＲ）−２−ｔ−ブチルジメチルシリルオキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサン：Ｉ．ｆ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）．
Ｉ．ｂ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）に関して、Ｉ．ｆ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）（１０ｇ，０．０３７ｍｍｏｌ）を淡黄色油状物として得られるＩ．ｆ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）（５．３ｇ，５９．７％）に変換した。
IR (film) : 2928, 2855, 1702, 1255, 1072, 837 cm^-1 ;
¹H-NMR (CDCl₃) : δ0 (6H,s), 0.85 (9H,s), 1.45 (1H,m), 1.78 (3H,m), 2.02 (2H,m), 2.5 (1H,m), 4.35 (1H,m), 8.81 (1H,s) ppm ;
UV (EtOH) : 205 nm ;
[α]_D ²⁵ : +70.4 (c=1.1 , EtOH).
【００７５】
実施例１３：（２Ｓ，３ａＳ，４ａＳ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−ｃカルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｂ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
ａ）メチル（１Ｒ，３Ｓ，５Ｒ）−３−アセトキシ−５−（４−ブロモベンゼンスルホニルオキシ）−シクロヘキサンカルボキシレート：２．４．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ａ＝ＣＯＯＣＨ_３）．
２．Ａ（Ｒ＝Ｈ）（１．４ｇ，６．４７ｍｍｏｌ）及び４−ブロモベンゼンスルホニルクロライド（４．２２ｇ，１６．１９ｍｍｏｌ）から２．４．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ）と同様にして反応を行なった。２．４．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ａ＝ＣＯＯＣＨ_３）（２．６ｇ，９６％）を白色結晶として得た。
mp : 110-111 °C ;
IR (film) : 2956, 1734, 1363, 1246, 1188, 822, 742 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ7.76 (2H, d, J=8.6Hz), 7.70 (2H, d, J=8.6Hz), 4.68 (1H, dddd, J=11.6, 11.6, 4.37, 4.37Hz), 4.46 (1H, dddd, 11.6, 11.6, 4.6, 4.6Hz), 3.69 (3H, s), 2.37 (1H, m), 2.28 (2H, m), 2.02 (3H, s), 1.58 (2H, m), 1.39 (1H, dd, J=24.0, 12.4Hz) ppm ;
MS (m/z) : 419 (M⁺, 1), 405 (1), 363 (3), 221 (10), 157 (34), 138 (70), 107 (15), 79 (68) ;
[α]_D ²⁵ : -10.65 (c=1.50, CHCl₃).
【００７６】
ｂ）メチル（１Ｒ，３Ｓ，５Ｒ）−５−（４−ブロモベンゼンスルホニルオキシ）−３−ヒドロキシ−シクロヘキサンカルボキシレート：２．５．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ａ＝ＣＯＯＣＨ_３）．
２．４．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ａ＝ＣＯＯＣＨ_３）（２．５５ｇ，６．０８ｍｍｏｌから、２．５．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ）と同様にして反応を行なった。２．５．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ａ＝ＣＯＯＣＨ_３）（２．２５ｇ，９８％）を白色結晶として得た。
mp : 95-98 °C ;
IR (film): 3397, 2954, 1734, 1396, 1186, 815, 740 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ7.76 (2H, d, J=8.6Hz), 7.70 (2H, d, J=8.6Hz), 4.46 (1H, dddd, J=11.5, 11.5, 4.5, 4.5Hz), 3.68 (3H, s), 3.64 (1H, m), 2.25 (4H, m), 1.60 (1H, dd, J=24.2, 12.5Hz), 1.48 (1H, dd, J=23.0, 11.5Hz), 1.35 (1H, dd, J=23.8, 12.5Hz) ppm ;
MS (m/z) : 377 (M⁺,1), 328 (3), 235 (10), 221 (13), 156 (85), 113 (100), 97 (52), 79 (53) ;
[α]_D ²⁵ : -17.13 (c=1.48, CHCl₃).
【００７７】
ｃ）メチル（１Ｒ，３Ｒ，５Ｒ）−３−ベンゾイルオキシ−５−（４−ブロモベンゼンスルホニルオキシ）−シクロヘキサンカルボキシレート：２．６．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ａ＝ＣＯＯＣＨ_３）
２．５．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ａ＝ＣＯＯＣＨ_３）（１．１５ｇ，３．０５ｍｍｏｌ）から、２．６．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。収率は１．１３ｇ（７３％）であった。
mp : 131-133 °C ;
IR (film) : 3420, 2948, 1717, 1362, 1186, 817, 707 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 7.95 (2H, d, J=7.4Hz), 7.72 (2H, d, J= 8.5Hz), 7.60 (1H, t, J=7.4Hz), 7.58 (2H, d, J=8.5Hz), 7.49 (2H, t, 7.7Hz), 5.46 (1H, m), 4.81 (1H, dddd, J=11.3, 11.3, 4.4, 4.4Hz), 2.85 (1H, dddd, J=12.5, 12.5, 3.7, 3.7Hz), 2.47 (1H, m), 2.20 (2H, m), 1.73 (3H, m) ppm ;
MS (m/z) : 497 (M⁺,1), 391 (4), 377 (10), 260 (100), 237 (8), 221 (25) ;
[α]_D ²⁵ : -59.32 (c=1.79, CHCl₃).
【００７８】
ｄ）メチル（１Ｒ，３Ｒ，５Ｒ−５−（４−ブロモベンゼンスルホニルオキシ）−３−ヒドロキシ−シクロヘキサンカルボキシレート：２．７．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ａ＝ＣＯＯＣＨ_３）．
２．６．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ａ＝ＣＯＯＣＨ_３）（２４０ｍｇ，０．４８３ｍｍｏｌ）から、２．７．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。収率は１６７ｍｇ（８８％）であった。
mp : 107-108 °C.
IR (film) : 3527, 2954, 1732, 1577, 1365, 1187, 940, 818 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ7.78 (2H, d, J=8.6Hz), 7.70 (2H, d, J= 8.6Hz), 4.87 (1H, dddd, J=10.9, 10.9, 4.5, 4.5 Hz), 4.31 (1H, m), 3.69 (3H, s), 2.86 (1H, dddd, J=12.1, 12.1, 3.7, 3.7Hz), 2.24 (1H, d, J=12.7Hz), 2.04 (1H, d, J=11.7Hz),1.94 (1H, d, J=14.0Hz), 1.65 (3H, m) ppm ;
MS (m/z) : 394 (M⁺+1, 1), 295 (2), 221 (4), 157 (11), 97 (10) ;
[α]_D ²⁵ : -38.75 (c=0.80, CHCl₃).
【００７９】
ｅ）メチル（１Ｒ，３Ｒ，５Ｒ）−５−（４−ブロモベンゼンスルホニルオキシ）−３−ｔ−ブチルジフェニルシリルオキシ−シクロヘキサンカルボキシレート：２．８．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
２．７．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ａ＝ＣＯＯＣＨ_３）（２９９ｍｇ，０．７６０ｍｍｏｌ）から、２．８．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。２．８．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（１９８ｍｇ，９３％）を粘性油状物として得た。
IR (film) : 2955, 1738, 1577, 1472, 1370, 1180, 947, 821, 703 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ7.71 (2H, d, J=8.8Hz), 7.34-7.60 (12H, m), 4.87 (1H, m), 4.17 (1H, bs), 3.78 (3H, m), 2.98 (1H, dddd, J=9.1, 9.1, 3.5, 3.5 Hz), 2.39 (1H, d, J=11.9Hz), 1.89 (1H, d, J=13.9Hz), 1.79 (1H, d, J=12.3Hz), 1.63 (1H, m), 1.34 (2H, m), 1.02 (9H, s), 0.91 (3H, s) ppm ;MS (m/z) : 599 (M⁺, 1), 419 (28), 337 (34), 293 (8), 199 (46), 139, (100), 107 (50), 79 (72) ;
[α]_D ²⁵ : +1.49 (c=1.75, CHCl₃).
【００８０】
ｆ）（２Ｓ，３ａＳ，４ａＳ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｂ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
Ｉ．ｂ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして、化合物２．８．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（２０６ｍｇ，０．３４４ｍｍｏｌ）をＩ．ｂ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（７９ｍｇ，７６％）に変換し、無色油状物を得た。．
IR (film) : 2952, 1725, 1428, 1113, 703 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ7.64 (4H, dd, J=6.20, 6.20Hz), 7.35-7.45 (6H, m), 3.89 (1H, dddd, J=7.7, 7.7, 7.7, 7.7Hz), 3.65 (3H, s), 2.28 (1H, dd, J=12.9, 8.2Hz), 2.12 (1H, dd, J=12.9, 7.1Hz), 1.91 (2H, m), 1.77 (1H, ddd, J=8.6, 5.0, 5.0Hz), 1.19 (1H, dd, J=8.6, 4.8Hz), 1.02 (9H, s), 0.44 (1H, dd, J=5.1, 5.1Hz) ppm .9, 7.1Hz), 1.91 (2H, m), 1.77 (1H, ddd, J=8.6, 5.0, 5.0Hz), 1.19 (1H, dd, J=8.6, 4.8Hz), 1.02 (9H, s), 0.44 (1H, dd, J=5.1, 5.1Hz) ppm
MS (m/z) : 394 (M⁺, 1), 363 (4), 337 (65), 259 (3), 213 (100), 199 (20), 135 (18), 77 (21) ;
[α]_D ²⁵ : -73.14 (c=1.75, CHCl₃).
【００８１】
実施例１４：（２Ｓ，３ａＳ，４ａＳ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−（ヒドロキシメチル）−ビシクロ［３．１．０］ヘキサン：Ｉ．ｂ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）．
Ｉ．ｂ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（１８８ｍｇ，１．２５３ｍｍｏｌ）から、Ｉ．ｂ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）と同様にして反応を行なった。シリカゲル上のフラッシュクロマトグラフィー（イソオクタン／酢酸エチル８３：１７）により精製し、Ｉ．ｂ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）（２４０ｍｇ，９６％）を粘性油状物として得た。
IR (film) : 3322, 2932, 1428, 1113, 702 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ7.75 (4H, m), 7.58 (6H, m), 3.97 (1H, dddd, J=7.1, 7.1, 7.1, 7.1Hz), 3.56 (2H, bs), 1.84-2.05 (3H, m), 1.12 (1H, m), 1.03 (9H, s), 0.34 (1H, dd, J=7.8, 5.4Hz), 0.13 (1H, dd, J=4.6, 4.6Hz) ppm ;
MS (m/z) :365 (M⁺-1, 1), 291 (3), 231 (10), 199 (100), 181 (12), 139 (27), 93 (77), 79 (24) ;
[α]_D ²⁵ : -25.74 (c=2.16, CHCl₃).
【００８２】
実施例１５：（２Ｓ，３ａＳ，４ａＳ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサン：Ｉ．ｂ．６（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）．
Ｉ．ｂ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）（２３０ｍｇ，０．６２７ｍｍｏｌ）から、Ｉ．ｂ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）と同様にして反応を行なった。Ｉ．ｂ．６（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）の収量は２１０ｍｇ（９２％）であった。
IR (film) : 3439, 3061, 2954, 2858, 1704, 1589, 1471, 1111, 1036, 823, 703 cm^-1 ;¹H-NMR (500 MHz, CDCl₃) : δ 8.85 (1H, s), 7.68-7.60 (4H, m), 3.99 (1H, q, J=7.4Hz), 2.30 (1H, dd, J=13.1, 8.0Hz), 2.03-1.98 (2H, m), 1.93-1.87 (2H, m), 1.22 (1H, dd, J=8.4, 6.0Hz), 1.02 (9H, s), 0.74 (1H, dd, J=5.3, 5.3Hz) ppm ;
[α]_D ²⁵ : -90.00 (c 1.00, CHCl₃).
【００８３】
実施例１６：（２Ｓ，３ａＳ，４ａＳ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−エチニル−ビシクロ［３．１．０］ヘキサン：Ｉ．ｂ．７（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝Ｃ≡ＣＨ）．
−７８℃に冷却した（ＭｅＯ）_２Ｐ（Ｏ）ＣＨＮ_２（１８８ｍｇ，１．２５３ｍｍｏｌ）のＴＨＦ（３ｍｌ）溶液にｔ−ＢｕＯＫ（１．２６ｍｌ，１．２６ｍｍｏｌ，ＴＨＦ中１．０Ｍ溶液）を滴下した。得られた混合液を黄色が残っている間、−７８℃で２０分間攪拌した。Ｉ．ｂ．６（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）（３８０ｍｇ，１．０４３ｍｍｏｌ）のＴＨＦ（３ｍｌ）溶液をゆっくり添加し、一晩攪拌した。温度は自然に−７８℃から室温に上がった。水（１０ｍｌ）とＥｔ_２Ｏ（２０ｍｌ）を加えて反応を終了させ、有機層を分離した後水層をＥｔ_２Ｏ（３ ×５０ｍｌ）で抽出し、ＭｇＳＯ_４で乾燥させた。残留物をＨＰＬＣ（ヘキサン／ＥｔＯＡｃ９６：４）で分離し、化合物Ｉ．ｂ．７（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝Ｃ≡ＣＨ）（３３８ｍｇ，９０％）を無色油状物として得た。
IR (film) : 3291, 3072, 2932, 2143, 1590, 1473, 1428, 1114, 1091, 824, 741 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 7.61-7.63 (4H, m), 7.34-7.43 (6H, m), 3.81 (1H, q, J=7.6Hz), 2.16 (1H, dd, J=12.5, 7.13Hz), 2.02 (1H, ddd, J=12.5, 8.1, 0.9Hz), 1.95 (1H, m), 1.93 (1H, s), 1.56 (1H, m), 1.02 (9H, s), 0.70 (1H, dd, J=8.3, 5.1Hz), 0.31 1H, t, J=5.0Hz) ppm ;
[α]_D ²⁵ : -86.30 (c=1.60, CHCl₃).
【００８４】
実施例１７：（２Ｓ，３ａＲ，４ａＲ−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｆ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
ａ）メチル（１Ｒ，３Ｒ，５Ｓ）−３−ｔ−ブチルジフェニルシリルオキシ−５−ヒドロキシ−シクロヘキサンカルボキシレート：３．８．ｂ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
２．Ａ（Ｒ＝Ｈ，Ａ＝ＣＯＯＣＨ_３）及びＴＢＤＰＳＣｌから、３．７．ｂ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）を用いて、実施例４の３．８．ａ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）と同様に反応を行なった。標題化合物を粘性油状物として得た；２段階に対して収率は９２％であった。
IR (film) : 3404, 2952, 1738, 1428, 1112, 1049, 807, 710 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 7.66 (4H, m), 7.40 (6H, m), 3.65 (3H; s), 3.60 (1H, dddd, J=10.9, 10.9, 4.3, 4.3 Hz), 3.41 (1H, m), 2.11 (4H, m), 1.50 (1H, dd, J=12.6, 12.6 Hz), 1.41 (1H, d, J=5.2 Hz), 1.34 (3H, m) ppm ;
MS (m/z) : 412 (M⁺, 1), 355 (5), 323 (67), 199 (100), 153 (37), 105 (21), 79 (85) ;
[α]_D ²⁵ : -16.44 (c=1.60, CHCl₃).
【００８５】
ｂ）メチル（１Ｓ，３Ｒ，５Ｓ）−３−ｔ−ブチルジフェニルシリルオキシ−５−トシルオキシ−シクロヘキサンカルボキシレート：３．６．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
３．８．ｂ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、２．４．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様に反応を行い、３．６．ｂを粘性油状物として得た。収率９４％であった。
IR (film) : 2955, 1738, 1363, 1178, 1111, 824, 704 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 7.69 (2H, d, J=8.3Hz), 7.58 (4H, m), 7.28 (2H, d, J=8.1Hz), 4.18 (1H, dddd, J=11.6, 11.6, 4.6, 4.6Hz) 3.62 (3H; s), 3.48 (1H, dddd, J=11.1, 11.1; 4.1, 4.1 Hz), 2.47 (3H, s), 2.15-1.99 (4H, m), 1.52 (1H, ddd, J=5.6, 5.57, 5.6Hz), 1.42 (1H, ddd, J=12.0, 12.0, 12.0Hz), 0.98 (9H, s) ppm ;
MS (m/z) : 567 (M⁺, 1), 509 (9), 451 (1), 353 (49), 337 (67), 293 (38), 213 (47), 139 (32), 91 (100), 79 (77) ;
[α]_D ²⁵ : +2.39 (c=1.17, CHCl₃).
【００８６】
ｃ）（２Ｓ，３ａＲ，４ａＲ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｆ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
３．６．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＢｒｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）からＩ．ｂ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）と同様に反応を行なった。収率は８１％であった。
IR (film) : 3287, 2934, 1732, 1457, 1281, 1017 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 3.73 (2H, m), 3.72 (3H; s), 2.53 (1H, dddd, J=12.2, 12.2, 3.4, 3.4 Hz), 2.26 (1H, d, J=11.3Hz), 2.17 (2H, d, J=11.7 Hz), 1.30 (2H, ddd, J=12.0, 12.0, 12.0 Hz), 1.23 (1H, ddd, J=11.4, 11.4, 11.4 Hz) ppm ;
MS (m/z) : 394 (M⁺, 1), 337 (31), 259 (5), 199 (55), 153 (48), 107 (100), 79 (52) ;
[α]_D ²⁵ : +31.97 (c=1.71, CHCl₃)
【００８７】
実施例１８：（２Ｓ，３ａＲ，４ａＲ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−（ヒドロキシメチル）−ビシクロ［３．１．０］ヘキサン：Ｉ．ｆ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）．
Ｉ．ｆ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、Ｉ．ｂ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）と同様に反応を行い，（２Ｓ，３ａＲ，４ａＲ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−（ヒドロキシメチル）−ビシクロ［３．１．０］ヘキサンＩ．ｆ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）を収率９８％で得た。
IR (film) : 3332, 2931, 1428, 1111, 1008, 822, 702 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 7.62 (4H, dd, J=7.9, 1.5Hz), 7.39 (6H, m), 4.37 (1H, t, J=6.27Hz), 3.57 (2H; s), 1.90-2.02 (3H, m), 1.80 (1H, d, J=13.8Hz), 1.21 (1H, t, J=4.1Hz), 1.15 (1H, m), 1.03 (9H, s), 0.60 (1H, m) ppm ;
MS (m/z) : 365 (M⁺-1, 1), 291 (6), 231 (17), 199 (100), 181 (17), 139 (28), 93 (79), 79 (16) ;
[α]_D ²⁵ : +5.56 (c=1.5, CHCl₃).
【００８８】
実施例１９：（２Ｓ，３ａＲ，４ａＲ）−２−ｔ−−ブチルジフェニルシリルオキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサン：Ｉ．ｆ．６（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）．
Ｉ．ｆ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）から、Ｉ．ｂ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）と同様にして反応を行なった。収率は９６％であった。
IR (film) : 2956, 1704, 1590, 1472, 1428, 1112, 1072, 822, 702 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 8.85 (1H, s), 7.61 (4H, m), 7.43 (2H, dt, J=7.0, 1.0Hz), 7.37 (4H, dt, J=7.0, 1.0Hz), 4.40 (1H, t, J=6.0Hz), 2.39 (1H, dd, J=14, 6.0Hz), 1.89 (1H, d, J=13.0Hz), 1.86 (1H, d, J=14.0Hz), 1.53 (1H, m), 1.04 (9H, s) ppm ;
[α]_D ²⁵ : +34.4 (c=1.6, CHCl₃).
【００８９】
実施例２０：（２Ｓ，３ａＲ，４ａＲ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−エチニル−ビシクロ［３．１．０］ヘキサン：Ｉ．ｆ．７（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝Ｃ≡ＣＨ）．
Ｉ．ｆ．６（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）から、Ｉ．ｂ．７（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝Ｃ≡ＣＨ）と同様にして反応を行なった。収率は８８％であった。
IR (film) : 3310 (s), 3071, 2931, 2857, 2113, 1590, 1472, 1428, 1378, 1362, 1299, 1262, 1234, 1198, 1113, 1026, 933, 913, 865, 822, 701 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ7.60 (4H, m), 7.42 (2H, td, J=2, 8Hz), 7.37 (4H, td, J=1, 8Hz), 4.32 (1H, m), 2.06 (2H, m), 2.04 (1H, dt, J=6, 14Hz), 1.90 (1H, s), 1.80 (1H, d, J=14Hz), 1.65 (1H, dt, J=5, 10Hz), 1.49 (1H, t, J=5Hz), 1.03 (9H, s), 1.03 (1H, m) ;
[α]_D ²⁵: +21.4 (c=1.2, CHCl₃)
【００９０】
実施例２１：（２Ｒ，３ａＳ，４ａＳ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−カルボメトキシ−エチニル−ビシクロ［３．１．０］ヘキサン：Ｉ．ａ．４Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
ａ）メチル（１Ｒ，３Ｓ，５Ｒ）−３−ｔ−ブチルジフェニルシリルオキシ−５−トシルオキシ−シクロヘキサンカルボキシレート：２．３．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
２．５．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）から、２．８．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。収率は９１％であった。
IR (film) : 2932, 2857, 1736, 1428, 1364, 1177, 1107, 929, 822, 703, 665 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 7.69 (2H, d, J=8.3Hz), 7.57 (4H, dm, J=7Hz), 7.44 (2H, q, J=7Hz), 7.36 (4H, t, J=8Hz), 7.28 (2H, d, J=8.4Hz), 4.16 (1H, tt, J=4, 12Hz), 3.63 (3H, s), 3.46 (1H, tt, J=4, 11Hz), 2.43 (3H, s), 2.13 (1H, dm, J=12Hz), 1.00 (9H, s) ppm ;
[α]_D ²⁵ : -3.07 (c=1.04, CHCl₃).
【００９１】
ｂ）（２Ｒ，３ａＳ，４ａＳ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ａ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
２．３．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、Ｉ．ｂ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。収率は７５％であった。
IR (film): 2932, 2857, 1723, 1589, 1472, 1428, 1297, 1148, 1112, 1088, 702 cm^-1;
¹H-NMR (500 MHz, CDCl₃) : δ 7.61 (4H, dd, J=1, 7Hz), 7.42 (2H, t, J=7Hz), 7.37 (4H, t, J=7Hz), 4.36 (1H, t, 6.1Hz), 3.63 (3H, s), 2.37 (1H, ddd, J=1, 6.4, 14Hz), 1.99 (1H, d, J=14hz), 1.96 (1H, dd, J=6, 14Hz), 1.87 (1H, dt, J=5, 9Hz), 1.82 (1H, d, J=14Hz), 1.63 (1H, dd, J=4, 5Hz), 1.50 (1H, dm, J=9Hz), 1.03 (9H, s) ppm ;
[α]_D ²⁵ : -30.8 (c=0.46, CHCl₃).
【００９２】
実施例２２：（２Ｒ，３ａＳ，４ａＳ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−（ヒドロキシメチル）−ビシクロ［３．１．０］ヘキサン：Ｉ．ａ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）．
Ｉ．ａ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、Ｉ．ｂ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）と同様にして反応を行い、計量可能な収量であった。．
IR (film): 3346, 2930, 1589, 1472, 1428, 1111, 1092, 1076, 1031, 822, 701 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 7.26 (4H, dd, J=1, 7Hz), 7.41 (2H, t, J=7Hz), 7.36 (4H, t, J=7Hz), 4.38 (1H, t, J=6.3Hz), 3.57 (2H, s), 2.00 (1H, dd, J=6, 13Hz), 1.95 (1H, dd, J=7, 14Hz), 1.92 (1H, d, J=14Hz), 1.80 (1H, dd, J=14Hz), 1.22 (2H, m), 1.15 (1H, m), 1.04 (9H, s), 0.60 (1H, m) ppm ;
[α]_D ²⁵ : -5.6 (c=1.7, CHCl₃).
【００９３】
実施例２３：（２Ｒ，３ａＳ，４ａＳ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサン：Ｉ．ａ．６（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）．
Ｉ．ａ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）から、Ｉ．ｂ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）と同様にして反応を行なった。収率は９３％であった。
IR (film) : 2931, 1701, 1589, 1472, 1196, 1008, 822, 702 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 8.85 (1H, s), 7.61 (4H, m), 7.43 (2H, t, J=7Hz), 7.37 (4H, t, J=7Hz), 4.41 (1H, t, J=6Hz), 2.39 (1H, dd, J=6, 14Hz), 1.04 (9H, s) ppm ;
[α]_D ²⁵ : -35.3 (c=1.6, CHCl₃).
【００９４】
実施例２４：（２Ｒ，３ａＲ，４ａＲ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｈ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
ａ）メチル（１Ｓ，３Ｓ，５Ｓ）−３−ｔ−ブチルジフェニル−５−トシルオキシ−シクロヘキサンカルボキシレート：３．１３．ｂ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
３．１２（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（４．８ｇ，１４．６３ｍｍｏｌ）から、２．８．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。収率は９０％であった。
IR (film) : 2954, 1731, 1272, 1176, 1107, 945, 813, 713, 664 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 7.53-7.25 (14H, m), 4.84 (1H, m), 3.68 (3H, s), 2.95 (1H, dt, J=3.3, 12.7Hz), 2.45 (3H, s), 2.37 (1H, d, J=12.4Hz), 1.84 (1H, d, J=12.7Hz), 1.60 (1H, m), 1.29 (3H, m) ppm ;
MS (m/z) : 566 (M⁺), 477, 431, 399, 353, 283, 225, 198, 139, 91 (base peak) ;
[α]_D ²⁵ : +7.82 (c=1.31, CHCl₃).
【００９５】
ｂ）（２Ｒ，３ａＲ，４ａＲ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−カルボメトキシ−ビシクロ［３．１．０］ヘキサン：Ｉ．ｈ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
３．１３．ｂ（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（７．３ｇ，１２．８９ｍｍｏｌ）から、Ｉ．ｂ．１（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行なった。収率は７９％であった。
IR (film) : 2952, 2858, 1723, 1428, 1370, 1219, 1112, 823, 741, 702 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 7.66-7.38 (10H, m), 3.89 (1H, m), 3.65 (3H, s), 2.12 (1H, m), 1.92 (2H, m), 1.77 (1H, m), 1.14 (2H, m), 1.02 (9H, s), 0.45 (1H, m) ppm ;
MS (m/z): 394 (M⁺), 393 (M⁺-1), 363, 351, 337, 296, 259, 213 (base peak), 183, 135, 105, 77.
[α]_D ²⁵ : +72.58 (c=1.08, CHCl₃).
【００９６】
実施例２５：２Ｒ，３ａＲ，４ａＲ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−（ヒドロキシメチル）−ビシクロ［３．１．０］ヘキサン：Ｉ．ｈ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）
Ｉ．ｈ．４（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、Ｉ．ｂ．２（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨ_２ＯＨ）と同様にして反応を行なった。収率は９８％であった。
IR (film): 3327, 2929, 2856, 1470, 1426, 1279, 1112, 1087, 1030, 822, 739, 700 IR (film): 3327, 2929, 2856, 1470, 1426, 1279, 1112, 1087, 1030, 822, 739, 700 ^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 7.65-7.35 (10H, m), 3.97 (1H, ddd, J=7.0, 7.2, 7.0), 3.55 (2H, bs), 2.04 (1H, m), 1.93 (1H, m), 1.87 (2H, m), 1.39 (1H, m), 1.02 (9H, s), 0.45 (1H, m), 0.13 (1H, m) ppm ;
MS (m/z) : 365 (M⁺-1), 322, 281, 237, 189 (base peak), 181, 139, 99, 77 ;
[α]_D ²⁵ : +24.77 (c=1.18, CHCl₃).
【００９７】
実施例２６：（２Ｒ，３ａＲ，４ａＲ）−２−ｔ−ブチルジフェニルシリルオキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサン：Ｉ．ｈ．６（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）
Ｉ．ｈ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）から、Ｉ．ｂ．３（Ｒ＝Ｈ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＨＯ）と同様にして反応を行なった。
IR (film) : 2931, 2857, 1708, 1472, 1388, 1362, 1200, 1113, 1093, 1036, 901, 823, 742, 612 cm^-1 ;
¹H-NMR (500 MHz, CDCl₃) : δ 8.87 (1H, s), 7.65-7.35 (10H, m), 3.98 (1H, m), 2.29 (1H, dd, J=12.9, 8.1Hz), 2.01 (2H, m), 1.89 (2H, m), 1.22 (1H, m), 1.02 (9H, s), 0.74 (1H, t, J=5.4Hz) ppm ;
MS (m/z) : 363 (M⁺+1), 332, 307 (base peak), 289, 277, 263, 229, 211, 199, 181, 151, 139, 121, 91, 77, 57, 41 ;
[α]_D ²⁵ : +91.49 (c=0.47, CHCl₃).
【００９８】
実施例２７：（１Ｒ，２Ｓ，３ａＳ，４ａＳ）−３ａ−カルボメトキシ−２−ｔ−ブチルジフェニルシリルオキシ−１−メチル−ビシクロ［３．１．０］ヘキサン：Ｉ．ａ．７（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
ａ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−ｔ−ブチルジフェニルシリルオキシ−４−メチル−５−アセトキシ−シクロヘキサン２．１．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
攪拌した２’Ｂ（Ｒ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）（０．８１ｇ，３．５２ｍｍｏｌ），イミダゾール（０．７２ｇ，１０．５７ｍｍｏｌ，９９％）及びＤＭＡＰ（４−ジメチルアミノピリジン；２２ｍｇ）の無水ＤＭＦ（１５ｍｌ）溶液にＴＢＤＰＳＣｌ（１．８ｍｌ，７．０４ｍｍｏｌ，９８％）を滴下した。得られた混合液を２０時間室温で攪拌した。終了後、反応溶液をｗａｔｅｒ−ＥｔＯＡｃ（８０ｍｌ）に注いだ。有機層を分離し、水層をＥｔＯＡｃ（５０ｍｌ × ３）で抽出した。結合した抽出物を飽和食塩水（３ × １０ｍｌ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濃縮して残留物を得た。残留物をＨＰＬＣ（イソオクタン／ＥｔＯＡｃ９：１）で精製し、２．１．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（１．３４ｇ，８４％）を得た。
[α]_D = +9.9 (CHCl₃, c = 0.65)
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.65-7.35 (10H, m), 4.59 (1H, dt, J=12.4, 4.5 Hz), 3.72 (1H, m), 3.62 (3H, s), 2.26 (1H, m), 2.09 (1H, m), 2.02 (3H, s), 1.81 (1H, dt, J=12.6, 4.1 Hz), 1.61 (1H, m), 1.08 (10H, s), 1.05 (3H, d, J=6.4 Hz).
IR (film) : 2954, 1737, 1428, 1364, 1239, 1111, 1037, 822, 740, 702 cm^-1MS (m/z) : 411 (M⁺-57), 369, 351, 317, 291, 259, 258, 241, 199, 181, 135, 121, 93, 43 (base peak).
【００９９】
ｂ）メチル９（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−ｔ−ブチルジフェニルシリルオキシ−４−メチル−５−ヒドロキシ−シクロヘキサンカルボキシレート２．２．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
室温の、攪拌した２．１．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（３９２ｍｇ，０．９９２ｍｍｏｌ）の無水ＭｅＯＨ（１０ｍｌ）溶液に、無水Ｋ_２ＣＯ_３（３０ｍｇ）を加えた。１０分後、２度目のＫ_２ＣＯ_３（１９ｍｇ）（合計：４９ｍｇ，０．４９６ｍｍｏｌ）を添加した。得られた混合液を６時間攪拌し、水とＥｔ_２Ｏ（７０ｍｌ：５０ｍｌ）の混合液に注いだ。有機層を分離し、水層をＥｔ_２Ｏ（５０ｍｌ × ３）で抽出し、ＭｇＳＯ_４で乾燥した。シリカ上のフラッシュクロマトグラフィー（イソオクタン／ＥｔＯＡｃ９：１）により分離し、ヒドロキシ化合物２．２．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（３４４ｍｇ，９８％）を無色油状物として得た。
IR (film) : 3448, 2954, 2858, 1737, 1654, 1472, 1362, 1279, 1240, 1173, 1008,852, 822, 795, 741, 702, 611 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.65 (4H, m), 7.44 (2H,m), 7.37 (4H, m), 3.69 (1H, m), 3.64 (3H, s), 3.51 (1H, m), 2.16 (1H, m), 2.08 (1H, m), 1.77 (1H, dt, J=12.6, 4.1 Hz), 1.69 (2H, t, J=8.9 Hz), 1.56 (1H, q, J=12.4 Hz), 1.37 (1H, d, J=5.3 Hz), 1.06 (9H, s), 1.02 (3H, d, J=7.0 Hz).
MS (m/z) : 337 (7), 309 (5), 291 (35), 199 (100), 156 (85), 181 (17), 153 (34), 121 (23), 93 (68), 57 (47).
[α]_D ²⁵ : +33.0 (c=0.54, CHCl₃)
【０１００】
ｃ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−ｔｅｒｔ−ブチルジフェニルシリルオキシ−４−メチル−５−トシルオキシ−シクロヘキサンカルボキシレート２．３．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）
２．２．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＭＳ，Ａ＝ＣＯＯＣＨ_３）（２７９ｍｇ，０．８２８ｍｍｏｌ）、ｐ−トルエンスルホニルクロライド（３２３ｍｇ，１．６９ｍｍｏｌ，９８％）、ＤＭＡＰ（５．１ｍｇ，０．０４２ｍｍｏｌ）の無水ＣＨ_２Ｃｌ_２（１０ｍｌ）混合溶液に０℃（アイスバス）でＥｔ_３Ｎ（３０８ μＬ，２．５４ｍｍｏｌ）を添加した。得られた混合液を３日間還流した；次にトルエンスルホニルクロライド（３２０ｍｇ，１．６９ｍｍｏｌ，９８％）、ＤＭＡＰ（５．１ｍｇ，０．０４２ｍｍｏｌ）及びＥｔ_３Ｎ（５００ μＬ）を添加した。得られた溶液を２日間還流した。ｐ−トルエンスルホニルクロライド（３２０ｍｇ，１．６９ｍｍｏｌ，９８％）、ＤＭＡＰ（５．１ｍｇ，０．０４２ｍｍｏｌ）及びＥｔ_３Ｎ（５００ μＬ）を再び添加し、もう１日還流を続けた。得られた混合液を２０ｍｌのＣＨ_２Ｃｌ_２で希釈し、飽和食塩水で洗浄し、水層をＥｔＯＡｃ（４×５０ｍｌ）で抽出した。結合した有機層をＭｇＳＯ_４で乾燥させた。溶液のろ過、濃縮、及びシリカ上のフラッシュクロマトグラフィー（イソオクタン／ＥｔＯＡｃ９：１）により２．３．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（３１６ｍｇ，８３．５％）を淡黄色油状物質として得た。
IR (film) : 2954, 2858, 1737, 1365, 1246, 1177, 1106, 955, 704, 667 cm^-11H-NMR (500 MHz, in CDCl₃, ppm) : 7.71 (2H, d, J=8.3 Hz), 7.58 (4H, m), 7.43 (2H, m), 7.37 (4H, m), 7.31 (2H, d, J=8.1 Hz), 4.27 (1H, dt, J=12.0, 4.7 Hz), 3.61 (3H, s), 3.57 (1H, ddd, J=10.6, 5.1, 4.6 Hz), 2.45 (3H, s), 2.17 (1H, m), 2.01 (1H, m), 1.81 (1H, dt, J=12.8, 4.2 Hz), 1.74 (1H, dd, J=12.6 Hz), 1.64 (2H,m), 1.02 (9H, s), 0.99 (3H,d,J=6.6 Hz).
MS (m/z) : 523 (25), 507 (1), 463 (1), 409 (3), 353 (94), 307 (20), 293 (18), 213 (30), 199 (32), 135 (35), 91 (100), 77 (30).
[α]_D ²⁵ : -10.0 (c=1.22, CHCl₃)
【０１０１】
ｄ）（１Ｒ，２Ｓ，３ａＳ，４ａＳ）−３ａ−カルボメトキシ−２−ｔ−ブチルジフェニルシリルオキシ−１−メチル−ビシクロ［３．１．０］ヘキサンＩ．ａ．７（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
トシレート２．３．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）（２４０ｍｇ，０．４１５ｍｍｏｌ）のｔｅｒｔ−ＢｕＯＨ（５ｍｌ）とＴＨＦ（２．８ｍｌ）溶液（４５°Ｃ）にｔｅｒｔ−ＢｕＯＫ（５４０ μＬ，０．５４ｍｍｏｌ，ｔｅｒｔ−ＢｕＯＨ中に１Ｍ溶液）を滴下した。得られた混合液を４５℃で１．５時間攪拌し、次に水とＥｔＯＡｃ（１００ｍｌ：５０ｍｌ）に注いだ。有機層を分離し、水層をＥｔＯＡｃ（３ × ５０ｍｌ）で抽出し、ＭｇＳＯ_４で乾燥させた。次に残留物をフラッシュクロマトグラフィー（イソオクタン／ＥｔＯＡｃ１００：２）により分離し、化合物Ｉ．ａ．７（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（１２２ｍｇ，７２．０％）を無色油状物として得た。
IR (film) : 2931, 1724, 1428, 1288, 1224, 1147, 1111, 1073, 1015, 933, 822, 740, 702, 609 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.61 (14H, m), 7.42 (2H, m), 7.36 (4H, t, J=7.2 Hz), 4.19 (1H, t, J=6.0 Hz), 3.62 (3H, s), 2.30 (2H, m), 1.97 (1H, d, J=14.2 Hz), 1.85 (1H, m), 1.64 (1H, t, J=4.6 Hz), 1.35 (1H, dd, J=8.7, 3.9 Hz), 1.09 (9H, s), 0.99 (3H, d, J=6.9 Hz).
MS (m/z) :
[α]_D ²⁵ : -13.2 (c=1.61, CHCl₃)
【０１０２】
実施例２８：（１Ｒ，２Ｓ，３ａＳ，４ａＳ）−３ａ−ヒドロキシメチル−２−ｔ−ブチルジフェニルシリルオキシ−１−メチル−ビシクロ［３．１．０］ヘキサンＩ．ａ．８（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）
Ｉ．ａ．７（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（１３６ｍｇ，０．３３ｍｍｏｌ）のＴＨＦ（１５ｍｌ）溶液（０℃）にＬｉＡｌＨ_４（０．８５ｍｌ，０．８５ｍｍｏｌ，ＴＨＦ中に１Ｍ溶液）を滴下した。得られた混合液をこの温度で１．５時間攪拌し、水（０．１ｍｌ）を加えた。反応混合液をセライトを用いてろ過し、濃縮した。残留物をフラッシュクロマトグラフィー（シリカゲル：イソオクタン／ＥｔＯＡｃ：７：３）により精製し、Ｉ．ａ．８（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）（１２４ｍｇ，９７．８％）を無色油状物として得た。
IR (film) : 3420, 2930, 1427, 1111, 1078, 1014, 701, 611, 504 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.63 (4H, m), 7.42 (2H, m), 7.36 (4H, m), 4.21 (1H, t, J=6.0 Hz), 3.54 (1H, dd, J=11.4, 5.6 Hz), 3.50 (1H, dd, J=11.4, 5.6 Hz), 2.29 (1H, m), 1.95 (1H, ddd, J=13.7, 6.0, 1.4 Hz), 1.23 (1H, t, J=4.12 Hz), 1.14 (1H, m), 1.08 (9H, s), 0.99 (3H, d, J=7.0 Hz), 0.41 (1H, dd, J=8.4, 4.3 Hz), 0.80 (1H, m).
MS (m/z) : 381 (M⁺+1, 1), 363 (22), 337 (1), 323 (22), 305 (5), 285 (9), 267 (24), 245 (63), 225 (19), 199 (83), 179 (19), 153 (29), 139 (51), 107 (100), 91 (58), 79 (72), 57 (86), 41 (78).
[α]_D ²⁵ : -2.6 (c=0.69, CHCl₃)
【０１０３】
実施例２９：（１Ｒ，２Ｓ，３ａＳ，４ａＳ）−３ａ−ホルミル−ｔ−ブチルジフェニルシリルオキシ−１−メチル−ビシクロ［３．１．０］ヘキサンＩ．ａ．９（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）
（ＣＯＣｌ）_２（１８ μＬ，０．２１ｍｍｏｌ）のＣＨ_２Ｃｌ_２（１．５ｍｌ）溶液（−７８℃）にＤＭＳＯ（３２ μＬ，０．４２ｍｍｏｌ）のＣＨ_２Ｃｌ_２（１００ μＬ）溶液を滴下した。混合液を−７８℃で２０分間攪拌し、次にアルコールＩ．ａ．８（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）（４０ｍｇ，０．１０５ｍｍｏｌ）のＣＨ_２Ｃｌ_２（１．５ｍｌ）溶液をくわえた。得られた白濁液を−７８℃で２０分間攪拌した。次にこの混合液を１時間かけて室温まで温めた。冷水を加えて反応を終了させ、有機層を分離し、水層をＥｔ_２Ｏ（３ × ５０ｍｌ）で抽出した後、ＭｇＳＯ_４で乾燥させた。残留物をＨＰＬＣ（イソオクタン／ＥｔＯＡｃ：９５：５）で分離し、化合物Ｉ．ａ．９（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）（３０ｍｇ，７５％）を無色油状物として得た。
IR (film) : 3420, 2930, 1427, 1111, 1078, 1014, 701, 611, 504 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm) : 8.80 (1H, s), 7.62 (4H, m), 7.42 (6H, m), 4.24 (1H, t, J=5.8 Hz), 2.32 (1H, dd, J=14.4, 6.1 Hz), 1.96 (2H, m), 1.84 (1H, d, J=14.4 Hz), 1.36 (1H, m), 1.08 (9H, s), 1.00 (3H, d, J=7.0 Hz), 0.91 (1H, d, J=6.8 Hz).
MS (m/z) : 378 (M⁺, 1), 361 (4), 321 (100), 303 (10), 285 (10), 267 (24), 263 (16), 243 (74), 225 (39), 199 (100), 183 (76), 165 (39), 139 (72), 135 (48), 105 (59), 91 (34), 77 (60), 57 (95), 41 (80).
[α]_D ²⁵ = -16.2 (c=0.59, CHCl₃)
【０１０４】
実施例３０：（１Ｓ，２Ｒ，３ａＲ，４ａＲ）−３ａ−カルボメトキシ−２−ｔｅｒｔ−ブチルジフェニルシリルオキシ−１−メチル−ビシクロ［３．１．０］ヘキサンＩ．ｆ．８（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
ａ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−トシルオキシ−４−メチル−５−アセトキシ−シクロヘキサンカルボキシレート３．４．ｃ（Ｒ＝Ｍｅ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）
２’Ｂ（Ｒ＝Ｍｅ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）（１．０５ｇ，４．５７ｍｍｏｌ）から、２．３．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は１．５１ｇ，８９％であった。
IR (film) : 2954, 1736, 1557, 1363, 1242, 1189, 1025, 956, 919, 667 cm^-11H-NMR (500 MHz, in CDCl₃, ppm) : 7.69 (2H, d, J=7.2 Hz), 7.38 (2H, d, J=7.2 Hz), 4.74 (1H, dt, J=12.2, 4.5 Hz), 4.49 (1H, dt, J=12.1, 4.7 Hz), 3.69 (3H, s), 2.46 (3H, s), 2.02 (3H, s), 1.98 (1H, dt, J=12.1, 4.7 Hz), 1.93 (1H, dt, J=12.6, 4.6 Hz), 1.81 (2H, dd, J=12.8 Hz), 1.63 (2H, dd, J=12.6 Hz), 0.97 (3H, d, J=6.9 Hz).
MS (m/z) : 384 (M⁺), 343, 326, 311, 300, 269, 258, 213, 170, 152, 111, 93, 43 (base peak).
[α]_D ²⁵ = +51.1 (c=0.59, CHCl₃)
【０１０５】
ｂ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−トシルオキシ−４−メチル−５−ヒドロキシ−シクロヘキサンカルボキシレート３．５．ｃ（Ｒ＝Ｍｅ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）
３．４．ｃ（Ｒ＝Ｍｅ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）から、２．２．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は９０％であった。
IR (film) : 3439, 2988, 1732, 1439, 1353, 1176, 1097, 1021, 945, 667 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.78 (2H, d, J=7.2 Hz), 7.32 (2H, d, J=7.2 Hz), 4.52 (1H, dt, J=10.8, 4.7 Hz), 3.69 (1H, m), 3.68 (3H, s), 2.45 (3H, s), 2.34 (1H, m), 2.25 (1H, m), 1.94 (2H, m), 1.87 (1H, dt, J=13.2, 4.5 Hz), 1.75 (1H, bs), 1.66 (1H, dd, J=11.9 Hz), 0.91 (3H, d, J=7.0 Hz).
MS (m/z) : 340 (M⁺-2), 295, 278, 247, 220, 194, 170, 155, 127 (base peak), 91, 87, 57.
[α]_D ²⁵ : +18.8 (c=0.41, CHCl₃)
【０１０６】
ｃ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−トシルオキシ−４−メチル−５−ｔｅｒｔ−ブチルジフェニルシリルオキシ−シクロヘキサンカルボキシレート３．６．ｃ（Ｒ＝Ｍｅ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
３．５．ｃ（Ｒ＝Ｍｅ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）から、２．１．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は８６％であった。
IR (film) : 2955, 1736, 1598, 1427, 1363, 1177, 1031, 955, 914, 863, 820, 741, 703, 667 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.69-7.38 (14H, m), 4.27 (1H, dt, J=12.1, 4.8 Hz), 3.61 (3H, s), 3.56 (1H, m), 2.44 (3H, s), 2.17 (1H, m), 2.02 (1H, m), 1.83 (1H, dt, J=12.5, 4.3 Hz), 1.73 (1H, dd, J=12.7 Hz), 1.63 (2H, m), 1.01 (9H, s), 0.99 (3H, d, J=7.2 Hz).
MS (m/z) : 523 (M⁺-57), 463, 403, 353, 351, 293, 227, 213, 135, 91 (base peak), 77.
[α]_D ²⁵ : -2.6 (c=0.94, CHCl₃)
【０１０７】
ｄ）（１Ｓ，２Ｒ，３ａＲ，４ａＲ）−３ａ−カルボメトキシ−２−ｔ−ブチルジフェニルシリルオキシ−１−メチル−ビシクロ［３．１．０］ヘキサンＩ．ｆ．８（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
３．６．ｃ（Ｒ＝Ｍｅ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、Ｉ．ａ．７（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。標題化合物を無色油状物として収率６８％で得た。
IR (film) : 2931, 2857, 1724, 1428, 1367, 1288, 1223, 1147, 1111, 1073, 1015, 934, 822, 740, 702, 609 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.62-7.31 (10H, m), 4.19 (1H, t, J=5.9 Hz), 3.59 (3H, s), 2.31 (2H, dd, J=13.7, 6.3 Hz), 1.96 (1H, d, J=14.5 Hz), 1.84 (1H, m), 1.64 (1H, t, J=4.6 Hz), 1.35 (1H, dd, J=12.8, 5.0 Hz), 1.25 (1H, br.), 1.07 (9H, s), 0.99 (3H, d, J=6.9 Hz), 0.91 (1H, m).
MS (m/z) : 408 (M⁺), 351, 323, 273, 213, 199, 153, 121 (base peak), 77. [α]_D ²⁵ : +13.9 (c=0.65, CHCl₃)
【０１０８】
実施例３１：（１Ｓ，２Ｒ，３ａＲ，４ａＲ）−３ａ−ヒドロキシメチル−２−ｔ−ブチルジフェニルシリルオキシ−１−メチル−ビシクロ［３．１．０］ヘキサンＩ．ｆ．９（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）
Ｉ．ｆ．８Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、Ｉ．ａ．８（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）と同様にして反応を行った。収率は９８％であった。
IR (film) : 3324, 2929, 2857, 1654, 1471, 1427, 1363, 1194, 1107, 1078, 1011, 822, 740, 701, 610 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.68-7.37 (10H, m), 4.21 (1H, t, J=6.0 Hz), 3.54 (1H, dd, J=11.4, 6.0 Hz), 3.52 (1H, dd, J=11.4, 6.0 Hz), 2.29 (1H, dd, J=11.3, 8.1 Hz), 1.94 (1H, dd, J=14.6, 5.9 Hz), 1.86 (1H, d, J=13.2 Hz), 1.23 (1H, t, J=4.1 Hz), 1.14 (1H, m), 1.07 (9H, s), 0.99 (3H, d, J=6.9 Hz), 0.89 (1H, m), 0.41 (dd, J=8.1, 4.3 Hz).
MS (m/z) : 323 (M⁺-57), 305, 267, 245, 199, 181, 139, 107.
[α]_D ²⁵ : +3.1 (c=0.93, CH₃Cl)
【０１０９】
実施例３２：（１Ｓ，２Ｒ，３ａＲ，４ａＲ）−３ａ−ホルミル−２−ｔ−ブチルジフェニルシリルオキシ−１−メチル−ビシクロ［３．１．０］ヘキサンＩ．ｆ．１０（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）
Ｉ．ｆ．９（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）から、Ｉ．ａ．９（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨＯ）と同様にして反応を行った。収率は２８％であった。
[α]_D ²⁵ : +15.8 (c=0.41, CH₃Cl)
¹H-NMR (500 MHz, in CDCl₃, ppm) : 8.80 (1H, s), 7.61-7.35 (10H, m), 4.24 (1H, t, J=5.8 Hz), 2.31 (2H, m), 1.96 (1H, m, dd, J=8.1, 5.9 Hz), 1.84 (1H, d, J=14.3 Hz), 1.37 (1H, dd, J=11.0, 7.1 Hz), 1.26 (1H, dd, J=9.7, 4.6 Hz), 1.07 (9H, s), 1.04 (3H, t, J=6.9 Hz).
IR (film) : 2959, 2857, 1703, 1471, 1391, 1383, 1274, 1215, 1191, 1111, 1109, 1009, 963, 823, 701 cm^-1.
MS (m/z) : 377 (M⁺-1, 5), 337 (75), 321 (M⁺-57, 8), 319 (10), 309 (10), 293 (6), 259 (12), 231 (20), 215 (16), 199 (100), 181 (30), 153 (20), 139 (60), 121 (95).
【０１１０】
実施例３３：（１Ｒ，２Ｓ，３ａＳ，４ａＳ）−３ａ−カルボメトキシ−２−ｔ−ブチルジフェニルシリルオキシ−１−エチル−ビシクロ［３．１．０］ヘキサンＩ．ａ．１０（Ｒ＝Ｅｔ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
ａ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−ｔ−ブチルジフェニルシリルオキシ−４−エチル−５−アセトキシ−シクロヘキサン２．１．ｄ（Ｒ＝Ｅｔ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
２’Ｃ（Ｒ＝Ｅｔ，Ｚ＝Ｍｅ，Ａ＝ＣＯＯＣＨ_３）から、３．４．ｃと同様にして反応を行った。収率は９２％であった。
[α]_D ²⁵ : +7.5 (c=0.59, CH₃Cl)
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.45-7.36 (10H, m), 4.62 (1H, dt, J=12.2, 4.4 Hz), 3.69 (1H, dt, J=11.5, 4.3 Hz), 3.61 (3H, s), 2.08 (2H, tt, J=8.8, 3.9 Hz), 2.01 (3H, s), 1.85 (2H, m), 1.60 (3H, m), 1.51 (1H, m), 1.06 (9H, s), 1.02 (3H, t, J=7.5 Hz).
IR (film) : 2954, 2848, 1739, 1462, 1428, 1364, 1238, 1194, 1178, 1110, 1034, 986, 812, 740, 702 cm^-1.
MS (m/z) : 482 (M⁺, 2), 468 (5), 451 (7), 425 (M⁺-57), 391 (1), 365 (80), 351 (25), 305 (15), 273 (20), 241 (100), 213 (88), 199 (92), 153 (56), 135 (75), 107 (85).
【０１１１】
ｂ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−ｔ−ブチルジフェニルシリルオキシ−４−エチル−５−ヒドロキシ−シクロヘキサンカルボキシレート２．２．ｄ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
２．１．ｄ（Ｒ＝Ｅｔ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、２．２．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は９８％であった。
[α]_D ²⁵ : +28.7 (c=0.19, CH₃Cl)
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.68 (10H, m), 3.68 (1H, dt, J=8.2, 4.2 Hz), 3.62 (3H, s), 3.57 (1H, dt, J=11.1, 4.6 Hz), 2.07 (1H, m), 1.85 (1H, t, J=4.1 Hz), 1.77 (1H, dt, J=8.6, 4.0 Hz), 1.71 (1H, tt, J=11.0, 4.0 Hz), 1.64 (2H, t, J=9.0), 1.59 (1H, overlap), 1.52 (1H, bs), 1.45 (1H, m), 1.06 (9H, s), 1.05 (3H, t, J=7.5).
IR (film) : 3435, 2995, 2858, 1736, 1589, 1460, 1427, 1363, 1271, 1236, 1172, 1111, 1050, 915, 875, 823, 740, 702, 647 cm^-1.
MS (m/z) : 383 (M⁺-57, 14), 351 (16), 323 (18), 305 (90), 273 (18), 253 (10), 227 (50), 199 (100), 183 (70), 153 (80), 107 (98).
【０１１２】
ｃ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−ｔ−ブチルジフェニルシリルオキシ−４−エチル−５−トシルオキシ−シクロヘキサンカルボキシレート２．３．ｄ（Ｒ＝Ｅｔ，Ｐ＝ＴＢＤＰＳ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）
２．２．ｄ（Ｒ＝Ｅｔ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、２．３．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は８２％であった。
[α]_D ²⁵ : -17.9 (c=0.59, CH₃Cl)
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.72-7.30 (14H, m), 4.28 (1H, dt, J=12.5, 4.5 Hz), 3.59 (3H, s), 3.55 (1H, dt, J=11.4, 4.3 Hz), 2.45 (3H, s), 1.96 (1H, tt, J=8.5, 4.1 Hz), 1.91 (1H, t, J=4.2Hz), 1.84 (1H, dt, J=8.5, 4.1 Hz), 1.77 (1H, m), 1.73 (1H, m), 1.53 (2H, m), 1.47 (1H, m), 1.02 (9H, s), 0.97 (3H, t, J=7.5 Hz).
IR (film) : 2957, 2858, 1738, 1598, 1487, 1462, 1428, 1360, 1277, 1189, 1111, 1030, 953, 885, 822, 741, 704 cm^-1.
MS (m/z) : 357 (M⁺-57, 45), 353 (100), 293 (22), 227 (5), 199 (48), 135 (70).
【０１１３】
ｄ）（１Ｒ，２Ｓ，３ａＳ，４ａＳ）−３ａ−カルボメトキシ−２−ｔ−ブチルジフェニルシリルオキシ−１−エチル−ビシクロ［３．１．０］ヘキサンＩ．ａ．１０（Ｒ＝Ｅｔ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
２．３．ｄ（Ｒ＝Ｅｔ，Ｐ＝ＴＢＤＰＳ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）から、Ｉ．ａ．７（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は７１％であった。
[α]_D ²⁵ : -33.3 (c=0.27, CH₃Cl)
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.63-7.35 (10H, m), 4.18 (1H, t, J=5.9 Hz), 3.61 (3H, s), 2.26 (1H, m), 2.06 (1H, m), 1.98 (1H, d, J=14.3 Hz), 1.92 (1H, m), 1.67 (1H, t, J=4.3 Hz), 1.48 (2H, m), 1.36 (1H, dd, J=8.7, 3.9 Hz), 1.05 (9H, s), 0.89 (3H, J=7.4 Hz).
IR (film) : 2958, 1723, 1427, 1366, 1298, 1224, 1148, 1111, 1064, 1028, 926, 821, 740, 610, 507 cm^-1.
MS (m/z) : 422 (M⁺, 2), 391 (4), 365 (M⁺-57, 40), 337 (8), 287 (12), 259 (10), 225 (8), 199 (65), 135 (100), 105 (38).
【０１１４】
実施例３４：（１Ｓ，２Ｒ，３ａＲ，４ａＲ）−３ａ−カルボメトキシ−２−ｔ−ブチルジフェニルシリルオキシ−１−エチル−ビシクロ［３．１．０］ヘキサンＩ．ｆ．１１（Ｒ＝Ｅｔ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
ａ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−メシルオキシ−４−エチル−５−アセトキシ−シクロヘキサンカルボキシレート３．４．ｄ（Ｒ＝Ｅｔ，Ｌ＝ＯＭｓ，Ａ＝ＣＯＯＣＨ_３）．
モノアセテート２’Ｃ（Ａ＝ＣＯＯＣＨ_３，Ｒ＝Ｅｔ，Ｚ＝Ｍｅ）（０．１ｇ，０．４１ｍｍｏｌ）、Ｅｔ_３Ｎ（０．３０ｍｌ，２．１０ｍｍｏｌ）のＣＨ_２Ｃｌ_２（５ｍｌ）溶液にＭｓＣｌ（９６ μＬ，１．２３ｍｍｏｌ）を室温で滴下した。得られた混合液を室温で１０時間攪拌した。反応溶液を氷水に注ぎ、ＡｃＯＥｔ（３ × ５０ｍｌ）で抽出した。結合した抽出物を飽和食塩水（３ × ５ｍｌ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濃縮して残留物を得た。得られた残留物をイソオクタン／ＥｔＯＡｃ（９０：１０）を溶離液としたＨＰＬＣで精製し、メシレート３．４．ｄ（Ａ＝ＣＯＯＣＨ_３，Ｒ＝Ｅｔ，Ｌ＝ＯＭｓ）（０．１１ｇ，８５％）を得た。
IR (film) : 2954, 1737, 1641, 1357, 1241, 1175, 952 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm) : 4.87 (1H, dt, J=10.9, 4.2 Hz), 4.75 (1H, dt, J=4.5, 10.9 Hz), 3.69 (3H, s), 3.00 (3H, s), 2.48 (1H, m), 2.23 (1H, bs), 2.13 (1H, dt, J=4.2, 11.8 Hz), 2.05 (3H, s), 2.01 (1H, d, J=8.8 Hz), 1.96 (1H, dt, J=13.3, 4.5 Hz), 1.83 (1H, m), 1.58 (2H, m), 1.01 (3H, s).
MS (m/z) : 322 (M⁺), 309, 291, 248, 227, 199, 166, 135, 107, 78, 43 (base peak).
[α]_D ²⁵ : +2.6 (c=1.08, CHCl₃)
【０１１５】
ｂ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−メシルオキシ−４−エチル−５−ヒドロキシ−シクロヘキサンカルボキシレート３．５．ｄ（Ａ＝ＣＯＯＣＨ_３，Ｒ＝Ｅｔ，Ｌ＝ＯＭｓ）
３．４．ｄ（Ｒ＝Ｅｔ，Ｌ＝ＯＭｓ，Ａ＝ＣＯＯＣＨ_３）から、２．５．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は９０％であった。
IR (film) : 3439, 2957, 1729, 1438, 1351, 1277, 1174, 944, 877, 838, 757,
530 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm) : 4.87 (1H, t, J=3.1 Hz), 3.91 (1H, t, J=2.9 Hz), 3.74 (3H, s), 3.00 (3H, s), 2.69 (1H, bs), 2.44 (1H, bs), 2.17 (1H, bs), 2.00 (2H, m), 1.84 (2H, dt, J=14.3, 4.7 Hz), 1.71 (2H, m), 1.03 (3H, t, J=7.4 Hz).
MS (m/z) : 281 (M⁺+1), 263, 249, 236, 200, 184, 166, 141, 125, 111, 87, 78, 55 (base peak).
[α]_D ²⁵ : +51.3 (c=0.61, CHCl₃)
【０１１６】
ｃ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｒ）−３−メシルオキシ−４−エチル−５−ｔ−ブチルジフェニルシリルオキシ−シクロヘキサンカルボキシレート３．６．ｄ（Ｒ＝Ｅｔ，Ｌ＝ＯＭｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
３．５．ｄ（Ｒ＝Ｅｔ，Ｌ＝ＯＭｓ，Ａ＝ＣＯＯＣＨ_３）から、２．８．ａ（Ｒ＝Ｈ，Ｌ＝ＯＴｏｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は８６％であった。
IR (film) : 2957, 2857, 1738, 1588, 1462, 1427, 1358, 1276, 1177, 1111, 1030, 949, 885, 823, 741, 703, 614 cm^-11H-NMR (500 MHz, in CDCl₃, ppm) : 7.65-7.35 (10H, m), 4.44 (1H, dt, J=12.2, 4.6 Hz), 3.67 (1H, dt, J=11.6, 4.2 Hz), 3.63 (3H, s), 2.79 (3H, s), 2.09 (1H, dt, J=12.9, 3.9 Hz), 2.06 (1H, m), 2.02 (2H, m), 1.85 (1H, m), 1.79 (1H, dd, J=12.8 Hz), 1.65, 1H, dt, J=13.1, 4.0 Hz), 1.49 (1H, m), 1.06 (9H, s), 1.04 (3H, t, J=7.5 Hz).
MS (m/z) : 461 (M⁺-57), 401, 365, 351, 305, 277, 231, 199, 167, 135, 107 (base peak).
[α]_D ²⁵ : -2.3 (c=0.35, CHCl₃)
【０１１７】
ｄ）（１Ｓ，２Ｒ，３ａＲ，４ａＲ）−３ａ−カルボメトキシ−２−ｔ−ブチルジフェニルシリルオキシ−１−エチル−ビシクロ［３．１．０］ヘキサンＩ．ｆ．１１（Ｒ＝Ｅｔ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
３．６．ｄ（Ｒ＝Ｅｔ，Ｌ＝ＯＭｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、Ｉ．ａ．７（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は７１％であった。
IR (film) : 2958, 1723, 1427, 1366, 1298, 1224, 1148, 1111, 1064, 1028, 926, 821, 740, 610, 507 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.63-7.35 (10H, m), 4.18 (1H, t, J=5.9 Hz), 3.61 (3H, s), 2.26 (1H, m), 2.06 (1H, m), 1.98 (1H, d, J=14.3 Hz), 1.92 (1H, m), 1.67 (1H, t, J=4.3 Hz), 1.48 (2H, m), 1.36 (1H, dd, J=8.7, 3.9 Hz), 1.05 (9H, s), 0.89 (3H, J=7.4 Hz).
MS (m/z) : 422 (M⁺, 2), 391 (4), 365 (M⁺-57, 40), 337 (8), 287 (12), 259 (10), 225 (8), 199 (65), 135 (100), 105 (38)．
［α］_Ｄ ^２５：＋２８．４（ｃ＝０．７５，ＣＨＣｌ_３）
【０１１８】
実施例３５：（１Ｒ，２Ｓ，３ａＲ，４ａＲ）−３ａ−カルボメトキシ−２−ｔ−ブチルジフェニルシリルオキシ−１−メチル−ビシクロ［３．１．０］ヘキサンＩ．ｅ．１（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
ａ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｓ）−３−ｔ−ブチルジフェニルシリルオキシ−４−メチル−５−ヒドロキシ−シクロヘキサンカルボキシレート３．２．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）．
２．２．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（１６７ｍｇ，０．３９２ｍｍｏｌ），ピコリン酸（２５７ｍｇ，２．０９２ｍｍｏｌ）及びトリフェニルホスフィン（５４８ｍｇ，２．０９２ｍｍｏｌ）のＴＨＦ溶液（−３８℃）にＤＩＡＤ（ジイソプロピルアゾジカルボキシレート；４１２ μＬ，２．０９２ｍｍｏｌ）を４分かけて滴下した。反応溶液を４．５時間攪拌し、一晩で室温まで戻った。得られた混合液を水とＥｔＯＡｃ（５０ｍｌ：５０ｍｌ）に注いだ。有機層を分離し、水層をＥｔＯＡｃ（３ × ５０ｍｌ）で抽出し、ＭｇＳＯ_４で乾燥させた。残留物をＨＰＬＣ（イソオクタン／ＥｔＯＡｃ９８：２）によって分離し、（４Ｓ，６Ｓ）−４−カルボメトキシ−６−ｔ−ブチルジフェニルシリルオキシ−１−メチルシクロヘキサン（１４２ｍｇ，８８．８％）を無色油状物として得た。
IR (film): 2953, 2856, 1738, 1428, 1247, 1168, 1111, 1068, 999, 893, 820, 741, 702, 614 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 7.71 (4H, m), 7.43 (2H, m), 7.38 (4H, m), 5.39 (1H, m), 4.25 (1H, bs), 3.60 (3H, s), 2.39 (1H, m), 2.19 (1H, m), 2.13 (1H, m), 2.04 (1H, m), 1.75 (1H, dd, J=22.3, 12.5Hz), 1.66 (3H, bs), 1.08 (9H, s).
MS (m/z): 387 (1), 361 (1), 351 (75), 319 (5), 273 (5), 273 (5), 213 (100), 183 (70), 137 (65), 105 (30), 77 (85).
[α]_D ²⁵ : +81.9 (c=1.91, CHCl₃)
【０１１９】
攪拌したシクロヘキサン（１１０ｍｇ，０．２７ｍｍｏｌ）のｄｉｇｌｙｍｅ（２ｍｌ）溶液（０℃）にボラン−ＴＨＦ錯体溶液（１．０Ｍ，３２５ μＬ，０．３２５ｍｍｏｌ，１．５ｅｑ）を滴下した。得られた溶液を４時間、０℃で攪拌した。ＴＨＦを除去し、ＴＡＯ（トリメチルアミンＮ−オキサイド，９０ｍｇ，０．８１ｍｍｏｌ）を加えた。混合液を加熱し、２時間還流した。得られた混合液を室温まで冷却し、ＥｔＯＡｃ（４エ４０ｍｌ）で抽出し、ＭｇＳＯ_４で乾燥させた。残留物をシリカ上のフラッシュクロマトグラフィーで分離し、ＨＰＬＣ（シクロヘキサン／ＥｔＯＡｃ：９：１）で精製して化合物３．２．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）（４６ｇ，４０．５％）を無色油状物として得た。
IR (film, cm^-1): 3453, 2954, 2858, 1737, 1462, 1428, 1379, 1272, 1195, 1111, 1032, 934, 823, 702.
¹H-NMR (500 MHz, in CDCl₃, ppm): 7.66 (4H, m), 7.42 (2H, m), 7.38 (4H, m), 4.17 (1H, dt, J=10.7, 4.7Hz), 3.88 (1H, bs), 3.62 (3H, s), 2.61 (1H, m), 1.85〜1.65 (5H, m), 1.06 (9H, s), 0.96 (3H, d, J=7.2Hz).
[α]_D ²⁵ : +39.4 (c=0.95, CHCl₃)
【０１２０】
ｂ）メチル（１Ｓ，３Ｓ，４Ｒ，５Ｓ）−３−ｔ−ブチルジフェニルシリルオキシ−５−メシルオキシ−４−メチル−シクロヘキサンカルボキシレート３．３．ｃ（Ｒ＝Ｍｅ，Ｌ＝ＯＭｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
３．２．ｃ（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、３．４．ｄ（Ｒ＝Ｅｔ，Ｌ＝ＯＭｓ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は８４．５％であった。
IR (film): 2952, 1732, 1470, 1427, 1357, 1275, 1177, 1112, 1029, 929, 904 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.65 (4H, t, J=8.0 Hz), 7.40 (6H, m), 4.80 (1H, bs), 4.06 (1H, m), 3.65 (3H, s), 2.70 (3H, s), 2.58 (1H, m), 2.04 (1H, bs), 1.98〜1.76 (4H, m), 1.06 (9H, s), 1.03 (3H, d, J=7.2 Hz).[α]_D ²⁵ : +30.3 (c=0.52, CHCl₃)
【０１２１】
ｃ）（１Ｒ，２Ｓ，３ａＲ，４ａＲ）−３ａ−カルボメトキシ−２−ｔ−ブチルジフェニルシリルオキシ−１−メチル−ビシクロ［３．１．０］ヘキサンＩ．ｅ．１（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）
３．３．ｃ（Ｒ＝Ｍｅ，Ｌ＝ＯＭｓ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）から、Ｉ．ａ．７（Ｒ＝Ｍｅ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＯＯＣＨ_３）と同様にして反応を行った。収率は６８．８％であった。
IR (film): 2951, 1725, 1428, 1259, 1238, 1111, 880, 814, 742, 702 cm^-1.¹H-NMR (500 MHz, in CDCl₃, ppm) : 7.63 (4H, m), 7.45〜7.35 (6H, m), 3.84 (1H, m), 3.64 (3H, s), 2.23 (1H, m), 2.02 (1H, m), 1.93 (1H, m), 1.60 (1H, m), 1.17 (1H, m), 1.04 (12H, bs), 0.56 (1H, m).
【０１２２】
実施例３６：（２Ｒ，３ａＳ，４ａＳ）−２−メチル−２−ヒドロキシ−３ａ−ヒドロキシメチル−ビシクロ［３．１．０］ヘキサン：Ｉ．ｉ．１（Ａ＝ＣＨ_２ＯＨ，Ｒ_１＝Ｍｅ：スキーム４）
ａ）（２Ｒ，３ａＳ，４ａＳ）−２−ヒドロキシ−３ａ−［（ベンゾイルオキシ）メチル］−ビシクロ［３．１．０］ヘキサン：４．１
Ｉ．ａ．５（Ｒ＝Ｈ，Ｐ＝ＴＢＤＰＳ，Ａ＝ＣＨ_２ＯＨ）（４．４５１ｇ，１２．１５ｍｍｏｌ）、ＤＭＡＰ（２５０ｍｇ，２．２７ｍｍｏｌ）及びＥｔ_３Ｎ（１６．５ｍｌ，１２１．１ｍｍｏｌ）のＣＨ_２Ｃｌ_２（５０ｍｌ）溶液（０℃）にベンゾイルクロライドを滴下した。混合液を２２時間室温で攪拌し、７０ｍｌのＣＨ_２Ｃｌ_２で希釈した。有機層を分離し，飽和食塩水（３ × １００ｍｌ）で洗浄し、ＭｇＳＯ_４で乾燥させた。残留物をフラッシュクロマトグラフィー（シリカゲル，イソオクタン／ＥｔＯＡｃ：１００：２．５）で精製し，対応するベンゾエート（５．５１ｇ，９６．５％）を無色油状物として得た。このベンゾエート（２．２２ｇ，４．７２ｍｍｏｌ）のＴＨＦ（４０ｍｌ）溶液にＴＢＡＦ（１４ｍｌ，１４ｍｍｏｌ，ＴＨＦ中１Ｍ）を加え、得られた溶液を室温で１４時間攪拌した。溶媒を真空下で蒸発させた。残留物を短いシリカゲルカラム（イソオクタン／ＥｔＯＡｃ：７：３）に通した。粗精製物をＨＰＬＣ（イソオクタン／ＥｔＯＡｃ：７：３）で精製し、化合物４．１（１．０３ｇ，９４．０％）を無色油状物として得た。
IR (film): 3413.8, 2928.3, 1714.1, 1602.1, 1452.1, 1277.5, 1115.1, 1070.0, 958.3, 808.3, 711.5 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 8.06 (2H, d, J=7.8Hz), 7.56 (1H, t, J=7.3Hz), 7.45 (1H, t, J=7.7Hz), 4.48 (1H, m), 4.34 (2H, dd, J=19.4, 11.5Hz), 2.23 (2H, m), 1.94 (1H, d, J=14.0Hz), 1.78 (1H, d, J=14.2Hz), 1.38 (1H, ddd, J=8.3, 4.3, 4.3Hz), 1.30 (1H, bs), 1.06 (1H, t, J=4.4Hz), 0.75 (1H, m)
MS (m/z): 232 (M⁺, 1), 214 (1), 199 (1), 189 (1), 161 (1), 149 (1), 127 (1), 110 (13), 105 (100), 77 (43). 67 (14).
[α]_D ²⁵ : -27.96 (c=1.47, CHCl₃).
【０１２３】
ｂ）（３ａＳ，４ａＳ）−３ａ−［（ベンゾイルオキシ）メチル］−ビシクロ［３，１，０］ヘキサン−２−オン：４．２
アルコール４．１（２０９ｍｇ，０．９０４ｍｍｏｌ）のＣＨ_２Ｃｌ_２（３０ｍｌ）溶液にピリジニウムジクロメート（ＰＤＣ，１．０７２ｇ，４．９７ｍｍｏｌ）を加え、得られた混合液を室温で１６時間攪拌した。得られた溶液を直接的にフラッシュクロマトグラフィー（シリカゲルカラム３×１５ｃｍ）（イソオクタン／ＥｔＯＡｃ：９：１〜８：２）で精製し、化合物４．２（１９７ｍｇ，９５％）を無色油状物として得た。
IR (film): 1745.0, 1715.9, 1451.2, 1355.4, 1272.1, 1155.7, 1111.3, 1069.9,
711.0 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 8.05 (2H, d, J=8.9Hz), 7.58 (1H, t, J=7.4Hz), 7.46 (2H, t, J=7.6Hz), 4.41 (2H, dd, J=29.6, 12.7Hz), 2.75 (2H, m), 2.41 (1H, d, J=9.0Hz), 2.28 (1H, d, J=9.3Hz), 1.68 (1H, m), 1.10 (1H, t, J=7.0Hz), 0.37 (1H, t, J=5.1Hz).
MS (m/z): 230 (M⁺, 1), 212 (1), 202 (6.9), 183 (1), 161 (1), 149 (1), 125 (1), 106 (13), 105 (100), 77 (46), 51 (20).
[α]_D ²⁵ : -36.50 (c=4.07, CHCl₃)
【０１２４】
ｃ）（２Ｒ，３ａＳ，４ａＳ）−２−メチル−２−ヒドロキシ−３ａ−ヒドロキシメチル−ビシクロ［３．１．０］ヘキサンＩ．ｉ．１（Ｒ_１＝Ｍｅ，Ａ＝ＣＨ_２ＯＨ）
ケトン４．２（１２０ｍｇ，０．５２ｍｍｏｌ）のＴＨＦ（４ｍｌ）溶液にＭｅＭｇＢｒのＥｔ_２Ｏ（１．５ｍｌ，３．０Ｍ）溶液を５分かけて−７８℃で滴下した。得られた混合液をこの温度で６時間攪拌し、次に室温まで一晩で戻した。氷冷した飽和ＮＨ_４Ｃｌ水溶液（０．２ｍｌ）を加えて反応を終了させた。得られた混合液を、ＭｇＳＯ_４を有する短いシリカゲルカラムに通した。残留物をＨＰＬＣ（イソオクタン／ＥｔＯＡｃ：５：５）で分離し、化合物Ｉ．ｉ．１（Ｒ_１＝Ｍｅ，Ａ＝ＣＨ_２ＯＨ）（５５ｍｇ，７４％）を白色固形物として得た。
IR (film): : 3288.4, 2931.3, 2858.5, 1459.1, 1370.2, 1260.7, 1183.9, 1135.7,1111.5, 1064.0, 1016.0, 922.6 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 3.58 (2H, s), 2.08 (1H, d, J=13.7Hz), 2.03 (1H, dd, J=13.8, 5.0Hz), 1.88 (1H, d, J=13.7Hz), 1.76 (1H, d, J=13.8Hz), 1.34 (3H, s), 1.29 (1H, bs), 1.21 (1H, m), 1.14 (1H, t, J=4.3Hz), 1.11 (1H, s), 0.57 (1H, dd, J=8.4, 4.5Hz).
MS (m/z): 124 (2), 109 (6), 93 (12), 81 (12), 71 (10), 67 (10), 55 (11), 43 (100).
[α]_D ²⁵ : -33.10 (c=1.17, MeOH)
【０１２５】
実施例３７：（２Ｒ，３ａＳ，４ａＳ）−２−メチル−２−ヒドロキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサンＩ．ｉ．２（Ｒ_１＝Ｍｅ，Ａ＝ＣＨＯ）
ＳＯ_３−ピリジン複合体（２．５ｅｑ，１４０ｍｇ）のＤＭＳＯ：ＣＨ_２Ｃｌ_２（５００ μＬ：２５０ μＬ）及びＥｔ_３Ｎ（２．５ｅｑ，１２０ μＬ）溶液に、Ｉ．ｉ．１（Ｒ_１＝Ｍｅ，Ａ＝ＣＨ_２ＯＨ）（１ｅｑ，５０ｍｇ，３５ μｍｏｌ）のＤＭＳＯ：ＣＨ_２Ｃｌ_２（５００ μＬ：２５０ μＬ）及びＥｔ_３Ｎ（２．５ｅｑ，１２０ μＬ）溶液を−１５℃で加えた。−１０℃〜−５℃で１時間攪拌した後、混合液をＥｔ_２Ｏ：飽和食塩水に注いだ。次に有機層を乾燥させた（ＭｇＳＯ_４）。溶媒を蒸発させた後、残留物をカラムクロマトグラフィー（Ｅｔ_２Ｏ：イソオクタン１：１〜Ｅｔ_２Ｏ：イソオクタン：メタノール：ＣＨ_２Ｃｌ_２１００：１００：１：２０）で精製し、Ｉ．ｉ．２（Ｒ_１＝Ｍｅ，Ａ＝ＣＨＯ）を無色油状物として得た（３７ｍｇ，７５％）。
IR (film) : 3441, 2929, 1694, 1435, 1258, 1105, 1049, 963, 893 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm): 8.81 (1H, s), 2.47 (1H, d, J=14Hz), 2.03 (2H, m), 1.91 (1H, t, J=5Hz), 1.88 (1H, d, J=13Hz), 1.81 (1H, d, J=14Hz), 1.49 (1H, ddt, J=9,5, 1Hz), 1.36 (3H, s).
[α]_D ²⁵ : -79.7 (c=1.22, CHCl₃)
【０１２６】
実施例３８：（２Ｒ，３ａＳ，４ａＳ）−２−エチル−２−ヒドロキシ−３ａ−ヒドロキシメチル−ビシクロ［３．１．０］ヘキサンＩ．ｉ．３（Ａ＝ＣＨ_２ＯＨ，Ｒ_１＝Ｅｔ）（スキーム４）
４．２から、Ｉ．ｉ．１（Ｒ_１＝Ｍｅ，Ａ＝ＣＨ_２ＯＨ）と同様にして反応を行った。収率は６６．６％であった。
IR (film): : 3275.4, 2921.3, 2858.5, 1431.8, 1284.3, 1237.3, 1122.3, 1068.0, 1027.8, 930.7 cm^-1
¹H-NMR (500 MHz, in CDCl₃, ppm): 3.59 (2H, d, J=5.6Hz), 2.03 (1H, d, J=13.6Hz), 1.99 (1H, dd, J=13.9, 4.9Hz), 1.83 (1H, d, J=13.7Hz), 1.72 (1H, d, J=13.8Hz), 1.55 (2H, q, J=6.4), 1.23 (2H, m), 1.16 (1H, t, J=4.2Hz), 1.04 (1H, s), 0.92 (3H, t, 7.4Hz), 0.54 (1H, dd, J=8.4, 4.3Hz).
MS (m/z): 138 (2), 123 (4), 109 (12.9), 97 (2), 91 (6), 79 (20), 72 (6), 67 (12.9), 57 (100), 43 (8).
[α]_D ²⁵ : -34.90 (c=0.928, MeOH)
【０１２７】
実施例３９：（２Ｒ，３ａＳ，４ａＳ）−２−エチル−２−ヒドロキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサンＩ．ｉ．４（Ａ＝ＣＨＯ，Ｒ_１＝Ｅｔ）
Ｉ．ｉ．３（Ｒ_１＝Ｅｔ，Ａ＝ＣＨ_２ＯＨ）から、Ｉ．ｉ．２（Ｒ_１＝Ｍｅ，Ａ＝ＣＨＯ）と同様にして反応を行った。収率は５０％であった。
IR (film): 3418, 2966, 1689, 1114, 1057, 982, 632 cm^-1 ;
¹H-NMR (500 MHz, in CDCl₃, ppm): 8.80 (1H, s), 2.09 (2H, m), 1.92 (1H, t, J=5.0Hz), 1.83 (1H, d, J=13.3Hz), 1.69 (1H, d, J=10.0Hz), 1.57 (2H, m), 1.49 (1H, m), 1.15 (1H, s), 0.93 (3H, t, J=7.4Hz).
[α]_D ²⁵ : -68.1 (c=0.30, CHCl₃)
【０１２８】
実施例４０：（２Ｒ，３ａＳ，４ａＳ）−２−［（ｔ−ブチルジフェニルシリルオキシ）−メチル］−３ａ−ヒドロキシメチル−ビシクロ［３．１．０］ヘキサンＩ．ｊ．１（Ａ＝ＣＨ_２ＯＨ，Ｐ＝ＴＢＤＰＳ）（スキーム４）
ａ）（３ａＳ，４ａＳ）−２−メチレン−３ａ−［（ベンゾイルオキシ）メチル］−ビシクロ［３．１．０］ヘキサン４．３
攪拌した鉛粉末の（５．７５ｇ）ＣＨ_２Ｂｒ_２（２．０２ｍｌ）及びＴＨＦ（４０ｍｌ）溶液に−７８℃で１０分かけてＴｉＣｌ_４を滴下した。混合液を８℃まで加熱し、この温度で７２時間攪拌し、活性成分の濃いグレーのスラリーを得た（Ｌｏｍｂａｒｄｏ試薬）。
【０１２９】
ケトン４．２（９８ｍｇ，０．４２６ｍｍｏｌ）のＣＨ_２Ｃｌ_２（８ｍｌ）溶液に、ケトンがなくなるまで分割してＬｏｍｂａｒｄｏ試薬を室温で添加した（ＴＬＣ）。反応混合液をＥｔ_２Ｏ（４０ｍｌ）で希釈し、飽和ＮａＨＣＯ_３を加え、攪拌を３０分間継続し、２つの透明な層を形成した。水層をＥｔ_２Ｏ（３×２５ｍｌ）及びＣＨ_２Ｃｌ_２（２×２５ｍｌ）で抽出した。結合した有機層をＭｇＳＯ_４で乾燥させた。残留物をフラッシュクロマトグラフィー（シリカゲル：ペンタン／エーテル：１００：１）で精製し、化合物４．３（６６ｍｇ，６７．９％）を無色油状物として得た。
IR (film): 2925.8, 1715.6, 1451.5,1269.7, 1111.0, 1069.0, 1026.1, 741.9, 710.7 IR (film): 2925.8, 1715.6, 1451.5,1269.7, 1111.0, 1069.0, 1026.1, 741.9, 710.7 ^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 8.07 (2H, d, J=7.3Hz), 7.56 (1H, t, J=7.4Hz), 7.45 (2H, t, J=7.7Hz), 4.81 (2H, d, J=12.4Hz), 4.38 (2H, s), 2.68 (2H, m), 2.43 (1H, d, J=15.4Hz), 2.28 (1H, d, J=15.6Hz), 1.36 (1H, m), 0.68 (1H, t, J=6.5Hz), 0.39 (1H, t, J=4.5Hz).
MS (m/z): 228 (M⁺, 1), 213 (1), 199 (1), 181 (2), 169 (1), 141 (1), 123 (5), 105 (100), 91 (88), 77 (57), 65 (7), 51 (20).
[α]_D ²⁵ : -51.90 (c=1.73, CHCl₃)
【０１３０】
ｂ）（２Ｒ，３ａＳ，４ａＳ）−２−［（ｔ−ブチルジフェニルシリルオキシ）−メチル］ −３ａ−ヒドロキシメチル−ビシクロ［３．１．０］ヘキサンＩ．ｊ．１（Ａ＝ＣＨ_２ＯＨ，Ｐ＝ＴＢＤＰＳ）及び（２Ｓ，３ａＳ，４ａＳ）−２−［（ｔ−ブチルジフェニルシリルオキシ）−メチル］−３ａ−ヒドロキシメチル−ビシクロ［３．１．０］ヘキサンＩ．ｋ．１（Ａ＝ＣＨ_２ＯＨ，Ｐ＝ＴＢＤＰＳ）
アルケン４．３（４９ｍｇ，０．２１ｍｍｏｌ）のＴＨＦ（６ｍｌ）溶液に−５℃でＢＨ_３．ＴＨＦを加えた、次に反応混合液をこの温度で３．５時間攪拌した反応を飽和ＮａＨＣＯ_３水溶液（３．９ｍｌ）及びＨ_２Ｏ_２（３０％）（３．９ｍｌ）で終了させた。反応液を室温まで温め、１．５時間攪拌した。この溶液をＥｔ_２Ｏ（２×２０ｍｌ）及びＥｔＯＡｃ（２×２０ｍｌ）抽出した。結合した有機層をＭｇＳＯ_４で乾燥させ、濃縮した。残留物を短いシリカゲルカラムに通し、粗生成物をＨＰＬＣ（イソオクタン／ＥｔＯＡｃ：７：３）で精製して、エピマーヒドロキシル化生成物（２Ｒ：２Ｓ；ｒａｔｉｏ，７５：２５，３９ｍｇ，７３．７％）を無色油状物として得た。
この混合液（３５ｍｇ，０．１４２ｍｍｏｌ）、イミタゾール（４９ｍｇ，０．７２０ｍｍｏｌ，５ｅｑ．）及びＤＭＡＰ（７．８ｍｇ，０．０６４ｍｍｏｌ，０．４５ｅｑ．）のＤＭＦ（３ｍｌ）溶液にＴＢＤＰＳＣｌを−０℃で滴下した；得られた混合液を室温で１９時間攪拌した。反応液をＥｔ_２Ｏ／水（５０ｍｌ／４０ｍｌ）に注いだ。そして、水層をＥｔ_２Ｏ（３×２０ｍｌ）及びＥｔＯＡｃ（２×２０ｍｌ）で抽出した。結合した有機層をＭｇＳＯ_４で乾燥させ、濃縮した。残留物をフラッシュクロマトグラフィー（シリカゲル：イソオクタン／ＥｔＯＡｃ：１００：２）で精製し、対応するシリルエーテル（５６ｍｇ，８１．３％）無色油状物として得た。
攪拌した、この混合液（５０ｍｇ，０．１０６ｍｍｏｌ）のＭｅＯＨ（０．２ｍｌＨ_２Ｏを有する６ｍｌ）溶液に室温でＫ_２ＣＯ_３（５０ｍｇ，０．５０５ｍｍｏｌ）を加えた。混合液を室温で２０時間攪拌し、固形物をろ過し、ろ液をＥｔ_２Ｏ（５０ｍｌ）で希釈し、飽和食塩水（２×２０ｍｌ）で洗浄し、ＭｇＳＯ_４で乾燥させ、溶媒を蒸発させた。残留物を短いシリカゲルカラムに通し、ＨＰＬＣ（イソオクタン／ＥｔＯＡｃ：７５：２５）で分離し、化合物Ｉ．ｊ．１（Ａ＝ＣＨ_２ＯＨ，Ｐ＝ＴＢＤＰＳ）（２４ｍｇ，６１．８％）及びＩ．ｋ．１（Ａ＝ＣＨ_２ＯＨ，Ｐ＝ＴＢＤＰＳ）（８ｍｇ，２０．４％）を無色油状物として得た。
ＭＳ（ｍ／ｚ）：３７９（Ｍ^＋−１，１），３０５（１），２７５（２），２２９（２），１９９（４７），１８１（７），１０７（１００），７９（５３）．
化合物Ｉ．ｊ．１（Ａ＝ＣＨ_２ＯＨ，Ｐ＝ＴＢＤＰＳ）
IR (film): 3342.5, 2930.3, 2858.0, 1471.8, 1427.7, 1389.8, 1111.9, 1008.2, 823.7, 739.7, 701.6 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 7.64 (4H, d, J=7.8Hz), 7.45〜7.35 (6H, m), 3.54 (2H, dd, J=14.4, 11.2Hz), 3.41(2H, d, J=7.4Hz), 2.61 (1H, m), 2.19〜2.09 (2H, m), 1.64 (1H, dd, J=13.5, 4.8Hz), 1.47 (1H, dd, J=13.6, 4.6Hz), 1.26 (1H, bs), 1.18 (1H, dt, J=8.6, 4.3, 4.3Hz), 1.02 (9H, s), 0.62 (1H, dd, J=8.4, 4.7Hz), 0.35 (1H, t, J=4.4Hz).
[α]_D ²⁵ :-13.05 (c=1.40, CHCl₃)
【０１３１】
化合物Ｉ．ｋ．１（Ａ＝ＣＨ_２ＯＨ，Ｐ＝ＴＢＤＰＳ）
IR (film): 3342.5, 2929.9, 2856.7, 1471.6, 1427.7, 1388.8, 1111.9, 1086.1, 1031.5, 1008.5, 823.7, 739.3, 701.5 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 7.64 (4H, d, J=6.7Hz), 7.39 (6H, m), 3.64 (1H, d, J=11.2Hz), 3.57 (3H, d, J=7.8Hz), 1.97〜1.87 (2H, m), 1.80 (1H, dd, J=12.3, 7.0Hz), 1.56 (2H, m), 1.22 (1H, m), 1.15 (1H, ddd, J=8.3, 4.1, 4.1Hz), 1.02 (9H, s), 0.52 (1H, t, J=4.3Hz), 0.41 (1H, dd, J=8.0, 5.0Hz).
［α］_D ^２５： −６．１６（ｃ＝１．６５，ＣＨＣｌ_３）
【０１３２】
実施例４１：（２Ｒ，３ａＳ，４ａＳ）−２−［（ｔ−ブチルジフェニルシリルオキシ）−メチル］−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサンＩ．ｊ．２（Ａ＝ＣＨＯ，Ｐ＝ＴＢＤＰＳ）（スキーム４）
（ＣＯＣｌ）_２（３０ μｌ，０．３４４ｍｍｏｌ）のＣＨ_２Ｃｌ_２（１ｍｌ）溶液に、−７８℃でＤＭＳＯ（３６．６ μＬ，０．５１５ｍｍｏｌ）のＣＨ_２Ｃｌ_２（１００ μＬ）溶液を滴下した。混合液を−７８℃で２０分間攪拌し、Ｉ．ｊ．１（Ａ＝ＣＨ_２ＯＨ，Ｐ＝ＴＢＤＰＳ）（１４ｍｇ，０．３７ｍｍｏｌ）のＣＨ_２Ｃｌ_２（０．５ｍｌ）溶液を加えた。得られた白濁液を−７８℃で２０分間攪拌し、Ｅｔ_３Ｎ（０．２ｍｌ，１．４３５ｍｍｏｌ）を滴下して、２０分間攪拌した。次に混合液を１時間かけて室温まで加熱した。冷水を加えて反応を終了させ、有機層を分離し、水層をＥｔ_２Ｏ（３×５０ｍｌ）で抽出してＭｇＳＯ_４で乾燥させた。残留物をＨＰＬＣ（ヘキサン／ＥｔＯＡｃ９５：５）で分離し、化合物Ｉ．ｊ．２（Ａ＝ＣＨＯ，Ｐ＝ＴＢＤＰＳ）（４ｍｇ，２８．７％）を無色油状物として得た。
IR (film): 2931, 2858, 1699, 1428, 1112, 824, 740, 613 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 8.83 (1H, s), 7.63 (4H, d, J=7.4Hz), 7.68-7.35 (6H, m), 3.43 (2H, d, J=5.5Hz), 2.68 (2H, m), 2.18 (1H, m), 2.02 (1H, m), 1.59 (1H, m), 1.51 (1H, d, J=8.0Hz), 1.25 (1H, bs), 1.02 (9H, s), 0.90 (1H, m).
MS (m/z): 337 (4), 307 (2), 293 (4), 259 (2), 217 (9), 199 (54), 183 (20), 135 (24), 105 (30), 93 (100)
[α]_D ²⁵ : -52.6 (c=0.27, CHCl₃).
【０１３３】
実施例４２：（２Ｓ，３ａＳ，４ａＳ）−２−［（ｔ−ブチルジフェニルシリルオキシ）−メチル］−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサンＩ．ｋ．２（Ａ＝ＣＨＯ，Ｐ＝ＯＴＢＤＰＳ）（スキーム４）
Ｉ．ｋ．１（Ａ＝ＣＨ_２ＯＨ，Ｐ＝ＴＢＤＰＳ）から、Ｉ．ｊ．２（Ａ＝ＣＨＯ，Ｐ＝ＴＢＤＰＳ）と同様にして反応を行った。収率は９２．８％であった。
IR (film): 2932, 2858, 1703, 1471, 1427, 1112, 824, 741, 702 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 8.96 (1H, s), 7.63 (4H, m), 7.48-7.35 (6H, m), 3.58 (2H, m), 2.05-1.88 (5H, m), 1.62 (1H, m), 1.34 (1H, dd, J=8.5, 5.5Hz), 1.20 (1H, t, J=5.4Hz), 1.02 (9H, s).
MS (m/z): 337 (15), 259 (14), 231 (30), 199 (100), 137 (20), 93 (60), 77 (70).
【０１３４】
実施例４３：（２Ｓ，３ａＳ，４ａＳ）−２−メチル−２−ヒドロキシ−３ａ−ヒドロキシメチル−ビシクロ［３．１．０］ヘキサンＩ．ｌ．１（Ａ＝ＣＨ_２ＯＨ，Ｒ_１＝ＣＨ_３）（スキーム４）
Ｈｇ（ＯＡｃ）_２（３５０ｍｇ，１．１０ｍｍｏｌ）の水（１．５ｍｌ）溶液にオレフィン４．３（１６４ｍｇ，０．７１９ｍｍｏｌ）のＴＨＦ（１．５ｍｌ）溶液を滴下した。３０分間室温で攪拌した後、ＮａＯＨ水溶液（１．５ｍｌ，３Ｎ）、次に０．５ＭＮａＢＨ_４の３ＮＮａＯＨ溶液（１．５ｍｌ）を加えた。ほとんどの水銀が凝固するまで、得られた混合液を室温で２時間攪拌した。固形物をろ過した。ろ液をＥｔ_２Ｏ（２×３０ｍｌ）及びＥｔＯＡｃ（２×３０ｍｌ）で抽出した。残留物にＫ_２ＣＯ_３（５００ｍｇ，５．０５ｍｍｏｌ）及びＭｅＯＨ（２ｍｌ）を加えた。混合液を室温で２０時間攪拌し、反応混合液を短いシリカゲルカラムに通した。粗生成物をＨＰＬＣ（シクロヘキサン／ＥｔＯＡｃ：６２：４５）で精製し、化合物Ｉ．ｌ．１（Ａ＝ＣＨ_２ＯＨ，Ｒ_１＝Ｍｅ）及びＩ．ｉ．１（Ａ＝ＣＨ_２ＯＨ，Ｒ_１＝Ｍｅ）（ｒａｔｉｏ：３：１，６８ｍｇ，６６．６％）を無色油状物として得た。
IR (film): : 3288.4, 2931.3, 2858.5, 1459.1, 1370.2, 1260.7, 1183.9, 1135.7,1111.5, 1064.0, 1016.0, 922.6 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 4.02 (1H, d, J=10.7Hz), 3.07 (1H, d, J=10.7Hz), 2.05 (2H, m), 1.65 (1H, bs), 1.52 (1H, d, J=12.8Hz), 1.37 (3H, m), 1.25 (3H, s), 1.05 (1H, dd, J=8.0, 4.8Hz), 0.49 (1H, t, J=4.3Hz).
【０１３５】
実施例４４：（２Ｓ，３ａＳ，４ａＳ）−２−メチル−２−ヒドロキシ−３ａ−ホルミル−ビシクロ［３．１．０］ヘキサンＩ．ｌ．２（Ａ＝ＣＨＯ，Ｒ_１＝Ｍｅ）（スキーム４）
Ｉ．ｌ．１（Ａ＝ＣＨ_２ＯＨ，Ｒ_１＝Ｍｅ）から、Ｉ．ｊ．２（Ａ＝ＣＨＯ，Ｐ＝ＴＢＤＰＳ）と同様にして反応を行った。収率は４８．２％であった。
IR (film) : 3429, 2967, 2929, 1691, 1377, 1249, 1102, 1036, 668 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 8.90 (1H, s), 2.66 (1H, dd, J=14.3, 2.4Hz), 1.98 (2H, m), 1.88 (1H, dd, J=8.5, 5.2Hz), 1.65 (1H, bs), 1.51 (2H, t, J=14.2Hz), 1.31 (3H, s), 1.14, (1H, t, J=5.2Hz).
MS (m/z) : 140 (M⁺, 2), 123 (10), 111 (10), 97 (15), 85 (25), 71 (25), 67 (30), 48 (100).
[α]_D ²⁵ : -99.3 (c=1.06, CHCl₃)
【０１３６】
実施例４５：（２Ｓ，３ａＳ，４ａＳ）−２−ヒドロキシ−２−ヒドロキシメチル−３ａ−［（ベンジルオキシ）メチル］−ビシクロ［３．１．０］ヘキサンＩ．ｍ（Ａ＝ＣＨ_２ＯＣＯＰｈ）（スキーム４）
４．３（６５ｍｇ，０．２８５ｍｍｏｌ）及びＮＭＯ（４８ｍｇ，０．３４４ｍｍｏｌ，１．２１ｅｑ）のアセトン／水（５ｍｌ：２．５ｍｌ）溶液に，ＯｓＯ_４水溶液（１２１ μｌ，０．０２ｍｍｏｌ，４ｗｔ％，０．０７ｅｑ）を０℃で加えた。得られた溶液を３９時間室温で攪拌し、亜ジチオン酸ナトリウム（７０ｍｇ）及びフロリジル（１５０ｍｇ）を加えた。黒色沈殿物をろ過して除去し、Ｅｔ_２Ｏ（２００ｍｌ）で洗浄した。溶媒を真空化で蒸発して除去した。残留物をわずかなアセトンを有するＥｔ_２Ｏ（１００：５）に溶解し、フロリジルを通してろ過した。粗混合物をＨＰＬＣ（シクロヘキサン／ＥｔＯＡｃ：７：３）で分離し、ほとんど少数の生成物であるＣ−２エピマーの化合物Ｉ．ｍを（ｒａｔｉｏ８５．１５）無色油状物として合わせて収率６４％で得た。
IR (film): : 3385.5, 2927.8, 1713.7, 1451.6, 1315.2, 1274.6, 1114.7, 1070.3, 1026.2, 934.5, 711.5 cm^-1.
¹H-NMR (500 MHz, in CDCl₃, ppm): 8.06 (2H, d, J=7.3Hz), 7.57 (1H, t, J=7.4Hz), 7.46 (2H, t, J=7.6Hz), 4.48 (1H, d, J=11.5Hz), 4.21 (1H, d, J=11.5Hz), 3.49 (2H, m), 2.58 (1H, s), 2.36 (1H, s), 2.16 (1H, d, J=14.6Hz), 2.12 (1H, dd, J=14.2, 6.3Hz), 1.94 (1H, t, J=14.1Hz), 1.89 (1H, t, J=14.1Hz), 1.65 (1H, d, J=14.2Hz), 1.07 (1H, dd, J=8.4, 5.3Hz), 0.47 (1H, t, J=4.6Hz).
MS (m/z): 262 (M⁺, 1), 244 (1), 232 (3), 213 (4), 203 (3), 176 (1), 163 (4), 145 (4), 123 (16), 105 (100), 77 (52), 67 (13).
[α]_D ²⁵ : -11.86 (c=1.53, CHCl₃).[0001]
The present invention relates to precursors effectively used in the synthesis of 19-nor-vitamin D analogs, as well as methods and intermediates for preparing them. More specifically, the present invention relates to an A-ring precursor of the above vitamin D analog. This A ring is represented by the following structure (see, for example, Mazur et al., Tetrahedron Letters 1995, 2987).
[0002]
[Chemical 8]

[0003]
A technique for synthesizing a bicyclo [3.1.0] hexane derivative as a 19-nor-A-ring precursor from (−)-quinic acid or cyclohexane-triol is described in M.M. Vandwalle et al. (Tetrahedron Letters, 1995, 36 (45), 8299-8302) have also been developed and are based on the known sigmatropic rearrangement from cyclopropyl alcohols to homoaryl alcohols. This possibility of rearrangement in natural vitamin D was first demonstrated by Mazur et al. (Op. Cit.). In addition, a synthesis technique from 2,4-pentane-dione was also reported (SZ Zhou, S. Anne, M. Vandwalle, Tetrahedron Letters, 1996, 37 (42), 7737-7640). 3-Cyclopentenol was also used as a precursor for the above preparation (W. Yong, M. Vandwalle; Synlett, 1996, 9, 911-912).
[0004]
These methods, however, have the following disadvantages:
The preparation from-(-)-quinic acid involves radical deoxygenation reactions which are difficult to control in mass production and use toxic tributyltin hydride;
The process from cyclohexanetriol is carried out through a number of steps (12) and requires two enzymatic reactions;
The starting material 3-cyclopentenol is not commercially available. It must be prepared from cyclopentadiene using a low yield hydroboration step. Furthermore, the cyclopropanation and introduction of formyl groups is cumbersome;
Synthesis starting from -2,4-pentanedione (10 steps) results in low yields in the first step to prepare the intermediate bisepoxide. Furthermore, because of their low molecular weight, some intermediates are volatile and difficult to purify in large scale processes.
[0005]
A wide range of 19-nor-A-ring precursors have been found to be prepared by starting from 3,5-dihydroxybenzoic acid derivatives or their 4-alkyl substituted analogs. These precursors can be obtained on a large scale by methods that are more effective than previously disclosed methods.
[0006]
Accordingly, in a first aspect, the present invention provides a compound of formula (I):
[0007]
[Chemical 9]

[0008]
Where
-A is -CH₂OH group, -CH₂-OCOR 'group, -COR "group, -CSR" group or ethynyl group;
-R is hydrogen or (C₁-C₆A) alkyl;
-R₁Is hydrogen, (C₁-C₆) Alkyl or-(CH₂)_n-An OP group;
-R₂Is hydrogen or an -OP group;
-R 'is (C₁-C₆) Alkyl or phenyl;
-R "is hydrogen, hydroxyl, (C₁-C₆) Alkyl, (C₁-C₆) Alkoxy, (C₁-C₆) Alkylthio or di (C₁-C₃) Alkylamino;
-P is hydrogen; (C₁-C₆) Alkanoyl; (C₁-C₄) Benzoyl optionally substituted with phenyl by alkyl, halogen or nitro;₁-C₆) Alkoxycarbonyl; each R₃Independently (C₁-C₆) -Si (R) representing alkyl or phenyl₃)₃Group; mono or di (C₁-C₆) Alkoxy (C₁-C₆) Alkyl; tetrahydrofuranyl; or tetrahydropyranyl;
-N is 0, 1, 2, 3, or 4:
A method for preparing a compound of
(I) Formula1

[0009]
Embedded image

[0010]
Where A is (C₁-C₆) Alkoxycarbonyl, preferably methoxycarbonyl or di (C₁-C₃) Alkylaminocarbonyl, R is as defined above;
Reacting the compound of claim 1 with a lipase in a vinyl fatty acid or acid anhydride,
(Ii) the resulting formula2Or2’
[0011]
Embedded image

[0012]
Where Z is (C₁-C₆) Alkyl, such as alkyl, preferably (C₁-C₃) Alkyl;
Converting the compound of formula I to the corresponding compound of formula (I);
It is related with the preparation method which consists of.
[0013]
As shown in General Scheme 1, the starting material used to prepare the A-ring precursor is hydrogenated to methyl 3,5-dihydroxy-benzoic acid or its ester, or its 4-alkyl substituted homologous ester. , P.M. Wang and J.W. It is obtained by performing a slightly modified method from the method described by Adams in J Am Chem Soc 1994, 116, 3296-3305.
[0014]
The first step consists of 1-alkoxy (or dialkylamino) carbonyl-3,5-dihydroxy-cyclohexane or a 4-alkyl substituted analogue thereof, for example a vinyl alkanoate such as vinyl acetate, vinyl propionate or vinyl butyrate. SAM II (lipase derived from Pseudomonas fluorescens), CCL (lipase derived from Candida cylindracea), PPL (lipase derived from porcine pancreas), in a solvent of an acid anhydride such as acetic anhydride, propionic anhydride, or butyric anhydride Using lipases such as PSL (lipase derived from Pseudomonas cepacia), GCL (lipase derived from Gotrichum candidum), etc. Preferably it consists of over 6 to 72 hours at 20 ° C., to non Hitoshika made to have catalyzed by the enzyme. By this step the corresponding alkyl (or dialkyl) (1S, 3S, 5R) -3-alkylcarbonyloxy-5-hydroxy or (1S, 3S, 4R, 5R) -4-alkyl-3-alkylcarbonyloxy-5 Hydroxy-cyclohexanecarboxylate (or carboxamide) 2 or the corresponding alkyl (or dialkyl) (1S, 3S, 5R) -5-alkylcarbonyloxy-3-hydroxy or (1S, 3S, 4R, 5R) -4 -Alkyl-5-alkylcarbonyloxy-3-hydroxy-cyclohexanecarboxylate (or carboxyamide) 2 'is obtained.
[0015]
Furthermore, asymmetric reaction by hydrolyzing the diester 3 by catalyzing the diester 3 with an enantioselective enzyme can occur because it leads to the same family of compounds.
[0016]
Schemes 2 and 3 include compounds described in Scheme 1.2Or2′, R = H, R₂Describes a method for synthesizing all diastereoisomers of general formula (I) with = OP.
[0017]
Compound to Compound (I) as shown in these schemes2Or2The transformation of 'is performed using one or more of the following steps which can be performed partially or totally in various orders depending on the resulting diastereoisomers: (1) Hydroxy groups Protection (eg, P = TBDMS, TBDPS), (2) ester hydrolysis, (3) inversion of 3 or 5-hydroxy groups, (4) formation of leaving groups (eg, L = OTos, OBros, OMs) (5) Base-containing ring closure reaction to the desired bicyclo [3.1.0] hexane, (6) Conversion of the carboalkoxy or carbamoyl functional group (A) to the desired substituent A.
[0018]
Steps (2) and (4) are known reactions well known to those skilled in the art. Step (1) consists of J. Am. Chem. Soc. (1972, 94, 6190) or Protective groups in Organic Synthesis, T .; W. Can be performed according to Greene, John Wiley Sons (New York). Step (3) can be carried out according to Synthesis (1981, 1) or by a two-step process (elimination reaction, hydroboration reaction). Step (5) may be performed according to Tetrahedron Letters, 1995, 36 (45), 8299-8302. Step (6) Gen. Chem. USSR 1964, 34, 1021.
[0019]
Scheme 2 specifically describes the synthesis of all diastereoisomers with a 3aS configuration (α-oriented cyclopropyl ring).
[0020]
Scheme 3 specifically describes the synthesis of all diastereoisomers with a 3aR configuration (β-oriented cyclopropyl ring).
[0021]
As shown in general scheme 4, R = H and A = CH₂The 3a hydroxymethyl-substituted bicyclo [3.1.0] hexane compound (I) of OH can be useful for the synthesis of A-ring precursors to vitamin D analogs that are modified with C-1. The possibility is that I.I. uses ketone 4.2 as an important intermediate. a (R = H, P = TBDPS, A = CH₂OH). Grignard reaction (eg R₁= Tertiary alcohols diastereoselectively by Me or Et). i is obtained, and at the same time removal of the protected ester functionality occurs. On the other hand, 4.3 is obtained by methyleneation of 4.2. The best results (68% yield) are obtained by the Lombardo method (Tetrahedron Lett., 1982, 23, 4293). Also, yields of 39% and 54% are obtained by Wittig or Tube reaction (J. Org. Chem., 1985, 50, 1212), respectively.
[0022]
The dihydroxylation of 4.3 leads to the desired diol I.D as the next major product of epimer 4.4. m. (Ratio 85:15: not shown here). On the other hand, the hydroboration of 4.3 gives 2R and 2S hydroxymethyl compounds in a ratio of 75:25 (73%). These epimeric alcohols were separated and formed after TBDPS ether formation I.D. j is obtained (81%) and then after ester hydrolysis I. k is obtained (81%). In 4.3, tertiary alcohol I.V. l, then I.I. i is obtained in a ratio of 75:25.
[0023]
The new method of preparing 19-nor A-ring precursors from 3,5-dihydroxybenzoic acid derivatives is shorter than previously described methods. The practical importance of the above pathway is mainly due to the fact that most of the intermediates are crystalline and can be purified by crystallization which is easier on a large scale than the traditional purification method by silica gel chromatography, Guarantees the high purity of the isomers.
[0024]
Embedded image

[0025]
Embedded image

[0026]
Embedded image

[0027]
Embedded image

[0028]
All the compounds (I) thus prepared have the configurations 2S, 3aS, 4aS (A is a formyl group, a hydroxymethyl group, an ethynyl group or a methoxycarbonyl group, and R and R₂Are both hydrogen and R₁Is -OSi (R₃)₃The compound is new).
[0029]
Accordingly, these novel compounds represent another feature of the present invention.
Preferred compounds (I) include
-A is -CH₂OH group, -CH₂-OCOR 'group, -COR "group or ethynyl group;
-R₁Is (C₁-C₆) Alkyl or-(CH₂)_n-An OP group;
-R 'is phenyl;
-R "is hydrogen;
-P is hydrogen or -Si (R₃)₃A group;
-N is 0 or 1
Compounds.
[0030]
Compound (I) is, for example, Tetrahedron Letters, 1996;37 (42): Vitamin D (19-nor, 1α, 25 (OH) according to the following scheme described in 7637-7640₂-D₃).
[0031]
Embedded image

[0032]
The present invention further relates to intermediates for preparing compound (I). In particular, the invention relates to formula (II):
[0033]
Embedded image

[0034]
In the formula:
-A and R are as defined above,
-R₄And R₅Each independently represents a P group, a mesyl group, a tosyl group, a brosyl group, or a trifluoromesyl group as defined above,
However, when A is methoxycarbonyl and R is hydrogen, the configuration of compound (II) is not 1R, 3R, 5R:
Of diastereoisomeric compounds of
[0035]
Also the formula2Or2':
[0036]
Embedded image

Where
-A and R are as defined above,
-Z is alkyl:
A compound of the formula1:
[0037]
Embedded image

[0038]
Where A is the same as defined above and R is (C₁-C₆) Is alkyl:
These compounds are also within the scope of the present invention.
[0039]
In this specification and the appended claims, “(C₁-C₃) Alkyl "," (C₁-C₄) Alkyl "or" (C₁-C₆The term “alkyl” refers to 1 to 3 groups (4 or 4 respectively) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl or hexyl. It is to be understood that a straight or branched hydrocarbon chain containing 6) carbon atoms is intended.
[0040]
"(C₁-C₆) Alkoxy "or" (C₁-C₆) "Alkylthio" means that R is (C₁-C₆It is to be understood that each of the OR and SR groups that are alkyl) is intended.
The invention will now be illustrated by the following preparation methods and examples.
[0041]
Preparation of intermediates of formula I
a) Cis, cis-3,5-dihydroxy-1- (methoxycarbonyl) cyclohexane: 1. A (R = H, A = COOCH₃)
Peng Wang and Julian Adams described J. W. et al. Am. Chem. Soc. Methyl 3,5-dihydroxybenzoate was hydrogenated in MeOH under conditions similar to those described in (1994, 116, 3296-3305).
5% Rh / Al containing methyl 3,5-dihydroxybenzoate (57.6 g, 0.629 mol, 97%), 0.1% AcOH₂O₃A solution of (5.76 g) in MeOH (400 ml) was added to the autoclave (1 L). Steam was applied twice using hydrogen in the autoclave (130 atm to 40 atm). The hydrogen pressure reached 130 atm and the temperature rose to 80-85 ° C. The hydrogen pressure decreases as the temperature rises. When the pressure dropped to 90 atm, the hydrogen pressure rose again to 130 atm. Hydrogenation was carried out at 80-85 ° C. and 130 atm for 12 hours, then heated to 150 ° C., correspondingly reaching a pressure of about 155 atm. The reaction lasted 36 hours. The catalyst is filtered, the filtrate is concentrated and the residue is crystallized from EtOAC / isooctane. A was obtained (31.1 g, yield 50%).
mp: 135.9 ° C;
UV (EtOH): 211.4 nm (ε = 90.9);
IR (KBr): 3284, 1734, 1259, 1015 cm^-1 ;
¹H-NMR (DMSO-d₆): δ1.13 (3H, m); 2.06 (3H, m); 2.30 (1H, m); 3.47 (2H, m); 3.61 (3H, s); 4.70 (2H, d) ppm.
[0042]
The same reaction as described above was performed except that methyl 3,5-dihydroxybenzoate was replaced with the following compound:
-Methyl 3,5-dihydroxy-4-methylbenzoate, or
-Methyl 3,5-dihydroxy-4-ethylbenzoate:
The following compounds were obtained:
-Methylol-cis-3,5-dihydroxy-4-methyl-cyclohexanecarboxylate: 1. B (R = Me, A = COOCH₃)
mp: 123 ° C;
¹H-NMR (500 MHz, CD_ThreeOD): δ3.698 (2H, dt, J = 4.0,12.0 Hz); 3.666 (3H, s); 2.40 (2H, tt, J = 4.0,13.0 Hz); 2.23 (1H, m); (2H, dt, J = 4.0,13.0 Hz); 1.54 (2H, q, J = 13.0 Hz); 0.88 (3H, d, J = 7.08 Hz) ppm.
-Methylol-cis-4-ethyl-3,5-dihydroxy-cyclohexanecarboxylate: 1. C (R = Et, A = COOCH₃)
mp: 94-96 ° C;
¹H-NMR (500 MHz, MeOD): δ3.72 (2H, dt, J = 10.9, 4.1 Hz), 3.66 (3H, s), 2.42 (1H, m), 1.86 (1H, bs), 1.79 (2H , dt, J = 12.8, 4.1 Hz), 1.59 (2H, d, J = 9.0 Hz), 1.46 (2H, m), 1.02 (3H, t, J = 7.5 Hz) ppm.
[0043]
Preparation of intermediates of formula 2 and 2 ′ (Scheme 1)
I) Enzymatic esterification of general formula (I) with diol
Ia) Methyl (1S, 3S, 5R) -3-acetoxy-5-hydroxy-cyclohexanecarboxylate: 2. A (R = H, Z = Me, A = COOCH₃)
Methyl cis, cis-3,5-dihydroxy-cyclohexanecarboxylate A (R = H, A = COOCH₃) (15.2 g, 87 mmol) and lipase derived from porcine pancreas (PPL-16.8 U / mg, 9.12 g) in a round flask, followed by addition of vinyl acetate (450 ml) at room temperature It was. The flask was replaced with nitrogen and the suspension was stirred in the dark for 22 hours. It was then filtered through a pad of celite to remove the lipase. The filtrate was evaporated and concentrated. The residue was isolated by filtration through a pad of silica gel (70-200 mesh, 45 g). Elution with toluene (210 mL), followed by a mixture of toluene / ethyl acetate = 75/25 (V / V, 210 mL), followed by a mixture of toluene / ethyl acetate = 50/50 (V / V, 210 mL) Elute and finally elute with ethyl acetate (240 mL) and after concentration 2. A (R = H, Z = Me, A = COOCH₃) (22.3 g, yield) was obtained as a yellow oil.
IR (film): 3447, 1734, 1243 cm^-1 ;
¹H-NMR (CDCl_Three): δ1.4 (3H, m), 2.1 (3H, s), 2.3 (5H, m), 3.7 (3H, s), 3.75 (1H, m), 4.7 (1H, m) ppm;
[α]_D ^{twenty five} : +22.4 (c = 1.25, CHCl_Three).
[0044]
Ib) Methyl (1R, 3S, 4S, 5R) -5-acetoxy-3-hydroxy-4-methylcyclohexanecarboxylate: 2 '. B (R = Me, Z = Me, A = COOCH₃) And methyl (1R, 3S, 4S, 5R) -5-acetoxy-3-hydroxy-4-ethylcyclohexanecarboxylate: 2 '. C (R = Et, Z = Me, A = COOCH₃)
From each of the following compounds by a procedure similar to that described for Ia except that PPL is replaced with SAM II, PSL or CCL:
-Methylolcis-3,5-dihydroxy-4-methyl-cyclohexanecarboxylate: 1. B (R = Me, A = COOCH₃)
-Methylolcis dihydroxy-4-ethyl-3,5-cyclohexanecarboxylate: 1. C (R = Et, A = COOCH₃)
The following compounds were obtained:
-Methyl (1R, 3S, 4S, 5R) -5-acetoxy-3-hydroxy-4-methyl-cyclohexanecarboxylate: 2 '. B (R = Me, Z = Me, A = COOCH₃):
IR (film): 3434, 1731, 1439, 1243, 1027 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ4.84 (1H, dt, J = 4.3, 4.3 Hz); 3.82 (1H, m); 3.69 (3H, s); 2.45 (1H, m); 2.32 (1H, d, J = 6.4 Hz) ; 2.05 (3H, s); 1.92 (2H, dt, J = 4.0,
4.0 Hz); 1.77 (3H, m); 0.96 (3H, d, J = 7.0 Hz) ppm;
MS (m / z): 231 (M +, 1); 213; 199; 186; 170; 152; 127; 111; 83; 87; 67; 43 (base peak);
[α]_D ^{twenty five} : -22.7 (c = 0.38, CHCl_Three).
Methyl (1R, 3S, 4S, 5R) -5-acetoxy-4-ethyl-3-hydroxy-cyclohexanecarboxylate: 2 '. C (R = Et, Z = Me, A = COOCH₃):
IR (film): 3421, 2958, 2360, 1733, 1437, 1239, 1027, 739 cm^-1
¹H-NMR (500 MHz, CDCl_Three): δ4.98 (1H, t, J = 4.1 Hz), 3.87 (1H, m), 3.69 (3H, s), 2.60 (1H, bs), 2.16 (2H, m), 2.02 (3H, s) , 1.84 (2H, m), 1.72 (1H, bs), 1.59 (2H, m), 1.47 (1H, m), 0.97 (3H, t, J = 7.5 Hz) ppm;
MS (m / z): 245 (M⁺+1), 233, 206, 184, 166, 141, 125, 111, 95, 87, 57, 43 (base peak).
[α]_D ^{twenty five}: -50.2 (c = 1.08, CHCl_Three).
[0045]
II) Enzymatic hydrolysis of diesters of formula 3
IIa) Methyl (1S, 3S, 5R) -3-acetoxy-5-hydroxy-cyclohexane-carboxylate: 2. A (R = H, Z = Me, A = COOCH₃)
2. Meso-diacetate A (R = H, Z = Me, A = COOCH₃) (92.1 mg, 0.36 mmol) of 3.0 ml CH₃To the CN solution was added 27.0 ml buffer (pH = 7.0), followed by SAM II (13.8 mg, 46.8 U / mg). The resulting mixture was stirred at room temperature and an accurately measured 1.0 M NaOH solution was added to keep the pH at 7.0. The reaction was measured by thin layer chromatographic analysis. NaCl was added to terminate the reaction and saturate the reaction solution. The reaction mixture was extracted with AcOEt (3 × 50 ml). The combined organic extracts were washed with saturated brine (3 x 10 ml) and MgSO₄Dried and concentrated. The residue was purified by HPLC eluting with isooctane / EtOAc (6: 4) and monoacetate2. A (R = H, Z = Me, A = COOCH₃) (30.1 mg, 38.9%) was obtained as a colorless oil.
[0046]
IIb) Methyl (1S, 3R, 4R, 5S) -3-butanoyloxy-5-hydroxy-4-methyl-cyclohexane-carboxylate: 2B (R = Me, Z = n-C)₃H₇, A = COOCH₃)
1. B (R = Me, A = COOCH₃) (0.2 g, 1.10 mmol) CH₂Cl₂To the (2 ml) solution was added butyric anhydride (538 μl, 3.29 mmol) at room temperature, followed by a solution of TMSoTf (trimethylsilyl triflate) (25 μl, 1M). The mixture was stirred at room temperature for 30 minutes, 2.5 ml of MeOH was added and stirred for an additional 2 hours, 5% NaHCO 3.₃The reaction was terminated. The reaction solution was washed with saturated brine (3 × 20 ml), washed with MgSO 4₄And concentrated to give a residue. The residue was purified by silica gel chromatography using isooctane: AcOEt (9: 1) as an eluent. B (R = Me, Z = n-C₃H₇, A = COOCH₃) (3.9 g, 98.8%) as a colorless oil. This meso-diester (110 mg, 0.34 mmol) in CH₃To the CN (2.0 ml) solution was added 22.0 ml of buffer (pH = 7.0) followed by SAM II (37 mg, 46.8 U / mg). The resulting mixture was stirred at room temperature and an accurately measured 1.0 M NaOH solution was added to keep the pH at 7.0. The reaction was measured by thin layer chromatographic analysis. NaCl was added to the reaction solution to terminate the reaction. The reaction mixture was extracted with EtOAc (3 x 50 ml) and MgSO₄And concentrated to give a residue. The residue was purified by HPLC eluting with isooctane / EtOAc (7: 3) to give monobutyrate2. B (R = Me, Z = n-C₃H₇, A = COOCH₃) (78 mg, 90%) was obtained as a colorless oil.
IR (film): 3495, 2964, 2878, 1731, 1438, 1281, 1183, 990 cm^-1,
¹H-NMR (CDCl_Three): 4.83 (1H, dt), 3.83 (1H, m), 3.68 (3H, s), 2.45 (1H, m), 2.32 (1H, m), 2.28 (2H, t, J = 7.9 Hz), 1.91 (2H, m), 1.82-1.62 (5H, m), 0.95 (6H, m).
[α]_D ^{twenty five} : +16.2 (c = 2.09, CHCl_Three)
MS: 259 (M⁺+1), 227, 214, 187, 170, 152, 127, 111, 93, 71, 43
[0047]
IIc) Methyl (1S, 3R, 4R, 5S) -3-acetoxy-5-hydroxy-4-methyl-cyclohexanecarboxylate: 2. C (R = Me, Z = Me, A = COOCH₃)
2. Meso-diacetate C (R = Me, Z = Me, A = COOCH₃To IIa) as described.
[α]_D ^{twenty five} : +20 (c = 2.9, CHCl_Three)
[0048]
IId) Methyl (1R, 3S, 4S, 5R) -5-acetoxy-3-hydroxy-4-methyl-cyclohexanecarboxylate: 2 '. B (R = Me, Z = Me, A = COOCH₃)
2. Meso-diacetate, except that PPL was used as the lipase. C (R = Me, Z = Me, A = COOCH₃To IIa) as described.
[α]_D ^{twenty five} : -19.5 (c = 2.88, CHCl_Three)
[0049]
Example 1: (2S, 3aS, 4aS) -2-t-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. b. 1 (A = COOCH₃, R = H, P = TBDMS)
a) Methyl (1R, 3S, 5R) -3-acetoxy-5-tosyloxy-cyclohexanecarboxylate: 2.4. a (R = H, L = OTos, A = COOCH₃)
1. Methyl (1S, 3S, 5R) -3-acetoxy-5-hydroxycyclohexanecarboxylate in a mixture of triethylamine (50 ml) and methylene chloride (10 ml) A (R = H, Z = Me, A = COOCH₃) (10.1 g, 43.7 mmol) and dimethylamino-pyridine (0.1 g) solution was added p-toluenesulfonyl chloride (13.3 g, 70 mmol) at 0 ° C. The resulting solution was stirred at 0 ° C. for 1 hour and then at room temperature for 22 hours. The reaction was terminated with water (300 ml) and extracted with methylene chloride. The organic layer is washed with water and MgSO₄Dried, filtered, and concentrated. The crude product is crystallized from EtOH, 2.4. a (R = H, L = OTos, A = COOCH₃) (13.2 g, 81.6%).
mp: 83.1 ° C;
IR (KBr): 1734, 1175 cm^-1 ;
¹H-NMR (CDCl_Three): δ 1.5 (3H, m), 2.0 (3H, s), 2.28 (4H, m), 2.47 (3H, s), 3.68 (3H, s), 4.4 (1H, m), 4.68 (1H, m ), 7.35 (1H, d, J = 8.5Hz), 7.8 (2H, d, J = 8.5 Hz) ppm.
[0050]
b) Methyl (1R, 3S, 5R) -3-hydroxy-5-tosyloxy-cyclohexanecarboxylate: 2.5. a (R = H, L = OTos, A = COOCH₃)
2.4. a (R = H, L = OTos, A = COOCH₃) (23.35 g, 63 mmol) in MeOH suspension was added potassium carbonate (4.36 g, 31 mmol). The resulting suspension was stirred for 30 minutes and poured into water (1.5 L). The precipitate is filtered and dried to 2.5. a was obtained (R = H, L = OTos, A = COOCH₃) (18.5 g, 89%).
mp: 98.4 ° C;
UV (EtOH): 225 nm (ε = 11935);
IR (KBr): 3447, 1719, 1176 cm^-1 ;
¹H-NMR (CDCl_Three): δ1.52 (4H, m), 2.25 (4H, m), 2.45 (3H, s), 3.6 (1H, m), 3.68 (3H, s), 4.42 (1H, m), 7.35 (2H, d, J = 8.5Hz), 7.8 (2H, d, J = 8.5 Hz) ppm; [α]_D ^{twenty five} : -19 (c = 1.00, EtOH)
[0051]
c) Methyl (1R, 3R, 5R) -3-benzoyloxy-5-tosyloxy-cyclohexanecarboxylate: 2.6. a (R = H, L = OTos, A = COOCH₃)
0 ° C., 2.5. a (R = H, L = OTos, A = COOCH₃) (18.35 g, 56 mmol), triphenylphosphine (18.4 g, 70 mmol), and benzoic acid (8.53 g, 70 mmol) in toluene (180 ml) and THF (70 ml). To was added diethyl azodicarboxylate (11 ml, 70 mmol). The resulting mixture was stirred at room temperature for 30 minutes, heptane (735 ml) was added, and the filtrate was concentrated by filtration. Toluene was added to the crude product and the resulting solution was filtered using a silica gel pad (30-70 mesh). Elution with toluene, followed by elution with a toluene / methylene chloride mixture and concentration gave a residue. The residue is crystallized from EtOH to 2.6. a (R = H, L = OTos, A = COOCH₃) (19.77 g, 82%).
mp: 76.2 ° C;
UV (EtOH): 227 nm (ε = 20840);
IR (KBr): 1709, 1177 cm^-1 ;
¹H-NMR (CDCl_Three): δ1.7 (3H, m), 2.14 (2H, m), 2.35 (3H, s), 2.48 (1H, m), 2.83 (1H, m), 3.18 (3H, s), 4.75 (1H, m), 5.43 (1H, m), 7.2 (2H, d, J = 11.4Hz), 7.5 (2H, d, J = 8.5Hz), 7.6 (1H, m), 7.75 (2H, d, J = 11.4 Hz), 7.94 (2H, d, J = 8.5Hz) ppm;
[α]_D ^{twenty five} : -65.8 (c = 0.98, EtOH).
[0052]
d) Methyl (1R, 3R, 5R) -3-hydroxy-5-tosyloxy-cyclohexanecarboxylate: 2.7. a (R = H, L = OTos, A = COOCH₃  )
2.6. a (R = H, L = OTos, A = COOCH₃) (19.77 g, 46 mmol) in MeOH suspension was added potassium carbonate (3.16 g, 22.9 mmol). The resulting mixture was stirred at room temperature for 6 hours and poured into water (1 L). The aqueous layer is extracted with diisopropyl oxide and MgSO.₄, Filtered and concentrated to 2.7. a (R = H, L = OTos, A = COOCH₃) (17.45 g, quantitative analysis) was obtained as an oil.
UV (EtOH): 224 nm (ε = 12262);
IR (KBr): 3525, 1731, 1174 cm^-1 ;
¹H-NMR (CDCl_Three): δ1.67 (3H, m), 2.1 (3H, m), 2.45 (3H, s), 2.85 (1H, m), 3.7 (3H, s), 4.3 (1H, s), 4.82 (1H, m), 7.35 (2H, d, J = 8.5Hz), 7.8 (2H, d, J = 8.5Hz) ppm;
[α]_D ^{twenty five} : -36.7 (c = 1.06, CHCl_Three)
[0053]
e) Methyl (1R, 3R, 5R) -3-t-butyldimethylsilyloxy-5-tosyloxy-cyclohexanecarboxylate: 2.8. a (R = H, L = OTos, P = TBDMS, A = COOCH₃)
2.7. a (R = H, L = OTos, A = COOCH₃) (17.45 g, 46 mmol) and imidazole (3.9 g, 57 mmol) in anhydrous dimethylformamide (80 ml) were added t-butyldimethylsilyl chloride (8.6 g, 57 mmol). It was. The resulting mixture was stirred at room temperature for 1.5 hours, poured onto water and extracted with toluene. The organic layer was washed with water and concentrated. The crude product is crystallized from heptane 2.8. a (R = H, L = OTos, P = TBDMS, A = COOCH₃) (13.94 g, 69%).
mp: 68.2 ° C;
UV (EtOH): 225 nm (ε = 12390);
IR (KBr): 2853, 1726, 1436, 1359, 1173, 831 cm^-1 ;
¹H-NMR (CDCl_Three): δ0.02 (3H, s), 0.05 (3H, s), 0.82 (9H, s), 1.55 (4H, m), 1.85 (2H, m), 2.45 (3H, s), 2.8 (1H, m), 3.67 (3H, s), 4.2 (1H, bs), 4.7 (1H, m), 7.33 (2H, d, J = 8.5Hz), 7.8 (2H, d, J = 8.5Hz) ppm;
[α]_D ^{twenty five} : -41.6 (c = 1.00, EtOH).
[0054]
f) (2S, 3aS, 4aS) -2-t-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. b. 1 (R = H, P = TBDMS, A = COOCH₃)
Stir 2.8 at 64 ° C. a (R = H, L = OTos, P = TBDMS, A = COOCH₃) (378.5 g, 856 mmol) in t-butanol was slowly added t-butanol solution (1.02 L) in potassium t-butyrate over 1 hour. Five minutes after the end of the addition, the resulting suspension was cooled to 30 ° C. and a saturated solution of ammonium chloride (3 L) was added. After 10 minutes, the aqueous layer was extracted with diisopropyl oxide. The organic layer is washed with water and MgSO₄Dried, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with a heptane / ethyl acetate mixture. b. 1 (R = H, P = TBDMS, A = COOCH₃) (211.3 g, 91.3%) as a yellow oil.
Eb₇₆₀ : 135 ° C;
UV (EtOH): 201 nm (ε = 742);
IR (film) 1726 cm^-1, 1458 cm^-1, 1437 cm^-1, 1254 cm^-1, 837 cm^-1 ;
¹H-NMR (CDCl_Three): δ0.01 (6H, s), 0.83 (9H, s), 1.28 (2H, m), 1.8 (2H, m), 2.11 (3H, m), 3.65 (3H, s), 3.9 (1H, m) ppm;
[α]_D ^{twenty five} : -43 (c = 1.04, EtOH).
[0055]
Example 2: (2S, 3aS, 4aS) -2-t-butyldimethylsilyloxy-3a- (hydroxymethyl) -bicyclo [3.1.0] hexane: I. b. 2 (R = H, P = TBDMS, A = CH₂OH)
(2S, 3aS, 4aS) -2-t-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane b. 1 (R = H, P = TBDMS, A = COOCH₃) (207.5 g, 768 mmol) in toluene (2.1 L) (-70 ° C.) was added 1.5 M diisobutylammonium hydride in toluene (1.25 L) over 1.5 hours. . After the addition was complete, a saturated solution of potassium sodium tartrate was slowly added and heated to 0 ° C. After stirring for 2 hours, the reaction mixture was extracted with toluene and the organic layer was washed with MgSO.₄And concentrated to the title compound I.I. b. There were obtained 142.9 g (88%) of 2 as a yellow oil.
IR (KBr): 3355, 1471, 1255, 835, 774 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.32 (1H, m), 0.5 (1H, m), 0.83 (9H, s), 1.16 (1H, m), 1.87 (5H, m), 3.54 (2H, m) , 4.0 (1H, m) ppm
[0056]
Example 3: (2S, 3aS, 4aS) -2-t-butyldimethylsilyloxy-3a-formyl-bicyclo [3.1.0] hexane: I. b. 3 (R = H, P = TBDMS, A = CHO)
I. b. 2 (R = H, P = TBDMS, A = CH₂OH) (69.6 g, 287 mmol) in methylene chloride (700 ml) was added pyridinium chlorochromate (68 g, 315 mmol) at room temperature. The resulting mixture was stirred vigorously for 1 hour. Heat to 35 ° C and then cool to 25 ° C. The suspension was filtered through a pad of celite and washed with methylene chloride and diisopropyl oxide. The organic layer was washed sequentially with water, a saturated solution of sodium bicarbonate, and water at pH 6-7. Combined organic layer is MgSO₄Dried, filtered, and concentrated. The residue (66.8 g) was purified by flash chromatography over florisil using heptane / ethyl acetate = 95/5 (V / V) as eluent. b. 3 (R = H, P = TBDMS, A = CHO) was obtained as a yellow oil (50.33 g, 73%).
UV (EtOH): 204 nm (ε = 6292);
IR (KBr): 1726, 1253, 1119, 838 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.87 (9H, s), 1.3 (2H, m), 1.85 (2H, m), 2.1 (3H, m), 4 (1H, m), 8.9 (1H, s) ppm;
[α]_D ^{twenty five} : -49.4 (c = 1.06, EtOH).
[0057]
Example 4: (2R, 3aR, 4aR) 2-t-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. h. 1 (R = H, A = COOCH₃, P = TBDMS)
a) Methyl (1R, 3S, 5S) -3-acetoxy-5-benzoyloxy-cyclohexanecarboxylate: 3.9. a (R = H, A = COOCH₃2.6. a (R = H, L = OTos, A = COOCH₃) Methyl (1S, 3S, 5R) -3-acetoxy-5-hydroxy-cyclohexanecarboxylate 2. A (R = H, Z = Me, A = COOCH₃) (25 g, 111.3 mmol) methyl (1R, 3S, 5S) 3-acetoxy-5-benzoyloxy-cyclohexanecarboxylate 3.9. a (R = H, A = COOCH₃) (32.4 g, 91%).
¹H-NMR (CDCl_Three): δ1.68 (3H, m), 2.05 (3H, s), 2.34 (3H, m), 2.92 (1H, m), 3.70 (3H, s), 5.18 (1H, m), 5.55 (1H, m), 7.50 (3H, m), 8.05 (2H, m) ppm;
[α]_D ^{twenty five}: +42.3 (c = 0.82, CHCl_Three)
[0058]
b) Methyl (1R, 3S, 5S) -5-benzoyloxy-3-hydroxy-cyclohexanecarboxylate: 3.10. a (R = H, A = COOCH₃) Methyl (1R, 3S, 5S) -3-acetoxy-5-benzoyloxy-cyclohexanecarboxylate: 3.9. a (R = H, A = COOCH₃) (32.4 g, 151, 9 mmol) 2.5. a (R = H, L = OTos, A = COOCH₃). The crude product is purified by flash chromatography on silica gel and 3.10. a (R = H, A = COOCH₃) (22.38 g, 79.5%).
¹H-NMR (CDCl_Three): δ 1.63 (4H, m), 1.92 (1H, s), 2.3 (2H, m), 2.86 (1H, m), 3.7 (3H, s), 4.1 (1H, m), 5.53 (1H, m ), 7.5 (3H, m), 8.0 (2H, m) ppm;
[α]_D ^{twenty five} : -13.5 (c = 1.43, CHCl_Three)
[0059]
c) Methyl (1S, 3S, 5S) -5-benzoyloxy-3-tosyloxy-cyclohexanecarboxylate: 3.11. a (R = H, L = OTos, A = COOCH₃)
Alcohol 3.10. a (R = H, A = COOCH₃) (25.2 g, 90.88 mmol) in 2.4. a (R = H, L = OTos, A = COOCH₃Tosylate. Purify by flash chromatography (heptane / ethyl acetate = 7/3) and crystallize from heptane / EtOH to give 3.11. a (R = H, L = OTos, A = COOCH₃) (39.75 g) was obtained in a measurable yield.
mp: 128.4 ° C;
IR (KBr): 2950, 1715, 1175, 939 cm^-1 ;
¹H-NMR (CDCl_Three): δ1.7 (3H, m), 2.18 (2H, m), 2.38 (3H, s), 2.5 (1H, m), 2.85 (1H, m), 3.68 (3H, s), 4.76 (1H, m), 5.43 (1H, m), 7.19 (2H, d), 7.5 (2H, d), 7.58 (1H, m), 7.77 (2H, d), 7.96 (2H, d) ppm;
[α]_D ^{twenty five} : +69 (c = 1.014, CHCl_Three).
[0060]
d) Methyl (1S, 3S, 5S) -5-hydroxy-3-tosyloxy-cyclohexanecarboxylate: 3.12. a (R = H, L = OTos, A = COOCH₃)
3.11. a (R = H, L = OTos, A = COOCH₃) (38.25 g, 88.4 mmol) to 2.7. a (R = H, L = OTos, A = COOCH₃  ) And methyl (1S, 3S, 5S) -5-hydroxy-3-tosyloxy-cyclohexanecarboxylate 3.12. a (R = H, L = OTos, A = COOCH₃) (29.25 g) was obtained as a yellow oil in a measurable yield.
¹H-NMR (CDCl_Three): δ1.6 (4H, m), 2.08 (3H, m), 2.47 (3H, s), 2.83 (1H, m), 3.68 (3H, s), 4.3 (1H, m), 4.82 (1H, m), 7.36 (2H, d), 7.8 (2H, d) ppm.
[0061]
e) Methyl (1S, 3S, 5S) -5-t-butyldimethylsilyloxy-3-tosyloxy-cyclohexanecarboxylate: 3.13. a (R = H, L = OTos, P = TBDMS, A = COOCH₃)
3.12. a (R = H, L = OTos, A = COOCH₃) (29.2 g, 89.07 mmol) to 2.8. a (R = H, L = OTos, P = TBDMS, A = COOCH₃The reaction was carried out in the same manner as in (1). Purification by flash chromatography on silica gel (heptane / ethyl acetate = 8/2) 3.13. a (R = H, L = OTos, P = TBDMS, A = COOCH₃) (34.8 g, 88%) as a yellow oil.
IR (film): 2953, 2855, 1725, 1278, 1177, 949 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, d), 0.85 (9H, s), 1.55 (3H, m), 1.88 (2H, m), 2.38 (1H, s), 2.48 (3H, s), 2.82 (1H, m) , 3.7 (3H, s), 4.2 (1H, m), 4.7 (1H, m), 7.8 (2H, d), 8.09 (2H, d) ppm;
[α]_D ^{twenty five} : +29.5 (c = 1.06, EtOH)
[0062]
f) (2R, 3aR, 4aR) -2-t-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. h. 1 (R = H, P = TBDMS, A = COOCH₃)
3.13. a (R = H, L = OTos, P = TBDMS, A = COOCH₃) (33.2 g, 75 mmol). b. 1 (A = COOCH₃, R = H, P = TBDMS). Purification by flash chromatography on silica gel (heptane / ethyl acetate = 95/5) and (2R, 3aR, 4aR) -2-tert-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] Hexane I. h. 1 (R = H, P = TBDMS, A = COOCH₃) (15.5 g, 78%) as a yellow oil.
IR (film): 2952, 2856, 1724, 1113, 837 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.85 (9H, s), 1.11 (1H, d), 1.27 (2H, m), 1.6 (3H, s), 1.8 (1H, m), 2.11 (3H, m) , 3.65 (3H, s), 3.9 (1H, m) ppm;
[α]_D ^{twenty five} : +38.3 (c = 1.122, EtOH)
[0063]
Example 5: (2R, 3aR, 4aR) -2-t-butyldimethylsilyloxy-3a- (hydroxymethyl) -bicyclo [3.1.0] hexane: I. h. 2 (R = H, P = TBDMS, A = CH₂OH)
(2R, 3aR, 4aR) -2-tert-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane h. 1 (R = H, P = TBDMS, A = COOCH₃) (15.15 g, 56 mmol). b. 2 (R = H, P = TBDMS, A = CH₂OH) using conditions similar to h. 2 (R = H, P = TBDMS, A = CH₂OH) (11.85 g, 87%).
IR (film): 3354, 2928, 2856, 1255, 835 cm^-1 ;
¹H-NMR (CDCl_Three): δ 0.1 (6H, s), 0.35 (1H, t), 0.5 (1H, t), 0.86 (9H, s), 1.17 (1H, s), 1.85 (5H, m), 3.52 (2H, m ), 4.0 (1H, m) ppm;
[α]_D ^{twenty five} : +17.4 (c = 1.15, EtOH)
[0064]
Example 6: (2R, 3aR, 4aR) -2-t-butyldimethylsilyloxy-3a-formyl-bicyclo [3.1.0] hexane: I. h. 3 (R = H, P = TBDMS, A = CHO)
I. h. 2 (R = H, P = TBDMS, A = CH₂OH) (11.3 g, 46.6 mmol) to I.I. b. 3 (R = H, P = TBDMS, A = CHO). h. 3 (R = H, P = TBDMS, A = CHO) (6.2 g, 55%) was obtained as a yellow oil.
UV (EtOH): 204.5 mm (ε = 6600);
IR (film): 2930, 2880, 2856, 1705, 1119, 1097, 836 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.83 (9H, s), 0.95 (1H, t), 1.22 (2H, m), 1.85 (2H, m), 2.1 (3H, m), 4.0 (1H, quintuplet) , 8.87 (1H, s) ppm;
[α]_D ^{twenty five} : +53.6 (c = 1.008, EtOH)
[0065]
Example 7: (2R, 3aR, 4aR) -2-t-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. a. 1 (R = H, P = TBDMS, A = COOCH₃)
a. Methyl (1R, 3S, 5R) -3-tert-butyldimethylsilyloxy-5-tosyloxy-cyclohexanecarboxylate: 2.3. a (R = H, L = OTos, P = TBDMS, A = COOCH₃)
Methyl (1R, 3S, 5R) -3-hydroxy-5-tosyloxy-cyclohexanecarboxylate: 2.5. a (R = H, L = OTos, A = COOCH₃) (29.3 g, 89.2 mmol) has a hydroxy functionality of 2.8. a (R = H, L = OTos, P = TBDMS, A = COOCH₃Protected in the same manner as 2.3). a (R = H, L = OTos, P = TBDMS, A = COOCH₃) (36,75 g, 93%).
mp: 70.9 ° C;
IR (KBr): 2957, 2855, 1734, 1174, 923 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.82 (9H, s), 1.41 (3H, m), 2.16 (4H, m), 2.46 (3H, s), 3.54 (1H, m), 3.69 (3H, s) , 4.41 (1H, m), 7.34 (2H, d), 7.8 (2H, d) ppm;
[α]_D ^{twenty five} : -8.2 (c = 1.2, EtOH)
[0066]
b) (2R, 3aS, 4aS) -2-t-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. a. 1 (R = H, P = TBDMS, A = COOCH₃)
2.3. a (R = H, L = OTos, P = TBDMS, A = COOCH₃) (34.81 g, 78.6 mmol). b. 1 (A = COOCH₃, R = H, P = TBDMS). Purification by flash chromatography on silica gel (heptane / ethyl acetate = 5/5) a. 1 (R = H, P = TBDMS, A = COOCH₃) (16.6 g, 78%) as a yellow oil.
IR (film): 2953, 2855, 1726, 1148, 836 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.86 (9H, s), 1.5 (5H, m), 2.1 (1H, m), 2.48 (1H, m), 3.68 (3H, s), 4.33 (1H, t) ppm;
[α]_D ^{twenty five} : -60.1 (c = 0.998, EtOH)
[0067]
Example 8: (2R, 3aS, 4aS) -2-t-butyldimethylsilyloxy-3a- (hydroxymethyl) -bicyclo [3.1.0] hexane: I. a. 2 (R = H, P = TBDMS, A = CH₂OH).
I. a. 1 (R = H, P = TBDMS, A = CH₂OH) (15.6 g, 57.7 mmol) to I.V. b. 2 (R = H, P = TBDMS, A = CH₂Reaction was carried out in the same manner as (OH). I. a. 2 (R = H, P = TBDMS, A = CH₂OH) (11.7 g, 83.7%) was obtained as a yellow oil.
IR (film): 3331, 2927, 2855, 1254, 1094, 1006, 835 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.5 (1H, m), 0.88 (9H, s), 1.19 (3H, m), 1.72 (2H, m), 2.1 (2H, m), 3.6 (2H, s) , 4.34 (1H, t) ppm;
[α]_D ^{twenty five} : -23.5 (c = 1.062, EtOH)
[0068]
Example 9: (2R, 3aS, 4aS) -2-t-butyldimethylsilyloxy-3a-formyl-bicyclo [3.1.0] hexane: I. a. 3 (R = H, P = TBDMS, CHO).
I. a. 2 (R = H, P = TBDMS, A = CH₂OH) (11.1 g, 45.5 mmol). b. 3 (R = H, P = TBDMS, A = CHO). a. 3 (R = H, P = TBDMS, A = CHO) (8.8 g, 80%) was obtained as a yellow oil.
UV (EtOH): 204.7 nm (ε = 6991);
IR (film): 2928, 2855, 1702, 1255, 1072, 837 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.85 (9H, s), 1.45 (1H, m), 1.78 (3H, m), 2.02 (2H, m), 2.5 (1H, m), 4.35 (1H, m) , 8.81 (1H, s) ppm;
[α]_D ^{twenty five} : -71.8 (c = 1.406, EtOH)
[0069]
Example 10: (2S, 3aR, 4aR) -2-t-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: f. 1 (R = H, P = TBDMS, A = COOCH₃).
a) Methyl (1R, 3S, 5R) -3-acetoxy-5-t-butyldimethylsilyloxy-cyclohexanecarboxylate: 3.7. a (R = H, P = TBDMS, A = COOCH₃)
1. methyl (1S, 3S, 5R) -3-acetoxy-5-hydroxy-cyclohexanecarboxylate A (R = H, A = COOCH₃) (45.5 g, 0.210 mmol) of 2.8. a (R = H, L = OTos, P = TBDMS, A = COOCH₃). Purified by flash chromatography on silica gel with a heptane / ethyl acetate (9/1) mixture as the eluent 3.7. a (R = H, P = TBDMS, A = COOCH₃) (69.97 g, 92%) was obtained as a yellow oil.
IR (film): 2953, 2856, 1736, 1240 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.8 (9H, s), 1.33 (4H, m), 2 (3H, s), 2.1 (2H, m), 2.32 (1H, m), 3.55 (1H, m) , 3.62 (3H, s), 4.66 (1H, m) ppm
[0070]
b) Methyl (1R, 3S, 5R) -5-t-butyldimethylsilyloxy-3-hydroxy-cyclohexanecarboxylate: 3.8. a (R = H, P = TBDMS, A = COOCH₃)
3.7. a (R = H, P = TBDMS, A = COOCH₃) (63.67 g, 0.1926 mmol) to 2.5. a (R = H, L = OTos, A = COOCH₃The reaction was carried out in the same manner as in (1). Purified by flash chromatography on silica gel using heptane / ethyl acetate (7/3) as the eluent 3.8. a (R = H, P = TBDMS, A = COOCH₃) (46, 24 g, 83%) was obtained as a yellow oil.
IR (film): 3404, 2952, 2856, 1736, 837 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.81 (9H, s), 1.3 (3H, m), 1.67 (1H, m), 2.13 (4H, m), 3.56 (2H, m), 3.63 (3H, s) ppm;
[α]_D ^{twenty five} : +6.8 (c = 1.036, CHCl_Three).
[0071]
c) Methyl (1S, 3S, 5R) -5-t-butyldimethylsilyloxy-3-tosyloxy-cyclohexanecarboxylate: 3.6. a (R = H, L = OTos, P = TBDMS, A = COOCH₃)
3.8. a (R = H, P = TBDMS, A = COOCH₃) (45.99 g, 0.159 mmol) to 2.4. a (R = H, L = OTos, A = COOCH₃The reaction was carried out in the same manner as above. Purified by flash chromatography on silica gel with heptane / ethyl acetate (8/2) as eluent, then crystallized from EtOH 3.6. a (R = H, L = OTos, P = TBDMS, A = COOCH₃) (53.7 g, 76%).
mp: 71 ° C;
IR (KBr): 2957, 2855, 1734, 1174, 923 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.82 (9H, s), 1.41 (3H, m), 2.16 (4H, m), 2.46 (3H, s), 3.54 (1H, m), 3.69 (3H, s) , 4.41 (1H, m), 7.34 (2H, d), 7.8 (2H, d) ppm;
[α]_D ^{twenty five} : +6.8 (c = 1.032, EtOH).
[0072]
d) (2S, 3aR, 4aR) -2-t-butyldimethylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. f. 1 (R = H, P = TBDMS, A = COOCH₃).
3.6. a (R = H, L = OTos, P = TBDMS, A = COOCH₃) (53.7 g, 0.121 mmol). b. 1 (R = H, P = TBDMS, A = COOCH₃The reaction was carried out in the same manner as in (1). I. f. 1 (R = H, P = TBDMS, A = COOCH₃) (24.48 g, 74.6%) was obtained as a pale yellow oil.
IR (film): 2953, 2856, 1726, 1148, 836 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.86 (9H, s), 1.5 (5H, m), 2.1 (1H, m), 2.48 (1H, m), 3.68 (3H, s), 4.33 (1H, t) ppm;
[α]_D ^{twenty five} : +62.9 (c 1.066, EtOH).
[0073]
Example 11  : (2S, 3aR, 4aR) -2-t-butyldimethylsilyloxy-3a- (hydroxymethyl) -bicyclo [3.1.0] hexane: I. f. 2 (R = H, P = TBDMS, A = CH₂OH)
I. f. 1 (R = H, P = TBDMS, A = COOCH₃) (10 g, 0.037 mmol). b. 2 (R = H, P = TBDMS, A = CH₂The reaction was carried out in the same manner as in (OH). I. f. 2 (R = H, P = TBDMS, A = CH₂OH) was obtained in measurable yield (10 g) as an oil.
IR (film): 3331, 2927, 2855, 1254, 1094, 1006, 835 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.5 (1H, m), 0.88 (9H, s), 1.19 (3H, m), 1.72 (2H, m), 2.1 (2H, m), 3.6 (2H, s) , 4.34 (1H, t) ppm;
[α]_D ^{twenty five} : +23.2 (c = 0.99, EtOH)
[0074]
Example 12: (2S, 3aR, 4aR) -2-t-butyldimethylsilyloxy-3a-formyl-bicyclo [3.1.0] hexane: I. f. 3 (R = H, P = TBDMS, A = CHO).
I. b. 3 (R = H, P = TBDMS, A = CHO) f. 2 (R = H, P = TBDMS, A = CH₂OH) (10 g, 0.037 mmol) as a pale yellow oil. f. 3 (R = H, P = TBDMS, A = CHO) (5.3 g, 59.7%).
IR (film): 2928, 2855, 1702, 1255, 1072, 837 cm^-1 ;
¹H-NMR (CDCl_Three): δ0 (6H, s), 0.85 (9H, s), 1.45 (1H, m), 1.78 (3H, m), 2.02 (2H, m), 2.5 (1H, m), 4.35 (1H, m) , 8.81 (1H, s) ppm;
UV (EtOH): 205 nm;
[α]_D ^{twenty five} : +70.4 (c = 1.1, EtOH).
[0075]
Example 13  : (2S, 3aS, 4aS) -2-t-butyldiphenylsilyloxy-3a-ccarbomethoxy-bicyclo [3.1.0] hexane: I. b. 4 (R = H, P = TBDPS, A = COOCH₃).
a) Methyl (1R, 3S, 5R) -3-acetoxy-5- (4-bromobenzenesulfonyloxy) -cyclohexanecarboxylate: 2.4. b (R = H, L = OBros, A = COOCH₃).
2. From A (R = H) (1.4 g, 6.47 mmol) and 4-bromobenzenesulfonyl chloride (4.22 g, 16.19 mmol) to 2.4. The reaction was carried out in the same manner as a (R = H, L = OTos). 2.4. b (R = H, L = OBros, A = COOCH₃) (2.6 g, 96%) was obtained as white crystals.
mp: 110-111 ° C;
IR (film): 2956, 1734, 1363, 1246, 1188, 822, 742 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ7.76 (2H, d, J = 8.6Hz), 7.70 (2H, d, J = 8.6Hz), 4.68 (1H, dddd, J = 11.6, 11.6, 4.37, 4.37Hz), 4.46 (1H, dddd, 11.6, 11.6, 4.6, 4.6Hz), 3.69 (3H, s), 2.37 (1H, m), 2.28 (2H, m), 2.02 (3H, s), 1.58 (2H, m), 1.39 (1H , dd, J = 24.0, 12.4Hz) ppm;
MS (m / z): 419 (M⁺, 1), 405 (1), 363 (3), 221 (10), 157 (34), 138 (70), 107 (15), 79 (68);
[α]_D ^{twenty five} : -10.65 (c = 1.50, CHCl_Three).
[0076]
b) Methyl (1R, 3S, 5R) -5- (4-bromobenzenesulfonyloxy) -3-hydroxy-cyclohexanecarboxylate: 2.5. b (R = H, L = OBros, A = COOCH₃).
2.4. b (R = H, L = OBros, A = COOCH₃) (2.55 g, 6.08 mmol from 2.5.a (R = H, L = OTos) and the reaction was carried out in the same manner as 2.5.b (R = H, L = OBros, A = COOCH₃) (2.25 g, 98%) was obtained as white crystals.
mp: 95-98 ° C;
IR (film): 3397, 2954, 1734, 1396, 1186, 815, 740 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ7.76 (2H, d, J = 8.6Hz), 7.70 (2H, d, J = 8.6Hz), 4.46 (1H, dddd, J = 11.5, 11.5, 4.5, 4.5Hz), 3.68 (3H, s), 3.64 (1H, m), 2.25 (4H, m), 1.60 (1H, dd, J = 24.2, 12.5Hz), 1.48 (1H, dd, J = 23.0, 11.5Hz), 1.35 (1H, dd , J = 23.8, 12.5Hz) ppm;
MS (m / z): 377 (M⁺, 1), 328 (3), 235 (10), 221 (13), 156 (85), 113 (100), 97 (52), 79 (53);
[α]_D ^{twenty five} : -17.13 (c = 1.48, CHCl_Three).
[0077]
c) Methyl (1R, 3R, 5R) -3-benzoyloxy-5- (4-bromobenzenesulfonyloxy) -cyclohexanecarboxylate: 2.6. b (R = H, L = OBros, A = COOCH₃)
2.5. b (R = H, L = OBros, A = COOCH₃) (1.15 g, 3.05 mmol) to 2.6. a (R = H, L = OTos, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 1.13 g (73%).
mp: 131-133 ° C;
IR (film): 3420, 2948, 1717, 1362, 1186, 817, 707 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 7.95 (2H, d, J = 7.4Hz), 7.72 (2H, d, J = 8.5Hz), 7.60 (1H, t, J = 7.4Hz), 7.58 (2H, d, J = 8.5Hz) , 7.49 (2H, t, 7.7Hz), 5.46 (1H, m), 4.81 (1H, dddd, J = 11.3, 11.3, 4.4, 4.4Hz), 2.85 (1H, dddd, J = 12.5, 12.5, 3.7, 3.7Hz), 2.47 (1H, m), 2.20 (2H, m), 1.73 (3H, m) ppm;
MS (m / z): 497 (M⁺, 1), 391 (4), 377 (10), 260 (100), 237 (8), 221 (25);
[α]_D ^{twenty five} : -59.32 (c = 1.79, CHCl_Three).
[0078]
d) Methyl (1R, 3R, 5R-5- (4-bromobenzenesulfonyloxy) -3-hydroxy-cyclohexanecarboxylate: 2.7.b (R = H, L = OBros, A = COOCH)₃).
2.6. b (R = H, L = OBros, A = COOCH₃) (240 mg, 0.483 mmol) to 2.7. a (R = H, L = OTos, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 167 mg (88%).
mp: 107-108 ° C.
IR (film): 3527, 2954, 1732, 1577, 1365, 1187, 940, 818 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ7.78 (2H, d, J = 8.6Hz), 7.70 (2H, d, J = 8.6Hz), 4.87 (1H, dddd, J = 10.9, 10.9, 4.5, 4.5 Hz), 4.31 (1H, m), 3.69 (3H, s), 2.86 (1H, dddd, J = 12.1, 12.1, 3.7, 3.7Hz), 2.24 (1H, d, J = 12.7Hz), 2.04 (1H, d, J = 11.7Hz) ), 1.94 (1H, d, J = 14.0Hz), 1.65 (3H, m) ppm;
MS (m / z): 394 (M⁺+1, 1), 295 (2), 221 (4), 157 (11), 97 (10);
[α]_D ^{twenty five} : -38.75 (c = 0.80, CHCl_Three).
[0079]
e) Methyl (1R, 3R, 5R) -5- (4-bromobenzenesulfonyloxy) -3-tert-butyldiphenylsilyloxy-cyclohexanecarboxylate: 2.8. b (R = H, L = OBros, P = TBDPS, A = COOCH₃).
2.7. b (R = H, L = OBros, A = COOCH₃) (299 mg, 0.760 mmol) to 2.8. a (R = H, L = OTos, P = TBDPS, A = COOCH₃The reaction was carried out in the same manner as in (1). 2.8. b (R = H, L = OBros, P = TBDPS, A = COOCH₃) (198 mg, 93%) as a viscous oil.
IR (film): 2955, 1738, 1577, 1472, 1370, 1180, 947, 821, 703 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ7.71 (2H, d, J = 8.8Hz), 7.34-7.60 (12H, m), 4.87 (1H, m), 4.17 (1H, bs), 3.78 (3H, m), 2.98 (1H, dddd, J = 9.1, 9.1, 3.5, 3.5 Hz), 2.39 (1H, d, J = 11.9Hz), 1.89 (1H, d, J = 13.9Hz), 1.79 (1H, d, J = 12.3Hz), 1.63 (1H, m), 1.34 (2H, m), 1.02 (9H, s), 0.91 (3H, s) ppm; MS (m / z): 599 (M⁺, 1), 419 (28), 337 (34), 293 (8), 199 (46), 139, (100), 107 (50), 79 (72);
[α]_D ^{twenty five} : +1.49 (c = 1.75, CHCl_Three).
[0080]
f) (2S, 3aS, 4aS) -2-t-butyldiphenylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. b. 4 (R = H, P = TBDPS, A = COOCH₃).
I. b. 1 (R = H, P = TBDMS, A = COOCH₃)) And compound 2.8. b (R = H, L = OBros, P = TBDPS, A = COOCH₃) (206 mg, 0.344 mmol). b. 4 (R = H, P = TBDMS, A = COOCH₃) (79 mg, 76%) to give a colorless oil. .
IR (film): 2952, 1725, 1428, 1113, 703 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ7.64 (4H, dd, J = 6.20, 6.20Hz), 7.35-7.45 (6H, m), 3.89 (1H, dddd, J = 7.7, 7.7, 7.7, 7.7Hz), 3.65 (3H, s ), 2.28 (1H, dd, J = 12.9, 8.2Hz), 2.12 (1H, dd, J = 12.9, 7.1Hz), 1.91 (2H, m), 1.77 (1H, ddd, J = 8.6, 5.0, 5.0 Hz), 1.19 (1H, dd, J = 8.6, 4.8Hz), 1.02 (9H, s), 0.44 (1H, dd, J = 5.1, 5.1Hz) ppm .9, 7.1Hz), 1.91 (2H, m ), 1.77 (1H, ddd, J = 8.6, 5.0, 5.0Hz), 1.19 (1H, dd, J = 8.6, 4.8Hz), 1.02 (9H, s), 0.44 (1H, dd, J = 5.1, 5.1 Hz) ppm
MS (m / z): 394 (M⁺, 1), 363 (4), 337 (65), 259 (3), 213 (100), 199 (20), 135 (18), 77 (21);
[α]_D ^{twenty five} : -73.14 (c = 1.75, CHCl_Three).
[0081]
Example 14: (2S, 3aS, 4aS) -2-t-butyldiphenylsilyloxy-3a- (hydroxymethyl) -bicyclo [3.1.0] hexane: I. b. 5 (R = H, P = TBDPS, A = CH₂OH).
I. b. 4 (R = H, P = TBDPS, A = COOCH₃) (188 mg, 1.253 mmol). b. 2 (R = H, P = TBDMS, A = CH₂The reaction was carried out in the same manner as in (OH). Purified by flash chromatography on silica gel (isooctane / ethyl acetate 83:17). b. 5 (R = H, P = TBDPS, A = CH₂OH) (240 mg, 96%) was obtained as a viscous oil.
IR (film): 3322, 2932, 1428, 1113, 702 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ7.75 (4H, m), 7.58 (6H, m), 3.97 (1H, dddd, J = 7.1, 7.1, 7.1, 7.1Hz), 3.56 (2H, bs), 1.84-2.05 (3H, m ), 1.12 (1H, m), 1.03 (9H, s), 0.34 (1H, dd, J = 7.8, 5.4Hz), 0.13 (1H, dd, J = 4.6, 4.6Hz) ppm;
MS (m / z): 365 (M⁺-1, 1), 291 (3), 231 (10), 199 (100), 181 (12), 139 (27), 93 (77), 79 (24);
[α]_D ^{twenty five} : -25.74 (c = 2.16, CHCl_Three).
[0082]
Example 15: (2S, 3aS, 4aS) -2-t-butyldiphenylsilyloxy-3a-formyl-bicyclo [3.1.0] hexane: I. b. 6 (R = H, P = TBDPS, A = CHO).
I. b. 5 (R = H, P = TBDPS, A = CH₂OH) (230 mg, 0.627 mmol). b. 3 (R = H, P = TBDMS, A = CHO). I. b. The yield of 6 (R = H, P = TBDPS, A = CHO) was 210 mg (92%).
IR (film): 3439, 3061, 2954, 2858, 1704, 1589, 1471, 1111, 1036, 823, 703 cm^-1 ;¹H-NMR (500 MHz, CDCl_Three): δ 8.85 (1H, s), 7.68-7.60 (4H, m), 3.99 (1H, q, J = 7.4Hz), 2.30 (1H, dd, J = 13.1, 8.0Hz), 2.03-1.98 (2H , m), 1.93-1.87 (2H, m), 1.22 (1H, dd, J = 8.4, 6.0Hz), 1.02 (9H, s), 0.74 (1H, dd, J = 5.3, 5.3Hz) ppm;
[α]_D ^{twenty five} : -90.00 (c 1.00, CHCl_Three).
[0083]
Example 16: (2S, 3aS, 4aS) -2-t-butyldiphenylsilyloxy-3a-ethynyl-bicyclo [3.1.0] hexane: I. b. 7 (R = H, P = TBDPS, A = C≡CH).
Cooled to -78 ° C (MeO)₂P (O) CHN₂To a solution of (188 mg, 1.253 mmol) in THF (3 ml) was added t-BuOK (1.26 ml, 1.26 mmol, 1.0 M solution in THF) dropwise. The resulting mixture was stirred at −78 ° C. for 20 minutes while the yellow color remained. I. b. 6 (R = H, P = TBDPS, A = CHO) (380 mg, 1.043 mmol) in THF (3 ml) was slowly added and stirred overnight. The temperature naturally rose from −78 ° C. to room temperature. Water (10 ml) and Et₂The reaction was terminated by adding O (20 ml), the organic layer was separated and the aqueous layer was Et.₂Extract with O (3 x 50 ml), MgSO₄And dried. The residue was separated by HPLC (hexane / EtOAc 96: 4) and compound I.I. b. 7 (R = H, P = TBDPS, A = C≡CH) (338 mg, 90%) was obtained as a colorless oil.
IR (film): 3291, 3072, 2932, 2143, 1590, 1473, 1428, 1114, 1091, 824, 741 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 7.61-7.63 (4H, m), 7.34-7.43 (6H, m), 3.81 (1H, q, J = 7.6Hz), 2.16 (1H, dd, J = 12.5, 7.13Hz), 2.02 (1H , ddd, J = 12.5, 8.1, 0.9Hz), 1.95 (1H, m), 1.93 (1H, s), 1.56 (1H, m), 1.02 (9H, s), 0.70 (1H, dd, J = 8.3 , 5.1Hz), 0.31 1H, t, J = 5.0Hz) ppm;
[α]_D ^{twenty five} : -86.30 (c = 1.60, CHCl_Three).
[0084]
Example 17: (2S, 3aR, 4aR-2-t-butyldiphenylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: If4 (R = H, P = TBDPS, A = COOCH₃).
a) Methyl (1R, 3R, 5S) -3-t-butyldiphenylsilyloxy-5-hydroxy-cyclohexanecarboxylate: 3.8. b (R = H, P = TBDPS, A = COOCH₃).
2. A (R = H, A = COOCH₃) And TBDPSCl, 3.7. b (R = H, P = TBDPS, A = COOCH₃) Of Example 4 of 3.8. a (R = H, P = TBDMS, A = COOCH₃The reaction was carried out in the same manner as in). The title compound was obtained as a viscous oil; the yield was 92% for the two steps.
IR (film): 3404, 2952, 1738, 1428, 1112, 1049, 807, 710 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 7.66 (4H, m), 7.40 (6H, m), 3.65 (3H; s), 3.60 (1H, dddd, J = 10.9, 10.9, 4.3, 4.3 Hz), 3.41 (1H, m), 2.11 (4H, m), 1.50 (1H, dd, J = 12.6, 12.6 Hz), 1.41 (1H, d, J = 5.2 Hz), 1.34 (3H, m) ppm;
MS (m / z): 412 (M⁺, 1), 355 (5), 323 (67), 199 (100), 153 (37), 105 (21), 79 (85);
[α]_D ^{twenty five} : -16.44 (c = 1.60, CHCl_Three).
[0085]
b) Methyl (1S, 3R, 5S) -3-t-butyldiphenylsilyloxy-5-tosyloxy-cyclohexanecarboxylate: 3.6. b (R = H, L = OTos, P = TBDPS, A = COOCH₃).
3.8. b (R = H, P = TBDPS, A = COOCH₃) To 2.4. a (R = H, L = OTos, A = COOCH₃) And the same reaction as in 3.6. b was obtained as a viscous oil. The yield was 94%.
IR (film): 2955, 1738, 1363, 1178, 1111, 824, 704 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 7.69 (2H, d, J = 8.3Hz), 7.58 (4H, m), 7.28 (2H, d, J = 8.1Hz), 4.18 (1H, dddd, J = 11.6, 11.6, 4.6, 4.6Hz ) 3.62 (3H; s), 3.48 (1H, dddd, J = 11.1, 11.1; 4.1, 4.1 Hz), 2.47 (3H, s), 2.15-1.99 (4H, m), 1.52 (1H, ddd, J = 5.6, 5.57, 5.6Hz), 1.42 (1H, ddd, J = 12.0, 12.0, 12.0Hz), 0.98 (9H, s) ppm;
MS (m / z): 567 (M⁺, 1), 509 (9), 451 (1), 353 (49), 337 (67), 293 (38), 213 (47), 139 (32), 91 (100), 79 (77);
[α]_D ^{twenty five} : +2.39 (c = 1.17, CHCl_Three).
[0086]
c) (2S, 3aR, 4aR) -2-t-butyldiphenylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. f. 4 (R = H, P = TBDPS, A = COOCH₃).
3.6. b (R = H, L = OBros, P = TBDPS, A = COOCH₃) To I. b. 1 (R = H, P = TBDMS, A = COOCH₃The reaction was carried out in the same manner as). The yield was 81%.
IR (film): 3287, 2934, 1732, 1457, 1281, 1017 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 3.73 (2H, m), 3.72 (3H; s), 2.53 (1H, dddd, J = 12.2, 12.2, 3.4, 3.4 Hz), 2.26 (1H, d, J = 11.3Hz), 2.17 (2H , d, J = 11.7 Hz), 1.30 (2H, ddd, J = 12.0, 12.0, 12.0 Hz), 1.23 (1H, ddd, J = 11.4, 11.4, 11.4 Hz) ppm;
MS (m / z): 394 (M⁺, 1), 337 (31), 259 (5), 199 (55), 153 (48), 107 (100), 79 (52);
[α]_D ^{twenty five} : +31.97 (c = 1.71, CHCl_Three)
[0087]
Example 18: (2S, 3aR, 4aR) -2-t-butyldiphenylsilyloxy-3a- (hydroxymethyl) -bicyclo [3.1.0] hexane: I. f. 5 (R = H, P = TBDPS, A = CH₂OH).
I. f. 4 (R = H, P = TBDPS, A = COOCH₃From I.). b. 2 (R = H, P = TBDMS, A = CH₂OH) and (2S, 3aR, 4aR) -2-t-butyldiphenylsilyloxy-3a- (hydroxymethyl) -bicyclo [3.1.0] hexane f. 5 (R = H, P = TBDPS, A = CH₂OH) was obtained in 98% yield.
IR (film): 3332, 2931, 1428, 1111, 1008, 822, 702 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 7.62 (4H, dd, J = 7.9, 1.5Hz), 7.39 (6H, m), 4.37 (1H, t, J = 6.27Hz), 3.57 (2H; s), 1.90-2.02 (3H, m ), 1.80 (1H, d, J = 13.8Hz), 1.21 (1H, t, J = 4.1Hz), 1.15 (1H, m), 1.03 (9H, s), 0.60 (1H, m) ppm;
MS (m / z): 365 (M⁺-1, 1), 291 (6), 231 (17), 199 (100), 181 (17), 139 (28), 93 (79), 79 (16);
[α]_D ^{twenty five} : +5.56 (c = 1.5, CHCl_Three).
[0088]
Example 19  : (2S, 3aR, 4aR) -2-t-butyldiphenylsilyloxy-3a-formyl-bicyclo [3.1.0] hexane: I. f. 6 (R = H, P = TBDPS, A = CHO).
I. f. 5 (R = H, P = TBDPS, A = CH₂OH) to I.I. b. 3 (R = H, P = TBDMS, A = CHO). The yield was 96%.
IR (film): 2956, 1704, 1590, 1472, 1428, 1112, 1072, 822, 702 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 8.85 (1H, s), 7.61 (4H, m), 7.43 (2H, dt, J = 7.0, 1.0Hz), 7.37 (4H, dt, J = 7.0, 1.0Hz), 4.40 (1H, t , J = 6.0Hz), 2.39 (1H, dd, J = 14, 6.0Hz), 1.89 (1H, d, J = 13.0Hz), 1.86 (1H, d, J = 14.0Hz), 1.53 (1H, m ), 1.04 (9H, s) ppm;
[α]_D ^{twenty five} : +34.4 (c = 1.6, CHCl_Three).
[0089]
Example 20: (2S, 3aR, 4aR) -2-t-butyldiphenylsilyloxy-3a-ethynyl-bicyclo [3.1.0] hexane: I. f. 7 (R = H, P = TBDPS, A = C≡CH).
I. f. 6 (R = H, P = TBDPS, A = CHO). b. 7 (R = H, P = TBDMS, A = C≡CH). The yield was 88%.
IR (film): 3310 (s), 3071, 2931, 2857, 2113, 1590, 1472, 1428, 1378, 1362, 1299, 1262, 1234, 1198, 1113, 1026, 933, 913, 865, 822, 701 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ7.60 (4H, m), 7.42 (2H, td, J = 2, 8Hz), 7.37 (4H, td, J = 1, 8Hz), 4.32 (1H, m), 2.06 (2H, m) , 2.04 (1H, dt, J = 6, 14Hz), 1.90 (1H, s), 1.80 (1H, d, J = 14Hz), 1.65 (1H, dt, J = 5, 10Hz), 1.49 (1H, t , J = 5Hz), 1.03 (9H, s), 1.03 (1H, m);
[α]_D ^{twenty five}: +21.4 (c = 1.2, CHCl_Three)
[0090]
Example 21  : (2R, 3aS, 4aS) -2-t-butyldiphenylsilyloxy-3a-carbomethoxy-ethynyl-bicyclo [3.1.0] hexane: I. a. 4 R = H, P = TBDPS, A = COOCH₃)
a) Methyl (1R, 3S, 5R) -3-t-butyldiphenylsilyloxy-5-tosyloxy-cyclohexanecarboxylate: 2.3. b (R = H, L = OTos, P = TBDPS, A = COOCH₃).
2.5. a (R = H, L = OTos, A = COOCH₃) To 2.8. a (R = H, L = OTos, P = TBDMS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 91%.
IR (film): 2932, 2857, 1736, 1428, 1364, 1177, 1107, 929, 822, 703, 665 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 7.69 (2H, d, J = 8.3Hz), 7.57 (4H, dm, J = 7Hz), 7.44 (2H, q, J = 7Hz), 7.36 (4H, t, J = 8Hz), 7.28 ( 2H, d, J = 8.4Hz), 4.16 (1H, tt, J = 4, 12Hz), 3.63 (3H, s), 3.46 (1H, tt, J = 4, 11Hz), 2.43 (3H, s), 2.13 (1H, dm, J = 12Hz), 1.00 (9H, s) ppm;
[α]_D ^{twenty five} : -3.07 (c = 1.04, CHCl_Three).
[0091]
b) (2R, 3aS, 4aS) -2-t-butyldiphenylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. a. 4 (R = H, P = TBDPS, A = COOCH₃)
2.3. b (R = H, L = OTos, P = TBDPS, A = COOCH₃) To I.V. b. 1 (R = H, P = TBDMS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 75%.
IR (film): 2932, 2857, 1723, 1589, 1472, 1428, 1297, 1148, 1112, 1088, 702 cm^-1;
¹H-NMR (500 MHz, CDCl_Three): δ 7.61 (4H, dd, J = 1, 7Hz), 7.42 (2H, t, J = 7Hz), 7.37 (4H, t, J = 7Hz), 4.36 (1H, t, 6.1Hz), 3.63 ( 3H, s), 2.37 (1H, ddd, J = 1, 6.4, 14Hz), 1.99 (1H, d, J = 14hz), 1.96 (1H, dd, J = 6, 14Hz), 1.87 (1H, dt, J = 5, 9Hz), 1.82 (1H, d, J = 14Hz), 1.63 (1H, dd, J = 4, 5Hz), 1.50 (1H, dm, J = 9Hz), 1.03 (9H, s) ppm;
[α]_D ^{twenty five} : -30.8 (c = 0.46, CHCl_Three).
[0092]
Example 22  : (2R, 3aS, 4aS) -2-t-butyldiphenylsilyloxy-3a- (hydroxymethyl) -bicyclo [3.1.0] hexane: I. a. 5 (R = H, P = TBDPS, A = CH₂OH).
I. a. 4 (R = H, P = TBDPS, A = COOCH₃From I.). b. 2 (R = H, P = TBDMS, A = CH₂The reaction was carried out in the same manner as (OH), and the yield was measurable. .
IR (film): 3346, 2930, 1589, 1472, 1428, 1111, 1092, 1076, 1031, 822, 701 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 7.26 (4H, dd, J = 1, 7Hz), 7.41 (2H, t, J = 7Hz), 7.36 (4H, t, J = 7Hz), 4.38 (1H, t, J = 6.3Hz), 3.57 (2H, s), 2.00 (1H, dd, J = 6, 13Hz), 1.95 (1H, dd, J = 7, 14Hz), 1.92 (1H, d, J = 14Hz), 1.80 (1H, dd, J = 14Hz), 1.22 (2H, m), 1.15 (1H, m), 1.04 (9H, s), 0.60 (1H, m) ppm;
[α]_D ^{twenty five} : -5.6 (c = 1.7, CHCl_Three).
[0093]
Example 23: (2R, 3aS, 4aS) -2-t-butyldiphenylsilyloxy-3a-formyl-bicyclo [3.1.0] hexane: I. a. 6 (R = H, P = TBDPS, A = CHO).
I. a. 5 (R = H, P = TBDPS, A = CH₂OH) to I.I. b. 3 (R = H, P = TBDMS, A = CHO). The yield was 93%.
IR (film): 2931, 1701, 1589, 1472, 1196, 1008, 822, 702 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 8.85 (1H, s), 7.61 (4H, m), 7.43 (2H, t, J = 7Hz), 7.37 (4H, t, J = 7Hz), 4.41 (1H, t, J = 6Hz), 2.39 (1H, dd, J = 6, 14Hz), 1.04 (9H, s) ppm;
[α]_D ^{twenty five} : -35.3 (c = 1.6, CHCl_Three).
[0094]
Example 24: (2R, 3aR, 4aR) -2-t-butyldiphenylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. h. 4 (R = H, P = TBDPS, A = COOCH₃).
a) Methyl (1S, 3S, 5S) -3-t-butyldiphenyl-5-tosyloxy-cyclohexanecarboxylate: 3.13. b (R = H, L = OTos, P = TBDPS, A = COOCH₃).
3.12 (R = H, L = OTos, A = COOCH₃) (4.8 g, 14.63 mmol) to 2.8. a (R = H, L = OTos, P = TBDS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 90%.
IR (film): 2954, 1731, 1272, 1176, 1107, 945, 813, 713, 664 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 7.53-7.25 (14H, m), 4.84 (1H, m), 3.68 (3H, s), 2.95 (1H, dt, J = 3.3, 12.7Hz), 2.45 (3H, s), 2.37 (1H , d, J = 12.4Hz), 1.84 (1H, d, J = 12.7Hz), 1.60 (1H, m), 1.29 (3H, m) ppm;
MS (m / z): 566 (M⁺), 477, 431, 399, 353, 283, 225, 198, 139, 91 (base peak);
[α]_D ^{twenty five} : +7.82 (c = 1.31, CHCl_Three).
[0095]
b) (2R, 3aR, 4aR) -2-t-butyldiphenylsilyloxy-3a-carbomethoxy-bicyclo [3.1.0] hexane: I. h. 4 (R = H, P = TBDPS, A = COOCH₃).
3.13. b (R = H, P = TBDPS, A = COOCH₃) (7.3 g, 12.89 mmol). b. 1 (R = H, P = TBDMS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 79%.
IR (film): 2952, 2858, 1723, 1428, 1370, 1219, 1112, 823, 741, 702 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 7.66-7.38 (10H, m), 3.89 (1H, m), 3.65 (3H, s), 2.12 (1H, m), 1.92 (2H, m), 1.77 (1H, m), 1.14 (2H , m), 1.02 (9H, s), 0.45 (1H, m) ppm;
MS (m / z): 394 (M⁺), 393 (M⁺-1), 363, 351, 337, 296, 259, 213 (base peak), 183, 135, 105, 77.
[α]_D ^{twenty five} : +72.58 (c = 1.08, CHCl_Three).
[0096]
Example 25: 2R, 3aR, 4aR) -2-t-butyldiphenylsilyloxy-3a- (hydroxymethyl) -bicyclo [3.1.0] hexane: I. h. 5 (R = H, P = TBDPS, A = CH₂OH)
I. h. 4 (R = H, P = TBDPS, A = COOCH₃From I.). b. 2 (R = H, P = TBDMS, A = CH₂The reaction was carried out in the same manner as in (OH). The yield was 98%.
IR (film): 3327, 2929, 2856, 1470, 1426, 1279, 1112, 1087, 1030, 822, 739, 700 IR (film): 3327, 2929, 2856, 1470, 1426, 1279, 1112, 1087, 1030 , 822, 739, 700^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 7.65-7.35 (10H, m), 3.97 (1H, ddd, J = 7.0, 7.2, 7.0), 3.55 (2H, bs), 2.04 (1H, m), 1.93 (1H, m), 1.87 ( 2H, m), 1.39 (1H, m), 1.02 (9H, s), 0.45 (1H, m), 0.13 (1H, m) ppm;
MS (m / z): 365 (M⁺-1), 322, 281, 237, 189 (base peak), 181, 139, 99, 77;
[α]_D ^{twenty five} : +24.77 (c = 1.18, CHCl_Three).
[0097]
Example 26: (2R, 3aR, 4aR) -2-t-butyldiphenylsilyloxy-3a-formyl-bicyclo [3.1.0] hexane: I. h. 6 (R = H, P = TBDPS, A = CHO)
I. h. 5 (R = H, P = TBDPS, A = CH₂OH) to I.I. b. 3 (R = H, P = TBDMS, A = CHO).
      IR (film): 2931, 2857, 1708, 1472, 1388, 1362, 1200, 1113, 1093, 1036, 901, 823, 742, 612 cm^-1 ;
¹H-NMR (500 MHz, CDCl_Three): δ 8.87 (1H, s), 7.65-7.35 (10H, m), 3.98 (1H, m), 2.29 (1H, dd, J = 12.9, 8.1Hz), 2.01 (2H, m), 1.89 (2H , m), 1.22 (1H, m), 1.02 (9H, s), 0.74 (1H, t, J = 5.4Hz) ppm;
MS (m / z): 363 (M⁺+1), 332, 307 (base peak), 289, 277, 263, 229, 211, 199, 181, 151, 139, 121, 91, 77, 57, 41;
[α]_D ^{twenty five} : +91.49 (c = 0.47, CHCl_Three).
[0098]
Example 27: (1R, 2S, 3aS, 4aS) -3a-carbomethoxy-2-t-butyldiphenylsilyloxy-1-methyl-bicyclo [3.1.0] hexane: I. a. 7 (R = Me, P = TBDPS, A = COOCH₃)
a) Methyl (1S, 3S, 4R, 5R) -3-tert-butyldiphenylsilyloxy-4-methyl-5-acetoxy-cyclohexane 2.1. c (R = Me, P = TBDPS, A = COOCH₃)
Stirred 2'B (R = Me, A = COOCH₃) (0.81 g, 3.52 mmol), imidazole (0.72 g, 10.57 mmol, 99%) and DMAP (4-dimethylaminopyridine; 22 mg) in anhydrous DMF (15 ml) in TBDPSCl (1.8 ml, 7.04 mmol, 98%) was added dropwise. The resulting mixture was stirred for 20 hours at room temperature. After completion, the reaction solution was poured into water-EtOAc (80 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 ml × 3). The combined extracts were washed with saturated brine (3 x 10 ml) and MgSO₄And concentrated to give a residue. The residue was purified by HPLC (isooctane / EtOAc 9: 1), 2.1. c (R = Me, P = TBDPS, A = COOCH₃) (1.34 g, 84%).
[α]_D = +9.9 (CHCl_Three, c = 0.65)
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.65-7.35 (10H, m), 4.59 (1H, dt, J = 12.4, 4.5 Hz), 3.72 (1H, m), 3.62 (3H, s), 2.26 (1H, m), 2.09 ( 1H, m), 2.02 (3H, s), 1.81 (1H, dt, J = 12.6, 4.1 Hz), 1.61 (1H, m), 1.08 (10H, s), 1.05 (3H, d, J = 6.4 Hz ).
IR (film): 2954, 1737, 1428, 1364, 1239, 1111, 1037, 822, 740, 702 cm^-1MS (m / z): 411 (M⁺-57), 369, 351, 317, 291, 259, 258, 241, 199, 181, 135, 121, 93, 43 (base peak).
[0099]
b) Methyl 9 (1S, 3S, 4R, 5R) -3-tert-butyldiphenylsilyloxy-4-methyl-5-hydroxy-cyclohexanecarboxylate 2.2. c (R = Me, P = TBDPS, A = COOCH₃)
2. Stir at room temperature 2.1. c (R = Me, P = TBDPS, A = COOCH₃) (392 mg, 0.992 mmol) in anhydrous MeOH (10 ml)₂CO₃(30 mg) was added. 10 minutes later, second K₂CO₃(19 mg) (total: 49 mg, 0.496 mmol) was added. The resulting mixture was stirred for 6 hours with water and Et.₂Poured into a mixture of O (70 ml: 50 ml). The organic layer is separated and the aqueous layer is Et.₂Extract with O (50 ml x 3), MgSO₄And dried. Separation by flash chromatography on silica (isooctane / EtOAc 9: 1), hydroxy compound 2.2. c (R = Me, P = TBDPS, A = COOCH₃) (344 mg, 98%) was obtained as a colorless oil.
IR (film): 3448, 2954, 2858, 1737, 1654, 1472, 1362, 1279, 1240, 1173, 1008,852, 822, 795, 741, 702, 611 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.65 (4H, m), 7.44 (2H, m), 7.37 (4H, m), 3.69 (1H, m), 3.64 (3H, s), 3.51 (1H, m), 2.16 (1H, m), 2.08 (1H, m), 1.77 (1H, dt, J = 12.6, 4.1 Hz), 1.69 (2H, t, J = 8.9 Hz), 1.56 (1H, q, J = 12.4 Hz), 1.37 ( 1H, d, J = 5.3 Hz), 1.06 (9H, s), 1.02 (3H, d, J = 7.0 Hz).
MS (m / z): 337 (7), 309 (5), 291 (35), 199 (100), 156 (85), 181 (17), 153 (34), 121 (23), 93 (68 ), 57 (47).
[α]_D ^{twenty five} : +33.0 (c = 0.54, CHCl_Three)
[0100]
c) Methyl (1S, 3S, 4R, 5R) -3-tert-butyldiphenylsilyloxy-4-methyl-5-tosyloxy-cyclohexanecarboxylate 2.3. c (R = Me, P = TBDPS, L = OTos, A = COOCH₃)
2.2. c (R = Me, P = TBDMS, A = COOCH₃) (279 mg, 0.828 mmol), p-toluenesulfonyl chloride (323 mg, 1.69 mmol, 98%), DMAP (5.1 mg, 0.042 mmol) in anhydrous CH₂Cl₂(10 ml) to the mixed solution at 0 ° C. (ice bath)₃N (308 μL, 2.54 mmol) was added. The resulting mixture was refluxed for 3 days; then toluenesulfonyl chloride (320 mg, 1.69 mmol, 98%), DMAP (5.1 mg, 0.042 mmol) and Et.₃N (500 μL) was added. The resulting solution was refluxed for 2 days. p-Toluenesulfonyl chloride (320 mg, 1.69 mmol, 98%), DMAP (5.1 mg, 0.042 mmol) and Et₃N (500 μL) was added again and reflux was continued for another day. The resulting mixture was added to 20 ml of CH₂Cl₂Diluted with brine, washed with brine and the aqueous layer was extracted with EtOAc (4 × 50 ml). Combined organic layer is MgSO₄And dried. Filtration, concentration of the solution and flash chromatography on silica (isooctane / EtOAc 9: 1) 2.3. c (R = Me, P = TBDPS, L = OTos, A = COOCH₃) (316 mg, 83.5%) was obtained as a pale yellow oil.
IR (film): 2954, 2858, 1737, 1365, 1246, 1177, 1106, 955, 704, 667 cm^-11H-NMR (500 MHz, in CDCl_Three, ppm): 7.71 (2H, d, J = 8.3 Hz), 7.58 (4H, m), 7.43 (2H, m), 7.37 (4H, m), 7.31 (2H, d, J = 8.1 Hz), 4.27 (1H, dt, J = 12.0, 4.7 Hz), 3.61 (3H, s), 3.57 (1H, ddd, J = 10.6, 5.1, 4.6 Hz), 2.45 (3H, s), 2.17 (1H, m), 2.01 (1H, m), 1.81 (1H, dt, J = 12.8, 4.2 Hz), 1.74 (1H, dd, J = 12.6 Hz), 1.64 (2H, m), 1.02 (9H, s), 0.99 (3H , d, J = 6.6 Hz).
MS (m / z): 523 (25), 507 (1), 463 (1), 409 (3), 353 (94), 307 (20), 293 (18), 213 (30), 199 (32 ), 135 (35), 91 (100), 77 (30).
[α]_D ^{twenty five} : -10.0 (c = 1.22, CHCl_Three)
[0101]
d) (1R, 2S, 3aS, 4aS) -3a-carbomethoxy-2-tert-butyldiphenylsilyloxy-1-methyl-bicyclo [3.1.0] hexane a. 7 (R = Me, P = TBDPS, A = COOCH₃)
Tosylate 2.3. c (R = Me, P = TBDPS, L = OTos, A = COOCH₃) (240 mg, 0.415 mmol) in tert-BuOH (5 ml) and THF (2.8 ml) (45 ° C) in tert-BuOK (540 μL, 0.54 mmol, in tert-BuOH) 1 M solution) was added dropwise. The resulting mixture was stirred at 45 ° C. for 1.5 hours and then poured into water and EtOAc (100 ml: 50 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 50 ml), MgSO₄And dried. The residue was then separated by flash chromatography (isooctane / EtOAc 100: 2). a. 7 (R = Me, P = TBDPS, A = COOCH₃) (122 mg, 72.0%) was obtained as a colorless oil.
IR (film): 2931, 1724, 1428, 1288, 1224, 1147, 1111, 1073, 1015, 933, 822, 740, 702, 609 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.61 (14H, m), 7.42 (2H, m), 7.36 (4H, t, J = 7.2 Hz), 4.19 (1H, t, J = 6.0 Hz), 3.62 (3H, s), 2.30 (2H, m), 1.97 (1H, d, J = 14.2 Hz), 1.85 (1H, m), 1.64 (1H, t, J = 4.6 Hz), 1.35 (1H, dd, J = 8.7, 3.9 Hz) , 1.09 (9H, s), 0.99 (3H, d, J = 6.9 Hz).
MS (m / z):
[α]_D ^{twenty five} : -13.2 (c = 1.61, CHCl_Three)
[0102]
Example 28: (1R, 2S, 3aS, 4aS) -3a-hydroxymethyl-2-tert-butyldiphenylsilyloxy-1-methyl-bicyclo [3.1.0] hexane a. 8 (R = Me, P = TBDPS, A = CH₂OH)
I. a. 7 (R = Me, P = TBDPS, A = COOCH₃) (136 mg, 0.33 mmol) in THF (15 ml) in LiAlH₄(0.85 ml, 0.85 mmol, 1 M solution in THF) was added dropwise. The resulting mixture was stirred at this temperature for 1.5 hours and water (0.1 ml) was added. The reaction mixture was filtered using celite and concentrated. The residue was purified by flash chromatography (silica gel: isooctane / EtOAc: 7: 3). a. 8 (R = Me, P = TBDPS, A = CH₂OH) (124 mg, 97.8%) was obtained as a colorless oil.
IR (film): 3420, 2930, 1427, 1111, 1078, 1014, 701, 611, 504 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.63 (4H, m), 7.42 (2H, m), 7.36 (4H, m), 4.21 (1H, t, J = 6.0 Hz), 3.54 (1H, dd, J = 11.4, 5.6 Hz) , 3.50 (1H, dd, J = 11.4, 5.6 Hz), 2.29 (1H, m), 1.95 (1H, ddd, J = 13.7, 6.0, 1.4 Hz), 1.23 (1H, t, J = 4.12 Hz), 1.14 (1H, m), 1.08 (9H, s), 0.99 (3H, d, J = 7.0 Hz), 0.41 (1H, dd, J = 8.4, 4.3 Hz), 0.80 (1H, m).
MS (m / z): 381 (M⁺+1, 1), 363 (22), 337 (1), 323 (22), 305 (5), 285 (9), 267 (24), 245 (63), 225 (19), 199 (83) , 179 (19), 153 (29), 139 (51), 107 (100), 91 (58), 79 (72), 57 (86), 41 (78).
[α]_D ^{twenty five} : -2.6 (c = 0.69, CHCl_Three)
[0103]
Example 29: (1R, 2S, 3aS, 4aS) -3a-formyl-t-butyldiphenylsilyloxy-1-methyl-bicyclo [3.1.0] hexane a. 9 (R = Me, P = TBDPS, A = CHO)
(COCl)₂(18 μL, 0.21 mmol) CH₂Cl₂DMSO (32 μL, 0.42 mmol) in CH (1.5 ml) solution (−78 ° C.)₂Cl₂(100 μL) solution was added dropwise. The mixture is stirred at −78 ° C. for 20 minutes, then alcohol I.V. a. 8 (R = Me, P = TBDPS, A = CH₂OH) (40 mg, 0.105 mmol) in CH₂Cl₂(1.5 ml) Added solution. The resulting cloudy liquid was stirred at −78 ° C. for 20 minutes. The mixture was then warmed to room temperature over 1 hour. Cold water is added to terminate the reaction, the organic layer is separated, and the aqueous layer is₂Extraction with O (3 x 50 ml) followed by MgSO₄And dried. The residue was separated by HPLC (isooctane / EtOAc: 95: 5) and compound I.I. a. 9 (R = Me, P = TBDPS, A = CHO) (30 mg, 75%) was obtained as a colorless oil.
IR (film): 3420, 2930, 1427, 1111, 1078, 1014, 701, 611, 504 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.80 (1H, s), 7.62 (4H, m), 7.42 (6H, m), 4.24 (1H, t, J = 5.8 Hz), 2.32 (1H, dd, J = 14.4, 6.1 Hz) , 1.96 (2H, m), 1.84 (1H, d, J = 14.4 Hz), 1.36 (1H, m), 1.08 (9H, s), 1.00 (3H, d, J = 7.0 Hz), 0.91 (1H, d, J = 6.8 Hz).
MS (m / z): 378 (M⁺, 1), 361 (4), 321 (100), 303 (10), 285 (10), 267 (24), 263 (16), 243 (74), 225 (39), 199 (100), 183 (76), 165 (39), 139 (72), 135 (48), 105 (59), 91 (34), 77 (60), 57 (95), 41 (80).
[α]_D ^{twenty five} = -16.2 (c = 0.59, CHCl_Three)
[0104]
Example 30: (1S, 2R, 3aR, 4aR) -3a-carbomethoxy-2-tert-butyldiphenylsilyloxy-1-methyl-bicyclo [3.1.0] hexane f. 8 (R = Me, P = TBDPS, A = COOCH₃)
a) Methyl (1S, 3S, 4R, 5R) -3-tosyloxy-4-methyl-5-acetoxy-cyclohexanecarboxylate 3.4. c (R = Me, L = OTos, A = COOCH₃)
2'B (R = Me, Z = Me, A = COOCH₃) (1.05 g, 4.57 mmol) to 2.3. c (R = Me, P = TBDPS, L = OTos, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 1.51 g, 89%.
IR (film): 2954, 1736, 1557, 1363, 1242, 1189, 1025, 956, 919, 667 cm^-11H-NMR (500 MHz, in CDCl_Three, ppm): 7.69 (2H, d, J = 7.2 Hz), 7.38 (2H, d, J = 7.2 Hz), 4.74 (1H, dt, J = 12.2, 4.5 Hz), 4.49 (1H, dt, J = 12.1, 4.7 Hz), 3.69 (3H, s), 2.46 (3H, s), 2.02 (3H, s), 1.98 (1H, dt, J = 12.1, 4.7 Hz), 1.93 (1H, dt, J = 12.6 , 4.6 Hz), 1.81 (2H, dd, J = 12.8 Hz), 1.63 (2H, dd, J = 12.6 Hz), 0.97 (3H, d, J = 6.9 Hz).
MS (m / z): 384 (M⁺), 343, 326, 311, 300, 269, 258, 213, 170, 152, 111, 93, 43 (base peak).
[α]_D ^{twenty five} = +51.1 (c = 0.59, CHCl_Three)
[0105]
b) Methyl (1S, 3S, 4R, 5R) -3-tosyloxy-4-methyl-5-hydroxy-cyclohexanecarboxylate 3.5. c (R = Me, L = OTos, A = COOCH₃)
3.4. c (R = Me, L = OTos, A = COOCH₃) To 2.2. c (R = Me, P = TBDPS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 90%.
IR (film): 3439, 2988, 1732, 1439, 1353, 1176, 1097, 1021, 945, 667 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.78 (2H, d, J = 7.2 Hz), 7.32 (2H, d, J = 7.2 Hz), 4.52 (1H, dt, J = 10.8, 4.7 Hz), 3.69 (1H, m), 3.68 (3H, s), 2.45 (3H, s), 2.34 (1H, m), 2.25 (1H, m), 1.94 (2H, m), 1.87 (1H, dt, J = 13.2, 4.5 Hz), 1.75 ( 1H, bs), 1.66 (1H, dd, J = 11.9 Hz), 0.91 (3H, d, J = 7.0 Hz).
MS (m / z): 340 (M⁺-2), 295, 278, 247, 220, 194, 170, 155, 127 (base peak), 91, 87, 57.
[α]_D ^{twenty five} : +18.8 (c = 0.41, CHCl_Three)
[0106]
c) Methyl (1S, 3S, 4R, 5R) -3-tosyloxy-4-methyl-5-tert-butyldiphenylsilyloxy-cyclohexanecarboxylate 3.6. c (R = Me, L = OTos, P = TBDPS, A = COOCH₃)
3.5. c (R = Me, L = OTos, A = COOCH₃) To 2.1. c (R = Me, P = TBDPS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 86%.
IR (film): 2955, 1736, 1598, 1427, 1363, 1177, 1031, 955, 914, 863, 820, 741, 703, 667 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.69-7.38 (14H, m), 4.27 (1H, dt, J = 12.1, 4.8 Hz), 3.61 (3H, s), 3.56 (1H, m), 2.44 (3H, s), 2.17 ( 1H, m), 2.02 (1H, m), 1.83 (1H, dt, J = 12.5, 4.3 Hz), 1.73 (1H, dd, J = 12.7 Hz), 1.63 (2H, m), 1.01 (9H, s ), 0.99 (3H, d, J = 7.2 Hz).
MS (m / z): 523 (M⁺-57), 463, 403, 353, 351, 293, 227, 213, 135, 91 (base peak), 77.
[α]_D ^{twenty five} : -2.6 (c = 0.94, CHCl_Three)
[0107]
d) (1S, 2R, 3aR, 4aR) -3a-carbomethoxy-2-tert-butyldiphenylsilyloxy-1-methyl-bicyclo [3.1.0] hexane f. 8 (R = Me, P = TBDPS, A = COOCH₃)
3.6. c (R = Me, L = OTos, P = TBDPS, A = COOCH₃From I.). a. 7 (R = Me, P = TBDPS, A = COOCH₃The reaction was carried out in the same manner as in (1). The title compound was obtained as a colorless oil in 68% yield.
IR (film): 2931, 2857, 1724, 1428, 1367, 1288, 1223, 1147, 1111, 1073, 1015, 934, 822, 740, 702, 609 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.62-7.31 (10H, m), 4.19 (1H, t, J = 5.9 Hz), 3.59 (3H, s), 2.31 (2H, dd, J = 13.7, 6.3 Hz), 1.96 (1H, d, J = 14.5 Hz), 1.84 (1H, m), 1.64 (1H, t, J = 4.6 Hz), 1.35 (1H, dd, J = 12.8, 5.0 Hz), 1.25 (1H, br.), 1.07 (9H, s), 0.99 (3H, d, J = 6.9 Hz), 0.91 (1H, m).
MS (m / z): 408 (M⁺), 351, 323, 273, 213, 199, 153, 121 (base peak), 77. [α]_D ^{twenty five} : +13.9 (c = 0.65, CHCl_Three)
[0108]
Example 31: (1S, 2R, 3aR, 4aR) -3a-hydroxymethyl-2-t-butyldiphenylsilyloxy-1-methyl-bicyclo [3.1.0] hexane f. 9 (R = Me, P = TBDPS, A = CH₂OH)
I. f. 8 R = Me, P = TBDPS, A = COOCH₃From I.). a. 8 (R = Me, P = TBDPS, A = CH₂Reaction was carried out in the same manner as in (OH). The yield was 98%.
IR (film): 3324, 2929, 2857, 1654, 1471, 1427, 1363, 1194, 1107, 1078, 1011, 822, 740, 701, 610 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.68-7.37 (10H, m), 4.21 (1H, t, J = 6.0 Hz), 3.54 (1H, dd, J = 11.4, 6.0 Hz), 3.52 (1H, dd, J = 11.4, 6.0 Hz), 2.29 (1H, dd, J = 11.3, 8.1 Hz), 1.94 (1H, dd, J = 14.6, 5.9 Hz), 1.86 (1H, d, J = 13.2 Hz), 1.23 (1H, t, J = 4.1 Hz), 1.14 (1H, m), 1.07 (9H, s), 0.99 (3H, d, J = 6.9 Hz), 0.89 (1H, m), 0.41 (dd, J = 8.1, 4.3 Hz).
MS (m / z): 323 (M⁺-57), 305, 267, 245, 199, 181, 139, 107.
[α]_D ^{twenty five} : +3.1 (c = 0.93, CH_ThreeCl)
[0109]
Example 32: (1S, 2R, 3aR, 4aR) -3a-formyl-2-t-butyldiphenylsilyloxy-1-methyl-bicyclo [3.1.0] hexane f. 10 (R = Me, P = TBDPS, A = CHO)
I. f. 9 (R = Me, P = TBDPS, A = CH₂OH) to I.I. a. The reaction was carried out in the same manner as 9 (R = Me, P = TBDPS, A = CHO). The yield was 28%.
[α]_D ^{twenty five} : +15.8 (c = 0.41, CH_ThreeCl)
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.80 (1H, s), 7.61-7.35 (10H, m), 4.24 (1H, t, J = 5.8 Hz), 2.31 (2H, m), 1.96 (1H, m, dd, J = 8.1 , 5.9 Hz), 1.84 (1H, d, J = 14.3 Hz), 1.37 (1H, dd, J = 11.0, 7.1 Hz), 1.26 (1H, dd, J = 9.7, 4.6 Hz), 1.07 (9H, s ), 1.04 (3H, t, J = 6.9 Hz).
IR (film): 2959, 2857, 1703, 1471, 1391, 1383, 1274, 1215, 1191, 1111, 1109, 1009, 963, 823, 701 cm^-1.
MS (m / z): 377 (M⁺-1, 5), 337 (75), 321 (M⁺-57, 8), 319 (10), 309 (10), 293 (6), 259 (12), 231 (20), 215 (16), 199 (100), 181 (30), 153 (20) , 139 (60), 121 (95).
[0110]
Example 33: (1R, 2S, 3aS, 4aS) -3a-carbomethoxy-2-tert-butyldiphenylsilyloxy-1-ethyl-bicyclo [3.1.0] hexane a. 10 (R = Et, P = TBDPS, A = COOCH₃)
a) Methyl (1S, 3S, 4R, 5R) -3-tert-butyldiphenylsilyloxy-4-ethyl-5-acetoxy-cyclohexane 2.1. d (R = Et, P = TBDPS, A = COOCH₃)
2'C (R = Et, Z = Me, A = COOCH₃) To 3.4. Reaction was carried out in the same manner as c. The yield was 92%.
[α]_D ^{twenty five} : +7.5 (c = 0.59, CH_ThreeCl)
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.45-7.36 (10H, m), 4.62 (1H, dt, J = 12.2, 4.4 Hz), 3.69 (1H, dt, J = 11.5, 4.3 Hz), 3.61 (3H, s), 2.08 ( 2H, tt, J = 8.8, 3.9 Hz), 2.01 (3H, s), 1.85 (2H, m), 1.60 (3H, m), 1.51 (1H, m), 1.06 (9H, s), 1.02 (3H , t, J = 7.5 Hz).
IR (film): 2954, 2848, 1739, 1462, 1428, 1364, 1238, 1194, 1178, 1110, 1034, 986, 812, 740, 702 cm^-1.
MS (m / z): 482 (M⁺, 2), 468 (5), 451 (7), 425 (M⁺-57), 391 (1), 365 (80), 351 (25), 305 (15), 273 (20), 241 (100), 213 (88), 199 (92), 153 (56), 135 (75), 107 (85).
[0111]
b) Methyl (1S, 3S, 4R, 5R) -3-tert-butyldiphenylsilyloxy-4-ethyl-5-hydroxy-cyclohexanecarboxylate 2.2. d (R = Me, P = TBDPS, A = COOCH₃)
2.1. d (R = Et, P = TBDPS, A = COOCH₃) To 2.2. c (R = Me, P = TBDPS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 98%.
[α]_D ^{twenty five} : +28.7 (c = 0.19, CH_ThreeCl)
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.68 (10H, m), 3.68 (1H, dt, J = 8.2, 4.2 Hz), 3.62 (3H, s), 3.57 (1H, dt, J = 11.1, 4.6 Hz), 2.07 (1H, m), 1.85 (1H, t, J = 4.1 Hz), 1.77 (1H, dt, J = 8.6, 4.0 Hz), 1.71 (1H, tt, J = 11.0, 4.0 Hz), 1.64 (2H, t, J = 9.0), 1.59 (1H, overlap), 1.52 (1H, bs), 1.45 (1H, m), 1.06 (9H, s), 1.05 (3H, t, J = 7.5).
IR (film): 3435, 2995, 2858, 1736, 1589, 1460, 1427, 1363, 1271, 1236, 1172, 1111, 1050, 915, 875, 823, 740, 702, 647 cm^-1.
MS (m / z): 383 (M⁺-57, 14), 351 (16), 323 (18), 305 (90), 273 (18), 253 (10), 227 (50), 199 (100), 183 (70), 153 (80) , 107 (98).
[0112]
c) Methyl (1S, 3S, 4R, 5R) -3-tert-butyldiphenylsilyloxy-4-ethyl-5-tosyloxy-cyclohexanecarboxylate 2.3. d (R = Et, P = TBDPS, L = OTos, A = COOCH₃)
2.2. d (R = Et, P = TBDPS, A = COOCH₃) To 2.3. c (R = Me, P = TBDPS, L = OTos, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 82%.
[α]_D ^{twenty five} : -17.9 (c = 0.59, CH_ThreeCl)
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.72-7.30 (14H, m), 4.28 (1H, dt, J = 12.5, 4.5 Hz), 3.59 (3H, s), 3.55 (1H, dt, J = 11.4, 4.3 Hz), 2.45 ( 3H, s), 1.96 (1H, tt, J = 8.5, 4.1 Hz), 1.91 (1H, t, J = 4.2 Hz), 1.84 (1H, dt, J = 8.5, 4.1 Hz), 1.77 (1H, m ), 1.73 (1H, m), 1.53 (2H, m), 1.47 (1H, m), 1.02 (9H, s), 0.97 (3H, t, J = 7.5 Hz).
IR (film): 2957, 2858, 1738, 1598, 1487, 1462, 1428, 1360, 1277, 1189, 1111, 1030, 953, 885, 822, 741, 704 cm^-1.
MS (m / z): 357 (M⁺-57, 45), 353 (100), 293 (22), 227 (5), 199 (48), 135 (70).
[0113]
d) (1R, 2S, 3aS, 4aS) -3a-carbomethoxy-2-tert-butyldiphenylsilyloxy-1-ethyl-bicyclo [3.1.0] hexane a. 10 (R = Et, P = TBDPS, A = COOCH₃)
2.3. d (R = Et, P = TBDPS, L = OTos, A = COOCH₃From I.). a. 7 (R = Me, P = TBDPS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 71%.
[α]_D ^{twenty five} : -33.3 (c = 0.27, CH_ThreeCl)
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.63-7.35 (10H, m), 4.18 (1H, t, J = 5.9 Hz), 3.61 (3H, s), 2.26 (1H, m), 2.06 (1H, m), 1.98 (1H, d, J = 14.3 Hz), 1.92 (1H, m), 1.67 (1H, t, J = 4.3 Hz), 1.48 (2H, m), 1.36 (1H, dd, J = 8.7, 3.9 Hz), 1.05 ( 9H, s), 0.89 (3H, J = 7.4 Hz).
IR (film): 2958, 1723, 1427, 1366, 1298, 1224, 1148, 1111, 1064, 1028, 926, 821, 740, 610, 507 cm^-1.
MS (m / z): 422 (M⁺, 2), 391 (4), 365 (M⁺-57, 40), 337 (8), 287 (12), 259 (10), 225 (8), 199 (65), 135 (100), 105 (38).
[0114]
Example 34: (1S, 2R, 3aR, 4aR) -3a-carbomethoxy-2-t-butyldiphenylsilyloxy-1-ethyl-bicyclo [3.1.0] hexane f. 11 (R = Et, P = TBDPS, A = COOCH₃).
a) Methyl (1S, 3S, 4R, 5R) -3-mesyloxy-4-ethyl-5-acetoxy-cyclohexane carboxylate 3.4. d (R = Et, L = OMs, A = COOCH₃).
Monoacetate 2'C (A = COOCH₃, R = Et, Z = Me) (0.1 g, 0.41 mmol), Et₃N (0.30 ml, 2.10 mmol) CH₂Cl₂MsCl (96 μL, 1.23 mmol) was added dropwise to the (5 ml) solution at room temperature. The resulting mixture was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and extracted with AcOEt (3 × 50 ml). The combined extracts were washed with saturated brine (3 x 5 ml) and MgSO₄And concentrated to give a residue. The resulting residue was purified by HPLC eluting with isooctane / EtOAc (90:10) to give mesylate 3.4. d (A = COOCH₃, R = Et, L = OMs) (0.11 g, 85%).
IR (film): 2954, 1737, 1641, 1357, 1241, 1175, 952 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 4.87 (1H, dt, J = 10.9, 4.2 Hz), 4.75 (1H, dt, J = 4.5, 10.9 Hz), 3.69 (3H, s), 3.00 (3H, s), 2.48 (1H, m), 2.23 (1H, bs), 2.13 (1H, dt, J = 4.2, 11.8 Hz), 2.05 (3H, s), 2.01 (1H, d, J = 8.8 Hz), 1.96 (1H, dt, J = 13.3, 4.5 Hz), 1.83 (1H, m), 1.58 (2H, m), 1.01 (3H, s).
MS (m / z): 322 (M⁺), 309, 291, 248, 227, 199, 166, 135, 107, 78, 43 (base peak).
[α]_D ^{twenty five} : +2.6 (c = 1.08, CHCl_Three)
[0115]
b) Methyl (1S, 3S, 4R, 5R) -3-mesyloxy-4-ethyl-5-hydroxy-cyclohexanecarboxylate 3.5. d (A = COOCH₃, R = Et, L = OMs)
3.4. d (R = Et, L = OMs, A = COOCH₃) To 2.5. a (R = H, L = OTos, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 90%.
IR (film): 3439, 2957, 1729, 1438, 1351, 1277, 1174, 944, 877, 838, 757,
530 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 4.87 (1H, t, J = 3.1 Hz), 3.91 (1H, t, J = 2.9 Hz), 3.74 (3H, s), 3.00 (3H, s), 2.69 (1H, bs), 2.44 (1H, bs), 2.17 (1H, bs), 2.00 (2H, m), 1.84 (2H, dt, J = 14.3, 4.7 Hz), 1.71 (2H, m), 1.03 (3H, t, J = 7.4 Hz).
MS (m / z): 281 (M⁺+1), 263, 249, 236, 200, 184, 166, 141, 125, 111, 87, 78, 55 (base peak).
[α]_D ^{twenty five} : +51.3 (c = 0.61, CHCl_Three)
[0116]
c) Methyl (1S, 3S, 4R, 5R) -3-mesyloxy-4-ethyl-5-t-butyldiphenylsilyloxy-cyclohexanecarboxylate 3.6. d (R = Et, L = OMs, P = TBDPS, A = COOCH₃)
3.5. d (R = Et, L = OMs, A = COOCH₃) To 2.8. a (R = H, L = OTos, P = TBDPS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 86%.
IR (film): 2957, 2857, 1738, 1588, 1462, 1427, 1358, 1276, 1177, 1111, 1030, 949, 885, 823, 741, 703, 614 cm^-11H-NMR (500 MHz, in CDCl_Three, ppm): 7.65-7.35 (10H, m), 4.44 (1H, dt, J = 12.2, 4.6 Hz), 3.67 (1H, dt, J = 11.6, 4.2 Hz), 3.63 (3H, s), 2.79 ( 3H, s), 2.09 (1H, dt, J = 12.9, 3.9 Hz), 2.06 (1H, m), 2.02 (2H, m), 1.85 (1H, m), 1.79 (1H, dd, J = 12.8 Hz ), 1.65, 1H, dt, J = 13.1, 4.0 Hz), 1.49 (1H, m), 1.06 (9H, s), 1.04 (3H, t, J = 7.5 Hz).
MS (m / z): 461 (M⁺-57), 401, 365, 351, 305, 277, 231, 199, 167, 135, 107 (base peak).
[α]_D ^{twenty five} : -2.3 (c = 0.35, CHCl_Three)
[0117]
d) (1S, 2R, 3aR, 4aR) -3a-carbomethoxy-2-tert-butyldiphenylsilyloxy-1-ethyl-bicyclo [3.1.0] hexane f. 11 (R = Et, P = TBDPS, A = COOCH₃).
3.6. d (R = Et, L = OMs, P = TBDPS, A = COOCH₃From I.). a. 7 (R = Me, P = TBDPS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 71%.
IR (film): 2958, 1723, 1427, 1366, 1298, 1224, 1148, 1111, 1064, 1028, 926, 821, 740, 610, 507 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.63-7.35 (10H, m), 4.18 (1H, t, J = 5.9 Hz), 3.61 (3H, s), 2.26 (1H, m), 2.06 (1H, m), 1.98 (1H, d, J = 14.3 Hz), 1.92 (1H, m), 1.67 (1H, t, J = 4.3 Hz), 1.48 (2H, m), 1.36 (1H, dd, J = 8.7, 3.9 Hz), 1.05 ( 9H, s), 0.89 (3H, J = 7.4 Hz).
MS (m / z): 422 (M⁺, 2), 391 (4), 365 (M⁺-57, 40), 337 (8), 287 (12), 259 (10), 225 (8), 199 (65), 135 (100), 105 (38).
[Α]_D ²⁵  : +28.4 (c = 0.75, CHCl₃)
[0118]
Example 35: (1R, 2S, 3aR, 4aR) -3a-carbomethoxy-2-t-butyldiphenylsilyloxy-1-methyl-bicyclo [3.1.0] hexane e. 1 (R = Me, P = TBDPS, A = COOCH₃)
a) Methyl (1S, 3S, 4R, 5S) -3-tert-butyldiphenylsilyloxy-4-methyl-5-hydroxy-cyclohexane carboxylate 3.2. c (R = Me, P = TBDPS, A = COOCH₃).
2.2. c (R = Me, P = TBDPS, A = COOCH₃) (167 mg, 0.392 mmol), picolinic acid (257 mg, 2.092 mmol) and triphenylphosphine (548 mg, 2.092 mmol) in THF (−38 ° C.) in DIAD (diisopropyl azodicarboxyl). Rate; 412 μL, 2.092 mmol) was added dropwise over 4 minutes. The reaction solution was stirred for 4.5 hours and allowed to return to room temperature overnight. The resulting mixture was poured into water and EtOAc (50 ml: 50 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 50 ml), MgSO₄And dried. The residue was separated by HPLC (isooctane / EtOAc 98: 2) and (4S, 6S) -4-carbomethoxy-6-tert-butyldiphenylsilyloxy-1-methylcyclohexane (142 mg, 88.8%) was Obtained as a colorless oil.
IR (film): 2953, 2856, 1738, 1428, 1247, 1168, 1111, 1068, 999, 893, 820, 741, 702, 614 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.71 (4H, m), 7.43 (2H, m), 7.38 (4H, m), 5.39 (1H, m), 4.25 (1H, bs), 3.60 (3H, s), 2.39 (1H, m), 2.19 (1H, m), 2.13 (1H, m), 2.04 (1H, m), 1.75 (1H, dd, J = 22.3, 12.5Hz), 1.66 (3H, bs), 1.08 (9H, s ).
MS (m / z): 387 (1), 361 (1), 351 (75), 319 (5), 273 (5), 273 (5), 213 (100), 183 (70), 137 (65 ), 105 (30), 77 (85).
[α]_D ^{twenty five} : +81.9 (c = 1.91, CHCl_Three)
[0119]
A borane-THF complex solution (1.0 M, 325 μL, 0.325 mmol, 1.5 eq) was added dropwise to a stirred diglyme (2 ml) solution of cyclohexane (110 mg, 0.27 mmol) (0 ° C.). did. The resulting solution was stirred for 4 hours at 0 ° C. THF was removed and TAO (trimethylamine N-oxide, 90 mg, 0.81 mmol) was added. The mixture was heated to reflux for 2 hours. The resulting mixture was cooled to room temperature, extracted with EtOAc (4 mL 40 ml), MgSO₄And dried. The residue was separated by flash chromatography on silica and purified by HPLC (cyclohexane / EtOAc: 9: 1) to give compound 3.2. c (R = Me, P = TBDPS, A = COOCH₃) (46 g, 40.5%) was obtained as a colorless oil.
IR (film, cm^-1): 3453, 2954, 2858, 1737, 1462, 1428, 1379, 1272, 1195, 1111, 1032, 934, 823, 702.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.66 (4H, m), 7.42 (2H, m), 7.38 (4H, m), 4.17 (1H, dt, J = 10.7, 4.7Hz), 3.88 (1H, bs), 3.62 (3H, s), 2.61 (1H, m), 1.85 to 1.65 (5H, m), 1.06 (9H, s), 0.96 (3H, d, J = 7.2Hz).
[α]_D ^{twenty five} : +39.4 (c = 0.95, CHCl_Three)
[0120]
b) Methyl (1S, 3S, 4R, 5S) -3-tert-butyldiphenylsilyloxy-5-mesyloxy-4-methyl-cyclohexanecarboxylate 3.3. c (R = Me, L = OMs, P = TBDPS, A = COOCH₃)
3.2. c (R = Me, P = TBDPS, A = COOCH₃) To 3.4. d (R = Et, L = OMs, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 84.5%.
IR (film): 2952, 1732, 1470, 1427, 1357, 1275, 1177, 1112, 1029, 929, 904 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.65 (4H, t, J = 8.0 Hz), 7.40 (6H, m), 4.80 (1H, bs), 4.06 (1H, m), 3.65 (3H, s), 2.70 (3H, s) , 2.58 (1H, m), 2.04 (1H, bs), 1.98 to 1.76 (4H, m), 1.06 (9H, s), 1.03 (3H, d, J = 7.2 Hz). [Α]_D ^{twenty five} : +30.3 (c = 0.52, CHCl_Three)
[0121]
c) (1R, 2S, 3aR, 4aR) -3a-carbomethoxy-2-tert-butyldiphenylsilyloxy-1-methyl-bicyclo [3.1.0] hexane e. 1 (R = Me, P = TBDPS, A = COOCH₃)
3.3. c (R = Me, L = OMs, P = TBDPS, A = COOCH₃From I.). a. 7 (R = Me, P = TBDPS, A = COOCH₃The reaction was carried out in the same manner as in (1). The yield was 68.8%.
IR (film): 2951, 1725, 1428, 1259, 1238, 1111, 880, 814, 742, 702 cm^-1.¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.63 (4H, m), 7.45-7.35 (6H, m), 3.84 (1H, m), 3.64 (3H, s), 2.23 (1H, m), 2.02 (1H, m), 1.93 ( 1H, m), 1.60 (1H, m), 1.17 (1H, m), 1.04 (12H, bs), 0.56 (1H, m).
[0122]
Example 36: (2R, 3aS, 4aS) -2-methyl-2-hydroxy-3a-hydroxymethyl-bicyclo [3.1.0] hexane: I. i. 1 (A = CH₂OH, R₁= Me: Scheme 4)
a) (2R, 3aS, 4aS) -2-Hydroxy-3a-[(benzoyloxy) methyl] -bicyclo [3.1.0] hexane: 4.1
I. a. 5 (R = H, P = TBDPS, A = CH₂OH) (4.451 g, 12.15 mmol), DMAP (250 mg, 2.27 mmol) and Et.₃N (16.5 ml, 121.1 mmol) CH₂Cl₂Benzoyl chloride was added dropwise to the (50 ml) solution (0 ° C.). The mixture was stirred for 22 hours at room temperature and 70 ml CH₂Cl₂Diluted with The organic layer was separated and washed with saturated brine (3 x 100 ml), MgSO₄And dried. The residue was purified by flash chromatography (silica gel, isooctane / EtOAc: 100: 2.5) to give the corresponding benzoate (5.51 g, 96.5%) as a colorless oil. TBAF (14 ml, 14 mmol, 1M in THF) was added to a solution of this benzoate (2.22 g, 4.72 mmol) in THF (40 ml) and the resulting solution was stirred at room temperature for 14 hours. The solvent was evaporated under vacuum. The residue was passed through a short silica gel column (isooctane / EtOAc: 7: 3). The crude product was purified by HPLC (isooctane / EtOAc: 7: 3) to give compound 4.1 (1.03 g, 94.0%) as a colorless oil.
IR (film): 3413.8, 2928.3, 1714.1, 1602.1, 1452.1, 1277.5, 1115.1, 1070.0, 958.3, 808.3, 711.5 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.06 (2H, d, J = 7.8Hz), 7.56 (1H, t, J = 7.3Hz), 7.45 (1H, t, J = 7.7Hz), 4.48 (1H, m), 4.34 (2H , dd, J = 19.4, 11.5Hz), 2.23 (2H, m), 1.94 (1H, d, J = 14.0Hz), 1.78 (1H, d, J = 14.2Hz), 1.38 (1H, ddd, J = 8.3, 4.3, 4.3Hz), 1.30 (1H, bs), 1.06 (1H, t, J = 4.4Hz), 0.75 (1H, m)
MS (m / z): 232 (M⁺, 1), 214 (1), 199 (1), 189 (1), 161 (1), 149 (1), 127 (1), 110 (13), 105 (100), 77 (43). (14).
[α]_D ^{twenty five} : -27.96 (c = 1.47, CHCl_Three).
[0123]
b) (3aS, 4aS) -3a-[(Benzoyloxy) methyl] -bicyclo [3,1,0] hexan-2-one: 4.2
Alcohol 4.1 (209 mg, 0.904 mmol) in CH₂Cl₂(30 ml) To the solution was added pyridinium dichromate (PDC, 1.072 g, 4.97 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The resulting solution was directly purified by flash chromatography (silica gel column 3 × 15 cm) (isooctane / EtOAc: 9: 1 to 8: 2) to give compound 4.2 (197 mg, 95%) as a colorless oil Obtained as a thing.
IR (film): 1745.0, 1715.9, 1451.2, 1355.4, 1272.1, 1155.7, 1111.3, 1069.9,
711.0 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.05 (2H, d, J = 8.9Hz), 7.58 (1H, t, J = 7.4Hz), 7.46 (2H, t, J = 7.6Hz), 4.41 (2H, dd, J = 29.6, 12.7Hz), 2.75 (2H, m), 2.41 (1H, d, J = 9.0Hz), 2.28 (1H, d, J = 9.3Hz), 1.68 (1H, m), 1.10 (1H, t, J = 7.0Hz), 0.37 (1H, t, J = 5.1Hz).
MS (m / z): 230 (M⁺, 1), 212 (1), 202 (6.9), 183 (1), 161 (1), 149 (1), 125 (1), 106 (13), 105 (100), 77 (46), 51 (20).
[α]_D ^{twenty five} : -36.50 (c = 4.07, CHCl_Three)
[0124]
c) (2R, 3aS, 4aS) -2-methyl-2-hydroxy-3a-hydroxymethyl-bicyclo [3.1.0] hexane i. 1 (R₁= Me, A = CH₂OH)
A solution of ketone 4.2 (120 mg, 0.52 mmol) in THF (4 ml) with MeMgBr in Et.₂O (1.5 ml, 3.0 M) solution was added dropwise at −78 ° C. over 5 minutes. The resulting mixture was stirred at this temperature for 6 hours and then allowed to return to room temperature overnight. Ice-cooled saturated NH₄Cl aqueous solution (0.2 ml) was added to terminate the reaction. The resulting mixture was added MgSO₄Through a short silica gel column with The residue was separated by HPLC (isooctane / EtOAc: 5: 5). i. 1 (R₁= Me, A = CH₂OH) (55 mg, 74%) was obtained as a white solid.
IR (film):: 3288.4, 2931.3, 2858.5, 1459.1, 1370.2, 1260.7, 1183.9, 1135.7,1111.5, 1064.0, 1016.0, 922.6 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 3.58 (2H, s), 2.08 (1H, d, J = 13.7Hz), 2.03 (1H, dd, J = 13.8, 5.0Hz), 1.88 (1H, d, J = 13.7Hz), 1.76 (1H, d, J = 13.8Hz), 1.34 (3H, s), 1.29 (1H, bs), 1.21 (1H, m), 1.14 (1H, t, J = 4.3Hz), 1.11 (1H, s) , 0.57 (1H, dd, J = 8.4, 4.5Hz).
MS (m / z): 124 (2), 109 (6), 93 (12), 81 (12), 71 (10), 67 (10), 55 (11), 43 (100).
[α]_D ^{twenty five} : -33.10 (c = 1.17, MeOH)
[0125]
Example 37: (2R, 3aS, 4aS) -2-methyl-2-hydroxy-3a-formyl-bicyclo [3.1.0] hexane i. 2 (R₁= Me, A = CHO)
SO₃-DMSO: CH of pyridine complex (2.5 eq, 140 mg)₂Cl₂(500 μL: 250 μL) and Et₃N (2.5 eq, 120 μL) solution with I.V. i. 1 (R₁= Me, A = CH₂OH) (1 eq, 50 mg, 35 μmol) of DMSO: CH₂Cl₂(500 μL: 250 μL) and Et₃N (2.5 eq, 120 μL) solution was added at −15 ° C. After stirring at −10 ° C. to −5 ° C. for 1 hour, the mixture was added to Et.₂O: Poured into saturated saline. The organic layer was then dried (MgSO₄). After evaporating the solvent, the residue was subjected to column chromatography (Et₂O: Isooctane 1: 1 to Et₂O: Isooctane: Methanol: CH₂Cl₂100: 100: 1: 20). i. 2 (R₁= Me, A = CHO) as a colorless oil (37 mg, 75%).
IR (film): 3441, 2929, 1694, 1435, 1258, 1105, 1049, 963, 893 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.81 (1H, s), 2.47 (1H, d, J = 14Hz), 2.03 (2H, m), 1.91 (1H, t, J = 5Hz), 1.88 (1H, d, J = 13Hz) , 1.81 (1H, d, J = 14Hz), 1.49 (1H, ddt, J = 9,5, 1Hz), 1.36 (3H, s).
[α]_D ^{twenty five} : -79.7 (c = 1.22, CHCl_Three)
[0126]
Example 38: (2R, 3aS, 4aS) -2-ethyl-2-hydroxy-3a-hydroxymethyl-bicyclo [3.1.0] hexane i. 3 (A = CH₂OH, R₁= Et) (Scheme 4)
From 4.2, I.I. i. 1 (R₁= Me, A = CH₂Reaction was carried out in the same manner as in (OH). The yield was 66.6%.
IR (film):: 3275.4, 2921.3, 2858.5, 1431.8, 1284.3, 1237.3, 1122.3, 1068.0, 1027.8, 930.7 cm^-1
¹H-NMR (500 MHz, in CDCl_Three, ppm): 3.59 (2H, d, J = 5.6Hz), 2.03 (1H, d, J = 13.6Hz), 1.99 (1H, dd, J = 13.9, 4.9Hz), 1.83 (1H, d, J = 13.7Hz), 1.72 (1H, d, J = 13.8Hz), 1.55 (2H, q, J = 6.4), 1.23 (2H, m), 1.16 (1H, t, J = 4.2Hz), 1.04 (1H, s), 0.92 (3H, t, 7.4Hz), 0.54 (1H, dd, J = 8.4, 4.3Hz).
MS (m / z): 138 (2), 123 (4), 109 (12.9), 97 (2), 91 (6), 79 (20), 72 (6), 67 (12.9), 57 (100 ), 43 (8).
[α]_D ^{twenty five} : -34.90 (c = 0.928, MeOH)
[0127]
Example 39: (2R, 3aS, 4aS) -2-ethyl-2-hydroxy-3a-formyl-bicyclo [3.1.0] hexane i. 4 (A = CHO, R₁= Et)
I. i. 3 (R₁= Et, A = CH₂OH) to I.I. i. 2 (R₁= Me, A = CHO). The yield was 50%.
IR (film): 3418, 2966, 1689, 1114, 1057, 982, 632 cm^-1 ;
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.80 (1H, s), 2.09 (2H, m), 1.92 (1H, t, J = 5.0Hz), 1.83 (1H, d, J = 13.3Hz), 1.69 (1H, d, J = 10.0Hz), 1.57 (2H, m), 1.49 (1H, m), 1.15 (1H, s), 0.93 (3H, t, J = 7.4Hz).
[α]_D ^{twenty five} : -68.1 (c = 0.30, CHCl_Three)
[0128]
Example 40: (2R, 3aS, 4aS) -2-[(t-butyldiphenylsilyloxy) -methyl] -3a-hydroxymethyl-bicyclo [3.1.0] hexane j. 1 (A = CH₂OH, P = TBDPS) (Scheme 4)
a) (3aS, 4aS) -2-Methylene-3a-[(benzoyloxy) methyl] -bicyclo [3.1.0] hexane 4.3
Stirred lead powder (5.75 g) CH₂Br₂(2.02 ml) and THF (40 ml) in TiCl over 10 minutes at −78 ° C.₄Was dripped. The mixture was heated to 8 ° C. and stirred at this temperature for 72 hours to give a dark gray slurry of the active ingredient (Lombardo reagent).
[0129]
Ketone 4.2 (98 mg, 0.426 mmol) in CH₂Cl₂To the (8 ml) solution, Lombardo reagent was added at room temperature in portions until no ketone was present (TLC). The reaction mixture is Et.₂Dilute with O (40 ml) and add saturated NaHCO₃And stirring was continued for 30 minutes to form two clear layers. Etch the water layer₂O (3 × 25 ml) and CH₂Cl₂Extracted (2 × 25 ml). Combined organic layer is MgSO₄And dried. The residue was purified by flash chromatography (silica gel: pentane / ether: 100: 1) to give compound 4.3 (66 mg, 67.9%) as a colorless oil.
IR (film): 2925.8, 1715.6, 1451.5,1269.7, 1111.0, 1069.0, 1026.1, 741.9, 710.7 IR (film): 2925.8, 1715.6, 1451.5,1269.7, 1111.0, 1069.0, 1026.1, 741.9, 710.7^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.07 (2H, d, J = 7.3Hz), 7.56 (1H, t, J = 7.4Hz), 7.45 (2H, t, J = 7.7Hz), 4.81 (2H, d, J = 12.4Hz) ), 4.38 (2H, s), 2.68 (2H, m), 2.43 (1H, d, J = 15.4Hz), 2.28 (1H, d, J = 15.6Hz), 1.36 (1H, m), 0.68 (1H , t, J = 6.5Hz), 0.39 (1H, t, J = 4.5Hz).
MS (m / z): 228 (M⁺, 1), 213 (1), 199 (1), 181 (2), 169 (1), 141 (1), 123 (5), 105 (100), 91 (88), 77 (57), 65 (7), 51 (20).
[α]_D ^{twenty five} : -51.90 (c = 1.73, CHCl_Three)
[0130]
b) (2R, 3aS, 4aS) -2-[(t-butyldiphenylsilyloxy) -methyl] -3a-hydroxymethyl-bicyclo [3.1.0] hexane j. 1 (A = CH₂OH, P = TBDPS) and (2S, 3aS, 4aS) -2-[(t-butyldiphenylsilyloxy) -methyl] -3a-hydroxymethyl-bicyclo [3.1.0] hexane k. 1 (A = CH₂OH, P = TBDPS)
Alkaline 4.3 (49 mg, 0.21 mmol) in THF (6 ml) at −5 ° C. with BH₃. THF was added and then the reaction mixture was stirred at this temperature for 3.5 hours to react with saturated NaHCO 3.₃Aqueous solution (3.9 ml) and H₂O₂(30%) (3.9 ml). The reaction was warmed to room temperature and stirred for 1.5 hours. This solution is₂Extracted with O (2 × 20 ml) and EtOAc (2 × 20 ml). Combined organic layer is MgSO₄Dried over and concentrated. The residue was passed through a short silica gel column and the crude product was purified by HPLC (isooctane / EtOAc: 7: 3) to give the epimer hydroxylated product (2R: 2S; ratio, 75:25, 39 mg, 73.7). %) As a colorless oil.
To a DMF (3 ml) solution of this mixture (35 mg, 0.142 mmol), imitazole (49 mg, 0.720 mmol, 5 eq.) And DMAP (7.8 mg, 0.064 mmol, 0.45 eq.). TBDPSCl was added dropwise at −0 ° C .; the resulting mixture was stirred at room temperature for 19 hours. The reaction solution is Et.₂Poured into O / water (50 ml / 40 ml). And the water layer is Et₂Extracted with O (3 × 20 ml) and EtOAc (2 × 20 ml). Combined organic layer is MgSO₄Dried over and concentrated. The residue was purified by flash chromatography (silica gel: isooctane / EtOAc: 100: 2) to give the corresponding silyl ether (56 mg, 81.3%) as a colorless oil.
Stir this mixture (50 mg, 0.106 mmol) in MeOH (0.2 ml H).₂6 ml) solution with O at room temperature₂CO₃(50 mg, 0.505 mmol) was added. The mixture was stirred at room temperature for 20 hours, the solid was filtered and the filtrate was Et.₂Dilute with O (50 ml) and wash with saturated brine (2 × 20 ml), MgSO 4₄And the solvent was evaporated. The residue was passed through a short silica gel column and separated by HPLC (isooctane / EtOAc: 75:25). j. 1 (A = CH₂OH, P = TBDPS) (24 mg, 61.8%) and I.I. k. 1 (A = CH₂(OH, P = TBDPS) (8 mg, 20.4%) was obtained as a colorless oil.
MS (m / z): 379 (M⁺-1, 1), 305 (1), 275 (2), 229 (2), 199 (47), 181 (7), 107 (100), 79 (53).
Compound I. j. 1 (A = CH₂OH, P = TBDPS)
IR (film): 3342.5, 2930.3, 2858.0, 1471.8, 1427.7, 1389.8, 1111.9, 1008.2, 823.7, 739.7, 701.6 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.64 (4H, d, J = 7.8Hz), 7.45-7.35 (6H, m), 3.54 (2H, dd, J = 14.4, 11.2Hz), 3.41 (2H, d, J = 7.4Hz) , 2.61 (1H, m), 2.19 to 2.09 (2H, m), 1.64 (1H, dd, J = 13.5, 4.8Hz), 1.47 (1H, dd, J = 13.6, 4.6Hz), 1.26 (1H, bs ), 1.18 (1H, dt, J = 8.6, 4.3, 4.3Hz), 1.02 (9H, s), 0.62 (1H, dd, J = 8.4, 4.7Hz), 0.35 (1H, t, J = 4.4Hz) .
[α]_D ^{twenty five} : -13.05 (c = 1.40, CHCl_Three)
[0131]
Compound I. k. 1 (A = CH₂OH, P = TBDPS)
IR (film): 3342.5, 2929.9, 2856.7, 1471.6, 1427.7, 1388.8, 1111.9, 1086.1, 1031.5, 1008.5, 823.7, 739.3, 701.5 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 7.64 (4H, d, J = 6.7Hz), 7.39 (6H, m), 3.64 (1H, d, J = 11.2Hz), 3.57 (3H, d, J = 7.8Hz), 1.97 to 1.87 (2H, m), 1.80 (1H, dd, J = 12.3, 7.0Hz), 1.56 (2H, m), 1.22 (1H, m), 1.15 (1H, ddd, J = 8.3, 4.1, 4.1Hz), 1.02 (9H, s), 0.52 (1H, t, J = 4.3Hz), 0.41 (1H, dd, J = 8.0, 5.0Hz).
[Α]_D ²⁵  : -6.16 (c = 1.65, CHCl₃)
[0132]
Example 41: (2R, 3aS, 4aS) -2-[(t-butyldiphenylsilyloxy) -methyl] -3a-formyl-bicyclo [3.1.0] j. 2 (A = CHO, P = TBDPS) (Scheme 4)
(COCl)₂(30 μl, 0.344 mmol) of CH₂Cl₂(1 ml) in solution at −78 ° C. with DMSO (36.6 μL, 0.515 mmol) in CH.₂Cl₂(100 μL) solution was added dropwise. The mixture was stirred at −78 ° C. for 20 minutes. j. 1 (A = CH₂OH, P = TBDPS) (14 mg, 0.37 mmol) in CH₂Cl₂(0.5 ml) solution was added. The resulting cloudy liquid was stirred at −78 ° C. for 20 minutes, and Et.₃N (0.2 ml, 1.435 mmol) was added dropwise and stirred for 20 minutes. The mixture was then heated to room temperature over 1 hour. Cold water is added to terminate the reaction, the organic layer is separated, and the aqueous layer is₂Extract with O (3 x 50 ml) and MgSO₄And dried. The residue was separated by HPLC (hexane / EtOAc 95: 5) to give compound I.I. j. 2 (A = CHO, P = TBDPS) (4 mg, 28.7%) was obtained as a colorless oil.
IR (film): 2931, 2858, 1699, 1428, 1112, 824, 740, 613 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.83 (1H, s), 7.63 (4H, d, J = 7.4Hz), 7.68-7.35 (6H, m), 3.43 (2H, d, J = 5.5Hz), 2.68 (2H, m) , 2.18 (1H, m), 2.02 (1H, m), 1.59 (1H, m), 1.51 (1H, d, J = 8.0Hz), 1.25 (1H, bs), 1.02 (9H, s), 0.90 ( 1H, m).
MS (m / z): 337 (4), 307 (2), 293 (4), 259 (2), 217 (9), 199 (54), 183 (20), 135 (24), 105 (30 ), 93 (100)
[α]_D ^{twenty five} : -52.6 (c = 0.27, CHCl_Three).
[0133]
Example 42: (2S, 3aS, 4aS) -2-[(t-butyldiphenylsilyloxy) -methyl] -3a-formyl-bicyclo [3.1.0] hexane k. 2 (A = CHO, P = OTBDPS) (Scheme 4)
I. k. 1 (A = CH₂OH, P = TBDPS). j. The reaction was carried out in the same manner as 2 (A = CHO, P = TBDPS). The yield was 92.8%.
IR (film): 2932, 2858, 1703, 1471, 1427, 1112, 824, 741, 702 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.96 (1H, s), 7.63 (4H, m), 7.48-7.35 (6H, m), 3.58 (2H, m), 2.05-1.88 (5H, m), 1.62 (1H, m), 1.34 (1H, dd, J = 8.5, 5.5Hz), 1.20 (1H, t, J = 5.4Hz), 1.02 (9H, s).
MS (m / z): 337 (15), 259 (14), 231 (30), 199 (100), 137 (20), 93 (60), 77 (70).
[0134]
Example 43: (2S, 3aS, 4aS) -2-methyl-2-hydroxy-3a-hydroxymethyl-bicyclo [3.1.0] hexane l. 1 (A = CH₂OH, R₁= CH₃(Scheme 4)
Hg (OAc)₂A solution of olefin 4.3 (164 mg, 0.719 mmol) in THF (1.5 ml) was added dropwise to a solution of (350 mg, 1.10 mmol) in water (1.5 ml). After stirring for 30 minutes at room temperature, aqueous NaOH (1.5 ml, 3N), then 0.5M NaBH₄Of 3N NaOH (1.5 ml) was added. The resulting mixture was stirred at room temperature for 2 hours until most of the mercury solidified. The solid was filtered. The filtrate is Et₂Extracted with O (2 × 30 ml) and EtOAc (2 × 30 ml). K on residue₂CO₃(500 mg, 5.05 mmol) and MeOH (2 ml) were added. The mixture was stirred at room temperature for 20 hours and the reaction mixture was passed through a short silica gel column. The crude product was purified by HPLC (cyclohexane / EtOAc: 62:45) to give compound I.I. l. 1 (A = CH₂OH, R₁= Me) and I.I. i. 1 (A = CH₂OH, R₁= Me) (ratio: 3: 1, 68 mg, 66.6%) was obtained as a colorless oil.
IR (film):: 3288.4, 2931.3, 2858.5, 1459.1, 1370.2, 1260.7, 1183.9, 1135.7,1111.5, 1064.0, 1016.0, 922.6 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 4.02 (1H, d, J = 10.7Hz), 3.07 (1H, d, J = 10.7Hz), 2.05 (2H, m), 1.65 (1H, bs), 1.52 (1H, d, J = 12.8Hz), 1.37 (3H, m), 1.25 (3H, s), 1.05 (1H, dd, J = 8.0, 4.8Hz), 0.49 (1H, t, J = 4.3Hz).
[0135]
Example 44: (2S, 3aS, 4aS) -2-methyl-2-hydroxy-3a-formyl-bicyclo [3.1.0] hexane l. 2 (A = CHO, R₁= Me) (Scheme 4)
I. l. 1 (A = CH₂OH, R₁= Me) from I.I. j. The reaction was carried out in the same manner as 2 (A = CHO, P = TBDPS). The yield was 48.2%.
IR (film): 3429, 2967, 2929, 1691, 1377, 1249, 1102, 1036, 668 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.90 (1H, s), 2.66 (1H, dd, J = 14.3, 2.4Hz), 1.98 (2H, m), 1.88 (1H, dd, J = 8.5, 5.2Hz), 1.65 (1H, bs), 1.51 (2H, t, J = 14.2Hz), 1.31 (3H, s), 1.14, (1H, t, J = 5.2Hz).
MS (m / z): 140 (M⁺, 2), 123 (10), 111 (10), 97 (15), 85 (25), 71 (25), 67 (30), 48 (100).
[α]_D ^{twenty five} : -99.3 (c = 1.06, CHCl_Three)
[0136]
Example 45: (2S, 3aS, 4aS) -2-hydroxy-2-hydroxymethyl-3a-[(benzyloxy) methyl] -bicyclo [3.1.0] hexane m (A = CH₂OCOPh) (Scheme 4)
To a solution of 4.3 (65 mg, 0.285 mmol) and NMO (48 mg, 0.344 mmol, 1.21 eq) in acetone / water (5 ml: 2.5 ml) was added OsO.₄  Aqueous solution (121 μl, 0.02 mmol, 4 wt%, 0.07 eq) was added at 0 ° C. The resulting solution was stirred for 39 hours at room temperature, and sodium dithionite (70 mg) and florisil (150 mg) were added. The black precipitate is filtered off and Et₂Washed with O (200 ml). The solvent was removed by evaporation under vacuum. The residue is Et with a little acetone₂Dissolved in O (100: 5) and filtered through Florisil. The crude mixture was separated by HPLC (cyclohexane / EtOAc: 7: 3) and almost no product, C-2 epimeric compound I.I. m was combined as a (ratio 85.15) colorless oil to give a yield of 64%.
IR (film):: 3385.5, 2927.8, 1713.7, 1451.6, 1315.2, 1274.6, 1114.7, 1070.3, 1026.2, 934.5, 711.5 cm^-1.
¹H-NMR (500 MHz, in CDCl_Three, ppm): 8.06 (2H, d, J = 7.3Hz), 7.57 (1H, t, J = 7.4Hz), 7.46 (2H, t, J = 7.6Hz), 4.48 (1H, d, J = 11.5Hz) ), 4.21 (1H, d, J = 11.5Hz), 3.49 (2H, m), 2.58 (1H, s), 2.36 (1H, s), 2.16 (1H, d, J = 14.6Hz), 2.12 (1H , dd, J = 14.2, 6.3Hz), 1.94 (1H, t, J = 14.1Hz), 1.89 (1H, t, J = 14.1Hz), 1.65 (1H, d, J = 14.2Hz), 1.07 (1H , dd, J = 8.4, 5.3Hz), 0.47 (1H, t, J = 4.6Hz).
MS (m / z): 262 (M⁺, 1), 244 (1), 232 (3), 213 (4), 203 (3), 176 (1), 163 (4), 145 (4), 123 (16), 105 (100), 77 (52), 67 (13).
[α]_D ^{twenty five} : -11.86 (c = 1.53, CHCl_Three).

Claims

Formula (I):

In the formula, —A is —CH ₂ OH group, —CH ₂ —OCOR ′ group, —COR ″ group, —CSR ″ group or ethynyl group,
-R is hydrogen or _(C 1 -C ₆₎ alkyl,
—R ₁ is hydrogen, (C ₁ -C ₆ ) alkyl or — (CH ₂ ) _n —OP group;
-R ₂ is hydrogen or -OP group,
-R 'is _(C 1 -C ₆₎ alkyl or phenyl,
—R ″ is hydrogen, hydroxyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, or di (C ₁ -C ₃ ) alkylamino ,
-P _{hydrogen; (C} 1 -C ₆₎ _{alkanoyl; (C} 1 -C ₄₎ alkyl, benzoyl phenyl by halogen or nitro is optionally _substituted; each _{_{_{R 3; (C 1 -C 6}}} ) alkoxycarbonyl —Si (R ₃ ) ₃ group independently representing (C ₁ -C ₆ ) alkyl or phenyl; mono- or di (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl; tetrahydrofuranyl; or tetrahydropyrani And
-N is a method for preparing a compound represented by 0, 1, 2, 3, or 4,
(I) Formula 1

In the formula, A is (C ₁ -C ₆ ) alkoxycarbonyl or di (C ₁ -C ₃ ) alkylaminocarbonyl, R is the same as defined above, and a lipase represented by vinyl Reacting in a fatty acid or acid anhydride;
(Ii) the obtained formula 2 or 2 ′

Where Z is alkyl;
A process comprising the step of converting the compound represented by formula (I) to the corresponding compound of formula (I).

The step (ii) comprises a step of converting a compound represented by the formula 2 or 2 ′, wherein Z is (C ₁ -C ₃ ) alkyl, into a corresponding compound represented by the formula (I). Preparation method.

A process according to claim 1 comprising reacting compound 1 wherein A is methoxycarbonyl.

The method according to claim 1, wherein the vinyl fatty acid is selected from the group consisting of vinyl acetate, vinyl propionate, and vinyl butyrate.

The method according to any one of claims 1 to 4, wherein the acid anhydride is selected from the group consisting of acetic anhydride, propionic anhydride, and butyric anhydride.

6. The method of any one of claims 1-5, wherein the lipase is selected from the group consisting of SAM II, PPL, CCL, PSL, and GCL.

The method according to any one of claims 1 to 6, wherein step (i) is carried out at 10 to 40 ° C.

The method according to any one of claims 1 to 7, wherein step (i) is carried out for 6 to 72 hours.

Step (ii) includes the following steps:
-Protection of the hydroxy group-Ester hydrolysis-Inversion of the 3- or 5-hydroxy group-Formation of a leaving group-Ring closure reaction containing a base to form the desired bicyclo [3.1.0] hexane-Carboalkoxy functionality 9. A process according to any one of claims 1 to 8 carried out by one or more transformations of a group or carbamoyl function into the desired substituent A.

Formula 2 or 2 ′:

Wherein, -A is _(C 1 -C ₆₎ alkoxycarbonyl or di _(C 1 -C ₃₎ alkyl aminocarbonyl, R is hydrogen or _(C 1 -C ₆₎ alkyl, -Z is an alkyl compounds represented by certain <br/>.

Formula 1:

Wherein, -A is _(C 1 -C ₆₎ alkoxycarbonyl or di _(C 1 -C ₃₎ alkyl aminocarbonyl, R represents is represented by <br/> is _(C 1 -C ₆₎ alkyl Compound.