JP3942828B2 - Boncrechinic acid precursor compound and method for producing the same - Google Patents

Description

【０００４】
ボンクレキン酸は最近の研究により細胞死の一つであるアポトーシスに対し阻害作用を有することが明らかとなったことから、アポトーシスの分子機構解明の研究をする上で必須の化合物として世界中の生化学者から注目を集めている。
ボンクレキン酸は、Pseudomonas cocovenenansという細菌が、ココナッツを培地とした場合に産生する化合物として単離されたが、実験条件の再現が困難であり、各国の研究者たちはその入手に難渋している。
ボンクレキン酸の化学的合成法としては、これまで報告が１例のみあるが（J.Am.Chem.Soc. 1984, 106, 462-463）、この方法では実質上必要量は得られない。
【０００５】
【発明が解決しようとする課題】
本発明は、ボンクレキン酸の実用的で簡便な合成方法を提供するためのボンクレキン酸前駆体であるボンクレキン酸のＣ_１〜Ｃ_１０セグメント（ボンクレキン酸分子の左半分）及びボンクレキン酸のＣ _１６ 〜Ｃ_２２セグメント（ボンクレキン酸分子の右半分の一部）の実用的で且つ効率的な製造方法を提供することを目的とする。
【０００６】
【課題を解決するための手段】
本発明は、下記（１）〜（８）の工程を含んでなるボンクレキン酸のＣ_１〜Ｃ_１０セグメントの製造方法に関する。
（１）一般式［１］
【化９６】

［式中、Ｒ^１は、
【化９７】

（但し、Ｒ^２は、ベンジル基、イソプロピル基又はメチル基を表し、Ｒ^３，Ｒ^４はそれぞれ独立して水素原子又はフェニル基を表す。）（以下、保護基Ａと略すことがある。）
又は
【化９８】

（以下、保護基Ｂと略すことがある。）
を表す。］で示される化合物を、一般式［２］
【化９９】

（式中、Ｒ^５は、ｔ−ブチルジフェニルシリル基、トリイソプロピルシリル基、ｔ−ブチルジメチルシリル基、トリエチルシリル基、トリメチルシリル基、ｐ−メトキシフェニルメチル基、ベンジル基、テトラヒドロピラニル基、メトキシメチル基、アセチル基又はメトキシエトキシメチル基を表し、Ｘ^１はハロゲン原子を表す。）で示される化合物と反応させて、一般式［３］
【化１００】

（式中、Ｒ^１，Ｒ^５は前記と同じ。）
で示される化合物とする工程。
（２）上記（１）で得られた一般式［３］で示される化合物を還元して、一般式［４］
【化１０１】

（式中、Ｒ^５は前記と同じ。）
で示されるアルコール体とする工程。
（３）上記（２）で得られたアルコール体を酸化して、一般式［５］
【化１０２】

（式中、Ｒ^５は前記と同じ。）
で示されるアルデヒド体とした後、一般式［６］
【化１０３】

（式中、Ｒ^８，Ｒ^９はそれぞれ独立してアルキル基を表す。また、Ｒ^８とＲ^９とが一緒になってアルキレン基を形成していてもよい。）で示されるジクロロメチルボロニックエステルと反応させて、一般式［７］
【化１０４】

（式中、Ｒ^５，Ｒ^８及びＲ^９は前記と同じ。）
で示されるボロニックエステル体とする工程。
（４）上記（３）で得られたボロニックエステル体を、一般式［８］
【化１０５】

（式中、Ｒ^６は、ｔ−ブチルジフェニルシリル基、トリイソプロピルシリル基、ｔ−ブチルジメチルシリル基、トリエチルシリル基、トリメチルシリル基、ｐ−メトキシフェニルメチル基、ベンジル基、テトラヒドロピラニル基、メトキシメチル基、アセチル基又はメトキシエトキシメチル基を表す。）で示される化合物と反応させて、一般式［９］
【化１０６】

（式中、Ｒ^５，Ｒ^６は前記と同じ。但し、Ｒ^５≠Ｒ^６）
で示されるカップリング体とする工程。
（５）上記（４）で得られたカップリング体を、一般式［１０］
【化１０７】

（式中、Ｒ^７は、ｔ−ブチルジフェニルシリル基、トリイソプロピルシリル基、ｔ−ブチルジメチルシリル基、トリエチルシリル基、トリメチルシリル基、ｐ−メトキシフェニルメチル基、ベンジル基、テトラヒドロピラニル基、メトキシメチル基、アセチル基又はメトキシエトキシメチル基を表し、Ｘ^２はハロゲン原子を表す。）で示される化合物と反応させて、一般式［１１］
【化１０８】

（式中、Ｒ^５，Ｒ^６及びＲ^７は前記と同じ。但し、Ｒ^５≠Ｒ^６且つＲ^５≠Ｒ^７）で示される化合物とする工程。
（６）上記（５）で得られた一般式［１１］で示される化合物の１０位の水酸基の保護基Ｒ^５を脱保護して、一般式［１２］
【化１０９】

（式中、Ｒ^６，Ｒ^７は前記と同じ。）で示されるアリルアルコール体とする工程。 （７）上記（６）で得られたアリルアルコール体の水酸基をハロゲン置換して、一般式［１３］
【化１１０】

（式中、Ｘ^３はハロゲン原子を表し、Ｒ^６，Ｒ^７は前記と同じ。）
で示されるハロゲン体とする工程。
（８）上記（７）で得られたハロゲン体を一般式［１４］
【化１１１】

（式中、Ｒ^１０は低級アルキル基又はアリール基を表し、Ｍはアルカリ金属原子を表す。）で示されるスルフィン酸塩と反応させて、一般式［１５］
【化１１２】

（式中、Ｒ^６，Ｒ^７及びＲ^１０は前記と同じ。）
で示されるスルホン体とする工程。
【０００７】
また、本発明は、上記ボンクレキン酸のＣ_１〜Ｃ_１０セグメントの製造方法に於ける各中間体とそれら中間体の製造方法に関する。
【０００８】
更に、本発明は、下記（１１）〜（１５）の工程を含んでなるボンクレキン酸のＣ _１６ 〜Ｃ_２２セグメントの製造法に関する。
（１１）一般式［２１］
【化１１３】

（式中、Ｒ^１１は水酸基の保護基を表す。）で示される化合物を還元して、一般式［２２］
【化１１４】

（式中、Ｒ^１１は前記と同じ。）
で示されるフラノール体とする工程。
（１２）上記（１１）で得られた一般式［２２］で示されるフラノール体を一般式［２３］
【化１１５】

（式中、Ｒ^１２はアルキル基、アリール基又はアラルキル基を表す。）で示されるホスホランと反応させて、一般式［２４］
【化１１６】

（式中、Ｒ^１１，Ｒ^１２は前記と同じ。）
で示される化合物とする工程。
（１３）上記（１２）で得られた一般式［２４］で示される化合物の７位の水酸基の保護基を脱保護して、一般式［２５］
【化１１７】

（式中、Ｒ^１２は前記と同じ。）
で示されるジヒドロキシ体とする工程。
（１４）上記（１３）で得られた一般式［２５］で示されるジヒドロキシ体の７位の水酸基をトシル化、メシル化又はハロゲン置換して、一般式［２６］
【化１１８】

（式中、Ｘ^１１はトシルオキシ基、メシルオキシ基又はハロゲン原子を表し、Ｒ^１２は前記と同じ。）
で示される化合物とする工程。
（１５）上記（１４）で得られた一般式［２６］で示される化合物を塩基で処理して、一般式［２７］
【化１１９】

（式中、Ｒ^１２は前記と同じ。）
で示される６，７−エポキシ体とする工程。
【０００９】
また、本発明は、上記ボンクレキン酸のＣ _１６ 〜Ｃ_２２セグメントの製造法に於ける各中間体とそれら中間体の製造法に関する。
【００１０】
本発明に係る上記工程（１）において、一般式［２］で示される化合物のＸ^１としては、例えば塩素、臭素、沃素等のハロゲン原子が挙げられるが、臭素原子又は沃素原子が好ましく、沃素原子が特に好ましい。
また、一般式［２］で示される化合物のＲ^５は、ｔ−ブチルジフェニルシリル基、トリイソプロピルシリル基、ｔ−ブチルジメチルシリル基、トリエチルシリル基、トリメチルシリル基、ｐ−メトキシフェニルメチル基、ベンジル基、テトラヒドロピラニル基、メトキシメチル基、アセチル基又はメトキシエトキシメチル基の何れでも良いが、ｔ−ブチルジフェニルシリル基、ｔ−ブチルジメチルシリル基等が特に好ましい。
一般式［１］で示される化合物を一般式［２］で示される化合物と反応させるに際しては、例えば、先ず一般式［１］で示される化合物をリチオ化又はナトリウム化した後、一般式［２］で示される化合物と反応させるのが好ましい。
リチオ化は、例えばジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン（ＴＨＦ）等のエーテル系溶媒中、ｎ−ブチルリチウム、フェニルリチウム、リチウムジイソプロピルアミド、或いはｎ−ブチルリチウムとジイソプロピルアミンとの組み合わせ等のリチオ化試薬を用いて、−５０℃以下、好ましくは−７０℃以下で、常法に従ってリチオ化反応させればよく、リチオ化後、これに一般式［２］で示される化合物を反応させれば、一般式［３］で示される化合物が容易に得られる。
一般式［２］で示される化合物を反応させる際の反応温度は、通常−５０〜−１０℃、好ましくは−４０〜−２０℃、反応時間は、通常１〜１０時間、好ましくは２〜５時間程度である。
【００１１】
また、ナトリウム化は、例えばＴＨＦ、ジエチルエーテル、ジイソプロピルエーテル等のエーテル系溶媒中、ヘキサメチルホスホルアミド（ＨＭＰＡ）の存在下、例えばビストリメチルシリルアミドナトリウム塩（ＮＨＭＤＳ）、水素化ナトリウム等のナトリウム化剤を用いて、−５０℃以下、好ましくは−７０℃以下で、常法に従ってナトリウム化反応させればよく、ナトリウム化後、これに一般式［２］で示される化合物を反応させれば、一般式［３］で示される化合物が容易に得られる。
一般式［２］で示される化合物を反応させる際の反応温度は、通常−５０℃以下、好ましくは−７０℃以下で、反応時間は、通常１〜１０時間、好ましくは２〜５時間程度である。
リチオ化、ナトリウム化の何れが好ましいかについては、種々の要因の絡みがあるので一概には言えないが、通常、一般式［１］において、Ｒ^１が保護基Ａの場合にはリチオ化が適しており、Ｒ^１が保護基Ｂの場合にはナトリウム化が適している。
【００１２】
本発明に係る上記工程（２）において、一般式［３］で示される化合物の還元は、還元後一般式［４］で示されるアルコール体となり得るような還元方法であればどのような還元方法でもよいが、通常は、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、水素化ホウ素カリウム、水素化ホウ素リチウム等の還元剤が好ましく用いられる。溶媒は、通常ＴＨＦ、ジエチルエーテル、ジイソプロピルエーテル等のエーテル系溶媒が用いられ、還元反応の反応温度は、通常０℃前後、反応時間は、通常数十分〜数時間程度である。
【００１３】
本発明に係る上記工程（３）において、一般式［６］で示される化合物及び一般式［７］で示される化合物のＲ^８，Ｒ^９で示されるアルキル基としては、例えばメチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基等、炭素数１〜６の低級アルキル基が挙げられ、直鎖状、分岐状の何れでもよく、また、Ｒ^８とＲ^９とが一緒になってアルキレン基を形成している場合のアルキレン基としては、例えばエチレン基、トリメチレン基、テトラメチレン基、１，２−ジメチルエチレン基、１，１，２，２−テトラメチルエチレン基等が挙げられる。
【００１４】
一般式［４］で示されるアルコール体を酸化してアルデヒド体とする反応に用いられる試薬としては、一般式［４］で示されるアルコール体を酸化してアルデヒド体とし得る試薬であればどのようなものでも良いが、例えば、塩化オキサリル及びジメチルスルホキシドと例えばトリエチルアミン等の塩基との組み合わせが挙げられる。この場合の反応溶媒としては、通常塩化メチレン、ジクロルメタン、クロロホルム等が用いられる。反応温度は通常−５０℃以下、好ましくは−７０℃以下で、反応時間は始め塩化オキサリル及びジメチルスルホキシドとアルコール体とを一緒にした時点で通常数十分程度、その後、更に例えばトリエチルアミン等の塩基を加え、更に数十分程度撹拌し、反応させればよい。
アルコール体を酸化してアルデヒド体とする反応に用いられる上記以外の試薬としては、例えば、クロロクロム酸ピリジニウム、二クロム酸ピリジニウム、Dess-Martin試薬（１，１，１−トリアセトキシ−１，１−ジヒドロ−１，２−ベンズイオドキソル−３（１Ｈ）−オン）、ＴＲＡＰ（テトラ−ｎ−プロピルアンモニウム パールテネイト）とＮ−メチルモルホリン Ｎ−オキシドとの組み合わせ試薬等が挙げられる。
【００１５】
アルデヒド体とジクロロメチルボロニックエステルとの反応は、通常ＴＨＦ等のエーテル系溶媒中、過剰量の無水塩化クロム及び過剰量の無水ヨウ化リチウムの存在下に反応が行われる。反応は通常室温で行われ、反応時間は通常数時間乃至十数時間である。
無水塩化クロムと無水ヨウ化リチウムとの組み合わせ以外に、無水塩化クロム、マンガン、無水ヨウ化リチウム及び塩化トリメチルシリルの組み合わせもある。
この場合には、無水塩化クロムの使用量が触媒量なので、工業的規模での生産を考えた場合には、有害な廃棄物の量が少なくなるという点でメリットがある。
【００１６】
本発明に係る上記工程（４）において、一般式［８］で示される化合物のＲ^６は、ｔ−ブチルジフェニルシリル基、トリイソプロピルシリル基、ｔ−ブチルジメチルシリル基、トリエチルシリル基、トリメチルシリル基、ｐ−メトキシフェニルメチル基、ベンジル基、テトラヒドロピラニル基、メトキシメチル基、アセチル基又はメトキシエトキシメチル基の何れでも良いが、ｐ−メトキシフェニルメチル基、ベンジル基等が特に好ましい。
一般式［７］で示されるボロニックエステル体と一般式［８］で示される化合物との反応は、通常パラジウム錯体触媒及びアルカリの存在下に行われる。パラジウム錯体触媒としては、３級ホスフィン又は３級ホスファイトを配位子とする低原子価錯体、或いは、３級ホスフィン又は３級ホスファイトを配位子として含まないパラジウム錯体と、３級ホスフィン又は／及び３級ホスファイトとを併用し、反応系中で形成させた３級ホスフィン又は／及び３級ホスファイトを配位子とする低原子価錯体等が挙げられ、好ましい具体例としては、３級ホスフィン又は３級ホスファイトを配位子とする低原子価錯体としては、例えばテトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム等が挙げられ、３級ホスフィン又は／及び３級ホスファイトと組み合わせて使用するパラジウム錯体としては、例えばジベンジリデンアセトンパラジウム・クロロホルム付加物、酢酸パラジウム等が挙げられる。
また、この反応に於いて用いられるアルカリとしては水酸化ナトリウム、水酸化カリウム等の水溶液が好ましく用いられる。
反応溶媒としては通常ＴＨＦ等のエーテル系溶媒が好ましく用いられ、反応は通常溶媒還流下に５〜１５時間位行われる。
【００１７】
本発明に係る上記工程（５）において、一般式［１０］で示される化合物のＸ^２としては、例えば塩素、臭素、沃素等のハロゲン原子が挙げられる。また、Ｒ^７は、ｔ−ブチルジフェニルシリル基、トリイソプロピルシリル基、ｔ−ブチルジメチルシリル基、トリエチルシリル基、トリメチルシリル基、ｐ−メトキシフェニルメチル基、ベンジル基、テトラヒドロピラニル基、メトキシメチル基、アセチル基又はメトキシエトキシメチル基の何れでも良いが、メトキシメチル基、アセチル基等が特に好ましい。
一般式［９］で示されるカップリング体と一般式［１０］で示される化合物との反応は通常塩基の存在下に行われる。ここで使用される塩基としては、例えばジイソプロピルエチルアミンや４−ジメチルアミノピリジン等の脂肪族や芳香族の３級アミン類が挙げられる。反応溶媒としては、通常塩化メチレン、ジクロルメタン、クロロホルム等が好ましく用いられ、反応は通常室温で数時間程度で充分である。
【００１８】
本発明に係る上記工程（６）において、一般式［１１］で示される化合物の１０位の水酸基の保護基Ｒ^５を脱保護して、一般式［１２］で示されるアリルアルコール体とする反応に用いられる脱保護試薬は、Ｒ^５の種類により自ずから異なるが、例えばＲ^５がｔ−ブチルジフェニルシリル基の場合には、例えばテトラブチルアンモニウムフルオリド等が好ましく用いられる。反応溶媒としては通常ＴＨＦ等のエーテル系溶媒が好ましく用いられ、反応は通常室温で数時間程度で充分である。
【００１９】
本発明に係る上記工程（７）において、一般式［１３］で示される化合物のＸ^３としては、例えば塩素、臭素、沃素等のハロゲン原子が挙げられる。
一般式［１１］で示されるアリルアルコール体の水酸基をハロゲン置換する際に用いられるハロゲン化剤としては、アルコール性の水酸基をハロゲン化し得るハロゲン化剤であればどのようなものでも良いが、例えば、四塩化炭素とトリフェニルホスフィンの組み合わせ、四臭化炭素とトリフェニルホスフィンの組み合わせ、三臭化リン、ヨウ化メチルとホスホン酸トリフェニルとの組み合わせ等が挙げられる。
反応溶媒としては、通常塩化メチレン、ジクロルエタン、クロロホルム等が好ましく用いられ、反応は通常室温で行われ反応時間は通常３〜８時間位である。
【００２０】
本発明に係る上記工程（８）において、一般式［１４］で示される化合物のＲ^１０で示される低級アルキル基としては、例えばメチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基等、炭素数１〜６の低級アルキル基が挙げられ、直鎖状、分子状の何れでもよく、また、Ｒ^１０で示されるアリール基としては、例えばフェニル基、トリル基、キシリル基、ナフチル基、メチルナフチル基等が挙げられる。また、Ｍで示されるアルカリ金属原子としては、例えばナトリウム、カリウム、リチウム等が挙げられる。
一般式［１３］で示されるハロゲン体と一般式［１４］で示される化合物との反応は、通常ジメチルホルムアミド（ＤＭＦ）溶媒中で行われる。反応温度は通常室温で反応時間は通常１０〜３０時間位である。
【００２１】
本発明のボンクレキン酸のＣ_１〜Ｃ_１０セグメントの製造方法に於いて、出発物質として用いられる一般式［２］で示される化合物は、例えば下記合成スキームに従って合成することが出来る。
【００２２】
【化１２４】

【００２３】
なお、上記反応スキームに於ける略号等の正式名称は以下のとおりである。
ＭＰＭＣｌ：ｐ−メトキシフェニルメチルクロライド
ＤＭＳＯ：ジメチルスルホキシド
ＭＰＭ：ｐ−メトキシフェニルメチル
ＴＢＤＰＳＣｌ：ｔ−ブチルジフェニルシリルクロライド
ＴＢＤＰＳ：ｔ−ブチルジフェニルシリル
４−ＤＭＡＰ：４−ジメチルアミノピリジン
ＤＤＱ：ジクロロジシアノベンゾキノン
Ｒｅｄ−Ａｌ：水素化ビス（２−メトキシエトキシ）アルミニウムナトリウム
また、本発明のボンクレキン酸のＣ_１〜Ｃ_１０セグメントの製造方法に於いて、一般式［７］で示されるボロニックエステル体と反応させる一般式［８］で示される化合物は、例えば下記合成スキームに従って合成することが出来る。なお、下記合成スキーム中の略号の意味は上記と同じである。
【００２４】
【化１２５】

【００２５】
本発明に係る上記工程（１１）において、一般式［２１］で示される化合物及び一般式［２２］で示される化合物のＲ^１１で示される水酸基の保護基としては、例えば、トリチル基（トリフェニルメチル基）、ｔ−ブチルジフェニルシリル基、トリイソプロピルシリル基、ｔ−ブチルジメチルシリル基、トリエチルシリル基、トリメチルシリル基、ｐ−メトキシフェニルメチル基、ベンジル基、テトラヒドロピラニル基、メトキシメチル基、メトキシエトキシメチル基が挙げられ、何れも使用可能であるが、トリチル基、ｔ−ブチルジメチルシリル基、ｔ−ブチルジフェニルシリル基等が特に好ましい。
一般式［２１］で示される化合物の還元は、還元後一般式［２２］で示されるフラノール体となり得るような還元方法であればどのような還元方法でもよいが、通常は、例えば、水素化ジイソブチルアルミニウム、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、水素化ホウ素カリウム、水素化ホウ素リチウム等の金属水素化物を用いて行われる。なかでも、水素化ジイソブチルアルミニウム及び水素化リチウムアルミニウムが特に好ましく用いられる。
反応は、通常、ベンゼン、トルエン等の芳香族炭化水素系溶媒やｎ−ヘキサン、石油エーテル等の脂肪族炭化水素系溶媒中で行われる。反応温度は、通常−５０℃以下、好ましくは−７０℃以下、反応時間は、反応温度その他の反応条件により自ずから異なり、一様ではないが、通常数十分〜数時間程度である。
なお、本工程で得られる一般式［２２］で示される化合物は、通常、精製することなく次の工程に用いられる。
【００２６】
本発明に係る上記工程（１２）において、一般式［２３］で示される化合物（ホスホラン）及び一般式［２４］で示される化合物のＲ^１２で示されるアルキル基としては、例えば、炭素数が１〜２０、好ましくは１〜１０、より好ましくは１〜６の直鎖状又は分枝状のアルキル基が挙げられ、より具体的には、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、第二級ブチル基、第三級ブチル基、ペンチル基、ヘキシル基などが挙げられる。
アリール基としては、例えば、炭素数６〜３０、好ましくは６〜２０、より好ましくは６〜１５の単環、多環又は縮合環式の芳香族炭化水素基が挙げられ、より具体的には、例えば、フェニル基、トリル基、キシリル基、ナフチル基、メチルナフチル基等が挙げられる。
アラルキル基としては、例えば、炭素数７〜３０、好ましくは７〜２０、より好ましくは７〜１５の単環、多環又は縮合環式のアラルキル基が挙げられ、より具体的には、例えば、ベンジル基、フェネチル基、ナフチルメチル基、ナフチルエチル基等が挙げられる。
一般式［２２］で示される化合物と一般式［２３］で示されるホスホランとの反応は、通常、ベンゼン、トルエン等の芳香族炭化水素系溶媒中で行われ、反応温度は、通常５０℃以上、好ましくは用いた溶媒の還流温度、反応時間は、他の反応条件により自ずから異なるが、通常数十分〜数時間程度である。
【００２７】
なお、工程（１２）において、一般式［２２］で示されるフラノール体を一般式［２３］で示されるホスホランと反応させて一般式［２４］で示される化合物（エステル体）とし、このエステル体をそのまま（１３）以降の工程に持っていく代わりに、エステル体を還元してアルコール体とし、更にこの水酸基を保護して、一般式［２４'］
【化１２６】

（式中、Ｒ_０ ^１３は水酸基の保護基を表す。）
で示される化合物とした後、（１３）以降の工程に進む方法も可能である。
この場合の、一般式［２４］で示される化合物（エステル体）を還元してアルコール体とする方法としては、例えば、還元剤として水素化ジイソブチルアルミニウムを用い、ＴＨＦ、塩化メチレン、トルエン等の溶媒中、−７８℃〜０℃で反応させる方法や、還元剤として水素化リチウムアルミニウムを使用し、ＴＨＦやジエチルエーテル中で反応させる方法等がある。また、得られたアルコール体の水酸基の保護基Ｒ_０ ^１３としては、例えば、ｔ−ブチルジフェニルシリル基、トリイソプロピルシリル基、ｔ−ブチルジメチルシリル基、トリエチルシリル基、トリメチルシリル基等が挙げられる。
【００２８】
本発明に係る上記工程（１３）において、一般式［２４］で示される化合物の７位の水酸基の保護基Ｒ^１１を脱保護して、一般式［２５］で示されるジヒドロキシ体とする反応に用いられる脱保護試薬は、Ｒ^１１の種類により自ずから異なるが、例えばＲ^１１がトリチル基の場合には、例えば、ｐ−トルエンスルホン酸、ギ酸、酢酸、塩酸、トリフルオロ酢酸等の酸触媒が用いられ、例えばＲ^１１がｔ−ブチルジメチルシリル基やｔ−ブチルジフェニルシリル基等の場合には、例えばテトラブチルアンモニウムフルオリド等が好ましく用いられる。反応溶媒としては、酸触媒を用いる系では、通常エタノール等のアルコール系溶媒が用いられ、テトラブチルアンモニウムフルオリド等が用いられる系では、通常ＴＨＦ等のエーテル系溶媒が好ましく用いられる。反応は前者の場合は通常室温で１〜６時間程度、後者の場合は通常室温で数十分程度である。
【００２９】
本発明に係る上記工程（１４）において、一般式［２６］で示される化合物のＸ^１１としては、トシルオキシ基（ｐ−トルエンスルホニルオキシ基）、メシルオキシ基基（メタンスルホニルオキシ基）、例えば塩素、臭素、沃素等のハロゲン原子が挙げられる。
一般式［２５］で示されるジヒドロキシ体の７位の水酸基をトシル化する場合に用いられる試薬としては、例えばトシルクロライドと塩基（例えばピリジン等）の組み合わせが挙げられ、反応溶媒としては、例えば塩化メチレン、ジクロロエタン、クロロホルム等のハロゲン化炭化水素等が挙げられる。反応温度は通常０〜室温程度、反応時間は通常数十分〜数時間程度である。
一般式［２５］で示されるジヒドロキシ体の７位の水酸基をメシル化する場合に用いられる試薬としては、例えばメシルクロライドと塩基（例えばピリジン等）の組み合わせが挙げられ、反応溶媒としては、例えば塩化メチレン、ジクロロエタン、クロロホルム等のハロゲン化炭化水素等が挙げられる。反応温度は通常０〜室温程度、反応時間は通常数十分〜数時間程度である。
一般式［２５］で示されるジヒドロキシ体の７位の水酸基をハロゲン置換する際に用いられるハロゲン化剤としては、アルコール性の水酸基をハロゲン化し得るハロゲン化剤であればどのようなものでも良いが、例えば、四塩化炭素とトリフェニルホスフィンの組み合わせ、四臭化炭素とトリフェニルホスフィンの組み合わせ、三臭化リン、ヨウ化メチルとホスホン酸トリフェニルとの組み合わせ等が挙げられ、反応溶媒としては、通常塩化メチレン、ジクロルエタン、クロロホルム等のハロゲン化炭化水素が好ましく用いられる。反応は通常室温で行われ反応時間は通常３〜８時間位である。
【００３０】
本発明に係る上記工程（１５）において、一般式［２６］で示される化合物を塩基で処理して、一般式［２７］で示される６，７−エポキシ体とする反応に用いられる塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、炭酸カリウム、炭酸ナトリウム等が挙げられる。反応溶媒としては、通常アセトン等のケトン類が用いられ、反応は通常溶媒還流下に３〜１０時間程度行われる。
【００３６】
本発明のボンクレキン酸のＣ _１６ 〜Ｃ_２２セグメントの製造方法に於いて、出発物質として用いられる一般式［２１］で示される化合物は、例えば下記合成スキームに従って合成することが出来る。なお、合成スキーム中のＴｒはトリチル基の略号である。
【００３７】
【化１２７】

【００４５】
【実施例】
次に実施例及び参考例により本発明をより詳細に説明するが、本発明はこれらの実施例、参考例に限定されるものではない。
【００４６】
参考例１ ４−（４−メトキシベンジルオキシ）−２−ブチン−１−オールの合成
２−ブチン−１，４−ジオール（３０．０ｇ、０．３４９ｍｏｌ) のＤＭＳＯ溶液（７０ｍｌ）に水酸化カリウム（２４．１ｇ、０．３６６ｍｏｌ）を加えた後、塩化ｐ−メトキシベンジル（２３．６ｍｌ、０．１７４ｍｏｌ）を滴下し、０℃で１０分間、さらに室温で１．５時間撹拌した。反応混合液を０℃に冷却し、飽和塩化アンモニウム水溶液を加えエーテルで希釈した後、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）で精製し、無色油状物としてモノ−ｐ−メトキシベンジルエーテル体（２４．９ｇ、６９％）を得た。

【００４７】
参考例２ ４−（４−メトキシベンジルオキシ）−２−ブテン−ｌ−オールの合成
参考例１で得られたモノ−ｐ−メトキシベンジルエーテル体（７．７ｇ、３７．２ｍｍｏｌ）をエーテル（６００ｍｌ）に溶かし、−２５℃に冷却した後、Ｒｅｄ−Ａｌ（６０％トルエン溶液：４４．７ｍｌ、１４８．９ｍｍｏｌ）をゆっくり滴下し、１．５時間撹拌した。この反応溶液に酢酸エチル（４０ｍｌ）、１Ｍ水酸化ナトリウム（６３ｍｌ）を加えた後、セライト濾過し濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル=２：３）により精製し、無色油状物としてトランスオレフィン体（７．５ｇ、９６％）を得た。

【００４８】
参考例３ １−ｔ−ブチルジフェニルシリルオキシ−４−（４−メトキシベンジルオキシ）−２−ブテンの合成
参考例２で得られたトランスオレフィン体（１．０ｇ、４．８ｍｍｏｌ）の塩化メチレン溶液（２０ｍｌ）にイミダゾール（０．６ｇ、８．６ｍｍｏｌ）、ｔ−ブチルジフェニルクロロシラン（１．５ｍｌ、５．８ｍｍｏｌ）、４−ジメチルアミノピリジン（４．９ｍｇ、０．００４ｍｍｏｌ）を加え、室温で０．５時間撹拌した。反応混合液に蒸留水を加え塩化メチレンで抽出した後、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１７：３）で精製し、無色油状物質としてｔ−ブチルジフェニルシリルエーテル体（２．０ｇ、９６％）を得た。
【００４９】
参考例４ ４−ｔ−ブチルジフェニルシリルオキシ−２−ブテン−１−オールの合成
参考例３で得られたｔ−ブチルジフェニルシリルエーテル体（２．０ｇ、４．６ｍｍｏｌ）を塩化メチレン／蒸留水（１８／１）に溶かし、２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン（１．４ｇ、６．０ｍｍｏｌ）を加え、室温で０．５時間撹拌した。反応混合液を塩化メチレンで希釈し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）で精製し、アリルアルコール体（０．９ｇ、６１％）を得た。

【００５０】
参考例５ １−ブロモ−４−ｔ−ブチルジフェニルシリルオキシ−２−ブテンの合成
参考例４で得られたアリルアルコール体（５００ｍｇ、１．５３１ｍｍｏｌ）を塩化メチレンに溶かし、トリフェニルホスフィン（４８２ｍｇ、１．８３８ｍｍｏｌ）、四臭化炭素（７６２ｍｇ、２．２９７ｍｍｏｌ）を加え室温で１０分間撹拌した。反応混合液を飽和炭酸水素ナトリウム水溶液で洗浄し、塩化メチレンで抽出した後、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１９：１）で精製し、臭素体（４８８ｍｇ、８２％）を得た。
【００５１】
参考例６ １−ｔ−ブチルジフェニルシリルオキシ−４−イオド−２−ブテンの合成
参考例４で得られたアリルアルコール体（７．１４ｇ、２１．８６８ｍｍｏｌ）をベンゼン（１４０ｍｌ）に溶かし、イミダゾール（３．７２ｇ、５４．６７１ｍｍｏｌ）、トリフェニルホスフィン（１１．４７ｇ、４３．７３７ｍｍｏｌ）、ヨウ素（１１．１０ｇ、４３．７３７ｍｍｏｌ）を加え室温で３０分間撹拌した。反応混合液を飽和チオ硫酸ナトリウム水溶液（３００ｍｌ×４）、飽和食塩水（１００ｍｌ×１）で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１９：１）で精製し、ヨウ素体（７．０ｇ、７４％）を得た。
【００５２】
参考例７ ４−（４−メトキシベンジルオキシ）−１−ブテンの合成
３−ブチン−１−オール（１０．０ｇ、０．１４３ｍｏｌ）のＴＨＦ溶液（２００ｍｌ）を０℃に冷却し、水素化ナトリウム（鉱油中６２．７％含有；１１．５ｇ、０．３００ｍｏｌ）を加え、１．５時間撹拌した後、塩化ｐ−メトキシベンジル（２６．８ｇ、２３．２ｍｌ、０．１７１ｍｏｌ）とヨウ化テトラ−ｎ−ブチルアンモニウム（１．６ｇ、４．３ｍｍｏｌ）を加え、室温で５時間撹拌した。反応混合液を０℃に冷却して水を加え、ヘキサンで希釈し、有機層を水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残留物を減圧蒸留（９９−１１６℃／１．５ｍｍＨｇ）し、無色油状物としてｐ−メトキシベンジルエーテル体（２１．２ｇ、７８％）を得た。
【００５３】
参考例８ ５−（４−メトキシベンジルオキシ）−２−ペンチン−１−オールの合成
参考例７で得られた４−（４−メトキシベンジルオキシ）−１−ブテン（２０．２ｇ、０．１０６ｍｏｌ）のＴＨＦ溶液（２２２ｍｌ）を−７８℃に冷却し、ｎ−ブチルリチウム（２．５２Ｍへキサン溶液；５０．４ｍｌ、０．１２７ｍｏｌ）を滴下し、２時間撹拌した後、同温下パラホルムアルデヒド（９．６ｇ、０．３１８ｍｏｌ）を加え、室温に昇温して２時間撹拌した。この反応溶液に水を加え、エーテルで希釈し、飽和食塩水を加えて分液した後、さらにエーテルで抽出し、有機層を無水硫酸マグネシウムで乾燥した後、濃縮した。残留物をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=3:1)により精製し、無色油状物としてアルコール体（１８．０ｇ、７７％）を得た。
【００５４】
参考例９ （Ｚ）−３−イオド−５−（４−メトキシベンジルオキシ）−２−ペンテン−１−オールの合成
Ｒｅｄ−Ａｌ（６５％トルエン溶液；２５．５ｍｌ、８１．８ｍｍｏｌ）のエーテル溶液（６０ｍｌ）を０℃に冷却し、参考例８で得られた５−（４−メトキシベンジルオキシ）−２−ペンチン−１−オール（８．２ｇ、３７．２ｍｍｏｌ）のエーテル溶液（１００ｍｌ）を滴下し、室温に昇温して４．５時間撹拌した。反応溶液を０℃に冷却し、酢酸エチル（４．２ｍｌ、４２．４ｍｍｏｌ）を加えた後、−５０℃に冷却し、ヨウ素（１４．２ｇ、５５．８ｍｍｏｌ）を加え、徐々に室温まで昇温して２時間撹拌した。反応溶液に飽和亜硫酸ナトリウム水溶液を加え、エーテルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）で精製し、黄色油状物としてヨウ化ビニル体（８．５ｇ、６６％）を得た。
^１H NMR (400MHz, CDCl_３) δ：
2.78(t, J=6.4Hz, 2H), 3.59(t, J=6.4Hz, 2H), 3.80(s, 3H),
4.19(d, J=5.5Hz, 2H), 4.46(s, 2H), 5.94(t, J=5.5Hz, 1H),
6.88(d, J=8.7Hz, 2H), 7.25(d, J=8.7Hz, 2H)。
^１３C NMR (75MHz, CDCl_３) δ：
45.10(t), 55.23(q), 67.19(t), 68.27(t), 72.67(t),
104.99(s), 113.76(d), 129.33(d), 130.03(s),
135.77(d), 159.17(s)。
【００５５】
実施例１ （Ｒ）−４−ベンジル−３−（（２Ｓ，４Ｅ）−６−ｔ−ブチルジフェニルシリルオキシ−２−メチル−５−ヘキセノイル）−１，３−オキサゾリジン−２−オンの合成
ジイソプロピルアミン（０．０７ｍｌ、０．５１４ｍｍｏｌ）のＴＨＦ溶液（１．５ｍｌ）を０℃に冷却し、ｎ−ブチルリチウム（１．５２Ｍへキサン溶液０．３４ｍｌ、０．５１４ｍｍｏｌ）を２０分以上かけて加え、同温にて３０分撹拌した。反応溶液を−７８℃に冷却し、（Ｒ）−４−ベンジル−３−プロピオニル−１，３−オキサゾリジン−２−オン（１００ｍｇ、０．４２９ｍｍｏｌ）のＴＨＦ溶液（２．０ｍｌ）溶液を２０分以上かけて加え、同温にて１時間撹拌した。これに参考例６で得られたヨウ素体（２８１ｍｇ、０．６４３ｍｍｏｌ）を１０分以上かけて加え、−４０℃から−２０℃で３．５時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、溶媒を留去した後、水を加えてエーテルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１）で精製し、無色油状のジアステレオマー混合物としてアルキル化体（１９６．１ｍｇ、８４％、d.r.＝９４：６）を得た。
^１H NMR (400MHz, CDCl_３) δ：
1.03(s, 9H), 1.18(d, J=6.8Hz, 3H),
2.23(ddd, J=13.7, 6.8, 6.8Hz, 1H),
2.51(ddd, J=13.7, 6.8, 6.8Hz, 1H),
2.61(dd, J=13.2, 10.0Hz, 1H),
3.27(dd, J=13.2, 3.2Hz, 1H),
3.85(ddq, J=6.8, 6.8, 6.8Hz, 1H), 4.11-4.19(m, 4H),
4.67(dddd, J=10.0, 7.7, 3.4, 3.2Hz, 1H),
5.64(dt, J=15.5, 4.6Hz, 1H),
5.72(ddd, J=15.5, 6.8, 6.8Hz, 1H),
7.16(d, J=6.8Hz, 2H), 7.27-7.40(m, 9H),
7.66(dd, J=5.9, 1.8Hz, 4H)。
^１３C NMR (75MHz, CDCl_３) δ
16.44(q), 19.16(s), 26.76(q), 36.40(t), 37.44(d),
38.04(t), 55.33(d), 64.18(t), 65.94(t), 127.02(d),
127.22(d), 127.59(d), 128.86(d), 129.35(d), 129.55(d),
131.61(d), 133.65(s), 133.70(s), 135.35(s), 135.47(d),
135.48(d), 153.05(s), 176.50(s)。
FT-IR (neat)
1782, 1699, 1386, 1112, 971, 703 cm^−１。
【００５６】
実施例２ （Ｓ）−６−ｔ−ブチルジフェニルシリルオキシ−２−メチル−４−ヘキセン−１−オールの合成
水素化リチウムアルミニウム（７９９ｍｇ、２１．０４３ｍｍｏｌ）のＴＨＦ溶液（３６ｍｌ）を０℃に冷却し、実施例１で得られたアルキル化体（３．８ｇ、７．０１４ｍｍｏｌ）のＴＨＦ溶液（４０ｍｌ）を滴下し、同温にて１．５時間撹拌した。反応溶液を０℃に保ったままエーテルで希釈しながら蒸留水を加え、室温で１時間撹拌した後、セライト濾過し、濾液を無水硫酸マグネシウムで乾燥した後、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１）で精製し、無色油状のアルコール体（１．８ｇ、６８％）を得た。
^１H NMR (400MHz, CDCl_３) δ：
0.91(d, J=6.4Hz, 3H), 1.05(s, 9H), 1.52(brs, 1H),
1.66-1.75(m, 1H), 1.92(ddd, J=13.2, 7.3, 6.8Hz, 1H),
2,14(ddd, J=13.7, 6.6, 6.4Hz, 1H),
3,44(dd, J=10.5, 6.4Hz, 1H),
3.50(dd, J=10.5, 5.9Hz, 1H),
4.17(d, J=4.1Hz, 2H), 5.58(dt, J=15.0, 4.6Hz, 1H),
5.67(dt, J=15.5, 6.8Hz, 1H), 7.36-7.44(m, 6H),
7.68(dd, J=7.7, 1.4Hz, 4H)。
^１３C NMR (75MHz, CDCl_３) δ：
16.35(q), 19.19(s), 26.80(q), 35.81(d), 36.06(t),
64.42(t), 67.79(t), 127.57(d), 128.95(d), 129.54(d),
130.46(d), 133.82(s), 135.51(d)。
FT-IR (neat)
3355, 1112, 971, 702 cm^−１。
【００５７】
実施例３ （Ｓ）−２−（７−ｔ−ブチルジフェニルシリルオキシ−３−メチル−１，５−ヘプタジエニル）−４，４，５，５−テトラメチル−１，３，２−ジオキサボロリジンの合成
塩化オキサリル（０．３１ｍｌ、３．５２２ｍｍｏｌ）の塩化メチレン溶液（４ｍｌ）を−７８℃に冷却し、ジメチルスルホキシド（０．３４ｍｌ、４．４０３ｍｍｏｌ）を加えた後、実施例２で得られたアルコール体（５４０．９ｍｇ、１．４６８ｍｍｏｌ）の塩化メチレン溶液（１０ｍｌ）を滴下し、１５分間撹拌した。同温にてトリエチルアミン（１．５３ｍｌ、１１．００６ｍｍｏｌ）を加え、１０分間撹拌した後、室温に昇温して１５分間撹拌した。反応溶液に蒸留水を加え、塩化メチレンで抽出した後、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した後、残留物をエーテルに溶かして濾過した。得られたアルデヒド（５６４．１ｍｇ）は精製することなく次の反応に付した。
^１H NMR (400MHz, CDCl_３) δ：
1.05(s, 9H), 1.09(d, J=6.8Hz, 3H), 2.08-2.18(m, 1H),
2.35-2.49(m, 2H), 4.14-4.17(m, 2H), 5.62-5.64(m, 2H),
7.31-7.44(m, 6H), 7.67(dd, J=7.7, 1.4Hz, 4H),
9.64(d, J=1.4Hz, 1H)。
^１３C NMR (75MHz, CDCl_３) δ：
12.95(q), 19.14(s), 26.75(q), 33.14(t), 46.00(d),
64.09(t), 126.71(d), 127.56(d), 129.56(d), 131.58(d),
133.64(s), 135.43(d), 204.48(d)。
アルゴン気流下、無水塩化クロム（１．５１ｇ、１２．３１１ｍｍｏｌ）のＴＨＦ（５ｍｌ）懸濁液にアルデヒド体（５６４．１ｍｇ、１．５３９ｍｍｏｌ）のＴＨＦ（９ｍｌ）溶液、４，４，５，５−テトラメチル−２−ジクロロメチル−２−ボラ−１，３−シクロペンタン（６４９ｍｇ、３．０７８ｍｍｏｌ）のＴＨＦ（９ｍｌ）溶液、無水ヨウ化リチウム（８２４ｍｇ、６．１５６ｍｍｏｌ）のＴＨＦ（７ｍｌ）溶液を加え、室温で１２時間撹拌した。反応溶液を蒸留水の中に注ぎ、エーテルで抽出した後、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１９：１）で精製し、無色油状のボロニックエステル体（５５３．９ｍｇ、７７％、２steps）を得た。
^１H NMR (400MHz, CDCl_３) δ：
0.99(d, J=6.4Hz, 3H), 1.05(s, 9H), 1.26(s, 16H),
1.95-2.04(m,IH), 2.15(ddd, J=13.2, 6.8, 6.4Hz, 1H),
2.26(ddd, J=13.2, 6.6, 6.4Hz, 1H),
4.15(d, J=4.6Hz, 2H), 5.40(dd, J=18.2, 0.9Hz, 1H),
5.55(dt, J=15.5, 4.6Hz, 1H),
5.63(dt, J=15.5, 6.8Hz, 1H),
6.57(dd, J=18.2, 6.4Hz, 1H),
7.35-7.43(m, 6H), 7.67(dd, J=7.7, 1.4Hz, 4H)。
【００５８】
実施例４ （２Ｚ,４Ｅ,６Ｓ,８Ｅ）−１０−ｔ−ブチルジフェニルシリルオキシ−３−（２−（４−メトキシベンジルオキシ）エチル）−６−メチル−２，４，８−デカトリエン−１−オールの合成
ジベンジリデンアセトンパラジウム・クロロホルム付加物（７．４ｍｇ、７．２μｍｏｌ）のＴＨＦ溶液（１ｍｌ）にトリフェニルホスフィン（１５．０ｍｇ、５７．３μｍｏｌ）のＴＨＦ溶液（１ｍｌ）を加えた後、参考例９で得られたヨウ化ビニル体（１６６．３ｍｇ、０．４７８ｍｍｏｌ）のＴＨＦ溶液（２ｍｌ）を加え、室温で１５分間撹拌した後、実施例３で得られたボロニックエステル（２５７．８ｍｇ、０．５２６ｍｍｏｌ）のＴＨＦ溶液（２ｍｌ）と２Ｎ水酸化ナトリウム水溶液（０．４８ｍｌ、０．９５５ｍｍｏｌ）を加え、１０時間還流した。反応溶液をエーテルで抽出した後、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）で精製し、黄色油状のカップリング体（２４０ｍｇ、７８％）を得た。
^１H NMR (400MHz, CDCl_３) δ：
0.99(d, J=6.8Hz, 3H), 1.04(s, 9H),
1.19-1.27(m, 1H, D_２0 exchange), 1.98-2.11(m, 2H),
2.22-2.31(m, 1H), 2.51(t, J=7.3Hz, 2H),
3.53(t, J=7.3Hz, 2H), 3.79(s, 3H), 4.15(d, J=3.6Hz, 2H),
4.25(d, J=6.8Hz, 2H), 4.42(s, 2H), 5.50(t, J=6.8Hz, 1H),
5.55-5.62(m, 2H), 5.66(dd, J=15.9, 7.3Hz, 1H),
6.22(d, J=16.0Hz, 1H), 6.86(d, J=8.3Hz, 2H),
7.24(d, J=8.3Hz, 2H), 7.35-7.43(m, 6H),
7.67(d, J=6.4Hz, 4H)。
^１３C NMR (75MHz, CDCl_３) δ：
19.16(s), 19.86(q), 26.78(q), 34.28(t), 37.38(d),
39.67(t), 55.18(q), 58.51(t), 64.40(t), 68.95(t),
72.43(t), 113.71(d), 123.62(d), 127.46(d), 127.55(d),
128.80(d), 129.20(d), 129.52(d), 130.36(d), 130.39(s),
133.79(s), 135.47(d), 135.89(s), 137.86(d), 159.10(s)。
【００５９】
実施例５ （２Ｚ,４Ｅ,６Ｓ,８Ｅ）−１０−ｔ−ブチルジフェニルシリルオキシ−３−（２−（４−メトキシベンジルオキシ）エチル）−１−（メトキシメトキシ）−６−メチル−２，４，８−デカトリエンの合成
実施例４で得られたカップリング体（２９６．９ｍｇ、０．５０８ｍｍｏｌ）の塩化メチレン（６ｍｌ）溶液に４−ジメチルアミノピリジン（０．６２ｍｇ、０．００５ｍｍｏｌ）、ジイソプロピルエチルアミン（０．１６ｍｌ、０．９１４ｍｍｏｌ）、クロロメチルメチルエーテル（０．０６ｍｌ、０．７６２ｍｍｏｌ）を加え、室温で２時間撹拌した。反応溶液を塩化メチレンで抽出した後、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１）で精製し、無色油状のメトキシメチルエーテル体（２６４．９ｍｇ、８３％）を得た。
^１H NMR (400MHz, CDCl_３) δ：
0.99(d, J=6.8Hz, 3H), 1.05(s, 9H),
2.00(ddd, J=13.7, 6.8, 6.8Hz, 1H),
2.09(ddd, J=13.7, 6.8, 6.4Hz, 1H),
2.26(dtq, J=7.3, 6.8, 6.8Hz, 1H), 2.52(t, J=7.3Hz, 2H),
3.35(s, 3H), 3.53(t, J=7.3Hz, 2H), 3.78(s, 3H),
4.15(t, J=4.1Hz, 2H), 4.18(d, J=6.8Hz, 2H),
4.41(s, 2H), 4.61(s, 2H), 5.45(t, J=6.8Hz, 1H),
5.54(dt, J=15.5, 4.1Hz, 1H),
5.61(ddd, J=15.5, 6.8, 6.4Hz, 1H),
5.67(dd, J=15.5, 7.3Hz, 1H),
6.22(d, J=15.5Hz, 1H), 6.85(d, J=8.7Hz, 2H),
7.23(d, J=8.7Hz, 2H), 7.34-7.42(m, 6H),
7.67(dd, J=7.7, 1.4Hz)。
^１３C NMR (75MHz, CDCl_３) δ：
19.17(s), 19.81(q), 26.80(q), 34.33(t), 37.35(d),
39.68(t), 55.18(q), 62.97(t), 64.42(t), 69.08(t),
72.44(t), 95.65(t), 113.71(d), 123.74(d), 124.40(d),
127.56(d), 128.82(d), 129.18(d), 129.52(d),
130.38(d), 130.50(s), 133.83(s), 135.48(d),
136.92(s), 137.85(d), 159.10(s)。
FT-IR (neat)
1613, 1513, 1248, 1111, 1039, 967, 822, 704 cm^−１。
【００６０】
実施例６ （２Ｅ,５Ｓ,６Ｅ,８Ｚ）−８−（２−（４−メトキシベンジルオキシ）エチル）−１０−（メトキシメトキシ）−５−エチル−２，６，８−デカトリエン−１−オールの合成
実施例５で得られた化合物（８８５．６ｍｇ、１．４０８ｍｍｏｌ）のＴＨＦ溶液（１８ｍｌ）を０℃に冷却し、テトラブチルアンモニウムフルオリド（１．０Ｍ ＴＨＦ溶液、７ｍｌ、７．０４１ｍｍｏｌ）を加え、室温で２時間撹拌した。反応溶液を塩化メチレンで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７：３）で精製し、無色油状のアリルアルコール体（５２５．８ｍｇ、９６％）を得た。

【００６１】
実施例７ （２Ｚ,４Ｅ,６Ｓ,８Ｅ）−１０−クロロ−３−（２−（４−メトキシベンジルオキシ）エチル）−１−（メトキシメトキシ）−６−メチル−２，４，８−デカトリエンの合成
実施例６で得られたアリルアルコール体（１９．７ｍｇ、０．０５ｍｍｏｌ）の塩化メチレン溶液（０．４ｍｌ）にトリフェニルホスフィン（３２ｍｇ、０．１２１ｍｍｏｌ）、四塩化炭素（０．０１５ｍｌ、０．１５１ｍｍｏｌ）を加え、室温で４．５時間撹拌した。反応溶液を飽和炭酸ナトリウム水溶液で洗浄し、塩化メチレンで抽出した後、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９３：７）で精製し、無色油状の塩素体（１５．５ｍｇ、７５％）を得た。

【００６２】
実施例８ （２Ｚ,４Ｅ,６Ｓ,８Ｅ）−１０−フェニルスルホニル−３−（２−（４−メトキシベンジルオキシ）エチル）−１−（メトキシメトキシ）−６−メチル−２，４，８−デカトリエンの合成
実施例７で得られた塩素体（４７４．７ｍｇ、１．１６１ｍｍｏｌ）のＤＭＦ溶液（９．５ｍｌ）にベンゼンスルフィン酸ナトリウム（２８５．８ｍｇ、１．７４１ｍｍｏｌ）を加え、室温で２０．５時間撹拌した。反応溶液に蒸留水を加えた後、エーテルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１）で精製し、無色油状のスルホン体（５１６．８ｍｇ、８７％）を得た。
^１H NMR(400MHz, CDCl_３) δ：
0.90(d, J=6.8Hz, 3H),
1.98(ddd, J=14.1, 6.8, 6.8Hz, 1H),
2.06(ddd, J=14.1, 6.8, 6.8Hz, 1H),
2.18(dtq, J=7.3, 6.8, 6.8Hz, 1H),
2.49(t, J=7.3Hz, 2H),
3.37(s, 3H), 3.52(t, J=7.3Hz, 2H),
3.73(d, J=6.8Hz, 2H),
3.80(s, 3H), 4.18(d, J=6.8Hz, 2H), 4.43(s, 2H),
4.62(s, 2H), 5.26(dt, J=15.5, 6.8Hz, 1H),
5.46(t, J=6.8Hz, 1H), 5.48(dt, J=15.5, 6.8Hz, 1H),
5.57(dd, J=15.9, 7.3Hz, 1H), 6.16(d, J=15.9Hz, 1H),
6.86(d, J=8.7Hz, 2H), 7.24(d, J=8.7Hz, 2H),
7.53(dd, J=7.3, 7.3Hz, 2H), 7.63(t, J=7.3Hz, 1H),
7.85(dd, J=7.3, 1.4Hz, 2H)。
^１３C NMR(75MHz, CDCl_３) δ：
19.74(q), 34.19(t), 36.92(d), 39.86(t), 55.19(q),
59.96(t), 62.88(t), 68.93(t), 72.42(t), 95.61(t),
113.69(d), 117.40(d), 124.15(d), 124.69(d),
128.34(d), 128.95(d), 129.15(d), 130.41(s),
133.54(d), 136.68(s), 136.92(d), 138.43(s),
139.43(d), 159.09(s)。
FT-IR (neat)
1612, 1513, 1306, 1248, 1146, 1088, 1037, 970, 821,
734 cm^−１。
【００６３】
実施例９ Ｎ−（（２Ｓ,４Ｅ）−６−ｔ−ブチルジフェニルシリルオキシ−２−メチル−５−ヘキセノイル）−１０，２−カンファーサルタムの合成
Ｎ−プロピオニル−１０，２−カンファーサルタム（１．１１ｇ、４．０８ｍｍｏｌ）のＴＨＦ溶液（５ｍｌ／ｍｍｏｌ）を−７８℃に冷却し、ビストリメチルシリルアミドナトリウム塩（１．０Ｍ ＴＨＦ溶液；４．９ｍｌ、４．８９ｍｍｏｌ）を１０分以上かけて加え、同温にて１時間撹拌した。これに参考例５で得られた臭素体（３．１８ｇ、８．１６ｍｍｏｌ）のＨＭＰＡ溶液（１．４ｍｌ、８．１６ｍｍｏｌ）を滴下し、３時間撹拌した後、０℃に昇温して１．５時間撹拌した。反応溶液に蒸留水を加え、エーテルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ベンゼン：ヘキサン＝７：３）で精製し、黄色結晶のジアステレオマー混合物としてアルキル化体（１．２２ｇ、５２％）を得、メタノールから３回再結晶後、ジアステレオマー比を約９３：７とした。
^１H-NMR (CDCl_３) δ：
0.93(s, 3H), 1.04(s, 9H), 1.07(s, 3H),
1.15(d, J=6.6Hz, 3H), 1.25-1.42(m, 2H),
1.77-2.06(m, 5H), 2.19-2.26(m, 1H),
2.38-2.46(m, 1H), 3.18(dq, J=6.6, 6.6 Hz),
3.40(d, J=13.8Hz, 1H), 3.48 (d, J=13.6Hz, 1H),
3.87(dd, J=7.2, 5.3Hz, 1H), 4.07-4.12(m, 2H),
5.54-5.68(m, 2H), 7.35-7.44(m, 6H), 7.64-7.67(m, 4H)。
【００６４】
実施例１０ （Ｓ）−６−ｔ−ブチルジフェニルシリルオキシ−２−メチル−４−ヘキセン−１−オールの合成
水素化リチウムアルミニウム（１０１．４ｍｇ、２．６７ｍｍｏｌ）のＴＨＦ溶液（５ｍｌ）を０℃に冷却し、実施例９で得られたアルキル化体（１．５５ｇ、２．６７ｍｍｏｌ）のＴＨＦ溶液（２６ｍｌ）を滴下し、室温にて０．５時間撹拌した。反応溶液を０℃に冷却し、エーテルで希釈しながら蒸留水を加え、室温で１時間撹拌した後、セライト濾過し、濾液を無水硫酸マグネシウムで乾燥した後、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１７：３）で精製し、無色油状のアルコール体（０．９５ｇ、９７％）を得た。
【００６５】
参考例１０ １,２：５,６−ジ−Ｏ−イソプロピリジエン−Ｄ−マンニトールの合成
減圧乾燥した塩化亜鉛（３４．２ｇ、２５１ｍｍｏｌ）に、アセトン（２００ｍｌ）を加え、室温で１時間撹拌し、２０℃に冷却した後、D-マンニトール（２１．４ｇ、１１７ｍｍｏｌ）を加え、完全に溶解するまで室温で撹拌した。０℃に冷却した後、炭酸カリウム（３５．７ｇ、２５８ｍｍｏｌ）と水（４０ｍｌ）の懸濁液を加えた。反応液を濾過した後、塩化メチレン（１５０ｍｌ）で洗浄した。この濾液（アセトン溶液）に飽和アンモニア水を加えて、塩基性にし、４０℃以下で、アセトンを減圧留去すると、結晶が析出した。得られた結晶を先の塩化メチレン洗浄液に溶解し、水層を分離した。有機層を冷水（１０ｍｌ）で洗浄し、炭酸カリウムで乾燥し、溶媒を減圧留去すると、１，２：５，６−ジ−Ｏ−イソプロピリジエン−Ｄ−マンニトール（３０．１ｇ）が無色針状結晶として得られた。この化合物は精製することなく次の反応に用いた。
ｍ.ｐ.: １０５．１℃−１０７．４℃。
【００６６】
参考例１１ エチル ４，５−Ｏ−イソプロピリジエン−（Ｓ）−４，５−ジヒドロキシ−２−ペンテノエートの合成
１,２：５,６−ジ−Ｏ−イソプロピリジエン−Ｄ−マンニトール（２５ｇ，９５ｍｍｏｌ）を５％炭酸水素ナトリウム水溶液（２５０ｍｌ）に溶解し、０℃に冷却し過ヨウ素酸ナトリウム（２５ｇ，１２０ｍｍol）を加えて、１時間撹拌した。その後、トリエチルフォスフォノアセテート（４２ｍｌ，２１０ｍｍｏｌ）と６Ｍ炭酸カリウム（３３０ｍｌ）を０℃で加え、室温で５時間撹拌した。反応液を酢酸エチル（２５０ｍｌ×３）で抽出し、飽和食塩水（３００ｍｌ）で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧留去し、エチル ４，５−Ｏ−イソプロピリジエン−（Ｓ）−４，５−ジヒドロキシ−２−ペンテノエート（５２．６ｇ）を無色油状物質として得た。この化合物は精製することなく次の反応に用いた。
^１H-NMR (300MHz,CDCl_３,TMS) δ:
1.28(3H, t, J=7Hz), 1.40(3H, s), 1.44(3H, s),
3.67(2H, q, J=7Hz), 4.23(2H, m), 4.67(1H, brq),
6.05(1H, dd, J=2Hz, 16Hz), 6.88(1H, dd, J=Hz, 16Hz)。
【００６７】
参考例１２ エチル ４，５−Ｏ−イソプロピリジエン（３Ｓ）−４，５−ジヒドロキシ−３−フェニルチオペンタノエートの合成
エチル ４，５−Ｏ−イソプロピリジエン−（Ｓ）−４，５−ジヒドロキシ−２−ペンテノエート（１５９ｇ）をベンゼン（５００ｍｌ）に溶解し、チオフェノール（９８ｍｌ，９３３ｍｍｏｌ）とジイソプロピルエチルアミン（１８１ｍｌ，１．０７ｍｏｌ）を加え、４２時間撹拌した。反応液を１０％炭酸ナトリウム水溶液（５００ｍｌ）で洗浄後、硫酸マグネシウムで乾燥させ、溶媒を減圧留去した後、ヘキサン／酢酸エチル（２０／１）で、シリカゲルカラムクロマトグラフィーに付すことにより、エチル ４，５−Ｏ−イソプロピリジエン（３Ｓ）−４，５−ジヒドロキシ−３−フェニルチオペンタノエート（１８２ｇ，参考例１０からの通算収率８２％）が淡黄色油状物質として得られた。
^１H-NMR (300MHz, CDCl_３, TMS) δ:
1.26(3H, t, J=7Hz), 1.32(3H, s), 1.38(3H, s),
2.51(1H, dd, J=9Hz, 16Hz), 2.91(1H, dd, J=5Hz, 16Hz),
3.31-3.51(1H, m), 3.70-4.25(5H, m), 7.22-7.35(3H, m),
7.35-7.52(2H, m)。
【００６８】
参考例１３ （３Ｓ）−５−ヒドロキシ−３−フェニルチオ−４−ペンタノリドの合成
エチル４，５−Ｏ‐イソプロピリジエン（３Ｓ）−４，５−ジヒドロキシ−３−フェニルチオペンタノエート（５６０ｍｇ，１．８ｍｍｏｌ）をエタノール（７．２ｍｌ）に溶解し、濃塩酸（０．８ｍｌ）を加え、３時間撹拌した。反応液の溶媒を減圧留去した後、塩化メチレン（１５ｍｌ×３）で抽出し、５％炭酸水素ナトリウム（２０ｍｌ）、飽和食塩水（３０ｍｌ）で洗浄後、硫酸マグネシウムで乾燥し、減圧留去すると、（３Ｓ）−５−ヒドロキシ−３−フェニルチオ−４−ペンタノリド（３４８ｍｇ）が黄色油状物質として得られた。この化合物は精製することなく次の反応に用いた。
^１H-NMR (300MHz, CDCl_３, TMS) δ:
2.28(1H, br.t, J=7Hz), 2.47(1H, br.q, J=6Hz, 7Hz),
2.54(1H, dd, J=7Hz, 16Hz), 2.72(1H, dd, J=9Hz, 18Hz),
2.91(1H, dd, J=8Hz, 18Hz), 3.06(1H, dd, J=9Hz, 18Hz),
3.61(1H, ddd, J=3Hz, 7Hz, 11Hz), 3.83-4.27(6H, m),
4.50(1H, m), 4.83(1H, m), 7.24-7.50(10H, m)。
【００６９】
参考例１４ （３Ｓ）−５−ヒドロキシ−３−フェニルスルフィニル−４−ペンタノリドの合成
（３Ｓ）−５−ヒドロキシ−３−フェニルチオ−４−ペンタノリド（１０ｇ，４４．６ｍｍｏｌ）を３０％過酸化水素水（１０．３ｍｌ，１１２ｍｍｏｌ）、酢酸（６．５ｍｌ）に溶解し、室温で２時間撹拌した。反応液を飽和食塩水（３０ｍｌ）で希釈し、塩化メチレン（６０ｍｌ×３）で抽出し、飽和食塩水（７０ｍｌ）で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧留去すると、（３Ｓ）−５−ヒドロキシ−３−フェニルスルフィニル−４−ペンタノリド（２２．１ｇ）が黄色油状物質として得られた。この化合物は精製することなく次の反応に用いた。
【００７０】
参考例１５ （Ｓ）−５−ヒドロキシ−２−ペンテン−４−オリドの合成
（３Ｓ）−５−ヒドロキシ−３−フェニルスルフィニル−４−ペンタノリド（１２ｇ，４９．３ｍｍｏｌ）をトルエン（５０ｍｌ）に溶解し、炭酸カルシウム（１８．３ｇ，１８２ｍｍｏｌ）を加え、３時間加熱還流した。反応液を濾過し、減圧留去し、得られた粗生成物を酢酸エチルで、シリカゲルカラムクロマトグラフィーに付すことにより、（Ｓ）−５−ヒドロキシ−２−ペンテン−４−オリド（３．８ｇ，３steps，５８％）を無色針状晶として得た。
ｍ.ｐ.：６２．５−６５．０℃。
^１H-NMR (300MHz, CDCl_３, TMS) δ:
2.09(1H, br.q), 3.80(1H, dd, J=5Hz, 12Hz),
4.00(1H, dd, J=4Hz, 12Hz), 5.16(1H, m),
6.21(1H, dd, J=2Hz, 7Hz), 7.48(1H, dd, J=1Hz, 7Hz)。
[α]_Ｄ ^２３：−121(c=0.58，H_２O)。
【００７１】
参考例１６ トリチルエーテル体の合成
（Ｓ）−５−ヒドロキシ−２−ペンテン−４−オリド (１００ｍｇ，０．８８ｍｍｏｌ）をピリジン（１．０ｍｌ）に溶解し、塩化トリチル（４８８ｍｇ，１．７５ｍｍｏｌ）を加えた後、１００℃で９０分間加熱した。その後飽和重曹水溶液（２ｍｌ）でピリジン塩酸塩を中和した後、塩化メチレン（１０ｍｌ×３）で抽出し、飽和重曹水溶液（１０ｍｌ）で洗浄した。硫酸マグネシウムで乾燥後、溶媒を減圧留去し、得られた粗生成物を酢酸エチル／ヘキサン（１／４）で、シリカゲルカラムクロマトグラフィーに付すことにより、トリチルエーテル体（３０２ｍｇ，８７％）を無色プリズム晶として得た。
ｍ.ｐ.：１２４．２℃−１３０．３℃。
【００７２】
参考例１７ （Ｓ）−３−カルボキシ−４−（１−ヒドロキシ−２−トリチルオキシメチル）−１−ピラゾリン−γ−ラクトンの合成
トリチルエーテル体（２．６ｇ，７．３ｍｍｏｌ）をテトラヒドロフラン（２０ｍｌ）に溶解し、ジアゾメタンのエーテル溶液（１００ｍｌ，２５．５ｍｍｏｌ）を加え、室温で２日間撹拌した。安息香酸で過剰のジアゾメタンを分解させた後、析出した結晶を濾取すると（Ｓ）−３−カルボキシ−４−（１−ヒドロキシ−２−トリチルオキシメチル）−１−ピラゾリン−γ−ラクトン（２．５ｇ，８６％）を無色プリズム晶として得た。
ｍ.ｐ.：１５１℃−１５３℃。
^１H-NMR (300MHz, CDCl_３, TMS) δ:
2.44(1H, m), 3.02(1H, m), 3.50(1H, m), 4.06(1H, m),
4.32(2H, m), 5.56(1H, m), 6.80(15H, m)。
【００７３】
参考例１８ （Ｓ）−４−メチル−５−トリチルオキシメチル−２（５Ｈ）−フラノンの合成
（Ｓ）−３−カルボキシ−４−（１−ヒドロキシ−２−トリチルオキシメチル）−１−ピラゾリン−γ−ラクトン（１．３ｇ，３．３４ｍｍｏｌ）をジオキサン（４０ｍｌ）に溶解し、５０時間加熱還流した。溶媒を減圧留去すると、（Ｓ）−４−メチル−５−トリチルオキシメチル−２（５Ｈ）−フラノン（１．２ｇ，９７％）が無色プリズム晶として得られた。
ｍ.ｐ.：１５９℃−１６２℃。
^１H-NMR (300MHz, CDCl_３, TMS) δ:
1.82(3H, s), 3.16(1H, dq, J=10Hz, J=4Hz),
3.62(1H, dq, J=10Hz, 3Hz), 4.68(1H, m), 5.74(1H, m),
6.80(15H, m)。
【００７４】
参考例１９ （Ｓ）−５−ヒドロキシメチル−４−メチル−２（５Ｈ）−フラノンの合成
（Ｓ）−５−ヒドロキシ−２−ペンテン−４−オリド（３００ｍｇ）をテトラヒドロフラン（２ｍｌ）に溶解し、０℃に冷却した。その後ジアゾメタン（１０ｍｌ）を加え、０℃で２日間撹拌した。反応液を４０℃に加熱し、ジオキサン（２４０ｍｌ）を加えて、２日間加熱還流した。反応液を減圧留去し、得られた粗生成物を塩化メチレン/メタノール（９７／３）で、シリカゲルカラムクロマトグラフィーに付すことにより所望の生成物（１９％，５６ｍｇ）が無色油状物質として得られた。
^１H-NMR (300 MHz, CDCl_３, TMS) δ:
2.11(3H, m), 2.22(1H, t, J=6.7Hz),
3.78(1H, ddd, J=4.2Hz, 6.7Hz, 12.6Hz),
4.07(1H, ddd, J=3Hz, 6.7Hz, 12.6Hz), 4.90(1H, m),
5.89(1H, m)。
[α]_Ｄ ^２３：−11.73・x (c=1.62，CHCl_３)。
【００７５】
実施例１１ （５Ｓ）−２，５−ジヒドロ−４−メチル−５−トリチルオキシメチル−２−フラノールの合成
アルゴン気流下、（Ｓ）−４−メチル−５−トリチルオキシメチル−２（５Ｈ）−フラノン（９０ｍｇ）をトルエン（３ｍｌ）に溶解し、−７８℃に冷却し、水素化ジイソブチルアルミニウム（０．４８ｍｌ）をゆっくり加え、−７８℃で撹拌した。反応液をエーテル（３ｍｌ）で希釈し、水（０．４８ｍｌ）を加え、０℃で１時間撹拌した。その後セライト濾過し、溶媒を減圧留去し、１４７．９ｍｇの所望の生成物が無色油状物質として得られた。この化合物は精製することなく次の反応に用いた。
【００７６】
実施例１２ （５Ｓ）−５−（ｔ−ブチルジメチルシリルオキシメチル）−２，５−ジヒドロ−４−メチル−２−フラノールの合成
アルゴン気流下、（Ｓ）−（５−ｔ−ブチルジメチルシリルオキシメチル）−４−メチル−２（５Ｈ）−フラノン（８０ｍｇ）をトルエン（４ｍｌ）に溶解し、−７８℃に冷却して、水素化ジイソブチルアルミニウム（０．４４ｍｌ）をゆっくり加え、−７８℃で撹拌した。反応液をジエチルエーテル（１０ｍｌ）で希釈し、水（４ｍｌ）を加え、０℃で１時間撹拌した。その後セライト濾過し、溶媒を減圧留去し、７５．２ｍｇの所望の生成物が無色油状物質として得られた。この化合物は精製することなく次の反応に用いた。
^１H-NMR (300MHz, CDCl_３, TMS) δ:
0.05(3H, s), 0.09(3H, s), 0.90(9H, s), 1.75(3H, s),
1.81(3H, s), 3.22(1H, d, J=11Hz), 3.32(1H, d, J=11Hz),
3.64(4H, m), 4.73(1H, m), 4.82(1H, m), 5.53(1H, br.s),
5.62(1H, br.s), 5.74(1H, d), 5.86(1H, d)。
IR(Neat): 3418 cm^−１。
【００７７】
実施例１３ （２Ｅ,４Ｚ,６Ｓ）−エチル ６−ヒドロキシ−２，５−ジメチル−７−トリチルオキシ−２，４−ヘプタジエノエートの合成
実施例１１で得られた（５Ｓ）−２，５−ジヒドロ−４−メチル−５−トリチルオキシメチル−２−フラノール（１２７ｍｇ，０．２７ｍｍｏｌ）をベンゼン（４ｍｌ）に溶解し、ホスホラン（１１７ｍｇ，０．３２ｍｍｏｌ）を加え、２時間加熱還流した。反応液を濃縮して溶媒を減圧留去し、得られた粗生成物を酢酸エチル／ヘキサン（１／９）で、シリカゲルカラムクロマトグラフィーに付すことにより、７５ｍｇ（実施例１１からの通算収率６０％）の所望の生成物が無色油状物質として得られた。
^１H-NMR (300 MHz, CDCl_３, TMS) δ:
1.32(3H, t, J=7Hz), 1.80(3H, s), 1.90(3H, s),
2.33(1H, br.s, D_２O exchangable), 3.20(2H, m),
4.24(2H, q, J=7Hz), 4.98(1H, m), 6.21(1H, d, J=12Hz),
7.35(16H, m)。
^１３C-NMR(75Hz, CDCl_３, TMS) δ:
168.5(s), 143.6(s), 132.3(d), 128.5(d), 127.7(d),
127.0(d), 126.4(s), 123.3(d), 86.9(s), 69.2(d),
66.0(t), 60.4(t), 19.4(q), 14.2(q), 12.2(q)。
IR(Neat): 3470, 1703, 1633, 1597 cm^−１。
MS(CI,isoBu)m/z:457(M^＋)。
【００７８】
実施例１４ （２Ｅ,４Ｚ,６Ｓ）−エチル ７−ｔ−ブチルジメチルシリルオキシ−６−ヒドロキシ−２，５−ジメチル−２，４−ヘプタジエノエートの合成
実施例１２で得られた（５Ｓ）−５−（ｔ−ブチルジメチルシリルオキシメチル）−２，５−ジヒドロ−４−メチル−２−フラノール（７４ｍｇ，０．２４ｍｍｏｌ）をベンゼン（２ｍｌ）に溶解し、ホスホラン（１３４ｍｇ，０．３６ｍｍｏｌ）を加え、２時間加熱還流した。反応液を濃縮して溶媒を減圧留去し、酢酸エチル／ヘキサン（１／９）で、シリカゲルカラムクロマトグラフィーに付すことにより、４６ｍｇ（実施例１２からの通算収率４３％）の所望の生成物が無色油状物質として得られた。

【００７９】
実施例１５ （２Ｅ,４Ｚ,６Ｓ）−エチル ６，７−ジヒドロキシ−２，５−ジメチル−２，４−ヘプタジエノエートの合成
実施例１３で得られた（２Ｅ,４Ｚ,６Ｓ）−エチル ６−ヒドロキシ−２，５−ジメチル−７−トリチルオキシ−２，４−ヘプタジエノエート（３０ｍｇ，０．０６６ｍｍｏｌ）をエタノール（１．５ｍｌ）に溶解し、ｐ−トルエンスルホン酸（０．５７ｍｇ，０．００３３ｍｍｏｌ）を加え、室温で４時間３０分撹拌した。反応液に飽和重曹水溶液（１０ｍｌ）を加えて、塩化メチレン（６０ｍｌ×３）で抽出し、飽和食塩水（４０ｍｌ）で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧留去して、得られた粗生成物をメタノール／クロロホルム（１／９）で、シリカゲルカラムクロマトグラフィーに付すことにより、１４．４ｍｇ（９９％）の所望の生成物が得られた。
^１H-NMR (300 MHz, CDCl_３, TMS) δ:
1.31(3H, t, J=7Hz), 1.98(6H, s), 2.25(1H, br.s),
3.54(3H, m), 4.22(2H, q, J=7Hz), 4.92(1H, m),
6.22(1H, d, J=12Hz), 7.46(1H, d, J=12Hz).
^１３C-NMR (75Hz, CDCl_３, TMS)δ:
168.9(s), 145.4(s), 132.3(d), 126.4(s), 122.9(d),
71.2(d), 65.3(t), 60.7(t), 19.7(q), 18.2(s), 14.2(q),
12.2(q).
IR (Neat): 3397, 1700, 1629, 1598, 1261,1111 cm^−１
[α]^Ｄ _２３：−19.5°(c=1.08, CHCl_３）
【００８０】
実施例１６ （２Ｅ,４Ｚ,６Ｓ）−エチル ６，７−ジヒドロキシ−２，５−ジメチル−２，４−ヘプタジエノエートの合成
実施例１４で得られた（２Ｅ,４Ｚ,６Ｓ）−エチル ７−ｔ−ブチルジメチルシリルオキシ−６−ヒドロキシ−２，５−ジメチル−２，４−ヘプタジエノエート（２４ｍｇ，０．０７３ｍｍｏｌ）をテトラヒドロフラン（１ｍｌ）に溶解し、テトラブチルアンモニウムフルオリド（０．０８７ｍｌ，０．０８７ｍｍｏｌ）を加え、室温で１０分間撹拌した。反応液に飽和塩化アンモニウム水溶液（５ｍｌ）を加え、塩化メチレン（１０ｍｌ×３）で抽出し、飽和食塩水（１０ｍｌ）で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧留去して得られた粗生成物をメタノール／クロロホルム（１／９）で、シリカゲルカラムクロマトグラフィーに付すことにより、１５ｍｇ（９７％）の所望の生成物が得られた。
^１H-NMR (300 MHz, CDCl_３, TMS) δ:
1.31(3H, t, J=7Hz), 1.98(6H, s), 2.25(1H, br.s),
3.54(3H, m), 4.22(2H, q, J=7Hz), 4.92(1H, m),
6.22(1H, d, J=12Hz), 7.46(1H, d, J=12Hz)。
^１３C-NMR (75Hz, CDCl_３, TMS) δ:
168.9(s), 145.4(s), 132.3(d), 126.4(s), 122.9(d),
71.2(d), 65.3(t), 60.7(t), 19.7(q), 18.2(s),
14.2(q), 12.2(q)。
IR(Neat): 3397, 1700, 1629, 1598, 1261, 1111 cm^−１。
[α]^Ｄ _２３：−19.5(c=1.08, CHCl_３）。
【００８１】
実施例１７ （２Ｅ,４Ｚ,６Ｓ）−エチル ６−ヒドロキシ−２，５−ジメチル−７−ｐ−トルエンスルホニルオキシ−２，４−ヘプタジエノエートの合成
（２Ｅ,４Ｚ,６Ｓ）−エチル ６，７−ジヒドロキシ−２，５−ジメチル−２，４−ヘプタジエノエート（１８０ｍｇ，０．８４ｍｍｏｌ）を塩化メチレン（０．５ｍｌ）、ピリジン（０．１７ｍｌ，１．６８ｍｍｏｌ）に溶解し、０℃に冷却した後、トシルクロリド（１６０ｍｇ，０．８４ｍｍｏｌ）を加え、室温で３０分間撹拌した。反応液を塩化メチレン（２０ｍｌ）で希釈し、１０％硫酸銅水溶液（２０ｍｌ）、飽和食塩水（２０ｍｌ）で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧留去して、酢酸エチル／ヘキサン（２／８）で、シリカゲルカラムクロマトグラフィーに付すことにより、２９６ｍｇ（９５％）の所望の生成物が得られた。

【００８２】
実施例１８ （２Ｅ,４Ｚ,６Ｓ）−エチル ６，７−エポキシ−２，５−ジメチル−２，４−ヘプタジエノエートの合成
（２Ｅ,４Ｚ,６Ｓ）−エチル ６−ヒドロキシ−２，５−ジメチル−７−ｐ−トルエンスルホニルオキシ−２，４−ヘプタジエノエート（３００ｍｇ，０．８１ｍｍｏｌ）をアセトン（１０ｍｌ）に溶解し、炭酸カリウム（５６２ｍｇ，４．０７ｍｍｏｌ）を加え、７時間加熱還流した。反応液を濃縮して溶媒を減圧留去し、塩化メチレン（１００ｍｌ）で希釈し、水（５０ｍｌ）で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧留去した。この粗生成物を酢酸エチル／ヘキサン（２／８）で、シリカゲルカラムクロマトグラフィーに付すことにより、所望の６，７−エポキシ体（１５０ｍｇ，９３％）が無色油状物質として得られた。

【００８３】
参考例２０ ３−ブロモ−２−プロピン−１−オールの合成
水酸化カルシウム（１８．５ｇ，０．２５ｍｏｌ）の水溶液（２００ｍｌ）を０℃に冷却し、臭素（７．７ｍｌ，０．１５ｍｏｌ）を滴下した。この溶液にジエチルエーテルを加え、−８℃に冷却して、徐々にプロパルギルアルコール（７．３ｇ，０．１３ｍｏｌ）を滴下した。その後室温に昇温し３時間攪拌した後、０℃に冷却し、チオ硫酸ナトリウム（５．２ｇ）を加え、２０分間攪拌した。反応液に濃塩酸（２５ｍｌ）を加えて固体を溶解し、ジエチルエーテル（１５０ｍｌｘ４）で反応液を抽出した。有機層を１０％炭酸ナトリウム水溶液（５０ｍｌ）で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、蒸留（３ｍｍＨｇ，４８℃）すると、３−ブロモ−２−プロピン−１−オール（４．４ｇ，２５％）が無色油状物質として得られた。
【００８４】
参考例２１ （Ｅ）−３−ブロモ−２−プロペン−１−オールの合成
窒素気流下、水素化リチウムアルミニウム（０．５７ｇ，１５ｍｍｏｌ）と塩化アルミニウム（１．４９ｇ，１１ｍｍｏｌ）にジエチルエーテル（１０ｍｌ）を−５℃でゆっくり滴下した後、３−ブロモ−２−プロピン−１−オール（１．０ｇ，７．５ｍｍｏｌ）を‐５℃でゆっくり滴下し、その後３時間加熱還流した。反応液に水（１０ｍｌ）を加えてセライト濾過し、濾液をジエチルエーテル（３０ｍｌ×３）で抽出し、飽和重曹水溶液（３０ｍｌ）で洗浄した。硫酸マグネシウムで乾燥後、溶媒を減圧留去し、得られた粗生成物を蒸留（１８ｍｍＨｇ，７８℃）すると（Ｅ）−３−ブロモ−２−プロペン−１−オール（４０７ｍｇ，４０％）が無色油状物質として得られた。
【００８５】
参考例２２ （Ｅ）−１−ブロモ−３−ｔ−ブチルジフェニルシリルオキシ−１−プロペンの合成
（Ｅ）−３−ブロモ−２−プロペン−１−オール（４０７ｍｇ，３ｍｍｏｌ）とイミダゾール（２８３ｍｇ，４．２ｍｍｏｌ）の塩化メチレン（５０ｍｌ）溶液に０℃でＴＢＤＰＳＣｌ（９７６ｍｇ，４ｍｍｏｌ）と４−ジメチルアミノピリジン（３６ｍｇ）を加え、４時間攪拌した。反応液を塩化メチレン（５０ｍｌ）で希釈し、水（５０ｍｌ）で洗浄した後、この水層から塩化メチレン（６０ｍｌ×３）で抽出し、有機層を合わせて硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた粗生成物を蒸留（２ｍｍＨｇ，２３０℃）すると、所望の生成物（１．２９ｇ，９７％）が無色油状物質として得られた。
【００８６】
参考例２３ （Ｅ）−５−ｔ−ブチルジフェニルシリルオキシ−３−ペンテン−１−インの合成
（Ｅ）−１−ブロモ−３−ｔ−ブチルジフェニルシリルオキシ−１−プロペン（３００ｍｇ，０．７８ｍｍｏｌ）をテトラヒドロフラン（９ｍｌ）に溶解し、これに塩化エチニルマグネシウム（４．８ｍｌ，２．３４ｍｍｏｌ）を加えた。
別に、トリス（ジベンジリデンアセトン）ジパラジウム（０）−クロロホルム付加物（２４ｍｇ）とトリフェニルフォスフィン（４８ｍｇ）をテトラヒドロフラン（６ｍｌ）に溶解し、溶液が紫から黄色に変化したのを確認した後、このパラジウム溶液を先の反応液に加え、７時間加熱還流した。反応液をエーテルで希釈し、飽和塩化アンモニウム（６０ｍｌ）、飽和食塩水（６０ｍｌ）で洗浄した後、硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物を酢酸エチル／ヘキサン（１／１６）で、シリカゲルカラムクロマトグラフィーに付すことにより、所望の生成物（１７５．５ｍｇ，５０％）が黄色油状物質として得られた。
^１H-NMR (300MHz，CDCl_３, TMS) δ:
1.05(9H, s), 2.88(1H, m), 4.24(2H, m),
5.91(1H, dd, J=2Hz, 16Hz), 6.29(1H, td, J=4Hz, J=16Hz),
7.40(6H, m), 7.65(4H, m)。
^１３C-NMR (75MHz, CDCl_３) δ:
143.8(s), 135.4(d), 131.2(s), 129.7(d), 127.7(d),
107.6(d), 83.0(s), 77.8(d), 63.4(t), 26.7(q), 20.3(s)。
IR (Neat): 3292, 2105, 953, 1113, 954 cm^−１。
【００９０】
【発明の効果】
本発明は、ボンクレキン酸の実用的で簡便な合成方法を提供するためのボンクレキン酸前駆体であるボンクレキン酸Ｃ_１〜Ｃ_１０セグメント（ボンクレキン酸分子の左半分）とボンクレキン酸Ｃ _１６ 〜Ｃ_２２セグメント（ボンクレキン酸分子の右半分の一部）の実用的で且つ効率的な製造方法を提供するものであり、本発明の方法によれば、ボンクレキン酸の大量供給が可能となるので、今後アポトーシスの研究が飛躍的に進展することが予想され、また、誘導体合成により多くの疾患の治療薬にも発展しうる可能性も充分考えられるので、斯業に貢献するところ甚だ大なる発明である。[0001]
BACKGROUND OF THE INVENTION
  Since the present invention has an inhibitory activity on apoptosis, C of boncrekinic acid, which is a precursor compound of boncrekinic acid, which is highly useful as an indispensable compound for studies on apoptosis, is disclosed.₁~ C₁₀Segment and boncrekinic acid C ₁₆ ~ C₂₂The present invention relates to a segment manufacturing method.
[0002]
[Prior art]
Bonglequinic acid is also called boncrecic acid and is generally known as an inhibitor of ATP-ADP exchange transporter, and is represented by the following structural formula.
[0003]
Embedded image

[0004]
Recent studies have revealed that boncrekinic acid has an inhibitory effect on apoptosis, one of the cell deaths. Biochemists around the world are indispensable to study the molecular mechanism of apoptosis. Has attracted attention from.
Bonglequinic acid was isolated as a compound produced by a bacterium called Pseudomonas cocovenenans when coconut was used as a medium, but it was difficult to reproduce the experimental conditions, and researchers in various countries had difficulty obtaining it.
Only one example of chemical synthesis of boncrekinic acid has been reported so far (J. Am. Chem. Soc.1984106, 462-463), this method does not provide the necessary amount.
[0005]
[Problems to be solved by the invention]
  The present invention relates to a boncrekinic acid precursor C which is a boncrekinic acid precursor for providing a practical and simple method for synthesizing boncrequinic acid.₁~ C₁₀Segment (left half of boncrekinic acid molecule) and C of boncrekinic acid ₁₆ ~ C₂₂Segment (right half of boncrekinic acid moleculePart ofIt is an object of the present invention to provide a practical and efficient production method.
[0006]
[Means for Solving the Problems]
The present invention provides C of boncrekinic acid comprising the following steps (1) to (8):₁~ C₁₀The present invention relates to a segment manufacturing method.
(1) General formula [1]
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[Wherein R¹Is
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(However, R²Represents a benzyl group, an isopropyl group or a methyl group, R³, R⁴Each independently represents a hydrogen atom or a phenyl group. (Hereafter, it may be abbreviated as protecting group A.)
Or
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(Hereinafter, it may be abbreviated as protecting group B.)
Represents. The compound represented by the general formula [2]
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(Wherein R⁵T-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxymethyl group, acetyl group or Represents a methoxyethoxymethyl group, X¹Represents a halogen atom. And the compound represented by the general formula [3]
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(Wherein R¹, R⁵Is the same as above. )
The process made into the compound shown by these.
(2) The compound represented by the general formula [3] obtained in the above (1) is reduced to give a general formula [4].
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(Wherein R⁵Is the same as above. )
The process which makes it the alcohol body shown by.
(3) The alcohol obtained in (2) above is oxidized to give the general formula [5]
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(Wherein R⁵Is the same as above. )
And then having the general formula [6]
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(Wherein R⁸, R⁹Each independently represents an alkyl group. R⁸And R⁹And may form an alkylene group together. And a dichloromethyl boronic ester represented by the general formula [7]
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(Wherein R⁵, R⁸And R⁹Is the same as above. )
The process which makes the boronic ester body shown by these.
(4) The boronic ester obtained in (3) above is represented by the general formula [8]
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(Wherein R⁶T-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxymethyl group, acetyl group or Represents a methoxyethoxymethyl group. ) To give a compound of the general formula [9]
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(Wherein R⁵, R⁶Is the same as above. However, R⁵≠ R⁶)
The process made into the coupling body shown by.
(5) The coupling body obtained in the above (4) is represented by the general formula [10].
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(Wherein R⁷T-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxymethyl group, acetyl group or Represents a methoxyethoxymethyl group, X²Represents a halogen atom. And the compound represented by the general formula [11]
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(Wherein R⁵, R⁶And R⁷Is the same as above. However, R⁵≠ R⁶And R⁵≠ R⁷The process made into the compound shown by this.
(6) Protecting group R for the hydroxyl group at position 10 of the compound represented by the general formula [11] obtained in (5) above⁵Is deprotected to give the general formula [12]
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(Wherein R⁶, R⁷Is the same as above. The process made into the allyl alcohol body shown by this. (7) The hydroxyl group of the allyl alcohol obtained in (6) above is substituted with halogen to give a compound of the general formula [13]
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(Where X³Represents a halogen atom, R⁶, R⁷Is the same as above. )
A process for producing a halogen compound represented by
(8) The halogen compound obtained in (7) above is represented by the general formula [14].
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(Wherein R¹⁰Represents a lower alkyl group or an aryl group, and M represents an alkali metal atom. And the sulfinic acid salt represented by the general formula [15]
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(Wherein R⁶, R⁷And R¹⁰Is the same as above. )
The process which makes a sulfone body shown by.
[0007]
In addition, the present invention provides C of the above boncrekinic acid.₁~ C₁₀The present invention relates to each intermediate in a method for producing a segment and a method for producing these intermediates.
[0008]
  Furthermore, the present invention provides the following (11) to(15)Boncrekinic acid C comprising the steps of ₁₆ ~ C₂₂It relates to the manufacturing method of the segment.
  (11) General formula [21]
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(Wherein R¹¹Represents a protecting group for a hydroxyl group. ) To reduce the compound represented by the general formula [22]
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(Wherein R¹¹Is the same as above. )
The process made into the furanol body shown by.
  (12) The furanol represented by the general formula [22] obtained in the above (11) is represented by the general formula [23].
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(Wherein R¹²Represents an alkyl group, an aryl group or an aralkyl group. In the general formula [24]
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(Wherein R¹¹, R¹²Is the same as above. )
The process made into the compound shown by these.
  (13) The protective group for the hydroxyl group at the 7-position of the compound represented by the general formula [24] obtained in the above (12) is deprotected to give the general formula [25]
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(Wherein R¹²Is the same as above. )
The process made into the dihydroxy body shown by these.
  (14) The hydroxyl group at the 7-position of the dihydroxy compound represented by the general formula [25] obtained in the above (13) is tosylated, mesylated or halogen-substituted to obtain the general formula [26]
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(Where X¹¹Represents a tosyloxy group, a mesyloxy group or a halogen atom, R¹²Is the same as above. )
The process made into the compound shown by these.
  (15) The compound represented by the general formula [26] obtained in the above (14) is treated with a base to obtain the general formula [27].
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(Wherein R¹²Is the same as above. )
The process made into the 6,7-epoxy body shown by these.
[0009]
  In addition, the present invention provides C of the above boncrekinic acid. ₁₆ ~ C₂₂The present invention relates to each intermediate in the method for producing a segment and a method for producing these intermediates.
[0010]
In the step (1) according to the present invention, X of the compound represented by the general formula [2]¹Examples of the halogen atom include halogen atoms such as chlorine, bromine and iodine, but a bromine atom or an iodine atom is preferable, and an iodine atom is particularly preferable.
In addition, R of the compound represented by the general formula [2]⁵T-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxymethyl group, acetyl group or Any of methoxyethoxymethyl groups may be used, but t-butyldiphenylsilyl group, t-butyldimethylsilyl group and the like are particularly preferable.
When the compound represented by the general formula [1] is reacted with the compound represented by the general formula [2], for example, first, the compound represented by the general formula [1] is lithiated or sodiumated, and then the general formula [2]. It is preferable to make it react with the compound shown by this.
Lithiation is a lithiation reagent such as n-butyllithium, phenyllithium, lithium diisopropylamide, or a combination of n-butyllithium and diisopropylamine in an ether solvent such as diethyl ether, diisopropyl ether or tetrahydrofuran (THF). Can be lithiated according to a conventional method at −50 ° C. or lower, preferably −70 ° C. or lower. After lithiation, the compound represented by the general formula [2] can be reacted. A compound represented by the formula [3] is easily obtained.
The reaction temperature for reacting the compound represented by the general formula [2] is usually −50 to −10 ° C., preferably −40 to −20 ° C., and the reaction time is usually 1 to 10 hours, preferably 2 to 5 It is about time.
[0011]
In addition, sodiumation is carried out in the presence of hexamethylphosphoramide (HMPA) in an ether solvent such as THF, diethyl ether, or diisopropyl ether, for example, sodium bistrimethylsilylamide (NHMDS), sodium hydride, or the like. Using an agent, it is sufficient to cause a sodium reaction at −50 ° C. or lower, preferably −70 ° C. or lower according to a conventional method. After sodiumation, a compound represented by the general formula [2] is reacted therewith. The compound represented by the general formula [3] can be easily obtained.
The reaction temperature for reacting the compound represented by the general formula [2] is usually −50 ° C. or lower, preferably −70 ° C. or lower, and the reaction time is usually 1 to 10 hours, preferably about 2 to 5 hours. is there.
Which of lithiation and sodiumation is preferable is unclear because there are various factors involved, but in general formula [1], R¹When is a protecting group A, lithiation is suitable and R¹When is a protecting group B, sodiumation is suitable.
[0012]
In the step (2) according to the present invention, any reduction method can be used as long as the reduction of the compound represented by the general formula [3] is a reduction method capable of becoming an alcohol form represented by the general formula [4] after reduction. However, usually, a reducing agent such as lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride and the like is preferably used. The solvent is usually an ether solvent such as THF, diethyl ether, diisopropyl ether, etc. The reaction temperature of the reduction reaction is usually around 0 ° C., and the reaction time is usually from several tens of minutes to several hours.
[0013]
In the step (3) according to the present invention, R of the compound represented by the general formula [6] and the compound represented by the general formula [7]⁸, R⁹Examples of the alkyl group represented by the formula include a lower alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group, which may be linear or branched. Well, also R⁸And R⁹Examples of the alkylene group in the case of forming an alkylene group together with, for example, ethylene group, trimethylene group, tetramethylene group, 1,2-dimethylethylene group, 1,1,2,2-tetramethylethylene Groups and the like.
[0014]
Any reagent that can be used to oxidize an alcohol form represented by the general formula [4] to form an aldehyde form can be used as long as it can oxidize the alcohol form represented by the general formula [4] to form an aldehyde form. For example, a combination of oxalyl chloride and dimethyl sulfoxide and a base such as triethylamine can be used. As the reaction solvent in this case, methylene chloride, dichloromethane, chloroform or the like is usually used. The reaction temperature is usually −50 ° C. or lower, preferably −70 ° C. or lower, and the reaction time is usually about several tens of minutes when oxalyl chloride and dimethyl sulfoxide are combined with the alcohol, and then, for example, a base such as triethylamine. Is added, and the mixture is further stirred for several tens of minutes to react.
Examples of reagents other than those used in the reaction to oxidize an alcohol form to form an aldehyde form include, for example, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin reagent (1,1,1-triacetoxy-1,1 -Dihydro-1,2-benziodoxol-3 (1H) -one), a combination reagent of TRAP (tetra-n-propylammonium pearl tenate) and N-methylmorpholine N-oxide, and the like.
[0015]
The reaction between the aldehyde and the dichloromethyl boronic ester is usually carried out in an ether solvent such as THF in the presence of an excess amount of anhydrous chromium chloride and an excess amount of anhydrous lithium iodide. The reaction is usually performed at room temperature, and the reaction time is usually several hours to tens of hours.
Besides the combination of anhydrous chromium chloride and anhydrous lithium iodide, there is also a combination of anhydrous chromium chloride, manganese, anhydrous lithium iodide and trimethylsilyl chloride.
In this case, since the amount of anhydrous chromium chloride used is a catalyst amount, there is an advantage in that the amount of harmful waste is reduced when considering production on an industrial scale.
[0016]
In the step (4) according to the present invention, R of the compound represented by the general formula [8]⁶T-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxymethyl group, acetyl group or Any of methoxyethoxymethyl groups may be used, but p-methoxyphenylmethyl group, benzyl group and the like are particularly preferable.
The reaction between the boronic ester represented by the general formula [7] and the compound represented by the general formula [8] is usually performed in the presence of a palladium complex catalyst and an alkali. As the palladium complex catalyst, a low valence complex having tertiary phosphine or tertiary phosphite as a ligand, or a palladium complex not containing tertiary phosphine or tertiary phosphite as a ligand, and tertiary phosphine or And / or tertiary phosphite, and a low valence complex having a tertiary phosphine or / and tertiary phosphite as a ligand formed in the reaction system. Preferred specific examples include 3 Examples of the low valence complex having a tertiary phosphine or tertiary phosphite as a ligand include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium and the like, and tertiary phosphine and / or tertiary phosphine. Examples of the palladium complex used in combination with phyto include dibenzylideneacetone palladium and chloro Lum adduct, palladium acetate and the like.
Further, as the alkali used in this reaction, an aqueous solution of sodium hydroxide, potassium hydroxide or the like is preferably used.
As the reaction solvent, usually an ether solvent such as THF is preferably used, and the reaction is usually performed for about 5 to 15 hours under reflux of the solvent.
[0017]
In the step (5) according to the present invention, X of the compound represented by the general formula [10]²Examples include halogen atoms such as chlorine, bromine and iodine. R⁷T-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxymethyl group, acetyl group or Any methoxyethoxymethyl group may be used, but a methoxymethyl group, an acetyl group, and the like are particularly preferable.
The reaction of the coupling compound represented by the general formula [9] and the compound represented by the general formula [10] is usually performed in the presence of a base. Examples of the base used here include aliphatic and aromatic tertiary amines such as diisopropylethylamine and 4-dimethylaminopyridine. As the reaction solvent, usually methylene chloride, dichloromethane, chloroform and the like are preferably used, and the reaction usually takes several hours at room temperature.
[0018]
In the step (6) according to the present invention, the protecting group R for the hydroxyl group at the 10-position of the compound represented by the general formula [11]⁵Is a deprotection reagent used in the reaction to form an allyl alcohol compound represented by the general formula [12].⁵Depending on the type, for example, R⁵When is a t-butyldiphenylsilyl group, for example, tetrabutylammonium fluoride is preferably used. As the reaction solvent, usually an ether solvent such as THF is preferably used, and the reaction usually takes several hours at room temperature.
[0019]
In the step (7) according to the present invention, X of the compound represented by the general formula [13]³Examples include halogen atoms such as chlorine, bromine and iodine.
The halogenating agent used for halogen substitution of the hydroxyl group of the allyl alcohol compound represented by the general formula [11] may be any halogenating agent capable of halogenating an alcoholic hydroxyl group. And a combination of carbon tetrachloride and triphenylphosphine, a combination of carbon tetrabromide and triphenylphosphine, phosphorus tribromide, a combination of methyl iodide and triphenylphosphonate, and the like.
As the reaction solvent, usually methylene chloride, dichloroethane, chloroform and the like are preferably used. The reaction is usually carried out at room temperature and the reaction time is usually about 3 to 8 hours.
[0020]
In the step (8) according to the present invention, R of the compound represented by the general formula [14]¹⁰Examples of the lower alkyl group represented by the formula include lower alkyl groups having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. But you can also use R¹⁰Examples of the aryl group represented by are phenyl group, tolyl group, xylyl group, naphthyl group, methylnaphthyl group and the like. Examples of the alkali metal atom represented by M include sodium, potassium, lithium and the like.
The reaction of the halogen compound represented by the general formula [13] and the compound represented by the general formula [14] is usually performed in a dimethylformamide (DMF) solvent. The reaction temperature is usually room temperature and the reaction time is usually about 10 to 30 hours.
[0021]
C of boncrekinic acid of the present invention₁~ C₁₀In the method for producing a segment, the compound represented by the general formula [2] used as a starting material can be synthesized, for example, according to the following synthesis scheme.
[0022]
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[0023]
In addition, formal names such as abbreviations in the above reaction scheme are as follows.
MPMCl: p-methoxyphenylmethyl chloride
DMSO: Dimethyl sulfoxide
MPM: p-methoxyphenylmethyl
TBDPSCl: t-butyldiphenylsilyl chloride
TBDPS: t-butyldiphenylsilyl
4-DMAP: 4-dimethylaminopyridine
DDQ: dichlorodicyanobenzoquinone
Red-Al: Bis (2-methoxyethoxy) aluminum sodium hydride
Further, C of the boncrekinic acid of the present invention₁~ C₁₀In the segment production method, the compound represented by the general formula [8] to be reacted with the boronic ester represented by the general formula [7] can be synthesized, for example, according to the following synthesis scheme. In addition, the meaning of the symbol in the following synthetic scheme is the same as the above.
[0024]
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[0025]
In the step (11) according to the present invention, R of the compound represented by the general formula [21] and the compound represented by the general formula [22]¹¹As the hydroxyl-protecting group represented by, for example, trityl group (triphenylmethyl group), t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxy group Phenylmethyl group, benzyl group, tetrahydropyranyl group, methoxymethyl group, methoxyethoxymethyl group can be used, and any of them can be used, but trityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc. Particularly preferred.
The reduction of the compound represented by the general formula [21] may be any reduction method as long as it can be converted to the furanol form represented by the general formula [22] after the reduction. This is performed using a metal hydride such as diisobutylaluminum, lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride and the like. Of these, diisobutylaluminum hydride and lithium aluminum hydride are particularly preferably used.
The reaction is usually carried out in an aromatic hydrocarbon solvent such as benzene or toluene, or an aliphatic hydrocarbon solvent such as n-hexane or petroleum ether. The reaction temperature is usually −50 ° C. or lower, preferably −70 ° C. or lower, and the reaction time naturally varies depending on the reaction temperature and other reaction conditions and is not uniform, but is usually about several tens of minutes to several hours.
In addition, the compound represented by General Formula [22] obtained in this step is usually used in the next step without purification.
[0026]
In the step (12) according to the present invention, R of the compound represented by the general formula [23] (phosphorane) and the compound represented by the general formula [24]¹²As the alkyl group represented by, for example, a linear or branched alkyl group having 1 to 20, preferably 1 to 10, more preferably 1 to 6 carbon atoms can be mentioned, and more specifically, Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a secondary butyl group, a tertiary butyl group, a pentyl group, and a hexyl group.
Examples of the aryl group include monocyclic, polycyclic or condensed cyclic aromatic hydrocarbon groups having 6 to 30 carbon atoms, preferably 6 to 20 carbon atoms, more preferably 6 to 15 carbon atoms, and more specifically. Examples thereof include a phenyl group, a tolyl group, a xylyl group, a naphthyl group, and a methylnaphthyl group.
Examples of the aralkyl group include monocyclic, polycyclic or condensed cyclic aralkyl groups having 7 to 30 carbon atoms, preferably 7 to 20 carbon atoms, more preferably 7 to 15 carbon atoms. Examples include a benzyl group, a phenethyl group, a naphthylmethyl group, and a naphthylethyl group.
The reaction of the compound represented by the general formula [22] and the phosphorane represented by the general formula [23] is usually performed in an aromatic hydrocarbon solvent such as benzene and toluene, and the reaction temperature is usually 50 ° C. or higher. Preferably, the reflux temperature of the solvent used and the reaction time are naturally several tens of minutes to several hours, although they naturally vary depending on other reaction conditions.
[0027]
In step (12), the furanol compound represented by the general formula [22] is reacted with the phosphorane represented by the general formula [23] to obtain a compound (ester compound) represented by the general formula [24]. Instead of taking the product as it is to the step (13) and subsequent steps, the ester form is reduced to an alcohol form, and this hydroxyl group is protected to give the general formula [24 ′]
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(Wherein R₀ ¹³Represents a protecting group for a hydroxyl group. )
It is also possible to proceed to the steps after (13) after preparing the compound represented by
In this case, as a method of reducing the compound (ester) represented by the general formula [24] to form an alcohol, for example, diisobutylaluminum hydride is used as a reducing agent, and a solvent such as THF, methylene chloride, toluene or the like. Among them, there are a method of reacting at −78 ° C. to 0 ° C. and a method of using lithium aluminum hydride as a reducing agent and reacting in THF or diethyl ether. In addition, hydroxyl protecting group R of the obtained alcohol₀ ¹³Examples thereof include t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, and trimethylsilyl group.
[0028]
In the step (13) according to the present invention, the protecting group R for the hydroxyl group at the 7-position of the compound represented by the general formula [24]¹¹Is a deprotection reagent used in the reaction to form a dihydroxy compound represented by the general formula [25].¹¹Depending on the type, for example, R¹¹Is a trityl group, for example, an acid catalyst such as p-toluenesulfonic acid, formic acid, acetic acid, hydrochloric acid, trifluoroacetic acid is used.¹¹Is a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, or the like, for example, tetrabutylammonium fluoride is preferably used. As a reaction solvent, an alcohol solvent such as ethanol is usually used in a system using an acid catalyst, and an ether solvent such as THF is preferably used in a system using tetrabutylammonium fluoride or the like. The reaction is usually about 1 to 6 hours at room temperature in the former case, and usually several tens of minutes at room temperature in the latter case.
[0029]
In the step (14) according to the present invention, X of the compound represented by the general formula [26]¹¹Examples thereof include a tosyloxy group (p-toluenesulfonyloxy group), a mesyloxy group (methanesulfonyloxy group), for example, a halogen atom such as chlorine, bromine and iodine.
Examples of the reagent used for tosylating the hydroxyl group at the 7-position of the dihydroxy compound represented by the general formula [25] include a combination of tosyl chloride and a base (for example, pyridine), and examples of the reaction solvent include chloride. And halogenated hydrocarbons such as methylene, dichloroethane, and chloroform. The reaction temperature is usually about 0 to room temperature, and the reaction time is usually several tens of minutes to several hours.
Examples of the reagent used in the case of mesylating the hydroxyl group at the 7-position of the dihydroxy compound represented by the general formula [25] include a combination of mesyl chloride and a base (for example, pyridine). Examples of the reaction solvent include chloride. And halogenated hydrocarbons such as methylene, dichloroethane, and chloroform. The reaction temperature is usually about 0 to room temperature, and the reaction time is usually several tens of minutes to several hours.
The halogenating agent used for halogen substitution of the 7-position hydroxyl group of the dihydroxy compound represented by the general formula [25] may be any halogenating agent capable of halogenating an alcoholic hydroxyl group. , For example, a combination of carbon tetrachloride and triphenylphosphine, a combination of carbon tetrabromide and triphenylphosphine, phosphorus tribromide, a combination of methyl iodide and triphenyl phosphonate, etc. Usually, halogenated hydrocarbons such as methylene chloride, dichloroethane and chloroform are preferably used. The reaction is usually carried out at room temperature, and the reaction time is usually about 3 to 8 hours.
[0030]
In the above step (15) according to the present invention, the base used in the reaction of treating the compound represented by the general formula [26] with a base to obtain the 6,7-epoxy compound represented by the general formula [27] Examples thereof include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and the like. As the reaction solvent, ketones such as acetone are usually used, and the reaction is usually performed for about 3 to 10 hours under reflux of the solvent.
[0036]
  C of boncrekinic acid of the present invention ₁₆ ~ C₂₂In the method for producing a segment, the compound represented by the general formula [21] used as a starting material can be synthesized, for example, according to the following synthesis scheme. Note that Tr in the synthesis scheme is an abbreviation for a trityl group.
[0037]
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[0045]
【Example】
EXAMPLES Next, although an Example and a reference example demonstrate this invention in detail, this invention is not limited to these Examples and a reference example.
[0046]
Reference Example 1 Synthesis of 4- (4-methoxybenzyloxy) -2-butyn-1-ol
After adding potassium hydroxide (24.1 g, 0.366 mol) to a DMSO solution (70 ml) of 2-butyne-1,4-diol (30.0 g, 0.349 mol), p-methoxybenzyl chloride (23. 6 ml, 0.174 mol) was added dropwise, and the mixture was stirred at 0 ° C. for 10 minutes and further at room temperature for 1.5 hours. The reaction mixture was cooled to 0 ° C., saturated aqueous ammonium chloride solution was added, diluted with ether, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain a mono-p-methoxybenzyl ether (24.9 g, 69%) as a colorless oil.

[0047]
Reference Example 2 Synthesis of 4- (4-methoxybenzyloxy) -2-buten-1-ol
The mono-p-methoxybenzyl ether compound (7.7 g, 37.2 mmol) obtained in Reference Example 1 was dissolved in ether (600 ml), cooled to −25 ° C., and then Red-Al (60% toluene solution: 44). 0.7 ml, 148.9 mmol) was slowly added dropwise and stirred for 1.5 hours. Ethyl acetate (40 ml) and 1M sodium hydroxide (63 ml) were added to the reaction solution, and the mixture was filtered through celite and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) to obtain a transolefin (7.5 g, 96%) as a colorless oil.

[0048]
Reference Example 3 Synthesis of 1-t-butyldiphenylsilyloxy-4- (4-methoxybenzyloxy) -2-butene
To a methylene chloride solution (20 ml) of the transolefin product (1.0 g, 4.8 mmol) obtained in Reference Example 2, imidazole (0.6 g, 8.6 mmol), t-butyldiphenylchlorosilane (1.5 ml, 5. 8 mmol) and 4-dimethylaminopyridine (4.9 mg, 0.004 mmol) were added, and the mixture was stirred at room temperature for 0.5 hour. Distilled water was added to the reaction mixture, extracted with methylene chloride, and then washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 17: 3) to obtain a t-butyldiphenylsilyl ether body (2.0 g, 96%) as a colorless oily substance.
[0049]
Reference Example 4 Synthesis of 4-t-butyldiphenylsilyloxy-2-buten-1-ol
The t-butyldiphenylsilyl ether form (2.0 g, 4.6 mmol) obtained in Reference Example 3 was dissolved in methylene chloride / distilled water (18/1) to give 2,3-dichloro-5,6-dicyano-1 , 4-Benzoquinone (1.4 g, 6.0 mmol) was added and stirred at room temperature for 0.5 hour. The reaction mixture was diluted with methylene chloride and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain an allyl alcohol form (0.9 g, 61%).

[0050]
Reference Example 5 Synthesis of 1-bromo-4-t-butyldiphenylsilyloxy-2-butene
The allyl alcohol form (500 mg, 1.531 mmol) obtained in Reference Example 4 was dissolved in methylene chloride, triphenylphosphine (482 mg, 1.838 mmol) and carbon tetrabromide (762 mg, 2.297 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Stir for minutes. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, extracted with methylene chloride, and then washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to obtain a bromine compound (488 mg, 82%).
[0051]
Reference Example 6 Synthesis of 1-t-butyldiphenylsilyloxy-4-iodo-2-butene
The allyl alcohol form (7.14 g, 21.868 mmol) obtained in Reference Example 4 was dissolved in benzene (140 ml), imidazole (3.72 g, 54.671 mmol), triphenylphosphine (11.47 g, 43.737 mmol). , Iodine (11.10 g, 43.737 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous sodium thiosulfate solution (300 ml × 4) and saturated brine (100 ml × 1). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to obtain an iodine form (7.0 g, 74%).
[0052]
Reference Example 7 Synthesis of 4- (4-methoxybenzyloxy) -1-butene
A solution of 3-butyn-1-ol (10.0 g, 0.143 mol) in THF (200 ml) was cooled to 0 ° C. and sodium hydride (containing 62.7% in mineral oil; 11.5 g, 0.300 mol) was added. After stirring for 1.5 hours, p-methoxybenzyl chloride (26.8 g, 23.2 ml, 0.171 mol) and tetra-n-butylammonium iodide (1.6 g, 4.3 mmol) were added, and room temperature was added. For 5 hours. The reaction mixture was cooled to 0 ° C., water was added, diluted with hexane, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was distilled under reduced pressure (99-116 ° C./1.5 mmHg) to obtain a p-methoxybenzyl ether (21.2 g, 78%) as a colorless oil.
[0053]
Reference Example 8 Synthesis of 5- (4-methoxybenzyloxy) -2-pentyn-1-ol
A THF solution (222 ml) of 4- (4-methoxybenzyloxy) -1-butene (20.2 g, 0.106 mol) obtained in Reference Example 7 was cooled to −78 ° C., and n-butyllithium (2. 52M hexane solution; 50.4 ml, 0.127 mol) was added dropwise and stirred for 2 hours, then paraformaldehyde (9.6 g, 0.318 mol) was added at the same temperature, and the mixture was warmed to room temperature and stirred for 2 hours. . Water was added to the reaction solution, diluted with ether, saturated brine was added for liquid separation, and the mixture was further extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain an alcohol form (18.0 g, 77%) as a colorless oil.
[0054]
Reference Example 9 Synthesis of (Z) -3-iodo-5- (4-methoxybenzyloxy) -2-penten-1-ol
An ether solution (60 ml) of Red-Al (65% toluene solution; 25.5 ml, 81.8 mmol) was cooled to 0 ° C., and 5- (4-methoxybenzyloxy) -2-pentyne obtained in Reference Example 8 was obtained. An ether solution (100 ml) of -1-ol (8.2 g, 37.2 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 4.5 hours. The reaction solution was cooled to 0 ° C., ethyl acetate (4.2 ml, 42.4 mmol) was added, then cooled to −50 ° C., iodine (14.2 g, 55.8 mmol) was added, and the temperature was gradually raised to room temperature. Warmed and stirred for 2 hours. A saturated aqueous sodium sulfite solution was added to the reaction solution, and the mixture was extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain a vinyl iodide form (8.5 g, 66%) as a yellow oily substance.
¹H NMR (400MHz, CDCl₃) δ:
2.78 (t, J = 6.4Hz, 2H), 3.59 (t, J = 6.4Hz, 2H), 3.80 (s, 3H),
4.19 (d, J = 5.5Hz, 2H), 4.46 (s, 2H), 5.94 (t, J = 5.5Hz, 1H),
6.88 (d, J = 8.7Hz, 2H), 7.25 (d, J = 8.7Hz, 2H).
¹³C NMR (75MHz, CDCl₃) δ:
45.10 (t), 55.23 (q), 67.19 (t), 68.27 (t), 72.67 (t),
104.99 (s), 113.76 (d), 129.33 (d), 130.03 (s),
135.77 (d), 159.17 (s).
[0055]
Example 1 Synthesis of (R) -4-benzyl-3-((2S, 4E) -6-tert-butyldiphenylsilyloxy-2-methyl-5-hexenoyl) -1,3-oxazolidine-2-one
A THF solution (1.5 ml) of diisopropylamine (0.07 ml, 0.514 mmol) is cooled to 0 ° C., and n-butyllithium (1.52 M hexane solution 0.34 ml, 0.514 mmol) is added over 20 minutes. And stirred at the same temperature for 30 minutes. The reaction solution was cooled to −78 ° C., and a solution of (R) -4-benzyl-3-propionyl-1,3-oxazolidine-2-one (100 mg, 0.429 mmol) in THF (2.0 ml) was added for 20 minutes. It added over the above and stirred at the same temperature for 1 hour. To this was added the iodine body (281 mg, 0.643 mmol) obtained in Reference Example 6 over 10 minutes, and the mixture was stirred at −40 ° C. to −20 ° C. for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, the solvent was distilled off, water was added, and the mixture was extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain an alkylated product (196.1 mg, 84%, dr. = 94: 6) as a colorless oily diastereomer mixture.
¹H NMR (400MHz, CDCl₃) δ:
1.03 (s, 9H), 1.18 (d, J = 6.8Hz, 3H),
2.23 (ddd, J = 13.7, 6.8, 6.8Hz, 1H),
2.51 (ddd, J = 13.7, 6.8, 6.8Hz, 1H),
2.61 (dd, J = 13.2, 10.0Hz, 1H),
3.27 (dd, J = 13.2, 3.2Hz, 1H),
3.85 (ddq, J = 6.8, 6.8, 6.8Hz, 1H), 4.11-4.19 (m, 4H),
4.67 (dddd, J = 10.0, 7.7, 3.4, 3.2Hz, 1H),
5.64 (dt, J = 15.5, 4.6Hz, 1H),
5.72 (ddd, J = 15.5, 6.8, 6.8Hz, 1H),
7.16 (d, J = 6.8Hz, 2H), 7.27-7.40 (m, 9H),
7.66 (dd, J = 5.9, 1.8Hz, 4H).
¹³C NMR (75MHz, CDCl₃) δ
16.44 (q), 19.16 (s), 26.76 (q), 36.40 (t), 37.44 (d),
38.04 (t), 55.33 (d), 64.18 (t), 65.94 (t), 127.02 (d),
127.22 (d), 127.59 (d), 128.86 (d), 129.35 (d), 129.55 (d),
131.61 (d), 133.65 (s), 133.70 (s), 135.35 (s), 135.47 (d),
135.48 (d), 153.05 (s), 176.50 (s).
FT-IR (neat)
1782, 1699, 1386, 1112, 971, 703 cm^-1.
[0056]
Example 2 Synthesis of (S) -6-t-butyldiphenylsilyloxy-2-methyl-4-hexen-1-ol
A THF solution (36 ml) of lithium aluminum hydride (799 mg, 21.04 mmol) was cooled to 0 ° C., and a THF solution (40 ml) of the alkylated product obtained in Example 1 (3.8 g, 7.014 mmol) was added. The solution was added dropwise and stirred at the same temperature for 1.5 hours. Distilled water was added while diluting with ether while maintaining the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 1 hour, filtered through Celite, and the filtrate was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain a colorless oily alcohol (1.8 g, 68%).
¹H NMR (400MHz, CDCl₃) δ:
0.91 (d, J = 6.4Hz, 3H), 1.05 (s, 9H), 1.52 (brs, 1H),
1.66-1.75 (m, 1H), 1.92 (ddd, J = 13.2, 7.3, 6.8Hz, 1H),
2,14 (ddd, J = 13.7, 6.6, 6.4Hz, 1H),
3,44 (dd, J = 10.5, 6.4Hz, 1H),
3.50 (dd, J = 10.5, 5.9Hz, 1H),
4.17 (d, J = 4.1Hz, 2H), 5.58 (dt, J = 15.0, 4.6Hz, 1H),
5.67 (dt, J = 15.5, 6.8Hz, 1H), 7.36-7.44 (m, 6H),
7.68 (dd, J = 7.7, 1.4Hz, 4H).
¹³C NMR (75MHz, CDCl₃) δ:
16.35 (q), 19.19 (s), 26.80 (q), 35.81 (d), 36.06 (t),
64.42 (t), 67.79 (t), 127.57 (d), 128.95 (d), 129.54 (d),
130.46 (d), 133.82 (s), 135.51 (d).
FT-IR (neat)
3355, 1112, 971, 702 cm^-1.
[0057]
Example 3 (S) -2- (7-t-butyldiphenylsilyloxy-3-methyl-1,5-heptadienyl) -4,4,5,5-tetramethyl-1,3,2-dioxaboro Synthesis of lysine
A solution of oxalyl chloride (0.31 ml, 3.522 mmol) in methylene chloride (4 ml) was cooled to −78 ° C., dimethyl sulfoxide (0.34 ml, 4.403 mmol) was added, and then the alcohol obtained in Example 2 was used. A solution of the body (540.9 mg, 1.468 mmol) in methylene chloride (10 ml) was added dropwise and stirred for 15 minutes. Triethylamine (1.53 ml, 11.006 mmol) was added at the same temperature, stirred for 10 minutes, then warmed to room temperature and stirred for 15 minutes. Distilled water was added to the reaction solution, extracted with methylene chloride, and then washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was dissolved in ether and filtered. The obtained aldehyde (564.1 mg) was subjected to the next reaction without purification.
¹H NMR (400MHz, CDCl₃) δ:
1.05 (s, 9H), 1.09 (d, J = 6.8Hz, 3H), 2.08-2.18 (m, 1H),
2.35-2.49 (m, 2H), 4.14-4.17 (m, 2H), 5.62-5.64 (m, 2H),
7.31-7.44 (m, 6H), 7.67 (dd, J = 7.7, 1.4Hz, 4H),
9.64 (d, J = 1.4Hz, 1H).
¹³C NMR (75MHz, CDCl₃) δ:
12.95 (q), 19.14 (s), 26.75 (q), 33.14 (t), 46.00 (d),
64.09 (t), 126.71 (d), 127.56 (d), 129.56 (d), 131.58 (d),
133.64 (s), 135.43 (d), 204.48 (d).
Under a stream of argon, a solution of anhydrous chrome chloride (1.51 g, 12.311 mmol) in THF (5 ml) in a THF (9 ml) solution of aldehyde (564.1 mg, 1.539 mmol), 4, 4, 5, 5 -Tetramethyl-2-dichloromethyl-2-bora-1,3-cyclopentane (649 mg, 3.078 mmol) in THF (9 ml), anhydrous lithium iodide (824 mg, 6.156 mmol) in THF (7 ml) And stirred at room temperature for 12 hours. The reaction solution was poured into distilled water, extracted with ether, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to obtain a colorless oily boronic ester (553.9 mg, 77%, 2 steps).
¹H NMR (400MHz, CDCl₃) δ:
0.99 (d, J = 6.4Hz, 3H), 1.05 (s, 9H), 1.26 (s, 16H),
1.95-2.04 (m, IH), 2.15 (ddd, J = 13.2, 6.8, 6.4Hz, 1H),
2.26 (ddd, J = 13.2, 6.6, 6.4Hz, 1H),
4.15 (d, J = 4.6Hz, 2H), 5.40 (dd, J = 18.2, 0.9Hz, 1H),
5.55 (dt, J = 15.5, 4.6Hz, 1H),
5.63 (dt, J = 15.5, 6.8Hz, 1H),
6.57 (dd, J = 18.2, 6.4Hz, 1H),
7.35-7.43 (m, 6H), 7.67 (dd, J = 7.7, 1.4Hz, 4H).
[0058]
Example 4 (2Z, 4E, 6S, 8E) -10-tert-butyldiphenylsilyloxy-3- (2- (4-methoxybenzyloxy) ethyl) -6-methyl-2,4,8-decatriene-1 -Synthesis of all
After adding a THF solution (1 ml) of triphenylphosphine (15.0 mg, 57.3 μmol) to a THF solution (1 ml) of dibenzylideneacetone palladium / chloroform adduct (7.4 mg, 7.2 μmol), Reference Example 9 A THF solution (2 ml) of the vinyl iodide obtained in (166.3 mg, 0.478 mmol) was added and stirred at room temperature for 15 minutes, and then the boronic ester (257.8 mg, 0) obtained in Example 3 was used. .526 mmol) in THF (2 ml) and 2N aqueous sodium hydroxide (0.48 ml, 0.955 mmol) were added and refluxed for 10 hours. The reaction solution was extracted with ether and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain a yellow oily coupling product (240 mg, 78%).
¹H NMR (400MHz, CDCl₃) δ:
0.99 (d, J = 6.8Hz, 3H), 1.04 (s, 9H),
1.19-1.27 (m, 1H, D₂0 exchange), 1.98-2.11 (m, 2H),
2.22-2.31 (m, 1H), 2.51 (t, J = 7.3Hz, 2H),
3.53 (t, J = 7.3Hz, 2H), 3.79 (s, 3H), 4.15 (d, J = 3.6Hz, 2H),
4.25 (d, J = 6.8Hz, 2H), 4.42 (s, 2H), 5.50 (t, J = 6.8Hz, 1H),
5.55-5.62 (m, 2H), 5.66 (dd, J = 15.9, 7.3Hz, 1H),
6.22 (d, J = 16.0Hz, 1H), 6.86 (d, J = 8.3Hz, 2H),
7.24 (d, J = 8.3Hz, 2H), 7.35-7.43 (m, 6H),
7.67 (d, J = 6.4Hz, 4H).
¹³C NMR (75MHz, CDCl₃) δ:
19.16 (s), 19.86 (q), 26.78 (q), 34.28 (t), 37.38 (d),
39.67 (t), 55.18 (q), 58.51 (t), 64.40 (t), 68.95 (t),
72.43 (t), 113.71 (d), 123.62 (d), 127.46 (d), 127.55 (d),
128.80 (d), 129.20 (d), 129.52 (d), 130.36 (d), 130.39 (s),
133.79 (s), 135.47 (d), 135.89 (s), 137.86 (d), 159.10 (s).
[0059]
Example 5 (2Z, 4E, 6S, 8E) -10-tert-butyldiphenylsilyloxy-3- (2- (4-methoxybenzyloxy) ethyl) -1- (methoxymethoxy) -6-methyl-2, Synthesis of 4,8-decatriene
To a solution of the coupling product (296.9 mg, 0.508 mmol) obtained in Example 4 in methylene chloride (6 ml), 4-dimethylaminopyridine (0.62 mg, 0.005 mmol), diisopropylethylamine (0.16 ml, 0 914 mmol) and chloromethyl methyl ether (0.06 ml, 0.762 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with methylene chloride and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain a colorless oily methoxymethyl ether (264.9 mg, 83%).
¹H NMR (400MHz, CDCl₃) δ:
0.99 (d, J = 6.8Hz, 3H), 1.05 (s, 9H),
2.00 (ddd, J = 13.7, 6.8, 6.8Hz, 1H),
2.09 (ddd, J = 13.7, 6.8, 6.4Hz, 1H),
2.26 (dtq, J = 7.3, 6.8, 6.8Hz, 1H), 2.52 (t, J = 7.3Hz, 2H),
3.35 (s, 3H), 3.53 (t, J = 7.3Hz, 2H), 3.78 (s, 3H),
4.15 (t, J = 4.1Hz, 2H), 4.18 (d, J = 6.8Hz, 2H),
4.41 (s, 2H), 4.61 (s, 2H), 5.45 (t, J = 6.8Hz, 1H),
5.54 (dt, J = 15.5, 4.1Hz, 1H),
5.61 (ddd, J = 15.5, 6.8, 6.4Hz, 1H),
5.67 (dd, J = 15.5, 7.3Hz, 1H),
6.22 (d, J = 15.5Hz, 1H), 6.85 (d, J = 8.7Hz, 2H),
7.23 (d, J = 8.7Hz, 2H), 7.34-7.42 (m, 6H),
7.67 (dd, J = 7.7, 1.4 Hz).
¹³C NMR (75MHz, CDCl₃) δ:
19.17 (s), 19.81 (q), 26.80 (q), 34.33 (t), 37.35 (d),
39.68 (t), 55.18 (q), 62.97 (t), 64.42 (t), 69.08 (t),
72.44 (t), 95.65 (t), 113.71 (d), 123.74 (d), 124.40 (d),
127.56 (d), 128.82 (d), 129.18 (d), 129.52 (d),
130.38 (d), 130.50 (s), 133.83 (s), 135.48 (d),
136.92 (s), 137.85 (d), 159.10 (s).
FT-IR (neat)
1613, 1513, 1248, 1111, 1039, 967, 822, 704 cm^-1.
[0060]
Example 6 (2E, 5S, 6E, 8Z) -8- (2- (4-methoxybenzyloxy) ethyl) -10- (methoxymethoxy) -5-ethyl-2,6,8-decatrien-1-ol Synthesis of
A THF solution (18 ml) of the compound obtained in Example 5 (885.6 mg, 1.408 mmol) was cooled to 0 ° C., and tetrabutylammonium fluoride (1.0 M THF solution, 7 ml, 7.041 mmol) was added. And stirred at room temperature for 2 hours. The reaction solution was diluted with methylene chloride and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain a colorless oily allyl alcohol (525.8 mg, 96%).

[0061]
Example 7 (2Z, 4E, 6S, 8E) -10-chloro-3- (2- (4-methoxybenzyloxy) ethyl) -1- (methoxymethoxy) -6-methyl-2,4,8-decatriene Synthesis of
To a methylene chloride solution (0.4 ml) of the allyl alcohol form (19.7 mg, 0.05 mmol) obtained in Example 6, triphenylphosphine (32 mg, 0.121 mmol) and carbon tetrachloride (0.015 ml, 0.005 ml) were added. 151 mmol) and stirred at room temperature for 4.5 hours. The reaction solution was washed with a saturated aqueous sodium carbonate solution, extracted with methylene chloride, and then washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 93: 7) to obtain a colorless oily chlorine (15.5 mg, 75%).

[0062]
Example 8 (2Z, 4E, 6S, 8E) -10-phenylsulfonyl-3- (2- (4-methoxybenzyloxy) ethyl) -1- (methoxymethoxy) -6-methyl-2,4,8- Synthesis of decatriene
Sodium benzenesulfinate (285.8 mg, 1.741 mmol) was added to a DMF solution (9.5 ml) of the chlorine form (474.7 mg, 1.161 mmol) obtained in Example 7, and the mixture was stirred at room temperature for 20.5 hours. did. Distilled water was added to the reaction solution, followed by extraction with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain a colorless oily sulfone compound (516.8 mg, 87%).
¹H NMR (400MHz, CDCl₃) δ:
0.90 (d, J = 6.8Hz, 3H),
1.98 (ddd, J = 14.1, 6.8, 6.8Hz, 1H),
2.06 (ddd, J = 14.1, 6.8, 6.8Hz, 1H),
2.18 (dtq, J = 7.3, 6.8, 6.8Hz, 1H),
2.49 (t, J = 7.3Hz, 2H),
3.37 (s, 3H), 3.52 (t, J = 7.3Hz, 2H),
3.73 (d, J = 6.8Hz, 2H),
3.80 (s, 3H), 4.18 (d, J = 6.8Hz, 2H), 4.43 (s, 2H),
4.62 (s, 2H), 5.26 (dt, J = 15.5, 6.8Hz, 1H),
5.46 (t, J = 6.8Hz, 1H), 5.48 (dt, J = 15.5, 6.8Hz, 1H),
5.57 (dd, J = 15.9, 7.3Hz, 1H), 6.16 (d, J = 15.9Hz, 1H),
6.86 (d, J = 8.7Hz, 2H), 7.24 (d, J = 8.7Hz, 2H),
7.53 (dd, J = 7.3, 7.3Hz, 2H), 7.63 (t, J = 7.3Hz, 1H),
7.85 (dd, J = 7.3, 1.4Hz, 2H).
¹³C NMR (75MHz, CDCl₃) δ:
19.74 (q), 34.19 (t), 36.92 (d), 39.86 (t), 55.19 (q),
59.96 (t), 62.88 (t), 68.93 (t), 72.42 (t), 95.61 (t),
113.69 (d), 117.40 (d), 124.15 (d), 124.69 (d),
128.34 (d), 128.95 (d), 129.15 (d), 130.41 (s),
133.54 (d), 136.68 (s), 136.92 (d), 138.43 (s),
139.43 (d), 159.09 (s).
FT-IR (neat)
1612, 1513, 1306, 1248, 1146, 1088, 1037, 970, 821,
734 cm^-1.
[0063]
Example 9 Synthesis of N-((2S, 4E) -6-t-butyldiphenylsilyloxy-2-methyl-5-hexenoyl) -10,2-camphorsultam
3. A THF solution (5 ml / mmol) of N-propionyl-10,2-camphorsultam (1.11 g, 4.08 mmol) was cooled to −78 ° C., and bistrimethylsilylamide sodium salt (1.0 M THF solution; 4. 9 ml, 4.89 mmol) was added over 10 minutes and stirred at the same temperature for 1 hour. To this was added dropwise an HMPA solution (1.4 ml, 8.16 mmol) of the bromine obtained in Reference Example 5 (3.18 g, 8.16 mmol), and the mixture was stirred for 3 hours. Stir for 5 hours. Distilled water was added to the reaction solution and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (benzene: hexane = 7: 3) to obtain an alkylated product (1.22 g, 52%) as a diastereomeric mixture of yellow crystals. After recrystallization from methanol three times, The diastereomeric ratio was about 93: 7.
¹H-NMR (CDCl₃) δ:
0.93 (s, 3H), 1.04 (s, 9H), 1.07 (s, 3H),
1.15 (d, J = 6.6Hz, 3H), 1.25-1.42 (m, 2H),
1.77-2.06 (m, 5H), 2.19-2.26 (m, 1H),
2.38-2.46 (m, 1H), 3.18 (dq, J = 6.6, 6.6 Hz),
3.40 (d, J = 13.8Hz, 1H), 3.48 (d, J = 13.6Hz, 1H),
3.87 (dd, J = 7.2, 5.3Hz, 1H), 4.07-4.12 (m, 2H),
5.54-5.68 (m, 2H), 7.35-7.44 (m, 6H), 7.64-7.67 (m, 4H).
[0064]
Example 10 Synthesis of (S) -6-t-butyldiphenylsilyloxy-2-methyl-4-hexen-1-ol
A solution of lithium aluminum hydride (101.4 mg, 2.67 mmol) in THF (5 ml) was cooled to 0 ° C. and the alkylated product obtained in Example 9 (1.55 g, 2.67 mmol) in THF (26 ml). ) Was added dropwise and stirred at room temperature for 0.5 hour. The reaction solution was cooled to 0 ° C., distilled water was added while diluting with ether, and the mixture was stirred at room temperature for 1 hour, filtered through Celite, and the filtrate was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 17: 3) to obtain a colorless oily alcohol (0.95 g, 97%).
[0065]
Reference Example 10 Synthesis of 1,2: 5,6-di-O-isopropylidene-D-mannitol
Acetone (200 ml) was added to zinc chloride (34.2 g, 251 mmol) dried under reduced pressure, stirred at room temperature for 1 hour, cooled to 20 ° C., and then D-mannitol (21.4 g, 117 mmol) was added. Stir at room temperature until dissolved. After cooling to 0 ° C., a suspension of potassium carbonate (35.7 g, 258 mmol) and water (40 ml) was added. The reaction mixture was filtered and washed with methylene chloride (150 ml). Saturated aqueous ammonia was added to the filtrate (acetone solution) to make it basic, and acetone was distilled off under reduced pressure at 40 ° C. or lower to precipitate crystals. The obtained crystals were dissolved in the previous methylene chloride washing solution, and the aqueous layer was separated. The organic layer was washed with cold water (10 ml), dried over potassium carbonate, and the solvent was distilled off under reduced pressure to give 1,2: 5,6-di-O-isopropylidene-D-mannitol (30.1 g) colorless. Obtained as needle-like crystals. This compound was used in the next reaction without purification.
m.p .: 105.1 ° C-107.4 ° C.
[0066]
Reference Example 11 Synthesis of ethyl 4,5-O-isopropylidene- (S) -4,5-dihydroxy-2-pentenoate
1,2: 5,6-di-O-isopropylidene-D-mannitol (25 g, 95 mmol) was dissolved in 5% aqueous sodium hydrogen carbonate solution (250 ml), cooled to 0 ° C. and sodium periodate (25 g, 120 mmol) was added and stirred for 1 hour. Thereafter, triethylphosphonoacetate (42 ml, 210 mmol) and 6M potassium carbonate (330 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate (250 ml × 3), washed with saturated brine (300 ml) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and ethyl 4,5-O-isopropylidene- (S ) -4,5-dihydroxy-2-pentenoate (52.6 g) was obtained as a colorless oil. This compound was used in the next reaction without purification.
¹H-NMR (300MHz, CDCl₃, TMS) δ:
1.28 (3H, t, J = 7Hz), 1.40 (3H, s), 1.44 (3H, s),
3.67 (2H, q, J = 7Hz), 4.23 (2H, m), 4.67 (1H, brq),
6.05 (1H, dd, J = 2Hz, 16Hz), 6.88 (1H, dd, J = Hz, 16Hz).
[0067]
Reference Example 12 Synthesis of ethyl 4,5-O-isopropylidene (3S) -4,5-dihydroxy-3-phenylthiopentanoate
Ethyl 4,5-O-isopropylidene- (S) -4,5-dihydroxy-2-pentenoate (159 g) was dissolved in benzene (500 ml), thiophenol (98 ml, 933 mmol) and diisopropylethylamine (181 ml, 1 0.07 mol) was added and stirred for 42 hours. The reaction solution was washed with 10% aqueous sodium carbonate solution (500 ml), dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography with hexane / ethyl acetate (20/1) to give ethyl. 4,5-O-isopropylidene (3S) -4,5-dihydroxy-3-phenylthiopentanoate (182 g, 82% overall yield from Reference Example 10) was obtained as a pale yellow oil.
¹H-NMR (300MHz, CDCl₃, TMS) δ:
1.26 (3H, t, J = 7Hz), 1.32 (3H, s), 1.38 (3H, s),
2.51 (1H, dd, J = 9Hz, 16Hz), 2.91 (1H, dd, J = 5Hz, 16Hz),
3.31-3.51 (1H, m), 3.70-4.25 (5H, m), 7.22-7.35 (3H, m),
7.35-7.52 (2H, m).
[0068]
Reference Example 13 Synthesis of (3S) -5-hydroxy-3-phenylthio-4-pentanolide
Ethyl 4,5-O-isopropylidene (3S) -4,5-dihydroxy-3-phenylthiopentanoate (560 mg, 1.8 mmol) was dissolved in ethanol (7.2 ml) and concentrated hydrochloric acid (0. 8 ml) was added and stirred for 3 hours. After evaporating the solvent of the reaction solution under reduced pressure, the mixture was extracted with methylene chloride (15 ml × 3), washed with 5% sodium hydrogen carbonate (20 ml) and saturated brine (30 ml), dried over magnesium sulfate, and evaporated under reduced pressure. Then, (3S) -5-hydroxy-3-phenylthio-4-pentanolide (348 mg) was obtained as a yellow oily substance. This compound was used in the next reaction without purification.
¹H-NMR (300MHz, CDCl₃, TMS) δ:
2.28 (1H, br.t, J = 7Hz), 2.47 (1H, br.q, J = 6Hz, 7Hz),
2.54 (1H, dd, J = 7Hz, 16Hz), 2.72 (1H, dd, J = 9Hz, 18Hz),
2.91 (1H, dd, J = 8Hz, 18Hz), 3.06 (1H, dd, J = 9Hz, 18Hz),
3.61 (1H, ddd, J = 3Hz, 7Hz, 11Hz), 3.83-4.27 (6H, m),
4.50 (1H, m), 4.83 (1H, m), 7.24-7.50 (10H, m).
[0069]
Reference Example 14 Synthesis of (3S) -5-hydroxy-3-phenylsulfinyl-4-pentanolide
(3S) -5-Hydroxy-3-phenylthio-4-pentanolide (10 g, 44.6 mmol) was dissolved in 30% aqueous hydrogen peroxide (10.3 ml, 112 mmol) and acetic acid (6.5 ml). Stir for hours. The reaction mixture was diluted with saturated brine (30 ml), extracted with methylene chloride (60 ml × 3), washed with saturated brine (70 ml), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give (3S) -5-Hydroxy-3-phenylsulfinyl-4-pentanolide (22.1 g) was obtained as a yellow oil. This compound was used in the next reaction without purification.
[0070]
Reference Example 15 Synthesis of (S) -5-hydroxy-2-pentene-4-olide
(3S) -5-hydroxy-3-phenylsulfinyl-4-pentanolide (12 g, 49.3 mmol) was dissolved in toluene (50 ml), calcium carbonate (18.3 g, 182 mmol) was added, and the mixture was heated to reflux for 3 hours. The reaction solution was filtered and evaporated under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography with ethyl acetate to give (S) -5-hydroxy-2-pentene-4-olide (3.8 g). , 3 steps, 58%) was obtained as colorless needles.
m.p .: 62.5-65.0 ° C.
¹H-NMR (300MHz, CDCl₃, TMS) δ:
2.09 (1H, br.q), 3.80 (1H, dd, J = 5Hz, 12Hz),
4.00 (1H, dd, J = 4Hz, 12Hz), 5.16 (1H, m),
6.21 (1H, dd, J = 2Hz, 7Hz), 7.48 (1H, dd, J = 1Hz, 7Hz).
[α]_D ²³: -121 (c = 0.58, H₂O).
[0071]
Reference Example 16 Synthesis of trityl ether
(S) -5-Hydroxy-2-pentene-4-olide (100 mg, 0.88 mmol) was dissolved in pyridine (1.0 ml), trityl chloride (488 mg, 1.75 mmol) was added, and then at 100 ° C. Heated for 90 minutes. Thereafter, pyridine hydrochloride was neutralized with a saturated aqueous sodium bicarbonate solution (2 ml), extracted with methylene chloride (10 ml × 3), and washed with a saturated aqueous sodium bicarbonate solution (10 ml). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography with ethyl acetate / hexane (1/4) to give a trityl ether (302 mg, 87%). Obtained as colorless prism crystals.
m.p .: 124.2 ° C-130.3 ° C.
[0072]
Reference Example 17 Synthesis of (S) -3-carboxy-4- (1-hydroxy-2-trityloxymethyl) -1-pyrazoline-γ-lactone
The trityl ether form (2.6 g, 7.3 mmol) was dissolved in tetrahydrofuran (20 ml), an ether solution of diazomethane (100 ml, 25.5 mmol) was added, and the mixture was stirred at room temperature for 2 days. After the excess diazomethane was decomposed with benzoic acid, the precipitated crystals were collected by filtration to give (S) -3-carboxy-4- (1-hydroxy-2-trityloxymethyl) -1-pyrazoline-γ-lactone (2 0.5 g, 86%) as colorless prism crystals.
m.p .: 151 ° C-153 ° C.
¹H-NMR (300MHz, CDCl₃, TMS) δ:
2.44 (1H, m), 3.02 (1H, m), 3.50 (1H, m), 4.06 (1H, m),
4.32 (2H, m), 5.56 (1H, m), 6.80 (15H, m).
[0073]
Reference Example 18 Synthesis of (S) -4-methyl-5-trityloxymethyl-2 (5H) -furanone
(S) -3-Carboxy-4- (1-hydroxy-2-trityloxymethyl) -1-pyrazoline-γ-lactone (1.3 g, 3.34 mmol) was dissolved in dioxane (40 ml) and heated for 50 hours. Refluxed. The solvent was distilled off under reduced pressure to obtain (S) -4-methyl-5-trityloxymethyl-2 (5H) -furanone (1.2 g, 97%) as colorless prism crystals.
m.p .: 159 ° C-162 ° C.
¹H-NMR (300MHz, CDCl₃, TMS) δ:
1.82 (3H, s), 3.16 (1H, dq, J = 10Hz, J = 4Hz),
3.62 (1H, dq, J = 10Hz, 3Hz), 4.68 (1H, m), 5.74 (1H, m),
6.80 (15H, m).
[0074]
Reference Example 19 Synthesis of (S) -5-hydroxymethyl-4-methyl-2 (5H) -furanone
(S) -5-hydroxy-2-pentene-4-olide (300 mg) was dissolved in tetrahydrofuran (2 ml) and cooled to 0 ° C. Then diazomethane (10 ml) was added and stirred at 0 ° C. for 2 days. The reaction solution was heated to 40 ° C., dioxane (240 ml) was added, and the mixture was heated to reflux for 2 days. The reaction solution was evaporated under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography with methylene chloride / methanol (97/3) to give the desired product (19%, 56 mg) as a colorless oil. It was.
¹H-NMR (300 MHz, CDCl₃, TMS) δ:
2.11 (3H, m), 2.22 (1H, t, J = 6.7Hz),
3.78 (1H, ddd, J = 4.2Hz, 6.7Hz, 12.6Hz),
4.07 (1H, ddd, J = 3Hz, 6.7Hz, 12.6Hz), 4.90 (1H, m),
5.89 (1H, m).
[α]_D ²³: −11.73 · x (c = 1.62, CHCl₃).
[0075]
Example 11 Synthesis of (5S) -2,5-dihydro-4-methyl-5-trityloxymethyl-2-furanol
Under an argon stream, (S) -4-methyl-5-trityloxymethyl-2 (5H) -furanone (90 mg) was dissolved in toluene (3 ml), cooled to −78 ° C., and diisobutylaluminum hydride (0. 48 ml) was slowly added and stirred at -78 ° C. The reaction mixture was diluted with ether (3 ml), water (0.48 ml) was added, and the mixture was stirred at 0 ° C. for 1 hr. The mixture was then filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 147.9 mg of the desired product as a colorless oil. This compound was used in the next reaction without purification.
[0076]
Example 12 Synthesis of (5S) -5- (t-butyldimethylsilyloxymethyl) -2,5-dihydro-4-methyl-2-furanol
Under a stream of argon, (S)-(5-tert-butyldimethylsilyloxymethyl) -4-methyl-2 (5H) -furanone (80 mg) was dissolved in toluene (4 ml), cooled to -78 ° C, Diisobutylaluminum hydride (0.44 ml) was slowly added and stirred at -78 ° C. The reaction mixture was diluted with diethyl ether (10 ml), water (4 ml) was added, and the mixture was stirred at 0 ° C. for 1 hr. The mixture was then filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 75.2 mg of the desired product as a colorless oil. This compound was used in the next reaction without purification.
¹H-NMR (300MHz, CDCl₃, TMS) δ:
0.05 (3H, s), 0.09 (3H, s), 0.90 (9H, s), 1.75 (3H, s),
1.81 (3H, s), 3.22 (1H, d, J = 11Hz), 3.32 (1H, d, J = 11Hz),
3.64 (4H, m), 4.73 (1H, m), 4.82 (1H, m), 5.53 (1H, br.s),
5.62 (1H, br.s), 5.74 (1H, d), 5.86 (1H, d).
IR (Neat): 3418 cm^-1.
[0077]
Example 13 Synthesis of (2E, 4Z, 6S) -ethyl 6-hydroxy-2,5-dimethyl-7-trityloxy-2,4-heptadienoate
(5S) -2,5-dihydro-4-methyl-5-trityloxymethyl-2-furanol (127 mg, 0.27 mmol) obtained in Example 11 was dissolved in benzene (4 ml) and phosphorane (117 mg, 0.32 mmol) was added and heated to reflux for 2 hours. The reaction solution was concentrated, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography with ethyl acetate / hexane (1/9) to give 75 mg (total yield from Example 11). 60%) of the desired product was obtained as a colorless oil.
¹H-NMR (300 MHz, CDCl₃, TMS) δ:
1.32 (3H, t, J = 7Hz), 1.80 (3H, s), 1.90 (3H, s),
2.33 (1H, br.s, D₂O exchangable), 3.20 (2H, m),
4.24 (2H, q, J = 7Hz), 4.98 (1H, m), 6.21 (1H, d, J = 12Hz),
7.35 (16H, m).
¹³C-NMR (75Hz, CDCl₃, TMS) δ:
168.5 (s), 143.6 (s), 132.3 (d), 128.5 (d), 127.7 (d),
127.0 (d), 126.4 (s), 123.3 (d), 86.9 (s), 69.2 (d),
66.0 (t), 60.4 (t), 19.4 (q), 14.2 (q), 12.2 (q).
IR (Neat): 3470, 1703, 1633, 1597 cm^-1.
MS (CI, isoBu) m / z: 457 (M⁺).
[0078]
Example 14 Synthesis of (2E, 4Z, 6S) -ethyl 7-t-butyldimethylsilyloxy-6-hydroxy-2,5-dimethyl-2,4-heptadienoate
Dissolve (5S) -5- (t-butyldimethylsilyloxymethyl) -2,5-dihydro-4-methyl-2-furanol (74 mg, 0.24 mmol) obtained in Example 12 in benzene (2 ml). Then, phosphorane (134 mg, 0.36 mmol) was added and the mixture was heated to reflux for 2 hours. The reaction solution was concentrated, the solvent was distilled off under reduced pressure, and subjected to silica gel column chromatography with ethyl acetate / hexane (1/9) to give 46 mg (43% overall yield from Example 12) of the desired product. The product was obtained as a colorless oil.

[0079]
Example 15 Synthesis of (2E, 4Z, 6S) -ethyl 6,7-dihydroxy-2,5-dimethyl-2,4-heptadienoate
(2E, 4Z, 6S) -ethyl 6-hydroxy-2,5-dimethyl-7-trityloxy-2,4-heptadienoate (30 mg, 0.066 mmol) obtained in Example 13 was added to ethanol (1 0.5 ml), p-toluenesulfonic acid (0.57 mg, 0.0033 mmol) was added, and the mixture was stirred at room temperature for 4 hours 30 minutes. A saturated aqueous sodium bicarbonate solution (10 ml) was added to the reaction mixture, and the mixture was extracted with methylene chloride (60 ml × 3), washed with saturated brine (40 ml), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel column chromatography with methanol / chloroform (1/9) to give 14.4 mg (99%) of the desired product.
¹H-NMR (300 MHz, CDCl₃, TMS) δ:
1.31 (3H, t, J = 7Hz), 1.98 (6H, s), 2.25 (1H, br.s),
3.54 (3H, m), 4.22 (2H, q, J = 7Hz), 4.92 (1H, m),
6.22 (1H, d, J = 12Hz), 7.46 (1H, d, J = 12Hz).
¹³C-NMR (75Hz, CDCl₃, TMS) δ:
168.9 (s), 145.4 (s), 132.3 (d), 126.4 (s), 122.9 (d),
71.2 (d), 65.3 (t), 60.7 (t), 19.7 (q), 18.2 (s), 14.2 (q),
12.2 (q).
IR (Neat): 3397, 1700, 1629, 1598, 1261,1111 cm^-1
[α]^D ₂₃: -19.5 ° (c = 1.08, CHCl₃)
[0080]
Example 16 Synthesis of (2E, 4Z, 6S) -ethyl 6,7-dihydroxy-2,5-dimethyl-2,4-heptadienoate
(2E, 4Z, 6S) -Ethyl 7-t-butyldimethylsilyloxy-6-hydroxy-2,5-dimethyl-2,4-heptadienoate (24 mg, 0.073 mmol) obtained in Example 14 Was dissolved in tetrahydrofuran (1 ml), tetrabutylammonium fluoride (0.087 ml, 0.087 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous ammonium chloride solution (5 ml) was added to the reaction mixture, and the mixture was extracted with methylene chloride (10 ml × 3), washed with saturated brine (10 ml), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel column chromatography with methanol / chloroform (1/9) to give 15 mg (97%) of the desired product.
¹H-NMR (300 MHz, CDCl₃, TMS) δ:
1.31 (3H, t, J = 7Hz), 1.98 (6H, s), 2.25 (1H, br.s),
3.54 (3H, m), 4.22 (2H, q, J = 7Hz), 4.92 (1H, m),
6.22 (1H, d, J = 12Hz), 7.46 (1H, d, J = 12Hz).
¹³C-NMR (75Hz, CDCl₃, TMS) δ:
168.9 (s), 145.4 (s), 132.3 (d), 126.4 (s), 122.9 (d),
71.2 (d), 65.3 (t), 60.7 (t), 19.7 (q), 18.2 (s),
14.2 (q), 12.2 (q).
IR (Neat): 3397, 1700, 1629, 1598, 1261, 1111 cm^-1.
[α]^D ₂₃: -19.5 (c = 1.08, CHCl₃).
[0081]
Example 17 Synthesis of (2E, 4Z, 6S) -ethyl 6-hydroxy-2,5-dimethyl-7-p-toluenesulfonyloxy-2,4-heptadienoate
(2E, 4Z, 6S) -ethyl 6,7-dihydroxy-2,5-dimethyl-2,4-heptadienoate (180 mg, 0.84 mmol) was added to methylene chloride (0.5 ml) and pyridine (0.17 ml). , 1.68 mmol) and cooled to 0 ° C., tosyl chloride (160 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with methylene chloride (20 ml), washed with 10% aqueous copper sulfate solution (20 ml) and saturated brine (20 ml), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate / hexane ( 2/8) and subjected to silica gel column chromatography to give 296 mg (95%) of the desired product.

[0082]
Example 18 Synthesis of (2E, 4Z, 6S) -ethyl 6,7-epoxy-2,5-dimethyl-2,4-heptadienoate
(2E, 4Z, 6S) -ethyl 6-hydroxy-2,5-dimethyl-7-p-toluenesulfonyloxy-2,4-heptadienoate (300 mg, 0.81 mmol) was dissolved in acetone (10 ml). , Potassium carbonate (562 mg, 4.07 mmol) was added, and the mixture was heated to reflux for 7 hours. The reaction solution was concentrated and the solvent was distilled off under reduced pressure, diluted with methylene chloride (100 ml), washed with water (50 ml) and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel column chromatography with ethyl acetate / hexane (2/8) to give the desired 6,7-epoxy compound (150 mg, 93%) as a colorless oil.

[0083]
Reference Example 20 Synthesis of 3-bromo-2-propyn-1-ol
An aqueous solution (200 ml) of calcium hydroxide (18.5 g, 0.25 mol) was cooled to 0 ° C., and bromine (7.7 ml, 0.15 mol) was added dropwise. Diethyl ether was added to the solution, cooled to −8 ° C., and propargyl alcohol (7.3 g, 0.13 mol) was gradually added dropwise. The mixture was then warmed to room temperature and stirred for 3 hours, cooled to 0 ° C., sodium thiosulfate (5.2 g) was added, and the mixture was stirred for 20 minutes. Concentrated hydrochloric acid (25 ml) was added to the reaction solution to dissolve the solid, and the reaction solution was extracted with diethyl ether (150 ml × 4). The organic layer was washed with 10% aqueous sodium carbonate solution (50 ml) and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure and distilled (3 mmHg, 48 ° C.) to give 3-bromo-2-propin-1-ol ( 4.4 g, 25%) was obtained as a colorless oil.
[0084]
Reference Example 21 Synthesis of (E) -3-bromo-2-propen-1-ol
Under a nitrogen stream, diethyl ether (10 ml) was slowly added dropwise to lithium aluminum hydride (0.57 g, 15 mmol) and aluminum chloride (1.49 g, 11 mmol) at −5 ° C., and then 3-bromo-2-propyne-1 -All (1.0 g, 7.5 mmol) was slowly added dropwise at -5 ° C and then heated to reflux for 3 hours. Water (10 ml) was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted with diethyl ether (30 ml × 3) and washed with a saturated aqueous sodium bicarbonate solution (30 ml). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was distilled (18 mmHg, 78 ° C.) to give (E) -3-bromo-2-propen-1-ol (407 mg, 40%). Obtained as a colorless oil.
[0085]
Reference Example 22 Synthesis of (E) -1-bromo-3-t-butyldiphenylsilyloxy-1-propene
To a solution of (E) -3-bromo-2-propen-1-ol (407 mg, 3 mmol) and imidazole (283 mg, 4.2 mmol) in methylene chloride (50 ml) at 0 ° C., TBDPSCl (976 mg, 4 mmol) and 4-dimethyl Aminopyridine (36 mg) was added and stirred for 4 hours. The reaction solution was diluted with methylene chloride (50 ml), washed with water (50 ml), extracted from this aqueous layer with methylene chloride (60 ml × 3), and the organic layers were combined and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was distilled (2 mmHg, 230 ° C.) to give the desired product (1.29 g, 97%) as a colorless oil.
[0086]
Reference Example 23 Synthesis of (E) -5-t-butyldiphenylsilyloxy-3-penten-1-yne
(E) -1-Bromo-3-tert-butyldiphenylsilyloxy-1-propene (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (9 ml), and ethynylmagnesium chloride (4.8 ml, 2.34 mmol) was dissolved therein. Was added.
Separately, tris (dibenzylideneacetone) dipalladium (0) -chloroform adduct (24 mg) and triphenylphosphine (48 mg) were dissolved in tetrahydrofuran (6 ml), and it was confirmed that the solution changed from purple to yellow. The palladium solution was added to the previous reaction solution and heated to reflux for 7 hours. The reaction mixture was diluted with ether, washed with saturated ammonium chloride (60 ml) and saturated brine (60 ml), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography with ethyl acetate / hexane (1/16) to give the desired product (175.5 mg, 50%) as a yellow oil.
¹H-NMR (300MHz, CDCl₃, TMS) δ:
1.05 (9H, s), 2.88 (1H, m), 4.24 (2H, m),
5.91 (1H, dd, J = 2Hz, 16Hz), 6.29 (1H, td, J = 4Hz, J = 16Hz),
7.40 (6H, m), 7.65 (4H, m).
¹³C-NMR (75MHz, CDCl₃) δ:
143.8 (s), 135.4 (d), 131.2 (s), 129.7 (d), 127.7 (d),
107.6 (d), 83.0 (s), 77.8 (d), 63.4 (t), 26.7 (q), 20.3 (s).
IR (Neat): 3292, 2105, 953, 1113, 954 cm^-1.
[0090]
【The invention's effect】
  The present invention relates to a boncrekinic acid C which is a boncrekinic acid precursor for providing a practical and simple method for synthesizing boncrequinic acid.₁~ C₁₀Segment (left half of boncrekinic acid molecule) and boncrekinic acid C ₁₆ ~ C₂₂Segment (right half of boncrekinic acid moleculePart of) Is practical and efficient, and according to the method of the present invention, it is possible to supply a large amount of boncrekinic acid. In addition, the possibility of developing into a therapeutic agent for many diseases by derivative synthesis is also fully considered, so it is a very large invention that contributes to this industry.

Claims (25)

Below (1) _C 1 _{-C 10} segment manufacturing method of bongkrekic acid process comprising to (8).
(1) General formula [1]

[Wherein R ¹ is

(However, R ² represents a benzyl group, an isopropyl group, or a methyl group, and R ³ and R ⁴ each independently represent a hydrogen atom or a phenyl group.)
Or

Represents. The compound represented by the general formula [2]

(Wherein R ⁵ represents t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxy group) It represents a methyl group, an acetyl group or a methoxyethoxymethyl group, and X ¹ represents a halogen atom).

(In the formula, R ¹ and R ⁵ are the same as above.)
The process made into the compound shown by these.
(2) The compound represented by the general formula [3] obtained in the above (1) is reduced to give a general formula [4].

(In the formula, R ⁵ is the same as above.)
The process which makes it the alcohol body shown by.
(3) The alcohol obtained in (2) above is oxidized to give the general formula [5]

(In the formula, R ⁵ is the same as above.)
And then having the general formula [6]

(Wherein R ⁸ and R ⁹ each independently represents an alkyl group. R ⁸ and R ⁹ may be combined to form an alkylene group.) Reaction with an ester gives the general formula [7]

(In the formula, R ⁵ , R ⁸ and R ⁹ are the same as above.)
The process which makes the boronic ester body shown by these.
(4) The boronic ester obtained in (3) above is represented by the general formula [8]

(In the formula, R ⁶ represents t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxy group) A methyl group, an acetyl group or a methoxyethoxymethyl group.) And a compound represented by the general formula [9]

(Wherein R ⁵ and R ⁶ are the same as above, provided that R ⁵ ≠ R ⁶ )
The process made into the coupling body shown by.
(5) The coupling body obtained in the above (4) is represented by the general formula [10].

(Wherein R ⁷ represents t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxy group) It represents a methyl group, an acetyl group or a methoxyethoxymethyl group, and X ² represents a halogen atom).

(Wherein R ⁵ , R ⁶ and R ⁷ are the same as above, provided that R ⁵ ≠ R ⁶ and R ⁵ ≠ R ⁷ ).
The process made into the compound shown by these.
(6) The protecting group R ⁵ at the 10-position hydroxyl group of the compound represented by the general formula [11] obtained in the above (5) is deprotected to give the general formula [12]

(Wherein R ⁶ and R ⁷ are the same as described above), and the step of making an allyl alcohol form. (7) The hydroxyl group of the allyl alcohol obtained in (6) above is substituted with halogen to give a compound of the general formula [13]

(Wherein X ³ represents a halogen atom, and R ⁶ and R ⁷ are the same as described above.)
A process for producing a halogen compound represented by
(8) The halogen compound obtained in (7) above is represented by the general formula [14].

(In the formula, R ¹⁰ represents a lower alkyl group or an aryl group, and M represents an alkali metal atom).

(In the formula, R ⁶ , R ⁷ and R ¹⁰ are the same as above.)
The process which makes a sulfone body shown by.   In the step (1), the compound represented by the general formula [1] is lithiated or sodiumated, then reacted with the compound represented by the general formula [2], and the compound represented by the general formula [3] The manufacturing method according to claim 1.   The production method according to claim 1 or 2, wherein in the step (2), the compound represented by the general formula [3] is reduced with lithium aluminum hydride to obtain a compound represented by the general formula [4].   In the step (3), an alcohol form represented by the general formula [4] is reacted with oxalyl chloride, dimethyl sulfoxide and a base to obtain an aldehyde form represented by the general formula [5]. The manufacturing method in any one of Claims 1-3 by making it react with the dichloromethyl boronic ester shown, and making it the boronic ester body shown by General formula [7].   The production method according to claim 4, wherein the aldehyde is reacted with dichloromethyl boronic ester in the presence of anhydrous chromium chloride and anhydrous lithium iodide.   In the step (4), a boronic ester represented by the general formula [7] is reacted with a compound represented by the general formula [8] in the presence of a palladium complex catalyst and an alkali, and represented by the general formula [9]. The manufacturing method according to any one of claims 1 to 5, wherein the coupling body is made.   In the step (5), a coupling product represented by the general formula [9] is reacted with a compound represented by the general formula [10] in the presence of a base to obtain a compound represented by the general formula [11]. Item 7. The production method according to any one of Items 1 to 6.   In the step (7), the hydroxyl group of the allyl alcohol form is substituted with chlorine using carbon tetrachloride and triphenylphosphine to obtain a halogen form represented by the general formula [13]. Manufacturing method. General formula [7]

(Wherein R ⁵ represents t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxy group) Represents a methyl group, an acetyl group or a methoxyethoxymethyl group, and R ⁸ and R ⁹ each independently represents an alkyl group, and R ⁸ and R ⁹ may together form an alkylene group. In the presence of a palladium complex catalyst and an alkali, the compound represented by the general formula [8]

(In the formula, R ⁶ represents t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxy group) (Represents a methyl group, an acetyl group or a methoxyethoxymethyl group).

(In the formula, R ⁵ and R ⁶ are the same as above.)
The manufacturing method of the compound shown by these. General formula [9]

(In the formula, R ⁵ and R ⁶ are each independently t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group. Represents a tetrahydropyranyl group, a methoxymethyl group, an acetyl group or a methoxyethoxymethyl group.)
A compound represented by The compound according to claim 10, wherein R ⁵ is a t-butyldiphenylsilyl group and R ⁶ is a p-methoxyphenylmethyl group. General formula [9]

(In the formula, R ⁵ and R ⁶ are each independently t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group. Represents a tetrahydropyranyl group, a methoxymethyl group, an acetyl group or a methoxyethoxymethyl group.) In the presence of a base, the compound represented by the general formula [10]

(Wherein R ⁷ represents t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, methoxy group) It represents a methyl group, an acetyl group or a methoxyethoxymethyl group, and X ² represents a halogen atom.), And is reacted with a compound represented by the general formula [11]

(In the formula, R ⁵ , R ⁶ and R ⁷ are the same as above.)
The manufacturing method of the compound shown by these. The production method according to claim 12, wherein R ⁵ is a t-butyldiphenylsilyl group, R ⁶ is a p-methoxyphenylmethyl group, and R ⁷ is a methoxymethyl group. General formula [11]

(Wherein R ⁵ , R ⁶ and R ⁷ are each independently t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, Represents a benzyl group, a tetrahydropyranyl group, a methoxymethyl group, an acetyl group or a methoxyethoxymethyl group.)
A compound represented by The compound according to claim 14, wherein R ⁵ is a t-butyldiphenylsilyl group, R ⁶ is a p-methoxyphenylmethyl group, and R7 is a methoxymethyl group. General formula [11]

(Wherein R ⁵ , R ⁶ and R ⁷ are each independently t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, wherein the deprotection of the protecting group R ⁵ of the 10-position of the hydroxyl groups of methoxymethyl group, a compound represented by the representative.) the acetyl group or methoxyethoxymethyl group, the general formula [ 12]

(Wherein R ⁶ and R ⁷ are the same as described above). The production method according to claim 16, wherein the protecting group R ^{5 for} the hydroxyl group at the 10-position of the compound represented by the general formula [11] is a t-butyldiphenylsilyl group, which is deprotected using tetrabutylammonium fluoride. . Formula [12]

(Wherein R ⁶ and R ⁷ are each independently t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, Represents a tetrahydropyranyl group, a methoxymethyl group, an acetyl group or a methoxyethoxymethyl group.)
A compound represented by Formula [12]

(Wherein R ⁶ and R ⁷ are each independently t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, A tetrahydropyranyl group, a methoxymethyl group, an acetyl group or a methoxyethoxymethyl group.), Wherein the hydroxyl group of the compound represented by the general formula [13]

(Wherein X ³ represents a halogen atom, and R ⁶ and R ⁷ are the same as described above.)
The manufacturing method of the compound shown by these.   The production method according to claim 19, wherein chlorine substitution is performed using carbon tetrachloride and triphenylphosphine. Formula [13]

(Wherein R ⁶ and R ⁷ are each independently t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, Represents a tetrahydropyranyl group, a methoxymethyl group, an acetyl group or a methoxyethoxymethyl group, and X ³ represents a halogen atom.)
A compound represented by The compound according to claim 21, wherein R ⁶ is a p-methoxyphenylmethyl group, R ⁷ is a methoxymethyl group, and X ³ is a chlorine atom. Formula [13]

(Wherein R ⁶ and R ⁷ are each independently t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, Represents a tetrahydropyranyl group, a methoxymethyl group, an acetyl group or a methoxyethoxymethyl group, and X ³ represents a halogen atom.) A compound represented by the general formula [14]

(Wherein R ¹⁰ represents a lower alkyl group or an aryl group, and M represents an alkali metal atom), and is reacted with a sulfinate represented by the general formula [15]

(In the formula, R ⁶ , R ⁷ and R ¹⁰ are the same as above.)
The manufacturing method of the compound shown by these. General formula [15]

(Wherein R ⁶ and R ⁷ are each independently t-butyldiphenylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, triethylsilyl group, trimethylsilyl group, p-methoxyphenylmethyl group, benzyl group, tetrahydropyranyl group, a methoxymethyl group, an acetyl group or a methoxyethoxymethyl group, R ¹⁰ is a lower alkyl group, or a phenyl group, a tolyl group, a xylyl group, an aryl selected from the group consisting of naphthyl and methylnaphthyl group Represents a group.)
A compound represented by The compound according to claim 24, wherein R ⁶ is a p-methoxyphenylmethyl group, R ⁷ is a methoxymethyl group, and R ¹⁰ is a phenyl group.