JP4283377B2 - Asymmetric epoxidation catalyst for enones and method for producing optically active epoxide using the same - Google Patents

Description

【０００７】
（式中、Ｒ₁、Ｒ₂は各々独立して、炭素数１〜２０の直鎖状、分枝状若しくは環式のアルキル基、芳香族基、炭素数１〜５のアルキル基で１〜５置換された芳香族基、炭素数１〜５のアルコキシ基で１〜５置換された芳香族基、ハロゲン元素で１〜５置換された芳香族基、芳香族基で置換された炭素数１〜５の直鎖状、分枝状若しくは環式アルキル基、又はハロゲン化芳香族基で置換された炭素数１〜５の直鎖状、分枝状若しくは環式アルキル基を表わす。）
で示されるエノン類と酸化剤を反応させることを特徴とする下記一般式（２）
【０００８】
【化４】

【０００９】
（式中、Ｒ₁、Ｒ₂は前記と同じ定義であり、＊印は光学活性炭素を示す。）
で示される光学活性エポキシドの製造方法である。
【００１０】
本発明を以下詳細に説明する。
【００１１】
本発明の触媒は、（Ａ）ビナフトールと、（Ｂ）ランタントリイソプロポキシドと、（Ｃ）ルチジン−Ｎ−オキサイド、１，３−ジメチル−２−イミダゾリジノン、ヘキサメチルホスホルトリアミド、トリフェニルフォスフィンオキサイド、トリ（２−メチルフェニル）フォスフィンオキサイド又はトリ（４−メチルフェニル）フォスフィンオキサイドを含有する。
【００１２】
本発明において、ビナフトールとしては、（Ｒ）−ビナフトール、（Ｓ）−ビナフトールが挙げられる。
【００１３】
本発明の触媒の構成比は、特に限定するものでないが、（Ｂ）ランタンイオン１モルに対して、（Ａ）ビナフトールが通常１〜３モル、（Ｃ）ルチジン−Ｎ−オキサイド、１，３−ジメチル−２−イミダゾリジノン、ヘキサメチルホスホルトリアミド、トリフェニルフォスフィンオキサイド、トリ（２−メチルフェニル）フォスフィンオキサイド又はトリ（４−メチルフェニル）フォスフィンオキサイドが通常０．１〜１０モル、好ましくは１〜１０モルである。
【００１４】
本発明の触媒は、エノン類の不斉エポキシ化反応に利用可能であり、高い反応性を示し、また生成物に高い光学純度を与える。
【００１５】
本発明の触媒を用い反応させることにより発現する光学絶対配置は、一般的には、触媒を構成するビナフトールの光学絶対配置に依存し、（Ｒ）−ビナフトールを用いた場合に、生成物の不斉炭素の光学絶対配置が（Ｒ）体になる基質は、（Ｓ）−ビナフトールを用いれば、生成物の不斉炭素の光学絶対配置は（Ｓ）体になる関係にある。但し、（Ｒ）−ビナフトールを用いれば、生成物の不斉炭素の光学絶対配置が（Ｒ）体になるというわけではなく、基質の種類等によって生成物の光学絶対配置は異なる。本発明の触媒を用いて不斉エポキシ化反応を行った場合、一般的には、（Ｒ）−ビナフトールを用いれば、生成するエノンのエポキシドの２位（α位）と３位（β位）の光学絶対配置は（２Ｓ，３Ｒ）になり、一方、（Ｓ）−ビナフトールを用いれば、（２Ｒ，３Ｓ）になる。
【００１６】
本発明の方法において、触媒の使用量は特に限定するものではないが、反応に具される基質に対して、ランタンイオンのモル数を基準として、０．０１〜５０モル％、さらに好ましくは０．１〜２５モル％の範囲である。
【００１７】
本発明の方法に適用可能な溶剤としては触媒及びエポキシ化反応に不活性溶剤であればあらゆる溶剤が適用可能であるが、触媒の安定性、エポキシ化反応の反応成績の面でジメチルエーテル、ジイソプロピルエーテル、１，２−ジメトキシエタン、テトラヒドロフラン（以下ＴＨＦと略す）等のエーテル系溶剤が好ましく、中でも最も高結果を与えるのはＴＨＦである。
【００１８】
溶剤の使用量としては、反応に具するエノンに対して重量換算で２〜２００倍量、さらに好ましくは５〜１００倍量の範囲である。
【００１９】
本発明の方法に適用可能なエノンとしては、下記一般式（１）
【００２０】
【化５】

【００２１】
（式中、Ｒ₁、Ｒ₂は各々独立して、炭素数１〜２０の直鎖状、分枝状若しくは環式のアルキル基、芳香族基、炭素数１〜５のアルキル基で１〜５置換された芳香族基、炭素数１〜５のアルコキシ基で１〜５置換された芳香族基、ハロゲン元素で１〜５置換された芳香族基、芳香族基で置換された炭素数１〜５の直鎖状、分枝状若しくは環式アルキル基、又はハロゲン化芳香族基で置換された炭素数１〜５の直鎖状、分枝状若しくは環式アルキル基を表わす。）
で示される化合物であればあらゆるものが適用可能であるが、具体的には、メチルビニルケトン、ｔｒａｎｓ−３−ペンテン−２−オン、ｔｒａｎｓ−３−ヘキセン−２−オン、ｔｒａｎｓ−３−ヘプテン−２−オン、ｔｒａｎｓ−３−オクテン−２−オン、ｔｒａｎｓ−３−ノネン−２−オン、エチルビニルケトン、ｔｒａｎｓ−４−ヘキセン−３−オン、ｔｒａｎｓ−４−へプテン−３−オン、ｔｒａｎｓ−４−オクテン−３−オン、ｔｒａｎｓ−４−ノネン−３−オン、イソプロピルビニルケトン、ｔｒａｎｓ−２−メチル−４−ヘキセン−３−オン、ｔｒａｎｓ−２−メチル−４−へプテン−３−オン、ｔｒａｎｓ−２−メチル−４−オクテン−３−オン、ｔｒａｎｓ−２−メチル−４−ノネン−３−オン、ｔｒａｎｓ−１，３−ジフェニル−２−プロピレンン−１−オン（カルコン）、ｔｒａｎｓ−２−メチル−５−フェニル−４−ペンテン−３−オン、４−メチル−１−フェニル−３−ペンテン−２−オン、４−フェニル−３−ブチレン−２−オン、６−フェニル−３−へキセン−２−オン、５−フェニル−３−ヘキセン−２−オン等が挙げられる。
【００２２】
本発明の方法において酸化剤として使用するＴＢＨＰは、市販のデカン等の溶液をそのまま用いても良いし、７０％又は９０％水溶液よりトルエン抽出し、硫酸マグネシウム等で乾燥の後、本発明に使用しても良い。また、ＴＢＨＰにこだわることなくクメンハイドロパーオキサイド等の他の酸化剤を用いても何等支障はなく、さらに、反応基質の種類によっては、クメンハイドロパーオキサイドを用いることによりほぼ定量的に純粋な光学活性体を与える場合もある。
【００２３】
酸化剤の使用量は、反応に具するエノンに対して理論的には等量で充分であるが、反応を完結させるために好ましくは１．１モル倍量以上使用する。
【００２４】
本発明の方法における反応温度は、エノンの基質の違いにより異なるが、通常−５０℃〜１００℃の範囲でき、反応時間としては、通常２４時間以内で反応が完結し、特にトリフェニルフォスフィンオキサイドを用いた場合においては、多くの場合において２時間以内に反応が完結する。
【００２５】
触媒調製時及び反応時に系内を脱水し、また触媒形成反応、エポキシ化反応を加速する目的で、必要に応じてゼオライトをエノンに対してあらゆる量比で使用可能であるが、通常エノン１ｍｍｏｌに対して１０ｍｇ〜２ｇ程度、好ましくは等重量程度使用する。ゼオライトの種類としてはモレキューラシーブ３Ａ、４Ａ、５Ａに代表されるＡ型ゼオライト、モレキュラシーブ１３Ｘ、Ｙ型、Ｌ型等様々なゼオライトが適用可能であるが、モレキューラシーブ４Ａが好ましい。
【００２６】
反応終了後、後処理、カラムクロマトグラフィー等で精製を行うことにより、目的物のα，β−エポキシケトンを高収率、高光学純度で得る。
【００２７】
【発明の効果】
本発明の触媒により、高反応性、高収率かつ高光学純度でのエノン類の不斉エポキシ化反応が提供されるので、本発明は各種医農薬中間体の製造方法として極めて有用である。
【００２８】
【実施例】
以下実施例により本発明を具体的に説明するが、本発明は実施例のみに限定されるものではない。なお、生成物の光学純度の検定は、以下のとおり実施した。
【００２９】
すなわち、ダイセル（株）のキラルカラムＯＢ−Ｈ又はＡＤを装着した高速液体クロマトグラフィーで行い、溶離溶媒：Ｈｅｘａｎｅ／ｉ−ＰｒＯＨ＝２／１〜１００／１（ｖｏｌ／ｖｏｌ）、流量１ｍｌ／ｍｉｎで測定した。
【００３０】
ｔｒａｎｓ−２，３−エポキシ−１，３−ジフェニルプロパン−１−オンの場合、キラルカラムＯＢ−Ｈを用い、溶離溶媒：Ｈｅｘａｎｅ／ｉ−ＰｒＯＨ＝２／１、流量１ｍｌ／ｍｉｎの条件下で、保持時間２４分に（２Ｓ，３Ｒ体）、３２分に（２Ｒ，３Ｓ体）の各エナンチオマーのピークが出現した。
【００３１】
実施例１
１０ｍｌのナス型フラスコにモレキュラーシーブス４Ａ（５０６ｍｇ）を入れ、真空ポンプで減圧下、ヒートガンで３０分加熱し、乾燥させた。室温まで冷却の後、トリフェニルフォスフィンオキサイド（２１．２ｍｇ、０．０７５８ｍｍｏｌ）、（Ｒ）−ビナフトール（７．２ｍｇ、０．０２５１ｍｍｏｌ）及びマグネチックスタラーチップを入れ反応系をアルゴンガスで置換した。次いで、ＴＨＦ（１ｍｌ）を加え、５分攪拌することにより溶解させた後、ランタンイソプロポキシド（Ｌａ（Ｏ−ｉＰｒ）３、８．０ｍｇ、０．０２５３ｍｍｏｌ）のＴＨＦ溶液（１．５２ｍｌ）を加え、１時間攪拌することにより触媒溶液を調製した。
【００３２】
得られた触媒溶液に、ＴＢＨＰのデカン溶液（５Ｍ、０．１５ｍｌ、０．７６ｍｍｏｌ）を加え３０分攪拌した後、カルコン（１０５．４ｍｇ、０．５０６ｍｍｏｌ）のＴＨＦ（１ｍｌ）溶液を加え反応を行った。反応の進行はシリカゲル薄層クロマトグラフィーにより、３０分後に終了したことを確認した。
【００３３】
反応終了後、シリカゲル５００ｍｇ、メタノール３ｍｌを添加し１５分攪拌し、次いで濾過、濃縮することにより残査を得、シリカゲルカラム（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３０／１）で精製精製することによりｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−１，３−ジフェニルプロパン−１−オンを無色透明なオイルして得た（収量：１１２．４ｍｇ、収率：９９％、光学純度：９６％ｅｅ）。
【００３４】
実施例２
実施例１と同じ反応装置を用い、トリフェニルフォスフィンオキサイドをトリ（４−メチルフェニル）フォスフィンオキサイド（２４．４ｍｇ、０．０７５８ｍｍｏｌ）に変えた以外は実施例１と同じ操作を行い触媒溶液を調製した。得られて触媒溶液を用い実施例１と同様にカルコンのエポキシ化反応を行い、３０分の反応でｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−１，３−ジフェニルプロパン−１−オン：１０７．８ｍｇを得た（収率：９５％、光学純度９４％ｅｅ、無色透明液体）。
【００３６】
実施例４
実施例１と同じ反応装置を用い、トリフェニルフォスフィンオキサイドをルチジン−Ｎ−オキサイドに変えた以外は実施例１と同じ操作を行い、３．０時間の反応で、ｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−１，３−ジフェニルプロパン−１−オンを収率９６％、光学純度７４％ｅｅで得た。
【００３７】
実施例５
実施例１と同じ反応装置を用い、トリフェニルフォスフィンオキサイドを１，３−ジメチル−２−イミダゾリノンに変えた以外は実施例１と同じ操作を行い、３．０時間の反応で、ｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−１，３−ジフェニルプロパン−１−オンを収率９７％、光学純度６８％ｅｅで得た。
【００３８】
実施例６
実施例１と同じ反応装置を用い、トリフェニルフォスフィンオキサイドをトリ（２−メチルフェニル）フォスフィンオキサイドに変えた以外は実施例１と同じ操作を行い、１．５時間の反応で、ｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−１，３−ジフェニルプロパン−１−オンを収率９６％、光学純度７３％ｅｅで得た。
【００３９】
比較例１
実施例１と同じ反応装置を用い、トリフェニルフォスフィンオキサイドを添加しない以外は実施例１と同じ試剤を用いて同様の操作を行い、３時間反応で、ｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−１，３−ジフェニルプロパン−１−オンを収率８６％、光学純度７３％ｅｅで得た。
【００４０】
実施例７
実施例１と同じ反応装置を用い、実施例１と同じ触媒溶液を調製した。用いるエノンをカルコンからｔｒａｎｓ−２−メチル−５−フェニル−４−ペンテン−３−オン（８７．７ｍｇ）に変更した以外同じ操作を行い、１２時間の反応でｔｒａｎｓ−（４Ｓ，５Ｒ）−エポキシ−２−メチル−５−フェニルペンタン−３−オン：６４．２ｍｇを得た（収率：６７％、光学純度：９６％ｅｅ、無色透明液体）。
【００４１】
実施例８
実施例１と同じ反応装置を用い、実施例１と同じ触媒溶液を調製した。用いるエノンをカルコンからｔｒａｎｓ−４−メチル−１−フェニル−２−ペンテン−１−オン（８７．７ｍｇ）に変更した以外同じ操作を行い、１時間の反応でｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−４−メチル−１−フェニルペンタン−１−オン：８５．２ｍｇを得た（収率：８９％、光学純度：９３％ｅｅ、無色透明液体）。
【００４２】
実施例９
実施例１と同じ反応装置を用い、実施例１と同じ触媒溶液を調製した。用いるエノンをカルコンからｔｒａｎｓ−４−フェニル−３−ブテン−２−オン（７４．０ｍｇ）に変更した以外同じ操作を行い、６時間の反応でｔｒａｎｓ−（３Ｓ，４Ｒ）−エポキシ−４−フェニルブタン−２−オン：７５．５ｍｇを得た（収率：９２％、光学純度：９３％ｅｅ、無色透明液体）。
【００４３】
実施例１０
実施例１と同じ反応装置を用い、実施例１と同じ触媒溶液を調製した。用いるエノンをカルコンからｔｒａｎｓ−６−フェニル−３−ヘキセン−２−オン（８８．２ｍｇ）に変更した以外同じ操作を行い、１時間の反応でｔｒａｎｓ−（３Ｓ，４Ｒ）−エポキシ−６−フェニルヘキサン−１−オン：８８．６ｍｇを得た（収率：９２％、光学純度：８７％ｅｅ、無色透明液体）。
【００４４】
実施例１１
実施例１と同じ反応装置を用い、ＴＢＨＰをクメンハイドロパーオキサイドにに変更した以外は実施例１と同じ操作を行い、１時間の反応でｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−１，３−ジフェニルプロパン−１−オンを収率９５％、光学純度：９９％ｅｅで得た。
【００４５】
実施例１２
実施例１と同じ反応装置を用い、モレキュラーシーブ−４Ａの使用量を５０６ｍｇから１００ｍｇに変更し、ＴＢＨＰをクメンハイドロパーオキサイドにに変更した以外は実施例１と同じ操作を行い、１０分の反応でｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−１，３−ジフェニルプロパン−１−オンを収率９７％、光学純度：９９．８％ｅｅで得た。
【００４６】
実施例１３
実施例１と同じ反応装置を用い、モレキュラーシーブ−４Ａの使用量を５０６ｍｇから２５ｍｇに変更し、ＴＢＨＰをクメンハイドロパーオキサイドにに変更した以外は実施例１と同じ操作を行い、１５分の反応でｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−１，３−ジフェニルプロパン−１−オンを収率９７％、光学純度：９９．８％ｅｅで得た。
【００４７】
実施例１４
実施例１と同じ反応装置を用い、トリフェニルフォスフィンオキサイドの使用量を２１．２ｍｇから７．０ｍｇに変更した以外は実施例１と同じ操作を行い、１時間の反応でｔｒａｎｓ−（２Ｓ，３Ｒ）−エポキシ−１，３−ジフェニルプロパン−１−オンを収率９１％、光学純度：９３％ｅｅで得た。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an asymmetric epoxidation catalyst for enones and a method for producing an optically active epoxide using the same.
[0002]
[Prior art]
As an asymmetric epoxidation reaction of enones, a compound having a carbon-carbon double bond adjacent to a carbonyl group such as chalcone in the presence of a complex catalyst prepared from a tetrahydrofuran solution of an optically active dihydroxy compound and a rare earth metal alkoxide. A method of asymmetric epoxidation with a hydroxy peroxide compound is known. Specifically, a tetrahydrofuran solution of (R) -binaphthol and lanthanum triisopropoxide is used as a (R) -lanthanum-binaphthoxide complex in the reaction. (JP-A-10-120668).
[0003]
[Problems to be solved by the invention]
However, in the method described in JP-A-10-120668, for example, when tert-butyl hydroperoxide (hereinafter abbreviated as TBHP) is used as the oxidizing agent, the target optically active epoxide is low in yield and low optical properties. It can only be obtained with purity. For this reason, in order to obtain satisfactory results, it was necessary to use binaphthol into which methylol was introduced at the 3-position, and to use cumene hydroperoxide (hereinafter abbreviated as CMHP) which is a special oxidizing agent.
[0004]
[Means for Solving the Problems]
As a result of intensive studies on the development of a catalyst having high reactivity and high optical purity, the present inventors have found that (A) binaphthol, (B) lanthanum triisopropoxide, and (C) lutidine-N-oxide, Selected from the group consisting of 1,3-dimethyl-2-imidazolidinone, hexamethylphosphortriamide, triphenylphosphine oxide, tri (2-methylphenyl) phosphine oxide and tri (4-methylphenyl) phosphine oxide The present invention has been completed by finding an asymmetric epoxidation catalyst of enones characterized by containing one of the above.
[0005]
That is, the present invention provides an asymmetric epoxidation catalyst of the above enones and the following general formula (1) in the presence of this catalyst.
[0006]
[Chemical 3]

[0007]
Wherein R ₁ and R ₂ are each independently a linear, branched or cyclic alkyl group having 1 to 20 carbon atoms, an aromatic group, or an alkyl group having 1 to 5 carbon atoms. 5 substituted aromatic groups, 1-5 substituted aromatic groups with 1-5 carbon atoms, 1-5 substituted aromatic groups with halogen elements, 1 carbon substituted with aromatic groups Represents a linear, branched or cyclic alkyl group having 5 to 5 carbon atoms, or a linear, branched or cyclic alkyl group having 1 to 5 carbon atoms substituted with a halogenated aromatic group.
The following general formula (2), characterized by reacting an enone represented by the formula (1) with an oxidizing agent
[0008]
[Formula 4]

[0009]
(In the formula, R ₁ and R ₂ have the same definitions as above, and * indicates optically active carbon.)
It is a manufacturing method of optically active epoxide shown by these.
[0010]
The present invention is described in detail below.
[0011]
The catalyst of the present invention comprises (A) binaphthol, (B) lanthanum triisopropoxide, (C) lutidine-N-oxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphotriamide, trimethyl It contains phenylphosphine oxide, tri (2-methylphenyl) phosphine oxide or tri (4-methylphenyl) phosphine oxide.
[0012]
In the present invention, binaphthol includes (R) -binaphthol and (S) -binaphthol.
[0013]
The composition ratio of the catalyst of the present invention is not particularly limited, but (A) binaphthol is usually 1 to 3 moles per mole of (B) lanthanum ion, (C) lutidine-N-oxide, 1, 3 -Dimethyl-2-imidazolidinone, hexamethylphosphotriamide, triphenylphosphine oxide, tri (2-methylphenyl) phosphine oxide or tri (4-methylphenyl) phosphine oxide is usually 0.1 to 10 mol , Preferably 1 to 10 mol.
[0014]
The catalyst of the present invention can be used for asymmetric epoxidation reaction of enones, exhibits high reactivity, and gives high optical purity to the product.
[0015]
The optical absolute configuration expressed by the reaction using the catalyst of the present invention generally depends on the optical absolute configuration of binaphthol constituting the catalyst. When (R) -binaphthol is used, the product has no When (S) -binaphthol is used as the substrate in which the optical absolute configuration of the asymmetric carbon is in the (R) form, the optical asymmetric configuration of the asymmetric carbon of the product is in the relationship of being in the (S) form. However, when (R) -binaphthol is used, the optical absolute configuration of the asymmetric carbon of the product does not become the (R) isomer, and the optical absolute configuration of the product varies depending on the type of substrate. When an asymmetric epoxidation reaction is carried out using the catalyst of the present invention, generally, when (R) -binaphthol is used, the 2-position (α-position) and 3-position (β-position) of the epoxide of the enone to be produced The optical absolute configuration of (2S, 3R) becomes (2S, 3R), while when (S) -binaphthol is used, it becomes (2R, 3S).
[0016]
In the method of the present invention, the amount of the catalyst used is not particularly limited, but is 0.01 to 50 mol%, more preferably 0, based on the number of moles of lanthanum ion with respect to the substrate included in the reaction. The range is from 1 to 25 mol%.
[0017]
As the solvent applicable to the method of the present invention, any solvent can be used as long as it is an inert solvent for the catalyst and the epoxidation reaction. However, dimethyl ether and diisopropyl ether in terms of the stability of the catalyst and the reaction result of the epoxidation reaction Ether solvents such as 1,2-dimethoxyethane and tetrahydrofuran (hereinafter abbreviated as THF) are preferred, and among them, THF gives the highest results.
[0018]
The amount of the solvent used is in the range of 2 to 200 times, more preferably 5 to 100 times the amount of enone included in the reaction in terms of weight.
[0019]
The enone applicable to the method of the present invention includes the following general formula (1)
[0020]
[Chemical formula 5]

[0021]
Wherein R ₁ and R ₂ are each independently a linear, branched or cyclic alkyl group having 1 to 20 carbon atoms, an aromatic group, or an alkyl group having 1 to 5 carbon atoms. 5 substituted aromatic groups, 1-5 substituted aromatic groups with 1-5 carbon atoms, 1-5 substituted aromatic groups with halogen elements, 1 carbon substituted with aromatic groups Represents a linear, branched or cyclic alkyl group having 5 to 5 carbon atoms, or a linear, branched or cyclic alkyl group having 1 to 5 carbon atoms substituted with a halogenated aromatic group.
Any compound can be used as long as it is a compound represented by the formula: methyl vinyl ketone, trans-3-penten-2-one, trans-3-hexen-2-one, trans-3-heptene. 2-one, trans-3-octen-2-one, trans-3-nonen-2-one, ethyl vinyl ketone, trans-4-hexen-3-one, trans-4-hept-3-one, trans-4-octen-3-one, trans-4-nonen-3-one, isopropyl vinyl ketone, trans-2-methyl-4-hexen-3-one, trans-2-methyl-4-heptene-3 -One, trans-2-methyl-4-octen-3-one, trans-2-methyl-4-nonen-3-one, trans-1,3-di Enyl-2-propylen-1-one (chalcone), trans-2-methyl-5-phenyl-4-penten-3-one, 4-methyl-1-phenyl-3-penten-2-one, 4- Phenyl-3-butylen-2-one, 6-phenyl-3-hexen-2-one, 5-phenyl-3-hexen-2-one and the like can be mentioned.
[0022]
TBHP used as an oxidizing agent in the method of the present invention may be a commercially available decane solution or the like, or extracted with 70% or 90% aqueous solution, dried with magnesium sulfate, etc., and used in the present invention. You may do it. Moreover, there is no problem even if other oxidizing agents such as cumene hydroperoxide are used without sticking to TBHP. Furthermore, depending on the type of reaction substrate, almost quantitatively pure optical can be obtained by using cumene hydroperoxide. In some cases, an active form is given.
[0023]
The amount of the oxidizing agent used is theoretically equivalent to the enone included in the reaction, but it is preferably used in an amount of 1.1 mol times or more in order to complete the reaction.
[0024]
Although the reaction temperature in the method of the present invention varies depending on the enone substrate, it can usually be in the range of −50 ° C. to 100 ° C., and the reaction time is usually completed within 24 hours. In particular, triphenylphosphine oxide. In many cases, the reaction is completed within 2 hours.
[0025]
For the purpose of dehydrating the system at the time of catalyst preparation and reaction, and accelerating the catalyst formation reaction and epoxidation reaction, zeolite can be used in any quantitative ratio with respect to enone as necessary. On the other hand, about 10 mg to 2 g, preferably about equal weight is used. Various types of zeolite such as A-type zeolite represented by molecular sieves 3A, 4A, and 5A, molecular sieve 13X, Y-type, and L-type are applicable as the type of zeolite, but molecular sieve 4A is preferable.
[0026]
After completion of the reaction, purification is carried out by post-treatment, column chromatography or the like to obtain the target α, β-epoxyketone in high yield and high optical purity.
[0027]
【The invention's effect】
Since the catalyst of the present invention provides an asymmetric epoxidation reaction of enones with high reactivity, high yield and high optical purity, the present invention is extremely useful as a method for producing various pharmaceutical and agrochemical intermediates.
[0028]
【Example】
EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited only to the examples. The optical purity of the product was tested as follows.
[0029]
That is, it was performed by high performance liquid chromatography equipped with a chiral column OB-H or AD of Daicel Corporation, and the elution solvent: Hexane / i-PrOH = 2/1 to 100/1 (vol / vol), with a flow rate of 1 ml / min. It was measured.
[0030]
In the case of trans-2,3-epoxy-1,3-diphenylpropan-1-one, a chiral column OB-H is used, and the elution solvent is Hexane / i-PrOH = 2/1, and the flow rate is 1 ml / min. A peak of each enantiomer of (2S, 3R form) appeared at a retention time of 24 minutes and (2R, 3S form) at 32 minutes.
[0031]
Example 1
Molecular sieves 4A (506 mg) was placed in a 10 ml eggplant-shaped flask, dried for 30 minutes with a heat gun under reduced pressure with a vacuum pump, and dried. After cooling to room temperature, triphenylphosphine oxide (21.2 mg, 0.0758 mmol), (R) -binaphthol (7.2 mg, 0.0251 mmol) and a magnetic stirrer chip were added, and the reaction system was replaced with argon gas. . Next, THF (1 ml) was added and dissolved by stirring for 5 minutes, and then a THF solution (1.52 ml) of lanthanum isopropoxide (La (O-iPr) 3, 8.0 mg, 0.0253 mmol) was added. In addition, a catalyst solution was prepared by stirring for 1 hour.
[0032]
TBHP in decane (5M, 0.15 ml, 0.76 mmol) was added to the resulting catalyst solution and stirred for 30 minutes, and then a solution of chalcone (105.4 mg, 0.506 mmol) in THF (1 ml) was added to react. went. The progress of the reaction was confirmed by silica gel thin layer chromatography to be completed after 30 minutes.
[0033]
After completion of the reaction, 500 mg of silica gel and 3 ml of methanol were added and stirred for 15 minutes, followed by filtration and concentration to obtain a residue, which was purified and purified on a silica gel column (Hexane / AcOEt = 30/1) to produce trans- (2S , 3R) -epoxy-1,3-diphenylpropan-1-one was obtained as a colorless and transparent oil (yield: 112.4 mg, yield: 99%, optical purity: 96% ee).
[0034]
Example 2
Using the same reactor as in Example 1, the same operation as in Example 1 was carried out except that triphenylphosphine oxide was changed to tri (4-methylphenyl) phosphine oxide (24.4 mg, 0.0758 mmol). Was prepared. The obtained catalyst solution was used to carry out the epoxidation reaction of chalcone in the same manner as in Example 1, and trans- (2S, 3R) -epoxy-1,3-diphenylpropan-1-one: 107.8 mg after 30 minutes of reaction. (Yield: 95%, optical purity 94% ee, colorless and transparent liquid).
[0036]
Example 4
Using the same reaction apparatus as in Example 1, except that triphenylphosphine oxide was changed to lutidine-N-oxide, the same operation as in Example 1 was performed, and trans- (2S, 3R) was performed for 3.0 hours. -Epoxy-1,3-diphenylpropan-1-one was obtained with a yield of 96% and an optical purity of 74% ee.
[0037]
Example 5
Using the same reaction apparatus as in Example 1, except that triphenylphosphine oxide was changed to 1,3-dimethyl-2-imidazolinone, the same operation as in Example 1 was performed. (2S, 3R) -epoxy-1,3-diphenylpropan-1-one was obtained with a yield of 97% and an optical purity of 68% ee.
[0038]
Example 6
Using the same reaction apparatus as in Example 1, except that triphenylphosphine oxide was changed to tri (2-methylphenyl) phosphine oxide, the same operation as in Example 1 was performed, and the reaction was performed for 1.5 hours. (2S, 3R) -epoxy-1,3-diphenylpropan-1-one was obtained with a yield of 96% and an optical purity of 73% ee.
[0039]
Comparative Example 1
Using the same reaction apparatus as in Example 1, except that triphenylphosphine oxide was not added, the same operation was performed using the same reagent as in Example 1, and the reaction was conducted for 3 hours with trans- (2S, 3R) -epoxy- 1,3-diphenylpropan-1-one was obtained with a yield of 86% and an optical purity of 73% ee.
[0040]
Example 7
Using the same reactor as in Example 1, the same catalyst solution as in Example 1 was prepared. The same operation was carried out except that the enone used was changed from chalcone to trans-2-methyl-5-phenyl-4-penten-3-one (87.7 mg), and trans- (4S, 5R) -epoxy was reacted for 12 hours. -2-Methyl-5-phenylpentan-3-one: 64.2 mg was obtained (yield: 67%, optical purity: 96% ee, colorless and transparent liquid).
[0041]
Example 8
Using the same reactor as in Example 1, the same catalyst solution as in Example 1 was prepared. The same operation was performed except that the enone used was changed from chalcone to trans-4-methyl-1-phenyl-2-penten-1-one (87.7 mg), and trans- (2S, 3R) -epoxy was reacted for 1 hour. -4-Methyl-1-phenylpentan-1-one: 85.2 mg was obtained (yield: 89%, optical purity: 93% ee, colorless and transparent liquid).
[0042]
Example 9
Using the same reactor as in Example 1, the same catalyst solution as in Example 1 was prepared. The same operation was carried out except that the enone used was changed from chalcone to trans-4-phenyl-3-buten-2-one (74.0 mg), and trans- (3S, 4R) -epoxy-4-phenyl was reacted for 6 hours. Butan-2-one: 75.5 mg was obtained (yield: 92%, optical purity: 93% ee, colorless and transparent liquid).
[0043]
Example 10
Using the same reactor as in Example 1, the same catalyst solution as in Example 1 was prepared. The same operation was performed except that the enone used was changed from chalcone to trans-6-phenyl-3-hexen-2-one (88.2 mg), and trans- (3S, 4R) -epoxy-6-phenyl was reacted for 1 hour. Hexan-1-one: 88.6 mg was obtained (yield: 92%, optical purity: 87% ee, colorless and transparent liquid).
[0044]
Example 11
Using the same reaction apparatus as in Example 1, except that TBHP was changed to cumene hydroperoxide, the same operation as in Example 1 was performed, and trans- (2S, 3R) -epoxy-1,3- Diphenylpropan-1-one was obtained with a yield of 95% and an optical purity of 99% ee.
[0045]
Example 12
Using the same reaction apparatus as in Example 1, the amount of molecular sieve-4A used was changed from 506 mg to 100 mg, and TBHP was changed to cumene hydroperoxide. Obtained trans- (2S, 3R) -epoxy-1,3-diphenylpropan-1-one with a yield of 97% and an optical purity of 99.8% ee.
[0046]
Example 13
Using the same reaction apparatus as in Example 1, the amount of molecular sieve-4A used was changed from 506 mg to 25 mg, and TBHP was changed to cumene hydroperoxide. Obtained trans- (2S, 3R) -epoxy-1,3-diphenylpropan-1-one with a yield of 97% and an optical purity of 99.8% ee.
[0047]
Example 14
Using the same reaction apparatus as in Example 1, except that the amount of triphenylphosphine oxide used was changed from 21.2 mg to 7.0 mg, the same operation as in Example 1 was performed, and trans- (2S, 3R) -epoxy-1,3-diphenylpropan-1-one was obtained with a yield of 91% and an optical purity of 93% ee.

Claims (3)

(A) binaphthol, (B) lanthanum triisopropoxide, and (C) lutidine-N-oxide, 1,3-dimethyl-2-imidazolidinone , triphenylphosphine oxide, tri (2-methylphenyl) phos Containing fin oxide or tri (4-methylphenyl) phosphine oxide, (B) 1 to 3 moles of (A) binaphthol, (C) lutidine-N-oxide, 1, 3 with respect to 1 mole of lanthanum ion -Dimethyl-2-imidazolidinone, triphenylphosphine oxide, tri (2-methylphenyl) phosphine oxide or tri (4-methylphenyl) phosphine oxide is 0.1 to 10 mol Asymmetric epoxidation catalyst solution of enones. In the presence of the catalyst solution according to claim 1, the following general formula (1)

(In the formula, R ₁ and R ₂ are each independently a linear, branched or cyclic alkyl group having 1 to 20 carbon atoms, an aromatic group, or an alkyl group having 1 to 5 carbon atoms. 5 substituted aromatic groups, 1-5 substituted aromatic groups with 1-5 carbon atoms, 1-5 substituted aromatic groups with halogen elements, 1 carbon substituted with aromatic groups Represents a linear, branched or cyclic alkyl group having 5 to 5 carbon atoms, or a linear, branched or cyclic alkyl group having 1 to 5 carbon atoms substituted with a halogenated aromatic group.
The following general formula (2), characterized by reacting an enone represented by the formula (1) with an oxidizing agent

(In the formula, R ₁ and R ₂ have the same definitions as above, and * indicates optically active carbon.)
The manufacturing method of the optically active epoxide shown by these. As enones represented by the general formula (1), chalcone, trans-2-methyl-5-phenyl-4-penten-3-one, or trans-4-methyl-1-phenyl-2-penten-1-one The method for producing an optically active epoxide according to claim 2, wherein tertiary butylhydroxyperoxide is reacted as an oxidizing agent.