JP2004269463A - Method for producing wine lactone and its intermediate and application thereof - Google Patents
Method for producing wine lactone and its intermediate and application thereof Download PDFInfo
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Abstract
Description
【0001】
【発明の属する技術分野】
本発明は、ワインラクトンの製造法及びワインラクトンを製造するのに極めて有効な中間体の製造方法並びにその応用に関する。
【0002】
【従来の技術】
ワインラクトン(化合物名:(3S,3aS,7aR)−テトラヒドロ−3,6−ジメチル−2−(3H)−ベンゾフラノン)は、天然中に存在する物質として、1975年I.A.Southwellにより、コアラの代謝物として単離され、1996年白ワインより発見されたことより、「ワインラクトン」と命名された化合物である。ワインラクトンの立体異性体は8種類存在し、1996年H.Guthにより全ての立体異性体が合成され、キラル分析により、天然に存在する化合物は(3S,3aS,7aR)体であることが確認された(下記、化合物(6)非特許文献1:Helv.Chim.Acta,79,1559,(1996).)。
【0003】
【化3】
「ワインラクトン」
【0004】
従来のワインラクトンの合成法の方法は、H. Guthらによる(非特許文献1:Helv.Chim.Acta,79,1559,(1996).)全立体異性体を合成する方法、Diels−Alder反応による6員環形成反応、ワインラクトンの3a位のメチル基と同じ立体化学を有するリモネンを出発物質として用いる方法があるが、Diels−Alder反応を用いた反応では酸化反応の収率が悪く、最終生成物の分離は非常に困難である。ワインラクトンの3a位のメチル基と同じ立体化学を有するリモネンを出発物質として用いる方法では3位の立体異性体の混合物が得られ、それらの分離も困難であるといった問題点があった。
【0005】
次に、P. A. Bartlett, C. F. Pizzoらによる方法は(非特許文献2: J. Org. Chem., 46, 3869−3900 (1981).)光学活性体アルコールから転位反応を用いて3a位の立体化学を完全に制御できるため、数ある立体異性体から選択的に合成できるという点では優れた方法であるが、出発物質である光学活性アルコールの入手が非常に困難であり、工業的に量産できる方法ではない。
【0006】
更に、E. J. Bergner, G. Helmchenらによる方法によると(非特許文献3: Eur. J. Org. Chem., 419−423 (2000).)光学活性配位子を用いたパラジウムによるマロン酸エステルの付加反応を行い、天然型ワインラクトンのみを得ているが、ラクトン化−ラクトン開裂−再環化という段階があり、工程数が多くなるため、収率が低くなるといった問題点があった。
【0007】
また、S. P. Chavanらによる方法は(非特許文献4: Tetrahedron Asymmetry, 12, 2985−2988 (2001).)天然型ワインラクトンの3a位と同じ立体化学を持つリモネンの変換によって合成するものであるが、3位のメチル基の立体混合物が得られるので、立体異性体が副生し収率が悪くなるという問題点があった。
【0008】
【課題を解決するための手段】
本発明者は上述した如き課題に鑑みて、鋭意研究を重ねた結果、ワインラクトンの製造工程において、化合物(2)に、オキサザボロリジンを不斉触媒として使用し、カルボニル基の還元反応を行い化合物(3)を得る工程を採ることにより、ワインラクトンの8種類の立体異性体のうち、選択的に天然型のワインラクトン(化合物名:(3s,3aS,7aR)−テトラヒドロ−33,6−ジメチル−2−(3h)−ベンゾフラノン)のみを高収率で製造できることを見出した。また、ワインラクトンの香料及び食品への使用用途も見いだし、ここに本発明を完成するに至った。
【0009】
本発明は、以下の合成法及び合成中間体を提供するものである。
項1.次の工程(B)を含む化合物(3)の製造法。
・工程(B):化合物(2)に、光学活性オキサザボロリジンを不斉触媒として使用して、カルボニル基の還元反応を行い化合物(3)を得る工程;
【0010】
【化4】
(式中R1は、炭素数1乃至4の低級アルキル基、R2はH又メチル基)
【0011】
項2.光学活性オキサザボロリジンが、(R)−5,5−ジフェニル−2−メチル−3,4−プロパノ−1,3,2−オキサザボロリジンである、項1に記載の化合物(3)の製造法。項3.次の工程(A)〜(E)を含む化合物(6)の製造法。
・工程(A):化合物(1)に、アルキル付加反応を行い化合物(2)を得る工程
・工程(B):化合物(2)に、オキサザボロリジンを不斉触媒として使用して、カルボニル基の還元反応を行い化合物(3)を得る工程
・工程(C):化合物(3)のエステル部の加水分解を行い化合物(4)を得る工程
・工程(D):化合物(4)をDCCによる環化反応を行い化合物(5)を得る工程
・工程(E):化合物(5)のメチル化反応により化合物(6)を得る工程
【0012】
【化5】
(式中R1は、項1と同義)
【0013】
項4.工程(B)中、オキサザボロリジンが、(R)−5,5−ジフェニル−2−メチル−3,4−プロパノ−1,3,2−オキサザボロリジンである、項3に記載の化合物(6)の製造法。
【0014】
更に本発明は、ワインラクトンの香料及び食品への使用用途に関する。
項5.化合物(6)を10−7〜104ppb含むことを特徴とする香料組成物。
項6.化合物(6)を10−10〜102ppb含むことを特徴とする飲食品。
【0015】
【発明の実施の形態】
まず、本発明は、ワインラクトンを製造するための中間体である、化合物(3)を製造する際、化合物(2)に、光学活性オキサザボロリジンを不斉触媒として使用して、カルボニル基の還元反応を行い化合物(3)を得る工程(〔工程B〕)を採ることである。
【0016】
〔工程B〕オキサザボロリジンを用いたカルボニル基の還元反応
【化6】
【0017】
本発明〔工程B〕において、(1)のアルキル付加体である式(2)で表される化合物(6−(カルボエトキシメチル)−3−メチル−2−シクロヘキセン−1−オン)に、光学活性オキサザボロリジンを不斉触媒として反応させ、式(2)のカルボニル基を還元して式(3)のアルコール体((1R,6s)−6−(カルボエトキシメチル)−3−メチル−2−シクロヘキセン−1−オール)とすることが特徴である。
【0018】
不斉触媒として使用する光学活性オキサザボロリジンは、式(A)の構造を有する化合物であり、式(A)中のR2が、水素或いは、メチル基、好ましくは、(R)−5,5−ジフェニル−2−メチル−3,4−プロパノ−1,3,2−オキサザボロリジンである。前述の通り、光学活性オキサザボロリジンを不斉触媒として使用することにより、カルボニル基を還元して生成するアルコール体の立体化学を制御することができる。最終的にワインラクトンを合成する場合には、アルコール体(3)の立体構造を有することが有効であるため、(R)−5,5−ジフェニル−2−メチル−3,4−プロパノ−1,3,2−オキサザボロリジンを使用することが好ましい。
【0019】
【化7】
式(A)
【0020】
この還元反応は、窒素ガス、アルゴンガスなどの不活性雰囲気下、より好ましくはアルゴンガス雰囲気下で行われ、反応温度や反応時間に特別な限定はないが、通常、反応容器に本発明の不斉触媒及び溶媒を加え、式(2)の化合物を溶媒に溶解して加えて、−30〜30℃程度に冷却し、5〜60分程度攪拌することにより行われる。また、式(2)の化合物1molに対し、不斉触媒を0.05〜0.5mol、好ましくは、0.05〜0.1mol用いられる。また、還元剤としては、ボラン−テトラヒドロフラン錯体が好ましく用いられ、溶媒には、エーテル系溶媒が好ましく用いられ、テトラヒドロフラン、ジエチルエーテルなどが用いられる。
【0021】
また、本発明で使用する不斉触媒は公知の方法により回収して、再利用することができる。
【0022】
次に、本発明は、次の工程(A)〜(E)を含むワインラクトン(化合物(6))の製造法に関する。
【0023】
工程(A):化合物(1)に、アルキル付加反応を行い化合物(2)を得る工程工程(A)は、化合物(1):3−メチル−2−シクロヘキセン−1−オンに、リチウムジイソプロピルアミド(LDA)、ハロゲン化酢酸アルキル:式(B)を反応させてアルキル付加を行い、化合物(2)のアルキル付加体を生成する反応である。この際、溶媒にヘキサメチルホスホルアミド(HMPA)を添加しておくのが好ましい。
【0024】
工程(B):化合物(2)に、オキサザボロリジンを不斉触媒として使用して、カルボニル基の還元反応を行い化合物(3)を得る工程
【0025】
工程(B)は、前述の通りである。工程(B)により、化合物(3)=アルコール体が生成するが、化合物(3)の立体異性体である化合物(3’)が副生する。
【0026】
工程(C):化合物(3)のエステル部の加水分解を行い化合物(4)を得る工程
工程(C)は、工程(B)によって得られた化合物(3)=ヒドロキシエステル体のエステル部を常法により加水分解を行う工程である。化合物(3’)も加水分解され、化合物(4’)が副生する。
【0027】
工程(D):化合物(4)をジシクロヘキシルカルボジイミド(DCC)による環化反応を行い化合物(5)を得る工程
工程(D)は、工程(C)によって得られた化合物(4)=ヒドロキシ酸にジシクロヘキシルカルボジイミドを反応させラクトン化させ、化合物(5)を得る工程である。化合物(4’)もラクトン環化し、化合物(5’)が副生するが、ここでカラムクロマトグラフィーなどの常法により、化合物(5)と化合物(5’)は簡単に分離することができる。
【0028】
工程(E):化合物(5)のメチル化反応により化合物(6)を得る工程
工程(E)は、分離した化合物(5)をハロゲン化メチルによりメチル化して、化合物(6)であるワインラクトンを得る工程である。
【0029】
前述の工程(B)以外の工程(A)、工程(C)、工程(D)、工程(E)は、既知の反応であるが、これら反応を組み合わせ、工程(A)〜(E)の反応を行うことにより、各種光学異性体のうちから天然型のワインラクトンのみを選択的に生成することができるものである。
【0030】
【化8】
【0031】
次に、本発明は化合物(6)(ワインラクトン)を10−7〜104ppb、より好ましくは、10−6〜103ppb含むことを特徴とする香料組成物に関するものである。香料は合成香料はもとより、天然物由来の香料であっても、ボディ感が不足したり、フルーツ系香料の場合は果汁感が損なわれたりすることが問題となっていたが、本発明により、これら果汁感やボディ感だけでなく、香料の起源物質の香りがよく再現されリアリティー感も付与されることが判った。
【0032】
本発明の香料組成物は、香料成分、ワインラクトンの他には、通常香料に含有する添加剤を含有することができ、例えば、エタノールやプロピレングリコール等の溶剤等を含有することが出来る。
【0033】
更に、本発明は、化合物(6)(ワインラクトン)を10−10〜102ppb、より好ましくは、10−9〜10ppb含むことを特徴とする飲食品に関する。例えば、飲料、アイスクリーム、シャーベット等の冷菓、ゼリー、プリン、水ようかん、くずきり等のデザート類、クッキー、ケーキ、チョコレート、チューインガム、まんじゅう等の菓子類、菓子パン、食パン等のパン類、ジャム、フラワーペースト等のフィリング類、ラムネ、タブレット、錠菓類等が挙げられ、特に飲料が好ましく、果汁入り飲料、果汁入り炭酸飲料等に好ましく用いられる。
これら飲食品に上記量添加することにより、元々の飲食品の風味を引き立て、果汁入り飲料などでは、果汁感やボディ感を付与することができる。なお、飲食品以外に、歯磨き、マウスウオッシュ、リップクリーム、口紅等の口腔用組成物やその他石鹸、香水、芳香剤、シャンプーなどの化粧品、香粧品等にも適応することが出来る。
【0034】
【実施例】
以下、本発明を実施例を用いて具体的に説明するが、本発明はこれらに何ら限定されるものではない。
【0035】
実施例1:ワインラクトンの合成
・工程(A):アルキル付加反応
ジイソプロピルアミン(16.8ml, 0120mmol)をテトラヒドロフラン400mlに溶解して0℃に冷却し、n−ブチルリチウム(1.56mol/l)を76ml滴下した。3−メチル−2−シクロヘキセン−1−オン(11.3ml, 100mmol)を滴下し、ヘキサメチルホスホルアミド50mlを加え、ブロモ酢酸エチル(16.6ml, 150mmol)を滴下し、1.5時間反応を行った。飽和塩化アンモニウム水溶液で反応を停止し、酢酸エチルで抽出を行った。油層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下溶媒を除去した。その残渣を蒸留により精製を行い、沸点101−105℃/0.1mmHgの留分を集め、アルキル付加体のケトエステル(2)(51.7mmol, 収率52%)を得た。
【0036】
アルキル付加体(2)
1H−NMR (CDCl3) : d=1.27 (3H, t, J=7.1Hz), 1.79 (1H, qd, J=11.7, 4.9Hz), 1.96 (3H, s), 2.12 (1H, dtd, J=12.4, 4.9, 2.7Hz), 2.27 (1H, dd, J=16.1, 7.6Hz), 2.26−2.32 (1H, m), 2.41−2.50 (1H, m), 2.72−2.79 (1H, m), 2.89 (1H, dd, J=16.1, 5.4Hz), 4.16 (2H, qd, J=7.1, 2.0Hz), 5.88 (1H, s).
13C−NMR (CDCl3) : d =14.11, 24.12, 28.40, 30.95, 34.49, 42.50, 60.37, 125.9, 162.0, 172.6, 199.1.
【0037】
・工程(B):オキサザボロリジンを用いたカルボニル基の還元反応
窒素雰囲気下、反応容器に(R)−5,5−ジフェニル−2−メチル−3,4−プロパノ−1,3,2−オキサザボロリジン(277mg, 1mmol)、テトラヒドロフラン1mlを入れ、ボラン−テトラヒドロフラン錯体(1.13mol/l)を2ml滴下し、ケトエステル(2)(3.92g, 20mmol)のテトラヒドロフラン溶液(10.6ml)を加えた。0℃に冷却し、ボラン−テトラヒドロフラン錯体(8.6ml)を滴下した。反応溶液を15分間攪拌した後、メタノールを3ml加え、塩化水素で飽和したジエチルエーテルを0.4ml滴下し、30分間攪拌した。減圧下溶媒を除去し、ベンゼン10mlを加えてさらに減圧下濃縮を行い、これを2回繰り返した。ジエチルエーテルを20ml加え、0℃に冷却した後、析出してくる白色結晶をろ過し、ろ液を飽和食塩水、飽和炭酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸水素ナトリウムで乾燥した。減圧下、溶媒を除去し、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=2:1)で精製を行い、 (3)+(3’)の混合物であるヒドロキシエステル(12.5mmol, 収率63%)を得た。
【0038】
アルコール体(3)
13C−NMR (CDCl3) : d =14.13, 23.01, 26.35, 29.25, 35.98, 37.92, 60.36, 71.37, 124.5, 137.2, 173.6.
アルコール体(3’)
13C−NMR (CDCl3) : d =14.13, 23.29, 23.33, 30.01, 36.32, 39.04, 60.26, 65.89, 123.0, 139.0, 173.6.
【0039】
・工程(C):エステル部の加水分解
(3)+(3’)の混合物であるヒドロキシエステル(250mg, 1.26mmol)をメタノール5mlに溶解し、30%−水酸化ナトリウム水溶液を2ml加えた。10分後、30%−塩酸で酸性にし、ジエチルエーテルで抽出を行った。油層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を除去し、ヒドロキシ酸(4)+(4’)の混合物の粗生成物を次の反応に用いた。
【0040】
・工程(D)DCCによるラクトン化反応
ヒドロキシ酸(4)+(4’)の混合物(約1.26mmol)をベンゼン5mlに溶解し、ジシクロヘキシルカルボジイミド(DCC, 287mg, 1.39mmol)を加え、20℃で15時間攪拌した。反応終了後、n−ヘキサンを加え、析出する固体をろ過し、ろ液を1N−塩酸、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下溶媒を除去した。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)で精製を行い、ラクトン(5)(0.64mmol, 収率51%)およびラクトン(5’)(0.17mmol, 13%)を得た。
【0041】
ラクトン(5)
1H−NMR (CDCl3) : d =1.44−1.54 (1H, m), 1.72−1.76 (1H, m), 1.78 (3H, s), 2.02 (2H, t, J=4.9Hz), 2.29 (1H, dd, J=17.1, 3.4Hz), 2.46−2.54 (1H, m), 2.72 (1H, dd, J=17.1, 8.1Hz), 4.80 (1H, t, J=4.4Hz), 5.62 (1H, m).
13C−NMR (CDCl3) : d =23.92, 24.13, 28.02, 33.09, 35.49, 76.94, 117.7, 143.1, 176.9.
【0042】
ラクトン(5’)
1H−NMR (CDCl3) : d =1.60−1.69 (1H, m), 1.70 (3H, s), 2.03−2.08 (1H, m), 2.11−2.21 (2H+1H, m), 2.27 (1H, dd, J=13.4, 15.9Hz), 2.54 (1H, ddd, J=15.9, 6.1, 1.0Hz), 4.41−4.44 (1H, m), 5.82 (1H, m).
13C−NMR (CDCl3) : d =22.90, 23.62, 30.80, 35.73, 42.12, 82.50, 120.0, 137.9, 176.9.
【0043】
・工程(E)ラクトン(5)のメチル化反応
ジイソプロピルアミン(0.1ml, 0.71mmol)をテトラヒドロフラン1mlに溶解して0℃に冷却し、n−ブチルリチウム(1.56mol/l)を0.46ml滴下した。前記ラクトン(5)(90mg, 0.59mmol)をテトラヒドロフラン1mlに溶解したものを反応容器に滴下し、ヨウ化メチル(0.05ml, 0.71mmol)を滴下した。20分後に水によって反応を停止し、ジエチルエーテルで抽出を行った。油層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下溶媒を除去した。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)で精製を行い、天然型ワインラクトン化合物(6)(0.45mmol, 収率76%)を得た。
【0044】
ワインラクトン化合物
1H−NMR (C6D6) : d =0.98 (3H, d, J=7.3Hz), 1.16−1.21 (2H, m), 1.41 (3H, s), 1.46−1.56 (2H, m), 1.56−1.61 (1H, m), 2.03 (1H, dq, I=1.5, 7.3Hz), 4.45 (1H, dq, J=6.6, 1.5Hz), 5.32 (1H, m).
13C−NMR (C6D6) : d =14.01, 22.16, 23.47, 25.70, 37.33, 40.24, 74.63, 119.6, 139.9, 178.3.
【0045】
実施例2:グレープフルーツ香料
実施例1で製造した天然型ワインラクトン化合物(6)を用いて下記処方通り配合し、常法にてグレープフルーツ香料を調製した。
グレープフルーツフレーバー処方
【0046】
【表1】
【0047】
グレープフルーツフレーバーに上記の処方のようにワインラクトンを添加すれば、ワインラクトンを添加しない香料Bと比較して、よりみずみずしい果汁感のあるナチュラルなグレープフルーツの特徴が強調された香料Aが得られた。
【0048】
実施例3:グレープフルーツジュース
下記表2のグレープフルーツジュース処方に従い、常法によりグレープフルーツジュースを調製した。
グレープフルーツジュース処方
【0049】
【表2】
【0050】
ワインラクトンが添加されているフレーバーAを使用した飲料Aは、添加していないフレーバーBを使用した飲料Bに較べて、天然グレープフルーツ様のボディ感や果汁感が向上した飲料が得られた。
【0051】
実施例4:天然型ワインラクトンの 100 %組成物と立体異性体混合物との比較
下記表3のグレープフルーツジュース処方に従い、常法によりグレープフルーツジュースを調製した。
グレープフルーツジュース処方
【0052】
【表3】
【0053】
天然体ワインラクトンのみが添加されている飲料Cは甘さやジューシー感があるといったみずみずしい果汁感のある飲料であるのに対し、天然体ワインラクトンとその異性体である(3R, 3aR, 7aS)−テトラヒドロ−3,6−ジメチル−2−(3H)−ベンゾフラノンの1:1混合物が添加されている飲料Dは飲料Cに比べるとみずみずしい果汁感が損なわれ、不快な重たさが加わった飲料となった。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing wine lactone, a method for producing an intermediate which is extremely effective for producing wine lactone, and an application thereof.
[0002]
[Prior art]
Wein lactone (compound name: (3S, 3aS, 7aR) -tetrahydro-3,6-dimethyl-2- (3H) -benzofuranone) is a substance which exists in nature in 1975. A. It is a compound that was isolated by Southwell as a metabolite of koala and was named "Wine Lactone" based on its discovery in white wine in 1996. There are eight types of stereoisomers of wine lactone. Guth synthesized all stereoisomers, and the chiral analysis confirmed that the naturally occurring compound was (3S, 3aS, 7aR) (Compound (6), Non-Patent Document 1: Helv. Chim. Acta, 79, 1559, (1996).).
[0003]
Embedded image
"Wine lactone"
[0004]
Conventional wine lactone synthesis methods are described in (Non-Patent Document 1: Helv. Chim. Acta, 79, 1559, (1996)) by Guth et al., A method for synthesizing all stereoisomers, a 6-membered ring-forming reaction by the Diels-Alder reaction, Although there is a method using limonene having the same stereochemistry as the methyl group as a starting material, in the reaction using the Diels-Alder reaction, the yield of the oxidation reaction is poor, and it is very difficult to separate the final product. The method using limonene having the same stereochemistry as the methyl group at the 3a-position of the wine lactone as a starting material produces a mixture of stereoisomers at the 3-position, and has a problem that it is difficult to separate them.
[0005]
Next, P. A. Bartlett, C.I. F. The method by Pizzo et al. (Non-Patent Document 2: J. Org. Chem., 46, 3869-3900 (1981)). Since the stereochemistry at the 3a-position can be completely controlled from an optically active alcohol using a rearrangement reaction, Although it is an excellent method in that it can be selectively synthesized from a number of stereoisomers, it is very difficult to obtain an optically active alcohol as a starting material, and it is not a method that can be mass-produced industrially.
[0006]
Further, E.I. J. Bergner, G .; According to the method of Helmchen et al. (Non-Patent Document 3: Eur. J. Org. Chem., 419-423 (2000).) An addition reaction of malonic ester with palladium using an optically active ligand is carried out to obtain a natural type. Although only wine lactone is obtained, there is a step of lactonization-lactone cleavage-recyclization, and there is a problem that the number of steps is increased and the yield is reduced.
[0007]
In addition, S.I. P. The method by Chavan et al. (Non-Patent Document 4: Tetrahedron Asymmetry, 12, 2985-2988 (2001).) Is synthesized by conversion of limonene having the same stereochemistry as position 3a of a natural wine lactone, but at position 3 Thus, there is a problem that the stereoisomer is by-produced and the yield is deteriorated since a steric mixture of methyl groups is obtained.
[0008]
[Means for Solving the Problems]
In view of the problems as described above, the present inventors have conducted intensive studies and as a result, in the process of producing wine lactone, using oxazaborolidine as an asymmetric catalyst for compound (2) to carry out the reduction reaction of the carbonyl group. By carrying out the step of obtaining compound (3), a natural type of wine lactone (compound name: (3s, 3aS, 7aR) -tetrahydro-33,6) is selectively obtained from eight kinds of stereoisomers of wine lactone. -Dimethyl-2- (3h) -benzofuranone) can be produced in high yield. In addition, the use of wine lactone in flavors and foods was also found, and the present invention was completed here.
[0009]
The present invention provides the following synthetic methods and synthetic intermediates.
Item 1. A method for producing a compound (3) comprising the following step (B).
Step (B): a step of subjecting compound (2) to a reduction reaction of a carbonyl group using optically active oxazaborolidine as an asymmetric catalyst to obtain compound (3);
[0010]
Embedded image
(Wherein R 1 is a lower alkyl group having 1 to 4 carbon atoms, and R 2 is H or a methyl group)
[0011]
Item 2. Item (3), wherein the optically active oxazaborolidine is (R) -5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine. Manufacturing method. Item 3. A method for producing a compound (6) comprising the following steps (A) to (E).
-Step (A): a step of subjecting compound (1) to an alkyl addition reaction to obtain compound (2).-Step (B): carbonyl of compound (2) using oxazaborolidine as an asymmetric catalyst. Step (C) of obtaining a compound (3) by subjecting a group to a reduction reaction to obtain a compound (4) by hydrolyzing an ester moiety of the compound (3): Step (D) of obtaining a compound (4) by DCC Step (E): Step of obtaining compound (6) by methylation reaction of compound (5) by cyclization reaction with compound (5)
Embedded image
(Wherein R 1 is as defined in item 1)
[0013]
Item 4. Item 3. The process according to item 3, wherein in the step (B), the oxazaborolidine is (R) -5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine. Production method of compound (6).
[0014]
Furthermore, the present invention relates to the use of wine lactone for flavors and foods.
Item 5. A fragrance composition comprising 10 -7 to 10 4 ppb of compound (6).
Item 6. Compound (6) a food or drink comprising 10 -10 ~10 2 ppb.
[0015]
BEST MODE FOR CARRYING OUT THE INVENTION
First, the present invention provides a method for producing a compound (3), which is an intermediate for producing a wine lactone, by using an optically active oxazaborolidine as an asymmetric catalyst for the compound (2). To obtain the compound (3) ([Step B]).
[0016]
[Step B] Reduction of carbonyl group using oxazaborolidine
[0017]
In the present [Step B], the compound (6- (carbethoxymethyl) -3-methyl-2-cyclohexen-1-one) represented by the formula (2), which is an alkyl adduct of (1), is optically treated. The active oxazaborolidine is reacted as an asymmetric catalyst to reduce the carbonyl group of the formula (2) to give an alcohol of the formula (3) ((1R, 6s) -6- (carbethoxymethyl) -3-methyl- 2-cyclohexen-1-ol).
[0018]
The optically active oxazaborolidine used as the asymmetric catalyst is a compound having the structure of the formula (A), wherein R 2 in the formula (A) is hydrogen or a methyl group, preferably (R) -5 , 5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine. As described above, by using optically active oxazaborolidine as an asymmetric catalyst, it is possible to control the stereochemistry of an alcohol compound formed by reducing a carbonyl group. In the final synthesis of wine lactone, it is effective to have the three-dimensional structure of the alcohol (3), so that (R) -5,5-diphenyl-2-methyl-3,4-propano-1 It is preferred to use 2,3,2-oxazaborolidine.
[0019]
Embedded image
Formula (A)
[0020]
This reduction reaction is carried out under an inert atmosphere such as nitrogen gas or argon gas, more preferably under an argon gas atmosphere, and there is no particular limitation on the reaction temperature or the reaction time. The reaction is carried out by adding a catalyst and a solvent, dissolving the compound of the formula (2) in the solvent, cooling to about -30 to 30 ° C., and stirring for about 5 to 60 minutes. The asymmetric catalyst is used in an amount of 0.05 to 0.5 mol, preferably 0.05 to 0.1 mol, per 1 mol of the compound of the formula (2). As the reducing agent, a borane-tetrahydrofuran complex is preferably used, and as the solvent, an ether solvent is preferably used, and tetrahydrofuran, diethyl ether and the like are used.
[0021]
The asymmetric catalyst used in the present invention can be recovered by a known method and reused.
[0022]
Next, the present invention relates to a method for producing wine lactone (compound (6)) including the following steps (A) to (E).
[0023]
Step (A): Step of obtaining a compound (2) by subjecting a compound (1) to an alkyl addition reaction Step (A) is a step of adding a compound (1): 3-methyl-2-cyclohexen-1-one to lithium diisopropylamide (LDA), alkyl halide acetate: a reaction for reacting the formula (B) to carry out alkyl addition to produce an alkyl adduct of the compound (2). At this time, it is preferable to add hexamethylphosphoramide (HMPA) to the solvent.
[0024]
Step (B): a step of subjecting compound (2) to a reduction reaction of a carbonyl group using oxazaborolidine as an asymmetric catalyst to obtain compound (3).
Step (B) is as described above. In the step (B), the compound (3) = alcohol is produced, but the compound (3 ′) which is a stereoisomer of the compound (3) is by-produced.
[0026]
Step (C): Step (C) of hydrolyzing the ester moiety of compound (3) to obtain compound (4) is performed by converting the ester moiety of compound (3) = hydroxyester obtained in step (B). This is a step of performing hydrolysis by a conventional method. Compound (3 ′) is also hydrolyzed, and compound (4 ′) is by-produced.
[0027]
Step (D): Step (D) of subjecting compound (4) to a cyclization reaction with dicyclohexylcarbodiimide (DCC) to obtain compound (5) is performed by converting compound (4) obtained in step (C) to a hydroxy acid This is a step of reacting dicyclohexylcarbodiimide to form a lacton to obtain a compound (5). The compound (4 ′) is also lactone-cyclized to produce the compound (5 ′) as a by-product. Here, the compound (5) and the compound (5 ′) can be easily separated by a conventional method such as column chromatography. .
[0028]
Step (E): Step of obtaining compound (6) by a methylation reaction of compound (5) In step (E), the separated compound (5) is methylated with a methyl halide to obtain a wine lactone that is a compound (6). This is the step of obtaining
[0029]
Steps (A), (C), (D), and (E) other than the above-mentioned step (B) are known reactions. These reactions are combined and the steps (A) to (E) are performed. By performing the reaction, it is possible to selectively produce only the natural type wine lactone from various optical isomers.
[0030]
Embedded image
[0031]
Next, the present invention compound (6) (Wine lactone) 10 -7 to 10 4 ppb, more preferably, to a perfume composition which comprises 10 -6 ~10 3 ppb. Flavors are not only synthetic fragrances, but also natural fragrances, but there is a problem that the body sensation is insufficient, or in the case of fruit-based fragrances, the juice sensation is impaired, but according to the present invention, It was found that not only the fruit juice and body sensation, but also the fragrance of the substance originating in the fragrance was well reproduced, giving a sense of reality.
[0032]
The fragrance composition of the present invention can contain, in addition to the fragrance component and wine lactone, additives usually contained in fragrances, for example, solvents such as ethanol and propylene glycol.
[0033]
Furthermore, the present invention relates to compounds (6) to (wine lactone) 10 -10 to 10 2 ppb, more preferably, about food or drink comprising 10 -9 ~10ppb. For example, beverages, desserts such as ice cream, sherbet, jelly, pudding, mizuyokan, kizukiri, etc., cookies, cakes, chocolates, chewing gum, sweets such as steamed buns, confectionery bread, breads such as bread, jams, and flowers Examples include fillings such as pastes, ramune, tablets, tablet confectionery and the like, and particularly preferred are beverages, and are preferably used for fruit juice drinks, fruit juice carbonated drinks, and the like.
By adding the above-mentioned amount to these foods and drinks, the flavor of the original foods and drinks can be enhanced, and a juice feeling and a body feeling can be imparted to a juice-containing beverage and the like. In addition to foods and drinks, the composition can be applied to oral compositions such as toothpaste, mouthwash, lip balm, lipstick, and other cosmetics such as soaps, perfumes, fragrances, shampoos, and shampoos.
[0034]
【Example】
Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.
[0035]
Example 1 Synthesis of Wine Lactone Step (A): Alkyl Addition Reaction Diisopropylamine (16.8 ml, 0120 mmol) was dissolved in 400 ml of tetrahydrofuran, cooled to 0 ° C., and n-butyllithium (1.56 mol / l) Was dropped dropwise. 3-Methyl-2-cyclohexen-1-one (11.3 ml, 100 mmol) was added dropwise, 50 ml of hexamethylphosphoramide was added, and ethyl bromoacetate (16.6 ml, 150 mmol) was added dropwise, and the mixture was reacted for 1.5 hours. Was done. The reaction was stopped with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The oil layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by distillation, and fractions having a boiling point of 101-105 ° C / 0.1 mmHg were collected to obtain an alkyl adduct ketoester (2) (51.7 mmol, yield 52%).
[0036]
Alkyl adduct (2)
1 H-NMR (CDCl 3 ): d = 1.27 (3H, t, J = 7.1 Hz), 1.79 (1H, qd, J = 11.7, 4.9 Hz), 1.96 (3H , S), 2.12 (1H, dtd, J = 12.4, 4.9, 2.7 Hz), 2.27 (1H, dd, J = 16.1, 7.6 Hz), 2.26− 2.32 (1H, m), 2.41-2.50 (1H, m), 2.72-2.79 (1H, m), 2.89 (1H, dd, J = 16.1,5) .4 Hz), 4.16 (2H, qd, J = 7.1, 2.0 Hz), 5.88 (1H, s).
13 C-NMR (CDCl 3 ): d = 14.11, 24.12, 28.40, 30.95, 34.49, 42.50, 60.37, 125.9, 162.0, 172.6 , 199.1.
[0037]
Step (B): Reduction reaction of carbonyl group using oxazaborolidine Under a nitrogen atmosphere, (R) -5,5-diphenyl-2-methyl-3,4-propano-1,3,2 is placed in a reaction vessel. -Oxazaborolidine (277 mg, 1 mmol) and 1 ml of tetrahydrofuran were added, 2 ml of borane-tetrahydrofuran complex (1.13 mol / l) was added dropwise, and a solution of ketoester (2) (3.92 g, 20 mmol) in tetrahydrofuran (10.6 ml) was added. ) Was added. After cooling to 0 ° C., a borane-tetrahydrofuran complex (8.6 ml) was added dropwise. After stirring the reaction solution for 15 minutes, 3 ml of methanol was added, and 0.4 ml of diethyl ether saturated with hydrogen chloride was added dropwise, followed by stirring for 30 minutes. The solvent was removed under reduced pressure, 10 ml of benzene was added, and the mixture was further concentrated under reduced pressure, and this was repeated twice. After adding 20 ml of diethyl ether and cooling to 0 ° C., the precipitated white crystals were filtered, and the filtrate was washed with saturated saline, saturated aqueous sodium carbonate solution and saturated saline, and dried over anhydrous sodium hydrogen sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and the hydroxy ester (12.5 mmol, 63% yield) as a mixture of (3) + (3 ′) was obtained. ) Got.
[0038]
Alcohol body (3)
13 C-NMR (CDCl 3 ): d = 14.13, 23.01, 26.35, 29.25, 35.98, 37.92, 60.36, 71.37, 124.5, 137.2. , 173.6.
Alcohol body (3 ')
13 C-NMR (CDCl 3 ): d = 14.13, 23.29, 23.33, 30.01, 36.32, 39.04, 60.26, 65.89, 123.0, 139.0 , 173.6.
[0039]
Step (C): Hydrolysis of Ester Portion Hydroxyester (250 mg, 1.26 mmol), which is a mixture of (3) + (3 ′), was dissolved in 5 ml of methanol, and 2 ml of a 30% aqueous sodium hydroxide solution was added. . After 10 minutes, the mixture was acidified with 30% hydrochloric acid and extracted with diethyl ether. The oil layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and a crude product of a mixture of hydroxy acid (4) + (4 ′) was used for the next reaction.
[0040]
Step (D) Lactonization reaction by DCC A mixture of hydroxy acid (4) + (4 ′) (about 1.26 mmol) was dissolved in 5 ml of benzene, and dicyclohexylcarbodiimide (DCC, 287 mg, 1.39 mmol) was added. Stirred at 150C for 15 hours. After completion of the reaction, n-hexane was added, the precipitated solid was filtered, the filtrate was washed with 1N hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification was performed by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain lactone (5) (0.64 mmol, yield 51%) and lactone (5 ′) (0.17 mmol, 13%). .
[0041]
Lactone (5)
1 H-NMR (CDCl 3 ): d = 1.44-1.54 (1H, m), 1.72-1.76 (1H, m), 1.78 (3H, s), 2.02 ( 2H, t, J = 4.9 Hz), 2.29 (1H, dd, J = 17.1, 3.4 Hz), 2.46-2.54 (1H, m), 2.72 (1H, dd) , J = 17.1, 8.1 Hz), 4.80 (1H, t, J = 4.4 Hz), 5.62 (1H, m).
13 C-NMR (CDCl 3 ): d = 23.92, 24.13, 28.02, 33.09, 35.49, 76.94, 117.7, 143.1, 176.9.
[0042]
Lactone (5 ')
1 H-NMR (CDCl 3 ): d = 1.60-1.69 (1H, m), 1.70 (3H, s), 2.03-2.08 (1H, m), 2.11 2.21 (2H + 1H, m), 2.27 (1H, dd, J = 13.4, 15.9 Hz), 2.54 (1H, ddd, J = 15.9, 6.1, 1.0 Hz) , 4.41-4.44 (1H, m), 5.82 (1H, m).
13 C-NMR (CDCl 3 ): d = 22.90, 23.62, 30.80, 35.73, 42.12, 82.50, 120.0, 137.9, 176.9.
[0043]
Step (E) Methylation reaction of lactone (5) Diisopropylamine (0.1 ml, 0.71 mmol) is dissolved in 1 ml of tetrahydrofuran, cooled to 0 ° C, and n-butyllithium (1.56 mol / l) is dissolved in 0 ml. .46 ml was added dropwise. A solution obtained by dissolving the lactone (5) (90 mg, 0.59 mmol) in 1 ml of tetrahydrofuran was dropped into the reaction vessel, and methyl iodide (0.05 ml, 0.71 mmol) was dropped. After 20 minutes, the reaction was stopped with water, and extraction was performed with diethyl ether. The oil layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification was performed by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain a natural wine lactone compound (6) (0.45 mmol, yield: 76%).
[0044]
Wine lactone compound
1 H-NMR (C 6 D 6 ): d = 0.98 (3H, d, J = 7.3 Hz), 1.16-1.21 (2H, m), 1.41 (3H, s), 1.46-1.56 (2H, m), 1.56-1.61 (1H, m), 2.03 (1H, dq, I = 1.5, 7.3 Hz), 4.45 (1H , Dq, J = 6.6, 1.5 Hz), 5.32 (1H, m).
13 C-NMR (C 6 D 6): d = 14.01, 22.16, 23.47, 25.70, 37.33, 40.24, 74.63, 119.6, 139.9, 178 .3.
[0045]
Example 2: Grapefruit flavor The natural wine lactone compound (6) produced in Example 1 was blended according to the following formulation, and a grapefruit flavor was prepared by a conventional method.
Grapefruit flavor formula [0046]
[Table 1]
[0047]
When wine lactone was added to the grapefruit flavor as described above, flavor A was obtained in which the characteristics of natural grapefruit having a more juicy natural feeling were emphasized compared to flavor B without wine lactone.
[0048]
Example 3: Grapefruit juice Grapefruit juice was prepared by a conventional method according to the grapefruit juice formulation shown in Table 2 below.
Grapefruit juice formulation [0049]
[Table 2]
[0050]
Beverage A using flavor A to which wine lactone was added resulted in a beverage having a natural grapefruit-like body feeling and juice feeling improved compared to beverage B using flavor B without addition.
[0051]
Example 4: Comparison of a 100 % composition of natural wine lactone with a mixture of stereoisomers A grapefruit juice was prepared by a conventional method according to the grapefruit juice formulation in Table 3 below.
Grapefruit juice formulation [0052]
[Table 3]
[0053]
Beverage C to which only the natural wine lactone is added is a drink having a fresh fruity feeling such as sweetness and juicy feeling, whereas natural wine lactone and its isomer (3R, 3aR, 7aS)- Beverage D to which a 1: 1 mixture of tetrahydro-3,6-dimethyl-2- (3H) -benzofuranone is added has a reduced fresh juice feeling compared to beverage C, and beverages with an unpleasant weight are added. became.
Claims (6)
・工程(B):化合物(2)に、光学活性オキサザボロリジンを不斉触媒として使用して、カルボニル基の還元反応を行い化合物(3)を得る工程;
Step (B): a step of subjecting compound (2) to a reduction reaction of a carbonyl group using optically active oxazaborolidine as an asymmetric catalyst to obtain compound (3);
・工程(A):化合物(1)に、アルキル付加反応を行い化合物(2)を得る工程
・工程(B):化合物(2)に、オキサザボロリジンを不斉触媒として使用して、カルボニル基の還元反応を行い化合物(3)を得る工程
・工程(C):化合物(3)のエステル部の加水分解を行い化合物(4)を得る工程
・工程(D):化合物(4)をDCCによりラクトン化させる反応を行い化合物(5)を得る工程
・工程(E):化合物(5)のメチル化反応により化合物(6)を得る工程
Step (A): a step of subjecting compound (1) to an alkyl addition reaction to obtain compound (2) Step (B): carbonyl of compound (2) using oxazaborolidine as an asymmetric catalyst Step (C) of obtaining a compound (3) by subjecting a group to a reduction reaction to obtain a compound (4) by hydrolysis of an ester moiety of the compound (3): Step (D) of obtaining a compound (4) by DCC Step (E): Step of obtaining compound (6) by methylation reaction of compound (5)
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2006027856A1 (en) * | 2004-09-10 | 2006-03-16 | San-Ei Gen F.F.I., Inc. | Processes for production of wine lactone and its intermediates and application of the lactone |
JP2009296951A (en) * | 2008-06-13 | 2009-12-24 | T Hasegawa Co Ltd | After-fanciness improver for roasted fancy drink or roasted fancy drink-flavored food/drink |
JP2010195765A (en) * | 2009-01-27 | 2010-09-09 | T Hasegawa Co Ltd | Method for producing wine lactone |
US8481759B2 (en) | 2011-06-01 | 2013-07-09 | Takasago International Corporation | Process for producing wine lactone |
WO2019198678A1 (en) * | 2018-04-11 | 2019-10-17 | 高砂香料工業株式会社 | Novel lactone compound and novel ether compound |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2010083894A (en) * | 2009-12-24 | 2010-04-15 | Sanei Gen Ffi Inc | Production method and application for wine lactone and intermediate thereof |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006027856A1 (en) * | 2004-09-10 | 2006-03-16 | San-Ei Gen F.F.I., Inc. | Processes for production of wine lactone and its intermediates and application of the lactone |
JP2009296951A (en) * | 2008-06-13 | 2009-12-24 | T Hasegawa Co Ltd | After-fanciness improver for roasted fancy drink or roasted fancy drink-flavored food/drink |
JP2010195765A (en) * | 2009-01-27 | 2010-09-09 | T Hasegawa Co Ltd | Method for producing wine lactone |
US8481759B2 (en) | 2011-06-01 | 2013-07-09 | Takasago International Corporation | Process for producing wine lactone |
WO2019198678A1 (en) * | 2018-04-11 | 2019-10-17 | 高砂香料工業株式会社 | Novel lactone compound and novel ether compound |
JPWO2019198678A1 (en) * | 2018-04-11 | 2021-04-30 | 高砂香料工業株式会社 | New lactone compound and new ether compound |
US11427554B2 (en) | 2018-04-11 | 2022-08-30 | Takasago International Corporation | Lactone compound and novel ether compound |
JP7401426B2 (en) | 2018-04-11 | 2023-12-19 | 高砂香料工業株式会社 | New lactone compounds and new ether compounds |
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