JPH0253411B2 - - Google Patents
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- Publication number
- JPH0253411B2 JPH0253411B2 JP60188483A JP18848385A JPH0253411B2 JP H0253411 B2 JPH0253411 B2 JP H0253411B2 JP 60188483 A JP60188483 A JP 60188483A JP 18848385 A JP18848385 A JP 18848385A JP H0253411 B2 JPH0253411 B2 JP H0253411B2
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- JP
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- Prior art keywords
- group
- compound
- cram
- formula
- carbon atoms
- Prior art date
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- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 18
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 150000002440 hydroxy compounds Chemical class 0.000 claims description 14
- 150000002902 organometallic compounds Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000012442 inert solvent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000000962 organic group Chemical group 0.000 claims description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- 150000001875 compounds Chemical class 0.000 description 11
- 150000003431 steroids Chemical group 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 125000003172 aldehyde group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- IXVMHGVQKLDRKH-VRESXRICSA-N Brassinolide Natural products O=C1OC[C@@H]2[C@@H]3[C@@](C)([C@H]([C@@H]([C@@H](O)[C@H](O)[C@H](C(C)C)C)C)CC3)CC[C@@H]2[C@]2(C)[C@@H]1C[C@H](O)[C@H](O)C2 IXVMHGVQKLDRKH-VRESXRICSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- IXVMHGVQKLDRKH-KNBKMWSGSA-N brassinolide Chemical compound C1OC(=O)[C@H]2C[C@H](O)[C@H](O)C[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)[C@@H](O)[C@H](O)[C@@H](C)C(C)C)CC[C@H]3[C@@H]21 IXVMHGVQKLDRKH-KNBKMWSGSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- -1 verklein Chemical compound 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000002642 lithium compounds Chemical class 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003505 terpenes Chemical group 0.000 description 2
- JGVXQQVUKNOCDJ-UHFFFAOYSA-N 4-methylbenzenesulfonate pyridin-1-ium Chemical compound c1cc[nH+]cc1.c1cc[nH+]cc1.Cc1ccc(cc1)S([O-])(=O)=O.Cc1ccc(cc1)S([O-])(=O)=O JGVXQQVUKNOCDJ-UHFFFAOYSA-N 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- BUIQRTDBPCHRIR-UHFFFAOYSA-L O[Cr](Cl)(=O)=O Chemical compound O[Cr](Cl)(=O)=O BUIQRTDBPCHRIR-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- MWOQRLMTLAHNFB-UHFFFAOYSA-N [Li]C#CC(C)C Chemical compound [Li]C#CC(C)C MWOQRLMTLAHNFB-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229950005228 bromoform Drugs 0.000 description 1
- INGGGNUCWJHFKD-UHFFFAOYSA-N chromium;pyridine Chemical compound [Cr].C1=CC=NC=C1 INGGGNUCWJHFKD-UHFFFAOYSA-N 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- SOCTUWSJJQCPFX-UHFFFAOYSA-N dichromate(2-) Chemical compound [O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O SOCTUWSJJQCPFX-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000003961 organosilicon compounds Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 239000003375 plant hormone Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
ａ 産業上の利用分野
本発明は、ヒドロキシ化合物の製造法に関する
ものである。更に詳しくは、光学活性のアセター
ルからCram体のヒドロキシ化合物を製造する方
法に関するものである。
ｂ 従来技術
従来、光学活性アルデヒド基をヒドロキシ基に
変換する方法は数多く知られている。殊にステロ
イド骨格を有する光学活性アルデヒドに対して、
そのアルデヒド基を立体特異的にヒドロキシル基
に転換する方法もまた知られている。
例えば下記式に示される如くステロイド骨格に
結合したアルデヒド基に、３−メチル−１−ブチ
ニルリチウムを作用させて、そのアルデヒド基を
ヒドロキシル基に変換する方法が知られている
〔Journal of the Chemical Society，Chemical
Communication 962（1980）参照〕。
〔上記反応式中Stはステロイド骨格を示す。〕
また上記方法と比べて類似のステロイド骨格を
有するアルデヒドに対して同様のリチウム化合物
を作用させてアルデヒド基をヒドロキシル基に転
換する方法が特開昭59−33300号公報に開示され
ている。
これらの方法は、いずれも植物生長ホルモンの
一種であるブラシノライド（Brassinolide）の合
成を目的として、その中間体の合成の反応に採用
されている。ブラシノライドの合成のためには上
記反応式において、Cram体が目的化合物であ
る。上記反応では、収率のみならずCram体の選
択性の向上がブラシノライドの収率および純度を
高めるために不可欠となる。
上記した２つの方法は、光学活性アルデヒド基
に対しリチウム化合物を作用させており、ヒドロ
キシ化合物の全収率は高々約68％に過ぎず、また
Cram体とanti−Cram体との割合はほぼ50：50で
ある。
そこで本発明者は、光学活性のアルデヒドから
誘導された特定の光学活性のアセタールを出発原
料とし、高転化率でしかもCram体の光学活性の
ヒドロキシ化合物を高選択率で得る方法について
研究を進めた結果本発明に到達したものである。
ｃ 発明の構成
すなわち、本発明は下記一般式〔Ｉ〕
〔但し式中Ｘは有機基を示し、Ｙは炭素数10以下
の炭化水素基、ｎは０または１を示す。〕
で表わされるアセタールを下記一般式〔〕
R1−Ｍ ……〔〕
〔但し式中R1はＺ−Ｃ≡Ｃ−またはCH2＝CH−
CH2−（ここでＺは炭素数10以下のアルキル基、
シクロアルキル基またはアリル基を示す）であ
り、Ｍは−SnR2 3または−SiR2 3を示すがＭが−
SiR2 3のときはR1はCH2＝CH−CH2−である。
またR2は炭素数１〜４のアルキル基を示す。〕
で表わされる有機金属化合物と不活性溶媒中で反
応せしめることを特徴とする下記一般式〔〕
〔但し式中Ｘ，ＹおよびR1は前記定義と同じも
のを示す。〕
で表わされるヒドロキシ化合物の製造法である。
かかる本発明によれば、前記一般式〔Ｉ〕のア
セタールに対して、前記一般式〔〕の有機錫化
合物または有機シリコン化合物を反応させること
によつて、ヒドロキシ化合物を高い転化率で得る
ことができ、しかも、ヒドロキシ化合物における
前記一般式〔〕のCram体の割合が80％以上、
好適条件下では85％以上の高選択率で生成する。
以下本発明方法について更に詳細に説明する。
本発明方法において、出発原料であるアセター
ルは、一般式〔Ｉ〕で表わされるが、ここでＸは
有機基であり、その例としてはステロイド骨格で
あつてもよくまたテルペン骨格であつてもよい。
さらにＸは、脂肪族−および／または脂環族−炭
化水素基であることができ、その炭化水素基には
酸素（Ｏ）、窒素（Ｎ）、硫黄（Ｓ）など原子を分
子中或いは側鎖に含んでいてもよい。Ｘは本発明
の反応条件下において不活性な基または結合であ
れば種々のものを有していても差支えない。Ｘは
一般的には炭素数30以下、好ましくは20以下のも
のが好適である。本発明方法は後述する説明から
明らかなように、光学活性のCram体のヒドロキ
シ化合物を高い選択率で得るのに適しているか
ら、その目的に応じてＸの骨格を選択することが
でき、Ｘがステロイドまたはテルペンの骨格であ
る場合に特に有利である。Ｘがステロイド骨格の
場合その骨格は、種々のステロイド骨格であれば
よく、殊に本発明の反応条件下で反応に関与しな
い結合もしくは基を有しているのが望ましい。ス
テロイド骨格は、ブラシノライドもしくはその類
縁体またはそれらの合成中間体であることができ
る。
前記一般式〔Ｉ〕のアセタールにおいてＹは炭
素数10以下、好ましくは５以下の炭化水素基であ
り、Ｘよりも炭素数が少ない方がよい。好ましい
具体例は炭素数５以下のアルキル基である。
本発明方法の原料である前記一般式〔Ｉ〕のア
セタールは、下記式
〔式中ＸおよびＹは前記定義と同じものを示す。〕
で表わされる光学活性アルデヒドに、（−）−
（2R，4R−ペンタンジオールの如きジオールを
作用させることにより容易に得ることができる。
前記一般式〔Ｉ〕のアセタールに反応せしめら
れる有機金属化合物は、一般式〔〕で表わされ
る。この化合物を更に具体的に示すと下記の化合
物で表わされる。
Ｚ−Ｃ≡Ｃ−SnR2 3 〔−ａ〕
CH2＝CH−CH2−SnR2 3 〔−ｂ〕
CH2＝CH−CH2−SiR2 3 〔−ｃ〕
〔但しこれら式中ＺおよびR2は前記定義と同じ
ものを示す。〕
前記一般式〔〕または〔−ａ〕において、
Ｚは炭素数10以下のアルキル基、シクロアルキル
基またはアリル基であり、これらのうち、炭素数
６以下の分枝もしくは直鎖のアルキル基、および
フエニル基が好ましい。またR2は炭素数１〜４
のアルキル基を示すが、具体的には、メチル基、
エチル基、プロピル基もしくはブチル基が挙げら
れる。
上記一般式〔〕の有機金属化合物の好ましい
例としては下記のものを示すことができる（下記
式中Buはブチル基、Meはメチル基を示す）。
H3C−CH2−CH2−CH2−Ｃ≡Ｃ−SnBu3
CH2＝CH−CH2−SnBu3
CH2＝CH−CH2−SiMe3
前記有機金属化合物〔〕は、原料アセタール
１モル当り、通常１モル以上、好ましくは1.2モ
ル以上使用するのが有利である。上限は特に制限
されないが、５モル以下、好ましくは３モル以下
が望ましい。
本発明方法における前記のアセタールと有機金
属化合物との反応は、不活性溶媒中で実施され
る。不活性溶媒としては、原料アセタール、有機
金属化合物および目的とするヒドロキシ化合物を
溶解することができ、またこれらと反応せず、反
応条件下で液状を呈するものが有利に使用され
る。特にこの反応では一般的にルイス酸を触媒と
して使用するので、この触媒の活性に悪影響を与
えない溶媒を使用するのが望ましい。かかる溶媒
としては、例えばジクロルメタン、クロルホル
ム、ブロモホルム、バークレン、クロルベンゼン
の如きハロゲン化炭化水素が好適である。
反応はルイス酸の存在下に行うのが望ましく、
そのルイス酸の例としては、TiCcl4，SnCl4，
AlCl3などが挙げられるが就中TiCl4が有利であ
る。
本発明におけるヒドロキシ化合物の合成は、約
−90〜−20℃の範囲、好ましくは約−90〜−50℃
の範囲の温度で行うのが一般的である。実際的に
はドライアイス−アセトンを用いて−78℃の温度
で、原料、溶媒および触媒を仕込み、その後次第
に昇温して−20℃まで、好ましくは−50℃まで反
応温度を上げて反応を完結させるのが望ましい。
本発明方法を実施する場合、アセタールと有機
金属化合物とを前記反応条件下で反応せしめ、得
られた反応混合物に常法により酸化剤を作用せし
めて酸化し、しかる後加水分解することにより目
的とするCram体のヒドロキシ化合物が得られ
る。この場合に使用される酸化剤としては、例え
ばピリジン−クロム錯体、重クロム酸塩、過マン
ガン酸塩などの種々の酸化剤が用いられる。また
加水分解は例えばKOH，NaOHの如き塩基の存
在下メタノールー水を加えることによつて容易に
行うことができる。
かくして本発明によれば、使用した有機金属化
合物におけるR1−基がアセタールに結合した
Cram体のヒドロキシ化合物が高転化率且つ高選
択率で得られる。
かかる本発明方法を利用することによつて、例
えば植物ホルモンとして有用なブラシノライド或
いはその類縁体を有利に合成することが可能とな
る。
以下実施例を掲げて本発明方法を詳述する。
実施例 １
本実施例においては、化合物の番号は、それぞ
れ下記のものを表わす。
なお、下記化学式中Ｘは下記ステロイド骨格を
示すものとする。
１−１ アセタールの合成
アルデヒド１〜（4.44gr，10mmole）と、（−）
−（2R，4R）−ペンタンジオール２〜（1.04gr，
10mmole）とをベンゼン（100ml）に溶解し、
ピリジニウム・トシラート（Pyridinium
tosylate；0.25gr，1mmole）を加えて、環流
しつつ、デーン−スターク・トラツプ（Dean
−Stark Trap）を用いて生成した水を除去し
た。約１時間の環流で反応は完結した。その後
ベンゼンを減圧下留去し、エーテルを加え、飽
和NaHCO3溶液で振つてエーテル抽出を行つ
た。エーテル層へ無水芒硝を用いて乾燥し、エ
ーテルを留去して後、95％以上の収率でアセタ
ール３〜が得られた。なおこの合成はR.
Sterzycki，Synthesis，724（1979）に従つて行
つた。
１−２ ヒドロキシ化合物の合成
前記の如くして得られたアセタール３
（1mmole，0.53gr）をセラムキヤツプのついた
枝付きフラスコ（50ml）に入れ、反応容器を窒
素置換し、反応系を窒素雰囲気下にした。乾燥
したCH2Cl2溶媒（５ml）を注射器を用いてフ
ラスコ内に入れ、フラスコをドライアイス−ア
セトンを用いて冷却した（約−78℃）。
マグネテイクスターラーを用いて撹拌しなが
ら、上記温度でTiCl4のCH2Cl2溶液（1M，
1mmole，１ml）を加えた。続いて有機錫化合
物４〜（1.2mmole，約0.48ml）を加え、温度を
−78℃から徐々に−50℃まで約２時間かけて昇
温した。メタノール−水（１：１，２ml）を加
えて反応を停止し、０℃でエーテル抽出を行つ
た。３回抽出を行いエーテル層を無水芒硝で乾
燥し、エーテルを留去してシリカゲルのシヨー
トカラムへ通した。Bu3Sn部分由来の不用物は
極性が低いため、CCl4（又はヘキサン）溶媒で
留出した。
得られた粗化合物５〜を精製することなく既知
の方法〔P.A.Bartlett，W.S.Johnson，J.D.
Elliott，J.Am.Chem.Soc.，105，2088（1983）
参照〕に従つて、酸化−加水分解を行つた。す
なわち、粗化合物５をCH2Cl2（５ml）に溶解
し、これにPCC（Pyridinium
Chlorochromate，クロルクロム酸ピリジニウ
ム）の0.24gr（1.5mmole）を加えて室温で一昼
夜撹拌した。次いでシリカゲルの短いカラムで
流出しCH2Cl2で残渣を洗い、カラムで流出し
有機化合物を取り出した。その結果化合物６〜が
90％以上の収率で得られた。この化合物６〜を精
製することなく、そのままテトラヒドロフラン
−メタノール−7.5MKOHの混合溶媒（４：
２：１の容積比率）2.5mlに加えて室温で４時
間撹拌した。
その後エーテルで３回抽出し、エーテル層を
飽和NH4Cl溶液で振り、無水芒硝で乾燥し、
シリカゲルカラムで精製するとヒドロキシ化合
物７〜（Cram体）およびそのanti−Cram体が得
られた。分析の結果アセタール３〜からのCram
体（７〜）およびanti−Cram体の合計収率は72
％であり、Cram体（７〜）：anti−Cram体の比
率は95：５であつた。
なお生成物におけるCram体とanti−Cram体
との比は400MHz1H NMRを用いて分析した。
NMR分析の結果上記生成物のａ，ｂ，ｃお
よびｄにおけるCDCl3中TMSからのppm値は
下記の通りであつた。
a. Industrial Application Field The present invention relates to a method for producing a hydroxy compound. More specifically, the present invention relates to a method for producing a Cram-type hydroxy compound from an optically active acetal. b. Prior Art Conventionally, many methods for converting an optically active aldehyde group into a hydroxy group are known. Especially for optically active aldehydes having a steroid skeleton,
Methods for stereospecifically converting the aldehyde group into a hydroxyl group are also known. For example, a method is known in which 3-methyl-1-butynyllithium acts on an aldehyde group bonded to a steroid skeleton to convert the aldehyde group into a hydroxyl group as shown in the following formula [Journal of the Chemical Society，Chemical
See Communication 962 (1980)]. [St in the above reaction formula represents a steroid skeleton. ] Furthermore, compared to the above method, JP-A-59-33300 discloses a method in which a similar lithium compound is applied to an aldehyde having a similar steroid skeleton to convert an aldehyde group into a hydroxyl group. All of these methods are employed for the synthesis reaction of intermediates for the purpose of synthesizing brassinolide, which is a type of plant growth hormone. For the synthesis of brassinolide, the Cram compound is the target compound in the above reaction formula. In the above reaction, it is essential to improve not only the yield but also the selectivity of the Cram compound in order to increase the yield and purity of brassinolide. In the two methods described above, a lithium compound acts on an optically active aldehyde group, and the total yield of hydroxy compounds is only about 68% at most.
The ratio of Cram bodies and anti-Cram bodies is approximately 50:50. Therefore, the present inventor conducted research on a method for obtaining a Cram-form optically active hydroxy compound with a high conversion rate and high selectivity using a specific optically active acetal derived from an optically active aldehyde as a starting material. As a result, we have arrived at the present invention. c. Structure of the invention That is, the present invention has the following general formula [I] [However, in the formula, X represents an organic group, Y represents a hydrocarbon group having 10 or less carbon atoms, and n represents 0 or 1. ] The acetal represented by the following general formula [] R 1 -M ... [] [However, in the formula, R 1 is Z-C≡C- or CH 2 = CH-
CH 2 − (where Z is an alkyl group having 10 or less carbon atoms,
(represents a cycloalkyl group or an allyl group), M represents -SnR 2 3 or -SiR 2 3 , and M represents -
In the case of SiR 2 3 , R 1 is CH 2 =CH−CH 2 −. Further, R 2 represents an alkyl group having 1 to 4 carbon atoms. ] The following general formula [] is characterized in that it is reacted with an organometallic compound represented by in an inert solvent. [However, in the formula, X, Y and R 1 are the same as defined above. ] This is a method for producing a hydroxy compound represented by: According to the present invention, a hydroxy compound can be obtained at a high conversion rate by reacting an organotin compound or an organosilicon compound of the general formula [] with the acetal of the general formula [I]. and the proportion of the Cram form of the general formula [] in the hydroxy compound is 80% or more,
Under suitable conditions, it is produced with a high selectivity of 85% or more. The method of the present invention will be explained in more detail below. In the method of the present invention, the acetal that is the starting material is represented by the general formula [I], where X is an organic group, such as a steroid skeleton or a terpene skeleton. .
Furthermore, X can be an aliphatic and/or alicyclic hydrocarbon group, and the hydrocarbon group has atoms such as oxygen (O), nitrogen (N), and sulfur (S) in the molecule or on the side. May be included in the chain. X may have various groups or bonds as long as they are inert under the reaction conditions of the present invention. Generally, X has 30 or less carbon atoms, preferably 20 or less carbon atoms. As is clear from the explanation given below, the method of the present invention is suitable for obtaining optically active Cram-form hydroxy compounds with high selectivity, so the skeleton of X can be selected depending on the purpose, and It is particularly advantageous when is a steroid or terpene backbone. When X is a steroid skeleton, the skeleton may be any of various steroid skeletons, and it is particularly desirable that the skeleton has a bond or group that does not participate in the reaction under the reaction conditions of the present invention. The steroid backbone can be brassinolide or an analog thereof or a synthetic intermediate thereof. In the acetal of the general formula [I], Y is a hydrocarbon group having 10 or less carbon atoms, preferably 5 or less carbon atoms, and preferably has fewer carbon atoms than X. A preferred specific example is an alkyl group having 5 or less carbon atoms. The acetal of the general formula [I], which is a raw material for the method of the present invention, has the following formula: [In the formula, X and Y are the same as defined above. ] In the optically active aldehyde represented by (-)-
(It can be easily obtained by reacting with a diol such as 2R,4R-pentanediol. The organometallic compound reacted with the acetal of the general formula [I] is represented by the general formula []. More specifically, it is represented by the following compound: Z-C≡C-SnR 2 3 [-a] CH 2 =CH-CH 2 -SnR 2 3 [-b] CH 2 =CH-CH 2 -SiR 2 3 [-c] [However, Z and R 2 in these formulas have the same meanings as defined above.] In the general formula [] or [-a],
Z is an alkyl group, a cycloalkyl group, or an allyl group having 10 or less carbon atoms, and among these, a branched or straight-chain alkyl group having 6 or less carbon atoms and a phenyl group are preferable. Also, R 2 has 1 to 4 carbon atoms.
represents an alkyl group, specifically a methyl group,
Examples include ethyl group, propyl group and butyl group. Preferred examples of the organometallic compound represented by the above general formula [] include the following (in the following formula, Bu represents a butyl group and Me represents a methyl group). H 3 C−CH 2 −CH 2 −CH 2 −C≡C−SnBu 3 CH 2 = CH-CH 2 -SnBu 3 CH 2 = CH-CH 2 -SiMe 3 It is advantageous to use the organometallic compound [] in an amount of usually 1 mol or more, preferably 1.2 mol or more, per 1 mol of raw material acetal. be. The upper limit is not particularly limited, but is preferably 5 mol or less, preferably 3 mol or less. The reaction of the acetal with the organometallic compound in the method of the invention is carried out in an inert solvent. As the inert solvent, one that can dissolve the raw material acetal, the organometallic compound, and the desired hydroxy compound, does not react with them, and is liquid under the reaction conditions is advantageously used. In particular, since a Lewis acid is generally used as a catalyst in this reaction, it is desirable to use a solvent that does not adversely affect the activity of the catalyst. Suitable examples of such solvents include halogenated hydrocarbons such as dichloromethane, chloroform, bromoform, verklein, and chlorobenzene. The reaction is preferably carried out in the presence of a Lewis acid,
Examples of Lewis acids include TiCcl 4 , SnCl 4 ,
Among them, TiCl 4 is advantageous, among which AlCl 3 is mentioned. The synthesis of hydroxy compounds in the present invention is carried out at temperatures ranging from about -90 to -20°C, preferably from about -90 to -50°C.
It is generally carried out at a temperature in the range of . In practice, the raw materials, solvent, and catalyst are prepared at a temperature of -78°C using dry ice-acetone, and then the reaction temperature is gradually raised to -20°C, preferably -50°C to carry out the reaction. It is desirable to complete it. When carrying out the method of the present invention, the acetal and the organometallic compound are reacted under the above-mentioned reaction conditions, the resulting reaction mixture is oxidized by the action of an oxidizing agent in a conventional manner, and then hydrolyzed to achieve the desired effect. A Cram-type hydroxy compound is obtained. As the oxidizing agent used in this case, various oxidizing agents such as pyridine-chromium complex, dichromate, permanganate, etc. are used. Further, hydrolysis can be easily carried out by adding methanol-water in the presence of a base such as KOH or NaOH. Thus, according to the invention, the R 1 − group in the organometallic compound used is bonded to an acetal.
A Cram-form hydroxy compound can be obtained with high conversion rate and high selectivity. By utilizing the method of the present invention, it becomes possible to advantageously synthesize, for example, brassinolide or its analogs useful as plant hormones. The method of the present invention will be described in detail below with reference to Examples. Example 1 In this example, compound numbers represent the following, respectively. In addition, in the following chemical formula, X shall represent the following steroid skeleton. 1-1 Synthesis of acetal Aldehyde 1~ (4.44gr, 10mmole) and (-)
-(2R,4R)-pentanediol 2~(1.04gr,
10mmole) in benzene (100ml),
Pyridinium tosylate
tosylate; 0.25gr, 1mmole), and while refluxing, Dean-Stark trap (Dean-Stark trap)
-Stark Trap) was used to remove the water produced. The reaction was completed after about 1 hour of reflux. Thereafter, benzene was distilled off under reduced pressure, ether was added, and the mixture was shaken with saturated NaHCO 3 solution to perform ether extraction. After drying the ether layer using anhydrous sodium sulfate and distilling off the ether, acetal 3 was obtained with a yield of 95% or more. This synthesis is performed by R.
Sterzycki, Synthesis, 724 (1979). 1-2 Synthesis of hydroxy compound Acetal 3 obtained as above
(1 mmole, 0.53 gr) was placed in a flask with side arms (50 ml) equipped with a serum cap, and the reaction vessel was purged with nitrogen to bring the reaction system under a nitrogen atmosphere. Dry CH 2 Cl 2 solvent (5 ml) was placed into the flask using a syringe and the flask was cooled (approximately -78°C) using dry ice-acetone. A solution of TiCl4 in CH2Cl2 ( 1M ,
1 mmole, 1 ml) was added. Subsequently, organotin compound 4~ (1.2 mmole, about 0.48 ml) was added, and the temperature was gradually raised from -78°C to -50°C over about 2 hours. The reaction was stopped by adding methanol-water (1:1, 2 ml) and extracted with ether at 0°C. Extraction was carried out three times, and the ether layer was dried over anhydrous sodium sulfate, the ether was distilled off, and the mixture was passed through a silica gel column. Since the waste derived from the Bu 3 Sn portion has low polarity, it was distilled using a CCl 4 (or hexane) solvent. The crude compounds 5~ obtained were purified by known methods [PA Bartlett, WS Johnson, JD
Elliott, J.Am.Chem.Soc., 105, 2088 (1983)
Oxidation-hydrolysis was carried out according to [Ref.]. That is, crude compound 5 was dissolved in CH 2 Cl 2 (5 ml), and PCC (Pyridinium
0.24 gr (1.5 mmole) of Chlorochromate (pyridinium chlorochromate) was added and stirred at room temperature overnight. It was then run through a short column of silica gel, the residue was washed with CH 2 Cl 2 , and the organic compounds were removed through a column. As a result, compound 6~
Obtained with a yield of over 90%. Without purifying this compound 6~, a mixed solvent of tetrahydrofuran-methanol-7.5MKOH (4:
2.5 ml (volume ratio of 2:1) and stirred at room temperature for 4 hours. It was then extracted three times with ether, the ether layer was shaken with saturated NH 4 Cl solution, dried over anhydrous sodium sulfate,
When purified using a silica gel column, hydroxy compound 7 (Cram form) and its anti-Cram form were obtained. As a result of analysis, Cram from acetal 3~
The total yield of isomer (7~) and anti-Cram isomer is 72
%, and the ratio of Cram body (7~):anti-Cram body was 95:5. Note that the ratio of the Cram form and the anti-Cram form in the product was analyzed using 400MHz 1 H NMR. As a result of NMR analysis, the ppm values of the above products a, b, c and d from TMS in CDCl 3 were as follows.
【表】
実施例 ２〜４
前記実施例１において、同じアセタール３〜を用
いて、有機錫化合物４〜に代え下記有機金属化合物
を同じモル量使用する以外同様にして反応を行つ
た。その結果は下記の通りであつた。[Table] Examples 2 to 4 Reactions were carried out in the same manner as in Example 1, using the same acetals 3 to 3, except that the same molar amounts of the following organometallic compounds were used in place of organotin compounds 4 to 4. The results were as follows.
【表】 Cram体とanti−Cram体の分析 (1) [Table] Analysis of Cram and anti-Cram bodies (1)
【表】 (2) [Table] (2)
Claims (1)
の炭化水素基、ｎは０または１を示す。〕 で表わされるアセタールを下記一般式〔〕 R1−Ｍ ……〔〕 〔但し式中R1はＺ−Ｃ≡Ｃ−またはCH2＝CH−
CH2−（ここでＺは炭素数10以下のアルキル基、
シクロアルキル基またはアリル基を示す）であ
り、Ｍは−SnR2 3または−SiR2 3を示すがＭが−
SiR2 3のときはCH2＝CH−CH2−である。 またR2は炭素数１〜４のアルキル基を示す。〕 で表わされる有機金属化合物と不活性溶媒中で反
応せしめることを特徴とする下記一般式〔〕 〔但し式中Ｘ，ＹおよびR1は前記定義と同じも
のを示す。〕 で表わされるヒドロキシ化合物の製造法。[Claims] 1 The following general formula [I] [However, in the formula, X represents an organic group, Y represents a hydrocarbon group having 10 or less carbon atoms, and n represents 0 or 1. ] The acetal represented by the following general formula [] R 1 -M ... [] [However, in the formula, R 1 is Z-C≡C- or CH 2 = CH-
CH 2 − (where Z is an alkyl group having 10 or less carbon atoms,
(represents a cycloalkyl group or an allyl group), M represents -SnR 2 3 or -SiR 2 3 , and M represents -
In the case of SiR 2 3 , CH 2 =CH−CH 2 −. Further, R 2 represents an alkyl group having 1 to 4 carbon atoms. ] The following general formula [] is characterized in that it is reacted with an organometallic compound represented by in an inert solvent. [However, in the formula, X, Y and R 1 are the same as defined above. ] A method for producing a hydroxy compound represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60188483A JPS6251628A (en) | 1985-08-29 | 1985-08-29 | Production of hydroxy compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60188483A JPS6251628A (en) | 1985-08-29 | 1985-08-29 | Production of hydroxy compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6251628A JPS6251628A (en) | 1987-03-06 |
| JPH0253411B2 true JPH0253411B2 (en) | 1990-11-16 |
Family
ID=16224519
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60188483A Granted JPS6251628A (en) | 1985-08-29 | 1985-08-29 | Production of hydroxy compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6251628A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06263652A (en) * | 1993-03-11 | 1994-09-20 | Central Glass Co Ltd | Production of optically active halogenated hydroxyolefins |
-
1985
- 1985-08-29 JP JP60188483A patent/JPS6251628A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6251628A (en) | 1987-03-06 |
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