JPH0227996A - Production of optically active cyclopentenol derivative - Google Patents
Production of optically active cyclopentenol derivativeInfo
- Publication number
- JPH0227996A JPH0227996A JP17886088A JP17886088A JPH0227996A JP H0227996 A JPH0227996 A JP H0227996A JP 17886088 A JP17886088 A JP 17886088A JP 17886088 A JP17886088 A JP 17886088A JP H0227996 A JPH0227996 A JP H0227996A
- Authority
- JP
- Japan
- Prior art keywords
- cis
- optically active
- group
- mixture
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- NWZXFAYYQNFDCA-UHFFFAOYSA-N cyclopenten-1-ol Chemical class OC1=CCCC1 NWZXFAYYQNFDCA-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 102000004190 Enzymes Human genes 0.000 claims abstract description 9
- 108090000790 Enzymes Proteins 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims abstract description 7
- 125000006239 protecting group Chemical group 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000002433 cyclopentenyl group Chemical class C1(=CCCC1)* 0.000 claims abstract 3
- 239000000126 substance Substances 0.000 claims abstract 3
- 229940088598 enzyme Drugs 0.000 abstract description 8
- 102000019280 Pancreatic lipases Human genes 0.000 abstract description 7
- 108050006759 Pancreatic lipases Proteins 0.000 abstract description 7
- 229940116369 pancreatic lipase Drugs 0.000 abstract description 7
- 108090000371 Esterases Proteins 0.000 abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 2
- 229910052760 oxygen Inorganic materials 0.000 abstract 2
- 239000001301 oxygen Substances 0.000 abstract 2
- 241000283690 Bos taurus Species 0.000 abstract 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 abstract 1
- 229960004373 acetylcholine Drugs 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 150000001941 cyclopentenes Chemical class 0.000 description 5
- -1 silyloxy-2-cyclopenten-1-ols Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108090001060 Lipase Proteins 0.000 description 3
- 239000004367 Lipase Substances 0.000 description 3
- 102000004882 Lipase Human genes 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 235000019421 lipase Nutrition 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 229940040461 lipase Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YNCKAQVPQJWLJW-UHFFFAOYSA-N (4-oxocyclopent-2-en-1-yl) acetate Chemical compound CC(=O)OC1CC(=O)C=C1 YNCKAQVPQJWLJW-UHFFFAOYSA-N 0.000 description 1
- OQOREVKIUBEVPH-UHFFFAOYSA-N 1-[tert-butyl(dimethyl)silyl]oxycyclopent-2-en-1-ol Chemical compound CC(C)(C)[Si](C)(C)OC1(O)CCC=C1 OQOREVKIUBEVPH-UHFFFAOYSA-N 0.000 description 1
- DHNDDRBMUVFQIZ-UHFFFAOYSA-N 4-hydroxycyclopent-2-en-1-one Chemical compound OC1CC(=O)C=C1 DHNDDRBMUVFQIZ-UHFFFAOYSA-N 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- CLRBSUZPPLTQGO-UHFFFAOYSA-N tert-butyl-cyclopent-2-en-1-yloxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1CCC=C1 CLRBSUZPPLTQGO-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は光学活性なシクロベンテノール誘導体の製造法
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active cyclobentenol derivatives.
さらに詳しく言えば、本発明は、一般式（式中、Ｒ１は
低級アルキル基、Ｒ２は水酸基の保護基であるシリル基
を表わす〉で表わされるシクロペンテン誘導体（シス体
、又は、シス・トランス混合物）を酵素で処理すること
を特徴とする一般式、
０Ｈ
（式中、Ｒ２は水酸基の保護基であるシリル基を表わす
。木は不斉中心を表わし、これに由来する立体異性体が
存在するが、本発明においては（Ｉｓ、４Ｒ）であるか
、（ＪＲ，４Ｓ）、または両者の任意の割合の混合物で
ある）で表わされる光学活性なシクロベンテノール誘導
体の製造方法を提供するものである。。More specifically, the present invention relates to a cyclopentene derivative (cis form or cis-trans mixture) represented by the general formula (wherein R1 represents a lower alkyl group and R2 represents a silyl group which is a hydroxyl group protecting group). The general formula, 0H (in the formula, R2 represents a silyl group that is a protecting group for a hydroxyl group. Wood represents an asymmetric center, and stereoisomers derived from this exist). , the present invention provides a method for producing an optically active cyclobentenol derivative represented by (Is, 4R), (JR, 4S), or a mixture of both in any proportion. ..
下記の式［１１ａ］で表わされる（Ｉｓ、４Ｒ）−４−
ｔｅｒｔ−ブチルジメチルジオキシリルオキシ−２−シ
クロペンテン−１−オールは、Ｈ
プロスタグランジンＥタイプの優れた合成原料であるが
、本発明者らは、一般式［１］で表わされるシクロペン
テン誘導体（シス体、あるいはシス・トランス混合物）
から不斉酵素加水分解反応により、式［１１ａ］を含む
一般式［１１］で表わされる光学活性なシクロベンテノ
ール誘導体を製造する優れた方法を提供することに成功
した。(Is, 4R)-4- represented by the following formula [11a]
Although tert-butyldimethyldioxylyloxy-2-cyclopenten-1-ol is an excellent raw material for the synthesis of H prostaglandin E type, the present inventors have developed a cyclopentene derivative ( cis form or cis-trans mixture)
We have succeeded in providing an excellent method for producing optically active cyclobentenol derivatives represented by general formula [11], including formula [11a], by an asymmetric enzymatic hydrolysis reaction.
従来、一般式［１１で表わされるシクロペンテン誘導体
に酵素を作用させて加水分解を行い、シクロベンテノー
ル誘導体を得たと言う報告は、黒体らによる柑橘類の果
皮より調製した酵素による加水分解のみが知られている
。Previously, there have been reports that cyclopentenol derivatives were obtained by hydrolyzing the cyclopentene derivative represented by the general formula [11] with enzymes, but the only known report was that of hydrolysis using enzymes prepared from citrus peels by Kurobita et al. It is being
（特許公報 昭５４−２６５２８）
しかしながら、この方法により得られるシクロペンテン
誘導体は光学活性体ではない。また、使用する酵素の調
製も煩雑であり、大量に入手することも困難である。(Patent Publication No. 54-26528) However, the cyclopentene derivative obtained by this method is not an optically active compound. Furthermore, the preparation of the enzyme used is complicated, and it is difficult to obtain it in large quantities.
本発明者らは、シクロペンテン誘導体［Ｉコを人手容易
な酵素を用いて、光学活性なシクロベンテノール誘導体
［■］を効率よく得ることに成功した。The present inventors succeeded in efficiently obtaining an optically active cyclobentenol derivative [■] using an enzyme that is easy to handle.
以下に本発明の詳細な説明する。The present invention will be explained in detail below.
本発明において用いられる酵素とは、加水分解する機能
を有する酵素であり、例えば、豚膵臓リパーゼ、Ｐｓｅ
ｕｄｏｍｏｎａｓ菌由来のリパーゼ＊ Ａｓｐｅｒｇｊ
ｌｌｕｓ菌由来のリパーゼなどのリパーゼ類や、肝臓エ
ステラーゼ。The enzyme used in the present invention is an enzyme having a hydrolyzing function, such as porcine pancreatic lipase, Pse
Lipase derived from Udomonas bacterium* Aspergj
Lipases such as lipase derived from S. llus and liver esterase.
膵臓エステラーゼ、アセチルコリンエステラーゼなどの
動物エステラーゼが挙げられる。中でも祖、または精製
した豚膵臓リパーゼが好ましい。特に、粗豚膵臓リパー
ゼは安価であり、かつ、大量に人手可能であり、より好
ましい。Examples include animal esterases such as pancreatic esterase and acetylcholinesterase. Among them, the original or purified porcine pancreatic lipase is preferred. In particular, crude porcine pancreatic lipase is more preferable because it is inexpensive and can be produced manually in large quantities.
光学活性な（Ｉｓ、４Ｒ）−４−シリルオキシ−２−シ
クロペンテン−１−オール類を得る場合は、豚膵臓リパ
ーゼを用いるのが特に好ましく、（ＩＲ，４Ｓ）−４−
シリルオキシ−２−シクロペンテン−１−オール類を得
る場合には、豚肝臓エステラーゼを用いるのが好ましい
。When obtaining optically active (Is,4R)-4-silyloxy-2-cyclopenten-1-ols, it is particularly preferable to use porcine pancreatic lipase, and (IR,4S)-4-
When obtaining silyloxy-2-cyclopenten-1-ols, it is preferable to use pig liver esterase.
本発明において用いられる反応溶媒としては、燐酸塩水
溶液などの緩衝液と、水溶性有機溶媒、たとえば、メタ
ノール、アセトン又はアセトニトリル等の混合溶媒が用
いられる。As the reaction solvent used in the present invention, a mixed solvent of a buffer such as a phosphate aqueous solution and a water-soluble organic solvent such as methanol, acetone or acetonitrile is used.
反応溶液のｐＨとしては実質的に酵素作用可能なｐＨで
あればよい。The pH of the reaction solution may be any pH that allows substantial enzymatic action.
基質として用いられる一般式［１１で表わされるシクロ
ペンテン誘導体は、４−ヒドロキシ−２−シクロペンテ
ン−１−オンから誘導し大量に得ることができる。そし
て一般式［Ｉ］はシス体とトランス体が存在するが、シ
ス体はもちろんのこと、シス体とトランス体の混合物で
も用いることができる。The cyclopentene derivative represented by the general formula [11] used as a substrate can be derived from 4-hydroxy-2-cyclopenten-1-one and obtained in large quantities. The general formula [I] has a cis form and a trans form, and not only the cis form but also a mixture of the cis form and the trans form can be used.
一般式［１］において、Ｒ１は、例えば、メチル基、エ
チル基、プロピル基、ブチル基、ペンチル基のような炭
素数１〜５の低級アルキル基であり、特にメチル基が安
価であり好ましい。In the general formula [1], R1 is, for example, a lower alkyl group having 1 to 5 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, or a pentyl group, and a methyl group is particularly preferred because it is inexpensive.
Ｒ２は水酸基の保護基であり、トリメチルシリル基、ト
リエチルシリル基、ｔｅｒｔ−ブチルジメチルシリル基
、メチルジイソプロピルシリル基のようなシリル基であ
る。R2 is a hydroxyl protecting group, and is a silyl group such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, or methyldiisopropylsilyl.
基質の濃度は実質的に酵素作用可能な濃度であるが、反
応溶媒に対し１〜２０重量％程度の濃度とするのが好ま
しい。The concentration of the substrate is such that it can substantially act as an enzyme, but it is preferably about 1 to 20% by weight relative to the reaction solvent.
反応時間は２〜１２０時間が好ましいが、これに限定さ
れるものではない。The reaction time is preferably 2 to 120 hours, but is not limited thereto.
反応温度は５〜２５℃が好ましいが、酵素反応可能な温
度であればよい。The reaction temperature is preferably 5 to 25°C, but any temperature that allows the enzymatic reaction may be used.
このようにして、本発明方法により 一般式［１１］で
表わされる光学活性なシクロベンテノール誘導体を製造
することができる。In this way, the optically active cyclobentenol derivative represented by the general formula [11] can be produced by the method of the present invention.
生成物の単離は、一般に使用される抽出有機溶媒（例え
ば、酢酸エチル、エーテル、クロロホルム等）で反応液
より生成物を抽出し、その後、溶媒留去等、通常の方法
で後処理することにより、粗生成物を得ることができる
。The product can be isolated by extracting the product from the reaction solution with a commonly used extraction organic solvent (e.g., ethyl acetate, ether, chloroform, etc.), and then post-processing by a usual method such as distilling off the solvent. A crude product can be obtained by:
粗生成物はカラムクロマトグラフィー法、調製用薄層ク
ロマトグラフィー法等によって精製できる。The crude product can be purified by column chromatography, preparative thin layer chromatography, or the like.
本発明でこのようにして得られた一般式［ｎ］で表わさ
れる光学活性なシクロベンテノール誘導体は、その水酸
基を酸化し、次いでα、β位をアルキル化することによ
りプロスタグランジンＥタイプに導くことができる重要
な中間体である。The optically active cyclobentenol derivative represented by the general formula [n] thus obtained in the present invention is converted into prostaglandin E type by oxidizing its hydroxyl group and then alkylating the α and β positions. It is an important intermediate that can lead to
このように、本発明はプロスタグランジン合成に極めて
有用な光学活性なシクロベンテノール誘導体の製造方法
を提供するものであり、その工業的価値は大きい。Thus, the present invention provides a method for producing optically active cyclobentenol derivatives that are extremely useful for prostaglandin synthesis, and has great industrial value.
以下に実施例を示すが、本発明はこれらに限定されるも
のではない。Examples are shown below, but the present invention is not limited thereto.
参考例１
４−アセトキシ−２−シクロペンテン−１−オン
４−ヒドロキシ−２−シクロペンテン−１−オン２９．
０２ｇ （０，３モル）をＴＨＦ１５００ ｍ ｌに溶
解し、無水酢酸４２． ５ｍｌ （０゜４５モル）と酢
酸ソーダ４９． ２ｇ （０，６モル）を加え、３５℃
で一晩攪拌した。Reference example 1 4-acetoxy-2-cyclopenten-1-one 4-hydroxy-2-cyclopenten-1-one 29.
0.2 g (0.3 mol) was dissolved in 1500 ml of THF, and 42.0 g of acetic anhydride was dissolved in 1500 ml of THF. 5 ml (0°45 mol) and sodium acetate 49. Add 2g (0.6 mol) and heat at 35°C.
The mixture was stirred overnight.
反応液に水を加え、有機層を分離した。水層部は、酢酸
エチルで抽出した。抽出液は先の有機層と合併し、飽和
食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。
濾過後、減圧濃縮して６０．０ｇの粗生成物を得た
。シリカゲルカラムクロマト精製し、２４．０ｇの目的
物を得た。 収率８０．０％
ＮＭＲ（ＣＤＣｌ２）δＨ＝ （９０ＭＨｚ）２．１１
ａｎｄ２．１３（３Ｈ，ｓ）＋２．３１ （ＩＨ，ｄｄ
、Ｊ＝２．４ａｎｄ１８．７Ｈｚ）、２．８６ （ＩＨ
，ｄｄ。Water was added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The extract was combined with the organic layer, washed with saturated brine, and dried over anhydrous magnesium sulfate.
After filtration, it was concentrated under reduced pressure to obtain 60.0 g of crude product. The product was purified by silica gel column chromatography to obtain 24.0 g of the desired product. Yield 80.0% NMR (CDCl2) δH = (90MHz) 2.11
and2.13 (3H, s) + 2.31 (IH, dd
, J=2.4and18.7Hz), 2.86 (IH
, dd.
Ｊ＝６．２ａｎｄ１８．７Ｈｚ）。J=6.2 and 18.7Hz).
５、 ８９ （ＩＨ，ｍ）、 ６． ３４ （ＩＨ。5, 89 (IH, m), 6. 34 (IH.
ｄｄ、Ｊ＝１．３ａｎｄ５．７Ｈｚ）。dd, J = 1.3 and 5.7 Hz).
７．６５ （ＩＨ，ｄｄ、Ｊ＝２．４ａｎｄ５．７Ｈｚ
）
参考例２
４−７セトキシー２−シクロペンテン−１−オール
４−アセトキシ−２−シクロペンテン−１−オン２４．
０ｇ （０，１７１モル）をメタノール７５０ｍ１に溶
解した。塩化第−セリウム７水和物６９．７ｇ（０，１
８７モル）を加え、水素化ホウ素ナトリウム７．２ｇを
数回に分けて、２０〜２３℃で加えた。7.65 (IH, dd, J=2.4and5.7Hz
) Reference Example 2 4-7 Setoxy-2-cyclopenten-1-ol 4-acetoxy-2-cyclopenten-1-one 24.
0 g (0,171 mol) was dissolved in 750 ml of methanol. Cerium chloride heptahydrate 69.7g (0,1
87 mol) was added thereto, and 7.2 g of sodium borohydride was added in several portions at 20-23°C.
２０℃で２０分間攪拌した後、飽和塩化アンモニウム水
溶液１ｉ５０ｍｌを加え、減圧濃縮した。After stirring at 20°C for 20 minutes, 1i50 ml of a saturated ammonium chloride aqueous solution was added, and the mixture was concentrated under reduced pressure.
濃縮残分にＩＮ−塩酸１９０ｍ１を加え、エーテルで５
回抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マ
グネシウムで乾燥した。Add 190ml of IN-hydrochloric acid to the concentrated residue, and dilute with ether for 50 minutes.
Extracted twice. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate.
濾過後、減圧濃縮して２１．９ｇの粗生成物を得た。シ
リカゲルカラムクロマト精製し、１７゜２ｇの目的物を
得た。 収率７１．１％本化合物はシス体とトランス体
の混合物でありその比はＮＭＲより３： ｌであった。After filtration, it was concentrated under reduced pressure to obtain 21.9 g of crude product. The product was purified by silica gel column chromatography to obtain 17.2 g of the desired product. Yield: 71.1% This compound was a mixture of cis and trans forms, and the ratio was 3:1 according to NMR.
ＮＭＲ（ＣＤＣ１３）δ＝（９０ＭＨｚ）１．６５ （
ＩＨ，ｍ）、２．０８ａｎｄ２、 １０ （３Ｈ，ｓ）
、 ２． ８２ （ＩＨ。NMR (CDC13) δ = (90MHz) 1.65 (
IH, m), 2.08and2, 10 (3H, s)
, 2. 82 (IH.
ｍ）、３．００ （ＩＨ，ｂｒ）、４．７４ａｎｄ５．
０８ （ＩＨ，ｍ）、５．５０ａｎｄ５．８０ （ＩＨ
，ｍ）、６．１０（２Ｈ，ｍ）
この５．０ｇをエーテル−〇−ヘキサン混合溶媒で再結
晶すると、シス−４−アセトキシ−２−シクロペンテン
−１−オール２．３ｇを得た。m), 3.00 (IH, br), 4.74and5.
08 (IH, m), 5.50and5.80 (IH
, m), 6.10 (2H, m) 5.0 g of this was recrystallized from a mixed solvent of ether-〇-hexane to obtain 2.3 g of cis-4-acetoxy-2-cyclopenten-1-ol.
参考例３
３−アセトキシ−５−ｔｅｒｔ−ブチルジメチルシリル
オキシ−１−シクロペンテン４−アセトキシ−２−シク
ロペンテン−１−オール１７．２ｇ（０，１２０モル）
をＤ Ｍ Ｆ１７０ｍｌに溶解し、ｔｅｒｔ−ブチルジ
メチルクロロシラン２０．２ｇ （０，１２２モル）と
イミダゾール８．３ｇ （０，１２２モル）を加え、室
温で４時間攪拌した。Reference example 3 3-acetoxy-5-tert-butyldimethylsilyloxy-1-cyclopentene 4-acetoxy-2-cyclopenten-1-ol 17.2 g (0,120 mol)
was dissolved in 170 ml of DMF, 20.2 g (0,122 mol) of tert-butyldimethylchlorosilane and 8.3 g (0,122 mol) of imidazole were added, and the mixture was stirred at room temperature for 4 hours.
水を加え、エーテルで４回抽出した。抽出液を飽和食塩
水で洗浄し、無水ｆｉＭ酸マグネシウムで乾燥した。濾
過後、減圧濃縮して３３．２ｇの粗生成物を得た。シリ
カゲルカラムクロマト精製し、２８．１ｇの目的物を得
た。Water was added and extracted four times with ether. The extract was washed with saturated brine and dried over anhydrous magnesium fiM acid. After filtration, it was concentrated under reduced pressure to obtain 33.2 g of crude product. The product was purified by silica gel column chromatography to obtain 28.1 g of the desired product.
収率 ９１．３％
ＮＭＲ（ＣＤＣ１３）δ＝ （９０ＭＨ２）０、 ０９
（６Ｈ，ｓ）、 ０． ９０ （９Ｈ。Yield 91.3% NMR (CDC13) δ = (90MH2) 0, 09
(6H,s), 0. 90 (9H.
Ｓ）、 １． ６０ （ＩＨ，ｍ）、 ２． ０
５（３Ｈ，ｓ）、 ２． ８９ （ＩＨ，ｍ）。S), 1. 60 (IH, m), 2. 0
5 (3H, s), 2. 89 (IH, m).
４、 ７１ ａｎｄ５． ０５ （１１−Ｌ ｍ）
＋５、 ６１ ａｎ ｄ ５．７６ （Ｉ Ｈ＋
ｒｎ） 。4, 71 and5. 05 (11-L m)
+5, 61 and 5.76 (I H+
rn).
５、 ９０ （２Ｆ！、 ｍ）
実施例１
（Ｉｓ、４Ｒ）−１Ｌ−ｔｅｒ Ｌ−ブチルジメチルシ
リルオキシ−２−シクａペンテン−１−オール
３−アセトキシ−５−ｔｅｒｔ−ブチルジメチルシリル
オキシ−１−シクロペンテン１０゜２ｇ（０，０４モル
）をメタノール２００ｍ１に溶解した。ｐＨ７のリン酸
緩衝液６１５ｍＬ粗豚膵臓リパーゼ（シグマ社製）５．
１２ｇを加え、１０〜１５℃で２４時間攪拌した。5, 90 (2F!, m) Example 1 (Is, 4R)-1L-ter L-butyldimethylsilyloxy-2-cyclopenten-1-ol 3-acetoxy-5-tert-butyldimethylsilyloxy- 10.2 g (0.04 mol) of 1-cyclopentene was dissolved in 200 ml of methanol. 615 mL of pH 7 phosphate buffer crude porcine pancreatic lipase (manufactured by Sigma)5.
12g was added and stirred at 10-15°C for 24 hours.
反応液をエーテル７００ｍ１で３回抽出し、無水硫酸マ
グネシウムで乾燥した。ｓ濾過後、減圧濃縮して１０．
２ｇの粗生成物を得た。The reaction solution was extracted three times with 700 ml of ether and dried over anhydrous magnesium sulfate. s After filtration, concentrate under reduced pressure and 10.
2 g of crude product was obtained.
シリカゲルカラムで精製し、トランスの原料アセテート
と（ＪＲ，４Ｓ）の原料アセテートの混合物を８．２５
ｇ回収した。Purified with a silica gel column, the mixture of raw material acetate of trans and raw material acetate of (JR, 4S) was 8.25
g was collected.
目的物は１．９３ｇ得た。1.93g of the target product was obtained.
収率 ２２．５％
［αコ ｏ ２＠ ＝＋２３． ８’ （ｃｏ、
９４゜ＣＨＣｌ３）
光学純度９９％ｅｅ以上
ＮＭＲ（ＣＤＣ＋３）δ＝（９０ＭＨｚ）０、 ０９
（６Ｈ，ｓ）、 ０． ９０ （９Ｈ。Yield 22.5% [α co o 2 @ = +23. 8' (co,
94°CHCl3) Optical purity 99%ee or higher NMR (CDC+3) δ = (90MHz) 0, 09
(6H,s), 0. 90 (9H.
ｓ）、 １． ５１ （ＩＨ，ｍ）、 １． ８９
（ＩＨ，ｂｒ）、２．６９ （ＩＨ，ｍ）。s), 1. 51 (IH, m), 1. 89
(IH, br), 2.69 (IH, m).
４、 ６５ （２Ｈ，ｂｒ）、 ５． ９２ （２Ｈ
。4, 65 (2H, br), 5. 92 (2H
.
ｍ）
実施例２
（Ｉｓ、４Ｒ）−４−ｔｅｒｔ−ブチルジメチルシリル
オキシ−２−シクロペンテン−１−オール
参考例２で得た、シス−４−アセトキシ−２−シクロペ
ンテン−１−オールを、参考例３と同様にシリル化し、
シス−３−アセトキシ−５−ｔｅｒｔ−ブチルジメチル
シリルオキシ−２−シクロペンテンを得た。この１．５
４ｇ（６ミリモル）をメタノール４０ｍ１に溶解した。m) Example 2 (Is, 4R)-4-tert-butyldimethylsilyloxy-2-cyclopenten-1-ol Cis-4-acetoxy-2-cyclopenten-1-ol obtained in Reference Example 2, Silylated in the same manner as in Example 3,
Cis-3-acetoxy-5-tert-butyldimethylsilyloxy-2-cyclopentene was obtained. This 1.5
4 g (6 mmol) were dissolved in 40 ml of methanol.
ｐＨ７のリン酸緩衝液９０ｍ１、粗豚膵臓リパーゼ（シ
グマ社製）０．８ｇを加え、１０℃で７０時間攪拌した
。実施例１と同様に後処理、精製を行い、シス−３−ア
セトキシ−５−ｔｅｒｔ−ブチルジメチルシリルオキシ
−２−シクロペンテンを０．７５ｇ回収した。90 ml of pH 7 phosphate buffer and 0.8 g of crude porcine pancreatic lipase (manufactured by Sigma) were added, and the mixture was stirred at 10° C. for 70 hours. Post-treatment and purification were performed in the same manner as in Example 1, and 0.75 g of cis-3-acetoxy-5-tert-butyldimethylsilyloxy-2-cyclopentene was recovered.
目的物は０．５９ｇ得た。0.59g of the target product was obtained.
収率 ４６．５％
［αコ ｏ ” ＝＋２３． ２’ （ｃＯ，９
４゜ＣＨＣｌ３）
光学純度９７％ｅｅ。Yield 46.5% [α co ” = +23.2' (cO,9
4°CHCl3) Optical purity 97%ee.
実施例３
（ＩＲ，４Ｓ）−４−ｔｅｒ ｔ−ブチルジメチルシリ
ルオキシ−２−シクロペンテン−１−オール
実施例２で回収したシス−３−アセトキシ−５−ｔｅｒ
ｔ−ブチルジメチルシリルオキシ−２−シクロペンテン
０．７５ｇ （２，９２ミリモル）をｐＨ７，３のリン
酸緩衝ｔ＆１５ｍ１、豚肝臓エステラーゼ懸濁液（シグ
マ社製）０゜３５ｍ１ （１０００ｕｎｉ Ｌｓ）を
加え、１５℃で７０時間攪拌した。この間、ＩＮ−苛性
ソーダ水溶液にてｐ）（を７〜７．５に保った。実施例
１と同様に後処理、精製を行い、目的物を０．５１ｇ得
た
［α］ｏ ２” ＝−１９，８° （ｃｏ、 ９４゜
ＣＨＣｌ３）
光学純度８３％ｅｅ。Example 3 (IR,4S)-4-ter t-butyldimethylsilyloxy-2-cyclopenten-1-ol Cis-3-acetoxy-5-ter recovered in Example 2
0.75 g (2.92 mmol) of t-butyldimethylsilyloxy-2-cyclopentene was added to 15 ml of phosphate buffer at pH 7.3 and 0°35 ml of pig liver esterase suspension (manufactured by Sigma) (1000 uni Ls). The mixture was stirred at 15°C for 70 hours. During this time, p) was maintained at 7 to 7.5 with an IN-caustic soda aqueous solution. Post-treatment and purification were performed in the same manner as in Example 1, and 0.51 g of the target product was obtained [α]o 2" = - 19,8° (co, 94° CHCl3) Optical purity 83%ee.
Claims (1)
護基であるシリル基を表わす）で表わされるシクロペン
テン誘導体（シス体、又は、シス・トランス混合物）を
酵素で処理することを特徴とする一般式、 ▲数式、化学式、表等があります▼［II］ （式中、Ｒ＾２は水酸基の保護基であるシリル基を表わ
す。＊は不斉中心を表わし、これに由来する立体異性体
が存在するが、本発明においては（１Ｓ、４Ｒ）である
か、 （１Ｒ、４Ｓ）、または両者の任意の割合の混合物であ
る。）で表わされる光学活性なシクロペンテノール誘導
体の製造方法。[Claims] There are general formulas, ▲mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R^1 represents a lower alkyl group, and R^2 represents a silyl group that is a protecting group for a hydroxyl group). There are general formulas, ▲mathematical formulas, chemical formulas, tables, etc.▼[II] (In the formula, R^2 is a hydroxyl group) characterized by treating the expressed cyclopentene derivative (cis form or cis-trans mixture) with an enzyme. represents a silyl group, which is a protecting group. * represents an asymmetric center, and stereoisomers derived from this exist, but in the present invention, it is (1S, 4R), (1R, 4S), or A method for producing an optically active cyclopentenol derivative represented by (a mixture of both in an arbitrary ratio).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17886088A JP2756790B2 (en) | 1988-07-18 | 1988-07-18 | Method for producing optically active cyclopentenol derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17886088A JP2756790B2 (en) | 1988-07-18 | 1988-07-18 | Method for producing optically active cyclopentenol derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0227996A true JPH0227996A (en) | 1990-01-30 |
| JP2756790B2 JP2756790B2 (en) | 1998-05-25 |
Family
ID=16055950
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17886088A Expired - Fee Related JP2756790B2 (en) | 1988-07-18 | 1988-07-18 | Method for producing optically active cyclopentenol derivative |
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| Country | Link |
|---|---|
| JP (1) | JP2756790B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003520018A (en) * | 1998-12-23 | 2003-07-02 | ロンザ ア−ゲ− | Method for producing optically active 1-amino-4- (hydroxylmethyl) -cyclopent-2-ene derivative |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0978567B1 (en) | 1997-12-29 | 2005-03-09 | Sanyo Shokuhin Co., Ltd. | Process for producing optically active alcohols |
-
1988
- 1988-07-18 JP JP17886088A patent/JP2756790B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003520018A (en) * | 1998-12-23 | 2003-07-02 | ロンザ ア−ゲ− | Method for producing optically active 1-amino-4- (hydroxylmethyl) -cyclopent-2-ene derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2756790B2 (en) | 1998-05-25 |
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