JP2613833B2 - Stereoselective process for producing optically active 11-methyl 12-membered lactones - Google Patents
Stereoselective process for producing optically active 11-methyl 12-membered lactonesInfo
- Publication number
- JP2613833B2 JP2613833B2 JP10242192A JP10242192A JP2613833B2 JP 2613833 B2 JP2613833 B2 JP 2613833B2 JP 10242192 A JP10242192 A JP 10242192A JP 10242192 A JP10242192 A JP 10242192A JP 2613833 B2 JP2613833 B2 JP 2613833B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- optically active
- producing optically
- lactones
- lipase
- 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.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims description 9
- 150000002596 lactones Chemical class 0.000 title description 6
- 230000000707 stereoselective effect Effects 0.000 title description 2
- 102000004882 Lipase Human genes 0.000 claims description 12
- 108090001060 Lipase Proteins 0.000 claims description 12
- 239000004367 Lipase Substances 0.000 claims description 12
- 235000019421 lipase Nutrition 0.000 claims description 12
- -1 methyl lactones Chemical class 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 5
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 claims description 2
- 241000589516 Pseudomonas Species 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 5
- 235000019387 fatty acid methyl ester Nutrition 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 4
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101000968491 Pseudomonas sp. (strain 109) Triacylglycerol lipase Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- 125000005480 straight-chain fatty acid group Chemical group 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 241000228245 Aspergillus niger Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 102000019280 Pancreatic lipases Human genes 0.000 description 1
- 108050006759 Pancreatic lipases Proteins 0.000 description 1
- 241000952054 Rhizopus sp. Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- OZKLKDKGPNBGPK-UHFFFAOYSA-N dodec-8-enoic acid Chemical compound CCCC=CCCCCCCC(O)=O OZKLKDKGPNBGPK-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- OAVPMNUQHOQNED-UHFFFAOYSA-N methyl 11-hydroxydodecanoate Chemical compound COC(=O)CCCCCCCCCC(C)O OAVPMNUQHOQNED-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102220201851 rs143406017 Human genes 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は光学活性メチル環状ラク
トン類、特に11位にメチル基を有する12員環ラクトン類
の立体選択的製造方法に関するものである。光学活性メ
チル環状ラクトン類は、一般に生理活性を示すものが多
く、医農薬品或いは医農薬品原料又は香料として有用で
ある。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stereoselective process for producing optically active methyl lactones, particularly 12-membered lactones having a methyl group at the 11-position. Many optically active methyl cyclic lactones generally show physiological activity and are useful as medicines and agricultural chemicals, raw materials for medicines and agricultural chemicals, or fragrances.
【０００２】[0002]
【従来の技術】メチル環状ラクトン類の製法としては、
ヒドロキシ基を有する直鎖脂肪酸メチルエステルとトリ
フェニルホスフィン及びジピリジルジスルフィドとの反
応により合成する方法が知られている。この製法は、反
応条件のコントロールが厳しく製造時の操作が複雑であ
る。更に、この製法は立体選択的にエステル縮合するも
のではない。従って、現在まで11位にヒドロキシ基を有
する直鎖脂肪酸メチルエステルより立体選択的に光学活
性11−メチル12員環ラクトン類を得る製造方法は開発さ
れていない。2. Description of the Related Art Methods for producing methyl cyclic lactones include:
A method of synthesizing a straight-chain fatty acid methyl ester having a hydroxy group with triphenylphosphine and dipyridyl disulfide is known. In this production method, the reaction conditions are strictly controlled and the operation during production is complicated. Furthermore, this method does not stereoselectively perform ester condensation. Therefore, to date, no production method has been developed to obtain stereoactively optically active 11-methyl 12-membered lactones from straight-chain fatty acid methyl esters having a hydroxy group at the 11-position.
【０００３】また、リパーゼを利用したラクトン化反応
は近年活発に研究されているが(H.Ohtaら、Chem. Let
t., 1775(1989))、ヒドロキシ脂肪酸エステルより光学
活性11−メチル12員環ラクトン類を立体選択的に製造し
た方法はない。The lactonization reaction using lipase has been actively studied in recent years (H. Ohta et al., Chem. Let.
t., 1775 (1989)), there is no method for stereoselectively producing optically active 11-methyl 12-membered lactones from hydroxy fatty acid esters.
【０００４】[0004]
【発明が解決しようとする課題】従って、本発明は、リ
パーゼを利用し、ヒドロキシ脂肪酸エステルより光学活
性11−メチル12員環ラクトン類を立体選択的に製造する
方法を提供することを目的とする。SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a method for stereoselectively producing an optically active 11-methyl 12-membered lactone from a hydroxy fatty acid ester using a lipase. .
【０００５】[0005]
【課題を解決するための手段】本発明は、式（Ｉ）：According to the present invention, there is provided a compound of formula (I):
【０００６】[0006]
【化３】 Embedded image
【０００７】で表されるラセミ体である化合物に、水分
の存在しない条件下で、リパーゼを作用させることによ
り、式（II）The lipase is allowed to act on the racemic compound represented by
【０００８】[0008]
【化４】 Embedded image
【０００９】で表されるＲ−体に富むメチルラクトンを
得ることを特徴とする光学活性メチルラクトン類の製造
方法である。好ましくは、本発明はリパーゼを用い、11
位にヒドロキシ基を有する直鎖脂肪酸メチルエステルを
有機溶媒中、分子内エステル縮合させることを特徴とす
る。本発明で使用できるリパーゼとして、シュードモナ
ス属 (Pseudomonus sp.)、アスペルギルス・ニガー (As
pergillus niger)、リゾプス属 (Rhizopus sp.) 等の微
生物産生リパーゼ、豚等の膵臓リパーゼが挙げられる
が、特に市販されているリパーゼＰＳまたはリパーゼＰ
が好ましく使用される。A process for producing optically active methyl lactones, characterized by obtaining an R-form-rich methyl lactone represented by the formula: Preferably, the invention uses lipase,
It is characterized by conducting intramolecular ester condensation of a straight-chain fatty acid methyl ester having a hydroxy group at an organic solvent in an organic solvent. Lipases that can be used in the present invention include Pseudomonus sp ., Aspergillus niger ( As
pergillus niger ), lipases produced by microorganisms such as Rhizopus sp ., pancreatic lipases from pigs, etc., and especially commercially available lipase PS or lipase P
Is preferably used.
【００１０】また、基質として、メチル （Ｅ）−１１
−ヒドロキシ−８−ドデセナート、メチル １１−ヒド
ロキシドデカナート等の11位にヒドロキシ基を有する飽
和又は不飽和の脂肪酸炭素数12の直鎖脂肪酸メチルエス
テルを使用する。更に、反応溶媒として、イソオクタ
ン、シクロヘキサン、四塩化炭素、ヘキサン、ヘプタ
ン、ベンゼン、トルエン等の有機溶媒を用いることがで
きるが、イソオクタンが好ましい。Further, methyl (E) -11 is used as a substrate.
A saturated or unsaturated fatty acid methyl ester having 12 carbon atoms and having a hydroxy group at the 11-position, such as -hydroxy-8-dodesenate and methyl 11-hydroxydodecanate, is used. Further, organic solvents such as isooctane, cyclohexane, carbon tetrachloride, hexane, heptane, benzene, and toluene can be used as the reaction solvent, but isooctane is preferred.
【００１１】更に、脱メタノール及び脱水剤として乾燥
モレキュラーシーブス４Ａ等を加えることにより反応が
促進される。Further, the reaction is promoted by adding de-methanol and dry molecular sieves 4A as a dehydrating agent.
【００１２】[0012]
【発明の効果】本発明によれば、容易に反応条件をコン
トロールでき、簡単な操作で光学活性11−メチル12員環
ラクトン類を立体選択的に得ることができる。According to the present invention, reaction conditions can be easily controlled, and optically active 11-methyl 12-membered lactones can be stereoselectively obtained by a simple operation.
【００１３】[0013]
【実施例】以下、更に本発明を代表的な実施例により具
体的に説明する。 実施例１ リパーゼとしてシュードモナス属（Pseudomonus sp.)由
来のリパーゼ（天野製薬製リパーゼＰ）(1g)、有機溶媒
としてイソオクタン(200ml) 、ヒドロキシ直鎖脂肪酸メ
チルエステルとしてメチル （Ｅ）−１１−ヒドロキシ
−８−ドデセナート（201mg)を混合し、更に乾燥モレキ
ューラーシーブ４Ａ(2g)を加え、65℃にて48時間攪拌し
た。反応液を濾過し、濾液より溶媒を留去後、シリカゲ
ルカラムクロマトグラフィーに付し、光学活性メチルラ
クトンである（Ｒ）−レシフェイオライド(13.3mg, 8
％) を光学純度94％で得た。 〔α〕D 25＋69.1°(c 0.57, CHCl3) IR (neat, cm-1) : 17201 H-NMR (CDCl3,δ) : 1.10-1.90(m, 8H), 1.23(d, J=6H
z, 3H),1.90-2.77(m, 6H), 4.60-5.00(m, 1H),5.00-5.5
0(m, 2H) MS m/z : 196(M+) 。EXAMPLES Hereinafter, the present invention will be described more specifically with reference to typical examples. Example 1 A lipase derived from Pseudomonus sp . (Lipase P manufactured by Amano Pharmaceutical) (1 g) as a lipase, isooctane (200 ml) as an organic solvent, methyl (E) -11-hydroxy- as a hydroxy straight-chain fatty acid methyl ester 8-Dodecenate (201 mg) was mixed, further dried molecular sieve 4A (2 g) was added, and the mixture was stirred at 65 ° C for 48 hours. The reaction solution was filtered, the solvent was distilled off from the filtrate, and the mixture was subjected to silica gel column chromatography to obtain (R) -recifeiolide (13.3 mg, 8
%) Was obtained with an optical purity of 94%. (Α) D 25 + 69.1 ° (c 0.57, CHCl 3 ) IR (neat, cm −1 ): 1720 1 H-NMR (CDCl 3 , δ): 1.10-1.90 (m, 8H), 1.23 (d, J = 6H
z, 3H), 1.90-2.77 (m, 6H), 4.60-5.00 (m, 1H), 5.00-5.5
0 (m, 2H) MS m / z: 196 (M + ).
【００１４】実施例２ リパーゼとしてシュードモナス属（Pseudomonus sp.)由
来のリパーゼ（天野製薬製リパーゼＰ）(2.5g)、有機溶
媒としてイソオクタン(500ml) 、ヒドロキシ直鎖脂肪酸
メチルエステルとしてメチル １１−ヒドロキシドデカ
ナート(502mg)を混合し、更に乾燥モレキューラーシー
ブ４Ａ(5g)を加え、65℃にて48時間攪拌した。反応液を
濾過し、濾液より溶媒を留去後、シリカゲルカラムクロ
マトグラフィーに付し、光学活性メチルラクトンである
（Ｒ）−１１−ヒドロキシドデカン酸ラクトン(25.4mg,
6％) を光学純度99％以上で得た。 〔α〕D 25−14.2°(c 1.27, CHCl3) 。Example 2 Lipase derived from Pseudomonus sp . (Lipase P manufactured by Amano Pharmaceutical) (2.5 g) as a lipase, isooctane (500 ml) as an organic solvent, methyl 11-hydroxydodeca as a hydroxy straight-chain fatty acid methyl ester Nart (502 mg) was mixed, dried molecular sieve 4A (5 g) was further added, and the mixture was stirred at 65 ° C. for 48 hours. The reaction solution was filtered, the solvent was distilled off from the filtrate, and the mixture was subjected to silica gel column chromatography to obtain an optically active methyl lactone (R) -11-hydroxydodecanoate lactone (25.4 mg,
6%) was obtained with an optical purity of 99% or more. [Α] D 25 -14.2 ° (c 1.27, CHCl 3 ).
【００１５】IR (neat, cm-1) : 17261 H-NMR (CDCl3,δ) : 1.10-1.88(m, 16H), 1.22(d, J=6
Hz, 3H),2.12-2.56(m, 2H), 5.02-5.22(m, 1H) MS m/z : 198(M+) 。IR (neat, cm -1 ): 1726 1 H-NMR (CDCl 3 , δ): 1.10-1.88 (m, 16H), 1.22 (d, J = 6
Hz, 3H), 2.12-2.56 (m, 2H), 5.02-5.22 (m, 1H) MS m / z: 198 (M + ).
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ１２Ｒ 1:38） ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 6 Identification code Agency reference number FI Technical display location C12R 1:38)
Claims (1)
条件下で、シュードモナス属由来のリパーゼを作用させ
ることにより、式（ＩＩ） 【化２】 で表されるＲ−体に富むメチルラクトンを得ることを特
徴とする光学活性メチルラクトン類の製造方法。1. A compound of formula (I): By reacting a lipase derived from the genus Pseudomonas on a racemic compound represented by the formula under the absence of water, the compound of formula (II) A process for producing optically active methyl lactones, characterized by obtaining an R-form-rich methyl lactone represented by the formula:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10242192A JP2613833B2 (en) | 1992-03-30 | 1992-03-30 | Stereoselective process for producing optically active 11-methyl 12-membered lactones |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10242192A JP2613833B2 (en) | 1992-03-30 | 1992-03-30 | Stereoselective process for producing optically active 11-methyl 12-membered lactones |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05268992A JPH05268992A (en) | 1993-10-19 |
| JP2613833B2 true JP2613833B2 (en) | 1997-05-28 |
Family
ID=14326992
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10242192A Expired - Lifetime JP2613833B2 (en) | 1992-03-30 | 1992-03-30 | Stereoselective process for producing optically active 11-methyl 12-membered lactones |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2613833B2 (en) |
-
1992
- 1992-03-30 JP JP10242192A patent/JP2613833B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05268992A (en) | 1993-10-19 |
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