JPH0776569A - Optically active 2-phenylthio-2-cycloalkene derivative and production thereof - Google Patents
Optically active 2-phenylthio-2-cycloalkene derivative and production thereofInfo
- Publication number
- JPH0776569A JPH0776569A JP24643893A JP24643893A JPH0776569A JP H0776569 A JPH0776569 A JP H0776569A JP 24643893 A JP24643893 A JP 24643893A JP 24643893 A JP24643893 A JP 24643893A JP H0776569 A JPH0776569 A JP H0776569A
- Authority
- JP
- Japan
- Prior art keywords
- phenylthio
- cycloalkene
- optically active
- formula
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 14
- 108090001060 Lipase Proteins 0.000 claims abstract description 23
- 239000004367 Lipase Substances 0.000 claims abstract description 23
- 102000004882 Lipase Human genes 0.000 claims abstract description 23
- 235000019421 lipase Nutrition 0.000 claims abstract description 23
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 241000589516 Pseudomonas Species 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 229920001567 vinyl ester resin Polymers 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000005809 transesterification reaction Methods 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 9
- 239000013543 active substance Substances 0.000 abstract description 5
- 239000003905 agrochemical Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 230000003287 optical effect Effects 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- -1 fatty acid ester Chemical class 0.000 description 14
- 239000002904 solvent Substances 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- BFJPSNYCYKMPQL-UHFFFAOYSA-N 2-phenylsulfanylcyclohex-2-en-1-ol Chemical compound OC1CCCC=C1SC1=CC=CC=C1 BFJPSNYCYKMPQL-UHFFFAOYSA-N 0.000 description 5
- CGUAZFPVCLUVCC-UHFFFAOYSA-N 2-phenylsulfanylcyclopent-2-en-1-ol Chemical compound OC1CCC=C1SC1=CC=CC=C1 CGUAZFPVCLUVCC-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- ODDAXFLUYJOFIS-UHFFFAOYSA-N (2-phenylsulfanylcyclohex-2-en-1-yl) acetate Chemical compound CC(=O)OC1CCCC=C1SC1=CC=CC=C1 ODDAXFLUYJOFIS-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 3
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- BDKCIMVMZRQNQP-UHFFFAOYSA-N 2-iodocyclopent-2-en-1-ol Chemical compound OC1CCC=C1I BDKCIMVMZRQNQP-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 101000968491 Pseudomonas sp. (strain 109) Triacylglycerol lipase Proteins 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QHDHNVFIKWGRJR-UHFFFAOYSA-N 1-cyclohexenol Chemical compound OC1=CCCCC1 QHDHNVFIKWGRJR-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- YKOMVWNSPSUBDS-UHFFFAOYSA-N 2-phenylsulfanylcyclohex-2-en-1-one Chemical compound O=C1CCCC=C1SC1=CC=CC=C1 YKOMVWNSPSUBDS-UHFFFAOYSA-N 0.000 description 1
- ICPWBZQTTNZFGD-UHFFFAOYSA-N 2-phenylsulfanylcyclopent-2-en-1-one Chemical compound O=C1CCC=C1SC1=CC=CC=C1 ICPWBZQTTNZFGD-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000588986 Alcaligenes Species 0.000 description 1
- 241000186063 Arthrobacter Species 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- DEYLLLWYLKGZEB-UHFFFAOYSA-N CN(C)NN1CC=CC=C1 Chemical compound CN(C)NN1CC=CC=C1 DEYLLLWYLKGZEB-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000588881 Chromobacterium Species 0.000 description 1
- 108010048733 Lipozyme Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000235395 Mucor Species 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 241000235527 Rhizopus Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- PWJAKCUMURLYPR-UHFFFAOYSA-N acetyl acetate;dichloromethane Chemical compound ClCCl.CC(=O)OC(C)=O PWJAKCUMURLYPR-UHFFFAOYSA-N 0.000 description 1
- AQRHTGSVDQECPZ-UHFFFAOYSA-N azane;lithium Chemical compound [Li].N AQRHTGSVDQECPZ-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001925 cycloalkenes Chemical class 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- PQANGXXSEABURG-UHFFFAOYSA-N cyclohexenol Natural products OC1CCCC=C1 PQANGXXSEABURG-UHFFFAOYSA-N 0.000 description 1
- PSBABBDEUFNFKJ-UHFFFAOYSA-N cyclopent-2-en-1-ol Chemical compound OC1CCC=C1 PSBABBDEUFNFKJ-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- GLVVKKSPKXTQRB-UHFFFAOYSA-N ethenyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC=C GLVVKKSPKXTQRB-UHFFFAOYSA-N 0.000 description 1
- LZWYWAIOTBEZFN-UHFFFAOYSA-N ethenyl hexanoate Chemical compound CCCCCC(=O)OC=C LZWYWAIOTBEZFN-UHFFFAOYSA-N 0.000 description 1
- UIWXSTHGICQLQT-UHFFFAOYSA-N ethenyl propanoate Chemical compound CCC(=O)OC=C UIWXSTHGICQLQT-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- FCCDDURTIIUXBY-UHFFFAOYSA-N lipoamide Chemical compound NC(=O)CCCCC1CCSS1 FCCDDURTIIUXBY-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- SNZXFRFQGXSSGN-UHFFFAOYSA-N phenylsulfanyloxysulfanylbenzene Chemical compound C=1C=CC=CC=1SOSC1=CC=CC=C1 SNZXFRFQGXSSGN-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
【0001】[0001]
【産業上の利用分野】本発明は、医薬、農薬等の出発物
質として有用な光学活性2−フェニルチオ−2−シクロ
アルケン誘導体、およびその製造法に関するものであ
る。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active 2-phenylthio-2-cycloalkene derivative useful as a starting material for medicines, agricultural chemicals and the like, and a method for producing the same.
【0002】[0002]
【従来の技術】光学活性2−フェニルチオ−2−シクロ
アルケン−1−オ−ルは水酸基とフェニルチオエ−テル
という異なる2つの置換基を持つ。これら置換基は、立
体選択的、あるいは立体特異的に各種官能基に変換する
ことが可能である。さらに分子内の二重結合を利用して
3位にも立体選択的、あるいは立体特異的に各種の官能
基を導くことができ、医薬、農薬などの原料となる光学
活性体のビルデングブロックとして有用な化合物であ
る。しかしながら、従来その光学活性体が合成されてお
らず、その有用性を充分評価することが出来なかった。
類縁な化合物である光学活性な2−ヨ−ド−2−シクロ
アルケン−1−オ−ル類の製造法は、ジョンソンら(Sy
nlett,813(1992) )によって、また光学活性な2−アル
コキシカルボニル−2−シクロアルケン−1−オ−ル類
の製造法は、高野ら(特願平4−190215)によっ
て報告されている。ジョンソンらの報告によれば、リパ
−ゼSP−435を用いたエステル交換反応の結果は、
基質に2−ヨ−ド−2−シクロペンテン−1−オ−ルを
用いた場合、S−体が、>98%eeで得られるのに対
し、2−シクロペンテン−1−オ−ルでは、16%ee
しか得られない。また、2−ブロモ−2−シクロアルケ
ン−1−オ−ルの場合は87%eeであり、10%ee
近く、2−ヨ−ド−2−シクロアルケン−1−オ−ルに
比較して光学収率は低くなっている。シクロアルケノ−
ル誘導体のリパ−ゼによる光学分割法においては、2位
の官能基によって、その光学収率が大きく異なると言え
る。さらに2−ヨ−ド−2−シクロアルケン−1−オ−
ルでは、置換基であるヨウ素に脱離性がある為、化合物
の安定性という点では問題がある。置換基がヨウ素であ
るため、求核置換反応に限定される欠点がある。更に2
ーヨードー2ーシクロヘキセンー1ーオールでは2ーヨ
ードー2ーシクロペンテンー1ーオールより光学収率が
低く充分汎用性のある製造方法とは言えない。2. Description of the Related Art Optically active 2-phenylthio-2-cycloalkene-1-ol has two different substituents, a hydroxyl group and phenylthioether. These substituents can be stereoselectively or stereospecifically converted into various functional groups. Furthermore, various functional groups can be introduced into the 3-position stereoselectively or stereospecifically by utilizing the double bond in the molecule, which is useful as a building block for optically active substances as raw materials for medicines, agricultural chemicals, etc. It is a compound. However, the optically active substance has not been synthesized so far, and its usefulness could not be sufficiently evaluated.
A method for producing optically active 2-iodo-2-cycloalkene-1-ols, which are related compounds, is described by Johnson et al.
nlett, 813 (1992)) and a method for producing optically active 2-alkoxycarbonyl-2-cycloalkene-1-ols are reported by Takano et al. (Japanese Patent Application No. 4-190215). According to a report by Johnson et al., The result of the transesterification reaction using lipase SP-435 was as follows.
When 2-iodo-2-cyclopentene-1-ol is used as the substrate, the S-form is obtained with> 98% ee, whereas 2-cyclopentene-1-ol is 16 % Ee
I can only get it. Further, in the case of 2-bromo-2-cycloalkene-1-ol, it is 87% ee and 10% ee.
Nearly, the optical yield is lower than that of 2-iodo-2-cycloalkene-1-ol. Cycloalkeno
It can be said that in the optical resolution method of a lipe derivative with a lipase, the optical yield thereof largely varies depending on the functional group at the 2-position. Furthermore, 2-iodo-2-cycloalkene-1-o-
However, iodine has a problem of stability, because iodine, which is a substituent, has a releasability. Since the substituent is iodine, it has a drawback that it is limited to the nucleophilic substitution reaction. 2 more
-Iodo-2-cyclohexen-1-ol has a lower optical yield than 2-iodo-2-cyclopenten-1-ol and cannot be said to be a sufficiently versatile production method.
【0003】[0003]
【発明が解決しようとする課題】以上に明らかなように
本発明の目的は、安定な化合物で、種々の置換基の導入
が容易な、汎用性のある光学活性体のビルデングブロッ
クとして有用な新規化合物とその製造法を提供すること
である。2−フェニルチオ−2−シクロアルケン−1−
オ−ルでは、チオフェニルの安定性には問題なく、他の
置換基への変換が容易である。As is clear from the above, the object of the present invention is a novel compound which is a stable compound and is useful as a building block of a versatile optically active substance in which various substituents can be easily introduced. It is to provide a compound and a method for producing the same. 2-phenylthio-2-cycloalkene-1-
With ole, there is no problem in the stability of thiophenyl, and conversion to other substituents is easy.
【化9】 [Chemical 9]
【化10】 [Chemical 10]
【化11】 例えば、上記に例示したように、ラネ−ニッケル触媒な
どを用いると、容易にフェニルチオを脱離させる事が可
能である。また四塩化チタンなどを用いてケトン体も得
ることも可能である。そして、分子内の二重結合にエス
テルを導入しさらにリチウム−アンモニアでチオフェニ
ルを引き抜き不飽和テルペンへの誘導も可能である。こ
の様に光学活性2−フェニルチオ−2−シクロアルケン
−1−オ−ルは、非常に汎用性の高い化合物なのであ
る。[Chemical 11] For example, as exemplified above, it is possible to easily eliminate phenylthio by using a Raney-nickel catalyst or the like. It is also possible to obtain a ketone body by using titanium tetrachloride or the like. It is also possible to introduce an ester into a double bond in the molecule and further draw thiophenyl with lithium-ammonia to induce an unsaturated terpene. Thus, the optically active 2-phenylthio-2-cycloalkene-1-ol is a very versatile compound.
【0004】[0004]
【課題を解決するための手段】本発明は、一般式(1)The present invention is based on the general formula (1)
【化12】 (式中、*は不斉炭素を示し、Rはアルキル基を示し、
nは1から4を示す。)で表される光学活性な2−フェ
ニルチオ−1−アシルオキシ−2−シクロアルケン、一
般式(2)[Chemical 12] (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) An optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the general formula (2)
【化13】 (式中、*は不斉炭素を示し、nは1から4を示す。)
で表される光学活性な2−フェニルチオ−2−シクロア
ルケン−1−オ−ル、あるいは一般式(3)[Chemical 13] (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
An optically active 2-phenylthio-2-cycloalkene-1-ol represented by or a general formula (3)
【化14】 (式中、nは1から4を示す。)で表されるラセミ体の
2−フェニルチオ−2−シクロアルケン−1−オ−ルを
リパーゼ存在下、アシル化剤とエステル交換することに
より一般式(1)[Chemical 14] (In the formula, n represents 1 to 4.) Racemic 2-phenylthio-2-cycloalkene-1-ol represented by the general formula by transesterification with an acylating agent in the presence of lipase. (1)
【化15】 (式中、*は不斉炭素を示し、Rはアルキル基を示し、
nは1から4を示す。)で表される光学活性な2−フェ
ニルチオ−1−アシルオキシ−2−シクロアルケンと一
般式(2)[Chemical 15] (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) And an optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the general formula (2)
【化16】 (式中、*は不斉炭素を示し、nは1から4を示す。)
で表される光学活性な2−フェニルチオ−2−シクロア
ルケン−1−オ−ルをそれぞれ得ることを特徴とする光
学活性2−フェニルチオ−2−シクロアルケン誘導体の
製造法と一般式(4)[Chemical 16] (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
And a general formula (4) for producing an optically active 2-phenylthio-2-cycloalkene derivative characterized by obtaining optically active 2-phenylthio-2-cycloalkene-1-ol represented by
【化17】 (式中、Rはアルキル基を示し、nは1から4を示
す。)で表されるラセミ体の2−フェニルチオ−1−ア
シルオキシ−2−シクロアルケンをリパ−ゼ存在下に加
水分解することにより一般式(1)[Chemical 17] (In the formula, R represents an alkyl group, and n represents 1 to 4.) Hydrolyzing a racemic 2-phenylthio-1-acyloxy-2-cycloalkene represented by the formula in the presence of lipase. By the general formula (1)
【化18】 (式中、*は不斉炭素を示し、Rはアルキル基を示し、
nは1から4を示す。)で表される光学活性な2−フェ
ニルチオ−1−アシルオキシ−2−シクロアルケンと一
般式(2)[Chemical 18] (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) And an optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the general formula (2)
【化19】 (式中、*は不斉炭素を示し、nは1から4を示す。)
で表される光学活性な2−フェニルチオ−2−シクロア
ルケン−1−オ−ルをそれぞれ得ることを特徴とする光
学活性2−フェニルチオ−2−シクロアルケン誘導体の
製造法に関する。[Chemical 19] (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
The invention relates to a method for producing an optically active 2-phenylthio-2-cycloalkene derivative, which comprises obtaining optically active 2-phenylthio-2-cycloalkene-1-ol represented by
【0005】本発明の出発物質であるラセミ体の2−フ
ェニルチオ−2−シクロアルケン−1−オ−ル(3)お
よび、2−フェニルチオ−1−アシルオキシ−2−シク
ロアルケン(4)は、以下の式の通り容易に合成するこ
とが可能である。The racemic 2-phenylthio-2-cycloalkene-1-ol (3) and 2-phenylthio-1-acyloxy-2-cycloalkene (4) which are the starting materials of the present invention are as follows: It can be easily synthesized according to the formula.
【0006】[0006]
【化20】 [Chemical 20]
【0007】まず市販のシクロアルカノンをN,N−ジ
メチルホルムアミド中、130℃、7時間加熱すること
によりトリメチルシリル化し、テトラブチルアンモニウ
ムフロリド存在下、テトラヒドロフラン溶液中ー78℃
で10分間、S−フェニルベンゼンチオサルフェ−トと
反応させ、2−フェニルチオシクロアルカン−1−オン
へと誘導する。2−フェニルチオシクロアルカン−1−
オンを塩化メチレン中、0℃でm−クロロ過安息香酸で
酸化し、無水酢酸−塩化メチレン中0℃でメタンスルホ
ン酸で6hrs処理し2−フェニルチオシクロアルケン
−1−オンとする。さらに2−フェニルチオシクロアル
ケン−1−オンは、水素化ホウ素ナトリウムなどの還元
剤で還元し、ラセミ体の2−フェニルチオ−2−シクロ
アルケン−1−オ−ル(3)を得ることができる。ま
た、ラセミ体の2−フェニルチオ−2−シクロアルケン
−1−オ−ル(3)を例えば、酸クロリド、トリエチル
アミンを用いる等の常法に従ってエステル化することに
より、一般式(4)で示されるラセミ体の2−フェニル
チオ−1−アシルオキシ−2−シクロアルケンを得るこ
とが出来る。First, commercially available cycloalkanone is trimethylsilylated by heating in N, N-dimethylformamide at 130 ° C. for 7 hours, and in a tetrahydrofuran solution at −78 ° C. in the presence of tetrabutylammonium fluoride.
And react with S-phenylbenzenethiosulfate for 10 minutes to induce 2-phenylthiocycloalkan-1-one. 2-phenylthiocycloalkane-1-
The one is oxidized with m-chloroperbenzoic acid in methylene chloride at 0 ° C. and treated with methanesulfonic acid in acetic anhydride-methylene chloride at 0 ° C. for 6 hrs to give 2-phenylthiocycloalkene-1-one. Further, 2-phenylthiocycloalkene-1-one can be reduced with a reducing agent such as sodium borohydride to obtain racemic 2-phenylthio-2-cycloalkene-1-ol (3). . In addition, racemic 2-phenylthio-2-cycloalkene-1-ol (3) is esterified according to a conventional method such as using acid chloride or triethylamine, and is represented by the general formula (4). A racemic 2-phenylthio-1-acyloxy-2-cycloalkene can be obtained.
【0008】また、本発明の製造法の反応経路は以下の
式に示される。The reaction route of the production method of the present invention is represented by the following formula.
【化21】 [Chemical 21]
【0009】ラセミ体の2−フェニルチオ−2−シクロ
アルケン−1−オ−ル(3)は、アシル化剤とリパ−ゼ
の懸濁液を加え、室温で攪はんすることにより、鏡像異
性体のどちらか一方が優先的にアシル化され、光学活性
な2−フェニルチオ−1−アシルオキシ−2−シクロア
ルケンと光学活性な2−フェニルチオ−2−シクロアル
ケン−1−オ−ルが得られる。反応時間は、処理量によ
って異なるが、1時間〜1カ月である。これらの分離法
としては、例えばカラムクロマトグラフィ−があり、そ
れぞれ鏡像体を分離することが可能である。Racemic 2-phenylthio-2-cycloalkene-1-ol (3) is enantiomerized by adding a suspension of an acylating agent and lipase and stirring at room temperature. Either one of the compounds is preferentially acylated to give an optically active 2-phenylthio-1-acyloxy-2-cycloalkene and an optically active 2-phenylthio-2-cycloalkene-1-ol. The reaction time is 1 hour to 1 month, depending on the amount of treatment. These separation methods include, for example, column chromatography, which can separate the enantiomers.
【0010】以上の製法において、使用するアシル化剤
は、脂肪酸エステル、安息香酸エステル類など、リパ−
ゼのエステル交換反応の基質となるものであれば幅広く
用いることが出来るが、好ましくは、酢酸ビニル、プロ
ピオン酸ビニル、カプロン酸ビニル、ラウリン酸ビニル
などのビニルエステルである。使用する有機溶媒は、ベ
ンゼン、トルエン、ヘキサン、ヘプタン、ジクロロメタ
ン、t−ブチルジメチルエ−テルなどが好ましいが、リ
パ−ゼの反応を阻害しないものであればその種類を問わ
ない。In the above production method, the acylating agent to be used is a fatty acid ester, benzoic acid ester, or the like.
Although it can be widely used as long as it can be a substrate for the transesterification reaction of zetin, vinyl esters such as vinyl acetate, vinyl propionate, vinyl caproate, and vinyl laurate are preferable. The organic solvent to be used is preferably benzene, toluene, hexane, heptane, dichloromethane, t-butyldimethyl ether, etc., but any kind of organic solvent may be used as long as it does not inhibit the lipase reaction.
【0011】ラセミ体の2−フェニルチオ−1−アシル
オキシ−2−シクロアルケン(4)は、リン酸緩衝液
(緩衝液/アセトン=9/1(v/v))にリパ−ゼを
加え加水分解反応させることにより、鏡像異性体のどち
らか一方が優先的に加水分解され光学活性な2−フェニ
ルチオ−2−シクロアルケン−1−オ−ルと光学活性な
2−フェニルチオ−1−アシルオキシ−2−シクロアル
ケンが得られる。この場合、リパ−ゼは固定化されてい
ても、いなくても良い。リン酸緩衝液はpH4〜9で、
好ましくは、pH7〜8である。The racemic 2-phenylthio-1-acyloxy-2-cycloalkene (4) is hydrolyzed by adding lipase to a phosphate buffer (buffer / acetone = 9/1 (v / v)). Upon reaction, either one of the enantiomers is preferentially hydrolyzed to give optically active 2-phenylthio-2-cycloalkene-1-ol and optically active 2-phenylthio-1-acyloxy-2- A cycloalkene is obtained. In this case, the lipase may or may not be immobilized. The phosphate buffer has a pH of 4-9,
The pH is preferably 7-8.
【0012】リパ−ゼは、菌の種類としてはシュ−ドモ
ナス、アルスロバクタ−、アルカリゲネス、アスペルギ
ルス、クロモバクテリウム、カンジダ、ムコ−ル、リゾ
プスなどがある。この菌体そのものを用いるか、その抽
出物を用いることもできる。さらに固定化して用いても
良い。また、動物の内臓から抽出することも可能であ
り、例えば豚や、牛の肝臓、あるいは膵臓等から抽出し
て得ることが出来る。そのほか市販されているものが使
用できる。例えば、リパ−ゼPS、OF、AY、AK
(以上、天野製薬製)、MY(名糖)、PPL(和光純
薬)、パラタ−ゼA、リポザイムIM、SP435(以
上、ノボノルディスク製)などがある。この中で特に好
ましくは、シュ−ドモナス菌由来のものである。Examples of the lipase include Pseudomonas, Arthrobacter, Alcaligenes, Aspergillus, Chromobacterium, Candida, Mucor, Rhizopus and the like. This bacterium itself can be used or its extract can be used. It may be further fixed and used. It can also be extracted from the internal organs of animals, for example, from the liver of pigs or cattle, or the pancreas. In addition, commercially available products can be used. For example, lipase PS, OF, AY, AK
(Above, manufactured by Amano Pharmaceutical Co., Ltd.), MY (name sugar), PPL (Wako Pure Chemical Industries), Paratase A, Lipozyme IM, SP435 (above, manufactured by Novo Nordisk). Of these, particularly preferred are those derived from Pseudomonas.
【0013】固定化担体としてはクロモソルブ、セライ
ト、セルロ−ス、カラギ−ナン、各種ポリマ−など、リ
パ−ゼの活性を阻害しないものであれば良い。The immobilization carrier may be chromosolve, celite, cellulose, carrageenan, various polymers or the like as long as it does not inhibit the activity of lipase.
【0014】[0014]
【発明の効果】以上説明した方法により、農薬、医薬等
の生理活性物質のビルデングブロックとして安定で、汎
用性の高い、新規の光学活性2−フェニルチオ−2−シ
クロアルケン−1−オ−ル及び、2−フェニルチオ−1
−アシルオキシ−2−シクロアルケンとその合成法を提
供できた。Industrial Applicability According to the method described above, a novel optically active 2-phenylthio-2-cycloalkene-1-ol which is stable as a building block for physiologically active substances such as agricultural chemicals and pharmaceuticals and has high versatility, and , 2-phenylthio-1
-Acyloxy-2-cycloalkene and its synthetic method could be provided.
【0015】[0015]
【実施例】以下、実施例により本発明を更に詳しく説明
するが、本発明は、これら実施例によって制限されるも
のではない。EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.
【0016】実施例1 (±)−2−フェニルチオ−2−シクロペンテノ−ルの
合成:2−フェニルチオ−2−シクロペンテノン(2.72
g,14.3mmol)をメタノ−ル(70ml)に溶解し、室温で三塩
化セリウム・7水和物(5.85g,15.7mmol)を加えた。0℃
まで冷却し、水素化ホウ素ナトリウム(544.0mg,14.3mmo
l)を滴下した。滴下終了後、0℃で1時間攪はんした。
その後、アセトン(1ml) を加え減圧下で溶媒を留去し
た。残さに水を加え、エ−テルで抽出し、飽和食塩水で
洗浄し、硫酸マグネシウムで乾燥した。減圧下で溶媒を
留去した後、残さをシリカゲルカラムクロマトグラフィ
−に付し、ジエチルエ−テル/n−ヘキサン(20%v/v)の
流分より黄色油状の(±)−2−フェニルチオ−2−シ
クロペンテノ−ル(2.61g,94.9%) を得た。 IR(neat):3500-3100, 1582cm-1.1 H-NMR(300MHz,CDCl3)δ:1.84-2.03(2H,m,1Hexchangeab
le with D2O), 2.25-2.43(2H,m),2.46-2.61(1H,m), 4.6
8(1H,t,J=3.3, 2.9Hz),5.92(1H,t,J=2.6, 1.8Hz), 7.21
-7.35(3H,m),7.37-7.44(2H,m). MS:m/z=192(M+,100%). HRMS:Calcd:C11H12OS:192.0609. FOUND:192.0623. C11H12OS:Calcd:C,68.73, H,6.30, S,16.65 Found:C,68.65, H,6.27, S,16.56Example 1 Synthesis of (±) -2-phenylthio-2-cyclopentenol: 2-phenylthio-2-cyclopentenone (2.72
g, 14.3 mmol) was dissolved in methanol (70 ml), and cerium trichloride heptahydrate (5.85 g, 15.7 mmol) was added at room temperature. 0 ° C
Cooled to sodium borohydride (544.0mg, 14.3mmo
l) was added dropwise. After the completion of dropping, the mixture was stirred at 0 ° C. for 1 hour.
Then, acetone (1 ml) was added and the solvent was distilled off under reduced pressure. Water was added to the residue, extracted with ether, washed with saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and a yellow oily (±) -2-phenylthio-2 was obtained from a fraction of diethyl ether / n-hexane (20% v / v). -Cyclopentenol (2.61 g, 94.9%) was obtained. IR (neat):. 3500-3100, 1582cm -1 1 H-NMR (300MHz, CDCl 3) δ: 1.84-2.03 (2H, m, 1Hexchangeab
le with D 2 O), 2.25-2.43 (2H, m), 2.46-2.61 (1H, m), 4.6
8 (1H, t, J = 3.3,2.9Hz), 5.92 (1H, t, J = 2.6,1.8Hz), 7.21
-7.35 (3H, m), 7.37-7.44 (2H, m). MS: m / z = 192 (M + , 100%). HRMS: Calcd: C 11 H 12 OS: 192.0609. FOUND: 192.0623. C 11 H 12 OS: Calcd: C, 68.73, H, 6.30, S, 16.65 Found: C, 68.65, H, 6.27, S, 16.56
【0017】実施例2 (±)−2−フェニルチオ−2−シクロヘキセノ−ルの
合成:2−フェニルチオ−2−シクロヘキセノン(3.63
g,17.8mmol)をメタノ−ル(90ml)に溶解し、室温で三塩
化セリウム・7水和物(7.27g,19.6mmol)を加えた。0℃
まで冷却し、水素化ホウ素ナトリウム(679.1mg,17.8mmo
l)を徐々に加えた。終了後、0℃で1時間攪はんした。
その後、アセトン(2ml) を加え減圧下で溶媒を留去し
た。残さに水(2ml) を加え、ジエチルエ−テルで抽出
し、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し
た。減圧下で溶媒を留去し、残さをシリカゲルカラムク
ロマトグラフィ−に付し、ジエチルエ−テル/n−ヘキ
サン(15 %v/v) の流分より黄色油状の(±)−2−フェ
ニルチオ−2−シクロヘキセノ−ル(3.47g,94.6%) を得
た。 IR(neat):3600-3100, 1581cm-1.1 H-NMR(300MHz,CDCl3)δ:1.50-2.00(4H,m),2.15-2.30(2
H,m),2.28(1H, br s, exchangeable withD2O), 4.05(1
H, br s), 6.26(1H,t, J=4.0,3.7Hz),7.20-7.40(5H,m). MS:m/z=206(M+), 110(100%). HRMS:Calcd:C12H14OS:206.0766. FOUND:206.0744. C12H14OS:Calcd:C,69.88, H,6.85, S,15.51 Found:C,69.59, H,6.67, S,15.29Example 2 Synthesis of (±) -2-phenylthio-2-cyclohexenol: 2-phenylthio-2-cyclohexenone (3.63
g, 17.8 mmol) was dissolved in methanol (90 ml), and cerium trichloride heptahydrate (7.27 g, 19.6 mmol) was added at room temperature. 0 ° C
Cooled to sodium borohydride (679.1mg, 17.8mmo
l) was gradually added. After the completion, the mixture was stirred at 0 ° C for 1 hour.
Then, acetone (2 ml) was added and the solvent was distilled off under reduced pressure. Water (2 ml) was added to the residue, the mixture was extracted with diethyl ether, washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, and a yellow oily (±) -2-phenylthio-2- was obtained from a fraction of diethyl ether / n-hexane (15% v / v). Cyclohexenol (3.47 g, 94.6%) was obtained. IR (neat):. 3600-3100, 1581cm -1 1 H-NMR (300MHz, CDCl 3) δ: 1.50-2.00 (4H, m), 2.15-2.30 (2
H, m), 2.28 (1H, br s, exchangeable withD 2 O), 4.05 (1
H, br s), 6.26 (1H, t, J = 4.0, 3.7Hz), 7.20-7.40 (5H, m) .MS: m / z = 206 (M + ), 110 (100%). HRMS: Calcd : C 12 H 14 OS: 206.0766. FOUND: 206.0744. C 12 H 14 OS: Calcd: C, 69.88, H, 6.85, S, 15.51 Found: C, 69.59, H, 6.67, S, 15.29
【0018】実施例3 (±)−1−アセトキシ−2−フェニルチオ−2−シク
ロペンテンの合成:実施例1で得られた(±)−2−フ
ェニルチオ−2−シクロペンテノ−ル(889.8mg,4.63 mm
ol) 、無水酢酸(1.31ml,13.9mmol) 、トリエチルアミン
(1.93ml,13.9mmol) 、4−N,N−ジヂメチルアミノピ
リジン(16.9mg,0.14mmol) を塩化メチレン(23ml)中、室
温で12時間攪はんした。その後、反応混合物を飽和食
塩水で洗浄し、硫酸マグネシウムで乾燥し、減圧下で溶
媒を留去した。残さをシリカゲルカラムクロマトグラフ
ィ−に付し、ジエチルエ−テル/n−ヘキサン(20%v/v)
の流分より無色油状の(±)−1−アセトキシ−2−フ
ェニルチオ−2−シクロペンテン(1.18g,93.8%) を得
た。 IR(neat):1735, 1581cm-1.1 H-NMR(300MHz,CDCl3)δ:1.96(3H,s), 1.83-2.00(1H,m) 2.30-2.44(2H,m), 2.44-2.62(1H,m),5.66(1H,t, J=4.7,
2.6Hz), 5.94(1H, br s),7.23-7.37(3H,m), 7.38-7.48
(2H,m). MS:m/z=234(M+), 174(100%). HRMS:Calcd:C13H14O2S:234.0715. FOUND:234.0715. C13H14O2S:Calcd:C,66.65, H,6.03, S,13.66 Found:C,66.48, H,5.92, S,13.51Example 3 Synthesis of (±) -1-acetoxy-2-phenylthio-2-cyclopentene: (±) -2-phenylthio-2-cyclopentenol (889.8 mg, 4.63 mm) obtained in Example 1
ol), acetic anhydride (1.31 ml, 13.9 mmol), triethylamine
(1.93 ml, 13.9 mmol) and 4-N, N-dimethylaminoaminopyridine (16.9 mg, 0.14 mmol) were stirred in methylene chloride (23 ml) at room temperature for 12 hours. Then, the reaction mixture was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and diethyl ether / n-hexane (20% v / v)
The colorless oily substance (±) -1-acetoxy-2-phenylthio-2-cyclopentene (1.18 g, 93.8%) was obtained from the above stream. IR (neat):. 1735, 1581cm -1 1 H-NMR (300MHz, CDCl 3) δ: 1.96 (3H, s), 1.83-2.00 (1H, m) 2.30-2.44 (2H, m), 2.44-2.62 (1H, m), 5.66 (1H, t, J = 4.7,
2.6Hz), 5.94 (1H, br s), 7.23-7.37 (3H, m), 7.38-7.48
(2H, m) .MS: m / z = 234 (M + ), 174 (100%). HRMS: Calcd: C 13 H 14 O 2 S: 234.0715. FOUND: 234.0715. C 13 H 14 O 2 S: Calcd: C, 66.65, H, 6.03, S, 13.66 Found: C, 66.48, H, 5.92, S, 13.51
【0019】実施例4 (±)−1−アセトキシ−2−フェニルチオ−2−シク
ロヘキセンの合成:実施例2で得られた(±)−2−フ
ェニルチオ−2−シクロヘキセノ−ル(918.6mg,4.45 mm
ol) 、無水酢酸(1.25ml,13.3mmol) 、トリエチルアミン
(1.85ml,13.3mmol) 、4−N,N−ジヂメチルアミノピ
リジン(16.2mg,0.13mmol) を塩化メチレン(22ml)中、室
温で12時間攪はんした。その後、反応混合物を飽和食
塩水で洗浄し、硫酸マグネシウムで乾燥し、減圧下で溶
媒を留去した。残さをシリカゲルカラムクロマトグラフ
ィ−に付し、ジエチルエ−テル/n−ヘキサン(15%v/v)
の流分より無色油状の(±)−1−アセトキシ−2−フ
ェニルチオ−2−シクロヘキセン(1.08g,97.9%) を得
た。 IR(neat):1731, 1581cm-1.1 H-NMR(300MHz,CDCl3)δ:1.60-1.90(4H,m), 1.93(3H,s) 2.10-2.40(2H,m), 5.29(1H,br s),6.34(1H,t, J=4.6,3.
7Hz), 7.20-7.40(5H,m). MS:m/z=248(M+), 188(100%). HRMS:Calcd:C14H16O2S:248.0871. FOUND:248.0858. C14H16O2S:Calcd:C,67.72, H,6.50, S,12.89 Found:C,67.69, H,6.51, S,12.86Example 4 Synthesis of (±) -1-acetoxy-2-phenylthio-2-cyclohexene: (±) -2-phenylthio-2-cyclohexenol (918.6 mg, 4.45) obtained in Example 2. mm
ol), acetic anhydride (1.25 ml, 13.3 mmol), triethylamine
(1.85 ml, 13.3 mmol) and 4-N, N-dimethylaminopyridine (16.2 mg, 0.13 mmol) were stirred in methylene chloride (22 ml) at room temperature for 12 hours. Then, the reaction mixture was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, diethyl ether / n-hexane (15% v / v)
A colorless oily (±) -1-acetoxy-2-phenylthio-2-cyclohexene (1.08 g, 97.9%) was obtained from the above stream. IR (neat):. 1731, 1581cm -1 1 H-NMR (300MHz, CDCl 3) δ: 1.60-1.90 (4H, m), 1.93 (3H, s) 2.10-2.40 (2H, m), 5.29 (1H , br s), 6.34 (1H, t, J = 4.6,3.
7Hz), 7.20-7.40 (5H, m) .MS: m / z = 248 (M + ), 188 (100%). HRMS: Calcd: C 14 H 16 O 2 S: 248.0871. FOUND: 248.0858. C 14 H 16 O 2 S: Calcd: C, 67.72, H, 6.50, S, 12.89 Found: C, 67.69, H, 6.51, S, 12.86
【0020】実施例5 (±)−2−フェニルチオ−2−シクロペンテノ−ルの
リパ−ゼによるエステル交換反応:実施例1で得られた
(±)−2−フェニルチオ−2−シクロペンテノ−ル
(1.04g,5.44mm ol) 、酢酸ビニル(5.0ml,54.4mmol)、リ
パ−ゼPS(天野製薬製、シュ−ドモナス菌由来、544m
g )を塩化メチレン(27ml)中、30℃で12日間攪はん
した。その後、反応液をセライトロ過し、減圧下で溶媒
を留去した。残さをシリカゲルカラムクロマトグラフィ
−に付し、ジエチルエ−テル/n−ヘキサン(10 〜20%v
/v) の流分より無色油状のR−(+)−1−アセトキシ
−2−フェニルチオ−2−シクロペンテン((644mg,50.
5%) 、[ α]D 29+80.0゜(c=1.28 ,CHCl3))と無色油状の
S−(−)−2−フェニルチオ−2−シクロペンテノ−
ル((487.6mg,46.6%) 、[ α]D 32-153.8゜(c=1.02,CHC
l3) )を得た。R−(+)−1−アセトキシ−2−フェ
ニルチオ−2−シクロペンテンの光学純度は、光学分割
HPLC(キラルセルOD、流出溶媒i−PrOH/n
−ヘキサン(1%v/v) )で93.2%eeであった。S−
(−)−2−フェニルチオ−2−シクロペンテノ−ルの
光学純度は、光学分割HPLC(キラルセルOD、流出
溶媒i−PrOH/n−ヘキサン(5%v/v))で100%
eeであった。Example 5 Transesterification of (±) -2-phenylthio-2-cyclopentenol with lipase: (±) -2-phenylthio-2-cyclopentenol obtained in Example 1
(1.04g, 5.44mmol), vinyl acetate (5.0ml, 54.4mmol), lipase PS (manufactured by Amano Pharmaceutical Co., Pseudomonas origin, 544m
g) was stirred in methylene chloride (27 ml) at 30 ° C. for 12 days. Then, the reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and diethyl ether / n-hexane (10 to 20% v
R-(+)-1-acetoxy-2-phenylthio-2-cyclopentene ((644 mg, 50.
5%), [α] D 29 + 80.0 ° (c = 1.28, CHCl 3 )) and colorless oily S-(−)-2-phenylthio-2-cyclopenteno-
((487.6mg, 46.6%), [α] D 32 -153.8 ° (c = 1.02, CHC
l 3 )). The optical purity of R-(+)-1-acetoxy-2-phenylthio-2-cyclopentene was determined by optical resolution HPLC (chiralcel OD, effluent solvent i-PrOH / n).
-Hexane (1% v / v)) was 93.2% ee. S-
The optical purity of (-)-2-phenylthio-2-cyclopentenol was 100% by optical resolution HPLC (chiralcel OD, eluent i-PrOH / n-hexane (5% v / v)).
It was ee.
【0021】実施例6 (±)−2−フェニルチオ−2−シクロヘキセノ−ルの
リパ−ゼによるエステル交換反応:実施例2で得られた
(±)−2−フェニルチオ−2−シクロヘキセノ−ル
(1.02g,4.97mm ol) 、酢酸ビニル(4.58ml,54.4mmol) 、
リパ−ゼPS(天野製薬製、シュ−ドモナス菌由来、49
7mg )を塩化メチレン(25ml)中、30℃で12日間攪は
んした。その後、反応液をセライトロ過し、減圧下で溶
媒を留去した。残さをシリカゲルカラムクロマトグラフ
ィ−に付し、ジエチルエ−テル/n−ヘキサン(5〜15%v
/v) の流分より無色油状のR−(+)−1−アセトキシ
−2−フェニルチオ−2−シクロヘキセン((599.3mg,4
8.5%) 、[ α]D 31+191.2゜(c=1 .29,CHCl3))と無色油状
のS−(−)−2−フェニルチオ−2−シクロヘキセノ
−ル((47 7.6mg,46.6%)、[ α]D 31-283.3゜(c=1.29,CHC
l3) )を得た。R−(+)−1−アセトキシ−2−フェ
ニルチオ−2−シクロヘキセンの光学純度は、光学分割
HPLC(キラルセルOD、流出溶媒i−PrOH/n
−ヘキサン(99%v/v))で98.0%eeであった。S−
(−)−2−フェニルチオ−2−シクロヘキセノ−ルの
光学純度は、光学分割HPLC(キラルセルOD、流出
溶媒i−PrOH/n−ヘキサン(5%v/v))で100%
eeであった。Example 6 Transesterification of (±) -2-phenylthio-2-cyclohexenol with lipase: (±) -2-phenylthio-2-cyclohexenol obtained in Example 2
(1.02g, 4.97mm ol), vinyl acetate (4.58ml, 54.4mmol),
Lipase PS (Amano Pharmaceutical, Pseudomonas origin, 49
7 mg) was stirred in methylene chloride (25 ml) at 30 ° C for 12 days. Then, the reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and diethyl ether / n-hexane (5-15% v
R-(+)-1-acetoxy-2-phenylthio-2-cyclohexene ((599.3 mg, 4
8.5%), [α] D 31 + 191.2 ° (c = 1.29, CHCl 3 )) and colorless oily S-(−)-2-phenylthio-2-cyclohexenol ((47 7.6 mg, 46.6 %), [Α] D 31 -283.3 ° (c = 1.29, CHC
l 3 )). The optical purity of R-(+)-1-acetoxy-2-phenylthio-2-cyclohexene was determined by optical resolution HPLC (chiralcel OD, effluent solvent i-PrOH / n).
-Hexane (99% v / v)) gave 98.0% ee. S-
The optical purity of (−)-2-phenylthio-2-cyclohexenol was 100% by optical resolution HPLC (chiralcel OD, eluent i-PrOH / n-hexane (5% v / v)).
It was ee.
【0022】実施例7 (±)−1−アセトキシ−2−フェニルチオ−2−シク
ロペンテンのリパ−ゼによる加水分解反応:実施例3で
得られた(±)−1−アセトキシ−2−フェニルチオ−
2−シクロペンテン( 965.6mg,4.12mmol) 、リパ−ゼP
S(天野製薬製、シュ−ドモナス菌由来、412mg )を
0.1Mリン酸バッファ−/アセトン(1:9 v/v,20ml)
中、30℃で12日間攪はんした。その後、反応液をセ
ライトロ過し、減圧下で溶媒を留去した。残さをシリカ
ゲルカラムクロマトグラフィ−に付し、ジエチルエ−テ
ル/n−ヘキサン(10 〜20%v/v) の流分より無色油状の
S−(−)−1−アセトキシ−2−フェニルチオ−2−
シクロペンテン((460.1mg,47.6%) 、[ α] D 30-84.0゜
(c=1.12,CHCl3) )と無色油状のR−(+)−2−フェ
ニルチオ−2−シクロペンテノ−ル((367.6mg,46.3%)
、[ α]D 32+154.1゜(c=1.10,CHCl3) )を得た。S−
(−)−1−アセトキシ−2−フェニルチオ−2−シク
ロペンテンの光学純度は、光学分割HPLC(キラルセ
ルOD、流出溶媒i−PrOH/n−ヘキサン(1%v/v)
)で93.2%eeであった。R−(+)−2−フェ
ニルチオ−2−シクロペンテノ−ルの光学純度は、光学
分割HPLC(キラルセルOD、流出溶媒i−PrOH
/n−ヘキサン(5%v/v))で100%eeであった。Example 7 Hydrolysis of (±) -1-acetoxy-2-phenylthio-2-cyclopentene with lipase: (±) -1-acetoxy-2-phenylthio-obtained in Example 3
2-Cyclopentene (965.6mg, 4.12mmol), Lipase P
S (Amano Pharmaceutical Co., Pseudomonas origin, 412 mg) was added with 0.1 M phosphate buffer / acetone (1: 9 v / v, 20 ml).
The mixture was stirred at 30 ° C. for 12 days. Then, the reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and a colorless oily S-(-)-1-acetoxy-2-phenylthio-2- was obtained from a stream of diethyl ether / n-hexane (10 to 20% v / v).
Cyclopentene ((460.1mg, 47.6%), [α] D 30 -84.0 °
(c = 1.12, CHCl 3 )) and colorless oily R-(+)-2-phenylthio-2-cyclopentenol ((367.6 mg, 46.3%)
, [Α] D 32 + 154.1 ° (c = 1.10, CHCl 3 )) were obtained. S-
The optical purity of (−)-1-acetoxy-2-phenylthio-2-cyclopentene was determined by optical resolution HPLC (chiralcel OD, eluent i-PrOH / n-hexane (1% v / v).
) Was 93.2% ee. The optical purity of R-(+)-2-phenylthio-2-cyclopentenol was measured by optical resolution HPLC (chiralcel OD, eluent i-PrOH).
/ N-hexane (5% v / v)) was 100% ee.
【0023】実施例8 (±)−1−アセトキシ−2−フェニルチオ−2−シク
ロヘキセンのリパ−ゼによる加水分解反応:実施例3で
得られた(±)−1−アセトキシ−2−フェニルチオ−
2−シクロヘキセン( 103.0mg,0.42mmol) 、リパ−ゼP
S(天野製薬製、シュ−ドモナス菌由来、41.5mg)を
0.1Mリン酸バッファ−/アセトン(1:9 v/v,2ml)
中、30℃で12日間攪はんした。その後、反応液をセ
ライトロ過し、減圧下で溶媒を留去した。残さをシリカ
ゲルカラムクロマトグラフィ−に付し、ジエチルエ−テ
ル/n−ヘキサン(5〜15%v/v) の流分より無色油状のS
−(−)−1−アセトキシ−2−フェニルチオ−2−シ
クロヘキセン((49.2mg,47.7%)、[ α]D 28-194.8゜(c=0.
47,CHCl3) )と無色油状のR−(+)−2−フェニルチ
オ−2−シクロヘキセノ−ル((38.4mg,44.8%)、[ α]D
31+277.6゜(c=1.32,CHCl3) )を得た。S−(−)−1−
アセトキシ−2−フェニルチオ−2−シクロヘキセンの
光学純度は、光学分割HPLC(キラルセルOD、流出
溶媒i−PrOH/n−ヘキサン(1%v/v) )で100%
eeであった。R−(+)−2−フェニルチオ−2−シ
クロヘキセノ−ルの光学純度は、光学分割HPLC(キ
ラルセルOD、流出溶媒i−PrOH/n−ヘキサン(5
%v/v))で100%eeであった。Example 8 Hydrolysis reaction of (±) -1-acetoxy-2-phenylthio-2-cyclohexene with lipase: (±) -1-acetoxy-2-phenylthio-obtained in Example 3
2-Cyclohexene (103.0mg, 0.42mmol), Lipase P
S (Amano Pharmaceutical, Pseudomonas origin, 41.5 mg) was added with 0.1 M phosphate buffer / acetone (1: 9 v / v, 2 ml).
The mixture was stirred at 30 ° C. for 12 days. Then, the reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and a colorless oily S was obtained from a stream of diethyl ether / n-hexane (5 to 15% v / v).
-(-)-1-acetoxy-2-phenylthio-2-cyclohexene ((49.2 mg, 47.7%), [α] D 28 -194.8 ° (c = 0.
47, CHCl 3 )) and colorless oily R-(+)-2-phenylthio-2-cyclohexenol ((38.4 mg, 44.8%), [α] D
31 + 277.6 ° (c = 1.32, CHCl 3 )) was obtained. S-(-)-1-
The optical purity of acetoxy-2-phenylthio-2-cyclohexene was 100% by optical resolution HPLC (chiralcel OD, eluent i-PrOH / n-hexane (1% v / v)).
It was ee. The optical purity of R-(+)-2-phenylthio-2-cyclohexenol was determined by optical resolution HPLC (chiralcel OD, eluent i-PrOH / n-hexane (5
% v / v)) was 100% ee.
Claims (7)
nは1から4を示す。)で表される光学活性な2−フェ
ニルチオ−1−アシルオキシ−2−シクロアルケン。1. A compound represented by the general formula (1): (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) An optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the formula:
で表される光学活性な2−フェニルチオ−2−シクロア
ルケン−1−オ−ル。2. A general formula (2): (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
An optically active 2-phenylthio-2-cycloalkene-1-ol represented by:
2−フェニルチオ−2−シクロアルケン−1−オ−ルを
リパーゼ存在下、アシル化剤とエステル交換することに
より一般式(1) 【化4】 (式中、*は不斉炭素を示し、Rはアルキル基を示し、
nは1から4を示す。)で表される光学活性な2−フェ
ニルチオ−1−アシルオキシ−2−シクロアルケンと一
般式(2) 【化5】 (式中、*は不斉炭素を示し、nは1から4を示す。)
で表される光学活性な2−フェニルチオ−2−シクロア
ルケン−1−オ−ルをそれぞれ得ることを特徴とする光
学活性2−フェニルチオ−2−シクロアルケン誘導体の
製造法。3. A compound represented by the general formula (3): (In the formula, n represents 1 to 4.) Racemic 2-phenylthio-2-cycloalkene-1-ol represented by the general formula by transesterification with an acylating agent in the presence of lipase. (1) [Chemical 4] (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) And an optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the general formula (2) (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
A method for producing an optically active 2-phenylthio-2-cycloalkene derivative, which comprises obtaining the optically active 2-phenylthio-2-cycloalkene-1-ol represented by
す。)で表されるラセミ体の2−フェニルチオ−1−ア
シルオキシ−2−シクロアルケンをリパ−ゼ存在下に加
水分解することにより一般式(1) 【化7】 (式中、*は不斉炭素を示し、Rはアルキル基を示し、
nは1から4を示す。)で表される光学活性な2−フェ
ニルチオ−1−アシルオキシ−2−シクロアルケンと一
般式(2) 【化8】 (式中、*は不斉炭素を示し、nは1から4を示す。)
で表される光学活性な2−フェニルチオ−2−シクロア
ルケン−1−オ−ルをそれぞれ得ることを特徴とする光
学活性2−フェニルチオ−2−シクロアルケン誘導体の
製造法。4. A compound represented by the general formula (4): (In the formula, R represents an alkyl group, and n represents 1 to 4.) Hydrolyzing a racemic 2-phenylthio-1-acyloxy-2-cycloalkene represented by the formula in the presence of lipase. According to the general formula (1) (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) And an optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the general formula (2) (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
A method for producing an optically active 2-phenylthio-2-cycloalkene derivative, which comprises obtaining the optically active 2-phenylthio-2-cycloalkene-1-ol represented by
ステルである光学活性2−フェニルチオ−2−シクロア
ルケン誘導体の製造法。5. The method for producing an optically active 2-phenylthio-2-cycloalkene derivative according to claim 3, wherein the acylating agent is a vinyl ester.
ナス菌由来である光学活性2−フェニルチオ−2−シク
ロアルケン誘導体の製造法。6. The method for producing an optically active 2-phenylthio-2-cycloalkene derivative according to claim 3, wherein the lipase is derived from Pseudomonas.
ナス菌由来である光学活性2−フェニルチオ−2−シク
ロアルケン誘導体の製造法。7. The method for producing an optically active 2-phenylthio-2-cycloalkene derivative according to claim 4, wherein the lipase is derived from Pseudomonas.
Priority Applications (1)
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JP24643893A JPH0776569A (en) | 1993-09-07 | 1993-09-07 | Optically active 2-phenylthio-2-cycloalkene derivative and production thereof |
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JPH0776569A true JPH0776569A (en) | 1995-03-20 |
Family
ID=17148472
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009232735A (en) * | 2008-03-26 | 2009-10-15 | Tadakatsu Bandai | Method for producing (1r, 2r)-1-acyloxy-3-cycloalkene or (1s, 2s)-3-cycloalken-1-ol |
-
1993
- 1993-09-07 JP JP24643893A patent/JPH0776569A/en active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009232735A (en) * | 2008-03-26 | 2009-10-15 | Tadakatsu Bandai | Method for producing (1r, 2r)-1-acyloxy-3-cycloalkene or (1s, 2s)-3-cycloalken-1-ol |
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