JP2002265412A - Novel cyclopentenone derivative - Google Patents
Novel cyclopentenone derivativeInfo
- Publication number
- JP2002265412A JP2002265412A JP2001110603A JP2001110603A JP2002265412A JP 2002265412 A JP2002265412 A JP 2002265412A JP 2001110603 A JP2001110603 A JP 2001110603A JP 2001110603 A JP2001110603 A JP 2001110603A JP 2002265412 A JP2002265412 A JP 2002265412A
- Authority
- JP
- Japan
- Prior art keywords
- group
- added
- cyclopentenone
- ether
- reduced pressure
- 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.)
- Withdrawn
Links
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical class O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 12
- 230000002194 synthesizing effect Effects 0.000 abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 8
- 150000001865 clavulones Chemical class 0.000 abstract description 4
- QXSYLWTUKSQQCP-KZCIJIKDSA-N 4-epiclavulone II Natural products CCCCCC=C/CC1(OC(=O)C)C=CC(=O)/C/1=C/C=C/C(CCC(=O)OC)OC(=O)C QXSYLWTUKSQQCP-KZCIJIKDSA-N 0.000 abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- QXSYLWTUKSQQCP-VZCZYXORSA-N clavulone II Chemical compound CCCCC\C=C/C[C@]1(OC(C)=O)C=CC(=O)\C1=C\C=C\[C@@H](CCC(=O)OC)OC(C)=O QXSYLWTUKSQQCP-VZCZYXORSA-N 0.000 abstract description 3
- 230000001766 physiological effect Effects 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- -1 2-octyl Chemical group 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 230000000704 physical effect Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 150000001864 clavulone derivatives Chemical class 0.000 description 4
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DHNDDRBMUVFQIZ-SCSAIBSYSA-N (4s)-4-hydroxycyclopent-2-en-1-one Chemical compound O[C@H]1CC(=O)C=C1 DHNDDRBMUVFQIZ-SCSAIBSYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229940127293 prostanoid Drugs 0.000 description 3
- 150000003814 prostanoids Chemical class 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- CNZGXYGHOQKZGR-QMMMGPOBSA-N (4r)-4-hydroxy-4-prop-2-ynylcyclopent-2-en-1-one Chemical compound C#CC[C@@]1(O)CC(=O)C=C1 CNZGXYGHOQKZGR-QMMMGPOBSA-N 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- DHNDDRBMUVFQIZ-UHFFFAOYSA-N 4-hydroxycyclopent-2-en-1-one Chemical group OC1CC(=O)C=C1 DHNDDRBMUVFQIZ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- DHNDDRBMUVFQIZ-BYPYZUCNSA-N (4r)-4-hydroxycyclopent-2-en-1-one Chemical compound O[C@@H]1CC(=O)C=C1 DHNDDRBMUVFQIZ-BYPYZUCNSA-N 0.000 description 1
- FDYSLTMXIYKVAI-UHFFFAOYSA-N 2-cyclopent-2-en-1-yloxyoxane Chemical compound C1=CCCC1OC1OCCCC1 FDYSLTMXIYKVAI-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- UDKMVJZZXDGFAE-UHFFFAOYSA-N 3-prop-2-ynylcyclopentene Chemical compound C#CCC1CCC=C1 UDKMVJZZXDGFAE-UHFFFAOYSA-N 0.000 description 1
- KNDDEJNSZWCUJL-UHFFFAOYSA-N 4-(oxan-2-yloxy)cyclopent-2-en-1-one Chemical compound C1=CC(=O)CC1OC1OCCCC1 KNDDEJNSZWCUJL-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 235000014653 Carica parviflora Nutrition 0.000 description 1
- ZFSOWVJWGBXQPK-UHFFFAOYSA-M Cl[Mg]CC#C Chemical compound Cl[Mg]CC#C ZFSOWVJWGBXQPK-UHFFFAOYSA-M 0.000 description 1
- 241000243321 Cnidaria Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- YLERVAXAQFOFRI-UHFFFAOYSA-M magnesium;propa-1,2-diene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C#C YLERVAXAQFOFRI-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960002523 mercuric chloride Drugs 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 238000006702 propargylation reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- NBNBICNWNFQDDD-UHFFFAOYSA-N sulfuryl dibromide Chemical compound BrS(Br)(=O)=O NBNBICNWNFQDDD-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-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
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- DCGLONGLPGISNX-UHFFFAOYSA-N trimethyl(prop-1-ynyl)silane Chemical compound CC#C[Si](C)(C)C DCGLONGLPGISNX-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は新規シクロペンテノ
ン誘導体に関するもので，医薬等の属する分野および他
の分野において要求されているプロスタノイドを合成す
るための有用な中間体を提供するものである。TECHNICAL FIELD The present invention relates to a novel cyclopentenone derivative, and provides a useful intermediate for synthesizing a prostanoid required in the field of medicine and other fields. .
【０００２】[0002]
【従来の技術】近年，海洋生物が生産する生理活性物質
が注目されている。ことに日本珊瑚のクラブラリア・ビ
リディスから抽出されるクラブロン類は抗腫瘍作用およ
び抗炎症作用を有しており，大いに注目されている。そ
して，クラブロン類の構造決定や生理活性の解明が盛ん
に行われ，有機合成の分野ではクラブロン類の合成法が
盛んに研究されている。2. Description of the Related Art In recent years, attention has been paid to physiologically active substances produced by marine organisms. In particular, clavrons extracted from crablaria viridis of Japanese coral have anti-tumor and anti-inflammatory effects and have been receiving much attention. In addition, the determination of the structure of clavrons and the elucidation of their physiological activities have been actively carried out, and in the field of organic synthesis, synthetic methods of clavrons have been actively studied.
【０００３】クラブロン類の中でも，クラブロンＩＩは
強い抗腫瘍作用が知られている。クラブロンはプロスタ
ノイドの一種であるが，下記構造式に示すようにその構
造的特徴として１２−位に酸素官能基を有すること，そ
して交差共役系が存在する点で従来から知られているプ
ロスタノイドと異なる。また，４−位と１２−位は不斉
炭素であり，立体選択的な合成が求められている。[0003] Among clavrons, clavulone II is known to have a strong antitumor effect. Clavron is a kind of prostanoid, but it is a prostanoid that has been known in the past because it has an oxygen functional group at the 12-position and a cross-conjugated system as shown in the following structural formula. It is different from a solenoid. In addition, the 4-position and 12-position are asymmetric carbons, and stereoselective synthesis is required.
【０００４】[0004]
【化２】 Embedded image
【０００５】従って，このクラブロンＩＩの合成は複雑
な工程を必要とされる。例えば，長岡らは（Ｓ）−４−
ヒドロキシシクロペンテノンを酢酸ｔ−ブチルのエノラ
ートと反応させ，１，４−ジヒドロキシ−２−シクロペ
ンテニル酢酸ｔ−ブチルとし，水酸基を保護した後，Ｌ
ｉＡｌＨ４でエステルを水酸基に還元，次いでＳｗｅｒ
ｎ酸化によりアルデヒドとした後，Ｗｉｔｔｉｇ反応に
よりω−鎖を構築している。その後，ＰＣＣで酸化して
シクロペンテノン骨格を形成，次いでα−鎖を導入する
方法を報告している［Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔ
ｔ．，２５，３６２１（１９８４）］。柴崎らは１，２
−ビス（トリメチルシリルオキシ）シクロペンテンをメ
チルリチウムでリチオ化し，２−オクチニルブロミドを
反応させ，２−（２−オクチニル）−２−ヒドロキシシ
クロペンテノンとし，これをＬｉｎｄｌａｒ触媒の存在
下Ｈ２で還元してω−鎖を構築している。その後，ＴＭ
Ｓトリフラートで２−位の水酸基のＴＭＳエーテルに，
そして１−位のケトンをシリルエノールエーテルとし，
次いでＰｄ（ＯＡｃ）２でシリルエノールエーテルをエ
ノンに変換して５−（トリメチルシリルオキシ）−５−
（２−オクテニル）−２−シクロペンテノンとしてい
る。この２−シクロペンテノンのケトンをＮａＢＨ４で
還元，次いでメタンスルホン酸無水物でメタンスルホナ
ートとし，このスルホン酸エステルを加水分解した後，
Ｃｏｌｌｉｎ酸化，次いで脱ＴＭＳ化を行なうことで４
−ヒドロキシ−２−シクロペンテノン骨格を形成してい
る。その後，α−鎖を導入し，クロマトグラフィーでジ
アステレオマーを分割するクラブロンＩＩの合成方法を
報告している［Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，
２６，３８４１（１９８５）］。Therefore, the synthesis of clavulon II requires a complicated process. For example, Nagaoka et al. (S) -4-
Hydroxycyclopentenone is reacted with an enolate of t-butyl acetate to give 1,4-dihydroxy-2-cyclopentenyl acetate t-butyl, and after protecting the hydroxyl group, L
Reduction of the ester to a hydroxyl group with iAlH 4 followed by Swer
After conversion to aldehyde by n-oxidation, an ω-chain is constructed by Wittig reaction. Thereafter, a method of oxidizing with PCC to form a cyclopentenone skeleton and then introducing an α-chain has been reported [Tetrahedron Let].
t. , 25 , 3621 (1984)]. Shibasaki et al.
- bis (trimethylsilyloxy) cyclopentene was lithiated with methyl lithium, 2-octyl reacting the sulfonyl bromide, 2- (2-octynyl) -2-hydroxy and cyclopentenone, reduced in the presence of H 2 Lindlar catalyst this To construct the ω-chain. Then, TM
To the TMS ether of the 2-position hydroxyl group with S triflate,
And the 1-position ketone is silyl enol ether,
The silyl enol ether is then converted to the enone with Pd (OAc) 2 to give 5- (trimethylsilyloxy) -5-
(2-octenyl) -2-cyclopentenone. The 2-cyclopropyl reducing the pen ketone tenons in NaBH 4, followed by a methanesulfonate in methanesulfonic anhydride, after hydrolyzing the sulfonic acid ester,
Collin oxidation followed by de-TMS conversion gives 4
-Hydroxy-2-cyclopentenone skeleton is formed. Thereafter, a method for synthesizing clavulon II in which an α-chain is introduced and the diastereomer is separated by chromatography has been reported [Tetrahedron Lett. ,
26 , 3841 (1985)].
【０００６】[0006]
【発明が解決しようとする課題】上記クラブロンＩＩの
合成法はいずれも天然クラブロンＩＩと同じ立体配置の
ものを得ることができる優れた合成法である。しかしな
がら，長岡らの方法はω−鎖の構築に多数の工程を必要
とし，また，柴崎らの方法は４−ヒドロキシシクロペン
テノン骨格の形成に多数の工程を必要としており，いず
れの方法も簡便な方法と言い難く，とても満足できるも
のでない。クラブロンＩＩあるいはその類縁体を簡便
に，しかも立体選択性を持って合成することが強く求め
られている。All of the above-mentioned methods for synthesizing clavulon II are excellent syntheses that can obtain those having the same configuration as natural clavulone II. However, the method of Nagaoka et al. Requires many steps for the construction of the ω-chain, and the method of Shibasaki et al. Requires many steps for the formation of the 4-hydroxycyclopentenone skeleton. It is hard to say, and it is not very satisfactory. There is a strong demand for synthesizing clavulon II or its analogs easily and with stereoselectivity.
【０００７】[0007]
【課題を解決するための手段】そこで，発明者は鋭意研
究を重ねた結果，本発明を完成するに至った。すなわ
ち，本発明は下記構造式で示される光学活性シクロペン
テノン誘導体に関するもので，クラブロン誘導体を合成
するための有用な中間体として供されるものである。Means for Solving the Problems Accordingly, the inventor has conducted intensive studies and, as a result, completed the present invention. That is, the present invention relates to an optically active cyclopentenone derivative represented by the following structural formula, which is provided as a useful intermediate for synthesizing a clavulone derivative.
【０００８】[0008]
【化３】 Embedded image
【０００９】（ただし，Ｒ１は水素，アシル基，テトラ
ヒドロピラニル基，メトキシメチル基，トリアルキルシ
リル基から選ばれ，Ｒ２は３−ヨードアリル基，３−ブ
ロモアリル基，３−クロロアリル基，プロパルギル基か
ら選ばれる） 本発明に係る上記式で表される化合物は文献未載の新規
化合物であり，その製造法としては，例えば，本発明化
合物の一つである（４Ｒ）−４−ヒドロキシ−４−（３
−ヨードアリル）−２−シクロペンテノンは，下記反応
式１に従って（４Ｓ）−４−ヒドロキシ−２−シクロペ
ンテノンから６工程で得ることができる。(Where R 1 is selected from hydrogen, acyl group, tetrahydropyranyl group, methoxymethyl group, and trialkylsilyl group; R 2 is 3-iodoallyl group, 3-bromoallyl group, 3-chloroallyl group, propargyl group) The compound represented by the above formula according to the present invention is a novel compound not described in any literature, and its production method includes, for example, one of the compounds of the present invention, (4R) -4-hydroxy- 4- (3
-Iodoallyl) -2-cyclopentenone can be obtained in 6 steps from (4S) -4-hydroxy-2-cyclopentenone according to the following reaction scheme 1.
【００１０】[0010]
【化４】 Embedded image
【００１１】上記反応式において，第Ｉ工程で使用しう
る溶媒はテトラヒドロフラン，エーテル，ジオキサン
等，あるいはこれらの混合溶媒が挙げられる。第ＩＩ工
程は塩化メチレン，クロロホルム，トルエン，テトラヒ
ドロフラン，エーテル等のごとき有機溶媒が挙げられ，
第ＩＩＩ工程はアセトン，アセトニトリル，テトラヒド
ロフラン，エーテル，ジオキサン等が挙げられ，第ＩＶ
工程はテトラヒドロフラン，エーテル，ジオキサン等が
あげられる。第Ｖ工程はメタノール，エタノール，テト
ラヒドロフラン，エーテル，ジオキサン等が挙げられる
が，好ましくはアルコール類である。第ＶＩ工程は塩化
メチレン，クロロホルム等とトルエン，ベンゼン等の混
合溶媒が挙げられる。反応温度は各工程それぞれ通常−
１００℃〜１００℃の範囲内で行なうことができるが，
好ましくは第Ｉ工程が−７８℃付近，第ＩＩ工程，第Ｉ
ＩＩ工程，第ＩＶ工程，第Ｖ工程，第ＶＩ工程は０℃〜
室温である。反応に要する時間は使用する溶媒，塩基，
反応温度により異なる。第Ｉ工程から第Ｖ工程は通常１
分〜１２時間の範囲内であるが，好ましくは１分〜３時
間の範囲内で適宜選択される。第ＶＩ工程は１時間〜２
４時間の範囲内で適宜選択される。反応混合物からの目
的物の単離，精製は，常法に従って容易に行なうことが
できる。例えば，ろ過，あるいはエーテル，ベンゼン，
トルエン，塩化メチレン，クロロホルム，酢酸エチルの
ごとき有機溶媒による抽出，またはシリカゲル，活性炭
素，デキストラン架橋重合体，スチレン，アクリル酸エ
ステルの多孔質重合体等を用いた各種クロマトグラフィ
ーを行なうことにより，単離，精製することができる。In the above reaction formula, the solvent that can be used in the step I includes tetrahydrofuran, ether, dioxane and the like, or a mixed solvent thereof. The second step includes an organic solvent such as methylene chloride, chloroform, toluene, tetrahydrofuran, ether and the like,
Step III includes acetone, acetonitrile, tetrahydrofuran, ether, dioxane and the like.
The process includes tetrahydrofuran, ether, dioxane and the like. The step V includes methanol, ethanol, tetrahydrofuran, ether, dioxane, etc., preferably alcohols. Step VI includes a mixed solvent of methylene chloride, chloroform or the like and toluene, benzene or the like. The reaction temperature is usually-
It can be performed within the range of 100 ° C to 100 ° C,
Preferably, Step I is around -78 ° C, Step II, Step I
Step II, Step IV, Step V and Step VI are performed at 0 ° C.
At room temperature. The time required for the reaction depends on the solvent, base,
Depends on reaction temperature. Steps I to V are usually 1
The time is selected from the range of minutes to 12 hours, preferably from 1 minute to 3 hours. Step VI is 1 hour to 2 hours
It is appropriately selected within a range of 4 hours. Isolation and purification of the target compound from the reaction mixture can be easily performed according to a conventional method. For example, filtration, or ether, benzene,
Extraction with an organic solvent such as toluene, methylene chloride, chloroform or ethyl acetate, or various chromatography using silica gel, activated carbon, dextran cross-linked polymer, porous polymer of styrene, acrylate, etc. Can be separated and purified.
【００１２】また，上記以外の本発明化合物である（４
Ｒ）−４−ヒドロキシ−４−プロパルギル−２−シクロ
ペンテノンは，下記反応式に従って（４Ｓ）−４−ヒド
ロキシ−２−シクロペンテノンから２工程で合成するこ
とができる。The compound of the present invention other than the above (4)
R) -4-Hydroxy-4-propargyl-2-cyclopentenone can be synthesized from (4S) -4-hydroxy-2-cyclopentenone in two steps according to the following reaction formula.
【００１３】[0013]
【化５】 Embedded image
【００１４】第１工程は４−位の水酸基を保護した後，
プロパルギル基を導入する工程である。この工程で用い
る保護基はテトラヒドロピラニル基，メトキシメチル
基，ベンジル基，ｐ−メトキシベンジル基，トリチル
基，２−トリメチルシリルエチル基，アリル基などから
選ばれる。プロパルギル基の導入にはプロパルギルマグ
ネシウムブロミド，プロパルギルマグネシウムクロリド
などが選ばれる。このプロパルギル化の際，充分なジア
ステレオ選択性が得られない場合はＨＰＬＣなどで，ジ
アステレオマーを分離することができる。第２工程は脱
保護と酸化の工程である。脱保護の条件は使用する保護
基により最適な条件が選ばれるが，保護基がテトラヒド
ロピラニル基の場合は酢酸酸性条件などが用いられる。In the first step, after protecting the hydroxyl group at the 4-position,
This is the step of introducing a propargyl group. The protecting group used in this step is selected from a tetrahydropyranyl group, a methoxymethyl group, a benzyl group, a p-methoxybenzyl group, a trityl group, a 2-trimethylsilylethyl group, an allyl group, and the like. For the introduction of a propargyl group, propargyl magnesium bromide, propargyl magnesium chloride and the like are selected. When sufficient diastereoselectivity cannot be obtained during the propargylation, diastereomers can be separated by HPLC or the like. The second step is a deprotection and oxidation step. Optimum conditions for deprotection are selected depending on the protecting group used. When the protecting group is a tetrahydropyranyl group, acidic conditions such as acetic acid are used.
【００１５】上記のごとく合成できる本発明化合物はク
ラブロン誘導体を合成するための有用な中間体として供
される。例えば，本発明化合物，（４Ｒ）−４−ヒドロ
キシ−４−（３−ヨードアリル）−２−シクロペンテノ
ンは，その水酸基を保護した後，Ｂ−アルキル−９−ボ
ラビシクロ［３．３．１］ノナンをＰｄ（０）の存在下
で反応させることにより，ω−鎖を延長することができ
る。次いで，塩基の存在下，α，β−不飽和アルデヒド
を反応させることによりα−鎖を導入し，クラブロン誘
導体を合成することができる。また，（４Ｒ）−４−ヒ
ドロキシ−４−プロパルギル−２−シクロペンテノンを
利用する場合，まず，水酸基を保護し，その後，芳香族
ヨージド，あるいはアルキルヨージドを反応させ，次い
でアルデヒドを反応させることによりクラブロン類縁体
を合成することができる。即ち，本発明化合物は３成分
連結法を用いてクラブロン誘導体，あるいは類縁体を合
成するために必要なシクロペンテノンで，４−位に水酸
基を有し，その絶対配位置はＲである。また，ω−鎖の
一部として３−ハロゲノアリル基，あるいはプロパルギ
ル基を有している。そして，このハロゲンは容易にアル
キル基などに変換でき，また，プロパルギル基も容易に
延長することができる。The compounds of the present invention which can be synthesized as described above are used as useful intermediates for synthesizing clavulone derivatives. For example, the compound of the present invention, (4R) -4-hydroxy-4- (3-iodoallyl) -2-cyclopentenone, after protecting its hydroxyl group, is B-alkyl-9-borabicyclo [3.3.1]. By reacting nonane in the presence of Pd (0), the ω-chain can be extended. Then, an α-chain is introduced by reacting an α, β-unsaturated aldehyde in the presence of a base to synthesize a clavulone derivative. When (4R) -4-hydroxy-4-propargyl-2-cyclopentenone is used, the hydroxyl group is protected first, and then an aromatic iodide or an alkyl iodide is reacted, and then an aldehyde is reacted. Thus, a clavulone analog can be synthesized. That is, the compound of the present invention is a cyclopentenone necessary for synthesizing a clavulone derivative or an analog using a three-component linking method. Further, it has a 3-halogenoallyl group or a propargyl group as a part of the ω-chain. The halogen can be easily converted to an alkyl group or the like, and the propargyl group can be easily extended.
【００１６】[0016]
【実施例】以下に本発明の好ましい実施例を記載する
が，これは例示の目的であり，本発明を制限するもので
はない。本発明の範囲内では変形が可能なことは当業者
には明らかであろう。DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of the present invention will be described below, but these are for the purpose of illustration and do not limit the present invention. It will be apparent to those skilled in the art that variations are possible within the scope of the invention.
【００１７】実施例１（３Ｒ，５Ｓ）−３，５−ジヒド
ロキシ−３−（３−トリメチルシリルプロパルギル）シ
クロペンテンの合成 テトラヒドロフラン４０ｍｌにジイソプロピルアミン２
４．５ｍｍｏｌを加え，０℃に冷却，アルゴン気流下，
１．５９Ｍのｎ−ブチルリチウムヘキサン溶液１４．２
ｍｌを加え，２０分間攪拌を続けた後，−２０℃に冷
却，次いで１−トリメチルシリルプロピン２２．５ｍｍ
ｏｌを含むテトラヒドロフラン５ｍｌを加え，−７８℃
に冷却，この溶液に（Ｒ）−４−ヒドロキシ−２−シク
ロペンテノン９．７９ｍｍｏｌを含むテトラヒドロフラ
ン１０ｍｌを加え，−７８℃で１０分間攪拌した。この
反応溶液をエーテルで希釈し，０℃にて飽和塩化アンモ
ニウム水溶液５０ｍｌに注ぎ，エーテル５０ｍｌ（Ｘ
３）で抽出し，抽出液をブリンで洗浄し，硫酸マグネシ
ウムを加え，ろ過，減圧下エーテルを留去した。残渣を
カラム精製し，減圧下溶媒を留去し，収率８５％で，
（３Ｒ，５Ｓ）−３，５−ジヒドロキシ−３−（３−ト
リメチルシリルプロパルギル）シクロペンテンの白色結
晶８．２９ｍｍｏｌを得た。Example 1 (3R, 5S) -3,5-dihydride
Roxy-3- (3-trimethylsilylpropargyl) si
Synthesis of Clopentene Diisopropylamine 2 in 40 ml of tetrahydrofuran
4.5 mmol was added, cooled to 0 ° C., and under an argon stream.
1.59 M n-butyllithium hexane solution 14.2
After stirring for 20 minutes, the mixture was cooled to −20 ° C., and then 12.5% of 1-trimethylsilylpropyne was added.
ol-containing tetrahydrofuran (5 ml), and added at −78 ° C.
Then, 10 ml of tetrahydrofuran containing 9.79 mmol of (R) -4-hydroxy-2-cyclopentenone was added to this solution, and the mixture was stirred at -78 ° C for 10 minutes. The reaction solution was diluted with ether, poured at 0 ° C. into 50 ml of a saturated aqueous ammonium chloride solution, and 50 ml of ether (X
The extract was extracted in 3), the extract was washed with brine, magnesium sulfate was added, and the mixture was filtered and ether was distilled off under reduced pressure. The residue was purified by column, and the solvent was distilled off under reduced pressure.
8.29 mmol of white crystals of (3R, 5S) -3,5-dihydroxy-3- (3-trimethylsilylpropargyl) cyclopentene were obtained.
【００１８】以下に主な物性値を示す。 融点：９８−１００℃，［α］Ｄ−９３．１°（ｃ＝
１．０，ＣＨＣｌ３），ＩＲ（ＫＢｒ）：３７２４ｃｍ
−１，２１８０ｃｍ−１，１３５３ｃｍ−１，１３０６
ｃｍ−１，１２４８ｃｍ−１，１０８２ｃｍ−１，１Ｈ
ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ３）：δ６．００
（１Ｈ，ｄｄ，Ｊ＝２．０，５．６Ｈｚ），５．９３
（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），４．７２（１Ｈ，
ｍ），２．５６（１Ｈ，ｄｄ，Ｊ＝６．９，１４．２Ｈ
ｚ），２．５４（２Ｈ，ｓ），１．８１（１Ｈ，ｄｄ，
Ｊ＝３．６，１４．２Ｈｚ），０．１７（９Ｈ，ｓ），
１３Ｃ ＮＭＲ（６７．８ＭＨｚ，ＣＤＣｌ３）：δ１
３８．４，１３６．２，１０２．３，８２．５，８１．
４，７５．５，４８．０，３２．４，０．００２The main physical properties are shown below. Melting point: 98-100 ° C, [α] D- 93.1 ° (c =
1.0, CHCl 3 ), IR (KBr): 3724 cm
−1 , 2180 cm −1 , 1353 cm −1 , 1306
cm -1, 1248cm -1, 1082cm -1 , 1 H
NMR (270 MHz, CDCl 3 ): δ 6.00
(1H, dd, J = 2.0, 5.6 Hz), 5.93
(1H, d, J = 5.6 Hz), 4.72 (1H,
m), 2.56 (1H, dd, J = 6.9, 14.2H
z), 2.54 (2H, s), 1.81 (1H, dd,
J = 3.6, 14.2 Hz), 0.17 (9H, s),
13 C NMR (67.8 MHz, CDCl 3 ): δ1
38.4, 136.2, 102.3, 82.5, 81.
4,75.5,48.0,32.4,0.002
【００１９】実施例２（３Ｒ，５Ｓ）−３，５−ビス
（トリエチルシリルオキシ）−３−（３−トリメチルシ
リルプロパルギル）シクロペンテンの合成 ジクロロメタン５０ｍｌに（３Ｒ，５Ｓ）−３，５−ジ
ヒドロキシ−３−（３−トリメチルシリルプロパルギ
ル）シクロペンテン９．７９ｍｍｏｌを溶解させ，アル
ゴン気流下，０℃にてイミダゾール４３．１ｍｍｏｌ，
ｔ−ブチルジメチルシリルクロリド２１．５ｍｍｏｌを
加え，次いで，エーテル３０ｍｌ，飽和塩化アンモニウ
ム水溶液５０ｍｌを加え分液した。水層をエーテル５０
ｍｌ（Ｘ３）で抽出し，有機層を合わせブリンで洗浄
後，硫酸マグネシウムを加え，ろ過，減圧下有機溶媒を
留去した。残渣をアセトン４０ｍｌに溶解し，０℃に冷
却した。この溶液にアルゴン気流下，Ｎ−ヨードスクシ
ンイミド１０．６ｍｍｏｌ，硝酸銀８．８０ｍｍｏｌを
加え，３．５時間攪拌を続けた。この反応液にエーテル
２０ｍｌ，飽和チオ硫酸ナトリウム水溶液３０ｍｌ，飽
和炭酸水素ナトリウム水溶液３０ｍｌを加え，有機層を
分離した。水層をエーテル５０ｍｌ（Ｘ３）で抽出し，
抽出液と先に分離した有機層を合わせ，ブリンで洗浄
後，硫酸マグネシウムを加え，ろ過，減圧下有機溶媒を
留去した。残渣をカラム精製し，減圧下溶媒を留去し，
収率８３％で，（３Ｒ，５Ｓ）−３，５−ビス（トリエ
チルシリルオキシ）−３−（３−トリメチルシリルプロ
パルギル）シクロペンテンの黄色液体４．０ｇを得た。Example 2 (3R, 5S) -3,5-bis
(Triethylsilyloxy) -3- (3-trimethylsi
Synthesis of (3R, 5S) -3,5-dihydroxy-3- (3-trimethylsilylpropargyl) cyclopentene 9.79 mmol was dissolved in 50 ml of dichloromethane, and 43.1 mmol of imidazole was dissolved at 0 ° C. in an argon stream.
21.5 mmol of t-butyldimethylsilyl chloride was added, and then 30 ml of ether and 50 ml of a saturated aqueous solution of ammonium chloride were added to carry out liquid separation. The aqueous layer is ether 50
The mixture was extracted with 100 ml (X3), the organic layers were combined, washed with brine, added with magnesium sulfate, filtered, and the organic solvent was distilled off under reduced pressure. The residue was dissolved in acetone (40 ml) and cooled to 0 ° C. 10.6 mmol of N-iodosuccinimide and 8.80 mmol of silver nitrate were added to this solution under an argon stream, and stirring was continued for 3.5 hours. 20 ml of ether, 30 ml of a saturated aqueous sodium thiosulfate solution, and 30 ml of a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted with 50 ml of ether (X3),
The extract and the previously separated organic layer were combined, washed with brine, added with magnesium sulfate, filtered, and the organic solvent was distilled off under reduced pressure. The residue was purified by column, and the solvent was distilled off under reduced pressure.
In a yield of 83%, 4.0 g of a yellow liquid of (3R, 5S) -3,5-bis (triethylsilyloxy) -3- (3-trimethylsilylpropargyl) cyclopentene was obtained.
【００２０】以下に主な物性値を示す。 ［α］Ｄ−５６．８°（ｃ＝１．０，ＣＨＣｌ３），Ｉ
Ｒ：３３１４ｃｍ−１，２９１２ｃｍ−１，１４５９ｃ
ｍ−１，１４２５ｃｍ−１，１３６７ｃｍ−１，１Ｈ
ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ３）：δ５．８２（１
Ｈ，ｄｄ，Ｊ＝５．３，７．６Ｈｚ），５．８０（１
Ｈ，ｄ，Ｊ＝７．６Ｈｚ），４．６９（１Ｈ，ｄｔ，Ｊ
＝５．３，７．６Ｈｚ），２．５９（２Ｈ，ｓ），２．
５７（１Ｈ，ｄｄ，Ｊ：９．６，１６．５Ｈｚ），１．
８４（１Ｈ，ｄｄｔ，Ｊ＝２．６，７．６，１６．５Ｈ
ｚ），０．９７，０．９４（１８Ｈ，２ｔ，Ｊ＝７．
９，８．２Ｈｚ），０．６１，０．６０（１２Ｈ，２
ｑ，Ｊ＝７．９，８．２Ｈｚ），１３Ｃ ＮＭＲ（６
７．８ＭＨｚ，ＣＤＣｌ３）：δ１３７．１，１３９．
４，９１．６，８４．６，７４．９，６９．１，３５．
３，６．９，６．８，４．８The main physical properties are shown below. [Α] D -56.8 ° (c = 1.0, CHCl 3 ), I
R: 3314 cm -1 , 2912 cm -1 , 1459c
m −1 , 1425 cm −1 , 1367 cm −1 , 1 H
NMR (270 MHz, CDCl 3 ): δ 5.82 (1
H, dd, J = 5.3, 7.6 Hz), 5.80 (1
H, d, J = 7.6 Hz), 4.69 (1H, dt, J)
= 5.3, 7.6 Hz), 2.59 (2H, s), 2.
57 (1H, dd, J: 9.6, 16.5 Hz);
84 (1H, ddt, J = 2.6, 7.6, 16.5H
z), 0.97, 0.94 (18H, 2t, J = 7.
9, 8.2 Hz), 0.61, 0.60 (12H, 2
q, J = 7.9, 8.2 Hz), 13 C NMR (6
7.8MHz, CDCl 3): δ137.1,139.
4,91.6,84.6,74.9,69.1,35.
3,6.9,6.8,4.8
【００２１】実施例３（３Ｒ，５Ｓ）−３，５−ビス
（トリエチルシリルオキシ）−３−（ヨードアリル）シ
クロペンテンの合成 エーテル２０ｍｌにシクロヘキセン３４．８ｍｍｏｌを
加え，０℃に冷却し，アルゴン気流下，ジメチルスルフ
ィドボラン１７．４ｍｍｏｌを加え，室温で１時間攪拌
した。その後，０℃に冷却し，エーテル１０ｍｌに（３
Ｒ，５Ｓ）−３，５−ビス（トリエチルシリルオキシ）
−３−（３−トリメチルシリルプロパルギル）シクロペ
ンテン５．８０ｍｍｏｌを溶解した溶液を加えた。１時
間後，この反応液に氷酢酸４ｍｌを加えて３０分間攪拌
した後，エーテル２０ｍｌと飽和炭酸水素ナトリウム４
０ｍｌを加え，有機層を分離した。水層をエーテル４０
ｍｌ（Ｘ３）で抽出し，抽出液と先に分離した有機層を
合わせ，ブリン４０ｍｌ（Ｘ３）で洗浄し，その後，硫
酸マグネシウムで加え，ろ過，減圧下有機溶媒を留去し
た。残渣をカラム精製し，減圧下，溶媒を留去し，収率
８２％で，（３Ｒ，５Ｓ）−３，５−ビス（トリエチル
シリルオキシ）−３−（３−ヨードアリル）シクロペン
テンの黄色液体２．３６ｇを得た。Example 3 (3R, 5S) -3,5-bis
(Triethylsilyloxy) -3- (iodoallyl) si
34.8 mmol of cyclohexene was added to 20 ml of synthetic ether of clopentene, cooled to 0 ° C., 17.4 mmol of dimethylsulfide borane was added under a stream of argon, and the mixture was stirred at room temperature for 1 hour. Then, the mixture was cooled to 0 ° C. and added to 10 ml of ether (3
(R, 5S) -3,5-bis (triethylsilyloxy)
A solution of 5.80 mmol of -3- (3-trimethylsilylpropargyl) cyclopentene was added. One hour later, 4 ml of glacial acetic acid was added to the reaction solution, and the mixture was stirred for 30 minutes.
0 ml was added and the organic layer was separated. The aqueous layer is ether 40
The extracted solution was combined with the previously separated organic layer, washed with 40 ml of Brine (X3), then added with magnesium sulfate, filtered, and the organic solvent was distilled off under reduced pressure. The residue was purified by column, the solvent was distilled off under reduced pressure, and a yellow liquid of (3R, 5S) -3,5-bis (triethylsilyloxy) -3- (3-iodoallyl) cyclopentene was obtained in a yield of 82%. .36 g were obtained.
【００２２】以下に主な物性値を示す。 ［α］Ｄ−３７．０°（ｃ＝１．０，ＣＨＣｌ３），Ｉ
Ｒ：２９１２ｃｍ−１，１４５９ｃｍ−１，１４１５ｃ
ｍ−１，１３６７ｃｍ−１，１Ｈ ＮＭＲ（２７０ＭＨ
ｚ，ＣＤＣｌ３）：δ６．２６（１Ｈ，ｄｔ，Ｊ＝６．
３，１２．９Ｈｚ），６．２４（１Ｈ，ｄ，Ｊ＝１２．
９Ｈｚ），５．７７（１Ｈ，ｄｔ，Ｊ＝５．６，７．３
Ｈｚ），５．７７（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），４．
６３（１Ｈ，ｄｄｄ，Ｊ＝１．３，５．３，５．６Ｈ
ｚ），２．４５（１Ｈ，ｄｄ，Ｊ＝６．９，１３．２Ｈ
ｚ），２．３６（１Ｈ，ｄ，Ｊ＝６．３Ｈｚ），２．２
６（１Ｈ，ｄｄ，Ｊ＝６．３，１４．５Ｈｚ），１．７
５（１Ｈ，ｄｄ，Ｊ＝５．３，１３．２Ｈｚ），０．９
６，０．９４（１８Ｈ，２ｔ，Ｊ＝７．９，８．３Ｈ
ｚ），０．６０（１２Ｈ，ｑ，Ｊ＝８．３Ｈｚ），１３
Ｃ ＮＭＲ（６７．８ＭＨｚ，ＣＤＣｌ３）：δ１３
８．３，１３７．８，１３５．５，８４．４，８４．
２，７４．６，４９．２，４７．９，７．０，６．８，
６．５，４．８The main physical properties are shown below. [Α] D −37.0 ° (c = 1.0, CHCl 3 ), I
R: 2912 cm -1 , 1459 cm -1 , 1415c
m −1 , 1367 cm −1 , 1 H NMR (270 MH
z, CDCl 3 ): δ 6.26 (1H, dt, J = 6.
3,12.9 Hz), 6.24 (1H, d, J = 12.
9Hz), 5.77 (1H, dt, J = 5.6, 7.3)
Hz), 5.77 (1H, d, J = 7.3 Hz), 4.
63 (1H, ddd, J = 1.3, 5.3, 5.6H
z), 2.45 (1H, dd, J = 6.9, 13.2H
z), 2.36 (1H, d, J = 6.3 Hz), 2.2
6 (1H, dd, J = 6.3, 14.5 Hz), 1.7
5 (1H, dd, J = 5.3, 13.2 Hz), 0.9
6, 0.94 (18H, 2t, J = 7.9, 8.3H
z), 0.60 (12H, q, J = 8.3 Hz), 13
C NMR (67.8 MHz, CDCl 3 ): δ13
8.3, 137.8, 135.5, 84.4, 84.
2,74.6,49.2,47.9,7.0,6.8,
6.5, 4.8
【００２３】実施例４（Ｒ）−４−ヒドロキシ−４−
（３−ヨードアリル）−２−シクロペンテノンの合成 メタノール１０ｍｌに（３Ｒ，５Ｓ）−３，５−ビス
（トリエチルシリルオキシ）−３−（３−ヨードアリ
ル）シクロペンテン４．７７ｍｍｏｌを溶解させ，０℃
に冷却し，（１Ｓ）−（＋）−１０−カンファースルホ
ン酸０．１３ｍｍｏｌを加え，２時間攪拌した。この反
応液をトリエチルアミン２０μｌで中和し，減圧下，溶
媒を留去した。残渣をジクロロメタン６０ｍｌに溶解さ
せ，アルゴン気流下，ＭｎＯ２４７．７ｍｍｏｌを加
え，室温で１４時間攪拌した。その後，セライトでろ過
し，減圧下有機溶媒を留去した。残渣をカラム精製し，
減圧下，溶媒を留去し，収率７５％で，（Ｒ）−４−ヒ
ドロキシ−４−（３−ヨードアリル）−２−シクロペン
テノンの黄色液体９４８．４ｍｇを得た。Example 4 (R) -4-hydroxy-4-
Synthesis of (3-iodoallyl) -2-cyclopentenone 4.77 mmol of (3R, 5S) -3,5-bis (triethylsilyloxy) -3- (3-iodoallyl) cyclopentene was dissolved in 10 ml of methanol, and 0 ° C.
Then, 0.13 mmol of (1S)-(+)-10-camphorsulfonic acid was added, and the mixture was stirred for 2 hours. The reaction solution was neutralized with 20 μl of triethylamine, and the solvent was distilled off under reduced pressure. The residue was dissolved in 60 ml of dichloromethane, 47.7 mmol of MnO 2 was added under an argon stream, and the mixture was stirred at room temperature for 14 hours. Thereafter, the mixture was filtered through Celite, and the organic solvent was distilled off under reduced pressure. The residue is purified by column,
The solvent was distilled off under reduced pressure to obtain 948.4 mg of a yellow liquid of (R) -4-hydroxy-4- (3-iodoallyl) -2-cyclopentenone in a yield of 75%.
【００２４】以下に主な物性値を示す。 ［α］Ｄ−７４．４°（ｃ＝０．５，ＣＨＣｌ３），Ｉ
Ｒ：３３５６ｃｍ−１，２９２６ｃｍ−１，１７１６ｃ
ｍ−１，１６０９ｃｍ−１，１５９０ｃｍ−１，１Ｈ
ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ３）：δ７．４５（１
Ｈ，ｄ，Ｊ＝５．６Ｈｚ），６．５３（１Ｈ，ｄｔ，Ｊ
＝１３，７．３Ｈｚ），６．２８（１Ｈ，ｄｔ，Ｊ＝
６．９，７．３Ｈｚ），６．１７（１Ｈ，ｄ，Ｊ＝５．
６Ｈｚ），２．６５（２Ｈ，ｄｄ，Ｊ＝１．３，６．９
Ｈｚ），２．５４（２Ｈ，ｄｄ ＡＢｓｙｓｔ，Ｊ＝１
８．５Ｈｚ），１３Ｃ ＮＭＲ（６７．８ＭＨｚ，ＣＤ
Ｃｌ３）：δ１６４．５，１３４．９，１３４．１，８
７．３，７８．６，４８．６，４５．１，ＭＳ（ＥＳＩ
−ＴＯＦ）：ｍ／ｚ［Ｃ８Ｈ９ＩＯ２＋Ｎａ］＋の理論
値；２６４．９７２６，実測値；２６４．９７２６The main physical properties are shown below. [Α] D -74.4 ° (c = 0.5, CHCl 3 ), I
R: 3356 cm -1 , 2926 cm -1 , 1716c
m -1, 1609cm -1, 1590cm -1 , 1 H
NMR (270 MHz, CDCl 3 ): δ 7.45 (1
H, d, J = 5.6 Hz), 6.53 (1H, dt, J)
= 13,7.3 Hz), 6.28 (1H, dt, J =
6.9, 7.3 Hz), 6.17 (1H, d, J = 5.
6Hz), 2.65 (2H, dd, J = 1.3, 6.9)
Hz), 2.54 (2H, dd ABsystem, J = 1)
8.5 Hz), 13 C NMR (67.8 MHz, CD
Cl 3 ): δ 164.5, 134.9, 134.1, 8
7.3, 78.6, 48.6, 45.1, MS (ESI
-TOF): m / z [C 8 H 9 IO 2 + Na] + of theory; 264.9726, found; 264.9726
【００２５】実施例５（３Ｒ，５Ｓ）−３−ヒドロキシ
−３−プロパルギル−５−（２−テトラヒドロピラニル
オキシ）シクロペンテンの合成 アルゴン気流下，テトラヒドロフラン１００ｍｌに
（Ｓ）−４−ヒドロキシ−２−シクロペンテノン３０
ｇ，ジヒドロピラン５０ｍｌを加え，氷冷し，カンファ
ースルホン酸１ｇを加え，室温で１時間攪拌した。その
後，トリエチルアミン０．６ｍｌを加え，減圧濃縮し
た。残渣をカラム精製し，減圧下溶媒を留去して（Ｓ）
−４−（２−テトラヒドロピラニルオキシ）−２−シク
ロペンテノン３６ｇを得た。アルゴン気流下，エーテル
１５０ｍｌにマグネシウム２．６ｇ，塩化第二水銀１０
ｍｇを懸濁させ，プロパルギルブロミドを滴下し，グリ
ニヤール試薬を調製した。このグリニヤール試薬を−７
８℃に冷却し，４−（２−テトラヒドロピラニルオキ
シ）−２−シクロペンテノン１０ｇを含むテトラヒドロ
フラン５０ｍｌを滴下し，その後，１時間攪拌した。反
応液を飽和塩化アンモニウム水溶液中に注ぎ，酢酸エチ
ルで３回抽出した。酢酸エチルを合わせ，飽和食塩水で
洗浄後，硫酸マグネシウムを加え，ろ過後，減圧下濃縮
した。残渣をカラム精製し，減圧下溶媒を留去して（３
Ｒ，５Ｓ）−３−ヒドロキシ−３−プロパルギル−５−
（２−テトラヒドロピラニルオキシ）シクロペンテン７
ｇを得た。Example 5 (3R, 5S) -3-hydroxy
-3-propargyl-5- (2-tetrahydropyranyl
Synthesis of ( oxy) cyclopentene (S) -4-hydroxy-2-cyclopentenone 30 in 100 ml of tetrahydrofuran under a stream of argon.
g, 50 ml of dihydropyran, ice-cooled, 1 g of camphorsulfonic acid, and stirred at room temperature for 1 hour. Thereafter, 0.6 ml of triethylamine was added, and the mixture was concentrated under reduced pressure. The residue is purified by column and the solvent is distilled off under reduced pressure (S)
36 g of -4- (2-tetrahydropyranyloxy) -2-cyclopentenone was obtained. In an argon stream, 2.6 g of magnesium and 150 g of mercuric chloride in 150 ml of ether.
mg was suspended and propargyl bromide was added dropwise to prepare a Grignard reagent. This Grignard reagent is added to -7
After cooling to 8 ° C., 50 ml of tetrahydrofuran containing 10 g of 4- (2-tetrahydropyranyloxy) -2-cyclopentenone was added dropwise, followed by stirring for 1 hour. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted three times with ethyl acetate. Ethyl acetate was combined, washed with saturated saline, added with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column and the solvent was distilled off under reduced pressure (3.
R, 5S) -3-Hydroxy-3-propargyl-5-
(2-tetrahydropyranyloxy) cyclopentene 7
g was obtained.
【００２６】以下に主な物性を示す。１ Ｈ ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ３）：δ６．０
１（１Ｈ，ｍ），４．７３（１Ｈ，ｍ），４．７０（１
Ｈ，ｍ），３．８８（１Ｈ，ｍ），３．５４（１Ｈ，
ｍ），２．５０（１Ｈ，ｓ），２．４０（２Ｈ，ｍ），
２．０１（２Ｈ，ｍ），１．２６−１．８６（６Ｈ，
ｍ）The main physical properties are shown below. 1 H NMR (270 MHz, CDCl 3 ): δ 6.0
1 (1H, m), 4.73 (1H, m), 4.70 (1
H, m), 3.88 (1H, m), 3.54 (1H,
m), 2.50 (1H, s), 2.40 (2H, m),
2.01 (2H, m), 1.26-1.86 (6H,
m)
【００２７】実施例６（Ｒ）−４−ヒドロキシ−４−プ
ロパルギル−２−シクロペンテノンの合成 （３Ｒ，５Ｓ）−３−ヒドロキシ−３−プロパルギル−
５−（２−テトラヒドロピラニルオキシ）シクロペンテ
ン１．１ｇを含むテトラヒドロフラン１０ｍｌに酢酸−
水（４：１）２５ｍｌを加え，室温で３時間攪拌後，減
圧下濃縮した。残渣をカラム精製し，減圧下溶媒を留去
して３，５−ジヒドロキシ−３−プロパルギルシクロペ
ンテン０．４４ｇを得た。この３，５−ジヒドロキシ−
３−プロパルギルシクロペンテン０．４４ｇを塩化メチ
レン２０ｍｌに溶解させ，次いで，活性二酸化マンガン
５ｇを加え，３７時間攪拌した。その後，セライトろ過
し，ろ液を減圧濃縮して残渣を得る。得られた残渣をカ
ラム精製し，減圧下溶媒を留去して（Ｒ）−４−ヒドロ
キシ−４−プロパルギル−２−シクロペンテノン０．３
ｇを得た。Example 6 (R) -4-hydroxy-4-p
Synthesis of lopargyl-2-cyclopentenone (3R, 5S) -3-hydroxy-3-propargyl-
Acetic acid was added to 10 ml of tetrahydrofuran containing 1.1 g of 5- (2-tetrahydropyranyloxy) cyclopentene.
25 ml of water (4: 1) was added, and the mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was purified by column and the solvent was distilled off under reduced pressure to obtain 0.44 g of 3,5-dihydroxy-3-propargylcyclopentene. This 3,5-dihydroxy-
0.44 g of 3-propargylcyclopentene was dissolved in 20 ml of methylene chloride, and then 5 g of activated manganese dioxide was added, followed by stirring for 37 hours. Then, the mixture is filtered through celite, and the filtrate is concentrated under reduced pressure to obtain a residue. The resulting residue was purified by column and the solvent was distilled off under reduced pressure to give (R) -4-hydroxy-4-propargyl-2-cyclopentenone 0.3.
g was obtained.
【００２８】以下に主な物性を示す。１ Ｈ ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ３）：δ７．４
９（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），６．２０（１Ｈ，
ｄ，Ｊ＝５．６Ｈｚ），２．５２−２．６８（４Ｈ，
ｍ），２．１４（１Ｈ，ｓ）The main physical properties are shown below. 1 H NMR (270 MHz, CDCl 3 ): δ 7.4
9 (1H, d, J = 5.6 Hz), 6.20 (1H,
d, J = 5.6 Hz), 2.52-2.68 (4H,
m), 2.14 (1H, s)
【００２９】[0029]
【発明の効果】本発明に係る化合物はクラブロンＩＩの
シクルペンテノン骨格，ω−鎖の一部として３−ハロゲ
ノアリル基あるいはプロパルギル基を有しており，ω−
鎖を極めて容易に構築することができる。また，クラブ
ロンＩＩの１２−位に相当する位置に水酸基を有してお
り，しかもその絶対配置は天然クラブロンＩＩと同じで
ある。そのため，本発明に係る化合物はクラブロン類合
成のための極めて有用な化合物と言える。The compound according to the present invention has a cyclcletenone skeleton of clavulon II, a 3-halogenoallyl group or a propargyl group as a part of the ω-chain,
Chains can be built very easily. It also has a hydroxyl group at the position corresponding to the 12-position of clavulon II, and its absolute configuration is the same as that of natural clavulon II. Therefore, the compound according to the present invention can be said to be a very useful compound for synthesizing clavulones.
Claims (1)
ル基，メトキシメチル基，トリアルキルシリル基から選
ばれ，Ｒ２は３−ヨードアリル基，３−ブロモアリル
基，３−クロロアリル基，プロパルギル基から選ばれ
る）で示される新規シクロペンテノン誘導体。(1) The following structural formula: (Where R 1 is selected from hydrogen, acyl group, tetrahydropyranyl group, methoxymethyl group, trialkylsilyl group, and R 2 is selected from 3-iodoallyl group, 3-bromoallyl group, 3-chloroallyl group, and propargyl group) ), A novel cyclopentenone derivative represented by the formula:
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001110603A JP2002265412A (en) | 2001-03-06 | 2001-03-06 | Novel cyclopentenone derivative |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001110603A JP2002265412A (en) | 2001-03-06 | 2001-03-06 | Novel cyclopentenone derivative |
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| Publication Number | Publication Date |
|---|---|
| JP2002265412A true JP2002265412A (en) | 2002-09-18 |
Family
ID=18962338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001110603A Withdrawn JP2002265412A (en) | 2001-03-06 | 2001-03-06 | Novel cyclopentenone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2002265412A (en) |
-
2001
- 2001-03-06 JP JP2001110603A patent/JP2002265412A/en not_active Withdrawn
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Legal Events
| Date | Code | Title | Description |
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| A300 | Application deemed to be withdrawn because no request for examination was validly filed |
Free format text: JAPANESE INTERMEDIATE CODE: A300 Effective date: 20080513 |