JPH0432808B2 - - Google Patents
Info
- Publication number
- JPH0432808B2 JPH0432808B2 JP309584A JP309584A JPH0432808B2 JP H0432808 B2 JPH0432808 B2 JP H0432808B2 JP 309584 A JP309584 A JP 309584A JP 309584 A JP309584 A JP 309584A JP H0432808 B2 JPH0432808 B2 JP H0432808B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- heptene
- methyl
- diol
- trityloxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 26
- 238000004519 manufacturing process Methods 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 6
- ILQQDSOBWMUGSI-JGVFFNPUSA-N (2s,4r)-4-methylhept-6-ene-1,2,4-triol Chemical compound C=CC[C@](O)(C)C[C@H](O)CO ILQQDSOBWMUGSI-JGVFFNPUSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 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 claims description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 150000001875 compounds Chemical class 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 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 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- JYVXNLLUYHCIIH-LURJTMIESA-N mevalonolactone Chemical compound C[C@]1(O)CCOC(=O)C1 JYVXNLLUYHCIIH-LURJTMIESA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000002009 diols Chemical class 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000013543 active substance Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- BUIQRTDBPCHRIR-UHFFFAOYSA-L O[Cr](Cl)(=O)=O Chemical compound O[Cr](Cl)(=O)=O BUIQRTDBPCHRIR-UHFFFAOYSA-L 0.000 description 1
- QPFYXYFORQJZEC-FOCLMDBBSA-N Phenazopyridine Chemical compound NC1=NC(N)=CC=C1\N=N\C1=CC=CC=C1 QPFYXYFORQJZEC-FOCLMDBBSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012213 gelatinous substance Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 150000002978 peroxides Chemical group 0.000 description 1
- 229940070891 pyridium Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Furan Compounds (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は新規な光学活性体(2S,4R)−4−メ
チル−6−ヘプテン−1,2,4−トリオール
(以下トリオール体と略す)およびその製造方法
に関するものである。
本発明のトリオール体は医薬品の合成中間体と
して、また微生物発酵の際の添加剤として重要な
光学活性メバロラクトンの合成中間体として有用
な化合物である。例えば本発明の化合物から
(R)−メバロラクトンおよび(S)−メバロラク
トンへは、次図に示される反応式に従つて製造で
きる。
詳しくは参考例において説明する。
従来メバロラクトンの合成方法は特公昭47−
48386号公報および特開昭47−20116号公報に開示
された方法等、いくつかの文献が散見される。し
かし光学活性のメバロラクトンを選択的に合成す
る方法は、微生物発酵による方法(Ota etal,J.
Org.Chem.47,2400(1982)およびC.J.Sih etal,
Tetrahedron Lett.−3415(1978)が報告されて
いるのみで純合成的に成功した例は知られていな
い。本発明者等は有機合成手法による光学活性な
メバロラクトンの不整合成方法につき鋭意研究の
結果、本発明に到達した。
すなわち本発明は、式〔1〕
で示される新規な光学活性体(2S,4R)−4−メ
チル−6−ヘプテン−1,2,4−トリオールお
よび次の反応工程からなるその製造方法である。
(1) (5S)−3−アリル−5−トリチルオキシメ
チルテトラヒドロフラン−2−オン〔2〕をオ
キソジペルオキシモリブデニウム・ピリジン・
ヘキサメチルホスホリツクスアミド(以下
MoOPHと略称す)で不整酸化し、(3R,5S)
−3−アリール−3−ヒドロキシ−5−トリチ
ルオキシメチルテトラヒドロフラン−2−〔3〕
−を得て、
(2) 更にこれに水素化リチウムアルミニウムを作
用させて開環し、(2S,4R)−ヒドロキシメチ
ル−1−トリチルオキシ−6−ヘプテン−2,
4−ジオール〔4〕を得て、
(3) 次いでこれにp−トルエンスルニルクロリド
を作用させて、(2S,4R)−4−トシルオキシ
メチル−1−トリチルオキシ−6−ヘプテン−
2,4−ジオール〔5〕を得て、
(4) 次いでこれを水素化リチウムアルミニウムの
存在下還元し、(2S,4R)−4−メチル−1−
トリチルオキシ−6−ヘプテン−2,4−ジオ
ール〔6〕として、
(5) 更にこれをメタノール中触媒量の塩酸で処理
してトリチル基をはずすことからなる式〔1〕
で示される(2S,4R)−4−メチル−6−ヘプ
テン−1,2,4−トリオールの製造方法。
これを反応式で図示すれば、次のようである。
本発明の出発原料である3−アリル−5−トリ
チルオキシメチルテトラヒドロフラン−2−オン
は、特開昭56−147780号公報に開示された方法に
よつてグルタミン酸から合成される。
本発明の第1工程で使われるMoOPHは、式
で示される構造を有する過酸化物であり、その製
造方法はE.Vedejs,J.Org.,43,188(1978)に記
載されている。また同文献にはカルボニル化合物
のα位炭素に水酸基をこのMoOPHによつて導入
する反応条件も記載されている。
本発明者等はこの特殊な酸化反応を3−アリル
−5−トリチルオキシメチルテトラヒドロ−2−
オンに施した場合、不整酸化反応が行われ、光学
活性な(3R,5S)−3−アリル−3−ヒドロキシ
−5−トリチルオキシメチルテトラヒドロフラン
−2−オンが好収率で得られる新規事実を見出
し、本発明の端緒とした。この反応機作について
は充分解明されているわけではないが、5位置換
のトリチルオキシメチル基のかさ高さにより、
MoOPHが高度に立体規制される為ではないかと
考えられる。
本発明の第2工程から第5工程までは、一般に
良く使われる有機合成反応であるので、詳しくは
実施例において説明する。
本発明の産業上利用される有利な点について略
述すると
(1) 光学活性体を好収率で合成できる。
(2) 原料の入手が容易である。
(3) 本発明の化合物から光学活性なメバロラ
クトンをはじめとして光学活性な医薬品類が
合成可能である。
以下実施例及び参考例により本発明を詳細に説
明する。
実施例 1
(3R,5S)−3−アリル−3−ヒドロキシ−5
−トリチルオキシメチルテトラヒドロフラン−2
−オン〔3〕の製造
ジイソプロピルアミン6.36g(0.063モル)、n
−ブチルリチウム(10w/vヘキサン溶液)38.4
ml(0.060モル)、テトラヒドロフラン80mlより調
製したリチウムジイソプロピルアミドのテトラヒ
ドロフラン溶液にアルゴン気流下−78℃で3−ア
リル−5−トリチルオキシメチルテトラヒドロフ
ラン−2−オン〔2〕11.9g(0.030モル)のテ
トラヒドロフラン溶液60mlを加え1.5時間攪拌し
た。これをMoOPHのテトラヒドロフラン溶液
200mlにアルゴン気流下−78℃で加え2.5時間攪拌
した。これに飽和硫酸ナトリウム溶液50mlを加え
室温に戻した後エーテルで抽出する。有機層を飽
和食塩水100mlで洗浄し、無水硫酸マグネシウム
で乾燥した後溶媒を留去して粗生成物14.9gを得
た。これをシリカゲルカラムクロマトグラフイー
(クロロホルム)で精製し、標題の化合物7.80g
を得た。分析値は次の通りで、収率は63%であつ
た。
NMRδ(ppm):2.17(m.2H.CH2 −CH−O)、
2.55(m.2H.CH2 −CH=)、3.30(m.2H.CH2 −
O)、4.50〜5.40(m.3H.CH−O,CH2 =CH)、
5.50〜6.30(m.1H.CH=CH2)、7.10〜7.60
(m.15H.arom−H)、
ΓIR(cm-1):3400(OH)、1765(C=O)
Γ〔α〕D:+34.7°(C.O.60,CHCl3)
実施例 2
2S,4R)−4−ヒドロキシメチル−1−トリチ
ルオキシ−6−ヘプテン−2,4−ジオール
〔4〕の製造
水素化リチウムアルミニウム3.80g(0.10モ
ル)をテトラヒドロフラン50mlに懸濁させ、アル
ゴン気流下氷冷で前記〔3〕の化合物8.28g
(0.002モル)のテトラヒドロフラン溶液50mlを滴
下し30分間攪拌した。これに30%アンモニア水20
mlを加え折出したゲル上物質をセライトを用いて
別し、液を無水硫酸マグネシウムで乾燥の
後、溶媒を留去して粗精製物8.00gを得た。これ
をシリカゲルカラムクロマトグラフイー(n−ヘ
キサン+エーテル)で精製し、標題の化合物4.55
gを得た。収率は54%、分析値は次の通りであつ
た。
ΓNMRδ(ppm):1.55(m.2H.CH2 −CH−O)、
2.33(d.2H.J=8Hz,CH2 −CH=)、3.03〜3.60
(m.7H、CH2 −O×2,OH×3)、3.87〜4.50
(m.1H.CH−O)、4.87〜5.27(m.2H.CH2 =CH)
5.60〜6.20(m.1H.CH=CH2)
ΓIR(cm-1):3350(OH)
Γ〔α〕D:+4.4°(C1.08,CHCl3)
実施例 3
(2S,4R)−4−トシルオキシメチル−1−ト
リチルオキン−6−ヘプテン−2,4−ジオール
〔5〕の製造
前記〔4〕の化合物3.76g(0.009モル)をピ
リジン50mlに溶解し、氷冷下p−トルエンスルホ
ニルクロライド12.9g(0.068モル)を加えて6
時間攪拌した。ピリジンを氷冷下真空ポンプを用
いて留去し、残渣をジクロロメタン100mlで抽出
した。これを水50ml、10%硫酸銅溶液50ml、水50
ml、飽和食塩水50mlで順次洗浄し、無水硫酸マグ
ネシウムで乾燥の後、溶媒を留去して粗精製物
14.2gを得た。シリカゲルカラムクロマトグラフ
イー(n−ヘキサン+酢酸エチル)によつて過剰
の−トルエンスルホニルクロリドを除き、標題の
化合物4.69gを得た。分析値は下記の如くであ
り、収率は91%であつた。
ΓNMRδ(ppm):1.55(d.2H.J=7Hz、CH2 −CH
−O)、2.38(s.3H.CH3)、2.30〜2.50(d.2H.CH2 −
CH=)、3.05(d.2H.J=6Hz、CH2 -0−CH−O)、
3.83(s.2H.CH2 −O)、4.00〜4.30(m.1H.CH−
O)、4.70〜5.20(m.2H.CH2 =CH)、5.25〜6.10
(m.1H.CH=CH2)、7.10〜7.90(m.19H,arom−
H)
ΓIR(cm-1):3500(OH)
実施例 4
(2S,4R)−4−メチル−1−トリチルオキシ
−6−ヘプテン−2,4−ジオール〔6〕の製造
水素化リチウムアルミニウム2.40g(0.063モ
ル)のテトラヒドロフラン溶液60mlにアルゴン気
流下氷冷で前記〔5〕の化合物4.50g(0.008モ
ル)のテトラヒドロフラン溶液40mlを滴下し、室
温で1時間攪拌した。これに30%アンモニア水20
mlを加え、析出したゲル上物質をセライトを用い
て別し、液にエーテル100mlを加え、水50ml、
飽和食塩水50mlで順次洗浄し、無水硫酸マグネシ
ウムで乾燥の後、溶媒を留去して粗生成物3.10g
を得た。これをシリカゲルカラムクロマトグラフ
イーn−ヘキサン+エーテル)で精製し、標題の
化合物2.50gを得た。分析値は下記の通りであ
り、収率は79%であつた。
ΓNMRδ(ppm):1.17(s.3H.CH3)、1.46〜1.80
(m.3H.CH2 −CH,OH)、2.34(d.2H、J=7Hz,
CH2−CH=)、2.97〜3.27(m.3H.OH.CH2 −CH
−O)、3.90〜4.40(m.1H.CH−O)、4.80〜5.30
(m.2H.CH2 =CH)、5.40〜6.20(m.1H.CH=
CH2)、7.10〜7.60(m.15H,arom−H)
ΓIR(cm-1):3600(OH)、1640(C=C)
実施例 5
(2S.4R)−4−メチル−6−ヘプテン−1,
2,4−トリオール〔1〕の製造
前記〔6〕の化合物1.00g(0.0025モル)をメ
タノール20mlに溶解し、これに氷冷下濃塩酸0.2
mlを加え、4時間攪拌した。これにメタノール30
mlを加え重炭酸ナトリウムで中和後、n−ヘキサ
ン20mlで2回洗浄した。メタノール層を無水硫酸
マグネシウムで乾燥の後、溶媒を留去して粗生成
物を得た。これをシリカゲルカラムクロマトグラ
フイー(n−ヘキサン+酢酸エチル)で精製し、
標題の化合物240mlを得た。収率は60%であり、
下記分析の結果本発明の化合物に相異ないことが
確認された。
ΓNMRδ(ppm):1.20(s.3H.CH3)、1.50〜1.80
(m.2H.CH2 −CH−O)、2.36(d.2H、J=7Hz,
CH2−CH=)、3.30〜4.60(m.6H.CH2 −O、OH
×3)、4.83〜5.30(m.2H.CH2 =CH)、5.43〜6.10
(m.1H.CH=CH2)
ΓIR(cm-1):3350(OH)、1640(C=C)
Γ〔α〕D:+13.8°(C 1.0、CHCl3)
ΓMass:C3H17O3
found 161.1178
cald. 161.1178
参考例 1
(R)−3−メチル−5−ヘキセン−1,3−
ジオール〔7〕の製造
前記〔1〕の化合物160ml(1.0m mole)をメ
タノール10mlに溶解し、氷冷下メタ過ヨウ素酸ナ
トリウム320mg(1.5m mole)の水溶液5mlを滴
下し30分間攪拌した。これに水素化ホウ素ナトリ
ウム75mg(2.0m mole)を加えて30分間攪拌の
後、メタノール20mlを加えセライトで過し、
液を濃縮した。残渣にジクロロメタン10mlを加え
無水硫酸マグネシウムで乾燥の後、溶媒を留去し
粗生成物130mgを得た。これをシリカゲルカラム
クロマトグラフイー(n−ヘキサン+酢酸エチ
ル)で精製し、標題の化合物120mgを得た。収率
は92%、分析はNMR、IR、Massで確認した。
参考例 2
(2RS、4S)−2,4−ジヒドロキシ−4−メ
チル−2,3,4,5−テトラヒドロピラン
〔8a〕の製造
前記〔7〕の化合物110mg(0.85m mole)をメ
タノール20mlに溶解し、−78℃でオゾンを30分間
導入した。窒素を30分間導入した後、硫化メチル
10mlを加え室温にもどし、溶媒を留去し、粗生成
物160mgを得た。これをシリカゲルカラムクロマ
トグラフイー(n−ヘキサン+酢酸エチル)で精
製し、標題の化合物110mgを得た。収率は98%、
分析はNMR、IR、Massで確認した。
参考例 3
(2RS、4R)−2,4−ジヒドロキシ−4−メ
チル−2,3,4,5−テトラヒドロピラン
〔8a〕の製造
前記〔1〕の化合物160mg(1.0m mole)をメ
タノール20mlに溶解し、−78℃でオゾンを40分間
導入した。窒素を45分間導入した後、水素化ホウ
素ナトリウム570mg(15m mole)を加え室温に
もどす。2時間後メタ過ヨウ素酸ナトリウム1.28
g(6.0m mole)の水溶液7mlを滴下し、3時間
攪拌した。セライトで過し、液を濃縮した残
渣にジクロメタン10mlを加え無水硫酸マグネシウ
ムで乾燥の後、溶液を留去して粗生成物100mgを
得た。これをシリカゲルカラムクロマトグラフイ
ー(n−ヘキサン+酢酸エチル)で精製し、標題
の化合物60mgを得た。収率は45%、分析は
NMR、IR、Massで確認した。
参考例 4
(S)−メバロラクトン〔9a〕の製造
前記〔8a〕の化合物80mg(0.61m mole)をジ
クロロメタン15mlに溶解し、ピリジウムクロロク
ロメイト650mg(3.0m mole)を加え、室温で14
時間攪拌した。溶媒を留去した後、残渣をシリカ
ゲルクロマトグラフイー(n−ヘキサン+酢酸エ
チル)で精製し、標題の化合物63mgを得た。収率
は80%、下記分析の結果、目的物に相異ない事が
確認された。
ΓNMRδ(ppm):1.37(s.3H.CH3)、1.90(m.2H.
CH2)、2.57(m.2H.【式】)、4.10〜4.80
(m.2H.CH2 −O)
ΓIR(cm-1):3400(OH)、1720(C=O)
Γ〔α〕D:+23.3°(C0.98、EtOH)
参考例 5
(R)−メバロラクトン〔9b〕の製造
前記〔8b〕の化合物50mg(0.38m mole)をジ
クロロメタン12mlに溶解し、ピリジニウムクロロ
クロメイト410mg(1.9m mole)を加え、室温で
14時間攪拌した。溶媒を留去した後、残渣をシリ
カゲルカラムクロマトグラフイー(n−ヘキサン
+酢酸エチル)で精製し、標題の化合物44mgを得
た。収率は89%であり、下記分析の結果目的物に
相異ない事が確認された。
ΓNMRδ(ppm):1.37(s.3H.CH3)、1.90(m.2H.
CH2)、2.57(m.2H.【式】)、4.10〜4.80
(m.2H.CH2 −O−)
ΓIR(cm-19:3400(OH)、1720(C=O)
Γ〔α〕D:−23.4°(C0.32、EtOH) Detailed Description of the Invention The present invention relates to a novel optically active substance (2S,4R)-4-methyl-6-heptene-1,2,4-triol (hereinafter abbreviated as triol) and a method for producing the same. be. The triol compound of the present invention is a compound useful as a synthetic intermediate for pharmaceuticals and for optically active mevalolactone, which is important as an additive in microbial fermentation. For example, (R)-mevalolactone and (S)-mevalolactone can be produced from the compound of the present invention according to the reaction formula shown in the following figure. Details will be explained in reference examples. The conventional method for synthesizing mevalolactone was
Several documents can be found here and there, such as methods disclosed in Japanese Patent Application Laid-open No. 48386 and Japanese Patent Application Laid-open No. 47-20116. However, the method for selectively synthesizing optically active mevalolactone is by microbial fermentation ( Ota etal, J.
Org.Chem. 47 , 2400 (1982) and CJSih etal,
Tetrahedron Lett.-3415 (1978) has been reported, and no examples of pure synthetic success are known. The present inventors have arrived at the present invention as a result of intensive research into a method for asymmetrically synthesizing optically active mevalolactone using organic synthesis techniques. That is, the present invention provides formula [1] This is a novel optically active substance (2S,4R)-4-methyl-6-heptene-1,2,4-triol represented by the following formula and a method for producing the same, which comprises the following reaction steps. (1) (5S)-3-allyl-5-trityloxymethyltetrahydrofuran-2-one [2] was converted into oxodiperoxymolybdenium pyridine.
Hexamethylphosphoric amide (hereinafter referred to as
asymmetric oxidation (abbreviated as MoOPH), (3R, 5S)
-3-aryl-3-hydroxy-5-trityloxymethyltetrahydrofuran-2-[3]
-, (2) This was further treated with lithium aluminum hydride to open the ring, giving (2S,4R)-hydroxymethyl-1-trityloxy-6-heptene-2,
4-diol [4] is obtained, (3) then treated with p-toluenesulnyl chloride to form (2S,4R)-4-tosyloxymethyl-1-trityloxy-6-heptene-
2,4-diol [5] was obtained, (4) which was then reduced in the presence of lithium aluminum hydride to form (2S,4R)-4-methyl-1-
Trityloxy-6-heptene-2,4-diol [6], (5) and further treating this with a catalytic amount of hydrochloric acid in methanol to remove the trityl group [1]
A method for producing (2S,4R)-4-methyl-6-heptene-1,2,4-triol shown by This reaction can be illustrated as follows. 3-allyl-5-trityloxymethyltetrahydrofuran-2-one, which is the starting material of the present invention, is synthesized from glutamic acid by the method disclosed in JP-A-56-147780. MoOPH used in the first step of the present invention has the formula It is a peroxide having the structure shown in the following, and its manufacturing method is described in E. Vedejs, J. Org., 43 , 188 (1978). The same document also describes reaction conditions for introducing a hydroxyl group into the α-position carbon of a carbonyl compound using MoOPH. The present inventors conducted this special oxidation reaction using 3-allyl-5-trityloxymethyltetrahydro-2-
When applied to ion, an asymmetric oxidation reaction takes place and optically active (3R,5S)-3-allyl-3-hydroxy-5-trityloxymethyltetrahydrofuran-2-one is obtained in good yield. This heading was used as the beginning of the present invention. The mechanism of this reaction is not fully understood, but due to the bulkiness of the trityloxymethyl group substituted at the 5-position,
This is thought to be because MoOPH is highly sterically regulated. The second to fifth steps of the present invention are commonly used organic synthesis reactions, and will be explained in detail in Examples. The industrially applicable advantages of the present invention are summarized as follows: (1) Optically active substances can be synthesized in good yields. (2) Raw materials are easily available. (3) Optically active pharmaceuticals including optically active mevalolactone can be synthesized from the compound of the present invention. The present invention will be explained in detail below using Examples and Reference Examples. Example 1 (3R,5S)-3-allyl-3-hydroxy-5
-trityloxymethyltetrahydrofuran-2
-Production of one [3] Diisopropylamine 6.36g (0.063mol), n
-Butyllithium (10w/v hexane solution) 38.4
11.9 g (0.030 mol) of 3-allyl-5-trityloxymethyltetrahydrofuran-2-one [2] was added to a tetrahydrofuran solution of lithium diisopropylamide prepared from 80 ml of tetrahydrofuran and 80 ml of tetrahydrofuran at -78°C under an argon atmosphere. 60 ml of the solution was added and stirred for 1.5 hours. This is a solution of MoOPH in tetrahydrofuran.
The mixture was added to 200 ml at -78°C under an argon stream and stirred for 2.5 hours. Add 50 ml of saturated sodium sulfate solution to this, return to room temperature, and extract with ether. The organic layer was washed with 100 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 14.9 g of a crude product. This was purified by silica gel column chromatography (chloroform) to yield 7.80 g of the title compound.
I got it. The analytical values were as follows, and the yield was 63%. NMRδ (ppm): 2.17 (m.2H. CH 2 -CH-O),
2.55 (m.2H. CH 2 −CH=), 3.30 (m.2H. CH 2 −
O), 4.50-5.40 (m.3H. CH −O, CH 2 = CH),
5.50~6.30 ( m.1H.CH = CH2 ), 7.10~7.60
(m.15H.arom-H), ΓIR (cm -1 ): 3400 (OH), 1765 (C=O) Γ [α] D : +34.7° (CO60, CHCl 3 ) Example 2 2S, 4R )-4-Hydroxymethyl-1-trityloxy-6-heptene-2,4-diol [4] 3.80 g (0.10 mol) of lithium aluminum hydride was suspended in 50 ml of tetrahydrofuran and cooled with ice under an argon stream. 8.28g of the compound [3] above
(0.002 mol) of tetrahydrofuran solution was added dropwise and stirred for 30 minutes. Add this to 30% ammonia water 20%
The precipitated gelatinous substance was separated using Celite, the liquid was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 8.00 g of a crude product. This was purified by silica gel column chromatography (n-hexane + ether) to obtain the title compound 4.55
I got g. The yield was 54%, and the analytical values were as follows. ΓNMRδ (ppm): 1.55 (m.2H. CH 2 −CH−O),
2.33 (d.2H.J=8Hz, CH2 −CH=), 3.03~3.60
(m.7H, CH2 -O×2, OH×3), 3.87~4.50
(m.1H. CH −O), 4.87~5.27 (m.2H. CH 2 = CH)
5.60 to 6.20 (m.1H. CH = CH 2 ) ΓIR (cm -1 ): 3350 (OH) Γ [α] D : +4.4° (C1.08, CHCl 3 ) Example 3 (2S, 4R) -4-Tosyloxymethyl-1-trityloquine-6-heptene-2,4-diol [5] Production of 3.76 g (0.009 mol) of the compound [4] above was dissolved in 50 ml of pyridine, and p-toluene was added under ice cooling. Add 12.9 g (0.068 mol) of sulfonyl chloride to 6
Stir for hours. Pyridine was distilled off using a vacuum pump under ice cooling, and the residue was extracted with 100 ml of dichloromethane. Add this to 50ml of water, 50ml of 10% copper sulfate solution, and 50ml of water.
ml and 50 ml of saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the crude product.
14.2g was obtained. Excess -toluenesulfonyl chloride was removed by silica gel column chromatography (n-hexane + ethyl acetate) to obtain 4.69 g of the title compound. The analytical values were as shown below, and the yield was 91%. ΓNMRδ (ppm): 1.55 (d.2H.J=7Hz, CH 2 −CH
−O), 2.38 (s.3H.CH 3 ), 2.30 to 2.50 (d.2H. CH 2 −
CH=), 3.05 (d.2H.J=6Hz, CH 2 -0 −CH−O),
3.83 (s.2H. CH 2 −O), 4.00~4.30 (m.1H. CH −
O), 4.70-5.20 (m.2H. CH 2 = CH), 5.25-6.10
(m.1H. CH = CH 2 ), 7.10~7.90 (m.19H, arom−
H) ΓIR (cm -1 ): 3500 (OH) Example 4 Production of (2S,4R)-4-methyl-1-trityloxy-6-heptene-2,4-diol [6] Lithium aluminum hydride 2.40 To 60 ml of a tetrahydrofuran solution containing 4.50 g (0.063 mol) of compound [5] was added dropwise under ice cooling under an argon stream, and the mixture was stirred at room temperature for 1 hour. Add this to 30% ammonia water 20%
ml, separate the precipitated gel substance using Celite, add 100 ml of ether, 50 ml of water,
After sequentially washing with 50 ml of saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 3.10 g of crude product.
I got it. This was purified by silica gel column chromatography (n-hexane + ether) to obtain 2.50 g of the title compound. The analytical values were as follows, and the yield was 79%. ΓNMRδ (ppm): 1.17 ( s.3H.CH3 ), 1.46~1.80
(m.3H. CH 2 −CH, OH), 2.34 (d.2H, J=7Hz,
CH 2 −CH=), 2.97 to 3.27 (m.3H.OH. CH 2 −CH
-O), 3.90~4.40 (m.1H. CH -O), 4.80~5.30
(m.2H. CH 2 = CH), 5.40~6.20 (m.1H. CH =
CH 2 ), 7.10-7.60 (m.15H, arom-H) ΓIR (cm -1 ): 3600 (OH), 1640 (C=C) Example 5 (2S.4R)-4-methyl-6-heptene -1,
Production of 2,4-triol [1] 1.00 g (0.0025 mol) of the compound [6] above was dissolved in 20 ml of methanol, and 0.2 g of concentrated hydrochloric acid was added to it under ice cooling.
ml and stirred for 4 hours. Add 30 methanol to this
After neutralizing with sodium bicarbonate, the mixture was washed twice with 20 ml of n-hexane. After drying the methanol layer over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product. This was purified by silica gel column chromatography (n-hexane + ethyl acetate),
240 ml of the title compound was obtained. The yield is 60%,
As a result of the analysis described below, it was confirmed that the compounds of the present invention are different from each other. ΓNMRδ (ppm): 1.20 ( s.3H.CH3 ), 1.50~1.80
(m.2H. CH 2 −CH−O), 2.36 (d.2H, J=7Hz,
CH 2 −CH=), 3.30 to 4.60 (m.6H. CH 2 −O, OH
×3), 4.83 to 5.30 (m.2H. CH 2 = CH), 5.43 to 6.10
(m.1H. CH = CH 2 ) ΓIR (cm -1 ): 3350 (OH), 1640 (C = C) Γ [α] D : +13.8° (C 1.0, CHCl 3 ) ΓMass: C 3 H 17 O 3 found 161.1178 cald. 161.1178 Reference example 1 (R)-3-methyl-5-hexene-1,3-
Production of diol [7] 160 ml (1.0 mmole) of the compound [1] above was dissolved in 10 ml of methanol, and 5 ml of an aqueous solution of 320 mg (1.5 mmole) of sodium metaperiodate was added dropwise under ice cooling, followed by stirring for 30 minutes. After adding 75 mg (2.0 mmole) of sodium borohydride and stirring for 30 minutes, 20 ml of methanol was added and filtered through Celite.
The liquid was concentrated. After adding 10 ml of dichloromethane to the residue and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 130 mg of a crude product. This was purified by silica gel column chromatography (n-hexane + ethyl acetate) to obtain 120 mg of the title compound. The yield was 92%, and analysis was confirmed by NMR, IR, and Mass. Reference Example 2 Production of (2RS, 4S)-2,4-dihydroxy-4-methyl-2,3,4,5-tetrahydropyran [8a] 110 mg (0.85 mmole) of the compound [7] above was added to 20 ml of methanol. It was dissolved and ozone was introduced for 30 minutes at -78°C. After introducing nitrogen for 30 minutes, methyl sulfide
10 ml was added, the temperature was returned to room temperature, and the solvent was distilled off to obtain 160 mg of a crude product. This was purified by silica gel column chromatography (n-hexane + ethyl acetate) to obtain 110 mg of the title compound. Yield is 98%,
The analysis was confirmed by NMR, IR, and Mass. Reference Example 3 Production of (2RS, 4R)-2,4-dihydroxy-4-methyl-2,3,4,5-tetrahydropyran [8a] 160 mg (1.0 mmole) of the compound [1] above was added to 20 ml of methanol. It was dissolved and ozone was introduced for 40 minutes at -78°C. After introducing nitrogen for 45 minutes, add 570 mg (15 mmole) of sodium borohydride and return to room temperature. 2 hours later Sodium metaperiodate 1.28
7 ml of an aqueous solution of g (6.0 mmole) was added dropwise thereto, and the mixture was stirred for 3 hours. After filtering through Celite and concentrating the liquid, 10 ml of dichloromethane was added to the residue, and after drying over anhydrous magnesium sulfate, the solution was distilled off to obtain 100 mg of a crude product. This was purified by silica gel column chromatography (n-hexane + ethyl acetate) to obtain 60 mg of the title compound. Yield is 45%, analysis is
Confirmed by NMR, IR, and Mass. Reference Example 4 Production of (S)-mevalolactone [9a] 80 mg (0.61 m mole) of the compound [8a] above was dissolved in 15 ml of dichloromethane, 650 mg (3.0 m mole) of pyridium chlorochromate was added, and the mixture was heated at room temperature for 14 min.
Stir for hours. After evaporating the solvent, the residue was purified by silica gel chromatography (n-hexane+ethyl acetate) to obtain 63 mg of the title compound. The yield was 80%, and the analysis below confirmed that it was the desired product. ΓNMRδ (ppm): 1.37 ( s.3H.CH3 ), 1.90 (m.2H.
CH 2 ), 2.57 (m.2H. [formula]), 4.10 to 4.80 (m.2H. CH 2 −O) ΓIR (cm -1 ): 3400 (OH), 1720 (C=O) Γ [α] D : +23.3° (C0.98, EtOH) Reference Example 5 Production of (R)-mevalolactone [9b] Dissolve 50 mg (0.38 mmole) of the compound [8b] above in 12 ml of dichloromethane, and prepare 410 mg of pyridinium chlorochromate. (1.9m mole) and at room temperature.
Stirred for 14 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography (n-hexane + ethyl acetate) to obtain 44 mg of the title compound. The yield was 89%, and the analysis below confirmed that it was the desired product. ΓNMRδ (ppm): 1.37 ( s.3H.CH3 ), 1.90 (m.2H.
CH 2 ), 2.57 (m.2H. [formula]), 4.10 to 4.80 (m.2H. CH 2 -O-) ΓIR (cm -1 9:3400 (OH), 1720 (C=O) Γ [α ] D : −23.4° (C0.32, EtOH)
Claims (1)
ン−1,2,4−トリオール 2 式〔2〕 (式中Trはトリチル基を表わす)で示される
(5S)−3−アリル−5−トリチルオキシメチル
テトラヒドロフラン−2−オンにオキソジペルオ
キシモリブデニウム・ピリジン・ヘキサメチルホ
スホリツクアミドを作用させて、不整酸化反応を
行い、式〔3〕 (式中Trは前記に同じ)で示される光学活性な
(3R,5S)−3−アリル−3−ヒドロキシ−5−
トリチルオキシメチルテトラヒドロフラン−2−
オンを得、更にこれに水素化リチウムアルミニウ
ムを作用させて開環し、式〔4〕 (式中Trは前記に同じ)で示される(2S,4R)
−4−ヒドロキシメチル−1−トリチルオキシ−
6−ヘプテン−2,4−ジオールを得て、次いで
これにp−トルエンスルホニルクロリドを作用さ
せて、式〔5〕 (式中Trは前記に同じ。Tsはトシル基を表わ
す。)で示される(2S,4R)−4−トシルオキシ
メチル−1−トリチルオキシ−6−ヘプテン−
2,4−ジオールを得て、次いでこれを水素化リ
チウムアルミニウムの存在下に還元し、式〔6〕 (式中Trは前記に同じ)で示される(2S,4R)
−4−メチル−1−トリチルオキシ−6−ヘプテ
ン−2,4−ジオールを得て、更にこれをメタノ
ール中触媒量の塩酸で処理して保護基をはずすこ
とからなる式〔1〕で示される(2S,4R)−4−
メチル−6−ヘプテン−1,2,4−トリオール
の製造方法。[Claims] 1 Formula [1] (2S,4R)-4-methyl-6-heptene-1,2,4-triol 2 represented by formula [2] (5S)-3-allyl-5-trityloxymethyltetrahydrofuran-2-one represented by (Tr represents a trityl group) is reacted with oxodiperoxymolybdenium pyridine hexamethylphosphoric amide, Perform an asymmetric oxidation reaction and form the formula [3] Optically active (3R,5S)-3-allyl-3-hydroxy-5- represented by (where Tr is the same as above)
Trityloxymethyltetrahydrofuran-2-
This is further treated with lithium aluminum hydride to open the ring, giving the formula [4] (2S, 4R) (where Tr is the same as above)
-4-hydroxymethyl-1-trityloxy-
6-heptene-2,4-diol was obtained and then treated with p-toluenesulfonyl chloride to form the formula [5] (2S,4R)-4-tosyloxymethyl-1-trityloxy-6-heptene- (in the formula, Tr is the same as above. Ts represents a tosyl group)
2,4-diol was obtained, which was then reduced in the presence of lithium aluminum hydride to form the formula [6] (2S, 4R) (where Tr is the same as above)
-4-Methyl-1-trityloxy-6-heptene-2,4-diol is obtained, which is further treated with a catalytic amount of hydrochloric acid in methanol to remove the protecting group, as shown by formula [1]. (2S, 4R) −4−
A method for producing methyl-6-heptene-1,2,4-triol.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP309584A JPS60146840A (en) | 1984-01-11 | 1984-01-11 | (2s,4r)-4-methyl-6-heptene-1,2,4-triol and preparation thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP309584A JPS60146840A (en) | 1984-01-11 | 1984-01-11 | (2s,4r)-4-methyl-6-heptene-1,2,4-triol and preparation thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS60146840A JPS60146840A (en) | 1985-08-02 |
JPH0432808B2 true JPH0432808B2 (en) | 1992-06-01 |
Family
ID=11547780
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP309584A Granted JPS60146840A (en) | 1984-01-11 | 1984-01-11 | (2s,4r)-4-methyl-6-heptene-1,2,4-triol and preparation thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS60146840A (en) |
-
1984
- 1984-01-11 JP JP309584A patent/JPS60146840A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS60146840A (en) | 1985-08-02 |
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