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For that reason, it is important to develop an asymmetric reaction to synthesize one effective enantiomer with high selectivity. Development of catalytic asymmetric reactions catalyzed by small molecules is one of the most important research topic in synthetic organic chemistry field from the viewpoint of energy conservation and environmental harmony. The organocatalysts without metal coordination have numerous advantage including stable in air, easy to handle and inexpensive. Presently, many research groups are effectively involving in development of next generation of environmentally friendly organocatalysts.\n The present study describes the design and synthesis of both like low molecular peptide amino amide alcohol and silyloxy substituted amino alcohol as novel multipoint recognition type organocatalysts. These catalysts were effectively applied to 1) asymmetric Michael reaction using amino amide alcohol organocatalyst and 2) asymmetric Diels-Alder (DA) reaction using silyloxy substituted amino alcohol organocatalyst. Reaction 1) gives a warfarin derivative with anticoagulant action and the adduct obtained from reaction 2) can be easily induced to α,β-unsaturated lactam which could be used for synthesis of microcolin derivatives acting on cytotoxicity and immunosuppression.\n1) We synthesized amino amide alcohol organocatalysts A and investigated catalytic activity for asymmetric Michael reaction of coumarins with α,β-unsaturated ketones. 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創薬を指向した新規有機分子触媒の開発とその不斉付加反応への応用研究
https://doi.org/10.15118/00009193
https://doi.org/10.15118/00009193179b5568-5c47-4745-b1d6-cba78db8ea5b
名前 / ファイル | ライセンス | アクション |
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A397 (2.6 MB)
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A397_summary (354.2 kB)
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Item type | 学位論文 / Thesis or Dissertation(1) | |||||
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公開日 | 2017-05-19 | |||||
タイトル | ||||||
言語 | ja | |||||
タイトル | 創薬を指向した新規有機分子触媒の開発とその不斉付加反応への応用研究 | |||||
言語 | ||||||
言語 | jpn | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||
資源タイプ | doctoral thesis | |||||
ID登録 | ||||||
ID登録 | 10.15118/00009193 | |||||
ID登録タイプ | JaLC | |||||
アクセス権 | ||||||
アクセス権 | open access | |||||
アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||
著者 |
熊谷, 淳
× 熊谷, 淳 |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | 医薬品を含む多くの生物活性化合物は光学活性物質であり, その鏡像異性体は異なる生体内活性を示すことが多いため, 有効な一方の鏡像異性体を高選択的に合成するための不斉合成反応の開発が重要である. ごく少量の不斉分子によって触媒化される触媒的不斉合成反応の開発は省エネルギーや環境調和の観点から有機合成化学領域の最も重要な研究課題の一つであり, 金属を含有しない有機分子触媒は空気中で安定であり取り扱いやすく安価であるという利点を有するため, 次世代の環境調和型触媒として現在活発に研究開発が行なわれている. 本論文は, 新規多点認識型有機分子触媒として低分子ペプチド型アミノアミドアルコールおよびシロキシ置換アミノアルコール有機分子触媒を設計し, それぞれ, 1) アミノアミドアルコール有機分子触媒を用いる不斉 Michael 付加反応, および 2) アミノアルコール有機分子触媒を用いる Diels-Alder (DA) 環化付加反応に適応し, それら有機分子触媒としての機能性を検討したものである. 反応 1) は抗血液凝固作用持つワルファリン誘導体を与え, また, 反応 2) から得られる付加体は細胞障害や免疫抑制に作用する microcolin 誘導体を得ることのできる α, β-不飽和ラクタムへ容易に誘導できる. 1) アミノアミドアルコール有機分子触媒 A を合成し, 触媒 A を用いるクマリン類と α, β-不飽和ケトン類との不斉 Michael 反応を検討した結果, 触媒 A が不斉触媒活性を示し, 優れた化学収率と良好な光学収率で光学活性ワルファリン誘導体を与えることを見出した. 2) β 位がシロキシ置換された様々なアミノアルコール有機分子触媒 B を合成し, 触媒 B を用いるアントロン類とマレイミド類との不斉 DA 反応を検討した結果, 触媒 B が不斉触媒活性を示し, ほぼ完全な化学収率と優れた光学収率で光学活性ヒドロアントラセン誘導体が得られることを見出した. 本研究において, その分子中に「基質との共有結合部位と 2 点の水素結合部位を併せ持つ多点認識型アミノアミドアルコール有機分子触媒」および「アミン塩基部位, 立体制御部位としてのシロキシ置換基および基質との水素結合部位を併せ持つ多点認識型シロキシ置換アミノアルコール有機分子触媒」を開発することに成功し, それらが創薬に有効な不斉 Michael 付加反応および不斉 DA 付加反応においてそれぞれ良好な不斉触媒活性を示すことを明らかにした. 本研究の成果は, 新薬創製の合成開発研究に大きく貢献できることが期待される. Many biologically active compounds, including drugs, are optically active substances that often its enantiomers display different in vivo activities. For that reason, it is important to develop an asymmetric reaction to synthesize one effective enantiomer with high selectivity. Development of catalytic asymmetric reactions catalyzed by small molecules is one of the most important research topic in synthetic organic chemistry field from the viewpoint of energy conservation and environmental harmony. The organocatalysts without metal coordination have numerous advantage including stable in air, easy to handle and inexpensive. Presently, many research groups are effectively involving in development of next generation of environmentally friendly organocatalysts. The present study describes the design and synthesis of both like low molecular peptide amino amide alcohol and silyloxy substituted amino alcohol as novel multipoint recognition type organocatalysts. These catalysts were effectively applied to 1) asymmetric Michael reaction using amino amide alcohol organocatalyst and 2) asymmetric Diels-Alder (DA) reaction using silyloxy substituted amino alcohol organocatalyst. Reaction 1) gives a warfarin derivative with anticoagulant action and the adduct obtained from reaction 2) can be easily induced to α,β-unsaturated lactam which could be used for synthesis of microcolin derivatives acting on cytotoxicity and immunosuppression. 1) We synthesized amino amide alcohol organocatalysts A and investigated catalytic activity for asymmetric Michael reaction of coumarins with α,β-unsaturated ketones. From the result, we found that the organocatalyst A exhibits asymmetric catalytic activity and gives optically active warfarin derivatives with excellent chemical yield and good optical yield. 2) We synthesized amino alcohol organocatalysts B with silyloxy substituted group at position and investigated catalytic activity for asymmetric DA reaction of anthrones with maleimides. From the result, we found that the organocatalyst B exhibits asymmetric catalytic activity and gives optically active hydroanthracene derivatives with almost complete chemical yield and excellent optical yield. In this study, we succeeded in developing two kind of multipoint recognition type organocatalysts, amino amide alcohol organocatalyst having both a covalent bonding site and two hydrogen bonding sites and a multipoint recognition type silyloxy substituted amino alcohol organocatalyst having amine basic site, silyloxy substituted group and hydrogen bonding site in the molecules. It was revealed that the synthesized new organocatalysts showed good asymmetric activity in asymmetric Michael reaction and asymmetric DA reaction toward drug discovery. We strongly believe that the results in this study can be expected to contribute greatly to synthetic development research on drug discovery. |
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言語 | ja | |||||
学位授与機関 | ||||||
学位授与機関識別子Scheme | kakenhi | |||||
学位授与機関識別子 | 10103 | |||||
言語 | ja | |||||
学位授与機関名 | 室蘭工業大学 | |||||
言語 | en | |||||
学位授与機関名 | Muroran Institute of Technology | |||||
学位名 | ||||||
言語 | ja | |||||
学位名 | 博士(工学) | |||||
学位の種別 | ||||||
ja | ||||||
課程博士 | ||||||
学位授与番号 | ||||||
学位授与番号 | 甲第397号 | |||||
報告番号 | ||||||
ja | ||||||
甲第397号 | ||||||
学位記番号 | ||||||
ja | ||||||
博甲第397号 | ||||||
研究科・専攻 | ||||||
ja | ||||||
工学専攻 | ||||||
学位授与年月日 | ||||||
学位授与年月日 | 2017-03-23 | |||||
日本十進分類法 | ||||||
主題Scheme | NDC | |||||
主題 | 501 | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
フォーマット | ||||||
内容記述タイプ | Other | |||||
内容記述 | application/pdf |