多機能有機分子触媒の開発と不斉ドミノ反応への応用

• Project Area: Advanced Molecular Transformations by Organocatalysts
• Project/Area Number: 26105737
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Osaka University
• Principal Investigator: 滝澤 忍 大阪大学, 産業科学研究所, 准教授 (50324851)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2015: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2014: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: 有機分子触媒 / 不斉触媒 / 不斉反応 / ドミノ反応 / 複素環化合物 / 酸塩基型触媒 / ルイス塩基 / ブレンステッド酸 / 酸 / 塩基 / ドミノ / エナンチオ選択的 / 位置選択的 / 環化付加 / 複素環

Outline of Annual Research Achievements

申請者は、二核バナジウム触媒や酸塩基有機分子触媒などの多機能不斉触媒の開発に成功している。本触媒を2-ナフトールのホモカップリング反応やエノンとカルボニル化合物との炭素－炭素結合形成反応である森田-Baylis-Hillman(MBH)反応に適用すると高効率で反応が進行する。触媒を構成する複数の活性化部位による基質の多点配向制御が重要な役割を担っており、酵素的作用機序を持つ触媒として数多くの知見を得ている。
本研究では、基質の活性化に金属を必要としない高活性な多機能酸塩基有機分子不斉触媒を創製と、開発した触媒を用いてMBH反応を基盤とする不斉ドミノ反応を開発を行った。医薬品原料や生物活性天然物の母格となる多置換・多官能性キラル有機化合物群の安全で効率的かつアトムエコノミカルな合成法の確立を目指した。反応基質の活性化に金属を用いずに二重活性化機構で反応を促進する不斉触媒の開発に取り組み、aza-MBH反応に有効な多点制御型不斉有機分子触媒の開発に成功した。触媒内に適切に配置した有機官能基のブレンステッド酸とルイス塩基部位が協調的に基質を活性化することで効率的に反応を促進することを突き止めた。
aza-MBH反応の生成物は高度に官能基化されたβ-アミノ酸誘導体であるため、高活性な金属触媒を使用した場合、生成物との副反応など反応制御が難しく、ドミノ反応への展開は困難であった。研究の結果、これまで報告例のなかった不斉aza-MBH型ドミノ反応の開発に、穏和な条件下で官能基選択的に反応を促進可能な多点制御型有機分子触媒を適用することで、医薬資源として有用な多置換・多官能性化合物を高立体選択的かつ簡便に合成することに成功した。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] アーヘン工科大学/ビーレフェルト大学(ドイツ)
• [Journal Article] Enantioselective organocatalytic oxidation of ketamine (2016)
  • Author(s): Takizawa, Shinobu; Kishi, Kenta; Abozeid, Mohamed Ahmed; Murai, Kenichi; Fujioka, Hiromichi; Sasai, Hiroaki
  • Journal Title: Organic & Biomolecular Chemistry Volume: 14 Issue: 2 Pages: 761-767
  • DOI: 10.1039/c5ob02042e
  • Peer Reviewed
• [Journal Article] Pd-catalyzed enantioselective intramolecular α-arylation of α-substituted cyclic ketones: Facile synthesis of functionalized chiral spirobicycles (2015)
  • Author(s): L. Fan, S. Takizawa, Y. Takeuchi, K. Takenaka, H. Sasai
  • Journal Title: Org. Biomol. Chem. Volume: 13 Issue: 17 Pages: 4837-4840
  • DOI: 10.1039/c5ob00382b
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structural Features and Asymmetric Environment of i-Pr-SPRIX Ligand (2015)
  • Author(s): Takenaka, K.; Lin, X.; Takizawa, S.; Sasai, H.
  • Journal Title: Chirality Volume: 27 Issue: 8 Pages: 532-537
  • DOI: 10.1002/chir.22467
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Enantioselective and aerobic oxidative coupling of 2-naphthol derivatives using chiral dinuclear vanadium(V) complex in water (2015)
  • Author(s): M. Sako, S. Takizawa, Y. Yoshida, H. Sasai
  • Journal Title: Tetrahedron: Asymmetry Volume: 26 Issue: 12-13 Pages: 613-616
  • DOI: 10.1016/j.tetasy.2015.05.002
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pd(II)-catalyzed diastereoselective and enantioselective domino cyclization/cycloaddition reactions of alkenyl oximes for polycyclic heterocycles with four chiral stereogenic centers (2015)
  • Author(s): M. A. Abozeid, S. Takizawa, H. Sasai
  • Journal Title: Tetrahedron Lett. Volume: 56 Issue: 29 Pages: 4316-4319
  • DOI: 10.1016/j.tetlet.2015.05.070
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] An enantioselective organocatalyzed aza-Morita－Baylis－Hillman reaction of isatin-derived ketimines with acrolein (2015)
  • Author(s): Y. Yoshida, M. Sako, K. Kishi, H. Sasai, S. Hatakeyama, S. Takizawa
  • Journal Title: Org. Biomol. Chem. Volume: 13 Issue: 34 Pages: 9022-9028
  • DOI: 10.1039/c5ob00874c
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phosphine-catalyzed β,γ-umpolung domino reaction of allenic esters: Facile synthesis of tetrahydrobenzofuranones bearing a chiral tetrasubstituted carbon stereogenic center (2015)
  • Author(s): S. Takizawa, K. Kishi, Y. Yoshida, S. Mader, F. A. Arteaga, S. Lee, M. Hoshino, M. Rueping, M. Fujita, H. Sasai
  • Journal Title: Angew. Chem., Int. Ed. Volume: 54 Issue: 51 Pages: 15511-15515
  • DOI: 10.1002/anie.201508022
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Vanadium in asymmetric synthesis: Emerging concepts in catalyst design and applications (2015)
  • Author(s): S. Takizawa, H. Groger, H. Sasai
  • Journal Title: Chem. Eur. J. Volume: 21 Issue: 25 Pages: 8992-8997
  • DOI: 10.1002/chem.201406444
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synthesis, Electronic, and Crystal Structures of Methoxycarbonyl-substituted 2,5-Di(1,3-dithiol-2-ylidene)-1,3-dithiolane-4-thione Derivatives (2014)
  • Author(s): Kazumasa Ueda, Hiroki Kusanagi, Hiroki Nanbo, Yoshiumi Kohno, Tomoe Egami, Keiko Miyabayashi, and Takeyuki Suzuki
  • Journal Title: Chemistry Letters Volume: 43 Issue: 8 Pages: 1224-1226
  • DOI: 10.1246/cl.140288
  • NAID: 130004427127
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Facile regio- and stereo-selective metal-free synthesis of all-carbon tetrasubstituted alkenes bearing a C(sp3)-F unit via dehydroxyfluorination of Morita-Baylis-Hillman (MBH) adducts (2014)
  • Author(s): S. Takizawa, F. A. Arteaga, K. Kishi, S. Hirata, H. Sasai
  • Journal Title: Org. Lett. Volume: 16 Issue: 16 Pages: 4162-4165
  • DOI: 10.1021/ol501855m
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Enantioselective Acid-Base Organocatalyzed Domino Reactions Based on aza-Morita-Baylis-Hillman Process (2014)
  • Author(s): 滝澤忍, 笹井宏明
  • Journal Title: Journal of Synthetic Organic Chemistry, Japan Volume: 72 Issue: 7 Pages: 781-796
  • DOI: 10.5059/yukigoseikyokaishi.72.781
  • NAID: 130004679609
  • ISSN: 0037-9980, 1883-6526
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Enantioselective organocatalyzed [3+2] annulation via umpolung domino reaction of allenoates (2016)
  • Author(s): K. Kishi, S. Takizawa, Y. Yoshida, S. Mader, M. Rueping, H. Sasai
  • Organizer: Aachen-Osaka Joint Symposium “Biotechnology and Chemistry for Green Growth”
  • Place of Presentation: 大阪 日本
  • Year and Date: 2016-03-09
  • Int'l Joint Research
• [Presentation] Enantioselective organocatalyzed synthesis of tetrahydrobenzofuranones bearing a tetrasubstituted stereogenic center (2016)
  • Author(s): K. Kishi, S. Takizawa, Y. Yoshida, S. Mader, M. Rueping, H. Sasai
  • Organizer: The 8th Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: 大阪 日本
  • Year and Date: 2016-01-21
  • Int'l Joint Research
• [Presentation] Enantioselective organocatalyzed formal [n+2] cycloaddition using allenoates (2015)
  • Author(s): S. Takizawa, H. Sasai
  • Organizer: PACIFICHEM 2015
  • Place of Presentation: ハワイ アメリカ
  • Year and Date: 2015-12-15
  • Int'l Joint Research / Invited
• [Presentation] Organocatalyzed synthesis of heterocycles bearing a chiral tetrasubstituted carbon center (2015)
  • Author(s): S. Takizawa, K. Kishi, H. Sasai
  • Organizer: The 13th International Kyoto Conference on New Aspects of Organic Chemistry
  • Place of Presentation: 京都 日本
  • Year and Date: 2015-11-09
  • Int'l Joint Research
• [Presentation] Enantioselective organocatalyzed formal cycloaddition reactions based on the aza-Morita-Baylis-Hillman process (2015)
  • Author(s): S. Takizawa, H. Sasai
  • Organizer: The 39th Naito Conference
  • Place of Presentation: 北海道 日本
  • Year and Date: 2015-07-13
  • Int'l Joint Research
• [Presentation] Stereoselective Construction of Chiral Tetrasubstituted Carbon Stereogenic Centers Via Organocatalytic Rauhut-Currier Reaction (2015)
  • Author(s): 滝澤忍，笹井宏明
  • Organizer: 日本化学会第95春季年会
  • Place of Presentation: 日本大学（千葉）
  • Year and Date: 2015-03-26 – 2015-03-29
  • Invited
• [Presentation] Enantioselective Rauhut-Currier Reaction Promoted by an Immobilized Organocatalyst (2015)
  • Author(s): 平田修一、岸鉄馬、滝澤忍、笹井宏明
  • Organizer: 日本化学会第95春季年会
  • Place of Presentation: 日本大学（千葉）
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] Development of Enantioselective Organocatalyzed Formal [n+2] Cycloaddition of Allenic Ester with Olefins (2015)
  • Author(s): 吉田泰志、滝澤忍、Fernando Arteaga-Arteaga、岸鉄馬、笹井宏明
  • Organizer: 日本化学会第95春季年会
  • Place of Presentation: 日本大学（千葉）
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] nantioselective Synthesis of Hetero Helicenes Bearing 1,2,3-Triazole Units (2015)
  • Author(s): 坂井智弘、吉田泰志、滝澤忍、笹井宏明
  • Organizer: 日本化学会第95春季年会
  • Place of Presentation: 日本大学（千葉）
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] Enantioselective Synthesis of Chiral Spiro Compounds and Their Applications to Organocatalysis (2015)
  • Author(s): 武内芳樹、Lulu Fan、滝澤忍、笹井宏明
  • Organizer: 日本化学会第95春季年会
  • Place of Presentation: 日本大学（千葉）
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] Enantio- and Diastereoselective Rauhut-Currier Reaction: Facile Synthesis of α-Methylidene-γ-Butyrolactones and γ-Butyrolactams (2014)
  • Author(s): Shinobu Takizawa, Kenta Kishi, Tue M.-N. Nguyen, Fernando A. Arteaga, Michitaka Suzuki, Hiroaki Sasai
  • Organizer: Advanced Molecular Transformations by Organocatalysts 2nd International Conference & 7th Symposium on Organocatalysis
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2014-11-21 – 2014-11-22
• [Presentation] ヘリセン及びヘリセン様化合物のエナンチオ選択的効率合成法の開発 (2014)
  • Author(s): 滝澤忍、辻原哲也、吉田泰志、小寺純平、佐古真、土井貴裕、笹井宏明
  • Organizer: 第40回反応と合成の進歩シンポジウム
  • Place of Presentation: 東北大学（宮城）
  • Year and Date: 2014-11-10 – 2014-11-11
• [Presentation] Enantioselective Organocatalyzed Formal [n+2] Cycloaddition Using Allenoates (2014)
  • Author(s): Shinobu Takizawa, Fernando A. Arteaga, Yasushi Yoshida, Michitaka Suzuki, Kenta Kishi, Tue M.-N. Nguyen, Hiroaki Sasai
  • Organizer: Molecular Chirality Asia 2014
  • Place of Presentation: Beijing, China
  • Year and Date: 2014-10-29 – 2014-10-31
• [Presentation] 有機分子触媒を用いるエナンチオ選択的分子内Rauhut-Currier反応によるα-メチリデン-γ-ブチロラクタムの効率的合成 (2014)
  • Author(s): 滝澤忍、岸鉄馬、Fernando Arteaga-Arteaga、笹井宏明
  • Organizer: 第64回日本薬学会近畿支部総会・大会
  • Place of Presentation: 京都薬科大学（京都）
  • Year and Date: 2014-10-11
• [Presentation] 有機触媒を用いる形式的環化付加反応とキラル四置換炭素を有する複素環合成への展開 (2014)
  • Author(s): 滝澤忍、Fernando Arteaga-Arteaga、吉田泰志、鈴木通恭、Tue M.-N. Nguyen、笹井宏明
  • Organizer: 第44回複素環化学討論会
  • Place of Presentation: 札幌市民ホール（北海道）
  • Year and Date: 2014-09-10 – 2014-09-12
• [Presentation] Organocatalyzed Enantioselective Reactions of Ketimines with Allenoates (2014)
  • Author(s): Shinobu Takizawa, Fernando A. Arteaga, Yasushi Yoshida, Michitaka Suzuki, Hiroaki Sasai
  • Organizer: Aachen-Osaka Joint Symposium
  • Place of Presentation: Aachen, Germany
  • Year and Date: 2014-09-03 – 2014-09-05
• [Presentation] Enantioselective Organocatalyzed Domino Process Based on aza-Morita-Baylis-Hillman-Type (aza-MBH) Reaction (2014)
  • Author(s): Shuichi Hirata, Shinobu Takizawa, Naohito Inoue, Fernando A. Arteaga, Yasushi Yoshida, Michitaka Suzuki, Hiroaki Sasai
  • Organizer: 248th ACS National Meeting & Exposition
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-08-10 – 2014-08-14
• [Presentation] 不斉有機分子触媒を用いるエナンチオ選択的aza-MBH型ドミノ反応の開発 (2014)
  • Author(s): 平田修一、滝澤忍、井上直人、Fernando Arteaga-Arteaga、吉田泰志、鈴木通恭、笹井宏明
  • Organizer: 日本プロセス化学会2014サマーシンポジウム
  • Place of Presentation: タワーホール船堀（東京）
  • Year and Date: 2014-07-31 – 2014-08-01
• [Presentation] 触媒的不斉連続反応によるキラルビルディングブロックの創出 (2014)
  • Author(s): 滝澤忍
  • Organizer: 第27回インターフェックスジャパン
  • Place of Presentation: 東京ビッグサイト（東京)
  • Year and Date: 2014-07-02 – 2014-07-04
• [Presentation] Enantioselective Synthesis of α-Methylidene-γ-Butyrolactones and γ-Butyrolactams: Intramolecular Rauhut-Currier Reaction Promoted by Bifunctional Organocatalysts (2014)
  • Author(s): Shinobu Takizawa, Tue M.-N. Nguyen, Kenta Kishi, Fernando A. Arteaga, Michitaka Suzuki, Hiroaki Sasai
  • Organizer: 15th Tetrahedron Symposium
  • Place of Presentation: London, UK
  • Year and Date: 2014-06-24 – 2014-06-27
• [Presentation] Enantioselective Organocatalyzed Formal [n+2] Cycloaddition Using Allenoates (2014)
  • Author(s): Shinobu Takizawa, Fernando A. Arteaga, Yasushi Yoshida, Michitaka Suzuki, Tue M.-N. Nguyen, Hiroaki Sasai
  • Organizer: 15th Tetrahedron Symposium
  • Place of Presentation: London, UK
  • Year and Date: 2014-06-24 – 2014-06-27
• [Presentation] 多機能有機分子触媒を用いるエナンチオ選択的ドミノ反応の開発 (2014)
  • Author(s): 滝澤忍
  • Organizer: 分子活性化－有機分子触媒合同シンポジウム
  • Place of Presentation: 北海道大学（北海道）
  • Year and Date: 2014-06-20 – 2014-06-21
• [Presentation] ヘリセン及びヘリセン様化合物の効率的不斉合成法の開発 (2014)
  • Author(s): 滝澤忍、吉田泰志、小寺純平、佐古真、土井貴裕、笹井宏明
  • Organizer: Symposium on Molecular Chirality 2014
  • Place of Presentation: 仙台国際センター（宮城)
  • Year and Date: 2014-06-06 – 2014-06-07
• [Book] In Domino Reactions: Concepts for Efficient Organic Synthesis (2014)
  • Author(s): Shinobu Takizawa, Hiroaki Sasai
  • Total Pages: 648
  • Publisher: Wiley-VCH Verlag GmbH & Co. KGaA
• [Remarks] 大阪大学 産業科学研究所 機能物質化学研究分野
  • URL: http://www.sanken.osaka-u.ac.jp/labs/soc/socmain.html