Development of Practical Methods for Molecular Transformation Using Multifunctional Chiral Catalysts

• Project Area: Middle molecular strategy: Creation of higher bio-functional molecules by integrated synthesis.
• Project/Area Number: 16H01152
• 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): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2016: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 不斉 / 四置換炭素 / 四級炭素 / 多機能触媒 / GSC / 環境調和 / 精密合成 / バナジウム / 有機化学 / 合成化学 / 触媒・化学プロセス / 有機分子触媒 / 卑金属触媒 / 酸化反応 / 連続反応 / マイクロミキサー / 固定化触媒 / 分子認識

Outline of Annual Research Achievements

本研究では、多機能不斉触媒の多点制御能を活用してラセミ体としての合成も難しい、多置換・多官能性キラル有機化合物群を触媒的かつエナンチオ選択的に合成する。そして不斉触媒をリサイクル可能な固定化触媒へと導き、省資源・環境調和型不斉反応プロセスへと展開する。さらに金属触媒と有機分子触媒が融合した新しい固定化触媒を開発し、より複雑な多成分連結反応へと適用する。生物活性天然物や医薬原料の供給に有効な実用的不斉分子変換法の確立を目指す。
今年度は、反応基質の多点制御活性化が可能な多機能有機分子不斉触媒を用い、不斉環化反応を基軸とする第四級不斉炭素や四置換不斉炭素の構築を試みた。第四級不斉炭素や四置換不斉炭素は立体的に込み合った構造であり、その合成には高い反応エネルギーを必要とする。目的の鏡像異性体以外の副生成物も生じやすく合成難易度は高い。ケチミンや四置換オレフィンを反応基質とする不斉付加反応が適用できればキラル四置換炭素の直接的構築法となる。しかしながら、例えばケチミンはアルジミンと比べ電子的・立体的要因で反応性・面選択性が乏しく不斉反応への展開が難しい。検討の結果、以下の3つの成果を得た。
１）バリンから誘導した新規酸塩基型有機分子不斉触媒をアクリロイルクロリドとアミノジエノンに作用させると、アミド化/Rauhut-Currier連続反応が進行して、キラル四置換及びキラル第四級炭素を連続で有するα-メチリデン-γ-ブチロラクタムが高収率・高エナンチオ選択的に得られることを見出した。
２）エナンチオ選択的藤原-守谷反応に、SPRIX配位子を用いるとキラル第四級炭素を有するTetrahydrocyclopenta[b]indoleが簡便に合成できることを見出した。
３）キラル四置換炭素を有するヒドロインドール及び、ヒドロベンゾフラノンの合成に有効な、極性転換型ダブルマイケル反応の開発に成功した。

Research Progress Status

平成29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成29年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Universite Paris-Sud(フランス)
• [Int'l Joint Research] Chung-Ang University(韓国)
• [Int'l Joint Research] パリ南大学(フランス)
• [Int'l Joint Research] 中央大学(韓国)
• [Journal Article] Enantioselective synthesis of spiro (isoxazole-isoxazoline) hybrid ligands (2018)
  • Author(s): B. M. Chaki, K. Wakita, S. Takizawa, K. Takenaka, H. Sasai
  • Journal Title: Heterocycles Volume: - Issue: 1 Pages: 493-505
  • DOI: 10.3987/com-18-s(t)41
  • Peer Reviewed
• [Journal Article] Asymmetric oxidative coupling of hydroxycarbazoles: Facile synthesis of (+)-bi-2-hydroxy-3-methylcarbazole (2018)
  • Author(s): Sako Makoto、Sugizaki Akimasa、Takizawa Shinobu
  • Journal Title: Bioorg. Med. Chem. Lett Volume: - Issue: 16 Pages: 2751-2753
  • DOI: 10.1016/j.bmcl.2018.02.033
  • Peer Reviewed
• [Journal Article] Chiral Organocatalyzed Intermolecular Rauhut–Currier Reaction of Nitroalkenes with Ethyl Allenoate (2017)
  • Author(s): S. Takizawa, M. Sako, K. Kishi, M. Shigenobu, G. Vo-Thanh, H. Sasai
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 65 Issue: 11 Pages: 997-999
  • DOI: 10.1248/cpb.c17-00554
  • NAID: 130006191501
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enantio- and Diastereoselective Betti/aza-Michael Sequence: Single Operated Preparation of Chiral 1,3-Disubstituted Isoindolines (2017)
  • Author(s): Takizawa Shinobu、Sako Makoto、Abozeid Mohamed Ahmed、Kishi Kenta、Wathsala H. D. P.、Hirata Shuichi、Murai Kenichi、Fujioka Hiromichi、Sasai Hiroaki
  • Journal Title: Organic Letters Volume: 19 Issue: 19 Pages: 5426-5429
  • DOI: 10.1021/acs.orglett.7b02693
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Reversal of Enantioselectivity Approach to BINOLs via Single and Dual 2-Naphthol Activation Modes (2017)
  • Author(s): Kim Hun Young、Takizawa Shinobu、Sasai Hiroaki、Oh Kyungsoo
  • Journal Title: Organic Letters Volume: 19 Issue: 14 Pages: 3867-3870
  • DOI: 10.1021/acs.orglett.7b01734
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Multifunctional catalysis: stereoselective construction of α-methylidene-γ-lactams via an amidation/Rauhut?Currier sequence (2017)
  • Author(s): Kishi Kenta、Arteaga Fernando Arteaga、Takizawa Shinobu、Sasai Hiroaki
  • Journal Title: Chemical Communications Volume: 53 Issue: 55 Pages: 7724-7727
  • DOI: 10.1039/c7cc02839c
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Enantioselective synthesis of tetrahydrocyclopenta[b]indole bearing a chiral quaternary carbon center via Pd(ii)?SPRIX-catalyzed C?H activation (2017)
  • Author(s): Abozeid Mohamed Ahmed、Sairenji Shiho、Takizawa Shinobu、Fujita Makoto、Sasai Hiroaki
  • Journal Title: Chemical Communications Volume: 53 Issue: 51 Pages: 6887-6890
  • DOI: 10.1039/c7cc03199h
  • Peer Reviewed
• [Journal Article] Determination of the absolute configuration of compounds bearing chiral quaternary carbon centers using the crystalline sponge method (2017)
  • Author(s): Sairenji Shiho、Kikuchi Takashi、Abozeid Mohamed Ahmed、Takizawa Shinobu、Sasai Hiroaki、Ando Yuichiro、Ohmatsu Kohsuke、Ooi Takashi、Fujita Makoto
  • Journal Title: Chem. Sci. Volume: 8 Issue: 7 Pages: 5132-5136
  • DOI: 10.1039/c7sc01524k
  • Peer Reviewed / Open Access
• [Journal Article] Short syntheses of 4-deoxycarbazomycin B, sorazolon E, and (+)-sorazolon E2 (2017)
  • Author(s): M. Sako, K. Ichinose, S. Takizawa, H. Sasai
  • Journal Title: Chem. Asian J. Volume: 12 Issue: 12 Pages: 1305-1308
  • DOI: 10.1002/asia.201700471
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Facile synthesis of spirooxindoles via an enantioselective organocatalyzed sequential reaction of oxindoles with ynone (2017)
  • Author(s): S. Takizawa, M. Kusaba, K. Kishi, B. Jianfei, T. Suzuki, H. Sasai
  • Journal Title: Heterocycles Volume: 95 Issue: 2 Pages: 761-767
  • DOI: 10.3987/com-16-s(s)86
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Organocatalyzed [4+2] annulation of all-carbon tetrasubstitued alkenes with allenoate: Synthesis of highly functionalized 2H, and 4H-puran derivatives (2016)
  • Author(s): T.-T.-D. Ngo, K. Kishi, M. Sako, M. Shigenobu, C. Bournaud, M. Toffano, R. Guillot, J.-P. Baltaza, S. Takizawa, H. Sasai, G. Vo.-Thanh
  • Journal Title: ChemstrySelect Volume: 1 Issue: 17 Pages: 5414-5420
  • DOI: 10.1002/slct.201601204
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Efficient Enantioselective Synthesis of Oxahelicenes Using Redox/Acid Cooperative Catalysts (2016)
  • Author(s): Sako, Makoto; Takeuchi, Y.; Tsujihara, Tetsuya; Kodera, J.; Kawano, T.; Takizawa, S.; Sasai, H.
  • Journal Title: Journal of the American Chemical Society Volume: 138 Issue: 36 Pages: 11481-11484
  • DOI: 10.1021/jacs.6b07424
  • Peer Reviewed
• [Journal Article] Copper-catalyzed divergent oxidative pathways of 2-naphthol derivatives: ortho-Naphthoquinones versus 2-BINOLs (2016)
  • Author(s): H. Y. Kim, S. Takizawa, K. Oh
  • Journal Title: Org. Biomol. Chem. Volume: 14 Issue: 30 Pages: 7191-7196
  • DOI: 10.1039/c6ob01183g
  • Peer Reviewed / Int'l Joint Research
• [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
• [Presentation] Vanadium(V) Complex-Catalyzed Enantioselective C-C Bond Forming Reactions (2017)
  • Author(s): Sako, M.; Takizawa, S.; Sasai, H.
  • Organizer: Biotechnology and Chemistry for Green Growth (JSPS Japanese-German Graduate Externship Program)
  • Int'l Joint Research
• [Presentation] Phosphine-Catalyzed Umpolung Tandem Michael Addition of Alkynylester (2017)
  • Author(s): Kishi, K.; Takizawa, S.; Kusaba, M.; Sasai, H.
  • Organizer: Biotechnology and Chemistry for Green Growth (JSPS Japanese-German Graduate Externship Program)
  • Int'l Joint Research
• [Presentation] Chiral Iron Catalysts Bearing SPRIX Ligand (2017)
  • Author(s): Niida, Y.; Takenaka, K.; Takizawa, S.; Sasai, H.
  • Organizer: Biotechnology and Chemistry for Green Growth (JSPS Japanese-German Graduate Externship Program)
  • Int'l Joint Research
• [Presentation] Vanadium(V) Complex-catalyzed Enantioselective C-C Bond Forming Reactions (2017)
  • Author(s): Sako, M.; Takizawa, S.; Sasai, H.
  • Organizer: The 19th IUPAC International Symposium on Organometallic Chemistry Directed Towards Organic Synthesis (OMCOS 19)
  • Int'l Joint Research
• [Presentation] Enantioselective Synthesis of Highly Functionalized Heterocycles via the Chiral Phosphine-catalyzed Domino Reaction (2017)
  • Author(s): Takizawa, S.; Kishi, K.; Kusaba, M.; Sasai, H.
  • Organizer: Chirality 2017
  • Int'l Joint Research
• [Presentation] Vanadium(V) Complex-catalyzed Enantioselective Oxidative Coupling of Monocyclic Phenol Derivatives (2017)
  • Author(s): Aoki, T.; Sako, M.; Takizawa, S.; Sasai, H.
  • Organizer: Chirality 2017
  • Int'l Joint Research
• [Presentation] Enantioselective Synthesis of α-Methylidene-γ-Lactams via Amidation and Rauhut-Currier Reaction Sequence (2017)
  • Author(s): Takizawa, S.; Kishi, K.; Sasai, H.
  • Organizer: The 11th International Symposium on Integrated Synthesis (ISONIS-11), The 3rd International Symposium on Middle Molecular Strategy (ISMMS-3)
  • Int'l Joint Research
• [Presentation] Enantioselective carbon-carbon bond-forming reactions catalyzed by vanadium(V) complexes (2017)
  • Author(s): S. Takizawa, M. Sako, H. Sasai
  • Organizer: Korean Chemical Society 120th General Meetings
  • Int'l Joint Research / Invited
• [Presentation] キラルな二核バナジウム触媒の開発と不斉炭素-炭素結合形成反応への応用 (2017)
  • Author(s): 滝澤忍
  • Organizer: 有機合成化学協会関西支部・2月セミナー「有機合成のニュートレンド」
  • Invited
• [Presentation] 二重活性化能を有する不斉触媒の開発と応用 (2016)
  • Author(s): 滝澤忍
  • Organizer: 平成28年度名城大学分子空間創製研究センター発足記念・第一回セミナー
  • Invited
• [Presentation] Enantioselective carbon-carbon bond-forming reactions catalyzed by vanadium(V) complexes (2016)
  • Author(s): S. Takizawa, M. Sako, H. Sasai
  • Organizer: The 10th International Vanadium Symposium Chemistry, Biological Chemistry & Toxicology (V10)
  • Int'l Joint Research / Invited
• [Presentation] Efficient enantioselective synthesis of oxahelicenes using redox/acid cooperative catalysts (2016)
  • Author(s): S. Takizawa
  • Organizer: JSPS Core-to-Core Program “Green Chemistry & Bio-sensing Devices”
  • Int'l Joint Research / Invited
• [Book] 有機分子触媒の開発と工業利用 (2018)
  • Author(s): 笹井宏明、滝澤忍
  • Total Pages: 330
  • Publisher: （株）シーエムシー出版
  • ISBN: 9784781313238
• [Book] 化学工業 (2017)
  • Author(s): 滝澤忍、笹井宏明
  • Total Pages: 80
  • Publisher: 化学工業社
• [Remarks] 大阪大学産業科学研究所 機能物質化学研究分野
  • URL: https://www.sanken.osaka-u.ac.jp/labs/soc/socmain.html
• [Remarks] 大阪大学産業科学研究所・機能物質化学研究室ホームページ
  • URL: http://www.sanken.osaka-u.ac.jp/labs/soc/socmain.html