Molecular Transformation Based on Integration of Asymmetric Domino Catalysis

• Project Area: Middle molecular strategy: Creation of higher bio-functional molecules by integrated synthesis.
• Project/Area Number: 18H04412
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• 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): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: フロー合成 / 機械学習 / 有機分子触媒 / ドミノ反応 / 不斉反応 / ガウス過程回帰 / 多機能触媒 / 四置換炭素 / ドミノ / フローケミストリー / キラル / ビヒドロキシカルバゾール / バナジウム錯体 / AI / 有機合成 / 不斉触媒

Outline of Annual Research Achievements

これまでバナジウム金属触媒、酸塩基型有機分子触媒、及び金属・有機分子ハイブリッド触媒等の多機能不斉触媒の開発に成功している。これら触媒を活用することで、光学活性オキサヘリセンや連続キラル四置換炭素を含む複素環、軸性キラリティーを有するアルカロイドなど、ラセミ体として得るのも困難な複雑化合物の短工程合成を可能としている。これら反応を効率的に促進するには、触媒を構成する複数の活性化部位による反応基質の多点配向制御が重要であり、酵素的作用機序を持つ不斉触媒としての知見も数多く得ている。
本研究では、多機能触媒が促進する連続反応を集積化し、バッチ法では合成が困難な多置換・多官能性キラル骨格の触媒的かつエナンチオ選択的構築法を開拓を目指した。複雑な多成分連結反応をマイクロフロー合成に組み込むことで、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した。
本年度は、フロー合成を用いた有機分子触媒によるエナンチオ選択的なドミノ反応の開発を行った。反応開発では、網羅的なスクリーニングや試行錯誤が必要とされ、膨大な時間やコストがかかることから迅速な最適化手法の開発が強く望まれている。特にフロー合成では、流速、管径、管長等、最適化すべき要素が増えるため、複雑な化合物を合成する「精密フロー合成」は困難とされていた。今回、機械学習法の1つであるガウス過程回帰法を新規反応開発の反応条件探索に活用することで、従来法に比べ大幅に少ない実験数で精密フロー合成の条件最適化に成功した。バリン由来のレアメタルフリー触媒を用いることで、わずか30秒で、複数の不斉中心を有する複素環化合物が原子効率100%（廃棄物ゼロ）で得られた。本研究は、世界初の機械学習法を活用した精密フロー合成および有機分子触媒による不斉反応プロセスである。この研究により、ファインケミカル類の開発研究の効率化が期待される。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Bielefeld大学(ドイツ)
• [Int'l Joint Research] Bielefeld University(ドイツ)
• [Journal Article] Organocatalytic Synthesis of Highly Functionalized Heterocycles by Enantioselective aza-Morita–Baylis–Hillman-Type Domino Reactions (2020)
  • Author(s): Takizawa Shinobu
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 68 Issue: 4 Pages: 299-315
  • DOI: 10.1248/cpb.c19-00900
  • NAID: 130007824930
  • ISSN: 0009-2363, 1347-5223
  • Year and Date: 2020-04-01
  • Peer Reviewed
• [Journal Article] Exploration of flow reaction conditions using machine-learning for enantioselective organocatalyzed Rauhut-Currier and [3+2] annulation sequence (2020)
  • Author(s): Kondo Masaru、Wathsala H. D. P.、Sako Makoto、Hanatani Yutaro、Ishikawa Kazunori、Hara Satoshi、Takaai Takayuki、Washio Takashi、Takizawa Shinobu、Sasai Hiroaki
  • Journal Title: Chemical Communications Volume: 56 Issue: 8 Pages: 1259-1262
  • DOI: 10.1039/c9cc08526b
  • Peer Reviewed
• [Journal Article] Enantioselective One-pot Synthesis of 3-Azabicyclo[3.1.0]hexanes via Allylic Substitution and Oxidative Cyclization (2020)
  • Author(s): Chaki, B. M.; Takenaka, K.; Zhu, L.; Tsujihara, T.; Takizawa, S.; Sasai, H.
  • Journal Title: Adv. Synth. Catal. Volume: 362 Issue: 7 Pages: 1537-1547
  • DOI: 10.1002/adsc.202000044
  • Peer Reviewed
• [Journal Article] Room‐Temperature, Metal‐Free, and One‐Pot Preparation of 2H‐Indazoles through a Mills Reaction and Cyclization Sequence (2019)
  • Author(s): Kondo Masaru、Takizawa Shinobu、Jiang Yuzhao、Sasai Hiroaki
  • Journal Title: Chemistry - A European Journal Volume: 25 Issue: 42 Pages: 9866-9869
  • DOI: 10.1002/chem.201902242
  • Peer Reviewed
• [Journal Article] 2.Chiral Dinuclear Vanadium Complex-mediated Oxidative Coupling of Resorcinols (2019)
  • Author(s): Makoto Sako, Takanori Aoki, Nadine Zumbrägel, Lukas Schober, Harald Gröger, Shinobu Takizawa, Hiroaki Sasai
  • Journal Title: J. Org. Chem. Volume: 84 Issue: 3 Pages: 580-1587
  • DOI: 10.1021/acs.joc.8b02494
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Concise, Catalyst-Free Synthesis of Davis’ Oxaziridines using Sodium Hypochlorite (2019)
  • Author(s): Kirihara Masayuki、Kitagawa Saori、Mori Hiromitsu、Odagiri Tatsuya、Suzuki Katsuya、Kikkawa You、Osugi Rie、Takizawa Shinobu、Kimura Yoshikazu
  • Journal Title: SynOpen Volume: 03 Issue: 01 Pages: 21-25
  • DOI: 10.1055/s-0037-1611722
  • Peer Reviewed
• [Journal Article] Chiral Vanadium Complex-catalyzed Enantioselective Oxidative Coupling Reactions (2018)
  • Author(s): Sako Makoto、Takizawa Shinobu、Sasai Hiroaki
  • Journal Title: Journal of Synthetic Organic Chemistry, Japan Volume: 76 Issue: 9 Pages: 874-884
  • DOI: 10.5059/yukigoseikyokaishi.76.874
  • NAID: 130007472395
  • ISSN: 0037-9980, 1883-6526
  • Year and Date: 2018-09-01
  • 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] 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] Phosphine-Catalyzed Dual Umpolung Domino Michael Reaction: Facile Synthesis of Hydroindole- and Hydrobenzofuran-2-Carboxylates (2018)
  • Author(s): Kishi, K.; Takizawa, S.; Sasai, H.
  • Journal Title: ACS catalysis Volume: 印刷中 Issue: 6 Pages: 5228-5232
  • DOI: 10.1021/acscatal.8b01011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Vanadium-Catalyzed Dehydrogenation of N-Heterocycles in Water (2018)
  • Author(s): Zumbragel Nadine、Sako Makoto、Takizawa Shinobu、Sasai Hiroaki、Groger Harald
  • Journal Title: Organic Letters Volume: 20 Issue: 16 Pages: 4723-4727
  • DOI: 10.1021/acs.orglett.8b01484
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Short Step Synthesis of Chiral Spirooxindoles via Sequential Reactions (2020)
  • Author(s): Tin Zar Aye, Matsuyama, N.; Mattan, I.; Kondo, M.; Takizawa, S.; Sasai
  • Organizer: The 23rd SANKEN International Symposium
  • Int'l Joint Research
• [Presentation] Machine‐learning assisted efficient exploration of suitable flow reaction conditions for organocatalyzed domino reaction (2020)
  • Author(s): Kondo, M.; Wathsala, H. D. P.; Sako, M.; Hanatani, Y.; Ishikawa, K.; Hara, S.; Takaai, T.; Washio, T.; Takizawa, S.; Sasai, H.
  • Organizer: The 23rd SANKEN International Symposium
  • Int'l Joint Research
• [Presentation] Chiral Dinuclear Vanadium Complex-mediated Oxidative Coupling of Resorcinols (2019)
  • Author(s): Sako, M.; Aoki, T.; Zumbragel, N.; Schober, L.; Groger, H.; Takizawa, S.; Sasai, H.
  • Organizer: THE 47th NAITO CONFERENCE ON C-H Bond Activation and Transformation
  • Int'l Joint Research
• [Presentation] Facile Enantioselective Synthesis of Hetero[9]helicenes Using Redox/acid Cooperative Catalysts (2019)
  • Author(s): Sako, M.; Tamori, Y.; Higashida, K.; Takizawa, S.; Sasai,
  • Organizer: 31st International Symposium on Chirality
  • Int'l Joint Research
• [Presentation] Organocatalytic Umpolung Michael Process: Synthesis of Highly Functionalized Ketones Bearing a Chiral Quaternary Carbon Center (2019)
  • Author(s): Hanatani, Y.; Kondo, M.; Takizawa, S.; Sasai, H.
  • Organizer: 31st International Symposium on Chirality
  • Int'l Joint Research
• [Presentation] Development of Vanadium-catalyzed Organic Reaction in Water (2019)
  • Author(s): Sako, M.; Zumbragel, N.; Takiishi, T.; Schober, S.; Groger, H.; Takizawa, S.; Sasai, H.
  • Organizer: The 4th International Symposium on Process Chemistry
  • Int'l Joint Research
• [Presentation] AI-Assisted Optimization for Synthesis of Spirooxindole Analogues via Enantioselective Domino Reaction in Flow System (2019)
  • Author(s): Wathsala, H. D. P.; Kondo, M.; Sako, M.; Hanatani, Y.; Hara, S.; Ishikawa, K.; Takaai, T.; Washio, T.; Takizawa, S.; Sasai, H
  • Organizer: The 4th International Symposium on Process Chemistry
  • Int'l Joint Research
• [Presentation] Asymmetric Synthesis of Spirooxindoles via Pictet-Spengler Reaction, Oxidative and Wagner-Meerwein Rearrangement (2019)
  • Author(s): Tin Zay Aye; Matsuyama, N.; Kondo, M.; Takizawa, S.; Sasai, H.
  • Organizer: International Congress on Pure and Applied Chemistry (ICPAC) Yangon 2019
  • Int'l Joint Research
• [Presentation] Enantioselective Synthesis of Highly Functionalized Heterocycles via Organocatalyzed Domino Reactions (2019)
  • Author(s): Takizawa, S.; Sako, M.; Wathsala, H. D. P.; Hanatani, Y.; Furukawa, T.; Matsuyama, N.; Tin Zar Aye; Sasai, H.
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research
• [Presentation] Facile Synthesis of Chiral Spirooxindoles via Pictet-Spengler/Oxidative Rearrangement (2019)
  • Author(s): Matsuyama, N.; Kondo, M.; Tin Zar Aye, Takizawa, S.; Sasai, H
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research
• [Presentation] Chiral Vanadium Complex-catalyzed Enantioselective Oxidative Hetero-coupling Reactions of Arenols (2019)
  • Author(s): Higashida, K.; Sako, M.; Takizawa, S.; Sasai, H.
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research
• [Presentation] Room-Temperature, Metal-Free and One-Pot Preparation of 2H-indazoles via a Mills Reaction and Cyclization Sequence (2019)
  • Author(s): Kondo, M.; Takizawa, S.; Jiang, Y.; Sasai, H.
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research
• [Presentation] Development of Umpolung Michael Reaction of Alkynyl Acid Esters (2019)
  • Author(s): Hanatani, Y.; Kondo, M.; Furukawa, T.; Sako, M.; Takizawa, S.; Sasai, H.
  • Organizer: ISONIS-12, ISMMS-5, ICAMS-2, and ICSFC; 12th International Joint Symposium on Synthetic Organic Chemistry
  • Int'l Joint Research
• [Presentation] Efficient Prediction of Flow Reaction Conditions Using Machine-Learning for Enantioselective Domino Reaction (2019)
  • Author(s): Kondo, M.; Wathsala, H. D. P.; Sako, M.; Hanatani, U.; Ishikawa, K.; Hara, S.; Takaai, T.; Washio, T.; Takizawa, S.; Sasai, H.
  • Organizer: 13th International CeBiTec Symposium - Multi-Step Syntheses in Biology & Chemistry, An International Young Investigator Conference
  • Int'l Joint Research
• [Presentation] Chiral Vanadium Complex-mediated oxa-Piancatelli Reaction and Pictet-Spengler Reaction/Aromatization Sequence (2019)
  • Author(s): Sako, M.; Schober, L.; Takiishi, T.; Groger, H.; Takizawa, S.; Sasai, H.
  • Organizer: 13th International CeBiTec Symposium - Multi-Step Syntheses in Biology & Chemistry, An International Young Investigator Conference
  • Int'l Joint Research
• [Presentation] Enantioselective Organocatalytic Synthesis of 1,3-Disubstituted Isoindolines by Betti/Azamichael Sequence (2019)
  • Author(s): Wathsala, H. D. P.; Sako, M.; Abozeid, M. A.; Kishi, K.; Hirata, S.; Murai, K.; Fujioka, H.; Takizawa, S. Sasai, H.
  • Organizer: 13th International CeBiTec Symposium - Multi-Step Syntheses in Biology & Chemistry, An International Young Investigator Conference
  • Int'l Joint Research
• [Presentation] グリーンケミストリー志向型不斉合成反応の開発と多官能性複素環骨格構築への応用 (2019)
  • Author(s): 滝澤忍
  • Organizer: 日本薬学会第139年会
  • Invited
• [Presentation] Enantioselective domino processes mediated by multifunctional catalysts -Towards environmentally benign asymmetric synthesis- (2019)
  • Author(s): S. Takizawa
  • Organizer: The 5th International Symposium toward the Future of Advanced Researches in Shizuoka University 2019
  • Int'l Joint Research / Invited
• [Presentation] Efficient Optimization of Enantioselective Domino Reaction Based on Bayesian Optimization (2019)
  • Author(s): Wathsala, H. D. P.; Kondo, M.; Sako, M.; Hara, S.; Ishikawa, K.; Takaai, T.; Takizawa, S.; Washio, T.; Sasai, H.
  • Organizer: The 22nd SANKEN International Symposium/17th SANKEN Nanotechnology International Symposium
  • Int'l Joint Research
• [Presentation] Enantioselective Rauhut-Currier sequence involving desymmetrization of cyclic dienones (2018)
  • Author(s): S. Takizawa, H. D. P. Wathsala, F. A. Arteaga, K. Kishi, H. Sasai
  • Organizer: The 4th International Symposium of Middle Molecular Strategy (ISMMS-4)
  • Int'l Joint Research / Invited
• [Presentation] Catalytic Enantioselective Sequential C-C Bond Forming Reactions in Flow System (2018)
  • Author(s): Wathsala, H. D. P.; Kishi, K.; Chen, Q.; Sako, M.; Takizawa, S.; Sasai, H.
  • Organizer: 21st SANKEN International Symposium
  • Int'l Joint Research
• [Presentation] Enantioselective Synthesis of Bicyclic Pyrrolidine Derivatives via One-pot Sequential Organo- and Pd-Catalysis (2018)
  • Author(s): Chaki, B. M.; Bai, J.; Takenaka, K.; Takizawa, S.; Sasai, H.
  • Organizer: 21st SANKEN International Symposium
  • Int'l Joint Research
• [Presentation] Catalytic Enantioselective Sequential C-C Bond Forming Reactions in Flow System (2018)
  • Author(s): Wathsala, H. D. P.; Kishi K.; Chen, Q.; Takizawa, S.; Sasai, H.
  • Organizer: The First International Conference on Automated Flow and Microreactor Synthesis (ICAMS-1)
  • Int'l Joint Research
• [Presentation] Vanadium Complex-catalyzed Enantioselective Synthesis of Oxa[9]helicenes (2018)
  • Author(s): Sako, M.; Takizawa, S.; Sasai, H.
  • Organizer: IRCCS-JST CREST Joint Symposium
  • Int'l Joint Research
• [Presentation] Enantioselective C-C Bond Forming Reactions Catalyzed by a Vanadium Complex (2018)
  • Author(s): Sako, M.; Aoki, T.; Sugizaki, A.; Tamori, Y.; Takizawa, S.; Sasai, H.
  • Organizer: IRCCS-JST CREST Joint Symposium
  • Int'l Joint Research
• [Presentation] Facile Synthesis of Spirooxindoles via Enantioselective Double Michael Reaction (2018)
  • Author(s): Kusaba, M.; Kishi, K.; Takizawa, S.; Bai, J.; Sasai, H.
  • Organizer: Biotechnology and Chemistry for Green Growth (JSPS Japanese-German Graduate Externship Program)
  • Int'l Joint Research
• [Presentation] Catalytic and Enantioselective Sequential Reaction in Flow System (2018)
  • Author(s): Wathsala, H. D. P.; Kishi, K.; Chen, Q.; Sako, M.; Takizawa, S.; Sasai, H.
  • Organizer: Biotechnology and Chemistry for Green Growth (JSPS Japanese-German Graduate Externship Program)
  • Int'l Joint Research
• [Presentation] Enantioselective Synthesis of Bicyclic Pyrrolidine Derivatives via One-Pot Organo and Palladium Catalysis (2018)
  • Author(s): Chaki, B. M.; Bai, J.; Takenaka, K.; Takizawa, S.; Sasai, H.
  • Organizer: Biotechnology and Chemistry for Green Growth (JSPS Japanese-German Graduate Externship Program)
  • Int'l Joint Research
• [Presentation] Chiral Vanadium Complex-catalyzed Enantioselective Oxidative Coupling Reactions of Polycyclic Phenol (2018)
  • Author(s): Sugizaki, A.; Sako, M.; Takizawa, S.; Sasai, H.
  • Organizer: Biotechnology and Chemistry for Green Growth (JSPS Japanese-German Graduate Externship Program)
  • Int'l Joint Research
• [Presentation] Chiral Dinuclear Vanadium Complex-mediated Oxidative Coupling of Monocyclic Phenols (2018)
  • Author(s): Sako, M.; Aoki, T.; Takizawa, S.; Sasai, H.
  • Organizer: 43rd International Conference on Coordination Chemistry (ICCC 2018)
  • Int'l Joint Research
• [Presentation] Enantioselective Oxidative C-H/C-H Coupling Catalyzed by Chiral Dinuclear Vanadium(V) Complex (2018)
  • Author(s): Sako, M.; Aoki, T.; Takizawa, S.; Sasai, H.
  • Organizer: The 4th International Symposium on C-H Activation (ISCHA4)
  • Int'l Joint Research
• [Presentation] Enantioselective Synthesis of Tetrahydrocyclopenta[b]indole Bearing a Chiral Quaternary Carbon Center via Pd(II)-SPRIX-catalyzed C-H Activation (2018)
  • Author(s): Takizawa, S.; Abozeid, M. A.; Sasai, H.
  • Organizer: The 4th International Symposium on C-H Activation (ISCHA4)
  • Int'l Joint Research
• [Presentation] Chiral Catalyzed Domino Reactions (2018)
  • Author(s): Kusaba, M.; Wathsala, H. D. P.; Sako, M.; Kishi, 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 Oxidative Hetero-coupling Reactions (2018)
  • Author(s): Jiang, Y.; Sako, M.; Takizawa, S.; Sasai, H.
  • Organizer: Biotechnology and Chemistry for Green Growth (JSPS Japanese-German Graduate Externship Program)
  • Int'l Joint Research
• [Presentation] Chiral Dinuclear Vanadium Complex-mediated Oxidative Coupling of Phenols (2018)
  • Author(s): Sako, M.; Aoki, T.; Takizawa, S.; Sasai, H.
  • Organizer: The 14th International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC-14)
  • Int'l Joint Research
• [Presentation] Enantioselective Synthesis of Bicyclic Pyrrolidine Derivatives via One-Pot Sequential Organo and Palladium Catalysis (2018)
  • Author(s): Chaki, B. M.; *Zhu, L.; Takenaka, K.; Bai, J.; Takizawa, S.; Sasai, H.
  • Organizer: The 14th International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC-14)
  • Int'l Joint Research
• [Presentation] Catalytic Enantioselective Sequential C-C Bond Forming Reactions in Flow System (2018)
  • Author(s): Wathsala, H. D. P.; Sako, M.; Kishi, K.; Takizawa, S.; Sasai, H.
  • Organizer: The 14th International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC-14)
  • Int'l Joint Research
• [Presentation] Facile Synthesis of Spirooxindoles via Enantioselective Double Michael Reaction (2018)
  • Author(s): Kusaba, M.; Kishi, K.; Bai, J.; Takizawa, S.; Sasai, H.
  • Organizer: The 14th International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC-14)
  • Int'l Joint Research
• [Remarks] 大阪大学産業科学研究所 機能物質化学研究分野 ホームページ
  • URL: http://www.sanken.osaka-u.ac.jp/labs/soc/socmain.html
• [Remarks] 滝澤忍 GoogleScholar
  • URL: https://scholar.google.co.jp/citations?hl=ja&user=Ern4ObsAAAAJ
• [Remarks] 滝澤忍 researchmap
  • URL: https://researchmap.jp/read0068650
• [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