二重活性化型有機分子触媒を用いるキラル多官能性化合物の合成と応用

• Project Area: Advanced Molecular Transformations by Organocatalysts
• Project/Area Number: 24105518
• 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): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000); Fiscal Year 2013: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2012: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 有機分子触媒 / 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 / 不斉 / ドミノ反応 / RC反応 / aza-MBH反応 / 酸塩基触媒 / 炭素‐炭素結合形成

Research Abstract

本研究の目的は、基質の活性化に金属を必要としない二重活性化能を有する高活性な酸-塩基型有機分子不斉触媒を創製し、開発した触媒を用いて森田-Baylis-Hillman(MBH)反応を基軸とする不斉連続的炭素－炭素結合生成反応（不斉ドミノ反応）を検討することにある。今年度は、医薬品原料や生物活性天然物の母格となる多置換・多官能性キラル化合物群の安全で効率的な合成法の確立を念頭に、含窒素環化合物であるアゼチジンやテトラヒドロピリジン類に注目した。これら複素環化合物は、薬理活性物質の母核として、また金属配位子としても興味深く、これまでに数多くの研究が報告されている。しかしながら、その光学活性体合成には多工程を必要とした。そこで入手容易なアレノエートを求核種とするケチミンとの形式的[n+2]不斉環化付加反応により、キラル四置換炭素を有する多置換アゼチジンおよびテトラヒドロピリジン類の簡便合成を試みた。非環状ケチミンとアレノエートを基質に反応条件を精査したところ、酸-塩基型不斉有機分子触媒β-isocupreidine（β-ICD）存在下、MS 3Aを添加し、THF:1,4-ジオキサン（1:2）の混合溶媒中、－5 ℃下で反応を行うと、高収率でアゼチジンが得られることを見出した。また、環状ケチミンとα位にメチル基を有するアレノエートとの反応において、モノアリールホスフィン触媒SITCPを用いると形式的[4+2]環化付加反応が高エナンチオ選択的に進行することが判明した。各種NMRデータ、単結晶X線構造解析、および類似光学活性体との旋光度の比較等から、形式的[2+2]環化付加反応ではアゼチジンがE選択的にR体で得られ、形式的[4+2]環化付加反応ではテトラヒドロピリジンが高位置選択的にR体で得られていることが分かった。本反応から得られる環化体は、β-アミノ酸誘導体であり、医薬品中間体等のキラルビルディングブロックとしての応用が期待される。

Current Status of Research Progress

Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Enantioselective Organocatalyzed Formal [4+2] Cycloaddition of Ketimines with Allenoates : Easy Access to a Tetrahydropyridine Framework with a Chiral Tetrasubstituted Stereogenic Carbon Center (2014)
  • Author(s): Takizawa, S. ; Arteaga, F. A. ; Yoshida. Y. ; Suzuki, M. ; Sasai, H.
  • Journal Title: Asian J. Org. Chem. Volume: 3 Issue: 4 Pages: 412-415
  • DOI: 10.1002/ajoc.201300244
  • Peer Reviewed
• [Journal Article] P-Chirogenic Organocatalysts : Application to the aza-Morita-Baylis-Hillman (aza-MBH) Reaction of Ketimines (2013)
  • Author(s): Takizawa, S. ; Remond, E. ; Arteaga, F. A. ; Yoshida. Y. ; Sridharan, V. ; Bayardon, J. ; Juge S. ; Sasai, H.
  • Journal Title: Chem. Commun. Volume: 49 Issue: 75 Pages: 8392-8394
  • DOI: 10.1039/c3cc44549f
  • Peer Reviewed
• [Journal Article] Organocatalyzed formal [2+2] cycloaddition of ketimines with allenoates: Facile access to azetidines with a chiral tetrasubstituted carbon stereogenic center (2013)
  • Author(s): Takizawa, S.; Arteaga, F. A.; Yoshida, Y.; Suzuki, M.; Sasai, H.
  • Journal Title: Org. Lett. Volume: 15 Issue: 16 Pages: 4142-4145
  • DOI: 10.1021/ol401817q
  • Peer Reviewed
• [Journal Article] Chiral Bifunctional Organocatalysts Bearing a 1,3-Propanediamine Unit for the aza-MBH Reaction (2013)
  • Author(s): Hirata, S. ; Tanaka, K. ; Matsui, K. ; Arteaga, F. A. ; Yoshida. Y. ; Takizawa, S. ; Sasai, H.
  • Journal Title: Tetrahedron : Asymmetry Volume: 24 Issue: 19 Pages: 1189-1192
  • DOI: 10.1016/j.tetasy.2013.08.005
  • Peer Reviewed
• [Journal Article] o-(Hydroxyalkyl)phenyl P-chirogenic phosphines as functional chiral Lewis bases (2013)
  • Author(s): Remond, E.; Bayardon, J.; Takizawa, S.; Rousselin, Y.; Sasai, H.; Juge, S.
  • Journal Title: Org. Lett. Volume: 15 Issue: 8 Pages: 1870-1873
  • DOI: 10.1021/ol400515e
  • Peer Reviewed
• [Journal Article] Facile Synthesis of a-Methylidene-y-Butyrolactones : Intramolecular Rauhut-Currier Reaction Promoted by Chiral Acid-Base Organocatalysts (2013)
  • Author(s): Takizawa, S. ; Nguyen, T. M.-N. ; Grossmann, A. ; Enders, D. ; Sasai, H.
  • Journal Title: Tetrahedron Volume: 69 Issue: 3 Pages: 1202-1209
  • DOI: 10.1016/j.tet.2012.11.046
  • Peer Reviewed
• [Journal Article] Vanadium-Catalyzed Enantioselective Friedel-Crafts-Type Reactions (2013)
  • Author(s): Takizawa, S. ; Arteaga, F. A. ; Yoshida. Y. ; Kodera, J. ; Nagata, Y. ; Sasai, H.
  • Journal Title: Dalton Trans. Volume: 42 Issue: 33 Pages: 11787-11790
  • DOI: 10.1039/c2dt32202a
  • Peer Reviewed
• [Journal Article] Enantioselective Synthesis of a-Alkylidene-y-Butyrolactones : Intramolecular Rauhut-Currior Reaction Promoted by Acid/Base Organocatalysts (2012)
  • Author(s): Takizawa, S. ; Nguyen, T. M.-N. ; Grossmann, A. ; Enders, D. ; Sasai H.
  • Journal Title: Angewandte Chemie International Edition Volume: 51 Issue: 22 Pages: 5423-5426
  • DOI: 10.1002/anie.201201542
  • Peer Reviewed
• [Journal Article] Design, and Synthesis of Spiro Bis(l, 2, 3-triazolium) Salts As Chiral Ionic Liquids (2012)
  • Author(s): Yoshida, Y. ; Takizawa, S. ; Sasai H
  • Journal Title: Tetrahedron : Asymmetry Volume: 23 Issue: 11-12 Pages: 843-851
  • DOI: 10.1016/j.tetasy.2012.06.007
  • Peer Reviewed
• [Presentation] Development of Chiral Catalyst Based on Functionalization of 1,2,3-Triazoles (2014)
  • Author(s): Yoshida, Y.; Takizawa, S.; Sasai, H.
  • Organizer: The 17th SANKEN International Symposium
  • Place of Presentation: Osaka, Japan
• [Presentation] Enantioselective Organocatalyzed Formal [n+2] Cycloaddition Using Ketimines and Allenoates (2014)
  • Author(s): Arteaga, F. A.; Takizawa, S.; Yoshida, Y.; Suzuki, M.; Sasai, H.
  • Organizer: The 17th SANKEN International Symposium
  • Place of Presentation: Osaka, Japan
• [Presentation] Chiral Trisimidazole-Catalyzed Friedel-Crafts (FC)-type Reaction (2014)
  • Author(s): Hirata, S.; Takizawa, S.; Murai, K.; Fujioka, H.; Sasai, H.
  • Organizer: The 17th SANKEN International Symposium
  • Place of Presentation: Osaka, Japan
• [Presentation] Development of New Efficient Synthesis Method of Spiro Bis(1,2,3-triazole)s and Their Applications (2013)
  • Author(s): Yoshida, Y.; Takizawa, S.; Sasai, H.
  • Organizer: Aachen-Osaka Symposium “Biological and Chemical Methods for Selective Catalysis”
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2013-03-11
• [Presentation] Enantioselective Pd(II)/Pd(IV) Catalysis Using SPRIX Ligand: Efficient Synthesis of Chiral Tetrahydrofuran Derivatives (2013)
  • Author(s): Takenaka, K.; Dhage, Y. D.; Takizawa, S.; Sasai, H
  • Organizer: Aachen-Osaka Symposium “Biological and Chemical Methods for Selective Catalysis”
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2013-03-11
• [Presentation] Enantioselective Synthesis of Alfa-Methylidene-Ganma-Butyrolactones: Intramolecular Rauhut-Currier Reaction Promoted by Acid/Base Organocatalysts (2013)
  • Author(s): Nguyen, T. M.-N.; Grossmann, A.; Takizawa, S.; Suzuki, M.; Enders, D.; Sasai, H.
  • Organizer: First Osaka University-EPFL International Symposium
  • Place of Presentation: Osaka, Japan
• [Presentation] Enantioselective Organocatalyzed Formal [n+2] Cycloaddition of Ketimines (2013)
  • Author(s): Arteaga, F. A.; Takizawa, S.; Yoshida, Y.; Suzuki, M.; Sasai, H.
  • Organizer: First Osaka University-EPFL International Symposium
  • Place of Presentation: Osaka, Japan
• [Presentation] Enantioselective Organocatalyzed Formal [n+2] Cycloaddition of Ketimines with Allenoates (2013)
  • Author(s): Arteaga, F. A.; Takizawa, S.; Yoshida, Y.; Suzuki, M.; Sasai, H.
  • Organizer: The 8th International Symposium on Integrated Synthesis
  • Place of Presentation: Nara, Japan
• [Presentation] Enantioselective Organocatalyzed Cycloadditions Based on the aza-Morita-Baylis-Hillman-type (aza-MBH) and Rauhut-Currier (RC) Proces (2013)
  • Author(s): Takizawa, S.; Sasai, H.
  • Organizer: The 8th International Conference on Cutting-Edge Organic Chemistry in Asia and The 4th New Phase International Conference on S Cutting-Edge Organic Chemistry in Asia
  • Place of Presentation: Osaka, Japan
• [Presentation] Acid-Base Organocatalyzed Enantioselective Synthesis of Highly Functionalized Heterocyclic Compounds (2013)
  • Author(s): Takizawa, S.; Nguyen, T. M.-N.; Inoue, N.; Hirata, S.; Sasai, H.
  • Organizer: 10th International Symposium on Carbanion Chemistry
  • Place of Presentation: Kyoto, Japan
• [Presentation] Enantioselective Organocatalyzed Formal [n+2] Cycloaddition of Ketimines (2013)
  • Author(s): Arteaga, F. A.; Takizawa, S.; Yoshida, Y.; Suzuki, M.; Sasai, H.
  • Organizer: 10th International Symposium on Carbanion Chemistry
  • Place of Presentation: Kyoto, Japan
• [Presentation] Enantioselective Organocatalyzed Aza-Morita-Baylis-Hillman (aza-MBH) Reraction of Ketimines (2013)
  • Author(s): Takizawa, S.; Remond, E.; Arteaga, F. A.; Yoshida, Y.; Sridharan, V.; Bayardon, J.; Juge, S.; Sasai, H.
  • Organizer: 15th Asian Chemical Congress
  • Place of Presentation: Sentosoa, Singapore
• [Presentation] Enantioselective Organocatalyzed aza-MBH Domino Reactions of Ketimine (2013)
  • Author(s): Takizawa, S.; Arteaga, F. A.; Yoshida, Y.; Sasai, H.
  • Organizer: The 16th International Symposium on Relations between Homogeneous and Heterogeneous Catalysis
  • Place of Presentation: Sapporo, Japan
• [Presentation] Enantioselective Synthesis of Multifunctional Heterocyclic Compounds via Acid-Base Organocatalysis (2013)
  • Author(s): Takizawa, S.; Nguyen, T. M.-N.; Inoue, N.; Hirata, S.; Sasai, H.
  • Organizer: 7th International Symposium on Acid-Base Catalysis
  • Place of Presentation: Tokyo, Japan
• [Presentation] Enantioselective C-C Bond Forming Reactions Using Multi-Functional Organocatalysts: aza-Morita-Baylis-Hillman (aza-MBH) Reaction of Ketimines (2013)
  • Author(s): Takizawa, S.
  • Organizer: 第1回 国際会議 (兼) 第6回 有機触媒シンポジウム
  • Place of Presentation: Otsu, Japan
  • Invited
• [Presentation] Enantioselective Organocatalyzed Aza-Morita-Baylis-Hillman (Aza-MBH) Reaction of Ketimines (2012)
  • Author(s): Takizawa, S.; Arteaga, A. F.; Yoshida, Y.; Vellaisamy, S.; Remond, E.; Bayardon, J.; Juge, S.; Sasai, H.
  • Organizer: First Japan-USA Organocatalytic Symposium
  • Place of Presentation: Hawaii, USA
  • Year and Date: 2012-12-15
  • Invited
• [Presentation] Enantioselective Organocatalyzed Aza-Morita-Baylis-Hillman (Aza-MBH) Reaction of Ketimines (2012)
  • Author(s): Takizawa, S.; Arteaga, A. F.; Yoshida, Y.; Vellaisamy, S.; Remond, E.; Bayardon, J.; Juge, S.; Sasai, H.
  • Organizer: Aachen-Osaka Symposium “Biological and Chemical Methods for Selective Catalysis”
  • Place of Presentation: Aachen, Germany
  • Year and Date: 2012-12-03
• [Presentation] Design and Synthesis of Organocatalysts Bearing Spiro Backbone (2012)
  • Author(s): Fan, L.; Takizawa, S.; Sasai, H.
  • Organizer: Aachen-Osaka Symposium “Biological and Chemical Methods for Selective Catalysis”
  • Place of Presentation: Aachen, Germany
  • Year and Date: 2012-12-03
• [Remarks] 大阪大学産業科学研究所・機能物質科学研究分野ホームページ
  • URL: http://www.sanken.osaka-u.ac.jp/labs/soc/socmain.html