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Creation of Asymmetric Catalysts Based on New Concept, and Their Application to Efficient Synthesis of Pharmaceutical Lead Compounds

Research Project

Project/Area Number 13307062
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

KANAI Motomu (2003)  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学系研究科, 助教授 (20243264)

柴崎 正勝 (2001-2002)  東京大学, 大学院・薬学系研究科, 教授 (30112767)

Co-Investigator(Kenkyū-buntansha) MATSUNAGA Shigeki  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Research Associate, 大学院・薬学系研究科, 助手 (50334339)
OHSHIMA Takashi  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Research, 大学院・薬学系研究科, 助手 (10313123)
金井 求  東京大学, 大学院・薬学系研究科, 助教授 (20243264)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥46,800,000 (Direct Cost: ¥36,000,000、Indirect Cost: ¥10,800,000)
Fiscal Year 2003: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2002: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2001: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Keywordsasymmetric catalyst / bifunctional catalysis / pharmaceutical lead / asymmetric synthesis / biologically active natural products / asymmetric cyanosil lation / asymmetric aldol reaction / asymmetric Mannich reaction / フッ化銅 / アルドール反応 / シアノアルキル化反応 / 直接的触媒的アルドール反応 / 触媒的不斉反応 / 触媒的不斉Strecker反応 / ジ置換アミノ酸 / 多点制御 / ルイス酸 / ブレンステツド塩基 / ルイス塩基 / 触媒的不斉全合成 / 多段階促進型不斉触媒 / 医薬品リード化合物 / 固相担持触媒 / 4級不斉中心
Research Abstract

We developed a chiral heteropolymetallic complex containing a lanthanide metal, alkali metal, and BINOL. This new catalyst promotes the direct enantioselective aldol reaction from unmodified ketones and aldehydes with high enantioselectivity. We also developed a novel chiral ligand, linked BINOL, and found that the zinc complex can promote very efficient C-C bond formation between a hydroxyl ketone and aldehydes or imines. The maximum catalyst turnover was reached up to 20000 with maintaining an excellent enantioselectivity. Moreover, we developed a new sugar-derived catalyst that can promote enantioselective cyanosilylation of ketones and ketoimines with high efficiency. Using these catalyses, we established efficient synthetic route of camptothecin (anticancer drug), oxybutynin (muscarinic receptor antagonist), and sorbinil (aldose reductase inhibitor). These synthetic route have a potential of being applied to industrial synthesis.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (60 results)

All Other

All Publications (60 results)

  • [Publications] S.Masumoto, H.Usuda, M.Suzuki, M.Kanai, M.Shibasaki: "Catalytic Enantioselective Strecker Reaction of Ketoimines"J.Am.Chem.Soc.. 125. 5634-5635 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] N.Yamagiwa, S.Matsunaga, M.Shibasaki: "Heterobimetallic Catalysis in Asymmetric 1,4-Addition of O-Alkylhydroxylamine to Enones"J.Am.Chem.Soc.. 125. 16178-16179 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] K.Majima, R.Takita, A.Okada, T.Ohshima, M.Shibasaki: "Catalytic Asymmetric Michael Reaction of β-Keto Esters : Effects of the Linker Heteroatom in Linked-BINOL"J.Am.Chem.Soc.. 125. 15837-15845 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] K.Funabashi, M.Jachmann, M Kanai, M.Shibasaki: "Multicenter Strategy for the Development of Catalytic Enantioselective Nucleophic Alkylation of Ketones : Me_2Zn Addition to α-Ketoesters"Angew.Chem.Int.Ed.. 42. 5489-5492 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] T.Ohshima, V.Gnanadesikan, T.Shibuguchi, Y.Fukuta, T.Nemoto, M.Shibasaki: "Enantioselective Syntheses of Aeruginosin 298-A and Its Analogues Using a Catalytic Asymmetric Phase-Transfer Reaction and epoxidation"J.Am.Chem.Soc.. 125. 11206-11207 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masakatsu Shibasaki, Futoshi Mitazaki: "Handbook of Organopalladium Chemistry for Organic Synthesis"Wiley Interscience. 3350 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Masumoto, H.Usuda, M.Suzuki, M.Kanai, M.Shibasaki: "Catalytic Enantioselective Strecker Reaction of Ketoimines"J.Am.Chem.Soc.. 125. 5634-5635 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] N.Yamagiwa, S.Matsunaga, M.Shibasaki: "Heterobimetallic Catalysis in Asymmetric 1,4-Addition of O-Alkylhydroxylamine to Enones"J.Am.Chem.Soc.. 125. 16178-16179 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] K.Majima, R.Takita, A.Okada, T.Ohshima, M.Shibasaki: "Catalytic Asymmetric Michael Reaction of β-Keto Esters : Effects of the Linker Heteroatom in Linked BINOL"J.Am.Chem.Soc.. 125. 15837-15845 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] K.Funabashi, M.Jachmann, M.Kanai, M.Shibasaki: "Multicenter Strategy for the Development of Catalytic Enantioselective Nucleophic Alkylation of Ketones : Me_2Zn Addition to α-Ketoesters"Angew.Chem.Int.Ed.. 42. 589-5492 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] T.Ohshima, V.Gnanadesikan, T.Shibuguchi, Y.Fukuta, T.Nemoto, M.Shibasaki: "Enantioselective Syntheses of Aeruginosin 298-A and Its Analogues Using a Catalytic Asymmetric Phase Transfer Reaction and epoxidation"J.Am.Chem.Soc.. 125. 11206-11207 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masakatsu Shibasaki, Futoshi Mitazaki: "Handbook of Organopalladium Chemistry for Organic Synthesis"Wiley Interscience. 1283-1315 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Oisaki, K., Suto, Y., Kanai, M., Shibasaki, M.: "A New Method for the Catalytic Aldol Reaction to Ketones"J.Am.Chem.Soc.. 125. 5644-5645 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Masumoto, S., Usuda, H., Suzuki, M., Kanai, M., Shibasaki, M.: "Catalytic Enantioselective Strecker Reaction of Ketoimines"J.Am.Chem.Soc.. 125. 5634-5635 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suto, Y, Kumagai, N., Matsunaga, S., Kanai, M., Shibasaki, M.: "Direct Catalytic Aldol-Type Reaction Using RCH_2CN"Organic Letters. 5. 3147-3150 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Funabashi K., Jachmann, M., Kanai, M., Shibasaki M.: "Multicenter Strategy for the Development of Catalytic Enantioselective Nucleophilic Alkylation of Ketones Me_2Zn Addition to α-Ketoesters"Angew.Chem.Int.Ed.. 42. 5489-5492 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Masumoto, S., Usuda, H., Suzuki, M., Kanai, M., Shibasaki, M.: "Catalytic Enantioselective Strecker Reaction of Ketoimines"J.Am.Chem.Soc.. 125. 5634-5635 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fujii, K., Maki, K., Kanai, M., Shibasaki, M.: "Formal Catalytic Asymmetric Total Synthesis of Fostriecin"Org.Lett.. 5. 733-736 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Usuda, H., Kanai, M., Shibasaki, M: "Studies toward the Total Synthesis of Garsubelin A : A Concise Synthesis of the 18-epi-Tricyclic Core"Org.Lett.. 4. 859-862 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Xu, Y., Ohori, K., Ohshima, T., Shibasaki, M.: "A practical large-scale synthesis of enantiomerically pure3-[bis(methoxyc arbonyl)methyl]cyclohexanone via catalytic asymmetric michael reaction"Tetrahedoron. 58. 2585-2588 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshikawa, N., Suzuki, T., Shibasaki, M.: "Diastereo-and Enantioslective Direct Catalytic aldol Reaction of 2-Hydroxyacetophenones with Aldehydes Promoted by a Heteropolymetallic Complex : Catalytic Asymmetric Synthesis of anti-12-Diols"J.Org.Chem.. 67. 2556-2565 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masumoto, S., Yabu, K., Kanai, M., Shibasaki, M.: "Practical synthesis of chiral ligands for catalytic enantioselective cyanosilylation of ketones"Tetrahedron Lett.. 43. 2919-2922 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yabu, K., Masumoto, S., Kanai, M., Curran, D.P., Shibasaki, M.: "Studies toward practical synthesis of (20S)-camptothecin family through catalytic enantioselective cyanosilylation of ketones : improved catalyst efficiency by ligand-tuning"Tetrahedron Lett.. 43. 2923-2588 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Usuda, H.Kanai, M.Shibasaki: "Studies toward the total synthesis of garsubellin A : synthesis of 8-deprenyl-garsubellin A"Tetrahedron Lett.. 43. 3621-3624 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamasaki, S., Fujii, K., Wada, R., Kanai, M., Shibasaki, M.: "A General Catalytic Allylation Using Allyltrimethoxysilane"J.Am.Chem.Soc.. 124. 6536-6537 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shibasaki, M., Yoshikawa, N.: "Lanthanide Complexes in Multifunctional Asymmetric Catalysis"Chem.Rev.. 102. 2187-2209 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takamura, M., Yanagisawa, H., Kanai, M., Shibasaki, M.: "Efficient synthesis of Antihyperglycemic (S)-α-Aryloxy-β-phenylpropionic Acid Using a functional Asymmetric Catalyst"Chem.Pharm.Bull.. 50. 1118-1121 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takita, R., Ohshima, T., Shibasaki, M.: "Highly enantioselective catalytic Michael reaction of α-substituted malonates using La-linked-BINOL complex in the presence of HFIP (1,1,1,3,3,3-hexafluoroisopropanol)"Tetrahedoron Lett.. 43. 4661-4665 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shibasaki, M., Kanai, M., Funabashi, K.: "Recent progress in asymmetric two-center catalysis"Chem. Commun.. 1989-1999 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Wada, R., Suto, Y., Kanai, M., Shibasaki, M.: "Dramatic Switching of Protein Kinase C Agonist/Antagonist Activity by Modifying the 12-Ester side Chain of Phorbol Esters"J.Am.Chem.Soc.. 124. 10658-10659 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshikawa, N., Shibasaki, M.: "Catalytic asymmetric synthesis of β-hydroxy-α-amino acid esters by direct aldol reaction of glycinate Schiff bases"Tetrahedron. 58. 8289-8298 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tian, J., Yoshikawa, N., Matsunaga, S., Shibasaki, M.: "Asymmetric Cyanation Reaction and sequential Asymmetric Cyanation-Nitroaldol Reaction Using a [YLi_3{(binaphthoxide)}] single Catalyst Component : Catalyst Tuning with Achiral Additives"Angew. Chemie. Int. Ed.. 41. 3636-3638 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kanai, M., Kuramochi, A., Shibasaki, M.: "Enhancement of Lewis Acidity by Ligand-Defined Metal Geometry : A Catalytic Allylation of Aldehydes with Allyltrimethylsilane"Synthesis. 14. 1956-1958 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masumoto, S.; Suzuki, M.; Kanai, M.; Shibasaki, M.: "A Practical synthesis of (S)-oxybutynin"Tetrahedron Lett.. 43. 8647-8651 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nemoto, T., Kakei, H., Gnanadesikan, V., Tosaki, S., Ohshima, T., Shibasaki, M.: "Catalytic Asymmetric Epoxidation of α,β-Unsaturated Amides : Efficient Synthesis of β-Aryl α-Hydroxy Amides Using a One-Pot Tandem Catalytic Asymmetric Epoxidation-Pd-Catalyzed Epoxide Opening Process"J.Am.Chem.Soc.. 124. 14544-14545 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohshima, T., Xu, Y., Takita, R., Shimizu, S., Zhong, D.; Shibasaki, M: "Enantioselective Total Synthesis of (-)-Strychnine Using the Catalytic Asymmetric Michael Reaction and Tandem Cyclization"J.Am.Chem.Soc.. 124. 14546-14547 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yabu, K., Masumoto, S., Kanai, M., Du, W, Curran, D.P., Shibasaki, M.: "CAMPTOTHECIN INTERMEDIATES USING CYANOSILYLATION OF KETONES PROMOTED BY D-GLUCOSE-DERIVED LANTHANIDE CATALYST"Heterocycles. 59. 369-385 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mizutani, T.; Honzawa, S.; Tosaki, S.; Shibasaki, M.: "Total Synthesis of (+/-)-Wortmannin"Angew.Chem.Int.Ed.. 41. 4680-4682 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shibuguchi, T., Fukuta, Y., Akachi, Y., Sekine, A., Ohshima T., Shibasaki, M.: "Development of new asymmetric two-center catalysts in phase-transfer reactions"Tetrahedoron Lett.. 43. 9539-9543 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tosaki, S., Nemoto, T., Ohshima, T., Shibasaki, M.: "Catalytic Asymmetric Synthesis of Both syn-and anti-3,5-Dihydroxy Esters: Application to 1,3-Polyol/α-Pyrone Natural Product Synthesis"Org.Lett.. 5. 495-498 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M: "Direct Catalytic Asymmetric Aldol Reaction of Hydroxyketones: Asymmetric Zn Catalysis with a Et_2Zn/Linked-BINOL Complex"J. Am. Chem. Soc.. 125. 2169-2178 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Harada, S.; Kumagai, N.; Kinoshita, T.; Matsunaga, S.; Shibasaki, M: "Direct Catalytic Asymmetric Michael Reaction of Hydroxyketones : Asymmetric Zn Catalysis with a Et_2Zn/Linked-BINOL Complex"J. Am. Chem. Soc.. 125. 2582-2590 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] N.Yoshikawa, M.Shibasaki: "Direct Catalytic Asymmetric Aldol Reactions Promoted by Novel Heterobimetallic Catalysts Possessing Strong Brφnsted Base : A New Strategy for the Development of Lewis Acid-Bronsted Base Bifunctinal Catalysts"Tetrahedron. 57. 2569-2579 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Shibasaki, M.Kanai: "Multifunctional Asymmetric Catalysis"Chem. Pharm. Bull. 49. 511-524 (2001)

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      2001 Annual Research Report
  • [Publications] N.Kumagai, S.Matsunaga, N.Yoshikawa, T.Ohshima, M.Shibasaki: "Direct Catalytic Enantio- and Diastereoselective Aldol Reaction Using a Zn-Zn-Linked-BINOL Complex : A. Practical Synthesis of syn-1, 2-Diols"Org. Lett.. 3. 1539-1542 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] G.Manickam, H.Nogami, M.Kanai, H.Groger, M.Shibasaki: "Anti-and Syn-Selective Cyanosilylation Reactions Promoted by a Sugar-Based Bifunctional Catalyst : Stereoselective Syntheses of Essential Building Blocks for HIV Protease Inhibitors and Bestatin"Synlett. 5. 617-620 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Yamada, G.Moll, M.Shibasaki: "The First Enantioselective and Diastereoselective Catalytic Nitro-Mannich Reaction : A New Entry to Chiral Vicinal Diamines"Synlett. 特別号. 980-982 (2001)

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      2001 Annual Research Report
  • [Publications] M.Takamura, K.Funabashi, M.Kanai, M.Shibasaki: "Catalytic Enantioselective Reissert-Type Reaction : Development and Application to the synthesis of a Potent NMDA Receptor Antagonist(-)L-689, 560 Using a Solid-Supported Catalyst"J. Am. Chem. Soc.. 123. 6801-6808 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] A.Okada, T.Ohshima, M.Shibasaki: "Highly regioselective synthesis of cyclic enol silyl ethers using ring-closing metathesis"Tetrahedron Lett.. 42. 8023-8027 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] N.Kumagai, S.Matsunaga M.Shibasaki: "Enantioselective 1, 4-Addition of Unmodified Ketone Catalyzed by a Bimetallic Zn-Zn-Linked-BINOL Complex"Org. Lett.. 3. 4251-4254 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] S.Matsunaga, T.Ohsima, M.Shibasaki: "Linked-BINOL- an Approach towards Practical Asymmetric Multifunctional Catalysis-"Adv. Synth. Catal.. 343. 1-13 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] A.Sekine, T.Ohshima, M.Shibasaki: "An Enantioselective Formal Synthesis of 4-demethoxydaunomycin Using the Catalytic Asymmetric Ring Opening Reaction of meso-epoxide With p-anisidine"Tetrahedron. 58. 75-82 (2002)

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      2001 Annual Research Report
  • [Publications] N.Tsuritani, K.Yamada, N.YoshikaWa, M.Shibasaki: "Catalytic Asymmetric Syntheses of ICI-199441 and CP-99994 Using Nitro-Mannich Reaction"Chem. Lett.. (印刷中). (2002)

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      2001 Annual Research Report
  • [Publications] T.Nemoto, T.Ohshima, M.Shibasaki: "Catalytic Asymmtrtic Epoxidation of a, b-Unsaturated Carbonyl Compounds"Journal of Synthetic Organic Chemistry, Japan. 60. 94-105 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Suzuki, N.Yamagiwa, Y.Matsuo, S.Sakamoto, K.Yamaguchi, M.Shibasaki, R.Noyori: "Catalytic asymmetric aldol reaction of ketones and aldehydes using chiral calcium alkoxides"Tetrahedron Lett.. 42. 4669-4671 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] S.Yamasaki, M.Kanai, M.Shibasaki: "Zirconium Alkoxides in Catalysis"Chem. Eur J.. 7. 4066-4073 (2001)

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      2001 Annual Research Report
  • [Publications] T.Nemoto, T.Ohshima, M.Shibasaki: "Catalytic Asymmetric Synthesis of a, b-Epoxy Esters, Aldehydes, Amides, and g, d-Epoxy b-Keto Esters : Unique Reactivity of a, b- Unsaturated Carboxylic Acid Imidazolides"J. Am. Chem. Soc.. 123. 9474-9475 (2001)

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      2001 Annual Research Report
  • [Publications] M.Kanai, Y.Hamashima, M.Takamura, M.Shibasaki: "Development and Application of Enantioselective Lewis Acid-Lewis Base Bifunctional Catalyst"Journal of Synthetic Organic Chemistry, Japan. 59. 767-778 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Yabu, S.Masumoto, S.Yamasaki, Y.Hamashima, M.Kanai, W.Du.D.P.Curran, M.Shibasaki: "Switching Enantiofacial Selectivites Using One Chiral Source : Catalytic Enantioselective Synthesis of the Key Intermediate for (20S)-Camptdhecin Family by (S)-Selective Cyanosylation of Ketones"J. Am. Chem. Soc.. 123. 9900-9909 (2001)

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      2001 Annual Research Report
  • [Publications] K Funabashi, H.Ratni, M.Kanai, M.Shibasaki: "Enantioselective Construction of Quaternary Stereocenter through a Reissert-Type Reactiion Catalyzed by an Electronically Tuned Bifunctional Catalyst : Efficient Synthesis of Various Biologically Significant compounds"J. Am. Chem. Soc.. 123. 10784-10785 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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