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Shu Kobayashi Professor, University of Tokyo Shu Kobayashi Shu Kobayashi Takeru Kobayashi David TILLY, Literature seminar, 19 August 2008 1 Since 2003, he is a director of ERATO project (JST) Since 1998 : Professor in the Graduate School of Pharmaceutical Sciences at the University of Tokyo I look great on this pic 2 Education and Academic career • 1983 : B.Sc.; The University of Tokyo (Professor Teruaki. Mukaiyama) • 1987 : Ph.D.; The University of Tokyo (Professor Mukaiyama) • 1988 : Assistant Professor; Science University of Tokyo (SUT) • 1991 : Lecturer ; Science University of Tokyo (SUT) • 1992 : Associate Professor; Science University of Tokyo (SUT) JST : Japan Science and Technology • • • • ERATO : Exploratory Research for Advanced Technology oh yeah France 1993 : Visiting Professor, Universite Louis Pasteur, Strasbourg, 1995 : Visiting Professor, University SORST : Solution OrientedKyoto Research for Science and Technology 1996 : Visiting Nijmegen University, Netherlands CREST : Core professor, Research for Evolutionary Science The and Technology 1997 : Visiting Professor, Phillipps-Universitat Marburg, Germany • • • • • 1997 : Special promoted Researcher (SUT, 1997-1998) 1997 : CREST Investigator (JST, 1997-2001) 1998 : Full Professor, The University of Tokyo 2002 : SORST Investigator (JST, 2002-2004) 2003 : ERATO Investigator (JST, 2003-) 3 MAJOR AWARDS EDITORIAL APPOINTMENTS 2006 Howard Memorial Lecturer 2006 Arthur C. Cope Scholar Awards 2005 JSPS Prize 2005 Mitsui Chemical Catalysis Science Award 2004 Manchester-Merck Lecturer 2003 Novo-Nortis Lectureship 2002 Nagoya Silver Medal 2002 Organic Reactions Lecturer 2001 Roche Lectureship 2001 NPS Distinguished Lecturer 2001 IBM Science Award 2000 Novartis Chemistry Lectureship 2000 MIT/Wyeth-Ayerst Lectureship 2000 Nagoya Lectureship 1999 Bio-Mega/Boehrinder Ingelheim Lecturer 1999 Merck-SFC Lectureship 1999 Wyeth-Ayerst Lectureship 1997 Springer Award in Organometallic Chemistry 1995 Kurata Research Foundation 1994 Ciba-Geigy Research Foundation 1993 Nissan Science Foundation for Younger Generation 1992 New Chemistry Institute Research Award 1992 Teijin Award in Synthetic Organic Chemistry, Japan 1991 The Chemical Society of Japan Award for Young Chemists Associate Editor, Journal of Combinatorial Chemistry (1999-) Associate Editor, Advanced Synthesis & Catalysis (2000-) Editorial Advisory Board, Molecules Online (1997-2000) Editorial Advisory Board, Synthesis (1999-) Editorial Advisory Board, Chemical Reviews (2000-) Organic & Biomolecular Chemistry, Editorial Board (2002-) 5000 US Dollars for himself 40 000 US Dollars as unrestricted research grant YAY! 4 Research Interests Organic reactions in water Development of Chiral Catalysts Synthesis of Biologically Important Molecules Polymersupported/incarcerated Catalysts 5 Organic reactions in Microchannels Microreactors (lab-on-a-chip) Lab-on-a-chip Device that integrates one or several laboratory functions on a single chip of only millimeters to a few square centimeters in size. LOCs deal with the handling of extremely small fluid volumes down to less than pico liters Chips-in-a-lab…yum! Chips-on-a-bike (1977-1983) 6 “A microfluidic Device for Conducting gas-liquid-solid Hydrogenation Reactions” Juta Kobayashi, Yuichiro Mori, Kuniaki Okamoto, Ryo Akiyama, Masaharu Ueno, Takehiko Kitamori, Shu Kobayashi Science 2004, 304, 1305-1308 7 Immobilization of Pd catalyst on the glass surface Microencapsulation of Pd catalyst 8 9 10 • Yields quantitative • No Pd leaching • 0.01mmol/hr •No loss of activity is chip is reused •Scale up possible by using chips in parallel •P H2=1 atm • For a recent review of microchannel reactors in organic synthesis, see : Chem. Asian. J. 2006, 1-2, 22-35 11 “Polymer Incarcerated Ruthenium Catalyst for Oxidation of Alcohols with Molecular Oxygen” Tsutomu Matsumoto, Masaharu Ueno, Juta Kobayashi, Hiroyuki Miyamura, Yuichiro Mori, Shu Kobayashi Adv. Synth. Catal. 2007, 349, 531-534 O2 (0.1 MPa) Polymer Incarcerated Ru (5 mol %) TEMPO (15 mol %) R OH 1, 2 DCE, 80 C, 2.5 hrs R O 12 Polystyrene based copolymer Choice of Ru important to avoid leaching and high catalytic activity 1- polymer micelle incarcerated Ru catalyst 13 Effect of Ruthenium Source 14 Scope 15 Recovery of Polymer Incarcerated Ru Catalyst Simple filtration, wash with DCM and drying of the solid to recover the catalyst 16 Application to Hydrogenation reactions H2 (1 atm) Polymer Incarcerated Pd (5 mol %) Starting material Product THF, rt Okamoto, K. ; Akiyama, R. ; Kobayashi, S. J. Org. Chem. 2004, 69, 2871-2873 17 Chemistry in water…very refreshing! “Carboxylic Acid Catalyzed Three-Component Aza-Friedel-Crafts Reactions in Water for the Synthesis of 3-Substituted Indoles” Seiji Shirakawa and Shu Kobayashi Org. Lett. 2006, 8, 4939-4942 18 A look at the reaction in water Aza Friedel Crafts reactions are difficult to control 19 Acid Catalyst optimization O + OMe NH2 Catalyst (5 mol %) H2O, rt, 24 hr N Me PMO NH 2 Np N Me 4a 2 Np N Me 5a 2 OMP = ortho-methoxyphenyl DS = dodecyl sulfate DBSA = dodecylbenzenesulfonic acid Length of alkyl chain crucial 20 Scope R4 R3 C9H19CO2H (10 mol %) H2O, rt, 24 hr N R2 + R4 R3 H CDI (2 equiv.) Sc(OTf)3 (10 mol %) PhMe, 70 C, 3 hr R1 NH2-OMP H N R4 R3 N R2 N R2 O R1 N PMO H NH R1 O OMe N N H 6a 6b N 6c N 6d Br N Et N N N N CDI 6e No metal 21 Further transformations CN bonds very reactive, can react with various nucleophiles in presence of DBSA or Sc(OTf)3 22 “Surfactant-Type Brønsted Acid Catalyzed Dehydrative Nucleophilic Substitutions of Alcohols in Water” Seiji Shirakawa and Shu Kobayashi Org. Lett. 2007, 9, 311-314 Dodecylbenzenesulfonic acid Dehydrative C-C bond formation in water Reaction on benzylic alcohols Poor leaving ability of hydroxy group compared to halides Dehydrations in water…of course Kobayashi! 23 Substitution of benzhydrols : scope of nucleophiles Both surfactant property and Bronsted acidity of DBSA are essential to promote the reaction efficiently 24 Substitution of Benzyl Alcohols : scope of alcohol starting material 25 Extention of the scope : C-Glycosylation of 1-hydroxy sugar Excellent B selectivity Compound 3b is an intermediate in the synthesis of Showdomycin 26 Concluding Remarks •Conceptually different approach to organic chemistry •Addresses issues of “green chemistry” •Research covers broad scope of topics in chemistry 27