Updated on 2025/07/16

写真a

 
FUWA Haruhiko
 
Organization
Faculty of Science and Engineering Professor
Other responsible organization
Applied Chemistry Course of Graduate School of Science and Engineering, Master's Program
Applied Chemistry Course of Graduate School of Science and Engineering, Doctoral Program
Contact information
The inquiry by e-mail is 《here
External link

Degree

  • Doctor of Science ( The University of Tokyo )

  • Master of Science ( The University of Tokyo )

Education

  • 2002.3
     

    The University of Tokyo   Graduate School of Science   Department of Chemistry   doctor course   completed

  • 1999.3
     

    The University of Tokyo   Graduate School of Science   Department of Chemistry   master course   completed

  • 1997.3
     

    The University of Tokyo   School of Science   Department of Chemistry   graduated

  • 1993.3
     

    宮城県仙台第二高等学校   graduated

Research History

  • 2017.4 -  

    "Professor, Faculty of Science and Engineering, Chuo University"

  • 2009.5 - 2017.3

    "Associate Professor, Graduate School of Life Sciences, Tohoku University"

  • 2007.4 - 2009.4

    "Assistant Professor, Graduate School of Life Sciences, Tohoku University"

  • 2006.7 - 2007.3

    "Research Associate, Graduate School of Life Sciences, Tohoku University"

  • 2005.4 - 2006.6

    "Postdoctoral Fellow, JSPS"

  • 2005.2 - 2005.3

    "Research Staff, Graduate School of Life Sciences, Tohoku University"

  • 2002.10 - 2005.1

    "Research Associate, Graduate School of Pharmaceutical Sciences, The University of Tokyo"

  • 2001.4 - 2002.9

    "Research Fellow, JSPS"

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Professional Memberships

  • 日本薬学会

  • 日本化学会

  • 有機合成化学協会

  • 日本ケミカルバイオロジー学会

Research Interests

  • Natural product chemistry

  • Synthetic organic chemistry

Research Areas

  • Nanotechnology/Materials / Structural organic chemistry and physical organic chemistry  / Synthetic Organic chemistry

  • Life Science / Bioorganic chemistry  / Bioorganic chemistry

  • Nanotechnology/Materials / Chemistry and chemical methodology of biomolecules  / Biomolecular chemistry

  • Life Science / Bioorganic chemistry  / Synthetic Organic chemistry

Papers

  • Total Synthesis of (−)-Enigmazole A by the Macrocyclization/Transannular Pyran Cyclization Strategy: Application to Structure–Activity Relationship Investigations Reviewed

    Kyoya Ohyama, Taisei Masuda, Keita Sakamoto, Atsushi Yoshimura, Kyoko Tatsumoto, Keisuke Murata, Haruhiko Fuwa

    The Journal of Organic Chemistry   90   2025.7

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Chemical Society (ACS)  

    DOI: 10.1021/acs.joc.5c01346

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  • Tandem Synthesis of Pyrrolidine and Piperidine Derivatives from Propargylic Alcohols Under Multimetallic Catalysis Invited Reviewed

    Tatsumi Ishii, Erika Nezu, Haruhiko Fuwa

    European Journal of Organic Chemistry   28   2025.4

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1002/ejoc.202500226

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  • Total Synthesis of Exiguolide Stereoisomers: Impact of Stereochemical Permutation on Reactivity, Conformation, and Biological Activity Reviewed

    Reika Murakami, Tomo Mori, Keisuke Murata, Haruhiko Fuwa

    The Journal of Organic Chemistry   90   753 - 767   2025.1

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Chemical Society (ACS)  

    DOI: 10.1021/acs.joc.4c02707

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  • Iriomoteolide-1a and -1b: Structure Elucidation by Integrating NMR Spectroscopic Analysis, Theoretical Calculation, and Total Synthesis Reviewed

    Tomohiro Obana, Miyu Nakajima, Kazuki Nakazato, Hayato Nakagawa, Keisuke Murata, Masashi Tsuda, Haruhiko Fuwa

    Journal of the American Chemical Society   146   29836 - 29846   2024.10

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Chemical Society (ACS)  

    DOI: 10.1021/jacs.4c11714

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  • Total Synthesis of (−)-Fasicularin Reviewed

    Yuki Takatori, Haruhiko Fuwa

    The Journal of Organic Chemistry   89   2024.7

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Chemical Society (ACS)  

    DOI: 10.1021/acs.joc.4c01447

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  • Total Synthesis of Marine Macrolide Natural Products by the Macrocyclization/Transannular Pyran Cyclization Strategy Invited Reviewed

    Haruhiko Fuwa

    SYNLETT   35   1488 - 1499   2024.7

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1055/a-2181-9876

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  • Total Synthesis of (−)-Enigmazole A by the Macrocyclization/Transannular Pyran Cyclization Strategy Reviewed

    Taisei Masuda, Kyoya Ohyama, Atushi Yoshimura, Haruhiko Fuwa

    Organic Letters   26   2045 - 2050   2024.3

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1021/acs.orglett.4c00290

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  • Atomic-resolution structure analysis inside an adaptable porous framework Reviewed

    Yuki Wada, Pavel M. Usov, Bun Chan, Makoto Mukaida, Ken Ohmori, Yoshio Ando, Haruhiko Fuwa, Hiroyoshi Ohtsu, Masaki Kawano

    Nature Communications   15   81   2024.1

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/s41467-023-44401-w

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  • Total Synthesis of (−)-Enigmazole B Reviewed

    Yoshihiro Goda, Haruhiko Fuwa

    Organic Letters   25   8402 - 8407   2023.12

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1021/acs.orglett.3c03002

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  • Au-catalyzed stereodivergent synthesis of 2,5-disubstituted pyrrolidines: total synthesis of (+)-monomorine I and (+)-indolizidine 195B Reviewed

    Hayato Nakagawa, Haruhiko Fuwa

    Chemical Communications   59   10121 - 10124   2023.8

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Royal Society of Chemistry (RSC)  

    A stereodivergent synthesis of 2,5-disubstituted pyrrolidines from readily available amino alkynes was made possible under Au catalysis.

    DOI: 10.1039/d3cc02453a

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  • Total Synthesis of (+)-Muricatetrocin B via a Late-Stage Co-Catalyzed Hartung–Mukaiyama Cyclization Reviewed

    Riko Minami, Tsubasa Kasai, Keisuke Murata, Haruhiko Fuwa

    Organic Letters   25   5745 - 5749   2023.8

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Chemical Society (ACS)  

    DOI: 10.1021/acs.orglett.3c01932

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  • Collective Asymmetric Total Synthesis of Cylindricines Reviewed

    Ryohei Hanzawa, Haruhiko Fuwa

    Organic Letters   25   1984 - 1988   2023.3

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1021/acs.orglett.3c00551

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  • An 11-Step Synthesis of (+)-Neopeltolide by the Macrocyclization/Transannular Pyran Cyclization Strategy Reviewed

    Kazuki Nakazato, Mami Oda, Haruhiko Fuwa

    Bulletin of the Chemical Society of Japan   96   257 - 267   2023.2

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1246/bcsj.20220340

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  • GIAO NMR Calculation-driven Stereochemical Assignment of Marine Macrolide Natural Products: Assessment of the Performance of DP4 and DP4+ Analyses and Assignment of the Relative Configuration of Leptolyngbyalide A–C/Oscillariolide Macrolactone Reviewed

    Keisuke Murata, Hirotoshi Mori, Haruhiko Fuwa

    Bulletin of the Chemical Society of Japan   95 ( 12 )   1775 - 1785   2022.11

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:The Chemical Society of Japan  

    DOI: 10.1246/bcsj.20220253

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  • Stereoselective Tandem Synthesis of Pyrrolidine Derivatives under Gold Catalysis: An Asymmetric Synthesis of (−)-Lepadiformine A Reviewed

    Atsushi Yoshimura, Ryohei Hanzawa, Haruhiko Fuwa

    Organic Letters   24   6237 - 6241   2022.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACS  

    DOI: 10.1021/acs.orglett.2c02007

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  • Total Synthesis of (+)-Neopeltolide by the Macrocyclization/Transannular Pyran Cyclization Strategy Reviewed

    Kazuki Nakazato, Mami Oda, Haruhiko Fuwa

    Organic Letters   24   4003 - 4008   2022.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACS  

    DOI: 10.1021/acs.orglett.2c01429

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  • Gambierol Blocks a K+ Current Fraction without Affecting Catecholamine Release in Rat Fetal Adrenomedullary Cultured Chromaffin Cells Reviewed

    E. Benoit, S. Schlumberger, J. Molgó, M. Sasaki, H. Fuwa, R. Bournaud

    Toxins   14   254   2022.4

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:MDPI  

    DOI: 10.3390/toxins14040254

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  • Tandem Macrolactone Synthesis: Total Synthesis of (−)-Exiguolide by a Macrocyclization/Transannular Pyran Cyclization Strategy Reviewed

    Daichi Mizukami, Kei Iio, Mami Oda, Yu Onodera, Haruhiko Fuwa

    Angewandte Chemie, International Edition   61   e202202549   2022.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Wiley-VCH  

    DOI: 10.1002/anie.202202549

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  • Determination of the toxicity equivalency factors for ciguatoxins using human sodium channels Reviewed

    S. Raposo-Garcia, M. C. Louzao, H. Fuwa, M. Sasaki, C. Vale, L. Botana

    Food and Chemical Toxicology   160   112812   2022.1

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier  

    DOI: 10.1016/j.fct.2022.112812

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  • Asymmetric Synthesis of (−)-Atorvastatin Calcium by Tandem Catalysis Reviewed

    Keisuke Murata, Riko Minami, Haruhiko Fuwa

    Bulletin of the Chemical Society of Japan   94 ( 8 )   2028 - 2035   2021.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:The Chemical Society of Japan  

    DOI: 10.1246/bcsj.20210178

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  • Ruthenium-Catalyzed Intramolecular Double Hydrofunctionalization of Alkynes. Synthesis of Spirocyclic Hemiaminal Ethers and Their Lewis Acid-Mediated Cleavage/Nucleophilic Addition Reviewed

    K. Nishimura, R. Hanzawa, T. Sugai, H. Fuwa

    The Journal of Organic Chemistry   86   6674 - 6697   2021.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACS  

    DOI: 10.1021/acs.joc.1c00443

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  • Stereoselective Synthesis of the Southern Hemisphere Acyclic Domain of Neaumycin B Reviewed

    H. Takeshita, T. Sugai, H. Fuwa

    The Journal of Organic Chemistry   86   6787 - 6799   2021.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACS  

    DOI: 10.1021/acs.joc.1c00508

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  • Cobalt-Catalyzed Hartung–Mukaiyama Cyclization of γ-Hydroxy Olefins: Stereocontrolled Synthesis of the Tetrahydrofuran Moiety of Amphidinolide N

    M. Ohta, S. Kato, T. Sugai, H. Fuwa

    The Journal of Organic Chemistry   86   5584 - 5615   2021.4

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACS  

    DOI: 10.1021/acs.joc.1c00085

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  • Total synthesis and complete configurational assignment of amphirionin-2 Reviewed

    S. Kato, D. Mizukami, T. Sugai, M. Tsuda, H. Fuwa

    Chemical Science   12 ( 3 )   872 - 879   2021.1

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:RSC  

    DOI: 10.1039/D0SC06021F

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  • Unified Total Synthesis of (–)-Enigmazole A and (–)-15-O-Methylenigmazole A Reviewed

    Keisuke Sakurai, Keita Sakamoto, Makoto Sasaki, Haruhiko Fuwa

    Chemistry - An Asian Journal   15   3494 - 3502   2020.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Wiley-VCH  

    DOI: 10.1002/asia.202001015

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  • Gambierol Potently Increases Evoked Quantal Transmitter Release and Reverses Pre- and Post-Synaptic Blockade at Vertebrate Neuromuscular Junctions Reviewed

    J. Molgo, S. Schulmberger, M. Sasaki, H. Fuwa, M. C. Louzao, L. M. Botana, D. Servent, E. Benoit

    Neuroscience   439   106 - 116   2020.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier  

    DOI: 10.1016/j.neuroscience.2019.06.024

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  • Tandem Three-Component Synthesis of syn-1,2- and syn-1,3-Diol Derivatives Invited Reviewed

    K. Murata, H. Takeshita, K. Sakamoto, H. Fuwa

    Chemistry - An Asian Journal   15 ( 6 )   807 - 819   2020.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Wiley-VCH  

    DOI: 10.1002/asia.201901660

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  • Total Synthesis, Stereochemical Revision, and Biological Assessment of Iriomoteolide‐2a Reviewed International journal

    K. Sakamoto, A. Hakamata, A. Iwasaki, K. Suenaga, M. Tsuda, H. Fuwa

    Chemistry - A European Journal   25 ( 36 )   8528 - 8542   2019.6

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    Iriomoteolide-2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG-75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide-2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide-2a featured a late-stage convergent assembly of three components by a Suzuki-Miyaura coupling, an esterification, and a ring-closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2-5 as candidates for the correct structure. Accordingly, total syntheses of 2-5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2-5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide-2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5/ent-5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent-5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products.

    DOI: 10.1002/chem.201900813

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  • Fluorescence-labeled neopeltolide derivatives for subcellular localization imaging Reviewed International journal

    S. Yanagi, T. Sugai, T. Noguchi, M. Kawakami, M. Sasaki, S. Niwa, A. Sugimoto, H. Fuwa

    Organic & Biomolecular Chemistry   17 ( 28 )   6771 - 6776   2019.6

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    Design, synthesis and functional analysis of fluorescent derivatives of neopeltolide, an antiproliferative marine macrolide, are reported herein. Live cell imaging using the fluorescent derivatives showed rapid cellular uptake and localization within the endoplasmic reticulum as well as the mitochondria.

    DOI: 10.1039/C9OB01276A

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  • Stereoselective Tandem Synthesis of syn-1,3-Diol Derivatives by Integrating Olefin Cross-Metathesis, Hemiacetalization, and Intramolecular Oxa-Michael Addition Reviewed

    Keisuke Murata, Keita Sakamoto, Haruhiko Fuwa

    Organic Letters   21 ( 10 )   3730 - 3734   2019.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Chemical Society  

    DOI: 10.1021/acs.orglett.9b01182

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  • Ruthenium-Catalyzed Intramolecular Double Hydroalkoxylation of Internal Alkynes Reviewed

    K. Iio, S. Sachimori, T. Watanabe, H. Fuwa

    Organic Letters   20   7851 - 7855   2018.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACS  

    DOI: 10.1021/acs.orglett.8b03368

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  • Total Synthesis of (−)‐Enigmazole A Reviewed

    K. Sakurai, M. Sasaki, H. Fuwa

    Angewandte Chemie, International Edition   57 ( 18 )   5143 - 5146   2018.4

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  • Total synthesis and stereochemical revision of iriomoteolide-2a Reviewed

    K. Sakamoto, A. Hakamata, M. Tsuda, H. Fuwa

    Angewandte Chemie, International Edition   57   3801 - 3805   2018.3

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  • A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells Reviewed

    Haruhiko Fuwa, Mizuho Sato

    MARINE DRUGS   15 ( 10 )   320   2017.10

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.3390/md15100320

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  • Tetracyclic Truncated Analogue of the Marine Toxin Gambierol Modifies NMDA, Tau, and Amyloid beta Expression in Mice Brains: Implications in AD Pathology Reviewed

    Eva Alonso, Andres C. Vieira, Ines Rodriguez, Rebeca Alvarino, Sandra Gegunde, Haruhiko Fuwa, Yuto Suga, Makoto Sasaki, Amparo Alfonso, Jose Manuel Cifuentes, Luis M. Botana

    ACS CHEMICAL NEUROSCIENCE   8 ( 6 )   1358 - 1367   2017.6

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    DOI: 10.1021/acschemneuro.7b00012

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  • (−)-Lyngbyaloside B, a Marine Macrolide Glycoside: Total Synthesis and Stereochemical Revision Reviewed

    H. Fuwa

    Strategies and Tactics in Organic Synthesis   12   143 - 168   2017

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    Language:English   Publishing type:Part of collection (book)   Publisher:Academic Press Inc.  

    DOI: 10.1016/B978-0-08-100756-3.00005-4

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  • Exploiting ruthenium carbene-catalyzed reactions in total synthesis of marine oxacyclic natural products Reviewed

    H. Fuwa, M. Sasaki

    Bulletin of the Chemical Society of Japan   89 ( 12 )   1403 - 1415   2016.12

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  • Diastereoselective Ring-Closing Metathesis as a Means to Construct Medium-Sized Cyclic Ethers: Application to the Synthesis of a Photoactivatable Gambierol Derivative Reviewed

    Yu Onodera, Kazuaki Hirota, Yuto Suga, Keiichi Konoki, Mari Yotsu-Yamashita, Makoto Sasaki, Haruhiko Fuwa

    JOURNAL OF ORGANIC CHEMISTRY   81 ( 18 )   8234 - 8252   2016.9

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    DOI: 10.1021/acs.joc.6b01302

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  • Effect of carbon chain length in acyl coenzyme A on the efficiency of enzymatic transformation of okadaic acid to 7-O-acyl okadaic acid Reviewed

    Sachie Furumochi, Tatsuya Onoda, Yuko Cho, Haruhiko Fuwa, Makoto Sasaki, Mari Yotsu-Yamashita, Keiichi Konoki

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   26 ( 13 )   2992 - 2996   2016.7

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    DOI: 10.1016/j.bmcl.2016.05.027

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  • Total Synthesis and Complete Stereostructure of a Marine Macrolide Glycoside, (-)-LyngbyalosideB Reviewed

    Haruhiko Fuwa, Naoya Yamagata, Yuta Okuaki, Yuya Ogata, Asami Saito, Makoto Sasaki

    CHEMISTRY-A EUROPEAN JOURNAL   22 ( 20 )   6815 - 6829   2016.5

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    DOI: 10.1002/chem.201600341

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  • Complete Stereochemical Assignment of Campechic Acids A and B Reviewed

    Ruri Isaka, Linkai Yu, Makoto Sasaki, Yasuhiro Igarashi, Haruhiko Fuwa

    JOURNAL OF ORGANIC CHEMISTRY   81 ( 9 )   3638 - 3647   2016.5

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    DOI: 10.1021/acs.joc.6b00290

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  • Toward the Total Synthesis of Amphidinolide N: Synthesis of the C8-C29 Fragment Reviewed

    Yuki Kawashima, Atsushi Toyoshima, Haruhiko Fuwa, Makoto Sasaki

    ORGANIC LETTERS   18 ( 9 )   2232 - 2235   2016.5

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1021/acs.orglett.6b00871

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  • Contemporary Strategies for the Synthesis of Tetrahydropyran Derivatives: Application to Total Synthesis of Neopeltolide, a Marine Macrolide Natural Product Reviewed

    Haruhiko Fuwa

    MARINE DRUGS   14 ( 4 )   65   2016.4

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.3390/md14040065

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  • Progress toward the Total Synthesis of Goniodomin A: Stereocontrolled, Convergent Synthesis of the C12-C36 Fragment Reviewed

    Haruhiko Fuwa, Seiji Matsukida, Taro Miyoshi, Yuki Kawashima, Tomoyuki Saito, Makoto Sasaki

    JOURNAL OF ORGANIC CHEMISTRY   81 ( 6 )   2213 - 2227   2016.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1021/acs.joc.5b02650

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  • Total synthesis, stereochemical revision, and biological evaluation of lyngbyaloside B, a marine macrolide glycoside

    H. Fuwa, Y. Okuaki, N. Yamagata, M. Sasaki

    Abstracts of PACIFICHEM2015   2015.12

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  • Concise synthesis of the C15-C38 fragment of okadaic acid, a specific inhibitor of protein phosphatases 1 and 2A Reviewed

    Haruhiko Fuwa, Keita Sakamoto, Takashi Muto, Makoto Sasaki

    TETRAHEDRON   71 ( 37 )   6369 - 6383   2015.9

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    DOI: 10.1016/j.tet.2015.04.001

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  • Potassium currents inhibition by gambierol analogs prevents human T lymphocyte activation Reviewed

    J. A. Rubiolo, C. Vale, V. Martin, H. Fuwa, M. Sasaki, L. M. Botana

    ARCHIVES OF TOXICOLOGY   89 ( 7 )   1119 - 1134   2015.7

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1007/s00204-014-1299-2

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  • Evaluation of gambierol and its analogs for their inhibition of human K(v)1.2 and cytotoxicity Reviewed

    Keiichi Konoki, Yuto Suga, Haruhiko Fuwa, Mari Yotsu-Yamashita, Makoto Sasaki

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   25 ( 3 )   514 - 518   2015.2

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    DOI: 10.1016/j.bmcl.2014.12.022

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  • Concise synthesis of the C15–C38 fragment of okadaic acid: Application of Suzuki–Miyaura reaction to spiroacetal synthesis Reviewed

    H. Fuwa, K. Sakamoto, T. Muto, M. Sasaki

    Organic Letters   17 ( 2 )   366 - 369   2015.2

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  • Concise synthesis of the A/BCD-ring fragment of gambieric acid A Reviewed

    Haruhiko Fuwa, Ryo Fukazawa, Makoto Sasaki

    FRONTIERS IN CHEMISTRY   2   116   2015.1

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.3389/fchem.2014.00116

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  • Total Synthesis, Stereochemical Reassignment, and Biological Evaluation of (-)-Lyngbyaloside B Reviewed

    Haruhiko Fuwa, Yuta Okuaki, Naoya Yamagata, Makoto Sasaki

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   54 ( 3 )   868 - 873   2015.1

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1002/anie.201409629

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  • STUDIES TOWARD THE TOTAL SYNTHESIS OF AMPHIDINOLIDE N: STEREOCONTROLLED SYNTHESIS OF THE C13-C29 SEGMENT Reviewed

    Makoto Sasaki, Yuki Kawashima, Haruhiko Fuwa

    HETEROCYCLES   90 ( 1 )   579 - 599   2015.1

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.3987/COM-14-S(K)66

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  • Programmed Cell Death Induced by (-)-8,9-Dehydroneopeltolide in Human Promyelocytic Leukemia HL-60 Cells under Energy Stress Conditions Reviewed

    Haruhiko Fuwa, Mizuho Sato, Makoto Sasaki

    MARINE DRUGS   12 ( 11 )   5576 - 5589   2014.11

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    DOI: 10.3390/md12115576

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  • Synthetic and structural studies on lyngbyaloside B, a cytotoxic marine macrolide glycoside

    H. Fuwa

    Abstracts of International Symposium on Chemical Biology of Natural Products   2014.10

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  • Total Synthesis and Complete Structural Assignment of Gambieric Acid A, a Large Polycyclic Ether Marine Natural Product Reviewed

    Makoto Sasaki, Haruhiko Fuwa

    CHEMICAL RECORD   14 ( 4 )   678 - 703   2014.8

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    DOI: 10.1002/tcr.201402052

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  • Synthesis and biological evaluation of (+)-neopeltolide analogues: Importance of the oxazole-containing side chain Reviewed

    Haruhiko Fuwa, Takuma Noguchi, Masato Kawakami, Makoto Sasaki

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   24 ( 11 )   2415 - 2419   2014.6

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    DOI: 10.1016/j.bmcl.2014.04.031

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  • Stereoselective Synthesis of Medium-Sized Cyclic Ethers: Application of C-Glycosylation Chemistry to Seven- to Nine-Membered Lactone-Derived Thioacetals and Their Sulfone Counterparts Reviewed

    Yuto Suga, Haruhiko Fuwa, Makoto Sasaki

    JOURNAL OF ORGANIC CHEMISTRY   79 ( 4 )   1656 - 1682   2014.2

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    DOI: 10.1021/jo4025545

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  • Total Synthesis and Structure Revision of Didemnaketal B Reviewed

    Haruhiko Fuwa, Takashi Muto, Kumiko Sekine, Makoto Sasaki

    CHEMISTRY-A EUROPEAN JOURNAL   20 ( 7 )   1848 - 1860   2014.2

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    DOI: 10.1002/chem.201303713

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  • Studies toward the total synthesis of iriomoteolide-2a

    H. Fuwa

    Abstracts of International Symposium on Chemical Biology of Natural Products   2013.10

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  • Synthesis and Biological Evaluation of Aspergillide A/Neopeltolide Chimeras Reviewed

    Haruhiko Fuwa, Kenkichi Noto, Masato Kawakami, Makoto Sasaki

    CHEMISTRY LETTERS   42 ( 9 )   1020 - 1022   2013.9

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    DOI: 10.1246/cl.130322

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  • Total synthesis and biological evaluation of marine macrolide natural products

    H. Fuwa

    Abstracts of the 70th Anniversary Symposium of the Chemical Society of Japan Tohoku Branch   94   2013.9

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  • Total Synthesis of the Proposed Structure of Didemnaketal B Reviewed

    Haruhiko Fuwa, Kumiko Sekine, Makoto Sasaki

    ORGANIC LETTERS   15 ( 15 )   3970 - 3973   2013.8

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    DOI: 10.1021/ol4017518

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  • Concise synthesis and biological assessment of (+)-neopeltolide and a 16-member stereoisomer library of 8,9-dehydroneopeltolide: Identification of pharmacophoric elements Reviewed

    Haruhiko Fuwa, Masato Kawakami, Kenkichi Noto, Takashi Muto, Yuto Suga, Keiichi Konoki, Mari Yotsu-Yamashita, Makoto Sasaki

    Chemistry - A European Journal   19 ( 25 )   8100 - 8110   2013.6

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    DOI: 10.1002/chem.201300664

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  • Total synthesis and biological evaluation of (+)-gambieric acid A and its analogues Reviewed

    K. Ishigai

    Chemistry - A European Journal   19 ( 17 )   5276 - 5288   2013.5

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  • Total Synthesis of 13-Demethyllyngbyaloside B Reviewed

    Haruhiko Fuwa, Naoya Yamagata, Asami Saito, Makoto Sasaki

    ORGANIC LETTERS   15 ( 7 )   1630 - 1633   2013.4

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    DOI: 10.1021/ol400408w

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  • Total synthesis and biological evaluation of (-)-exiguolide analogues: importance of the macrocyclic backbone Reviewed

    Haruhiko Fuwa, Kana Mizunuma, Makoto Sasaki, Takaya Suzuki, Hiroshi Kubo

    ORGANIC & BIOMOLECULAR CHEMISTRY   11 ( 21 )   3442 - 3450   2013

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    DOI: 10.1039/c3ob40131f

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  • A CONCISE SYNTHESIS OF THE AB-RING FRAGMENT OF (-)-GAMBIEROL Reviewed

    Haruhiko Fuwa, Kazuaki Hirota, Makoto Sasaki

    HETEROCYCLES   86 ( 1 )   127 - 132   2012.12

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    DOI: 10.3987/COM-12-S(N)21

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  • Tandem catalysis in domino olefin cross-metathesis/intramolecular oxa-conjugate cyclization: concise synthesis of 2,6-cis-substituted tetrahydropyran derivatives Reviewed

    Haruhiko Fuwa, Takuma Noguchi, Kenkichi Noto, Makoto Sasaki

    ORGANIC & BIOMOLECULAR CHEMISTRY   10 ( 40 )   8108 - 8112   2012.10

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    DOI: 10.1039/c2ob26189h

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  • Total synthesis and structure-activity relationships of marine macrolide natural products

    H. Fuwa

    Abstracts of International Symposium on Chemical Biology of Natural Products   2012.10

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  • P-60 Synthesis and Biological Evaluation of Structurally Simplified Analogues of Gambierol(Poster Presentation)

    Suga Yuto, Fuwa Haruhiko, Goto Tomomi, Konno Yu, Sasaki Makoto, Alonso Eva, Vale Carmen, Botana Luis Miguel

    Symposium on the Chemistry of Natural Products, symposium papers   ( 54 )   633 - 638   2012.9

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    Gambierol (1), a polycyclic ether natural neurotoxin isolated from the ciguatera causative dinoflagellate, Gambierdiscus toxicus has been reported to be a potent and subtype-selective blocker of voltage-gated potassium channels (VGPCs). Previous studies of marine polycyclic ether molecules have suggested the importance of the whole skeleton of polycyclic ether for potent biological activity. We have previously investigated the peripheral structure-activity relationships of Gambierol, however, it remained unclear whether the full length of polycyclic ether skeleton is essential for its toxicity. In this presentation, we designed and synthesized two structurally simplified analogues of Gambierol comprising BCDEFGH- and EFGH- rings of the parent compound (2 and 3). Surprisingly, both analogues showed comparable potency to Gambierol on VGPCs inhibition in cerebellar granule cells of mice. These results indicated that we obtained the easily synthesized analogues of Gambierol that have potent biological activity. Moreover, to investigate the additional functions of truncated analogues, we examined the effect of these compounds in a model of Alzheimer's disease (AD) obtained from triple transgenic mice, which expresses amyloid beta (An) accumulation and tau hyperphosphorylation. In vitro preincubation of the neurons of these mice with Gambierol or analogues decreased steady-state level of the NMDA receptor subunit 2A without affecting the 2B subunit. In addition, treatment of these compounds reduced the intra- and extracellular levels of Aβ and the levels of hyperphosphorylated tau. This study constitutes the first discovery of designed structurally simplified analogues of polycyclic ether compound possessing potent biological activity. Furthermore, it suggested the practicality of gambierol and analogues as chemical probes for understanding the function of VGPCs and the mechanism of modulation of the accumulation of Aβ and hyperphosphorylated tau by NMDA receptors.

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  • 32 Total Synthesis and Complete Stereostructure of Gambieric Acid A(Oral Presentation)

    Fuwa Haruhiko, Ishigai Kazuya, Hashizume Keisuke, Sasaki Makoto

    Symposium on the Chemistry of Natural Products, symposium papers   ( 54 )   187 - 192   2012.9

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    Gambieric acid A (1) is a marine polycyclic ether natural product that was isolated from the ciguatera causative dinoflagellate Gambierdiscus toxicus. Despite its structural similarity to ciguatoxins and brevetoxins, 1 only weakly binds to voltage-gated sodium channels and does not exhibit lethal toxicity against mice at 1 mg/kg (ip). Instead, 1 displays extraordinary potent antifungal activity against Aspergillus niger. Our previous studies on the synthesis and NMR analysis of suitably designed model compounds have strongly suggested that the stereochemical assignment of the originally proposed structure of 1 is questionable and led us to propose that the absolute configuration of the polycyclic ether domain of 1 is opposite to that of the natural product. Here, we disclose the first total synthesis and complete stereostructure of 1. The B-ring was first synthesized based on our methodology for the synthesis of medium-sized cyclic ethers. The A-ring was next forged via stereoselective bromoetherification. Suzuki-Miyaura coupling of the A/B-ring exo-olefin with an acetate-derived enol phosphate followed by ring-closing metathesis (RCM) constructed the D-ring, and mixed-thioacetalization and one-pot oxidation/methylation methodologies were used to close the C-ring. The A/BCD- and F'GHIJ-ring fragments were coupled by means of Suzuki-Miyaura coupling. After establishment of the C25 stereogenic center by exploiting the conformational bias of the F'-ring, oxidative cleavage of the F'-ring followed by elaboration of the E-ring via stereoselective allylation of a mixed thioacetal by using glycosylation chemistry, and ensuing closure of the F-ring furnished the entire polycyclic ether backbone. Finally, the J-ring side chain was introduced by means of modified Julia-Kocienski olefination to complete the first total synthesis of gambieric acid A (1). The spectroscopic data, optical rotation value, and antifungal activity of synthetic 1 matched those of the natural product. Thus, our total synthesis confirmed the correctness of our revised structure and unambiguously established the complete stereostructure of 1.

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  • Effect of Gambierol and Its Tetracyclic and Heptacyclic Analogues in Cultured Cerebellar Neurons: A Structure-Activity Relationships Study Reviewed

    Sheila Perez, Carmen Vale, Eva Alonso, Haruhiko Fuwa, Makoto Sasaki, Yu Konno, Tomomi Goto, Yuto Suga, Mercedes R. Vieytes, Luis M. Botana

    CHEMICAL RESEARCH IN TOXICOLOGY   25 ( 9 )   1929 - 1937   2012.9

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    DOI: 10.1021/tx300242m

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  • Stereoselective Synthesis of the C1-C16 Fragment of Goniodomin A Reviewed

    Motohiro Nakajima, Haruhiko Fuwa, Makoto Sasaki

    BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN   85 ( 9 )   948 - 956   2012.9

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    DOI: 10.1246/bcsj.20120152

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  • Total Synthesis and Complete Stereostructure of Gambieric Acid A Reviewed

    Haruhiko Fuwa, Kazuya Ishigai, Keisuke Hashizume, Makoto Sasaki

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   134 ( 29 )   11984 - 11987   2012.7

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    DOI: 10.1021/ja305864z

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  • TOTAL SYNTHESIS OF TETRAHYDROPYRAN-CONTAINING NATURAL PRODUCTS EXPLOITING INTRAMOLECULAR OXA-CONJUGATE CYCLIZATION Reviewed

    Haruhiko Fuwa

    HETEROCYCLES   85 ( 6 )   1255 - 1298   2012.6

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    DOI: 10.3987/REV-12-730

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  • 海洋天然物のケミカルバイオロジー:ブリオスタチンとイグジグオリドへの合成化学的アプローチ

    不破春彦

    化学と生物   50 ( 6 )   404 - 405   2012.6

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    DOI: 10.1271/kagakutoseibutsu.50.404

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  • Design and Synthesis of Skeletal Analogues of Gambierol: Attenuation of Amyloid-beta and Tau Pathology with Voltage-Gated Potassium Channel and N-Methyl-D-aspartate Receptor Implications Reviewed

    Eva Alonso, Haruhiko Fuwa, Carmen Vale, Yuto Suga, Tomomi Goto, Yu Konno, Makoto Sasaki, Frank M. LaFerla, Mercedes R. Vieytes, Lydia Gimenez-Llort, Luis M. Botana

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   134 ( 17 )   7467 - 7479   2012.5

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    DOI: 10.1021/ja300565t

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  • Stereoselective Synthesis of 2,6-Cis-Substituted Tetrahydropyrans: Bronsted Acid-Catalyzed Intramolecular Oxa-Conjugate Cyclization of alpha,beta-Unsaturated Ester Surrogates Reviewed

    Haruhiko Fuwa, Naoki Ichinokawa, Kenkichi Noto, Makoto Sasaki

    JOURNAL OF ORGANIC CHEMISTRY   77 ( 6 )   2588 - 2607   2012.3

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    DOI: 10.1021/jo202179s

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  • Total Synthesis of (-)-Brevenal: A Streamlined Strategy for Practical Synthesis of Polycyclic Ethers Reviewed

    Makoto Ebine, Haruhiko Fuwa, Makoto Sasaki

    CHEMISTRY-A EUROPEAN JOURNAL   17 ( 49 )   13754 - 13761   2011.12

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    DOI: 10.1002/chem.201101437

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  • Recent Applications of the Suzuki-Miyaura Cross-coupling to Complex Polycyclic Ether Synthesis Reviewed

    Haruhiko Fuwa, Makoto Ebine, Makoto Sasaki

    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN   69 ( 11 )   1251 - 1262   2011.11

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  • Studies toward the total synthesis of gambieric acids, potent antifungal polycyclic ethers: convergent synthesis of a fully elaborated GHIJ-ring fragment Reviewed

    Koichi Tsubone, Keisuke Hashizume, Haruhiko Fuwa, Makoto Sasaki

    TETRAHEDRON   67 ( 35 )   6600 - 6615   2011.9

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    DOI: 10.1016/j.tet.2011.05.082

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  • A new strategy for the synthesis of substituted dihydropyrones and tetrahydropyrones via palladium-catalyzed coupling of thioesters Reviewed

    Haruhiko Fuwa, Kana Mizunuma, Seiji Matsukida, Makoto Sasaki

    TETRAHEDRON   67 ( 27-28 )   4995 - 5010   2011.7

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    DOI: 10.1016/j.tet.2011.03.114

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  • Comparative Cytotoxicity of Gambierol versus Other Marine Neurotoxins Reviewed

    E. Cagide, M. C. Louzao, B. Espina, I. R. Ares, M. R. Vieytes, M. Sasaki, H. Fuwa, C. Tsukano, Y. Konno, M. Yotsu-Yamashita, L. A. Paquette, T. Yasumoto, L. M. Botana

    CHEMICAL RESEARCH IN TOXICOLOGY   24 ( 6 )   835 - 842   2011.6

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    DOI: 10.1021/tx200038j

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  • Biosynthesis-Inspired Intramolecular Oxa-Conjugate Cyclization of alpha,beta-Unsaturated Thioesters: Stereoselective Synthesis of 2,6-cis-Substituted Tetrahydropyrans Reviewed

    Haruhiko Fuwa, Kenkichi Noto, Makoto Sasaki

    ORGANIC LETTERS   13 ( 7 )   1820 - 1823   2011.4

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    DOI: 10.1021/ol200333p

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  • A Convergent Synthesis of the C1-C16 Segment of Goniodomin A via Palladium-Catalyzed Organostannane-Thioester Coupling Reviewed

    Haruhiko Fuwa, Motohiro Nakajima, Jinglu Shi, Yoshiyuki Takeda, Tomoyuki Saito, Makoto Sasaki

    ORGANIC LETTERS   13 ( 5 )   1106 - 1109   2011.3

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    DOI: 10.1021/ol1031409

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  • Total synthesis and biological assessment of (–)-exiguolide and analogues

    H. Fuwa

    Asian International Symposium   2011.3

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  • Total Synthesis and Biological Assessment of (-)-Exiguolide and Analogues Reviewed

    Haruhiko Fuwa, Takaya Suzuki, Hiroshi Kubo, Takao Yamori, Makoto Sasaki

    CHEMISTRY-A EUROPEAN JOURNAL   17 ( 9 )   2678 - 2688   2011.2

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    DOI: 10.1002/chem.201003135

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  • Suppression of Colon Cancer Metastasis by Aes through Inhibition of Notch Signaling Reviewed

    Masahiro Sonoshita, Masahiro Aoki, Haruhiko Fuwa, Koji Aoki, Hisahiro Hosogi, Yoshiharu Sakai, Hiroki Hashida, Arimichi Takabayashi, Makoto Sasaki, Sylvie Robine, Kazuyuki Itoh, Kiyoko Yoshioka, Fumihiko Kakizaki, Takanori Kitamura, Masanobu Oshima, Makoto Mark Taketo

    CANCER CELL   19 ( 1 )   125 - 137   2011.1

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    DOI: 10.1016/j.ccr.2010.11.008

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  • Palladium-Catalyzed Synthesis of N- and O-Heterocycles Starting from Enol Phosphates Reviewed

    Haruhiko Fuwa

    SYNLETT   ( 1 )   6 - 29   2011.1

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    DOI: 10.1055/s-0030-1259104

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  • Synthetic studies on goniodomin A: convergent assembly of the C15-C36 segment via palladium-catalyzed organostannane-thioester coupling Reviewed

    Tomoyuki Saito, Haruhiko Fuwa, Makoto Sasaki

    TETRAHEDRON   67 ( 2 )   429 - 445   2011.1

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    DOI: 10.1016/j.tet.2010.11.017

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  • Studies toward the total synthesis of gambieric acids: convergent synthesis of the GHIJ-ring fragment having a side chain Reviewed

    Koichi Tsubone, Keisuke Hashizume, Haruhiko Fuwa, Makoto Sasaki

    TETRAHEDRON LETTERS   52 ( 4 )   548 - 551   2011.1

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    DOI: 10.1016/j.tetlet.2010.11.127

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  • Total Synthesis of Structurally Complex Marine Oxacyclic Natural Products Reviewed

    Haruhiko Fuwa

    BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN   83 ( 12 )   1401 - 1420   2010.12

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    DOI: 10.1246/bcsj.20100209

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  • Convergent Assembly of the Spiroacetal Subunit of Didemnaketal B Reviewed

    Haruhiko Fuwa, Sayaka Noji, Makoto Sasaki

    ORGANIC LETTERS   12 ( 22 )   5354 - 5357   2010.11

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    DOI: 10.1021/ol1024713

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  • The marine polyether gambierol enhances muscle contraction and blocks a transient K+ current in skeletal muscle cells Reviewed

    Sebastien Schlumberger, Gilles Ouanounou, Emmanuelle Girard, Makoto Sasaki, Haruhiko Fuwa, M. Carmen Louzao, Luis M. Botana, Evelyne Benoit, Jordi Molgo

    TOXICON   56 ( 5 )   785 - 791   2010.10

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    DOI: 10.1016/j.toxicon.2010.06.001

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  • Total Synthesis of (-)-Exiguolide

    Fuwa Haruhiko, Sasaki Makoto

    Symposium on the Chemistry of Natural Products, symposium papers   ( 52 )   181 - 186   2010.9

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    (-)-Exiguolide was isolated from the sponge Geodia exigua collected off Amami-Oshima, Japn, by Ohta, Ikegami, and co-workers. The gross structure including the relative stereochemistry was established through extensive 2D NMR studies, conformational analysis on the basis of ^3J_<H,H> values and NOE correlations, and JBCA method. The molecular structure, characterized by the 20-membered macrolactone core embedded with a methylene bis(tetrahydropyran) substructure, is related to that of bryostains. (-)-Exiguolide inhibits fertilization of the sea urchin gametes but not embryogenesis of the fertilized egg. These structural and biological aspects led to an assumption that (-)-exiguolide may represent a simplified analogue of the bryostatins by Nature and render this natural product an intriguing target for organic chemists. Herein, we present the enantioselective total synthesis of (-)-exiguolide, the nturally occurring enantiomer, for the first time. The methylene bis(tetrahydropyran) substructure was efficiently constructed in a convergent fashion. Thus, the readily available C1-C7 and C8-C16 segments were assembled through olefin cross-metathesis, and two tetrahydreopyran rings were successively forged via intramolecular oxa-conjugate cyclization and reductive etherification. Stereoselective formation of the sterically encumbered C16-C17 double bond was achieved via Julia-Kocienski olefination. The 20-membered macrolactone framework was constructed in an excellent yield by means of Yamaguchi macrolactonization. An alternative approach toward the macrocycle based on ring-closing metathesis was less effecient than the macrolactonization approach. Finally, the (E,Z,E)-triene side chain was introduced in a stereoselective manner via Suzuki-Miyaura coupling under exceptionally mild conditions.

    DOI: 10.24496/tennenyuki.52.0_181

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  • An enantioselective total synthesis of aspergillides A and B Reviewed

    Haruhiko Fuwa, Hiroshi Yamaguchi, Makoto Sasaki

    TETRAHEDRON   66 ( 38 )   7492 - 7503   2010.9

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    DOI: 10.1016/j.tet.2010.07.062

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  • Studies toward the Total Synthesis of Gambieric Acids: Stereocontrolled Synthesis of a DEFG-Ring Model Compound Reviewed

    Haruhiko Fuwa, Sayaka Noji, Makoto Sasaki

    JOURNAL OF ORGANIC CHEMISTRY   75 ( 15 )   5072 - 5082   2010.8

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    DOI: 10.1021/jo1008146

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  • A concise total synthesis of (±)-centrolobine Reviewed

    H. Fuwa, K. Noto, M. Sasaki

    Heterocycles   82 ( 1 )   641 - 647   2010.6

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  • An efficient synthesis of 2,6-disubstituted 2,3-dihydro-4H-pyran-4-ones Reviewed

    H. Fuwa, S. Matsukida, M. Sasaki

    Synlett   1239 ( 1242 )   2010.5

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    DOI: 10.1055/s-0029-1219794

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  • Calcium Oscillations Induced by Gambierol in Cerebellar Granule Cells Reviewed

    E. Alonso, C. Vale, M. Sasaki, H. Fuwa, Y. Konno, S. Perez, M. R. Vieytes, L. M. Botana

    JOURNAL OF CELLULAR BIOCHEMISTRY   110 ( 2 )   497 - 508   2010.5

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    DOI: 10.1002/jcb.22566

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  • An Efficient Synthesis of 2,6-Disubstituted 2,3-Dihydro-4H-pyran-4-ones via Sonogashira Coupling of p-Toluenethiol Esters Reviewed

    Haruhiko Fuwa, Seiji Matsukida, Makoto Sasaki

    SYNLETT   ( 8 )   1239 - 1242   2010.5

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    DOI: 10.1055/s-0029-1219794

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  • A Unified Total Synthesis of Aspergillides A and B Reviewed

    Haruhiko Fuwa, Hiroshi Yamaguchi, Makoto Sasaki

    ORGANIC LETTERS   12 ( 8 )   1848 - 1851   2010.4

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    DOI: 10.1021/ol100463a

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  • Stereoselective Synthesis of Substituted Tetrahydropyrans via Domino Olefin Cross-Metathesis/Intramolecular Oxa-Conjugate Cyclization Reviewed

    Haruhiko Fuwa, Kenkichi Noto, Makoto Sasaki

    ORGANIC LETTERS   12 ( 7 )   1636 - 1639   2010.4

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    DOI: 10.1021/ol100431m

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  • Total Synthesis of (-)-Exiguolide Reviewed

    Haruhiko Fuwa, Makoto Sasaki

    ORGANIC LETTERS   12 ( 3 )   584 - 587   2010.2

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    DOI: 10.1021/ol902778y

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  • Highly efficient synthesis of medium-sized lactones via oxidative lactonization: concise total synthesis of isolaurepan Reviewed

    Makoto Ebine, Yuto Suga, Haruhiko Fuwa, Makoto Sasaki

    ORGANIC & BIOMOLECULAR CHEMISTRY   8 ( 1 )   39 - 42   2010

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    DOI: 10.1039/b919673k

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  • A Concise Total Synthesis of (+)-Neopeltolide

    Haruhiko Fuwa, Asami Saito, Makoto Sasaki

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   49 ( 17 )   3041 - 3044   2010

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    DOI: 10.1002/anie.201000624

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  • A Concise Total Synthesis of (+)-Neopeltolide Reviewed

    Haruhiko Fuwa, Asami Saito, Makoto Sasaki

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   49 ( 17 )   3041 - 3044   2010

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    DOI: 10.1002/anie.201000624

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  • Toward the Total Synthesis of Goniodomin A, An Actin-Targeting Marine Polyether Macrolide: Convergent Synthesis of the C15-C36 Segment Reviewed

    Tomoyuki Saito, Haruhiko Fuwa, Makoto Sasaki

    ORGANIC LETTERS   11 ( 22 )   5274 - 5277   2009.11

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    DOI: 10.1021/ol902217q

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  • Studies toward the Total Synthesis of Gambieric Acid A

    Fuwa Haruhiko, Ishigai Kazuya, Noji Sayaka, Tsubone Koichi, Hashizume Keisuke, Sasaki Makoto

    Symposium on the Chemistry of Natural Products, symposium papers   ( 51 )   359 - 364   2009.9

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    Gambieric acids (GAs) are marine polycyclic ether natural products, isolated from the ciguatera causative dinoflagellate Gambierdiscus toxicus by Nagai, Yasumoto, and co-workers. The molecular architecture of GAs is composed of a nonacyclic polyether core and a side chain including a tetrahydrofuran. GAs show minimal toxocity against mammalians but display extraordinary potent antifungal activity against Aspergillus niger. The highly complicated structures coupled with the interesting biological activity make GAs attractive synthetic targets. We have previously reported the synthesis of the B-J-ring polycyclic ether core of gambieric acid A (GAA). Herein we report our efforts toward the total synthesis of GAA, which culminated in the stereochemical reassignment of the nonacyclic polyether core and the synthesis of the A/B-, DEFG-, and GHJI-ring fragments. The synthesis and NMR analysis of the A/BC-ring fragment of gambieric acid B confirmed that the absolute configuration of the polycyclic ether core of GAs is opposite to that of the originally proposed structure. Accordingly, we synthesized the A/B-ring fragment of GAA wigh the correct stereochemistry, wherein the A-ring was constructed via a Suzuki-Miyaura coupling and a diastereoselective iodoetherification. We devised a new strategy for the stereocontrolled synthesis of the DEFG-ring fragment of GAs, wherein a Suzuki-Miyaura coupling was implemented as the fragment assembly process and a seven-membered cyclic ether was utilized as a template for controlling the C25 stereogenic center. We also completed the synthesis of the GHIJ-ring fragment of GAs in a convergent manner. The G- and J-rings were assembled through an aldol coupling and the H- and I-rings were constructed by cyclodehydration and reductive etherification, respectively.

    DOI: 10.24496/tennenyuki.51.0_359

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  • Stereocontrolled Synthesis of the DEFG-ring Skeleton of Gambieric Acids Reviewed

    Haruhiko Fuwa, Sayaka Noji, Makoto Sasaki

    CHEMISTRY LETTERS   38 ( 8 )   866 - 867   2009.8

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    DOI: 10.1246/cl.2009.866

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  • Proteomic Analysis Reveals Multiple Patterns of Response in Cells Exposed to a Toxin Mixture Reviewed

    Gian Luca Sala, Giuseppe Ronzitti, Makoto Sasaki, Haruhiko Fuwa, Takeshi Yasumoto, Albertino Bigiani, Gian Paolo Rossini

    CHEMICAL RESEARCH IN TOXICOLOGY   22 ( 6 )   1077 - 1085   2009.6

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    DOI: 10.1021/tx900044p

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  • Synthetic Studies on Gambieric Acids, Potent Antifungal Polycyclic Ether Natural Products: Reassignment of the Absolute Configuration of the Nonacyclic Polyether Core by NMR Analysis of Model Compounds Reviewed

    Haruhiko Fuwa, Kazuya Ishigai, Tomomi Goto, Akihiro Suzuki, Makoto Sasaki

    JOURNAL OF ORGANIC CHEMISTRY   74 ( 11 )   4024 - 4040   2009.6

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    DOI: 10.1021/jo900332q

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  • 抗腫瘍性マクロリド (+)-ネオペルトリドの全合成 Reviewed

    佐々木誠, 不破春彦

    ファルマシア   45 ( 5 )   439 - 443   2009.5

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  • Synthesis of 2-Substituted Indoles and Indolines via Suzuki-Miyaura Coupling/5-endo-trig Cyclization Strategies Reviewed

    Haruhiko Fuwa, Makoto Sasaki

    JOURNAL OF ORGANIC CHEMISTRY   74 ( 1 )   212 - 221   2009.1

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    DOI: 10.1021/jo801985a

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  • Total Synthesis and Biological Evaluation of (+)-Neopeltolide and Its Analogues Reviewed

    Haruhiko Fuwa, Asami Saito, Shinya Naito, Keiichi Konoki, Mari Yotsu-Yamashita, Makoto Sasaki

    CHEMISTRY-A EUROPEAN JOURNAL   15 ( 46 )   12807 - 12818   2009

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    DOI: 10.1002/chem.200901675

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  • P-34 Second-generation Total Synthesis of (-)-Brevenal(Poster Presentation)

    EBINE Makoto, FUWA Haruhiko, SASAKI Makoto

    Symposium on the Chemistry of Natural Products, symposium papers   ( 50 )   641 - 646   2008.9

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    Brevenal is a pentacyclic polyether natural product isolated from the red tide dinoflagellate Karenia brevis. This natural product competitively displaces tritiated dihydrobrevetoxin-B ([^3H]-PbTx3) from voltage-sensitive sodium channels in a dose dependent manner, whereas it showed no toxicity in a fish bioassay. Moreover, brevenal increased tracheal mucus velocity in picomolar concentrations in an animal model of asthma. Thus, brevenal represents a potential lead for the development of novel therapeutic agents for treatment of mucociliary dysfunction associated with cystic fibrosis and other lung disorders. Toward elucidation of the biological mode of action at the molecular level and establishment of the structure-activity relationships, it is essential to develop an efficient, scalable, and flexible synthetic route to brevenal; however, our first-generation total synthesis involved lengthy fragment syntheses and tedious and capricious manipulations unsuitable for scale-up. Herein, we describe a highly convergent and efficient synthesis of the pentacyclic polyether core 2, which is a key intermediate in the previous synthesis. The present synthesis features i) highly efficient and scalable synthesis of the AB- and DE-ring fragments and ii) two-fold use of our Suzuki-Miyaura coupling/mixed thioacetalization-based convergent strategy for the synthesis of polycyclic ether frameworks. Our second-generation synthesis (total number of steps: 59; longest linear sequence: 32) is considerably more efficient than the original one (total number of steps: 73; longest linear sequence: 50).

    DOI: 10.24496/tennenyuki.50.0_641

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  • P-72 Total Synthesis of Natural Products Based on Suzuki-Miyaura Coupling(Poster Presentation)

    Fuwa Haruhiko, Naito Shinya, Goto Tomomi, Sasaki Makoto

    Symposium on the Chemistry of Natural Products, symposium papers   ( 50 )   755 - 760   2008.9

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    In modern organic synthesis, the Suzuki-Miyaura coupling has been extensively utilized in the synthesis of structurally complex natural products and pharmaceuticals due to the powerful C-C bond forming ability, mild reaction conditions, and compatibility with virtually all functional groups. Although aryl and alkenyl halides and their triflate counterparts are generally used as an electrophilic component in the Suzuki-Miyaura coupling, α-heteroatom substituted alkenyl halides and triflates, potentially useful precursors for the synthesis of heterocycles, are difficult to prepare and handle because of their inherent instability. During the course of our synthetic studies on marine polycyclic ether natural products, we found that lactone-derived enol phosphates are stable enough for isolation/purification and are sufficiently reactive under the Suzuki-Miyaura conditions to yield cross-coupled products in high yields. Our continuous efforts to broaden the scope of the alkenyl phosphate-based palladium chemistry have culminated in the development of several efficient methods for the synthesis of heterocycles such as dihydropyrans and indoles. Here we report the total synthesis of cytotoxic marine metabolites, attenols A and B and (+)-neopeltolide, exploiting our recently developed strategy for the synthesis of dihydropyrans based on a sequential Suzuki-Miyaura coupling/ring-closing metathesis.

    DOI: 10.24496/tennenyuki.50.0_755

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  • A New Method for the Generation of Indole-2,3-quinodimethanes from Allenamides Reviewed

    Haruhiko Fuwa, Tomomi Tako, Makoto Ebine, Makoto Sasaki

    CHEMISTRY LETTERS   37 ( 9 )   904 - 905   2008.9

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    DOI: 10.1246/cl.2008.904

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  • TOTAL SYNTHESIS OF ISOINDOLOBENZAZEPINE ALKALOIDS, LENNOXAMINE AND CHILENINE, BASED ON PALLADIUM-CATALYZED REDUCTION OF ALKENYL PHOSPHATES Reviewed

    Haruhiko Fuwa, Makoto Sasaki

    HETEROCYCLES   76 ( 1 )   521 - 539   2008.9

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  • An efficient strategy for the synthesis of endocyclic enol ethers and its application to the synthesis of spiroacetals Reviewed

    Haruhiko Fuwa, Makoto Sasaki

    ORGANIC LETTERS   10 ( 12 )   2549 - 2552   2008.6

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    DOI: 10.1021/ol800815t

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  • Stereocontrolled synthesis of the A/B-ring fragment of gambieric acid B: Reassignment of the absolute configuration of the polycyclic ether region Reviewed

    Haruhiko Fuwa, Tomomi Goto, Makoto Sasaki

    ORGANIC LETTERS   10 ( 11 )   2211 - 2214   2008.6

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    DOI: 10.1021/ol800642t

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  • Total synthesis of (-)-brevenal: A concise synthetic entry to the pentacyclic polyether core Reviewed

    Makoto Ebine, Haruhiko Fuwa, Makoto Sasaki

    ORGANIC LETTERS   10 ( 11 )   2275 - 2278   2008.6

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    DOI: 10.1021/ol800685c

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  • Convergent strategies for the total synthesis of polycyclic ether marine metabolites Reviewed

    Makoto Sasaki, Haruhiko Fuwa

    NATURAL PRODUCT REPORTS   25 ( 2 )   401 - 426   2008

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    DOI: 10.1039/b705664h

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  • Total synthesis of (+)-neopeltolide Reviewed

    Haruhiko Fuwa, Shinya Naito, Tomomi Goto, Makoto Sasaki

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   47 ( 25 )   4737 - 4739   2008

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    DOI: 10.1002/anie.200801399

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  • Recent advances in the synthesis of marine polycyclic ether natural products Reviewed

    Haruhiko Fuwa, Makoto Sasaki

    CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT   10 ( 6 )   784 - 806   2007.11

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  • Strategies for the synthesis of 2-substituted indoles and indolines starting from acyclic alpha-phosphoryloxy enecarbamates Reviewed

    Haruhiko Fuwa, Makoto Sasaki

    ORGANIC LETTERS   9 ( 17 )   3347 - 3350   2007.8

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    DOI: 10.1021/ol071312a

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  • Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic gamma-secretase inhibitors Reviewed

    Haruhiko Fuwa, Yasuko Takahashi, Yu Konno, Naoto Watanabe, Hiroyuki Miyashita, Makoto Sasaki, Hideaki Natsugari, Toshiyuki Kan, Tohru Fukuyama, Taisuke Tomita, Takeshi Iwatsubo

    ACS CHEMICAL BIOLOGY   2 ( 6 )   408 - 418   2007.6

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    DOI: 10.1021/cb700073y

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  • Stereoselective synthesis of the AB-ring fragment of gambieric acid A Reviewed

    Haruhiko Fuwa, Akihiro Suzuki, Kazushi Sato, Makoto Sasaki

    HETEROCYCLES   72 ( 1 )   139 - 144   2007.4

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  • An efficient method for the synthesis of enol ethers and enecarbamates. Total syntheses of isoindolobenzazepine alkaloids, lennoxamine and chilenine Reviewed

    Haruhiko Fuwa, Makoto Sasaki

    ORGANIC & BIOMOLECULAR CHEMISTRY   5 ( 12 )   1849 - 1853   2007

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    DOI: 10.1039/b706087d

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  • A strategy for the synthesis of 2,3-disubstituted indoles starting from N-(o-halophenyl)allenamides Reviewed

    Haruhiko Fuwa, Makoto Sasaki

    ORGANIC & BIOMOLECULAR CHEMISTRY   5 ( 14 )   2214 - 2218   2007

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    DOI: 10.1039/b707338k

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  • A new method for the generation of indole-2,3-quinodimethanes and 2-(N-alkoxycarbonylamino)-1,3-dienes. Intramolecular Heck/Diels Alder cycloaddition cascade starting from acyclic alpha-phosphono enecarbamates Reviewed

    Haruhiko Fuwa, Makoto Sasaki

    CHEMICAL COMMUNICATIONS   ( 27 )   2876 - 2878   2007

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    DOI: 10.1039/b704374k

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  • Concise and short synthesis of functionalized 5,6-dihydropyridin-2-ones by means of palladium(0)-catalyzed cross-coupling of ketene aminal phosphates Reviewed

    Haruhiko Fuwa, Akane Kaneko, Yasuaki Sugimoto, Taisuke Tomita, Takeshi Iwatsubo, Makoto Sasaki

    HETEROCYCLES   70 ( 1 )   101 - +   2006.12

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  • Total synthesis, structure revision, and absolute configuration of (-)-brevenal Reviewed

    Haruhiko Fuwa, Makoto Ebine, Andrea J. Bourdelais, Daniel G. Baden, Makoto Sasaki

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   128 ( 51 )   16989 - 16999   2006.12

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    DOI: 10.1021/ja066772y

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  • 39 Total Synthesis and Structural Revision of Marine Polyether Natural Product Brevenal

    Fuwa Haruhiko, Ebine Makoto, Ishioka Hiroki, Sasaki Makoto

    Symposium on the Chemistry of Natural Products, symposium papers   ( 48 )   229 - 234   2006.9

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    Brevenal is a polyether natural product isolated from laboratory cultures of the Florida red tide-forming dinoflagellate, Karenia Brevis. Its gross structure, including relative stereochemistry, was disclosed based on extensive 2D NMR studies. It has been reported that brevenal competitively displaces tritiated dihydrobrevetoxin from voltage-sensitive Na^+ channels and acts as a natural brevetoxin antagonist in vivo. More importantly, brevenal improved tracheal mucus velocity in picomolar concentrations in an animal model of asthma. Thus, it may be a source of novel therapeutic agents for treatment of cystic fibrosis and other respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). Intrigued by these biological profiles of brevenal, we embarked on the total synthesis of brevenal by means of our developed convergent methodology. Suzuki-Miyaura coupling of the AB ring enol phosphate 6 and an alkylborane derived from the DE ring exo-olefin 7 proceeded smoothly to afford coupling product 23. The C ring was then constructed by mixed-thioacetalization followed by one-pot oxidation/methylation. After construction of the left-hand (E,E)-diene side chain by means of CuTC-mediated Stille coupling, the total synthesis was completed by installing the right-hand (Z)-diene chain via Wittig reaction. However, ^1H and ^<13>C NMR spectra of synthetic 1 were not identical with those of the natural product. Detailed NMR studies suggested that the true structure of brevenal is the C26-epimer of the originally proposed structure. This notion is also supported by the postulated biosynthetic pathway of marine polyether natural products. In the event, this proved to be correct as the spectroscopic data of synthetic 2 were completely identical with those of the natural product. In addition, the optical rotation of synthetic 2 matched the value for the natural product. Thus, we succeeded in unambiguous determination of the absolute configuration of brevenal through our total synthesis endeavor.

    DOI: 10.24496/tennenyuki.48.0_229

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  • Effect of ciguatoxin 3C on voltage-gated Na+ and K+ currents in mouse taste cells Reviewed

    Valeria Ghiaroni, Haruhiko Fuwa, Masayuki Inoue, Makoto Sasaki, Keisuke Miyazaki, Masahiro Hirama, Takeshi Yasumoto, Gian Paolo Rossini, Giuseppe Scalera, Albertino Bigiani

    CHEMICAL SENSES   31 ( 7 )   673 - 680   2006.9

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    DOI: 10.1093/chemse/bjl008

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  • Synthesis of biotinylated photoaffinity probes based on arylsulfonamide gamma-secretase inhibitors Reviewed

    Haruhiko Fuwa, Kenichi Hiromoto, Yasuko Takahashi, Satoshi Yokoshima, Toshiyuki Kan, Tohru Fukuyama, Takeshi Iwatsubo, Taisuke Tomita, Hideaki Natsugari

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   16 ( 16 )   4184 - 4189   2006.8

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    DOI: 10.1016/j.bmcl.2006.05.091

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  • Total synthesis of the proposed structure of brevenal Reviewed

    Haruhiko Fuwa, Makoto Ebine, Makoto Sasaki

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   128 ( 30 )   9648 - 9650   2006.8

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    DOI: 10.1021/ja062524q

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  • Synthesis of the JK/LM-ring model of prymnesins, potent hemolytic and ichthyotoxic polycyclic ethers isolated from the red tide alga Prymnesium parvum: confirmation of the relative configuration of the K/L-ring juncture Reviewed

    Makoto Sasaki, Naoki Takeda, Haruhiko Fuwa, Ryulchi Watanabe, Masayuki Satake, Yasukatsu Oshima

    TETRAHEDRON LETTERS   47 ( 32 )   5687 - 5691   2006.8

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    DOI: 10.1016/j.tetlet.2006.06.032

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  • P-561 TOTAL SYNTHESIS OF THE PROPOSED STRUCTURE OF BREVENAL

    Fuwa Haruhiko, Ebine Makoto, Sasaki Makoto

    International Symposium on the Chemistry of Natural Products   2006   "P - 561"   2006.7

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    DOI: 10.24496/intnaturalprod.2006.0__P-561_

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  • Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates Reviewed

    Yasuko Takahashi, Haruhiko Fuwa, Akane Kaneko, Makoto Sasaki, Satoshi Yokoshima, Hifumi Koizumi, Tohru Takebe, Toshiyuki Kan, Takeshi Iwatsubo, Taisuke Tomita, Hideaki Natsugari, Tohru Fukuyama

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   16 ( 14 )   3813 - 3816   2006.7

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    DOI: 10.1016/j.bmcl.2006.04.025

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  • Divergent synthesis of multifunctional molecular probes based on caprolactam-derived γ-secretase inhibitors and their molecular targets

    H. Fuwa

    Abstracts of 25th IUPAC International Conference on Biodiversity and Natural Products   2006.7

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  • C-terminal fragment of presenilin is the molecular target of a dipeptidic gamma-secretase-specific inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) Reviewed

    Yuichi Morohashi, Toshiyuki Kan, Yusuke Tominari, Haruhiko Fuwa, Yumiko Okamura, Naoto Watanabe, Chihiro Sato, Hideaki Natsugari, Tohru Fukuyama, Takeshi Iwatsubo, Taisuke Tomita

    JOURNAL OF BIOLOGICAL CHEMISTRY   281 ( 21 )   14670 - 14676   2006.5

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    DOI: 10.1074/jbc.M513012200

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  • The sodium channel of human excitable cells is a target for gambierol Reviewed

    M. Carmen Louzao, Eva Cagide, Mercedes R. Vieytes, Makoto Sasaki, Haruhiko Fuwa, Takeshi Yasumoto, Luis M. Botana

    CELLULAR PHYSIOLOGY AND BIOCHEMISTRY   17 ( 5-6 )   257 - 268   2006

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  • Synthesis and biological evaluation of gambierol analogues: Efforts toward the development of biotinylated photoaffinity labeling probes

    H. Fuwa

    Abstracts of PACIFICHEM2005   2005.12

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  • Inhibition of voltage-gated potassium currents by gambierol in mouse taste cells Reviewed

    Ghiaroni, V, M Sasaki, H Fuwa, GP Rossini, G Scalera, T Yasumoto, P Pietra, A Bigiani

    TOXICOLOGICAL SCIENCES   85 ( 1 )   657 - 665   2005.5

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    DOI: 10.1093/toxsci/kfi097

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  • Synthetic studies on 3-arylquinazolin-4-ones: intramolecular nucleophilic aromatic substitution reaction of 2-carboxamido-3-arylquinazolin-4-ones and its application to the synthesis of secondary aryl amines Reviewed

    H Fuwa, T Kobayashi, T Tokitoh, Y Torii, H Natsugari

    TETRAHEDRON   61 ( 17 )   4297 - 4312   2005.4

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    DOI: 10.1016/j.tet.2005.02.038

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  • Intramolecular nucleophilic aromatic substitution reaction of 2-carboxamido-3-arylquinazolin-4-ones and its application to the synthesis of secondary aryl amines Reviewed

    H Fuwa, T Kobayashi, T Tokitoh, Y Torii, H Natsugari

    SYNLETT   ( 14 )   2497 - 2500   2004.11

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    DOI: 10.1055/s-2004-8354805

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  • 64(P-47) Diverted Total Synthesis and Biological Evaluation of Gambierol Analogues

    Fuwa Haruhiko, Natsugari Hideaki, Kainuma Noriko, Tachibana Kazuo, Satake Masayuki, Sasaki Makoto

    Symposium on the Chemistry of Natural Products, symposium papers   ( 46 )   359 - 364   2004.10

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    Marine polycyclic ether class of natural products, brevetoxins and ciguatoxins being representative, has attracted a great deal of attention of chemists and biologists due to the unusually complex and gigantic molecular architecture as well as potent and diverse biological activities. Gambierol is a marine polycyclic ether isolated as a toxic constituent from the cultured cells of the ciguatera causative dinoflagellate Gambierdiscus toxicus. It is known that gambierol exerts potent toxicity against mice (MLD 50 μg/kg, ip) and the symptoms caused in mice resemble those shown by ciguatoxins, implying that gambierol is also relevant to the ciguatera seafood poisoning. Recently, Inoue et al. have disclosed that gambierol inhibits competitively the binding of brevetoxin PbTx-3 to the voltage-sensitive sodium channel in excitable membranes. However, extremely limited availability of this toxin from natural sources has prevented further detailed biological studies. We have accomplished the first total synthesis of gambierol based on our developed Suzuki-Miyaura coupling-based strategy. Herein we report the structure-activity relationships of gambierol aiming at establishment of a rational basis for the development of probe molecules useful for biochemical studies. There exist only a few precedents of structure-activity relationship studies on marine polyether natural products, probably due to the difficulties of providing ample quantities of these natural products as well as altering the structure of highly gigantic and complex molecules by chemical means. We surmised that these difficulties could be overcome by synthesizing a diverse set of analogues from a simple yet advanced intermediate of the total synthesis (diverted total synthesis). We have synthesized up to 18 structural analogues and evaluated their biological activity. MLD value against mice (ip) was used as an index. It has been shown that the presence of the C28-C29 and C32-C33 double bonds and an appropriate length of the side chain are crucial structural elements for exerting potent toxicity. The C30 axial methyl group was found to enhance the toxicity, but it is not an essential functional group. Partial reduction of the conjugated diene system within the side chain resulted in a great decrease in toxicity. On the other hand, analogues possessing isomeric conjugated diene still displayed significant activity. These suggest that the planar nature of the conjugated diene system would be an important structural feature. Interestingly, modification of the C1 or C6 hydroxyl groups has almost no influence on the toxicity. In the case of 1-deoxy and 1-O-methylgambierol, however, mice death occurred in 45-140 min (3-10 times longer than gambierol and other active analogues), suggesting the possibility that Cl hydroxyl group is relevant to the bioavailability of the molecule.

    DOI: 10.24496/tennenyuki.46.0_359

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  • Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity Reviewed

    H Fuwa, N Kainuma, K Tachibana, C Tsukano, M Satake, M Sasaki

    CHEMISTRY-A EUROPEAN JOURNAL   10 ( 19 )   4894 - 4909   2004.10

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    DOI: 10.1002/chem.200400355

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  • Total synthesis of polycyclic ether natural products based on Suzuki-Miyaura cross-coupling Reviewed

    M Sasaki, H Fuwa

    SYNLETT   ( 11 )   1851 - 1874   2004.9

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    DOI: 10.1055/s-2004-830860

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  • Synthetic studies on antascomicin A: construction of the C18-C34 fragment Reviewed

    H Fuwa, Y Okamura, H Natsugari

    TETRAHEDRON   60 ( 25 )   5341 - 5352   2004.6

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    DOI: 10.1016/j.tet.2004.04.072

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  • Convergent synthesis of the ABCDE ring fragment of ciguatoxins Reviewed

    H Fuwa, S Fujikawa, K Tachibana, H Takakura, M Sasaki

    TETRAHEDRON LETTERS   45 ( 24 )   4795 - 4799   2004.6

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    DOI: 10.1016/j.tetlet.2004.04.083

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  • Highly efficient synthesis of medium-sized lactams via intramolecular Staudinger-aza-Wittig reaction of omega-azido pentafluorophenyl ester: synthesis and biological evaluation of LY411575 analogues Reviewed

    H Fuwa, Y Okamura, Y Morohashi, T Tomita, T Iwatsubo, T Kan, T Fukuyama, H Natsugari

    TETRAHEDRON LETTERS   45 ( 11 )   2323 - 2326   2004.3

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    DOI: 10.1016/j.tetlet.2004.01.087

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  • Pathological effects on mice by gambierol, possibly one of the ciguatera toxins Reviewed

    E Ito, F Suzuki-Toyota, K Toshimori, H Fuwa, K Tachibana, M Satake, M Sasaki

    TOXICON   42 ( 7 )   733 - 740   2003.12

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    DOI: 10.1016/j.toxicon.2003.09.011

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  • Synthesis and biological evaluation of gambierol analogues Reviewed

    H Fuwa, N Kainuma, M Satake, M Sasaki

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   13 ( 15 )   2519 - 2522   2003.8

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    DOI: 10.1016/S0960-894X(03)00467-0

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  • 海産ポリエーテル毒ガンビエロールの全合成

    佐々木誠, 不破春彦

    化学と生物   41 ( 5 )   283 - 285   2003.8

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  • Diazonamideの全合成:十年後に確定した分子構造

    不破春彦

    ファルマシア   39 ( 7 )   699 - 700   2003.7

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  • ガンビエロールの全合成:107段階の軌跡

    不破春彦, 佐々木誠

    化学   58 ( 5 )   32 - 37   2003.5

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  • Total synthesis of (-)-gambierol Reviewed

    H Fuwa, N Kainuma, K Tachibana, M Sasaki

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   124 ( 50 )   14983 - 14992   2002.12

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    DOI: 10.1021/ja028167a

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  • 27 Total Synthesis of Gambierol

    Fuwa Haruhiko, Sasaki Makoto, Tachibana Kazuo

    Symposium on the Chemistry of Natural Products, symposium papers   ( 44 )   157 - 162   2002.9

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    Gambierol (1) is a marine polycyclic ether toxin isolated from the ciguatera causative dinoflagellate Gambierdiscus toxicus. The toxin exhibits potent toxicity against mice (LD_<50> 50μg/kg, ip), and the symptoms caused in mice resemble those shown by ciguatoxins, implying that gambierol is also responsible for ciguatera fish poisoning. However, extremely limited availability from natural sources hampered further detailed biological studies, and therefore, sample supply by practical chemical synthesis is strongly demanded. The chemical structure is characterized by the octacyclic polyether core with 18 stereogenic centers and labile triene side chain that includes conjugated (Z,Z)-diene. Herein we report the first total synthesis of gambierol, featuring convergent synthesis of the octacyclic polyether core via our B-alkyl Suzuki-Miyaura coupling strategy and stereoselective construction of the sensitive triene side chain through the Pd(PPh_3)_4/CuCl/LiCl promoted Stille coupling. The ABC ring fragment 5 was synthesized from the known olefin 7, representing the B ring. The C6 hydroxy group was installed stereoselectively by Sharpless asymmetric epoxidation of allylic alcohol 8 and subsequent reductive cleavage of the derived hydroxy epoxide. Intramolecular hetero-Michael reaction of 10 was utilized for stereoselective formation of the A ring to give 11 as a single stereoisomer. The C ring was constructed via 6-endo cyclization of vinyl epoxide 14 to afford tricyclic compound 15, which was then converted to 5 without incident. Synthesis of the EFGH ring fragment 6 started from the known ester 16. Construction of the H ring was performed by use of a SmI_2-mediated reductive cyclization methodology developed by Nakata. 6-Endo cyclization of vinyl epoxide 19 cleanly afforded the GH ring fragment 20, which was readily converted to methyl ketone 21. Reductive cyclization of 21 under Nakata conditions gave the FGH ring fragment 22, which was then transformed into the targeted fragment 6 by standard chemistry. The convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) was successfully achieved by using the B-alkyl Suzuki-Miyaura coupling to yield the cross-coupled product 23 in gratifying 86% yield. Subsequent elaboration to the octacyclic polyether core 4 of gambierol was accomplished from 23 in only six steps. Compound 4 was converted to tertiary alcohol 26 in six steps via an introduction of the double bond within the H ring by Ito-Saegusa protocol. An array of careful protective group manipulations and installation of a (Z)-vinyl bromide unit led to triol 29. Cross-coupling of 29 with the known (Z)-vinyl stannane 3 under the Pd(PPh_3)_4/CuCl/LiCl promoted Stille conditions furnished gambierol 1. Spectroscopic data (^1H and ^<13>C NMR, FIRMS, CD) and mouse lethality of synthetic 1 were identical with those of authentic natural sample.

    DOI: 10.24496/tennenyuki.44.0_157

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  • Total synthesis of gambierol Reviewed

    H Fuwa, M Sasaki, M Satake, K Tachibana

    ORGANIC LETTERS   4 ( 17 )   2981 - 2984   2002.8

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    DOI: 10.1021/o1026394b

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  • A general strategy for the convergent synthesis of fused polycyclic ethers via B-alkyl Suzuki coupling: synthesis of the ABCD ring fragment of ciguatoxins Reviewed

    M Sasaki, M Ishikawa, H Fuwa, K Tachibana

    TETRAHEDRON   58 ( 10 )   1889 - 1911   2002.3

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  • Synthetic studies toward gambierol. Convergent synthesis of the octacyclic polyether core Reviewed

    H Fuwa, M Sasaki, K Tachibana

    ORGANIC LETTERS   3 ( 22 )   3549 - 3552   2001.11

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    DOI: 10.1021/ol0166597

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  • Synthetic studies on a marine polyether toxin, gambierol: stereoselective synthesis of the EFGH ring system via B-alkyl Suzuki coupling Reviewed

    H Fuwa, M Sasaki, K Tachibana

    TETRAHEDRON   57 ( 15 )   3019 - 3033   2001.4

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  • Synthetic studies on a marine polyether toxin, gambierol: stereoselective synthesis of the FGH ring system via B-alkyl Suzuki coupling Reviewed

    H Fuwa, M Sasaki, K Tachibana

    TETRAHEDRON LETTERS   41 ( 43 )   8371 - 8375   2000.10

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  • Convergent synthesis of an HIJK ring model of ciguatoxin via Suzuki cross-coupling reaction Reviewed

    M Sasaki, K Noguchi, H Fuwa, K Tachibana

    TETRAHEDRON LETTERS   41 ( 9 )   1425 - 1428   2000.2

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  • A general method for convergent synthesis of polycyclic ethers based on Suzuki cross-coupling: Concise synthesis of the ABCD ring system of ciguatoxin Reviewed

    M Sasaki, H Fuwa, M Ishikawa, K Tachibana

    ORGANIC LETTERS   1 ( 7 )   1075 - 1077   1999.10

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  • New strategy for convergent synthesis of trans-fused polyether frameworks based on palladium-catalyzed Suzuki cross-coupling reaction Reviewed

    M Sasaki, H Fuwa, M Inoue, K Tachibana

    TETRAHEDRON LETTERS   39 ( 49 )   9027 - 9030   1998.12

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Books

  • Modern Natural Product Synthesis

    H. Fuwa( Role: ContributorPursuing Step Economy in Total Synthesis of Complex Marine Macrolide Natural Products)

    Springer, Singapore  2024.5  ( ISBN:9789819716197

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  • Marine Natural Products (Topics in Heterocyclic Chemistry, vol. 58)

    T. Sugai, H. Fuwa( Role: ContributorTotal Synthesis of (−)-Enigmazole A)

    Springer, Singapore  2020.11 

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    Responsible for pages:pp. 361-386   Language:English   Book type:Scholarly book

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  • 天然有機化合物の全合成:独創的なものづくりの反応と戦略 (CSJカレントレビュー)

    不破春彦, 佐々木誠( Role: Contributor13章 ガンビエロール構造簡略体の設計・合成・生物機能)

    化学同人  2018.3 

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  • Strategies and Tactics in Organic Synthesis (Vol. 12)

    H. Fuwa( Role: Contributor(−)-Lyngbyaloside B, a Marine Macrolide Glycoside: Total Synthesis and Stereochemical Revision)

    Elsevier  2016 

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    Responsible for pages:143-168   Language:English   Book type:Scholarly book

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  • Seafood and Freshwater Toxins: Pharmacology, Physiology, and Detection, 3rd Edition

    edited by Luis, M, Botana,eds( Role: Joint authorGambierol: Synthetic aspects)

    CRC Press  2014.3 

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    Responsible for pages:895-924   Language:English   Book type:Scholarly book

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  • Toxins and Biologically Active Compounds from Marine Microalgae

    edeted by Gian, Paolo Rossini( Role: Joint authorTotal synthesis of marine polycyclic ether natural products)

    CRC Press  2014.2 

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    Responsible for pages:348-412   Language:English   Book type:Scholarly book

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  • 天然物合成で活躍した反応「実験のコツとポイント」

    ( Role: Joint author鈴木ー宮浦カップリング)

    化学同人 有機合成化学協会編  2011.10 

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    Responsible for pages:48-49   Language:Japanese   Book type:Scholarly book

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MISC

  • Total Synthesis of (−)-Exiguolide, a Potent Anticancer Marine Macrolide Invited Reviewed

    Haruhiko Fuwa

    HETEROCYCLES   104 ( 10 )   1709 - 1709   2022.7

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    DOI: 10.3987/rev-22-983

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  • Structure determination, correction, and disproof of marine macrolide natural products by chemical synthesis Invited Reviewed

    H. Fuwa

    Organic Chemistry Frontiers   8   3990 - 4023   2021.7

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    DOI: 10.1039/D1QO00481F

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  • Synthesis-driven stereochemical assignment of marine polycyclic ether natural products Invited Reviewed

    H. Fuwa

    Marine Drugs   19   257   2021.4

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    DOI: 10.3390/md19050257

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  • タンデム反応と複雑天然物の全合成 Invited

    村田佳亮, 不破春彦

    化学工業   71   117 - 124   2020.2

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  • Total Synthesis of a Marine Macrolide Natural Product, Iriomoteolide-2a: The Fundamental Role of Total Synthesis in Natural Product Chemistry Invited Reviewed

    Keita Sakamoto, Haruhiko Fuwa

    Journal of Synthetic Organic Chemistry, Japan   77 ( 8 )   831 - 840   2019.8

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    DOI: 10.5059/yukigoseikyokaishi.77.831

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  • Total Synthesis and Chemical Biology of Marine Macrolide Natural Products

    67 ( 9 )   668 - 675   2016.9

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  • A new method for the generation of indole-2,3-quinodimethanes and 2-(N-alkoxycarbonylamino)-1,3-dienes. Intramolecular Heck/Diels-Alder cycloaddition cascade starting from acyclic alpha-phosphoryloxy enecarbamates (pg 2876, 2007)

    Haruhiko Fuwa, Makoto Sasaki

    CHEMICAL COMMUNICATIONS   ( 29 )   3106 - 3106   2007

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  • A strategy for the synthesis of 2,3-disubstituted indoles starting from N-(o-halophenyl)allenamides (Vol 5, pg 2214, 2007)

    Haruhiko Fuwa, Makoto Sasaki

    ORGANIC & BIOMOLECULAR CHEMISTRY   5 ( 15 )   2506 - 2506   2007

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  • 天然物合成中間体からのγ-セクレターゼ阻害剤の探索

    小泉一二三, 高瀬真衣, 下川淳, 竹部享, 星野健太, 北陽一, 冨成祐介, 高橋宴子, 杉本康昭, 不破春彦, 富田泰輔, 横島聡, 菅敏幸, 夏苅英昭, 岩坪威, 福山透

    日本薬学会年会要旨集   126th ( 4 )   2006

  • 新規γ-セクレターゼ阻害剤の探索研究:ジヒドロピリドン誘導体の短段階迅速合成

    兼子茜, 不破春彦, 杉本康昭, 富田泰輔, 岩坪威, 佐々木誠

    化学系学協会東北大会プログラムおよび講演予稿集   2006   2006

  • カプロラクタム系γ-セクレターゼ阻害剤を基盤とする高機能プローブの創製

    今野悠, 不破春彦, 佐々木誠, 高橋宴子, 菅敏幸, 福山透, 夏苅英昭, 富田泰輔, 岩坪威

    日本薬学会年会要旨集   126th ( 4 )   2006

  • Presenilin-1 is a molecular target of a dipeptidic gamma-secretase inhibitor, DAPT

    Y Morohashi, Y Tominari, N Watanabe, T Kan, H Fuwa, H Natsugari, T Fukuyama, T Tomita, T Iwatsubo

    NEUROBIOLOGY OF AGING   25   S566 - S567   2004.7

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  • Synthesis and biological evaluation of LY411575 analogues

    H. Fuwa

    Abstracts of 2nd World Congress of Pharmaceutical Society   2004.5

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  • γセクレターゼ阻害剤LY411575を基盤とするプローブ分子探索研究

    不破春彦, 諸橋雄一, 岡村裕美子, 富田泰輔, 岩坪威, 菅敏幸, 福山透, 夏苅英昭

    日本薬学会年会要旨集   124th ( 2 )   2004

  • Total synthesis of a marine polyether toxin, gambierol

    Haruhiko Fuwa, Makoto Sasaki

    Journal of Synthetic Organic Chemistry, Japan   61 ( 8 )   742 - 751   2003.8

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    The first total synthesis of gambierol, a marine polycyclic ether toxin, has been achieved. Highly efficient synthesis of the ABC and EFGH ring fragments allowed us to prepare those two advanced intermediates in multi-gram quantities. The key feature of the present total synthesis is the B-alkyl Suzuki-Miyaura coupling tactics, which culminated in the union of the advanced intermediates and convergent synthesis of the octacyclic polyether core. Introduction of the sensitive triene side chain via Pd (PPh3) 4/CuCl/LiCl-promoted Stille coupling was conducted at the final step of the synthesis.<BR>The present total synthesis supplied useful quantities of gambierol and its structural analogues for detailed biological studies : an interesting observation was gained through pathological studies. Also, preliminary structure-activity relationship studies revealed that the functionalities present in the H ring and unsaturated side chain are crucial for potent toxicity against mice.

    DOI: 10.5059/yukigoseikyokaishi.61.742

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    Other Link: https://jlc.jst.go.jp/DN/JALC/00230309041?from=CiNii

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Presentations

  • マクロ環化と渡環反応を基盤とするマクロリドの新合成戦略:Exiguolide の16工程全合成

    水上大地, 飯尾 慶, 小田真実, 小野寺 悠, 不破春彦

    第63回天然有機化合物討論会  2021.9 

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  • 複雑な海洋天然物の全合成

    不破春彦

    有機合成化学協会関西支部有機合成夏期セミナー「明日の有機合成化学」  ( 大阪 )   2019.8  有機合成化学協会関西支部

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  • タンデム反応を基盤とした新合成法の開発 Invited

    不破春彦

    第9回有機分子構築法夏の勉強会  ( 湯河原 )   2019.5 

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  • 変異c-kit発現細胞に選択的に作用する複雑天然物の全合成と構造活性相関解析

    不破春彦

    公益財団法人旭硝子財団2018助成研究発表会  ( 東京 )   2018.7  公益財団法人旭硝子財団

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  • Total synthesis, stereochemical revision, and biological evaluation of lyngbyaloside B, a marine macrolide glycoside International conference

    H. Fuwa, Y. Okuaki, N. Yamagata, M. Sasaki

    Abstracts of PACIFICHEM2015  ( Honolulu, Hawaii )   2015.12  PACIFICHEM2015

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  • 複雑天然物の全合成と構造改訂

    平成27年度化学系学協会東北大会  2015.9 

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  • リングビアロシドBの全合成と完全立体構造決定

    不破春彦, ほか

    第57回天然有機化合物討論会  2015.9 

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  • 海洋マクロリド天然物の全合成とケミカルバイオロジー

    日本化学会第95春季年会委員会企画「天然物化学研究の最前線」  2015.3 

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  • Synthetic and structural studies on lyngbyaloside B, a cytotoxic marine macrolide glycoside International conference

    H. Fuwa

    Abstracts of International Symposium on Chemical Biology of Natural Products  2014.10  新学術領域研究(研究領域提案型)「天然物ケミカルバイオロジー」

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  • Studies toward the total synthesis of iriomoteolide-2a International conference

    H. Fuwa

    Abstracts of International Symposium on Chemical Biology of Natural Products  2013.10  新学術領域研究(研究領域提案型)「天然物ケミカルバイオロジー」

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  • Total synthesis and biological evaluation of marine macrolide natural products International conference

    H. Fuwa

    Abstracts of the 70th Anniversary Symposium of the Chemical Society of Japan Tohoku Branch  2013.9  日本化学会東北支部

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  • 海洋天然物の効率的全合成と高活性構造単純化類縁体の創出

    新学術領域研究(研究領域提案型)「天然物ケミカルバイオロジー」第4回公開シンポジウム  2013.5 

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  • Total synthesis and structure-activity relationships of marine macrolide natural products International conference

    H. Fuwa

    Abstracts of International Symposium on Chemical Biology of Natural Products  2012.10  新学術領域研究(研究領域提案型)「天然物ケミカルバイオロジー」

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  • ガンビエル酸Aの全合成と完全立体構造決定

    不破春彦, 石貝和也, 橋詰佳佑, 佐々木誠

    第54回天然有機化合物討論会  2012.9 

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  • 微量複雑海洋天然物の全合成とケミカルバイオロジーへの展開

    東北大学GCOEプログラム分子系高次構造体化学国際教育研究拠点シンポジウム2011  2011.11 

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  • 海洋天然物(–)-exiguolideの全合成と生物活性評価

    日本薬学会東北支部第10回化学系薬学若手研究者セミナー/日本薬学会東北支部  2011.8 

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  • Total synthesis and biological assessment of (–)-exiguolide and analogues International conference

    H. Fuwa

    Asian International Symposium  2011.3  日本化学会

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  • Concise total synthesis of (+)-neopeltolide International conference

    H. Fuwa, A. Saito, M. Sasaki

    Abstracts of PACIFICHEM2010  ( Honolulu, Hawaii )   2010.12  PACIFICHEM2010

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  • (-)-Exiguolideの全合成

    不破春彦, 佐々木誠

    第52回天然有機化合物討論会  2010.10 

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  • 複雑な構造を有する海洋天然有機化合物の効率的全合成

    日本化学会第90春季年会要旨集  2010.3 

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  • 海産マクロリド天然物ネオペルトリドの全合成と構造活性相関

    平成21年度化学系学協会東北大会  2009.9 

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  • スピロアセタールの効率的構築法の開発:アテノールの全合成

    不破春彦, 佐々木誠

    日本化学会第88春季年会  2008.3 

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  • アルケニルホスフェートを出発原料とする有機分子構築法

    第42回天然物化学談話会  2007.7 

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  • 海産ポリエーテル系天然物ブレベナールの全合成と構造改訂

    不破春彦, 海老根真琴, 石岡裕貴, 佐々木誠

    第48回天然有機化合物討論会  2006.10 

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  • リン酸エステルを脱離基とするPd(0)触媒反応を用いる複素環合成

    第5回日本薬学会東北支部若手研究者セミナー  2006.9 

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  • Divergent synthesis of multifunctional molecular probes based on caprolactam-derived γ-secretase inhibitors and their molecular targets International conference

    H. Fuwa

    Abstracts of 25th IUPAC International Conference on Biodiversity and Natural Products  ( Kyoto )   2006.7  International Union of Pure and Applied Chemistry

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  • Synthesis and biological evaluation of gambierol analogues: Efforts toward the development of biotinylated photoaffinity labeling probes International conference

    H. Fuwa

    Abstracts of PACIFICHEM2005  ( Honolulu, Hawaii )   2005.12  PACIFICHEM2005

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  • 海産ポリエーテル系天然物の全合成研究と生命科学的展開

    第40回天然物化学談話会  2005.7 

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  • ブレベナールの全合成研究

    不破春彦, 海老根真琴, 佐々木誠

    日本化学会第85春季年会  2005.3 

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  • ガンビエロールの全合成

    不破春彦, 佐々木誠, 橘和夫

    第82回有機合成シンポジウム  2002.11 

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  • ガンビエロールの全合成

    不破春彦, 佐々木誠, 橘和夫

    第44回天然有機化合物討論会  2002.10 

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  • ガンビエロールの全合成研究

    不破春彦, 佐々木誠, 橘和夫

    日本化学会第81春季年会要旨集  2002.3 

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  • ガンビエロールの全合成研究−EFGH環部の合成−

    不破春彦, 佐々木誠, 橘和夫

    日本化学会第79春季年会  2001.3 

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  • 海産ポリエーテル化合物ガンビエロールの合成研究

    不破春彦, 佐々木誠, 橘和夫

    日本化学会第78春季年会  2000.3 

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  • 鈴木クロスカップリング反応を用いる収束的ポリ環状エーテル合成法の開発とシガトキシン合成への応用

    1999年有機合成若手研究者のためのセミナー  1999.11 

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  • 鈴木クロスカップリング反応を用いる収束的ポリエーテル骨格合成法の開発とシガトキシン合成への応用

    佐々木誠, 不破春彦, 石川誠, 橘和夫

    第75回有機合成シンポジウム  1999.6 

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  • 収束的ポリ環状エーテル合成法の開発

    佐々木誠, 不破春彦, 井上将行, 橘和夫

    日本化学会第75秋季年会  1998.9 

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Awards

  • 令和6年度手島精一記念研究賞 研究論文賞

    2025.3   東京科学大学  

  • 科学技術分野の文部科学大臣表彰若手科学者賞

    2011.4   文部科学省   海洋天然有機化合物の高効率的全合成の研究

  • 日本化学会第59回進歩賞

    2010.3   日本化学会   複雑な構造を有する海洋天然有機化合物の効率的全合成

  • 第50回天然有機化合物討論会奨励賞(ポスター発表の部)

    2008.10   天然有機化合物討論会   鈴木-宮浦カップリング反応を基盤とする天然物全合成

  • 第4回天然物化学談話会奨励賞

    2004.7   天然物化学談話会   海産毒ガンビエロール全合成と多様性志向型全合成による構造活性相関

  • 第44回天然有機化合物討論会奨励賞(口頭発表の部)

    2002.10   天然有機化合物討論会   ガンビエロールの全合成

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Research Projects

  • 計算化学が先導する複雑大員環天然物の構造決定と全合成の高効率化

    Grant number:25K01906  2025.4 - 2028.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)  中央大学

    不破 春彦

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    Authorship:Principal investigator 

    Grant amount: \18720000 ( Direct Cost: \14400000 、 Indirect Cost: \4320000 )

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  • 複雑海洋天然物の実践的全合成と構造改変による立体配座・活性制御

    2022.4 - 2025.3

    日本学術振興会  基盤研究(C) 

    不破 春彦

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    Grant type:Competitive

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  • アンフィジニウム属渦鞭毛藻の有用二次代謝産物の探索と開発

    2021.4 - 2025.3

    基盤研究(B) 

    津田正史

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    Grant type:Competitive

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  • 超活性抗腫瘍性海洋天然物の全合成研究

    2019.10 - 2020.9

    山田科学振興財団  研究援助 

    不破 春彦

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount: \2000000 ( Direct Cost: \2000000 )

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  • Total Synthesis, Structure Determination, and Bioactive Stereostructure of Complex Macrolides

    Grant number:17K01941  2017.4 - 2020.3

    日本学術振興会  Grants-in-Aid for Scientific Research  基盤研究(C)  Chuo University

    不破 春彦

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount: \4680000 ( Direct Cost: \3600000 、 Indirect Cost: \1080000 )

    Total synthesis of the proposed structure of iriomoteolide-2a has been achieved. Our synthesis involved: 1) convergent assembly of important fragments via a Suzuki-Miyaura reaction and an esterification, and 2) forging the macrocyclic skeleton by means of a ring-closing metathesis. However, the NMR spectra of our synthetic material did not match those of natural iriomoteolide-2a. Synthesis/NMR analysis of model compounds and careful inspection of the NMR data of the authentic sample, followed by total syntheses of possible structures enabled us to determine the absolute configuration of iriomoteolide-2a.
    Total synthesis of enigmazole A has been completed. The salient features of our synthesis include: 1) a stereoselective tandem synthesis of the tetrahydropyran ring, 2) a Au(I)-catalyzed Meyer-Schuster rearrangement of a propargylic benzoate, and 3) a macrocyclic ring-closing metathesis.

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  • Total Synthesis of Complex Marine Natural Products Based on Tandem Reactions

    2018.12 - 2019.11

    内藤記念科学振興財団  内藤記念科学奨励金・研究助成 

    不破 春彦

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount: \3000000 ( Direct Cost: \3000000 )

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  • Development and Application of New Synthetic Strategy toward Marine Macrolides

    2018.4 - 2019.3

    東京応化科学技術振興財団  研究費の助成 

    不破 春彦

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount: \1000000 ( Direct Cost: \1000000 )

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  • Total Synthesis, Complete Stereostructure. and Structure-Activity Relationship of Complex Macrocyclic Natural Products

    2016.11 - 2017.10

    住友財団  基礎科学研究助成 

    不破 春彦

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount: \1300000 ( Direct Cost: \1300000 )

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  • Total Synthesis and Structure-Activity Relationship of Complex Natural Product That Exhibits Selective Cytotoxicity Against Cells Expressing Mutant c-Kit

    2015.4 - 2017.3

    旭硝子財団  第1分野(化学・生命科学系)研究奨励 

    不破 春彦

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount: \2000000 ( Direct Cost: \2000000 )

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  • Synthesis and functional analysis of novel biologically active molecules based on complex macrolide natural products

    Grant number:25282228  2013.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)  Tohoku University

    Sasaki Makoto, FUWA Haruhiko

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    Grant amount: \18590000 ( Direct Cost: \14300000 、 Indirect Cost: \4290000 )

    Our research focused on the efficient total synthesis of structurally complex marine macrolide natural products with significant biological activities to investigate and exploit their biological functions. A convergent synthesis of a fully functionalized macrolactone core of goniodomin A, a polyether macrolide that targets actin cytoskeleton, has been accomplished. An efficient, convergent total synthesis of polycavernoside B, a lethal glycosidic macrolide isolated from the red alga, has been achieved for the first time. In addition, efficient synthetic routes to the C1-C13 and C8-C29 fragments of amphidinolide N, an extremely potent cytotoxic macrolide, have been developed in a convergent manner.

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  • 微量複雑海洋天然物の合理的構造単純化及び作用解析

    Grant number:26102708  2014.4 - 2016.3

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)  東北大学

    不破 春彦

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    Grant amount: \5330000 ( Direct Cost: \4100000 、 Indirect Cost: \1230000 )

    本年度は前年度に引き続き,複雑海洋天然物イリオモテオリド-2aの全合成研究を行った。昨年度末までに,イリオモテオリド-2a提出構造式には帰属の誤りがあることが明らかとなった。そこで,本天然物に含まれる不斉炭素原子の立体配置の帰属を再検証することにした。合成品と天然標品のNMRスペクトルデータを比較した結果,C12/C13の相対配置の帰属に誤りがあり,C13位を起点に相対配置が決定されたC15及びC16位の立体配置も誤っているものと考えた。
    以上の経緯から,提出構造式の13,15,16-epi体を新たなターゲット分子に設定した。この際,ビステトラヒドロフラン部分構造は,Sharpless不斉エポキシ化とエポキシド連続環化反応を一挙に達成する新しい戦略で立体選択的に構築することに成功した。その後は提出構造式の全合成法に則り,13,15,16-epi体の全合成を達成した。しかしまたも,合成品の1H及び13C NMRスペクトルデータは天然標品のそれと一致しなかった。
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    本年度はまた複雑海洋天然物ネオペルトリドの蛍光標識プローブを創出し,生細胞における局在解析を行った。独自の構造活性相関解析の知見を踏まえ,8,9-デヒドロネオペルトリド(8,9-DNP)のC11位を修飾して蛍光色素を連結させ,数種の蛍光標識プローブを取得した。細胞増殖阻害試験と生細胞染色試験でプローブを評価した結果,BODIPY-FLを導入した8,9-DNP-BODIPYが最も優れたパフォーマンスを示した。8,9-DNP-BODIPYとオルガネラマーカーによる生細胞二重染色試験を行った結果,本化合物は主として小胞体に速やかに集積し,親化合物である8,9-DNPにより蛍光染色が競争的に阻害された。領域内の共同研究者による線虫初期胚の染色実験でも同様の結果が得られた。

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  • Synthesis and functional analysis of ion channel selective inhibitors based on polycyclic ethers

    Grant number:23102016  2011.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)  Tohoku University

    Sasaki Makoto, FUWA HARUHIKO, KONOKI KEIICHI

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    Grant amount: \34580000 ( Direct Cost: \26600000 、 Indirect Cost: \7980000 )

    Gambierol is a structurally complex marine polycyclic ether natural product that exhibits potent inhibitory activity against voltage-gated potassium ion channels (Kv channels) with specific subtype selectivity. In order to clarify skeletal structure-activity relationship, hepta-, tetra-, and tricyclic analogues of gambierol were synthesized and tested for inhibitory activity against Kv1.2 channel, which was stably expressed in Chinese hamster ovary (CHO) cells. It was revealed that tetracyclic analogue of gambierol comprising the right-hand EFGH-ring with a triene side chain is the minimal structural unit for inhibitory activity against Kv1.2 channels. Furthermore, we designed and synthesized photoaffinity probe based on the structure of the tetracyclic analogue to identify the binding site of the ligand on Kv channels.

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  • 実用的全合成に立脚した微量複雑海洋天然物ケミカルバイオロジー

    Grant number:24102507  2012.4 - 2015.3

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)  東北大学

    不破 春彦

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    Grant amount: \6370000 ( Direct Cost: \4900000 、 Indirect Cost: \1470000 )

    本年度は,渦鞭毛藻Amphidinium sp.の培養藻体から単離・構造決定されたイリオモテオリド-2aのC6-C18ビステトラヒドロフラン部分構造及びC19-C28側鎖構造の立体選択的でスケーラブルな合成法の確立を行った。
    C9位の不斉中心の制御には,野上らが開発した不斉アリルトランスファー反応を用いることで,C6-C11部分構造のスケールアップを容易にした。一方,C12-C18部分構造は市販のベンジル(S)-グリシジルエーテルを原料とし,既報の手法に従い合成した。得られた両部分構造をオレフィン交差メタセシス反応により連結した後,C11位の不斉中心をCBS還元により,C12, C13位不斉中心はSharpless不斉エポキシ化反応によりを制御した。続いて2つのテトラヒドロフラン環の立体特異的な構築を行った。C9位ヒドロキシ基の脱保護と続く弱酸処理により,C9-C12テトラヒドロフランはヒドロキシエポキシドの分子内環化反応により構築した。生じたC13位ヒドロキシ基をメシル化した後,塩基性条件下でC16位ベンゾイルオキシ基の脱保護と分子内環化を一挙に行い,C13-C16テトラヒドロフラン環を構築した。
    一方,C19-C28側鎖構造は(R)-リンゴ酸を出発原料とし,Seebachアルキル化,野崎ー檜山ー岸反応,Brown不斉アリル化反応を鍵段階とする直裁的な合成法により,数百ミリグラムオーダーで合成した。
    以上,イリオモテオリド-2aの構造的特徴であるC6-C18ビステトラヒドロフラン部分構造及びC19-C28側鎖構造に関する,高立体選択的かつスケーラブルな合成法の開発に成功した。当該部分構造のスケーラブルな合成法は,天然物そのものに限らず,類縁体や標識化合物の合成に不可欠で,イリオモテオリド-2aの全合成とケミカルバイオロジー研究を大きく前進させる成果と考えられる。

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  • Unified Total Synthesis and Structure-Activity Relationships of Marine Macrolide Natural Products of Cyanobacteria Origin

    Grant number:23681045  2011.4 - 2014.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (A)  Tohoku University

    FUWA Haruhiko

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    Grant amount: \26000000 ( Direct Cost: \20000000 、 Indirect Cost: \6000000 )

    This project pursued unified total synthesis and structure-activity relationships of marine macrolide natural products of cyanobateria origin. Our concise synthesis of neopeltolide, a highly potent antiproliferative macrolide, enabled us to elucidate its pharmacophoric structural elements required for potent activity. Several truncated neopeltolide analogues with nanomolar activity were successfully designed on the basis of our pharmacophore model. Concise total synthesis of lyngbyaloside B, a moderately cytotoxic macrolide glycoside, and its 13-demethyl analogue was also achieved. Design, synthesis, and biological evaluation of chimeric macrolides were undertaken to show that polyketide macrolides offer unique structural motifs useful for the development of novel antiproliferative agents.

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  • Mechanisms of an anti-cancer effect of a novel marine natural compound, exiguolide.

    Grant number:23659427  2011 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research  Tohoku University

    KUBO Hiroshi

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    Grant amount: \3640000 ( Direct Cost: \2800000 、 Indirect Cost: \840000 )

    The aim of this experiment is to elucidate the mechanisms of an anti-cancer effect of a novel marine natural compound, exiguolide. The cell cycle of cultured cancer cells was arrested with apoptotic cells death under incubation with exiguolide. Tumor growth was also attenuated by the treatment with exiguolide in the in vivo xenograft model in mice. Several kinases were involved in this anti-cancer effect. Then, we synthesized exiguolide analogues with modified structures. Some of the analogues had a similar anti-cancer effect in both in vitro and in vivo. These results will bring the basis for developing a new anti-cancer drug, which can be clinically applicable.

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  • Total Synthesis and Functional Analysis of Complex Natural Products

    Grant number:21241050  2009 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)  Tohoku University

    SASAKI Makoto, FUWA Haruhiko, KONOKI Keiichi

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    Grant amount: \26780000 ( Direct Cost: \20600000 、 Indirect Cost: \6180000 )

    Efficient synthetic routes to architecturally complex natural products with potent biological activities and molecular weights over 500 have been developed for exploring their biological functions. In particular, the first total synthesis and complete stereostructure determination of gambieric acid A have been accomplished. An efficient total synthesis of polycavernoside A has been also achieved in a convergent approach. In addition, efficient synthetic routes to the C1. C16 and C12. C36 fragments of goniodomin A have been developed by exploiting Stille-type coupling of thioesters.

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  • Total synthesis of a natural HIV protease inhibitor and its partial structures

    Grant number:21710216  2009 - 2010

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)  Tohoku University

    FUWA Haruhiko

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    Grant amount: \4290000 ( Direct Cost: \3300000 、 Indirect Cost: \990000 )

    HIV protease is an enzyme responsible for the proteolysis of the polyprotein expressed by the retrovirus to produce matured proteins necessary for proliferation and infection. Thus, the inhibition of HIV protease represents an important therapeutic strategy for HIV-infected patients. In the present study, we have investigated synthetic routes toward marine natural products didemnaketals and their partial structures. We have completed the stereoselective syntheses of the C1-C11 acyclic domain and C9-C28 spiroacetal domain of didemnaketal B.

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  • Development of new strategies for the synthesis of nitrogen heterocycles and its application to the search for γ-secretase inhibitors

    Grant number:19710177  2007 - 2008

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)  Tohoku University

    FUWA Haruhiko

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    Grant amount: \2810000 ( Direct Cost: \2600000 、 Indirect Cost: \210000 )

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  • グルタミン酸受容体サブタイプ選択的な生体機能分子の創製と機能解析

    Grant number:16073202  2004 - 2007

    日本学術振興会  科学研究費助成事業  特定領域研究  東北大学

    佐々木 誠, 及川 雅人, 不破 春彦, 酒井 隆一, 島本 啓子

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    Grant amount: \57300000 ( Direct Cost: \57300000 )

    グルタミン酸受容体は高等動物の中枢神経シナプスにおいて興奮性神経伝達の中心的役割を司るのみならず、記憶や学習などの高次脳機能、種々の脳疾患における神経細胞死に深く関与している。グルタミン酸受容体は数多くのサブタイプに細分化されているが、個々の生理機能は未だ完全には明らかにされていない。本研究では、グルタミン酸受容体サブタイプ選択的なアゴニストである海綿由来の興奮性アミノ酸ダイシハーベインおよびネオダイシハーベインAとそれらの類縁体の効率的全合成と構造展開により、サブタイプ選択的な生体機能分子の創製と機能解析を目的とした。
    ネオダイシハーベインA類縁体全合成における重要中間体から、N-Boc保護1,2-アミノアルコールの分子内S_N2環化反応により6員環上の官能基導入を行い、ダイシハーベインの全合成を達成した。さらに、ヨードアミノ環化によるC8位アミノ基の立体選択的導入法を開発し、より効率的な全合成ルートを確立した。
    ダイシハーベインおよびネオダイシハーベインAとGluR5カイニン酸受容体リガンド結合ドメインとの複合体のX線結晶構造解析に初めて成功し、原子レベルでその結合様式を明らかにした。
    上記合成ルートを利用して、ダイシハーベイン類縁体を合成し、構造活性相関研究の結果からC9α水酸基が受容体との結合に重要であることが示唆された。また、ネオダイシハーベインAの構造類縁体について詳細な生物活性評価を行い、2,4-エピ体がGluR5およびGluR6カイニン酸受容体に対する機能的アンタゴニストとして機能する初めての化合物であることを明らかにした。

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  • 中員環ラクタムの効率的構築法の開発とそのγセクレターゼ阻害剤探索研究への応用

    Grant number:16710154  2004 - 2006

    日本学術振興会  科学研究費助成事業  若手研究(B)  東京大学

    不破 春彦

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    Grant amount: \2300000 ( Direct Cost: \2300000 )

    アルツハイマー病(AD)による死亡者は全世界で年間数百万人とも報告されており、その根治療法の確立は現代医学において解決すべき急務の課題である。ADの発症機構として提唱されているアミロイドβ(Aβ)仮説によれば、アスパラギン酸プロテアーゼであるγセクレターゼの機能を阻害しAβ産生を抑制するアプローチが、根治療法開発の一つの切り口である。米国EliLilly社が開発したγセクレターゼ阻害剤LY411575は、最も強力にAβ産生を阻害する低分子の一つである。
    本研究ではLY411575の構造的特徴である中員環ラクタムに着目し、その効率的構築法を検討した。既存の方法、すなわちBeckmannあるいはSchmidt転位では中員環ラクタムを収率良く得ることは困難であったが、ω-azidopentafluorophenyl esterの分子内Staudinger-aza-Wittig反応を用いると、多種多様な中員環ラクタムを効率的に構築できることを見出した。本反応の機構は次のように推察した:ホスフィンとアジド基とのStaudinger反応により生じたイミノホスホランが直ちに活性化エステルと分子内aza-Wittig反応を起こして不安定なイミノエーテルを生成し、これが加水分解を受けてラクタムが生じる。つぎに、LY411575の構造改変体の合成とそのAβ産生阻害活性の評価を行った。その結果、種々の置換基を導入しても、活性の低下を引き起こさない化学修飾に適切な部位が明らかとなり、適当なリンカーを介してベンゾフェノンやフルオレセインを導入した光親和性標識化プローブや蛍光プローブの開発にも成功した。現在、合成プローブを用いた有機化学レベルにおけるγセクレターゼの機能解析を検討している。

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    Marine Drugs誌   編集委員  

  • 2022.3 - 2024.2

    日本化学会 関東支部   常任幹事  

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    有機合成化学協会   編集委員  

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