Updated on 2024/02/02

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

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

    Haruhiko Fuwa

    SYNLETT   2023.9

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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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  • 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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    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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    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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    © The Royal Society of Chemistry 2020. Amphirionin-2 is a linear polyketide metabolite that exhibits potent and selective cytotoxic activity against certain human cancer cell lines. We disclose herein the first total synthesis of amphirionin-2 and determination of its absolute configuration. Our synthesis featured an extensive use of cobalt-catalyzed Mukaiyama-type cyclization of γ-hydroxy olefins for stereoselective formation of all the tetrahydrofuran rings found in the natural product, and a late-stage Stille-type coupling for convergent assembly of the entire carbon backbone. Four candidate diastereomers of amphirionin-2 were synthesized in a unified, convergent manner, and their spectroscopic/chromatographic properties were compared with those of the authentic material. The present study culminated in the reassignment of the C5/C7 relative configuration, assignment of the C12/C18 relative configuration, and determination of the absolute configuration of amphirionin-2.

    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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    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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    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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    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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    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)   Publisher:MDPI AG  

    Neopeltolide, an antiproliferative marine macrolide, is known to specifically inhibit complex III of the mitochondrial electron transport chain (mETC). However, details of the biological mode-of-action(s) remain largely unknown. This work demonstrates potent cytotoxic activity of synthetic neopeltolide analogue, 8,9-dehydroneopeltolide (8,9-DNP), against starved human pancreatic adenocarcinoma PANC-1 cells and human non-small cell lung adenocarcinoma A549 cells. 8,9-DNP induced rapid dissipation of the mitochondrial membrane potential and depletion of intracellular ATP level in nutrient-deprived medium. Meanwhile, in spite of mTOR inhibition under starvation conditions, impairment of cytoprotective autophagy was observed as the lipidation of LC3-I to form LC3-II and the degradation of p62 were suppressed. Consequently, cells were severely deprived of energy sources and underwent necrotic cell death. The autophagic flux inhibited by 8,9-DNP could be restored by glucose, and this eventually rescued cells from necrotic death. Thus, 8,9-DNP is a potent anti-austerity agent that impairs mitochondrial ATP synthesis and cytoprotective autophagy in starved tumor cells.

    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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    Gambierol and its two, tetra- and heptacyclic, analogues have been previously proved as promising molecules for the modulation of Alzheimer's disease (AD) hallmarks in primary cortical neurons of 3xTg-AD fetuses. In this work, the effect of the tetracyclic analogue of gambierol was tested in vivo in 3xTg-AD mice (10 months old) after 1 month of weekly treatment with 50 mu g/kg. Adverse effects were not reported throughout the whole treatment period and no pathological signs were observed for the analyzed organs. The compound was found in brain samples after intraperitoneal injection. The tetracyclic analogue of gambierol elicited a decrease of amyloid beta(1-42) levels and a dose-dependent inhibition of beta-secretase enzyme-1 activity. Moreover, this compound also reduced the phosphorylation of tau at the 181 and 159/163 residues with an increase of the inactive isoform of the glycogen synthase kinase-3 beta. In accordance with our in vitro neuronal model, this compound produced a reduction in the N2A subunit of the N-methyl-D-aspartate (NMDA) receptor. The combined effect of this compound on amyloid beta(1-42) and tau phosphorylation represents a multitarget therapeutic approach for AD which might be more effective for this multifactorial and complex neurodegenerative disease than the current treatments.

    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.  

    This account describes our endeavors on the total synthesis and structure elucidation of a marine macrolide glycoside, (−)-lyngbyaloside B. This natural product was isolated as a moderately cytotoxic constituent from the Palauan cyanobacterium Lyngbya sp. Our investigation started with the total synthesis of a nonnatural analog, (−)-13-demethyllyngbyaloside B, which was completed by exploiting an esterification/ring-closing metathesis strategy for the construction of the macrocyclic framework. Our efforts toward (−)-lyngbyaloside B were frustrated by the difficulties associated with the construction of the macrocycle involving an acylated tertiary alcohol. Eventually, the first total synthesis of the proposed structure of (−)-lyngbyaloside B was completed via an acyl ketene macrocyclization to forge the macrocyclic backbone. Because the proposed structure turned out to be erroneously assigned, we deduced the correct structure of (−)-lyngbyaloside B on the basis of the NMR data of the authentic material and molecular modeling. Ultimately, our revised structure was unambiguously verified through total synthesis.

    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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    This paper describes a concise synthesis of six- to eight-membered alpha,alpha'-substituted cyclic ethers by exploiting diastereoselective ring-closing metathesis (RCM) of 1,4-pentadien-3-yl ether derivatives. The RCM precursors could be efficiently prepared via a vinylation of the corresponding a-acetoxy ether derivatives using divinylzinc. Diastereoselective RCM of 1,4-pentadien-3-yl ether derivatives afforded a series of six- to eight-membered alpha,alpha'-substituted cyclic ethers with moderate to good diastereoselectivity. The stereochemical consequence of the diastereoselective RCM appeared to be dependent on the structure of the ring being forged. The diastereoselectivity of six- and seven-membered cyclic ethers appeared to be largely under kinetic control irrespective of the catalyst reactivity, whereas that of an eight-membered cyclic ether could be controlled by the catalyst reactivity. Finally, the diastereoselective RCM chemistry was applied to the synthesis of a biotin-tagged photoactivatable derivative of gambierol.

    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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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PERGAMON-ELSEVIER SCIENCE LTD  

    Okadaic acid (OA), a product of dinoflagellate Prorocentrum spp., is transformed into 7-O-acyl OA in various bivalve species. The structural transformation proceeds enzymatically in vitro in the presence of the microsomal fraction from the digestive gland of bivalves. We have been using LC-MS/MS to identify OA-transforming enzymes by detecting 7-O-acyl OA, also known as dinophysistoxin 3 (DTX3). However, an alternative assay for DTX3 is required because the OA-transforming enzyme is a membrane protein, and surfactants for solubilizing membrane proteins decrease the sensitivity of LC-MS/MS. The present study examined saturated fatty acyl CoAs with a carbon chain length of 10 (decanoyl), 12 (dodecanoyl), 14 (tetradecanoyl), 16 (hexadecanoyl) and 18 (octadecanoyl) as the substrate for the in vitro acylation reaction. Saturated fatty acyl CoAs with a carbon chain length of 14, 16 and 18 exhibited higher yields than those with a carbon chain length of 10 or 12. Acyl CoAs with carbon chain lengths from 14 to 18 and containing either a diene unit, an alkyne unit, or an azide unit in the carbon chain were synthesized and shown to provide the corresponding DTX3 with a yield comparable to that of hexadecanoyl CoA. The three functional units can be conjugated with fluorescent reagents and are applicable to the development of a novel assay for DTX3. (C) 2016 Elsevier Ltd. All rights reserved.

    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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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-V C H VERLAG GMBH  

    We have described in detail the total synthesis of both the proposed and correct structures of (-)-lyngbyalosideB, which facilitated the elucidation of the complete stereostructure of this natural product. Our study began with the total synthesis of 13-demethyllyngbyalosideB, in which an esterification/ring-closing metathesis (RCM) strategy was successfully used for the efficient construction of the macrocycle. We also established reliable methods for the introduction of the conjugated diene side chain and the l-rhamnose residue onto the macrocyclic framework. However, the esterification/RCM strategy proved ineffective for the parent natural product because of the difficulties in acylating the sterically encumbered C-13 tertiary alcohol; macrolactionization of a seco-acid was also extensively investigated under various conditions without success. We finally completed the total synthesis of the proposed structure of (-)-lyngbyalosideB by means of a macrolactonization that involves an acyl ketene as the reactive species. However, the NMR spectroscopic data of our synthetic material did not match those of the authentic material, which indicated that the proposed structure must be re-examined. Inspection of the NMR spectroscopic data of the natural product and molecular mechanics calculations led us to postulate that the configuration of the C-10, C-11, and C-13 stereogenic centers had been incorrectly assigned in the proposed structure. Finally, our revised structure of (-)-lyngbyalosideB was unambiguously verified through total synthesis.

    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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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER CHEMICAL SOC  

    Campechic acids A and B are anti-invasive polyketide antibiotics isolated from Streptomyces sp. CHI93 strain. Herein we describe stereoselective synthesis of the C-16-C-30 fragment of campechic acids A and B via a biosynthesis-inspired epoxide-opening cascade and its NMR spectroscopic comparison with the authentic degradation product, resulting in configurational assignment of the C-21, C-24, C-25, and C-28 stereogenic centers and reassignment of the C-18 stereogenic center.

    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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    A synthesis of the C8-C29 fragment of amphidinolide N, a potent cytotoxic macrolide isolated from the marine dinoflagellate Amphidinium sp., has been achieved. The key features of the synthesis involve a convergent union of the C9-C15 and C16-C29 fragments by Steglich esterification and the construction of a pyran unit through a Tebbe methylenation/ring-closing metathesis sequence.

    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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    Tetrahydropyrans are structural motifs that are abundantly present in a range of biologically important marine natural products. As such, significant efforts have been paid to the development of efficient and versatile methods for the synthesis of tetrahydropyran derivatives. Neopeltolide, a potent antiproliferative marine natural product, has been an attractive target compound for synthetic chemists because of its complex structure comprised of a 14-membered macrolactone embedded with a tetrahydropyran ring, and twenty total and formal syntheses of this natural product have been reported so far. This review summarizes the total and formal syntheses of neopeltolide and its analogues, highlighting the synthetic strategies exploited for constructing the tetrahydropyran ring.

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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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    Goniodomin A is a marine polyether macrolide natural product isolated from the dinoflagellate Alexandrium hiranoi. In this paper, we report stereocontrolled, convergent synthesis of a fully functionalized C12-C36 fragment of goniodomin A. The synthesis of the C12-C25 vinylstannane involved a Wittig reaction and a reductive cycloetherification for the construction of the dihydropyran ring. The C26-C36 thioester was synthesized via a Nozaki-Hiyama-Kishi reaction of an aldehyde and an iodoalkyne, the former of which was easily prepared from (R)-malic add as a chiral source by taking advantage of substrate-controlled diastereoselective reactions. Finally, a palladium-catalyzed coupling of the C12-C25 vinylstannane and the C26-C36 thioester completed the synthesis of the target compound.

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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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    A marine polyether natural product okadaic acid is known to be a potent and specific inhibitor of protein phosphatases 1 and 2A. Herein, concise synthesis of the C15-C38 fragment of okadaic acid is reported. We investigated two different strategies for the construction of two spiroacetal substructures found in the target compound. The first strategy involved Suzuki Miyaura coupling for the synthesis of endocyclic enol ethers and subsequent spiroacetalization. The second strategy exploited Suzuki-Miyaura coupling for the synthesis of exo-olefins as the precursor of spiroacetals. An alkynylaluminum-anomeric sulfone coupling effectively assembled the key spiroacetal substructures and completed the target compound. (C) 2015 Elsevier Ltd. All rights reserved.

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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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    Gambierol is a marine polycyclic ether toxin, produced along with ciguatoxin congeners by the dinoflagellate Gambierdiscus toxicus. We have recently reported that two truncated skeletal analogs of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound showed similar potency to gambierol on voltage-gated potassium channels (Kv) inhibition in neurons. Gambierol and its truncated analogs share the main crucial elements for biological activity, which are the C28=C29 double bond within the H-ring and the unsaturated side chain. Since Kv channels are critical for the regulation of calcium signaling, proliferation, secretion and migration in human T lymphocytes, we evaluated the activity of both the tetracyclic and heptacyclic analogs of gambierol on potassium currents in resting T lymphocyte and their effects on interleukin-2 (IL-2) release and gene expression in activated T lymphocytes. The results presented in this work clearly demonstrate that both truncated analogs of gambierol inhibit Kv channels present in resting T lymphocytes (Kv1.3) and prevented lymphocyte activation by concanavalin A. The main effects of the heptacyclic and tetracyclic analogs of gambierol in human T cells are: (1) inhibition of potassium channels in resting and concanavalin-activated T cells in the nanomolar range, (2) inhibition of IL-2 release from concanavalin-activated T cells and (3) negatively affect the expression of genes involved in cell proliferation and immune response observed in concanavalin-activated lymphocytes. These results together with the lack of toxicity in this cellular model, indicates that both analogs of gambierol have additional potential for the development of therapeutic tools in autoimmune diseases.

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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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    Gambierol and its heptacyclic and tetracyclic analogs were tested for inhibitory activity against the human voltage-gated potassium channel Kv1.2 (hKv1.2), which was stably expressed in Chinese hamster ovary (CHO) cells. Gambierol, the heptacyclic analog, and the tetracyclic analog inhibited the potassium current evoked by a step pulse from -80 mV to 40 mV. The IC50 values for the three compounds were 0.75 +/- 0.15 nM, 7.6 +/- 1.2 nM, and 28 +/- 4.0 nM (the mean +/- SEM, n = 3), respectively. The cytotoxic activity was examined in order to assess a relationship between cytotoxicity and inhibition of the hKv1.2. The IC50 values for gambierol, the heptacyclic analog, and the tetracyclic analog in the wild-type CHO cells were 95 +/- 7.1 lM, 6.5 +/- 0.8 lM(the mean +/- SEM, n = 3), and > 100 lM (n = 3), respectively, whereas those in the CHO cells stably expressing hKv1.2 were 78 +/- 5.8 lM, 6.0 +/- 1.0 lM (the mean +/- SEM, n = 3), and > 100 lM (n = 3). These results suggested that cytotoxicity is not triggered by inhibition of the human Kv1.2. The electrophysiological recording at the resting potential in the presence of gambierol, the heptacyclic analog, and the tetracyclic analog revealed the dose-dependent leak current, which was largest when the heptacyclic analog was administered to the cells. We thus propose that the leak current induced by these compounds might cause a fatal effect on the cultured cells. (C) 2014 Elsevier Ltd. All rights reserved.

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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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    Gambieric acid A (GAA) and its congeners belong to the family of marine polycyclic ether natural products. Their highly complex molecular architecture and unique biological activities have been of intense interest within the synthetic community. We have previously reported the first total synthesis, stereochemical reassignment, and preliminary structure activity relationships of GAA. Here we disclose a concise synthesis of the A/BCD-ring fragment of GAA. The synthesis started from our previously reported synthetic intermediate that represents the A/B-ring. The C-ring was synthesized via an oxiranyl anion coupling and a 6-endo cyclization, and the D-ring was forged by means of an oxidative lactonization and subsequent palladium-catalyzed functionalization of the lactone ring. In this manner, the number of linear synthetic steps required for the construction of the C- and D-rings was reduced from 22 to 11.

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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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    (-)-Lyngbyaloside B is a 14-membered macrolide glycoside isolated from the marine cyanobacterium Lyngbya sp. as a cytotoxic substance by Moore and co-workers. The first total synthesis of (-)-lyngbyaloside B and the reassignment of its stereostructure is described. The synthesis features an Abiko-Masamune aldol reaction, a vinylogous Mukaiyama aldol reaction, and a macrocyclization involving an acyl ketene intermediate for the construction of the macrocyclic backbone, which contains an acylated tertiary alcohol. The antiproliferative activity of selected compounds against a small panel of human cancer cell lines is also reported.

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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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    A stereocontrolled synthesis of the C13-C29 segment of amphidinolide N, a marine macrolide natural product that is extremely potent cytotoxic, is described.

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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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    (+)-Neopeltolide is a marine macrolide natural product that exhibits potent antiproliferative activity against several human cancer cell lines. Previous study has established that this natural product primarily targets the complex III of the mitochondrial electron transport chain. However, the biochemical mode-of-actions of neopeltolide have not been investigated in detail. Here we report that (-)-8,9-dehydroneopeltolide (8,9-DNP), a more accessible synthetic analogue, shows potent cytotoxicity against human promyelocytic leukemia HL-60 cells preferentially under energy stress conditions. Nuclear morphology analysis, as well as DNA ladder assay, indicated that 8,9-DNP induced significant nuclear condensation/fragmentation and DNA fragmentation, and these events could be suppressed by preincubating the cells with a pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD). Immunoblot analysis demonstrated the release of cytochrome c from the mitochondria and the cleavage of full-length caspase-3 and poly(ADP-ribose) polymerase (PARP). These results indicated that 8,9-DNP induced caspase-dependent apoptotic programmed cell death under energy stress conditions. It was also found that 8,9-DNP induced non-apoptotic cell death in the presence/absence of zVAD under energy stress conditions. Immunoblot analysis showed the intracytosolic release of apoptosis-inducing factor (AIF), although it did not further translocate to the nucleus. It appears most likely that, in the presence of zVAD, 8,9-DNP triggered necrotic cell death as a result of severe intracellular ATP depletion.

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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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    More than thirty years after the discovery of polycyclic ether marine natural products, they continue to receive intense attention from the chemical, biological, and pharmacological communities because of their potent biological activities and highly complex molecular architectures. Gambieric acids are intriguing polycyclic ethers that exhibit potent antifungal activity with minimal toxicity against mammals. Despite the recent advances in the synthesis of this class of natural products, gambieric acids remain unconquered due to their daunting structural complexity, which poses a formidable synthetic challenge to organic chemists. This paper reviews our long-term studies on the total synthesis, complete configurational reassignment, and structure-activity relationships of gambieric acid A over the last decade.

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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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    We describe the synthesis and biological evaluation of (+)-neopeltolide analogues with structural modifications in the oxazole-containing side chain. Evaluation of the antiproliferative activity of newly synthesized analogues against A549 human lung adenocarcinoma cells and PANC-1 human pancreatic carcinoma cells have shown that the C19-C20 and C26-C27 double bonds within the oxazole-containing side chain and the terminal methyl carbamate group are essential for potent activity. (C) 2014 Elsevier Ltd. All rights reserved.

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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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    Stereoselective synthesis of alpha,alpha'-substituted medium-sized cyclic ethers has been achieved by means of nucleophilic substitution of the corresponding lactone-derived thioacetals and their sulfone counterparts. Nucleophilic substitution of medium-sized lactone-derived thioacetals could be achieved efficiently either by (i) activation with NIS/TMSOTf in the presence of allyltrimethylsilane or TMSCN or by (ii) oxidation to the corresponding sulfones followed by treatment with an appropriate organometallic species such as divinylzinc or dimethyl(2-phenylethynyl)aluminum. Interestingly, the stereochemical consequence was found to be largely dependent on the local structure of substrates. In some cases, the gauche steric interaction developed in the transition state was considered to be responsible for the observed diastereoselectivity. The present method enables an efficient synthesis of a variety of alpha,alpha'-substituted seven- to nine-membered cyclic ethers from readily accessible lactone precursors.

    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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    Didemnaketal B, a structurally complex spiroacetal that exhibits potent HIV-1 protease inhibitory activity, was originally discovered by Faulkner and his colleagues from the ascidian Didemnum sp. collected at Palau. Its absolute configuration was proposed on the basis of degradation/derivatization experiments of the authentic sample. However, our total synthesis of the proposed structure of didemnaketal B questioned the stereochemical assignment made by Faulkner et al. Here we describe in detail our first total synthesis of the proposed structure 2 of didemnaketal B, which features 1) a convergent synthesis of the C7-C21 spiroacetal domain by means of a strategy exploiting Suzuki-Miyaura coupling, 2) an Evans syn-aldol reaction and a vinylogous Mukaiyama aldol reaction for the assembly of the C1-C7 acyclic domain, and 3) a Nozaki-Hiyama-Kishi reaction for the construction of the C21-C28 side chain domain. The NMR spectroscopic discrepancies observed between synthetic 2 and the authentic sample as well as careful inspection of the Faulkner's stereochemical assignment led us to postulate that the absolute configuration of the C10-C20 domain of 2 has been erroneously assigned. Accordingly, the total synthesis of the revised structure 65 was achieved to show that the NMR spectroscopic properties of synthetic 65 were in good agreement with those of the authentic sample. Furthermore, application of the phenylglycine methyl ester ( PGME) method to the C7-C21 spiroacetal domain enabled us to establish the absolute configuration of didemnaketal B.

    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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    In this study, stereoisomeric aspergillide A/neopeltolide chimeras were synthesized in a parallel manner, and their antiproliferative activity was evaluated to demonstrate the potential utility of the 14-membered macrolactone structure embedded with a tetrahydropyran substructure as a template for developing natural product-like antiproliferative agents.

    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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    Total synthesis of the proposed structure of didemnaketal B has been accomplished. The C7-C21 spiroacetal domain was synthesized by exploiting our Suzuki-Miyaura coupling/spiroacetalization strategy. The C1-C7 acyclic domain was constructed via an Evans syn-aldol reaction and a vinylogous Mukaiyama aldol reaction. Finally, the C22-C28 side chain was introduced by means of a Nozaki-Hiyama-Kishi reaction. Comparison of the NMR spectroscopic data of our synthetic material with those of the authentic sample revealed that the proposed structure requires stereochemical reassignment.

    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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    We describe herein a concise synthesis of (+)-neopeltolide, a marine macrolide natural product that elicits a highly potent antiproliferative activity against several human cancer cell lines. Our synthesis exploited the powerful bond-forming ability and high functional group compatibility of olefin metathesis and esterification reactions to minimize manipulations of oxygen functionalities and to maximize synthetic convergency. Our findings include a chemoselective olefin cross-metathesis reaction directed by H-bonding, and a ring-closing metathesis conducted under non-high dilution conditions. Moreover, we developed a 16-member stereoisomer library of 8,9-dehydroneopeltolide to systematically explore the stereostructure-activity relationships. Assessment of the antiproliferative activity of the stereoisomers against A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma, HT-1080 human fibrosarcoma, and P388 murine leukemia cell lines has revealed marked differences in potency between the stereoisomers. This study provides comprehensive insights into the structure-activity relationship of this important antiproliferative agent, leading to the identification of the pharmacophoric structural elements and the development of truncated analogues with nanomolar potency. SAR of (+)-neopeltolide: A modular synthetic route to (+)-neopeltolide, a potent antiproliferative marine macrolide, was established by exploiting the esterification/olefin metathesis strategy, and a 16-member stereoisomer library of 8,9-dehydeoneopeltolide was developed to elucidate the stereostructure- activity relationships (see figure). Copyright © 2013 WILEY-VCH Verlag GmbH &amp
    Co. KGaA, Weinheim.

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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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    Total synthesis of 13-demethyllyngbyaloside B, an unnatural analogue of a marine macrolide glycoside lyngbyaloside B, has been achieved. The 14-membered macrocyclic backbone was constructed in a convergent manner via esterification and ring-closing metathesis. The bromodiene side chain was introduced by means of a Stille-type reaction and a subsequent bromodesilylation. Finally, the rhamnopyranose unit was stereoselectively introduced by glycosylation under Schmidt conditions.

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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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    (-)-Exiguolide (1), isolated from the marine sponge Geodia exigua, has been shown to inhibit the growth of the A549 human lung adenocarcinoma and NCI-H460 human lung large cell carcinoma cells in vitro. In this study, we synthesized structural analogues of 1 to explore its skeletal structure-activity relationships and found that the C18 methyl group and the configuration of the C16-C17 double bond of 1 are important for the potent antiproliferative activity. Furthermore, we prepared a series of side-chain analogues of 1 by diversification of a late-stage intermediate of our total synthesis, and found that the triene side chain of 1 could be modified to some extent without significant loss of activity, provided a Lewis basic heteroatom is placed at the terminus.

    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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    We describe herein a concise synthesis of the AB-ring fragment of gambierol, wherein silver(I) trifluoromethanesulfonate-catalyzed 6-endo cyclization of a hydroxy ynone was exploited for the formation of the A-ring.

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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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    Herein, we describe the concise synthesis of 2,6-cis-substituted tetrahydropyran derivatives based on a domino olefin cross-metathesis/intramolecular oxa-conjugate cyclization (CM/IOCC) reaction. We have found that the domino CM/IOCC of delta-hydroxy olefins with alpha,beta-unsaturated carbonyl compounds (e.g., trans-crotonaldehyde or N-acryloyl-2,5-dimethylpyrrole) could be efficiently achieved in the presence of the second-generation Hoveyda-Grubbs catalyst under elevated temperature conditions, directly affording 2,6-cis-substituted tetrahydropyrans in excellent yields with synthetically useful diastereoselectivity ("auto-tandem catalysis"). In addition, we have found that the domino CM/IOCC of delta-hydroxy olefins with alpha,beta-unsaturated carbonyl compounds could be achieved simply by performing CM in the presence of a Bronsted acid in CH2Cl2 at 25-35 degrees C, which delivered 2,6-cis-substituted tetrahydropyrans in good yields with excellent diastereoselectivity ("orthogonal-tandem catalysis"). To understand the mechanism of auto-tandem catalysis in the domino CM/IOCC reaction, we have investigated the role of ruthenium hydride complexes in the IOCC of a zeta-hydroxy alpha,beta-unsaturated ketone as a model case.

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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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    Language:Japanese   Publisher:Symposium on the chemistry of natural products  

    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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    The polycyclic ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse biological activities. Gambierol is a marine polycyclic ether toxin, first isolated along with ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound gambierol and the analogues evaluated in this work share the main crucial elements for biological activity, previously described to be the C28=C29 double bond within the H ring and the unsaturated side chain [Fuwa, H., Kainuma, N., Tachibana, K., Tsukano, C., Satake, M., and Sasaki, M. (2004) Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity. Chem. Eur. J. 10, 4894-4909]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of voltage-gated sodium channels (Nay), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a "loss of function" effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of gambierol elicited synchronous calcium oscillations similar to those previously described for gambierol in cultured cerebellar neurons. Neither gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of gambierol exhibited lethality in mice after ip injection of 50 or 80 mu g/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for gambierol and its tetracyclic and heptacyclic analogues and indicate a "loss of function" effect on potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of therapies against ciguatera poisoning and potassium channel-related diseases.

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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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    Stereoselective synthesis of the C1-C16 fragment of the antifungal marine polyether macrolide goniodomin A is described. A Stille-type coupling of organostannanes and thioesters was exploited as the key carbon carbon bondforming process, namely for the formation of the C7-C8 and C11-C12 bonds. Construction of the spiroacetal domain via acid-catalyzed acetalization of a triol-enone 30 unexpectedly provided a mixture of natural 11S spiroacetal 2, unnatural 11R spiroacetal 32, and constitutional isomer 33. Fortunately, it was eventually found that protection of the C5 hydroxy group as its acetate facilitated the isolation of natural 11S isomer 47 via acid-catalyzed equilibration of unnatural 11R isomer 48 and avoided the formation of a constitutional isomer, thereby increasing the efficacy of the spiroacetalization process.

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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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    Total synthesis of gambieric acid A, a potent antifungal polycyclic ether metabolite, has been accomplished for the first time, which firmly established the complete stereostructure of this natural product.

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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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    A growing number of tetrahydropyran-containing biologically active substances are being discovered from nature. Intramolecular oxa-conjugate cyclization (IOCC) is known as one of the most powerful methodologies for the stereoselective synthesis of substituted tetrahydropyran derivatives, although there is clearly room for methodological improvement. In this review, we describe our successful total synthesis of tetrahydropyran-containing natural products by exploiting IOCC and the discoveries that we have made during the course of the synthetic campaigns.

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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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    Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K-v channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage gated potassium channels (K-v) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (A beta) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K+ currents, a reduction in the extra- and intracellular levels of A beta, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K-v channels as well as the molecular mechanism of A beta metabolism modulated by NMDA receptors.

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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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    Intramolecular oxa-conjugate cyclization (IOCC) of alpha,beta-unsaturated carbonyl compounds, triggered by deprotonation with a base, represents a straightforward method for the synthesis of tetrahydropyrans. However, it has been known that stereochemical outcome of IOCC depends on the local structure substrates and sometimes requires harsh reaction conditions and/or prolonged reaction times for selective formation of 2,6-cis-substituted tetrahydropyrans. These shortcomings limit the feasibility of IOCC in the context of complex natural product synthesis. In this paper, we describe Bronsted acid-catalyzed IOCC of alpha,beta-unsaturated ester surrogates (e.g., alpha,beta-unsaturated thioesters, oxazolidinone imides, and pyrrole amides) under mild reaction conditions, which affords a series of synthetically versatile 2,6-cis-substituted tetrahydropyran derivatives with good to excellent stereoselectivity (dr from 7:1 to >20:1). These alpha,beta-unsaturated carbonyl compounds were found to be more reactive than the corresponding oxoesters that are generally unreactive toward Bronsted acid-catalyzed intramolecular oxa-conjugate additions. The product tetrahydropyrans could be transformed into various derivatives in an efficient manner, highlighting the usefulness of our methodology.

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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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    We describe a streamlined strategy for the practical synthesis of trans-fused polycyclic ethers and its application to a concise total synthesis of (-)-brevenal, a new pentacyclic polyether natural product with intriguing biological activities. The B-, D-, and E-rings were constructed by TEMPO/PhI(OAc)2-mediated oxidative lactonization of the corresponding 1,6-diols, with minimal need for manipulation of oxygen functionalities. The B- and E-ring lactones were appropriately functionalized by SuzukiMiyaura coupling of lactone-derived enol phosphates and subsequent stereoselective hydroboration. The A-ring was formed by our mixed thioacetalization methodology. The AB- and DE-ring fragments were assembled through SuzukiMiyaura coupling, and the C-ring was forged in the same manner as that for the A-ring. More than two grams of the pentacyclic polyether core of (-)-brevenal have been synthesized by the synthetic route developed in this study.

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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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    The ladder-shaped polycyclic ether marine natural products present formidable and challenging synthetic targets due to their structural complexity, and exceptionally potent biological activities. Over the past decade, however, the limited availability of these substances from natural sources has precluded detailed biological studies. There has been an urgent need for means to supply useful quantities of these natural products and their analogues by total synthesis. We have developed a highly convergent strategy for the rapid and efficient assembly of polycyclic ether arrays, which relies on the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of cyclic enol triflates or phosphates. The utility of this strategy has been demonstrated by its application to the convergent total synthesis of the polycyclic ether class of natural products.

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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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    A stereocontrolled synthesis of a fully elaborated GHIJ-ring fragment of gambieric acids, which are potent antifungal polycyclic ether natural products, has been accomplished. The synthesis features convergent assembly of the tetracyclic polyether skeleton through aldol coupling/cyclodehydration/reductive etherification processes and stereoselective construction of the J-ring side chain by a CeCl(3)-promoted Julia-Kocienski olefination. (C) 2011 Elsevier Ltd. All rights reserved.

    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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    In this paper, we describe a new strategy for the synthesis of substituted dihydropyrones and tetrahydropyrones. By exploiting palladium-catalyzed coupling of thioesters with terminal alkynes or alkenylboronic acids, a variety of beta-hydroxy ynones or enones, respectively, could be prepared in an efficient manner under mild conditions. AgOTf-promoted intramolecular oxa-conjugate cyclization of beta-hydroxy ynones provided 2,6-substituted dihydropyrones in excellent yields. On the other hand, acid-catalyzed cyclization of beta-hydroxy enones caused racemization of the product 2,6-substituted tetrahydropyrones due to its reversible nature. Eventually, stereoselective hydrogenation of substituted dihydropyrones was found to be a solid and efficient approach for the synthesis of 2,6-cis-substituted tetrahydropyrone derivatives. (C) 2011 Elsevier Ltd. All rights reserved.

    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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    Many microalgae produce compounds that exhibit potent biological activities. Ingestion of marine organisms contaminated with those toxins results in seafood poisonings. In many cases, the lack of toxic material turns out to be an obstacle to make the toxicological investigations needed. In this study, we evaluate the cytotoxicity of several marine toxins on neuroblastoma cells, focusing on gambierol and its effect on cytosolic calcium levels. In addition, we compared the effects of this toxin with ciguatoxin, brevetoxin, and gymnocin-A, with which gambierol shares a similar ladder-like backbone, as well as with polycavernoside A analogue 5, a glycosidic macrolide toxin. For this purpose, different fluorescent dyes were used: Fura-2 to monitor variations in cytosolic calcium levels, Alamar Blue to detect cytotoxicity, and Oregon Green 514 Phalloidin to quantify and visualize modifications in the actin cytoskeleton. Data showed that, while gambierol and ciguatoxin were successful in producing a calcium influx in neuroblastoma cells, gymnocin-A was unable to modify this parameter. Nevertheless, none of the toxins induced morphological changes or alterations in the actin assembly. Although polycavernoside A analogue 5 evoked a sharp reduction of the cellular metabolism of neuroblastoma cells, gambierol scarcely reduced it, and ciguatoxin, brevetoxin, and gymnocin-A failed to produce any signs of cytotoxicity. According to this, sharing a similar polycyclic ether backbone is not enough to produce the same effects on neuroblastoma cells; therefore, more studies should be carried out with these toxins, whose effects may be being underestimated.

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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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    Intramolecular oxa-conjugate cyclization of alpha,beta-unsaturated thioesters under Bronsted acid catalysis, inspired by biosynthesis of polyketide natural products, provides a variety of 2,6-cis-substituted tetrahydropyran derivatives with excellent diastereoselectivities. An added bonus of this methodology is that the product tetrahydropyrans could be readily elaborated to various derivatives by exploiting the unique reactivity of the thioester group.

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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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    A convergent synthesis of the C1-C16 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product, has been achieved via a 2-fold application of palladium-catalyzed organostannane-thioester coupling.

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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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    We describe herein an enantioselective total synthesis of (-)-exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross-metathesis for the assembly of readily available acyclic segments and intramolecular oxa-conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20-membered macrocyclic framework was constructed in an efficient manner by means of Julia-Kocienski coupling and Yamaguchi macrolactonization. Finally, the (E,Z,E)-triene side chain was introduced stereoselectively via Suzuki-Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (-)-exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI-H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure-activity relationships of (-)-exiguolide, which elucidated that the C5-methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity.

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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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    Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in Apc(Delta 716) intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.

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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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    In this Account, we describe our efforts in the development of new synthetic strategies for the construction of N- and O-heterocycles by exploiting palladium-catalyzed reactions using enol phosphates as an electrophilic component.

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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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    A stereocontrolled convergent synthesis of the C15-C36 segment of goniodomin A, a potent anti-angiogenic marine polyether macrolide, has been achieved using Stille-type cross-coupling reaction of a vinylstannane and a thioester as a key segment assembly process. (C) 2010 Elsevier Ltd. All rights reserved.

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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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    A stereocontrolled synthesis of the GHIJ-ring fragment having a side chain of gambieric acids, which are potent antifungal polycyclic ether natural products, has been achieved. The synthesis features convergent assembly of the tetracyclic polyether skeleton by using aldol coupling and stereoselective construction of the J-ring side chain by a cerium chloride-promoted Julia-Kocienski reaction. (C) 2010 Elsevier Ltd. All rights reserved.

    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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    Total synthesis of structurally complex marine oxacyclic natural products, (-)-gambierol, (-)-brevenal, and (+)-neopeltolide, has been accomplished by exploiting Suzuki-Miyaura coupling of enol phosphates, paving the way for biological investigations on these scarcely available substances.

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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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    A highly convergent synthesis of the C9-C28 spiroacetal subunit of didemnaketal B has been accomplished. Assembly of the C9-C15 alkylborate and C16-C21 enol phosphate by means of Suzuki-Miyaura coupling and acid-catalyzed cyclization of the derived dihydroxy enol ether enabled a rapid and efficient construction of the spiroacetal subunit. The C22-C28 side chain was incorporated via Nozaki-Hiyama-Kishi coupling to complete the synthesis.

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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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    Gambierol is a complex marine toxin first isolated with ciguatoxins from cell cultures of the toxic dinoflagellate Gambierdiscus toxicus. Despite the chemical complexity of the polycyclic ether toxin, the total successful synthesis of gambierol has been achieved by different chemical strategies. In the present work the effects of synthetic gambierol on mouse and frog skeletal neuromuscular preparations and Xenopus skeletal myocytes have been studied. Gambierol (0.1-5 mu M) significantly increased isometric twitch tension in neuromuscular preparations stimulated through the motor nerve. Less twitch augmentation was observed in directly stimulated muscles when comparing twitch tension-time integrals obtained by nerve stimulation. Also, gambierol induced small spontaneous muscle contraction originating from presynaptic activity that was completely inhibited by D-tubocurarine. Gambierol slowed the rate of muscle action potential repolarization, triggered spontaneous and/or repetitive action potentials, and neither affected action potential amplitude nor overshoot in skeletal muscle fibers. These results suggest that gambierol through an action on voltage-gated K+ channels prolongs the duration of action potentials, enhances the extent and time course of Ca2+ release from the sarcoplasmic reticulum, and increases twitch tension generation. Further evidence is provided that gambierol at sub-micromolar concentrations blocks a fast inactivating outward K+ current that is responsible for action potential prolongation in Xeno pus skeletal myocytes. (C) 2010 Elsevier Ltd. All rights reserved.

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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.

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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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    An enantioselective total synthesis of aspergillides A and B has been accomplished on the basis of a unified synthetic strategy that exploits stereodivergent intramolecular oxa-conjugate cyclization and Yamaguchi macrolactonization. (C) 2010 Elsevier Ltd. All rights reserved.

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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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    A stereocontrolled convergent synthesis of a DEFG-ring model compound of gambieric acids, highly potent antifungal marine polycyclic ether natural products, has been achieved based on Suzuki-Miyaura coupling. Conformational analysis of the model compound revealed that the nine-membered F-ring exists exclusively as a single stable conformer, as opposed to that of ciguatoxins.

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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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    Gambierol is a marine polyether ladder toxin derived from the dinoflagellate Gambierdiscus toxicus. To date, gambierol has been reported to act either as a partial agonist or as an antagonist of sodium channels or as a blocker of voltage-dependent potassium channels. In this work, we examined the cellular effect of gambierol on cytosolic calcium concentration, membrane potential and sodium and potassium membrane currents in primary cultures of cerebellar granule cells. We found that at concentrations ranging from 0.1 to 30 mu M, gambierol-evoked [Ca(2+)]c oscillations that were dependent on the presence of extracellular calcium, irreversible and highly synchronous. Gambierol-evoked [Ca(2+)]c oscillations were completely eliminated by the NMDA receptor antagonist APV and by riluzole and delayed by CNQX. In addition, the K(+) channel blocker 4-aminopyridine (4-AP)-evoked cytosolic calcium oscillations in this neuronal system that were blocked by APV and delayed in the presence of CNQX. Electrophysiological recordings indicated that gambierol caused membrane potential oscillations, decreased inward sodium current amplitude and decreased also outward IA and IK current amplitude. The results presented here point to a common mechanism of action for gambierol and 4-AP and indicate that gambierol-induced oscillations in cerebellar neurons are most likely secondary to a blocking action of the toxin on voltage-dependent potassium channels and hyperpolarization of sodium current activation. J. Cell. Biochem. 110: 497-508, 2010. (C) 2010 Wiley-Liss, Inc.

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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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    An efficient strategy for the synthesis of 2,6-disubstituted 2,3-dihydro-4H-pyran-4-ones has been developed, which relied on Sonogashira coupling of alkynes and p-toluenethiol esters and AgOTf-promoted 6-endo-dig cyclization of the derived beta-hydroxy ynones.

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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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    An enantioselective total synthesis of aspergillides A and B has been accomplished based on a unified strategy, wherein a hydroxy-directed, highly chemoselective olefin cross-metathesis and a diastereoselective intramolecular oxa-conjugate cyclization were employed to forge the 2,6-substituted tetrahydropyran substructure.

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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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    A novel strategy for the stereoselective synthesis of substituted tetra hydropyrans has been developed on the basis of a domino olefin cross-metathesis/intramolecular oxa-conjugate cyclization catalyzed by the Hoveyda-Grubbs second-generation catalyst.

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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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    Total synthesis of (-)-exiguolide, the natural enantiomer, has been accomplished for the first time. The bis(tetrahydropyran) subunit was efficiently synthesized via consecutive olefin cross-metathesis/intramolecular oxa-conjugate addition/reductive etherification. Construction of the 20-membered macrocycle was achieved by Yamaguchi macrolactonization. Stereoselective introduction of the (E,Z,E)-triene side chain via Suzuki-Miyaura coupling completed the total synthesis.

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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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    A catalytic amount of TEMPO in the presence of PhI(OAc)(2) effected oxidative lactonization of 1,6- and 1,7-diols, directly affording seven- and eight-membered lactones, respectively, in good yields.

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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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    Stereoselective convergent synthesis of the C15-C36 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product, has been achieved. The present synthesis features palladium(0)-catalyzed, copper(I)-mediated Liebeskind-Srogl cross-coupling as the fragment assembly process.

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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.

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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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    A stereocontrolled entry to the DEFG-ring skeleton of gambieric acids, potent antifungal polycyclic ether natural products, has been developed based on the Suzuki-Miyaura coupling as the fragment assembly process and the use of an oxepane as a template for controlling the C25 stereogenic center.

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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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    We have used proteomic analyses to probe the responses induced by a pair of marine biotoxins, okadaic acid (OA) and gambierol (GB), added alone or in combination to a cultured cell line and carried out a preliminary investigation into the possible interactions between toxins possessing two different molecular mechanisms of action at a cellular level. When MCF-7 cells were treated with OA, we found that cellular levels of 30 proteins were significantly affected, including several isoforms of nonphosphorylated and phosphorylated hsp 27, as well as enzymes involved in the maintenance of nucleoside triphosphate pools and the control of redox states of the cell. When we repeated our analysis using GB, nine proteins were significantly affected, including some isoforms of nonphosphorylated hsp 27, as well as semenogelin-1, myosin-7, and the ATP synthase subunit delta. The combined addition of OA and GB to MCF-7 cells, in turn, affected 14 proteins, including some isoforms of nonphosphorylated and phosphorylated hsp 27, as well as myosin-7, the ATP synthase subunit delta, and enzymes involved in the control of redox states of the cell. If components affected by either OA or GB, as well as by the combined treatment, were classified according to the detected changes, two sets of data were obtained, including the components whose levels were found affected by the combined treatment, regardless of the effect observed after addition of only one agent, and those that had been found affected in cells that had been challenged with only one toxin but not when cells had been subjected to the combined treatment. Multiple patterns of responses to the toxin mixture were recorded in the two sets, consisting of both independent and interacting actions, among which we detected synergistic, similar, and antagonistic effects.

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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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    A highly stereocontrolled, convergent synthesis of the A/B-ring fragment of gambieric acids (GAs) has been developed on the basis of (i) a Suzuki-Miyaura coupling of the C1-C6 alkylborate and the C7-C17 vinyl iodide and (ii) a diastereoselective haloetherification for the construction of the A-ring tetrahydrofuran as key steps. Inspection of the (1)H and (13)C NMR chemical shifts of the synthesized A/B-ring model compounds led to a stereochemical reassignment of the absolute configuration of the polycyclic ether core of GAS. This structure revision was further supported by a synthesis of the A/BC-ring model compound of gambieric acid B and a comparison of its (1)H and (13)C NMR data with those of the natural product.

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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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    New strategies for the synthesis of 2-substituted indoles and indolines using acyclic, imide-derived enol phosphates which were readily prepared from o-haloanilides have been developed based on Suzuki-Miyaura coupling-cyclization sequences. A highly chemoselective cross-coupling of imide-derived enol phosphates with boron nucleophiles under Suzuki-Miyaura conditions allowed for the efficient preparation of various N-(o-halophenyl)enecarbamates that served as useful precursors for subsequent 5-endo-trig Heck or 5-endo-trig aryl radical cyclizations to furnish 2-substituted indoles or indolines, respectively. Furthermore, a one-pot Suzuki-Miyaura Coupling-cyclization cascade starting from enol phosphates has been developed, which was Successfully applied to the efficient synthesis of an indol-2-yl-1H-quinolin-2-one KDR inhibitor.

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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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    The stereocontrolled total synthesis of the originally proposed (1) and correct (2) structures of (+)-neopeltolide, a novel marine macrolide natural product with highly potent anti-proliferative activity against several cancer cell lines as well as potent antifungal activity, has been achieved by exploiting a newly developed Suzuki-Miyaura coupling/ring-closing metathesis strategy. Alkylborate 44, which was generated in situ from iodide 34, was coupled with enol phosphate 8 by a Suzuki-Miyaura coupling. Ring-closing metathesis of the derived diene 45 followed by stereoselective hydrogenation afforded tetrahydropyran 47 as a single stereoisomer in high overall yield from 34. Our convergent strategy enabled us to construct the 14-membered macrolactone core structure of 2 in a rapid and efficient manner. Total synthesis and biological evaluation of synthetic intermediates and designed synthetic analogues, performed to establish the structure-activity relationships of 2, led to the discovery of a structurally simple yet potent cytotoxic analogue, 9-demethylneopeltolide (54).

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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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    A new method for the generation of indole-2,3-quinodi-methanes based on a palladium-catalyzed cascade process starting from N-(o-iodophenyl)allenamides has been developed.

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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 method for the synthesis of enol ethers and enecarbamates has been developed based on palladium(0)-catalyzed chemoselective reduction of alkenyl phosphates. This method has been applied successfully to the total synthesis of two isoindolobenzazepine alkaloids, lennoxamine and chilenine.

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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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    An efficient strategy for the synthesis of endocyclic enol ethers based on a Suzuki-Miyaura coupling/ring-closing metathesis sequence has been developed. The strategy has successfully been applied to the synthesis of spiroacetals, including cytotoxic marine metabolites attenols A and B.

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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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    Total synthesis of (-)-brevenal, a novel marine polycyclic ether natural product, is described. Highly efficient and scalable entries to the AB-ring exo-olefin and the DE-ring enol phosphate and a rapid construction of the C-ring by means of our Suzuki-Miyaura coupling-based strategy realized a concise synthesis of the pentacyclic skeleton of (-)-brevenal. The present synthesis is considerably more efficient than our previous synthesis (longest linear sequence: 50 steps from 2-deoxy-D-ribose).

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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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    Stereocontrolled synthesis of the A/B-ring fragment of the originally assigned structure of gambieric acid B and its possible diastereomers has been accomplished. Detailed comparison of their (1)H and (13)C NMR data with those of the corresponding moiety of the natural product culminated in a stereochemical reassignment of the absolute configuration of the polycyclic ether region of gambieric acid B.

    DOI: 10.1021/ol800642t

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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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    Marine polycyclic ether natural products continue to fascinate chemists and biologists due to their exceptionally large and complex molecular architectures and potent and diverse biological activities. Tremendous progress has been made over the past decade toward the total synthesis of marine polycyclic ether natural products. In this area, a convergent strategy for assembling small fragments into an entire molecule always plays a key role in successful total synthesis. This review describes our efforts to develop convergent strategies for the synthesis of polycyclic ethers and their application to the total synthesis of gambierol, gymnocin-A, and brevenal, and to the partial synthesis of the central part of ciguatoxins and the nonacyclic polyether skeleton of gambieric acids.

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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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  • 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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    For more than twenty years, chemists and biologists have been fascinated by the highly complex molecular architectures and the diverse and potent biological activities of marine polycyclic ether natural products. Given the scarce availability of these intriguing substances from natural sources, total chemical synthesis is the only way to obtain sufficient quantities for biological investigation. This review describes recent synthetic advances in the field of marine polycyclic ether natural products and their successful implementation in total synthesis endeavors.

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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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    Strategies have been developed for the synthesis of 2-substituted indoles and indolines starting from acyclic alpha-phosphoryloxy enecarbamates. A highly chemoselective cross-coupling of N-(o-bromophenyl)-alpha-phosphoryloxyenecarbamates with boron nucleophiles enabled the efficient preparation of various N-(o-bromophenyl)enecarbamates, which served as useful precursors for subsequent Heck-type cyclization or 5-endo-trig aryl radical cyclization to furnish 2-substituted indoles or indolines, respectively.

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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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    Divergent synthesis of multifunctional molecular probes based on caprolactam-derived dipeptidic -secretase inhibitors (GSIs), Compound E (CE) and LY411575 analogue (DBZ), was efficiently accomplished by means of Cu(I)-catalyzed azide/alkyne fusion reaction. Photoaffinity labeling experiments using these derivatives coupled to photoactivatable and biotin moieties provided direct evidence that the molecular targets of CE and DBZ are the N-terminal fragment of presenilin 1 within the -secretase complex. Moreover, these photoprobes directly targeted signal peptide peptidase. These data suggest that the divergent synthesis of molecular probes has been successfully applied to characterize the interaction of GSIs with their molecular targets and define the structural requirements for inhibitor binding to intramembrane-cleaving proteases.

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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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    Stereoselective synthesis of the AB-ring fragment of gambieric acid A has been accomplished, wherein (i) an acetylide-aldehyde coupling for fragment assembly and (ii) construction of the tetrahydrofuran A-ring via a diastereoselective bromoetherification were successfully employed as key transformations.

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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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    An efficient method for the synthesis of enol ethers and enecarbamates has been developed based on catalytic hydrosilane reduction of alpha-phosphonoxy enol ethers and alpha-phosphonoxy enecarbamates. This method has been applied to the total syntheses of two isoindolobenzazepine alkaloids, lennoxamine and chilenine.

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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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    A strategy for the synthesis of 2,3-disubstituted indole derivatives based on an intramolecular carbopalladation-anion capture cascade has been developed, wherein construction of the pyrrole ring and functionalisation of the indole C2 and C3 positions were achieved by extensive use of palladium( 0)catalysed coupling reactions.

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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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    An intramolecular Heck/Diels-Alder cycloaddition cascade starting from acyclic alpha-phosphono enecarbamates has been developed to prepare nitrogen heterocycles via indole-2,3-quinodimethanes and 2-(N-alkoxycarbonylamino)-1,3-dienes.

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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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    A concise and short synthetic entry to 5,6-dihydropyridin-2-one derivatives has been developed by means of palladium(0)-catalyzed cross-coupling of cyclic ketene aminal phosphates.

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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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    Total synthesis of structure 1 originally proposed for brevenal, a nontoxic polycyclic ether natural product isolated from the Florida red tide dinoflagellate, Karenia brevis, was accomplished. The key features of the synthesis involved (i) convergent assembly of the pentacyclic polyether skeleton based on our developed Suzuki-Miyaura coupling chemistry and (ii) stereoselective construction of the multi-substituted (E,E)-dienal side chain by using copper(I) thiophen-2-carboxylate (CuTC)-promoted modified Stille coupling. The disparity of NMR spectra between the synthetic material and the natural product required a revision of the proposed structure. Detailed spectroscopic comparison of synthetic 1 with natural brevenal, coupled with the postulated biosynthetic pathway for marine polyether natural products, suggested that the natural product was most likely represented by 2, the C26 epimer of the proposed structure 1. The revised structure was finally validated by completing the first total synthesis of (-)-2, which also unambiguously established the absolute configuration of the natural product.

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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.

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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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    The marine dinoflagellate Gambierdiscus toxicus produces highly lipophilic, polycyclic ether toxins that cause a seafood poisoning called ciguatera. Ciguatoxins (CTXs) and gambierol represent the two major causative agents of ciguatera intoxication, which include taste alterations (dysgeusiae). However, information on the mode of action of ciguatera toxins in taste cells is scarce. Here, we have studied the effect of synthetic CTX3C (a CTX congener) on mouse taste cells. By using the patch-clamp technique to monitor membrane ion currents, we found that CTX3C markedly affected the operation of voltage-gated Na+ channels but was ineffective on voltage-gated K+ channels. This result was the exact opposite of what we obtained earlier with gambierol, which inhibits K+ channels but not Na+ channels. Thus, CTXs and gambierol affect with high potency the operation of separate classes of voltage-gated ion channels in taste cells. Our data suggest that taste disturbances reported in ciguatera poisoning might be due to the ability of ciguatera toxins to interfere with ion channels in taste buds.

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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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    Synthesis and biological evaluation of an arylsulfonamide class of gamma-secretase inhibitors are described. Design, synthesis, and biological evaluation of multifunctional molecular probes harboring a benzophenone photophore as a cross-linking group and a biotin tag are also reported. (c) 2006 Elsevier Ltd. All rights reserved.

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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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  • 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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    Synthesis of the JK/LM-ring model of prymnesins, polycyclic ether toxins isolated from the red tide phytoflagellate, Pryninesilun parvian, is described. Comparison of the H-1 and C-13 NMR data of the synthetic model with those reported for prymnesins confirmed the reported configurational assignment of the K/L-ring juncture. (c) 2006 Elsevier Ltd. All rights reserved.

    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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    Screening of our in-house compound library comprised of intermediates of natural product synthesis projects resulted in discovering two novel gamma-secretase inhibitors, which coincidently had similar moieties, that is, cyclohexenone and two aryl groups arranged on the core six-membered ring. Structure-activity relationship studies of these compounds were also developed. (c) 2006 Elsevier Ltd. All rights reserved.

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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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    gamma-Secretase is a multimeric membrane protein complex composed of presenilin (PS), nicastrin, Aph-1 and, Pen-2 that is responsible for the intramembrane proteolysis of various type I transmembrane proteins, including amyloid beta-precursor protein and Notch. The direct labeling of PS polypeptides by transition-state analogue gamma-secretase inhibitors suggested that PS represents the catalytic center of gamma-secretase. Here we show that one of the major gamma-secretase inhibitors of dipeptidic type, N-[N-( 3,5- difluorophenacetyl)-L-alanyl]-S- phenylglycine t-butyl ester (DAPT), targets the C-terminal fragment of PS, especially the transmembrane domain 7 or more C-terminal region, by designing and synthesizing DAP-BpB (N-[N-(3,5- difluorophenacetyl)-L-alanyl]-(S)-phenylglycine4-(4-(8-biotinamido) octylamino)benzoyl)benzyl) methylamide), a photoactivable DAPT derivative. We also found that DAP-BpB selectively binds to the high molecular weight gamma-secretase complex in an activity-dependent manner. Photolabeling of PS by DAP-BpB is completely blocked by DAPT or its structural relatives (e.g. Compound E) as well as by arylsulfonamides. In contrast, transition-state analogue inhibitor L-685,458 or alpha-helical peptidic inhibitor attenuated the photolabeling of PS1 only at higher concentrations. These data illustrate the DAPT binding site as a novel functional domain within the PS C-terminal fragment that is distinct from the catalytic site or the substrate binding site.

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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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    Background: Gambierol is a polycyclic ether toxin with the same biogenetic origin as ciguatoxins. Gambierol has been associated with neurological symptoms in humans even though its mechanism of action has not been fully characterized. Methods: We studied the effect of gambierol in human neuroblastoma cells by using bis-oxonol to measure membrane potential and FURA-2 to monitor intracellular calcium. Results: We found that this toxin: i) produced a membrane depolarization, ii) potentiated the effect of veratridine on membrane potential iii) decreased ciguatoxin-induced depolarization and iv) increased cytosolic calcium in neuroblastoma cells. Conclusion: These results indicate that gambierol modulate ion fluxes by acting as a partial agonist of sodium channels. Copyright (c) 2006 S. Karger AG, Basel.

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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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    Ciguatera is a food poisoning caused by toxins of Gambierdiscus toxicus, a marine dinoflagellate. The neurological features of this intoxication include sensory abnormalities, such as paraesthesia, heightened nociperception, and also taste alterations. Here, we have evaluated the effect of gambierol, one of the possible ciguatera toxins, on the voltage-gated ion currents in taste cells. Taste cells are excitable cells endowed with voltage-gated Na+, K+, and Cl- currents (I-Na, I-K, and I-Cl, respectively). By applying the patch-clamp technique to single cells in isolated taste buds obtained from the mouse vallate papilla, we have recorded such currents and determined the effect of bath-applied gambierol. We found that this toxin markedly inhibited I-K in the nanomolar range (IC50 of 1.8 nM), whereas it showed no significant effect on I-Na or I-Cl even at high concentration (1 mu M). The block of I-K was irreversible even after a 50-min wash. In addition to affecting the current amplitude, we found that gambierol significantly altered both the activation and inactivation processes of I-K. In conclusion, unlike other toxins involved in ciguatera, such as ciguatoxins, which affect the functioning of voltage-gated sodium channels, the preferred molecular target of gambierol is the voltage-gated potassium channel, at least in taste cells. Voltage-gated potassium currents play an important role in the generation of the firing pattern during chemotransduction. Thus, gambierol may alter action potential discharge in taste cells and this could be associated with the taste alterations reported in the clinical literature.

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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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    The general synthesis and a novel intramolecular nucleophilic aromatic substitution (SNAr) reaction of 2-carboxamido-3-arylquinazolin-4-ones, a potentially useful scaffold in the field of medicinal chemistry, are described. The synthetic utility of the SNAr reaction as a tool for the synthesis of secondary aryl amines, including diaryl amines, is also demonstrated. (c) 2005 Elsevier Ltd. All rights reserved.

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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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    A novel intramolecular nucleophilic aromatic substitution reaction of 2-carboxamido-3-arylquinazolin-4-one derivatives induced by base treatment and its application to the expeditious synthesis of secondary aryl amines, including diaryl amines, are described.

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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.

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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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    Gambierol is a polycyclic ether toxin, which has been isolated from the marine dinoflagellate Gambierdiscus toxicus. A series of gambierol analogues have been prepared from an advanced intermediate of our total synthesis of gambierol and investigated for their toxicity against mice, thus providing the first systematic structure-activity relationships (SAR) of this polycyclic ether class of marine toxin. The SAR studies described herein clearly indicate that 1) the C28=C29 double bond within the H ring and the unsaturated side chain are the crucial structural elements required for exerting potent biological activity and 2) the C1 and C6 hydroxy groups, the C30 methyl group, and the C37=C38 double bond have little influence on the degree of neurotoxicity against mice.

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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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    The polycyclic ether class of marine natural products presents formidable and challenging synthetic targets due to their structural complexity and exceptionally potent biological activities. We have developed a highly convergent strategy for the assembly of a huge polycyclic ether array, which features Suzuki-Miyaura cross-coupling of alkylboranes, generated from exocyclic enol ethers, with cyclic ketene acetal triflates or phosphates combined with reductive ring-closure. The utility of this strategy was demonstrated by its application to synthetic studies on ciguatoxins, and the total syntheses of gambierol and gymnocin-A.

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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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    Stereoselective synthesis of the C18-C34 fragment of antascomicin A is described. Construction of the C27-C34 carbocycle moiety was achieved via catalytic Ferrier carbocylization and Johnson-Claisen rearrangement, which was converted to iodide 2 by use of asymmetric alkylation and Sharpless epoxidation as key transformations. Coupling of iodide 2 and sulfone 3 furnished the C18-C34 fragment. (C) 2004 Elsevier Ltd. All rights reserved.

    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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    Synthesis of the ABCDE ring fragment of ciguatoxins has been achieved in a highly stereocontrolled and convergent manner via the B-alkyl Suzuki-Miyaura conpling-based approach. (C) 2004 Elsevier Ltd. All rights reserved.

    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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    A highly efficient method for the synthesis of medium-sized lactams based on intramolecular Staudinger-aza-Wittig reaction of omega-azido pentafluorophenyl ester has been developed. A variety of 7-10 membered lactams were synthesized in excellent yields. Application of the method to the synthesis of analogues of a potent gamma-secretase inhibitor LY411575 and their biological evaluation are also described. (C) 2004 Elsevier Ltd. All rights reserved.

    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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    Gambierol was isolated from Gambierdiscus toxicus, which causes ciguatera fish poisoning. The acute toxicological effects induced in mice by synthesized gambierol were studied. The lethal doses were about 80 mug/kg by i.p. and i.v., and 150 mug/kg by p.o. The main injury by this toxin was observed in the lung, and secondary in the heart, resulting in systemic congestion. Another toxic effect was seen in the stomach, inducing hypersecretion and ulceration. With survival from the severe stage during the initial 3 h, recovery was favorable, especially after 4 days. Additional effects were not evident during 1-week post-administration observation. (C) 2003 Elsevier Ltd. All rights reserved.

    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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    Gambierol is a polycyclic ether toxin, isolated as a toxic constituent from the marine dinoflagellate Gambierdiscus toxicus. We describe here the synthesis and biological evaluation of structural analogues of gambierol. The present preliminary structure-activity relationship studies clearly indicate that the H ring functionality and the unsaturated side chain of gambierol are crucial for its potent toxicity. (C) 2003 Elsevier Ltd. All rights reserved.

    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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    The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh3)(4)/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B - AB - ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which Sml(2)-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh3)(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1).

    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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    The first total synthesis of gambierol, a marine polycyclic ether toxin, has been achieved. The synthesis features the Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling for the stereoselective construction of the sensitive triene side chain that includes a conjugated (Z,Z)-diene moiety.

    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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    A new method for convergent coupling of fused polycyclic ethers has been developed, which relies on B-alkyl Suzuki cross-coupling of lactone-derived enol triflates or phosphates. The strategy was successfully applied to a convergent synthesis of the ABCD ring fragment 4 of ciguatoxins, the causative toxin for ciguatera fish poisoning. The synthetic route includes a convergent union of the B and D rings (18 and 29c, respectively) by the B-alkyl Suzuki coupling, introduction of a double bond into the D ring followed by reductive closure of the tetrahydropyran C ring to afford the BCD ring system 51, and, finally, ring-closing metathesis reaction to construct the oxepene A ring. (C) 2002 Elsevier Science Ltd. All rights reserved.

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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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    A convergent synthetic route to the octacyclic polyether core of gambierol, a marine polycyclic ether toxin, has been developed, The synthesis involves construction of two fragments representing the ABC and EFGH ring systems followed by their coupling via a B-alkyl Suzuki reaction.

    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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    A synthetic route to the EFGH ring system (3) of gambierol (1), a marine polyether toxin isolated from the dinoflagellate Gambierdiscus toxicus, has been developed. The present synthesis features convergent coupling of the F and H rings followed by ring-closure of the G ring based on the B-alkyl Suzuki reaction of lactone-derived enol phosphates. An angular methyl group at C23 was stereoselectively introduced by treatment of sulfone 32 with trimethylaluminum. Installation of a tertiary alcohol at C21 was accomplished through stereo-selcetive dihydroxylation of exo-methylene 36 followed by selective formation of the primary p-toluensulfonate and treatment of the resultant monotosylate 40 with lithium aluminum hydride. Finally, formation of the E ring as a lactone form completed the synthesis of 3. (C) 2001 Elsevier Science Ltd. All rights reserved.

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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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    A synthetic route to the FGH ring system of gambierol, a marine polyether toxin isolated from the dinoflagellate Gambierdiscus toxicus, has been developed. The present synthesis features B-alkyl Suzuki coupling of the F and H rings, followed by ring-closure of the G ring and stereoselective installation of 1,3-diaxial methyl groups at C21 and C23. (C) 2000 Elsevier Science Ltd. All rights reserved.

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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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    Convergent synthesis of HIJK ring model compound 1 of ciguatoxin is described. The present synthesis relied on a palladium-catalyzed Suzuki cross-coupling reaction between eight-membered ketene acetal phosphate 2 and seven-membered alkylborane 6. (C) 2000 Elsevier Science Ltd. All rights reserved.

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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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    A general method for convergent assembly of polyether structure has been developed based on palladium(0)-mediated Suzuki cross-coupling reaction of alkylboranes with cyclic ketene acetal phosphates. The present method allowed for coupling of medium-sited ether rings and thus a concise synthesis of the ABCD ring system of ciguatoxins has been achieved.

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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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    A new strategy for convergent synthesis of trans-fused polyethers based on palladium(0)-catalyzed Suzuki cross-coupling reaction of alkylboranes with cyclic enol triflates has been developed. The present method allows to construct polyether frameworks rapidly and efficiently. (C) 1998 Elsevier Science Ltd. All rights reserved.

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Books

  • 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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  • Total Synthesis of (−)-Enigmazole A

    T. Sugai, H. Fuwa( Role: Contributor)

    Springer  2020.11 

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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 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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  • 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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  • 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

  • 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

  • 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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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (other)   Publisher:The Society of Synthetic Organic Chemistry, Japan  

    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

  • 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

Research Projects

  • 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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  • 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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  • 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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Allotted class

  • 2023   卒業研究Ⅰ   Department

  • 2023   卒業研究Ⅱ   Department

  • 2023   応用化学実験2   Department

  • 2023   応用有機化学1   Department

  • 2023   有機化学1   Department

  • 2023   生物有機化学   Department

  • 2023   応用化学特殊論文研修Ⅰ   Graduate school

  • 2023   応用化学特殊論文研修Ⅱ   Graduate school

  • 2023   応用化学特殊論文研修Ⅲ   Graduate school

  • 2023   応用化学特殊論文研修Ⅳ   Graduate school

  • 2023   応用化学特殊論文研修Ⅴ   Graduate school

  • 2023   応用化学特殊論文研修Ⅵ   Graduate school

  • 2023   応用化学特論   Graduate school

  • 2023   応用化学論文研修第一   Graduate school

  • 2023   応用化学論文研修第三   Graduate school

  • 2023   応用化学論文研修第二   Graduate school

  • 2023   応用化学論文研修第四   Graduate school

  • 2023   有機合成化学特論   Graduate school

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Committee Memberships

  • 2020.5 - Now

    Marine Drugs誌   編集委員  

  • 2022.3 - 2024.2

    日本化学会 関東支部   常任幹事  

  • 2019.4 - 2021.3

    有機合成化学協会   編集委員  

  • 2009.4 - 2015.12

    有機合成化学協会東北支部   常任幹事  

  • 2007.10 - 2015.10

    天然物化学談話会   世話人  

  • 2013.11 -  

    Frontiers in Chemistry誌   編集委員  

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Social Activities

  • Marine Drugs誌編集委員

    Role(s): Editer, Advisor, Planner

    MDPI  2020.3 -  

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  • 有機合成化学協会誌編集委員

    Role(s): Editer

    有機合成化学協会  2019.3 -  

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