Updated on 2025/06/09

写真a

 
YOSHIMITSU Takehiko
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
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Degree

  • 博士（薬学） ( 東北大学 )

Research Interests

  • Synthetic organic chemistry

  • Natural product synthesis

  • medicinal chemistry

  • 有機合成化学

  • 天然物合成

  • 医薬化学

Research Areas

  • Life Science / Pharmaceutical chemistry and drug development sciences

Education

  • Tohoku University   大学院薬学研究科 博士後期課程  

    1992.4 - 1995.3

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    Country： Japan

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  • Tohoku University    

    - 1995

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  • Tohoku University     大学院薬学研究科 博士前期課程

    1990.4 - 1992.3

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  • Tohoku University   薬学部   製薬化学科

    1986.4 - 1990.3

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    Country： Japan

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  • Tohoku University    

    - 1990

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Research History

  • Osaka University

    2016 - 2018

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  • - 岡山大学医歯薬学総合研究科 教授

    2016

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  • - Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2016

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  • The University of Tokushima   Faculty of Engineering, Department of Chemical Science and Technology

    2013

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  • Kyushu University   Institute for Materials Chemistry and Engineering

    2012

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  • Osaka University

    2006 - 2016

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  • Associate Professor,Graduate School of Pharmaceutical Sciences

    2006 - 2016

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  • Meiji Pharmaceutical University

    2003 - 2006

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  • Senior Assistant Professor

    2003 - 2006

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  • Meiji Pharmaceutical University

    1997 - 2003

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  • Research Associate

    1997 - 2003

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  • Massachusetts Institute of Technology

    1995 - 1997

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Committee Memberships

  • 日本薬学会   代議員  

    2020.4 - 2022.3   

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    Committee type：Academic society

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  • 日本薬学会   代議員  

    2013.4 - 2016.3   

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    Committee type：Academic society

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  • 公益社団法人有機合成化学協会   有機合成化学協会誌編集協力委員  

    2011.4 - 2013.3   

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    Committee type：Academic society

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  • The 5th Seoul-Kyoto-Osaka Joint Symposium on Pharmaceutical Sciences for Young Scientists   Organizing committee member  

    2010.5   

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    Committee type：Academic society

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  • 第7回次世代を担う有機化学シンポジウム   実行委員長  

    2009.7   

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    Committee type：Academic society

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  • 第3回日本薬学会化学系薬学部会若手教員会議   議長  

    2009.7   

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    Committee type：Academic society

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  • 公益社団法人日本薬学会   ファルマシアトピックス専門小委員  

    2009.4 - 2011.3   

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    Committee type：Academic society

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  • 第6回次世代を担う有機化学シンポジウム   世話人  

    2008.5   

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  • 第128会日本薬学会一般シンポジウム「分子の新機能が拓く有機合成化学」   オーガナイザー  

    2008.3   

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  • 第5回次世代を担う有機化学シンポジウム   世話人  

    2007.5   

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  • 日本薬学会   日本薬学会近畿支部委員  

    2007.4 - 2017.3   

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  • The 3rd Seoul-Kyoto-Osaka Joint Symposium on Pharmaceutical Sciences for Young Scientists   Scientific Committee Member  

    2006.11   

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Papers

  • Asymmetric Total Synthesis of Chlorosulfolipid

    Yoshimitsu Takehiko, Fukumoto Naoya, Nakatani Ryo, Kojima Naoto, Kobayashi Akihiro, Tanaka Tetsuaki

    Symposium on the Chemistry of Natural Products, symposium papers   ( 52 )   7 - 12   2010.9

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

    Natural chlorosulfolipids that possess an unusual polychlorinated linear hydrocarbon motif have gained considerable attention due to their toxicological propertied (Figure 1). In quest for deeper knowledge of their risks and effects on human health, we initiated a research program that would allow us to chemically produce the lipids in sufficient quantities to facilitate biological investigations. In this presentation, we will disclose the asymmetric total synthesis of (+)-bexachlorosulfolipid (1), a toxic substance isolated from the Adriatic mussesl Mytilus galloprovincialis. 1. Stereospecific Multiple Chlorination of Epoxides Our initial effort was to establish a means for preparing chiral polychlorinated hydrocarbon motifs by nuclephilic chlorinaton reactions of readily available epoxides with N-chlorosuccinimide (NCS)/organophosphine reagents. The investigation led to the discovery that NCS/Ph_3P was best suited for this transformation and was applicable to various epoxides having eleborate structures to furnixh chiral polychlorides. 2. Asymmetric Total Synthesis of (+)-Hexachlorosulfolipid Our approach to (+)-hexachlorosulfolipid (1) features the use of the NCS/Ph_3P-mediated dichlorinations of epoxides. Installation of the vicinal dichloro functionality into chiral epoxide 7 (>98% ee) was successfully achieved using NCS/Ph_3P in toluene at 90℃ to afford dichloride 8 in 85% yield as a single isomer. Removal of the pivalic group of 8 followed by oxidation with Dess-Martin periodinane under buffered conditions delivered dichloroaldehyde 1, which was immediately reacted with allyltrimethylsilane in the presence of BF_3・OEt_2 to afford anti-chlorohydrin 9. Contrary to our expectations, all the efforts to make the desired all-syn chloro triad 11 from this alcohol by simple chlorination of the hydroxyl group were unfruitful due to the concomitant occurrence of elimination reactions. However, the epoxide-dichlorination method was again found to be suitable tor this process. Thus, dichloroalcohol 9 was first transformed into trans-epoxide 10 which, in turn, was subjected to dichlorination under Ph_3P/NCS conditions to furnish trichloride 11 in 70% yield. The stereoselective allylic hydreoxylation followed by olefin metathesis with 2-butene efficiently produced (E)-alkene 13 (E:Z = ca. 17:1). The Marko-Maguire dichlorination (KMnO_4/BnEt_3NCl/TMSCl) of this alcohol furnished desired (2R,3S)-pentachloride 18 as the majou product possessing all the requisite stereocenters relevant to the natural compound. Further simple transformations of peptachloride 18 eventually furnished (+)-hexachlorosulfolipid (1). The spectroscopic and analytical data of the synthetic compound were in good agreement wigh those recorded in the literature. The optical rotation of our material 1 was [α]^<24>_D+49 (c 0.59, MeOH)[lit. [α]^<25>_D +20.4 (c 0.0015, MeOH)], indicating that the absolute configuration of natural sulfolipid was as proposed by Ciminiello and Fattorusso.

    DOI： 10.24496/tennenyuki.52.0_7

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  • C-H Transformation at Functionalized Alkanes Reviewed

    Shun-Ichi Murahashi, Yoshinori Yamamoto, Gan B. Bajracharya, Claudio Nicolau, Mikel Oiarbide, Yoshitaka Hamashima, Mikiko Sodeoka, Armando Córdova, Barry B. Snider, Takehiko Yoshimitsu, Francesco Minisci, Ombretta Porta, Brian M. Stoltz, David C. Ebner, A. Ganesan, Stefan Kaskel, Jesffls A. Varela, Gerald Dyker, Andrea Christiansen, Armin Börner, Seijiro Matsubara, Jean-Cédric Frison, Julien Legros, Carsten Bolm, Minsheng He, Aiwen Lei, Xumu Zhang, Bengü Sezen, Dalibor Sames

    Handbook of C-H Transformations: Applications in Organic Synthesis   2   317 - 496   2008.1

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    Language：English   Publishing type：Part of collection (book)   Publisher：John Wiley and Sons  

    DOI： 10.1002/9783527619450.ch8

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  • Practical chiral route to muscarine and its three diastereomers.

    OHSHIBA Yukio, YOSHIMITSU Takehiko, OGASAWARA Kunio

    Chemical and Pharmaceutical Bulletin   43 ( 6 )   1067 - 1069   1995

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    Language：English   Publisher：The Pharmaceutical Society of Japan  

    A practical route to all possible stereoisomers of the muscarine alkaloids in optically pure forms has been developed starting from a readily accessible chiral starting material.

    DOI： 10.1248/cpb.43.1067

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  • 13 THE KATSUKI-SHARPLESS ASYMMETRIC EPOXIDATION OF ALKENYLETHYLENE GLYCOL AND ITS UTILIZATION FOR THE NATURAL PRODUCT SYNTHESIS

    Takano S., Iwabuchi Y., Yoshimitsu T., Ogasawara K.

    Symposium on the Chemistry of Natural Products, symposium papers   ( 33 )   94 - 100   1991.9

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

    Unprecedented high enantiospecific epoxidation of alkenylethylene glycol substrates under the Katsuki-Sharpless asymmetric conditions has been first recognized. Both dissymmetric and symmetric (C_2 and Cs) substrates underwent facile epoxidation in highly enantio- and diastereo-specific manners with inversed selection modes established in the conventional allylic alcohol substrates. Thus, dissymmetric and C_2-symmetric substrates afforded the corresponding epoxides in inversed enantio- and diastereo-selection modes, while C_2 (meso)-symmetric substrate afforded the epoxide in inversed enantioselection mode. Moreover, complete enantio- and diastereo-selective discrimination of two chemically equivalent vinyl groups in 2,2-bis-vinylethylene glycol substrate has also been observed under the epoxidation conditions. The observed stereochemical outcome, especially, that observed with the C_2 (meso) and the 2,2-bis-divinyl substrates, seemed to support that the monomer mechanism rather than the dimer mechanism is involved in the reaction of the 2-alkenyl-1,2-ethyleneglycol substrates. As a practical application of the present finding, a new enantiocontrolled synthesis of L-erythro- and D-threo-sphingosines has been established using the epoxides obtained from the C_2- and the Cs-symmetric substrates, respectively.

    DOI： 10.24496/tennenyuki.33.0_94

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Books

  • クロロスルホリピッド－全合成の新たな標的－

    化学工業  2014 

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  • Stereoselective Synthesis of Halogenated Natural Products, Chapter 43

    John Wiley & Sons  2013 

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  • Triethylborane in Handbook of Reagents for Organic Synthesis; Reagents for Direct Functionalization of C-H Bonds

    Wiley-VCH  2006 

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  • Triethylborane in Encyclopedia of Reagents for Organic Synthesis

    John Wiley & Sons  2005 

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  • Radical Alpha-Functionalization of Ethers in Handbook of C-H Transformations

    Wiley VCH Verlag GmbH  2005 

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MISC

  • Total Synthesis of (±)-Rhazinilam via Red-Light-Driven Zinc(II)porphyrin-Catalyzed Radical Cyclization of N-Substituted Pyrrole Reviewed

    Yusuke Okanishi, Yoshitatsu Yotsumoto, Takehiko Yoshimitsu

    Organic Letters   2025.5

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：American Chemical Society (ACS)  

    DOI： 10.1021/acs.orglett.5c01681

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  • Red-Light-Promoted Radical Cascade Reaction to Access Tetralins and Dialins Enabled by Zinc(II)porphyrin, A Light-Flexible Catalyst Reviewed

    Yusuke Okanishi, Otoki Takemoto, Sanpou Kawahara, Satoshi Hayashi, Toshikatsu Takanami, Takehiko Yoshimitsu

    Organic Letters   2024.4

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：American Chemical Society (ACS)  

    DOI： 10.1021/acs.orglett.4c01112

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  • Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction Reviewed International coauthorship International journal

    Daigo Sawaki, Yanyan Zhang, Amel Mohamadi, Maria Pini, Zaineb Mezdari, Larissa Lipskaia, Suzain Naushad, Lucille Lamendour, Dogus Murat Altintas, Marielle Breau, Hao Liang, Maissa Halfaoui, Thaïs Delmont, Mathieu Surenaud, Déborah Rousseau, Takehiko Yoshimitsu, Fawzia Louache, Serge Adnot, Corneliu Henegar, Philippe Gual, Gabor Czibik, Geneviève Derumeaux

    JCI Insight   8 ( 8 )   2023.4

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    Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：American Society for Clinical Investigation  

    DOI： 10.1172/jci.insight.145811

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  • Radical-Based Route to Functionalized Tetralin: Formal Total Synthesis of (±)-Hamigeran B International journal

    Yusuke Okanishi, Tohru Ishikawa, Takuya Jinnouchi, Satoshi Hayashi, Toshikatsu Takanami, Hiroshi Aoyama, Takehiko Yoshimitsu

    The Journal of Organic Chemistry   88 ( 2 )   1085 - 1092   2023.1

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    Publisher：American Chemical Society (ACS)  

    DOI： 10.1021/acs.joc.2c02552

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  • Organic redox cascade cyclization of 2-alkynylquinones by ascorbic acid in combination with a copper catalyst and its application to formal synthesis of liphagal International coauthorship International journal

    Taejoo Jeong, Yusuke Okanishi, Sora Yotsui, In Su Kim, Takehiko Yoshimitsu

    New Journal of Chemistry   47 ( 7 )   3425 - 3429   2023

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    Publisher：Royal Society of Chemistry (RSC)  

    The combination of a quinone-ascorbic acid organic redox reaction and a concomitant copper catalysis in situ enables new approach to hydroxybenzofurans with structural variations.

    DOI： 10.1039/d2nj05724g

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  • A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor Reviewed International coauthorship

    T. R. Caulfield, K. E. Hayes, Y. Qiu, M. Coban, J. Seok Oh, A. L. Lane, T. Yoshimitsu, L. Hazlehurst, J. A. Copland, H. W. Tun

    10   1047   2020.10

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    Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

    DOI： 10.3390/biom10101407

    DOI： 10.3390/biom10101407

  • A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor Reviewed International coauthorship International journal

    Thomas R. Caulfield, Karen E. Hayes, Yushi Qiu, Mathew Coban, Joon Seok Oh, Amy L. Lane, Takehiko Yoshimitsu, Lori Hazlehurst, John A. Copland, Han W. Tun

    Biomolecules   10 ( 10 )   1407 - 1407   2020.10

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    Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：MDPI AG  

    Chloroethylagelastatin A (CEAA) is an analogue of agelastatin A (AA), a natural alkaloid derived from a marine sponge. It is under development for therapeutic use against brain tumors as it has excellent central nervous system (CNS) penetration and pre-clinical therapeutic activity against brain tumors. Recently, AA was shown to inhibit protein synthesis by binding to the ribosomal A-site. In this study, we developed a novel virtual screening platform to perform a comprehensive screening of various AA analogues showing that AA analogues with proven therapeutic activity including CEAA have significant ribosomal binding capacity whereas therapeutically inactive analogues show poor ribosomal binding and revealing structural fingerprint features essential for drug-ribosome interactions. In particular, CEAA was found to have greater ribosomal binding capacity than AA. Biological tests showed that CEAA binds the ribosome and contributes to protein synthesis inhibition. Our findings suggest that CEAA may possess ribosomal inhibitor activity and that our virtual screening platform may be a useful tool in discovery and development of novel ribosomal inhibitors.

    DOI： 10.3390/biom10101407

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  • Total Synthesis of (±)-Liphagal via Organic-Redox-Driven Palladium-Catalyzed Hydroxybenzofuran Formation Reviewed

    Eriko Tao, Masaki Inoue, Taejoo Jeong, In Su Kim, Takehiko Yoshimitsu

    The Journal of Organic Chemistry   85 ( 14 )   9064 - 9070   2020.7

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：American Chemical Society (ACS)  

    DOI： 10.1021/acs.joc.0c00965

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  • Chemical Syntheses and Biological Studies of Agelastatin A, a Bioactive Marine Heterocycle Gifted from Nature Invited Reviewed

    Takehiko Yoshimitsu

    HETEROCYCLES   100 ( 11 )   1735 - 1735   2020.5

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：The Japan Institute of Heterocyclic Chemistry  

    DOI： 10.3987/rev-20-929

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  • Strategic use of nitrogen free radicals in natural product synthesis: Total synthesis of agelastatin A Reviewed

    YOSHIMITSU Takehiko

    Synthetic Organic Chemistry, Japan   77 ( 5 )   472 - 481   2019.5

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    Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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  • Ru(II)-Catalyzed C-H Aminocarbonylation of N -(Hetero)aryl-7-azaindoles with Isocyanates

    Taejoo Jeong, Suk Hun Lee, Rina Chun, Sangil Han, Sang Hoon Han, Yeong Uk Jeon, Jihye Park, Takehiko Yoshimitsu, Neeraj Kumar Mishra, In Su Kim

    Journal of Organic Chemistry   83 ( 8 )   4641 - 4649   2018.4

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    Language：English   Publisher：American Chemical Society  

    DOI： 10.1021/acs.joc.8b00388

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  • Visceral Adipose Tissue Drives Cardiac Aging Through Modulation of Fibroblast Senescence by Osteopontin Production. International coauthorship International journal

    Daigo Sawaki, Gabor Czibik, Maria Pini, Julien Ternacle, Nadine Suffee, Raquel Mercedes, Geneviève Marcelin, Mathieu Surenaud, Elisabeth Marcos, Philippe Gual, Karine Clément, Sophie Hue, Serge Adnot, Stéphane N Hatem, Izuru Tsuchimochi, Takehiko Yoshimitsu, Corneliu Hénégar, Geneviève Derumeaux

    Circulation   138 ( 8 )   809 - 822   2018

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    Language：English  

    BACKGROUND: Aging induces cardiac structural and functional changes linked to the increased deposition of extracellular matrix proteins, including OPN (osteopontin), conducing to progressive interstitial fibrosis. Although OPN is involved in various pathological conditions, its role in myocardial aging remains unknown. METHODS: OPN deficient mice (OPN-/-) with their wild-type (WT) littermates were evaluated at 2 and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. OPN expression was determined by reverse-transcription polymerase chain reaction, immunoblot and immunofluorescence. Luminex assays were performed to screen plasma samples for various cytokines/adipokines in addition to OPN. Similar explorations were conducted in aged WT mice after surgical removal of visceral adipose tissue (VAT) or treatment with a small-molecule OPN inhibitor agelastatin A. Primary WT fibroblasts were incubated with plasma from aged WT and OPN-/- mice, and evaluated for senescence (senescence-associated β-galactosidase and p16), as well as fibroblast activation markers (Acta2 and Fn1). RESULTS: Plasma OPN levels increased in WT mice during aging, with VAT showing the strongest OPN induction contrasting with myocardium that did not express OPN. VAT removal in aged WT mice restored cardiac function and decreased myocardial fibrosis in addition to a substantial reduction of circulating OPN and transforming growth factor β levels. OPN deficiency provided a comparable protection against age-related cardiac fibrosis and dysfunction. Intriguingly, a strong induction of senescence in cardiac fibroblasts was observed in both VAT removal and OPN-/- mice. The addition of plasma from aged OPN-/- mice to cultures of primary cardiac fibroblasts induced senescence and reduced their activation (compared to aged WT plasma). Finally, Agelastatin A treatment of aged WT mice fully reversed age-related myocardial fibrosis and dysfunction. CONCLUSIONS: During aging, VAT represents the main source of OPN and alters heart structure and function via its profibrotic secretome. As a proof-of-concept, interventions targeting OPN, such as VAT removal and OPN deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. Our work uncovers OPN's role in the context of myocardial aging and proposes OPN as a potential new therapeutic target for a healthy cardiac aging.

    DOI： 10.1161/CIRCULATIONAHA.117.031358

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  • Total Synthesis of (-)-Agelastatin A: An SH2’ Radical Azidation Strategy

    Tsuchimochi, I, Kitamura, Y, Aoyama, H, Akai, S, Nakai, K, Yoshimitsu, T

    Chemical Communications   2018

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  • 2-aminoethoxydiphenyl borate provides an anti-oxidative effect and mediates cardioprotection during ischemia reperfusion in mice

    Hirofumi Morihara, Masanori Obana, Shota Tanaka, Ikki Kawakatsu, Daisuke Tsuchiyama, Shota Mori, Hiroshi Suizu, Akiko Ishida, Rumi Kimura, Izuru Tsuchimochi, Makiko Maeda, Takehiko Yoshimitsu, Yasushi Fujio, Hiroyuki Nakayama

    PLoS ONE   12 ( 12 )   650 - 659   2017.12

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    Language：English   Publisher：Public Library of Science  

    DOI： 10.1371/journal.pone.0189948

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  • Regioselective Rearrangement of 4,4-Disubstituted 2-Hydroxycyclohexa-2,5-Dienones under Deoxyfluorination Conditions

    Keita Takubo, Ahmed A. B. Mohamed, Takafumi Ide, Kazuyuki Saito, Takashi Ikawa, Takehiko Yoshimitsu, Shuji Akai

    JOURNAL OF ORGANIC CHEMISTRY   82 ( 24 )   13141 - 13151   2017.12

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  • Compounds, compositions, and methods of agelastatin alkaloids: patent evaluation of WO2015042239 (A1) International coauthorship International journal

    Takehiko Yoshimitsu, Han W. Tun

    EXPERT OPINION ON THERAPEUTIC PATENTS   27 ( 2 )   113 - 119   2017.2

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  • Radical Cyclization Strategies in Total Syntheses of Bioactive Fused Cyclic Natural Products

    Takehiko Yoshimitsu

    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN   74 ( 4 )   350 - 359   2016.4

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    Language：Japanese   Publishing type：Book review, literature introduction, etc.  

    Web of Science

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  • Diversity Oriented Synthesis of Allocolchicinoids with Fluoro and/or Oxygen Substituent(s) on the C-Ring from a Single Common Intermediate

    Keita Takubo, Kazunori Furutsu, Takafumi Ide, Hiroyuki Nemoto, Yuko Ueda, Kazutake Tsujikawa, Takashi Ikawa, Takehiko Yoshimitsu, Shuji Akai

    EUROPEAN JOURNAL OF ORGANIC CHEMISTRY   2016 ( 8 )   1562 - 1576   2016.3

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  • 生物活性縮環天然物の全合成におけるラジカル環化戦略

    好光健彦

    有機合成化学協会誌   74   350 - 359   2016

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  • 解説「Grob型環開裂」

    有機合成化学協会誌   74   379 - 379   2016

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  • Total Synthesis of Clavilactone B: A Radical Cyclization Fragmentation Strategy

    Hiroshi Suizu, Daisuke Shigeoka, Hiroshi Aoyama, Takehiko Yoshimitsu

    ORGANIC LETTERS   17 ( 1 )   126 - 129   2015.1

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  • A commentary on‘Classic Addition Reaction Gets A Makeover’ in Science & Technology, News of The Week in Chemical & Engineering News

    Takehiko Yoshimitsu

    Chemical & Engineering News   93 ( 3 )   2015

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  • Enantiospecific Synthesis and Cytotoxicity Evaluation of Ligudentatol: A Programmed Aromatization Approach to the 2,3,4-Trisubstituted Phenolic Motif via Visible-Light-Mediated Group Transfer Radical Cyclization

    Gamal A. I. Moustafa, Hiroshi Suizu, Hiroshi Aoyama, Masayoshi Arai, Shuji Akai, Takehiko Yoshimitsu

    CHEMISTRY-AN ASIAN JOURNAL   9 ( 6 )   1506 - 1510   2014.6

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  • Endeavors to Access Molecular Complexity: Strategic Use of Free Radicals in Natural Product Synthesis

    Takehiko Yoshimitsu

    CHEMICAL RECORD   14 ( 2 )   268 - 279   2014.4

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  • A new route to platencin via decarboxylative radical cyclization

    Gamal A. I. Moustafa, Yuki Saku, Hiroshi Aoyama, Takehiko Yoshimitsu

    CHEMICAL COMMUNICATIONS   50 ( 99 )   15706 - 15709   2014

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  • An integrated approach to the discovery of potent agelastatin A analogues for brain tumors: chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses International coauthorship International journal

    Zhimin Li, Daisuke Shigeoka, Thomas R. Caulfield, Takashi Kawachi, Yushi Qiu, Takuma Kamon, Masayoshi Arai, Han W. Tun, Takehiko Yoshimitsu

    MEDCHEMCOMM   4 ( 7 )   1093 - 1098   2013.7

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  • Formal synthesis of (-)-agelastatin A: an iron(II)-mediated cyclization strategy

    Daisuke Shigeoka, Takuma Kamon, Takehiko Yoshimitsu

    BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY   9   860 - 865   2013.5

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  • Structure-activity relationships of hybrid annonaceous acetogenins: Powerful growth inhibitory effects of their connecting groups between heterocycle and hydrophobic carbon chain bearing THF ring on human cancer cell lines

    Naoto Kojima, Tetsuya Fushimi, Takahiro Tatsukawa, Takehiko Yoshimitsu, Tetsuaki Tanaka, Takao Yamori, Shingo Dan, Hiroki Iwasaki, Masayuki Yamashita

    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY   63   833 - 839   2013.5

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  • Potent growth inhibitory activity of (+/-)-platencin towards multi-drug-resistant and extensively drug-resistant Mycobacterium tuberculosis

    Gamal A. I. Moustafa, Shoji Nojima, Yoshi Yamano, Akio Aono, Masayoshi Arai, Satoshi Mitarai, Tetsuaki Tanaka, Takehiko Yoshimitsu

    MEDCHEMCOMM   4 ( 4 )   720 - 723   2013.4

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  • Dichlorination of olefins with NCS/Ph3P

    Yasumasa Kamada, Yuta Kitamura, Tetsuaki Tanaka, Takehiko Yoshimitsu

    ORGANIC & BIOMOLECULAR CHEMISTRY   11 ( 10 )   1598 - 1601   2013

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  • Double C-H Functionalization in Sequential Order: Direct Synthesis of Polycyclic Compounds by a Palladium-Catalyzed C-H Alkenylation-Arylation Cascade

    Hiroaki Ohno, Mutsumi Iuchi, Naoto Kojima, Takehiko Yoshimitsu, Nobutaka Fujii, Tetsuaki Tanaka

    CHEMISTRY-A EUROPEAN JOURNAL   18 ( 17 )   5352 - 5360   2012.4

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  • Pharmacokinetics of Agelastatin A in the central nervous system International coauthorship International journal

    Zhimin Li, Takuma Kamon, David A. Personett, Thomas Caulfield, John A. Copland, Takehiko Yoshimitsu, Han W. Tun

    MEDCHEMCOMM   3 ( 2 )   233 - 237   2012.2

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  • Stereoselective alpha-Quaternization of 3-Methoxycycloalk-2-enones via 1,4-Diastereoinduction of Alkoxy Dienolates

    Gamal A. I. Moustafa, Yasumasa Kamada, Tetsuaki Tanaka, Takehiko Yoshimitsu

    JOURNAL OF ORGANIC CHEMISTRY   77 ( 2 )   1202 - 1207   2012.1

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  • Stereoconvergent route to chiral cyclohexenone building blocks: formal synthesis of (-)-dysidiolide

    Gamal A. I. Moustafa, Yasumasa Kamada, Tetsuaki Tanaka, Takehiko Yoshimitsu

    ORGANIC & BIOMOLECULAR CHEMISTRY   10 ( 43 )   8609 - 8615   2012

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  • Intramolecular iron(II)-catalyzed aminobromination of allyl N-tosyloxycarbamates

    Takuma Kamon, Daisuke Shigeoka, Tetsuaki Tanaka, Takehiko Yoshimitsu

    ORGANIC & BIOMOLECULAR CHEMISTRY   10 ( 12 )   2363 - 2365   2012

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  • Design and synthesis of C35-fluorinated solamins and their growth inhibitory activities against human cancer cell lines

    Naoto Kojima, Yuki Suga, Hiromi Hayashi, Takao Yamori, Takehiko Yoshimitsu, Tetsuaki Tanaka

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   21 ( 19 )   5745 - 5749   2011.10

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  • Total Synthesis of (+/-)-Platencin

    Takehiko Yoshimitsu, Shoji Nojima, Masashi Hashimoto, Tetsuaki Tanaka

    ORGANIC LETTERS   13 ( 14 )   3698 - 3701   2011.7

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  • Total Synthesis of (+/-)-Kainic Acid: A Photochemical C-H Carbamoylation Approach

    Takuma Kamon, Yayoi Irifune, Tetsuaki Tanaka, Takehiko Yoshimitsu

    ORGANIC LETTERS   13 ( 10 )   2674 - 2677   2011.5

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  • Asymmetric Total Synthesis of (+)-Danicalipin A

    Takehiko Yoshimitsu, Ryo Nakatani, Akihiro Kobayashi, Tetsuaki Tanaka

    ORGANIC LETTERS   13 ( 5 )   908 - 911   2011.3

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  • Convergent synthesis of fluorescence-labeled probes of Annonaceous acetogenins and visualization of their cell distribution

    Naoto Kojima, Takekuni Morioka, Daisuke Urabe, Masahiro Yano, Yuki Suga, Naoyoshi Maezaki, Ayako Ohashi-Kobayashi, Yasuyuki Fujimoto, Masatomo Maeda, Takao Yamori, Takehiko Yoshimitsu, Tetsuaki Tanaka

    BIOORGANIC & MEDICINAL CHEMISTRY   18 ( 24 )   8630 - 8641   2010.12

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  • Asymmetric Total Synthesis of (+)-Hexachlorosulfolipid, a Cytotoxin Isolated from Adriatic Mussels

    Takehiko Yoshimitsu, Naoya Fukumoto, Ryo Nakatani, Naoto Kojima, Tetsuaki Tanaka

    JOURNAL OF ORGANIC CHEMISTRY   75 ( 16 )   5425 - 5437   2010.8

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  • Studies of the Asymmetric Total Synthesis of Clavilactone D by the &apos;Lariat&apos; Cyclization Strategy

    Takehiko Yoshimitsu, Shoji Nojima, Masashi Hashimoto, Koji Tsukamoto, Tetsuaki Tanaka

    SYNTHESIS-STUTTGART   17 ( 17 )   2963 - 2969   2009.9

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  • Total Synthesis of the beta-Catenin Inhibitor, (-)-Agelastatin A: A Second-Generation Approach Based on Radical Aminobromination

    Takehiko Yoshimitsu, Tatsunori Ino, Naoyuki Futamura, Takuma Kamon, Tetsuaki Tanaka

    ORGANIC LETTERS   11 ( 15 )   3402 - 3405   2009.8

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  • SYNTHESIS OF CHAETOMELLIC ANHYDRIDE A, A POTENT INHIBITOR OF RAS PROTEIN FARNESYLTRANSFERASE

    Takehiko Yoshimitsu, Yoshimasa Arano, Tomohiro Kaji, Tatsunori Ino, Hiroto Nagaoka, Tetsuaki Tanaka

    HETEROCYCLES   77 ( 1 )   179 - 186   2009.1

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  • Enantiocontrolled Synthesis of Polychlorinated Hydrocarbon Motifs: A Nucleophilic Multiple Chlorination Process Revisited

    Takehiko Yoshimitsu, Naoya Fukumoto, Tetsuaki Tanaka

    JOURNAL OF ORGANIC CHEMISTRY   74 ( 2 )   696 - 702   2009.1

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  • Total Synthesis of (-)-Agelastatin A

    Takehiko Yoshimitsu, Tatsunori Ino, Tetsuaki Tanaka

    ORGANIC LETTERS   10 ( 23 )   5457 - 5460   2008.12

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  • Synthesis of (+/-)-aphanorphine: a new approach to tricyclic 3-benzazepine scaffold using two radical C-C bond-forming reactions

    Takehiko Yoshimitsu, Chie Atsumi, Emiko Iimori, Hiroto Nagaoka, Tetsuaki Tanaka

    TETRAHEDRON LETTERS   49 ( 29-30 )   4473 - 4475   2008.7

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  • New Free radical-based methods for producing heteroatom-containing molecular skeletons

    90 ( 1 )   99 - 101   2008

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  • Radical fixation of functionalized carbon resources: alpha-sp(3)C-H carbamoylation of tertiary amines with aryl isocyanates

    Takehiko Yoshimitsu, Kenichi Matsuda, Hiroto Nagaoka, Koji Tsukamoto, Tetsuaki Tanaka

    ORGANIC LETTERS   9 ( 24 )   5115 - 5118   2007.11

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  • 解説「Barton反応」

    好光健彦

    有機合成化学協会誌   65   727 - 727   2007

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  • フリーラジカルによるα-ヘテロ原子置換sp3炭素―水素結合の新変換法の発見と進展

    好光健彦

    ファルマシア‐最前線‐   43 ( 3 )   219 - 223   2007

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    Language：Japanese   Publisher：公益社団法人日本薬学会  

    CiNii Article

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  • 高反応性ラジカル種が誘起する炭素-炭素および炭素-水素結合変換と生物活性物質合成への活用

    好光健彦, 長岡博人, 田中徹明

    有機合成化学協会誌   65   665 - 676   2007

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  • 現代化学 増刊43 最新有機合成化学 ヘテロ原子・遷移金属化合物を用いる合成, 奈良坂紘一,岩澤伸治編, 東京化学同人, B5, 220頁, 4,410円

    好光 健彦

    ファルマシア   41 ( 8 )   740 - 740   2005.8

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    Language：Japanese   Publisher：公益社団法人日本薬学会  

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  • Radical hydroxyalkylation of C-H bond adjacent to nitrogen of tertiary amides, ureas, and amines

    T Yoshimitsu, Y Arano, H Nagaoka

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   127 ( 33 )   11610 - 11611   2005.8

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  • Radical alpha-C-H hydroxyalkylation of ethers and acetal

    T Yoshimitsu, Y Arano, H Nagaoka

    JOURNAL OF ORGANIC CHEMISTRY   70 ( 6 )   2342 - 2345   2005.3

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  • Studies on the total synthesis of (-)-CP-263,114

    T Yoshimitsu, S Sasaki, Y Arano, H Nagaoka

    JOURNAL OF ORGANIC CHEMISTRY   69 ( 26 )   9262 - 9268   2004.12

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    Language：English   Publishing type：Book review, literature introduction, etc.  

    DOI： 10.1021/jo048681u

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  • Total synthesis of (+)-muconin

    T Yoshimitsu, T Makino, H Nagaoka

    JOURNAL OF ORGANIC CHEMISTRY   69 ( 6 )   1993 - 1998   2004.3

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  • Synthesis of (-)-muricatacin via alpha- and alpha '-C-H bond functionalization of tetrahydrofuran

    T Yoshimitsu, T Makino, H Nagaoka

    JOURNAL OF ORGANIC CHEMISTRY   68 ( 19 )   7548 - 7550   2003.9

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  • Hydroxyalkylation of alpha-C-H bonds of tetrahydrofuran with aldehydes in the presence of triethylborane and tert-butyl hydroperoxide

    T Yoshimitsu, Y Arano, H Nagaoka

    JOURNAL OF ORGANIC CHEMISTRY   68 ( 2 )   625 - 627   2003.1

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  • Synthesis of the CD ring system of paclitaxel by atom-transfer radical annulation reaction

    T Yoshimitsu, H Nakajima, H Nagaoka

    TETRAHEDRON LETTERS   43 ( 47 )   8587 - 8590   2002.11

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  • Asymmetric synthesis of the core structure of (-)-CP-263,114

    T Yoshimitsu, S Yanagisawa, H Nagaoka

    ORGANIC LETTERS   2 ( 23 )   3751 - 3754   2000.11

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  • New route to the synthesis of the illudane skeleton by Michael-Michael-elimination reaction

    K Tokuzaki, Y Kanemitu, T Yoshimitsu, H Nagaoka

    TETRAHEDRON LETTERS   41 ( 31 )   5923 - 5926   2000.7

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  • New method for the synthesis of alpha-substituted tetrahydrofuran-2-methanols through diastereoselective addition of THF to aldehydes mediated by Et3B in the presence of air

    T Yoshimitsu, M Tsunoda, H Nagaoka

    CHEMICAL COMMUNICATIONS   ( 17 )   1745 - 1746   1999.9

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  • An approach to the synthesis of CP-263,114: complementary routes to the bicyclic ring system via two kinds of fragmentation reaction

    T Yoshimitsu, M Yanagiya, H Nagaoka

    TETRAHEDRON LETTERS   40 ( 28 )   5215 - 5218   1999.7

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  • A new synthetic route for construction of the core of zaragozic acids

    H Koshimizu, T Baba, T Yoshimitsu, H Nagaoka

    TETRAHEDRON LETTERS   40 ( 14 )   2777 - 2780   1999.4

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  • Application of newly developed anti-selective aldol methodology: Synthesis of C6-C13 and C19-C28 fragments of miyakolide

    T Yoshimitsu, JJ Song, GQ Wang, S Masamune

    JOURNAL OF ORGANIC CHEMISTRY   62 ( 26 )   8978 - 8979   1997.12

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    Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

    DOI： 10.1021/jo971863m

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Awards

  • Scientific Award

    2024.3   Electric Technology Research Foundation of Chugoku  

    Takehiko Yoshimitsu

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  • Scientific Award from The Okayama Foundation for Science and Technology

    2023   The Okayama Foundation for Science and Technology  

    Takehiko Yoshimitsu

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  • 大阪大学総長による表彰

    2014  

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    Country：Japan

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  • Presidential Awards for Excellence (Osaka University)

    2014  

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  • 第11回 有機合成化学協会関西支部賞

    2013  

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    Country：Japan

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  • アジア最先端有機化学国際会議 Asian Core Program (ACP) Lectureship Award (Singapore)

    2013  

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  • The Society of Synthetic Organic Chemistry, Japan. The 11th Kansai Branch Award

    2013  

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  • アジア最先端有機化学国際会議 Asian Core Program (ACP) Lectureship Award (Thailand)

    2008  

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Research Projects

  • ラジカル反応を駆動する新規触媒の創製と天然物合成

    Grant number：21K06476  2021.04 - 2024.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    好光 健彦

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    Grant amount：\4160000 （ Direct expense: \3200000 、 Indirect expense：\960000 ）

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  • Development of synthetic strategies towards bioactive polycyclic natural products via catalytic radical cascade transformations

    Grant number：18K06578  2018.04 - 2022.03

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

    Yoshimitsu Takehiko

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

    In the present study, we developed new radical cascade reactions that feature environmentally-benign catalytic chemical transformations with high energy efficiency to produce polycyclic organic molecules. In addition, we devised synthetic routes to bioactive natural products based on the radical cascade reactions; 1) the formal total synthesis of antiviral marine natural product hamigeran B was accomplished by a visible-light-mediated radical cascade transformation; 2) a new means for accessing a hydroxybenzofuran from an alkynylquinone under quinone-hydroquinone organic redox conditions was developed, enabling the total synthesis of liphagal, a natural PI3kα inhibitor.

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  • Development of new therapeutic agents derived from Wnt signaling inhibitor for treating brain cancer

    Grant number：15K14977  2015.04 - 2018.03

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

    Yoshimitsu Takehiko

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    Grant amount：\3770000 （ Direct expense: \2900000 、 Indirect expense：\870000 ）

    Agelastatin A (AA) exhibits potent antiproliferative activity against cancer cell lines by inhibiting the Wnt/beta-catenin pathway responsible for cellular processes. The present study was undertaken to develop new therapeutic agents derived from AA for treating brain cancer and has culminated in the following achievements. 1) A new synthetic route to AA and AA derivatives was established by employing radical azidation of a silyl enol ether. The route enabled facile access to AA analogs with varying N1-substituents. Furthermore, AA analogs that exhibit potent inhibitory activity were identified by the structure-activity relationship (SAR) study. 2) A new method for the catalytic radical oxyazidation of alkenes was developed. 3) The divergent synthetic route successfully provided access to three chemical probes applicable for identifying the molecular target of AA. However, none of the probes were found to exert desirable activities.

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  • Development of New Means of Asymmetric Halogenation and Total Synthesis of Bioactive Halogenated Natural Products

    Grant number：24590008  2012.04 - 2016.03

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

    Yoshimitsu Takehiko

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

    The chemical synthesis of organohalogens has become a focal point of intensive studies in organic synthesis. In the present study, we established a synthetic route to napyradiomycin A1, a chlorinated antibiotic isolated from the culture broth of Chainia rubra MG802-AF1. Extensive screening of amine ligands in combination with Willgerodt reagent (PhICl2) led to the development of a C2-symmetric catalyst applicable to asymmetric dichlorination of allylic alcohols. We have also found that an enantioenriched dichloride is produced from a dehydro-α-lapachone derivative in some, albeit small, degree of asymmetric induction under the Nicolaou conditions using (DHQD)2PHAL-PhICl2, paving the way to asymmetric synthesis of the natural antibiotic. In addition, biological evaluation of the synthetic intermediates has culminated in the discovery of a new analogue useful for further medicinal studies.

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  • Development of synthetic methodology to supply materials for understanding of physiological system

    Grant number：22136006  2010.04 - 2015.03

    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)

    HARI Yoshiyuki, YOSHIMITSU Takehiko, KODAMA Tetsuya, KOJIMA Naoto

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    Grant amount：\58240000 （ Direct expense: \44800000 、 Indirect expense：\13440000 ）

    For understanding of physiological system, it is essential to validate in silico physiological and pathological platform by biological experiments. The following two themes in this 5-year project were carried out; (i) the development of new synthetic methods capable of efficiently producing chemical compounds and (ii) the supply of chemical compounds utilized in biological experiments to validate the platform. During this project, we succeeded in developing a number of new synthetic methods applicable to an easy access to chemical compounds with unique skeletons as well as the synthesis of the derivatives with structural variations. In addition, collaborative researches with many groups in the project “HD physiology” were performed through the supply of the chemical compounds synthesized by us. These results could not only contribute to the progress of the “HD physiology” project but also give practical and useful information for drug-discovery research.

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  • Development of new radical chemistry-based strategies for the construction of densely functionalized organic molecules

    Grant number：21590009  2009 - 2012

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

    YOSHIMITSU Takehiko

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    Bioactive natural products often possess unique chemical structures with dense functionalities, serving as a useful medicinal resource. The authors have been engaged in synthetic radical chemistry that would revolutionize strategies for providing access to this class of attractive molecules. In the present study, we succeeded in devising new radical reactions associated with sp3carbon-hydrogen (sp3C-H) transformation (photochemical sp3C-H carbamoylation of tertiary amines) and iron(II)-catalyzed aminohalogenation reactions of N-tosyloxycarbamates, and accomplished radical chemistry-based total syntheses of bioactive natural products including kainic acid, platencin, and agelastatin A. Furthermore, we developed a novel means for asymmetric synthesis, which employsremote stereoinduction that allows facile construction of carbocyclic building blocks bearing quaternary stereocenters. The biological evaluation of platencin prepared by the above-mentioned total synthesishas allowed the authors to assess its significant inhibitory activity against multi-drug-resistant Mycobacterium tuberculosis, adding a new dimension to the development of antitubercular agents.

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  • Studies on the total synthesis of nitrogen-containing natural organic compounds aimed at the development of anticancer and analgesic research

    Grant number：19590006  2007 - 2008

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

    YOSHIMITSU Takehiko

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    耐え難い苦痛を伴う癌が死因の上位を占める現在の日本においては、有効な制癌剤の開発は勿論のこと、患者の生活の質の向上につながる鎮痛剤の開発が強く望まれる。我々は、高反応性窒素および炭素種を駆使した有機分子の短工程高度官能基化を基盤として、抗腫瘍活性天然物agelastatin A、鎮痛活性先導化合物 aphanorphineならびにそれらの誘導体の新規合成法を確立し、制癌と疼痛制御に資する優れた医薬資源の人工的獲得に成功した

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  • Development of novel metal-mediated reaction and their application to domino cyclization

    Grant number：18390004  2006 - 2008

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

    TANAKA Tetsuaki, YOSHIMITSU Takehiko, KOJIMA Naoto

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    Grant amount：\10580000 （ Direct expense: \9200000 、 Indirect expense：\1380000 ）

    遷移金属やランタノイド金属の化学は新反応の宝庫として近年特に注目を集めている研究領域である. これらの金属は, 典型金属には見られない特異な化学的性質を持ち,従来の手法では成し得なかった新規化学変換法や合成困難な物質の効率的かつ簡便な合成を次々に可能にしている. また, 環境調和型の合成化学が求められる今日, 触媒的な連続反応を開発することは極めて重要である. このような観点から, 報告者らは, 金属錯体の潜在特性を駆使した新規反応の開発に取り組み, 平成18~20年度に以下に示す新規反応の開発に成功した. (1) アリールラジカルを用いる新規スピロ環形成反応, (2) アレンの連続環化反応による複素環の新規合成法, (3) エンアレン類の[2+2]熱環化反応による複素環の新規合成法, (4) 求核部位を有するアレニルブロモアルケンの一挙環化反応, (5) プロパルギルブロミドを用いるドミノ型二環性骨格構築法, (6) オキシムエーテルに対するHeck 型反応, (7) パラジウム触媒を用いた芳香環C-H活性化を含む連続的閉環反応による多環式複素環の一挙合成, (8) パラジウム触媒を用いた不斉転位反応.

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  • HIF-1α阻害剤マナサンチンBのバイオプローブ化

    Grant number：18032048  2006 - 2007

    日本学術振興会  科学研究費助成事業  特定領域研究

    田中 徹明, 前崎 直容, 好光 健彦, 小島 直人, 田中 徹明

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    Grant amount：\5600000 （ Direct expense: \5600000 ）

    日本人の死因の第一位を占めるだけでなく、世界的にも増加の一途を辿っているがんの克服を目指す研究は、極めて重要である。我々は、興味深い構造を有する生理活性天然物をモチーフとして利用する有機化学的アプローチによって、がん克服に資するべく研究を行い、平成19年度に以下の成果を得た。
    1.がんの増殖を促進するといわれる転写因子Hypoxia Inducible Factor-1α(HIF-1α)の強力な阻害作用をもつTHFリグナン類の基本合成法の確立、並びに、そのプローブ化を目指した研究を展開し、コアとなる2,5-ジアリールTHF骨格の立体選択的合成に成功した。
    2.チロシンキナーゼ阻害活性を有する10員環クラビラクトンDの全合成研究を行い、Nozaki-Hiyama-Kishi反応を鍵反応として基本骨格となるflavidulol骨格を構築することに成功した。
    3.興味深い抗腫瘍活性を有するアセトゲニン類をリードとする新規抗がん剤の開発研究として、例を見ない含フッ素アセトゲニン類の合成に着手し、既存のアセトゲニン類の2級水酸基をフッ素に置換した新規含フッ素アセトゲニンの合成に成功した。また,合成した含フッ素アセトゲニン類のがん細胞パネル試験による評価を行ったところ,リードとした天然物に比べて特定のがん細胞に対する活性が選択的に増強されるという興味深い結果を得た.

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  • 細胞増殖抑制新規多ハロゲン化スルホリピッド類の不斉全合成と医薬資源開拓

    Grant number：16790021  2004 - 2006

    日本学術振興会  科学研究費助成事業  若手研究(B)

    好光 健彦

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    Grant amount：\3200000 （ Direct expense: \3200000 ）

    複雑な構造と高い反応性を併せ持つ多官能性有機物質の創製、変換、供給は、有機合成化学の重要な一領域をなす。しかしながら、多官能性有機物質のひとつであり、興味深い医薬資源としての可能性を秘める多連続不斉ハロゲン化合物は必ずしも活発な合成研究の対象とはなっておらず、これらの化合物を立体制御下に得る手法は少ない。我々は、アドリア海に生息するイガイより単離された細胞増殖抑制新規多ハロゲン化スルホリピッドを標的とする合成研究を通じて、ハロゲン置換炭素の立体制御手法を開発するとともに、制がんに関わる新たな医薬資源となり得る不斉ハロゲン化合物を獲得すべく本研究を行った。
    本研究で我々は、アルケン類の不斉酸化によって得られるエポキシドのハロゲン化反応を基盤とするvic-ジクロロ化合物およびクロロヒドリン類の立体選択的合成手法を確立した。すなわち、種々の光学活性エポキシドに対し、N-クロロコハク酸イミド-トリフェニルボスフィンを作用させると、不斉炭素上でのWalden反転を伴う求核置換反応が進行し、シスあるいはトランスエポキシドからそれぞれ対応するアンチあるいはシンvic-ジクロロ化合物が良好な収率で立体特異的に得られ、一方、N-クロロコハク酸イミド-トリブチルボスフィンを作用させるとクロロヒドリン類が得られることを見出した。さらに我々は、ビスエポキシドに対して本手法を適用することにより、4連続不斉中心からなるハロゲン化合物の新規短工程合成経路を開拓するとともに、標的海洋天然物のC1-C14フラグメントの合成を行った。

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  • エーテル類のsp3C-H結合活性化反応の開発と天然物合成への活用

    Grant number：14771255  2002 - 2003

    日本学術振興会  科学研究費助成事業  若手研究(B)

    好光 健彦

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    Grant amount：\2700000 （ Direct expense: \2700000 ）

    従来、有機フリーラジカルやカルベンあるいは超強酸によって行われてきた不活性な炭素-水素(C-H)結合の官能基化は、遷移金属の活用を背景に目覚ましく進展している。中でも、C-H結合活性化を起点とする炭素-炭素(C-C)結合形成は、有機分子構築の新手法をもたらすことから非常に重要視されている。我々は、ラジカル反応の活用を基盤とする有機合成化学的研究を進めてきたが、この過程で環状エーテル類のα-C-H結合を一工程でC-C結合に変える興味深い反応を見出した。すなわち、テトラヒドロフランのα-C-H結合のヒドロキシアルキル化反応である。本反応はC-H官能基化法としてはむしろ従来のラジカル手法に分類されはするが、遷移金属によるC-H活性化法に匹敵する簡便さを有し、しかも入手容易でバリエーションに富む原料から一挙に高度に官能基化された物質を合成できるという特徴を持つ。また、本反応は、これまで困難とされてきた炭素ラジカル種とカルボニル化合物の分子間付加の成功をも意味し、環状エーテル類のα位がヒドロキシアルキル基で置換された構造を持つ多くの生理活性天然物の合成における斬新な方法論をもたらす。
    昨年度に引き続き、本平成15年度の研究では、有機合成の新領域を拓く可能性を秘めた上記C-H官能基化手法の開拓とともに、顕著な生理活性を持つ天然物の合成への活用を検討した。その結果、本手法を基盤とする抗腫瘍活性天然物(-)-ムリカタシンならびに(+)-ムコニンの合成を達成した。さらに、光照射によるヒドロキシアルキル化反応の開発にも成功した。以上の研究成果は、有機合成化学とラジカル化学の両分野において重要な新知見となる。

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  • Rasファルネシル化酵素阻害活性を有するCP-263,114の全合成研究

    Grant number：12771369  2000 - 2001

    日本学術振興会  科学研究費助成事業  奨励研究(A)

    好光 健彦

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

    制癌剤への応用が期待されるras-ファルネシル化酵素阻害物質として見い出された(-)-CP-263,114は,生理活性と構造の両面から強い関心が寄せられている天然物であり,国内外の全合成研究における興味の対象となっている.我々は,本天然物の全合成を通して有用な医薬品を創製し,有機合成化学的側面から制癌研究を推進すると共に,合成化学め発展をもたらす新手法と戦略の開発を目指して研究を進めてきた.
    前年度の研究で,我々は,独自のラジカル反応を基盤とする(-)-CP-263,114の複雑かつ特異な骨格の構築に成功した.本13年度,この基本戦略にのっとって全合成経路の開拓を更に押し進めた結果,17位側鎖の導入をはじめとする種々の変換を経て,標的天然物の全合成に極めて重要な中間体を合成することに成功した.また,全合成の完成に必要な官能基・置換基を備えた本中間体から天然物に至る今後の合成計画では,無水マレイン酸構造の構築と7位に位置するC1-C6アルケニル側鎖の導入が残る課題となる.本年度の研究によってこれらの解決に対する幾つかの予備的知見を得ることにも成功した.
    以上,制癌剤のリード化合物として注目されている(-)-CP-263,114の全合成に極めて重要な中間体の合成を達成した.本年度に展開した研究によって得られた成果は,ラジカル反応を機軸とする(-)-CP-263,114の全合成の完成に向けた今後の研究の有力な基盤となる.

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